A Concise Approach for Producing Optically Pure Carboxylic Acid Segments for the Synthesis of Bicyclic Depsipeptide Histone Deacetylase Inhibitors

Article abstract of DOI:10.1055/s-0037-1612059

Optically pure carboxylic acid segments, which are common key intermediates for the synthesis of naturally occurring bicyclic depsipeptide histone deacetylase inhibitors, have been produced efficiently. The method features the chromatographic separation of two diastereomers, which were formed by direct amide condensation of racemic (3 RS,4 E)-3-hydroxy-7-mercaptohept-4-enoic acid (rac -Hmh) with chiral amino acids. This approach offers a reliable and practical method for producing optically pure carboxylic acid segments, which can facilitate easier access to important anticancer agents derived from them.

Full text of DOI:10.1055/s-0037-1612059

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
paper
A
en
K. Narita et al.
Paper
Synthesis
A Concise Approach for Producing Optically Pure Carboxylic Acid
Segments for the Synthesis of Bicyclic Depsipeptide Histone
Deacetylase Inhibitors
Koichi Naritaa
Noel Sayara
1) amide condensation;
then separation
R
OH
Ken Saijob
Chikashi Ishiokab
Tadashi Katoh*a
CO2H
+
H2N
CO2Me
TrS
2) saponification
racemate
chiral amino acid ester
0
0
0
0-
0
0
0
3-3
7
1
5-0
9
6
1
(R = i-Pr, CH2CH2SMe, n-Bu, Bn)
a Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical
University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
b Department of Clinical Oncology, Institute of Development, Aging and
Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-
8575, Japan
OH
O
OH
R
R
O
+
2
3’
2
3’
TrS
TrS
N
CO2H
N
CO2H
H
H
(2R,3’R) [optically pure, 49–50%]
(2R,3’S) [optically pure, 48–50%]
katoh@tohoku-mpu.ac.jp
Dedicated to Professor Tohru Fukuyama, Nagoya University, Japan on his
70th birthday
Received: 12.11.2018
Accepted after revision: 11.12.2018
Published online: 05.02.2019
nyl side-chain interacts with the zinc cation located at the
binding pocket of the HDACs, resulting in a potent inhibito-
ry effect.
DOI: 10.1055/s-0037-1612059; Art ID: ss-2018-f0757-op
Structurally, FK228 is a 16-member bicyclic depsipep-
tide comprising L-valine, (3S,4E)-3-hydroxy-7-mercapto-
hept-4-enoic acid (Hmh), D-valine, D-cysteine, dehydrobu-
tyrine (Dhb), and a characteristic disulfide bond linkage.
Since the discovery of FK228, several bicyclic depsipeptide
HDAC inhibitors with similar structures have been isolated
from bacterial fermentation, which include FR901375 (2),4
spiruchostatins A–D (3–6),5,6 burkholdacs A (7) and B (8),7
and thailandepsins A–F (7–12)8 (thailandepsins A and C are
identical to burkholdacs B and A, respectively). To the best
of our knowledge, these are the only members of the natu-
ral bicyclic depsipeptide family that have been isolated so
far. The potentially therapeutic biological characteristics
and unique structural features of 1–12 have made them at-
tractive targets for total synthesis, and several such meth-
ods of synthesizing these natural products have been pub-
lished in the literature.9–15
Our previously reported synthetic pathway to FK228 (1)
is outlined in Scheme 1 in a retrosynthetic fashion.9a The
method features the direct condensation of amine segment
14 and carboxylic acid segment 15 (or 16b) followed by the
Mitsunobu macrolactonization of the corresponding seco-
acid 13 and intramolecular disulfide bond formation, which
leads to the target molecule 1. Note that the carboxylic acid
segment 15 (or 16b) possesses the opposite stereochemis-
try at the C3′ hydroxy group relative to the natural stereo-
chemistry at the C1 position of 1 (the C3′ position in 15 cor-
responds to the C1 position in 1). The amine segment 14
was readily assembled by the successive condensation of L-
threonine derivative 17, L-valine methyl ester 18, and D-
Abstract Optically pure carboxylic acid segments, which are common
key intermediates for the synthesis of naturally occurring bicyclic depsi-
peptide histone deacetylase inhibitors, have been produced efficiently.
The method features the chromatographic separation of two diastereo-
mers, which were formed by direct amide condensation of racemic
(3RS,4E)-3-hydroxy-7-mercaptohept-4-enoic acid (rac-Hmh) with chiral
amino acids. This approach offers a reliable and practical method for
producing optically pure carboxylic acid segments, which can facilitate
easier access to important anticancer agents derived from them.
Key words synthetic intermediate, histone deacetylase inhibitor,
natural product, bicyclic depsipeptide, total synthesis
The U.S. Food and Drug Administration (FDA) approved
the use of bicyclic depsipeptide FK228 [romidepsin (1), Fig-
ure 1] as an anticancer agent for the treatment of cutaneous
T-cell lymphoma (CTCL) in 2009 and the treatment of pe-
ripheral T-cell lymphoma (PTCL) in 2011.1 Subsequently,
this agent was approved in Korea, Australia, Canada, and Is-
rael for the treatment of the same hematologic cancers, and
in 2017, the Japanese Ministry of Health, Labor and Welfare
(MHLW) approved FK228 for treating recurring or intracta-
ble PTCL. FK228 was first discovered by researchers from
the Fujisawa Pharmaceutical Co. Ltd. (now Asteras Pharma
Inc.) in 1994, who isolated it from a culture broth of Chro-
mobacterium violaceum (No. 968).2 In 2002, Yoshida et al.
demonstrated a molecular mechanism by which FK228 in-
hibits histone deacetylase (HDAC).3 That mechanism acti-
vates FK228, which itself serves as a stable prodrug, by the
reductive cleavage of the disulfide bond after it is incorpo-
rated into cells, and a released sulfhydryl group in the bute-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

B
K. Narita et al.
Paper
Synthesis
Me
Me
L-Val
Me
Me
O
O
O
Dhb
Me
Me
Me
Me
O
OH
N
H
N
N
Me
Me
N
H
H
O
O
H
N
NH
NH
TrS
O
NH
O
O
O
H
O
S
OH
S
O
S
S
O
D-Cys
HN
STr
Me
O
S
S
HN
O
HN
1
NH
OH
H
N
H
Me
H
N
H
N
N
O
O
Hmh
O
O
O
O
O
O
Me
Me
Me
Me
Me
D-Val
Me
Me
Me
13
FK228 (romidepsin) (1)
FR901375 (2)
FK228 (romidepsin) (1)
Me
O
OH
R
Me
Me
Me
O
OR
O
OH
R1
Me
O
N
H
2
3’
TrS
N
CO2H
+
NH
O
O
NH
H
S
S
OH
NH
O
O
15: R = PMB
16b: R = H
S
O
HN
STr
14
O
S
H2N
H
HN
N
H
O
N
O
O
OR
Me
Me
O
R2
CO2H
SMe
+
3
TrS
spiruchostatin A (3): R1 = i-Pr, R2 = Me
spiruchostatin B (4): R1 = s-Bu, R2 = Me
spiruchostatin C (5): R1 = i-Bu, R2 = Me
spiruchostatin D (6): R1 = R2 = i-Pr
2
Me
OH
H2N
CO2Me
burkholdac A (7): R = i-Pr
(thailandepsin C)
burkholdac B (8): R = s-Bu
(thailandepsin A)
20: R = PMB
21: R = H (Hmh)
22b
CO2H
FmocHN
17
thailandepsin E (9): R = i-Bu
OH
R
H2N
Me
CO2Me
Me
PMP
N
N
N
O
O
+
NH
O
N
S
O
TrS
S
S
18
19
O
O
Ph
OHC
O
24
HN
23
BocHN
CO2H
STr
H
N
O
thailandepsin B (10): R = s-Bu
thailandepsin D (11): R = i-Pr
thailandepsin F (12): R = i-Bu
O
OH
HO
OH
CO2H
HO2C
Me
25
26
Figure 1 Structures of FK228 (romidepsin, 1), FR901375 (2), spi-
ruchostatins A–D (3–6), burkholdac A (thailandepsin C, 7), burkholdac
B (thailandepsin A, 8), and thailandepsins E (9), B (10), D (11), F (12)
Scheme 1 Our previously reported approach to FK228 (romidepsin, 1)
cysteine derivative 19. On the other hand, the carboxylic
acid segment 15 (or 16b), which contains the most synthet-
ically challenging unit 20 (or Hmh, 21), was prepared by Ju-
lia–Kocienski olefination of sulfone 23 [accessed from 1,3-
propanediol (25)] with chiral aldehyde 24 [accessed from D-
malic acid (26)] followed by condensation with D-valine
methyl ester (22b). In this approach, D-malic acid (26) was
used as a chiral building block to definitively establish the
C3 stereochemistry of intermediate 20 (or 21). However, a
multi-step sequence was necessary for accessing the key
carboxylic acid segment 15 (or 16b) (i.e., 14 total steps from
25 and 26 with a 12.3% overall yield in the longest liner se-
quence), which is the primary disadvantage of our previous
synthesis of 1.9a
Several studies have been reported on different ap-
proaches used to obtain optically active Hmh (21 or ent-
2116), which can be classified into three categories (Scheme
2, eq. 1–3). In the first total synthesis of FK228 (1) by Simon
et al.,9d Hmh (21) was synthesized in a yield of 95% with
98% ee by a catalytic asymmetric aldol reaction between al-
dehyde 27 and ketene acetal 28 under Carreira’s conditions
using a chiral ligand A (eq. 1, 27 + 28 → 29). However,
Wentworth, Janda et al.10b and Ganesan et al.11e inde-
pendently revealed that they had encountered difficulties
reproducing the 98% ee reported by Simon et al.9d for this
asymmetric aldol reaction (i.e. 27 + 28 → 29) in their total
syntheses of 2 and 3, respectively.17 Given these, Went-
worth, Janda et al.,10b Ganesan et al.,11e and Doi, Takahashi
et al.11d independently developed alternative methods for
preparing ent-21 via the diastereoselective aldol reaction
(eq. 2, 27 + 30 → 31, 35–94% yield, 71–88% de). Williams et
al.9b also developed an alternative approach to 21 (eq. 3),
which involves a Noyori asymmetric ketone reduction using
catalyst B followed by an E-selective alkyne reduction (cf.
32 → 33, 58% yield, 2 steps, 98% ee) as pivotal steps. This
approach made it possible to access 21 on a multigram
scale, although the reaction time in the Noyori asymmetric
reduction was much longer (~4 days), and the delicate step-
wise addition of catalyst B was necessary to complete the
reaction. In addition, a multi-step sequence of reactions (5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

C
K. Narita et al.
Paper
Synthesis
steps) was required for the subsequent conversion of 33
into 21. Summarizing the above, some of these methods of
synthesizing optically active Hmh (21 or ent-21) are useful,
although most of them include one or more complications.
Therefore, a more efficient and facile method for preparing
21 (or 16b) is still necessary to provide a reliable and prac-
tical source for the easier access to this class of pharmaceu-
tically important natural products.
ester moiety of the resulting separated products provided
target molecules 16b–e and 34b–e. We believe that this ap-
proach is one of the most expeditious and simple methods
of generating the common key components of the naturally
occurring bicyclic depsipeptide HDAC inhibitors (cf. Figure
1, the red-colored portions in the structures 1, 2, and 6–12),
though it involves tedious chromatographic separation.
OH
R
+
CO2H
(1) Simon’s approach (1996)
H2N
CO2Me
TrS
Ti(Oi-Pr)4, PhMe
3,5-di-tert-butylsalicylaldehyde
rac-21
22b–e
O
OTMS
OBn
+
b: R = i-Pr
condensation/
separation
TrS
H
c: R = CH2CH2SMe
d: R = n-Bu
27
28
NH2
OH
e: R = Bn
OH
R
O
3’
2
TrS
N
CO2H
H
A
OH
OH
16b–e: (2R,3’R)
34b–e: (2R,3’S)
CO2Bn
CO2H
TrS
TrS
Scheme 3 Outline of our alternative approach to the optically pure
carboxylic acid segments 16b–e (2R,3′R) and 34b–e (2R,3′S)
29 (95%, 98% ee)
21
(2) Wentworth-Janda’s (2003), Ganesan’s (2004), and Doi-Takahashi’s
(2004) approaches
As Scheme 4 shows, initially, we pursued the synthesis
of rac-21 from known aldehyde 27, which was prepared
from commercially available acrolein (35) in 2 steps in an
overall yield of 60% according to the reported method.10b
The aldol reaction of 27 with the lithium enolate of ethyl
acetate [generated in situ by reaction with lithium diiso-
propylamide (LDA)] provided the desired product rac-36 in
88% yield as a racemic mixture. Alkaline hydrolysis of the
ethyl ester moiety of rac-36 resulted in the production of
corresponding rac-21 in excellent yield (92%).
Y
O
O
+
Me
N
X
TrS
H
*
R3
27
R2
R1
30 (X, Y = O or S)
Y
X
OH
O
OH
TrS
N
CO2H
TrS
*
R3
R1 R2
ent-21
31 (35–94%, 71–88% de)
Ref. 10b
O
O
a
(3) Williams’ approach (2008)
H
TrS
H
Me
Ts
2 steps
(60% overall yield)
35
27
Ph
Ph
N
1) i-PrOH,
Ru
N
H
OH
OH
b
OMe
OMe
O
CO2Et
CO2H
Me
Me
B
TrS
TrS
rac-36
rac-21
2) Vitride® (Red-Al®)
TBDPSO
32
Scheme 4 Synthesis of rac-21. Reagents and conditions: (a) EtOAc, LDA,
THF, –78 °C, 1 h, 88%; (b) aq 10% NaOH, EtOH, rt, 1 h, 92%.
5 steps
OH
OH
OMe
OMe
CO2H
TBDPSO
33 (58%, 2 steps, 98% ee)
TrS
21
Next, as Table 1 shows, we investigated the synthesis of
optically pure amidecarboxylic acid methyl esters 37a–e
and 38a–e by condensation of rac-21 with five commercial-
ly available chiral amino acid derivatives [i.e., D-alanine
methyl ester (22a), D-valine methyl ester (22b), D-methi-
onine methyl ester (22c), D-norleucine methyl ester (22d),
and D-phenylalanine methyl ester (22e)], which, except for
22e, represent key amino acid components adjacent to the
Hmh moiety in the natural bicyclic depsipeptides 1–12. In
this reaction, the most critical issue is whether the result-
ing pairs of diastereomers (i.e., 37a/38a, 37b/38b, 37c/38c,
37d/38d, and 37e/38e) can be separated using a conven-
Scheme 2 Previously reported approaches on the optically active Hmh
(21 or ent-21) by other groups
As outlined in Scheme 3, this study proposes an alterna-
tive approach to produce optically pure carboxylic acid seg-
ments 16b–e (2R,3′R) and 34b–e (2R,3′S). The key aspect of
this approach was found to be the direct amide condensa-
tion of racemic Hmh (rac-21) with chiral amino acids 22b–
e and subsequent chromatographic separation of the result-
ing two diastereomeric mixtures. Hydrolysis of the methyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

D
K. Narita et al.
Paper
Synthesis
tional column chromatographic technique. Among the five
pairs of diastereomers 37a–e/38a–e, four of them (37b–
e/38b–e, excluding 37a/38a) were separable by silica gel
column chromatography using hexane/EtOAc 1:1 as the
eluting solvent. The target products 37b–e (less polar) and
38b–e (more polar) were obtained in optically pure forms
in excellent yields (48–50%, Table 1, entries 2–5) after three
(or four) times of repeated purification by silica gel column
chromatography.
OPMB
R
a
+
CO2H
HCl·H2N
22b–e
CO2Me
TrS
ent-20
OR
R
O
b: R = i-Pr
3’
TrS
N
CO2Me
c: R = CH2CH2SMe
d: R = n-Bu
H
39b–e: R = PMB
38b–e: R = H
e: R = Bn
b
Scheme 5 Determination of the stereochemistry at the C3′ position in
compounds 38b–e. Reagents and conditions: (a) PyBOP, i-Pr2NEt, MeCN,
rt, 2 h, 96% for 39b, 99% for 39c, 99% for 39d, 96% for 39e; (b) DDQ,
CH2Cl2/H2O, rt, 81% for 38b, 83% for 38c, 73% for 38d, 83% for 38e.
Table 1 Investigation on the Synthesis of Optically Pure Hmh-Contain-
ing Key Intermediates 37a–e (2R,3′R) and 38a–e (2R,3′S)
R
OH
PyBOP, i-Pr2NEt
CO2H
+
HCl•H2N
CO2Me
TrS
TrS
Consequently, the other less polar products 37b–e pos-
sessed the opposite 3′R-configuration. Finally, alkaline hy-
drolysis of the methyl ester moiety in 37b–e and 38b–e fur-
nished the corresponding carboxylic acids 16b–e and 34b–e
in yields of 93–98% (Scheme 6). The carboxylic acid seg-
ments 16b can be utilized for the synthesis of FK228 (1)9
and FR9001375 (2),10b in which macrolactonization occurs
via inversion of the C3′ stereochemistry. On the other hand,
the carboxylic acid segments 34b–d can be used to synthe-
size spiruchostatin D (6),13 burkholdacs A (7) and B (8),14
and thailandepsins A–F (7–12),15 in which the macrolacton-
ization proceeds by retaining the C3′ stereochemistry.
MeCN, rt, 2 h
rac-21
OH
22a–e
OH
R
R
O
O
+
2
2
3’
3’
TrS
N
CO2Me
N
CO2Me
H
H
38a–e (2R,3’S)
37a–e (2R,3’R)
Entry
Amino acid derivatives 22a–ea
Yield (%)b
37a–e
38a–e
c
c
1
2
3
4
5
D-Ala-OMe (22a: R = Me)
D-Val-OMe (22b: R = i-Pr)
D-Met-OMe (22c: R = CH2CH2SMe)
D-Nle-OMe (22d: R = n-Bu)
D-Phe-OMe (22e: R = Bn)
–
–
49
50
49
49
48
49
49
50
OH
R
O
2
3’
TrS
N
CO2Me
TrS
H
a Amino acid derivatives 22a–e were used in the form of their hydrochlo-
ride salt.
37b–e (2R,3’R)
OH
R
O
b Isolated yield after three (or four) times repetition of purification by silica
gel column chromatography (three times repetition for 37b/38b, 37c/38c,
and 37d/38d; four times repetition for 37e/38e).
c The corresponding two diastereomers (i.e., 37a/38a) could not be sepa-
rated by silica gel column chromatography (98% yield for a mixture of
37a/38a).
a
2
3’
N
CO2H
H
16b–e (2R,3’R)
b: R = i-Pr
OH
R
O
c: R = CH2CH2SMe
d: R = n-Bu
2
3’
e: R = Bn
TrS
N
CO2Me
TrS
H
Unfortunately, D-alanine-containing diastereomers
37a/38a could not be separated by column chromatography
using silica gel (Table 1, entry 1). Instead, a mixture of
37a/38a was obtained in a virtual quantitative yield (98%).
From these results, it was revealed that the size of the alkyl
side chains in amino acid moieties is a crucial factor in the
chromatographic separation of these types of diastereo-
meric mixtures.
38b–e (2R,3’S)
OH
R
O
a
2
3’
N
CO2H
H
34b–e (2R,3’S)
Scheme 6 Synthesis of the optically pure carboxylic acid segments
16b–e and 34b–e. Reagents and conditions: (a) 1.0 M LiOH, MeOH, rt,
4 h, 93% for 16b, 93% for 16c, 98% for 16d, 94% for 16e, 92% for 34b,
94% for 34c, 94% for 34d, 94% for 34e.
The stereochemistries at the C3′ position of the separat-
ed products 37b–e and 38b–e were unambiguously deter-
mined by chemical correlation, as shown in Scheme 5. The
known O-PMB-protected Hmh9a [ent-20, prepared from L-
malic acid (ent-26)] was condensed with D-amino acids
22b–e to give the corresponding amidecarboxylic acid
methyl esters 39b–e in 96–99% yields. Deprotection of the
O-PMB group from 39b–e provided authentic samples of
38b–e (73–83% yield), which were identical with the more
polar products 38b–e possessing 3′S-configuration in 1H
and 13C NMR spectra.
In summary, a concise approach was developed to pro-
duce optically pure carboxylic acid segments 16b–e and
34b–e, which represent common key intermediates for the
synthesis of bicyclic depsipeptide HDAC inhibitors. The
method features chromatographic separation of the two di-
astereomers (cf. Table 1, 37b–e vs 38b–e) formed by amide
condensation of racemic Hmh (rac-21) with chiral amino
acids 22b–e. Compared with previously reported approach-
es, the primary advantage of this proposed method is its
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E
K. Narita et al.
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Synthesis
shorter number of reaction steps, easier operation, higher
overall yields, and use of less expensive starting material
and reagents. Although chromatographic separation is a te-
dious technique, especially, when it is conducted on a large
scale, this method made it possible to produce optically
pure materials 16b–e (2R,3′R) and 34b–e (2R,3′S) on 500–
600 milligram scales in laboratory synthesis.18 By utilizing
the synthetic samples of 34c (R = CH2CH2SMe) and 34d (R =
n-Bu) as the key carboxylic acid segments, the syntheses of
thailandepsins D–F (9, 11, and 12) were efficiently achieved
for the first time, which is the subject of our next study.19
(RS,E)-3-Hydroxy-7-(tritylthio)hept-4-enoic Acid (rac-21)
Aq 10% NaOH (2.50 mL) was added dropwise to a stirred solution of
rac-36 (1.10 g, 2.5 mmol) in MeOH (25 mL) at rt. After 1 h, aq 10% HCl
was added to the mixture at 0 °C until pH 6. After concentration of the
reaction mixture in vacuo, H2O (20 mL) was added, and the resulting
mixture was extracted with EtOAc (3 × 20 mL). The combined extracts
were washed with brine (2 × 20 mL) and dried (Na2SO4). Concentra-
tion of the solvent in vacuo afforded a residue, which was purified by
column chromatography (CHCl3/MeOH 8:1) to give rac-21 (951 mg,
92%) as a colorless amorphous solid. Recrystallization from hex-
ane/EtOAc (1:1) gave an analytical sample of rac-21 as pale yellow
needles; mp 131–133 °C.
IR (KBr): 3395, 3055, 3030, 2924, 1711, 1594, 1489, 1443, 1279, 1183,
1033, 970, 910, 742, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.05–2.10 (m, 2 H), 2.19–2.23 (m, 2 H),
2.49–2.59 (m, 2 H), 4.45 (dd, J = 11.2, 7.3 Hz, 1 H), 5.42 (dd, J = 15.6,
6.3 Hz, 1 H), 5.59 (dt, J = 15.6, 6.8 Hz, 1 H), 7.19–7.41 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 31.3, 31.4, 41.2, 66.6, 68.5, 126.6 (3 C),
127.8 (6 C), 129.6 (6 C), 130.7, 131.6, 144.9 (3 C), 176.9.
All reactions involving air- and moisture-sensitive reagents were car-
ried out using oven dried glassware and standard syringe-septum cap
techniques. Routine monitoring of the reaction was 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 nm) with the solvents indicated. All sol-
vents and reagents were used as supplied with the following excep-
tions. THF was freshly distilled from Na metal/benzophenone under
argon. MeCN was distilled from CaH2 under argon. Measurements of
optical rotations were performed with a Anton Paar MCP-100 auto-
matic digital polarimeter. 1H 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. Stan-
dard abbreviations are used for denoting multiplicities. IR spectral
measurements were carried out with a JASCO FT/IR-4100 spectro-
photometer. Low- and high-resolution mass (HRMS) spectra were
measured on a JEOL JMS-700 high resolution mass spectrometer.
HRMS (FAB): m/z calcd for C26H26O3SNa [(M + Na)+]: 441.1500; found:
441.1513.
Methyl (R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-
methylbutanoate (37b) and its 2-[(S,E)]-Isomer (38b)
i-Pr2NEt (2.40 mL, 14 mmol) was added dropwise to a stirred solution
of rac-21 (1.00 g, 2.4 mmol) and D-valine methyl ester hydrochloride
(22b; 601 mg, 3.6 mmol) in MeCN (24 mL) containing PyBOP (1.86 g,
3.6 mmol) at rt under argon. After 2 h, concentration of the solvent in
vacuo afforded a residue, which was purified by column chromatogra-
phy (hexane/EtOAc 1:1) to give 37b (332 mg, 26%, less polar), 38b
(335 mg, 26%, more polar), and a mixture of 37b and 38b (596 mg,
47%). The mixture of 37b and 38b was separated by additional twice
repetition of column chromatography. Totally, 626 mg (49%) of 37b
and 606 mg (48%) of 38b were obtained.
Ethyl (RS,E)-3-Hydroxy-7-(tritylthio)hept-4-enoate (rac-36)
EtOAc (1.60 mL, 17 mmol) was added slowly to a stirred solution of
LDA (17 mmol) [prepared from n-BuLi in hexane (1.6 M solution,
11.5 mL, 18 mmol) and i-Pr2NH (2.50 mL, 17 mmol)] in THF (17
mL) at –78 °C under argon. After 30 min, (E)-5-(tritylthio)pent-2-enal
(27;10b 1.84 g, 5.1 mmol) in THF (17 mL) was added to the above mix-
ture at –78 °C. After 1 h, the reaction was quenched with sat. aq NH4Cl
(20 mL) at –78 °C, and the resulting mixture was extracted with
EtOAc (3 × 20 mL). The combined extracts were washed with brine
(2 × 30 mL) and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(hexane/EtOAc 2:1) to give rac-36 (2.02 g, 88%) as a colorless solid.
Recrystallization from hexane/EtOAc (3:1) gave an analytical sample
of rac-36 as colorless granules; mp 94–96 °C.
37b
Colorless viscous liquid; [α]D25 –0.6 (c 1.0, CHCl3).
IR (neat): 3326, 3057, 2962, 1741, 1649, 1535, 1490, 1443, 1372,
1313, 1266, 1207, 1033, 974, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8
Hz, 3 H), 2.04–2.22 (m, 5 H), 2.12–2.22 (m, 3 H), 2.35 (dd, J = 15.1, 8.8
Hz, 1 H), 2.45 (dd, J = 15.1, 3.9 Hz, 1 H), 3.44 (br s, 1 H), 3.72 (s, 3 H),
4.39–4.43 (m, 1 H), 4.55 (dd, J = 8.3, 4.9 Hz, 1 H), 5.42 (dd, J = 15.1, 6.8
Hz, 1 H), 5.56 (dt, J = 15.6, 5.9 Hz, 1 H), 6.40 (d, J = 8.8 Hz, 1 H), 7.16–
7.41 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 17.7, 18.9, 31.2, 31.3, 31.4, 42.6, 52.1,
56.9, 66.6, 69.1, 126.6 (3 C), 127.8 (6 C), 129.5 (6 C), 130.1, 132.2,
144.9 (3 C), 171.6, 172.4.
IR (KBr): 3454, 3056, 2980, 2925, 1733, 1594, 1489, 1444, 1371, 1275,
1182, 1097, 1033, 971, 852, 743, 700, 620 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 6.3 Hz, 3 H), 2.04–2.10 (m, 2
H), 2.18–2.22 (m, 2 H), 2.42–2.52 (m, 2 H), 2.86 (d, J = 4.4 Hz, 1 H),
4.14 (q, J = 7.2 Hz, 2 H), 4.40–4.46 (m, 1 H), 5.38–5.44 (m, 1 H), 5.53–
5.61 (m, 1 H), 7.19–7.41 (m, 15 H).
HRMS (FAB): m/z calcd for C32H38NO4S [(M + H)+]: 532.2522; found:
532.2535.
13C NMR (100 MHz, CDCl3): δ = 14.1, 31.3, 31.4, 41.4, 60.7, 66.6, 68.6,
126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 130.1, 132.0, 144.9 (3 C), 172.2.
38b
Colorless viscous liquid; [α]D25 –12.6 (c 1.0, CHCl3).
HRMS (FAB): m/z calcd for C28H31O3S [(M + H)+]: 447.1994; found:
447.1992.
IR (neat): 3320, 3057, 2963, 2928, 1741, 1650, 1538, 1489, 1443,
1313, 1209, 1153, 1034, 974, 744, 700 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

F
K. Narita et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8
Hz, 3 H), 2.04–2.09 (m, 2 H), 2.12–2.22 (m, 3 H), 2.34–2.46 (m, 2 H),
3.43 (br s, 1 H), 3.73 (s, 3 H), 4.40–4.44 (m, 1 H), 4.54 (dd, J = 8.8, 4.9
Hz, 1 H), 5.42 (dd, J = 15.1, 6.3 Hz, 1 H), 5.57 (dt, J = 15.1, 6.8 Hz, 1 H),
6.40 (d, J = 8.3 Hz, 1 H), 7.18–7.44 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 17.8, 19.0, 31.0, 31.3, 31.4, 43.0, 52.2,
57.1, 66.6, 69.2, 126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 130.0, 132.2,
144.9 (3 C), 171.7, 172.5.
Methyl (R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]hex-
anoate (37d) and Its 2-[(S,E)]-Isomer (38d)
i-Pr2NEt (2.40 mL, 14 mmol) was added dropwise to a stirred solution
of rac-21 (1.00 g, 2.4 mmol) and D-norleucine methyl ester hydro-
chloride (22d; 651 mg, 3.6 mmol) in MeCN (24 mL) containing PyBOP
(1.86 g, 3.6 mmol) at rt under argon. After 2 h, concentration of the
solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 1:1) to give 37d (126 mg, 10%, less
polar), 38d (176 mg, 13%, more polar), and a mixture of 37d and 38d
(990 mg, 76%). The mixture of 37d and 38d was separated by addi-
tional twice repetition of column chromatography. Totally, 640 mg
(49%) of 37d and 638 mg (49%) of 38d were obtained.
HRMS (FAB): m/z calcd for C32H38NO4S [(M + H)+]: 532.2522; found:
532.2536.
Methyl (R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-4-
(methylthio)butanoate (37c) and its 2-[(S,E)]-Isomer (38c)
37d
i-Pr2NEt (2.40 mL, 14 mmol) was added dropwise to a stirred solution
of rac-21 (1.00 g, 2.4 mmol) and D-methionine methyl ester hydro-
chloride (22c; 716 mg, 3.6 mmol) in MeCN (24 mL) containing PyBOP
(1.86 g, 3.6 mmol) at rt under argon. After 2 h, concentration of the
solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 1:1) to give 37c (415 mg, 31%, less
polar), 38c (354 mg, 26%, more polar), and a mixture of 37c and 38c
(580 mg, 43%). The mixture of 37c and 38c was separated by addi-
tional twice repetition of column chromatography. Totally, 675 mg
(50%) of 37c and 668 mg (49%) of 38c were obtained.
Colorless viscous liquid; [α]D25 –0.8 (c 0.85, CHCl3).
IR (neat): 3056, 2954, 2928, 2861, 1742, 1648, 1648, 1595, 1541,
1489, 1443, 1374, 1213, 1154, 1081, 1034, 971, 849, 744, 700, 676,
621 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.22–1.35 (m, 4
H), 1.59–1.71 (m, 1 H), 1.78–1.87 (m, 1 H), 2.05–2.09 (m, 2 H), 2.18–
2.22 (m, 2 H), 2.35 (dd, J = 15.3, 8.6 Hz, 1 H), 2.44 (dd, J = 15.3, 3.2 Hz,
1 H), 3.43 (br s, 1 H), 3.74 (s, 3 H), 4.42 (br s, 1 H), 4.60 (td, J = 7.7, 5.4
Hz, 1 H), 5.42 (dd, J = 15.4, 6.3 Hz, 1 H), 5.55 (dt, J = 15.4, 6.6 Hz, 1 H),
6.36 (d, J = 7.8 Hz, 1 H), 7.21–7.40 (m, 15 H).
37c
13C NMR (100 MHz, CDCl3): δ = 13.7, 22.1, 27.2, 31.2, 31.3, 31.9, 42.5,
51.9, 52.2, 66.5, 69.0, 126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 130.0, 132.2,
144.9 (3 C), 171.5, 173.1.
Colorless viscous liquid; [α]D25 –8.2 (c 0.85, CHCl3).
IR (neat): 3308, 3057, 2951, 2919, 1742, 1649, 1541, 1489, 1442,
1364, 1274, 1216, 1176, 1034, 971, 744, 701 cm–1
.
HRMS (FAB): m/z calcd for C33H40NO4S [(M + H)+]: 546.2633; found:
1H NMR (400 MHz, CDCl3): δ = 1.91–2.00 (m, 1 H), 2.04–2.10 (m, 5 H),
2.10–2.26 (m, 3 H), 2.35 (dd, J = 15.1, 8.8 Hz, 1 H), 2.44 (dd, J = 15.4,
3.2 Hz, 1 H), 2.46–2.53 (m, 2 H), 3.28 (d, J = 3.4 Hz, 1 H), 3.75 (s, 3 H),
4.40–4.44 (m, 1 H), 4.72 (td, J = 7.3, 4.9 Hz, 1 H), 5.42 (dd, J = 15.6, 6.3
Hz, 1 H), 5.57 (dt, J = 15.6, 5.9 Hz, 1 H), 6.54 (d, J = 7.8 Hz, 1 H), 7.19–
7.44 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 15.5, 29.9, 31.3, 31.4, 31.5, 42.7, 51.4,
52.6, 66.6, 69.1, 126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 130.0, 132.1,
144.5 (3 C), 171.4, 172.3.
546.2676.
38d
Colorless viscous liquid; [α]D25 –13.1 (c 0.85, CHCl3).
IR (neat): 3058, 2955, 2928, 2861, 1741, 1539, 1488, 1443, 1374,
1281, 1217, 1183, 1082, 972, 850, 679, 661, 617 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H), 1.22–1.38 (m, 4
H), 1.60–1.68 (m, 1 H), 1.78–1.87 (m, 1 H), 2.04–2.10 (m, 2 H), 2.18–
2.23 (m, 2 H), 2.31–2.43 (m, 2 H), 3.50 (br s, 1 H), 3.74 (s, 3 H), 4.40–
4.44 (m, 1 H), 4.58 (td, J = 7.7, 5.4 Hz, 1 H), 5.41 (dd, J = 15.6, 6.3 Hz, 1
H), 5.57 (dt, J = 13.8, 6.6 Hz, 1 H), 6.36 (d, J = 7.8 Hz, 1 H), 7.21–7.40
(m, 15 H).
HRMS (FAB): m/z calcd for C32H38NO4S2 [(M + H)+]: 564.2242; found:
564.2228.
38c
13C NMR (100 MHz, CDCl3): δ = 13.6, 22.0, 27.2, 31.1, 31.3, 31.6, 42.8,
52.0, 52.1, 66.4, 68.9, 126.5 (3 C), 127.7 (6 C), 129.5 (6 C), 129.7, 132.3,
144.8 (3 C), 171.6, 173.2.
Colorless viscous liquid; [α]D25 –21.0 (c 1.0, CHCl3).
IR (neat): 3309, 3057, 2951, 2918, 1741, 1651, 1534, 1489, 1443,
1367, 1273, 1224, 1178, 1034, 973, 910, 743, 701 cm–1
.
HRMS (FAB): m/z calcd for C33H40NO4S [(M + H)+]: 546.2633; found:
1H NMR (400 MHz, CDCl3): δ = 1.95–1.99 (m, 1 H), 2.06–2.09 (m, 5 H),
2.12–2.23 (m, 3 H), 2.33–2.40 (m, 2 H), 2.50 (t, J = 7.6 Hz, 2 H), 3.34 (d,
J = 2.9 Hz, 1 H), 3.75 (s, 3 H), 4.40–4.45 (m, 1 H), 4.71 (td, J = 7.6, 5.0
Hz, 1 H), 5.41 (dd, J = 15.6, 6.3 Hz, 1 H), 5.57 (dt, J = 15.6, 6.3 Hz, 1 H),
6.55 (d, J = 7.8 Hz, 1 H), 7.19–7.41 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 15.5, 30.0, 31.3, 31.4, 31.5, 43.0, 51.5,
52.6, 66.6, 69.2, 126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 130.2, 132.1,
144.9 (3 C), 171.6, 172.4.
546.2674.
Methyl (R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-
phenylpropanoate (37e) and Its 2-[(S,E)]-Isomer (38e)
i-Pr2NEt (2.40 mL, 14 mmol) was added dropwise to a stirred solution
of rac-21 (1.00 g, 2.4 mmol) and D-phenylalanine methyl ester hydro-
chloride (22e, 773 mg, 3.6 mmol) in MeCN (24 mL) containing PyBOP
(1.86 g, 3.6 mmol) at rt under argon. After 2 h, concentration of the
solvent in vacuo afforded a residue, which was purified by column
chromatography (hexane/EtOAc 1:1) to give 37e (421 mg, 30%, less
polar), 38e (179 mg, 13%, more polar), and a mixture of 37e and 38e
(771 mg, 56%). The mixture of 37e and 38e was separated by addi-
tional three repetitions of column chromatography. Totally, 682 mg
(49%) of 37e and 684mg (50%) of 38e were obtained.
HRMS (FAB): m/z calcd for C32H38NO4S2 [(M + H)+]: 564.2242; found:
564.2222.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

G
K. Narita et al.
Paper
Synthesis
37e
Methyl (R)-2-{(S,E)-3-[(4-Methoxybenzyl)oxy]-7-(tritylthio)hept-
Colorless viscous liquid; [α]D25 –26.6 (c 1.1, CHCl3).
4-enamido}-4-(methylthio)butanoate (39c)
i-Pr2NEt (0.28 mL, 1.7 mmol) was added dropwise to a stirred solu-
tion of ent-209a (150 mg, 0.28 mmol) and D-methionine methyl ester
hydrochloride (22c; 83.3 mg, 0.42 mmol) in MeCN (6.0 mL) contain-
ing PyBOP (217 mg, 0.42 mmol) at rt under argon. After 2 h, concen-
tration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 2:1) to give 39c (188 mg,
99%) as a colorless viscous liquid; [α]D25 –15.2 (c 1.0, CHCl3).
IR (neat): 3309, 3059, 3029, 2951, 1744, 1651, 1532, 1491, 1443,
1368, 1217, 1081, 1034, 973, 854, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.03–2.08 (m, 2 H), 2.17–2.22 (m, 2 H),
2.28 (dd, J = 15.1, 8.8 Hz, 1 H), 2.37 (dd, J = 15.4, 3.2 Hz, 1 H), 3.06 (dd,
J = 14.1, 5.9 Hz, 1 H), 3.15 (dd, J = 13.9, 5.6 Hz, 1 H), 3.15 (d, J = 3.4 Hz,
1 H), 3.73 (s, 3 H), 4.34–4.37 (m, 1 H), 4.88 (dt, J = 7.8, 5.9 Hz, 1 H),
5.38 (dd, J = 15.6, 6.3 Hz, 1 H), 5.53 (dt, J = 14.6, 6.3 Hz, 1 H), 6.25 (d,
J = 7.8 Hz, 1 H), 7.07–7.10 (m, 2 H), 7.18–7.22 (m, 3 H), 7.24–7.43 (m,
15 H).
IR (neat): 3438, 1734, 1647, 1514, 1443, 1363, 1300, 1248, 1174,
1077, 1032, 972 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.82–1.91 (m, 1 H), 1.99–2.17 (m, 3 H),
2.02 (s, 3 H), 2.21–2.25 (m, 2 H), 2.36–2.43 (m, 3 H), 2.51 (dd, J = 8.8,
15.1 Hz, 1 H), 3.73 (s, 3 H), 3.79 (s, 3 H), 4.10 (dt, J = 2.9, 8.3 Hz, 1 H),
4.31 (d, J = 11.2 Hz, 1 H), 4.51 (d, J = 10.7 Hz, 1 H), 4.65–4.70 (m, 1 H),
5.32 (dd, J = 7.8, 15.6 Hz, 1 H), 5.59 (dt, J = 6.8, 15.1 Hz, 1 H), 6.83 (d,
J = 8.3 Hz, 2 H), 7.01 (d, J = 8.3 Hz, 1 H), 7.19–7.45 (m, 17 H).
13C NMR (100 MHz, CDCl3): δ = 31.3, 31.4, 37.8, 42.6, 52.4, 53.0, 66.6,
69.1, 126.6 (3 C), 127.2, 127.8 (6 C), 128.6 (2 C), 129.2 (2 C), 129.6 (6
C), 130.1, 132.1, 135.7, 144.9 (3 C), 171.2, 171.9.
HRMS (FAB): m/z calcd for C36H38NO4S [(M + H)+]: 580.2522; found:
580.2543.
13C NMR (100 MHz, CDCl3): δ = 15.4, 29.9, 31.2, 31.4, 31.8, 42.7, 51.3,
52.3, 55.3, 66.6, 70.0, 76.7, 113.8 (3 C), 126.6 (2 C), 127.9 (6 C), 129.6
(6 C), 129.7 (2 C), 129.9, 130.3, 133.0, 144.9 (3 C), 159.3, 170.6, 172.4.
38e
Colorless viscous liquid; [α]D25 –35.7 (c 1.1, CHCl3).
IR (neat): 3314, 3057, 3029, 2951, 1742, 1649, 1534, 1490, 1443,
HRMS (EI): m/z calcd for
683.2741.
C
40H45NO5S2 [M+] 683.2739; found:
1367, 1217, 1081, 1034, 971, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.02–2.08 (m, 2 H), 2.17–2.21 (m, 2 H),
2.26–2.37 (m, 2 H), 3.06 (dd, J = 13.7, 6.3 Hz, 1 H), 3.16 (dd, J = 13.9,
5.6 Hz, 1 H), 3.25 (d, J = 3.4 Hz, 1 H), 3.75 (s, 3 H), 4.34–4.39 (m, 1 H),
4.86 (dt, J = 7.8, 6.3 Hz, 1 H), 5.35 (dd, J = 15.6, 6.3 Hz, 1 H), 5.53 (dt, J =
15.1, 6.8 Hz, 1 H), 6.26 (d, J = 7.8 Hz, 1 H), 7.08–7.10 (m, 2 H), 7.18–
7.22 (m, 3 H), 7.25–7.41 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 31.3, 31.4, 37.7, 42.8, 52.4, 53.1, 66.6,
69.2, 126.6 (3 C), 127.2, 127.9 (6 C), 128.6 (2 C), 129.2 (2 C), 129.6 (6
C), 130.2, 132.1, 135.7, 144.9 (3 C), 171.4, 172.0.
Methyl (R)-2-{(S,E)-3-[(4-Methoxybenzyl)oxy]-7-(tritylthio)hept-
4-enamido}hexanoate (39d)
i-Pr2NEt (0.24 mL, 1.7 mmol) was added dropwise to a stirred solu-
tion of ent-209a (150 mg, 0.28 mmol) and D-norleucine methyl ester
hydrochloride (22d; 75.8 mg, 0.42 mmol) in MeCN (6.0 mL) contain-
ing PyBOP (217 mg, 0.42 mmol) at rt under argon. After 2 h, concen-
tration of the solvent in vacuo afforded a residue, which was purified
by column chromatography (hexane/EtOAc 2:1) to give 39d (183 mg,
99%,) as a colorless viscous liquid; [α]D25 –6.5 (c 1.0, CHCl3).
HRMS (FAB): m/z calcd for C36H38NO4S [(M + H)+]: 580.2522; found:
580.2526.
IR (neat): 3309, 3057, 2953, 2929, 2860, 1743, 1652, 1613, 1514,
1443, 1362, 1248, 1080, 821, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J = 7.1 Hz, 3 H), 1.14–1.28 (m, 4
H), 1.53–1.60 (m, 1 H), 1.70–1.77 (m, 1 H), 2.04–2.25 (m, 4 H), 2.38
(dd, J = 15.4, 3.2 Hz, 1 H), 2.51 (dd, J = 15.4, 8.8 Hz, 1 H), 3.71 (s, 3 H),
3.78 (s, 3 H), 4.10 (td, J = 8.3, 3.4 Hz, 1 H), 4.31 (d, J = 10.7 Hz, 1 H),
4.51 (d, J = 10.7 Hz, 1 H), 4.55 (td, J = 7.7, 5.2 Hz, 1 H), 5.32 (dd, J = 15.6,
8.3 Hz, 1 H), 5.59 (dt, J = 15.1, 6.6 Hz, 1 H), 6.81–6.84 (m, 2 H), 6.95 (d,
J = 8.3 Hz, 1 H), 7.19–7.45 (m, 17 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 22.2, 27.4, 31.2, 31.4, 32.0, 42.7,
52.0, 52.1, 55.2, 66.6, 70.1, 76.8, 113.8 (2 C), 126.6 (3 C), 127.9 (6 C),
129.5 (6 C), 129.7 (2 C), 130.0, 130.3, 132.9, 144.9 (3 C), 159.2, 170.5,
173.0.
Methyl (R)-2-{(S,E)-3-[(4-Methoxybenzyl)oxy]-7-(tritylthio)hept-
4-enamido}-3-methylbutanoate (39b)
i-Pr2NEt (0.28 mL, 1.7 mmol) was added dropwise to a stirred solu-
tion of ent-209a (150 mg, 0.28 mmol) and D-valine methyl ester hy-
drochloride (22b; 70.0 mg, 0.42 mmol) in MeCN (6.0 mL) containing
PyBOP (217 mg, 0.42 mmol) at rt under argon. After 2 h, concentra-
tion of the solvent in vacuo afforded a residue, which was purified by
column chromatography (hexane/EtOAc 2:1) to give 39b (173 mg,
96%) as a colorless viscous liquid; [α]D25 –8.2 (c 1.0, CHCl3).
IR (neat): 3340, 3057, 3029, 2961, 2932, 1741, 1659, 1613, 1514,
1443, 1303, 1248, 1208, 1080, 1034, 821, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.77 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8
Hz, 3 H), 2.03–2.18 (m, 3 H), 2.21–2.25 (m, 2 H), 2.41 (dd, J = 15.4, 3.7
Hz, 1 H), 2.53 (dd, J = 15.1, 8.3 Hz, 1 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 4.10
(td, J = 8.2, 3.6 Hz, 1 H), 4.32 (d, J = 10.7 Hz, 1 H), 4.51 (d, J = 10.7 Hz, 1
H), 4.53 (dd, J = 9.3, 5.4 Hz, 1 H), 5.33 (dd, J = 15.4, 8.0 Hz, 1 H), 5.59
(dt, J = 15.4, 6.7 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 1
H), 7.18–7.45 (m, 17 H).
13C NMR (100 MHz, CDCl3): δ = 17.7, 19.0, 31.0, 31.3, 31.4, 42.7, 51.9,
55.2, 56.9, 66.6, 70.1, 76.7, 113.7 (2 C), 126.6 (3 C), 127.8 (6 C), 129.5
(6 C), 129.7 (2 C), 129.9, 130.3, 132.9, 144.8 (3 C), 159.2, 170.6, 172.4.
HRMS (FAB): m/z calcd for C41H47NO5SNa [M + Na]+: 688.3073; found:
688.3087.
Methyl (R)-2-{(S,E)-3-[(4-Methoxybenzyl)oxy]-7-(tritylthio)hept-
4-enamido}-3-phenylpropanoate (39e)
i-Pr2NEt (0.28 mL, 1.7 mmol) was added dropwise to a stirred solu-
tion of ent-209a (150 mg, 0.28 mmol) and D-phenylalanine methyl es-
ter hydrochloride (22e; 89.9 mg, 0.42 mmol) in MeCN (6.0 mL) con-
taining PyBOP (217 mg, 0.42 mmol) at rt under argon. After 2 h, con-
centration of the solvent in vacuo afforded a residue, which was
purified by column chromatography (hexane/EtOAc 2:1) to give 39e
HRMS (FAB): m/z calcd for C40H46NO5S [(M + H)+]: 652.3097; found:
652.3092.
25
(186 mg, 96%) as a colorless amorphous solid; [α]D –24.0 (c 1.0,
CHCl3).
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IR (neat): 3343, 3059, 3029, 2951, 1746, 1668, 1613, 1514, 1443,
1363, 1079, 1034, 821, 744, 700 cm–1
Deprotection of the O-PMB Group in Compound 39e Leading to
Compound 38e
.
1H NMR (400 MHz, CDCl3): δ = 2.04–2.14 (m, 2 H), 2.15–2.22 (m, 2 H),
2.36 (dd, J = 15.4, 3.7 Hz, 1 H), 2.44 (dd, J = 15.4, 8.0 Hz, 1 H), 2.96 (dd,
J = 13.7, 6.8 Hz, 1 H), 3.08 (dd, J = 13.9, 5.6 Hz, 1 H), 3.67 (s, 3 H), 3.78
(s, 3 H), 4.03 (td, J = 8.0, 3.7 Hz, 1 H), 4.24 (d, J = 11.2 Hz, 1 H), 4.44 (d,
J = 11.2 Hz, 1 H), 4.84 (dd, J = 13.4, 7.1 Hz, 1 H), 5.19 (dd, J = 15.4, 8.0
Hz, 1 H), 5.50 (dt, J = 15.1, 6.8 Hz, 1 H), 6.78–6.81 (m, 2 H), 6.92 (d, J =
7.8 Hz, 1 H), 7.02–7.04 (m, 2 H), 7.10–7.14 (m, 2 H), 7.17–7.42 (m, 18
H).
13C NMR (100 MHz, CDCl3): δ = 31.2, 31.4, 37.9, 42.7, 52.1, 53.2, 55.2,
66.6, 69.8, 76.4, 113.8 (2 C), 126.6 (3 C), 127.0, 127.8 (6 C), 128.5 (2 C),
129.2 (2 C), 129.5 (8 C), 129.9, 130.2, 133.0, 136.1, 144.9 (3 C), 159.2,
170.3, 172.0.
DDQ (121 mg, 0.53 mmol) was added in small portions to a stirred
solution of 39e (186 mg, 0.27 mmol) in CH2Cl2/H2O (9:1, 5.5 mL) at rt.
After 1 h, the mixture was diluted with CHCl3 (30 mL), and the organic
layer was washed with sat. aq NaHCO3 (2 × 10 mL) and brine (2 × 10
mL), and dried (MgSO4). Concentration of the solvent in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane/EtOAc 1:1) to give 38e (128 mg, 83%) as a colorless viscous liquid.
The IR, MS, and both 1H and 13C NMR spectra of this sample were
identical with those recorded for compound 38e prepared from com-
pound rac-21 and compound 22e.
(R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-methyl-
butanoic Acid (16b)
HRMS (FAB): m/z calcd for C44H46NO5S [(M + H)+]: 700.3097; found:
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 37b
(624 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 16b (568 mg, 93%) as a colorless amor-
phous solid; [α]D25 –2.4 (c 1.0, CHCl3).
700.3104.
Deprotection of the O-PMB Group in Compound 39b Leading to
Compound 38b
DDQ (118 mg, 0.52 mmol) was added in small portions to a stirred
solution of 39b (170 mg, 0.26 mmol) in CH2Cl2/H2O (9:1, 5.0 mL) at rt.
After 1 h, the mixture was diluted with CHCl3 (30 mL), and the organic
layer was washed with sat. aq NaHCO3 (2 × 10 mL) and brine (2 × 10
mL), and dried (MgSO4). Concentration of the solvent in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane/EtOAc 1:1) to give 38b (112 mg, 81%) as a colorless viscous liquid.
The IR, MS, and both 1H and 13C NMR spectra of this sample were
identical with those recorded for compound 38b prepared from com-
pound rac-21 and compound 22b.
IR (neat): 3338, 3057, 3017, 2964, 2930, 1717, 1647, 1541, 1489,
1444, 1217, 1034, 971, 744, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8
Hz, 3 H), 2.01–2.07 (m, 2 H), 2.17–2.20 (m, 3 H), 2.38–2.45 (m, 2 H),
4.36–4.41 (m, 1 H), 4.52 (dd, J = 8.5, 4.6 Hz, 1 H), 5.39 (dd, J = 15.4, 6.1
Hz, 1 H), 5.52 (dt, J = 15.6, 6.3 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 7.17–
7.40 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 17.6, 19.0, 30.8, 31.3, 31.4, 42.7, 57.1,
66.6, 69.1, 126.6 (3 C), 127.8 (6 C), 129.5 (6 C), 130.2, 132.0, 144.8 (3
C), 172.3, 174.5.
Deprotection of the O-PMB Group in Compound 39c Leading to
Compound 38c
DDQ (125 mg, 0.55 mmol) was added in small portions to a stirred
solution of 39c (188 mg, 0.27 mmol) in CH2Cl2/H2O (9:1, 5.5 mL) at rt.
After 3 h, the mixture was diluted with CHCl3 (30 mL), and the organic
layer was washed with sat. aq NaHCO3 (2 × 10 mL) and brine (2 × 10
mL), and dried (MgSO4). Concentration of the solvent in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane/EtOAc 1:1) to give 38c (127 mg, 83%) as a colorless viscous liquid.
The IR, MS, and both 1H and 13C NMR spectra of this sample were
identical with those recorded for compound 38c prepared from com-
pound rac-21 and compound 22c.
HRMS (FAB): m/z calcd for C31H36NO4S [(M + H)+]: 518.2365; found:
518.2357.
(R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-4-(meth-
ylthio)butanoic Acid (16c)
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 37c
(675 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 16c (615 mg, 93%) as a colorless amorphous
solid; [α]D25 +5.7 (c 0.91, CHCl3).
Deprotection of the O-PMB Group in Compound 39d Leading to
Compound 38d
DDQ (125 mg, 0.55 mmol) was added in small portions to a stirred
solution of 39d (183 mg, 0.27 mmol) in CH2Cl2/H2O (9:1, 5.5 mL) at rt.
After 1 h, the mixture was diluted with CHCl3 (30 mL), and the organic
layer was washed with sat. aq NaHCO3 (2 × 10 mL) and brine (2 × 10
mL), and dried (MgSO4). Concentration of the solvent in vacuo afford-
ed a residue, which was purified by column chromatography (hex-
ane/EtOAc 1:1) to give 38d (109 mg, 73%) as a colorless viscous liquid.
The IR, MS, and both 1H and 13C NMR spectra of this sample were
identical with those recorded for compound 38d prepared from com-
pound rac-21 and compound 22d.
IR (neat): 3320, 3057, 2922, 2853, 1716, 1645, 1594, 1489, 1443,
1281, 1218, 1184, 1034, 971, 744, 618 cm–1
.
1H NMR (400 MHz, CDCl3/CD3OD 10:1): δ = 1.89–1.98 (m, 1 H), 2.03–
2.14 (m, 6 H), 2.18–2.22 (m, 2 H), 2.30–2.42 (m, 2 H), 2.47–2.54 (m, 2
H), 4.35–4.40 (m, 1 H), 4.43–4.46 (m, 1 H), 5.42 (dd, J = 15.4, 6.1 Hz, 1
H), 5.54 (dt, J = 15.6, 6.3 Hz, 1 H), 7.06–7.49 (m, 15 H).
13C NMR (100 MHz, CDCl3/CD3OD 10:1): δ = 15.1, 29.5, 30.1, 31.2,
31.4, 42.9, 52.5, 66.5, 68.8, 126.5 (3 C), 127.7 (6 C), 129.4 (6 C), 129.6,
132.4, 144.7 (3 C), 172.2, 173.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

I
K. Narita et al.
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Synthesis
HRMS (FAB): m/z calcd for C31H36NO4S2 [(M + H)+]: 550.2086; found:
550.2070.
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 34b (542 mg, 92%) as a colorless amor-
phous solid; [α]D25 –16.9 (c 1.0, CHCl3).
(R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]hexanoic
Acid (16d)
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 37d
(640 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 16d (612 mg, 98%) as a colorless amor-
phous solid; [α]D25 +0.4 (c 1.1, CHCl3).
IR (neat): 3330, 3057, 3018, 2964, 2928, 1716, 1646, 1541, 1489,
1444, 1218, 1034, 972, 744, 700, 617 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8
Hz, 3 H), 2.01–2.07 (m, 2 H), 2.12–2.20 (m, 3 H), 2.38 (d, J = 6.3 Hz, 2
H), 4.41–4.46 (m, 2 H), 5.38 (dd, J = 15.2, 6.0 Hz, 1 H), 5.53 (dt, J = 15.0,
6.3 Hz, 1 H), 6.85 (d, J = 8.3 Hz, 1 H), 7.18–7.44 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 17.7, 19.2, 30.4, 31.3, 31.4, 43.4, 57.5,
66.6, 69.2, 126.6 (3 C), 127.9 (6 C), 129.5 (6 C), 130.0, 132.0, 144.8 (3
C), 172.6, 175.1.
IR (neat): 3324, 3058, 2956, 2928, 2861, 1717, 1645, 1541, 1489,
1444, 1217, 1082, 1034, 972, 744, 617 cm–1
.
HRMS (FAB): m/z calcd for C31H36NO4S [(M + H)+]: 518.2365; found:
518.2383.
1H NMR (400 MHz, CDCl3): δ = 0.86–0.89 (m, 3 H), 1.23–1.30 (m, 4 H),
1.65–1.70 (m, 1 H), 1.84–1.87 (m, 1 H), 2.03–2.08 (m, 3 H), 2.19 (t, J =
7.3 Hz, 2 H), 2.35 (dd, J = 15.1, 8.3 Hz, 1 H), 2.42 (dd, J = 15.1, 3.4 Hz, 1
H), 4.39–4.42 (m, 1 H), 4.53 (dd, J = 12.7, 7.3 Hz, 1 H), 5.41 (dd, J =
15.4, 6.1 Hz, 1 H), 5.54 (dt, J = 15.6, 6.3 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 1
H), 7.18–7.44 (m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 22.2, 27.4, 31.3, 31.4, 31.6, 42.6,
52.3, 66.6, 69.1, 126.6 (3 C), 127.9 (6 C), 129.6 (6 C), 130.3, 132.0,
144.9 (3 C), 172.1, 175.8.
(R)-2-[(S,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-4-(meth-
ylthio)butanoic Acid (34c)
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 38c
(668 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the mixture was
stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at 0 °C until
pH 6. After concentration of the reaction mixture in vacuo, H2O (10
mL) was added, and the resulting mixture was extracted with EtOAc
(3 × 10 mL). The combined extracts were washed with brine (2 × 10
mL), and dried (Na2SO4). Concentration of the solvent in vacuo afford-
HRMS (FAB): m/z calcd for C32H37NO4SNa [(M + Na)+]: 554.2341;
found: 554.2338.
ed
a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 34c (612 mg, 94%) as a colorless amorphous
(R)-2-[(R,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-phenyl-
propanoic Acid (16e)
solid; [α]D25 –7.0 (c 1.6, CHCl3).
IR (neat): 3316, 3057, 2923, 2853, 1717, 1644, 1592, 1488, 1443,
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 37e
(682 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the mixture was
stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at 0 °C until
pH 6. After concentration of the reaction mixture in vacuo, H2O (10
mL) was added, and the resulting mixture was extracted with EtOAc
(3 × 10 mL). The combined extracts were washed with brine (2 × 10
mL), and dried (Na2SO4). Concentration of the solvent in vacuo afford-
ed a residue, which was purified by column chromatography (CH-
Cl3/MeOH 8:1) to give 16e (629 mg, 94%) as a colorless amorphous
solid; [α]D25 –3.1 (c 0.91, CHCl3).
1281, 1219, 1184, 1034, 970, 743, 620 cm–1
.
1H NMR (400 MHz, CDCl3/CD3OD 10:1): δ = 1.84–1.94 (m, 1 H), 2.02–
2.12 (m, 6 H), 2.16–2.23 (m, 2 H), 2.30–2.35 (m, 2 H), 2.46–2.54 (m, 2
H), 4.39–4.44 (m, 2 H), 5.40 (dd, J = 15.4, 6.1 Hz, 1 H), 5.54 (dt, J = 15.6,
6.3 Hz, 1 H), 7.18–7.55 (m, 15 H).
13C NMR (100 MHz, CDCl3/CD3OD 10:1): δ = 15.1, 29.5, 30.2, 31.2,
31.4, 43.3, 52.9, 66.5, 68.8, 126.5 (3 C), 127.7 (6 C), 129.4 (6 C), 129.5,
132.4, 144.7 (3 C), 172.3, 174.3.
HRMS (FAB): m/z calcd for C31H36NO4S2 [(M + H)+]: 550.2086; found:
550.2094.
IR (neat): 3316, 3060, 3029, 2925, 2853, 1715, 1644, 1495, 1444,
1217, 1082, 1034, 972, 744, 700, 620 cm–1
.
1H NMR (400 MHz, CDCl3/CD3OD 10:1): δ = 2.00–2.04 (m, 2 H), 2.14–
2.30 (m, 4 H), 2.99 (dd, J = 13.7, 7.8 Hz, 1 H), 3.19 (dd, J = 13.9, 4.1 Hz,
1 H), 4.22–4.26 (m, 1 H), 4.58–4.61 (m, 1 H), 5.30 (dd, J = 15.4, 6.1 Hz,
1 H), 5.43 (dt, J = 15.1, 6.3 Hz, 1 H), 7.15–7.39 (m, 20 H).
13C NMR (100 MHz, CDCl3/CD3OD 10:1): δ = 31.1, 31.3, 37.1, 42.2,
54.5, 66.4, 68.7, 126.5 (3 C), 126.6, 127.7 (6 C), 128.2 (2 C), 129.1 (2 C),
129.4 (6 C), 129.5, 132.2, 136.9, 144.7 (3 C), 172.2, 172.3.
(R)-2-[(S,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-4-(meth-
ylthio)butanoic Acid (34d)
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 38d
(638 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 34d (587 mg, 94%) as a colorless amor-
phous solid; [α]D25 –13.6 (c 1.0, CHCl3).
HRMS (FAB): m/z calcd for C35H36NO4S [(M + H)+]: 566.2365; found:
566.2378.
(R)-2-[(S,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-methyl-
butanoic Acid (34b)
IR (neat): 2956, 2928, 2861, 2360, 2341, 2087, 1644, 1557, 1540,
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 38b
(606 mg, 1.1 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
1488, 1444, 1219, 1033, 970, 742, 700, 669, 618 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

J
K. Narita et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.24–1.38 (m, 4
H), 1.61–1.73 (m, 1 H), 1.81–1.93 (m, 1 H), 2.02–2.06 (m, 2 H), 2.17–
2.20 (m, 1 H), 2.38 (d, J = 6.1 Hz, 2 H), 4.39–4.55 (m, 2 H), 5.40 (dd, J =
15.4, 6.1 Hz, 1 H), 5.51–5.61 (m, 1 H), 6.98–7.03 (m, 1 H), 7.18–7.40
(m, 15 H).
13C NMR (100 MHz, CDCl3): δ = 13.7, 22.1, 27.4, 31.2, 31.3, 31.4, 43.3,
52.4, 66.5, 69.0, 126.6 (3 C), 127.8 (6 C), 129.6 (6 C), 129.9, 132.1,
144.9 (3 C), 172.5, 175.6.
(c) Ueda, H.; Manda, T.; Matsumoto, S.; Mukumoto, S.;
Nishigaki, F.; Kawamura, I.; Shimomura, K. J. Antibiot. 1994, 47,
315.
(3) Furumai, R.; Matsuyama, A.; Kobashi, N.; Lee, K.-H.; Nishiyama,
M.; Nakajima, H.; Tanaka, A.; Komatsu, Y.; Nishino, N.; Yoshida,
M.; Horinouchi, S. Cancer Res. 2002, 62, 4916.
(4) Okuhara, M.; Goto, T.; Fujita, T.; Hori, Y.; Ueda, H. Jpn. Kokai
Tokkyo Koho JP 3141296, 1991.
(5) Spiruchostatins A (3) and B (4), see: (a) Masuoka, Y.; Nagai, A.;
Shin-ya, K.; Furihata, K.; Nagai, K.; Suzuki, K.; Hayakawa, Y.;
Seto, H. Tetrahedron Lett. 2001, 42, 41. Spiruchostatin C (5), see:
(b) Shindo, N.; Terada, A.; Mori, M.; Amino, N.; Hayata, K.; Nagai,
K.; Hayakawa, Y.; Shin-ya, K.; Masuoka, Y. (Yamanouchi Phar-
maceutical Co. Ltd.) Jpn. Kokai Tokkyo Koho JP 348340A, 2001.
Spiruchostatin D (6), see: (c) Nagai, K.; Taniguchi, M.; Shindo,
N.; Terada, Y.; Mori, M.; Amino, N.; Suzumura, K.; Takahashi, I.;
Amase, M. (Yamanouchi Pharmaceutical Co. Ltd.) PCT WO
20460 A1, 2004.
(6) Spiruchostatin A (3, registered as both YM753 and OBP-801) is
currently in human clinical trials (phase I) as a potential anti-
cancer therapy in the United States.
(7) Biggins, J. B.; Gleber, C. D.; Brady, S. F. Org. Lett. 2011, 13, 1536.
(8) (a) Wang, C.; Flemming, C. J.; Cheng, Y.-Q. Med. Chem. Commun.
2012, 3, 976. (b) Wang, C.; Henkes, L. M.; Doughty, L. B.; He, M.;
Wang, D.; Meyer-Almes, F. J.; Cheng, Y.-Q. J. Nat. Prod. 2011, 74,
2031.
HRMS (FAB): m/z calcd for C32H37NO4SNa [(M + Na)+]: 554.2341;
found: 554.2336.
(R)-2-[(S,E)-3-Hydroxy-7-(tritylthio)hept-4-enamido]-3-phenyl-
propanoic Acid (34e)
Aq 1 M LiOH (4.0 mL) was added dropwise to a stirred solution of 38e
(684 mg, 1.2 mmol) in MeOH (12 mL) at 0 °C, and the reaction mix-
ture was stirred at rt for 2 h. Aq 1 M HCl was added to the mixture at
0 °C until pH 6. After concentration of the reaction mixture in vacuo,
H2O (10 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 10 mL). The combined extracts were washed with brine
(2 × 10 mL), and dried (Na2SO4). Concentration of the solvent in vacuo
afforded a residue, which was purified by column chromatography
(CHCl3/MeOH 8:1) to give 34e (625 mg, 94%) as a colorless amorphous
solid; [α]D25 –10.0 (c = 1.0, CHCl3).
IR (neat): 3320, 3059, 3029, 2925, 1741, 1644, 1580, 1490, 1443,
1217, 1081, 1034, 972, 751, 700, 617 cm–1
.
(9) Total synthesis of FK228 (1, romidepsin): (a) Narita, K.; Kikuchi,
T.; Watanabe, K.; Takizawa, T.; Yamori, T.; Yoshida, M.; Katoh, T.
Chem. Eur. J. 2009, 15, 11174. (b) Greshock, T. J.; Johns, D. M.;
Noguchi, Y.; Williams, R. M. Org. Lett. 2008, 10, 613. (c) Wen, S.;
Packham, G.; Ganesan, A. J. Org. Chem. 2008, 73, 9353. (d) Li, K.
W.; Wu, J.; Xing, W.; Simon, J. A. J. Am. Chem. Soc. 1996, 118,
7237.
(10) Total synthesis of FR901375 (2): (a) Narita, K.; Katoh, Y.; Ojima,
K.; Dan, S.; Yamori, T.; Ito, A.; Yoshida, M.; Katoh, T. Eur. J. Org.
Chem. 2016, 5667. (b) Chen, Y.; Gambs, C.; Abe, Y.; Wentworth,
P. Jr.; Janda, K. D. J. Org. Chem. 2003, 68, 8902.
1H NMR (400 MHz, CDCl3/CD3OD 10:1): δ = 1.97–2.02 (m, 2 H), 2.12–
2.26 (m, 4 H), 2.91 (dd, J = 13.7, 8.8 Hz, 1 H), 3.20 (dd, J = 13.9, 4.1 Hz,
1 H), 4.32 (dd, J = 11.7, 6.3 Hz, 1 H), 4.58–4.62 (m, 1 H), 5.28 (dd, J =
15.6, 5.9 Hz, 1 H), 5.42 (dt, J = 15.6, 6.3 Hz, 1 H), 7.14–7.41 (m, 20 H).
13C NMR (100 MHz, CDCl3/CD3OD 10:1): δ = 31.2, 31.3, 36.9, 43.2,
54.8, 66.4, 68.6, 126.5 (3 C), 126.5, 127.7 (6 C), 128.2 (2 C), 129.0 (2 C),
129.3, 129.4 (6 C), 132.3, 137.0, 144.7 (3 C), 172.3, 172.4.
HRMS (FAB): m/z calcd for C35H35NO4SK [(M + K)+]: 604.1924; found:
604.1911.
(11) Total synthesis of spiruchostatin
A (3): (a) Yoshida, M.;
Sasahara, K.; Doi, T. Tetrahedron 2015, 71, 7647. (b) Calandra, N.
A.; Cheng, Y. L.; Kocak, K. A.; Miller, J. S. Org. Lett. 2009, 11, 1971.
(c) Takizawa, T.; Watanabe, K.; Narita, K.; Kudo, K.; Oguchi, T.;
Abe, H.; Katoh, T. Heterocycles 2008, 76, 275. (d) Doi, T.; Iijima,
Y.; Shin-ya, K.; Ganesan, A.; Takahashi, T. Tetrahedron Lett. 2006,
47, 1177. (e) Yurek-George, A.; Habens, F.; Brimmell, M.;
Packham, G.; Ganesan, A. J. Am. Chem. Soc. 2004, 126, 1030.
(12) Total synthesis of spiruchostatin B (4): (a) Fuse, S.; Okada, K.;
Iijima, Y.; Munakata, A.; Machida, K.; Takahashi, T.; Takagi, M.;
Shin-ya, K.; Doi, T. Org. Biomol. Chem. 2011, 9, 3825.
(b) Takizawa, T.; Watanabe, K.; Narita, K.; Kudo, K.; Oguchi, T.;
Abe, H.; Katoh, T. Chem. Commun. 2008, 1677.
Funding Information
Financial support was provided by the Japan Agency for Medical Re-
search and Development (Grant: Translational Research Network Pro-
gram) and Ministry of Education, Culture, Sports, Science and
Technology of Japan (Grant: Strategic Research Foundation Program
at Private Universities S15110010L).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612059.
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(13) Total synthesis of spiruchostatins C (5) and D (6): Narita, K.;
Fukui, Y.; Sano, Y.; Yamori, T.; Ito, A.; Yoshida, M.; Katoh, T. Eur.
J. Med. Chem. 2013, 60, 295.
References
(14) Total synthesis of burkholdacs A (7, thailandepsin C) and/or B
(8, thailandepsin A): (a) Fukui, Y.; Narita, K.; Dan, S.; Yamori, T.;
Ito, A.; Yoshida, M.; Katoh, T. Eur. J. Med. Chem. 2014, 76, 301.
(b) Liu, J. Y.; Ma, X.; Liu, Y.; Wang, Z.; Kwong, S.; Ren, Q.; Tang, S.;
Meng, Y.; Xu, Z.; Ye, T. Synlett 2012, 23, 783. (c) Benelkebir, H.;
Donlevy, A. M.; Packham, G.; Ganesan, A. Org. Lett. 2011, 13,
6334.
(1) (a) Van der Molen, K. M.; McCulloch, W.; Pearce, C. J.; Oberlies,
N. H. J. Antibiot. 2011, 64, 525. (b) Grant, C.; Rahman, F.; Piekarz,
R.; Peer, C.; Frye, R.; Robey, R. W.; Gardner, E. R.; Figg, W. D.;
Bates, S. E. Expert Rev. Anticancer Ther. 2010, 10, 997.
(2) (a) Ueda, H.; Nakajima, H.; Hori, Y.; Fujita, T.; Nishimura, M.;
Goto, T.; Okuhara, M. J. Antibiot. 1994, 47, 301. (b) Shigematsu,
N.; Ueda, H.; Takase, S.; Tanaka, H. J. Antibiot. 1994, 47, 311.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K

K
K. Narita et al.
Paper
Synthesis
(15) Total synthesis of thailandepsin B (10): (a) Narita, K.; Katoh, T.
Chem. Pharm. Bull. 2016, 64, 913. (b) Cheng, Y.-Q.; Yang, S.;
Wang, P. (ChinAn PharmaTech Wuhan Co., Ltd.) PCT WO
131355A1, 2015.
Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(d) For the Mitsunobu method, see: Mitsunobu, O. Synthesis
1981, 1.
(17) We also could not reproduce the Simon’s asymmetric aldol
reaction (i.e., Scheme 2, eq. 1, 27 + 28 → 29, 95% yield with 98%
ee). Our several follow-up experiments resulted in poor yield
(~20%) of 29 with 95–98% ee.
(16) (a) Being different from the case of the syntheses of FK228 (1)
and FR901375 (2), the enantiomer of 21 (ent-21) is necessary
for the key intermediate of spiruchostatins 3–6, burkholdacs
7and 8, and thailandepsins 7–12. This is because, in those syn-
theses, typical macrolactonization methods (e.g., the Shiina
method and the Yamaguchi method), which proceed via reten-
tion of the stereochemistry at the hydroxy group, were
employed instead of the Mitsunobu macrolactonization
method. (b) For the Shiina method, see: Shiina, I.; Katoh, T.;
Nagai, S.; Hashizume, M. Chem. Rec. 2009, 9, 305. (c) For the
Yamaguchi method, see: Inanaga, J.; Hirata, K.; Saeki, H.;
(18) (a) Based on the present study, industrial synthesis of FK-A11,
which is
a novel bicyclic depsipeptide histone deacetyl-
ase/phosphatidylinositol 3-kinase dual inhibitor under preclini-
cal trials, has been carried out at Hamari Chemicals, Ltd. (Osaka,
Japan). (b) cf. Saijo, K.; Imai, H.; Chikamatsu, S.; Narita, K.;
Katoh, T.; Ishioka, C. Cancer Sci. 2017, 108, 1469.
(19) Sayar, N.; Narita, K.; Katoh, T. Synthesis 2019, 51, in press, DOI:
10.1055/s-0037-1611707.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–K