An efficient and simple synthesis of (-)-wine lactone

Article abstract of DOI:10.1016/S0957-4166(01)00511-0

A short and efficient diastereoselective snythesis of(-)-wine lactone (-)-4a involving FeCl₃/NaI-mediated iodolactonization of γδ-unsaturated acid 7 as the key step is described.

Full text of DOI:10.1016/S0957-4166(01)00511-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2985–2988
An efficient and simple synthesis of (−)-wine lactone
Subhash P. Chavan,* Rajendra K. Kharul, Anil K. Sharma and Sambhaji P. Chavan
Division Of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 16 October 2001; accepted 7 November 2001
Abstract—A, short and efficient diastereoselective synthesis of (−)-wine lactone (−)-4a involving FeCl3/NaI-mediated iodolac-
tonization of g,d-unsaturated acid 7 as the key step is described. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
non-stereoselective and lead to the formation of other
stereoisomers whereas the recent asymmetric synthesis
by Helmchen et al.10 involves the use of expensive
palladium complexes and a large number of steps.
Iodolactonization and iodoetherification are important
both as synthetic reactions and for the structural eluci-
dation of organic compounds.1 Iodolactonization was
utilized effectively for stereoselective functional group
incorporation
and
manipulation
in
Corey’s
2. Results and discussion
prostaglandin synthesis1c as well as in a total synthesis
of the tumor inhibitors Vernolepin, and Vernomenin2
and in vitamin D2 and D3 synthesis.3 Iodolactonization
and iodoetherification reactions are important for
structural elucidation e.g. from endo/exo isomeric mix-
tures, the endo isomer gives a quantitative yield of
iodolactones and iodoethers, whereas the exo-isomer is
inert, thus enabling the determination of the propor-
tions of the isomers in the mixture. Because of the
importance of the reaction we have recently developed
an efficient reagent system viz. FeCl3/NaI for iodolac-
tonization and iodoetherification4 (Scheme 1).
We report herein the diastereoselective synthesis of
enantiomerically pure wine lactone (−)-4a and its C(3)-
epimer (+)-4b from (+)-isolimonene 5 employing the
iodolactonization protocol developed by us (FeCl3/NaI)
as the key step.
The retrosynthetic plan for our synthesis is outlined in
Scheme 2.
Delighted with the results obtained during the iodolac-
tonization reaction of g,d-unsaturated acids mediated
by FeCl3/NaI, we extended this methodology to a short
and efficient synthesis of the (3a,4,5,7a-tetrahydro 3,6-
dimethylbenzofuran-2(3H)-ones5,6 (−)-wine lactone,
(−)-4a and its endo-C(3) epimer (+)-4b, which are
known odorants of different white wine varieties
Recently, (−)-4a was also isolated from orange juice
and black pepper.8
Scheme 1.
Wine lactone has been synthesized in both racemic9 and
diastereomerically pure form.7,10 Earlier syntheses are
* Corresponding author.
Scheme 2.
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00511-0

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S. P. Cha6an et al. / Tetrahedron: Asymmetry 12 (2001) 2985–2988
3. Experimental
3.1. General comments
As detailed in Scheme 2, the key intermediate iodolac-
tone (−)-8a could be obtained by iodolactonization of
the corresponding acid 7. To obtain the g,d-unsaturated
acid, the ideal starting material was (+)-isolimonene 5
which is a readily available natural product.
Melting points are uncorrected. 1H and 13C NMR
spectra were recorded on 200 and 50 MHz in CDCl3
using TMS as an internal standard. IR spectra were
recorded in CHCl3 on FT-IR spectrometer. GC analy-
sis was performed on Chrompack b-CD (25 m×0.25
mm) at 180°C. Optical rotations were recorded on a
Jasco P-1020 polarimeter using sodium vapor lamp.
THF was freshly distilled from sodium benzophenone
ketyl prior to use. Starting material (+)-isolimonene 5
was purified by column chromatography prior to use.
The alcohol 611 and acid 712 were prepared by literature
methods. All the reactions were monitored by TLC on
0.25 mm Merck Kieselgel TLC plate using ethanolic
p-anisaldehyde solution with heating for visualization.
Chromatography was performed on silica gel (60–120
mesh).
To accomplish the synthesis of iodolactones (−)-8a and
(+)-8b, (+)-isolimonene 5 was hydroborated regioselec-
tively with 9-BBN followed by oxidation with alkaline
H2O2 to furnish alcohol 6 as mixture of diastereomers
(d.r. 1:1) in 76% yield (Scheme 3). The diastereomeric
mixture of alcohol 6 was oxidized with Jones’ reagent
to yield the corresponding acid 7 in 78% yield. The
diastereomeric mixture of g,d-unsaturated acid 7 was
then subjected to the iodolactonization protocol devel-
oped by us4 using the FeCl3/NaI reagent system (for 1
equiv. of the acid, 2 equiv. each of FeCl3 and NaI were
used in refluxing CH3CN). This furnished the
diastereomeric iodolactones (−)-8a and (+)-8b in 59%
overall yield in the ratio 60:40. It is pertinent to men-
tion that the conventional iodolactonization protocol
(I2, saturated NaHCO3)1d,e,f furnished the iodolactones
in somewhat lower yield (52%). At this stage the
diastereomers (−)-8a and (+)-8b were separated by care-
ful column chromatography (60–120 silica gel, eluent:
ethyl acetate:pet. ether 0.75:99.25).
3.2. Idolactones (−)-8a and (+)-8b
To a solution of acid 24 (1.5 g, 8.93 mmol) in acetoni-
trile (12 mL) was added anhydrous FeCl3 (2.901 g,
17.86 mmol) and NaI (2.68 g, 17.86 mmol), in CH3CN
(35 mL). The solution was stirred under reflux for 2.5 h.
The reaction mixture was then cooled to room temper-
ature, quenched with water (8 mL) and extracted with
dichloromethane (4×30 mL). The organic layer was
washed with saturated Na2S2O3 (25 mL), water (25
mL), and finally with brine (25 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated on
rotary evaporator under reduced pressure to furnish the
crude mixture of epimeric iodolactones (−)-8a and (+)-
8b in the ratio 60:40 (1.55 g, 59%). The iodolactones
were separated by careful column chromatography (60–
120 mesh, eluent: ethyl acetate:pet ether 0.75:99.25)
Dehydrohalogenation of iodolactone (−)-8a with DBU
in THF furnished natural (−)-wine lactone (−)-4a in
76% yield. The wine lactone thus obtained had identical
spectral properties (1H and 13C NMR, IR) and specific
rotation as compared to a sample of the natural isomer.
Additionally the synthetic wine lactone was found to
have >99% e.e. as judged by GC analysis on
Chrompack b-CD (25 m×0.25 mm) at 180°C. Similarly,
the diastereomeric iodolactone (+)-8b was also dehy-
drohalogenated with DBU to furnish the C(3)-epimer
(+)-4b. Alternatively, wine lactone (−)-4a could be read-
ily converted10 to its C(3)-epimer (+)-4b.
Iodolactones (−)-8a and (+)-8b were also obtained as an
epimeric mixture by the conventional method using
Scheme 3. (a) (i) 9-BBN, THF, 0°C–rt, 15 h, (ii) NaOH, H2O2, 0°C–rt, 1 h, 76%; (b) Jones’ oxidation, 0°C–rt, 2 h, 78%; (c)
NaI/FeCl3, CH3CN, reflux, 2.5 h, 59%; (d) DBU/THF, rt, 5 h.

S. P. Cha6an et al. / Tetrahedron: Asymmetry 12 (2001) 2985–2988
2987
saturated NaHCO3/I2 in diethyl ether at 0°C in 52%
(s, CꢀO). Mass (m/z): 166 (M+, 22), 151 (37), 138 (12),
123 (14), 107 (40), 93 (100), 79 (87), 67 (52), 55 (88).
C10H14O2 (166.22). Calcd: C, 72.26; H, 8.49; found: C,
72.37; H, 8.46%.
yield.1f
3.2.1. [(3S,3aS,6R,7R,7aR)-(3a,4,5,6,7,7a)-Hexahydro-
3,6-dimethylbenzofuran-2(3H)-one, iodolactone (−)-8a.
Mp 75–76°C; e.e.=98.99%; tR [(−)-8a]: 29.152 min;
[h]2D0−37.3 (c=3, CHCl3); IR wmax (CHCl3) cm−1: 2965,
3.2.4.
(+)-(3R,3aS,7aR)-3a,4,5,7a-Tetrahydro-3,6-di-
methylbenzofuran-2(3H)-one: (+)-4b. A solution of (+)-
8b (0.250 g, 0.85 mmol) and DBU (0.166 g, 1.09 mmol)
in dry tetrahydrofuran (10 mL) was stirred at room
temperature for 5 h. Aqueous HCl (6N, 15 mL) was
added and the mixture was extracted with diethyl ether
(4×20 mL). The combined organic layer was washed
with water (5 mL), brine (5 mL) and dried over anhy-
drous Na2SO4, concentrated on rotary evaporator at
reduced pressure to furnish crude wine lactone (+)-4b.
The lactone was purified by column chromatography
(eluent: ethyl acetate:pet. ether 1:99). The lactone was
further purified by crystallization from ethyl acetate/
hexane. Yield: 0.1 g (71%); mp (Lit.): 58–60°C (57–
59°C); e.e.=99.86%; tR [(−)-4a]: 13.271 min, [h]2D0 (Lit.)
+112.15; (c=3, CHCl3), [+112, (c=3, CHCl3)] IR wmax
1
2873, 1780, 1455, 1385; H NMR (200 MHz, CDCl3): l
1.01 (d, 3H, J=6.34 Hz, -CHCH3), 1.29 (d, 3H, J=
7.33 Hz, -COCHCH3), 1.39–1.47 (m, 4H, -CH2), 1.81–
1.93 (m, 1H, -COCHCH3), 2.35–2.51 (m, 2H, -CH2),
4.66 (t, 1H, J=3.76 Hz, -CHI), 4.92 (dd, 1H, J=3.92
Hz, -CHO); 13C NMR (50 MHz, CDCl3): l 14.02 (q,
-CHCH3), 22.26 (q, -COCHCH3), 26.37 (t, -CH2),
28.06 (t, -CH2), 31.81 (d, -CHCH3), 38.81 (d, -CH),
41.55 (d, -CHI), 43.39 (d, -COCHCH3), 81.73 (d,
CHO), 179.07 (s, CO). Mass (m/z): 294 (M+, 8), 167
(76), 149 (18), 121 (48), 93 (100), 81 (32), 67 (11),
C10H15IO2 (294.13). Calcd: C, 40.83; H, 5.14; I, 43.14;
found: C, 40.90; H, 5.20; I, 42.71%.
1
(CHCl3) cm−1: 3020, 2981, 2935, 1761, 1216; H NMR
3.2.2. [(3R,3aS,6R,7R,7aR)-(3a,4,5,6,7,7a)-Hexahydro-
3,6-dimethylbenzofuran-2(3H)-one, iodolactone (+)-8b.
Mp 72–73°C; e.e.=99.06%; tR [(+)-8b]: 31.022 min,
[h]2D0 +21.63 (c=3, CHCl3); IR wmax (CHCl3) cm−1:
2965, 2934, 2875, 1781, 1455, 1385, 1328; 1H NMR
(200 MHz, CDCl3): l 0.94 (d, 3H, J=5.37 Hz,
-CHCH3), 1.29 (d, 3H, J=6.98 Hz, -COCHCH3), 1.21–
1.43 (m, 4H, -CH2), 1.64–1.75 (m, 1H), 2.74–2.83 (m,
2H), 4.72–4.77 (m, 2H); 13C NMR (50 MHz, CDCl3): l
8.93 (q, -CHCH3), 23.28 (t, CH2), 23.70 (q,
-COCHCH3), 27.85 (t, -CH2), 30.66 (d, -CHCH3),
35.66 (d, -CH), 42.25 (d, -CHI), 42.59 (d, -COCHCH3),
82.23 (d, CHO), 179.07 (s, CO). Mass (m/z): 294 (M+,
7), 167 (94), 149 (18), 121 (54), 93 (100), 77 (12), 67 (8),
C10H15IO2 (294.13). Calcd: C, 40.83; H, 5.14; I, 43.14;
found: C, 40.95; H, 5.02; I, 42.83%.
(200 MHz, CDCl3): l 1.12–1.16 (m, 1H, CH2), 1.19 (d,
3H, J=7.35 Hz, CHCH3), 1.66–1.70 (m, 1H, CH2),
1.79 (s, 3H, CHꢀCCH3), 1.95–2.03 (m, 2H, CH2), 2.23–
2.31 (m, 1H, CHCHCH3), 2.89 (dq, 1H, J=7.52 Hz,
J=7.33 Hz, CH-CH3), 4.60–4.64 (m, 1H, CHO), 5.65–
5.68 (m, 1H, HCꢀC); 13C NMR (50 MHz, CDCl3): l
9.13 (q, CHCH3), 19.51 (t, CH2), 23.62 (q, CꢀCH3),
28.73 (t, CH2), 37.62 (d, CHCHCH3), 40.05 (d,
CHCH3), 74.56 (d, CHO), 116.80 (s, ꢀCH), 143.92 (s,
H3CCꢀ), 178.33 (s, CꢀO). Mass (m/z): 166 (M+, 32),
151 (57), 138 (12), 123 (19), 93 (100), 79 (65), 55 (39);
C10H14O2 (166.22). Calcd: C, 72.26; H, 8.49; found: C,
72.40; H, 8.52%.
4. Conclusions
3.2.3.
(−)-(3S,3aS,7aR)-3a,4,5,7a-Tetrahydro-3,6-di-
Thus, we have achieved a short and efficient synthesis
of (−)-wine lactone from (+)-isolimonene utilizing the
iodolactonization protocol developed by us (FeCl3/NaI)
as the key step.
methylbenzofuran-2(3H)-one: wine lactone, (−)-4a. A
solution of (−)-8a (0.250 g, 0.85 mmol) and DBU (0.166
g, 1.09 mmol) in dry tetrahydrofuran (10 mL) was
stirred at room temperature for 5 h. Aqueous HCl (6N,
15 mL) was added and the mixture was extracted with
diethyl ether (4×20 mL). The combined organic layer
was washed with water (5 mL), brine (5 mL) and dried
over anhydrous Na2SO4, concentrated on rotary evapo-
rator at reduced pressure to furnish crude wine lactone
(−)-4a. The lactone was purified by column chromatog-
raphy (eluent: ethyl acetate:pet. ether 1:99). The lactone
was further purified by crystallization from ethyl ace-
tate/hexane. Yield: 0.107 g (76%); mp (Lit.): 49–50°C
(48–50°C); e.e.=99.58%; tR [(−)-4a]: 10.939 min, [h]D20
(Lit.): −13.5 (c=3, CHCl3), [−13.1 (c=3, CHCl3); IR
Acknowledgements
R.K.K., A.K.S. and S.P.C. thank CSIR, New Delhi for
senior research fellowships. Funding from Young Sci-
entist Award, CSIR, New Delhi is also gratefully
acknowledged.
References
wmax (CHCl3) cm−1: 3020, 2981, 2935, 1761, 1216; H
1
NMR (200 MHz, CDCl3): l 1.25 (d, 3H, J=7.39 Hz,
CHCH3), 1.73 (s, 3H, HCꢀCCH3), 1.77–2.02 (m, 4H,
CH2), 2.19–2.32 (m, 1H, -CH-CH-CH3), 2.34–2.45 (m,
1H, -CHCH3), 4.85–4.90 (m, 1H, CHO), 5.51 (m, 1H,
CꢀCH); 13C NMR (50 MHz, CDCl3): l 13.62 (q,
CHCH3), 21.85 (t, CH2), 23.29 (q, CꢀCH3), 25.53 (t,
CH2), 37.11 (d, CHCH3), 39.90 (d, CHCHCH3), 74.89
(d, CHO), 18.49 (d, ꢀCH), 140.84 (s, CH3Cꢀ), 179.51
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