Quinuclidines, chiral catalysts

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

This has become something of a standard reaction, since several authors have successfully used different chiral catalysts to effect the conversion in very high chemical and enantiomeric yield. Bergson and Langstrom (41) were the first to show that acrolein and a-isopropylacrolein added to 2-carbomethoxy-l-indanone (A in eq. [6]) in benzene in the presence of the strongly basic tertiary amine (/ )-( + )-2-(hydroxymethyl)quinuclidine to yield optically active ketoesters. Unfortunately, the quinuclidine catalyst was not enantiomerically pure, and neither the chemical nor the optical yields of the aldehydo ester analogous to B (eq. [6]) were reported. 

Early work from the McIntosh group [1 lh,85] and extensive research from the Dehmlow group [24e-i,48b] concerning chiral catalyst design is noted. Recently, Lygo and co-workers have reported short enantio- and diastereoselective syntheses of the four stereoisomers of 2-(phenylhydroxymethyl)quinuclidine. The authors report that these compounds, which contain the basic core structure of the cinchona alkaloids, will be examined as possible chiral control elements in a variety of asymmetric transformations [86]. 

The first chiral catalysts were developed from achiral molecules such as DABCO, quinuclidine, indolizine or pyrrolizine-derived catalysts by introducing asymmetric functions. Hirama and co-workers examined chiral C2-symmetric 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes such as 2,3-(dibenzoxymethyl)-DABCO (29) as catalysts for asymmetric MBH reaction between 4-nitro-benzaldehyde 27 and methyl vinyl ketone (MVK, 28) (Scheme 5.6) [57]. The additive function of the catalyst compared to the achiral DABCO resulted, however, in diminished reactivity, and the reaction required high pressure in order to... 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

The matching and mismatching of chiral olefin 54 and catalyst was examined briefly by using stoichiometric quantities of osmium tetroxide with achiral and chiral ligands [60], The monothio acetal derived from camphor (54) was dihydroxylated with osmium tetroxide in the presence of quinuclidine, DHQD-OAc, or DHQ-OAc, With the achiral quinuclidine as ligand, the ratio of (2S,3R) to (2R,3S) diasteriomers 55 and 56 was 2.5 1. With DHQD-OAc as the chiral ligand, catalyst and substrate are matched and the ratio is enhanced to 40 1 while with DHQ-OAc catalyst and substrate are mismatched and a reversed selectivity of 1 16 is observed. 

Using a chiral auxiliary via an amide or ester leads to asymmetric induction. Aryl aldehydes and conjugated ketones were condensed using proline, leading to modest enantioselectivity. °° Chiral biaryl catalysts have been used with trialkyl-phosphines, giving good enantioselectivity. ° Chiral quinuclidine catalysts lead to... 

Balan, D., Adolfsson, H. Chiral quinuclidine-based amine catalysts for the asymmetric one-pot, three-component aza-Baylis-Hillman reaction. Tetrahedron Lett, 2003, 44, 2521-2524. 

Standard reaction conditions. Catalysed reactions were conducted at 293 K in a Baskerville stainless steel reactor of volume 150 ml. 7.2 ml pyruvate ester (65 mmol) and alkaloid (0.17 mmol cinchonidine (50 mg) or 0.17 mmol quinuclidine (19 mg) or 0.17 mmol of each) were dissolved in 12.5 ml dichloromethane and added to the catalyst (250 mg) in the reactor. The reactor was operated at 30 bar in a constant pressure mode. Product analysis was by chiral gas chromatography to determine the enantiomeric excess (ee) and by GCMS to determine the masses of higher molecular weight products. 

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