Total synthesis of spiruchostatin A - A potent histone deacetylase inhibitor

Article abstract of DOI:10.3987/COM-07-S(N)5

Total synthesis of spiruchostatin A (1), a potent histone deacetylase inhibitor, was achieved; the method features (i) Julia-Kocienski olefination of sulfone 10 and aldehyde 11 to install the requisite (E)-olefin unit present in segment 6, (ii) amide coup

Full text of DOI:10.3987/COM-07-S(N)5

HETEROCYCLES, Vol. 76, No. 1, 2008
275
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 275 - 290. © The Japan Institute of Heterocyclic Chemistry
Received, 14th December, 2007, Accepted, 10th March, 2008, Published online, 11th March, 2008. COM-07-S(N)5
TOTAL SYNTHESIS OF SPIRUCHOSTATIN A—A POTENT HISTONE
DEACETYLASE INHIBITOR
Toshiya Takizawa, Kazuhiro Watanabe, Koichi Narita, Kyosuke Kudo,
Takamasa Oguchi, Hideki Abe, and Tadashi Katoh*
Laboratory of Medicinal Synthetic Chemistry, Department of Chemical
Pharmaceutical Science, Tohoku Pharmaceutical University, Komatsushima,
Aoba-ku, Sendai 981-8558, Japan. E-mail: katoh@tohoku-pharm.ac.jp
Abstract – Total synthesis of spiruchostatin A (1), a potent histone deacetylase
inhibitor, was achieved; the method features (i) Julia–Kocienski olefination of
sulfone 10 and aldehyde 11 to install the requisite (E)-olefin unit present in
segment 6, (ii) amide coupling of segment 5 with segment 6 to produce the key
seco-acid 4, and (iii) macrolactonization of 4 employing Shiina reagent to
efficiently construct the desired 15-membered macrocyclic compound 32.
INTRODUCTION
Spiruchostatins A (1) and B (2) (Figure 1), isolated from a culture broth of Pseudomonas sp. by Shin-ya
et al.1 in 2001, exhibit potent histone deacetylase (HDAC) inhibitory activity.2 HDAC is the enzyme that
catalyzes the hydrolysis of acetylated lysine residues on proteins, particularly on histones. 3 It has been
Me
O
OH
R
Me
5”
N
H
Me
O
Me
O
NH
O
NH
O
S
S
S
O
O
S
HN
HN
H
N
H
N
O
O
O
O
Me
Me
Me
1 : spiruchostatin A ( R = Me )
2 : spiruchostatin B ( R = Et )
3 : FK228 ( FR901228 )
Figure 1. Structures of spiruchostatins A (1), B (2), and FK228 (FR901228) (3)
This paper is dedicated to Professor Ryoji Noyori on the occasion of his 70th birthday.

276
HETEROCYCLES, Vol. 76, No. 1, 2008
reported that HDAC inhibitors can cause growth arrest in a wide range of transformed cells and can
inhibit the growth of human tumor xenografts.4 These natural products, therefore, are expected to be
promising candidates for novel molecular-targeted anticancer agents. Structurally, 1 and 2 are
15-membered bicyclic depsipeptides consisting of (3S,4R)-statine, D-cysteine, D-alanine,
(3R,4E)-3-hydroxy-7-mercapto-4-heptenoic acid, and characteristic disulfide bond linkage. The
structurally closely related 16-membered bicyclic depsipeptide FK228 (FR901228) (3) is also a potent
HDAC inhibitor isolated from the fermentation broth of Chromobacterium violaceum by Fujisawa
Pharmaceutical Co. Ltd. (now Astellas Pharm Inc.).5
The attractive biological properties and intriguing structural features prompted us to undertake a project
directed toward the total synthesis of 1–3. To date, two total syntheses of 3 have been reported by Simon
et al.6 in 1996 and Williams et al.7 in 2008, and two total syntheses of 1 have been reported by Ganesan et
al.8 in 2004 and Doi–Takahashi et al.9 in 2006. Recently, we accomplished the first total synthesis of 2,10
which resulted in the establishment of the stereochemistry of 2 at C5” (spiruchostatin numbering). Herein,
we report the total synthesis of 1 based on the same strategy developed in our laboratory.10
RESULTS AND DISCUSSION
Our synthetic plan for spiruchostatin A (1) is outlined in Scheme 1. The targeted molecule 1 should be
synthesized by macrolactonization of seco-acid 4 followed by a disulfide bond formation according to the
OH
Me
OTBS
Me
CO2H
Me
O
Me
O
O
NH
NH
TrS
S
O
S
STr
OH
HN
HN
H
N
H
N
O
O
O
Me
O
Me
1 : spiruchostatin A
4
Me
Me
O
H
N
CO2H
TrS
H2N
TrS
+
CO2Allyl
N
H
O
PMBO
Me
OTBS
6
5
PMP
O
Me
N
N
BocHN
TrS
CO2H
H2N
CO2Me
CHO
N
O
Me
N
O
TrS
S
CH3CO2Et
Me
12
NHBoc
O
Ph
OHC
7
8
9
10
11
Scheme 1. Synthetic plan for spiruchostatin A (1). TBS = tert-butyldimethylsilyl, Tr (trityl) = triphenylmethyl,
Boc = tert-butoxycarbonyl, PMB = 4-methoxybenzyl, PMP = 4-methoxyphenyl.

HETEROCYCLES, Vol. 76, No. 1, 2008
277
protocols reported previously.8,9 The key feature of this scheme is expected to be a highly convergent
assembly of 4 by direct coupling of segment 5 and segment 6 via amide bond formation. Segment 5
would be prepared via an aldol coupling of N-Boc-D-valinal (7)11 with ethyl acetate (8) and subsequent
condensation with D-cysteine derivative 9.12 On the other hand, segment 6 would be produced via
Julia–Kocienski olefination13 of sulfone 10 accessible from 1,3-propanediol with aldehyde 1114 available
from L-malic acid, and subsequent condensation with D-alanine methyl ester (12).
We initially pursued the synthesis of segment 5 shown in Scheme 2. Aldol coupling of the known
N-Boc-D-valinal (7)11 with the lithium enolate of ethyl acetate (8) provided the desired coupling product
14 (30%) and the undesired stereoisomer 13 (63%). Conversion of 13 to 14 by inversion of the hydroxy
group was then investigated; the sequence involved Jones oxidation15 and subsequent stereoselective
reduction of the resulting ketone 15. After several experiments, the best result was obtained using KBH4
at −40°C, which provided the desired product 14 with an 82% yield and high stereoselectivity (14/13 =
16:1). When LiBH4 or NaBH4 was used as a reducing agent, a lower stereoselectivity of 14/13 was
observed (4:1 to 7:1). To continue the synthesis, ethyl ester 14 was then transformed to allyl ester 19 via a
four-step operation involving protection of the hydroxy group in 14 (84%), saponification of the ester
moiety in the resulting TBS ether 16 (82%), formation of an allyl ester from the liberated carboxylic acid
17 (91%), and deprotection of the N-Boc group in 18 (90%). Condensation of amine 19 with
N-Boc-S-trityl-L-cysteine (9)12 furnished the desired coupling product 20 with an 88% yield. Finally,
deprotection of the N-Boc group in 20 afforded the requisite segment 5 with a quantitative yield.
OH
OH
Me
Me
Me
a
CO2Et
CO2Et
CHO
+
Me
Me
Me
NHBoc
NHBoc
NHBoc
14
13
7
Me
O
c
b
CO2Et
Me
NHBoc
15
Me
Me
OTBS
CO2R1
Me
O
h
d
e
RHN
14
CO2Allyl
OTBS
N
H
Me
CO2H
BocHN
TrS
NHR2
TrS
i
16 : R1 = Et, R2 = Boc
17 : R1 = H, R2 = Boc
18 : R1 = Allyl, R2 = Boc
19 : R1 = Allyl, R2 = H
9
20 : R = Boc
5 : R = H
f
g
Scheme 2. Synthesis of segment 5. Reagents and conditions: (a) LDA, MeCO2Et (8), THF, –78˚C; at –78˚C, add. 7,
63% for 13, 30% for 14 (13/14 = ca. 2:1); (b) Jones reagent, acetone, 0˚C to rt, 80%; (c) KBH4, MeOH, –40˚C, 82% for
14, 6% for 13 (14/13 = 16:1); (d) TBSCl, imidazole, DMF, rt, 84%; (e) 1 M NaOH, EtOH, rt, 82%; (f) allyl bromide,
K2CO3, DMF, rt, 91%; (g) TMSOTf, 2,6-lutidine, CH2Cl2, rt; MeOH, rt, 90%; (h) 9, PyBOP, i-Pr2NEt, MeCN, rt, 88%; (i)
TMSOTf, 2,6-lutidine, CH2Cl2, rt, 99%. LDA = lithium diisopropylamide, TMSOTf = trimethylsilyl
trifluoromethanesulfonate, PyBOP = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate.

278
HETEROCYCLES, Vol. 76, No. 1, 2008
We next synthesized segment 6, the coupling partner of 5, as shown in Scheme 3. Sulfone 10, a substrate
for the crucial Julia–Kocienski olefination,13 was prepared with high efficiency from the known
3-(4-methoxybenzyloxy)propan-1-ol (21)16 via a four-step sequence involving formation of the
S-tetrazole 22 under Mitsunobu conditions17 (95%), Molybdenum-mediated oxidation18 of 22,
deprotection of the PMB group in sulfone 23 (94% in two steps), and substitution of the primary hydroxy
group in 24 with a S-trityl group under Mitsunobu conditions17 (96%). The crucial Julia–Kocienski
olefination of 10 with the known aldehyde 11,14 readily prepared from L-malic acid, proceeded smoothly
to form the desired coupling product 25 as an inseparable mixture of E/Z-stereoisomers (E/Z = 5:1 at 400
1
MHz H NMR) in 66% yield. Reductive acetal opening of the E/Z-mixture 25 with DIBAL19 at 0°C
produced the desired E-olefinic primary alcohol 26a as a major product (60%) along with the undesired
Z-olefinic isomer 26b (12%); at this stage, the E/Z-isomers could be separated by silica gel column
chromatography. Dess–Martin oxidation20 of 26a followed by Pinnick oxidation21 of the resulting
aldehyde 27 produced the corresponding carboxylic acid 28 with a 66% yield in two steps. Compound 28
was finally converted to the requisite segment 6 (88% overall yield) by condensation with D-alanine
methyl ester (12) followed by saponification of the methyl ester moiety of the resulting amide 29.
N
N
N
N
a
b
N
N
PMBO
OH
N
N
X
S
PMBO
S
O
O
Ph
Ph
21
22
23 : X = OPMB
24 : X = OH
10 : X = STr
c
d
PMP
OPMB
OPMB
e
PMP
O
O
f
OH
STr
OH
+
TrS
TrS
O
g
O
26a
26b
25 ( E/Z = ca. 5:1 )
OHC
11
H
N
i
TrS
TrS
CO2R
Me
X
26a
CO2Me
PMBO
H2N
O
PMBO
27 : X = CHO
28 : X = CO2H
Me
12
29 : R = Me
6 : R = H
h
j
Scheme 3. Synthesis of segment 6. Reagents and conditions: (a) 1-phenyl-1H-tetrazole-5-thiol, DEAD, PPh3, THF, rt,
95%; (b) Mo7O24(NH4)6·4H2O, 30% H2O2, EtOH, rt; (c) DDQ, CH2Cl2/H2O, rt, 94% (2 steps); (d) TrSH, DEAD, PPh3,
CH2Cl2, reflux, 96%; (e) LiN(SiMe3)2, DMF, –60˚C; at –60˚C, add. 11, –60 to 0˚C, 66% (E/Z = ca. 5:1); (f) DIBAL,
toluene, 0˚C, 60% for 26a, 12% for 26b; (g) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0˚C to rt, 88%; (h) NaClO2,
NaH2PO4, DMSO/H2O, 0˚C to rt, 75%; (i) D-alanine methyl ester (12), PyBOP, i-Pr2NEt, MeCN, 0˚C to rt, 90%; (j) 1 M
LiOH, MeOH, rt, 98%. DEAD = diethyl azodicarboxylate, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DIBAL =
diisobutylaluminium hydride.

HETEROCYCLES, Vol. 76, No. 1, 2008
279
OR
Me
OTBS
Me
TrS
CO2H
CO2Allyl
OTBS
STr
Me
O
Me
Me
O
CO2Allyl
NH
TrS
NH
Me
O
a
c
OPMB
TrS
+
NH
STr
OH
STr
H
N
OR
HN
HN
HO2C
H
N
H
N
2
H2N
O
O
O
Me
5
O
6
O
Me
Me
4 : R = TBS
30 : R = PMB
31 : R = H
b
Scheme 4. Synthesis of seco-acid 4. Reagents and conditions: (a) HATU, HOAt, i-Pr2NEt, CH2Cl2, –30°C, 94%;
(b) DDQ, CH2Cl2/H2O, rt, 89%; (c) Pd(PPh3)4, morpholine, THF, rt, 99%; HATU = O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-
tetramethyluronium hexafluorophosphate, HOAt = 1-hydroxy-7-azabenzotriazole,
After thus synthesizing the requisite segments 5 and 6, we investigated the synthesis of seco-acid 4, a
substrate for the following crucial macrolactonization, by assembling the two segments as shown in
Scheme 4. Initial attempts to achieve the pivotal amide coupling of 5 with 6 under conventional
conditions22 (e.g., PyBOP, EDCI/HOBt, or HATU, rt) resulted in failure; considerable epimerization was
observed at the C2 stereogenic center (D-alanine part in 30), while the coupling product 30 was produced
with a good yield (~ 80%). After several experiments, we solved this epimerization problem using a
combination of HATU and HOAt at low temperature. Treatment of 5 and 6 with HATU (1.3 equiv) and
HOAt (1.3 equiv) in the presence of i-Pr2NEt (2.5 equiv) in CH2Cl2 at −30°C for 2 h produced the desired
coupling product 30 with a 94% yield without appreciable epimerization at C2. The coupling product 30
was then converted to the requisite seco-acid 4 with an overall yield of 88% via alcohol 31 by successive
removal of both the PMB and allyl protecting groups.
Having synthesized seco-acid 4 in a highly convergent manner, the stage was set for the crucial
macrolactonization event. In the previous two total syntheses of spiruchostatin A (1), Ganesan et al.
successfully achieved macrolactonization of the O-triisopropylsilyl (TIPS) variant of 4 (R = TIPS) by the
Yamaguchi method (2,4,6-trichlorobenzoyl chloride, Et3N, MeCN/THF, 0 – 20°C; DMAP, toluene, 50°C,
53%);8 furthermore, Doi–Takahashi et al. efficiently performed macrolactonization of the
O-non-protected variant of 4 (R = H) by the Shiina method [2-methyl-6-nitrobenzoic anhydride (MNBA),
DMAP, CH2Cl2, rt, 67%].9 Given these results, we investigated macrolactonization of 4 under different
conditions as shown in Scheme 5 (4 → 32 in Scheme 5) and Table 1. As expected, the best result was
obtained with the Shiina method23 (entry 1). Thus, treatment of a dilute solution of 4 in CH2Cl2 (1.0 mM)
with MNBA (1.3 equiv) and DMAP (3.0 equiv) at room temperature for 15 h produced the desired
macrocyclic compound 32 with an 89% yield (entry 1). When macrolactonization was performed as per
the Yamaguchi method24 (entry 2) or the Mukaiyama–Corey–Nicolaou method25 (entry 3), the yield of 32

280
HETEROCYCLES, Vol. 76, No. 1, 2008
OTBS
Me
OTBS
Me
OR
Me
CO2H
Me
O
Me
Me
O
NH
NH
O
NH
O
O
Table 1
a
S
TrS
TrS
STr
O
OH
O
STr
S
HN
HN
HN
H
N
H
N
H
N
O
O
O
O
O
Me
O
Me
Me
4
32
33 : R = TBS
1 : R = H ( spiruchostatin A
b
)
Scheme 5. Synthesis of spiruchostatin A (1) via the critical macrolactonization. Reagents and conditions:
(a) I2, MeOH/CH2Cl2, rt, 80%; (b) HF·pyridine, pyridine, rt, 92%.
Table 1. Macrolactonization of seco-acid 4 producing to macrocyclic compound 32.
Entry
Reagents and Conditions
Yield of 32 [%]
1a
2b
MNBA (1.3 equiv), DMAP (3.0 equiv), CH2Cl2, rt, 15 h
89
67
2,4,6-trichlorobenzoyl chloride (5.0 equiv), Et3N (5.0 equiv), THF, 0°C to rt;
DMAP (3.0 equiv), toluene, 60°C, 16 h
3c
2,2-dipyridyl disulfide (3.0 equiv), Ph3P (1.5 equiv), toluene, 80°C, 10 h
36
a Shiina method. b Yamaguchi method. c Mukaiyama–Corey–Nicolaou method.
was relatively lower (67% and 36%, respectively). Ultimately, simultaneous S-Tr deprotection and
disulfide bond formation of 32 (80%) by brief exposure to iodine in dilute MeOH solution (0.5 mM) at
ambient temperature6–10,26 and subsequent deprotection of the TBS group of the resulting disulfide 33
24
(92%) with HF·pyridine, resulted in the completion of the total synthesis of spiruchostatin A (1), [α]D
1
−61.1 (c = 0.14, MeOH) {lit.1 [α]D −63.6 (c = 0.14, MeOH)}. The spectroscopic properties (IR, H and
13C NMR, and MS) of the synthetic sample 1 were identical with those reported for natural 1.
CONCLUSION
We accomplished a total synthesis of spiruchostatin A (1) in a convergent manner starting from
N-Boc-D-valinal (7), aldehyde 11 derived from L-malic acid, and sulfone 10 arising from 1,3-propanediol.
The key elements of the synthesis are (i) Julia–Kocienski olefination of sulfone 10 and aldehyde 11 to
install the requisite (E)-olefin unit present in the critical segment 6, (ii) condensation of segment 5 with
segment 6 under mild conditions to directly assemble the crucial seco-acid 4, and (iii) macrolactonization
of 4 using Shiina reagent (MNBA) to efficiently construct the desired 15-membered macrocyclic
compound 32. The explored synthetic route has a potential for producing various structural types of
spiruchostatin analogs due to its generality and flexibility. These efforts are currently under way.

HETEROCYCLES, Vol. 76, No. 1, 2008
281
EXPERIMENTAL
General Procedures: All reactions involving air- and moisture-sensitive reagents were carried out using oven
dried glassware and standard syringe-septum cap techniques. Routine monitorings of reaction were carried out
using glass-supported Merck silica gel 60 F254 TLC plates. Flash column chromatography was performed on Kanto
Chemical Silica Gel 60N (spherical, neutral 40–50 µm) with the solvents indicated. All solvents and reagents were
used as supplied with following exceptions. Tetrahydrofuran (THF) and Et2O were freshly distilled from Na
metal/benzophenone under argon. Toluene was distilled from Na metal under argon. N,N-Dimethylformamide
(DMF), dimethyl sulfoxide (DMSO), CH2Cl2, MeCN, pyridine, and N,N-diisopropylamine were distilled from
calcium hydride under argon. Measurements of optical rotations were performed with a JASCO DIP-370 automatic
digital polarimeter. Melting points were taken on a Yanaco MP-3 micro melting point apparatus and are
1
uncorrected. H and 13C NMR spectra were measured with a JEOL AL-400 (400 MHz) spectrometer. Chemical
shifts were expressed in ppm using Me4Si (δ = 0) as an internal standard. The following abbreviations are used:
singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), multiplet (m), and broad (br). Infrared (IR) spectral
measurements were carried out with a JASCO FT/IR-4100 spectrometer. Low- and High-resolution mass (HRMS)
spectra were measured on a JEOL JMS-DX 303/JMA-DA 5000 SYSTEM high resolution mass spectrometer.
(3R,4R)-Ethyl 4-(tert-butoxycarbonylamino)-3-hydroxy-5-methylhexanoate (13) and its (3S,4R)-isomer (14):
A solution of EtOAc (8) (8.3 mL, 87 mmol) in THF (10 mL) was added slowly to a stirred solution of lithium
diisopropylamide (LDA) (19 mmol) [prepared from n-BuLi in hexane (1.6 M solution, 54.4 mL, 87 mmol) and
i-Pr2NH (12.8 mL, 91 mmol)] in dry THF (50 mL) at −78˚C. After 30 min, (2R)-2-[(tert-
butoxycarbonyl)amino]-3-methylbutylaldehyde (7)11 (3.50 g, 17 mmol) in THF (50 mL) was added to the above
mixture at −78˚C. After 40 min, the reaction was quenched with 2 M HCl (20 mL) at −78˚C, and the resulting
mixture was extracted with AcOEt (2 x 80 mL). The combined extracts were washed with saturated aqueous
NaHCO3 (2 x 40 mL) and brine (2 x 40 mL), then dried over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography (hexane/EtOAc, 5:1→4:1) to 13 (3.17 g, 63%,
less polar) and 14 (1.51 g, 30%, more polar).
25
13: colorless oil, [α]D +43.8° (c 1.00, CHCl3); IR (neat): 3363, 2967, 1696, 1526, 1466, 1391, 1173, 1071, 1038,
1
986, 868, 758, 611, 467 cm−1; H NMR (400 MHz, CDCl3): δ 0.96 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz),
1.28 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 1.83–1.91 (1H, m), 2.45 (1H, A part of ABX, J = 2.7, 16.7 Hz), 2.55 (1H, B
part of ABX, J = 9.8, 16.7 Hz), 3.15 (1H, t, J = 9.5 Hz), 3.39 (1H, d, J = 2.9 Hz), 4.16 and 4.19 (2H, ABq, J = 7.3
Hz), 4.24–4.28 (1H, m), 4.91 (1H, d, J = 10.3 Hz); 13C NMR (100 MHz, CDCl3): δ 14.1, 19.5, 19.7, 28.3 (3C), 30.3,
39.1, 59.6, 60.8, 67.0, 79.0, 156.4, 173.6; HRMS (EI) calcd for C14H27NO5 (M+), 289.1889, found 289.1884.
25
14: colorless oil, [α]D −9.0° (c 1.02, CHCl3); IR (neat): 3445, 2978, 2876, 2361, 1715, 1505, 1367, 1175, 1024,
1
951, 916, 870, 758, 666, 542 cm−1; H NMR (400 MHz, CDCl3): δ 0.88 (3H, d, J = 6.8 Hz), 0.94 (3H, d, J = 6.8
Hz), 1.28 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 2.09–2.17 (1H, m), 2.47 (1H, A part of ABX, J = 2.9, 16.6 Hz), 2.59 (1H,
B part of ABX, J = 9.3, 16.6 Hz), 3.34 (1H, d, J = 4.9 Hz), 3.50–3.56 (1H, m), 3.90–3.96 (1H, m), 4.14–4.21 (2H,
m), 4.45 (1H, br d, J = 9.8 Hz); 13C NMR (100 MHz, CDCl3): δ 14.1, 16.2, 20.1, 27.5, 28.3 (3C), 38.4, 58.7, 60.8,

282
HETEROCYCLES, Vol. 76, No. 1, 2008
69.2, 79.5, 156.4, 173.2; HRMS (EI) calcd for C14H27NO5 (M+), 289.1889, found 289.1903.
(R)-Ethyl 4-(tert-butoxycarbonylamino)-5-methyl-3-oxohexanoate (15): 2.6 M Jones reagent (5.99 mL, 15
mmol) was added dropwise to a stirred solution of 13 (3.00 g, 10 mmol) in acetone (80 mL) at 0°C. After stirring
was continued at rt for 1 h, the mixture was diluted with Et2O (300 mL). The organic layer was washed with
saturated aqueous NaHCO3 (2 x 80 mL) and brine (2 x 80 mL), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc, 8:1→4:1) to
25
give 15 (2.38g, 80%) as a colorless oil. [α]D –16.5° (c 1.09, CHCl3); IR (neat): 2974, 2936, 2878, 1715, 1653,
1505, 1393, 1368, 1314, 1242, 1173, 1034, 872, 779, 654, 594 cm−1; 1H NMR (400 MHz, CDCl3): δ 0.81 (3H, d, J
= 0.9 Hz), 1.01 (3H, d, J = 6.9 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 2.24 (1H, m), 3.53 (2H, s), 4.18 (1H, d, J
= 7.1 Hz), 4.21 (1H, d, J = 7.1 Hz), 4.33 (1H, dd, J = 4.1, 8.9 Hz), 5.67 (1H, d, J = 8.2 Hz); 13C NMR (100 MHz,
CDCl3): δ 14.0, 19.6, 28.1 (3 C), 29.4, 47.0, 61.3, 64.2, 79.8, 89.7, 155.7, 166.6, 202.1; HRMS (EI) calcd for
C14H25NO5 (M+), 287.1733, found 287.1744.
Stereoselective reduction of 15 leading to 14: KBH4 (1.94 g, 36 mmol) was added in small portions to a stirred
solution of 15 (2.06 g, 7.2 mmol) in MeOH (70 mL) at −40°C. After 5 h, the reaction was quenched with 10%
aqueous citric acid at 0°C (adjusted pH 3). After concentration of the solvent in vacuo, water (30 mL) was added,
and the resulting mixture was extracted with CH2Cl2 (4 x 30 mL). The combined extracts were washed with brine
(2 x 30 mL), then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc, 5:1→4:1) to give 14 (1.70 g, 82%) along with 13 (124 mg, 6%). The
IR, 1H and 13C NMR, mass spectra of these samples were identical with those recorded for 13 and 14.
(3S,4R)-Ethyl 4-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsiloxy)-5-methylhexanoate (16): tert-
Butyldimethylsilyl chloride (TBSCl) (1.04 g, 6.9 mmol) was added to stirred solution of 14 (665 mg, 2.3 mmol) in
DMF (10 mL) containing imidazole (940 mg, 14 mmol) at rt. After 24 h, the reaction mixture was diluted with
Et2O (120 mL), and the organic layer was washed successively with 3% aqueous HCl (2 x 30 mL), saturated
aqueous NaHCO3 (2 x 30 mL) and brine (2 x 30 mL), then dried over Na2SO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc, 10:1→5:1) to give 16
(779 mg, 84%) as a colorless oil. [α]D25 +3.0° (c 1.01, CHCl3); IR (neat): 3389, 2961, 2361, 2340, 1559, 1507, 1474,
1
1175, 1084, 774, 434 cm−1; H NMR (400 MHz, CDCl3): δ 0.04 (3H, s), 0,09 (3H, s), 0.87–0.88 (12H, m), 0.92
(3H, d, J = 6.8 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.43 (9H, s), 1.93–1.99 (1H, m), 2.44 (1H, A part of ABX, J = 6.3,
15.6 Hz), 2.53 (1H, B part of ABX, J = 5.4, 15.6 Hz), 3.47–3.53 (1H, m), 4.07–4.22 (3H, m), 4.46 (1H, br d, J =
10.7 Hz); 13C NMR (100 MHz, CDCl3): δ −4.9, −4.7, 14.1, 16.8, 17.9, 20.5, 25.7 (3C), 27.9, 28.4 (3C), 40.0, 59.5,
60.5, 70.1, 78.9, 155.9, 171.8; HRMS (EI) calcd for C20H41NO5Si (M+), 403.2754, found 403.2750.
(3S,4R)-Allyl 4-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsiloxy)-5-methylhexanoate (18): 1 M NaOH
(30.0 mL, 30 mmol) was added dropwise to a stirred solution of 16 (2.42 g, 6.0 mmol) in EtOH (60 mL) at rt. After
6 h, the reaction was diluted with 10% aqueous HCl (50 mL) at 0°C, and the resulting mixture was extracted with
EtOAc (3 x 60 mL). The combined extracts were washed with brine (2 x 40 mL), then dried over Na2SO4.

HETEROCYCLES, Vol. 76, No. 1, 2008
283
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
(hexane/EtOAc, 10:1→2:1) to give 17 (1.85 g, 82%) as a white amorphous solid.
Allyl bromide (0.72 mL, 8.6 mmol) was added to a stirred solution of 17 (1.85 g, 4.9 mmol) in DMF (50 mL)
containing K2CO3 (2.06 g, 15 mmol) at rt. After 6 h, the reaction was diluted with water (20 mL) at rt, and the
resulting mixture was extracted with Et2O (4 x 40 mL). The combined extracts were washed successively with 3%
aqueous HCl (2 x 30 mL), saturated aqueous NaHCO3 (2 x 30 mL) and brine (2 x 30 mL), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
25
(hexane/EtOAc, 5:1) to give 18 (1.86 g, 91%) as a pale yellow oil. [α]D +4.1° (c 1.03, CHCl3); IR (neat): 3370,
1
2931, 1720, 1703, 1501, 1255, 1083, 990, 777 cm−1; H NMR (400 MHz, CDCl3): δ 0.04 (3H, s), 0.10 (3H, s),
0.87–0.88 (12H, m), 0.93 (3H, d, J = 6.8 Hz), 1.43 (9H, s), 1.91–2.00 (1H, m), 2.48 (1H, dd, J = 6.8, 15.6 Hz), 2.57
(1H, dd, J = 5.8, 15.6 Hz), 3.51 (1H, ddd, J = 4.4, 6.3, 10.7 Hz), 4.21 (1H, dd, J = 6.3, 12.2 Hz), 4.44 (1H, d, J =
10.1 Hz), 4.56 (1H, A part of ABX, J = 1.5, 1.5, 5.9, 13.1 Hz) 4.60 (1H, B part of ABX, J = 1.0, 1.5, 5.9, 13.1 Hz),
5.24 (1H, ddd, J = 1.5, 2.9, 10.7 Hz), 5.33 (1H, ddd, J = 1.5, 2.9, 17.1 Hz), 5.88–5.97 (1H, m); 13C NMR (100 MHz,
CDCl3): δ −4.9, −4.7, 16.7, 17.9, 20.5, 25.7 (3C), 27.9, 28.4 (3C), 40.0, 59.5, 65.3, 70.1, 79.0, 118.5, 132.0, 155.9,
171.5; HRMS (EI) calcd for C21H41NO5Si (M+), 415.2754, found 415. 2758.
(3S,4R)-Allyl 4-[(S)-2-(tert-butoxycarbonylamino)-3-(tritylthio)propanamido]-3-(tert-butyldimethylsiloxy)-5-
methylhexanoate (20): Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.87 mL, 4.8 mmol) was added to a
stirred solution of 18 (260 mg, 0.63 mmol) in CH2Cl2 (10 mL) in the presence of 2,6-lutidine (0.70 mL, 6.0 mmol)
at rt. After 30 min, MeOH (2.0 mL) was added to the reaction mixture at 0°C. After stirring at rt for 3 h, the
reaction mixture was concentrated in vacuo to afford 19 (178 mg, 90%) as a colorless oil. This material was
immediately used for the next reaction due to its instability (prone to form a γ-lactam ring).
N,N-Diisopropylethylamine (0.25 mL, 1.5 mmol) was added dropwise to a stirred solution of the crude amine 19
(178 mg, 0.57 mmol) and N-Boc-S-trityl-L-cysteine (9)12 (314 mg, 0.68 mmol) in MeCN (10 mL) containing
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (382 mg, 0.73 mmol) at rt under
argon. After 3 h, the mixture was diluted with Et2O (80 mL), and the organic layer was washed successively with
3% aqueous HCl (2 x 30 mL), saturated aqueous NaHCO3 (2 x 30 mL) and brine (2 x 30 mL), then dried over
Na2SO4. Concentration of the solvent in vacuo to afford a residue, which was purified by column chromatography
25
(hexane/EtOAc, 1:1) to give 20 (378 mg, 88%) as a colorless oil. [α]D +3.5° (c 1.03, CHCl3); IR (neat): 3325,
1
2960, 2856, 1735, 1690, 1522, 1171, 1094, 777 cm−1; H NMR (400 MHz, CDCl3): δ 0.01 (3H, s), 0.06 (3H, s),
0.79–0.85 (15H, m), 1.77 (9H, s), 1.94–2.01 (1H, m), 2.42 (1H, dd, J = 6.8, 15.6 Hz), 2.51–2.56 (2H, m), 2.71 (1H,
dd, J = 7.3, 13.2 Hz), 3.73–3.83 (2H, m), 3.80–3.86 (1H, m), 4.11–4.16 (1H, m), 4.46–4.56 (2H, m), 4.71 (1H, br d,
J = 6.8 Hz), 5.21 (1H, dd, J = 1.0, 10.7 Hz), 5.29 (1H, dd, J = 1.5, 16.1 Hz), 5.82–5.92 (1H, m), 6.08 (1H, br d, J =
13
9.8 Hz), 7.19–7.43 (15H, m); C NMR (100 MHz, CDCl3): δ −4.8, −4.6, 16.5, 17.9, 20.4, 25.7 (3C), 27.7, 28.2
(3C), 33.0, 39.9, 53.7, 57.9, 65.3, 67.2, 69.8, 80.2, 118.4, 126.8 (3C), 128.0 (6C), 129.6 (6C), 132.0, 144.5 (3C),
155.5, 170.6, 171.4; HRMS (EI) calcd for C43H61N2O6SSi (M++1), 761.4019, found 761.4037.
(3S,4R)-Allyl 4-[(S)-2-amino-3-(tritylthio)propanamido]-3-(tert-butyldimethylsiloxy)-5-methylhexanoate (5):
Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.20 mL, 6.6 mmol) was added dropwise to a stirred solution

284
HETEROCYCLES, Vol. 76, No. 1, 2008
of 20 (630 mg, 0.83 mmol) in CH2Cl2 (18 mL) containing 2,6-lutidine (0.96 mL, 8.3 mmol) at rt. After 1 h, MeOH
(2.0 mL) was added to the reaction mixture at 0°C. After 1 h, the mixture was concentrated in vacuo to afford a
residue, which was purified by column chromatography (hexane/EtOAc, 5:1) to give 5 (542 mg, 99%) as a white
25
amorphous solid. [α]D +1.6° (c 1.01, CHCl3); IR (neat): 3365, 2929, 2856, 1753, 1673, 1509, 1255, 1174, 1092,
1
777, 701 cm−1; H NMR (400 MHz, CDCl3): δ 0.02 (3H, s), 0.06 (3H, s), 0.08–0.88 (15H, m), 1.22 (2H, br s),
1.94–2.02 (1H, m), 2.43 (1H, dd, J = 6.3, 16.1 Hz), 2.50–2.57 (2H, m), 2.73 (1H, dd, J = 3.4, 12.7), 3.07 (1H, dd, J
= 3.4, 8.3 Hz), 3.77 (1H, ddd, J = 4.4, 6.3, 10.7 Hz), 4.16 (1H, dt, J = 5.9, 6.3 Hz), 4.52 (2H, d, J = 5.9 Hz), 5.22
(1H, dd, J = 1.0, 9.3 Hz), 5.29 (1H, dd, J = 1.0, 16.8 Hz), 5.83–5.93 (1H, m), 7.17–7.45 (16H, m); 13C NMR (100
MHz, CDCl3): δ−4.9, −4.6, 16.6, 17.9, 20.6, 25.7 (3C), 27.6, 37.3, 40.2, 53.9, 57.7, 65.1, 66.9, 69.9, 118.4, 126.7
(3C), 127.9 (6C), 129.5 (6C), 131.9, 144.6 (3C), 171.3, 172.8; HRMS (FAB+) calcd for C38H53N2O4SSi (M++1),
661.3466, found 661.3478.
5-[3-(4-Methoxybenzyloxy)propylthio]-1-phenyl-1H-tetrazole (22): Diethyl azodicarboxylate (DEAD) in
toluene (2.2 M in solution, 23.4 mL, 52 mmol) was added dropwise to a stirred solution of
3-(4-methoxybenzyloxy)propan-1-ol (21)16 (9.18 g, 47 mmol) in THF (500 mL) containing Ph3P (13.5 g, 52 mmol)
and 1-phenyl-1H-tetrazol-5-thiol (9.17 g, 52 mmol) at rt under argon. After 5 h, the reaction mixture was
concentrated in vacuo to afford a residue, which was purified by column chromatography (hexane/EtOAc, 2:1) to
give 22 (15.8 g, 95%) as a white amorphous solid. IR (KBr): 2857, 2546, 2347, 1596, 761, 694, 636 cm−1; 1H NMR
(400 MHz, CDCl3): δ 2.13 (2H, ddd, J = 5.8, 6.9, 13.2 Hz), 3.49 (2H, t, J = 6.9 Hz), 3.58 (2H, t, J = 5.8 Hz), 3.79
13
(3H, s), 4.43 (2H, s), 6.85–6.88 (2H, m), 7.23–7.26 (2H, m), 7.52–7.59 (5H, m); C NMR (100 MHz, CDCl3): δ
29.2, 30.3, 55.2, 67.6, 72.6, 113.8, 123.8, 129.3 (3C), 129.7 (3C), 130.0, 130.2, 133.7, 154.3, 159.2; HRMS (EI)
calcd for C18H20N4O2S (M+), 356.1307, found 356.1320.
1-Phenyl-5-[3-(tritylthio)propylsulfonyl]-1H-tetrazole (10): Hexaammonium heptamolybdate tetrahydrate
[Mo7O24(NH4)6·4H2O] (1.08 g, 0.87 mmol) in 30% aqueous H2O2 (9.38 mL, 83 mmol)] was added dropwise to a
stirred solution of 22 (3.10 g, 8.7 mmol) in EtOH (90 mL) at 0°C, and the mixture was allowed to warm up to rt.
After 18 h, the reaction was diluted with water (20 mL) at rt, and the resulting mixture was extracted with EtOAc
(3 x 80 mL). The organic layer was washed with saturated aqueous Na2S2O3 (3 x 40 mL) and brine (2 x 40 mL),
then dried over MgSO4. Concentration of the solvent in vacuo afforded a residue, which was purified by short-pass
column chromatography (hexane/EtOAc, 3:1) to give 23 (3.30 g), which was used for the next reaction without
further purification.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (3.86 g, 17 mmol) was added in small portions to a stirred
solution of 23 (3.30 g, 8.5 mmol) in CH2Cl2/H2O 9:1 (150 mL) at rt. After 3 h, the mixture was diluted with CH2Cl2
(50 mL), and the organic layer was washed with saturated aqueous NaHCO3 (2 x 40 mL) and brine (2 x 40 mL),
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc, 2:1) to give 24 (2.33 g, 94%, two steps) as a colorless oil.
Diethyl azodicarboxylate (DEAD) in toluene (2.2 M in solution, 0.68 mL, 1.5 mmol) was added dropwise to a
stirred solution of 24 (200 mg, 0.75 mmol) in CH2Cl2 (10 mL) containing Ph3P (391 mg, 1.5 mmol) and
triphenylmethyl thiol (412 mg, 1.5 mmol) at rt under argon. The mixture was heated at reflux for 7 h under argon.

HETEROCYCLES, Vol. 76, No. 1, 2008
285
After cooling, the reaction mixture was concentrated in vacuo to afford a residue, which was purified by column
chromatography (hexane/EtOAc, 6:1) to give 10 (377 mg, 96%) as a white solid. Recrystallization from
hexane/AcOEt afforded white needles, mp 117–119ºC. IR (KBr): 2360, 1593, 1339, 761, 744, 700 cm−1; 1H NMR
(400 MHz, CDCl3): δ 1.82–1.89 (2H, m), 2.39 (2H, t, J = 6.8 Hz), 3.56 (2H, dd, J = 5.4, 10.2 Hz), 7.18–7.65 (20H,
13
m); C NMR (100 MHz, CDCl3): δ 21.5, 30.0, 54.9, 67.2, 125.1, 126.9 (3C), 128.0 (6C), 129.5 (6C), 129.7 (3C),
131.4, 132.9, 144.4 (3C), 153.3; HRMS (FAB+) calcd for C29H27N4O2S2 (M++1), 527.1575, found 527.1578.
(2S,4S)-2-(4-Methoxyphenyl)-4-[(E/Z)-4-(tritylthio)but-1-enyl]-1,3-dioxane (25): Lithium bis(trimethylsilyl)-
amide in THF (1.0 M solution, 8.90 mL, 8.9 mmol) was added dropwise to a stirred solution of 10 (4.26 g, 8.1
mmol) and (4S)-2-(4-methoxyphenyl)-1,3-dioxane-4-carbaldehyde (11)14 (2.68 g, 12 mmol) in DMF (200 mL) at
−60°C under argon. After 2 h, the mixture was gradually warmed up to 0°C over 2 h. The reaction was quenched
with saturated aqueous NH4Cl (20 mL) at 0°C. The resulting mixture was extracted with Et2O (3 x 150 mL), and
the combined extracts were washed with brine (2 x 100 mL), then dried over Na2SO4. Concentration of the solvent
in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc, 6:1) to give 25 (2.79 g,
66%) as a mixture of olefinic isomers (E/Z = 5:1) as a colorless oil. IR (neat): 2955, 2849, 2025, 1954, 1615, 1372,
1302, 747, 702 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.51 (1H, t, J = 12.1 Hz), 1.81–1.91 (1H, m), 2.09 (2H, t, J =
6.8 Hz), 2.19 (2H, d, J = 6.8 Hz), 3.78 (3H, s), 3.93 (1H, dt, J = 2.4, 12.1 Hz), 4.21–4.26 (2H, m), 5.45–5.50 (1H,
13
m), 5.61 (1H, t, J = 6.8 Hz), 6.85 (1H, dd, J = 1.9, 4.8 Hz), 7.17–7.44 (20H, m); C NMR (100 MHz, CDCl3): δ
31.3, 55.3, 66.9, 77.3, 101.2, 113.5, 126.5 (3C), 127.4 (3C), 127.8 (7C), 129.6 (9C), 130.3, 131.1, 144.9 (3C),
159.9; HRMS (FAB+) calcd for C34H35O3S (M++1), 523.2306, found 523.2327.
(S,E)-3-(4-Methoxybenzyloxy)-7-(tritylthio)hept-4-en-1-ol (26a) and its (S,Z)-isomer (26b): Diiso-
butylaluminum hydride (DIBAL) in toluene (1.0 M solution, 6.74 mL, 6.7 mmol) was added dropwise to a stirred
solution of 25 (E/Z = 5:1) (1.53 g, 2.9 mmol) in toluene (40 mL) at 0°C under argon. After 5 h, the reaction mixture
was quenched with 10% aqueous NaOH (10 mL) at 0°C. The resulting mixture was extracted with Et2O (3 x 60
mL), and the combined extracts were washed with brine (3 x 40 mL), then dried over Na2SO4. Concentration of the
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc, 3:1) to give
26a (921 mg, 60%, more polar) and 26b (184 mg, 12%, less polar).
25
1
26a: colorless oil, [α]D −33.1° (c 1.02, CHCl3); IR (neat): 3418, 1666, 1612, 1034, 972, 767, 743, 700 cm−1; H
NMR (400 MHz, CDCl3): δ 1.66–1.74 (1H, m), 1.78–1.86 (1H, m), 2.14 (2H, t, J = 6.8 Hz), 2.22 (2H, d, J = 6.8
Hz), 3.66–3.76 (2H, m), 3.79 (3H, s), 3.89 (1H, dt, J = 4.4, 8.2 Hz), 4.23 (1H, d, J = 11.2 Hz), 4.51 (1H, d, J = 11.2
Hz), 5.33 (1H, dd, J = 8.2, 15.5 Hz), 5.53 (1H, dd, J = 6.8, 13.6 Hz), 6.84 (1H, dd, J = 1.9, 6.8 Hz), 7.18–7.43 (19H,
13
m); C NMR (100 MHz, CDCl3): δ 31.2, 31.6, 37.9, 55.3, 60.8, 66.5, 69.6, 79.1, 113.8, 126.6 (3C), 127.8 (6C),
129.4 (3C), 129.6 (6C), 130.3, 131.5, 132.2, 144.9 (3C), 159.1; HRMS (FAB+) calcd for C34H35O3S (M+−1),
523.2307, found 523.2298.
26b: colorless oil, [α]D25 −10.2° (c 0.94, CHCl3); IR (neat) : 3397, 2865, 1716, 1612, 1443, 1034, 743, 700 cm−1; 1H
NMR (400 MHz, CDCl3): δ 1.57–1.64 (1H, m), 1.76–1.85 (1H, m), 2.04–2.25 (4H, m), 2.46 (1H, d, J = 4.4 Hz),
3.64–3.76 (2H, m), 3.78 (3H, s), 4.17 (1H, d, J = 11.2 Hz), 4.23 (1H, d, J = 4.4 Hz), 4.45 (1H, d, J = 11.2 Hz), 5.37
13
(1H, dd, J = 9.2, 10.6 Hz), 5.46–5.52 (1H, m), 6.84 (2H, dd, J = 1.9, 6.3 Hz), 7.15–7.46 (17H, m); C NMR (100

286
HETEROCYCLES, Vol. 76, No. 1, 2008
MHz, CDCl3): δ 26.9, 31.8, 37.7, 55.2, 60.8, 66.6, 69.8, 73.6, 113.8 (2C), 126.6 (3C), 127.8 (6C), 129.3 (2C),
129.4 (3C), 129.5 (6C), 130.4, 131.2, 131.6, 144.8 (3C), 159.2; HRMS (FAB+) calcd for C34H35O3S (M+−1),
523.2307, found 523.2298.
(S,E)-3-(4-Methoxybenzyloxy)-7-(tritylthio)hept-4-enoic acid (28): Dess-Martin periodinane (1.07 g, 2.5 mmol)
was added in small portions to a stirred solution of 26a (660 mg, 1.3 mmol) in CH2Cl2 (60 mL) containing NaHCO3
(1.06 g, 13 mmol) at rt. After 1 h, the reaction was quenched with saturated aqueous Na2S2O3 (10 mL) at 0°C, and
the resulting mixture was extracted with CHCl3 (3 x 50 mL). The combined extracts were washed with brine (2 x
30 mL), then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/EtOAc, 3:1) to give 27 (578 mg, 88%) as a colorless oil.
A solution of NaClO2 (80% purity, 635 mg, 5.6 mmol) and NaH2PO4·2H2O (876 mg, 5.6 mmol) in water (10 mL)
were added dropwise to a stirred solution of 27 (578 mg, 1.1 mmol) in DMSO (40 mL) at 0°C, and stirring was
continued for 1 h at rt. The reaction was quenched with saturated aqueous Na2S2O3 (20 mL) at 0°C. The resulting
mixture was extracted with Et2O (3 x 100 mL), and the combined extracts were washed with brine (2 x 60 mL),
then dried over Na2SO4. Concentration of the solvent in vacuo afforded 28 (448 mg, 75%), which was used for the
25
next reaction without further purification. [α]D −17.8° (c 1.25, CHCl3); IR (neat): 2835, 1738, 1713, 1668, 1644,
1594, 743, 700, 676 cm−1; 1H NMR (400 MHz, CDCl3): δ 2.12–2.19 (2H, m), 2.21–2.25 (2H, m), 2.48 (1H, dd, J =
4.8, 15.5 Hz), 2.61 (1H, dd, J = 8.2, 15.5 Hz), 3.78 (3H, s), 4.12 (1H, dt, J = 4.8, 8.2 Hz), 4.29 (1H, d, J = 11.2 Hz),
4.52 (1H, d, J = 11.2 Hz), 5.31 (1H, dd, J = 8.2, 15.0 Hz), 5.56–5.63 (1H, m), 6.82 (2H, d, J = 8.8 Hz), 7.13–7.45
13
(19H, m); C NMR (100 MHz, CDCl3): δ 31.2, 31.4, 40.9, 55.2, 66.6, 69.8, 75.5, 77.2, 113.8 (2C), 126.6 (3C),
127.8, 127.9 (8C), 129.4, 129.5 (3C), 129.8, 129.9, 133.3, 144.9 (3C), 159.2, 175.9; HRMS (FAB+) calcd for
C34H35O4S (M++1), 539.2256, found 539.2273.
(R)-Methyl 2-[(S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio)hept-4-enamido]propanoate (29): N,N-Diisopropyl-
ethylamine (1.12 mL, 6.6 mmol) was added dropwise to a stirred solution of 28 (507 mg, 0.94 mmol) in MeCN (20
mL) and D-alanine methyl ester (12) (261 mg, 1.9 mmol) containing (benzotriazol-1-yloxy)-
tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (981 mg, 1.9 mmol) at rt under argon. After 2 h, the
reaction mixture was diluted with EtOAc (120 mL). The organic layer was washed successively with 10% aqueous
HCl (2 x 30 mL), saturated aqueous NaHCO3 (2 x 30 mL) and brine (2 x 20 mL), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
25
(hexane/EtOAc, 1:1) to give 29 (528 mg, 90%) as a colorless oil. [α]D −7.9° (c 1.00, CHCl3); IR (neat): 3318,
2867, 2836, 1745, 1659, 1513, 1247, 973, 744, 700 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.30 (3H, d, J = 7.3 Hz),
2.09–2.17 (2H, m), 2.22 (2H, t, J = 6.7 Hz), 2.35 (1H, dd, J = 3.8, 15.3 Hz), 2.48 (1H, dd, J = 8.6, 15.3 Hz), 3.72
(3H, s), 3.79 (3H, s), 4.08 (1H, dt, J = 3.3, 8.2 Hz), 4.30 (1H, d, J = 10.6 Hz), 4.49–4.59 (2H, m), 5.30 (1H, q, J =
7.7 Hz), 5.54–5.61 (1H, m), 6.82 (2H, d, J = 8.6 Hz), 6.89 (1H, d, J = 7.7 Hz), 7.19–7.42 (17H, m); 13C NMR (100
MHz, CDCl3): δ 18.2, 31.2, 31.4, 42.7, 47.8, 52.2, 55.2, 66.5, 69.9, 76.5, 113.8, 126.6 (6C), 127.8 (6C), 129.5,
129.6 (4C), 129.9, 130.3, 132.8, 144.8 (4C), 159.2, 170.2, 173.3; HRMS (FAB+) calcd for C38H42NO5S (M++1),
624.2783, found 624.2776.

HETEROCYCLES, Vol. 76, No. 1, 2008
287
(R)-2-[(S,E)-3-(4-Methoxybenzyloxy)-7-(tritylthio)hept-4-enamido]propanoic acid (6): 1 M LiOH (3.00 mL,
3.0 mmol) was added dropwise to a stirred solution of 29 (470 mg, 0.75 mmol) in MeOH (15 mL) at rt. After 3 h,
10% aqueous HCl was added to the mixture at 0°C until pH was 6. The resulting mixture was extracted with
EtOAc (3 x 30 mL), and the combined extracts were washed with saturated aqueous NaHCO3 (2 x 30 mL) and
brine (2 x 30 mL), then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was
purified by column chromatography (CHCl3/MeOH, 9:1) to give 6 (450 mg, 98%) as a white amorphous solid.
[α]D25 −1.8° (c 1.00, CHCl3); IR (KBr): 2931, 2868, 1730, 1632, 1614, 744, 700 cm−1; 1H NMR (400 MHz, CDCl3):
δ 1.32 (3H, d, J = 6.8 Hz), 2.10–2.15 (2H, m), 2.21 (2H, d, J = 6.8 Hz), 2.40 (1H, dd, J = 3.4, 15.6 Hz), 2.49 (1H,
dd, J = 8.8, 15.6 Hz), 3.78 (3H, s), 4.08 (1H, dt, J = 3.4, 8.2 Hz), 4.25 (1H, d, J = 10.7 Hz), 4.44 (1H, t, J = 6.8 Hz),
4.49 (1H, d, J = 11.2 Hz), 5.29 (1H, dd, J = 8.2, 15.6 Hz), 5.59 (1H, dd, J = 6.8, 15.6 Hz), 6.82 (2H, d, J = 8.2 Hz),
13
7.00 (1H, d, J = 6.8 Hz), 7.17–7.42 (17H, m); C NMR (100 MHz, CDCl3): δ 18.1, 31.5, 31.7, 42.6, 48.5, 55.5,
66.9, 70.3, 77.6, 114.1, 126.9 (3C), 128.1 (6C), 129.8 (6C), 130.0 (3C), 130.4 (2C), 133.3, 145.1 (3C), 159.5, 171.7,
176.4; HRMS (FAB+) calcd for C37H40NO5S (M++1), 610.2627, found 610.2627.
(3S,4R)-Allyl 3-(tert-butyldimethylsiloxy)-4-[(S)-2-[(R)-2-[(S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio)hept-
4-enoylamino]propionylamino]-5-methylhexanoate (30): N,N-Diisopropylethylamine (37 µL, 0.22 mmol) was
added dropwise to a stirred solution of 5 (56.0 mg, 85 µmol) and 6 (51.7 mg, 85 µmol) in CH2Cl2 (4.0 mL)
containing O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) (41.9 mg,
0.11 mmol) and 1-hydroxy-7-azabenzotriazol (HOAt) (15.0 mg, 0.11 mmol) at −30°C under argon. After 2 h, the
reaction mixture was diluted with CHCl3 (60 mL). The organic layer was washed successively with 10% aqueous
HCl (2 x 20 mL), saturated aqueous NaHCO3 (2 x 20 mL) and brine (2 x 20 mL), then dried over Na2SO4.
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
25
(hexane/EtOAc, 1:1) to give 30 (99.8 mg, 94%) as a colorless viscous liquid. [α]D +14.8° (c 1.03, CHCl3); IR
(neat): 3283, 3059, 2927, 1736, 1632, 1513, 1247, 1035, 988, 777 cm−1; 1H NMR (400 MHz, CDCl3): δ 0.01 (3H,
s), 0.06 (3H, s), 0.79–0.84 (15H, m), 1.16 (3H, d, J = 6.8 Hz), 1.89–1.98 (1H, m), 2.06–2.13 (2H, m), 2.19–2.24
(2H, m), 2.29–2.34 (1H, dd, J = 3.4, 13.9 Hz), 2.34–2.54 (4H, m), 2.77 (1H, dd, J = 8.2, 13.0 Hz), 3.79 (3H, s),
3.90 (1H, q, J = 8.2 Hz), 4.01 (1H, dt, J = 3.4, 8.2 Hz), 4.13–4.18 (2H, m), 4.28 (1H, t, J = 10.6 Hz), 4.47–4.55 (2H,
m), 5.19–5.32 (3H, m), 5.41 (1H, dt, J = 6.8, 15.5 Hz), 5.83–5.91 (1H, m), 6.10 (1H, d, J = 10.6 Hz), 6.54 (1H, d, J
= 7.7 Hz), 6.82 (1H, d, J = 8.2 Hz), 6.95 (1H, d, J = 6.8 Hz), 7.14–7.44 (30H, m); 13C NMR (100 MHz, CDCl3): δ
−4.7, −4.6, 16.7, 17.2, 17.9, 20.4, 25.7, 27.8, 31.2, 31.4, 32.8, 39.6, 42.4 (4C), 48.7, 52.3, 55.3, 58.3, 65.2, 66.5,
67.0, 69.5, 70.0, 76.4, 77.2, 113.9, 118.4, 126.6 (3C), 126.8 (3C), 127.8 (6C), 128.0 (8C), 129.4 (6C), 129.5 (3C),
129.7 (4C), 129.8, 130.0, 132.0, 132.9, 144.3 (3C), 144.8, 159.3, 169.8, 171.1, 171.6, 172.2; HRMS (FAB+) calcd
for C75H89N3O8S2SiNa (M++Na), 1274.5757, found 1274.5737.
(3S,4R)-3-(tert-Butyldimethylsiloxy)-4-[(S)-2-[(R)-2-[(S,E)-3-hydroxy-7-(tritylthio)hept-4-enoylamino]propi-
onylamino]-5-methylhexanoic acid (4): 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (27.9 mg, 0.12
mmol) was added in small portions to a stirred solution of 30 (76.9 mg, 61 µmol) in CH2Cl2/H2O 9:1 (1.5 mL) at rt.
After 3 h, the mixture was diluted with CHCl3 (30 mL), and the organic layer was washed with saturated aqueous
NaHCO3 (2 x 10 mL) and brine (2 x 10 mL), then dried over Na2SO4. Concentration of the solvent in vacuo

288
HETEROCYCLES, Vol. 76, No. 1, 2008
afforded a residue, which was purified by column chromatography (hexane/EtOAc, 3:2) to give 31 (61.9 mg, 89%)
as a colorless viscous liquid.
Morpholine (9.5 µL, 0.11 mmol) was added dropwise to a stirred solution of 31 (61.9 mg, 55 µmol) in dry THF
(3.0 mL) containing Pd(PPh3)4 (6.3 mg, 54 µmol) at rt under argon. After 30 min, the reaction mixture diluted with
EtOAc (70 mL), and the organic layer was washed successively with 10% aqueous HCl (2 x 15 mL) and brine (2 x
15 mL), then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by
column chromatography (CHCl3/MeOH, 9:1) to give 4 (58.4 mg, 99%) as a white amorphous solid. [α]D25 –1.6° (c
1.00, CHCl3); IR (KBr): 3287, 2928, 2365, 1738, 1634, 1536, 1254, 1033, 971 cm−1; 1H NMR (400 MHz, CDCl3):
δ 0.04 (3H, s), 0.05 (3H, s), 0.76–0.88 (15H, m), 1.28 (3H, d, J = 6.8 Hz), 1.92–2.08 (3H, m), 2.17–2.56 (7H, m),
2.72 (1H, dd, J = 7.3, 12.2 Hz), 3.79–3.82 (1H, m), 4.08–4.15 (2H, m), 4.35–4.41 (2H, m), 5.30 (1H, dd, J = 5.9,
15.1 Hz), 5.42 (1H, dt, J = 6.3, 15.1), 6.40 (1H, d, J = 10.2 Hz), 6.56 (1H, d, J = 6.8 Hz), 7.16–7.42 (30H, m); 13C
NMR (100 MHz, CDCl3):δ −4.8, −4.5, 16.4, 17.7, 17.8, 20.3, 25.7, 27.7, 31.2, 31.3, 33.1, 43.9 (4C), 49.4, 53.0,
59.0, 66.6, 67.0, 69.0, 77.2, 126.6 (3C), 126.8 (3C), 126.7, 126.8, 127.8 (6C), 127.9, 128.0 (8C), 129.4 (6C), 129.5
(3C), 129.8, 132.3, 144.3 (3C), 144.8, 170.3, 171.7, 172.6, 174.4; HRMS (FAB+) calcd for C64H77N3O7S2SiNa
(M++Na), 1114.4869, found 1114.4851.
(2S,6R,9S,12R,13S)-13-(tert-Butyldimethylsiloxy)-12-isopropyl-6-methyl-2-[(E)-4-(tritylthio)but-1-enyl]-9-
(tritylthiomethyl)-1-oxa-5,8,11-triazacyclopentadecane-4,7,10,15-tetraone (32): A solution of 4 (36.0 mg, 33
µmol) in CH2Cl2 (33 mL, 1.0 mM concentration) was added very slowly to a stirred solution of
2-methyl-6-nitrobenzoic anhydride (MNBA) (14.9 mg, 43 µmol) in CH2Cl2 (4.0 mL) containing
4-(dimethylamino)pyridine (DMAP) (12.2 mg, 0.10 mmol) at toom temperature over 14 hours. After 1 h, the
mixture was diluted with CH2Cl2 (40 mL), and the organic layer was washed with saturated aqueous NaHCO3 (2 x
10 mL), water (2 x 10 mL) and brine (2 x 10 mL), then dried over Na2SO4. Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography (CHCl3/MeOH, 20:1) to give 32 (31.8 mg, 89%)
25
as a white amorphous solid. [α]D −11.4° (c 1.00, CHCl3); IR (KBr): 3296, 2957, 1650, 1595, 1537, 1258, 1034,
970 cm−1; 1H NMR (400 MHz, CDCl3): δ −0.05 (3H, s), 0.02 (3H, s), 0.75–0.86 (15H, m), 1.34 (3H, d, J = 6.8 Hz),
2.00–2.08 (3H, m), 2.15 (2H, t, J = 6.8 Hz), 2.37–2.44 (4H, m), 2.64 (1H, d, J = 7.8 Hz), 3.30–3.35 (2H, m), 3.57
(1H, t, J = 8.8 Hz), 4.09–4.13 (2H, m), 5.29 (1H, dd, J = 6.8, 15.1 Hz), 5.52–5.58 (1H, m), 5.61 (1H, dt, J = 6.3,
15.1 Hz), 6.39 (1H, br s), 6.77 (1H, br s), 7.70 (1H, d, J = 9.8 Hz), 7.16–7.42 (30H, m); 13C NMR (100 MHz,
CDCl3): δ−4.9, −4.1, 15.5, 16.5, 17.9, 20.6, 25.7, 27.4, 31.0, 31.3, 33.9, 41.9, 42.2 (4C), 49.9, 56.8, 59.2, 66.6, 66.8,
68.6, 71.2, 77.2, 126.6 (3C), 126.8 (2C), 127.9, 127.8 (6C), 128.0 (10C), 129.5 (9C), 132.9, 144.5 (3C), 144.8,
169.9, 170.1, 170.2, 172.3; HRMS (FAB+) calcd for C64H75N3O6S2SiNa (M++Na), 1096.4763, found 1096.4771.
(1S,5S,6R,9S,20R,E)-5-(tert-Butyldimethylsilyloxy)-6-isopropyl-20-methyl-2-oxa-11,12-dithia-7,19,22-
triazabicyclo[7.7.6]docos-15-ene-3,8,18,21-tetraone (33): A solution of 32 (30.0 mg, 28 µmol) in CH2Cl2/MeOH
9:1 (16 mL) was added dropwise to a vigorously stirring solution of I2 (71.0 mg, 0.28 mmol) in CH2Cl2/MeOH 9:1
(56 mL, 0.5 mM concentration) over 10 min at rt. After 10 min, the reaction was quenched with 10% aqueous
Na2S2O3 (20 mL) at rt. The resulting mixture was diluted with CH2Cl2 (60 mL), and the organic layer was washed
with saturated aqueous NaHCO3 (2 x 20 mL) and brine (2 x 20 mL), then dried over Na2SO4. Concentration of the

HETEROCYCLES, Vol. 76, No. 1, 2008
289
solvent in vacuo afforded a residue, which was purified by column chromatography (CHCl3/MeOH, 20:1) to give
25
33 (13.2 mg, 80%) as a white amorphous solid. [α]D −1.8° (c 1.02, CHCl3); IR (KBr): 3334, 2930, 1746, 1667,
1
1538, 1257, 1034, 973 cm−1; H NMR (400 MHz, CDCl3): δ 0.10 (3H, s), 0.16 (3H, s), 0.88 (3H, d, J = 7.3 Hz),
0.92 (9H, s), 0.96 (3H, d, J = 7.3 Hz), 1.49 (3H, d, J = 7.3 Hz), 2.16–2.21 (1H, m), 2.50–2.61 (3H, m), 2.62-2.72
(3H, m), 2.95–3.12 (4H, m), 3.12 (2H, dd, J = 6.8, 13.1 Hz), 3.49–3.60 (1H, br m), 4.24–4.30 (1H, m), 4.82 (1H, dt,
J = 3.4, 9.8 Hz), 4.96–5.00 (1H, m), 5.68–5.72 (2H, m), 6.19 (1H, s), 6.34 (1H,br s), 6.73 (1H, d, J = 9.8 Hz), 7.22
13
(1H, d, J = 6.8 Hz); C NMR (100 MHz, CDCl3): δ −4.9, −4.3, 16.8, 17.1, 17.9, 21.0, 25.7 (2C), 29.1 (2C), 34.3,
40.0, 40.6, 41.0, 52.1, 53.7, 62.8, 67.4 (2C), 68.9, 77.2, 129.2, 132.6, 168.9, 170.9, 171.2; HRMS (FAB+) calcd for
C26H46N3O6S2Si (M++H), 588.2597, found 588.2609.
Spiruchostatin A (1): HF·pyridine (0.20 mL) was added to a stirring solution of 33 (13.0 mg, 22 µmol) in pyridine
(1.0 mL) at rt. After 14 h, the reaction mixture was diluted with EtOAc (40 mL), and the organic layer was washed
successively with 3% aqueous HCl (3 x 10 mL), saturated aqueous NaHCO3 (2 x 10 mL) and brine (2 x 10 mL),
then dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by column
chromatography (CHCl3/MeOH, 10:1) to give 1 (spiruchostatin A) (9.6 mg, 92%) as a white amorphous solid.
25
[α]D −69.9° (c 0.14, MeOH) {lit.1 [α]D −63.6° (c 0.14, MeOH)}; IR (neat): 3375, 2933, 1633, 1542, 1160, 755
cm−1; 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, d, J = 6.8 Hz), 1.03 (3H, d, J = 6.8 Hz), 1.51 (3H, d, J = 7.3 Hz),
2.38–2.47 (2H, m), 2.56 (1H, d, J = 13.2 Hz), 2.70–2.77 (5H, m), 3.15 (1H, d, J = 7.3, 13.2 Hz), 4.25 (1H, dq, J =
3.9, 7.3 Hz), 4.54–4.59 (1H, m), 4.89 (1H, dt, J = 3.9, 9.3 Hz), 5.50 (1H, s), 5.65 (1H, d, J = 15.1 Hz), 5.92 (1H, s),
13
6.39 (1H, s), 6.71 (1H, d, J = 9.3 Hz), 7.40 (1H, d, J = 6.8 Hz); C NMR (100 MHz, CDCl3): δ 16.7, 19.6, 20.6,
29.6, 33.3, 39.6, 40.7, 40.9, 52.3, 54.3, 63.8, 69.3, 70.5, 77.2, 128.6, 133.6, 169.0, 170.6, 170.9, 171.9; HRMS
(FAB+) calcd for C20H32N3O6S2 (M++1), 474.1732, found 474.1750. The IR, 1H and 13C NMR, and HRMS spectrum
are essentially identical with those reported for natural spiruchostatin A.1
ACKNOWLEDGEMENTS
We are grateful to Dr. Kazuo Shin-ya, National Institute of Advanced Industrial Science and Technology, and
Professor Takayuki Doi, Tohoku University, for providing us with copies of the 1H and 13C NMR spectra of natural
and synthetic spiruchostatin A (1). We also thank Associate Professor Isamu Shiina, Tokyo University of Science,
for valuable discussions and suggestions. This work was supported by a Grant-in-Aid for Scientific Research on
Priority Area (no.17035073) and a Grant-in-Aid for High Technology Research Program from the Ministry of
Education, Culture, Sports, Science and Technology of Japan (MEXT).
REFERENCES AND NOTES
1. Y. Masuoka, A. Nagai, K. Shin-ya, K. Furihata, K. Nagai, K. Suzuki, Y. Hayakawa, and H. Seto, Tetrahedron
Lett., 2001, 42, 41.
2. S. E. Rundlett, A. A. Carmen, R. Kobayashi, S. Bavykin, B. M. Turner, and M. Grunstein, Proc. Natl. Acad.
Sci. USA, 1996, 93, 14503.
3. Recent reviews: (a) C. M. Grozinger and S. L. Schreiber, Chem. Biol., 2002, 9, 3. (b) P. A. Marks, T. Miller,

290
HETEROCYCLES, Vol. 76, No. 1, 2008
and V. M. Richon, Curr. Opin. Pharmacol., 2003, 3, 344.
4. T. A. Miller, D. J. Witter, and S. Belvedere, J. Med. Chem., 2003, 46, 5097.
5. H. Ueda, H. Nakajima, Y. Hori, T. Fujita, M. Nishimura, T. Goto, and M. Okuhara, J. Antibiot., 1994, 47, 301.
6. K. W. Li, J. Wu, W. Xing, and J. A. Simon, J. Am. Chem. Soc., 1996, 118, 7237.
7. T. J. Greshock, D. M. Johns, Y. Noguchi, and R. M. Williams, Org. Lett., 2008, 10, 613.
8. (a) A. Yurek-George, F. Habens, M. Brimmell, G. Packham, and A. Ganesan, J. Am. Chem. Soc., 2004, 126,
1030. (b) S. M. Davidson, P. A. Townsend, C. Carroll, A. Yurek-George, K. Balasubramanyam, T. K. Kundu,
A. Stephanou, G. Packham, A. Ganesan, and D. S. Latchman, Chem. BioChem., 2005, 6, 162.
9. T. Doi, Y. Iijima, K. Shin-ya, A. Ganesan, and T. Takahashi, Tetrahedron Lett., 2006, 47, 1177.
10. T. Takizawa, K. Watanabe, K. Narita, T. Oguchi, H. Abe, and T. Katoh, Chem. Commun., published on the
web, February 05, 2008 (DOI:10.1039/B718310K).
11. J.-A. Fehrentz and B. Castro, Synthesis, 1983, 676.
12. K. R. West, K. D. Bake, and S. Otto, Org. Lett., 2005, 7, 2615.
13. (a) P. R. Blakemore, W. J. Cole, P. J. Kocienski, and A. Morley, Synlett, 1998, 26. (b) P. R. Blakemore, J.
Chem. Soc., Perkin Trans. 1, 2002, 2563.
14. R. W. Hoffmann, G. Mas, and T. Brandl, Eur. J. Org. Chem., 2002, 3455.
15. (a) G. I. Poos, G. E. Arth, R. E. Beyler, and L. H. Sarett, J. Am. Chem. Soc., 1953, 75, 422. (b) R. E. Jones and
F. W. Kocher, J. Am. Chem. Soc., 1954, 76, 3682. (c) J. A. Glinski, B. S. Joshi, Q. P. Jiang, and S. W. Pelletier,
Heterocycles, 1988, 27, 185.
16. O. Barun, K. Kumar, S. Sommer, A. Langerak, T. U. Mayer, O. Müller, and H. Waldmann, Eur. J. Org. Chem.,
2005, 4773.
17. (a) O. Mitsunobu, Synthesis, 1981, 1. (b) R. Dembinski, Eur. J. Org. Chem., 2004, 2763.
18. P. J. Kocienski, A. Bell, and P. R. Blakemore, Synlett, 2000, 365.
19. (a) Y. Ito, Y. Ohnishi, T. Ogawa, and Y. Nakahara, Synlett, 1998, 1102. (b) S. Takano, M. Akiyama, S. Sato,
and K. Ogasawara, Chem. Lett., 1983, 1953.
20. (a) R. L. Amey and J. C. Martin, J. Am. Chem. Soc., 1978, 100, 300. (b) R. L. Amey and J. C. Martin, J. Am.
Chem. Soc., 1979, 101, 5294. (c) D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
21. B. S. Bal, W. E. Childers Jr, and H. W. Pinnick, Tetrahedron, 1981, 37, 2091.
22. G. Benz, in Comprehensive organic synthesis, ed. by B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol.
6, p.381.
23. (a) I. Shiina, M. Kubota, and R. Ibuka, Tetrahedron Lett., 2002, 42, 7535. (b) I. Shiina, Chem. Rev., 2007, 107,
239.
24 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, and M. Yamaguchi, Bull. Chem. Soc. Jpn., 1979, 52, 1989.
25. (a) T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron Lett., 1970, 11, 1901. (b) E. J. Corey and K. C.
Nicolaou, J. Am. Chem. Soc., 1974, 96, 5614. (c) T. Sasaki, M. Inoue, and M. Hirama, Tetrahedron Lett., 2001,
42, 5299.
26. (a) B. Kamber, A. Hartmann, K. Eisler, B. Riniker, H. Rink, P. Sieber, and W. Rittel, Helv. Chim. Acta, 1980,
63, 899. (b) S. Kato, Y. Hamada, and T. Shioiri, Tetrahedron Lett., 1986, 27, 2653.