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.

Origin of Diastereocontrol in the Oxy‐Michael Reactions of δ‐Lactol Anions: A Computational and Experimental Study

“…The energies in Scheme 3 predict a kinetic cis/trans ratio (i.e., of products cis-16/trans-16) at 195 K of 70:1. In previous experimental studies, the trans isomer is hardly ever observed in these reactions by 1 H NMR spectroscopic analysis, [12,15] consistent with the reaction producing this high diastereoselectivity. The difference in solvation energies between transition-states 10 and 15 accounts for the majority of the calculated energy difference between them (3.1 of the 3.6 kcal mol À1 ).…”

“…[15] The use of a crown ether in the Michael addition reaction means that the "naked" anion assumption is valid. [25] Deprotonation of an anomeric mixture of lactol 1 with potassium hexamethyldisilazide and addition of crown ether [12] sets up an equilibrium of "naked" anions 3-6 and their open-chain forms that can then be reacted with an electrophile (Scheme 2). Assuming that the alkylation is irreversible and, therefore, under kinetic control, a full analysis of the stereoselectivity requires determination of the equilibrium ratios of anions 3-6, [26] the activation energy for their interconversion and the activation energy for the reactions of lactolates 3-6 with an electrophile.…”

“…[12] This reaction has been extended to a range of Michael acceptors [13] and has found use in the syntheses of biologically active b-amino alcohols. [14] The high C6-C2 stereocontrol has also been observed in the reactions of the corresponding potassium salts with alkyl and acyl halides and with acetic anhydride.…”

“…With these structures located, attention was turned to the reaction with nitroolefins. The high diastereoselectivity at the b-centre in adduct 2 is consistent across a wide range of alkyl and aryl-substituted nitroethenes, [12] so the reaction between 1-nitropropene and the anion of lactol 1 was studied to reduce computational demand. Despite this, location of the oxy-Michael transition states proved difficult.…”

Asymmetric Intramolecular Oxa‐Michael Reactions of Cyclohexadienones Catalyzed by a Primary Amine Salt

“…When the reaction was catalyzed by the benzoic acid salt of (1R,2R)-diphenylethylenediamine (DPEN), 60 % ee was obtained. The enantioselectivity dropped significantly when the reaction was catalyzed by catalysts derived from (R,R)-DPEN: primary/tertiary amine catalyst 2 b, primary amine/hydrogen bonding catalyst 2 c and catalyst 3 (entries [4][5][6]. With these moderate results in hand, we introduced a tert-butyl group into the catalyst scaffold, [13] and the resulting catalyst 6 showed excellent stereocontrolling ability in regulating the enantioselectivity (À94 % ee).…”