Enzymatic resolution of (±)-2-exo-7-syn-7-(1-propynyl)norbornan-2- ol, a key synthetic intermediate for jasmonoids

Article abstract of DOI:10.1515/znb-2008-1217

Lipase-catalyzed resolution of 2-exo-7-syn-7-(1′-propynyl)norbornan- 2-ol, a key synthetic intermediate for jasmonoids, was achieved using vinyl chloroacetate as an acyl donor.

Full text of DOI:10.1515/znb-2008-1217

Note
1441
Enzymatic Resolution of ( )-2-Exo-7-
syn-7-(1-propynyl)norbornan-2-ol,
a Key Synthetic Intermediate for
Jasmonoids
Scheme 1. Synthesis of ( )-methyl tuberonate (1).
Hiromasa Kiyota, Daisuke Nakashima,
Shigefumi Kuwahara, and Takayuki Oritani
Department of Bioscience and Biotechnology for Future
Bioindustry, Graduate School of Agricultural Science,
Tohoku University, 1-1 Tsutsumidori-Amamiya, Aoba-ku,
Sendai, 981-8555 Japan
Reprint requests to Dr. Hiromasa Kiyota,
Tel. and Fax: +81 22 717 8785.
E-mail: kiyota@biochem.tohoku.ac.jp
Z. Naturforsch. 2008, 63b, 1441 – 1442;
received June 25, 2008
Lipase-catalyzed resolution of 2-exo-7-syn-7-(1ꢀ-propyn-
yl)norbornan-2-ol, a key synthetic intermediate for jasmono-
ids, was achieved using vinyl chloroacetate as an acyl donor.
Key words: Enzymatic Resolution, Lipases,
Transesterification, Chloroacetate,
Bicyclo[2.2.1]heptan-2-ol
Scheme 2. Enzymatic resolution of ( )-2. (a) Ac2O,
Py (99 %); (b) chloroacetyl chloride, Py, Et2O (92 %);
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ꢀ
◦
(c) Chirazyme L-9, c.-f., C2, lyo., i-Pr2O, 20 C; (d) i.
3,5-dinitrobenzoyl chloride, pyridine, DMAP, Et2O (quant.);
ii. recrystallization from i-Pr2O (58 %); (e) i. PDC, CHCl3;
ii. H2, Pd-C, MeOH.
Introduction
Jasmonoids are distributed as various biologically
active compounds such as plant hormones [1] and per-
fumes [2], and sometimes show even therapeutic ac-
tivity [3]. We have achieved the total synthesis of
methyl tuberonate (1), a strong potato tuber-forming
substance, in a racemic form [4] from norbornene
(Scheme 1). In order to prepare the optically active
product, we focused on the enzymatic resolution of the
synthetic intermediate alcohols such as 2. Enzymatic
reaction has been one of the methods of choice to get
optically active organic compounds under mild condi-
tions [5]. Here we describe the results of the resolution
of the sterically hindered alcohol ( )-2.
was introduced. Transesterification of ( )-2 with vinyl
R
ꢀ
chloroacetate catalyzed by Chirazyme L-9 (Mucor
miehei, Roche) afforded (–)-2 (88 % ee) and chloroac-
etate (–)-4 at 57% conversion (Scheme 2). The enan-
tiomeric purity was determined by HPLC analysis of
the corresponding MTPA ester, and the E value was
calculated as 14. Enzymatic hydrolysis of ( )-4 re-
sulted in poor selectivity. The product (–)-2 was fur-
ther purified by recrystallization of its 3,5-dinitro-
benzoate 5 up to > 99 % ee. The product of another
run (–)-2 (73% ee) was converted into its saturated
keto derivative 6 to determine the absolute config-
uration. The sign of optical rotation of 6 ([α]D18
+24◦ (c = 0.25, MeOH)) compared with those of (+)-
=
Results and Discussion
norcamphor ([α]D = +31◦) and (+)-camphor [[α]2D0
=
+54.9◦ (c = 5, EtOH)] revealed the stereochemistry as
drawn in Scheme 2 [6]. The similar Cotton curves of
6 and (+)-camphor in the CD spectra also support this
conclusion.
At first, transacetylation of ( )-2 and hydroly-
sis of its acetate ( )-3 were tried, however, neither
proceeded using various commercial lipases and es-
terases. Then the more reactive chloroacetyl group
c
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1442
Note
The alcohols 2 resolved in this experiment will be was chromatographed on SiO2 (hexane/EtOAc = 30 : 1) to
give ( )-4 (209 mg, 0.922 mmol, 92 %) as a colorless oil. –
IR: ν = 3100 (s), 1750 (s, C=O), 1720 (s, C=O), 1340
(m), 1310 (s), 1180 (s), 1070 (m), 1040 (m), 1045 (m),
1000 (m), 980 (m) cm−1. – 1H NMR (500 MHz, CDCl3):
δ = 1.1 – 1.2 (m, 2 H), 1.50 – 1.64 (m, 2 H), 1.79 (d, J =
1.5 Hz, 3 H, CH3), 1.89 (dd, J = 13.5, 8.0 Hz, 1 H), 2.04
(dq, J = 13.5, 3.0 Hz, 1 H), 2.30 – 2.36 (m, 2 H), 2.46 (d,
J = 4.5 Hz, 1 H), 4.03 (s, 2 H, CH2Cl), 4.69 (dd, J = 7.5,
3.0 Hz, 1 H, 2-H). – MS (FAB): m/z = 133 [M+H–ClCH2
COOH]+, 149 [M–ClCH2CO]+, 177 [M–CH3]+, 225, 227
M+. – HRMS (FAB, NOBA+PEG+NaCl): m/z = 227.0835
(calcd. 227.0838 for C12H16O237Cl, [M]+).
useful chiral building blocks for valuable compounds.
The results also have exemplified a lipase-catalyzed
transesterification of a rather hindered hydroxy group.
Experimental Section
General
Optical rotation: Horiba SEPA-300. NMR: Varian Gem-
ini 2000 (300 MHz) and Varian Inova 500 (500 MHz).
IR: Jasco Report-100. MS: Jeol JMS-700. HPLC: Hitachi
L-6000 pump & Hitachi L-4200 UV/Vis detector. Column
chromatography: Merck silica gel 60 (70 – 230 mesh).
(1S∗,2S∗,4S∗,7R∗)-7-(1ꢀ-Propynyl)bicyclo[2.2.1]hept-2-yl
(–)-(1S,2S,4S,7R)-3 (lipase-catalyzed transesterification)
acetate (( )-3)
A suspension of ( )-2 (150 g, 1.00 mmol), vinyl
chloroacetate (0.30 mL, 0.36 g, 3.0 mmol, 3 eq.) and
To a solution of ( )-2 (1.68 g, 11.2 mmol) in pyridine
(3.4 g, 43 mmol) was added Ac2O (4.08 g, 40.0 mmol) at
20 ◦C, and the mixture was stirred for 12 h at 20 ◦C, then di-
luted with Et2O, dil. HCl (5 times), sat. aq. NaHCO3 soln.
and brine, dried with MgSO4 and concentrated in vacuo.
The residue was chromatographed on SiO2 (hexane/EtOAc =
30 : 1) to give ( )-3 (2.12 g, 99 %) as a colorless oil. – IR:
ν = 3060 (s), 1730 (s, C=O), 1360 (m), 1245 (s, C–O),
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Chirazyme L-9, c.-f., C2, lyo. (50 mg, 0.65 units) in i-
Pr2O (5 mL) was stirred at 20 ◦C for 6 h, and the mixture was
filtered through a Celite pad. The filtrate was concentrated
in vacuo. The residue was chromatographed on silica gel
(hexane/EtOAc = 10 : 1) to give (–)-3 [129 mg, 0.57 mmol,
57 %, [α]2D3 = −16.2◦ (c = 1.05, i-Pr2O)] and (–)-2 [65 mg,
0.43 mmol, 43 %, [α]2D3 = −8.1◦ (c = 0.93, i-Pr2O)] as color-
less oils.
1220 (m), 1080 (s), 1045 (m), 1020 (m) cm−1. – H NMR
1
(300 MHz, CDCl3): δ = 1.13 (d, J = 4.9 Hz, 1 H), 1.15
(d, J = 4.9 Hz, 1 H), 1.42 – 1.62 (m, 2 H), 1.81 (d, J =
2.4 Hz, 3 H, CH3C≡), 1.85 – 1.9 (m, 1 H), 1.95 – 2.0 (m,
1 H), 2.03 (s, 3 H, CH3C=O), 2.30 (m, 2 H), 2.41 (d,
J = 4.1 Hz, 1 H), 4.58 (dd, J = 7.4, 3.6 Hz, 1 H, 2-H). –
MS (EI): m/z = 117 [M–AcOH–CH3]+, 132 [M–AcOH]+,
150 [M+H–Ac]+, 177 [M–CH3]+, 192 M+). – HRMS (EI):
m/z = 192.1150 (calcd. 192.1150 for C12H16O2, M+).
HPLC Analysis of the MTPA esters
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Column: Daicel Chiralcel OD (4.6×250 mm); eluent:
hexane/i-PrOH = 100 : 1, 1.0 mL min−1 at 20 ◦C; detection:
254 nm; tR = 70 (80.1 %) and 9.5 (4.9 %) min: 88 % ee.
HPLC Analysis of the 3,5-DNB ester
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Column: Daicel Chiralcel OD (4.6×250 mm); eluent:
hexane/i-PrOH = 9 : 1, 1.0 mL min−1 at 20 C; detection:
◦
(1S∗,2S∗,4S∗,7R∗)-7-(1ꢀ-Propynyl)bicyclo[2.2.1]hept-2-yl
chloroacetate (( )-4)
254 nm; tR = 28 (< 0.5 %) and 38 (> 99.5 %) min: > 99 %
ee.
To a solution of ( )-2 (150 mg, 0.999 mmol) and pyri-
Acknowledgements
dine (0.50 g, 6.3 mmol) in dry Et2O was added chloroacetyl
◦
We thank Roche Diagnostics K. K. for the gifts of various
lipases. This work was partially supported by a Grant-in-aid
for Scientific Research from the Japan Society for the Pro-
motion of Science (19580120).
chloride (339 mg, 2.98 mmol) at −20 C. The mixture was
◦
stirred for 12 h at 20 C, then diluted with Et2O, washed
with dil. HCl (5 times), sat. aq. NaHCO3 soln. and brine,
dried with MgSO4 and concentrated in vacuo. The residue
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[6] Dictionary of Organic Compounds, Vol. 1 (5th Ed.)
(Ed.: J. Buckingham), Chapman and Hall, New York,
London, Toronto, 1982, pp. 970 – 971.
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