Synthesis of analogues

Once a compound with the desired odour properties has been discovered it is normal practice to prepare a range of analogues. The reasons for this are two-fold firstly, materials with even better odour characteristics than the parent compound may be identified (i.e. lead optimization) and, secondly, information about the structural requirements for the desired odour characteristics are acquired. The latter is of particular importance when filing a patent. 

Another example of analogue synthesis dates back to the 1960s. As mentioned above, the first phenylpropanal to be discovered with a white, floral odour was cyclamen aldehyde, 3-(4-isopropylphenyl)-2-methylpropanal (2). As the name implies, its odour is reminiscent of wild cyclamen. However, at low concentrations the odour possesses a hydroxycitronellal-like note. Consequently, it was common practice in the 1960s to replace hydroxycitronellal, which is unstable in alkaline media and irritating to the skin, with cyclamen aldehyde. However, from an odour point of view the substitution was not entirely satisfactory. The discovery of the closely related r-butyl analogues (3 and 6) resulted in a certain improvement (Givaudan Corp., 1959 Boelens and Wobben, 1980). Both of these compounds have a more pronounced muguet floral odour. 

Berends and van der Linde (1967) synthesized and organoleptically-assessed 24 analogues of cyclamen aldehyde (26). They varied the nature of the alkyl substituent in the para position, altered the position 

Another example of analogue synthesis dates back to the 1960s. As mentioned above, the first phenylpropanal to be discovered with a 

1) The cyclamen character is most clearly discernible in compounds with a branched alkyl group at the para or meta position, where the branch is present at the C atom linked to the phenyl ring (e.g. Rl = CH(CH3)2). 

2) Where the branch is at a C atom farther removed from the nucleus, the cyclamen character diminishes and the odour becomes more muguet (e.g. R1 = — CH2C(CH3)3). 

3) The introduction of an alkyl substituent at the alpha position in relation to the aldehyde group causes a decrease in odour intensity. 

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Example Compound (27) was needed for synthesis of analogues of vernolepin, an anti-tumour compound. Robinson disconnection suggests unsymmetrical ketone (28)... 

Scheme 4.29. Synthesis of analogues of the indole alkaloid vindoline.

It was Breslow (Breslow, 1982 Breslow et ai., 1982) who first paid attention to this theory. Knowing that the pentachlorocyclopentadienyl cation (Breslow et ai, 1964 Saunders et ai, 1973), the hexachlorobenzene dication (Wasserman et al., 1974) and the 2,3,6,7,10,11-hexamethoxy-triphenylene (HMT, [36]) dication are all ground-state triplets, in good agreement with theory, Breslow and coworkers set out on the synthesis of analogues that should have lower oxidation potentials, be chemically more stable and therefore form CT complexes more readily (Fig. 21c Breslow et al., 1982, 1984 Breslow, 1985, 1989 LePage and Breslow, 1987). 

Although only a few condensed 5 6 or 5 5 aromatic pyrazole derivatives can be isolated from biological sources, the chemistry of condensed pyrazoles has received considerable interest. Condensed pyrazoles with an indene skeleton can be considered as purine analogues and, as such, are expected to have biological activity. The discovery of the xanthene oxidase inhibitory action of pyrazolo[3,4-fiT pyrimidine and the cAMP phos-phodiasterase inhibitory action of pyrazolo[l,5-a]pyrimidines has stimulated considerable interest in the synthesis of analogues of both ring systems. 

L. Hough, E. Tarelli, and A. C. Richardson, Chemical modification of trehalose. Part VI. The synthesis of analogues containing 2,2 -dideoxy functions, /. Chem. Soc., Sect. C (1971) 1732-1738. 

Moloney and co-workers (64) also made use of the morpholinone template in the synthesis of analogues of the kainoid group of amino acids. Treatment of the template under the conditions reported by Harwood furnished the expected adducts. In keeping with earlier observations, the reaction proceeded with complete facial selectivity generating the new C(3) stereogenic center with complete control. 

It was known from the work of Richards that RNase A could be cleaved between residues 20 and 21 by digestion with subtilisin. 29 The N-terminal 20-residue peptide (S-peptide) could be separated from the 104-residue 21-124 protein (S-protein), and each was enzymatically inactive however, when they were mixed in a 1 1 ratio, full RNase activity was regenerated even though the covalent bond between residues 20 and 21 was not re-formed. This finding was the basis for a great many structure/function studies by the synthesis of analogues of the S-peptide and their noncovalent recombination with natural S-protein.13"31 ... 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

The phosphonates are of interest as reagents for the synthesis of difluoro-alkenes, and as building blocks for the synthesis of analogues or chemical mimics of important phosphate esters. The chemistry was reviewed recently... 

The category Id cyclization has also been applied to 4-aminoindoles of the type found in the indolelactam tumour promoters such as lyngbyatoxin A and pendolmycin. In a synthesis of analogues of lyngbyatoxin A the isoxazoline 8.4A was constructed as a key intermediate ]. Reductive cleavage of the isoxazoline ring generated 8.4B which was cyclized by reaction with terf-butyldimethylsilyl triflate (Entry 6, Table 8.1). The cyclization of a thioamide was a key step in the synthesis of pendolmycin[5] (Entry 7, Table 8.1). 

Acylation of the keto acid (637) leads to the isobenzopyrylium salt (638) (77CHE1183). However, the isobenzopyrylium salt (639), a potential intermediate for the synthesis of analogues of berberine alkaloids, results from the formylation of the substituted ketone or the isochromanone (640) using dichloromethyl butyl ether (Scheme 251) (81CHE221). A second product, the 5-oxoniachrysene (641), is formed and this compound may also be obtained by reaction of the isobenzopyrylium salt with phosphorus pentachloride and then with triethylamine. The intermediacy of a cyclic vinyl ether is proposed. 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

A microwave-assisted Fischer indole synthesis under solvent-free conditions with Montmorillonite K10 clay modified with zinc chloride was employed in a key step of the synthesis of analogues of the cytostatic natural product, Sempervirine (Scheme 3.6)8. A dedicated laboratory microwave synthesizer was utilised. 

Metal-free corrinoids are produced by photosynthetic bacteria.863 This allows the synthesis of analogues of vitamin B12 having other metals present, such as zinc, copper or rhodium. The... 

In their work on the synthesis of analogues of the tryptophan amino acid, Carlier et al. found that when product 71 is treated with 1.5equiv of (Me0)2P(0)CH-(NHCbz)CC>2Me in the presence of a base, 72 is formed after the olefination reaction by extrusion of benzyl alcohol (Equation 10) <2002JOC6256>. 

Synthesis of Analogues of Folic Acid, Aminopterin and Methotrexate as Antitumour Agents... 

An early synthesis of folic acid developed by chemists at American Cyanamid involved condensation of 2,4,5-triamino-6-hydroxypyrimidine, 2,3-dibromopropionaldehyde and p-aminobenzoylglutamic acid (Scheme 3.9) [55a-d].This three-component procedure has become known as the Waller condensation, and has been widely employed for the synthesis of analogues because of the ease with which the various components of the condensation can be varied. Products from this three-component reaction, however, are mixtures of 6- and 7-substituted regioisomers. 

The synthesis of analogues of FA and MTX in which a nitrogen atom has been interposed between the benzene ring and the glutamate side-chain has been reported Scheme 3.128) [254,255]. Treatment of 2,10-diacetylpteroic... 

Acylaminoimidazole 1-oxide 276 was prepared like 3-hydroxyimidazole 1-oxide 267 replacing amine with hydrazine. Only one example has been reported but other reactions for preparation of 3-hyd roxyi midazoIe 1-oxide 267 offer opportunities for synthesis of analogues of 276 after replacement of amine with hydrazine as the starting material (2004USP248958) (Scheme 80). 

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