Asymmetric synthesis of (E)-dehydroapratoxin A

Article abstract of DOI:10.1016/j.tetlet.2011.05.107

An asymmetric approach to key intermediate 17 starting from lactone 7 is described, in which Evan's alkylation and CBS-catalyzed reduction are used for construction of the chiral centers, respectively. Thus, the synthesis of (E)-dehydroapratoxin A 6 could

Full text of DOI:10.1016/j.tetlet.2011.05.107

Tetrahedron Letters 52 (2011) 4598–4601
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of (E)-dehydroapratoxin A
Jing-Yi Ma a, Wei Huang a, Bang-Guo Wei a,b,
⇑
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric approach to key intermediate 17 starting from lactone 7 is described, in which Evan’s
alkylation and CBS-catalyzed reduction are used for construction of the chiral centers, respectively. Thus,
the synthesis of (E)-dehydroapratoxin A 6 could be accomplished in a general fashion, therein FDPP has
been proven as an efficient condensation reagent for the coupling of amine 25 and carboxylic acid 24.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 April 2011
Revised 16 May 2011
Accepted 24 May 2011
Available online 25 July 2011
Keywords:
Depsipeptide
Marine cyanobacteria
Apratoxin
Total synthesis
Macrolactamization
Introduction
Apratoxins A–C (1–3) were isolated from the remarkably pro-
lific Lyngbya majuscula collected in Guam and Palau.5 Apratoxin E
5 was also isolated from Lyngbya bouillonii collected in Guam,6
while apratoxin D 4 from a variety of the same species was col-
lected in Papua New Guinea (Fig. 1).7 All of those isolated marine
Marine cyanobacteria have stimulated enormous efforts for drug
discovery or probe due to their complex molecular structures and
remarkable biological activities.1 Most of these secondary metabo-
lites are predominantly modified peptides, depsipeptides, polyke-
tides, and peptide–polyketide hybrids.2 Although several bioactive
compounds have been advanced to phase II clinical trial for treat-
ment cancers,3,4 many other cyanobacterial metabolites still remain
further search either for new pharmaceutically relevant lead com-
pounds or for their modes of action. As a prime instance, apratoxins
exhibit potent cancer growth inhibitory activity by inducing G1
phase specific cell cycle arrest and apoptosis.4
S
N
H
N
O
O
N
O
O
O
O
S
H
N
(S)
(S)
N
O
O
N
N
HO
O
N
O
O
Apratoxin E 5
O
O
S
H
N
O
R2
O
N
N
R1
N
O
N
O
O
Apratoxin A
Apratoxin B
Apratoxin C
Apratoxin D
1
2
3
4
R1= Me; R2 = t-Bu
R1= H; R2 = t-Bu
R1= Me; R2 = i-Pr
O
O
N
O
N
R1= Me; R2
=
(E)-Dehydroapratoxin A
6
⇑
Corresponding author. Tel./fax: +86 21 54237757.
E-mail address: bgwei1974@fudan.edu.cn (B.-G. Wei).
Figure 1. The structures of apratoxin A–E and (E)-dehydroapratoxin A.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.107

J.-Y. Ma et al. / Tetrahedron Letters 52 (2011) 4598–4601
4599
secondary metabolites show potent in vitro cytotoxicity against
LoVo cell lines (0.36–10.8 nM) and the KB (0.52–21.3 nM).5a,6
Due to its high efficacy for cancer cell growth inhibition and
intriguing structure, tremendous efforts have been devoted to the
asymmetric synthesis of apratoxin A8 and its analogs,8f,g,9 as well
as its mechanism of action.4,10 Dehydroapratoxin A5b 6, eliminated
from apratoxin A under weakly acidic conditions, suggests that the
elimination obviously affects the potency of cytotoxicity against
the HT-29 colon adenocarcinoma (IC50 41 nM for 6) and LeLa cer-
vical carcinoma (IC50 121 nM for 6).6 Interestingly, there exists a
significant correlation between the cytotoxicity of apratoxin family
members and their proportion of the trans amide isomer [in NMR
(CDCl3), apratoxins A 1, >90%; apratoxin B 2, ꢀ75%; apratoxin C
3, >90%; apratoxin E 5, ꢀ60% and (E)-dehydroapratoxin A 6,
ꢀ40%],5b but it is unknown whether those family compounds dis-
play different stereochemistry in the aqueous solution.6 In more
recent years, most studies have been focused on apratoxin A and
its oxazoline analogs, only little research on other members of
apratoxins and their analogs.8g It prompts us to develop a general
approach for synthesis of a series of apratoxins, and to study their
structure–activity relationship, as one part of our continuous inter-
est in pursuing some concise synthesis of piperidine alkaloids, dep-
sipeptides and ceramides.11 Herein we present a general method
for asymmetric synthesis of (E)-dehydroapratoxin A 6.
Peptide formation Thiazoline construction
S
H
N
O
34
Wittig reaction
N
O
N
O
O
O
O
N
O
6
N
Macrocyclization
(E)-Dehydroapratoxin A 6
S
O
NH2
HO
N
O
N
O
+
O
O
N
O
Fmoc
N
OAllyl
STrt
O
25
24
AllylO
HO
NH2
O
O
O
7
21
Results and discussion
+
Our synthetic strategy for asymmetric synthesis of (E)-dehydro-
apratoxin A 6 has been illustrated in Scheme 1. We envisaged to se-
lect the macrolactamization as the final step, without trouble for the
epimerization at the C34 position in our target, which usually oc-
curred in the synthesis of apratoxin A and its analog.8,9 The methods
for the formation of thiazoline ring and tripeptide fragment 25 are
similar to the previously reported method for the synthesis of apra-
toxin A and its analogs.8,9 However, we hope to improve the yield by
other condensation reagents in the connection of fragment 25 and
24. Furthermore, in our synthetic route, our aim is to achieve a scal-
able method for preparation of the free acid part 20 using the asym-
metric methylation induced by chiral auxiliary and stereoselective
reduction, which could be further used for asymmetric synthesis
of a series of apratoxins and their analogs.
The first challenge in our synthetic synthesis was the preparation
of the enantiopure (3S,5S)-7-(tert-butyldimethylsilyloxy)-2,2,5-
trimethylheptan-3-ol 17. The synthesis was achieved from commer-
cially starting material lactone 7, as outlined in Scheme 2. Following
treatment of lactone 7 with sodium hydroxide and subsequent pro-
tection (TBSCl, Imidazole) of the primary alcohol, free acid 8 was
achieved in 81% overall yield. Then, intermediate 8 was activated
with ethyl chlorocarbonate and subsequently the resulting mixture
was treated with lithium salt of oxazolidinone to afford amide 9 in
74% yield, which was methylated with MeI at ꢁ78 °C to afford prod-
uct 10 with high diasteroselectivity (dr >98:2) in 76% yield. Removal
of the auxiliary12 (LiBH4, H2O) produced the primary alcohol 11 in
93% yield. Mesylation (MsCl, TEA) and nucleophilic substitution
(NaCN, DMSO) afforded cyanide 12 in 95% overall yield. Then reduc-
tion of the compound 12 with DIBAL-H13 at ꢁ78 °C gave the corre-
sponding aldehyde without further purification, which was
oxidized with NaClO214 in the presence of 2-methyl-2-butene to af-
ford acid 13 in 90% overall yield. The compound 13 was easily con-
verted to the Weinreb amide 14 in the presence of HATU15 in 89%
yield. To prepare the ketone 15, the Weinreb amide 14 was treated
with a solution of tert-butylmagnesium chloride to give desired ke-
tone 15 in low yield. But when a solution of tert-butyllithium
(2.0 mmol in Et2O) was used, the reaction was quickly finished at
ꢁ10 °C for 5 min and produced 15 in 81% yield. The keto functional-
ity in 15 was stereoselectively reduced to alcohol by using a catalytic
TBSO
O
15
O
OTBS
20
Asymmetric Reduction
Scheme 1. The retrosynthetic analysis of (E)-dehydroapratoxin A.
Bn
O
(S)
OTBS
OH
a
b
TBSO
O
N
O
O
O
O
7
8
9
Bn
(S)
OTBS
c
d
HO
O
N
(S)
(S)
OTBS
O
O
11
10
O
OTBS
g
e
f
NC
(S)
(R)
HO
OTBS
12
13
O
OTBS
O
h
OMe
i
(S)
TBSO
TBSO
N
(S)
14
15
OH
OTBS
j
(S)
(S)
(S)
(S)
HO
16
17
Scheme 2. Reagents and conditions: (a) (i) NaOH, H2O, reflux, 4 h; (ii) TBSCl, Imi.,
DMAP, DMF, overnight, 81% (two steps); (b) ClCOOC2H5, THF, 0 to ꢁ78 °C, 1 h, then
(S)-4-benzyl-oxazolidinone, n-BuLi, THF, ꢁ78 °C to rt, 6 h, 74%; (c) NaHMDS, MeI,
THF, ꢁ78 °C to rt, overnight, 76%; (d) LiBH4, MeOH, THF, 0 °C, 4 h, 93%; (e) (i) MsCl,
TEA, DCM, rt, 30 min; (ii) KCN, DMSO, 60 °C, 4 h, 95% (two steps); (f) (i) DIBAL-H,
DCM, ꢁ78 °C, 2 h; (ii) NaClO2, NaH2PO4ꢂ2H2O, 2-methyl-2-butene, t-BuOH, H2O,
0 °C, 2 h, 90%; (g) NHMe(OMe)ꢂHCl, HATU, DIPEA, DMF, 0 °C to rt, 5 h, 89%; (h) t-
BuLi, Et2O, ꢁ10 °C, 5 min, 81%; (i) (R)-CBS, toluene, 40 °C, 6 h, 92%; (j) (i) 2,6-
lutidine, TBSOTf, DCM, 0 °C to rt, 3 h; (ii) p-TsOH, MeOH, rt, 2 h, overall yield 92%.

4600
J.-Y. Ma et al. / Tetrahedron Letters 52 (2011) 4598–4601
amount of Corey’s chiral borane, R-CBS catalyst16 in the presence of
BH3ꢂDMS to yield a partly separable mixture of products 16 (syn/
anti = 88:12) in 92% combined yield. Finally, protection (TBSOTf,
2,6-lutidine) of the compound 16 and subsequent selective depro-
tection (p-TsOH, MeOH) afforded the desired primary alcohol 17 in
92% overall yield.
produced secondary alcohol, which was directly esterified with N-
Fmoc-Pro-OH under Yamaguchi condition18 to give 23 in 94% yield.
Then compound 23 was treated with POPh3/Tf2O19 in CH2Cl2 at
0 °C to form the desired thiazoline, which was subsequently trea-
20
ted with N-methylaniline in the presence of Pd(PPh3)4 to give
free acid 24 in 78% overall yield21 (Scheme 4).
With key intermediate 17 in hand, the fragment 20 was easily
prepared by Wittig reaction (Scheme 3). Swern oxidization17 of
alcohol 17 with DMSO/(COCl)2 at ꢁ78 °C provided unpurified alde-
hyde 18, which was directly subjected to Wittig reaction with
Ph3P@C(CH3)COOC2H5 to generate single isomer of olefin 19 in
86% isolated overall yield. Then, hydrolysis of olefin 19 with
LiOHꢂH2O gave the corresponding carboxylic acid 20 in 94% yield.
The fragment 21 was easily synthesized by the known meth-
od.8e Then condensation between amine 21 and carboxylic acid
20 in the presence of HATU afforded amide 22 in 89% yield.
Removal of silyl-protecting group with a solution of 6 N HCl/EtOAc
Tripeptide 25 was prepared by sequential coupling of N-meth-
ylisoleucine allyl ester with N-Boc-N-methylalanine and N-Fmoc-
O-methyltyrosine by the known method.8e Although HATU or
PyAOP was reported to be an effective reagent for the condensation
between similar amine 25 and carboxylic acid 24 in robust chem-
istry,8b,e we had tested several condensation reagents and found
that the yield of compound 26 was very low (about 39%). We
thought that the slightly different structure might affect the yield
of condensation. Gratefully, when pentafluorophenyl diphenylph-
ophinate (FDPP)22 was used, the condensation of amine 25 with
carboxylic acid 24 in acetonitrile at 0 °C smoothly produced amide
26 in 91% yield.23 Sequential cleavage of allyl ester by N-methylan-
iline in the presence of Pd(PPh3)4 and removal of the Fmoc protect-
ing group with Et2NH/CH3CN afforded the cyclization precursor
without further purification. Finally, the macrolactamization of
the crude cyclization precursor was performed with HATU/DIEA
to give crude (E)-dehydroapratoxin A 6 in 42% yield24 over three
steps. The crude dehydroapratoxin A 6 was further purified by RP
C18 HPLC with 80% aqueous CH3CN (Sepax-tech Amethyst C18
semipreparative column, 250 mm ꢃ 150 mm, 10 mL/min, refrac-
OTBS
OTBS
a
b
HO
O
18
17
HO
C2H5O
tive index detection) {½a D25
ꢄ
ꢁ146.8 (c 0.4, MeOH), lit.5b
½
a 2D5
ꢄ
ꢁ133
c
O
OTBS
O
OTBS
(c 0.30, MeOH)}, and afforded the sample with a satisfied purity
(up to 99%), which was determined by HPLC (Kromasil C18
19
20
column, 5
lm, 4.6 ꢃ 150 mm; 1.0 mL/min; UV 220 nm; retention
Scheme 3. Reagents and conditions: (a) DMSO, (COCl)2, ꢁ78 °C, 30 min, 96%; (b)
time is 11.29 min) using 80% aqueous CH3CN. The structure of
Ph3P@C(CH3)COOC2H5, toluene, rt, 4 h, 90%; (c) LiOHꢂH2O, THF, MeOH, H2O, rt, 3 h,
94%.
S
H
O
N
N
STrt
HO
+
O
a
N
O
O
a
AllylO
24 + 25
NH2
O
OTBS
b
O
O
20
O
N
21
Fmoc
N
OAllyl
O
STrt
NH
26
O
S
H
O
N
O
O
N
O
OTBS
O
22
N
O
O
STrt
b
O
O
O
N
NH
H
N
OH
O
O
O
O
27
S
N
23
FmocN
H
O
N
O
S
N
O
O
c
N
O
c
O
O
O
N
O
N
FmocN
HO
O
24
(E)-Dehydroapratoxin A 6
Scheme 4. Reagents and conditions: (a) HATU, DIPEA, DMF, 0 °C to rt, overnight,
89%; (b) (i) 6 N HCl, EA, 0 °C, 3 h, 97%; (ii) Fmoc-Pro-OH, 2,4,6-trichlorobenzoyl
chloride, DIPEA, DMAP, 0 °C to rt, overnight, 94%; (c) (i) POPh3, Tf2O, DCM, 0 °C,
30 min, 87%; (ii) Pd(PPh3)4, N-methylaniline, rt, 2 h, 90%.
Scheme 5. Reagents and conditions: (a) FDPP, DIPEA, 0 °C to rt, overnight, 91%; (b) (i)
Pd(PPh3)4, N-methylaniline, rt, 2 h; (ii) Et2NH, MeCN, rt, 15 min; (c) HATU, DIPEA,
DCM(0.001 M), 0 °C to rt, 2d, 42% (three steps).

J.-Y. Ma et al. / Tetrahedron Letters 52 (2011) 4598–4601
4601
12. Smith, A. B., III; Lee, D. J. Am. Chem. Soc. 2007, 129, 10957.
13. Qi, X.-X.; Wang, X.-L.; Wang, L.-M.; Wang, Q.; Cheng, S.-X.; Suo, J.-S.; Chang, J.-
B. Eur. J. Med. Chem. 2005, 40, 805.
14. Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559.
15. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
dehydroapratoxin A 6 was further confirmed by two-dimensional
NMR spectroscopic data, and the spectroscopic data of 1H and
13C NMR agreed with that of the reported data (Scheme 5).5b
16. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551; (b)
Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611; (c) Corey, E. J.; Helal, C.
J. Angew. Chem., Int. Ed. 1998, 37, 1986.
Conclusion
17. Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
18. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
In summary, the key intermediate 17 was achieved by a gram
scalable method, thereby one approach was established by asym-
metric synthesis of (E)-dehydroapratoxin A 6 from the commercially
starting material lactone 7 in a general fashion. Furthermore, FDPP
was found to be an efficient condensation reagent for the coupling
of amine 25 and free acid 24. Synthesis of other apratoxins and their
analogs through the intermediate 17 is now in progress in our
laboratory.
19. You, S.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003, 42, 83.
20. Ciommer, M.; Kunz, H. Synlett 1991, 593.
21. The date of compound 24: ½a D25
= ꢁ80.6 (c 3.72, CHCl3); IR (film): mmax 3418,
ꢄ
2958, 2924, 2860, 1705, 1652, 1575, 1451, 1417, 1356, 1196, and 1176 cmꢁ1
;
1H NMR (400 MHz, CDCl3, mixture of rotamers) d: 10.12 (brs, 1H), 7.78 (d,
J = 7.6 Hz, 2H), 7.71–7.63 (m, 1.5H), 7.60 (d, J = 7.6 Hz, 0.5H), 7.42 (dd, J = 7.6,
7.2 Hz, 2H), 7.37–7.31 (m, 2H), 6.95–6.88 (m, 1H), 6.25 (dd, J = 6.8, 7.2 Hz,
0.6H), 6.12 (dd, J = 6.8, 7.2 Hz, 0.4H), 5.35–5.25 (m, 1H), 4.97–4.88 (m, 1H),
4.59–4.46 (m, 2H), 4.39 (dd, J = 10.0, 7.6 Hz, 0.6H), 4.31 (dd, J = 7.4, 7.2 Hz,
0.6H), 4.27–4.18 (m, 0.8H), 3.78–3.66 (m, 1H), 3.65–3.55 (m, 1H), 3.39 (dd,
J = 10.8, 8.4 Hz, 0.4H), 3.29 (dd, J = 10.4, 8.4 Hz, 0.6H), 2.93 (dd, J = 10.8, 9.6 Hz,
0.4H), 2.81 (dd, J = 10.8, 8.4 Hz, 0.6H), 2.48–2.23 (m, 2.1H), 2.22–2.04 (m, 3.1H),
2.03–1.88 (m, 6H), 1.85–1.74 (m, 0.8H), 1.62–1.41 (m, 2.8H), 1.35–1.24 (m,
0.4H), 0.96 (d, J = 6.8 Hz, 1.6H), 0.93 (s, 9H), 0.75 (d, J = 6.8 Hz, 1.4H) ppm; 13C
NMR (125 MHz, CDCl3, mixture of rotamers) d: 172.6, 172.5, 172.1, 154.8,
154.5, 144.2, 144.1, 143.9, 141.9, 141.8, 141.3, 140.5, 139.0, 134.6, 132.5, 132.2,
132.0, 130.8, 129.1, 128.6, 127.7, 127.1, 125.3, 120.0, 79.8, 79.3, 74.4, 74.1, 67.8,
67.6, 59.6, 59.4, 47.3, 47.0, 46.5, 37.4, 37.1, 36.8, 34.7, 34.3, 34.1, 31.3, 30.0,
29.7, 29.3, 25.9, 24.4, 23.4, 21.1, 20.8, 14.6, and 12.8 ppm; MS(ESI) m/z: 694.9
(M+Na+); HRMS (MALDI/DHB) calcd for [C39H48N2O6S+H+]: 673.3311, found:
673.3292.
Acknowledgments
We thank the National Natural Science Foundation of China
(21072034, 20832005, and 20702007), and Key Laboratory of Syn-
thetic Chemistry of Natural Substances, SIOC of Chinese Academy
of Sciences, as well as the National Basic Research Program (973
program) of China (Grant No. 2010CB912600) for financial support.
The authors also thank Dr. Xin-Sheng, Lei for helpful suggestions.
22. Chen, S.; Xu, J. Tetrahedron Lett. 1991, 32, 6711.
Supplementary data
23. The date of compound 26: ½a D25
= ꢁ115.6 (c 1.01, CHCl3); IR (film): mmax 3428,
ꢄ
2959, 2925, 2855, 1738, 1705, 1634, 1583, 1513, 1451, 1416, 1355, 1248, and
Supplementary data ((copies of 1H, 13C NMR for compounds 24,
26 and (E)-dehrdroapratoxin A 6) are available online with this pa-
per in Science Direct) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.107.
1179 cmꢁ1 1H NMR (400 MHz, CDCl3, mixture of rotamers) d: 7.78 (d, J = 6.8 Hz,
;
2H), 7.71–7.57 (m, 2H), 7.41 (dd, J = 7.6, 7.2 Hz, 2H), 7.32 (dd, J = 7.6, 7.2 Hz, 2H),
7.12 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.45 (dd, J = 6.8, 6.2 Hz, 0.7H), 6.30
(dd, J = 7.2, 6.8 Hz, 1H), 6.21 (dd, J = 7.2, 6.8 Hz, 1H), 6.09 (dd, J = 6.8, 6.4 Hz,
0.3H), 5.96–5.84 (m, 1H), 5.55 (dd, J = 13.6, 6.4 Hz, 0.2H), 5.44 (dd, J = 13.2,
6.8 Hz, 0.8H), 5.32 (d, J = 17.6 Hz, 1H), 5.28–5.13 (m, 3H), 4.97 (d, J = 10.0 Hz, 1H),
4.91 (dd, J = 10.2, 10.0 Hz,1H), 4.62 (d, J = 5.2 Hz, 2H), 4.57–4.43 (m, 2H), 4.34
(dd, J = 10.0, 7.6 Hz, 0.5H), 4.30 (dd, J = 7.2, 6.4 Hz, 0.5H), 4.25–4.17 (m, 1H), 3.78
(s, 3H), 3.75–3.65 (m, 1H), 3.64–3.54 (m, 1H), 3.36 (dd, J = 10.0, 9.6 Hz, 0.4H) 3.27
(dd, J = 10.4, 8.8 Hz, 0.6H), 3.13–3.03 (m, 1H), 3.01 (s, 3H), 2.94–2.81 (m, 2H),
2.79 (s, 3H), 2.45–2.22 (m, 2H), 2.20–2.02 (m, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.84–
1.72 (m, 1H), 1.60–1.41 (m, 2H), 1.35–1.22 (m, 6H), 1.05–0.94 (m, 7H), 0.94–0.86
(m, 10.5H), 0.75 (d, J = 6.4 Hz, 1.5H) ppm; 13C NMR (125 MHz, CDCl3, mixture of
rotamers) d: 172.6, 171.9, 171.5, 170.6, 168.2, 158.7, 154.7, 144.3, 144.1, 141.3,
132.9, 132.6, 132.2, 131.8, 130.4, 128.5, 128.0, 128.6, 128.4, 127.7, 127.1, 125.2,
120.0, 118.7, 114.0, 79.3, 74.5, 67.5, 65.4, 60.5, 59.6, 59.3, 55.2, 50.5, 49.6, 47.3,
47.0, 46.4, 37.8, 37.5, 36.8, 34.7, 34.3, 34.0, 33.3, 31.3, 31.0, 30.6, 30.0, 29.7, 29.4,
25.9, 25.1, 24.4, 23.3, 21.0, 20.7, 15.8, 14,6, 14.4, 13.4, and 10.6 ppm; MS(ESI) m/z:
1124.8 (M+Na+); HRMS (MALDI/DHB) calcd for [C63H83N5O10S+H+]: 1102.5939,
found: 1102.5933.
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Soc. 2001, 123, 5418; (b) Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.
Bioorg. Med. Chem. 2002, 10, 1973.
6. Matthew, S.; Schupp, P. J.; Luesch, H. J. Nat. Prod. 2008, 71, 1113.
7. Gutiérrze, M.; Suyama, T. L.; Engen, N.; Wingerd, J. S.; Matainaho, T.; Derwick,
W. H. J. Nat. Prod. 2008, 71, 1099.
8. Total synthesis of apratoxin A for see: (a) Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5,
1281; (b) Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125, 8734; (c) Chen, J.;
Forsyth, C. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12067; (d) Ma, D.; Zou, B.; Cai,
G.; Hu, X.; Liu, J. O. Chem. Eur. J. 2006, 12, 7615; (e) Doi, T.; Numajiri, Y.;
Munakata, A.; Takahashi, T. Org. Lett. 2006, 8, 531; (f) Numajiri, Y.; Takahashi,
T.; Doi, T. Chem. Asian J. 2009, 4, 111; (g) Doi, T.; Numajiri, Y.; Munakata, A.;
Takahashi, T.; Takagi, M.; Shin-ya, K. Chem. Asian J. 2011, 6, 180.
9. (a) Zou, B.; Wei, J.; Cai, G.; Ma, D. Org. Lett. 2003, 5, 3503; (b) Gilles, A.;
Martinez, J.; Cavelier, F. J. Org. Chem. 2009, 74, 4298.
24. The date of E-dehydroapratoxin A 6: ½a D25
ꢄ
= ꢁ146.8 (c 0.40, MeOH); IR (film):
m
max 3306, 2958, 2924, 2853, 1742, 1644, 1512, 1455, 1247, and 1177 cmꢁ1 1H
;
NMR (600 MHz, CDCl3, mixture of rotamers M/m = 3:2) d: 7.22–7.12 (m, 2H),
6.88–6.79 (m, 2H), 6.52 (d, J = 10.2 Hz, 0.6H), 6.39–6.30 (m, 1.4H), 6.19 (d,
J = 9.4 Hz, 0.4H), 5.95 (br d, J = 9.2 Hz, 0.3H), 5.49–5.45 (m, 0.6H), 5.43–5.38 (m,
0.4H), 5.38–5.33 (m, 0.6H), 5.11 (d, J = 10.8 Hz, 0.4H), 5.10–5.06 (m, 0.4H), 5.02
(dd, J = 11.6, 1.2 Hz, 0.4H), 4.99 (dd, J = 12.4, 1.6 Hz, 0.6H), 4.82 (d, J = 11.2 Hz,
0.6H), 4.78–4.73 (m, 0.6H), 4.40–4.36 (m, 0.6H), 4.22–4.18 (m, 0.4H), 4.17–4.12
(m, 0.4H), 4.06–4.01 (m, 0.6H), 3.80–3.77 (m, 3H), 3.67–3.59 (m, 1H), 3.48 (dd,
J = 10.2, 8.8 Hz, 0.4H), 3.43 (dd, J = 10.2, 9.0 Hz, 0.6H), 3.37–3.33 (m, 0.4H), 3.23
(dd, J = 12.6, 11.4 Hz, 0.6H), 3.19–3.11 (m, 1H), 3.10–3.06 (m, 0.4H), 2.94–2.89
(m, 2H), 2.88–2.85 (m, 1H), 2.84–2.78 (m, 2H), 2.71–2.59 (m, 3H), 2.31–2.22
(m, 1H), 2.08–1.87 (m, 10H), 1.74–1.53 (m, 3H), 1.35–1.45 (m, 0.6H), 1.36–1.24
(m, 1.8H), 1.13 (d, J = 6.0 Hz, 1.8H), 1.02 (d, J = 5.6 Hz, 1.8H), 0.98–0.86 (m,
13.6H), 0.86–0.82 (m, 1.8H), 0.66 (d, J = 6.0 Hz, 1.8H) ppm; 13C NMR (125 MHz,
CDCl3, mixture of rotamers) d: 173.1, 173.0, 172.6, 172.0, 171.1, 170.6, 170.4,
170.2, 170.0, 169.9, 169.5, 167.5, 158.6, 139.4, 139.3, 136.4, 135.6, 132.1, 131.7,
130.7, 130.5, 128.6, 128.4, 128.3, 114.0, 113.8, 77.9, 73.1, 72.9, 60.5, 59.6, 58.8,
58.0, 57.0, 55.3, 53.9, 50.7, 50.3, 47.5, 47.3, 39.3, 38.8, 38.0, 37.1, 37.0, 36.7,
35.1, 34.7, 34.1, 34.0, 33.8, 30.8, 30.1, 29.7, 29.5, 29.4, 29.3, 28.8, 28.2, 26.1,
26.0, 25.9, 25.8, 25.7, 25.4, 25.1, 21.2, 21.1, 15.4, 14.7, 14.3, 14.1, 13.9, 13.8,
13.4, 12.7, 10.2, and 9.8 ppm; MS(ESI) m/z: 844.5 (M+Na+); HRMS (MALDI/
DHB) calcd for [C45H67N5O7S+Na+]: 844.4659, found: 844.4652.
10. (a) Liu, Y.; Law, B. K.; Luesch, H. Mol. Pharmacol. 2009, 76, 91; (b) Shen, S.;
Zhang, P.; Lovchik, M. A.; Li, Y.; Tang, L.; Chen, Z.; Zeng, R.; Ma, D.; Yuan, J.; Yu,
Q. J. Cell Biol. 2009, 185, 629.
11. (a) Liu, R.-C.; Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19,
2731; (b) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett.
2009, 50, 4046; (c) Ma, J.-Y.; Xu, L.-F.; Huang, W.-F.; Wei, B.-G.; Lin, G.-Q.
Synlett 2009, 1307; (d) Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-G.
Tetrahedron Lett. 2010, 51, 4317.