WO2010022148A1 - Methods for the preparation of irciniastatin and analogs thereof - Google Patents

Abstract

Methods for the preparation of irciniastatins, including (+)-irciniastatin A and (-)- irciniastatin B, as well as analogs thereof, are described.

Description

METHODS FOR THE PREPARATION OF IRCINIASTATIN AND ANALOGS THEREOF

GOVERNMENT SUPPORT

The research carried out in this application was supported, in part, by a grant from the National Institute of Health (National Cancer Institute) through grant CA-19033. Pursuant to 35 U. S. C. § 202, the government may have rights in any patent issuing from this application.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/090,086, filed August 19, 2008, and U.S. Provisional Application No. 61/096379, filed September 12, 2008, both of which are incorporated by reference in their entireties.

TECHNICAL FIELD

The present invention is directed to methods for the preparation of irciniastatins, as well as methods for the preparation of analogs thereof.

BACKGROUND

In 2004, the laboratories of Pettit and coworkers first published the isolation, structural elucidation, and biological activity of (+)-irciniastatin A and (-)-irciniastatin B.

(+)-lrciniastatin A (Psymberin) R₁ = OH, R₂ = H (-)-lrciniastatin B R₁ = R₂ = O

Pettit, G. R.; Xu, J. P.: Chapuis. J. C; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. Journal of Medicinal Chemistry 2004, 47, 1 149-1 152. Pettit and coworkers first collected samples containing irciniastatins A and B from the Indo-Pacific marine sponge Ircinia ramosa near Samporna, Borneo in 1991 . The dichloromethane-methanol extracts exhibited strong activity (GI50 - 10^'2 μg/mL) against the P388 murine lymphocytic leukemia cancer cell line. Unfortunately, recollection on a larger scale to allow for isolation of the individual constituents was not permitted (political obstacles) and so the extracts were preserved for later use. As isolation techniques advanced over the past decade, irciniastatins A and B were isolated as an individual constituent (34.7 mg and 2.2 mg, respectively) from the initial dichloromethane-methanol extracts.

After isolating irciniastatins A and B, Pettit and coworkers tested the compound against six human cancer cell lines, the P388 murine lymphocytic leukemia cell line used to guide their fractionation/isolation efforts, and human umbilical vein endothelial cells (HUVEC) (Table 1.1 ). Id

Table 1.1. Growth Inhibition of Cancer Cell Lines (GI₅0, μg/ml) by Irciniastatin A and B Cancer Cell Line Irciniastatin Λ Irciniastatin B pancreas BXPC-3 0.0038 0.00073 breast MCF-7 0.0032 0.0005

CNS SF-268 0.0034 0.00066 lung NCI-H460 O.OOOl 0.0012 colon KM20L2 0.0027 0.0021 prostate DU-145 0.0024 0.0016 leukemia P388 0.00413 0.006 normal endothelial HUVI;C <0.0005 NI)

Additionally, (+)-irciniastatin A was evaluated against the panel of 60 human cancer cell lines within the NCT Developmental Therapeutics in Vitro Screening Program (Table 1.2).

Table 1.2. Differential Sensitivities (LC₅₀) of Several NCI 60 Cell Lines to (+)-lrciniastatin A Cell Line L.C50 (M) Cell Line I.C50 (M) leukemia melanoma

CCRF-CEM >2.5 x 10-5 LOX IMVI >2.5 x 10-5

HL-60(TB) >2.5 x 10-5 MALME-3M <2.5 x 10-9

K-562 >2.5 x 10-5 SK-MEL-2 >2.5 x 10-5

MOLT-4 >2.5 x 10-5 SK-MEL-5 <2.5 x 10-9

RPMI-8226 >2.5 x 10-5 UΛCC-257 >2.5 x 10-5

SR >2.5 x 10-5 UACC-62 <2.5 x 10-9 breast cancer colon cancer

MCF7 >2.5 x 10-5 HCC-2998 3.6 x 10-7

HS 578T >2.5 x 10-5 HCT-1 16 <2.5 x 10-9

MDΛ-MB-435 <2.5 x 10-9 I IT29 >2.5 x 10-5

NCI/ΛDR-RES 1.9 x 10-5 SW-620 >2.5 x 10-5

T-47D 1.36 x 10-5

(+)-lrciniastatin A exhibits activities in the low nanomolar range for the MDA-MB-35 breast cancer, SK-MEL-28 and UACC-62 melanoma, and the HCT-1 16 colon cancer cell lines with an activity differential of greater than 10,000-fold as compared to other cell lines within their respective subsets. Burres, N. S.; Clement. J. J Cancer Res. 1989, 49. 2935-2940; Kobayashi. J. i.; Itagaki, F.; Shigemori, H.: Sasaki, T. Journal of Natural Products 1993. 56. 976-981 ; West, L. M; Northcote, P. T.: Hood, K. A.; Miller, J. H.; Page, M. I. Journal of Natural Products 2000, 63, 707-709; Hood, K. A.; West. L. M.; Northcote, P. T.; Berridge. M. V.; Miller. J. H. Apoptosis 2001, 6, 207-219; Paul, G. K.; Gunasekera. S. P.; Longley, R. E.; Pomponi, S. A. Journal of Natural Products 2002. 65. 59-61.

(+)-Irciniastatin A was also evaluated in the NCI Developmental Therapeutics Program hollow fiber assay using several solid tumor cell lines resulting in an overall score of 34 (compounds considered active score 20 or higher), based on scores of 28 against intraperatineal fibers and 6 against subcutaneous fibers. Robinson, S. J.; Tenney. K.: Yee. D. F.; Martinez. L.: Media, J. E.; Valeriote, F. A.; vanSoest, R. W. M.: Crews. P. Journal of Natural Products 2007. 70, 1002- 1009.

Their impressive biological profile makes the irciniastatins attractive targets for total synthesis. To date, there have been only two total syntheses of irciniastatin A. Jiang, X.; Garcia- Fortanet, J.; DeBrabander, J. K. Journal of the American Chemical Society 2005, 127, 1 1254- 1 1255; Huang, X.; Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Organic Letters 2007, 9, 2597-2600. The De Brabander synthesis of (+)-irciniastatin A was accomplished in a longest linear sequence of 21 steps from commercially available starting materials in an overall yield of 6.1%. The Schering-Plough synthesis of (+) irciniastatin A was accomplished in a longest linear sequence of 25 steps from commercially available starting materials in an overall yield of 2.5%.

As such, more efficient syntheses of the irciniastatins are needed.

SUMMARY

Methods for the preparation of irciniastatins are described. According to the invention. compounds of formula I

are subjected to reaction conditions sufficient to provide a compound of formula II

wherein R₂ is a C|._f, alkyl group; R_N is an amine protecting group; R₃ is at least one C₁.₆ alky], substituted alkyl, halogen, -OH, -OR¹, or carbonyl: wherein R¹ is a hydroxy! protecting group; and R₄ is at least one C₁.₆ alkyl, substituted alkyi, halogen, -OH, or OR; wherein R is a phenolic protecting group; and wherein R is a protecting group that is orthogonal to R¹; and converting the compound of formula TI to the irciniastatin.

Also within the scope of the invention are compounds of formula XlII

I O wherein R_]0 is Ci-₆ alkyl group substituted with at least one ORi₂ or carbonyl, each Ri i is independently Q._ό alkyl, and Ru and Rn are orthogonal protecting groups, as well as methods of their preparation and use in the preparation of irciniastatins.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention is directed to methods of preparing irciniastatins. As used herein,

15 the "'irciniastatin" refers to the general class of compounds, including analogs and homologs. characterized by linked substituted tetrahydropyran and dihydroisocoumarin moieties with pendant hydroxyl amido side chain, generally in a spatial orientation consistent with either (+)- irciniastatin A or (-)-irciniastatin B, and with a multiplicity of chiral centers throughout. Unless otherwise indicated, any reference to the terms "an irciniastatin'' or "the irciniastatin^"' or portion 0 thereof are intended to refer to this general class of compounds, including any analog or homolog. containing conjoined substituted tetrahydropyran and dihydroisocoumarin moieties and an amido linked sidechain. generally in a spatial orientation consistent with (+)-irciniastatin A and (-)-irciniastatin B, without regard to the specific substitueπts on any of these moieties, or without regard to the stereochemistry of any individual chiral carbon center. As set forth herein, for example, there is represented di-alkoxy substitution on the aromatic portion of the "dihydroisocoumarin moiety" and multiple alkyl and alkoxide substituents.on the '"tetrahydropyran moiety." One skilled in the art will appreciate that the synthetic regimes described herein are not limited to these substituents so that the use of the terms or representations of a '^•dihydroisocoumarin moiety" or a "tetrahydropyran moiety" are intended to accommodate other substitutents beyond those actually shown, for example, each may be optionally substituted with one or more C|.₆ alkyl, substituted alkyl, halogen, -OH, protected -OH, or carbonyl. Similarly, use of the term "amido-linked sidechain" is intended to describe a C_M alkyl chain, optionally substituted with a C_M alkyl. C_M alkenyl, alcohol, orthogonally protected alcohol, or C_M alkoxide.

According to the methods of the invention, a compound of formula 1

is subjected to reaction conditions sufficient to provide a compound of formula 11

wherein R₂ is a Q.₆ alkyl group; RN is an amine protecting group; R₃ is at least one Ci_-6 alkyl. substituted alkyl, halogen, -OH. -OR¹, or carbonyl; wherein R¹ is a hydroxyl protecting group; and R₄ is at least one Ci_6 alkyl, substituted alkyl. halogen, -OH, or OR; wherein R is a phenolic protecting group; and wherein R is a protecting group that is orthogonal to R¹. The compound of formula II is then converted to the irciniastatin. In preferred embodiments, the irciniastatin is irciniastatin A. In other embodiment, the irciniastatin is irciniastatin B. As used herein, "alkyl" refers to straight-chain and branch hydrocarbon groups such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter-butyl. pentyl, and hexyl. "C|.₆alkyP' refers to alkyl groups having from 1 to 6 carbon atoms.

As used herein, "substituted alkyl" refers to an alkyl group including one or more functional groups such as alkyl. halogen, hydroxyl, amino, and cyano.

As used herein, "protecting group" are those moieties introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups are known in the art, and those skilled in the art would readily be able to select and use appropriate protecting groups through routine experimentation. For example, see T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2006.

As used herein, "amine protecting group" refers to a protecting group for an amine. Amine protecting groups are known in the art and include, for example, carbamates. Preferred carbamate groups are those containing hindered primary, secondary, or tertiary alkoxy groups. In particularly preferred embodiments, R_N is 9-fluorenylmethyl carbamate (Fmoc), 2,2,2- trichloroethyl carbamate, 2-trimethylsilylethylcarbamate (Teoc), t-butyl carbamate (Boc), allyl carbamate (Alloc), benzylcarbamate (Cbz), m-nitrophenyl carbamate, or p-methoxyphenyl carbamate.In preferred embodiments of the invention, the amine protecting group is (trimethylsilyl)ethocycarbonyl.

As used herein, "hydroxyl protecting group" refers to a protecting group for a hydroxyl. Hydroxyl protecting groups are known in the art and include, for example, trialkylsilyl. In preferred embodiments, Ri is t-butyldimethylsilyl.

As used herein, "phenolic protecting group" refers to a protecting group for a phenol. Phenolic protecting groups are known in the art and include, for example, benzyl and trialkylsilylethoxymethyl. In preferred embodiments, R is benzyl. In other embodiments, R is (2-trimethylsilyl)ethoxymethyl.

As used herein, halogen refers to F, Cl, or Br.

As used herein, "orthogonal," when used to describe hydroxyl and/or phenolic protecting groups of the invention, refers to a strategy allowing the protection and deprotection of multiple -OH groups one at the time each with a dedicated set of reaction conditions without affecting the other. Developed originally in carbohydrate syntheses, it is now well known by those skilled in the art that the reactions of alcohols with compounds such as siloxy methyl halides, silyl alkoxymethyl halides (e.g., 2-(trimethylsilyl)-ethoxymethyl chloride), substituted phenoxy methyl halides, or alkoxy halides form the corresponding protecting group ethers, which can be reversed under varying hydrolysis conditions. Herein, use of the designations R and R|. for example, may refer to the same or different such protecting groups.

In the methods of the invention, the compound of formula I is converted to the compound of formula II by subjecting the compound of formula I to conditions sufficient to effect a Curtius rearrangement. A Curtius rearrangement is a chemical reaction that involves the rearrangement of an acyl azide, for example, the compound of formula 1, to an isocyanate. The isocyanate can then be trapped by a variety of nucleophiles.

In preferred methods of the invention, the conditions sufficient to produce the compound of formula II comprise heating the compound of formula I in an organic solvent, for example. toluene, benzene, or xylene, for a time sufficient to generate an isocyante of formula III

and treating the isocyanate of formula III with an alcohol. The isocyanate of formula III can be treated with the alcohol either in situ or after purification. In certain embodiments, the alcohol is 9-fluorenylmethanol, 2,2,2-trichloroethanol. 2-trimethylsilylethanol, t-butanol, allyl alcohol, benzyl alcohol, m-nitrophenyl alcohol, or p-methoxyphenyl alcohol. In preferred embodiments, the alcohol is trimethysilylethanol.

Preferably, the compound of formula TII is

In preferred embodiments of the invention, the compound of formula I is

In other embodiments, the compound of formula I is

The compounds of formula I can be prepared using any methods known to those skilled in the art. In preferred embodiments, a compound of formula T can be prepared by reacting a compound of formula VI:

with a compound of formula V

under conditions sufficient to produce a compound of formula VIl

and more preferably, the compound of formula VII is

wherein each R₂ is independently Ci^alkyl. The compound of formula VII can be 5 converted to the irciniastatin using techniques and methods known in the art.

In some embodiments, the compound of formula VI is

In still other embodiments, the compound of formula VI is

I O In preferred embodiments, Ri is methyl or ethyl.

In other embodiments, the compound of formula V is

wherein R₂ is preferably methyl or ethyl.

In preferred embodiments, the compound of formula VIl is

In accordance with certain preferred embodiments of this invention, an irciniastatin is provided via a synthetic scheme which includes the preparing the compound of formula I. the attachment of the amido linked sidechain proceeds by using the moiety described in formula VIlI

wherein R_x may be any C_M alkyl chain, optionally substituted with a Ci_-4 alkyl, Cj_-4 alkenyl, alcohol, orthogonally protected alcohol, Ci_-4 alkoxide, or other substituent.

The moiety designated L can be any group such as pivaloyl, alkyl sulfonyl, aryl sulfonyl. or other moiety that make the OL group a labile, or ready, leaving group. This list is not intended to be exhaustive, and those skilled in the art will appreciate the other opportunities for this group.

In certain embodiments, the compound of formula VIII is

Reaction of the compound of formula VIIl with a compound of formula II, under conditions known to those skilled in the art - for example, de-protecting the amino group, allowing it to react with the labilized carboxyl moiety in formula VlII - yields a compound of formula IX.

In certain embodiments, the compound of formula IX is

Additional reactions can be applied to further modify the compound of formula IX, depending on specific interest. For example, selective removal of the orthogonal protecting R and Ri groups from

I O and asymmetric reduction of the C- 15 carbonyl yields (+)-irciniastatin A.

In accordance with certain preferred embodiments of this invention, a compound of formula X can be prepared by deprotecting a compound of formula TX, under conditions sufficient to produce a compound of formula XlT; and oxidizing the compound of formula XIT under sufficient conditions to form a compound of formula X. Those skilled in the art would 15 appreciate the choice of protecting groups that would allow the selective remove of Ri, while retaining the remaining protecting groups.

In one embodiment, then, the compound of formula X is:

In accordance with certain preferred embodiments of this invention, a tetrahydropyran compound of formula XIII are provided by the cyclization of a compound of formula XIV,

wherein R_Hι is

alkyl group substituted with at least one ORn or carbonyl group, Rn are independently C|.ή alkyl groups, and Rn and R1₂ are orthogonal protecting groups.

One of the many advantages of this method is the ability to selectively introduce chirality to the carbon atoms in the compounds of formulae XIIT and XIV, for example by stereoselective epoxidations and reductions of achiral precursors to a compound of formula XIV. One skilled in the art would know how to affect these stereoselective epoxidations and reductions. As but one example of many possibilities on this theme, the compound of formula XIV is 1

and the tetrahydropyran compound of formula XUl is

which contain the stereochemistries corresponding to those found in the irciniastatins.

This embodiment is also not limited to the case where the free alcohol described in structure XFV is isolated prior to affecting the cyclization. As but one example of many possibilities on this theme, compounds of formula XIIl can also be prepared by the aldol reaction of ketones with an aldehyde compound of formula XV.

O OR₁₃ O

_H^X>!Λ_{0R)i (χv)}

For example, it is possible to produce the product where the compound of formula XlV is

by first reacting the compound of formula XV

with 2-butanone, followed by cyclization. Similarly, one skilled in the art would appreciate that this method can be employed using homologs and substituted homologs of 2-butanone.

15

The methods of the invention are particularly described in the synthetic schemes that follow. The sequences set forth herein are illustrative only, and are not intended to limit the scope of the invention. Those skilled in the art will appreciate that modifications to the followed synthetic schemes can be performed without detracting from the spirit of the invention. 0 Preferred methods for preparing compounds of formula V are set forth in Scheme 1. Aryl aldehyde 2.4 is a compound of formula V having three R₄ groups — two OR groups and a methyl group, wherein each R is benzyl. A compound wherein R is (2-trimethylsilyl)ethoxymethyl can be prepared by treating homophthalate 2.6 with SEMCl. Scheme 1

61 %, 2 steps

Bis-benzyl Ether 2.21

Aryl Aldehyde 2 4

One exemplar)' synthesis of a compound of formula VI is set forth in Schemes 2-4. Schemes 2-4 depict a method of prepared a compound of formula VI that is tetrahydropyran 2.5 wherein R3 is three groups - two methyl groups and an ORi group wherein R= is a trialkylsilyl group, Le , t-butyldimethylsilyl.

Scheme 2

Homopropargyllic Acid (+) 2 11

A, Oxone, K₂CO₃ CH₃CN, buffer

73%

Vinyl Iodide (-) 2 26 11 1 mixture of epoxides

78% Diene (-) 2 7

Scheme 3

1) Pd₂(dba)₃ CHCI₃

TBS Ester (+) 2 34

DIBAL, CH₂CI₂ 97%

Allylic Alcohol (+) S2 5 92% Epoxide (+) 2 35 Scheme 4

Epoxide (+) 2.35 70%, 2 steps Ester (+) 2.36

Me₂SO₄, NaH

THF * 87%

Tetrahydropyran (+) 2 5

Compounds of formula VI can also be prepared according to the methods set forth in Schemes 5 and 6.

Scheme 5

OH OH I) NaH, TBSCI, THF OTBS O

2) Paπkh-Doering [O] 85%, 2 steps

D VlOl 3.13 Aldehyde 3.7

TBSOTf, 2,6-tutιdιne CH₂CI₂ 96%

Scheme 6

I) TEMPO₁ NaCI₂O₁ NaOCI,

OTBS OTBS buffer, CH₃CN 2) TMSCHN₂, MeOH , CH₂CI₂ HF pyr, pyr

94%, 2 steps

THF, r.t.

Epoxide (+) 3.14 72%

Ester (+) 3.15

1 ) 2-butanone, (-)-DIPCI,

O OTBS O Et₃N, Et₂O ^ 86%, d.r. = 5:1

2) 20 mol% CSA, CH₂CI₂ ' 74% of desired isomer

Alcohol (+) 3.16 Aldehyde (+) 3.9

O₂Me

Tetrahydropyran (+) 3.18

Tetrahydropyran (+) 3.5

With compounds of formulas V and VI in hand, the synthesis of the irciniastatin can proceed. An exemplary method of formula a compound of formula IT is set forth in Scheme 7. Aldol condensation of compounds 2.4 and 2.5 produced beta hydroxylketone 2.46. Reduction of the ketone, followed by hydrolysis of the methyl ester produced acid 2.48. After conversion to the corresponding azide using sodium azide. the Cuitius rearrangement is effected by heating the azide in toluene followed by treatment with TMSEtOH to form a compound of formula II.

I O Protection of the secondary hydroxyl of the compound of formula II was performed using TBSOTf to produce compound 2.49.

Scheme 7

Aryl Aldehyde 2 4 Tetrahydropyran (+) 2 5

(+) 2 46

2) TBSOTf, 2,6-lutιdιne 63%, 2 steps *"

An alternative sequence, wherein OR is OSEM, is set forth in Scheme 8.

Scheme 8

The sidechain portion of an irciniastatin can be prepared, for example, according to Scheme 9.

Scheme 9

Acetonide (+) 2.14

Conversion to an irciniastatin, for example, irciniastatin A, can be accomplished 5 according to the sequence set forth in Scheme 10.

Scheme I O

(+)-lrciniastatin A

EXPERIMENTAL SECTION

I O Reactions were carried out in flame-dried or oven dried glassware under an argon atmosphere unless noted otherwise. Anhydrous diethyl ether and tetrahydrofuran were obtained from a Pure Solve™ PS-400 or distilled from sodium/benzophenone under an argon atmosphere. Dichloromethane was obtained from the Pure Solve™ PS-400 or distilled over calcium hydride under an argon atmosphere. Triethylamine, 2,6-lutidine, diisopropylethylamine, pyridine, and

1 5 hexamethylphosphoramide were freshly distilled from calcium hydride under an argon atmosphere. All chemicals were purchased from Aldrich, Acros, TCI, or Strem. Alkyl lithium reagents were purchased from Aldrich or Acros and titirated using the N-benzylbenzamide protocol (J. Organomet. Chem., 1997, 542, 281.)- Reactions were magnetically stirred unless stated otherwise and monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates. Silica gel chromatography was performed utilizing ACS grade solvents and silica gel from either Silicycle or Sorbent Technologies.

Infrared spectra were obtained using a Jascl FT/IR-480 plus spectrometer. Optical rotations were obtained using either a Jasco D1P-370 polarimeter or a Jasco P2000 polarimeter. Proton magnetic resonance spectra and carbon magnetic resonance spectra were obtained on either a Bruker AMX 500 MHz or a Bruker Avance III 500 MHz spectrometer. Chemical shifts are reported relative to chloroform (δ 7.26) or methanol (δ 4.78) for ¹H ΝMR spectra and chloroform (δ 77.23), methanol (δ 49.3), or benzene (δ 128.0) for ¹³C spectra. High-resolution mass spectra were measured at the University of Pennsylvania or at the University of Delaware.

Diol (+)-S2.1. A 2 Ν HCl solution (10 mL) was added to acetonide (+)-2.14 (0.836 g, 4.18 mmol) at rt. After 30 min, the reaction was quenched with sat. NaHCO₃ until all gas evolution had ceased. The reaction was then extracted with EtOAc and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (40% EtOAc/hexanes) provided (+)- S2.1 (0.650 g, 97% yield) as a colorless oil. [a]* +21.8 (c 1.5, CHCl₃); IR (neat) 3416, 2932, 1646. 1456, 1092, 1050 Cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 4.79 (s, I H), 4.76 (s, I H), 3.72-3.58 (m. 3H), 3.47-3.42 (m, I H)_.. 3.37 (s, 3H), 3.33 (s, I H), 3.16 (s, I H), 2.24 (ddd, ./= 20.0, 14.4, 6.4 Hz. 2H), 1 .75 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.49, 1 13.2, 81 .7, 72.8, 63.3, 58.4, 38.9, 22.9; high resolution mass spectrum (CI+) m/z 161.1 177 [(M+H)~; calcd for C₈H₁₇O₃: 161.1 178].

Pivalate Ester (+)-2.16. To a 0 ⁰C of (+)-S2.1 (0.243 g, 1.52 mmol) in pyridine (4 mL) was added trimethylacetyl chloride (0.205 mL, 1.67 mmol). The reaction was allowed to warm to rt and after 1 h the reaction was cooled to 0 °C and H;O (5 mL) was added. The reaction was diluted with Et₂O (5 mL) and washed successively with 5 mL each of sat. NaHCθ₃, 1 N HCI, and brine. The organic layer was then dried over MgSθ₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-2.16 (0.325 g, 88% yield). [a]_]? +23.9 (c 1.1. CHCI₃); IR (neat) 3467. 2971 _,. 2935, 1 728, 1457, 1286, 1 163, 1 103 cm^"1: ¹H NMR (500 MHz, CDCl₃) δ 4.84 (s, I H), 4.81 (s, I H), 4.23 (dd, J = 1 1.7, 3.5 Hz, I H), 4.16 (dd, J = 1 1.6, 6.8 Hz, I H), 3.92-3.82 (m, IH), 3.48-3.39 (m, IH), 3.40 (s, 3H), 2.39 (d, J= 4.8 Hz, I H), 2.29 (ddd, J = 19.4, 14.4, 6.2 Hz, 2H), 1.79 (s, 3H), 1.22 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 179.0, 142.6, 1 13.3, 80.6, 71.4. 65.6, 58.4, 39.0, 38.4, 27.4, 23.0; high resolution mass spectrum (ES+) m/z 245.1743 [(M+Hf; calcd for Ci₃H₂₅O₄: 245.1753].

TBS alcohol (+)-2.17. A solution of pivalate ester (+)-2.16 (0.121 g, 0.495 mmol) in CH₂CI₂ (5 mL) was cooled to -78 ⁰C and 2,6-lutidine (0.1 15 mL, 2.0 equiv.) was added followed by TBSOTf (0.136 mL, 1.2 equiv.). After 1 h, the reaction was diluted with ether (5 mL) and washed with sat. CuSO₄ and brine (5 mL each). The organic layer was dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (+)-2.17 (0.169 g, 95% yield) as a colorless oil. [α]]? +0.4 (c 5.3, CHCI₃); IR (neat) 2957, 2931 , 2860, 1733, 1468, 1283, 1254, 1 157, 1 1 16 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 4.79 (s, IH), 4.76 (d, J = 0.9 Hz, I H), 4.15 (dd, J = 1 1.5, 4.5 Hz, I H), 4.02 (dd, J= 1 1.5, 5.3 Hz, I H), 3.90-3.85 (m, I H), 3.37 (s, 3H), 3.39-3.33 (m, I H), 2.23 (dd, J= 14.5, 4.3 Hz, I H), 2.18 (dd, J = 14.4, 8.4 Hz, I H), 1.75 (s, 3H), 1.20 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H); '³C NMR (125 MHz, CDCl₃) δ 178.5, 143.1 , 1 12.7, 81.6, 72.3, 65.8, 58.7, 39.3, 38.9, 27.5, 25.9, 23.0, 18.2, -4.5; high resolution mass spectrum (ES+) m/z 381.2420 [(M+Na)"; calcd for C₁₉H₃₈O₄SiNa: 381.2437].

Alcohol (+)-2.18. A solution of (+)-2.17 in CH₂CI₂ was cooled to -78 ⁰C and DIBAL-H was added dropwise over 5 min. The reaction was stirred for 5 min and then quenched with slow addition of MeOH (0.5 mL). The reaction was warmed to rt and sat. Rochelle's salt (5 mL) was added. The solution was stirred for 2 h then extracted with Et₂O (3 x 5 mL). The combined organic layers were then dried over MgSU₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-2.18 (0.123 g, 95% yield) as a colorless oil. [α]² _D° +5.9 {c 0.7, CHCI₃): IR (neat) 3450, 2931 , 2900, 2858, 1646, 1597, 1465, 1377, 1253, 1 101 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 4.82 (s, IH), 4.80 (s, IH), 3.75-3.60 (m_.. 3H), 3.43 (s, 3H)_; 3.45-3.39 (m, I H), 2.27 (dd, J = 14.4, 4.1 Hz, I H), 2.22-2.15 (m, 2H), 1.78 (s, 3H), 0.91 (s, 9H), 0.10 (s, 6H); ¹³C NMR (125 MHz, CDCI₃) δ 143.1 , 1 12.9, 82.2, 74.6, 64.1 , 59.3, 40.4, 26.1. 23.0, 18.3, -1.3, - 4.4; high resolution mass spectrum (ES+) m/z 297.1863 [(M+Na)'; calcd for Ci₄H₃OO₂SiNa: 297.1862].

Aldehyde (-)-S2.2. To a 0 ⁰C solution of alcohol (+)-2.18 (0.123 g, 0.448 mmol) in DMSO (0.32 mL, 10 equiv.) and CH₂Cl₂ (4.5 mL) was added /-Pr₂NEt (0.234 mL. 3.0 equiv.) followed by SO₃.pyridine (0.213 g, 3.0 equiv.). After 10 min, the reaction was diluted with H₂O (2 mL) and brine (2 mL). The layers were separated and the aqueous layer was extracted with CH₂CI₂ (3 x 10 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-S2.2 (0.1 16 g, 95% yield) as a colorless oil. [α]² _D° -24.6 (c 1 .5, CHCI₃); IR (neat) 2932, 2858, 1 734, 1465, 1370, 1255, 1 146, 1 1 1 1 , 1028 cm^" '; ¹H NMR (500 MHz, CDCl₃) δ 9.59 (d, ./= 0.9 Hz, I H), 4.83 (s, 2H), 4.14 (dd, ./= 2.4, 0.9 Hz, 1 H), 3.60 (ddd, J = 7.0, 7.0, 2.6 Hz, 1 H), 3.39 (s, 3H), 2.28 (dddd, J = 13.9, 13.9, 13.9, 7.0 Hz, 2H), 1 .68 (s, 3H), 0.94 (s. 9H), 0.10 (s, 3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 203.6, 141.8, 1 14.5, 83.1 , 78.7, 58.1 , 38.7, 26.0, 22.8, 18.4, -^.6, -^.8; high resolution mass spectrum (ES+) m/z 295.1 705 [(M+Na)^τ; calcd for C₄H₂₈O₃SiNa: 295.1706].

Acid H-2.2. Aldehyde (-)-S2.2 (0.1 16 g, 0.425 mmol) was dissolved in /-BuOH (7 mL) and H₂O (7 mL) and cooled to 0 ⁰C. To this solution was added 2-methyl-2-butene (3 mL), NaH₂PO₄^H₂O (0.662 g, 10 equiv.), and then NaClO₂ (0.583 g, 10 equiv.). After 30 min, the reaction was poured onto sat. NH₄CI (10 mL) and water was added to dissolve all solids that had precipitated. The reaction was extracted with EtOAc (5 x 10 mL) and then the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (25% EtOAc/hexanes) provided (-)-2.2 (0.1 12 g, 91 % yield) as a white, viscous foam. [α]^: _D° -5.8 (c 0.7. CHCI₃); IR (neat) 2932. 2858, 1726, 1464, 1366, 1255, 1 157, 1 1 13 cm-¹: ¹H NMR (500 MHz, CDCI₃) δ 4.83 (s, l H), 4.80 (s, I H), 4.41 (d, J= 1.9 Hz, IH), 3.67-3.63 (m, IH), 3.43 (s, 3H), 2.31 (dd, ./ = 14.4, 8 2 Hz, I H), 2.19 (dd, J= 14.3, 5.1 Hz, I H), 1.76 (s, 3H). 0.94 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H): ¹³C NMR (125 MHz. CDCI₃) δ 173.3. 14! .9, 1 13.7. 82.0. 73.8, 58.5, 38.2, 25.9, 22.9, 18.3. -4 5, -5.3; high resolution mass spectrum (ES+) m/z 31 1.1665 [(M+Na)~; calcd for Ci₄H₂₈O4SiNa: 31 1.1655].

Bis-Benzy] Ether 2.21. Homophthalate 2.6 (0.308 g, 1.21 mmol) was dissolved in DMF (4.0 mL) at rt and K₂CO₃ (0.1 84 g, 1.1 equiv) was added followed by benzyl bromide (0.145 mL, 1.0 equiv.) and tetrabutylammonium iodide (0.045 g. 0.1 equiv.). The reaction was heated to 70 ⁰C and after 4 h, no benzyl bromide was present by TLC analysis. The reaction was cooled to rt and additional K₂CO₃ (0.184 g, 1.1 equiv) and benzyl bromide (0.145 mL, 1.0 equiv.) were added. The reaction was heated back to 70 ⁰C. After 18 h, the reaction was cooled to rt and sat. NaHCO₃ (4 mL) was added and the reaction extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with sat. NaHCO₃, brine, and then dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes) provided diester 2.21 (0.518 g. 99% yield) as a white, amorphous solid. IR (neat) 3064, 3032, 2950, 2875, 1732, 1596, 1454, 1318, 1267, 1 153, 1091 cm^"1; ¹H NMR (500 MHz, CDCl₃) 7.40-7.28 (m, 10H), 6.50 (s, I H), 5.04 (s, 2H). 5.02 (s, 2H), 3.85 (s, 3H), 3.71 (s, 2H), 3.69 (s, 3H), 2.16 (s, 3H); ¹³C NMR ( 125 MHz, CDCI₃) δ 171.2, 168.7, 158.6, 155.3, 137.0. 136.9, 132.8, 128.8, 128.7, 128.5. 128.2, 128.0, 127.3, 127.1 , 1 19.8, 1 17.7, 98.2, 71.2, 70.6, 82.2. 36.2, 1 1.7; high resolution mass spectrum (ES+) m/z 457.1639 [(M+Na)⁺; calcd for C₂₆H₂₆O₆Na: 457.1627].

Aryl Acid 2.22. A solution of diester 2.21 (0.518 g, 1.19 mmol) in CH₂Cl₂ (6 mL) and MeOH (6 mL) was cooled to 0 °C and solid KOH (1.34 g, 20 equiv.) was added. Once all the KOH had dissolved, the cold bath was removed and the reaction stirred at rt. After 3 h, the reaction was cooled back to O ⁰C and acidified to pH 2 with 3 N HCl. The reaction was then extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over MgSO^ and concentrated to provide diester 2.22 (0.463 g, 93% yield) which, was taken forward without purification. IR (neat) 2950, 2925, 1710, 1595, 1454, 1322, 1267, 1 155, 1092 cπT¹ ; ¹H NMR (500 MHz, CDCI₃) δ 7.38-7.32 (m, 10H), 6.51 (s, I H), 5.04 (s, 4H), 3.92 (s, 3H), 3.69 (s, 2H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 171.8, 171.1 , 159.5, 156.2, 136.8, 136.6, 133.0, 128.9, 128.8, 128.3, 128.2, 127.3, 127.2. 120.5, 1 16.3, 98.3, 71 .4, 70.6, 53.1 , 37.9, 1 1.7: high resolution mass spectrum (ES+) m/z 419.1487 [(M-Hf; calcd for C₂₅H₂₃O₆: 419.1495].

Aryl Alcohol 2.23. A solution of acid 2.22 (0.38 g, 0.90 mmol) in THF (9 mL) was cooled to 0 ⁰C and BH₃.SMe₂ (1.8 mL, I M solution in THF, 2.0 equiv.) was added dropwise. After 15 min, the cold bath was removed and the reaction stirred at rt for 5 h. The reaction was quenched slowly with MeOH (1 mL) and extracted with CH₂CI₂ (4 x 15 mL). The combined organic layers were then dried over MgSOa and concentrated. Flash chromatography (25% EtOAc/hexanes) provided alcohol 2.23 (0.31 g, 85% yield) as a white foam. IR (neat) 3409, 2949, 2886, 1723. 1594, 1454, 1319, 1273, 1 154, 1091 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.26 (m, 10H), 6.40 (s_r IH). 5.04 (s, 2H), 5.02 (s, 2H), 3.88 (s, 3H), 3.83 (dd, J = 7.0, 7.0 Hz, 2H), 2.90 (dd. J = 7.0, 7.0 Hz, 2H), 2.57 (s. I H). 2.20 (s, 3H); ¹³C NMR ( 125 MHz, CDCI₃) δ 1 70.4. 158.8, 154.9, 137.0, 136.9, 136.6. 128.8, 128.7, 128.2. 128.1. 127.3, 127.2. 1 18.8, 1 18.0, 97.3_.. 71.1. 70.5, 62.6, 52.6, 34.4, 1 1.5; high resolution mass spectrum (ES+) m/z 429.1693 [(M+Na)⁴; calcd for C₂₅H₂₆O₅Na: 429.1678].

Aryl Aldehyde 2.4. Alcohol 2.23 (0.261 g, 0.643 mmol) was dissolved in CH₂CI₂ (8 niL) and DMSO (6.5 mL) and cooled to 0 ⁰C. Next, Et₃N (0.90 mL, 10 equiv.) was added followed by SO₃.pyridine (0.41 g, 4 equiv.). After 30 min at 0 ⁰C. the cold bath was removed and the reaction stirred at rt. After 2 h, the reaction was diluted with sat. NaHCO₃ (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with 1 M NaHSO-) (10 mL), sat. NaHCO₃ (10 mL), and brine (10 mL) and then dried over MgSθ4 and concentrated. Flash chromatography (10% EtOAc/hexanes) provided aldehyde 2.4 (O. I 13 g, 88% yield) as a colorless oil. IR (neat) 3064, 3032, 2948, 1723, 1595, 1454, 1324, 1270, 1 158, 1089 cm^"1: ¹H NMR (500 MHz, CDCI₃) δ 9.67 (dd, J= 1.5, 1.5 Hz, 1 H), 7.40-7.34 (m, 1 OH), 6.54 (s, 1 H), 5.07, (s, 2H), 5.04 (s, 2 H), 3.86 (s, 3H), 3.71 (d, J = 1.6 Hz, 2H), 2.13, (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 198.7, 168.7, 158.8, 155.5, 136.9, 136.7, 131.1 , 128.8, 128.7, 128.2, 128.1 , 127.3, 127.1. 1 19.8, 1 17.9, 98.3, 71.2, 70.6, 52.3, 46.0_r 1 1.8; high resolution mass spectrum (ES+) ni/z 405.1701 [(M+HV ; calcd for C₂₅H₂₅O₅: 405.1702].

Homopropargyllic alcohol (+)-2.11. To a -78 ⁰C solution of THF (600 mL) was added propyne (100 g, 4 equiv.) via subsurface cannula to dissolve the gas in the THF. Next, a solution of «-BuLi (570 mL, 2.2 M in hexanes, 2 equiv.) was cooled to -78 ⁰C and added to the propyne solution over 1 h via cannula. After stirring for 1.5 h at — 78 ⁰C (S)-l ,2-epoxybutane [(-)-2.24] (45 g, 0.625 mol) was added via cannula over 25 min followed by addition of BF₃«OEt₂ over 45 min via cannula. After stirring for 1.5 h at —78 °C, the reaction was quenched with sat. NaHCO₃ until all gas evolution ceased (ca. 3 h). The layers were separated and the aqueous layer extracted with EtiO (3 x 500 mL). The combined organic layers were dried over MgSO₄ and concentrated in a 0 ⁰C bath (to minimize loss of product due to slight volatility) to provide (+)- 2.11 (55.6 g, 79%) as a colorless oil. [α]∞ +1 1.0 (c 1.3, CHCI₃); IR (neat) 3382, 2964, 2922, 1461 , 1435, 1335, 1245, 1 1 12, 1063, 1020 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 3.69-3.55 (m, I H), 2.37 (ddddd, J = 16.4, 4.9, 2.5, 2.5, 2.5 Hz, 1 H)_; 2.24 (ddddd, J = 16.4. 7.2, 2.5, 2.5, 2.5 Hz, I H), 1.95 (d, J = 4.8 Hz, I H), 1.80 (dd, ./ = 2.5, 2.5 Hz, 3H), 1.64-1.48 (m, 2H), 0.94 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 78.3, 75.5, 71.7, 29.2, 27.3, 10.1 , 3.6; low resolution mass spectrum (ES+) m/z 112.10 [(M+)⁺; calcd for C₇Hi₂O: 1 12.0888].

AIkyne (-)-2.25. To a solution of (+)-2.11 (1 8.5 g, 0.165 mol) in CH₂Cl₂ (184 mL) and cyclohexane (368 mL) at rt was added benzyl-2,2,2-trichloiOacetimidate (50.0 g, 1.2 equiv) followed by dropwise addition of TfOH (0.73 mL, 0.05 equiv.) The solution turned cloudy and light brown as the reaction progressed. After 6 h, hexane (600 mL) was added and the solution stirred 30 min to precipitate solids and then the suspension was filtered. The filtrate was washed with sat. NaHCO₃ (200 mL), which was then back extracted with CH₂Cl₂ (3 x 100 mL). The combined organic layers were then dried over MgSO₄ and concentrated. The concentrate was diluted with 10% EtOAc/hexanes (200 mL) to facilitate further precipitation of solids and then filtered. The filtrate was then concentrated and purified by flash chromatography (0.5% EtOAc/hexanes to 1 % EtOAc/hexanes) to provide (-)-2.25 (30.4 g, 91 % yield) as a light yellow oil. [αft° -27.6 (c- 1.4, CHCl₃); IR (neat) 2964, 2919, 2873, 1496, 1454, 1348, 1207, 1 108, 1071 , 1028 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 7.44-7.22 (m, 5H), 4.60 (dd, J = 58.0, 1 1 .8 Hz. 2H). 3.45 (dddd, J= 6.7, 6.7, 5.1. 5.1 Hz, I H), 2.45 (ddddd, J= 16.5, 5.1 , 2.5, 2.5, 2.5 Hz, IH), 2.41- 2.32 (m, 2H), 1.81 (dd, J = 2.5, 2.5 Hz, 3H). 1 .77-1.60 (m, 2H), 0.97 (dd, J = 7.4, 7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 138.9, 128.5, 127.9. 127.7, 79.1 , 77.2, 76.1 , 71 .4, 26.8, 23.8, 9.8, 3.7; high resolution mass spectrum (ES+) m/z 202.1354 [(M)'; calcd for Ci₄Hi₉O: 202.1358].

Vinyl iodide (— )-2.26. To a flask protected from light was added bis(cyclopentadienyl) zirconium(IV) chloride (0.313 g, 2.0 equiv.) and THF (1 mL). The solution was cooled to 0 ⁰C and DIBAL-H (1.07 mL, 1 M in hexanes, 2.0 equiv.) was added dropwise. After 30 min at 0 ⁰C, alkyne (-)-2.25 (0.108g. 0.534 mmol) was dissolved in THF (0.3 mL) and added to the in situ generated Schwartz reagent. The flask and syringe were then flushed with TTTF (0.3 mL) into the reaction. The reaction flask was then placed in a 50 ⁰C oil bath. After 1 h, the reaction was cooled to 0 ⁰C and N-iodosuccinimide (0.265 g, 2.2 equiv) was added. After 10 min, the reaction was quenched with sat. ΝaHC0₃ (10 mL) and then filtered through a 1 cm plug of silica gel. The silica gel was rinsed with EtOAc and the layers separated. The aqueous layer was then extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (-)-2.26 (135 mg, 77% yield. >20: 1 selectivity) as a colorless oil. [α]² _D° -4.4 (c 1.0, CHCl₃); TR (neat) 3030, 2963, 2931 , 2872, 1454, 1351 , 1092, 1065, 1028 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.27 (m, 5H), 6.24 (dd, J= 7.5, 6.8 Hz, I H), 4.54 (s, 2H). 3.37 (dddd, J = 5.9, 5.9, 5.9, 5.9 Hz, I H), 2.39 (s, 3H), 2.36-2.17 (m, 2H), 1 .62-1.52 (m, 2H), 0.95 (dd, ./= 7.4, 7.4 Hz. 3H).; ¹³C NMR (125 MHz, CDCI₃) δ 138.9, 137.7, 128.6, 127.9, 127.7, 95.3, 79.3, 71 .4. 34.8, 27.9. 26.8, 9.9.; high resolution mass spectrum (ES+) m/z 353.0386 [(M+Na)^H ; calcd for Ci₄Hi₉IONa: 353.0378].

Diene (-)-2.7. Vinyl iodide (-)- 2.26 (6.02 g, 18.2 mmol) was dissolved in anhydrous DMF (70 mL) in a sealable tube. Methyl acrylate (2.35 g, 1.5 equiv.) was added followed by Pd(OAc)₂ (0.81 7 g, 0.20 equiv.), NaHCO3 (3.06 g, 2.0 equiv.), and Bu₄NI (6.73 g, 1.0 equiv.). The tube was flushed with argon, sealed, and heated to 100 ⁰C over 1 h. After 7 h at 100 ⁰C, the reaction was cooled to 0 ⁰C and sat. NH₄CI (100 mL) added. The reaction was then filtered and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H₂O, sat. NaHCO₃, and brine (100 mL each). The organic layer was then dried over MgSO4 and concentrated. Flash chromatography (3% EtOAc/hexanes to 5% EtOAc/hexanes to 8% EtOAc/hexanes) provided diene (-)-2.7 (4.1 1 g, 78% yield) as a light yellow oil. [α]² _D° -1 1 .7 (c 1 .0, CHCI₃); IR (neat) 3033, 2963, 2873, 1719, 1624, 1310, 1 194, 1 169, 1 123, 1097 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.26 (m, 5H). 5.97 (dd, J = 8.0, 8.0 Hz, 1 H), 5.81 (d, J = 15.5 Hz, I H), 4.53 (s, 3H), 3.77 (s. 3H), 3.47 (ddd, ./= 12.0, 6.0, 6.0 Hz, I H), 2.51 -2.43 (m, 2H), 1.78 (s, 3H), 1.57-1.64 (m, 3H), 0.94 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.2, 149.9, 138.9, 138.4, 134.3, 128.6, 127.9, 127.8, 1 15.6, 79.8, 71.4. 51.7, 33.3, 27.0, 12.6, 9.9; high resolution mass spectrum (ES+) m/z 289.1823 [(M+Na)⁺; calcd for Ci₅H₂₅O₃: 289.1804].

Epoxide (+)-2.28. Diene (-)-2.7 (2.94 g, 10.2 mmol) was dissolved in CH₃CN (460 mL). Na₂B₄O₇ buffer (0.05 M, 1 15 mL) was added followed Bu₄NHSO₄ (0.425 g) and ketone catalyst H-2.27 (1.32 g, 0.50 equiv.). Oxone (8.77g, 1.4 equiv) was dissolved in Na₂EDTA buffer (59 mL, 4 x 10^"4 M) and K₂CO₃ (8.31 g, 5.9 equiv.) was dissolved in H₂O (59 mL). The two solutions were then added simultaneously over 3 h via a dual-syringe pump. After the addition was complete, water was added to dissolve any solids that had formed and the reaction extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (200 mL). dried over MgSO₄, and concentrated. Flash chromatography (5% EtOAc/hexanes to 8% EtOAc/hexanes) provided (+)-2.28 (2.27 g, 73% yield, β:α = 14: 1 ) as a colorless oil. [α|_D ²⁰ +2.2 (c 1 .7. CHCI₃): IR (neat) 2966, 2932. 2876, 1726, 1654, 1436, 131 1. 1 170, 1094 cm^'1 ; ¹ H NMR (500 MHz, CDCl₃) δ 7.34-7.31 (m, 5H). 6.75 (d, J = 15.5 Hz, I H), 6.00 (d, ./ = 16.0 Hz, I H). 4.53 (dd, J= 46.5, 1 1.5 Hz, 2H), 3.75 (s, 3H), 3.59-3.55 (m, I H), 3.00 (dd, J= 6.5, 6.5 Hz. I H), 1.85 (ddd, J = 14.5, 8.0, 5.5 Hz, I H), 1.76 (ddd, J = 4.5, 6.5, 4.5 Hz. I H), 1. 68-1.60 (m, 2H), 1.41 (s, 3H), 0.95 (dd, J = 7.5, 7.5 Hz, 3H); '³C NMR (125 MHz, CDCl₃) δ 166.8, 150.4. 138.8, 128.6, 128.0. 127.9, 121.3, 78.0, 71.6, 63.8, 58.9, 51.9. 33.2, 27.0, 15.7, 9.5: high resolution mass spectrum (ES+) m/z 3271578 [(M+Na)^x; calcd for Ci₈H₂₄O₄Na: 3271572].

Alcohol (+)-2.29. To a solution of compound (+)-2.28 (60 mg, 0.20 mmol) in CH₂Cl₂ (3 mL) was added H₂O (21 μL, 6 equiv.) The reaction was cooled to -40 ⁰C and Me₃Al (0.98 mL, 10 equiv., 2 M in hexanes) was added. After 30 min, the reaction was warmed to 0 ⁰C and the reaction quenched with slow addition Of H₂O (1 mL) followed by addition of 1 N HCl (3 mL) to break up the emulsion. The reaction was extracted with CH₂CI₂ (3 x 10 mL) and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes) provided (+)-2.29 (53 mg, 84% yield) as a colorless oil. [α]² _D° +31.7 (c 1.6. CHCI₃); IR (neat) 3490, 2964, 2875, 1723, 1651 , 1435, 1314, 1201 , 1 173, 1060 cm-¹; ¹H NMR (500 MHz, CDCI₃) 7.38-7.26 (m, 5H), 7.04 (d, J = 16.1 Hz, I H), 5.81 (d, ./ = 16.1 Hz, I H), 4.54 (dd, J = 40.1 , 1 1.6 Hz, 2H), 3.73 (s, 3H), 3.70 (d, J = 8.9, 1 H), 3.65-3.59 (m, I H), 2.75 (s, I H), 1.91 -1.66 (m, I H), 1.65-1.50 (m, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.91 (dd, J = 7.5, 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.5, 155.9, 138.6, 128.7, 128.0, 128.0, 1 19.2, 78.9, 74.5, 71.6, 51 .7. 41.6, 34.2, 26.1 , 22.9, 22.9, 10.2; high resolution mass spectrum (ES+) m/z 343.1876 [(M+Na)⁺; calcd for Ci₉H₂₈O₄Na: 343.1886].

PMB ether (+)-2.31. To a solution of (+)-2.29 (0.906 g, 2.83 mmol) in CH₂Ch (9 niL) and cyclohexane (18 niL) at rt was added £>-methoxybenzyl-2,2,2-trichloroacetimidate (3.2 g, 4.0 equiv) followed by addition of TfOH (3 μL. 0.01 equiv.) The solution turned cloudy and light brown as the reaction progressed. After 30 min, hexane (20 mL) was added to precipitate solids and the suspension was filtered. The filtrate was washed with sat. NaHCO₃ (25 mL), which was then back-extracted with CH₂CN (3 x 25 mL). The combined organic layers were then dried over MgSO,) and concentrated. The concentrate was diluted with 10% EtOAc/hexanes (25 mL) to facilitate further precipitation of solids and then filtered. The filtrate was then concentrated and purified by flash chromatography (3% EtOAc/hexanes to 5% EtOAc/hexanes) to provide (+)-2.31 (0.910 g, 73% yield) as a light yellow oil. [a]²" +43.5 (c 1.6, CHCI₃); IR (neat) 2962, 2875, 2360, 2340, 1722, 1613, 1513, 1248, 1 173, 1064 cm^"1: ¹H NMR (500 MHz, CDCI₃) δ 7.44-7.28 (m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 16.0 Hz. I H), 6.87 (d, J = 8.5 Hz, 2H), 5.83 (d, J = 16.0 Hz, I H), 4.49 (dd, J = 135.1 , 12.0 Hz, 2H), 4.41 (dd. J = 54.7, 10.5 Hz, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.66-3.56 (m, I H), 3.50 (d, J = 9.7, I H), 1.72-1.58 (m, 3H), 1.56- 1.48 (m, I H), 1.12 (s, 3H), 1.12 (s, 3H), 0.93 (dd, J = 7.4, 7.4 Hz, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 167.5, 159.2, 156.5, 139.2, 131.2, 129.2, 128.5, 127.8, 127.6, 1 18.6, 1 13.9, 83.0, 76.9, 74.9, 70.0, 55.4, 51.6, 42.7. 36.5, 26.2, 23.4, 23.4, 9.1 ; high resolution mass spectrum (ES+) m/z 440.2568 [(M+)'; calcd for C₂₇H₃₆O₅: 440.2563].

Allylic alcohol (+)-S2.3. A solution of (+)-2.31 ( 1.76 g, 4.0 mmol) in CH₂CI₂ (20 niL) was cooled to -78 ⁰C and DTBAL-H (1.06 ml, 1.0 M in hexanes, 2.1 equiv.) was slowly added. After 5 min. the reaction was quenched with MeOH (5 mL) followed by addition of sat. Rochelle's salt (I O mL). The solution was stirred for 2.5 h and the layers were separated. The aqueous layer was extracted with CH₂CN (3 x 20 mL), and the combined organic layers were dried over MgSO₄ and then concentrated. Flash chromatography (25 % EtOAc/hexanes) provided (+)-S2.3 (1.56 g, 95%) as a colorless oil. [α]² _D° +65.0 (c 1.0, CHCl₃); IR (neat) 3425, 2961 , 2931 , 2873, 1613, 1513, 1464, 1248, 1087, 1063, 1035 cm^'1: ¹H NMR (500 MHz, CDCI₃) δ 7.41 -7.26 (m, 5H), 7.20 (d, J = 8.5 Hz, 2H), 6.85 (d_.. J = 8.6 Hz, 2H), 5.77 (d, J = 15.8 Hz, 1 H), 5.60 (ddd, J = 15.8, 5.9. 5.9 Hz, I H), 4.47 (dd, J = 130.8, 1 1.6 Hz, 2H), 4.40 (dd, J = 57.5, 10.8 Hz. 2H), 4.10 (dd, J = 5.8, 5.8 Hz, 2H), 3.79 (s, 3H), 3.58 (ddd, ./= 6.5, 4.2, 2.3 Hz, 1 H). 3.40 (dd, J= 10.0, 1.5 Hz, I H), 1.74-1.53 (m, 3H), 1.48 (ddd, ./ = 14.5. 10.0, 2.2 Hz, I H), 1.07 (s, 3H), 1 .06 (s. 3H), 0.90 (dd, J = 7.5, 7.5 Hz. 3H); ¹³C NMR (125 MHz, CDCI₃) δ 159.2, 140.6. 139.3, 131 .6. 129.2, 128.6. 127.9. 127.7. 126.5, 1 13.9, 83.6. 77.2. 74.9, 70.0, 64.4, 55.5, 41.7. 36.5, 26.3, 24.5, 23.8. 9.3; high resolution mass spectrum (ES+) m/z 435.2514 [(M+Na/; calcd for C₂₆H₃₆O₄Na: 435.25121.

Epoxy alcohol (+)-2.32. To freshly activated 3 A molecular sieves (0.2 g) in CH₂CI₂ (2 mL) was added (+)-DlPT (31.8 μL, 0.12 equiv.). The solution was cooled to -20 ⁰C and Ti(O-Z-Pr)₄ (37.3 μL. 0.1 equiv.) was added followed by J-BuOOH (0.687 mL. 5.5 M in decane, 3.0 equiv.) The reaction was stirred for 30 min and then (+)-S2.3 (0.521 g, 1.26 mmol) dissolved in CH₂CI₂ (1 .5 ml) was added via syringe. The flask and syringe were rinsed with CH₂Cl₂ (2 x 0.8 mL) into the reaction flask. After 2 h, 10% aq. citric acid (10 mL) was added and the reaction wanned to rt. After 1 h at rt, the reaction was filtered through celite, and the celite washed with CH₂CI₂ (10 mL). The layers were separated and the aqueous layer extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were dried over MgSθ₄ and concentrated. Flash chromatography (25% EtOAc/hexanes) provided (+)-2.32 (0.524 g, 97% yield, dr. > 20: 1 ) as a colorless oil. [a]% +56.9 (c 0.8, CHCl₃); IR (neat) 3435, 2964. 2932, 2874, 1612, 1514, 1455, 1248, 1088, 1064, 1034 cm-¹; ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.26 (m, 5H)_; 7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, ./ = 8.6 Hz, 2H)_; 4.48 (dd, J = 138.6, 1 1.6 Hz, 2H), 4.42 (dd, J = 47.4, 1 1.0 Hz, 2H), 3.85-3.80 (m, I H), 3.79 (s, 3H), 3.63-3.52 (m, 2H), 3.52 (dd, J = 10.0, 1.4 Hz, I H), 3.05 (dd, J = 4.8, 2.6 Hz, I H), 2.94 (d, J = 2.4 Hz, I H), 1.82-1.50 (m, 4H), 0.93 (s. 3H), 0.93 (dd, J = 7.6_.. 7.6 Hz, 3H), 0.87 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 159.2, 139.2, 131.4, 128.9, 128.6, 128.0, 127.7, 1 13.9, 82.4, 77.0, 74.6, 70.0, 62.2, 61.4, 55.6, 55.5_., 39.2, 36.2, 26.3, 20.4, 19.0, 9.2; high resolution mass spectrum (ES+) m/z 451.2444 [(M+Na)"; calcd for C₂₆H₃₆O₅Na: 451.2460].

Aldehyde (+)-S2.4. To a 0 ⁰C solution of (+)-2.32 (0.233 g, 0.545 mmol) in DMSO (6 inL) arid CH₂CI₂ (7 mL) was added Et₃N (0.76 niL, 10 equiv.) followed by SO₃.pyridine (0.347 g, 4 equiv.). After 1.5 h, NaHCO₃ (4 mL) was added, the layers separated, and the aqueous layer was extracted 3 x 10 mL Et₂O. The combined organic layers were then washed with I M NaHSO₄, sat. NaHCO₃, and brine (10 mL each). The organic layer was then dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-S2.4 (1.43 g, 99% yield) as a colorless oil. [α]∞ +1 15.0 (c 1.2, CHCI₃); IR (neat) 2964, 2931 , 2876, 1728, 1613, 1514, 1464, 1248, 1090, 1064, 1035 cm⁰; ¹H NMR (500 MHz, CDCI₃) δ 9.01 (d, J = 6.1 Hz, I H), 7.44-7.27 (m, 5H), 7.19 (d. J = 8.4 Hz, 2H), 6.86 (d. J = 8.5 Hz, 2H), 4.49 (dd, J = 143.1 , 1 1.6 Hz, 2H), 4.40 (dd, ./ = 26.3, 10.9 Hz, 2H). 3.80 (s, 3H), 3.64-3.58 (m, I H), 3.56 (d, J = 9.8 Hz, I H), 3.27 (dd, J = 6.1 , 1.8 Hz, I H), 3.21 (d, J = 1.8, I H), 1.83-1.49 (m, 4H), 0.95 (s. 3H), 0.93 (dd, J= 7.5, 7.5 Hz, 3H), 0.88 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 199.1 , 159.4, 139.1. 131.1 , 129.2, 128.6, 127.9, 127.8, 1 14.0. 82.1, 76.9, 74.8, 70.0, 62.0, 56.9, 55.5, 39.6, 36.2, 26.2, 20.3, 19.1 , 9.1 ; high resolution mass spectrum (ES+) m/z 449.2305 [(M+Na)⁺; calcd for C₂₆H₃₄O₅Na: 449.2304].

Ester (+)-2.8. A solution of (+)-S2.4 (0.445 g, 1.04 mmol) in CH₂Cl₂ (5 mL) was cooled to 0⁰C and a solution of carbomethoxy triphenylphosphonium ylide (2.9) in CH₂Cl₂ (5 mL) was added over 1 min. The reaction was allowed to warm to rt and after 30 min, the solvent was evaporated. Flash chromatography (8% EtOAc/hexanes) provided (+)-2.8 (0.453 g.90% yield) as a light yellow oil. [α]∞ +48.7 (c 1.4, CHCl₃); IR (neat) 2962, 2876, 1725, 1612, 1513, 1463, 1304, 1249, 1172, 1090, 1064 cm-'; ¹HNMR (500 MHz, CDCl₃) δ 7.41-7.26 (m, 5H), 7.17 (d, J = 8.5 Hz, 2H), 6.85 (d, J= 8.5 Hz₅2H), 6.66 (dd, J= 15.7, 7.0 Hz, IH)₅6.05 (d, J= 15.7 Hz, IH), 4.48 (dd, J= 139.9, 11.6 Hz.2H), 4.40 (dd, J= 28.5, 11.0 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.63-3.56 (m, IH), 3.53 (d, J =9.2 Hz, IH), 3.35 (dd, J= 6.9, 1.7 Hz, IH), 2.88 (d, J= 1.9 Hz. IH).1.81-1.50(m, 4H), 0.94 (s.3H), 0.93 (dd, J= 7.4.7.4 Hz.3H), 0.86 (s, 3H); ¹³CNMR (125 MHz, CDCI₃) δ 166.4, 159.3.145.6, 139.2, 131.3.129.0, 128.6, 128.6, 127.9, 127.7.123.2, 114.0, 82.1, 76.9, 74.6, 70.0, 67.0, 55.5, 53.8, 51.9. 39.9, 36.1, 26.3, 20.7. 18.6, 9.2; high resolution mass spectrum (ES+) m/z 505.2553 [(M+Na)'; calcd for C₂QH₃₈O₆Na: 505.2566].

Alcohol (+)-2.33. To freshly distilled dioxane (2 mL) was added Pd₂(dba)₃.CHCl₃ (46 mg, 0.05 equiv.) and K-Bu₃P (13 μL, 0.06 equiv.)^'. Next, a solution OfHCO₂H (0.20 mL, 6.0 equiv.) and Et₃N (0.25 mL, 2 equiv.) in dioxane (1 mL) was added. This mixture was stirred at rt for 10 min and then a solution of epoxide (+)-2.8 (0.452 g, 0.937 mmol) in dioxane (1.5 mL) was added via cannula. The flask and cannula were rinsed with dioxane (2 x 1 mL) into the reaction flask. After 4.5 h, the reaction mixture was filtered through a 1 cm plug of silica gel and the silica gel washed with CH₂CI₂ (20 mL). The filtrate was concentrated and subjected to flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes to 15% EtOAc/hexanes) to provide (+)-2.33 (0.421 g, 93% yield) as a colorless oil. [α]^: _D° +95.5 (c 0.7, CHCI₃); IR (neat) 3464, 2963, 2875, 1722.1613.1514, 1249, 1173.1063, 1036 Cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.26 (m.5H), 7.13 (d. J =8.2 Hz, 2H), 7.08(ddd,J= 14.8, 7.2.7.2 Hz, IH).6.83 (d, J= 8.3 Hz, 2H). 5.90 (d, J= 15.6 Hz, IH), 4.49 (dd. J = 150.3, 11.9 Hz, 2H), 4.38 (dd, J= 61.0.10.8 Hz, 2H), 4.16 (s, IH), 3.79 (s, 3H), 3.71 (s, 3H), 3.59-3.56 (m, IH), 3.54 (d, J = 9.2 Hz, IH), 2.25 (m, 2H), 1.91-1.67 (m, 3H), 1.62 (ddd, J= 14.1, 7.1, 7.1 Hz, IH), 1.08 (s, 3H), 0.93 (dd, J= 7.4, 7.4 Hz, 3H), 0.83 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.1, 159.5, 148.0, 139.1, 130.4, 129.2, 128.6, 128.0, 127.8, 122.6, 114.1, 86.7, 77.1, 75.3, 75.0, 70.1, 55.5, 51.5,41.5, 35.8.35.1, 26.3, 23.3, 20.4, 9.2; high resolution mass spectrum (ES+) m/z 485.2888 [(M+H)⁺; calcd for C₂₉H_4IO₆: 485.2903].

TBS ether (+)-2.34. To a 0 ⁰C solution of (+)-2.33 (0.789 g, 1.63 mmol) in CH₂CI₂ (16.3 mL) was added 2,6-lutidine (0.38 mL, 2.0 equiv.) followed by dropwise addition of TBSOTf (0.45 mL, 1 .2 equiv.). After 20 min, sat. NaHCOs (10 mL) was added and the layers separated. The aqueous layer was extracted CH₂CI₂ (3 x 15 mL), and the combined organic layers were dried over MgSθ₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (+)-2.34 (0.965 g, 99% yield) as a colorless oil. [α]^: _D° +42.1 (c 0.9, CHCI₃); IR (neat) 2956, 2931 , 2881. 2855, 1725, 1513, 1463, 1249, 1 170, 1073 cm-¹; ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.26 (m, 5IT), 7.20 (d, J = 8.5 Hz, 2H), 7.06 (ddd, J= 15.7, 8.3, 6.4 Hz, IH), 6.86 (d, J= 8.5 Hz, 2H). 5.76 (d, J = 15.7 Hz, I H), 4.48 (dd, J= 156.4, 1 1.4 Hz, 2H), 4.39 (dd, J = 72.5, 1 1.1 Hz, 2H), 3.80 (s, 3H). 3.73 (s. 3H), 3.65 (dd, J = 6.4, 4.0 Hz, 1 H). 3.60-3.55 (m. J= 9.9, 5.5 Hz, I H). 3.52 (dd, J = 6.5, 5.0 Hz, I H), 2.51 (ddd. J = 14.9, 4.2, 4.2 Hz. I H), 2.36 (ddd. J = 15.0, 7.5, 7.5 Hz. I H), 1.74-1.64 (m, I H), 1.65-1.58 (m, I H). 1.56 (dd, J = 5.9, 5.9 Hz, 2H). 0.95 (s, 3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90 (s. 9H), 0.89 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz. CDCI₃) δ 167.1 , 159.2, 148.6, 139.2, 131.7. 129.0, 128.6, 127.8, 127.7. 122.2, 1 13.9, 81.3, 77.3, 76.6. 75.0. 70.3, 55.5, 51.5, 44.7, 36.2. 36.1, 26.3, 26.2, 21.0, 20.1 , 18.6. 9.2, -3.2. -3.8; high resolution mass spectrum (ES+) m/∑ 621.3605 [(M+Na)⁺; calcd for C₃₅H₅₄O₆SiNa: 621.3588].

Allylic alcohol (+)-S2.5. A solution of (+)-2.34 (1.43 g, 2.38 mmol) in CH₂CI₂ (12 mL) was cooled to -78 ⁰C and DIBAL-H (1.06 mL, 1.0 M in hexanes, 2.1 equiv.) was added slowly over 5 min. After 2 min, the reaction was quenched with methanol (1 mL) followed by addition of sat. Rochelle's salt (10 mL). The solution was stirred for 2 h and the layers were separated. The aqueous layer was extracted with CH₂CI₂ (3 x 25 mL), and the combined organic layers were dried over MgSO₄ and then concentrated. Flash chromatography (5 % EtOAc/hexanes) provided (+)-S2.5 (1.32 g, 97%) as a colorless oil. [αJ² _D° +47.7 (c 0.7, CHCI₃); IR (neat) 3444, 2958, 2930, 2880. 2855, 1613, 1514, 1463, 1249, 1070 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.41 -7.27 (m, 5H), 7.21 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.74 (ddd, J = 15.2, 7.2 Hz, I H), 5.55 (ddd, J = 15.4, 5.8, 5.8 Hz, 1 H), 4.49 (dd, J = 142.1 , 1 1.1 Hz, 2H), 4.42 (dd, J = 84.5, 1 1.1 Hz, 2H)_.. 4.03-3.91 (m, 2H), 3.80 (s. 3H), 3.64-3.59 (m, I H), 3.58 (dd, J = 9.7, 1.3 Hz, I H), 3.55 (dd, J = 5.3, 5.3 Hz, I H). 2.41 (ddd, J = 14.5, 5.4 Hz, IH), 2.19 (ddd, J = 14.0, 6.7 Hz, I H). 1 .75-1.64 (m, I H), 1.64-1.49 (m, 3H), 1.47 (dd, J = 6.0, 6.0 Hz, I H), 0.98 (s, 3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 3H), 0.04 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 139.1 , 131.8. 131.4, 130.7, 129.0, 128.6, 128.1 , 127.7, 1 13.9, 80.9, 77.3, 75.0, 70.5, 63.8, 55.5, 45.0, 36.4. 36.0, 26.3, 26.3, 21.0, 19.9, 18.6, 9.2, -3.1 , -3.9; high resolution mass spectrum (ES+) m/z 593.3651 [(M+Na)⁺; calcd for C₃₄H₅₄O₅SiNa: 593.3639].

Epoxide (+)-2.35. To freshly activated 3 A molecular sieves (0.4 g) in CH₂Cl₂ (4.6 πiL) was added (-)-DTPT (58 μL, 0.12 equiv.) The solution was cooled to -20 ⁰C and Ti(O-Z-Pr)₄ (68 μL, 0.1 equiv.) was added followed by /-BuOOH (1.26 mL, 5.5 M in decane, 3.0 equiv.) The reaction was stirred for 30 min and then (+)-S2.5 (1.32 g, 2.31 mmol) dissolved in CH₂Cl₂ (2 ml) was added via cannula. The flask and cannula were rinsed with CH₂Cl₂ (2 x 1.5 mL) into the reaction flask. After 4 h, 10% aq. citric acid (10 mL) was added and the reaction warmed to rt. After 2 h. the layers were separated and the aqueous layer extracted with CH₂CI₂ (3 x 25 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes to 15% EtOAc/hexanes) provided (+)-2.35 (1.24 g, 92% yield, dr > 20:1 ) as a colorless oil. [α]² _D° +72.4 (c 1.9, CHCl₃); IR (neat) 3444, 2957, 2930, 2881 , 2856, 1613, 1514, 1463, 1249, 1071 CiV; ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.27 (m, 5H), 7.22 (d. J = 8.5 Hz. 2H), 6.86 (d, J= 8.6 Hz, 2H), 4.46 (dd, J= 153.9, 1 1.4 Hz, 2H), 4.44 (dd, J= 66.0, 10.8 Hz, 2H), 3.80 (s, 3H), 3.78-3.71 (m, 2H), 3.62-3.51 (m, 2H), 3.49 (dd, J = 9.3, 2.0 Hz, I H). 3.10 (ddd. J = 6.8, 4.7, 2.1 Hz, I H), 2.70 (dd. J = 4.3, 2.6 Hz, IH), 1.80-1.64 (m, 3H), 1.64-1.50 (m, 3H), 0.98 (s. 3H), 0.92 (s, 12H), 0.92 (dd, J = 7.4, 7.4 Hz, 3H), 0.1 1 (s, 3H), 0.10 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 159.2, 139.3, 131.7, 129.0, 128.5, 127.9, 127.6, 1 13.9, 81.4, 77.3, 75.1 , 75.0, 70.0, 61 .7, 59.9, 55.5, 53.7. 44.2, 35.9, 35.1 , 26.4, 26.2, 20.9, 20.0, 18.6, 9.2, -3.5, - 3.6; high resolution mass spectrum (ES+) m/z 609.3596 [(M+Na)⁺; calcd for C₃₄H₅₄O₆SiNa: 609.3588].

Ester (+)-2.36. Epoxy alcohol (+)-2.35 was dissolved in CH₃CN (12 mL) and then TEMPO (15 mg, 0.08 equiv.) was added followed by pH 7 buffer (12 mL). Next, NaClO₂ (0.42 g, 2.5 equiv.) was added in one portion followed by dropwise addition of NaOCl (0.32 mL, 5 wt% solution, 0.2 equiv.). After 1.5 h, anhydrous Na₂SO₃ (0.49 g, 3.2 equiv.) was added and the reaction stirred for 30 min, upon which, the solution turned from orange to colorless. The reaction was acidified to pH 4 with 10% aq. citric acid solution and then extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over MgSO₄ and concentrated. The unpurified acid was then dissolved in Et₂O (24 mL) and cooled to 0 ⁰C. A solution Of CH₂N₂ in Et₂O was then added dropwise until gas evolution ceased and the reaction turned light yellow. Argon was bubbled through the reaction mixture for 15 min to remove any excess CH₂N₂ and then the reaction was concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-2.36 (0.557 g, 76% yield, 2 steps) as a colorless oil. [α]² _D° +86.8 (c 1.0, CHCI₃); IR (neat) 2957, 2931 , 2882, 2857. 1754, 1513, 1458, 1249, 1065 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 7.41 -7.27 (m. 5H), 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.45 (dd, J = 162.5, 11.5 Hz, 2H), 4.42 (dd, J = 69.0, 10.9 Hz, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.75-3.70 (m, I H), 3.60-3.53 (m₅ I H), 3.49-3.42 (m, I H), 3.31 (ddd, J = 6.5, 4.5, 1.8 Hz, I H), 3.04 (d, J = 1.8 Hz, IH), 1.80 (ddd, J = 14.5, 7.7, 4.5 Hz, I H), 1.71 -1.64 (m, 2H), 1.64- 1 .56 (m, IH), 1.54 (dd, J= 7.6. 4.5 Hz, 2H), 0.96 (s, 3H). 0.93- 0.90 (m. 15H), 0.12 (s, 3H), 0.09 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 169.9, 159.2, 139.3, 131 .6, 129.0. 128.6, 127.8. 127.7, 1 13.9, 81.4, 77.1 , 75.1 , 74.9, 70.0, 56.6, 55.5, 54.7, 52.5, 44.2, 35.9, 34.8, 26.4, 26.1 , 21.0, 20.0, 1 8.6, 9.1 , -3.6, -3.6: high resolution mass spectrum (ES+) m/z 637.3521 [(M+Na)⁴ ; calcd for C₃₅Hs₄O₇SiNa: 637.3537].

Alcohol (+)-2.37. A solution of (+)-2.36 (1.32 g, 2.14 mmol) in CH₂Cl₂ (22 mL) and pH 7 buffer (5.4 mL) was cooled to 0 ⁰C and DDQ (0.542 g, 1.1 equiv) was added in three portions over 1 min. After 45 min, the reaction was diluted with CH₂Cl₂ (20 mL) and filtered through Celite. The Celite was then washed with sat. NaHCO₃ (10 mL). The layers were separated and the aqueous layer extracted with CH₂Cl₂ (3 x 20 mL). The combine organic layers were then dried with MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes until the anisaldehyde eluted then 10% EtOAc/hexanes) provided (+)-2.37 (0.998g, 94% yield) as a light yellow oil. [α]² _D° +54.3 (c 0.7, CHCI₃); IR (neat) 3494, 2957, 2930, 2880, 2855, 1755, 1452.

1254, 1204, 1058 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 7.42-7.23 (m. 5H), 4.58 (dd. J = 46.5,

1 1.6 Hz, 2H), 3.91 (dd, ./ = 8.8, 3.2 Hz, I H), 3.84 (s. I H). 3.82-3.76 (m. I H), 3.77 (s, 3H), 3.69 (ddd, J = 1 1.4, 5.9, 5.9 Hz, I H), 3.32 (ddd, J = 7.9, 3.3, 1.9 Hz, IH), 3.23 (d, J = 1.8 Hz. I H),

1.98 (ddd, J = 14.8, 8.2, 3.4 Hz, I H), 1.69-1.52 (m. 3H), 1.50-1.45 (m, 2H), 0.95 (s, 3H), 0.94-

0.91 (m, 12H), 0.72 (s, 3H), 0.16 (s. 3H), 0.15 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.6,

139.5, 128.5. 127.9, 127.6, 79.5. 78.2, 72.2, 71.4, 56.6 54.4, 52.7, 40.9, 36.1 , 35.2. 27.5, 26.3,

22.5, 20.0, 18.5, 9.9, -3.7, -4.1 ; high resolution mass spectrum (ES+) m/z 495.3125 [(M+H)^*; calcd for C₂₇H₄₇O₆Si: 495.3142].

Alcohol (+)-2.38. To a solution of (+)-2.37 (0.998 g. 2.02 mmol) in CH₂CI₂ (40 niL) was added camphorsulfonic acid (94 mg, 0.2 equiv). After stirring for 5 h at rt, sat. NaHCO₃ (20 mL) was added and the reaction mixture stirred for 10 min. The layers were separated and the aqueous layer extracted with CH₂CI₂ (4 x 15 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (+)-2.38 (0.91 7g, 92%) as a colorless oil. [α]² _D° +38.1 (c 1.6, CHCl₃); IR (neat) 3461 , 2956. 2930, 2857, 1741 , 1471 , 1437, 1360, 1256, 1080 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.17 (m, 5H), 4.54 (dd, J = 41.3, 1 1.5 Hz, 2H), 4.23 (dd, J = 5.8, 4.0 Hz, IH), 4.07 (dd, J = 9.9, 3.5 Hz, I H), 3.78 (s, 3H), 3.80-3.75 (m, IH), 3.63 (dd, J = 3.8, 3.8 Hz, I H), 3.56-3.48 (m, I H), 2.87 (d, J = 6.2 Hz, I H), 2.31 (dd, J = 13.0. 13.0 Hz. 1 H). 2.06 (ddd, J = 13.4. 10.0, 3.1 Hz, 1 H), 1 .71 - 1 .48 (m, 3H), 1.36 (ddd. J = 13.6, 3.9, 3.9 Hz. I H), 1.01 (s, 3H), 0.92 (dd, J = 7.5, 7.5 Hz, 3H), 0.90 (s, 9H). 0.86 (s, 3H). 0.05 (s. 3H), 0.03 (s, 3H); ¹³C NMR (125 MHz. CDCI₃) δ 173.2, 139.5. 128.5, 128.4, 128.0, 127.5, 77.9, 73.8, 73.7, 71 .6, 67.6. 52.6, 37.3. 33.0, 30.1 , 27.2. 26.5, 26.0. 21.5. 18.2, 9.6, -4.4, -4.9; high resolution mass spectrum (ES+) m/z 517.2970 [(M+Naf: calcd for C₂₇H₄₆O₆SiNa: 517.2962].

Methyl ether (+)-2.40. A solution of (+)-2.38 (0.236g, 0.478 mmol) in THF (5 mL) was cooled to 0 ⁰C and NaH (29 mg, 60% in mineral oil, 1.5 equiv.) added in one portion. After 20 min, Me₂SO4 (59 μL, 1.3 equiv.) was added dropwise and the reaction allowed to warm to rt. After 1.5 h, the reaction was quenched with sat. NaHCOs (5 mL). The layers were separated and the aqueous layer extracted with CH₂CU (5 x 15 mL). The combined organic layers were then dried over MgSU4 and concentrated. Flash chromatography (3% EtOAc/hexanes to 5% EtOAc/hexanes) provided (+)-2.40 (0.229g, 94% yield) as a colorless oil. [α]∞ +20.0 (c 2.8, CHCl₃); IR (neat) 2956, 2931 , 2857, 1751 , 1462, 1359, 1256, 1 195, 1 126, 1083, 1006 cm^-l; ¹H NMR (500 MHz, CDCl₃) δ 7.44-7.14 (m, 5H), 4.54 (dd, J= 29.4, 1 1.4 Hz, 2H), 4.08 (ddd, J = 7.1 , 4.2, 4.2 Hz, I H), 3.89 (d, J= 6.4 Hz, I H), 3.74 (s, 3H). 3.70 (dd, J = 1 1.3, 1.5 Hz, I H).. 3.59 (dd, J= 6.5, 3.4 Hz, I H). 3.50-3.44 (m, I H), 3.39 (s, 3H), 2.08 (dd. J= 12.7. 12.7 Hz, I H), 1.98 (ddd, J= 13.7, 7.6, 3.5 Hz, 1H). 1.70-1 .48 (m. 4H), 1.00 (s. 3H), 0.92 (dd, J= 7.6, 7.6 Hz, 3H), 0.90 (s, 9H), 0.85 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.8, 139.8, 128.4, 127.8, 127.4, 83.2, 78.0, 77.9, 73.5, 71.6, 68.4, 58.8, 52.1, 37.9, 33.7, 30.7, 27.4, 26.0, 25.9, 19.2, 18.2, 9.6, -4.3, ^.9; high resolution mass spectrum (ES+) m/z 531.3139 [(M+Na)⁺; calcd for C₂₈H₄₈O₆SiNa: 531.31 18].

Alcohol (+)-S2.6. To a solution of (+)-2.40 (0.229 g, 0.450 mmol) in EtOAc (4.5 mL) was added 10% Pd/C (0.025 g). The reaction flask was purged with H₂ and then a balloon of H₂ was attached to the flask. After 5 h at rt. the reaction mixture was filtered through a pad of Celite and the Celite rinsed with CH₂Cb (10 mL). The reaction was concentrated and then flash chromatography (10% EtOAc/hexanes) provided (+)-S2.6 (0.182 g, 97%) as a colorless oil. [α]² _D ^Q +12.7 (c 3.6, CHCl₃); IR (neat) 3557, 2955, 2930, 2857, 1730, 1463, 1285, 1254, 1 127, 1082 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 4.08 (d, J = 9.0 Hz, I H), 4.04-4.00 (m, I H), 3.81 (s, 3H), 3.59-3.53 (m, 2H), 3.53-3.46 (m, I H), 3.41 (s, 3H), 2.92 (d, J= 4.1 Hz, I H), 1.93 (ddd, J = 13.8, 4.2, 2.8 Hz, I H), 1.74 (ddd, J = 13.8, 10.4, 5.7 Hz, I H), 1.60 (dd, J = 12.3, 12.3 Hz, I H), 1 .53-1.34 (in, 3H), 0.94 (dd, J = 7.4, 7.4 Hz, 3H), 0.89 (s, 12H), 0.83 (s, 3H), 0.05 (s, 3H), 0.04 (s. 3H); ¹³C NMR (125 MHz, CDCl₃) δ 173.1 , 81.0, 76.1, 72.6, 72.2, 68.8, 58.8, 52.6, 39.0, 36.5, 30.4, 30.2, 26.0, 23.8, 18.2, 14.2, 10.6, -4.1, -4.8; high resolution mass spectrum (ES+) m/∑ 441.2642 [(M+Na)⁺; calcd for C₂]H₄₂O₆SiNa: 441.2649].

Tctrahydropyran (+)-2.5. A solution of (+)-S2.6 (0.187g, 0.446 mmol) in CH₂Cl₃ (4.5 mL) was cooled to 0 ⁰C and NaHCOj (56 mg, 1.5 equiv.) was added followed by Dess-Martin periodinane (0.568 g, 3 equiv.). After 1 h at 0 ⁰C, H₂O. sat. NaHCO₃, and CH₂Cl₂ (5 mL each) were added. The solution was stirred until the organic layer went clear (ca. 30 min). The layers were separated and the aqueous layer extracted with CH₂CI₂ (3 x 10 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-2.5 (0.181 g, 97% yield) as a colorless oil. [α]² _D° +l 6.5 (c 1 .7, CHCI₃); IR (neat) 2954, 2934, 2886, 2858. 1754, 1722. 17.1 12, 1462, 1361 , 1255, 1 1 19, 1073 cm-¹; ¹H NMR (500 MHz, CDCl₃) δ 4.10 (dd, J= 10.6, 2.5 Hz, I H), 4.04 (ddd, J= 1 1.9, 4.5, 2.3 Hz. I H), 3.80 (d, J= 4.5 Hz, IH), 3.70 (s, 3H), 3.53 (dd, J = 2.7, 2.7 Hz I H), 3.40 (s, 3H), 2.60- 2.38 (m, 3H), 2.23 (dd, J= 14.5, 2.5 Hz, I H), 1 .96 (ddd, J= 14.1 , 12.0, 2.4 Hz, I H), 1 .40 (ddd, J = 13.8, 3.1 , 2.5 Hz, I H), 1.04 (dd. J = 7.3, 7.3 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.80 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 210.4, 171.7, 82.5, 77.4, 73.1 , 69.8, 58.8, 52.2, 42.6, 38.1 , 37.2, 30.3, 26.0, 25.1, 18.2, 17.9, 7.8, -4.2, -4.8; high resolution mass spectrum (ES+) m/z 439.2491 [(M+Na)⁺; calcd for C₂₁H₄₀O₆SiNa: 439.2492].

Ester (-)-2.43. Acid (-)-2.2 (0.1 12 g, 0.387 mmol) was dissolved in MeOH (2.0 mL) and CH₂Cl₂ (2.0 mL) and cooled to 0 °C. TMSCHN₂ (ca. 0.2 mL, 2.0 M in Et₂O) was then added dropwise until all gas evolution had ceased and the solution turned light yellow. Argon was bubbled through the reaction for 10 min and then the reaction concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-2.43 (88 mg, 75% yield) as a colorless oil. [α]_D ^:o -13.0 (c 1.0, CHCI₃); IR (neat) 2955, 2930, 2898, 2858, 1760, 1732, 1463, 1254, 1157, 1115 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 4.80 (d, J = 13.0 Hz, 2H), 4.30 (d, J = 4.0 Hz, IH), 3.73 (s_; 3H), 3.61 (ddd,./= 6.5, 6.5, 4.0 Hz, IH); 3.39 (s, 3H), 2.27 (d, J= 6.0 Hz.2H), 1.76 (s, 3H), 0.91 (s, 9H), 0.06 (s, 6H);¹³C NMR (125 MHz, CDCI₃) δ 172.8, 142.6, 113.0, 82.3.73.6, 58.4, 52.0, 39.0, 25.9, 23.0, 18.4, -4.9, -5.0; high resolution mass spectrum (ES+) m/z 325.1800 [(M+Na)'; calcd for Ci₅H₃₀O₄SiNa: 325.1811].

β-Hydroxy ketone (+J-2.46. A solution of ketone (+)-2.5 (0.113 g, 0.271 mmol) in CH₂Cl₂ (1.5 mL) was cooled to -78⁰C and CI₂BPh (42 μL, 1.2 equiv.) was added. After stirring for 20 min, /-Pr₂NEt (71 μL. 1.5 equiv.) was added dropwise. The reaction was stirred for I h at -78⁰C, warmed to 0⁰C over 10 min, then stirred 1 h at 0⁰C. After cooling back to -78⁰C, aldehyde 2.4 (0.131 g, 1.2 equiv.) was dissolved in CH₂CU (1.0 mL) and added to the boron enolate dropwise over 10 min. After 4 h at -78⁰C, the reaction was quenched with a 1 : 1 mixture of MeOH/pH 7 buffer (6 mL). After warming to rt, the reaction was neutralized to pH 7 with pH 8 buffer and stirred for 1 h at rt. The layers were separated and the aqueous layer extracted with CH₂Cl₂ (3 x 10 mL). The combined organic layers were then dried over MgSCM and concentrated. Flash chromatography (25% EtOAc/hexanes) provided (+)-2.46 (0.191 g, 86% yield, dr > 20:1) as a colorless oil. [α]² _D° +27.3 (c 2.0. CHCI₃): IR (neat) 3439, 2952, 2930.2858, 1747. 1717, 1595, 1457, 1271, 1158, 1095.1074 cm^"1; ¹HNMR (500 MHz, CDCl₃) δ 7.40-7.27 (m.10H), 6.45 (s, IH), 5.05-4.98 (m.4H).4.13-4.03 (m, 2H), 3.95 (d, J= 6.1 Hz, IH), 3.85 (s, 3H), 3.72 (s, 3H), 3.64 (dd, .7=7.8, 3.8 Hz. IH), 3.54 (d, J= 5.7 Hz, IH), 3.41 (s, 3H), 3.06 (dd, J= 16.3, 9.4 Hz, IH), 2.88 (dd, J= 14.2, 3.3 Hz, IH), 2.72-2.66 (m, IH), 2.62 (dd, J= 14.1.10.2 Hz, IH), 2.55 (dd,J= 16.4, 2.9Hz, IH), 2.21 (s, 3H), 1.96(ddd,J= 13.8, 5.8, 3.9 Hz, IH), 1.62-1.55 (m. IH), 1.21 (d, J= 7.1 Hz, 3H), 0.96 (s, 3H), 0.90 (s, 9H), 0.85 (s, 3H), 0.04 (s.3H).0.04 (s, 3H).; '³C NMR (125 MHz. CDCl₃) δ 212.5, 171.6, 170.7, 158.9, 155.2, 137.2, 137.0, 136.9.128.9.128.8, 128.7, 128.2, 128.1, 127.3, 127.2, 127.1, 119.3, 117.8, 97.5, 82.3, 76.7, 73.1, 71.6, 71.2.70.5. 70.1.58.8, 53.2, 52.6.52.2, 42.4, 38.1, 35.8, 30.1, 26.0, 24.5, 18.2, 17.6, 11.8., 11.4,-4.3,-4.8; high resolution mass spectrum (ES+) m/z 843.4132 [(M+Na)"; calcd for C₄e,H₆₄θnSiNa: 843.41 16].

Diol (+)-2.47. A solution of ketone (+)-2.46 (0.066 g, 0.081 mmol) in THF (4.7 mL) was cooled to -30 ⁰C and catecholborane (0.172 mL, 20 equiv.) was added dropwise. The reactions was warmed to 4 ⁰C and stirred for 44 h and then quenched with sat. NaHCCb (2 mL). The reaction was extracted with EtOAc (3 x 5 mL) and the combined organic layers were then dried over MgSC>4 and concentrated. Flash chromatography (20% EtOAc/hexanes) provided (+)-2.47 (55 mg, 83% yield, dr = 13: 1) as a colorless oil. [α]£ +12.4 (c 1.7, CHCl₃); IR (neat) 3482, 2953, 2890, 2858, 1737, 1593, 1455, 1275, 1 158, 1 124, 1073, 1008 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 7.50-7.27 (m, 10H), 6.46 (s, I H), 5.06-4.98 (m, 4H), 4.16-4.10 (m. IH), 4.08-4.01 (m, I H), 3.98 (d, J = 7.9 Hz, I H), 3.90-3.84 (m, IH), 3.87 (s, 3H)_.. 3.81 -3.78 (m, I H), 3.79 (s, 3H), 3.68 (s, I H), 3.56-3.52 (m, 2H), 3.40 (s, 3H), 2.86 (d, J = 6.7 Hz, 2H), 2.25 (s. 3H), 1 .94 (ddd, J = 13.8, 3.9, 3.9 Hz, I H), 1.83 (ddd, .7 = 14.2, 10.2, 10.2 Hz, I H). 1.73-1.64 (m, I H). 1 .53 (ddd, J = 6.5, 6.5, 6.5 Hz, IH), 1.47 (d, J = 14.7 Hz. IH), 1.00 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.89 (s. 3H), 0.86 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H).; ¹³C NMR (125 MHz, CDCI₃) δ 171 .6, 1 70.3, 158.7, 154.9, 137.7, 137.1 , 128.8, 128.7, 128.2, 128.0, 127.3, 127.2, 1 19.5, 1 18.2_.. 97.3, 8_,1.9, 81 .2, 76.5, 75.8, 72.4, 71.7, 71.2, 70.5, 58.8, 52.5, 42.2, 39.2, 36.0, 33.7, 30.1 , 26.0, 24.2, 18.2, 15.4, 1 1.9, 6.1 , —4.1 , —4.8; high resolution mass spectrum (ES+) m/z 845.4264 [(M+Na)' ; calcd for C₄₆H₆₆O_nSiNa: 845.4272].

Aminal (+)-2.49. A solution of (+)-2.47 (44.7 mg, 0.054 mmol) was dissolved in MeOH (3.4 mL) and cooled to 0 ⁰C followed by addition Of H₂O (20 μL, 20 equiv.) and LiOH (26 mg, 20 equiv.). The cold bath was removed and the reaction allowed to warm to rt. After 40 h, the reaction was quenched by diluting with EtOAc (3 mL) and acidified to pH 2 with 1 M NaHS(V H₂O (3 mL) was added and the reaction extracted with EtOAc (5 x 5 mL). The combined organic layers were then dried over MgSO₄ and concentrated to provide acid 2.48 (41 mg, 97% yield), which was used without further purification. A solution of the unpurified dihydroisocoumarin acid (32 mg. 0.041 mmol) in acetone (2.0 mL) was cooled to 0 ⁰C and i- Pr₂NEt (1 7 μL, 2.4 equiv ) was added followed by addition of isobiityl chloroformate ( 12 μL, 2.2 equiv.) After 45 min at 0 ⁰C. NaNs ( 14 mg, 5.0 equiv.) was dissolved in H₂O (0.3 mL) and added to the reaction over 2 min. After 20 min, cold H₂O (2 mL) was added and the reaction extracted with cold EtOAc (3 x 3 mL). The combined organic layers were dried thoroughly over MgSO<i and concentrated. The residue was azeotroped with benzene (3 x 2 mL) and then placed on the vacuum pump for 30 min. The unpurified acyl azide was dissolved in toluene (2.0 mL). the reaction flask fitted with a reflux condenser, and then heated to 80 ⁰C. After 45 min. 2- trimethylsilylethanol (0.1 18 mL, 20 equiv.) was added through the top of the reflux condenser. After 2 h. the reaction was cooled to rt and the solvent evaporated. Flash chromatography ( 10% EtOAc/hexanes to 20% EtOAc/hexanes) provided (+)-2.49 (27 mg. 74% yield) as a colorless oil. [α]£ +29.7 (c 1.0, CHCl₃); IR (neat) 3325, 2953, 2896, 2858. 1717, 1592, 1459. 1248. 1 1 55. 1072 Cm-VH NMR (SOO MHz, CDCI₃) 5 7.63-7.27 (m, 10H), 6.47 (s, I H). 5.38 (d, ./= 10.1 Hz, IH). 5.17 (dd, J = 33.6, 12.5 Hz, 2H), 5.03 (s, 2H), 4.90 (dd, J = 10.0, 2.5 Hz, I H), 4.33 (ddd, J = 1 1.7, 6.9, 2.3 Hz. I H), 4.26-4.10 (m, 3H), 3.98 (d, J = 9.3 Hz, IH), 3.67 (s, I H), 3.63 (d. J = 10.7 Hz, IH), 3 57 (dd, .7 = 4.9. 3.2 Hz, IH), 3.37 (s, 3H), 3.12 (dd. J = 16.4, 2.1 Hz. I H). 2.83 (dd, J= 16.4. 1 1.9 Hz, I H), 2.43-2.31 (m, 1 H), 2.15 (s, 3H), 1.94-1.78 (m, 2H). 1.45 (d, J = 1 5.0 Hz, I H), 1.13 (d, J= 6.9 Hz, 3H), 1.02-0.92 (m. 2H) 1.01 (s, 3H). 0.90 (s, 9H), 0.89 (s, 3H), 0 05 (s, 3H). 0.04 (s. 3H), 0.02 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 163.6, 161.1. 160.3, 157.2. 142.2, 137.1. 136 6. 128.9. 128.7, 128.5, 128.3, 127.9, 127.3. 127.1 , 1 16.3, 108.2, 98.2, 83.7. 83.6, 79.2, 73.0, 72.8, 71.4, 70.4, 68.0. 63.7, 55.8. 43.5. 38.1 , 32.8. 31 .1 , 29.8, 26.1. 26.0, 18.2, 17.8. 1 1.4, 10.2, -1.3, -4.3, -4.8; high resolution mass spectrum (ES+) m/∑ 914.4707 [(M+Na)^' ; calcd for C₄QH₇₃NO₁₀Si₂Na: 914.4671].

SiIyI ether (+)-2.3. A solution of (+)-2.49 (27 mg, 0.030 mmol) in CH₂Cl₂ (0.4 mL) was cooled to 0 ⁰C and 2,6-lutidine (7 μL, 2.0 equiv.) added followed by dropwise addition of TBSOTf (14 μL, 2.0 equiv.). After 1 h, CH₂Ch (1 mL) and sat. NaHCO₃ (2 mL) were added and the reaction wanned to rt. The layers were separated and the aqueous layer extracted with CH₂Cb (3 x 5 mL). Preparative TLC (25% EtOAc/hexanes, 500 micron plate) provided (+)-2.3 (22 mg, 73%) as a colorless oil. [α]^: _D ^ϋ +4.6 (c 0.3, CHCI₃); IR (neat) 2953, 2927, 2857. 1719, 1592. 1462, 1382, 1250, 1 155, 1084 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 7.57-7.26 (m, 10H), 6.50 (s, I H), 5.45 (d, J = 9.6 Hz, 1 H), 5.1 7 (dd, J = 33.2, 12.2 Hz, 2H), 5.10-5.02 (m, 2H), 4.82 (d, J = 8.0 Hz. 1 H). 4.26-4.08 (m, 3H), 4.00 (s, I H), 3.59 (dd, J = 3.9, 3.9 Hz, I H), 3.37 (s, 3H), 3.39-3.32 (m, I H), 3.1 1 (d, J = 16.3 Hz, IH), 2.65 (dd, J= 16.5,_.12.1 Hz, IH), 2.28 (dd, J= 1 1.6, 1 1.6 Hz, I H), 2.15 (s, 3H), 2.05- 1.94 (m, I H), 1.87-1.75 (m, I H), 1.71 -1.57 (m, IH), 1.49 (ddd, J = 8.4, 3.8, 3.8 Hz, I H), 1.09 (d, J= 6.7 Hz, 3H), 0.98 (s, 3H), 0.91 (s, 9H), 0.90-0.83 (m, 2H) 0.87 (s, 3H), 0.80 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.00 (s, 9H), -0.01 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 163.7, 161.1 , 160.4, 157.2, 141.8, 137.0, 136.6, 128.9, 128.7, 128.4, 127.9, 127.4, 127.1 , 1 16.0, 108.3, 98.1 , 84.4, 79.8, 77.6, 73.6, 71.3, 70.4, 68.8, 67.8, 63.6, 56.1. 39.9, 37.6. 32.8, 31.7, 29.9, 26.8, 26.2, 26.0, 18.4, 1 8.2, 17.8, 11.4, 9.0, -1.3, -3.3, -4.3, -4.7; high resolution mass spectrum (ES+) m/z 1028.5526 [(M+Na)⁺; calcd for C₅₅H₈₇NOi₀Si₃Na: 1028.5536].

Amide (-)-2.54. Acid (-)-2.2 (45 mg, 2 equiv.) was dissolved in CH₂Cl₂ (1 mL) and cooled to 0 ⁰C. O.xalyl chloride (52 μL, 8.0 equiv.) and DMF (8 μL) were added. After 30 min at 0 °C, the cold bath was removed and the reaction stirred at rt for 1.75 h. The solvent was evaporated and the unpurified acid chloride placed on the vacuum pump for 20 min, then dissolved in THF (0.7 mL). Carbamate 2.53 (18 mg, 0.073 mmol) was dissolved in THF (0.7 mL), cooled to -78°C, and /7-BuLi (36 μL, 2.2 M in hexanes, 1.1 equiv.) added dropwise. After 20 min, the solution of acid chloride was added dropwise over 5 min. After I h at -78⁰C. the reaction was warmed to 0 0C for 30 min then quenched with sat. NH₄CI (2 mL). The reaction was extracted with CH₂CI₂ (3 x 3 mL) and then the combined organic layers were dried over MgSO4 and concentrated. Preparative thin layer chromatography (500 micron prep plate, 20% EtOAc/hexanes) provided (- 5 )-2.54 (9.2 mg, 23% yield). [α]_D ²⁰ -8.7 (c 1.0, CHCl₃); IR (neat) 2954, 2930, 2898, 2855, 1732, 1389. 1252. 1 180, 1 151 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 7.30-7.22 (m, 5H), 5.69 (d, J = 4.5 Hz, I H). 4.94 (ddd, J = 15.0. 15.0, 15.0 Hz, 2H), 4.74 (d, ./ = 17.5 Hz, 2H), 4.26 (ddddd, ./ = 1 1.0. 1 1 .0, 1 1.0, 8.5, 8.5 Hz. 2H), 3.49 (ddd, J= 9.5. 4.5, 2.5 Hz, I H), 3.28 (s, 3H). 3.27 (dd. J = 15.0. 9.5 Hz. I H), 2.13 (d. J = 14.5 Hz, I H), 1.69 (s, 3H). 1.02 (dd. J = 9.0, 9.0 Hz, 2H). 0.91 (s,0 9H), 0.07 (s, 3H), 0.05 (s, 12H) ; ¹³C NMR (125 MHz, CDCl₃) δ 176.0, 154.7, 143.3, 137.8, 128.5, 128.3, 127.5, 1 12.3, 82.1 , 73.6, 66.0, 58.2, 47.8, 38.8, 28.2, 26.0, 23.1 , 18.5, 17.6, -1 .4, - 4.6, -4.8; high resolution mass spectrum (ES+) m/z 544.2894 [(M+Na)^~; calcd for C₂₇H₄₇NO₅Si₂Na: 544.2891].

<.

Amide (+)-2.56. Method A. Acid (-)-2.57 (34 mg, 2 equiv.) was dissolved in CH₂Cb (1 mL) and cooled to 0 ⁰C. Oxalyl chloride (40 μL, 8.0 equiv) and DMF (8 μL) were added. After 30 min at 0 ⁰C, the cold bath was removed and the reaction stirred at rt for 2 h. The solvent was evaporated and the unpurified acid chloride placed on the vacuum pump for 15 min, then0 dissolved in THF (0.5 mL). Carbamate 2.53 (13 mg, 0.073 mmol) was dissolved in THF (0.5 mL), cooled to -78°C, and H-BuLi (26 μL, 2.2 M in hexanes, 1.1 equiv.) added dropwise. After 20 min, the solution of acid chloride was added dropwise over 5 min. After 1 h at -78°C, the reaction was warmed to 0 ⁰C for 30 min then quenched with sat. NH₄CI (2 mL). The reaction was extracted with CH₂Cl₂ (3 x 3 mL) and then the combined organic layers were dried over5 MgSO4 and concentrated. Preparative thin layer chromatography (500 micron prep plate, 20% EtOAc/hexanes) provided (+)-2.56 (26 mg, 85% yield). Method B. Acid (-)-2.57 (30 mg, I equiv.) was dissolved in CH₂Cl₂ (1 mL) and cooled to 0 ⁰C and /-Pr₂NEt (19 μL, 1 .1 equiv.) was added followed by trimethylacetyl chloride (13 μL, 1.05 equiv.) After 45 min at 0 ⁰C, sat. NH₄CI (2 mL) was added followed by enough H₂O to dissolve any solids. The layers were0 separated and the aqueous layer extracted with CH₂CI₂ (3 x 3 mL). The combined organic layers were then dried over MgSO._? and concentrated. The unpurified mixed anhydride was azeotroped with benzene (2 x 3 mL), placed on the vacuum pump for 30 min, and then dissolved in THF (0.5 mL). Carbamate 2.53 (25 mg. 0.10 mmol) was dissolved in THF (0.5 mL), cooled to -78°C. and «-BuLi (45 μL, 2.2 M in hexanes, 1.1 equiv.) added dropwise. After 20 min, the solution of acid chloride was added dropwise over 5 min. After 1 h at -78°C, the reaction was warmed to 0 ⁰C for 30 min then quenched with sat. NH₄CI (2 mL). The reaction was extracted with CH₂Cb (3 x 3 mL) and then the combined organic layers were dried over MgSO4 and concentrated. Preparative thin layer chromatography (500 micron prep plate, 20% EtOAc/hexanes) provided (+)-2.56 (38 mg, 70% yield). [α]_D ²⁰ +16.8 (c 1.0, CHCI₃); TR (neat) 2953, 2898, 1735, 1707, 1388, 1250, 1 1 89, 1 1 14_.. 1064, 1036 cm^"1: ¹H NMR (500 MHz, CDCI₃) δ 7.30-7.22 (m, 5H), 5.63 (d. J = 5.0 Hz, I H), 4.95 (dd, J = 90.5, 14.5 Hz, 2H) 4.75 (d, J= 16.5 Hz, 2H), 4.73 (dd, J = 28.5, 7.5 Hz, 2H), 4.26 (dd, ./ = 9.0, 9.0 Hz, 2H), 3.67-3.55 (m, 3H), 3.32 (s, 3H), 2.36 (dd, ./ = 14.5, 9.0 Hz, I H), 2.19 (d, ./= 13.0 Hz, I H), 1.71 (s, 3H), 1 .03-0.99 (m, 2H), 0.90-0.77 (m, 2H), 0.04 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 174.9, 154.4, 143.0, 137.8. 128.5, 128.1 , 127.5, 1 12.6, 95.2, 80.6, 77.6, 66.1. 65.9, 58.2, 47.6, 39.0, 23.0, 18.3, 17.6, -1 .2, -1.4; high resolution mass spectrum (ES+) m/z 560.2856 [(M+Na)'; calcd for C₂₇H₄₇NO_nSMNa: 560.2840].

SEM ether (-)-S2.7. A solution of (+)-2.16 (0.221 g, 0.905 mmol) in CH₂CI₂ (3 mL) was cooled to 0 ⁰C and /-Pr₂NEt (0.395 mL, 2.5 equiv.) was added, followed by dropwise addition of SEMCI (0.320 mL, 2.0 equiv.). The reaction was allowed to warm to rt and after 2 Ii , sat. NH₄Cl was added. The reaction was extracted with CH₂Cl₂ (3 x 10 mL) and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-S2.7 (338 mg, 99% yield). [α]² _D° -6.3 (c 2.9. CHCI₃); IR (neat) 3457, 2925, 1 728, 1480, 1283, 1249, 1 159, 1 107, 1031 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 4.81 (s, I H), 4.78 (s, I H), 4.74 (dd, ./ = 14.7, 6.9 Hz, 2H), 4.29 (dd, J= 1 1.8, 3.9 Hz, I H), 4.1 1 (dd, J = 1 1 .8, 6.2 Hz, I H), 3.84-3.79 (m, I H), 3.68 (ddd, J = 10.1 , 6.3, 6.3 Hz, I H), 3.59 (ddd, J = 10.0, 6.5, 6.5 Hz, 1 H), 3.51 -3.46 (m, 1 H), 3.39 (s, 3H), 2.32-2.19 (m, 2H), 1.77 (s, 3H), 1.19 (s, 9H) 0.99-0.82 (m, 2H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 178.4, 142.7, 1 13.0, 95.0, 80.3, 76.8, 65.6, 64.0, 58.6, 39.4. 39.0. 27.4, 23.0, 18.2, -1.2; high resolution mass spectrum (ES+) m/z 397.2372 [(M+Na)" ; calcd for C₉H₃₈O₅SiNa: 397.2387].

Alcohol (+)-2.58. A solution of (-)-S2.7 (0.339g, 0.905 mmol) in CH₂Cl₂ (4.5 mL) was cooled to -78 °C and DlBAL-H (2.0 mL. I M in toluene. 2.2 equiv.) was added dropwise. After 5 min, the reaction was quenched with MeOH (0.5 mL). The reaction was allowed to warm to rt before EtOAc (5 mL) and sat. Rochelle's salt (5 mL) were added. After 1 h, the organic layer transitioned from cloudy to clear. The layers were separated and the aqueous layer extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-2.58 (0.249 g, 95% yield). [α]² _D° +31.7 (c 1.2, CHCI₃); IR (neat) 3457, 2952, 2925, 2892. 1650, 1457, 1378. 1249, 1 102, 1054. 1025 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 4.82 (s, I H), 4.78 (s. 1 H), 4.76 (dd, ./ = 58.6. 7.0 Hz, 2H), 3.79-3.68 (m. 3H), 3.65-3.56 (m, 2H). 3.49 (ddd, J = 7.6, 4.8. 4.8 Hz, I H), 3.41 (s, 3H), 3.21 (dd, J = 8.3, 4.2 Hz, I H), 2.31 (dd, J = 14.4, 7.6 Hz, I H), 2.21 (dd, J = 14.4, 5.3 Hz, I H), 1.77 (s. 3H), 0.99-0.92 (m. 2H), 0.02 (s, 9H): ¹³C NMR (125 MHz, CDCI₃) δ 142.6, 1 13.2. 95.6, 82.6, 81.0, 66.0, 62.7, 58.6, 39.5, 23.0. 18.3. -1.3: high resolution mass spectrum (ES+) m/z 313.1821 [(M+Na)': calcd for C₁₄H₃₀O₄SiNa: 313.181 1 ].

Aldehyde (-)-S2.8. A solution of (+)-2.58 (0.1 17 g, 0.404 mmol) in DMSO (0.29 mL, 10 equiv.) and CH₂Cl₂ (4 mL) was cooled to 0 ⁰C and /-Pr₂NEt (0.212 mL, 3 equiv.) was added followed by SO₃«pyι idine (0.193 g, 3 equiv.) in one portion. After 5 min, brine (10 mL) and H₂O (2 mL) were added and the reaction was warmed to rt. The layers were separated and the aqueous layer was extracted CH₂Cl₂ (3 x 10 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-S2.8 (0.1 13 g, 97%) as a colorless oil. [α]² _D° -9.1 (c 0.9, CHCl₃): IR (neat) 2952. 2892. 2825. 1732, 1450, 1376, 1249. 1 108, 1060, 1029 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 9.66 (d, J= 1.4 Hz, I H), 4.85 (s. I H). 4.84 (s, I H), 4.80 (dd, J = 19.4, 6.9 Hz. 2H). 4.1 I (dd, J = 2.8, 1 .5 Hz, I H), 3.75-3.69 (m. 2H). 3.65 (ddd, J = 9.8, 9.8, 6.9 Hz, IH), 3.41 (s, 3H), 2.33 (dddd, J = 14.1 , 14.1 , 14.1. 6.9 Hz, 2H), 1 .72 (s, 3H), 0.92 (ddd. J = 10.1 , 6.6, 3.3 Hz, 2H), 0.02 (s, 9H); ¹³C NMR ( 1 25 MHz, CDCl₃) δ 202.4, 141.7, 1 14.4, 96.3, 82.5, 81.8, 66.1 , 58.1, 38.9, 22.8, 18.2, 1.2; high resolution mass spectrum (ES+) m/z 31 1.1666 [(MH-Na)⁺: calcd for Ci₄H₂₈O₄SiNa: 31 1.1655].

5 Acid H-2.57. Aldehyde (-)-S2.8 (0.203 g, 0.704 mmol) was dissolved in /-BuOH (7.5 mL) and H₂O (7.5 mL). The solution was cooled to 0 °C followed by addition of 2-methyl-2-butene (6 mL), NaH₂PO₄.H₂O (0.550 g, 5 equiv.), and NaClO₂ (0.483 g, 80 wt%, 5 equiv.). After i 5 min, the reaction was poured onto sat. NH4CI ( I O mL) and extracted thoroughly with EtOAc. The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (25%

I O EtOAc/hexanes to 40% EtOAc/hexanes) provided (-)-2.57 (0.196 g, 92% yield) as a colorless oil. [α]]° -1 8.6 (c 1.1 , CHCl₃); IR (neat) 2953, 2925, 1725, 1649, 1376, 1252, 1 1 10, 1060, 1030 cm-¹; ¹H NMR (500 MHz. CDCl₃) δ 4.83 (s, I H), 4.81 (s, I H), 4.78 (s. 2H). 4.39 (d, J = 3.1 Hz, 1 H), 3.75 (ddd. J = 8.2, 5.2, 3.2 Hz. I H), 3.68 (dd, J = 8.5, 8.5 Hz. 2H), 3.43 (s, 3H), 2.39 (dd. J = 14.6, 8.0 Hz. I H), 2.28 (dd, J = 14.6, 5.2 Hz, I H). 1.76 (s, 3H), 0.96-0.87 (m, 2H). 0.01 (s.

15 9H); ¹³C NMR (125 MHz, CDCI₃) δ 175.0, 141.9, 1 13.5, 95.1 , 81 .0, 76.2, 66.3, 58.3, 38.7, 22.9, 18.2, -1 .3; high resolution mass spectrum (ES+) m/z 327.1614 [(M+Na)^"; calcd for Ci₄H₂₈O₅SiNa: 327.1604].

0 Aminal (+)-2.60. To a solution of ester (+)-2.40 (77.2 mg, 0.152 mmol) in MeOH (3 mL) was added H₂O (55 μL, 20 equiv.) followed by LiOH (73 mg, 20 equiv.). After stirring for 6 h at rt. the reaction was acidified to pH 3 with I M aq. NaHSO₄. The reaction was extracted with EtOAc (5 x 10 mL) and the combined organic layers were then dried over MgSO₄ and concentrated to afford acid 2.59 (71 mg, 95% yield). The unpurified acid was dissolved in 5 acetone (7.2 mL) and cooled to 0 ⁰C followed by addition Of Z-Pr₂NEt (61 μL, 2.4 equiv.) and isobutylchloroformate (41 μL, 2.2 equiv.). After 1 h. NaN₃ (47 mg, 5 equiv.) was dissolved in H?O (0.9 mL) and added to the mixed anhydride. After 5 min, the reaction was diluted with H^O (5 mL) and extracted with EtOAc (3 x 5 mL). The combine organic layers were dried over MgSO₄ and concentrated. The acyl azide was then dissolve in toluene (7.2 mL), the flask sealed, and heated to 80 ⁰C. After 1 h, the flask was cooled slightly and 2-trimethylsilyl ethanol (0.41 mL, 20 equiv.) was added and the flask heated back to 80 ⁰C. After 3 h, the reaction was cooled to it and the solvent evaporated. Flash chromatography (5% EtOAc/hexanes) provided (+)-2.60 (53.5 mg, 61% yield, 2 steps) as a light yellow oil. [αp_n° +22.6 (c 1.0, CHCl₃); IR (neat) 2955,

2930, 2850, 1 724, 1500, 1251 , 1 125, 1066 cm^"1: ¹H NMR (500 MHz, CDCI₃) δ 7.40-7.21 (m. 5H), 5.42 (d. J = 8.9 Hz, I H). 4 86 (dd. J = 8.2, 2.9 Hz, I H), 4.59-4.43 (m. 2H). 4.22-4.06 (m, 2H), 3.82 (ddd, J = 8.4, 4.3, 4.3 Hz, IH), 3.61-3.56 (m, 2H), 3.55-3.49 (m, IH), 3.38 (s, 3H), 2.13 (dd, J = 12.6, 12.6 Hz, IH), 1.85 (ddd, J = 13.4. 8.2, 3.4 Hz, I H), 1.64-1.49 (m. 4H), 1.01 - 0.95 (m, 2H) 0.97 (s. 3H), 0.91 (s, 9H), 0.91 (dd, J= 7.2, 7.2 Hz, 3H), 0.85 (s, 3H). 0.05 (s, 3H), 0.05 (s, 3H), 0.02 (s, 9H): ¹³C NMR (125 MHz, CD₃OD) δ 159.5, 140.6, 129.4. 129.3, 128.7, 84.4, 80.1. 78.5. 74.5, 72.9, 64.3, 56.0, 39.4, 35.3, 32.2, 28.5, 26.5. 25.6. 19.1 , 18.8, 1 7.6, 10.0. - 1 .4, -4.0, -4.7; high resolution mass spectrum (ES+) mJz 632.3806 [(M+Na)": calcd for C₃₃HSgNO₆Si₂Na: 632.37791.

OBn

Protected amide (-)-2.62. Acid (-)-2.57 (47 mg. 2 equiv.) was dissolved in CH₂Cl₂ (4.8 mL) and cooled to 0 ⁰C and /-Pr₂NEt (29 μL, 1.1 cquiv.) was added followed by trimethylacetyl chloride (20 μL, 1.05 equiv.) After 45 min at 0 ⁰C, sat. NH₄Cl (3 mL) was added followed by enough H₂O to dissolve any solids. The layers were separated and the aqueous layer extracted with CH₂CI₂ (2 x 5 mL). The combined organic layers were then dried over MgSO₄ and concentrated. The unpurified mixed anhydride was azeotroped with benzene (2 x 3 mL), placed on the vacuum pump for 30 min, and then dissolved in THF (0.6 mL). A solution of (+)-2.60 in THF (0.6 mL) was cooled to -78 ⁰C and LiHMDS (67 μL, 1.07 M in THF 1.1 equiv.) was added dropwise over 1 min. After stirring for 30 min at -78 °C, the mixed anhydride solution was added dropwise over 5 min. After 1.5 h at -78 ⁰C, the reaction was warmed to --40 ⁰C over 1 h and stirred for 1.5 h. The reaction was quenched with sat. NH₄CI (2 mL), warmed to rt, and then diluted with CH₂Ch (5 mL). The layers were separated and the aqueous layer extracted with CH₂Cb (3 x I O mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-2.62 (33.4 mg, 57% yield) along with recovered starting material (6.6 mg, 21 % yield). [α]² _D° -3.0 (c 0.5, CHCl₃): IR (neat) 2954, 2931 , 2858, 1732, 1456, 1382, 1250, 1096, 1064 cπT¹; ¹H NMR (SOO MHz, CDCI₃) δ 7.38-7.20 (m, 5H), 5.55 (d, J= 6.0 Hz, I H), 5.36 (d, J = 4.1 Hz, IH), 4.76 (s, 2H), 4.74 (s, 2H), 4.56-4.49 (m, 2H), 4.39 (d, J = 5.0 Hz, IH), 4.31-4.24 (m, 2H), 3.74-3.58 (m, 3H), 3.56 (dd, ./ = 7.6, 3.8 Hz, IH), 3.50 (d, J = 10.4 Hz, IH), 3.50-3.45 (m, I H), 3.34 (s, 3H), 3.32 (s, 3H), 2.33 (dd, J = 15.1, 9.4 Hz, IH), 2.24 (d, J= 14.4 Hz, IH), 1.87 (ddd, J= 13.5, 5.4, 4.1 Hz, I H), 1.80- 1.73 (m, I H). 1.72 (s, 3H). 1.64 (dd, ./ = 14.3, 9.2 Hz, I H), 1.61 -1.51 (m, 3H), 1 .12-1.03 (m, 2H), 0.93 (s. 3H), 0.91 (s, 9H), 0.93-0.87 (m, 5H), 0.84 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s. 9H). -0.01 (s, 9H); ¹³C NMR ( 125 MHz, CDCI₃) δ 1 75.2, 154.7. 143.1. 139.9, 128.4, 127.7, 127.3, 1 12.4, 95.1 , 81.0, 78.0, 77.3, 77.1. 73.4, 71.0, 69.5, 66.1 , 66.0, 58.0, 57.2, 38.5, 38.2, 34.3, 32.1 , 27.1 , 26.1, 26.0, 25.3, 23.2, 18.3, 18.2, 17.8, 17.7, 9.2, -1.2, -1.4, -4.1, -4.8; high resolution mass spectrum (ES+) m/z 918.5375 [(M+Na)~; calcd for C₄₆H₈₅NOu₁Si₃Na: 918.5379].

Amide (+)-2.63. A solution Of MgBr₂ (0.131 g, 20 equiv.) in MeNO₂ (77 μL, 40 equiv.) and Et₂O (0.36 mL) was added to neat (-)-2.62 (32.1 mg, 0.036 mmol). The flask was flushed with argon and sealed to prevent solvent evaporation. After 7 h, the reaction was quenched with H₂O ( I mL) and extracted with Et₂O (3 x 3 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (20% EtOAc/hexanes to 40% EtOAc/hexanes to 60% EtOAc/hexanes) provided (+)-2.63 ( 1 5.3 mg. 69% yield) as a colorless oil. [α]^: _D ⁿ +12.6 (c- 0.5, CHCl₃); IR (neat) 3398, 2391 , 2864, 1667, 151 1 , 1460, 1362, 1254, 1090 cm^"1 ; ¹ H NMR (500 MHz, CDCl₃) δ 7.40-7.27 (m, 5H), 5.17 (dd, J= 9.1 , 6.6 Hz, IH), 4.80 (s, 1 H), 4.76 (s, 1 H), 4.41 (dd, J= 30.3, 10.8 Hz, 2H), 3.96 (s, IH), 3.82 (dd, J= 1 1.2, 5.5 Hz, I H), 3.76-3.69 (m, I H), 3.62 (ddd,./= 8.1, 3.7, 3.7 Hz, 2H), 3.50 (s, IH), 3.52-3.42 (m, IH), 3.39 (s, 3H), 3.30 (s, 3H), 2.31 (dd,J= 14.6,9.4Hz, IH), 2.12 (dd, J = 14.6.3.0Hz, IH), 1.90 (dd, J = 12.2, 12.2Hz, IH), 1.83 (ddd, J= 13.6, 5.3, 4.2 Hz_.. IH), 1.73 (s, 3H), 1.72-1.62 (m, 3H), 1.55-1.43 (m, IH), 0.95 (dd, J= 7.4, 7.4 Hz, 3H), 0.95 (s, 3H), 0.91 (s, 9H), 0.86 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 172.9, 142.0, 140.1, 128.9, 128.6, 127.9, 113.5, 81.8, 81.1, 81.1, 77.8, 77.1 , 73.9, 72.6, 70.5, 69.9, 57.4, 56.8, 38.6, 38.0, 33.6, 32.0, 27.4, 26.3, 25.4, 23.3, 18.5, 10.3. - 4.1, —4.6; high resolution mass spectrum (ES+) m/z 644.3951 [(M+Na) ; calcd for C₃₄H₅₉NO₇SiNa: 644.3959].

Aminal (-)-2.64. To a solution of (+)-2.63 (8 mg.0.013 mmol) in DMF (0.12 mL) was added

TASF (36 mg, 10 equiv.) in one portion. The reaction was heated to 60⁰C and after 8 h, sat. NaHCO^ (0.5 mL) and H₂O (0.5 mL) were added. The reaction was extracted with EtOAc (5 x 1 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (40% EtOAc/hexanes to 60% EtOAc/hexanes) provided (-)-2.64 (6.4 mg.98% yield) as an amorphous white solid. [α]² _D°-14.l (c 0.5, CHCl₃); IR (neat) 3397, 2963, 2932. 2873, 1666, 1513, 1452, 1378, 1096, 1073 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 7.38-7.24 (m, 5H), 5.25 (dd, J= 9.1, 7.6 Hz, IH), 4.79 (s, IH), 4.75 (s, IH), 4.37 (dd, J= 37.3, 10.6 Hz, 2H), 3.87-3.80 (m, 2H), 3.79-3.73 (m, IH), 3.72-3.70 (m, 2H), 3.58 (ddd, J = 9.4, 3.3, 3.3 Hz, IH), 3.38 (s, 3H), 3.40-3.36 (m, IH), 3.26 (s, 3H), 2.30 (dd, J= 14.6, 9.4Hz, IH), 2.10 (dd, J= 14.6. 3.1 Hz, IH), 1.95 (ddd, J= 13.5, 3.9, 3.9 Hz, IH), 1.79 (ddd, J= 13.6, 10.1, 5.6 Hz, IH), 1.76- 1.73 (m, IH), 1.72 (s, 3H), 1.71-1.64 (m, 2H), 1.54-1.45 (m, 2H), 0.98 (s, 3H), 0.97 (dd,J= 7.4, 7.4 Hz, 3H), 0.89 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 173.3, 142.5, 138.4, 128.8, 128.6, 128.0, 113.0, 80.8.79.8, 76.8, 75.6, 72.4, 72.1, 71.4, 67.3, 57.6, 57.1, 38.4, 37.4, 32.5, 30.7, 26.6, 23.8, 22.9, 14.4, 10.4; high resolution mass spectrum (ES+) m/z 530.3106 [(M+Na)¹; calcd for C₂₈H₄₅NO₇Na: 530.3094].

N-acyl Aminal (+)-2.65. To a solution of (-)-2.64 (3.4 mg, 6.7 μmol) in THF (0.2 mL) cooled to -78 ⁰C was added Lithium di-tert-butylbi phenyl (LiDBB) until the solution maintained a dark blue color. The reaction was stirred for 1.5 h and then quenched with sat. NaHCCb (1 rnL) and extracted with EtOAc (5 x 1 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (60% EtOAc/hexanes) provided (+)-2.65 (2.7 mg, 97% yield) as a white, amorphous solid. [α]² _D° +12.4 (c 0.3, CHCl₃); IR (neat) 3389, 2925, 1660, 1519, 1455, 1377_.. 1 1 16, 1071 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 7.08 (d, J= 9.6 Hz, I H), 5.40 (dd, J = 9.4, 9.4 Hz, I H), 4.85 (s, I H), 4.82 (s, I H), 4.41 (dd, J= 2.9, 2.9 Hz, I H), 3.81 -3.72 (m, 2H), 3.65 (ddd, J = 1 1.0, 4.9, 4.9 Hz, I H), 3.59-3.51 (m, I H), 3.45 (s, 3H), 3.48-3.42 (m,- 1 H), 3.39 (s, 3H), 3.04 (d, J= 6.0 Hz, I H), 2.36 (dd, J= 14.5, 9.1 Hz, I H), 2.20 (dd, J= 14.6, 3.8 Hz. I H), 2.06 (ddd, J = 13.3, 4.4, 1.1 Hz, IH), 1.85-1.79 (m, IH), 1.78 (s, 3H), 1.49-1.38 (m, 4H), 0.94 (s, 3H), 0.93 (dd, J = 7.4 Hz, 3H), 0.86 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 1 73.7, 142.2, 1 13.4, 80.6, 78.9, 75.5, 73.8, 72.3, 72.2, 69.6, 57.9, 56.7, 38.7, 37.5, 36.6_.. 30.4, 30.0, 29.6, 22.9, 12.7, 10.7; high resolution mass spectrum (ES+) m/∑ 440.2623 [(M+Naf; calcd for C_2IH₃₉NO₇Na: 440.2625].

Ester H-2.66. Acid (-)-2.57 (98 mg, 0.318 mmol) was dissolved in MeOH ( 1.6 mL) and CH₂CI: (1.6 mL) and cooled to 0 ⁰C. TMSCHN: (ca. X.XX mL, X.X M in Et_:O) was then added dropwise until all gas evolution had ceased and the solution turned light yellow. Argon was bubbled through the reaction for 10 min and then the reaction concentrated. Flash chromatography (5% EtOAc/hexanes) provided (-)-2.66 (92 mg, 90% yield) as a colorless oil. [α]_D ²° - 28.4 (c 1 , CHCl₃); rR (neat) 2952, 2898, 1754, 1437, 1250, 1 198, 1 1 13, 1062, 1038 cm^" '; ¹H NMR (500 MHz, CDCl₃) δ 4.80 (d, J= 18.0 Hz, 2H), 4.73 (d, J= 1.5 Hz, 2H). 4.31 (d. J = 4.0 Hz, I H), 3.74 (s, 3H), 3.68-3.61 (m, 3H), 3.39 (s, 3H), 2.35 (dd, J= 14.5, 8.0 Hz, I H), 2.27 (dd, J= 14.5, 5.0 Hz, I H), 1.75 (s, 3H), 0.89 (dd, J= 10.0, 7.5 Hz, 2H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 171.6, 142.3, 1 13.2, 94.8, 80.9, 76.2, 66.0, 58.3, 52.1 , 38.9, 23.0, 18.2, - 1.3; high resolution mass spectrum (ES+) m/z 341.1760 [(M+Na)⁺: calcd for Ci₅H₃₀O₅SiNa: 341.1760].

Bis-SEM Ether 2.69. A solution of homophthalate 2.6 (0.305 g, 1.20 mmol) in THF (6 itiL) was cooled to 0 ⁰C and NaH (0.106 g, 60 wt%, 2.2 equiv.) was added. After 5 min, SEMCl (0.53 mL, 2.5 equiv.) was added dropwise. The reaction was allowed to warm to it, and after 30 min the reaction was quenched with slow addition of MeOH (0.5 mL). Sat. NaHCO₃ (5 mL)was added and the reaction was extracted with CH₂CI₂ (3 x 10 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided 2.69 (0.61 1 g, 99% yield) as a colorless oil. IR (neat) 2952, 2898, 1736. 1597, 1314, 1266, 1250, 1 158, 1067 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 6.94 (s, I H), 5.22 (s, 2H). 5.1 7 (s, 2H), 3.85 (s, 3H), 3.77-3.69 (m, 4H), 3.67 (s, 5H), 2.12 (s, 3H), 0.98-0.91 (m, 4H), 0.00 (s, 9H), 0.00 (s, 9IT); ¹³C NMR (125 MHz, CDCI₃) δ 171.1 , 168.6, 157.4, 153.8, 132.3, 120.7, 1 19.0, 101.9, 94.0, 93.4, 66.5, 66.5, 52.2, 52.2, 36.3, 18.3, 18.2, 1 1.7, -1.2; high resolution mass spectrum (ES+) m/z 537.2303 [(M+Na)⁺; calcd for C₂₄H₄₂O₈Si₂Na: 537.2316].

Aryl Acid S2.9. Diester 2.69 (0.421 g, 0.818 mmol) was dissolved in CH₂CI₂ (4 mL) and MeOH (4 mL) then cooled to 0 ⁰C. Solid KOH (0.918 g, 20 equiv.) was added and the reaction warmed to rt. After stirring for 3 h at rt, the reaction was acidified to pH 3 with a 1 M NaHSO₄ solution. The reaction was extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (25% EtOAc. hexanes to 40% EtOAc/hexanes) provided acid S2.9 (0.408 g, 99% yield) as a white foam. TR (neat) 2952. 2898, 1729, 1597, 1477, 1268, 1250, 1 158, 1065 cm^"'; ¹H NMR (500 MHz, CDCl₃) δ 6.96 (s, I H), 5.23 (s, 2H), 5.18 (s, 2H), 3.90 (s, 3H), 3.74 (dd, J= 8.5, 8.5 Hz, 4H), 3.67 (s, 2H), 2.17 (s, 3H), 0.95 (dd, J= 8.5, 8.5 Hz, 4H), 0.00 (s, 18H); ¹³C NMR (125 MHz, CDCl₃) δ 173.9, 170.1 , 158.0, 154.3, 132.1 , 121.2, 1 1 8.0, 102.0, 93.9, 93.3, 66.6, 66.6, 52.8, 37.3, 18.3, 18.2, 1 1.7, -1.2; high resolution mass spectrum (ES+) m/z 523.2160 [(M+Na)⁺; calcd for C₂₃H₄₀O₈Si₂Na: 523.2159].

Aryl Alcohol S2.10. Acid S2.9 (0.225 g, 0.45 mmol) was dissolved in THF (4.5 mL) and cooled to 0 ⁰C. To this solution was added BH₃.SMe₂ (0.1 12 mL, 1 M solution in THF, 2.5 equiv.) dropwise over 2 min. The ice bath was removed and the reaction stirred at rt. After 2 h, the reaction was quenched with MeOH (1 mL) and diluted with brine (4 mL) and water (4 mL). The reaction was extracted with CH₂CI₂ (3 x 10 mL) and the combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided alcohol S2.10 (0.1 18 g, 86% yield) as a colorless oil. IR (neat) 2952, 2897, 1725, 1 594, 1272, 1248, 1 1 1 1 , 1072, 1054 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 6.89 (s, I H), 5.22 (s, 2H), 5.1 7 (s, 2H), 3.89 (s, 3H), 3.80 (ddd, J = 6.5, 6.5, 6.5 Hz, 2H), 3.77-3.71 (m, 4H), 2.86 (dd, J = 6.7, 6.7 Hz, 2H), 2.34 (dd, J = 5.6. 5.6 Hz, IH), 2.15 (s, 3H), 0.99-0.87 (m, 4H), 0.01 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 170.2, 157.6, 153.4, 136.1 , 1 19.9, 1 19.4, 101.1 , 93.8. 93.4, 66.5, 66.5, 62.2, 52.6, 34.5, 1 8.3, 18.2, I 1.5, -1.2; high resolution mass spectrum (ES+) m/z 509.2361 [(M+Na)⁺; calcd for C₂₃H₄₂O₇Si₂Na: 509.23671.

Aldehyde 2.70. Procedure A: Alcohol S2.10 (0.129 g, 0.265 mmol) was dissolved in CH₂CI₂

(2.7 mL) and DMSO (0.21 mL, 10 equiv.) and cooled to 0 °C. Next, /-Pr₂NEt (0.139 mL, 3 equiv.) was added followed by SO_3^pyridine (0.127 g, 3 equiv.). After 30 min at 0 °C, the reaction was diluted with H₂O (2 mL) and brine (5 mL) followed be extraction with CH₂Cl₂ (3 x 10 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided aldehyde 2.70 (0.1 13 g, 88% yield) as a light yellow oil. Procedure B: A solution of 2.69 (0.104 g, 0.202 mmol) in CH₂CI₂ (2.0 mL) was cooled to -78 ⁰C and DlBAL-H (0.22 mL, 1 M solution in toluene, 1.1 equiv.) was added dropwise over 15 min. After 5 min, the reaction was quenched with MeOH. The reaction was allowed to warm to it before EtOAc (5 mL) and sat. Rochelle's salt (5 mL) were added. After 1 h, the organic layer transitioned from cloudy to clear. The layers were separated and the aqueous layer extracted with 3 x 20 mL EtOAc. The combined organic layers were dried over MgSO^ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided 2.70 (0.64 g. 66% yield) as a light yellow oil. TR (neat) 2953, 2901 , 1726, 1595, 1477. 1272, 1251 , 1 157, 1 1 10, 1065 cm^"1: ¹H NMR (500 MHz, CDCI₃) 9.62 (dd, ./ = 1.8. 1.8 Hz, I H), 6.97 (s, I H), 5.24 (s, 2H), 5.19 (s. 2H), 3.85 (s. 3H), 3.79-3.71 (m. 4H), 3.64 (d, ./ = 1.8 Hz. 2H), 2.08 (s. 3H), 0.99-0.91 (m, 4H), 0.00 (s. 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 198.7, 168.7. 157.7, 154.0, 130.5, 120.8, 1 19.3, 102.1 , 93.9, 93.4, 66.6, 66.6, 52.3, 46.1 , 1 8.3, 18.2, 1 1 .9, -1.2; high resolution mass spectrum (ES+) m/z 507.2210 [(M+Na)^"1 ; calcd for C₂₃H₄₀O₇Si₂Na: 507.221 1 ].

β-Hydroxy ketone (+)-2.71. A solution of ketone (+)-2.5 (0.140 g, 0.336 mmol) in CH₂CI₂ (3.4 mL) was cooled to -78 ⁰C and Cl₂BPh (52 μL, 1.2 equiv.) was added. After stirring for 20 min. /-Pr₂NEt (88 μL, 1.5 equiv.) was added dropwise. The reaction was stirred for 1 h at -78 ⁰C. warmed to 0 ⁰C over 10 min, then stirred for 1 h at 0 ⁰C. After cooling back to -78 ⁰C. aldehyde 2.70 (0.237g. 1.45 equiv.) was dissolved in CH₂Cl₂ ( 1.5 mL) and added to the boron enolate dropwise over 15 min. After 1 h at -78 ⁰C, the reaction was quenched with a 1 : 1 mixture of MeOH/pH 7 buffer (6 mL). After warming to 0 °C, the reaction was neutralized to pH 7 with pH 8 buffer and stirred for 1 Ii at 0 ⁰C. The layers were separated and the aqueous layer extracted with CH₂Cl₂ (3 x 15 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (15% EtOAc/hexanes) provided (+)-2.71 (0.273 g, 90% yield) as a single diastereomer. [α]² _D° +30.0 (c 0.9, CHCl₃); IR (neat) 3467, 2952, 2896, 1731 , 1593, 1463, 1253, 1064 Cm^ ¹H NMR (SOO MHz₁ CDCl₃) S o-SS (S, I H), 5.21 (s, 2H), 5.15 (d, J = 2.3 Hz, 2H). 4.09 (dd, J= 1 1.1 , 5.7 Hz, I H), 4.07-4.00 (m, 2H), 3.94 (d, J = 6.1 Hz. I H), 3.87 (s. 3H), 3.78-3.70 (m, 4H), 3.72 (s, 3H), 3.64 (dd, ./= 7.8, 3.8 Hz_; I H), 3.43 (d../ = 5.6 Hz, I H), 3.40 (s, 3H), 3.06 (dd, J = 16.4, 9.4 Hz, IH), 2.84 (dd, J= 14.2, 3.2 Hz, I H), 2.75-2.63 (m, I H), 2.61 -2.50 (m, 2H), 2.16 (s, 3H), 1.95 (ddd, J = 13.8, 5.8, 3.9 Hz, I H), 1.57 (ddd, J = 13.3, 7.8. 4.9 Hz, I H), 1.19 (d, J= 7.1 Hz, 3H), 0.95 (s, 3H), 0.98-0.92 (m, 4H)_., 0.90 (s, 9H), 0.84 (s, 3H), 0.04 (s. 6H), 0.01 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 212.5. 171 .6. 170.7, 157.8, 153.7, 136.6, 120.3, 1 19.1 , 101.1 , 93.9, 93.3, 82.4, 76.7, 73.1 , 71.6, 70.1 , 66.5, 66.5, 58.8, 53.2, 52.7, 52.2, 42.5, 38.1 , 35.9, 30.1 , 26.0, 24.9, 18.3, 18.2, 17.6, 1 1.8, 1 1.4, -1 .2, -4.3, -4.8; high resolution mass spectrum (ES+) m/z 923.4782 [(M+Na)'; calcd for C₄₄H_8nOi₃Si₃Na: 923.4805].

Diol (+)-S2.11. A solution (+)-2.71 (0.1 16 g, 0.129 mmol) in THF (1.4 mL) and MeOH (0.46 niL) was cooled to -78 ⁰C and Et₂BOMe (0.167 mL, 1 M in THF, 1.3 equiv.) was added dropwise. After 25 min, NaBH₄ (10 mg, 2.0 equiv.) was added and the reaction was strirrβd at - 78 ⁰C. After 1 h, the reaction was warmed to 0 °C over 10 min and then stirred for 30 min. EtOAc (2 mL) was added followed by H₂O (2 mL) and a 1 : 1 solution of MeOH/30% aq. H₂O₂ (5 mL). After 1 h, the reaction was extracted with EtOAc (3 x 10 mL) and the combined organic layers were treated with solid Na₂S₂O₃ to destroy any remaining peroxide. The organic layer was then filtered and washed with sat. Na₂S₂O₃, dried over MgSO₄, and concentrated. Flash chromatography (15% EtOAc/hexanes to 25% EtOAc/hexanes) provided (+)-S2.11 (0.109 g, 95% yield, dr > 20: 1 ) as a colorless oil. [α]∞ +10.3 (c 1.0, CHCl₃); IR (neat) 3500, 2953, 2896, 2857, 1734, 1593, 1253, 1 157, 1 1 15, 1065 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 6.87 (s, I H), 5.21 (s, 2H), 5.16 (s, 2H), 4.16-4.10 (m. I H), 4.02 (dd, J= 7.5, 4.9 Hz. I H), 3.97 (d, J= 7.9 Hz, I H), 3.88 (s, 3H). 3.84 (dd, J = 12.9, 7.1 Hz, I H), 3.78 (s, 3H), 3.76-3.70 (m, 4H), 3.65 (s, I H), 3.56-3.50 (m, 2H), 3.39 (s, 3H), 2.85-2.80 (m, 2H), 2.20 (s, 3H), 1.93 (ddd, J = 13.8, 4.0, 4.0 Hz, I H), 1.83 (ddd, J = 14.2, 10.3, Hz, I H), 1.72- 1.63 (m, I H), 1 .51 (d, J= 7.0 Hz, I H), 1.45 (d. J = 14.7 Hz, I H). 0.98 (d, J = 6.9, 3H), 0.96-0.92 (m, 4H), 0.90 (s, 9H), 0.88 (s, 3H). 0.85 (s, 3H), 0.04 (s. 3H), 0.04 (s, 3H), 0.01 (s, 9H), 0.00 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 171.3. 169.9, 157.2, 153.1, 136.9, 120.2, 1 19.2, 100.6, 93.6, 93.1, 81.7, 80.9, 76.2, 75.5, 72.1 , 71.4, 66.2, 66.2, 58.5, 52.2, 52.2, 41 .9, 38.9, 35.8, 33.4, 29.8, 25.7, 24.0, 1 8.0, 17.9, 1 5.1 , 1 1 .7, 5.8, - 1 .5, -4.4. -5.0; high resolution mass spectrum (ES+) ιn/z 925.5000 [(M+NaV ; calcd for C₄₄H₈₂Oi₃Si₃Na: 925.4961 ].

Acid (+)-2.72. A solution of (+)-S2.11 (20.6 mg, 0.023 mmol) was dissolved in MeOH (1.1 niL) and cooled to 0 ⁰C. Next, H₂O (8 μL, 20 equiv.) was added followed by LiOH (1 1 mg, 20 equiv.). The cold bath was removed and the reaction allowed to warm to rt. After 28 h, due to bis-acid formation, the reaction was quenched by diluting with EtOAc and acidified to pH 5 with 5% aq. AcOH. Brine (2 niL) was added and the reaction extracted with EtOAc (5 x 3 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (0.1 % AcOH in 30% EtOAc/hexanes to 0.2% AcOH in 60% EtOAc/hexanes) provided (+)-2.72 ( 17 mg, 87% yield). [α]^: _D° +31.4 (c 1.1. CHCI₃); IR (neat) 3467, 2953. 2898, 2858, 1720. 1592, 1250, 1 107, 1065 cm^"1 ; ¹H NMR (500 MHz. CDCI₃) δ 6.95 (s, I H), 5.30 (dd, J = 20.0, 7.0 Hz. 2H), 5.27 (s, 2H), 4.33 (ddd, J = 12.1 , 5.8, 2.5 Hz, IH), 4.23 (dd, J = 10.9, 6.6 Hz, I H), 4.15 (d, J = 7.3 Hz, I H), 3.87-3.79 (m, 3H), 3.78-3.72 (m, 2H), 3.64-3.57 (m, 2H), 3.45 (s, 3H), 3.03 (dd, J = 16.5, 2.4 Hz, I H), 2.91 (dd, J= 16.4, 12.2 Hz, I H), 2.24-2.07 (m, I H), 2.12 (s, 3H), 2.01 (dd, J = 10.6, 7.0 Hz, I H), 1.97-1.92 (m, I H), 1.66 (ddd, J = 13.7, 6.8, 4.7 Hz, I H), 1.54 (d, J = 15.0 Hz, I H). 1.08 (d, J = 7.0 Hz, 3H), 0.97 (s. 3H), 0.99-0.94 (m, 4H), 0.91 (s, 9H), 0.88 (s, 3H), 0.06 (s, 6H), 0.01 (s, 9H), 0.00 (s. 9H); ¹³C NMR (125 MHz, CDCl₃) δ 172.3, 164.1 , 160.1 , 1 59.2, 141.9, 1 17.45, 109.0, 102.1 , 94.4, 93.1. 82.2, 81.9, 79.0, 72.7, 71.9, 69.8, 66.8, 66.8, 58.7, 41.7, 38.7, 33.0, 30.6, 29.5, 26.0, 25.0, 18.3, 18.3, 18.2, 1 1.4, 9.7, 9.7, -1.2, -1.2, -4.2, -4.8: high resolution mass spectrum (ES+) m/z 879.4569 [(M+Na)'; calcd for C₄₂H₇₆OuSi₃Na: 879.4543].

Aminal (+)-2.73. A solution of (+)-2.72 (54 mg, 0.063 mmol) in acetone (3.2 mL) was cooled to 0⁰C and /-Pr₂NEt (24 μL, 2.2 equiv.) was added followed by dropwise addition of isobutyl chloroformate (20 μL.2.4 equiv.) After 45 min at 0⁰C, NaN₃ (21 mg, 5 equiv.)was dissolved in H₂O (0.4 mL) and added to the reaction over 2 min. After 20 min, cold H₂O (2 mL) was added and the reaction extracted with cold EtOAc (3 x5 mL). The combined organic layers were dried thoroughly over MgS(Xj and concentrated. The residue was azeotroped with benzene (3 x5 mL) and placed on the vacuum pump for 30 min. The unpurified acyl azide was dissolved in toluene (3.2 mL), the reaction flask fitted with a reflux condenser, and then heated to 80⁰C. After 45 min, 2-trimethylsilyl ethanol (0.181 mL, 20 equiv.) was added through the top of the reflux condenser. After 2 h, the reaction was cooled to rt and the solvent evaporated. Flash chromatography (10% EtOAc/hexanes to 25% EtOAc/hexanes) provided (+)-2.73 (45 mg, 74% yield) as a colorless oil. [α]£ +8.4 (c 0.5, CHCl₃): IR (neat) 3501, 3315, 2953, 2901, 2857.1719, 1595, 1249, 1108, 1064 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 6.94 (s, IH), 5.37 (d, J= 10.1 Hz, IH), 5.29 (dd, .7=23.9.6.8 Hz, 2H), 5.26 (s, 2H)_; 4.89 (dd, ./= 10.0, 2.6Hz. IH), 4.31 (ddd,J = 11.6, 6.9.2.4 Hz, IH), 4.24-4.08 (m, 2H), 3.97 (d, ./ = 9.4 Hz, IH), 3.88-3.72 (m, 4H).3.65 (s. IH), 3.62 (d. J = 10.4 Hz. IH).3.56 (dd, J= 4.9, 3.2 Hz. IH).3.36 (s, 3H), 3.10 (dd, J= 16.4, 2.1 Hz, lH)_;2.82(dd. J= 16.4.11.9Hz, IH), 2.45-2.28 (m, IH), 2.12 (s, 3H).1.91-1.80 (m, J = 12.5, 8.0 Hz, 2H), 1.53-1.37 (m, 2H), 1.11 (d, J = 6.9 Hz, 3H), 1.00 (s, 3H), 0.98-0.93 (m, 6H), 0.90 (s, 9H), 0.88 (s, 3H), 0.05 (s, 3H), 0.04 (s_..3H), 0.02 (s, 9H), 0.00 (s, 9H), 0.00 (s, 9H): ¹³C NMR (125 MHz, CDCl₃) δ 163.5, 159.9, 159.1, 157.2, 141.9, 117.4. 109.4, 102.2, 94.4, 93.1, 83.8, 83.6, 79.4, 77.4, 73.0, 72.7, 68.0, 66.8, 66.7, 63.7, 55.8, 43.4, 38.1, 32.9, 31.1, 29.7, 26.1, 26.0, 18.4, 18.3, 18.2, 17.8, 11.4, 10.2, -1.1, -1.2, -1.3, -4.3, -4.8; high resolution mass spectrum (ES+) m/∑ 994.5354 [(M+Na)⁺; calcd for C₄₇H₈₉NO₁₂Si₄Na: 994.5360].

Silyl ether (+)-2.74. A solution of (+)-2.73 (19.6 mg, 0.020 mmol) in CH₂Cl₂ (0.2 mL) was cooled to 0⁰C and 2,6-lutidine (9.5 μL, 4.0 equiv.) was added followed by dropwise addition of TBSOTf(IO μL.2.1 equiv.). After 45 min, CH₂CI₂ (1 mL) and sat. NaHCO₃ (2 mL) added and the reaction allowed to warm to rt. The layers were separated and the aqueous layer extracted with CH₂Cl₂ (3 x 5 mL). Preparative TLC (25% EtOAc/hexanes, 500 micron plate) provided (+)-2.74 (20 mg, 91%) as a colorless oil. [α]² _D° +36.0 (c 0.8, CHCl₃); IR (neat) 2954, 2928.2896, 2857, 1725, 1594, 1472, 1250, 1108, 1063 cm¹; ¹H NMR (500 MHz, CDCI₃) δ 6.93 (s, IH), 5.45 (d, J = 9.7 Hz, IH), 5.30 (dd, J = 22.0, 6.5 Hz, 2H), 5.27 (s, 2H), 4.82 (d, J = 9.6 Hz, IH), 4.23-4.07 (m, 3H), 4.00 (d, J= 8.7 Hz, IH), 3.88-3.78 (m, 2H), 3.75 (dd, J= 8.7, 7.9 Hz.2H), 3.58 (dd, J= 3.8, 3.8 Hz. IH), 3.37 (s, 3H), 3.34 (d, J= 11.6Hz. IH), 3.09 (d, J= 15.3 Hz, IH), 2.64 (dd, J= 16.4, 12.1 Hz, IH).2.32-2.22 (m, IH), 2.12 (s, 3H), 2.03-1.92 (m. IH). 1.87-1.77 (m, IH).1.62 (dd, J= 11.6, Il 6 Hz, IH), 1.48(ddd,J = 13.7, 8.2.8.2 Hz. IH), 1.07(d,./=67 Hz, 3H).0.97 (s.3H), 0.9-0.93 (m.6H), 0.91 (s, 9H), 0.86 (s, 3H), 0.80 (s, 9H), 0.09 (s, 3H)₅ 0.07 (s, 3H), 0.06 (s.3H), 0.01 (s, 3H), 0.00 (s, 9H), 0.00 (s, 18H); ¹³C NMR (125 MHz, CDCI?) δ 163.5, 159.8, 159.1, 157.2, 141.4, 117.2, 109.5, 102.3, 94.5,93.1, 84.4, 79.9,77.7, 77.2, 73.6, 68.9, 67.8, 66.8.66.7, 63.6.56.1, 39.9, 37.6, 32.9, 31.7, 29.9.26.8, 26.2, 26.0.18.4, 18.3, 18.3. 18.2, 17.8, 11.4, 9.1, -1.1, -1.2, -1.3, -3.3. -4.2, -A.I, -4.7; high resolution mass spectrum (ES+) m/z 1108.6233 [(M+Na)⁺; calcd for C₅₃H₁₀₂NOi₂Si₅Na: 1108.6225].

Amide (+)-2.75. A solution of acid (-)-2.57 (47 mg.4 equiv.) in CH₂Cl₂ (1.5 mL) was cooled to 0⁰C and /-Pr₂NEt (30 μL, 1.1 equiv.) was added followed by trimethylacetyl chloride (20 μL, 1.05 equiv.) After 30 min at 0⁰C, sat. NH₄CI (3 mL) was added followed by enough H₂O to dissolve any solids. The layers were separated and the aqueous layer extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were then dried over MgSO4 and concentrated. The unpurifϊed mixed anhydride was azeotroped with benzene (3 x 3 mL), placed on the vacuum pump for 30 min, and then dissolved in THF (0.4 mL). A solution of (+)-2.74 (41.5 mg. 0.038 mmol) in THF (0.4 mL) was cooled to -78 ⁰C and LiHMDS (0.152 mL, 0.5M in THF, 2.0 equiv.) was added dropwise over 1 min. The solution was stirred for 30 min at -78 ⁰C and then the solution of mixed anhydride was added dropwise over 5 min. The reaction was stirred at -78 ⁰C for 45 min, then warmed to —60 ⁰C and stirred for 30 min. Sat. NH₄CI (2 mL) was added and the reaction allowed to warm to rt. The reaction was extracted with CH₂CI₂ (4 x 5 mL). The combined organic layers were then dried over MgSO₄ and evaporated. Preparative chromatography (20% EtOAc/hexanes, 1000 micron plate) provided (+)-2.75 (41.2 mg, 79% yield) as a colorless oil. [α]² _D° +40.2 (c 0.4, CHCl₃); IR (neat) 2953, 2896, 2857, 1726, 1591 ,

1467, 1250, 1 1 10, 1063 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 6.92 (s, I H), 5.66 (d, J = 4.6 Hz, I H). 5.34-5.25 (m, 4H), 5.1 7 (d, J = 4.9 Hz, I H), 4.77 (d, J = 1 1.5 Hz, 2H), 4.63 (dd, ./ = 23.1. 6.6 Hz, 2H), 4.33-4.27 (m. 2H). 4.20 (ddd, ./ = 12.1 , 8.4. 2.0 Hz, 1 H), 4.12 (ddd, ./ = 10.0, 2.9, 2.9 Hz. I H), 3.90-3.78 (m, 2H), 3.78-3.73 (m, 2H), 3.65-3.59 (m, I H). 3.59-3.49 (m, 3H), 3.34 (s, 3H), 3.28 (s, 3H), 3.14 (d, J= 9.6 Hz, IH), 3.10 (dd, J = 16.5, 2.0 Hz, I H), 2.93 (dd, J= 16.4, 12.6 Hz, 1 H), 2.30 (dd, J = 14.7, 9.0 Hz, I H), 2.22 (d, J = 12.7 Hz, I H), 2.19 (s, 3H), 2.07-1.96 (m, 2H), 1 .81 (dd, J = 14.0, 10.3 Hz, IH), 1.75 (s, 3H), 1.69 (ddd. J = 13.2, 10.8, 6.5 Hz, I H), 1.61 (ddd, J= 13.6, 9.5, 3.2 Hz, 2H), 1.10 (d, J= 6.6 Hz, 3H), 1.10-1.04 (m, 2H), 1.00-0.93 (m, 4H), 0.90 (s, 12H), 0.87-0.80 (m, 2H), 0.83 (s, 3H), 0.78 (s, 9H), 0.05 (s, 15H), 0.04 (s, 3H), 0.01 (s, 9H), 0.00 (s, 9H), -0.02 (s, 3H), -0.05 (s, 9H); ¹³C NMR (125 MHz, CDCI₃) δ 174.9. 163.7, 159.8, 1 59.1 , 154.5, 142.9, 142.1. 1 17.5, 1 13.0, 109.5, 102.2, 95.3, 94.5, 93.1. 88.5, 81.3. 80.2, 75.7, 74.9, 73.0, 69.3, 66.8, 66.8, 66.3, 66.1 , 58.3. 56.8, 40.7, 39.2. 39.1 , 35.3, 30.5, 30.0, 28.7, 26.1, 26.0, 24.2, 23.1 , 18.3, 18.3, 18.3, 18.2, 17.8, 13.6, 1 1.4, 9.1, -1.2, -1.2, -1.3, -1.4, -3.1 , - 4.0, -4.5, -4.7.; high resolution mass spectrum (ES+) m/z 1394.7849 [(M+Na)^f ; calcd for C₆₇H₁₂₉NOi₆Si₆Na: 1394.7825].

Trciniastatin A (+)-2.1. Compound (+)-2.75 (9.8 mg, 7.1 μmol) was dissolved in DMF (0.16 mL) and TASF (30 mg, 15 equiv.) was added. The reaction was heated to 50 ⁰C. After 48 h, the reaction was diluted with EtOAc and sat. NH₄Cl (1 mL) was added followed by enough HjO (0.5 mL) to dissolve any solids. The reaction was extracted with EtOAc (4 x 2 mL). The combined organic layers were then dried over MgSO₄ and evaporated. Preparative TLC (70% EtOAc/hexanes, 500 micron plate provided (+)-2.1, irciniastatin A, (1.7 mg) along with a mono- protected compound (SEM group on one of the phenolic oxygens). The mono-protected compound was dissolved in Et₂O (0.3 mL) and MeNO? (20 μL) was added followed by MgBr₂ (13 mg, 20 equiv.). After stirring for 15 min at rt, the reaction was diluted with EtOAc (2 mL) and sat. NaHCθ₃ (1 mL) was added. The reaction was extracted with EtOAc (5 x 1 mL) and the combined organic layers were then dried over MgSO₄ and concentrated. Preparative TLC (60% EtOAc/hexanes, 500 micron plate) provided an additional 1.5 mg of the natural product to give a total of 3.2 mg (74% yield, 2 steps) of (+)-2.1 (irciniastatin A). [α]² _D° +21 .0 (c 0.1 , CHCI₃): IR (neat) 3366, 2965, 2928, 2853, 1654, 1515, 1459, 1381, 1254, 1 173. 1 107, 1067 cm^'1; ¹ H NMR (500 MHz, CD₃OD) δ 6.25 (s, IH), 5.38 (d, J = 8.2 Hz, I H), 4.74 (s, I H), 4.72 (s, I H), 4.49 (ddd. J = 12.2. 5.9, 3.1 Hz, IH), 4.35 (d. J = 2.6 Hz. I H), 3.97-3.92 (m, 2H). 3.67 (ddd, ./ = 9.3, 3.4, 2.7 Hz, 1 H), 3.59 (dd, ./ = 10.9, 4.5 Hz, 1 H), 3.50 (dd, J = 10.1 , 1.3 Hz, 1 H), 3.35 (s, 3H), 3.21 (s, 3H). 3.13 (dd, J= 16.7, 3.1 Hz, I H), 2.86 (dd, J= 16.7, 12.2 Hz, I H), 2.35 (dd, J= 14.6, 9.3 Hz, I H), 2.1 1 (dd, J = 14.1 , 3.6 Hz, 2H), 2.10 (s, 3H), 2.02 (ddd, J = 13.6, 4.3, 2.8 Hz. I H), 1.91 (ddddd, J = 6.9, 6.9, 6.9, 6.9, 2.7 Hz, I H). 1.77 (ddd, J = 13.7, 1 1.1 , 6.3 Hz. 2H), 1.72 (s, 3H), 1.68 (ddd, J = 14.5, 3.2, 1.9 Hz, 2H), 1.10 (d, J = 7.0, 3H), 0.97 (s, 3H), 0.90 (s. 3H); ¹³C NMR (125 MHz. CD₃OD) S 176.3, 172.5, 164.7, 163.8, 144.0, 141.3, 1 15.4, 1 13.1 , 101.6, 101 .5, 82.8, 82.3, 82.1, 79.9, 74.2, 73.6, 73.4, 72.2, 57.8, 56.7, 43.4, 39.9, 38.8. 34.5, 30.6, 29.6. 23.8, 23.0, 14.1 , 10.9, 9.3; high resolution mass spectrum (ES+) m/z 632.3038 [(M+Naf : calcd for C₃₁H₄₇NOnNa: 632.3047].

Alcohol S3.1. To a 0 ⁰C solution of diol 3.13 (0.50 g, 4.8 mmol) in THF (24 mL) was added 60% NaH (0.19 g, 1.0 equiv.) in three equal portions over 5 min. After 10 min, TBSCl (0.72 g, 1 equiv.) dissolved in THF (5 mL) was added dropwise. After 4 h, the reaction was quenched with MeOH (2 mL). Sat. NaHCO₃ (15 mL) was added and the reaction extracted with CH₂Cb (3 x 10 mL). The combined organic layers were then dried over MgSθ₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided S3.1 (0.93 g. 89% yield) as a colorless oil. IR (neat) 3389, 2955, 2929, 2858, 1472. 1254, 1096, 1047 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 3.46 (s, 4H). 2.86 (dd, J = 5.5, 5.5 Hz, I H), 0.90 (s, 9H). 0.88 (s, 6H), 0.06 (s, 6H); ¹³C NMR (125 MHz, CDCI₃) δ 73.0, 72.5, 36.6, 26.0. 21.7, 18.4, -5.4; high resolution mass spectrum (CI+) m/z 219.1794 L(M+H)⁺; calcd FOr C_n H₂₇O₂Si: 219.1780].

Aldehyde 3.7. To a 0 ⁰C solution of S3.1 (1.51 g, 6.91 mmol) in DMSO (4.9 mL, 10 equiv.) and CH₂Cl₂ (35 mL) was added Et₃N (2.89 mL, 3 equiv.) followed by SO₃.pyridine (3.25 g, 3 equiv.). After 1 h, brine (20 mL) and H₂O (5 mL) were added. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic layers were then dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes) provided 3.7 (1.43 g. 96% yield) as a light yellow oil. IR (neat) 2956, 2930. 2893, 2858. 1733, 1472, 1257. 1 104 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 9.55 (s, I H). 3.58 (s, 2H), 1.03 (s. 6H), 0.85 (s. 9H), 0.02 (s, 6H); ¹³C NMR (125 MHz, CDCI₃) δ 206.3, 68.6. 48.3, 26.0. 18.7, 1 8.4. -5.4; high resolution mass spectrum (CI+) m/z 215.1453 [(M-H)^": calcd for C_nH₂₃O₂Si: 21 5.1468].

Alcohol (+)-3.11. To a suspension of N-Ts-L-tryptophan (5.1 5 g. 1 .2 equiv.) in CH₂CI₂ ( 1 50 mL) was added Cl₂BPh (1.87 mL, 1 .2 equiv.) dropwise. After 2 h at rt, the mixture was concentrated in vacuo, rc-butyronitrile (50 mL) added, and the solution cooled to -78 ⁰C. A mixture of aldehyde 3.7 (2.6 g, 12.0 mmol), ketene acetal 3.12 (3.86 g, 1.5 equiv.), and isopropanol ( 1.38 mL. 1 .5 equiv) in «-butyronitrile (15 mL) was added over 2 h via syringe pump. After an additional 2 h at -78 ⁰C, the solution was warmed to 0 ⁰C over 30 min. followed by addition of sat. NaHCθ₃ (20 mL) and brine (20 mL). The resulting solution was extracted with Et₂θ (3 x 30 mL). The combined organic layers were then dried over MgSO₄ and evaporated. Flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes to 15% EtOAc/hexanes) provided (+)-3.11 (2.49 g. 66% yield) as a single enantiomer, as determined by Mosher ester analysis. [α]² _D° +27.9 (c 0.6, CHCl₃): IR (neat) 3486, 2953, 2929, 2858, 1726, 1657. 1471 , 1258, 1092 cm^'1; ¹H NMR (500 MHz. CDCl₃) δ 7.10 (ddd, ./ = 15.6. 7.2, 7.2, Hz, I H). 5.91 (ddd, ./ = 15.7, 1.5, 1.5. Hz, IH), 3.75 (d, 7 = 3.2. IH), 3.71 (s, 3H), 3.63 (ddd, J = 10.0, 2.9, 2.9 Hz, I H). 3.49 (d, J = 2.0 Hz, 2H), 2.37 (dd. J = 14.5. 6.8 Hz. I H), 2.26 (dddd, J = 14.6, 10.0, 7.5, 1.4 Hz. I H), 0.91 (s. 3H), 0.89 (s. 9H), 0.85 (s, 3H), 0.07 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 167.1. 147.9. 122.6, 78.3. 73.6, 51.6, 38.6, 35.5, 26.0, 22.6, 19.0, 18.3, -5.4, - 5.5; high resolution mass spectrum (ES+) m/z 317.2137 [(M+H)⁺; calcd for C]OH₃₃O₄Si: 317.2148].

(Λ)-Mosher Ester (+)-S3.2. A solution of (+)-3.11 (5.0 mg, 15.8 μmol) in CH₂CI₂ (0.32 mL) was cooled to 0 ⁰C and (S)-Mosher's acid chloride (8 mg, 2 equiv.) was added, followed by DMAP (8 mg, 4 equiv.) and Et₃N (4.4 μL, 2 equiv.). After 45 min, sat. NaHCO₃ (0.5 mL) was added and the reaction extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO₄ and concentrated. Preparative thin layer chromatography (500 micron prep plate, 25% EtOAc/hexanes) provided (+)-S3.2 (8 mg, 94% yield). [α]² _D° +4.3 (c 0.5. CHCl₃): IR (neat) 2953, 2929, 2857, 1728, 1660, 1471. 1254, 1 170, 1 104, 1012 crrT¹; ¹H NMR (500 MHz, CDCI₃) δ 7.54-7.33 (m, 5H), 6.87 (ddd, J = 15.1 , 8.8, 6.0 Hz, I H). 5.78 (d, J = 1 5.6 Hz, I H), 5.33 (dd, J = 9.4, 3.2 Hz, IH), 3.70 (s, 3H), 3.45 (s, 3H), 3.31 (s, 2H), 2.68-2.59 (m. I H), 2.50- 2.39 (m. IH), 0.91 (s, 3H), 0.89 (s, 9H), 0.88 (s, 3H), 0.02 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 166.5, 166.0, 145.1 , 131.9, 129.8, 128.6, 128.1 , 124.7, 123.8, 122.4, 79.0, 69.3, 55.4, 51.7, 39.8, 33.5, 26.0, 21.1 , 20.9, 18.4, -5.4, -5.5; high resolution mass spectrum (ES+) m/z 533.2556 [(M+HV ; calcd for C₂₆H₄₀F₃O₆Si: 533.2546].

(5)-Mosher Ester (-)-S3.3. A solution of (+)-3.11 (5.0 mg, 15.8 μmol) in CH₂CI₂ (0.32 mL) was cooled to 0 ⁰C and (/?)-Mosher^*s acid chloride (8 mg, 2 equiv.) was added, followed by DMAP (8 mg, 4 equiv.) and Et₃N (4.4 μL, 2 equiv.). After 45 min, sat. NaHCO₃ (0.5 mL) was added and the reaction extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO₄ and concentrated. Preparative thin layer chromatography (500 micron prep plate, 25% EtOAc/hexanes) provided (-)-S3.3 (7 mg, 94% yield). [α]∞ -4.2(c 0.5, CHCl₃); IR (neat) 2953, 2933, 2857, 1747, 1729, 1660, 1471 , 1256, 1 184. 1 104, 1015 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 7.54-7.35 (m, 5 H), 6.88 (ddd, ./ = 15.5, 8.7, 5.8 Hz, 1 H), 5.81 (ddd, J = 15.6, 1.6, 1.2 Hz. 1 H), 5.34 (dd, J = 9.3. 3.2 Hz, 1 H), 3.71 (s, 3 H), 3.51 (d, J = 1.0 Hz, 3 H), 3.29 (ddd. J = 9.9, 9.9, 9.9 Hz, 2 H), 2.66 (dddd, J = 15.4, 5.5, 3.2, 1.9 Hz, IH). 2.54-2.44 (m, I H), 0.89 (s. 9H), 0.88 (s, 3H), 0.85 (s, 3H), 0.01 (s, 6H).; ¹³C NMR (125 MHz, CDCI₃) δ 166.5, 166.0, 145.2, 132.1 , 129.8, 128.5, 127.9, 124.8, 123.8, 122.5, 79.3, 69.2, 55.5, 51.7, 39.9, 33.5, 26.0, 21.1 , 20.8, 18.4, -5.4, -5.5; high resolution mass spectrum (ES+) m/z 533.2543 [(M+H)^~; calcd for C₂₆H₄₀F₃O₆Si: 533.2546].

Bis-silyl ether (+)-3.13. To a 0 ⁰C solution of (+)-3.11 (0.226 g, 0.714 mmol) in CH₂Cl₂ (7.1 mL) was added 2,6-lutidine (0.164 mL, 2.0 equiv.) followed by dropwise addition of TBSOTf

(0.246 mL, 1.5 equiv.). After 1 h, sat. NaHCO₃ (5 mL) was added and the layers separated. The aqueous layer was extracted with CH₂CI₂ (3 x 10 mL), and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (2% EtOAc/hexanes to 5%

EtOAc/hexanes) provided (+)-3.13 (0.269 g, 96% yield) as a colorless oil. [α]*' +3.6 (c 1 .0, CHCl₃); IH (neat) 2955, 2930, 2886, 2857, 1730, 1657, 1472, 1257, 1090 cm^"1; ¹H NMR (500

MHz, CDCI₃) δ 7.12-6.92 (m, 1 H), 5.81 (ddd, J = 15.7, 1.5, 1.5 Hz, 1 H), 3.74 (dd, J = 6.4, 4.4

Hz, I H), 3.72 (s, 3H), 3.30 (dd, J = 36.2, 9.6 Hz, 2H), 2.48 (dddd, J= 15.0, 6.4, 4.4, 1 .7 Hz, I H).

2.36-2.27 (m, I H), 0.89 (s, 9H), 0.83 (s, 3H), 0.79 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 6H); ¹³C NMR (125 MHz, CDCI₃) δ 167.1 , 148.9, 122.0, 75.1 , 69.7, 51.6, 41.1 , 36.6, 26.2, 26.1 , 21.3, 20.9, 1 8.5, 18.4, -3.5. -4.1 , -5.2, -5.3; high resolution mass spectrum (ES+) m/z 431.2997 [(M+H)⁺; calcd for C₂₂H₄₇O₄Si₂: 431.3013].

Allylic alcohol (-)-S3.4. A solution of (+)-3.13 (0.217 g, 0.504 mmol) in CH₂Cl₂ (I O mL) was cooled to -78 °C and DlBAL-H (1.06 mL, 1.0 M in hexanes, 2.1 equiv.) was slowly added. After 5 min, the reaction was quenched with MeOH (0.5 mL) and allowed to warm to rt. Sat. Rochelle's salt (10 mL) and EtOAc (10 mL) were added and the solution stirred for 1 h. H₂O (10 mL) was then added to dissolve the suspended solids and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5 % EtOAc/hexanes to 10% EtOAc/hexanes) provided (-)-S3.4 (0.237 g, 99%) as a colorless oil. [α]² _D° -3.4 (c 1.0, CHCI₃); IR (neat) 3327, 2955, 2929, 2892, 2857, 1715, 1472, 1254, 1091 , 1006 cm^"1; ¹H NMR (500 MHz. CDCl₃) δ 5.82-5.57 (m, 2H), 4.09 (d, J = 5.7, 2H), 3.64 (dd, J = 6.3, 4.3 Hz, I H), 3.31 (dd, J= 28.1 , 9.5 Hz, 2H), 2.36 (ddd, J = 14.7, 4.8, 4.8 Hz, IH), 2.16 (ddd, J = 14.5, 7.1 , 7.1 Hz, I H), 0.89 (s, 21 H), 0.80 (s, 3H), 0.04 (s, 3H), 0.02 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 132.3, 130.1 , 75.9. 69.9, 64.1 , 41.2, 36.5, 26.3, 26.2, 21.4, 20.8, 18.5, 1 8.4, -3.2, -4.1 , -5.2, -5.3: high resolution mass spectrum (ES+) m/z 403.3065 [(M+H)⁺; calcd for C₂]H₄₇O₃Si₂: 403.3063].

Epoxide (+)-3.14. To freshly activated 3 A molecular sieves (0.2 g) was added (-)-DIPT (1 5 μL. 0.24 equiv.) in CH₂CI₂ (0.5 mL). The solution was cooled to -20 ⁰C and Ti(O-Z-Pr)₄ (18 μL, 0.2 equiv.) in CH₂CI₂ (0.5mL) was added followed by /-BuOOH (0.176 mL, 5 M in decane, 3.0 equiv.) The reaction was stirred for 30 min and then (-)-S3.4 (0.1 18 g, 0.293 mmol) dissolved in CH₂Cl₂ (1 ml) was added via syringe. The flask and syringe were rinsed with CH₂Cl₂ (0.4 mL) into the reaction flask. After 4 h, 10% aq. citric acid (2 mL) was added and the reaction warmed to rt. After 1 h at rt, brine (3 mL) was added, the layers were separated, and the aqueous layer extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes to 15% EtOAc/hexanes) provided (+)-3.14 (0.108 g, 88% yield) as a 13: 1 inseparable mixture of epoxides. [α]² _D° +24.3 (c 1.0. CHCI₃); IR (neat) 3430, 2955, 2929, 2895, 2857, 1472. 1254, 1091 , 1009 cm^"1; ¹H NMR (500 MHz, CDCI₃) δ 3.91 (ddd, J = 12.5, 5.4, 2.4 Hz, I H), 3.80 (dd, ./= 7.4. 3.8 Hz, I H), 3.60 (ddd, J= 12.5, 7.2, 4.4 Hz, I H), 3.31 (dd, J= 33.5, 9.6 Hz, 2H), 3.12 (ddd, J = 6.9, 4.5, 2.3 Hz, I H), 2.93 (ddd, J = 4.6, 2.4, 2.4 Hz, I H). 1.80 (dd. J = 7.1 , 5.8 Hz, I H), 1.79- 1.72 (m, I H), 1.65 (ddd, J = 14.6, 7.0. 3.8 Hz, I H), 0.90 (s. 9H), 0.89 (s, 9H). 0.83 (s, 3H), 0.79 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H). 0.01 (s, 6H); ¹³C NMR (125 MHz. CDCl₃) δ 73.7. 69.7, 61 .9, 60.1 , 54.1 , 40.7, 35 5, 26.3, 26.1 , 21.5. 20.5, 18.6, 18.5, -3.8, -4.0, -5.2, -5.3; high resolution mass spectrum (ES+) m/z 441.2846 [(M+Na)⁺; calcd for C₂]H₄₆O₄Si₂Na: 441.2833]. ^'

Ester (+)-3.15. Alcohol (+)-3.14 (0.199 g, 0.474 mmol) in CH₃CN (4.7 niL) was treated with TEMPO (6 mg, 0.08 equiv.) followed by addition of pH 7 buffer (4.7 mL). The reaction was then treated with NaCIO₂, followed by dropwise addition of NaOCI (0.1 8 mL, 5% aq. solution). After 2 h, sodium sulfite (200 mg, 3.3 equiv.) was added and the reaction stirred for 30 min. where the solution turned from a light orange color to colorless. The reaction was acidified to pH 4 with 10% aq. citric acid and extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over MgSO₄ and concentrated. The unpurified acid was dissolved in CH₂CN (2.4 mL) and MeOH (2.4 mL). The solution was cooled to 0 ⁰C and TMS-diazomethanc (0.28 mL. 2 M in Et₂O, 1.2 equiv.) was added dropwise until the solution remained yellow in color. Argon gas was bubbled through the reaction for 10 min and then the solvent evaporated. Flash chromatography (5% EtOAc/hexanes) provided (+)-3.15 (0.195 g, 91 % yield, 2 steps) as a colorless oil. [α]² _n° +15.8 (c 1.0. CHCl₃); IR (neat) 2955, 2930, 2887, 2857, 1759, 1472. 1254, 1201 , 1089, 1006 cm^"1: ¹H NMR (500 MHz, CDCl₃) δ 3.81 (dd, J = 7.4, 3.8 Hz, I H), 3.75 (s, 3H), 3.30 (ddd, J = 6.5, 4.5, 1.9 Hz, I H), 3.30 (dd, J = 30.1, 9.6 Hz, 2H), 3.22 (d, J = 1.9 Hz, I H), 1.80 (ddd, J = 14.6, 7.4, 4.5 Hz, I H), 1.67 (ddd, J = 14.7, 6.8, 3.8 Hz, I H). 0.90 (s, 9H). 0.88 (s. 9H). 0.83 (s, 3H), 0.78 (s, 3H). 0.10 (s, 3H), 0.08 (s, 3H). 0.01 (s, 6H); '³C NMR (125 MHz. CDCI₃) δ 169.9, 73.6, 69.6, 56.9, 54 6. 52.5. 40.7, 35.5, 26.3, 26.1 , 21 .3. 20 7. 18.6. 18.5, -3.8, -4.0, -5.2. -5.3: high resolution mass spectrum (ES+) m/z 469.2778 [(M+Na)' : calcd for

C₂₂H₄₆O₅Si₂Na: 469.2782].

Alcohol (+)-3.16. To bis-silyl ether (+)-3.15 (72.0 mg, 0.159 mmol) was added a HF-pyridine/pyridine/THF solution (0.64 mL, 10 equiv. HF, stock solution made up of 0.5 mL HF-pyridine, t .0 mL pyridine, and 5.0 mL THF). After stirring 20 h at rt. sat. NaHCO₃ (5 mL) was added slowly. Once all gas evolution had ceased, the reaction was extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash Chromatography (5% EtOAc/hexanes to 10% EtOAc/liexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes) provided (+)-3.16 as a single diastereomer (37.2 mg, 72% yield) as a colorless oil. [α]=° +46.8 (c 0.5, CHCI₃); IR (neat) 3465, 2955. 2930, 2857, 1 744, 1446. 1290, 1253, 1205, 1089, 1051 , 1004 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 3.80 (dd, J = 7.4, 3.8 Hz, 111), 3.77 (s, 3H), 3.59 (d, J = 10.9 Hz. I H), 3.36-3.27 (m, 2H). 3.26 (d, J = 1.7 Hz, I H), 2.37 (s, I H). 1.95 (ddd, J= 14.8, 7.4, 3.9 Hz, 1 H), 1.67 (ddd, J= 14.8, 7.3, 3.8 Hz, I H), 0.99 (s, 3H), 0.91 (s, 9H), 0.81 (s. 3H), 0.14 (s, 3H), 0.14 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.6, 76.7. 70.0, 56.6, 54.5, 52.7, 39.6, 35.6, 26.2, 23.0, 21.5, 18.4, -3.9, -4.0; high resolution mass spectrum (ES+) mlz 355.1908 [(M+Na)' : calcd for C)₆H₃₂O₅SiNa: 355.1917].

Tetrahydropyran (— )-3.17. This compound was obtained in 14% yield as a byproduct during the reaction to provide alcohol (+)-3.16. [α]² _D° -26.8 (c 1.0, CHCl₃); IR (neat) 3459. 2955. 2928. 2856, 1740, 1465. 1255, 1 144, 1088, 1065 cm^"1; ¹H NMR (500 MHz, CDCI₃) 4.29 (dd. ./ = 5.1 , 2.9 Hz. I H), 4.02 (ddd, J = 12.0. 2.5, 2.5 Hz, I H), 3.78 (s, 3H), 3.65 (d, J = 10.9 Hz. I H). 3.56 (s. I H). 3.26 (d. J = 10.9 Hz, I H), 2.93 (d, J = 5.9 Hz, I H), 2.09 (ddd. J = 14.0, 12.3. 2.3 Hz, I H), 1.21 (ddd, J = 13.8, 2.7, 2.7 Hz, I H), 0.98 (s, 3H), 0.90 (s, 9H), 0.76 (s. 3H). 0.04 (s, 3H), 0.02 (s. 3H); ¹³C NMR (125 MHz. CDCI₃) δ 172.9, 73.5, 73.4, 72.9, 72.8, 52.6, 35.2, 30.1 , 26.0, 23.6, 22.9, 18.3, -4.4, -4.7; high resolution mass spectrum (ES+) m/z 355.1907 [(M+Na)" ; calcd for C₁₆H₃₂O₅SiNa: 355.1917].

Aldehyde (+)-3.9. To a solution of (+)-3.16 (0.025 g. 0.075 mmol) in CH₂Cl₂ (0.75 mL) and DMSO (0.75 mL) at 0 ⁰C was added Et₃N (0.105 mL, 10 equiv.) followed by SO₃.pyridine (0.047 g, 4 equiv.) in one portion. After 2 h, sat. NaHCO₃ (4 mL) was added and the layers separated. The aqueous layer was extracted with CH₂Cl₂ (3 x 5 mL) and the combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (5% EtOAc/hexaπes to 10% EtOAc/hexanes to 20% EtOAc/hexanes) provided (+)-3.9 (23.5 mg, 95% yield) as a light yellow oil. [ct]∞ +22.9 (c 0.5, CHCl₃); IR (neat) 2955, 2931 , 2857. 1754, 1448, 1291 , 1254, 1205, 1093 cm^"1; ¹H NMR (500 MHz, CDCl₃) δ 9.56 (s, I H), 4.06 (dd, J= 7.9, 3.6 Hz. I H), 3.77 (s. 3H), 3.28 (ddd_; J = 7.5, 3.8, 1.9 Hz. 1 H), 3.24 (d, J= 1.9 Hz, IH). 1.90 (ddd, ./ = 14.6, 7.9. 3.8 Hz, I H). 1.54 (ddd, J = 14.7, 7.5, 3.6 Hz, I H), 1.06 (s, 3H). 1.02 (s, 3H), 0.88 (s, 9H), 0.13 (s. 3H), 0.08 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 205.8, 169.4. 73.7, 56.0, 54.4, 52.7, 51.3, 35.7, 26.1. 19.3. 18.4, 1 7.7, -3.9, -4.0; high resolution mass spectrum (ES+) m/∑ 353.1753 [(M+Na) ; calcd for C₁₆H_3OO₅SiNa: 353.1761].

Tetrahydropyran (+)-3.18. To a solution of (-)-DΪPCl (0.035 g. 1.8 equiv.) in Et₂O (0.4 mL) cooled to -78 ⁰C was added Et₃N (0.021 mL. 2.5 equiv.) followed by slow dropwise addition of 2-butanone (3.10) (0.010 mL, 1.8 equiv.). The solution immediately turned cloudy white. After stirring for 2 h at -78 ⁰C, aldehyde (+)-3.9 (0.020 g, 0.061 mmol) was dissolved in Et₂O (0.4 in L) and added dropwise to the boron enolate over 5 min via syringe. The flask and syringe were then rinsed with Et₂O (0.4 mL) and the rinse added to the reaction over 2 min. After stirring at -78 ⁰C for 5 h, the solution was warmed to -40 ⁰C over 1 h and held at -40 ⁰C. After 12 h, the reaction was warmed to 0 ⁰C and a 1 : 1 :1 mixture of MeOH/pH 7 buffer/30% aq. H₂O₂ (1 mL) was added. After 1 h, sat. Na₂S₂O₃ (4 mL) was added very slowly over 30 min to destroy any remaining peroxides. The reaction was then extracted with CH₂CI₂ (3 x 10 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography ( 10% EtOAc/hexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes) provided the aldol product (0.020 g, 86% yield) as a 5: 1 mixture of diastereomers. The aldol products were dissolved in CH₂CI: ( 1 mL) and CSA (2.3 mg, 0.2 equiv.) was added. After 2 h, sat. NaHCO₃ (2 niL) added and the reaction stirred for 5 min. The layers were separated and the aqueous layer was extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were dried over MgSC>₄ and concentrated. Flash chromatography (10% EtOAc/hexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes) provided (+)-3.18 ( 14.8 mg, 60% yield over 2 steps for the major diastereomer) and (-)-3.19 (2.9 mg, 12% yield over 2 steps for the minor diastereomer). Major diastereomer: [α]» +9.8 (c 0.5, CHCI₃); IR (neat) 2954, 2930, 2861, 1741, 1714, 1461, 1388, 1366, 1258, 1074 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 4.26 (dd, J = 6.3, 4.2 Hz, IH), 4.15 (ddd, J = 8.0, 3.8, 3.8 Hz, I H), 4.06 (dd, J= 10.0, 3.5 Hz, IH), 3.78 (s, 3H), 3.64 (dd, J = 5.0, 3.3 Hz, I H), 2.93 (d, J = 63 Hz, I H), 2.57 (dd, 7 = 15.6, 3.6 Hz, I H), 2.50-2.42 (m, 2H), 2.05 (ddd, J= 13.5, 9.3, 3.2 Hz, I H), 1.45-1.38 (m, I H), 1.40-1.36 (m, I H), 1.05 (dd, J = 7.3, 7.3 Hz, 3H), 1.00 (s, 3H), 0.92 (s, 9H), 0.85 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H); ¹³C NMR (125 MHz, CDCI₃) δ 210.8. 173.3. 77.7, 73.5, 73.4, 68.8, 52.7, 42.4, 37.5, 36.9, 29.8, 26.0, 25.8, 20.7, 18.2, 7.9, -4.4, -4.8; high resolution mass spectrum (ES+) m/∑ 425.2330 [(M+Na)⁺; calcd for C₂OH₃₈O₆SiNa: 425.2336]. Minor diastereomer: [α]² _D° -38.7 (c 0.8, CHCI₃); IR (neat) 3480, 2955, 2930, 2885, 2857, 1741 , 1719, 1255, 1096, 1060, 1008 cm^'1; ¹H NMR (500 MHz, CDCI₃) δ 4.24 (dd, J = 6.0, 3.3 Hz, I H), 4.17 (dd, J= 10.5, 2.3 Hz, I H), 4.08 (ddd. J = 12.2, 2.7, 2.7 Hz, I H), 3.75 (s, 3H), 3.55 (dd, J= 2.7. 2.7 Hz, I H), 2.79 (d, J= 6.1 Hz, I H), 2.59-2.40 (m, 3H), 2.25 (dd, J = 14.9, 2.4 Hz, I H), 2.04 (ddd, J= 14.2, 12.2, 2.4 Hz, I H), 1.22 (ddd, J= 13.4, 3.0. 3.0 Hz, I H), 1 .04 (dd, .7 = 7.3, 7.3 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 3H), 0.81 (s, 3H). 0.04 (s, 3H), 0.01 (s, 3H); ¹³C NMR ( 125 MHz, CDCI₃) δ 210.8, 172.9, 76.3, 74.9, 73.9, 73.4, 52.6, 42.8, 37.4, 37.2, 30.0, 26.0, 23.7, 19.7, 18.3, 7.8, -4.4, -4.7; high resolution mass spectrum (ES+) m/z 425.2336 [(M+Na)⁺; calcd for C₂₀H₃₈O₆SiNa: 425.2336].

Tetrahydropyran (+)-3.5. To a 0 ⁰C solution of (+)-3.l8 (14.8 mg, 0.036 mmol) in CH₂Cl₂

(0.1 8 mL) was added proton sponge (95 mg, 12.0 equiv.) followed by Me₃BOF4 (54 mg, 1 0 equiv). The reaction was then stirred at it. After 4 h, 10% aq. citric acid (2 mL) added. The layers were separated and the aqueous layer extracted CH₂Cl₂ (3 x 5 mL). The combined organic layers were washed with 10% aq. citric acid (4 mL) and then brine (4 rnL). The organic layer was then dried over MgSθ₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (+)-3.5 (14.2 mg, 92% yield) as a colorless oil. All spectral data matched that of the ketone fragment constructed during the first-generation approach, [α]²^ +16.5 (c 1.7, CHCl₃); IR (neat) 2954, 2934, 2886, 2858_., 1754, 1722, 1712, 1462, 1361 , 1255, 1 1 19, 1073 cm^'1; ¹H NMR (500 MHz, CDCl₃) 4.08 (dd, J = 1 1 :3, 6.0 Hz, I H), 3.99 (dd, ./ = 9.6, 3.0 Hz, I H), 3.90 (d, J = 6.4 Hz, I H), 3.73 (s. 3H), 3.62 (dd, J = 7.5, 3.6 Hz, I H), 3.40 (s, 3H), 2.91 (dd, J = 15.2, 9.7 Hz, I H). 2.56-2.29 (m. 3H), 1 .93 (ddd. J = 13.8, 6.1 , 3.9 Hz, I H) 1 .60 (add, J= 12.7. 9.0, 5.3 Hz, I H), 1 .03 (dd, J = 7.3, 7.3 Hz. 3H). 0.96 (s. 3H), 0.90 (s, 9H), 0.83 (s, 3H). 0.04 (s. 6H); ¹³C NMR ( 125 MHz, CDCI₃) δ 210.4, 171.7, 82.5, 77.4, 73.1 , 69.8, 58.8, 52.2, 42.6, 38.1 , 37.2, 30.3, 26.0, 25.1 , 18.2, 17.9, 7.8, -4.2, -4.8; high resolution mass spectrum (ES+) m/z 439.2491 [(M+Naf; calcd for C_2IH₄₀O₆SiNa: 439.2492].

Tetrahyd ropy ran (-)-3.19. To a solution of (+)-DΪPCl (0.042 g, 1 .8 equiv.) in Et₂O (0.5 mL) cooled to -78 ⁰C was added Et₃N (0.025 mL, 2.5 equiv.) followed by slow dropwise addition of 2-butanone (3.10) (0.017 mL, 2.6 equiv.). The solution immediately turned cloudy white. After stirring for 2 h at -78 ⁰C, aldehyde (+)-3.9 (0.024 g, 0.073 mmol) was dissolved in Et₂O (0.5 mL) and added dropwise to the boron enolate over 5 min via syringe. The flask and syringe were then rinsed with Et₂O (0.3 mL) and the rinse added to the reaction over 2 min. After stirring at -78 ⁰C for 6 h, the solution was warmed to —40 ⁰C over 1 h and held at -40 ⁰C. After 16 h, the reaction was warmed to 0 ⁰C and a 1 : 1 : 1 mixture of MeOH/pH 7 buffer/30% aq. H₂O₂ (1.5 mL) was added. After 1 h, sat. Na₂S₂O₃ (4 mL) was added very slowly over 30 min to destroy any remaining peroxides. The reaction was then extracted with CH₂CI₂ (4 x 5 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes) provided the aldol product as a 5: 1 mixture of diastereomers. The aldol products were dissolved in CH₂CI₂ (1 .5 mL) and CSA (3 mg, 0.2 equiv.) was added. After 2 h, sat. NaHCO₃ (2 mL) added and the reaction stirred for 5 min. The layers were separated and the aqueous layer was extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were dried over MgSO₄ and concentrated. Flash chromatography (10% EtOAc/hexanes to 15% EtOAc/hexanes to 20% EtOAc/hexanes) provided (-)-3.19 (23 mg, 79% yield over 2 steps). This compound was also previously synthesized as the minor diastereomer obtained during the formation of tetrahydropyran (+)-3.18. [α]_j,° -38.7 (c 0.8, CHCI₃); IR (neat) 3480, 2955. 2930, 2885, 2857, 1741 , 1719, 1255, 1096_.. 1060, 1008 cm^'1; ¹H NMR (500 MHz, CDCl₃) δ 4.24 (dd, ./ = 6.0, 3.3 Hz, 1 H), 4.17 (dd, ./ = 10.5, 2.3 Hz, 1 H), 4.08 (ddd, J = 12.2, 2.7, 2.7 Hz, I H), 3.75 (s, 3H), 3.55 (dd, J= 2.7, 2.7 Hz, I H), 2.79 (d, J= 6.1 Hz, I H), 2.59-2.40 (m, 3H), 2.25 (dd, J = 14.9, 2.4 Hz, IH), 2.04 (ddd, J = 14.2, 12.2, 2.4 Hz, I H), 1.22 (ddd. J = 13.4, 3.0, 3.0 Hz. I H), 1.04 (dd, J = 7.3, 7.3 Hz, 3H), 0.91 (s, 9H). 0.87 (s. 3H), 0.81 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 210.8, 172.9, 76.3, 74.9, 73.9, 73.4, 52.6, 42.8, 37.4, 37.2, 30.0, 26.0, 23.7, 19.7, 18.3, 7.8, -4.4, -4.7; high resolution mass spectrum (ES+) m/z 425.2336 [(M+Na)' ; calcd for C₂₀H₃₈O₆SiNa: 425.2336].

2,6-c«-Tetrahydropyran (-)-3.20. A solution of (-)-3.19 (0.014 g, 0.035 mmol) in THF (0.7 mL) was cooled to 0 °C and NaH (2 mg. 60% in mineral oil, 1.5 equiv.) was added in one portion. After 20 min, Me^SO₄ (5 μL, 1.3 equiv.) was added dropwise and the reaction allowed to warm to rt. After 1.5 h, the reaction was quenched with sat. NaHCO₃ (2 mL). The layers were separated and the aqueous layer extracted with CH₂CI₂ (4 x 3 mL). The combined organic layers were then dried over MgSθ₄ and concentrated. Flash chromatography (10% EtOAc/hexanes) provided (-)-3.20 (13 mg, 89% yield) as a colorless oil. [α]^ -63.6 (c 0.7. CHCl₃); IR (neat) 2954, 2935, 2885, 2855, 1752, 1718, 1463, 1256, 1 193, 1093, 1058 cm ¹ ; ¹H NMR (500 MHz. CDCI₃) δ 4.10 (dd, J = 10.6, 2.5 Hz. I H), 4.04 (ddd, J= 1 1.9, 4.5, 2.3 Hz, I H), 3.80 (d, J= 4.5 Hz, IH), 3.70 (s, 3H). 3.53 (dd, J = 2.7, 2.7 Hz I H), 3.40 (s, 3H), 2.60-2.38 (m, 3H). 2.23 (dd, J = 14.5, 2.5 Hz, I H), 1.96 (ddd, J= 14.1. 12.0, 2.4 Hz. I H), 1.40 (ddd, J = 13.8. 3.1 , 2.5 Hz, I H), 1 .04 (dd, J = 7.3, 7.3 Hz. 3H). 0.90 (s, 9H), 0.89 (s, 3H). 0.80 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H): ¹³C NMR ( 125 MHz, CDCl₃) δ 21 1.1 , 171.3, 83.7, 76.7, 74.9, 73.4, 59.1 , 52.0, 43.0, 37.5, 37.0, 30.9, 26.1 , 23.8, 19.8, 18.3, 7.8, -4.3, -4.7; high resolution mass spectrum (ES+) m/z 439.2480 [(M+Na)⁺; calcd for C₂]H₄₀O₆SiNa: 439.2492]. As those skilled in the art will appreciate, numerous modifications and variations of the present invention are possible in light of these teachings, and all such are contemplated hereby. In particular, it is understood that numerous modifications to both the overall synthetic schemes and to the eventual target molecules and intermediates will fall within the skill of the routineer. In particular, it is within the present invention to provide homologs and analogs of (+) irciniastatin A and (-) irciniastatin B, as well as the molecules themselves. It is therefore understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein, and the scope of the invention is intended to encompass all such variations.

Claims

What is Claimed:

1. A method for preparing an irciniastatin comprising: subjecting a compound of formula I

to reaction conditions sufficient to provide a compound of formula II

wherein

R₂ is a Ci_6 alkyl group;

R_N is an amine protecting group;

R₃ is at least one Cue alkyl, substituted alkyl, halogen, -OH, -OR¹, or carbonyl; wherein R¹ is a hydroxyl protecting group; and R₄ is at least one

alkyl, substituted alkyl, halogen, -OH, or OR; wherein R is a phenolic protecting group; and wherein R is a protecting group that is orthogonal to R¹; and converting the compound of formula II to the irciniastatin.

2. The method of claim 1 , wherein the reaction conditions sufficient to provide the compound of formula II comprise: heating the compound of formula I in an organic solvent for a time sufficient to generate an isocyante of formula III

and treating the isocyanate of formula III with an alcohol that is 9-fluorenylmethanol, 2,2,2- trichloroethanol, 2-trimethylsilylethanol, t-butanol, allyl alcohol, benzyl alcohol, m- nitrophenyl alcohol, or p-methoxyphenyl alcohol to produce the compound of formula II.

3. The method of claim 2, wherein the alcohol is trimethylsilylethanol.

4. The method of any of the preceding claims, wherein the solvent is toluene, benzene, or xylene.

5. The method of any of the preceding claims, wherein the compound of formula I is

6. The method of any of the preceding claims, wherein the compound of formula I is

7. The method of any of the preceding claims, wherein the compound of formula I is prepared by reacting a compound of formula VI:

with a compound of formula V

under conditions sufficient to produce a compound of formula VII

wherein each R₂ is independently C_halky!; and converting the compound of formula VII into the compound of formula I.

8. The method of claim 7, wherein the compound of formula VI is

9. The method of claim 7, wherein the compound of formula VI is

10. The method of claim 8, wherein the compound of formula V is

11. The method of claim 8, wherein the compound of formula VII is

12. The method of any of the preceding claims, wherein R₁ is a trialkylsilyl group.

13. The method of any of the preceding claims, wherein R₁ is a t-butyldimethylsilyl group.

14. The method of any of the preceding claims, wherein R is 2-(trialkylsilyl) ethoxymethyl.

15. The method of any of the preceding claims, wherein R is 2-(trimethylsilyl) ethoxymethyl.

16. The method of any of the preceding claims, wherein R is benzyl.

17. The method of any of the preceding claims, wherein the irciniastatin is irciniastatin A.

18. The method of any of the preceding claims, wherein the irciniastatin is irciniastatin B.

19. A compound of formula XIII

wherein

R_1O is Ci_₆ alkyl group substituted with at least one OR₁₂ or carbonyl, each R₁₁ is independently Cue alkyl, and

Ro and R₁₂ are orthogonal protecting groups.

20. The compound of claim 19, wherein the compound of formula XIII is

1