The first asymmetric total synthesis of (R)-tuberolactone, (S)-jasmine lactone and (R)-δ-decalactone

Article abstract of DOI:10.1016/j.tetlet.2006.08.135

A general synthetic approach has been developed for the first asymmetric total synthesis of tuberolactone 1, jasmine lactone 2 and δ-decalactone 3. The key step is the selective hydrogenation of triple and endocyclic double bonds in the key intermediate 4.

Full text of DOI:10.1016/j.tetlet.2006.08.135

Tetrahedron Letters 47 (2006) 8179–8181
The first asymmetric total synthesis of (R)-tuberolactone,
(S)-jasmine lactone and (R)-d-decalactoneI
Gowravaram Sabitha,* V. Bhaskar and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 July 2006; revised 23 August 2006; accepted 31 August 2006
Available online 28 September 2006
Abstract—A general synthetic approach has been developed for the first asymmetric total synthesis of tuberolactone 1, jasmine
lactone 2 and d-decalactone 3. The key step is the selective hydrogenation of triple and endocyclic double bonds in the key inter-
mediate 4.
Ó 2006 Elsevier Ltd. All rights reserved.
Chiral lactones are functionalities commonly present in
a number of natural products that function as phero-
mones or medicinal compounds.1 They have often
served as intermediates for the synthesis of other natural
products.2 Lactones possessing alkyl side chains have
attracted much attention from synthetic and medicinal
chemists due to their biological activity.3 The short
chain alkyl homologues are volatile and important
aroma compounds in food and beverages. Natural
perfumes4 are obtained from plants by separation proce-
dures such as distillation. They are mostly oily materials,
and can be extracted from flowers, fruits, seeds, woods,
branches and leaves, bark or roots. Flower scents have
been popular among people of every period and culture.
The most important of these scents are rose, jasmine,
lilac, tuberose, gardenia, etc. The examples here are
tuberolactone 1 and jasmine lactone 2.
in jasmine7 (Jasminum grandiflorum L.) and tuberose
oils.5 Jasmine lactone is also found in gardenia flowers.
( )-Tuberolactone8 has been synthesized from ( )-
jasmine lactone via sulfenylation-sulfoxide pyrolysis
and from acrolein dimer.9 Jasmine lactone9,10 and its
analogues11 have been synthesized and their odour
characteristics examined. d-Decalactone 3 was identified
for the first time in cashew apple products produced
from the cashew tree (Anacardium occidentale L.), which
is an indigenous Brazilian tree, found primarily in the
northeastern coastal region.12 It also occurs in products
such as cheese, butter, coconut and strawberry, and the
odour is sweet, creamy and milky. Racemic d-decalac-
tone is readily accessible from the Baeyer–Villiger reac-
tion of the corresponding 2-substituted cyclopentanone.
The resolution of jasmine lactone13,14 and d-decalac-
tone13 has been investigated.
Tuberolactone 1 was identified as a trace constituent in
tuberose oil,5 from the flowers of Polyanthes tuberose L.
This lactone has a close structural relationship to the
well-known, olfactively interesting compound jasmine
lactone found in the same oil, and therefore it is
assumed to be of special olfactive importance. In com-
parison to the racemate, this enantiomer is more pleas-
ant with regard to the tuberose note, but has less
volume.6 Both (ꢀ) and (+)-jasmine lactones 2 are present
Owing to their specific odour impressions and low
threshold concentrations, these lactones play an impor-
tant role as fragrant and flavouring materials, and there-
fore practical syntheses are in great demand.
To the best of our knowledge, there is no report on the
asymmetric synthesis of these three lactones 1–3. In con-
nection with our studies on the synthesis of naturally
occurring lactones,15 the obvious structural similarities
of 1–3 prompted us to develop a first asymmetric route
for the total synthesis of (R)-(ꢀ)-tuberolactone, (S)-(+)-
jasmine lactone and (R)-d-decalactone, respectively (see
Scheme 1).
Keywords: Natural products; Chiral lactones; Hydrogenation; Flavour;
Fragrance; Asymmetric synthesis.
q IICT Communication No: 060334.
*
The syntheses of tuberolactone, jasmine lactone and d-
decalactone began with the known epoxide 6, prepared
Corresponding author. Tel./fax: +91 40 27160512; e-mail: sabitha@
iictnet.org
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.135

8180
G. Sabitha et al. / Tetrahedron Letters 47 (2006) 8179–8181
O
O
O
O
O
O
(S)-(+)-jasmine lactone 2
(R)-(-)-tuberolactone 1
(R)-decalactone 3
O
O
OH
OPMB
5
4
O
OPMB
6
Scheme 1. Retrosynthetic plan.
OH
OH
a
b
O
OPMB
OPMB
OPMB
6
5
7
OTBDMS
CHO
OTBDMS
e
f
c
OR
10
8, R = PMB
9, R = H
d
O
OTBDMS
O
g
CO2Me
11
4
Scheme 2. Reagents and conditions: (a) lithium acetylide, ethylenediamine complex, DMSO, 6 h, rt, 84%; (b) (i) Li/liq NH3, dry THF, ꢀ78 °C, (ii)
EtBr, THF, 3–4 h, 68%; (c) TBDMSCl, imidazole, DCM, rt, 1–1.5 h, 89%; (d) DDQ, DCM/H2O (9:1), rt, 30 min, 94%; (e) IBX, DMSO, 0 °C to rt,
1–2 h, 91%; (f) (i) NaH/THF, ꢀ78 °C, 30 min, (ii) (CF3CH2O)2P(O)CH2COOCH3, THF, 30–45 min, 82%; (g) p-TSA/MeOH, rt, 3–4 h, 76%.
O
O
O
O
c
a
4
(R)-(-)-tuberolactone 1
(R)-decalactone 3
b
O
O
(S)-(+)-jasmine lactone 2
Scheme 3. Reagents and conditions: (a) H2, Lindlar cat., EtOAc, quinoline, 2 h, 88%; (b) H2, excess Lindlar cat., EtOAc, quinoline, 12 h, 38%;
(c) H2, 10% Pd/C, EtOAc, rt, 4 h, 87%.
by Jacobsen’s hydrolytic kinetic resolution method.16
lithium acetylide provided homopropargylic alcohol 7
The opening of enantiomerically pure epoxide 6 with
(Scheme 2), which was subjected to alkylation with ethyl

G. Sabitha et al. / Tetrahedron Letters 47 (2006) 8179–8181
8181
7. Winter, M.; Malet, G.; Pfeiffner, M.; Demole, E. Helv.
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8. Dubs, P.; Stussi, R. Helv. Chim. Acta 1978, 61, 998–1003.
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bromide to afford alkylated compound 5 in 68% yield.
The secondary hydroxyl group in compound 5 was silyl-
ated using TBDMSCl and imidazole in DCM to afford
8 in 89% yield. After removal of the PMB group with
DDQ,17 the alcohol 9 was oxidized to the corresponding
aldehyde 10. Aldehyde 10 was immediately subjected to
Still–Gennari modification of the Horner–Emmons
reaction,18 to furnish Z-unsaturated carboxylic ester 11
in 82% yield. The cyclization of ester was achieved by
treating with p-TSA in methanol to afford 4 by in situ
deprotection of TBDMS group. This key intermediate
was utilized for the synthesis of three target molecules
(Scheme 3).19 Thus, partial hydrogenation of the triple
bond in compound 4 over Lindlar’s catalyst afforded
tuberolactone 1 in 88% yield. Whereas, treatment of 4
with excess Lindlar’s catalyst in EtOAc, quinoline for
12 h yielded jasmine lactone 2 in 38% yield and hydro-
genation of triple and endocyclic double bonds in the
presence of 10% Pd/C in EtOAc furnished d-decalactone
3 in 87% yield.
16. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
17. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021–3028.
18. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Dondio, G.;
Raimondi, L. Tetrahedron 1987, 43, 2369–2387; (b) Still,
W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
19. (6S)-6-(2-Pentynyl)-5,6-dihydro-2H-2-pyranone 4: yellow
In conclusion, the first asymmetric total synthesis of
tuberolactone, jasmine lactone and d-decalactone has
been accomplished in eight steps from the same starting
material. The selective hydrogenations are the key steps
involved in the synthesis of these fragrant d-lactones.
Acknowledgments
25
liquid, ½aꢁD ꢀ39.32 (c 1, CHCl3); IR (neat): 2975, 2925,
1726, 1427, 1386, 1246, 1148, 1049 cmꢀ1 1H NMR
;
V.B. thank UGC, New Delhi, for the award of a
Fellowship.
(300 MHz, CDCl3): d 1.16 (t, J = 7.5 Hz, 3H), 2.12–2.25
(m, 2H), 2.40–2.76 (m, 2H), 4.44–4.56 (br s, 1H, CH–O),
6.04 (dd, J = 9.8, 1.5 Hz, 1H), 6.85–6.94 (m, 1H, CH@C–
C@O); 13C NMR (50 MHz, CDCl3): d 163.5, 144.7, 120.8,
84.9, 76.4, 75.6, 72.9, 27.9, 24.7, 13.7, 12.0; LCMS: m/z
165 (M+1); HRMS: m/z 170.226 (calcd for C10H18O2,
170.250).
References and notes
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Ohloff, G. Fort. Chem. Org. Nat. 1978, 35, 431–527; (c)
Davies-Coleman, M. T.; Rivett, D. E. A. Fort. Chem. Org.
Nat. 1989, 55, 1–35; (d) Fukusaki, E.; Senda, S.; Naka-
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Mori, K. Tetrahedron 1989, 45, 3233–3298; (f) Fujita, T.;
Nishimura, H.; Kaburagi, K.; Mizutani, J. Phytochemistry
1994, 36, 23–27; (g) Nyandat, E.; Rwekika, E.; Galeffi, C.;
Palazzino, G.; Nicoletti, M. Phytochemistry 1993, 33,
1493–1496; (h) Andrianaivoravelona, J. O.; Sahpaz, S.;
Terreaux, C.; Hostettmann, K.; Stoeckli-Evans, H.; Ras-
olondramanitra, J. Phytochemistry 1999, 52, 265–269; (i)
Pereda-Miranda, R.; Garcia, M.; Delgado, G. Phytochem-
istry 1990, 29, 2971–2974.
25
(6R)-Tuberolactone 1: clear colorless liquid; ½aꢁD ꢀ30.16
(c 1, CHCl3); IR (neat): 2964, 3015, 1725, 1635, 1386,
1247, 1150, 1048, 815 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 0.97 (t, J = 7.78 Hz, 3H), 2.02–2.57 (m, 6H), 4.36–4.44
(m, 1H, CH–O), 5.30–5.39 (m, 1H, CH@CH), 5.50–5.58
(m, 1H, CH@CH), 5.98 (dt, J = 9.30, 2.34 Hz, 1H, @CH–
C@O), 6.82 (m, 1H, CH@C–C@O); 13C NMR (75 MHz,
CDCl3):d 164.2, 144.8, 135.4, 122.0, 121.3, 76.6, 37.8, 32.3,
29.6, 28.6, 20.6, 13.9; LCMS: m/z 189 (M+Na); HRMS:
m/z 164.167 (calcd for C10H12O2, 164.203).
25
(6S)-Jasmine lactone 2: colorless liquid; ½aꢁD +18.9 (c 1,
CHCl3), lit.13 +17.6 (c 0.38 CHCl3); IR (neat): 2959, 1729,
1
1453, 1415, 1302, 1148, 1110, 1046, 906 cmꢀ1; H NMR
(200 MHz, CDCl3): d 0.99 (t, J = 7.0 Hz, 3H), 1.42–2.68
(m, 10H), 4.16–4.36 (br s, 1H, CH–O), 5.25–5.63 (m, 2H,
CH@CH); 13C NMR (75 MHz, CDCl3): d 171.8, 135.1,
122.3, 76.6, 33.3, 29.6, 29.4, 27.2, 20.7, 14.0; LCMS: m/z
191 (M+Na); HRMS: m/z 166.201 (calcd for C10H14O2,
166.219).
2. Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.;
Suzuki, H.; Fylaktakidou, K. C.; Baudoin, O.; van Delft,
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Chem., Int. Ed. 2000, 39, 2980–3010.
5. Kaiser, R.; Lamparsky, D. Tetrahedron Lett. 1976, 1659–
1661.
25
(R)-d-Decalactone 3: colorless liquid; ½aꢁD +52.2 (c 1,
CHCl3), lit.13 +56.7 (c 1.79 CHCl3); IR (neat): 2931, 2861,
1736, 1463, 1379, 1340, 1243, 1184, 1118, 1036, 930; 1H
NMR (200 MHz, CDCl3): d 0. 90 (t, J = 6.80 Hz, 3H),
1.21–2.62 (m, 14H), 4.19–4.30 (br s, 1H, CH–O); 13C
NMR (75 MHz, CDCl3): d 172.0, 80.5, 31.4, 29.3, 27.6,
24.4, 22.3, 18.3, 13.8; LCMS: m/z 193, (M+Na); HRMS:
m/z 168.197 (calcd for C10H16O2, 168.234).
6. Bourdineaud, J.-P.; Ehret, C.; Petrzilka, M. Optically
Active Lactones. World Patent, WO/94107887, April 19,
1994.