Asymmetric Protonation of Enolate of α-Ammo Acid Derivatives Using Chiral Proton Sources

前手性金属烯醇酸盐的不对称质子化已成为制备非外消旋羰基化合物的有效方法。到目前为止，已经合成了许多手性酸，并已用于对映选择性质子化。然而，关于α-氨基酸衍生物的烯醇酸盐的质子化反应具有很高的不对称诱导性的报道很少。在本研究中，我们研究了α-氨基酸衍生物的烯醇酸盐与含有不对称2-恶唑啉的手性醇或由α-氨基酸衍生的手性酰胺的不对称质子化反应。我们以前已经证明，具有不对称2-恶唑啉环的(S，S)-酰亚胺及其相关的酰亚胺是由2-烷基环己酮等单酮衍生的锂的不对称质子化反应的有效手性质子源。我们设想，如果将这些手性亚胺应用于α-氨基酸衍生物的烯醇酸盐的质子化反应，则可以通过简单地改变Chira-…来选择性地获得L-和D-Chira-氨基酸因此，我们初步考察了含有不对称2-恶唑环的苯甲酸或苯甲醇衍生物作为丙氨酸衍生物的不对称质子化反应的手性质子源的可能性，发现手性苄基仲醇的一个非对映异构体提供了中等的对映选择性。合成了以四氢呋喃(THF)环取代苯环为骨架的手性叔醇，并观察到这些手性醇在不对称质子化反应中对映体选择性的提高。在上述结果的基础上，我们进一步设计了新的手性酰胺类化合物作为手性质子源，可以由现成的α-氨基酸合成。用L-叔亮氨酸、生物素前体和环十二胺衍生的手性酰胺质子化丙氨酸衍生物的锂时，得到了80%ee的富R产物。这些手性酰胺也被发现是其他α-氨基酸衍生物的锂的不对称质子化的有效试剂。较少

Asymmetric protonation of prochiral metal enolates has become an efficient way of preparing nonracemic carbonyl compounds. Numerous chiral acids have been synthesized to date and have been utilized in enantioselective protonations. However, there are few reports on the protonation of enolates of α-amino acid derivatives giving high asymmetric induction.In this research, we examined the asymmetric protonation of enolates of α-amino acid derivatives with chiral alcohols possessing an asymmetric 2-oxazoline or chiral amides derived from α-amino acids. We have previously shown that (S,S)-imide and related imides possessing an asymmetric 2-oxazoline ring are efficient chiral proton sources for asymmetric protonation of lithium enolates derived from simple ketones such as 2-alkylcyclohexanones. We envisaged that if these chiral imides were applied to the protonation of enolates of α-amino acid derivatives, both L- and D-α-amino acids might be selectively obtained simply by changing the chira … More l proton source.Thus, we initially investigated the possibility of benzoic acid or benzyl alcohol derivatives bearing an asymmetric 2-oxazoline ring as chiral proton sources for the asymmetric protonation of lithium enolate of an alanine derivative and found that one diastereomer of a chiral benzylic secondary alcohol provided a moderate enantioselectivity. Chiral tertiary alcohols having a tetrahydrofuran (THF) ring in place of a benzene ring as a backbone were also synthesized and an increase in enantioselectivity was observed in the asymmetric protonation using these chiral alcohols. On the basis of the aforementioned results we further designed new chiral amides as chiral proton sources which can be synthesized from readily available α-amino acids. When the lithium enolate of alanine derivative was protonated with a chiral amide derived from L-tert-Leucine, biotin precursor, and cyclododecylamine, R-enriched product was obtained with 80% ee. These chiral amides were also found to act as effective asymmetric protonating agents for lithium enolates of other α-amino acid derivatives. Less