An enantiospecific formal total synthesis of (-)-aplysin and (-)-debromoaplysin

Article abstract of DOI:10.1016/S0040-4039(01)00842-5

An enantiospecific approach to marine sesquiterpenes (-)-debromoaplysin and (-)-aplysin, starting from (R)-limonene employing a Claisen rearrangement as the key step, is described.

Full text of DOI:10.1016/S0040-4039(01)00842-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4913–4914
An enantiospecific formal total synthesis of (−)-aplysin and
(−)-debromoaplysin
A. Srikrishna* and N. Chandrasekhar Babu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 3 April 2001; accepted 16 May 2001
Abstract—An enantiospecific approach to marine sesquiterpenes (−)-debromoaplysin and (−)-aplysin, starting from (R)-limonene
employing a Claisen rearrangement as the key step, is described. © 2001 Elsevier Science Ltd. All rights reserved.
Aplysin 1, one of the first halogenated marine sesquiter-
penes to be reported, was isolated from the red alga
Laurencia and the sea hare Aplysia. The logical bio-
genetic precursor debromoaplysin 2 and the related
debromoaplysinol 3, aplysinol 4 and isoaplysin 5 have
also been isolated from these species,1 and some of
them exhibit antifeedant properties. The presence of an
interesting tricyclic structure and associated properties
made these compounds attractive synthetic targets.2
Besides a few approaches to racemic aplysins, two
enantioselective strategies have been reported for
debromoaplysin and aplysin.2 Herein, we report an
enantiospecific approach to debromoaplysin 2 and
aplysin 1 starting from the monoterpene (R)-limonene 6
and employing a Claisen rearrangement as the key step.
Scheme 1. To begin with, (R)-limonene 6 was converted
into the allyl alcohol 8 in three steps4 viz controlled
ozonolysis, intramolecular aldol condensation and
reduction of the aldehyde. The key intermediate 7, [h]D24
+81.5 (c 1.4, CHCl3), was obtained by coupling the allyl
alcohol 8 with m-cresol under Mitsunobu conditions5
employing triphenylphosphine and diisopropyl azodi-
carboxylate (DIAD) in 83% yield. Thermal activation
of the ether 7 in N,N-dimethylaniline in a sealed tube at
180°C for 72 h generated a 5:1:2 mixture of the cyclised
products 9† and 10 derived from the ortho Claisen
rearrangement, and the para Claisen rearrangement
product 11, in 64% yield, which were separated by silica
gel and silver nitrate impregnated silica gel column
chromatography. Next, attention was turned towards
conversion of 9 into aplysins via degradation of the
isopropenyl group employing a Criegee rearrangement.6
Thus, ozonolysis of the compound 9 in methanol–meth-
ylene chloride followed by treatment of the resulting
methoxyhydroperoxide with acetic anyhydride, triethyl-
It was anticipated that
a stereoselective Claisen
rearrangement3 of the m-cresyl ether 7 of the allyl
alcohol 8 followed by cyclisation could generate the
aplysin carbon framework directly. The synthetic
sequence starting from (R)-limonene 6 is depicted in
X
1. X = Br; Y = H
2. X = Y = H
3. X = H; Y = OH
4. X = Br; Y = OH
5. X = H; Y = Br
HO
O
O
Y
7
8
6
* Corresponding author. Fax: 91-80-3600683; e-mail: ask@orgchem.iisc.ernet.in
† All the compounds exhibited spectral data consistent with their structures. Selected spectral data for the compound 9: isolated yield 40%; [h]2D2
−50.2 (c 1.4, CHCl3). IR (neat): wmax/cm−1 1645, 1621, 1591, 1090, 887. 1H NMR (300 MHz, CDCl3+CCl4): l 6.90 (1H, d, J 7.5 Hz), 6.61 (1H,
d, J 7.5 Hz), 6.50 (1H, br s), 4.87 (1H, s), 4.69 (1H, s), 2.64 (1H, t, J 9.0 Hz), 2.28 (3H, s), 2.10–1.80 (2H, m), 1.86 (3H, s), 1.70–1.55 (2H, m),
1.20 (3H, s), 1.15 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 157.1 (C), 144.9 (C), 137.7 (C), 135.4 (C), 122.8 (CH), 121.3 (CH), 111.4 (CH2),
110.7 (CH), 98.5 (C), 56.3 (CH), 53.4 (C), 39.2 (CH2), 26.6 (CH2), 24.7 (CH3), 23.6 (CH3), 21.6 (CH3), 16.8 (CH3). For the acetate 12: [h]2D4 −49.9
(c 4.5, CHCl3). IR (neat): wmax/cm−1 1742. 1H NMR (300 MHz, CDCl3+CCl4): l 6.94 (1H, d, J 7.2 Hz), 6.61 (1H, d, J 7.2 Hz), 6.47 (1H, br
s), 5.20 (1H, br s), 2.29 (3H, s), 2.07 (3H, s), 2.00–1.55 (4H, m), 1.35 (3H, s), 1.30 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 169.3 (C), 157.7
(C), 138.1 (C), 132.5 (C), 122.5 (CH), 121.5 (CH), 110.0 (CH), 98.8 (C), 81.8 (CH), 53.2 (C), 41.3 (CH2), 28.9 (CH2), 22.9 (CH3), 21.6 (CH3),
21.1 (CH3), 17.0 (CH3).
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00842-5

4914
A. Srikrishna, N. C. Babu / Tetrahedron Letters 42 (2001) 4913–4914
HO
e
a-c
d
8
7
6
9
+
O
O
+
f,g
(+)-13
10
9
10
11
g
i
h
f
(-)-2, (-)-1
O
O
O
OAc
O
(-)-14
(-)-12
(-)-13
Scheme 1. Reagents, conditions and yields: (a) O3/O2, CH2Cl2–MeOH (5:1), −70°C; Me2S, rt, 5 h; 70%; (b) piperidine, AcOH,
C6H6, reflux, 1 h, 75%; (c) CeCl3·6H2O, NaBH4, MeOH, 0°C, 0.5 h, 92%; (d) m-cresol, PPh3, DIAD, rt, 10 h, 83%; (e) PhNMe2,
sealed tube, 180°C, 72 h, 64%; (f) O3/O2, CH2Cl2–MeOH (5:1), −70°C; Ac2O, NEt3, DMAP, C6H6, reflux, 75%; (g) K2CO3,
MeOH, rt, 2 h; PCC, NaOAc, CH2Cl2, rt, 1 h; 86%; (h) MeMgI, Et2O; POCl3–py, rt;7 (i) reference 2d.
References
amine and 4-dimethylaminopyridine (DMAP) in reflux-
ing benzene generated the acetate 12† in 75% yield.
Hydrolysis of the acetate followed by oxidation of the
resultant alcohol with PCC–NaOAc transformed the
acetate 12 into the ketone 13, [h]2D4 −313 (c 3.6, CHCl3),
which exhibited spectral data identical to that of the
racemic7 compound. As expected, the same sequence
transformed the minor isomer 10 into the enantiomeric
ketone (+)-13, [h]2D3 +295 (c 0.35, CHCl3). The ketone
(−)-13 was then transformed7 into the olefin (−)-14,
[h]2D3 −102 (c 0.5, CHCl3) {lit.2d [h]2D5 −113 (c 0.2,
CHCl3}, via a Grignard reaction followed by dehydra-
1. (a) Yamamura, S.; Hirata, Y. Tetrahedron 1963, 19,
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2. For synthesis of racemic aplysin and debromoaplysins,
see: (a) Harrowven, D. C.; Lucas, M. C.; Howes, P. D.
Tetrahedron Lett. 1999, 40, 4443; and Tetrahedron 2001,
57, 791 and references cited therein. For synthesis of
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Ronald, R. C.; Gewali, M. B.; Ronald, B. P. J. Org.
Chem. 1980, 45, 2224. For enantioselective synthesis of
(−)-aplysins, see: (c) Takano, S.; Moriya, M.;
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Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto,
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1
tion, which exhibited H and 13C NMR spectral data
identical to that reported.2d Since the olefin (−)-14 has
already been transformed2c,d into (−)-debromoaplysin 2
and (−)-aplysin 1, via catalytic hydrogenation and
bromination, the present sequence constitutes an enan-
tiospecific total synthesis of these marine sesquiterpe-
nes. Currently, we are investigating the extension of this
methodology to other related sesquiterpenoids.
3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1.
4. For a five step synthesis of 8, see: Wolinsky, J.; Sla-
baugh, M. R.; Gibson, T. J. Org. Chem. 1964, 29, 3740.
5. Hughes, D. L. Org. React. 1992, 42, 335.
Acknowledgements
6. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24,
2363.
We thank the CSIR, New Delhi for the award of a
research fellowship to N.C.B.
7. Biswas, S.; Ghosh, A.; Venkateswaran, R. V. J. Org.
Chem. 1990, 55, 3498.
.