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ACKNOWLEDGMENTS
We thank J. Perrino and D.-H. Chen (Stanford University) for
assistance with initial negative-stain and cryo-EM condition
screening.Funding:This work was supported by the National
Institutes of Health (grants R01GM087934 and R35GM141799 to
C.K.; grant F32GM136039 to D.P.C.; and grants R01GM079429,
P41GM103832, S10OD021600, and U24GM129541 to W.C.).
Author contributions:C.K., W.C., D.P.C., and K.Z. conceived of
the experimental design and project aims. C.S.C. provided key
reagents and advice on best practices for their utilization. D.P.C.
and K.Z. collected all of the non–cryo-EM experimental data, which
were analyzed by all authors. K.Z., X.L., and S.-H.R. conducted
preliminary experiments that informed the experiments described
in this manuscript. K.Z. and S.L. performed the cryo-EM data
collection and processing steps that led to the final deposited
cryo-EM maps. K.Z. and D.P.C. refined the models. G.D.P.
conducted the Q-score analysis and generated movies S2 and S3.
C.K., W.C., and C.S.C. supervised all experiments. D.P.C. and
C.K. wrote the initial manuscript, which was then revised and
edited by all authors.Competing interests:The authors declare
no competing financial interests.Data and materials availability:
All cryo-EM maps and atomic coordinates have been deposited
in the Protein Data Bank under accession codes 7M7E, 7M7F,
7M7G, 7M7H, 7M7I, and 7M7J and in the Electron Microscopy Data
Bank under accession codes EMD-23710, EMD-23711, EMD-23712,
EMD-23713, EMD-23714, and EMD-23715. All other data are
present in the main text or the supporting materials.
SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abi8358
Materials and Methods
Supplementary Text
Figs. S1 to S24
Tables S1 to S3
References ( 41 – 69 )
Movies S1 to S3
MDAR Reproducibility Checklist
2 April 2021; accepted 9 September 2021
10.1126/science.abi8358
ORGANIC CHEMISTRYCarbonyl 1,2-transposition through
triflate-mediateda-amination
Zhao Wu, Xiaolong Xu, Jianchun Wang, Guangbin Dong*To date, it remains challenging to selectively migrate a carbonyl oxygen within a given molecular
scaffold, especially to an adjacent carbon. In this work, we describe a simple one- or two-pot protocol
that transposes a ketone to the vicinal carbon. This approach first converts the ketone to the
corresponding alkenyl triflate, which can then undergo the palladium- and norbornene-catalyzed
regioselectivea-amination and ipso-hydrogenation enabled by a bifunctional hydrogen and nitrogen
donor. The resulting“transposed enamine”intermediate can subsequently be hydrolyzed to produce the
1,2-carbonyl–migrated product. This method allows rapid access to unusual bioactive analogs through
late-stage functionalization.T
he specific position of a carbonyl group
in a compound can strongly influence
that compound’s biological and physi-
cal properties, as well as its strategic
use as a synthetic intermediate. For ex-
ample, transposition of the C3-OH to the ad-
jacent C2 position in ursolic acid (Fig. 1A)
resulted in a 13-fold potency boost for inhibit-
ing glycogen phosphorylase ( 1 ). Likewise, the
compound derived from the C2-carbonyl isomer
of nortropinone showed a ninefold increase
in activity against aminoglycoside-induced
hearing loss compared with the correspond-
ing C3 analog ( 2 ). From a synthesis-planning
viewpoint, efficient carbonyl 1,2-transposition
methods could also simplify the construc-
tion of complex target molecules by allow-
ing strategic bond disconnections with more
accessible substrates; for example, the total
syntheses of cascarillone and lycoraminone
would be streamlined with a more effi-
cient carbonyl 1,2-migration strategy (Fig. 1B)
( 3 , 4 ).
Carbonyl 1,2-transposition has not been a
trivial process (Fig. 1C) ( 5 – 7 ). Currently, the
most general strategy usesa-functionalizations
of ketones to introduce a carbonyl surrogate,
followed by a series of downstream trans-
formations ( 8 – 10 ). Alternative tactics involve
forming a three-membered ring or a 1,2-dione
intermediate, which can be desymmetrized
to afford the formal carbonyl-migrated pro-
ducts. Besides the need for a long synthetic
sequence, substrate specificity and regiose-
lectivity are additional concerns associated
with the desymmetrization approaches ( 11 – 14 ).
Hence, a general, regioselective, and straight-
forward carbonyl 1,2-transposition method
with broad functional group (FG) toleranceremains an important goal. Given the ease of
forming alkenyl sulfonates (e.g., triflates) from
carbonyl compounds, we conceived the idea
of developing a triflate-mediateda-amination
process ( 15 ) to access a transposed enamine
intermediate, which could undergo in situ hy-
drolysis to generate the carbonyl 1,2-migrated
product (Fig. 1D). The key enamine-forming
step involves simultaneous addition of a hy-
dride to the ipso position (where the triflate
was located) and a nitrogen substituent to
the vicinal alkenyl carbon (theaposition).
We aimed to achievea-amination and ipso-
hydrogenation of alkenyl triflates by means
of cooperative catalysis with palladium and
norbornene (Pd/NBE) ( 16 – 19 ).
Pd/NBE cooperative catalysis, which was
originally discovered by Catellani ( 20 ), has
been extensively developed for arene func-
tionalization since 1997 ( 16 – 19 ). By contrast,
its use in functionalizing nonaromatic sub-
strates has been very rare ( 21 , 22 ); in particular,
it has not been used to introduce heteroatom
substituents to alkenyl substrates. To realize the
proposeda-amination and ipso-hydrogenation
of alkenyl triflates through Pd/NBE cataly-
sis, two major challenges must be addressed
(Fig. 2). First, after the oxidative addition with
Pd(0) and migratory insertion of the resulting
alkenyl-Pd(II) species into NBE to avoid the
undesired 3-exo-trig cyclization that produces
side productB(a known major competing
pathway) ( 23 ), the NBE cocatalyst must have
a rigid substituent such as an amide moiety
at the C2 position (the carbon bonded to Pd)
to strongly favor formation of the key alkenyl-
norbornyl palladacycle (ANP) ( 21 ). Although the
added steric hindrance on NBE may not hamper
the reaction with less bulky electrophiles (e.g.,
primary alkyl halides), it could considerably
retard the reaction when using more sterically
demanding amine electrophiles. A sluggish
amination would cause the premature hydride
terminations—which form side productsA734 5 NOVEMBER 2021•VOL 374 ISSUE 6568 science.orgSCIENCE
Department of Chemistry, University of Chicago, Chicago, IL
60637, USA.
*Corresponding author. Email: [email protected]RESEARCH | REPORTS