Direct Proline‐Catalyzed Asymmetric α‐Aminoxylation of Ketones

Abstract

Optically active a-hydroxy carbonyl compounds, important building blocks in organic synthesis, can be prepared by several methods such as the electrophilic a-hydroxylation of enolates using chiral oxaziridines as the oxidizing agent.[1] As for methods based on asymmetric catalytic reactions, there are several, including the asymmetric dihydroxylation of enol ethers developed by Sharpless et al., [2] the asymmetric epoxidation of silyl enol ethers with a chiral dioxirane, [3] and the asymmetric epoxidation of enol ether with a chiral Mn-salen catalyst.[4] Recently Yamamoto et al. have developed an excellent asymmetric, catalytic nitroso-aldol reaction:[5] a catalytic amount of a binap-AgOTf complex promotes the reaction of tin enolate and nitrosobenzene, affording an a-aminoxy ketone, which is easily converted into the a-hydroxy ketone. In most of these reactions, however, the ketones must be converted into isolable enolate or enol derivatives, and there is as yet no direct catalytic method for the synthesis of chiral a-hydroxy ketones from the corresponding ketones. In this communication, we disclose the direct catalytic enantioselective a-aminoxylation of ketones, which is complementary to the recent asymmetric a-aminoxylation of aldehydes. [6] Proline [7] has been found to be an excellent catalyst of asymmetric aldol [8] and Mannich reactions [9] and of the asymmetric a-amination of carbonyl compounds.[10] In our continuing research on asymmetric reactions catalyzed by proline, [6c, 9c, 11] we have found the asymmetric a-aminoxylation of a ketone: The reaction of cyclohexanone and nitrosobenzene was conducted in dimethyl sulfoxide (DMSO) at room temperature in the presence of a catalytic amount of lproline. The desired a-aminoxylated cyclohexanone 1 was obtained in 31 % yield, along with the a,a'-diaminoxylated product 2 in 11 % yield [Eq. (1)

Thermal Effects in the Organocatalytic Asymmetric α‐Amination of Disubstituted Aldehydes with Azodicarboxylates: A High‐Temperature Organocatalysis

“…[4] Recently discovered by List and Jørgensen, the asymmetric proline-catalyzed α-amination of achiral linear aldehydes and ketones with azodicarboxylates provides the corresponding aminated carbonyl compounds in good yield and excellent enantioselectivities. [5,6] This concept of enamine catalysis which refers to the formation of nucleophilic enamine intermediates from aldehydes or ketones with the chiral organocatalyst has been extended to aldol, [7,8] Mannich, [9] and Michael-type reactions, [10] as well as to α-functionalizations such as alkylations, [11] hydroxylations [12,13] and halogenations. [14,15] Based on the protocol developed by List and Jørgensen, we have been able to show that this strategy could also be duced reaction time.…”

Stereoselective total synthesis of verbalactone

“…Oxidation of 8 under Swern condition gave the corresponding aldehyde 8a. This aldehyde was subjected to a-aminoxylation [16][17][18] catalyzed by L-proline, followed by in situ reduction using NaBH 4 to furnish the required a-amino-substituted diol 8b. The reductive hydrogenation of a-amino-substituted diol using 10 % Pd-C in methanol afforded the chiral diol 9 in 72 % yield ([97 % de).…”

Total Synthesis of Marine Natural Products: Cephalosporolides

“…DIBAL-H reduction of the latter to aldehyde and organocatalytic a-aminoxylation [27] followed by in situ NaBH 4 reduction and reductive hydrogenation afforded the chiral diol 34 in good yield (> 97 % de). Benzaldehyde dimethyl acetal protection of diol 34 and regioselective opening of cyclic acetal with DIBAL-H gave the corresponding primary alcohol which was converted into the iodide 35.…”

“…Subsequent ozonolysis of 39 gave the corresponding aldehyde and subsequent Wittig olefination followed by hydrogenation gave 40. Reduction of 40 with DIBAL-H under controlled conditions afforded the corresponding aldehyde, which was subjected to a-aminoxylation [27] followed by reduction with NaBH 4 and reductive hydrogenation to give the chiral diol 41. Subsequent tosylation and treatment with K 2 CO 3 in MeOH gave the epoxide in good yield.…”