Short new route to the chiral spiro-tetrahydrofuran subunit common to some terpenoids

Article abstract of DOI:10.1080/00397910500180295

Synthetic strategy based on a stereoselective iodoetherification reaction of a carvone-derived hydroxyalkene unit has been developed for the asymmetric synthesis of the key spiro-tetrahydrofuran subunit common to some naturally occurring terpenoids. Copyright Taylor & Francis, Inc.

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Short New Route to the Chiral
Spiro‐Tetrahydrofuran Subunit
Common to Some Terpenoids
Shital K. Chattopadhyay a , Swastik Karmakar a
Kaushik Sarkar a
&
a Department of Chemistry , University of Kalyani ,
Kalyani, West Bengal, India
Published online: 18 Aug 2006.
To cite this article: Shital K. Chattopadhyay , Swastik Karmakar & Kaushik Sarkar
(2005) Short New Route to the Chiral Spiro‐Tetrahydrofuran Subunit Common to
Some Terpenoids, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:16, 2125-2132
To link to this article: http://dx.doi.org/10.1080/00397910500180295
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Synthetic Communicationsw, 35: 2125–2132, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500180295
Short New Route to the Chiral
Spiro-Tetrahydrofuran Subunit
Common to Some Terpenoids
Shital K. Chattopadhyay, Swastik Karmakar,
and Kaushik Sarkar
Department of Chemistry, University of Kalyani, Kalyani,
West Bengal, India
Abstract: Synthetic strategy based on a stereoselective iodoetherification reaction of a
carvone-derived hydroxyalkene unit has been developed for the asymmetric synthesis
of the key spiro-tetrahydrofuran subunit common to some naturally occurring terpe-
noids.
Keywords: Spirocycle, carvone, Barbier reaction, iodoetherification, terpenoid
INTRODUCTION
The spiro-tetrahydrofuran subunit embodied in the structure 1 (Fig. 1) is a
common structural feature found in some norisoprenoid spiroethers that
have flavoring and organoleptic properties such as theaspirone (2)[1] and vetis-
pirane (3),[2] the principal aroma components of tea and vanilla respectively.
The basic ring system is also found in the marine natural products dactyl-
oxenes B[3] and C[4] (3, 4). Because of their interesting structural features
and importance as flavoring and organoleptic agents, a number of synthetic
efforts have been devoted[5] to the synthesis of these natural products as
well as some of their analogues.[6] With a few exceptions, the great
majority of these approaches have utilized a- or b-ionones as the starting
Received in India February 5, 2005
Address correspondence to Shital K. Chattopadhyay, Department of Chemistry,
University of Kalyani, Kalyani 741235, West Bengal, India. E-mail: skchatto@
yahoo.com
2125

2126
S. K. Chattopadhyay, S. Karmakar, and K. Sarkar
Figure 1. Natural products containing spirotetrahydrofuron subunit 1.
material, and the spiro-tetrahydrofuran unit has been constructed by dehy-
dration of a diol unit. A conceptually different approach[7] is Paquette’s
oxonium-ion-induced pinacol rearrangement of a tailored substrate as
described for the synthesis of theaspirone. In continuation of our work[8] on
the utility of carvone as a chiral-pool material, herein we describe our
efforts toward the synthesis of the key spiro-tetrahydrofuran unit present in
some of these natural products.
RESULTS AND DISCUSSION
Our synthetic approach commenced from the cheaper, more available R(2)-
carvone, which was readily elaborated to the hydroxyketone 8 (Scheme 1) via
a two-step sequence involving reductive methylation of the derived epoxy-
ketone 7 as described previously.[9] Although none of the projected natural
products contain the pendant isopropenyl group, the conversion of the latter
to the required enone functionality through a Criegge-type rearrangement
has been amply demonstrated.[10] However, for the present study, the isopro-
penyl group in 8 was reduced to the corresponding saturated ketone 9. In line
with our earlier observations,[8] Barbier-type addition of 4-bromo-1-butene to
9 proceeded with high diastereoselectivity, and the diol 10 was obtained in
good yield after removal of the minor isomer (6%). Iodoetherification of
chiral hydroxylalkenes has emerged[11] as a valuable tool for the stereoselec-
tive construction of several oxacyclic systems with various levels of 1,2-, 1,3-
or 1,4-asymmetric inductions.[12] We wondered whether iodoetherification of
the hydroxyalkene 10 would provide any useful level of stereoselectivity.
When the halocyclization of 10was attempted withiodine in acetonitrile in the
presence of sodium bicarbonate, the isomeric iodoethers 11, 12 formed in good
yield but as an inseparable mixture (ꢀ60 : 40). However, upon reduction[13] with
tributyltin hydride in the presence of azoisobutyronitrile (AIBN), a separable

Chiral Spiro-Tetrahydrofuran Subunit
2127
Scheme 1. (i) H2O2, NaOH, 08C, 4 h, 98%; (ii) Li, NH3, MeI, 2 338C to rt, 3 h, 61%;
(iii) H2, Pd-C (10%), ethanol, rt, 4 h, 94%; (iv) 4-bromo-1-butene, Li, THF, ultrasound,
rt, 0.5 h, 61%; (v) I2, NaHCO3, CH3CN, 08C, 4 h, 70%; (vi) n-Bu3SnH, AIBN, benzene,
reflux, 5 h, 74%; (vii) p-nitrobenzoyl chloride, Et3N, CH2Cl2, 4 h, 92%.
mixture of the spiro-tetrahydrofurans 13, 14 were obtained as viscous liquids in
good yield. Although the gross structures of the products were easily secured
from their spectroscopic properties, assignment of the stereochemistry at the
newly formed stereocenter (C2) in either of these products proved to be difficult.
To this end, the corresponding p-nitrobenzoates 15, 16 were prepared using con-
ventional conditions. However, although the products were obtained as colorless
low-melting solids, suitable crystals for examination could not be obtained.
In short, we have demonstrated that the spiro-tetrahydrofuran ring system
found in some important natural products could be conveniently prepared
using iodoetherification of an appropriate hydroxyalkene derived from
carvone.[14] The marginal 1,4-asymmetric induction observed during the
process may provide access to the proper stereoisomers as well as
analogues of some of the natural products mentioned.

2128
S. K. Chattopadhyay, S. Karmakar, and K. Sarkar
EXPERIMENTAL
Melting points were determined in a sulphuric-acid bath and are uncorrected.
IR spectra were recorded on a Perkin Elmer 1330 apparatus purchased in a
1
DST-FIST grant. H NMR and 13C NMR spectra were recoded on a Bruker
300-MHz instrument at the Indian Institute of Chemical Biology, Kolkata,
India. Mass spectra and elemental analyses were obtained as a paid service
from CDRI, Lucknow & I.I.C.B., Kolkata, India. Silica gel (60–120 mesh)
was obtained from Spectrochem, India. Peteroleum ether refers to the
fraction boiling in the range 60–808C.
(3R, 5S)-3-Hydroxy-5-isopropyl-2,2-dimethylcyclohexan-1-one (9): A
solution of the hydroxyketone 8 (2.00 g, 10.9 mmol) in dry ethanol (30 mL)
was vigorously stirred under a hydrogen atmosphere in the presence of
Pd-C (10%, 10 mg) for 24 h at room temperature. The heterogeneous
mixture was then filtered through celite and the filter cake was washed with
ethanol. The combined organic solution was then concentrated in vacuo to
leave the crude product as a colorless liquid, which was purified by chromato-
graphy over silica gel using a mixture of petroleum ether and ethyl acetate
(10 : 1) as eluent. The product was obtained as a colorless viscous liquid
(1.89 g, 94%).
[a]D: þ13.35 (c, 1.7 in CHCl3). IR (neat): 3392, 2958, 1704, 1041 cm21
.
1H NMR (300 MHz, CDCl3): d ¼ 3.67–3.3.62 (m, 1 H), 3.53 (brs, 1 H), 1.78–
1.63 (m, 3 H), 1.52–1.38 (m, 3 H), 1.11 (s, 3 H), 0.84 (s, 3H), 0.82 (s, 3 H),
0.79 (s, 3 H). Anal. calcd. for C11H20O2 (184.28): C, 71.70; H, 10.94. Found:
C, 71.55; H, 11.08.
(1S, 3R, 5S)-1-(3-butenyl)-5-isopropyl-2,2-dimethylcyclohexane-1,3-diol
(10): A heterogeneous mixture of the saturated ketone 9 (1.80 g, 9.77 mmol),
4-bromo-1-butene (3 mL, 29.4 mmol) and small pieces of lithium (411 mg,
59 mmol) in dry tetrahydrofuran (40 mL) was sonicated under nitrogen atmos-
phere for 30 min. The reaction mixture was then cooled to 08C and carefully
quenched by dropwise addition of methanol (1 mL) followed by saturated
ammonium-chloride solution (10 mL). It was then extracted with ether
(3 ꢀ 50 mL) and the combined extract was washed sequentially with water
(1 ꢀ 50 mL) and brine (1 ꢀ 50 mL), and then dried (Na2SO4). It was
filtered, and the filtrate was concentrated to leave the crude product as a pale
yellow oil, which was purified by chromatography over silica gel using a
mixture of petroleum ether and ethyl acetate (9 : 1) as eluent. The product
was obtained as a colorless viscous liquid (1.45 g, 61%).
[a]D: þ10 (c, 0.25 in CHCl3). IR (neat): 3400, 2990, 1650, 1110 cm21
.
1H NMR (300 MHz, CDCl3): d ¼ 5.92–5.79 (m, 1 H), 5.06 (d, 1 H,
J ¼ 17.2 Hz), 4.97 (d, 1 H, J ¼ 10.1 Hz), 3.82 (dd, 1 H, J ¼ 11.7, 4.3 Hz),
2.19–2.08 (m, 2 H), 1.77–1.65 (m, 3 H), 1.59–1.41 (m, 3H), 1.25–1.09
(m, 2 H), 1.11 (s, 3 H), 0.92 (d, 3H, J ¼ 5.9 Hz), 0.88 (d, 3 H, J ¼ 5.9 Hz),

Chiral Spiro-Tetrahydrofuran Subunit
2129
0.83 (s, 3 H). 13C NMR (75 MHz, CDCl3): d ¼ 139.5 (d), 114.4 (t), 79.4 (d),
77.3 (s), 40.1 (s), 35.8 (t), 34.9 (t), 32.3 (d), 32.0 (d), 31.7 (t), 26.8 (t), 23.8 (q),
20.6 (q), 19.8 (q), 19.4 (q). Anal. calcd. for C15H28O2 (240.38): C, 74.95; H,
11.74. Found: C, 75.19; H, 11.98.
(2R/S,5S,7R,9S)-2-(iodomethyl)-9-isopropyl-6,6-dimethyl-1-oxaspiro[4.5]
decan-7-ol (11 and 12): Iodine (1.03 g, 8.10 mmol) and sodium bicarbonate
(680 mg, 8.10 mmol) were sequentially added to a stirred solution of the
hydroxyalkene 10 (650 mg, 2.71 mmol) in dry acetonitrile (15 mL) at 08C
under a nitrogen atmosphere, and stirring was continued for 4 h. The
mixture was then diluted with ether (100 mL) and the ether solution was
washed successively with sodium thiosulphate solution (10%, 3 ꢀ 50 mL),
sodium bicarbonate solution (5%, 3 ꢀ 50 mL), and brine (1 ꢀ 50 mL). It
was then dried (Na2SO4) and filtered, and the filtrate was concentrated to
leave the crude product as a pale yellow liquid, which was purified by chrom-
atography over silica gel using petroleum ether–ethyl acetate mixture (19 : 1)
as eluent. The mixture of the diastereomers 11 and 12 was obtained as a
colorless liquid (702 mg, 70.6%).
Data for the mixture: IR (KBr): 3417, 2926, 2872, 1466, 1364, 1261, 1024,
802 cm21. 1H NMR (300 MHz, CDCl3): d ¼ 4.16–4.06 (m, 1 H), 3.80–3.70
(m, 2 H), 3.35–3.19 (m, 1 H), 2.16–2.10 (m, H), 1.74–1.58 (m, H), 1.31–
1.20 (m, H), 0.98 (d, 3 H, J ¼ 3.6 Hz), 0.93 (s, 3 H), 0.88 (d, 3H,
J ¼ 6.5 Hz), 0.79 (s, 3 H). 13C NMR (75 MHz, CDCl3): d 89.5, 79.3, 75.6,
75.3, 74.6, 43.8, 42.9, 38.6, 38.4, 37.8, 36.3, 33.7, 33.3, 32.6, 32.3, 32.2,
21.0, 19.9, 19.8, 19.6, 19.5, 16.1, 12.3, 11.5. Anal. calcd. for C15H27IO2
(366.28): C, 49.19; H, 7.43; I, 34.65. Found: C, 49.45; H, 7.60; I, 34.96.
(2R/S,5S,7R,9S)-9-isopropyl-2,6,6-trimethyl-1-oxaspiro[4,5]decan-7-ol
(13 and 14): A solution of tri-n-butyltinhydride (0.96 mL, 3.56 mmol) in dry
and degassed benzene (2 mL) was added dropwise to a refluxing solution of
the mixture of 11 and 12 (650 mg, 1.78 mmol) and AIBN (292 mg,
1.78 mmol) in dry and degassed benzene (5 mL), and refluxing was
continued for 5 h. It was then concentrated in vacuo and the residual mass
was purified by flash chromatography using a mixture of petroleum ether–
EtOAc (19 : 1) as eluent.
The major product was obtained as a colorless viscous liquid (191 mg,
45%). [a]D: þ3.5 (c, 0.4 in CHCl3). IR (neat): 3400, 2960, 2880, 1450,
1
1400, 1380, 1080, 1010 cm21. H NMR (300 MHz, CDCl3): d ¼ 4.02–3.93
(m, 1 H), 3.75 (dd, 1 H, J ¼ 11.7, 4.5 Hz), 2.08–1.87 (m, 2 H), 1.75–1.39
(m, 4 H), 1.36–1.18 (m, 4 H), 1.20 (d, 3 H, J ¼ 6.3 Hz), 0.99 (s, 3 H), 0.88
(d, 3 H, J ¼ 5.2 Hz), 0.86 (d, 3 H, J ¼ 4.9 Hz), 0.79 (s, 3 H). 13C NMR
(75 MHz, CDCl3): d ¼ 88.1 (s), 77.0 (d), 75.1 (d), 42.9 (s), 38.6 (t), 36.6
(d), 34.1 (t), 33.8 (t), 33.7 (t), 32.4 (d), 22.5 (q), 20.0 (q), 19.9 (q), 19.7 (q),
16.4 (q). m/z (EI, 70 eV): 240 (Mþ),197, 179, 124, 71, 57, 43. Anal. calcd.
for C15H28O2 (240.38): C, 74.95; H, 11.74. Found: C, 75.19; H, 11.96.

2130
S. K. Chattopadhyay, S. Karmakar, and K. Sarkar
The minor isomer was also obtained as a colorless viscous liquid (124 mg,
29%). [a]D: þ8 (c, 0.1 in MeOH). IR (neat): 3412, 2965, 1445, 1230 cm21
.
1H NMR (CDCl3, 300 MHz): d ¼ 4.15–3.90 (m, 1 H), 3.45–3.25 (m, 1 H),
2.32–2.15 (m, 2 H), 1.96–1.95 (m, 2 H), 1.64–1.56 (m, 2 H), 1.28–1.10
(m, 4 H), 1.20 (d, 3 H, J ¼ 4.5 Hz), 0.97 (s, 3 H), 0.94 (s, 3 H), 0.87 (d, 3 H,
J ¼ 1.6 Hz), 0.85 (d,
3
H, J ¼ 1.6 Hz).13C NMR (75 MHz,
CDCl3): d ¼ 87.6(s), 77.4 (d), 74.5 (d), 42.1 (s), 38.4 (t), 36.9 (d), 34.7 (t),
34.0 (t), 33.5 (t), 31.8 (d), 22.8 (q), 20.1 (q), 19.7 (q), 19.5 (q), 16.3 (q).
Anal. calcd. for C15H28O2 (240.38): C, 74.95; H, 11.74. Found: C, 75.08;
H, 11.88.
(2R/S,5S,7R,9S)-9-isopropyl-2,6,6-trimethyl-1-oxaspiro[4.5]dec-7-yl-4-
nitro-benzoate (15 and 16): 4-Nitrobenzoyl chloride (86 mg, 0.5 mmol) was
added in one portion to a stirred solution of the major alcohol 13/14 (100 mg,
0.41 mmol) and triethylamine (0.23 mL, 0.83 mmol) in dry dichloromethane
(2 mL), and the resulting mixture was stirred for 4 h at room temperature. It
was then diluted with dichloromethane (20 mL) and the organic extract was
washed with hydrochloric acid (5%, 2 ꢀ 10 mL), sodium bicarbonate (10%,
2 ꢀ 20 mL), water (2 ꢀ 10 mL), and then dried (Na2SO4). It was then
filtered and the filtrate was concentrated to leave the crude product as a
brownish oil, which was purified by chromatography over silica gel using a
mixture of petroleum ether–EtOAc (49 : 1) as eluent. The product 15/16
was obtained as a colorless solid (150 mg, 92%).
Mp 648C. [a]D: þ25 (c, 0.5 in CHCl3). IR (neat): 2960, 1720, 1600, 1520,
1340, 1310, 1220, 1109 cm21. 1H NMR (300 MHz, CDCl3): d ¼ 8.29 (d, 2 H,
J ¼ 8.8 Hz), 8.21 (d, 2 H, J ¼ 8.8 Hz), 5.30 (dd, 1 H, J ¼ 11.8, 4.6 Hz), 4.04–
3.97 (m, 1 H), 2.09–2.01 (m, 1H), 1.97–1.88 (m, 2H), 1.79–1.72 (m, 2 H),
1.53–1.47 (m, 2 H), 1.45–1.36 (m, 3 H), 1.22 (d, 3 H, J ¼ 7.1 Hz), 1.02
(s, 3 H), 0.95 (s, 3 H), 0.88 (s, 3 H, J ¼ 7.8 Hz), 0.85 (d, 3 H, J ¼ 8.0 Hz).
13C NMR (75 MHz, CDCl3): d ¼ 164.1 (s), 150.4 (s), 136.4 (s), 130.6 (d),
123.5 (d), 87.5 (s), 80.2 (d), 77.4 (d), 42.2 (s), 38.2 (t), 36.1 (d), 33.7 (t),
32.2 (d), 30.1 (t), 29.7 (t), 22.2 (q), 19.9 (q), 19.7 (q), 19.4 (q), 17.7 (q).
HRMS: m/z calcd. for C22H31NO5: 389.22021, found: 389.22028.
The minor alcohol 14/13 analogously gave the p-nitrobenzoate derivative
16/15 as a colorless solid. Mp. 598C. [a]D: þ7.3 (c, 0.3 in CHCl3). IR (neat):
1
2965, 1714, 1330, 1233, 1115 cm21. H NMR (300 MHz, CDCl3): d ¼ 8.29
(d, 2 H, J ¼ 8.8 Hz), 8.20 (d, 2 H, J ¼ 8.9 Hz), 4.90 (dd, 1 H, J ¼ 10.9,
4.4 Hz), 4.11–4.05 (m, 1 H), 2.11–2.00 (m, 2H), 1.82–1.75 (m, 2H), 1.68–
1.52 (m, 3 H), 1.48–1.34 (m, 3 H), 1.24 (d, 3 H, J ¼ 6.09 Hz), 1.18 (s, 3 H),
0.95 (s, 3 H), 0.90 (d, 3 H, J ¼ 6.6 Hz), 0.88 (d, 3 H, J ¼ 6.6 Hz). 13C NMR
(75 MHz, CDCl3): d 164.2 (s), 150.5 (s), 136.1 (s), 130.6 (d), 123.5 (d), 87.2
(s), 79.4 (d), 76.0 (d), 43.0 (s), 38.3 (t), 38.2 (d), 34.0 (t), 32.3 (d), 31.3 (t),
29.6 (t), 22.4 (q), 21.3 (q), 19.8 (q), 19.5 (q), 17.0 (q). m/z (EI, 70 eV): 389
(Mþ, 10%), 346 (38%), 179 (100%). Anal. calcd. for C22H31NO5 (389.49):
C, 67.84; H, 8.02; N, 3.59. Found: C, 68.16; H, 8.29; N, 3.44.

Chiral Spiro-Tetrahydrofuran Subunit
ACKNOWLEDGMENT
2131
Financial assistance from Council of Scientific and Industrial Research
(CSIR), New Delhi (Grant No. 01/1676/00/EMR-II) is gratefully acknowl-
edged. One of the authors (S. K. C.) is also grateful to G. Pattenden, Notting-
ham University, U.K., for the accurate mass data of one of the compounds and
to G. Mehta and A. Srikrishna, I.I.Sc, Bangalore, for spectral help and encour-
agement.
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