Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
J Org Chem. 2017 Dec 1;82(23):12447-12466. doi: 10.1021/acs.joc.7b02233. Epub 2017 Nov 1.
The asymmetric syntheses of a range of N- and O-protected 3-deoxy-3-aminosphingoid bases have been achieved using two complementary approaches. dl-Serine was converted to a racemic N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester which was resolved using a parallel kinetic resolution (PKR) strategy upon reaction with a pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide, giving the corresponding enantio- and diastereoisomerically pure β,γ-diamino esters. Alternatively, elaboration of l-serine gave the corresponding enantiopure N,N-dibenzyl-protected γ-amino-α,β-unsaturated ester, and doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide was found to proceed under the dominant stereocontrol of the lithium amide reagent in both cases, thus augmenting the accessible range of β,γ-diamino esters. Both of these protocols were expanded to include in situ oxidation of the enolate formed upon conjugate addition, giving access to the corresponding α-hydroxy-β,γ-diamino esters. Elaboration of these β,γ-diamino and α-hydroxy-β,γ-diamino esters gave the protected forms of the 3-deoxy-3-aminosphingoid base targets.
已经使用两种互补的方法实现了一系列 N-和 O-保护的 3-脱氧-3-氨基神经鞘氨醇碱基的不对称合成。dl-丝氨酸被转化为外消旋的 N,N-二苄基保护的γ-氨基-α,β-不饱和酯，该酯在与假对映体混合物的锂（R）-N-苄基-N-（α-甲基苄基）酰胺和锂（S）-N-3,4-二甲氧基苄基-N-（α-甲基苄基）酰胺反应时，采用平行动力学拆分（PKR）策略进行拆分，得到相应的对映异构体和非对映异构体纯的β,γ-二氨基酯。或者，通过对 l-丝氨酸进行修饰，得到相应的对映体纯的 N,N-二苄基保护的γ-氨基-α,β-不饱和酯，并且发现锂 N-苄基-N-（α-甲基苄基）酰胺的对映体的双非对映选择性共轭加成在两种情况下都以锂酰胺试剂的主要立体控制进行，从而增加了β,γ-二氨基酯的可及范围。这两种方案都被扩展到包括在共轭加成形成的烯醇化物的原位氧化，从而得到相应的α-羟基-β,γ-二氨基酯。这些β,γ-二氨基和α-羟基-β,γ-二氨基酯的修饰得到了 3-脱氧-3-氨基神经鞘氨醇碱基目标物的保护形式。
