WO2025083208A1

WO2025083208A1 - Synthesis of morpholine derivatives and compounds therefore

Info

Publication number: WO2025083208A1
Application number: PCT/EP2024/079499
Authority: WO
Inventors: Martin BUESCHLEB; Florent Beaufils; John Proudfoot
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2023-10-19
Filing date: 2024-10-18
Publication date: 2025-04-24
Anticipated expiration: 2026-04-19

Abstract

The present invention relates to a synthesis method for morpholine derivatives, including a ring-formation out of a 1,2-amino alcohol and a compound of formula (I) whereby LG is a nucleophilic leaving group and R₁ to R₇ are as herein defined.

Description

Synthesis of morpholine derivatives and compounds therefore

Field of the invention

The present application relates to the synthesis of morpholine derivatives, especially of anthracycline derivatives containing such morpholine derivatives as well as compounds that are useful in these synthesis procedures.

Background

Morpholine derivatives are widely present in natural compounds as well as in certain fungicides.

Especially important are Anthracy clines. Anthracyclines are among the most effective anticancer treatments ever developed and are considered to be effective against more types of cancer than any other class of chemotherapeutic agents. Although some anthracyclines may be obtainable from bacteria, especially the Streptomyces bacterium, there is a constant need for new synthesis methods for anthracycline derivatives.

Certain anthracyclines such as PNU-159682 comprise a morpholine ring. Such morpholinyl anthracyclines are useful in the preparation of antibody-drug conjugates (ADCs) which find application in cancer treatment (see WO 2016/102679).

PNU-159682

It is hence one object of the present invention to provide a new and potentially improved synthesis method of morpholines, especially methods that could lead to new synthesis routes to morpholinyl anthracycline derivatives. These and further objects are met with methods and means according to the independent claims of the present invention. The dependent claims are related to specific embodiments.

Summary of the Invention

The present invention provides a method of preparing a morpholine derivative, comprising contacting a 1,2-amino alcohol and a compound of formula (I) or a salt or solvate thereof in the presence of a base:

whereby LG is a nucleophilic leaving group, Ri is selected from the group consisting of hydrogen, C1-4 alkyl, and C 1-4 halogenalkyl, and R2 to R7 are independently from each other hydrogen or -X_m-Y-Z_n-R*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, - CR*2-, -O-, -S-, -NR*-, -N(C₂H₄)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and -CR*=CR*- in a way that no O and/or S atoms are directly bound to each other, wherein each R* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy.

Surprisingly it has been found that by doing so morpholine derivatives can be synthesized easily and in a straightforward matter. Generic group definition: Throughout the description and claims generic groups have been used, for example alkyl, alkoxy, aryl. Unless otherwise specified the following are preferred groups that may be applied to generic groups found within compounds disclosed herein: alkyl: linear and branched Ci-8-alkyl, preferably "Ci-_n-alkyl", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term Ci-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H₃C-CH(CH₃)-, H3C-CH2-CH2-CH2-, H₃C-CH2-CH(CH₃)-, H₃C-CH(CH₃)-CH2-, H₃C-C(CH₃)2-, H3C-CH2-CH2-CH2-CH2-, H₃C-CH2-CH2-CH(CH₃)-, H₃C-CH2-CH(CH₃)-CH2-, H₃C-CH(CH₃)-CH2-CH2-, H₃C-CH2-C(CH₃)2-, H₃C-C(CH₃)2-CH2-, H₃C-CH(CH3)-CH(CH₃)- and H₃C-CH2-CH(CH2CH₃)-. alkenyl: C2-6-alkenyl, preferably "C2-m-alkyl", wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a double bond. For example the term C2-6-alkenyl includes ethenyl (vinyl), propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl and hexadienyl. The generic terms propenyl, butenyl, pentenyl, hexenyl, etc. without any further definition include all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop- 1-enyl and prop-2-enyl (allyl), butenyl includes but-l-enyl, but-2-enyl, but-3-enyl, 1 methyl- prop-l-enyl, l-methyl-prop-2-enyl etc. cycloalkyl: C3-8-cycloalkyl, preferably "Cs-k-cycloalkyl", wherein k is an integer selected from 3, 4, 5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to k C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. alkoxy: Ci-6-alkoxy, preferably "alkoxy" defines an alkyl, wherein one or more -CH2- groups are replaced by an oxygen atom. Examples include: H3CO-, H3COCH2-, H3COCH2CH2O-. halogen: selected from the group consisting of: F; Cl; Br and I, The term "halogenalkyl" defines an alkyl, wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H2FC-, HF2C-, F3C-, EEBrC- and BrEEC-CEE-. Preferably the halogenalkyl is selected from the group consisting of mono, di, tri-, poly and perhalogenated linear and branched Ci-8-alkyl.

The term "halogenalkoxy" defines an alkoxy, wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Preferably halogenalkoxy is selected from the group consisting of mono, di, tri-, poly and perhalogenated linear and branched Ci- 8-alkoxy. Examples include: F3CO-, F3CCH2CH2O-, H2FCCH2O- and H2CICCH2O-.

The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which is optionally further fused to a second five- or six-membered, carbocyclic group which is aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term "heterocyclic ring" or "heterocyclyl" means a saturated, unsaturated or aromatic mono- or polycyclic ring system, containing one or more heteroatoms selected from N, O, S, SO or SO2. The term "heterocyclic ring" or "heterocyclyl" is intended to include all the possible isomeric forms.

Thus, the term "heterocyclic ring" or "heterocyclyl" includes the following exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained):

The term "heteroaromatic ring" or "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromatic ring, containing one or more heteroatoms selected from N, O, S, SO or SO2. The term "heteroaromatic ring" or "heteroaryl" is intended to include all the possible isomeric forms.

Thus, the term "heteroaromatic ring" or "heteroaryl" includes the following exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained):

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. Unless otherwise specified the following are more preferred group restrictions that may be applied to groups found within compounds disclosed herein: alkyl: linear and branched Ci-6-alkyl, more preferred methyl, ethyl, propyl, isopropyl, butyl, isobutyl alkenyl: Cs-6-alkenyl, cycloalkyl: Ce-8-cycloalkyl, alkoxy: Ci-4-alkoxy, preferred methoxy and ethoxy,

It should be noted that throughout the application the terms “LG” or “R_x” shall always refer to the same moiety, unless otherwise noted.

The term “leaving group” especially means a molecular fragment of a formula that can depart from the formula by cleaving a bond between the fragment and the rest of the formula.

The term “nucleophilic” especially means and/or includes that the leaving group (after it is no longer bound to the rest of the formula) contains a free electron pair and is thus a Lewis-base.

Preferred nucleophilic leaving groups include hydroxyl, halogens, pseudohalogens, organic and inorganic ethers and esters, with tritiates, tosylates, nosylates and mesylates especially preferred. Especially preferred nucleophilic leaving groups are hydroxyl, halogens, tosylates and nosylates, most preferred bromides and tosylates.

The term “substituted” especially means in the context of the present invention that the molecular fragment referred to may have at least one residue that is not hydrogen or deuterium, wherein the residue in particular is a residue that is selected from the group consisting of halogen, -OH, Ci-6 alkyl, Ci-6 halogenalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy. The term “unsubstituted” especially means in the context of the present invention that the molecular fragment referred to may have no residues other than hydrogen or deuterium, except for the residues already mentioned to be bound to the fragment. The term “morpholine derivative” especially means any compound that comprises a morpholine ring, wherein the morpholine ring may be comprised in the compound in any way, for example as an appended substituent or as part of a polycyclic ring system. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc…) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as solvates thereof such as for instance hydrates. According to a preferred embodiment of the present invention, any of R2 to R7, when selected from -X_m-Y-Z_n-R^*, may be an alkyl, and preferably selected from linear or branched C1-6-alkyl, more preferably C1-5-alkyl, more preferably H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H₃C-C(CH₃)₂-, H₃C-CH₂-CH₂-CH₂-CH₂-, H₃C-CH₂-CH₂-CH(CH₃)-, H₃C-CH₂-CH(CH₃)-CH₂-, H₃C-CH(CH₃)-CH₂-CH₂-, H₃C-CH₂-C(CH₃)₂-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. According to a preferred embodiment of the present invention, any of R₂ to R₇, when selected from -Xm-Y-Zn-R^*, may be a halogenalkyl, and preferably selected from linear or branched C1-6-alkyl wherein one or more hydrogen atoms are replaced by a halogen atom, preferably selected from among fluorine, chlorine or bromine. More preferably the halogenalkyl is selected from halogenated C1-5-alkyl. Particularly preferred, the halogenalkyl is H2FC-, HF2C-, F3C-, H2BrC- or BrH2C-CH2-. According to a preferred embodiment of the present invention, any of R₂ to R₇, when selected from -Xm-Y-Zn-R^*, may be an alkoxy, and preferably selected from Cl-4-alkoxy, preferred methoxy, ethoxy, H3COCH2- and H3COCH2CH2O-. According to a preferred embodiment of the present invention, any of R₂ to R₇, when selected from -Xm-Y-Zn-R^*, may be a halogenalkoxy, and preferably selected from Cl-4-alkoxy wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine. More preferably, the halogenalkoxy is selected from the group consisting of: F3CO-, F3CCH2CH2O-, H2FCCH2O- and H2ClCCH2O-. According to a preferred embodiment of the present invention, any of R₂ to R₇, when selected from -Xm-Y-Zn-R^*, may be a cycloalkyl, and preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. According to a preferred embodiment of the present invention, any of R₂ to R₇, when selected from -Xm-Y-Zn-R^*, may be an alkenyl, and preferably selected from ethenyl (vinyl), propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl and hexadienyl. According to a preferred embodiment of the present invention, any of R2 to R7, when selected from -Xm-Y-Zn-R^*, have a Y selected from a five-membered heterocyclic ring, wherein the heterocyclic ring preferably comprises 1, 2, or 3 heteroatoms. Preferably, Y is a substituted or unsubstituted 5-membered heteroaromatic ring. According to one preferred embodiment, the heterocyclic ring comprises only O and/or N as heteroatoms. Preferably, the heteroaryl ring comprises only O and/or N as heteroatoms. According to one preferred embodiment, the heterocyclic ring is selected from pyrazole, 1,2,3-triazole, and furan, each of which is optionally substituted with a C1-6-alkyl. According to a preferred embodiment of the present invention, R₂ to R₇, when selected from - Xm-Y-Zn-R^*, may be independently from each other selected from the group consisting of alkoxy and halogenalkoxy, more preferably selected from the group consisting of methyloxy, chloroethoxy and fluoroethyloxy; -OEtOMe, -OEtCF₃, -OEtSMe, -OEtNHAlloc, - OEtCO2allyl,

, wherein * denotes the binding position. Preferably, the “alkyl” substituent on the 1,2,3-triazole in the above formula is a linear or branched C_1-6 alkyl, in particular a linear or branched C_1-3 alkyl. According to a preferred embodiment of the present invention, in the compound of formula (I) at least one of R₂ to R₇ is not hydrogen. According to a preferred embodiment of the present invention each R^* is independently selected from H or C_1-4 alkyl. According to an alternatively preferred embodiment of the present invention each R^* is independently selected from H or halogen. According to an alternatively preferred embodiment of the present invention each R^* is hydrogen. According to a preferred embodiment of the present invention, R₁ is hydrogen. According to a preferred embodiment of the invention, if at least one of R2 and R3 is not hydrogen, the corresponding R₂ and/or R₃ is selected in a way that it is bound to the main molecule via an oxygen atom. According to a preferred embodiment of the invention, R₂ and R₃ are each independently hydrogen or -O-[CH₂]_q-R₁₄, wherein: q is an integer selected from 1, 2 and 3, R₁₄ is selected from the group consisting of: hydrogen, halogen, C_1-3alkyl, C_1-3halogenalkyl, C_1-3alkoxy, C_1-3thioalkyl, C_1-3aminoalkyl, -N(R_14a)₂, -C(O)R_14b, -C(O)OR_14b, -OC(O)R_14b and a five-membered heterocyclic ring optionally substituted by one or more R14c, R_14a is at each occurrence independently selected from the group consisting of: hydrogen and -COOR14b, R14b is at each occurrence independently selected from the group consisting of: C1-4alkyl and C_2-4alkenyl, R14c is selected from the group consisting of: C1-3alkyl, C2-3alkenyl, C3-4cycloalkyl, C1- 3halogenalkyl, C1-3alkoxy and C1-3halogenalkoxy. Preferably, one of R2 and R3 is -O-[CH2]q-R14, wherein q and R14 are as defined above. According to a preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof has a chiral or stereogenic center. Especially preferred is that the stereogenic center is in α-position to the carbonyl group, i.e. that R2 and R3 are not identical. It should be noted that the inventive method especially is of use in case the compound of formula (I), salt or solvate thereof, is chiral or has a stereogenic center. In this case in many applications the formation of only one isomer is observed or one isomer is formed in great excess. Preferably, one of R2 and R3 is not hydrogen. According to a preferred embodiment of the present invention, one of R₂ and R₃ is hydrogen and the other one is selected from -X_m-Y-Z_n-R^* wherein each -X- and each -Z- is independently selected from -Y, -CR^*2-, -O-, -S-, -NR*-, -N(C2H4)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, or -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C_1-6 halogenalkoxy. Preferably, one of R2 and R3 is C1-6alkoxy, in particular C1-3alkoxy. Especially preferred is that one of R2 and R3 is -O-C1-6alkyl, in particular -O-C1-3alkyl. In a preferred embodiment, one of R₂ and R Preferably, one of R2 and R3 is hydrogen and the other one is C1-6alkoxy, in particular C1-3 alkoxy. Especially preferred is that one of R2 and R3 is hydrogen and the other one is -O-C1-6 alkyl, in particular -O-C_1-3 alkyl, in particular -O-CH₃. According to a preferred embodiment of the invention, one of R2 and R3 is not hydrogen and the other is hydrogen. According to a preferred embodiment of the invention, one of R4 and R5 is not hydrogen and the other is hydrogen. According to an alternative preferred embodiment, R₄ and R₅ are each independently selected from the group consisting of: hydrogen, C_1-3alkyl, C_1-3alkoxy and C_1- 3halogenalkyl. According to an alternative preferred embodiment, both of R4 and R5 are hydrogen. According to an alternative preferred embodiment, one of R4 or R5 is hydrogen and the other is C_1-3alkyl, C_1-3alkoxy or C_1-3halogenalkyl. According to a preferred embodiment of the invention, only one of R6 and R7 is not hydrogen and the other is hydrogen, according to an alternative preferred embodiment, both of R₆ and R7 are hydrogen. According to a preferred embodiment of the invention, R₁, R₆ and R₇ are hydrogen. According to a preferred embodiment of the invention, R1, R3, R5, R6 and R7 are hydrogen. According to a preferred embodiment of the invention, R₁, R₃, R₅, R₆, and R₇ are hydrogen and R2 and R4 are selected from -Xm-Y-Zn-R^* wherein each -X- and each -Z- is independently selected from

or -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy. According to a preferred embodiment of the invention, R₁, R₃, R₅, R₆, and R₇ are hydrogen and R2 is selected from -Xm-Y-Zn-R^* wherein each -X- and each -Z- is independently selected from -Y-, -CR^*2-, -O-, -S-, -NR*-, -N(C2H4)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, or - CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C_1-6 halogenalkyl, C_3-4 cycloalkyl, C_2-6 alkenyl, C_1-6 alkoxy, and C_1-6 halogenalkoxy; and R₄ is selected from the group consisting of alkyl, halogenalkyl, cycloalkyl, alkenyl, alkoxy, and halogenalkoxy. According to a preferred embodiment of the invention, R₁, R₄, R₅, R₆ and R₇ are hydrogen. According to a preferred embodiment of the invention, R1, R3, R4, R5, R6 and R7 are hydrogen. According to a preferred embodiment of the invention, R1, R3, R4, R5, R6 and R7 are hydrogen and R₂ is selected from -X_m-Y-Z_n-R^* wherein each -X- and each -Z- is independently selected from -Y-, -CR^* ₂-, -O-, -S-, -NR*-, -N(C₂H₄)₂N-, -CO-, -COO-, -OCO- , -NH(CO)O-, or -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N₃, and C_1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy. According to a preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof has the following formula (Ia):

with LG and R₂ as defined above. In formula (Ia), R₂ is preferably not hydrogen. According to a preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof has the following formula (Ib):

with LG and R2 as defined above. In formula (Ib), R2 is preferably not hydrogen. According to a preferred embodiment of the present invention, LG is selected from the group consisting of: hydroxyl, halogen, tosylate and nosylate. According to a preferred embodiment of the present invention, LG is bromine or tosylate. According to a preferred embodiment of the present invention, R2 is -OCH3. According to a preferred embodiment of the present invention, LG is bromine or tosylate, and R2 is -OCH3. According to a preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of the following formulae:

,

wherein R’ is selected from the group consisting of -OEtCF₃, -OEtSMe, - OEtNHAlloc, -OEtCO2allyl, chloroethoxy, fluoroethoxy,

, wherein * denotes the binding position. Preferably, the “alkyl” substituent on the 1,2,3-triazole in the above formula is a linear or branched C_1-6 alkyl, in particular a linear or branched C_1-3 alkyl. According to a preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of the following formulae:

,

wherein R’ is selected from the group consisting of -OEtCF₃, -OEtSMe, - OEtNHAlloc, -OEtCO₂allyl, chloroethoxy, fluoroethoxy,

, wherein * denotes the binding position. According to a preferred embodiment of the invention, the compound of formula (I) is:

. According to one preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof, is provided in a mixture with a compound of formula (I*), salt or solvate thereof

whereby LG is a nucleophilic leaving group, R₁ is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 halogenalkyl, and R2 to R7 are independently from each other hydrogen or -X_m-Y-Z_n-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, - CR^*2-, -O-, -S-, -NR*-, -N(C2H4)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N₃, and C_1-4 alkyl, and wherein a maximum of one of all X and Z is selected from Y wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five- membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C_3-4 cycloalkyl, C_2-6 alkenyl, C_1-6 alkoxy, and C_1-6 halogenalkoxy, wherein at least one of R2 to R7 is not hydrogen. It is to be understood that all definitions of LG and R₁ to R₇ and preferred embodiments illustrated above for formula (I) when referring to the method according to the present invention are equally applicable to the compound of formula (I*). According to a preferred embodiment of the present invention, the compound of formula (I) may be provided in a mixture with a compound of formula (I*), wherein all of LG and R1 to R7 are selected the same between the compound of formula (I) and formula (I*). According to a preferred embodiment of the present invention the compound of formula (I) and formula (I*) are regio-isomers. It has been surprisingly found that the method according to the present invention may be performed using a compound of formula (I) in the presence of a compound of formula (I*), while still obtaining the desired morpholine derivative. Particularly, it has been found that the morpholine derivative may be obtained in acceptable purity and even without obtaining the other plausible regio-isomer based on the compound of formula (I*). This may be particularly useful in cases where it is difficult to obtain a compound of formula (I) that is free from the corresponding regio-isomer according to formula (I*). In case the compound of formula (I) is provided in a mixture with the compound of formula (I*) the mixture may contain the compounds in a molar ratio of compound of formula (I) to compound of formula (I*) in the range of ≥ 1:10 to ≤ 10:1, preferably ≥ 1:5 to ≤ 5:1, more preferably ≥ 1:4 to ≤ 4:1, more preferably ≥ 1:3 to ≤ 3:1, more preferably ≥ 1:2 to ≤ 2:1, for example 1:1. According to a preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof has the following formula (Ia):

wherein the compound of formula (Ia) is provided in a mixture with a compound of formula (Ia*), salt or solvate thereof

with LG and R₂ as defined above. In formula (Ia) and (Ia*), R₂ is preferably not hydrogen. According to a preferred embodiment of the present invention, the compound of formula (I), salt or solvate thereof has the following formula (Ib):

(Ib*), with LG and R₂ as defined above. In formula (Ib) and (Ib*), R₂ is preferably not hydrogen. According to a preferred embodiment of the invention, the compound of formula (I), salt or solvate thereof, is provided in a mixture with a compound of formula (I*), salt or solvate thereof wherein the compound of formula (I) is

and the compound of formula (I*) is

_{whereby the “}

_{” in this context means and/or includes an optional bond to any further} moiety within the 1,2-amino alcohol molecule, which may or may not be present. The 1,2- amino alcohol can be employed as a free base, as a salt and/or as a solvate. Preferably the ratio (mole:mole) of the compound of formula (I), or salt or solvate thereof, to the 1,2-amino alcohol is ≥ 0.5:1 and ≤5:1, preferably ≥ 0.7:1 and ≤3:1, more preferred ≥ 1:1 and ≤2:1, most preferred ≥ 1.1:1 and ≤1.5:1. Preferably the ratio (mole:mole) of the compound of formula (I), or salt or solvate thereof, to the 1,2-amino alcohol is of approximately 1:1 or of approximately 1.5:1. According to a preferred embodiment, the method is carried out at a temperature of -78 °C to +60 °C. Preferably the method is carried out at room temperature, in particular at a temperature of approximately +22 °C, ± 5 °C. Preferred bases include trialkylamines, especially N,N-diisopropylethylamine (DIPEA) or Triethylamine, 4-Dimethylaminopyridine (DMAP), 2,6-lutidine, 1,4- Diazabicyclo[2.2.2]octane (DABCO), 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), pyridine or mixtures thereof. Preferably, the base is selected from trialkylamines, especially N,N- diisopropylethylamine (DIPEA) or Triethylamine, Dimethylaminopyridine (DMAP) or mixtures thereof. Preferably, the base is DIPEA. Preferably the ratio (mole:mole) of the base to the 1,2-amino alcohol is ≥ 1:1 and ≤10:1, preferably ≥ 1.5:1 and ≤6:1, more preferred ≥ 2:1 and ≤3:1. Preferably the ratio (mole:mole) of the base to the 1,2-amino alcohol is of approximately 2.5:1. According to one embodiment of the present invention, the method can be carried out without an additional solvent, whereby it is especially preferred that the base is a liquid. However according to a preferred embodiment, the method is preferably carried out in the presence of a solvent, with dipolar aprotic solvents being especially preferred. Preferred solvents include amine-based solvents, such as DMF or dimethylacetamide, dimethyl sulfoxide (DMSO), nitrile-based solvents, especially acetonitrile, benzonitrile, propionitrile, ether-based solvents, especially glyme, diglyme, triglyme, MeTHF, Et₂O, methyl tert-butyl ether (MTBE), THF, dioxane, NMP, DCM, toluene or mixtures thereof. Preferred solvents include: N,N-dimethylformamide (DMF), dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile (MeCN) and mixtures thereof with DMF being most preferred. According to a preferred embodiment, the method is carried out in N,N-dimethylformamide (DMF) and the base is N,N-diisopropylethylamine (DIPEA). According to a preferred embodiment the 1,2-amino alcohol is part of a five- or six- membered ring. In the course of the reaction then a tricyclic structure is formed. The method according to the invention is preferably carried out under an inert atmosphere, in particular of nitrogen. According to a preferred embodiment, the 1,2-amino alcohol has the following formula (IIa) or is a salt or solvate thereof:

whereby R8 is selected from the group consisting of: a) -C(O)-[CH2]w-OR9 with w= 0 or 1, R9 being Hydrogen, silyl or linear or branched C1- 6 alkyl, preferably methyl; b) hydroxy, C1-6 alkoxy or substituted or unsubstituted amine; c) – V – L1 – L2 – L3 – W, whereby V and W are optional linkers, L1 to L3 are linkers, where at least two of L₁ to L₃ are mandatory; d) -C≡ CH or -C≡ CSiMe₃; and e) –C(O)-NH-[CH2]v-L2, –C(O)-NH-[CH₂]_v-L₂ – L₃ – W, –C(O)-[CH₂]_v-NH-L₂, –C(O)-[CH₂]_v-NH-L₂ – L₃ – W, –C(O)-NH-[CH2]v-NH-L2, and –C(O)-NH-[CH2]v-NH-L2 – L3 – W, with v=2 to 4. According to a preferred embodiment, the 1,2-amino alcohol has the following formula (IIb) or is a salt or solvate thereof:

whereby R₈ is selected from the group consisting of: a) -C(O)-[CH₂]_w-OR₉ with w= 0 or 1, R₉ being Hydrogen, silyl or linear or branched C₁- 6 alkyl, preferably methyl; b) hydroxy, C1-6 alkoxy or substituted or unsubstituted amine; c) – V – L₁ – L₂ – L₃ – W, whereby V and W are optional linkers, L₁ to L₃ are linkers, where at least two of L1 to L3 are mandatory; d) -C≡ CH or -C≡ CSiMe3; and e) –C(O)-NH-[CH₂]_v-L₂, –C(O)-NH-[CH₂]_v-L₂ – L₃ – W, –C(O)-[CH2]v-NH-L2, –C(O)-[CH2]v-NH-L2 – L3 – W, –C(O)-NH-[CH₂]_v-NH-L₂, and –C(O)-NH-[CH₂]_v-NH-L₂ – L₃ – W, with v=2 to 4. According to a preferred embodiment, R₈ is selected from the group consisting of: -C(O)- [CH2]w-OH, – V – L1 – L2 – L3 – W, –C(O)-NH-[CH2]v-L2, –C(O)-NH-[CH2]v-L2 – L3 – W, –C(O)-[CH₂]_v-NH-L₂, –C(O)-[CH₂]_v-NH-L₂ – L₃ – W, –C(O)-NH-[CH₂]_v-NH-L₂ and – C(O)-NH-[CH₂]_v-NH-L₂ – L₃ – W, wherein: w is 0 or 1, preferably w is 1, V and W are optional linkers, L1 to L3 are linkers, where at least two of L1 to L3 are mandatory, preferably V, W, and L₁ to L₃ are as defined hereinbelow, v is 2 to 4, preferably v is 2. The 1,2-amino alcohol of formula (IIa) or (IIb) can also be referred to as an anthracycline derivative. The term “linker structure” as used herein below refers in particular to the R₈ groups which comprise V, L1, L2, L3 and W. The optional linker V can be any chemical linker structure known in the prior art, that has been used in ADCs to allow specific release of the toxin upon internalization into cancer cells (see e.g. McCombs / Owen, The AAPS Journal, Vol. 17, No. 2, March 2015, 339 -351) Some examples for such linkers described in the prior art, which are only provided by way of example and not intended to be limiting, are shown below:

The optional linker W can be any chain of amino acids with up to 20 amino acids allowing optimal conjugation of a binding protein to the unitary chain of linkers V, L₁, L₂, L₃ or variations thereof, in particular to L3. Furthermore, when present in formula (IIa) or (IIb), linker structures are provided, that allow site-specific conjugation of the morpholine-derivatives to suitable binding proteins, e.g, and preferably to antibodies, to obtain a binding protein drug conjugate (BPDC), preferably an ADC. The derivatives obtained according to the method of the invention can thus be used to produce site-specifically conjugated, homogeneous BPDCs, which can be used in therapeutic applications, like anti cancer therapy. The binding protein, which can bind to and direct the BPDC to a specific target molecule, can be selected, for example, from the group consisting of an antibody, modified antibody format, antibody derivative or fragment, antibody-based binding protein, oligopeptide binder and/or an antibody mimetic, as defined in WO2016/102679. Said specific target molecule of the binding protein of a BPDC can be selected, for example, from the group consisting of a receptor, an antigen, a growth factor, a cytokine, and/or a hormone. According to a preferred embodiment, when the 1,2-amino alcohol is of formula (IIa) or (IIb) and it comprises L1, the linker structure comprises, as L1, an alkylenediamino linker -NH- (CH₂)_r-NH-, r ≥ 1 and ≤ 11, preferably r=2, which is conjugated to the anthracycline derivative by means of a first amide bond and conjugated to the carboxy-terminus of the oligo-glycine peptide by means of a second amide bond. According to another preferred embodiment, when the 1,2-amino alcohol is of formula (IIa) or (IIb) and it comprises L1, the linker structure comprises, as L1, an alkyleneamine linker - (CH2)s-NH-, s ≥ 1 and ≤ 11, preferably s=2, that is conjugated to the carboxy-terminus of the oligo-glycine peptide by means of an amide bond. According to another preferred embodiment, when the 1,2-amino alcohol is of formula (IIa) or (IIb) and it comprises L₂, the linker structure comprises, as L_2, an oligo-glycine peptide (Gly)_l coupled to said anthracycline derivative, directly or by means of another linker L₁, in such a way that the oligo-glycine (Gly)l peptide has a free amino terminus, and wherein l is an integer between ≥ 1 and ≤ 21. In each case the oligo-glycine peptide (Gly)l (also called Glyl-stretch herein) is an oligo-glycine peptide-stretch. In one particularly preferred embodiment, l is an integer between ≥ 2 and ≤ 10, preferably ≥ 2 and ≤ 6. Most preferred, l = 2, 3 or 5. According to another preferred embodiment, when the 1,2-amino alcohol is of formula (IIa) or (IIb) and it comprises L₃, the linker structure L₃ comprises a peptide motif that results from specific cleavage of a sortase enzyme recognition motif. The sortase enzyme recognition motifs can be conjugated to the (Gly)l linker that is conjugated to the anthrac ogy disclosed in WO2014140317. During the conjugation process, one glycine residue from the (Gly)_l linker is released. Said sortase enzyme recognition motif preferably comprises one of the following amino acid sequences (shown in N-terminus to C-terminus direction): LPXTG, LPXSG, and/or LAXTG. It is noteworthy to mention that, while these three peptide stretches are shown above in the classical N-terminus -> C-terminus direction, that the L residue is the one that is fused to the C-terminus of the binding protein, or to the C-terminus of linker W, by means of a peptide bond. The 5th amino acid residue (G of L3) is removed upon conjugation to the (Gly)l peptide, while the 4th T or S amino acid residue of L₃ is the one that is actually conjugated to the N- terminus of the (Gly)_l peptide. The following table thus gives an overview of preferred embodiments of the L1 - L3, which may be present in the compound of formula (IIa) or (IIb):

As discussed, it is noteworthy that, once integrated in the linker structure and conjugated to L₂, L₃ lacks the 5th amino acid residue (C-terminal G). In the table above, said C-terminal G is thus shown in parentheses. According to a preferred embodiment, the 1,2-amino alcohol is doxorubicin or a stereoisomer, salt or solvate thereof. Preferably the 1,2-amino alcohol is doxorubicin or doxorubicin hydrochloride. According to a preferred embodiment, the method relates to the synthesis of morpholine derivatives having the following structure:

from a 1,2-amino alcohol of formula (IIa) or (IIb) as defined above, or a salt or solvate thereof and a compound of formula (Ib) as defined above, or a salt or solvate thereof: comprising the step of contacting the two compounds in the presence of a base, wherein R2 and R₈ are as defined above. Preferably, said step is carried out in a dipolar aprotic solvent. The present invention furthermore relates to a compound of formula (I) or a salt or solvate thereof:

whereby LG is a nucleophilic leaving group, R₁ is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 halogenalkyl, and R2 to R7 are independently from each other hydrogen or -Xm-Y-Zn-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, -

way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N₃, and C_1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five- membered heterocyclic ring the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C_1-6 alkyl, C_1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy, wherein at least one of R2 to R7 is not hydrogen. It is to be understood that all definitions of LG and R1 to R7 and preferred embodiments illustrated above for formula (I) when referring to the method according to the present invention are equally applicable to the compound of formula (I) itself according to the present invention. The present invention furthermore relates to a compound of the following formula (III) or a salt or solvate thereof:

with LG, R1, and R2-R7 being as defined above, wherein at least one of R2 to R7 is not hydrogen, and R₁₀ being either hydrogen or -(C=O)-R₁₃, with R₁₃ being C_1-6-alkyl or phenyl. It is to be understood that all definitions and preferred embodiments of LG and R1 to R7 illustrated above for formula (I) are equally applicable to formula (III). According to a preferred embodiment, R10 is -H or - (C=O)CH3. According to a preferred embodiment, the compound of formula (III) is selected from the group consisting of the following formulae:

,

wherein -R¹⁵ is selected from -OMe, -SMe, and -CH2F, and -R¹⁶ is selected from -

, wherein R¹⁷ is selected from

wherein * denotes the binding position. According to a preferred embodiment, the compound of formula (III) is according to the following:

. According to a preferred embodiment, the compound of formula (III) is according to the following:

. The present invention furthermore relates to a method of preparing a compound of formula (I) or a salt or solvate thereof according to the present invention, starting from a compound of formula (III) or a salt or solvate thereof according to the present invention, comprising the steps of: a) In case that R10 is not hydrogen, converting R10 to hydrogen; and b) Oxidation of the compound of formula (III) or the salt or solvate thereof to achieve the compound of formula (I) or the salt or solvate thereof. Step a) is preferably an ester cleavage, whereby basic conditions are preferred. Step b) can be achieved via the known oxidation procedures, whereby the “Swern-type” oxidation protocols involving the reduction of a sulfoxide compound, preferably DMSO have shown the best results in practice. According to one preferred embodiment of the method of preparing a compound of formula (I) of the present invention, the compound of formula (III) or a salt or solvate thereof is provided in a mixture with a compound of formula (III*), salt or solvate thereof

with LG, R1, and R2-R7 being as defined above, wherein at least one of R2 to R7 is not hydrogen, and R₁₀ being either hydrogen or -(C=O)-R₁₃, with R₁₃ being C_1-6-alkyl or phenyl. It is to be understood that all definitions of LG and R1 to R7 and preferred embodiments illustrated above for formula (III) when referring to the method according to the present invention are equally applicable to the compound of formula (III*). According to a preferred embodiment of the present invention, the compound of formula (III) may be provided in a mixture with a compound of formula (III*), wherein all of LG and R₁ to R₇ are selected the same between the compound of formula (III) and formula (III*). According to a preferred embodiment of the present invention the compound of formula (III) and formula (III*) are regio-isomers. It has been surprisingly found that the method according to the present invention may be performed using a compound of formula (III) in the presence of a compound of formula (III*), since resulting compounds of formula (I) and (I*) may still be used for obtaining the desired morpholine derivative. Particularly, since it has been found that the morpholine derivative may be obtained in acceptable purity and even without obtaining the other plausible regio-isomer based on the compound of formula (I*), this may also apply for the compounds of formula (III). This may be particularly useful in cases where it is difficult to obtain a compound of formula (III) that is free from the corresponding regio-isomer according to formula (III*). In case the compound of formula (III) is provided in a mixture with the compound of formula (III*) the mixture may contain the compounds in a molar ratio of compound of formula (III) to compound of formula (III*) in the range of ≥ 1:10 to ≤ 10:1, preferably ≥ 1:5 to ≤ 5:1, more preferably ≥ 1:4 to ≤ 4:1, more preferably ≥ 1:3 to ≤ 3:1, more preferably ≥ 1:2 to ≤ 2:1, for example 1:1. According to a preferred embodiment of the invention, the compound of formula (III), salt or solvate thereof, is provided in a mixture with a compound of formula (III*), salt or solvate thereof wherein the compound of formula (III) is

and the compound of formula (III*) is

. The present invention furthermore relates to a compound of the following formula (IV), or a salt or solvate thereof:

with LG, R1, and R2-R7 being as defined above, wherein at least one of R2 to R7 is not hydrogen, and R11 and R12 being independently from each other selected from hydrogen or C_1-6-alkyl. It is to be understood that all definitions and preferred embodiments of LG and R1 to R7 illustrated above for formula (I) are equally applicable to formula (III). According to a preferred embodiment, R11 and R12 are hydrogen. According to a preferred embodiment, the compound of formula (IV) is selected from the group consisting of the following formulae:

wherein -R¹⁸ is selected from Br, -OMe, -SMe, and -CH2F, and -R¹⁶ is selected from -

, wherein R¹⁷ is selected from

wherein * denotes the binding position. The present invention furthermore relates to a method of preparing a compound of formula (I) or a salt or solvate thereof according to the present invention starting from a compound of formula (IV) or a salt or solvate thereof according to the present invention, comprising the step of ozonolysis of the compound of formula (IV) or the salt or solvate thereof followed by reductive workup to achieve the compound of formula (I) or the salt or solvate thereof. The compounds of formula (I) can be made from these compounds of formulae (III) and (IV) via straightforward synthetic routes, also the compounds of formulae (III) and (IV) can be made via easily available synthetic methods and commercial starting materials, for example as described in the Examples below. The present invention provides a method of preparing a morpholine derivative, comprising A) preparing a compound of formula (I) or a salt or solvate thereof

whereby LG is a nucleophilic leaving group, R1 is selected from the group consisting of hydrogen, C_1-4 alkyl, and C_1-4 halogenalkyl, and R₂ to R₇ are independently from each other hydrogen or -X_m-Y-Z_n-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, - CR^*2-, -O-, -S-, -NR*-, -N(C2H4)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C_1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy, starting from a compound of formula (III) or a salt or solvate thereof

with LG, R₁, and R₂-R₇ being as defined above, wherein at least one of R₂ to R₇ is not hydrogen, and R10 being either hydrogen or -(C=O)-R13, with R13 being C1-6-alkyl or phenyl, comprising the steps of: a) In case that R₁₀ is not hydrogen, converting R₁₀ to hydrogen; and b) Oxidation of the compound of formula (III) or the salt or solvate thereof to achieve the compound of formula (I) or the salt or solvate thereof, B) contacting a 1,2-amino alcohol and the compound of formula (I) or a salt or solvate thereof in the presence of a base. It is to be understood that all definitions of LG and R1 to R7 and preferred embodiments illustrated with respect to the general method based on formula (I) according to the present invention are equally applicable to the method starting from formula (III). The present invention provides a method of preparing a morpholine derivative, comprising A) preparing a compound of formula (I) or a salt or solvate thereof

(I) whereby LG is a nucleophilic leaving group, R1 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 halogenalkyl, and R2 to R7 are independently from each other hydrogen or -X_m-Y-Z_n-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, - CR^*2-, -O-, -S-, -NR*-, -N(C2H4)2N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and -CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy, starting from a compound of formula (IV) or a salt or solvate thereof

with LG, R1, and R2-R7 being as defined above, wherein at least one of R2 to R7 is not hydrogen, and R11 and R12 being independently from each other selected from hydrogen or C_1-6-alkyl, comprising the step of ozonolysis of the compound of formula (IV) or the salt or solvate thereof followed by reductive workup to achieve the compound of formula (I) or the salt or solvate thereof; B) contacting a 1,2-amino alcohol and the compound of formula (I) or a salt or solvate thereof in the presence of a base. It is to be understood that all definitions of LG and R1 to R7 and preferred embodiments illustrated with respect to the general method based on formula (I) according to the present invention are equally applicable to the method starting from formula (IV). Detailed Description of the Invention Before the invention is described in more detail, it is to be understood that this invention is not limited to the particular component parts of the compounds described or process steps of the methods described as such compounds and methods may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include singular and/or plural referents unless the context clearly dictates otherwise. It is moreover to be understood that, in case parameter ranges are given which are delimited by numeric values, the ranges are deemed to include these limitation values. It is further to be understood that embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another. Features discussed with one embodiment are meant to be disclosed also in connection with other embodiments shown herein. If, in one case, a specific feature is not disclosed with one embodiment, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment, but that just for purposes of clarity and to keep the specification in a manageable volume this has not been done. Furthermore, the content of the prior art documents referred to herein is incorporated by reference. This refers, particularly, for prior art documents that disclose standard or routine methods. In that case, the incorporation by reference has mainly the purpose to provide sufficient enabling disclosure, and avoid lengthy repetitions. Examples While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed em illed in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Where the preparation of starting compounds is not described, they are commercially available or their synthesis is described in the prior art or they may be prepared analogously to known prior art compounds or methods described herein. It is to be understood that compounds of a certain formula may be converted into different compounds of the same formula. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art. Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). If a chemical structure is depicted without exact configuration of a stereo center, e.g. of an asymmetrically substituted carbon atom, then both configurations shall be deemed to be included and disclosed in such a representation. The representation of a stereo center in racemic form shall always deem to include and disclose both enantiomers (if no other defined stereo center exists) or all other potential diastereomers and enantiomers (if additional, defined or undefined, stereo centers exist). The following examples illustrate, but do not limit the scope of the invention. Table of abbreviations Ac: acetyl Ac₂O: acetic anhydride Ag2O: silver oxide Alloc: allyloxycarbonyl BaCO₃: barium carbonate °C: degree Celsius cHex: cyclohexane Cl: chloro Cs2CO3: cesium carbonate d: days/doublet (NMR) DABCO: 1,4-Diazabicyclo[2.2.2]octane DCM: dichloromethane dd: doublet of doublets ddd: doublet of doublet of doublets dt: doublet of triplets DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMS: dimethylsulfide DMSO: dimethyl sulfoxide eq.: equivalents Et₂O: diethyl ether Et4NBr: tetraethylammonium bromide EtOAc: ethyl acetate EtOH: ethanol g: gram ¹H: hydrogen h: hours HCl: hydrogen chloride H2O: water HOAc: acetic acid Hz: Hertz KI: potassium iodide J: scalar coupling constant L: liter M: molar m: multiplet MeCN: acetonitrile MeOH: methanol min: minute mL: milli liter MPLC: medium pressure liquid chromatography Ms: methanesulfonyl MS: molecular sieves MTBE: methyl tert-butyl ether N: normal NaBH4: sodium borohydride NaHCO3: sodium hydrogencarbonate NaIO₄: sodium metaperiodate Na2SO4: sodium sulfate NEt3: triethylamine NH₃: ammonia NMR: nuclear magnetic resonance O3: ozone py: pyridine pyr SO_3: pyridine sulfurtrioxide Rf: retention factor (TLC) rt: room temperature t: triplet TBAB: tetrabutylammonium bromide TBAF: tetrabutylammonium fluoride THF: tetrahydrofuran TLC: thin layer chromatography pTs: paratoluenesulfonyl Synthesis of (S)-2-(2-hydroxy)-2-methoxyethan-1-ol In the following the synthesis of (S)-2-(2-hydroxy)-2-methoxyethan-1-ol, out of which the compounds of fo inose.

1) Synthesis (3R,4S,5S)-2-methoxytetrahydro-2H-pyran-3,4,5-triol A solution of (3R,4S,5S)-tetrahydro-2H-pyran-2,3,4,5-tetraol (25 g, 170 mmol, 1.0 eq.) in 5% methanolic hydrogen chloride (300 mL, from acetyl chloride and methanol at 0 °C) was refluxed overnight under a nitrogen atmosphere. The solution was neutralized by addition of solid sodium carbonate, filtered, and concentrated under reduced pressure. The crude product was triturated in EtOH and the precipitate was filtered and dried to afford (3R,4S,5S)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (14.3 g, 87.1 mmol, 52 %) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 4.59 (d, J = 6.3 Hz, 2H), 4.52 (d, J = 2.7 Hz, 2H), 3.69 (dt, J = 4.3, 2.0 Hz, 1H), 3.59 – 3.53 (m, 3H), 3.42 (dd, J = 11.9, 3.0 Hz, 1H), 3.24 (s, 3H). 2) Synthesis of (S)-2-(2-hydroxyethoxy)-2-methoxyethan-1-ol Sodium periodate (43 g, 200 mmol, 2.2 eq.) was added to a solution of (3R,4S,5S)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (13.5 g, 91.1 mmol, 1.0 eq.) in water (210 mL) at 0 °C and the reaction mixture was stirred for 2 h, when a precipitate was formed barium carbonate (17.9 g, 91 mmol, 1.0 eq.) and Ethanol (80 mL) were added and stirring continued for 30 min. The precipitate was filtered off and the filtrate was concentrated to 30 % of the original volume under vacuum to afford dialdehyde (Rf = 0.90, DCM/MeOH 80/20). Methanol (60 mL) was added to the aqueous solution, then NaBH₄ (1.76 g, 45 mmol, 0.5 eq.) was added portion wise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, and TLC (DCM/MeOH 4:1, KMnO₄) showed no more starting material. The mixture was neutralized with 2M H2SO4 to pH 7, then filtered and concentrated under reduced pressure. The crude product was dissolved in DCM, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford (S)-2-(2- hydroxyethoxy)-2-methoxyethan-1-ol as a colorless oil (8.60 g, 63.2 mmol, 69%). ¹H NMR (400 MHz, DMSO-d₆) δ 4.72 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 5.0 Hz, 1H), 4.39 (t, J = 5.4 Hz, 1H), 3.62 – 3.56 (m, 1H), 3.53 – 3.43 (m, 3H), 3.36 (d, J = 5.2 Hz, 2H), 3.28 (s, 3H). Route 1) Synthesis of morpholine derivatives via unselective tosylation In the following the synthesis of morpholine derivatives via a first route (“unselective tosylation”) is described, which follows the following path:

1) Synthesis of (S)-2-(2-hydroxyethoxy)-2-methoxyethyl 4-methylbenzenesulfonate and (S)-2-(2-hydroxy-1-methoxyethoxy)ethyl 4-methylbenzenesulfonate 2a and 2b To a solution of (S)-2-(2-hydroxy)-2-methoxyethan-1-ol (1.79 g, 13.1 mmol, 1.0 eq.) in anhydrous DCM (102 mL) was added Ag2O (4.57 g, 19.7 mmol, 1.5 eq.), pTsCl (2.76 g, 14.5 mmol, 1.1 eq.) and KI (436 mg, 2.63 mmol, 0.2 eq.) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 °C, when TLC (cHex/EtOAc 1:1, KMnO₄) showed complete conversion of the starting material. The reaction mixture was poured over Celite and the Celite washed with DCM (3*30 mL). The crude product was concentrated under reduced pressure and purified by MPLC (120 g silica, cHex 100 % 1 CV to EtOAc 100 % over 10 CV) to afford an inseparable 2:3 regioisomeric mixture of (S)-2-(2-hydroxy-1-methoxyethoxy)ethyl 4-methylbenzenesulfonate and (S)-2-(2-hydroxyethoxy)-2-methoxyethyl 4- methylbenzenesulfonate 2a/2b (2.93 g, 10.1 mmol, 77 %) as a colorless oil. R_f = 0.15 (cHex/EtOAc 1:1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d, regioisomeric mixture) δ 7.79 (dd, J = 8.5, 1.1 Hz, 4H), 7.39 – 7.30 (m, 4H), 4.65 (t, J = 5.3 Hz, 1H), 4.47 (t, J = 5.2 Hz, 1H), 4.21 – 4.17 (m, 2H), 4.01 (d, J = 5.3 Hz, 2H), 3.89 – 3.83 (m, 2H), 3.53 (s, 1H), 3.43 (d, J = 1.4 Hz, 1H), 3.39- 3.33 (m, 6H), 2.46 (s, 3H), 2.42 (s, 3H). 2) (S)-2-(1-methoxy-2-oxoethoxy)ethyl 4-methylbenzenesulfonate 3a To a solution of oxalyl chloride (230 µL, 334 mg, 2.63 mmol, 1.6 eq.) in anhydrous DCM (16 mL) was added anhydrous DMSO (250 µL, 274 mg, 3.50 mmol, 2.1 eq.) at -78 °C under a nitrogen atmosphere and the reaction solution was stirred at -78 °C for 20 min. A solution of (S)-2-(2-hydroxy-1-methoxyethoxy)ethyl 4-methylbenzenesulfonate and (S)-2-(2- hydroxyethoxy)-2-methoxyethyl 4-methylbenzenesulfonate and (2:3, 480 mg, 1.65 mmol, 1.0 eq.) in anhydrous DCM (8 mL) was slowly added at -78 °C and the reaction solution stirred at -78 °C for 1 h. Afterwards, anhydrous NEt₃ (733 µL, 5.26 mmol, 3.2 eq.) was added at - 78 °C and the reaction mixture was warmed to room temperature over 45 min. H2O (40 mL) was added and the aqueous layer was extracted with DCM (3*30 mL). The combined organic layers were washed with brine (40mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was adsorbed on silica (2 g) with DCM and purified by MPLC (40 g silica, cHex 100 % 1 CV to EtOAc 100 % over 10 CV) to afford (S)-2-(1-methoxy- 2-oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (39 mg, 0.14 mmol, 8 %) as well as (S)-2- methoxy-2-(2-oxoethoxy)ethyl 4-methylbenzenesulfonate (80 mg, 0.28 mmol, 17 %) 3b as colorless oils each. R_f = 0.18 (cHex/EtOAc 1:1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d) δ 9.36 (d, J = 1.3 Hz, 1H), 7.78 (td, J = 5.4, 4.4, 2.1 Hz, 2H), 7.41 – 7.29 (m, 2H), 4.54 (d, J = 1.3 Hz, 1H), 4.26 – 4.15 (m, 2H), 3.92 – 3.71 (m, 2H), 3.40 (s, 3H), 2.43 (d, J = 2.7 Hz, 3H). 3) Synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione 4 To a solution of doxorubicin (75 mg, 0.14 mmol, 1.0 eq.) and (S)-2-(1-methoxy-2- oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (40 mg, 0.14 mmol, 1.0 eq.) in anhydrous DMF (2.9 mL) was slowly added DIPEA (54 µL, 0.34 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h and concentrated under high vacuum. The crude product was purified by silica column chromatography (10 g silica, DCM 100 % 3 CV, 0.5 % MeOH 3 CV, 1% MeOH 3 CV, 1.5 % MeOH 5 CV, 2 % MeOH 3 CV) to afford (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione 4 (46 mg, 0.072 mmol, 52 %) as a red solid. R_f = 0.30 (DCM/MeOH 95:5, visible light) ¹H NMR (400 MHz, Chloroform-d) δ 13.82 (s, 1H, 6-OH or 11-OH), 13.19 (s, 1H, 6-OH or 11-OH), 8.05 (dd, J = 7.7, 1.1 Hz, 1H, H-3), 7.80 (dd, J = 8.5, 7.7 Hz, 1H, H-2), 7.42 (dd, J = 8.6, 1.1 Hz, 1H, H-3), 5.51 (t, J = 5.6 Hz, 1H, H-1'), 5.33 (dd, J = 3.9, 2.2 Hz, 1H, H-7), 4.88 (s, 1H, OH), 4.78 (d, J = 3.9 Hz, 2H, H-14), 4.73 (d, J = 1.9 Hz, 1H, H-2''), 4.50 (d, J = 1.9 Hz, 1H, H-1''), 4.11 (s, 4H, H-4', 4-OMe), 4.08 – 3.99 (m, 1H, H-5'), 3.95 (t, J = 10.1 Hz, 1H, H-3''), 3.67 – 3.56 (m, 1H, H-3''), 3.48 (s, 3H, 2'-OMe), 3.46 – 3.37 (m, 1H, H-3'), 3.27 (dd, J = 19.0, 2.0 Hz, 1H, H-10), 3.05 (d, J = 18.8 Hz, 1H, H-10) 3.03 (s, 1H, OH), 2.86 (d, J = 11.8 Hz, 1H, H-4''), 2.81-2,73 (m, 1H, H-4''), 2.53 (dt, J = 14.7, 2.2 Hz, 1H, H-8), 2.13 (dd, J = 14.7, 3.9 Hz, 1H, H-8), 2.11-2,03 (m, 1H, H-2'), 1.80-1,72 (m, 1H, H-2'), 1.42 (d, J = 6.5 Hz, 3H, H-6'). It is remarkable that although in this finishing step a mixture of two compounds 3a and 3b is used, only the compound 3a reacts and only one product is formed. The plausible regioisomeric side product where the methoxy group would be in para-position to the oxygen atom of the oxazole ring could not be isolated. Route 2) Synthesis of morpholine derivatives via selective tosylation In the following the synthesis of morpholine derivatives via a second route (“selective tosylation”) is described, which follows the following path:

1) Synthesis of (S)-2-(2-acetoxy-1-methoxyethoxy)ethyl acetate 5 (S)-2-(2-hydroxy)-2-methoxyethan-1-ol 1 (8.2 g, 60 mmol, 1.0 eq.) was dissolved in pyridine (160 mL). Acetic anhydride (12.0 g, 120 mmol, 2.0 eq.) was added to the mixture at 0°C under a nitrogen atmosphere. the mixture was stirred at 0°C for 30 min then at room temperature overnight. The completion of the reaction was confirmed by TLC (cHex:EtOAc, 1:1, KMnO4, R_f= 0.65). The s crude product was purified by MPLC (40 g Silica cartridge: 100 % cHex for 2 CV, 0 to 100 % EtOAc over 10 CV, 4 CV EtOAc 100 %) to afford (S)-2-(2-acetoxy-1-methoxyethoxy)ethyl acetate 5 (11.5 g, 50.9 mmol, Quant) as a colorless oil. TLC: R_f= 0.65 (cHex, EtOAc 1:1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d) δ 4.69 (t, J = 5.4 Hz, 1H), 4.23 (dd, J = 5.3, 4.3 Hz, 2H), 4.12 (dd, J = 5.4, 1.9 Hz, 2H), 3.82 (ddd, J = 11.3, 5.2, 4.3 Hz, 1H), 3.74 (ddd, J = 11.3, 5.2, 4.3 Hz, 1H), 3.40 (s, 3H), 2.09 (d, J = 1.7 Hz, 6H). 2) Synthesis of (S)-2-(2-hydroxyethoxy)-2-methoxyethyl acetate 6 To a solution of (S)-2-(2-acetoxy-1-methoxyethoxy)ethyl acetate 5 (1.00 g, 4.54 mmol, 1.0 eq.) in aqueous phosphate buffer pH 7 (450 ml) and THF (45 mL) was added Amano Lipase from Pseudomas fluorescens (1.36 g, 300 mg/mmol) at room temperature. The reaction was stirred overnight at room temperature and then extracted with DCM (3*400 mL, milky suspension). The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-(2-hydroxyethoxy)-2-methoxyethyl acetate 6 (0.725 g, 4.07 mmol, 100 %) TLC: R_f= 0.35 (cHex, EtOAc: 1:1, KMnO₄) ¹H NMR (500 MHz, Chloroform-d) δ 4.67 (t, J = 5.3 Hz, 1H), 4.14 (dd, J = 11.7, 5.3 Hz, 2H), 3.75 (q, J = 4.1 Hz, 2H), 3.43 (s, 3H), 2.10 (s, 3H). 3) Synthesis of (S)-2-methoxy-2-(2-(tosyloxy)ethoxy)ethyl acetate 7a To a solution of (S)-2-(2-hydroxyethoxy)-2-methoxyethyl acetate 6 (0.10 g, 0.56 mmol, 1.0 eq.) in Dichloromethane (3 mL) was added successively DABCO (0.060 g, 0.56 mmol, 1.0 eq.) and pTsCl (0.12 g, 0.67 mmol, 1.2 eq.) at 0°C under a nitrogen atmosphere (fresh ice, monitored with thermometer) then the mixture was warmed to 5°C (slow warming up over 30 min). The completion of the reaction was confirmed by TLC (cHex, EtOAc 1: 1, KMnO₄, R_f = 0.45). The reaction was quenched by addition of a saturated aqueous NH4Cl solution, the layers were separated, the aqueous layer was reextracted with DCM (3*25 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by MPLC (12 g Silica cartridge, 100 % cHex for 2CV, from 0 to 100% EtOAc during 10 CV, then 2 CV 100% EtOAc) to afford (S)-2-methoxy-2-(2- (tosyloxy)ethoxy)ethyl acetate 7a (0.12 g, 0.36 mmol, 64%) as a slightly yellow oil. TLC: R_f = 0.45 (cHex, EtOAc 1: 1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.62 (t, J = 5.4 Hz, 1H), 4.21 – 4.14 (m, 2H), 4.03 (dd, J = 5.4, 0.7 Hz, 2H), 3.80 (ddd, J = 11.6, 4.9, 4.1 Hz, 1H), 3.76 – 3.70 (m, 1H), 3.34 (s, 3H), 2.45 (s, 3H), 2.07 (s, 3H). 4) Synthesis of (S)-2-(2-hydroxy-1-methoxyethoxy)ethyl 4- methylbenzenesulfonate 2a (S)-2-methoxy-2-(2-(tosyloxy)ethoxy)ethyl acetate 7a (0.700 g, 2.11 mmol, 1.0 eq.) was stirred with methanolic ammonia (7M, 47 mL) at room temperature overnight under a nitrogen atmosphere. The solvent was removed under reduced pressure to afford (S)-2-(2-hydroxy-1- methoxyethoxy)ethyl 4-methylbenzenesulfonate 2a (610 mg, 2.10 mmol, quant.) as a colorless liquid, which was used in the next step without purification. ¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.48 (t, J = 5.2 Hz, 1H), 4.22 – 4.18 (m, 2H), 3.90 – 3.84 (m, 1H), 3.74 (ddd, J = 11.7, 5.5, 4.3 Hz, 1H), 3.54 (d, J = 5.3 Hz, 2H), 3.38 (s, 3H), 2.45 (s, 3H). 5) Synthesis of (S)-2-(1-methoxy-2-oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (S)-2-(2-hydroxy-1-methoxyethoxy)ethyl 4-methylbenzenesulfonate 2a (42 mg, 0.14 mmol, 1.0 eq.) was dissolved in DCM (1.4 mL), and DIPEA (0.11 g, 0.15 mL, 0.87 mmol, 6.0 eq.) was added, followed by DMSO (0.10 mL, 1.4 mmol, 10 eq.) and pyridine--sulfur trioxide (1/1) (69 mg, 0.43 mmol, 3.0 eq.) at room temperature and the mixture was stirred at room temperature for 2h, ¹H NMR showed a complete conversion. Saturated NaHCO₃ (15 mL) was added, the layers were separated, the aqueous layer was extracted with DCM (3*20 mL), dried over Na2SO4 and concentrated under reduced pressure. Crude (S)-2-methoxy-2-(2- oxoethoxy)ethyl 4-methylbenzenesulfonate 3a after the aqueous work-up was engaged in the next step without further purification TLC: R_f = 0.18 (cHex/EtOAc 1:1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d) δ 9.30 (d, J = 1.3 Hz, 1H), 7.73 (td, J = 5.4, 4.4, 2.1 Hz, 2H), 7.36 – 7.24 (m, 2H), 4.48 (d, J = 1.3 Hz, 1H), 4.21 – 4.10 (m, 2H), 3.87 – 3.66 (m, 2H), 3.35 (s, 3H), 2.38 (d, J = 2.7 Hz, 3H). 6) (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione To a solution of doxorubicin (75 mg, 0.14 mmol, 1.0 eq.) and (S)-2-methoxy-2-(2- oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (40 mg, 0.14 mmol, 1.0 eq., Ts overintegrated to 6 instead of 2) in anhydrous DMF (2.9 mL) was slowly added DIPEA (54 µL, 0.34 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with H₂O and lyophilized overnight. The crude product was purified by MPLC (12 g silica, DCM 100 % to 3 % MeOH over 20 min) to afford (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione 4 (23 mg, 0.036 mmol, 26 %) as a red solid. R_f = 0.70 (DCM/MeOH 9:1, visible light) ¹H NMR (400 MHz, Chloroform-d) δ 13.82 (s, 1H, 6-OH or 11-OH), 13.19 (s, 1H, 6-OH or 11-OH), 8.05 (dd, J = 7.7, 1.1 Hz, 1H, H-3), 7.80 (dd, J = 8.5, 7.7 Hz, 1H, H-2), 7.42 (dd, J = 8.6, 1.1 Hz, 1H, H-3), 5.51 (t, J = 5.6 Hz, 1H, H-1'), 5.33 (dd, J = 3.9, 2.2 Hz, 1H, H-7), 4.88 (s, 1H, OH), 4.78 (d, J = 3.9 Hz, 2H, H-14), 4.73 (d, J = 1.9 Hz, 1H, H-2''), 4.50 (d, J = 1.9 Hz, 1H, H-1''), 4.11 (s, 4H, H-4', 4-OMe), 4.08 – 3.99 (m, 1H, H-5'), 3.95 (t, J = 10.1 Hz, 1H, H- 3''), 3.67 – 3.56 (m, 1H, H-3''), 3.48 (s, 3H, 2'-OMe), 3.46 – 3.37 (m, 1H, H-3'), 3.27 (dd, J = 19.0, 2.0 Hz, 1H, H-10), 3.05 (d, J = 18.8 Hz, 1H, H-10) 3.03 (s, 1H, OH), 2.86 (d, J = 11.8 Hz, 1H, H-4''), 2.81-2,73 (m, 1H, H-4''), 2.53 (dt, J = 14.7, 2.2 Hz, 1H, H-8), 2.13 (dd, J = 14.7, 3.9 Hz, 1H, H-8), 2.11-2,03 (m, 1H, H-2'), 1.80-1,72 (m, 1H, H-2'), 1.42 (d, J = 6.5 Hz, 3H, H-6'). Route 3) Synthesis of morpholine derivatives via bromination In the following the synthesis of morpholine derivatives via a third route (“bromination”) is described, which follows the following path:

1) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c To a solution of (S)-2-(2-hydroxyethoxy)-2-methoxyethan-1-ol 1 (0.200 g, 1.47 mmol, 1.0 eq.) in acetonitrile (12 mL) at room temperature under nitrogen atmosphere was added successively Tetraethylammonium bromide (0.71 g, 2.20 mmol, 1.5 eq.) and Lutidine (0.47 g, 4.41 mmol, 3.0 eq.). DAST (0.28 mL, 2.2 mmol, 1.5 eq.) was then added. The solution was stirred for 1.5 h at room temperature, the reaction completion was confirmed by TLC (cHex:EtOAc 1:1, KMNO4). The reaction mixture was quenched by aqueous sodium carbonate (5%) and the aqueous layer was extracted with Dichloromethane (3*30 mL). The combined organic layers were washed with 10% HCl (1*25 mL), water (1*25 mL), brine (1*25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by MPLC (25 g silica cartridge, cHex 100%, 0 to 100% EtOAc over 10 CV then 2 CV 100% EAtOc) to afford (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c (0.24 g, 1.20 mmol, 82 %) TLC: Rf= 0.30 (cHex, EtOAc: 1:1, KMnO4) ¹H NMR (400 MHz, Chloroform-d) δ 4.57 (t, J = 5.3 Hz, 1H), 4.02 (dt, J = 11.4, 5.8 Hz, 1H), 3.86 (dt, J = 11.0, 6.0 Hz, 1H), 3.63 (d, J = 5.3 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.45 (s, 3H). 2) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c To a solution of (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c (200 mg, 1.00 mmol, 1.0 eq.) in Dichloromethane (10 mL) was added DIPEA (0.75 mL, 6.00 mmol, 6.0 eq.) in one portion at room temperature under a nitrogen atmosphere, followed by a dropwise addition of DMSO (0.7 mL, 10 mmol, 10 eq.). The reaction solution was stirred at room temperature for 5 min, then sulfur trioxide pyridine (0.480 g, 3.00 mmol, 3.0 eq.) was added in portion and the reaction mixture was stirred for 1 h at room temperature. A small aliquot was concentrated under reduced pressure and analyzed by ¹H NMR, which showed an over-integration of the methoxy signal, and no more SM. The crude reaction mixture was directly filtered over a Celite Pad and washed with dichloromethane to afford (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c (240 mg, 1.20 mmol, 120 % containing DMSO and DIPEA) as a yellow liquid. 3) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c To a solution of (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c (1.90 g, 9.55 mmol, 1.03 eq.) in anhydrous DCM (93 mL, 0.1 M), trichloroisocyanuric acid (2.15 g, 9.27 mmol, 1.0 eq.) and TEMPO (72 mg, 0.464 mmol, 0.05 eq.) were successively added. The reaction mixture was stirred 10 minutes at rt until complete conversion of starting material (checked by TLC cHex/EtOAc 1:1, R_f = 0.35, KMnO₄). The suspension was then passed through a short pad of silica (2-3 cm). The filter was washed first with DCM to remove yellowish impurity and then with a mixture DCM/EtOAc 4:1 to remove the aldehyde from silica. The filtrate was concentrated under reduced pressure (bath 30 °C) and purified by silica chromatography (Cartridge 40 g, cHex/EtOAc 100:02 CV -> 100:0 to 70:3010 CV -> 70:30 -> 50:505 CV -> 50:505 CV) to afford (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c as yellowish oil (882 mg, 48%). ¹H NMR (400 MHz, Chloroform-d) δ 9.42 (d, J = 1.4 Hz, 1H), 4.57 (d, J = 1.4 Hz, 1H), 3.96 – 3.79 (m, 4H), 3.43 (s, 3H). 4) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c To a solution of (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c (135 mg, 0.678 mmol, 1.0 eq.) in anhydrous dichloromethane (6.7 mL) was added DIPEA (555 µL, 3.19 mmol, 4.7 eq.), DMSO (1.45 mL, 20.3 mmol, 30 eq.) and pyridine SO₃ (335 mg, 2.10 mmol, 3.1 eq.) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1.5 h. A saturated solution of NaHCO3 (8 mL) was added and the reaction was vigorously stirred for 30 min and slowly warmed to room temperature. Dichloromethane (15 mL) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2*20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure at 30 °C to afford (S)-2-(2-bromoethoxy)-2- methoxyacetaldehyde 3c (117 mg, purity: 70%) as a yellow oil, which was used in the next step without further purification. Rf = 0.18 (cHex/EtOAc 1:1, KMnO4) ¹H NMR (400 MHz, Chloroform-d) δ 9.42 (d, J = 1.4 Hz, 1H), 4.57 (d, J = 1.4 Hz, 1H), 3.96 – 3.79 (m, 4H), 3.43 (s, 3H). 5) Synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione 4 To a solution of doxorubicin (324 mg, 0.596 mmol, 1.0 eq.) and (S)-2-bromoethoxy-2- methoxyacetaldehyde 3c (117 mg, 0.596 mmol, 1.0 eq.) in anhydrous DMF (11 mL) was slowly added DIPEA (260 µL, 1.49 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under high vacuum. The crude product was purified by silica chromatography (15 g silica, DCM 100 % 3 CV, 0.5 % MeOH 3 CV, 1% MeOH 3 CV, 1.5 % MeOH 5 CV, 2 % MeOH 3 CV, 4 % MeOH 1 CV) to afford (8S,10S)-6,8,11-trihydroxy-8-(2- hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione 4 (146 mg, 0.228 mmol, 38 %) as a red solid. Rf = 0.70 (DCM/MeOH 9:1, visible light) ¹H NMR (400 MHz, Chloroform-d) δ 13.82 (s, 1H, 6-OH or 11-OH), 13.19 (s, 1H, 6-OH or 11-OH), 8.05 (dd, J = 7.7, 1.1 Hz, 1H, H-3), 7.80 (dd, J = 8.5, 7.7 Hz, 1H, H-2), 7.42 (dd, J = 8.6, 1.1 Hz, 1H, H-3), 5.51 (t, J = 5.6 Hz, 1H, H-1'), 5.33 (dd, J = 3.9, 2.2 Hz, 1H, H-7), 4.88 (s, 1H, OH), 4.78 (d, J = 3.9 Hz, 2H, H-14), 4.73 (d, J = 1.9 Hz, 1H, H-2''), 4.50 (d, J = 1.9 Hz, 1H, H-1''), 4.11 (s, 4H, H-4', 4-OMe), 4.08 – 3.99 (m, 1H, H-5'), 3.95 (t, J = 10.1 Hz, 1H, H-3''), 3.67 – 3.56 (m, 1H, H-3''), 3.48 (s, 3H, 2'-OMe), 3.46 – 3.37 (m, 1H, H-3'), 3.27 (dd, J = 19.0, 2.0 Hz, 1H, H-10), 3.05 (d, J = 18.8 Hz, 1H, H-10) 3.03 (s, 1H, OH), 2.86 (d, J = 11.8 Hz, 1H, H-4''), 2.81-2,73 (m, 1H, H-4''), 2.53 (dt, J = 14.7, 2.2 Hz, 1H, H-8), 2.13 (dd, J = 14.7, 3.9 Hz, 1H, H-8), 2.11-2,03 (m, 1H, H-2'), 1.80-1,72 (m, 1H, H-2'), 1.42 (d, J = 6.5 Hz, 3H, H-6'). Alternative synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12- dione 4 in DIPEA only: To a doxorubicin hydrochloride (85 mg, 0.15 mmol, 1.0 eq.) and (S)-2-bromoethoxy-2- methoxyacetaldehyde 3c (50 mg, purity 70 %, 1.2 eq.) was added DIPEA (3.2 mL, 0.05 mM) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under high vacuum. The crude product was purified by silica chromatography (12 g silica, DCM 100 % 3 CV, to 5 % MeOH over 10 CV) to afford (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione 4 (14 mg, 0.022 mmol, 14 %) as a red solid. Alternative synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12- dione 4 using (R)-2-bromoethoxy-2-methoxyacetaldehyde: To a doxorubicin hydrochloride (65 mg, 0.11 mmol, 1.0 eq.) and (R)-2-bromoethoxy-2- methoxyacetaldehyde (33 mg, purity 70 %, 1.2 eq.) in anhydrous MeCN (48 mL, 0.05 m^M) was added DIPEA (48 µL, 0.28 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 d. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica chromatography (12 g silica, DCM 100 % 3 CV, to 5 % MeOH over 10 CV) to afford (8S,10S)- 6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy- 1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione 4 (70 mg, 0.11 mmol, 97 %) as a red solid (inversion of configuration at the C bearing OMe in the morpholine ring as the ¹H NMR matches the previously prepared PNU-1596824). It is remarkable that although using (R)-2-bromoethoxy-2-methoxyacetaldehyde instead of (S)- 2-bromoethoxy-2-methoxyacetaldehyde in the finishing step the same product is formed and not, as expected, the respective diastereomer. Route 4) Synthesis of morpholine derivatives via selective bromination In the following the synthesis of morpholine derivatives via a fourth route (“selective bromination”) is described, which follows the following path:

1) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyethyl acetate 7b To a stirred solution of (S)-2-(2-hydroxyethoxy)-2-methoxyethyl acetate 6 (0.100 g, 0.561 mmol, 1.0 eq.) in dichloromethane (10mL) at room temperature under a nitrogen atmosphere was added successively Tetrabutylammonium bromide (0.271 g, 0.842 mmol, 1.5 eq.), and 2,6- Lutidine (0.196 mL, 1.68 mmol, 3.0 eq.). XtalFluor-E (0.193 g, 0.842 mmol, 1.5 eq.) was then added and the solution was stirred for 1.5 h at room temperature. The TLC (cHex, EtOAc: 1:1, KMnO4) showed complete conversion of the starting material. The reaction mixture was quenched by aqueous sodium carbonate (5%, 20 mL) and the aqueous layer was extracted with dichloromethane (3*15 mL). The combined organic layers were washed with 10% HCl (1*20 mL), water (1*20 mL), brine (1*20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in under reduced pressure. The crude product was purified by MPLC (silica 25g, 100% cHex for 1 CV, then 0 to 100% EtOAc over 10 CV, and 2 CV for 100% EtOAc) to afford (S)-2-(2-bromoethoxy)-2-methoxyethyl acetate 7b (95 mg, 0.39 mmol, 70 %) TLC: Rf= 0.45 (cHex, EtOAc: 1:1, KMnO4) ¹H NMR (400 MHz, Chloroform-d) δ 4.71 (t, J = 5.4 Hz, 1H), 4.13 (dd, J = 5.4, 1.3 Hz, 2H), 3.95 (dt, J = 10.9, 6.1 Hz, 1H), 3.85 (dt, J = 11.0, 6.2 Hz, 1H), 3.52 – 3.45 (m, 2H), 3.43 (s, 3H), 2.09 (s, 3H) 2) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c To a solution of (S)-2-(2-bromoethoxy)-2-methoxyethyl acetate (90.0 mg, 373 µmol, 1.0 eq.) in MeOH (3 mL) was added a saturated methanolic solution Ammonia (7.0 M, 8.27 mL, 57.9 mmol, 155 eq.). The reaction was stirred overnight at room temperature under a nitrogen atmosphere. The TLC (cHex, EtOAc: 1:1, KMnO₄) showed complete conversion of the starting material and the reaction mixture was concentrated under reduced pressure to afford (S)-2-(2- bromoethoxy)-2-methoxyethan-1-ol 2c (72 mg, 0.36 mmol, 97 %) TLC: R_f= 0.30 (cHex, EtOAc: 1:1, KMnO₄) ¹H NMR (400 MHz, Chloroform-d) δ 4.57 (t, J = 5.3 Hz, 1H), 4.02 (dt, J = 11.1, 5.8 Hz, 1H), 3.86 (dt, J = 11.1, 6.0 Hz, 1H), 3.63 (dd, J = 5.3, 0.7 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.46 (s, 3H). 3) Synthesis of (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c (S)-2-(2-bromoethoxy)-2-methoxyethan-1-ol 2c (190 mg, 0.950 mmol, 1.0 eq.) was dissolved in Dichloromethane (10 mL), DIPEA (778 µL, 4.47 mmol, 4.7 eq.) was added in one portion at room temperature under a nitrogen atmosphere, followed by a dropwise addition of DMSO (0.74 g, 0.67 mmol, 10 eq). The mixture was stirred at room temperature for 5 min, then sulfur trioxide pyridine (0.450 g, 2.86 mmol, 3.0 eq.) was added portionwise and the mixture was stirred for 1 h at room temperature. A small aliquot was concentrated under reduced pressure and analyzed by ¹H NMR, which showed no more starting material. The crude was directly purified by MPLC (silica 25g, 100% cHex for 1 CV, then 0 to 100% EtOAc over 10 CV, and 2 CV for 100% EtOAc) to afford (S)-2-(2-bromoethoxy)-2-methoxyacetaldehyde 3c (600 mg, still containing DIPEA and DMSO). ¹H NMR (400 MHz, Chloroform-d) δ 9.46 (d, J = 1.4 Hz, 1H), 4.62 (d, J = 1.4 Hz, 1H), 4.01 – 3.83 (m, 4H), 3.43 (s, 3H). 4) Synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione 4 To a solution of doxorubicin (90 mg, 0.17 mmol, 1.0 eq.) and (S)-2-bromoethoxy-2- methoxyacetaldehyde 3c (50 mg, 0.25 mmol, 1.5 eq.) in anhydrous DMF (3.2 mL) was slowly added DIPEA (72 µL, 0.41 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was lyophilized. The crude product was purified by silica chromatography (12 g silica, DCM 100 % to 3 % MeOH over 20 min) to afford (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1- methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione 4 (19 mg, 0.030 mmol, 18 %) as a red solid. Rf = 0.70 (DCM/MeOH 9:1, visible light) ¹H NMR (400 MHz, Chloroform-d) δ 13.82 (s, 1H, 6-OH or 11-OH), 13.19 (s, 1H, 6-OH or 11-OH), 8.05 (dd, J = 7.7, 1.1 Hz, 1H, H-3), 7.80 (dd, J = 8.5, 7.7 Hz, 1H, H-2), 7.42 (dd, J = 8.6, 1.1 Hz, 1H, H-3), 5.51 (t, J = 5.6 Hz, 1H, H-1'), 5.33 (dd, J = 3.9, 2.2 Hz, 1H, H-7), 4.88 (s, 1H, OH), 4.78 (d, J = 3.9 Hz, 2H, H-14), 4.73 (d, J = 1.9 Hz, 1H, H-2''), 4.50 (d, J = 1.9 Hz, 1H, H-1''), 4.11 (s, 4H, H-4', 4-OMe), 4.08 – 3.99 (m, 1H, H-5'), 3.95 (t, J = 10.1 Hz, 1H, H-3''), 3.67 – 3.56 (m, 1H, H-3''), 3.48 (s, 3H, 2'-OMe), 3.46 – 3.37 (m, 1H, H-3'), 3.27 (dd, J = 19.0, 2.0 Hz, 1H, H-10), 3.05 (d, J = 18.8 Hz, 1H, H-10) 3.03 (s, 1H, OH), 2.86 (d, J = 11.8 Hz, 1H, H-4''), 2.81-2,73 (m, 1H, H-4''), 2.53 (dt, J = 14.7, 2.2 Hz, 1H, H-8), 2.13 (dd, J = 14.7, 3.9 Hz, 1H, H-8), 2.11-2,03 (m, 1H, H-2'), 1.80-1,72 (m, 1H, H-2'), 1.42 (d, J = 6.5 Hz, 3H, H-6'). Route 5) Synthesis of morpholine derivatives via hydroalkoxylation In the following the synthesis of morpholine derivatives via a fifth route (“hydroalkoxylation”) is described, which follows the following path:

1) Synthesis of 1-methoxypropa-1,2-diene 9 To KOtBu (487 mg, 4.34 mmol, 0.1 eq.) was added Methyl propargyl ether 8 (3.60 mL, 43.4 mL, 1.0 eq.) at room temperature under a nitrogen atmosphere. An exothermic reaction was observed and the resulting brown suspension was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and the reflux condenser was replaced by a short distillation bridge. Distillation at 85 °C afforded 1-methoxypropa-1,2-diene 9 (2.44 g, 34.8 mmol, 80 %) as a colorless liquid. ¹H NMR (60 MHz, Chloroform-d) δ 6.77 (1 H, t, J = 5.9 Hz), 5.48 (2 H, d, J = 5.9 Hz), 3.42 (3 H, s) 2) Synthesis of (S)-2-((1-methoxyallyl)oxy)ethyl 4-methylbenzenesulfonate 12 A solution of 2-hydroxyethyl 4-methylbenzenesulfonate 11 (0.100 g, 0.462 mmol, 1.0 eq.), 1- methoxypropa-1,2-diene 9 (0.194 g, 2.77 mmol, 6.0 eq. or 3*2.0 eq. added after 1 h each to the reaction mixture), and triethylamine (0.14 g, 0.19 mL, 1.39 mmol, 3.0 eq.) in acetonitrile (6 mL) was added to at room temperature under a nitrogen atmosphere to a flask containing Tris(dibezylideneacetone)dipalladium (0.021 g, 0.023 mmol, 0.05 eq), N,N'-((1S,2S)- cyclohexane-1,2-diyl)bis(2-(diphenylphosphaneyl)-1-naphthamide) (0.018 g, 0.023 mmol, 0.05 eq). The resulting mixture was heated at 70°C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by MPLC (12 g silica cartridge, 100 % cHex 1 cv to 20 % EtOAc over 10 cv, then from 20 to 100 % EtOAc over 5 CV) to afford (S)-2-((1-methoxyallyl)oxy)ethyl 4- methylbenzenesulfonate 12 (70 mg, 0.24 mmol, 53 %, e.r.: 93:7) as a colorless liquid. ¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 5.71 (ddd, J = 17.5, 10.6, 4.5 Hz, 1H), 5.40 – 5.28 (m, 2H), 4.82 (dt, J = 4.5, 1.3 Hz, 1H), 4.18 (dd, J = 5.5, 4.2 Hz, 1H), 3.76 – 3.70 (m, 1H), 3.64 (dt, J = 11.7, 4.8 Hz, 1H), 3.28 (s, 3H), 2.45 (s, 3H). 3) Synthesis of (S)-2-(1-methoxy-2-oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (S)-2-((1-methoxyallyl)oxy)ethyl 4-methylbenzenesulfonate 12 (100 mg, 349 µmol, 1.0 eq.) was dissolved in dichloromethane (15 mL). The solution was cooled to -78°C, a stream of O3/O2 was introduced through a disposable pipet for a period of 2h. The reaction mixture was purged with a stream of N2 and DMS (0.256 mL, 3.49 mmol, 10 eq.) was added at -78 °C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The crude reaction mixture was concentrated under reduced pressure to afford (S)-2-(1-methoxy-2- oxoethoxy)ethyl 4-methylbenzenesulfonate 3a as a colorless liquid, which was used in the next step without further purification. ¹H NMR (400 MHz, Chloroform-d) δ 9.38 (d, J = 1.4 Hz, 1H), 7.80 (d, J = 8.3 Hz, 6H), 7.40 – 7.32 (m, 7H), 4.55 (d, J = 1.4 Hz, 1H), 3.91 – 3.74 (m, 3H), 3.42 (s, 3H), 2.45 (t, J = 2.2 Hz, 9H). 4) Synthesis of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10- tetrahydrotetracene-5,12-dione 4 To a solution of doxorubicin (75 mg, 0.14 mmol, 1.0 eq.) and (S)-2-(1-methoxy-2- oxoethoxy)ethyl 4-methylbenzenesulfonate 3a (60 mg, 0.21 mmol, 1.5 eq.) in anhydrous DMF (2.8 mL) was slowly added DIPEA (54 µL, 0.34 mmol, 2.5 eq.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was lyophilized. The crude product was purified by silica chromatography (12 g silica, DCM 100 % to 3 % MeOH over 20 min) to afford (8S,10S)-6,8,11-trihydroxy-8- (2-hydroxyacetyl)-1-methoxy-10-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro- 1H-pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12- dione 4 (20 mg, 0.031 mmol, 23 %) as a red solid. R_f = 0.70 (DCM/MeOH 9:1, visible light) ¹H NMR (400 MHz, Chloroform-d) δ 13.82 (s, 1H, 6-OH or 11-OH), 13.19 (s, 1H, 6-OH or 11-OH), 8.05 (dd, J = 7.7, 1.1 Hz, 1H, H-3), 7.80 (dd, J = 8.5, 7.7 Hz, 1H, H-2), 7.42 (dd, J = 8.6, 1.1 Hz, 1H, H-3), 5.51 (t, J = 5.6 Hz, 1H, H-1'), 5.33 (dd, J = 3.9, 2.2 Hz, 1H, H-7), 4.88 (s, 1H, OH), 4.78 (d, J = 3.9 Hz, 2H, H-14), 4.73 (d, J = 1.9 Hz, 1H, H-2''), 4.50 (d, J = 1.9 Hz, 1H, H-1''), 4.11 (s, 4H, H-4', 4-OMe), 4.08 – 3.99 (m, 1H, H-5'), 3.95 (t, J = 10.1 Hz, 1H, H-3''), 3.67 – 3.56 (m, 1H, H-3''), 3.48 (s, 3H, 2'-OMe), 3.46 – 3.37 (m, 1H, H-3'), 3.27 (dd, J = 19.0, 2.0 Hz, 1H, H-10), 3.05 (d, J = 18.8 Hz, 1H, H-10) 3.03 (s, 1H, OH), 2.86 (d, J = 11.8 Hz, 1H, H-4''), 2.81-2,73 (m, 1H, H-4''), 2.53 (dt, J = 14.7, 2.2 Hz, 1H, H-8), 2.13 (dd, J = 14.7, 3.9 Hz, 1H, H-8), 2.11-2,03 (m, 1H, H-2'), 1.80-1,72 (m, 1H, H-2'), 1.42 (d, J = 6.5 Hz, 3H, H-6'). The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting.

Claims

What is claimed is: 1. A method of preparing a morpholine derivative, comprising the step of contacting a 1,2-amino alcohol and a compound of formula (I) or a salt or solvate thereof in the presence of a base: R₅ R₄

(I) whereby LG is a nucleophilic leaving group, R₁ is selected from the group consisting of hydrogen, C_1-4 alkyl, and C_1-4 halogenalkyl, and R₂ to R₇ are independently from each other hydrogen or -Xm-Y-Zn-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, -CR^* ₂-, -O-, -S-, -NR*-, -N(C₂H₄)₂N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and - CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N₃, and C_1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C1-6 alkyl, C1-6 halogenalkyl, C3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy.

2. The method according to claim 1, whereby at least one of R2 to R7 is not hydrogen.

3. The method according to any one of claims 1 or 2, whereby the compound of formula (I) has a chiral or stereogenic center.

4. The method according to any one of claims 1 to 3, the compound of formula (I) having the formula (Ia):

wherein LG and R2 are as defined in claim 1.

5. The method according to any one of claims 1 to 4, whereby - LG is bromine or tosylate, and/or - R2 is -OCH3.

6. The method according to any one of claims 1 to 5, whereby the compound of formula (I) is selected from the group consisting of the following formulae: ,

,

, wherein * denotes the binding position.

7. The method according to any one of claims 1 to 6, whereby the ratio (mole:mole) of the compound according to formula (I) or the salt or solvate thereof to the 1,2-amino alcohol is ≥ 0.5:1 and ≤5:1.

8. The method according to any one of the claims 1 to 7, whereby the 1,2-amino alcohol is part of a five- or six membered ring.

9. A compound of formula (I) or a salt or solvate thereof:

whereby LG is a nucleophilic leaving group, R1 is selected from the group consisting of hydrogen, C_1-4 alkyl, and C_1-4 halogenalkyl, and R₂ to R₇ are independently from each other hydrogen or -Xm-Y-Zn-R^*, wherein each -X- and each -Z- is independently selected from the group consisting of -Y-, -CR^* ₂-, -O-, -S-, -NR*-, -N(C₂H₄)₂N-, -CO-, -COO-, -OCO-, -NH(CO)O-, and - CR^*=CR^*- in a way that no O and/or S atoms are directly bound to each other, wherein each R^* is independently selected from the group consisting of hydrogen, halogen, N3, and C1-4 alkyl, and wherein a maximum of one of all -X- and -Z- is selected from -Y-, wherein m is an integer selected from 1 to 6, n is an integer selected from 0 to 6, and Y is a single bond or a five-membered heterocyclic ring, the five-membered heterocyclic ring being optionally substituted with at least one residue selected from the group consisting of halogen, -OH, C_1-6 alkyl, C_1-6 halogenalkyl, C_3-4 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, and C1-6 halogenalkoxy, wherein at least one of R2 to R7 is not hydrogen.

10. The compound of formula (I) or the salt or solvate thereof according to claim 9, wherein the compound of formula (I) is selected from the group consisting of the following formulae: ,

,

wherein R’ is selected from the group consisting of -OEtCF₃, -OEtSMe, -OEtNHAlloc, - OEtCO2allyl, chloroethoxy, fluoroethoxy,

wherein * denotes the binding position.

11. A compound of formula (III) or a salt or solvate thereof:

with LG, R1, and R2-R7 being as defined in claim 9 or 10, wherein at least one of R2 to R₇ is not hydrogen, and R₁₀ being either hydrogen or -(C=O)-R₁₃, with R₁₃ being C_1-6-alkyl or phenyl.

12. The compound of formula (III) or the salt or solvate thereof according to claim 11, wherein the compound of formula (III) is selected from the group consisting of the following formulae:

, wherein R¹⁷ is selected from

wherein * denotes the binding position.

13. A compound of formula (IV) or a salt or solvate thereof:

with LG, R1, and R2-R7 being as defined in claim 9 or 10, wherein at least one of R2 to R₇ is not hydrogen, and R₁₁ and R₁₂ being independently from each other selected from hydrogen or C_1-6-alkyl.

14. The compound of formula (IV) or the salt or solvate thereof according to claim 13, wherein the compound of formula (IV) is selected from the group consisting of the following formulae:

wherein -R¹⁸ is selected from Br, -OMe, -SMe, and -CH₂F, and -R¹⁶ is selected from

, wherein R¹⁷ is selected from

wherein * denotes the binding position.

15. A method of preparing a compound of formula (I) or a salt or solvate thereof according to any one of claims 9 or 10 starting from a compound of formula (IV) or a salt or solvate thereof according to any one of claims 13 or 14, comprising the step of ozonolysis of the compound of formula (IV) or the salt or solvate thereof followed by reductive workup to achieve the compound of formula (I) or the salt or solvate thereof.