Copper-Catalyzed Enantio- and Diastereoselective Addition of Silicon Nucleophiles to 3,3-Disubstituted Cyclopropenes

Article abstract of DOI:10.1002/chem.201904272

A highly stereocontrolled syn-addition of silicon nucleophiles across cyclopropenes with two different geminal substituents at C3 is reported. Diastereomeric ratios are excellent throughout (d.r.≥98:2) and enantiomeric excesses usually higher than 90 %, even reaching 99 %. This copper-catalyzed C?Si bond formation closes the gap of the direct synthesis of α-chiral cyclopropylsilanes.

Full text of DOI:10.1002/chem.201904272

DOI: 10.1002/chem.201904272
Communication
&
Asymmetric Catalysis
Copper-Catalyzed Enantio- and Diastereoselective Addition of
Silicon Nucleophiles to 3,3-Disubstituted Cyclopropenes
Liangliang Zhang and Martin Oestreich*[a]
ors is a prominent example (Scheme 1, top).[3] CuI-NHC[4]
Abstract: A highly stereocontrolled syn-addition of silicon
(NHC=N-heterocyclic carbene) as well as CuII-bipyridine[5] com-
nucleophiles across cyclopropenes with two different
plexes do promote these reactions with high fidelity. A related
geminal substituents at C3 is reported. Diastereomeric
enantioselective addition to strained alkenes, such as cyclopro-
ratios are excellent throughout (d.r.ꢀ98:2) and enantio-
meric excesses usually higher than 90%, even reaching
99%. This copper-catalyzed CꢁSi bond formation closes
the gap of the direct synthesis of a-chiral cyclopropylsi-
lanes.
penes, is not known to date (Scheme 1, bottom).[6,7] The result-
ing silylated cyclopropanes are versatile building blocks in or-
ganic synthesis,[8] yet is their direct preparation by CꢁSi bond
formation at an existing cyclopropane skeleton rare.[9–12] Ge-
vorgyan and co-workers developed palladium- and platinum-
catalyzed diastereoselective insertion reactions of cyclopro-
penes into SiꢁSn and SiꢁH bonds, respectively.[9] Established
methods therefore start with silicon-containing substrates,[13]
and a common method is the cyclopropanation of vinylsi-
lanes.[14] A fascinating approach by Ito, Sawamura, and co-
workers involving a regioselective copper-catalyzed borylation
of vinylsilanes containing an allylic leaving group by a 3-exo-tet
ring closure stands out.[15] The idea to access silylated cyclopro-
panes from cyclopropenes was inspired by Marek’s[16] and, in
particular, Tortosa’s[17] work. Tortosa and co-workers have ac-
complished a copper-catalyzed desymmetrization of cyclopro-
penes by borylation.[17] We report here a highly stereoselective
silylation of cyclopropenes without the aid of a directing
group (Scheme 1, bottom).[18]
Silylboronic acid esters are highly useful silicon pronucleo-
philes which have had significant impact on synthetic silicon
chemistry.[1] A broad variety of enantioselective CꢁSi bond for-
mations can be achieved by using these Si–B reagents,[2] and
their copper-catalyzed addition across a,b-unsaturated accept-
We started our investigation by reacting 3-phenyl-3-methyl-
cyclopropene (1a) with Me2PhSiBpin (2a)[19a] (1.5 equiv) in the
presence of Cu(CH3CN)4PF6 as the copper precatalyst in THF at
08C (Table 1). NaOtBu (0.5 equiv) was used as an alkoxide base
and MeOH (3.0 equiv) as a proton source (see the Supporting
Information for the complete set of optimization data). With
no ancillary ligand, almost no conversion of the cyclopropene
was seen (<5%, entry 1). This situation changed completely in
the presence of bidentate phosphine ligands. Excellent diaste-
reoselectivity was obtained with binap ligands L1–L3, and the
enantioinduction increased with the steric demand of the PAr2
groups (entries 2–4). This high level of stereocontrol could not
be further improved by changing the solvent to toluene or by
lowering the reaction temperature to ꢁ208C (entries 5 and 6).
A similar outcome was found with segphos ligands L4 and L5
(entries 7 and 8), and we eventually continued with L5, which
led to the formation of the silylated cyclopropane 3aa in good
yield with a diastereomeric ratio (d.r.) ꢀ98:2 and an enantio-
meric excess (ee) of 97%.
Scheme 1. Copper-catalyzed enantioselective addition of SiꢁB reagents
across activated alkenes. EWG=electron-withdrawing group.
R3Si=triorganosilyl.
[a] L. Zhang, Prof. Dr. M. Oestreich
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201904272.
We then examined the substitution pattern of the cyclopro-
pene (1a–s, Scheme 2). Yields were generally good, and the
level of enantioselection was consistently high. 3-Arylated cy-
clopropenes bearing a substituent in the para or/and meta po-
sition(s) were tested, and it was found that the X group did
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Table 1. Selected examples of the optimization reactions.[a]
Entry
Copper/Ligand
Yield [%]
d.r.[b]
ee [%][c]
1
2
3
4
5[d]
6[e]
7
Cu(CH3CN)4PF6
n.d.
71
73
73
81
74
73
74
–
–
Cu(CH3CN)4PF6/L1
Cu(CH3CN)4PF6/L2
Cu(CH3CN)4PF6/L3
Cu(CH3CN)4PF6/L3
Cu(CH3CN)4PF6/L3
Cu(CH3CN)4PF6/L4
Cu(CH3CN)4PF6/L5
ꢀ98:2
ꢀ98:2
ꢀ98:2
96:4
ꢀ98:2
97:3
80
90
96
84
92
92
97
8
ꢀ98:2
[a] All reactions were performed on a 0.20 mmol scale with the isolated
yield determined after flash chromatography on silica gel. [b] Determined
by 1H NMR analysis. [c] Determined by HPLC analysis on a chiral station-
ary phase. [d] Toluene instead of THF. [e] Run at ꢁ208C. n.d.=not deter-
mined. binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl. sephos=
5,5’-bis(diphenylphosphanyl)-4,4’-bi-1,3-benzodioxol.
not exert any electronic effect on either yield or stereoselectiv-
ity (1a–j!3aa–ja); the silylated cyclopropanes were all isolat-
ed as single diastereomers (d.r.ꢀ98:2). Likewise, a thien-2-yl as
well as naphthyl groups were tolerated (1k–m!3ka–ma).
Bulkier alkyl groups instead of the methyl group at C3 of the
cyclopropene had no influence on the enantiofacial selectivity,
but a little on diastereoselectivity; yields were lower with in-
creasing steric demand (1n–p!3na–pa). These results imply
that the diastereoselectivity is affected by the steric discrimina-
tion of geminal substituents (Aryl/Me vs. Ph/Alkyl). This obser-
vation was also made when replacing the phenyl by a benzyl
group (Ph/Me versus Bn/Me); the diastereomeric ratio dropped
from ꢀ98:2 to 85:15 (1q!3qa). In turn, a spiro derivative re-
acted with high diastereoselectivity but in low yield (1r!3ra).
For completion, the 3,3-diphenyl-substituted cyclopropene af-
forded the silylated cyclopropane in good yield and with high
ee (1s!3sa).
Scheme 2. Scope I: Variation of the cyclopropene.[a–c] [a] All reactions were
performed on a 0.20 mmol scale with the isolated yield determined after
flash chromatography on silica gel. [b] Diastereomeric ratios determined by
1H NMR analysis. [c] Enantiomeric excesses determined by HPLC analysis on
chiral stationary phases.
the Supporting Information). tBu(Me)PhSiBpin (2c) did yield
trace amounts of 3ac, and the diastereomeric ratio of 62:38 is
due to the stereogenicity at the silicon atom; no formation of
3ad was seen with Ph3SiBpin (2d). Trialkylsubstituted SiꢁB re-
agents 2e–g,[19b] even with a tBu group attached to the silicon
atom, reacted in mediocre yields. Enantio- and diastereocontrol
were excellent though.
Running the reaction 1g!3ga on a tenfold scale was nei-
ther detrimental to yield nor stereoselectivity (Scheme 4, top).
From this sample, single crystals suitable for X-ray diffraction
were obtained.[20] The absolute and relative configuration of
3ga was found to be R,S. The stereochemistry of the other
silylated cyclopropanes was assigned accordingly. Also, oxida-
tive degradation of the CꢁSi bond in (R,S)-3ga employing the
Tamao–Fleming protocol was attempted.[21] This transformation
is usually low yielding due to competing ring opening.[22] The
We next probed the transfer of different silyl groups from si-
lylboronic acid esters R3SiBpin 2b–g[19] to model compound 1a
(Scheme 3). It became quickly clear at the size of the silyl
group substantially influences the yield. MePh2SiBpin (2b) fur-
nished acceptable 65% yield (1a!3ab). The enantiomeric
excess was 97% ee and was even higher with another substitu-
ent in the para position (not shown; additional substrates in
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stereo- (d.r.ꢀ98:2) and enantioselectivity (96% ee). The syn-ad-
dition of the silylcopper intermediate to the cyclopropene was
confirmed by 2D NOE measurements between the ring proton
in 3aa-d2 and the methyl groups on the ring and the silicon
atom (see the Supporting Information for details). To gain fur-
ther mechanistic insight, an additional deuterium-labeling ex-
periment was performed (1a!3aa-d1, Scheme 4, bottom).
MeOH was replaced by CD3OD as an exogenous proton
source, and 3aa-d1 was isolated in 71% yield and 82% deuteri-
um incorporation. This corroborates that the proton originates
from the alcohol additives.
Based on these observations and literature precedence,[1,2]
we propose the catalytic cycle shown in Scheme 5. The silicon
nucleophile (=silylcopper complex) is generated by transmeta-
lation of the SiꢁB linkage at the CuꢁO bond of the in situ
Scheme 3. Scope II: Variation of silylboronic acid ester.[a–c] [a] All reactions
were performed on a 0.20 mmol scale with the isolated yield determined
after flash chromatography on silica gel. [b] Diastereomeric ratios deter-
1
mined by H NMR analysis. [c] Enantiomeric excesses determined by HPLC
analysis on chiral stationary phases. [d] Diastereomeric ratio determined by
GLC and GC-MS analysis. n.r.=no reaction.
Scheme 5. Proposed mechanism.
formed copper alkoxide. Cyclopropene 1 then coordinates to
copper to form a p-complex followed by syn-addition of the
CuꢁSi bond across the strained alkene.[24] Diastereofacial selec-
tivity is likely controlled by sterics with the bond formation oc-
curring on the side of smaller R2 (usually methyl) and opposite
to larger R1 (usually aryl). Protonation of the CuꢁC bond with
MeOH releases the cyclopropane 3 and closes the catalytic
cycle.
Scheme 4. Determination of the absolute configuration (top) and deuteri-
um-labeling experiments (bottom). [a] Deuteration grade estimated by NMR
analysis.
corresponding alcohol was obtained in 6% yield with d.r.ꢀ
98:2 and 92% ee under retention of the configuration (see the
Supporting Information for details).
In summary, we described here the first example of a highly
enantio- and diastereoselective addition of silylboronic acid
esters across a broad range of prochiral 3,3-disubstituted cyclo-
propenes. It is a syn-addition that does not rely on a coordinat-
ing/directing group. The silyl-substituted cyclopropanes were
obtained in good yields and with superb stereoselectivity. Ex-
pansion of this methodology is currently underway in our lab-
oratory.
To learn about the stereochemical course of the copper-cata-
lyzed addition of the silicon nucleophile across the CꢁC
double bond, we subjected dideuterated cyclopropene 1a-
[23]
2
d2 (>99% H) to the standard setup (Scheme 4, bottom). Cy-
clopropane 3aa-d2 did form in 72% yield with excellent dia-
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Acknowledgements
L.Z. thanks the China Scholarship Council for a predoctoral fel-
lowship (2017–2021), and M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship. We are grate-
ful to Dr. Elisabeth Irran (TU Berlin) for the X-ray crystal-struc-
ture analysis.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · boron · copper · silicon ·
strained molecules
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Manuscript received: September 17, 2019
Accepted manuscript online: September 18, 2019
Version of record online: && &&, 0000
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Communication
COMMUNICATION
&
Asymmetric Catalysis
L. Zhang, M. Oestreich*
&& – &&
Copper-Catalyzed Enantio- and
Diastereoselective Addition of Silicon
Nucleophiles to 3,3-Disubstituted
Cyclopropenes
Silicon meets strain: A robust copper-
catalyzed CꢁSi bond formation enables
the direct synthesis of a-chiral cyclopro-
pylsilanes from cyclopropenes. The syn-
addition across the strained alkene
occurs highly diastereo- and enantiose-
lectively with discrimination of the
geminal substituents at C3 (see scheme;
segphos=5,5’-bis(diphenylphosphanyl)-
4,4’-bi-1,3-benzodioxol).
Chem. Eur. J. 2019, 25, 1 – 5
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