Phosphine-catalyzed asymmetric additions of malonate esters to γ-substituted allenoates and allenamides

Abstract

Because carbonyl groups are ubiquitous in organic chemistry, the ability to synthesize functionalized carbonyl compounds, particularly enantioselectively, is an important objective. We have developed a straightforward and versatile method for catalytic asymmetric carbon-carbon bond formation at the γ-position of carbonyl compounds, specifically, phosphine-catalyzed additions of malonate esters to γ-substituted allenoates and allenamides. Mechanistic studies have provided insight into the reaction pathway.here are a variety of powerful methods for functionalizing carbonyl compounds in the α-and the β-positions, including classic approaches such as reacting enolates with electrophiles and adding nucleophiles to α,β-unsaturated carbonyl compounds (1, 2). In contrast, there are few general processes for incorporating new substituents in the γ-position of carbonyl compounds, particularly catalytic asymmetric reactions that form carboncarbon bonds (3).In pioneering early investigations, Trost and Lu demonstrated that phosphines can catalyze additions of certain carbon, nitrogen, and oxygen nucleophiles to the γ-position of 2-butynoates and 2,3-butadienoates (Eq. 1, EWG ¼ ester), as well as related compounds (4-8); for these electrophiles, the γ-carbon of the product is not a stereocenter. In contrast, for additions to homologues of these electrophiles, there is the potential to simultaneously form a new bond and to control the stereochemistry of the γ-carbon (Eq. 2). Until recently, however, there were only isolated examples of intermolecular reactions of this type [≤30% yield (9-11); instead, another phosphine-catalyzed process, isomerization to the dienone (Eq. 2) (12, 13), often intervened], and there were no reports of an enantioselective variant.

Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs

“…78 Unlike previous examples, promoting efficient proton transfer required only a small amount (10 mol %) of 2-methoxyphenol and the reaction could be conducted at much lower temperatures to ensure good enantiocontrol.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…Very good yields and excellent ee values are found in these reactions promoted by a chiral phosphine 272 (Scheme 160). [302] Denmark et al reported reactions of N-silyl oxyketene imines and aromatic aldehydes. The products are very valuable building blocks that are isolated in excellent enantio-as well as diastereoselectivity accompanied by very good yields.…”

Cyclopropyl Iminium Activation: Reactivity Umpolung in Enantioselective Organocatalytic Reaction Design

“…While various activation modes that allow for a (a 2 /d 2 ), b (a 3 ), g (d 4 ), and e (d 6 ) functionalization have been reported through secondary amine organocatalysis, [2] umpolung strategies remain elusive outwith the confines of SOMO activation [2b] and processes mediated by N-heterocyclic carbenes (NHCs). [3,4] Because pyrrolidine-and imidazolidinone-based organocatalysts require carbonyl substrates to generate the transient intermediates that are central for catalysis, the substrate scope is limited to aldehydes and ketones with varying degrees of unsaturation. With a view to extending the substrate scope of secondary-amine-catalyzed processes, and providing an entry point into the design of homologous variants of addition reactions to a,b-unsaturated iminium ions, we began exploring the reactivity of cyclopropane carbaldehydes.…”

“…Initially, the commonly used reagents 9 and 11 were selected as the Cl À and Cl + sources, respectively. Catalyst screening using a variety of secondary amine organocatalysts (1)(2)(3)(4)(5)(6)(7)(8) quickly revealed that the firstgeneration MacMillan catalyst 5 furnished the expected 1,3-dichloride with the highest levels of diastereo-and enantiocontrol ( 9). It is important to note that no reaction is observed in the absence of a secondary amine catalyst.…”