was found to be optimal (for detailed op-
timization, see table S5). Theb-to-amigrated
products ( 40 and 41 )wereformedwith
complete retention of the relative stereo-
chemistry. Thesea,b-dialkylated products
such as 40 and 41 have not been reported
previously and could serve as useful syn-
thetic intermediates. Moreover, a two-step
protocol converted (+)-apoverbenone to
(–)-pinocamphone ( 42 ). Furthermore, this
strategy could be particularly useful for pre-
paring enantioenricheda-alkylated ketones,
as direct asymmetric nonallylica-alkylation
of ketones remains challenging ( 33 – 35 ).
For example, by taking advantage of the
well-established enantioselective conju-
gate alkyl addition ( 36 ),a-ethylated ketone 43
was obtained in excellent enantioselectiv-
ity with the ketone 1,2-migration strategy
(Fig. 4C).
Finally, the general synthetic utility of this
method was explored (Fig. 5). Diels-Alder re-
actions with electron-rich dienes represent
one of the most widely used methods to con-
struct cyclohexanones and have been applied
in numerous total syntheses ( 37 ). For instance,
when Danishefsky’s diene reacts with Michael
acceptors, cyclohexanones with the electron-
withdrawing group at the C4 position are ob-
tained ( 38 ). In this work, through trapping
the silyl-enol-ether intermediate in situ as
the corresponding alkenyl triflate, the Diels-
Alder products with inverse regioselectivity
(an electron-withdrawing group placed at the
C3 position) were obtained in good efficiency
(Fig. 5A). This sequence offers a distinct and
modular approach to access multisubstituted
cyclohexanones that would otherwise be in-
accessible by the Diels-Alder strategy. Besides
protons, other electrophiles can also be used
to trap the enamine intermediate. For example,
an alkylative ketone 1,2-migration was realized
by using allyl bromide as the electrophile
to generate theipsoC–C bond–forming pro-
duct ( 46 ) (Fig. 5B). In addition, asymmetric
conjugate addition followed by this carbonyl
1,2-migration can introduce ag-stereocenter
in an enantioselective manner. This approach
is exemplified in the asymmetric synthesis
of an antagonist of the orexin receptor ( 50 ),
which was previously prepared through a
chiral resolution approach (Fig. 5C) ( 39 , 40 ).
In this approach, the alcohol intermediate
( 49 ) can be accessed through a known di-
astereoselective reduction of enantioenriched
ketone 48 ( 40 ) that was synthesized via the
sequence of asymmetric conjugate addition
( 36 ) and ketone 1,2-migration with good over-
all yield.
The steroids dihydrotestosterone acetate
and dihydrocholesterone were previously
transformed to their bioactive“C2-oxo”ana-
logs in five steps with <39% ( 41 ) and 10% ( 12 )
overall yields, respectively (Fig. 5D). The former
synthesis also suffered from poor regioselec-
tivity (1:1.2), which complicated the product
purification. With the same starting materials,
this carbonyl 1,2-transposition method allows
a two-step synthesis of these products as single
regioisomers in good yields ( 51 and 53 ). Sim-
ilarly, the“C2-oxo”oleanolic acid derivative,
which is a glycogen phosphorylase inhibitor,
was previously prepared through a three-step
sequence with a 37% overall yield yet low se-
lectivity ( 42 ). By comparison, our method can
deliver the same product with fewer steps,
higher overall yield, and complete regioselec-
tivity ( 52 ). Finally,trans-decalone 54 , a key
intermediate in the total synthesis of palles-
censin A ( 43 ), was previously constructed from
Wieland-Miescher ketone in eight steps with
21% total yield (Fig. 5E) ( 44 ). By comparison,
starting from the readily available geranyl
bromide, we synthesized the same ketone
intermediate 54 in only three steps with 32%
overall yield. Given the convenience and broad
FG tolerance of this ketone transposition
method,weanticipateitswidespreadappli-
cationincomplexmoleculesynthesisand
the efficient preparation of FG-transposed ana-
logs, which should benefit medicinal chemistry
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ACKNOWLEDGMENTS
S. Ochi and X. Liu are acknowledged for x-ray crystallography.
Funding:Financial support from the University of Chicago
and NIGMS (1R01GM124414-01A1) is acknowledged. X.X.
thanks ShanghaiTech University for a fellowship.Author
contributions:Z.W., X.X., and J.W. discovered the reaction.
Z.W., J.W., and G.D. conceived the idea. Z.W., X.X., and
J.W. conducted the experimental investigation. Z.W. and G.D.
wrote the manuscript. G.D. directed the research.Competing
interests:The authors declare that they have no competing
interests.Data and materials availability:Metrical parameters
for the structure of 38 are available free of charge from
the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.
uk/) under reference number CCDC 2062517. All other data
are available in the main text or the supplementary
materials.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abl7854
Materials and Methods
Supplementary Text
Tables S1 to S5
Spectral Data
X-ray Data
References ( 45 Ð 76 )4 August 2021; accepted 29 September 2021
10.1126/science.abl7854740 5 NOVEMBER 2021•VOL 374 ISSUE 6568 science.orgSCIENCE
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