Polycavernoside A: The Prins Macrocyclization Approach

Article abstract of DOI:10.1021/ja1009579

An intramolecular Prins macrocyclization reaction was successfully employed in the synthesis of polycavernoside A.

Full text of DOI:10.1021/ja1009579

Published on Web 03/11/2010
Polycavernoside A: The Prins Macrocyclization Approach
Sang Kook Woo and Eun Lee*
Department of Chemistry, College of Natural Sciences, Seoul National UniVersity, Seoul 151-747, Korea
Received February 2, 2010; E-mail: eunlee@snu.ac.kr
Scheme 2. Preparation of the Acyclic Ester Intermediate
Polycavernoside A (1) was isolated by Yasumoto from the edible
red alga PolycaVernosa tsudai as a causative toxin of sudden human
intoxication in Guam in 1991.1 The proposed macrolactone
disaccharide structure was confirmed via the first total synthesis
by Murai, which also established the absolute stereochemistry.2 In
the Murai synthesis, Yamaguchi lactonization of the hydroxycar-
boxylic acid precursor containing a preformed oxane subunit yielded
a key macrolide intermediate. Similar strategies were also adopted
in the later syntheses by Paquette3 and White.4,5 We were intrigued
by the possibility of using an intramolecular Prins macrocyclization
protocol6-8 in the synthesis of 1. Aldehydo homoallylic alcohol B
may undergo a Prins cyclization reaction to produce macrolactone
A, from which the known macrolactone intermediate 2 may be
prepared. The success of this macrobicyclization reaction would
hinge on the viability of the macrocyclic oxocarbenium ion C
(Scheme 1).
Scheme 1. Retrosynthetic Analysis
Acetate protection of the secondary hydroxyl group in 11 and
TBS deprotection led to acetal homoallylic alcohol 12. The crucial
Prins macrocyclization reaction of 12 proceeded smoothly in the
presence of TES triflate, TMS acetate, and acetic acid6 to produce
an 85% yield of a product mixture containing mainly (6:1) the
desired macrolactone 13 (Scheme 3). The minor product was the
acetoxy epimer. Treatment of 13 with excess ozone led to diketone
aldehyde 14 as expected. Problems arose when 14 was subjected
to the Takai conditions;11 only a complex product mixture was
obtained, and it was not possible to obtain the desired iodoolefin.
The diketone functionality obviously interfered under the Takai
conditions. Selective protection of the aldehyde or diketone group
appeared to be impractical, and acetate removal was also sluggish.
It was then decided to employ diol intermediate 15 in the Prins
macrocyclization step; this diol can be prepared from 11 via TBS
deprotection. The rationale was that the extra hydroxyl group would
not participate in the formation of a cyclic oxocarbenium ion that
is also an eight-membered heptanolactone. In practice, acetal diol
15 underwent Prins macrocyclization smoothly under the usual
conditions, producing mainly (5.5:1) macrolactone 16 (Scheme 4).
The intramolecular alkyne hydration reaction proceeded pre-
dominantly in the 6-endo mode, mainly producing cyclic enol ether
17 from alkynol 16 in the presence of a platinum(II) catalyst.12
Oxidation of 17 with dimethyldioxirane and addition of methanol
led to a hydroxy ketal intermediate, which was converted into keto
ketal 18 under Ley oxidation conditions.13 The corresponding
aldehyde was prepared via ozonolysis of 18, which was converted
into the corresponding iodoolefin under Takai conditions. Prolonged
exposure to the Takai conditions also resulted in the rearrangement
In practice, the reaction of hydroxyacetaldehyde tosylate (3) with
the Nokami alcohol 49 under acidic conditions produced homoallylic
alcohol 5. The epoxide generated from 5 was reacted with the
known alkyne 610 after lithiation, and enynol 7 was prepared
smoothly. TBDPS deprotection, regioselective tosylation, TBS
protection of the secondary hydroxyl group, and iodide substitution
produced primary iodide 8 without difficulty. Lithium-halogen
exchange and reaction with the known aldehyde 94b led to the
formation of secondary alcohol products (1:1.4), which were
converted into the corresponding ketone. DDQ deprotection of
the PMB group and reduction with tetramethylammonium
triacetoxyborohydride led to the predominantly (6:1) anti diol
product, which was condensed with carboxylic acid 10 to
produce ester 11 (Scheme 2).
9
4564 J. AM. CHEM. SOC. 2010, 132, 4564–4565
10.1021/ja1009579  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Prins Cyclization and Preparation of a Diketone
Aldehyde Intermediate
The present scheme represents a facile route to polycavernoside
A (1). In particular, the key bicyclic macrolactone 16 was prepared
directly from an acyclic precursor, 15. Future studies will focus on
further applications of the Prins macrocyclization strategy in the
synthesis of complex natural products.
Acknowledgment. This work was supported by a National
Research Foundation (NRF) grant funded by the Ministry of
Education, Science, and Technology, Republic of Korea, through
the Center for Bioactive Molecular Hybrids (R11-2003-019-00000-
0). This research was also supported by the NRF Basic Science
Research Program funded by the Ministry of Education, Science,
and Technology (KRF-2008-314-C00198). BK21 Graduate Fel-
lowship Grants to S.K.W. are gratefully acknowledged.
Supporting Information Available: Selected experimental proce-
dures and 1H and 13C NMR spectra of selected intermediates. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 1147–1148. For isolation of new analogues of poly-
cavernoside A, see: (b) Yotsu-Yamashita, M.; Seki, T.; Paul, V. J.; Naoki,
H.; Yasumoto, T. Tetrahedron Lett. 1995, 36, 5563–5566. (c) Yotsu-
Yamashita, M.; Abe, K.; Seki, T.; Fujiwara, K.; Yasumoto, T. Tetrahedron
Lett. 2007, 48, 2255–2259.
Scheme 4. Alternative Prins Cyclization and Synthesis of
Polycavernoside A (1)
(2) (a) Fujiwara, K.; Murai, A.; Yotsu-Yamashita, M.; Yasumoto, T. J. Am.
Chem. Soc. 1998, 120, 10770–10771. (b) Hayashi, N.; Mine, T.; Fujiwara,
K.; Murai, A. Chem. Lett. 1994, 23, 2143–2146. (c) Fujiwara, K.; Amano,
S.; Oka, T.; Murai, A. Chem. Lett. 1994, 23, 2147–2150. (d) Fujiwara, K.;
Amano, S.; Murai, A. Chem. Lett. 1995, 24, 191–192. (e) Fujiwara, K.;
Amano, S.; Murai, A. Chem. Lett. 1995, 24, 855–856.
(3) (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) Johnston, J. N.; Paquette,
L. A. Tetrahedron Lett. 1995, 36, 4341–4344. (d) Paquette, L. A.;
Pissarnitski, D.; Barriault, L. J. Org. Chem. 1998, 63, 7389–7398.
(4) (a) 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. (b) 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.
(5) For further studies of polycavernoside A synthesis, see: (a) Barry, C. S.;
Bushby, N.; Harding, J. R.; Willis, C. L. Org. Lett. 2005, 7, 2683–2686.
(b) Pe´rez-Balado, C.; Marko´, I. E. Tetrahedron Lett. 2005, 46, 4887–4890.
(c) Pe´rez-Balado, C.; Marko´, I. E. Tetrahedron 2006, 62, 2331–2349.
(6) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 3242–
3244.
(7) For examples of intramolecular Prins cyclization, see: (a) Schulte-Elte,
K. H.; Hauser, A.; Ohloff, G. HelV. Chim. Acta 1979, 62, 2673–2680. (b)
Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.;
Chang, M. H. Org. Lett. 2002, 4, 2025–2028.
(8) For more recent examples of intramolecular Prins macrocyclization, see:
(a) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem. Soc. 2008,
130, 804–805. (b) Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am.
Chem. Soc. 2008, 130, 6658–6659. (c) Bahnck, K. B.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2008, 130, 13177–13181. (d) Gesinski, M. R.; Tadpetch,
K.; Rychnovsky, S. D. Org. Lett. 2009, 11, 5342–5345.
(9) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.; Kataoka,
K. J. Am. Chem. Soc. 2001, 123, 9168–9169.
(10) 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, 8019–8021.
to the five-membered-ring hemiacetal. Basic hydrolysis led to the
known intermediate 2. Glycosylation of 2 in the presence of the
known glycosyl sufide 19,4b oxidative benzyl deprotection of the
benzyl ether group with DDQ, and a Stille-type coupling reaction
with the known dienylstannane 203b led to (-)-polycavernoside
A (1).
(11) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–
7410.
(12) Bhunia, S.; Wang, K.-C.; Liu, R.-S. Angew. Chem., Int. Ed. 2008, 47, 5063–
5066.
(13) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc.,
Chem. Commun. 1987, 1625–1627.
JA1009579
9
J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4565