Hajos-Parrish reaction mechanism

Hajos, Zoltan George

Biography:

Organic chemist, born 1926 (Budapest, Hungary). MS, Technical University, Budapest, 1947. Ph.D. (Technical Sciences) Technical University, Budapest, 1950. Assistant Professor Technical University, Budapest, Hungary 1948-1957. Research scientist Princeton University, Princeton, NJ 1957-1960; Hoffmann-La Roche, Inc. Nutley, NJ 1960-1970; University of Vermont, Burlington, VT 1972-1973; University of Toronto, Ontario, Canada 1973-1974; R.W.Johnson Pharmaceutical Research Institute, Raritan, NJ 1975-1990.

Achievements include publications and patents in the field of total and asymmetric synthesis of medicinal-organic compounds. Heterogeneous catalysis; Inhibitor Effect in Autoxidation Processes; Hydrolysis and Esterification catalysed by Ion Exchange Resins; Stereospecific preparation of glycosides from sugar acetates; Amino acid catalyzed asymmetric syntheses of chiral synthons. Synthesis of hydrophenanthrenes, steroidal hormones, heterocyclics, (i.e. tetrahydrofuran derivatives, dioxanes and purines). Author: Aldol and Related Reactions pp. 1-84 in Techniques and Applications in Organic Synthesis, Vol.1, Carbon-Carbon Bond Bond Formation. Robert L. Augustine, Editor, Marcel Dekker Inc., New York and Basel, 1979. Lectures at the 145th, 148th, 150th National ACS meetings, and at the Gordon Research Conferences in Natural Product Chemistry in 1970 and at the Research Conference on Heterocyclic Compounds in 1989. Citizen of the U.S.A. Married to Katherine Birnbaum. Emeritus Member of the American Chemical Society and of the Society of the Sigma Xi.

An essay by Zoltan Hajos entitled Proline Catalyzed Asymmetric Cyclization.Theory of the Reaction mechanism can be found on the ChemWeb Preprint server under http://www.sciencedirect.com/preprintarchive/article/B7J22-4DNMR08-22/2/7e47d5d0bd80be28df693b74ec631b3e Chemistry Preprint Archive, Volume 2002, Issue 9, September 2002, Pages 84-100. It is an extension of the original publication on Asymmetric Synthesis of Bicyclic Intermediates of Natural Product Chemistry by Zoltan G. Hajos and David R. Parrish, J.Org.Chem. 1974, 39, 1615-1621.

The carbinolamine mechanism described in both papers has had an unwitting support in a more recent paper entitled "beta-Homoamino acids as catalysts on enantioselective intra- and intermoelcular aldol reactions" by Michael Limbach, Tetrahedron Letters 47 (2006) 3843-3847. The triketone starting material 2- methyl-2-(3-oxobutyl)-1,3-cyclopentanedione gave the expected optically active bicyclic ketol (+)-(3aS,7aS)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)- indanedione with (S)-(-)-proline catalyst. On the other hand, the stereochemical outcome is reversed with ee selectivities of up to 83% by using the homologue amino acid catalysts, such as (S)-(beta)-homoproline, [(pyrrolidine-(2S)-yl) acetic acid]. The virtual anomaly can nicely be explained with a top side approach of the bulkier beta amino acids to the above described triketone starting material of reflective symmetry. The top side approach resulted in the formation of an enantiotopic carbinolamine to give the (-)-(3aR,7aR) bicyclic ketol enantiomer identical to the one obtained with unnatural (R)-(+)-proline.

Hajos and Parrish needed the starting material triketone 1 for their asymmetric synthesis. The synthesis of 1 has been described by them in J.Org.Chem., 1974, 39, pp 1612-1615. Another Hajos and Parrish paper in J.Org.Chem., 1974 39, 1615-1621 describes that starting with the triketone 1 and executing the experiments at ambient temperature using a catalytic amount (3% molar equiv.) of (S)-(-)-proline Hajos and Parrish could isolate the optically active intermediate bicyclic ketol (+)-2 a prerequisite of elucidating the reaction mechanism. This was most likely the reason for Professor Claude Agami to call the reaction the Hajos-Parrish reaction in his paper in J.Chem.Soc., Chemical Commun., 1985, 441-442. Compound (+)-2 could be converted to its dehydration product (+)-3 in excellent chemical and optical yield.

                                        

The last few lines of the Hajos and Parrish 1974 paper read: "We believe our results may be considered an example of a simplified model of a biological system in which (S)-(-)-proline plays the role of an enzyme." This has been referred to in a publication by Mohammad Movassaghi and Eric N. Jacobsen of the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA: The Simplest "Enzyme" Science, 6 December 2002, Vol. 298, 1904-1905.

 

The intermediate of the carbinolamine mechanism put forward by Hajos in 1974 is shown in Figure A. The stereochemical assignment of the carbinolamine substituents has been changed as suggested by Professor Michael Jung. The carbinolamine is tautomeric to the iminium hydroxide intermediate shown in Figure B. Enolization of the side chain methyl ketone caused by the iminium hydroxide would then be followed by ring closure to the above shown ketol product (+)-2 under the influence of a catalytic amount of (S)-(-)-proline.

 

                                        

      

 

                        Figure A                                                          Figure B

 

 

Minimization studies of the iminium hidroxide intermediate using the CambridgeSoft Corporation's Chem3D MM2 energy minimization menu based on Allinger's Molecular Mechanics force field version2 showed a difference of 2.6932 kcal/mole in favor of this 2(S)- intermediate over the one with the 2(R)-configuration.

In order to establish whether or not an enamine mechanism was operational Hajos and Parrish executed the proline catalyzed asymmetric ring closure in the presence of H218O as follows.

The triketone starting material 2-Methyl-2-(3-oxobutyl)-1,3-cyclopentanedione (1.0 mmol) has been stirred under argon at RT for 1 week in 1.0 mL acetonitrile containing 40 mg of H2 18O and (S)-(-)-proline(0.03 mmol). The optically active bicyclic ketol(+)-(3aS,7aS)-3a,4,7,7a-Tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indandione was isolated in 22% yield by preparative thin layer chromatography. Mass spectral analysis for 18O-labeled CO2 of the sample showed only 7.2% 18O-enrichment.

In a highly important control experiment 1.0 mmol of the optically active bicyclic ketol reaction product was stirred under argon at RT for 1 week in 1.0 mL acetonitrile containing 40 mg of H218O and 0.03 mmol of (S)-(-)-proline. Mass spectral analysis for 18 O-labeled CO2 of the optically active bicyclic ketol showed 33.1% 18O-enrichment.

The asymmetric ring closure of the triketone thus did not confirm 18O incorporation into the optically active bicyclic ketol in any significant measure (7.2% 18O-enrichment) thereby contradicting the enamine mechanism. However, the control experiment showed that the optically active bicyclic ketol reaction product incorporated nearly five times more 18O (33.1% 18O- enrichment).

It should be emphasized that the 18O studies have been executed under very similar conditions to the actual asymmetric ring closure experiments always avoiding an overload by H218O.This way Hajos and Parrish tried to keep 18O incorporation into the reaction product at a minimum (for more details see J.Org.Chem., 1974, 39, pages 1619 and 1621).

In the aforementioned ChemWeb preprint article it was emphasized that there is no problem to accept the enamine mechanism for the antibody catalyzed enantioselective Robinson annulation. It is well known that, antibody catalyzed reactions may proceed contrary to the small molecule catalyzed reactions. Antibodies for instance catalyze ring closures in formal violation of Baldwin's rules.

Further calculations after the ChemWeb publication using the CambridgeSoft Corporation's Chem3D MM2 energy minimization menu based on Allinger's Molecular Mechanics force field version2 led to the conclusion that the template mechanism gives lower energy levels than either the carbinolamine or the enamine pathways. Due to this realization a cooperation has been established resulting in a paper entitled "Proline-catalysed asymmetric ketol cyclizations: The template mechanism revisited." (R. Malathi, D. Rajagopal, Zoltan G. Hajos and S. Swaminathan, J. Chem. Sci., Vol. 116, No. 3, May 2004, pp. 159-162.Indian Academy of Sciences.) Modeling was done using Builders software in INSIGHT II. The models were minimized using force field CFF91 using DISCOVER software.

It is highly probable that, the template mechanism postulated for the amino acid catalyzed intramolecular reactions should also be operational for the intermolecular reactions catalyzed by proline or other amino acids. Several papers suggested a favorable effect of water in the amino acid catalyzed intermolecular aldol reactions. Postulating an enamine mechanism in the presence of water is contrary to the requirements of enamine formation. By assuming the template mechanism for the intermolecular aldol reactions it is not necessary to invoke esoteric mechanistic ideas to support the existence of water sensitive enamine intermediates.

A preprint by Zoltan Hajos entitled "Amino Acid Assisted Chemical Catalytic Computing Device" can be located on the ChemWeb Preprint server under http://www.sciencedirect.com/preprintarchive/article/B7J22-4D5K021-2/2/de2189148a7ca02ca87ea9e6072862ad. Chemistry Preprint Archive, Volume 2004, Issue 2, February 2004, Pages 15-21. It describes the concept of an amino acid assisted Chemical Catalytic Computing Device (CCCD). The technical design of a prototype CCCD will have to involve the know-how of nanotechnology and combinatorial devices.

To see the Biography in Hungarian language click on:
http://web.t-online.hu/zghajos/Hajos-Zoltan-G-Magyar-Biografia.htm .

E-mail address of Zoltan G. Hajos: zghajos@t-online.hu