Catalytic asymmetric cyclopropanation of enones with dimethyloxosulfonium methylide promoted by a La-Li3-(Biphenyldiolate)3 + NaI complex

Article abstract of DOI:10.1021/ja076797c

Catalytic asymmetric cyclopropanation of enones with dimethyloxosulfonium methylide using a La-Li₃-(biphenyldiolate)₃ + NaI complex is described. The present method is complementary to the previously reported catalytic enantioselective methods in terms of ylides used, and trans products were exclusively obtained in good yield (96-73%) and high enantioselectivity (99-84% ee). Use of biphenyldiol 1b-H₂ and NaI additive was essential to achieve high enantioselectivity. Copyright

Full text of DOI:10.1021/ja076797c

Published on Web 10/11/2007
Catalytic Asymmetric Cyclopropanation of Enones with
Dimethyloxosulfonium Methylide Promoted by a La-Li3-(Biphenyldiolate)3 +
NaI Complex
Hiroyuki Kakei, Toshihiko Sone, Yoshihiro Sohtome, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received September 8, 2007; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
The cyclopropane unit is a common structural motif in biologi-
cally active natural and unnatural compounds. Its unique reactivity
and structural properties have led chemists to develop a new
methodology for cyclopropanation.1 Among the methods available,
cyclopropanation using ylides proceeds chemoselectively with
electron deficient olefins.2 Therefore, the method is complementary
to other variants, such as the Simmons-Smith type reaction and
the carbenoid-mediated reaction. Catalytic highly enantioselective
Simmons-Smith-type and carbenoid-mediated cyclopropanations
have been established;1,3 however, catalytic asymmetric cyclopro-
panation of electron deficient olefins with ylides is rare.4,5
Aggarwal4a and Gaunt4b reported pioneering studies on enantio-
selective cyclopropanations via the catalytic generation of chiral
sulfonium and ammonium ylides. On the other hand, MacMillan
Figure 1. Structures of (S)-La-M3-(ligand)3 complex, (S)-BINOL, and
realized high enantiocontrol by activating the electrophiles, R,â-
unsaturated aldehydes, with an organocatalyst.5a,6 High enantio-
selectivity was achieved using stabilized sulfonium ylides with a
â-ketone unit. With a Lewis acidic metal complex, a more reactive
sulfonium ylide was applicable; however, stoichiometric amounts
of a chiral ligand and a Lewis acid were required to obtain high
enantioselectivity (>90% ee).7 Thus, the development of a catalytic
cyclopropanation with a reactive ylide is desirable. Herein we report
a catalytic asymmetric Corey-Chaykovsky cyclopropanation of
enones2 with dimethyloxosulfonium methylide promoted by a La-
Li3-(biphenyldiolate)3 + NaI system (Figure 1, 1a-c). A NaI
additive as well as biphenyldiol 1b both had a key role in achieving
high enantioselectivity (up to 99% ee).
Initial optimization studies with dimethyloxosulfonium methylide
2 and enone 3a using heterobimetallic La-Li3-(ligand)3 com-
plexes8 are summarized in Table 1. On the basis of our recent
finding that biphenyldiols are sometimes superior to BINOL in rare
earth metal catalysts,9 we examined both BINOL and biphenyldiols
as ligands. When using ylide 2 prepared from trimethyloxosul-
fonium iodide and NaH (entries 1-2), 4a was obtained in 38% ee
with ligand 1a (entry 2), while the use of BINOL resulted in 1%
ee (entry 1). With ylide 2 prepared from trimethyloxosulfonium
chloride and NaH, however, the enantioselectivity decreased to 6%
ee (entry 4, ligand 1a). We assumed that the difference in entries
2 and 4 was due to NaI included in the ylide 2 solution in entry 2.
The beneficial effects of NaI on enantioselectivity were confirmed
by the reaction of ylide 2 prepared from trimethyloxosulfonium
chloride and NaH with 30 mol % of NaI additive, giving 4a in
37% ee (entry 5). Further optimizations of the NaI amount (entry
6), the solvent (entry 7), biphenyldiols (entries 7-11, 1a-c), and
additive (entries 10-11, MS 4 Å) revealed that 10 mol % of the
La-Li3-(1b)3 complex with NaI (10 mol %) and MS 4 Å additives
was the best combination, giving 4a in 86% yield and 89% ee (entry
11). Slow addition of enone 3a over 1.5 h was effective to improve
enantioselectivity, giving 4a in 97% yield and 97% ee (entry 12).
The optimized reaction conditions were applicable to various
enones, giving exclusively trans adducts in all entries (Table 2).
(S)-biphenyldiols 1a-H2, 1b-H2, and 1c-H2.
Table 1. Optimization of Reaction Conditions
additive
slow
time yield
(h) (%)
ee
entry
ligand
(mol %)
solvent
addition
(%)
1a
2a
3b
4b
5b
6b
7b
8b
9b
BINOL none
THF
THF
THF
THF
THF
THF
-
-
-
-
-
-
-
-
-
-
-
72 71
72 72 38
72 71
20 51
30 37 37
24 36 53
24 45 55
18 43 51
24 42 13
18 69 82
18 86 89
20 97 97
1
1a
none
BINOL none
1
6
1a
1a
1a
1a
1b
1c
none
NaI (30)
NaI (10)
NaI (10)
NaI (10)
NaI (10)
THF/tolc
THF/tolc
THF/tolc
10b 1a
11b 1b
12b 1b
NaI (10) + MS 4 Å THF/tolc
NaI (10) + MS 4 Å THF/tolc
NaI (10) + MS 4 Å THF/tolc
d
+
a Ylide 2 was prepared from trimethyloxosulfonium iodide and NaH.
b Ylide 2 was prepared from trimethyloxosulfonium chloride and NaH.
c THF/toluene ) 4/5. d 3a in THF/toluene was added slowly over 1.5 h.
Chalcone derivatives with either electron-withdrawing or electron-
donating substituents (entries 2-5) as well as heteroaryl-substituted
enones (entries 6-8) were applicable with 5 mol % catalyst loading,
giving products in high enantioselectivity (93-99% ee). Reaction
of 3i with two carbon-carbon double bonds proceeded chemo-
selectively at the electron deficient carbon-carbon double bond
(entry 9). With dienone 3j, 1,4-addition proceeded selectively, and
the trans-R,â-cyclopropyl adduct 4j was obtained in 89% yield and
91% ee (entry 10). Alkyl ketones 3k and 3l were also applicable
(entries 11-12). Catalyst loading was successfully reduced to 2.5
and 1 mol %, while maintaining good enantioselectivity (entries
13-15). Equation 1 illustrates preliminary investigation to further
extend the substrate scope to a carboxylic acid derivative. Cyclo-
propanation of R,â-unsaturated N-acylpyrrole 5 proceeded smoothly
using 5 mol % of catalyst and 1.0 equiv of ylide 2, giving product
9
13410
J. AM. CHEM. SOC. 2007, 129, 13410-13411
10.1021/ja076797c CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Cyclopropanation of Various
J. Corey at Harvard University for fruitful discussion on the reaction
mechanism and additive effects. H.K. is grateful for financial
support by a JSPS fellowship.
Enonesa
Supporting Information Available: Experimental procedures,
spectra data of new compounds, determination of absolute configura-
tions, additive effects, and ESI-MS data. This material is available free
of charge via the Internet at http://pubs.acs.org.
yieldb
(%)
ee
enone
cat/NaI
time
(h)
entry
R1
R2
(x mol %)
(%)
1
2
3
4
5
6
7
8
9
Ph
4-Cl-C6H4
4-MeO-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
5
5
5
5
5
5
5
5
5
5
5
10
2.5
1
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
96
93
95
92
93
96
94
91
92
89
74
73
90
82
94
94
93
97
96
95
99
99
95
96
91
84
94
93
97
94
References
(1) A review of stereoselective cyclopropanations: Lebel, H.; Marcoux, J.;
Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
4-Cl-C6H4
4-MeO-C6H4 3e
2-furyl
2-thienyl
4-pyridyl
(2) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(3) For selected recent examples with high ee, see Simmons-Smith type:
(a) Denmark, S. E.; O’Connor, S. P.; Wilson, S. R. Angew. Chem., Int.
Ed. 1998, 37, 1149. (b) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am.
Chem. Soc. 2001, 123, 12168 and references therein. Metallocarbenoid-
mediated reaction: (c) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.;
Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726. (d) Nishiyama, H.; Itoh,
Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc. 1994, 116,
2223. (e) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897. (f) Kanchiku, S.; Suematsu,
H.; Matsumoto, K.; Uchida, T.; Katsuki, T. Angew. Chem., Int. Ed. 2007,
46, 3889 and references therein. For other examples, see a review in ref
1.
3f
3g
3h
3i
3j
3k
3l
3a
3f
3g
4-allyl-O-C6H4 Ph
Ph -CHdCHPh
10
11c CH3
Ph
Ph
Ph
2-furyl
2-thienyl
12
iPr
13d Ph
14d Ph
15d Ph
1
a Reaction was performed in THF/toluene ) 4/5 (0.1 M on enones 3) at
-55 °C with MS 4 Å. Enone 3 in THF/toluene was added slowly over 2
h, and 1.2 equiv of ylide 2 prepared from trimethyloxosulfonium chloride
and NaH were used unless otherwise noted. b Isolated yield. c 4k was
volatile; 1.4 equiv of ylide 2 were used in entry 11. d Enone 3 was added
slowly over 3 h (entry 13) and 4 h (entries 14-15).
(4) Catalytic generation of chiral ylides: (a) Aggarwal, V. K.; Alonso, E.;
Fang, G. Y.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int.
Ed. 2001, 40, 1433 and references therein. (b) Papageorgiou, C. D.; Cubillo
de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004,
43, 4641.
(5) Catalytic activation of electrophiles: (a) Kunz R. K.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 3240. For similar works, (b) Hartikka,
A.; Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874. (c) Hartikka, A.;
Slo´sarczyka, A. T.; Arvidsson, P. I. Tetrahedron: Asymmetry 2007, 18,
1403.
(6) For other organocatalytic approach, see also (a) Arai, S.; Nakayama, K.;
Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999, 40, 4215. (b) Rios, R.;
Sunde´n, H.; Vesely, J.; Zhao, G.-L.; Dziedzic, P.; Co´rdova, A. AdV. Synth.
Catal. 2007, 349, 1028. (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W.
J. Am. Chem. Soc. 2007, 129, 10886.
6 in 68% yield and 98% ee. N-Acylpyrrole moiety in 6 was readily
converted into ethyl ester by treatment with NaOEt in 94% yield.10
(7) With stoichiometric amount of Lewis acids and a chiral ligand: Mamai,
A.; Madalengoitia, J. S. Tetrahedron Lett. 2000, 41, 9009.
(8) Review of heterobimetallic rare earth-alkali metal-BINOL complexes:
Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(9) Synthesis of ligand 1b-H2: (a) Harada, T.; Tuyet, T. M. T.; Oku, A. Org.
Lett. 2000, 2, 1319. Utility of biphenyldiols as rare earth metal
complexes: (b) Kakei, H.; Tsuji, R.; Ohshima, T.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2007, 2, 257 and references
therein. (c) Tosaki, S.-y.; Hara, K.; Gnanadesikan, V.; Morimoto, H.;
Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2006, 128, 11776. Use as alkaline earth metal complex:
(d) Yamaguchi, A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2007, 9, 3387.
In the present system, the best yield and enantioselectivity was
obtained with the NaI additive. ESI-MS analysis supported the idea
that a partial alkali metal exchange occurred in the presence of
NaI to afford a La-Li2-Na-(1b)3 complex in situ.11,12 A control
experiment with 10 mol % of La-Na3-(1b)3 complex alone under
the optimized conditions (slow addition, MS 4 Å) gave 4a from
3a in only 5% ee and 44% yield, while 10 mol % of La-Na3-
(1b)3 + LiI complex gave 4a in 88% ee and 94% yield. The results
also support the importance of Li/Na mixture system.11,13 On the
basis of previous structural analysis of heterobimetallic rare earth-
alkali metal-BINOL complexes and the effects of alkali metals
on enantioselectivity in other reactions,14,15 we speculate that the
partial alkali metal exchange in the present system would slightly
modify the asymmetric environment, thereby resulting in better yield
and enantioselectivity in the present reaction. Further mechanistic
studies to elucidate the precise role of NaI on enantioselectivity
are ongoing.
In summary, we achieved a catalytic asymmetric cyclopropana-
tion of enones and an N-acylpyrrole with dimethyloxosulfonium
methylide 2 using a La-Li3-(biphenyldiolate 1b)3 + NaI complex.
The present system is complementary to previously reported
organocatalytic methods in terms of ylide utilized,4,5 and products
were obtained in good yield (97-73%) and high ee (99-84%) with
1-10 mol % catalyst loading. The use of biphenyldiol 1b-H2 and
the NaI additive was important to achieve high enantioselectivity.
Further mechanistic studies16 as well as applications of the mixed-
alkali metal system in other asymmetric reactions are in progress.
(10) Utility of R,â-unsaturated N-acylpyrrole as an ester surrogate: Matsunaga,
S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 7559 and references therein.
(11) For more detailed results and discussion of the NaI and LiI effects, see
Supporting Information.
(12) Peaks corresponding to [La-Li3-Na-(1b)3]+ and [La-Li2-Na2-(1b)3]+
were observed (see Supporting Information).
(13) 10 mol % of La-Na3-(1b)3 + Bu4NI complex gave 4a in only 6% ee
and 46% yield, suggesting that I- would not be so important in this system.
(14) Drastic alkali metal effects on enantioselectivity were observed when
comparing the La-Li3-(BINOLate)3 complex and the La-Na3-
(BINOLate)3 complex in asymmetric 1,4-addition reaction.(a) Sasai, H.;
Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995,
117, 6194. For recent studies on the effects of alkali metals, see: (b)
Wooten, A. J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2007, 9, 3359. See
also, a review in ref 8.
(15) For structural analysis of heterobimetallic rare earth-alkali metal-BINOL
complexes, see a review in ref 7. See also: (a) Aspinall, H. C.; Bickley,
J. F.; Dwyer, J. L. M.; Greeves, N.; Kelly, R. V.; Steiner, A. Organo-
metallics 2000, 19, 5416. (b) Wooten, A. J.; Carroll, P. J.; Walsh, P. J.
Angew. Chem., Int. Ed. 2006, 45, 2549. (c) Di Bari, L.; Lelli, M.;
Pintacuda, G.; Pescitelli, G.; Marchetti, F.; Salvadori, P. J. Am. Chem.
Soc. 2003, 125, 5549.
(16) Although any proposed reaction mechanism is speculative at present, there
are two possibilities. One is simple Lewis acid-accelerated mechanism,
and the other mechanism is dual control of both enone 3 and ylide 2 by
the La-Li3-(1b)3 + NaI complex. Similar dual control mechanism is
proposed by MacMillan (see ref 5a). Interaction of ylide 2 with catalyst
might be operative through oxygen atom of ylide 2 in the latter case.
Mechanistic aspects of the present reaction will be reported in due course
as a full article. We proposed related dual control mechanism in aza-
Michael reaction of alkoxylamines: Yamagiwa, N.; Qin, H.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419.
Acknowledgment. This work was supported by Grant-in-Aid
for Specially Promoted Research from MEXT. We thank Prof. E.
JA076797C
9
J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007 13411