Total synthesis of (-)-mintlactone

Article abstract of DOI:10.1016/S0040-4039(00)93463-4

The first total, stereodirected synthesis of (-)-mintlactone is described. A stereoselective, radical-mediated ring closure was the key step in the synthesis.

Full text of DOI:10.1016/S0040-4039(00)93463-4

Tetrahedron Letters, Vo1.32, No.38, pp 5191-5192, 1991
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T O T A L S Y N T H E S I S
OF
( - ) - M I N T L A C T O N E
M i g u e l C a r d aa a n d J. A l b e r t o M a r c ob
abDepartamento de Qulmica Orgfmica, Colegio Universitario de Castell6rg E-12080 Castell6n, and
Departamento de Quimica Orgfmica, Facultad de Qutmicas, Universidad de Valencia, E-46100
Burjassot, Valencia, Spain.
Abstract: The first total, stereodirected synthesis of (-)-mintlactone is described. A stereoselective, radical-mediated
ring closure was the key step in the synthesis.
The essential oil of Mentha piperita L. (peppermint oil), one of the most important commercial
flavoring materials, is produced in many countries. Its chemical composition has been thoroughly
investigated, more than 300 components having been reported. A m o n g the minor constituents,
(-)-mintlactone 1 and ( +)-isomintlactone 2 were isolated from a sample of American peppermint
oil.1 Before their first description as natural products, these compounds had been reported among the
products formed during photooxidation of menthofurane. 2'3 Racemic 1 was also an intermediate in a
total synthesis of menthofurane.4 Very recently, a further, nonselective synthesis of racemic 1 and 2 has
been published.5 We now wish to report the first stereodirected synthesis of optically active 1, using the
chiral enone 36 as the starting material. The key step in the syntheses was the radical mediated ring
closure 5 --" 6.
2
o
~
"'"o
Hydride reduction of ( - )-3 ( > 95% ee)6 gave the allylic alcohol 4, which was then transformed
into the bromoacetal 5 by reaction with NBS at -40 °C in ethyl vinyl ether as the solvent.7 Tri-n-butyltin
hydride promoted the reductive ring closure under homolytic conditions7'8 to the acetal
6
(diastereoisomeric mixture), which was then oxidized by Jones reagent to the stereochemically
homogeneous lactone 7.9 Debenzylation to 8 was best performed by hydrogenolysis with Pd(OH)2 as
catalyst, 11 which proved superior to Pd/C in terms of both yield and reactivity. In view of the presence
of the lactone ring, a radical method was selected for the reductive elimination of the hydroxyl group.
Acylation of 8 with O-phenyl chlorothionoformate 12 gave 9, which was then treated with tri-n-butyltin
hydride and A1BN in refluxing toluene. Lactone 10 was obtained in 62% overall yield from 8.
Methylation of 10 via the enolate generated with LDA took place stereoselectively from the less
hindered c~ face, yielding 11, a dihydro derivative of ( -)-mintlactone. Finally, dehydrogenation of 11 to
5191

5192
1 was p e r f o r m e d in 3 3 % o v e r a l l yield via the phenylselenenyl derivative 1213. The o b t a i n e d
( -)-mintlactone was identical in its spectral and physical properties with the p r o d u c t described in the
bibliography. 1"4
~ n a ~ OB~I e ~ ~ i
v
- o
~
6
o
4
~=.
b
-c.
oEt
c.2Br
_
OBn
h
J
7
f
C
8
R=Ott
R==OC(=S)OPh
R=H
C
11__ R=tt R'=ble
12 R=Me R'=SePh
i
g
~
a: NaBH4, CeCI3, EtOH, 0 °C, 45 min, 98%. b. NBS, excess EtOCH =CH2, -40 °C, 4 h, 90% ¢: Bu3SnH, AIBN, CsH6, A, 4
h, 93%. d: Jones reagent, acetone, 0 °C, 15 rain, 92%. e: H2, Pal(OH)2, EtOAc, 30 min, 98%. f: CIG(S)OPh, DMAR MeCN,
r.t., 15 h, 83%. g: Bu3SnH, AIBN, Tol, 4, 2.5 h, 75%. h: LDA, THE -78 °C, 1 h, then Mel/HMPA]THF, 1 h at -78 °C and 40 min
at -50 °C, 60%. i: LDA, THE -78 °C, 1 h, then PhSeGI/HMPA/THF, 40 rain at -78 °C and 40 min at -50 °C, 40%. j:
H202/'[HF/AcOH, 0 *C, 1 h, 82%.
Acknowledgements- The authors thank Mrs. A. Boeckmann for her collaboration in the experimental work.
Financial support by the University of Valencia (Acci6n Integrada 1990) is also acknowledged.
LITERATURE
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9. Oxidation with m-CPBA/BF3 (ref. 10) gave lower yields (60%).
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(Received in UK 20 June 1991)