Asymmetric nitroallylation of arylboronic acids with nitroallyl acetates catalyzed by chiral rhodium complexes and its application in a concise total synthesis of optically pure (+)-γ-lycorane

Article abstract of DOI:10.1021/ol051795n

(Chemical Equation Presented) A new rhodium-catalyzed highly enantioselective nitroallylation of 2-nitrocyclohex-2-enol esters with arylboronic acids is described. A rhodium complex of [RhOH(COD)]₂ and optically pure BINAP is the optimal cataly

Full text of DOI:10.1021/ol051795n

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4285-4288
Asymmetric Nitroallylation of
Arylboronic Acids with Nitroallyl
Acetates Catalyzed by Chiral Rhodium
Complexes and Its Application in a
Concise Total Synthesis of Optically
Pure (+)-γ-Lycorane
Lin Dong, Yan-Jun Xu, Lin-Feng Cun, Xin Cui, Ai-Qiao Mi, Yao-Zhong Jiang, and
Liu-Zhu Gong*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince
and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, and Graduate
School of Chinese, Academy of Sciences, Beijing, China
gonglz@cioc.ac.cn
Received July 28, 2005
ABSTRACT
A new rhodium-catalyzed highly enantioselective nitroallylation of 2-nitrocyclohex-2-enol esters with arylboronic acids is described. A rhodium
complex of [RhOH(COD)]2 and optically pure BINAP is the optimal catalyst that provides good yields and high enantioselectivities ranging
from 90 to 99% ee for various arylboronic acids at 50
achieved on the basis of this new method.
°C. A concise total synthesis of optically pure (+)-γ-lycorane in overall 38% yield was
Nitroallyl acetates 1 were first introduced as multiple
coupling reagents to react with two different nucleophilic
components (Nu1 and Nu2) by Seebach and Knochel (Scheme
1).1 The resulting nitroalkanes 3 can be transformed into a
variety of useful compounds because the nitro group can be
converted into various functionalities.2 Although various
types of nucleophiles have been evaluated with regard to
their ability to couple with nitroallyl acetates 1 in good
results,1,3 this useful transformation has not yet been a
catalytic asymmetric process. Thus, the development of the
catalytic asymmetric reaction of nitroallyl acetates with
nucleophiles is of great importance in organic synthesis.
Hayashi and co-workers reported that the 1,4-addition of
1-nitrocyclohexene (4)4 with phenylboronic acid5 in the
presence of a rhodium complex of (S)-binap occurred via a
rhodium nitronate intermediate 5 to afford 2-phenyl-1-
nitrocyclohexane (6) in a high yield and excellent enanti-
oselectivity (eq 1).
Scheme 1. Nitroallyl Acetates Potentially Coupled with
Different Nucleophiles
(1) (a) Knochel, P.; Seebach, D. Tetrahedron Lett. 1981, 22, 3223. (b)
Seebach, D.; Knochel, P. NouV. J. Chim. 1981, 5, 75. (c) Seebach, D.;
Knochel, P. HelV. Chim. Acta 1984, 67, 261.
(2) Ono, N. The nitro group in organic synthesis; Wiley-VCH: New
York, 2001.
10.1021/ol051795n CCC: $30.25
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Published on Web 08/23/2005

complex of [Rh(acac)(C2H4)]2 with (R)-BINAP under the
standard conditions used for rhodium-catalyzed 1,4-addition
of arylboronic acids to nitroalkenes.4 We were delighted to
observe that the reaction gave the desired product 2a, the
structure of which was confirmed by X-ray diffraction
(Figure 1),9 with high enantioselectivity of 94% ee (entry
Despite the success in the rhodium-catalyzed 1,4-addition
of nitrocylcohexene with arylboronic acids,4 so far it is not
clear if the reaction of a 2-nitrocyclohex-2-enol ester such
as 1a with an arylboronic acid in the presence of a chiral
rhodium complex can undergo the 1,4-addition of phenyl-
boronic acid and then â-elimination of an ester group via an
assumed intermediate 76 to regenerate the catalyst and
liberate compound 2a (eq 2). To address this question, we
describe here the first asymmetric nitroallylation of arylbo-
ronic acids with nitroallyl acetate 1a and its structural
analogues in the presence of chiral rhodium complexes to
generate chiral nitroalkenes 2 with high enantioselectivities.
The utility of this method is also demonstrated in a concise
asymmetric total synthesis of optically pure (+)-γ-lycorane.7,8
Figure 1. X-ray structure of 2a.
1). The absolute configuration of the stereogenic center was
determined to be R by correlation with a known compound
(see the Supporting Information). However, the product was
only isolated in 30% yield because the starting substrate 1a
decomposed at 100 °C. Thus, optimization of the reaction
conditions is required (Table 1). The use of pivalic acid
We first reacted acetic acid 2-nitrocyclohex-2-enyl ester
(1a) with phenylboronic acid, catalyzed by a rhodium
Table 1. Rhodium-Catalyzed Asymmetric Nitroallylation of
2-Nitrocyclohex-2-enol Esters 1 with Phenylboronic Acida
(3) (a) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem.
Soc. 1990, 112, 7625. (b) Denmark, S. E.; Kramps, L. A.; Montgomery, J.
I. Angew. Chem., Int. Ed. 2002, 41, 4122. (c) Denmark, S. E.; Montgomery,
J. I. Angew. Chem., Int. Ed. 2005, 44, 3732.
(4) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716.
(5) For asymmetric 1,4-addition of arylboronic acids with electron-
deficient olefins, see a recent review: Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829.
(6) A â-oxygen elimination was proposed as a key step for the
asymmetric ring-opening reaction of oxanorbornene derivatives with
arylboronic acids catalyzed by chiral rodium complexes, see the leading
references: (a) Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org.
Lett. 2002, 4, 1311. (b) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem.
Res. 2003, 36, 48. (c) Marakami, M.; Igawa, H. Chem. Commun. 2002,
390.
entry
metal
1
T (°C) time (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
Rh(acac)(C2H4)2 1a 100
Rh(acac)(C2H4)2 1b 100
Rh(acac)(C2H4)2 1c 100
5
5
5
30
30
48
20
41
55
56
94
95
93
94
94
97
97d
[RhCl(COD)]2
1a 100
5
Rh(acac)(C2H4)2 1a
[Rh(OH)(COD)]2 1a
[Rh(OH)(COD)]2 1a
50
50
50
20
20
20
(7) For total syntheses of racemic γ-lycorane, see: (a) Ueda, N.;
Tokuyama, T.; Sakan, T. Bull. Chem. Soc. Jpn. 1966, 39, 2012. (b) Irie,
H.; Nishitani, Y.; Sugita, M.; Uyeo, S. J. Chem. Soc., Chem. Commun.
1970, 1313. (c) Tanaka, H.; Nagai, Y.; Irie, H.; Uyeo, S.; Kuno, A. J. Chem.
Soc., Perkin Trans. 1 1979, 874. (d) Genem, B. Tetrahedron Lett. 1971,
12, 4105. (e) Hara, H.; Hoshino, O.; Umezawa, B. Tetrahedron Lett. 1972,
13, 5031. (f) Umezawa, B.; Hoshino, O.; Sawaki, S.; Sato, S.; Numao, N.
J. Org. Chem. 1977, 42, 4272. (g) Iida, H.; Yuasa, Y.; Kibayashi, C. J.
Am. Chem. Soc. 1978, 100, 3598. (h) Iida, H.; Yuasa, Y.; Kibayashi, C. J.
Org. Chem. 1979, 44, 1074. (i) Higashiyama, H.; Honda, T.; Otomasu, H.;
Kametani T. Planta Med. 1983, 48, 268. (j) Sugiyama, N.; Narimiya, M.;
Iida, H.; Kibuchi, T. J. Heterocycl. Chem. 1988, 25, 1455. (k) Ba¨ckvall, J.
E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J. Org. Chem. 1991, 56,
2988. (l) Pearson W. H.; Sckeryantz, J. M. J. Org. Chem. 1992, 57, 6783.
(m) Grotjahn, D. B.; Vollhardt, P. C. Synthesis 1993, 579. (n) Banwell, M.
G.; Wu, A. W. J. Chem. Soc., Perkin Trans. 1 1994, 2671. (o) Angle, S.
R.; Boyce, J. P. Tetrahedron Lett. 1995, 36, 6185. (p) Ikeda, M.; Ohtani,
S.; Sato, T.; Ishibashi, H. Synthesis 1998, 1803. (q) Huang-Cong, X.;
Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2125. (r) Padwa,
A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001, 66, 1716. (s) Tamura,
O.; Matsukida, H.; Toyao, A.; Takeda, Y.; Ishibashi, H. J. Org. Chem.
2002, 67, 5537. (t) Shao, Z.; Chen, J.; Huang, R.; Wang, C.; Li, L.; Zhang,
H. Synlett 2003, 2228. (u) Yasuhara, T.; Osafune, E.; Nishimura, K.;
Yamashita, M.; Yamada, K.-i.; Muraoka, O.; Tomioka, K. Tetrahedron Lett.
2004, 45, 3043. (v) Gao, S.; Tu, Y. Q.; Song, Z.; Wang, A.; Fan, X.; Jiang,
Y. J. Org. Chem. 2005, 70, 6523.
a The reaction of arylboronic acid was performed in the presence of 5
mol % of rhodium complex and 6 mol % of (R)-BINAP in a solvent mixture
of dioxane/H2O ) 10/1. b Isolated yield. c The ee values were determined
by GC. d The ligand is (S)-BIANP.
2-nitro-cyclohex-2-enyl ester 1b to replace 1a as a substrate
did not suppress the decomposition, and a low yield was
(8) For total syntheses of optically active (+)-γ-lycorane, see: (a)
Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.; Mori, M. J.
Org. Chem. 1995, 60, 2016. (b) Cossy, J.; Tresnard, L.; Pard, D. G. Eur.
J. Org. Chem. 1999, 1925. (c) Banwell, M. G.; Harvey, J. E.; Hockless, D.
C. J. Org. Chem. 2000, 65, 4241.
(9) Crystal data of 2a: C12H13NO2, MW) 203.23, orthorhombic, space
group P212121, a ) 6.1206(5) Å, b ) 12.592(1) Å, c ) 14.007(1) Å, R )
90°, â ) 90°, γ ) 90°, U ) 1079.57(12) Å3, T ) 290(2) K, Z ) 4, Dc )
1.250 mg/m3, µ ) 0.085 mm-1, λ ) 0.71073 Å, F(000) 432, crystal size:
0.56 × 0.50 × 0.42 mm3, 1483 reflections collected, 1380 [R(int) ) 0.0122];
refinement method: full-matrix least-squares on F 2; goodness-of-fit on F 2
) 0.961, final R indices [I > 2σ(I)] R1 ) 0.0327, wR2 ) 0.0652.
4286
Org. Lett., Vol. 7, No. 19, 2005

still observed, with a maintained enantioselectivity (entry 2).
Although a higher yield was observed for 1c, the enantiose-
lectivity decreased slightly (entry 3). The yield could be
slightly improved to 41% by performing the reaction at 50
°C (entry 5). Screening of the transition-metal source
Total syntheses of racemic γ-lycorane have been
reported by several groups.7 A number of efforts8 have
also been reported toward asymmetric syntheses of optic-
ally active (+)-γ-lycorane with only one example regard-
ing the asymmetric catalytic construction of stereogenic
centers with 46% ee,8a a concisely asymmetric catalytic
total synthesis of optically pure (+)-γ-lycorane is there-
fore of great importance. Our newly developed nitroallyl-
ation of acetic acid 2-nitrocyclohex-2-enyl ester (1a) can
be used for the concise asymmetric total synthesis of
(+)-γ-lycorane (Scheme 2). The nitroallylation of 1a with
10
revealed that [Rh(OH)(COD)]2 is a better precatalyst
(entries 1-6). Thus, further improvement in the yield and
the enantioselectivity was achieved by using a rhodium
complex generated in situ from [Rh(OH)(COD)]2 and (R)-
or (S)-BINAP, which catalyzed the reaction in good yield
with 97% ee at 50 °C, and the decomposition of 1a was
minimized (entries 6 and 7). Despite the moderate yield
observed for the reaction, considering that the transformation
proceeds in a two-step reaction sequence (eq 2), the rhodium
complex of [Rh(OH)(COD)]2 and BINAP can be considered
an optimal catalyst system.
Scheme 2. Highly Enantioselective Total Synthesis of
(+)-γ-Lycorane
To determine if the optimal catalyst generated from [Rh-
(OH)(COD)]2 and (S)-BINAP maintains a generally high
enantioselectivity for aryl boronic acids, the nitroallylation
of a range of aryl boronic acids bearing either electron-
donating or -withdrawing substituents with 1a was examined.
As shown in Table 2, the reactions gave desired products in
Table 2. Nitroallylation of Acetic Acid 2-Nitrocyclohex-2-enol
Ester 1a with Arylboronic Acidsa
3,4-methylenedioxyphenylboronic acid in the presence
of 5 mol % of rhodium complex of [Rh(OH)(COD)]2 and
(S)-BINAP gave the product 2i in 65% yield and with
98% ee. The treatment of 2i with methyl acetate and lith-
ium diisopropylamine (LDA) at -78 °C furnished com-
pound 8 with a high diastereomeric ratio of 7:1 in favor of
the cis,cis-diastereomer. The cis,cis-8 was subjected to a
hydrogenation catalyzed by Raney nickel under 80 atm
of hydrogen at 55 °C, which directly formed lactam 9
in 95% yield. A modified Pictet-Spengler ring closure13
of 9 with paraformaldehyde and trifluoroacetic acid afford-
ed 10 in 88% yield. Reduction of 10 with lithium alum-
inum hydride gave (+)-γ-lycorane in 98% yield with an
optical rotation that is consistent with that of the natural
product.12 The overall yield of this concise total synthe-
sis of optically pure (+)-γ-lycorane from 1a is 38%.
Logically, (-)-γ-lycorane can be synthesized by this
strategy starting with the nitroallylation of 1a with
3,4-methylenedioxyphenylboronic acid in the presence
of the rhodium complex of [Rh(OH)(COD)]2 and
(R)-BINAP.
entry
product
Ar
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
56
63
58
64
61
67
52
58
97
95
96
99
98
90
94
96
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-tBu-C6H4
4-CF3C6H4
3-MeOC6H4
2g
2h
a All reactions were carried out on a 0.3 mmol scale (see the Supporting
Information). b Isolated yields. c Determined by HPLC or GC.
good yields and excellent enantioselectivities ranging from
90 to 99% ees. The electron nature of the substituent in
arylboronic acids does not considerably affect the reaction.
However, the enantioselectivity is to some degree dependent
on the steric bulkiness of the arylboronic acids. For example,
an enantioselectivity of only 90% ee was observed for 4-tert-
butylphenylboronic acid, which is much lower than those
of its structural analogues.
γ-Lycorane is a deoxygenated skeleton of Amarylliaceae
alkaloids.11 All of the ring junctures of γ-lycorane are cis.12
In conclusion, we have developed the first enantio-
selectiverhodium-catalyzed nitroallylation of nitroallyl
acetates with arylboronic acids. This study demonstrates
(10) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002,
124, 10984.
(11) (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 30, p 251. (b) Hoshino, O. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol. 51, p 323.
(12) Kotera, K. Tetrahedron 1961, 12, 248.
(13) Fan, C.-A.; Tu, Y.-Q.; Song, Z.-L.; Zhang, E.; Shi, L.; Wang, M.;
Wang, B.; Zhang, S.-Y. Org. Lett. 2004, 6, 4691.
Org. Lett., Vol. 7, No. 19, 2005
4287

that the rhodium complex of [RhOH(COD)]2 and optically
pure BINAP is an optimal catalyst, which provides
igh enantioselectivities ranging from 90 to 99% ees for
various arylboronic acids. A concise total synthesis of
optically pure (+)-γ-lycorane in overall 38% yield was
accomplished on the basis of this new method. Application
of this method to the asymmetric synthesis of other alkaloids
is under development.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(Grant Nos. 203900505 and 20325211).
Supporting Information Available: Experimental details
and selected HPLC and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051795N
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Org. Lett., Vol. 7, No. 19, 2005