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

Abstract

Herein, we report the enantio- and diastereoselective formation of trans-iodo- and trans-chlorocyclopropanes from α-iodo- and α-chlorozinc carbenoids by using a dioxaborolane-derived chiral ligand. The synthetically useful iodocyclopropane building blocks were derivatized by an electrophilic trapping of the corresponding cyclopropyl lithium species or a Negishi coupling to give access to a variety of enantioenriched 1,2,3-substituted cyclopropanes. The synthetic utility of this method was demonstrated by the formal synthesis of an HIV-1 protease inhibitor. In addition, the related stereoselective bromocyclopropanation was also investigated. New insights about the relative electrophilicity of haloiodomethylzinc carbenoids are also presented.

Total Synthesis of Clavosolide A via Asymmetric Alcohol‐Mediated Carbonyl Allylation: Beyond Protecting Groups or Chiral Auxiliaries in Polyketide Construction

“…The resulting cyclopropylcarbinyl alcohol 7 was converted to the tosylate and exposed to LiBH 4 in ether solvent to furnish cyclopropyl iodide 8 . Cyclopropyl iodides participate in lithium–halogen exchange and may be captured by diverse electrophiles with complete retention of configuration . Conversion of 8 to the corresponding cyclopropyl lithium followed by treatment with aldehyde 9 (prepared via DIBAL reduction of xylopyranoside 5 ) delivered the desired carbonyl addition product 10 , but as an equimolar mixture of C9 epimers across a range of solvents (Scheme ).…”

Asymmetric Cyclopropanation Reactions

“…Then the same research group studied this reaction in detail. 29 For instance, the reaction was scaled up to 10 mmol to provide product from cinnamyl alcohol in 64% yield with a diastereomeric ratio of 9:1 and 96% ee. Moreover, the synthetic usefulness of the iodocyclopropane was demonstrated by an electrophilic trapping of the corresponding cyclopropyllithium species or a Negishi coupling with retention of configuration, to give access to a variety of enantioenriched 1,2,3-trisubstituted cyclopropanes.…”

Mechanism‐Driven Elaboration of an Enantioselective Bromocyclopropanation Reaction of Allylic Alcohols

“…[3] Among the different cyclopropanation approaches,one of the most straightforward methods involves the use of asubstituted zinc carbenoids. [4,5] Fore xample,i th as been shown that a-halocarbenoids can deliver enantiomerically pure chloro- [6] and fluorocyclopropanes, [7] which are valuable scaffolds present in numerous natural and synthetic bioactive molecules. [8,9] Iodocyclopropanes can also be obtained by this strategy,t hus allowing further derivatization.…”

“…[6,10a] For example,i odoform is used in the iodocyclopropanation and chlorodiiodomethane leads to chlorocyclopropanes.H owever,i na na ttempt to utilize bromodiiodomethane to generate bromocyclopropanes,w es urprisingly found that significant amounts of the undesired iodocyclopropane were formed over the desired bromo-substituted product (Scheme 2). [6] To rationalize these results,t wo possible scenarios were envisioned (Scheme 3): a) diethylzinc reacts with both the CÀ Iand C À Br bonds leading to amixture of the reagents A and B,r espectively (thus forming both ethyl iodide and ethyl bromide as by-products);a nd/or b) the diethylzinc reacts preferentially with the CÀIb ond but as ubsequent halogen scrambling allows the formation of both the (diiodomethyl)zinc bromide A and (bromoiodomethyl)zinc iodide B.…”