Amino-zinc-ene-enolate cyclisation: A short access to (2S,3R)- and (2S,3S)-3-benzylprolines (3-benzylpyrrolidine-2-carboxylic acids)

Article abstract of DOI:10.1016/j.tetlet.2004.01.039

The synthesis of 3-benzylprolines can be easily achieved in a diastereoselective and enantioselective way via amino-zinc-ene-enolate cyclisation. Transmetalation of the cyclic zinc intermediate with Pd ₂(dba)₃/P(o-Tolyl)₃

Full text of DOI:10.1016/j.tetlet.2004.01.039

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2185–2187
Amino-zinc-ene-enolate cyclisation: a short access to (2S,3R)- and
(2S,3S)-3-benzylprolines (3-benzylpyrrolidine-2-carboxylic acids)
ꢀ
Jean Quancard, Herve Magellan, Solange Lavielle, Gerard Chassaing and
ꢀ
Philippe Karoyan*
UMR CNRS 7613, Structure et Fonction de Molꢀecules Bioactives, Universitꢀe Paris VI, case 45, 4 place Jussieu,
75252 Paris Cedex 05, France
Received 4 November 2003; revised 5 January 2004; accepted 9 January 2004
Abstract—The synthesis of 3-benzylprolines can be easily achieved in a diastereoselective and enantioselective way via amino-zinc-
ene-enolate cyclisation. Transmetalation of the cyclic zinc intermediate with Pd2(dba)3/P(o-Tolyl)3 allowed functionalisation with an
aromatic ring. One-pot hydrogenolysis and Boc-protection led to the cis-isomer readily usable for peptide synthesis. The trans-
isomer was obtained by epimerisation of the a-centre in a sealed tube at 200 °C.
Ó 2004 Elsevier Ltd. All rights reserved.
Proline chimeras that combine amino acid side-chain
functionality with conformational rigidity are poten-
tially valuable for a wide field of biological applications.
For example, in SAR studies of biologically active
peptides, these proline analogues are used to replace
native residues with the aimof probing both the infor-
mation brought by the side chain and the conformation
(around the peptide backbone and the side chain) of the
native residue.1 Functionalised prolines have also been
viewed as templates for the introduction of chemical
diversity into polyproline oligomers (e.g., polyproline II
helix) allowing inhibition of protein–protein inter-
actions.2 Moreover, we have recently demonstrated that
3-substituted prolines with the appropriate side-chain
represent valuable tools to mimic natural b-turns of
types I, II and II0 found in proteins.3
ety of new organometallics7 allowing reaction pathways
not available for the zinc derivative. This point was
demonstrated in the case of the amino-zinc-ene-enolate
cyclisation by the synthesis of various prolinoamino
acids after transmetalation of the zinc intermediate with
copper salts (e.g., prolinomethionines,8 prolinogluta-
mics9 and prolinoleucines10;11). Transmetalation of
organozinc compounds with Pd(0) (first reported by
Negishi)12 allows coupling with an aryl iodide. We
report here its application to the short synthesis of
Boc-protected (2S,3R)- and (2S,3S)-3-benzyl-pyrroli-
dine-2-carboxylic acids for which only long and racemic
syntheses have been proposed.13;14
The commercially available olefin 115 was converted in
a one-pot procedure to the 3-benzyl derivative 2 as
described in Scheme 1: after deprotonation with LDA
Several approaches have been reported for the synthesis
of these compounds but these lead however to cis/trans
mixtures or to racemates.4;5 We have reported the
amino-zinc-ene-enolate cyclisation as a straightforward
method for the asymmetric synthesis of cis-3-substituted
prolines.6 Trans-isomers can be obtained by simple
epimerisation of the a-centre. The value of this
approach is linked to the relative stability of zinc
intermediates, which can be transmetalated into a vari-
in THF at )78 °C, the lithiumenolate of amino ester
1
was transmetalated with zinc bromide (3 equiv, 1 M in
ether). Warming up to room temperature led to a cyclic
organozinc intermediate presenting
a cis relative
stereochemistry as previously demonstrated.6 This
intermediate was then submitted to a subsequent
transmetalation with the active Pd(0) catalyst generated
in situ fromPd (dba)3 and tri-o-tolylphosphine.16 Cou-
2
pling with iodo-benzene was performed at room tem-
perature to give 2 in reasonable yield (50%).17
One-pot hydrogenolysis over palladiumcharcoal and
Boc protection led to optically pure (2S,3R)-3-benzyl-1-
(tert-butyloxycarbonyl)-pyrrolidine-2-carboxylic acid 3
Keywords: Amino-zinc-ene-enolate cyclisation.
* Corresponding author. Tel.: +33-1-4427-3842; fax: +33-1-4427-3843;
e-mail: karoyan@ccr.jussieu.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.039

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J. Quancard et al. / Tetrahedron Letters 45 (2004) 2185–2187
References and notes
i
ii
1. Quancard, J.; Karoyan, P.; Sagan, S.; Convert, O.;
Lavielle, S.; Chassaing, G.; Lequin, O. Eur. J. Biochem.
2003, 270, 2869, and references cited therein.
2. Ragin, A. D.; Morgan, R. A.; Chmielewski, J. Chem. Biol.
2002, 8, 943.
COOBn
N
2
N
COOH
COOBn
N
Boc
3
Ph
Ph
1
Scheme 1. (i) THF, LDA, )78 °C, ZnBr2, )78 °C to rt, then
Pd2(dba)3/P(o-Tolyl)3, Ph–I, rt, 50% (ii) H2, Pd/C, Boc2O, MeOH,
80%.
3. Quancard, J.; Karoyan, P.; Lequin, O.; Wenger, E.;
Aubry, A.; Lavielle, S.; Chassaing, G.; Tetrahedron Lett.;
2004, 45, 623.
4. Kamenacka, T. M.; Park, Y.-J.; Lin, L. S.; Lanza, T. J.;
Hagmann, W. K. Tetrahedron Lett. 2001, 42, 8571.
5. Pellegrini, N.; Schmitt, M.; Guery, S.; Bourguignon, J.-J.
Tetrahedron Lett. 2002, 43, 3243.
6. (a) Karoyan, P.; Chassaing, G. Tetrahedron Lett. 1997, 38,
85; (b) Lorthiois, E.; Marek, I.; Normant, J. Tetrahedron
Lett. 1997, 38, 39.
7. Knochel, P.; Perea, J. J. A.; Jones, P. Tetrahedron 1998,
54, 8275.
8. Karoyan, P.; Chassaing, G. Tetrahedron: Asymmetry
1997, 8, 2025.
9. Karoyan, P.; Chassaing, G. Tetrahedron Lett. 2002, 43, 253.
10. Karoyan, P.; Quancard, J.; Vaissermann, J.; Chassaing, G.
J. Org. Chem. 2003, 68, 2256.
ii, iii
i
COOH
COOBn
NH
.HCl
N
4
COOBn
N
Ph
Ph
6
5
iv,v
COOH
N
11. Karoyan, P.; Chassaing, G. Tetrahedron Lett. 2002, 43,
1221.
Boc
7
12. Negishi, E. Acc. Chem. Res. 1982, 15, 340.
13. Lavielle, S.; Brunissen, A.; Carruette, A.; Garret, C.;
Chassaing, G. Eur. J. Pharm. 1994, 258, 273.
14. 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, 20, 2615.
15. Both enantiomers are commercially available from Senn
Chemicals AG, Switzerland.
Scheme 2. (i) THF, LDA, )78 °C, ZnBr2, )78 °C to rt, then
Pd2(dba)3/P(o-Tolyl)3, Ph–I, rt, 50%, (ii) H2, Pd/C, MeOH, (iii) 1M
HCl, 90%, (iv) H2O, sealed tube, 200 °C, (v) Boc2O, K2CO3, H2O/
dioxane (1:1).
16. Dexter, C. S.; Jackson, R. F. W. J. Chem. Soc., Chem.
Commun. 1998, 75.
in 80% yield.17 The synthesis of the trans-isomer 7 was
performed as described in Scheme 2. After the same
17. (2S,3R)-3-benzyl-1(-1-phenyl-ethyl)-pyrrolidine-2-carbox-
ylic acid benzyl ester 2. LDA (2.5 mL, 5 mmol) was added
to a solution of amine 1 (5 mmol) in dry THF (10 mL) at
)78 °C followed by ZnBr2 (1 M, 15 mL). The mixture was
allowed to warmup slowly to rt and stirred for 4 h. Iodo-
benzene (6.5 mmol), Pd(dba)2 (0.162 mmol) and P(o-
Tolyl)3 (0.65 mmol) were then successively added and the
mixture was stirred for 30 min. Et2O was added and the
organic layer was washed with NH4Cl, dried over MgSO4
and concentrated in vacuo. The residue was purified by
flash chromatography (cyclohexane/ethyl acetate, 97:3) to
reaction sequence starting formthe enantiomer
4,
compound 5 was obtained.17 The hydrogenolysis over
palladiumcharcoal followed by acidification with 1 M
HCl led to compound 6, which was isolated as a white
solid.17 The epimerisation of the a-centre was performed
by heating derivative 6 at 200 °C in a sealed tube.9 No
side-product was detected, and a cis/trans ratio (28/72)
was obtained in favour of the thermodynamically more
stable trans isomer. The value of the cis/trans ratio is a
result of the steric hindrance existing between both
substituents of the pyrrolidine ring. Indeed, under the
same conditions, complete epimerisation of the a-centre
was observed in the case of prolinoleucine (unpublished
results).
give a yellow oil (50%). ½aŠ20 )44.5° (c 1, CHCl3); 1H NMR
D
(250 MHz, CDCl3) d: 7.35–7.04, (m, 15H), 5.17–5.02 (AB,
3
3
2H), 3.71 (q, 1H, J ¼ 6:8 Hz), 3.50 (d, 1H, J ¼ 8:0 Hz),
3.10–3.02 (m, 1H), 2.92–2.82 (m, 1H), 2.80–2.73 (m, 1H),
2.66–2.56 (m, 1H), 2.27–2.18 (m, 1H), 1.81–1.67 (m, 2H),
1.33 (d, 3H, 3J ¼ 6:8 Hz). 13C NMR (68.5 MHz, CDCl3) d:
173.2, 144.5, 140.4, 135.8, 128.7, 128.6, 128.5, 128.3, 127.4,
127.0, 126.0, 66.6, 65.9, 61.6, 50.1, 43.8, 37.0, 29.6, 22.8.
Anal. Calcd for C27H29NO2: C, 81.17; H, 7.32; N, 3.51.
Found: C, 81.04; H, 7.41; N, 3.66.
After Boc-protection, a sequence of recrystallisations
(ether/pentane) gave optically pure (2S,3S)-3-benzyl-1-
(tert-butyloxycarbonyl)-pyrrolidine-2-carboxylic acid 7. 17
(2S,3R)-3-benzyl-1-(tert-butyloxycarbonyl)-pyrrolidine-2-
20
carboxylic acid 3: mp: 103–105 °C, ½aŠ 14° (c 1, CHCl3);
In conclusion, a short and efficient synthesis of both
diastereoisomers of cis (2S,3R)- and trans (2S,3S)-3-
benzyl-1-(tert-butyloxycarbonyl)-pyrrolidine-2-carbox-
ylic acids has been achieved using the amino-zinc-eno-
late cyclisation reaction and a cross-coupling reaction
with Pd(0). The cis isomer was obtained in two steps
whereas four steps were required for the trans isomer.
This strategy is to be applied to other aromatic sub-
stituents in order to obtain a library of 3-benzylproline
derivatives.
D
1H NMR (250 MHz, CDCl3) d: 9.33 (br s, 1H), 7.31–7.15
(m, 5H), 4.43 and 4.35 (2d, Boc cis/trans isomerisation,
1H, 3J ¼ 8:0 and 8.3 Hz), 3.76–3.55 (m, 1H), 3.33–3.17 (m,
1H), 3.14–2.99 (m, 1H), 2.75–2.50 (m, 1H), 2.45–2.36 (m,
1H), 1.92–1.71 (m, 2H), 1.46–1.43 (2s, Boc cis/trans
isomerisation, 9H). 13C NMR (68.5 MHz, CDCl3): d
177.5, 176.4, 154.8, 153.9, 139.8, 139.5, 128.7, 128.5,
126.4, 80.4, 62.6, 62.2, 46.1, 45.7, 44.3, 43.5, 36.3, 29.6,
28.8, 28.3 Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59;
N, 4.59. Found: C, 66.74; H, 7.70; N, 4.75.

J. Quancard et al. / Tetrahedron Letters 45 (2004) 2185–2187
2187
(2R,3S)-3-benzyl-1(-1-phenyl-ethyl)-pyrrolidine-2-carbox-
ylic acid benzyl ester 5. Same protocol starting from amine
(m, 1H), 3.39–3.28 (m, 1H), 3.01–2.91 (m, 2H), 2.52–2.41
(m, 1H), 2.08–1.95 (m, 1H), 1.88–1.74 (m, 1H). 13C NMR
(68.5 MHz, D2O) d: 171.0, 139.5, 129.3, 129.1, 127.1, 63.4,
44.8, 42.2, 34.6, 28.5.
20
D
1
4 yielding a yellow oil. ½aŠ 44.3° (c 1, CHCl3); H NMR
(250 MHz, CDCl3) d: 7.35–7.04, (m, 15H), 5.17–5.02 (AB,
2H), 3.71 (q, 1H, 3J ¼ 6:8 Hz), 3.50 (d, 1H, 3J ¼ 8 Hz),
3.10–3.02 (m, 1H), 2.92–2.82 (m, 1H), 2.80–2.73 (m, 1H),
2.66–2.56 (m, 1H), 2.27–2.18 (m, 1H), 1.81–1.67 (m, 2H),
1.33 (d, 3H, 3J ¼ 6:8 Hz). 13C NMR (68.5 MHz, CDCl3) d:
173.2, 144.5, 140.4, 135.8, 128.7, 128.6, 128.5, 128.3, 127.4,
127.0, 126.0, 66.6, 65.9, 61.6, 50.1, 43.8, 37.0, 29.6, 22.8.
Anal. Calcd for C27H29NO2: C, 81.17; H, 7.32; N, 3.51.
Found: C, 81.12; H, 7.30; N, 3.56.
(2S,3S)-3-benzyl-1-(tert-butyloxycarbonyl)-pyrrolidine-2-
20
carboxylic acid 7: mp: 90–92 °C, ½aŠ )34.9° (c 1, CHCl3);
D
1H NMR (250 MHz, CDCl3) d: 9.65 (br s, 1H), 7.31–7.17
(m, 5H), 4.09 and 3.97 (2d, Boc cis–trans isomerisation,
1H, 3J ¼ 4:3 and 4.6 Hz), 3.67–3.32 (m, 2H), 3.03–2.94 (m,
1H), 2.80–2.52 (m, 2H), 2.01–1.88 (m, 1H), 1.73–1.55 (m,
1H), 1.48–1.43 (2s, Boc cis/trans isomerisation, 9H). 13C
NMR (68.5 MHz, CDCl3) d: 178.6, 176.3, 155.6, 154.0,
138.9, 129.0, 128.6, 126.5, 81.0, 80.5, 64.0, 45.9, 45.8, 45.4,
44.0, 38.9, 29.2, 29.0, 28.4, 28.3 Anal. calcd for
C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.89;
H, 7.49; N, 4.74.
(2R,3S)-3-benzyl-pyrrolidine-2-carboxylic acid hydrochlo-
ride 6. White powder after washing with CH2Cl2. mp: 180–
183 °C, ½aŠ20 12.7° (c 1, MeOH); 1H NMR (250 MHz, D2O)
D
d: 7.38–7.27, (m, 5H), 4.44 (d, 1H, 3J ¼ 7:1 Hz), 3.62–3.53