[63126-47-6]  · C6H13NO  · (S)-2-Methoxymethylpyrrolidine  · (MW 115.20)

(chiral auxiliary; asymmetric syntheses with SMP enamines2 and SMP amides;3 asymmetric Birch reductions;4 asymmetric Diels-Alder reactions5)

Alternate Name: SMP.

Physical Data: bp 75 °C/40 mmHg; d 0.930 g cm-3; nD20 1.4467; aD20 -3 to -4° (neat).

Solubility: sol H2O, ether, dichloromethane.

Form Supplied in: colorless liquid.

Handling, Storage, and Precautions: store at 0-4 °C under an argon atmosphere.

General Considerations.

Since the pioneering times of the mid-1970s, (S)-2-methoxymethylpyrrolidine has been one of the most generally useful chiral auxiliaries in asymmetric synthesis, with a very broad range of applications. As a proline derivative, it generally shows high stereoselectivities due to the rigidity of the five-membered ring and the ability to coordinate metal fragments6,7 (see also (S)-1-Amino-2-methoxymethylpyrrolidine, SAMP).

Lithiated SMP formamides and thioformamides have been used as acylanion equivalents (d1 synthons) in the synthesis of enantiomerically pure a-hydroxy ketones and vicinal diols.7 Metalated SMP aminonitriles have been used in nucleophilic acylation reactions to give a-hydroxy ketones.8

SMP enamines have a very broad range of applications as d2 synthons. Cyclohexanone SMP enamine can be used for efficient Michael additions to nitroalkenes, Knoevenagel acceptors,2a,b and to a nitroallylic ester in a [3 + 3] carbocyclization2c with excellent stereoselectivities (eq 1). The synthesis of g-oxo-a-amino acids using SMP enamines has been developed (eq 2).2d

SMP amide enolates have been employed by several research groups. Alkylation of SMP amide enolates gives a-substituted acids (eq 3).3a,b Excellent yields and stereoselectivities are observed in the Birch reduction of aromatic SMP amides with subsequent alkylation (eq 4).4

SMP amides have been used in vanadium(II)-promoted pinacol cross-coupling3c,d and in asymmetric oxidations with chiral oxaziridines.3e The diastereoselective addition of thiocarboxylic acids to 1-(2-methylacryloyl) SMP amides3f and the stereocontrolled addition of various organometallics to a-keto SMP amides3g have been studied.

Metalated SMP allylamines or enamines have been used as the first chiral homoenolate equivalents (d3 synthons; eq 5).9

SMP is a useful chiral auxiliary in various cycloaddition reactions. Chiral 2-amino-1,3-dienes have been used in the Diels-Alder reaction with 2-aryl-1-nitroethylenes,5a,b and 5-aryl-2-methyl-substituted 4-nitrocyclohexanones were obtained in excellent enantiomeric purities (ee = 95-99%) and diastereoselectivities (ds = 75-95%; eq 6). The photo-Diels-Alder reaction of SMP acrylonitrile with 1-acetylnaphthalene has been carried out.5b After hydrolysis of the adduct, the 1,4-diketone was obtained in excellent enantiomeric purity (ee &egt; 97%; eq 7).

Stereoselective Diels-Alder reactions have been performed variously, using chirally modified sulfines as dienophiles,5c chiral ynamines,5d SMP enamines,5e SMP acrylamides,5f and the in situ preparation of SMP N-acylnitroso dienophiles.9g,h,i The [2 + 2] cycloaddition reactions of chiral keteniminium salts obtained from SMP amides with alkenes have been studied.10

Various metalated chiral organosilicon compounds bearing the SMP moiety have been alkylated to synthesize chiral alcohols.11 Excellent regio- and stereoselectivities have been observed in the alkylation of chiral silylpropargyl anions (eq 8).11f

The elegant application of SMP as a chiral leaving group has been studied,13 using chiral nitroalkenes in the reaction with zinc enolates.12 The coupling products were obtained in very good yields and enantiomeric purities (eq 9). SMP methyl-2-cycloalken-1-ones undergo conjugate addition with lithium diorganocuprates followed by elimination of the chiral auxiliary to form optically active cycloalkanones (eq 10).

Various other applications are conjugate addition,14 the ultrasound-promoted perfluoralkylation of SMP enamines,15 the enantioselective fluorodehydroxylation of SMP 1-yl-sulfur trifluoride,16 asymmetric telomerization of butadiene,17 the chiral modification of ruthenium clusters,18 and the application of SMP amide bases.19

Related Reagents.


1. Review (literature up to 1985): Enders, D.; Kipphardt, H. Nachr. Chem. Tech. Lab. 1985, 33, 882.
2. (a) Blarer, S. J.; Seebach, D. CB 1983, 116, 2250 and 3086. (b) Blarer, S. J.; Schweizer, W. B.; Seebach, D. HCA 1982, 65, 1693. (c) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. JACS 1990, 112, 7625. (d) Kober, R.; Papadopoulos, K.; Miltz, W.; Enders, D.; Steglich, W.; Reuter, H.; Puff, H. T 1985, 41, 1637. (e) Risch, N.; Esser, A. LA 1992, 233. (f) Hodgson, A.; Marshall, J.; Hallett, P.; Gallagher, T. JCS(P1) 1992, 2169. (g) Renaud, P.; Schubert, S. SL 1990, 624.
3. (a) Sonnet, P. E.; Heath, R. R. JOC 1980, 45, 3137. (b) Evans, D. A.; Takacs, J. M. TL 1980, 21, 4233. (c) Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni, P. TA 1990, 1, 355. (d) Annunziata, R.; Cinquini, M.; Cozzi, F.; Giaroni, P.; Benaglia, M. T 1991, 47, 5737. (e) Davis, F. A.; Ulatowski, T. G.; Haque, M. S. JOC 1987, 52, 5288. (f) Effenberger, F.; Isak, H. CB 1989, 122, 553. (g) Fujisawa, T.; Ukaji, Y.; Funabora, M.; Yamashita, M.; Sato, T. BCJ 1990, 63, 1894.
4. (a) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. JACS 1988, 110, 7828. (b) Schultz, A. G.; Green, N. J. JACS 1991, 113, 4931. (c) Schultz, A. G.; Taylor, R. E. JACS 1992, 114, 3937. (d) Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. TL 1992, 33, 6611.
5. (a) Enders, D.; Meyer, O.; Raabe, G. S 1992, 1242. (b) Barluenga, J.; Aznar, F.; Valdes, C.; Martin, A.; Garcia-Granda, S.; Martin, E. JACS 1993, 115, 4403. (c) Döpp, D.; Pies, M. CC 1987, 1734. (d) Van den Broek, L. A. G. M.; Posskamp, P. A. T. W.; Haltiwanger, R. C.; Zwanenburg, B. JOC 1984, 49, 1691. (e) Van Elburg, P. A.; Honig, G. W. N.; Reinhoudt, D. N. TL 1987, 28, 6397. (f) Bäckvall, J.-E., Rise, F. TL 1989, 30, 5347. (g) Lamy-Schelkens, H.; Ghosez, L. TL 1989, 30, 5891. (h) Brouillard-Poichet, A.; Defoin, A.; Streith, J. TL 1989, 30, 7061. (i) Defoin, A.; Pires, J.; Tissot, I.; Tschamber, T.; Bur, D.; Zehnder, M.; Streith, J. TA 1991, 2, 1209. (k) Defoin, A.; Brouillard-Poichet, A.; Streith, J. HCA 1992, 75, 109.
6. (a) Enders, D.; Eichenauer, H. AG 1976, 93, 579. (b) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum, H.; Dörr, H.; Du Preez, N. P.; Ehrig, V.; Langer, W.; Nüssler, C.; Oei, H. A.; Schmidt, M. HCA 1977, 60, 301. (c) Enders, D.; Fey, P.; Kipphardt, H. OPP 1985, 17, 1.
7. (a) Enders, D.; Lotter, H. AG 1981, 93, 831. (b) Enders, D. In Current Trends in Organic Synthesis; Nozaki, H., Ed.; Pergamon: Oxford, 1983; p 151.
8. Enders, D.; Lotter, H.; Maigrot, N.; Mazaleyrat, J.-P.; Welvart, Z. NJC 1984, 8, 747. (b) Maigrot, Mazaleyrat, J.-P.; Welvart, Z. CC 1984, 40.
9. (a) Ahlbrecht, H.; Bonnet, G.; Enders, D.; Zimmermann, G. TL 1980, 21, 3175. (b) Ahlbrecht, H.; Enders, D.; Santowski, L.; Zimmermann, G. CB 1989, 122, 1995. (c) Ahlbrecht, H.; Sommer, H. CB 1990, 123, 829.
10. (a) Saimoto, H.; Houge, C.; Hesbain-Frisque, A. M.; Mockel, A.; Ghosez, L. TL 1983, 24, 2251. (b) Houge, C.; Frisque-Hesbain, A. M.; Ghosez, L. JACS 1984, 104, 2920.
11. (a) Chan, T. H.; Pellon, P. JACS 1989, 111, 8737. (b) Chan, T. H.; Wang, D. TL 1989, 30, 3041. (c) Lamothe, S.; Chan, T. H. TL 1991, 32, 1847. (d) Chan, T. H.; Nwe, K. T. JOC 1992, 57, 6107. (e) Lamothe, S.; Cook, K. L.; Chan, T. H.; CJC 1992, 70, 1733. (f) Hartley, R. C.; Lamothe, S.; Chan, T. H. TL 1993, 34, 1449.
12. (a) Fuji, K.; Node, M.; Nagasawa, H.; Naniwa, Y.; Terada, S. JACS 1986, 108, 3855. (b) Fuji, K.; Node, M.; Nagasawa, H.; Naniwa, Y.; Taga, T.; Machida, K.; Snatzke, G. JACS 1989, 111, 7921. (c) Fuji, K.; Node, M. S 1991, 603.
13. (a) Tamura, R.; Katayama, H.; Watabe, K.; Suzuki, H. T 1990, 46, 7557. (b) Tamura, R.; Watabe, K.; Katayama, H.; Suzuki, H.; Yamamoto, Y. JOC 1990, 55, 408. (c) Tamura, R.; Watabe, K.; Ono, N.; Yamamoto, Y. JOC 1992, 57, 4895.
14. (a) Bertz, S. H.; Dabbagh, G.; Sundararajan, G. JOC 1986, 51, 4953. (b) Dieter, R. K.; Tokles, M. JACS 1987, 109, 2040. (c) Dieter, R. K.; Lagu, B.; Deo, N.; Dieter, J. TL 1990, 31, 4105. (d) Quinkert, G.; Müller, T.; Königer, A.; Schultheis, O.; Sickenberger, B.; Dürner, G. TL 1992, 33, 3469. (e) Schultz, A. G.; Harrington, R. E. JACS 1991, 113, 4926. (f) Schultz, A. G.; Lee, H. TL 1992, 33, 4397. (g) Schultz, A. G.; Holoboski, M. A. TL 1993, 34, 3021. (h) Schultz, A. G.; Lee, H. TL 1993, 34, 4397.
15. Kitazume, T.; Ishikawa, N. JACS 1985, 107, 5186.
16. Hann, G. L.; Sampson, P. CC 1989, 1650.
17. Keim, W.; Köhnes, A.; Roethel, T.; Enders, D. JOM 1990, 382, 295.
18. Süss-Fink, G.; Jenke, T.; Heitz, H.; Pellinghelli, M. A.; Tiripicchio, A. JOM 1989, 379, 311.
19. Hendrie, S. K.; Leonard, J. T 1987, 43, 3289.

Dieter Enders & Martin Klatt

RWTH Aachen, Germany

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