Kenner synthesis

Substituted pyrrole-2-carboxylic esters 19 are synthesized from A-tolylsulfonyl glycine ester 17 and vinyl ketones Kenner synthesis) [42]. By Michael addition and intramolecular aldol addition, they first yield pyrrolidine-2-carboxylic esters 18. These are converted into pyrroles by succesive H2O and sulfmic acid eliminations. 

G.W. Kenner, Synthesis of peptides. Chem. Ind. 1951,15 G.W. Kenner, R.J. Stedman. Peptides. Part I. The synthesis of peptides through anhydrides of sulfuric acid. J. Chem. Soc. 1952, 2067-2076... 

Substituted pyrrole-2-carboxylic esters 53 are synthesized from N-tolylsulfonyl glycine ester 51 and vinyl ketones (Kenner synthesis) [117]. 

BaddUey,)., Kenner, G.W., Lythgoe, B., Todd, A.R. (1944) Experiments on the Synthesis of Purine Nucleosides. Part X. A Synthesis of 9-D-Ribopyranosidoadenine. Journal of the Chemical Society, 657-659. 

Kenner GW, McDermott JR, Sheppard RC. The safety catch principle in solid-phase peptide synthesis. J Chem Soc Chem Comm 1971 636-637. 

GW Kenner, JH Seely. Phenyl esters for C-terminal protection in peptide synthesis. 

The described procedure is based on the methods of Johnson and Ambler 3 and Anderson et al.,4 as modified by Ulbricht and Price.5 This procedure is illustrative of a general method of preparing pyrimidines, wherein one condenses thiourea, guanidine, or an amidine with alkoxymethylenemalonic esters, alkoxy-methylenecyanoacetic esters, or alkoxymethylenemalononitrile. Kenner and Todd recently reviewed the synthesis of pyrimidines.6... 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

In order to classify the types of reactions that can be used for 1,3-thiazine synthesis, Cain and Warrener (70AJC51) chose a way similar to that proposed for pyrimidines by Kenner and Todd (57M12). 

Figure 12 A solid-phase total synthesis of the antimycobacterial cyclodepsipeptide kaha-lalide A. The synthesis relies on the Kenner safety-catch linker for attachment to the peptide backbone, followed by macrocyclative cleavage of the linear depsipeptide...

The sensitivity of thioester groups to aminolysis by piperidine has prevented the use of thioester-based linkers for Fmoc SPPS. Two groups d have adapted a modified form of Kenner s acylsulfonamide safety-catch linkerf for the synthesis of C-terminal thioester peptides using Fmoc protocols (Scheme 8). This approach is promising and future studies will more fully analyze the limitations of the method. 

The safety catch principle for the solid-phase preparation of C-ternninal modified peptides requires the bond between the handle and the first residue to be stable to the normal conditions of SPPS. However, at the end of the synthesis, a chennical transformation of the linker substituent makes the key bond labile to nucleophiles. The 4-sulfanylphenol 44b ti and the sulfonamide 45 (Kenner) resins are two examples of safety catch resins. Thus, in the first case, which is only compatible with the Boc/Bzl strategy, once the peptide chain is elongated, treatment of the peptide-resin with hydrogen peroxide converts the sulfide into the corresponding sulfone, which makes the bond labile to nucleophiles. In the second case, N-methylation with diazomethane leads to an N-methylated peptidyl-sulfonannide-resin, from which peptides can also be cleaved by nucleophiles. 

To obtain neurokinin-1 (NKi) receptor antagonists. Cooper and co-workers [410] synthesized a series of variously substituted indoles by means of a Fischer indole synthesis on a solid phase. Thus, EUman resin [411], based on Kenner s safety-catch Hnker [318], was first reacted with 4-(4-chlorobenzoyl)butyric acid affording (598) and then treated with differently substituted phenyUiydrazines, affording the required indoles (599). These compounds were then cleaved from the resin using bromoacetonitrile, and subsequently coupled in solution with the desired amines under standard conditions (600) (Scheme 125). 

Reduction of phenols [1, 252, after citation of ref. 3]. In achieving the synthesis of triptindane (11), Thompson obtained the methyl ether (8a) as an intermediate, demethylated it to (9), and effected deoxygenation to (11) by the method of Kenner and Williams consisting in reaction with diethyl phosphonate or mesyl chloride and reduction of the diethyl phosphate or the mesylate ester with sodium in liquid ammonia yields, first procedure 58% second procedure 36%. 

Olefin synthesis from a,p-unsaturated ketones. Ireland and Pflster1 have extended the procedure of Kenner and Williams (1,248, ref. 2) for deoxygenation of phenols to conversion of a,/3-unsaturated ketones into olefins. For example, the a,)3-unsaturated ketone (1) was reduced by lithium-ammonia to give an enolate anion which reacted with diethyl phosphorochloridate to give the phosphate ester (2) in 56% yield. This ester was reduced in high yield by lithium in a mixture of ethylamine and r-butanol to the olefin (3). It is noteworthy that only one olefin is formed. Actually the conversion of (1) into (3) can be carried out in 50% yield without isolation of the diethyl enol phosphate. 

Peptide synthesis. Based on analogy with use of onium salts derived from DMSO, Kenner and co-workers9 developed a useful new method of peptide synthesis. Tosic anhydride10 is allowed to react for 15 min. with excess hexa-methylphosphoric triamide to form the ditosylate (1). The solution is then cooled... 

The authors are grateful to Mallinckrodt Speciality Chemicals for support of the research work regarding their own approaches to morphine. We thank Kenner Rice (NIH) for reading the manuscript and for providing information connected to the use of morphine and derivatives and Professor David R. Dalton of Temple University for sharing with us a copy of a recent dissertation. Scott Richardson of Mallinckrodt Specialty Chemicals is acknowledged for sharing with us a review of morphine synthesis. 

Improved synthesis of (+)- morphine, (+)-codeine and (+)-heroine Rice, Kenner C. Iijima, Ikuo Brossi, Arnold... 

Primary diazoalkanes, i. e., monosubstituted diazomethanes, are more stable than the corresponding secondary (disubstituted) diazoalkanes. In the series of primary diazoalkanes, the tendency for decomposition increases from diazomethane to 1-diazooctane (Adamson and Kenner, 1935). The remarkable stability of silylated diazoalkanes (Seyferth et al., 1968, 1972 Seyferth and Flood, 1971) has led to investigations on their use in synthesis as a stable and safe substitute for diazomethane (Aoyama and Shioiri, 1981 Mori et al., 1982 Shioiri et al., 1990 Anderson and Anderson, 1991, see Sect. 2.6). (Trimethylsilyl)diazomethane is now commercially available (Petrarch). 

Morphine s synthesis remains a serious challenge to this day. Until recently, the formal synthesis published by Kenner Rice [16] was its most efficient preparation. In 2009, Magnus reported a route to codeine with a reported overall yield of approximately 17% [17]. All academic s)mtheses reported in the literature, creative as these may be, suffer from lack of practicality, with the sole exception of Rice s disclosure, which has potential for scale-up. 

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