Highly Diastereoselective Synthesis of Homoallylic Alcohols Bearing Adjacent Quaternary Centers Using Substituted Allylic Zinc Reagents

Link: JACS ASAP

Hongjun Ren, Guillaume Dunet, Peter Mayer, and Paul Knochel*

Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München, Germany

A recent report from the Knochel lab. The paper reported an improved method in generating allylzinc chloride reagents from corresponding allyl chlorides through zinc dust insertion upon activation with LiCl. This is an improvement over previous method of generating allylzinc species from the corresponding allyl bromides as that method does not allow efficient generation of reagents with substitutions on allylic systems due to extensive formation of homocoupling by-products.

In this improved system, several allylzinc chloride reagents could be prepared in good yield with only moderate homocoupling observed, thus allowing efficient generation of allylzinc species not possible to prepare by other means (Scheme 1).

As for the cinnamyl system, both allyl chloride and allyl phosphate could be used to prepare the corresponding allylzinc species readily (1e and 1f).

Allylzinc reagents thus generated were used in several nucleophilic additions to demonstrate their utilities as seen in Table 1. All additions to carbonyl compounds happened under very mild conditions to afford the homoallylic alcohols in excellent yields. The reaction was also found to be highly diatereoselective furnishing products in excellent dr in all cases.

Besides high diastereoselectivities, the reaction was also chemoselective as demonstrated in entries 6 and 7 when allylzinc reagent added to carbonyl group in the presence of chloride and azide group alpha to the carbonyl. In addition, the reagent also added to an aldehyde in the presence of free NH2 without problem (entry 3).

Additionally, in cases of substituted allylzinc reagent (1c), it added regiospecifically to provide homoallylic alcohols containing two contiguous quarternary stereocenters in excellent yields and diastereoselectivities (entries 9 and 10).

Reagent 1e containing cinnamyl system was found to participate in highly diastereoselective and regiospecific additions to methyl ketone furnishing products (4a-e) in excellent yields and drs.

Mechanism of addition was proposed to follow a zinc-chelated 6-membered chair-like transition state as seen below.

In the cases of products 4a, 4c, and 4d, the structures were readily established by comparison to literature precedents. As for products 4b and 4e whose structures were not possible to assess directly, these compounds were converted to tetrahydrofuran derivatives 5 and 6 which therefore confirmed the generality cyclic transition state 7.