Enantioselective synthesis of sabina ketone

Article abstract of DOI:10.1016/S0040-4039(03)01629-0

Both enantiomers of sabina ketone were efficiently prepared via an easy synthesis of 1-diazo-5-methylene-6-methylheptan-2-one, starting from succinic anhydride, followed by its highly enantioselective cyclization catalyzed by chiral dirhodium(II) compound

Full text of DOI:10.1016/S0040-4039(03)01629-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6683–6685
Enantioselective synthesis of sabina ketone
Mario Barberis and Julia Pe´rez-Prieto*
Departamento de Qu´ımica Orga´nica/ICMOL, Universidad de Valencia, Av. Vicent Andre´s Estelle´s s/n, 46100 Burjassot,
Valencia, Spain
Received 27 June 2003; revised 30 June 2003; accepted 30 June 2003
Abstract—Both enantiomers of sabina ketone were efficiently prepared via an easy synthesis of 1-diazo-5-methylene-6-methylhep-
tan-2-one, starting from succinic anhydride, followed by its highly enantioselective cyclization catalyzed by chiral dirhodium(II)
compounds having ortho-metalated phosphines as ligands.
© 2003 Published by Elsevier Ltd.
The bicyclo[3.1.0]hexane ring structure is present in a
considerable number of natural monoterpenes and
sesquiterpenes including the norterpene, sabina ketone
1. This ketone is an intermediate in the synthesis of
important chemicals such as sabinene and sabinene
hydrates (Chart 1).1 Partial syntheses of optically active
sabina ketone have been reported starting from (+)-
sabinene,2 or through cyclopropanation of chiral ketals
derived from 3-[(1-methyl)ethyl]-2-cyclopenten-1-one.3
However, (+)-sabinene is both expensive and not read-
ily available, and the two synthetic routes produce 1
with a low yield. Several total syntheses of this ketone,
in the racemic form, have also been published.1b,4,5 One
of them starts from ethyl isopropylcyanoacetate and
uses 1-diazo-5-methylene-6-methylheptan-2-one (2) as
the key intermediate.4 The proposed synthesis of the
diazo 2 requires too many steps and its cyclization to
sabina ketone, catalyzed by copper, occurs with moder-
ate yield.
Previous studies, using simple model compounds, have
shown the versatility of chiral dirhodium(II) com-
pounds Rh2(O2CF3)2(PC)2 [(3), PCH=triaryl phos-
phine], to accomplish enantioselective intramolecular
cyclopropanation of 1-diazo-2-alkanones6 (Fig. 1). It
appeared of interest to extent this chemistry to the
synthesis of natural sabina ketone and its enantiomer
using a simple, straightforward total synthesis that
could be upscaled for large production.
Chart 1. Structures of sabina ketone, sabinene hydrates and
diazo compound 2.
Keywords: sabina ketone; dirhodium(II) compounds; asymmetric syn-
thesis.
Figure 1. Structures of chiral dirhodium(II) compounds hav-
ing metalated phosphines as ligands.
* Corresponding author. Fax: (34)-96-3544939; e-mail: julia.perez@
uv.es
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01629-0

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M. Barberis, J. Pe´rez-Prieto / Tetrahedron Letters 44 (2003) 6683–6685
References
1. (a) Daly, J. W.; Green, F. C.; Eastman, R. H. J. Am.
Chem. Soc. 1958, 80, 6330; (b) Fanta, W. J.; Erman, W. F.
J. Org. Chem. 1968, 33, 1656; (c) Gaoni, Y. Tetrahedron
1972, 28, 5525; (d) Galopin, C. C. Tetrahedron Lett. 2001,
42, 5589.
2. Griesbaum, K.; Hilb, M.; Bosch, J. Tetrahedron 1996, 52,
14813. Jacs 1971.
3. Mash, E. A.; Nelson, K. A. Tetrahedron 1987, 43, 679.
4. Mori, K.; Ohki, M.; Matsui, M. Tetrahedron 1970, 26,
2821.
Scheme 1. Synthesis of 1-diazo-5-methylene-6-methylheptan-
2-one (2). Reagents and conditions: (a) PrMgCl, Fe(acac)3,
THF, 0°C; (b) Ph3PCH3Br, BuLi, DMSO, rt; (c) ClCO2Et,
CH2N2.
i
Table 1. Cyclopropanation of diazo compound 2 using
dirhodium(II) complexes with ortho-metalated aryl phos-
phine ligands
5. (a) Hamon, D. P. G.; Shirley, N. J. Aust. J. Chem. 1987,
40, 1321; (b) Alexandre, C.; Rouessac, F. Bull. Chem. Soc.
Jpn. 1972, 45, 2241.
6. Barberis, M.; Pe´rez-Prieto, J.; Herbst, K.; Lahuerta, P.
Organometallics 2002, 21, 1667.
7. Schick, H.; Ludwig, R. Synthesis 1992, 4, 369.
8. Boer, Th.; Backer, H. J. In Organic Syntheses; Rabjohn,
N., Ed.; Wiley: New York, 1963; Vol. IV, p. 250.
9. Synthesis of 5-methyl-4-oxohexanoic acid (4). To a solution
of succinic anhydride (4.8 g, 48 mmol) and Fe(acac)3 (0.51
g, 1.4 mmol) in THF (50 mL) a dropwise solution of
isopropyl magnesium chloride (20 mL, 2 M in diethyl
ether) was added, and the reaction mixture was stirred
overnight at 0°C. The mixture was acidified with HCl 10%,
extracted with dichloromethane (3×10 mL), and the
organic layer was washed with NaOH 10% (3×10 mL).
The aqueous solution was acidified with HCl 10% and
extracted with dichloromethane. The extract was washed
with water, dried (MgSO4) and concentrated yielding com-
PCH
Rh(II) chirality Yield (%)
E.e.a (%)
(C6H5)3P
(p-CH3C6H4)3P (P)-3b
(m-CH3C6H4)3P (M)-3c
(M)-3a
99
99
99
94 (1S,5R)
89 (1R,5S)
94 (1S,5R)
a E.e. values calculated in this report were based on GC analysis with
a 2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl-b-CDX column.
The present work reports a short, efficient and practical
synthesis of (+)- and (−)-1 starting from the cheap and
available succinic anhydride. Thus, isopropyl magne-
sium chloride was reacted with succinic anhydride in
THF at 0°C in the presence of iron(III) acetylacetonate
[Fe(acac)3] leading to 5-methyl-4-oxohexanoic acid
(4)4,7 in a 50% yield. Reaction of 4 with methyl-
triphenylphosphonium bromide and butyllithium pro-
vided the 4-isopropylpent-4-enoic acid (5) which, upon
reaction with methyl chloroformate followed by addi-
tion of freshly prepared diazomethane, led to diazo 2 in
65% yield over the two steps9 (Scheme 1).
1
pound 44,7 (3 g, 50%) of: H NMR (CDCl3, 300 MHz) l
1.05 (6H, d, J=6.9 Hz), 2.57 (3H, m), 2.69 (2H, m), 10.77
(1H, bs) ppm. 13C NMR (CDCl3, 300 MHz) l 18.6, 28.2,
34.9, 41.1, 179.3, 213.1 ppm. MS m/z (rel. int. %) 144 (M+
1), 102 (43), 73 (26), 71 (19). HRMS calcd for C7H12O2:
144.0786. Found: 144.0785.
Synthesis of 4-isopropylpent-4-enoic acid (5). Butyllithium
(11 mL, 1.6 M in hexane) was added to a solution of
methyltriphenylphosphonium bromide (6.2 g, 17 mmol) in
DMSO (40 mL), and the mixture was stirred for 1 h at
room temperature. Then, a solution of the 4 (2.5 g, 17
mmol) and butyllithium (11 mL, 1.6 M in hexane) in THF
(20 mL) was added, and the mixture was stirred overnight.
The solution was quenched with water, acidified with HCl
10% and extracted with dichloromethane (3×10 mL), and
the organic layer was washed with NaOH 10%. The
aqueous solution was acidified with HCl 10% and
extracted with dichloromethane. The extract was washed
with water, dried (MgSO4) and concentrated. The crude
containing compound 54 was employed for the next step
without further purification.
Next, cyclization of diazo 2 was performed in refluxing
pentane using three different dirhodium(II) com-
pounds9 (Table 1). Sabina ketone was obtained with
high yields in all the cases (99%) and the enantio-
selectivity values were high to excellent (between 89 and
94% e.e.). The configuration of the ketone depends on
the chirality of the catalyst.
In view of the above results, this work constitutes an
interesting strategy to the synthesis of both enantiomers
of sabina ketone and therefore the entrance to provide
several important chiral monoterpenes.
Synthesis of 1-diazo-5-methylene-6-methylheptan-2-one (2).
Diazo compound 2 was prepared from 5 by reaction with
methyl chloroformate, followed by treatment with freshly
prepared diazomethane.8 The crude was chromatographed
on silica gel with hexane/ethyl acetate (20:1) to give diazo
1
Acknowledgements
ketone 2 (1.9, 65%). H NMR (CDCl3, 300 MHz) l 0.91
(6H, d, J=6.8 Hz), 2.04–2.28 (3H, m), 2.30–2.42 (2H, m),
We thank the Direccion General de Investigacion Cien-
tifica y Tecnica (DGICYT) (Project PB98-1437) for
financial support. Mario Barberis thanks to the Gener-
alitat Valenciana for a pre-doctoral fellowship.
4.52 (1H, s), 4.66 (1H, s), 5.15 (1H, bs) ppm.
Catalytic experiments. The catalytic reactions were per-
formed dissolving the catalyst (1.5 mg, [substrate]/[Rh(II)
complex]=100) in dry refluxing pentane (30 mL) under an

M. Barberis, J. Pe´rez-Prieto / Tetrahedron Letters 44 (2003) 6683–6685
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1
argon atmosphere. The 1-diazo-5-isopropyl-4-penten-2-
one (35 mg) was added to the solution and the mixture
stirred for 1 h (the reaction, monitored by TLC, indicated
completely transformation of the diazo compound). The
reaction mixture was cooled to room temperature, the
solvent evaporated and the crude product was filtered
through a short chromatography column to eliminate the
catalyst. The yield of the reaction was calculated by pro-
ton H NMR and the cyclization product was purified by
HPLC (hexane/ethyl acetate, 10: 1, tR=12.37), enan-
tiomeric excesses were determined by GC analysis [oven
temp. 100°C for 2 min, then 5°C/min to 180°C, tR=9.99
for (1S,5R) and tR=10.66 for (1R,5S)]. The configura-
tion was determined by correlation of the sign of the
rotation of polarized light with that of the known enan-
tiomer.3