Enantiospecific synthesis of (+)-hernandulcin

Article abstract of DOI:10.1016/j.tetlet.2008.06.066

The sesquiterpene (+)-hernandulcin has been enantiospecifically synthesized starting from (-)-neoisopulegol in seven steps and in 25% overall yield.

Full text of DOI:10.1016/j.tetlet.2008.06.066

Tetrahedron Letters 49 (2008) 4997–4998
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantiospecific synthesis of (+)-hernandulcin
*
Francesco G. Gatti
Dipartimento di Chimica dei Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico, Via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The sesquiterpene (+)-hernandulcin has been enantiospecifically synthesized starting from (ꢀ)-neoiso-
pulegol in seven steps and in 25% overall yield.
Received 5 May 2008
Revised 11 June 2008
Accepted 13 June 2008
Available online 18 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Metalation
Sesquiterpene
Epoxidation
Sweetener
Enone
The consumption of sucrose-free foods in the United States is
drastically increased over the last decades. Among all artificial
sweeteners or so called sugar substitutes, aspartame, saccharin,
and cyclamate are without doubt the most popular and employed
in the food industry. However, questions regarding the safety of
these sweeteners, renewed by a recent study promoted by the Cal-
ifornian Environmental Protection Agency, concluded that an
increase in the number of people with brain tumor might be
associated with the use of these substances. Thus, the discovery
of new sugar substitutes gained interest in the scientific commu-
nity.1 In the 1985, Kinghorn et al. isolated, from the leaves and
flowers of the tropical American plant Lippia dulcis (Verbenaceae),
the substance 1, which, they called (+)-hernandulcin in honor of
the Spanish physician Hernández who first described the sweet
property of this herb.2 This compound represents a breakthrough
in the field of natural sugar substitutes, since it has been the first
bisabolene sesquiterpene that resulted intensively sweet. In con-
trast, the natural occurring epihernandulcin 2 resulted bitter. The
bisabolenes (+)-4b-hydroxy hernandulcin 3 and lippidulcine A 4
have been successively isolated from the same herb.3,4
Recently, Cheon et al. described a new synthesis of 1 starting
from the commercially available (ꢀ)-isopulegol, improving the
overall yield up to 15%.7 However, this synthesis suffers from
two main drawbacks: (i) it is not enantiospecific and (ii) it makes
use of the highly toxic selenium chemistry and the harmful hexa-
methylphosporamide (HMPA) in the last step.
R
O
O
O
H
H
H
OH
1, R= H
3, R=OH
OH
OH
OH
2
4
Keeping this in mind we disclosed the first enantiospecific syn-
thesis of 1 starting from (+)-neoisopulegol.
Indeed, both reported synthesis introduce the stereocentre
at C(20) carbon by epoxidation, with m-chloroperbenzoic acid
(MCPBA), of the double bond of (+)-limonene and (ꢀ)-isopulegol,
respectively. However, both reactions give a mixture of the corre-
sponding epoxides with modest selectivity, and, then require col-
umn chromatographic separation of the diastereoisomers. In
contrast, it is known from literature that the epoxidation of (+)-
neoisopulegol is highly selective.8 Thus, we envisaged in the (+)-
neoisopulegol the most appropriate building block for the prepara-
tion of 1. The (+)-neoisopulegol can be easily prepared from the
(ꢀ)-isopulegol9 in two steps (72% overall yield).8a
The stereochemistry of 1 has been unambiguously assigned
from Mori et al. by total synthesis starting from (+)-limonene
and in 1% overall yield.5 Attempts to synthesize derivatives of 1,
with similar taste properties, showed that the C(1) carbonyl group,
the tertiary hydroxyl group and the two double bonds are crucial
structural elements for the perception of its sweet taste.6 More-
over, Mori has shown that only the (6S,20S)-1 enantiomer is sweet.5
The synthesis of 1 is summarized in Scheme 1. Metalation of
(+)-neoisopulegol with butyllithium (2.2 equiv) and potassium-
tert-butoxide (1.0 equiv) in hexane at 0 °C followed by addition
* Tel.: +39 02 23993072; fax: +39 02 23993080.
E-mail address: Francesco.Gatti@polimi.it.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.066

4998
F. G. Gatti / Tetrahedron Letters 49 (2008) 4997–4998
a
b
c
d
83%
92%
72%
96%
OH
OH
O
H
H
H
OH
OH
H
H
O
OH
OH
e
5
6
7
8
85%
f
g
1
61%
92%
O
O
H
H
OTMS
10
OTMS
9
Scheme 1. Reagents and conditions: (a) (i) BuLi, t-BuOK, hexane, 0 °C; 4 h; (ii) BrCH2CH@C(CH3)2; ꢀ10 °C, 1 h; (b) TBHP, cat. VO(acac), benzene, rt, 12 h; (c) LiAlH4, THF, 0°C,
1 h; (d) DMP, CH2Cl2; rt, 4 h; (e) TMSCl, CH2Cl2/pyridine (2:1), 0.5 h; (f) (i) LDA, TMSCl, ꢀ78 °C, THF; (ii) DMSO, cat. Pd(OAc)2, 50 °C, O2, 36 h; (g) TBAF, CH3CN, 0.5 h.
of prenylbromide (3-methyl-2-butenylbromide) at ꢀ10 °C gave
yield. The spectral data were in agreement with those already
reported.
dienol 5 (½a 2D5
ꢁ
+19.6 (c 3.7, CHCl3)) in 83% yield.10 Epoxidation of
the latter with tert-butylhydroperoxide (TBHP) in the presence of
a catalytic amount of VO(acac)2 in benzene at room temperature
In summary, (+)-hernandulcin has been enantiospecifically syn-
thesized in seven steps from (+)-neoisopulegol in a 25% overall
yield (18% overall yield from (ꢀ)-isopulegol). This synthetic strat-
egy might be useful for the preparation of other sesquiterpenes
such as 4, which has been isolated in an amount too small to be
tasted as sweeteners.
gave exclusively the diastereoisomer 6 (½a D25
ꢁ
+36.6, c 3.0, CHCl3)
in 92% yield.8,11 Then, 6 was reduced with LiAlH4 in THF at 0 °C
to give the diol 7 in almost quantitative yield as a white solid.
The latter was oxidized with Dess-Martin periodinane (DMP)12 in
CH2Cl2 at room temperature to give ketone 8 (½a D25
ꢀ10.0 (c 1.2,
ꢁ
CHCl3), ½a 2D5
ꢁ
ꢀ9.2 (c 1.0, EtOH), lit. ½a D25
ꢁ
ꢀ14.0 (c 0.11, EtOH)7) in
Acknowledgments
72% yield.
Finally, we investigated a new way to convert ketone 8 to enone
1 avoiding the highly toxic selenium chemistry adopted by Cheon.
First, we tried the iperiodine chemistry, recently developed by
Nicolaou et al. Direct oxidation of 8 to give 1 with o-iodoxybenzoic
acid (IBX) at high temperature (80 °C) in DMSO failed, indeed, after
12 h all the starting material was recovered.13 A more efficient evo-
lution of this new methodology consists in the oxidation of the silyl
Cofin-Murst is acknowledged for financial support. We thank
Perfetti s.p.a. for providing 20 g of (ꢀ)-isopulegol.
References and notes
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Chem. Pharm. Bull. 2005, 53, 1175–1177; (b) Ono, M.; Tsuru, T.; Abe, H.; Eto, S.;
Okawa, M.; Abe, F.; Kinjo, J.; Ikeda, T.; Nohora, T. J. Nat. Prod. 2006, 69, 1417–
1420.
enol ethers by using IBXꢂN-oxide complexes to give the
a,b-unsat-
urated ketones under milder conditions (room temperature) and in
better yields.14 First, the tertiary hydroxyl group of ketone 8 was
protected with chlorotrimethylsilane (TMSCl) in CH2Cl2/pyridine
(2:1) to give 9 (½a D25
ꢁ
ꢀ11.2 (c 1.2, CHCl3), ½a D25
ꢀ14.3 (c 1.3, EtOH),
ꢁ
lit. ½a 2D6
ꢁ
ꢀ16.3 (c 0.12, EtOH)7) in 85% yield. Then, the kinetic silyl
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Tetrahedron 1986, 42, 5895–5900.
6. Compadre, C. M.; Hussain, R. A.; Lopez de Compadre, R. L.; Pezzuto, J. M.;
Kinghorn, A. D. Experientia 1988, 44, 447–449.
enol ether was generated by treatment of 9 with lithium di-isopro-
pylamide (LDA) and TMSCl at ꢀ78 °C in THF, and, after standard
work-up, was directly submitted to the oxidation step without
any further purification.
7. (a) Kim, J. H.; Lim, H. J.; Cheon, S. H. Tetrahedron Lett. 2002, 43, 4721–4722; (b)
Kim, J. H.; Lim, H. J.; Cheon, S. H. Tetrahedron 2003, 59, 7501–7507.
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P. J.; Pontiroli, A.; Qun, L. J. Chem. Soc., Chem. Commun. 1996, 15, 1743–1744.
9. (a) Akutagawa, S. The main preparations of (ꢀ)-isopulegol are by Takasago
process or enzymatic resolution. In Chirality in Industry; Collins, A. N.,
Sheldrake, G. N., Crosby, J., Eds.; Wiley, 1992. Chapter 16; (b) Serra, S.;
Brenna, E.; Fuganti, C.; Maggioni, F. Tetrahedron: Asymmetry 2003, 14, 3313–
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124, 2245–2258.
However, treatment of the latter with IBX and 4-methoxy-pyr-
idine-N-oxide (MPO) in DMSO at room temperature gave just trace
of enone 10. In contrast, the oxidation of the silyl enol ether, using
the method of Saegusa–Larock,15 with a catalytic amount of
Pd(OAc)2 (30%, in weight) in DMSO at 50 °C under an oxygen atmo-
sphere, gave enone 10 (½a D25
ꢁ
+7.8 (c 1.1, CHCl3), ½a D25
ꢁ
+9.0 (c 1.2,
EtOH), lit. ½a 2D7
ꢁ
+9.7 (c 0.14, EtOH)7) in 61% yield (over the two
steps).
Finally, the cleavage of the silyl protective group was accom-
plished by treatment of 10 with tetra-n-butylammonium fluoride
(TBAF) in MeCN at room temperature to give (+)-hernandulcin 1
14. Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int.
Ed. 2002, 41, 996–1000.
15. (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013; (b) Larock, R.
C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36,
2423–2426.
(½a 2D5
ꢁ
104.0 (c 0.8, EtOH), lit. ½a D25
ꢁ
+109 (c 0.11, EtOH),2 lit. ½a D20
ꢁ
+122 (c 0.111, EtOH),5 lit. ½a D26
ꢁ
+110.5 (c 0.11, EtOH)7) in 92%