Synthesis Elaboration

The most widely used method of synthesizing oxadiazoles is the cyclization of O-acylamidoximes. Aldoximes (I) may be used as starting compounds for amidoximes (3) by the pathway shown in Eq. (1). The amidoximes may then be converted into 0-acyl derivatives (4), long7-8 

Many variations on the pathway represented by Eq. (1) are successful. For example, the amidoxime can be made by heating a nitrile with hydroxylamine hydrochloride10-17 and in other ways. 

In addition to the acid anhydride12,14,17-19 shown as the source of the carbon at C-5 in the final product [Eq. (1)], ketene,20 reactive acids such as formic21 and acrylic,22 acid chlorides,10,23-26 esters,27 ortho esters,28-34 ethyl oxalate,35 amides,35 and iminoethers36 [Eqs. (12-14)] may also furnish the C-5 carbon. 

The reaction of amides35 with amidoxime salts is especially felicitous because no solvent is needed and recovery is simple. The two components are melted together at 160-180° for 10 minutes, and water is lost at the elevated temperature. Both aliphatic and aromatic (di- and monosubstituted) amidoximes give yields in the range 60-90%. Whether an O-acyl (or an TV-acyl) intermediate (4) is formed has not been determined. 

With very reactive acid chlorides, such as chloroacetyl chloride,11 dichloroacetyl chloride,13 a-chloropropionyl chloride,37 and perfluoro- 

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A synthesis elaborated by the BASF affords directly pear ester 232 with about 85 % of the isomer with (Z)-geometry of the C-4 double bond. This synthesis involves reaction of phosphorane 93 with fumaric ester aldehyde 233 (sodium amide technique). The latter is formal by ozonolysis of sorbic ester163) (Scheme 45). Principally, the same method was published by a Belgian research group, leading to 70% of (2 ,4Z)-2,4-isomer 164>. 

Chapter 3 describes how Verilog HDL constructs are collectively used to model hardware elements. While Chapter 2 describes the mapping of Verilog HDL to logic gates, this chapter describes the opposite scenario, which is, how to model a hardware element in Verilog HDL for synthesis. Elaborate examples are provided for many common hardware elements, such as multiplexers, counters, decoders and arithmetic-logic-units. 

Because of the possibility of pyrrole double bond migration, all the above syntheses were carried out via 2,3-dihydroindole intermediates which ultimately required a dehydrogenation step. The synthesis elaborated by Oppolzer 201) is exceptional as the indole nucleus was kept intact throughout the entire reaction sequence (Scheme 41). The strategy relied on concomitant formation of rings C and D by an intramolecular [4+2]... 

The EROS (Elaboration of Reactions for Organic Synthesis) system [26] is a knowledge-based system which was created for the simulation of organic reactions. Given a certain set of starting materials, EROS investigates the potential reaction pathways. It produces sequences of simultaneous and consecutive reactions and attempts to predict the products that will be obtained in those reactions. 

A more elaborate variation gives a generell amino acid synthesis. If the reaction between an aldehyde and cyanide is done in the presence of ammonia, the product is an a-amino-nitrile ... 

The amino add analysis of all peptide chains on the resins indicated a ratio of Pro Val 6.6 6.0 (calcd. 6 6). The peptides were then cleaved from the resin with 30% HBr in acetic acid and chromatogra phed on sephadex LH-20 in 0.001 M HCl. 335 mg dodecapeptide was isolated. Hydrolysis followed by quantitative amino acid analysis gave a ratio of Pro Val - 6.0 5.6 (calcd. 6 6). Cycll2ation in DMF with Woodward s reagent K (see scheme below) yielded after purification 138 mg of needles of the desired cyc-lododecapeptide with one equiv of acetic add. The compound yielded a yellow adduct with potassium picrate, and here an analytically more acceptable ratio Pro Val of 1.03 1.00 (calcd. 1 1) was found. The mass spectrum contained a molecular ion peak. No other spectral measurements (lack of ORD, NMR) have been reported. For a thirty-six step synthesis in which each step may cause side-reaaions the characterization of the final product should, of course, be more elaborate. 

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

In a more elaborate and specific synthesis, the terpenoid indole skeleton found in haplaindole G, which is isolated from a blue-green alga, was constructed by addition of a nucleophilic formyl equivalent to enone 6.5A. Cyelization and aromatization to the indole 6.6B followed Hg -catalysed unmasking of the aldehyde group[6]. 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

Ak2o has been iastmmental ia developiag a new process for the stereospecific synthesis of 1,4-cyclohexane diisocyanate [7517-76-2] (21). This process, based on the conversion of poly(ethylene terephthalate) [25038-59-9] circumvents the elaborate fractional crystallisation procedures required for the existing -phenylenediamine [108-45-2] approaches. The synthesis starts with poly(ethylene terephthalate) (PET) (32) or phthaUc acid, which is converted to the dimethyl ester and hydrogenated to yield the cyclohexane-based diester (33). Subsequent reaction of the ester with ammonia provides the desired bisamide (34). The synthesis of the amide is the key... 

Griseofulvia [126-07-8] (54) coataias the pblorogluciaol aucleus. It is an important oral antifungal agent ia humans and animals, elaborated by certain strains of Penicillium. One synthesis of griseofulvia is based oa the appropriately substituted pblorogluciaol (196). Uvaretia [58449-06-2] (55), which is extracted from JJvaria acuminata inhibits lymphocytic leukemia (200). 

Extension of the appHcations of polymethine dyes has required special spectral and other characteristics. As a rule, the search for and synthesis of promising new compounds having desired properties imply the preliminary estimation of their most important parameters on the basis of elaborated theoretical conceptions. Thus, an effective way of governing electron properties consists of the variation of molecular topology of polymethines. 

Cyclization of Aliphatic Precursors. This strategy consists of assembling the key functional groups in an aUphatic format, cyclizing to a cyclopentane intermediate, and completing the synthesis by further elaboration of the side chains. One appHcation of this strategy is as follows ... 

Extension of the Phosphorane Route. Ample evidence of the versatihty of the phosphorane synthesis strategy is provided by the proliferation of penems that followed. Nucleophilic displacement of the acetate function of the acetoxy-azetidinone (51, R = OCOCH ) [28562-53-0] (86) provided azetidinones where R = SCOCH, SCSSC2H, and SCSOC2H, which on elaboration gave the penems (52, R = CH ) (87), (52, R = SC2H ) (88), (52, R = 0C2H ) (89). Similar treatment of 3-substituted (or disubstituted) acetoxyazetidinones allowed the synthesis of a number of 2-substituted- 6-alkyl-and 6,6-dialkylpenems (90). 

Puromycin. Puromycin (19), elaborated by S. alboniger (1—4), inhibits protein synthesis by replacing aminoacyl-tRNA at the A-site of peptidyltransferase (48,49). Photosensitive analogues of (19) have been used to label the A-site proteins of peptidyltransferase and tRNA (30). Compound (19), and its carbocycHc analogue have been used to study the accumulation of glycoprotein-derived free sialooligosaccharides, accumulation of mRNA, methylase activity, enzyme transport, rat embryo development, the acceptor site of human placental 80S ribosomes, and gene expression in mammalian cells (51—60). 

Scientists at Merck developed a cephalosporin synthesis based on the addition of azidoacetyl chloride to 1,3-thiazines (56). Although this gives the incorrect 7a -epimer (57), it could be equilibrated to a mixture of 7-amino epimers (see Section 5.10.3.3) from which the desired 7/3-isomer could be separated and further elaborated to cephalosporins (B-82MI51001). 

Since a few protective groups cannot satisfy all these criteria for elaborate substrates, a large number of mutually complementary protective groups are needed and, indeed, are becoming available. In early syntheses the chemist chose a standard derivative known to be stable to the subsequent reactions. In a synthesis of callistephin chloride the phenolic —OH group in 1 was selectively protected as an acetate. In the presence of silver ion the aliphatic hydroxyl group in 2 displaced... 

Ethers are among the most used protective groups in organic synthesis. They vary from the simplest, most robust, methyl ether to the more elaborate, substituted, trityl ethers developed for use in nucleotide synthesis. They are formed and removed under a wide variety of conditions. Some of the ethers that have been used to protect alcohols are included in Reactivity Chart 1. ... 

Biosynthesis Production, by synthesis or degradation, of a chemical compound by living organism, plant or animal cells, or enzymes elaborated by diem. 

The first synthesis of the potent antitumor agent maytansine was carried out by the elaboration of aldehyde D, an intermediate in the enantioselective synthesis of (-)-A/-methylmaysenine (Ref. 1,2), using enantioselective and diastereoselective steps. 

Whereas ATP made in glycolysis and the TCA cycle is the result of substrate-level phosphorylation, NADH-dependent ATP synthesis is the result of oxidative phosphorylation. Electrons stored in the form of the reduced coenzymes, NADH or [FADHa], are passed through an elaborate and highly orga-... 

Reagent-controlled asymmetric cyclopropanation is relatively more difficult using sulfur ylides, although it has been done. It is more often accomplished using chiral aminosulfoxonium ylides. Finally, more complex sulfur ylides (e.g. 64) may result in more elaborate cyclopropane synthesis, as exemplified by the transformation 65 66 ... 

Moody s synthesis of promothiocin 43 provided evidence that the Bohlmann-Rahtz method can be used for the rapid synthesis of complex pyridines. Oxazaole 44 was treated with alkynyl ketone 45 to afford 46 in 83% yield. The ester moiety of 46 was elaborated into a thiazole substituent providing entry into the northeast quadrant of 43. 

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