Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Catalyse Moléculaire - LCM

HENRI B. KAGAN


Professeur Emerite
Equipe de Catalyse Moléculaire-ICMMO - Bât 420
Université Paris-Sud 11
15, rue Georges Clemenceau
91405 Orsay Cedex
FRANCE

Tel : +33 1.69.15.78.95
Fax : +33 1.69.15.46.80
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Past Research
The main results for the last 15 years will be briefly detailed here, for the previous work see refs 1-135 in " Publications ".

Divalent lanthanides

We described in 1977 a mild preparation of diodosamarium (ref. 94) and subsequently studied the main patterns of reactivity of this new reagent in organic chemistry (refs 117, 123-125, 128, 134, 135). More recently we have focussed our research on specific reactions, for example the reactions given by acid chlorides or P-Cl compounds (refs 125, 137, 179, 184). The evaluation of the divalent derivatives (SmCp2, SmBr2 or SmCl2) has also been performed. It was found that some quite stable organosamariums could be generated in THF from SmCp2 and benzylic or allylic halides (refs 182,194). These organosamariums may react with various electrophiles. Their low basicities made possible 1,2-addition on ketones prone to enolization. Dibromosamarium is an excellent reagent for the pinacolization of aliphatic ketones (ref. 204).

The reactivity of SmI2 in various solvents (nitriles, THP) has been investigated. THP allows interesting chemistry, not possible in THF, because it is a poorer H-donor and it is also more stable towards acid chlorides (refs 237, 246).

The mechanism of the samarium Barbier reaction has been clarified (ref. 232). It was established that the C-C coupling involves a reactive organosamarium and not a radical coupling as initially proposed.

The catalytic effect of NiI2 on the enhancement of reactivity of SmI2 for various organic transformations has been discovered (ref. 236). In many cases it avoids the addition of HMPA to the THF solutions of diiodosamarium. Some new reactions are now possible by this procedure, such as the nucleophilic acylation of esters (ref. 236). This process involves the treatment of a mixture of an acid chloride and an ester by SmI2 in presence of a catalytic amount of NiI2. A mixed enediolate is formed in situ which can be quenched by various electrophiles. For example, protonolysis gives mixed ?-ketols.

Trivalent lanthanides

Some samarium(III) alkoxides (prepared in various ways with the help of SmI2) are good catalysts for Meerwein-Ponndorf-Verley-Oppenauer reactions (refs 141,158). They nicely catalyze the terminal epoxide rearrangement into methyl ketones (ref. 149). It was also discovered that some lanthanide(III) complexes are good catalysts for aldol addition, cyanohydrin forming and oxirane ring opening reactions (refs 162,164)..

Chiral phosphines : synthesis and use in asymmetric catalysis

This is a topic in our group which has remained under investigation since our initial report in 1971 of the diop synthesis.

Some chiral diphosphines with an additional Lewis acid center have been synthetized with the hope of increasing the enantioselectivity of hydrogenation of alkenes bearing a basic group located at some distance from the double bond. In this perspective boradiop, a boron analog of diop has been prepared as well as 6-endo-hydroxynorphos (refs 197,203). Various chiral hydroxyphosphines were later elaborated, the hydroxyl group allowing the introduction of a Lewis acid center (B, Al, etc).

Asymmetric synthesis of sulfoxides

IIn 1984 we discovered an efficient enantioselective oxidation of sulfides to sulfoxides by t-BuOOH, in the presence of a stoichiometric amount of a water-modified Sharpless reagent (refs 136,139). This method has been improved greatly, especially using cumyl hydroperoxide, giving up to 99% ee in many cases (refs 209,223). A catalytic version has been realized with another titanium complex obtained by the combination Ti(O-iPr)4/DET/iPrOH=1:4:4, in presence of molecular sieves (refs 229,134), giving ees up to 90-94%.

Another route to chiral, sulfoxides was based on the preparation of a chiral cyclic sulfite easily obtained in two steps from ethyl lactate (ref. 196). The sequential addition of two different organometallics on the sulfite generate sulfoxides with very high ee's. This method is especially convenient to prepare t-alkyl sulfoxides.

Asymmetric synthesis of ferrocenes with planar chirality

Two methods have been developed based on a diastereoselective orthometallation of some monosubstituted ferrocenes possesing a chiral auxiliary (with ortho-directing properties).

In the chiral acetal route, ferrocene carboxaldehyde was transformed into the acetal of (S)-1,2,4-butanetriol. The CH2OH and ferrocenyl groups are 1,3-cis to each other in the metadioxane ring. The CH2OH group was transformed into CH2OMe which acts as a powerful ortho-directing group. Deprotonation at -78°C and electrophilic quenching, followed by hydrolysis provided orthosubstituted ferrocene carboxaldehydes (>98% ee). The stereochemistry of the reaction has been clarified. This method has been applied to the synthesis of many enantiopure ferrocenes carboxaldehydes with planar chirality (refs 200,239). These orthosubstituted ferrocene carboxaldehydes are themselves good starting material for the synthesis of more complex molecules. For example, chiral ferrocenyl carbocations have been synthesized and used as Lewis acid catalyst (ref. 235).

The sulfoxide route was another original approach to produce enantiomerically pure 1,2-disubstituted ferrocenes. In the first step ferrocene sulfoxides Fc-S(O)-R were prepared with high ee by asymmetric synthesis. For R=t-Bu or Ph asymmetric oxidation of the corresponding sulfide was applied, if R=p-Tol asymmetric oxidation or the Andersen may be used. Deprotonation by LDA is highly diastereoselective (refs 199,243). It was found that orthosubstituted p-tolyl sulfoxide reacted at sulfur, releasing a lithio orthosubstituted ferrocene which could be quenched by an electrophile. In this way many 1,2-disubstituted ferrocenes (>98% ee) were prepared in moderate to good yields (ref. 243).

Catalytic asymmetric reduction of ketones

Trialkoxysilanes (HSi(OMe)3 or HSi(OEt)3) were used to reduce various prochiral ketones in presence of the monolithio salt of binol which acted as a catalyst (5% eq). Enantiomeric excesses up to 90% have been observed (ref. 238). It is very likely the reaction proceeds through a hypervalent silicon intermediate.

Various hydroxythiols have been screened as catalyst for the borane reduction of acetophenone, catalytic activity is good but the enantioselectivity is moderate (ref. 247)..

Nonlinear effects in asymmetric catalysis

In 1986 we discovered the first examples of nonlinear effects in asymmetric catalysis, where there was no proportionality between the ee of the auxiliary and the ee of product (ref.155). We subsequently gave some mathematical models to discuss these effects (ref. 211). The nonlinear effect (NLE) originates from the formation of diastereomeric species when the chiral auxiliary is not enantiomerically pure, either inside or outside the catalytic cycle. We classified the observed effects as (+)-NLE and (-)-NLE where "asymmetric amplification" and "asymmetric depletion" respectively occured. We used NLEs as "indicators" to follow the tuning of a chiral catalyst (ref. 244).

The notion of the NLE has been extended to a case where two different catalysts (pseudo-enantiomers) give rise to products of opposite configuration (ref. 224). Finally, the situation where an enantiomerically impure reagent has been used was investigated (Ipc2BCl + acetophenone) (refs 220, 240). As the concentration of reagent varies with the conversion the ee of the products becomes a function of both the relative amounts of reagent/substrate and conversion.

Nonlinear effects are now widely used in asymmetric catalysis as a mechanistic tool. We published in 1998 a large review article covering the first ten years of investigation on NLE (ref. 23 in " Reviews and Books "). For more recent reviews see refs 25, 26, the special case of asymmetric amplification has been also considered (ref. 22)

Asymmetric synthesis : miscellaneous

A one-pot multi-substrate screening for asymmetric catalysis has been described (ref. 241).

The conceptual aspects of tandem asymmetric reactions on a substrate with two prochiral centers has been discussed and illustrated by asymmetric hydrogenation of bisdehydrodipeptides (ref. 211).