(1S,9S)-1,9-Bis{[(t-butyl)dimethylsilyloxy]methyl}-5-cyanosemicorrin1

(1; R = CH2OSiMe2-t-Bu)

[105251-52-3]  · C24H45N3O2Si2  · (1S,9S)-1,9-Bis{[(t-butyl)dimethylsilyloxy]methyl}-5-cyanosemicorrin  · (MW 463.81) (2; R = CMe2OH)

[105251-53-4]  · C16H25N3O2  · (1S,9S)-1,9-Bis[(1-hydroxy-1-methyl)ethyl]-5-cyanosemicorrin  · (MW 291.39) (3; R = CO2Me)

[105251-49-8]  · C14H17N3O4  · Dimethyl (1S,9S)-5-cyanosemicorrin-1,9-dicarboxylate  · (MW 291.31)

(chiral ligands for enantiocontrol of metal-catalyzed reactions such as cobalt-catalyzed conjugate reduction of a,b-unsaturated carboxylic esters and amides or copper-catalyzed cyclopropanation of alkenes)1

Physical Data: (1) mp 75-76 °C, [a]D -64.7° (c 1.0, CHCl3 at rt); (2) mp 162 °C, [a]D -82.0°; (3) mp 78-79 °C, [a]D -145°.

Solubility: insol H2O; (1) sol in all common organic solvents, including n-hexane; (2) and (3) sol CH2Cl2, alcohol, THF, and EtOAc, insol hexane, slightly sol diethyl ether.

Form Supplied in: white crystalline solid; (1) and (3) are commercially available.

Handling, Storage, and Precautions: as crystalline solids, semicorrins of this type are stable at ambient temperature; for longer periods, storage at -20 °C is recommended.

Preparation of Semicorrin Ligands and Metal Complexes.

The crystalline diesters (S,S)-(-)-(3) and (R,R)-(+)-(3) are readily synthesized in enantiomerically pure form starting from L-pyroglutamic acid (-)-(4) or its enantiomer (eq 1).2 By selective transformation of the ester groups, a wide range of semicorrin derivatives with different substituents at the stereogenic centers is accessible.2,3 Among the various derivatives that have been prepared, semicorrins (1) and (2) proved to be the most versatile ligands for the stereocontrol of metal-catalyzed reactions.

Semicorrins form stable chelate complexes with a variety of metal ions such as CoII, RhI, PdII, or CuII. Depending on the metal ion, the ligand structure, and the reaction conditions, mono- or bis(semicorrinato) complexes are obtained.2,3

Enantioselective Conjugate Reduction of a,b-Unsaturated Carboxylic Esters and Amides.

Cobalt semicorrin complexes are highly efficient catalysts for the reduction of electrophilic C=C bonds, using Sodium Borohydride as reducing agent.1 In the presence of 0.1-1 mol % of catalyst, formed in situ from Cobalt(II) Chloride and ligand (1), esters of b-disubstituted a,b-unsaturated carboxylic acids are cleanly reduced to the corresponding saturated esters in essentially quantitative yield and with high enantioselectivity.1,3b,4 The best results are obtained in a mixture of ethanol and a polar aprotic solvent such as DMF or diglyme under careful exclusion of oxygen. The reduction of ethyl geranate (eq 2) and the corresponding (Z) isomer (eq 3) are typical examples. Both reactions lead to ethyl citronellate with 94% ee. Depending on the double bond geometry, either the (R) or (S) enantiomer is obtained. The isolated double bond is inert under these conditions. During aqueous workup, the chiral ligand (3) forms a catalytically inactive bis(semicorrinato)cobalt(II) complex, and can be recovered by decomplexation with acetic acid.

Even higher selectivities approaching 99% ee have been obtained with primary and secondary carboxamides (eqs 4 and 5).5 With substrates of this type, the catalyst system can undergo more than 5000 turnovers without significant loss of selectivity. An analogous diene-carboxamide was found to react with high regio- and enantioselectivity to give the corresponding g,d-unsaturated amide with a preference of >95:5 over the a,b-unsaturated isomer (eq 5). Tertiary carboxamides react rather sluggishly and with distinctly lower selectivity. The method cannot be applied to a,b-unsaturated ketones because the uncatalyzed nonstereoselective reaction with NaBH4 proceeds at a similar rate as the cobalt-catalyzed process.

Deuteration experiments showed that the b-H atom in the product stems from borohydride whereas the a-H atom is introduced by proton transfer from ethanol.3b Formation of the a-(C-H) bond is nonstereoselective; accordingly, the reduction of analogous substrates with an a- instead of a b-disubstituted double bond leads to racemic products (a mechanistic model rationalizing the stereoselectivity of (semicorrinato)cobalt catalysts is available1).

Enantioselective Cyclopropanation of Alkenes.

Semicorrin copper complexes catalyze the reaction of diazo compounds with alkenes leading to optically active cyclopropanes.1,6 The highest enantiomeric excesses have been obtained with the bulky ligand (2). The stable crystalline bis(semicorrinato)copper(II) complex (5) serves as a convenient catalyst precursor. The actual catalyst, which is presumed to be a mono(semicorrinato)copper(I) complex, is generated in situ by heating in the presence of the diazo compound or by reduction with Phenylhydrazine at rt. Alternatively, the catalyst can be prepared from the free ligand and Copper(I) t-Butoxide. Reactions are usually carried out at rt in an apolar solvent such as dichloroethane using 1 mol % of catalyst. The best results are obtained with terminal alkenes or dienes and certain 1,2-disubstituted alkenes which react with alkyl diazoacetates to give the corresponding cyclopropanecarboxylates with high enantioselectivity (eqs 6-8). The relatively poor trans/cis selectivity is a general problem which is also encountered with other catalysts.7 Recently, even higher enantiomeric excesses have been achieved with substrates of this type, using cationic CuI complexes of C2-symmetric bis(oxazolines) (6) (see (S,S)-2,2-(Dimethylmethylene)bis(4-t-butyl-2-oxazoline)) or 5-aza-semicorrins (7).1,8

(Semicorrinato)copper catalysts have also been used for intramolecular cyclopropanation reactions of alkenyl diazo ketones (eqs 9 and 10).9 In this case the (semicorrinato)copper catalyst derived from complex (5) proved to be superior to related methylene-bis(oxazoline)copper complexes. Interestingly, analogous allyl diazoacetates react with markedly lower enantioselectivity under these conditions, in contrast to the results obtained with chiral RhII complexes which are excellent catalysts for intramolecular cyclopropanations of allyl diazoacetates but give poor enantioselectivities with alkenyl diazo ketones (see Dirhodium(II) Tetrakis(methyl 2-pyrrolidone-5(S)-carboxylate)).7 Moderate enantioselectivities in the reactions shown in eqs 9 and 10 have been reported for (salicylaldiminato)copper catalysts (77% and 34% ee, respectively).10


1. (a) Pfaltz, A. ACR 1993, 26, 339. (b) Pfaltz, A. In Modern Synthetic Methods; Scheffold, R., Ed.; Springer: Berlin, 1989; pp 199-248.
2. Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A.; Keller, W.; Kratky, Ch. HCA 1988, 71, 1541.
3. (a) Fritschi, H. Dissertation, ETH-Zürich, No. 8951, 1989. (b) Leutenegger, U. Dissertation, ETH-Zürich No. 9091, 1990.
4. Leutenegger, U.; Madin, A.; Pfaltz, A. AG 1989, 101, 61; AG(E) 1989, 28, 60.
5. (a) von Matt, P.; Pfaltz, A. TA 1991, 2, 691. (b) von Matt, P. Dissertation, University of Basel, 1993.
6. Fritschi, H.; Leutenegger, U.; Pfaltz, A. HCA 1988, 71, 1553.
7. Doyle, M. P. RTC 1991, 110, 305.
8. Leutenegger, U.; Umbricht, G.; Fahrni, Ch.; von Matt, P.; Pfaltz, A. T 1992, 48, 2143.
9. C. Piqué, Dissertation, University of Basel, 1993.
10. Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H. P. TL 1990, 31, 6969.

Andreas Pfaltz

University of Basel, Switzerland



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