Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines

Article abstract of DOI:10.1016/j.tetasy.2010.11.017

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[b]pyrrole-6a(1H)-carboxylic acid ('2,3-propanoproline'), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-

Full text of DOI:10.1016/j.tetasy.2010.11.017

Tetrahedron: Asymmetry 21 (2010) 2868–2871
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines
Natalia A. Kopylova a,b, Oleksandr O. Grygorenko b,c, Igor V. Komarov b, , Ulrich Groth a
⇑
a Department of Chemistry and Konstanz Research School of Chemical Biology, University of Konstanz, Universitätsstr. 10, Konstanz 78457, Germany
b Kyiv National Taras Shevchenko University, Organic Chemistry Department, 64 Volodymyrska Street, Kyiv 01601, Ukraine
c Enamine Ltd, 23 Alexandra Matrosova Street, Kyiv 01103, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopen-
ta[b]pyrrole-6a(1H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on
tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall syn-
thetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino
acid.
Received 2 November 2010
Accepted 25 November 2010
Available online 20 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The design and synthesis of compounds, which mimic useful
properties of peptides, known as peptidomimetics, is an active area
of research over the last few decades.1 The main driving force in
this area is the possibility of creating novel drugs by mimicking
the biological activities of peptides. The progress towards pepti-
domimetic drugs is slow, which is caused by their instability
in vivo, poor bioavailability and toxicity, all of which are unwanted
for a drug candidate. Nevertheless, several approaches to solve
these problems have been developed; one of them is the incorpo-
ration of unnatural, conformationally restricted amino acid (CRAA)
residues into a target peptidomimetic, in place of their natural
counterparts in the peptide prototype.2 Apart from increasing the
hydrolytic stability of the peptidomimetics, the CRAA can also
stabilize the biologically active conformation by fixing a certain
peptidomimetic geometry and freeze intramolecular motions. This,
in turn, can in principle lead to favourable free energy of binding of
the peptidomimetics to biological targets and hence to more selec-
tive and efficient biological action.3 This idea is widely exploited by
Nature, which can be exemplified by one of the proteinogenic ami-
no acids—proline. Due to the intrinsic conformational properties,
proline residue has often been considered as a target for replace-
ment with more rigid (usually bicyclic) counterparts when design-
Compound 1 has already been reported in the literature. Early
papers reported the synthesis of racemic derivatives of 1, namely,
N-Boc protected derivative,9 or the corresponding N-benzylamino-
nitrile,10 the free amino acids were not characterized. Two recently
published stereoselective syntheses of 111,12 have illustrated the
applications of highly interesting and novel chemistry, but the tar-
get compounds were obtained by multi-step syntheses in low
overall total yields. Therefore, we used another strategy, which
previously showed its efficiency in the synthesis of other bicyclic
amino acids performed in our group.13 The key transformation in
this strategy is a tandem Strecker-intramolecular nucleophilic
cyclization reaction. Obtaining enantiopure compounds relied on
the chromatographic separation of the diastereomeric aminonitr-
iles. Therefore, the
c-functionalized carbonyl compound 2 was
used as the key intermediate in the synthesis of 2,3-propanopro-
line 1 (Scheme 1).
The c-bromoketone 2 was prepared by alkylation of the com-
mercially available ethyl 2-oxocyclopentanecarboxylate 3 with
1,2-dibromoethane and potassium carbonate in refluxing acetone,
followed by decarboxylation in hydrobromic acid (Scheme 2).14
The key step of the synthesis of 2,3-propanoproline was the
reaction of 2 with the chiral aminonitrile 4 containing the (1S)-
ing bioactive peptidomimetics; in particular, TGF
a
analogues,4 PEP
(
a
)-phenylethylamine fragment. Enantiomerically pure
synthesized from (1S)- -phenylethylamine and acetone cyanohy-
drine according to a procedure described in the literature.13a The
reaction of the -bromoketone 2 with 4 led to a mixture of two
4 was
inhibitors,5 HIV-1 protease inhibitors,6 FKBP12 ligands,7 HCV pro-
a
tease inhibitors8 can be mentioned as examples.
Herein, we report the synthesis of a conformationally restricted
proline analogue—hexahydrocyclopenta[b]pyrrole-6a(1H)-carbox-
ylic acid 1 (‘2,3-propanoproline’, or ‘bicycloproline’), which might
be used as a building block to construct peptidomimetics.
c
compounds in 60% total yield (Scheme 3). Theoretically, the forma-
tion of four diastereomers is possible in this case; however, the
signals of only two aminonitriles were present in the 1H and 13C
NMR spectra of the crude product. Despite the use of a chiral
auxiliary, the stereoselectivity of the reaction was very low: the
diastereomers of 5 were isolated in a ꢀ1:1 ratio. However, using
⇑
Corresponding author. Tel.: +38 067 5001151; fax: +38 044 2393315.
E-mail address: ik214@yahoo.com (I.V. Komarov).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.017

N. A. Kopylova et al. / Tetrahedron: Asymmetry 21 (2010) 2868–2871
2869
O
O
O
Br
OEt
N
H
HOOC
1
2
3
Scheme 1.
O
O
O
O
O
Br(CH2)2Br
aq. HBr
75%
Br
OEt
Br
OEt
K2CO3
65%
2
3
Scheme 2.
H
H
H
O
reflux
60%
H2SO4
Br
+
N
Ph
N
CN
NC
Ph
N
N
89-91%
NC
H2NOC
Ph
4
2
Ph
5
5
6
Scheme 3.
aq. HCl
chromatographic separation, the diastereomers of 5 were obtained
in enantiomerically and chemically pure form.
H
The next step was the synthesis of amino acids from each dia-
stereomer of 5. Hydrolysis of amino nitriles and deprotection via
hydrogenolysis were carried out in similar procedures that were
already described in the literature.13 However, reflux of 5 in aque-
ous HCl did not lead to the desired amino acids; instead, elimina-
tion of HCN was observed. Therefore, we used the stepwise
hydrolysis of the nitrile group in the molecule of 5. First, the corre-
sponding amides 6 were obtained from 2-cyanopyrrolidines 5 in
89% total yield; then, 6 were hydrolysed to give the amino acids
7, which were used in the next step without isolation. Cleavage
H
H2, Pd/C
N
66-68%
HOOC
Ph
.
N
HCl
(from 6)
HOOC
H
1
7
Scheme 4.
of the (1S)-(a)-phenylethylamine fragment in 7 was carried out
by hydrogenolysis over 10% Pd/C. Zwitter-ionic amino acids 1 were
obtained after ion-exchange chromatography (Scheme 4).
H
H
NOE
The calculated energies and their differences between cis- and
trans-fused bicyclo[3.3.0]octanes reported by Gordon et al.15
showed that the cis-fused products are appreciably energetically
favourable; the average energy difference was 7–8 kcal/mol, there-
fore, it is reasonable to assume that under equilibrium conditions,
the trans-fused compounds would equilibrate to the cis-isomers.
Based on the calculation results mentioned above, and suggesting
that the reactions leading to 5 are reversible, we assumed that only
cis-isomers of the amino acid 1 were obtained in the synthesis. The
experimental evidence of the proposed stereochemistry was ob-
tained from NOESY experiments with derivatives 8. Compounds
8 were obtained in 79% yield by reduction of 5 with LiAlH4
(Scheme 5). Correlations between 5-CH and 1-CH2NH2 groups were
observed in the NOESY spectra of both diastereomers, which is
only possible in the case of the cis-configuration.
LiAlH4
79%
N
N
H2NOC
H2N
Ph
6a
Ph
8a
H
H
NOE
LiAlH4
74%
N
N
H2NOC
Ph
H2N
Ph
To determine the absolute configurations of the products, the
enantiomeric amino acids 1 were transformed to their N-Boc-
protected derivatives 9 (Scheme 6)16 the specific rotations of
which are described in the literature. The specific rotations were
6b
8b
Scheme 5.

2870
N. A. Kopylova et al. / Tetrahedron: Asymmetry 21 (2010) 2868–2871
4.2. (3aS,6aS)-1-[(1S)-1-Phenylethyl]hexahydrocyclopenta[b]-
H
H
pyrrole-6a(1H)-carbonitrile 5a and (3aR,6aR)-1-[(1S)-1-
phenylethyl]hexahydrocyclopenta[b]pyrrole-6a(1H)-
carbonitrile 5b
Boc2O
NaOH
67%
N
N
HOOC
9a
HOOC
HOOC
H
Boc
Aminonitrile 4 (12.19 g, 0.065 mol, 1.05 equiv) was added to a
solution of 2 (11.79 g, 0.062 mol, 1 equiv) in 200 ml of dry acetoni-
trile. The mixture was refluxed for 48 h, then poured into an excess
of 10% sodium hydroxide solution and extracted with DCM. The
combined extracts were dried (MgSO4) and evaporated under re-
duced pressure. The residue was chromatographed (gradient
petroleum ether/Et2O, 20:1–10:1 as an eluent) to give 4.40 g
(0.018 mol, 30%) of 5a and 4.51 g (0.019 mol, 30%) of 5b.
1a
H
H
Boc2O
NaOH
62%
N
N
HOOC
9b
H
Boc
1b
Compound 5a: 1H NMR (400 MHz, CDCl3), d: 7.24–7.14 (m, 5H,
CH arom), 3.60 (q, J = 6.5 Hz, 1H, CH(CH3)), 2.97 (m, 1H, CH), 2.59
(dd, J = 9.5, 6.8 Hz, 1H, CH2), 2.24–2.15 (m, 2H, CH2, CH2), 1.97–
1.69 (m, 5H, CH2, CH2, CH2, CH2), 1.45 (m, 1H, CH2), 1.36 (d,
J = 6.5 Hz, 3H, CH(CH3)), 1.26 (m, 1H, CH2). 13C NMR (100 MHz,
CDCl3), d: 145.6, 128.4, 127.0, 126.8, 121.3, 67.9, 62.7, 55.0, 53.9,
Scheme 6.
determined for both isomers 9a {½a D25
¼ þ6:8 (c 0.73, CHCl3)} and
ꢁ
9b {½a 2D5
¼ ꢂ7:0 (c 0.73, CHCl3)}. Comparison with the literature
ꢁ
41.9, 33.1, 30.5, 26.1, 24.5. IR (ATR, cmꢂ1): 2218 (
(m/z): 240 (M+), 225, 163, 105 (PhCH(CH3)). Anal. Calcd for
16H20N2: C, 79.96; H, 8.39; N, 11.66. Found: C, 79.72; H, 8.37; N,
11.70.
Compound 5b: 1H NMR (400 MHz, CDCl3), d: 7.45–7.27 (m, 5H,
m(C„N)). MS
data for 9a11,12 {½a D25
¼ þ6:9 (c 0.75, CHCl3)} allowed us to assign
ꢁ
the absolute configuration for 9 and hence all the compounds
C
mentioned in this study.
3. Conclusion
CH arom), 3.88 (q, J = 6.5 Hz, 1H, CH(CH3)), 3.06 (m, 1H, CH), 2.89
(m, 1H, CH2), 2.58 (m, 1H, CH2), 2.00 (m, 1H, CH2), 1.76–1.54 (m,
2H, CH2, CH2), 1.42 (d, J = 6.5 Hz, 3H, CH(CH3)), 1.49–1.19 (m, 5H,
CH2, CH2, CH2, CH2). 13C NMR (100 MHz, CDCl3), d: 144.9, 128.2,
127.4, 127.1, 126.8, 69.4, 59.0, 52.5, 51.0, 38.5, 33.4, 30.7, 25.6,
A novel approach to cis-2,3-propanoproline 1 has been devel-
oped. The use of a chiral auxiliary did not lead to diastereoselectivity
of the key transformations; however, diastereomeric intermediates
were easily separable, which allowed us to obtain both enantiomers
of 1. The synthetic scheme included six steps and resulted in 18%
overall yield of the title compounds; hence the method can be used
for the multigram preparations of 1.
21.3. IR (ATR, cmꢂ1): 2217 ( (C„N)). MS (m/z): 240 (M+), 225,
m
163, 105 (PhCH(CH3)). Anal. Calcd for C16H20N2: C, 79.96; H,
8.39; N, 11.66. Found: C, 79.72; H, 8.40; N, 11.62.
4.3. (3aS,6aS)-1-((1S)-1-Phenylethyl)hexahydrocyclopenta[b]-
4. Experimental
4.1. General
pyrrole-6a-carboxylic acid amide 6a
At first, 18.22 ml of concentrated H2SO4 was slowly added to a
solution of 2.77 g (0.012 mol) of 5a in hexane at ꢂ10 °C. The mix-
ture was stirred at ꢂ10 °C for 3 h, then at 0 °C for 3 h and at room
temperature for 48 h. The reaction mixture was poured onto ice
and made basic with a saturated aqueous ammonia solution. The
product was extracted with diethyl ether. The combined extracts
were dried over MgSO4 and evaporated under reduced pressure
to give 2.65 g (0.01 mmol, 89%) of the product 6a. 1H NMR
(400 MHz, CDCl3), d: 7.31–7.18 (m, 5H, CH arom), 6.86 (s, 1H,
NH2), 5.15 (s, 1H, NH2), 3.85 (q, J = 6.8 Hz, 1H, CH(CH3)), 3.20 (dd,
J = 8.8, 7 Hz, 1H, CH2), 2.80 (m, 1H, CH2), 2.53 (q, J = 8.3 Hz, 1H,
CH), 2.27 (m, 1H, CH2), 1.99–1.90 (m, 2H, CH2, CH2), 1.77–1.67
(m, 3H, CH2, CH2), 1.56 (dd, J = 12.3, 5.3 Hz, 1H, CH2), 1.44 (d,
J = 6.8 Hz, 3H, CH(CH3)), 1.22 (m, 1H, CH2). 13C NMR (100 MHz,
CDCl3), d: 180.9, 144.9, 128.2, 127.3, 126.9, 78.6, 57.3, 52.5, 47.3,
Ketone 2 was prepared as previously described.14 All reagents
were purchased from Acros, Sigma–Aldrich, Fluka, Merck, ABCR,
AlfaAesar and used without further purification. Solvents were
dried when necessary by standard methods. The progress of the
reactions was checked by thin layer chromatography (TLC) on poly-
meric plates Polygram Sil G/UV254 (0.2 mm of silica gel, Macherey-
Nagel, Düren, Germany), or on aluminium plates from Merck (Silica
Gel 60 or neutral alumina, F254). The spots were observed under a
UV-lamp or visualized by phosphorus-molybdenum acid pentahy-
drate (5% solution in EtOH). Column chromatography was
performed using MN Kieselgel 60 M (silica gel, 40–63 lm
230–400 mesh ASTM, Macherey-Nagel, Düren, Germany). Analyti-
cal HPLC was performed on Merck RP-18 column (250 ꢃ 4.1 mm)
using gradient or isocratic elution by acetonitrile/water mixture
(UV detection at 254 nm). IR-Spectroscopy was performed on
35.5, 30.9, 30.2, 27.9, 21.4. IR (ATR, cmꢂ1): 3439 (
(NH2)), 1674 (
(C@O)). MS (GC–MS): m/z = 258 (M+), 214, 110,
105 (PhCH(CH3)). Anal. Calcd for C16H22N2O: C, 74.38; H, 8.58; N,
m(NH2)), 3255
(m
m
Perkin Elmer Spectrum 100 Series FT-IR.; mmax is given for the main
absorption bands. 1H and 13C NMR spectra were recorded on Jeol
JNM-LA 400 or Bruker Avance 400 at 400 and 100.62 MHz, respec-
tively, using the residual solvent signal as the internal standard;
chemical shifts (d) are expressed in ppm and coupling constants
(J) in Hertz. Rotation angles were measured on the Perkin-Elmer
241 polarimeter with 5 s integration time. GC–MS was performed
on Agilent 7890/5975 GC/MSD System equipped with Phenomenex
10.84. Found: C, 74.65; H, 8.60; N, 10.81. [
MeOH).
a
]
D = ꢂ13.9 (c 0.33,
4.4. (3aR,6aR)-1-((1S)-1-Phenylethyl)hexahydrocyclopenta[b]-
pyrrole-6a-carboxylic acid amide 6b
Compound 6b was prepared from 5b analogously to 6a. Yield
91%. 1H NMR (400 MHz, CDCl3), d: 7.58 (s, 1H, NH2), 7.35–7.24
(m, 5H, CH arom), 5.52 (s, 1H, NH2), 3.56 (q, J = 6.5 Hz, 1H,
CH(CH3)), 2.61 (m, 2H, CH, CH2), 2.39 (m, 1H, CH2), 2.25 (m, 1H,
CH2), 1.97 (m, 1H, CH2), 1.90–1.77 (m, 3H, CH2, CH2), 1.71 (m,
1H, CH2), 1.39 (dd, J = 12.6, 5.0 Hz, 1H, CH2), 1.30 (d, J = 6.8 Hz,
Zebron ZB-5 column (30 ꢃ 0.25 ꢃ 0.25
lm). Helium was used as a
carrier gas. Measurement conditions MS: EI, 70 eV. EI-MS and
FAB-MS were performed on Finnigan MAT8200 mass spectrometer.
ESI-MS was performed on Bruker micrOTOF II in positive mode
(Bruker Daltonics).

N. A. Kopylova et al. / Tetrahedron: Asymmetry 21 (2010) 2868–2871
2871
3H, CH(CH3)), 1.16 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3), d:
(m, 1H, CH2), 2.56 (d, J = 13 Hz, 1H,CH2), 2.35 (m, 1H, CH2), 2.30
(m, 1H, CH), 1.87 (m, 1H, CH2), 1.85 (s, 2H, NH2), 1.81–1.65 (m,
3H, CH2, CH2, CH2), 1.40 (m, 1H, CH2), 1.37 (d, J = 6.5 Hz, 3H,
CH(CH3)), 1.34 (m, 1H, CH2), 1.27 (dd, J = 12.1, 5.5 Hz, 1H, CH2),
1.15 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3), d: 147.0, 128.2,
127.1, 126.6, 75.1, 59.4, 50.8, 50.1, 48.6, 33.8, 31.7, 30.5, 26.2,
23.5. MS (GC–MS): m/z = 242 (M+ꢂ2), 214, 110, 79, 51.
182.4, 146.0, 128.5, 127.1, 126.8, 77.2, 60.8, 53.9, 51.3, 33.6, 30.2,
28.0, 27.9, 22.8. IR (ATR, cmꢂ1): 3425 (
m(NH2)), 3232 (m(NH2)),
1628 (C@O). MS (GC–MS): m/z = 258 (M+), 214, 110, 105
(PhCH(CH3)). Anal. Calcd for C16H22N2O: C, 74.38; H, 8.58; N,
10.84. Found: C, 74.51; H, 8.56; N, 10.82. [
MeOH).
a]
D = ꢂ27.6 (c 0.53,
4.5. ((3aS,6aS)-Hexahydrocyclopenta[b]pyrrole-6a-carboxylic
acid 1a
4.9. (3aS,6aS)-Hexahydrocyclopenta[b]pyrrole-1,6a-dicarboxylic
acid 1-tert-butyl ester 9a
At first, 6 M hydrochloric acid was added to 6 (2.38 g, 9 mmol).
The resulting mixture was refluxed overnight then cooled, filtered
and evaporated under reduced pressure. Water was added and
subsequently removed by evaporation under reduced pressure.
This operation was repeated twice to remove the excess HCl. To
the solid residue obtained, absolute ethanol was added, and the
resulting mixture was refluxed, then cooled and left in an ice bath
for 3 h. Ammonium hydrochloride was filtered off, and the filtrate
was evaporated to dryness. The solid obtained was dissolved in
methanol and hydrogenated (10% Pd/C, 50 atm, 35 °C) for 36 h.
The catalyst was filtered off, and the solvent was removed by ro-
tary evaporation. The crude product was purified using ion-ex-
change chromatography (strong cationite, 3.5% aqueous ammonia
solution as an eluent). Yield of the product 1a—0.95 g (6 mmol,
68%). 1H NMR (400 MHz, CD3OD), d: 3.29 (m, 2H, CH2), 2.93 (m,
1H, CH), 2.32 (m, 1H, CH2), 2.20 (m, 1H, CH2), 2.08–1.76 (m, 4H,
CH2, CH2, CH2), 1.72 (m, 1H, CH2), 1.60 (m, 1H, CH2). 13C NMR
(100 MHz, CD3OD), d: 177.3, 80.8, 50.5, 47.3, 37.4, 33.9, 32.0,
27.1. MS (m/z): 155 (M+), 126, 110, 83, 55. Anal. Calcd for
C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 62.04; H, 8.43; N,
Di-tert-butyl dicarbonate (0.113 g, 0.52 mol, 1.1 equiv) was
added to a mixture of a 1a solution (0.073 g, 0.47 mol, 1 equiv) in
THF and a 1 M solution of aqueous sodium hydroxide (0.3 ml).
The reaction mixture was stirred at rt for 36 h. The THF was then
evaporated, and the aqueous phase was acidified to pH ꢀ2–3 by
the addition of an aqueous solution of 1% hydrochloric acid. The
white precipitate was filtered and dried in vacuo to give 0.08 g of
the product 9a (0.14 mol, 67%). [a]D = +6.8 (c 0.73, CHCl3). For other
spectroscopic and physical data, see the literature.11
4.10. (3aR,6aR)-hexahydrocyclopenta[b]pyrrole-1,6a-
dicarboxylic acid 1-tert-butyl ester 9b
Compound 9b was prepared from 1b analogously to 9a. Yield
62%. [
a
]
D = ꢂ7.0 (c 0.73, CHCl3). All other data were identical to
those for the enantiomer 9b.
Acknowledgement
This work was supported by Konstanz Research School Chemical
Biology (KoRS-CB).
9.01. [
a]
D = ꢂ45 (c 0.4, MeOH).
4.6. ((3aR,6aR)-Hexahydrocyclopenta[b]pyrrole-6a-carboxylic
References
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pyrrol-6a(1H)-yl]methyl}amine 8a
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To a stirred suspension of LiAlH4 (0.059 g, 1.6 mmol) in dry THF,
a solution of 5a (0.2 g, 0. 8 mmol) in dry THF was added dropwise
under nitrogen. The reaction mixture was refluxed for 3.5 h and
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3.81 (q, J = 6.8 Hz, 1H CH(CH3)), 3.13 (t, J = 8 Hz, 1H, CH2), 2.77 (m,
1H, CH2), 2.36 (s, 2H, NH2), 2.22 (m, 1H, CH), 2.12 (d, J = 13 Hz, 1H,
CH2), 1.98 (d, J = 13 Hz, 1H, CH2), 1.93 (m, 1H, CH2), 1.87–1.66 (m,
3H, CH2, CH2, CH2), 1.42 (d, J = 6.8 Hz, 3H, CH(CH3)), 1.39 (m, 1H,
CH2), 1.35 (m, 1H, CH2), 1.24 (m, 2H, CH2, CH2). 13C NMR
(100 MHz, CDCl3), d: 147.1, 128.1, 126.54, 126.49, 75.8, 56.0,
47.8, 47.3, 46.4, 33.9, 32.8, 30.5, 26.0, 22.4. MS (GC–MS):
m/z = 242 (M+ꢂ2), 214, 110, 79, 51.
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4.8. {[(3aR,6aR)-1-[(1S)-1-Phenylethyl]hexahydrocyclopenta[b]-
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3.69 (q, J = 6.5 Hz, 1H, CH(CH3)), 2.94 (d, J = 13 Hz, 1H, CH2), 2.68
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