Total Synthesis of Penicibilaenes via C-C Activation-Enabled Skeleton Deconstruction and Desaturation Relay-Mediated C-H Functionalization

Article abstract of DOI:10.1021/jacs.1c04335

Herein, we describe the first total synthesis of sesquiterpene penicibilaenes A and B through a "C-C/C-H"approach. In the "C-C"stage, the Rh-catalyzed "cut-and-sew"transformation between trisubstituted alkene and cyclobutanone has been employed to constru

Full text of DOI:10.1021/jacs.1c04335

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Total Synthesis of Penicibilaenes via C−C Activation-Enabled
Skeleton Deconstruction and Desaturation Relay-Mediated C−H
Functionalization
Yibin Xue and Guangbin Dong*
Cite This: J. Am. Chem. Soc. 2021, 143, 8272−8277
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ABSTRACT: Herein, we describe the first total synthesis of sesquiterpene penicibilaenes A and B through a “C−C/C−H”
approach. In the “C−C” stage, the Rh-catalyzed “cut-and-sew” transformation between trisubstituted alkene and cyclobutanone has
been employed to construct the unique tricyclo[6.3.1.01,5]dodecane skeleton and the all-carbon quaternary center. Critical linker and
Lewis acid effects have been identified for the C−C activation process. In the “C−H” stage, a desaturation relay-based strategy
involving consecutive ketone α,β-dehydrogenation and β-functionalization has been adopted to introduce the 1,3,5-triad
stereocenters to the core. The synthesis of penicibilaenes A and B has been completed in 13 and 14 steps, respectively, in the longest
linear sequence.
erpenes and their derivatives have been a rich source of
therapeutic agents, agrochemicals, and fragrances.1 In
bridged and fused rings. In addition, the resulting carbonyl
moiety could provide a convenient handle for site-selective C−
H functionalization.6 Thus, terpene synthesis could also be
envisioned to go through a closely related but complementary
strategy, which utilizes C−C activation to construct the core
skeleton7 and then ketone-directed or -mediated C−H
functionalization to introduce the substituents (Scheme 1B).
Comparing to the “two-phase” strategy, one subtle difference
with this “C−C/C−H” approach is that not all carbons in the
terpene core need to be introduced in the “C−C” stage, as
some carbon substituents can be installed in the later “C−H”
stage. Herein, we describe a proof-of-concept of utilizing this
“C−C/C−H” strategy in a concise total synthesis of
penicibilaenes A (1) and B (2).
T
addition, they often exhibit intriguing and complex chemical
structures, such as bridged/fused rings and diverse substitu-
tions. As such, terpenes have been highly attractive target
molecules in the synthetic community.2 Inspired by the
biosynthesis of terpenes, a “two-phase” strategy has been
advanced by Baran and co-workers, leading to a number of
elegant total syntheses since 2009.3 This strategy involves a
cyclase phase to first build the carbon backbone from a linear
or less complex precursor, followed by an oxidase phase to
install oxygen functionalities at proper positions (Scheme
1A).3 Notably, in the cyclase phase, polyene cyclization and
Isolated from the marine fungus Penicillium bilaiae MA-267
by Wang and co-workers in 2014, sesquiterpene penicibilaenes
A (1) and B (2) display selective and potent activity against
the plant pathogenic fungus Colletotrichum gloeosporioides,
which is responsible for anthracnose in many fruits and
vegetables.8 In particular, penicibilaene B even shows better
efficacy than broad-spectrum antibiotic zeocin. To the best of
our knowledge, total synthesis of penicibilaenes has not been
reported. These sesquiterpenes possess interesting chemical
structures, including a tricyclo[6.3.1.01,5]dodecane skeleton
constituted by [3.3.1]-bridged and [4.3.0]-fused junctions, as
well as five adjacent stereocenters with one being all-carbon
quaternary. Of note, the substitutions on the tricyclic skeleton
exhibit a 1,3,5-triad pattern. While a number of efficient and
Scheme 1. Approaches for Terpene Synthesis
Received: April 26, 2021
Published: May 26, 2021
various cycloadditions, such as Diels−Alder reaction and
Robinson annulation, are commonly employed for synthesizing
multiring systems.3 On the other hand, the transition-metal-
catalyzed C−C activation4 of cyclic ketones followed by
insertion of an unsaturated 2π-unit, namely, a “cut-and-sew”
process,5 has been found useful for constructing various
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© 2021 American Chemical Society
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stereoselective approaches are known to form 1,3,5-triad
stereocenters, e.g., aldol-type condensations and allylation
followed by oxidative cleavage, they would require disconnect-
ing the carbon skeletons of the target compounds (Scheme
2A). We questioned whether such 1,3,5 “skipped” functional
be rapidly prepared via a Cu-mediated three-component
coupling, ultimately from three commercially available
chemicals: cyclobutanone 7, enoate 8, and ynoate 9. It is
noteworthy that an ester moiety is strategically introduced in
the tricycle intermediate 5 because it can (i) greatly simplify
substrate preparation and (ii) play a pivotal role in the “cut-
and-sew” reaction (vide infra).
Scheme 2. Our Strategy to Synthesize Penicibilaenes
The synthesis began with the preparation of the “cut-and-
sew” precursor, cyclobutanone 6 (Scheme 3). Reduction of
Scheme 3. Synthesis of the “Cut-and-Sew” Precursor
ester 8 by DIBAL-H,11 followed by bromination, delivered
allylbromide 10 in good yield.12 Meanwhile, Hunsdiecker
reaction with carboxylic acid 713 and subsequent protection of
the ketone moiety gave cyclobutyl bromide 11. With these two
bromides in hand, cyclobutanone 6 was efficiently prepared in
one step by a copper-mediated three-component coupling14
using commercially available ynoate 9 as the linchpin. The
reaction started with generation of the cyclobutyl lithium
t
through treatment of bromide 11 with BuLi, followed by
transmetalation to a copper(I) salt. The generated cuprate
then underwent cis-addition into the electrophilic alkynyl
group in a regioselective manner, and the resulting vinyl
cuprate intermediate was quenched by reactive allyl bromide
10. Upon in situ ketal hydrolysis, cyclobutanone 6 was isolated
in good overall yield, despite the complexity of the cascade
sequence. The copper(I) salt had a significant influence on the
efficiency of the three-component coupling (for details, see
Supporting Information): CuBr·SMe2 proved to be optimal,
and additional dimethyl sulfide ligand was also beneficial.
The stage was then set for the key “cut-and-sew” step to
construct the tricyclo[6.3.1.01,5]dodecane skeleton. Compared
to benzocyclobutenones,5a,15 intramolecular [4 + 2] cyclo-
addition with saturated cyclobutanones are generally more
challenging due to (i) competing decarbonylation to form
cyclopropanes16 and (ii) lack of rigid scaffolds to promote
cyclization. Clearly, the linkers between cyclobutanones and
olefins play a critical role in the “cut-and-sew” reaction, as they
can provide favorable conformations for the desired cycliza-
tion. To date, only three kinds of linkers including benzo-,
amide-, and malonate-based ones (Lk1−3) have succeeded in
this type of annulation reactions (Figure 1).5b A strong
Thorpe−Ingold effect appears to be important for bridged-ring
formation. In the context of penicibilaene synthesis, a number
of carbon-based linkers were attempted in the proposed “cut-
and-sew” reaction. Using the native trisubstituted alkene as the
linker (Lk4), the olefin moiety proved to be labile and tended
to isomerize under the reaction conditions. “Masked” alkenes,
such as epoxide (Lk5), tertiary alcohol (Lk6), and ether
(Lk7), were also prepared;17 however, they proved to be either
unstable or inactive for cyclization. Finally, the ester-
substituted alkenyl linker (Lk8) was found to be ideal. The
groups can be installed through an alternative “desaturation
relay” process,9 in which a single carbonyl moiety can be used
as the initiation group (at the C1 position) to install a hydroxy
moiety at the C3 position through α,β-desaturation and
conjugate addition.10 Upon converting the C1 carbonyl to the
desired moiety, the C3-OH can be oxidized to a ketone, which
could enable another β-functionalization at the C5 position
through the carbonyl desaturation and conjugate addition.
From the retrosynthetic viewpoint (Scheme 2B), the C13
methyl group in penicibilaenes A (1) and B (2) could be
introduced in the late stage via the desaturation-based β-
functionalization from intermediate 3. It can be further
envisaged that the C4 oxygen functional group can also be
installed via a similar desaturation-based β-functionalization
sequence from ketone 4, and the C6 tertiary alcohol
stereocenter can be introduced through an axial-selective
carbonyl addition reaction (vide infra). The core tricyclic
skeleton in 5 is then expected to be constructed by the “cut-
and-sew” reaction through C−C activation of cyclobutanone 6.
Finally, the precursor (6) for the “cut-and-sew” is proposed to
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a
Table 1. Selected Optimization of the “Cut-and-Sew” Step
Figure 1. Linker effect in the “cut-and-sew” reaction.
conjugation and the electron-withdrawing feature of the ester
moiety inhibited double-bond migration. The enhanced
rigidity of the tetrasubstituted alkene and the buttressing
effect between the methyl and the ester groups are expected to
be factors that benefit the cyclization. More importantly, with
the ester moiety, synthesis of the “cut-and-sew” precursor
became much simpler (vide supra, the three-component
coupling).
a
Unless otherwise mentioned, the reaction was run on a 0.05 mmol
b
scale. Determined by GC using 1-methylnaphthalene as the internal
standard. Toluene was used as the solvent. Isolated yield. The
reaction was run on a gram scale.
c
d
e
Besides the linker, another challenge of the proposed “cut-
and-sew” reaction was the use of a trisubstituted alkene as the
coupling partner. The carboacylation between saturated
cyclobutanones and trisubstituted alkenes has been rare due
to the steric hindrance.18 Hence, a more efficient catalytic
system was needed to realize this transformation. It was not
surprising that, under the prior optimal conditions (entry 1,
Table 1),19 the reaction with substrate 6 gave no desired
product. Interestingly, by adding zinc chloride as a Lewis
acid,5a the desired “cut-and-sew” product 5 was obtained in
12% yield (entry 2, Table 1), although the exact role of the
Lewis acid remains unclear at this stage. In addition, zinc
triflate was found to be more effective than zinc chloride likely
due to enhanced Lewis acidity (entry 3, Table 1). Notably, the
use of 2-aminopyridines as a temporary directing group
(DG)4a,20 was critical to avoid competing decarbonylation by
forming the corresponding imine intermediate.4a Reducing the
loading of the temporary DG and prolonging the reaction time
further improved the yield (entries 4 and 5, Table 1).
Moreover, the effect of the DG substituent was subsequently
examined. By increasing the size of the 3-substituent on the
DG, the yield was enhanced accordingly. It is possible that, like
the linker effect (vide supra), the larger sterics on the DG can
provide a more conformationally rigid intermediate that would
be beneficial for the cyclization. However, further increasing
the bulkiness on the DG, such as using 2-amino-3-
trimethylsilylpyridine, only gave a trace amount of the product.
Finally, after changing the solvent from 1,4-dioxane to toluene
and buffering the reaction with a bulky pyridine base, a
consistent yield can be obtained on a gram scale (entries 8 and
9, Table 1). Through this “cut-and-sew” transformation, the A/
B rings and the all-carbon C1 quaternary center were
simultaneously constructed. Note that, besides the cyclo-
pentenyl moiety, mono- and 1,1-disubstituted alkenes can also
be efficiently coupled to form bridged bicycles, which implies
some generality of this method (for details, see the Supporting
Information).
The ester moiety in ketone 5 can be conveniently removed
by a sequence of hydrolysis and Barton decarboxylation
(Scheme 4). X-ray structures of the carboxylic acid (12) and
the hydrazone derivative of the decarboxylation product (13)
were obtained to allow unambiguous characterization. With a
scalable route to access the tricyclic compound (4), the stage
was now set for introducing the required functional groups to
the core skeleton. Initial attempts of various ketone- and
alcohol-directed β-C−H functionalizations, including Sanford
C−H acetoxylation (proceeded with poor conversion),21
Schonecker−Baran C−H oxidation (occurred at the undesired
C5 position),22 and Hartwig C−H silylation (occurred at the
undesired C14 position),23 were not fruitful, likely due to the
relatively rigid scaffold that lacks favorable conformation to
access the desired C4 methylene. Ultimately, α,β-desaturation
under the Stahl conditions,24 followed by conjugate
borylation25 and oxidation, installed a hydroxy group at the
C4 position in moderate yield. Alternatively, a three-step
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Scheme 4. Completing the Synthesis of Penicibilaenes A and B
protocol involving regioselective enolization, selenylation, and
selenoxide-mediated syn-elimination can afford a 68% yield of
enone 14. The C4-alcohol provided a convenient handle to
allow a stereoselective methyl addition of the C6-ketone
through chelation control. Treatment of ketone 15 with LaCl3
and MeMgBr26 delivered 1,3-diol 16 as a single diastereomer
in 88% yield, which was further oxidized by IBX27 to produce
ketone 3. At this stage, a new carbonyl moiety was introduced
at the C4 position, with stereochemistry at the C5 and C6
positions correctly set.
further prepared from penicibilaene A in good yield via a
chemoselective acylation of the secondary alcohol.
In summary, we have described the first total synthesis of
penicibilaenes A (1) and B (2) in 13 and 14 steps, respectively,
in the longest linear sequence from commercially available
starting materials. The synthesis features a deconstructive
formation of the tricyclic skeleton via C−C activation of
cyclobutanones and the use of carbonyl desaturation relay to
replace β-C−H bonds with the desired functional groups. Such
a “C−C/C−H” approach may inspire alternative bond-
disconnecting strategies for natural product syntheses. In
addition, the discovery of a new linker system and a Lewis acid
effect in the Rh-catalyzed “cut-and-sew” reaction between
cyclobutanones and bulky alkenes could have broader
implications on preparing other all-carbon bridged/fused rings.
To complete the synthesis, another β-functionalization
installing a methyl group at the C2 positionwas required.
Due to the presence of a labile C6 tertiary alcohol, various
ketone desaturation conditions were found unsuccessful to
introduce the cyclopentenone moiety. Eventually, the use of
Mukaiyama’s one-pot desaturation method28 with N-tert-butyl
phenylsulfinimidoyl chloride (19) as the reagent delivered the
desired enone product (17) in 51% yield without the need to
protect the C6 alcohol. The unique half-cage structure of
enone 17 allowed a copper-mediated conjugate addition29
selectively at the convex face to furnish the methyl group as a
single diastereomer. The choice of the methyl nucleophile
appears to be important; the nickel-mediated conjugate
addition30 also gave the desired product, albeit in low
diastereoselectivity. In the end game, an alcohol-directed syn-
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04335.
Experimental procedures, spectral data (PDF)
Accession Codes
CCDC 2078710 and 2078965 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
31
reduction of ketone 18 by NMe4·BH(OAc)3 delivered
penicibilaene A (1) in 88% yield. Penicibiaene B (2) was
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Transition Metal Complexes. Chem. Rev. 2017, 117, 9404−9432.
(e) Deng, L.; Dong, G. Carbon-Carbon Bond Activation of Ketones.
Trends Chem. 2020, 2, 183−198. (f) Murakami, M.; Ishida, N.
Cleavage of Carbon-Carbon σ-Bonds of Four-Membered Rings.
Chem. Rev. 2021, 121, 264−299.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
(5) (a) Xu, T.; Dong, G. Rhodium-Catalyzed Regioselective
Carboacylation of Olefins: A C-C Bond Activation Approach for
Accessing Fused-Ring Systems. Angew. Chem., Int. Ed. 2012, 51,
7567−7571. (b) Chen, P. H.; Billett, B. A.; Tsukamoto, T.; Dong, G.
Cut and Sew” Transformations via Transition-Metal-Catalyzed
Carbon-Carbon Bond Activation. ACS Catal. 2017, 7, 1340−1360.
(6) For reviews on site-selectivte C−H functionalization and site-
selectivity, see: (a) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.;
Dong, G. Transition Metal-Catalyzed Ketone-Directed or Mediated
C-H Functionalization. Chem. Soc. Rev. 2015, 44, 7764−7786.
(b) Hartwig, J. F. Catalyst-Controlled Site-Selective Bond Activation.
Acc. Chem. Res. 2017, 50, 549−555. (c) Huang, Z.; Dong, G. Site-
Selectivity Control in Organic Reactions: A Quest To Differentiate
Reactivity among the Same Kind of Functional Groups. Acc. Chem.
Res. 2017, 50, 465−471.
Guangbin Dong − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0003-1331-6015; Email: gbdong@
uchicago.edu
Author
Yibin Xue − Department of Chemistry, University of Chicago,
Chicago, Illinois 60637, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04335
Notes
The authors declare no competing financial interest.
(7) (a) Murakami, M.; Ishida, N. Potential of Metal-Catalyzed C-C
Single Bond Cleavage for Organic Synthesis. J. Am. Chem. Soc. 2016,
138, 13759−13769. (b) Wang, B.; Perea, M. A.; Sarpong, R.
Transition Metal-Mediated C-C Single Bond Cleavage: Making the
Cut in Total Synthesis. Angew. Chem., Int. Ed. 2020, 59, 18898−
18919.
(8) Meng, L. H.; Li, X. M.; Liu, Y.; Wang, B. G. Penicibilaenes A and
B, Sesquiterpenes with a Tricyclo[6.3.1.01,5]dodecane Skeleton from
the Marine Isolate of Penicillium bilaiae MA-267. Org. Lett. 2014, 16,
6052−6055.
ACKNOWLEDGMENTS
■
NIGMS (2R01GM109054) and University of Chicago are
acknowledged for research support. We thank Mr. Shusuke
Ochi and Dr. Xin Liu from University of Chicago for X-ray
crystallography. Umicore AG & Co. KG is acknowledged for a
generous donation of Rh salts. Mr. Benjamin L Ratchford from
University of Chicago is thanked for proofreading the
Supporting Information.
(9) For a recent review on desaturation-mediated β C−H
functionalization, see: Wang, C.; Dong, G. Catalytic β-Functionaliza-
tion of Carbonyl Compounds Enabled by α,β-Desaturation. ACS
Catal. 2020, 10, 6058−6070.
(10) Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Allyl-
Palladium-Catalyzed Ketone Dehydrogenation Enables Telescoping
with Enone α,β-Vicinal Difunctionalization. Angew. Chem., Int. Ed.
2017, 56, 8258−8262.
(11) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P.
Intramolecular Schmidt Reaction Involving Primary Azidoalcohols
under Nonacidic Conditions: Synthesis of Indolizidine (−)-167B. J.
Am. Chem. Soc. 2009, 131, 17746−17747.
(12) Kim, D. D.; Lee, S. J.; Beak, P. Asymmetric Lithiation-
Substitution Sequences of Substituted Allylamines. J. Org. Chem.
2005, 70, 5376−5386.
(13) Li, X.; Danishefsky, S. J. Cyclobutenone as a Highly Reactive
Dienophile: Expanding Upon Diels-Alder Paradigms. J. Am. Chem.
Soc. 2010, 132, 11004−11005.
(14) Zhu, N.; Hall, D. G. Effect of Additives on the Sterochemical
Integrity and Reactivity of α-Alkoxycarbonyl Alkenylcopper Inter-
mediates. Optimal Conditions for the Synthesis of Isomerically Pure
Tetrasubstituted Alkenes. J. Org. Chem. 2003, 68, 6066−6069.
(15) (a) Xu, T.; Ko, H. M.; Savage, N. A.; Dong, G. Highly
Enantioselective Rh-Catalyzed Carboacylation of Olefins: Efficient
Syntheses of Chiral Poly-Fused Rings. J. Am. Chem. Soc. 2012, 134,
20005−20008. (b) Xu, T.; Dong, G. Coupling of Sterically Hindered
Trisubstituted Olefins and Benzocyclobutenones by C-C Activation:
Total Synthesis and Structural Revision of Cycloinumakiol. Angew.
Chem., Int. Ed. 2014, 53, 10733−10736. (c) Deng, L.; Chen, M.;
Dong, G. Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-
Cycloclavine via Asymmetric C-C Activation. J. Am. Chem. Soc. 2018,
140, 9652−9658. (d) Qiu, B.; Li, X. T.; Zhang, J. Y.; Zhan, J. L.;
Huang, S. P.; Xu, T. Catalytic Enantioselective Synthesis of 3,4-
Polyfused Oxindoles with Quaternary All-Carbon Stereocenters: A
Rh-Catalyzed C-C Activation Approach. Org. Lett. 2018, 20, 7689−
7693. (e) Zhang, Y.; Shen, S.; Fang, H.; Xu, T. Total Synthesis of
Galanthamine and Lycoramine Featuring an Early-Stage C-C and a
Late-Stage Dehydrogenation via C-H Activation. Org. Lett. 2020, 22,
1244−1248.
REFERENCES
■
(1) Breitmaier, E. Terpenes: Flavors, Fragrances, Pharmaca,
Pheromones; Wiley-VCH: Weinheim, 2006.
(2) (a) Cherney, E. C.; Baran, P. S. Terpenoid-Alkaloids: Their
Biosynthetic Twist of Fate and Total Synthesis. Isr. J. Chem. 2011, 51,
391−405. (b) Justicia, J.; de Cienfuegos, L. A.; Campana, A. G.;
Miguel, D.; Jakoby, V.; Gansauer, A.; Cuerva, J. M. Bioinspired
Terpene Synthesis: a Radical Approach. Chem. Soc. Rev. 2011, 40,
3525−3537. (c) Urabe, D.; Asaba, T.; Inoue, M. Convergent
Strategies in Total Syntheses of Complex Terpenoids. Chem. Rev.
2015, 115, 9207−9231. (d) Brill, Z. G.; Condakes, M. L.; Ting, C. P.;
Maimone, T. J. Navigating the Chiral Pool in the Total Synthesis of
Complex Terpene Natural Products. Chem. Rev. 2017, 117, 11753−
11795.
(3) For selected examples and reviews, see: (a) Chen, K.; Baran, P.
S. Total Synthesis of Eudesmane Terpenes by Site-Selective C-H
Oxidations. Nature 2009, 459, 824−828. (b) Ishihara, Y.; Baran, P. S.
Two-Phase Terpene Total Synthesis: Historical Perspective and
Application to the Taxol® Problem. Synlett 2010, 2010, 1733−1745.
(c) Foo, K.; Usui, I.; Gotz, D. C. G.; Werner, E. W.; Holte, D.; Baran,
P. S. Scalable, Enantioselective Synthesis of Germacrenes and Related
Sesquiterpenes Inspired by Terpene Cyclase Phase Logic. Angew.
Chem., Int. Ed. 2012, 51, 11491−11495. (d) Jorgensen, L.; McKerrall,
S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. 14-Step
Synthesis of (+)-Ingenol from (+)-3-Carene. Science 2013, 341, 878−
882. (e) Wilde, N. C.; Isomura, M.; Mendoza, A.; Baran, P. S. Two-
Phase Synthesis of (−)-Taxuyunnanine D. J. Am. Chem. Soc. 2014,
136, 4909−4912. (f) Kanda, Y.; Nakamura, H.; Umemiya, S.;
Puthukanoori, R. K.; Appala, V. R. M.; Gaddamanugu, G. K.; Paraselli,
B. R.; Baran, P. S. Two-Phase Synthesis of Taxol. J. Am. Chem. Soc.
2020, 142, 10526−10533.
(4) (a) Jun, C. H. Transition Metal-Catalyzed Carbon-Carbon Bond
Activation. Chem. Soc. Rev. 2004, 33, 610−618. (b) Dong, G., Ed. C-C
Bond Activation; Springer-Verlag: Berlin, 2014; Vol. 346. (c) Souillart,
L.; Cramer, N. Catalytic C-C Bond Activations via Oxidative Addition
to Transition Metals. Chem. Rev. 2015, 115, 9410−9464.
(d) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent Methodologies
That Exploit C-C Single-Bond Cleavage of Strained Ring Systems by
8276
https://doi.org/10.1021/jacs.1c04335
J. Am. Chem. Soc. 2021, 143, 8272−8277

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(16) For a seminal work on the cyclobutanone/olefin coupling, see:
Murakami, M.; Itahashi, T.; Ito, Y. Catalyzed Intramolecular Olefin
Insertion into a Carbon-Carbon Single Bond. J. Am. Chem. Soc. 2002,
124, 13976−13977.
(17) These substrates were prepared via a different and longer
synthetic route from substrate 6.
(18) To our knowledge, the only example was shown by Cramer
with a benzene-like substrate: Souillart, L.; Parker, E.; Cramer, N.
Highly Enantioselective Rhodium(I)-Catalyzed Activation of Enan-
tiotopic Cyclobutanone C-C Bonds. Angew. Chem., Int. Ed. 2014, 53,
3001−3005.
(19) Ko, H. M.; Dong, G. Cooperative Activation of Cyclobutanones
and Olefins Leads to Bridged Ring Systems by a Catalytic [4 + 2]
Coupling. Nat. Chem. 2014, 6, 739−744.
(20) Xia, Y.; Dong, G. Temporary or Removable Directing Groups
Enable Activation of Unstrained C-C Bonds. Nat. Rev. Chem. 2020, 4,
600−614.
(21) Desai, L. V.; Hull, K. L.; Sanford, M. S. Palladium-Catalyzed
Oxygenation of Unactivated sp3 C-H Bonds. J. Am. Chem. Soc. 2004,
126, 9542−9543.
(22) (a) Schonecker, B.; Zheldakova, T.; Liu, Y.; Kotteritzsch, M.;
Gunther, W.; Gorls, H. Biomimetic Hydroxylation of Nonactivated
CH2 Groups with Copper Complexes and Molecular Oxygen. Angew.
Chem., Int. Ed. 2003, 42, 3240−3244. (b) See, Y. Y.; Herrmann, A. T.;
Aihara, Y.; Baran, P. S. Scalable C-H Oxidation with Copper:
Synthesis of Polyoxypregnanes. J. Am. Chem. Soc. 2015, 137, 13776−
13779.
(23) Li, B.; Driess, M.; Hartwig, J. F. Iridium-Catalyzed
Regioselective Silylation of Secondary Alkyl C-H Bonds for the
Synthesis of 1,3-Diols. J. Am. Chem. Soc. 2014, 136, 6586−6589.
(24) (a) Diao, T.; Stahl, S. S. Synthesis of Cyclic Enones via Direct
Palladium-Catalyzed Aerobic Dehydrogenation of Ketones. J. Am.
Chem. Soc. 2011, 133, 14566−14569. (b) Pan, G. F.; Zhu, X. Q.; Guo,
R. L.; Gao, Y. R.; Wang, Y. Q. Synthesis of Enones and Enals via
Dehydrogenation of Saturated Ketones and Aldehydes. Adv. Synth.
Catal. 2018, 360, 4774−4783.
(25) Lee, K. S.; Zhugralin, A. R.; Hoveyda, A. H. Efficient C-B Bond
Formation Promoted by N-Heterocyclic Carbenes: Synthesis of
Tertiary and Quaternary B-Substituted Carbons through Metal-Free
Catalytic Boron Conjugate Additions to Cyclic and Acyclic α,β-
Unsaturated Carbonyls. J. Am. Chem. Soc. 2009, 131, 7253−7255.
(26) (a) Krasovskiy, A.; Kopp, F.; Knochel, P. Soluble Lanthanide
Salts (LnCl3·2LiCl) for the Improved Addition of Organomagnesium
Reagents to Carbonyl Compounds. Angew. Chem., Int. Ed. 2006, 45,
497−500. (b) Breitler, S.; Carreira, E. M. Total Synthesis of
(+)-Crotogoudin. Angew. Chem., Int. Ed. 2013, 52, 11168−11171.
(27) For a recent example, see: Boyko, Y. D.; Huck, C. J.; Ning, S.;
Shved, A. S.; Yang, C.; Chu, T.; Tonogai, E. J.; Hergenrother, P. J.;
Sarlah, D. Synthetic Studies on Selective, Proapoptotic Isomalabar-
icane Triterpenoids Aided by Computational Techniques. J. Am.
Chem. Soc. 2021, 143, 2138−2155.
(28) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. A New and One-Pot
Synthesis of α,β-Unsaturated Ketones by Dehydrogenation of Various
Ketones with N-tert-butyl Phenylsulfinimidoyl Chloride. Chem. Lett.
2000, 29, 1250−1251.
(29) Cao, M. Y.; Ma, B. J.; Lao, Z. Q.; Wang, H.; Wang, J.; Liu, J.;
Xing, K.; Huang, Y. H.; Gan, K. J.; Gao, W.; Wang, H.; Hong, X.; Lu,
H. H. Optically Active Flavaglines-Inspired Molecules by a Palladium-
Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkyla-
tion. J. Am. Chem. Soc. 2020, 142, 12039−12045.
(30) Qu, Y.; Wang, Z.; Zhang, Z.; Zhang, W.; Huang, J.; Yang, Z.
Asymmetric Total Synthesis of (+)-Waihoensene. J. Am. Chem. Soc.
2020, 142, 6511−6515.
(31) Evans, D. A.; Chapman, K. T.; Carreira, E. M. Directed
Reduction of β-Hydroxy Ketones Employing Tetramethylammonium
Triacetoxyborohydride. J. Am. Chem. Soc. 1988, 110, 3560−3578.
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