Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues.
Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues.
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DOI：
10.1021/ja809842b
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发表时间：
2009-04-08
影响因子：
15
通讯作者：
Boger DL
中科院分区：
文献类型：
--
作者：
Ishikawa H;Colby DA;Seto S;Va P;Tam A;Kakei H;Rayl TJ;Hwang I;Boger DL
长春质碱与文多灵直接偶联以提供长春碱的发展的全部细节与关键的机制和标记研究一起沿着描述。在Fe（III）促进的偶联反应之后，通过产生假定的长春质碱自由基阳离子引发，该阳离子经历随后的氧化断裂和与文多灵的非对映选择性偶联，将得到的反应混合物加入Fe（III）-NaBH 4/空气溶液中，导致C15′-C20′双键的氧化和中间体亚胺鎓离子的还原，直接得到长春碱（40-43%）和亮苷（20-23%），其天然存在的C20′醇异构体。具有天然C16′立体化学的偶联产物的收率接近或超过80%，异构C20′醇的总收率> 60%。Fe（III）-NaBH 4/空气氧化反应的初步研究显示了一个可推广的三取代烯烃范围，确定了氧化碳上O2陷阱的替代方案，为C20′官能化长春碱提供了一个独特的入口，并为观察到的C20′非对映选择性提供了初步见解。在这种偶联反应中通过Δ19′，20 ′-脱水长春碱进行的外长春质碱的使用的第一公开内容也详细描述了相同的立体化学结果。取代长春质碱N-甲基或文多灵N-甲酰基排除了Fe（III）促进的偶联，而文多灵的潜在关键C16甲氧基的去除不会不利地影响偶联效率。这些研究的扩展提供了通过N-去甲基长春碱（36，也是一种天然产物）、16-去甲氧基长春碱（44）和4-去乙酰氧基-16-去甲氧基长春碱（47）的长春新碱（2）的全合成，我们现在可以认为这两种产物都可能是由C. roseus，脱乙酰长春碱（62）和4-脱乙酰氧基长春碱（59），以及一系列在文多灵亚基中具有系统修饰的关键类似物。他们的生物学评价提供了对vindoline亚基内促进活性的关键功能的额外见解，并为在未来研究中探索1和2结构中的进一步，更深层次的变化奠定了基础。
Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)–NaBH4/air solution leads to oxidation of the C15′–C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40–43%) and leurosidine (20–23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)–NaBH4/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identified alternatives to O2 trap at the oxidized carbon, provides a unique entry into C20′ functionalized vinblastines, and affords initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ19′,20′-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.
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影响因子：
7.3
作者：
BARNETT, CJ;CULLINAN, GJ;NELSON, RL
通讯作者：
NELSON, RL
DOI：
10.2174/1568011023354452
发表时间：
2002-01-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Duflos, Alain;Kruczynski, Anna;Barret, Jean-Marc
通讯作者：
Barret, Jean-Marc
DOI：
10.1039/c39930001496
发表时间：
1993-10-07
影响因子：
--
作者：
GUNIC, E;TABAKOVIC, I;GASIC, MJ
通讯作者：
GASIC, MJ
影响因子：
3.6
作者：
BORNMANN, WG;KUEHNE, ME
通讯作者：
KUEHNE, ME
影响因子：
8.4
作者：
BAGULEY, BC;HOLDAWAY, KM;ZWI, LJ
通讯作者：
ZWI, LJ