(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) catalyzed kinetic resolution of racemic secondary benzylic alcohols with free carboxylic acids by asymmetric esterification

Article abstract of DOI:10.1039/c1ob05736g

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to attain good chemical yields of the products. It was determined that diphenylacetic acid could be employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1 positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid, functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols having branched aliphatic alkyl chains at the C-1 positions.

Full text of DOI:10.1039/c1ob05736g

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PAPER
(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) catalyzed kinetic resolution
of racemic secondary benzylic alcohols with free carboxylic acids by
asymmetric esterification†
Kenya Nakata and Isamu Shiina*
Received 10th May 2011, Accepted 25th July 2011
DOI: 10.1039/c1ob05736g
(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer
catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral
carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to
attain good chemical yields of the products. It was determined that diphenylacetic acid could be
employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic
resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1
positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid,
functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols
having branched aliphatic alkyl chains at the C-1 positions.
Since Na´jera et al. first attempted to use chiral guanidine as a basic
catalyst for asymmetric syntheses in 1994,1 numerous efforts have
been devoted to develop useful chiral guanidine-type catalysts for
this purpose.2 To the best of our knowledge, however, almost all
chiral guanidines have been used for the deprotonation stages
in the asymmetric catalyses, and nucleophilic chiral guanidine
species have still not yet been designed. Recently, we reported
new methods for the kinetic resolution (KR) of not only racemic
secondary alcohols3,4 but also racemic a-arylpropanoic acids5,6
using carboxylic anhydride as a condensation reagent in the pres-
ence of the chiral acyl-transfer catalysts, such as (S)-tetramisole,7
(R)-BTM,7 and (S)-b-Np-BTM5b (Fig. 1). In this communication,
we first used the chiral N-methylbenzoguanidine (R)-1 as a new
nucleophilic catalyst for the KR of the racemic secondary benzylic
alcohols by the asymmetric esterification with achiral carboxylic
acids via the in situ formation of mixed anhydrides using pivalic
anhydride as a coupling reagent.
The hydrochloric acid salt of the racemic 9-methyl-2-phenyl-
9-hydro-2-imidazolino[1,2-a]benzimidazole (1) was produced by
Anisimova et al. in 1986,8 but there has been no literature reference
for the preparation of the chiral N-methylbenzoguanidine ((R)-
NMBG) ((R)-1) until now, therefore, we decided to develop an
alternative route for the synthesis of the chiral catalyst (R)-1 as
shown in Scheme 1.
Department of Applied Chemistry, Faculty of Science, Tokyo Univer-
sity of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.
E-mail: shiina@rs.kagu.tus.ac.jp
† Electronic supplementary information (ESI) available: Experimen-
tal procedures, spectroscopic data of synthetic intermediates and
products, and Cartesian coordinates of transition states. See DOI:
10.1039/c1ob05736g
Scheme 1 Synthesis of (R)-(+)-N-methylbenzoguanidine ((R)-NMBG)
((R)-1).
Fig. 1 Structures of (S)-tetramisole, (R)-benzotetramisole ((R)-BTM), (S)-b-Np-BTM, and (R)-N-methylbenzoguanidine ((R)-NMBG) ((R)-1).
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Table 1 Examination of the effect of the solvents and co-bases for the
KR of ( )-7
Table 2 (R)-NMBG-catalyzed KR of ( )-7 using various carboxylic acids
Entry
R
Yield (8; 7) (%) ee (8; 7) (%)
s
Entry
Solvent
i-Pr2NEt
Yield (8a; 7) (%)
ee (8a; 7) (%)
s
1
2
3
4
5
6
7
Ph(CH2)2
Ph(CH2)3
Et
(a) 51; 41
87; 87
90; 43
92; 53
92; 55
84; 65
90; 89
87; 99
42
29
42
42
22
55
73
a
(b) 34; 57
(c) 40; 51
(d) 38; 54
1
2
3
4
5
6
CH2Cl2
CH2Cl2
Et2O
Et2O
AcOEt
AcOEt
—
᭺
—
20; 70
22; 58
45; 45
47; 48
43; 51
48; 51
91; 51
88; 51
88; 84
90; 77
93; 70
90; 69
31
26
40
43
54
40
b
a
(CH3)2CH(CH2)2
b
CH2=CHCH2CH2 (e) 46; 51
c-C6H11
Ph2CH
᭺
a
(f) 47; 47
(g) 55; 41
—
b
᭺
a Without i-Pr2NEt. b With i-Pr2NEt.
Table 3 (R)-NMBG-catalyzed KR of several racemic secondary benzylic
alcohols ( )-9a–d with diphenylacetic acid or 3-phenylpropanoic acid
First, treatment of N-methylbenzimidazole (2) with butyl-
lithium and carbon tetrachloride was carried out according
to a known literature method9 and the desired 2-chloro-N-
methylbenzimidazole (3) was predominantly obtained in 53% yield
with a small amount of the undesired butylated product 4 (13%).
The transformation of 3 into (R)-NMBG ((R)-1) was successfully
accomplished through the coupling with (R)-2-phenylglycinol,
mesylation of the resulting chiral amino alcohol (R)-5 and the
successive annulation of an intermediary (R)-6 via the one-pot
operation based on similar previous studies (79% yield for 2
steps).5b
Entry
R
Time/h Yield (10/11; 9) (%) ee (10/11; 9) (%)
s
1a
2a
3a
4a
5b
6b
Me (a) 12
Et (b) 12
i-Pr (c) 24
t-Bu (d) 24
i-Pr (c) 24
t-Bu (d) 24
48; 45
50; 50
45; 50
9; 91
89; 80
92; 87
88; 73
87; 8
90; 97
94; 72
43
68
34
15
85
67
50; 38
38; 46
With the new catalyst (R)-NMBG ((R)-1) in hand, we then
examined the effect of the solvents and co-bases on the (R)-
NMBG-mediated KR of the racemic 1-phenylpropanol (( )-7)
with 3-phenylpropanoic acid using pivalic anhydride at room
temperature for 12 h, which were the modified reaction conditions
established in our preliminary research (Table 1). When the
reaction was carried out in dichloromethane as the solvent in
the absence or presence of i-Pr2NEt, the desired chiral ester (R)-8a
was obtained with good s-values,10 however, the chemical yield
was moderate, as listed in Entry 1 or 2. Fortunately, we found that
the acceleration of the reaction was accomplished in diethyl ether
or ethyl acetate solvent and higher s-values were also observed
in these reactions (Entries 3–6). Interestingly, almost the same
s-values were attained whether or not i-Pr2NEt was used as the
co-base. We decided that the conditions used in Entry 3 (in diethyl
ether without using tertiary amines) would be applied for our
further studies of the KR of racemic secondary benzylic alcohols.
We next used a variety of carboxylic acids for the (R)-NMBG-
catalyzed KR of ( )-7 with pivalic anhydride in diethyl ether
at room temperature for 24 h in order to optimize the acyl
donor’s structure (Table 2). As shown by Entries 1–5, several
carboxylic acids possessing less-hindered substituents at the C-
1 positions were applied for the KR of ( )-7, and it was found
that both the reactivity and the selectivity were not so varied
according to the main frameworks of the acyl donors. Among
them, the highest yield of the desired ester 8a (51%) and the highest
enantioselectivity (s = 42) were simultaneously obtained when 3-
phenylpropanoic acid was used as the acyl donor (Entry 1). It
was further revealed that the employment of more hindered acyl
donors, such as cyclohexanecarboxylic acid and diphenylacetic
a Diphenylacetic acid was used as the acyl donor. The corresponding esters
(R)-10a–d were produced. b 3-Phenylpropanoic acid was used as the acyl
donor. The corresponding esters (R)-11c,d were produced.
acid, improved the enantioselectivities of the KR of ( )-7 without
any loss of reactivities as shown by Entries 6 and 7 (s = 55 and 73).
In order to explore the scope and limitation of these reactions,
we further examined the asymmetric esterification of dipheny-
lacetic acid with several racemic benzylic alcohols ( )-9a–d, which
have different aliphatic substituents at the C-1 positions (R =
Me, Et, i-Pr, and t-Bu) as listed in Table 3. When we carried
out the KR of ( )-9a and 9b bearing the normal aliphatic alkyl
chains at the C-1 positions (R = Me and Et) under the standard
reaction conditions (in diethyl ether at room temperature for 12 h),
nearly half the amounts of the desired (R)-carboxylic esters ((R)-
10a and (R)-10b) and the unreacted (S)-alcohols ((S)-9a and
(S)-9b) were obtained in high yields with good enantiopurities
(Entries 1 and 2, s = 43 and 68). Asymmetric esterification of
the racemic 2-methyl-1-phenylpropanol (( )-9c; R = i-Pr) with
diphenylacetic acid also produced a good enantioselectivity as
shown in Entry 3 (s = 34), although this process required a longer
reaction time (24 h) to complete conversion of half the amount of
( )-9c into the corresponding chiral ester (R)-10c because ( )-
9c has a relatively large steric hindrance around the hydroxyl
group.
When the reaction of 2,2-dimethyl-1-phenylpropanol (( )-9d;
R = t-Bu) including the hindered t-Bu group was carried out under
the standard reaction conditions, the reactivity was drastically
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Table 4 (R)-NMBG-catalyzed KR of a variety of racemic secondary
benzylic alcohols ( )-12Aa–f and ( )-12Ba–f with diphenylacetic acid
the highest value (95% ee) when ( )-12Be was employed under the
above stated reaction conditions (s = 98, Entry 11).
Determination of the transition state forming the optically
active (R)-ester ((R)-10a) from (R)-1-phenyl-1-ethanol ((R)-9a)
uisng the zwitterionic intermediate (z-int), which was generated
from the mixed anhydride and (R)-NMBG, was carried out using
DFT calculations at the B3LYP/6-31G*//B3LYP/6-31G* level
according to the former report on the KR of the racemic 2-
hydroxyalkanoates3d and 2-arylpropanoic acids.5b,11 Among sev-
eral calculated transition states forming the desired ester (R)-
10a from (R)-9a, the most stable structure (R)-ts-1 is depicted
in Scheme 2. The Cartesian coordinates of the three-dimensional
structures of the transition states in Scheme 2 are shown in the
ESI.†
We noted the stacking correlation between the benzene ring
and the plane surface of the conjugated aromatics in the N-
methylbenzoguanidium salt. The alcohol (R)-9a has a rigid struc-
ture in which the conformation is restricted by the coordination
of oxygen in the acyl donor moiety onto hydrogen at the C-1
Yield
(13; 12) (%)
ee (13; 12)
Entry
Ar
(%)
s
1
2
3
4
p-MeC6H4
p-MeOC6H4
p-FC6H4
o-MeC6H4
a-Np
(Aa)
(Ab)
(Ac)
(Ad)
(Ae)
(Af)
(Ba)
(Bb)
(Bc)
(Bd)
(Be)
(Bf)
45; 54
44; 43
47; 50
50; 50
50; 50
52; 48
48; 50
50; 50
47; 53
49; 51
47; 53
50; 42
89; 78
86; 85
81; 75
90; 87
88; 87
85; 83
93; 80
89; 86
84; 78
92; 83
95; 82
90; 91
42
37
21
54
44
32
64
50
27
66
98
60
5
6a
7
b-Np
p-MeC6H4
p-MeOC6H4
p-FC6H4
o-MeC6H4
a-Np
8
9a
10
11a
12
˚
position in (R)-9a (2.172 A). The distance of the forming C–
b-Np
O bond (between the carbonyl carbon of the acid component
a The reaction was carried out for 6 h.
˚
and the oxygen of hydroxy) is 2.036 A, and the distance of the
cleaved O–H bond (between oxygen and hydrogen in hydroxy) is
˚
1.387 A. By the calculated bond distances of these elements, it is
reduced and a low yield of (R)-10d was attained (Entry 4; 9%).
However, the yield of an alternative desired ester (R)-11d increased
to an acceptable level (Entry 6; 38%) along with a high enantios-
electivity (s = 67) by employing 3-phenylpropanoic acid as a less-
hindered acyl donor for ( )-9d instead of using diphenylacetic acid
(cf. Entry 4). The KR of ( )-9c with 3-phenylpropanoic acid, which
was proved to be a suitable acyl donor for the hindered substrates,
was reexamined under the above conditions, and we observed
remarkable improvements in the chemical yield and enantiopurity
of the desired ester (R)-11c as shown in Entry 5 (50% yield, 90%
ee, s = 85).
Then, we performed the (R)-NMBG-catalyzed KR of a variety
of racemic secondary benzylic alcohols ( )-12Aa–f and ( )-12Ba–
f for evaluating of the generality of this novel method (Table
4). Because racemic alcohols ( )-12Aa–f and ( )-12Ba–f do not
possess bulky aliphatic alkyl chains at the C-1 positions (R = Me
and Et), the KRs of ( )-12Aa–f and ( )-12Ba–f were carried out
using diphenylacetic acid as the optimized acyl donor for less
bulky substrates. All the reactions produced very good results,
and nearly half amounts of the corresponding chiral carboxylic
esters ((R)-13Aa–f and (R)-13Ba–f) and the unreacted chiral
alcohols ((S)-12Aa–f and (S)-12Ba–f) were produced with high
enantioselectivities (s = >20). As shown by Entries 1–3, the KR
of ( )-12Aa–c afforded good s-values irrespective of the electronic
effect at the para position on the aromatic rings of the alcohols.
The reaction of ( )-12Ad smoothly proceeded in spite of the steric
effect at the ortho position on the aromatic ring and showed the
best result among Entries 1–6 (s = 54, Entry 4). When we carried
out the reaction of 2-naphthoethanols ( )-12Ae and ( )-12Af,
good s-values were also obtained in both cases irrespective of
the positions of the substituted groups on the naphthalene rings
(Entries 5 and 6). We observed the tendency to have better results
for the reactions of ( )-12Ba–f in comparison to those of ( )-12Aa–
f (s = 27–98 in Entries 7–12 versus s = 21–54 in Entries 1–6). For
example, the enantiopurity of the desired ester (R)-13Be reached
supported that (i) the nucleophilic attack of the alcohol on the
carbonyl group and (ii) the deprotonation of the hydroxyl group
with the carboxylate anion simultaneously proceeded under the
concerted reaction mechanism to form the desired chiral ester
(R)-10a.
On the other hand, two different structures ((S)-ts-2a and (S)-ts-
2b) derived from (S)-1-phenyl-1-ethanol ((S)-9a) with z-int were
found to produce the opposite stereoisomer (S)-10a via similar
transacylation processes. The coordination of oxygen in the acyl
donor moiety onto hydrogen at the C-1 position in (S)-9a is not
observed in the structure (S)-ts-2a, therefore, the relative energy
of the (S)-ts-2a considerably increases (Erel = +6.20 kcal mol-1)
compared with the value of the stable transition state (R)-ts-1
(Erel = 0.00 kcal mol-1). Another transition state (S)-ts-2b is the
rotamer of (S)-ts-2a, and (S)-ts-2b has a conformation in which
the coordination of oxygen in the acyl donor moiety onto hydrogen
at the C-1 position in (S)-9a exists. However, the structure (S)-ts-
2b has a higher energy (Erel = +3.67 kcal mol-1) compared to that
of (R)-ts-1 (Erel = 0.00 kcal mol-1) because the methyl group at the
C-1 position in (S)-9a should be very close to the plane surface of
the conjugated aromatics in the N-methylbenzoguanidium salt.12
This steric effect considerably increases the structural energy of
(S)-ts-2b, and the reaction pathway to give the undesired ester
(S)-10a is effectively prevented in the key transacylation process.
We finally reexamined the efficiency of the asymmetric esterifi-
cation catalyzed by the representative three nucleophilic catalysts,
(S)-tetramisole, (R)-BTM, and (R)-NMBG (Table 5). When the
racemic alcohol ( )-7 (= 9b) was treated with diphenylacetic acid
in the absence or presence of i-Pr2NEt in diethyl ether under the
identical reaction conditions, the corresponding diphenylacetate
10b and the recovered alcohol 7 were produced with good to high
enantioselectivities (10b; 81–95% ee, 7; 48–87% ee). The use of
(S)-tetramisole without i-Pr2NEt afforded the lower yield of the
desired ester 10b compared to the reaction which was carried out
using i-Pr2NEt (Entries 1 (10b; 38%) versus 2 (10b; 41%)). The
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Scheme 2 Optimized transition state geometries to form (R)-1-phenylethyl diphenylacetate ((R)-10a) or (S)-1-phenylethyl diphenylacetate ((S)-10a)
from (R)-1-phenyl-1-ethanol ((R)-9a) or (S)-1-phenyl-1-ethanol ((S)-9a) Using DFT calculations at the B3LYP/6-31G*//B3LYP/6-31G* level.
same tendency was also observed in the (R)-BTM-mediated KR
(Kinetic Resolution) of the racemic 7 with diphenylacetic acid
using pivalic anhydride; that is, the desired diphenylacetate 10b
was formed in a relatively lower yield (44%) with a fairly good
selectivity (s = 96) by the reaction in the absence of i-Pr2NEt of
Entry 3, and the better yield of 10b (47%) with a lower selectivity
(s = 35) was attained by the reaction in the presence of i-Pr2NEt
as shown in Entry 4. A most ideal result occurred with Entry 5 in
which (R)-NMBG was used as a nucleophilic catalyst without i-
Pr2NEt, and the quantitative yields of the desired ester (10b; 50%)
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Table 5 Examination of the nucleophilic catalysts and co-bases for the
KR of ( )-7
Acknowledgements
This study was partially supported by a Research Grant from the
Toray Science Foundation.
References
1 R. Chinchilla, C. Na´jera and P. Sa´nchez-Agullo´, Tetrahedron: Asym-
metry, 1994, 5, 1393.
2 For a recent review, see: D. Leow and C.-H. Tan, Synlett, 2010, 11,
1589, and references cited therein.
Yield
(10b; 7) (%) (%)
ee (10b; 7)
Entry
Catalyst
i-Pr2NEt
s
3 (a) I. Shiina and K. Nakata, Tetrahedron Lett., 2007, 48, 8314; (b) I.
Shiina, K. Nakata, M. Sugimoto, Y. Onda, T. Iizumi and K. Ono,
Heterocycles, 2009, 77, 801; (c) K. Nakata and I. Shiina, Heterocycles,
2010, 80, 169; (d) I. Shiina, K. Nakata, K. Ono, M. Sugimoto and A.
Sekiguchi, Chem.–Eur. J., 2010, 16, 167.
4 For another example of asymmetric esterification of racemic 1,2-diols,
see: R. Hrdina, C. E. Mu¨ller and P. R. Schreiner, Chem. Commun.,
2010, 46, 2689.
a
1
2
3
4
5
6
(S)-Tetramisole
(S)-Tetramisole
(R)-BTM
—
᭺
—
᭺
—
᭺
38; 62
41; 59
44; 53
47; 53
50; 50
51; 48
91c;48d
33
16
96
35
68
24
b
81c;51d
95; 81
89; 71
92; 87
82; 79
a
b
(R)-BTM
a
(R)-NMBG
(R)-NMBG
b
a Without i-Pr2NEt. b With i-Pr2NEt. c (S)-10b was obtained instead
of forming (R)-10b. d (R)-7 (= 9b) was obtained instead of forming (S)-7
(= 9b).
5 (a) I. Shiina, K. Nakata and Y. Onda, Eur. J. Org. Chem., 2008, 5887;
(b) I. Shiina, K. Nakata, K. Ono, Y. Onda and M. Itagaki, J. Am. Chem.
Soc., 2010, 132, 11629.
6 For another examples of asymmetric esterification of racemic car-
boxylic acids, see: (a) K. Ishihara, Y. Kosugi, S. Umemura and A.
Sakakura, Org. Lett., 2008, 10, 3191; (b) A. Sakakura, S. Umemura
and K. Ishihara, Synlett, 2009, 1647; (c) X. Yang and V. B. Birman,
Adv. Synth. Catal., 2009, 351, 2301.
7 (a) V. B. Birman and X. Li, Org. Lett., 2006, 8, 1351; (b) V. B. Birman
and L. Guo, Org. Lett., 2006, 8, 4859.
8 (a) V. A. Anisimova, M. V. Levchenko and A. F. Pozharskii, Khim.
Geterotsikl. Soedin., 1986, 7, 918; (b) V. A. Anisimova, M. V. Levchenko
and A. F. Pozharskii, Chem. Heterocycl. Compd., 1986, 22, 732.
9 (a) C. Boga, E. D. Vecchio, L. Forlani and P. E. Todesco, J. Organomet.
Chem., 2000, 601, 233; (b) C. Boga, E. D. Vecchio, L. Forlani, L.
Milanesi and P. E. Todesco, J. Organomet. Chem., 1999, 588, 155.
10 H. B. Kagan and J. C. Fiaud, Top. Stereochem., 1988, 18, 249.
11 All calculations were performed with the program package Spartan ‘08
V1.2.0 of Wavefunction Inc. (http://www.wavefun.com).
and the recovered alcohol (7; 50%) were achieved with a good
selectivity (s = 68). It was found that the addition of i-Pr2NEt to
this reaction system decreased the enantioselectivity of the KR of
racemic 7 as shown in Entry 6 (s = 24). Regarding the yields and
the ee’s of not only the desired diphenylacetate 10b, but also the
recovered alcohol 7, the (R)-NMBG-catalyzed KR of the racemic
alcohol 7 without i-Pr2NEt has been determined as the most ef-
fective protocol for the simultaneous formation of the two desired
chiral compounds 10b (92% ee) and 7 (87% ee). It is noteworthy
that the tertiary amine-free reaction conditions in Entry 5 have
the advantage of atom-economy to produce both the chiral ester
10b and the chiral alcohol 7 in very high yields without using an
excess amount of the basic reagent.
In conclusion, (R)-(+)-N-methylbenzoguanidine ((R)-NMBG)
was found to be a new and efficient acyl-transfer catalyst for the
KR of racemic secondary benzylic alcohols with free carboxylic
acids in the presence of pivalic anhydride. This reaction does not
require the use of additional co-bases, such as tertiary amines,
to produce the desired chiral esters in high yields. A variety of
optically active secondary alcohols and their carboxylic esters
were efficiently produced in high ee’s by this novel asymmetric
esterification. Further studies of other utilities of (R)-NMBG are
now in progress in this laboratory.
12 Transition state energies of (R)-ts-1, (S)-ts-2a, and (S)-ts-2b were
also calculated using a polarization function including p functions
on hydrogen atoms (6-31G**), a diffuse function (6-31+G*), and
an advanced combination (6-31+G**), and the following similar re-
sults were obtained. E(R)-ts-1(B3LYP/6-31G**//B3LYP/6-31G*) =
-2130.9227176 au (Erel = 0.00 kcal mol-1), E(S)-ts-2a(B3LYP/6-
31G**//B3LYP/6-31G*) = -2130.9126403 au (Erel = +6.32 kcal mol-1),
E(S)-ts-2b(B3LYP/6-31G**//B3LYP/6-31G*) = -2130.9166457 au
(Erel = +3.81 kcal mol-1); E(R)-ts-1(B3LYP/6-31+G*//B3LYP/6-
31G*)
= -2130.9146371 au (Erel =
0.00 kcal mol-1), E(S)-ts-
2a(B3LYP/6-31+G*//B3LYP/6-31G*) = -2130.9044371 au (Erel
=
+6.40 kcal mol-1), E(S)-ts-2b(B3LYP/6-31+G*//B3LYP/6-31G*) =
-2130.9083136 au (Erel = +3.97 kcal mol-1); E(R)-ts-1(B3LYP/6-
31+G**//B3LYP/6-31G*) = -2130.9862929 au (Erel = 0.00 kcal mol-1),
E(S)-ts-2a(B3LYP/6-31+G**//B3LYP/6-31G*) = -2130.9759809 au
(Erel = +6.47 kcal mol-1), E(S)-ts-2b(B3LYP/6-31+G**//B3LYP/6-
31G*) = -2130.9802310 au (Erel = +3.80 kcal mol-1).
7096 | Org. Biomol. Chem., 2011, 9, 7092–7096
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