Enantioselective Diels–Alder Reaction of 1,2-Dihydropyridines with Aldehydes Using β-Amino Alcohol Organocatalyst

Abstract

The enantioselective Diels-Alder reaction of 1,2-dihydropyridines with aldehydes using an easily prepared optically active β-amino alcohol catalyst was found to provide optically active isoquinuclidines, an efficient synthetic intermediate of pharmaceutically important compounds such as oseltamivir phosphate, with a satisfactory chemical yield and enantioselectivity (up to 96%, up to 98% ee). In addition, the obtained highly optically pure isoquinuclidine was easily converted to an optically active piperidine having four successive carbon centers.

Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3‐Dipolar Cycloaddition of Nitrones to α,β‐Unsaturated Aldehydes

“…Amino alcohols 3a – 3d , which have an aliphatic or aromatic substituent at the β‐position, were easily obtained by using a Grignard reaction to obtain the corresponding α‐amino acid esters, and the bulkier β‐amino alcohols 5a – 5d , which have several different silyl groups bonded to the oxygen atom at the γ‐position, were also easily prepared2d by treating amino diol 4 with R′OTf [R′ = TES (triethylsilyl), TIPS (triisopropylsilyl), TBDMS ( tert ‐butyldimethylsilyl), TPS (triphenylsilyl), and OTf = trifluoromethanesulfonate]. In addition, the bulkiest β‐amino alcohol catalyst 1 , which contained a super silyl group6 on the oxygen atom at the γ‐position was also easily obtained in 53 % yield by the reaction between 4 and TTMSSOTf 2a. Catalyst 6 , which has a trimethylsilyl‐protected (TMS = trimethylsilyl) hydroxy group was obtained in moderate yield from the reaction of 1 with TMSOTf.…”

“…On the basis of the high enantiopurity (95 % ee ) of optically active endo ‐DC adduct 9 , which was obtained from the reaction of nitrone 7 with α,β‐unsaturated aldehyde 8 , and studies of the mechanism of amino organocatalyzed cycloadditions by Ishihara, Seebach, Melchiorre, and our group,2a,8 a plausible model for the mechanism of this enantioselective reaction is proposed (Scheme ). The combination of catalyst 1 , α,β‐unsaturated aldehyde 8 , and TfOH is thought to form intermediate I‐1 , in which there is less steric interaction between the TTMSS substituent on the oxygen atom at the γ‐position of the catalyst and the olefin portion of the dienophile 9.…”

Total synthesis of (+)-gelsemine via an organocatalytic Diels–Alder approach

“…If intermediate 3 is made asymmetric, then gelsemine will be made asymmetric. Thus, after a brief literature search 58 59 , an asymmetric Diels–Alder reaction was designed and the synthesis began with dihydropyridine 1 ( Fig. 6 ), which may be prepared from 4-methylpyridine in large scale 60 .…”

Catalytic Efficiency of Primary β‐Amino Alcohols and Their Derivatives in Organocatalysis

“…Inspired by these results and taking advantage of the catalytic efficiency of β‐amino alcohols, we next studied DA cycloaddition intensively with use of several 1,2‐dihydropyridines 10 and various acroleins 11 together with simple β‐amino alcohol salts 5 to improve the yields and stereoselectivities . Here we screened various β‐amino alcohol salt combinations with various Brønsted acids (CF 3 CO 2 H, CBr 3 CO 2 H, CH 3 CO 2 H, HCl, CCl 3 CO 2 H), but the TFA salts of the β‐amino alcohols gave the best results.…”