[59983-39-0]  · C6H14N2O  · (S)-1-Amino-2-methoxymethylpyrrolidine  · (MW 130.19)

(chiral auxiliary; Enders' reagent; diastereo- and/or enantioselective alkylations,2,3 aldol reactions,4 Michael additions5 and reductive or alkylative aminations,6 resolutions,7 ee determinations8)

Alternate Name: SAMP.

Physical Data: bp 186-187 °C; d 0.977 g cm-3; n20D 1.4650; a20D -80 to -82° (neat).

Solubility: sol H2O, ether, dichloromethane.

Form Supplied in: colorless liquid or as crystalline colorless oxalate.

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

Since the pioneering times of the mid-1970s, (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) and its enantiomer RAMP have been among the most powerful 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 fragments9 (see also (S)-2-Methoxymethylpyrrolidine, SMP).

The procedure involves the transformation of carbonyl compounds to the corresponding SAMP or RAMP hydrazones, metalation, trapping of the intermediate azaenolates with various electrophiles, and either hydrazone cleavage (carbonyl compounds) or hydrazone reduction/N-N bond cleavage (amines).

The synthetic utility of the SAMP/RAMP hydrazone method is demonstrated in particular in the stereoselective alkylation of aldehyde2 and ketone3 SAMP/RAMP hydrazones. A great number of natural products have been synthesized using this method, like the principal alarm pheromone of the leaf cutting ant Atta texana (eq 1),3a the C(1)-C(15) segment of FK 506 (eq 2),2b the amino acid MeBMT (eq 3),2c and (-)-methyl kolavenate (eq 4).3b

2,2-Dimethyl-1,3-dioxan-5-one SAMP/RAMP hydrazones3f-j were used as dihydroxyacetonephosphate equivalents in the synthesis of C2 symmetric ketones (eq 5),3g aza sugars with novel substitution patterns,3h or C5 to C9 deoxy sugars.3i SAMP hydrazones of 2-oxo esters represent novel phosphoenolpyruvate (PEP) equivalents.3k,l a,a-Disubstituted spiroacetals are accessible via the alkylation of ketone SAMP/RAMP hydrazones.3m

The aggregation pheromone of Drosophila mulleri, (S)-2-tridecanol acetate, is obtainable by alkylation of propiophenone SAMP hydrazone followed by a Baeyer-Villiger reaction of the ketone (eq 6).3n

The relative and absolute configuration of Stigmatellin A, one of the most potent inhibitors of the electron transport chain, was determined via alkylation of diethyl ketone SAMP hydrazone.3o

The aldol reaction is the preferred method for the stereoselective synthesis of 1,3-dioxygenated building blocks. In 1978, Enders et al.4a,b reported the first enantioselective aldol reaction in the difficult case of a-unsubstituted b-ketols using SAMP and RAMP. Diastereo- and enantiomerically pure syn-b-ketols are available by aldol reaction of SAMP/RAMP hydrazones (eq 7).4c

The aggregation pheromone of the rice and maize weevil was synthesized by aldol reaction of an enantiomerically pure a-silyl ketone, obtained by the SAMP/RAMP hydrazone method,10a-d with various aldehydes (eq 8).4d

The utility of the SAMP/RAMP hydrazone method in dia-stereo- and enantioselective Michael additions was demonstrated in the synthesis of 5-oxo esters5a-e (eq 9),5b d-lactones (eq 10),5c,e,f oxo diesters and dinitriles,5g heterocyclic compounds (eq 11),5h MIRC (Michael initiated ring closure) reactions,5i and 2-substituted 4-oxo sulfones.5i

Organotin reagents can be added to cyclic a,b-unsaturated SAMP/RAMP hydrazones (eq 12).5k

Lithiated N-protected SAMP can be used as an ammonia equivalent in Michael and tandem Michael additions to a,b-unsaturated esters (eq 13).5l Furthermore, SAMP and RAMP can be employed for the asymmetric synthesis of a- and/or b-substituted primary amines with high regio-, diastereo-, and enantioselectivities.6 This variant involves hydrazone reduction with a subsequent N-N bond cleavage and can be combined with a prior a-alkylation, as described above.

This method was recently used in the synthesis of different natural products, like the ladybug defence alkaloid harmonine,6d a- and b-amino acetals and acids (eq 14),6e,f and both enantiomers of the hemlock alkaloid coniine,6g utilizing the nucleophilic 1,2-addition of organolithium and -lanthanoid reagents to SAMP/RAMP hydrazones.

The alkylation of SAMP/RAMP hydrazones with heteroelectrophiles leads to enantiomerically pure a-silyl aldehydes and ketones (eq 15),10a-d a-sulfenyl aldehydes and ketones (eq 16),10e and a-hydroxy aldehydes and ketones (eq 17).10f

These very interesting chiral building blocks are employed in aldol reactions,4d and in the synthesis of enantiomerically pure vicinal diols (eq 18)10g,h and 3-oxo esters and acids bearing quarternary stereogenic centers (eq 19).10i

Further applications can be mentioned briefly. SAMP was used in the resolution of 4-demethoxy-7-deoxydaunomycinone,7 in ee determinations (Scheme 1),8 as a chelate for tetracarbonylmolybdenum complexes,11 in intramolecular Heck reactions,12 as polysilylated hydrazine,13 in the enantioselective synthesis of isoquinuclidines,14 and in the conversion of hydrazones to aldehydes15 and nitriles.16 The structure of a chiral lithium SAMP hydrazone azaenolate has been determined.17 In cases where SAMP did not lead to satisfactory inductions, a modified auxiliary, (S)-1-amino-2-dimethylmethoxymethylpyrrolidine (SADP),18 enhanced the stereochemical control.

1. Reviews (literature up to 1987): (a) Enders, D. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, p 275. (b) Enders, D.; Fey, P.; Kipphardt, H. OS 1987, 65, 173, 183.
2. (a) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Dolle, R. E. JACS 1981, 103, 6967. (b) Kocienski, P.; Stocks, M.; Donald, D.; Cooper, M.; Manners, A. TL 1988, 29, 4481. (c) Beulshausen, T.; Groth, U. M.; Schöllkopf, U. JACS 1994, in press. (d) Enders, D.; Dyker, H. LAC 1990, 1107. (e) Schmidt, U.; Siegel, W.; Mundinger, K. TL 1988, 29, 1269. (f) Hauck, R. S.; Wegner, C.; Blumtritt, P.; Fuhrhop, J. H.; Nau, H. Life Sci. 1990, 46, 513. (g) Kündig, P.; Liu, R.; Ripa, A. HCA 1992, 75, 2657.
3. (a) Enders, D.; Eichenauer, H. AG 1979, 91, 425; AG(E) 1979, 18, 397. (b) Hideo, I.; Mitsugu, M.; Kimikazu, O.; Tokoroyama, T. CC 1987, 358. (c) Pennanen, S. I. ACS 1981, B35, 555. (d) Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M. T 1982, 38, 3705. (e) Fischer, J.; Kilpert, C.; Klein, U.; Steglich, W. T 1986, 42, 2063. (f) Enders, D.; Bockstiegel, B. S 1989, 493. (g) Enders, D.; Gatzweiler, W.; Jegelka, U. S 1991, 1137. (h) Enders, D.; Jegelka, U. SL 1992, 999. (i) Enders, D.; Jegelka, U.; Dücker, B. AG 1993, 105, 423; AG(E) 1993, 32, 423. (j) Enders, D.; Jegelka, U. TL 1993, 34, 2453. (k) Enders, D.; Dyker, H.; Raabe, G. AG 1992, 104, 649; AG(E) 1992, 31, 618. (l) Enders, D.; Dyker, H.; Raabe, G. SL 1992, 901. (m) Enders, D.; Gatzweiler, W.; Dederichs, E. T 1990, 46, 4757. (n) Enders, D.; Plant, A. LA 1991, 1241. (o) Enders, D.; Osborne, S. CC 1993, 424. (p) Sainsbury, M.; Williams, C. S.; Naylor, A.; Scopes, D. I. C. TL 1990, 31, 2763. (q) Sainsbury, M.; Mahon, M. F.; Williams, C. S.; Naylor, A.; Scopes, D. I. C. T 1991, 47, 4195. (r) Ziegler, F. E.; Becker, M. R. JOC 1990, 55, 2800. (s) Warshawsky, A. M.; Meyers, A. I. JACS 1990, 112, 8090. (t) Andersen, M. W.; Hildebrandt, B.; Hoffmann, R. W. AG 1991, 103, 90; AG(E) 1991, 30, 90. (u) Clark, J. S.; Holmes, A. B. TL 1988, 29, 4333. (v) Carling, R. W.; Curtis, N. R.; Holmes, A. B. TL 1989, 30, 6081. (w) Curtis, N. R.; Holmes, A. B.; Looney, M. G.; Pearson, N. D.; Slim, G. C. TL 1991, 32, 537. (x) Hart, T. W.; Guillochon, D.; Perrier, G.; Sharp, B. W.; Toft, M. P.; Vacher, B.; Walsh, R. J. A. TL 1992, 33, 7211.
4. (a) Enders, D.; Friedrich, E.; Lutz, W.; Pieter, R. AG 1978, 90, 219; AG(E) 1978, 17, 206. (b) Enders, D.; Eichenauer, H.; Pieter, R. CB 1979, 112, 3703. (c) Enders, D. Chem. Scr. 1985, 25, 139. (d) Enders, D.; Lohray, B. B. AG 1988, 100, 594; AG(E) 1988, 27, 581. (e) Enders, D.; Dyker, H.; Raabe, G. AG 1993, 105, 420; AG(E) 1993, 32, 421.
5. (a) Enders, D.; Papadopoulos, K. TL 1983, 24, 4967. (b) Enders, D.; Papadopoulous, K.; Rendenbach, B. E. M.; Appel, R.; Knoch, F. TL 1986, 27, 3491. (c) Enders, D.; Rendenbach, B. E. M. Pestic. Sci. Biotechnol., Proc. Int. Congr. Pestic. Chem., 6th 1986, 17. (d) Enders, D.; Rendenbach, B. E. M. T 1986, 42, 2235. (e) Enders, D.; Rendenbach, B. E. M. CB 1987, 120, 1223. (f) Tietze, L. F.; Schneider, C. JOC 1991, 56, 2476. (g) Enders, D.; Demir, A. S.; Rendenbach, B. E. M. CB 1987, 1731. (h) Enders, D.; Demir, A. S.; Puff, H.; Franken, S. TL 1987, 28, 3795. (i) Enders, D.; Scherer, H. J.; Raabe, G. AG 1991, 103, 1676; AG(E) 1991, 30, 1664. (j) Enders, D., Papadopoulos, K.; Herdtweck, E. T 1993, 49, 1821. (k) Enders, D.; Heider, K. AG 1993, 105, 592; AG(E) 1993, 32, 598. (l) Enders, D.; Wahl, H.; Bettray, W. AG 1995, 107, 527; AG(E) 1995, 34, 455.
6. (a) Enders, D.; Schubert, H.; Nübling, C. AG 1986, 98, 1118; AG(E) 1986, 25, 1109. (b) Denmark, S. E.; Weber, T.; Piotrowski, D. W. JACS 1987, 109, 2224. (c) Weber, T.; Edwards, J. P.; Denmark, S. E. SL 1989, 20. (d) Enders, D.; Bartzen, D. LAC 1991, 569. (e) Enders, D.; Funk, R.; Klatt, M.; Raabe, G.; Hovestreydt, E. R. AG 1993, 105, 418; AG(E) 1993, 32, 418. (f) Enders, D.; Klatt, M.; Funk, R. SL 1993, 226. (g) Enders, D.; Tiebes, J. LAC 1993, 173. (h) Denmark, S. E.; Nicaise, O. SL 1993, 359.
7. Dominguez, D.; Ardecky, R. J.; Cava, M. P. JACS 1983, 105, 1608.
8. (a) Günther, K.; Martens, J.; Messerschmidt, M. J. Chromatogr. 1984, 288, 203. (b) Effenberger, F.; Hopf, M.; Ziegler, T.; Hudelmeyer, J. CB 1991, 124, 1651. (c) Harden, R. C.; Rackham, D. M. J. High Resolut. Chromatogr. 1992, 15, 407.
9. (a) Enders, D.; Eichenauer, H. AG 1976, 93, 579. (b) Enders, D.; Fey, P.; Kipphardt, H. OPP 1985, 17, 1.
10. (a) Enders, D.; Bhushan, B. B. AG 1987, 99, 359; AG(E) 1987, 26, 351. (b) Enders, D.; Bhushan, B. B. AG 1988, 100, 594; AG(E) 1988, 27, 581. (c) Bhushan, B. B.; Enders, D. HCA 1989, 72, 980. (d) Bhushan, B. B.; Zimbinski, R. TL 1990, 31, 7273. (e) Enders, D.; Schäfer, T. publication in preparation. (f) Enders, D.; Bhushan, V. TL 1988, 29, 2437. (g) Enders, D.; Nakai, S. HCA 1990, 73, 1833. (h) Enders, D.; Nakai, S. CB 1991, 124, 219. (i) Enders, D.; Zamponi, A.; Raabe, G. SL 1992, 897.
11. Ehlers, J.; Tom Dieck, H. Z. Anorg. Allg. Chem. 1988, 560, 80.
12. Grigg, R.; Dorrity, M. J. R.; Malone, J. F.; Mongkolaussavaratana, T.; Norbert, W. D. J. A.; Sridharan, V. TL 1990, 31, 3075.
13. Hwu, J. R.; Wang, N. T 1988, 44, 4181.
14. (a) Mehmandoust, M.; Marazano, C.; Singh, R.; Cesario, M.; Fourrey, J. L.; Das, B. C. TL 1988, 29, 4423. (b) Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.; Das, B. C. SL 1992, 431.
15. Enders, D.; Bhushan V. Z. Naturforsch., Teil B 1987, 42B, 1595; Enders, D.; Plant, A. SL 1990, 725.
16. (a) Moore, J. S.; Stupp, S. I. JOC 1990, 55, 3374. (b) Enders, D.; Plant, A. SL 1994, 1054.
17. Enders, D.; Bachstädter, G.; Kremer, K. A. M.; Marsch, M.; Harms, K.; Boche, G. AG 1988, 100, 1580; AG(E) 1988, 27, 1522.
18. Enders, D.; Kipphardt, H.; Gerdes, P.; Breña-Valle, J.; Bushan, V. Bull. Soc. Chim. Belg. 1988, 97, 691. Applications: (a) Enders, D.; Müller, S.; Demir, A. S. TL 1988, 29, 6437. (b) Enders, D.; Dyker, H.; Raabe, G. AG 1993, 105, 420; AG(E) 1993, 32, 421. (c) Enders, D.; Bhushan, V. TL 1988, 29, 2437.

Dieter Enders & Martin Klatt

RWTH Aachen, Germany

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