Chemo-enzymatic preparations of (R)- and (S)-3-iodocyclohex-2-en-1-yl acetate

Article abstract of DOI:10.1081/SCC-120021839

Kinetic resolutions by lipase-catalyzed transesterification with 3-iodocyclohex-2-en-1-ol or 3-iodocyclohex-2-en-1-yl acetate followed by inversion of the chirality of the optically active alcohol without separation from the acetate have allowed the preparation of (R)- and (S)-3-iodocyclohex-2-en-1-yl acetate with more than 70% yield and more than 85% ee.

Full text of DOI:10.1081/SCC-120021839

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Chemo-enzymatic Preparations of (R)- and (S)-3-
Iodocyclohex-2-en-1-yl Acetate
J. P. Barnier a & L. Blanco a
a Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire et des
Matériaux d'Orsay, Université de Paris-Sud, Orsay, France
Version of record first published: 20 Aug 2006.
To cite this article: J. P. Barnier & L. Blanco (2003): Chemo-enzymatic Preparations of (R)- and (S)-3-Iodocyclohex-2-en-1-yl
Acetate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:14,
2487-2496
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2487–2496, 2003
Chemo-enzymatic Preparations of
(R)- and (S )-3-Iodocyclohex-2-en-1-yl Acetate
*
J. P. Barnier and L. Blanco
Laboratoire des Carbocycles (Associe au CNRS),
Institut de Chimie Moleculaire et des Materiaux
d’Orsay, Universite de Paris-Sud, Orsay, France
ABSTRACT
Kinetic resolutions by lipase-catalyzed transesterification with
3-iodocyclohex-2-en-1-ol or 3-iodocyclohex-2-en-1-yl acetate fol-
lowed by inversion of the chirality of the optically active alcohol
without separation from the acetate have allowed the preparation
of (R)- and (S)-3-iodocyclohex-2-en-1-yl acetate with more than
70% yield and more than 85% ee.
*Correspondence: L. Blanco, Laboratoire des Carbocycles (Associe au CNRS),
Institut de Chimie Moleculaire et des Materiaux d’Orsay, Bat. 420, Universite
de Paris-Sud, 91405 Orsay, France; Fax: þ33 01 69 15 62 78; E-mail: lublanco@
icmo.u-psud.fr.
2487
DOI: 10.1081/SCC-120021839
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2488
Barnier and Blanco
INTRODUCTION
Optically active 3-iodocyclohex-2-en-1-ols may be regarded as chi-
rons in the sense proposed by E. J. Corey. They were used to prepare
enantiomerically enriched unsubstituted and 3-substituted cyclohex-
2-en-1-ols[1–3] and also optically active endo-bicyclo[4.1.0]hexan-2-ol deri-
vatives[3] (Sch. 1).
Optically active (R)- and (S)-3-iodocyclohex-2-en-1-ol have been pre-
pared[1] after resolution of the corresponding racemic phthalic half ester,
by preferential crystallization of the salt obtained from (S)-phthalate and
cinchonine (3–4 days) or that obtained from (R)-phthalate and cincho-
nidine (2–3 days). In both cases a diastereomerically pure salt was
obtained after four recrystallizations. Treatment of these salts with
acidic medium and reaction with LiAlH4 of the phthalic half esters deliv-
ers the enantiopure (R)- and (S)-3-iodocyclohex-2-en-1-ol[4] (Sch. 2).
This article concerns a faster enzymatic method to prepare optically
active 3-iodocyclohex-2-en-1-ols.
To our knowledge the preparation of optically active 3-iodocyclohex-
2-en-1-ol by lipase-catalyzed resolution or by treatment of 3-iodocyclo-
hex-2-en-1-one with a chiral reducing agent has not been reported. A
close analogue to this iodocyclohexenol is probably 3-bromocyclohex-
2-en-1-ol. Reduction of 3-bromocyclohex-2-en-1-one with complexes of
LiAlH4 with DARVON or NOVRAD alcohols allows the preparation of
Scheme 1.
Scheme 2.

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(R)- and (S)-3-Iodocyclohex-2-en-1-yl
2489
optically active 3-bromocyclohex-2-en-1-ol with, at best, 60% enantio-
meric excess.[5] The (R)- and (S)-3-bromocyclohex-2-en-1-ol were
prepared with higher enantiomeric excesses (ee ꢀ 79%) when the
corresponding racemic chloroacetate was subjected to hydrolysis in the
presence of lipase P-30.[4] The enantiomeric ratio (E ) of this reaction,
calculated from the reported enantiomeric excess of the product (eep) and
that of the remaining chloroacetate (ees), was about 21.[6] A higher enan-
tiomeric ratio (E ¼ 44) was reported for the transesterification of vinyl
acetate with this 3-bromocyclohexenol in the presence of lipase from
Pseudomonas cepacia immobilized on Hyflo Supercel.[7]
The transesterification of isopropenyl acetate with 2-iodocyclohex-
2-en-1-ol afforded a lower enantioselectivity (E ¼ 50) when using the
lipase from Pseudomonas cepacia as compared to the immobilized recom-
binant Candida antarctica lipase B (E ꢁ 450).[8] Therefore we decided to
try the resolution of 3-iodocyclohex-2-en-1-ol by enzymatic reaction
using the lipase B from Candida antarctica.
RESULTS AND DISCUSSION
Racemic 3-iodocyclohex-2-en-1-ol 3 was prepared by LiAlH4-
mediated reduction of 3-iodocyclohex-2-en-1-one 2,[1] itself obtained by
treatment of commercial cyclohexan-1,3-dione 1 with triphenylphosphine
diiodide and triethylamine in acetonitrile[9] (Sch. 3)
Transesterification of isopropenyl acetate with 3-iodocyclohexenol 3
was performed at 37ꢂC in tert-butyl methyl ether in the presence of
NovozymÕ
(62% weight based on alcohol) and the conversion (c)
[10]
1
was monitored by H-NMR. After 55 min (c ꢃ 50%) the reaction was
stopped by removal of the enzyme by filtration, and the unreacted iodo-
cyclohexenol 3-(S ) and the iodocyclohexenyl acetate 4-(R) were separated
by silica gel column chromatography. The absolute configuration of the
major enantiomers of these optically active compounds was attributed by
comparison of the chiroptical properties of 3-(S ) with those described
in the literature.[2] The enantiomeric excess (ees) of alcohol 3-(S ) was
Scheme 3.

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2490
Barnier and Blanco
determined by HPLC using a chiral column (Pharmachir 4C) of the
phenylcarbamate 5-(S ) obtained by reaction of this alcohol with phenyl
isocyanate in the presence of DABCO. Enantiomeric excess (eep) of ace-
tate 4-(R) was measured by the same method as above after treatment
with LiAlH4 to deliver the corresponding alcohol 3-(R) and formation of
the phenylcarbamate 5-(R)[11] (Sch. 4).
Enantiomeric excess of the isolated 3-iodocyclohexenol 3-(S ) (46%
yield) and that of the iodocyclohexenyl acetate 4-(R) (42.5% yield) were
respectively 83% and 94%. Using the usual formulas[6] it was calculated
that the transformation was stopped when c was equal to 47% and E of
the reaction was approximatively 84.
When the objective is the preparation of one enantiomer of this class
of secondary alcohol by resolution, the major drawback is the loss of half
of the starting racemic mixture. One way to overcome this limitation is to
perform an inversion at the chiral centre of one of the optically active
compounds.[12] Inversion of chirality of the alcohol 3-(S ) (83% ee) by
the Mitsunobu method[13] using acetic acid allowed the isolation of the
iodocyclohexenyl acetate 4-(R) with 74% ee (Sch. 5).
Although this inversion occured with some loss of the enantiomeric
excess, a more convenient sequence to prepare the optically active ester
4-(R) was envisaged owing to the high enantioselectivity of the enzy-
matic reaction. By performing the lipase-catalyzed transesterification
with a conversion slightly greater than 50%, an optically active alcohol
with a higher enantiomeric excess could be obtained, followed by an
inversion of alcohol chirality without separation from the optically
active acetate.
Scheme 4.

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(R)- and (S)-3-Iodocyclohex-2-en-1-yl
2491
Scheme 5.
Scheme 6.
Transesterification of isopropenyl acetate with iodocyclohexenol 3 in
the presence of NovozymÕ was performed for 90 min. The crude mixture
of optically active alcohol 3-(S ) and ester 4-(R) was treated as above by
the Mitsunobu method with acetic acid. The iodocyclohexenyl acetate
4-(R) was isolated in 70% yield and high enantiomeric excess (90%)
after only one chromatographic purification for this two steps sequence
(Sch. 6).
In order to prepare selectively the iodocyclohexenyl acetate 4-(S ) by
a lipase-catalyzed reaction/inversion of alcohol chirality sequence, we
decided to attempt the transesterification of the racemic acetate 4 with
propan-1-ol in the presence of a lipase. The racemic ester 4 was easily
prepared by treatment of alcohol 3 with acetic anhydride in the presence
of 4-dimethylaminopyridine (DMAP). The calculated enantiomeric ratio
(E ¼ 25) of the NovozymÕ-catalyzed reaction seemed too low to obtain
the desired ester with a good enantiomeric excess after the Mitsunobu
reaction. With the lipase from Pseudomonas cepacia (LPS) (170% weight
based on ester) the reaction was much slower and the enantioselectivity
was higher (E ¼ 267) (Sch. 7).
Transesterification of iodocyclohexenyl acetate 4 with propan-1-ol
in the presence of LPS was performed for 18 h. After treatment of
the crude reaction mixture with acetic acid using the Mitsunobu
method and silica gel chromatography, the iodocyclohexenyl acetate
4-(S ) was isolated in 82% yield and 85.5% enantiomeric excess
(Sch. 8).

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Barnier and Blanco
Scheme 7.
Scheme 8.
It is notable that a single recrystallization of the phenylcarbamate
5-(S ) prepared from the acetate 4-(S ) afforded an increase in the
enantiomeric excess from 85.5% to 99.7%.
EXPERIMENTALPART
3-iodocyclohex-2-en-1-one 2[8] and 3-iodocyclohex-2-en-1-ol 3[2] were
prepared as reported in the literature. Dry solvents were obtained
as follows: diethyl ether was distilled over LiAlH4 and THF over
sodium-benzophenone radical-anion, tert-butyl methyl ether was filtered
through a pad of basic alumina (activity I).
Preparation of Racemic 3-Iodocyclohex-3-en-1-yl Acetate 4
To a solution of 168 mg of iodocylohexenol 3 (0.75 mmol) in 2 mL of
ether maintained under argon atmosphere were added 80 mL of acetic

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(R)- and (S)-3-Iodocyclohex-2-en-1-yl
2493
anhydride (0.80 mmol) and 12 mg of DMAP (0.1 mmol). After stirring for
1 h the solvent was evaporated under reduced pressure and a silica gel
column chromatography (pentane/ether: 95/5) provided 180 mg of 3-
iodocyclohex-3-en-1-yl acetate 4 (90%). IR (film) (cmÀ1): 1735 (ꢀC¼O),
1
1634 (ꢀC¼C). H NMR (200 MHz, CDCl3) ꢁ: 6.49–6.00 (m, 1H, –CH¼),
5.72–5.62 (m, 1H, CH-OAc), 2.70–2.48 (m, 2H), 2.07 (s, 3H), 2.00–1.59
(m, 4H). 13C NMR (63 MHz, CDCl3) ꢁ: 170.27 (–C¼O), 135.50 (–CH¼),
103.74 (–CI¼), 69.25 (CH-O), 39.17, 26.66, 21.33, 21.11. Anal. calcd.
for C8H11IO2: C, 36.10; H, 4.13; O, 12.03. Found: C, 36.35; H, 4.23;
O, 11.81.
Preparation of (R)-3-Iodocyclohex-3-en-1-yl Acetate 4-(R)
Thirty milligrams of NovozymÕ were added to a solution of 115 mg
of alcohol 3 (0.50 mmol) and 0.1 mL of isopropenyl acetate (0.91 mmol)
in 1.5 mL of tBuOMe and the mixture was shaken for 90 min at 37ꢂC.
The immobilized enzyme was removed by filtration and washed with
tBuOMe. The filtrate was concentrated under reduced pressure, the
remaining mixture of optically active alcohol 3-(S ) and acetate 4-(R)
was diluted with 1 mL of ether and a solution of 68 mg of triphenyl-
phosphine (0.26 mmol) in 1 mL of ether was added. A solution of 45 mg
of DEAD (0.26 mmol) and 16 mg of acetic acid (0.26 mmol) in 1 mL
of ether was subsequently added dropwise at 20ꢂC and allowed to
react for 1 h. The solvent was removed under reduced pressure and
4 mL of a mixture ether/pentane (1/1) were added. The suspension
was filtered and the solvent was removed under reduced pressure.
Silica gel column chromatography (pentane/ether: 95/5) of the crude
20
product provided 94 mg of the purified acetate 4-(R) (70%), ½ꢂŠ
þ
D
132 (c ¼ 1.90, THF).
Preparation of (S )-3-Iodocyclohex-3-en-1-yl Acetate 4-(S)
Zero point four four millimolar of acetate 4 was treated with 200 mg
(2.66 mmol) of dry propan-1-ol and 200 mg of LPS in 2 mL of dry
tBuOMe at 37ꢂC. After 18 h stirring, the crude enzyme was removed
by filtration, washed with tBuOMe and the solvent was evaporated
under reduced pressure. The remaining product was diluted in 1 mL of
ether and 64 mg of triphenylphosphine (0.24 mmol) were added followed

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2494
Barnier and Blanco
by a solution of 43 mg of DEAD (0.24 mmol) and 15 mg of acetic acid
(0.24 mmol) in 1 mL of ether. This was allowed to react for 1 h at 20ꢂC.
After evaporation of the solvent, precipitation and separation of
triphenylphosphine oxide as above, the crude product was purified by
silica gel column chromatography (pentane/ether: 95/5) to provide
20
95.5 mg of the acetate 4-(S ) (82%), ½ꢂŠ À130.5 (c ¼ 1.04, THF).
D
Synthesis of 3-Iodocyclohex-3-en-1-ol 3-(R) or
3-(S ) from Acetates 4-(R) and 4-(S )
A solution of 80 mg of acetate (0.3 mmol) in 1 mL of ether was added
dropwise with a syringe at 20ꢂC to a solution of 10 mg of LiAlH4
(0.26 mmol) in 2 mL of ether and the mixture was stirred for 1 h.
Hydrolysis was performed with wet Na2SO4 and, after filtration and
evaporation of the solvent, silica gel column chromatography (pen-
tane/ether: 80/20) of the crude product gave 64 mg of the corresponding
20
alcohol (95%). 3-(R) ½ꢂŠ þ11.1 (c ¼ 0.68, CHCl3) from acetate 4-(R)
D
20
D
20
D
(½ꢂŠ þ132). Litt. ½ꢂŠ þ12.8 (c ¼ 0.416, CHCl3) for pure (R) alcohol.[2]
20
D
20
D
3-(S ) ½ꢂŠ À11 (c ¼ 1.96, CHCl3) from acetate 4-(S ) (½ꢂŠ þ132).
Synthesis of O-3-Iodocyclohex-3-en-1-yl-N-phenyl Carbamate
5-(S ) or 5-(R) from Alcohols 3-(S ) and 3-(R)
To a solution of 27 mg of alcohol (0.12 mmol) in 2 mL of THF under
argon atmosphere were added 13 mL of phenyl isocyanate (0.12 mmol)
and 3 mg of DABCO (27 mmol). The reaction mixture was stirred for
1 h at 20ꢂC, and the solvent was removed under reduced pressure. Silica
gel column chromatography of the crude product (pentane/ether: 97/3)
afforded 34 mg of pure phenylcarbamate (81%). Enantiomeric
excesses were determined by HPLC on a Pharmachir 4C column
(250 ꢄ 4.6 mm), eluent hexane/ethanol: 94/6, flow rate: 1.5 mL/min, reten-
tion times: t5-(R) ¼ 11.8 min, t5-(S) ¼ 14.3 min. 5-(R) ee ¼ 90% from alcohol
20
20
D
3-(R) (½ꢂŠD þ11.1). 5-(S ) ee ¼ 85.5% from alcohol 3-(S ) (½ꢂŠ À11). This
solid carbamate was recrystallized in pentane at À10ꢂC: ee ¼ 99.7%,
m.p. ¼ 80ꢂC. 1H NMR (250 MHz, CDCl3) ꢁ: 7.42–7.24 (m, 4H),
7.12–7.02 (m, 1H), 6.62 (broad s, 1H), 6.57–6.49 (m, 1H), 5.25–5.12 (m,
1H), 2.70–2.40 (m, 1H), 2.04–1.60 (m, 4H). 13C NMR (63 MHz, CDCl3)
ꢁ: 152.75 (C¼O), 137.65 (C-NH), 135.74 (CH¼), 129.03, 123.48, 118.62,

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(R)- and (S)-3-Iodocyclohex-2-en-1-yl
2495
103.92 (–CI¼), 70.07, 39.28, 26.98, 21.36. Anal. calcd. for C13H14INO2: C,
45.48; H, 4.08. Found: C, 45.66; H, 4.15.
ACKNOWLEDGMENT
We are grateful to Novo Nordisk A/S (Denmark) for a gift of
NovozymÕ.
REFERENCES
1. Mori, K.; Tamada, S.; Uchida, M.; Mizumachi, N.; Tachibana, Y.;
Matsui, M. Tetrahedron 1978, 34, 1901–1905.
2. The pallado-catalyzed preparation of optically active (3-hydroxy-
cyclohex-1-enyl)phosphonate was reported from enantiomerically
enriched 3-bromocyclohex-2-en-1-ol: Attolini, M.; Bouguir, F.;
Iacazio, G.; Peiffer, G.; Maffei, M. Tetrahedron 2001, 57, 537–543.
3. Barnier, J.-P.; Morisson, V.; Volle, I.; Blanco, L. Tetrahedron:
Asymmetry 1999, 10, 1107–1117.
4. Enantiomeric excesses of (R)- and (S)-3-iodocyclohex-2-en-1-ol were
determined after transformation to 3-methylcyclohex-2-en-1-ol
(Seudenol), by 1H-NMR of the corresponding a-methoxy a-
trifluoromethylphenylacetate and from its chiroptical properties.
5. Paquette, L.A.; Elmore, S.W.; Combrink, K.D.; Hickey, E.R.;
Rogers, R.D. Helv. Chim. Acta 1992, 75, 1755–1771.
6. c ¼ ees/ees þ eep; E ¼ Ln[(1ꢀees)(eep/ees þ eep)]/Ln[(1 þ ees)(eep/ees þ
eep)].
7. Carrea, G.; Danieli, B.; Palmisano, G.; Riva, S.; Santagostino, M.
Tetrahedron: Asymmetry 1992, 3, 775–784.
8. Johnson, C.R.; Sakaguchi, H. Synlett 1992, 813–816.
9. Piers, E.; Nagakura, I. Synth. Commun. 1975, 5, 193–199.
10. NovozymÕ was an immobilized form of lipase B from Candida
antarctica prepared by Novo Nordisk A/S (Denmark). Now a
similar immobilized-enzyme, named ChirazymeÕ L-2, c-f, C2
Lyo., is prepared by Boehringer Mannheim GmbH.
11. Enantiomeric excesses of optically active acetates 4-(S ) and 4-(R)
(prepared from alcohol 3-(R)) could be determined by gas
chromatography on a chiral capillary column (Cydex B). With a
25 m column (0.25 mn id, gas carrier: helium, P ¼ 70 KPa, 80ꢁC)
the retention times were around 2 h but the separation of the
enantiomers was not sufficient to obtain accurate measurements.

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2496
Barnier and Blanco
12. Lallemand, J.-Y.; Leclaire, M.; Levet, R.; Aranda, G. Tetrahedron:
Asymmetry 1993, 4, 1775–1778.
13. Mitsunobu, O. Synthesis 1981, 1–28.
Received in the Netherlands May 22, 2002