Vitamin B12 derivatives as natural asymmetric catalysts: enantioselective cyclopropanation of alkenes.

Article abstract of DOI:10.1021/jo049870f

Vitamin B(12) derivatives were found for the first time to be general and efficient catalysts for asymmetric cyclopropanation of alkenes with ethyl diazoacetate (EDA). Among several common derivatives, aquocobalamin (B(12a)) was shown to be the most effec

Full text of DOI:10.1021/jo049870f

Vita m in B12 Der iva tives a s Na tu r a l Asym m etr ic Ca ta lysts:
En a n tioselective Cyclop r op a n a tion of Alk en es
Ying Chen and X. Peter Zhang*
Department of Chemistry, University of Tennessee, Knoxville, Tennessee 37996-1600
pzhang@utk.edu
Received J anuary 22, 2004
Vitamin B12 derivatives were found for the first time to be general and efficient catalysts for
asymmetric cyclopropanation of alkenes with ethyl diazoacetate (EDA). Among several common
derivatives, aquocobalamin (B12a) was shown to be the most effective catalyst for a variety of alkenes,
providing cis-dominant cyclopropanes in excellent yields and moderate enantioselectivity. Reactivity
studies under different conditions suggest that the active species in the proposed catalytic cycle is
the base-on cob(II)alamin (B12r) that is generated possibly via in situ reduction of B12a by EDA.
In tr od u ction
The vitamin B12 and its derivatives are the first known
naturally occurring organometallic compounds that play
a number of essential roles in biological systems.1 They
share the common cobalamin structure (Figure 1), the
core of which is a low-spin Co(III) complex of corrin
macrocycle that is highly substituted by methyl and
amide groups in the periphery. In addition to the four
equatorial nitrogen atoms of the corrin ring, the metal
center is further coordinated by an intramolecularly
bound 5,6-dimethylbenzimidazole at the lower axial site
and a sixth ligand R at the upper axial site. The nature
of the ligand R gives rise to the different derivatives of
vitamin B12 such as cyanocobalamin (CNCbl, R ) CN),
methylcobalamin (MeCbl, R ) CH3), coenzyme B12
(AdoCbl, R ) 5′-deoxyadenosyl), aquocobalamin (B12a, R
) HO‚HCl), and the reduced form cob(II)alamin (B12r, R
) e) (Figure 1). Among a number of essential functions
in biological systems, the vitamin B12-dependent enzymes
are notably known for mediating diverse isomerization
reactions that correspond to intramolecular 1,2-shift
between an H atom and an O, N, or C group on vicinal
carbons and for promoting ribonucleotide reductase (RR)
in the reduction of the ribose to the deoxyribose moiety
during the first step of the biosynthesis of DNA.1 The
fascinating structures, the unique catalytic activities, and
their intriguing mechanisms2 have attracted the growing
interest of scientists from numerous disciplines ever since
the landmark establishment of the structure of vitamin
B12 half a century ago.3
F IGURE 1. Structures of vitamin B12 derivatives.
Inspired by the extraordinary catalytic abilities of the
natural organometallic system, there have been continu-
ous searches for new catalytic reactions of vitamin B12
derivatives in nonbiological environments. As a result,
a number of vitamin B12-mediated chemical transforma-
tions that are unknown for vitamin B12-dependent en-
zymes have been discovered, including new carbon-
carbon bond formation reactions.4 Of special interest in
organic synthesis is the possibility that vitamin B12
(3) (a) Hodgkin, D. C., Pickworth, J .; Robertson, J . H.; Trueblood,
K. N.; Prosen, R. J .; White, J . G. Nature 1956, 176, 325. (b) Lenhert,
P. G.; Hodgkin, D. C. Nature 1961, 192, 937. (c) Hodgkin, D. C. Science
1965, 150, 979.
(4) (a) Branchaud, B. P.; Friestad, G. K. In Encyclopedia of Reagents
for Organic Synthesis; Paguette, L., Ed.; Wiley: New York, 1995; pp
5511-5514. (b) Pattenden, G. Chem. Soc. Rev. 1988, 17, 361. (c)
Scheffold, R.; Abrecht, S.; Orlinski, R.; Ruf, H.-R.; Stamouli, P.;
Tinembart, O.; Walder, L.; Weymuth, C. Pure Appl. Chem. 1987, 59,
363. (d) Scheffold, R.; Rytz, G.; Walder, L., In Modern Synthetic
Methods; Scheffold, R., Ed.; Wiley: New York, 1983; Vol. 3, pp 355-
440. (e) Shey, J .; McGinley, C. M.; McCauley, K. M.; Dearth, A. S.;
Young, B. T.; van der Donk, W. A. J . Org. Chem. 2002, 67, 837 and
references therein. (f) Njue, C. K.; Nuthakki, B.; Vaze, A.; Bobbitt, J .
M.; Rusling, J . F. Electrochem. Commun. 2001, 3, 733.
* To whom correspondence should be addressed. Fax: 865-974-3454.
(1) (a) Chemistry and Biochemistry of B12; Banerjee, R., Ed.; Wiley-
Interscience: New York, 1999. (b) Vitamin B12 and B12 Proteins;
Krautler, B., Arigoni, D., Golding, B. T., Eds.; Wiley-VCH: Weinheim,
1998. (c) Schneider, Z.; Stroinski, A. Comprehensive B12; W. de
Gruyter: Berlin, 1987. (d) B12; Dolphin, D., Ed.; Wiley-Interscience:
New York, 1982. (e) Pratt, J . M. Inorganic Chemistry of Vitamin B12
;
Academic Press: London, 1972.
(2) (a) Halpern, J . Science 1985, 227, 869. (b) Pratt, J . M. Pure Appl.
Chem. 1993, 65, 1513.
10.1021/jo049870f CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/03/2004
J . Org. Chem. 2004, 69, 2431-2435
2431

Chen and Zhang
TABLE 1. Cyclop r op a n a tion of Styr en e w ith
EDA-Ca ta lyzed by Vita m in e B12 Der iva tivesa
SCHEME 1. Cyclop r op a n a tion of Alk en es
Ca ta lyzed by Vita m in B12 Der iva tives
entry
cobalaminb
temp (°C)
yieldc
cis:transc
ee(%)d
1
2
3
4
5
6
7
8
CNCbl
CNCbl
MeCbl
MeCbl
AdoCbl
AdoCbl
B12a
23
80
23
80
23
80
23
80
1
34
3
86
7
82
13
98
-(-)
56:44
57:43
61:39
56:44
61:39
67:33
61:39
47(29)
63(35)
62(52)
59(32)
61(51)
78(59)
64(54)
derivatives can be used as asymmetric catalysts in view
of the natural existence of multiple stereogenic centers
surrounding the metal center.5 Demonstrated examples
of vitamin B12-mediated enantioselective processes are
presently limited to conjugate reduction of R,â-unsatur-
ated carbonyl compounds6 and isomerization reactions
of cyclic compounds such as epoxides, aziridines, and
cyclopropanes.7 As part of our research program of
metalloporphyrin-based catalysis8 and considering the
close structural relationship between porphyrin and
corrin macrocycles, we became interested in exploring the
application of vitamin B12 derivatives as natural asym-
metric catalysts for important organic transformations
such as carbon-carbon bond formation reactions. We
reveal herein that vitamin B12 derivatives are general
and efficient catalysts for asymmetric cyclopropanation
of alkenes with ethyl diazoacetate (EDA), producing cis-
dominant cyclopropanes in excellent yields and moderate
enantioselectivity (Scheme 1). This represents the first
example of a vitamin B12 system that is effective for
mediating this class of important reactions.9
B12a
a
Carried out in TFE for 24 h under N2 with 1.0 equiv of styrene,
1.2 equiv of EDA, and 2 mol % vitamin B12 derivative. Concentra-
tion: 0.5 mmol styrene/2 mL TFE. See Figure 1. c Determined
b
d
by GC. Determined by chiral GC: cis(trans).
Although all the reactions were operated with styrene
as the limiting reagent, the dimerization products of
EDA, ethyl maleate, and fumarate were not observed or
observed in a very small amount. This desirable feature
is atypical for most of known cyclopropanation catalytic
systems9,10 as large excesses of alkenes have to be applied
to minimize the common side products. Among the
vitamin B12 derivatives, the catalytic efficiency varied
from moderate for CNCbl to high for MeCbl and AdoCbl
to excellent for B12a. This reactivity trend can be readily
explained by the relative lability of the ligand R of the
vitamin B12 derivatives (Figure 1).4e,11 At 80 °C, the use
of B12a as the catalyst resulted in the quantitative
formation of the cis-dominant cyclopropanes (cis:trans )
61:39) in moderate enantioselectivities (cis 64% ee; trans
54% ee) (Table 1, entry 8). Although the yield was much
lower, the enantioselectivity of B12a could be further
improved when the reaction was performed at room
temperature (cis 78% ee; trans 59% ee) (Table 1, entry
7).
The finding of TFE as the most effective solvent
resulted from a detailed study of solvent effect on the
catalytic reaction. As indicated in Table 2, the catalytic
activity of B12a has a remarkable solvent dependence. The
initial use of common organic solvents such as toluene
and chlorobenzene resulted in low yields and low selec-
tivities (Table 2, entries 1 and 2). Improvements were
obtained when more polar solvents such as tetrahydro-
furan, acetonitrile, dimethylformamide, and dimethyl
sulfoxide were employed (Table 2, entries 3-6). This led
to the attempts of using alcohols as reaction solvents, as
they are known to well solubilize vitamin B12 derivatives
including B12a. Although both methanol and ethanol gave
poor results (Table 2, entries 7 and 8), further improve-
ments in both yields and selectivities were noted when
higher alcohols such as 2-propanol, 1-butanol, and 1-hex-
anol were utilized (Table 2, entries 9-11). Among all
solvents tested, the fluorinated ethanol TFE was found
to afford the desired product in the best yield and
selectivity, suggesting factors besides solubility may play
important roles in the catalytic process (Table 2, entry
12).
Resu lts a n d Discu ssion
The catalytic activities of the four common vitamin B12
derivatives CNCbl, MeCbl, AdoCbl, and B12a (Figure 1)
were investigated for cyclopropanation reaction using
styrene as a model substrate and ethyl diazoacetate
(EDA) as a carbene source. The reactions were carried
out under a nitrogen atmosphere for 24 h at room
temperature or 80 °C in trifluoroethanol (TFE), the most
effective solvent found for the system (vide infra), with
1.2 equiv of EDA, using 2 mol % vitamin B12 derivative
per styrene. As shown in Table 1, all of the derivatives
were capable of catalyzing the reaction to give cis-
dominant cyclopropanes with observed asymmetric in-
ductions for both the diasteromers. An elevated reaction
temperature was needed for high-yielding reactions, as
the reaction rates were slow at room temperature.
(5) Pfaltz, A. In Modern Synthetic Methods; Scheffold, R., Ed.;
Springler-Verlag: Berlin, 1989; Vol. 5, pp 199-248.
(6) (a) Fischli, A.; Suss, D. Helv. Chim. Acta 1979, 62, 48. (b) Fischli,
A.; Suss, D. Helv. Chim. Acta 1979, 62, 2361. (c) Fischli, A.; Daly, J . J .
Helv. Chim. Acta 1980, 63, 1628. (d) Fischli, A. Helv. Chim. Acta 1982,
65, 2697.
(7) (a) Su, H.; Waldler, L.; Zhang, Z.-D.; Scheffold, R. Helv. Chim.
Acta 1988, 71, 1073. (b) Busato, S.; Tinembart, O.; Zhang, Z.-D.;
Scheffold, R. Tetrahedron 1990, 46, 3155. (c) Bonhote, P.; Scheffold,
R. Helv. Chim. Acta 1991, 74, 1425. (d) Zhang, Z.-D.; Scheffold, R. Helv.
Chim. Acta 1993, 76, 2602. (e) Troxler, T.; Scheffold, R. Helv. Chim.
Acta 1994, 77, 1193.
(8) (a) Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J . Org.
Chem. 2003, 68, 3714. (b) Chen, Y.; Huang, L.; Zhang, X. P. J . Org.
Chem. 2003, 68, 5925. (c) Chen, Y.; Huang, L.; Zhang, X. P. Org. Lett.
2003, 5, 2493. (d) Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X. P. J . Org.
Chem. 2003, 68, 8179. (e) Lee, M.-Y.; Chen, Y.; Zhang, X. P. Organo-
metallics 2003, 22, 4905.
(10) Ikeno, T.; Iwakura, I.; Yamada, T. J . Am. Chem. Soc. 2002, 124,
15152.
(9) (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (b) Doyle, M.
P.; Ren, T. Prog. Inorg. Chem. 2001, 49, 113. (c) Doyle, M. P.;
Protopopova, M. N. Tetrahedron 1998, 54, 7919. (d) Doyle, M. P.;
Forbes, D. C. Chem. Rev. 1998, 98, 911. (e) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091. (f) Padwa, A.; Krumpe, K. E. Tetrahedron
1992, 48, 5385-5453. (g) Salaun, J . Chem. Rev. 1989, 89, 1247.
(11) (a) Hamza, M. S. A.; Zou, X.; Brown, K. L.; van Eldik, R. J .
Chem. Soc., Dalton Trans. 2002, 3832. (b) Hamza, M. S. A.; Zou, X.;
Brown, K. L.; van Eldik, R. Inorg. Chem. 2001, 40, 5440. (c) Marques,
H. M.; Bradley, J . C.; Brown, K. L.; Brooks, H. Inorg. Chim. Acta 1993,
209, 161. (d) Brown, K. L.; Satyanarayana, S. Inorg. Chim. Acta 1992,
201, 113.
2432 J . Org. Chem., Vol. 69, No. 7, 2004

Vitamin B12 Derivatives as Asymmetric Catalysts
TABLE 2. Solven t Effect on Cyclop r op a n a tion of
TABLE 4. Cyclop r op a n a tion of Alk en es w ith EDA
a
a
Styr en e w ith EDA by B12a
Ca ta lyzed by B12a
entry
solvent
toluene
chlorobenzene
tetrahydrofuran
acetonitrile
dimethylformamide
dimethylsulfoxide
methanol
ethanol
2-propanol
1-butanol
1-hexanol
yieldb
cis:transb
ee(%)c
1
2
3
4
5
6
7
8
9
35
39
55
55
52
59
45
49
66
63
72
98
39:61
52:48
43:57
64:46
68:32
62:38
65:35
64:36
63:37
65:35
64:36
61:39
7(1)
34(7)
17(5)
34(21)
48(28)
47(31)
53(41)
49(34)
45(32)
48(35)
48(36)
64(54)
10
11
12
trifluoroethanol
a
Carried out at 80 °C for 24 h under N2 with 1.0 equiv of
styrene, 1.2 equiv of EDA, and 2 mol % B12a. Concentration: 0.5
b
mmol styrene/2 mL solvent. Determined by GC. c Determined by
chiral GC: cis(trans).
TABLE 3. Cyclop r op a n a tion of Styr en e w ith EDA by
B12a u n d er Differ en t Con d ition sa
B12a
(mol%)
temp
(°C)
time
(h)
yield
(%)b
entry
cis:transb
ee(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
2
2
2
5
10
1
0.5
2
5
10
2
5
80
80
80
80
80
80
80
50
50
50
23
23
23
24
13
4
98
93
83
95
99
89
57
61
72
78
13
19
34
61:39
61:39
61:39
60:40
60:40
61:39
61:39
65:35
65:35
65:35
67:33
67:33
67:33
64(54)
64(54)
64(55)
64(55)
65(54)
62(54)
59(50)
72(57)
73(62)
73(61)
78(59)
78(66)
77(65)
24
24
24
24
24
24
24
24
24
24
10
a
Carried out at 80 °C in TFE for 12-15 h under N2 with 1.0
a
Carried out in TFE under N2 with 1.0 equiv of styrene, 1.2
equiv of EDA, and catalytic amount of B12a. Concentration: 0.5
equiv of alkene, 1.2 equiv of EDA, and 2 mol % of B12a. Concentra-
tion: 0.5 mmol alkene/2 mL TFE. Isolated yields. c Determined
b
b
mmol styrene/2 mL TFE. Determined by GC. c Determined by
by GC. Determined by chiral GC: cis(trans). e Determined by 1H
d
NMR using Eu(hfc)3 as a chiral shift reagent. f Not resolved. No
g
chiral GC: cis(trans).
diastereomer.
In addition to the solvent effect, the catalytic reaction
by B12a in TFE was evaluated under various conditions,
including catalyst loading, reaction temperature, and
reaction time (Table 3). At 80 °C using 2 mol % B12a, the
reaction time could be shortened from 24 to 13 h without
significantly affecting the yield and selectivity, although
a lower yield was observed when the reaction was stopped
within 4 h (Table 3, entries 1-3). Although increase in
catalyst loading had no obvious improvement in selectiv-
ity (Table 3, entries 4 and 5), reduction in catalyst
loadings resulted in lower yields (Table 3, entries 6 and
7). The reaction could proceed at 50 °C and even at room
temperature, but in slower rates that resulted in incom-
plete conversions within 24 h (Table 3, entries 8 and 11).
The lower yields could be improved when higher catalyst
loadings were employed (Table 3, entries 9, 10, 12, and
13). In all cases, lower reaction temperatures gave better
diastereoselectivity and enantioselectivity.
Under the current optimized reaction conditions for
styrene (using 2 mol % B12a at 80 °C for 12-15 h in TFE),
the substrate scope of the cyclopropanation reaction by
B12a was further explored with a variety of alkenes. The
results obtained with a series of styrene derivatives are
given in Table 4. Similar to styrene (Table 4, entry 1),
alkyl-substituted derivatives such as those having a
methyl group at the para, meta, or ortho postion or a tert-
butyl group at the para position were suitable substrates,
giving the corresponding cis-dominant cyclopropanes in
excellent isolated yields and moderate enantioselectivities
(Table 4, entries 3-6). Whereas styrene derivatives with
electron-withdrawing substituents such as trifluoro-
methyl and bromo groups gave relatively lower isolated
yields, the cyclopropanation of the electron-rich styrene
4-methoxystyrene proceeded in excellent isolated yield.
High-yielding cyclopropanation reactions were also
achieved for R-substituted styrenes with both aliphatic
and aromatic groups (Table 4, entries 9 and 10). In
addition, 2-vinylnaphthalene could be effectively cyclo-
propanated. For all styrene derivatives, the diastereo-
selectivity and enantioselectivity were found similar to
those of styrene substrate.
The catalytic cyclopropanation by vitamin B12 deriva-
tives is assumed to proceed via a carbene transfer
mechanism similar to that proposed for other metal-
mediated cyclopropanation systems (Scheme 2).9 The Co-
(III) center of vitamin B12 is presumably reduced in situ
12
by EDA to the catalytically active Co(II) form B12r
,
which reacts with EDA to afford the cobalt-carbene
(12) Salomon, R. G.; Kochi, J . K. J . Am. Chem. Soc. 1973, 95, 3300.
J . Org. Chem, Vol. 69, No. 7, 2004 2433

Chen and Zhang
SCHEME 2. P r op osed Cyclop r op a n a tion
Mech a n ism by Vita m in B12
known for vitamin B12-dependent enzymes. The catalytic
system operates with alkenes as limiting reagents and
requires no slow addition of diazo compounds. In view of
these attractive characteristics together with their com-
mercial availability from natural resources and industrial
fermentation at relatively low costs, vitamin B12 deriva-
tives may prove to be useful asymmetric catalysts for the
efficient synthesis of cyclopropanes from alkenes. Efforts
are underway to further improve its enantioselectivity
and to elucidate the underlying mechanism.
.
TABLE 5. Ad d itive Effects on Cyclop r op a n a tion of
a
Styr en e w ith EDA Ca ta lyzed by B12a
Exp er im en ta l Section
temp yield
entry
additive (equiv)
HCO2Na (0.1)
NaBH4 (0.2)
HCO2Na (0.2)
NaBH4 (0.3)
N-methylimidazole (0.5)
(°C) (%)b cis:transb ee(%)c
Gen er a l Con sid er a tion s. All reactions were carried out
in oven-dried glassware using standard Schlenk techniques.
All solvents were of liquid chromatography grade quality.
Alkenes, vitamin B12, B12a and methylcobalamin were pur-
chased and used without further purification. Proton and
carbon nuclear magnetic resonance spectra (1H NMR and 13C
NMR) were recorded on a 300 MHz spectrometer and refer-
enced with respect to internal TMS standard or residual
solvent. Thin-layer chromatography was carried out on silica
gel 60 F-254 TLC plates.
1
2
3
4
5
80
80
23
23
80
99
99
10
18
98
62:38
66:34
66:34
67:33
61:39
67(57)
67(50)
75(64)
77(63)
62(63)
a
Carried out in TFE for 24 h under N2 with 1.0 equiv of styrene,
1.2 equiv of EDA, and 2 mol % of B12a. Concentration: 0.5 mmol
styrene/2 mL TFE. Determined by GC. c Determined by chiral
b
GC: cis(trans).
Gen er a l P r oced u r es for Cyclop r op a n a tion Rea ction .
Catalyst (2 mol %) was placed in an oven-dried, resealable
Schlenk tube. The tube was capped with a Teflon screwcap,
evacuated, and backfilled with nitrogen. The screwcap was
replaced with a rubber septum, and 1.0 equiv of alkene (0.5
mmol) was added via syringe, followed by solvent (1 mL), 1.2
equiv of EDA, and solvent again (1 mL). The tube was purged
with nitrogen for 1 min, and its contents were stirred at
constant temperature in an oil bath. After the reaction
finished, the resulting mixture was cooled to room temperature
and concentrated. The residue was purified by flash silica gel
chromatography to give the product.
intermediate A with concomitant release of nitrogen.
Carbene transfer from intermediate A to alkene sub-
strate yields the cyclopropane product and regenerates
the active B12r to turn over the catalytic cycle. UV-vis
studies on the reaction of B12a with EDA showed the
formation of the Co(II) form B12r but not the Co(I) form
13
B12s
.
Reactivity studies in the presence of external
reducing agents such as sodium formate and sodium
14
borohydride, which are known to reduce B12a to B12r
,
Eth yl 2-p h en ylcyclop r op a n e-1-ca r boxyla te16 was syn-
thesized from styrene. 1H NMR (300 MHz, CDC13) trans-
isomer: δ 7.09-7.31 (m, 5H), 4.17 (q, J ) 7.2 Hz, 2H), 2.52
(ddd, J ) 9.3, 6.6, 4.2 Hz, 1H), 1.90 (ddd, J ) 8.7, 5.4, 4.5 Hz,
1H), 1.60 (ddd, J ) 9.0, 5.1, 4.2 Hz, 1H), 1.30 (ddd, J ) 8.4,
6.6, 4.8 Hz, 1H), 1.28 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz,
CDC13) trans-isomer: δ 173.4, 140.1, 128.4, 126.4, 126.1, 60.7,
are also consistent with the proposed Co(II) active
species. For example, nearly identical results were
obtained between styrene reactions in the presence
(Table 5, entries 1-4) and absence (Table 1, 7 and 8) of
the reducing agents. Indistinguishable results were also
attained between reactions with (Table 5, entry 5) and
without (Table 1, entry 8) the addition of potential
coordinating ligands such as N-methylimidazole,15 sug-
gesting that the Co centers in the catalytic cycle are in
base-on forms. Attempts to reveal the nature of inter-
mediate A have so far been inconclusive. Among several
possible structures, the intermediate A could be consid-
ered as a cobalt(III)-carbene complex having a Co-C
single bond with carbon-based radical character, an
unusual metal-carbene structure that was recently pro-
posed for 3-oxobutylideneaminato- and salen-cobalt-based
cyclopropanation systems.10
1
26.2, 24.2, 17.1, 14.3. H NMR (300 MHz, CDC13) cis-isomer:
δ 7.18-7.28 (m, 5H), 3.88 (q, J ) 7.2 Hz, 2H), 2.59 (m, 1H),
2.08 (ddd, J ) 9.0, 7.8, 5.6 Hz, 1H), 1.72 (ddd, J ) 6.3, 4.9, 4.4
Hz, 1H), 1.32 (ddd, J ) 8.9, 7.9, 5.0 Hz, 1H), 0.97 (t, J ) 7.2
Hz, 3H). 13C NMR (75 MHz, CDC13) cis-isomer: δ 170.9, 136.5,
129.2, 127.8, 126.6, 60.1, 25.4, 21.7, 14.0, 11.1.
E t h yl 2-(4-m et h oxyp h en yl)cyclop r op a n e-1-ca r b oxy-
la te17 was synthesized from 4-methoxystyrene. 1H NMR (300
MHz, CDC13) trans-isomer: δ 7.03 (d, J ) 8.7 Hz, 2H), 6.82
(d, J ) 8.7 Hz, 2H), 4.16 (q, J ) 7.2 Hz, 2H), 3.78 (s, 3H), 2.48
(ddd, J ) 9.2, 6.6, 4.2 Hz, 1H), 1.82 (ddd, J ) 8.7, 5.4, 4.2 Hz,
1H), 1.55 (ddd, J ) 9.6, 5.1, 4.2 Hz, 1H), 1.28 (t, J ) 7.2 Hz,
3H), 1.25 (m, 1H). 13C NMR (75 MHz, CDC13) trans-isomer:
δ 173.5, 158.3, 132.0, 127.3, 113.8, 60.6, 55.3, 25.6, 23.8, 16.7,
14.2. 1H NMR (300 MHz, CDC13) cis-isomer: δ 7.18 (d, J )
8.1 Hz, 2H), 6.80 (d, J ) 8.1 Hz, 2H), 3.89 (q, J ) 7.2 Hz, 2H),
3.77 (s, 3H), 2.52 (m, 1H), 2.03 (ddd, J ) 9.3, 7.8, 5.7 Hz, 1H),
1.64 (m, 1H), 1.29 (ddd, J ) 9.3, 8.1, 5.4 Hz, 1H), 1.01 (t, J )
7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) cis-isomer: δ 171.0,
158.2, 130.2, 128.5, 113.2, 60.1, 55.1, 24.8, 21.6, 14.0, 11.2.
Eth yl 2-(4-tr iflu or om eth ylp h en yl)cyclop r op a n e-1-ca r -
boxyla te17 was synthesized from 4-trifluoromethylstyrene. 1H
NMR (300 MHz, CDC13) trans-isomer: δ 7.53 (d, J ) 8.1 Hz,
2H), 7.20 (d, J ) 8.1 Hz, 2H), 4.18 (q, J ) 7.2 Hz, 2H), 2.56
(ddd, J ) 9.0, 6.0, 4.2 Hz, 1H), 1.90 (ddd, J ) 8.7, 5.4, 4.2 Hz,
Con clu sion s
In summary, we have demonstrated for the first time
that vitamin B12 derivatives efficiently catalyze asym-
metric cyclopropanation of alkenes, an important class
of carbon-carbon bond formation reaction that is un-
(13) Pratt, J . M. Inorganic Chemistry of Vitamin B12; Academic
Press: London, 1972; Chapter 7, pp 96-113.
(14) Wolak, M.; Zahl, A.; Schneppensieper, T.; Stochel, G.; van Eldik,
R. J . Am. Chem. Soc. 2001, 123, 9780.
(15) (a) Marques, H. M.; Marsh, J . H.; Mellor, J . R.; Munro, O. Q.
Inorg. Chim. Acta 1990, 170, 259. (b) Sirovatka, J . M.; Finke, R. G. J .
Am. Chem. Soc. 1997, 119, 3057. (c) Sirovatka, J . M.; Finke, R. G.
Inorg. Chem. 1999, 38, 1697. (d) Cregan, A. G.; Brasch, N. E.; van
Eldik, R. Inorg. Chem. 2001, 40, 1430.
(16) Sanders, C. J .; Gillrspie, K. M.; Scott, P. Tetrahedron Asym-
metry 2001, 12, 1055.
(17) Bachmann, S.; Mezzetti, A. Helv. Chim. Acta 2001, 84, 3063.
2434 J . Org. Chem., Vol. 69, No. 7, 2004

Vitamin B12 Derivatives as Asymmetric Catalysts
1H), 1.66 (ddd, J ) 9.3, 5.7, 4.5 Hz, 1H), 1.30 (ddd, J ) 8.4,
6.0, 4.8 Hz, 1H), 1.29 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz,
CDC13) trans-isomer: δ 172.9, 144.4, 128.9, 126.4, 125.4, 60.9,
cis-isomer: δ 171.0, 137.2, 136.4, 130.1, 127.7, 127.3, 126.2,
60.1, 25.3, 21.6, 21.3, 14.0, 11.0.
Eth yl 2-[4-(ter t-bu tyl)p h en yl]cyclop r op a n e-1-ca r boxy-
la te17 was synthesized from 4-tert-butylstyrene. 1H NMR (300
MHz, CDC13) trans-isomer: δ 7.31 (d, J ) 8.1 Hz, 2H), 7.04
(d, J ) 8.1 Hz, 2H), 4.16 (q, J ) 7.2 Hz, 2H), 2.49 (ddd, J )
9.6, 6.6, 4.2 Hz, 1H), 1.88 (m, 1H), 1.58 (m, 1H), 1.30 (m, 1H),
1.30 (s, 9H), 1.27 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz,
CDC13) trans-isomer: δ 173.5, 149.4, 137.1, 125.8, 125.3, 60.6,
1
25.7, 24.5, 17.1, 14.2. H NMR (300 MHz, CDC13) cis-isomer:
δ 7.53 (d, J ) 8.1 Hz, 2H), 7.38 (d, J ) 8.1 Hz, 2H), 3.89 (q, J
) 7.2 Hz, 2H), 2.59 (m, 1H), 2.14 (ddd, J ) 9.3, 8.1, 5.7 Hz,
1H), 1.74 (m, 1H), 1.39 (m, 1H), 0.99 (t, J ) 7.2 Hz, 3H). 13C
NMR (75 MHz, CDC13) cis-isomer: δ 170.9, 141.0, 129.9, 126.4,
125.0, 60.6, 25.3, 22.2, 14.2, 11.6.
1
Eth yl 2-m eth yl-2-p h en ylcyclop r op a n e-1-ca r boxyla te17
was synthesized from R-methylstyrene. 1H NMR (300 MHz,
CDC13): trans-isomer: δ 7.18-7.30 (m, 5H), 4.19 (q, J ) 7.2
Hz, 2H), 1.96 (dd, J ) 8.1, 5.7 Hz, 1H), 1.52 (s, 3H), 1.42 (m,
2H), 1.29 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) trans-
isomer: δ 172.2, 145.9, 128.4, 127.3, 126.4, 60.5, 30.5, 27.8,
20.7, 19.8, 14.4. 1H NMR (300 MHz, CDC13) cis-isomer: δ
7.17-7.28 (m, 5H), 3.84 (m, 2H), 1.90 (dd, J ) 7.8, 5.4 Hz,
1H), 1.78 (m, 1H), 1.46(s, 3H), 1.14 (dd, J ) 7.8, 4.2 Hz, 1H),
0.94 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) cis-
isomer: δ 171.2, 141.8, 128.7, 128.1, 126.6, 60.0, 32.0, 28.5,
28.4, 19.4, 13.9.
34.4, 31.3, 25.8, 24.1, 16.9, 14.2. H NMR (300 MHz, CDC13)
cis-isomer: δ 7.28 (d, J ) 8.7 Hz, 2H), 7.19 (d, J ) 8.7 Hz,
2H), 3.87 (q, J ) 7.2 Hz, 2H), 2.53 (m, 1H), 2.04 (ddd, J ) 9.6,
8.1, 5.7 Hz, 1H), 1.69 (m, 1H), 1.30 (m, 1H), 1.29 (s, 9H), 0.92
(t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) cis-isomer: δ
171.3, 149.6, 133.7, 129.2, 125.0, 60.3, 34.6, 31.6, 25.3, 22.1,
14.2, 11.4.
Eth yl 2,2-d ip h en ylcyclop r op a n e-1-ca r boxyla te17 was
1
synthesized from 1,1-diphenylethylene. H NMR (CDC13): δ
7.13-7.35 (m, 10H), 3.90 (m, 2H), 2.53 (dd, J ) 8.1, 6.3 Hz,
1H), 2.16 (dd, J ) 5.7, 4.8, 1H), 1.56 (dd, J ) 8.1, 4.8 Hz, 1H),
0.99 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13): δ 170.5,
144.8, 140.2, 129.7, 128.3, 128.2, 127.5, 126.9, 126.4, 60.3, 39.7,
28.9, 20.0, 13.9.
Eth yl 2-(4-m eth ylp h en yl)cyclop r opa n e-1-ca r boxyla te18
was synthesized from 4-methylstyrene. 1H NMR (300 MHz,
CDC13) trans-isomer: δ 7.08 (d, J ) 8.1 Hz, 2H), 6.99 (d, J )
8.1 Hz, 2H), 4.16 (q, J ) 7.2 Hz, 2H), 2.56 (ddd, J ) 9.0, 6.3,
3.9 Hz, 1H), 2.31 (s, 3H), 1.86 (ddd, J ) 8.4, 5.1, 4.2 Hz, 1H),
1.57 (m, 1H), 1.28 (m, 1H), 1.27 (t, J ) 7.2 Hz, 3H). 13C NMR
(75 MHz, CDC13) trans-isomer: δ 173.5, 137.0, 136.0, 129.1,
126.1, 60.6, 25.9, 24.0, 20.9, 16.9, 14.2. 1H NMR (300 MHz,
CDC13) cis-isomer: δ 7.15 (d, J ) 8.1 Hz, 2H), 7.06 (d, J ) 8.1
Hz, 2H), 3.89 (q, J ) 7.2 Hz, 2H), 2.53 (m, 1H), 2.29(s, 3H),
2.04 (ddd, J ) 9.0, 8.1, 5.7 Hz, 1H), 1.67 (m, 1H), 1.30 (m,
1H), 1.00 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) cis-
isomer: δ 171.1, 136.1, 133.4, 129.1, 128.6, 60.1, 25.2, 21.6,
21.0, 14.0, 11.2.
Eth yl 2-(4-br om op h en yl)cyclop r op a n e-1-ca r boxyla te19
was synthesized from 4-bromostyrene. 1H NMR (300 MHz,
CDC13) trans-isomer: δ 7.39 (d, J ) 8.7 Hz, 2H), 6.97 (d, J )
8.7 Hz, 2H), 4.17 (q, J ) 7.2 Hz, 2H), 2.47 (ddd, J ) 9.6, 6.9,
4.5 Hz, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.28 (t, J ) 7.2 Hz,
3H), 1.26 (m, 1H). 13C NMR (75 MHz, CDC13) trans-isomer:
δ 173.1, 139.1, 131.5, 127.9, 120.1, 60.8, 25.5, 24.1, 17.0, 14.2.
1H NMR (300 MHz, CDC13) cis-isomer: δ 7.38 (d, J ) 8.1 Hz,
2H), 7.14 (d, J ) 8.1 Hz, 2H), 3.90 (q, J ) 6.9 Hz, 2H), 2.50
(m, 1H), 2.08 (ddd, J ) 9.3, 8.1, 5.7 Hz, 1H), 1.67 (m, 1H),
1.34 (ddd, J ) 8.4, 7.5, 5.1 Hz, 1H), 1.02 (t, J ) 7.2 Hz, 3H).
13C NMR (75 MHz, CDC13) cis-isomer: δ 170.7, 135.6, 131.0,
130.9, 120.5, 60.3, 24.9, 21.8, 14.9, 11.3.
Eth yl 2-(2-m eth ylp h en yl)cyclop r op a n e-1-ca r boxyla te
was synthesized from 2-methylstyrene. 1H NMR (300 MHz,
CDC13) trans-isomer: δ 6.98-7.17 (m, 4H), 4.20 (q, J ) 7.2
Hz, 2H), 2.51 (ddd, J ) 9.0, 6.6, 4.2 Hz, 1H), 2.38 (s, 3H), 1.78
(m, 1H), 1.57 (m, 1H), 1.31 (m, 1H), 1.29 (t, J ) 7.2 Hz, 3H).
13C NMR (75 MHz, CDC13) trans-isomer: δ 173.9, 138.0, 137.8,
Eth yl 2-(2-n a p h th a len yl)cyclop r op a n e-1-ca r boxyla te20
was synthesized from 2-vinylnaphthalene. 1H NMR (300 MHz,
CDC13) trans-isomer: δ 7.79 (m, 3H), 7.56 (s, 1H), 7.43 (m,
2H), 7.20(dd, J ) 8.4, 2,4 Hz, 1H), 4.19 (q, J ) 7.2 Hz, 2H),
2.69 (ddd, J ) 9.6, 6.9, 4.5 Hz, 1H), 1.68 (m, 1H), 1.60 (m,
1H), 1.42 (ddd, J ) 8.4, 6.6, 4.5 Hz, 1H), 1.32 (t, J ) 7.2 Hz,
3H). 13C NMR (75 MHz, CDC13) trans-isomer: δ 173.4, 137.5,
133.3, 132.2, 128.1, 127.6, 127.4, 126.2, 125.4, 124.7, 124.5,
60.7, 26.4, 24.1, 17.0, 14.2. 1H NMR (300 MHz, CDC13) cis-
isomer: δ 7.75 (m, 4H), 7.41 (m, 3H), 3.82 (q, J ) 6.9 Hz, 2H),
2.71 (q, J ) 8.1 Hz, 1H), 2.14 (ddd, J ) 9.6, 8.1, 5.7 Hz, 1H),
1.84 (m, 1H), 1.40 (m, 1H), 0.90 (t, J ) 7.2 Hz, 3H). 13C NMR
(75 MHz, CDC13) cis-isomer: δ 170.9, 134.0, 133.1, 132.3,
127.9, 127.6, 127.5, 127.3, 125.8, 125.4, 60.1, 25.6, 21.9, 14.0,
11.3.
1
129.8, 126.7, 125.8, 60.6, 24.6, 22.3, 19.5, 15.3, 14.3. H NMR
(300 MHz, CDC13) cis-isomer: δ 7.10-7.22 (m, 4H), 3.84 (q, J
) 7.2 Hz, 2H), 2.44 (q, J ) 8.4 Hz, 1H), 2.34 (s, 3H), 2.15 (ddd,
J ) 9.0, 8.1, 5.4 Hz, 1H), 1.74 (m, 1H), 1.34 (m, 1H), 0.93 (t, J
) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13) cis-isomer: δ 171.1,
138.1, 134.8, 129.3, 129.1, 126.7, 125.3, 60.0, 24.4, 21.1, 19.3,
13.9, 11.2.
Eth yl 2-(3-m eth ylp h en yl)cyclop r opa n e-1-ca r boxyla te19
was synthesized from 3-methylstyrene. 1H NMR (300 MHz,
CDC13) trans-isomer: δ 6.88-7.19 (m, 4H), 4.16 (q, J ) 7.2
Hz, 2H), 2.48 (ddd, J ) 9.3, 6.6, 4.2 Hz, 1H), 2.32 (s, 3H), 1.89
(m, 1H), 1.58 (m, 1H), 1.29 (m, 1H), 1.27 (t, J ) 7.2 Hz, 3H).
13C NMR (75 MHz, CDC13) trans-isomer: δ 173.4, 140.0, 138.1,
128.3, 127.2, 126.9, 123.1, 60.6, 26.1, 24.1, 21.3, 17.0, 14.2. 1H
NMR (300 MHz, CDC13) cis-isomer: δ 6.99-7.17 (m, 4H), 3.88
(q, J ) 7.2 Hz, 2H), 2.54 (m, 1H), 2.31(s, 3H), 2.05 (ddd, J )
9.6, 8.1, 5.7 Hz, 1H), 1.68 (m, 1H), 1.29 (ddd, J ) 8.7, 7.8, 4.8
Hz, 1H), 0.98 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDC13)
Ack n ow led gm en t. We are grateful for financial
support of this work from the Department of Chemistry
of the University of Tennessee. We thank Dr. Lingyu
Huang for initial investigation on this project.
Note Ad d ed a fter ASAP P ostin g. Reference 4f was
not included in the version posted ASAP March 3, 2004;
the corrected version was posted March 10, 2004.
(18) Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J . Org.
Chem. 2001, 66, 8260.
J O049870F
(19) Hixson, S. S.; Franke, L. A.; Gere, J . A.; Xing, Y. J . Am. Chem.
Soc. 1988, 110, 3601.
(20) Solladie-Cavallo, A.; Isarno, T. Tetrahedron Lett. 1999, 40, 1579.
J . Org. Chem, Vol. 69, No. 7, 2004 2435