Regio- A nd Diastereoselective Copper-Catalyzed Carbometalation of Cyclopropenylsilanes

Article abstract of DOI:10.1021/acs.orglett.9b03531

We therein report a regio- A nd diastereoselective copper-catalyzed carbometalation of enantioenriched readily available cyclopropenylsilanes as a synthetic tool to access a large family of stereodefined fully-(hexa)-substituted cyclopropanes.

Full text of DOI:10.1021/acs.orglett.9b03531

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regio- and Diastereoselective Copper-Catalyzed Carbometalation of
Cyclopropenylsilanes
Yair Cohen and Ilan Marek*
Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Technion City, Haifa, 3200009, Israel
S
* Supporting Information
ABSTRACT: We therein report a regio- and diastereoselec-
tive copper-catalyzed carbometalation of enantioenriched
readily available cyclopropenylsilanes as a synthetic tool to
access a large family of stereodefined fully-(hexa)-substituted
cyclopropanes.
n the past few decades, we have witnessed tremendous
progress in controlling quaternary carbon stereocenters
Scheme 1. Selective Ring-Opening of Three-Membered
Rings
I
within acyclic molecular backbones.1 In this context, our group
has been particularly interested in the direct2 or remote3
stereocontrolled metal-induced ring fragmentation of poly-
substituted cyclopropanes as a synthetic tool to reach these
skeletons. For instance, ω-alkenyl cyclopropanes 13a,b or
alkenyl cyclopropyl alcohols 23c or 32 were excellent substrates
for Zr- or Pd-triggering cyclopropane ring-opening. These
remote functionalization reactions resulted in the efficient
production of acyclic molecular skeletons 4−6 possessing
several stereogenic centers including the expected quaternary
center as a unique diastereoisomer (path a, Scheme 1). To
further extend the complexity of our final products, we were
interested to develop strategies with the presence of either a
stereodefined quaternary allylsilane 7 or vinylsilane 8 for
potential subsequent transformations. However, at this point,
we were more concerned by the preparation of the required
starting materials (9 and 10) than that by the metal-mediated
ring-opening reactions per se. Indeed, we have already observed
that the selective ring-opening triggered by Pd-catalyzed Heck
reaction is rather insensitive to the nature of the substituents at
the quaternary stereocenter.2,3 On the other hand, the
straightforward preparation of fully substituted cyclopropanes
9 and 10 as a single diastereoisomer represented an interesting
synthetic challenge (path b, Scheme 1). The elaboration of
congested systems on a small ring adds a level of complexity as
exemplified by the difficulty to selectively construct contiguous
quaternary carbon stereocenters.1a−d,4 Two ambitious tasks
would entail the preparation of these cyclopropyl rings: first,
the preparation of these fully substituted three-membered rings
diastereoisomerically pure and enantiomerically enriched;
then, the use of a single and unique precursor for the synthesis
of 9 and 10 at will.
synthesized diastereo- and enantioselectively starting from a
common cyclopropene precursor 11 (Scheme 2).
Indeed, cyclopropenes 11 may be accessed through a Rh-
catalyzed decomposition of diazoesters in the presence of
terminal alkynes. Key to the success of our plan was that an
enantioselective version of this [2 + 1] cycloaddition process
Any new strategy answering all these criteria would certainly
be highly desirable and would represent a powerful addition to
the field of small ring chemistry.5 Based on our recently
acquired experience on the catalytic enantioselective 1,2-
bisalkylation of cyclopropenes5d,g and previous publications by
Nakamora, Fox, and Lautens,6 we surmised that fully
substituted cyclopropyl carbinols 9 and 10 could be
Received: October 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03531
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Straightforward Preparation of the Starting
Materials
Scheme 3. Copper-Catalyzed Carbomagnesiation of
Cyclopropenylsilanes 11a−j
has been reported (Scheme 2).7 Cyclopropenyl esters were
thus engaged in a subsequent metalation−silylation sequence8
before reduction to lead to the unique required precursors 11.
Based on the stabilization of carbanion α to silicon,9 we were
confident that the regioselectivity of the carbometalation
should be controlled; the diastereoselectivity should result
from a chelated intermediate (Scheme 2). Although the
chelated nature of the metalated cyclopropyl species A should
also control the configurational stability of the resulting
carbanion, α-metalated silylated species are subject to
epimerization into thermodynamically more stable entities.10
Only complete control of the configurational stability could
lead to a single diastereoisomer. Based on these assumptions,
we performed the copper-catalyzed carbomagnesiation reac-
tion of 11a in Et2O at room temperature. We were delighted to
observe a smooth and completely regio- and diastereoselective
carbometalation. The corresponding product 12a was isolated
as a single regio- and diastereoisomer after hydrolysis in less
than 1 h as summarized in Scheme 3. At the outset, a scale-up
experiment established our confidence in the robustness of the
current method, as 12a could be prepared on a 1.5 g scale.
Scaling up this reaction showed no loss of regio- and
diastereoselectivity. Despite the steric hindrance around the
tertiary organometallic species, we were pleased to see that the
intermolecular reaction with an electrophile was possible. The
products of electrophile incorporation were obtained as a
single diastereoisomer in moderate to good yields (12b and
12c, Scheme 3). The relative configuration was established by
X-ray analysis of 12c (CCDC 1942906; see Supporting
Information) and confirmed our assumptions regarding the
selectivity of the reaction. The configuration of all other
products was assigned by analogy. It should be noted that
aldehyde could also be added but without any diastereose-
lectivity at the carbinol center (not shown in Scheme 3). A
large variety of primary alkyl and allyl Grignard reagents could
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DOI: 10.1021/acs.orglett.9b03531
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Letter
be added on the cyclopropenyl ring with similar yields and
selectivities (12c−m, Scheme 3); however, secondary Grignard
reagents failed to react most probably for steric reasons
(Scheme 3, bottom).
Products possessing a remote double bond for subsequent
Pd-catalyzed isomerization could also be easily achieved either
through the double bond incorporated as a nucleophilic
species (12m, Scheme 3) or as electrophiles (12b,e,k,y,
Scheme 3), or both (12i, Scheme 3). The nature of the
substituents on the silicon atom could also be varied (PhMe2Si,
Me3Si, PhCH2Me2Si, Me(CH2)3Si, Me2HSi) without again
changing the overall outcome of the reaction (12a and 12o−z,
Scheme 3).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03531.
■
S
Experimental procedures, characterization data for all
new compounds, and crystallographic data (PDF)
Accession Codes
CCDC 1942906 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,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
However, the bulky tBuMe2Si group on the cyclopropene
(11i, Scheme 3, bottom) does not allow the carbometalation
to proceed.
Finally, we were interested to apply our strategy to the
preparation of fully substituted cyclopropanes, and although
11j could not lead to the addition product (Scheme 3,
bottom), 11f−h possessing less sterically hindered substituents
on the silicon could lead to the expected products. For
instance, when MeMgBr was added to an ethereal solution of
11f,g,h, in the presence of CuI (10 mol %), the carbometalated
products 12w,x, and z were respectively obtained in good
yields as a unique diastereoisomer. Addition of allyl bromide to
the resulting cyclopropylmagnesium bromide remarkably
provides the fully substituted cyclopropane 12y. It should be
emphasized that, in all examples investigated in this study, the
corresponding α-silylated cyclopropylmagnesium species
showed remarkable configurational stability and no epimeriza-
tion was observed. Using this strategy, enantiomerically
enriched fully substituted cyclopropane can therefore be easily
prepared in relatively a few chemical steps as described in
Scheme 4. The RhII-catalyzed enantioselective addition of ethyl
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chilanm@technion.ac.il.
ORCID
Ilan Marek: 0000-0001-9154-2320
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project has received funding from the Ministry of Science
and Technology (Grant No. 2023994) and from the Israel
Science Foundation administrated by the Israel Academy of
Sciences and Humanities (Grant No. 330/17).
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