Comforth reaction

In the experience of the present author, minor deviations from this procedure may result in decreased yields. Oxalacetic acid of high quality is essential, and this should be verified by a melting-point determination prior to use. Decarboxylation of oxalacetate has been reported111 to occur rapidly at pH 7, and it should be kept to a minimum by maintaining the pH as close to 10 as possible when dissolving the oxalacetic acid. A modification of the Comforth reaction is the co-balt(II)-ion-catalyzed condensation of D-erythrose 4-phosphate with oxalacetate to give 3-deoxyheptulosonic acid 7-phosphate112 (as a mixture of the arabino and ribo isomers). Other procedures for the preparation of KDO will be discussed in subsections 3 and 4 of this Section. 

A new general synthesis of substituted formylpyrroles 106 has been developed starting from ketones and 4-formyloxazoles. The aldol adducts undergo a cascade sequence of reactions which ends with the formation of a pyrrole. The reaction is intended as a vinylogous extension of the Comforth reaction, hydrolysis of formyloxazoles, and allows the synthesis of a large series of 4-and 5-substituted 2-formylpyrroles <07OL1875>. 

Oxazoles from Imidates/Thioimidates—Comforth Reaction... 

Williams and McClymont have observed that acylation reactions of the dianion of 2-(5-oxazolyl)-l,3-dithiane (15) lead to formation of 4,5-disubstituted oxazole products through a Comforth rearrangement pathway under base-induced, low-temperature conditions. For example, deprotonation of 15 with LiHMDS (3.0 equivalents) at -78°C, followed by addition of benzoyl chloride or p-chlorobenzoyl chloride and warming to 0°C, provided 16 in 74% and 47% yield, respectively. 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

Ingham describes two by-products isolated in these reactions, (a) arylene-mandeloamides (8) formed in the presence of water and (b) diazines (11) resulting from dimerization of the chloroimine. Reconsideration by Comforth and Comforth demonstrated that reaction of 5 with water actually produces oxazolidone 9/... 

Vladimir Prelog and John W. Comforth (V. P.) stereochemistry of organic molecules and reactions, (J. C.) stereochemistry of enzyme-catalyzed reactions... 

Charon and Szabo17 demonstrated that chromophore 4 may be produced to a significant extent from a 5-O-substituted derivative of KDO (which does not contain a free diol grouping at C-4-C-5). These authors synthesized 3-deoxy-5-0-methyl-2-octulosonic acid (7 configuration at C-5-C-7, arabino at C-4, unknown) by the Comforth reaction18,19 from 4-0-formyl-2-0-methyl-D-arabinose (see Scheme 4 and Section IV,1). Compound 7 gave a millimolar extinction coefficient of 13 in the TBA assay (as compared to 92 5 for KDO). Based on this result, Charon and Szabo17 formulated for the TBA reaction of 5-0-... 

Following the synthesis by Comforth and his associates18 of NeuAc from oxalacetate and 2-acetamido-2-deoxy-D-mannose, Ghalambor and Heath29,31 prepared KDO (isolated as the crystalline methyl 2,4,5,7,8-penta-0-acetyl-3-deoxy-D-manno-2-octulopyranosonate, 70) from D-arabinose and oxalacetate by an analogous reaction (see Scheme 20). 

Fig. 3. Reaction of H with Me-CHCl-CHO. Plot of transition states energies versus e, angle of rotation around Cl—C2. The solid (dashed) curve corresponds to transitions states 5 (res. 6) leading to the major (minor) product, according to Comforth s rule. The dotted curve is the conformational energy curve of Me-CHa—CHO. (Taken from Ref. , with permission of the publisher)...

John Comforth Great Britain stereochemisitry of enzyme-catalyzed reactions... 

Many additional examples of the elucidation of prostereoisomerism in biochemical reactions could be given, for example the elegant elucidation by Comforth and coworkers 111, n8,137) of the biosynthesis of squalene, which was recognized by the Nobel prize in chemistry in 1975, or the recent studies of the enzymatic decarboxylation of tyrosine 138) and histidine 139) and of the condensation of homoserine with cysteine to give lanthionine 140), but the examples already provided should illustrate the principles and techniques involved in such studies. 

Isatin reacts with ammonium hydroxide or ammonium acetate to furnish a mixture of compounds. Amongst them are isamic acid and its corresponding amide, isamide. Since 1877 there had been a discussion as to their structure, which in 1976 was finally elucidated, by Sir John Comforth on the basis of chemical and spectroscopic data228. Isamic acid can be regarded as a dimer formed by the addition/condensation of one equivalent of ammonia with two equivalents of isatin. This intermediate suffers lactonization and subsequent conversion to isamic acid by an internal nucleophilic attack, where upon the acid is converted to isamide by reaction with a second equivalent of ammonia. 1-Methylisatin reacts similarly, furnishing N-methylisamic acid (Scheme 51). 

On the other hand, the reaction of this chloride with anilines always led to isatin-3-imines. In an attempt to rationalize these contradictory results, it was proposed that 2-chloro-3H-indol-3-one was the substrate but that this compound, which reacts with nucleophiles at the C-2 position, readily hydrolyzed in solvents containing water, thus yielding isatin and products resulting from attack at C-3. Sir John Comforth revisited the chemistry of this... 

Another stereochemical aspect of these Diels-Alder reactions which has been studied by the Vedejs group is the facial selectivity in cycloadditions of chiral thioaldehydes. For instance, thioaldehyde (184), generated by the photochemical method, added to cyclopentadiene to give exo adducts (185) and (186) Jong with endo isomers (187) and (188) (Scheme 24). As was the case for achiral thioaldehydes, the endo adducts predominated (-9 1). The facial selectivity obtained can be rationalized via a Felkin-Anh or Comforth model for asymmetric induction. 

Additions of allyltributyltin to an a-oxygenated aldehyde are also influenced by the choice of Lewis acid (Table 7) [16]. The relative stereochemistry of the adduct is a result of the facial preference for attack on the aldehyde-Lewis acid complex by the stannane. The reaction involving BF3 OEta is subject to Felkin-Ahn/Comforth control whereas MgBr2 and TiCU in CH2CI2 proceed by chelation control. In THF the... 

When treated with potassium artiide in liquid ammonia, suitably substituted and activated pyrimidines are converted into imidazoles, a ring eontraction which has been shown by labelling to involve cleavage of the 5,6 bond (Scheme 6.1.6). 5-Amino-4-chloro-2-phenylpyrimidine is converted under the reaction conditions into 4-cyano-2-phenylimidazole in 30-35% yield, rather better than is achieved by Comforth s method (using aminoacetonitrile with... 

Less acidic than Ti and Zi chloroderivatives, MeTi(OPr )3 perfoims chelation-controlled addition to chiral alkoxy ketones as well as or better than organomagnesium compounds, but fails to chelate to aldehydes or hindered ketones. Should the formation of a cyclic chelation intermediate be forbidden, the reaction is subject to nonchelation control, according to Ae Felkin-Anh (or Comforth) model. Under these circumstances, the ratio of the diastereomeric products is inverted in favor of the anti-Cram product(s). In the case of benzil (83 Scheme 7) this can be accounted for by the unlikely formation of a cyclic intermediate such as (85), and thus the preferential intermediacy of the open chain intermediate (86) that leads to the threo compound (88). This view is substantiated by the fact that replacement of titanium with zirconium, which is characterized by longer M—O bonds, restores the possibility of having a cyclic intermediate and, as a consequence, leads to the erythro meso) compound (87) thus paralleling the action of Mg and Li complexes. 

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