In view of the wide range of biological activities, pyrro-
lidine derivatives and cyclic amino acids have received much
attention. For example, pyrrolidine-3-carboxylate has been
utilized as a â-turn motif in a GPIIb/IIIa antagonist.7 Some
of these derivatives have been proven to be enzyme inhibi-
tors8 or neurotransmitters.9 They can also be incorporated
as a 3,4-dehydro-isoproline peptidomimetic scaffold or be
used as intermediates to construct alkaloid natural products
and drug candidates.10
As part of our ongoing project on the synthesis of
heterocyclic structures by RCM,11 we report herein a
straightforward method for the preparation of pyrrolidine
derivatives by Lewis acid assisted RCM of diallylamine
substrates.
The synthesis of chiral diallylamine precursors was based
on the known procedure12 from commercially available L-R-
amino acids and shown in Scheme 1.
Figure 1. Ruthenium catalysts investigated.
employed as the catalyst at 40 °C in CH2Cl2. The starting
material, 4, was recovered in 89-93% yield after 24 h, and
the catalyst decomposed. The reaction only gave very poor
results even with highly active catalysts such as 8, 9, or 10.
With catalyst 8, we obtained the RCM product 13 only in
11% yield. When 9 or 10 was employed, the isolated yield
of 13 was less than 25% in both cases. We ran the reaction
in different solvents (1,2-dichloroethane and toluene) at
higher temperature with a higher catalyst loading of 10 (15
mol % vs 5 mol %); however, the efficiency of the reaction
did not improve.
It was reported that catalyst 6b could catalyze the RCM
reaction of hydrochloride salts of amino dienes.5f To obtain
compound 13 in a reasonable yield, this method was applied
to the RCM reaction of the hydrochloride salt of methyl
2-diallylamino-3-phenyl-propanoate, 14 (Scheme 2). To our
surprise, the reaction afforded the pyrrole 15 in 73% isolated
yield, instead of the corresponding pyrrolidine 13. This result,
to some extent, is consistent with Stevens4a and Yang’s
observations.13
Scheme 1. Synthesis of Diallylamines
Initial studies were focused on examining the feasibility
of the RCM and optimizing reaction conditions that could
be applied to various diallylamines. The RCM reaction of
methyl 2-diallylamino-3-phenyl-propanote (4) was chosen
as a model reaction and a series of Grubbs-type Ru catalysts
(Figure 1) were tested.
The catalyst screening indicated that the model reaction
(Table 1) did not work at all when 5, 6a, 7, 11, or 12 was
(5) (a) Evans, P.; Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M.
Tetrahedron Lett. 1999, 40, 3021. (b) Mori, M.; Sakakibara, N.; Kinoshita,
A. J. Org. Chem. 1998, 63, 6082. (c) Williams, R. M.; Liu, J. J. Org. Chem.
1998, 63, 2130. (d) Furstner, A.; Koch, D.; Langemann, K.; Leitner, W.;
Six, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2466. (e) Miller, S. J.;
Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855. (f) Fu, G. C.; Nguyen,
S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856.
Table 1. Ru-Catalyzed RCM Reaction of 4
(6) An example of RCM of ortho-halo and ortho-vinyl anilines, see:
Evans, P.; Grigg, R.; Monteith, M. Tetrahedron Lett. 1999, 40, 5247.
(7) Hoekstra, W. J.; Maryanoff, B. E.; Damiano, B. P.; Andrade-Gordon,
P.; Cohen, J. H.; Costanzo, M. J.; Haertlein, B. J.; Hecker, L. R.; Hulshizer,
B. L.; Kauffman, J. A.; Keane, P.; McComsey, D. F.; Mitchell, J. A.; Scott,
L.; Shah, R. D.; Yabut, S. C. J. Med. Chem. 1999, 42, 5254.
(8) Wang, C.-L. J.; Taylor, T. L.; Mical, A. J.; Spitz, S.; Reilly, T. M.
Tetrahedron Lett. 1992, 33, 667.
catalyst
solvent temp (°C) time (h) yield of 13 (%)a
(9) (a) Fallorni, M.; Porcheddu, A.; Giacomello, G. Tetrahedron:
Asymmetry 1997, 8, 1633. (b) Hamilton, G. S.; Huang, Z.; Yang, X.-J.;
Patch, R. J.; Naranyan, B. A.; Ferkany, J. W. J. Org. Chem. 1993, 58,
7262.
(10) (a) O’Hagan, D.Nat. Prod. Rep. 2000, 17, 435. (b) O’Hagan, D.
Nat. Prod. Rep. 1997, 14, 637. (c) Morgans, D. J.; Stork, G. Tetrahedron
Lett. 1979, 20, 1959.
(11) Xiao, W.-J.; Ung, T. A.; Pederson, R. L. The 6th National
Conference on Phosphorus Chemistry & Chemical Engineering, Wuhan,
China, Sept., 2003; p 136.
(12) (a) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769. (b)
Mancilla, T.; Carrillo, L.; Zamudio-Rivera, L. S.; Beltran, H. I.; Farfan, N.
Org. Prep. Proced. Int. 2001, 33, 341. (c) Mancilla, T.; Carrillo, L.;
Zamudio-Rivera, L. S.; Beltran, H. I.; Farfan, N. Org. Prep. Proced. Int.
2002, 34, 87. (d) Majumdar, K. C.; Kundu, A. K.; Chatterjee, P. J. Chem.
Res., Synop. 1996, 460.
5 (5 mol %)
6a (5 mol %)
7 (5 mol %)
8 (5 mol %)
9 (5 mol %)
10 (5 mol %)
11 (5 mol %)
12 (5 mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
40
40
40
40
40
40
40
80
110
48
48
48
48
48
48
48
48
36
12
0
0
0
11
17
24
0
0
27
19
10 (15 mol %) DCEb
10 (15 mol %) toluene
a Isolated yield. b 1,2-Dichloroethane.
872
Org. Lett., Vol. 7, No. 5, 2005