Quinine-mediated parallel kinetic resolution of racemic cyclic anhydride: stereoselective synthesis, relative and absolute configuration of novel alicyclic β-amino acids

Article abstract of DOI:10.1016/j.tetasy.2007.02.019

Four endo-isomers of (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid (+)-1 (Icofungipen) have been prepared in enantiomerically pure form. Three endo-isomers were obtained by quinine-mediated kinetic resolution of a racemic anhydride, followed by Curtius rearrangement. The fourth isomer was obtained by an exo-endo isomerization of (+)-1. The assignment of the absolute configuration is based either on the Cotton effect in the CD spectra or in correlation to already known structures.

Full text of DOI:10.1016/j.tetasy.2007.02.019

Tetrahedron: Asymmetry 18 (2007) 635–644
Quinine-mediated parallel kinetic resolution of racemic
cyclic anhydride: stereoselective synthesis, relative and
absolute configuration of novel alicyclic b-amino acids
a,
a
b,ꢀ
b
*
ˇ
ˇ
´
´
Zdenko Hamersak, Marin Roje, Amir Avdagic and Vitomir Sunjic
aDepartment of Organic Chemistry and Biochemistry, Rudjer Bosˇkovic´ Institute, PO Box 180, 10002 Zagreb, Croatia
bGSK Research Centre Zagreb, Prilaz baruna Filipovic´a 29, 10000 Zagreb, Croatia
Received 23 January 2007; accepted 19 February 2007
Abstract—Four endo-isomers of (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid (+)-1 (Icofungipen) have been prepared in
enantiomerically pure form. Three endo-isomers were obtained by quinine-mediated kinetic resolution of a racemic anhydride, followed
by Curtius rearrangement. The fourth isomer was obtained by an exo–endo isomerization of (+)-1. The assignment of the absolute
configuration is based either on the Cotton effect in the CD spectra or in correlation to already known structures.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
b-Amino acids are certainly of less importance than their a-
5
1
analogues, but they do exhibit interesting biological activ-
ity and are present in peptides and different heterocycles.1
While less explored alicyclic b-amino acids have been
found to be useful chiral auxiliaries and building blocks,
some exhibit pharmacological activity.2 (1R,2S)-2-Amino-
cyclopentanecarboxylic acid (cispentacin)3 and (1R,2S)-2-
amino-4-methylenecyclopentanecarboxylic acid (+)-1 (Ico-
fungipen)4 are antifungals; cispentacin is also a component
of the antibiotic amipurimicyn.2 The efficient asymmetric
synthesis of (+)-1 and cispentacine was developed based
on quinine-mediated enantioselective alcoholysis (desym-
metrization) of meso-anhydrides.5,6 Chan and Deng7
recently accomplished the successful parallel kinetic resolu-
tion (PKR) of racemic succinic anhydrides using a modified
cinchona alkaloid. This finding prompted our attempts to
prepare enantiomerically pure structural isomers of 1 with
an endocyclic double bond (2–5) (Fig. 1).
H2N
COOH
COOH
H2N
COOH
(+)-1
O
O
O
2
meso-6
2 1
H2N
H2N
COOH
H2N
COOH
5
3
4
Figure 1.
Our first objective was to attain high enantioselectivity with
low regio-selectivity in the solvolysis of rac-7, producing
two structurally isomeric, enantiomerically enriched
cis-products. Their epimerization at the a-C atom to a car-
boxyalkyl group is expected to afford the subsequent struc-
tural isomers, which are the more stable trans-products
(Scheme 1).
Conceptually, all the enantiomerically pure structural iso-
mers can be made via the parallel kinetic resolution of
rac-7 by intervention of the same chiral auxiliary, quinine.
2. Results and discussion
*
Corresponding author. Tel.: +3851 4571 300; fax: +3851 4680 108;
e-mail: hamer@irb.hr
ꢀ
Since the tendency of the exocyclic double bond in the five-
and six-membered rings is to migrate into the ring,8 we
´
Present address: PLIVA R&D Institute, Prilaz baruna Filipovica 29,
10000 Zagreb, Croatia.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.019

636
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
O
O
O
rac-7
O
O
O
O
H2N
HOOC
H2N
HOOC
R
R
R
R
O
O
O
O
O
O
O
O
H2N
HOOC
H2N
HOOC
R
R
R
R
O
O
O
O
Scheme 1.
began the synthesis by preparing rac-7 from meso-6, avail-
able from rac-8, an intermediate in the preparation of (+)-
1. In refluxing toluene, catalyzed by p-TsOH, meso-6 was
isomerized in 87% yield into rac-7 (Scheme 2). The kinetic
resolution of rac-7 was completed by alcoholysis with
trans-cinnamyl alcohol in the presence of quinine at
ꢀ15 ꢁC. This approach resulted with a 30:70 mixture of
monoesters 9 and 10 (determined by NMR or by HPLC
on Chiralpak AD). This mixture appeared to be insepara-
ble by either crystallization (oily) or chromatography.
The preparative HPLC separation of the 9/10 mixture on
a Chiralpak AD column followed by analysis on Chiralpak
AS showed 97% ee for 9; using a Chiralcel OD, 42% ee for
10 was determined.
but the enantiopuritiy of cis-monoester 10 was higher
(75% ee).
However, the enantiopurity of trans-monoester 9 remained
consistently high. Bolm studied the quinine-mediated open-
ing of meso-anhydrides with various alcohols and found
that in all cases, the monoesters with an (R)-configuration
on the C-atom bearing an ester group were preferably
formed in high ee’s.5 The formation of trans-monoester 9
can be explained by the mechanism shown in Scheme 4.
The preferred opening of the (1R,2S)-enantiomer of 7 leads
to (1R,2S)-10 as the major enantiomer, with an (R)-config-
uration on the C-atom bearing the cinnamoyl ester group,
while the less reactive (1S,2R) enantiomer of 7 produced
the minor enantiomer (1S,2R)-10.
To confirm the cis-configuration of 9 and 10, the mixture of
monoesters was converted to dicarboxylic acids 13 and 14
(Scheme 3). However, NMR spectra revealed the existence
of two diastereomers in the same 3:7 ratio, suggesting that
one dicarboxylic acid had a trans-configuration. In order to
define the carboxylic acid with a trans-configuration pure
cis-dicarboxylic acid 14 was prepared via hydrolysis of
rac-7, while trans-dicarboxylic acid 13 was obtained by
isomerization of trans-acid 8. 1H NMR coupling constants
between the C(1) and C(2) protons were found to be 9 Hz
for the cis-derivative and 7 Hz for the trans-derivative.
Comparison of NMR data revealed that monoester 9 had
trans-configuration.
To explain the formation of trans-9, a keto–enol equilib-
rium at one stereogenic centre could be considered.
Although Rappoport9 has shown theoretically and experi-
mentally that enols of carboxylic acid anhydrides are unli-
kely, and we also have not detected the enol form of 7 using
NMR, we propose the formation of trans-9 via an unde-
tectable quantity of the enol form 7a in the equilibrium
with the dicarbonyl form. The enol form 7a is stabilized
by conjugation and is opened towards (1R,2R)-9, in accor-
dance with Bolm5 and others findings,10 with simultaneous
epimerization at the second chiral centre.
In the next step, the 9/10 monoester mixture was converted
into the protected b-amino acid esters by Curtius rear-
rangement using diphenyl phosphoryl azide and triethyl-
amine. This was followed by reaction of the intermediate
isocyanate with cinnamyl alcohol in refluxing toluene
(Scheme 2). Crystallization of the crude product from
EtOH/hexane (1:1) afforded an 11/12 mixture (3:7) in
70% yield. Pure (ꢀ)-12 (96% ee) was obtained upon two
Next, the influence of the base catalyst and reaction condi-
tions on the unusual epimerization on the pathway to
trans-9 from rac-7 was examined (Table 1). We found both
to have only minor effects on the 9/10 ratio (entries 3–5).
Even when the reaction was performed without base (entry
6) the same, ca. 30:70 ratio, was obtained. At a lower tem-
perature (entry 2), conversion was not complete after 8 h,

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
637
epimerization at C(1). A small amount (less than 5%) of
non-epimerized product was removed by chromatography
on silica gel, producing pure (+)-15 in 75% yield. Deprotec-
tion was performed as described for 11/12 to obtain pure
(+)-5 in 62% yield.
p-TsOH, toluene
(EtCO)2O
135 °C
reflux
O
O
O
HOOC
COOH
O
O
O
rac-7
For the determination of the absolute configuration, enan-
tiomerically pure cis isomers (+)-3 and (ꢀ)-2 were also pre-
pared according to the published procedure (Scheme 6).11
The exocyclic double bond of (+)-1 (99.5% ee) was shifted
to the endo position in the presence of TMSCl/NaI in ace-
tonitrile, and two structural isomers were converted, with-
out separation, to fmoc-derivatives (+)-16 and (ꢀ)-17;
according to HPLC a 65:35 mixture was obtained. Crystal-
lization from EtOAc/hexane (1:2) afforded (+)-16 in 35%
yield, while (ꢀ)-17 was obtained as a dicyclohexylamine
salt from the mother liquor in 5% yield. Amino acids
(ꢀ)-2 and (+)-3 were isolated upon deprotection by mor-
pholine in 86% and 78% yield, respectively.
meso-6
8
ROH =
Ph
OH
ROH, quinine, -15 °C
+
O
O
HOOC
HOOC
R
R
O
O
3 : 7
9 (97% ee)
10 (42% ee)
For all four enantiomers of endo-b-amino acids 2–5, the
specific rotation sign was determined; the sign was negative
for 2 and 4 and positive for 3 and 5. The absolute configu-
ration of (ꢀ)-2 and (+)-3 was (1R,5S) and (1R,2S), respec-
tively; both are chemically correlated to (+)-1 (Scheme 6),
whose (1R,2S)-absolute configuration was straightforward
to determine.5 In order to obtain information about the
absolute configurations of the two remaining endo-com-
pounds, CD spectra of all isomers were recorded (Fig. 2).
1. (PhO)2PON3, Et3N
2. ROH
O
O
O
O
NH
O
NH
R
R
R
O
R
O
O
(-)-12 (96% ee)
(-)-11 (99% ee)
The CD spectra of (ꢀ)-2 and (+)-5 exhibit the most inten-
sive and nearly enantiomorphic curves in the region of the
electronic transitions of the C@C and C@O double bonds
with a small (5–7 nm) shift of the two maxima in the spec-
trum of (ꢀ)-2 to the longer wavelengths. Interestingly, the
CD of (+)-1 is less intense than that of any other endo-iso-
mer by an order of magnitude, indicating a nearly parallel
position of the transition moments in the two chromo-
phores, C@C and C@O. It was repeatedly shown that
the absolute configuration of chiral compounds with a
C@C bond at the allylic position12 could be determined
from the CD, based on exciton coupling with the second
chromophore distant from the olefin chromophore.
Although compounds (ꢀ)-2 and (+)-5 comprised such
homoconjugated, twisted chromophores, and exhibit
strong CDs of the opposite sign, we hesitated to use them
in an attempt to assign absolute configuration. In order
to reliably assign the absolute configuration of (ꢀ)-4 and
(+)-5, using (ꢀ)-2 as the control, the CD spectra were
run of their respective bis-cinnamoyl derivatives (ꢀ)-11
and (ꢀ)-12 (Figs. 3 and 4).
Pd(OAc)2, PPh3,
morpholine, EtOH
H2N
COOH
(-)-4
H2N
COOH
(-)-2
Scheme 2.
recrystallizations from abs EtOH in 21% yield, while two
recrystallizations of the mother liquor material, enriched
in 11 from EtOH/hexane (1:14), afforded 97% pure (ꢀ)-
11 (99% ee) in 10% yield.
In the last step, protective groups in (ꢀ)-11 and (ꢀ)-12
were removed by the transallylation of morpholine as a
nucleophile in refluxing ethanol. The reaction was cata-
lyzed with palladium acetate–triphenyl phosphine. The pre-
cipitated products were crystallized from aqueous ethanol
yielding b-amino acids (ꢀ)-2 and (ꢀ)-4 in 65% and 70%
yield, respectively.
These compounds consist of two independent, degenerate
cinnamate chromophores as well as double-bond chromo-
phore.13 Their CD spectra are therefore dominated by
two Cotton effects at longer wavelengths, ca. 253–260 nm,
1
due to the La transitions of two chromophores. The sec-
1
ond Cotton effect is due to the coupling of Bb transitions
trans-b-Amino acid (+)-5 was prepared by starting from
amino protected ester (ꢀ)-12 (Scheme 5). Base-catalyzed
hydrolysis of the ester group with potassium hydroxide in
aqueous methanol was accompanied with almost complete
at the shorter wavelength, ca. 193–199 nm. Since the ole-
finic chromophore is also asymmetrically perturbed by sub-
stituents and/or the skeletal strain of the double bond,
overlap of additional Cotton effects complicates the CD

638
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
+
O
O
HOOC
Ph
R =
HOOC
R
R
O
O
10
9
Pd(OAc)2, PPh3,
morpholine, EtOH
+
HOOC
COOH
HOOC
COOH
14
13
TMSCl
NaI
H2O
O
O
HOOC
COOH
O
8
7
Scheme 3.
Table 1. Influence of base and conditions on the opening of anhydride 7
Entry
Base (equimolar)
Conditions
cis/trans Ratio (% ee)
Yield (%)
1
2
3
4
5
6
Quinine
Quinine
Quinine
Triethylamine
Pyridine
Toluene, ꢀ15 ꢁC, 8 h
67(42):33(97)
77(75):23(98)
66(40):34(96)
79(rac):21(rac)
75(rac):25(rac)
72(rac):28(rac)
98
60
96
98
90
70
Toluene/CCl4 (1:1), ꢀ50 ꢁC, 8 h
Toluene, rt, 3 h
Toluene, rt, 2 h
Toluene, rt, 6 h
Toluene, 80 ꢁC, overnight
Without base
ROH =
Ph
OH
curve of the double bond chromophore. The cinnamate
conformation is corroborated by MM2 calculations for
(ꢀ)-11 (dihedral angle ꢀ169ꢁ) and (ꢀ)-12 (dihedral angle
+28ꢁ). These calculations indicated the most stable confor-
mations and consequently indicated the positions of the
electric transition moments, which greatly simplified the
application of exciton coupling (EC). The weak EC of
the two cinnamate chromophores in the CD spectra of
(ꢀ)-11 and (ꢀ)-12 is expected because of the small value
of the dihedral angle between them. For trans-relative con-
figuration in (ꢀ)-11, the exciton chirality is not affected by
conformational change as much as it is by cis-oriented
chromophoric units in (ꢀ)-12. As shown in Figure 3, the
253 nm negative Cotton effect in the CD spectra of (ꢀ)-
11 reflects a negative chirality between two cinnamate chro-
mophores on C(1) and C(2) revealing (1R,2R)-absolute
configuration. In the case of compound (ꢀ)-12, the
259 nm positive cinnamate Cotton effect reflects a positive
chirality between two cinnamate chromophores on C(1)
and C(5)13 and also shows (1R,5S) absolute configuration.
HO
O
O
O
O
O
O
O
R
R
O
O
H
R
7a
(1S,2R)-7
O
H
(1R,2S)-7
O
H
(S)
(R)
(S)
(R)
(R)
(R)
ROOC
COOH
HOOC
COOR
HOOC
COOR
minor enantiomer
exclusive enantiomer
major enantiomer
10
9
Scheme 4.

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
639
KOH, aq. MeOH
O
O
O
O
O
NH
COOH
(+)-15
NH
R
R
R
O
(-)-12 (96% ee)
Ph
R =
Pd(OAc)2, PPh3,
morpholine, EtOH
H2N
COOH
(+)-5
Scheme 5.
endo-isomers of Icofungipen, a cyclic b-amino acid with a
broad-of spectrum antifungal activity. The key step of
the synthesis was the quinine-mediated parallel kinetic
resolution of anhydride rac-7 during which an interest-
ing cis–trans isomerization was observed, allowing access
to new b-amino acid building blocks with defined
chirality.
H2N
COOH
(+)-1 (>99.5% ee)
1. TMSCl, NaI
2. Fmoc-OSu, Na2CO3
4. Experimental
4.1. General
FmocHN
COOH
FmocHN
COOH
Mps were determined on an Electrothermal 9100 apparatus
in open capillaries and are not corrected. Optical rotations
were measured using the Optical Activity AA-10 automatic
17
16
morpholine,
EtOH
morpholine,
EtOH
1
polarimeter. H and 13C NMR spectra were recorded on
Bruker AV 300 and AV 600 spectrometers, IR spectra on
a Bruker ABB Bomen instrument, and CD spectra on a
JASCO-810 spectropolarimeter at 25 ꢁC. For chemical pur-
ity determination and monitoring of the progress of the
reactions, HP 5890 GC and HP 1090 HPLC chromato-
graphs were used. Compounds (+)-1, 6 and 8 were ob-
tained from PLIVA d.d., while all other reagents and
solvents were purchased from commercial sources and were
used without purification.
H2N
COOH
(+)-3
H2N
COOH
(-)-2
Scheme 6.
Since no bond breaking occurs from (ꢀ)-11 and (ꢀ)-12 to
(ꢀ)-4 and (ꢀ)-2, respectively, the targeted b-amino
acids possess the same absolute configuration as deter-
mined by CD for their precursors. Finally, the absolute
configuration (1S,5S) of (+)-5 is defined by its chemical
correlation to (1R,5S)-(ꢀ)-12, in which the configuration
at C(1) is inverted, going from a cis- to trans-isomer
(Scheme 5).
4.2. 5-Methyl-4,6a-dihydro-3aH-cyclopenta[c]furan-1,3-
dione 7
p-TsOHÆH2O (1.0 g) was suspended in toluene (300 mL).
After H2O had been azeotropically removed, anhydride 6
(20.0 g, 131.5 mmol) was added and refluxed for 4 h. The
cooled solution was filtered, evaporated and distilled on
Kugelrohr apparatus (125 ꢁC/0.5 mmHg). Yield: 17.5 g
(87%), GC purity 99% (HP-17 column). Mp 49.5–51.5 ꢁC.
1H NMR (CDCl3): d = 1.81 (s, 3H), 2.75 (d, J = 17.4 Hz,
1H), 2.89 (dd, J = 17.5 Hz, 10.2 Hz, 1H), 3.74 (dd,
J = 10.0 Hz, 8.3 Hz, 1H), 4.08 (d, J = 7.7 Hz, 1H), 5.36
(s, 1H). 13C NMR (CDCl3): 15.48, 39.89, 43.87, 53.12,
118.56, 144.63, 171.52, 174.71.
3. Conclusion
In conclusion, we have synthesized and determined the
absolute configuration of four enantiomerically pure

640
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
Figure 2. CD spectra of (+)-1 (
), (ꢀ)-2 (
), (+)-3 (
), (ꢀ)-4 (
) and (+)-5 (
) in H2O.
4.3. (1R,2R)-4-Methyl-2-(3-phenyl-allyloxycarbonylamino)-
cyclopent-3-enecarboxylic acid 9 and (1S,5R)-3-methyl-5-(3-
phenyl-allyloxycarbonylamino)-cyclopent-2-enecarboxylic
acid 10
30 min of heating, the warm solution was filtered and left
to crystallize at 4 ꢁC for 24 h. The precipitate was collected
on a filter to afford 30.5 g (70%) of 11/12 (30:70, Nucleosil
100-5 RP18, 50–100% MeOH in 20 min at 254 nm). After
two recrystallizations from abs EtOH 9.0 g (21%) of 12,
which was 98% pure by HPLC (96% ee; Chiralpak AD,
22% EtOH, 0.4% AcOH, hexane to 100%), was obtained.
The mother liquor after the first crystallization was evapo-
rated (16.8 g of 11/12 60:40 mixture) and crystallized twice
from EtOH/hexane (1:14) to yield 4.2 g (10%) of 11 (97%
pure, 99% ee). By recycling the mother liquors and crystal-
lization from a solvent mixture depending on the ratio of
isomers, practically all of the material could be separated,
although with much lower ee of 12.
Quinine (36.0 g, 110 mmol) was suspended in toluene
(400 mL) followed by anhydride 8 (17.0 g, 111 mmol) and
trans-cinnamyl alcohol (22.4 g, 168 mmol). The reaction
mixture was stirred at ꢀ15 ꢁC for 8 h. The toluene solution
was then washed with 1 M HCl (2 · 150 mL), H2O, and ex-
tracted with 2% K2CO3 (1 · 400, 2 · 200 mL). The aqueous
extracts were washed with EtOAc, and acidified to pH 2
with dil HCl. The product was extracted with CH2Cl2 to af-
ford 31.5 g (98%, yellowish oil) of a 3:7 9/10 mixture, which
was used in the next step without further purification.
25
Compound 11: mp 115.0–116.5 ꢁC; ½aꢁD ¼ ꢀ101 (c 1,
1
For chiral HPLC analysis, the 9/10 mixture was purified on
a short silica gel column and separated on Chiralpak AD
(18% EtOH, 0.4% AcOH, hexane to 100%, 254 nm). The
same mobile phase was used for the analysis of collected
9 on Chiralpak AS and 10 on Chiralcel OD to reveal
97% ee for 9 and 42% ee for 10.
CH2Cl2). H NMR (CDCl3): d = 1.74 (s, 3H), 2.50–2.70
(m, 2H), 2.90–3.05 (m, 1H), 4.60–5.10 (m, 5H), 5.24 (s,
1H), 6.20–6.30 (m, 2H), 6.55–6.70 (m, 2H), 7.20–7.40 (m,
10H). 13C NMR (CDCl3): d = 16.21, 19.20, 51.37, 61.22,
65.24, 123.13, 123.75, 126.43, 126.48, 127.77, 12783,
128.41, 133.44, 133.86, 136.19, 142.51, 155.26, 174.03. IR
(KBr): 3306, 3025, 2936, 1721, 1687, 1538, 1246, 1169,
4.4. (ꢀ)-(1R,2R)-4-Methyl-2-(3-phenyl-allyloxycarbonyl-
amino)-cyclopent-3-enecarboxylic acid 3-phenyl-allyl ester
11 and (ꢀ)-(1R,5S)-3-methyl-5-(3-phenyl-allyloxycarbon-
ylamino)-cyclopent-2-enecarboxylic acid 3-phenyl-allyl ester
12
967, 742, 691 cmꢀ1
. Anal. Calcd. for C26H27NO4
(417.50): C, 74.80; H, 6.52; N, 3.35. Found: C, 74.37; H,
6.77; N, 3.68.
25
Compound 12: mp 135.5–137.0 ꢁC; ½aꢁD ¼ ꢀ129 (c 1,
1
CH2Cl2). H NMR (CDCl3): d = 1.76 (s, 3H), 2.35–2.45
A solution of a 9/10 mixture (31.3 g, 109 mmol), triethyl-
amine (15.0 mL, 109 mmol), and diphenyl phosphoryl
azide (23.0 mL, 109 mmol) in dry toluene (230 mL) was
stirred for 2 h at rt and then for 1 h at 90 ꢁC. The solution
of trans-cinnamyl alcohol (16.5 g, 125 mmol) in toluene
(20 mL) was added and the reaction mixture was then
heated at reflux overnight. To the cooled solution EtOAc
(300 mL) was added and washed with satd NaHCO3. The
solvent was evaporated and the crude product mixture
was dissolved by heating in 500 mL of EtOH/hexane
(1:1) together with about 1 g of active charcoal. After
(m, 1H), 2.50–2.60 (m, 1H), 3.68 (d, J = 5.5 Hz, 1H),
4.55–4.75 (m, 5H), 5.34 (s, 1H), 5.61 (d, J = 10 Hz, 1H),
6.15–6.35 (m, 2H), 6.55–6.65 (m, 2H), 7.20–7.40 (m, 10H).
13C NMR (CDCl3): d = 16.78, 42.66, 52.69, 53.30, 65.04,
65.23, 121.31, 122.78, 123.76, 126.41, 126.47, 127.73,
127.90, 128.39, 128.40, 133,31, 134.12, 136.01, 136.19,
143.53, 158,67, 172.51. IR (KBr): 3347, 3031, 2928, 2851,
1725, 1687, 1527, 1260, 1171, 1030, 951, 745, 683 cmꢀ1
.
Anal. Calcd for C26H27NO4 (417.50): C, 74.80; H, 6.52;
N, 3.35. Found: C, 74.49; H, 6.34; N, 3.20.

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
641
Figure 3. CD (
) and UV (
) spectra of (ꢀ)-11 in MeCN.
4.5. (+)-(1S,5S)-3-Methyl-5-(3-phenyl-allyloxycarbonyl-
amino)-cyclopent-2-enecarboxylic acid 15
J = 16 Hz, 1H), 7.24–7.40 (m, 5H), 10.4 (br s, 1H). 13C
NMR (CDCl3): d = 16.50, 43.79, 54.54, 58.68, 65.88,
120.78, 123.44, 126.64, 128.04, 128.59, 134.09, 136.25,
141.58, 156.41, 177.17. IR (KBr): 3323, 3063, 2918, 1686,
. Anal. Calcd for
C17H19NO4 (301.34): C, 67.76; H, 6.36; N, 4.65. Found:
C, 67.38; H, 6.11; N, 4.98.
To a suspension of 12 (96% ee) (1.5 g, 3.6 mmol) in MeOH
(30 mL) and H2O (20 mL), KOH (1.0 g) was added and
stirred at 50 ꢁC for 2 h. H2O (30 mL) was added, the solu-
tion washed with EtOAc, acidified with dil HCl to pH 2
and extracted with EtOAc. The crude product was purified
on silica gel using diisopropyl ether/toluene/AcOH
(60:30:0.3). Yield: 0.81 g (75%); mp 125–127 ꢁC;
1541, 1275, 1229, 972, 694 cmꢀ1
4.6. (ꢀ)-(1R,5S)-5-Amino-3-methyl-cyclopent-2-enecarb-
oxylic acid 2
25
1
½aꢁD ¼ þ46 (c 1, CH2Cl2). H NMR (CDCl3): d = 1.74 (s,
3H), 2.17 (d, J = 16 Hz, 1H), 2.86 (dd, J = 16 Hz, 7 Hz,
1H), 3.49 (s, 1H), 4.52 (s, 1H), 4.72 (s, 2H), 5,18 (d,
J = 6 Hz, 1H), 5.34 (s, 1H), 6.24–6.30 (m, 1H), 6.63 (d,
To a suspension of 12 (5.0 g; 12 mmol), Ph3P (32 mg;
0.12 mmol) and morpholine (2.6 mL; 30 mmol) in 25 mL
of abs EtOH, Pd(OAc)2 (ꢂ2 mg) was added. The reaction

642
Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
Figure 4. CD (
) and UV (
) spectra of (ꢀ)-12 in MeCN.
mixture was refluxed for 2 h, cooled and left to crystallizing
for 2 h at rt. The precipitate was filtered out, washed with
EtOH on a filter and recrystallized from 90% EtOH to yield
1.11 g (65%) of 97% pure 2 (Nucleosil 100-5 RP18, 10%
aqueous MeOH, 1% H3PO4 at 206 nm for 10 min; then
gradient to 100% MeOH in 15 min at 254 nm); mp
181.23. IR (KBr): 3437, 3049, 2922, 2088, 1656, 1561,
1387, 1272, 780 cmꢀ1
Anal. Calcd for C7H11NO2
(141.17): C, 59.56; H, 7.85; N, 9.92. Found: 59.23; H,
7.87; N, 9.73.
.
4.8. (+)-(1S,5S)-5-Amino-3-methyl-cyclopent-2-enecarb-
oxylic acid 5
25
1
190 ꢁC (lit.14 190 ꢁC); ½aꢁD ¼ ꢀ115 (c 1, H2O). H NMR
(D2O): d = 1.68 (d, J = 1 Hz, 3H), 2.61 (dd, J = 16 Hz,
4 Hz, 1H), 2.61 (dd, J = 16.5 Hz, 7.5 Hz, 1H), 3.51–3.58
(m, 1H), 3.88–3.96 (m, 1H), 5.37 (d, J = 1.5 Hz, 1H). 13C
NMR (D2O): d = 16.50, 40.09, 52.37, 52.45, 123.66,
141.12, 179.69. IR (KBr): 3438, 3052, 2946, 2183, 1654,
1552, 1506, 1393, 1176, 834 cmꢀ1. Anal. Calcd for
C7H11NO2 (141.17): C, 59.56; H, 7.85; N, 9.92. Found:
59.20; H, 7.67; N, 9.63.
The reaction was performed as described for 3. Starting
from 750 mg of 13 of 160 mg (62%) of 5 was obtained.
25
1
Mp 224 ꢁC, ½aꢁD ¼ þ216 (c 0.8, H2O). H NMR (D2O):
d = 1.74 (s, 3H), 2.28 (d, J = 16.5 Hz, 1H), 2.88 (dd,
J = 16.5 Hz, 7 Hz, 1H), 3.39 (s, 1H), 4.06–4.09 (m, 1H),
5.37 (s, 1H). 13C NMR (D2O): d = 16.13, 41.83, 54.54,
59.87, 122.90, 140.76, 180.46. IR (KBr): 3421, 2964, 2932,
1634, 1574, 1606, 1393, 1213, 743 cmꢀ1. Anal. Calcd for
C7H11NO2 (141.17): C, 59.56; H, 7.85; N, 9.92. Found:
C, 59.39; H, 7.56; N, 10.11.
4.7. (ꢀ)-(1R,2R)-2-Amino-4-methyl-cyclopent-3-enecarb-
oxylic acid 4
The reaction was performed as described for 3. Starting
from 6.0 g of 11, 1.45 g (70%) of 98% pure 4 was obtained.
Mp 220 ꢁC; ½aꢁD ¼ ꢀ180 (c 0.6, H2O). H NMR (D2O):
d = 1.70 (s, 3H), 2.37 (dd, J = 16.5 Hz, 4.0 Hz, 1H),
2.65–2.90 (m, 2H), 4.39 (s, 1H), 5.27 (s, 1H). 13C NMR
(D2O): d = 15.66, 40.67, 50.46, 61.10, 119.36, 149.21,
4.9. ( )-trans-4-Methyl-cyclopent-3-ene-1,2-dicarboxylic
acid 13
25
1
A mixture of NaI (1.0 g 6.5 mmol) and TMSCl (4.5 mL,
9.3 mmol) in acetonitrile (50 mL) was stirred at rt for
30 min. trans-Dicarboxylic acid 8 (1.0 g, 5.8 mmol) was

Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
643
added and stirred for 5 h at 75 ꢁC. Upon cooling to rt,
4.12. (ꢀ)-(1R,5S)-5-(9H-Fluoren-9-ylmethoxycarbonyl-
20 mL of H2O was added, and most of the solvent evapo-
rated. EtOAc extraction afforded an oily product, which
was recrystallized from EtOH/hexane to obtain 450 mg
(45%) of pure 13. Mp 133–135 ꢁC. 1H NMR (CDCl3):
d = 1.75 (s, 3H), 2.62 (dd, J = 16.5 Hz, 7 Hz, 1H), 2.72
(dd, J = 16.5 Hz, 8 Hz, 1H), 3.60 (dt, J = 9 Hz, 7 Hz,
1H), 4.00 (dq, J = 7 Hz, 1.5 Hz, 1H), 5.36 (s, 1H), 11.8
(br s, 2H). 13C NMR (CDCl3): 16.19, 39.89, 44.79, 53.56,
120.73, 141.99, 179.71, 180.80. IR (KBr): 3020, 2921,
1708, 1444, 1427, 1291, 1271, 1226, 942 cmꢀ1. Anal. Calcd
for C8H10O4 (170.16): C, 56.47; H, 5.92; Found: C, 56.78;
H, 5.70.
amino)-3-methyl-cyclopent-2-enecarboxylic acid 17
The first mother liquor obtained after the crystallization of
16 was evaporated, containing 1.85 g (5 mmol) of 16/17
(40/60 ratio). The residue was dissolved in 100 mL
CH2Cl2/hexane (3:7) and treated with dicyclohexylamine
(0.60 mL, 3.6 mmol). The precipitated salt was collected
on a filter, suspended in CH2Cl2 and the free acid liberated
with dil HCl. This procedure was repeated with 1 equiv of
dicyclohexylamine calculated on the quantity of 17 in the
mixture to obtain 0.46 g (5%) of 17, which was 97% pure.
25
Mp 61–63 ꢁC; ½aꢁD ¼ ꢀ91 (c 1, CH2Cl2). 1H NMR
(DMSO-d6): d = 1.73 (s, 3H), 2.41 (d, J = 7 Hz, 2H), 3.52
(d, J = 7 Hz, 1H), 4.12–4.48 (m, 4H), 5.21 (s, 1H), 7.28–
7.92 (m, 8H), 12.0 (br s, 1H). 13C NMR (DMSO-d6):
d = 17.20, 41.71, 47.14, 53.48, 54.36, 66.08, 120.52,
122.62, 125.75, 126.69, 127.54, 127.58, 128.08, 141.11,
141.15, 142.58, 144.20, 144.45, 156.14, 173.76. IR (KBr):
3408, 3313, 3063, 2935, 1715, 1512, 1450, 1344, 1230,
741 cmꢀ1. Anal. Calcd for C22H21NO4 (363.41): C, 72.71;
H, 5.82; N, 3.85. Found: C, 72.91; H, 5.52; N, 3.48.
4.10. ( )-cis-4-Methyl-cyclopent-3-ene-1,2-dicarboxylic acid
14
Anhydride 7 (300 mg, 2 mmol) was suspended in H2O
(20 mL) and stirred at 60 ꢁC for 1 h. The clear solution
was extracted with EtOAc to give 330 mg (97%) of pure
1
product. Mp 140–142 ꢁC. H NMR (CDCl3): d = 1.79 (s,
3H), 2.48 (dd, J = 16 Hz, 9 Hz, 1H), 2.93 (dd, J = 16 Hz,
9 Hz, 1H), 3.46 (psq, J = 9 Hz, 1H), 3.79 (d, J = 9 Hz,
1H), 5.35 (s, 1H), 11.6 (br s, 2H). 13C NMR (CDCl3):
d = 16.68, 37.98, 46.59, 53.12, 120.72, 145.07, 180.34,
180.56. IR (KBr): 3068, 2943, 2916, 1703, 1414, 1320,
1230, 813 cmꢀ1. Anal. Calcd for C8H10O4 (170.16): C,
56.47; H, 5.92; Found: C, 56.29; H, 5.66.
4.13. (+)-(1R,2S)-2-Amino-4-methyl-cyclopent-3-enecarb-
oxylic acid 3
A solution of 16 (3.3 g; 9.1 mmol) and morpholine (1.3 mL,
15 mmol) in 40 mL of abs. EtOH was refluxed for 3 h. The
solvent was evaporated; H2O (50 mL) was added and
washed with hexane (3 · 50 mL). The aqueous solution
was concentrated and passed through a short column of
Amberlite XAD-16. Evaporation of the eluate afforded
1.18 g of the crude product, which was recrystallized from
94% EtOH. Yield: 1.01 g (78%), HPLC purity 96% (Nucleo-
sil 100-5 RP18, 10% aqueous MeOH, 1% H3PO4, at 206 nm
4.11. (+)-(1R,2S)-2-(9H-Fluoren-9-ylmethoxycarbonyl-
amino)-4-methyl-cyclopent-3-enecarboxylic acid 16
A mixture of NaI (4.0 g 26 mmol) and TMSCl (4.5 mL,
35 mmol) in acetonitrile (200 mL) was stirred at rt for
30 min, (+)-1 (4.0 g, 28 mmol) was added and stirred over-
night at 75 ꢁC. Upon cooling to rt, 2 mL of H2O was added
and most of the solvent was evaporated in vacuum. The
residue was dissolved in H2O (100 mL) and washed with
CH2Cl2 (5 · 50 mL). To the aqueous solution, Na2CO3
(15 g) was added, followed by the portionwise addition of
a dioxane solution of 9-fluorenylmethyl-succinimidylcar-
bonate (9.5 g, 28 mmol) at 0 ꢁC. The reaction mixture
was stirred at rt for 6 h, after which H2O (100 mL) was
added and the aqueous solution was washed with diisoprop-
yl ether (3 · 50 mL). The aqueous solution was acidified to
pH 2 with dil HCl and extracted with diisopropyl ether.
The crude product contained a 65/35 ratio of 16/17 (deter-
mined by HPLC; Nucleosil 100-5, 3% EtOH in CH2Cl2),
and was recrystallized 3 times from EtOAc/hexane (1:2)
to afford 3.44 g (35%) of 16, 96% HPLC purity. Mp 144–
for 10 min; then gradient to 100% MeOH in 15 min at
25
254 nm). Mp 219–220 ꢁC (lit.14 221 ꢁC); ½aꢁD ¼ þ65 (c
0.8, H2O). 1H NMR (D2O): d = 1.72 (s, 3H), 2.51 (d,
J = 8 Hz, 2H), 3.25 (psq, J = 8 Hz, 1H), 4.15 (d,
J = 8 Hz, 1H), 5.38 (s, 1H). 13C NMR (D2O): d = 16.74,
39.32, 47.30, 57.54, 120.79, 151.41, 180.37. IR (KBr):
3429, 3138, 2911, 1649, 1625, 1563, 1398, 1282, 1175,
986, 798 cmꢀ1. Anal. Calcd for C7H11NO2 (141.17): C,
59.56; H, 7.85; N, 9.92. Found: C, 59.25; H, 8.05; N,
9.76.
4.14. (ꢀ)-(1R,5S)-5-Amino-3-methyl-cyclopent-2-enecarb-
oxylic acid 2
25
1
146 ꢁC; ½aꢁD ¼ þ78 (c 1, CH2Cl2). H NMR (DMSO-d6):
d = 1.73 (s, 3H), 2.17–2.26 (m, 1H), 2.70–2.79 (m, 1H),
3.22–3.36 (m, 2H), 4.10–4.25 (m, 2H), 4.80–4.95 (m, 1H),
5.21 (s, 1H), 7.28–7.92 (m, 8H), 12.05 (br s, 1H). 13C
NMR (DMSO-d6): d = 16.90, 37.85, 47.15, 47.67, 50.04,
66.06, 120.49, 120.51, 124.02, 125.84, 126.07, 127.53,
128.05, 128.07, 141.14, 143.14, 144.19, 144.55, 155.81,
173.68. IR (KBr): 3423, 3305, 3269, 2926, 1711, 1655,
1412, 1350, 1213, 1054, 740 cmꢀ1. Anal. Calcd for
C22H21NO4 (363.41): C, 72.71; H, 5.82; N, 3.85. Found:
C, 72.43; H, 5.55; N, 3.72.
The reaction was performed as described for 3. Starting
from 330 mg of 17 of 110 mg (86%) of 97% pure 2 was ob-
25
tained. Mp 189–190 ꢁC (lit.14 190 ꢁC); ½aꢁD ¼ ꢀ115 (c 1,
1
H2O). H NMR (D2O): d = 1.68 (d, J = 1 Hz, 3H), 2.61
(dd, J = 16 Hz, 4 Hz, 1H), 2.61 (dd, J = 16.5 Hz, 7.5 Hz,
1H), 3.51–3.58 (m, 1H), 3.88–3.96 (m, 1H), 5.37 (d,
J = 1.5 Hz, 1H). 13C NMR (D2O): d = 16.50, 40.09,
52.37, 52.45, 123.66, 141.12, 179.69. IR (KBr): 3438,
3052, 2946, 2183, 1654, 1552, 1506, 1393, 1176, 834 cmꢀ1
.
Anal. Calcd for C7H11NO2 (141.17): C, 59.56; H, 7.85;
N, 9.92. Found: C, 59.35; H, 7.98; N, 9.73.

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Z. Hamersˇak et al. / Tetrahedron: Asymmetry 18 (2007) 635–644
6. Mittendorf, J.; Benet-Bucholz, J.; Fey, P.; Mohrs, K.-H.
Acknowledgment
Synthesis 2003, 136–140.
7. (a) Chen, Y.; Deng, L. J. Am. Chem. Soc. 2001, 123, 11302–
11303; (b) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003,
103, 2965–2984.
8. Smith, M. B.; March, J. March’s Advanced Organic Chem-
istry; John Wiley & Sons: New York, 2001; pp 770–771.
9. Rappoport, Z.; Lei, Y. X.; Yamataka, H. Helv. Chim. Acta
2001, 84, 1405–1431.
ˇ
The authors wish to thank Mr. D. Ziher, from PLIVA
Structure and Analysis Department, for recording the
CD spectra.
References
1. (a) Juaristi, E. Enantioselective Synthesis of b-Amino Acids;
John Wiley & Sons: Canada, 1997; pp 45–61; (b) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117–128.
10. Spivey, A. C.; Andrews, B. I. Angew. Chem., Int. Ed. 2001, 40,
3131–3134.
11. Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-K.;
Schmidt, A.; Scho¨nfeld, W. Biorg. Med. Chem. Lett. 2003, 13,
433–436.
12. (a) Harada, N.; Iwabuchi, J.; Yokota, Y.; Uda, H.; Nakani-
shi, K. J. Am. Chem. Soc. 1981, 103, 5590–5591; (b) Rosini,
C.; Giacomelli, G.; Salvadori, P. J. Org. Chem. 1984, 49,
3394–3395; (c) Skowronek, P.; Gawronski, J. Tetrahedron
Lett. 2000, 41, 2975–2977; (d) Molinski, T. F.; Brzezinski, L.
J.; Leahy, J. W. Tetrahedron: Asymmetry 2002, 13, 1013–
1016.
13. Nakanishi, K.; Berova, N.; Woody, R. W. Circular Dichro-
ism, Principles and Applications, 2nd ed.; Wiley-VCH: New
York, 2000; pp 337–376.
2. Fulo¨p, F. Chem. Rev. 2001, 101, 2181–2204.
¨
3. (a) Konishi, M.; Nishio, M.; Saitoh, K.; Miyaki, T.; Oki, T.;
Kawaguchi, H. J. Antibiot. 1989, 42, 1749–1755; (b) Oki, T.;
Hirano, M.; Tomatsu, K.; Numata, K.; Kamei, H. J.
Antibiot. 1989, 42, 1756–1762; (c) Iwamoto, T.; Tsuii, E.;
Ezaki, M.; Fujie, A.; Hashimoto, S.; Okuhara, M.; Kohsaka,
M.; Imanaka, H.; Kawabata, K.; Inamoto, Y.; Sakane, K. J.
Antibiot. 1990, 43, 1–7; (d) Kawabata, K.; Inamoto, Y.;
Sakane, K.; Iwamoto, T.; Hashimoto, S. J. Antibiot. 1990, 43,
513–518.
4. Sordera, L. A.; Castaner, J.; Bozzo, J. Drugs Future 2002, 27,
1049.
5. Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberg, C. P. R.
Tetrahedron: Asymmetry 2003, 14, 3455–3467.
14. Mittendorf, J.; Kunisch, F.; Plempel, M. Ger. Offen. DE
4217776, 1993; Chem. Abstr. 1994, 121, 83988.