Chemical Research and Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, USA.
J Org Chem. 2010 Apr 2;75(7):2236-46. doi: 10.1021/jo902710s.
A new and general method for asymmetric synthesis of either enantiomer of 2-substituted pyrrolidines from a single starting material is described. Reductive cyclization of (S(S))-gamma-chloro-N-tert-butanesulfinyl ketimines with LiBHEt(3) in THF at -78 to 23 degrees C afforded (S(S),R)-N-tert-butanesulfinyl-2-substituted pyrrolidines in excellent yields (88-98%) and with high diastereoselectivity (99:1). The diastereoselectivity is controlled effectively by the choice of reducing agent. Thus, the corresponding epimers of (S(S),S)-2-substituted pyrrolidines were synthesized in good yields (87-98%) and with high diastereoslectivity (1:99) by simply switching the reducing agent from LiBHEt(3) to DIBAL-H/LiHMDS. Deprotection of N-tert-butanesulfinyl-2-substituted pyrrolidines using 4 N HCl in dioxane and MeOH gave the corresponding enantiomers of 2-substituted pyrrolidines in quantative yield. This method was found to be effective for a variety of substrates including aromatic, heteroaromatic, and aliphatic substituents. Extension of this methodology to the formation of 2-substituted piperidines is also illustrated. Reductive cyclization of (S(S))-delta-chloro-N-tert-butanesulfinyl ketimine with LiBHEt(3) in THF at -78 to 23 degrees C or DIBAL-H/LiHMDS in toluene at -78 to 0 degrees C afforded the (S(S),R)-N-tert-butanesulfinyl-2-substituted piperidines in excellent yield (98%) and with high diastereoselectivity (99:1) or (S(S),S)-N-tert-butanesulfinyl-2-substituted piperidines in good yield (98%) and with high diastereoselectivity (1:99), respectively.
描述了一种从单一原料不对称合成 2-取代吡咯烷的对映异构体的新的通用方法。（S(S））-γ-氯-N-叔丁基亚磺酰基酮亚胺与 LiBHEt(3)在 THF 中于-78 至 23°C 还原环化，得到（S(S），R）-N-叔丁基亚磺酰基-2-取代吡咯烷，产率优异（88-98%），非对映选择性高（99:1）。还原剂的选择有效地控制了非对映选择性。因此，通过简单地将还原剂从 LiBHEt(3)切换为 DIBAL-H/LiHMDS，可分别以良好的收率（87-98%）和高非对映选择性（1:99）合成相应的（S(S），S）-2-取代吡咯烷外消旋体。用 4N HCl 在二恶烷和 MeOH 脱除 N-叔丁基亚磺酰基-2-取代吡咯烷，得到相应的 2-取代吡咯烷对映体，产率定量。该方法对各种取代基（包括芳香族、杂芳香族和脂肪族取代基）都有效。还说明了该方法在形成 2-取代哌啶中的扩展。（S(S））-δ-氯-N-叔丁基亚磺酰基酮亚胺与 LiBHEt(3)在 THF 中于-78 至 23°C 或 DIBAL-H/LiHMDS 在甲苯中于-78 至 0°C 还原环化，分别以优异的收率（98%）和高非对映选择性（99:1）或（S(S），S）-N-叔丁基亚磺酰基-2-取代哌啶，以良好的收率（98%）和高非对映选择性（1:99）得到（S(S），R）-N-叔丁基亚磺酰基-2-取代哌啶。
