Total synthesis of (-)-polycavernoside A: Suzuki-Miyaura coupling approach

Article abstract of DOI:10.1021/ol301278e

A total synthesis of (-)-polycavernoside A, a marine lethal toxin isolated from the edible alga Gracilaria edulis, has been achieved via a convergent approach. The synthesis is highlighted by catalytic asymmetric syntheses of the two key fragments and their union through Suzuki-Miyaura coupling and Keck macrolactonization.

Full text of DOI:10.1021/ol301278e

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3186–3189
Total Synthesis of (ꢀ)-Polycavernoside A:
SuzukiꢀMiyaura Coupling Approach
Yusuke Kasai, Takanori Ito, and Makoto Sasaki*
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku,
Sendai 980-8577, Japan
masasaki@bios.tohoku.ac.jp
Received May 9, 2012
ABSTRACT
A total synthesis of (ꢀ)-polycavernoside A, a marine lethal toxin isolated from the edible alga Gracilaria edulis, has been achieved via a
convergent approach. The synthesis is highlighted by catalytic asymmetric syntheses of the two key fragments and their union through
SuzukiꢀMiyaura coupling and Keck macrolactonization.
Polycavernoside A (1, Figure 1) was isolated in 1993 by
Yasumoto and co-workers, together with a minor analogue
polycavernoside B, as causative toxins for the fatal human
poisoning that occurred in Guam in 1991 and in the
Philippines in 2002ꢀ2003, due to ingestion of the edible
red alga Gracilaria edulis (Polycavernosa tsudai).1,2
The LD99 value of 1 in mice (ip) was estimated to be
200ꢀ400 μg/kg. The planar structure of 1 was elucidated
on the basis of extensive 2D NMR studies, which showed it
to be a novel glycosylated macrolide.1 The complete stereo-
chemistry, including the absolute configuration, was estab-
lished by the Murai group with their first total synthesis of
(ꢀ)-polycavernoside A in 1998.3 Thereafter, five congeners,
polycavernosides A2, A3, B2, C, and C2, were isolated as
minute constituents from G. edulis and structurally deter-
mined by Yotsu-Yamashita et al.4 The structure of 1consists
Figure 1. Structures of polycavernosides A and B.
(1) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am.
Chem. Soc. 1993, 115, 1147–1148.
(2) Yotsu-Yamashita, M.; Yasumoto, T.; Yamada, S.; Bajarias,
of a 16-membered macrolactone adorned with tetrasubsti-
tuted tetrahydropyran and five-membered hemiacetal rings,
F. F. A.; Formeloza, M. A.; Romero, M. L.; Fukuyo, Y. Chem. Res.
Toxicol. 2004, 17, 1265–1271.
(3) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T.
J. Am. Chem. Soc. 1998, 120, 10770–10771.
(4) (a) Yotsu-Yamashita, M.; Seki, T.; Paul, V. J.; Naoki, H.;
Yasumoto, T. Tetrahedron Lett. 1995, 36, 5563–5566. (b) Yotsu-Yamashita,
M.; Abe, K.; Seki, T.; Fujiwara, K.; Yasumoto, T. Tetrahedron Lett. 2007,
48, 2255–2259.
a conjugated triene side chain appended at C15, and a highly
O-methylated L-fucosyl-D-xylose unit attached at C5.
The complex molecular architecture of polycavernoside
A, coupled with the lethal toxicity and very limited avail-
ability from natural sources, makes this natural substance
an attractive target molecule for total synthesis. While four
r
10.1021/ol301278e
Published on Web 06/06/2012
2012 American Chemical Society

total syntheses3,5 and several synthetic approaches6 have been
reported to date, its detailed mechanism of action still remains
unresolved due to the lack of natural sample.7 Herein, we
report a new convergent total synthesis of polycavernoside A
based on a SuzukiꢀMiyaura coupling strategy.
fragments 4 and 5, of comparable complexity, would be
constructed through catalytic asymmetric reactions.
The synthesis of the C1ꢀC8 exo-olefin 4 started with the
known enone 6, which is readily available in three steps
from 1,3-propanediol.10 Catalytic asymmetric hetero-
DielsꢀAlder reaction between silyloxy diene 7, derived
from 6 (TMSTOf, Et3N, room temperature), and aldehyde
811 was promoted by the Jacobsen tridentate chromium-
(III) catalyst 9 (3 mol %)12 and afforded the desired
cycloadduct 10 (Scheme 2). Subsequent treatment with
K2CO3 in MeOH produced a 6:1 mixture of ketone 11a
with the desired stereochemistry at C4 and its isomer 11b,
which was separated by flash column chromatography on
silica gel. Isomerization of the undesired 11b was realized
by using DBU (toluene, room temperature) and gave a
10:1 mixture of 11a and 11b. After two cycles of isomer-
ization, the desired 11a was obtained in 60% overall yield
Our retrosynthetic analysis of polycavernoside A (1) is
illustrated in Scheme 1. We envisioned that the known
intermediate 2, which was used in all previous total
syntheses,3,5 would be derived from bis-pyran 3 through
oxidation of the enol ether moiety to the C9ꢀC10 diketone
functionality followed by macrolactone formation. The
cyclic enol ether 3, in turn, could be constructed by
SuzukiꢀMiyaura coupling of an alkylborane generated
from the exo-olefin 4 and enol triflate 5.8,9 These two key
Scheme 1. Retrosynthetic Analysis
from 6. Luche reduction of 11a (NaBH4, CeCl3 7H2O,
3
MeOH, ꢀ20 °C)13 delivered alcohol 12 in 94% yield as a
single stereoisomer at C5. At this stage, the enantiomeric
excess (96% ee) and the absolute configuration of 12 were
1
established by H NMR analysis of its Mosher esters.14
After protection as a triisopropylsilyl (TIPS) ether, selec-
tive deprotection of the TBS group and iodination of the
resultant alcohol gave iodide 13 in 86% yield (three steps).
Treatment of 13 with t-BuOK furnished the exo-olefin 4,
which was directly used in the next coupling reaction (see
Scheme 4).
The synthesis of the C9ꢀC16 enol triflate 5 commenced
with (R)-(þ)-citronellal (97.2% ee), which was converted
into alcohol 14 via a six-step sequence15 (Scheme 3).
Ozonolysis of the double bond gave aldehyde 15 in 92%
yield. Catalytic asymmetric allylation of 15 with prenyl
bromide was carried out using the chiral sulfonamide
ligand 16 and following the procedure of Kishi and co-
workers;16 it provided alcohol 17 (31%) and the corre-
sponding diol (69%) as single stereoisomers, respectively.
Reprotection of the primary alcohol of the latter as its TBS
ether afforded 17 in 86% yield. Asymmetric dihydroxyla-
tion of the terminal alkene using (DHQ)2PYR as a chiral
ligand17 led to triol 18 in 97% yield. Selective protection of
the primary alcohol as its tert-butyldiphenylsilyl (TBDPS)
ether, removal of the TBS group under acidic conditions
(5) (a) Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem.
Soc. 1999, 121, 4542–4543. (b) Paquette, L. A.; Barriault, L.; Pissarnitski,
D.; Johnston, J. N. J. Am. Chem. Soc. 2000, 122, 619–631. (c) White, J. D.;
Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy,
P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem. Soc. 2001, 123, 8593–
8595. (d) Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.;
Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org.
Chem. 2005, 70, 5449–5460. (e) Woo, S. K.; Lee, E. J. Am. Chem. Soc.
2010, 132, 4564–4565.
(10) Robertson, J.; Dallimore, J. W. P.; Meo, P. Org. Lett. 2004, 6,
3857–3859.
(11) Keck, G. E.; Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel,
J. A.; McLaws, M. D.; Krishnamurthy, D.; Cee, V. J. Angew. Chem., Int.
Ed. 2001, 40, 231–234.
ꢀ
ꢀ
(6) (a) Perez-Balado, C.; Marko, I. E. Tetrahedron 2006, 62, 2331–
2349. (b) Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L. Org. Lett.
ꢀ
ꢀ
ꢀ
2005, 7, 2683–2686. (c) Perez-Balado, C.; Marko, I. E. Tetrahedron Lett.
2005, 46, 4887–4890. (d) Dumeunier, R.; Marko, I. E. Tetrahedron Lett.
(12) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398–2400.
2000, 41, 10219–10222.
(7) (a) Cagide, E.; Louzao, M. C.; Ares, I. R.; Vieytes, M. R.; Yotsu-
Yamashita, M.; Paquette, L. A.; Yasumoto, T.; Botana, L. M. Cell.
Physiol. Biochem. 2007, 19, 185–194. (b) Barriault, L.; Boulet, S. L.;
Fujiwara, K.; Murai, A.; Paquette, L. A.; Yotsu-Yamashita, M. Bioorg.
Med. Chem. Lett. 1999, 9, 2069–2072.
(8) For selected reviews on SuzukiꢀMiyaura coupling, see:
(a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4544–4568. (c) Suzuki, A. Angew. Chem., Int. Ed.
2011, 50, 6722–6737.
(13) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(b) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
(14) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096. (b) Hoye, T. R.; Jeffrey, C. S.; Shao, F.
Nat. Protoc. 2007, 2, 2451–2458. See the Supporting Information for
details.
(15) Lee, E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim, M. S.; Yun, J. K.
J. Org. Chem. 1994, 59, 1444–1456.
(16) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126,
12248–12249.
(9) For recent reviews, see: (a) Sasaki, M.; Fuwa, H. Synlett 2004,
1851–1874. (b) Sasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 856–871.
(c) Sasaki, M.; Fuwa, H. Nat. Prod. Rep. 2008, 25, 401–426. (d) Fuwa, H.
Bull. Chem. Soc. Jpn. 2010, 83, 1401–1420.
(17) (a) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu,
D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785–3786. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
Org. Lett., Vol. 14, No. 12, 2012
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Scheme 2. Synthesis of the C1ꢀC8 exo-Olefin 4
Scheme 3. Synthesis of the C9ꢀC16 Enol Triflate 5
(CSA, MeOH), andoxidativelactonization ofthe resultant
1,5-diol with TEMPO and PhI(OAc)218 delivered lactone
19 in 76% yield for the three steps. The residual secondary
alcohol was then protected as its triethylsilyl (TES) ether
to give 20 in quantitative yield which, upon treatment with
KHMDS and PhNTf2 (HMPA, THF, ꢀ78 °C), furnished
the desired enol triflate 5.
With the requisite fragments in hand, we next turned
our attention to their union through SuzukiꢀMiyaura
coupling.8,9 After extensive experimentation, Suzukiꢀ
Miyaura coupling of the alkylborane generated from
exo-olefin 4 (9-BBN-H, THF, 0 °C to room temperature)
with enol triflate 5 was achieved under the conditions
individually oxidized tothe sameketone22inhigh yields.20
Selective cleavage of the TES ether and oxidative removal
of the PMB group afforded diol 23 in 98% yield for the
two steps. The primary alcohol of diol 23 was selectively
oxidized with TEMPO/PhI(OAc)2 in CH2Cl2/H2O (10:1)21
to provide the corresponding carboxylic acid in 97% yield.
Subsequent macrolactonization proved to be more difficult
than expected. After extensive experimentation, it was
finally found that the best result was obtained by using
Keck protocol22 employing DCC, pyridine, and PPTS23
under reflux to afford macrolactone 24 in quantitative
yield.24 The primary TBDPS ether was selectively cleaved
which used aqueous Cs2CO3 as a base, PdCl2(dppf)
3
CH2Cl2 as a catalyst, and Ph3As as a coligand in DMF/
THF at room temperature, affording the desired coupled
product 3 in high yield.19 The cyclic enol ether moiety
of 3 was then oxidized with m-chloroperoxybenzoic acid
(m-CPBA) in CH2Cl2/MeOH to afford an inconsequential
epimeric mixture of alcohols 21a and 21b in 66 and 25%
overall yields from 13, respectively. These alcohols were
with buffered HF pyridine, and oxidation of the resulting
alcohol with DessꢀMartin periodinane25 followed by
3
ꢀ
(21) (a) van den Bos, L. J.; Codee, J. D. C.; van der Toorn, J. C.;
Boltje, T. J.; van Boom, J. H.; Overkleeft, H. S.; van der Marel, G. A.
Org. Lett. 2004, 6, 2165–2168. (b) Epp, J. B.; Widlanski, T. S. J. Org.
Chem. 1999, 64, 293–295.
(22) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394–2395.
(23) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.;
Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990,
112, 7407–7408.
(24) Fujiwara et al. reported that Yamaguchi lactonization of a
substrate closely related to 23 proceeded smoothly to give the corre-
sponding 16-membered macrolactone in good yield. However, macro-
lactonization of a hydroxy acid derived from 23 under Yamaguchi or
Shiina conditions resulted in only a low yield of 24.
(25) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(18) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams,
J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57–59.
(19) SuzukiꢀMiyaura coupling of the phosphate counterpart re-
sulted in a low yield of 3 [Pd(PPh3)4, PdCl2(dppf) CH2Cl2, or PdCl2-
3
(dppf) CH2Cl2/Ph3As] presumably due to the low reactivity.
3
(20) 10β-Alcohol 21a was labile even under mild acidic conditions.
For example, Swern oxidation of 21a caused partial cleavage of the
methyl acetal and resulted in a low yield of ketone 22 (37%).
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Org. Lett., Vol. 14, No. 12, 2012

Scheme 4. Fragment Coupling and Completion of the Synthesis of Polycavernoside A
Takai reaction (CHI3, CrCl2)26 led to (E)-vinyliodide 25 in
61% yield (three steps). Treatment of 25 with TFA/THF/
H2O (1:2:2)3 effected deprotection of the TIPS ether and
methyl acetal with concomitant reconstruction of the five-
membered hemiacetal to afford alcohol 2 in 98% yield.
Finally, glycosylation of 2 with thioglycoside 265c,d
under the influence of NBS27 (41%), oxidative cleavage
of the benzyl ether with DDQ (68%), and Stille coupling
withthe known dienylstannane 275a,b (45%) completed the
synthesis of (ꢀ)-polycavernoside A (1).
to form the macrolactone core. Our convergent fragment
coupling strategy allows for the preparation of sufficient
quantities of polycavernoside A itself and its analogues for
detailed biological studies. Further studies along this line are
underway and will be reported in due course.
Acknowledgment. We thank Takasago International
Co. for providing us (R)-(þ)-citronellal. This work was
supported by Grants-in-Aid from Scientific Research (A)
(No. 21241050) and Scientific Research (C) (No. 22603001)
from Japan Society for the Promotion of Sciences
(JSPS) and the Tohoku University Global COE program
“International Center of Research & Education for Mole-
cular Complex Chemistry”.
In summary, an efficient total synthesis of polycaverno-
side A has been accomplished via a convergent approach
(a longest linear sequence of 29 steps and 2.4% overall yield
from commercially available (R)-(þ)-citoronellal). The
synthesis features catalytic asymmetric syntheses of the
C1ꢀC8 and C9ꢀC16 fragments and their assembly through
SuzukiꢀMiyaura coupling and Keck macrolactonization
Supporting Information Available. Experimental proce-
dures, characterization data, and copies of 1Hand13CNMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(26) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410.
(27) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430–2434.
The authors declare no competing financial interest.
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