An enantio- and diastereocontrolled route to mintlactone and isomintlactone using a chiral cyclohexadienone equivalent

Article abstract of DOI:10.1055/s-1998-1747

An enantio- and diastereocontrolled route to mintlactone and isomintlactone, aroma components of important commercial flavoring materials, has been established using a chiral cyclohexadienone synthetic equivalent.

Full text of DOI:10.1055/s-1998-1747

June 1998
SYNLETT
655
An Enantio- and Diastereocontrolled Route to Mintlactone and Isomintlactone Using A
Chiral Cyclohexadienone Equivalent
Masahiro Shimizu, Takashi Kamikubo, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81-22-217-6845; E-mail konol@mail.cc.tohoku.ac.jp
Received 19 March 1998
Abstract: An enantio- and diastereocontrolled route to mintlactone and
isomintlactone, aroma components of important commercial flavoring
materials, has been established using
synthetic equivalent.
a chiral cyclohexadienone
We prepared both enantiomeric tricyclic dienones
2
in high
1
enantiomeric excess from meso tricyclic diol 1 by either enzymatic or
2
catalytic asymmetrization as the key step. Because
2
allows
diastereoselective functionalization of its enone functionality under
various conditions as well as generating a cyclohexene functionality
with removal of cyclopentadiene on thermolysis, optically active 2 may
3
be used as a chiral cyclohexadienone synthetic equivalent (Scheme 1).
Actually, we have so far been constructing a variety of natural products
enantio- and diastereoselectively using optically pure 2 as the starting
4
material . In this paper we wish to report an enantio- and
diastereocontrolled synthesis of two monoterpene lactones, (–)-
mintlactone (–)-3 and (–)-isomintlactone (–)-4, starting from the (+)-
enantiomer of chiral cyclohexadienone synthetic equivalent 2.
Figure 1
27
the endo-alcohol 7, [α]
–59.8 (c 1.0, CHCl ), as a single product.
3
D
Since thermolysis of the alcohol 7 gave a complex mixture, 7 was first
29
transformed into the acetate 8, [α]
+26.8 (c 1.1, CHCl ), which, on
3
D
thermolysis in diphenyl ether at 260 °C, afforded the cyclohexenyl
acetate 9, excellently, as the single product. Hydrolysis of 9 gave the
29
trans-substituted cyclohexenol (–)-10, [α]
50% overall yield from (+)-2.
+196 (c 0.7, CHCl ), in
3
D
On the other hand, the same cyclohexadienone equivalent (+)-2 was first
transformed into the β-methylenone (+)-5 via a one-pot four-step
4b,8
sequence
in 78% yield. Thus, (+)-2 was treated with
triphenylphosphine and tertbutyldimethylsilyl triflate (TBSOTf) in THF
at –78 °C to generate the 3-phosphonium-silylenol ether which, in the
same flask, was sequentially treated with butyllithium and
30
Scheme 1
formaldehyde to furnish (+)-5, [α]
+280 (c 0.9, CHCl ), after acid-
3
D
hydrolytic workup. Treatment of (+)-5 with diisobutylaluminum
9,10
11
hydride
(DIBAL) in the presence of copper (I) iodide in THF
(–)-Mintlactone (–)-3 and (+)-isomintlactone (+)-4 were isolated from
containing hexamethylphosphoric triamide (HMPA) (20%) at –78 °C
an important commercial flavoring material, American peppermint oil,
the essential oil of Mentha piperita, both as minor constituents . The
5
allowed stereoselective 1,4-reduction to give the endo-methyl ketone 11,
27
[α]
+226 (c 1.2, CHCl ), in 80% yield. Reduction of 11 with DIBAL
enantiomeric (+)-mintlactone (+)-3 and (–)-isomintlactone (–)-4 were
recently isolated from the essential oil of the woods of Bursera
D
3
26
gave stereoselectively the endo-alcohol 12, mp 47.5 °C, [α]
–40.8 (c
D
6
1.1, CHCl ), which, in contrast to the exo-methyl counterpart 7, gave the
graveolens as key aroma components (Fig. 1).
3
29
cis-substituted cyclohexenol (–)-13, [α]
–29.9 (c 1.5, CHCl ), in 71%
3
7
D
Although several syntheses of optically active mintlactone 3 and
yield without decomposition on thermolysis (Scheme 2). The observed
neat reaction of 12 was presumed to be due to repulsive 1,3-interaction
between the two endo-substituents which, at the same time, forces the
hydroxy group farther away from the cyclopentene olefin functionality
in the molecule to prevent undesirable side reactions such as ether
formation.
7
isomintlactone 4 have been reported, no procedure capable of
producing these two monoterpene lactones in both enantiomeric forms
in a highly enantio- and diastereoselective way has appeared to date
7c
besides the procedure using a chiral citronellal. We, therefore,
investigated chiral construction of mintlactone 3 and isomintlactone 4
intending to develop an enantio- and diastereodivergent route to either
of the two natural products in optically pure forms using either (+)- or
(–)-2 as the starting material.
The described preparation of the diastereomeric cyclohexenols (–)-10
and (–)-13 from the same cyclohexadienone equivalent (+)-2 implies
formal acquisition of their enantiomers (+)-10 and (+)-13 as we have
1
To realize our intention, we chose (+)-cyclohexadienone equivalent
1,2
also obtained the enantiomeric cyclohexadienone equivalent (–)-2.
(+)-2 as the starting material. Thus, treatment of (+)-2 with lithium
29
dimethylcuprate gave the exo-methyl ketone 6, [α]
+184 (c 1.0,
Having established the route to the two diastereomeric cyclohexenols
(–)-10 and (–)-13 in enantiomerically pure forms, their conversion into
(–)-mintlactone (–)-3 and (–)-isomintlactone (–)-4 was next examined.
D
CHCl ), stereoselectively. Reduction of 6 with diisobutylaluminum
3
hydride (DIBAL) also proceeded selectively from the exo-face to give

656
LETTERS
SYNLETT
Scheme 2
Scheme 3
7a,b,d
30
Reaction of (–)-10 with ethyl 1-propenyl ether (1.2 equiv.) in the
presence of N-bromosuccinimide (NBS) (1.1 equiv.) in ether produced
the bromo-acetal 14 excellently as a mixture of diastereomers. The
(4%) to give (–)-isomintlactone
(–)-4, mp 78.5-80.5 °C, [α]
D
12
5c
25
–75.9 (c 0.7, EtOH) [natural for (+)-enantiomer :mp 77-79 °C, [α]
+76.9 (c 5, EtOH)], and its exo-olefin isomer 18, [α]
EtOH) [natural : for (–)-enantiomer, [α] –120 (c 0.5, CHCl ) ] in
yields of 30 and 25%, respectively, after separation. The latter
compound was isomerized to the former compound
reflux with a catalytic amount of Rh(III) chloride
ethanol. Thus, total yield of (–)-isomintlactone (–)-4 from 16 was 51 %.
D
7d
31
+111.0 (c 0.9,
D
7b
7b
mixture without separation was next refluxed with sodium
D
3
13
borohydride in butanol in the presence of a catalytic amount each of
7a,d
tributylstannyl chloride (5 mol %) and azobisisobutyronitrile (AIBN)
(0.3 mol %) to give the cyclic acetal 15 as a mixture of four
diastereomers. The mixture without separation was then reacted with m-
in 90% yield on
(15 mol %) in
7d,16
chloroperbenzoic acid (mCPBA) in the presence of a catalytic amount of
On the other hand, (–)-13 was transformed in the same way into the γ-
lactone 21 in 67% overall yield through the bromo-acetal 19 and the
14
boron trifluoride etherate (BF ·OEt ) (10 mol %) in dichloromethane
3
2
to give the α-methyl-γ-lactone 16 in 71% yield as a 55:45 mixture at the
α stereogenic center of the γ-lactone moiety. Without separation, the
mixture was treated with phenylselenyl chloride in the presence of
cyclic acetal 20. In contrast to 16, the same two-step dehydrogenation
7a,d
step of 21 proceeded in a regioselective manner
to give (–)-
15
17
29
5b
mintlactone (–)-3, [α]
–56.3 (c 0.7, EtOH) [natural : [α] –51.8 (c
D
D
7d
lithium diisopropylamide (LDA) to give the selenide 17 as
a
10, EtOH); synthetic : [α] –56.6 (c 2.2, EtOH)], in 45% overall yield
D
diastereomeric mixture which immediately was treated with 30%
hydrogen peroxide in THF containing a catalytic amount of acetic acid
as a single product via the single selenide 22 (Scheme 3).

June 1998
SYNLETT
657
In summary, we have developed an enantio- and diastereoselective route
to enantiomeric mintlactone and isomintlactone, both of which are
present in nature, starting from an appropriate enantiomer of the chiral
cyclohexadienone synthetic equivalent.
(7) Chiral syntheses of mintlactone 3 and isomintlactone 4: (a) Carda,
M.; Marco, J. A. Tetrahedron Lett. 1991, 32, 5191. (b) Carda, M.;
Marco, J. A. Tetrahedron 1992, 48, 9789. (c) Shishido, K.; Irie,
O.; Shibuya, M. Tetrahedron Lett. 1992, 33, 4589. (d) Crisp, G. T.;
Meyer, A. G. Tetrahedron 1995, 51, 5831. (e) Lohray, B. B.;
Nandanan, E.; Bhushan, V. Indian J. Chem. 1997, 36B, 226.
References and Notes
(8) Kozikowski, A. P.; Jung, S. H. J. Org. Chem. 1986, 51, 3402.
(1) Takano, S.; Higashi, Y.; Kamikubo, T.; Moriya, M.; Ogasawara,
(9) Takano, S.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1997, 765.
K. Synthesis 1993, 948.
(2) Hiroya, K.; Kurihara, Y.; Ogasawara, K. Angew. Chem. Int. Ed.
Engl. 1995, 34, 2287.
(10) Tsuda, T.; Fujii, T.; Kawasaki, K.; Saegusa, T. J. Chem. Soc.,
Chem. Commun. 1980, 1013.
(3) Ogasawara, K. Pure & Appl. Chem. 1994, 66, 2119.
(11) Ashby, E. C.; Lin, J. J. Tetrahedron Lett. 1975, 44; Ashby, E. C.;
Lin, J. J.; Kovar, R. J. Org. Chem. 1976, 41, 1939.
(4) Recent examples, (a) A ring precursor of calcitriol: Kamikubo, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1995, 1951.
(b) (R)-Mevalonolactone: Shimizu, M.; Kamikubo, T.;
Ogasawara, K. Tetrahedron: Asymmetry 1997, 8, 2519. (c) (–)-
Mesembrine and (+)-Sceletium Alkaloid A4: Kamikubo, T.;
Ogasawara, K. Chem. Commun. in press.
(12) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J.
Am. Chem. Soc. 1982, 104, 5564.
(13) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554.
(14) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
419.
(5) (a) Fujita, S.; Fujita, Y. Nippon Nogeikagaku Kaishi, 1972, 46,
303. (b) Sakata, I.; Hashizume, T. Agric. Biol. Chem. 1973, 37,
2441. (c) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T.
Agric. Biol. Chem. 1980, 44, 1535.
(15) Zipkin, R. E.; Natale, N. R.; Tafer, I. M.; Hutchins, R. O. Synthesis
1980, 3904.
(16) Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J.
Am. Chem. Soc. 1976, 98, 7102.
(6) Iwabuchi, H. 41st Symposium on the Chemistry of Terpenes,
Essential Oils and Aromatics, Morioka, Japan, Oct. 10-12, 1997,
Abstract Paper pp. R1-R4.
1
(17) All stable compounds had spectroscopic data (IR, H NMR, mass,
high resolution mass) consistent with the assigned structure.