A Novel One-Step Diastereo- and Enantioselective Formation of trans-Azetidinones and Its Application to the Total Synthesis of Cholesterol Absorption Inhibitors

Abstract

An efficient and practical asymmetric process was developed for the synthesis of azetidinone-based cholesterol absorption inhibitors. Key to this synthesis was the discovery of a novel one-step diastereo- and enantioselective formation of trans beta-lactams starting from commercially available 3(S)-hydroxy-gamma-lactone. Various trans beta-lactams can be prepared in good yields and with better than 95:5 enantio- and diastereoselctivity. A Lewis acid-catalyzed aldol condensation and a highly enantioselective oxazaborolidine-catalyzed chiral reduction completes the side chain.

Cardiovascular Drugs

“…Buflomedil (170) has like bencyclane besides the vasodilator also antispasmodic properties. It is made by alkylation of pyrrolidine with 4-chlorobutyronitrile, followed by a Friedel-Crafts acylation of 1,3,5-trimethoxybenzene [384].…”

“…This chiral reduction yielded the desired alcohol in a diastereoselectivity of 93-95 %[175]. Further methods for preparation of ezetimibe are described and patented in[169][170][171][172][173][174].…”

Diastereoselective Imino-Aldol Condensation of Chiral 3-(p-Tolylsulfinyl)-2-furaldimine and Ester Enolates.

“…66) The relationship of the esters 4i and 5i with the b-lactams 10i and 11i was confirmed by chemical correlation: the amino esters 4i and 5i were cyclized, respectively, into 10i and 11i upon treatment with lithium hexamethyldisilazide. [12][13][14][30][31][32][33][34][35][36] Although the detailed reaction mechanism is not clear, it is likely that some facts obtained are consistent with the stereochemical outcome which involves a Zimmerman-Traxler transition state model 67,68) (Fig. 3).…”

“…12-14) Chiral versions of these condensations have also been devised by the use of imines with a chiral auxiliary, [1][2][3][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] chiral ester enolate derivatives, [30][31][32][33][34][35][36] and chiral Lewis acids. [37][38][39][40][41] In the course of our studies on remote asymmetric induction using chiral sulfoxides, we previously reported the lanthanoid triflate-catalyzed Mukaiyama aldol reaction of sulfinyl aldehyde 1 with silyl ketene acetals.…”

“…Of the synthetic routes to b-lactams that have been reported, Lewis acid-promoted [1][2][3] and catalyzed [4][5][6][7][8][9][10][11] condensations of imines with silyl ketene acetals and imino-aldol condensations with ester enolates are powerful methods which involve the efficient construction of stereogenic centers of the b-lactam moiety. [12][13][14] Chiral versions of these condensations have also been devised by the use of imines with a chiral auxiliary, [1][2][3][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] chiral ester enolate derivatives, [30][31][32][33][34][35][36] and chiral Lewis acids. [37][38][39][40][41] In the course of our studies on remote asymmetric induction using chiral sulfoxides, we previously reported the lanthanoid triflate-catalyzed Mukaiyama aldol reaction of sulfinyl aldehyde 1 with silyl ketene acetals.…”