Enantioselective synthesis of (-)-γ-jasmolactone

Article abstract of DOI:10.1016/S0957-4166(00)00444-4

The title compound was prepared in seven steps starting from the commercially available 4-ketopimelic acid. The key step features an enantioselective lactonization promoted by PPL.

Full text of DOI:10.1016/S0957-4166(00)00444-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4609–4615
Enantioselective synthesis of (−)-g-jasmolactone
Lauri J. Missio and J. Valdir Comasseto*
Instituto de Qu´ımica, Universidade de Sa˜o Paulo, C. P. 26077, 05599-070 Sa˜o Paulo SP, Brazil
Received 26 October 2000; accepted 31 October 2000
Abstract
The title compound was prepared in seven steps starting from the commercially available 4-ketopimelic
acid. The key step features an enantioselective lactonization promoted by PPL. © 2000 Published by
Elsevier Science Ltd.
1. Introduction
The g-butyrolactone backbone is present in a number of biologically active natural products.
Recent reports in the literature illustrate this fact.1 The physiological activity of such lactones
often depends on the configuration of the stereogenic centers present in their structure.2–6
According to a patent7 the organoleptic properties of g-jasmolactone (Z-7-decen-4-olide) 1 are
described as fruity, flowery, green, creamy, sweet and juicy. This compound has an association
with peaches and tropical fruits and can enhance the fruit flavor in food stuffs or drinks.7
Several syntheses of 1 were described in the literature,8–12 however, none of them were
enantioselective. In 1993, Fuganti et al. reported that (R)-1, obtained from linolenic acid by
action of Pichia stipitis and ohmeri, was identified as one of the main aroma constituents of
white peaches.13 In that work it was only mentioned that the (S)-1 isomer was a minor
constituent of the mixture.
As part of an ongoing program on the enantioselective synthesis of g-butyrolactones in course
in our laboratory, we devised the synthesis of (S)-1 according to the retrosynthetic analysis
shown in Scheme 1.
* Corresponding author. E-mail: jvcomass@iq.usp.br
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00444-4

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Scheme 1.
2. Results and discussion
Initially we synthesized racemic 1 in four steps, starting from the commercially available
4-ketopimelic acid 2. Reduction of the keto group of 2 with sodium borohydride gave lactone
3 on acidic work up. Reduction of 3 with borane·dimethylsulfide (BMS) gave alcohol 4 which
was oxidized to aldehyde 5 by PCC. A Wittig olefination completed the sequence giving racemic
1 (Scheme 2).
Scheme 2. Reagents and conditions: (i) NaBH4, THF, 3 h, rt (90%); (ii) BMS, THF, 2 h, rt (92%); (iii) PCC, CH2Cl2,
2 h, rt (91%); (iv) C3H7PPh3Br, LHMDS, THF (55%)
(S)-1 was prepared according to Scheme 3. The key step was the synthesis of (S)-8 lactone,
which featured a lipase enantioselective lactonization of the prochiral diester 7.14 Compound 7
was prepared by benzylation of 2 followed by reduction of the keto group with sodium
borohydride. Lactone (S)-8 was obtained in 90% e.e. by pig pancreatic lipase (PPL) lactoniza-
tion of 7, as shown by chiral HPLC analysis. The (S) configuration of the stereogenic center of
lactone 8 was attributed by comparison of its specific rotation with the literature data.14 The
benzyl group of lactone 8 was hydrogenolysed by H2/Pd giving (S)-3. The measured specific
rotation for compound (S)-3 was compared with the published one,14 showing that racemization
did not occur. The compound was allowed to stand for 4 days at room temperature and the
specific rotation was measured again. No change was observed, showing that no racemization
occurred. Compound (S)-3 was submitted to BMS reduction followed by PCC oxidation to give
(S)-5. A Wittig olefination led to (S)-1. The enantiomeric excess of the final product (87%) was
determined by means of gas chromatography.
The Wittig olefination step gave (S)-1 as a 85:15 mixture of Z:E isomers which were separated
by column chromatography on silica gel impregnated with AgNO3,15 eluting with hexane:ethyl
acetate (7:3). The product is a colorless oil presenting an odor of peaches.
In conclusion, we have described the first enantioselective synthesis of the g-jasmolactone.
Using the common intermediate 7 the enantioselective syntheses of other g-butyrolactones are
underway in our group.

L. J. Missio, J. V. Comasseto / Tetrahedron: Asymmetry 11 (2000) 4609–4615
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Scheme 3. Reagents and conditions: (i) CsCO3, DMF/MeOH, pH 7.0, BnBr, 17 h, rt (84%); (ii) NaBH4, Et2O/MeOH,
2 h, −20°C (95%); (iii) PPL, Et2O, 24 h, 30°C (74%); (iv) Pd/C 10%, H2, 1 atm, 3 h (95%); (v) BMS, THF, 2 h, rt
(90%); (vi) PCC, CH2Cl2, 2 h, rt (90%); (vii) C3H7PPh3Br, LHMDS, THF, (55%)
3. Experimental
3.1. General
The NMR spectra were recorded on Bruker DRX-400, 500 and Varian FT-300 spectrometers
using TMS as internal reference (1H NMR) and the central peak of the CDCl3 signal (13C
NMR). IR spectra were obtained with a Perkin–Elmer 1600 grating infrared spectrophotometer.
The GC analyses were performed on a Hewlett–Packard 5890(II) instrument with a capillary
crosslinked 5% Ph-Me silicone column (25 m×0.20 mm×0.33 um) and with a chiral column
packed with b-cyclodextrin. The mass spectra were performed on GC-MS HP 5890/5988A.
Optical rotations were measured on a Jasco, DIP 370 Digital polarimeter. Enantiomeric excesses
were determined by chiral HPLC analysis with Shimadzu LC10AD.
3.2. 3-(5-Oxotetrahydro-2-furanyl)propanoic acid 3
4-Ketopimelic acid 2 (1.0 g; 5.74 mmol) was dissolved in dry THF (30 mL) and then sodium
borohydride (0.8 g; 24 mmol) was added. The mixture was stirred for 3 h at room temperature.
The solvent was evaporated and to the residue was added 8 M HCl (10 mL). The aqueous phase
was extracted with methylene dichloride (3×50 mL). The organic phase was dried with MgSO4
1
and the solvent was evaporated, giving pure 3. Yield: 0.816 g (90%). H NMR (400 MHz,
CDCl3): l (ppm) 1.86–1.95 (m, 1H); 1.97–2.06 (m, 2H); 2.36–2.44 (m, 1H); 2.53–2.60 (m, 4H);
4.59 (dddd, J=8.16 Hz, J=8.15 Hz, J=6.78 Hz, J=5.02 Hz, 1H); 10.67 (sl, 1H); 13C NMR
(100 MHz, CDCl3): l (ppm) 177.5; 177.2; 79.8; 30.2; 29.8; 28.4; 27.5; IR (KBr) (cm−1): 3489;
2933, 1768; 1727; MS: (m/z) (%rel.): 44 (51.8); 85 (100); 98 (0.4); 112 (1.1).

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3.3. 3-(5-Hydroxypropyl)tetrahydro-2-furanone 4
In a three necked flask, under nitrogen, compound 3 (2.12 g; 13.44 mmol) was dissolved in dry
THF (90 mL). Then BH3·SMe2 (1.61 mL; 16.12 mmol, c=10 M) was added via a syringe. The
mixture was allowed to stir at room temperature for 2 h. Then methanol (30 mL) was added and
distilled afterwards. The residue was dissolved in methanol (10 mL), dried with MgSO4, the
solvent was evaporated and the residue was purified by silica gel column chromatography
1
eluting with ethyl acetate. Yield: 1.78 g (92%). H NMR (400 MHz, CDCl3): l (ppm) 1.63–1.94
(m, 5H); 2.32–2.46 (m, 1H); 2.53–2.57 (m, 2H); 3.65 (t, J=5.45 Hz, 2H); 4.56 (dddd, J=7.58
Hz, J=7.05 Hz, J=6.50 Hz, J=5.41 Hz, 1H); 13C NMR (100 MHz, CDCl3): l (ppm) 177.8;
81.2; 61.8; 32.0; 28.9; 28.4; 28.0; IR (KBr) (cm−1): 3464; 2938, 1763; MS: (m/z) (%rel.): 31 (88.2);
44 (70.3); 60 (5.1); 85 (100); 113 (1.6).
3.4. 3-(5-Oxotetrahydro-2-furanyl)propanal 5
PCC (0.621 g, 2.76 mmol) and sodium acetate (0.044 g; 0.52 mmol) were dissolved in dry
CH2Cl2 (10 mL). Then alcohol 4 (0.2 g; 1.38 mmol), dissolved in dry CH2Cl2 (5 mL), was added.
The initially yellow solution turned brown and was stirred for 2 h at room temperature. Then
the solution was filtered through a column containing Celite and activated charcoal. The solvent
1
was evaporated and the residue was used without purification. Yield: 0.18 g (91%). H NMR
(400 MHz, CDCl3): l (ppm) 1.83–1.96 (m, 2H); 2.01–2.09 (m, 1H); 2.33–2.42 (m, 1H); 2.53–2.58
(m, 2H); 2.67–2.71 (m, 2H); 4.54 (dddd, J=9.36 Hz, J=8.32 Hz, J=6.65 Hz, J=4.14 Hz, 1H);
9.82 (t, J=0.95 Hz, 1H); 13C NMR (100 MHz, CDCl3): l (ppm) 200.8; 176.8; 79.5; 39.7; 30.4;
28.6; 27.7; IR (KBr) (cm−1): 2948, 1765; 1720; MS (m/z) (%rel.): 41 (61.6); 56 (58.9). 85 (100);
98 (23.3); 114 (15.1).
3.5. ( )-k-Jasmolactone 1
To a suspension of propyltriphenyl phosphonium bromide (0.51 g; 1.25 mmol) in dry THF (2
mL) was added lithium bis(trimethylsilyl)amide (LHMDS) (1.5 mL; 1.5 mmol). The resulting
purple solution was stirred for 10 min at 0°C and the aldehyde 5 (0.142 g; 1.1mmol), dissolved
in dry THF (2 mL), was added. The THF was evaporated and the residue was dissolved with
ethyl acetate (3×30 mL). The organic phase was washed with ammonium chloride solution and
brine, dried with MgSO4 and evaporated. The residue was purified by silica gel column
1
chromatography eluting with hexane:ethyl acetate (7:3). Yield: 0.082 g (55%). H NMR (400
MHz, CDCl3): l (ppm) 0.96 (t, J=7.56 Hz; 1H); 1.61–1.68 (m, 1H); 1.76–1.91 (m, 2H);
2.02–2.08 (m, 2H); 2.17–2.21 (m, 2H); 2.30–2.36 (m, 1H); 2.52–2.55 (m, 1H); 4.50 (dddd; J=8.12
Hz; J=6.76 Hz; J=6.65 Hz; J=5.17 Hz; 1H); 5.31 (dtt; J=10.75 Hz; J=7.29 Hz; J=1.54 Hz,
1H); 5.43 (dtt; J=10.75 Hz; J=7.29 Hz; J=1.54 Hz, 1H); 13C NMR (100 MHz, CDCl3): l
(ppm) 177.0; 132.7; 126.9; 80.1; 35.3; 28.5; 27.7; 22.7; 20.2; 14.0; IR (KBr) (cm−1): 2936, 1775;
MS (m/z) (%rel.): 68 (100); 85 (40.9), 108 (11.4); 168 (M+).
The spectroscopic data are in agreement with those of the literature.2
3.6. Dibenzyl 4-ketoheptanoate 6
Compound 2 (0.82 g; 4.75 mmol) was dissolved in methanol:water (10:1) (22 mL). Then a 20%
aqueous solution of CsCO3 was added until pH 7.0. The solvents were evaporated under

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vacuum. DMF (2×50 mL) was added and distilled afterwards. Then dry DMF (50 mL) was
added under nitrogen. To the solution was added recently distilled benzyl bromide (1.24 mL;
10.45 mmol) and the mixture was stirred for 17 h. The solvent was evaporated and then aqueous
NaHCO3 (2×10 mL) was added. The aqueous phase was extracted with methylene dichloride
and dried with MgSO4. The product was used without further purification. Yield: 1.74 g (84%).
1H NMR (400 MHz, CDCl3): l (ppm) 2.64 (t, J=6.40 Hz, 4H); 2.77 (t, J=6.40 Hz, 4H); 5.10
(s, 4H); 7.30–7.37 (m, 10H); 13C NMR (100 MHz, CDCl3): l (ppm) 206.8; 172.5; 135.9; 128.6;
128.2; 66.5; 37.1; 28.0; IR (KBr) (cm−1): 2948, 1731; 1706; 1327; 625, 726.
3.7. Dibenzyl 4-hydroxyheptanodiate 7
Compound 6 (0.3 g; 1.3 mmol) was dissolved in a mixture of ether:methanol 4:1 (25 mL).
Sodium borohydride (0.05 g, 1.2 mmol) was added at −20°C. The reaction was monitored by
1
TLC eluting with ether:hexane (6:4) and by H NMR. After 2 h, 5% aqueous NaHCO3 (10 mL)
was added and the reaction mixture was extracted with cold ether (3×20 mL). The organic phase
was dried with MgSO4, evaporated and the residue was purified by silica gel chromatography
eluting with ether:hexane (6:4).
1
Yield: 0.29 g (95%). H NMR (200 MHz, CDCl3): l (ppm) 1.61–1.89 (m, 10H); 2.51 (t,
J=8.00 Hz, 4H); 3.63–3.69 (m, 1H); 5.30 (s, 4H); 7.22–7.48 (m, 10H); 13C NMR (50 MHz,
CDCl3): l (ppm) 173.7; 135.7; 128.4; 128.1; 70.1; 65.0; 32.1; 30.5; IR (KBr) (cm−1): 3454; 2931,
1733; 1497; 698, 747.
3.8. (S)-Dibenzyl 3-(5-oxotetrahydro-2-furanyl)propanoate 8
In a round bottomed flask compound 7 (0.117 g, 0.32 mmol) was dissolved in dry ether (3
mL) and then PPL (0.3 g) was added. The mixture was further stirred for 24 h at 30°C. The
reaction was monitored by TLC eluting with ether:hexane (6:4). The enzyme was filtered and the
product was purified by silica gel column chromatography eluting with ether:hexane (6:4).
1
Yield: 0.059 g (74%). H NMR (400 MHz, CDCl3): l (ppm) 1.81–1.92 (m, 1H); 1.94–2.07 (m,
2H); 2.30–2.38 (m, 1H); 2.49–2.58 (m, 4H); 4.53 (dddd, J=8.19 Hz, J=7.60 Hz, J=7.02 Hz,
J=5.27 Hz, 1H); 5.13 (s, 2H); 7.25–7.35 (m, 5H); 13C NMR (50 MHz, CDCl3): l (ppm) 176.5;
172.1; 135.5; 128.2; 128.0; 127.9; 79.2; 66.0; 30.2; 29.8; 28.3; 27.4; IR (KBr) (cm−1): 2929, 1773;
733; 699.
The enantiomeric excess of the lactone was determined by chiral HPLC. Stationary phase:
,
amylose tris[(S)-1-phenylethylcarbamate] coated onto APS-Nucleosil (500 A, 7 mm, 20% w/w);
mobile phase: [hexane:isopropanol (8:2)]; flow rate: 0.5 mL/min). The enantiomeric excess was
90%. The [h]D measured was compared with the published one: [h]2D5 found: −42.15 (c 0.74,
CH2Cl2), [h]2D5 literature:14 −40.86 (c 0.74, CH2Cl2).
3.9. (S)-3-(5-Oxotetrahydro-2-furanyl)propanoic acid 3
Compound (S)-8 (0.41 g, 1.64 mmol) was dissolved in MeOH (5 mL). Then Pd/C 10% (0.2
g) was added and the mixture was stirred under a H2 atmosphere for 3 h at room temperature.
The catalyst was filtered through silica gel and Celite. The solvent was evaporated and the
product was used without further purification. Yield: 0.245 g (95%). The spectral data are
identical to those observed for racemic 3 (Section 3.2) and are in agreement with those of the

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L. J. Missio, J. V. Comasseto / Tetrahedron: Asymmetry 11 (2000) 4609–4615
literature.14 The [h]D25 measured was compared with the published one: [h]2D5 found: −42.86 (c
0.77, H2O), [h]2D5 literature:14 −39.86 (c 0.77, H2O).
3.10. (S)-3-(5-Hydroxypropyl)tetrahydro-2-furanone 4
(S)-4 was prepared by a procedure similar to that described for racemic 4 (Section 3.3). The
spectral data agree with those of racemic 4 and are in agreement with those of the literature.14
3.11. (S)-3-(5-Oxotetrahydro-2-furanyl)propanal 5
(S)-5 was prepared by a procedure similar to that described for racemic 5 (Section 3.4). The
spectral data agree with those of racemic 5 and are in agreement with those of the literature.14
3.12. (S)-(−)-k-Jasmolactone 1
(S)-1 was prepared by a procedure similar to that described for racemic 1 (Section 3.5). The
spectral data agree with those of racemic 1. The enantiomeric excess (87%) was measured by
using a gas chromatograph equipped with a b-cyclodextrin (Supelco™) capillary column (30 m,
0.25 mm, i.d. 0.25 mm film thickness); the carrier gas was H2 set at 14 KPa column head pressure
and the column temperature program was 30 min at 100°C, 1°C min−1 to 180°C and held at
180°C for 20 min. The on-column injector and the detector were at 250 and 300°C, respectively.
[h]2D5: −22.35, c=0.85; CHCl3.
Acknowledgements
The authors thank FAPESP and CNPq for support.
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