My watch list
my.chemeurope.com  
Login  

Hajos-Parrish-Eder-Sauer-Wiechert reaction



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 it is considered an important contribution to asymmetric organocatalysis. It has been used extensively as a tool in steroid synthesis.

Additional recommended knowledge


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. 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 [4]

In a 2000 study the same group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerable more proline [5]:

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 [6]:

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 [7]


In 2002 the Macmillan group demonstrated the proline Aldol reaction with different aldehydes [8]:

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) [9] and according to a mechanism by Houk (2001) [10] [11] a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding.

The reaction mechanism as proposed by the Barbas/List group in 2000 for the intermolecular reactions [5] is based also on enamine formation and the observed stereoselectivity based on the Zimmerman-Traxler model favoring Re face approach:

This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami [9] is disputed by List also based on reaction kinetics [12]. 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 [13]. 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:

The equilibrium constant for this reaction is only 0.12 leading List to conclude that the involvement of oxazolidinone is only parasitic. This view is contested by Seebach and Eschenmoser who in 2007 published a 47 page (!) article [14] in which they argue that oxazolidinones in fact play a pivotal role in proline catalysis. One of the things they did was reacting a oxazolidinone with the activated aldehyde chloral in an aldol addition:

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 [15]. 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 [16] 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.

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. ^ 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
  5. ^ a b 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
  6. ^ 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
  7. ^ 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
  8. ^ 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
  9. ^ a b 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 Pascard doi:doi:10.1016/S0040-4020(01)91242-6
  10. ^ 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
  11. ^ 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
  12. ^ 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
  13. ^ 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
  14. ^ 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
  15. ^ 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
  16. ^ W. J. Rutter, Fed. Proc. 1964, 23,1248;
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Hajos-Parrish-Eder-Sauer-Wiechert_reaction". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE