Total synthesis of (-)-amphidinolide E

Article abstract of DOI:10.1002/anie.200603363

The unique structural features of the cytotoxic marine macrolide (-)-amphidinolide E make it an intriguing synthetic target. Its total synthesis has now been completed by employing a radical cyclization of a β-alkoxy acrylate to form the oxolane ring, a Kocienski-Julia olefination to create the E C=C bond, and a lactonization reaction to close the macrocyclic ring. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200603363

Angewandte
Chemie
Natural Products Synthesis
DOI: 10.1002/anie.200603363
Total Synthesis of (ꢀ)-Amphidinolide E**
Chan Hyuk Kim, Hyo Jung An, Won Kyo Shin, Wei Yu,
Sang Kook Woo, Soon Kyu Jung, and Eun Lee*
Amphidinolide E (1) is a unique 18-membered macrolide
isolated from the Y-5’ strain of the dinoflagellate Amphidi-
nium sp.[1] It exhibits cytotoxic activity against L1210 (IC50
=
2.0 mgmLꢀ1) and L5178Y (IC50 = 4.8 mgmLꢀ1) murine leuke-
mia cells in vitro. Owing to its unique structural features and
limited availability, amphidinolide E (1) has been the target
of intense synthetic studies.[2] We report herein the results of
our recent efforts towards the total synthesis of 1.
According to our retrosynthetic analysis, 1 could be
synthesized by lactonization of the seco acid A, which we
intended to prepare by the Julia coupling of fragments B and
C. In this way, potential problems arising from the intrinsic
lability at C2 of 1 would only be faced at the end of the
synthetic sequence. We also decided to introduce the triene
side chain relatively early in the synthesis, thus forestalling
difficulties which might arise from manipulations of the
unstable macrolide intermediates. Fragment B may be
obtained from the known tartrate acetonide precursors, and
fragment C may be prepared from fragment D. Fragment D
may in turn be obtained by radical cyclization of the b-alkoxy
acrylate derivative E, which should be accessible from
fragment F (Scheme 1).
Scheme 1. Retrosynthetic analysis of 1.
For the synthesis of fragment B, methyl (S)-3-hydroxy-2-
methylpropanoate (2; commercially available) was converted
into the corresponding TBDPS ether, from which vinyl
boronic acid 3 was obtained through reduction, oxidation,
Corey–Fuchs homologation,[3] and hydroboration–hydroly-
sis.[4] Suzuki coupling[5] of 3 with the known vinyl iodide 4[6]
proceeded smoothly, and the resulting diene was transformed
into aldehyde 5 by removal of the TBS protecting group and
oxidation (Scheme 2).
Scheme 2. Preparation of fragment B: a) TBDPSCl, imidazole, CH2Cl2,
08C!RT; b) LiBH4, Et2O; c) SO3·pyridine, Et3N, DMSO/CH2Cl2 (1:1),
08C!RT; d) CBr4, Ph3P, Zn, CH2Cl2, 08C!RT; e) nBuLi, THF, ꢀ788C;
f) BHBr2·SMe2, CH2Cl2, 08C!RT; H2O/Et2O (1:3), 08C!RT; g) 3,
[Pd(PPh3)4], TlOEt, THF/H2O (4:1); h) PPTS, EtOH; i) SO3·pyridine,
Et3N, DMSO/CH2Cl2 (1:1), 08C!RT. DMSO=dimethyl sulfoxide,
PPTS=pyridinium p-toluenesulfonate, TBDPS=tert-butyldiphenylsilyl,
TBS=tert-butyldimethylsilyl.
The known diol 6[7] served as the starting material in the
synthesis of fragment C. DDQ oxidation of 6 provided the
corresponding PMP cyclic acetal, which was converted into
aldehyde 7 by MOM protection of the remaining hydroxy
group and reduction with DIBAL. Roush crotylation[8] of 7 by
treatment with boronate 8 provided a product mixture that
contained mainly the desired homoallylic alcohol 9 (d.r. 16:1).
TIPS protection of 9 and oxidative deprotection of the acetal
with CAN produced diol 10. Selective tosylation of the
primary hydroxy group in 10, treatment with ethyl propiolate,
and substitution of the tosylate group with iodide led to the b-
alkoxy acrylate 11. Radical cyclization[9] of 11 proceeded
smoothly in the presence of tris(trimethylsilyl)silane and
triethylborane, and the oxolane product 12 was obtained in
high yield (Scheme 3).
[*] C. H. Kim, H. J. An, W. K. Shin, W. Yu, S. K. Woo, S. K. Jung,
Prof. E. Lee
Department of Chemistry
College of Natural Sciences
Seoul National University
Seoul 151-747 (Korea)
Fax: (+82)2-889-1568
E-mail: eunlee@snu.ac.kr
[**] This work was supported by a grant from MarineBio21, Ministry of
Maritime Affairs and Fisheries, Korea and a grant from the Center
for Bioactive Molecular Hybrids (Yonsei University and KOSEF).
BK21 graduate fellowship grants to C. H. Kim, H. J. An, W. Yu, and
S. K. Jung and Seoul Science Fellowship grants to C. H. Kim are
gratefully acknowledged.
Hydroboration–oxidation of alkene 12 produced the
corresponding primary alcohol, which was converted into
the corresponding aldehyde. At this point, a variety of
methods were tested to find an effective way to build up the
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 8019 –8021
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8019

Communications
DIBAL reduction of 16 produced the corresponding
aldehyde, which was transformed into the homologous
aldehyde by Wittig methoxymethylidenation and hydrolysis.
Further reduction with NaBH4, Mitsunobu-type substitution
of the primary hydroxy group with thiol 18, and selective
oxidation led to sulfone 19. Conditions for the Kocienski–
Julia reaction[14] between sulfone 19 and aldehyde 5 were then
investigated; the best result was obtained when the lithio
derivative of sulfone 19 prepared in THF was treated with
aldehyde 5 in DMF/DMPU (3:1) at ꢀ788C. In this way, a
product mixture in which the major isomer was the desired
E alkene 20 was obtained in 74% yield (E/Z 10:1). The
selective removal of the TBDPS group in 20 was possible
under alkaline conditions, but the oxidative conversion of the
primary hydroxy group into a carboxylic acid group proved
painfully difficult; for example, Dess–Martin oxidation
resulted in a scrambling of the NMR spectroscopic signals
from the side-chain region. Eventually, it was found that
treatment of the primary alcohol with IBX[15] provided the
corresponding aldehyde cleanly. The aldehyde was then
converted into the hydroxy carboxylic acid 21 by oxidation
with sodium chlorite and removal of the TIPS protecting
group (Scheme 4).
Scheme 3. Preparation of fragment C: a) DDQ, 3-Š MS, CH2Cl2, 08C;
b) MOMCl, DIPEA, DMAP, CH2Cl2, reflux; c) DIBAL, CH2Cl2, ꢀ788C;
d) 8, 4-Š MS, toluene, ꢀ788C; e) TIPSOTf, collidine, CH2Cl2; f) CAN,
MeCN/H2O (9:1), 08C; g) TsCl, Et3N, CH2Cl2, 08C; h) CHCCO2Et,
NMM, CH2Cl2; i) NaI, acetone, reflux; j) (TMS)3SiH, Et3B, toluene,
ꢀ208C; k) (Sia)2BH, THF, 08C; NaBO3·4H2O, H2O; l) Dess–Martin
periodinane, pyridine, CH2Cl2, 08C!RT; m) 13, Cs2CO3, EtOH, 08C!
RT; n) CH2CH2, [(H2IMes2)RuCl2(P(c-Hex)3)], CH2Cl2; 15, sealed tube,
408C. CAN=ceric ammonium nitrate, DIBAL=diisobutylaluminum
hydride, DIPEA=N,N-diisopropylethylamine, DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMAP=4-dimethylaminopyridine, Mes=
mesityl, MOM=methoxymethyl, NMM=N-methylmorpholine,
PMB=p-methoxybenzyl, PMP=p-methoxyphenyl, Sia=siamyl,
TIPS=triisopropylsilyl, Tf=trifluoromethanesulfonyl, TMS=trimethyl-
silyl, Ts=p-toluenesulfonyl.
side chain. For example, a Nozaki–Hiyama–Kishi reaction[10]
of the aldehyde with 1-iodo-4-methyl-1,4-pentadiene[11] pro-
ceeded efficiently to yield a mixture of allylic alcohols, which
was eventually converted into the desired triene 16 by
oxidation and Wittig olefination. Alternatively, the alkyne
14 was obtained from the aldehyde by treatment with
diazophosphonate 13.[12] Alkyne 14 was first treated with
ethylene in the presence of the second-generation Grubbs
catalyst,[13] and the crude product was treated with 2-methyl-
1,4-pentadiene (15; commercially available). In this way, the
desired triene 16 was obtained in 65% yield accompanied by
diene 17 in 19% yield. Subjection of the isolated sample of
diene 17 to the same reaction conditions provided an
additional amount of triene 16 (10%).
Scheme 4. Synthesis of amphidinolide E (1): a) DIBAL, THF, ꢀ788C;
b) (Ph3P+CH2OMe)Clꢀ, tBuOK, THF, 08C!RT; Hg(OAc)2, THF/H2O
(10:1), 08C; c) NaBH4, MeOH; d) 18, PPh3, DIAD, THF; H2O2,
(NH4)6[Mo7O24]·4H2O, EtOH; e) LiHMDS, THF, ꢀ78!ꢀ408C; 5,
DMF/DMPU (3:1), ꢀ788C!RT; f) 15% NaOH/DMPU (1:10); g) IBX,
DMSO/THF (1:1); h) NaClO2, NaH2PO4, tBuOH/2-methyl-2-butene/
H2O (1:1:1); i) TBAF, THF; j) EtOCCH, [{RuCl2(p-cymene)}2], toluene,
08C!RT; CSA, RT!508C; k) 4n HCl, MeOH. CSA=camphorsulfonic
acid, DIAD=diisopropylazodicarboxylate, DMF=N,N-dimethylform-
amide, DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
HMDS=hexamethyldisilazide, IBX=2-iodoxybenzoic acid,
TBAF=tetrabutylammonium fluoride.
8020 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 8019 –8021

Angewandte
Chemie
For the lactonization of 21, the protocol of Kita et al.[16]
gave the best result; thus, macrolide 22 was produced in 44%
yield. It was not possible to obtain 22 in reasonable yield
under Yamaguchi lactonization conditions. Finally, removal
of the MOM protecting group and cleavage of the acetonide
under acidic conditions produced amphidinolide E (1) in
77% yield.[17]
In summary, a radical cyclization reaction of a b-alkoxy
acrylate was employed for the stereoselective construction of
the oxolane unit in our synthesis of amphidinolide E (1). The
general fragility of 1, particularly at C2 and C24, necessitated
careful analysis and the judicious choice of reaction con-
ditions for the successful culmination of the total synthesis.
Lambert, E. Mertz, J. B. Shotwell, J. M. Tinsley, P. Va, W. R.
Roush, Org. Lett. 2005, 7, 2405 – 2408; c) J. A. Marshall, G.
Schaaf, A. Nolting, Org. Lett. 2005, 7, 5331 – 5333.
[3] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769 – 3772.
[4] H. C. Brown, N. G. Bhat, V. Somayaji, Organometallics 1983, 2,
1311 – 1316.
[5] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 – 2483;
b) S. A. Frank, H. Chen, R. K. Kunz, M. J. Schnaderbeck, W. R.
Roush, Org. Lett. 2000, 2, 2691 – 2694.
[6] L. O. Haustedt, S. B. Panicker, M. Kleinert, I. V. Hartung, U.
Eggert, B Niess, H. M. R. Hoffmann, Tetrahedron 2003, 59,
6967 – 6977.
[7] J. Uenishi, M. Ohmi, K. Matsui, M. Iwano, Tetrahedron 2005, 61,
1971 – 1979.
[8] W. R. Roush, K. Ando, D. B. Powers, A. D. Palkowitz, R. L.
Halterma, J. Am. Chem. Soc. 1990, 112, 6339 – 6348.
[9] For examples of the radical cyclization of b-alkoxy acrylates and
b-alkoxy methacrylates, see: a) E. J. Kang, E. J. Cho, M. K. Ji,
Y. E. Lee, D. M. Shin, S. Y. Choi, Y. K. Chung, J.-S. Kim, H.-J.
Kim, S.-G. Lee, M. S. Lah, E. Lee, J. Org. Chem. 2005, 70, 6321 –
6329; b) H. Y. Song, J. M. Joo, J. W. Kang, D.-S. Kim, C.-K. Jung,
H. S. Kwak, J. H. Park, E. Lee, C. Y. Hong, S. Jeong, K. Jeon,
J. H. Park, J. Org. Chem. 2003, 68, 8080 – 8087; c) E. J. Jeong,
E. J. Kang, L. T. Sung, S. K. Hong, E. Lee, J. Am. Chem. Soc.
2002, 124, 14655 – 14662; d) E. Lee, S. J. Choi, H. Kim, H. O.
Han, Y. K. Kim, S. J. Min, S. H. Son, S. M. Lim, W. S. Jang,
Angew. Chem. 2002, 114, 184 – 186; Angew. Chem. Int. Ed. 2002,
41, 176 – 178.
[10] Y. Okude, S. Hirano, T. Hiyama, H. Nozaki, J. Am. Chem. Soc.
1977, 99, 3179 – 3181.
[11] Prepared by the hydrozirconation–iodination of 2-methylpent-1-
en-4-yne.
[12] a) S. Ohira, Synth. Commun. 1989, 19, 561 – 564; b) S. Mꢀller, B.
Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996, 521 – 522.
[13] a) H. Y. Lee, B. G. Kim, M. L. Snapper, Org. Lett. 2003, 5, 1855 –
1858; b) T. W. Funk, J. Efskind, R. H. Grubbs, Org. Lett. 2005, 7,
187 – 190.
[14] a) P. R. Blackemore, W. J. Cole, P. J. Kocienski, A. Morley,
Synlett 1998, 26 – 28; b) P. Liu, E. N. Jacobsen, J. Am. Chem. Soc.
2001, 123, 10772 – 10773.
Experimental Section
Macrolide 22: Ethoxyacetylene (40% in hexanes, 0.030 mL,
0.13 mmol) was added to a solution of the seco acid 21 (52.6 mg,
0.0873 mmol) and [{RuCl2(p-cymene)}2] (1.0 mg, 0.0016 mmol) in
toluene (8 mL) at 08C. The resulting mixture was warmed to room
temperature and stirred for a further 30 min. The dark red solution
was then filtered through a pad of silica gel, and the silica gel was
washed with dry Et2O (50 mL) under a nitrogen atmosphere. The
filtrate was concentrated under reduced pressure. The crude ethox-
yvinyl ester was dissolved in toluene (3 mL) and added to a solution
of CSA (2.0 mg, 0.0087 mmol) in toluene (14 mL). The reaction
mixture was heated to 508C and stirred at this temperature for 2 h,
then filtered through a pad of silica gel and concentrated. The residue
was purified by flash column chromatography (hexanes/EtOAc, 10:1)
to afford lactone 22 (22.5 mg, 44%).
Rf = 0.45 (hexanes/EtOAc, 4:1); 1H NMR (500 MHz, CDCl3): d =
6.30 (dd, J = 14.9, 10.8 Hz, 1H), 6.19 (dd, J = 14.9, 10.8 Hz, 1H), 6.04
(d, J = 15.7 Hz, 1H), 5.68–5.76 (m, 2H), 5.55 (dd, J = 14.7, 9.3 Hz,
2H), 5.31 (ddd, J = 15.2, 8.6, 1.5 Hz, 1H), 5.12 (d, J = 7.1 Hz, 1H),
4.98 (s, 1H), 4.87 (s, 1H), 4.73 (s, 1H), 4.70 (s, 1H), 4.67 (d, J = 6.8 Hz,
1H), 4.64 (dd, J = 10.3, 1.2 Hz, 1H), 4.02 (t, J = 8.5 Hz, 1H), 3.98 (t,
J = 8.5 Hz, 1H), 3.72 (dd, J = 8.9, 1.3 Hz, 1H), 3.52 (td, J = 9.3, 6.4 Hz,
1H), 3.36 (s, 3H), 3.24–3.32 (m, 2H), 2.77 (d, J = 7.1 Hz, 2H), 2.30–
2.39 (m, 3H), 1.86–1.98 (m, 2H), 1.82 (dd, J = 14.3, 11.9 Hz, 1H), 1.71
(s, 3H), 1.62–1.70 (m, 1H), 1.46–1.54 (m, 2H), 1.43 (s, 3H), 1.43 (s,
3H), 1.26–1.32 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H), 1.11–1.19 (m, 1H),
0.91 ppm (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 174.5,
144.5, 144.1, 138.5, 135.8, 135.4, 133.3, 131.3, 127.9, 127.7, 125.4, 115.7,
110.8, 109.0, 97.2, 83.0, 82.3, 80.7, 79.2, 78.0, 77.7, 77.2, 56.3, 44.0, 41.3,
35.8, 32.1, 31.6, 28.8, 27.7, 27.1, 27.1, 22.5, 17.1, 14.7 ppm. IR (neat):
n˜max = 3443, 3063, 3078, 2981, 2929, 1732, 1653, 1604, 1454, 1377, 1238,
1171, 1090, 1030, 991, 885, 758, 580 cmꢀ1; MALDI-TOF MS: m/z 607
[M+Na]+; HRMS (FAB): m/z calcd for C35H52O7Na [M+Na]+:
607.3611, found: 607.3627; [a]2D5 = ꢀ178.7 (c = 0.46, CHCl3).
[15] M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem. 1999, 64,
4537 – 4538.
[16] a) Y. Kita, H. Maeda, K. Omori, T. Okuno, Y. Tamura, J. Chem.
Soc. Perkin Trans. 1 1993, 2999 – 3005; b) B. M. Trost, J. D.
Chisholm, Org. Lett. 2002, 4, 3743 – 3745.
[17] [a]3D0 = ꢀ131.1 (c = 0.21, CHCl3); the specific rotation of the
natural sample was not reported.[1]
Received: August 17, 2006
Published online: November 9, 2006
Keywords: anticancer agents · macrolides ·
.
marine natural products · radical cyclization · total synthesis
[1] a) J. Kobayashi, M. Ishibashi, T. Murayama, M. Takamatsu, M.
Iwamura, Y. Ohizumi, T. Sasaki, J. Org. Chem. 1990, 55, 3421 –
3423; b) T. Kubota, M. Tsuda, J. Kobayashi, J. Org. Chem. 2002,
67, 1651 – 1656.
[2] For reports on the partial synthesis of 1, see: a) M. K. Gurjar, S.
Mohapatra, U. D. Phalgune, V. G. Puranik, D. K. Mohapatra,
Tetrahedron Lett. 2004, 45, 7899 – 7902; b) C. L. Heitzman, W. T.
Angew. Chem. Int. Ed. 2006, 45, 8019 –8021
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8021