Highly Diastereoselective Oxy‐Michael Additions of Enantiopure δ‐Lactol Anions to Nitroalkenes: Asymmetric Synthesis of 1,2‐Amino Alcohols

Abstract

The abundance of bioactive natural and unnatural products that contain the 1,2-amino alcohol motif continues to stimulate the development of new methods for their efficient asymmetric synthesis. Whereas 1,2-amino alcohols derived from proteinogenic amino acids are readily accessible, nonproteinogenic amino acid derived amino alcohols require efficient enantioselective routes.[1] Methods for the asymmetric synthesis of 1,2-amino alcohols with a stereogenic hydroxy-substituted carbon center are relatively uncommon, even though these materials and their derivatives are widespread in nature and routinely exploited in asymmetric synthesis. [2] Stimulated by the utility of 1,2-amino alcohols and encouraged by the lack of a general synthetic approach to such compounds, we recently became interested in developing asymmetric methods for their synthesis. Although a logical retrosynthetic disconnection is based on an asymmetric nitroaldol reaction, [3] our approach relies on the stereoselective Michael addition of a chiral water equivalent 1 to readily available nitroalkenes 2. As in many asymmetric catalytic processes, the levels of asymmetric induction in the nitroaldol reaction are substrate dependent, and in the worst cases there is no way of increasing the enantiopurity of the product. In the oxy-Michael addition approach the chirality in the nucleophile allows the separation of the diastereomeric products 3 and hence the isolation of enantiopure material after auxiliary removal. However, ideally the chirality of the nucleophile will induce high levels of stereoselectivity in the formation of the stereogenic center b to N, and subsequent nitro-group manipulation and nondestructive removal of the auxiliary will free the deprotected oxy-Michael product 4 (Scheme 1).The strength of this concept was recognized previously by Enders et al., [4] who used the sodium salt of N-formylnor-[*] Dr.

Organocatalytic Name Reactions Enabled by NHCs

“…It takes place between active methylene with α,β-unsaturated carbonyl compound, leading to C-C bond formation. Furthermore, asymmetric Michael addition has been known since the 1980s [144][145][146][147][148][149]. In addition, the umpolung effect forced by imines is known to take place in this type of synthesis [150].…”

Nitroalkenes as Amination Tools

“…Reduction of the nitro group and protection of the obtained primary amine has to precede the cleavage of the benzyl ether with sodium in liquid ammonia to afford the enantioenriched N -Boc amino alcohol 37 . A related approach employs chiral lactol 38 as a source of the alkoxide anion in reactions with various nitroalkenes (Scheme 3.19 ) [41] .…”

Catalytic Asymmetric β‐Peroxidation of Nitroalkenes

“…Indeed, only a few examples of stereoselective oxa-Michael reactions were reported by the groups of Enders, [8] Dixon [9] and Jørgensen. [10] We have recently developed a simple methodology for the highly enantioselective epoxidation of a,benones catalyzed by diaryl-2-pyrrolidinemethanol compounds and tert-butyl hydroperoxide (TBHP) as the oxidant.…”