Hajos-Parrish-Eder-Sauer-Wiechert reaction
Encyclopedia
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
and Schering AG. Discovered in the 1970s 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 enedione through the loss of water from the ketol paved the way of asymmetric organocatalysis
. It has been used extensively as a tool in the synthesis of steroids and other enantiomerically pure molecules.
Figure 1.
In the original reaction shown in Figure 1. 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
. As shown above, Hajos and Parrish worked at ambient temperature in dimethylformamide
(DMF) solvent using a catalytic amount (3% molar equiv.) of (S)-(-)-proline enabling them to isolate the optically active intermediate bicyclic ketol. Thus, they described the first use of proline in a catalytic asymmetric aldol reaction.
The Schering group worked under 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 ketol but instead the condensation product (7aS)-7a-methyl-2,3,6,7-tetrahdroindol-1,5-dione through the loss of water. Thirty-seven years later a new group at Schering AG published the continuation of the earlier Schering work [3]. Instead of the aforementioned non biological conditions the new group used the Hajos-Parrish catalytic procedure. Thus, they could isolate the optically active 6,5-bicyclic ketol described so far only in the Hajos-Parrish publications [1],[2] .
Hajos and Parrish 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
. The structure of this ketol and its ethyl homologue are shown as follows.
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.
In a 2000 study the Barbas group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerably more proline :
The authors noted the similarity of proline, the aldolase antibodies they had created and natural aldolase enzymes aldolase A all of which 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.
Notz and List went on to expand the utility of this reaction to the synthesis of 1,2-diols :
In their full account of their 2000 Communication, the group revealed that 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, while catalysis with (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts formed the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.
The asymmetric synthesis of the Wieland-Miescher ketone
(1985) is another intramolecular reaction also based on proline, that was explored by the Barbas group in 2000. In this study the Barbas group demonstrated for the first time that proline can catalyze the cascade Michael-aldol reaction through combined iminium-enamine catalysis. This work is significant because despite the 30 year history and application of the Hajos-Parrish reaction in industry, the triketone substrate for this reaction had always been synthesized in a discrete independent step, demonstrating that there was a fundamental lack of understanding of the chemical mechanism of this reaction. The Barbas group had reported the aldolase antibody catalyzed iminium-enamine Robinson annulation in their 1997 study that marked the beginning of their studies in the area now called organocatalysis. In a report published in 2002 Carlos F. Barbas III said: "Work in the 1970s on proline-catalyzed intramolecular aldol addition reactions by synthetic organic chemists Zoltan G. Hajos and David R. Parrish of the chemical research department at Hoffmann-La Roche, Nutley, N.J., inspired us to look more closely at parallels between small-molecule catalysts and enzymes".
In 2002 the Macmillan group was the first to demonstrate the proline catalyzed Aldol reaction between different aldehyde
s. This reaction is unusual because in general aldehydes will self-condense.
The organocatalytic intermolecular aldol reaction is now known as the Barbas-List Aldol reaction.
intermediate.[2] The Agami mechanism (1984) has an enamine
intermediate with two proline units involved in the transition state
(based on experimental reaction kinetics) and according to a mechanism by Houk (2001) a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding.
The hemiaminal
(carbinolamine) put forward by Hajos in 1974 can change to a tautomeric iminium hydroxide intermediate.The iminium hydroxide ion caused enolization of the side chain methyl ketone would be followed by ring closure to the above shown optically active bicyclic ketol product (see Figure 1.) under the influence of the catalytic amount of (S)-(-)-proline.
The Hajos 1974 carbinolamine mechanism has had an unwitting support in a more recent paper by Michael Limbach. 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)-β-homoproline, [(pyrrolidine-(2S)-yl) acetic acid]. The virtual anomaly can be explained with a top side approach of the bulkier beta amino acids to the above triketone starting material of reflective symmetry. The top side approach results in the formation of an enantiotopic carbinolamine to give the (-)-(3aR,7aR)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indanedione bicyclic ketol enantiomer identical to the one obtained with unnatural (R)-(+)-proline. List in 2010 on the other hand is perplexed and surprised that Hajos rejected the enamine mechanism, certainly in light of earlier work by Spencer in 1965 on amine catalysed aldol reactions. It is interesting and surprising that Eder, Sauer and Wiechert have not attempted to explain the reaction mechanism. [3]
The reaction mechanism
as proposed by the Barbas group in 2000 for the intermolecular reactions is based also on enamine
formation and the observed stereoselectivity
based on the Zimmerman-Traxler model favoring Re face approach. This is the same mechanism proposed by Barbas for aldolase antibodies reported by the group in 1995:
This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami is disputed by Barbas based on the lack of a non-linear effects and supported by later studies of List based on reaction kinetics. The general mechanism is further supported 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. The Hajos and Parrish experiment with a stoechiometric amount of labeled water (H218O) supported the carbinolamine mechanism.[2]
In the same study [20] 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.
Blackmond in 2004 also found oxazolidinones as intermediates (NMR) in a related proline-catalysed α-aminooxylation of propanal with nitrosobenzene
:
Chiong Teck Wong of the Institute of High Performance Computing Singapore studied the similar oxyamination reaction of nitrosobenzene with butanal using a chiral prolinol
silyl ether catalyst. His studies strongly suggest that the catalyst generates the enol, and forms an enol-catalyst complex. Nitsosobenzene subsequently reacts with the enol-catalyst complex to afford the (S)-N-nitroso aldol product in agreement with Pauling’s chart of electronegativity. Sodiumborohydride reduction of the primarily formed aldol products gave the corresponding alcohols in good yield and excellent enantioselectivity in the ratio of PN/PO=>99:1 as shown in the Scheme below. Wong suggests that the reaction mechanism of the (S)-Cat catalyzed N-nitroso aldol reaction between nitrosobenzene and butanal proceeds via an enol intermediate and not via an enamine intermediate.
The view of oxazolidinones as a parasitic species is contested by Seebach and Eschenmoser who in 2007 published a 47 page (!) article 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:
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. 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 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.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
is a proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
catalysed asymmetric Aldol reaction
Aldol reaction
The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
. The reaction is named after its principal investigators from Hoffmann-La Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
and Schering AG. Discovered in the 1970s 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 enedione through the loss of water from the ketol paved the way of asymmetric organocatalysis
Organocatalysis
In organic chemistry, the term Organocatalysis refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds...
. It has been used extensively as a tool in the synthesis of steroids and other enantiomerically pure molecules.
Figure 1.
In the original reaction shown in Figure 1. naturally occurring chiral proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
is the chiral catalyst in an Aldol reaction
Aldol reaction
The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
. The starting material is an achiral triketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess
Enantiomeric excess
The enantiomeric excess of a substance is a measure of how pure it is. In this case, the impurity is the undesired enantiomer .-Definition:...
. As shown above, Hajos and Parrish worked at ambient temperature in dimethylformamide
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
(DMF) solvent using a catalytic amount (3% molar equiv.) of (S)-(-)-proline enabling them to isolate the optically active intermediate bicyclic ketol. Thus, they described the first use of proline in a catalytic asymmetric aldol reaction.
The Schering group worked under non biological conditions using (S)-Proline (47 mol%), 1N perchloric acid
Perchloric acid
Perchloric acid is the inorganic compound with the formula HClO4. Usually encountered as an aqueous solution, this colourless compound is a strong acid comparable in strength to sulfuric and nitric acids. It is a powerful oxidizer, but its aqueous solutions up to appr. 70% are remarkably inert,...
, in acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
at 80 °C. Hence, they could not isolate the Hajos, Parrish intermediate bicyclic ketol but instead the condensation product (7aS)-7a-methyl-2,3,6,7-tetrahdroindol-1,5-dione through the loss of water. Thirty-seven years later a new group at Schering AG published the continuation of the earlier Schering work [3]. Instead of the aforementioned non biological conditions the new group used the Hajos-Parrish catalytic procedure. Thus, they could isolate the optically active 6,5-bicyclic ketol described so far only in the Hajos-Parrish publications [1],[2] .
Hajos and Parrish 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
Digitoxigenin
Digitoxigenin is cardenolide, obtained especially by hydrolysis of digitoxin , which is the aglycon of digitoxin....
. The structure of this ketol and its ethyl homologue are shown as follows.
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.
In a 2000 study the Barbas group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerably more proline :
The authors noted the similarity of proline, the aldolase antibodies they had created and natural aldolase enzymes aldolase A all of which operate through an enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
intermediate. In this reaction the large concentration of acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
(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.
Notz and List went on to expand the utility of this reaction to the synthesis of 1,2-diols :
In their full account of their 2000 Communication, the group revealed that 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, while catalysis with (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts formed the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.
The asymmetric synthesis of the Wieland-Miescher ketone
Wieland-Miescher ketone
The Wieland–Miescher ketone is a racemic bicyclic diketone and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer,...
(1985) is another intramolecular reaction also based on proline, that was explored by the Barbas group in 2000. In this study the Barbas group demonstrated for the first time that proline can catalyze the cascade Michael-aldol reaction through combined iminium-enamine catalysis. This work is significant because despite the 30 year history and application of the Hajos-Parrish reaction in industry, the triketone substrate for this reaction had always been synthesized in a discrete independent step, demonstrating that there was a fundamental lack of understanding of the chemical mechanism of this reaction. The Barbas group had reported the aldolase antibody catalyzed iminium-enamine Robinson annulation in their 1997 study that marked the beginning of their studies in the area now called organocatalysis. In a report published in 2002 Carlos F. Barbas III said: "Work in the 1970s on proline-catalyzed intramolecular aldol addition reactions by synthetic organic chemists Zoltan G. Hajos and David R. Parrish of the chemical research department at Hoffmann-La Roche, Nutley, N.J., inspired us to look more closely at parallels between small-molecule catalysts and enzymes".
In 2002 the Macmillan group was the first to demonstrate the proline catalyzed Aldol reaction between different aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s. This reaction is unusual because in general aldehydes will self-condense.
The organocatalytic intermolecular aldol reaction is now known as the Barbas-List Aldol reaction.
Reaction mechanism
Several reaction mechanisms for the triketone reaction have been proposed over the years. Hajos and Parrish proposed the enamine mechanism in their paper [2] . However, their experiment with a stoichiometric amount of labeled water (H218O) supported a carbinolamine mechanism.Therefore, Hajos put forward (1974) a hemiaminalHemiaminal
A hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: -C-. R can be hydrogen or an alkyl group...
intermediate.[2] The Agami mechanism (1984) has an enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
intermediate with two proline units involved in the transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
(based on experimental reaction kinetics) and according to a mechanism by Houk (2001) a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding.
The hemiaminal
Hemiaminal
A hemiaminal is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: -C-. R can be hydrogen or an alkyl group...
(carbinolamine) put forward by Hajos in 1974 can change to a tautomeric iminium hydroxide intermediate.The iminium hydroxide ion caused enolization of the side chain methyl ketone would be followed by ring closure to the above shown optically active bicyclic ketol product (see Figure 1.) under the influence of the catalytic amount of (S)-(-)-proline.
The Hajos 1974 carbinolamine mechanism has had an unwitting support in a more recent paper by Michael Limbach. 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)-β-homoproline, [(pyrrolidine-(2S)-yl) acetic acid]. The virtual anomaly can be explained with a top side approach of the bulkier beta amino acids to the above triketone starting material of reflective symmetry. The top side approach results in the formation of an enantiotopic carbinolamine to give the (-)-(3aR,7aR)-3a,4,7,7a-tetrahydro-3a-hydroxy-7a-methyl-1,5(6H)-indanedione bicyclic ketol enantiomer identical to the one obtained with unnatural (R)-(+)-proline. List in 2010 on the other hand is perplexed and surprised that Hajos rejected the enamine mechanism, certainly in light of earlier work by Spencer in 1965 on amine catalysed aldol reactions. It is interesting and surprising that Eder, Sauer and Wiechert have not attempted to explain the reaction mechanism. [3]
The reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
as proposed by the Barbas group in 2000 for the intermolecular reactions is based also on enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...
formation and the observed stereoselectivity
Stereoselectivity
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during the non-stereospecific creation of a new stereocenter or during the non-stereospecific transformation of a pre-existing one...
based on the Zimmerman-Traxler model favoring Re face approach. This is the same mechanism proposed by Barbas for aldolase antibodies reported by the group in 1995:
This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami is disputed by Barbas based on the lack of a non-linear effects and supported by later studies of List based on reaction kinetics. The general mechanism is further supported by List by the finding that in a reaction carried out in labeled
Isotopic labeling
Isotopic labeling is a technique for tracking the passage of a sample of substance through a system. The substance is 'labeled' by including unusual isotopes in its chemical composition...
water (H218O), the oxygen isotope finds its way into the reaction product. The Hajos and Parrish experiment with a stoechiometric amount of labeled water (H218O) supported the carbinolamine mechanism.[2]
In the same study [20] the reaction of proline with acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
to the oxazolidinone (in DMSO
Dimethyl sulfoxide
Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...
) was examined:
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
Nitrosobenzene
Nitrosobenzene is the organic compound with the formula C6H5NO. The compound can be viewed as hybrid of singlet O2 and azobenzene. This diamagnetic species exists in equilibrium with its dimer.-Preparation:...
:
Chiong Teck Wong of the Institute of High Performance Computing Singapore studied the similar oxyamination reaction of nitrosobenzene with butanal using a chiral prolinol
Prolinol
Prolinol is a chiral amino-alcohol that is used as a chiral building block in organic synthesis. It exists as two enantiomers: the D and L forms.-Preparation:Prolinol is obtained by reduction of the amino acid proline using lithium aluminium hydride...
silyl ether catalyst. His studies strongly suggest that the catalyst generates the enol, and forms an enol-catalyst complex. Nitsosobenzene subsequently reacts with the enol-catalyst complex to afford the (S)-N-nitroso aldol product in agreement with Pauling’s chart of electronegativity. Sodiumborohydride reduction of the primarily formed aldol products gave the corresponding alcohols in good yield and excellent enantioselectivity in the ratio of PN/PO=>99:1 as shown in the Scheme below. Wong suggests that the reaction mechanism of the (S)-Cat catalyzed N-nitroso aldol reaction between nitrosobenzene and butanal proceeds via an enol intermediate and not via an enamine intermediate.
2009-811.svg.png)
The view of oxazolidinones as a parasitic species is contested by Seebach and Eschenmoser who in 2007 published a 47 page (!) article 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
Chloral
Chloral, also known as trichloroacetaldehyde, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless oily liquid that is soluble in a wide range of solvents...
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. 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 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.