Syntheses of enantiomerically pure 2-substituted pyrrolidin-3-ones via lithiated alkoxyallenes -: An auxiliary-based synthesis of both enantiomers of the antibiotic anisomycin
Syntheses of enantiomerically pure 2-substituted pyrrolidin-3-ones via lithiated alkoxyallenes -: An auxiliary-based synthesis of both enantiomers of the antibiotic anisomycin
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DOI：
10.1002/hlca.200590143
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发表时间：
2005-01-01
影响因子：
1.8
通讯作者：
Reissig, HU
中科院分区：
文献类型：
--
作者：
Kaden, S;Brockmann, M;Reissig, HU
以‘二丙酮-果糖’取代的丙二烯1和N-Boc保护的亚胺前驱体2a为起始原料，制备了抗生素苯甲酸的两个对映体盐酸盐。在2a中加入过量的锂离子得到2：1的非对映异构体混合物3a，它们在碱基促进下环化为4a(方案2)。4a的两个非对映异构体被分离并转化为对映体纯的吡咯烷酮-3-酮(2R)-5a和(2S)-5a。类似的序列产生了N-TOS保护的化合物(2R)-5b和(2S)-5b。化合物5a转化为硅烯醇醚6，并通过随后的区域和立体选择性氢化反应生成吡咯烷衍生物7(方案3)。直截了当的官能团转化得到了茴香素的盐酸盐9(方案3)。(2R)系列提供了天然对映体的盐酸盐(2R)-9，而(2S)系列提供了对映体(2S)-9。合成天然产物的全序列包括10个步骤和8个纯化中间体，总收率为8%。我们对这种类型的羟基吡咯烷的立体化学发散方法是高度灵活的，应该可以很容易地制备许多类似物。
The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the 'diacetone-fructose'-substituted allene 1 and the N-Boc-protected imine precursor 2a. Addition of an excess of lithiated I to 2a provided a 2: 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin-3-ones (2R)-5a and (2S)-5a. A similar sequence yielded the N-Tos-protected compounds (2R)-5b and (2S)-5b. Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio- and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional-group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)-9 of the natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)-9. The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.