One-step assembling reaction to the pentacyclic acetal of pinnatoxins

Article abstract of DOI:10.1039/b104200a

Treatment of acyclic tetraketone 8 with HF-py in MeCN afforded the pentacyclic system 1 in pinnatoxins with a high selectivity in good yield.

Full text of DOI:10.1039/b104200a

One-step assembling reaction to the pentacyclic acetal of pinnatoxins
Jun Ishihara, Shingo Tojo, Akio Kamikawa and Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
E-mail: amurai@sci.hokudai.ac.jp; Fax: +81-11-706-2714; Tel: +81-11-706-2714
Received (in Cambridge, UK) 9th May 2001, Accepted 13th June 2001
First published as an Advance Article on the web 11th July 2001
Treatment of acyclic tetraketone 8 with HF·py in MeCN
afforded the pentacyclic system 1 in pinnatoxins with a high
selectivity in good yield.
The intramolecular acetal functionalities widely appear as
subunits of many biologically active natural products, including
polyether ionophores, and the construction of these acetal
systems represents a synthetic challenge.1,2 The favored
conformation of the spiroacetal is predictable on the basis of
stabilizing anomeric and exo-anomeric effects that direct C–O
bonds to axial positions on the respective rings.3 Pinnatoxins,
which were isolated from Pinna muricata by Uemura, included
the unique dispiroacetal and bicycloacetal moieties in their
Scheme 1
skeletons.4 Recently, Kishi and co-workers accomplished the
total synthesis of pinnatoxin A, and the absolute stereochem-
Prior to one-step assembling reaction, stepwise acetalization
istry was determined at the same time.5,6 Independently, we
reported an efficient formation of the trioxadispiroacetal
moieties,7 and also the construction of the BCDEF ring system
of pinnatoxins, however acetal formation of the BCDEF ring
system was rather problematic as an undesired acetal was
generated as a major product.8 On our way to the syntheses, it
was found that both of the BCD-fragment and the EF-fragment
could be constructed under the same conditions. These results
suggested the possibility of a one-step formation of two
intramolecular acetals, which would allow fewer steps and
seemed to be more attractive. Herein, we describe a one-step
assembling reaction to the pentacyclic system of pinnatoxin A,
1† (Fig. 1).
was elucidated, which involves the construction of the BCD-
ring after formation of diacetal moiety (Scheme 2). The
acetalization reaction of 39 was performed with HF·py in MeCN
at 23 °C for 4 h to afford the desired compound 1 in 90% yield
as a sole component of the pentacyclic compounds in spite of
the possibility of eight products.10 According to our previous
results, the acetal formation of BCD-ring would be controlled
by the thermodynamic effect,11 which is based on the anomeric
effect enhanced by the presence of an a-ketone.12
Since formation of the BCD-ring acetal proceeded independ-
ently of the EF-ring, the one-step assembling reaction to the
pentacyclic system seemed to be realized. Reaction of 4 and 5,
followed by oxidation and desulfurization,13 gave a coupled
ketone in 84% yield in 4 steps (Scheme 3). The MMTr‡ group
was detached with PPTS in MeOH and CH2Cl2 to the alcohol in
86% yield,14 which was subsequently oxidized to aldehyde 7 in
99% yield. Analogous reaction of the sulfone 6 and 7 proceeded
moderately to furnish another coupled ketone in 60% yield in 3
steps, which was converted to tetraketone 8 by ruthenium
oxidation in 77%. Now the precursor for cyclization was
obtained in our hands. When 8 was exposed to HF·py in MeCN
at 24 °C for 7.5 h, the desired pentacyclic acetal compound 1
was produced as a single pentacyclic isomer in 71% yield,
which was accompanied by a mixture of by-products lacking
the pentacyclic system. The incompletely cyclized by-products
were convertible to 1 under the same conditions. Eventually, the
desired 1 was provided in an 83% combined yield from 8. On
the other hand, in the case of THF as a solvent, the reaction
afforded the pentacyclic compound as a mixture of three
isomers (9+10+ 1 = 2+1+1) in 83% yield (Scheme 4). When this
In our initial efforts, tetra-TBS‡ compound 2 was selected as
a precursor for the cyclization in the unnatural enantiomeric
form (Scheme 1). Various conditions were examined, however,
none of the acidic conditions provided compound ent-1. Upon
terminating the reaction after 1 hour, it seemed that the TBS
groups at C-29 and 30 positions still remained intact, while the
BCD-ring moiety might be gradually formed. At longer reaction
time, the cyclic products were overreacted to afford a complex
mixture, including b-eliminated and retro-aldol compounds.
These results suggested that the formation of the EF-ring should
precede the cyclization of the BCD-ring, which implied the
faster hydrolysis of the protective groups at C-29 and 30 than
the others. Therefore, 29,30-di-TES compound, which would be
more detachable than di-TBS, was directed at the next stage.
Fig. 1
Scheme 2
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Chem. Commun., 2001, 1392–1393
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104200a

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yield. Further synthetic study is now under way in our
laboratory.
This study was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan (11780410, J. I.).
Notes and references
† 1: colorless oil. [a]D22 +19.7 (c 0.14, CHCl3); 1H-NMR (C6D6, 400 MHz)
d 7.32 (2H, d, J 8.5 Hz), 7.25–7.06 (5H, m), 6.85 (2H, d, J 8.5), 4.79 (1H,
d, J 6.8), 4.68 (1H, dd, J 1.3, 4.6), 4.65 (1H, d, J 6.8), 4.51–4.43 (2H, m),
4.43 (1H, d, J 11.2), 4.43–4.32 (3H, m), 4.23 (1H, d, J 12.2), 3.85 (1H, dd,
J 6.6, 10.0 Hz), 3.82 (1H, dd, J 8.3, 8.7), 3.69 (1H, dd, J 8.3, 8.7), 3.67–3.58
(3H, m), 3.57 (1H, dd, J 1.3, 3.4), 3.30 (3H, s), 2.83 (1H, ddd, J 2.4, 8.8,
12.2), 2.62 (1H, ddd, J 7.4, 12.7, 14.6), 2.37–2.28 (1H, m), 2.32 (1H, dd, J
6.8, 14.2), 2.25–2.13 (3H, m), 2.08–1.96 (4H, m), 1.94–1.83 (1H, m),
1.79-1.65 (3H, m), 1.63–1.53 (2H, m), 1.46–1.17 (4H, m), 1.13 (3H, d, J
6.8), 0.98 (2H, t, J 8.5), and 20.01 (9H, s); 13C-NMR (C6D6, 100 MHz) d
201.5, 159.7, 138.7, 131.4, 129.4, 128.6, 127.9, 114.1, 108.9, 108.7, 108.5,
94.8, 78.3, 77.8, 73.8, 73.5, 73.0, 70.0, 68.5, 68.1, 67.2, 65.4, 54.9, 45.6,
40.1, 38.6, 35.9, 35.2, 34.0, 33.0, 32.5, 31.3, 30.3, 29.5, 20.6, 18.4, and 17.0;
IR (neat), nmax 2926, 2855, 1733, 1612, 1514, 1454, 1367, 1303, 1249,
1099, 1036, 984, 952, 861, 836, 749, and 698 cm21; FD-HR-MS: found:
796.4228, calcd. for C44H64O11Si (M+): 796.4218.
‡ SEM = 2,2-(trimethylsilyl)ethoxymethyl. TBS = tert-butyldimethyl-
silyl. MMTr = 4-methoxyphenyldiphenylmethyl. DMPI = Dess-Martin
periodinane {IUPAC name: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benz-
iodoxol-3(1H)-one}. MPM = 4-methoxybenzyl.
Scheme 3 (a) 5, BuLi, THF, 278 °C, 30 min, then 4, 278 °C, 30 min; (b)
Swern oxidation; (c) (i) SmI2, MeOH, THF, 0 °C, 30 min, (ii) Al(Hg), THF–
H2O (10+1), 23 °C, 16 h (84% in 4 steps); (d) PPTS (cat.), MeOH–CH2Cl2
(1+50), 21 °C, 10.5 h (88%); (e) DMPI,‡ NaHCO3, CH2Cl2, 23 °C, 20 h
(99%); (f) 6, BuLi, Et2O, 278 °C, 30 min, then 7, 278 °C, 15 min; (g)
DMPI, NaHCO3, CH2Cl2, 23 °C, 11.5 h; (h) SmI2, MeOH, THF, 0 °C, 30
min (60% in 3 steps); (i) RuO2·H2O, NaIO4, CCl4–MeCN–pH 7 buffer
(1+1+1.5), 23 °C, 195 min (77%); (j) HF·py, MeCN, 24 °C, 7.5 h (83% after
one recycle).
1 For reviews on spiroketal synthesis see: A. F. Kluge, Heterocycles,
1986, 24, 1699; T. L. B. Boivin, Tetrahedron, 1987, 43, 3309; F. Perron
and K. F. Albizati, Chem. Rev., 1989, 89, 1617; V. Vaillancourt, N. E.
Pratt, F. Perron and K. F. Albizati, Total Synth. Nat. Prod., 1992, 8, 533;
M. A. Brimble and F. A. Far, Tetrahedron, 1999, 55, 7661.
2 F. Perron and K. F. Albizati, J. Org. Chem., 1989, 54, 2047; M. A.
Brimble and G. M. Williams, Tetrahedron Lett., 1990, 31, 3043; M. A.
Brimble and G. A. Williams, J. Org. Chem., 1992, 57, 5818; K. Horita,
S. Nagato, Y. Oikawa and O. Yonemitsu, Tetrahedron Lett., 1987, 28,
3253; D. R. Williams, P. A. Jass and R. D. Gaston, Tetrahedron Lett.,
1993, 34, 3231; G. J. McGarvey and M. W. Stepanian, Tetrahedron
Lett., 1996, 37, 5461; G. J. McGarvey, M. W. Stepanian, A. R. Bressette
and J. F. Ellena, Tetrahedron Lett., 1996, 37, 5465.
3 P. Delongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, Oxford, pp. 4–53, 1983.
4 D. Uemura, T. Chou, T. Haino, A. Nagatsu, S. Fukuzawa, S. Z. Zeng
and H. S. Chen, J. Am. Chem. Soc., 1995, 117, 1155; T. Chou, O. Kamo
and D. Uemura, Tetrahedron Lett., 1996, 37, 4023; T. Chou, T. Haino,
M. Kuramoto and D. Uemura, Tetrahedron Lett., 1996, 37, 4027.
5 J. A. McCauley, K. Nagasawa, P. A. Lander, S. G. Mischke, M. A.
Semones and Y. Kishi, J. Am. Chem. Soc., 1998, 120, 7647.
6 For synthetic studies see: T. Noda, A. Ishiwata, S. Uemura, S. Sakamoto
and M. Hirama, Synlett, 1998, 298; B. D. Suthers, M. F. Jacobs and W.
Kiching, Tetrahedron Lett., 1998, 39, 2621; A. Ishiwata, S. Sakamoto,
T. Noda and M. Hirama, Synlett, 1999, 692; A. Nitta, A. Ishikawa, T.
Noda and M. Hirama, Synlett, 1999, 695.
Scheme 4
7 T. Sugimoto, J. Ishihara and A. Murai, Tetrahedron Lett., 1997, 38,
7379.
mixture of 9, 10, and 1 was treated with HF·py in MeCN–H2O
(20+1) at 21 °C for 24 h, 1 was generated in 77% yield. The
exclusive formation of 1 seems to be reasonable judging from
the results of MM2* calculation using MacroModel 6.5 for the
relative energies of the compounds, which suggested that the
potential energy of 1 would be > 3.5 kcal mol21 lower than any
others. In addition, the axial preference of the C–O bond of the
cyclic acetal would be enhanced by the presence of an a-ketone
due to the cyclic stereoelectronic effect of p-electron donation.
The acetalization in THF proceeded under the kinetic control,
while the thermodynamic effect played an important role in the
case of MeCN. The difference between the selectivities in
MeCN and THF were induced by the solvation effect, which
appeared in the glycosidation, involving the intermediacy of the
acetonitrilium ion.15 Thus, the one-step assembling reaction of
the tetraketone to the complicated acetal was achieved to
provide selectively the pentacyclic compound in an excellent
8 T. Sugimoto, J. Ishihara and A. Murai, Synlett, 1999, 541.
9 A. Kamikawa, J. Ishihara and A. Murai, unpublished results.
10 The structure of 1 was determined by NMR spectroscopy (1H-,13C-
NMR, DQFCOSY, HMQC, HMBC, and NOESY spectra).
11 J. Ishihara, T. Sugimoto and A. Murai, Synlett, 1998, 603.
12 A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen, Springer-Verlag, Berlin, Heidelberg, New York, pp. 20–23,
1983.
13 G. A. Molander, Chem. Rev., 1992, 92, 29.
14 R. W. Armstrong, J.-M. Beau, S. H. Cheon, W. J. Christ, H. Fujioka,
W.-H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J.
Martinelli, W. W. McWhorter, M. Mizuno, M. Nakata, A. E. Stutz, F. X.
Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J. Uenishi, J. B. White and
M. Yonaga, J. Am. Chem. Soc., 1989, 111, 7525.
15 P. Sinay and J. R. Pougny, Tetrahedron Lett., 1976, 4073; R. R. Schmidt
and J. Michel, Carbohydr. Chem., 1985, 4, 141; R. U. Lemieux and
R. M. Ratcliffe, Can. J. Chem., 1979, 57, 1244.
Chem. Commun., 2001, 1392–1393
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