Nickel-Catalyzed Cross-Coupling of Vinyl Dioxanones to Form Enantiomerically Enriched Cyclopropanes

Article abstract of DOI:10.1021/jacs.7b03371

Under the conditions of nickel(0) catalysis, enantiomerically enriched vinyl dioxanones engage boroxines or B₂(pin)₂ in stereospecific cross-coupling to form diverse tetrasubstituted cyclopropanes bearing all-carbon quaternary stereocenters. The collective data corroborate a mechanism involving nickel(0)-mediated benzylic oxidative addition with inversion of stereochemistry followed by reversible olefin insertion to form a (cyclopropylcarbinyl)nickel complex, which upon reductive elimination releases the cyclopropane.

Full text of DOI:10.1021/jacs.7b03371

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Cross-Coupling of Vinyl Dioxanones to Form
Enantiomerically Enriched Cyclopropanes
Yi-An Guo, Tao Liang, Seung Wook Kim, Hongde Xiao, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
Scheme 1. Synthesis of Enantiomerically Enriched
Cyclopropanes from Vinyl Dioxanones by Way of Transient
(Cyclopropylcarbinyl)nickel Species
ABSTRACT: Under the conditions of nickel(0) catalysis,
enantiomerically enriched vinyl dioxanones engage borox-
ines or B2(pin)2 in stereospecific cross-coupling to form
diverse tetrasubstituted cyclopropanes bearing all-carbon
quaternary stereocenters. The collective data corroborate a
mechanism involving nickel(0)-mediated benzylic oxida-
tive addition with inversion of stereochemistry followed by
reversible olefin insertion to form a (cyclopropylcarbinyl)-
nickel complex, which upon reductive elimination releases
the cyclopropane.
yclopropanes appear as substructures across diverse
1
Csecondary metabolites
and are frequently found in
(200 mol%) in toluene (0.1 M) at 60 °C. To our delight,
cyclopropane 3a was formed in 36% yield as a single
diastereomer. Conversion was found to be sensitive to
concentration and temperature. At 45 °C under otherwise
identical conditions, a 53% yield of cyclopropane 3a was
obtained. Using the nickel catalyst modified by PCy2Ph (20
mol%), cyclopropane 3a was obtained in 77% yield. Finally, at a
slightly higher concentration (toluene, 0.2 M), an 85% yield of
cyclopropane 3a was achieved (eq 1). Stereospecificity was
corroborated by chiral stationary phase HPLC analysis of
cyclopropane 3a. The relative stereochemistry of cyclopropane
3a was confirmed by single crystal X-ray diffraction analysis. p-
Tolylboronic acid also delivers cyclopropane 3a (eq 1), but in a
slightly lower yield. Application of these optimal conditions to
commercial medicines, agrochemicals and fragrances.2 Hence,
the development of methods for cyclopropane formation
represents a persistent challenge in chemical research.3
Among the most effective methods for the preparation of
enantiomerically enriched cyclopropanes is the reaction of
olefins with metal carbenoids.3 Here, we report a strategy for
the asymmetric synthesis of cyclopropanes under the
conditions of metal-catalyzed cross-coupling. Specifically,
nickel(0) catalysts4,5 react with enantiomerically enriched 4-
aryl-5-vinyl-1,3-dioxanones to form (cyclopropylcarbinyl)-
nickel(II) species, which, in the presence of organoboron
reagents or B2(pin)2, deliver cyclopropanes in a stereospecific
manner. Thus, the enantioselective synthesis of tetra-
substituted cyclopropanes bearing all-carbon quaternary stereo-
centers is achieved (Scheme 1).
In connection with ongoing investigations into the formation
of C−C bonds via hydrogenation and transfer hydrogenation,6
we recently reported an iridium-catalyzed coupling of primary
alcohols with isoprene oxide to form products of tert-
(hydroxy)-prenylation, a byproduct-free transformation that
occurs with exceptional control of anti-diastereo- and enantio-
selectivity.7 It was posited that cyclic carbonates derived from
these reaction products should be predisposed toward cyclo-
propane formation under cross-coupling conditions, as geminal
substitution of the neopentyl glycol precludes competing β-
hydride elimination of the σ-benzylmetal intermediate and
should conformationally bias the system toward olefin
insertion8 via the Thorpe−Ingold effect.9 However, the facility
of conventional benzylic cross-coupling rendered the feasibility
of the proposed cyclopropane formation uncertain.10
unsubstituted methyl carbonate model-1a did not result in
cyclopropane formation; rather, the indicated product obtained
through β-hydride elimination of the σ-benzyl intermediate was
In an initial experiment, vinyl dioxanone 1a was exposed to
the catalyst derived from Ni(cod)2 (10 mol%) and PCy3 (20
mol%) in the presence of tri(p-tolyl)boroxine 2a and K3PO4
Received: April 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b03371
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Journal of the American Chemical Society
Communication
Table 1. Stereospecific Nickel-Catalyzed Cross-Coupling of
Vinyl Dioxanones 1a−1i with Tri(p-tolyl)boroxine 2a to
Table 2. Stereospecific Nickel-Catalyzed Cross-Coupling of
Vinyl Dioxanones 1a or 1h with Boroxines 2b−2d to Form
a
a
Form Cyclopropanes 3a−3i
Cyclopropanes 3j−3o
a
Yields of material isolated by silica gel chromatography. All reactions
were conducted using enantiomerically enriched starting materials. See
Supporting Information for further experimental details.
Table 3. Stereospecific Nickel-Catalyzed Cross-Coupling of
Vinyl Dioxanones 1a, 1b, 1d, 1f and 1h with B2(pin)2 to
a
Form Cyclopropanes 3p−3t
a
Yields of material isolated by silica gel chromatography. All reactions
were conducted using enantiomerically enriched starting materials. See
Supporting Information for further experimental details.
formed (eq 2). Cyclic carbonate 1a reacted more efficiently
than related acyclic carbonates, suggesting the internal alkoxide
generated upon ionization−decarboxylation facilitates group
transfer from boron to nickel through an internal boron ate-
complex.
Optimal conditions utilizing tri(p-tolyl)boroxine 2a were
applied to a structurally diverse set of enantiomerically enriched
vinyl dioxanones 1a−1i (Table 1). Vinyl dioxanones bearing a
variety of substituted aromatic (1a−1d) and heteroaromatic
(1e−1i) rings were converted to cyclopropanes 3a−3i in good
yield with complete levels of diastereoselectivity. Relative
stereochemistry was assigned in analogy to that determined
for 3a. Although the preexisting non-epimerizable quaternary
stereocenter serves as an “internal standard,” stereospecificity
was spot-checked for compounds 3a, 3b, 3d and 3h. Notably,
unlike prior work involving nickel-catalyzed benzylic sub-
stitution, extended aromatic systems are not required.11
Standard conditions also were applied to the coupling of
vinyl dioxanones 1a and 1h with boroxines 2b−2d, which
incorporate p-CF3-phenyl, p-methoxyphenyl and (E)-styryl
moieties, respectively (Table 2). The resulting cyclopropanes
3j−3o were formed in good yield in a completely stereo-
selective fashion. The coupling of vinyl dioxanones 1a, 1b, 1d,
1f and 1f with B2(pin)2 under standard conditions delivers the
cyclopropylcarbinyl boronates 3p−3t in good yield with
complete stereocontrol (Table 3).12 To briefly illustrate the
a
Yields of material isolated by silica gel chromatography. All reactions
were conducted using enantiomerically enriched starting materials. See
Supporting Information for further experimental details.
utility of coupling products, the neopentyl alcohol 3a was
subjected to Jones oxidation to provide the cyclopropyl
carboxylic acid 4a in good yield (eq 3). Additionally, the
cyclopropylcarbinyl alcohol 3h was exposed to Mitsunobu
conditions in the presence of phthalimide to furnish 4b in
excellent yield (eq 4).
B
DOI: 10.1021/jacs.7b03371
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Journal of the American Chemical Society
Communication
samples; single crystal X-ray diffraction data for 3a
(PDF)
Crystallographic data for 3a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*mkrische@mail.utexas.edu
ORCID
Michael J. Krische: 0000-0001-8418-9709
Notes
The authors declare no competing financial interest.
a
Scheme 2. General Catalytic Mechanism
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research.
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A general mechanism for stereospecific cyclopropane
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03371.
Experimental procedures and spectral data; HPLC traces
corresponding to racemic and enantiomerically enriched
C
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D
DOI: 10.1021/jacs.7b03371
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