Synthesis of enantiopure quaternary prolines by a metathesis process of 2,5-ethenoproline derivatives

Article abstract of DOI:10.1055/s-0030-1257907

A novel azabicyclic amino acid was synthesized in both enantiopure forms. The ring-opening metathesis of methyl N-(tert-butoxycarbonyl)-7-azabicyclo[2.2. 1]hept-2-ene-1-carboxylates was used as a method for accessing a new family of enantiopure proline analogues. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257907

PAPER
3353
Synthesis of Enantiopure Quaternary Prolines by a Metathesis Process of
2,5-Ethenoproline Derivatives
E
nantiopu
a
re
Q
uaterna
v
ry
P
rolines ier Carreras, Alberto Avenoza,* Jesús H. Busto,* Jesús M. Peregrina
Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, UA-CSIC, 26006 Logroño, Spain
Fax +34(941)299621; E-mail: alberto.avenoza@unirioja.es; E-mail: hector.busto@unirioja.es
Received 20 April 2010
thesis of new complex analogues of proline by means of
Abstract: A novel azabicyclic amino acid was synthesized in both
methathesis processes. The enantiopure 7-azanorbornene
enantiopure forms. The ring-opening metathesis of methyl N-(tert-
1 (Figure 1) has been synthesized by Rapoport et al. in 17
butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene-1-carboxylates was
used as a method for accessing a new family of enantiopure proline
analogues.
steps and 10% overall yield starting from L-serine.12
We recently developed a synthesis of the racemic 7-aza-
norbornene 2, which can be regarded as a 2,5-ethenopro-
line derivative (Figure 1), and we have explored some
metathesis reactions of this substance to give several pro-
line analogues.13 We therefore attempted to obtain com-
pound 2 in both enantiopure forms for use in the synthesis
of the corresponding enantiopure amino acids, and we at-
tempt to use the products in metathesis processes to syn-
thesize enantiopure a-substituted proline derivatives. The
strategy that we used to resolve the rac-2 involved the
hydrolysis of the corresponding methyl ester with lithium
hydroxide to give the acid rac-3, which was treated
with methyl L-serinate in the presence of O-(benzo-
triazol-1-yl)-N,N,N¢,N¢-tetramethyluronium tetrafluoro-
borate (TBTU) and N,N-diisopropylethylamine (DIPEA)
to give amides 4 and 5 as a diastereoisomeric mixture.
These diastereoisomers could be separated by column
chromatography to give 45% of 4 and 43% of 5
(Scheme 1).
Key words: metathesis, bicyclic compounds, heterocycles, amino
acids, stereoselective synthesis
Syntheses of conformationally constrained acyclic1 and
cyclic2 unnatural amino acids present new possibilities for
producing innovative peptidomimetics.3 In this context,
proline analogues that incorporate an a-quaternary stereo-
genic center are of particular interest, given the key role of
proline in the stabilization of secondary structures of pep-
tides, and hence in their biological activity.4 In particular,
pyrrolidine derivatives with a 2,2,5-trisubstitution pattern
occur in a range of natural products,5 including fusarin,
bohemamine, (+)-NP25302, lepadiformine, kaitocepha-
lin, and their analogues, and their synthesis is therefore of
considerable interest.6
On the other hand, the 7-azabicyclo[2.2.1]heptane struc-
ture has attracted the attention of chemists because of its
presence in the biologically active compound epibati-
dine.7 The incorporation of a carboxylic acid group at
the 1-position in this system provides 7-azabicy-
clo[2.2.1]heptane-1-carboxylic acid,8 a conformationally
constrained proline analogue that has been named 2,5-eth-
anoproline.9 This moiety been incorporated in several
peptides to modify their conformation and activity.10
rac-2
LiOH⋅H2O
MeOH–H2O, r.t.
Boc
N
HO2C
Cbz
N
Boc
N
rac-3
1) L-Ser-OMe, TBTU,
DIPEA, MeCN, r.t.
2) column
chromatography
tBuO2C
(1S,4R)-
MeO2C
rac-
1
2
Boc
N
S
Boc
N
R
Figure 1 Bridgehead-substituted azanorbornene systems
R
S
O
O
Bicyclic systems, such as norbornene, are excellent start-
ing materials for the synthesis of complex molecules by
metathesis processes.11 We hypothesized that the incorpo-
ration of a carboxylic acid function at the 1-position of the
7-azanorbornene structure would open the way to the syn-
NH
NH
S
S
HO
HO
CO2Me
CO2Me
5
4
Scheme 1 Diastereoisomeric resolution
To determine the absolute configuration of these diastereo-
isomers, we transformed isomer 4 into a compound of
known configuration. Acid hydrolysis of compound 4 fol-
SYNTHESIS 2010, No. 19, pp 3353–3357
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1257907; Art ID: P06210SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

3354
J. Carreras et al.
PAPER
lowed by protection of the carboxylic acid and amino with ethylene as the CM partner15 in an attempt to obtain
groups as methyl ester and tert-butoxycarbonyl (Boc) novel nonracemic amino acids. When we carried out this
groups, respectively, gave the corresponding enantiomer reaction with compound (1R,4S)-2 for 24 hours at 55 °C
of 2. This was converted into the azanorbornene 1, as pre- in the presence of an ethylene atmosphere in chloroform
viously described by Rapoport et al,12 by transformation containing the Grubbs second-generation catalyst, we ob-
of the Boc group in a benzyloxycarbonyl (Cbz) group and tained an 89% yield of the pyrrolidine (2R,5S)-7. Howev-
of the methyl ester group into tert-butyl ester group by er, when we used toluene as the solvent at 80 °C for six
treatment with N,N-dimethylformamide di-tert-butyl ace- hours, the yield increased to 92%. We therefore used the
tal (Scheme 2).
revised conditions in the ROM–CM of enantiomer
(1S,4R)-2 to give the pyrrolidine (2S,5R)-7. The reactions
occurred without any loss of chirality because chiral infor-
mation is transferred to the cyclic compound in this
ROM–CM process (Scheme 4).
1) TFA, r.t.
1) 6 M HCl, 100 °C
2) AcCl, MeOH, 0 °C
3) Boc2O, Et3N,
THF–H2O, r.t.
2) CbzCl, DIPEA, MeCN, r.t.
3) LiOH·H2O, MeOH–H2O, r.t.
4) (t-BuO)2CHNMe2,
toluene, reflux
(1R,4S)-2
(1R,4S)-1
4
63%
59%
MesN
Cl
NMes
Scheme 2 Determination of the absolute configurations
H2C CH2,
Boc
N
Ru
toluene,
80 ºC
BocN
Ph
Cl
The specific rotation of 1 derived from 4 {[a]D20 –9.1 (c
0.96, CHCl3)} was the opposite to that described in the
literature12 {[a]D20 +9.0 (c 1.00, CHCl3)} for the (1S,4R)-
enantiomer. We therefore assigned the (1R,4S)-configura-
tion to the bridgehead carbons in compound 4 and, in turn,
the (1S,4R)-configuration was assigned to the correspond-
ing carbon atoms in compound 5.
P(Cy)3
92%
CO2Me
(2R,5S)-7
MeO2C
(1R,4S)-2
Scheme 4 Ring-opening metathesis–cross metathesis process
We were able to prepare proline analogues by simple
transformations of the new enantiopure pyrrolidine
(2R,5S)-7. Hydrolysis of (2R,5S)-7 with 6 M aqueous hy-
drochloric acid gave the corresponding amino acid
(2R,5S)-8, an a-vinyl-a-amino acid containing a proline
structure. Hydrogenation of pyrrolidine (2R,5S)-7 over
palladium/carbon and subsequent hydrolysis gave the
quaternary a-ethylproline (2S,5R)-9. Identical procedures
were used to obtain the corresponding enantiomeric a-vi-
nyl-a-amino acid (2S,5R)-8 and the saturated amino acid
(2R,5S)-9 from pyrrolidine (2S,5R)-7. The specific rota-
tions of these compounds were identical to those of the
enantiomers previously synthesized, but with opposite
signs (Scheme 5).
Acid hydrolyses of diastereoisomers 4 and 5 should pro-
vide both enantiomers of amino acid 6 (7-azabicy-
clo[2.2.1]hept-2-ene-1-carboxylic acid); however, all
attempts to separate these amino acids from the methyl L-
serinate hydrochloride byproduct were unsuccessful. For
this reason, after acid hydrolysis, the azabicyclic amino
acids were newly protected to permit the purification of
the enantiomers (1R,4S)-2 and (1S,4R)-2. Subsequent hy-
drolysis gave the corresponding amino acids (1R,4S)-6
and (1S,4R)-6, which can be regarded as 3,4-dehydropro-
line analogues and named as 2,5-ethano-3,4-dehydropro-
lines. 3,4-Dehydroproline itself is an important inhibitor
of proline hydroxylation in peptides.14 Indeed, an increase
in activity has been observed in peptides in which proline
has been replaced by 3,4-dehydroproline14 (Scheme 3).
H
H
6 M HCl, 100 °C
97%
N
H
H
Cl
Cl
Cl
N
CO2H
6 M HCl, 100 °C
97%
(1R,4S)-2
(2R,5S)-7
(2R,5S)-8
HO2C
Et
1) Pd/C, MeOH
2) 6 M HCl, 100 °C
(1R,4S)-6
H
1) 6 M HCl, 100 °C
2) AcCl, MeOH, 0 °C
3) Boc2O, Et3N,
THF–H2O, r.t.
N
H
H
H
Cl
95%
N
6 M HCl,
100 °C
Et
CO2H
5
(1S,4R)-2
(2S,5R)-9
63%
97%
HO2C
(1S,4R)-6
Scheme 5 Synthesis of new enantiopure proline analogues
Scheme
3
Synthesis of (1R,4S)- and (1S,4R)-7-azabi-
In conclusion, we have synthesized both enantiomers of
7-azabicyclo[2.2.1]hept-2-ene-1-carboxylic acids in pure
forms by a resolution method. The intermediate methyl
N-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene-
1-carboxylates 2 were used in a ROM–CM processes to
cyclo[2.2.1]hept-2-ene-1-carboxylic acid hydrochlorides
Having obtained compounds (1R,4S)-2 and (1S,4R)-2 in
enantiopure forms, we decided to explore their ring-open-
ing metathesis–cross metathesis (ROM–CM) reactions
Synthesis 2010, No. 19, 3353–3357 © Thieme Stuttgart · New York

PAPER
Enantiopure Quaternary Prolines
3355
HRMS (EI) m/z [M + Na]+ calcd for C16H24N2NaO6: 363.1527;
found: 363.1534.
give a new family of enantiomerically pure a-vinyl- and
a-ethylprolines.
Solvents were purified by standard procedures. Column chromatog-
raphy was performed on silica gel (230–400 mesh). Organic solns
were dried over anhyd Na2SO4 and, when necessary, concentrated
under reduced pressure using a rotary evaporator. NMR spectra
were recorded on Bruker Avance and Bruker ARX spectrometers at
400 or 300 MHz (1H) and at 100 or 75 MHz (13C); signals are re-
ported in ppm downfield from TMS. Melting points were deter-
mined on a melting-point apparatus and are uncorrected. Optical
rotations were measured on a Perkin-Elmer 341 polarimeter in 1.0
dm cells of 1.0 or 0.3 mL capacity. Electrospray mass spectra were
recorded on a Bruker micrOTOF-Q spectrometer; accurate mass
measurements were obtained with sodium formate used as an exter-
nal reference.
7-tert-Butyl 1-Methyl (1R,4S)-7-Azabicyclo[2.2.1]hept-2-ene-
1,7-dicarboxylate [(1R,4S)-2]
Ester 4 (200 mg, 0.59 mmol) was suspended in 6 M aq HCl (6 mL),
and the mixture was stirred for 24 h at 100 °C. The solvent was then
evaporated. AcCl (8 mL) was added dropwise to MeOH (25 mL)
cooled in ice, and the soln was stirred for 10 min and then added to
the crude reaction mixture. The resulting soln was stirred at the re-
flux for 24 h, then cooled and concentrated under reduced pressure
to give the corresponding methyl ester as a colorless oil. This was
suspended in 9:1 THF–H2O (20 mL) and the pH was adjusted to 11–
12 with Et3N. Boc2O (515 mg, 2.36 mmol) was added and the mix-
ture was stirred at r.t. for 48 h. The organic solvent was removed in
vacuo, and the residue was partitioned between EtOAc (15 mL) and
2 M aq HCl (10 mL). The organic layer was washed with brine (10
mL), dried, filtered, and concentrated. The residue was purified by
column chromatography [silica gel, hexane/EtOAc (8:2)] to give
(1R,4S)- and (1S,4R)-N-(tert-butoxycarbonyl)-7-azabicy-
clo[2.2.1]hept-2-ene-1-carboxylic Acid (rac-3)
LiOH·H2O (215 mg, 5.13 mmol) was added to a soln of ester rac-2
(260 mg, 1.03 mmol) in 4:1 MeOH–H2O (15 mL). The mixture was
stirred at r.t. for 48 h and then washed with EtOAc (10 mL). The
aqueous layer was acidified with 2 M aq HCl and extracted with 3:1
CHCl3–i-PrOH (3 × 15 mL). The organic layer was dried, filtered,
and concentrated to give a white solid that was used in the following
step without purification; yield: 201 mg (82%); mp 148–149 °C.
1H NMR (300 MHz, CDCl3): d = 1.22–1.31 (m, 1 H), 1.44 (s, 9 H),
1.57–1.68 (m, 1 H), 1.98–2.07 (m, 1 H), 2.20–2.31 (m, 1 H), 4.67–
4.83 (m, 1 H), 6.31 (d, J = 5.1 Hz, 1 H), 6.50 (d, J = 5.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.8, 28.2, 30.5, 62.8, 72.9, 83.1,
133.9, 136.0, 156.7, 172.9.
HRMS (ESI): m/z [M + Na]+ calcd for C12H17NNaO4: 262.1055;
found: 262.1050.
20
(1R,4S)-2 as a colorless oil; yield: 94 mg (63%, three steps); [a]D
–2.5 (c 1.0, CHCl3). The spectral data agreed with those reported in
the literature.13a
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO4: 254.1392; found:
254.1388.
7-Benzyl 1-tert-Butyl (1R,4S)-7-Azabicyclo[2.2.1]hept-2-ene-
1,7-dicarboxylate [(1R,4S)-1]
F3CCO2H (0.5 mL) was added to a soln of diester (1R,4S)-2 (59 mg,
0.23 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at r.t.
for 3 h. The solvent was then removed under reduced pressure, the
residue was dissolved in Et2O (10 mL), and the soln was concentrat-
ed; this operation was repeated several times until a colorless oil
was obtained. This product was dissolved in MeCN and treated with
DIPEA (96 mL, 0.55 mmol) and benzyl chloroformate (47 mL, 0.33
mmol), and the mixture was stirred at r.t. for 24 h. The organic sol-
vent was evaporated and the residue was purified by column chro-
matography [silica gel, hexane–EtOAc (8:2)] to give 53 mg of the
corresponding derivative containing N-Cbz and CO2Me groups.
This compound (53 mg, 0.18 mmol) was dissolved in 4:1 MeOH–
H2O (15 mL), and LiOH·H2O (75 mg, 1.80 mmol) was added. The
mixture was stirred at r.t. for 24 h, then washed with EtOAc (10
mL). The aqueous layer was acidified with 2 M aq HCl and extract-
ed with 3:1 CHCl3–i-PrOH (3 × 10 mL). The combined organic lay-
er was dried, filtered, and evaporated to give 40 mg of the
corresponding acid, which was used in the next step without purifi-
cation. The acid was dissolved in dry toluene (8 mL) and (t-
BuO)2CHNMe2 (0.14 mL, 0.60 mmol) was added dropwise to the
mixture. The soln was then refluxed for 1 h, cooled, and washed se-
quentially with H2O (5 mL), sat. aq NaHCO3 (5 mL), and brine (5
mL). The organic layer was dried and the soln was concentrated.
The resulting product was purified by column chromatography [sil-
ica gel, hexane–EtOAc (7:3)] to give a (1R,4S)-1 as a colorless oil;
tert-Butyl 1-({[(1S)-1-(Hydroxymethyl)-2-methoxy-2-oxoeth-
yl]amino}carbonyl)-1S,4R)-7-azabicyclo[2.2.1]hept-2-ene-7-
carboxylic Acid (4) and tert-Butyl 1-({[(1S)-1-(Hydroxymethyl)-
2-methoxy-2-oxoethyl]amino}carbonyl)-1R,4S)-7-azabicy-
clo[2.2.1]hept-2-ene-7-carboxylic Acid (5)
A soln of carboxylic acid rac-3 (400 mg, 1.67 mmol) in MeCN (15
mL) was treated with DIPEA (1.40 mL, 8.36 mmol), L-Ser-OMe
(305 mg, 2.01 mmol), and TBTU (645 mg, 2.01 mmol). The mix-
ture was stirred at r.t. for 16 h and then evaporated to give a residue
that was purified by column chromatography [silica gel, hexane–
EtOAc (2:8)] to give compounds 4 and 5.
4: yield: 256 mg (45%); [a]D22 +96.9 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.21–1.30 (m, 1 H), 1.38 (s, 9 H),
1.45–1.53 (m, 1 H), 1.88–1.96 (m, 1 H), 2.16–2.23 (m, 1 H), 3.77
(s, 3 H), 3.79–3.85 (m, 1 H), 4.22–4.32 (m, 1 H), 4.63–4.69 (m, 2
H), 6.22 (d, J = 5.9 Hz, 1 H), 6.32 (dd, J = 5.9, 2.1 Hz, 1 H), 6.74
(d, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.3 (CH2), 25.6, 28.0, 52.6, 55.3,
61.5, 61.9, 73.0, 81.8, 134.9, 135.2, 155.8, 169.0, 170.8.
20
yield: 34 mg (52%, four steps); [a]D –9.1 (c 0.96, CHCl3). The
spectral data agreed with those reported in the literature.12b
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO4: 330.1700; found:
330.1698.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24N2NaO6: 363.1527;
found: 363.1532.
5: yield: 245 mg (43%); [a]D22 +37.6 (c 1.0, CHCl3).
7-tert-Butyl 1-Methyl (1S,4R)-7-Azabicyclo[2.2.1]hept-2-ene-
1,7-dicarboxylate [(1S,4R)-2]
By using the same method as described for its enantiomer, diester
(1S,4R)-2 was prepared from compound 5 (170 mg, 0.50 mmol);
yield: 80 mg (63%); [a]D20 +2.9 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO4: 254.1392; found:
254.1386 .
1H NMR (400 MHz, CDCl3): d = 1.16–1.24 (m, 1 H), 1.38 (s, 9 H),
1.52–1.60 (m, 1 H), 2.08–2.20 (m, 2 H), 3.81 (s, 3 H), 3.83–3.90 (m,
1 H), 4.25–4.33 (m, 1 H), 4.65–4.71 (m, 1 H), 4.76–4.82 (m, 1 H),
6.23–6.30 (m, 1 H), 6.61–6.73 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.4, 28.1, 30.0, 52.7, 55.4, 61.7,
63.9, 74.0, 82.0, 134.3, 135.5, 157.7, 169.4, 171.0.
Synthesis 2010, No. 19, 3353–3357 © Thieme Stuttgart · New York

3356
J. Carreras et al.
PAPER
(1R,4S)-7-Azabicyclo[2.2.1]hept-2-ene-1-carboxylic Acid Hy-
drochloride [(1R,4S)-6]
HRMS (ESI): m/z [M + H]+ calcd for C9H14NO2: 168.1019; found:
168.1027.
Diester (1R,4S)-2 (30 mg, 0.12 mmol) was suspended in 6 M aq HCl
(4 mL) and the mixture was heated overnight at 100 °C. The solvent
was evaporated and the residue was purified (C18 reverse-phase
Sep-Pack cartridge) to give a white solid; yield: 20 mg (97%); mp
> 250 °C; [a]D20 +32.3 (c 1.0, MeOH).
1H NMR (300 MHz, D2O): d = 1.55–1.65 (m, 1 H), 1.80–1.90 (m, 1
H), 2.19–2.29 (m, 2 H), 4.70–4.77 (m, 1 H), 6.45 (dd, J = 6.0, 2.1
Hz, 1 H), 6.48 (d, J = 6.0 Hz, 1 H).
(2S,5R)-2,5-Divinyl-L-proline Hydrochloride [(2S,5R)-8]
By using the same method as described for its enantiomer (2R,5S)-
8, carboxylic acid (2S,5R)-8 was obtained starting from compound
(2S,5R)-7 (23 mg, 0.08 mmol); yield: 16 mg (97%); [a]D20 +25.7 (c
1.0, MeOH).
HRMS (ESI): m/z [M + H]+ calcd for C9H14NO2: 168.1019; found:
168.1024.
13C NMR (75 MHz, D2O): d = 23.1, 26.7, 61.0, 75.0, 132.8, 133.8,
(5R)-2,5-Diethyl-L-proline Hydrochloride [(2S,5R)-9]
172.0.
A soln of the divinyl compound (2R,5S)-7 (28 mg, 0.10 mmol) in
degassed MeOH (8 mL) was added to a suspension of 10% Pd/C (20
mg) in degassed MeOH (5 mL) and hydrogenated with H2 at atmo-
spheric pressure overnight. The mixture was then filtered through
Celite and concentrated to give a colorless oil; yield: 25 mg (99%).
HRMS (ESI): m/z [M + H]+ calcd for C7H10NO2: 140.0706; found:
140.0710
(1S,4R)-7-Azabicyclo[2.2.1]hept-2-ene-1-carboxylic Acid Hy-
drochloride [(1S,4R)-6]
By using the same method as described for its enantiomer (1R,4S)-
The oil was treated with 6 M aq HCl (5 mL) and the resulting mix-
ture was kept overnight at 100 °C. The solvent was evaporated and
the residue was purified [C18 reverse-phase Sep-Pack cartridge] to
give amino acid (2S,5R)-9 as a yellow oil; yield: 19 mg (95%);
[a]D20 –41.2 (c 1.0, MeOH).
1H NMR (400 MHz, D2O): d = 0.88 (t, J = 7.5 Hz, 3 H), 0.92 (t, J =
7.5 Hz, 3 H), 1.59–1.82 (m, 3 H), 1.84–1.95 (m, 1 H), 2.03–2.20 (m,
3 H), 2.37–2.48 (m, 1 H), 3.53–3.64 (m, 1 H).
13C NMR (100 MHz, D2O): d = 8.5, 10.3, 25.0, 27.9, 28.9, 33.7,
62.9, 73.7, 173.5.
HRMS (ESI): m/z [M + H]+ calcd for C9H18NO2: 172.1332.
6, the acid (1S,4R)-6 was obtained starting from compound (1S,4R)-
20
2 (27 mg, 0.11 mmol); yield: 18 mg (97%); [a]D –30.7 (c 0.80,
MeOH).
HRMS (ESI): m/z [M + H]+ calcd for C7H10NO2: 140.0706; found:
140.0717.
1-tert-Butyl 2-Methyl (2R,5S)-2,5-Divinylpyrrolidine-1,2-dicar-
boxylate [(2R,5S)-7]
A soln of (1R,4S)-2 (60 mg, 0.24 mmol) and Grubbs’s second gen-
eration catalyst (8 mg, 0.010 mmol) in toluene (7 mL) was saturated
with ethylene and kept under an ethylene atmosphere at 80 °C for 6
h with stirring. The solvent was then removed under reduced pres-
sure and the residue was purified by column chromatography [silica
gel, hexane–EtOAc (8:2)] to give a colorless oil; yield: 61 mg
(92%); [a]20D +63.5 (c 1.0, CHCl3).
1H NMR (400 MHz, 340 K, DMSO-d6): d = 1.32 (s, 9 H), 1.62–1.70
(m, 1 H), 2.03–2.17 (m, 3 H), 3.66 (s, 3 H), 4.36–4.53 (m, 1 H),
5.00–5.21 (m, 4 H), 5.75–5.88 (m, 1 H), 6.33 (dd, J = 17.4, 10.7 Hz,
1 H,).
(5S)-2,5-Diethyl-L-proline Hydrochloride [(2R,5S)-9]
By using the method described for its enantiomer (2S,5R)-9, com-
pound (2R,5S)-9 was obtained starting from compound (2S,5R)-7
20
(19 mg, 0.07 mmol); yield: 13 mg (95%), [a]D +38.5 (c 1.0,
MeOH).
HRMS (ESI): m/z 172.1337 [M + H]+; calcd for C9H18NO2:
172.1332; found: 172.1331.
13C NMR (100 MHz, 340 K, DMSO-d6): d = 27.6, 28.6, 36.6, 51.7,
61.0, 69.6, 78.8, 112.8, 114.0, 137.7, 138.8, 152.4, 172.4.
Acknowledgment
HRMS (ESI): m/z [M + Na]+ calcd for C15H23NNaO4: 304.1519;
found: 304.1525.
We thank the Ministerio de Ciencia e Innovación and FEDER (pro-
ject CTQ2009-13814/BQU), and the Gobierno de La Rioja for
grants for J.C. and for the Colabora 2007/18 project.
1-tert-Butyl 2-Methyl (2S,5R)-2,5-Divinylpyrrolidine-1,2-dicar-
boxylate [(2S,5R)-7]
References
By using the same method as described for its enantiomer, (2R,5S)-
7, diester (2S,5R)-7 was obtained starting from compound (1S,4R)-
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20
2 (53 mg, 0.21 mmol); yield: 54 mg (92%); [a]D –60.4 (c 0.80,
CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H23NNaO4: 304.1519;
found: 304.1529.
(5S)-2,5-Divinyl-L-proline Hydrochloride [(2R,5S)-8]
Diester (2R,5S)-7 (30 mg, 0.11 mmol) was suspended in 6 M aq HCl
(4 mL), and the mixture was heated overnight at 100 °C. The sol-
vent was evaporated and the residue was purified [C18 reverse-phase
20
Sep-Pack cartridge] to give a yellow oil; yield: 21 mg (97%); [a]D
–28.7 (c 1.0, MeOH).
1H NMR (400 MHz, D2O): d = 1.93–2.02 (m, 1 H), 2.20–2.28 (m, 1
H), 2.30–2.40 (m, 1 H), 2.50–2.59 (m, 1 H), 4.20–4.29 (m, 1 H),
5.34–5.52 (m, 4 H), 5.88 (ddd, J = 17.9, 10.2, 8.0 Hz, 1 H), 6.05 (dd,
J = 17.4, 10.8 Hz, 1 H).
13C NMR (100 MHz, D2O): d = 29.1, 33.2, 62.8, 73.8, 121.6, 122.8,
132.1, 132.6, 173.2.
Synthesis 2010, No. 19, 3353–3357 © Thieme Stuttgart · New York

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Synthesis 2010, No. 19, 3353–3357 © Thieme Stuttgart · New York