Diastereo-, Enantio-, and anti-Selective Formation of Secondary Alcohol and Quaternary Carbon Stereocenters by Cu-Catalyzed Additions of B-Substituted Allyl Nucleophiles to Carbonyls

Abstract

A general method for the synthesis of secondary homoallylic alcohols containing α-quaternary carbon stereogenic centers in high diastereo- and enantioselectivity (up to >20:1 dr and >99:1 er) is disclosed. Transformations employ readily accessible aldehydes, allylic diboronates, and a chiral copper catalyst and proceed by γ-addition of in situ generated enantioenriched boron-stabilized allylic copper nucleophiles. The catalytic protocol is general for a wide variety of aldehydes as well as a variety of 1,1-allylic diboronic esters. Hammett studies disclose that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.

Expedient Dual Co/Organophotoredox Catalyzed Stereoselective Synthesis of All‐Carbon Quaternary Centers

“…This trend is opposite to what was previously seen in a similar allylation reaction catalyzed by Cu [3c] . In contrast to previous studies, [3c, 16] the dr of the product is not substrate‐controlled, but is likely induced by a preference for a ( Z )‐configured allylic intermediate in the cobalt cycle that continues through a Zimmerman–Traxler transition state (Scheme 4 d) with a preference of a pseudo ‐equatorial positioning of the aldehyde Ph substituent [3b] . Initially we assumed that the higher diastereocontrol in the presence of more electron‐rich aldehyde substrates may be controlled by a stronger intramolecular hydrogen‐bonding between the pendent OH‐group and the aldehyde thereby stabilizing the ( Z )‐allylic transition state.…”

“…A clear negative trend was observed, i.e., electron‐donating groups strongly favor the production of the syn isomer, whereas with electron‐withdrawing groups this effect is diminished. This trend is opposite to what was previously seen in a similar allylation reaction catalyzed by Cu [3c] . In contrast to previous studies, [3c, 16] the dr of the product is not substrate‐controlled, but is likely induced by a preference for a ( Z )‐configured allylic intermediate in the cobalt cycle that continues through a Zimmerman–Traxler transition state (Scheme 4 d) with a preference of a pseudo ‐equatorial positioning of the aldehyde Ph substituent [3b] .…”

Expedient Dual Co/Organophotoredox Catalyzed Stereoselective Synthesis of All‐Carbon Quaternary Centers

“…Traditionally, constitutionally stable stereodefined g,g-disubstituted allyl-metal species are able to resolve such issues but their synthesis typically requires multiple steps, they need to be used in excess, and produce copious amounts of metal-containing waste. [3] Therefore, the design of alternative catalytic methods that can mediate the stereoselective coupling of inexpensive and modular starting materials while creating all-carbon quaternary stereocenters remains highly desirable.…”

Reactivity Trends with Borylalkyl Copper(I) Species

“…1,1‐Allylic diboronic esters can be activated by chiral copper catalysts to generate the corresponding enantioenriched boron‐stabilized allylic copper nucleophile that react with accessible aldehydes to promote the γ‐addition (Scheme 10). [15] This strategy generates secondary homoallylic alcohols containing α‐quaternary stereogenic carbon in high diastereo‐ and enantioselectivity (up to >20 : 1 dr and >99 : 1 er). The catalytic protocol is general for a wide variety of aldehydes and Hammett studies disclosed that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.…”

“…A catalytic cycle has been suggested to justify the CuO t Bu / phosphoramidite catalyzed additions of B‐substituted allyl nucleophiles to aldehydes. In parallel, a stereochemical model has been proposed to rationalize the diastereo‐, enantio‐, and anti ‐selective formation of secondary alcohol and quaternary carbon stereocenters [15] . Authors suggest that the reaction likely proceeds via S E 2′ transmetalation of (L)Cu−OMe with 1,1‐allylic diboronic esters followed by a rapid 1,3‐suprafacial shift to the less sterically encumbered boron‐stabilized allyl copper species (Scheme 11).…”