Development of Enantioselective Lithium-Isothiourea-Boronate–Catalyzed Matteson Homologations

Abstract

Our group’s discovery of lithium-isothiourea-boronate–catalyzed Matteson homologations is chronicled. Chiral thiourea dual–hydrogen bond donors were initially found to promote enantioselective dichloromethyl boronate rearrangements, albeit with poor reproducibility. Systematic investigations of the fate of the thiourea led to the discovery that lithium-isothiourea-boronate derivatives were being generated in situ as highly enantioselective catalytically active species. The optimal lithium-isothiourea-boronate catalyst displays significant generality in the rearrangement of primary alkyl migrating groups, affording synthetically valuable α-chloro boronic ester products with consistently high enantioselectivities. The catalyst is proposed to act as a structurally rigid chiral framework that precisely positions two lithium cations to enable a dual-lithium–mediated chloride abstraction.

Enantioselective Potassium-Catalyzed Wittig Olefinations

“…These spectral changes are in good agreement with predicted IR spectra of the amide–metal–boronate chelates. In contrast, the spectrum of Li-3f reveals a redshift of both peaks by roughly 40 cm –1 , in good agreement with the calculated amide–metal–isothiourea chelate (for in-depth discussion of IR spectra, see the Supporting Information (SI)). , …”

“…An X-ray crystal structure analysis of K-3f ·THF revealed an unusual macrocyclic chelate in which the potassium cation is coordinated between the amide oxygen and the anterior boronate oxygen (Figure A). This ligation mode is dramatically different from the five-membered amide–Li–isothiourea chelate previously observed in the X-ray structure of a lithium–isothiourea–boronate derivative. , …”

“…In contrast, the spectrum of Li-3f reveals a redshift of both peaks by roughly 40 cm −1 , in good agreement with the calculated amide−metal−isothiourea chelate (for in-depth discussion of IR spectra, see the Supporting Information (SI)). 36,37 These fundamental differences in chelation mode were found to translate into differences in relative Lewis acidity, as demonstrated in a Gutmann−Beckett analysis 38,39 (Figure 1C). A slight tempering of the Lewis acidity of K-3f relative to KHMDS and of Na-3f relative to NaHMDS is observed, whereas a significant increase in Lewis acidity is measured for Li-3f relative to LiHMDS.…”

“…35 Recently, our group discovered novel chiral lithium− isothiourea−boronate derivatives that catalyze highly enantioselective Matteson homologation reactions (Scheme 1D). 36,37 Given the observed effects of lithium salts on the rate and stereoselectivity of standard Wittig reactions, we considered whether this new family of chiral Lewis acids might exert enantiocontrol over Wittig reactions that generate axially chiral alkenes. In particular, we envisioned that chiral alkali-metalbased Lewis acids might catalyze the addition of non-stabilized phosphorus ylides to 4-substituted cyclohexanones to generate enantioenriched OPA intermediates (Scheme 1E).…”

“…This ligation mode is dramatically different from the five-membered amide−Li− isothiourea chelate previously observed in the X-ray structure of a lithium−isothiourea−boronate derivative. 36,37 To assess the relevance of these solid-state structural differences to the corresponding solution structures, solution IR spectra of M-3f (M = Li, Na, K) were acquired and compared to spectra of the two chelates predicted by DFT (Figure 1B). The unmetalated isothiourea−boronate 3f (M = H) exhibits absorbances corresponding to the amide C−O (1660 cm −1 ) and isothiourea N−C−N (1590 cm −1 ) moieties that are closely reproduced in the calculated spectrum.…”