Synthetic study of pinnatoxin A: Intramolecular Diels-Alder approach to the AG-ring

Article abstract of DOI:10.1055/s-1999-2743

A chiral quaternary carbon (C5) with the G-ring of pinnatoxin A has been diastereoselectively constructed via an intramolecular Diels-Alder reaction.

Full text of DOI:10.1055/s-1999-2743

692
LETTER
Synthetic Study of Pinnatoxin A: Intramolecular Diels-Alder Approach to the
AG-ring
Akihiro Ishiwata, Satoshi Sakamoto, Takeshi Noda, and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and Technology Corporation (JST),
Sendai 980-8578, Japan
Fax +81(22)217-6566; E-mail hirama@ykbsc.chem.tohoku.ac.jp
Received 30 March 1999
biological activity as a Ca2+ channel activator4 aroused our
Abstract: A chiral quaternary carbon (C5) with the G-ring of pin-
interest in a total synthesis. The total synthesis of ent-pin-
natoxin A has been diastereoselectively constructed via an intramo-
natoxin A (1) recently reported by Kishi·s group has es-
tablished the absolute stereochemistry.5 The synthesis
seems to be rather linear and the stereoselectivity in the
penultimate intramolecular Diels-Alder reaction (IMDA)
was not very high. A more convergent strategy that cou-
ples the two unique structural units, BCD-ring unit (2)6,7
and AEGF-ring unit (3) (Scheme 1), is attractive, because
it would allow the synthesis of a number of related ana-
logs for a detailed study of the structure-activity relation-
ship. We report here a diastereoselective IMDA approach
to constructing the G-ring of 3 from triene (4).
lecular Diels-Alder reaction.
Key words: pinnatoxin A, diastereoselectivity, Ca2+channel, in-
tramolecular Diels-Alder reaction, convergent synthesis
Me
Me
1
A
HN+
5
G
31
Ð
H
CO2
O
ent-Pinnatoxin A
28
B
F
O
OH
O
E
(1)
C
O
HO
O
Me
26
Me
D
1
Me
RO
OTBPS
O
Me
O
R
B
+
5
RO
G
C
31
OR
O
O
HO
28
Me
H
D
OR
26
OH
OR
R
AGEF ring unit (3)
BCD ring unit (2)
Me
TIPSO
O
Me
O
5
28
OBn
31
MPMO
OTBS
4
Scheme 2 illustrates the stereoselective synthesis of the
dienophile (9). Protection of the a,b-epoxy alcohol (5)8 as
a benzyl ether followed by ring-opening under Pfalts·
conditions9 provided the syn-dimethyl moiety (6) regiose-
lectively. After hydrogenolysis of the benzyl ether, the re-
sulting 1,2-diol was oxidatively cleaved and then treated
with methyl (triphenylphosphoranylidene)acetate to give
the a,b-unsaturated ester (7). The unsaturated ester (7)
was converted to aldehyde (8) via hydrogenation and
DIBAH-reduction. After a-methylenation of the aldehyde
TBPS = tert-butyldiphenylsilyl; TIPS = triisopropylsilyl;
TBS = tert-butyldimethylsilyl; MPM = p-methoxyphenylmethyl
Scheme 1
Pinnatoxin A, recently isolated from the shellfish Pinna
muricata,1 is a member of the marine toxins which pos-
sess a spiro-linked cyclic imine within a carbocyclic mac-
roring system.2,3 The unique structure and potent
Synlett 1999, No. 6, 692–694 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Study of Pinnatoxin A: Intramolecular Diels-Alder Approach to the AG-ring
693
(8) using Eschenmoser reagent,10 NaClO2 oxidation gave IMDA of 4 was examined under various conditions: under
dienophile (9) in good yield.
reflux in toluene, 4 was recovered. At higher temperature
in xylene (reflux, 28 days), IMDA of 4 proceeded slowly
to give an endo-type cycloadduct (14) as the sole product
in 85% yield; in mesitylene (reflux), the reaction was
complete within 7 days (78%) (Scheme 4). None of the
possible endo-type diastereomer (15)17 nor any exo-type
adducts such as 16 were detected. Lewis acid catalysts,
such as MAD18a and Eu(fod)3,18b did not affect the endo
preference. The stereochemistry of 14 was assigned in a
NOE experiment.19 The exclusive formation of 14, which
has a correct stereochemistry at the C5 quaternary carbon,
was attributable to the C30 bulky substituent: the enoate
moiety approaches anti to the C30-OTBS group in the
transition state model (17).17 IMDA reaction of the epimer
(18) of 4, therefore, showed a low diastereoselectivity
(19a : 19b = 30 : 70) (Scheme 5). Furthermore, the triene
(20), which has the two-carbon longer chain, was subject-
ed to IMDA reaction. The major product was also an endo
adduct (21) but the diastereoselectivity was completely
reversed (Scheme 6).
Me
TIPSO
O
The chiral diol (10)11 derived from D-glucose was con-
verted to 11 via protection of the primary alcohol and the
secondary alcohol as the trityl ether and TBS ether, re-
spectively, followed by regioselective reductive ring
cleavage of p-methoxybenzylidene acetal with DIBAL-H
(Scheme 3).12 The aldehyde obtained by Swern oxidation
of 11 was subjected to Wadsworths-Emmons olefination
with 1213 under mild conditions14 and further Wittig olefi-
nation to give the diene (13). Esterification of the carbox-
ylic acid (9) with the alcohol which was obtained by
selective deprotection of the trityl ether of 13 with
Et2AlCl15 proceeded successfully under Mitsunobu
conditions16 to give the Diels-Alder precursor (4) in 85%
yield.
xylene
reflux
Me
O
28d
(95%)
30
29
MPMO
OBn
OTBS
18
Me
Me
Me
TIPSO
O
TIPSO
O
Me
O
O
+
H
H
MPMO
MPMO
OBn
OTBS
OBn
OTBS
19b
19a
30
: 70
Scheme 5
TIPSO
Me
Me
Me
TIPSO
O
Me
31
137 ~ 164¡C
78 ~ 85%
5
Me
Me
O
Me
TBSO
O
MPMO
4
TBSO
O
5
31
O
O
30
30
Me
H
26
toluene
reflux
H
MPMO
OTBS
H
O
OMPM
OBn
O
OMPM
OTBS
OBn
endo-adduct (14)
17
7d
(60%)
H
OTES
Me
OTES
Me
Me
OTBS
OBn
TIPSO
OTBS
20
OBn
TIPSO
O
21 (> 5 : 1)
O
Me
O
O
Scheme 6
5
5
31
31
H
H
MPMO
MPMO
OBn
In conclusion, we have demonstrated that the IMDA ap-
proach via 4 leads to the correct stereochemistry at the C5
chiral quaternary carbon of the G-ring of 3, which is one
of the most challenging problems in the synthesis of 1.
OTBS
OBn
OTBS
exo-adduct (16)
endo-adduct (15)
Scheme 4
Synlett 1999, No. 6, 692–694 ISSN 0936-5214 © Thieme Stuttgart · New York

694
A. Ishiwata et al.
LETTER
(3 eq), MeOH, -20~rt, 12 h (81%, in 2 steps); 3) (MeO)2POMe
(1.6 eq), n-BuLi (1.5 eq), THF, –78~–50°C (96%).
(14) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush, T. Sakai, Tetrahedron Lett., 1984,
25, 2183.
Further study directed toward total synthesis of 1 includ-
ing the epimerization at C31 is currently underway in our
laboratory.
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2641.
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Oxford, 1991; Vol. 5, p 513; W. R. Roush, B. B. Brown, J. Am.
Chem. Soc., 1993, 115, 2268.
Acknowledgement
We are grateful to Dr. Masako Ueno, and Mr. Kazuo Sasaki (Instru-
mental Analysis Center for Chemistry, Tohoku University) for their
assistance in NMR measurement. This work was supported in part
by a grant from the Ministry of Education, Science, Sports and Cul-
ture, Japan.
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References and Notes
(19) 14 ([a]D25 18.8° (c 0.80, CHCl3)): IR(film) 2954, 2866, 1723,
1613, 1516, 1464, 1251, 1189, 1112, 1031, 884, 837, 758, 679
(cm–1); 1H NMR ((CD3)2CO, 600 MHz) d 7.28 (5 H, m,
PhCH2O), 7.23 (2 H, m, MPM), 6.85 (2 H, d, J = 8.6 Hz,
MPM), 5.39 (1 H, brs, H32), 4.67 (1 H, brd, J = 12.0, 8.0 Hz,
H28), 4.69 (1 H, d, J = 11.2 Hz, MPM), 4.57 (1 H, d, J = 11.2
Hz, MPM), 4.35 (1 H, d, J = 11.9 Hz, PhCH2O), 4.33 (1 H, d,
J = 11.9 Hz, PhCH2O), 4.09 (1 H, brs, H30), 4.00 (1 H, brd, J
= 12.0 Hz, H28), 3.82 (1 H, d, J = 12.0 Hz, H34), 3.79 (1 H, d,
J = 12.0 Hz, H34), 3.72 (3 H, s, MPM), 3.56 (1 H, dd, J = 9.8,
7.5 Hz, H1), 3.52 (1 H, bt, J = 7.5, 1.5 Hz, H29), 3.46 (1 H, dd,
J = 9.8, 6.4 Hz, H1), 2.64 (1 H, brs, H31), 2.47 (1 H, m, H4),
2.29 (2 H, m, H35, H39), 1.97 (1 H, m, H3), 1.92 (1 H, m,
H35), 1.58 (1 H, qdd, J = 7.0, 7.0, 3.2 Hz, H2), 1.45 (2 H, m,
H4, H39), 1.10–1.00 (21 H, m, SiCH(CH3)2), 0.88 (9 H, m,
SiC(CH3)3), 0.77 (3 H, d, J = 7.0 Hz, C2(CH3)), 0.74 (3 H, d,
J = 7.0 Hz, C3(CH3)), 0.07 (3 H, s, SiCH3), 0.05 (3 H, s,
SiCH3). 13C NMR ((CD3)2CO, 150 MHz) d >150 (C6=O,
MPM), 139.75 (Bn), 137.72 (C33), 131.14 (MPM), 130.36
(MPM), 128.99 (Bn), 128.46 (Bn), 128.13 (Bn), 124.22 (C32),
114.42 (MPM), 78.08 (C29), 77.36 (C30), 74.35 (C34), 74.29
(MPM), 72.09 (Bn), 67.28 (C1), 64.70 (C28), 55.44 (MeO),
50.90 (C5), 47.36 (C31), 43.82 (C4), 43.46 (C2), 43.38 (C3),
33.06 (C35), 28.48 (SiC(CH3)3), 26.44 (SiC(CH3)3), 24.66
(C39), 18.79 (SiC(CH3)3), 18.41 (SiCH(CH3)2), 15.21 (C3-
CH3), 12.76 (SiCH(CH3)2), 11.82 (C2-CH3), –4.45 (SiCH3).
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Article Identifier:
1437-2096,E;1999,0,06,0692,0694,ftx,en;Y07199ST.pdf
Synlett 1999, No. 6, 692–694 ISSN 0936-5214 © Thieme Stuttgart · New York