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

前手性金属烯醇酯的不对称质子化反应已成为制备非外消旋羰基化合物的有效方法。迄今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-氨基酸衍生物烯醇化产物的质子化反应具有高度不对称诱导作用的报道很少。在本研究中，我们研究了α-氨基酸衍生物烯醇化物与具有不对称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。我们之前已经证明，（S，S）-亚胺和具有不对称2-恶唑啉环的相关亚胺是由简单酮（如2-烷基环己酮）衍生的锂烯醇酯不对称质子化的有效手性质子源。我们设想，如果将这些手性亚胺应用于α-氨基酸衍生物烯醇化产物的质子化，只需改变质子源，就可以选择性地得到L-和D-α-氨基酸。因此，我们初步研究了苯甲酸或苯甲醇衍生物携带不对称2-恶唑啉环作为丙氨酸衍生物烯酸锂不对称质子化的手性质子源的可能性，发现手性苯仲醇的一种非对映体提供了适度的对映选择性。还合成了以四氢呋喃环代替苯环为主链的手性叔醇，并观察到这些手性醇在不对称质子化反应中的对映选择性增加。在上述结果的基础上，我们进一步设计了新的手性酰胺作为手性质子源，可以由易得的α-氨基酸合成。将丙氨酸衍生物烯酸锂与l -叔亮氨酸、生物素前体和环十二烷基胺合成的手性酰胺进行质子化反应，得到含80% ee的富r产物。这些手性酰胺也被发现是其他α-氨基酸衍生物的锂烯醇酸酯的有效不对称质子化剂。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