Crystallization-Induced Diastereomer Transformations of Donor-Acceptor Cyclopropanes

Abstract

We report the first crystallization-induced diastereomer transformations (CIDTs) of donor-acceptor (D-A) cyclopropanes, providing access to important chiral nonracemic building blocks for stereospecific and stereoselective transformations. Lewis acids rapidly epimerize aniline-substituted D-A cyclopropanes through reversible C-C bond cleavage. Formation of the conjugate acid anilinium salt concurrently slows epimerization and enhances the crystallinity of the cyclopropanes. We present the first example of a temperature-dependent switchable stereoselective crystallization, which enables isolation of either diastereomer with high yield and diastereoenrichment. As a complement to the Lewis acid activation paradigm, solvent-promoted epimerization is demonstrated to enable a spontaneous CIDT of an aniline-substituted D-A cyclopropane in the absence of a Lewis acid. In both approaches, products can be isolated by direct filtration of the reaction mixture without the need for further purification. The latter approach was demonstrated on a multidecagram scale. Through manipulation of the aniline and ester functional handles, this method enables access to diastereo- and enantiopure cyclopropanes and derivatives thereof.

Figure 1.

(a) Freebasing 3a·HCl in the absence of a Lewis acid affords the aniline 3a as a single diastereomer. (b) Lewis acid-promoted cyclopropane epimerization over time. Circle: 3c·NBSA; triangle: 3c.

Figure 2.

Temperature-dependent stereocontrol enables access to either diastereomer in excellent yield. ^aTriethylamine could be replaced with free aminopyridine 3e to eliminate trace (<5%) Et₃N·DNBSA from the precipitated material. The identity of the base had no effect on the selectivity of the reaction.

Figure 3.

(a) Methanol promotes spontaneous diastereoenrichment of cyclopropane 5 in under 45 min. (b) Conditions: (i) B₂(OH)₄, 4,4′-bipyridyl, DMSO, 30 min; (ii) MeOH, 1 h; yield reported over 2 steps; absolute stereochemistry determined by X-ray crystallography. (c) Decagram scale synthesis of cyclopropane 5: (i) DCC, MeCN, 6 h; (ii) 4-NO₂PhCHO (1 equiv), K₂CO₃ (2 equiv), Ac₂O, 85 °C, 4 h; (iii) Me₃SOI, KO^tBu, DMSO, 30 min; (iv) B₂(OH)₄, 4,4′-bipyridyl, DMSO, 1 h; (v) MeOH, 1 h.

Figure 4.

Synthetic manipulations of diastereo- and enantiopure cyclopropanes.

Scheme 1.. (a) Stereospecific Reactions of Electron-Neutral Donor–Acceptor Cyclopropanes. (b) DyKAT Manifold of Electron-Rich Donor–Acceptor Cyclopropanes Enabled by Chiral Lewis Acid Catalysis. (c) Hypothesized Crystallization-Induced Diastereomer Transformation Platform of Aminoaryl Donor–Acceptor Cyclopropanes

Scheme 2.. Synthesis of Cyclopropanes and Classical Resolution of Cyclopropane 3a·HCl^a

^aConditions: (i) ArCHO (1.00 equiv), AcOH (0.1 equiv), piperidine (0.1 equiv), PhMe, reflux; (ii) Me₃SOI (1.3 equiv), KO^tBu (1.3 equiv), DMSO/THF (1:1 v/v); (iii) HCl in MeOH; (iv) K₂CO₃ (2 equiv), Ac₂O, 85 °C, 24 h; (v) B₂(OH)₄, 4,4′-bipyridyl, DMF, 20 min.

Scheme 3.. Brønsted Acid/Solvent-Promoted CIDT^a

^aProduct isolated by filtration from the crude reaction mixture.