Synthesis of enantioenriched allenes from 1,1-cyclopropanediesters

Article abstract of DOI:10.1021/ol902766f

[Chemical equation presented] Highly substituted alienes were obtained by the S_N2′ addition of organocuprate reagents on 2-propargyl-1,1-cyclopropanediesters. This new methodology permits the synthesis of highly enantioenriched allenes as the r

Full text of DOI:10.1021/ol902766f

ORGANIC
LETTERS
2010
Vol. 12, No. 3
564-567
Synthesis of Enantioenriched Allenes
from 1,1-Cyclopropanediesters
Pascal Ce´rat, Philipp J. Gritsch, Se´bastien R. Goudreau, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received November 30, 2009
ABSTRACT
Highly substituted allenes were obtained by the SN2′ addition of organocuprate reagents on 2-propargyl-1,1-cyclopropanediesters. This new
methodology permits the synthesis of highly enantioenriched allenes as the reaction proceeds with retention of the enantiomeric purity of the
starting cyclopropane. The use of higher order cuprates was instrumental in obtaining the reported results.
Electrophilic cyclopropane derivatives possessing two
geminal electron-withdrawing groups1 have attracted
considerable interest as versatile 1,3-zwitterionic or elec-
trophilic synthons.2 These valuable intermediates have
been applied toward the enantioselective synthesis of
complex molecules, as they are readily reactive in
cycloaddition reactions3 and nucleophilic additions,4
retaining the stereogenic information of the starting
cyclopropane. Generally, 1,5-addition is observed in these
processes, except in the particular case of the addition of
organocuprates on a vinylcyclopropane, where only the
1,7-addition product was obtained.2a,5 From this observa-
tion, we envisioned that the synthesis of enantioenriched
allenes might be achieved by the addition of organocuprates
to optically active propargylcyclopropanes.6,7
(1) For recent examples on the synthesis of electrophilic cyclopropanes,
see: (a) Moreau, B.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 18014–
18015. (b) Gonza´lez-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.;
Kolotuchin, S.; Soumeillant, M. AdV. Synth. Catal. 2008, 350, 813–816.
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10158. (d) Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem., Int. Ed.
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Org. Chem. 2009, 74, 470–473. (f) Marcoux, D.; Azzi, S.; Charette, A. B.
J. Am. Chem. Soc. 2009, 131, 6970–6972. (g) Lindsay, V. N. G.; Lin, W.;
Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383–16385. (h) Marcoux,
D.; Goudreau, S. R.; Charette, A. B. J. Org. Chem. 2009, 74, 8939–8955.
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66–72. (b) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165–198. (c) Reissig, H.-U.; Zimmer,
R. Chem. ReV. 2003, 103, 1151–1196. (d) Yu, M.; Pagenkopf, B. L.
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V. Chem. ReV. 2007, 107, 3117–3179.
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England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002, 80, 992–
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.
10.1021/ol902766f  2010 American Chemical Society
Published on Web 01/05/2010

Continuous efforts have been invested in the synthesis
of allenes, and its unique chiral structure was accessed
by multiple strategies.8,9 Although few catalytic enantiose-
lective methods have been reported to date,10 expedient
syntheses of enantioenriched allenes remains a challenge.
Allenes may be synthesized by formal SN2′ displacement of
propargylic alcohols, although many other leaving groups
have been used, such as carbonates, sulfonates, ethers,
ꢀ-lactones, halides, epoxides, and aziridines.8 Allenes are
present in many biologically active compounds, and they
have proven to be highly valuable substrates in the synthesis
of complex molecules (Scheme 1).8,11,12
previously developed in our group.1e,h Since previously
reported cycloaddition reactions using the cyclopropane 3a
as a substrate led to poor results,6 we were concerned by
the compatibility of the substrate under nucleophilic addition
conditions and the lack of selectivity for 1,5- vs 1,7-additions.
Inspired by reported works on the addition of organo-
metallic reagents on 2-vinyl-1,1-cyclopropanediesters,5 we
started to look at higher order cuprates as source of soft
nucleophiles.13 Interestingly, forming the reagent from 2.2
equiv of PhMgBr and 1.1 equiv of CuBr·DMS led to very
promising results: 52% yield of the allene 1a was obtained
as the only product (Table 1, entry 1). Other copper
Scheme 1. Synthetic Utilities of the Allene Scaffold 1
Table 1. Optimization
entry
PhX
reagent
yielda (%)
1
2
3
4
5
6
7
8
9
PhMgBr (2.2 equiv) CuBr·DMS (1.1 equiv)
PhMgBr (2.2 equiv) CuI (1.1 equiv)
PhMgBr (2.2 equiv) CuCN (1.1 equiv)
PhMgBr (1.1 equiv) CuCN (1.1 equiv)
PhMgBr (1.1 equiv) (2-Th)Cu(CN)Li (1.1 equiv)
PhMgBr (2.2 equiv)
52
76
92
59
46
0
89
0
49
0
PhLi (2.2 equiv)
CuCN (1.1 equiv)
PhLi (2.2 equiv)
PhMgBr (1.1 equiv) Ph2Zn (1.1 equiv)
10 Ph2Zn (1.1 equiv)
11 Ph2Zn (1.1 equiv)
12 Ph2Zn (1.1 equiv)
CuCN (5 mol %)
CuOTf (5 mol %)
51
49
a Isolated yields.
sources were examined, and the best result was achieved
with CuCN with 92% yield without any 1,5-addition
Herein, we describe a new methodology to synthesize
allenes from propargylcyclopropanes by the SN2′ addition
of organocuprates. The retention of the enantiomeric purity
during the process allows the synthesis of highly enan-
tioenriched allenes.
We began our study by the addition of different
nucleophilic phenyl reagents on the propargylcyclopropane
3a. This cyclopropane was easily accessible by a method
(9) Selected examples: (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc.
1996, 118, 4492–4493. (b) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000,
122, 10470–10471. (c) Fu¨rstner, A.; Me´ndez, M. Angew. Chem., Int. Ed.
2003, 42, 5355–5357. (d) Pu, X.; Ready, J. M. J. Am. Chem. Soc. 2008,
130, 10874–10875. (e) Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge,
T. J.; Williams, L. J. J. Am. Chem. Soc. 2009, 131, 12910–12911.
(10) (a) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001,
123, 12915–12916, and references cited therein. (b) Han, J. W.; Tokunaga,
N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915–12916. (c) Ogasawara,
M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003,
5, 217–219. (d) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem.
Soc. 2005, 127, 14186–14187. (e) Li, C.-Y.; Wang, X.-B.; Sun, X.-L.; Tang,
Y.; Zheng, J.-C.; Xu, Z.-H.; Zhou, Y.-G.; Dai, L.-X. J. Am. Chem. Soc.
2007, 129, 1494–1495. (f) Liu, H.; Leow, D.; Huang, K.-W.; Tan, C.-H.
J. Am. Chem. Soc. 2009, 131, 7212–7213.
(6) For examples of cycloaddition reactions involving 2-propargyl-1,1-
cyclopropanediesters protected as cobalt complexes, see: (a) Christie,
S. D. R.; Davoile, R. J.; Elsegood, M. R. J.; Fryatt, R.; Jones, R. C. F.;
Pritchard, G. J. Chem. Commun. 2004, 2474–2475. (b) Christie, S. D. R.;
Davoile, R. J.; Jones, R. C. F. Org. Biomol. Chem. 2006, 4, 2683–2684.
(c) Christie, S. D. R.; Davoile, R. J.; Elsegood, M. R. J.; Fryatt, R.; Jones,
R. C. F.; Pritchard, G. J. Chem. Commun. 2004, 2474–2475.
(11) Ma, S. Chem. ReV. 2005, 105, 2829–2872.
(7) During the preparation of this manuscript, Fu¨rstner published the
addition of i-PrMgCl on propargylcyclopropane 3a catalyzed by Fe(acac)3
to form the allene 1f. However, only one example was reported, and the
retention of the stereochemistry was not demonstrated: Sherry, B. D.;
Fu¨rstner, A. Chem. Commun. 2009, 7116–7118.
(12) For examples of reactions using the allene scaffold 1, see: (a)
Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am.
Chem. Soc. 1999, 121, 5348–5349. (b) Brummond, K. M.; Chen, H.; Sill,
P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186–15187. (c) Ma, S.; Jiao,
N. Angew. Chem., Int. Ed. 2002, 41, 4737–4740. (d) Zhu, G.; Zhang, Z.
Org. Lett. 2004, 6, 4041–4044. (e) Wender, P. A.; Croatt, M. P.; Deschamps,
N. M. Angew. Chem., Int. Ed. 2006, 45, 2459–2462. (f) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066–9073. (g) Luzung, M. R.; Mauleo´n, P.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 12402–12403. (h) Trillo, B.; Lo´pez, F.; Gul´ıas, M.;
Castedo, L.; Mascaren˜as, J. L. Angew. Chem., Int. Ed. 2008, 47, 951–954.
(i) Saito, N.; Tanaka, Y.; Sato, Y. Org. Lett. 2009, 11, 4124–4126.
(8) For reviews, see: (a) Sydnes, L. K. Chem. ReV. 2003, 103, 1133–
1150. (b) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004. (c) Hoffmann-Ro¨der, A.; Krause, N. Angew.
Chem., Int. Ed. 2004, 43, 1196–1216. (d) Krause, N.; Hoffmann-Ro¨der, A.
Tetrahedron 2004, 60, 11671–11694. (e) Brummond, K. M.; DeForrest,
J. E. Synthesis 2007, 795–818. (f) Ogasawara, M. Tetrahedron: Asymmetry
2009, 20, 259–271.
Org. Lett., Vol. 12, No. 3, 2010
565

product observed (entry 3). Modifying the nature of the
reagent by using 1.1 equiv of PhMgBr with 1.1 equiv of
CuCN was detrimental to the reaction, affording only 59%
yield. Lithiated species can be employed instead of
Grignard reagents without significantly altering the yield
(89%, entry 7). As expected, control experiments using
PhMgBr or PhLi without any source of copper led to a
mixture of 1,2-addition products, and no allenic compound
was observed (entries 6 and 8).5a Interestingly, phenyl
zincate also produced a 1,7-addition on the activated
cyclopropane 3a to generate the allene 1a, albeit in
moderate yield (49%, entry 9). Diphenylzinc did not
produce the allene in these conditions, but using CuCN
or CuOTf as the catalyst afforded the desired product in
51% and 49% yields, respectively (entries 11 and 12).
Overall, after extensive optimization of the temperature,
solvents, and amounts of reagents, we found that the best
reaction conditions were to use 2.2 equiv of Grignard or
organolithium reagents with 1.1 equiv of CuCN in Et2O
at rt.
Table 2. Scope Study
Having these optimal conditions in hand, we studied
the scope of the reaction. Different aryl or alkyl cuprates
successfully underwent 1,7-addition (Table 2, entries
1-7). Primary, secondary, and even tertiary alkyl cuprates
were well tolerated, providing yields of the corresponding
allenes ranging from 78% to 89% (entries 3-7). Substi-
tuted alkynes were also investigated by the addition of
methyl cuprate: 84% and 73% yields were obtained,
respectively, with an alkyl- and an aryl-substituted alkyne
(entries 8 and 9). In the latter case, a 1,7:1,5 ratio of 5:1
was obtained; however, using MeCu(CN)MgBr with
n-Bu3P increased this ratio to 10:1.14 Interestingly, a bulky
silyl group afforded the allene in good yields without any
1,5-addition (entry 10). Tetrasubstituted allenes were also
accessible by this method, as 77% yield was obtained in
the addition of ethyl cuprate to the corresponding cyclo-
propane (R1 ) Ph, R2 ) Me, entry 11).
Considering the high importance of enantioenriched
allenes, we wondered if these conditions proceed with
retention of the enantiomeric purity of the starting
cyclopropanes. Although it is known that SN2′ additions
on propargylic leaving groups preserve the stereogenic
information,8,9a there are no such examples with propar-
gylcyclopropanes, and the retention of the stereogenic
information has not been reported in the case of 1,7-addition
on vinylcyclopropanes. To our delight, starting from the
cyclopropane ent-3a in 96% ee afforded the allene ent-1a
in 96% ee (Table 1, entry 1), demonstrating the high potential
of this method in enantioselective synthesis. Indeed, we
synthesized allene 1l, an intermediate in the reported
synthesis of methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (Phero-
mone of Acanthoscelides obtectus),15 in 86% yield and
a Isolated yield. b Ratio between 1,7- and 1,5-addition products
determined by 1H NMR on the crude reaction mixture. c ent-1a was obtained
in 96% ee starting from cyclopropane ent-3a in 96% ee. d A 1,7:1,5 ratio
of 10:1 was obtained when MeCu(CN)MgBr (1.1 equiv) and nBu3P (2.2
equiv) were used.
retention of the enantiomeric purity (Scheme 2). This formal
enantioselective synthesis also confirmed the absolute ster-
eochemistry of the allene and thereby the anti selectivity of
the addition.
(13) For reviews, see: (a) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski,
J. A. Tetrahedron 1984, 40, 5005–5038. (b) Lipshutz, B. H. Synthesis
1987, 1987, 325–341. (c) Lipshutz, B. H. Synlett 1990, 1990, 119–128.
(d) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–589. (e)
Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186–204.
(14) Krause, N.; Hoffmann-Ro¨der, A.; Canisius, J. Synthesis 2002, 1759–
1774.
The proposed mechanism for this transformation begins
with the complexation of the copper reagent to the triple
(15) Ogasawara, M.; Nagano, T.; Hayashi, T. J. Org. Chem. 2005, 70,
5764–5767.
(16) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726–3730.
566
Org. Lett., Vol. 12, No. 3, 2010

Scheme 2
.
Formal Synthesis of the Natural Allene 4
Scheme 3. Proposed Mechanism
bond (Scheme 3). Then follows an antiperiplanar opening
of the cyclopropane forming the allenyl copper enolate
that undergoes reductive elimination to generate the
substituted allene. This mechanism previously proposed
for SN2′ additions of cuprates on propargylic deriv-
atives8c,16 is in accordance with the retention of the
enantiomeric purity of the starting material and the absolute
stereochemistry observed.
In summary, we described the synthesis of allenes by
the SN2′ addition of organocuprates to propargylcyclo-
propanes. This new methodology allows the synthesis of
enantioenriched tetrasubstituted allenes. We believe that
this reaction will find applications in asymmetric synthesis,
as it was demonstrated in the formal synthesis of methyl
(R,E)-(-)-tetradeca-2,4,5-trienoate. Further applications
of electrophilic cyclopropanes will be published in due
course.
Acknowledgment. This work was supported by NSERC
(Canada), the Canada Foundation for Innovation, the Canada
Research Chair Program, and the Universite´ de Montre´al.
We also thank Jad Tannous (Universite´ de Montre´al) for SFC
separations. P.C. is grateful to NSERC (PGS M) and Banque
Nationale for postgraduate fellowships. P.J.G. is grateful to
Technische Universita¨t Wien for an undergraduate fellow-
ship. S.R.G. is grateful to NSERC (PGS D) and Fondation
J.A. DeSe`ve for postgraduate fellowships.
Supporting Information Available: Experimental pro-
cedure for the preparation of compounds and spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL902766F
Org. Lett., Vol. 12, No. 3, 2010
567