Hajos-Parrish-Eder-Sauer-Wiechert reaction

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The Hajos-Parrish-Eder-Sauer-Wiechert reaction in organic chemistry is a proline catalysed asymmetric Aldol reaction. The reaction is named after its principal investigators from Hoffmann-La Roche [1] [2] and Schering AG [3]. Discovered in the 1970's the original Hajos-Parrish catalytic procedure shown in the reaction equation leading to the optically active bicyclic ketol as well as the Eder-Sauer-Wiechert modification leading to the optically active dione paved the way of asymmetric organocatalysis. It has been used extensively as a tool in steroid synthesis.


The Hajos-Parrish-Eder-Sauer-Wiechert reaction

In the original reaction naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. Hajos and Parrish worked at ambient temperature using a catalytic amount (3% molar equiv.) of (S)-(-)-proline enabling them to isolate the optically active intermediate bicyclic ketol.

They investigated further the exact configuration of the above cis-fused-7a-methyl- 6,5-bicyclic-ketol by circular dichroism, and these results were confirmed by a single-crystal X-ray diffraction study. The centro symmetrical crystal of the corresponding racemic ketol without a heavy atom label has been obtained by the use of racemic proline. It showed by X-ray diffraction an axial orientation of the angular methyl group and an equatorial orientation of the hydroxyl group in the chair conformer of the six-membered ring. This is in good agreement with the crystal structure of the CD-ring of digitoxigenin. [4] The structure of this ketol and its ethyl homologue are shown as follows.

File:Hajos-Parrish-ketols-2.jpg

Similar studies of the 7a-ethyl-homologue showed that the ethyl bicycic ketol existed in a cis conformation in which the 7a-ethyl group is equatorially oriented and the hydroxyl group is axially oriented in the chair form of the six-membered ring as shown above. The reason for a preference for this conformation could be enhanced 1,3-diaxial interaction in the other cis conformer between the angular ethyl group and the axial hydrogens at C-4 and C-6 in the six membered ring [1,2].

The Schering group used non biological conditions using (S)-Proline (47 mol%), 1N perchloric acid, in acetonitrile at 80 °C. Hence, they could not isolate the Hajos, Parrish intermediate bicyclic ketols but instead the condensation product [5].

In a 2000 study the List group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerably more proline [6]:

Aldol Barbas 2000

The authors noted the similarity of proline with the enzyme aldolase A which both operate through an enamine intermediate. In this reaction the large concentration of acetone (one of the two reactants) suppresses various possible side-reactions: reaction of the ketone with proline to a oxazolidinone and reaction of the aldehyde with proline to a azomethine ylide.

The List group expanded the utility of this reaction to the synthesis of 1,2-diols [7]:

Synthesis of diols Notz 2000

In a screening program, proline together with the thiazolium salt 5,5-dimethyl thiazolidinium-4-carboxylate were found to be the most effective catalysts among a large group of amines [8]

The asymmetric synthesis of the Wieland-Miescher ketone (1985) is another intramolecular reaction also based on proline, a reaction revisited by the Barbas group in 2000,[9] after the discovery of the proline-catalyzed intermolecular aldol reaction by List et al.

In 2002 the Macmillan group demonstrated the proline Aldol reaction with different aldehydes [10]:

Aldol Macmillan 2002

This reaction is unusual because in general aldehydes will self-condense.

Reaction mechanism

Several reaction mechanisms for the triketone reaction have been proposed over the years. The one put forward by Hajos (1974) features a hemiaminal intermediate. The Agami mechanism (1984) has an enamine intermediate with two proline units involved in the transition state (based on experimental reaction kinetics) [11] and according to a mechanism by Houk (2001) [12] [13] a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding.

Aldol triketone Mechanisms

The reaction mechanism as proposed by the List group in 2000 for the intermolecular reactions [6] is based also on enamine formation and the observed stereoselectivity based on the Zimmerman-Traxler model favoring Re face approach:

Aldol Mechanism List 2000

This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami [11] is disputed by List also based on reaction kinetics [14]. The general mechanism is further supported (again by List) by the finding that in a reaction carried out in labeled water (H218O), the oxygen isotope finds its way into the reaction product [15]. This rules out the non-enamine Hajos mechanism. In the same study the reaction of proline with acetone to the oxazolidinone (in DMSO) was examined:

Oxazolidinone formation by reaction Of ketone with proline

The equilibrium constant for this reaction is only 0.12 leading List to conclude that the involvement of oxazolidinone is only parasitic.

Blackmond in 2004 also found oxazolidinones as intermediates (NMR) in a related proline-catalysed α-aminooxylation of propanal with nitrosobenzene [16]:

proline-catalysed α-aminooxylation

The view of oxazolidinones as a parasitic species is contested by Seebach and Eschenmoser who in 2007 published a 47 page (!) article [17] in which they argue that oxazolidinones in fact play a pivotal role in proline catalysis. One of the things they did was reacting an oxazolidinone with the activated aldehyde chloral in an aldol addition:

ChloralAldolSeebach2007

In 2008, Barbas in an essay addressed the question why it took until the year 2000 before interest regenerated for this seemingly simple reaction 30 years after the pioneering work by Hajos and Parrish and why the proline catalysis mechanism appeared to be an enigma for so long [18]. One explanation has to do with different scientific cultures: a proline mechanism in the context of aldolase catalysis already postulated in 1964 by a biochemist [19] was ignored by organic chemists. Another part of the explanation was the presumed complexity of aldolase catalysis that dominated chemical thinking for a long time. Finally, research did not expand in this area at Hoffmann-La Roche after the resignation of ZGH in November, 1970.

Origin of the name of the reaction

The name for this reaction took some time to develop. In 1985 Professor Agami and associates were the first to name the proline catalyzed Robinson annulation the Hajos-Parrish reaction [20]. In 1986 Professor Henri B.Kagan and Professor Agami [21] still called it the Hajos-Parrish reaction in the Abstract of this paper. In 2001 Professor Kagan published a paper entitled “Nonlinear Effects in Asymmetric Catalysis: A Personal Account” in Synlett [22]. In this paper he introduced the new title the Hajos-Parrish-Wiechert reaction. In 2002 Professor Benjamin List added two more names and introduced the term Hajos-Parrish-Eder-Sauer-Wiechert reaction [23].Scientific papers published as late as 2008 in the field of organocatalysis use either the 1985, 2001 or 2002 names of the reaction.

References

  1. Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971
  2. Asymmetric synthesis of bicyclic intermediates of natural product chemistry Zoltan G. Hajos, David R. Parrish J. Org. Chem.; 1974; 39(12); 1615-1621. doi:10.1021/jo00925a003
  3. New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures Angewandte Chemie International Edition in English Volume 10, Issue 7, Date: July 1971, Pages: 496-497 Ulrich Eder, Gerhard Sauer, Rudolf Wiechert doi:10.1002/anie.197104961
  4. The crystal structure of digitoxigenin, Karle, I.L., and Karle, J., Acta Cryst.,Sect.B25,434-442(1969).
  5. Proline-catalyzed asymmetric reactions Tetrahedron Report Number 10450 Tetrahedron Volume 58, Issue 28, 8 July 2002, Pages 5573-5590 Benjamin List doi:10.1016/S0040-4020(02)00516-1
  6. 6.0 6.1 Proline-Catalyzed Direct Asymmetric Aldol Reactions Benjamin List*, Richard A. Lerner, and Carlos F. Barbas III J. Am. Chem. Soc. 2000, 122, 2395-2396 doi:10.1021/ja994280y
  7. Catalytic Asymmetric Synthesis of anti-1,2-Diols Wolfgang Notz and Benjamin List J. Am. Chem. Soc. 2000; 122(30) pp 7386 - 7387; (Communication) DOI: 10.1021/ja001460v
  8. Amino Acid Catalyzed Direct Asymmetric Aldol Reactions: A Bioorganic Approach to Catalytic Asymmetric Carbon-Carbon Bond-Forming Reactions Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. (Article); 2001; 123(22); 5260-5267. doi:10.1021/ja010037z
  9. A proline-catalyzed asymmetric Robinson annulation reaction Tetrahedron Letters, Volume 41, Issue 36, September 2000, Pages 6951-6954 Tommy Bui and Carlos F. Barbas doi:10.1016/S0040-4039(00)01180-1
  10. The First Direct and Enantioselective Cross-Aldol Reaction of Aldehydes Alan B. Northrup and David W. C. MacMillan J. AM. CHEM. SOC. 2002, 124, 6798-6799 doi:10.1021/ja0262378
  11. 11.0 11.1 Stereochemistry-59 : New insights into the mechanism of the proline-catalyzed asymmetric robinson cyclization; structure of two intermediates. asymmetric dehydration Tetrahedron, Volume 40, Issue 6, 1984, Pages 1031-1038 Claude Agami, Franck Meynier, Catherine Puchot, Jean Guilhem and Claudine PascardError: Bad DOI specified!
  12. The Origin of Stereoselectivity in Proline-Catalyzed Intramolecular Aldol Reactions Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. (Communication); 2001; 123(51); 12911-12912. doi:10.1021/ja011714s
  13. Transition States of Amine-Catalyzed Aldol Reactions Involving Enamine Intermediates: Theoretical Studies of Mechanism, Reactivity, and Stereoselectivity Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001; 123(45); 11273-11283 doi:10.1021/ja011403h
  14. Kinetic and Stereochemical Evidence for the Involvement of Only One Proline Molecule in the Transition States of Proline-Catalyzed Intra- and Intermolecular Aldol Reactions Linh Hoang, S. Bahmanyar, K. N. Houk, and Benjamin List J. AM. CHEM. SOC. 2003, 125, 16-17 doi:10.1021/ja028634o
  15. Asymmetric Catalysis Special Feature Part II: New mechanistic studies on the proline-catalyzed aldol reaction Benjamin List, Linh Hoang, and Harry J. Martin PNAS 2004 101: 5839-5842; doi:10.1073/pnas.0307979101
  16. Probing the Active Catalyst in Product-Accelerated Proline-Mediated Reactions Iwamura, H.; Wells, D. H., Jr.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. (Communication); 2004; 126(50); 16312-16313. doi:10.1021/ja0444177
  17. Are Oxazolidinones Really Unproductive, Parasitic Species in Proline Catalysis? - Thoughts and Experiments Pointing to an Alternative View Helvetica Chimica Acta Volume 90, Issue 3, Date: March 2007, Pages: 425-471 Dieter Seebach, Albert K. Beck, D. Michael Badine, Michael Limbach, Albert Eschenmoser, Adi M. Treasurywala, Reinhard Hobi, Walter Prikoszovich, Bernard Linder doi:10.1002/hlca.200790050
  18. Organocatalysis Lost: Modern Chemistry, Ancient Chemistry, and an Unseen Biosynthetic Apparatus Carlos F. Barbas III Angew. Chem. Int. Ed. 2008, 47, 42–47 doi:10.1002/anie.200702210
  19. W. J. Rutter, Fed. Proc. 1964, 23,1248;
  20. Agami, C.; Levisalles, J.; Puchot, C. J. Chem. Soc., Chem. Commun. 1985, 8, 441-442
  21. J. Am. Chem. Soc. 1986, 108, 2353-2357
  22. Synlett 2001, No. SI, 888–899
  23. B. List, Tetrahedron 58 (2002) 5573-5590

hu:Hajos–Parrish–Eder–Sauer–Wiechert-reakció


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