Enantioselective synthesis of benzylic stereocentres via Claisen rearrangement of enantiomerically pure allylic alcohols: Preparation of (R)- and (S)-3-methyl-2-phenylbutylamine

Article abstract of DOI:10.1016/S0957-4166(03)00454-3

The Johnson-Claisen rearrangement of enantiopure allylic alcohols in triethylorthopropionate is the key step for the preparation of chiral molecules with benzylic stereogenic carbon atoms bearing an isopropyl moiety. The synthetic procedure is applied to the preparation of (R)- and (S)-3-methyl-2-phenylbutylamine.

Full text of DOI:10.1016/S0957-4166(03)00454-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2401–2406
Enantioselective synthesis of benzylic stereocentres via Claisen
rearrangement of enantiomerically pure allylic alcohols:
preparation of (R)- and (S)-3-methyl-2-phenylbutylamine
Elisabetta Brenna,* Claudio Fuganti, Francesco G. Gatti, Massimo Passoni and Stefano Serra
Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico,
Istituto CNR per la Chimica del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
Received 16 May 2003; accepted 10 June 2003
Abstract—The Johnson–Claisen rearrangement of enantiopure allylic alcohols in triethylorthopropionate is the key step for the
preparation of chiral molecules with benzylic stereogenic carbon atoms bearing an isopropyl moiety. The synthetic procedure is
applied to the preparation of (R)- and (S)-3-methyl-2-phenylbutylamine.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
verapamil8 respectively (Scheme 1). We combined the
kinetic resolution of allylic alcohols mediated by lipases
with the Claisen rearrangement, according to the mod-
ifications of Johnson and Ireland, and transferred a C2
fragment to the benzylic carbon atom.
Benzylic stereogenic carbon atoms very often occur in
the skeleton of important organic molecules. This struc-
tural moiety can be found in thousands of isolated
natural products, e.g. the Sceletium alkaloids, calame-
nene terpenes, several therapeutic agents, such as the
profen non-steroidal anti-inflammatory drugs, and
some of the top ten single-enantiomer drugs,1 i.e.
paroxetine, clopidogrel and sertraline.
Catalytic access to enantiomerically enriched molecules
with benzylic stereocentres has been accomplished, for
example, by hydrogenation,2 by metallobenzene addi-
tion technology,3 by the reaction of benzyllithium
derivatives,4 by enantioselective alkylation of arene
rings with carbonyls and electron poor olefins,5 or by
intramolecular Heck reactions.6
A general successful approach to the preparation of
chiral molecules is based on the intramolecular chiral-
ity-transfer processes (the so-called self-immolative
reactions), in which a stereocentre is sacrificed while
another is enantiospecifically created. A catalytic enan-
tioselective reaction is usually combined with an enan-
tiospecific intramolecular reaction, typically
a
rearrangement. We successfully adopted this strategy
for the creation of the tertiary and quaternary benzylic
stereocentres, of the chiral drugs baclofen7 and
Scheme 1.
We then decided to investigate the potential of this
synthetic route as a general method for the creation of
* Corresponding author. E-mail: elisabetta.brenna@polimi.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00454-3

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E. Brenna et al. / Tetrahedron: Asymmetry 14 (2003) 2401–2406
Scheme 2.
benzylic stereogenic centres, by converting, for exam-
ple, a CH3CHCOOEt fragment, easily introduced by a
Claisen rearrangement with ethyl orthopropionate, into
an isopropyl substituent, which is much more difficult
to locate on benzylic positions. The Ar-CH-CH(CH)3
moiety can be found in all the derivatives of 3-methyl-
2-aryl-butyric acid, such as the pyrethroid pesticide
fenvalerate, and in several other structurally related
compounds, e.g. the anti-tussive drug isoaminile, and
the resolving agent 3-methyl-2-phenylbutylamine 1. The
most common synthetic approaches described in the
literature for this kind of substrate are summarised in
Scheme 2. They consist of classical resolutions (A9) or
bio-catalysed kinetic resolutions (B10) of racemic sub-
strates already bearing the isopropyl group. As an
alternative, the isopropyl moiety has been introduced
by enantioselective alkylation of the benzylic carbon
atom (C11, D12), or by enantioselective addition to
double bonds (E13, F14). Aryl magnesium bromide addi-
tion to chiral olefinic compounds (G15), cuprate addi-
tion to chiral carbonates derived from menthone (H16),
hydrogenation of double bonds (I17), and isomerisation
of allylic alcohols (L18) mediated by chiral phosphines
have been also exploited.
ence of vinyl acetate as an acyl donor.20 Acetate (R)-3
(ee=98% ee, HPLC) and alcohol (S)-2 (ee=98%,
HPLC) were separated by column chromatography.
Acetate 3 was hydrolysed, and (R)-and (S)-2 were
submitted separately to Johnson–Claisen rearrangement
in ethyl orthopropionate, at 140°C, in the presence of a
catalytic amount of propionic acid. Acids (RS,S)- and
(RS,R)-4 were quantitatively recovered, after treatment
of the crude product of the Claisen rearrangement with
refluxing NaOH 10%. LiAlH4 reduction gave alcohols
5, which were treated with p-toluensulphonyl chloride,
and reduced to convert the CH3CHCOOH fragment
into an isopropyl unit, and obtain (R)- and (S)-6. The
Johnson–Claisen rearrangement is a suprafacial, con-
certed, nonsynchronous pericyclic process, that can be
considered as an intramolecular SN2% process: Alcohol
(E,R)-2 afforded derivative (E,R)-6.21 Ozonolysis of the
double bond and NaBH4 quenching afforded alcohols
(S)- and (R)-7. The amine functionality was introduced
through a classical sequence, via azide intermediates 8.
(S)-1 (ee=96%, HPLC of the corresponding trifl-
uoroacetic amide) and (R)-1 (ee=94%, HPLC of the
Herein we report on the preparation of both enan-
tiomers of amine 1, in order to show the efficiency and
the applicability of our synthetic approach.
2. Results and discussion
3-Methyl-2-phenylbutylamine 1 has recently been intro-
duced as a new and versatile chiral base for the classical
resolution of chiral acids, in particular of the a-aryl
propionic type.19 To date, optically active 1 has been
obtained by resolution with mandelic acid,9c by
enzyme-mediated hydrolysis of a suitable amide,10a or
by bio-catalysed hydration of a nitrile derivative.10b
The application of our synthetic route required the
preparation of allylic alcohol 2, which was easily
obtained by NaBH4 reduction of benzalacetone
(Scheme 3). The kinetic resolution of ( )-2 was accom-
plished by Lipase PS-mediated transesterification in
t-butyl methyl ether, at room temperature, in the pres-
Scheme 3. Reagents and conditions: (i) NaBH4, CH2Cl2,
MeOH; (ii) Lipase PS, t-butylmethylether, vinyl acetate; (iii)
CH3CH(OEt)3, acid propionic; NaOH 10%; (iv) LiAlH4,
THF; (v) p-TosCl, pyridine; (vi) O3, MeOH–CH2Cl2; then
NaBH4; (vii) NaN3, aq. EtOH; (viii) LiAlH4, Et2O.

E. Brenna et al. / Tetrahedron: Asymmetry 14 (2003) 2401–2406
2403
corresponding trifluoroacetic amide) were obtained in
4. Experimental
very good overall yields, and both fully characterised as
free bases22 and as hydrochloride salts.
Burkholderia cepacia lipase (Lipase PS, Amano Phar-
maceuticals Co., Japan) was employed in this work.
GC-MS analyses were performed on a HP 6890 gas-
chromatograph equipped with a 5973 mass-detector,
using a HP-5MS column (30 m×0.25 mm×0.25 mm).
The following temperature program was employed:
60°C (1 min)/6°/min/150° (1 min)/12°/min/280° (5 min).
Chiral HPLC analyses of compounds 1 (as trifluoroac-
etamide 1-NHCOCF3) and 2 were performed on a
Chiralcel OD column (Daicel-Japan) installed on a
Merck-Hitachi L-6200 apparatus: 0.6 mL/min, UV
detector (210 nm for 1-NHCOCF3, 254 nm for 2),
hexane/isopropanol 95:5. The following retention times
were observed: (R)-1-NHCOCF3 tR=10.24 min, (S)-1-
NHCOCF3 tR=14.37 min; (R)-2 tR=19.91 min; (S)-2
3. Conclusions
Recently the need for enantiopure molecules has grown
greatly. The general opinion is that it is much better to
put human beings in contact with the single enan-
tiomers of chiral molecules. According to a recent
review,23 since 1990 the proportion of single-enantiomer
drugs among approved new chemical entities worldwide
has been consistently greater than that of racemates.
The strategy of the chiral switch has also been intro-
duced in the area of fragrance chemistry: Enantiomeri-
cally enriched odorants are now widely studied.24
1
tR=29.28 min. H NMR spectra were recorded at rt on
The optimisation of our procedure is aimed to comple-
ment the synthetic tools that can be satisfactorily
employed for the preparation of enantiopure com-
pounds. Our method has the great advantage of being a
catalytic, rather than a stoichiometric resolution which
affords both the enantiomers of the desired com-
pounds. Allylic alcohols of type 9 are the starting
materials of our synthetic route (Scheme 4). These can
easily be prepared by the methods of classical organic
chemistry, e.g. aldol condensation, condensation of aro-
matic ketones with acetonitrile and subsequent homolo-
gation,8 dehydration of hydroxy ketones of type 10.
Transesterification, mediated by lipases, is a quick and
efficient method to obtain two enantiopure isomers of
the starting allylic alcohol. The wide commercial
availability of the lipases gives the chance to find the
right enzyme for each substrate. The Johnson–Claisen
rearrangement allows for the transfer of a C2 or C3 unit
to a benzylic carbon atom with high stereoselection.
The C3 moiety can be converted into an isopropyl unit.
The remaining double bond can be manipulated
according to several procedures, for example it can be
submitted to ozonolysis, and a CH2OH or a COOH
substituent can be created. A tertiary or quaternary
benzylic stereogenic carbon atom in structures 11 and
12 can be prepared with high stereoselection, by means
of high yield reactions, occurring in mild conditions,
using common reagents, and simple laboratory
apparatus.
a Bruker AC-250 spectrometer (250 MHz 1H). The
chemical shift scale was based on internal tetra-
methylsilane. Optical rotations were measured on a Dr.
Kernchen Propol digital automatic polarimeter. Micro-
analyses were determined on a Analyzer 1106 Carlo
Erba. TLC analyses were performed on Merck
Kieselgel 60 F254 plates. All the chromatographic sepa-
rations were carried out on silica gel columns. ( )-(E)-
4-Phenyl-3-buten-2-ol 2 was prepared according to Ref.
20c.
4.1. (2R,3E)-2-Acetoxy-4-phenyl-but-3-ene (R)-3 and
(2S,3E)-4-phenyl-3-buten-2-ol (S)-2
A mixture of ( )-2 (20 g, 0.135 mol), lipase (10 g) and
vinyl acetate (20 mL) in t-butylmethyl ether (150 mL)
was stirred at rt for 24 h. The residue obtained upon
evaporation of the filtered reaction mixture was chro-
matographed, using hexane:ethyl acetate 9:1 as the
eluent with the acetate (R)-3 (10.5 g, 41%) and alcohol
(S)-2 (7.59 g, 38%) being recovered. Acetate (R)-3:
ee=98% (HPLC of the corresponding alcohol), [h]2D0=
+139.6 (c 3.18, CHCl3) [lit.20b [h]D20=+142.2, ee=99% (c
1
1, CHCl3)]; H NMR: l 7.40–7.20 (5H, m, aromatic
hydrogens), 6.59 (1H, d, J=15.7, PhCHꢀ), 6.18 (1H,
dd, J=6.8, 15.7, PhCHꢀCH), 5.52 (1H, m, CHOAc),
2.07 (3H, s, OAc), 1.40 (3H, d, J=6.8, CH3CH); GC/
MS: tR=16.99 min; m/z: 190 (M+, 18), 148 (65), 129
(100), 115 (69).
Scheme 4.

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E. Brenna et al. / Tetrahedron: Asymmetry 14 (2003) 2401–2406
Alcohol (S)-2: ee=98% (HPLC), [h]2D0=−30.0 (c 1.22,
CHCl3) [lit.20b [h]D20=−32.0, ee=98% (c 1.8, CHCl3)];
1H NMR: l 7.43–7.16 (5H, m, aromatic hydrogens),
6.56 (1H, d, J=15.7, PhCHꢀ), 6.26 (1H, dd, J=6.1,
15.7, PhCH=CH), 4.48 (1H, quintuplet, J=6.1,
CHOH), 1.37 (3H, d, J=6.1, CH3CH); GC/MS: tR=
13.89 min; m/z: 148 (M+, 75), 129 (47), 115 (50), 105
(100), 91 (53).
5.1, 11.1, CHOH of the minor diastereoisomer), 3.54
(dd, J=5.5, 11.1, CHOH of the minor diastereoiso-
mer), 3.44 (dd, J=5.0, 10.5, CHOH of the main
diastereoisomer), 3.28 (dd, J=5.5, 10.5, CHOH of the
main diastereoisomer), 3.17 (t, J=8.3, CHPh of the
main diastereoisomer), 3.08 (t, J=8.3, CHPh of the
minor diastereoisomer), 1.96 (1H, m, CHCH3), 1.66
(3H, m, CH3Cꢀ), 0.97 (d, J=6.7, CH3CH of the main
diastereoisomer), 0.76 (d, J=6.7, CH3CH of the minor
diastereoisomer); GC/MS: tR=18.07, m/z: 190 (M+, 5),
131 (100), 115 (12), 91 (23).
4.2. (2R,3E)-4-Phenyl-3-buten-2-ol (R)-2
Acetate (R)-3 (10.4 g, 0.055 mol) was hydrolysed with
KOH (4.59 g, 0.082 mol) in methanol (70 mL). After
the usual work-up, alcohol (R)-2 (9.67 g, 93%) was
recovered by column chromatography, eluting with
hexane:ethyl acetate 9:1: ee=98% (HPLC), [h]2D0=+31.4
(c 1.38, CHCl3). 1H NMR and MS spectra were in
accordance with those described for the enantiomer.
4.6. (2RS,3R,4E)-2-Methyl-3-phenyl-hex-4-en-1-ol
(RS,R)-5
Acid (RS,R)-4 (8.20 g, 0.040 mol) was treated with
LiAlH4 (1.53 g, 0.040 mol) in THF (200 mL). After the
usual work-up, alcohol (RS,R)-5 (5.32 g, 70%) was
recovered as a 1:1.5 mixture of two diastereoisomers
1
4.3. (2RS,3S,4E)-2-Methyl-3-phenyl-hex-4-enoic acid
(RS,S)-4
(1H NMR). H NMR and MS spectra were in accor-
dance with those described for the enantiomers.
A solution of (R)-2 (9.50 g, 0.064 mol) in triethyl
orthopropionate (200 mL), in the presence of propionic
acid (0.5 mL) was heated at 140°C, removing ethanol
by distillation. The residue, obtained upon evaporation
of the solvent, was treated with NaOH 10% (50 mL) in
refluxing ethanol (200 mL). The mixture was poured
into water, acidified with 10% HCl, and extracted with
diethyl ether. The organic phase was dried over
Na2SO4, and evaporated under reduced pressure, to
give the title compound as a mixture 1:1.6 (1H NMR)
of two diastereoisomers (11.1 g, 85%): 1H NMR: l
7.40–7.10 (5H, m, aromatic hydrogens), 5.72–5.40 (2H,
m, CHꢀCH), 3.47 (m, CHPh of the main diastereoiso-
mer), 3.36 (m, CHPh of the minor diastereoisomer),
2.78 (1H, m, CHCH3), 1.66 (d, J=4.6, CH3Cꢀ of the
main diastereoisomer), 1.60 (d, J=5.6, CH3Cꢀ of the
minor diastereoisomer), 1.21 (d, J=6.4, CH3CH of the
main diastereoisomer), 0.96 (d, J=7.0, CH3CH of the
minor diastereoisomer); GC/MS: tR=19.28 min minor
diastereoisomer, m/z: 204 (M+, 1), 131 (100), 115 (11),
91 (23); tR=19.46 min main diastereoisomer, m/z: 204
(M+, 4), 131 (100), 115 (9), 91 (23).
4.7. (2E,4R)-5-Methyl-4-phenyl-hex-2-ene (R)-6
p-Toluenesulphonyl chloride (11.0 g, 0.058 mol) was
added to a solution of alcohol (RS,S)-5 (7.30 g, 0.038
mol) in pyridine (40 mL). After work-up, the residue
was dissolved in THF (30 mL) and dropped into a
solution of LiAlH4 (1.44 g, 0.038 mol) in refluxing THF
(150 mL). After work-up, (R)-6 (4.43 g, 67%) was
recovered by column chromatography, eluting with
hexane: [h]D20=−59.4 (c 2.68, CHCl3) [lit.21 (S)-6 [h]2D0=
1
+79.9 (heptane)]; H NMR: l 7.45–7.0 (5H, m, aro-
matic hydrogens), 5.62 (1H, ddq, J=15.3, 8.8, 1.3,
CH-CHꢀ), 5.43 (1H, dq, J=15.3, 6.2, ꢀCHCH3), 2.82
(1H, t, J 8.8, CHPh), 1.89 (1H, m, CH(CH3)2), 1.65
(3H, dd, J=6.2, 1.3, CꢀCMe2) 0.93 (3H, d, J=6.6,
CH3CH), 0.74 (3H, d, J=6.6, CH3CH); GC/MS: tR=
12.31 min; m/z: 174 (M+, 6), 131 (100), 115 (12), 91
(23).
4.8. (4S,2E)-5-Methyl-4-phenyl-hex-2-ene (S)-6
According to the procedure described for (RS,S)-5,
alcohol (RS,R)-5 (5.20 g, 0.027 mol) gave (S)-6 (3.00 g,
64%): [h]2D0=+ 58.3 (c 1.27, CHCl3) [lit.21 (S)-6 [h]2D0=
+79.9 (heptane)]; 1H NMR and MS spectra were in
accordance with those described for the enantiomer.
4.4. (2RS,3R,4E)-2-Methyl-3-phenyl-hex-4-enoic acid
(RS,R)-4
According to the procedure described for (R)-2, alcohol
(S)-2 (7.40 g, 0.050 mol) gave the title compound as a
1:1.5 (1H NMR) mixture of two diastereoisomers (8.26
g, 81%). H NMR and MS spectra were in accordance
with those described for the enantiomers.
4.9. (2S)-3-Methyl-2-phenyl-butan-1-ol (S)-7
1
A solution of (R)-6 (4.35 g, 0.025 mol) in CH2Cl2:
methanol 1:1 (150 mL) was treated with ozone at
−78°C. The reaction mixture was quenched with
NaBH4. After the usual work-up, alcohol (S)-7 (3.24 g,
79%) was recovered, after column chromatography,
using hexane:ethyl acetate 9:1 as the eluent: [h]2D0=
+12.4 (c 1.20, CHCl3) [lit.25 (R)-7 [h]2D0=−13.1 (c 2.06,
CH2Cl2), ee=99%]; 1H NMR: l 7.48–7.12 (5H, m,
aromatic hydrogens), 3.94 (1H, dd, J 11.0, 5.3 CHOH),
3.82 (1H, dd, J 11.0, 8.8, CHOH), 1.01 (3H, d, J=6.6,
CH3CH), 0.74 (3H, d, J=6.6, CH3CH); GC/MS: tR=
13.67 min; m/z: 164 (M+, 16), 133 (52), 91 (100).
4.5. (2RS,3S,4E)-2-Methyl-3-phenyl-hex-4-en-1-ol
(RS,S)-5
Acid (RS,S)-4 (11.0 g, 0.054 mol) was treated with
LiAlH4 (2.04 g, 0.054 mol) in THF (200 mL). After the
usual work-up, alcohol (RS,S)-5 (7.39 g, 72%) was
recovered as a 1:1.5 mixture of two diastereoisomers
1
(1H NMR): H NMR: l 7.34–7.13 (5H, m, aromatic
hydrogens), 5.74–5.42 (2H, m, CHꢀCH), 3.67 (dd, J=

E. Brenna et al. / Tetrahedron: Asymmetry 14 (2003) 2401–2406
2405
4.10. (2R)-3-Methyl-2-phenyl-butan-1-ol (R)-7
4. (a) Magnus, M.; Magnus, P. Nature 1997, 38, 3491; (b)
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According to the procedure described for (R)-6, deriva-
tive (S)-6 (2.90 g, 0.017 mol) gave (R)-7 (2.18 g, 80%):
[h]D20=−11.9 (c 0.96, CHCl3) [lit.25 (R)-7 [h]2D0=−13.1 (c
2.06, CH2Cl2), ee=99%]; 1H NMR and MS spectra
were in accordance with those described for the
enantiomer.
4.11. (S)-3-Methyl-2-phenyl-butylamine (S)-1
p-Toluensulphonyl chloride (5.33 g, 0.028 mol) was
added to a solution of alcohol (S)-7 (3.10 g, 0.019 mol)
in pyridine (20 mL). After work-up, the residue was
dissolved in aqueous ethanol (20 mL); NaN3 (3.08 g,
0.0475 mol) was added. The reaction mixture was
refluxed for 10 h. After work-up, the residue was
dissolved in diethyl ether (10 mL) and dropped into a
suspension of LiAlH4 (0.866 g, 0.023 mol) in refluxing
diethyl ether (50 mL). Amine (S)-(−)-1 was isolated as
HCl salt (2.46 g, 65%). (S)-1·HCl: mp=160°C; [h]2D0=
1
−17.6 (c 0.81, MeOH); H NMR (D2O): l 7.40–7.20
(5H, m, aromatic hydrogens), 3.41 (1H, dd, J=4.4,
12.9, CHN), 3.20 (1H, t, J=12.9, CHN), 2.58 (1H, m,
CHPh), 1.86 (1H, m, CHCH3), 0.92 (3H, d, J=6.6,
CH3CH), 0.65 (3H, d, J=6.6, CH3CH). (S)-1 (free
base): ee=96% (HPLC of the corresponding trifl-
uoroacetamide); [h]D20=−12.9 (c 1.12, CHCl3) [lit.22 (R)-
1
1: [h]2D0=−1.5 (neat)]; H NMR: l 7.42–7.34 (5H, m,
aromatic hydrogens), 3.07 (1H, dd, J=4.4, 12.8, CHN),
2.90 (1H, dd, J=9.7, 12.8, CHN), 2.32 (1H, m, CHPh),
1.86 (1H, m, CHCH3), 0.92 (3H, d, J=6.6, CH3CH),
0.72 (3H, d, J=6.6, CH3CH); GC/MS: tR=12.76 min;
m/z: 163 (M+, 5), 146 (11), 132 (27), 117 (25), 91 (100).
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M.; Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry 1996,
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4.12. (R)-3-Methyl-2-phenyl-butylamine (R)-1
According to the procedure described for (S)-7, deriva-
tive (R)-7 (2.05 g, 0.0125 mol) gave (R)-(+)-1·HCl (1.64
g, 66%). (R)-1·HCl: mp=155°C; [h]2D0=+16.9 (c 0.59,
MeOH); (R)-1 (free base): ee=94% (HPLC of the
corresponding trifluoroacetamide); [h]2D0=+12.1 (c 1.15,
1
CHCl3) [lit.22 (R)-1: [h]2D0=−1.5 (neat)]. H NMR and
MS spectra were in accordance with those described for
the enantiomers.
11. Vicario, J. L; Badia, D.; Dominguez, E.; Carrillo, L. J.
Acknowledgements
Org. Chem. 1999, 64, 4610.
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COFIN-Murst is acknowledged for financial support.
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