Highly diastereoselective formation of 1,2,3-trisubstituted cyclopropane derivatives

Article abstract of DOI:10.1021/ol051653t

(Chemical Equation Presented) A highly diastereoselective formation of cyclopropane derivatives was reported. When the chiral phenylvinyl epoxide reacted with lithiated 2-alkyl-1,3-dithiane or lithiated alkyl carbonanion in the presence of HMPA, cyclopropanes bearing stereochemistry at all three positions on the ring were readily obtained in high yields of 80-97% and high dr values of 68:32-99:1. This reaction was supposed to be a tandem conjugation addition-epoxide opening sequence.

Full text of DOI:10.1021/ol051653t

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4057-4059
Highly Diastereoselective Formation of
1,2,3-Trisubstituted Cyclopropane
Derivatives
Xingang Xie,† Guoren Yue,†,‡ Shouchu Tang,† Xing Huo,† Qiren Liang,†
Xuegong She,*,†,§ and Xinfu Pan*,†
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou UniVersity, 730000, Lanzhou, P. R. China, and State Key Laboratory for Oxo
Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China
shexg@lzu.edu.cn
Received July 14, 2005
ABSTRACT
A highly diastereoselective formation of cyclopropane derivatives was reported. When the chiral phenylvinyl epoxide reacted with lithiated
2-alkyl-1,3-dithiane or lithiated alkyl carbonanion in the presence of HMPA, cyclopropanes bearing stereochemistry at all three positions on
the ring were readily obtained in high yields of 80−97% and high dr values of 68:32−99:1. This reaction was supposed to be a tandem
conjugation addition epoxide opening sequence.
−
Domino reactions have become very powerful synthetic tools
in organic synthesis. They not only reduce the production
of waste and the consumption of solvents; they also create
several bonds in one sequence without the isolation of
intermediates. Importantly, if cyclizations are involved in this
sequence, in most cases, ring closure proceeds in a highly
stereoselective fashion. This makes domino reactions highly
attractive for natural product synthesis and related applica-
tions.1 Michael-induced ring-closing (MIRC) reactions play
an important role in this field of chemistry, and many
synthetic applications have been described in the literature
so far.2
cinnamate derivatives as Michael acceptors in MIRC reac-
tions, and they were only used to synthesize 1,2-disubstituted
cyclopropanes.3 Herein, we report a new approach to
synthesize 1,2,3-trisubstituted cyclopropanes with high di-
astereoselectivity using unactivated phenylvinyl epoxides as
the Michael acceptors.
Initially, we attempted to study the SN2′ reaction of the
racemic phenylvinyl epoxide 1a under the reaction conditions
reported by A. B. Smith, III.4 Lithiated 2-ethyl-1,3-dithiane
2a was first examined as a nucleophile. In the presence of
HMPA, the reaction of 2a with 1a proceeded smoothly at
-50 to -20 °C in anhydrous THF. However, to our surprise,
In this reaction, olefins that behave as the Michael acceptor
must be activated by one or two strong electron-withdrawing
groups. There were few literature examples using unactivated
(1) Reviews: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131-163. (b) Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.
(c) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
(2) (a) Little, R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609-
2612. (b) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 1015-1036.
* To whom correspondence should be addressed. Fax: +86-931-
8912582.
(3) (a) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F.
Chem. Eur. J. 1999, 5, 2055-2068. (b) Majumdar, S.; de Meijere, A.;
Marek, I. Synlett 2002, 423-426.
(4) Smith, A. B., III; Pitram, S. M.; Gaunt, M. J.; Kozmin, S. A. J. Am.
Chem. Soc. 2002, 124, 14516-14517.
† Lanzhou University.
‡ Current address: Department of Chemistry, Hexi University, 734000,
Zhangye, Gansu, P. R. China.
§ Chinese Academy of Sciences.
10.1021/ol051653t CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/05/2005

Scheme 1. Cyclopropanation of Phenyl Vinyl Epoxide with
Table 1. Cyclopropanation of Substituted Phenyl Vinyl
Epoxide with Lithiated 2-Ethyl-1,3-dithiane
Lithiated 2-Ethyl-1,3-dithiane
entrya
1
R1
R2
3
yieldb
we did not obtain the expected product of SN2 or SN2′
reaction. Instead, a single product was obtained in high yield,
which was identified as 1,2,3-trisubstituted cyclopropane 3a
by NMR and X-ray analysis (Scheme 1).5 Further studies
showed that HMPA6 and low reaction temperature were
critical for this reaction to proceed. In the absence of HMPA,
no reaction took place, and the starting material 1a was
completely recovered. When the reaction was warmed to
room temperature, the reaction mixture became complex, and
it was difficult to separate the desired product 3a. Moreover,
the solvent played an important role in this reaction. For
example, the use of anhydrous THF as the solvent led to the
formation of 3a in high yield, whereas in toluene and ethyl
ether the reaction did not proceed satisfactorily. Several other
1
2
3
4
5
6
7c
1a
1b
1c
1d
1e
1f
Ph
4-Cl-Ph
Ph
4-Cl-Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
4-Cl-Ph
4-CH3-Ph
Bu
3a
3b
3c
3d
3e
90
95
88
91
80
1g
H
Ph
a Reaction conditions: 1 mmol of substrate (1), 2 mmol of lithiated
carbon anions (2a), 3 mmol of HMPA, 10 mL of anhydrous THF, -50 to
-20 °C, 20 h. See Supporting Information for details. b Isolated yield.
c Mixture of SN2 and SN2′ products were obtained in ratio of 1:4 in a total
yield of 80%.
the aryl group on the epoxide ring was replaced by an alkyl
group such as n-butyl (Table 1, entry 6), the reaction was
complex, and the desired cyclopropane product was obtained
only in a minor amount. Consistent with Smith’s result,4
when vinyl epoxide was used as the substrate (Table 1, entry
7), a mixture of SN2 and SN2′ products was obtained in 80%
yield. Therefore, it is crucial to have an aryl group on the
termination of the olefins and an aryl group on the termina-
tion of the epoxide for this cyclopropanation reaction to occur
under the current reaction conditions.
Table 2. Cyclopropanation of Chial Phenyl Vinyl Epoxide
with RLi
Figure 1. X-ray structure of 3a (CCDC deposition no. 222201).
yield
(%)b
entrya
R
3
drc
racemic vinyl epoxides7 were applied under the same
conditions to demonstrate the utility of this cyclopropanation
reaction, and the results are summarized in Table 1. When
monoepoxides of diaryl-substituted dienes were examined
(Table 1, entries 1-5), 1,2,3-trisubstituted cyclopropanes
were obtained as the single products in high yields. When
1
2
3
4
5
6
7
8
9
2-ethyl-1,3-dithianyl
2-methyl-1,3-dithianyl
1,3-dithianyl
2-(n-propanyl)-1,3-dithianyl
2-(i-propanyl)-1,3-dithianyl
2-(n-butyl)-1,3-dithianyl
2-(i-butyl)-1,3-dithianyl
2-(1-propenyl)-1,3-dithianyl
3a′
3f
3g
3h
3i
3j
3k
3l
97 98:2
95 99:1
90 95:5
92 95:5
92 99:1
96 99:1
93 98:2
89 97:3
(5) Crystal data for 3a: C22H26OS2, Mr ) 370.55, orthorhombic, space
group P2(1)2(1)2(1), a ) 6.604(1) Å, b ) 15.346(2) Å, c ) 19.811(3) Å,
â ) 90 (1)°, V ) 2007.7(4) Å3, Z ) 4, Fcalcd ) 1.226 g/cm3, µ ) 0.272
mm-1, F(000) ) 792, 1.68 e 2θ e 27.23°, -8 e h e 8, -19 e k e 19,
-25 e l e 25, 5561 data collected, 4493 unique data (Rint) 0.0144), 3302
data with I > 2σ(I), 232 refined parameters, GOF(F2) ) 0.885, R1 ) 0.0530,
wR2 ) 0.0788. The X-ray crystallographic structure of 3c is shown in Figure
1. The crystallographic data have been deposited at the Cambrigde
Crystallographic Data Center as supplementary publication No. CCDC
222201.
2-(3-methyl-1-propenyl)-1,3-dithianyl 3m 91 85:15
Me
n-Bu
10
11
3n
3o
90 68:32
95 95:5
a Reaction conditions: 1 mmol of substrate (1), 2 mmol of lithiated
carbonanions (2), 3 mmol of HMPA, 10 mL of anhydrous THF, -50 to
-20 °C, 20 h. See Supporting Information for details. b Isolated yield. c Dr
values were determined by HPLC (see Supporting Information).
4058
Org. Lett., Vol. 7, No. 18, 2005

To further investigate the stereoselectivity of this cyclo-
propanation reaction, optically pure epoxide 1a′ was chosen
as the model Michael acceptor; it was prepared from
(trans,trans)-1, 4-diphenyl-1, 3-butadiene by Shi’s method.8
A variety of 1,3-dithianyllithiums were used to react with
compound 1a′, and the results are summarized in Table 2
(entries 1-9). The corresponding cyclopropanation products
3 were obtained in high yield (89-97%) and high diaste-
reoselectivity (85:15-99:1). More interestingly, under the
same reaction conditions, alkyllithium reagents also proved
to be good nucleophiles, converting compound 1a′ into the
corresponding cyclopropane derivatives in 90-95% yield
(Table 2, entries 10 and 11). For n-butyllithium, the
diastereoselective ratio of the cyclopropane product 3o was
as high as 95:5, whereas methyllithium gave product 3n in
a 68:32 diastereomeric ratio.
On the basis of the experimental results, an MIRC
mechanism is suggested (Scheme 2). This cyclopropanation
reaction probably involves a tandem conjugation addition-
epoxide-opening sequence.
In summary, we have developed a new and highly
diastereoselective process for the synthesis of 1,2,3-trisub-
stituted cyclopropane derivatives in high yields. Using this
strategy, cyclopropane derivatives bearing stereochemistry
Scheme 2. Supposed Mechanism
at all three positions on the ring can be easily synthesized.
Investigation of the mechanism and further application of
this reaction in synthesis are underway.
Acknowledgment. We are grateful for the generous
financial support by the Special Doctorial Program Funds
of the Ministry of Education of China (20040730008), A
Hundred Talents Program of CAS, NSFC (QT program,
No.20372026) and the key grant project of Chinese ministry
of Education(No.105169).
(6) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001, 123, 6527-
6535.
(7) Racemic vinyl expoxides were easily obtained in high yield starting
from the corresponding allyl alcohols via m-CPBA epoxidation, Swern
oxidation, and wittig olfination sequences; see Supporting Information for
details.
Supporting Information Available: Typical experimen-
tal details and characterization data for all new compounds,
as well as crystal data of 3a (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z. X.; Shi, Y. J. Org.
Chem. 1998, 63, 2948-2953.
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