Tandem catalytic enantio‐ and diastereoselective synthesis of cyclopropyl alcohols using aryl aldehydes

Abstract

The prevalence of cyclopropanes in biologically active compounds has fueled many investigations into their preparation. Despite significant advances, more efficient methods for their catalytic enantioselective synthesis remain in demand. Previously, we reported a novel tandem approach to diastereo‐ and enantioenriched cyclopropyl alcohols. Our method involved an initial asymmetric C–C bond formation by addition of organozinc reagents to aldehydes catalyzed by a (−)‐MIB‐based catalyst. The resulting allylic zinc alkoxides were then subject to directed cyclopropanations. Although this approach provided cyclopropyl alcohols with very high enantio‐ and diastereoselectivity, it was successful with only aliphatic aldehydes. Aryl aldehyde substrates, on the other hand, exhibited low conversion and variable diastereomeric ratios. The present study is aimed at raising the stereoselectivity and yield of the aforementioned tandem reaction with aryl aldehyde substrates to make the method synthetically useful. Herein, we report the successful optimization of aryl aldehyde substrates in our one‐pot tandem approach leading to cyclopropyl alcohols with high yields and enantio‐ and diastereoselectivities. Copyright © 2012 John Wiley & Sons, Ltd.

Efficient Approaches to the Stereoselective Synthesis of Cyclopropyl Alcohols

“…Aromatic aldehydes gave low yields under these conditions. By doubling the concentration in the cyclopropanation step, however, yields in the 70–80% range were observed (entries 9 and 10) …”

“…By doubling the concentration in the cyclopropanation step, however, yields in the 70À80% range were observed (entries 9 and 10). 25 3.2. Tandem Asymmetric Synthesis of syn-Vinyl Cyclopropyl Alcohols.…”

Simmons–Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review

“…(+)-Trans-chrysanthemic acid 1, (+)-curacin A 2, 1-aminocyclopropanecarboxylic acid (ACC) 3, saxagliptin 4, lenvatinib 5 and tasimelteon 6 are examples of some biologically active natural products, whose total synthesis involve Simmons-Smith cyclopropanation as the main step. The structures of these heterocyclic scaffolds are given below (Figure 3) [19][20][21][22][23].…”

“…(+)-Trans-chrysanthemic acid 1, (+)-curacin A 2, 1-aminocyclopropanecarboxylic acid (ACC) 3, saxagliptin 4, lenvatinib 5 and tasimelteon 6 are examples of some biologically active natural products, whose total synthesis involve Simmons-Smith cyclopropanation as the main step. The structures of these heterocyclic scaffolds are given below (Figure 3) [19][20][21][22][23]. Moreover, Simmons-Smith reagent is also involved in the efficient asymmetric cyclopropanations of various other heterocyclic scaffolds, such as bicyclic olefins (e.g., bicyclo [2.2.l] heptene and bicyclo [2.2.ll] heptadiene) [8] and a variety of chiral auxiliaries including chiral ketals, allylic alcohols, allylic ethers, enol ethers, chiral enamides and vinyl boronic esters [3,24,25].…”