Synthesis of (+)-hernandulcin and (+)-epihernandulcin

Article abstract of DOI:10.1016/S0040-4039(02)00939-5

(+)-Hernandulcin 1, an extremely sweet bisabolane-type sesquiterpene, and (+)-epihernandulcin 2 were synthesized in six steps from (-)-isopulegol with 15 and 11 percent overall yields, respectively.

Full text of DOI:10.1016/S0040-4039(02)00939-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4721–4722
Synthesis of (+)-hernandulcin and (+)-epihernandulcin
Jung Hun Kim, Hyun Jin Lim and Seung Hoon Cheon*
College of Pharmacy & Research Institute of Drug Development, Chonnam National University, 300 Yongbong-Dong, Buk-Ku,
Kwangju 500-757, South Korea
Received 20 April 2002; revised 8 May 2002; accepted 16 May 2002
Abstract—(+)-Hernandulcin 1, an extremely sweet bisabolane-type sesquiterpene, and (+)-epihernandulcin 2 were synthesized in
six steps from (−)-isopulegol with 15 and 11% overall yields, respectively. © 2002 Elsevier Science Ltd. All rights reserved.
nesium chloride in the absence of CuI gave 7 in quanti-
tative yield. Oxidation of the secondary alcohol in 6 to
the ketone 8 ([h]2D5 −14.0° (c=0.11, EtOH)) was carried
out in the presence of tetra-n-propylammonium per-
ruthenate (TPAP, 0.06 equiv.), and N-methylmorpho-
line N-oxide (1.5 equiv.) in CH2Cl2 with 75% yield.
Either Swern7 oxidation or Dess–Martin8 periodinane
oxidation gave variable results. Protection of the ter-
tiary alcohol in 8 with chlorotrimethylsilane (3 equiv.)
in pyridine afforded 9 ([h]2D6 −16.3° (c=0.12, EtOH)) in
82% yield. Treatment of 9 with LDA (1 equiv.),
phenylselenyl chloride (1.3 equiv.) and HMPA (1.3
equiv.) in THF at −78°C afforded selenide 10 (64%)
which was subjected to an oxidative elimination with
30% H2O2 in CH2Cl2 containing pyridine to afford 11
([h]2D7 +9.7° (c=0.14, EtOH)) in 82% yield. Finally
deprotection of the trimethylsilyl group with 40% HF
(+)-Hernandulcin 1 was isolated from Lippia dulcis
Trev. (Verbenaceae) by Kinghorn and his co-workers in
1985.1 The structure of hernandulcin was determined by
NMR studies1 and the absolute stereochemistry was
established by chemical method of synthesizing all four
possible stereoisomers from (R)- and (S)-limonene by
Mori and Kato.2 It was found that only (6S,1%S)-(+)-
hernandulcin possesses sweetness.2 (+)-Hernandulcin is
1500 times sweeter than sucrose on a weight basis,
although its sweetness was considered somewhat less
pleasant than that of sucrose, and some bitterness,
off-taste and after-taste were perceived as well.3 The
synthesis of racemic hernandulcin has been reported4
but the synthesis of (6S,1%S)-(+)-hernandulcin has not
been published except the one reported by Mori and
Kato.2 In this paper we wish to disclose some results
culminating in the total synthesis of (6S,1%S)-(+)-her-
nandulcin 1 and (6S,1%R)-(+)-epihernandulcin 2.
in CH3CN gave (6S,1%S)-(+)-hernandulcin 1 ([h]D26
+
110.5° (c=0.11, EtOH), lit. [h]2D5 +109° (c=0.11,
EtOH),1 [h]2D0 +122° (c=0.111, EtOH),2a [h]2D2 +126°
(c=0.113, EtOH)2b) in quantitative yield. Following the
same sequences of reactions as described above
(6S,1%R)-(+)-epihernandulcin 2 ([h]2D7 +141.0° (c=0.12,
EtOH), lit. [h]D15 +141° (c=0.111, EtOH))2b,9 was also
synthesized starting from the epoxide 5 (Scheme 1).
Epoxidation of (−)-isopulegol 3 with m-chloroperben-
zoic acid in dry CH2Cl2 at 0°C under Ar furnished a
mixture of two diastereomers which were separated by
column chromatography (hexane: ethyl acetate=7:2) to
give a less polar 4 ([h]3D0 −17.9° (c=10, ethyl acetate),
48% yield) and a more polar isomer 5 ([h]3D0 −16.6°
(c=10, ethyl acetate), 32% yield).5 A number of
attempts were made to improve the stereoselectivity of
the homoallylic epoxidation but none gave better
results. Opening of the epoxide 4 with prenylmagne-
sium chloride (freshly prepared from prenyl chloride
and an excess of Mg in THF) in the presence of
purified6 copper(I) iodide (0.05 equiv.) in dry THF at
−30°C under Ar gave 6 ([h]2D7 +47.3° (c=0.11, EtOH))
in 95% yield. Opening of the epoxide 4 with prenylmag-
In conclusion, we have completed an enantiospecific
total synthesis of (+)-hernandulcin 1 and (+)-epihernan-
dulcin 2 in six steps from (−)-isopulegol with 15 and
11% overall yields, respectively.
Acknowledgements
This work was supported by grant No. 98-0403-12-01-3
from the Basic Research program of the Korea Science
and Engineering Foundation.
* Corresponding author. Tel.: +82-62-530-2929; fax: +82-62-530-2911;
e-mail: shcheon@chonnam.ac.kr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00939-5

4722
J. H. Kim et al. / Tetrahedron Letters 43 (2002) 4721–4722
OH
OH
OH CH2
H
O
H
O
H
a
+
CH3
CH3
CH3
80%
H3C
H3C
H3C
4
5
3
b
c
99%
OH
95%
OH
CH3
CH3
OH
OH
CH3
CH3
H
H
CH3
CH3
CH2
CH3
OH
O
CH3
CH3
H
H3C
H3C
7
6
H3C
2
d
75%
OTMS
CH3
O
CH3
CH3
OH
O
CH3
CH3
CH3
H
H
e
82%
H3C
H3C
8
9
f
54%
OTMS
OH
O
CH3
CH3
O
CH3
CH3
H
CH3
H
CH3
g
99%
H3C
H3C
11
1
Scheme 1. Reagents and conditions: (a) m-chloroperbenzoic acid, CH2Cl2, 0°C, 3 h; (b) 4-chloro-2-methyl-2-butene, Mg turnings,
1,2-dichloromethane, THF, CuI, −30°C, 1.5 h; (c) 4-chloro-2-methyl-2-butene, Mg turnings, 1,2-dichloromethane, THF, −30°C,
,
1.5 h; (d) tetra-n-propylammonium perruthenate, N-methylmorpholine N-oxide, molecular sieves (4 A), CH2Cl2, rt, 15 min; (e)
TMSCl, pyridine, 0.5 h; (f) LDA, phenylselenyl chloride, HMPA, THF, −78°C, 2 h; then 30% H2O2, pyridine, CH2Cl2, 0°C, 15
min; (g) 40% HF, CH3CN, 15 min.
References
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obtained for all new compounds reported herein.