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Nonlinear Effects in Asymmetric Catalysis: a Personal Account Henri B 888 ACCOUNT Nonlinear Effects in Asymmetric Catalysis: A Personal Account Henri B. Kagan Laboratoire de Synthèse Asymétrique (ESA 8075), Institut de Chimie Moleculaire d’Orsay, Université Paris-Sud, 91405 Orsay, France Fax+33-1-69-15-46-80; E-mail: [email protected] Received 7 April 2001 Dedicated to Professor R. Noyori for his fundamental contributions to organic chemistry and asymmetric catalysis. of diastereomeric aggregate formation). Uskokovic et al. Abstract: The discovery of nonlinear effects (NLE) is recalled, and the main features of NLE are described. The origin of the nonlinear discovered that the nmr spectrum of dihydroquinine race- effects is discussed. The asymmetric amplification is especially mic or enantiopure are not identical, because of diastereo- 14 considered. The concept on nonlinear effects has been extended to meric solute-solute interactions. Horeau and Guetté pseudo-enantiomeric catalysts, to chiral reagents and to kinetic res- discussed in details in 1974 the diastereomeric interac- olution. The use of NLE as a mechanistic tool is underlined. tions in solution between enantiomers.15 In 1976 Wynberg Key words: asymmetric amplification, asymmetric catalysis, and Feringa demonstrated that some diastereoselective re- asymmetric depletion, asymmetric synthesis, chiral auxiliary, non- actions can give a different stereochemical outcome if the linear effects substrates are not enantiomerically pure.16 The authors called this effect “antipodal interaction effect”, it is relat- ed to non-bonded interactions. 1 Introduction In 1985 I was invited by Prof. Agami to give a seminar in Université Paris VI. After my lecture I discussed with This article does not intend to detail the area of nonlinear Prof. Agami, and he tell me that he was investigating the effects for which already exist many review articles in mechanism of the Hajos-Parrish-Wiechert aldol cyclisa- journals or books.1-7 I would like to explain how we en- tion of triketone 3 into ketol 4.17,18 The mechanistic details tered in that field, and what were the early investigations were unknown at that time. The Agami group interesting- as well as the main subsequent developments. ly discovered that the reaction was second-order with the 19,20 I became involved in asymmetric catalysis in the late six- catalyst. This means that two proline molecules were presumably involved in the reaction, as described for 5. I ties, when we developed the use of C2-symmetric chiral diphosphines such as (–)-diop 1.8,9 We also looked at suggested to use non-enantiopure proline to get an addi- some monophosphines, which gave much less enantiose- tional indication of the participation of two proline mole- lective catalysts than camp 2.10 At that time I considered cules. The experiments were quickly done, showing what could be the behaviour of a rhodium catalyst with a values of ee for ketol 4 lower than expected by applying non-enantiopure ligand. I suspected some complications the usual rule eq. 1 which relates ee of product (eeprod) and for the monodentate phosphines, since two ligands are in- ee of auxiliary (eeaux). volved possibly giving rise to diastereomeric catalysts.11 We checked that with diop 1 of 50% ee the asymmetric ee =ee ee hydrogenation of (Z)-N-acetyl-dehydrophenylalanine prod max aux gave N-acetylphenylalanine with exactly half of the value Equation 1 observed with enantiopure diop (40% ee versus 80% ee). We envisaged to investigate the behaviour of some non- enantiopure monophosphines, but the project was stopped In eq. (1) eemax is the ee value of product observed by because of lack of easily available enantioselective mono- using enantiopure catalyst. phosphines. However, I remained convinced that the ac- Simultaneously, we investigated the asymmetric sulfoxi- cumulation of chiral ligands in a catalyst should dation 6 ® 7 by changing the enantiomeric excess of di- sometimes give unpredictible results if the initial material ethyl tartrate.21 There was a significant departure to is not enantiopure. I worked until 1968 in the laboratory linearity, especially when DET was below 70% ee. The of Prof. Horeau in College of France, and I kept contact sulfoxide 7 had an ee much lower than that calculated with him later, then I was aware of the literature dealing from eq. 1. Finally the Sharpless epoxidation of geraniol with diastereomeric associations in solution. For example 8 was checked and gave an epoxide 8 of higher ee than Horeau clearly demonstrated that optical purity (mea- predicted from eq. 1. We decided with Prof. Agami to sured by polarimetry) and enantiomeric excess (measured write a joint paper which was published in 198625 (see by any reliable method) are not always equivalent.13 The section 2). departure to linearity occurs when the solvent favours au- toassociations of the chiral solute. This has been well es- tablished with 2-ethyl 2-methyl succinic acid, which gave an important deviation to linearity in chloroform (because Synlett 2001, No. SI, 888–899 ISSN 0936-5214 © Thieme Stuttgart · New York ACCOUNT Nonlinear Effects in Asymmetric Catalysis: A Personal Account 889 Me 2 Nonlinear effects H OMe O PPh P 2 The three curves obtained in the 1986 paper are repro- PPh O 2 duced in Scheme 2. The departure to the straight line com- H 1 2 puted by eq. 1 is significant, although not very high. However it was enough to clearly show a breaking of the proportionality rule as described by eq. 1. In conclusion there are three possibilities of curves when plotting ee O O prod versus ee of chiral auxiliary (eemax), as indicated in 1% (S)-proline Scheme 3. We soon introduced a vocabulary to define the O O departure to the linearity in the graph eeprod = f(eeaux). The O HO 3 O 4 curve above the straight line was said to characterise a positive nonlinear effect, abbreviated as (+)-NLE. This is to recall that the size of the enantiomeric excess (in abso- N O lute sense) is higher than the value calculated by eq. 1 5 H (|eeprod|> |eelinear|]. When the curve is below the straight CO2 H line (|eeprod|< |eelinear|], the phenomenon was called nega- N CO2H tive nonlinear effect [(–)-NLE]. We used this vocabulary since 198726, we learned that Mikami et al. independently 27 O proposed the same convention. For conveniency we S S draw the graphs as indicated in Scheme 3, whatever are Me t-BuOOH Me the absolute configurations of the product or of the chiral 28 Me Ti(Oi-Pr)4/(+)-DET/H2O Me auxiliary. = 1:2:1 67After our 1986 paper, there were no other reports in that area, until a publication of Oguni et al. in 1988 which de- O t-BuOOH scribed a strong positive nonlinear effect in the addition of OH OH diethylzinc on benzaldehyde catalyzed by PDB 12 30 Ti(Oi-Pr)4/(+)-DET (Scheme 4). The authors proposed to use the expression = 1:1 “asymmetric amplification” as synonymous of (+)-NLE. We later similarly introduced the expression “asymmetric depletion” as equivalent to (–)-NLE.29 In 1989, R. Noyori 8 9 et al. published an important paper where the formation of Scheme 1 11 was catalysed by DAIB 13.31 The size of the asymmet- ric amplification was impressive : for example 13 of 15% ee gave product 11 in 95% ee, not too far from the maxi- mum value of 98% ee with the enantiopure catalyst. The paper also afforded some mechanistic investigations al- lowing to discuss of the origin of the nonlinear effect (vide Biographical Sketch Henri B. Kagan was born de France. In 1965 he was organic synthesis and stere- in Boulogne-Billancourt, research associate at Uni- ochemistry. His current re- France in December 1930. versity of Texas, Austin (Pr search interests are mainly He graduated from Sorbon- T. Mabry). In 1967 he be- related to new aspects of ne and Ecole Nationale came professor in Univer- asymmetric catalysis. He Supérieure de Chimie de sité Paris-Sud, where he is has been the recipient of Paris in July 1954. He got a emeritus professor since various awards and distinc- PhD in College de France in 1999. He is member of the tions over the years, includ- 1960 (Paris) under the su- french Academy of Scienc- ing the 2001 Wolf Prize in pervision of Dr J. Jacques. es. He was the supervisor of Chemistry shared with Profs After his PhD he became re- 60 PhD and 60 postdoctoral R. Noyori and K. B. Sharp- search associate with pro- fellows. He developed re- less. fessor A. Horeau in College searches in various area of Synlett 2001, No. SI, 888–899 ISSN 0936-5214 © Thieme Stuttgart · New York 890 H. B. Kagan ACCOUNT Scheme 2 Early examples of nonlinear effects25 O Cat*: 12 or 13 HO H + Et Zn Ph H 2 Ph Et 10 11 (R) (with 12) (S) (with 13) t-Bu N NMe2 OH OH 12 (-)-PDB 13 (-)-DAIB Scheme 4 3 About the origin of nonlinear effects My personal perception of the abnormal behaviour con- Scheme 3 nected with the use of non-enantiopure auxiliaries was the possible occurrence of diastereomeric species, not present in the enantiopure system. infra). Narasaka et al. observed in 1989 a (+)-NLE in a Di- els-Alder reaction catalysed by a titanium/binol Lewis ac- The simple model, based on organometallic chemistry, that we soon envisaged, was symbolised as ML2 (M and L id, at low eeaux the reaction medium was not homogeneous because of the precipitation of some titanium complex- stand for metal and ligand, respectively). It is indeed quite es.32 In 1990 Mikami and Nakai used a titanium-binol cat- common to find a catalyst involving two chiral ligands. A mathematical model was then devised, assuming reaction alyst in the glyoxylate-ene reaction, they observed a 25 substantial asymmetric amplification.33 After 1990 an in- rates first-order with substrate and catalyst.
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