A simple enantioselective route toward (R)- and (S)-Rolipram via anhydride desymmetrization

Article abstract of DOI:10.1016/j.tetasy.2013.01.009

A highly enantioselective metal-free synthesis of both enantiomers of Rolipram is reported. The key stereoinductive step is a cinchona alkaloid catalyzed opening of a cyclic anhydride prepared from isovanillin, where both enantiomers are available using t

Full text of DOI:10.1016/j.tetasy.2013.01.009

Tetrahedron: Asymmetry 24 (2013) 217–222
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A simple enantioselective route toward (R)- and (S)-Rolipram via anhydride
desymmetrization
⇑
´
Trpimir Ivšic, Zdenko Hameršak
´
Department of Organic Chemistry and Biochemistry, Rudjer Boškovic Institute, PO Box 180, 10002 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 December 2012
Accepted 16 January 2013
A highly enantioselective metal-free synthesis of both enantiomers of Rolipram is reported. The key ste-
reoinductive step is a cinchona alkaloid catalyzed opening of a cyclic anhydride prepared from isovanillin,
where both enantiomers are available using the same chiral catalyst in two protocols. An extended one-
pot Curtius sequence provides the lactam directly from the desymmetrization product after enrichment
in high yield and excellent ee.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
knowledge, the only published protocol suitable for the larger pro-
duction of both enantiomers proceeds through the resolution of
Rolipram 1, a cyclic derivate of GABA is a compound possessing
antidepressive,1 antiinflammatory,2 antipsyhotic,3 and neuropro-
tective4 effects, among others. Biological activity is drawn from
the selective inhibition of cAMP-selective phosphodiesterase activ-
ity (PDE), and recent animal studies show promise in ameliorating
Alzheimer’s disease5 and regeneration of the spinal axon.6 There is
also growing excitement that PDE inhibitors may target multiple
aspects of the tumor microenvironment, bearing potential for ther-
apeutical use in the future.7
racemic intermediate.23
In addition, we present herein a simple metal-free route toward
Rolipram (Fig. 1), whereby both enantiomers are obtained using
the same readily available catalyst in two protocols for the selec-
tive opening of anhydride 3.
2. Results and discussion
Anhydride 3 was prepared according to the Smith and Kort pro-
tocol,24 starting with aldehyde 2. The latter is readily available
from isovanillin through a single O-alkylation step in 95% yield.25
The piperidine catalyzed condensation of 2 with ethylacetoacetate
was performed in ethanol, from which the product precipitated. In
sequence, hydrolysis with concentrated alkali yielded a glutaric
acid intermediate in the form of crystals upon dilution and acidifi-
cation. If used for the reaction, diluted alkali produces a certain
amount of side product24 that is harder to separate. Treatment of
the glutaric acid intermediate with acetic anhydride at reflux
allowed for the isolation of anhydride 3 after crystallization in a
60% overall yield from aldehyde 2 (Fig. 2).
The enantioselective desymmetrization of cyclic meso-anhy-
drides26,27 has already been identified as a convenient method
for stereoinduction in the total syntheses of biologically active sub-
stances,28–30 including Pregabalin,31 Biotin,32 Baclofen,33 etc.
Procedures using stoichiometric quantities of natural cinchona
alkaloids for the opening of succinic anhydrides at low tempera-
tures was developed by Bolm et al.34 If a catalytic amount of alka-
loid is used at room temperature instead, a drastic reduction of
selectivity is observed. Alternatively, a catalytic amount of modi-
fied cinchona alkaloids including ethers,35 ureas or thioureas,36
and sulfonamides37 was also found to steer the reaction toward
the desired enantiomer.
Although Rolipram is commercially available in the racemic
form, its enantiomers show different biological activities,1,8 and a
simple method for obtaining both of them in sufficient quantities
is desirable. Several asymmetric routes have been reported up to
date; the chirality was, for example, induced via addition of
arylboronic acids to aminobutenoic acid,9 ethyl-
crotonate,10 or an
,b-unsaturated
c
-phthalimido-
a
c
-lactam;11 via reduction of
c
-phthalimido12 or azido13 substituted
a,b-unsaturated esters;
via carbon–hydrogen insertion;14 via Michael addition of malonate
to nitroolefins15–18 or nitroalkanes to enals.19–21
While excellent ees are obtained using some of the above meth-
ods, high-priced metals or complex organocatalysts are typically
used in the chirality inducing step. Moreover, to obtain the product
in both enantiomeric forms, two chiral modifiers need to be pre-
pared first, which may present a problem at the time if they turn
out to be unequally reactive in the synthesis. The pathways men-
tioned, thus, tend to be impractical for greater production of both
enantiomers. On the other hand, Rolipram may be prepared as a
racemate on a multigram scale and resolved using the semiprepar-
ative simulated moving bed chromatography.22 To the best of our
⇑
Corresponding author. Tel.: +385 1 4571 300; fax: +385 14680108.
E-mail address: hamer@irb.hr (Z. Hameršak).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.009

´
218
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 24 (2013) 217–222
O
O
HN
O
O
O
O
OH
(R)-1
quinine
O
CHO
O
O
O
O
isovanilline
3
HN
(S)-1
O
Figure 1. Retrosynthetic analysis of Rolipram 1.
O
O
O
O
O
1. EtOH
O
O
piperidine
O
+
2
2. KOH
3. Ac2O
OEt
60%
CHO
O
2
3
Figure 2. Preparation of anhydride 3.
In contrast, glutaric anhydrides tend to show different behav-
ometric protocol, all with comparable yields and ees. Thus, the
availability of both product enantiomers over this pathway was
not limited by access to the two chiral catalysts.
iors. While both stoichiometric and catalytic opening with natural
alkaloids proceed in moderate enantioselectivity at room temper-
ature, the products formed are of opposite configurations.38
Quite recently, we published a work on optimization of the cat-
alytic room temperature protocol using alkaloids as an organic acid
salt, showing that the opposite pathway can be further improved
to a synthetically useful level.39 Consequently, both enantiomers
of the product were available with the same naturally occurring
chiral catalyst, solely by altering the protocol.
On the other hand, modified cinchona alkaloids, if used for the
opening of the more demanding glutaric anhydrides (compared
to the succinic), produce inferior results with the same catalyst
loading,36 and the resolution of enantiomers may nevertheless be
needed in order to reach a satisfactory enantiopurity.
In the case of glutaric anhydrides, especially when both product
enantiomers are required in larger quantities, the ease of the pro-
tocols utilizing inexpensive natural alkaloids turns out to be
advantageous. The latter were our primary choice for anhydride
desymmetrization in our synthesis of Rolipram. After opening of
3 with benzyl alcohol, monoester 4 was obtained preferentially
when quinine was used as a catalyst in stoichiometric amount.
The same catalyst produced the opposite ent-4 if catalytic condi-
tions with xanthene-9-carboxylic acid (X9C) were employed
(Fig. 3). In contrast, quinidine, (the pseudoenantiomer of quinine)
yielded 4 when used in a catalytic procedure, and ent-4 in a stoichi-
Typically, somewhat lower yields of the isolated monoesters are
found in anhydride desymmetrizations compared to the conver-
sions.40 The loss of the products is attributed to the emulsification
properties of their salts during the workup which comprises of suc-
cessive washing of alkaline aqueous monoester solutions with an
organic solvent to remove residual alcohol.31,39 In fact, during the
present work, monoester 4 was found to be completely hydrolyzed
in 2 h by a 2% carbonate solution. In addition, the room tempera-
ture catalytic protocol requires removal of the carboxylic acid addi-
tive, which is accomplished by fine tuning the pH down to the
point where only the additive remains dissolved. While monoes-
ters 4 and 5 appear as solids, both issues were resolved by a slow
addition of the bulk mixture to the buffer solution, after which the
product was isolated by filtration. Regeneration of the acid additive
was possible by acidification of the residing mother liquor, previ-
ously washed with organic solvent.
Thus, after the usual removal of the alkaloid and the solvent,
monoesters 4 and 5 were purified, both from the acid and the ex-
cess alcohol in a convenient isolation step without product loss.
The results of anhydride 3 openings utilizing both the catalytic
and stoichiometric protocols are summarized in Table 1.
As both benzyl (Bn) and cinnamyl (Cinn) monoesters are white
solids, some enantiomeric enrichment was accomplished by

´
219
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 24 (2013) 217–222
O
O
O
O
O
O
quinine, a)
quinine, b)
or
or
COOR
quinidine, b)
COOR
quinidine, a)
(S)
(R)
+ ROH
HOOC
ent-4, ent-5
HOOC
O
O
O
3
4, 5
95% ee, 69% yield
4
5
R=Bn:
R=Cinn:
92% ee, 70% yield
after enrichment
Figure 3. Cinchona catalyzed opening of anhydride 3. Both product enantiomers are available with the same chiral catalyst. Conditions: (a) alkaloid (0.1 equiv), X9C
(0.2 equiv), rt, then resolution with PEA or (b) alkaloid (1.1 equiv), ꢀ30 °C, then resolution with PEA.
Table 1
Enantioselective opening of 3 with natural cinchona alkaloidsa
Entry
Methodb
R0OH
Temp
rt
Time
Yield (%)
eed (%)
Product configuration
1
2
3
4
5
6
A(0.1 QD+X)
B(1.1 Q)
A(0.1 Q+X)
B(1.1 QD)
A(0.1 QD+X)
B(1.1 Q)
BnOH
BnOH
BnOH
BnOH
CinnOH
CinnOH
3 days
7 days
3 days
7 days
3 days
3 days
98
94
94
93
95
72c
71
73
62
68
73
74
(R)
(R)
(S)
(S)
(R)
(R)
ꢀ30 °C
rt
ꢀ30 °C
rt
ꢀ30 °C
a
Reactions were carried out with 10 mmol of anhydride, 0.1 M solution in toluene, and 1.5 equiv of alcohol until complete conversion was reached.
Methods: (A) 0.1 equiv of quinidine (QD) or quinine (Q), 0.2 equiv of xanthene-9-carboxylic acid (X); (B) 1.1 equiv of quinine (Q) or quinidine (QD).
Reaction was quenched after time indicated.
b
c
d
Determined by chiral HPLC.
spontaneous crystallization from 2-propanol. However, the maxi-
mum ee obtained this way was about 90%. Alternatively, the reso-
lution of (S)-phenylethylamine (PEA) salts allowed for the
enrichment of benzyl product 4 from 73% ee to 95% ee by a single
crystallization proceeding in a 73% yield from the desymmetriza-
tion product (Fig. 3). The enriched monoesters were used in the
next step after liberation from the salt.
O
O
O
O
Various protected unnatural aminoacids29,31,33,41 are available
from succinic or glutaric acid monoesters through the one-pot se-
quence employing a Curtius rearrangement. The azide initially
formed is thermally rearranged into an unstable isocyanate inter-
mediate which reacts with a nucleophile to yield an N-protected
aminoester.42 However, during the deprotection step in a recent
Pregabalin synthesis, intramolecular formation of a lactam was ob-
served as an unwanted side reaction of a free amine and a neigh-
boring ester group.31 In the case of Rolipram, in contrast, the
aforementioned pathway toward the lactam becomes more inter-
esting, so a question arises as to whether a cyclization would pro-
ceed in the Curtius sequence if the free amine was formed directly.
This could be accomplished if aqueous acid was used in the place of
a nucleophile to hydrolyze the isocyanate intermediate formed in
the rearrangement, followed by loss of carbon dioxide.43
COOR
HN
HOOC
O
4, 5
(R)-(-)-Rolipram
1. DPPA, TEA
95 °C
2. RT, 5% HCl
3. 110 °C
O
O
O
O
COOR
HOOC
HN
O
Herein we have demonstrated that the cyclization indeed fol-
lows the thermal decarboxylation in the same step. In both cases,
starting from monoester 4 or 5, the isolated product was character-
ized as Rolipram (Fig. 4).
ent-4
(S)-(+)-Rolipram
As a result, the need for protection and subsequent deprotection
of the amine was avoided. The lactam was produced directly from
the enriched monoester in a 51% yield over an extended one pot
Curtius sequence without the isolation of unstable intermediates.
from R=Bn 95% ee, 51% yield
from R=Cinn 92% ee, 53% yield
Figure 4. One pot extended Curtius reaction featuring lactam cyclization of 1.

´
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 24 (2013) 217–222
220
4.3. 4-(3-Cyclopentyloxy-4-methoxy-phenyl)-dihydro-pyran-
2,6-dione 3
3. Conclusion
In conclusion, a simple metal-free enantioselective synthesis of
both enantiomers of Rolipram has been developed. Chirality was
introduced through the desymmetrization of glutaric anhydride 3
catalyzed by a natural cinchona alkaloid. Both enantiomers of the
intermediary monoesters were available with a single chiral cata-
lyst in a convenient synthesis starting from isovanillin.
An extended Curtius reaction of the enantiomerically enriched
intermediary monoester through a one pot sequence yielded Roli-
pram of 95% ee in 51% yield. All stable intermediates were easily
purified; chromatography was not needed except for the isolation
of the final product.
The glutaric acid from the previous procedure (2.71 g,
8.42 mmol) was dissolved in acetic anhydride (9 mL). The mixture
was heated to 110 °C for 30 min and left to cool down to room tem-
perature. After evaporation, the residue was crystallized from chlo-
roform (4 mL) and diisopropyl ether (25 mL) to achieve 2.39 g
(93%) of anhydride 5. Mp 101.0–101.4 °C. 1H NMR (300 MHz,
CDCl3, d): 1.52–1.68 (m, 2H); 1.78–1.98 (m, 6H); 2.83 (dd,
J1 = 17.6, J2 = 10.9 Hz, 2H); 3.08 (dd, J1 = 17.6, J2 = 4.6 Hz, 2H);
3.30–3.42 (m, 1H); 3.83 (s, 3H); 4.71–4.79 (m, 1H); 6.66–6.74 (m,
2H); 6.85 (d, J = 8.2 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3, d):
24.02; 32.81; 33.61; 37.39; 56.13; 80.74; 112.47; 113.26; 118.07;
131.43; 148.25; 149.89; 165.97 ppm. HRMS (MALDI): m/z: calcd
for C17H20O5H [M+H+] 305.1384; found: 305.1378.
4. Experimental
General methods: All reactions were conducted under an argon
atmosphere unless otherwise noted. Aldehyde 2 was prepared
according to the literature.25 Triethylamine was dried over KOH
prior to use. Toluene was dried in situ by distillation of azeotrope.
All other reagents and solvents were purchased from commercial
sources and used without purification. Column chromatography
was performed on silica gel (silica gel 60, 70–230 mesh, Fluka).
1H and 13C NMR were recorded on a Bruker AV 300 spectrometer.
Chemical shifts (dH and dC) are quoted in parts per million (ppm),
referenced to TMS. High resolution mass spectrometry (HRMS)
was performed on a 4800 Plus MALDI TOF/TOFAnalyzer. Optical
rotations were measured using an Optical Activity AA-10 auto-
matic polarimeter. Melting points were determined on a Electro-
thermal 9100 apparatus in open capillaries and are not corrected.
4.4. (R)-3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pentanedioic
acid monobenzyl ester 4
4.4.1. Method A
Quinidine (0.320 g, 0.98 mmol, 0.1 equiv) was dissolved with
xanthene-9-carboxylic acid (0.46 g, 2.02 mmol, 0.205 equiv) and
anhydride 3 (3 g, 9.8 mmol, 1 equiv) in toluene (98 mL, 0.1 M with
respect to the anhydride). Benzyl alcohol (1.5 mL, 1.60 g,
14.8 mmol, 1.5 equiv) was added and the reaction mixture was
stirred at room temperature for 3 days. The reaction was quenched
with 5% HCl (100 mL). The organic layer was washed with water,
dried over Na2SO4 and evaporated to dryness. The residual white
solid was dissolved in MeOH (15 mL) and added dropwise to a stir-
red phosphate buffer pH 5.4 (2.667 g of NaH2PO4ꢂ2H2O and 1.167 g
of citric acid monohydrate in 150 mL of water). White crystals
(4.0 g, 98%) were collected, washed with water and dried. Enantio-
meric purity (ee 71%) was determined by chiral HPLC (Chiralcel OD,
hexane/EtOH/TFA = 95:5:0.1, 280 nm, 1 mL minꢀ1, tmajor = 17.3 -
min, tminor = 19.4 min).
4.1. 2,4-Diacetyl-3-(3-cyclopentyloxy-4-methoxy-phenyl)-
pentanedioic acid diethyl ester
Benzaldehyde 2 (22.32 g, 0.1 mol, 1 equiv) and ethylacetoace-
tate (27 mL, 0.21 mol, 2.1 equiv) were dissolved in absolute etha-
nol (100 mL). Piperidine (3 mL) was added and reaction stirred
for 2 days at rt. The precipitated product was filtered, washed with
ethanol and used in the next step without further purification
(34.3 g, 73%).
4.4.2. Method B
Benzyl alcohol (1.5 mL, 1.60 g, 14.8 mmol, 1.5 equiv) was added
to the solution of anhydride 3 (3 g, 9.8 mmol) and quinine (3.52 g,
1.1 equiv) in toluene (98 mL, 0.1 M with respect to anhydride)
cooled to ꢀ30 °C,. The reaction was stirred at ꢀ30 °C for 7 days
and 5% HCl (100 mL) was added. The isolation of the product was
performed as in method A. 1H NMR (300 MHz, CDCl3, d): 1.53–
1.67 (m, 2H); 1.75–1.94 (m, 6H); 2.62–2.84 (m, 4H); 3.34–3.62
(m, 1H); 3.80 (s, 3H); 4.66–4.74 (m, 1H); 5.01 (s, 2H); 6.70–6.78
(m, 3H); 7.16–7.34 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3, d):
24.02; 32.71; 32.75; 37.63; 40.46; 40.70; 55.98; 66.29; 80.28;
112.03; 114.37; 118.97; 128.06; 128.14; 128.46; 134.51; 135.67;
4.2. 3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pentanedioic acid
The diethyl ester from the previous procedure (47 g, 0.1 mol)
was added to a solution of KOH (62 g) in water (50 mL) and ethanol
(40 mL). After 4 days stirring at room temperature the brownish
mixture was diluted with water (50 mL) and slowly acidified with
conc. HCl to pH 1. The crystals were filtered, washed with water
and dried over Na2SO4 to obtain 24.2 g (74%) of the title compound.
Combined mother liquor and washings were extracted with ethyl
acetate (2 ꢁ 50 mL). Upon drying and evaporation the brownish
oily residue was triturated with chloroform (20 mL) to yield an
additional 3.8 g (15%) of product. Mp 176.7–177.5 °C. 1H NMR
(300 MHz, DMSO, d): 1.52–1.60 (m, 2H); 1.66–1.74 (m, 4H);
1.81–1.89 (m, 2H); 2.48 (dd, J1 = 15.5, J2 = 8.6 Hz, 2H); 2.60 (dd,
J1 = 15.5, J2 = 6.4 Hz, 2H); 3.26–3.40 (m, 1H); 3.69 (s, 3H); 4.73–
4.77 (m, 1H); 6.74 (dd, J1 = 8.4, J2 = 2.1 Hz, 1H); 6.80–6.84 (m,
2H); 12.01 (br s, 2H) ppm. 13C NMR (75 MHz, DMSO, d): 23.95;
32.63; 37.96; 40.80; 55.96; 79.82; 112.60; 115.04; 119.76;
147.52; 148.93; 171.43; 177.07 ppm.
mmax(KBr) = 3459, 3038,
2965, 2873, 2842, 2680, 2570, 1736, 1686, 1589, 1514, 1425,
1388, 1357, 1260, 1213, 1166, 1137, 1020, 983, 805, 735 cmꢀ1
;
HRMS (MALDI): m/z: calcd for C24H28O6Na [M+Na+] 435.1778;
found: 435.1781.
4.5. Enantiomeric enrichment of (R)-4
A mixture of ester 4 (4.29 g, 10.41 mmol, 73% ee) and (S)-phen-
ylethylamine (1.33 mL, 1.27 g, 10.41 mmol) was heated in methyl
isobutyl ketone (40 mL) and diisopropyl ether (40 mL) until a clear
solution was obtained. At 45 °C a few milligrams of seed crystals
were added. A crystal slurry was stirred at 45 °C for 1 h and then
at rt overnight. Filtration yielded white crystals of amine salt
(4.05 g, 73% yield, 95% ee).
136.20; 147.04; 148.66; 173.37 ppm.
mmax(KBr) = 3482, 2965,
2943, 2912, 2834, 2672, 2578, 1704, 1594, 1518, 1427, 1348,
1337, 1313, 1297, 1257, 1240, 1169, 1139, 1032, 992, 943, 853,
810 cmꢀ1
;
HRMS (MALDI): m/z: calcd for C17H22O6K [M+K+]
(S)-PEA salt was suspended in toluene (50 mL) and stirred with
5% HCl (30 mL) until a clear solution was obtained. The organic
361.1049; found: 361.1050.

´
221
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 24 (2013) 217–222
layer was washed once again with 3% HCl and then with brine. The
toluene solution can be used directly in the subsequent reaction;
otherwise, evaporation of solvent provided monoester 4 quantita-
mmax(KBr) = 3200, 3085, 2964, 2870, 2834, 1709, 1688, 1518,
1263, 1238, 1164, 1144, 1029, 816 cmꢀ1; HRMS (MALDI): m/z:
calcd for C16H21NO3H+ [M+H+] 276.1594; found 276.1600.
tively. Mp 104.7–106.0 °C. ½a D25
¼ þ5:2 (c 0.764, CH2C2).
ꢃ
4.9. (R)-(ꢀ)-Rolipram
4.6. (R)-3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pentanedioic
acid monocinnamyl ester 5
½
a 2D6
ꢃ
¼ ꢀ29:9 (c 0.586, MeOH) for 95% ee, lit.17
½
a 2D5
ꢃ
¼ ꢀ31:0 (c
1.05, MeOH) for >99% ee.
The product was synthesized according to the method A or
method B, with cinnamyl alcohol instead of benzyl alcohol (see
Table 1). Enantiomeric purity was determined by chiral HPLC (Chi-
ralcel AS, hexane/EtOH/TFA = 9:1:0.01, 280 nm, 1 mL minꢀ1, tmi-
nor = 16.4 min, tmajor = 19.5 min). 1H NMR (300 MHz, CDCl3, d):
1.54–1.64 (m, 2H); 1.76–1.95 (m, 6H); 2.62–2.82 (m, 4H); 3.56–
3.64 (m, 1H); 3.78 (s, 3H); 4.66 (d, J = 6.4 Hz, 2H); 4.73–4.77 (m,
1H); 6.12–6.20 (m, 1H); 6.56 (d, J = 15.9 Hz, 1H); 6.73–6.80 (m,
3H); 7.24–7.38 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3, d): 23.99;
32.73; 32.76; 37.63; 40.47; 40.73; 55.95; 65.03; 80.39; 112.13;
114.53; 119.08; 122.98; 126.57; 128.00; 128.55; 134.10; 134.63;
4.10. (S)-(+)-Rolipram
The product was prepared as the opposite enantiomer in an
analogous reaction sequence from anhydride 3. ½a D25
¼ þ30:5 (c
ꢃ
0.605, MeOH) for 95% ee, lit.23
98.95% ee.
½ ꢃ ¼ þ31 (c 0.6, MeOH) for
a rDt
Acknowledgment
We thank the Ministry of Science, Education and Sports of the
Republic of Croatia for financing (Grant No. 098-0982933-2908).
136.16; 147.56; 149.01; 171.35; 177.21 ppm.
mmax(KBr) = 3451,
3057, 2956, 2871, 2836, 2677, 2563, 1731, 1691, 1579, 1431,
1255, 1138, 965, 803 cmꢀ1
;
HRMS (MALDI): m/z: calcd for
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A mixture of ester 5 (1.7 g, 3.88 mmol, 73% ee) and (S)-phenyl-
ethylamine (0.49 mL, 0.47 g, 3.88 mmol) was heated in 2-propanol
(10 mL) and diisopropyl ether (20 mL) until a clear solution was
obtained. At 45 °C, a few milligrams of seed crystals were added.
The crystal slurry was stirred at 45 °C for 1 h and then at rt over-
night. Filtration yielded white crystals of amine salt (1.57 g, 73%
yield, 92% ee).
S-PEA salt was suspended in toluene (50 mL) and stirred with
5% HCl (30 mL) until a clear solution was obtained. The organic
layer was washed once again with 3% HCl and then with brine.
The toluene solution can be used directly in the subsequent reac-
tion; otherwise evaporation of solvent provides monoester 5 quan-
titatively. Mp 89.4–91.0 °C. ½a D25
¼ ꢀ7:3 (c 0.41, MeOH).
ꢃ
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4.8. (R)-(ꢀ)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-pyrrolidin-
2-one 1
Dry triethylamine (0.60 mL, 4.32 mmol, 1.1 equiv) and diph-
enylphosphorylazide (0.85 mL, 3.93 mmol, 1 equiv) were added
under argon to a solution of optically enriched monoester 4
(1.62 g, 3.93 mmol, 1 equiv, 95% ee) in dry toluene (15 mL). The
reaction was heated to 90 °C for 30 min and cooled down to room
temperature. Dilute hydrochloric acid (5% HCl, 15 mL) was added
and the mixture was stirred vigorously overnight. The layers were
separated, the organic layer washed with water (15 mL) and left at
reflux (110 °C) overnight. Upon cooling down to room tempera-
ture, the mixture was washed with 2% Na2CO3 (15 mL) and then
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matography (methanol/dichloromethane 5:95). The enantiomeric
purity was determined as 95% (Chiralcel AS, ethanol, 280 nm,
0.8 ml minꢀ1
,
tmajor = 10.5 min, tminor = 13.7 min). Compound
characterization: white crystals, mp 130.6–131.4 °C (lit.22 130.5–
131.5 °C); 1H NMR (300 MHz, CDCl3, d): 1.54–1.68 (m, 2H); 1.78–
1.98 (m, 6H); 2.47 (dd, 1H, J1 = 16.8 J2 = 8.9 Hz, 1H); 2.71 (dd,
J1 = 16.8 Hz, J2 = 8.9 Hz, 1H); 3.34–3.44 (m, 1H); 3.55–3.69 (m,
1H); 3.71–3.80 (m, 1H); 3.83 (s, 3H); 4.71–4.81 (m, 1H); 6.46 (s,
1H); 6.74–6.86 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3, d): 24.00;
32.82; 38.11; 40.00; 49.75; 56.19; 80.68; 112.38; 114.00; 118.84;
134.64; 147.98; 149.28; 177.74 ppm.
30. Keen, S. P.; Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.; Davies, A. J.; Dolling, U.
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´
´
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