Beyond the Corey–Chaykovsky Reaction: Synthesis of Unusual Cyclopropanoids via Desymmetrization and Thereof

Article abstract of DOI:10.1002/asia.201901108

Desymmetrization-based protocols for the synthesis of highly functionalized indeno-spirocyclopropanes and cyclopropa-fused indanes have been established through unexpected reactions triggered by the Corey–Chaykovsky reagent. These structures were further elaborated in one step to privileged scaffolds such as fluorenones, indenones, and naphthaphenones. For instance, an acid-catalyzed transformation of indeno-spirocyclopropanes provided fluorenones via a homo-Nazarov-type cyclization, and naphthaphenones were obtained via an acid-catalyzed cyclopropane ring-opening/retro-Michael sequence.

Full text of DOI:10.1002/asia.201901108

DOI: 10.1002/asia.201901108
Communication
Beyond the Corey–Chaykovsky Reaction: Synthesis of Unusual
Cyclopropanoids via Desymmetrization and Thereof
Kaushalendra Patel+, Uttam K. Mishra+, Dipto Mukhopadhyay, and S. S. V. Ramasastry*[a]
and conformational rigidity offered by cyclopropanes during
drug design and development.[2] In addition, the strained
Abstract: Desymmetrization-based protocols for the syn-
three-membered carbocycles can undergo a broad spectrum
of ring transformations to generate new molecular architec-
tures.[3] These impressive features promoted synthetic chemists
to develop newer synthetic routes for the synthesis of cyclo-
propanes.[4]
thesis of highly functionalized indeno-spirocyclopropanes
and cyclopropa-fused indanes have been established
through unexpected reactions triggered by the Corey–
Chaykovsky reagent. These structures were further elabo-
rated in one step to privileged scaffolds such as fluore-
nones, indenones, and naphthaphenones. For instance, an
acid-catalyzed transformation of indeno-spirocyclopro-
panes provided fluorenones via a homo-Nazarov-type cyc-
lization, and naphthaphenones were obtained via an acid-
catalyzed cyclopropane ring-opening/retro-Michael se-
quence.
Some of the prominent methods for the preparation of cy-
clopropanes include: (i) the halomethyl-metal-mediated reac-
tions (for example, the Simmons-Smith reaction), (ii) metal-cata-
lyzed decomposition of diazo compounds, (iii) the nucleophilic
addition-ring closure sequence (for example, the Kulinkovich
cyclopropanation, reactions mediated by ylides, etc.).[4] Among
them, the Corey-Chaykovsky reaction is a metal-free cyclopro-
panation strategy facilitated by sulfur ylides and it is applicable
to a wide-range of electron-deficient olefins.[5] This reaction
can also be employed for the synthesis of epoxides and aziri-
dines from carbonyls and imines, respectively. The nucleophilic
character of the Corey-Chaykovsky reagent [dimethyloxosulfo-
nium methylide (DOSM)] is also known to trigger unexpected
rearrangements which often provide access to otherwise diffi-
cult-to-access cyclopropanoids.[6]
Cyclopropanes are important structural units present in several
bioactive natural products and pharmaceutically relevant com-
pounds including a few marketed drugs (Figure 1).[1] Medicinal
chemists take advantage of the enhanced metabolic stability
While sulfur ylides have widespread applications in organic
synthesis, to our knowledge, these species are yet to be em-
ployed in a desymmetrization process. Desymmetrization is a
powerful means of achieving architectural complexity.[7] This
strategy often allows the incorporation of multiple stereogenic
centers in a single step. Here, we demonstrate an efficient and
straightforward desymmetrization strategy facilitated by the
DOSM for the formation of cyclopropanoids possessing up to
three contiguous stereogenic centers (Scheme 1). The reaction
also involves the formation of three new carbon-carbon bonds.
To establish a desymmetrizing event facilitated by the
DOSM, we have chosen 1a as the model substrate,
Scheme 2.[8] It is anticipated that the reaction of 1a with
DOSM can involve an initial Michael addition followed by
either an aldol-type reaction (path-a) or a Michael reaction
(path-b) leading to the formation of zwitterionic species A or
B, respectively.[9] A subsequent 1,3-proton shift provides eno-
lates C or D, which can form indanone 2a or fused-cyclohepta-
nedione 3a, respectively, via the nucleophilic displacement of
the dimethylsulfoxonium group. On the other hand, the forma-
tion of the epoxide 4a and the cyclopropane 5a can also be
expected under the reaction conditions. However, under the
standard conditions, only the indanone 2a was obtained in
90% yield in 2.5:1 diastereomeric ratio.
Figure 1. Representative cyclopropane-containing bioactive natural products
and medicinally important compounds.
[a] K. Patel,+ U. K. Mishra,+ D. Mukhopadhyay, Dr. S. S. V. Ramasastry
Organic Synthesis and Catalysis Lab
Department of Chemical Sciences
Indian Institute of Science Education and Research (IISER) Mohali
Knowledge City, Sector 81, S. A. S. Nagar, Manauli PO, Punjab 140306
(India)
E-mail: ramsastry@iisermohali.ac.in
Homepage: http://14.139.227.202/faculty/sastry/
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201901108.
This manuscript is part of a special issue celebrating the 20th anniversary of
the Chemical Research Society of India (CRSI). A link to the Table of Con-
tents of the special issue will appear here when the complete issue is pub-
lished.
Encouraged by the unusual and straightforward transforma-
tion leading to the formation of highly functionalized inda-
none incorporated with three contiguous stereogenic centers,
one of them being a spiro carbon, and others being a tetra-
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Table 1. Scope for indeno-spirocyclopropanes 2.[a,b]
Scheme 1. This work: Unexpected desymmetrizing events triggered by
DOSM, and elaboration to certain privileged structures.
[a] Isolated yield after column chromatography. [b] The diastereomeric
ratio (d.r.) was obtained from the 1H NMR of the crude reaction mixture.
A narrow yield range (72–92%) indicates the generality and re-
liability of the method.
With the encouraging results obtained for enone-enones 1,
the reaction of enone-enone 6a under the prototypical condi-
tions was considered, Table 2.[11] To our surprise, the cyclopro-
pa-fused indane 7a was isolated in 59% yield in 2.5:1 diaste-
reoselectivity. The structure and the relative stereochemistry of
the major diastereomer was assigned based on the x-ray crys-
tal structure obtained for 7a.[10] The formation of 7a can be ra-
tionalized by considering a Michael/Michael sequence on 6a,
initiated by the DOSM. The so formed zwitterion E then under-
goes a 1,3-proton shift and the resultant enolate F facilitates
the formation of 7a by eliminating DMSO. In this manner, a va-
riety of cyclopropa-fused indanes (7b–7j) were synthesized.[12]
Some of the salient features of this reaction are: (i) aryl ketones
possessing both electron-donating as well as electron-with-
drawing groups were well-tolerated (7b–7h), (ii) consistent re-
sults were obtained despite the presence of strong electron-
donating groups on the aryl backbone (7i and 7j), (iii) three
contiguous stereogenic centers, one of them being a quaterna-
ry carbon, and three new CÀC bonds formed in a single syn-
thetic operation.
Scheme 2. Highly selective formation of indeno-spirocyclopropane 2a
among several other possibilities.
substituted carbon and a tertiary carbon, we proceeded to in-
vestigate the scope and generality of the reaction, Table 1.
A diverse set of otherwise difficult-to-access indeno-spirocy-
clopropanes (2b–2k) were conveniently synthesized in a one-
step process, Table 1. The structures including the relative ste-
reochemistry of major isomers were assigned based on the x-
ray diffraction analysis of 2h.[10] The diastereoselectivity in each
case was determined by the analysis of the 1H-NMR of the
crude reaction mixture. It is interesting to note that the pres-
ence of strong electron-donating groups on the aromatic back-
bone as well as on the enone, which in general are undesired
for nucleophile-induced reactions, display no noticeable
impact, indeed the reactions are complete within 30 min (for
example, 2b–2e and 2g–2j). The reaction is also found to be
general with aliphatic substituents on the enone moiety (2k).
Having successfully established efficient methods for the
synthesis of new classes of cyclopropanoids such as 2 and 7,
we turned our attention to demonstrate the synthetic utility of
these compounds by considering a few elaborations.
With the presence of allylic-benzylic tertiary alcohol moiety
in 2, it was envisioned that its reaction under acidic conditions
could trigger cationic cyclizations. Accordingly, when 2a was
treated with a catalytic amount of PTSA at an elevated temper-
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Table 2. Scope for cyclopropa-fused indanes 7.[a]
Scheme 3. Unexpected formation of fluorenones 8 from indeno-spirocyclo-
propanes 2.
[a] Isolated yield after column chromatography. [b] The diastereomeric
ratio (d.r.) was obtained from the 1H NMR of the crude reaction mixture.
ature, an exclusive formation of the fluorenone 8a was realiz-
ed, Scheme 3. As indicated in G, a formal homo-Nazarov-type
cyclization of vinyl-cyclopropyl cationic system[13] generates
tetrahydrofluorenyl cation H, which undergoes deprotonation
followed by aromatization to provide the fluorenone 8a. In-
trigued by the unexpected outcome and having realized the
significance of fluorenones,[9,14] we verified the generality of
the reaction in few other cases (8b–8 f). All the reactions were
found to be extremely efficient and provided fluorenones in
excellent yields.
Scheme 4. Acid-catalyzed ring-opening of spirocyclopropanes 2 to inden-
ones 9, and the conversion of indenones 9 to fluorenones 8.
During the optimization of the reaction described in
Scheme 3 (conversion of 2 to 8), we made an interesting ob-
servation. When the reaction of 2a was performed in metha-
nol, the b-styryl indenone 9a was obtained in 73% yield,
Scheme 4. In this manner, few other indenones (9b and 9c)
were prepared. The mechanism of formation of 9 from 2 can
be conveniently explained as depicted in J.
Further, when 9b was treated with a Lewis acid such as
Sc(OTf)3, the fluorenone 8e was obtained in excellent yield,
Scheme 4. This transformation indicates that the PTSA-promot-
ed reaction of 2 in methanol could also have delivered fluore-
nones 8 in the presence of PTSA, but the reversibility that pre-
vails due to the strong nucleophilic solvent (methanol) has re-
sulted in the formation of only 9. It could indeed be the
reason why indenone 9b could be readily converted to fluore-
none 8e in a non-alcoholic solvent under mild (Lewis) acidic
conditions.
Next, a synthetic elaboration of cyclopropa-fused indanes 7
was also considered, Scheme 5. It was hypothesized that the
activation of cyclopropyl keto moiety in 7 might involve the
cleavage of the CÀC bond that experiences the most overlap-
ping with the carbonyl group and trigger further bond reor-
ganizations. As per the plan, when 7a was treated with a cata-
lytic amount of PTSA at elevated temperature, interestingly, 2-
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Scheme 5. Acid-catalyzed ring-opening/aromatization sequence of cyclopro-
pa-fused indanes 7 to 2-naphthaphenones 10.
naphthaphenone 10a was isolated in 92% yield. The other
naphthaphenones (10b and 10c) were obtained analogously
in excellent yields. As of the mechanism of the formation of
10, activation of the carbonyl group by the acid and a subse-
quent ring-opening of the cyclopropane leads to the formation
of the benzylic cation L, which converts to the dihydronaph-
thalene M. Aromaticity is achieved by the acid-catalyzed retro-
Michael reaction of M.
In conclusion, we presented serendipitous transformations
triggered by DOSM for the synthesis of otherwise difficult-to-
access cyclopropanoids. Furthermore, one-step synthetic elab-
orations were established to access privileged structures such
as fluorenones, indenones, and naphthaphenones with unusu-
al substitution patterns. The methods described herein are op-
erationally straightforward one-pot synthetic transformations,
which are mechanistically intriguing. Efforts to extend these
methods to new substrate classes are in progress and the de-
tails will be communicated in due course.
[8] 1a or its analogues are not known in the literature. See the Supporting
Information for details about the synthesis.
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[10] CCDC 1917783 (for 2h) and 1918037 (for 7a) contain the supplementa-
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charge by The Cambridge Crystallographic Data Centre.
Acknowledgements
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Information for details.
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IISER Mohali is thanked for funding, and for the NMR, mass
and departmental X-ray facilities. S.S.V.R. thanks DST for the
Swarnajayanti fellowship, and SERB for the Core Research
Grant (CRG/2018/000016). K.P., U.K.M. and D.M. thank IISER
Mohali for research fellowships.
Conflict of interest
[14] a) O. A. Akrawi, A. Khan, M. Hussain, H. H. Mohammed, A. Villinger, P.
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The authors declare no conflict of interest.
Manuscript received: August 9, 2019
Revised manuscript received: September 11, 2019
Keywords: Corey-Chaykovsky reagent
·
cyclopropanes
·
desymmetrization · rearrangements · sulphur ylides
Accepted manuscript online: September 12, 2019
Version of record online: && &&, 0000
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COMMUNICATION
Kaushalendra Patel, Uttam K. Mishra,
Dipto Mukhopadhyay,
S. S. V. Ramasastry*
&& – &&
Beyond the Corey–Chaykovsky
Reaction: Synthesis of Unusual
Cyclopropanoids via
Above and beyond: A set of desym-
metrization events triggered by the
Corey–Chaykovsky reagent are reported.
Thereby, efficient and straightforward
synthetic routes for indeno-spirocyclo-
propanes and cyclopropa-fused indanes
have been established. These structures
were transformed in one step to privi-
leged structures such as fluorenones, in-
denones, and naphthaphenones. The
methods described herein can have im-
plications in medicinal chemistry as well
as materials science.
Desymmetrization and Thereof
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