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.

Bicyclic Pyrazolidinone Derivatives from Diastereoselective Catalytic [3 + 3]-Cycloaddition Reactions of Enoldiazoacetates with Azomethine Imines

“…Recent reports have demonstrated considerable interest in the development of effective methodologies for formal [3 + 3]-cycloaddition transformations 1 catalyzed by transition metal compounds 2,3 or organocatalysts. 4 Generation of metallo-vinylcarbene-like intermediates has been the key to successes in transition metal catalyzed reactions, as we have recently demonstrated through efficient and highly stereoselective formal [3 + 3]-cycloaddition reactions between hydrazones 3a or nitrones 3b,c and vinylcarbene intermediates derived from vinylogous attack of the electrophilic metal vinylcarbenes on nucleophilic reactants and are completed by intramolecular electrophilic addition that is coupled with catalyst dissociation (Scheme 1).…”

“…They offer convenient methodologies for the synthesis of a diverse array of heterocyclic compounds in high yields and selectivities. In an effort to broaden the scope of [3 + 3]-cycloaddition reactions with conveniently accessible enoldiazoacetates we have employed azomethine imine reactants, 5 whose ability to undergo cycloaddition has recently been reported with metal catalyst-derived vinylcarbenes derived from propargyl esters 2c and (2-acetoxymethyl-2-propenyl)trimethylsilane. 2d …”

A quantitative approach to nucleophilic organocatalysis

“…The demonstration of general base catalysis for these reactions furthermore rules out Hayashi’s proposal of a concerted ene reaction for the formation of tetrahydropyridines by the diphenylprolinol-catalyzed reaction of α,β-unsaturated aldehydes with enamides [52] and is in line with Wang’s stepwise mechanism with initial formation of 19 [62]. …”

Diarylprolinol Silyl Ethers: Development and Application As Organocatalysts

“…The reaction of 87 with a,b-unsaturated aldehydes 62 proceeded via a sequence of ene/isomerization/hydrolysis/aminoacetalization reactions in tandem, representing a formal aza-[3þ3] cycloaddition reaction (Scheme [13][14][15][16][17][18][19][20]. This is a very rare example where a piperidine derivative can be assembled using a [3þ3] cycloaddition reaction, in an enantioselective and catalytic fashion [66].…”