Highly Enantio- and Diastereoselective One-Pot Methods for the Synthesis of Halocyclopropyl Alcohols

Abstract

The lack of methods for the stereoselective transfer of functionalized carbenoids is one of the most significant deficiencies of Simmons–Smith cyclopropanation reactions. Outlined herein are one-pot methods for the catalytic asymmetric synthesis of halocyclopropyl alcohols with up to four stereogenic centers from achiral starting materials. The first method involves asymmetric alkyl addition to a conjugated enal to generate an allylic alkoxide followed by tandem diastereoselective iodo-, bromo- or chlorocyclopropanation to furnish halocyclopropyl alcohols. Enantioselectivities in these processes range from 89–99% and dr > 20:1 were achieved with all substrates optimized. The second method consists of an asymmetric vinylation of a saturated or aromatic aldehyde followed by a diastereoselective iodocyclopropanation to produce iodocyclopropyl alcohols with enantioselectivities between 86 and 99% and dr > 20:1. These complementary methods enable the efficient synthesis of a variety of halocyclopropyl alcohols in one-pot procedures. Preliminary efforts to functionalize iodocyclopropanes involve reaction with an excess of LiCu(n-Bu)2 to generate the cyclopropyl cuprate. This intermediate can be quenched with allyl bromides to generate the allylated cyclopropyl alcohols without loss of enantio- or diastereoselectivity.

Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

“…Upon combining CF 3 CH 2 OZnCH 2 I with zinc β-alkoxy enamine intermediates, we were pleased to see formation of the desired cyclopropyl amines as a single diastereomer, although the yields were moderate. As we have observed with other systems,19,64,65 the cyclopropanation proceeds in low to moderate yield in the presence of the triethylborane, a byproduct formed in the transmetalation of the β-amino vinyl group from boron to zinc (Scheme 6). To achieve high yields the triethyborane was removed from the reaction mixture before the cyclopropanation step.…”

“…Our approach to the catalytic enantio- and diastereoselective synthesis of amino cyclopropyl carbinols is based on our prior efforts involving the diastereoselective directed cyclopropanation of allylic alcohols 19, 64, 65. At the outset of this study, however, it was not clear how the nitrogen of the enamine would impact the reactivity of the double bond toward cyclopropanation or if it would affect the diastereoselectivity.…”

Highly Enantioselective Synthesis of 1,2,3‐Substituted Cyclopropanes by Using α‐Iodo‐ and α‐Chloromethylzinc Carbenoids

“…Interestingly, the reaction of an unprotected alcohol was successful when an additional equivalent of t BuLi was employed (Table 3, entries 7–9). A mixed cuprate could also be prepared from the iodocyclopropylmethanol 5 a and was subsequently treated with allyl bromide to provide the corresponding allylated derivative in good yield (Scheme ) 8f…”

Stereoselective CH Borylations of Cyclopropanes and Cyclobutanes with Silica‐Supported Monophosphane–Ir Catalysts

“…[15] The CÀH borylation occurred with exclusive regio-and stereoselectivity at the three-membered ring CÀH bond located g to the pyridine N atom in favor of the cis configuration, which indicates N-to-Ir coordination leading to a five-membered iridacyclic reaction pathway. [17] Single-crystal X-ray diffraction confirmed the stereochemistry and intramolecular NÀB coordination. [16] Aromatic CÀH borylation on the pyridine ring, benzylic CÀH borylation, and ring-opening of the cyclopropane were not observed.…”