Tandem Hydroalumination/Cu-Catalyzed Asymmetric Vinyl Metalation as a New Access to Enantioenriched Vinylcyclopropane Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b01661

Herein, we report the first enantio- and diastereoselective addition of stereodefined vinyl organometallic reagents to cyclopropenes. The operationally simple tandem hydroalumination and copper-catalyzed vinylmetalation allows for the unique access of a diverse set of enantioenriched vinylcyclopropane derivatives.

Full text of DOI:10.1021/acs.orglett.7b01661

Letter
pubs.acs.org/OrgLett
Tandem Hydroalumination/Cu-Catalyzed Asymmetric Vinyl
Metalation as a New Access to Enantioenriched Vinylcyclopropane
Derivatives
Daniel S. Muller,† Veronika Werner,† Sema Akyol,‡ Hans-Gunther Schmalz,‡ and Ilan Marek*,†
̈
̈
†The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva Center for
Computational Quantum Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
‡University of Cologne, Department of Chemistry, Greinstrasse 4, 50939 Koeln, Germany
S
* Supporting Information
ABSTRACT: Herein, we report the first enantio- and diastereoselective
addition of stereodefined vinyl organometallic reagents to cyclopropenes. The
operationally simple tandem hydroalumination and copper-catalyzed vinyl-
metalation allows for the unique access of a diverse set of enantioenriched
vinylcyclopropane derivatives.
inylcyclopropanes (VCPs) are reactive entities, well-
known to participate in various rearrangements such as
V
the renowned divinylcylopropane−cycloheptadiene or
vinylcyclopropane−cyclopentene rearrangement.1 Further-
more, the reactivity of vinylcyclopropanes has also been
extensively exploited in transition-metal catalysis to access
molecular structures of high complexity.2 Importantly, VCPs
are also found in natural products, insecticides, drugs, and other
biologically active compounds such as carenes, sesquicarenes,
sirenines, dictyopterenes, pyrethrine, and ambrutucin.3 Among
the few nonauxiliary based methods that exist to access
enantiomerically enriched VCPs,4 the most straightforward
approach would be the asymmetric metal-catalyzed decom-
position of vinyldiazoacetates, but it proceeds efficiently mainly
for terminal alkenes.5 The complementary strategy, namely the
metal-catalyzed reaction of diazoesters with dienes, is highly
enantioselective, but is usually restricted to symmetric or cyclic
dienes.6 Other enantioselective methods such as the Simmons−
Smith reaction on dienol7 or Michael-initiated ring closure have
also been reported.8 Recently, our group has described the
copper catalyzed carbozincation and carbomagnesiation of
cyclopropenes to afford highly enantioenriched and diaster-
eoisomerically pure polysubstituted cyclopropanes (see i,
Figure 1).9 We anticipated that a related process using easily
accessible vinyl Grignard reagents would offer a facile and short
access to vinyl-substituted cyclopropanes, but in contrast to our
expectations, early scouting studies showed that the addition
reaction of 1-(E)-hexenylmagnesium bromide led to a complete
racemic mixture with all chiral ligands and copper salts tested.
Although much less common than the addition of other
organometallic species, the catalytic enantioselective addition of
vinylaluminum species to various Michael acceptors have
recently emerged as a direct access to vinylated products.10
We were therefore intrigued by the possibility of performing
the asymmetric copper-catalyzed vinyl alumination reactions of
cyclopropene derivatives as a new approach to diastereo- and
enantiomerically enriched VCPs (see ii, Figure 1). Our model
Figure 1. Vinylcyclopropanes through carbometalation reactions on
cyclopropenes.
experiment consisted in the hydroalumination reaction of 5-
chloropentyne followed by the addition of a catalytic amount of
copper salt and chiral ligand in Et2O at 0 °C (Figure 2).
However, the copper-catalyzed vinylalumination reaction was
revealed to be much more challenging than expected, as no
traces of VCPs were observed after hydrolysis but rather the
formation of higher molecular weight materials (see i, with
(R)H8-BINAP L2 as representative chiral ligand, Figure 2).11
Importantly, we found that the addition of Et2Zn was crucial to
promote clean vinylmetalation of cyclopropenes12 (see ii,
Received: June 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01661
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Letter
Figure 2. Et2Zn, a crucial additive for successful carbometalation of
cyclopropenes. GC: gas chromatography.
Figure 2; see Supporting Information (SI) for a full list of MXn
tested). The addition of 1.0−1.5 equiv of Et2Zn to the 1.2 equiv
of vinylaluminum species afforded the best results. Less
equivalents of Et2Zn resulted in a drop in yield whereas more
than 1.5 equiv of Et2Zn led to a significant increase in either the
transfer of an ethyl or isobutyl group to the cyclopropene (see
ii, with the same (R)-H8-BINAP L2 as the representative chiral
ligand, Figure 2).13
With the optimized conditions in hand, the screening of
several chiral phosphorus based ligands and copper salts was
carried out (Figure 3) to finally identify either (R)-DTBM-
SEGPHOS (L8) or SchmalzPhos (L9),14 with copper(I)-
thiophene-2-carboxylate (CuTC) as the copper salt, as the
most efficient catalysts to provide the expected VCPs in
outstanding diastereoselectivities and good enantioselectivities
(entries 8 and 10, Figure 3; see SI for a complete table of all the
ligands evaluated) but still with minor formation of A and B
resulting from the transfer of 2−10% of ethyl and 2−9% of iBu
groups, respectively.
In general, bulky ligands as well as polar solvents favor alkyl
transfer products whereas solvents with low coordinating
abilities and phosphorus ligands with small steric bulk favor
the vinyl-transfer product (Figure 3; see SI for additional
information). In contrast to the previously reported enantio-
selective copper-catalyzed carbozincation and carbomagnesia-
tion where Cu(CH3CN)4PF6 was the best source of copper
salt, the highest percentage of vinyl transfer possessing the best
diastereo- and enantiomeric ratios was observed with CuTC
(compare entries 8 and 9 with entries 11 and 12; Figure 3).9a,b
It should be noted that this particular vinylmetalation reaction
must address several major difficulties for an efficient catalytic
system, as it requires not only efficiency to avoid the formation
of dimers and higher molecular weight materials but also
selectivity for the transfer of only the vinyl moiety while
inducing high diastereo- and enantioselectivities. Opting for the
best combination for all these requirements (Figure 3, entries 8
and 10), we set out to investigate the scope of the nucleophilic
component of the reaction (Part a, Figure 4). We found that
the diastereoisomeric ratios are consistently very high for all
vinylmetalations tested and, in all cases, the nucleophile is
introduced syn to the methyl group. Enantiomeric ratios are in
Figure 3. Optimization of the Cu-Catalyzed enantioselective vinyl-
alumination with cyclopropene 1a. Reactions were run on a 0.25 mmol
scale. If not otherwise noted, full conversion was observed. aAll
reactions contain ∼50% of hydrocarbon solvents originating from
b
DIBAL-H and cyclopropene solutions. Estimated by GC or GC-MS
c
d
analysis. Determined by chiral GC. The opposite enantiomer was
e
f
observed with L9. No conversion observed. No addition of Et2Zn,
∼30% conversion; 0% product formation. CuTC = copper(I)
thiophene-2-carboxylate. ND = not determined.
the range of 85:15 except for the 1-octenyl product 2d that
reaches 89:11. We were particularly delighted to introduce the
vinylcyclopropane nucleophile to furnish the bis-cyclopropane
2g with excellent diastereoisomeric and good enantiomeric
ratios albeit in lower yield. The carbometalation with β-
styrenylaluminum was particularly pleasing, as the hydro-
alumination of phenyl acetylene usually leads to approximately
25% of Ph−CC−Al(iBu)2 which typically hampers copper
catalysis.15 However, in this particular case, the reaction has to
be performed in the presence of (R)-BINAP as the chiral ligand
to produce 2h in good yield and enantiomeric ratio. Chloro-
substituted as well as sterically more demanding vinylaluminum
reagents were successfully incorporated, albeit the latter with
lower enantioselectivity and a higher ratio of alkyl transfer
B
DOI: 10.1021/acs.orglett.7b01661
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Letter
cyclopropanes in natural products, drugs, and insecticides, we
were intrigued if whether our developed enantioselective
vinylmetalation procedure would also proceed for the simple
dimethylcyclopropene substrate.16 Indeed, the desired product
2o was obtained in good enantioselectivity demonstrating the
capacity of the chiral catalyst to differentiate the enantiotopic
faces of small substrates.
Finally, the corresponding metalated VCPs can be further
functionalized (Figure 5). The configuration of the cyclo-
Figure 4. Scope of the Cu-catalyzed enantioselective vinylalumination
of cyclopropenes. Reactions were conducted on 0.5 mmol scale
material. Enantioselectivity was determined by chiral HPLC.
Diastereoselectivity was determined by GC or 1H NMR analysis.
Alkyl transfer was estimated by GC. aLow yield due to difficult
Figure 5. Miscellaneous reactions.
propane after deuterolysis confirmed the expected cis-adition of
the organometallic species during the carbometalation reaction
(2p),17 and transmetalation to copper allowed an allylic
substitution reaction to proceed and afford tetrasubstituted
cyclopropane 2q. Further postfunctionalization can also be
easily achieved. For instance, cross-metathesis using Grubbs’
second generation catalyst efficiently produced 2r and oxidative
cleavage following Jin’s procedure18 yielded known aldehyde
2s, which confirmed the absolute configuration.19
In summary, we have successfully developed a new general
procedure for the challenging enantioselective tandem hydro-
alumination−vinylmetalation reaction employing commercially
available (R)-DTBM-SEGPHOS L8 or SchmalzPhos ligand L9.
These procedures are suitable for a wide range of vinyl
nucleophiles and cyclopropene substrates, allowing the syn-
thesis of the important vinylcyclopropane motif.
b
separation from A and B. Compound 2h decomposes during GC
analysis; therefore, no alkyl transfer of the crude reaction could be
c
determined. Yield determined for inseparable mixture of 2j and side-
products A and B. dLow yield due to volatility of the product;
percentage of A and B could not be determined due to the high
volatility of these products. ND = not determined.
(products 2a, 2i, and 2j). We were delighted to confirm that
SchmalzPhos ligand L9 combines also all the desired attributes
(selectivity for the ligand transfer, diastereo- and enantiose-
lectivities) and is comparable to ligand L8 in most of the cases,
surpassing all other chiral ligands (Figure 4, ent-2a, ent-2d, ent-
2g) albeit in lower enantiomeric ratio for a slightly bulkier
vinylaluminum derivative such as ent-2g. Subsequently, several
cyclopropenes were subjected to the optimized reaction
conditions (Part b, Figure 4). Cyclopropenes with electron-
withdrawing (1k) and -donating groups (1l) afforded the
desired product with consistent levels of enantioselectivity.
Rigid scaffolds on the cyclopropene substrate led to slightly
higher levels of alkyl transfer (2m) whereas a less encumbered
substrate (2n) gave very low levels of alkyl transfer as a mixture
of two diastereomers. Unexpectedly, product 2n was obtained
as the opposite diastereoisomer of trans-2n when ligand L9 was
used. Due to the importance of geminal dimethyl-substituted
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01661.
Experimental procedures and characterization data for all
1
products, including H and 13C NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b01661
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Alexakis, A. Chem. - Eur. J. 2013, 19, 15226. (d) Cottet, P.; Muller, D.
̈
AUTHOR INFORMATION
■
S.; Alexakis, A. Org. Lett. 2013, 15, 828. (e) Muller, D. S.; Alexakis, A.
̈
Corresponding Author
*E-mail: chilanm@tx.technion.ac.il.
ORCID
Org. Lett. 2012, 14, 1842. (f) Muller, D. S.; Tissot, M.; Alexakis, A. Org.
̈
Lett. 2011, 13, 3040. (g) May, T. L.; Dabrowski, J. A.; Hoveyda, A. H.
J. Am. Chem. Soc. 2011, 133, 736. (h) Muller, D.; Hawner, C.; Tissot,
̈
M.; Palais, L.; Alexakis, A. Synlett 2010, 2010, 1694.
Hans-Gunther Schmalz: 0000-0003-0489-1827
̈
(11) Aluminium etherates (e.g., L. Et3Al−Et2O) are known to
catalyze the dimerization and oligomerization of cyclopropenes:
Ilan Marek: 0000-0001-9154-2320
(a) Binger, P.; Schafer, H. Tetrahedron Lett. 1975, 16, 4673. (b) Richey,
̈
Notes
H. G.; Smith, M. A. Organometallics 2007, 26, 609.
The authors declare no competing financial interest.
(12) Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339.
(13) At this point we can only speculate about the role of diethyl zinc
in the complex reaction mixture containing three metals (Al, Zn, Cu).
Transmetalation from aluminum to zinc comparable to the B/Zn
exchange might be one explanation, but Et2Zn can also be seen as a
Lewis acid thus activating the cyclopropene.
ACKNOWLEDGMENTS
■
This research was supported by the European Research Council
under the European Community’s Seventh Framework
Program (ERC Grant Agreement No. 338912) and by the
Israel Science Foundation administrated by the Israel Academy
of Sciences and Humanities (140/12). I.M. is holder of the Sir
Michael and Lady Sobell Academic Chair.
(14) Dindarog
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