Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines

Abstract

The piperidine ring system is one of the most common structural subunits in natural products and biologically significant compounds.[1] The aza Diels-Alder reaction [2] and the aza [3+3] cycloaddition reaction [3] are straightforward synthetic methods for making piperidine ring systems. Several methods have been developed for formal aza [3+3] cycloaddition reactions, such as reactions of 1,3-cyclic sulfonates with C/N dianions, [4] vinylogous amides with a,b-unsaturated iminium ions, [5] and aziridines with Pd-trimethylenemethane complexes.[6] In spite of these formal aza [3+3] cycloaddition methods, and to the best of our knowledge, an enantioselective catalytic version has not been reported.Asymmetric catalytic reactions promoted by organocatalysts is a rapidly growing area of research.[7] Our group developed diarylprolinol silyl ether as an effective catalyst in the Michael reaction, [8] the ene reaction, [9] the Diels-Alder reaction, [10] the tandem Michael/Henry reaction, [11] and the Michael reaction of nitroalkanes.[12] At the time of our first report, the group of Jørgensen also developed the same type of catalyst; [13] the diarylprolinol silyl ether catalyst has been widely used in enantioselective reactions. [14] We have applied diphenylprolinol silyl ether to the reaction of a,b-unsaturated aldehydes with enecarbamates and found that a formal aza [3+3] cycloaddition reaction proceeds in a highly enantioselective manner as reported herein (Figure 1).Enecarbamates and enamides have been successfully utilized as reactive nucleophiles by the group of Kobayashi, [15] and Terada et al. recently used them in an aza-ene-type reaction.[16] Having reported the asymmetric ene reaction of cyclopentadiene, [9] we employed an enamide and an a,bunsaturated aldehyde with the expectation that an ene reaction would occur. Notably, the asymmetric, catalytic intermolecular ene reaction of a,b-enals as enophiles is rare.[9]The reaction of cinnamaldehyde and N-(1-phenylvinyl)acetamide 9 was selected as a model reaction and we expected that an amine catalyst and cinnamaldehyde would afford an iminium ion, which would react with enamide 9 to generate 7 by an ene reaction, to afford ketoaldehyde 5[17] after hydration (Scheme 1). When cinnamaldehyde and enamide 9 were treated with a catalytic amount of diphenylprolinol trimethylsilyl ether (1), ketoaldehyde 5 was obtained in 18 % yield in nearly optically pure form along with an unexpected piperidine derivative (6) in 47 % yield as a mixture of a and b isomers (44:56). The a and b isomers were separated and their optical purities were found to be the same (87 % ee, Table 1, entry 1). A pure sample of the a isomer resulted in a Figure 1. Organocatalysts examined in the present study. Scheme 1. The reaction mechanism of 5 and 6.

Matrix‐free detection of intact ions from proteins in argon‐cluster secondary ion mass spectrometry

“…For example, Hayashi et al. reported an enantioselective, formal aza‐[3+3] cycloaddition reaction for their construction2 and Chen et al. introduced two aza‐Diels–Alder reactions for the formation of piperidines with high enantioenrichment 3.…”

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

“…We used this asymmetric Michael reaction as a key step in the recent one‐pot synthesis of (−)‐oseltamivir,6 in a one‐pot synthesis of ABT‐341,7 and in a three‐pot synthesis of prostaglandin E 1 methyl ester,8 in which excellent enantioselectivities were realized. On the other hand, in reactions such as the formal aza [3+3] cycloaddition reaction of α,β‐unsaturated aldehydes and enecarbamates,9 the enantioselectivity is not perfect in the presence of diphenylprolinol TMS ether, and diphenylprolinol tert ‐butyldimethylsilyl (TBS) ether was found to be a superior enantioselective organocatalyst relative to the trimethylsilylated analogue. In these cases, the more bulky silyl group increased the enantioselectivity of the reaction.…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…Recently, Hayashi et al [117] employed enamides and a,b-unsaturated aldehydes to construct the piperidine ring system. The reaction occurred as a domino Michael/acetalization sequence, also named a formal aza A C H T U N G T R E N N U N G [3+3] cycloaddition or cascade aza-ene-type cyclization, which afforded the piperidine derivatives as a (minor) and b (major) isomers.…”