Efficient construction of a-spirocyclopropyl lactones: iridium-salen- catalyzed asymmetric cyclopropanation

Full text of DOI:10.1002/anie.200805527

Angewandte
Chemie
DOI: 10.1002/anie.200805527
Cyclopropanation
Efficient Construction of a-Spirocyclopropyl Lactones: Iridium–Salen-
Catalyzed Asymmetric Cyclopropanation**
Masami Ichinose, Hidehiro Suematsu, and Tsutomu Katsuki*
Chiral 1,4-cycloheptadiene structures are found in various
natural products, and several useful methods for their
construction have been reported.[1,2] Davies and co-workers
developed a tandem asymmetric cyclopropanation[3]–Cope
rearrangement with a-alkenyl a-diazoacetates as a carbene
source in the presence of a rhodium catalyst as an efficient
method for the synthesis of these structures.[4] Although the
first cyclopropanation step was highly enantioselective, the
yields of some reactions were unsatisfactory as a result of
undesired side reactions.[5] Recently, Doyle and co-workers
reported that cyclopropanation with the vinyl diazolactone 1
in the presence of the catalyst [Rh2((S,R)-MenthAZ)4] gave
a-spirocyclopropyl lactones in good yields; E (trans) selec-
tivity and enantioselectivity were moderate to good
(Scheme 1).[6] Since unsaturated lactones can be converted
cyclopropanation catalysis: Complex 2 catalyzes the cyclo-
propanation of not only simple olefins but also heterocyclic
compounds, such as benzofuran, with an a-diazoacetate at
À788C with high Z (cis) selectivity and high enantioselectivity
(Scheme 2).[7] Thus, we were intrigued by the possibility of
Scheme 2. Asymmetric cyclopropanation with the [Ir(salen)] complex
2.
carrying out asymmetric cyclopropanation reactions with 1 in
the presence of complex 2.
Scheme 1. Asymmetric cyclopropanation with the vinyl diazolactone 1.
MenthAZ=dirhodium(II) tetrakis[1R,2S,5R-menthyl 2-oxaazetidine-4S-
carboxylate].
We first examined the cyclopropanation of styrene
(10 equiv) with 1 in the presence of 2 (1 mol%) at À788C
(Table 1). The reaction in THF proceeded rapidly with good
diastereo- and enantioselectivity, and to our delight[8] with
trans rather than cis diastereoselectivity (Table 1, entry 1).
The trans selectivity and enantioselectivity were improved
when the reaction was carried out in acetone (Table 1,
entry 2). Finally, the reaction in dichloromethane was found
to proceed with almost complete trans selectivity and
enantioselectivity (Table 1, entry 3). We observed previously
that the dimerization of a-diazoacetates was accelerated by
complex 2;[7] however, the dimerization of 1 was found to be
much slower. When the quantity of styrene was halved
(5 equiv), the reaction also proceeded with high selectivity in
good yield (Table 1, entry 4). However, the yield of the
desired product was insufficient when the reaction was
carried out with just one equivalent of styrene; 1H NMR
spectroscopic analysis of the reaction mixture showed the
formation of a significant amount of 3,6-dihydro-3-hydroxy-
into various functional groups, these reaction products are
intrinsically versatile and useful building blocks. These
products were also converted into 1,4-cycloheptadiene deriv-
atives by heating after reduction with LiAlH4.[6]
We found recently that iridium–salen complexes with an
aryl group at the apical position show unique asymmetric
[*] M. Ichinose, H. Suematsu, Prof. T. Katsuki
Department of Chemistry, Faculty of Science
Graduate School, Kyushu University
Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
Fax: (+81)92-642-2607
E-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
[**] Financial support (Specially Promoted Research 18002011 and the
Global COE Program, “Science for Future Molecular Systems”)
through a Grant-in-Aid for Scientific Research from MEXT (Japan) is
gratefully acknowledged. H.S. is grateful for a JSPS Research
Fellowship for Young Scientists.
2H-pyran-2-one, a product resulting from insertion into an
[9]
À
O H bond of water (Table 1, entry 5). To suppress the
À
formation of the undesired O H-insertion product, we
carried out the reaction in the presence of 4 ꢀ molecular
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805527.
Angew. Chem. Int. Ed. 2009, 48, 3121 –3123
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3121

Communications
Table 1: Optimization of the iridium-catalyzed asymmetric cyclopropa-
nation of styrene.[a]
Table 2: Asymmetric cyclopropanation of various olefins.[a]
Entry
Styrene
[equiv]
Solvent
Yield [%][b]
trans/cis[c]
ee [%][d]
Entry
R1
R2
Yield [%][b]
trans/cis[c]
ee [%][d]
1
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
4-CH3-C6H4
2-MeO-C6H4
3-MeO-C6H4
2-Cl-C6H4
3-Cl-C6H4
2-naphthyl
Ph
H
H
H
H
H
H
H
H
H
H
Me
99 (>99)
99 (>99)
92 (97)
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
86:14
97
99
99
99
99
99
98
99
98
99
99
1
2
3
4
10
10
10
5
1
2
THF
82
>99
>99
92
88:12
92:8
84
86
99
99
99
99
99
2[e]
3[e]
4
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
>99:1
>99:1
>99:1
>99:1
>99:1
94 (98)
5
6
99 (>99)
96 (>99)
93 (97)
86 (88)
87 (90)
5
24[e]
94
6[f]
7[f,g]
7[e,f]
8[f,g]
9[f,g]
10[e,h]
11
2
85
94:6
>99:1
82:18
[a] The reaction of styrene and 1 (0.1 mmol) was carried out at À788C in
a solvent (0.24 mL) in the presence of 2 (1.0 mol% with respect to 1)
under N2, unless otherwise mentioned. [b] Yield of the isolated product.
[c] The trans/cis ratio was determined by 1H NMR spectroscopic analysis
(400 MHz). [d] The ee value of the trans isomer was determined by HPLC
analysis on a chiral phase (Daicel chiralcel OB-H). [e] The major product
was 3,6-dihydro-3-hydroxy-2H-pyran-2-one. [f] Molecular sieves (4 ꢀ)
were added. [g] The reaction was carried out on a 1.0 mmol scale.
67 (73)
99 (>99)
12
H
99 (>99)
>99:1
98
13
H
98 (>99)
>99:1
98
14[i]
15[i]
H
H
79 (83)
92 (98)
95:5
99
99
>99:1
À
sieves. Although the undesired O H insertion was suppressed
16
H
97 (>99)
>99:1
98
well under these conditions, the reaction with one equivalent
of styrene was slow. With two equivalents of styrene, the
product was obtained with excellent stereoselectivity (trans/
cis > 99:1, 99% ee (trans isomer)) in good yield (Table 1,
entry 6). The reaction was also efficient on a 1 mmol scale
(Table 1, entry 7).
[a] The reaction was carried out on a 0.1 mmol scale (with respect to 1) at
À788C in the presence of 4 ꢀ molecular sieves (MS; 20 mg) in CH2Cl2
(0.20 mL) under N2, unless otherwise mentioned. [b] Yield of the isolated
product. The value in the parentheses is the yield determined by 1H NMR
spectroscopy with 1-bromonaphthalene as an internal standard. [c] The
trans/cis ratio was determined by 1H NMR spectroscopic analysis
(400 MHz). [d] The ee value was determined as described in the
Supporting Information. [e] The reaction was carried out with five
equivalents of the olefin. [f] The reaction was carried out with 5 mol% of
2. [g] The reaction was carried out with 10 equivalents of the olefin.
[h] The reaction was carried out at À608C. [i] The reaction was carried out
with 3 mol% of 2.
We examined the transformation of a variety of olefin
substrates under the optimized conditions (Table 2). The
reactions of 4-substituted styrene derivatives proceeded with
high enantio- (99% ee) and trans selectivity (> 99:1),
although the enantioselectivity was slightly lower when
4-methoxystyrene was used (97% ee; Table 2, entries 1–5).
The reactions of 2- and 3-methoxystyrene also proceeded with
high enantio- and trans selectivity (Table 2, entries 6 and 7);
with 2- and 3-chlorostyrene, high enantioselectivity and good
trans selectivity (86:14 and 94:6, respectively) were observed
(Table 2, entries 8 and 9). Substitution at the 2- and/or 3-
position reduced the reactivity of the substrate to some extent
(Table 2, entries 7–10). The reaction of a-methylstyrene also
proceeded with excellent enantioselectivity and in good yield,
albeit with moderate trans selectivity (Table 2, entry 11). The
reactions of various 1,3-butadiene derivatives occurred at the
terminal double bond with excellent trans selectivity and
enantioselectivity to furnish the desired dialkenyl cyclopro-
pane products in good yields, irrespective of the substitution
pattern of the internal 3-alkenyl moiety of the substrate
(Table 2, entries 12–16). Although the presence of a substitu-
ent at C3 made the reaction slower, the products were
obtained in acceptable yields when the catalyst loading was
increased to 3 mol% under otherwise identical conditions
(Table 2, entries 14 and 15).
specifically. Although the cyclopropane substrates included a
small amount of the cis isomer, each product was a single
isomer, because only the trans isomer underwent the rear-
rangement (Scheme 3).[10]
Hydrolysis of the resulting 1-alkenyl 5-oxaspiro[2.5]oct-7-
en-4-ones took place with a Cope rearrangement at room
temperature to give 1,4-cycloheptadiene derivatives stereo-
Scheme 3. Cope rearrangement of 1,2-divinyl cyclopropanes.
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2009, 48, 3121 –3123
3122
www.angewandte.org

Angewandte
Chemie
5047 – 5060; c) M. Inoue, M. W. Carson, A. J. Frontier, S. J.
In summary, we have developed a powerful method for
the synthesis of 5-oxaspiro[2.5]oct-7-en-4-ones, versatile
chiral building blocks, in a highly enantio- and trans-selective
manner with the iridium–salen catalyst 2. The cyclopropana-
tion of aryl- and alkenyl-substituted olefins proceeded with
excellent enantioselectivity (ꢀ 97% ee) and high trans selec-
tivity (ꢀ 94:6, with the exception of two examples). In
particular, all the reactions of 1,3-dienes showed excellent
enantio-, regio- and trans selectivity, irrespective of the
substitution pattern of the internal conjugated alkenyl
group. Upon hydrolysis, the 1-alkenyl spirocyclopropyl lac-
tone products underwent stereospecific Cope rearrangement
at room temperature to furnish 1,4-cycloheptadiene deriva-
tives.
Danishefsky, J. Am. Chem. Soc. 2001, 123, 1878 – 1889;
d) H. M. L. Davies, O. Loe, D. G. Stafford, Org. Lett. 2005, 7,
5561 – 5563; e) J. Nikolai, O. Loe, P. M. Dominiak, O. O. Gerlitz,
J. Autschbach, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129,
10763 – 10772; f) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10,
573 – 576.
[3] For reviews covering asymmetric cyclopropanation, see: a) H.
Level, J. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003,
103, 977 – 1050; b) H. M. Davies, E. Antoulinakis, Org. React.
2001, 57, 1 – 326; c) A. Padwa, K. E. Krumpe, Tetrahedron 1992,
48, 5385 – 5453.
[4] a) H. M. L. Davies, D. G. Stafford, B. D. Doan, J. H. Houser, J.
Am. Chem. Soc. 1998, 120, 3326 – 3331; b) H. M. L. Davies, P. R.
Bruzinski, D. H. Lake, N. Kong, M. J. Fall, J. Am. Chem. Soc.
1996, 118, 6897 – 6907.
[5] a) H. M. L. Davies, L. M. Hodges, J. J. Matasi, T. Hansen, D. G.
Stafford, Tetrahedron Lett. 1998, 39, 4417 – 4420; b) P. Buluga-
hapitiya, Y. Landais, L. Parra-Rapado, D. Planchenault, V.
Weber, J. Org. Chem. 1997, 62, 1630 – 1641; c) Y. Landais, D.
Planchenault, V. Weber, Tetrahedron Lett. 1994, 35, 9549 – 9552;
d) H. M. L. Davies, N. J. S. Huby, W. R. Cantrell, Jr., J. L. Olive,
J. Am. Chem. Soc. 1993, 115, 9468 – 9479.
Experimental Section
Typical procedure (Table 1, entry 7): Styrene (0.23 mL, 2.0 mmol) was
added with a syringe to a mixture of 1 (124.1 mg, 1.0 mmol) and 4 ꢀ
molecular sieves (200 mg) in dry dichloromethane (2.0 mL) in a
Schlenk tube (10 mL) at room temperature under N2. The resulting
mixture was cooled to À788C and stirred for 10 min. Complex 2
(11.1 mg, 10.0 mmol) was then added, and the reaction mixture was
stirred for 2 days. The mixture was then allowed to warm to room
temperature, passed through a pad of silica gel to remove the catalyst,
and concentrated on a rotary evaporator. The residue was submitted
to 1H NMR spectroscopic analysis to determine the trans/cis ratio
(>99:1) and purified by chromatography on silica gel (hexane/
diisopropyl ether 1:0–7:1) to give trans-3a (170.2 mg, 85%) as a white
solid. The ee value of the trans product was determined by HPLC
analysis (Daicel chiralcel OB-H; 99% ee).
[6] D. Bykowski, K.-H. Wu, M. P. Doyle, J. Am. Chem. Soc. 2006,
128, 16038 – 16039.
[7] a) S. Kanchiku, H. Suematsu, K. Matsumoto, T. Uchida, T.
Katsuki, Angew. Chem. 2007, 119, 3963 – 3965; Angew. Chem.
Int. Ed. 2007, 46, 3889 – 3891; b) H. Suematsu, S. Kanchiku, T.
Uchida, T. Katsuki, J. Am. Chem. Soc. 2008, 130, 10327 – 10337.
[8] The cis-dialkenyl cyclopropane is the starting material required
for the subsequent Cope rearrangement.
À
[9] For examples of O H insertion reactions, see: a) M. P. Doyle,
M. A. McKervey, T. Ye, Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds, Wiley, New York, 1998,
chap. 8; b) T. Ye, M. A. McKervey, Chem. Rev. 1994, 94, 1091 –
1160; c) D. J. Miller, C. J. Moody, Tetrahedron 1995, 51, 10811 –
10843; d) Y. Landais, D. Planchenault, V. Weber, Tetrahedron
Lett. 1994, 35, 9549 – 9552; e) E. Aller, D. S. Brown, G. G. Cox,
D. J. Miller, C. J. Moody, J. Org. Chem. 1995, 60, 4449 – 4460;
f) M. P. Doyle, M. Yan, Tetrahedron Lett. 2002, 43, 5929 – 5931;
g) S.-F. Zhu, C. Chen, Y. Cai, Q.-L. Zhou, Angew. Chem. 2008,
120, 946 – 948; Angew. Chem. Int. Ed. 2008, 47, 932 – 934.
[10] Although the absolute configuration of the cyclopropanation
and Cope rearrangement products was not determined, we could
determine the relative configuration of the Cope rearrangement
product derived from the cyclopropanation product in entry 12
of Table 2 by X-ray crystallographic analysis. CCDC 708640
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Received: November 12, 2008
Published online: March 25, 2009
Keywords: asymmetric catalysis · cyclopropanation · iridium ·
.
salen ligands · spiro compounds
[1] a) M. A. Battiste, P. M. Pelpherey, D. L. Wright, Chem. Eur. J.
2006, 12, 3438 – 3447; b) B. M. Trost, H. C. Shen, D. B. Horne,
F. D. Toste, B. G. Steinmetz, C. Koradin, Chem. Eur. J. 2005, 11,
2577 – 2590; c) P. A. Wender, L. O. Haustedt, J. Lim, J. A. Love,
T. J. Williams, J.-Y. Yoon, J. Am. Chem. Soc. 2006, 128, 6302 –
6303.
[2] For the synthesis of 1,4-cyclohexadiene-containing natural
products, see: a) K. Kawazu, Agric. Biol. Chem. 1980, 44,
1367 – 1372; b) A. D. Patil, A. J. Freyer, L. Kilmer, P. Offen, B.
Carte, A. J. Jurewiez, R. K. Johnson, Tetrahedron 1997, 53,
Angew. Chem. Int. Ed. 2009, 48, 3121 –3123
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3123