Lipase-catalyzed kinetic resolution of cyclic trans-1,2-diols bearing a diester moiety: Synthetic application to chiral seven-membered-ring α,α-disubstituted α-amino acid

Article abstract of DOI:10.1021/jo701317d

(Chemical Equation Presented) Chiral cycloalkane-trans-1,2-diols (±)-3 and (±)-8 having a diester moiety have been prepared from dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and acidic hydrolysis. Kinetic

Full text of DOI:10.1021/jo701317d

Lipase-Catalyzed Kinetic Resolution of Cyclic trans-1,2-Diols
Bearing a Diester Moiety: Synthetic Application to Chiral
Seven-Membered-Ring r,r-Disubstituted r-Amino Acid
Masakazu Tanaka,*,† Yosuke Demizu,†, Masanobu Nagano,†,§ Mariko Hama,†
Yukio Yoshida,† Masaaki Kurihara,‡ and Hiroshi Suemune*,†
Graduate School of Pharmaceutical Sciences, Kyushu UniVersity, Fukuoka 812-8582, Japan, and DiVision
of Organic Chemistry, National Institute of Health Sciences, Tokyo 158-8501, Japan
mtanaka@phar.kyushu-u.ac.jp; suemune@phar.kyushu-u.ac.jp
ReceiVed June 20, 2007
Chiral cycloalkane-trans-1,2-diols (()-3 and (()-8 having a diester moiety have been prepared from
dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and
acidic hydrolysis. Kinetic resolution of racemic cyclopentane-trans-1,2-diol (()-3 by lipase-catalyzed
transesterification afforded an optically active monoacetate (-)-5 of 95% ee in 46% yield and the recovered
diol (-)-3 of 92% ee in 51% yield, and that of cycloheptane-trans-1,2-diol (()-8 gave a monoacetate
(+)-10 of 95% ee in 51% yield and the diol (-)-8 of >99% ee in 43% yield, respectively. The enantiomer
selectivity of racemic cyclic trans-1,2-diols bearing a diester moiety by lipases (Amano PS and Amano
AK) was opposite to that of the reported simple racemic cycloalkane-trans-1,2-diols. To explain the
lipase-catalyzed enantiomer selectivity, computer modeling of lipase-substrate complexes was performed.
Furthermore, the optically active diester (-)-8 could be efficiently converted into an optically active
seven-membered-ring R,R-disubstituted amino acid (4R,5R)-(-)-15.
Introduction
acid can be applied to asymmetric ring transformation reactions
and asymmetric ring cleavage reactions. The optically active
cyclic trans-1,2-diols could be easily prepared by lipase-
catalyzed kinetic resolution of the racemic diols, or the
corresponding racemic diacetates.3
Chiral C2-symmetrical 1,2-diols have widely been used as
chiral auxiliaries and chiral ligands for many asymmetric
reactions.1 For instance, we focused our previous studies on
asymmetric syntheses using chiral cyclic 1,2-diols of the C2-
axis, especially optically active cycloalkane-1,2-diols, and
revealed that the cyclic 1,2-diols, i.e., cyclohexane-trans-1,2-
diol and cycloheptane-trans-1,2-diol, are very useful as a chiral
auxiliary for asymmetric reactions.2 Furthermore, we reported
that a combination of optically active cyclic 1,2-diols and Lewis
(2) Chiral cyclic 1,2-diols and their application to asymmetric reactions
by us. See: (a) Sakai, K.; Suemune, H. Tetrahedron: Asymmetry 1993, 4,
2109-2118. (b) Kiguchi, T.; Tsurusaki, Y.; Yamada, S.; Aso, M.; Tanaka,
M.; Sakai, K.; Suemune, H. Chem. Pharm. Bull. 2000, 48, 1536-1540. (c)
Tanaka, M.; Toyofuku, E.; Demizu, Y.; Yoshida, O.; Nakazawa, K.; Sakai,
K.; Suemune, H. Tetrahedron 2004, 60, 2271-2281. (d) Suemune, H.; Aso,
M. J. Synth. Org. Chem., Jpn. 2005, 63, 807-814.
(3) Lipase-catalyzed kinetic resolution of cyclic 1,2-diols. See: (a) Xie,
Z. F.; Nakamura, I.; Suemune, H.; Sakai, K. J. Chem. Soc., Chem. Commun.
1988, 966-967. (b) Seemayer, R.; Schneider, M. P. J. Chem. Soc., Chem.
Commun. 1991, 49-50. (c) Kazlauskas, R. J.; Weissfloch, A. N. E.;
Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656-2665. (d)
Caron, G.; Kazlauskas, R. J. J. Org. Chem. 1991, 56, 7251-7256. (e)
Naemura, K.; Fukuda, R.; Kurata, M.; Konishi, M.; Hirose, K.; Tobe, Y.
Tetrahedron: Asymmetry 1995, 6, 2385-2394.
* To whom correspondence should be addressed. Phone: + 81-92-642-6604.
Fax: + 81-92-642-6545.
† Kyushu University.
Present address: Nagasaki University, Nagasaki 852-8521.
‡ National Institute of Health Sciences.
§ Research Fellow of the Japan Society for the Promotion of Science.
(1) Bhowmick, K. C.; Joshi, N. N. Tetrahedron: Asymmetry 2006, 17,
1901-1929 and references cited therein.
10.1021/jo701317d CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/22/2007
7750
J. Org. Chem. 2007, 72, 7750-7756

Preparation of Cycloalkane-trans-1,2-diols
SCHEME 1
SCHEME 2
Here we describe a concise synthesis of optically active cyclic
1,2-diols having a diester moiety by using olefin metathesis and
lipase-catalyzed kinetic resolution, and insight into the enanti-
omer selectivity of lipase Amano PS using computer modeling.
As an application of the optically active diol having a diester,
we designed and synthesized a chiral seven-membered-ring R,R-
disubstituted R-amino acid:4 (4R,5R)-1-amino-4,5-di(methoxy)-
cycloheptanecarboxylic acid {(4R,5R)-Ac7cdOM}, in which the
R-carbon atom is not a chiral center but asymmetric centers
exist at the side-chain cycloheptane.5-7
a diester moiety were also prepared from 6, as shown in Scheme
1. The spectroscopic data of all compounds supported their
structures.
Lipase-Catalyzed Kinetic Resolution of Racemic Cyclic
1,2-Diols. At first, we attempted to kinetically resolve racemic
diacetates (()-4 and (()-9 by using lipase-catalyzed hydrolysis
in phosphate buffer.3,9 Unfortunately, neither the diacetate (()-4
nor (()-9 could be well dissolved in phosphate buffer, even
though a small amount of acetone was added as a cosolvent.
Thus, the lipase-catalyzed hydrolysis of diacetates (()-4 and
(()-9 did not proceed, and monoacetates could not be detected
at all.
Next, we examined the kinetic resolution of diols (()-3 and
(()-8 by using lipase-catalyzed transesterification. The trans-
esterification of racemic (()-diol (100 mg) was performed by
using lipase (100 mg) in vinyl acetate (5 mL) at 40 °C, and
after 72 h the reaction was terminated by filtration. The results
of kinetic resolutions are summarized in Table 1. As expected,
transesterification of the five-membered-ring diol (()-3 cata-
lyzed by Amano PS lipase10 smoothly proceeded to give a
monoacetate (-)-5 of 95% ee in 37% yield and the recovered
diol (-)-3 of 66% ee in 56% yield (entry 1), and the reaction
was reproducible on a large scale (entry 2) with better yield for
(-)-5 and better ee for (-)-3. The diol (-)-3 and the
monoacetate (-)-5 products could be well separated by column
chromatography on silica gel. Solvolysis of monoacetate (-)-5
with K2CO3 in MeOH afforded (+)-diol 3 in quantitative yield.
Results and Discussion
Preparation of Cyclic C2-Symmetric 1,2-Diols Having a
Diester Moiety. We prepared racemic trans-3,4-dihydroxy-1,1-
bis(methoxycarbonyl)cyclopentane 3 and trans-4,5-dihydroxy-
1,1-bis(methoxycarbonyl)cycloheptane 8 starting from dimethyl
malonate.8 That is to say, dialkylation of dimethyl malonate
with allyl bromide and 4-bromo-1-butene afforded dienes 1
(98%) and 6 (96%), respectively. Olefin metathesis of 1 with
Grubbs catalyst gave cyclopentene 2 in 80% yield.8 Epoxidation
of 2 with MCPBA, followed by hydrolysis with 3% aqueous
sulfuric acid afforded cyclic trans-1,2-diol (()-3 having a diester
moiety in 82% yield. Acetylation with Ac2O in pyridine
produced diacetate (()-4 in 98% yield. In a similar manner,
cycloheptane-trans-1,2-diol (()-8 and its diacetate (()-9 having
(4) (a) Tanaka, M. J. Synth. Org. Chem., Jpn. 2002, 60, 125-136. (b)
Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9,
3517-3599. (c) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645-732. (d) Vogt, H.; Bra¨se, S. Org. Biomol. Chem.
2007, 5, 406-430 and references cited therein.
(5) (a) Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H.
Angew. Chem., Int. Ed. 2004, 43, 5360-5363. (b) Tanaka, M.; Anan, K.;
Demizu, Y.; Kurihara, M.; Doi, M.; Suemune, H. J. Am. Chem. Soc. 2005,
127, 11570-11571. (c) Tanaka, M. Yakugaku Zasshi 2006, 126, 931-944.
(d) Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349-358.
(6) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001,
66, 2667-2673.
(9) Recent publications of lipase-catalyzed kinetic resolution of racemic
alcohols. For example, see: (a) Ema, T.; Fujii, T.; Ozaki, M.; Korenaga,
T.; Sakai, T. Chem. Commun. 2005, 4650-4651. (b) Akita, H.; Takano,
Y.; Nedu, K.; Kato, K. Tetrahedron: Asymmetry 2006, 17, 1705-1714. (c)
Akai, S.; Tanimoto, K.; Kanao, Y.; Egi, M.; Yamamoto, T.; Kita, Y. Angew.
Chem., Int. Ed. 2006, 45, 2592-2595 and references cited therein.
(10) Amano PS is a Burkholderia cepacia lipase, which was formerly
used as Pseudomonas fluorescens lipase (PFL) or P. cepacia lipase, and
Amano AK is now classified as Pseudomonas fluorescens lipase.
(7) Part of this work has already been presented in the Japanese Peptide
Symposium. See: Hama, M.; Tanaka, M.; Yoshida, Y.; Demizu, Y.;
Kurihara, M.; Suemune, H. Peptide Science 2006; Proceedings of the
International Conference of the 43rd Japanese Peptide Symposium and 4th
Peptide Engineering Meeting; Japanese Peptide Society: Minoh, Osaka,
Japan, 2006; pp 39-40.
(8) Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E. T. Chem.
Commun. 1999, 601-602.
J. Org. Chem, Vol. 72, No. 20, 2007 7751

Tanaka et al.
TABLE 1. Lipase-Catalyzed Kinetic Resolution of Diols (()-3 and (()-8 by Transesterification
monoacetate
reaction
diol
entry
substrate
lipase
time (h)
yield
ee
yield
ee
1
2
3
4
5
6
7
8
9
(()-3
(()-3
(()-8
(()-8
(()-8
(()-8
(()-8
(()-8
(()-8
Amano PS
Amano PS
Amano PS
Amano AYS
F-AP 15
Amano AS
Amano AK
Amano AK
Amano AK
72a
72b
72a
72a
72a
72a
72a
24c
96c
(-)-5: 37%
(-)-5: 46%
(+)-10: 11%
(+)-10: 2%
(-)-10: 3%
(-)-10: 4%
(+)-10: 44%
(+)-10: 33%
(+)-10: 51%
95% ee
95% ee
>99% ee
40% ee
91% ee
96% ee
94% ee
>99% ee
95% ee
(-)-3: 56%
(-)-3: 51%
(-)-8: 87%
(-)-8: 97%
(+)-8: 96%
(+)-8: 95%
(-)-8: 51%
(-)-8: 65%
(-)-8: 43%
66% ee
92% ee
10% ee
d
d
d
84% ee
56% ee
>99% ee
a A mixture of (()-diol (100 mg) and lipase (100 mg) in vinyl acetate (5 mL) was stirred at 40 °C. b A mixture of (()-3 (0.74 g) and Amano PS (2.2 g)
in vinyl acetate (50 mL) was stirred at 30 °C. c The reaction was performed at 55 °C. d Not determined.
SCHEME 3
On the other hand, transesterification of the seven-membered-
ring diol (()-8 by Amano PS in vinyl acetate proceeded
sluggishly to yield monoacetate (+)-10 of >99% ee in 11%
chemical yield and the recovered diol (-)-8 of 10% ee in 87%
yield after 72 h (entry 3). The transesterification required a long
reaction time, and even after 72 h the yield of monoacetate was
not satisfactory. Thus, the Amano PS-catalyzed transesterifi-
cation reaction is not practical for the kinetic resolution of the
diol (()-8. Therefore, we examined several kinds of lipases such
as Amano AYS, F-AP 15, and Amano AS. We summarize the
results in entries 4-9 of Table 1. The use of Amano AYS, F-Ap
15, and Amano AS did not improve the efficiency of transes-
terification (entries 4-6). However, it is noteworthy that the
configurations of monoacetates (-)-5 and (+)-10 may be R,R
transesterification by F-AP 15 or Amano AS afforded the
configuration, and that of both unreacted diols (-)-3 and (-)-8
monoacetate (-)-10 showing the minus sign of specific rotation,
may be S,S.
albeit the yields of (-)-10 were very low. These results mean
To determine the absolute configuration of diols 3 and 8,
that lipases Amano PS and AS show different enantiomer
both enantiomers of the 1,2-diols were converted into the
selectivity. That is to say, Amano PS acylated (+)-8, whereas
corresponding dibenzoates 11 and 12, respectively (Scheme 4).
Amano AS acylated the enantiomer (-)-8. Finally, we found
The CD spectrum of dibenzoate 11 derived from (-)-3, which
that the kinetic resolution with Amano AK10 in vinyl acetate
was not taken up by Amano PS, showed negative first Cotton
produced the monoacetate (+)-10 of 94% ee in 44% yield and
effect at 238 nm and positive second Cotton effect at 222 nm
the diol (-)-8 of 84% ee in 51% yield (entry 7). Fortunately,
in the case of Amano AK-catalyzed transesterification, the
shortening of the reaction time (24 h) and the optimized reaction
temperature (55 °C) improved the enantiomeric excess of
(negative chirality), and that derived from (+)-3, which was
prepared from (-)-5 by solvolysis, showed positive first Cotton
effect and negative second Cotton effect (positive chirality).
These CD spectra indicate that the configuration of the unreacted
monoacetate (+)-10 to >99% ee (33% yield), and prolongation
(-)-3 is R,R, and that of (+)-3 is S,S, on the basis of the exciton
of the reaction time (96 h) improved that of diol (-)-8 to >99%
ee (43% yield), (entries 8 and 9). Hydrolysis of acetate in (+)-
10 gave the enantiomeric diol (+)-8 in quantitative yield. Thus,
both enantiomers of the seven-membered-ring diol 8 could be
practically synthesized in high enantiomeric excess by using
Amano AK-catalyzed transesterification.
chirality method.11 Also, the CD spectrum of 12 derived from
(-)-8, which was not taken up by either Amano PS or Amano
AK, indicated that the first Cotton effect (236 nm) was negative
and the second Cotton effect (223 nm) was positive (negative
chirality), and that derived from (+)-10 showed the reverse
situation (positive chirality). According to the dibenzoate
chirality rule, these CD spectra indicate that the configuration
of the unreacted (-)-8 is R,R, and that of (+)-8 is S,S. The
assignment of the absolute configurations is not in accord with
that of the reported data, in which the lipase-catalyzed kinetic
resolutions of racemic cycloalkane-1,2-diols were described.
Thus, we also confirmed the absolute configuration of (-)-3
by conversion to a known compound, and by the comparison
of its specific rotation. The diol function in (-)-3 was protected
Determination of Absolute Configuration of Cyclic 1,2-
Diols. It is known that in the case of Amano PS-catalyzed kinetic
resolution of simple cyclic (()-trans-1,2-diols, the transesteri-
fication by Amano PS preferentially converts (R,R)-diols into
(R,R)-monoacetates, but (S,S)-diols remain intact or are less
reactive than (R,R)-diols. In some conditions, the esterification
proceeds further, and (R,R)-diacetates and (S,S)-monoacetates
would be obtained (Scheme 3; eq 1).3b On the other hand, in
the case of Amano PS-catalyzed hydrolysis of simple cyclic
(()-diacetates, the lipase takes up (R,R)-diacetates and releases
(R,R)-monoacetates, but (S,S)-diacetates are not taken up by
lipase and remain unchanged (Scheme 3; eq 2).3 That is to say,
the active site of lipase Amano PS exclusively recognizes and
takes up (R,R)-enantiomers, but not (S,S)-enantiomers. Following
this empirical rule, we arbitrarily assumed that the absolute
as MOM ether, and the specific rotation of 13 showed [R]23
D
+3.5. Compound 13 was also prepared by us starting from
dimethyl L-(+)-tartrate and dimethyl malonate, and the specific
(11) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley & Sons, Inc.: New York, 1996; pp 1043-1050. (b) Nakanishi,
K.; Berova, N.; Woody, R. W., Eds. Circular Dichroism: Principles and
Applications; VCH: New York, 1994.
7752 J. Org. Chem., Vol. 72, No. 20, 2007

Preparation of Cycloalkane-trans-1,2-diols
FIGURE 1. X-ray crystallographic analysis of lipase-inhibitor complex reported by Kazlauskas et al.13d (a) Hydrogen-bonding pattern of inhibitor
and lipase (Amano PS). (b) X-ray structure of inhibitor in the active site. For the calculation, the alcohol part, which is highlighted in the red
square, is replaced with 1,2-diol or monoacetate.
SCHEME 4
We found experimentally that Amano PS characteristically
recognizes enantiomers of the cyclic trans-1,2-diols. The Amano
PS takes up the simple (R,R)-cycloalkane-1,2-diols in its active
site and converts them into (R,R)-acetates.3 In contrast to the
R,R enantiomer recognition of the simple cyclic 1,2-diols, the
enzyme took up the (S,S)-cycloalkane-1,2-diols bearing a diester
moiety to produce (S,S)-monoacetates, whereas the cyclic (R,R)-
diols having a diester remained intact. That is to say, the R,R
and S,S enantiomer-recognition of cyclic 1,2-diols by Amano
PS is opposite between the plain cycloalkane-1,2-diols and the
cycloalkane-1,2-diols having a diester moiety. Thus, the diester
moiety on the cycloalkane strongly affects the chiral recognition
of cyclic 1,2-diols by the enzyme.
SCHEME 5
We explored the influence of the diester moiety on Amano
PS-enantiomer discrimination by using molecular modeling.
The enantiomer selectivities observed are probably the result
of a complex interplay between Amano PS and the substrate,
including structural changes, and therefore we do not intend to
quantitatively discuss the detailed lipase-cyclic 1,2-diol inter-
mediates, though exquisite quantitative analyses have already
been reported by several groups.13-15 On the basis of the X-ray
crystallographic data of Amano PS-phosphate inhibitor com-
plex (PDB entry 1YS1) reported by Kazlauskas,13d the alcohol
part of the lipase-inhibitor complex was replaced with chiral
five-membered-ring 1,2-diols and their monoacetates. These
complexes were assumed to be phosphate analogues of the
tetrahedral transition state. A conformational search (Mixed
MCMM/Low Mode, AMBER*) with MacroModel produced
global minimal energy complexes (Figure 1).
rotation of (S,S)-13 showed [R]24 -3.6.12 Thus, the absolute
D
configuration of (-)-3 was unambiguously determined to be
3R,4R. These absolute configurations are opposite to the
aforementioned empirical assignments by the Amano PS-chiral
recognition.
Insight into Lipase-Catalyzed Enantiomer-Selective Trans-
esterification by Computer Modeling. With regard to the
enantiomer recognition of chiral alcohols by Amano PS, several
groups reported the structure of lipase and the complex between
lipase and chiral alcohols or their phosphate inhibitors based
on X-ray crystallographic analysis13 and also based on
modeling.9a,14 They analyzed the substrate (inhibitor) complex
bound to lipase, and proposed several models to explain the
enantiomer recognition by Amano PS. The lipase Amano PS is
an R/â hydrolase. Its active site consists of catalytic triad
residues Asp264, His286, and Ser87, and the amide hydrogens
of residues Gln88 and Leu17 (oxyanion hole) also contribute
to catalysis by hydrogen bonding to the oxyanion intermediate.
In the case of plain cyclopentane-trans-1,2-diols, no large
energy difference was observed between the global minimum-
energy structures of R,R and S,S enantiomers. On the other hand,
calculations for the Amamo PS complexes with their monoac-
etates showed that the (R,R)-monoacetate complex was more
stable than the (S,S)-enantiomer complex by 5.4 kcal/mol (Figure
2a,b). These calculations are in good accord with the experi-
mental findings that both (R,R)- and (S,S)-diols were monoa-
cylated by Amano PS, and the enantiomer discrimination was
attained by the kinetic resolution of the corresponding monoac-
etate to (R,R)-diacetate (Scheme 3, eq 1). In the case of
cyclopentane-1,2-diols 3 having a diester moiety, the global
minimum-energy calculation estimated that the Amano PS
(12) Synthesis of (S,S)-13 from dimethyl L-(+)-tartrate has already been
presented. See: Demizu, Y.; Tanaka, M.; Kurihara, M.; Suemune, H. Peptide
Science 2002; Proceedings of the 39th Japanese Peptide Symposium;
Japanese Peptide Society: Minoh, Osaka, Japan, 2003; pp 321-322.
(13) (a) Kim, K. K.; Song, H. K.; Shin, D. H.; Hwang, K. Y.; Suh, S.
W. Structure 1997, 5, 173-185. (b) Schrag, J. D.; Li, Y.; Cygler, M.; Lang,
D.; Burgdorf, T.; Hecht, H.-J.; Schmid, R.; Schomburg, D.; Rydel, T. J.;
Oliver, J. D.; Strickland, L. C.; Dunaway, C. M.; Larson, S. B.; Day, J.;
McPherson, A. Structure 1997, 5, 187-202. (c) Luic´, M.; Tomic´, S.; Lesˇcˇic´,
I.; Ljubovic´, E.; Sˇepac, D.; Sˇunjic´, V.; Vitale, L.; Saenger, W.; Kojic´-Prodic´,
B. J. Biochem. 2001, 268, 3964-3973. (d) Mezzetti, A.; Schrag, J. D.;
Cheong, C. S.; Kazlauskas, R. J. Chem. Biol. 2005, 12, 427-437.
(14) (a) Schulz, T.; Pleiss, J.; Schmid, R. D. Protein Sci. 2000, 9, 1053-
1062. (b) Tafi, A. T.; van-Almsick, A.; Corelli, F.; Crusco, M.; Laumen,
K. E.; Schneider, M. P.; Botta, M. J. Org. Chem. 2000, 65, 3659-3665.
(15) Tuomi, W. V.; Kazlauskas, R. J. J. Org. Chem. 1999, 64, 2638-
2647.
J. Org. Chem, Vol. 72, No. 20, 2007 7753

Tanaka et al.
FIGURE 2. Computer modeling of transition state analogue-Amano PS complexes. (a, b) Modeling of the transition state analogue of plain (S,S)-
and (R,R)-monoacetate in the active site of Amano PS. The (R,R)-enantiomer was more stable than the (S,S)-enantiomer by 5.4 kcal/mol. (c, d)
Modeling of the transition state analogue of (S,S)- and (R,R)-diol 3 having a diester moiety in the active site. A hydrogen bond between the diester
moiety and Thr18 is observed. The (S,S)-enantiomer was more stable than the (R,R)-enantiomer by 8.1 kcal/mol.
complex with (S,S)-cyclopentane-1,2-diol (+)-3 was more
favorable than that with (R,R)-diol (-)-3 by + 8.1 kcal/mol
(Figure 2c,d). In the calculated structures of both the (R,R)- and
(S,S)-diol complexes, a hydrogen bond between the carbonyl
function of the diester (substrate) and the hydroxyl function of
the amino acid residue (Thr 18) was observed. The hydrogen
bond may be crucial for the reversal of the enantiomeric
selectivity. Although it is known that the calculated energies
of lipase-small molecule complexes are not a reliable basis to
judge whether a conformation is catalytically relevant,15 in our
cases, comparison of the calculated energies matched the
experimental finding that (S,S)-cyclopentane-1,2-diol (+)-3 was
preferentially acylated. The phosphates used here correspond
to the heptanoyl ester, not the acetyl group, and the enantiomer
discrimination is determined by the kinetic constant (kcat/Km;
reaction rate kcat and binding constant Km). Moreover, a stable
nonproductive binding complex that would not lead to acylation
may exist in the case of the slow reactive enantiomer. Regardless
of the exact mechanisms and the aforementioned issues, this
simple calculation can be applied to predict the enantio-
preference of Amano PS toward the cyclic 1,2-diols, and the
reversal of enantiomer selectivity can be well explained.
Synthesis of Optically Active Seven-Membered-Ring R,R-
Disubstituted Amino Acid. We have already reported chiral
cyclic R,R-disubstituted R-amino acids in which the R-carbon
atom is not a chiral center but chiral centers existing at the side
chain cyclopentane.5 By using these R,R-disubstituted amino
acids, we controlled the helical-screw direction of their peptide
foldamers without a chiral center on the peptide backbone.
As an application for an optically active cyclic 1,2-diol, we
synthesized a new chiral cyclic R,R-disubstituted R-amino acid
having a seven-membered ring: (4R,5R)-1-amino-4,5-di-
(methoxy)cycloheptanecarboxylic acid {15: (4R,5R)-Ac7cdOM},
which is an analogue of the five-membered-ring one.5a That is
to say, methylation of the diol function in (-)-8 with MeI and
Ag2O gave a dimethoxy compound (-)-14 in 99% yield. Partial
hydrolysis of the diester under basic conditions, followed by
Curtius rearrangement16 and workup with benzyl alcohol
produced the cyclic amino acid Cbz-{(4R,5R)-Ac7cdOM}-OMe
(-)-15 in 92% yield without any problem.
7754 J. Org. Chem., Vol. 72, No. 20, 2007

Preparation of Cycloalkane-trans-1,2-diols
SCHEME 6
DAICEL-CHIRALPAK AD; eluent, 10% i-PrOH in hexane; flow
rate, 1.0 mL; detection, RI; retention time (tR): (()-3: tR ) 16
and 18 min, (R,R)-(-)-3: tR ) 18 min].
(S,S)-(+)-3,4-Dihydroxy-1,1-bis(methoxycarbonyl)cyclopen-
tane (3). Solvolysis of (-)-5 by treatment with K2CO3 in MeOH
afforded (S,S)-(+)-3 in quantitative yield. (S,S)-(+)-3: colorless
crystals; [R]31 +12.0 (c 1.00, CHCl3).
D
Kinetic Resolution of (()-8. Amano AK-catalyzed transesteri-
fication of (()-8 afforded monoacetate (+)-10 (51%, 95% ee) and
the diol (-)-8 (43%, >99% ee). (+)-10: a colorless oil; [R]26
D
Conclusion
+16.0 (c 1.04, CHCl3); IR (neat) 3468 (br), 1728 cm-1; H NMR
1
We synthesized the cycloalkane-trans-1,2-diols 3 and 8
bearing a diester moiety by using olefin metathesis with Grubbs
catalyst, followed by epoxidation and acidic hydrolysis. The
Amano PS-catalyzed kinetic resolution of racemic diol (()-3
by transesterification afforded the enantiomerically enriched
monoaceate (S,S)-(-)-5 (95% ee) in 46% yield and the diol
(R,R)-(-)-3 (92% ee) in 51% yield. Furthermore, the Amano
AK-catalyzed transesterification of the seven-membered-ring
(()-8 gave the highly enantiomerically enriched monoacetate
(S,S)-(+)-10 (>99% ee) and the diol (R,R)-(-)-8 (>99% ee),
by tuning the reaction conditions. It is noteworthy that the lipases
Amano PS and Amano AK took up the (S,S)-diols 3 and 8 in
their active site, but not the (R,R)-enantiomers. In the case of
the reported simple cycloalkane-1,2-diols, the active site of
Amano PS took up and acylated the opposite (R,R)-enantiomers.
To explain the influence of the diester moiety on the enantiomer
selectivity, we performed calculations for the lipase-substrate
complexes by using computer modeling. The calculation showed
that in the case of simple cyclopentane-1,2-diol, the (R,R)-
monoacetate-lipase complex was more stable than the (S,S)
complex, and in the case of cyclopentane-1,2-diol 3 having a
diester, the (S,S)-diol-lipase complex was more stable than the
(R,R) complex. These calculated results are in good agreement
with the experimental results. As an application of the optically
active 1,2-diol, we efficiently synthesized the chiral cyclic R,R-
disubstituted amino acid (4R,5R)-Ac7cdOM (-)-15, in which the
R-carbon atom is not an asymmetric center.
(400 MHz, CDCl3) δ 4.64 (m, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.68
(m, 1H), 2.40 (br, 1H), 2.25-2.42 (m, 2H), 2.08 (s, 3H), 1.72-
2.05 (m, 4H), 1.64-1.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
172.5, 172.3, 171.1, 80.3, 74.8, 56.2, 52.6, 52.5, 27.9, 27.3, 27.1,
25.3, 21.2; FAB(+)HRMS calcd for C13H21O7 (M+ + H) 289.1287,
found 289.1294. Enantiomeric excess of monoacetate 10 was
determined by HPLC [column, DAICEL-CHIRALPAK AD; eluent,
10% i-PrOH in hexane; flow rate, 1.0 mL; detection, RI; retention
time: (()-10: tR ) 16 and 17 min, (+)-10: tR ) 17 min]. (R,R)-
(-)-8: colorless crystals; mp 59-61 °C; [R]26 -16.7 (c 1.01,
D
CHCl3). Enantiomeric excess of diol 8 was determined by HPLC
[column, TOSOH-BP developing column; eluent, 10% i-PrOH in
hexane; flow rate, 1.0 mL; detection, RI; retention time: (()-8:
tR ) 7 and 8 min, (-)-8: tR ) 8 min].
(S,S)-(+)-4,5-Dihydroxy-1,1-bis(methoxycarbonyl)cyclohep-
tane (8). Solvolysis of (+)-10 by treatment with K2CO3 in MeOH
afforded (S,S)-(+)-8 (quantitative). Colorless crystals; [R]31D +15.4
(c 1.05, CHCl3).
(4R,5R)-(-)-4,5-Dimethoxy-1,1-bis(methoxycarbonyl)cyclo-
heptane {(-)-14}. A suspension of (-)-8 (1.30 g, 5.28 mmol) and
Ag2O (24.5 g, 105 mmol) in MeI (30 mL) was vigorously stirred
and refluxed under an Ar atmosphere. After being stirred for 10
days, the Ag2O was filtered off, and the filtrate was concentrated
in vacuo to leave a solid, which was purified by column chroma-
tography on silica gel. The fraction eluted with 20% EtOAc in
hexane afforded (-)-14 (1.43 g, 99%) as colorless crystals. Mp
51-53 °C (from CHCl3/hexane); [R]24 -2.90 (c 1.23, CHCl3);
D
1
IR (KBr) 2952, 2823, 1733 cm-1; H NMR (400 MHz, CDCl3) δ
3.71 (s, 6H), 3.35 (s, 6H), 3.26 (m, 2H), 2.20 (m, 2H), 1.99 (m,
2H), 1.70-1.80 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 172.7,
82.7, 56.6, 56.5, 52.4, 25.9, 23.5; FAB(+)MS m/z 275 (M+ + H).
Anal. Calcd for C13H22O6: C, 56.92; H, 8.08. Found: C, 56.55; H,
7.92.
Experimental Section
Kinetic Resolution of (()-3 by Transesterification. A mixture
of diol (()-3 (100 mg, 0.459 mmol) and Amamo PS (100 mg) in
vinyl acetate (5 mL) was vigorously stirred at 40 °C for 72 h. The
lipase was filtered off, and the filtrate was evaporated in vacuo to
afford a residue, which was purified by column chromatography
on silica gel. The fraction eluted with 30% EtOAc in hexane
afforded monoacetate (-)-5 (44 mg, 37%, 95% ee), and that eluted
with EtOAc gave diol (-)-3 (56 mg, 56%, 66% ee). (-)-5: 95%
Methyl (4R,5R)-(-)-1-Benzyloxycarbonylamino-4,5-(dimethox-
y)cycloheptanecarboxylate [Cbz-{(R,R)-Ac7cdOM}-OMe; 15]. A
solution of (-)-14 (1.26 g, 4.60 mmol) in MeOH (50 mL) and 0.1
N aqueous NaOH solution (70 mL) was stirred overnight from at
0 °C to room temperature. The solution was acidified with 10%
aqueous HCl to pH 3-4, and then MeOH was evaporated. The
aqueous solution was extracted with EtOAc and dried over Na2-
SO4. Removal of the solvent afforded a crude monocarboxylic acid
that was used for the next reaction without purification. A solution
of the crude carboxylic acid, Et3N (700 mg, 6.90 mmol), and
diphenylphosphoryl azide (DPPA; 1.90 g, 6.90 mmol) in toluene
(20 mL) was refluxed for 1.5 h under an Ar atmosphere. Then,
benzyl alcohol (0.7 mL, 6.9 mmol) was added to the solution, and
the whole was refluxed for 3 days. After being cooled to room
temperature, the solution was diluted with EtOAc, washed with
2% aqueous HCl, 5% aqueous NaHCO3, and brine, and dried over
MgSO4. After removal of the solvent, the residue was purified by
column chromatography on silica gel (60% EtOAc in hexane) to
give (-)-15 (1.54 g, 92%) as a colorless oil. [R]24D -8.32 (c 1.04,
ee; a colorless oil; [R]24 -14.0 (c 1.00, CHCl3); IR (neat) 3507
D
(br), 1736 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.93 (m, 1H), 4.21
(m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.82 (dd, J ) 6.7, 15.0 Hz,
1H), 2.76 (br, 1H), 2.68 (dd, J ) 6.4, 14.4 Hz, 1H), 2.38 (dd, J )
4.5, 15.0 Hz, 1H), 2.78 (dd, J ) 4.3, 14.4 Hz, 1H), 2.04 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 172.6, 171.7, 171.1, 81.1, 76.2,
57.6, 53.1, 52.9, 39.9, 37.4, 20.9; FAB(+)HRMS calcd for C11H17O7
(M+ + H) 261.0974, found 261.1024. (R,R)-(-)-3: 92% ee (entry
2); colorless crystals; mp 72-74 °C; [R]24D -11.2 (c 1.00, CHCl3).
Enantiomeric excess of diols 3 was determined by HPLC [column,
(16) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
94, 6203-6205. (b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron
1974, 30, 2151-2157. (c) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.;
Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64,
6411-6417. (d) Ghosh, A. K.; Fidanze, S. J. Org. Chem. 1998, 63, 6146-
6152. (e) Spino, C.; Godbout, C. J. Am. Chem. Soc. 2003, 125, 12106-
12107.
1
CHCl3); IR (neat) 3346, 2936, 2823, 1732, 1520 cm-1; H NMR
(400 MHz, CDCl3) δ 7.31-7.38 (m, 5H), 5.08 (s, 2H), 5.04 (s,
1H), 3.68 (br s, 3H), 3.35 (s, 6H), 3.17-3.30 (m, 2H), 2.32 (m,
1H), 2.03 (m, 2H), 1.60-1.90 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 174.7, 155.2, 136.2, 128.4, 128.0, 127.9, 82.8, 82.0, 66.6,
J. Org. Chem, Vol. 72, No. 20, 2007 7755

Tanaka et al.
61.7, 56.6, 56.4, 52.4, 29.7, 27.7, 22.8, 21.8; FAB(+)HRMS calcd
for C19H28NO6 (M+ + H) 366.1917, found 366.2014.
chain conformation of lipase and part of hexylphosphonic acid were
fixed during the conformational search.
Computer Modeling of Transition State Analogues-Amamo
PS Complex. All molecular modelings and calculations were
performed with MacroModel version 8.1 (Schrodinger, LLC), using
the Mixed MCMM/Low Mode procedure and AMBER* force field.
For modeling, the X-ray crystal structure of Burkholderia cepacia
lipase (Amano PS) complexed with hexylphosphonic acid (R)-2-
methyl-3-phenylpropyl ester, which is a covalently docked tetra-
hedron transition state mimic, was obtained from the Protein Data
Bank (PDB entry, 1YS1). The water molecules were removed and
hydrogen atoms were added with use of the MacroModel protocol.
Initial structures were manually built by replacing the alcohol part
(indicated in the red square, Figure 1) of hexylphosphonic acid ester
in the 1YS1 structure with the enantiomers of cyclic 1,2-diols and
their monoacetates. To determine the global minimum-energy
structures of these complexes, a systematic conformational search
protocol (Mixed MCMM/Low Mode) was employed. AMBER*
was used as a Force Field. More than 1000 conformers were energy
minimized for each model. The backbone conformation and side-
Acknowledgment. This work was in part supported by a
Grant-in-Aid for Scientific Research (B) from the Japan Society
for the Promotion of Science, by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 19028052, Chemistry of
Concerto Catalysis), and from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and was also
supported by a grant from the NOVARTIS Foundation (Japan)
for the Promotion of Science.
Supporting Information Available: Preparation of (()-3, 5,
8, and 10, and their benzoate derivatives, spectroscopic data, and
1
copies of H NMR or 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO701317D
7756 J. Org. Chem., Vol. 72, No. 20, 2007