Intramolecular Oxamidation of UnsaturatedO-Alkyl Hydroxamates: A Remarkably Versatile Entry to Hydroxy Lactams

Abstract

The development of a versatile method for the preparation of 5 to 8-membered hydroxy lactams, involving the iodine(III)-mediated oxamidation of unsaturated O-alkyl hydroxamates is described. This transformation, which is believed to proceed through the intermediacy of singlet nitrenium and bicyclic N-acyl-N-alkoxyaziridinium ions, is in most of the 22 cases examined, both stereospecific and/or highly regioselective.The reaction of singlet nitrenium ions1 with alkenes has long been known to proceed in stereospecific fashion to generate aziridinium ions.2 However, in comparison to the reaction of carbenes, their isoelectronic congeners, this process has until recently, received scant attention,3 -5 despite the growing importance of both aziridines and aziridinium ions in organic synthesis.6 While this reflects the harsh conditions traditionally required for formation of these reactive electrophiles, the iodine(III)-mediated oxidation of O-alkyl hydroxamates 1 offers convenient access to O-stabilized nitrenium ions (7 in Scheme 1). 1b Having successfully employed the cyclization of these species with arenes as a route to azaspiranes, 7 we became intrigued by the possibility that intramolecular addition of nitrenium ions generated from unsaturated hydroxamates 1 would not only yield bicyclic N-acyl-N-alkoxyaziridinium ions 4, but through concerted ring opening of these products, offer a means to accomplish cyclofunctionalization. Herein, we report the successful development of this reaction as a highly versatile method for the preparation of 5 to 8-membered hydroxy lactams 3. 8,9 Our preliminary studies focused on substrate 1a which, upon treatment with phenyliodine(III) bis(trifluoroacetate) (PIFA) in CH 2 Cl 2 , smoothly underwent cyclization to form anti-addition product 2a in high yield (eq 1). In light of the lability of this ester, a methanol-ammonia quench was employed to remove the trifluoroacetate group and provided α-hydroxyalkyl lactam 3a as a single diastereomer in excellent yield. Importantly, we have found that addition of trifluoroacetic acid to the oxamidation reaction significantly accelerates this process and, in most cases, improves its efficiency (Table 1). That acid catalysis plays a significant role in the formation of 2a is also apparent from the inhibitory effect of acid scavengers and the failure of both PhI(OAc) 2 and Pb(OAc)4 to mediate cyclofunctionalization.10 , 11wardropd@uic.edu. Supporting Information Available: Characterization, procedures and stereochemical assignments. This material is free of charge via the Internet at http://pubs.acs.org. Employing these optimal conditions, a range of unsaturated hydroxamates was screened. As is apparent from Table 1, this reaction is characterized by broad substrate scope and, in most cases, is both stereospecific and highly regioselective. In the case of 1,2-disubstituted alkenes, concerted ion pair collapse of bicyclic aziridinium ions 4c-e occurs solely at the less encumbered α position to yield α-hydroxyalkyl lactams, while bicyclo[2...

Recent Developments in Methodology for the Direct Oxyamination of Olefins

“…[62] In a departure from SanMartins system, the amide 91 is activated directly with a methoxy group.…”

Flexible Gold‐Catalyzed Regioselective Oxidative Difunctionalization of Unactivated Alkenes

“…[3] These transformations rely on the oxidation of Pd II to Pd IV species to facilitate the formation of CÀX bonds. [4,5] Coppercatalyzed [6] and also metal-free [7] reactions have been reported although the required acidic media in the later processes might limit its potential application in more elaborated settings [Eq. (1); TFA = trifluoroacetic acid]. Our research group has recently combined the unique carbophilicity of gold complexes with the Au I /Au III redox catalytic cycles to design new transformations.…”

Nitrenium Ion-Mediated Alkene Bis-Cyclofunctionalization: Total Synthesis of (−)-Swainsonine

“…15 Having successfully utilized this methodology in the stereocontrolled synthesis of the piperidine core of the azasugar castanospermine, 16 we were prompted to consider whether this chemistry might also be brought to bear on (-)-swainsonine. Herein we report the successful development of an efficient route to this indolizidine alkaloid, in which the pyrrolidine ring and C-8a/8 threo stereodiad of the target are simultaneously established in a substrate-controlled nitrenium ion oxamidation reaction.…”

“…Employing our previously reported oxamidation conditions, 15 cyclization of substrate 6 was now accomplished by treatment with phenyliodine(III) bis(trifluoroacetate) (PIFA, 1.2 equiv) and trifluoroacetic acid (1 equiv) in methylene chloride at 0 °C (Scheme 3). After 9 h, the reaction was simply concentrated to provide a 6:1 mixture of bis-cyclization products 12 and 13 .…”

“…26 At this point, assignment of the relative C2′ stereochemistry in 12 was made difficult by the conformational freedom of the C6-C2′ bond, although was assumed to be R in view of the stereospecificity of the oxamidation process with respect to alkene geometry. 15 …”