与癌症相关的糖类抗原Globo-H六糖的全合成进展

Globo-H作为一种和乳腺癌、前列腺癌相关的复杂糖类抗原,其发现为糖类疫苗开发和癌症免疫治疗带来了机遇,但如何高效、高纯地获得合成糖类抗原,以供研究和临床应用,也向寡糖合成方法学提出了挑战.综述了1995年Danishefsky首次以糖烯组装策略全合成Globo-H以来的各种新方法,如:Schmidt的三氯乙酰亚胺酯法、Boons的双向糖苷化法、Wong的基于糖基给体活性差异的一锅煮策略、Seeberger的液相线性合成和固相自动组装法、Huang的多组份反复预活化一锅煮法和最新报道的酶法.就糖合成方法学而言,硫苷法依旧可称为"明星方法",糖烯、三氯乙酰亚胺酯和氟代糖也普遍采用,磷酸酯糖基给体在固相合成中的应用正显示出其新的活力.这些方法代表了当今糖化学的水平和发展趋势.     

Total Synthesis of the Complete Protective Antigen of Vibrio cholerae O139

The first chemical synthesis of the complete protective O‐antigen of a human‐disease‐causing pathogenic bacterium is described. The synthesis involved a protecting‐group strategy that facilitated the regioselectivity of the key transformations, stereoselective glycosylation reactions, and enabled the one‐step global deprotection of the completely assembled, fully protected, phosphorylated hexasaccharide by hydrogenation/hydrogenolysis. The final amino‐group‐functionalized, linker‐equipped antigen was obtained in a form ready for conjugation to suitable carriers, for example, proteins, to yield immunogens.     

Collective Total Synthesis of 4-Azafluorenone Alkaloids

4-Azafluorenones are typically obtained by acid-mediated cyclization of 2-arylnicotinates. However, this approach fails to give 5-oxygenated 4-azafluorenones due to lactonization of 2-(2-alkoxy)phenylnicotinate intermediates. Herein, we report two modifications of established approaches to 4-azafluorenone synthesis that, either in combination or by themselves, enable the flexible preparation of 4-azafluorenones with diverse oxygenation patterns in the benzenoid ring. Undesired lactonization was circumvented via tert-butyl hydroperoxide (TBHP)-mediated radical cyclization of 2-aryl-3-(hydroxymethyl)pyridines. In the absence of suitable protecting groups for phenolic intermediates, bromide substituents were regioselectively introduced as latent hydroxy groups and later converted under palladium catalysis. We present the first total syntheses of five 4-azafluorenone alkaloids muniranine, darienine, 5,8-dimethoxy-7-hydroxyonychine, 5,6,7,8-tetramethoxyonychine, and 6,8-dihydroxy-7-methoxyonychine in addition to new total syntheses of six 4-azafluorenone alkaloids and one related pyridocoumarin alkaloid.     

Total Synthesis of Siomycin A: Completion of the Total Synthesis

The total synthesis of siomycin A ( 1 ), a representative compound of the thiostrepton family of peptide antibiotics, was achieved by incorporating the five synthetic segments A ( 2 ), B ( 3 ), C ( 4 ), D ( 5 ), and E ( 6 ). The dehydropiperidine segment A ( 2 ) was esterified with the dihydroquinoline segment C ( 4 ), and the subsequent coupling with the β‐phenylselenoalanine dipeptide segment D ( 5 ) at the segment C portion followed by lactamization between the segments A and D gave segment A‐C‐D ( 27 ). This was amidated with the pentapeptide segment B ( 3 ) at the segment A portion followed by one‐pot cyclization (between segments A and B) and elongation (with the β‐phenylselenoalanine dipeptide segment E ( 6 ) at the segment A portion), thus furnishing siomycin A ( 1 ).     

Stereoselective Total Synthesis of 4‐Ketoclonostachydiol

An efficient stereoselective total synthesis of the bioactive 14‐membered natural macrocyclic bislactone 4‐ketoclonostachydiol is described. The strategy involves a Jacobsen's hydrolytic kinetic resolution (HKR), epoxide opening, MacMillan α‐hydroxylation, Horner? Wadsworth? Emmons olefination, a Grignard reaction, and Hoveyda? Grubbs‐II‐catalyzed ring‐closing metathesis (RCM) as key steps.     

Total Synthesis of Two 4, 5-Dioxo-seco-eudesmane Sesquiterpenes

A facile synthetic route to two seco-eudesmane, 4, 5-dioxo-10-epi-4, 5-seco-γ-eudesmane (1) and 4, 5-dioxo-10-epi-4, 5-seco-γ-eudesmol (2) from ( )-dihydrocarvone has been described. Avoiding expensive reagents, this highly economic method especially suits for the synthesis of 4, 5-seco-eudesman-type and ophianon-type sesquiterpenes with a double bond at position 11 and 12.     

A General Method for Synthesis of GPI Anchors Illustrated by the Total Synthesis of the Low-Molecular-Weight Antigen from Toxoplasma gondii

Building blocks: A new, general synthetic strategy, which allows the construction of branched glycosylphosphatidylinositols (GPIs), enables the synthesis of parasitic glycolipid 1 from Toxoplasma gondii. In addition, the structure is further confirmed by recognition of monoclonal antibodies.     

3-氧-11,12,13-三羟基桉烷-4-烯的简便全合成

报道了一种全合成3-氧-11,12,13-三羟基桉烷-4-烯(1)的简便方法. 对于该化合物及其衍生物的药理活性研究目前正在进行中.     

Combretastatin A-4 全合成中的光化学Wittig反应

在天然产物Combretastatin A-4全合成的关键步骤——Wittig反应中,引入紫外(254nm)辐射,结果使得Wittig反应的产率从原有的65％提高到83．6％。特别是其产物的Z-式立体异构体选择性大大提高,从原来的Z／E之比为3．6提高到11．5,笔者推测这种光化学反应是按双自由基机理进行。     

Synthesis of a Potential 10E4 Tetrasaccharide Antigen Involved in Scrapie Pathogenesis

To test the hypothesis that tetrasaccharide 3 is involved in scrapie pathogenesis, tetrasaccharide derivative 32 functionalized with an amine linker at the reducing end was synthesized. A (2 + 2) glycosylation approach was chosen to furnish the target compound in fully protected form. To investigate its biological role, tetrasaccharide 32 was further functionalized to the corresponding thiol 33 using Traut's reagent. During the course of the synthesis, the N,N‐diacetyl protecting group proved surprisingly labile to radical and acidic conditions.     

An Improved Synthesis of Tn Antigen

Tn (GalNAc(1?O-Ser/Thr) 6 is a human tumor-associated carbohydrate antigen1. Protein conjugates of Tn antigen have a role for the active specific immunotherapy of cancer. The total synthesis of Tn antigen has been reported2 by glycosidating between 3,4,6-tri-O-acetyl-2-azido-2-deoxy-(-D-galactopyranosyl chloride and L-serine derivative, then removing the protecting groups. In this route, the key intermediate 3,4,6-tri-O-acetyl-2-azido-2-deoxy-(-D-galactopyranosyl chloride was afforded by …     

A Rapid Synthesis of 4‐Oxazolidinones: Total Synthesis of Synoxazolidinones A and B

A five‐step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4‐oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.     

平板霉素的全合成研究综述

平板霉素由于其强有力的抗菌能力、全新的作用机理和新颖的分子结构, 自2006年被发现起就引起了合成化学家们的广泛关注. 对平板霉素的全合成及其结构类似物的合成进行了综述和介绍.     

Convergent Synthesis of Naphthylisoquinoline Alkaloids: Total Synthesis of (+)-O-Methylancistrocline

A highly convergent synthesis of the methyl ether derivative 2a of the naphthylisoquinoline alkaloid ancistrocline (2) is described. The key step involves a stereoselective biaryl coupling between the chiral oxazoline 3 and the Grignard reagent 4 derived from the optically active tetrahydroisoquinoline 8. The atropisomeric mixture was then converted to the separable acetamides 11 and 12, which were obtained in a ratio of 16:84 and an overall yield of 32% for the three steps. The major atropisomer 12 was then converted into O-methylancistrocline (2a), which was identical to a semisynthetic sample derived from the related alkaloid ancistrocladinine (14).     

Structure-Pattern-Based Total Synthesis

In this article the concept of structure-pattern-recognition and its application to total synthesis is summarized. By applying this synthetic strategy to the two biogenetically unrelated natural product families Sarpagine and Stemona alkaloids, a drastic increase of synthetic efficiency could be achieved. To highlight its potential, this strategy is compared with some elegant target-oriented syntheses. The importance of strategic planning and synthesis design is clearly demonstrated.     

Facile Total Synthesis of Three Natural 1,7-Diaryl-4-hepten-3-ones

Linear 1,7-diarylheptanoids (Ar¹-C₇-Ar²) are a large group of interesting natural products isolated from plants belonging to Alinia,Curcuma, Zingiber, Alnua,Centridobium and Acer genera used as traditional medicines in some oriental countries¹. Pharmacological experiments exhibited that some of them had many physiological actions such as anti-inflammatory, antifungicial, antioxidative,antihepatotoxic activities and so on². Three natural compounds 1³, 2⁴ and 3⁵ (gingerone C) having 1,7-diaryl-4-hepten-3-one skeleton were isolated from the rhizomes of Alpinia offocinarum, the wood of Alnus japonica and the rhizomes of Zingiber officinale respectively. Their structures were elucidated as 1,7-diphenylhept-4-en-3-one(1), 1,7-bis(4-hydroxyphenyl)hept-4-en-3-one(2) and 1-(3-hydroxyl-4-methoxyphenyl)-7-(4-hydroxyphenyl)hept-4-en-3-one(3) by spectral method. Herein, we wish to report facile total synthesis of these three natural compounds. Their synthetic routes were shouwn in scheme.     

新型含磷抗原的合成

肽键的水解在生命化学中起着重要的作用, 利用人工合成的抗原诱导具备天然肽酶活性的抗体酶具有深远意义, 因而众多的工作集中于催化酰胺键和肽键水解的抗体酶的研究. 这些工作通常是以Paulling的过渡态理论为指导, 以磷为中心原子设计合成类似肽键或酰胺键水解过渡态结构的过渡态类似物. 然而按照这种方法得到的抗体酶很少具有肽酶活性. 金声等[1]曾以CPA的肽底物马脲酰苯丙氨酸为模型, 以四面体过渡态类似物为基础, 用硫代替磷, 设计合成了新型半抗原[2]. 制备了相应的具有活性的抗体酶, 然而这样的结果尚不能说明以硫原子代替磷原子的方法的优越性, 因此有必要以磷原子为中心原子合成出一个类似抗原, 将其诱导出的抗体相互比较, 才能得到有意义的结论. 本文报道了含磷抗原的合成, 合成路线如下:     

Total Synthesis of Tubulysin U and Its C‐4 Epimer

The Tup fragments of tubulysins were synthesized with a tandem reaction as the key step, and unexpected diastereoselectivity was observed in the first Grignard addition stage. The coupling of the enolate of a thiazolyl ketone with chiral sulfinimines furnished the backbone of the Tuv fragment with over 100:1 d.r. and high yield. Thus, tubulysin U and C‐4 epi‐tubulysin U were prepared in a highly selective and efficient manner. The results of the MTT assay furthermore indicated that C‐4 epi‐tubulysin U maintained significant growth inhibition activities against several cancer cell lines.     

Total Synthesis of Cyclothialidine

A total synthesis of cyclothialidine ( 1 ), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis, is described. The synthetic concept was tested by preparing the lactone 13 (Scheme 2) which contains the characteristic bicyclic core entity of 1 . Key features of the synthesis of 1 are: preparation of 3,5-dihydroxy-2,6-dimethylbenzoic acid ( 23 ) from 3,5-dihydroxybenzoic acid ( 19 ) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N-bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc-Ser-Cys-OMe ( 11 ); cyclization of the ω-hydroxy acid 29 29 to the 12-membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy (Scheme 4). Optically pure cis-N-(tert-butoxycarbonyl)-3-hydroxy-L -proline ((–)- 14 ) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase-catalyzed enantiospecific acetate hydrolysis (Scheme 3). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1 , e.g., via the intermediate 30 .