Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

Abstract

SummaryAn effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor.

Synthesis of 1,3-diaryl-spiro[azetidine-2,3′-indoline]-2′,4-dionesviathe Staudinger reaction:cis- ortrans-diastereoselectivity with different addition modes

“…A similar approach was previously proposed for the synthesis of combretastatin analogues. 20 A number of alternative methods have been described in the literature for the formation of the b-lactam cycle including the Rh-or Ir-catalyzed reductive Mannich-type reaction, 21,22 the Reformatsky reaction using Schiff bases and a-bromosubstituted esters derivatives, 20,23 the direct regiospecic metal-catalyzed carbonilation of aziridines, 24 the intramolecular nucleophilic Fig. 1 Spiro-oxindoles SAR405838 and APG-115, 16,17 which are currently under clinical trials, and dispiro-oxindole KM-140 have successfully completed preclinical studies.…”

Reductive Carbon–Carbon Bond Forming Reactions with Carbonyls Mediated by Rh–H Complexes

“…Therefore we investigated the conditions again and found that using [RhCl(cod)] 2 greatly improved the yields in the reductive Mannich reaction. [ 19 ] The results by using the improved condition are summarized in Table 5. Most of the synthesized β‐lactams were obtained with dramatically improved yields.…”

“…Bearing in mind the background, we have accomplished a new route to (±)‐ezetimibe by using our reductive Mannich reaction, which was short synthetic steps, and high total yields (Scheme 8). [ 19 ] After that, several effective synthetic methods have still been developed. [ 24 ]…”

“…[ 25 ] The synthesized chiral lactones and imine ( 9o ) were treated with Et 2 Zn and BF 3 · Et 2 O in the presence of the Rh catalyst according to our previous method. [ 19 ] Unfortunately, although both of the yields and diastereoselectivities on the β‐lactam ring were poor, the reaction gave the β‐lactams ( 10o ). Following the deprotection of [(3 R ,4 S )‐(3 S )/(3 S ,4 R )‐(3 S )]‐ 10o led to the desired product as the diastereomeric mixture on β‐lactam ring.…”

“…[25] The synthesized chiral lactones and imine (9o) were treated with Et 2 Zn and BF 3 •Et 2 O in the presence of the Rh catalyst according to our previous method. [19] Unfortunately, although both of the yields and diastereoselectivities on the -lactam ring were poor, the reaction gave the -lactams Scheme 9. Examination for the asymmetric synthesis of ezetimibe.…”