Transition metal-catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry

Abstract

Because the backbone of most organic molecules is composed primarily of carbon-carbon bonds, the development of efficient methods for their construction is one of the central challenges of organic synthesis. Transition metal-catalyzed cross-coupling reactions between organic electrophiles and nucleophiles serve as particularly powerful tools for achieving carbon-carbon bond formation. Until recently, the vast majority of cross-coupling processes had used either aryl or alkenyl electrophiles as one of the coupling partners. In the past 15 years, versatile new methods have been developed that effect cross-couplings of an array of alkyl electrophiles, thereby greatly expanding the diversity of target molecules that are readily accessible. The ability to couple alkyl electrophiles opens the door to a stereochemical dimension-specifically, enantioconvergent couplings of racemic electrophiles-that substantially enhances the already remarkable utility of cross-coupling processes.

Fig. 1

Transition-metal-catalyzed cross-coupling to form carbon–carbon bonds. A: General scheme. B: Application of a Suzuki cross-coupling to form a C_sp2–C_sp2 bond in an industrial synthesis of Boscalid.

Fig. 2

Bioactive compounds that include an array of alkyl–alkyl bonds.

Fig. 3

Stereochemistry as an added dimension in cross-coupling reactions of alkyl electrophiles. A: Aryl electrophiles versus alkyl electrophiles. B: Use of a chiral catalyst to control stereochemistry: enantioconvergent cross-couplings of racemic alkyl electrophiles.

Fig. 4

Recent progress in transition-metal-catalyzed alkyl–alkyl coupling.

Fig. 5

Mechanistic aspects of metal-catalyzed cross-couplings, illustrated for palladium. A: An outline of a catalytic cycle. B: β-Hydride elimination as a side reaction.

Fig. 6

Cross-couplings of primary alkyl electrophiles: Early (pre-2000) methods. A: Examples. B: An application in the total synthesis of a natural product. C: Use of nucleophiles that have improved functional-group compatibility.

Fig. 7

Cross-couplings of primary alkyl electrophiles: Recent (post-2000) methods that use alkylboron reagents as nucleophiles. A: Examples. B: Applications in the total synthesis of natural products.

Fig. 8

Cross-couplings of primary alkyl electrophiles: Recent (post-2000) methods that use alkylzinc reagents as nucleophiles. A: Examples. B: An application in the total synthesis of a natural product.

Fig. 9

Cross-couplings of secondary alkyl electrophiles: Early (pre-2000) methods. A: Examples. B: An application in the total synthesis of a natural product.

Fig. 10

Cross-couplings of secondary alkyl electrophiles: Recent (post-2000) methods that use nucleophiles that have improved functional-group compatibility. A: Alkylboron reagents. B: Alkylzinc reagents. C: An application in synthesis.

Fig. 11

Catalytic asymmetric carbon–carbon bond formation. A: Enantioconvergent cross-coupling via a radical intermediate. B: Methods for activated electrophiles. C: An application in the total synthesis of a natural product.

Fig. 12

Enantioconvergent cross-couplings of unactivated alkyl electrophiles, directed by the indicated functional groups.

Fig. 13

Enantioconvergent alkyl–alkyl cross-couplings. A: Use of a racemic electrophile or a racemic nucleophile. B: Enantioconvergent nickel-catalyzed coupling of a racemic alkylzinc reagent. C: Doubly stereoconvergent coupling of a racemic electrophile and a racemic nucleophile.

Fig. 14

Cross-couplings of tertiary alkyl electrophiles. A: Early methods. B: Recent method that uses a nucleophile that has improved functional-group compatibility.

Fig. 15

Alkyl–alkyl cross-coupling.