Asymmetric Au(i)-catalyzed synthesis of bicyclo[4.1.0]heptene derivatives via a cycloisomerization process of 1,6-enynes

Article abstract of DOI:10.1039/b913554e

The enantioselective asymmetric gold-catalyzed cycloisomerization reactions of heteroatom tethered 1,6-enynes are conducted in the presence of a chiral cationic Au(i) catalyst ((R)-4-MeO-3,5-(t-Bu)₂-MeOBIPHEP-(AuCl) ₂/AgOTf system) i

Full text of DOI:10.1039/b913554e

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Asymmetric Au(I)-catalyzed synthesis of bicyclo[4.1.0]heptene derivatives
via a cycloisomerization process of 1,6-enynesw
´
Chung-Meng Chao, Denis Beltrami, Patrick Y. Toullec and Veronique Michelet*
Received (in Cambridge, UK) 7th July 2009, Accepted 29th September 2009
First published as an Advance Article on the web 14th October 2009
DOI: 10.1039/b913554e
The enantioselective asymmetric gold-catalyzed cycloisomerization
reactions of heteroatom tethered 1,6-enynes are conducted in the
presence of a chiral cationic Au(I) catalyst ((R)-4-MeO-3,5-
(t-Bu)2-MeOBIPHEP-(AuCl)2/AgOTf system) in toluene under
mild conditions and lead to functionalized bicyclo[4.1.0]heptene
derivatives in excellent enantiomeric excesses ranging from
90–98%.
Table 1 Cycloisomerization of enyne 1a
Entry
Solvent
T/1C
t/min
Yield (%)a
ee (%)b
The construction of bicyclo[4.1.0]heptene derivatives is of
particular interest, given their synthetic challenge and potential
applications as intermediates for natural or biologically active
1
2
3
4
5
6
7
Toluene
CH2Cl2
Et2O
RT
RT
RT
RT
RT
RT
0
30
25
25
25
600
600
120
57
26
35
43
10c
—
56
92 (ꢀ)
70 (ꢀ)
91 (ꢀ)
85 (ꢀ)
compounds.1 The groups of Blum and Furstner independently
¨
THF
d
—
CH3CN
MeNO2
Toluene
reported the synthesis of this structural moiety during
their study of the cycloisomerization of heteroatom-linked
1,6-enynes in the presence of Pt catalysts.2 This type of
reactivity (Scheme 1) relying on the carbophilic Lewis acid
behaviour of late transition metals has also been observed
with gold complexes.3,4 Indeed, during the last decade, gold
catalysis has emerged as an ever increasing area of research in
line with the flurry of highly selective chemical transformations
mediated.5
—
96 (ꢀ)
a
b
c
d
Isolated yield. Determined by HPLC. Conversion. Not
determined.
Our ongoing research program on metal-catalyzed cyclo-
isomerization reactions6 with a special emphasis on asymmetric
catalytic processes7 prompted us to examine possibility that
chiral gold(I) complexes might act as promoters for this
reaction.8 Asymmetric gold-catalyzed examples are still
scarce,9 and to the best of our knowledge, enantioselective
gold-catalyzed cyclopropanation reactions are so far limited
to the reports by Toste’s group on the cycloisomerization
of propargylic esters.10 We wish, therefore, to report the
asymmetric gold-catalyzed cycloisomerization of 1,6-enynes
leading to bicyclo[4.1.0]heptene derivatives.
Initial experiments were performed using substituted
propargylic 1,6-enyne 1a as a model substrate. The cyclo-
isomerization was first attempted in the presence of 3 mol% of
7d,e,9,11
(R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP-(AuCl)2
associated
with silver salt AgOTf (6 mol%) under various solvent and
temperature conditions (Table 1). The chiral gold complex was
prepared according to a literature procedure.11 As anticipated,
the reaction proceeded smoothly, and afforded the desired
alkene 2a in 57% yield and 92% ee (Table 1, entry 1).12
The reaction was found to be highly solvent-dependent as
enantiomeric excesses vary from 70–92% (Table 1, entries 1–7)
in various solvents. The use of acetonitrile or nitromethane led
to low conversion and sluggish reaction, respectively (Table 1,
entries 5–6).
Toluene was chosen as the reaction solvent for further
optimizations. Decreasing the temperature to 0 1C allowed
the formation of 2a in an excellent enantiomeric excess (96%),
despite a prolonged reaction time (Table 1, entry 7). The
stereoselectivity was based on the proposed mechanism for
the Pt-catalyzed reaction.2,13 The 6-endo-type nucleophilic
attack of the alkene group stereospecifically leads to the
formation a cyclopropylcarbene and is followed by a 1,2-hydride
shift (Scheme 1).14 The absolute configuration, which had
never been determined in the presence of iridium or platinum
for nitrogen-linked enynes,8 was assigned via a concerted
Scheme 1 Proposed intermediates for metal-catalyzed cycloisomerization
reaction.
´
Laboratoire Charles Friedel, Ecole Nationale Superieure de Chimie de
Paris UMR 7223, 11 rue P. et M. Curie, F-75231 Paris Cedex 05,
France. E-mail: veronique-michelet@chimie-paristech.fr
w Electronic supplementary information (ESI) available: Experimental
procedure and full analyses of cyclopropanes 2a–k. See DOI:
10.1039/b913554e
ꢁc
This journal is The Royal Society of Chemistry 2009
6988 | Chem. Commun., 2009, 6988–6990

View Article Online
Table 2 Asymmetric gold-catalyzed cycloisomerization of 1,6-enynes 1b–j
Entry
Enyne
Time (h)
Product
Yield (%)a
ee (%)b
1
2
3
4
5
6
7c
1b
1c
1d
1e
1f
R2 = 3,4-OCH2OC6H3
R2 = 3,5-Me2C6H3
R2 = Ph
R2 = 4-CO2MeC6H4
R2 = 4-NO2C6H4
R2 = 3-BrC6H4
1
3.5
16
15
15
13
6
2b
2c
2d
2e
2f
55
54
34
25
39
59
47
96 (ꢀ)
93 (+)
98 (+)
94 (ꢀ)
96 (ꢀ)
95 (ꢀ)
96 (ꢀ)
1g
1a
2g
2a
R2 = 4-MeOC6H4
8
9
1h
1i
R2 = Ph
R2 = 3-BrC6H4
0.7
0.7
2h
2i
2j
51
61
90 (+)
96 (ꢀ)
10
1j
22
24
91 (+)
a
b
Isolated yield. Determined by HPLC analysis. 1 mol% catalyst, 2 mol% AgOTf, toluene, RT.
c
use of ab initio time-dependant density functional theory
calculations and by circular dichroism on compound 2d (see
the ESIw).15
We then decided to evaluate the reactivity of other enynes
under the optimized conditions. According to classical
methodologies,14 we prepared several 1,6-enynes bearing an
oxygen atom as a link between the alkene and the alkyne
Scheme 2 Asymmetric gold-catalyzed cycloisomerization of nitrogen-
moieties. We were pleased to find that the use of 3 mol% of
(R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP-(AuCl)2 associated with
6 mol% of AgOTf afforded the corresponding bicyclo[4.1.0]-
heptenes 2b–j (Table 2). We were delighted to find that the
stereoselectivity of the cycloisomerization process was high in
the presence of a variety of disubstituted alkynes. Substitution
of the alkyne partner either by a phenyl or an aryl, bearing an
electron-donating or -withdrawing group (Table 2, entries 1–6)
led to the corresponding bicyclic derivatives 2b–g with high ee
values (94–98%).12 Functional groups such as CO2Me and
NO2 (Table 2, entries 4–5) or bromine (Table 2, entry 6) are
well tolerated. The functionalized cyclopropane 2g was, for
example, isolated in 59% yield and 95% ee (Table 2, entry 6).
The catalyst loading was successfully reduced to 1 mol% in the
case of enyne 1a and afforded product 2a in good yield and
high enantiomeric excess after 6 h at room temperature
(Table 2, entry 7).
tethered enynes.
of the (R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP-(AuCl)2/AgOTf
system successfully allowed the formation of 2k with 74%
conversion and 98% ee at 60 1C in toluene. The reaction was
slower than in the case of oxygen-tethered enynes, and higher
ee values were obtained at 40 and 60 1C compared to room
temperature. Further studies will be dedicated to explain this
intriguing observation.
In conclusion, we have developed an asymmetric gold-
catalyzed cycloisomerization reaction that provides bicyclo-
[4.1.0]heptene derivatives. The combination of atropisomeric
chiral ligand 4-MeO-3,5-(t-Bu)2-MeOBIPHEP associated to
Au(I) and silver salts promotes the enantioselective rearrangement
of oxygen and nitrogen-tethered 1,6-enynes under mild conditions.
The enantiomerically enriched functionalized cyclopropyl
heterocycles were isolated in low to moderate yields, and with
excellent ee values ranging from 90–98%. Further studies will
be focused on applications of this methodology.
The catalytic system was also evaluated for oxygen-linked
enynes 1h–i possessing an electron-rich aromatic alkene
substituent. The enantiomerically enriched bicyclic derivatives
2h–i were isolated in good yields, and in 90 and 96% ee,
respectively. The enantioselective process was not limited to
aryl-substituted alkynes as the ethyl derivative 2j was obtained
in 91% ee, despite a low yield (Table 2, entry 10).
This work was supported by the Centre National de la
Recherche Scientifique and the Ministere de l0Education et de
la Recherche. C.-M. C. is grateful to the Ministere de
l0Education et de la Recherche for a grant. The authors thank
Dr M. Scalone (Hoffmann-La Roche) for generous gift of
4-MeO-3,5-(t-Bu)2-MeOBIPHEP ligand. We are also grateful
The asymmetric cycloisomerization was also tested in
the case of nitrogen-linked 1,6-enyne 1k (Scheme 2). The use
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6988–6990 | 6989

View Article Online
to Dr I. Ciofini (UMR 7575, Laboratoire d’Electrochimie et
7 (a) L. Charruault, V. Michelet, R. Taras, S. Gladiali and
J.-P. Genet, Chem. Commun., 2004, 850; (b) V. Michelet,
L. Charruault, S. Gladiali and J.-P. Genet, Pure Appl. Chem.,
2006, 78, 397; (c) P. Y. Toullec, C.-M. Chao, Q. Chen, J.-P. Genet
and V. Michelet, Adv. Synth. Catal., 2008, 350, 2401;
(d) C.-M. Chao, E. Genin, P. Y. Toullec, J.-P. Genet and
V. Michelet, J. Organomet. Chem., 2009, 694, 538;
(e) C.-M. Chao, M. R. Vitale, P. Y. Toullec, J.-P. Genet and
V. Michelet, Chem.–Eur. J., 2009, 15, 1319.
8 For Ir- and Pt-catalyzed asymmetric studies limited to nitrogen-
tethered enyne substrates, see: (a) T. Shibata, Y. Kobayashi,
S. Maekawa, N. Toshida and K. Takagi, Tetrahedron, 2005, 61,
9018; (b) D. Brissy, M. Skander, H. Jullien, P. Retailleau and
A. Marinetti, Org. Lett., 2009, 11, 2137; (c) D. Brissy, M. Skander,
P. Retailleau and A. Marinetti, Organometallics, 2007, 26, 5782;
(d) D. Brissy, M. Skander, P. Retailleau, G. Frison and
A. Marinetti, Organometallics, 2009, 28, 140.
Chimie Analytique) for the ab initio calculations.
Notes and references
1 For representative examples, see: (a) A. K. Mandal, D. P. Borude,
R. Armugasamy, N. R. Soni, D. G. Jawalker, S. W. Mahajan,
K. R. Ratman and A. D. Goghare, Tetrahedron, 1986, 42, 5715
and references cited therein; (b) J. R. Tessier, in Recent Advances in
the Chemistry of Insect Control, ed. N. F. Janes, Royal Chem. Soc.,
London, 1985, p. 26.
2 (a) J. Blum, H. Beer-Kraft and Y. Badrieh, J. Org. Chem., 1995, 60,
5567; (b) A. Furstner, H. Szillat and F. Stelzer, J. Am. Chem. Soc.,
¨
2000, 122, 6785; (c) A. Furstner, F. Stelzer and H. Szillat, J. Am.
¨
Chem. Soc., 2001, 123, 11863; (d) M. Me
C. Nevado, D. J. Cardenas and A. M. Echavarren, J. Am. Chem.
´
ndez, M. P. Munoz,
´
Soc., 2001, 123, 10511; (e) C. Nevado, C. Ferrer and
A. M. Echavarren, Org. Lett., 2004, 6, 3191; (f) C. Ferrer,
M. Raducan, C. Nevado, C. K. Claverie and A. M. Echavarren,
Tetrahedron, 2007, 63, 6306.
9 For recent reviews, see: (a) N. Bongers and N. Krause, Angew.
Chem., Int. Ed., 2008, 47, 2178 and references cited therein;
(b) R. A. Widenhoefer, Chem.–Eur. J., 2008, 14, 5382.
10 (a) I. D. G. Watson, S. Ritter and F. D. Toste, J. Am. Chem. Soc.,
2009, 131, 2056; (b) M. J. Johansson, D. J. Gorin, S. T. Staben and
F. D. Toste, J. Am. Chem. Soc., 2005, 127, 18002.
3 For an excellent review on cyclopropane formations via cyclo-
isomerization reactions, see: (a) C. Bruneau, Angew. Chem., Int.
Ed., 2005, 44, 2328. For seminal examples, see recent reviews:
(b) V. Michelet, P. Y. Toullec and J.-P. Genet, Angew. Chem., Int.
Ed., 2008, 47, 4268; (c) E. Jimenez-Nunez and A. M. Echavarren,
Chem. Rev., 2008, 108, 3326.
11 For the synthesis of the gold complex, see: (a) C. Liu and
R. A. Widenhoefer, Org. Lett., 2007, 9, 1935; (b) M. P. Munoz,
J. Adrio, J. C. Carretero and A. M. Echavarren, Organometallics,
2005, 24, 1293. For the synthesis and applications of (R)-4-MeO-
3,5-(t-Bu)2-MeOBIPHEP, see: R. Schmid, E. A. Broger,
M. Cereghetti, Y. Crameri, J. Foricher, M. Lalonde,
R. K. Muller, M. Scalone, G. Schoettel and U. Zutter, Pure Appl.
Chem., 1996, 68, 131 and references cited therein.
4 (a) C. Nieto-Oberhuber, M. P. Munoz, E. Bunuel, C. Nevado,
D. J. Cardenas and A. M. Echavarren, Angew. Chem., Int. Ed.,
2004, 43, 2402; (b) S. I. Lee, S. M. Kim, M. R. Choi, S. Y. Kim and
Y. K. Chung, J. Org. Chem., 2006, 71, 9366; (c) S. M. Kim, J. H. Park,
S. Y. Choi and Y. K. Chung, Angew. Chem., Int. Ed., 2007, 46, 6172.
5 For representative recent examples, see: (a) A. Arcadi, Chem. Rev.,
2008, 108, 3266; (b) N. T. Patil and Y. Yamamoto, Chem.
Rev., 2008, 108, 3395; (c) Z. Li, C. Brouwer and C. He,
Chem. Rev., 2008, 108, 3239; (d) H. C. Shen, Tetrahedron, 2008,
64, 3885; (e) R. Skouta and C.-J. Li, Tetrahedron, 2008, 64, 4917;
(f) A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev., 2008, 37,
1766; (g) J. Muzart, Tetrahedron, 2008, 64, 5815; (h) A. S. K. Hashmi,
Chem. Rev., 2007, 107, 3180; (i) D. J. Gorin and F. D. Toste, Nature,
2007, 446, 395; (j) A. S. K. Hashmi and G. J. Hutchings, Angew.
Chem., Int. Ed., 2006, 45, 7896; (k) E. Jimenez-Nunez and
A. M. Echavarren, Chem. Commun., 2007, 333.
12 A total conversion was observed within a short time and the
formation of the desired product was accompanied by several
degradation products.
13 (a) C. Nevado, D. J. Cardenas and A. M. Echavarren, Chem.–Eur.
´
J., 2003, 9, 2627; (b) E. Soriano, P. Ballesteros and J. Marco-
Contelles, Organometallics, 2005, 24, 3172; (c) E. Soriano and
J. Marco-Contelles, J. Org. Chem., 2005, 70, 9345;
(d) E. Soriano, P. Ballesteros and J. Marco-Contelles, J. Org.
Chem., 2004, 69, 8018.
14 For selected analogous 1,2-hydride shifts on 1,5-enynes, see:
(a) E. Mainetti, V. Mouries, L. Fensterbank, M. Malacria and
J. Marco-Contelles, Angew. Chem., Int. Ed., 2002, 41, 2132;
6 (a) C. Nevado, L. Charruault, V. Michelet, C. Nieto-Oberhuber,
M. P. Munoz, M. Mendez, M.-N. Rager, J.-P. Genet and
´
(b) V. Mamane, T. Gress, H. Krause and A. Furstner, J. Am.
¨
Chem. Soc., 2004, 126, 8654; (c) Y. Harrak, C. Blazykowski,
M. Bernard, K. Cariou, E. Mainetti, V. Mouries,
A.-L. Dhimane, L. Fensterbank and M. Malacria, J. Am. Chem.
Soc., 2004, 126, 8656; (d) M. R. Luzung, J. P. Markham and
F. D. Toste, J. Am. Chem. Soc., 2004, 126, 10858; (e) F. Gagosz,
Org. Lett., 2005, 7, 4129; (f) C. Blazykowski, Y. Harrak,
C. Brancour, K. Nakama, A.-L. Dhimane, L. Fensterbank and
M. Malacria, Synthesis, 2007, 2037; (g) J. Marco-Contelles,
N. Arroyo, S. Anjum, E. Mainetti, N. Marion, K. Cariou,
G. Lemiere, V. Mouries, L. Fensterbank and M. Malacria, Eur.
J. Org. Chem., 2006, 4618; (h) S. Couty, C. Meyer and J. Cossy,
Tetrahedron, 2009, 65, 1809.
A. M. Echavarren, Eur. J. Org. Chem., 2003, 706; (b) E. Genin,
L. Leseurre, P. Y. Toullec, J.-P. Genet and V. Michelet, Synlett,
2007, 1780; (c) L. Leseurre, P. Y. Toullec, J.-P. Genet and
V. Michelet, Org. Lett., 2007, 9, 4049; (d) E. Genin,
P. Y. Toullec, S. Antoniotti, C. Brancour, J.-P. Genet and
V. Michelet, J. Am. Chem. Soc., 2006, 128, 3112;
(e) S. Antoniotti, E. Genin, V. Michelet and J.-P. Genet, J. Am.
Chem. Soc., 2005, 127, 9976; (f) P. Y. Toullec, E. Genin,
L. Leseurre, J.-P. Genet and V. Michelet, Angew. Chem., Int.
Ed., 2006, 45, 7427; (g) L. Leseurre, C.-M. Chao, T. Seki,
E. Genin, P. Y. Toullec, J.-P. Genet and V. Michelet, Tetrahedron,
2009, 65, 1911; (h) C.-M. Chao, P. Y. Toullec and V. Michelet,
Tetrahedron Lett., 2009, 50, 3719; (i) P. Y. Toullec, T. Blarre and
V. Michelet, Org. Lett., 2009, 11, 2888.
15 P. J. Stephens, D. M. McCann, E. Butkus, S. Stoncius,
J. R. Cheeseman and M. J. Frisch, J. Org. Chem., 2004, 69, 1948.
ꢁc
This journal is The Royal Society of Chemistry 2009
6990 | Chem. Commun., 2009, 6988–6990