Lipase TL-mediated kinetic resolution of 5-benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol at low temperature: Concise asymmetric synthesis of both enantiomers of a piperazic acid derivative

Article abstract of DOI:10.1021/jo034441n

Lipase TL-mediated kinetic resolution of (± )-5-benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol (5) at low temperature proceeded to give the corresponding (S)-alcohol 5 and (R)-acetate 6 in quantitative yields with high enantiomeric purity. The addition of bases such as pyridine, DMAP, 2,4- and 2,6-lutidines, or triethylamine considerably enhanced the rate of kinetic resolution. The alcohol (S)-5 and the acetate (R) -6 were converted to piperazic acid derivatives (R)- and (S)-3, respectively, via the intramolecular Mitsunobu reaction as a key step.

Full text of DOI:10.1021/jo034441n

Lip a se TL-Med ia ted Kin etic Resolu tion of
5-Ben zyloxy-1-ter t-bu tyld im eth ylsilyloxy-2-p en ta n ol a t Low
Tem p er a tu r e: Con cise Asym m etr ic Syn th esis of Both En a n tiom er s
of a P ip er a zic Acid Der iva tive
Yutaka Aoyagi, Yoshihiro Saitoh, Tasuku Ueno, Mai Horiguchi, and Koichi Takeya*
School of Pharmacy, Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, J apan
Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
takeyak@ps.toyaku.ac.jp; rmw@chem.colostate.edu
Received April 7, 2003
Lipase TL-mediated kinetic resolution of (()-5-benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol
(5) at low temperature proceeded to give the corresponding (S)-alcohol 5 and (R)-acetate 6 in
quantitative yields with high enantiomeric purity. The addition of bases such as pyridine, DMAP,
2,4- and 2,6-lutidines, or triethylamine considerably enhanced the rate of kinetic resolution. The
alcohol (S)-5 and the acetate (R)-6 were converted to piperazic acid derivatives (R)- and (S)-3,
respectively, via the intramolecular Mitsunobu reaction as a key step.
In tr od u ction
Piperazic acids (2) are nonproteinogenic amino acids
containing a cyclic hydrazine skeleton. Piperazic acid
itself inhibits γ-aminobutyric acid (GABA) uptake1 and
substituted piperazic acids are key amino acid compo-
nents of several biologically active natural peptides,
including sanglifehrins,2,3 novel cyclophilin-binding com-
pounds, polyoxypeptin,4 a potent inducer of apoptosis in
human pancreatic carcinoma cells, and matlystatins.5
Interestingly, GE3 (1)6,7 (Figure 1) and related com-
pounds such as azinothricin8 and A83586C,9 novel dep-
sipeptide antitumor antibiotics produced by Streptomyces
sp., include both enantiomers of piperazic acid in their
structures.
F IGURE 1. Structures of GE3 and piperazic acids.
tides.10 During the course of our continuing research on
the lipase TL-mediated kinetic resolution of benzoin,11,12
we have found that lipase TL is an efficient enzyme for
the kinetic resolution of several types of alcohols at low
temperature. In this paper, we describe the kinetic
resolution of (()-5-benzyloxy-1-tert-butyldimethylsilyl-
oxy-2-pentanol (5) by lipase TL and the conversion of
alcohol (S)-5 and acetate (R)-6 to the corresponding
piperazic acids. Lipases, which are employed widely in
the synthesis of optically pure compounds, catalyze not
only the hydrolysis of natural esters but also hydrolysis
and transesterification of a wide range of unnatural
substrates. The empirical rule that predicts the enan-
tiomeric preference of lipases has been proposed by
A number of methods have been reported to synthesize
the piperazic acid portion of biologically active depsipep-
(1) Horton, R. W.; Collins, J . F.; Anlezark, G. M.; Meldrum, B. S.
Eur. J . Pharmacol. 1979, 59, 75-83.
(2) Sanglier, J .-J .; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke,
M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.;
Schilling, W. J . Antibiot. 1999, 52, 466-473.
(3) Fehr, T.; Kallen, J .; Oberer, L.; Sanglier, J .-J .; Schilling, W. J .
Antibiot. 1999, 52, 474- 479.
(4) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.; Kondo, S.;
Naganawa, H.; Kinoshita, N.; Hashizume, H.; Hamada, M.; Takeuchi,
T.; Ohba, S. Tetrahedron Lett. 1998, 39, 1389-1392.
(5) Haruyama, H.; Ohkuma, Y.; Nagaki, H.; Ogita, T.; Tamaki, K.;
Kinoshita, T. J . Antibiot. 1994, 47, 1473-1480.
(6) Agatsuma, T.; Sakai, Y.; Mizukami, T.; Saitoh, Y. J . Antibiot.
1997, 50, 704-708.
(7) Sakai, Y.; Yoshida, T.; Tsujita, T.; Ochiai, K.; Agatsuma, T.;
Saitoh, Y.; Tanaka, F.; Akiyama, T.; Akinaga, S.; Mizukami, T. J .
Antibiot. 1997, 50, 659-664.
(8) Maehr, H.; Liu, C.-M.; Palleroni, N. J .; Smallheer, J .; Todaro,
L.; Williams, T. H.; Blount, J . F. J . Antibiot. 1986, 39, 17-25.
(9) Smitka, T. A.; Deeter, J . B.; Hunt, A. H.; Mertz, F. P.; Ellis, R.
M.; Boeck, L. D.; Yao, R. C. J . Antibiot. 1988, 41, 726-733.
(10) Ciufolini, M. A.; Xi, N. Chem. Soc. Rev. 1998, 27, 437-445.
(11) Aoyagi, Y.; Agata, N.; Shibata, N.; Horiguchi, M.; Williams, R.
M. Tetrahedron Lett. 2000, 41, 10159-10162.
(12) Aoyagi, Y.; Iijima, A.; Williams, R. M. J . Org. Chem. 2001, 66,
8010-8014.
10.1021/jo034441n CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/08/2003
J . Org. Chem. 2003, 68, 6899-6904
6899

Aoyagi et al.
F IGURE 2. Empirical rule that summarizes the enantiopreference of lipases toward chiral secondary alcohols.
Kazlauskas et al.13,14 The recognition of alcohols by a
lipase from Candida rugosa (CRL) was discussed on the
basis of X-ray crystal structures of covalent complexes
of CRL with transition-state analogues for the hydrolysis
of menthyl esters.15 In our previous papers11,12 on the
lipase TL-mediated kinetic resolution of (()-benzoin, only
(S)-benzoin was recognized and underwent transesteri-
fication to give the (S)-benzoin acetate. The stereorecog-
nition of benzoin by lipase TL was identified with the
empirical rule already proposed in which the reactive
enantiomer is that in which the large and medium groups
are disposed as in Figure 2.13,14
methylmorpholine N-oxide (NMO)16 from commercially
available 4-penten-1-ol (7). The primary hydroxyl group
of 8 was protected by using tert-butyldimethylsilyl chlo-
ride and imidazole to give the monoprotected alcohol 5.
Acetylation of 5 was carried out to obtain racemic acetate
6 (Scheme 2).
SCHEME 2. Syn th esis of r a c-Alcoh ols (5 a n d 9)
a n d Th eir Aceta tes (6 a n d 10)a
This indicates the lipase TL-mediated reaction should
give (R)-acetate 6 when (()-5 is employed as a substrate.
Retrosynthetic analysis for the preparation of both enan-
tiomers of piperazic acid 3 via kinetic resolution of (()-5
is shown in Scheme 1.
a
Reagents and conditions: (i) NaH/BnBr; (ii) OsO4/NMO; (iii)
SCHEME 1. Syn th etic Str a tegy for th e Syn th esis
of (R)- a n d (S)-3
TBSCl/imidazole/DMF/0 °C then rt; (iv) TBDPSCl/imidazole/
DMF/0 °C then rt; (v) Ac2O/DMAP/CH2Cl2/0 °C then rt.
In the same way, alcohol 8 was protected with a tert-
butyldiphenylsilyl group to give 9. With racemic second-
ary alcohols 5 and 9 in hand, the lipase TL-mediated
kinetic resolution of 5 was examined under various
reaction conditions. Enantiomeric ratios for acetate 6 and
recovered alcohol 5 were determined by HPLC analysis,
using a chiral column (CHIRALCEL OD-H), and are
shown in Table 1. Initially, several kinds of solvents were
employed. Among these solvents, hexane gave the best
chemical yields and enantiomeric ratios (entries 1-6).
It is known that addition of crown ethers17,18 and amino
alcohols19-21 affects the hydrolysis of esters, and that
addition of crown ethers also enhances the rate of
transesterification with use of enzymes in apolar organic
solvents.22,23 To identify other nonhazardous and com-
mercially available additives to effect the lipase TL-
mediated kinetic resolution, we carried out the resolution
using several bases (entries 7-13). Among those exam-
ined, DMAP, 2,4-lutidine, 2,6-lutidine, and pyridine were
found to be effective. DMAP, in particular, which is the
most basic of these additives, considerably enhanced the
Piperazic acid derivatives (S)- and (R)-3 could be
synthesized from hydrazino alcohols (S)- and (R)-4 via
an intramolecular Mitsunobu reaction. Compound 4
might be prepared by introduction of a hydrazino skel-
eton to compound 6. Enantiomerically pure alcohol 5 and
acetate 6 should be obtained by lipase TL-mediated
kinetic resolution of (()-5, which can be prepared from
commercially available 4-penten-1-ol (7) in three steps:
benzylation of a hydroxyl group, dihydroxylation of a
double bond, and finally silylation.
(16) Isobe, M.; Nishikawa, T.; Pikul, S.; Goto, T. Tetrahedron Lett.
1987, 28, 6485-6488.
Resu lts a n d Discu ssion
(17) Guo, Z.-W.; Sih, C. J . J . Am. Chem. Soc. 1989, 111, 6836-6841.
(18) Nagao, Y.; Tohjo, T.; Kaneuchi, T.; Yukimoto, Y.; Kume, M.
Chem. Lett. 1992, 1817-1820.
First, diol 8 was prepared via benzylation and dihy-
droxylation with catalytic osmium tetroxide and N-
(19) Itoh, T.; Ohira, E.; Takagi, Y.; Nishiyama, S.; Nakamura, K.
Bull. Chem. Soc. J pn. 1991, 64, 624-627.
(20) Itoh, T.; Hiyama, Y.; Betchaku, A.; Tsukube, H. Tetrahedron
Lett. 1993, 34, 2617-2620.
(13) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656-2665.
(21) Comai, K.; Sullivan, A. N. J . Pharm. Sci. 1982, 71, 418-421.
(22) Reinhoudt, D. N.; Eendeback, A. M.; Nijenhuis, W. F.; Verboom,
W.; Kloosterman, M.; Schoemaker, H. E. J . Chem. Soc., Chem.
Commun. 1989, 399-400.
(14) Weissfloch, A. N. E.; Kazlauskas, R. J . J . Org. Chem. 1995, 60,
6959-6969.
(15) Cygler, M.; Grochulski, P.; Kazlauskas, R. J .; Schrag, J . D.;
Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta, A. K. J . Am. Chem.
Soc. 1994, 116, 3180-3186.
(23) Odell, B.; Earlam, G. J . Chem. Soc., Chem. Commun. 1985,
359-361.
6900 J . Org. Chem., Vol. 68, No. 18, 2003

5-Benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol
TABLE 1. Lip a se TL-Med ia ted Kin etic Resolu tion of (()-5 u n d er Va r iou s Con d ition sa
acetate (R)-6
recovered (S)-5
yield (%)b ee (%)c
reaction
time (h)
reaction
temp (°C)
entry
solvent
additive (equiv)
yield (%)b
ee (%)c
cd
Ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27f
28f
29f
30f
benzene
THF
hexane
AcOEt
DMSO
DMF
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
6
12
24
1
3
6
12
24
48
48
48
48
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
5
0
-5
-10
none
none
none
none
none
none
11
16
36
35
16
17
44
62
31
56
44
34
50
33
35
42
47
50
27
32
42
30
41
54
52
56
46
50
47
48
92
98
90
96
92
98
94
68
96
90
98
96
94
98
94
94
92
96
96
92
94
98
96
96
92
82
96
96
98
98
88
78
64
60
77
82
55
40
68
43
56
62
50
65
61
56
42
50
68
62
56
70
59
45
47
42
45
49
50
53
12
20
48
56
20
4
0.12
0.17
0.35
0.37
0.18
0.04
0.42
0.58
0.20
0.51
0.45
0.32
0.49
0.32
0.36
0.27
0.50
0.48
0.25
0.40
0.43
0.27
0.33
0.45
0.52
0.54
0.49
0.49
0.48
0.46
27
120
31
86
29
103
66
17
62
62
244
77
106
156
56
45
79
152
67
45
69
141
79
121
110
46
162
162
307
254
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
i-Pr2NEt (5.0)
DMAP (5.0)
NaHCO3 (5.0)
2,4-lutidine (5.0)
2,6-lutidine (5.0)
pyrimidine (5.0)
pyridine (5.0)
pyridine (0.5)
pyridine (1.0)
pyridine (2.5)
pyridine (10.0)
pyridine (20.0)
pyridine (5.0)
pyridine (5.0)
pyridine (5.0)
DMAP (5.0)
DMAP (5.0)
DMAP (5.0)
DMAP (5.0)
DMAP (5.0)
pyridine (5.0)
pyridine (5.0)
pyridine (5.0)
pyridine (5.0)
68
92
24
92
80
46
92
46
54
34
92
90
32
62
71
36
48
80
98
98
92
92
90
82
a
All reactions were carried out under an Ar atmosphere. Lipase TL (250 mg) and solvent (5 mL) were employed in the reactions.
Isolated yields. c The enantiomeric excesses (ee) were determined by means of HPLC with a Chiralcel OD-H column. Conversion
b
d
calculated from c ) ee(5)/(ee(5) + ee(6)) according to ref 24. e E ) ln[1 - c(1 + ee(6))]/ln[1 - c(1 - ee(6))]. See ref 24. f Lipase TL (500 mg)
and solvent (10 mL) were employed in the reactions.
reaction rate (entry 8). Weak bases such as sodium
bicarbonate and pyrimidine gave essentially the same
results as in the absence of base (entries 9 and 12). Next,
the number of equivalents of pyridine was examined.
When 5 equiv of pyridine were employed in the reaction,
satisfactory yields and enantiomeric excess were obtained
(entry 13 vs entries 14 to 18). When DMAP (5 equiv) was
used, the yield of (R)-acetate 6 was increased up to 50%
within 6 h (entries 22-26 and 8). On the other hand, in
the case of pyridine it took 48 h until all (R)-5 was
consumed (entries 19-21 and 13).
However, although DMAP considerably enhanced the
kinetic resolution, pyridine, which is cheaper, was se-
lected for use in a practical synthesis. Interestingly,
kinetic resolution of alcohol 9 did not proceed under the
reaction conditions. This indicates that the identity of the
protecting group on the primary hydroxyl group of 8 is
important and that the steric bulk of the tert-butyldiphe-
nylsilyl group may abrogate binding of the substrate to
the enzyme-active site. There are very few reports
concerning cold active enzyme-mediated transesterifica-
tions. Sakai et al. reported that enhancement of the
enantioselectivity in lipase-mediated kinetic resolutions
of 3-phenyl-2H-azirine-2-methanol by lowering the tem-
perature to -40 °C was observed.25 Thus, the kinetic
resolution of 5 at low temperature was examined (entries
27-30). When the kinetic resolutions were carried out
at lower temperatures, the yields of the acetate were the
same as that at room temperature after 48 h and the
enantiomeric excess of the acetate was extremely high,
so lowering the temperature increased the E value. This
indicates that lipase TL can function as a cold active
enzyme.26 The absolute configuration of acetate 6 was
determined as depicted in Scheme 3. Deacetylation of
(R)-6 with ethylmagnesium bromide was followed by
desilylation with TBAF to give diol 8 in 83% overall yield
over two steps. The enantiomeric ratio was determined
to be 99:1 and the specific optical rotation was +4.8. As
the optical rotation of (S)-diol 8 was reported in the
literature to be -10.0,27 the absolute configuration of
compound 8 obtained from our synthesis was thus
determined to be R. As a result, the absolute stereochem-
istry of the recovered alcohol was deduced to be S.
(25) Sakai, T.; Kawabata, I.; Kishimoto, T.; Ema, T.; Utaka, M. J .
Org. Chem. 1997, 62, 4906-4907.
(26) Tsuruta, H.; Aizono, Y. Nippon Oyo Koso Kyokaishi 2001, 36,
31-37.
(24) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294-7299.
(27) Matsumoto, K.; Fuwa, S.; Shimojo, M.; Kitajima, H. Bull. Chem.
Soc. J pn. 1996, 69, 2977-2987.
J . Org. Chem, Vol. 68, No. 18, 2003 6901

Aoyagi et al.
SCHEME 3. P r ep a r a tion of (R)-8
with that reported in the literature ([R]D -30.8).32
Furthermore, HPLC analysis with a CHIRALCEL OD-H
allowed measurement of the enantiomeric purity of (R)-3
as being greater than 98% ee. Next, we prepared the
antipode, (R)-3, from alcohol (S)-5 using almost the same
procedure depicted in Scheme 4 except for acetylation of
(S)-5. (S)-6 was converted to (R)-3 in 17% overall yield.
The optical rotation and the enantiomeric excess of (R)-3
were +34.3 and >98% ee, respectively.
SCHEME 4. Con ver sion of (R)-6 to P ip er a zic Acid
Der iva tive (S)-3a
In summary, lipase TL-mediated kinetic resolution of
(()-5 at low temperature proceeded smoothly in the
presence of bases such as pyridine, 2,4-lutidine, and
DMAP to give the corresponding acetate (R)-6 and
recovered alcohol (S)-5 in good yields with high enantio-
meric purity. (R)-6 and (S)-5 were converted to both
enantiomers of a piperazic acid derivative 3 having three
different protecting groups. The application of this meth-
odology to the total synthesis of GE3 families is under
investigation and will be reported in due course.
a
Reagents and conditions: (i) H2, 10% Pd/C, MeOH, rt; (ii)
Dess-Martin periodinane, CHCl3, rt; (iii) BocNHNH2, EtOH,
AcOH, rt, then NaBH3CN, rt; (iv) CbzCl, NaHCO3, CHCl3, rt; (v)
K2CO3, MeOH; (vi) EtOOCNdNCOOEt, PPh3, THF, reflux; (vii)
(a) TBAF, THF, rt, (b) J ones oxidation, acetone, H2O, rt, (c)
TMSCHN2, MeOH, rt; (viii) TFA, CH2Cl2 (1:2), 0 °C, rt.
Exp er im en ta l Section
Rep r esen ta tive P r oced u r e for Lip a se TL-Med ia ted
Kin etic Resolu tion of (()-5. To a solution of (()-5 (0.5 g,
1.54 mmol), vinyl acetate (2.58 g, 30 mmol), and dry pyridine
(0.64 g, 8.0 mmol) in dry hexane (25 mL) was added lipase TL
(1.25 g) at -5 °C under an Ar atmosphere. The mixture was
stirred at the same temperature for 48 h. The catalyst was
separated off by filtration through Celite 545. The filtrate was
washed with cooled 1 N HCl (3 × 30 mL), sat. NaHCO3 (3 ×
30 mL), and sat. NaCl (3 × 30 mL), dried over MgSO4, and
filtered, and the solvents were evaporated in vacuo to give an
oily residue, which was purified with MPLC (hexane:AcOEt
5:1) to give (R)-6 as a colorless oil (0.27 g, 47%, 98% ee) and
(S)-5 (0.25 g, 50%, 90% ee) as a colorless oil. The physical and
spectral data were identical with those of the racemates except
for the optical rotation (see Supporting Information).
Conversion of the optically active acetate (R)-6 to (S)-
piperazic acid was carried out as shown in Scheme 4.
Acetate (R)-6 was hydrogenated in the presence of 10%
palladium on carbon to give an alcohol (R)-11 in 99%
yield. Oxidation of (R)-11 with Dess-Martin periodi-
nane28,29 gave aldehyde (R)-12 in quantitative yield. The
reductive amination of aldehyde (R)-12 with tert-butyl
carbazate and sodium cyanoborohydride in a mixture of
acetic acid and methanol was carried out according to
the Ernholt method30 to give the corresponding hydrazine
(R)-13 in 67% yield. Protection of (R)-13 with CbzCl and
hydrolysis of (R)-14 were carried out successively to give,
in 71% overall yield over two steps, a hydrazine-alcohol
(R)-4, which served as a substrate for the intramolecular
Mitsunobu reaction. With use of (R)-4, the intramolecular
Mitsunobu reaction was carried out to give the corre-
sponding cyclized product (S)-15 in 86% yield. Finally,
(S)-15 was desilylated with TBAF, oxidized with J ones
reagent,31 and methylated with trimethylsilyl diazo-
methane to afford (S)-16 in 81% yield. This product
should prove to be a useful amino acid component for the
synthesis of biologically active cyclic depsipeptides such
as GE3 as it has three orthogonal protecting groups. To
determine the enantiomeric excess of (S)-16, removal of
the Boc group was conducted in the usual manner. The
optical rotation of (S)-3 was -34.4, which is consistent
(R)-6: [R]D +14.2 (c 0.22, CHCl3). (S)-5: [R]D +3.0 (c 0.63,
CHCl3). The percent ee of the product was determined by
means of the HPLC method described below.
Deter m in a tion of En a n tiom er ic Excess (ee) of Recov-
er ed (S)-Alcoh ol 5 a n d Its (R)-Aceta te 6 by Mea n s of
HP LC An a lysis w ith a Ch ir a l Colu m n . Column: Daicel
CHIRALCEL OD-H column (4.6 × 250 mm). Solvent: hexane:
iPrOH 100:1. UV wavelength: 257 nm. Flow rate: 0.5 mL/
min. Pressure: 20 kg/cm2. (R)-acetate 6; tR ) 12.0 min. (S)-
acetate 6; tR ) 10.0 min. (R)-alcohol 5; tR ) 18.0 min.
(S)-alcohol 5; tR ) 22.0 min.
Acetyla tion of (S)-5-Ben zyloxy-1-ter t-bu tyld im eth yl-
silyloxy-2-p en ta n ol (5). To a mixture of (S)-5 (2.1 g, 6.48
mmol, 96% ee), DMAP (0.08 g, 0.65 mmol), and pyridine (0.77
g, 9.72 mmol) in CHCl3 (65 mL) was added dropwise Ac2O (0.79
g, 7.72 mmol) at 0 °C under an Ar atmosphere. The mixture
was stirred at room temperature for 14 h, poured into ice-
water (100 mL), diluted with AcOEt (100 mL), and separated.
The aqueous phase was extracted with AcOEt (2 × 50 mL).
The combined organic phases were washed with sat. NaCl (3
× 100 mL), dried over MgSO4, and filtered, and the solvents
were evaporated in vacuo to give an oily residue, which was
(28) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
(29) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(30) Ernholt, B. V.; Thomsen, I. B.; B., J . K.; Bols, M. Synlett 1999,
701-704.
(31) Oba, M.; Miyakawa, A.; Nishiyama, K.; Terauchi, T.; Kainosho,
M. J . Org. Chem. 1999, 64, 9275-9278.
(32) Dragovich, P. S.; Tada, H.; Zhou, R. Heterocycles 1995, 41,
2487-2498.
6902 J . Org. Chem., Vol. 68, No. 18, 2003

5-Benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol
purified with MPLC (hexane:AcOEt 4:1) to give (S)-6 as a
colorless oil (2.19 g, 92%, 96% ee). The physical data for (S)-6
were identical with those of (()-6 except for the optical rotation
(see Supporting Information). (S)-6: [R]D -14.4 (c 0.23, CHCl3).
cording to the procedure described above. [R]D -24.5 (c 1.07,
CHCl3). The spectral data and HRMS of (S)-12 were identical
with those of (R)-12.
Red u ctive Am in a tion of (R)-12. To a solution of tert-
butylcarbazate (0.97 g, 7.3 mmol) in dry MeOH (10 mL) was
added (R)-12 (1.0 g, 3.7 mmol) in dry MeOH (8 mL) at 0 °C
under an Ar atmosphere. The reaction mixture was stirred at
room temperature for 1 h and then cooled to 0 °C. AcOH (0.36
mL, 6.3 mmol) was added and the mixture was stirred for 10
min. NaBH3CN (1.30 g, 21.0 mmol) was then added and the
mixture was stirred at room temperature for 1 h. The solvents
were evaporated in vacuo and then phosphate buffer solution
(pH 7.2, 50 mL) and AcOEt (50 mL) were added. The organic
layer was separated and the aqueous layer was extracted with
AcOEt (2 × 30 mL). The combined organic layers were washed
with sat. NaCl (3 × 30 mL), dried over MgSO4, and filtered,
and the solvents were evaporated in vacuo to give an oily
residue, which was purified with MPLC (hexane:AcOEt 2:1)
to give (R)-13 as a colorless oil (0.96 g, 67%). [R]D +10.7 (c
Deter m in a tion of Absolu te Con figu r a tion of th e Ac-
eta te (R)-6, w h ich Wa s Obta in ed in th e Kin etic Resolu -
tion . To a mixture of (R)-acetate 6 (0.22 g, 0.60 mmol) and
dry Et2O (15 mL) was added 1.0 M EtMgBr (15.0 mL, 15.0
mmol) at 0 °C under an Ar atmosphere. After the reaction
mixture had been stirred at 0 °C for 1 h, sat. NH4Cl (10 mL)
was added. The aqueous solution was extracted with AcOEt
(3 × 15 mL). The combined organic phases were washed with
sat. NaCl (3 × 30 mL), dried over MgSO4, and filtered, and
the solvents were evaporated in vacuo to give an oily residue,
which was purified with MPLC (hexane:AcOEt 5:1) to give a
mixture (0.20 g) of 5 and 5-benzyloxy-1-tert-butyldimethyl-
silyloxy-1-pentanol, which was subjected to the next reaction
without further separation. To a THF solution (13 mL) of the
mixture (0.20 g) thus obtained was added 1.0 M TBAF (1.25
mL, 1.25 mmol) in THF. The reaction mixture was stirred at
room temperature for 1 h. AcOEt (30 mL) was then added.
The organic phase was washed with sat. NaCl (3 × 20 mL),
dried over MgSO4, and filtered, and the solvents were evapo-
rated in vacuo to give an oily residue, which was purified with
MPLC (CHCl3:MeOH 10:1) to give (R)-8 as a colorless oil (0.11
g, 83%). The spectral data of 8 were identical with those
reported by Matsumoto et al.27 The ee of the product was 88%
on the basis of HPLC analysis. (Column: Daicel CHIRALCEL
OB column (4.6 × 250 mm). Solvent: hexane:EtOH 9:1. UV
wavelength: 257 nm. Flow rate: 0.5 mL/min. Pressure: 20
kg/cm2. (R)-diol 8; tR ) 27.0 min. (S)-diol 8; tR ) 42.0 min. (R)-
8: [R]D +6.6 (c 0.79, CHCl3).)
Hyd r ogen olysis of (R)-Aceta te 6. In the presence of 10%
Pd/C (0.16 g), a MeOH solution (60 mL) of (R)-acetate 6 (1.6
g, 4.4 mmol) was stirred at room temperature under a H2
atmosphere (1 atm) for 0.5 h. After removal of the catalyst by
filtration through Celite 545, the filtrate was concentrated in
vacuo to give an oily residue, which was purified with MPLC
(hexane:AcOEt 1:1) to give (R)-alcohol 11 as a colorless oil (1.2
g, 99%). [R]D +20.6 (c) 0.42, CHCl3); 1H NMR (400 MHz, 300
K, CDCl3) δ 4.91 (m, 1H), 3.65 (t, 2H, J ) 9.1 Hz), 3.64 (d, 2H,
J ) 5.2 Hz), 2.05 (s, 3H), 1.66-1.57 (m, 4H), 1.71 (m, 1H),
0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, 300 K, CDCl3)
δ 170.8, 74.3, 64.2, 62.6, 28.3, 26.8, 25.8, 21.2, 18.2, -5.4; IR
(film) 3437 (OH), 1741 (CdO); HRMS (ESI) calcd for C13H28O4-
SiNa 299.1655 (M+ + Na), found 299.1628.
1
1.63, CHCl3); H NMR (400 MHz, 300 K, CDCl3) δ 6.05 (br s,
1H), 4.89 (m, 1H), 3.62 (d, 2H, J ) 5.1 Hz), 2.84 (t, 2H, J )
7.1 Hz), 2.04 (s, 3H), 1.68-1.46 (m, 4H), 1.46 (s, 9H), 0.87 (s,
9H), 0.04 (s, 6H); 13C NMR (100 MHz, 300 K, CDCl3) δ 170.7,
80.4, 64.2, 51.7, 28.4, 28.0, 25.8, 23.5, 21.2, 18.2, -5.4; IR (film)
3583 (NH), 1739, 1716 (CdO); HRMS (ESI) calcd for C18H38
-
N2O5SiNa 413.2448 (M+ + Na), found 413.2447.
Red u ctive Am in a tion of (S)-12. Reductive amination of
(S)-12 gave (S)-13 in 58% yield according to the procedure
described above. [R]D -10.3 (c 1.10, CHCl3). The spectral data
and HRMS of (S)-13 were identical with those of (R)-13.
Ca r boben zoxyla tion of (R)-13. To a mixture of (R)-13 (6.3
g, 16.5 mmol), CHCl3 (25 mL), and 1 N NaHCO3 (25 mL) was
added CbzCl (3.57 g, 21.0 mmol) dropwise at 0 °C. After the
reaction mixture was stirred vigorously at 0 °C for 1.5 h, the
organic layer was separated. The aqueous layer was extracted
with CHCl3 (2 × 30 mL). The combined organic layers were
washed with sat. NaCl (3 × 30 mL), dried over MgSO4, and
filtered, and the solvents were evaporated in vacuo to give an
oily residue, which was purified with MPLC (hexane:AcOEt
3:1) to give (R)-14 as a colorless oil (8.2 g, 97%). [R]D +5.5 (c
1
1.02, CHCl3); H NMR (500 MHz, 300 K, CDCl3) δ 7.34 (br s,
5H), 6.44 (0.7 H, br s), 6.18 (0.3 H, br s), 5.14 (br s, 2H), 4.89
(br s, 1H), 3.62 (br s, 2H), 3.53 (br s, 2H), 2.04 (s, 3H), 1.62 (br
d, 4H), 1.40 (br m, 9H), 0.87 (s, 9H), 0.04 (s, 6H); 13C NMR
(125 MHz, 300 K, CDCl3) δ 170.7, 136.0, 128.5, 128.0, 81.4,
74.1, 67.9, 64.1, 49.8, 28.1, 27.5, 25.8, 23.0, 21.1, 18.2, -5.4;
IR (film) 3312 (NH), 1739, 1717 (CdO); HRMS (ESI) calcd for
Hyd r ogen olysis of (S)-Aceta te 6. Hydrogenolysis of (S)-6
gave (S)-11 in 95% yield according to the procedure described
above. [R]D -18.6 (c 1.07, CHCl3). The spectral data and HRMS
of (S)-11 were identical with those of (R)-11.
C
26H44N2O7SiNa 547.2816 (M+ + Na), found 547.2799.
Ca r boben zoxyla tion of (S)-13. Carbobenzoxylation of (S)-
13 gave (S)-14 in 98% yield according to the procedure
described above. [R]D -5.6 (c 1.05, CHCl3). The spectral data
and HRMS of (S)-14 were identical with those of (R)-14.
Oxid a tion of (R)-Alcoh ol 11. To a solution of (R)-11 (1.58
g, 5.7 mmol) in dry CHCl3 (80 mL) was added Dess-Martin
periodinane28,29 (3.60 g, 8.6 mmol) in portions at 0 °C. After
the reaction mixture had been stirred at room temperature
for 2 h, sat. Na2S2O3 (3 × 40 mL) and sat. NaHCO3 (40 mL)
were added. The resulting mixture was stirred at room
temperature for 0.5 h. The reaction mixture was diluted with
AcOEt (80 mL) and separated. The organic layer was washed
with sat. NaCl (3 × 40 mL), dried over MgSO4, and filtered,
and the solvents were evaporated in vacuo to give an oily
residue, which was purified with MPLC (hexane:AcOEt 3:1)
to give (R)-12 as a colorless oil (1.56 g, quantitative yield). [R]D
+25.1 (c 1.28, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3) δ
9.75 (t, 1H, J ) 1.4 Hz), 4.88 (m, 1H), 3.65 (dd, 1H, J ) 10.8,
5.1 Hz), 3.61 (dd, 1H, J ) 10.8, 5.0 Hz), 2.49 (td, 2H, J ) 7.8,
1.4 Hz), 2.03 (s, 3H), 2.01-1.84 (m, 2H), 0.87 (s, 9H), 0.03 (s,
6H); 13C NMR (100 MHz, 300 K, CDCl3) δ 201.3, 170.6, 73.5,
63.9, 39.8, 25.7, 23.1, 21.0, 18.2, -5.5; IR (film) 1739 (CdO);
HRMS (ESI) calcd for C13H26O4SiNa 297.1498 (M+ + Na),
found 297.1477.
Dea cetyla tion of (R)-14. To a mixture of (R)-14 (1.0 g, 1.9
mmol), MeOH (22 mL), and H2O (11 mL) was added powdered
K2CO3 (4.0 g, 28.6 mmol) at room temperature. After the
reaction mixture was stirred at room temperature for 6 h,
AcOEt (100 mL) was added and the layers separated. The
organic layer was washed with sat. NaCl (3 × 50 mL), dried
over MgSO4, and filtered, and the solvents were evaporated
in vacuo to give an oily residue, which was purified with MPLC
(hexane:AcOEt 2:1) to give (R)-4 as a colorless oil (0.67 g, 73%).
1
[R]D -1.5 (c 0.81, CHCl3); H NMR (500 MHz, 300 K, CDCl3)
δ 7.33 (br m, 5H), 6.49 (br s, 0.7 H), 6.27 (br s, 0.3 H), 5.15 (br
s, 2H), 3.56 (br m, 4H), 3.37 (br s, 1H), 2.29 (s, 3H), 1.77 (m,
1H), 1.64 (br s, 1H), 1.41 (br m, 11H), 0.90 (s, 9H), 0.06 (s,
6H); 13C NMR (125 MHz, 300 K, CDCl3) δ 156.1, 136.1, 128.4,
128.1, 81.5, 71.5, 67.9, 67.2, 50.4, 50.0, 29.7, 28.1, 25.9, 23.3,
18.3, -5.36, -5.41; IR (film) 3464 (OH), 3302 (NH), 1712
(CdO); HRMS (ESI) calcd for C24H42N2O6SiNa 505.2710 (M+
+ Na), found 505.2678.
Oxid a tion of (S)-Alcoh ol 11. Oxidation of (S)-11 gave (S)-
12 with Dess-Martin periodinane in quantitative yield ac-
Dea cetyla tion of (S)-14. Deacetylation of (S)-14 gave (S)-4
in 64% yield according to the procedure described above. [R]D
J . Org. Chem, Vol. 68, No. 18, 2003 6903

Aoyagi et al.
+1.4 (c 0.93, CHCl3). The spectral data and HRMS of (S)-4
were identical with those of (R)-4.
(br m, 1H), 4.00 (br m, 1H), 3.00 (br s, 1H), 2.88 (br s, 3H),
1.92 (br m, 1H), 1.81 (br m, 2H), 1.56 (br m, 1H), 1.39 (s, 1.39);
13C NMR (125 MHz, 300 K, CDCl3) δ 208.9, 170.4, 155.3, 154.4,
136.4, 136.0, 128.6, 128.4, 128.2, 128.0, 127.7, 82.1, 68.3, 68.1,
67.5, 59.6, 57.8, 57.5, 56.5, 54.7, 52.2, 52.0, 49.5, 48.4, 48.0,
45.0, 43.6, 42.3, 42.1, 28.0, 25.7, 25.2, 24.4, 20.3, 20.0, 17.3,
17.1; IR (film) 1728, 1708 (CdO); HRMS (ESI) calcd for
In tr a m olecu la r Mitsu n obu Rea ction of (R)-4. To a THF
(330 mL) solution of (R)-4 (0.80 g, 1.66 mmol) and PPh3 (1.70
g, 6.64 mmol) was added DEAD (0.94 g, 5.0 mmol) at reflux
and under an Ar atmosphere. The reaction mixture was
refluxed for 0.5 h. After evaporation of the solvents, the oily
residue was purified with MPLC (hexane:AcOEt 3:1) to give
(S)-15 as a colorless oil (0.67 g, 86%). [R]D -24.1 (c 1.07,
C
19H26N2O6Na 401.1689 (M+ + Na), found 401.1691.
P r ep a r a t ion of (R)-Met h yl 1-Ben zyloxyca r b on yl-2-
1
CHCl3); H NMR (500 MHz, 300 K, CDCl3) δ 7.36-7.28 (m,
bu toxyca r bon ylp ip er a zic Acid 16. Desilylation, oxidation,
and methylation of (R)-15 gave (R)-16 in 88% yield according
to the procedure described above. [R]D +36.3 (c 1.09, CHCl3).
The spectral data and HRMS of (R)-16 were identical with
those of (S)-16.
5H), 5.15 (d, 1H, J ) 12.4 Hz), 5.11 (d, 1H, J ) 12.4 Hz), 4.31
(br s, 0.7H), 4.10 (dt, 1H, J ) 12.5, 4.6 Hz), 4.00 (m, 0.3H),
3.81 (dd, 0.3H, J ) 10.0, 5.0 Hz), 3.70 (br m, 0.7H), 3.59-3.52
(m, 1H), 3.07 (br s, 0.3H), 2.96 (br s, 0.7H), 1.80 (m, 2H), 1.65
(br m, 1H), 1.50-1.32 (m, 10H), 0.88 (s, 2.7H), 0.85 (s, 6.3H),
0.05 (s, 0.9H), 0.04 (s, 0.9H), 0.00 (s, 4.2H); 13C NMR (125 MHz,
300 K, CDCl3) δ 155.5, 136.4, 128.5, 128.1, 127.9, 81.2, 67.4,
61.1, 61.0, 60.3, 53.6, 44.0, 28.10, 25.8, 22.6, 22.2, 21.0, 19.3,
18.9, 18.1, 14.2, -5.4, -5.5; IR (film) 1703 (CdO); HRMS (ESI)
calcd for C24H40N2O5SiNa 487.2604 (M+ + Na), found 487.2616.
In tr a m olecu la r Mitsu n obu Rea ction of (S)-4. The in-
tramolecular Mitsunobu reaction of (S)-4 gave (R)-15 in 77%
yield according to the procedure described above. [R]D +26.2
(c 1.11, CHCl3). The spectral data and HRMS of (R)-15 were
identical with those of (S)-15.
Dep r otection of (S)-16. To a solution of (S)-16 (0.13 g, 0.35
mmol) in CH2Cl2 (1.2 mL) was added TFA (0.6 mL) at 0 °C.
After the reaction mixture had been stirred at the same
temperature for 3 h, the solvents was evaporated in vacuo.
The residue was diluted with AcOEt (50 mL) and the organic
phase was washed with sat. NaHCO3 (3 × 20 mL) and sat.
NaCl (3 × 20 mL), dried over MgSO4, and filtered, and the
solvents were evaporated in vacuo to give an oily residue,
which was purified with MPLC (hexane:AcOEt 2:1) to give
(S)-3 as a colorless oil (0.08 g, 84%). [R]D -34.4 (c 1.95, CHCl3)
(-30.8°);32 1H NMR (500 MHz, 300 K, CDCl3) δ 7.37-7.29 (m,
5H), 5.17 (s, 2H), 4.53 (br s, 1H), 3.99 (br d, 1H, J ) 13.0 Hz),
3.71 (s, 3H), 3.55 (dd, 1H, J ) 10.1, 3.2 Hz), 3.14 (1H, br dd,
J ) 11.0, 11.0 Hz), 2.08-2.04 (m, 1H), 1.77-1.67 (m, 2H), 1.59
(br m, 1H); 13C NMR (125 MHz, 300 K, CDCl3) δ 171.3, 155.2,
136.4, 128.5, 128.1, 127.9, 67.5, 58.3, 52.0, 44.7, 27.3, 23.2; IR
(film) 3307 (NH), 1739, 1699 (CdO); HRMS (ESI) calcd for
P r ep a r a tion of (S)-Meth yl 1-Ben zyloxyca r bon yl-2-bu -
toxyca r bon ylp ip er a zic Acid 16. To a solution of (S)-15 (0.20
g, 0.43 mmol) in dry THF (8.6 mL) was added 1.0 M TBAF in
THF (0.9 mL, 0.9 mmol) at room temperature under an Ar
atmosphere. The reaction mixture was stirred at the same
temperature for 10 min and then diluted with AcOEt (30 mL).
The organic solvent was washed with sat. NaCl (3 × 20 mL),
dried over MgSO4, filtered, and evaporated in vacuo to give
an oily residue, which was purified with MPLC (hexane:AcOEt
1:1) to give the corresponding alcohol as a colorless oil (0.18
g, quantitative yield). To a solution of the alcohol thus obtained
(0.18 g, 0.43 mmol) in Me2CO (9 mL) was added J ones reagent
(0.7 mL, 1.8 mmol), prepared from CrO3 (2.67 g), sulfuric acid
(2.3 mL), and H2O (5.8 mL). The mixture was stirred at room
C
14H19N2O4 279.1345 (M+ + H), found 279.1370.
Dep r otection of (R)-16. Removal of the Boc group on (R)-
16 gave (R)-3 in 80% yield according to the procedure described
above. [R]D +34.4 (c 1.95, CHCl3). The spectral data and HRMS
of (R)-3 were identical with those of (S)-3.
Deter m in a tion of th e En a n tiom er ic Excess (ee) of (S)-
P ip er a zic a cid 3 a n d Its An tip od e (R)-3 by Mea n s of
HP LC An a lysis w ith a Ch ir a l Colu m n . Column: Daicel
CHIRALCEL OD-H column (4.6 × 250 mm). Solvent: hexane:
iPrOH 95:5. UV wavelength: 257 nm. Flow rate: 0.5 mL/min.
Pressure: 20 kg/cm2. (S)-3; tR) 40 min. (R)-3; tR ) 46 min.
i
temperature for 1 h then quenched with PrOH (3 mL), and
the insoluble materials were removed by filtration through
Celite 545. The filtrate was diluted with AcOEt (30 mL),
washed with sat. NaCl (3 × 20 mL), dried over MgSO4, and
filtered, and the solvents were evaporated in vacuo to give the
corresponding acid as a crude material (0.20 g), which was
employed in the next reaction without further purification. To
a solution of the crude acid (0.20 g) in MeOH (4 mL) was added
2.0 M TMSCHN2 in hexane (0.4 mL, 0.8 mmol) at room
temperature. After the reaction, the organic solvent was
evaporated in vacuo to give an oily residue, which was purified
with MPLC (hexane:AcOEt 3:1) to give (S)-16 as a colorless
oil (0.13 g, 81%, 3 steps overall yield). [R]D -33.4 (c 1.02,
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Science and Culture (to Y.A.). This mate-
rial is based upon work supported by the National
Science Foundation under Grant No. 0202827 (to
R.M.W.). We thank Meito Sangyo Co., Ltd., for their
generous gift of lipase TL. The authors are grateful to
Dr. Rhona J . Cox for help with writing this paper.
1
CHCl3); H NMR (500 MHz, 300 K, CDCl3) δ (major isomer)
7.40-7.28 (m, 5H), 5.22 (d, 1H, J ) 12.0 Hz), 5.12 (d, 1H, J )
12.0 Hz), 5.02 (br s, 1H), 4.19 (br d, 1H, J ) 12.6 Hz), 3.55 (br
s, 3H), 2.90 (br m, 1H), 2.11 (br d, 1H, J ) 13.3 Hz), 1.93-
1.83 (m, 1H), 1.76 (br m, 1H), 1.59 (br m, 1H), 1.34 (br s, 9H);
1H NMR (500 MHz, 393 K, DMSO-d6) δ 7.39-7.25 (m, 5H),
5.14 (d, 1H, J ) 12.7 Hz), 5.07 (br d, 1H, J ) 12.7 Hz), 4.85
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 8 to 16; experimental procedure for the preparation
of rac-alcohol 5 and its acetate 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O034441N
6904 J . Org. Chem., Vol. 68, No. 18, 2003