Rapid access to cis 3-substituted prolines

Article abstract of DOI:10.1016/S0040-4039(03)01476-X

The O-triflate of 2-cyano-3-oxopyrrolidine was obtained and used in a palladium coupling reaction. The resulting Δ²-pyrrolidine derivatives allowed diastereocontrol at C2 and C3 after catalytic hydrogenation and led to chiral 3-substituted prol

Full text of DOI:10.1016/S0040-4039(03)01476-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6779–6780
Rapid access to cis 3-substituted prolines
Nadia Pellegrini, Martine Schmitt* and Jean-Jacques Bourguignon
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Universite´ Louis Pasteur, Faculte´ de
Pharmacie, 74 Route du Rhin, 67401 Illkirch Cedex, France
Received 6 June 2003; revised 12 June 2003; accepted 14 June 2003
Abstract—The O-triflate of 2-cyano-3-oxopyrrolidine was obtained and used in a palladium coupling reaction. The resulting
D2-pyrrolidine derivatives allowed diastereocontrol at C2 and C3 after catalytic hydrogenation and led to chiral 3-substituted
prolines as conformationally constrained amino acids.
© 2003 Elsevier Ltd. All rights reserved.
The introduction of a proline ring into bioactive pep-
tides restricts their conformational flexibility. This
approach helps to study specific conformational
requirements for small peptidic ligands for binding.1,2
Recent efforts in our laboratory focused on new strate-
gies towards proline derivatives as conformationally
constrained amino acids.3 More recently 2-cyano-3-oxo
pyrrolidine was used in a Wittig reaction for the prepa-
ration of glutamate and arginine semi-rigid com-
pounds.3 In this work, the 3-OTf of 2-cyano-3-oxo
pyrrolidine was used as an efficient intermediate for
typical Pd coupling reactions.
Because of the presence in the O-Tf 2 of the more
electron-withdrawing group (cyano group) combined
with N-Boc protection when compared to carboxylate,4
the prototropic rearrangement led to a quantitative
migration of the double bond between C2 and C3. By
catalytic hydrogenation, the pure cis isomer could be
obtained as a racemate mixture.
Boc-protected 3-oxo-2-cyanopyrrolidine 1 was obtained
in good yield by the procedure described previously
(Scheme 2).3 The triflate 2 was prepared using a con-
ventional procedure (triflic anhydride, triethylamine
and a catalytic amount of DMAP).5 This enol triflate
was submitted to various palladium coupling reactions
as indicated in Table 1.6 Catalytic hydrogenation of
dihydropyrroles 3 afforded 2,3-cis substituted deriva-
tives 4.7 After deprotection of Boc protecting group and
N-benzoylation, the cyano group could be converted
into an amide by TMSCl and H2O,8 or into an ester as
previously described.3 These compounds constitute
semi-rigid derivatives of phenylalanine (5a, R=Ph) or
tyrosine (5c, R=p-MeOPh).
More recently, an enantioselective approach to 3-sub-
stituted prolines has been reported by Kamenecka et al.
by palladium-mediated coupling using the correspond-
ing enol triflate obtained after oxidation of the avail-
able 3-(R)-hydroxy-2-(S)-proline ethyl ester (Scheme
1).4 However, the enol intermediate presented a double
bond between C3 and C4 and catalytic hydrogenation
of corresponding products resulting from coupling reac-
tions provided final products with only good to modest
diastereoselectivity.4
Scheme 1.
Keywords: prolines; Pd coupling; peptidomimetics.
* Corresponding author. Tel.: +33 390 24 42 31; fax: +33 390 24 43; e-mail: 10schmitt@pharma.u-strasbg.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01476-X

6780
N. Pellegrini et al. / Tetrahedron Letters 44 (2003) 6779–6780
Scheme 2. Reagents and conditions: (i) Tf2O, TEA, DMAP, CH2Cl2; (ii) a. PdCl2(dppf), K2CO3, toluene/MeOH (9/1), rt, b. PdCl2,
PPh3, CuI, TEA, CH3CN, rt; (iii) H2, Pd/C, EtOH; (iv) 1. HCl/EtOAc, 2. PhCOCl, TEA, DCM, 3. TMSCl, H2O.
Table 1.
at 85°C for 9 h, cooled, concentrated and purified by silica
gel chromatography. H NMR (300 MHz, CDCl3) of 3b:
1.57 (s, 9H, Boc), 3.15 (t, 2H, CH2), 3.85 (s, 3H, OMe),
3.91 (t, 2H, CH2N), 6.45–6.5 (m, 1H, Har.), 6.9–6.95 (m,
1H, Har.), 7.1–7.3 (m, 2H, Har.).
1
R
Cpd 3 (%)
Cpd 4 (%)
Cpd 5 (%)
C6H5
3-MeO-C6H4
4-MeO-C6H4
3a (78)
3b (62)
3c (60)
4a (80)
4b (87)
4c (75)
5a (71)
5b (63)
5c (65)
(b) To a solution of 0.3 mmol of 3 and 0.45 mmol of
alkyne in acetonitrile (8 ml) was added 16 mg (0.06 mmol)
of PPh3, 6 mg (0.03 mmol) of CuI, 0.06 ml (0.45 mmol) of
TEA and 6 mg (0.03 mmol) of PdCl2. The reaction mix-
ture was stirred at room temperature for 9 h, concentrated
3d (50)
–
–
1
3e (81)
4e (67)
–
and purified by silica gel chromatography. H NMR (300
MHz, CDCl3) of 3e: 1.55 (s, 9H, Boc), 2.80, (t, 2H, CH2),
3.90 (t, 2H, CH2N), 4.20 (d, 2H, CH2-NHBoc), 4.8–7.0 (s,
1H, NH).
Yields are not optimized.
7. All compounds 4 are characterized by an AB system (H2
1
and H3) in their H NMR spectrum.
Taking into account the easy transformation of the
cyano group into carboxylate3 or carboxamide,8 this
approach using 2-cyano-3-OTriflate pyrrolidine is use-
ful for building new proline derivatives. Moreover it
may be also applied to building new bicyclic nitrogen-
containing alkaloids with a cis junction.
For example, compound 4c: 1H NMR A part of AB
system (300 MHz, CDCl3): 4.70 (d, 0.6H, H2), 4.84 (d,
0.4H, H2). (300 MHz, d6-DMSO): 4.10 (d, 1H, H2).
As expected for tertiary amides, two different isomers
could be identified in the 300 MHz NMR spectrum
(CDCl3) of 4c: The C2ꢀH methine appeared at 4.70 (60%)
and 4.84 ppm (40%) as a part of an AB system, whereas
only one isomer was identified in d6-DMSO solution. This
observation confirmed the presence of two isomers, but
only one 2,3-cis diastereoisomer.
References
1. Hirschmann, R.; Veber, D. F. Bioorg. Chem. 1978, 7, 447.
2. Toniolo, C. Int. J. Protein Res. 1990, 35, 287 and refer-
ences cited therein.
8. Basu, M. K. Luo, F. T. Tetrahedron Lett. 1998, 39,
3005–3006. Typical procedure: 2 equiv. of TMSCl is added
to 1 equiv. of nitrile at 0°C and followed by the drop wise
addition of 2 equiv. of water and allowed to warm up to
25°C in 2 h. The reaction mixture is neutralized with
saturated bicarbonate solution at 0–5°C and extracted
with dichloromethane, dried over MgSO4, concentrated
3. Pellegrini, N.; Schmitt, M.; Guerry, S.; Bourguignon, J. J.
Tetrahedron Lett. 2002, 43, 3243–3246.
4. Kamenecka, T. M.; Park, Y. J.; Lin, L. S.; Lanza, T.;
Hagmann, W. K. Tetrahedron Lett. 2001, 42, 8571–8573.
5. Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4,
1599–1602.
1
and purified by silica gel chromatography. H NMR (200
MHz, CDCl3) of 5c: 1.9–2.1 (m, 2H, CH2), 2.2–2.4 (m, 1H,
H1), 3.6–3.8 (m, 2H, CH2N), 3.8 (s, 3H, OMe), 4.7 (d, 1H,
H2), 5.6 (s, 1H, NH2), 6.7 (s, 1H, NH2), 6.9 (d, 2H, Har.),
7.1–7.6 (m, 7H, Har.).
6. Typical procedure: (a) To a solution of 0.3 mmol of 3 and
0.45 mmol of boronic acid in toluene/methanol (10/1, v/v,
8 ml) was added 0.06 g (0.45 mmol) of K2CO3 and 12 mg
(5 mol%) of PdCl2(dppf). The reaction mixture was stirred