Total synthesis of amphidinolide y by formation of trisubstituted (E)-double bond via ring-closing metathesis of densely functionalized alkenes

Article abstract of DOI:10.1021/ol0710360

Amphidinolide Y, a 17-membered cytotoxic macrolide isolated from marine dinoflagellates, has been synthesized via ring-closing metathesis to assemble the congested trisubstituted (E)-double bond. The seco precursor was prepared from readily available chir

Full text of DOI:10.1021/ol0710360

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2585-2588
Total Synthesis of Amphidinolide Y by
Formation of Trisubstituted (E)-Double
Bond via Ring-Closing Metathesis of
Densely Functionalized Alkenes§
Jian Jin,† Yile Chen,† Yannian Li,† Jinlong Wu,† and Wei-Min Dai*,†,‡
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang
UniVersity, Hangzhou 310027, China, and Department of Chemistry, The Hong Kong
UniVersity of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
chdai@ust.hk; chdai@zju.edu.cn
Received May 10, 2007
ABSTRACT
Amphidinolide Y, a 17-membered cytotoxic macrolide isolated from marine dinoflagellates, has been synthesized via ring-closing metathesis
to assemble the congested trisubstituted (E)-double bond. The seco precursor was prepared from readily available chiral synthons with the
tetrahydrofuran ring formed via 5-endo epoxide ring-opening cyclization. It was found that the C6-keto seco substrate showed higher reactivity
toward Grubbs’ second generation catalyst while Schrock’s Mo catalyst was completely inactive for formation of the macrocycle.
Metathesis reactions of alkenes and alkynes1 have emerged
as the enabling tools for carbon-carbon bond formation. In
particular ring-closing metathesis (RCM) has been applied
in total syntheses of complex natural products1e for as-
sembling macrocycles as an alternative to the classic Pd-
catalyzed cross-coupling reactions2 and macrolactonization.3
Amphidinolide Y 1 belongs to a family of biologically
significant secondary metabolites (Figure 1).4,5 It was isolated
from cultures of symbiotic marine dinoflagellates Amphi-
dinium sp. and exhibits cytotoxicity against L1210 and KB
cell lines with IC50 values of 0.8 and 8.0 µg/mL, respectively.
Macrolide 1 features a 17-membered ring lactone possessing
trisubstituted and conjugate (E)-double bonds and a trans
fused tetrahydrofuran ring. It exists as an equilibrium mixture
of 6-keto and 6(9)-hemiacetal forms (1a/1b ) 5:1-9:1) in
§ Dedicate to Prof. Yoshimitsu Nagao on the occasion of his 65th
birthday.
4,6
CDCl3 and can be oxidized with Pb(OAc)4 to give
† Zhejiang University.
‡ HKUST.
(2) For a recent review, see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442-4489.
(1) For reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413-4450. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-
3043. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(d) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (e)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490-4527. (f) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem., Int. Ed.
2006, 45, 6086-6101. (g) Schrock, R. R.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 42, 4592-4633. Also see: Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vols. 1, 2, 3.
(3) For a recent review, see: Parenty, A.; Moreau, X.; Campagne, J.-M.
Chem. ReV. 2006, 106, 911-939.
(4) For isolation of amphidinolide Y, see: Tsuda, M.; Izui, N.; Shimbo,
K.; Sato, M.; Fukushi, E.; Kawabata, J.; Kobayashi, J. J. Org. Chem. 2003,
68, 9109-9112.
(5) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77-93.
(6) For the first total synthesis of amphidinolide Y, see: Fu¨rstner, A.;
Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006, 128, 9194-9204.
10.1021/ol0710360 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/31/2007

Figure 1. Structures of amphidinolides X and Y and strategic bond
disconnection of amphidinolide Y.
amphidinolide X 2.7,8 We envisaged a RCM strategy for
constructing the congested R-branched trisubstituted (E)-
double bond of 1 (Figure 1). We were specifically interested
in addressing the influence of C7, C9, and C10 functionalities
on RCM reactions in view of the fact that prior studies failed
in assembling macrocyclic trisubstituted (E)-alkenes via
RCM.9 Moreover, it is of interest to establish a total synthesis
of 1 not requiring protection of the C6-keto group and to
execute the 17-membered ring formation without relying on
the conformation-restricted acetal derivative of 1b.6
According to the bond disconnections in Figure 1, the
fragments 3 and 4 are obtained (Figure 2). The triol mono-
PMP ether (R)-5,10 readily prepared in >96% ee, was used
as the C6-C9 subunit and was joined with the lithium
species derived from iodide (R)-6.11 It was then followed
by performing an anti-selective aldol reaction12 and the Wittig
Figure 2. Retrosynthetic analysis of amphidinolide Y.
olefination. Thus, the C1-C11 fragment 3 was retrosyn-
thetically disconnected into the chiral synthons (R)-5 and
(R)-6. The B-alkyl Suzuki cross-coupling13 was used for
cleaving the C12-C13 bond in 4, and it is followed by a
5-endo epoxide ring-opening cyclization of 7 to form the
tetrahydrofuran unit (Figure 2).14 We prepared 8a in >96%
ee from (S)-5 by forming the C19-C20 bond via Wittig
olefination and hydrogenation.14a It was proved that 8a gave
higher enantioselectivity in Sharpless asymmetric allylic
epoxidation than 8b.6,8 The acid-catalyzed 5-endo cyclization
of epoxy alcohol 7a failed14a but the activated vinyl epoxide
7b underwent cyclization to give the desired product 9
(Scheme 1).15,16 Moreover, the vinyl group in 9 could be
used to facilitate the B-alkyl Suzuki cross-coupling reaction.
Thus, 9 was protected as the TES ether 10 followed by
(7) For isolation of amphidinolide X, see: Tsuda, M.; Izui, N.; Shimbo,
K.; Sato, M.; Fukushi, E.; Kawabata, J.; Katsumata, K.; Horiguchi, T.;
Kobayashi, J. J. Org. Chem. 2003, 68, 5339-5345.
(8) For the first total synthesis of amphidinolide X, see: Lepage, O.;
Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970-15971.
(9) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169-171. (b) Andrus,
M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.; Glancey, R. R.;
Ma, W. J. Org. Chem. 2003, 68, 8162-8169. (c) Mulzer, J.; Pichlmair, S.;
Green, M. P.; Marques, M. M. B.; Martin, H. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11980-11985. (d) Wilson, M. S.; Woo, J. C. S.; Dake,
G. R. J. Org. Chem. 2006, 71, 4237-4245. (e) Helmboldt, H.; Ko¨hler, D.;
Hiersemann, M. Org. Lett. 2006, 8, 1573-1576. (f) Smith, A. B., III;
Mesaros, E. F.; Meyer, E. A. J. Am. Chem. Soc. 2006, 128, 5292-5299.
For formation of trisubstituted (Z)-alkenes using Schrock’s Mo catalyst,
see: (g) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302-
10316 and references cited therein. (h) May, S. A.; Grieco, P. A. Chem.
Commun. 1998, 1597-1598. For use of RCM in total synthesis of
amphidinolides E, T1, T3, T4, and T5, see: (i) A¨ıssa, C.; Riveiros, R.;
Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003, 125, 15512-15520 and
references cited therein. (j) Va, P.; Roush, W. R. Org. Lett. 2007, 9, 307-
310 and references cited therein.
Scheme 1. Synthesis of C12-C21 Fragment 4
(10) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805-10816.
(11) (a) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857-186. (b) Bailey,
W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404-5406.
(12) For anti-selective aldehyde crotylation, see: (a) Brown, H. C.; Bhat,
K. J. Am. Chem. Soc. 1986, 108, 293-294. (b) Roush, W. R.; Halterman,
R. L. J. Am. Chem. Soc. 1986, 108, 294-296. (c) Hackman, B. M.;
Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375-4377.
2586
Org. Lett., Vol. 9, No. 13, 2007

hydroboration (1.5 equiv 9-BBN) to give 11. The latter,
without isolation, was coupled with 2-bromo-1-propene at
room temperature in the presence of 3 equiv of K3PO4, 5
mol % Pd(OAc)2, and 6 mol % of the Aphos 1217,18 to furnish
13. After removal of the TES group in 13, the C12-C21
fragment 4 was obtained in 70% overall yield from 10.
Synthesis of the seco intermediates 21-23 is shown in
Scheme 2. The diastereomers 19 and 6-epi-19 were prepared,
KOTMS22 gave the carboxylic acid which was then con-
densed with 4 under the Yamaguchi conditions23 to furnish
the (6S)-ester 21. The minor (6R)-epimer 22 was prepared
from 6-epi-19 in almost the same overall yield. The C6-
ketone 23 could be synthesized from either 21 or 22. For
example, selective desilylation of 21 followed by DMP
oxidation24 formed 23 in 77% overall yield.
Scheme 3 and Table 1 summarize the RCM reactions of
Scheme 2. Synthesis of Seco Intermediates 21-23
Scheme 3. RCM Reactions of 21-23 and Total Synthesis of
1
in a parallel fashion, by a sequence of 17 step reactions from
(R)-5 in a combined overall yield of 16.7% (see Supporting
Information for detail). The C9-C10 anti-aldol was installed
by the reaction of chiral ester 1619 followed by Dibal-H
reduction to remove the chiral auxiliary.20 The C6 stereo-
chemistry of 19 and 6-epi-19 was determined by the Mosher
esters21 of 20. Cleavage of the methyl ester in 19 by
(13) For a recent review, see: Chemler, S. R.; Trauner, D.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-4568.
(14) (a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177-1180.
For other syntheses, see: (b) Rodr´ıguez-Escrich, C.; Olivella, A.; Urp´ı, F.;
Vilarrasa, J. Org. Lett. 2007, 9, 989-992. (c) Doan, H. D.; Gallon, J.; Piou,
A.; Vate`le, J.-M. Synlett. 2007, 983-985.
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V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335-
5340.
21-23. It has been known that R-branched trisubstituted (E)-
alkene embedded in a macrocycle poses a challenge for
RCM.9a-e Moreover, structural variations including stere-
omers and protecting groups25 may render RCM fruitless or
may end up with the undesired (Z)-alkenes.9f Hoveyda et al.
prepared a 14-membered trisubstituted (Z)-alkene using 20
mol % Schrock’s catalyst 32.9g In contrast, May and Grieco
obtained a 1:1 mixture of 16-membered trisubstituted (E)-
(16) (a) Narayan, R. S.; Sivakumar, M.; Bouhle, E.; Borhan, B. Org.
Lett. 2001, 3, 2489-2492. (b) Narayan, R. S.; Borhan, B. J. Org. Chem.
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Lett. 2004, 45, 1999-2001. (b) Dai, W.-M.; Zhang, Y. Tetrahedron Lett.
2005, 46, 1377-1381.
(18) The reaction of 11 with 2-bromo-1-propene could be accomplished
by using 15 mol % PdCl2 and 16 mol % dppf as the catalyst system (rt, 12
h) in 71% overall yield for the conversion of 10 to 4.
(19) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586-2587. (b) Inoue, T.; Liu, J.-F.; Buske, D.; Abiko, A. J. Org.
Chem. 2002, 67, 5250-5256. For application in total synthesis, see: (c)
Amarasinghe, K. K. D.; Montgomery, J. J. Am. Chem. Soc. 2002, 124,
9366-9367. (d) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J.
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Prinz, H.; Waldmann, H. J. Org. Chem. 2004, 69, 459-467.
(20) Reduction using LiAlH4 as reported in ref 19 caused cleavage and
migration of TES ether, which could be avoided by using Dibal-H.
(21) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
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Org. Lett., Vol. 9, No. 13, 2007
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23 demonstrated higher reactivity after treatment with 5
portions of 10 mol % 30a, each added at 12 h intervals with
refluxing for a total of 3 days. The desired RCM product 29
(40%) and the byproduct 26 (40%) were isolated as an
inseparable mixture (entry 6 and Figure S3 in Supporting
Information). In contrast to the Ru catalyst 30a, the keto
substrate 23 remained unchanged when treating with 20 mol
% Schrock’s Mo catalyst 32 in CH2Cl2 (refluxing for 22 h,
Table 1, entry 7) and in PhH (24 h at 60 °C, Table 1, entry
8).9g,27 Finally, after global desilylation with HF‚Py, 29 was
converted into amphidinolide Y 1 in 87% yield as a 5:1
mixture (Scheme 3). Our synthetic 1 is identical with all
reported spectral data.4,6 The specific optical rotation of our
Table 1. Results of RCM Reactions of 21-23 in CH2Cl2
entry
substrates and conditionsa
yield (%)b
1
2
3
4
5
6
7
8
21, 25 mol % 30a, reflux, 20 h
21, 25 mol % 30a, reflux, 5 d
21, 50 mol % 30a, reflux, 5 d
21, 100 mol % 30a, reflux, 30 h
22, 50 mol % 30a, reflux, 5 d
23, 50 mol % 30a, reflux, 3 d
23, 20 mol % 32, reflux, 22 h
23, 20 mol % 32, 60 °C, 22 hf
NRc (21, >95)
NDd (21, 67)
NDd (21, 40)
24, 50; 27, 40
e
26, 40; 29, 40
NRc (23, >95)
NRc (23, >95)
a The catalyst 30a was added in portions. See text for details. b Estimated
values based on 1H NMR spectra of the reaction mixtures. For entries 4
and 6, the yields are for the isolated materials. c No reaction. d Not
determined. Formation of 24 and 27 was confirmed along with the recovered
21. e 22 was recovered together with unidentified byproduct(s). f PhH was
used as the solvent.
sample 1 is [R]17 -32.7 (c 1.00, CHCl3), which is in
D
excellent agreement with the values of [R]17 -33 (c 1.00,
D
CHCl3)4 and [R]17 -28.0 (c 1.00, CHCl3).6,28
D
In summary, we have successfully accomplished the
second total synthesis of amphidinolide Y 1 based on RCM
of densely functionalized substrates for assembling the (E)-
trisubstituted alkene. This strategy tolerates the R-oxygenated
keto group which proves advantageous for facilitating the
RCM reaction. The efficiency of the RCM reaction suffers
from a collective steric effect of the multiple functionalities
appended on the carbon chain where the reacting alkenes
are hosted; our total synthesis is the first demonstration of
RCM in constructing the unique 17-membered ring system
of amphidinolide Y, which possesses both (E)-trisubstituted
and (E)-conjugate double bonds. New catalysts and strategies
are still needed for the RCM substrates of great structural
complexity and diversity.
and (Z)-alkenes with 32.9h According to Ulman and Grubbs,26
the bulkier monosubstituted alkenes were significantly
resistant to metathesis, while geminally substituted terminal
alkenes and trans-â-methylstyrene did not undergo metath-
esis at 35 °C with the first generation Ru catalyst. We
assumed that a Ru initiator such as 30a should first form
two ruthenacyclobutanes 33 and 34 with the 2,3-configura-
tion in 33 being favored for sterically hindered monosub-
stituted alkenes.26 It is expected that the dense functionalities
of C9-TBSO,25 C7-TESO, and C6-TESO (for 21 and 22) or
C6-keto (for 23), might deteriorate the productive RCM
pathways by formation of the styrene-derived byproducts
24-26 via 33 when ruthenium(II) benzylidene 30a is
employed.
We found that 21 did not undergo reactions in PhMe or
with the initiator 31. Thus, the RCM reactions of 21-23
were carried out in CH2Cl2 with the initiator 30a. It was
found that 30a must be added in portions and in total
amounts higher than 25 mol % to see metathesis reactions
occurring (Table 1, entries 1-3). When four portions of 25
mol % each of 30a were injected into the reaction mixture
of 21 at the reaction time of 0, 2, 4, and 6 h followed by
refluxing for a total of 30 h, the desired RCM product 27
was isolated as an inseparable mixture with the byproduct
24 in 90% combined yield (entry 4 and Figure S1 in
Supporting Information). In contrast, the (6R)-epimer 22
failed to produce the desired product 28 (entry 5 and Figure
S2 in Supporting Information). To our delight, the C6-ketone
Acknowledgment. This work is supported in part by the
research grants from The National Natural Science Founda-
tion of China (Grant No. 20432020) and Zhejiang University,
China. We thank Ms. Li-Ping Li, College of Pharmaceutical
Sciences, Zhejiang University, for assistance in using JASCO
P-1030 polarimeter. W.-M. Dai is the recipient of the Cheung
Kong Scholars Award of The Ministry of Education of
China.
Supporting Information Available: Experimental pro-
cedures, compound characterization, and Figures S1-S3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0710360
(27) Additional RCM reactions were investigated as given in Supporting
Information.
(28) The results of amphidinolide Y total synthesis were presented at
3rd Yoshimasa Hirata Memorial Lecture, Nagoya, Japan, Feb. 6, 2007.
(26) Ulman, M.; Grubbs, R. H. Organometallics 1998, 17, 2484-2489.
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