(2S,2S)-2-Hydroxymethyl-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine1

[66283-23-6]  · C11H22N2O  · (2S,2S)-2-Hydroxymethyl-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine  · (MW 198.35)

(chiral ligand for alkyllithium,2 dialkylmagnesium,3 alkynyllithium,4 and functionalized organolithiums5 in the enantioselective addition to aldehydes; accelerates the basicity of alkyllithiums;5 catalyzes the addition of dialkylzinc to aldehyde2)

Physical Data: bp 112 °C/4.5 mmHg; [a]28D -130° (c 0.36, EtOH).

Solubility: sol hexane, toluene, Me2O, Et2O, n-Pr2O, THF, dimethoxymethane.

Preparative Method: reduction of N-[N(-benzyloxycarbonyl)prolyl]proline methyl ester with Lithium Aluminum Hydride affords the title reagent in 81% yield.

Enantioselective Addition of Alkyllithium Reagents to Aldehydes.

(2S,2S)-2-Hydroxymethyl-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine (1) is a chiral amino alcohol which binds well to alkyllithium reagents.2 Enantioselective addition of n-Butyllithium to benzaldehyde in the presence of (1) in a mixed solvent of Me2O and dimethoxymethane (DMM) (1:1) at -123 °C affords (S)-1-phenylpentan-1-ol with 95% ee in 77% yield.2 In the addition to 3-methylbutanal, the corresponding (S)-alcohol is obtained in 80% ee (eq 1).

These ee's are higher than those of the preceding reports1a and are comparable with those of the reports appearing afterwards.1b,c It should be noted that the absolute configuration of the alcohol obtained in the addition of EtLi to PhCHO depends on the solvent employed [(R): EtOH; (S): DMM]. The sense of the enantioselectivity of the addition of Methyllithium is opposite to that of BuLi. When the derivative of (1) possessing a neopentyl group (2) is used in the addition of MeLi to PhCHO, (R)-1-phenylethanol with 86% ee is obtained in 82% yield.2b

Enantioselective Addition of Dialkylmagnesium to Aldehydes.

Amino alcohol (1) is a chiral ligand for dialkylmagnesium reagents in the enantioselective addition to aldehydes.3 Reaction of Et2Mg with PhCHO in the presence of (1) in toluene at -110 °C affords (R)-1-phenylpropan-1-ol with 92% ee in 74% yield. When n-Bu2Mg is employed, (R)-1-phenylpentan-1-ol with 88% ee is obtained in 94% yield. It should be noted that the sense of the enantioselectivity of n-Bu2Mg-(1) is opposite to that of n-BuLi-(1) (eq 2).

Enantioselective Addition of Alkynyllithium to Aldehydes.

The enantioselective addition of alkynyllithium to aldehydes in the presence of (1) provides optically active propargylic alcohols. (S)-1-Phenyl-2-propyn-1-ol with 92% ee is obtained in 87% yield from the enantioselective addition of Lithium (Trimethylsilyl)acetylide to PhCHO in the presence of (1) and the subsequent removal of the Me3Si group (eq 3).4a

Optically active aliphatic propargylic alcohols are converted to corticoids (90% ee) via biomimetic polyene cyclization,4b and to 5-octyl-2(5H)-furanone.4c The ee's of propargylic alcohols obtained by this method are comparable with those of the enantioselective reduction of alkynyl ketones with metal hydrides,6 catalytic enantioselective alkylation of alkynyl aldehydes with dialkylzincs using a chiral catalyst ((S)-Diphenyl(1-methylpyrrolidin-2-yl)methanol) (DPMPM),7a and the enantioselective alkynylation of aldehydes with alkynylzinc reagents using N,N-dialkylnorephedrines.7b,c

Enantioselective Addition of Functionalized Organolithiums to Aldehydes.

Amino alcohol (1) is a chiral ligand for various functionalized organolithiums derived from acetonitrile and N-nitrosodimethylamine (eq 4).

An optically active b-hydroxy nitrile with 40% ee is obtained from the reaction of LiCH2CN with PhCHO in the presence of (1).5 The same compound with higher ee (93% ee) is obtained using cyanomethylzinc bromide and the chiral ligand DPMPM.8

Amino alcohol (1) accelerates the basicity of BuLi. Thus methyl phenyl sulfide is deprotonated by BuLi in the presence of (1) to afford PhSCH2Li. Deprotonation does not occur without (1). Enantioselective addition of PhSCH2Li to PhCHO using (1) affords an optically active b-hydroxy sulfide, which is converted to (R)-2-phenyloxirane with 68% ee.5

Addition of Diethylzinc to Benzaldehyde.

The addition of Diethylzinc to PhCHO without added catalysts is very sluggish. Amino alcohol (1) acts as a catalyst precursor for the addition of Et2Zn to PhCHO under mild conditions to afford 1-phenylpropan-1-ol in 76% yield (eq 5).2b,3 Although the obtained alcohol is racemic, the result of the addition of Et2Zn to PhCHO in the presence of amino alcohol (1) led to the recently developed highly enantioselective addition of Et2Zn to PhCHO using chiral amino alcohols.1b,c


1. (a) Solladié, G. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1983; Vol. 2, pp 157-199. (b) Soai, K.; Niwa, S. CRV 1992, 92, 833. (c) Noyori, R.; Kitamura, M. AG(E) 1991, 30, 49.
2. (a) Mukaiyama, T.; Soai, K.; Kobayashi, S. CL 1978, 219. (b) Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. JACS 1979, 101, 1455.
3. Sato, T.; Soai, K.; Suzuki, K.; Mukaiyama, T. CL 1978, 601.
4. (a) Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. CL 1979, 447. (b) Johnson, W. S.; Frei, B.; Gopalan, A. S. JOC 1981, 46, 1512. (c) Mukaiyama, T.; Suzuki, K. CL 1980, 255.
5. Soai, K.; Mukaiyama, T. BCJ 1979, 52, 3371.
6. Brinkmeyer, R. S.; Kapoor, V. M. JACS 1977, 99, 8339.
7. (a) Soai, K.; Niwa, S. CL 1989, 481. (b) Niwa, S.; Soai, K. JCS(P1) 1990, 937. (c) Tombo, G. M. R.; Didier, E.; Loubinoux, B. SL 1990, 547.
8. Soai, K.; Hirose, Y.; Sakata, S. TA 1992, 3, 677.

Kenso Soai

Science University of Tokyo, Japan



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