Enantioselective synthesis of both enantiomers of methyl dihydrojasmonate using solid-liquid asymmetric phase-transfer catalysis

Article abstract of DOI:10.1021/ol006207e

Both enantiomers of methyl dihydrojasmonate (-)-1 and (+)-1 were obtained by a short route using asymmetric Michael addition of dimethyl malonate onto pentyl enone 3, followed by nonracemizing demethoxycarbonylation. The key enantioselective step involves a new system of asymmetric solid - liquid phase-transfer catalysis using solvent-free conditions. Enantiomeric excess as high as 90% (91% yield) was achieved.

Full text of DOI:10.1021/ol006207e

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2959-2962
Enantioselective Synthesis of Both
Enantiomers of Methyl
Dihydrojasmonate Using Solid−Liquid
Asymmetric Phase-Transfer Catalysis
,†
Thierry Perrard,† Jean-Christophe Plaquevent,* Jean-Roger Desmurs,‡ and
Dominique He´brault‡
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes - IRCOF, UPRES-A CNRS
6014, Faculte´ des Sciences, rue Tesnie`re, F-76821 Mont Saint Aignan Cedex, France,
and Rhodia Organique Fine, Centre de Recherche de Lyon, 85, aVenue des Fre`res
Perret, BP 62, F-69192 Saint Fons Cedex, France
jean-christophe.plaqueVent@uniV-rouen.fr
Received June 15, 2000
ABSTRACT
Both enantiomers of methyl dihydrojasmonate (−)-1 and (+)-1 were obtained by a short route using asymmetric Michael addition of dimethyl
malonate onto pentyl enone 3, followed by nonracemizing demethoxycarbonylation. The key enantioselective step involves a new system of
asymmetric solid−liquid phase-transfer catalysis using solvent-free conditions. Enantiomeric excess as high as 90% (91% yield) was achieved.
(-)-Methyl dihydrojasmonate (-)-1 and its epimer (+)-2
are unnatural compounds, which have important olfactory
properties (jasmine-like odor). Both compounds are con-
stituents of famous fragrances.1 Moreover, the natural parent
compounds show hormonal activities in some plants.2
Figure 1), which is a fragrance isolated from Jasminum
grandiflorum L.3 Enantioselective syntheses of (-)-1 and
(+)-2 have been published; the enantioselective steps
described relying either on enamine alkylation of a chiral
precursor,4 on catalytic asymmetric hydrogenation,5 or on a
variant of the Claisen rearrangement.6
The compound (+)-2 epimerizes easily into (-)-1 under
mild acidic or basic conditions.1 The synthesis of trans-
(-)-1 has often been realized by hydrogenation of the natural
parent compound, i.e., trans-(-)-methyl jasmonate (see
Our strategy consisted of building (-)-1 using as the key
* To whom correspondence should be addressed. Fax: +33 (0)2 35 52
29 71.
† Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes - IRCOF.
‡ Centre de Recherche de Lyon.
(1) Frater, G.; Bajgrowicz, J A.; Kraft, P. Tetrahedron 1998, 54, 7633.
(2) Ravid, U.; Ikan, R.; Sachs, R M. J. Agric. Food Chem. 1975, 23,
835. Ishikawa, A.; Yoshihara, T.; Nakamura, K. Biosci. Biotech. Biochem.
1994, 58, 544 and references therein. Ishikawa, A.; Yoshihara, T.;
Nakamura, K. Plant Mol. Biol. 1994, 26, 403. Zhang, Z.-P.; Krumm, T.;
Baldwin, T. I. J. Chem. Ecol. 1997, 23, 2777. Koda Y. Phytochemistry
1991, 30, 1435. Bodnaryk, R.; Yoshihara, T. J. Chem. Ecol. 1995, 21, 1735.
Seto, H.; Kamuro, Y.; Oian, Z.; Shimizu, T. J. Pesticide Sci. 1992, 17, 61.
(3) Demole, P. E. Fragrance Chemistry; Theimer, E. T., Ed.; Academic
Press: Orlando, 1982.
Figure 1. Structures of trans-methyl jasmonate and dihydrojas-
monates.
10.1021/ol006207e CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/31/2000

step an asymmetric Michael addition of dimethyl malonate
onto the enone 3 (Scheme 1).7
Table 1. Michael Addition of Dimethyl Malonate onto Enone
3 (Potassium Carbonate as Base, 0.16 Equiv)
catalyst
(equiv)
malonate
(equiv)
T
(+)-4 ee
(yield,a %)
(-)-4 ee
(yield,a %)
Scheme 1
entry
(°C)
1
2
3
4
5
6
7
8
9
5 (0.10)
5 (0.10)
5 (0.10)
5 (0.10)
5 (0.10)
5 (0.14)
5 (0.12)
6 (0.10)
7 (0.12)
8 (0.11)
9 (0.11)
1
2
0
0
0
0
0
31
32
37
42
43
10
20
30
30
30
30
30
30
30
-10 48
-20 54 (75)
-20 no reaction
-20
-20 90 (91)
-20 67 (21)
We decided to promote Michael addition under asym-
metric phase-transfer catalysis and to use Krapcho conditions8
to achieve the demethoxycarbonylation of 4, thus giving 1
(Scheme 2). This approach was inspired by recent advances
80 (60)
10
11
a ee was determined by NMR in the presence of Pr(hfc)3 and confirmed
by chiral HPLC. Absolute configuration of stereogenic centers was
determined by chemical correlation after non racemic demethoxycarbon-
ylation and yields quoted are after purification by flash-chromatography.
Scheme 2
Optimization of experimental conditions led us to use
simple inorganic bases such as potassium carbonate11 and
an excess of dimethyl malonate,12 which played the dual role
(9) Corey, E. J.; Noe, M. C.; Xu, F.; Tetrahedron Lett. 1998, 39, 5347.
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
Lygo, B.; Wainwrigh, P. G. Tetrahedron Lett. 1997, 38, 8595. O’Donnell,
M. J. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publisher Inc.:
New York, 1993; Chapter 8, p 389; Tetrahedron, Symposia in print, 1999,
55 (20).
(10) For a previous description and structure determination of quininium
derivatives, see: Stone, P. M. Ph.D. Thesis, Brandeis University, Waltham,
Massachusetts, 1993. Pochapsky, T. C.; Stone, P. M. J. Am. Chem. Soc.
1991, 113, 1460. Hofstetter, C.; Stone Wilkinson, P.; Pochapsky, T. C. J.
Org. Chem. 1999, 64, 8794. N-9-Antracenylmethylquininium chloride 8:
To a suspension of quinine (2 g, 6.16 mmol) in toluene (40 mL) was added
9-(chloromethyl)anthracene (1.43 g, 6.29 mmol), and the mixture was stirred
at reflux for 2.5 h. The mixture was cooled to room temperature, poured
onto 100 mL of diethyl ether, and filtered. The solids were washed with
diethyl ether and then dried in a vacuum at 50 °C. The yellow residue was
collected in dichloromethane (100 mL), and the resulting suspension was
refluxed for 2 h and then cooled to -15 °C. At this temperature was added
diethyl ether (20 mL), and the suspension was filtered. The solids were
collected and dried to give a light-brown solid (1.67 g, 49%). 1H NMR
(CDCl3): δ ) 1.40 (m, 2H); 1.84 (m, 1H); 2.16 (m, 3H); 2.62 (t, 1H, J )
10.5 Hz); 2.83 (m, 1H); 3.44 (m, 1H); 3.92 (s, 3H); 4.35 (t, 1H, J ) 7.4
Hz); 4.91 (d, 1H, J ) 3.8 Hz); 4.98 (d, 1H, J ) 2.0 Hz); 5.12 (m, 1H);
5.50 (m, 1H); 6.24 (d, 1H, J ) 13.6 Hz); 6.95 (d, 1H, J ) 13.6 Hz); 7.05
(d, 1H, J ) 5.1 Hz); 7.24-7.65 (m, 5H); 7.71 (d, 1H, J ) 2.5 Hz); 7.83 (d,
1H, J ) 8.2 Hz); 7.90-8.05 (m, 4H); 8.37 (s, 1H); 8.52 (d, 1H, J ) 8.8
Hz); 8.58 (d, 1H, J ) 4.5 Hz); 9.08 (d, 1H, J ) 9.0 Hz). 13C NMR
(CDCl3): δ ) 22.6; 25.4; 25.8; 38.3; 52.4; 56.3; 56.9; 61.0; 65.9; 70.8;
112.0; 117.6; 118.0; 120.9; 120.95; 123.9; 124.9; 125.6; 125.8; 126.3; 127.8;
128.5; 128.8; 129.8; 130.8; 131.1; 131.8; 132.0; 132.8; 133.2; 136.5; 143.5;
144.3; 147.5; 158.0. IR (cm-1): 3014; 2952; 2398; 1620; 1509; 1471; 1450;
in the field of asymmetric phase-transfer catalysis using
derivatives of Cinchona alkaloids.9,10
We have tested the following chiral catalysts (Table 1),
the structures of which are shown in Figure 2.
1428; 915. MS (FAB+): 515 (M•+); 325; 191; 136. Mp: 190 °C dec. [R]20
D
) -415 (c ) 0.8, CHCl3). Anal. Calcd: C, 76.28; H, 6.40; N, 5.08.
Found: C, 75.98; H, 6.44; N, 5.36.
(4) Hill, R. K.; Edwards, A. G. Tetrahedron 1965, 21, 1501.
(5) Ets Roure-Bertrand Fils & Justin Dupont SA, no. US3978108, filed
the 12/17/71. Hasegawa K. K, no. JP224916, filed the 10/11/85. Firmenich
SA, no. CH96/2, 750, filed the 11/07/96. Firmenich SA, no. WO96/00206,
filed the 21/06/95. Firmenich SA, no. US5874600, filed the 07/10/97.
Firmenich SA, no. WO/9800776, filed the 05/19/98. See also: Dobbs, D
A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch, V.; Lenoir, J. Y.; Geneˆt,
J. P.; Wiles, J.; Bergens, S. H. Angew. Chem., Int. Ed. 2000, 39, 1992.
(6) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2000, 39, 569.
(7) The enone is commercially available from Aldrich and can also be
synthesized using Rhoˆne Poulenc Industrialisation procedure.
(8) Krapcho, A. P. Synthesis 1982, 805. Krapcho, A. P. Synthesis 1982,
893.
(11) Potassium carbonate can be replaced by either rubidium and cesium
carbonate or by Schwesinger’s bases as well as potassium tert-butoxide;
on the other hand, lithium or sodium carbonate and potassium hydrogen
carbonate failed to promote the reaction.
(12) The excess of dimethyl malonate was removed and easily recycled
by simple distillation after workup. Methyl 1-carboxymethyl-1-((1R,2S)-
2-pentyl-3-oxocyclopentyl)acetate ((+)-4): To a solution of 0.10 g of enone
3 (0.66 mmol, 1 equiv) in 2.50 mL of methyl malonate (20 mmol, 30 equiv),
40.2 mg of catalyst 8 (0.07 mmol, 0.11 equiv), and 12.4 mg of potassium
carbonate (0.09 mmol, 0.14 equiv) were successively added. After magnetic
stirring at -20 °C for 43 h, the reaction mixture was diluted with 20 mL
of diethyl ether. The organic layer was washed successively by 2 × 5 mL
of aqueous HCl (0.1 N), by 5 mL of water and 2 × 5 mL of brine. The
2960
Org. Lett., Vol. 2, No. 19, 2000

ee. Entries 5-7 showed that the best conditions of temper-
ature were about -20 °C. Entries 7-11 clearly demonstrated
that the benzyl group (catalyst 9) is less efficient than the
N-9-methylanthracenyl group and that the cinchonidine
derivative (catalyst 5) is less selective than quinine derivative
(catalyst 8). We also observed the pseudoenantiomeric effect
when testing the N-alkylated quinidinium catalyst 7 in the
reaction, compared to the stereoselectivity of the N-alkylated
quininium catalyst 8. Nevertheless, yield and ee were slightly
lower. When the oxygen atom was protected with an allyl
group (catalyst 6, Corey’s catalyst), no reaction took place.
As previously assumed,14 we believe that a free hydroxyl
function on the alkaloid is directly involved in the reactivity
of the catalytic system.
Regarding the mechanism of asymmetric induction, we
believe that the three-dimensional arrangement of the catalyst
is similar to the conformation described by Corey.9 Accord-
ing to this hypothesis, the bulky substituents (N-9-anthracenyl
and 6-methoxyquinoline) block two of the accessible faces
to the ammonium ion and limit the area for the positioning
of the dimethyl malonate anion. Thus, the approach of the
electrophile could be directed by three criteria:
(1) hydrogen bonding between the free hydroxyl function
of the catalyst and the carbonyl function of the electrophile,
as indicated by the unreactivity of the O-allylated catalyst
(Table 1, entry 8).
(2) van der Waals interactions between the methoxy group
of the catalyst and the electron-deficient carbon atom of the
polarized enone. The lack of methoxy group in the cinchoni-
dine series thus explains the decrease in asymmetric induction
(Table 1, entry 7).
(3) Steric interactions between the 6-methoxyquinoline and
N-9-anthracenyl groups of the catalyst with the pentyl chain
of the electrophile 3. N-Benzyl catalyst 9 is thus less selective
(Table 1, entry 11), and the use of 2-cyclopenten-1-one as
electrophilic reagent gave only 50% ee (91% yield). For this
Figure 2. Structures of the catalysts.
of the reagent and the liquid organic phase. The use of an
additional solvent (dichloromethane, diethyl ether, methyl
tert-butyl ether, toluene, or THF) totally inhibited the Michael
addition. Solid-liquid asymmetric phase-transfer catalysis
has been previously studied by Loupy et al., who showed
that both chemical yield and enantiomeric excess could be
increased under such conditions.13
(13) Loupy, A.; Sansoulet, J.; Zaparucha, A.; Merienne, C. Tetrahedron
Lett. 1989, 30, 333. Loupy, A.; Bram, G.; Sansoulet, J. New J. Chem. 1992,
16, 233. Loupy, A.; Zaparucha, A. Tetrahedron Lett. 1993, 34, 473. Mirza-
Aghayan, M.; Etemad-Moghadam, G.; Zaparucha, A.; Berlan, J.; Loupy,
A.; Koenig, M. Tetrahedron: Asymmetry 1995, 6, 2643.
(14) Colonna, S.; Annunziata, R. Afinidad 1980, 38, 501. Loupy, A.;
Bram, G.; Sansoulet, J. New. J. Chem. 1992, 16, 233.
(15) (+)-Methyl dihydrojasmonate((+)-1): (trans-methyl ((1S,2S)-2-
pentyl-3-oxocyclopentyl)acetate): To 3 mL of DMSO were added 0.15 g
of (+)-4 (0.53 mmol, 1 equiv) and 10 µL of distilled water (0.55 mmol,
1.05 equiv). The mixture was stirred for 5 h at 190 °C with a previously
heated mineral oil bath. At room temperature, the reaction mixture was
poured into 40 mL of ethyl ether. The organic layer was washed with 3 ×
5 mL of water, 5 mL of brine, dried over anhydrous magnesium sulfate
and concentrated. Traces of DMSO were removed under reduced pressure
and residual oil was flash-chromatographed on silica gel (eluant: heptane
80/diethyl ether 20) to give 0.07 g of a colorless oil (60% yield). 1H NMR
(CDCl3): δ ) 0.84 (t, 3H, J ) 6.5 Hz); 1.10-1.60 (m, 9H); 1.75 (m, 1H);
2.00-2.40 (m, 5H); 2.60 (qn, 1H, J ) 10.4 Hz); 3.67 (s, 3H). 13C NMR
(CDCl3): δ ) 13.9; 22.3; 26.2; 27.1; 27.6; 32.0; 37.6; 37.9; 38.8; 51.5;
54.1; 172.5; 219.6. IR (cm-1): 2960; 2928; 1737; 1436; 1195; 1168. GC/
SM(EI): 226 (M•+); 195; 156; 109; 96; 83; 67; 55. Bp: 108 °C (0.3 mm
Hg). GC on chiral column (Supelco â-dex 120 (15 m/0.25 mm) 1.3 mL‚
min-1): 34.40 and 34.63 min and measurements of optical rotations clearly
showed that the reaction occurred without any racemization, as checked
on several samples starting with variously enriched (+)-4 and (-)-4 (lit.
Entries 1-5 (Table 1) clearly showed that increasing the
amount of dimethyl malonate up to 30 equiv increased the
organic layer was then dried over anhydrous magnesium sulfate, filtered,
and evaporated. The crude pale yellow oil was distilled in a bulb-to-bulb
apparatus (Kugelrohr distillation) to remove and recycle methyl malonate.
Finally, flash chromatography on silica gel (eluant: heptane 70/diethyl ether
30) of the crude residue yielded 0.17 g (91%) of a colorless oil (after a
treatment with charcoal). 1H NMR (CDCl3): δ ) 0.80 (t, 3H, J ) 6.7 Hz);
1.10-1.75 (m, 9H); 1.90-2.35 (m, 4H); 2.50-2.65 (m, 1H); 3.45 (d, 1H,
J ) 7.3 Hz); 3.70 (s, 6H). 13C NMR (CDCl3): δ ) 13.9; 22.4; 24.4; 25.8;
28.3; 31.9; 37.2; 40.2; 52.0; 52.4; 54.4; 168.3; 218.9. IR (cm-1): 2920;
1736; 1436; 1140. GC/SM(EI): 284 (M+•); 214; 153; 133; 109; 100; 95;
83; 69; 55. Bp: 127 °C (0.3 mmHg). 1H NMR (CDCl3 + 80% mol Pr-
(hfc)3) of methyl ester: 3.30 (s, integration: 5 mm); 3.18 (s, integration:
86 mm); 3.00 (s, integration: 86 mm); 2.93 (s, integration: 5 mm). 90%
(( 2%) ee. [R]20 ) +19.7 (c ) 3.0, CHCl3). HPLC on chiral column
[R]20 ) +33.8 (c ) 0.9, CHCl3) Demole, E.; Lederer, E.; Mercier, D.;
D
D
CHIRALCEL OD (eluant: heptane 99/IPA 1; detection UV, λ ) 226 nm;
rate: 0.55 mL‚min-1): 32.53 and 35.15 min (90% ee). Anal. Calcd for
C15H24O5: C, 63.36; H, 8.51. Found: C, 63.58; H, 8.77.
HelV. Chim. Acta 1962, 45, 675. Cross, B. E.; Webster, G. R. B.; J. Chem.
Soc. C 1970, 1839). Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found:
C, 68.64; H, 9.98.
Org. Lett., Vol. 2, No. 19, 2000
2961

reason, we believe the enone 3 has few possible alternative
orientations to fit in the catalyst. The most likely approach
is shown in the Figure 3.
onate. In this case, the Re face of the prochiral enone 3 is
more accessible for the nucleophilic attack of dimethyl
malonate. It leads to compound (+)-4 with the observed
absolute configuration (1R,2S).
Finally, having in hand compound 4 highly enantiomeri-
cally enriched, we achieved the synthesis of both enantiomers
of methyl dihydrojasmonate 1 using the Krapcho procedure
(Scheme 1). We observed no racemization during this
demethoxycarbonylation step, as confirmed by optical rota-
tions and GC analyses of compounds (+)-1 and (-)-1.15
Moreover, this chemical correlation allowed us to assign the
absolute configuration of the stereogenic centers of enanti-
omers (+)-4 and (-)-4.
In conclusion, this solid-liquid asymmetric phase-transfer
catalytic process constitutes a new and efficient method for
access to both enantiomers of methyl dihydrojasmonate 1.
The main advantages of this procedure are the following:
(1) the asymmetric Michael addition is solvent free. (2) Two
contiguous stereogenic centers are built in the same step on
the electrophilic substrate. (3) High enantioselectivities are
reached even though no stereogenic center is created on the
nucleophilic reagent (a common requirement for high enan-
tioselection).16 (4) There is convenient access to both
enantiomers of methyl dihydrojasmonate starting from the
same precursor, taking advantage of the pseudoenantiomeric
effect of Cinchona derivatives.
Figure 3. Model of asymmetric induction.
The hydrogen bonding ensures the proximity of the
reactive centers and significantly stabilizes the model. The
putative transition-state assembly shown in the Scheme 3
can explain the enantioselective addition of dimethyl mal-
Scheme 3
Extension of the method to other prochiral enones is in
progress.
OL006207E
(16) For a recent related example of highly enantioselective Michael
reaction, see: Zhang, F.-Y.; Corey, E. J. Org. Lett 2000, 2, 1097.
2962
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