Highly enantioselective construction of a chiral tertiary carbon center by alkynylation of a cyclic N-acyl ketimine:: An efficient preparation of HIV therapeutics
Highly enantioselective construction of a chiral tertiary carbon center by alkynylation of a cyclic N-acyl ketimine:: An efficient preparation of HIV therapeutics
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DOI：
10.1002/anie.200352301
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Si, YG
中科院分区：
文献类型：
--
作者：
Jiang, B;Si, YG
近年来，通过醛和乙二胺的对映选择性烷基化反应合成仲醇、仲丙醇和丙醇胺的方法学研究取得了很大进展。然而，在酮和酮胺的基础上加成碳亲核试剂不对称合成叔醇和卡宾胺的研究已经经历了相当大的挫折。人类免疫缺陷病毒(HIV)容易发生变异，进而导致抗药性。二氢喹唑啉DPC961和DPC083是第二代HIV非核苷类逆转录酶抑制剂(NNRTI)，与Efavirenz(Sustiva)相比具有更强的效力。[2]DPC 961目前正在进行临床评估，因为它对野生型HIV-1的活性以及对含有K103N的HIV和其他NNRTI抗性突变病毒的增强效力。[3]合成这类NNRTI的挑战是以不对称的方式形成叔卡宾胺。这些化合物的合成包括将乙酰镁与含手性辅助取代基的2(3H)-喹唑烷酮[4]进行1，4-非对映选择性加成，或以金鸡纳锂生物碱[5]或4-β-吗啉-3-α-醇锂作为手性调节剂，将乙酰化锂与环状N-酰基酮进行1，2-不对映选择性加成。
Recently great efforts have been made on developing methodology for generating secondary carbinols as well as secondary propargyl alcohol and propargyl amine by enantioselective alkynylation of aldehydes and aldimines.[1] However, the asymmetric synthesis of tertiary carbinols and carbinamines by addition of carbon nucleophiles to ketones and ketimines has experienced considerable frustration. Human immunodeficiency virus (HIV) is prone to mutation, which in turn leads to drug resistance. Dihydroquinazolines DPC961 and DPC083 are second-generation HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency when compared to Efavirenz (Sustiva).[2] DPC 961 is currently undergoing clinical evaluation owing to its activity against wild-type HIV-1 and its increased potency toward the K103N-containing HIV as well as other NNRTI-resistant mutant viruses.[3]The challenge for synthesizing this class of NNRTIs is to form a tertiary carbinamine in an asymmetric manner. The syntheses of these compounds include diastereoselective 1, 4-addition of a magnesium acetylide to 2 (3H)-quinazolinone containing a chiral auxiliary substituent [4] or 1, 2-enantioselective addition of a lithium acetylide to a cyclic N-acyl ketimines using lithium cinochona alkaloids [5] or lithium 4β-morpholinocaran-3α-ol as a chiral moderator.[6] The asymmetric addition step, for which