TWI828311B - 合成化合物、包含該合成化合物的套組及其用途 - Google Patents
合成化合物、包含該合成化合物的套組及其用途 Download PDFInfo
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- TWI828311B TWI828311B TW111134068A TW111134068A TWI828311B TW I828311 B TWI828311 B TW I828311B TW 111134068 A TW111134068 A TW 111134068A TW 111134068 A TW111134068 A TW 111134068A TW I828311 B TWI828311 B TW I828311B
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- benzyl
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- galacto
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Abstract
本揭示內容是關於一種化合物及其於預斷或診斷神經退化性疾病的用途。所述化合物具有式(I)的結構，
依據本揭示內容的實施方式，所述神經退化性疾病可以是阿茲海默症、帕金森氏症、亨汀頓氏舞蹈症、額顯葉失智症、弗里德希氏失調症、老年性黃斑部病變或庫茲德賈克氏病。
Description
本揭示內容是關於預斷及/或診斷疾病的領域。更具體來說，本揭示內容是關於利用合成的神經節苷脂(ganglioside)來預斷及/或診斷神經退化性疾病。
神經退化是一種因神經元結構及功能漸進性喪失(包含突觸功能障礙及神經元凋亡)所導致的疾病。位於大腦不同區域的神經退化會造成不同的神經退化性疾病，例如影響數千萬人的阿茲海默症(Alzheimer’s disease,AD，一種老年人最常見的失智症)，以及帕金森氏症(Parkinson disease,PD)及亨汀頓氏舞蹈症(Huntington’s disease,HD)等運動神經元退化性疾病。失智症是指某些心智功能(例如記憶力、專注力及抽象思考能力)顯著喪失的疾病。AD是其中一種最常見的失智症。在AD患者中，有五種廣泛研究之源自腦脊液(cerebrospinal fluid,CSF)及大腦影像的AD病理學生物標記。該些生物標記分別是於CSF中減少的Aβ42、於CSF中增加的磷酸化tau蛋白及tau蛋白總量、於PET、PET類澱粉蛋白影像中減少的氟化去氧葡萄糖攝取，以及結構性MRI測量之腦萎縮。然而，相關領域至今仍缺乏血液相關的生物標記(包含Aβ的含量)，可據以輔助診斷AD。儘管如此，基於可及性及侵入性較低的採檢流程，相關領域仍高度需要針對血漿而非CSF的分析研究。
HD的特徵在於認知能力下降、運動障礙及行為異常。HD是一種體染色體顯性遺傳的疾病，主要由編碼亨汀頓蛋白(Huntingtin，一種廣泛表現的蛋白)的基因中CAG三核苷酸重複異常擴增所導致。在HD病患中，CAG的重複數會高於35，而正常CAG的重複數則會低於35。研究指出，CAG的重複數值愈多，HD的發病時間會愈早。然而，HD的基因檢測僅能偵測出具有罹患風險的個體，卻無法預測其發病時間。早期HD臨床生物標記對於HD的外顯前階段(pre-manifest stages of HD；以下簡稱「前-HD」(pre-HD))相當重要，臨床醫療人員可藉此在產生疾病相關症狀之前，及時對前-HD及早期HD病患投予干預療法。
神經節苷脂是一種含有唾液酸的醣神經鞘脂質(glycosphingolipid,GSL)，在所有脊椎動物細胞之細胞膜外葉(outer leaflet)中皆會表現，其中又以神經系統的表現量最高。神經節苷脂參與多種生物功能，包含作為抗原、細菌毒素的受體、細胞附著的介質，以及訊息傳遞的介質及調節子。神經節苷脂於神經系統的表現具有細胞特異性及發育調控性，且其數量及種類在細胞分化過程中會產生巨大的變化。已知神經節苷脂在神經發育及再生過程中扮演著重要的角色，而抗-神經節苷脂抗體則會減損該些過程。當免疫耐受機制失調，而自體抗原會被自體抗體或細胞成分辨識時，就會造成自體免疫。在諸如AD、PD及HD等神經退化性疾病的病理分析中，皆可觀察到腦部神經節苷脂狀態的改變。可於患有周邊神經病變及免疫相關神經性疾病之病患的血漿中偵測到抗-神經節苷脂抗體。
如上所述，早期診斷神經退化性疾病對於後續可能的藥物治療及改善病患的健康生活而言相當重要。研發對神經退化性疾病具有靈敏度及專一性的生物標記將有助於臨床診斷。理想的生物標記應可指示疾病相關病理改變的具體特徵，同時具備非侵入性、高成本效益及對偵測方法具備靈敏度等特性。
有鑑於此，相關領域亟需一種新穎的生物標記，可用以預斷及/或早期診斷神經退化性疾病，據以改善病患的生活品質及壽命。
發明內容旨在提供本揭示內容的簡化摘要，以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述，且其用意並非在指出本發明實施例的重要/關鍵元件或界定本發明的範圍。
本揭示內容是關於五種合成的神經節-寡醣(ganglio-oligosaccharide)，可個別作為用以預斷及/或診斷神經退化性疾病的生物標記。因此，本揭示內容亦提供一種利用合成的神經節-寡醣來預斷及/或診斷神經退化性疾病的方法。
本揭示內容的第一態樣是關於一種具有式(I)結構的化合物，
其中，
R1是H，或是可任選取代的
、
、
或
；
R2是可任選取代的乙醯基或
；以及
R3及R4個別是H，或是可任選取代的
或
。
依據某些實施方式，式(I)化合物是以下任一種化合物：
，或是
本揭示內容的第二態樣是關於一種用以預斷及/或診斷神經退化性疾病的藥學套組。本發明藥學套組包含二種化合物，其中一種化合物具有式(I)的結構，另一種化合物則是選自由
、
，以及
所組成的群組。
本揭示內容亦提供一種藉由一個體之生物檢體來預斷或診斷神經退化性疾病的方法。本發明方法包含：(a)混合所述生物檢體及式(I)化合物，以形成第一免疫複合體(immunocomplex)；(b)使抗-IgM抗體與步驟(a)之第一免疫複合體反應，以形成第二免疫複合體，其中該抗-IgM抗體是與一報導分子連接；(c)決定步驟(b)之報導分子的訊號強度；以及(d)基於步驟(c)決定的訊號強度來預斷或診斷神經退化性疾病，其中當所述訊號強度高於一對照檢體之訊號強度時，代表個體罹患神經退化性疾病或具有罹患神經退化性疾病的風險。
本揭示內容的另一態樣是關於一種用以治療一個體之神經退化性疾病的方法，包含：(a)由所述個體取得生物檢體；(b)混合步驟(a)之生物檢體與式(I)化合物，以形成第一免疫複合體；(c)使抗-IgM抗體與步驟(b)之第一免疫複合體反應，以形成第二免疫複合體，其中該抗-IgM抗體是與一報導分子連接；
(d)決定步驟(c)之報導分子的訊號強度；以及(e)基於步驟(d)決定的訊號強度對個體投予一有效量之抗-神經退化治療，其中所述個體之生物檢體的訊號強度高於一對照檢體之訊號強度。
所述生物檢體可以是全血檢體、血清檢體或血漿檢體。
依據本揭示內容某些實施例，對照檢體是源自一健康個體。
依據目的之不同，與抗-IgM抗體連接的報導分子可以是標籤分子、放射性分子、螢光分子、磷光分子、化學冷光分子或酵素。
可藉由本發明化合物、藥學套組及/或方法評估及決定的神經退化性疾病可以是阿茲海默症(Alzheimer’s disease,AD)、帕金森氏症(Parkinson disease,PD)、亨汀頓氏舞蹈症(Huntington’s disease,HD)、額顯葉失智症(frontotemporal dementia,FTD)、弗里德希氏失調症(Friedreich's ataxia)、老年性黃斑部病變(age-related macular degeneration)或庫茲德賈克氏病(Creutzfeldt-Jakob disease)。
所述個體是一哺乳動物；較佳地，是一人類。
在參閱下文實施方式後，本發明所屬技術領域中具有通常知識者當可輕易瞭解本發明之基本精神及其他發明目的，以及本發明所採用之技術手段與實施態樣。
為讓本發明的上述與其他目的、特徵、優點與實施例能更明顯易懂，所附圖式之說明如下：
第1圖是依據本揭示內容實施例1.1所繪示之結果，其闡述NC、前-HD個體及HD病患血漿中IgM的總量。將等量的血漿注至硝化纖維膜後，以槽墨法(slot blotting)定量分析IgM總量。各點代表單一個體之檢體。以單向
ANOVA及Tukey’s Post Hoc檢定來分析NC、前-HD個體及HD病患之間的統計差異。
為了使本揭示內容的敘述更加詳盡與完備，下文針對了本發明的實施態樣與具體實施例提出了說明性的描述；但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而，亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
為便於理解，在此收集本揭示內容所使用的詞彙。除非本說明書另有定義，此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。
在本揭示內容中，若「可任選取代的」(optionally substituted)一詞置於化合物(例如，單醣或多醣)之選擇的前方時，意指該選擇中每種化合物皆可為有取代的(substituted)或無取代的(unsubstituted)。舉例來說，「可任選取代的
、
、
或
」一詞等
同於「可任選取代的
、可任選取代的
、可任選取代的
或可任選取代的
」。
「取代的」(substituted)一詞包含以有機化合物所有可能的取代基或本揭示內容所述之任一取代基進行的取代，其可導致穩定化合物的形成。
值得注意的是，在具有一或多個掌性中心之化合物名稱未明確闡述該些中心的立體化學時，該名稱包含純立體異構物及其混合物。此外，圖式中任何未滿足價數(unsatisfied valences)的原子皆假設與足夠的氫原子連接，以滿足其價數。
在本揭示內容中，「預斷」(prognosis)一詞是指預測一疾病的結果，舉例來說，好或壞的結果(例如，發生神經退化性疾病的可能性)。當可想見，「預斷」(prognosis)一詞並非意指可100%準確預測疾病發生或結果的能力。相反地，本發明所屬技術領域具有通常知識者當可理解，「預斷」(prognosis)一詞是指某一病程或結果發生可能性的增加；亦即，相較於不具備特定條件(例如，具有低表現量之可辨識本發明化合物之抗-IgM抗體)的個體，一具有特定條件(例如，具有高表現量之可辨識本發明化合物之抗-IgM抗體)的個體更易發生某一病程或結果。良好的預斷包含預測發生神經退化性疾病(例如，AD或HD)的低可能性，而不利的預斷包含預測發生神經退化性疾病的高可能性。
「診斷」(diagnosis)一詞是指習知技藝人士可據以評估及/或決定一病患是否罹患一特定疾病或病症之機率(可能性)的方法。在本揭示內容中，「診斷」(diagnosis)包含利用本發明化合物的表現量(非必要地可與其他臨床特徵結合)藉由一個體之檢體來診斷(即，發生或未發生)神經退化性疾病。此種診斷不必然是100%準確地確定。許多生物標記可作為多種病症發生的指標。習知技藝人士不會單以生物標記的分析結果作為判斷資訊，而是會結合其他臨床指標來達到診斷目的。因此，相較於位在預定診斷閾值一側的測量值，位在預定診斷閾值另一側的生物標記測量值指出個體發生疾病的可能性更大。
「個體」(subject)一詞是指包含人類的哺乳動物，其可以本揭示內容之化合物、套組及/或方法進行評估及決定。除非另有所指，否則「個體」(subject)一詞同時意指男性及女性。
「健康個體」(healthy subject)一詞是指未罹患疾病(例如，神經退化性疾病)的個體。舉例來說，健康個體未曾診斷罹患疾病，且未出現與該疾病相關之二或多種(例如，二、三、四或五種)症狀。
雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值，此處已盡可能精確地呈現具體實施例中的相關數值。然而，任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處，「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是，「約」一詞代表實際數值落在平均值的可接受標準誤差之內，視本發明所屬技術領域中具有通常知識者的考量而定。除了實驗例之外，或除非另有明確的說明，當可理解此處所用的所有範圍、數量、數值與百分比(例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此，除非另有相反的說明，本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值，且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。在此處，將數值範圍表示成由一端點至另一段點或介於二端點之間；除非另有說明，此處所述的數值範圍皆包含端點。
在不和上下文衝突的情形下，本說明書所用的單數名詞涵蓋該名詞的複數型；而所用的複數名詞時亦涵蓋該名詞的單數型。
本揭示內容部分是基於發明人發現個體體內某些抗-神經節苷脂抗體的表現量與神經退化性疾病(舉例來說，AD、PD、HD、FTD、弗里德希氏
失調症、老年性黃斑部病變及庫茲德賈克氏病)的發生相關，其中相較於具有低表現量的個體，具有高表現量的個體更易罹患神經退化性疾病。據此，本揭示內容旨在提供數種用以偵測個體之抗-神經節苷脂抗體的標的化合物，據以決定該個體是否具有罹患神經退化性疾病的風險。本揭示內容亦提供利用該些標的化合物來評估神經退化性疾病的發生或發生可能性的方法。
本揭示內容的第一態樣因此是關於一種具有式(I)結構的化合物，
依據本揭示內容某些實施方式，
R1是H，或是可任選取代的
、
、
或
；
R2是可任選取代的乙醯基或
；以及
R3及R4個別是H，或是可任選取代的
或
。
依據本揭示內容某些實施例，式(I)化合物可以是以下任一種化合物：
或
依據本揭示內容某些實施方式，式(I)化合物可用以確認個體是否罹患輕度認知障礙(mild cognitive impairment,MCI)，其中在罹患MCI的個體體
內，對式(I)化合物具有專一性的抗-IgM抗體表現量會高於健康個體或AD病患體內抗體的表現量。
依據本揭示內容某些實施方式，式(I)化合物可作為一種用以確認HD外顯前階段之個體(前-HD；即，尚未產生臨床症狀之個體)的生物標記，其中相較於健康個體及HD病患，前-HD個體含有較高表現量之對式(I)化合物具專一性的抗-IgM抗體。
本揭示內容的第二態樣是關於一種藥學套組，其包含式(I)化合物作為第一化合物，以及選自以下群組的第二化合物：
以及
依據本揭示內容某些實施方式，所述藥學套組可用以區分罹患MCI的個體與健康個體，其中藥學套組包含化合物1-1(G19)作為第一化合物，以及G3、G4、G9、G21、G23、G24或G27作為第二化合物。亦或是，藥學套組可包含化合物1-2(G25)作為第一化合物，以及G3、G4、G9、G21、G23、G24或G27作為第二化合物，據以達到預斷及/或診斷的功效。
依據本揭示內容某些實施方式，所述藥學套組可用以確認罹患MCI或AD的個體；在該些實施方式中，藥學套組包含化合物1-3(G18)作為第一化合物，以及G9、G10、G11、G14、G21、G23、G24或G27作為第二化合物。亦或是，藥學套組可包含化合物1-2(G25)作為第一化合物，以及G9、G10、G11、G14、G21、G23、G24或G27作為第二化合物，據以預斷及/或診斷疾病。
在某些操作實施例中，本發明用以區分前-HD個體與健康個體的藥學套組包含化合物1-5(G20)作為第一化合物，以及G17作為第二化合物。
依據某些實施方式，本發明用以確認前-HD個體與HD病患的藥學套組包含化合物1-5(G20)作為第一化合物，以及G1-G17、G21-G24或G27-G28中的任一種化合物作為第二化合物。
所述藥學套組包含可分別放置本揭示內容之第一及第二化合物的二種容器，其中所述容器可以由玻璃或塑膠等不同材料所製備。套組可更包含位於容器上或附加於容器的標籤或套裝軟體。所述標籤或套裝軟體用以指示使用者如何使用本發明藥學套組來評估神經退化性疾病。此外或亦或是，套組可更包含第三容器，用以放置緩衝液或稀釋劑，例如磷酸鹽緩衝液、林格氏液(Ringer’s solution)或葡萄糖溶液。套組可更包含其他商業或使用者需要的材料，包含其他緩衝液、稀釋劑、過濾器、盤皿、玻片及試管。
本揭示內容的第三態樣旨在提供一種用以預斷及/或診斷一個體之神經退化性疾病的方法，其係利用本發明化合物來分析源自個體之生物檢體，以達到預斷及/或診斷疾病的目的。本發明方法包含以下步驟：(a)混合生物檢體及式(I)化合物，以形成第一免疫複合體；(b)使抗-IgM抗體與步驟(a)之第一免疫複合體反應，以形成第二免疫複合體，其中抗-IgM抗體是與一報導分子連接；(c)決定步驟(b)之報導分子的訊號強度；以及(d)基於步驟(c)決定的訊號強度來預斷或診斷神經退化性疾病。
一般來說，個體是一哺乳動物；較佳為人類。生物檢體可以是全血檢體、血清檢體、血漿檢體，或是任何含有抗體(即，IgM、IgG、IgA、IgE及/或IgD抗體)的組織或生物體液。依據本揭示內容一操作實施例，生物檢體是血漿檢體。
在步驟(a)中，先將生物檢體(例如，血漿檢體)與式(I)化合物混合。混合後，式(I)化合物會與生物檢體中的抗-神經節苷脂抗體反應，形成第一免疫複合體(即，化合物-抗體之免疫複合體，其中抗體可以是IgM、IgG、IgA、IgE或IgD的形式)。依據使用目的之不同，可先將式(I)化合物固定於一盤皿或玻
片上，再加人生物檢體。或者是，可將式(I)化合物懸浮於溶液中，接著再與生物檢體混合。較佳地，在進行步驟(b)之前，移除未結合的化合物/抗體。
在步驟(b)中，將與報導分子連接的抗-IgM抗體加至第一免疫複合體(即，化合物-抗體之免疫複合體)中。所述抗-IgM抗體可專一辨識並結合至第一免疫複合體的IgM抗體部分，進而形成第二免疫複合體(即，化合物-IgM抗體-抗-IgM抗體之複合體)。較佳地，在進行步驟(c)之前，移除未結合的抗-IgM抗體。
習知技藝人士可選擇適當的報導分子與抗-IgM抗體連接。例示性之報導分子包含標籤分子、放射性分子、螢光分子、磷光分子、化學冷光分子及酵素。
接著，於步驟(c)測量報導分子所發散的訊號強度。測量方法會隨著報導分子種類的不同而有所差異。舉例來說，當報導分子是螢光分子時，可利用流式細胞儀或微陣列掃描器來測量其訊號強度。或者是，當報導分子是化學冷光分子時，可利用化學冷光分子讀取器來測量其發散的訊號強度。
如步驟(d)所述，臨床醫療人員或習知技藝人士可依據訊號強度來預斷及/或診斷神經退化性疾病。依據本揭示內容某些實施方式，當訊號強度高於對照檢體之訊號強度時，則該個體罹患神經退化性疾病或是具有罹患神經退化性疾病的風險。對照檢體可以源自一健康個體，或收集不同供體檢體的資料庫。
基於預斷及/或診斷結果，臨床醫療人員或習知技藝人士可及時對有需要的個體(例如，罹患神經退化性疾病的個體)投予治療(例如，抗-神經退化治療)。因此，本揭示內容的另一態樣是關於一種用以治療一個體之神經退化性疾病的方法，包含：(a)由所述個體取得生物檢體；
(b)混合步驟(a)之生物檢體與式(I)化合物，以形成第一免疫複合體；(c)使抗-IgM抗體與步驟(b)之第一免疫複合體反應，以形成第二免疫複合體，其中該抗-IgM抗體是與一報導分子連接；(d)決定步驟(c)之報導分子的訊號強度；以及(e)基於步驟(d)決定的訊號強度，對個體投予一有效量之抗-神經退化治療，其中所述個體之生物檢體的訊號強度高於對照檢體之訊號強度值。
本發明治療方法之步驟(a)到(d)與預斷/診斷方法之步驟(a)到(c)相似；為求簡潔，在此不再贅述。
在步驟(e)中，是對個體投予抗-神經退化治療以改善及/或減緩其與神經退化性疾病相關的病症，其中所述個體的訊號強度高於對照檢體(例如，健康個體的血漿檢體，或收集不同供體檢體的資料庫)的訊號強度。例示性之抗-神經退化治療包含，但不限於，多巴胺促效劑(例如，阿朴嗎啡(apomorphine)、麥角鹼衍生物(bromocriptine)、稠環乙脲(lisurid)、培高利特(pergolid)、二氫-α-麥角克普汀(dihydro-α-ergocryptine)、卡麥角林(cabergoline)、羅替戈汀(rotigotine)、普拉克索(pramipexol)、羅平尼咯(ropinirol)、吡貝地爾(piribedil)及左旋多巴(levodopa))、單胺氧化酶B(monoaminooxidase B,MAO-B)的抑制劑(例如，希利治林(selegiline)及雷莎吉蘭(rasagiline))、N-甲基D-天門冬胺酸鹽(N-Methyl D-Aspartate,NMDA)的拮抗劑(例如，金剛烷胺(amantadine)及美金剛(memantine))、麩醯胺酸鹽受體的拮抗劑(例如，利魯唑(riluzole))、抗膽鹼劑(例如，甲磺醯芐托品(benztropine mesylate)、比培力汀(biperiden)、二苯安明(diphenhydramine)及苯海索(trihexyphenidyl))、抗氧化劑(例如，薑黃素、維生素C、維生素E、類黃酮(flavonoid)及多酚類(polyphenols))、組蛋白去乙醯酶的抑制劑(例如，丁酸鈉鹽(sodium butyrate)、苯丁酸(phenylbutyrate)及辛二醯苯胺異羥肟酸(suberoylanilide hydroxamic acid))，以及其組合。
下文提出多個實驗例來說明本發明的某些態樣，以利本發明所屬技術領域中具有通常知識者實作本發明，且不應將這些實驗例視為對本發明範圍的限制。據信習知技藝者在閱讀了此處提出的說明後，可在不需過度解讀的情形下，完整利用並實踐本發明。此處所引用的所有公開文獻，其全文皆視為本說明書的一部分。
材料
由Sigma-Aldrich及Acros購買商業溶劑及試劑，未進一步純化即直接使用。
一般方法
法用前，將用以醣化的分子篩4Å(MS-4Å；Reidel-deHaen編號：31812)於350℃加熱10小時，使其粉碎及活化。利用分析型TLC盤(PLC矽膠-60，F254，2毫米)監測反應，並以UV(254奈米)進行觀察，或是藉由酸性鉬酸銨鈰溶液(ceric ammonium molybdate)或茴香醛(p-anisaldehyde)染色觀察。以矽膠(40-63微米)、LiChroprep® RP8(40-63微米)及LiChroprep® RP18(40-63微米)進行快速管柱色層分析。
儀器
利用NMR光譜儀(600MHz/150MHz)記錄質子核磁共振(1H NMR)光譜及碳核磁共振(13C NMR)光譜。以每百萬分單位數(parts per million(ppm)；δ級)來記錄質子的化學位移，並與四甲矽烷(tetramethylsilane；δ=0)進行比對分析。同樣以每百萬分單位數(ppm,δ級)來記錄碳的化學位移，並以四甲矽烷(δ=0)進行校正。以無畸變增強極化轉移技術(distortionless enhancement by polarization transfer,DEPT 135)來確認多重性(multiplicity)。將數據表示如下：
化學位移、多重性(s=單峰(singlet)、d=二重峰(doublet)、t=三重峰(triplet)、q=四重峰(quartet)、m=多重峰(multiplet)、br=寬峰(broad))、以Hz為單位的耦合常數(J)，以及積分。利用BioTOFTM III來得到高解析質譜，以UltraflexTM II TOF/TOF來得到MALDI-TOF MS。
收集血漿檢體
由健康個體、前-HD個體及HD病患收集人類血漿檢體。全面編碼檢體以保護病患隱私。
由健康個體、輕度認知障礙(mild cognitive impairment,MCI)及AD病患收集人類血漿檢體。全面編碼檢體以保護病患隱私。藉由數種臨床診斷(例如，病史、身體檢查、CT掃描、核磁共振影像)來區分健康個體及病患的血漿檢體。
製備聚醣微陣列(glycan microarray)
以探針將約0.7奈升之100μM含有胺的聚醣由96孔盤轉置到具有NHS塗層的載玻片上，據以列印微陣列，其中所述聚醣是溶於一含有300mM磷酸鈉緩衝液(pH 8.5)及0.05% TritonTM X-100的列印緩衝液中。各聚醣由下到上點漬10個重複，將二種聚醣點漬於同一列中，其係水平放置於各子陣列/網格中。共有28個不同的聚醣點漬於各子陣列/網格中，一片陣列玻片包含16種用以分析不同血漿檢體的相同網格。將列印得到的玻片於溼度為80%的環境中反應一小時，之後乾燥處理至隔日。將玻片儲存於室溫乾燥箱中，以待後續使用。在進行結合試驗前，以含有3%牛血清白蛋白(bovine serum albumin,BSA)的磷酸鹽緩衝液(phosphate buffered saline,PBS；pH 7.4)處理玻片，之後以蒸餾水及PBS洗滌玻片二次。
血漿的聚醣微陣列分析
利用0.05% Tween® 20/3% BSA/PBS緩衝液(pH 7.4)以1：100的比例稀釋健康個體、前-HD階段個體及HD病患的血漿檢體後，將稀釋檢體加至聚醣微陣列的網格中，接著放置在密閉盒中於加溼器中搖晃1小時。之後，以含有0.05% Tween® 20的PBS緩衝液(pH 7.4)、PBS緩衝液(pH 7.4)及蒸餾水洗滌玻片三次。將與Cy3鍵結的山羊抗-人類IgM抗體加至玻片後，將玻片置於加溼器中搖晃1小時。以含有0.05% Tween® 20之PBS緩衝液(pH 7.4)、含有0.05% TritonTM X-100之PBS緩衝液(pH 7.4)、PBS緩衝液(pH 7.4)及蒸餾水洗滌玻片三次後，風乾處理。利用微陣列螢光晶片讀取器以635奈米波長掃瞄玻片。
槽墨分析
以TBS緩衝液(100mM Tris-HCl,150mM NaCl,pH 7.4)稀釋所有血漿檢體後，利用含有NC膜的48孔洞點墨裝置進行真空過濾。以10%之溶於TBS緩衝液的牛奶處理膜1小時。利用TBS緩衝液洗滌膜二次。為分析IgM總量，將膜與HRP連接之抗-IgM二級抗體反應1小時。為分析岩藻醣化成分(fucosylated components)的含量，將膜與凝集素反應1小時。之後，以TBS緩衝液洗滌膜二次，再與HRP連接之卵白素二級抗體反應1小時。再次以TBS緩衝液洗滌膜二次，接著利用化學冷光受質進行呈色反應。藉由軟體來定量分析數據。
資料分析
利用軟體進行數據資料的螢光分析。扣除各抗體點的局部背景值。計算相同陣列中重複點的數值。在分析人口統計特徵時，是利用SPSS程式以卡方檢定(Chi-square test)分析性別，以不成對Student’s t檢定分析CAG重複數，並以單向ANOVA分析年齡。當P值<0.05時，視為具有統計意義。以Pearson評估28種聚醣與年齡的相關性。為了確定用以檢測疾病進程的聚醣，利用邏輯式迴歸來計算勝率比(odds ratios,ORs)及95%信賴區間(confidence interval,CI)。使用SAS程式中的逐步選取(stepwise)、向前選取(forward)及向後選取(backward)
演算法。以接收器操作特徵曲線(Receiver-operating characteristic,ROC)分析來區分正常對照組與前-HD個體的差異，以及前-HD個體與HD病患的差異。以具有95%信賴區間的曲線下面積(area under the curve,AUC)來評估靈敏度及專一性。
4-甲苯基5-胺-9-O-苄基5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯/Methyl(4-methylphenyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-di-O-chloroacetyl-3,5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosid)onate(18)
在0℃的氬氣環境中，將吡啶(4.82毫升，59.59毫莫耳，15.00當量)及氯乙醯氯(1.26毫升，15.84毫莫耳，4.00當量)加至含有4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(17)(2.00公克，3.97毫莫耳，1.00當量)的無水CH2Cl2(80毫升)溶液中。於0℃攪拌1小時後，將反應混合物倒入1M HCl溶液中。以二份CH2Cl2洗滌水相。利用飽和NaHCO3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸
發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(18)(2.39公克，3.64毫莫耳，92%)。1H NMR(600MHz,CDCl3)δ 7.23-7.37(m,7H),7.12(d,2H,J=8.1Hz),5.38(dd,1H,J=9.8,1.6Hz),5.34(br-s,1H),5.30(dt,1H,J=9.8,2.3Hz),4.58(d,1H,J=12.0Hz),4.34(d,1H,J=12.0Hz),4.15(d,1H,J=15.3Hz),4.04(d,1H,J=15.4Hz),4.03(dd,1H,J=9.9,1.7Hz),3.95(d,1H,J=15.0Hz),3.86(ddd,1H,J=13.5,10.0,3.6Hz),3.78(d,1H,J=14.8Hz),3.74(dd,1H,J=11.4,2.0Hz),3.61(dd,1H,J=11.5,2.7Hz),3.55(s,3H),3.06(dd,1H,J=12.0,3.7Hz),2.96(ddd,1H,J=10.4,10.3,1.4Hz),2.34(s,3H),2.09(t,12.4Hz)；13C NMR(150MHz,CDCl3)δ 167.99,167.96,166.44,159.06,140.78,137.23,136.25,130.02,128.81,128.49,128.40,124.81,88.53,77.61,75.11,73.59,70.75,70.54,66.58,57.85,53.24,41.18,40.46,37.70,21.53；HRMS(ESI-TOF)計算得C29H31NO10SCl2Na[M+Na]+ 678.0943，發現678.0941。
5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-2-(二丁基磷醯基)-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯/Methyl(5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-di-O-chloroacetyl-2-(dibutylphosphoryl)-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosid)onate(10)
在0℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(N-iodosuccinimide，1.47公克，6.53毫莫耳，2.00當量)及0.5M三氟甲磺酸(1.96毫升，0.98毫莫耳，0.30當量)的無水Et2O溶液加至含有4-甲苯基5-胺-9-O-苄基
-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(18)(2.15公克，3.27毫莫耳，1.00當量)、磷酸丁脂(1.83毫升，9.84毫莫耳，3.00當量)及粉碎活化MS-4Å的無水CH2Cl2(80毫升)溶液中。於相同溫度攪拌至隔日後，以CH2Cl2稀釋反應混合物，並以矽藻土墊過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3的混合液中。以二份CH2Cl2萃取水層。以飽和NaHCO3溶液、飽和Na2S2O3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-2-(二丁基磷醯基)-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(10)(2.16公克，2.91毫莫耳，89%)。1H NMR(600MHz,CDCl3)δ 7.21-7.35(m,5H),5.39(dd,1H,J=9.8,1.6Hz),5.38(br-s,1H),5.32(dt,1H,J=9.8,2.1Hz),4.57(d,1H,J=12.1Hz),4.45(dd,1H,J=10.0,1.6Hz),4.34(d,1H,J=12.1Hz),4.26(d,1H,J=15.2Hz),4.14(d,1H,J=15.3Hz),3.96-4.07(m,6H),3.82(d,1H,J=14.9Hz),3.79(s,3H),3.66(dd,1H,J=11.3,1.8Hz),3.55(dd,1H,J=11.3,2.8Hz),3.23(t,1H,J=10.1Hz),2.86(dd,1H,J=12.2,3.7Hz),2.61(t,1H,J=12.8Hz),1.58-1.63(m,4H),1.32-1.39(m,4H),0.891(t,3H,J=7.5Hz),0.889(t.3H,J=7.4Hz)；13C NMR(150MHz,CDCl3)δ 168.1,167.7(d,7.5Hz,3 J C-Hax(2.59)=6.0Hz),166.4,159.2,137.2,128.8,128.4,98.9(d,7.5Hz),76.1,75.4,73.6,70.22,70.16,68.2(d,6.0Hz),68.1(d,6.0Hz),66.6,57.2,53.7,41.1,40.5,37.3(d,4.4Hz),32.3(d,6.0Hz),32.2(d,6.0Hz),18.79,18.76,13.8,13.7；HRMS(ESI-TOF)計算得C30H42NO14PCl2Na[M+Na]+ 794.1618，發現794.1614。
4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯/ Methyl(4-methylphenyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-7,8-O-isopropylidene-2-thio-D-glycero-α-D-galacto-2-nonulopyranosid)onate(19)
在室溫的氬氣環境中，將10-樟腦磺酸(0.67公克，2.88毫莫耳，0.60當量)加至含有4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(17)(2.42公克，4.81毫莫耳，1.00當量)的2,2’-二甲氧基丙烷(30毫升)溶液中。於室溫攪拌1小時後，以三乙胺中和反應混合物，之後進行真空蒸發。以矽膠(70：30己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(19)(2.36公克，4.34毫莫耳，90%)。1H NMR(600MHz,CDCl3)δ 7.52(d,2H,J=8.1Hz),7.23-7.31(m,5H),7.14(d,2H,J=8.0Hz),5.17(br-s,1H),4.47(dd,1H,J=12.6,6.5Hz),4.46(d,1H,J=11.9Hz),4.31(d,1H,J=12.0Hz),4.00(d,1H,J=6.7Hz),3.86-3.91(m,1H),3.73-3.78(m,2H),3.63-3.68(m,2H),3.54(s,3H),3.17(dd,1H,J=11.8,3.5Hz),2.32(s,3H),2.17(t,1H,J=12.1Hz),1.71(s,3H),1.39(s,3H)；13C NMR(150MHz,CDCl3)δ 168.5,159.6,140.6,138.3,137.1,129.8,128.6,128.1,127.9,125.4,110.5,89.1,77.8,77.1,76.3,75.9,73.2,67.9,58.1,52.9,37.6,26.7,25.9,21.6；HRMS(ESI-TOF)計算得C28H33NO8SNa[M+Na]+ 566.1825，發現566.1821。
5-胺-9-O-苄基-5-N,4-O-羰基-2-(二丁基磷醯基)-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯/ Methyl(5-amino-9-O-benzyl-5-N,4-O-carbonyl-2-(dibutylphosphoryl)-3,5-dideoxy-7,8-O-isopropylidene-D-glycero-α-D-galacto-2-nonulopyranosid)onate(9)
在0℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(2.32公克，10.31毫莫耳，2.00當量)及0.5M三氟甲磺酸溶液(3.09毫升，1.55毫莫耳，0.30當量)的無水Et2O溶液加至含有4-甲苯基5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-2-硫基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(19)(2.80公克，5.15毫莫耳，1.00當量)、磷酸丁脂(2.87毫升，15.43毫莫耳，3.00當量)及粉碎活化MS-4Å的無水CH2Cl2(110毫升)溶液中。於相同溫度攪拌至隔日後，以CH2Cl2稀釋反應混合物，再以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3的混合液中。以二份CH2Cl2萃取水層。以飽和NaHCO3溶液、飽和Na2S2O3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到5-胺-9-O-苄基-5-N,4-O-羰基-2-(二丁基磷醯基)-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(9)(2.85公克，4.53毫莫耳，88%)。1H NMR(600MHz,CDCl3)δ 7.25-7.35(m,5H),5.34(br-s,1H),4.59(s,2H),4.47(dd,1H,J=12.6,6.5Hz),4.32(dd,1H,J=9.7,1.6Hz),3.97-4.13(m,8H),3.80(s,3H),3.65(t,1H,J=10.5Hz),2.95(dd,1H,J=11.8,3.5Hz),2.33(t,1H,J=12.8Hz),1.60-1.67(m,4H),1.47(s,3H),1.35-1.42(m,4H),1.33(s,3H),0.92(t,3H,J=7.4Hz),0.90(t.3H,J=7.4Hz)；13C NMR(150MHz,CDCl3)δ 168.1,159.7,138.4,128.6,128.3,127.9,109.7,99.6(d,6.2Hz),76.5,76.4,75.6,
73.6,68.8,68.5(d,5.7Hz),68.1(d,6.2Hz),58.0,53.4,38.4(d,8.0Hz),32.34(d,7.6Hz),32.28(d,7.6Hz),26.6,25.3,18.8,13.8；HRMS(ESI-TOF)計算得C29H44NO12PNa[M+Na]+ 652.2499，發現652.2493。
4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-1-硫基-α-D-半乳哌喃糖苷/4-methylphenyl 2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-7,8-O-isopropylidene-D-glycero-α-D-galacto-2-nonulopyranoylonate)-1-thio-α-D-galactopyranoside(20)
在-78℃的氬氣環境中，將TBSOTf(0.93毫升，4.05毫莫耳，1.40當量)加至含有5-胺-9-O-苄基-5-N,4-O-羰基-2-(二丁基磷醯基)-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(9)(2.12公克，3.37毫莫耳，1.20當量)、4-甲苯基2-O-苯甲醯基-6-O-苄基-1-硫基-β-D-半乳哌喃糖苷(12)(1.35公克，2.81毫莫耳，1.00當量)及粉碎活化MS-4Å的無水CH2Cl2(50毫升)溶液中。於相同溫度攪拌1小時後，以三乙胺中和反應混合物，並以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3的混合液中。以二份CH2Cl2萃取水層。以鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-1-硫基-β-D-半乳哌喃糖苷(20)(2.31公克，2.57毫莫耳，90%，僅α)。以1H NMR分析來決定α/β比例。1H NMR(600MHz,CDCl3)δ 8.02(dd,2H,J=7.7,1.3Hz),7.58(t,1H,J=7.5Hz),7.45(t,2H,J=7.8Hz),7.34(d,2H,J=8.1Hz),7.25-7.31(m,10H),7.01(d,2H,J=8.1Hz),5.42(t,1H,J=9.8Hz),5.30(br-s,1H),4.69(d,1H,J=10.1Hz),4.55(dd,2H,J=14.6,11.8Hz),4.51(t,2H,J=12.8Hz),4.44(dt,1H,J=5.1,6.8Hz),4.30(dd,1H,J=9.5,3.1Hz),4.13(d,1H,J=2.9Hz),4.03(dd,1H,J=7.1,2.0Hz),3.92(ddd,1H,J=12.8,11.4,3.6Hz),3.87(d,1H,J=9.9Hz),3.86(dd,1H,J=10.0,3.1Hz),3.75-3.82(m,3H),3.67(d,1H,J=5.5Hz),3.66(s,3H),3.43(t,1H,J=10.8Hz),2.60(dd,1H,J=12.0,3.6Hz),2.27(s,3H),1.95(t,1H,J=12.5Hz),1.41(s,3H),1.30(s,3H)；13C NMR(150MHz,CDCl3)δ 168.7,165.3,159.7,138.27,138.25,138.0,133.6,133.2,129.9,129.81,129.78,129.2,128.8,128.7,128.6,128.1,128.0,127.9,109.2,100.0,87.2,77.6,76.9,76.3,75.7,75.4,75.2,73.8,73.7,69.6,68.9,68.7,68.6,58.3,53.5,36.6,27.1,24.7,21.3；HRMS(ESI-TOF)計算得C48H53NO14SNa[M+Na]+ 922.3084，發現922.3091。
4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷/4-methylphenyl 2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-7,8-O-isopropylidene-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-1-thio-β-D-galactopyranoside(21)
在室溫的氬氣環境中，將無水吡啶(0.61毫升，7.54毫莫耳，3.00當量)、4-二甲胺基吡啶(dimethylaminopyridine，31毫克，2.54毫莫耳，0.10當量)及氯甲酸2,2,2-三氯乙酯(2,2,2-trichloroethyl chloroformate，0.69毫升，5.01毫莫耳，2.00當量)加至含有4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-1-硫基-β-D-半乳哌喃糖苷(20)(2.26公克，2.51毫莫耳，1.00當量)的無水CH2Cl2(35毫升)溶液中。於相同溫度攪拌1小時後，將反應混合物倒入1M HCl中冷卻。以二份CH2Cl2萃取水層。以1M HCl溶液、飽和NaHCO3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷(21)(2.54毫克，2.36毫莫耳，94%)。1H NMR(600MHz,CDCl3)δ 8.06(dd,2H,J=8.3,1.2Hz),7.59(t,1H,
J=7.5Hz),7.46(t,2H,J=7.7Hz),7.34(d,2H,J=8.2Hz),7.22-7.31(m,10H),7.02(d,2H,J=8.2Hz),5.47(t,1H,J=10.0Hz),5.40(d,1H,J=2.9Hz),5.32(br-s,1H),4.78(d,1H,J=11.8Hz),4.73(d,1H,J=10.0Hz),4.64(d,1H,J=11.8Hz),4.58(d,1H,J=11.9Hz),4.55(d,1H,J=11.9Hz),4.48(dd,1H,J=10.0,2.9Hz),4.47(s,2H),4.42(dd,1H,J=12.8,5.9Hz),4.02(dd,1H,J=7.1,2.2Hz),3.92(d,2H,J=5.9Hz),3.84(ddd,1H,J=12.8,11.4,3.5Hz),3.80(d,1H,J=6.1Hz),3.78(dd,1H,J=9.6,2.4Hz),3.67(dd,1H,J=10.2,6.5Hz),3.66(s,3H),3.60(dd,1H,J=9.9,5.9Hz),3.38(t,1H,J=10.1Hz),2.55(dd,1H,J=12.0,3.5Hz),2.28(s,3H),1.90(t,1H,J=12.5Hz),1.44(s,3H),1.31(s,3H)；13C NMR(150MHz,CDCl3)δ 167.5,165.1,159.7,153.8,138.4,138.2,137.9,133.8,133.2,130.1,129.9,129.6,129.2,128.8,128.61,128.56,128.1,127.95,127.91,109.0,100.4,94.7,87.8,76.6,76.4,75.4,75.3,74.9,73.9,73.5,72.9,68.9,68.8,68.5,58.5,53.4,36.5,27.5,24.7,21.4；HRMS(ESI-TOF)計算得C51H54NO16SCl3Na[M+Na]+ 1096.2127，發現1096.2113。
4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷/4-methylphenyl 2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-1-thio-β-D-galactopyranoside(22)
於室溫，將10-樟腦磺酸(0.27公克，1.16毫莫耳，1.00當量)加至含有4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-7,8-O-亞異丙基-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷(21)(1.24公克，1.15毫莫耳，1.00當量)的甲醇(35毫升)溶液中。於室溫攪拌至隔日後，以三乙胺中和反應混合物，並進行真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷(22)(1.13公克，1.09毫莫耳，95%)。1H NMR(600MHz,CDCl3)δ 8.00(d,2H,J=7.4Hz),7.51(t,1H,J=7.5Hz),7.26-7.39(m,14H),7.04(d,2H,J=8.0Hz),5.80(br-s,1H),5.21(d,1H,J=3.1Hz),4.80(d,1H,J=11.8Hz),4.65(d,1H,J=11.9Hz),4.54(s,2H),4.47(d,1H,J=11.8Hz),4.45(d,1H,J=11.5Hz),4.40-4.57(m,2H),3.87(t,1H,J=6.4Hz),3.83(ddd,1H,J=13.2,11.1,3.6Hz),3.75(s,3H),3.65-3.77(m,4H),3.58(dd,1H,J=9.7,6.9Hz),3.50-3.53(m,2H),3.11(br-s,1H),3.05(t,1H,J=9.7Hz),2.68(dd,1H,J=11.8,3.2Hz),2.29(s,3H),1.98(t,1H,J=12.5Hz)；13C NMR(150MHz,CDCl3)δ 167.9,159.5,154.2,138.6,137.83,137.75,133.7,133.4,129.9,128.9,128.8,128.6,128.3,128.1,128.0,127.9,99.6,94.6,79.2,77.6,76.0,74.7,73.9,73.8,73.3,71.3,69.3,68.0,58.4,53.7,35.4,21.4；HRMS(ESI-TOF)計算得C48H50NO16SCl3Na[M+Na]+ 1056.1814，發現1056.1812。
4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-β-D-半乳哌喃糖苷/ 4-methylphenyl 2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-di-O-chloroacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranoylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-1-thio-β-D-galactopyranoside(23)
在-78℃的氬氣環境中，將TMSOTf(1.11毫升，6.12毫莫耳，2.20當量)加至含有4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-α-D-半乳哌喃糖苷(22)(2.89公克，2.79毫莫耳，1.00當量)、5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-2-(二丁基磷醯基)-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃壬酮糖甲酯(10)(4.14公克，5.58毫莫耳，2.00當量)及粉碎活化MS-4Å的無水CH2Cl2(36毫升)與乙腈(24毫升)混合液中。於相同溫度攪拌2小時後，以飽和NaHCO3溶液中和反應混合物，並以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3溶液中。以二份CH2Cl2萃取水層。以鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-α-D-半乳哌喃糖苷(23)(3.86公克，2.46毫莫耳，88%，α/β=
>95/5)。以1H NMR分析來決定α/β比例。1H NMR(600MHz,CDCl3)δ 8.05(d,2H,J=7.7Hz),7.59(t,1H,J=7.4Hz),7.47(t,2H,J=7.7Hz),7.22-7.37(m,15H),7.10(d,2H,J=5.9Hz),7.04(d,2H,J=8.0Hz),5.75(br-s,1H),5.38(dd,1H,J=10.2,1.2Hz),5.31(dt,1H,J=9.9,2.2Hz),5.29(br-s,1H),5.13(d,1H,J=3.1Hz),4.79(d,1H,J=11.8Hz),4.66(d,1H,J=11.8Hz),4.59(d,1H,J=12.1Hz),4.47(d,1H,J=11.8Hz),4.45(d,1H,J=11.8Hz),4.33-4.37(m,3H),4.17-4.23(m,3H),3.93(d,1H,J=14.9Hz),3.80-3.85(m,3H),3.75(s,3H),3.72(s,3H),3.66-3.74(m,5H),3.49-3.58(m,4H),3.38(d,1H,J=8.7Hz),3.17(br-s,1H),2.99(t,1H,J=10.4Hz),2.77(dd,1H,J=12.2,3.3Hz),2.69(br-s,1H),2.65(dd,1H,J=11.7,3.0Hz),2.28(s,3H),2.04(t,1H,J=12.8Hz),1.81(t,1H,J=12.5Hz)；13C NMR(150MHz,CDCl3)δ 168.4,167.9,167.7,167.2,159.3,159.1,154.1,138.5,137.7,137.1,137.0,133.7,133.3,130.0,129.9,128.84,128.79,128.7,128.6,128.44,128.42,128.30,128.25,128.2,128.09,128.06,127.9,101.3,99.0,94.6,78.2,77.8,76.6,76.0,74.5,74.4,74.2,74.0,73.9,73.6,73.5,72.6,70.3,69.4,68.0,67.1,58.9,57.5,53.7,53.5,41.5,40.4,37.2,35.8；HRMS(ESI-TOF)計算得C70H73N2O26SCl5Na[M+Na]+ 1587.2513，發現1587.2524。
5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-di-O-chloroacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2- nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(8)
在室溫的氬氣環境中，將含有N-碘代琥珀醯亞胺(0.61公克，2.71毫莫耳，2.20當量)及0.5M三氟甲磺酸的無水Et2O(0.50毫升，0.25毫莫耳，0.20當量)溶液加至含有4-甲苯基2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-1-硫基-α-D-半乳哌喃糖苷(23)(1.94公克，1.24毫莫耳，1.00當量)、5-氯戊基-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(11)(1.37公克，2.47毫莫耳，2.00當量)及粉碎活化MS-4Å的無水CH2Cl2(21毫升)及無水乙腈(14毫升)混合液中。於相同溫度攪拌30分鐘後，以CH2Cl2稀釋反應混合物，再以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3溶液中。以二份CH2Cl2萃取水層。以飽和NaHCO3溶液、飽和Na2S2O3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(50：50己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃
糖苷(8)(1.99公克，1.00毫莫耳，81%)。1H NMR(600MHz,CDCl3)δ 7.95(d,2H,J=7.6Hz),7.58(t,1H,J=7.4Hz),7.45(t,2H,J=7.7Hz),7.19-7.37(m,28H),7.12(d,2H,J=6.8Hz),5.94(br-s,1H),5.39(dd,1H,J=10.2,1.3Hz),5.35(dt,1H,J=10.1,2.6Hz),5.30(br-s,1H),5.11(d,1H,J=3.3Hz),4.91(d,1H,J=10.8Hz),4.86(d,1H,J=11.8Hz),4.85(d,1H,J=11.0Hz),4.79(d,1H,J=10.8Hz),4.70(d,1H,J=11.0Hz),4.66(d,1H,J=11.9Hz),4.60(d,2H,J=12.1Hz),4.17-4.38(m,11H),3.94(d,1H,J=14.9Hz),3.89(t,1H,J=9.4Hz),3.78-3.86(m,4H),3.76(s,3H),3.69-3.73(m,2H),3.68(s,3H),3.63(t,1H,J=8.5Hz),3.50-3.55(m,6H),3.44(t,2H,J=6.7Hz),3.30-3.43(m,6H),3.26(t,2H,J=8.9Hz),3.19(dt,1H,J=9.5,2.7Hz),3.00(t,1H,J=10.7Hz),2.79(dd,1H,J=12.1,3.3Hz),2.72(t,1H,J=9.8Hz),2.50(dd,1H,J=12.1,3.3Hz),2.05(t,1H,J=12.8Hz),1.83(t,1H,J=12.4Hz),1.69-1.75(m,2H),1.41-1.63(m,4H)；13C NMR(150MHz,CDCl3)δ 168.4,167.9,167.3,167.2,159.2,159.1,154.1,139.2,138.7,138.5,137.8,137.1,136.9,133.8,129.8,129.6,128.9,128.81,128.78,128.61,128.58,128.49,128.46,128.4,128.1,128.06,128.03,127.9,127.85,127.76,127.4,103.6,101.3,100.2,99.5,94.6,82.8,82.0,78.5,78.0,77.3,77.1,76.7,76.6,75.6,75.0,74.8,74.5,74.3,74.2,74.0,73.7,73.6,72.8,71.6,70.3,69.8,69.3,68.1,67.1,59.2,57.5,53.7,53.4,45.0,41.5,40.4,37.3,35.0,32.5,29.1,23.7；HRMS(ESI-TOF)計算得C95H104N2O32Cl6Na[M+Na]+ 2017.4601，發現2017.4623。
5-胺戊基4-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷/
5-aminopentyl 4-O-(5-acetoamide-3,5-dideoxy-8-O-(5-acetoamide-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranosylonate)-β-D-galactopyranoside)-β-D-glucopyranoside(1)(No.19(G19)
於室溫，將LiOH(179毫克)至加含有5-疊氮基戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(8)(300毫克，0.15毫莫耳，1.00當量)之15毫升1,4-二
烷及15毫升H2O混合液中。於80℃攪拌30小時後，真空蒸發反應混合物。逆相管柱色層分析法(LiChroprep® RP-18)純化殘餘物。於室溫，將NaHCO3(1.50公克)及乙酐(750毫升)加至含有上述殘餘物之45毫升H2O溶液中。於相同溫度攪拌1小時，將NaHCO3(1.50公克)及乙酐(750毫升)加入反應混合物。於相同溫度再攪拌1小時，於室溫將LiOH(1.50公克)加至反應混合物。於相同溫度攪拌12小時後，真空蒸發反應混合物。以逆相管柱色層分析法(LiChroprep® RP-18)純化殘餘物。於室溫，將NaN3(37毫克，0.57毫莫耳，5.00當量)及KI(2毫克，0.01毫莫耳，0.10當量)加至含有上述殘餘物的10毫升無水DMF溶液中。於60℃攪拌至隔日，真空蒸發反應混合物。以逆相管柱色層分析法(LiChroprep® RP-18)純化殘餘物。於室溫，將Pd(OH)2(750毫克)加至含有上述殘餘物之15毫升甲醇及15毫升H2O混合液中。於室溫、H2環境中攪拌至隔日，利用矽藻土墊過
濾反應混合物後，真空蒸發濾液。藉由逆相管柱色層分析法(LiChroprep® RP-18)純化殘餘物，以得到5-胺戊基4-O-(3-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷(1)(92毫克，0.09毫莫耳，60%)。1H NMR(600MHz,CDCl3)δ 4.51(d,1H,J=7.9Hz),4.48(d,1H,J=8.0Hz),4.18(dd,1H,J=12.2,3.6Hz),4.13(m,1H),4.08(dd,1H,J=9.9,3.1Hz),4.00(dd,1H,J=12.2,2.0Hz),3.95(d,1H,J=3.1Hz),3.79-3.93(m,7H),3.54-3.76(m,15H),3.30(dd,1H,J=9.2,8.2Hz),3.00(t,2H,J=7.5Hz),2.77(dd,1H,J=12.3,4.6Hz),2.67(dd,1H,J=12.3,4.4Hz),2.06(s,3H),2.02(s,3H),1.64-1.75(m,6H),1.43-1.48(m,2H)；13C NMR(150MHz,CDCl3)δ 177.7,176.2,176.1,105.4,104.8,103.3,102.9,80.9,80.7,78.2,78.0,77.5,77.1,76.7,75.6,75.4,74.5,72.8,72.0,71.9,71.2,70.8,70.6,70.2,65.3,64.3,63.8,62.7,55.0,54.5,43.2,42.4,42.1,30.9,29.1,25.0,24.8；HRMS(ESI-TOF)計算得C39H66N3O27[M-H]- 1008.3884，發現1008.3887。
5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(2-O-benzoyl-6-O-benzyl-3-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(24)
於室溫，將Et3N(0.47毫升，3.62毫莫耳，3.00當量)加至含有5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-雙-O-氯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(8)(2.40公克，1.20毫莫耳，1.00當量)之10毫升無水CH2Cl2及15毫升甲醇混合液中。於相同溫度攪拌2小時，以Amberlite IR-120樹脂中和並過濾反應混合物。真空蒸發濾液。以矽膠(40：60己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油
-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(24)(1.59公克，0.86毫莫耳，72%)。1H NMR(600MHz,CDCl3)δ 7.95(d,2H,J=7.6Hz),7.58(t,1H,J=7.4Hz),7.42(t,2H,J=7.8Hz),7.36(d,2H,J=7.4Hz),7.23-7.32(m,22H),7.17-7.21(m,6H),6.21(br-s,1H),5.76(br-s,1H),5.16(d,1H,J=3.1Hz),4.92(d,1H,J=10.8Hz),4.88(d,1H,J=11.8Hz),4.85(d,2H,J=11.2Hz),4.79(d,1H,J=10.7Hz),4.71(d,1H,J=11.1Hz),4.64(d,1H,J=11.9Hz),4.57(d,1H,J=12.2Hz),4.52(d,1H,J=12.6Hz),4.50(d,1H,J=12.8Hz),4.42(d,1H,J=11.6Hz),4.38(d,1H,J=11.6Hz),4.31(d,1H,J=12.2Hz),4.25(d,1H,J=11.6Hz),4.24(d,1H,J=7.7Hz),4.18(d,1H,J=11.6Hz),4.15(br-s,1H),3.92-3.97(m,2H),3.89(t,1H,J=9.3Hz),3.81-3.86(m,2H),3.75-3.77(m,1H),3.67(s,3H),3.62(s,3H),3.62-3.68(m,4H),3.47-3.57(m,9H),3.44(t,2H,J=6.7Hz),3.41-3.44(m,1H),3.35(dd,2H,J=8.0,9.1Hz),3.24-3.32(m,2H),3.19(dt,1H,J=10.0,2.9Hz),2.90(dd,2H,J=11.7,3.2Hz),2.50(d,1H,J=9.3Hz),2.08(t,1H,J=12.5Hz),1.95(t,1H,J=12.3Hz),1.71-1.75(m,2H),1.56-1.64(m,2H),1.42-1.53(m,2H)；13C NMR(150MHz,CDCl3)δ168.8,167.2,160.2,160.0,154.2,139.2,138.7,138.5,137.9,137.8,137.2,133.9,129.8,129.5,128.9,128.8,128.7,128.60,128.57,128.5,128.4,128.1,128.0,127.9,127.82,127.78,127.42,103.7,99.9,99.8,94.6,82.7,82.0,77.1,76.8,76.4,75.7,75.1,74.8,74.6,74.5,74.1,73.9,73.8,73.7,73.5,72.3,71.7,71.6,71.2,71.0,69.8,68.2,67.0,59.7,57.4,53.7,53.5,45.1,35.8,32.5,29.1,23.7；HRMS(ESI-TOF)計算得C91H102N2O30Cl4Na[M+Na]+ 1865.5169，發現1865.5176。
5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡 喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(2-O-benzoyl-6-O-benzyl-3-O-(methyl 7-O-acetyl-5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-O-diacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-4-O-(2,2,2-trichloroethoxycarbonyl)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(25)
於室溫，將乙酐(0.45毫升，4.73毫莫耳，9.00當量)、吡啶(0.51毫升，6.31毫莫耳，12.00當量)及DMAP(6毫克，0.05,0.10當量)加至含有5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(24)(970毫克，0.53毫莫耳，1.00當量)之25毫升無水CH2Cl2溶液中。於相同溫度攪拌1小時，將反應混合物倒入1M HCl溶液中。以二份CH2Cl2萃取水相。利用飽和NaHCO3溶液及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(57：43己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基
-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(25)(893毫克，0.45毫莫耳，85%)。1H NMR(600MHz,CDCl3)δ 8.12(d,2H,J=7.3Hz),7.54(t,1H,J=7.4Hz),7.47(t,2H,J=7.7Hz),7.17-7.35(m,28H),6.99(d,1H,J=5.5Hz),6.98(d,1H,J=7.7Hz),5.75(br-s,1H),5.34-5.37(m,2H),5.30(d,1H,J=11.2Hz),5.28(d,1H,J=11.3Hz),5.10(d,1H,J=3.1Hz),4.94(d,1H,J=10.9Hz),4.91(dd,1H,J=6.1,2.0Hz),4.85(d,1H,J=11.9Hz),4.84(d,1H,J=11.2Hz),4.83(d,1H,J=8.5Hz),4.79(d,1H,J=10.7Hz),4.70(d,1H,J=11.1Hz),4.64(d,1H,J=11.9Hz),4.59(d,1H,J=12.1Hz),4.54(d,1H,J=12.1Hz),4.42(d,1H,J=11.2Hz),4.20-4.36(m,7H),4.08(d,1H,J=10.0Hz),4.05(dd,1H,J=5.6,3.1Hz),3.90(t,1H,J=9.3Hz),3.74(s,3H),3.72-3.86(m,5H),3.71(s,3H),3.43(t,2H,J=6.7Hz),3.40-3.60(m,8H),3.29-3.36(m,3H),3.18-3.20(m,1H),2.97(t,1H,J=10.6Hz),2.86(dd,1H,J=12.1,3.4Hz),2.61(t,1H,J=10.4Hz),2.58(dd,1H,J=11.9,3.5Hz),2.16(s,3H),2.01(t,1H,J=12.8Hz),1.88(s,3H),1.76(s,3H),1.70-1.75(m,3H),1.55-1.63(m,2H),1.40-1.52(m,2H)；13C NMR(150MHz,CDCl3)δ 171.3,170.44,170.38,168.0,167.9,168.4,159.4,159.1,154.0,139.3,138.77,138.76,137.9,137.4,136.9,133.6,130.2,129.8,129.0,128.75,128.69,128.53,128.51,128.48,128.4,128.34,128.26,128.2,128.03,127.97,127.8,127.7,127.5,127.4,103.6,100.9,100.7,98.5,94.8,82.9,82.1,76.9,76.7,76.12,76.06,75.6,75.0,74.8,74.2,73.9,73.8,73.6,73.3,72.1,71.2,71.7,71.3,69.7,68.9,68.3,67.9,67.6,67.4,59.0,57.9,53.4,53.3,45.1,37.4,36.2,32.5,29.2,23.7,21.6,20.8,20.7；HRMS(ESI-TOF)計算得C97H108N2O33Cl4Na[M+Na]+ 1991.5486，發現1991.5492。
5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯 乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(2-O-benzoyl-6-O-benzyl-3-O-(methyl 7-O-acetyl-5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-O-diacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(26)
於室溫，將活化的Zn粉(1.43公克，21.87毫莫耳，50.00當量)加至含有5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-4-O-(2,2,2-三氯乙氧羰基)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(25)(865毫克，0.44毫莫耳，1.00當量)之20毫升無水THF及5毫升酯酸混合液中。於相同溫度攪拌1小時，利用乙酸乙酯稀釋反應混合物，並以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3溶液中。以二份乙酸乙酯萃取水層。利用鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(45：55己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲
酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(26)(763毫克，0.42毫莫耳，95%)。1H NMR(600MHz,CDCl3)δ 7.97(d,2H,J=7.7Hz),7.56(t,1H,J=7.4Hz),7.43(t,2H,J=7.7Hz),7.20-7.34(m,28H),7.14-7.15(m,2H),5.65(br-s,1H),5.39(br-s,1H),5.36(t,1H,J=8.9Hz),5.32(d,1H,J=10.8Hz),5.30(d,1H,J=10.3Hz),5.01(t,1H,J=4.1Hz),4.94(d,1H,J=10.8Hz),4.82(d,1H,J=11.0Hz),4.78(d,2H,J=9.3Hz),4.66(d,1H,J=11.0Hz),4.59(d,1H,J=12.2Hz),4.53(d,1H,J=12.1Hz),4.52(d,1H,J=11.6Hz),4.37(d,1H,J=11.9Hz),4.29-4.33(m,4H),4.23(d,1H,J=7.8Hz),4.21(dd,1H,J=9.9,3.5Hz),4.07(d,1H,J=9.9Hz),3.96(dd,1H,J=7.7,3.6Hz),3.80-3.90(m,7H),3.76(s,3H),3.64(dd,1H,J=8.7,7.2Hz),3.55(s,3H),3.52-3.56(m,4H),3.38-3.48(m,8H),3.34(t,2H,J=8.5Hz),3.22(dt,1H,J=9.7,2.0Hz),3.01(t,1H,J=10.5Hz),2.97(dd,1H,J=12.1,3.2Hz),2.75(t,1H,J=10.4Hz),2.52(br-s,1H),2.43(dd,1H,J=12.0,3.5Hz),2.17(s,3H),2.09(t,1H,J=12.8Hz),1.96(t,1H,J=12.5Hz),1.87(s,3H),1.70-1.74(m,2H),1.64(s,3H),1.55-1.61(m,2H),1.41-1.52(m,2H)；13C NMR(150MHz,CDCl3)δ 171.3,170.8,170.5,168.1,167.7,164.9,159.5,159.2,139.3,138.74,138.67,138.2,137.5,137.4,133.6,129.9,129.8,128.9,128.74,128.67,128.6,128.5,128.4,128.31,128.29,128.25,128.18,128.1,128.0,127.9,127.8,127.7,127.4,103.6,101.5,100.7,99.6,83.0,82.1,76.9,76.4,75.49,75.46,75.4,75.0,74.9,74.7,74.1,73.7,73.64,73.59,73.4,73.2,72.6,71.1,69.7,69.4,68.9,68.4,68.23,68.15,67.8,67.5,58.8,57.9,53.5,53.2,45.1,37.5,35.1,32.5,29.2,23.7,21.5,20.8,20.5；HRMS(ESI-TOF)計算得C94H107N2O31ClNa[M+Na]+ 1817.6444，發現1817.6444。
5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-叔丁基二甲基-矽基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基
-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(4-O-(6-O-acetyl-4-O-benzyl-3-O-tert-butyldimethyl-silyl-2-deoxy-2-(2,2,2-trichloroethyoxycarbonylamino)-β-D-galactopy-ranoside)-2-O-benzoyl-6-O-benzyl-3-O-(methyl 7-O-acetyl-5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-O-diacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(27)
在-20℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(345毫克，1.53毫莫耳，4.00當量)及0.5M三氟甲磺酸的無水Et2O(0.23毫升，0.12毫莫耳，0.30當量)溶液加至含有5-氯戊基4-O-(2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(26)(688毫克，0.38毫莫耳，1.00當量)、4-甲苯基6-O-乙醯基-4-O-苄基-3-O-叔丁基二甲基-
矽基-2-去氧-1-硫基-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷(16)(813毫克，1.15毫莫耳，3.00當量)及粉碎活化MS-4Å的無水CH2Cl2(13毫升)溶液中。於相同溫度攪拌2小時。利用CH2Cl2稀釋反應混合物，並以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3的混合液中。以二份CH2Cl2萃取水層。利用飽和NaHCO3、飽和Na2S2O3及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(55：45己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-叔丁基二甲基-矽基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙-去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(27)(829毫克，0.35毫莫耳，92%)，(旋轉異構體A：B的比例=88：12)。旋轉異構體A：1H NMR(600MHz,CDCl3)δ 7.95(d,2H,J=7.6Hz),7.54(t,1H,J=7.4Hz),7.44(t,2H,J=7.7Hz),7.17-7.39(m,32H),7.07(d,2H,J=6.0Hz),6.76(t,1H,J=7.4Hz),5.82(br-s,1H),5.32-5.37(m,3H),5.25(d,1H,J=10.6Hz),5.250(d,1H,J=10.6Hz),5.248(d,1H,J=10.1Hz),5.08(d,1H,J=11.1Hz),4.93(d,1H,J=9.7Hz),4.88(d,1H,J=11.8Hz),4.82(d,1H,J=6.4Hz),4.81(d,1H,J=11.3Hz),4.72-4.77(m,3H),4.65(d,1H,J=7.7Hz),4.58(d,1H,J=12.1Hz),4.57(d,1H,J=12.1Hz),4.50(d,1H,J=11.2Hz),4.47(d,1H,J=11.4Hz),4.36(d,1H,J=11.3Hz),4.31(d,2H,J=12.1Hz),4.26(d,1H,J=11.8Hz),4.19-4.22(m,3H),4.09-4.13(m,2H),4.00(dd,1H,J=9.7,1.6Hz),3.93(d,1H,J=9.8Hz),3.82-3.86(m,5H),3.742(s,3H),3.736(s,3H),3.72-3.80(m,4H),3.62-3.66(m,3H),3.56(d,1H,J=1.2Hz),3.52(t,1H,J=9.0Hz),3.47-3.52(m,2H),3.42(t,2H,J=6.7Hz),3.31-3.45(m,5H),3.27(dd,1H,J=9.0,8.1Hz),3.13-3.15(m,1H),2.94(t,2H,J=10.4Hz),2.88(dd,1H,J=11.9,3.2
Hz),2.47(br-d,1H,J=8.3Hz),2.16(s,3H),1.98(t,1H,J=12.6Hz),1.90(s,3H),1.81(s,3H),1.72(s,3H),1.69-1.74(m,3H),1.53-1.59(m,2H),1.39-1.51(m,2H),0.88(s,9H),0.08(s,3H),0.05(s,3H)；13C NMR(150MHz,CDCl3)δ 171.3,170.8,170.7,170.6,168.5,168.3,164.3,159.3,154.2,139.0,138.9,138.79,138.75,137.5,137.3,133.6,130.0,129.5,128.9,128.8,128.6,128.5,128.4,128.3,128.1,128.0,127.9,127.82,127.76,127.7,127.5,103.6,100.5,100.0,99.9,96.1,82.6,81.9,76.6,76.5,76.2,76.0,75.7,75.2,75.1,74.9,74.6,74.2,74.1,73.63,73.56,73.5,73.3,71.9,71.2,70.9,69.7,69.2,68.8,68.3,67.7,63.4,59.2,57.9,55.4,53.7,53.5,45.1,37.5,35.4,32.5,29.2,26.0,23.7,21.7,20.9,20.7,20.6,18.2,-3.9,-4.9；HRMS(ESI-TOF)計算得C118H141N3O38Cl4SiNa[M+Na]+ 2398.7614，發現2398.7629。
5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙-去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(4-O-(6-O-acetyl-4-O-benzyl-2-deoxy-2-(2,2,2-trichloroethyoxycarbonyl amino)-β-D-galactopyranoside)-2-O-benzoyl-6-O-benzyl-3-O-(methyl 7-O-acetyl-5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-di-deoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-O-diacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(7)
在0℃的氬氣環境中，將48% BF3．OEt2(0.78毫升，2.64毫莫耳，6.00當量)加至含有5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-叔丁基二甲基矽基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(27)(1.02公克，0.44毫莫耳，1.00當量)的無水乙腈(22毫升)溶液中。於相同溫度攪拌30分鐘，將反應混合物倒入飽和NaHCO3溶液中。以二份乙酸乙酯洗滌水相。利用鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(50：50己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(7)(801毫克，0.35毫莫耳，80%)。1H NMR(600MHz,CDCl3)δ 7.93(d,2H,J=7.6Hz),7.55(t,1H,J=7.4Hz),7.44(t,2H,J=7.7Hz),7.20-7.36(m,32H),7.09-7.10(m,2H),6.94(t,1H,J=7.3Hz),6.09(d,1H,J=5.9Hz),5.83(br-s,1H),5.35-5.40(m,3H),5.26(dd,1H,J=10.2,1.5Hz),
5.06(d,1H,J=12.0Hz),4.93(d,1H,J=11.3Hz),4.90(d,1H,J=10.1Hz),4.827(d,1H,J=11.1Hz),4.826(dd,1H,J=5.2,2.4Hz),4.75(d,1H,J=10.0Hz),4.72(d,2H,J=10.7Hz),4.64(t,2H,J=11.5Hz),4.57(t,2H,J=12.0Hz),4.56(d,1H,J=8.7Hz),4.41(s,2H),4.31(dd,1H,J=12.1,3.6Hz),4.29(d,1H,J=11.3Hz),4.21-4.23(m,3H),4.09-4.14(m,2H),4.00(dd,1H,J=9.8,1.4Hz),3.78-3.98(m,10H),3.75(s,3H),3.74-3.77(m,1H),3.73(s,3H),3.67(dd,1H,J=11.4,8.3Hz),3.49-3.61(m,7H),3.42(t,2H,J=6.6Hz),3.36-3.45(m,5H),3.30(t,1H,J=8.5Hz),3.17(br-d,1H,J=9.2Hz),2.94(t,1H,J=10.6Hz),2.88(dd,1H,J=11.9,3.2Hz),2.84(t,1H,J=10.4Hz),2.43(dd,1H,J=12.2,3.6Hz),2.15(s,3H),2.03(t,1H,J=13.0Hz),1.97(t,1H,J=12.6Hz),1.86(s,3H),1.79(s,3H),1.69-1.74(m,2H),1.68(s,3H),1.54-1.59(m,2H),1.40-1.51(m,2H)；13C NMR(150MHz,CDCl3)δ 171.3,170.8,170.7,170.6,168.3,167.6,164.2,159.29,159.26,157.2,138.8,138.72,138.68,138.3,137.6,137.3,133.7,129.9,129.4,129.0,128.8,128.69,128.67,128.51,128.46,128.38,128.36,128.3,128.2,128.1,128.0,127.8,127.71,127.67,127.6,127.5,103.6,102.2,100.5,100.2,100.0,95.9,82.7,82.0,76.63,76.58,76.2,76.1,75.94,75.87,75.2,75.1,75.0,74.9,74.8,74.1,73.8,73.63,73.56,73.5,72.2,70.9,69.7,68.82,68.79,68.3,67.75,67.69,63.0,59.1,57.9,56.0,53.7,53.5,45.1,37.6,35.2,32.5,29.2,23.7,21.7,20.9,20.6,20.5；HRMS(ESI-TOF)計算得C112H127N3O38Cl4Na[M+Na]+ 2284.6749，發現2284.6758。
5-胺戊基4-O-(4-O-(2-乙醯胺基-2-去氧-β-D-半乳哌哺糖苷)-3-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃酮酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷/5-aminopentyl 4-O-(4-O-(2-acetoamino-2-deoxy-β-D-galactopyranoside)-3-O-(5-acetoamino-3,5-dideoxy-8-O-(5-acetoamino-3,5-dideoxy-D-glycero-α-D-
galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-β-D-galactopyranoside)-β-D-glucopyranoside(2)(No.18)(G18)
於室溫，將5毫升1M NaOH溶液加至含有5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(7)(260毫克，0.11毫莫耳，1.00當量)的10毫升THF溶液中。於80℃攪拌至隔日後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫，將NaHCO3(500毫克)及乙酐(250毫升)加至含有上述殘餘物的7.5毫升1,4-二
烷及7.5毫升H2O混合液中。於相同溫度攪拌1小時，將NaHCO3(500毫克)及乙酐(250毫升)加至反應混合物。於相同溫度再攪拌1小時，於室溫將LiOH(500毫克)加至反應混合物。於相同溫度攪拌12小時後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫，將NaN3(37毫克，0.57毫莫耳，5.00當量)及KI(2毫克，0.01毫莫耳，0.10當量)加至含有上述殘餘物之10毫升無水DMF溶液中。於60℃攪拌至隔日後，真空蒸發反應混合物。藉由逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫，將催化劑AcOH及Pd(OH)2(375毫克)加至含有上
述殘餘物之7.5毫升甲醇及7.5毫升H2O混合液中。於室溫、H2環境中攪拌至隔日，利用矽藻土過濾反應混合物，並真空蒸發濾液。逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物，以得到5-胺戊基4-O-(4-O-(2-乙醯胺基-2-去氧-β-D-半乳哌喃糖苷)-3-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃酮酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷(2)(58毫克，0.05毫莫耳，45%)。1H NMR(600MHz,CDCl3)δ 4.68(d,1H,J=8.4Hz),4.48(d,1H,J=8.3Hz),4.47(d,1H,J=8.2Hz),4.17(dd,1H,J=12.1,4.0Hz),4.14(dd,1H,J=10.2,2.5Hz),4.08-4.10(m,1H),4.02(d,1H,J=1.8Hz),3.98(d,1H,J=10.7Hz),3.56-3.94(m,27H),3.38(dd,1H,J=9.8,8.1Hz),3.28(t,1H,J=8.5Hz),2.99(t,2H,J=7.5Hz),2.75(dd,1H,J=12.3,4.5Hz),2.67(dd,1H,J=12.2,4.2Hz),2.06(s,3H),2.03(s,3H),2.01(s,3H),1.63-1.77(m,6H),1.42-1.47(m,2H)；13C NMR(150MHz,CDCl3)δ 177.71,177.68,177.6,176.1,176.0,105.48,105.45,104.7,103.22,103.20,81.07,80.96,78.5,77.5,77.3,77.2,77.1,77.0,76.4,75.5,75.4,74.5,73.5,72.8,72.4,72.0,71.2,70.8,70.4,65.3,64.2,63.7,63.4,62.7,55.2,55.1,54.5,43.2,42.1,42.0,30.9,29.1,25.3,25.1,24.78,24.75；HRMS(ESI-TOF)計算得C47H79N4O32[M-H]- 1211.4677，發現1211.4675。
2-{[(1S,2R)-i-(6-{[2-({6-[(5-胺戊基)氧基]-4,5-二羥-2-(羥甲基)氧雜-3-基}氧基)-5-{[4,5-二羥-3-(2-羥基乙醯胺)-6-(羥甲基)氧雜-2-基]氧基}-3-羥基-6-(羥甲基)氧雜-4-基]氧基}-6-羧基-4-羥基-3-(2-羥基乙醯胺)氧雜-2-基)-1,3-二羥丙酮-2-基]氧基}-4-羥基-5-(2-羥基乙醯胺)-6-[(1R,2R)-1,2,3-三羥丙基]
烷-2-羧酸/2-{[(1S,2R)-1-(6-{[2-({6-[(5-aminopentyl)oxy]-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl}oxy)-5-{[4,5-dihydroxy-3-(2-hydroxyacetamido)-6-(hydroxymethyl)
oxan-2-yl]oxy}-3-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-6-carboxy-4-hydroxy-3-(2-hydroxyacetamido)oxan-2-yl)-1,3-dihydroxypropan-2-yl]oxy}-4-hydroxy-5-(2-hydroxyacetamido)-6-[(1R,2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylic acid(3)(No.26)(G26)
於室溫，將LiOH(5.0毫莫耳，50.0當量)加至含有7(230毫克，0.1毫莫耳，1.00當量)的1,4-二
烷(5.00毫升)及H2O(5.00毫升)混合液中。於80℃攪拌36小時後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物，以得到產物殘餘物。於0℃，將NaHCO3(2.5毫莫耳，25.0當量)及苄氧基乙醯氯(benzloxyacetyl chloride，2.5毫莫耳，25.0當量)加至含有上述殘餘物之1,4-二
烷(5.00毫升)及H2O(5.00毫升)混合液中。於相同溫度攪拌1小時後，於0℃將NaHCO3(2.5毫莫耳，25.0當量)及苄氧基乙醯氯(2.5毫莫耳，25.0當量)加至反應混合物。以相同溫度攪拌1小時後，將LiOH(5.0毫莫耳，50.0當量)加至反應混合物。以相同溫度攪拌12後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫，將NaN3(37毫克，0.57毫莫耳，5.00當量)及KI(2毫克，0.01毫莫耳，0.10當量)加至含有上述殘餘物之10毫升無水DMF溶液中。於60℃攪拌至隔日後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。將Pd(OH)2(1毫莫耳)加至含有上述殘餘物之甲醇(2.00毫升)及H2O(2.00毫升)混合液中。於H2環境中氫解
(hydrogenolyze)反應混合物12小時，過濾反應混合物後，真空蒸發濾液。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物，以得到α(2→8)GD2NGc 3(53毫克，0.04毫莫耳，42%)。1H NMR(600MHz,CDCl3)δ 4.43(d,1H,J=7.9Hz),4.39(d,1H,J=8.0Hz),4.14(d,1H,J=7.9Hz),4.11(d,1H,J=2.9Hz),3.98(d,1H,J=2.1Hz),3.92-3.87(m,3H),3.86-3.78(m,6H),3.75-3.50(m,27H),3.30(t,1H,J=9.8Hz),3.21(t,1H,J=7.5Hz),2.90(t,1H,J=7.4Hz),2.71-2.68(m,2H),2.64-2.61(m,1H),1.72-1.64(m,2H),1.63-1.52(m,2H),1.51-1.47(m,2H),1.39-1.30(m,2H)；13C NMR(150MHz,CDCl3)δ 176.1,175.7,175.4,173.7,171.0,102.6,102.3,102.0,100.5,100.2,78.5,78.2,75.5,74.8,74.7,74.5,74.3,74.0,73.4,72.8,72.5,72.3,71.8,70.9,70.4,70.0,69.6,69.0,68.5,68.4,68.2,67.9,67.7,67.4,62.5,61.6,61.2,61.0,60.0,52.2,51.4,40.6,39.4,30.9,28.4,21.4,20.0；HRMS(ESI-TOF)計算得C47H80N4O35[M-H]- 1261.4681，發現1261.4676。
5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-(2-O-苯甲醯基-3,4,6-三-O-苄基-β-D-半乳哌喃糖苷)-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷/5-chloropentyl 4-O-(4-O-(6-O-acetyl-4-O-benzyl-3-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-galactopyranoside)-2-deoxy-2-(2,2,2-trichloroethyoxy-carbonylamino)-β-D-galactopyranoside)-2-O-benzoyl-6-O-benzyl-3-O-(methyl 7-O-acetyl-5-amino-9-O-benzyl-5-N,4-O-carbonyl-3,5-dideoxy-8-O-(methyl 5-amino-9-O-benzyl-5-N,4-O-carbonyl-7,8-O-diacetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-
nonulopyranoylonate)-β-D-galactopyranoside)-2,3,6-tri-O-benzyl-β-D-glucopyranoside(6)
在-35℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(95毫克，0.42毫莫耳，2.80當量)及0.5M三氟甲磺酸之無水Et2O(90微升，0.05毫莫耳，0.30當量)溶液加至含有5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(7)(340毫克，0.15毫莫耳，1.00當量)、4-甲苯基-2-O-苯甲醯基-3,4,6-三-O-苄基-β-D-半乳哌喃糖苷(28)(248毫克，0.38毫莫耳，2.50當量)及粉碎活化MS-4Å之無水CH2Cl2(6毫升)溶液中。於相同溫度攪拌1小時，利用CH2Cl2稀釋反應混合物後，以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3的混合液中。以二份CH2Cl2萃取水層。利用飽和NaHCO3、飽和Na2S2O3及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(50：50己烷-乙酸乙酯)層析分離殘餘物，以得到5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-(2-O-苯甲醯基-3,4,6-三-O-苄基-β-D-半乳哌喃糖苷)-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰
基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(6)(386毫克，0.14毫莫耳，93%)。1H NMR(600MHz,CDCl3)δ 8.09(d,2H,J=7.3Hz),8.04(d,2H,J=7.3Hz),7.54(t,1H,J=7.4Hz),7.48(t,3H,J=7.4Hz),7.41-7.42(m,2H),7.15-7.38(m,43H),7.03-7.09(m,4H),6.90(d,2H,J=6.1Hz),6.87(t,1H,J=7.2Hz),5.74(dd,1H,J=10.1,8.0Hz),5.67(br-s,1H),5.39(br-s,1H),5.30(s,2H),5.22(t,1H,J=9.0Hz),5.04-5.12(m,4H),5.00(d,1H,J=11.3Hz),4.83(d,1H,J=11.0Hz),4.79(d,1H,J=6.6Hz),4.75(d,1H,J=8.2Hz),4.74(d,1H,J=10.1Hz),4.683(d,1H,J=11.3Hz),4.679(d,1H,J=11.1Hz),4.58-4.64(m,6H),4.50(d,2H,J=12.4Hz),4.46(s,2H),4.44(d,1H,J=11.2Hz),4.37(d,1H,J=12.2Hz),4.34(d,1H,J=12.1Hz),4.31(d,1H,J=10.6Hz),4.29(d,1H,J=12.0Hz),4.221(d,1H,J=8.1Hz),4.217(d,1H,J=9.6Hz),4.18(d,1H,J=10.6Hz),4.00-4.10(m,6H),3.73(s,3H),3.69(s,3H),3.67-3.84(m,8H),3.44(t,2H,J=6.6Hz),3.41-3.61(m,14H),3.20-3.31(m,5H),2.98(t,1H,J=10.1Hz),2.92(dd,1H,J=11.9,3.0Hz),2.88(dd,1H,J=12.0,3.3Hz),2.48(t,1H,J=10.3Hz),2.17(s,3H),2.16(t,1H,J=11.6Hz),1.99(t,1H,J=12.8Hz),1.90(s,3H),1.80(s,3H),1.74(s,3H),1.71-1.76(m,2H),1.56-1.64(m,2H),1.43-1.53(m,3H)；13C NMR(150MHz,CDCl3)δ 171.3,170.5,170.3,170.2,168.2,168.0,165.4,164.7,159.3,159.0,153.8,138.8,138.74,138.73,738.369,138.61,138.5,138.0,137.7,137.3,136.6,133.4,133.1,130.1,130.0,129.4,129.0,128.71,128.68,128.59,128.55,128.5,128.4,128.34,128.31,128.29,128.26,128.2,128.1,128.0,127.9,127.8,127.74,128.69,127.64,127.60,127.53,127.48,127.4,103.5,101.9,100.7,100.5,98.6,98.2,96.7,82.9,82.1,79.8,76.7,76.6,76.3,76.2,75.5,75.4,75.3,75.0,74.9,74.8,74.6,74.29,74.36,74.1,73.9,73.8,73.73,73.69,73.6,73.2,
73.1,72.1,72.0,71.7,71.4,71.1,69.6,68.8,68.71,68.65,68.2,67.7,67.6,63.0,58.9,57.8,55.4,53.4,53.2,45.0,37.4,37.0,32.5,29.1,23.7,21.6,20.8,20.5；HRMS(ESI-TOF)計算得C146H157N3O44Cl4Na2[M+2Na]2+ 1421.9423，發現1421.9431。
5-胺戊基4-O-(4-O-(2-乙醯胺基-3-O-(β-D-半乳哌喃糖苷)-2-去氧-β-D-半乳哌喃糖苷)-3-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃酮酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷/5-aminopentyl 4-O-(4-O-(2-acetoamino-3-O-(β-D-galactopyranoside)-2-deoxy-β-D-galactopyranoside)-3-O-(5-acetoamino-3,5-dideoxy-8-O-(5-acetoamino-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-D-glycero-α-D-galacto-2-nonulopyranoylonate)-β-D-galactopyranoside)-β-D-glucopyranoside(5)(No.20)(G20)
於室溫，將6毫升1M NaOH溶液加至含有5-氯戊基4-O-(4-O-(6-O-乙醯基-4-O-苄基-3-O-(2-O-苯甲醯基-3,4,6-三-O-苄基-β-D-半乳哌喃糖苷)-2-去氧-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷)-2-O-苯甲醯基-6-O-苄基-3-O-(7-O-乙醯基-5-胺-9-O-苄基-5-N,4-O-羰基-3,5-雙去氧-8-O-(5-胺-9-O-苄基-5-N,4-O-羰基-7,8-O-聯乙醯-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸甲酯)-D-甘油-α-D-半乳-2-吡喃酮酸甲酯)-β-D-半乳哌喃糖苷)-2,3,6-三-O-苄基-β-D-
葡萄哌喃糖苷(6)(156毫克，0.056毫莫耳，1.00當量)之12毫升THF溶液中。於80℃攪拌至隔日後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫，將NaHCO3(400毫克)及乙酐(200毫升)加至含有上述殘餘物之6.0毫升1,4-二
烷及6.0毫升H2O混合液中。於相同溫度攪拌1小時，將NaHCO3(400毫克)及乙酐(200毫升)加至反應混合物。於相同溫度再攪拌1小時，於室溫將LiOH(400毫克)加至反應混合物。於相同溫度攪拌12小時後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫將NaN3(18毫克，0.277毫莫耳，5.00當量)及KI(1毫克，0.006毫莫耳，0.10當量)加至含有上述殘餘物之8毫升無水DMF溶液中。於60℃攪拌至隔日後，反應混合物真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。於室溫將催化劑AcOH及Pd(OH)2(400毫克)加至含有上述殘餘物之8.0毫升甲醇及8.0毫升H2O混合液中。於室溫、H2環境中攪拌至隔日，利用矽藻土墊過濾反應混合物，接著真空蒸發濾液。利用逆相管柱色層分析法(LiChroprep® RP-18)純化殘餘物，以得到5-胺戊基4-O-(4-O-(2-乙醯胺基-3-O-(β-D-半乳哌喃糖苷)-2-去氧-β-D-半乳哌喃糖苷)-3-O-(5-乙醯胺基-3,5-雙去氧-8-O-(5-乙醯胺基-3,5-雙去氧-D-甘油-α-D-半乳-2-吡喃神經胺酸酯)-D-甘油-α-D-半乳-2-吡喃酮酸酯)-β-D-半乳哌喃糖苷)-β-D-葡萄哌喃糖苷(5)(37毫克，0.027毫莫耳，48%)。1H NMR(600MHz,CDCl3)δ 4.74(d,1H,J=8.4Hz),4.52(d,1H,J=10.1Hz),4.50(d,1H,J=10.3Hz),4.48(d,1H,J=8.0Hz),4.15-4.19(m,3H),4.09-4.11(m,1H),4.05(d,1H,J=2.3Hz),3.98-4.02(m,2H),3.88-3.95(m,5H),3.57-3.86(m,28H),3.52(dd,1H,J=9.9,7.9Hz),3.39(dd,1H,J=9.8,8.0Hz),3.29(t,1H,J=8.6Hz),3.00(t,2H,J=7.6Hz),2.76(dd,1H,J=12.3,4.6Hz),2.68(dd,1H,J=12.2,4.2Hz),2.07(s,3H),2.03(s,3H),2.02(s,3H),1.78(t,1H,J=12.2Hz),1.73(t,1H,J=12.2Hz),1.63-1.71(m,4H),1.43-1.48(m,2H)；13C NMR(150MHz,
CDCl3)δ 174.93,174.90,174.8,173.4,173.3,104.6,102.7,102.4,102.0,100.53,100.45,79.8,78.3,78.2,75.8,74.9,74.8,74.5,74.31,74.29,74.1,73.7,72.7,72.6,72.4,71.7,70.6,70.0,69.6,69.2,68.54,68.46,68.08,68.06,67.8,62.5,61.4,60.9,60.8,60.6,59.9,52.3,51.7,51.3,40.4,39.3,39.1,28.1,26.4,22.5,22.3,22.01,21.98；HRMS(ESI-TOF)計算得C53H89N4O37[M-H]- 1373.5206，發現1373.5201。
4-((1S,2R)-1,2,3-三(2-氯乙醯氧基)丙基)-6-(3-(苄醯氧基)-6-(苄氧甲基)-5-羥基-2-(p-甲苯硫基)-四氫-2H-哌喃-4-基氧)-2-側氧-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽/Methyl 4-((1S,2R)-1,2,3-tris(2-chloroacetoxy)propyl)-6-(3-(benzoyloxy)-6-(benzyloxymethyl)-5-hydroxy-2-(p-tolylthio)-tetrahydro-2H-pyran-4-yloxy)-2-oxo-hexahydro-2H-pyrano[3,4-d]oxazole-6-carboxylate(28)
在-78℃的氬氣環境中，將TBSOTf(0.960毫升，4.19毫莫耳，1.50當量)加至含有4-((1S,2R)-1,2,3-三(2-氯乙醯氧基)丙基)-6-(二丁氧基磷醯氧基)-2-側氧-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽(methyl 4-((1S,2R)-1,2,3-tris(2-chloroacetoxy)propyl)-6-(dibutoxyphosphoryl-oxy)-2-oxo-hexahydro-2H-pyrano[3,4-d]oxazole-6-carboxylate)(15)(2.65公克，3.64毫莫耳，1.30當量)、4-甲苯基2-O-苯甲醯基-6-O-苄基-1-硫基-β-D-半乳哌喃糖苷(12)(1.34公克，2.80毫莫耳，1.00當量)及粉碎活化MS-4Å之TBSOTf(0.960毫升，4.19毫莫耳，1.50當量)無水CH2Cl2(50毫升)溶液中。於相同溫度攪拌1.5小時，以三乙胺中和反應混合物後，利用矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3混合液中。以二份CH2Cl2萃取水層。利用鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(60：40己烷-乙酸乙酯)層析分離殘餘物，以得到28(2.57公克，2.57毫莫耳，92%，僅α)。以1H NMR分析來決定α/β比例。1H NMR(600MHz,CDCl3)δ 8.11(d,2H,J=7.2Hz),7.63(t,1H,J=7.7Hz),7.51(t,2H,J=7.5Hz),7.25-7.32(m,7H),7.02(d,2H,J=7.8Hz),5.67(dd,1H,J=10.3,1.5Hz),5.27(t,1H,
J=9.7Hz),5.15(br-s,1H),5.05(d,1H,J=9.6Hz),4.86(d,1H,J=10.2Hz),4.56(s,2H),4.41(d,1H,J=1.4Hz),4.39(d,1H,J=1.8Hz),4.28-4.32(m,1H),4.14(d,1H,J=1.8Hz),4.11-4.13(m,1H),4.04(d,1H,J=2.0Hz),4.02(s,2H),3.78-3.82(m,4H),3.66-3.76(m,1H),3.68(s,3H),3.28(s,2H),2.84-2.90(m,2H),2.59(br-s,1H),2.28(s,3H),1.99(t,1H,J=12.6Hz)；13C NMR(150MHz,CDCl3)δ 168.8,168.2,167.3,167.0,158.9,138.5,138.2,133.5,130.5,130.3,129.8,128.8,128.6,128.5,128.0,127.8,98.8,86.6,76.7,76.5,75.9,73.8,73.5,70.0,69.3,69.2,67.8,67.6,63.3,57.3,53.7,41.5,40.6,39.7,37.0,21.4；HRMS(ESI-TOF)計算得C44H46Cl3NO17SNa[M+Na]+ 1020.1450，發現1020.1442。
4-((1S,2R)-1,2,3-三(2-氯乙醯氧基)丙基)-6-(2-(4,5-雙(苄氧基)-2-(苄氧甲基)-6-(5-氯戊氧基)-四氫-2H-哌喃-3-基氧)-3-(苄醯氧基)-6-(苄氧甲基)-5-羥基-四氫-2H-哌喃-4-基氧)-2-側氧-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽/Methyl 4-((1S,2R)-1,2,3-tris(2-chloroacetoxy)propyl)-6-(2-(4,5-bis(benzyl-oxy)-2-(benzyloxymethyl)-6-(5-chloropentyloxy)-tetrahydro-2H-pyran-3-yloxy)-3-(benzoyloxy)-6-(benzyloxymethyl)-5-hydroxy-tetrahydro-2H-pyran-4-yloxy)-2-oxo-hexahydro-2H-pyrano[3,4-d]oxazole-6-carboxylate(29)
在0℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(0.59公克，2.62毫莫耳，2.00當量)及0.5M三氟甲磺酸之無水Et2O(0.79毫升，0.39毫莫耳，0.30當量)溶液加至含有4-((1S,2R)-1,2,3-三(2-氯乙醯氧基)丙基)-6-(3-(苄醯氧
基)-6-(苄氧甲基)-5-羥基-2-(p-甲苯硫基)-四氫-2H-哌喃-4-基氧)-2-側氧-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽(28)(1.54公克，1.31毫莫耳，1.50當量)、5-氯戊基-2,3,6-三-O-苄基-β-D-葡萄哌喃糖苷(11)(1.37公克，2.47毫莫耳，2.00當量)及粉碎活化MS-4Å之無水CH2Cl2(30毫升)溶液中。於相同溫度攪拌1小時，藉由CH2Cl2稀釋反應混合物後，以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3混合液中。以二份CH2Cl2萃取水層。利用飽和NaHCO3、飽和Na2S2O3及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(50：50己烷-乙酸乙酯)層析分離殘餘物，以得到29(1.48公克，1.31毫莫耳，79%)。1H NMR(600MHz,CDCl3)δ 8.08(d,2H,J=7.2Hz),7.61(t,1H,J=7.5Hz),7.43(t,2H,J=7.8Hz),7.35(d,2H,J=7.2Hz),7.20-7.29(m,18H),5.64(dd,1H,J=10.1,1.4Hz),5.32(t,1H,J=9.5Hz),5.15(s,1H),5.06(d,1H,J=2.0Hz),4.97(d,1H,J=7.9Hz),4.93(d,1H,J=10.9Hz),4.83(d,1H,J=11.4Hz),4.66(d,1H,J=10.8Hz),4.14-4.39(m,2H),4.33(d,2H,J=11.4Hz),4.24-4.29(m,3H),4.13(d,2H,J=15.6Hz),4.05-4.14(m,3H),3.99(s,2H),3.81-3.88(m,2H),3.75(t,1H,J=8.3Hz),3.65(s,3H),3.62-3.66(m,2H),3.55-3.58(m,3H),3.442(s,2H),3.44(d,2H,J=11.4Hz),3.28-3.41(m,4H),2.87(t,1H,J=10.5Hz),2.80(dd,1H,J=11.3,2.1Hz),2.54(br-s,1H),2.03(t,1H,J=12.5Hz),1.71-1.76(m,2H),1.57-1.64(m,2H),1.41-1.49(m,2H)；13C NMR(150MHz,CDCl3)δ 168.5,168.1,167.3,166.9,164.9,158.9,139.3,138.7,138.6,138.3,133.6,130.2,130.1,128.9,128.51,128.47,128.46,128.4,128.1,127.9,127.8,127.70,127.65,127.6,127.4,103.6,100.7,99.2,83.1,82.2,76.9,76.6,75.4,75.3,74.9,74.6,73.51,73.47,73.3,72.3,72.0,70.1,69.8,69.1,68.1,67.7,67.0,63.3,57.3,53.7,45.1,41.3,40.5,39.7,36.8,36.5,32.5,29.2,24.9,23.7；HRMS(ESI-TOF)計算得C69H77Cl4NO23Na[M+Na]+ 1450.3538，發現1450.3535。
6-(2-(4,5-雙(苄氧基)-2-(苄氧甲基)-6-(5-氯戊氧基)-四氫-2H-哌喃-3-基氧)-5-(6-(乙醯氧甲基)-5-(苄氧基)-4-(叔丁基二甲基矽氧基)-3-((2,2,2-三氯乙氧)羰基)-四氫-2H-哌喃-2-基氧)-3-(苄醯氧基)-6-(苄氧甲基)-四氫-2H-哌喃-4-基氧)-2-側氧-4-((1R,2R)-1,2,3-三羥丙基)-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽/Methyl 6-(2-(4,5-bis(benzyloxy)-2-(benzyloxymethyl)-6-(5-chloropentyl-oxy)-tetrahydro-2H-pyran-3-yloxy)-5-(6-(acetoxymethyl)-5-(benzyloxy)-4-(tert-butyldimethylsilyloxy)-3-((2,2,2-trichloroethoxy)carbonyl)-tetrahydro-2H-pyran-2-yloxy)-3-(benzoyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-4-yloxy)-2-oxo-4-((1R,2R)-1,2,3-trihydroxypropyl)-hexahydro-2H-pyrano[3,4-d]oxazole-6-carboxylate(14)
在-25℃的氬氣環境中，將含有N-碘代琥珀醯亞胺(0.56公克，2.49毫莫耳，2.00當量)及0.5M三氟甲磺酸之無水Et2O(0.75毫升，0.37毫莫耳，0.30當量)溶液加至含有4-((1S,2R)-1,2,3-三(2-氯乙醯氧基)丙基)-6-(2-(4,5-雙(苄氧基)-2-(苄氧甲基)-6-(5-氯戊氧基)-四氫-2H-哌喃-3-基氧)-3-(苄醯氧基)-6-(苄氧甲基)-5-羥基-四氫-2H-哌喃-4-基氧)-2-側氧-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽(29)(1.78公克，1.24毫莫耳，1.00當量)、4-甲苯基6-O-乙醯基-4-O-苄基-3-O-叔丁基二甲基-矽基-2-去氧-1-硫基-2-(2,2,2-三氯乙氧羰基胺)-β-D-半乳哌喃糖苷
(16)(1.32公克，1.87毫莫耳，1.50當量)及粉碎活化MS-4Å之無水CH2Cl2(30毫升)溶液中。於相同溫度攪拌2小時，利用CH2Cl2稀釋反應混合物後，以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3及飽和Na2S2O3混合液中。以二份CH2Cl2萃取水層。利用飽和NaHCO3、飽和Na2S2O3及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(55：45己烷-乙酸乙酯)層析分離殘餘物，以得到產物(2.13公克，1.06毫莫耳，85%)。於室溫，將硫脲(80.0毫克，1.01毫莫耳，6.00當量)及2,6-二甲基比啶(60微升，0.51毫莫耳，3.00當量)加至含有產物之(0.34公克，0.17毫莫耳，1.00當量)DMF(7毫升)溶液中。於60℃攪拌5小時後，將反應混合物倒入冰的1M HCl中。以二份乙酸乙酯萃取水層。利用飽和NaHCO3、飽和Na2S2O3及鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(55：45己烷-乙酸乙酯)層析分離殘餘物，以得到14(0.21公克，0.12毫莫耳，69%)。1H NMR(600MHz,CDCl3)δ 7.85(d,2H,J=7.6Hz),7.51(t,1H,J=7.4Hz),744-7.17(m,25H),7.14(d,2H,J=7.6Hz),6.71(t,1H,J=7.4Hz),6.15(br-s,2H),5.22(t,1H,J=7.9Hz),5.12(d,1H,J=11.0Hz),4.91(m,2H),4.85-4.72(m,6H),4.64(d,1H,J=12.0Hz),4.57(d,1H,J=11.3Hz),4.52(d,1H,J=12.6Hz),4.27(d,1H,J=12.3Hz),4.24(t,1H,J=4.5Hz),4.23(d,1H,J=12.3Hz),4.04-4.02(m,3H),3.84(t,1H,J=9.8Hz),3.82(s,3H),3.80-3.70(m,5H),3.67-3.65(m,2H),3.60-3.57(m,5H),3.51(t,1H,J=9.0Hz),3.49-3.47(m,2H),3.43(t,2H,J=6.7Hz),3.42-3.38(m,3H),3.24(t,2H,J=8.9Hz),3.11(d,1H,J=9.5Hz),2.44(d,1H,J=9.1Hz),2.33(t,1H,J=12.4Hz),1.97(s,3H),1.73-1.9(m,2H),1.59-1.63(m,2H),1.49-1.42(m,2H),0.90(s,9H),0.17(s,3H),0.14(s,3H)；13C NMR(150MHz,CDCl3)δ171.3,169.7,164.1,160.1,154.1,138.8,138.6,138.5,138.4,138.3,133.5,129.6,129.2,129.0,128.7,128.5,128.4,128.3,128.2,128.1,128.0,128.8,127.7,127.5,127.4,127.3,103.5,102.6,101.3,100.1,96.0,82.3,81.4,76.4,76.0,75.7,75.0,
74.9,74.8,74.4,73.5,73.4,71.3,71.2,71.0,69.5,69.0,67.8,63.6,62.7,57.3,54.9,54.4,44.9,32.3,31.9,30.0,29.7,29.6,29.4,28.9,27.0,25.8,23.3,22.7,20.9,18.0,14.1,-4.1,-5.0；HRMS(ESI-TOF)計算得C87H108Cl4N2O27SiNa[M+Na]+ 1803.5561，發現1803.5553。
(1S,2R)-1-((3aR,4R,6R,7aS)-6-((2R,3R)-3-((3aR,4R,6S,7aS)-6-(((2R,3S,4S,5R,6S)-3-(((2S,3R,4R,5S,6R)-6-(乙醯氧甲基)-5-(苄氧基)-4-((叔丁基二甲基矽基)氧基)-3-(((2,2,2-三氯乙氧)羰基)胺)四氫-2H-哌喃-2-基)氧基)-5-(苄醯氧基)-2-((苄氧基)甲基)-6-(((2R,3R,5R,6R)-4,5-雙(苄氧基)-2-((苄氧基)甲基)-6-((5-氯戊基)氧基)四氫-2H-哌喃-3-基)氧基)四氫-2H-哌喃-4-基)氧基)-6-(甲氧羰基)-2-氧代六氫-2H-哌喃並[3,4-d]
唑-4-基)-2,3-二羥丙氧基)-6-(甲氧羰基)-2-氧代六氫-2H-哌喃並[3,4-d]
唑-4-基)丙烷-1,2,3-三乙酸三酯/(1S,2R)-1-((3aR,4R,6R,7aS)-6-((2R,3R)-3-((3aR,4R,6S,7aS)-6-(((2R,3S,4S,5R,6S)-3-(((2S,3R,4R,5S,6R)-6-(acetoxymethyl)-5-(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-3-(((2,2,2-trichloroethoxy)carbonyl)amino)tetrahydro-2H-pyran-2-yl)oxy)-5-(benzoyloxy)-2-((benzyloxy)methyl)-6-(((2R,3R,5R,6R)-4,5-bis(benzyloxy)-2-((benzyloxy)methyl)-6-((5-chloropentyl)oxy)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-6-(methoxycarbonyl)-2-oxohexahydro-2H-pyrano[3,4-d]oxazol-4-yl)-2,3-dihydroxypropoxy)-6-(methoxycarbonyl)-2-oxohexahydro-2H-pyrano[3,4-d]oxazol-4-yl)propane-1,2,3-triyltriacetate(13)
在-78℃的氬氣環境中，將TBSOTf(47微升，0.20毫莫耳，1.50當量)加至含有6-(2-(4,5-雙(苄氧基)-2-(苄氧甲基)-6-(5-氯戊氧基)-四氫-2H-哌喃-3-基氧)-5-(6-(乙醯氧甲基)-5-(苄氧基)-4-(叔丁基二甲基矽氧基)-3-((2,2,2-三氯
乙氧)羰基)-四氫-2H-哌喃-2-基氧)-3-(苄醯氧基)-6-(苄氧甲基)-四氫-2H-哌喃-4-基氧)-2-側氧-4-((1R,2R)-1,2,3-三羥丙基)-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽(14)(240毫克，0.13毫莫耳，1.00當量)、6-(二丁氧基磷醯氧基)-2-側氧-4-((1S,2R)-1,2,3-三乙醯氧基丙基)-六氫-2H-哌喃並[3,4-d]
唑-6-甲基羧酸鹽(methyl 6-(dibutoxyphosphoryloxy)-2-oxo-4-((1S,2R)-1,2,3-triacetoxypropyl)-hexahy-dro-2H-pyrano[3,4-d]oxazole-6-carboxylate)(32)(130毫克，0.20毫莫耳，1.50當量)及粉碎活化MS-4Å之無水CH2Cl2(10毫升)溶液中。於相同溫度攪拌1.5小時，利用飽和NaHCO3溶液中和反應混合物，並以矽藻土墊進行過濾。將濾液倒入飽和NaHCO3溶液中。以二份CH2Cl2萃取水層。利用鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。以矽膠(40：60己烷-乙酸乙酯)層析分離殘餘物，以得到13(240毫克，0.11毫莫耳，82%，α/β=>95/5)。以1H NMR分析來決定α/β比例。1H NMR(600MHz,CDCl3)δ 7.74(d,2H,J=7.8Hz),7.58(t,1H,J=7.4Hz),7.47-7.13(m,27H),6.66(t,1H,J=7.3Hz),6.06(br-s,1H),5.47(t,1H,J=8.7Hz),5.30(dt,1H,J=9.9,2.2Hz),5.21(t,1H,J=8.7Hz),5.12(d,1H,J=11.0Hz),5.01(d,1H,J=10.3Hz),4.94-4.92(m,2H),4.85(d,1H,J=11.8Hz),4.80(br-s,2H),4.73(t,2H,J=10.7Hz),4.65(d,1H,J=8.18Hz),4.58(d,1H,J=9.0Hz),4.54(d,1H,J=11.0Hz),4.49-4.46(m,2H),4.29(d,1H,J=10.5Hz),4.225(dd,1H,J=9.9,1.5Hz),4.21-4.16(m,5H),3.97(d,1H,J=3.0Hz),3.94-3.86(m,5H),3.85(s,3H),3.82(s,3H),3.81-3.77(m,3H),3.71-3.69(m,4H),3.66(d,1H,J=1.9Hz),3.61-3.59(m,2H),3.52-3.48(m,3H),3.42(t,2H,J=6.8Hz),3.38-3.31(m,3H),3.20(t,1H,J=9.0Hz),3.06(d,1H,J=9.7Hz),3.02(t,1H,J=10.2Hz),2.91(dd,1H,J=12.2,3.4Hz),2.46(dd,1H,J=11.7,3.0Hz),2.22(s,3H),2.19(s,3H),1.97(s,3H),1.92(s,3H),1.74-1.69(m,2H),1.59-1.55(m,2H),1.49-1.42(m,2H),0.89(s,9H),0.17(s,3H),0.12(s,3H)；13C NMR(150MHz,CDCl3)δ172.3,171.8,171.7,170.6,
167.9,167.6,164.3,160.3,154.2,139.1,138.9,138.8,138.7,137.5,136.3,132.6,130.2,129.3,128.9,128.7,128.6,128.5,128.4,128.2,128.1,128.0,127.9,127.8,127.7,127.6,127.5,102.5,101.6,100.7,100.1,96.3,83.6,81.0,78.6,76.5,76.2,76.1,75.2,75.1,75.0,74.9,74.5,74.2,74.1,73.6,73.5,73.4,73.3,71.9,71.2,70.9,69.8,69.1,68.5,68.1,67.2,64.4,59.2,57.1,55.9,53.2,53.0,44.1,38.5,35.6,34.5,29.8,26.6,23.7,21.7,20.9,20.5,20.2,19.2,-3.8,-5.1；HRMS(ESI-TOF)計算得C104H129Cl4N3O38SiNa[M+Na]+ 2218.6675，發現2218.6675。
(2S,4S,5R,6R)-5-乙醯胺-6-((1R,2R)-3-(((2R,4S,5R,6R)-5-乙醯胺-2-羧基-4-羥基-6-((1R,2R)-1,2,3-三羥丙基)四氫-2H-哌喃-2-基)氧基)-1,2-二羥丙基)-2-(((2R,3S,4R,5R,6S)-3-(((2S,3R,4R,5R,6R)-3-乙醯胺-4,5-二羥-6-(羥甲基)四氫-2H-哌喃-2-基)氧基)-6-(((2R,3S,5R,6R)-6-((5-胺戊基)氧基)-4,5-二羥-2-(羥甲基)四氫-2H-哌喃-3-基)氧基)-5-羥基-2-(羥甲基)四氫-2H-哌喃-4-基)氧基)-4-羥基四氫-2H-哌喃-2-羧酸/(2S,4S,5R,6R)-5-acetamido-6-((1R,2R)-3-(((2R,4S,5R,6R)-5-acetamido-2-carboxy-4-hydroxy-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2-dihydroxypropyl)-2-(((2R,3S,4R,5R,6S)-3-(((2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-6-(((2R,3S,5R,6R)-6-((5-aminopentyl)oxy)-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-5-hydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)oxy)-4-hydroxytetrahydro-2H-pyran-2-carboxylic acid(4)(No.25)(G25)
在0℃的氬氣環境中，將48% BF3．OEt2(75微升，0.57毫莫耳，6.00當量)加至含有(1S,2R)-1-((3aR,4R,6R,7aS)-6-((2R,3R)-3-((3aR,4R,6S,7aS)-6-(((2R,3S,4S,5R,6S)-3-(((2S,3R,4R,5S,6R)-6-(乙醯氧甲基)-5-(苄氧基)-4-((叔丁基二甲基矽基)氧基)-3-(((2,2,2-三氯乙氧)羰基)胺)四氫-2H-哌喃-2-基)氧基)-5-(苄醯氧基)-2-((苄氧基)甲基)-6-(((2R,3R,5R,6R)-4,5-雙(苄氧基)-2-((苄氧基)甲基)-6-((5-氯戊基)氧基)四氫-2H-哌喃-3-基)氧基)四氫-2H-哌喃-4-基)氧基)-6-(甲氧羰基)-2-氧代六氫-2H-哌喃並[3,4-d]
唑-4-基)-2,3-二羥丙氧基)-6-(甲氧羰基)-2-氧代六氫-2H-哌喃並[3,4-d]
唑-4-基)丙烷-1,2,3-三乙酸三酯(13)(210毫克，0.10毫莫耳，1.00當量)之無水乙腈(10毫升)溶液中。於相同溫度攪拌30分鐘後，將反應混合物倒入飽和NaHCO3溶液中。以二份乙酸乙酯萃取水相。利用鹽水洗滌合併萃取物後，經MgSO4乾燥，並進行過濾及真空蒸發。於室溫將LiOH(5.0毫莫耳，50.0當量)加至含有殘餘物(170毫克，0.1毫莫耳，1.00當量)之1,4-二
烷(5.00毫升)及H2O(5.00毫升)混合液中。於80℃攪拌36小時後，真空蒸發反應混合物。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物，以得到產物殘餘物。於室溫將NaHCO3(5.0毫莫耳，50.0當量)及乙酐(5.0毫莫耳，50.0當量)加至含有上述殘餘物之H2O(3.00毫升)溶液中。於相同溫度攪拌1小時後，將NaHCO3(5.0毫莫耳，50.0當量)及乙酐(5.0毫莫耳，50.0當量)加至反應混合物。於相同溫度攪拌1小時後，將LiOH(5.0毫莫耳，50.0當量)加至反應混合物中。於相同溫度攪拌12小時後，真空蒸發反應混合物。利用逆相管柱色層分析法
(LiChroprep® RP-18)來純化殘餘物。於室溫將NaN3(37毫克，0.57毫莫耳，5.00當量)及KI(2毫克，0.01毫莫耳，0.10當量)加至含有上述殘餘物之10毫升無水DMF溶液中。於60℃攪拌至隔日後，真空蒸發反應混合物。以逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物。將Pd(OH)2(1毫莫耳)加至含有上述殘餘物之甲醇(2.00毫升)及H2O(2.00毫升)混合液中。於H2環境中氫解反應混合物12小時。過濾反應混合物後，真空蒸發濾液。利用逆相管柱色層分析法(LiChroprep® RP-18)來純化殘餘物，以得到α(2→9)GD2 4(55毫克，0.05毫莫耳，45%)。1H NMR(600MHz,CDCl3)δ 4.67(d,1H,J=8.5Hz),4.52(d,1H,J=7.9Hz),4.48(d,1H,J=8.0Hz),4.14(dd,1H,J=9.8,2.8Hz),4.10(d,1H,J=2.8Hz),3.99(d,1H,J=1.7Hz),3.97-3.92(m,10H),3.91(d,1H,J=2.2Hz),3.89-3.58(m,16H),3.56(dd,1H,J=9.3,1.3Hz),3.47(d,1H,J=10.3Hz),3.36(t,1H,J=12.1Hz),3.29(t,1H,J=8.5Hz),2.99(t,2H,J=7.5Hz),2.73(dd,1H,J=12.3,4.5Hz),2.67(dd,1H,J=12.4,4.5Hz),2.04(s,3H),2.03(s,3H),2.01(s,3H),1.93(t,2H,J=12.1Hz),1.71-1.64(m,4H),1.48-1.43(m,2H)；13C NMR(150MHz,CDCl3)δ 174.94,174.90,174.8,174.1,173.6,102.7,102.5,102.0,101.5,100.1,78.7,78.6,77.1,74.8,74.4,74.3,74.1,72.9,72.7,72.4,71.7,71.2,70.8,70.5,70.0,68.9,68.3,67.8,64.8,62.6,61.1,60.6,52.2,51.9,51.5,48.8,40.1,39.3,36.9,28.1,26.5,26.3,23.2,22.5,22.1,22.0,21.99；HRMS(ESI-TOF)計算得C47H80N4O32[M-H]- 1213.4834，發現1213.4830。
實施例1 評估罹患前-HD或HD的個體
本實施例將分析合成的神經節-寡醣於評估罹患HD或罹患HD風險的用途。分別將結果闡述於第1圖及表1-3。
1.1 正常對照組、前-HD及HD病患之血漿中抗-聚醣抗體量的差異
在利用聚焦聚醣陣列進行檢測時，首先以合成的哺乳動物神經節苷脂來製備聚醣陣列，其中是藉由陣列點漬器將上述28種化學合成之聚醣(針對神經節苷脂之聚醣部分所設計)以阿莫耳(atto-mole)的使用量點漬於陣列上(表1)。將陣列設計為各聚醣具有10個以上的重複點漬。同時，由正常對照組(normal control,NC)(n=42)、前-HD個體(n=16)及HD病患(n=39)收集血漿檢體(表2)。聚醣的使用量為阿莫耳等級。表2總結了個體數量、性別分佈及臨床資料。阻斷(blocking)陣列後，將1微升之稀釋100倍的人類血漿加至陣列。利用具有螢光標識之IgG或IgM的二級抗體來顯示結合訊號。
結果指出，僅有自體-IgM(auto-IgM)抗體可顯示出對照組及疾病檢體的差異，自體-IgG(auto-IgG)抗體則無法顯示出此差異，推測可能是由於人體聚醣的低免疫原性(low immunogenicity)所導致。因此，進一步分析可辨識點漬聚醣的天然IgM抗體。比對NC、前-HD及HD病患血漿中不同抗-聚醣IgM的抗體量(結果未顯示)。有趣的是，在未表現任何臨床症狀的前-HD個體中，可發現IgM的抗體量具有顯著的差異性。具體來說，相較於抗-聚醣IgM僅會低量表現於NC個體及HD病患，抗-聚醣IgM在前-HD個體體內具有較高的表現量；此結果暗示，除了檢測基因之外，亦可藉由偵測前-HD的IgM抗體量來分析其異常狀態。此外，於前-HD及HD組別具有表現差異的IgM，可作為區分由前-HD轉變為HD階段或指示HD嚴重程度之潛力型生物標記。基於在聚醣陣列中，大多數自體-聚醣IgM抗體於前-HD個體具有較高的表現量，接著檢測此現象是否因前-HD個體體內IgM總量較高所導致。因此，以槽墨分析檢測等量之不同群組的血漿，並以抗-IgM二級抗體來偵測IgM總量。結果指出，在NC個體、前-HD個體及HD病
患之間並無差異，證實聚醣陣列中訊號的改變對自體-聚醣抗體具有特異性(第1圖)。
1.2 正常對照組中自體-聚醣抗體量及年齡的相關性
為了解各自體-聚醣抗體及個體年齡的關聯性，對正常對照組中28種自體-聚醣抗體及年齡進行Pearson相關的成對分析。每一個聚醣皆賦予一聚醣編號(G1到G28)，以便於統計分析。結果指出，除了G12(岩藻醣化GM1)及G18(GD2)之外，大多數自體-聚醣抗體與個體年齡皆不具相關性(結果未顯示)。有趣的是，許多自體-聚醣抗體彼此之間呈現顯著的正相關性。除了G13(p=0.1397)之外，聚醣G1與G2到G28皆呈現高度的正相關性(結果未顯示)。然而，G13、G20、G22及G27與其他自體-聚醣抗體訊號僅具中度或低度相關性(結果未顯示)。推測此相關性可能是由聚醣結構之間的相似性所造成。
1.3 對28種聚醣進行邏輯迴歸分析以尋找具有潛力的生物標記
接著，對聚醣陣列訊號進行單變量分析，以確認具有潛力的生物標記。首先利用邏輯迴歸分析來確認候選標記。比對以下三種族群，包含：(1)NC個體與前-HD個體；(2)前-HD個體與HD病患；以及(3)NC個體與HD病患。結果總結於表3。此分析的顯著量納入了多重比較，其中是使用Bonferroni校正p值(0.05/28=約0.0018)。在分析NC與前-HD個體時，相較於對照組，大多數聚醣於前-HD病患具有較高的訊號強度，其對應之勝率比>1。其中，G8、G17及G20訊號的p值皆小於0.0018。在分析前-HD個體與HD病患時，勝率比為<1。G8、G9、G11、G14、G18、G20、G23及G27的p值亦小於0.0018。在分析NC個體與HD病患時，G1、G4及G5的p值皆小於0.0018，其中此3種聚醣的勝率比皆<1。
接著，亦使用多重邏輯迴歸分析來篩選獨立因子，以區分HD狀態。三組分析皆包含年齡。由於NC個體無法取得重複數值，因此重複數值僅呈現於第2組(前-HD與HD)。納入所有在Bonferroni分析中具有顯著性(p<0.0018)
的聚醣訊號。區分第1組(NC與前-HD)的獨立因子包含年齡、G8、G17及G20。該些聚醣在Bonferroni分析中皆具有顯著性。區分第2組(前-HD與HD)的獨立因子包含年齡、重複數、G8、G9、G11、G14、G18、G20、G23及G27。該些聚醣在Bonferroni分析中的p值皆<0.0018。區分第3組(NC與HD)的獨立因子包含年齡、G4及G5。使用包含逐步選取、向前選取及向後選取三種選取法。將三種方法中AIC值最小的模型視為擬合度最佳的模型。結果指出，向後選取法是最適合分析三組差異的方法(結果未顯示)。在區分NC及前-HD組別時，G17(p<0.0351)與G20(GD1b)(p<0.0472)為具有潛力的候選生物標記(結果未顯示)。在區分前-HD與HD組別時，包含年齡(p<0.0083)、重複數(p<0.0295)及G20(GD1b)(p<0.0057)為三種候選生物標記；在區分NC及HD組別時，僅G5(SiaGalGalNAc)具有區分潛力(p<0.0009)(結果未顯示)。
1.4 合併具有潛力的聚醣標記可改善臨床診斷的AUC
為進一步評估多變量邏輯迴歸分析篩選得到之獨立因子的臨床表現，分析接收器操作特徵曲線(ROC)的曲線下面積(AUC)。計算篩選得到之抗-聚醣抗體作為HD之血漿生物標記的靈敏度及專一性。在比對前-HD個體與HD病患時，年齡、重複數及G20的AUC分別為0.79(95% CI,0.62-0.95)、0.74(95% CI,0.68-1)及0.81(95% CI,0.65-0.97)(結果未顯示)。合併年齡及重複數可將AUC提升至0.86(95% CI,0.74-0.99；結果未顯示)。此外，若進一步合併新穎的生物標記G20(GD1b)，則可將AUC分數提高至0.95(95% CI,0.85-1；結果未顯示)。此種合併對NC及前-HD組別可產生最佳的區分能力。亦以G17、G20及G17加G20來分析NC與前-HD個體。G17與G20的AUC分別為0.79(95% CI,0.62-0.97)及0.83(95% CI,0.68-0.99)(結果未顯示)。合併G17與G20可些微改善AUC至0.84(95% CI,0.68-1；結果未顯示)。然而，當與G17或G20的AUC相比，此差異並無統計意義。在分析NC與HD時，G5的AUC為0.72(95% CI,0.31-0.83；結果未
顯示)。整體來說，該些結果發現並證實一種新穎之生物標記G20(GD1b)，可據以區分NC及前-HD組別。
總結上述，本實施例的數據指出NC個體、前-HD個體及HD病患的血漿中自體-聚醣抗體存在著顯著的差異。值得注意的是，大多數改變的自體-聚醣抗體傾向在前-HD個體中增加，而在HD病患中減少；僅抗-岩藻醣化GM1及抗-岩藻醣化GM3由NC個體到HD病患皆維持增加的趨勢。此結果指出岩藻醣化於HD的異常表現量。統計分析數據指出，若將年齡及CAG重複數與抗-GD1b抗體反應結合，可將區分前-HD及HD個體的AUC數值由0.86增加到0.95。
實施例2 評估罹患MCI或AD的個體
除了HD之外，本研究亦分析合成的神經節-寡醣於評估罹患AD或罹患AD風險的用途。分別將結果闡述於表4-5。
2.1 正常對照組、MCI及AD病患之血漿中抗-聚醣抗體量的差異
收集正常對照組、MCI及AD病患的血漿，並進行聚焦聚醣陣列分析。使用的檢體包含23個正常對照檢體、67個MCI檢體以及54個AD病患檢體。藉由陣列點漬器將28種化學合成之聚醣(表1)點漬於陣列上，以製備聚焦聚醣陣列。聚醣的使用量為阿莫耳等級。將陣列設計為各聚醣具有10個以上的重複點漬；如之前方法所述，於阻斷陣列後，將1微升之稀釋100倍的人類血漿加至陣列，並依據先前方法所述之步驟進行後續流程。利用具有螢光標識之IgM的二級抗體來顯示結合訊號。
於NC、MCI及AD病患的血漿中可偵測到抗-聚醣IgM抗體量的改變(結果未顯示)。結果指出，相較於正常對照組及AD病患，MCI組別具有較高量的抗-聚醣抗體(結果未顯示)。大多數的抗-聚醣抗體含量會於MCI階段增加，而於AD階段減少(結果未顯示)。此外，亦分析正常對照組及AD病患體內抗體量
的改變。有趣的是，相較於正常對照組，僅有抗-GM2抗體會於AD病患體內顯著減少(結果未顯示)。其餘則於AD病患血漿中呈現高表現量。將28種抗-聚醣抗體的訊號強度總結於表4。由於表現強度差異過大會影響顯著性的判讀，因此使用曼-惠特尼U檢定(Mann-Whitney U test)來呈現結果。結果指出，除了G10(p=0.2638)之外，所有聚醣訊號在NC與MCI組別之間皆具有顯著性。同時，除了G13(p=0.1184)之外，所有聚醣訊號在MCI與AD亦具有統計差異。然而，在區分NC與AD組別時，僅某些訊號具有顯著差異，包含G2(p=0.0446)、G4(p=0.0446)、G8(p=0.0446)、G10(p<0.001)、G12(p=0.016)、G16(0.0472)、G19(p=0.0295)、G21(p=0.0449)、G24(p=0.0255)及G27(p=0.0024)。
2.2 正常對照組中自體-聚醣抗體量、MMSE評分及年齡的相關性
為確認血漿中自體-聚醣抗體與年齡是否具有相關性，以Pearson相關性來分析訊號強度(結果未顯示)。結果指出，除了G3(正相關，p=0.0002)、G19(正相關，p=0.0295)及G25(正相關，p=0.0425)之外，大多數自體-聚醣抗體與年齡不具相關性(結果未顯示)。亦分析自體-聚醣抗體量與MMSE評分之間的相關性；結果證實，除了G13(負相關，p=0.0192)之外，自體-聚醣抗體量與MMSE評分差異不具相關性(結果未顯示)。有趣的是，除了G10之外，自體-聚醣抗體彼此之間呈現高度正相關性(結果未顯示)。數據暗示聚醣結構的相似性可能會影響自體-抗體的辨識。
2.3 對28種聚醣進行邏輯迴歸分析以尋找具有潛力的生物標記
利用邏輯迴歸分析來確認28種自體-聚醣抗體中可能的候選標記。將正常對照個體、MCI個體及AD病患分為以下三組：<1>正常對照組與MCI；<2>MCI與AD病患；<3>正常對照組與AD病患；結果闡述於表5。以Bonferroni校正進行多重比對。可觀察到三組中各聚醣候選標記表現的差異。在第一組中，G3、G4、G9、G19、G21、G23、G24、G25及G27的p值皆小於0.0018，
勝率比>1。在第二組中，G9、G10、G11、G14、G18、G21、G23、G24、G25及G27的p值皆小於0.0018，勝率比<1。最後，唯有G10(及G27)於第三組具有顯著差異，且勝率比<1。此外，將各組具有潛力的候選聚醣與二因子(例如，年齡及MMSE評分)結合，進行篩選流程。使用包含逐步選取、向前選取及向後選取三種選取法進行邏輯迴歸分析。較低的AIC數值表示該方法為適當的篩選方法。以向前選取法來分析第一組，且結果指出年齡(p=0.0529)、MMSE評分(p=0.0152)、G4(p=0.1478)及G27(p=0.0251)為具有潛力的候選標記。有趣的是，第二組利用向後選取篩選出包含MMSE評分(p=0.0001)、G4(p=0.0032)及G11聚醣(p=0.0032)三種候選標記。三種方法均適用於第三組篩選，結果僅指出MMSE評分(p=0.0252)單一種候選標記。
2.4 合併具有潛力的聚醣標記可改善臨床診斷的AUC
為評估具有潛力的候選聚醣，建立接收器操作特徵曲線(ROC)來評估抗-聚醣抗體作為AD之血漿生物標記的靈敏度及專一性。偵測AD的疾病進程對臨床診斷而言相當重要。即使正常對照組與AD病患的AUC不具有顯著差
異，在分析正常對照組與MCI個體時，卻可發現年齡、MMSE評分、G4及G27的曲線下面積(AUC)分別為0.73(95% CI,0.61-0.85)、0.83(95% CI,0.74-0.92)、0.87(95% CI,0.77-0.96)及0.92(95% CI,0.85-0.98)(結果未顯示)。合併4種因子可將AUC數值改善至0.96(95% CI,0.92-0.999；結果未顯示)。在分析MCI個體與AD病患時，MMSE評分、G10及G11的AUC數值分別為0.94(95% CI,0.897-0.99)、0.898(95% CI,0.84-0.95)及0.82(95% CI,0.75-0.90)(結果未顯示)。合併MMSE評分、G10及G11的AUC顯示最佳的靈敏度及專一性：0.99(95% CI,0.98-1；結果未顯示)。整體來說，該些結果證實三種標記可作為診斷AD進程的分子生物標記。
總結上述，本揭示內容提供數種合成的神經節-寡醣，可用以預斷AD及HD等神經退化性疾病的發生。基於分析數據，習知技藝人士可診斷出早期的神經退化性疾病，據以對有需要的個體(例如，具有高度罹患神經退化性疾病風險的個體，或是罹患早期神經退化性疾病的個體)及時投予治療，以改善個體的生活品質及壽命。
雖然上文實施方式中揭露了本發明的具體實施例，然其並非用以限定本發明，本發明所屬技術領域中具有通常知識者，在不悖離本發明之原理與精神的情形下，當可對其進行各種更動與修飾，因此本發明之保護範圍當以附隨申請專利範圍所界定者為準。
Claims (7)
- 一種化合物，其係選自由，以及所組成的群組。
- 一種藥學套組，包含一第一化合物，其係選自由，以及所組成的群組；以及一第二化合物，其係選自由、，以及所組成的群組。
- 一種藉由一個體之生物檢體來預斷或診斷該個體之神經退化性疾病的方法，包含：(a)混合該生物檢體及請求項1所述之化合物，以形成一第一免疫複合體；(b)使一抗-IgM抗體與步驟(a)之第一免疫複合體反應，以形成一第二免疫複合體，其中該抗-IgM抗體是與一報導分子連接；(c)決定步驟(b)之報導分子的訊號強度；以及(d)基於步驟(c)決定的訊號強度來預斷或診斷該神經退化性疾病，其中當該訊號強度高於一對照檢體之訊號強度時，代表該個體罹患該神經退化性疾病 或是具有罹患該神經退化性疾病的風險，其中該神經退化性疾病是阿茲海默症或亨汀頓氏舞蹈症。
- 如請求項3所述之方法，其中該對照檢體是源自一健康個體。
- 如請求項3所述之方法，其中該生物檢體是一全血檢體、一血清檢體或一血漿檢體。
- 如請求項3所述之方法，其中該報導分子是一標籤分子、一放射性分子、一螢光分子、一磷光分子、一化學冷光分子或一酵素。
- 如請求項3所述之方法，其中該個體是人類。
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2022
- 2022-09-08 TW TW111134068A patent/TWI828311B/zh active
- 2022-09-08 US US18/690,712 patent/US20240409570A1/en active Pending
- 2022-09-08 WO PCT/US2022/042938 patent/WO2023039090A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9340812B2 (en) * | 2012-08-20 | 2016-05-17 | Academia Sinica | Large scale enzymatic synthesis of oligosaccharides |
| WO2017046172A1 (en) * | 2015-09-16 | 2017-03-23 | Universität Basel | Carbohydrate ligands that bind to antibodies against glycoepitopes of glycosphingolipids |
Non-Patent Citations (1)
| Title |
|---|
| 網路文獻 STN Registry RN928618-14-8, RN1204190-05-5, RN1204190-07-7 CAS 2007/3/29, 2010/1/29 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW202313062A (zh) | 2023-04-01 |
| WO2023039090A1 (en) | 2023-03-16 |
| US20240409570A1 (en) | 2024-12-12 |
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