Synthesis of the B,C,D,E,F-ring fragment of pinnatoxins

Article abstract of DOI:10.1055/s-1999-2689

Construction of the B,C,D,E,F-ring of pinnatoxins is disclosed. Julia coupling reaction between the E,F-ring fragment (C₂₆-C₃₁) as the sulfone and the B,C,D-ring fragment (C₁₀-C₂₅) as the aldehyde proceeded smoo

Full text of DOI:10.1055/s-1999-2689

LETTER
541
Synthesis of the B,C,D,E,F-Ring Fragment of Pinnatoxins
Tetsuya Sugimoto, Jun Ishihara, Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan
Fax 81-11-706-2714; E-mail: amurai@sci.hokudai.ac.jp
Received 24 February 1999
to afford 6 in 73% yield. When the reaction was carried
out at rt, elimination of the benzyloxy group took place to
give the allene compound. Sharpless AE of 6 provided ep-
oxide 7 in 93% yield in 92% ee.6 The epoxide was opened
regioselectively with Ti(OiPr)4 and benzoic acid to afford
8 in 94% yield. The benzoyl group in 8 was cleaved with
NaOH aq in MeOH (94% yield) and the primary hydroxyl
group of the resulting triol compound was protected as a
Abstract: Construction of the B,C,D,E,F-ring of pinnatoxins is dis-
closed. Julia coupling reaction between the E,F-ring fragment (C26-
C31) as the sulfone and the B,C,D-ring fragment (C10-C25) as the al-
dehyde proceeded smoothly to afford the B,C,D,E,F-ring system
via acetalization.
Key words: pinnatoxin, dispiroacetal, trioxadispiro[5.1.5.2]penta-
decane dioxabicyclo[3.2.1]octane
Pinnatoxins are potent shellfish toxins isolated from Pin-
na muricata,1 and their unique structures and biological
properties have attracted the attention of scientists.2 Re-
cently, we reported the stereoselective construction of the
dispiroacetal core (C10-C24 fragment) of pinnatoxins.3 In
this report, the synthesis of the B,C,D,E,F-ring system 2 is
described.
Our retrosynthetic pathway is shown in Scheme 1. The
coupling of the E,F-ring part and the dispiroacetal core
34, 5 would be effected by Julia coupling reaction. All the
chiral centers in sulfone 4 could be introduced by Sharp-
less asymmetric epoxidation (AE).
Scheme 1
Propargyl alcohol was protected as its benzyl ether which,
upon addition to the p-formaldehyde, gave the primary al-
cohol 5 in 82% yield for 2 steps (Scheme 2). The triple
bond was reduced with LAH in THF at low temperature
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542
T. Sugimoto et al.
LETTER
pivaloate ester to obtain 9 in 76% yield. Silylation of two ture was oxidized with Dess-Martin periodinane to keto-
secondary hydroxyl groups with TBSOTf and detachment sulfone. The subsequent desulfonylation reaction with
of the primary pivaloyl group gave 10 in 98% yield for 2 Al(Hg) was somewhat troublesome, e.g., the reaction of-
steps. Oxidation of 10 with Dess-Martin periodinane and ten stopped without completion. Eventually, the coupled
the following Wittig reaction provided the ester 11 (86% product 16 was provided in 53% overall yield. Under both
yield, 2 steps), which was reduced with DIBAL to allyl al- aqueous and non-aqueous conditions (46% HF aq in
cohol 12 in 99% yield. Sharpless AE of 12 proceeded with MeCN and SiF4 in MeCN, respectively), the deprotection
excellent selectivity; when the substrate of 92% ee was
treated under the standard conditions, the epoxide 13 was
obtained in >98% ee as a result of kinetic resolution.7 On
the other hand, when 12 was exposed to m-CPBA, the op-
posite and high stereoselectivity was observed according
to the literature.8 Regioselective opening of the epoxide
was effected by Me2CuLi in ether at -30 °C to give 14 in
96% yield. The primary hydroxyl group of 14 was con-
verted to phenyl sulfide in 76% yield with N-(phenyl-
thio)phthalimide and Bu3P in CH2Cl2. The remaining sec-
ondary hydroxyl group was protected as SEM ether in a
quantitative yield. Finally, the sulfide group was oxidized
with m-CPBA to provide sulfone 4 in 95% yield.
In order to construct the E,F-ring fragment, we examined
the coupling of 4 and the acetalization reaction as model
studies (Scheme 3). The coupling reaction of 4 and hydro-
cinnamaldehyde 15 proceeded under the standard Julia
coupling conditions and the resulting diastereomeric mix-
Synlett 1999, No. 5, 541–544 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the B,C,D,E,F-Ring Fragment of Pinnatoxins
543
and the following acetalization reaction occurred to pro-
duce predominantly bicyclo compound 17 having the nat-
ural relative configuration, albeit the C28 SEM group was
cleaved under the reaction conditions. These results re-
vealed that the bicyclo system of 17 was more favored
than the other isomers, which finding was in good agree-
ment with the results of MM2 calculations.9 Keeping
these results in mind, we aimed to construct the
B,C,D,E,F-ring fragment 2.
Compound 18 was prepared by our previous procedure4
and its tertiary hydroxyl group was protected as TES ether
to afford 19 in 95% yield (Scheme 4). The benzyl group
was detached selectively with Raney nickel and the result-
ing primary hydroxyl group was oxidized to aldehyde 3.
The Julia coupling between 3 and 4 proceeded smoothly
and the subsequent oxidation reaction gave keto-sulfone
20. The desulfonylation reaction was performed with
SmI2 in THF/MeOH at -95 ~ -80 °C. The product was an
unexpected diastereomeric mixture of a-iodo-ketones 21a
and 21b. Although the stereochemistry at C26 was not de-
termined, 21a and 21b were obtained in 21% and 34%
yields from aldehyde 3, respectively, along with the re-
covery of unreacted sulfone 4 (58% yield). The a-iodo-ke-
tones 21a and 21b were reduced easily with a Zn-Cu
couple to the corresponding ketone 22 in 79% and 90%
yields, respectively. The final acetalization reaction was
first examined with 46% aq. HF-MeCN. When the reac-
Figure
curred. The reaction appeared to be in equilibrium within
10 min judging from TLC and further treatment (up to 4.5
h) was not effective. The product consisted of a 4.3:1 mix-
ture of 25 and 26 in 100% total yield on the basis of NMR
analysis.
tion mixture was stirred at rt for 6 h, all silicon protecting The structures of 25 and 26 were confirmed by HMBC,
groups were removed, and the isolated yield of penta-cy- HSQC, and NOE experiments (Figure). The characteristic
clic compound 23 resulted only in 40%. When a mixture NOE’s correlations between H12 and H23 were observed
of 46% aq. HF-MeCN-THF (1:10:2) was used,10 the reac- in 26, which exactly corresponded to the B,C,D,E,F-ring
tion proceeded sluggishly, and after 11 h, 23 was obtained part of pinnatoxins A, B, and C. These results could open
in 60% yield along with a mixture of the compounds 24 in an alternate route to providing the compound 26 preferen-
32% yield which had two TBS groups and no TES and tially having the desired configuration on several recycles
SEM groups. The latter was further treated with HF·Py in of 25.
THF at rt for 67 h to afford 53% of 23. As a result, the
yield of 23 amounted to 78% from 22. When 22 was di-
rectly reacted with HF·Py in THF at rt for 24 h, the yield
of 23 was only 48%.
In conclusion, we have demonstrated the construction of
all acetal rings of pinnatoxins. Further efforts toward the
total synthesis of pinnatoxins are underway in our labora-
tory.
Then, the isomerization of 23 to the compound having the
natural relative stereochemistry was attempted. In order to
cleave the intramolecular hydrogen-bonding, two hydrox-
References and Notes
(1) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A; Fukuzawa,
S.; Zeng, S. Z.; Chen, H. S. J. Am. Chem. Soc. 1995, 117,
1155. (b) Chou, T.; Kamo, O.; Uemura, D. Tetrahedron Lett.
1996, 37, 4023. (c) Chou, T.; Haino, T.; Kuramoto, M.;
Uemura, D. Tetrahedron Lett. 1996, 37, 4027; (d) The
absolute configuration of natural pinnatoxin A was
determined synthetically as enantiomer of 1: McCauley, J. A.;
Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones, M.
A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(2) Synthetic studies on pinnatoxins: (a) Noda, T; Ishiwata, A.;
Uemura, S.; Sakamoto, S.; Hirama, M. Synlett 1998, 298. (b)
Suthers, B. D.; Jacobs, M. F.; Kiching, W. Tetrahedron Lett.
1998, 39, 2621. Total synthesis of ent-pinnatoxin A (1): ref.
1d.
yl groups were protected as TBS ethers. When the diol 23
was reacted with TBSOTf-2,6-lutidine (1:2) in CH2Cl2 at
rt for 4 h, the products 2511 and 2612 were obtained in 49%
and 34% yields, respectively. Further treatment effected
no change. It is to be noted that the isomerization at C19
was not completed under standard silylation conditions, in
contrast with the results of Kishi’s report.1d When each
sample of pure 25 or 26 was stirred with TBSOTf-2,6-lu-
tidine (1:2) and MeOH in CH2Cl2, no reaction was ob-
served. These results indicate that the isomerization in
question occurred before the two hydroxyl groups were si-
lylated. Once the two hydroxyl groups had been silylated,
the TfOH-2,6-lutidine system no longer promoted the
isomerization. When 25 was exposed to more acidic con-
ditions (cat. CSA in CH2Cl2), the isomerization to 26 oc-
(3) (a) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett.
1997, 38, 7379. (b) Ishihara, J.; Sugimoto, T.; Murai, A.
Synlett 1998, 603.
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544
T. Sugimoto et al.
LETTER
(4) The B,C,D-ring part was prepared according to our previous
report, except for the sulfone segment which was prepared
from the known epoxide5 as follows:
(11) 25: [a]D18 -61.7 (c 0.12, CHCl3); 1H NMR (500 MHz, CDCl3),
d 0.02 (3H, s), 0.04 (3H, s), 0.08 (6H, s), 0.82 (3H, d, J = 6.6
Hz, H36), 0.88 (9H, s), 0.90 (9H, s), 1.19 (1H, dq, J = 3.0, 12.7
Hz, H22ax), 1.28 (3H, s, H37), 1.41 (1H, brt, J = 13.5 Hz,
H26ax), 1.42 (1H, m, H13ax), 1.50 (1H, dd, J = 5.8, 13.5 Hz,
H26eq), 1.55 (1H, m, H20a), 1.56 (1H, m, H17a), 1.56 (1H, m,
H21ax), 1.57 (1H, m, H13eq), 1.57 (1H, m, H14eq), 1.64 (1H,
m, H20b), 1.68 (2H, m, H11), 1.74 (1H, dd, J = 10.8, 14.0 Hz,
H24a), 1.87 (1H, m, H18a), 1.88 (1H, m, H21eq), 1.95 (1H, m,
H18b), 1.96 (1H, m, H22eq), 2.19 (1H, m, H27), 2.20 (1H, dd,
J = 3.0, 14.0 Hz, H24b), 2.21 (1H, dt, J = 4.2, 13.2 Hz,
H14ax), 2.28 (1H, dt, J = 9.3, 11.6 Hz, H17b), 3.47 (1H, m,
H28), 3.49 (2H, t, J = 6.3 Hz, H10), 3.61 (1H, dd, J = 7.3, 10.0
Hz, H31a), 3.76 (1H, dd, J = 6.4, 10.0 Hz, H31b), 3.80 (3H, s,
MPM), 3.95 (1H, m, H12), 4.12 (1H, m, H30), 4.13 (1H, m,
H23), 4.21 (1H, dd, J = 2.0, 4.4 Hz, H29), 4.36 (1H, d,
J = 11.5 Hz, MPM), 4.41 (1H, d, J = 11.5 Hz, MPM), 4.49
(1H, d, J = 12.4 Hz, Bn), 4.63 (1H, d, J = 12.4 Hz, Bn), 6.86
(2H, d, J = 8.8 Hz, MPM), 7.24 (2H, d, J = 8.8 Hz, MPM),
7.29-7.37 (5H, m, Bn).
(5) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.;
Rapoport, H. Synthesis 1992, 621.
(6) Katsuki, T.; Lee, A. W. N.; Ma, P.; Martin, V. S.; Masamune,
S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org.
Chem. 1982, 47, 1373.
(7) (a) Isobe, M.; Kitamura, M.; Mio, S.; Goto, T. Tetrahedron
Lett. 1982, 23, 221. (b) Kitamura, M.; Isobe, M.; Ichikawa, Y.;
Goto, T. J. Org. Chem. 1984, 49, 3517.
(8) Maruyama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.; Miyazawa,
M.; Miyashita, M. Tetrahedron Lett. 1998, 39, 4517.
(9) The relative energy differences among the model compounds
are shown below: The calculation was performed by Cache
Mechanics 3.6.
(12) 26: [a]D20 -85 (c 0.02, CHCl3); 1H NMR (400 MHz, C6D6), d
0.05 (3H, s), 0.06 (3H, s), 0.10 (3H, s), 0.16 (3H, s), 0.97 (3H,
d, J = 6.9 Hz, H36), 0.99 (9H, s), 1.00 (9H, s), 1.314 (3H, s,
H37), 1.33-1.36 (1H, m), 1.38-1.42 (1H, m), 1.47-1.52 (1H,
m), 1.61-1.93 (10H, m), 2.06 (1H, dt, J = 7.8, 13.8 Hz,
H26ax), 2.10-2.20 (3H, m, H27, H11), 2.16 (1H, dd, J = 6.6,
14.5 Hz, H24a), 2.25-2.33 (2H, m), 2.44 (1H, dd, J = 5.0, 14.5
Hz, H24b), 3.32 (3H, s, MPM), 3.54 (1H, dd, J = 7.8, 9.4 Hz,
H31a), 3.59 (1H, dd, J = 1.8, 4.0 Hz, H28), 3.69 (1H, dd,
J = 5.5, 9.4 Hz, H31b), 3.76 (1H, m, H30), 3.97 (1H, m, H23),
4.19 (1H, d, J = 12.0 Hz), 4.32 (1H, d, J = 12.0 Hz), 4.32-4.42
(4H, m, H10, H12, H29), 4.47 (1H, d, J = 11.9 Hz), 4.53 (1H,
d, J = 11.9 Hz), 6.85 (2H, d, J = 8.8 Hz, MPM), 7.10 (2H, m,
Bn), 7.18-7.22 (3H, m, Bn), 7.37 (2H, d, J = 8.8 Hz, MPM).
(10) Since the solubility of 22 in MeCN was very low, THF was
required as a co-solvent for larger scale reaction.
Article Identifier:
1437-2096,E;1999,0,05,0541,0544,ftx,en;Y02699ST.pdf
Synlett 1999, No. 5, 541–544 ISSN 0936-5214 © Thieme Stuttgart · New York