A novel short synthesis of norbisabolide

Article abstract of DOI:10.1016/S0040-4039(02)00814-6

A novel two-step synthesis of norbisabolide is reported involving free radical addition of Meldrum's acid to (R)-(+)-limonene using cerium(IV) ammonium nitrate (CAN) followed by decarboxylation with poly-4-vinylpyridine.

Full text of DOI:10.1016/S0040-4039(02)00814-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4535–4536
A novel short synthesis of norbisabolide†
S. B. Solabannavar, V. B. Helavi, Uday V. Desai and R. B. Mane*
Department of Chemistry, Shivaji University, Kolhapur 416004, India
Received 14 December 2001; revised 17 April 2002; accepted 25 April 2002
Abstract—A novel two-step synthesis of norbisabolide is reported involving free radical addition of Meldrum’s acid to
(R)-(+)-limonene using cerium(IV) ammonium nitrate (CAN) followed by decarboxylation with poly-4-vinylpyridine. © 2002
Elsevier Science Ltd. All rights reserved.
Norbisabolide 4 is a C12-terpene lactone isolated from
the root bark of Atalantia monophylla.1 It has been
synthesised by Kocienski2 and Ho3 from limonene via
limonene epoxide by eight and five steps, respectively,
in moderate yields. Limonene has also been directly
converted into norbisabolide by Fukamiya4 and
Gardrat5 in 7% and 43% yields, respectively. We report
here a short and efficient synthesis of norbisabolide
from (R)-(+)-limonene 1 and Meldrum’s acid 2 medi-
ated by cerium(IV) ammonium nitrate (CAN).
transformations6 and also for the generation of free
radicals which add to carbon–carbon double bonds to
yield interesting products.7 Meldrum’s acid is a versatile
reagent, which has attracted considerable attention in
organic synthesis.8 Our interest9 in Meldrum’s acid has
prompted us to exploit this highly acidic active methyl-
ene compound in a free radical addition reaction using
CAN. This is the first report of the free radical addition
of Meldrum’s acid to olefins.
CAN-mediated free radical addition of Meldrum’s acid
CAN is a well known oxidant used in many organic
to (R)-(+)-limonene 1 yielded the lactone carboxylic
Scheme 1.
* Corresponding author. Fax: +091-0231-692333; e-mail: rbmane@yahoo.com
† Dedicated to the memory of the late Dr. Nitiraj R. Mane.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00814-6

4536
S. B. Solabanna6ar et al. / Tetrahedron Letters 43 (2002) 4535–4536
acid† 3 which on decarboxylation with poly-4-vinyl
pyridine in DMF or pyridine furnished norbisabolide‡ 4
(diastereoisomeric mixture, 54:46) (Scheme 1) in good
yields (96 and 62%). Decarboxylation using poly-4-
vinylpyridine gave pure product in higher yield in com-
parison to decarboxylation in pyridine. The probable
mechanism7 involves addition of Meldrum’s acid radi-
cal to the double bond followed by cyclisation to give a
g-lactone. The regioselectivity of addition can be
explained on the basis of a steric effect where the bulky
Meldrum’s acid radical adds to the less hindered double
bond in the chain.
Advantages of the method are that the lactone car-
boxylic acid is obtained in a pure form by bicarbonate
extraction from the unreacted starting materials and
that decarboxylation is almost quantitative. g-Lactones
constitute important structural features of many natu-
ral products and also serve as intermediates in the
synthesis of important compounds. The generality of
this reaction for the synthesis of other g-lactones will be
explored.
References
1. Shringarpure, J. D.; Sabata, B. K. Ind. J. Chem. 1975, 13,
24.
2. Feldstein, G.; Kocienski, P. J. Synth. Commun. 1977, 7, 27.
3. Ho, T. L. Synth. Commun. 1983, 13, 341.
4. Fukamiya, N.; Oki, M.; Okano, M.; Arantani, T. Chem.
Ind. (Lond.) 1981, 96.
5. Gadrat, C. Synth. Commun. 1984, 14, 1191.
6. Ho, T. L. Synthesis 1973, 347.
† Lactone carboxylic acid 3: To a stirred mixture of (R)-(+)-limonene
(2.72 g, 0.02 mole) and Meldrum’s acid (2.88 g, 0.02 mole) in
acetonitrile (40 ml) was added cerium(IV) ammonium nitrate (21.92
g, 0.04 mole) batchwise at 5°C over 15 min. The reaction mixture
was stirred for an additional 30 min until completion of the reaction
(TLC and disappearance of the CAN colour). It was then diluted
with water (50 ml) and extracted with ether. The ether extract was
washed with sodium bicarbonate solution and the bicarbonate layer
was acidified and extracted with ether. The ether layer was washed
with water, dried (anhydrous sodium sulphate), and the solvent
removed to furnish the lactone carboxylic acid 3 (3.6 g, 76%) as a
viscous liquid. IR (neat): 3650–3000 (broad, -COOH), 1750 (broad
and strong carbonyl group of lactone and carboxylic group), 1610,
7. Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev.
1997, 26, 127.
8. McNab, H. Chem. Soc. Rev. 1978, 7, 345.
9. (a) Mane, R. B.; Krishna Rao, G. S. Chem. Ind. 1976, 786;
(b) Desai, D. G.; Mane, R. B. Chem. Ind. 1982, 809; (c)
Bandgar, B. P.; Jagdale, M. H.; Mane, R. B.; Salunkhe,
M. M. Ind. J. Chem. 1985, 24B, 1057; (d) Patil, S. V.;
Mane, R. B.; Salunkhe, M. M. Chem. Ind. 1991, 24; (e)
Kumbhar, P. P.; Salunkhe, M. M.; Mane, R. B. Ind. J.
Chem. 1991, 30B, 891.
1190, 904 and 728 cm−1 1H NMR (300 MHz, CDCl3): l 1.36 and
.
1.43 (54:46, 3H, two singlets for methyl groups in two diastereoiso-
mers), 1.57 (3H, br. s, vinylic-CH3), 1.25–2.65 (9H, m, 4 methylenes
and methine-H), 3.85 (1H, m, methine-H), 5.29 (1H, br. s, vinylic-
H), 8.83 (1H, br. s, -COOH). 13C NMR (CDCl3, DEPT spectrum):
l 21.61, 22.30, 22.89, 23.41 (two methyl groups in two diastereoiso-
mers); 23.89, 25.61, 29.99, 33.89, 34.55, 34.91 (methylenes); 43.06,
43.26 (methine-C); 46.57, 47.30 (methine-C); 88.43 (quaternary C);
119.09, 119.31 (vinylic-CH); 133.61, 133.86 (vinylic-C); 170.55 (car-
bonyl); 171.98 (carbonyl). Further signals are observed due to
diastereoisomers. Anal. C13H18O4: requires: C, 65.55; H, 7.56%;
found: C, 65.67; H, 7.48%.
‡ Norbisabolide 4: By decarboxylation of 3 with poly-4-vinylpyridine:
To the lactone carboxylic acid 3 (0.952 g, 4 mmole) in DMF (5 ml)
was added poly-4-vinylpyridine (0.5 g) and the mixture stirred for 2
h at 80°C after which the reaction was complete (TLC). The
reaction mixture was cooled, filtered and the filtrate diluted with
water (20 ml) and extracted with ether. The ether extract was
washed with aqueous sodium bicarbonate, water and dried (anhy-
drous sodium sulphate). Removal of ether furnished norbisabolide 4
(diastereoisomeric mixture) as a single product as indicated by TLC
(0.742 g, 96%). An analytical sample was prepared by passing it
through a column of silica gel using pet-ether. Bp 170–175°C/8 mm.
1
IR (neat): 1770 cm−1. H NMR (300 MHz, CDCl3): l 1.30 and 1.33
(54:46, 3H, two singlets for methyl groups in two diastereoisomers),
1.61 and 1.64 (54:46, 3H, two singlets for vinylic methyl groups in
two diastereoisomers), 1.65–2.30 (9H, m, four methylenes and one
methine-H), 2.58 (2H, m, methylene adjacent to keto group), 5.38
(1H, m, vinylic-H). 13C NMR (CDCl3, DEPT spectrum): l 21.83,
22.71, 23.04, 23.19 (two methyl groups in two diastereoisomers);
25.76, 28.52, 29.88, 30.13, 30.76 (methylenes); 42.74 and 42.89
(methine-C); 88.26 (quaternary C); 119.09 and 119.38 (vinylic-CH);
133.24 and 133.53 (vinylic-C); 176.06 (lactone carbonyl). Further
signals were observed due to diastereoisomers. MS: m/e 194 (M+),
99 (100). Anal. C12H18O2: requires: C, 74.23; H, 9.28%; found: C,
74.34; H, 9.32%.