ACYCLIC DIASTEREOSELECTIVE SYNTHESIS USING TARTRATE ESTER MODIFIED CROTYLBORONATES - DOUBLE ASYMMETRIC REACTIONS WITH ALPHA-METHYL CHIRAL ALDEHYDES AND SYNTHESIS OF THE C(19)-C(29) SEGMENT OF RIFAMYCIN-S
ACYCLIC DIASTEREOSELECTIVE SYNTHESIS USING TARTRATE ESTER MODIFIED CROTYLBORONATES - DOUBLE ASYMMETRIC REACTIONS WITH ALPHA-METHYL CHIRAL ALDEHYDES AND SYNTHESIS OF THE C(19)-C(29) SEGMENT OF RIFAMYCIN-S
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DOI：
10.1021/ja00173a024
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发表时间：
1990-08-15
影响因子：
15
通讯作者：
ANDO, K
中科院分区：
文献类型：
--
作者：
ROUSH, WR;PALKOWITZ, AD;ANDO, K
酒石酸酯改性丁基硼酸酯1、2和α的双不对称反应。描述了-甲基手性醛。1和2的适当对映体与-烷氧基的反应。-甲基丙醛11提供的加合物12、13和14的最小非对映选择性为90%，只要为11选择最佳的羟基保护基团。因此，TBDMS保护的乙醛11a是匹配双不对称反应生成12a和14a的最佳底物，而TBDPS保护的11b是不匹配双不对称反应生成13b和15b的最佳前体。在11和手性烯丙基硼酸16的反应中，立体选择性对保护基团的依赖性也类似。这是从这些和其他数据（c.f., . sigma .DELTA. DELTA. g.d bldag）推断出来的。数据如表四所示)。-烷氧醛取代基对酒石酸酯烯丙硼酸酯双不对称反应的非对映选择性有显著的负面影响，特别是涉及2和16的双不对称反应。对“烷氧基效应”存在的进一步了解是由1,2和16与醛20的双不对称反应提供的，醛20缺乏令人反感的。β。烷氧基组。这些实验（表V）表明，20的非对映选择性，特别是与2和16的反应（. sigma .DELTA. DELTA. DELTA. g.d bldag）。= 1.7-1.8 kcal mol-1)与11（典型的. sigma .DELTA. DELTA. g.d bldag）的患者相比显著改善。= 1.1-1.4千卡摩尔-1)。通过使用试剂28和29，结合先前在这些实验室开发的具有更高对映选择性的N，N " -二苯基-N，N " -乙基酰胺助剂，也可以提高11和20的烯丙基和(E)-丁基的立体选择性（表六）。从这些研究中得到的加合物23已经转化为内酯27，一种已知的Prelog-Djerassi内酯酸的前体。提出了一个经验模型，使人们能够预测1和2将在复杂的综合问题中发挥最大作用的情况。因此，通过与合适的。α相匹配的双不对称反应，可以制备具有分支甲基间反关系的二丙酸亚结构7和9，具有很高的非对映选择性。-甲基手性醛底物，而甲基支间具有syn关系的亚结构8和10则较难通过错配双不对称反应制备。此外，随着手性醛固有的非对面相偏好的增加，7和9的制备容易程度以及8和10的制备困难程度预计会增加。因此，在全合成中应用该技术时，应最大限度地增加1,3-反支链甲基关系的键结构数量，并尽早引入较困难的1,3-反支链甲基单元。这些原理在利福霉素S的环桥C(19)-C（29）段的高度非对映选择性合成中得到了说明。该合成具有四个C-C键形成反应，涉及手性丁基和烯丙酸技术，产率为15%，对源自(S)-11b的16步序列具有78%的立体选择性。
Double asymmetric reactions of the tartrate ester modified crotylboronates 1 and 2 and .alpha.-methyl chiral aldehydes are described. The reactions of the appropriate enantiomers of 1 and 2 with .beta.-alkoxy-.alpha.-methylpropionaldehydes 11 provide adducts 12, 13, and 14 with a minimum diastereoselectivity of 90%, provided that the optimal hydroxyl protecting group is selected for 11. Thus, TBDMS protected aldehyde 11a is the optimal substrate for the matched double asymmetric reactions leading to 12a and 14a, while the TBDPS protected 11b is the optimal precursor to 13b and 15b via mismatched double asymmetric reactions. A similar dependence of stereoselectivity on the protecting group is seen in the reactions of 11 and chiral allylboronate 16. It is inferred from these and other data (c.f., .SIGMA..DELTA..DELTA.G.dbldag. data provided in Table IV) that .beta.-alkoxy aldehyde substituents have a significant, negative impact on the diastereoselectivity of the double asymmetric reactions of the tartrate allyloboronates, especially those involving 2 and 16. Additional insight into the existence of the "alkoxy effect" is provided by the double asymmetric reactions of 1, 2, and 16 with aldehyde 20 that lacks an offending .beta.-alkoxy group. These experiments (Table V) show that the diastereoselectivity of the reactions of 20 especially with 2 and 16 (.SIGMA..DELTA..DELTA.G.dbldag. = 1.7-1.8 kcal mol-1) are significantly improved relative to those with 11 (typically .SIGMA..DELTA..DELTA.G.dbldag. = 1.1-1.4 kcal mol-1). Improvements in stereoselectivity of the allyl- and (E)-crotylborations of both 11 and 20 are also possible by using reagents 28 and 29 incorporating the more highly enantioselective N,N''-dibenzyl-N,N''-ethylenetartramide auxiliary previously developed in these laboratories (Table VI). Adduct 23 deriving from these studies has been converted into lactone 27, a known precursor of the Prelog-Djerassi lactonic acid. An empirical model is presented that enables one to predict the situations in which 1 and 2 will be maximally effective in complex synthetic problems. Thus, dipropionate substructures 7 and 9 with anti relationships between branching methyl groups can be prepared with very high diastereoselectivity via matched double asymmetric reactions with the appropriate .alpha.-methyl chiral aldehyde substrate, while substructures 8 and 10 with syn relationships between methyl branches are more difficult to prepare via mismatched double asymmetric reactions. Moreover, the ease of preparation of 7 and 9, and the difficulty with 8 and 10, is expected to increase as the intrinsic diastereofacial preference of the chiral aldehyde increases. Accordingly, the number of bond constructions leading to 1,3-anti branching methyl relationships should be maximized when applying this technology in total synthesis, and the more difficult 1,3-syn branching methyl units should be introduced as early as possible. These principles are illustrated in a highly diastereoselective synthesis of the C(19)-C(29) segment of the ansa bridge of rifamycin S. This synthesis features four C-C bond forming reactions involving the chiral crotyl- and allylboronate technology and proceeds in 15% yield and with 78% stereoselectivity for the 16-step sequence originating from (S)-11b.