John Cornforth

Failure to verify a reported synthesis of the aconitine skeleton

Abstract Attempts to verify the first three stages of a claimed synthesis of the aconitine skeleton (Samir Chatterjee, Tetrahedron Lett. 3249 (1979) have given totally different results. It is concluded that the reported products of these three stages were not in fact obtained.

Syntheses of 3-methylpyrrole via methyl 4-methylpyrrole-2-carboxylate. A thermal oxazolone–pyrone rearrangement

3-Ethoxy-2-methylpropenal with hippuric acid and acetic anhydride gave 4-(3-ethoxy-2-methylallyl-idene)-2-phenyloxazol-5(4H)-one. By successive treatment with methanolic potassium hydroxide, acetic–hydrochloric acid, and methanolic sodium methoxide, methyl 4-methylpyrrole-2-carboxylate was formed in high overall yield, and was converted into 3-methylpyrrole by hydrolysis and decarboxylation. The oxazolone with sodium hydroxide in acetone or dioxane gave 4-(3-hydroxy-2-methylallylidene)-2-phenyloxazol-5(4H)-one, isomerized in boiling acetone, or on melting, to 3-benzoylamino-5-methylpyran-2-one. 3-Ethoxy-2-methylpropenal condensed with glycine methyl ester to give an enaminal, cyclized in moderate yield to methyl 4-methylpyrrole-2-carboxylate.

4-(2'-hydroxyphenylmethylene)-2-phenyloxazol-5(4H)-one : a comedy of errors

Eighteen publications since 1955 have described properties and reactions of the title compound. All these reports are erroneous and refer, variously, to three other substances. All literature reports of the analogous 4-(2′-hydroxyphenylmethylene)-2-methyloxazol-5(4H)-one also need revision. A convenient synthesis of the title compound 3(RH), its chemical and physical properties, and its rearrangement to 3-benzoylamino-1 -benzopyran-2-one 1, are reported here for the first time. A mechanism is presented for the observed course of Plochl–Erlenmeyer syntheses with salicylaldehyde and with 2-acetoxybenzaldehyde.

Synthesis of substituted dibenzophospholes. Part 7. Regiospecific synthesis of 4,6-diaryl-3,7-dioxydibenzophospholes from 2,2′4,4′-tetranitrobiphenyl

3,3‴-Dimethyl -2′,2″,4″,6′-tetranitro-5,5‴-di-t-butyl-m-quaterphenyl did not undergo selective alkoxydenitration at the 2′ and 4″ positions, but when acetoxymethyl groups were placed at the 2 and 2‴ positions, treatment with sodium methoxide caused regiospecific cyclization at these positions and formation of a bibenzochromenyl. Other reagents led to a mixture of two regioisomers. The two remaining nitro groups were replaced via a diamine and a di-iodide by a phosphinic ester bridge. The pyran rings could then be opened by boron tribromide to afford a 4,6-diaryldibenzophosphole. The two bromomethyl groups in this intermediate were converted after acetylation into dimethylphosphonomethyl groups and one atropisomer (the meso isomer) was isolated. Some analogous experiments in the biphenyl series are reported.

The synthesis and nmr characterization of a series of 1,4-dihydro-1,4- ethanonaphthalene epoxides

Abstract A series of syn and anti epoxides derived from 5,8-disubstituted-1,4-dihydro-1,4-ethano-naphthalenes have been prepared. The role of the solvent on epoxidation stereochemistry has been explored. The structures of the epoxides were assigned with the aid of proton NMR coupled with chemical shift reagents. The C-13 spectra have also been assigned, and an unusual γ-effect of the epoxide structure noted.

Comment on a paper by Samir Chatterjee.

All claims in the paper cited (Tetrahedron Lett. 3249 (1979)) should be accepted as fact after, but not before, verification by independent experiment.

Review Lecture: The Imitation of Enzymic Catalysis

This lecture is a report of progress in work that began at Shell Research Ltd’s Milstead Laboratory and has continued at the University of Sussex. I had spent some ten years studying the substrate sterochemistry of enzymes. No one who has done this could fail to be impressed by the stereochemical precision with which enzymes handle their substrates, even when the nature of the product does not exact a stereospecific treatment. It is hard to resist the conclusion that this specificity is an integral and not an incidental feature of the enormous efficiency of enzymes as catalysts. Naturally, like everyone who has worked with enzymes, I form hypotheses about this or that enzymic catalysis; some of these ideas have been testable by stereochemical methods or by various types of isotopic labelling. Further progress can be, and is being, made by the intensive study of particular enzymes, but to someone like myself who is interested in chemical reactions and chemical synthesis it was more attractive to attempt, on the basis of knowledge and conjecture about the nature of enzymic catalysis, to devise synthetic catalysts having the properties of stereospecificity, positional specificity and high efficiency. Without at present presuming to excel or even equal catalytic powers that are thought to have evolved by trial and error over thousands of millions of years, one can, by making the assumption that catalytic activity of this type is not uniquely a property of proteins, substitute the resources of organic chemistry as a whole for the rigours of polypeptide synthesis.

Synthesis of substituted dibenzophospholes. Part 8. Synthesis and resolution of atropisomers of a 4,6-diaryldibenzophosphole

Regiospecific replacement of the 4″- and 6′-nitro groups in a 2′,2″,4″,6′-tetranitro-m-quaterphenyl by alkoxy groups has been effected in two ways: (i) the dialkali salts of α-oximinoalkanoic acids replaced one nitro group by a hydroxy group; after O-alkylation the other alkoxydenitration was effected by sodium benzaldehyde oxime followed by O-alkylation; (ii) both nitro groups were replaced by treatment with sodium 2,2-dimethoxy-1,2-diphenylethanone oximate followed by acidic hydrolysis, alkaline cleavage, and O-alkylation. From the product, synthetic procedures already developed gave 3,7-di-isopropoxy-5-methoxy-4,6-bis-(4-methoxy-2-methyl)dibenzophosphole 5-oxide, separated by chromatography into one racemic and two meso forms. The thermal interconversion of the three forms was demonstrated and measured. The racemic form was resolved by high-performance liquid chromatography (h.p.l.c.) on a chiral column.

Asymmetry and enzyme action

It must, I think, be rare to be rewarded so generously for work that was so purely a pleasure in planning and execution. I shah try, in return, to impart some of that pleasure today. In 1948, a short but historic note by Alexander Ogston appeared in the scientific magazine Nature, demonstrating the importance of a particular type of stereochemical thinking in relation to biochemical processes catalysed by enzymes_ Up to that time I had, as an organic chemist interested in the synthesis of natural products, the same kind of feeling for stereochemistry that a motorist might have for a system of oneway streets a set of rules forming one more obstacle on the way to a destination_ But 19.48 was a year in which, as well as continuing cohaboration with Robert Robinson on the total synthesis of sterols, I had begun to co-operate with biological scientists at the National Institute for Medical Research; so that Ogston’s note was a seed that germinated the more readily in my mindThe essential principles of the three-dimensional structure of organic molecules had been correctly formulated by the first Nobel laureate in Chemistry, Jacobus van% Hoff, as early as 1874, In particular he (and independently Le Bel) gave a structural basis to Louis Pasteur’s discovery that certain molecules can exist in two opficaZZy active forms that differ from each other in their effect on a beam of plane polarized light; the plane of polarization is rotated to the right when the beam passes through a solution of one form, and to the left when the other form is substituted_ van% Hoff theorized that when a carbon atom in a molecule is attached to its maximum number of four other atoms, these occupy the four apices of a tetrahedron, with the carbon atom in the middle. Another way of saying the same thing is that the four atoms keep as far away from each other as they can, given that they are bound at fixed distances from the central atom. If these four atoms are all different, or at any rate if each forms part of a different group of atoms, they can occupy two distinct spatial arrangements that are chiral: their relationship is that of a right hand with a

A general reagent for O-phosphonomethylation of phenols

Diethyl 4-chlorophenylsulfonyloxymethylphosphonate, ClC6H4SO2OCH2P(O)(OEt)2, has been established as the reagent of choice for conversion of phenols via alkali phenoxides into phenoxymethylphosphonates. With other leaving groups (iodide, methanesulfonate, toluene-4-sulfonate), or with the dimethyl instead of the diethyl ester, concomitant formation of alkyl phenyl ethers reduced the yields. The reactions proceeded easily in polar aprotic solvents, usually at room temperature, and yields were excellent. The products were easily converted by mild alkaline hydrolysis into monoesters, or into phosphoric acids via cleavage with iodotrimethylsilane. Some phenols were also converted into diethyl aryloxymethylphosphonates by incorporation into mixed formals by reaction with 2,4-dichlorophenoxymethyl chloride, followed by Lewis acid-catalysed transfer of an aryloxymethyl group to triethyl phosphite.