A short enantioselective synthesis of (R)-(+)-γ-jasmolactone

Article abstract of DOI:10.1081/SCC-120039490

(R)-(+)-γ-Jasmolactone (1b) was synthesized in 92%ee in two steps, starting from the easily prepared (S)-(-)-3-(5-oxo-tetrahydro-furan-2-yl)- propionic acid benzyl ester (2). The key step features an inversion of configuration of the stereogenic center.

Full text of DOI:10.1081/SCC-120039490

This article was downloaded by: [McGill University Library]
On: 04 December 2012, At: 13:24
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Short Enantioselective
Synthesis of
(R)‐(+)‐γ‐Jasmolactone
Giuliano C. Clososki a , Lauri J. Missio a & João V.
Comasseto a
a Instituto de Química, Universidade de São Paulo,
C.P. 26077, São Paulo, 05599‐070, SP, Brazil
Version of record first published: 10 Jan 2011.
To cite this article: Giuliano C. Clososki, Lauri J. Missio & João V. Comasseto
(2004): A Short Enantioselective Synthesis of (R)‐(+)‐γ‐Jasmolactone, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:13, 2371-2377
To link to this article: http://dx.doi.org/10.1081/SCC-120039490
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to

date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or
damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2371–2377, 2004
A Short Enantioselective Synthesis of
(R)-(1)-g-Jasmolactone
*
Giuliano C. Clososki, Lauri J. Missio, and Joa˜o V. Comasseto
´
Instituto de Quımica, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
ABSTRACT
(R)-(þ)-g-Jasmolactone (1b) was synthesized in 92% ee in two steps,
starting from the easily prepared (S)-(2)-3-(5-oxo-tetrahydro-furan-
2-yl)-propionic acid benzyl ester (2). The key step features an inversion
of configuration of the stereogenic center.
Key Words: g-Jasmolactone; Enantioselective synthesis; Stereogenic
center; Column chromatography.
INTRODUCTION
Recently, we reported the first enantioselective synthesis of (S)-(2)-g-
jasmolactone (1a).[1] This compound and its antipode (R)-(þ)-g-jasmolactone
*
´
Correspondence: Joa˜o V. Comasseto, Instituto de Quımica, Universidade de Sa˜o
Paulo, C.P. 26077, Sa˜o Paulo 05599-070, SP, Brazil; Fax: þ55(11)3815-5579;
E-mail: jvcomass@iq.usp.br.
2371
DOI: 10.1081/SCC-120039490
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2372
Clososki, Missio, and Comasseto
(1b) present important organoleptic properties, described as fruity, flowery,
green, creamy, sweet, and juicy.[2a,b] The properties confer to g-jasmolactone
a practical importance, and several patents are dedicated to its synthesis and
industrial use.[2] Biologically active natural products are nowadays syn-
thesized enantioselectively since their physiological activities often depend
on the configuration of the stereogenic center present in its structure.[3] In
the case of jasmolactones (1), it was reported that (R)-(þ)-g-jasmolactone
(1b) is more intense and its flowery note is sweeter than that of (S)-(2)-g-
jasmolactone (1a).[2b] In view of this fact, we decided to synthesize
(R)-(þ)-g-jasmolactone using the same chiral g-butyrolactone 2 used to syn-
thesize 1a,[1] according to the retrosynthetic analysis shown in Sch. 1. Com-
pound 2 was prepared some time ago by Gutman and coworkers[4a] in good
yields and enantiomeric excess starting from the commercially available
4-ketopimelic acid (3). (4-Ketopimelic acid and their corresponding esters
can also be prepared by an organic synthesis procedure: see Ref.[4b].) The
preparation of 2 features an enantiolactonization promoted by porcine pig
pancreatic lipase (PPL), which gave 2 in c.a. 95% ee.[1,4a] The bifunctional
nature of this chiral block transforms it into an attractive precursor of chiral
g-butyrolactones, which are flavor components[2b] and sex attractant phero-
mones.[5] In spite of this potential versatility, to our knowledge, this precursor
of chiral g-butyrolactones has not been intensively employed in enantioselec-
tive synthesis of natural g-butyrolactones.
Scheme 1.

Enantioselective Synthesis of (R)-(1)-g-Jasmolactone
2373
RESULTS AND DISCUSSION
Our synthetic approach to 1 shows that compound 2 can be used as a chiral
precursor to both R- and S-g-butyrolactones. The S antipode of g-jasmolactone
(1a) was prepared in our previous work[1] by transformation of the ester function
of (S)-(þ)-2 into an aldehyde, followed by a Wittig olefination with triphenyl-
propylidenephosphorane. In this way, the integrity of the stereogenic center
was preserved and the product was (S)-(2)-jasmolactone (1a).[1]
In the present work, we performed a selective reduction of the lactone
group of 2 maintaining the ester group intact. This transformation was achieved
by reaction of 2 with a slight excess of DIBAL-H in THF at 2788C. This
reagent promotes the transformation of esters into aldehydes through the
respective hemiacetals.[6]
Reduction of lactones with the same reagent leads to the corresponding
lactols.[6,7] Careful control of the reaction conditions allows for the selective
transformation of a lactone into a lactol without reduction of the ester group.[8]
In the present case, lactol 4 was obtained in 71% yield as a colorless oil, which
presented an optical rotation of þ15.9 (Sch. 2). This reaction promotes a
change in the priority order of the substituents around the stereogenic center,
which becomes R.
Since compound 4 showed to be unstable, it was reacted with an excess of
triphenylpropylidenephosphorane in DMSO at room temperature immediately
after purification. The first equivalent of the phosphorane probably opens the
lactol ring by a proton abstraction of the lactol OH, leading to the aldehyde
intermediate 5 (Sch. 3). Then, a Wittig reaction with a second equivalent
of triphenylpropylidenephosphorane transforms the aldehyde into an olefine,
and the alkoxy oxygen at C4 promotes a transesterification reaction of the ben-
zylester group generating the lactone ring of 1b. This sequence of reactions led
to (R)-(þ)-jasmolactone (1b) as an 89 : 11 mixture of Z : E isomers, which
were separated by column chromatography on silica gel impregnated with
AgNO3, eluting with hexane : ethyl acetate (7 : 3). The enantiomeric excess
of the final product 1b (92%) was determined by means of chiral gas
chromatography.
Compound 1b presented an intense and persistent odor of peaches, and its
spectral data were identical to those of compound 1a.[1] The specific rotation
Scheme 2.

2374
Clososki, Missio, and Comasseto
Scheme 3.
of 1b was þ39.07, opposite to the observed one for compound 1a (2 39.63),[1]
which led us to attribute the R-configuration to the stereogenic center of 1b. In
addition, the signs of rotation determined for compounds 1a and 1b in this
work agree with those reported in the literature, respectively, for (S) and
(R)-g-jasmolactone.[2b] To the best of our knowledge, this is the first enantio-
selective synthesis of (R)-(þ)-g-jasmolactone.[9] (The biogeneration of (R)-Z-
7-decen-4-olide (1b) from linolenic acid by the action of Pichia stipitis and
ohmeri was reported. Compound 1b was formed along with a number of
other compounds. A kinetic resolution of racemic g-jasmolactone by lipases
gave (þ)-(R)-g-jasmolactone and (2)-(S)-g-jasmolactone in 60% and
66% ee, respectively, as described in Ref.[2b].)
In conclusion, we have described the first enantioselective synthesis of
(R)-(þ)-g-jasmolactone (1b), using the same chiral building block used to
synthesize (S)-(2)-g-jasmolactone (1a). This fact demonstrated that com-
pound 2 is a versatile building block for the enantioselective synthesis of
both enantiomers of naturally occurring g-butyrolactones.
EXPERIMENTAL
The NMR spectra were recorded on a Brucker DRX-500 spectrometer,
using TMS (1H NMR) and the central peak of the CDCl3 signal (13C NMR)
as internal reference. IR spectra were obtained with an FTIR BOMEM
MB100 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 mm) and on a Shimadzu
GC-17A instrument equipped with a CHIRASIL-DEX CD (CROMPACK)
chiral phase capillary column (30 m ꢀ 0.25 mm ꢀ 0.25 mm). The mass spec-
tra were performed on Shimadzu GC-17A/QP5050A spectrometer. Optical
rotations were measured on a JASCO, DIP 370 digital polarimeter. The

Enantioselective Synthesis of (R)-(1)-g-Jasmolactone
2375
enzymatic reactions were monitored in a Shimadzu LC10AD HPLC. (S)-(2)-
3-(5-Oxo-tetrahydro-furan-2-yl)-propionic acid benzyl ester (2) was prepared
as described previously.[1,4a]
R-(1)-3-(5-Hydroxy-tetrahydro-furan-2-yl)-propionic acid benzyl
ester (4). (S)-(2)-3-(5-Oxo-tetrahydro-furan-2-yl)-propionic acid benzyl
ester (2) (1.71 g, 6.90 mmol, 92% ee by HPLC[1]) was dissolved in dry THF
(48 mL) and then DIBAL-H (1 M solution in hexane, 7.18 mL, 7.18 mmol)
at 2788C under N2 was added dropwise. After 2 hr of stirring at the same
temperature, the reaction mixture was quenched with a saturated potassium
sodium tartrate solution (15 mL) and it was vigorously stirred for 3 hr at
room temperature. The organic layer was separated, and the aqueous layer
was extracted with diethyl ether, dried with MgSO4, and concentrated in
vacuum. The crude product was purified by silica gel column chromatography
eluting with diethyl ether : hexane (1 : 1). Yield: 1.22 g (71%). 1H NMR
(500 MHz, CDCl3): d (ppm) 1.49–2.20 (m, 6H); 2.30–2.38 (m, 2H); 4.01–
4.28 (m, 1H); 5.12–5.13 (m, 2H); 5.41–5.49 (m, 1H); 7.26–7.36 (m, 5H).
13C NMR (125 MHz, CDCl3): d (ppm). 8–34, 65, 77–80, 97, 130–140,
173–174. IR (KBr) (cm21): 3417, 2945, 1728. MS (m/z) (% rel.): 91 (100),
107 (16), 114 (81), 248 (7) (Mþ 2 2). Anal. calcd for C14H18O4: C, 67.18;
H, 7.25. Found: C, 66.65; H, 7.08. [a]2D0 ¼ þ15.9 (c ¼ 0.79, CH2Cl2).
R-(1)-Jasmolactone (1b). Sodium hydride as a 60% dispersion in
mineral oil (0.042 g, 1.05 mmol) was washed with several portions of dry hexane
in a nitrogen atmosphere and then suspended in dry DMSO (4 mL). The
mixture was slowly heated to 758C with efficient stirring in order to keep
hydrogen gas evolution under control. After the gas evolution stopped, stirring
was continued at 758C for 10 min, and then the solution was cooled to room
temperature. This solution was slowly added to a solution of triphenylpropyl
phosphonium bromide (0.39 g, 1 mmol) dissolved in dry DMSO (4 mL). An
exothermic reaction occurred leading to a deep-red solution. After stirring
for 15 min at room temperature, compound 4 (0.122 g, 0.49 mmol) in dry
DMSO (0.5 mL) was added and the stirring was continued for 2 hr. The reac-
tion mixture was quenched with saturated NH4Cl solution. The organic layer
was separated, and the aqueous layer was extracted with diethyl ether, dried
with MgSO4, and concentrated in vacuum. The crude product was purified
by silica gel column chromatography eluting with ethyl acetate : hexane
(7 : 3). Yield: 0.068 g (82%) Z/E ¼ 89 : 11. The isomers were separated by
silver nitrate impregnated silica gel column chromatography eluting with
ethyl acetate : hexane (3 : 7). 1H NMR (500 MHz, CDCl3): d (ppm) 0.96
(t, J ¼ 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, 2H); 4.50
(dddd, J ¼ 8.12 Hz, J ¼ 6.76 Hz, J ¼ 6.65 Hz, J ¼ 5.17 Hz, 1H); 5.31 (dtt,
J ¼ 10.75 Hz, J ¼ 7.29 Hz, J ¼ 1.54 Hz, 1H); 5.43 (dtt, J ¼ 10.75 Hz,

2376
Clososki, Missio, and Comasseto
J ¼ 7.29 Hz, J ¼ 1.54 Hz, 1H). 13C NMR (125 MHz, CDCl3): d (ppm)
14.0, 20.2, 22.7, 27.7, 28.5, 35.3, 80.1, 126.9, 132.7, 177.0. IR (KBr)
(cm21): 2937; 1775. MS (m/z) (%rel.): 68 (100), 85 (40.9), 108 (11.4), 168
(Mþ). [a]2D0 ¼ þ 39.07 (c ¼ 0.28, CH2Cl2). All the analytical data agree
with those of racemic 1 and with those of the S-(2)-jasmolactone, except
the sign of rotation, which is the opposite of the observed one for (2)-1a.[1]
Enantiomeric Purity
The enantiomeric excess of (R)-(þ)-g-jasmolactone (92%) was deter-
mined by carefully adjusting the analysis parameters of the gas chromatograph
equipped with a CHIRASIL-DEX CD (CROMPACK) chiral phase capillary
column. Chiral separations were performed using the following gradient
temperature program: 908C (20 min)–1208C (30 min) at 18C/min gradient.
Carrier gas flow (H2) was 3.9 mL/min. The injector and detector temperatures
were maintained at 2508C and 2708C, respectively.
ACKNOWLEDGMENTS
G. C. Clososki and L. J. Missio thank FAPESP for fellowships. J. V.
Comasseto thanks FAPESP, CNPq, and CAPES for support.
REFERENCES
1. Missio, L.J.; Comasseto, J.V. Enantioselective Synthesis of (2)-g-Jasmo-
lactone. Tetrahedron: Asymmetry 2000, 11, 4609 (and references therein)
(Corrigenda—Tetrahedron: Asymmetry 2003, 14, 145).
2. (a) Vlas, A. Flavouring Composition Containing g-Jasmolactone, the Use
of Such a Flavouring Composition of g-Jasmolactone per se for Flavour-
ing Foodstuffs as well as the Flavoured Foodstuffs Obtained. EP0473842-
A1, 1992; (b) Bourdineaud, J.P.; Ehret, C.; Petrzilka, M. Optically Active
Lactones. International Patent WO94/07887, 1994; (c) Saito, T.;
Unno, Y.; Inai, T.; Arai, S. Flavor Enhancer for Fermented Food and
Drink. JP2001112431-A2, 2001; (d) Takagi, K.; Masamishi, I. Production
of cis-7-decen-4-olide. JP02282377-A2, 1990; (e) Takagi, K.; Katsuta, Y.;
Yamamoto, N. Production of cis-7-decen-4-olide. JP02282376-A2, 1990.
3. (a) Sheldon, R.A. Chirotechnology: Industrial Synthesis of
Optically Active Compounds; Marcel Dekker: New York, 1993;
(b) Trost, B.M. Stereocontrolled Organic Synthesis; Oxford: Cambridge,

Enantioselective Synthesis of (R)-(1)-g-Jasmolactone
2377
1994; (c) Yamamoto, T.; Ogura, M.; Amano, A.; Adachi, K.; Haginara, T.;
Kanisawa, T. Synthesis and odor of optically active 2-n-hexyl- and 2-n-
heptylcyclopentanone and the corresponding d-lactones. Tetrahedron
Lett. 2002, 43, 9081.
4. (a) Gutman, A.L.; Bravdo, T. Enzyme-catalyzed enantioconvergent lacto-
nization of g-hydroxy diesters in organic solvents. J. Org. Chem. 1989,
54, 4263; (b) Emerson, W.S.; Longley, R.I., Jr. Diethyl g-oxopimelate.
Org. Synth. Coll. 1963, 4, 302.
5. (a) Leal, W.S.; Kuwahara, S.; Ono, M.; Kubota, S. (R,Z)-7,15-Hexadeca-
dien-4-olide, sex pheromone of the yellowish elongate chafer, Hepto-
phylla picea. Bioorg. Med. Chem. 1996, 4, 315; (b) Tumlinson, J.H.;
Klein, M.G.; Doolittle, R.E.; Ladd, T.L.; Proveax, A.T. Identification of
female Japanese beetle sex-pheromone—inhibition of male response by
an enantiomer. Science 1977, 197, 789; (c) Mori, K. Organic synthesis
and chemical ecology. Acc. Chem. Res. 2000, 33, 102.
6. Seyden-Pene, J. Reductions by the Alumino and Borohydrides in Organic
Synthesis; VCH Publishers: Chicago, 1991.
¨
7. Wyss, von H.; Vogeli, U.; Scheffold, R. Stereoselective hydride reduction
of tetronic acid derivatives—synthesis of branched chain tetrofuranoses.
Helv. Chim. Acta 1981, 64, 775.
8. Kido, F.; Tsutsumi, K.; Maruta, R.; Yoshikoshi, A. Lactone annulation of
b-keto esters with b-vinylbutenolide and the total synthesis of racemic
frullanolide. J. Am. Chem. Soc. 1979, 101, 6420.
9. Fuganti, C.; Grasselli, P.; Zucchi, G.; Allegrone, G.; Barbeni, M. On the
microbial biogeneration of (R)-g-jasmolactone. Bioorg. Med. Chem. Lett.
1993, 3, 2777.
Received in the USA March 2, 2004