Hajos-Parrish reaction
mechanism
Hajos, Zoltan George
Biography:
Organic
chemist, born 1926 (
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.,
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,
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
Further calculations after
the ChemWeb publication using the CambrdigeSoft
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.
Please note the new URL
address of the Hajos Zoltan George Biography:
http://web.t-online.hu/zghajos/index.htm
.
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