[144993-81-7]  · C8H17NO2  · trans-2,5-Bis(methoxymethyl)pyrrolidine  · (MW 159.23) (S,S)-(+)

[93621-94-4] (R,R)-(-)


(chiral auxiliary with C2 symmetry;1 used as a chiral auxiliary for alkylations, acylations, reductions, cycloadditions, and radical additions)

Physical Data: colorless oil; bp 110-115 °C/15 mmHg; for S,S-form, [a]D = +7.8° (c = 3.0, EtOH).

Solubility: sol methylene chloride, chloroform, ethanol.

Form Supplied in: not commercially available.

Analysis of Reagent Purity: 13C NMR (d 27.7, 56.7, 58.8, 76.1 ppm).

Handling, Storage, and Precautions: irritant; use only in a fume hood.

Chiral Amines with C2 Symmetry.

trans-2,5-Dimethylpyrrolidine (1)2 was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis.1,2a Since that time a number of related systems have been developed including the title compound (2) and (4).1 These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis,3 the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of trans-N-benzylpyrrolidine-2,5-dicarboxylic acid,4 although other preparations have been reported.5 In general, pyrrolidines (2) and (3) have been used interchangeably and will be the primary focus of this entry.

Alkylation of Amides Derived from C2-Symmetric Pyrrolidines.

Alkylation of amides derived from either pyrrolidine (2) or (3) are highly stereoselective (eq 1).4a The reaction is successful for a large variety of amide derivatives4a,6 and alkylating agents.7 Upon hydrolysis of the amide, chiral acids are produced (eq 2). This method has been used to prepare a-amino6d and a-hydroxy acids.6a The diastereoselectivity observed is greater than for amides derived from prolinol (5).3 While the degree of the stereoselectivity is almost identical for amides derived from either (2) or (3), the method for removal of the chiral auxiliary does differ (eq 2). In keeping with earlier results from the prolinol-derived amides,3 the hydrolysis is best effected via the hydroxymethyl derivative (10). For derivative (8) this means that the methyl ether is first cleaved with either Boron Trichloride4a or Boron Tribromide.8 In the case of the methoxymethyl derivative (9), refluxing in aqueous acid simultaneously effects both cleavage of the methoxymethyl ether and hydrolysis to the chiral acid.

Reduction of a- and b-Ketoamides Derived from C2-Symmetric Pyrrolidines.

By analogy to the alkylation reaction discussed above, acylation of the enolate derived from amide (8) produces the b-ketoamide (11) as a single diastereomer (eq 3).9 Subsequent reduction of the ketone produces either the syn9 or anti10 b-hydroxyamides with high diastereoselectivity (eqs 4 and 5). Pyrrolidine-derived a-ketoamides have also been shown to react stereospecifically with reducing agents,11 as well as with other organometallic reagents.12

Cycloaddition Reactions.

Chiral acrylamides derived from pyrrolidines (2) or (3) undergo stereoselective [4 + 2] cycloaddition reactions with a variety of cyclic dienes.8a,13 Similarly, nitroso compounds derivatized with pyrrolidine (2) and generated in situ give cycloadducts with a high degree of stereoselectivity (eq 6).8a,14 Intramolecular [2 + 2] cycloadditions involving pyrrolidine-derived keteniminium salts have been shown to produce chiral cyclobutanones.4b

Other Reactions.

Other reactions in which pyrrolidines (2) and (3) have been used as chiral auxiliaries include radical additions,8b electrocyclizations,15 and Wittig rearrangements.7b

1. Whitesell, J. K. CRV 1989, 89, 1581.
2. (a) Whitesell, J. K.; Felman, S. W. JOC 1977, 42, 1663. (b) Schlessinger, R. H.; Iwanowicz, E. J. TL 1987, 28, 2083. (c) Short, R. P.; Kennedy, R. M.; Masamune, S. JOC 1989, 54, 1755.
3. Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. PAC 1981, 53, 1109.
4. (a) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. TL 1984, 25, 857. (b) Chen, L-y.; Ghosez, L. TL 1990, 31, 4467.
5. (a) Takano, S.; Moriya, M.; Iwabuchi, Y.; Ogasawara, K. TL 1989, 30, 3805. (b) Marzi, M.; Minetti, P.; Misiti, D. T 1992, 48, 10 127. (c) Yamamoto, Y.; Hoshino, J.; Fujimoto, Y.; Ohmoto, J.; Sawada, S. S 1993, 298.
6. (a) Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M. TL 1985, 26, 1343. (b) Hanamoto, T.; Katsuki, T.; Yamaguchi, M. TL 1986, 27, 2463. (c) Katsuki, T.; Yamaguchi, M. TL 1987, 28, 651. (d) Ikegami, S.; Uchiyama, H.; Hayama, T.; Katsuki, T.; Yamaguchi, M. T 1988, 44, 5333.
7. (a) Katsuki, T.; Yamaguchi, M. TL 1985, 26, 5807. (b) Uchikawa, M.; Hanamoto, T.; Katsuki, T.; Yamaguchi, M. TL 1986, 27, 4577.
8. (a) Lamy-Schelkens, H.; Ghosez, L. TL 1989, 30, 5891. (b) Veit, A.; Lenz, R.; Seiler, M. E.; Neuburger, M.; Zehnder, M.; Giese, B. HCA 1993, 76, 441.
9. Ito, Y.; Katsuki, T.; Yamaguchi, M. TL 1984, 25, 6015.
10. Ito, Y.; Katsuki, T.; Yamaguchi, M. TL 1985, 26, 4643.
11. Kawanami, Y.; Fujita, I.; Asahara, S.; Katsuki, T.; Yamaguchi, M. BCJ 1989, 62, 3598.
12. Kawanami, Y.; Fujita, I.; Ogawa, S.; Katsuki, T. CL 1989, 2063.
13. Kawanami, Y.; Katsuki, T.; Yamaguchi, M. BCJ 1987, 60, 4190.
14. (a) Gouverneur, V.; Ghosez, L. TL 1990, 1, 363. (b) Gouverneur, V.; Ghosez, L. TL 1991, 32, 5349.
15. Fuji, K.; Node, M.; Naniwa, Y.; Kawabata, T. TL 1990, 31, 3175.

Patrick G. McDougal

Reed College, Portland, OR, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.