First chiral synthesis of the N-terminal amino acid congener of nikkomycin Z based on lipase-catalyzed enantioselective acetylation of a primary alcohol possessing two stereogenic centers

Article abstract of DOI:10.1016/j.tetasy.2006.06.010

A stereoselective synthesis of a versatile chiral synthon possessing two stereogenic centers, (2S,3S)-3-[2-(5-benzyloxypyridyl)]-2-methyl-1,3-propane diol 12 (>99% ee), was achieved by using a chemo-enzymatic method. The conversion of (2S,3S)-12 to the ho

Full text of DOI:10.1016/j.tetasy.2006.06.010

Tetrahedron: Asymmetry 17 (2006) 1705–1714
First chiral synthesis of the N-terminal amino acid congener of
nikkomycin Z based on lipase-catalyzed enantioselective
acetylation of a primary alcohol possessing two stereogenic centers
Hiroyuki Akita,* Yoshiki Takano, Katsushi Nedu and Keisuke Kato
School of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 8 May 2006; accepted 5 June 2006
Abstract—A stereoselective synthesis of a versatile chiral synthon possessing two stereogenic centers, (2S,3S)-3-[2-(5-benzyloxypyridyl)]-
2-methyl-1,3-propane diol 12 (>99% ee), was achieved by using a chemo-enzymatic method. The conversion of (2S,3S)-12 to the homo-
chiral intermediate (2S,3S,4S)-2-benzyloxycarbonylamino-4-[2-(5-benzyloxypyridyl)]-4-tert-butyldimethylsilyloxy-3-methylbutanoic
acid 2 corresponding to the N-terminal amino acid congener of nikkomycin Z 1 is described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
acid congener 2 and uracil polyoxin C 3.3 A convenient
synthesis of 3 from D-(ꢀ)-ribose was already reported
by us.4 We now report the first stereoselective synthesis
of (2S,3S,4S)-2 based on a combination of chemical diaste-
reoselectivity and enzymatic enantioselectivity (Scheme 1).
Nikkomycins are peptidyl nucleoside antibiotics which
have been isolated from the culture broths Streptomyces
tendae1 and Streptomyces cacaoi subsp. Asoensis.2 These
antibiotics are potent competitive inhibitors of chitin syn-
thetase and exhibit antifungal, insecticidal, and acaricidal
activities. The synthesis of nikkomycin Z 1 has already
been achieved based upon the separation of a diastereo-
meric mixture of products, which were obtained by the
condensation of ( )-a-amino-c-hydroxy-b-methylbutanoic
2. Results and discussion
Benzylation of 4 followed by successive treatment with
m-chloroperbenzoic acid (MCPBA) and Ac2O gave acetate
BnO
Me
COOH
O
HO
N
Me
O
COOH
tBuMe2SiO
NHCbz
S,3S,4S)-2
O
N
NH
N
N
H
(2
OH NH2
HO
Nikkomycin Z 1
+
COOH
O
O
O
OH
N
NH
H2N
O
OH
HO
Uracil polyoxin C 3
Scheme 1.
*
Corresponding author. Fax: +81 474 76 6195; e-mail: akita@phar.toho-u.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.010

1706
H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
6, which was deacetylated to afford alcohol 7 in 43% over-
all yield (four steps). Swern oxidation of 7 provided alde-
hyde 8 in 95% yield, which was subjected to the
Reformatsky reaction to afford a 1:1 mixture of b-hydr-
oxy-a-methyl esters ( )-anti-9 and ( )-syn-10 in 89% yield.
Oxidation of this mixture furnished b-keto ester ( )-11
lipase Amano P from Pseudomanas sp. was found to give
the (2R,3R)-monoacetate 16 (59%, 59% ee) and the un-
changed (2S,3S)-12 (38%, 97% ee) in the presence of vinyl
acetate as an acyl donor in diisopropyl ether as shown in
Table 1 (entry 1). The E value of the present enzymatic
esterification was found to be 15.2. The recovered
(2S,3S)-12 having 97% ee was again subjected to the same
5
(99% yield), which was reduced with n-Bu4NBH4 to give
the ( )-anti-9 (76% yield) together with the ( )-syn-10
(7% yield) with high anti-diastereoselectivity (anti/
syn = 10:1). In order to confirm the stereochemistry of
the reaction products, both ( )-9 and ( )-10 were reduced
to diols ( )-12 (81% yield) and ( )-13 (64% yield), respec-
tively, which were converted to acetonides ( )-14 (80%
yield) and ( )-15 (81% yield), respectively. The 2,3-trans
configuration in ( )-14 and the 2,3-cis configuration in
( )-15 were confirmed by the fact that coupling constants
due to the C2- and C3-hydrogens of ( )-14 and ( )-15 were
10.3 and 2.8 Hz, respectively. Consequently, it was found
that b-hydroxy esters ( )-9 and ( )-10 possessed the anti-
and syn-structures, respectively. This high anti-diastereo-
selectivity in n-Bu4NBH4 mediated reduction of ( )-11
was explained by a Felkin–Anh model6 as shown in
Figure 1 (Scheme 2).
enzymatic acetylation as in the case of entry 1 for 2.5 h to
26
give (2S,3S)-12 (65%, ½aꢁD ¼ ꢀ28:6 (c 0.92, CHCl3), >99%
ee by HPLC analysis) and (2S,3S)-16 (32%, 93% ee) (entry
2). On the other hand, (2R,3R)-12 (59% ee) derived from
(2R,3R)-16 possessing 59% ee was again subjected to the
same enzymatic acetylation as in the case of entry 1 for
1 h to afford (2R,3R)-16 (66%, 95% ee) and (2S,3S)-12
(27%, 32% ee) (entry 3). Furthermore, (2R,3R)-12 (95%
ee) derived from (2R,3R)-16 possessing 95% ee was again
subjected to the same enzymatic acetylation as in the case
of entry
3
for 1 h to afford (2R,3R)-16 (74%,
29
½aꢁD ¼ þ19:6 (c 0.98, CHCl3), >99% ee by HPLC analysis)
and (2R,3R)-12 (24%, 80% ee) (entry 4). The enantiomeric
excess of the enzymatic reaction products was determined
by HPLC on CHIRALCEL OD (250 · 4.6 mm) for
(2S,3S)-12 and AS (250 · 4.6 mm) for (2R,3R)-16 columns.
In order to confirm the absolute structure of (+)-(2R,3R)-
16, (+)-(2R,3R)-16 was successfully converted to diacetate
(2R,3R,4R)-28. Silylation of (+)-(2R,3R)-16 followed by
deacetylation and oxidation gave aldehyde 19 in 37% over-
all yield (three steps). Treatment of 19 with LiC(SMe)3 fol-
lowed by Hg2+ provided a 10:1 mixture of 2-hydroxy esters
(20 and 21, 20:21 = 10:1) in 72% yield. Treatment of this
mixture with fluoride ion furnished c-lactones 22 (74%
yield) and 23 (7% yield). The C2-configurations of ( )-22
and ( )-23 were confirmed by NOE studies as shown in
Figure 2. The high 2,3-syn-diastereoselectivity in the reac-
tion of 19 and LiC(SMe)3 was explained by a Felkin–
O
Me
COOMe
H-
Ar
H
Figure 1.
For the purpose of obtaining the optically active diol 12,
( )-12 was subjected to screening experiments using several
kinds of commercially available lipases. Among them,
R1O
BnO
BnO
BnO
d
Me
b
e,d
88%
N
N
N
COOMe
55%
CH3
4
CH2OR2
6
N
8
CHO
95%
R1=H
R2=Ac
O
( )-11
a
c
R1=Bn 5 (91%)
R2=H 7 (85%)
BnO
BnO
BnO
Me
Me
Me
i
g
3
N
N
COOMe
N
N
2
N
80%
81%
OH
OH OH
O
O
f
( )-anti-9 (76%)
( )-12
J2,3=10.3 Hz
( )-14
BnO
h
BnO
BnO
Me
Me
Me
2
i
3
COOMe
N
64%
81%
OH OH
( )-13
OH
O
O
J2,3=2.8 Hz
( )-syn-10 (7%)
( )-15
Scheme 2. Reagents and conditions: (a) BnBr, NaH, MeOH; (b) i. MCPBA, CH2Cl2; ii. Ac2O, reflux; (c) K2CO3, MeOH; (d) DMSO, (COCl)2, CH2Cl2,
then Et3N, ꢀ78 ꢁC; (e) MeCH(Br)COOMe, Zn, PhH, reflux; (f) n-Bu4NBH4, MeOH, ꢀ78, ꢀ40, 0 ꢁC; (g) LiAlH4, THF; (h) NaBH4, MeOH; (i)
Me2C(OMe)2, CSA, PhH.

H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
Table 1. Enantioselective acetylation of ( )-12 in the presence of lipase Amano P
BnO
1707
BnO
Me
Me
vinyl acetate, lipase Amano P
(i-Pr)2O, 30ºC
( )-12
+
N
N
OH OR3
OR3
OH
,3 )-12
,3 )-16
R3=H; (2
R3=Ac; (2
S
S
,3
S)-12
R3=H; (2
R
R
R
,3S
)-16
R3=Ac; (2
R
Entry
Substrate (g)
Time (h)
Product (%, % ee)
1
2
3
4
(
)-12 (10.32 g)
2.5
2.5
1
(2S,3S)-12 (38%, 97% ee)
(2S,3S)-12 (65%, >99% ee)
(2S,3S)-12 (27%, 32% ee)
(2R,3R)-12 (24%, 80% ee)
(2R,3R)-16 (59%, 59% ee)
(2S,3S)-12 (97% ee, 3.922 g)
(2R,3R)-12 (59% ee, 5 g)a
(2R,3R)-12 (95% ee, 3.3 g)b
(2S,3S)-16 (32%, 93% ee)
(2R,3R)-16 (66%, 95% ee)
(2R,3R)-16 (74%, >99% ee)
1
a (2R,3R)-12 (59% ee) was obtained by deacylation of (2R,3R)-16 (59% ee) with K2CO3 in MeOH.
b (2R,3R)-12 (95% ee) was obtained by deacylation of (2R,3R)-16 (95% ee) with K2CO3 in MeOH.
28
noic acid 29 {½aꢁD ¼ ꢀ5:4 (c 0.79, CHCl3), 69% overall
yield from (2S,3S,4S)-27)} by applying the reported meth-
od.3 The NMR data of the (2S,3S,4S)-2 synthesized were
identical with those of the reported ( )-2.3 In this process,
epimerization at the C2-position of ( )-27 was found not
to occur because amino protection of ( )-27 as a benzyl-
oxycarbonyl group and desilylation of ( )-2 followed by
c-lactonization furnished the same compound ( )-28,
respectively (Scheme 3).
4%
3.6%
O
5%
Me
H
OH
O
H
H
Me
OH
H
O
O
N
N
BnO
BnO
( )-22
( )-23
H
H
9%
Figure 2.
Anh model6 as shown in Figure 3. Conversion of the hy-
droxyl group in 22 to an amino group in 27 was achieved
in 53% overall yield (three steps). Treatment of 22 with
I2/Ph3P gave the corresponding iodide, which was treated
with NaN3 to afford 24 (58%), 25 (9%), and 26 (29%).
Treatment of 24 with Ph3P/H2O gave the desired amine
27 in 91% yield. Deprotection of 27 followed by acetylation
gave the desired diacetate 28 {[a]D = ꢀ13.5 (c 0.2, MeOH)}
in 80% overall yield (two steps), which was identical with
an authentic sample (2S,3S,4S)-282 {[a]D = +13.9 (c 0.5,
MeOH)} obtained from the degradation product of natural
nikkomycin Z 1 except for the sign of specific rotation.
From these conversion experiments, the configuration of
the enzymatic acetylation product (+)-16 was determined
to be 2R,3R, and thence that of (ꢀ)-12 was confirmed to
be 2S,3S. Enzymatic acetylation of (2S,3S)-12 with vinyl
In conclusion, n-Bu4NBH4 reduction of b-keto ester ( )-11
afforded the ( )-anti-b-hydroxy ester 9 (83% yield) with
10:1 anti-diastereoselectivity. An enantioselective esterifica-
tion of ( )-anti-diol 12 derived from ( )-9 using lipase
Amano P provided the enantiomerically pure (2S,3S)-12,
which was converted to the N-terminal amino acid conge-
ner (2S,3S,4S)-2 for the synthesis of nikkomycin Z 1 in 9%
overall yield (fourteen steps).
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. 1H
and 13C NMR spectra were recorded on JEOL EX 400
spectrometer in CDCl3. Carbon substitution degrees were
established by DEPT pulse sequence. The fast atom bom-
bardment mass spectra (FAB-MS) were obtained with
JEOL JMS-DX 303 spectrometer. IR spectra were re-
corded with JASCO FT/IR-300 spectrometer. The HPLC
system was composed of two SSC instruments (ultraviolet
(UV) detector 3000B and flow system 3100). Optical rota-
tions were measured with a JASCO DIP-370 digital pola-
rimeter. All evaporations were performed under reduced
pressure. For column chromatography, silica gel (Kieselgel
60) was employed.
acetate provided acetate (2S,3S)-16 in 87% yield, which
26
was converted to c-lactone (2S,3S,4S)-27 {½aꢁD ¼ ꢀ18:0
(c 0.7, CHCl3)} in 14% overall yield (nine steps) in the same
way as in the case of (2R,3R,4R)-27. Alkaline treatment of
(2S,3S,4S)-27 followed by ion-exchange resin gave the
intermediary carboxylic acid, which was converted to the
desired (2S,3S,4S)-2-benzyloxycarbonylamino-4-[2-(5-benz-
yloxypyridyl)]-4-tert-butyldimethylsilyloxy-3-methylbuta-
O
BnO
R =
Me
Me
R
N
3.2. 5-Benzyloxy-2-methylpyridine 5
-C(SMe)3
tBuMe2SiO
H
H
To a well-stirred solution of 5-hydroxy-2-methylpyridine
Figure 3.
4 (10 g, 92 mmol) in DMF (50 ml) at 0 ꢁC, NaH in oil

1708
H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
BnO
BnO
BnO
72%
Me
Me
Me
COOMe
N
N
N
CHO
42%
OR4 OR3
tBuMe2SiO
tBuMe2SiO
OH
)-20
)-21
R3=Ac R4=H; (2
R
,3
R3=Ac R4=SiMe2But; (2
R3=H R4=SiMe2But; (2
R
)-16
(2S,3R)-19
α-OH; (2
β-OH; (2
R
,3
R
R
,4
R
a
b
S,3
,4R
R,3R
)-17 (97%)
R
,3
R
)-18 (92%)
BnO
BnO
Me
Me
S
R
R
R
OH
OH
N
R
+
N
R
O
O
O
(2R,3R,4R)-22 (74%)
(2
S,3R,4R)-23 (7%)
O
R1O
BnO
+
BnO
Me
Me
R
Me
R5
R
R
R
O
S
R
N3
+
(2
R,3R,4R)-22
N
R
N
N
O
O
O
O
O
R1=Bn R5=N3; (2
R1=Bn R5=NH2; (2
R1=Ac R5=NHAc; (2
R
,3
,3
,3
R
,4
,4
,4
R
)-24 (58%)
)-27 (91%)
)-28 (80%)
(2S,3
R,4R
)-25 (9%)
(4R)-26 (29%)
g
h
R
R
R
R
R
R
BnO
BnO
Me
Me
S
i
a-c
56%
j
d-g
26%
(2
R,3S
)-19
(2S,3S,4S)-2
(2
S,3
S)-12
S
S
NH2
N
87%
N
69%
OH OAc
)-16
O
(2S
,3S
(2S,3S,4S)-27
O
BnO
k
Me
l
( )-2
( )-27
NHCbz
N
73%
77%
O
( )-29
O
t
Scheme 3. Reagents and conditions: (a) BuMe2SiCl, imidazole, DMF; (b) K2CO3, MeOH; (c) PCC; (d) i. n-BuLi, CH(SMe)3, ꢀ78 ꢁC; ii. HgCl2, HgO,
MeOH, H2O; (e) Bu4N+Fꢀ, THF; (f) i. Ph3P, I2, THF; ii. NaN3, DMF; (g) Ph3P, H2O, 60 ꢁC; (h) i. H2, 5% Pd–C; ii. Ac2O, pyridine; (i) vinyl acetate,
lipase Amano P, 30 ꢁC, 12 h; (j) i. KOH, THF, H2O, 0 ꢁC; ii. Dowex-50WX8-400; iii. N-methyl-N-(tbutyldimethylsilyl)trifluoroacetamide, iv.
N-(benzyloxycarbonyloxy)-succinimide; (k) CbzCl, NaHCO3, dioxane; (l) i. Bu4N+Fꢀ; ii. DCC.
(55–75%, 4.63 g) and benzyl bromide (17.3 g, 101 mmol)
were added and the whole mixture was stirred for
30 min. The reaction mixture was diluted with H2O and
extracted with Et2O. The organic layer was dried over
MgSO4 and evaporated to give a crude residue, which
was chromatographed on silica gel (300 g, n-hexane/
EtOAc = 1:1) to give 5 (16.64 g, 91%) as a colorless oil.
5: IR (neat): 1255 cmꢀ1. NMR: d 2.47 (3H, s), 5.05
(2H, s), 7.03 (1H, d, J = 8.8 Hz), 7.15 (1H, dd, J = 2.9,
8.3 Hz), 8.25 (1H, d, J = 2.9 Hz). Anal. Calcd for
C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.19;
H, 6.80; N, 6.87.
237 mmol) was added and the whole mixture was stirred
for 1 h at room temperature. The reaction mixture was
diluted with 7% aqueous NaHCO3 and the organic layer
was separated. The organic layer was dried over MgSO4
and evaporated to give a crude residue, which was used
without further purification. A mixture of the crude residue
and Ac2O (35.74 g, 350 mmol) was heated at 120 ꢁC for
40 min, and the reaction mixture was diluted with Et2O.
The organic layer was dried over MgSO4 and evaporated
to give a crude residue, which was chromatographed on sil-
ica gel (300 g, n-hexane/EtOAc = 9:1) to give 6 (23.88 g,
55%) as a colorless oil. 6: IR (neat): 1739 cmꢀ1. NMR: d
2.13 (3H, s), 5.11 (2H, s), 5.15 (2H, s), 7.25 (1H, dd,
J = 2.9, 8.3 Hz), 7.28 (1H, d, J = 8.3 Hz), 7.34–7.44 (5H,
m), 8.37 (1H, d, J = 2.9 Hz). Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.09;
H, 6.47; N, 5.24.
3.3. 2-Acetoxymethyl-5-benzyloxypyridine 6
To a well stirred solution of 5 (33.48 g, 168 mmol) in
CHCl3 (300 ml) at 0 ꢁC, m-chloroperbenzoic acid (40.94 g

H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
1709
3.4. 5-Benzyloxy-2-hydroxymethylpyridine 7
(200 g, n-hexane/EtOAc = 10:1) to give 11 (14.48 g, 99%)
as colorless needles (n-hexane/EtOAc). Compound 11:
mp 57–58 ꢁC, IR (KBr): 1738, 1216 cmꢀ1. NMR: d 1.47
(3H, d, J = 7.0 Hz), 3.66 (3H, s), 4.74 (1H, q,
J = 7.0 Hz), 5.17 (2H, s), 7.33 (1H, dd, J = 2.9, 8.8 Hz),
7.34–7.43 (5H, m), 8.06 (1H, d, J = 8.8 Hz), 8.37 (1H, d,
J = 2.9 H). Anal. Calcd for C17H17NO4: C, 68.21; H,
5.73; N, 4.68. Found: C, 67.78; H, 6.03; N, 4.55. FAB-
MS m/z: 300 (M++1). (3) To a well-stirred solution of
n-Bu4BH4 (4.34 g, 16.8 mmol) in MeOH (70 ml) was added
a solution of 11 (5.0 g, 16.7 mmol) in MeOH (30 ml) at
ꢀ78 ꢁC, and the mixture was stirred at ꢀ40 ꢁC for 1 h
and at 0 ꢁC for 30 min. After acetone (20 ml) was added
to the reaction mixture, the whole mixture was stirred at
0 ꢁC for 1 h. The mixture was diluted with H2O and ex-
tracted with CHCl3. The organic layer was washed with
brine and dried over MgSO4. The organic layer was evapo-
rated to give a crude residue, which was chromatographed
on silica gel (100 g, n-hexane/EtOAc = 4:1) to give ( )-syn-
10 (0.383 g, 7%) as colorless needles (n-hexane/EtOAc) and
( )-anti-9 (3.83 g, 76%) as colorless needles (n-hexane/
EtOAc) in elution order. Compound ( )-syn-10: mp 50–
51 ꢁC, IR (KBr): 3228, 1728 cmꢀ1. NMR: d 1.04 (3H, d,
J = 7.3 Hz), 2.92 (1H, dq, J = 4.4, 7.3 Hz), 3.68 (3H, s),
4.20 (1H, br s), 5.07 (2H, s), 5.10 (1H, d, J = 4.0 Hz),
7.26 (2H, s), 7.31–7.42 (5H, m), 8.29 (1H, s). Anal. Calcd
for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.48; H, 6.43; N, 4.64. Compound ( )-anti-9: mp 87–
88 ꢁC, IR (KBr): 3323, 1731 cmꢀ1. NMR: d 1.09 (3H, d,
J = 7.1 Hz), 2.99 (1H, dq, J = 7.1 Hz), 3.68 (3H, s), 4.14
(1H, br s), 4.80 (1H, d, J = 7.0 Hz), 5.10 (2H, s), 7.21–
7.44 (7H, m), 8.31 (1H, d, J = 2.4 Hz). Anal. Calcd for
C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 68.00;
H, 6.29; N, 4.68.
To a well-stirred solution of 6 (11.01 g, 42.8 mmol) in
MeOH (300 ml) at 0 ꢁC, K2CO3 (5.94 g, 43 mmol) was
added and the whole mixture was stirred for 1 h at room
temperature. The reaction mixture was evaporated and a
residue was diluted with H2O and extracted with EtOAc.
The organic layer was dried over MgSO4 and evaporated
to give a crude residue, which was chromatographed on
silica gel (100 g, n-hexane/EtOAc = 1:1) to give 7 (7.86 g,
85%) as colorless needles (n-hexane/EtOAc). Compound
6: mp 67–68 ꢁC, IR (KBr): 3196 cmꢀ1. NMR: d 4.68 (2H,
s), 5.09 (2H, s), 7.20 (1H, d, J = 8.8 Hz), 7.26 (1H, dd,
J = 2.4, 8.8 Hz), 8.29 (1H, d, J = 2.4 Hz). Anal. Calcd for
C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.40;
H, 6.00; N, 6.51.
3.5. 5-Benzyloxy-2-formylpyridine 8
To a well-stirred solution of DMSO (19.6 ml, 276 mmol) in
CH2Cl2 (100 ml) was added oxalyl chloride (11.7 ml,
138 mmol) at ꢀ78 ꢁC, and the mixture was stirred for
30 min. A solution of 7 (14.84 g, 69 mmol) in CH2Cl2
(30 ml) was added and the mixture was stirred for
30 min, Et3N (76.3 ml, 552 mmol) was added and the mix-
ture was stirred at room temperature for 1 h. The mixture
was diluted with 1 M aqueous HCl and extracted with
Et2O. The organic layer was washed with brine and dried
over MgSO4. The organic layer was evaporated to give a
crude residue, which was chromatographed on silica gel
(200 g, n-hexane/EtOAc = 4:1) to give 8 (13.96 g, 95%) as
colorless needles (n-hexane/EtOAc). Compound 8: mp
64–66 ꢁC, IR (KBr): 1703 cmꢀ1. NMR: d 5.20 (2H, s),
7.36 (1H, dd, J = 2.9, 8.8 Hz), 7.95 (1H, d, J = 8.8 Hz),
8.51 (1H, d, J = 2.4 Hz), 8.99 (1H, d, J = 1.0 Hz). FAB-
MS m/z: 214 (M++1).
3.7. ( )-anti-3-[2-(5-Benzyloxypyridyl)]-2-methyl-1,3-
propanediol 12
3.6. ( )-Methyl anti-3-[2-(5-benzyloxypyridyl)]-3-hydroxy-
2-methylpropanoate 9 and ( )-methyl syn-3-[2-(5-benzyl-
oxypyridyl)]-3-hydroxy-2-methylpropanoate 10
To a suspension of LiAlH4 (1.89 g, 49.8 mmol) in dry THF
(150 ml) was added a solution of ( )-10 (14.1 g, 46.8 mmol)
in dry THF (90 ml) at room temperature, and the reaction
mixture was stirred for 1 h at the same temperature. After
the addition of acetone (11 ml) and EtOAc (150 ml), the
whole mixture was filtered with the aid of Celite and the
precipitate was washed with EtOAc. The combined organic
layer was dried over MgSO4 and evaporated. The residue
was crystallized from benzene to give crystals ( )-12
(10.32 g, 81%) as colorless needles (n-hexane/EtOAc).
(1) A stirred mixture of 8 (11.71 g, 55 mmol), methyl
a-bromopropanoate (11 g, 65.9 mmol) and activated Zn
dust [prepared from Zn (7 g)] in dry benzene (200 ml)
was refluxed for 90 min. The reaction mixture was diluted
with H2O and 1 M aqueous HCl, and extracted with
EtOAc. The organic layer was washed with brine and dried
over MgSO4. Evaporation of the organic solvent provided
a crude oily product, which was chromatographed on silica
gel (300 g, n-hexane/EtOAc = 5:1) to afford a 1:1 mixture
(14.72 g, 89%) of ( )-anti-9 and ( )-syn-10. (2) To a well-
stirred solution of DMSO (13.9 ml, 196 mmol) in CH2Cl2
(100 ml) was added oxalyl chloride (12.8 ml, 147 mmol)
at ꢀ78 ꢁC, and the mixture was stirred for 30 min. A solu-
tion of the above-mentioned mixture (14.72 g, 48.9 mmol)
in CH2Cl2 (30 ml) was added and the mixture was stirred
for 30 min, Et3N (40.6 ml, 293 mmol) was added and the
mixture was stirred at room temperature for 1 h. The mix-
ture was diluted with 1 M aqueous HCl and extracted with
Et2O. The organic layer was washed with brine and dried
over MgSO4. The organic layer was evaporated to give a
crude residue, which was chromatographed on silica gel
Compound ( )-12: mp 64–65 ꢁC; IR (KBr): 3351 cmꢀ1
.
NMR: d 0.86 (3H, d, J = 7.3 Hz), 2.06–2.13 (1H, m),
3.62 (1H, dd, J = 6.8, 11.2 Hz), 3.69 (1H, dd, J = 3.9,
11.2 Hz), 4.67 (1H, d, J = 6.4 Hz), 5.11 (2H, s), 7.24 (1H,
d, J = 8.8 Hz), 7.28 (1H, dd, J = 2.5, 8.8 Hz), 7.35–7.44
(5H, m), 8.29 (1H, d, J = 2.5 Hz). Anal. Calcd for
C16H19NO3: C, 70.31; H, 7.01; N, 5.13. Found: C, 69.96;
H, 7.05; N, 5.16.
3.8. Acetonide formation of ( )-12
A mixture of ( )-12 (0.521 g, 1.9 mmol), 2,2-dimethoxy-
propane (4 ml) and camphorsulfonic acid (CSA; 0.177 g,
0.76 mmol) in benzene (5 ml) was stirred for 12 h at room

1710
H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
temperature. The reaction mixture was diluted with 7%
aqueous NaHCO3 and extracted with EtOAc. The organic
layer was washed with saturated brine and dried over
MgSO4. Evaporation of the organic solvent gave a residue
which was chromatographed on silica gel (30 g, n-hexane/
EtOAc = 3:1) to afford ( )-14 (0.478 g, 80%) as colorless
needles (n-hexane/EtOAc). Compound ( )-14: mp 74–
75 ꢁC; IR (KBr): 1237, 1277, 1022 cmꢀ1. NMR: d 0.66
(3H, d, J = 6.8 Hz), 1.48 (3H, s), 1.56 (3H, s), 1.97–2.06
(1H, m), 3.71 (1H, dd, J = 6.4, 11.7 Hz), 3.82 (1H, dd,
J = 4.9, 11.7 Hz), 4.59 (1H, d, J = 10.3 Hz), 5.10 (2H, s),
7.26–7.43 (2H, m), 8.30 (1H, d, J = 2.4 Hz). Anal. Calcd
for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.38; H, 7.43; N, 4.47.
at room temperature. The reaction mixture was diluted
with 1 M aqueous HCl and extracted with EtOAc. The
organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (30 g, n-hexane/
EtOAc = 3:1) to afford diacetate (0.102 g, 14.9%) from
n-hexane/EtOAc = 5:1 elution, ( )-16 (0.292 g, 48.6%)
and monoacetate (0.026 g, 4.4%) from n-hexane/
EtOAc = 4:1 elution, and ( )-12 (0.156 g, 30%) from
n-hexane/EtOAc = 1:1 elution. Compound ( )-16: color-
less oil. IR (neat): 3418, 1732, 1247 cmꢀ1. NMR: d 0.95
(3H, d, J = 6.8 Hz), 1.91 (3H, s), 2.22–2.28 (1H, m), 4.02
(1H, br s), 4.06 (1H, dd, J = 5.9, 1.0 Hz), 4.10 (1H, dd,
J = 5.9, 11.0 Hz), 4.59 (1H, d, J = 5.4 Hz), 5.11 (2H, s),
7.16–7.43 (7H, m), 8.29 (1H, d, J = 2.9 Hz). Anal. Calcd
for C18H21NO4: C, 68.57; H, 6.67; N, 4.44. Found: C,
68.19; H, 6.86; N, 4.38.
3.9. ( )-syn-3-[2-(5-Benzyloxypyridyl)]-2-methyl-1,3-prop-
anediol 13
To a solution of ( )-10 (0.811 g, 2.7 mmol) in MeOH
(12 ml) was added NaBH4 (0.205 g, 5.4 mmol) in MeOH
at 0 ꢁC, and the reaction mixture was stirred for 1 h at
the same temperature. After the addition of acetone
(2 ml) and EtOAc (50 ml), the whole mixture was filtered
with the aid of Celite and the precipitate was washed with
EtOAc. The combined organic layer was dried over MgSO4
and evaporated. The residue was chromatographed on
silica gel (30 g, n-hexane/EtOAc = 2:1) to afford ( )-13
(0.472 g, 64%) as colorless needles (n-hexane/EtOAc).
3.12. HPLC analysis of the racemic alcohol ( )-12 and
acetate ( )-16 by using a chiral column
Two racemates ( )-12 and ( )-16 gave individually two
well separated peaks. Compound ( )-12; 75.1 and
85.0 min corresponding to each enantiomer under the fol-
lowing analytical conditions (column, CHIRALCEL OD
(250 · 4.6 mm); eluent, n-hexane/EtOH = 40:1; detection,
UV at 254 nm; flow rate, 1 ml/min). Compound ( )-16;
38.6 and 56.9 min corresponding to each enantiomer un-
der the following analytical conditions (column, CHI-
RALCEL AS (250 · 4.6 mm); eluent, n-hexane/
EtOH = 40:1; detection, UV at 254 nm; flow rate, 1 ml/
min).
Compound ( )-13: mp 77–78 ꢁC; IR (KBr): 3339 cmꢀ1
.
NMR: d 0.71 (3H, d, J = 7.0 Hz), 2.06–2.12 (1H, m),
3.69 (1H, dd, J = 4.4, 10.8 Hz), 3.75 (1H, dd, J = 6.6,
10.8 Hz), 4.98 (1H, d, J = 3.1 Hz), 5.09 (2H, s), 7.24 (1H,
d, J = 8.6 Hz), 7.29 (1H, dd, J = 2.8, 8.6 Hz), 7.31–7.43
(5H, m), 8.26 (1H, d, J = 2.8 Hz). Anal. Calcd for
C16H19NO3: C, 70.31; H, 7.01; N, 5.13. Found: C, 70.07;
H, 7.02; N, 5.10.
3.13. Enzymatic resolution
(1) A mixture of ( )-12 (5.00 g, 18.3 mmol), vinyl acetate
(3.1 g, 36 mmol) and lipase ‘Amano P’ (2.5 g) in diisoprop-
yl ether (1000 ml) was stirred at 33 ꢁC for 2.5 h. This enzy-
matic reaction was carried out twice and the total amount
of the used substrate ( )-12 was 10.32 g. The reaction mix-
ture was filtered with the aid of Celite and the precipitate
was washed with EtOAc. The combined organic solvent
was evaporated to give a residue, which was chromato-
graphed on silica gel (100 g) to afford (2R,3R)-16
(7.058 g, 59%, 59% ee) from n-hexane/EtOAc = 2:1 elution
and (2S,3S)-12 (3.922 g, 38%, 97% ee) from n-hexane/
EtOAc = 1:2 elution. Enantiomeric excess (ee) of
(2R,3R)-16 and (2S,3S)-12 was analyzed by HPLC. (2) A
mixture of (2S,3S)-12 (97% ee, 3.922 g, 14.4 mmol), vinyl
acetate (2.473 g, 28.8 mmol) and lipase ‘Amano P’ (2 g)
in diisopropyl ether (800 ml) was stirred at 33 ꢁC for
2.5 h. The reaction mixture was worked up in the same
3.10. Acetonide formation of ( )-13
A mixture of ( )-13 (0.367 g, 1.3 mmol), 2,2-dimethoxy-
propane (4 ml) and camphorsulfonic acid (CSA; 0.125 g,
0.54 mmol) in benzene (5 ml) was stirred for 12 h at room
temperature. The reaction mixture was diluted with 7%
aqueous NaHCO3 and extracted with EtOAc. The organic
layer was washed with saturated brine and dried over
MgSO4. Evaporation of the organic solvent gave a residue,
which was chromatographed on silica gel (30 g, n-hexane/
EtOAc = 3:1) to afford ( )-15 (0.341 g, 81%) as colorless
needless (n-hexane/EtOAc). Compound ( )-15: mp 78–
79 ꢁC; IR (KBr): 1240, 1198, 1014 cmꢀ1. NMR: d 0.78
(3H, d, J = 7.0 Hz), 1.52 (3H, s), 1.54 (3H, s), 2.02–2.08
(1H, m), 3.70 (1H, dd, J = 1.3, 11.5 Hz), 4.31 (1H, dd,
J = 2.8, 11.5 Hz), 5.10 (2H, s), 5.16 (1H, d, J = 2.8 Hz),
7.24–7.43 (7H, m), 8.31 (1H, d, J = 2.9 Hz). Anal. Calcd
for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.59; H, 7.50; N, 4.54.
way as for case (1) to afford (2S,3S)-16 (1.448 g, 32%,
26
93% ee) and (2S,3S)-12 (2.549 g, 65%, ½aꢁD ¼ ꢀ28:6 (c
0.92, CHCl3); corresponds to >99% ee). (3) A mixture of
(2R,3R)-16 (59% ee, 7.0851 g, 22.4 mmol), K2CO3
(6.194 g, 44.8 mmol) in MeOH (80 ml) was stirred for
40 min at room temperature. The reaction mixture was
diluted with H2O and extracted with EtOAc. The organic
layer was washed with brine and dried over MgSO4. Evap-
oration of the organic solvent gave crude (2R,3R)-12
(6.117 g, >99%). A mixture of (2R,3R)-12 (5 g, 18.3 mmol),
3.11. ( )-anti-1-Acetoxy-3-[2-(5-benzyloxypyridyl)]-2-
methyl-3-propanol 16
A mixture of ( )-12 (0.521 g, 1.91 mmol) and Ac2O
(0.193 ml, 2.0 mmol) in pyridine (2 ml) was stirred for 1 h

H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
1711
vinyl acetate (3.1 g, 36 mmol) and lipase ‘Amano P’
3.16. (2R,3R)-3-[2-(5-Benzyloxypyridyl)]-3-tert-butyldi-
methylsilyloxy-2-methylpropanal 19
(2.5 g) in diisopropyl ether (1000 ml) was stirred at 33 ꢁC
for 1 h. The reaction mixture was worked up in the
same way as for case (1) to afford (2R,3R)-16 (3.808 g,
66%, 95% ee) and (2R,3R)-12 (1.35 g, 27%, 32% ee).
(4) A mixture of (2R,3R)-16 (95% ee, 3.808 g, 12.1 mmol),
K2CO3 (3.344 g, 24.2 mmol) in MeOH (40 ml) was
stirred for 40 min at room temperature. The reaction mix-
ture was diluted with H2O and extracted with EtOAc. The
organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic solvent gave crude
(2R,3R)-12 (3.30 g, >99%). A mixture of (2R,3R)-12
(3.30 g, 12.1 mmol), vinyl acetate (2.081 g, 24.2 mmol)
and lipase ‘Amano P’ (1.65 g) in diisopropyl ether
(700 ml) was stirred at 33 ꢁC for 1 h. The reaction mixture
A mixture of (2R,3R)-18 (3.173 g, 8.2 mmol), PCC (3.59 g,
16.3 mmol) in CH2Cl2 (150 ml) was stirred for 10 h at room
temperature. The reaction mixture was directly subjected to
chromatography on Florisil (40 g, AcOEt) to afford a resi-
due, which was again chromatographed on silica gel (40 g,
n-hexane/EtOAc = 8:1) to afford (2R,3R)-19 (1.311 g, 42%)
27
as a colorless oil. Compound (2R,3R)-19: ½aꢁD ¼ þ84:2 (c
0.92, CHCl3); IR (neat): 1725 cmꢀ1. NMR: d ꢀ0.12 (3H,
s), 0.08 (3H, s), 0.90 (9H, s), 0.96 (3H, d, J = 6.8 Hz),
2.78–2.85 (1H, m), 5.04 (1H, d, J = 5.9 Hz), 5.10 (2H, s),
7.28–7.44 (7H, m), 8.27 (1H, d, J = 2.4 Hz), 9.78 (1H, s).
FAB-MS m/z: 386 (M++1).
was worked up in the same way as for case (1) to afford
29
(2R,3R)-16 (2.817 g, 74%, ½aꢁD ¼ þ19:6 (c 0.98, CHCl3);
3.17. (2R,3R,4R)-4-[2-(5-Benzyloxypyridyl)]-2-hydroxy-3-
methyl-butano-4-lactone 22 and (2S,3R,4R)-4-[2-(5-benzyl-
oxypyridyl)]-2-hydroxy-3-methyl-butano-4-lactone 23
corresponds to >99% ee) and (2R,3R)-12 (0.768 g, 24%,
80% ee).
3.14. (2R,3R)-1-Acetoxy-3-[2-(5-benzyloxypyridyl)]-3-tert-
butyldimethylsilyloxy-2-methyl-propane 17
(1) To a solution of tris(methylthio)methane (0.80 g,
5.09 mmol) in THF (15 ml) at ꢀ78 ꢁC was added n-BuLi
(1.53 M in hexane, 2.9 ml (4.4 mmol)) under an argon
atmosphere, and the reaction mixture was stirred at
ꢀ78 ꢁC for 20 min and at ꢀ20 ꢁC for 1 h. To the generated
carbanion solution was added a solution of aldehyde 19
(1.31 g, 3.39 mmol) in THF (5 ml) at ꢀ78 ꢁC, and the
whole mixture was stirred at ꢀ78 ꢁC for 2 h and at 0 ꢁC
for 2 h. The reaction mixture was diluted with H2O and
extracted with EtOAc. The organic layer was washed with
saturated brine, dried over MgSO4, and evaporated. The
residue was dissolved in a mixed solvent (MeOH (12 ml)
and H2O (1 ml)), and HgCl2 (4.2 g, 15.3 mmol) and HgO
(3.3 g, 15.3 mmol) were added to the above solution at
room temperature and the mixture was stirred for 4 h at
the same temperature. The reaction mixture was filtered
with the aid of Celite and the filtrate was condensed to give
a residue, which was treated with saturated NH4Cl and ex-
tracted with CHCl3. The organic layer was dried over
MgSO4 and evaporated to give a residue, which was chro-
matographed on silica gel (45 g, n-hexane/EtOAc = 10:1)
to afford a 10:1 mixture of a-hydroxy esters (20 and 21,
1.09 g, 72%) as a colorless oil. (2) To a solution of a-hydr-
oxy esters (20 and 21, 1.09 g, 2.45 mmol) in THF (20 ml) was
added tetrabutylammonium fluoride TBAF (1.28 g,
4.9 mmol), and the reaction mixture was stirred for 3 h at
room temperature. The reaction mixture was diluted with
H2O and extracted with EtOAc. The organic layer was
washed with brine and dried over MgSO4. Evaporation
of the organic solvent gave a residue, which was chromato-
graphed on silica gel (25 g, n-hexane/EtOAc = 5:1) to
afford (2S,3R,4R)-23 (0.049 g, 7%) from n-hexane/
EtOAc = 3:1 elution as colorless oil and (2R,3R,4R)-22
(0.544 g, 74%) as colorless needles from n-hexane/
A mixture of (2R,3R)-16 (2.895 g, 9.2 mmol), tert-butyl-
dimethylsilyl chloride (TBDMSCl; 2.77 g, 18.4 mmol),
and imidazole (1.87 g, 27.6 mmol) in DMF (10 ml) was
stirred for 12 h at room temperature. The reaction mixture
was diluted with H2O and extracted with EtOAc. The
organic layer was dried over MgSO4 and evaporated to
give a residue, which was chromatographed on silica gel
(60 g, n-hexane/EtOAc = 15:1) to afford (2R,3R)-17
(3.835 g, 97%) as a colorless oil. Compound (2R,3R)-17:
27
½aꢁD ¼ þ52:3 (c 0.77, CHCl3); IR (neat): 1739,
1246 cmꢀ1. NMR: d ꢀ0.26 (3H, s), 0.03 (3H, s), 0.84
(3H, d, J = 6.8 Hz), 0.88 (9H, s), 1.95 (3H, s), 2.17–2.24
(1H, m), 4.04 (1H, dd, J = 6.4, 10.7 Hz), 4.12 (1H, dd,
J = 4.4, 10.7 Hz), 4.68 (1H, d, J = 6.4 Hz), 5.09 (2H, s),
7.24–7.44 (7H, m), 8.25 (1H, d, J = 2.4 Hz). FAB-MS
m/z: 430 (M++1). Anal. Calcd for C24H35NO4Si:
C, 67.13; H, 8.16; N, 3.26. Found: C, 66.94; H, 8.62; N,
3.07.
3.15. (2R,3R)-3-[2-(5-Benzyloxypyridyl)]-3-tert-butyldi-
methylsilyloxy-2-methyl-1-propanol 18
A mixture of (2R,3R)-17 (3.835 g, 8.9 mmol), K2CO3
(4.95 g, 35.8 mmol) in MeOH (50 ml) was stirred for 2 h
at room temperature. The reaction mixture was diluted
with H2O and extracted with EtOAc. The organic layer
was washed with brine and dried over MgSO4. Evapora-
tion of the organic solvent gave a residue, which was chro-
matographed on silica gel (60 g, n-hexane/EtOAc = 5:1) to
afford (2R,3R)-18 (3.173 g, 92%) as a colorless oil. Com-
27
pound (2R,3R)-18: ½aꢁD ¼ þ54:2 (c 0.886, CHCl3); IR
(neat): 2943, 1255 cmꢀ1. NMR: d ꢀ0.13 (3H, s), 0.08
(3H, s), 0.82 (3H, d, J = 7.3 Hz), 0.91 (9H, s), 2.16–2.18
(1H, m), 3.34 (1H, dd, J = 7.3, 11.7 Hz), 3.62 (1H, dd,
J = 4.4, 11.7 Hz), 3.90 (1H, br s), 4.91 (1H, d,
J = 5.4 Hz), 5.10 (2H, s), 7.26–7.44 (7H, m), 8.25 (1H, d,
J = 2.9 Hz). FAB-MS m/z: 388 (M++1). Anal. Calcd for
C22H33NO3Si: C, 68.22; H, 8.53; N, 3.62. Found: C,
68.01; H, 9.00; N, 3.54.
EtOAc = 1:1 elution. Compound (2R,3R,4R)-22: mp 114–
27
115 ꢁC (n-hexane/EtOAc); ½aꢁD ¼ ꢀ3:1 (c 0.707, CHCl3);
IR (neat): 3109, 1801 cmꢀ1. NMR: d 1.27 (3H, d,
J = 6.4 Hz), 2.57–2.67 (1H, m), 4.17 (1H, dd, J = 6.4,
8.3 Hz), 4.70 (1H, d, J = 7.8 Hz), 4.97 (1H, d,
J = 7.8 Hz), 5.12 (2H, s), 7.29–7.43 (7H, m), 8.35 (1H, d,
J = 2.9 Hz). FAB-MS m/z: 300 (M++1). Anal. Calcd for
C17H17NO3: C, 68.21; H, 5.73; N, 4.68. Found: C, 68.09;

1712
H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
28
H, 5.75; N, 4.66. Compound (2S,3R,4R)-23: ½aꢁD ¼ ꢀ36:1
H2O, the reaction mixture was directly chromatographed
on silica gel (20 g, CHCl3/MeOH = 50:1) to afford
(c 0.676, CHCl3); IR (neat): 3218, 1784, 1262 cmꢀ1
.
NMR: d 1.24 (3H, d, J = 6.8 Hz), 2.95–3.03 (1H, m),
4.71 (1H, d, J = 7.3 Hz), 5.12 (2H, s), 5.18 (1H, d,
J = 3.4 Hz), 7.23–7.43 (7H, m), 8.35 (1H, dd, J = 1.5,
2.0 Hz). FAB-MS m/z: 300 (M++1). Anal. Calcd for
C17H17NO3: C, 68.21; H, 5.73; N, 4.68. Found: C, 67.87;
H, 5.69; N, 4.70.
(2R,3R,4R)-27 (0.146 g, 91%) as a colorless oil. Com-
29
pound (2R,3R,4R)-27: ½aꢁD ¼ þ18:1 (c 0.52, CHCl3); IR
(KBr): 3436, 1770, 1268 cmꢀ1. NMR: d 1.27 (3H, d,
J = 6.4 Hz), 1.71 (2H, br s), 2.30–2.40 (1H, m), 3.40
(1H, d, J = 11.2 Hz), 4.92 (1H, d, J = 9.8 Hz), 5.13 (2H,
s), 7.26–7.44 (7H, m), 8.34 (1H, d, J = 2.9 Hz). FAB-MS
m/z: 299 (M++1).
3.18. (2R,3R,4R)-2-Azido-4-[2-(5-benzyloxypyridyl)]-3-
methyl-butano-4-lactone 24, (2S,3R,4R)-2-azido-4-[2-(5-
benzyloxypyridyl)]-3-methyl-butano-4-lactone 25, and (4R)-
4-[2-(5-benzyloxypyridyl)]-3-methyl-2-buteno-4-lactone 26
3.20. (2R,3R,4R)-2-Acetoamino-4-[2-(5-acetoxypyridyl)]-3-
methyl-butano-4-lactone 28
A solution of (2R,3R,4R)-27 (0.125 g, 0.42 mmol) in MeOH
(5 ml) was subjected to catalytic hydrogenolysis using 5%
Pd–C (0.085 g) at ordinary temperature, and the reaction
mixture was filtered with the aid of Celite. The filtrate was
condensed to give a residue, which was treated with Ac2O
(0.25 g, 2.45 mmol) in pyridine (0.5 ml). The reaction mix-
ture was diluted with H2O and extracted with EtOAc. The
organic layer was evaporated to give a residue, which was
chromatographed on silica gel (10 g, CHCl3/MeOH = 70:1)
to afford (2R,3R,4R)-28 (0.114 g, 80%) as colorless needles.
To a solution of (2R,3R,4R)-22 (0.30 g, 1 mmol), triphenyl-
phosphine (Ph3P; 0.525 g, 2 mmol) and imidazole (0.136 g,
2 mmol) in THF (10 ml) was added a solution of I2
(0.381 g, 1.5 mmol) in THF (3 ml) at 0 ꢁC, and the reaction
mixture was stirred for 30 min. After addition of one drop
of H2O, the reaction mixture was directly chromato-
graphed on silica gel (20 g, n-hexane/EtOAc = 5:1) to af-
ford 2-iodo compound. To a mixture of sodium azide
(NaN3; 0.095 g, 1.47 mmol) in DMF (10 ml) was added a
solution of the above iodo compound in THF (1 ml), and
the reaction mixture was stirred for 1 h at room tempera-
ture. The reaction mixture was diluted with H2O and
extracted with EtOAc. The organic layer was washed with
saturated brine and dried over MgSO4. Evaporation of the
organic solvent gave a residue, which was chromato-
graphed on silica gel (25 g, n-hexane/EtOAc = 5:1) to af-
ford (2S,3R,4R)-25 (0.028 g, 9%) as colorless needles and
(2R,3R,4R)-24 (0.189 g, 58%) as colorless oil from n-
hexane/EtOAc = 9:1 elution and (4R)-26 (0.082 g, 29%)
Compound (2R,3R,4R)-28: mp 205–207 ꢁC (CHCl3/
27
MeOH); ½aꢁD ¼ ꢀ13:5 (c 0.2, MeOH); IR (KBr): 3292,
1787, 1198 cmꢀ1. NMR: d 1.30 (3H, d, J = 6.8 Hz), 2.09
(3H, s), 2.35 (3H, s), 2.58–2.65 (1H, m), 4.62 (1H, dd,
J = 7.8, 11.2 Hz), 5.05 (1H, d, J = 9.3 Hz), 6.26 (1H, d,
J = 7.8 Hz), 7.53 (2H, dd, J = 2.4, 8.3 Hz), 8.39 (1H, d,
J = 2.4 Hz). FAB-MS m/z: 293 (M++1). Anal. Calcd for
C14H16N2O5: C, 57.53; H, 5.52; N, 9.59. Found: C, 57.14;
H, 5.70; N, 9.21.
as colorless needles from n-hexane/EtOAc = 7:1 elution.
3.21. (2S,3S)-1-Acetoxy-3-[2-(5-benzyloxypyridyl)]-2-
methyl-3-propanol 16
29
Compound (2R,3R,4R)-24: ½aꢁD ¼ þ107:8 (c 0.55, CHCl3);
IR (neat): 2111, 1784 cmꢀ1. NMR: d 1.28 (3H, d,
J = 6.3 Hz), 2.53–2.63 (1H, m), 4.03 (1H, d, J = 11.7 Hz),
4.97 (1H, d, J = 9.8 Hz), 5.12 (2H, s), 7.25–7.44 (7H, m),
8.35 (1H, d, J = 2.9 Hz). FAB-MS m/z: 325 (M++1). Anal.
Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.28. Found:
A mixture of (2S,3S)-12 (>99% ee, 2.05 g, 7.5 mmol),
vinyl acetate (2.07 g, 24.0 mmol) and lipase ‘Amano P’
(1.02 g) in diisopropyl ether (400 ml) was stirred at
33 ꢁC for 12 h. The reaction mixture was worked up in
the same way as ( )-12 to afford (2S,3S)-16 (2.06 g,
C, 63.02; H, 5.05; N, 17.01. Compound (2S,3R,4R)-25: mp
30
107–109 ꢁC (n-hexane/EtOAc); ½aꢁD ¼ ꢀ139:1 (c 0.675,
87%). Spectral data of (2S,3S)-16 were identical with
29
CHCl3); IR (KBr): 2106, 1771, 1210 cmꢀ1. NMR: d 1.20
(3H, d, J = 6.8 Hz), 2.95–3.05 (1H, m), 4.65 (1H, d,
J = 7.3 Hz), 5.10 (1H, d, J = 4.9 Hz), 5.12 (2H, s), 7.33–
7.43 (7H, m), 8.34 (1H, d, J = 1.5 Hz). FAB-MS m/z: 300
(M++1). Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97;
those of ( )-16. Compound (2S,3S)-16: ½aꢁD ¼ ꢀ19:7 (c
0.98, CHCl3).
3.22. (2S,3S)-1-Acetoxy-3-[2-(5-benzyloxypyridyl)]-3-tert-
butyldimethylsilyloxy-2-methyl-propane 17
N, 17.28. Found: C, 63.18; H, 4.95; N, 16.97. Compound
30
(4R)-26: mp 89–90 ꢁC (n-hexane/EtOAc); ½aꢁD ¼ þ2:0
A mixture of (2S,3S)-16 (2.75 g, 8.7 mmol), tert-butyldi-
methylsilyl chloride (TBDMSCl; 2.63 g, 17.4 mmol) and
imidazole (1.78 g, 26.2 mmol) in DMF (10 ml) was stirred
for 12 h at room temperature. The reaction mixture was
worked up in the same way as (2R,3R)-17 to afford
(2S,3S)-17 (3.5 g, 93%). Spectral data of (2S,3S)-17 were
(c 0.94, CHCl3); IR (KBr): 3443, 2921, 1752, 1646,
1291 cmꢀ1. NMR: d 2.01 (3H, s), 5.11 (2H, s), 5.82 (1H,
s), 5.89 (1H, s), 7.21–7.44 (7H, m), 8.35 (1H, d,
J = 2.5 Hz). FAB-MS m/z: 282 (M++1). Anal. Calcd for
C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.40;
H, 5.38; N, 5.03.
identical with those of (2R,3R)-17. Compound (2S,3S)-
28
17: ½aꢁD ¼ ꢀ52:8 (c 0.98, CHCl3).
3.19. (2R,3R,4R)-2-Amino-4-[2-(5-benzyloxypyridyl)]-3-
methyl-butano-4-lactone 27
3.23. (2S,3S)-3-[2-(5-Benzyloxypyridyl)]-3-tert-butyldimeth-
ylsilyloxy-2-methyl-1-propanol 18
A mixture of (2R,3R,4R)-24 (0.175 g, 0.54 mmol) and
Ph3P (0.17 g, 0.65 mmol) in THF (5 ml) was stirred for
30 min at room temperature. After addition of 0.7 ml of
A mixture of (2S,3S)-17 (2.58 g, 6.0 mmol), K2CO3 (3.32 g,
24.4 mmol) in MeOH (50 ml) was stirred for 2 h at room

H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
1713
temperature. The reaction mixture was worked up in the
same way as (2R,3R)-18 to afford (2S,3S)-18 (2.3 g, 98%).
mixture of sodium azide (NaN3, 0.095 g, 1.47 mmol) in
DMF (10 ml) was added a solution of the above iodo
compound in THF (1 ml) and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture
was worked up in the same way as preparation of
(2R,3R,4R)-24, (2S,3R,4R)-25, and (4R)-26 to afford
(2R,3S,4S)-25 (0.028 g, 10%) as colorless needles,
(2S,3S,4S)-24 (0.195 g, 60%) as a colorless oil and (4R)-26
Spectral data of (2S,3S)-18 were identical with those
28
of (2R,3R)-18. Compound (2S,3S)-18: ½aꢁD ¼ ꢀ54:3 (c
0.975, CHCl3).
3.24. (2S,3S)-3-[2-(5-Benzyloxypyridyl)]-3-tert-butyldimeth-
ylsilyloxy-2-methylpropanal 19
(0.084 g, 30%) as colorless needles. Compound (2S,3S,4S)-24:
29
A mixture of (2S,3S)-18 (3.06 g, 7.9 mmol), PCC (3.46 g,
15.7 mmol) in CH2Cl2 (30 ml) was stirred for 10 h at room
temperature. The reaction mixture was worked up in the
same way as (2R,3R)-19 to afford (2S,3S)-19 (1.83 g,
½aꢁD ¼ ꢀ107:3 (c 0.545, CHCl3), (2R,3S,4S)-25: mp 110–
30
111 ꢁC (n-hexane/EtOAc); ½aꢁD ¼ þ139:1 (c 0.58, CHCl3),
30
(4S)-26: mp 90–91 ꢁC (n-hexane/EtOAc); ½aꢁD ¼ ꢀ2:1
(c 0.91, CHCl3).
60%). Spectral data of (2S,3S)-19 were identical with those
28
of (2R,3R)-19. Compound (2S,3S)-19: ½aꢁD ¼ ꢀ84:3 (c
3.27. (2S,3S,4S)-2-Amino-4-[2-(5-benzyloxypyridyl)]-3-
methyl-butano-4-lactone 27
0.99, CHCl3).
3.25. (2S,3S,4S)-4-[2-(5-Benzyloxypyridyl)]-2-hydroxy-3-
methyl-butano-4-lactone 22 and (2R,3S,4S)-4-[2-(5-benzyl-
oxypyridyl)]-2-hydroxy-3-methyl-butano-4-lactone 23
A mixture of (2S,3S,4S)-24 (0.165 g, 0.51 mmol) and Ph3P
(0.16 g, 0.61 mmol) in THF (5 ml) was stirred for 30 min at
room temperature. After addition of 0.7 ml of H2O, the
reaction mixture was directly chromatographed on silica
gel (20 g, CHCl3/MeOH = 50:1) to afford (2S,3S,4S)-27
(1) To a solution of tris(methylthio)methane (0.76 g,
4.8 mmol) in THF (10 ml) at ꢀ78 ꢁC was added n-BuLi
(1.53 M in hexane, 2.7 ml (4.2 mmol)) under argon atmo-
sphere, and the reaction mixture was stirred at ꢀ78 ꢁC
for 20 min and at ꢀ20 ꢁC for 1 h. To the carbanion solu-
tion generated was added a solution of (2S,3S)-19
(1.24 g, 3.21 mmol) in THF (5 ml) at ꢀ78 ꢁC, and the
whole mixture was stirred at ꢀ78 ꢁC for 2 h and at 0 ꢁC
for 2 h. The reaction mixture was diluted with H2O and ex-
tracted with EtOAc. The organic layer was washed with
saturated brine, dried over MgSO4, and evaporated. The
residue was dissolved in a mixed solvent (MeOH (24 ml)
and H2O (2 ml)) and HgCl2 (3.94 g, 14.5 mmol) and HgO
(3.14 g, 14.5 mmol) were added to the above solution at
room temperature and the mixture was stirred for 4 h at
the same temperature. The reaction mixture was worked
up in the same way as a-hydroxy esters (20 and 21) to
afford a mixture of a-hydroxy esters (20 and 21, 0.944 g,
66%). (2) To a solution of a-hydroxy esters (20 and 21,
0.918 g, 2.1 mmol) in THF (17 ml) was added TBAF
(1.1 g, 4.1 mmol), and the reaction mixture was stirred
for 2 h at room temperature. The reaction mixture was
worked up in the same way as preparation of
(2R,3R,4R)-22 and (2S,3R,4R)-23 to afford (2R,3S,4S)-23
(0.045 g, 7%) and (2S,3S,4S)-22 (0.456 g, 74%). Compound
(0.139 g, 92%) as a colorless oil. Compound (2S,3S,4S)-
26
27: ½aꢁD ¼ ꢀ18:0 (c 0.7, CHCl3). FAB-MS m/z: 299
(M++1).
3.28. (2S,3S,4S)-2-Benzyloxycarbonylamino-4-[2-(5-benzyl-
oxypyridyl)]-4-tert-butyldimethylsilyloxy-3-methylbutanoic
acid 2
To a solution of (2S,3S,4S)-27 (0.13 g, 0.44 mmol) in THF
(1 ml) was added aqueous KOH (KOH (0.086 g)–H2O
(1 ml)) at 0 ꢁC, and the reaction mixture was stirred for
3 h at room temperature. The reaction mixture was directly
subjected to chromatography (Dowex 50WX8-400 (4 g;
1 M aqueous NH3) and elution and was evaporated under
reduced pressure. The resulting residue (crude c-hydroxy-
b-methyl-a-amino acid) was dried for 12 h. To a solution
of the resulting residue in MeCN (4 ml) was added
N-methyl-N-(t-butyldimethylsilyl)-trifluoroacetamide, and
the whole mixture was stirred for 36 h at room tempera-
ture. Then N-(benzyloxycarbonyl)-succinimide (0.16 g,
0.64 mmol) was added to the above reaction mixture and
the whole mixture was further stirred for 36 h at room tem-
perature. To the reaction mixture were added 5% aqueous
KH2PO4 (30 ml) and brine (20 ml), and the reaction mix-
ture was extracted with AcOEt (20 ml · 3). The organic
layer was dried over MgSO4 and evaporated to afford a
residue. A mixture of the above residue and K2CO3
(0.05 g) in a mixed solvent (THF (2 ml)/MeOH (2 ml)/
H2O (2 ml)) was stirred for 30 min at room temperature.
The reaction mixture was diluted with H2O (10 ml) and
brine (20 ml), and extracted with AcOEt (20 ml · 2). The
organic layer was dried over MgSO4 and evaporated to
give a residue, which was chromatographed on silica gel
(7 g, CHCl3/MeOH = 50:1–20:1) to afford a colorless
(2S,3S,4S)-22:
mp
115–116 ꢁC
(n-hexane/EtOAc);
26
½aꢁD ¼ þ3:15 (c 0.825, CHCl3). Compound (2R,3S,4S)-
27
23: ½aꢁD ¼ þ36:9 (c 0.453, CHCl3).
3.26. (2S,3S,4S)-2-Azido-4-[2-(5-benzyloxypyridyl)]-3-
methyl-butano-4-lactone 24, (2R,3S,4S)-2-azido-4-[2-(5-
benzyloxypyridyl)]-3-methyl-butano-4-lactone 25, and (4S)-
4-[2-(5-benzyloxypyridyl)]-3-methyl-2-buteno-4-lactone 26
To a solution of (2S,3S,4S)-22 (0.30 g, 1 mmol), triphenyl-
phosphine (Ph3P, 0.525 g, 2 mmol) and imidazole (0.136 g,
2 mmol) in THF (10 ml) was added a solution of I2
(0.381 g, 1.5 mmol) in THF (3 ml) at 0 ꢁC, and the reaction
mixture was stirred for 30 min. After addition of one drop
of H2O, the reaction mixture was worked up in the same
way as (2R,3R,4R)-22 to afford 2-iodo compound. To a
amorphous product (2S,3S,4S)-2 (0.169 g, 69%). Com-
28
pound (2S,3S,4S)-2: mp 60–61 ꢁC; ½aꢁD ¼ ꢀ5:44 (c 0.79,
CHCl3). IR (KBr): 2938, 1722, 1250, 1079 cmꢀ1 1H
.
NMR (CDCl3): d ꢀ0.14 (3H, s), 0.06 (3H, s), 0.80 (3H,
d, J = 6.8 Hz), 0.89 (9H, s), 2.24 (1H, m), 4.19 (1H, dd,
J = 7.8, 8.3 Hz), 5.03–5.08 (3H, m), 5.12 (2H, s), 5.68

1714
H. Akita et al. / Tetrahedron: Asymmetry 17 (2006) 1705–1714
(1H, d, J = 7.8 Hz), 7.2–7.6 (12H, m), 8.26 (1H, d,
J = 2.4 Hz). 13C NMR (CDCl3): d 173.5 (s), 156.3 (s),
154.8 (s), 152.5 (s), 136.5 (s), 135.6 (s), 134.0 (d), 128.8
(d), 128.5 (d), 128.5 (d), 128.0 (d), 127.9 (d), 127.6 (d),
124.7 (d), 123.2 (d), 73.6 (d), 70.8 (t), 66.9, (t), 56.7 (d),
44.6 (d), 25.8 (q), 18.0 (s), 10.9 (q), ꢀ5.0, (q), ꢀ5.2 (q).
FAB-MS m/z: 565 (M++1). Anal. Calcd for C31H40N2O6Si:
C, 65.93; H, 7.14; N, 4.96. Found: C, 65.45; H, 7.27; N, 4.64.
the reaction mixture was stirred for 3 h at 50 ꢁC. The reac-
tion mixture was evaporated under reduced pressure and
the resulting residue was dried for 2 h. To a mixture of
the above residue in MeCN (6 ml) was added 1,3-dic-
yclohexylcarbodiimide (DCC; 0.072 g, 0.35 mmol), and
the reaction mixture was stirred for 1 h at room tempera-
ture. The reaction mixture was evaporated to give a
residue, which was chromatographed on silica gel (5 g,
n-hexane/EtOAc = 2:1) to afford ( )-29 (0.029 g, 74%) as
a colorless oil. The NMR data of the present ( )-29 were
identical with those of the previous ( )-29 described in (1).
3.29. ( )-(2,3)-trans-(3,4)-trans-2-Benzyloxycarbonylamino-
4-[2-(5-benzyloxypyridyl)]-3-methyl-butano-4-lactone 29
(1) To a solution of ( )-27 (0.085 g, 0.29 mmol) in dioxane
(3 ml) were added 7% aqueous NaHCO3 (1 ml) and 30%
References
carbobenzyloxy
chloride
(CbzCl)–toluene
solution
(0.25 ml), and the reaction mixture was stirred for 2 h at
room temperature. The reaction mixture was diluted with
H2O and extracted with AcOEt (20 m · 3). The organic
layer was dried over MgSO4 and evaporated to afford a
residue, which was chromatographed on silica gel (5 g, n-
hexane/EtOAc = 2:1) to give ( )-29 (0.090 g, 73%) as col-
orless oil. Compound ( )-29: IR (KBr): 3330, 2927, 1785,
1532 cmꢀ1. NMR (CDCl3): d 1.26 (d, J = 7.4 Hz, 3H),
2.60–2.70 (1H, m), 4.36 (1H, t, J = 9.2 Hz), 4.97 (1H, d,
J = 9.5 Hz), 5.11 (2H, s), 5.45 (1H, d, J = 8.2 Hz), 7.32–
7.44 (12H, m), 8.34 (1H, d, J = 2.2 Hz). FAB-MS m/z:
433 (M++1). (2) To a solution of ( )-2 (0.05 g, 0.09 mmol)
in THF (4 ml) was added TBAF (0.102 g, 0.32 mmol) and
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