Synthesis of (-)-mintlactone via intramolecular Wittig-Horner reaction

Article abstract of DOI:10.1081/SCC-120039484

An efficient synthesis of (-)-mintlactone has been described starting from (+)-pulegone and employing the intramolecular Wittig-Horner reaction as the key step.

Full text of DOI:10.1081/SCC-120039484

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2323–2329, 2004
Synthesis of (2)-Mintlactone via
Intramolecular Wittig–Horner
Reaction
Rajesh K. Pandey, Rajesh K. Upadhyay,
*
Sandip S. Shinde, and Pradeep Kumar
Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune, India
ABSTRACT
An efficient synthesis of (2)-mintlactone has been described starting from
(þ)-pulegone and employing the intramolecular Wittig–Horner reaction
as the key step.
Key Words: Mintlactone; Intramolecular Wittig–Horner reaction;
Phosphonate; Stereoselectivity.
*
Correspondence: Pradeep Kumar, Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune 411008, India; Fax: 0091-20-25893614;
E-mail: tripathi@dalton.ncl.res.in.
2323
DOI: 10.1081/SCC-120039484
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Pandey et al.
INTRODUCTION
(2)-Mintlactone 1 and (þ)-isomintlactone 2 (Fig. 1) are monoterpenic
compounds found as minor components in the essential oil of several Mentha
species.
These two diastereomeric p-menthanolides were isolated for the first
time in 1968 from Mentha cardiaca[1] and later from M. Pulegium L.[2] and
from a variety of M. arvensis known as Shubi.[3] The essential oil of Mentha
piperita L.(peppermint oil), one of the most important commercial flavoring
material is produced in many countries. Its chemical composition has been
investigated showing more than 300 minor volatile components.[4] Among
the minor constituents 1 and 2 are reported to be present in the oil of
M. piperita L.[5]
The relative and absolute configurations of these two lactones were
assigned by Takahashi et al.[6] Their synthesis has attracted attention of many
organic chemists as is evident by number of literature reports[7] including a
recent review article dealing with this subject (for the syntheses of mintlactone,
see: review article,[8]). Most of the synthetic approaches are either nonstereose-
lective or suffer from low overall yields and/or large number of steps involved.
As a part of our research interest in developing methodologies using phosphorus
ylides and their subsequent application to biologically useful compounds,[9] we
report here an efficient and enantioselective route to the synthesis of title com-
pound starting from (þ)-pulegone employing intramolecular Wittig-Horner
reaction as the key step.
RESULTS AND DISCUSSION
The synthesis of (2)-mintlactone started from (þ)-pulegone 3 as depicted
in Sch. 1. (þ)-Pulegone 3 was reduced to cis-pulegol 4[10] using sodium
Figure 1. Structure of (2)-mintlactone 1 and (þ)-isomintlactone 2.

Synthesis of (2)-Mintlactone
2325
.
Scheme 1. Reagents and conditions: (a) CeCl3 7H2O, MeOH, NaBH4, 08C, 30 min,
98%; (b) O3, CH2Cl2, 2788C, 45 min, 95%; (c) (EtO)2P(O)CH(Me)COOH 6, DCC,
CH2Cl2, 08C-rt, 24 hr, 85%; (d) NaH, THF, reflux, 6 hr, 90%.
borohydride and cerium chloride in 98% yield and 90% ee,a [a]D25 2103 (c 1,
MeOH). Compound 4 was subjected to ozonolysis to afford 2-hydroxy-4-
methylcyclohexanone 5 in excellent yield. The other component 6, required
for the synthesis of phosphonate 7 was prepared in two steps in the following
way. The Arbuzov reaction between triethylphosphite and ethyl 2-bromo-
propionate furnished triethyl 2-phosphonopropionate[11] which on subsequent
hydrolysis with 85% aqueous potassium hydroxide gave the desired acid 6 in
90% yield. The coupling of alcohol 5 with acid 6 was readily performed under
neutral condition using DCC as dehydrating agent to afford 2-(diethoxy-
phosphoryl)propionic acid 5-methyl-2-oxocyclohexyl ester 7 in 85% yield,
[a]2D5 þ39.0 (c 2, CHCl3) which on treatment with sodium hydride in THF
furnished (2)-mintlactone 1 in 90% yield [a]2D5 257.0 (c 2, CHCl3) [Lit.[7d]
[a]2D5 257.0 (c 2.4, CHCl3)].
aThe enantiomeric excess was determined by HPLC. HPLC model: Merck-Hitachi
Lachrom PDA system D-7000 series; Column: Lichrospher RP-18 (4 mm
ID ꢀ 125 mm); Mobile phase: methanol: water: (90 : 10); Flow: 1 mL/min.

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Pandey et al.
EXPERIMENTAL
Solvents were purified and dried by standard procedure before use;
petroleum ether of boiling range 60–808C was used. Optical rotations were
measured using sodium D line on a JASCO P-1020 microprocessor base
polarimeter. Infrared spectra were recorded on ATI MATTSON RS-1
FT-IR spectrometer. 1H NMR and 13C NMR spectra were recorded on Bruker
AC-200 spectrometer. The chemical shifts were expressed in ppm (d) down
field from TMS with residual CDCl3 (d 7.27) as internal standard. Mass
spectra were obtained with TSQ 70, Finningen MAT mass spectrometer.
2-Hydroxy-4-methylcyclohexanone (5). To a solution of cis-pulegol 4
(7.0 g, 45.5 mmol) in dichloromethane (75 mL) cooled to 2788C was bubbled
ozone. The color of reaction mixture became blue–green over a period of
45 min. Then oxygen was passed for 15 min and dimethyl sulfide (2 mL)
was added. The reaction mixture was stirred at 08C for 15 min and then at
room temperature for 15 min. The evaporation of solvent gave the product 5
(5.53 g, 95%) as a viscous liquid, which was subsequently used in the next
reaction without any further purification. [a]2D5 215.8 (c 0.54, CHCl3). IR
1
(Neat): cm21 3443, 2930, 1719, 1672, 1455. H NMR (200 MHz, CDCl3):
d ¼ 1.00 (d, J ¼ 7.4 Hz, 3H), 1.11–2.60 (m, 7H), 3.85 (bs, 1H), 4.20
(m, 1H). 13C NMR (200 MHz, CDCl3): d ¼ 18.85, 27.50, 35.00, 36.35,
40.35, 88.85, 208.25. EIMS (m/z): Mþ 128 (24), 112 (12), 84 (100), 71
(57). Anal. calc. for C7H12O2: C, 65.59; H, 9.44; Found: C, 65.34; H, 9.17.
2-(Diethoxyphosphoryl)propionic acid 5-methyl-2-oxo-cyclohexyl
ester (7). To a solution of 2-hydroxy-4-methylcyclohexanone 5 (2.50 g,
19.5 mmol) and 2-(diethoxyphosphoryl)propionic acid 6 (4.10 g, 19.5 mmol)
in dry dichloromethane (25 mL) cooled to 08C was added DCC (4.82 g,
23.4 mmol) under vigorous stirring. The reaction mixture was stirred at
room temperature for 24 hr under nitrogen. Solid was separated by filtration,
water was added to the filtrate, and extracted with dichloromethane
(2 ꢀ 50 mL). The combined organic layers were washed with water, brine,
and dried over Na2SO4. The evaporation of solvent gave the crude product
which on purification by silica gel column chromatography using petroleum
ether : ethyl acetate (4 : 6) as eluent afforded the phosphonate 7 (5.31 g,
85%) as a viscous liquid. [a]D25 þ39.0 (c 2, CHCl3). IR (Neat): cm21 2930,
1727, 1455. 1H NMR (200 MHz, CDCl3): d ¼ 1.02 (d, J ¼ 7 Hz, 3H),
1.27–1.55 (m, 12H), 2.04–2.29 (m, 2H), 2.42 (m, 2H), 3.09–3.24 (m, 1H),
4.08–4.21 (m, 4H), 5.20–5.30 (m, 1H). 13C NMR (200 MHz, CDCl3):
d ¼ 10.73, 15.28, 19.88, 29.58, 33.99, 36.49, 37.04, 38.33, 39.00, 39.66,
61.81, 75.20, 167.57, 202.60. EIMS (m/z): Mþ 320 (2), 261 (5), 219 (5),
179 (27), 151 (44), 123 (100), 81 (95), 65 (54). Anal. calc. for C14H25O6P:
C, 52.49; H, 7.87; Found: C, 52.75; H, 7.53.

Synthesis of (2)-Mintlactone
2327
(2)-Mintlactone (1). To a solution of phosphonate 7 (750 mg,
2.34 mmol) in dry THF (35 mL) was added sodium hydride [(225 mg,
4.69 mmol) 50% in mineral oil washed with THF]. The reaction mixture
was refluxed for 6 hr, cooled to room temperature and then water was
added. The reaction mixture was then extracted with ethyl acetate
(3 ꢀ 25 mL). The organic layer was separated, washed with brine, and dried
over anhydrous Na2SO4. Evaporation of solvent gave the crude product
which on silica gel column chromatography using petroleum ether : ethyl
acetate (9 : 1) as eluent afforded (2)-mintlactone 1 (350 mg, 90%) as an oil.
[a]2D5 257 (c 2, CHCl3) [lit.[7d] [a]D25 257 (c 2.4, CHCl3). IR (Neat): cm21
2929, 2870, 1754, 1688, 1455. 1H NMR (200 MHz, CDCl3): d ¼ 1.00
(d, J ¼ 6.6 Hz, 3H), 1.10–1.50 (m, 2H), 1.75 (m, 1H), 1.80 (t, J ¼ 1.4 Hz,
3H). 1.95–2.25 (m, 2H), 2.41 (m, 1H), 2.82 (m, 1H), 4.61 (m, 1H).
CONCLUSION
In conclusion, a very short synthesis of (2)-mintlactone has been
achieved starting from commercially available (þ)-pulegone and using intra-
molecular Wittig-Horner reaction as the key step. The synthetic strategy
described here has significant potential for further extension to (þ)-isomintlac-
tone via Mitsunobu inversion of configuration. Currently studies are in pro-
gress in this direction.
ACKNOWLEDGMENTS
RKP thanks CSIR, New Delhi for award of senior research fellowship.
We are grateful to Dr. M. K. Gurjar, Head, Organic Chemistry: Technology
Division for his constant encouragement and support. This is NCL
communication No. 6657.
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Received in India February 17, 2004