An efficient synthesis of (S)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) via quinine-mediated desymmetrization of cyclic anhydride

Article abstract of DOI:10.1016/j.tetasy.2007.06.014

A highly enantioselective synthesis of (S)-3-aminomethyl-5-methylhexanoic acid 1 (Pregabalin) is reported. The key step of the synthesis is a quinine-mediated ring opening of 3-isobutylglutaric anhydride with cinnamyl alcohol. A Curtius rearrangement and subsequent deprotection provides 1 in high yield and excellent enantiomeric excess.

Full text of DOI:10.1016/j.tetasy.2007.06.014

Tetrahedron: Asymmetry 18 (2007) 1481–1485
An efficient synthesis of (S)-3-aminomethyl-5-methylhexanoic
acid (Pregabalin) via quinine-mediated desymmetrization
of cyclic anhydride
a,
a
b
*
ˇ
´
´
Zdenko Hamersak, Irena Stipetic and Amir Avdagic
aDepartment of Organic Chemistry and Biochemistry, Rudjer Bosˇkovic´ Institute, PO Box 180, 10002 Zagreb, Croatia
bPLIVA Research and Development Ltd, Prilaz Baruna Filipovic´a 29, 10000 Zagreb, Croatia
Received 15 May 2007; accepted 13 June 2007
Abstract—A highly enantioselective synthesis of (S)-3-aminomethyl-5-methylhexanoic acid 1 (Pregabalin) is reported. The key step of the
synthesis is a quinine-mediated ring opening of 3-isobutylglutaric anhydride with cinnamyl alcohol. A Curtius rearrangement and sub-
sequent deprotection provides 1 in high yield and excellent enantiomeric excess.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ylhexanoic acid rac-1 with (S)-(+)-mandelic acid. The fact
that the resolutions provide Pregabalin in about 30% yield
motivated us to explore the option of an enantioselective
desymmetrization of 2.
(S)-3-Aminomethyl-5-methylhexanoic acid 1 (Pregabalin),
was designed as a more potent gabapentine substitute, an
anticonvulsant drug used for neuropatic pain treatment.
It has also been found to be more active in preclinical mod-
els of epilepsy.1 Since only the (S)-enantiomer possesses the
required biological activity, stereoselective syntheses of (S)-
pregabalin are of great interest. The first syntheses were
evaluated by Hoekstra et al.2 in the Warner–Lambert lab-
oratories, including several manufacturing processes. More
recent examples of stereoselective syntheses of (S)-prega-
2. Results and discussion
3-Isobutylglutaric anhydride 2 was prepared starting from
cyanoacetamide and isovaleraldehyde by a modified
procedure of Day and Thorpe,4 without the isolation of
intermediates (Scheme 1). The piperidine catalyzed conden-
sation of 2 equiv of cyanoacetamide with isovaleraldehyde
was performed in a two-phase system (water–dichloro-
methane, emulsion), which ensured acceptable fluidity of
the reaction mixture. Upon hydrolysis with 6 M hydrochlo-
ric acid, the crude product was converted to the anhydride
by the action of acetic anhydride. Pure 3-isobutylglutaric
anhydride 2 was obtained by vacuum distillation in 65%
yield.
´
balin and its analogues are covered by a review of Ordonez
and Cativiela.3 One of the preferred processes comprises of
the aminolysis of 3-isobutylglutaric anhydride 2 followed
by a Hoffman rearrangement.2 Enantiopurity was obtained
either by the resolution of the intermediary amide with (R)-
(+)-1-phenylethylamine or racemic 3-aminomethyl-5-meth-
O
OH
O
1. H2O/CH2Cl2
piperidine
O
O
2. HCl
H
O
H2N
O
+
2
O
CN
O
3. Ac2O
H2N
2
1
O
(65%)
2
*
Scheme 1.
Corresponding author. Fax: +385 1 4680108; e-mail: hamer@irb.hr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.014

1482
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 1481–1485
Desymmetrization of meso compounds has proven to be a
valuable approach in the synthesis of chiral compounds.5
The first catalytic ring opening of cyclic anhydrides was
reported by Oda6 and shortly thereafter by Aitken.7 When
cinchona alkaloids were used as catalysts and methanol as
the nucleophile, monoesters were obtained in about 70%
ee. Deng8 has reported excellent enantioselectivities (90–
98%) using modified bis-cinchona alkaloids—(DHQ)2AQN
and (DHQD)2AQN. Since the use of catalytic quantities of
alkaloids is practically limited to methanol as the nucleo-
phile and requires several days for completion, we decided
to utilize Bolm’s9 findings and use an equimolar quantity
of base. As the stereochemical outcome of the desymmetri-
zation of cyclic anhydrides was found to be highly predict-
able,9–11 quinine was employed as the base.
All racemic and enantiomerically enriched monoesters
appeared to be oily materials; consequently further
enantiomeric enrichment needed to be performed via
diastereomeric salts. Amongst the variety of chiral amines
screened, (S)-1-phenylethylamine [(S)-PEA] proved to
be the best choice in combination with the cinnamyl
monoester.
On a preparative scale, the reactions were performed at
ꢀ30 ꢁC in toluene with 1.1 equiv of quinine and 1.3 equiv
of cinnamyl alcohol (Scheme 3). After 28 h, the reaction
was stopped by dil. HCl and solvent was evaporated.
HPLC analysis revealed 72% ee. The oily residue was dis-
solved in MTBE, warmed to 45 ꢁC and (S)-PEA then
added, followed by seed crystals. The crystal slurry was
stirred for another 12 h at 25 ꢁC to yield pure S-PEA salt
in 73% yield and 97% ee upon filtration. This method en-
sures not only an acceptable enrichment of enantiopurity,
but also opens up the possibility of avoiding the usual
tedious work-up, which comprises of successive washing
of alkaline aqueous solution of the monoester with organic
solvent to remove residual alcohol.9
In preliminary experiments (Table 1, Scheme 2) the influ-
ence of base quantity, temperature and the choice of nucleo-
phile on the reaction was examined. The alcoholic
nucleophiles used were chosen for the reason of their spe-
cific cleavage as protective groups.12 Comparable results
were obtained with benzyl and cinnamyl alcohols. A
decrease in temperature of 10 ꢁC resulted in an increase
of ee by more than 5% with all nucleophiles. The reaction
with p-methoxybenzyl alcohol was significantly faster,
however, in these cases, lower ees were obtained. The lower
ee resulting from the use of just 1 equiv of the base was no-
ticed by Bolm13 with methanol as the nucleophile. Never-
theless, we wanted to verify if the same effect was present
with cinnamyl alcohol. Lower yields on isolated mono-
esters 3a–c compared to the conversion can be attributed
to the emulsification properties of their potassium salts
during the work-up.
In the next step, the liberated monoester ester 3a was con-
verted into the protected b-amino acid ester derivative 4 by
a
Curtius rearrangement using diphenyl phosphoryl
azide-triethylamine followed by reaction of the intermedi-
ate isocyanate with cinnamyl alcohol in refluxing toluene.
The crude oily product contained about 10% cinnamyl
alcohol, together with some minor impurities and was used
in the next step without purification. Small quantities of the
material were purified by chromatography, although the
method is highly impractical for scale-up.
In the last step, the protective groups in 4 were removed by
transallylation of morpholine as a nucleophile in refluxing
ethanol, catalyzed with palladium acetate-triphenyl phos-
phine. The precipitated product was crystallized from
aqueous 2-propanol. Pregabalin 1 was obtained in 62%
yield (calculated from monoester 3a) and 99.7% ee. It
was reported by Hoekstra et al.2 that, when a free amino
group exists in the neighbourhood of an ester group during
Pregabaline syntheses, a significant amount of lactame 7 is
formed. However, during the synthesis of cyclic b-amino
acids by the same reaction sequence,14 we observed that
the cinnamyl ester group was cleaved faster than the
carbonylamino protection. With that fact in mind we
hoped that the lactam formation would be largely sup-
pressed. Indeed, only about 5% of lactam 7 was formed
during the reaction.
Table 1. Influence of base quantity, conditions and nucleophile on
opening of anhydride 2a
R/equiv
Quinine
(equiv)
ꢁC
Time
(h)
Yieldb
(%)
eec
(%)
3a
3b
3c
3a
3b
3c
3a
3a
Cinnamyl/2
p-Metoxybenzyl/2
Benzyl/2
Cinnamyl/2
p-Metoxybenzyl/2
Benzyl/2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.1
ꢀ15
ꢀ15
ꢀ15
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
22
8
78
74
69
78
68
72
68
85
61
50
58
67
58
64
62
69
18
23
12
23
23
25
Cinnamyl/2
Cinnamyl/1.3
a The reactions were performed with 1.0 g of anhydride in 50 mL of tol-
uene and were quenched with 5% HCl when over 95% of the anhydride
had been consumed.
b Isolated yield.
c Determined by chiral HPLC.
The fact that the starting compound 4 was to be used as a
crude material and that, under such circumstances present
impurities can influence the efficiency of palladium acetate-
triphenyl phosphine catalyzed deprotection and enlarge the
quantity of lactam by-product, forced us to examine an
alternative route from 3a to 1. Therefore, instead of cinn-
amyl alcohol, the benzyl alcohol was used in the Curtius
rearrangement. Cinnamyl protection of 5 was cleaved by
palladium acetate-triphenyl phosphine as before, to afford
amino-protected acid 6, which was purified via its sodium
salt. Finally, Pregabalin 1 was obtained by Pd/C catalyzed
RO
O
O
quinine, toluene
ROH
O
OH
O
3a-c
O
2
Scheme 2.

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 1481–1485
1483
1. quinine, toluene
cinnamyl alc.
O
-30 °C, 24 h
O
97% ee
O
O
2. resol. (S)-PEA
(72%)
O
O
HOOC
3a
2
1. (PhO)2PON3, Et3N
2. benzyl alc.
1. (PhO)2PON3, Et3N
2. cinnamyl alc.
O
O
HN
O
O
O
5
O
O
HN
4
Pd(OAc)2, PPh3,
morpholine, EtOH
(88%)
OH
O
NH
7
Pd(OAc)2, PPh3,
morpholine, EtOH
(62%)
O
O
O
O
H2 Pd/C
N
H
OH
aq. MeOH
(60%)
99.7% ee
6
H2N
1
Scheme 3.
hydrogenation in 53% yield (calculated from monoester 3a)
and 99.7% ee.
rotations were measured using Optical Activity AA-10
automatic polarimeter. 1H and 13C NMR spectra were
recorded on a Bruker AV 300 and AV 600 spectrometers,
IR spectra on a Bruker ABB Bomen instrument. For the
chemical purity determination, and monitoring of the
progress of the reactions HP 5890 GC, and HP 1090 HPLC
chromatographs were used. Ees of monoestes 3a–c were
determined on Chiralpak AS column (n-hexane–EtOH–
TFA, 95:5:0.2). The enantiomeric purity of 1 was deter-
mined by conversion to its derivative with Marfey’s reagent
(N-a-(2,4-dinitro-5-fluorophenyl)-L-alaninimide)15 followed
by analysis on a Nucleosil 100-5 C18 column (0.05 M
aqueous triethylamine (pH adjusted to 3 with H3PO4)–
acetonitrile, 55:45). All other reagents and solvents were
purchased from commercial sources and used without
purification.
3. Conclusion
In conclusion, a convenient enantioselective synthesis of (S)-
3-aminomethyl-5-methylhexanoic acid 1 (Pregabalin) was
developed. The key step of the synthesis was a quinine-med-
iated opening of 3-isobutylglutaric anhydride with cinnamyl
alcohol. The Curtius rearrangement of the intermediary
monoester and subsequent cleavage of protective groups
afforded Pregabalin in 45% overall yield and 99.7% ee.
4. Experimental
4.1. General
4.2. 3-Isobutylglutaric anhydride 2
Melting points were determined on Electrothermal 9100
apparatus in open capillaries and are not corrected. Optical
Cyanoacetamide (52.0 g, 0.62 mol) was suspended in
220 mL of water and heated to 30 ꢁC until it dissolved.

1484
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 1481–1485
The solution was cooled to 20 ꢁC, after which piperidine
(2 mL, 1.72 g, 20.2 mmol) was added, followed by isovaler-
aldehyde (33.6 mL, 26.8 g, 0.31 mol) over 10 min while
keeping the temperature below 25 ꢁC. After 15 min of stir-
ring, the reaction mixture became turbid and 160 mL of
dichloromethane was added. The resulting thick emulsion
was stirred for another 6 h at 22–25 ꢁC. Concd HCl
(220 mL) was added, after which dichloromethane was dis-
tilled out, followed by a few millilitres of aq HCl until the
reaction mixture temperature reached 108 ꢁC. The reaction
mixture was refluxed for 20 h after which an oily product
was collected with dichloromethane (50 + 30 mL). Most
of the solvent was distilled. Acetic anhydride (110 mL)
was then added and the reaction mixture kept at gentle
reflux for 2 h accompanied by separation of residual dichlo-
romethane and acetic acid formed. The majority of the ace-
tic anhydride was removed by vacuum distillation at
20 mmHg and then upon rejection of the small prefraction,
the main fraction was collected at 100–105 ꢁC/0.5 mmHg to
yield 34 g (65%) of anhydride 2, which was >98% pure by
1.70 (m, 1H), 2.38–2.48 (m, 5H), 4.73 (dd, 2H,
J1 = 6.5 Hz, J2 = 1.2 Hz), 6.27 (dt, 1H J1 = 15.8 Hz,
J2 = 6.5 Hz), 6.65 (d, 1H, J = 15.8 Hz), 7.22–7.40 (m,
5H). 13C NMR (CDCl3), d/ppm: 22.3, 25.1, 29.6, 38.3,
38.5, 43.3, 64.9, 122.9, 126.5, 127.9, 128.5, 134.18, 136.1,
172.2, 178.6. IR (film on KBr): 2956, 2927, 2871, 1734,
. Anal. Calcd for
C18H24O4 (304.38): C, 71.03; H, 7.95. Found: C, 70.86;
H, 8.02.
1707, 1168, 966, 745, 692 cmꢀ1
4.4. (ꢀ)-(S)-5-Methyl-3-[(3-phenyl-allyloxycarbonilamino)-
methyl]-hexanoic acid 3-phenyl-allyl ester 4
To a dry toluene solution (140 mL) of monoester 3a
(18.6 g, 60.6 mmol) and triethylamine (8.3 mL, 60.6 mmol)
diphenylphosphoryl azide (13.0 mL, 60.6 mmol) was added
at 20 ꢁC. The reaction mixture was stirred for 30 min and
then slowly warmed to 90 ꢁC. When nitrogen evolution
ceased (30–45 min), cinnamyl alcohol (9.7 g, 72.7 mmol)
was added and the mixture was refluxed overnight. The
reaction mixture was washed with a solution of 1% NaNO2
and 1.5% NaHCO3 in H2O (2 · 100 mL) and with H2O
(100 mL). Evaporation of the solvent yielded 24.9 g of
crude oily carbamate, which was used without further puri-
fication in the next step. For characterization, the product
1
GC. H NMR (CDCl3), d/ppm: 0.91 (d, 6H, J = 6.6 Hz),
1.27 (t, 2H, J = 7.1 Hz), 1.61–1.75 (m, 1H), 2.12–2.50 (m,
3H), 2.85 (dd, 2H, J1 = 17 Hz, J2 = 4.1 Hz). 13C NMR
(CDCl3), d/ppm: 21.8, 24.2, 25.9, 35.4, 43.1, 166.5.
4.3. (ꢀ)-(R)-3-Isobutyl-pentanedioic acid mono-(3-phenyl-
was purified on silica gel using EtOAc–hexane (1:1) as elu-
allyl) ester 3a
25
ent. Mp 53.5–54.5 ꢁC; ½aꢁD ¼ ꢀ4:3 (c 20, EtOH). 1H NMR
(CDCl3), d/ppm: 0.88 (d, 3H, J = 6.4 Hz), 0.90 (d, 3H,
J = 6.4 Hz), 1.09–1.25 (m, 2H), 1.63–1.71 (m, 1H), 2.15–
2.38 (m, 3H), 3.05–3.18 (m, 1H), 3.25–3.33 (m, 1H),
4.68–4.75 (m, 4H), 4.96 (br s, 1H), 6.22–6.32 (m, 2H),
6.62 (d, 1H, J = 15.8 Hz), 6.65 (d, 1H, J = 15.8 Hz),
7.15–7.50 (m, 10H). 13C NMR (CDCl3), d/ppm: 22.5,
25.0, 33.5, 37.3, 41.3, 44.6, 65.0, 65.3, 122.9, 123.8,
126.45, 126.5, 127.8, 127.9, 128.4, 128.5, 133.4, 134.2,
136.0, 136.2, 156.3, 172.8. IR (KBr): 3355, 3026, 2957,
To a suspension of quinine (31.5 g, 97 mmol) and cinnamyl
alcohol (17.7 g, 132 mmol) in toluene (370 mL), a solution
of anhydride 2 (15.0 g, 88 mmol) in 10 mL of toluene was
added over 10 min while keeping the temperature at
ꢀ30 ꢁC. The reaction mixture was stirred at the same tem-
perature for 24 h after which it was then allowed to warm-
up (for 4–5 h) to ꢀ5 ꢁC. The toluene solution was washed
with 5% HCl (250 mL), brine (150 mL) and evaporated.
HPLC analysis revealed 72% ee. The oily residue was dis-
solved in 200 mL of MTBE, warmed to 45 ꢁC and (S)-
phenylethyl amine (8.6 g, 70 mmol) was added, followed
by few milligrams of seed crystals. The crystal slurry was
stirred at 45 ꢁC for an hour and then at rt overnight. Filtra-
1726, 1692, 1682, 1534, 1252, 1178, 968, 751, 691 cmꢀ1
.
Anal. Calcd for C27H33NO4 (435.56): C, 74.45; H, 7.64;
N, 3.22. Found: C, 74.65; H, 7.88; N, 3.02.
tion yielded 27.3 g (73%) of amine salt (97% ee).
4.5. (+)-(S)-3-Aminomethyl-5-methyl-hexanoic acid 1
25
½aꢁD ¼ ꢀ7:0 (c 1, EtOH), mp = 108.5–110 ꢁC. 1H NMR
(CDCl3), d/ppm: 0.85 (d, 6H, J = 6.4 Hz), 1.12–1.15 (m,
2H), 1.50–1.60 (m, 6H), 2.01–2.14 (m, 2H), 2.21–2.40 (m,
3H), 4.19 (q, 1H, J = 6.7 Hz), 4.69 (d, 2H, J = 6.2 Hz),
6.25 (dt, 1H, J1 = 15.8 Hz, J2 = 6.5 Hz), 6.62 (d, 1H,
J = 15.8 Hz), 7.18–7.43 (m, 10H). 13C NMR (CDCl3), d/
ppm: 22.4, 22.5, 22.6, 25.0, 30.2, 38.9, 40.7, 43.5, 50.8,
64.7, 123.2, 126.2, 126.4, 127.7, 127.8, 128.4, 128.6, 133.9,
136.1, 142.3, 172.8, 178.0. IR (KBr): 2952, 2923, 2867,
A solution of crude carbamate 4 (24.9 g) in abs EtOH
(100 mL) was refluxed for 10 min, and then cooled to
70 ꢁC. Morpholine (21 mL, 230 mmol) was added followed
by triphenylphosphine (120 mg, 0.46 mmol) and Pd(OAc)2
(3 mg, 0.01 mmol). The reaction mixture was refluxed for
3 h, and then slowly cooled to room temperature. After
5 h, the product was collected by filtration and dried at re-
duced pressure (6.9 g, 71%, 99.1% ee). Crystallization from
aqueous 2-PrOH afforded 6.0 g (62% from 3a) of pure ami-
no acid (99.7% ee). Mp 195 ꢁC (decomp.) lit.2 177–179 ꢁC
2702, 1742, 1541, 1401, 1161, 1142, 970, 751, 698 cmꢀ1
.
25
25
The (S)-PEA salt was suspended in toluene (150 mL) and
stirred with 3% HCl (100 mL) until a clear solution was ob-
tained. The organic layer was washed once again with 3%
HCl (30 mL) and brine (50 mL). The toluene solution can
be used directly in the subsequent reaction; otherwise evap-
oration of solvent provides monoester 3a quantitatively.
(decomp.), ½aꢁD ¼ þ10:8 (c 1, H2O), (lit.2 ½aꢁD ¼ þ10:1 (c
1.1, H2O). 1H NMR (D2O), d/ppm: 0.87 (d, 3H,
J = 6.5 Hz), 0.89 (d, 3H, J = 6.5 Hz), 1.21 (t, 2H,
J = 7.0 Hz), 1.58–1.72 (m, 1H), 2.07–2.35 (m, 3H), 2.90–
3.05 (m, 2H). 13C NMR (D2O), d/ppm: 21.6, 22.1, 24.5,
41.8, 40.7, 40.9, 43.8, 181.3. IR (KBr): 2956, 2925, 1641,
1549, 1390, 1332, 1278, 700 cmꢀ1. Anal. Calcd for
C8H17NO2 (159.23): C, 60.35; H, 10.76; N, 8.80. Found:
C, 60.61; H, 10.53; N, 8.99.
25
1
Compound 3a: ½aꢁD ¼ ꢀ0:53 (neat) H NMR (CDCl3), d/
ppm: 0.87 (d, 6H, J = 6.5 Hz), 1.21–1.27 (m, 2H), 1.56–

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 1481–1485
1485
4.6. (ꢀ)-(S)-3-(Benzyloxycarbonylamino-methyl)-5-methyl-
4.8. (+)-(S)-3-Aminomethyl-5-methyl-hexanoic acid 1 from 6
hexanoic acid 3-phenyl-allyl ester 5
Benzyl-carbamate 6 (12.7 g, 43 mmol) was dissolved in
100 mL of methanol, 0.6 g of Pd/C (10%) was added, after
which the mixture was hydrogenated at rt and 10 bar of
hydrogen pressure.
To a dry toluene solution (100 mL) of monoester 3a
(15.0 g, 49 mmol), triethylamine (6.7 mL, 49 mmol) and
diphenylphosphoryl azide (10.5 mL, 49 mmol) were added
at 20 ꢁC. The reaction mixture was stirred for 30 min and
then slowly warmed to 90 ꢁC. When nitrogen evolution
ceased (30–45 min), benzyl alcohol (6.3 g, 49 mmol) was
added and the mixture refluxed overnight. The reaction
mixture was washed with a solution of 1% NaNO2 and
1.5% NaHCO3 in H2O (2 · 100 mL), then with H2O
(100 mL) and evaporated under reduced pressure to yield
18.4 g of crude oily carbamate, which was used without
further purification in the next step. For spectroscopic
After 15 h, 50 mL of water was added, warmed to 50 ꢁC
and filtered hot. The filter was carefully washed with hot
aqueous methanol. The filtrate was concentrated to
25 mL. 2-Propanol (100 mL) was added and left to crystal-
lize for 3 h. Filtration yielded 4.1 g (60%) of Pregabaline 1
1
(99.7% ee). The IR, H NMR and 13C NMR spectra are
coincidental to those of 1 obtained from 4.
determination the product was purified by chromatogra-
25
phy on silica gel. ½aꢁD ¼ ꢀ4:2 (c 20, EtOH). 1H NMR
Acknowledgements
(CDCl3), d/ppm: 0.82–0.93 (m, 6H), 1.13–1.20 (m, 2H),
1.60–1.70 (m, 1H), 2.14–2.42 (m, 3H), 3.06–3.16 (m,
1H), 3.23–3.33 (m, 1H), 4.70–4.75 (m, 2H), 4.95 (br s,
1H), 5.06–5.10 (m, 2H), 6.26 (dt, 1H, J1 = 15.8 Hz,
J2 = 6.5 Hz), 6.63 (d, 1H, J = 15.8 Hz), 7.13–7.45 (m,
10H). 13C NMR (CDCl3), d/ppm: 22.5, 22.6, 25.0, 33.5,
37.2, 41.3, 44.6, 65.0, 66.5, 122.9, 126.5, 128.0, 128.4,
128.5, 134.2, 136.0, 156.4, 172.7. IR (film on KBr):
3346, 3033, 2954, 2935, 2867, 1726, 1523, 1247, 1169,
This work was supported by PLIVA d.d. and Ministry of
Science, Education and Sports (Project 0982933-2908).
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.
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´
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8. Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122,
9542–9543.
9. Bolm, C.; Schifers, I.; Atodiresei, I.; Hackenberger, P. R.
Tetrahedron: Asymmetry 2003, 14, 3455–3467.
10. Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965–
2983.
11. Spivey, A. C.; Andrews, B. L. Angew. Chem., Int. Ed. 2001,
40, 3131–3134.
A solution of crude carbamate 5 (18.4 g) in abs EtOH
(100 mL) was refluxed for 10 min, and then cooled to
70 ꢁC. Morpholine (8.1 mL, 90 mmol) was added followed
by triphenylphosphine (95 mg, 0.36 mmol) and Pd(OAc)2
(2 mg, 0.009 mmol). The reaction mixture was refluxed
for 3 h. Most of the solvent was evaporated at a reduced
pressure, 200 mL of 3% Na2CO3 and 80 mL of EtOAc
were added. The mixture was stirred for 15 min, after
which the aqueous layer was separated and washed again
with EtOAc. Upon acidification to pH 1.5 with concd
HCl, extraction with CH2Cl2 afforded 12.7 g (88% from
25
monoester 3a) of oily benzyl-carbamate 6. ½aꢁD ¼ ꢀ4:4
1
(c 25, EtOH). H NMR (DMSO), d/ppm: 0.81–0.85 (m,
6H), 1.00–1.16 (m, 2H), 1.55–1.66 (m, 1H), 1.91–2.27
(m, 3H), 2.84–3.09 (m, 2H), 5.01 (s, 2H), 7.26–7.28 (m,
5H). 13C NMR (DMSO), d/ppm: 22.9, 23.2, 25.1, 33.6,
37.6, 41.4, 44.3, 65.6, 128.1, 128.2, 128.7, 137.8, 156.8,
174.4. IR (film on KBr): 3340, 2956, 2929, 2871, 1708,
12. Kociensky, P. J. Protecting Groups; Thieme: Stuttgart, New
York, 1994.
13. Bolm, C.; Schifers, I.; Dinter, C. L.; Gerlach, A. J. Org.
Chem. 2000, 65, 6901–6984.
ˇ
´
´
14. Hamersˇak, Z.; Roje, M.; Avdagic, A.; Sunjic, V. Tetrahedron:
1534, 1258, 697 cmꢀ1
. Anal. Calcd for C16H23NO4
Asymmetry 2007, 18, 635–644.
(293.36): C, 65.51; H, 7.90; N, 4.77. Found: C, 65.78;
H, 8.12; N, 4.51.
15. Bruckner, H.; Keller-Hoehl, C. Chromatographia 1990, 30,
¨
621–629.