Regio- and Diastereoselective Copper-Catalyzed Carbomagnesiation for the Synthesis of Penta- and Hexa-Substituted Cyclopropanes

Article abstract of DOI:10.1002/anie.202102509

Despite the highly strained nature of cyclopropanes possessing three vicinal quaternary carbon stereocenters, the regio- and diastereoselective copper-catalyzed carbomagnesiation reaction of cyclopropenes provides an easy and efficient access to these novel persubstituted cyclopropyl cores with a complete regio- and diastereoselectivity.

Full text of DOI:10.1002/anie.202102509

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11804–11808
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Copper Catalysis Very Important Paper
Regio- and Diastereoselective Copper-Catalyzed Carbomagnesiation
for the Synthesis of Penta- and Hexa-Substituted Cyclopropanes
Yair Cohen, Andrꢀ U. Augustin, Laura Levy, Peter G. Jones, Daniel B. Werz, and Ilan Marek*
Abstract: Despite the highly strained nature of cyclopropanes
possessing three vicinal quaternary carbon stereocenters, the
regio- and diastereoselective copper-catalyzed carbomagnesia-
tion reaction of cyclopropenes provides an easy and efficient
access to these novel persubstituted cyclopropyl cores with
a complete regio- and diastereoselectivity.
ment of new strategies allowing the preparation of vicinal
stereocenters within acyclic systems by selective ring-opening
of polysubstituted cyclopropanes[5] (see Scheme 1b for
a recent representative example).[6] Nevertheless, none of
our approaches reported so far allowed the formation of
vicinal quaternary stereocenters.[7] One of the reasons was the
lack of methods to selectively prepare persubstituted cyclo-
propanes 1 as unique diastereomers. Despite a few reports of
the synthesis of polysubstituted cyclopropanes,[8] persubsti-
tuted analogs were still inaccessible. Such stereodefined
persubstituted strained rings are potential substrates for
subsequent selective carbon-carbon bond cleavage (Sche-
me 1c).[5] From the onset, it was clear that the selective
formation of three vicinal quaternary carbon stereocenters in
a cyclopropane should generate much torsional strain, as all
bonds are eclipsed.[9] Based on these combined torsional and
ring strain constraints, we initially restricted our efforts to the
selective formation of persubstituted silyl cyclopropanes 2,
hoping that the longer carbon-silicon bond would allow an
easier preparation.[10] In addition, the formation of 2 might
serve as a source of vicinal carbon-persubstituted cyclo-
propanes after subsequent Hiyama-type cross-coupling
reactions.[11] Although we were pleased to report the prepa-
ration of compounds 2 as single diastereomers,[12] all our
attempts to engage them in cross-coupling reactions were
unsuccessful.
M
odern stereoselective synthesis relies on the efficient and
straightforward development of strategies that allow the rapid
preparation of complex molecular architectures from simple
starting materials.[1] In the last decade, numerous approaches
have been reported in the literature to construct aliphatic
chains possessing vicinal stereocenters[2] but the synthetic
difficulty drastically rises on increasing the degree of sub-
stitution. For instance, the diastereoselective formation of
three vicinal tertiary stereocenters is nowadays moderately
well established,[3] but the equivalent formation of two or
three vicinal quaternary carbon stereocenters still represents
an important chemical challenge (Scheme 1a).[4] In recent
years, we have been particularly interested in the develop-
As we were seeking a diastereoselective access to
persubstituted cyclopropanes possessing only carbon-based
side chains, we then reconsidered the copper-catalyzed
carbomagnesiation reaction of persubstituted cyclopropenes
as a potential method.[13]
To control the regioselectivity of the carbometallation
reaction, we hypothesized that the presence of a p-hybridized
carbon center linked to the sp2 carbon center of the cyclo-
propene should not only increase the reactivity of the addition
reaction of the organometallic species but also control the
regioselectivity. The diastereoselectivity would then be
steered, in non-polar solvents, by the chelation of the
organometallic species by the ester (Scheme 2).[14] We started
our investigation by preparing various arylated cyclopropenes
3a–m, easily accessible by the well reported Rh-catalyzed
decomposition of diazoacetate with arylated alkynes.[15] The
copper-catalyzed carbomagnesiation of 3a then proceeded
smoothly at À258C to yield 4a in excellent yield as a single
diastereomer. As expected, the preferred regioisomer origi-
nates from the formation of the stabilized benzylic organo-
metallic intermediate; importantly, the formation of a single
diastereomer indicates that the in situ formed benzyl cyclo-
propyl magnesium species is configurationally stable under
the experimental condition. As the copper-catalyzed carbo-
Scheme 1. Formation of vicinal stereocenters and persubstituted cyclo-
propanes.
[*] Y. Cohen, Dr. A. U. Augustin, L. Levy, Prof. Dr. I. Marek
Schulich Faculty of Chemistry, Technion—Israel Institute of Tech-
nology
Technion City, Haifa, 3200009 (Israel)
E-mail: chilanm@technion.ac.il
Homepage: https://ilanmarek.technion.ac.il
Prof. Dr. P. G. Jones
Technische Universitꢀt Braunschweig, Institute of Inorganic and
Analytical Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
Prof. Dr. D. B. Werz
Technische Universitꢀt Braunschweig, Institute of Organic Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102509.
11804
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example, to provide 4b, possessing two vicinal quaternary
carbon centers with similar diastereoselectivity. The comple-
mentary diastereomeric pair was also prepared, by formally
exchanging the alkyl substituent at the cyclopropenyl core
and the alkyl group of the Grignard reagent (compare 4a and
4b with 4c and 4d, Scheme 2), formed as a single diastereo-
mer in all cases. Scaling up the reaction to gram scale did not
affect the overall outcome of the reaction (4e, Scheme 2). The
nature of the alkyl group of the cyclopropenes and also of the
Grignard reagent can be varied (4l–o, Scheme 2). Changing
the electronic properties of the aromatic ring from electron-
rich (4 f–p, Scheme 2) via electron-neutral (4q) to electron-
poor (4r and 4s, Scheme 2) altered neither the reaction nor
the selectivity. In addition, a few heteroaromatics, such as
ferrocene or thiophene, as aromatic groups also allowed the
transformation and delivered the desired products with
similarly high regio- and diastereomeric ratios (4t–v,
Scheme 2). It should also be noted that the copper-catalyzed
carbomagnesiation proceeds fast enough at the strained
double bond, while functional groups such as ester or nitriles
remain intact. However, secondary Grignard reagents could
not be satisfactorily added, and the presence of secondary
alkyl side chains on the cyclopropenes drastically decreases
the yield of the transformation. Finally, when the persubsti-
tuted cyclopropenes 3l and 3m were used as starting
materials, the transformation proceeded similarly to provide,
after reaction of the resulting cyclopropyl magnesium inter-
mediate with allyl bromide, persubstituted cyclopropanes 4w
and 4x as unique diastereomers. These promising results
confirm that our proposed strategy does indeed allow the
formation of three vicinal quaternary carbon stereocenters at
all three carbons of the three-membered ring.
Having established the protocol for a regio- and diaste-
reoselective carbometallation of polysubstituted cyclopro-
penes possessing an aromatic group, we then turned our
attention to the reactivity of alkenyl cyclopropenes 5 (for all
preparative details, see Supporting Information) as this
should provide a new approach to the important molecular
motif of polysubstituted alkenyl cyclopropanes 6.[17] Although
the carbometallation of alkenyl-cyclopropenyl esters was not
very conclusive, we were able to observe that the copper-
catalyzed carbomagnesiation of alkenyl cyclopropyl carbinols
5a–g proceeded smoothly in only 2 h at room temperature to
provide the corresponding alkenyl-cyclopropanes 6a–q as
single diastereomers.
The products of the copper-catalyzed carbomagnesiation
of 5 were obtained with a wide variety of Grignard reagents.
Primary (Scheme 3, 6a and 6b), secondary (Scheme 3, 6c),
allyl (Scheme 3, 6d), benzyl (Scheme 3, 6e) and aryl
(Scheme 3, 6 f) Grignard nucleophiles were all successfully
added, with good yields and selectivities. Tertiary alkyl
Grignards, however, failed to react with the corresponding
alkenyl cyclopropyl carbinol 5a. The regioselectivity and
relative configuration were confirmed by X-ray analysis of
6 f,[18] and the configurations of all other products were
assigned by analogy. The in situ formed cyclopropyl Grignard
intermediate could then react with various electrophiles (such
as allyl and propargyl bromide, CO2 or elemental selenium
followed by MeI) to provide the allylated, allenylated, lactone
Scheme 2. Copper-catalyzed carbomagnesiation of aryl-substituted
cyclopropenyl esters.
magnesiation is a syn-addition across the double bond,[13] the
relative configuration was easily established by determining
the coupling constant of the two hydrogens of 4a (J =
5.97 Hz).[16] Cyclopropyl copper reacts smoothly with an
electrophile, for example, allyl bromide as representative
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formation of alkynyl-cyclopropanes 8. However, the selectiv-
ity of the carbometallation reaction could become a problem,
because the carbocupration of alkynes is a well-known
reaction and usually proceeds at similar temperature.[19]
We did indeed observe that the copper-catalyzed carbo-
magnesiation of alkynyl-cyclopropenyl carbinol 7a was
completely stereo- and regioselective, providing, at room
temperature, the corresponding alkynyl cyclopropane carbi-
nol 8a as a single product with an outstanding diastereose-
lectivity (Scheme 4). Various Grignard nucleophiles were
added, such as primary (Scheme 4, 8a–c) and secondary
(Scheme 4, 8d and 8e) alkyls, with similar efficiency. The
intermediate cyclopropyl Grignard reacts efficiently with
electrophiles such as allyl bromide or dimethylformamide to
afford 8g and 8h as single diastereomers (Scheme 4). In the
latter case, a single lactol is formed because of steric
constraints in the final product. The regioselectivity and
relative configuration was confirmed by X-ray analysis of 8h
(Scheme 4).[20] Finally, when the reaction was performed on
the persubstituted alkynyl-cyclopropenyl carbinol 7c, the
resulting alkynyl persubstituted cyclopropane derivative 8i
was obtained in 44% yield as a unique diastereomer, together
with its allenyl counterpart, the latter resulting from equili-
bration of the propargyl Grignard intermediate with the
allenylmagnesium bromide intermediate (see Supporting
Information).
Scheme 3. Copper-catalyzed carbomagnesiation of alkenyl-substituted
cyclopropenyl carbinols.
or SeMe products, respectively, in good yields and as unique
diastereomers (Scheme 3, 6g–j). In addition, various substi-
tution patterns of the alkenyl fragments are compatible with
our experimental conditions, as the initial stereochemistry of
the external double bond is preserved in the products
(Scheme 3, 6k–p). Finally, this approach also allows the
preparation of persubstituted alkenyl cyclopropane 6q in
66% yield as a unique diastereomer, underlining, once again,
the power of this strategy for the formation of fully (hexa)-
substituted alkenyl cyclopropanes as a single isomer.
Having successfully synthesized stereodefined polysubsti-
tuted aryl- and alkenyl-cyclopropanes, we wondered whether
we could extend this concept of carbometallation to the
Scheme 4. Copper-catalyzed carbomagnesiation of alkynyl-substituted
cyclopropenyl carbinols.
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J. Huang, K. Guo, J. Gong, Z. Yang, Org. Lett. 2018, 20, 1857 –
In conclusion, we have developed, for the first time, an
efficient and broadly applicable approach to the synthesis of
polysubstituted and stereodefined cyclopropyl rings possess-
ing vicinal quaternary carbon stereocenters. Despite the
highly strained nature of these ring systems, the regio- and
diastereoselective copper-catalyzed carbomagnesiation reac-
tion of persubstituted cyclopropenes represents an excellent
access to persubstituted cyclopropane derivatives as single
diastereomers. We are currently investigating the selective
ring-opening of these molecular backbones as a new route to
vicinal quaternary stereocenters in acyclic systems.
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This project has received funding from the Israel Science
Foundation (grant N8 330/17) and by the Ministry of Science
and Technology (grant 2023994). I.M. is holder of the Sir
Michael and Lady Sobell Academic Chair.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: carbon quaternary stereocenters ·
copper-catalyzed carbomagnesiation · diastereoselectivity ·
persubstituted cyclopropanes
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[18] The relative stereochemistry of 6 f was determined by X-ray
structure analysis. Deposition Number 2050906 (for 6f) contains
the supplementary crystallographic data for this paper. These
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Crystallographic Data Centre and Fachinformationszentrum
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[20] The relative stereochemistry of 8h was determined by X-ray
structure analysis. Deposition Number 2026400 (for 8h) contains
the supplementary crystallographic data for this paper. These
data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
Manuscript received: February 18, 2021
Accepted manuscript online: March 20, 2021
Version of record online: April 14, 2021
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