Synthetic studies towards iriomoteolide-1a: Construction of the C13-C23 fragment

Article abstract of DOI:10.1055/s-0029-1217728

A stereoselective synthesis of the C13-C23 segment of iriomoteolide-1a was achieved using, as key steps, a highly stereocontrolled crotylation to build the stereocenters at C18 and C19 and a Julia-Kocienski olefination to establish the C15-C16 E-olefin mo

Full text of DOI:10.1055/s-0029-1217728

LETTER
2469
Synthetic Studies towards Iriomoteolide-1a: Construction of the C13–C23
Fragment
S
ynthetic Studie
h
s
towardsIr
e
iomoteolide
n
-1a gqing Ye, Lisheng Deng, Shan Qian, Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
Received 8 June 2009
workers, has nine stereocenters, an acid-labile cyclic b,g-
Abstract: A stereoselective synthesis of the C13–C23 segment of
unsaturated acetal unit, four hydroxyl groups and three
iriomoteolide-1a was achieved using, as key steps, a highly stereo-
controlled crotylation to build the stereocenters at C18 and C19 and
a Julia–Kocienski olefination to establish the C15–C16 E-olefin
endogenous double bonds, and exhibits extremely potent
cytotoxicity IC50 values of 2 and 3 ng mL–1 against human
moiety.
B lymphocyte DG-75 cells and Epstein–Barr virus infect-
ed human B lymphocyte, respectively, although the mech-
anism of action still remains unknown.4 Structural
elucidation of iriomoteolide-1a was conducted by a com-
bination of spectroscopic methods (ESI-HRMS, IR, and
NMR) and a modified Mosher’s protocol.4
Key words: iriomoteolide-1a, macrolide, dihydroxylation, crotyla-
tion, Julia–Kocienski olefination
Dinoflagellates have been reported to produce structurally
unique metabolites with significant biological activi-
ties.1A series of macrolides known as amphidinolides
have been isolated from Dinoflagellate Amphidinium spe-
cies.2 Owing to their potent cytotoxicity and intriguing
structural features, these macrolides, as attractive targets,
have inspired substantial synthetic studies.3 For example,
iriomoteolide-1a (1),4 a 20-membered macrolide isolated
from the Amphidinium species in 2007 by Tsuda and co-
Due to its significant biological activity and challenging
structure, iriomoteolide-1a (1) has attracted great synthet-
ic interests.5 However, to the best of our knowledge, no to-
tal synthesis of 1 has been reported to date. As part of our
ongoing studies directed toward the syntheses of various
natural products of the amphidinolide family,3d,6 we
would like to herein present the assembly of the C13–C23
fragment 4 of iriomoteolide-1a. Our retrosynthetic analy-
OH
OTBDPS
OTBS
OH
19
13
13
19
23
23
OH
O
O
O
O
O
O
1
1
H
MOMO
OH
MOMO
2
iriomoteolide-1a (1)
Br
12
OTBDPS
OTBS
H
OMOM
O
OEt
+
13
23
1
OTBS
O
4
MOMO
Julia–Kocienski
coupling
3
TBSO
TBSO
N
N
OTBDPS
+
N
H
N
S
O
O
O
Ph
OTBS
5
6
Scheme 1 Retrosynthetic analysis of iriomoteolide-1a (1)
SYNLETT 2009, No. 15, pp 2469–2472
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217728; Art ID: W08709ST
© Georg Thieme Verlag Stuttgart · New York

2470
Z. Ye et al.
LETTER
OTBS
ether was reduced with diisobutylaluminum hydride
(DIBAL-H) followed by Swern oxidation to provide alde-
hyde 5 (93% yield over the two steps), one of the two piec-
es for Julia–Kocienski reaction.9
OH
O
O
O
O
OTBS
O
O
OH
b
a
The synthesis of sulfone segment 6 commenced from me-
thyl ketone 12,10 a known intermediate easily preparable
from commercially available (S)-(–)-ethyl lactate 11
(Scheme 3). Treatment of 12 with (EtO)2P(O)CH2CO2Et
prepared in situ under standard Horner–Wadsworth–
Emmons conditions provided the E-olefin 13 in 93% yield
as a single product. Subsequently, stereoselective reduc-
tion of the double bond in 13 was called for to furnish the
stereocenter at C21. After screening several conditions,
the NaBH4/NiCl2·6H2O system was found to be the best,
affording the desired product with moderate selectivity
(dr > 5:1).11 The resulting ester was then reduced with
DIBAL-H to give 14 in excellent yield over the two steps
(85%). Next, asymmetric crotylation12 of aldehyde 14 us-
ing the chiral trans-crotylboronate 15 (derived from L-di-
isopropyl tartrate) proceeded smoothly to give alcohol 16
in 98% yield with good diastereoselectivity (dr > 10:1) fa-
voring the anti-isomer. Hydroxyl protection followed by
hydroboration–oxidation yielded the primary alcohol 17.
Finally, conversion of 17 to Kocienski-type sulfone 6 was
carried out smoothly by a two-step sequence including a
Mitsunobu reaction13 and an oxidation according to the
literate procedures.14
OMe
OMe
OMe
7
9
8
TBSO
TBSO
TBSO
c
d
H
O
OH
TBSO
10
5
Scheme 2 Reagents and conditions:
a) (DHQ)2PHAL,
K2OsO2(OH)4, K3Fe(CN)6, K2CO3, t-BuOH–H2O (1:1), 0 °C; b) TBSOTf,
2,6-lutidine, CH2Cl2, r.t., 95% (two steps); c) DIBAL-H, toluene, –78 °C,
97%; d) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 96%.
sis of 1 is outlined in Scheme 1. We envisaged an access
to the iriomoteolide-1a (1) from its precursor 2 through a
late-stage intramolecular hemiacetalation. The C13–C23
segment (4), may be disconnected as a stereochermically
elaborate aldehyde bearing five stereocenters, while the
key trans double bond can be constructed by a Julia–
Kocienski coupling between aldehyde 5 and sulfone 6.7
As shown in Scheme 2, aldehyde 5 possessing a chiral a-
tertiary hydroxyl group could be prepared from olefin 7 as
a starting material. Sharpless dihydroxylation8 of 7 in the
presence of AD-mix-b at 0 °C afforded in high enantiose-
lectivity diol 8 (ee >95%), which in turn was protected
with TBSOTf and 2,6-lutidine in CH2Cl2 to provide 9 in
95% yield over the two steps. Then the resulting silyl
With the two segments 5 and 6 in hand, we then investi-
gated their coupling by the Julia–Kocienski reaction. As
given in Scheme 4, the deprotonation of 6 with LHMDS
in DMF–HMPA at –40 °C followed by treating with 5 led
to the required E-isomer with excellent selectivity (dr >
20:1).7,15 Finally, selective removal of a primary TBS
OTBDPS
OTBDPS
OH
ref. 10
a
EtO2C
EtO2C
O
11
12
13
OTBDPS
OTBDPS
e, f
d
b, c
OHC
OH
14
16
N
OTBDPS
N
OTBDPS
N
g, h
N
HO
S
O
O
Ph
OTBS
17
OTBS
6
N
N
CO2i-Pr
CO2i-Pr
O
N
B
N
SH
O
Ph
(R,R)-15
18
Scheme 3 Reagents and conditions: a) NaH, (EtO)2P(O)CH2CO2Et, THF, 0 °C; then 12, r.t., 93%; b) NiCl2·6H2O, NaBH4, MeOH, –78 °C
then r.t., 90%; c) DIBAL-H, CH2Cl2–toluene, –78 °C, 94%; d) 15, 4 Å MS, toluene, –78 °C, 98%; e) TBSOTf, 2,6-lutidine, CH2Cl2, r.t., 100%
f) BH3·SMe2, THF, r.t.; then 2.5 M NaOH, 30% H2O2, r.t., 83%; g) 18, DIAD, Ph3P, THF, r.t., 96%; h) (NH4)6Mo7O24·4H2O, 30% H2O2, EtOH
r.t., 97%.
Synlett 2009, No. 15, 2469–2472 © Thieme Stuttgart · New York

LETTER
Synthetic Studies towards Iriomoteolide-1a
2471
O.; Fluegge, S. Angew. Chem. Int. Ed. 2007, 46, 5545.
OTBDPS
OTBS
a
(k) Lu, L.; Zhang, W.; Carter, R. J. Am. Chem. Soc. 2008,
130, 7253. (l) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.;
Woo, S. K.; Jung, S. K.; Lee, E. Chem. Asian J. 2008, 3,
1523. (m) Rodríguez-Escrich, C.; Urpí, F.; Vilarrasa, J. Org.
Lett. 2008, 10, 5191. (n) Barbazanges, M.; Meyer, C.;
Cossy, J. Org. Lett. 2008, 10, 4489. (o) Ko, H. M.; Lee,
C. W.; Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung,
Y. K.; Lee, E. Angew. Chem. Int. Ed. 2009, 48, 2364.
(p) Yadav, J. S.; Reddy, C. S. Org. Lett. 2009, 11, 1705.
(q) Fürstner, A.; Kattnig, E.; Kelter, G.; Fiebig, H. H. Chem.
Eur. J. 2009, 15, 4030. (r) Fürstner, A.; Flügge, S.;
Larionov, O.; Takahashi Yohei; Kubota, T.; Kobayashi, J.
Chem. Eur. J. 2009, 15, 4011. (s) Fürstner, A.; Bouchez,
L. C.; Morency, L.; Funel, J. A.; Liepins, V.; Porée, F. H.;
Gilmour, R.; Laurich, D.; Beaufils, F.; Tamiya, M. Chem
Eur. J. 2009, 15, 3983.
+
TBSO
5
6
OTBS
19
OTBDPS
OTBS
b, c
H
OTBS
O
4
Scheme 4 Reagents and conditions: a) 6, LiHMDS, DMF–HMPA,
–40 °C, 10 min; then 5, warm to r.t., 50%; b) HF·py, pyridine, THF,
r.t., 80%; c) TPAP, NMO, 4 Å MS, CH2Cl2, 90%.
group in 19 in the presence of HF·py and subsequent Ley
oxidation afforded the desired aldehyde 4 in 72% yield
over the two steps.16
(4) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.;
Kobayashi, J.; Fukushi, E.; Kawabata, J.; Ozawa, T.;
Masuda, A.; Kitaya, Y.; Omasa, K. J. Org. Chem. 2007, 72,
4469.
(5) (a) Fang, L. J.; Xue, H. R.; Yang, J. Org. Lett. 2008, 10,
4645. (b) Ghosh, A. K.; Yuan, H. Tetrahedron Lett. 2009,
50, 1416.
(6) (a) Deng, L. S.; Ma, Z. X.; Zhang, Y. Z.; Zhao, G. Synlett
2007, 87. (b) Deng, L. S.; Ma, Z. X.; Zhao, G. Synlett 2008,
728.
(7) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
In conclusion, we have developed a highly stereocon-
trolled synthesis of the C13–C23 segment 4 of iriomo-
teolide-1a in eleven steps and 21% overall yield in the
longest linear sequence from methyl ketone 11 featuring a
highly selective Julia–Kocienski coupling. Further inves-
tigations directed toward the total synthesis of iriomo-
teolide-1a are currently under way in our laboratory.
(8) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem.
Soc. 1995, 117, 10805.
Supporting Information for this article is available online at
(9) Aldehyde 5: [a]D22 –6.4 (c 1.01, CHCl3). IR (film): 2956,
2929, 2858, 1740, 1472, 1255, 1108, 837, 777 cm–1. 1H
NMR (300 MHz, CDCl3): d = 9.60 (s, 1 H), 3.66 (m, 2 H),
1.24 (s, 3 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.11 (s, 6 H), 0.03
(s, 6 H). 13C NMR (75 MHz, CDCl3): d = 204.5, 80.7, 68.4,
25.8, 25.7, 20.0, 18.2, 18.2, –2.6, –2.6, –5.6, –5.7. ESI-MS:
m/z = 387.2 [M + MeOH + Na]+. ESI-HRMS: m/z calcd for
C16H36O3Si2Na+ [M + Na]+: 355.2108; found: 355.2095.
(10) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am.
Chem. Soc. 1991, 113, 5354.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to National Natural Science Foundation of China
for financial support (No.20172064, 203900502, 20532040), QT
program, Shanghai Natural Science Council, and Excellent Young
Scholars Foundation of National Natural Science Foundation of
China (20525208).
(11) (a) Yamashita, S.; Iso, K.; Hirama, M. Org. Lett. 2008, 10,
3413. (b) Shigehisa, H.; Mizutani, T.; Tosaki, S.; Ohshima,
T.; Shibasaki, M. Tetrahedron 2005, 61, 5057.
References and Notes
(c) Molander, G. A.; Quirmbach, M. S.; Silva, L. F.;
Spenver, K. C. Jr.; Balsells, J. Org. Lett. 2001, 15, 2257.
(12) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339.
(13) Mitsunobu, O. Synthesis 1981, 1.
(1) (a) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.
Tetrahedron Lett. 1986, 27, 5755. (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.
(14) Sulfone 6: [a]D24 –21.4 (c 1.62, CHCl3). IR (film): 3077,
2957, 2929, 2857, 1593, 1498, 1463, 1428, 1379, 1342,
1256, 1153, 1110, 1078, 1035, 951, 835, 774 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.71–7.66 (m, 6 H), 7.61 (m, 3 H),
7.42–7.35 (m, 6 H), 3.95–3.88 (m, 1 H), 3.80–3.77 (m, 1 H),
3.68–3.56 (m, 2 H), 1.99–1.93 (m, 1 H), 1.87–1.82 (m, 1 H),
1.72–1.64 (m, 2 H), 1.45 (m, 1 H), 1.37–1.30 (m, 1 H), 1.03
(s, 9 H), 1.00 (d, J = 7.5 Hz, 3 H), 0.98 (d, J = 6.6 Hz, 3 H),
0.93 (d, J = 6.6 Hz, 3 H), 0.87 (s, 9 H), 0.01 (s, 3 H), –0.02
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 153.4, 135.9,
135.9, 134.9, 134.0, 133.1, 131.3, 129.6, 129.6, 129.4,
127.6, 127.3, 125.0, 74.5, 72.5, 54.4, 37.0, 36.8, 35.4, 27.0,
25.9, 22.6, 20.3, 19.3, 18.0, 16.1, 14.6, –4.3, –4.5. ESI-MS:
m/z = 757.2 [M + Na]+. HRMS (MALDI): m/z calcd for
C39H58N4O4Si2SNa+ [M + Na]+: 757.3633; found: 757.3610.
(15) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
(16) Aldehyde 4: [a]D24 –22.6 (c 0.66, CHCl3). IR (film): 3584,
3072, 3050, 2956, 2930, 2893, 2858, 1472, 1463, 1428,
(2) (a) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451.
(b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(3) For the synthesis of various amphidinolides since 2006, see:
(a) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.;
Jung, S. K.; Lee, E. Angew. Chem. Int. Ed. 2006, 45, 8019.
(b) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128,
15960. (c) Fürstner, A.; Kattnig, E.; Lepage, O. J. Am.
Chem. Soc. 2006, 128, 9194. (d) Deng, L. S.; Huang, X. P.;
Zhao, G. J. Org. Chem. 2006, 71, 4625. (e) Ghosh, A. K.;
Gong, G. J. Org. Chem. 2006, 71, 1085. (f) Jin, J.; Chen,
Y.; Li, Y.; Wu, J.; Dai, W. M. Org. Lett. 2007, 9, 2585.
(g) Va, P.; Roush, W. R. Org. Lett. 2007, 9, 307. (h) Va, P.;
Roush, W. R. Tetrahedron 2007, 63, 5768. (i) Fürstner, A.;
Bouchez, L. C.; Funel, J.-A.; Liepins, V.; Porée, F.-H.;
Gilmour, R.; Beaufils, F.; Laurich, D.; Tamiya, M. Angew.
Chem. Int. Ed. 2007, 46, 9265. (j) Fürstner, A.; Larionov,
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Z. Ye et al.
LETTER
1378, 1361, 1255, 1110, 1029, 975, 938, 835, 739, 702
cm–1. 1H NMR (500 MHz, CDCl3): d = 9.33 (s, 1 H), 7.69–
7.66 (m, 4 H), 7.43–7.35 (m, 6 H), 5.76–5.70 (m, 1 H), 5.26
(d, J = 15.6 Hz, 1 H), 3.79–3.77 (m, 1 H), 3.58–3. 56 (m, 1
H), 2.10–2.04 (m, 1 H), 1.81–1.75 (m, 1 H), 1.72–1.67 (m, 1
H), 1.57–1.50 (m, 2 H), 1.37 (s, 3 H), 1.26–1.20 (m, 1 H),
1.06 (s, 9 H), 0.96 (d, J = 6.0 Hz, 3 H), 0.93 (s, 9 H), 0.91 (d,
J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.85 (d, J = 6.9 Hz, 3 H), 0.11
(s, 3 H), 0.10 (s, 3 H), –0.00 (s, 3 H), –0.02 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d = 135.9, 135.9, 135.1, 135.0, 134.2,
130.1, 29.5, 129.4, 127.5, 127.3, 75.7, 74.8, 72.6, 71.4, 37.7,
37.0, 35.8, 34.1, 27.1, 25.9, 25.8, 23.6, 19.9, 19.4, 18.1, 15.8,
15.2, –2.3, –4.3, –4.4. ESI-MS: m/z = 749.4 [M + Na]+.
HRMS (MALDI): m/z calcd for C42H74O4Si3Na+ [M + Na]+:
749.4803; found: 749.4787.
Synlett 2009, No. 15, 2469–2472 © Thieme Stuttgart · New York

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