Enzyme-mediated synthesis of (S)- And (R)-verapamil

Article abstract of DOI:10.1002/1099-0690(200104)2001:7<1349::AID-EJOC1349>3.0.CO;2-9

A lipase-mediated synthesis of (S)- And (R)-verapamil is described. The key steps of the synthetic sequence are the enantioselective acetylation, mediated by Lipase PS, of allylic alcohol (Z)-(±)-2, affording the acetate derivative (Z,R)-(-)-3 (ee 92%) and the Ireland-Claisen rearrangement of this latter and of its enantiomer (Z,S)-(+)-3 (ee 92%) to afford acid derivatives (E,R)-(-)-4 (ee 94%) and (E,S)-(+)-4 (ee 93%), precursors of (S)- and (R)-verapamil, respectively.

Full text of DOI:10.1002/1099-0690(200104)2001:7<1349::AID-EJOC1349>3.0.CO;2-9

FULL PAPER
Enzyme-Mediated Synthesis of (S)- and (R)-Verapamil
Elisabetta Brenna,*[a] Claudio Fuganti,[a] Piero Grasselli,[a] and Stefano Serra[a]
Keywords: Chiral drugs / Ireland rearrangement / Kinetic resolution / Lipases / Verapamil
A lipase-mediated synthesis of (S)- and (R)-verapamil is de-
(ee 92%) and the Ireland−Claisen rearrangement of this lat-
scribed. The key steps of the synthetic sequence are the en- ter and of its enantiomer (Z,S)-(+)-3 (ee 92%) to afford acid
antioselective acetylation, mediated by Lipase PS, of allylic
alcohol (Z)-(±)-2, affording the acetate derivative (Z,R)-(−)-3
derivatives (E,R)-(−)-4 (ee 94%) and (E,S)-(+)-4 (ee 93%), pre-
cursors of (S)- and (R)-verapamil, respectively.
Introduction
of enantiopure (ϩ)-1 and (؊)-1, and wish to report on the
results of this research in this paper.
Verapamil (1) belongs to the phenylalkylamine class of
calcium channel blockers, characterized by a 5-amino-2-al-
kyl-2-phenylpentanenitrile moiety. It is widely used in ra-
cemic form for the treatment of vasospastic and classical
angina pectoris and of superventricular tachycardia. The
two enantiomers of verapamil have different pharmacoki-
netic and pharmacodynamic properties.[1] It has been
shown that (S)-(Ϫ)-1 is more effective as a calcium channel
blocker, while the R enantiomer is of potential interest for
the treatment of multiple drug resistance during cancer
therapy.[2] Thus, the development of stereoselective strat-
egies to both of the enantiopure forms of verapamil would
be highly desirable.
Only two methods for the preparation of enantiopure
(Ϫ)- and (ϩ)-1 have been reported in the literature. The
first one[3] was based on the classical resolution of diaster-
eoisomeric salts of the key intermediate 3,4-dimethoxy-
phenyl-2-isopropyl-2-penten-4-oic acid by recrystallisation.
A certain number of patents involving similar resolution
procedures have also been registered.[4]
The second synthetic pathway to the enantiopure forms
of verapamil, adhering to the so-called strategy of the pool
of chirality, employed optically active (2S)-(ϩ)- and (2R)-
(Ϫ)-1,2-propanediol as starting materials.[5] In 1996, a re-
newal of interest in the matter was witnessed after the ap-
pearance of a paper describing a quite general route for the
synthesis of enantiomerically pure precursors of 5-amino-
2-alkyl-2-phenylpentanenitrile, starting from commercially
available chiral derivatives.[6] Both enantiomers of noremo-
pamil were prepared in 98% ee.
Results and Discussion
The first key step of our synthetic pathway (Scheme 1) is
the enantioselective acetylation, mediated by Lipase PS, of
allylic alcohol (Z)-(Ϯ)-2, affording the acetate derivative
(Z,R)-(Ϫ)-3. The second is the IrelandϪClaisen rearrange-
ment of this latter, and of its enantiomer (Z,S)-(ϩ)-3, to
afford acid derivatives (E,R)-(Ϫ)-4 and (E,S)-(ϩ)-4, respect-
ively. By means of unexceptional but high-yielding organic
reactions, we were able to homologate the CH2COOR frag-
ment into the CH2CH2CH2Cl substituent, and to convert
the propenyl unit into a CN group. Enantiomerically en-
riched chloro derivatives (S)-(Ϫ)-5 and (R)-(ϩ)-5 afforded
(S)-(Ϫ)-1 and (R)-(ϩ)-1, respectively, on treatment with N-
methylhomoveratrylamine.[3]
Racemic (Z)-2 was prepared according to the synthetic
procedure reported in Scheme 2. Condensation of 3,4-dime-
thoxyphenyl isopropyl ketone with acetonitrile in the pres-
ence of butyllithium afforded, after dehydration in toluene
catalysed by 4-toluenesulfonic acid, a 1.5:1 mixture (1H
NMR) of (Z)- and (E)-6. DIBAL-H reduction to aldehydes
(Z)- and (E)-7 (1.4:1, GC-MS), followed by treatment with
methylmagnesium bromide in THF, afforded a 1.5: 1 mix-
ture (GC-MS) of Z and E allylic alcohols 2. Easy chroma-
tographic separation of the corresponding acetate derivat-
ives, followed by alcoholic potassium hydroxide saponifica-
tion, allowed us to isolate racemic (Z)- and (E)-2.
The stereochemistry of the double bond was defined by
1H NMR spectra analysis: strong NOE effects were ob-
served between HϪC(5) and the vinylic hydrogen in deriva-
tive (Z)-3, and between HϪC(5) and HϪC(2) in derivative
(E)-3.
In the past we have been involved in the synthesis of op-
tically active intermediates of verapamil by means of an ap-
proach mediated by bakers’ yeast.[7] Recently, we have suc-
cessfully applied
a
lipase-catalysed stereoselective
Both the racemic allylic alcohols (Z)- and (E)-2 were sub-
mitted to lipase-mediated acetylation. Biotransformation
was observed only in the presence of Lipase PS as a cata-
lyst, in diethyl ether solution, using vinyl acetate as an acyl
donor. Other enzymes (such as Candida rugosa lipase and
porcine pancreatic lipase) that had been active in the
acetylation of disubstituted allylic alcohols[10] did not con-
acetylation of allylic alcohols to the synthesis of chiral
drugs[8,9] and fragrances.[10Ϫ13] We devised a possible means
to exploit this kind of kinetic resolution for the preparation
[a]
Dipartimento di Chimica del Politecnico, Centro CNR per la
Chimica delle Sostanze Organiche Naturali,
Via Mancinelli 7, 20131 Milano, Italy
Eur. J. Org. Chem. 2001, 1349Ϫ1357
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0407Ϫ1349 $ 17.50ϩ.50/0
1349

E. Brenna, C. Fuganti, P. Grasselli, S. Serra
FULL PAPER
vert these trisubstituted allylic alcohol derivatives (Z)- and
(E)-2 at all.
Alcohol derivatives (Z)-(Ϯ)-2 and (E)-(Ϯ)-2 gave (Z,R)-
(Ϫ)-3 ([α]2D0 ϭ Ϫ16, c ϭ 1.05, CH2Cl2; ee ϭ 92%, HPLC;
c[14] ϭ 34%, E[14] ϭ 35 after 108 h reaction time), and
(E,R)-(ϩ)-3 ([α]D20 ϭ 95, c ϭ 1.48, CH2Cl2; ee ϭ 92%,
HPLC of the corresponding alcohol; c ϭ 45%, E ϭ 67 after
24 h reaction time), respectively. In both cases the R config-
uration was assigned to C(-2); indeed, acetate derivative
(Z,R)-(Ϫ)-3 was correlated to methyl (R)-(Ϫ)-O-benzoyl-
lactate ([α]2D0 ϭ Ϫ13.5, c ϭ 3.2 CHCl3) through a synthetic
path we have already described (Scheme 3).[10]
Scheme 3. i. Lipase PS, diethyl ether, vinyl acetate; column chroma-
tography; ii. 4-toluenesulfonyl chloride, pyridine; iii. sodium acetate
in dimethylformamide; iv. KOH in methanol.
Scheme 1. Ar ϭ 3,4-dimethoxyphenyl; R ϭ isopropyl.
Kinetic resolution of (Z)-(Ϯ)-2 was very slow: conversion
had only reached 34% even after 108 h reaction time. Ac-
cordingly, access to (Z,S)-(ϩ)-3 by chemical acetylation of
the surviving alcohol (Z,S)-(Ϫ)-2 (ee ϭ 47%, HPLC) could
not be satisfactorily achieved. Inversion of the configura-
tion of the stereogenic carbon atom of the enzymically
acetylated product was performed (Scheme 3): saponifica-
tion of (Z,R)-(Ϫ)-3, followed firstly by treatment with 4-
toluenesulfonyl chloride in pyridine and then by acetate dis-
placement, gave (Z,S)-(ϩ)-3 (ee ϭ 92%). In order to limit
the quantity of waste material, and to enrich the starting
alcoholic mixture in the enantiomer transformed effectively
by Lipase PS, alcohol (Z,S)-(Ϫ)-2 (ee ϭ 47%, HPLC) was
submitted to same procedure to yield (Z,R)-(ϩ)-2 (ee ϭ
40%). Starting from 50 g of (Z)-(Ϯ)-2, nearly 30 g of (Z,R)-
(Ϫ)-3 (ee ϭ 92%) were recovered: half of this quantity was
used to prepare (Z,S)-(ϩ)-3 (ee ϭ 92%, HPLC).
When derivative (E,R)-(ϩ)-3 (ee ϭ 92%) was subjected
to rearrangement conditions according to Ireland’s proced-
ure,[15] racemic acid (E)-4 (identified by HPLC of the cor-
responding methyl ester) was obtained. The acetate derivat-
ive recovered unchanged from this reaction was found to be
a 6:4 mixture (GC-MS) of (E,R)-(ϩ)-3 (ee ϭ 92%, HPLC
Scheme 2. i: acetonitrile, butyllithium, THF; 4-toluenesulfonic acid
in toluene; ii: DIBAL-H in toluene; iii: methylmagnesium bromide
in THF; iv: acetic anhydride in pyridine; column chromatography;
v: KOH in methanol.
1350
Eur. J. Org. Chem. 2001, 1349Ϫ1357

Enzyme-Mediated Synthesis of (S)- and (R)-Verapamil
FULL PAPER
of the corresponding alcohol) and (Z,R)-(Ϫ)-3 (ee ϭ 90%,
HPLC). Thus, the racemisation occurring during the
sigmatropic rearrangement could be attributed to the iso-
merisation of the double bond, probably promoted by the
basic medium of the Ireland reaction. It is known[16] that
Claisen-type rearrangement of diastereoisomeric allylic al-
cohols that display the same configuration at the ste-
reogenic carbon atom and opposite configuration at the
double bond affords the two enantiomers of the corres-
ponding γ,δ-unsaturated ester derivative.
We then found evidence of the peculiar mobility of this
double bond towards the isopropyl unit while we were at-
tempting the synthesis of acid 8 (to be used as a precursor
of alcohol 2) by saponification with alcoholic potassium hy-
droxide of ester 9a (Scheme 4 ). A 6:4 mixture of the two
regioisomer 8 and 10 was invariably obtained.
Scheme 5. Transition states and final products of IrelandϪClaisen
rearrangement of the two isomers of allylic alcohol (Z)-2
through a concerted rearrangement, we looked for simple
high-yielding reactions with which to manipulate interme-
Scheme 4
Ester 9a was obtained as a single diastereoisomer from diates (ϩ)- and (Ϫ)-4 and prepare (ϩ)- and (Ϫ)-1
3,4-dimethoxyphenylisopropyl ketone, by means of
a
(Scheme 6).
Reformatsky reaction followed by dehydration. This deriv-
Acid derivative (E,R)-(Ϫ)-4 was esterified by treatment
ative was found to be the precursor of allylic alcohol (Z)-2: with diazomethane in diethyl ether to afford the methyl es-
thus cis stereochemistry could be ascribed to its double ter derivative (E,R)-(Ϫ)-11 (ee ϭ 93%, HPLC). The intro-
bond. A search in the literature revealed that two con- duction of an extra carbon atom into the CH2COOCH3
trasting 1H NMR spectra of the unsubstituted derivative 9b fragment was achieved by nucleophilic cyanide anion sub-
had been reported.[17,18] One[17] assigned the trans config- stitution on the tosylate derivative (E,R)-(Ϫ)-13. Hydrolysis
uration to the substrate displaying HϪC(4) at δ ϭ 4.11 as of the nitrile group with KOH 20% in diethylene glycol,
a septet and HϪC(2) at 5.70 as a singlet, and the cis config- esterification with diazomethane, DIBAL-H reduction and
uration to the substrate with HϪC(4) at δ ϭ 2.65 as a acetylation with acetic anhydride in pyridine yielded com-
double septet and HϪC(2) at 5.87 as a doublet. In the other pound (E,R)-(Ϫ)-18. This latter was subjected to ozonolysis
paper,[18] the assignment was the exact opposite. The effect under strictly controlled conditions: quenching of the reac-
of the methoxy groups of the aromatic rings being quite tion mixture with triphenylphosphane afforded aldehyde
negligible, our stereochemical assignment of compound 9a, (S)-(Ϫ)-19. The formyl group was converted into a CN
based on the chemical correlation to derivative (Z)-2, en- group by treatment with hydroxylamine hydrochloride and
dorsed the NMR spectroscopic data reported in refer- sodium acetate in ethanol, followed by acetic anhydride.
ence[14] [9a, δH, J in Hz: 6.84 (d, 1 H, J ϭ 8), 6.68 (dd, 1 Derivative (S)-(Ϫ)-20 was hydrolysed, using potassium hy-
H, J ϭ 8, 2), 6.65 (d, 1 H, J ϭ 2), 5.83 (d, 1 H, J ϭ 0.7), droxide in refluxing methanol, to alcohol derivative (S)-
3.99 (q, 2 H, J ϭ 7), 3.88 (s, 3 H), 3.86 (s, 3 H), 2.65 (1 H, (Ϫ)-21 ([α]2D0 ϭ Ϫ11.5, c ϭ 2.75 CHCl3; optical purity ϭ
d septet, J ϭ 7, 0.7), 1.08 (m, 9 H)].
91% ee; ref.[5] [α]D20 ϭ Ϫ12.6, c ϭ 3.84 CHCl3).
When derivative (Z,R)-(Ϫ)-3 was submitted to Ireland re-
Optically active (S)-(Ϫ)-21 was quantitatively converted
action conditions, (E,R)-(Ϫ)-4 (ee ϭ 94%, HPLC of the into chloro derivative (S)-(؊)-5 ([α]2D0 ϭ Ϫ 11.2, c ϭ 1.15,
corresponding ester) was obtained, bond formation occur- methanol; optical purity: 91% ee; ref.[3] [α]D20 ϭ Ϫ12.3, c ϭ
ring on the si face of the allylic double bond. The config- 1, methanol) by treatment with triphenylphosphane in car-
urational assignment was based on the analysis of the chair- bon tetrachloride. Coupling of S-(Ϫ)-5 with N-methyl-
like transition states reported in Scheme 5, and was con- homoveratrylamine at 130 °C afforded S-(Ϫ)-1 (the specific
firmed at the end of the synthetic sequence.
rotatory power was determined on the corresponding HCl
The Ireland rearrangement is a suprafacial, concerted, salt: [α]2D0 ϭ Ϫ8.2, c ϭ 5.08, ethanol; optical purity 92% ee;
nonsynchronous pericyclic process that may be considered ref.[3]: [α]D20 ϭ Ϫ8.9, c ϭ 5.00, ethanol).
as an intramolecular SN2Ј process; as the stereochemistry
Enantiomer (R)-1 was produced analogously (the specific
of the resulting double bond is E [J(H-4/H-5) ϭ 16 Hz), the rotatory power was determined on the corresponding hy-
Z,R acetate derivative can afford only the R enantiomer.
drochloride: [α]2D0 ϭ ϩ8.3, c ϭ 5.05, ethanol; optical purity:
Having achieved optical activation by enzymatic kinetic 93% ee; ref. 3: [α]2D0 ϭ ϩ8.9, c ϭ 5.00, ethanol) from optic-
resolution and constructed the tetrasubstituted stereocentre ally active (Z,S)-(ϩ)-3 by the same synthetic sequence.
Eur. J. Org. Chem. 2001, 1349Ϫ1357
1351

E. Brenna, C. Fuganti, P. Grasselli, S. Serra
FULL PAPER
Scheme 6. i: lithium diisospropylamide, trimethylchlorosilane, then room temp., MeOH; ii: diazomethane in diethyl ether; iii: DIBAL-H
in toluene; iv: 4-toluenesulfonyl chloride in pyridine; v: NaCN in DMSO; vi: KOH 20% in diethylene glycol; vii: acetic anhydride in
pyridine; viii: ozone, dichloromethane/ methanol 1:1; then triphenylphosphane; ix: hydroxylamine hydrochloride, sodium acetate in eth-
anol; x: acetic anhydride, sodium acetate, reflux; xi: KOH in methanol, reflux; xii: triphenylphosphane in carbon tetrachloride; xiii: N-
methylhomoveratrylamine.
Conclusions
slow and possible only in the presence of Lipase PS. The
trans arrangement of the same substituents in diastereo-
isomer (E)-(Ϯ)-2 results in a very fast, enantiospecific, Lip-
ase PS-mediated acetylation.
This is the first enzymatic synthesis of the enantiomeric
forms of verapamil. The other two known approaches are
based on the classical resolution of diastereoisomeric
salts,[3] and on the use of components from the pool of chir-
ality.[5] The starting racemic allylic alcohol could easily be
obtained in a multigram scale synthesis from commercially
available veratraldehyde, in good overall yield.
Experimental Section
Lipase PS Burkholderia cepacia (Amano Pharmaceuticals Co., Na-
goya, Japan) was employed in this work. Ϫ Chiral HPLC analyses
were performed on a Merck-Hitachi L-6200 apparatus: Chiralcel
OD (Daicel-Japan) column, 0.6 mL/min, UV detector (254 nm). Ϫ
1H NMR spectra were recorded in CDCl3 solutions at room tem-
perature unless otherwise stated, on a Bruker AC-250 spectrometer
(250 MHz 1H). The chemical shift scale was based on internal
tetramethylsilane. J values are in Hz. Optical rotations were meas-
Both enantiomers [(Z,R)-3 and (Z,S)-(ϩ)-3] were ob-
tained by combining Lipase PS-catalysed acetylation with
inversion of the configuration of the stereocentre at certain
stages of the synthetic sequence. Enrichment of the starting
allylic alcohol mixture into the enantiomer preferentially
converted by Lipase allowed us to obtain (Z,R)-(Ϫ)-3 in
48% yield. The sluggishness of the kinetic resolution was
overcome by performing two subsequent enzymatic ured on a Jasco DIP 181 digital polarimeter. Ϫ Microanalyses were
determined on a Carlo Erba Analyzer 1106. GC-MS analyses were
performed on an HP 6890 gas chromatograph equipped with a
5973 mass detector, using an HP-5MS column (30m ϫ 0.25 mm ϫ
0.25µm). The following temperature programs were employed: A)
60 °C (1 min)/ 6°/min/150° (1 min)/12°/min/280° (5 min); B) 100 °C
(1 min)/ 10°/min/200° (1 min)/5°/min/280° (5 min). Ϫ TLC analyses
were performed on Merck Kieselgel 60 F254 plates. All the chroma-
tographic separations were carried out on silica gel columns.
acetylations: the first on racemic (Z)-2, the second on
(Z,R)-(ϩ)-2, showing ee ϭ 40%. Compound (Z,S)-(ϩ)-3
was then prepared from (Z,R)-(Ϫ)-3.
Stereospecific IrelandϪClaisen rearrangement allowed us
to create the quaternary carbon atom characteristic of vera-
pamil under the strict steric control of the enantiomerically
enriched starting allylic acetate. Derivatives (E,R)-(Ϫ)-4
and (E,S)-(ϩ)-4 were converted into (S)-(Ϫ)-1 and (R)-(ϩ)-
1, respectively, through conventional organic reactions,
characterised by high yields of conversion, and the use of
very common reagents, under mild conditions.
1-(3,4-Dimethoxyphenyl)-2-methylpropan-1-ol: A solution of iso-
propylmagnesium bromide (prepared from 334 g of isopropyl brom-
ide and 62 g of magnesium) in THF (1000 mL) was added dropwise
to a solution of 3,4-dimethoxybenzaldehyde (300 g, 1.81 mol) in
THF (1000 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h. After the usual workup, the residue was puri-
fied by crystallisation from hexane to give the title compound in
The results of this work once again[8Ϫ10] highlight the
effectiveness of enzymes, and in particular of lipases,[19,20]
in resolution processes of racemic substrates, such as allylic
alcohols,[21,22] to which classical methods of crystallisation
of diastereoisomeric salts are not easily applied. The struc-
tural pattern of (Z)-(Ϯ)-2, characterised by a cis-trisubsti-
1
pure form (280 g, 74%); m.p. 56 °C. Ϫ H NMR: δH ϭ 6.87 (s, 1
H, aromatic hydrogen), 6.81 (m, 2 H, aromatic hydrogens), 4.26 [d,
J ϭ 7.2, 1 H, C(1)H], 3.87 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 1.92
tuted double bond, makes the enzymatic acetylation very [septet, J ϭ 7, 1 H, C(2)H], 1.0 (d, J ϭ 7, 3 H, CH3CH), 0.78 (d,
1352 Eur. J. Org. Chem. 2001, 1349Ϫ1357

Enzyme-Mediated Synthesis of (S)- and (R)-Verapamil
FULL PAPER
J ϭ 7, 3 H, CH3CH). Ϫ C12H18O3: calcd. C 68.55, H 8.63; found
C 68.60, H 8.67).
(Z)-7 (120 g, 0.515 mol) in diethyl ether at 0 °C. The reaction mix-
ture was stirred at room temperature for 1 h. After the usual
workup, the residue was chromatographed on a silica gel column,
eluting with hexane/ethyl acetate 6:4. A 1.5:1 mixture of (Z)- and
(E)-2 (GC-MS) was obtained (103 g, 80%). Ϫ GC-MS progr. temp.
A: tR ϭ 21.56 min (Z), 22.25 min (E); m/z ϭ 250 [Mϩ], 232, 217,
201, 189. Ϫ C15H22O3: calcd. C 71.97, H 8.86; found C 71.93, H
8.82.
3,4-Dimethoxyphenyl Isopropyl Ketone: Oxidation of 1-(3,4-dime-
thoxyphenyl)-2-methylpropan-1-ol (280 g, 1.33 mol) according to
Jones’s procedure gave, after purification by silica gel column chro-
matography using hexane/ethyl acetate (9:1) as eluent, the title com-
pound in pure form (226 g, 82%). Ϫ 1H NMR: δH ϭ 7.59 [dd, J ϭ
2.1, 8.3, 1 H, aromatic hydrogen C(6)H], 7.55 (d, J ϭ 2.1, 1 H,
aromatic hydrogen C(2)H], 6.89 [d, J ϭ 8.3, 1 H, aromatic hydrogen
C(5)H], 3.94 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 3.54 [septet, J ϭ
6.7, 1 H, CH(Me)2], 1.21 [d, J ϭ 6.7, 6 H, CH(CH3)2]. Ϫ Ϫ
C12H16O3: calcd. C 69.21, H 7.74; found C 69.26, H 7.78.
(E)-3-(3,4-Dimethoxyphenyl)-1,4-dimethylpent-2-enyl Acetate [(E)-
(؎)-3) and (Z)-3-(3,4-Dimethoxyphenyl)-1,4-dimethylpent-2-enyl
Acetate [(Z)-(؎)-3)]: The 1.8:1 mixture of (Z)- and (E)-2 (above,
103 g, 0.412 mol) was acetylated with acetic anhydride in pyridine,
and the corresponding diastereoisomeric acetates were separated
by column chromatography, eluting with hexane/ethyl acetate (9:1).
The fractions eluted first gave (E)-(Ϯ)-3 (42.1 g, 35%). Ϫ 1H NMR:
δH ϭ 6.85Ϫ6.65 (m, 3 H, aromatic hydrogens), 5.82 (m, 1 H,
CHOAc), 5.26 (d, J ϭ 8.9, 1 H, CHϭC), 3.88 (s, 6 H, 2OMe), 3.18
[septet, J ϭ 7, 1 H, CH(Me)2], 2.06 (s, 3 H, CH3CO), 1.36 (d, J ϭ
6.6, 3 H, CH3CH), 1.04 and 1.05 [2 overlapping d, J ϭ 7, 6 H,
CH(CH3)2]. Ϫ GC-MS progr. temp. A: tR ϭ 23.11 min, m/z ϭ 292
[Mϩ], 232, 217, 207, 189. Ϫ C17H24O4: calcd. C 69.84, H 8.27;
found C 68.93, H 8.32.
3-(3,4-Dimethoxyphenyl)-3-hydroxy-4-methylpentanenitrile: A 10 
solution of butyllithium (162 mL, 1.62 mol) in ether/hexane was
added dropwise to a solution of acetonitrile (66 g, 1.62 mol) in
THF (1000 mL) at Ϫ50 °C. After 30 min, a solution of 3,4-dime-
thoxyphenyl isopropyl ketone (226 g, 1.08 mol) in THF (300 mL)
was added at Ϫ50 °C. The reaction mixture was allowed to warm
to room temperature and then stirred for 2 h. The reaction mixture
was poured into 10% HCl, and extracted with diethyl ether. The
organic phase was dried on sodium sulfate, and concentrated under
reduced pressure, to give a residue (208 g, 77%) which was submit-
1
ted to subsequent reaction without any further purification. Ϫ H
The fractions eluted second gave (Z)-(Ϯ)-3 (62.6 g, 52%). Ϫ 1H
NMR: δH ϭ 6.90Ϫ6.50 (m, 3 H, aromatic hydrogens), 5.38 (dd, 1
H, J ϭ 8.9, 1.16, CHϭC), 5.20 (m, 1 H, CHOAc), 3.89 (s, 3 H,
OMe), 3.87 (s, 3 H, OMe), 2.52 [d, septet, J ϭ 7, 1.16, 1 H,
CH(Me)2], 1.99 (s, 3 H, CH3CO), 1.20 (d, J ϭ 6.1, 3 H, CH3CH),
1.02 and 1.01 [2 overlapping d, J ϭ 7, 6 H, CH(CH3)2]. Ϫ GC-MS
progr. temp. A: tR ϭ 22.25 min, m/z ϭ 292 [Mϩ], 232, 217, 207,
189. Ϫ C17H24O4: calcd. C 69.84, H 8.27; found C 68.87, H 8.31.
NMR: δH ϭ 7.1Ϫ6.88 (m, 3 H, aromatic hydrogens), 3.90 (s, 3 H,
OMe), 3.89 (s, 3 H, OMe), 2.90 (s, 2 H, CH2CN), 2.25 [septet, J ϭ
7, 1 H, CH(Me)2], 0.96 (s, 3 H, CHCH3), 0.82 (s, 3 H, CHCH3).
Ϫ GC-MS: progr. temp. A, tR ϭ 23.23 min, m/z ϭ 249 [Mϩ], 231,
165. Ϫ C14H19NO3: calcd. C 67.45, H 7.68, N 5.62; found C 67.41,
H 7.63, N 5.67.
(E)- and (Z)-3-(3,4-Dimethoxyphenyl)-4-methylpent-2-enenitrile (6):
A solution of 3-(3,4-dimethoxyphenyl)-3-hydroxy-4-methylpent-
anenitrile (208 g, 0.835 mol) in toluene (1000 mL) was refluxed for
2 h in the presence of a catalytic amount of 4-toluenesulfonic acid.
After the usual workup, the residue was chromatographed on a
silica gel column, eluting with hexane/ethyl acetate (7:3). The first
eluted fractions gave a 1.6:1 mixture of (Z)- and (E)-6 (152 g. 79%)
(E)-(؎)-3-(3,4-Dimethoxyphenyl)-1,4-dimethylpent-2-enol (2): A so-
lution of (E)-(Ϯ)-3 (42.1 g, 0.144 mol) and potassium hydroxide
(14.2 g, 0.216 mol) in methanol (250 mL) was refluxed for 1 h.
After the usual workup, (E)-(Ϯ)-3 (35.0 g, 97%) was recovered. Ϫ
1H NMR: δH ϭ 6.90Ϫ6.60 (m, 3 H, aromatic hydrogens), 5.32 (d,
1 H, J ϭ 8.9, CHϭC), 4.82 (m, 1 H, CHOH), 3.88 (s, 6 H, 2OMe),
3.07 [1 Heptet, J ϭ 7, CH(Me)2], 1.33 (d, J ϭ 7, 3 H, CH3CH),
1.09 and 1.05 [2 overlapping d, J ϭ 7, 6 H, CH(CH3)2].
1
Ϫ H NMR: δH ϭ 7.05Ϫ6.70 (m, 6 H, aromatic hydrogens of the
two diastereoisomers), 5.29 (m, 2 H, CHϭC of the two diastereo-
isomers), 3.92 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.90 (s, 3 H,
OMe), 3.89 (s, 3 H, OMe), 3.31 [septet, J ϭ 7, CH(Me)2 of the
minor diastereoisomer], 2.87 [d, septet, J ϭ 7, 1.16, CH(Me)2 of
the major diastereoisomer], 1.29 and 1.11 [2 d, J ϭ 7, 6 H,
CH(CH3)2 of the two diastereoisomers]. Ϫ GC-MS progr. temp. A:
tR ϭ 22.37 min (E), 22.40 (Z); m/z ϭ 231 [Mϩ], 216, 138. Ϫ
C14H17NO2: calcd. C, 72.70, H 7.41, N 6.06; found C 72.75, H
7.46, N 6.09.
(Z)-(؎)-3-(3,4-Dimethoxyphenyl)-1,4-dimethylpent-2-enol (2): A so-
lution of (Z)-(Ϯ)-3 (62.6 g, 0.214 mol) and potassium hydroxide
85% (21.2 g, 0.322 mol) in methanol (300 mL) was refluxed for 1 h.
After the usual workup, (Z)-(Ϯ)-3 (52.1 g, 97%) was recovered. Ϫ
1H NMR: δH ϭ 6.90Ϫ6.60 (m, 3 H, aromatic hydrogens), 5.42 (dd,
J ϭ 8.9 and 1.16, 1 H, CHϭC), 4.18 (m, 1 H, CHOH), 3.89 (s, 3
H, OMe), 3.87 (s, 3 H, OMe), 2.52 [d, septet, J ϭ 7 and 1.16, 1 H,
CH(Me)2], 1.21 (d, J ϭ 6.1, 3 H, CH3CH), 1.02 and 1.01 [2 overlap-
ping d, J ϭ 7, 6 H, CH(CH3)2].
(E)- and (Z)-3-(3,4-Dimethoxyphenyl)-4-methylpent-2-enal (7): A
1.5  solution of DIBAL-H in toluene (660 mL, 0.990 mol) was
added dropwise to a solution of (E)- and (Z)-6 (152 g, 0.660 mol)
in toluene (1000 mL) at Ϫ20 °C. The reaction mixture was stirred
at Ϫ20 °C for 2 h. After the usual workup, a 1.4:1 (GC-MS) mix-
ture of (Z)- and (E)-7 was obtained (120 g, 78%), and used without
Enzyme-Catalysed Acetylations: A mixture of (Z)-(Ϯ)-2 (50.0 g),
lipase (50.0 g), and vinyl acetate (80 mL) in diethyl ether (400 mL)
was stirred at room temperature for 18 h. The residue obtained
upon evaporation of the filtered reaction mixture was chromato-
graphed, eluting with hexaneǞhexane 1:ethyl acetate 1. The first
eluted fractions provided the acetate derivative (Z,R)-(Ϫ)-3 (18.2 g,
30%): [α]2D0 ϭ Ϫ16, c ϭ 1.05, CH2Cl2; ee 92% HPLC: hexane/2-
propanol (95:5) tR (Z,R)-(Ϫ)-3 ϭ 9.4 min, tR (Z,S)-(ϩ)-3 ϭ
11.4 min, (E ϭ 35; c ϭ 34%). Ϫ 1H NMR in accordance with that
of the racemate. The last eluted fractions afforded the unchanged
alcohol (Z,S)-(Ϫ)-2 (34.3 g, 68%) showing ee ϭ 47% (HPLC hex-
ane/2-propanol, 95:5; tR (Z,R)-(ϩ)-2 ϭ 23.0 min, tR (Z,S)-(Ϫ)-2 ϭ
1
any further purification. Ϫ H NMR: δH ϭ 9.44 (d, J ϭ 8, 1 H,
CHO), 7.0Ϫ6.6 (m, 3 H, aromatic hydrogens), 6.06 (d, J ϭ 8, 1 H,
CHϭC), 3.92 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 2.80 [septet, J ϭ
7, 1 H, CH(Me)2], 1.13 [s, 6 H, CH(CH3)2]. Ϫ GC-MS progr. temp.
A: tR ϭ 22.32 min (Z), 22.45 min (E); m/z ϭ 234 [Mϩ], 219, 203,
191. Ϫ C14H18O3: calcd. C 71.77, H 7.74; found C 71.72, H 7.78.
(E)- and (Z)-3-(3,4-Dimethoxyphenyl)-1,4-dimethylpent-2-enol (2):
A 3  solution of methylmagnesium bromide in diethyl ether
(258 mL, 0.772 mol) was added dropwise to a solution of (E)- and
1
32 min). Ϫ H NMR in accordance with that of the racemate.
Eur. J. Org. Chem. 2001, 1349Ϫ1357
1353

E. Brenna, C. Fuganti, P. Grasselli, S. Serra
FULL PAPER
According to the same procedure, (E)-(Ϯ)-2 (20.0 g) gave (E,R)-
Methyl (4E,3R)-(؊)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-eno-
(ϩ)-3 (8.91 g, 38%) after 24 h reaction time: [α]2D0 ϭ 95, c ϭ 1.48, ate [(Ϫ)-11]: Treatment of a solution of acid (Ϫ)-4 (6.20 g, 0.021
CH2Cl2; ee ϭ 92% HPLC of the corresponding alcohol: hexane/2-
propanol, 95:5; tR (E,R)-(ϩ)-2 ϭ 27.1 min, tR (E,S)-(Ϫ)-2 ϭ
22.4 min; E ϭ 67; c ϭ 45%). Ϫ H NMR in accordance with that
mol) in ethyl ether with a solution of diazomethane in ethyl ether
quantitatively gave methyl ester (Ϫ)-11 (6.35 g, 97%). Ϫ [α]2D0
Ϫ57, (c ϭ 0.60, CH2Cl2); ee ϭ 95% HPLC hexane/2-propanol
ϭ
1
1
of the racemate. The recovered alcohol (Z,S)-(Ϫ)-2 (14.9 g, 51%) (99:1), tR (E,R)-(Ϫ)-11 ϭ 24.8 min. Ϫ H NMR: δH ϭ 6.75Ϫ6.90
showed ee ϭ 76% (HPLC); [α]2D0 ϭ Ϫ19.4, c ϭ 0.675, CH2Cl2. Ϫ
(m, 3 H, aromatic hydrogens), 5.70 [dq, J ϭ 16 and 1.1, 1 H,
C(4)H], 5.56 [dq, J ϭ 16 and 6, 1 H, C(5)H], 3.86 (s, 3 H, OMe),
3.82 (s, 3 H, OMe), 3.42 (s, 3 H, COOMe), 2.78 (d, J ϭ 14, 1 H,
CHϪCOOMe), 2.69 (d, J ϭ 14, 1 H, CHϪCOOH), 2.51 [septet,
J ϭ 7, 1 H, CH(Me)2], 1.83 (dd, J ϭ 6 and 1.1, 3 H, CH3CϭC),
0.88 (d, J ϭ 7, 3 H, CH3CH), 0.78 (d, J ϭ 7, 3 H, CH3CH). Ϫ
GC-MS progr. temp. A: tR ϭ 23.88 min (E), m/z ϭ 306 [Mϩ],
263, 203, 189. Ϫ C18H26O4: calcd. C 70.56, H 8.55; found C 70.60,
H 8.51.
1H NMR in accordance with that of the racemate.
By the same procedure, (Z)-2 (ee ϭ 40%, 25.0 g, 0.10 mol) afforded
(Z,R)-(Ϫ)-3 (8.76 g, 30%).
General Procedure for Acetate Displacement: The appropriate al-
lylic alcohol (10.0 g, 0.040 mol) was treated with 4-toluenesulfonyl
chloride (11.4 g, 0.060 mol) in dichloromethane (100 mL) and pyr-
idine (25 mL). After the usual workup, the tosylate derivative was
subjected to acetate displacement in refluxing dimethylformamide
solution (250 mL) in the presence of sodium acetate (4.92 g, 0.060
mol). The appropriate acetate derivative was recovered from the
reaction mixture by column chromatography.
Methyl (4E,3S)-(؉)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-eno-
ate [(؉)-11]: Treatment of a solution of acid (ϩ)-4 (6.40 g, 0.022
mol) in ethyl ether with a solution of diazomethane in ethyl ether
quantitatively gave methyl ester (ϩ)-11 (6.56 g, 97%): [α]2D0 ϭ ϩ 55,
(c ϭ 0.54, CH2Cl2); ee ϭ 95% HPLC: hexane/2-propanol (99:1), tR
(E,S)-(ϩ)-11 ϭ 21.8 min. The analytical data were in accordance
with those of (Ϫ)-11.
According to this procedure, (Z,S)-(Ϫ)-2 (ee 47%, 34.0 g, 0.136
mol) gave (Z,R)-(ϩ)-2 (ee ϭ 40%, 25 g, 73%) after hydrolysis of
the resulting acetate derivative by treatment with potassium hy-
droxide in refluxing methanol.
(4E,3R)-(؊)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-enol [(؊)-
12]: A 65wt.-% Red-Al solution in toluene (9.5 mL, 0.031 mol) was
added to a solution of (Ϫ)-11 (6.30 g, 0.021 mol) in toluene at 0
°C. The solution was stirred at room temperature for 1 h; methanol
was then added. The reaction mixture was poured into water, and
extracted with ethyl acetate. The organic phase, dried on sodium
sulfate, was concentrated under reduced pressure to afford a residue
which was chromatographed on a silica gel column, eluting with
hexane-ethyl acetate (1:1). Compound (Ϫ)-12 was obtained in a
pure state (5.16 g, 89%) : [α]2D0 ϭ Ϫ 37, c ϭ 0.41, CH2Cl2. Ϫ 1H
NMR: δH ϭ 6.90Ϫ6.75 (m, 3 H, aromatic hydrogens), 5.70Ϫ5.50
[m, 2 H, C(4)H and C(5)H], 3.85 (s, 6 H, 2OMe), 3.43 (m, 1 H,
CHOH), 3.25 (m, 1 H, CHOH), 2.12 (m, 2 H, CH2CH2OH), 1.94
[m, 1 H, CH(Me)2], 1.83 (d, J ϭ 4.6, 3 H, CH3CϭC), 0.85 (d, J ϭ
7, 3 H, CH3CH), 0.71 (d, J ϭ 7, 3 H, CH3CH). Ϫ GC-MS: temp.
progr. B, tR ϭ 15.23 min, m/z ϭ 278 [Mϩ], 235, 217, 202, 191. Ϫ
C17H26O3: calcd. C 73.35, H 9.41; found C 73.38, H 9.43.
By this procedure, (Z,R)-(ϩ)-2 [4.9 g, 0.060 mol; ee 92%; [α]2D0
19.4 c, 0.40 CH2Cl2; obtained from 18 g (Z,R)-(Ϫ)-3 (ee ϭ92%)]
gave (Z,S)-(ϩ)-3 (13.3 g, 76%): [α]2D0 ϭ 15, c ϭ 1.13, CH2Cl2
ϭ
General Procedure for Ireland Rearrangement: A solution of 2 
lithium diisopropylamide (0.051 mol, 26 mL) was added dropwise
to a solution of the appropriate allylic acetate (10.0 g, 0.034 mol)
in THF at Ϫ78 °C. After 5 min, trimethylchlorosilane (0.051 mol,
6.5 mL) was added in one batch. The cooling bath was removed;
the reaction mixture was allowed to warm to room temperature
over 30 min, then refluxed for 3 h. Methanol (10 mL) was added,
the reaction mixture was stirred at room temperature for 10 min,
then poured into a 5% aqueous sodium hydroxide solution
(100 mL). This aqueous solution was washed with ethyl ether
(washings discarded), and acidified with concentrated hydrochloric
acid. The product acid was isolated by dichloromethane extraction.
By this procedure (Z,R)-(Ϫ)-3 (10.0 g, 0.034 mol) gave (E,R)-(Ϫ)-
3-(3,4-dimethoxyphenyl)-3-isopropylhex-4-enoic
acid
[(Ϫ)-4;
(4E,3S)-(؉)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-enol
[(؉)-12)]: Compound (ϩ)-11 (6.50 g, 0.021 mol) was converted into
the title compound by the same procedure as described for the pre-
paration of its (E,R)-(Ϫ) enantiomer from (Ϫ)-11 (5.45 g, 91%):
[α]2D0 ϭ 34, (c ϭ 0.35, CH2Cl2); the analytical data were in accord-
ance with those of the corresponding enantiomer.
6.21 g, 63%]. Ϫ [α]2D0 ϭ Ϫ9, (c ϭ 0.90, methanol); ee ϭ 95% HPLC
of the corresponding methyl ester hexane/2-propanol (99:1) tR (S)-
(ϩ)-11 ϭ 21.8 min, tR (R)-(Ϫ)-11 ϭ 24.8 min; E). Ϫ 1H NMR:
δH ϭ 6.75Ϫ6.90 (m, 3 H, aromatic hydrogens), 5.71 [dq, J ϭ 16
and 1.6, 1 H, C(4)H], 5.56 [dq, J ϭ 16 and 6, 1 H, C(5)H], 3.85 (s,
3 H, OMe), 3.82 (s, 3 H, OMe), 2.81 (d, J ϭ 14.5, 1 H,
CHϪCOOH), 2.73 (d, J ϭ 14.5, 1 H, CHϪCOOH), 2.47 [septet,
J ϭ 7, 1 H, CH(Me)2], 1.82 (dd, J ϭ 6 and 1.6, 3 H, CH3CϭC),
0.85 (d, J ϭ 7, 3 H, CH3CH), 0.77 (d, J ϭ 7, 3 H, CH3CH). Ϫ
GC-MS progr. temp. A: tR ϭ 24.66 min, m/z ϭ 292 [Mϩ], 249, 203,
189. Ϫ C17H24O4: calcd. C 69.84, H 8.27; found C 68.81, H 8.24.
(4E,3R)-(؊)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-enyl Tosyl-
ate [(؊)-13]: A solution of derivative (Ϫ)-12 (5.10 g, 0.018 mol) in
pyridine (30 mL) was treated with 4-toluenesulfonyl chloride
(5.12 g, mol). After the usual workup, purification of the residue
by column chromatography gave tosylate (Ϫ)-13 (7.17 g, 92%); m.p.
1
64 °C. Ϫ [α]2D0 ϭ Ϫ5, (c ϭ 1.61, CH2Cl2). Ϫ H NMR: δH ϭ 7.65
By this procedure, (Z,S)-(ϩ)-3 (10.0 g, 0.034 mol) gave (E,S)-(ϩ)-
(m, 2 H, aromatic hydrogens), 7.10Ϫ7.35 (m, 4 H, aromatic hydro-
gens), 6.80Ϫ6.60 (m, 3 H, aromatic hydrogens), 5.55 [dq, J ϭ 1.16
and 16, 1 H, C(4)H] 5.39 [dq, J ϭ 6 and 16, 1 H, C(5)H], 3.90Ϫ3.80
(2 s ϩ m, 7 H, 2OMe ϩ CHOTs), 3.53 (m, 1 H, CHOTs), 2.45
(s, 3 H, CH3ϪC6H4ϪSO2), 2.30Ϫ1.95 [m, 3 H, CH2CH2OTs ϩ
CH(Me)2], 1.77 (dd, J ϭ 1.16 and 6, 3 H, CH3CϭC), 0.80 (d, J ϭ
7, 3 H, CH3CH), 0.65 (d, J ϭ 7, 3 H, CH3CH). Ϫ GC-MS: temp.
progr. B, tR ϭ 29.91 min, m/z ϭ 432 [Mϩ], 389, 217. Ϫ C24H32O2S:
calcd. C 66.64, H 7.46, S 7.41; found C 66.68, H 7.39, S 7.45.
3-(3,4-dimethoxyphenyl)-3-isopropylhex-4-enoic
acid
[(ϩ)-4;
6.42 g, 65%]. Ϫ [α]2D0 ϭ 7, (c ϭ 0.85, methanol); ee ϭ 95% HPLC
of the corresponding methyl ester; the analytical data were in ac-
cordance with those of (Ϫ)-4.
By this procedure, (E,R)-(ϩ)-3 (10.0 g, 0.034 mol) gave (E)-(Ϯ)-3-
(3,4-dimethoxyphenyl)-3-isopropylhex-4-enoic acid [(Ϯ)-4; 4.84 g,
48%] (HPLC of the corresponding methyl ester); m.p. 85 °C; the
analytical data were in accordance with those of (Ϫ)-4.
1354
Eur. J. Org. Chem. 2001, 1349Ϫ1357

Enzyme-Mediated Synthesis of (S)- and (R)-Verapamil
FULL PAPER
(4E,3S)-(؉)-3-(3,4-Dimethoxyphenyl)-3-isopropylhex-4-enyl Tosyl-
ate [(؉)-13]: Tosylate (ϩ)-13 (7.64 g, 90%) was obtained from de-
rivative (ϩ)-12 (5.40 g, 0.012 mol) by the same procedure as used
for the preparation of (Ϫ)-13: [α]2D0 ϭ 3, (c ϭ 1.65, CH2Cl2); the
analytical data were in accordance with those of (Ϫ)-13.
methanol was then added. The reaction mixture was poured into
water and extracted with ethyl acetate. The organic phase, dried on
sodium sulfate, was concentrated under reduced pressure, to afford
a residue that was chromatographed on a silica gel column, eluting
with hexane-ethyl acetate, 1:1. The compound (Ϫ)-17 was obtained
1
in a pure state (2.76 g, 84%) [α]2D0 ϭ Ϫ26, c ϭ 0.91 CH2Cl2. Ϫ H
(5E,4R)-(؊)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enenitrile
[(؊)-14]: A mixture of tosylate (؊)-13 (7.10 g, 0.016 mol) and so-
dium cyanide (1.22 g, 0.024 mol) in dimethyl sulfoxide (39 mL) was
stirred at 80 °C for 2 h. After the usual workup, purification of the
residue by column chromatography, using hexane-ethyl acetate 7:3
as an eluent, gave the title compound in pure form (4.01 g, 85%).
NMR: δH ϭ 6.90Ϫ6.70 (m, 3 H, aromatic hydrogens), 5.70Ϫ5.40
[m, 2 H, C(5)H and C(6)H], 3.87 (s, 3 H, OMe), 3.86 (s, 3 H, OMe),
3.50 (t, J ϭ 6.7, 2 H, CH2OH), 2.18 [septet, J ϭ 6.7, 1 H,
CH(Me)2], 1.83 (d, J ϭ 5, 3 H, CH3CϭC), 1.1Ϫ1.80 (m, 4 H,
CH2CH2CH2OH), 0.84 (d, J ϭ 7, 3 H, CH3CH), 0.73 (d, J ϭ 7, 3
H, CH3CH). Ϫ GC-MS progr. temp. A: tR ϭ 24.78 min, m/z ϭ
292 [Mϩ], 249, 231, 216, 203, 189. Ϫ C18H28O3 calcd. C 73.93, H
9.65; found C 73.97, H 9.69.
1
Ϫ [α]2D0 ϭ Ϫ25, (c ϭ 1.01, CH2Cl2). Ϫ H NMR: δH ϭ 6.80Ϫ6.60
(m, 3 H, aromatic hydrogens), 5.70 Ϫ5.40 [m, 2 H, C(4)H and
C(5)H], 3.87 (s, 6 H, 2OMe), 2.30Ϫ1.60 (m, 8 H, CH2CH2CN ϩ
CH(Me)2 ϩ CH3CϭC), 0.86 (d, J ϭ 7, 3 H, CH3CH), 0.70 (d, J ϭ
7, 3 H, CH3CH). Ϫ GC-MS: temp. progr. B, tR ϭ 16.48 min, m/z ϭ
287 [Mϩ], 272, 256, 244, 189. Ϫ C18H25NO2: calcd. C 75.22, H
8.77, N 4.87; found C 68.81, H 8.24.
(5E,4S)-(؉)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-en-1-ol
[(؉)-17]: Ester derivative (ϩ)-16 (3.40 g, 0.011 mol) was converted
into the title compound by the same procedure as described for the
preparation of its enantiomer (2.54 g, 80%): [α]2D0 ϭ 24, (c ϭ 0.85,
CH2Cl2). The analytical data were in accordance with those of the
corresponding enantiomer.
(5E,4S)-(؉)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enenitrile
[(؉)-14]: The title compound (4.37 g, 84%) was obtained from (ϩ)-
13 (7.60 g, 0.018 mol) by the same procedure as used to prepare its
(Ϫ) enantiomer. [α]2D0 ϭ 24, (c ϭ 0.95, CH2Cl2); the analytical data
were in accordance with those of the corresponding enantiomer.
(5E,4R)-(؊)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enyl
Acetate [(؊)-18]: Treatment of alcohol (Ϫ)-17 (2.78 g, 9.2 mmol)
with acetic anhydride (5 mL) in pyridine (10 mL) gave the corres-
ponding acetate (Ϫ)-18, which was purified by column chromato-
graphy, eluting with hexane/ethyl acetate 8:2 (3.01 g, 98%). Ϫ [α]
(5E,4R)-(؊)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enoic Acid
[(؊)-15]: A mixture of (Ϫ)-14 (4.00 g, 0.014 mol) and 20% KOH
(10 mL) in diethylene glycol (20 mL) was refluxed for 1 h. After the
usual workup, the title compound was recovered in pure form
(3.43 g, 81%) [α]2D0 ϭ Ϫ 20.6, c ϭ 1.50, methanol. Ϫ 1H NMR:
20
1
ϭ Ϫ 28, (c ϭ 0.92, CH2Cl2). Ϫ H NMR: δH ϭ 6.80 (m, 3 H,
D
aromatic hydrogens), 5.70Ϫ5.40 [m, 2 H, C(4)H and C(5)H], 3.92
(t, J ϭ 6.7, 2 H, CH2OAc), 3.87 [s, 3 H, OMe), 3.86 [s, 3 H, OMe),],
2.16 [septet, J ϭ 6.7, 1 H, CH(Me)2], 2.01 (s, 3 H, CH3COO), 1.83
(d, J ϭ 5.5, 3 H, CH3CϭC), 1.1Ϫ1.80 (m, 4 H, CH2CH2CH2OAc),
0.83 (d, J ϭ 7, 3 H, CH3CH), 0.73 (d, J ϭ 7, 3 H, CH3CH); GC-
MS progr. temp. B: tR ϭ 17.47 min, m/z ϭ 334 [Mϩ], 291, 231, 189.
Ϫ C20H30O: calcd. C 71.82, H 9.04; found C 71.87, H 9.09.
δH ϭ 6.79 (m, 3 H, aromatic hydrogens), 5.70 Ϫ5.40 [m, 2 H, C(4)H
and C(5)H], 3.86 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 2.20Ϫ1.70 (m,
8 H, CH2CH2COOH ϩ CH(Me)2 ϩ CH3CϭC), 0.85 (d, J ϭ 7, 3
H, CH3CH), 0.71 (d, J ϭ 7, 3 H, CH3CH). Ϫ GC-MS: temp. progr.
B, tR ϭ 17.47 min, m/z ϭ 306 [Mϩ], 289, 277, 263, 203. Ϫ
C18H26O4: calcd. C 70.56, H 8.55; found C 70.59, H 8.58.
(5E,4S)-(؉)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enyl
Acetate [(؉)-18]: Treatment of alcohol (ϩ)-17 (2.50 g, 9.2 mmol)
with acetic anhydride (5 mL) in pyridine (10 mL) gave the corres-
ponding acetate (ϩ)-18, which was purified by column chromato-
(5E,4S)-(؉)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-enoic
Acid [(؉)-15]: The title compound (3.48 g, 79%) was obtained from
derivative (؉)-14 (4.30 g, 0.015) by the same procedure as used to
prepare its (Ϫ) enantiomer: [α]2D0 ϭ 19.3, (c ϭ 1.20, methanol); the
analytical data were in accordance with those of the correspond-
ing enantiomer.
graphy, eluting with hexane/ethyl acetate 8:2 (2.84 g, 98%). [α]2D0
ϭ
26, (c ϭ 0.85, CH2Cl2); the analytical data were in accordance with
those of the corresponding enantiomer.
(4S)-(؊)-4-(3,4-Dimethoxyphenyl)-4-formyl-5-methylhexyl acetate-
[(؊)-19]: Ozonolysis of derivative (Ϫ)-18 (3.00 g, 9.8 mmol) in
dichloromethane/methanol 1:1 solution (30 mL) gave, after treat-
ment with triphenylphosphane, aldehyde (Ϫ)-14 (1.97 g, 68%). Ϫ
Methyl (5E,4R)-(؊)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-en-
oate [(؊)-16]: The title compound was obtained (3.54 g, 98%) by
treatment of the corresponding acid (Ϫ)-15 (3.40 g, 0.011 mol) with
diazomethane in diethyl ether: [α]2D0 ϭ Ϫ47, (c ϭ 0.95, CH2Cl2). Ϫ
1H NMR: δH ϭ 6.76 (m, 3 H, aromatic hydrogens), 5.70 Ϫ5.40 [m,
2 H, C(5)H and C(6)H], 3.87 (s, 6 H, 2OMe), 3.58 (s, 3 H, CO-
1
[α]2D0 ϭ Ϫ 43, (c ϭ 0.42, CH2Cl2). Ϫ H NMR: δH ϭ 9.81 (s, 1 H,
CHO), 6.88 [d, J ϭ 8, 1 H, aromatic hydrogen C(5)H], 6.71 [dd,
J ϭ 2 and 8, 1 H, aromatic hydrogen C(6)H], 6.66 [d, J ϭ 2, 1 H,
aromatic hydrogen C(2)H], 4.00 (t, J ϭ 6, 2 H, CH2OAc) 3.89 (s,
3 H, OMe), 3.87 (s, 3 H, OMe), 2.38 [septet, J ϭ 7, 1 H, CH(Me)2],
2.02 (s, 3 H, CH3COO), 1.90 (m, 2 H, CH2CH2CH2OAc), 1.41 (m,
2 H, CH2CH2CH2OAc), 0.94 (d, J ϭ 7, 3 H, CH3CH), 0.86 (d,
J ϭ 7, 3 H, CH3CH). Ϫ GC-MS progr. temp. B: tR ϭ 18.29 min,
m/z ϭ 322 [Mϩ], 293, 233, 219, 191, 177, 165. Ϫ C18H26O5: calcd.
C 67.06, H 8.13; found C 67.01, H 8.16.
OMe), 2.20Ϫ1.70 (m, 8 H, CH2CH2COOMe ϩ CH(Me)2
ϩ
CH3CϭC), 0.85 (d, J ϭ 7, 3 H, CH3CH), 0.71 (d, J ϭ 7, 3 H,
CH3CH). Ϫ GC-MS progr. temp. A: tR ϭ 24.95 min, m/z ϭ 320
[Mϩ], 277, 245, 217, 203. Ϫ C19H28O4: calcd. C 71.22, H 8.81;
found C 71.27, H 8.86.
Methyl (5E,4S)-(؉)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-en-
oate [(؉)-16]: The title compound (3.41, 97%) was obtained from
acid (ϩ)-15 (3.40 g, 0.011 mol) by the same procedure as used to
prepare its (Ϫ) enantiomer: [α]2D0 ϭ 44, (c ϭ 0.90, CH2Cl2).
(4R)-(؉)-4-(3,4-Dimethoxyphenyl)-4-formyl-5-methylhexyl Acetate
[(؉)-19]: Ozonolysis of derivative (ϩ)-18 (2.50 g, 7.5 mmol) in
dichloromethane/methanol 1:1 solution (30 mL) gave, after treat-
ment with triphenylphosphane, aldehyde (ϩ)-19 (1.66 g, 69%): [α]
(5E,4R)-(؊)-4-(3,4-Dimethoxyphenyl)-4-isopropylhept-5-en-1-ol
[(؊)-17]: A 65% wt. Red-Al solution in toluene (5 mL, 0.0165 mol)
was added to a solution of ester (Ϫ)-16 (3.40 g, 0.011 mol) in tolu- 20 ϭ 42, (c ϭ 0.35, CH2Cl2). The analytical data were in accordance
D
ene at 0 °C. The solution was stirred at room temperature for 1 h;
Eur. J. Org. Chem. 2001, 1349Ϫ1357
with those of the corresponding enantiomer.
1355

E. Brenna, C. Fuganti, P. Grasselli, S. Serra
FULL PAPER
(4S)-(؊)-4-Cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl Acetate
[(؊)-20]: Derivative (Ϫ)-19 (1.97 g, 6.1 mmol) was treated with hy-
droxylamine chloride (0.64 g, 9.15 mmol) in ethanol (10 mL) in the
presence of sodium acetate (0.75 g, 6.1 mmol). After the usual
workup, the oxime derivative was refluxed in acetic anhydride to
give, after purification on column chromatography eluting with
(2R)-(؉)-5-Chloro-2-(3,4-dimethoxyphenyl)-2-isopropylpentane-
nitrile [(؉)-5]: Alcohol derivative (ϩ)-21 (0.90 g, 3.2 mmol) was
converted into (ϩ)-5 (0.92 g, 96%) according to the same procedure
for the conversion of (Ϫ)-21 into (Ϫ)-5: [α]2D0 ϭ 11.0, (c ϭ 1.22
methanol); ref.[3] [α]2D0 ϭ 11.6, (c ϭ 1 methanol); the 1H NMR was
in accordance with that of the enantiomer.
hexane/ethyl acetate 1:1, nitrile (Ϫ)-15 (1.52 g, 75%). Ϫ [α]2D0
ϭ
Ϫ19.5, (c ϭ 0.75, CH2Cl2). Ϫ 1H NMR: δH ϭ 6.95Ϫ6.85 (m, 3 H,
aromatic hydrogens), 4.00 (t, J ϭ 6.4, 2 H, CH2OAc) 3.90 (s, 3 H,
OMe), 3.89 (s, 3 H, OMe), 2.18 (m, 1 H, CHH CH2CH2OAc), 2.08
[septet, J ϭ 7, 1 H, CH(Me)2], 2.02 (s, 3 H, CH3COO), 1.85 (m, 1
H, CHHCH2CH2OAc), 1.71 (m, 1 H, CH2CHHCH2OAc), 1.41 (m,
1 H, CH2CHHCH2OAc), 1.20 (d, J ϭ 7, 3 H, CH3CH), 0.81 (d,
J ϭ 7, 3 H, CH3CH). Ϫ GC-MS progr. temp. B: tR ϭ 17.71 min,
m/z ϭ 319 [Mϩ], 277, 235, 216, 207, 185. Ϫ C18H25NO4: calcd. C
67.69, H 7.89, N 4.39; found C 67.63, H 7.83, N 4.43.
(S)-(؊)-Verapamil: A mixture of chloro derivative (Ϫ)-5 (1.20 g,
12.6 mmol) and N-methylhomoveratrylamine (5.01 g) was heated
at 130 °C for 1 h. The reaction mixture was treated with a 1 
solution of sodium hydroxide and extracted with diethyl ether. The
title compound was recovered by column chromatography, eluting
with dichloromethane/methanol 97:3 (1.77 g, 91%). Ϫ [α]2D0 ϭ Ϫ8.2,
1
(c ϭ 5.08 ethanol); ref.[4]: [α]2D0 ϭ Ϫ8.9, (c ϭ 5.00 ethanol). Ϫ H
NMR: δH ϭ 6.94 (dd, J ϭ 8 and 2, 1 H, aromatic hydrogen), 6.89
(d, J ϭ 2, 1 H, aromatic hydrogen), 6.84 (d, J ϭ 8, 1 H, aromatic
hydrogen), 6.79 (d, J ϭ 8, 1 H, aromatic hydrogen), 6.71 (d, J ϭ
2, 1 H, aromatic hydrogen), 6.68 (dd, J ϭ 8 and 2 1 H, aromatic
hydrogen), 3.90 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 3.86 (s, 3 H,
OMe), 3.85 (s, 3 H, OMe), 2.68 (m, 2 H), 2.52 (m, 2 H), 2.36 (m,
2 H), 2.18 (s, 3 H, NMe), 2.11 (m, 1 H), 2.07 [septet, J ϭ 7, 1
H,CH(Me)2], 1.83 (m, 1 H), 1.55 (m, 1 H), 1.19 (m ϩ d, J ϭ 7, 4
H), 0.80 (d, J ϭ 7, 3 H, CH3CH)
(4R)-(؉)-4-Cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl Acetate
[(؉)-20]: Derivative (ϩ)-19 (1.66 g, 5.2 mmol) was converted in de-
rivative (ϩ)-20 (1.19 g, 73%) by the same procedure as for the con-
version of (Ϫ)-19 into (Ϫ)-20. The analytical data were in accord-
ance with those of the corresponding enantiomer: [α]2D0 ϭ 19.1, (c ϭ
0.80, CH2Cl2)
(2S)-(؊)-2-(3,4-Dimethoxyphenyl)-5-hydroxy-2-isopropylpen-
tanenitrile [(؊)-21]: A solution of compound (Ϫ)-20 (1.50 g,
4.7 mmol), and potassium hydroxide 85% (0.47 g, 7.05 mmol) in
methanol (20 mL) was refluxed for 2 h. After the usual workup,
the residue was purified on a silica gel column chromatography,
using hexane/ acetate 3:7 as an eluent, to afford derivative (Ϫ)-21
(R)-(؉)-Verapamil: Chloro derivative (ϩ)-5 (0.92 g, 3.12 mmol) was
converted into the title compound by the same procedure as de-
scribed for (S)-(Ϫ)-verapamil (1.36 g, 92%): the specific rotatory
power was determined on the corresponding HCl salt: [α]2D0
ϭ
ϩ8.3, (c ϭ 5.05 in ethanol); ref.[4]: [α]2D0 ϭ ϩ8.8, (c ϭ 5.00 ethanol).
The 1H NMR spectrum was in accordance with that of the (Ϫ)-en-
antiomer.
(1.19 g, 92%): [α]2D0 ϭ Ϫ 11.5, (c ϭ 2.75 CHCl3); optical purity ϭ
1
91% ee ref.[5]: [α]2D0 ϭ Ϫ12.6, (c ϭ 3.84 CHCl3). Ϫ H NMR: δH
ϭ
6.93 [dd, J ϭ 8 and 2, 1 H, aromatic hydrogen C(6)H], 6.88 [d, J ϭ
2, 1 H, aromatic hydrogen C(2)H], 6.86 [d, J ϭ 8, 1 H, aromatic
hydrogen C(5)H], 3.89 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 3.60 (m,
2 H, CH2OH), 2.21 (ddd, J ϭ 13, 11 and 4, 1 H, CHH
CH2CH2Oac), 2.09 [septet, J ϭ 7, 1 H, CH(Me)2], 1.93 (ddd, J ϭ
[1]
J. A. Longstreth, ‘‘Verapamil, a chiral challenge to the pharma-
cokinetic and pharmacodynamic assessment of bioavailability
and bioequivalence’’, in ‘‘Drug Stereochemistry: analytical
methods and pharmacology’’, (Ed.: I. W. Wainer), Marcel
Dekker, 1993, New York.
13, 11 and 4,
1 H, CHHCH2CH2OAc), 1.62 (m, 1 H,
CH2CHHCH2OAc), 1.28 (m, 1 H, CH2CHHCH2OAc), 1.19 (d,
J ϭ 7, 3 H, CH3CH), 0.81 (d, J ϭ 7, 3 H, CH3CH). Ϫ GC-MS:
temp. progr. B, tR ϭ 16.61 min, m/z ϭ 277 [Mϩ], 234, 216, 185.
[2]
C. Stinson, Chem. Eng. News 1993, 374.
H. Ramuz, Helv. Chim. Acta 1975, 58, 2050.
H. J. Traiber, M. Raschack, F. Dengel, Ger. Patent 2 059 985,
1972; Ger. Patent 2 059 923, 1972
L. J. Theodore, W. L. Nelson, J. Org. Chem. 1987, 52, 1309.
J. Gilmore, W. Prowse, D. Steggles, M. Urquhart, J. Olkowski,
J. Chem. Soc., Perkin Trans.1 1996, 2845.
E. Brenna, N. Caraccia, G. Fogliato, G. Fronza, C. Fuganti,
Tetrahedron 1997, 53, 10555.
E. Brenna, N. Caraccia, C. Fuganti, D. Fuganti, P. Grasselli,
Tetrahedron: Asymmetry 1997, 8, 3801.
E. Brenna, C. Fuganti, D. Fuganti, P. Grasselli, L. Malpezzi,
G. Pedrocchi-Fantoni, Tetrahedron 1997, 53, 17769.
E. Brenna, C. Fuganti, P. Grasselli, M. Redaelli, S. Serra, J.
Chem. Soc., Perkin. Trans. 1 1998, 4129.
[3]
[4]
(2R)-(؉)-2-(3,4-Dimethoxyphenyl)-5-hydroxy-2-isopropylpen-
tanenitrile [(؉)-21]: Derivative (ϩ)-20 (1.19 g, 3.7 mmol) was con-
verted into derivative (ϩ)-21 (0.92 g, 90%) by the same procedure
as for the conversion of (Ϫ)-20 into (Ϫ)-21: [α]2D0 ϭ 10, (c ϭ 2.90
CHCl3); the analytical data were in accordance with those of the
enantiomer (Ϫ)-21.
[5]
[6]
[7]
[8]
[9]
(2S)-(؊)-5-Chloro-2-(3,4-dimethoxyphenyl)-2-isopropylpenta-
nenitrile [(؊)-5]: A solution of alcohol derivative (Ϫ)-21 (1.19 g,
4.3 mmol) and triphenylphosphane (2.25 g, 8.6 mmol) in carbon
tetrachloride (20 mL) was refluxed for 2 h. The title compound was
recovered from the reaction mixture by column chromatography
[10]
[11]
J. Aleu, E. Brenna, C. Fuganti, S. Serra, J. Chem. Soc., Perkin.
Trans. 1 1999, 271.
E. Brenna, G. Fronza, C. Fuganti, A. Righetti, S. Serra, Helv.
Chim. Acta 1999, 82, 1762.
E. Brenna, G. Fronza, C. Fuganti, L. Malpezzi, A. Righetti, S.
Serra, Helv. Chim. Acta 1999, 82, 2246.
[12]
(1.20 g, 95%): [α]2D0 ϭ Ϫ 11.2, (c ϭ 1.15 methanol); optical purity ϭ
1
91% ee; ref.[3] [α]2D0 ϭ Ϫ12.3, c ϭ 1 methanol. Ϫ H NMR: δH
ϭ
[13]
6.94 [dd, J ϭ 8 and 2, 1 H, aromatic hydrogen C(6)H], 6.88Ϫ6.84
[two overlapping doublets J ϭ 2 and 8, 2 H, aromatic hydrogens
C(2)H and C(5)H], 3.90 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 3.49
(m, 2 H, CH2Cl), 2.23 (ddd, J ϭ 13, 12 and 4, 1 H, CHH
CH2CH2Cl), 2.15 Ϫ2.00 (m, 2 H, CH(Me)2 ϩ CHHCH2CH2OCl),
1.87 (m, 1 H, CH2CHHCH2Cl), 1.47 (m, 1 H, CH2CHHCH2Cl),
1.20 (d, J ϭ 7, 3 H, CH3CH), 0.82 (d, J ϭ 7, 3 H, CH3CH). Ϫ
GC-MS: temp. progr. B, tR ϭ 16.05 min, m/z ϭ 295 [Mϩ], 252, 189.
[14]
Conversion (c) and enantiomeric ratio (E) were calculated ac-
cording to: C.-S. Chen, Y. Fujimoto, G. Girdaukas, C. H. Sih,
J. Am. Chem. Soc. 1982, 104, 7294.
[15]
R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.
F. E. Ziegler, Chem. Rev. 1988, 88, 1425.
A. Oku, M. Abe, M. Iwamoto, J. Org. Chem. 1994, 59, 7445.
S. Labo, V. J. Hruby, Tetrahedron Lett. 1996, 37, 1563.
[16]
[17]
[18]
1356
Eur. J. Org. Chem. 2001, 1349Ϫ1357

Enzyme-Mediated Synthesis of (S)- and (R)-Verapamil
FULL PAPER
[19]
[22]
R. J. Kazlauskas, U. T. Born Scheuer, in Biotechnology Ϫ Series
U. Bornscheuer, S. Schapöhler, T. Scheper, K. Schügerl, Tetra-
hedron: Asymmetry 1991, 2, 1011.
Received September 13, 2000
(Eds.: H. J. Rehm, G. Reed, A. Pühler, P. J. W. Stadler, D. R.
Kelly), (1998) vol. 8a, pp. 37Ϫ191.
R. D. Schimd, R. Verger, Angew. Chem. Int. Ed. 1998, 37, 1608.
A. K. Gupta, R. J. Kazlauskas, Tetrahedron: Asymmetry 1993,
[20]
[O00472]
[21]
4, 879.
Eur. J. Org. Chem. 2001, 1349Ϫ1357
1357