Enantioselective Metallophosphite-Catalyzed C-Acylation of Nitrones

Abstract

This communication details the asymmetric metallophosphite-catalyzed 1,3-silylacylation of nitrones (eq 1). This reaction provides access to enantiomerically enriched N-aryl α-amino ketones and, to the best of our knowledge, constitutes the first example of direct C-acylation of nitrones.(1).α-Amino ketones are useful building blocks in organic chemistry. 1 The addition of stoichiometric acyl anion equivalents to imines represents a useful synthetic method that introduces this versatile functional group. 2-5 In a seminal advance, Murry and Frantz described thiazolium carbene-catalyzed aza-benzoin additions between aldehydes and acyl imines generated in situ from tosylamides. 6 In 2005, Miller and co-workers developed an asymmetric variant using a thiazolylalanine-derived catalyst and electron-deficient aryl aldehydes as the acyl donors. 7 Good enantioselectivities were obtained (~75-85%), which increased to 98% for many products upon recrystallization, albeit at the expense of yield. The enantiomeric excess of the products was found to be dependent upon reaction time as racemization occurred under the basic reaction conditions (excess R 3 N).Our laboratory has recently developed metallophosphites 8,9 as a new family of umpolung catalysts for the enantioselective C-acylation of aldehydes and alkenes. 10-12 We were interested in testing the notion that these catalysts could be employed for the asymmetric Cacylation of C=N π bonds as well. We hypothesized that strong nucleophilicity and low basicity of metallophosphites could allow us to develop an asymmetric acylation that would include electron-neutral and electron-rich substrates.A potential complication with the use of imines in the projected application was the appreciable endothermicity of the requisite turnover-enabling [1,4]-O→N silyl transfer (Scheme 1, 4 → 5). 13 We hypothesized that nitrones 14 could be superior azomethine electrophiles due to the reestablishment of thermoneutrality via a [1,5]-O→O silyl transfer (6 → 7). Indeed, in the examination of a range of imine and imine-derived electrophiles as coupling partners with acyl silanes, productive coupling was only observed with nitrone electrophiles (Figure 1). An Naryl moiety was optimal and the N-o-methoxyphenyl (N-OMP) derivative 19 was initially selected as a substrate for optimization.

Acylsilanes: valuable organosilicon reagents in organic synthesis

“…Metallophosphites have also been used in the enantioselective addition of acylsilanes to nitrones for the formation of N-aryl-a-amino ketones. 132 Scheidt and co-workers reported the thiazolium-catalysed sila-Stetter reaction of acylsilanes 308 with unsaturated compounds 309 (Scheme 81). 133 Through the addition of a neutral Lewis base catalyst, acyl anion precursors could be formed from acylsilanes in the presence of thiazolium catalyst, which underwent conjugate addition with a,b-unsaturated ketones.…”

Photochemically Induced Silylacylations of Alkynes with Acylsilanes

“…In contrast, analogous silylacylations starting from acylsilanes appear to be under‐represented2 although arguably leading to valuable synthetic products (Scheme ). Only recently, acylations of aldehydes (benzoin condensations),3a–c ketones,3d,e α,β‐unsaturated carbonyls,3f–h nitrones,3i and imines3j with acylsilanes have been reported, which involve the intermediacy of polarity‐reversed carbonyl anions being formed by catalysts such as KCN, La(CN) 3 , metallophosphites, or thiazolium salts 3. Alkynyl‐substituted acylsilanes can cyclize under rhodium catalysis, but subsequently the silyl group is lost 4.…”

Towards Tartaric‐Acid‐Derived Asymmetric Organocatalysts

“…Incorporation of an additional element of chirality in the ketal part of the catalyst (compound 100 ), however, resulted in a significantly improved enantioselectivity for a broad scope of different Michael acceptors (Scheme 27 – upper reaction) 44b. In contrast, the enantioselective C-acylation of nitrones 102 could be carried out in good yields and with high selectivities with phosphite catalyst 96b (Scheme 27 – lower reaction) 44c…”