Diastereoselective addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones

Abstract

The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here we describe how an umpolung strategy that involves the addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones-directed by the alkoxide of the 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide-leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonyl hydrazones with α-quaternary centres. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl, as well as alkenyl, aryl, allenyl and alkynyl groups. Subsequent hydrolysis of the β-hydroxy N-sulfonyl hydrazone products produces the corresponding β-hydroxy ketones. In addition to hydrolysis, the hydrazone products are poised to undergo numerous different known synthetic transformations via well-established chemistry, which would provide access to a wide array of useful structures.

Stereodivergent Synthesis of β,γ-Fused Bicyclic γ-Lactones via a Multicomponent Ring-Expansion Cascade

“…This is consistent with our prior observations in which compounds with up to three contiguous quaternary centers were able to be formed from azoalkene species. 10,35 As further confirmation of the stereochemistry, an X-ray crystal structure was obtained for compound 38. 34 The transformation was also effective with a b-methyl-substituted a-epoxy hydrazone (Scheme 1; R 1 = H, R 2 = Me, n = 1).…”

“…34 At this point, we undertook preliminary investigations into the mechanism of the reaction. On the basis of previous experience, 10 we suspected that the transformation was proceeding via a 3-alkoxy-1-N-(2-nitro)phenyl azopropene intermediate (cf. 14, Figure 1).…”

“…More recently, we demonstrated the considerable synthetic utility of 3-alkoxy-1-N-toluenesulfonyl azopropenes in the context of the addition of Grignard reagents ( Figure 1C). 10 That transformation proved remarkable in its ability to deliver sterically hindered products in a highly stereocontrolled fashion-including those containing quaternary centers-and also in enabling the incorporation of a wide range of carbon-based substituents spanning the sp 3 , sp 2 , and sp hybridization states.…”

Tipping the balance: theoretical interrogation of divergent extended heterolytic fragmentations

“…Carbon-carbon (C-C), carbonheteroatom (C-X), and heteroatom-heteroatom (X-Y) heterolytic fragmentation reactions offer methods for synthesizing structural motifs (some found in complex natural products) that might be difficult to synthesize using methods focused on bond formation. [1][2][3][4][5][6][7] Despite their continued use in organic synthesis [8][9][10][11][12][13][14][15][16][17] and their relevance to reactions occurring in mass spectrometers, 18 the application of heterolytic fragmentations in which multiple s-bonds are cleaved in synthetic campaigns is limited by putative strict conformational requirements (e.g., an anti-periplanar conformation for the bonds that cleave during fragmentation; Scheme 1). 4,19 Few theoretical and mechanistic studies [20][21][22][23][24] have provided insight into the physical underpinnings for this class of reaction since the seminal work of Grob.…”

Iron Catalyzed Highly Enantioselective Epoxidation of Cyclic Aliphatic Enones with Aqueous H2O2

“…Cyclic -epoxide enones are structures found in a number of natural products, 36 and are also valuable synthons that can be further elaborated into precious building blocks for organic synthesis. 37 However, their asymmetric epoxidation is notoriously difficult. Modest to good enantioselectivities have been obtained with chiral hydroperoxides, 38,39 poly(aminoacids) catalysts, 40 ammonium salt catalysts, [41][42][43] and metal based catalysts 21,22,44,45 , but excellent enantioselectivities have only been described by List and co-workers using cinchona alkaloid derived organocatalysts and hydrogen peroxide as oxidant.…”