[64030-44-0]  · C11H16N2  · (S)-2-(Anilinomethyl)pyrrolidine  · (MW 176.25)

(chiral ligand of LiAlH4 for enantioselective reduction of ketones;2 can form chiral aminals for diastereoselective alkylation,3,4 1,2-,5 and 1,4-additions6)

Physical Data: bp 111-112 °C/0.55 mmHg; [a]24D +19.7° (c 1.04, EtOH).

Solubility: sol ether, THF.

Form Supplied in: colorless oil.

Preparative Methods: reaction of (S)-N-(benzyloxycarbonyl)proline with (1) ethyl chloroformate and N-methylmorpholine, (2) aniline, (3) hydrogenolysis with Pd/C, and (4) reduction with LiAlH4 affords the title compound in 59% overall yield.2b

Enantioselective Reduction of Ketones.

(S)-2-(Anilinomethyl)pyrrolidine (1) is a chiral ligand which, in combination with Lithium Aluminum Hydride, generates a chiral reagent for the enantioselective reduction of ketones. (S)-1-Phenylethanol with 92% ee is obtained from the enantioselective reduction of acetophenone with LiAlH4-(1) (eq 1).2a,b When (S)-2-(2,6-xylidinomethyl)pyrrolidine is used instead of (1), the ee of the alcohol obtained reaches 95%.2c The ee's of aromatic alcohols obtained using LiAlH4-(1) are comparable with other highly enantioselective reductions1 and with highly enantioselective alkylation of aldehydes.7

Diastereoselective Alkylation of Chiral Keto- and Formylaminals.

Diamine (1) forms a chiral ketoaminal by condensation with phenylglyoxal monohydrate. Diastereoselective addition of a Grignard reagent to the ketoaminal and subsequent hydrolysis affords optically active t-a-hydroxyaldehydes with >94% ee (eq 2).3a Various a-hydroxyaldehydes are synthesized by this method.3b Diastereoselectivities are comparable with those of the reactions of chiral 1,3-oxathiane.8

The method has been applied to the diastereoselective synthesis of naturally occurring compounds such as frontalin (84-100% ee)3c and (-)-malyngolide (95% ee).3d On the other hand, diastereoselective alkylation of chiral formylaminal with Grignard reagents and the subsequent hydrolysis afford optically active S-a-hydroxyaldehydes with moderate stereoselectivity (60% ee).4

Diastereoselective 1,2- and 1,4-Additions of Chiral Aminals.

The organolithium reagent derived from a chiral bromoaminal and BuLi adds to pentanal to afford an optically active lactol. Subsequent oxidation affords the optically active lactone with 88% ee (eq 3).5

Diastereoselective 1,4- (conjugate) additions of Grignard reagents to a chiral a,b-unsaturated aminals afford optically active 3-substituted succinaldehydic acid methyl esters with 85-93% ee (eq 4).6

Related Reagents.

(2S,4S)-2-(Anilinomethyl)-1-ethyl-4-hydroxypyrrolidine; (R,R)-1,2-Diphenyl-1,2-diaminoethane N,N-Bis[3,5-bis(trifluoromethyl)benzenesulfonamide]; (2S,2S)-2-Hydroxymethyl-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine.

1. Grandbois, E. R.; Howard, S. I.; Morrison, J. D. In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 2, Chapter 3.
2. (a) Mukaiyama, T,; Asami, M.; Hanna, J.; Kobayashi, S. CL 1977, 783. (b) Asami, M.; Ohno, H.; Kobayashi, S.; Mukaiyama, T. BCJ 1978, 51, 1869. (c) Asami, M.; Mukaiyama, T. H 1979, 12, 499.
3. (a) Mukaiyama, T.; Sakito, Y.; Asami, M. CL 1978, 1253. (b) Mukaiyama, T.; Sakito, Y.; Asami, M. CL 1979, 705. (c) Sakito, Y.; Mukaiyama, T. CL 1979, 1027. (d) Sakito, Y.; Tanaka, S.; Asami, M.; Mukaiyama, T. CL 1980, 1223.
4. Asami, M.; Mukaiyama, T. CL 1983, 93.
5. Asami, M.; Mukaiyama, T. CL 1980, 17.
6. Asami, M.; Mukaiyama, T. CL 1979, 569.
7. Soai, K.; Niwa, S. CRV 1992, 92, 833.
8. Eliel, E. L.; Koskimies, J. K.; Lohri, B. JACS 1978, 100, 1614.

Kenso Soai

Science University of Tokyo, Japan

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