Synthetic studies toward amphidinolide H1: Segment C14-C26

Article abstract of DOI:10.1055/s-2006-956498

Stereoselective synthesis of the C14-C26 moiety of amphidinolide H1 is described. The key features of the approach include the convergent fragment assembly with a highly diastereoselective aldol reaction to establish the C18 stereochemistry and using comm

Full text of DOI:10.1055/s-2006-956498

LETTER
87
Synthetic Studies toward Amphidinolide H1: Segment C14–C26
S
ynthetic Studie
i
s
towa
s
rd
A
mphi
h
dinolide H1:
e
Segment
C
n
14–C26 g Deng, Zhixiong Ma, Yazhu Zhang, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
Received 25 August 2006
aldol coupling
Abstract: Stereoselective synthesis of the C14–C26 moiety of
OH
18
O
Pd-catalyzed
Stille cross-coupling
amphidinolide H1 is described. The key features of the approach
include the convergent fragment assembly with a highly diastereo-
selective aldol reaction to establish the C18 stereochemistry and
using commercially available chiral pool.
OH
22
20
14
HO
13
25
O
Key words: amphidinolide H1, macrolide, aldol reaction, Wittig
reaction, dihydroxylation
OH
6
1
Mitsunobu
esterification
7
O
RCM
O
amphidinolide H1 (1)
A family of structurally diverse macrolides, the so-called
amphidinolides, was obtained from marine dinoflagel-
lates of the genus Amphidinium living in symbiosis with
Okinawan acoel flatworm Amphiscolops spp.1,2 Amphidi-
nolide H1 (1) and its congeners H2–H53a are a group of
26-membered macrolides bearing unique structural
features such as an allyl epoxide or vicinally located one-
carbon branches.3b
OH
O
OH
HO
OH
O
O
6
O
The gross structure of 1 was elucidated by the means of
2D NMR data, and the absolute stereochemistry was de-
termined on the basis of X-ray diffraction analysis and
degradation.4 It exhibits extremely potent cytotoxicity
against murine lymphoma L1210 and human epidermoid
carcinoma KB cell lines, which may result not only from
the characteristic groups such as S-cis-diene and the allyl
epoxide but also from its unique 3D structure.5 Due to its
biological activity and challenging structure, amphidino-
lide H1 represents an attractive synthetic interest,6,7 yet no
total synthesis of 1 has been reported to date. Very recent-
ly, we have finished the total synthesis of amphidinolide
T3 and formal synthesis of amphidinolide T4.8b Herein,
we describe the stereoselective synthesis of the C14–C26
fragment 12 of amphidinolide H1.
SnBu3
OTBS O
13
OMOM
18
20
22
I
MOMO
7
O
25
OTES
7
8
OTBDPS
1
OH
9
O
O
OMOM
22
CHO
20
10
TMS
MOMO
11
25
OTBDPS
OTES
Scheme 1 Retrosynthetic analysis of amphidinolide H1 (1)
As shown in Scheme 1, our initial retrosynthetic approach
involves an intramolecular ring-closing metathesis
(RCM) of alkene 6, which might be obtained from inter-
mediates 7, 8 and 9 either via an intermolecular Stille
coupling reaction, or via a Mitsunobu esterification. The
C14–C26 segment 7 of the top half of amphidinolide H1
could be furnished by an aldol coupling between the alde-
hyde 10 and methyl ketone 11.
methyl (R)-3-hydroxyl-2-methylpropionate or by the
Lewis acid mediated alkylation of N-propionyloxazolidi-
none with benzyl chloromethyl ether (Scheme 2).8
Treatment of alcohol 13 with mesyl chloride and triethyl-
amine in dichloromethane at 0 °C followed by displace-
ment of the resulting mesylate with sodium cyanide in
dimethyl sulfoxide at 60 °C provided cyanide 14 in 97%
yield. Diisobutylaluminum hydride (DIBAL-H) reduction
of cyanide 14 and subsequent treatment of the correspond-
ing aldehyde with sodium borohydride gave the primary
alcohol 15 in a good yield. After protection of the hydrox-
yl group of 15 with tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf), reductive removal of the
The synthesis of aldehyde 10 could be achieved by a mul-
tistep sequence9 from the known chiral alcohol 13, which
can be easily prepared either from commercially available
SYNLETT 2007, No. 1, pp 0087–0090
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-956498; Art ID: W17506ST
© Georg Thieme Verlag Stuttgart · New York

88
L. Deng et al.
LETTER
O
O
O
O
a, b
c, d
a, b
HO
TBDPSO
BnO
CN
H
BnO
BnO
OH
OH
15
13
14
19
20
OH
e, f
h, i
g
c
HO
OTBDPS
OTBDPS
OTBS
OTBS
EtOOC
EtOOC
21
O
17
16
OTES
O
d, e
j, k
H
OTBS
22
TMS
TMS
10
18
OMOM
OTES
f
Scheme 2 Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C;
(b) NaCN, DMSO, 60 °C, 97% over two steps; (c) DIBAL-H,
CH2Cl2, 0 °C, 91%; (d) NaBH4, CH2Cl2–MeOH, 0 °C–r.t., 85%; (e)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 96%; (f) Li, NH3 (l), THF, –78
°C, 99%; (g) DMP, CH2Cl2, NaHCO3, 84%; (h) CBr4, PPh3, 2,6-luti-
dine, CH2Cl2, 88%; (i) n-BuLi, TMSCl, THF, –78 °C, 97%; (j) CSA,
MeOH; (k) (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N, –40 °C,
82% over two steps.
OTBDPS
EtOOC
23
OMOM
OMOM
OTES
g
N
OTBDPS
MeO
O
OMOM
24
benzyl group in the resulting silyl ether was achieved in
the presence of lithium–ammonia at –78 °C to provide 16
in 99% yield. Oxidation of 16 using the Dess–Martin
periodinane followed by treatment of the corresponding
aldehyde with tetrabromomethane and triphenylphos-
phine led to the a,a-dibromoalkene in 88% yield,10 which
was next converted into trimethylsilyl alkyne 18 (97%)
using n-butyllithium and trimethylsilyl chloride (TMSCl)
at room temperature. After selective desilylation of 18
with 10-camphorsulfonic acid (CSA) in methanol, the
resulting alcohol was subjected to Swern oxidation con-
ditions to give the desired aldehyde 10 in 82% yield.11
OMOM
OTES
OTBDPS
O
11
OMOM
Scheme 3 Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C;
(b) Ph3P=CHCO2Et, benzene, 80 °C, 94% over two steps; (c) TE-
SOTf, 2,6-lutidine, 0 °C, 98%; (d) (DHQ)2PHAL, OsO4·H2O,
K3Fe(CN)6, K2CO3, NaHCO3, MeSO2NH2, tert-BuOH–H2O; (e)
MOMCl, DIPEA, TBAI, CH2Cl2, 40 °C, 86% over two steps; (f)
MeON(Me)H·HCl, LHMDS, THF, –50 °C, 98%; (g) MeLi, THF,
–78 °C, 98%.
to an aldol product in 63% yield with excellent diastereo-
selectivity (dr > 15:1), which was in contrast to the work
on synthetic studies toward amphidinolide B by
Pattenden’s and Kobayashi’s groups.7e,i In their efforts,
non-chelating silyl protecting groups17 were employed on
C21 of the enolate. We speculated that the good selectiv-
ity at C18 might be attributed to the existence of the a-
chelating MOM group on the enolate, as shown in the
model TS on the basis of published literature.7b,18 How-
ever, a lower selectivity (dr 5:1) occurred when methyl
ketone 26 was applied in the aldol reaction with 10. It was
noteworthy that the solvent was important in this reaction
and diethyl ether did not give a good result (dr 3:1). Fur-
thermore, the enolate generated from lithium diisopropyl-
amide in tetrahydrofuran or in diethyl ether gave poor
selectivity. The stereochemistry at C18 of 25 was in
accordance with that in 1 on the basis of Mosher ester
analysis.19 Finally, protection of the resulting secondary
alcohol with TBSOTf provided the desired segment 12 in
97% yield.20
As outlined in Scheme 3, the synthesis of the C19–C26
fragment 11 was investigated using commercially avail-
able alcohol 19,12 which was conveniently converted into
20 by silylation and stereoselective methylation according
to the published procedures.13 DIBAL-H reduction of 15
followed by the Wittig reaction using Ph3P=CHCO2Et
afforded E olefin 21 in 94% yield in two steps. After sily-
lation of the resulting alcohol with triethylsilyl tri-
fluoromethanesulfonate (TESOTf), enoate 22 was then
dihydroxylated with AD-mix-a*14 in tert-butanol–water
at 0 °C to give a diol, which in turn was protected as meth-
oxymethyl (MOM) ether to provide ester 23 in a good
yield (86% over two steps). Various conditions were
screened for the formation of the Weinreb amide 24. Alu-
minum reagents gave poor yields of the triethylsilyl ether
23 (Me3Al, CH2Cl2, –10 °C–r.t., 11% yield). However, a
solution was found by using the modified method devel-
oped by Merck (LHMDS, THF, –50 °C) which afforded
the desired amide 24 in 98% yield.15 Next, the formation
of the methyl ketone 11 proceeded smoothly by treatment
of 24 with methyllithium at –78 °C.16
In summary, we have synthesized the C14–C26 segment
12 via a highly concise and convergent strategy in nine
steps from silyl ether 20 and 46% overall yield. A highly
diastereoselective aldol reaction was featured in this
approach. Further investigation toward the total synthesis
of amphidinolide H1 is currently underway in our
laboratory.
With the required two segments in hand, our subsequent
design strategy called for the assembly of the aldehyde 10
and methyl ketone 11 (Scheme 4). Treatment of 11 with
lithium hexamethyldisilazide (LHMDS) in tetrahydro-
furan at –78 °C followed by adding the precooled 10 led
Synlett 2007, No. 1, 87–90 © Thieme Stuttgart · New York

LETTER
Synthetic Studies toward Amphidinolide H1: Segment C14–C26
89
(6) Amphidinolide H1: (a) Chakraborty, T. K.; Suresh, V. R.
O
O
Tetrahedron Lett. 1998, 39, 7775. (b) Chakraborty, T. K.;
Suresh, V. R. Tetrahedron Lett. 1998, 39, 9109. (c) Sato,
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2000, 41, 503. (d) Liesener, F. P.; Kalesse, M. Synlett 2005,
2236. (e) Liesener, F. P.; Jannsen, U.; Kalesse, M. Synthesis
2006, 2590.
Li
20
a
10 + 11
18
O
H
H
21
MOM
TS
OH
(7) Structurally related amphidinolides B: (a) Gopalarathnam,
A.; Nelson, S. G. Org. Lett. 2006, 8, 7. (b) Zhang, W.;
Carter, R. G. Org. Lett. 2005, 7, 4209. (c) Zhang, W.;
Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69,
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K.; Thippeswamy, D. Synlett 1999, 150. (h) Eng, H. M.;
Myles, D. C. Tetrahedron Lett. 1999, 40, 2279.
Me
O
OMOM
Me
TMS
MOMO
OTBDPS
25
OTES
OTBS
O
(i) Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J. J.
Chem. Soc., Perkin Trans. 1 1999, 1163. (j) Ishiyama, H.;
Takemura, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 1999,
55, 4583. (k) Ohi, K.; Nishiyama, S. Synlett 1999, 573.
(l) Ohi, K.; Nishiyama, S. Synlett 1999, 571. (m) Cid, M.
B.; Pattenden, G. Synlett 1998, 540. (n) Chakraborty, T. K.;
Thippeswamy, D.; Jayaprakash, S. J. Indian Chem. Soc.
1998, 75, 741. (o) Lee, D.-H.; Rho, M.-D. Bull. Korean
Chem. Soc. 1998, 19, 386. (p) Ohi, K.; Shima, K.; Hamada,
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Lett. 1997, 565. (s) Lee, D.-H.; Lee, S.-W. Tetrahedron Lett.
1997, 38, 7909.
Me
OMOM
Me
b
TMS
MOMO
OTBDPS
12
OTES
O
O
O
OTBDPS
Me
OTES
26
Scheme 4 Reagents and conditions: (a) 11, LHMDS, THF, –78 °C,
20 min, then 10, –78 °C, 2 h, 63%; (b) TBSOTf, 2,6-lutidine, CH2Cl2,
0 °C, 97%.
(8) (a) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57,
5292. (b) Deng, L. S.; Zhao, G. J. Org. Chem. 2006, 71,
4625.
(9) For related references on synthesis of 10: (a) Prusov, E.;
Röhm, H.; Maier, M. E. Org. Lett. 2006, 8, 1025.
(b) Dandapani, S.; Jeske, M.; Curran, D. P. J. Org. Chem.
2005, 70, 9447. (c) Araki, K.; Saito, K.; Arimoto, H.;
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(e) Lautens, M.; Stammers, T. A. Synthesis 2002, 1993.
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J. Am. Chem. Soc. 2001, 123, 5925. (g) Ghosh, A. K.;
Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66, 8973.
(h) Kurosawa, S.; Mori, K. Eur. J. Org. Chem. 1999, 955.
(i) Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem.
1997, 62, 1691. (j) Eguchi, T.; Terachi, T.; Kakinuma, K. J.
Chem. Soc., Chem. Commun. 1994, 137.
Acknowledgment
We are grateful to National Natural Science Foundation of China
(No. 20525208, 20532040, 20390057 and 20372072), QT program
and Shanghai Natural Science Council for financial support.
References and Notes
(1) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.
Tetrahedron Lett. 1986, 27, 5755.
(10) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769.
(2) Reviews: (a) Ishibashi, M.; Kobayashi, J. Heterocycles
1997, 44, 543. (b) Kobayashi, J.; Ishibashi, M. In
Comprehensive Natural Products Chemistry, Vol. 8; Mori,
K., Ed.; Elsevier: New York, 1999, 619. (c)Chakraborty,T.
K.; Das, S. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1,
131. (d) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21,
77.
(3) (a) Kobayashi, J.; Shimbo, K.; Sato, M.; Tsuda, M. J. Org.
Chem. 2002, 67, 6585. (b) Kobayashi, J.; Shigemori, H.;
Ishibashi, M.; Yamasu, T.; Hirota, H.; Sasaki, T. J. Org.
Chem. 1991, 56, 5221.
(11) Aldehyde 6: Rf 0.41 (PE–EtOAc, 20:1); [a]D26 +4.7 (c =
0.70, CHCl3). IR (film): 2962, 2169, 1729, 1250 cm–1. 1H
NMR (300 MHz, CDCl3): d = 9.78 (t, J = 2.1 Hz, 1 H), 2.96–
3.03 (m, 1 H), 2.45–2.63 (m, 2 H), 1.23 (d, J = 7.2 Hz, 3 H),
0.13 (s, 9 H). 13C NMR (75 MHz, CDCl3): d = 201.1, 109.2,
85.6, 49.8, 21.6, 20.9, 0.1. HRMS (EI): m/z [M]+ calcd for
C9H16OSi: 168.0970; found: 168.0972.
(12) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron
1978, 34, 1449.
(13) (a) Beach, J. W.; Kim, H. O.; Jeong, L. S.; Nampalli, S.;
Islam, Q.; Ahn, S. K.; Babu, J. R.; Chu, C. K. J. Org. Chem.
1992, 57, 3887. (b) Herdeis, C.; Lütsch, K. Tetrahedron:
Asymmetry 1993, 4, 121.
(4) Kobayashi, J.; Shimbo, K.; Sato, M.; Shiro, M.; Tsuda, M.
Org. Lett. 2000, 2, 2805.
(5) Kobayashi, J.; Shimbo, K.; Sato, M.; Tsuda, M. J. Org.
Chem. 2002, 67, 6585.
Synlett 2007, No. 1, 87–90 © Thieme Stuttgart · New York

90
L. Deng et al.
LETTER
(18) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett.
(14) AD-mix-a*: OsO4·H2O (1 mol%), (DHQ)2PHAL (2 mol%),
K3Fe(CN)6 (3 equiv), K2CO3 (3 equiv), NaHCO3 (3 equiv),
and MeSO2NH2 (1 equiv). The reaction occurred at a
significantly slower rate using commercially available AD-
mix-a.
(15) (a) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461. (b) i-PrMgCl as the base did not give a
satisfactory result (54% yield).
1994, 35, 8537.
(19) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092. (b) Dale, J. A.; Mosher,
H. S. J. Am. Chem. Soc. 1973, 95, 512. (c) Dd value [Dd
(ppm, 300 MHz, CDCl3) = dS – dR] obtained for S and R
Mosher esters of 20 are as follows: H-16, –0.04; H16Me,
–0.05; H-18, –0.08; H-19, +0.05; H-21, +0.08; H-22, +0.04;
H23-Me, +0.07; H-25, +0.02; H-26, +0.02.
(16) Methyl ketone 11: Rf 0.36 (PE–EtOAc, 15:1); [a]D26 +3.1
(c = 0.76, CHCl3). IR (film): 2955, 1717, 1030 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.65–7.68 (m, 4 H), 7.26–7.42
(m, 6 H), 4.59–4.70 (m, 4 H), 4.06 (d, J = 5.1 Hz, 1 H), 3.82
(m, 1 H), 3.71 (m, 1 H), 3.42 (ddd, J = 5.1, 10.2, 10.5 Hz, 2
H), 3.32 (s, 3 H), 3.31 (s, 3 H), 2.18 (m, 3 H), 1.77–1.89 (m,
2 H), 1.41–1.48 (m, 1 H), 1.04 (s, 9 H), 1.01 (d, J = 6.9 Hz,
(20) C14–C26 segment of 1: Rf 0.48 (PE–EtOAc, 19:1); [a]D
26
+15.6 (c = 1.70, CHCl3). IR (film): 2956, 2163, 1719 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.65–7.67 (m, 4 H), 7.34–
7.43 (m, 6 H), 4.58–4.64 (m, 4 H), 4.33–4.37 (m, 1 H), 4.13
(d, J = 4.2 Hz, 1 H), 3.82 (m, 1 H), 3.70 (m, 1 H), 3.51 (ddd,
J = 5.1, 8.1, 10.2 Hz, 1 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 2.90
(dd, J = 4.8, 10.8 Hz, 1 H), 2.60 (dd, J = 4.8, 10.8 Hz, 1 H),
2.42–2.50 (m, 1 H), 1.86 (m, 2 H), 1.54–1.65 (m, 3 H), 1.35–
1.42 (m, 1 H), 1.15 (d, J = 9.6 Hz, 3 H), 1.04 (s, 9 H), 1.01
(d, J = 6.6 Hz, 3 H), 0.90 (t, J = 7.8 Hz, 9 H), 0.85 (s, 9 H),
0.54 (q, J = 7.8 Hz, 6 H), 0.13 (s, 9 H), 0.09 (s, 3 H), 0.05 (s,
3 H). 13C NMR (75 MHz, CDCl3): d = 209.0, 135.6, 133.5,
129.6, 127.7, 111.8, 97.6, 97.0, 84.4, 84.1, 82.1, 72.0, 68.1,
66.7, 56.4, 56.2, 46.3, 44.4, 38.5, 31.8, 26.9, 25.9, 23.1, 21.1,
19.2, 18.0, 16.1, 7.0, 5.1, 0.2, –4.4, –4.6. HRMS (ESI): m/z
[M + Na]+ calcd for C50H88O8Si4: 951.5498; found:
951.5449.
3 H), 0.89 (t, J = 7.8 Hz, 9 H), 0.52 (q, J = 7.8 Hz, 6 H). 13
NMR (75 MHz, CDCl3): d = 208.4, 135.6, 133.5, 129.7,
127.7, 97.9, 97.4, 84.5, 81.8, 71.8, 67.9, 56.4, 56.2, 38.7,
31.4, 27.2, 26.9, 19.2, 15.6, 6.9, 5.0. HRMS (MALDI): m/z
[M + Na]+ calcd for C35H58O7Si2Na: 669.3605; found:
669.3613.
C
(17) (a) Keck, G. A.; Castellino, S. Tetrahedron. Lett. 1987, 28,
281. (b) Frye, S. V.; Eliel, E. Tetrahedron Lett. 1986, 27,
3223.
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