Stereospecific Synthesis of Enantioenriched Alkylidenecyclobutanones via Formal Vinylidene Insertion into Cyclopropanone Equivalents

Article abstract of DOI:10.1021/acs.orglett.1c02303

1-Sulfonylcyclopropanols are employed here as efficient cyclopropanone equivalents in a formal vinylidene insertion process, providing the first general synthetic route to enantioenriched alkylidenecyclobutanones. The addition of an alkenyl-Grignard reage

Full text of DOI:10.1021/acs.orglett.1c02303

pubs.acs.org/OrgLett
Letter
Stereospecific Synthesis of Enantioenriched
Alkylidenecyclobutanones via Formal Vinylidene Insertion into
Cyclopropanone Equivalents
Christopher M. Poteat and Vincent N. G. Lindsay*
Cite This: Org. Lett. 2021, 23, 6482−6487
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ABSTRACT: 1-Sulfonylcyclopropanols are employed here as
efficient cyclopropanone equivalents in a formal vinylidene
insertion process, providing the first general synthetic route to
enantioenriched alkylidenecyclobutanones. The addition of an
alkenyl-Grignard reagent leads to an alkenylcyclopropanol capable
of electrophilic activation by N-bromosuccinimide, triggering a regio- and stereospecific 1,2-migration and affording
alkylidenecyclobutanones after elimination. Activation of the intermediate with other electrophiles such as HCl or mCPBA leads
to the formation of various chiral cyclobutanones and γ-lactones via alternative pathways.
Scheme 1. Reactivity of Various Cyclopropanone
Equivalents and Application in (3 + 1) Ring Expansion
Processes
he ring expansion or ring opening of strained cyclic
Tcompounds constitutes a key strategy in organic synthesis
for the elaboration of complex molecules.1 The relevance of
cyclobutanone derivatives in this regard cannot be under-
stated,2 with countless strain-releasing transformations now
available to synthetic chemists, thus allowing rapid access to a
range of structurally complex and diverse scaffolds. More
particularly, alkylidenecyclobutanones3,4 have been employed
as privileged substrates in stereospecific ring opening or
rearrangements3a,b and constitute divergent substrates leading
to functionalized cyclobutanones via the conjugate addition of
heteronucleophiles3c,4m or organometallic reagents,3d,e,4p con-
jugate reduction,3f−h,4c,n or hydroformylation reactions.3i
Moreover, these species have been employed as unique
precursors of oxatetramethyleneethane intermediates via
photoinduced electron transfer.3j−l While they can be accessed
in their racemic form by a variety of approaches including the
[2 + 2] cycloaddition of ketenes with allenes,4a−d the
carbonylation or oxidation of alkylidenecyclopropanes,4e−i
the rearrangement of 1-alkynylcyclopropanols,4j−l or via
classical condensation or cyclization strategies,4m−r the general
stereoselective access to alkylidenecyclobutanones still remains
elusive. An interesting approach to racemic cyclobutanones
reported by Wasserman and coworkers involves the electro-
philic activation and ring expansion of 1-vinylcyclopropanol,
which, in turn, can be synthesized by vinyl Grignard addition
to hemiketal 1, used as a cyclopropanone surrogate (Scheme
1a).5,6 Although cyclobutanone derivatives are relatively stable
to isolation and storage, cyclopropanones are often highly
unstable and prone to multiple decomposition pathways,1d,7,8
and it is thus often more convenient to form them in situ via
elimination from a surrogate such as 1 (Scheme 1b).7d,9
Hemiketals 1 require harsh conditions to equilibrate to the
cyclopropanone due in part to the poor leaving group ability of
alkoxides, which often leads to low yields of desired rearranged
products, as exemplified here in a racemic cyclobutanone
synthesis (29% overall yield; see Scheme 1a).5a Recently, our
group reported an expedient synthesis of optically active 1-
sulfonylcyclopropanols 2,10 which constitute stable yet highly
reactive and modular surrogates of cyclopropanone deriva-
Received: July 9, 2021
Published: August 9, 2021
https://doi.org/10.1021/acs.orglett.1c02303
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6482−6487
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tives.11 This approach constitutes the first general enantiose-
lective route to cyclopropanone equivalents, and later allowed
us to access enantioenriched 4-substituted β-lactams using a
formal nitrene insertion reaction with simple N-substituted
hydroxylamines as reagents (Scheme 1c).10
Scheme 2. Scope of Accessible Alkylidenecyclobutanones by
Formal Vinylidene Insertion into Cyclopropanone
Equivalents
a b
,
Cognizant of the superior reactivity of surrogates 2 toward
the addition of organometallic reagents to afford chiral tertiary
cyclopropanols,11a we envisioned that they would constitute
privileged substrates for the production of optically active
cyclobutanones via an analogous stereospecific ring expansion
pathway. Herein we report the first general route to
enantioenriched alkylidenecyclobutanones via a formal vinyl-
idene insertion process into chiral cyclopropanones starting
from readily accessible 1-sulfonylcyclopropanols 2 as surro-
gates (Scheme 1d). The addition of an alkenyl nucleophile to
substrates 2 followed by appropriate electrophilic activation
with N-bromosuccinimide (NBS) was found to trigger a fully
regio- and stereospecific 1,2-migration, leading to a bromocy-
clobutanone prone to elimination. A number of chiral
alkylidenecyclobutanones could be obtained through variation
of the alkenyl nucleophile and cyclopropanone substituents,
and alternative activation of the allylic alcohol with HCl or
mCPBA led to the controlled formation of chiral saturated
cyclobutanones and γ-lactones instead. Other applications of
this chemistry documented here include the synthesis of β-
aminocyclobutanones via in situ aza-Michael addition, the use
of a β-bromo alkylidenecyclobutanone as a cross-coupling
partner and the stereospecific formation of α-quaternary
cyclobutanones. Considering the relevance of chiral cyclo-
butanones and alkylidenecyclobutanones as strained building
blocks in synthesis,2,3 this work should find broad applicability
in the elaboration of complex and biologically relevant
molecules.
Our preliminary studies focused on the addition of
vinylmagnesium bromide to substrate 2a to yield the
corresponding 1-vinylcyclopropanol and identified the use of
an excess organometallic reagent at −78 °C as crucial to the
overall reaction efficiency.12 We also observed that NBS was a
superior electrophile to trigger the subsequent ring expansion,
presumably via an hydroxycyclopropylbromonium species,
leading to quantitative NMR yields of the ring-expanded
bromocyclobutanone from the crude 1-vinylcyclopropanol
intermediate. This brominated product was found to be highly
sensitive to elimination,13 which prompted us to pursue a one-
pot sequence to alkylidenecyclobutanones 3. To our delight,
optimal conditions for the overall process from 2a were rapidly
identified, involving the sequential stoichiometric addition of
NBS and Et3N at room temperature to the crude 1-
vinylcyclopropanol intermediate, affording 3a in 76% isolated
yield from 1-sulfonylcyclopropanol 2a with complete regio-
and stereospecificity (Scheme 2). Using our previously
developed two-step sequence to enantioenriched cyclopropa-
none equivalents from methyl phenyl sulfone10 and to explore
the scope of accessible alkylidenecyclobutanones, diverse chiral
substrates 2a−2g were synthesized and submitted to our
formal vinylidene insertion sequence. When employing
vinylmagnesium bromide as nucleophile, chiral methylenecy-
clobutanones 3a−3e were obtained in moderate to good
overall yields and high enantiomeric purity, tolerating
monosubstituted (3a−3c), gem-disubstituted (3d), or 2,3-
disubstituted (3e) substrates with similar efficiency. In the case
of 3d, additional time and heat were required for the
elimination to proceed, presumably due to increased steric
a
b
Isolated yields from 2a−2g. Enantiomeric excesses were deter-
mined by HPLC analysis using a chiral stationary phase (ee of starting
material 2 in parentheses). Isolated in 83% purity. Heated to reflux
for 18 h after the addition of Et3N. Racemic substrate 2e was used.
c
d
e
hindrance at the site of deprotonation. The use of
commercially available 2-methyl-1-propenylmagnesium bro-
mide as a nucleophile led to tetrasubstituted olefin 3f in
moderate yield. Employing freshly prepared trans-β-styrenyl-
magnesium bromide efficiently gave access to β-phenyl
alkylidenecyclobutanones 3g−3i in various E:Z ratios, where
alkene isomerization was found to occur during chromatogra-
phy.4j,12 Gratifyingly, all products 3a−3i were obtained as
single regioisomers without the need for purification of the
vinylcyclopropanol intermediates, and no significant loss of
stereochemical information was observed in any case,
confirming the stereospecificity of the 1,2-migration occurring
upon olefin bromination.
Interestingly, the alkylidenecyclobutanone initially produced
can be directly employed as an electrophile in an aza-Michael
reaction in one pot, leading to the clean formation of a β-
aminoketone such as 4 (Scheme 3). Upon heating and
Scheme 3. Direct Synthesis of Enantioenriched β-
Aminoketone 4 by One-Pot aza-Michael Addition of the
Succinimide Byproduct
a b
,
a
b
Isolated yield from 2a. Enantiomeric excess was determined by
HPLC analysis using a chiral stationary phase.
addition of a catalytic amount of Yb(OTf)3 as a Lewis acid, the
succinimide byproduct liberated during olefin activation can
act as a nucleophile in the final step to directly afford protected
β-amino cyclobutanone 4 with high efficiency. A single trans
diastereomer of the cyclobutanone is obtained in the process,
likely due to thermodynamic keto−enol equilibration occur-
ring under these conditions.4n,6f
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The addition of a 1-substituted alkenyl−metal reagent such
as α-styrenylmagnesium bromide as the initial nucleophile in
this transformation efficiently leads to an enantioenriched α-
quaternary β-bromocyclobutanone (e.g., 5), which cannot
undergo further elimination to an alkene following 1,2-
migration (Scheme 4a). When ethynylmagnesium bromide is
Scheme 5. Alternative Activation of the Vinylcyclopropanol
Intermediate with HCl or mCPBA (a) and Stereospecific
Synthesis of γ-Lactones via One-Pot Baeyer−Villiger
a b
,
Oxidation (b)
Scheme 4. Synthesis and Application of Brominated
Cyclobutanones 5 and 6 via the Addition of α-
Styrenylmagnesium Bromide (a) or Ethynylmagnesium
a b
,
Bromide (b) as Initial Nucleophiles
a
b
a
b
Isolated yields from 2a or 2c. Enantiomeric excesses were
Isolated yields. Enantiomeric excesses were determined by HPLC
c
determined by HPLC analysis using a chiral stationary phase. ee of
starting material 2a or 2c in parentheses.
analysis using a chiral stationary phase.
employed instead, the 1-alkynylcyclopropanol initially formed
undergoes an analogous rearrangement upon activation with
NBS, directly affording β-brominated alkylidenecyclobutanone
6 (Scheme 4b). This compound can then be effectively
employed as a substrate in a Suzuki cross-coupling reaction to
furnish an ester-functionalized alkylidenecyclobutanone 7.
Such a sequence should prove particularly useful as an
alternative route to alkylidenecyclobutanones when functional
group compatibility is an issue during either the initial
Grignard addition or the electrophilic alkene activation step.
The stereospecific 1,2-migration of the ring expansion
sequence can also be triggered by the addition of electrophiles
other than NBS to the crude 1-vinylcyclopropanol inter-
mediate, directly leading to the corresponding saturated chiral
cyclobutanones in moderate to good overall yields (Scheme
5).5a,9a,b For example, treatment of this intermediate with a few
drops of concentrated HCl in CH2Cl2 at room temperature led
to enantioenriched α-methylated cis-cyclobutanone 8 as a
single diastereomer following protonation of the vinyl group
and 1,2-migration (Scheme 5a, top). The stoichiometric
addition of mCPBA instead led to epoxidation of the allylic
alcohol, initiating a stereospecific 1,2-migration and affording
cis-β-hydroxycyclobutanone 9 in good overall yield (Scheme
5a, bottom). During this process, we observed the formation of
a small amount of γ-lactone 10a, presumably arising from
Baeyer−Villiger oxidation of product 9, even when only 1
equiv of mCPBA was added for the epoxidation step. This
result highlights the fact that β-hydroxycyclobutanone 9
constitutes a particularly reactive ketone in such a strain-
releasing esterification, which prompted us to investigate a
one-pot double ring expansion sequence in the presence of 2
equiv of mCPBA, directly affording optically active cis-γ-
lactones 10a and 10b in good overall yields (Scheme 5b). This
diastereoselective formal [3 + 1 + 1] sequence should prove
highly useful considering the relevance of chiral γ-lactones in
the formation of biologically active compounds.14
accessible 1-sulfonylcyclopropanols as versatile surrogates.10,11
The addition of an alkenyl nucleophile followed by electro-
philic activation of the resulting crude allylic alcohol with NBS
triggers a stereospecific ring expansion occurring in a fully
regioselective manner, favoring the migration of the most
substituted (stereogenic) carbon of the cyclopropyl group.
Other activating agents such as HCl or mCPBA efficiently led
to the formation of chiral saturated cis-cyclobutanones instead,
which can be further expanded to cis-γ-lactones in situ by
Baeyer−Villiger oxidation. Considering the prevalence of chiral
cyclobutanones2 and alkylidenecyclobutanones3 as strained
intermediates and of chiral γ-lactones in medicinal chemistry,14
this work should prove useful in the synthesis of biologically
relevant molecules.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02303.
Experimental details and spectroscopic data (PDF)
Accession Codes
CCDC 2089064 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
Corresponding Author
■
Vincent N. G. Lindsay − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695,
United States; orcid.org/0000-0002-7126-325X;
Email: vlindsa@ncsu.edu
In summary, the first general synthesis of enantioenriched
alkylidenecyclobutanones is reported via a formal vinylidene
insertion into cyclopropanone derivatives, starting from readily
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Letter
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(3) For selected applications of alkylidenecyclobutanones, see:
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Gazzard, L.; Kumar, S.; Li, X.; Liu, W.; Mendonca, R.; Pavana, R. K.;
Potturi, H.; Shao, C.; Velvadapu, V.; Waldo, J. P.; Wu, G.; Yuen, P.-
w.; Zhang, Z.; Zhang, Y.; Harris, S. F.; Oh, A. J.; DiPasquale, A.;
Dement, K.; La, H.; Goon, L.; Gustafson, A.; VanderPorten, E. C.;
Mautino, M. R.; Liu, Y. Implementation of the CYP Index for the
Design of Selective Tryptophan-2,3-dioxygenase Inhibitors. ACS Med.
Christopher M. Poteat − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02303
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Prof. André B. Charette on the occasion of his
60th birthday. This work was supported by North Carolina
State University startup funds. All X-ray, nuclear magnetic
resonance (NMR) spectroscopy, and high-resolution mass
spectrometry (HRMS) measurements were performed by the
Molecular Education, Technology, and Research Innovation
Center (METRIC) at NC State University, which is supported
by the State of North Carolina. We are grateful to Dr. Roger D.
Sommer (METRIC, NC State University) for the X-ray
analysis of 10b, visualized here using CYLView.15 C.M.P. is
grateful to NC State University for a Percy Lavon Julian Award
in Organic Chemistry.
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