Asymmetric synthesis of 3-alkyl substituted prolines by alkylation of a chiral sulfone

Article abstract of DOI:10.1016/S0040-4039(01)02391-7

Preparation of 3-alkyl substituted prolines was achieved by alkylation of a chiral sulfone obtained from the amino-zinca-ene-enolate cyclization.

Full text of DOI:10.1016/S0040-4039(01)02391-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1221–1223
Asymmetric synthesis of 3-alkyl substituted prolines by
alkylation of a chiral sulfone
Philippe Karoyan* and Ge´rard Chassaing
UMR 7613, ‘Structure et Fonction de Mole´cules Bioactives’, Universite´ Paris VI, case 182, 4 place Jussieu,
75252 Paris cedex 05, France
Received 19 November 2001; revised 14 December 2001; accepted 19 December 2001
Abstract—Preparation of 3-alkyl substituted prolines was achieved by alkylation of a chiral sulfone obtained from the
amino–zinca-ene–enolate cyclization. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The alkylation of 4-oxoproline enolate A led a mixture
of cis/trans isomer and a variable amount of dialkyl-
ated product.1,3 The alkylation of 2-amino-ketene S,S-
acetals B provides also a mixture of racemic cis/trans
isomers.8 The alkylation of sulfonyl carbanions of
pyrrolidine C was found to be highly diastereoselective,
but the desulfonylation step provided a mixture of
cis/trans isomers.2 We have previously reported that
asymmetric amino–zinc–enolate cyclization leading to
precursor D is a powerful and straightforward method
for the synthesis of cis-3-substituted proline deriva-
tives.9 This methodology was firstly applied to asym-
metric syntheses of 3-prolinovaline, 3-prolino-
methionine and 3-prolinoglutamic derivatives.9–11 How-
ever, the cyclic organozinc reagent, even after
transmetallation with the THF soluble copper salt
CuCN–2LiCl12 was unreactive towards non-activated
alkyl-electrophiles. Thus, the introduction at the C-3
position of alkyl chain could not be directly achieved
from these organometallic species. We wish to report
here the synthesis of the sulfone 8 as a versatile precur-
sor of 3-alkyl prolines. Indeed, the regioselective depro-
Proline derivatives are used for replacing natural amino
acids in peptides because their conformational rigidity
allows to better understand the bioactive conformation
of peptides.1–3 Furthermore, functionalized pyrrolidine
rings derived from proline have also been viewed as
constrained non-peptide b-turn mimetics.4 In this
regard, 3-substituted prolines, chimeras combining
amino acid side-chain functionality with proline confor-
mational rigidity have been used as probes in structure–
activity relationship studies of biologically active
peptides (such as tachykinins, bradykinins, opioid pep-
tides…)1,5 and as scaffolds to build up low-molecular
weight primary screening libraries.6,7
Four synthetic methodologies have been developed for
the synthesis of 3-substituted prolines allowing the
introduction of various chains on precursors, namely A,
B, C and D.
O M
M
tonation in
a position of the sulfone allowed
A
B
S
alkylations with various alkyl-electrophiles as described
in Scheme 1 and Table 1.
CO2P'
N
P
N
P
S
R
M
CO2P'
N
P
2. Results and discussion
SO2Ph
M
C
D
The thioether 7 was obtained in a ‘one-pot’ procedure
starting from the previously described olefin 1.9,10 This
olefin was subjected to cyclization as described in
Scheme 1. The lithium enolate obtained by deprotona-
tion of 1 with LDA (1 equiv.) in THF at low tempera-
ture was transmetalated with zinc bromide (2.5 equiv. 1
M in ether). Cyclisation occurred by warming up the
OTHP
CO2P'
N
P
N
P
M = metal
* Corresponding author. Tel: 01-44-27-38-42. Fax: 01-44-27-71-50;
e-mail: karoyan@ccr.jussieu.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02391-7

1222
P. Karoyan, G. Chassaing / Tetrahedron Letters 43 (2002) 1221–1223
SO2Ph
SPh
i
ii
CO2CH3
CO2CH3
N
N
N
CO2CH3
Ph
Me
Ph
R
Me
iii
7
8
R
Ph
Me
VII
1
R
SO2Ph
iV
R
V -VI
CO2CH3
CO2H
CO2CH3
N
N
HCl.
H
CO2H
N
N
HCl.
H
11 a-d
12-d
Ph
Me 10 a-d
9 a-d
Ph
Me
Scheme 1. (i) THF, LDA, −78°C, ZnBR2, −78°C to rt, then CuCN–2LiCl, PhSSO2Ph. (ii) CH2Cl2, TFA (4 equiv.), mCpBA (2
equiv.). (iii) THF–DMPU (3:1), −78°C, LDA, RX. (iv) MeOH, Na/Hg (4 equiv.), KH2PO4 (3 equiv.). (v) H2/PdC/MeOH. (vi)
HCl 6N, reflux. (vii) H2O, sealed tube, 190°C.
Table 1. 3-Alkylprolinoamino acids obtained
Entry
RX
9 yield (%) (dr·aSO2) a
10 yield (%) b
11 yield (%) b
a
b
c
CH3I
92 (66/34)
68 (76/24)
68 (50/50)
69 (56/44)
84
76
72
73
80
73
76
78
BrCH2CO2tBu
(CH3)2CHCH2I
BrCH2Ph
d
a The diastereomeric ratios (dr) were determined by 1H NMR spectroscopy following the integration values of the chiral auxiliary methyl group.
b Isolated yields of analytically pure products (1H, 13C NMR, HRMS or microanalysis).15
reaction mixture to room temperature. After a new
transmetalation step with the THF soluble CuCN salts,
the organozinccopper species were reacted with
PhSSO2Ph13 leading to compound 7 as a single iso-
mer.15 This compound was then oxidized in sulfone 8
by mCpBA (2 equiv.) in the presence of TFA (4 equiv.)
to avoid N-oxidation.15
References
1. Sharma, R.; Lubell, W. D. J. Org. Chem. 1996, 61, 202
and references cited therein.
2. Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.;
Potier, P. J. Org. Chem. 1997, 62, 765.
3. Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.;
Witte, D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan,
A. M. J. Med. Chem. 1991, 34, 455.
This general precursor has the 2S,3R configuration as
previously demonstrated by hydrolysis of the zinc
derivative.9 It was then subjected to a second deproto-
nation by LDA, the steric hindrance of the chiral
auxiliary on the nitrogen prevented the abstraction of
the proton a to the ester function.14 The carbanion of
sulfone 8 was cleanly alkylated in the position a to the
sulfone group after deprotonation by LDA at low
temperature in a THF–DMPU mixture (3:1) and subse-
quent addition of the electrophile, leading to derivative
9a–d with formation of a new chiral center on the b%
carbon.15 The diastereoisomeric ratios were poor but
desulfonylation step by Na/Hg amalgam led in all cases
to derivatives 10a–d as single isomers.15 Nitrogen
deprotection (hydrogenolysis) and methyl ester hydroly-
sis by refluxing 6N HCl led to compounds 11a–d.15
4. Horwell, D. C.; Naylor, D.; Willems, H. M. G. Bioorg.
Med. Chem. Lett. 1997, 7, 31.
5. Sagan, S.; Karoyan, Ph.; Chassaing, G.; Lavielle, S. J.
Biol. Chem. 1999, 34, 23770.
6. Karoyan, Ph.; Triolo, A.; Nannicini, R.; Giannotti, D.;
Altamura, M.; Chassaing, G.; Perrotta, E. Tetrahedron
Lett. 1999, 40, 71.
7. Murphy, M. M.; Schullek, J. R.; Gordon, E. M.; Gallop,
M. A. J. Am. Chem. Soc. 1995, 117, 7029.
8. Moss, W. O.; Jones, A. C.; Wisedale, R.; Mahon, M. F.;
Molloy, K. C.; Bradbury, R. H.; Hales, N. J.; Gallagher,
T. J. Chem. Soc. Perkin Trans. 1 1992, 2615.
9. Karoyan, Ph.; Chassaing, G. Tetrahedron Lett. 1997, 38,
85.
10. Karoyan, Ph.; Chassaing, G. Tetrahedron: Asymmetry
1997, 8, 2025.
trans Isomers can be obtained from the cis isomers by
inversion of the a-center in thermodynamic conditions.
For example, the trans isomer of 11d was obtained by
heating the cis-derivatives at 190°C in a sealed tube.11
11. Karoyan, Ph.; Chassaing, G. Tetrahedron Lett. 2002, 43,
253.
12. Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61, 5743.
13. Chemla, F.; Karoyan, Ph. Org. Synth. 2000, 78, 99.
14. Karoyan, Ph.; Chassaing, G. Peptides 2000, 373.
15. Experimental part for selected products: All compounds
had the expected analytical and spectroscopic properties.
7: General procedure for the cyclization–transmetallation
reaction.9,10 From amine 1 (12.25 g, 50 mmol), THF (150
ml), LDA (25 ml, 50 mmol), ZnBr2 (1 M, 150 ml),
In conclusion, the combination of both amino–zinc–
enolate cyclization and alkylation of the chiral sulfone
allows to obtain a wide variety of cis 3-substituted
prolines which can be epimerized in trans 3-substituted
prolines.

P. Karoyan, G. Chassaing / Tetrahedron Letters 43 (2002) 1221–1223
1223
CuCN–2LiCl (1 M, 50 ml), PhSSO2Ph (12.5g, 50 mmol),
yielding after purification by flash chromatography
(cyclohexane–ethylacetate, 9:1) a colorless glue (13.2 g,
74%): [h]2D5 −23 (c 1, CHCl3); 1H NMR (250 MHz,
CDCl3): l 7.59–7.44 (m, 10H), 3.97–3.89 (q, 1H), 3.90 (s,
3H), 3.74–3.71 (d, 1H J3=7.5 Hz), 3.32–3.14 (m, 3H),
3.01–2.75 (m, 2H), 2.49–2.3 (m, 1H), 2.15–1.9 (m, 1H),
1.63–1.60 (d, 3H). 8: mCpBA (7.3 g, 32 mmol) was added
to a cold solution (0°C) of 7 in CH2Cl2 (100 ml) and TFA
(5 ml, 64 mmol). After 1 h stirring, the organic layer was
washed with 10% NaHCO3 (3×), dried over MgSO4,
concentrated and purified by flash chromatography
(cyclohexane–ethylacetate, 7:3), yielding 9.8 g (80%) of a
colorless glue. [h]2D5 −32 (c 1, CHCl3); 1H NMR (250
MHz, CDCl3): l 8.14–8.11 (d, 2H), 7.94–7.79 (m, 3H),
7.55–7.44 (m, 5H), 3.94–3.91 (q, 1H), 3.85 (s, 3H), 3.69–
3.66 (d, 1H J3=7.5 Hz), 3.47–3.45 (m, 1H), 3.28–3.20 (m,
3H), 3.03–3.00 (m, 1H), 2.51–2.39 (m, 1H), 2.15–2.03 (m,
1H), 1.61–1.59 (d, 3H). General condition for alkylation:
LDA (1 equiv.) was added to a dry THF–DMPU (3:1)
solution of the sulfone 8 at −78°C under argon. After few
seconds stirring, the electrophile (3 equiv.) was added at
this temperature. The reaction mixture was stirred until
complete decoloration (5–20 min) and brought to rt.
Ether was added and the organic layer was washed twice
with aq. satd NH4Cl solution, dried over MgSO4. Pale
yellow oils were obtained after concentration. The crude
materials were purified by flash chromatography. General
condition for desulfonylation: KH2PO4 (3 equiv.) and 3%
Na/Hg amalgam (4 equiv.) were added to dry solution of
9 (1 equiv.) in distilled MeOH (6 ml/mmol). The mixture
was vigorously stirred for 1 h at rt. After filtration over a
Celite pad, the crude material was concentrated and
purified by flash chromatography. 11a: 1H NMR (250
MHz, D2O): l 4.50–4.47 (d, 1H J3=7.5 Hz), 3.70–3.63
(m, 1H), 3.54–3.46 (m, 1H), 2.75–2.6 (m, 1H), 2.41–2.33
(m, 1H), 2.02–1.94 (m, 1H), 1.8–1.6 (m, 1H), 1.5–1.25 (m,
1H), 1.13–1.07 (tr, 3H). MH+: Anal. calcd (found): 144
(144). 11b: 1H NMR (250 MHz, D2O): l 4.48–4.45 (d, 1H
J3=7.5 Hz), 3.75–3.60 (m, 1H), 3.55–3.40 (m, 1H), 2.85–
2.55 (m, 3H), 2.48–2.33 (m, 1H), 2.1–1.85 (m, 2H), 1.8–
1.7 (m, 1H). MH+: Anal. calcd (found): 188 (188). 11c:
1H NMR (250 MHz, D2O): l 4.50–4.47 (d, 1H J3=7.5
Hz), 3.74–3.64 (m, 1H), 3.54–3.43 (m, 1H), 2.85–2.75 (m,
1H), 2.44–2.30 (m, 1H), 2.06–1.95 (m, 1H), 1.8–1.6 (m,
2H), 1.5–1.3 (m, 3H), 1.02–1.01 (d, 3H), 0.99–0.98 (d,
3H). MH+: Anal. calcd (found): 186 (186), [h]2D5 −19 (c 1,
H2O), mp: 88°C. 11d: 1H NMR (250 MHz, D2O): l
7.40–7.27 (m, 5H), 4.34–4.31 (d, 1H J3=7.5 Hz), 3.58–
3.52 (m, 1H), 3.38–3.30 (m, 1H), 2.79–2.57 (m, 3H),
2.30–2.21 (m, 1H), 1.92–1.81 (m, 2H), 1.62–1.59 (m, 1H).
MH+: Anal. calcd (found): 220 (220), [h]D25 −6 (c 1, H2O),
mp: 176°C.