Compounds labeling, stereospecific

Buchwald, Friedman and Knowles succeeded in preparing 2,4-dinitrophenyl phosphate in which the three free oxygen atoms on phosphate were labeled stereospecifically with different isotopes of oxygen. Solvolysis of this compound in methanol and analysis of the methyl phosphate product showed that the reaction had proceeded with inversion of configuration at phosphorus (79). This remarkable experiment supports a concerted bimolecular displacement mechanism, with no metaphosphate intermediate, for the solvolysis of 2,4-dinitrophenyl phosphate in methanol. However, it does not rigorously exclude a stepwise mechanism in which a metaphosphate intermediate with a very short lifetime is formed and reacts with methanol faster than it rotates, and it does not provide direct evidence for a bimolecular, concerted reaction with solvent water. 

Part—VI has been solely devoted to Miscellaneous Assay Methods wherein radioimmunoassay (RIA) (Chapter 32) has been discussed extensively. Various arms of theoretical aspects viz., hapten determinants and purity importance of antigenic determinants and analysis of competitive antibody binding of isotopically labeled compounds. The applications of RIA in pharmaceutical analysis, such as morphine, hydromorphone and hydrocordone in human plasma clonazepam, flurazepam in human plasma chlordiazepoxide in plasma barbiturates, flunisolide in human plasma have been described elaborately. Lastly, the novel applications of RIA-techniques, combined RIA-technique-isotope dilution and stereospecificity have also been included to highlight the importance of RIA in the analytical armamentarium. 

The stereospecific labeling of the anti methyl by deuterium in compound 20 to produce substrate 21 (Table 3) was required in order to study the syn/anti regioselectivity of the ene allylic hydroperoxides. The ene products in different solvents showed a preference for hydrogen abstraction from the methyl syn to the phenyl group. The magnitude of this selectivity depends on solvent polarity. On increasing the solvent polarity, a substantial increase in the amount of syn product occurs (Table 3). 

The ester-substituted complex (34) has been used in synthesis of (+)- and (-)-shikimic acid, an important intermediate in the biosynthesis of aromatic compounds, as well as stereospecifically deuterium labeled shikimic acid.60 Addition of hydroxide anion to (+)-(34) gives the diene complex (+)-(182),... 

Young, D. W. Stereospecific Synthesis of Tritium Labelled Organic Compounds using Chemical and Biological Methods, Vol. 4, p. 177, ibid. 1978... 

The phenyl ring of styrene substrates directs a syn selectivity in their ene reactions with singlet oxygen [71], This effect was demonstrated by the photo-oxygenation of (3,(3-dimethyl styrene. This substrate, a part of the ene product, produces the 1,2-dioxetane and two diastereomeric diendoperoxides [72,73], as shown in Scheme 12. The stereospecific labeling of the anti methyl by deuterium in compound 24 to produce substrate 25 was required in order to study the syn/anti stereoselectivity of the ene products. 

The intermediate bicyclo[2,2,l]heptyl cation has been written in Fig. 1 in its unbridged form by analogy with conclusions reached from studies of the Bamford-Stevens reaction of 18 stereospecifically deuteriated in either the 6-exo- or 6-endo positions (Nickon and Werstiuk, 1966). Under aprotic conditions (diglyme/sodium methoxide), the product is entirely norticyclene (19), formed without loss of deuterium in keeping with carbene formation followed by intramolecular insertion. Under standard protic conditions, 19 still constitutes more than 90% of the reaction product, but 19% of the label is lost from ea o-deuteriated starting material and 52% from the endo-deuteriated compound,... 

For the concerted decomposition of N-nitroso compounds in (58), we require only that the orbitals labeled and three-membered ring and forbidden for the five-membered ring. The elimination of dinitrogen oxide from N-nitrosoaziridines is syn stereospecific (Clark and... 

As a whole, such high stereospecificity is difficult to attain by chemical catalysis, although asymmetric synthesis has developed markedly in recent years.80) Stereospecificity has been applied to the production of optically active compounds such as amino acids, and also to the synthesis of stereospecifically isotope-labeled compounds, the synthesis of which is not easily achieved by a chemical method (Table I. 3).75)... 

Mevalonic acid is indeed the true precursor of the terpenes but it is a C6 compound and so it must lose a carbon atom to give the C5 precursor. The spare carbon atom becomes C02 by an elimination reaction. First, the primary alcohol is pyrophosphorylated with ATP (Chapter 49) then the CO2H group and the tertiary alcohol are lost in a concerted elimination. We know it is concerted because labelling the diastereotopic hydrogen atoms on the CH2CO2H group reveals that the elimination is stereospecific. 

For acyclic alkenes, the facile rearrangement process obviates most possibilities of stereoselective transformation. The one exception is that of stereospecific isotopic labelling, for which hydrozirconation is a potentially powerful technique compounds of type Bu CHDCHDX (36), useful for NMR-based mechanistic studies, are conveniently obtained as in Scheme 9. This requires that four separate processes — hydrozirconation of alkyne, cleavage of alkeiiylzirconium, hydrozirconation of alkene and cleavage of alkylzirconium — all be completely stereospecific. 

The later study of Cooke and Andrews on the parent bicyclo[3.1.0]hexene did not fully concur with the conclusions of Doering and co workers. The racemization of optically active bicyclo[3.1.0]hex-2-ene-2,4,4-d3 was found to occur 1.33 0.15 times faster than scrambling of the deuterium. Furthermore, the mechanistic quadrisection that Doering and Schmidt had achieved by resolution of optically active compounds, was in this case studied by introduction of a single stereospecific deuterium label on C(4) (see Figure 29). 

The factors that make ene and retro-ene reactions proceed are nicely illustrated by a synthesis of enantiopure, isotopically labeled acetic acid CH(D)(T)C02H, a useful compound for studying the mechanisms of enzyme-catalyzed reactions. One ene and one retro-ene reaction occur in this synthesis. The ene reaction is driven by formation of a new tr bond at the expense of a C=C tt bond the retro-ene reaction is driven by the formation of a C=0 77 bond. Note that both pericyclic reactions proceed stereospecifically, even at the very high temperatures required for them to proceed ... 

Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes. The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1). In some cases oxidation rather than fluorination occurred. Stereospecifically deuterium-labelled allylic isoprenoid diphosphates, e.g. (1), have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and Sn2 displacement with pyrophosphate (Scheme 2). ... 

---