Science - 31 January 2020

SCIENCE sciencemag.org

GRAPHIC: A. KITTERMAN/

SCIENCE

By Jianyu Xu and Mary P. Watson

T

ransition metal–based catalysts can

chaperone carbon-carbon (C–C) bond

formation between an electrophilic

and a (usually) nucleophilic partner.

Reactions such as the palladium (Pd)–

based Suzuki–Miyaura cross-coupling

rival amide-bond formation in frequency

of use ( 1 ). Such Pd-based cross-couplings

join unsaturated carbon atoms, as in aryl-

aryl couplings, but many recent efforts have

focused on alkyl-alkyl cross-couplings ( 2 ).

Chiral nickel (Ni)–based catalysts

have enabled both efficient C–C

bond formation as well as con-

trol over the stereochemistry of a

stereocenter on the electrophilic-

partner alkyl group. Similar control

has only been demonstrated for a

single cyclic nucleophilic partner,

and this nucleophile has also been

needed for the selective formation

of stereocenters on both alkyl frag-

ments. On page 559 of this issue,

Huo et al. ( 3 ) demonstrate that a

single chiral Ni catalyst can join

two alkyl groups with high levels of

control over the orientations of the

neighboring stereocenters.

Alkyl-alkyl bonds are found in

most synthetic targets of pharma-

ceutical and agrichemical interest,

but forming these linkages remains

challenging in many synthetic

contexts ( 4 ). Classic alkylation re-

actions that proceed through ca-

nonical SN1 and SN2 mechanisms

have several drawbacks, including

the need for harsh carbon nucleo-

philes and specific steric require-

ments, the presence of competitive

elimination pathways, and a dearth

of opportunities for controlling the

stereochemistry of the products. By

changing the reaction mechanism,

transition-metal catalysis can over-

come these limitations but presents

its own challenges. In particular,

the alkylmetal intermediates can

decompose through competitive

pathways to form alkenes instead of

the desired cross-coupling products. Such

decomposition pathways are theoretically

possible with each alkyl reagent, so alkyl-

alkyl couplings have double the potential

for this fate.

Through appropriate choice of ligand and

control of the redox potentials of the cata-

lyst, these undesired reactions can be miti-

gated. Zultanski and Fu demonstrated that

alkyl electrophiles could be used effectively

in cross-couplings ( 5 ). This work, along with

studies by other groups, established that

these reactions proceed through a mecha-

nism distinct from Pd-catalyzed aryl-aryl

couplings. The alkyl electrophiles are ac-

tivated through single-electron transfer to

form configurationally unstable radical in-

termediates. Recognizing that this instability

presented the opportunity for having the cat-

alyst control which radical proceeds, Fischer

and Fu demonstrated that chiral ligands can

induce asymmetry in these cross-couplings

( 6 ). This approach allowed both enantio-

mers of a chiral electrophile to be converted

stereoconvergently to a single enantiomer of

the product (see the figure, top).

By contrast, the development of a

stereoconvergent cross-coupling of a

racemic chiral alkyl nucleophile has

proven more challenging. Although

such methods have been developed

to form alkyl-vinyl and alkyl-aryl

bonds ( 7 ), only a single alkyl nucleo-

phile had been successfully used in

stereoconvergent alkyl-alkyl cross-

couplings. In the coupling of this

nucleophile, the chiral catalyst dif-

ferentiated a methylene (CH 2 ) versus

a tert-butyl carbamate (NBoc) in a

cyclic substrate ( 8 ).

The method of Huo et al. over-

comes this restriction by using acy-

clic b-zincated amide nucleophiles

and a Ni catalyst equipped with a

chiral bidentate ligand (see the fig-

ure, middle). The authors hypoth-

esize that the bidentate nature of

the ligand enables coordination of

the substrate amide to Ni and that

this coordination allows differentia-

tion of two alkyl groups. The varia-

tion possible within this family of

b-zincated amides is notable and

shows a broad tolerance for many

different functional groups.

In addition to this dramatic ad-

vance in the nucleophilic partner,

Huo et al. demonstrate a solution to

an even greater challenge in alkyl-

alkyl cross-couplings. The coupling

of two secondary alkyl groups has

proven difficult, and only limited

examples have been reported. The

increased steric demand of both al-

kyl groups often prevents them from

being effectively loaded onto the Ni

catalyst. With a related Ni catalyst,

again equipped with a bidentate li-

gand, Huo et al. coupled two second-

ORGANIC CHEMISTRY

Stitching two chiral centers with one catalyst

A single catalyst joins alkyl groups with control over stereochemistry of both fragments

Department of Chemistry and Biochemistry,

University of Delaware, Newark, DE 19716, USA.

Email: [email protected]

Chiral electrophilic partners

In prior alkyl-alkyl cross-couplings, both enantiomers of a chiral

electrophile (E+) were converted to a single orientation of product.

Chiral nucleophilic partners

Huo et al. now show that a chiral catalyst is efective in stereoconvergent

couplings of a whole family of chiral nucleophilic partners.

Double control

The catalyst delivers one stereoisomer of the four possibilities.

Br

BrZn

BrZn

BrZn

BrZn

E+

E+

Br

Nuc partner

Chiral Ni catalyst

E+ partner

Chiral Ni catalyst

Chiral Ni

catalyst

Br

Br

Nuc

High selectivity

for single

product

High selectivity

for single

product

High selectivity

for single

product

Nuc

Orienting alkyl-alkyl cross-couplings

Carbon-carbon bond formation between chiral alkyl centers (bearing

different groups shown in color; Br, bromine, Zn, zinc) with nickel (Ni)

catalysts is extended to a variety of nucleophile (Nuc) partners.

31 JANUARY 2020 • VOL 367 ISSUE 6477 509

Published by AAAS