Total synthesis of (+)-exiguolide

Article abstract of DOI:10.1002/anie.200705018

(Chemical Presented) The unique 16-membered macrolide (+)-exiguolide (1) was the target of a total synthesis featuring radical and Prins cyclizations of β-alkoxyacrylates, along with ring-closing olefin metathesis. The structure incorporates two cis-2,6-disubstituted oxane rings where one of the rings has an exocyclic enoate group. The successful synthesis of 1, isolated from a marine sponge, led to the unambiguous determination of its absolute stereochemistry.

Full text of DOI:10.1002/anie.200705018

Angewandte
Chemie
DOI: 10.1002/anie.200705018
Natural Product Synthesis
Total Synthesis of (+)-Exiguolide**
Min Sang Kwon, Sang Kook Woo, Seong Wook Na, and Eun Lee*
In memory of A. I. Scott
Exiguolide (1) is a unique 16-membered macrolide isolated
from the marine sponge Geodia exigua Thiele (order Astro-
phorida, family Geodiidae).[1] It specifically inhibits fertiliza-
tion of sea urchin (Hemicentrotuspulcherrimus ) gametes but
not embryogenesis of the fertilized egg.The macrolide
structure incorporates two cis-2,6-disubstituted oxane rings,
one of which carries an exocyclic enoate appendage reminis-
cent of bryostatins.The unique structural features and
interesting biological activity of 1 has generated considerable
interest in this compound, and herein we report our recent
results for the total synthesis of 1.
Scheme 1 shows the retrosynthetic analysis of 1.Thus, the
target would be synthesized through a ring-closing olefin
metathesis reaction of the carboxylate ester A followed by
construction of the triene side chain.Fragments B and C are
the constituents of the ester A.Fragment B may be obtained
from Prins cyclization[2] of the b-alkoxyacrylate D, which
should be accessible from the oxane derivative E.Fragment E
may in turn be obtained by radical cyclization[3] of the
b-alkoxyacrylate F.
hydrolyzed to a mixture ( ꢀ 3:1) of alcohols, which was then
converted into the ketone derivative 7 by Dess–Martin
oxidation.There were signs of partial ( ꢀ 7:1) racemization[7]
in the Prins cyclization step.The keto ester 7 was converted
into the keto acid 8 by dimethyl ketalization–hydrogenolysis,
Dess–Martin oxidation, and rhodium-catalyzed methylena-
tion[8] of the product aldehyde, followed by hydrolysis–
deketalization and subsequent chromatographic separation.
The known aldehyde 9[9] served as the starting material in
the synthesis of the C fragment (Scheme 3).Brown crotyla-
tion[10] of 9 produced the allylic alcohol 10, but a Sharpless
kinetic resolution[11] step had to be included for improvement
of the enantiomeric purity.For preparation of the final
For synthesis of the B fragment, the secondary alcohol 3
was prepared from the known aldehyde 2[4] through Brown
allylation,[5] hydroboration–oxidation, and protection of the
primary hydroxy group with TBS (Scheme 2).The reaction of
3 with methyl propiolate in the presence of N-methylmorpho-
line produced the corresponding b-alkoxyacrylate derivative,
which was converted into the iodide 4 by cleavage of the TBS
group and iodide substitution.Radical cyclization [3] of 4 in the
presence of 1-ethylpiperidinium hypophosphite and triethyl-
borane in ethanol[6] proceeded efficiently and selectively to
yield, almost quantitatively, the oxane 5.DIBAL reduction of
5 and a second Brown allylation led to a homoallylic
secondary alcohol product, from which a second b-alkoxya-
crylate derivative 6 was obtained by reaction with methyl
propiolate.In the presence of trifluoroacetic acid, Prins
cyclization[2] of 6 was successful and the products were
[*] M. S. Kwon, S. K. Woo, S. W. Na, 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 M.S.K. are gratefully acknowl-
edged. We thank Prof. S. Ohta for providing the spectroscopic data
of exiguolide.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Retrosynthetic analysis of exiguolide (1).
Angew. Chem. Int. Ed. 2008, 47, 1733 –1735
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 3. Synthesis of the C fragment. Reagents and conditions:
a)( Z)-MeCHCHCH2B(dIpc)2 (2.0 equiv), THF, ꢁ788C; then H2O2,
NaOH, 64%; b)Ti(O iPr)4, d-(ꢁ)-DIPT, TBHP, 4-Š M.S., CH2Cl2, 44%;
c)CHCMgCl, 5 mol% [Pd(Ph 3P)4], THF, 08C; then reflux, 69%;
d)Jones reagent, acetone, 0 8C, 57%; e)CH 2N2, Et2O, 08C, 82%.
DIPT=diisopropyl tartrate, Ipc=isopinocampheyl, M.S.=molecular
sieves, TBHP=tert-butyl hydroperoxide.
Scheme 2. Synthesis of the B fragment. Reagents and conditions:
a)CH 2CHCH2B(dIpc)2, THF, ꢁ808C; then H2O2, NaOH, 96%;
b)(sia) 2BH, THF, 08C; then H2O2, NaOH, 85%; c)TBSCl, imidazole,
DMAP, CH2Cl2, 91%; d)CHCCO 2Me, NMM, CH2Cl2, 94%; e)conc.
HCl, MeOH, 100%; f)I 2, Ph3P, imidazole, THF, 92%; g)H 3PO2,
1-ethylpiperidine, Et3B, EtOH, 99%; h)DIBAL, CH 2Cl2, ꢁ788C, 88%;
i)CH CHCH2B(dIpc)2, Et2O, ꢁ808C; then H2O2, NaOH, 85%;
2
j)CHCCO 2Me, NMM, CH2Cl2, 94%; k)TFA, CH 2Cl2, 08C!RT;
l)K 2CO3, MeOH, (81%, over 2 steps); m) DMP, CH 2Cl2, 88%; n)cat.
H2SO4, HC(OMe)3/MeOH (4:1); then TEA; then H2, Pd/C, 84%;
o)DMP, CH 2Cl2, 88%; p)TMSCHN 2, 2.5 mol% [(Ph3P)3RhCl], Ph3P,
iPrOH, THF, 92%; q)LiOH, MeOH/H 2O (4:1); then 2.0 m HCl, 87%.
Bn=benzyl, DIBAL=diisobutylaluminum hydride, DMAP=4-dimeth-
ylaminopyridine, DMP=Dess–Martin periodinane, Ipc=isopinocam-
pheyl (superscript d implies that it was prepared from (+)-a-pinene),
NMM=N-methylmorpholine, sia=siamyl, TBS=tert-butyldimethyl-
silyl, TEA=triethylamine, TFA=trifluoroacetic acid, TMS=trimethyl-
silyl.
fragment for the triene synthesis, the known vinyl iodide 11[12]
was treated with ethynyl magnesium chloride.[13] Subsequent
oxidation and treatment with diazomethane gave the desired
enyne 12.
Scheme 4. Synthesis of (+)-exiguolide (1). Reagents and conditions:
a) 10, DCC, DMAP, CH2Cl2 (0.1m) , 70%; b)16 (30 mol%), benzene
(5 mm), reflux, 44%; c) 17, NaHMDS, THF, ꢁ788C; then 14, ꢁ78!
408C, 77%; d) 12, [Pd(Ph3P)4] (5 mol%), CuI, TEA, THF, 90%; e) H2,
Lindlar cat., quinoline, EtOAc, 75%. DCC=1,3-dicyclohexylcarbodi-
imide, HMDS=hexamethyldisilazane.
Esterification between keto acid 8 with alcohol 10
proceeded smoothly in the presence of dicyclohexylcarbodii-
mide and dimethylaminopyridine[14] to yield ester 13
(Scheme 4).The crucial intramolecular olefin metathesis
reaction of 13 employed the second-generation Hoveyda–
Grubbs catalyst 16[15] and gave macrolide 14 in 44% yield.
The correct exocyclic enoate isomer 15 was obtained as the
major isomer (5.8:1) when 14 was treated with the sodium
enolate of the chiral phosphonate 17.[16,17] Sonogashira
coupling[18] of 15 with enyne 12 proceeded smoothly, and
partial hydrogenation of the product in the presence of
Lindlar catalyst produced (+)-exiguolide (1), which proved to
be the enantiomer of the natural macrolide[19]
.
In this synthesis, radical and Prins cyclization reactions of
b-alkoxyacrylate substrates were judiciously employed for
stereoselective construction of the oxane units in (+)-
exiguolide (1).The absolute stereochemistry of the natural
product was unambiguously determined through the total
synthesis.
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1733 –1735

Angewandte
Chemie
[2] For recent examples of b-alkoxyacrylate Prins cyclization, see
Experimental Section
a) D.J.Hart, C.E.Bennett, Org. Lett. 2003, 5, 1499 – 1502; b) G.
Frµter, U.Müller, P.Kraft, Helv. Chim. Acta 2004, 87, 2750 –
Macrolide 14: A solution of allylic alcohol 10 in CH2Cl2 (1.5 mL),
DCC (44 mg, 0.213 mmol), and DMAP (5 mg, 0.041 mmol) were
added successively to a solution of acid 8 (58 mg, 0.179 mmol) in
CH2Cl2 (0.5 mL) at room temperature. After 30 min, the reaction
mixture was diluted with hexanes (2 mL) and subsequent flash
chromatography on silica gel (hexanes/EtOAc, 10:1) of the crude
product gave ester 13 (69 mg, 70%). Rf = 0.38 (hexanes/EtOAc, 4:1);
1H NMR (500 MHz, CDCl3): d = 6.48 (dd, J = 6.5, 14.5 Hz, 1H), 6.41
(d, J = 14.5 Hz, 1H), 5.76–5.69 (m, 1H), 5.65–5.58 (m, 1H), 5.15 (t, J =
6.5 Hz, 1H), 5.12–5.07 (m, 2H), 4.98–4.93 (m, 2H), 4.09–4.04 (m, 1H),
3.90–3.84 (m, 1H), 3.37–3.32 (m, 1H), 3.27–3.23 (m, 1H), 2.66 and
2.54 (ABX, JAB = 15.3 Hz, JAX = 7.8 Hz, JBX = 4.8 Hz, 2H), 2.50–2.23
(m, 4H), 2.01–1.95 (m, 1H), 1.82–1.79 (m, 1H), 1.62–1.42 (m, 6H),
1.28–1.13 (m, 4H), 1.04 (d, J = 7.0 Hz, 3H), 0.97 ppm (d, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3): d = 206.4, 169.4, 144.4, 142.0,
138.4, 116.7, 113.6, 80.9, 79.0, 75.7, 74.3, 73.7, 73.4, 47.2, 47.1, 43.7,
2763; c) C.S.Barry, N.Bushby, J.R.Harding, C.L.Willis,
Org.
Lett. 2005, 7, 2683 – 2686; d) C.S. Barry, J.D. Elsworth, P.T.
Seden, N.Bushby, J.R.Harding, R.W.Alder, C.L.Willis,
Lett. 2006, 8, 3319 – 3322.
Org.
[3] For recent examples of b-alkoxyacrylate radical cyclization, see
a) C.H.Kim, H.J.An, W.K.Shin, W.Yu, S.K.Woo, S.K.Jung,
E.Lee, Angew. Chem. 2006, 118, 8187 – 8189; Angew. Chem. Int.
Ed. 2006, 45, 8019 – 8021; b) 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;
c) 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; 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.
42.7, 41.5, 41.2, 34.6, 32.1, 31.9, 23.8, 21.5, 15.4 ppm; IR (neat): n˜max
=
2925, 1731, 1614, 1177 cmꢁ1
; MS m/z (EI, relative intensity):
544([M+], 10), 417 (35), 323 (100), 307 (59), 255 (41), 237 (24), 195
(14), 157 (37), 135 (34), 93 (49), 79 (51), 55 (49); HRMS (EI): m/z
[4] A.K.Ghosh, Y.Wang, J.T.Kim, J. Org. Chem. 2001, 66, 8973 –
8982.
calcd for C25H37O5I [M+]: 544.1686; found: 544.1686; [a]2D5
ꢁ14.2 degcm3 gꢁ1 dmꢁ1 (c = 0.004 gcmꢁ3, CHCl3).
=
[5] P.K.Jadhav, K.S.Bhat, P.T.Perumal, H.C.Brown,
J. Org.
Chem. 1986, 51, 432 – 439.
[6] E.Lee, H.O.Han, Tetrahedron Lett. 2002, 43, 7295 – 7296.
[7] The minor product is presumably formed by epimerization at C3
and C7; for a thorough discussion of the racemization problem in
Prins cyclization, see R.Jasti, S.D.Rychnovsky, J. Am. Chem.
Soc. 2006, 128, 13640 – 13648.
[8] H.Lebel, V.Paquet, J. Am. Chem. Soc. 2004, 126, 320 – 328.
[9] B.M.Trost, M.U.Frederiksen, J.P.N.Papillon, P.E.Harring-
ton, S.Shin, B.T.Shireman, J. Am. Chem. Soc. 2005, 127, 3666 –
3667.
[10] H.C. Brown, K.S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919 –
5923.
[11] Y.Kitano, T.Matsumoto, T.Wakasa, S.Okamoto, T.Shimazaki,
Y.Kobayashi, F.Sato, K.Miyaji, K.Arai, Tetrahedron Lett. 1987,
28, 6351 – 6354.
The second-generation Hoveyda–Grubbs catalyst (24 mg,
0.038 mmol) was added to
a solution of ester 13 (69 mg,
0.127 mmol) in benzene (25 mL), and the reaction mixture was
heated under reflux.After 10 h, the reaction mixture was exposed to
air for 2 h at room temperature.The solvent was then removed under
reduced pressure and the crude product was purified by flash
chromatography (hexanes/EtOAc, 15:1) to afford macrolide 14
1
(29 mg, 44%). Rf = 0.30 (hexanes/EtOAc, 4:1); H NMR (500 MHz,
CDCl3): d = 6.51 (dd, J = 6.5, 14.5 Hz, 1H), 6.38 (d, J = 14.5 Hz, 1H),
5.45 (dd, J = 9.5, 5.0 Hz, 1H), 5.20 (dd, J = 1.0, 6.0 Hz, 1H), 5.11 (dd,
J = 9.5, 15.0 Hz, 1H), 4.10–4.04 (m, 1H), 3.45 (t, J = 10.8 Hz, 1H),
3.31 (dd, J = 10.3, 8.8 Hz, 1H), 3.18 (t, J = 11.3 Hz, 1H), 2.63–2.55 (m,
2H), 2.54–2.47 (m, 1H), 2.45–2.31 (m, 5H), 1.85–1.77 (m, 2H), 1.63–
1.39 (m, 5H), 1.29–1.08 (m, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.95 ppm (d,
J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d = 206.2, 170.1, 142.8,
136.4, 131.8, 80.0, 79.8, 76.3, 75.2, 74.6, 73.3, 48.0, 46.8, 44.1, 43.3, 41.5,
41.3, 33.3, 32.6, 31.8, 24.1, 22.0, 14.5 ppm; IR (neat): n˜max = 2929, 2865,
1739, 1612, 1372, 1213, 1175, 1090, 974, 862 cmꢁ1; MS m/z (CI, relative
intensity): 561([M++1], 13), 545 (5), 517 (100), 499 (12), 481 (4), 437
(7), 421 (6), 409 (11), 389 (83), 371 (14), 357 (6), 345 (8), 323 (4), 295
(4), 255 (28), 237 (8), 217 (6), 199 (4), 121 (11); HRMS (CI): calcd for
[12] P.Wipf, S.Lim, Angew. Chem. 1993, 105, 1095 – 1097; Angew.
Chem. Int. Ed. Engl. 1993, 32, 1068 – 1071.
[13] E.Negishi, M.Kotora, C.Xu,
8960.
J. Org. Chem. 1997, 62, 8957 –
[14] B.Neises, W.Steglich, Angew. Chem. 1978, 90, 556 – 557; Angew.
Chem. Int. Ed. Engl. 1978, 17, 522 – 524.
[15] S.B.Garber, J.S.Kingsbury, B.L.Gray, A.H.Hoveyda,
J. Am.
C23H34O5I
[M+ + 1]:
517.1451;
found:
517.1450;
[a]2D5
=
Chem. Soc. 2000, 122, 8168 – 8179.
+ 15.5 degcm3 gꢁ1 dmꢁ1 (c = 0.008 gcmꢁ3, CHCl3).
[16] a) K.Tanaka, Y.Ohta, K.Fuji, Tetrahedron Lett. 1993, 34, 4071 –
4074; b) K.Tanaka, K.Otsubo, K.Fuji, Tetrahedron Lett. 1996,
37, 3735 – 3738.
Received: October 30, 2007
Published online: January 23, 2008
[17] D.A.Evans, P.C.Carter, E.M.Carreira, A.B.Charette, J.A.
Prunet, M.Lautens, J. Am. Chem. Soc. 1999, 121, 7540 – 7552.
[18] K.Sonogashira, Y.Toda, N.Hagihara, Tetrahedron Lett. 1975,
16, 4467 – 4470.
Keywords: macrolides · natural products · total synthesis
.
[19] The specific rotation of the final synthetic product: [a]D25
=
+119 degcm3 gꢁ1 dmꢁ1 (c = 0.0011 gcmꢁ3, CHCl3); and of the
[1] S.Ohta, M.M.Uy, M.Yanai, E.Ohta, T.Hirata, S.Ikegami,
natural
sample:[1]
[a]2D5 = ꢁ92.5 degcm3 gꢁ1 dmꢁ1
(c =
Tetrahedron Lett. 2006, 47, 1957 – 1960.
0.00069 gcmꢁ3, CHCl3).
Angew. Chem. Int. Ed. 2008, 47, 1733 –1735
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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