cyclohexanones ( 18 to 21 ) in good yields,
complementary to enone conjugate addi-
tion chemistry. Conversely,b-substituted
cyclohexanones could be transformed to the
g-substituted cyclohexanones in good yields
( 22 to 26 ), which are nontrivial to prepare
through conventional methods. Whereas the
regioselectivity of the enolization step varied
from 4.7:1 to 11:1 (favoring deprotonation at
the less sterically hindered side), the amina-
tion occurred almost exclusively to yield the
major (less bulky) isomers in all cases ( 22
to 26 and 37 ). Notably, a terminal alkene
( 22 ) remained intact, and no isomerization
was observed under these conditions. Cyclo-
hexanones witha-quaternary centers ( 27 , 30 ,
and 31 ),a,b-cyclopropane ( 28 ), anda-ester
( 29 ) substituents also reacted to generate
the desired products that are difficult to
access otherwise. Moreover,a-substituted
cyclopentanone 32 and the 5-5 bicyclic
ketone ( 33 ) derived from the Pauson-Khand
reaction proved competent substrates. A
variety of FGs, including aryl chloride ( 11 ),
nitrile ( 10 ), nitro ( 13 ), benzyl ether ( 20 ), sul-
fonamide ( 21 ), olefin ( 22 , 30 , and 34 ), acetal
( 31 ), ester ( 12 and 28 ), lactone ( 34 and 38 ),
thiophene ( 8 and 14 ), quinazoline ( 23 and
24 ), theophylline ( 25 ), and indole ( 26 ), were
all compatible with these conditions. More-
over, alkenyl triflates derived from natural
products, such as tropinone ( 35 ), nopinone
( 36 ), hyodeoxycholic acid ( 37 ), anda-santonin
( 38 ) underwent smooth reactions to af-ford the corresponding carbonyl-migrated
analogs.
As mentioned, convertingb-substituted cy-
clohexanones to theg-substituted analogs
is straightforward because of the favored
enolization process; however, migrating the
carbonyl in the other direction and form-
ing thea-substituted products would be
more difficult because the corresponding
kinetically disfavored enolates are gener-
ally formed in low yields and with poor se-
lectivity (Fig. 4A). In addition, the presence
of theb-substituent in the desired alkenyl
triflate can hinder the C–H palladation step,
similar to the“meta constraint”observed for
aromatic substrates ( 31 ). Therefore, realizing
such a“b-to-a”transformation is difficult.738 5 NOVEMBER 2021•VOL 374 ISSUE 6568 science.orgSCIENCE
Fig. 4. Surmounting theb-constraint via conjugate addition.(A)b-substituted
cyclohexanones can be transformed tog-substituted analogs by using this
method; however, migration to the more sterically congesteda-positions is
more challenging. (B) Two-step“b-to-a”migration protocol is achieved
through conjugate addition or alkenyl triflate formation, followed by the
Pd/NBE catalysis. (C) Asymmetric conjugate addition or ketone 1,2-migration
cascade provides the access toa-stereocenter. BPE, bis(phospholano)
ethane; cat., catalyst; Cbz, benzyloxycarbonyl; er, enantiomeric ratio; Bn,
benzyl; OBz, benzoate; pdts, products; RM, organometallic reagents;
rsm, recovered starting material.RESEARCH | REPORTS