Cyclopentane-based Cyclopentanes

The name naphthenic acid is derived from the early discovery of monobasic carboxyUc acids in petroleum, with these acids being based on a saturated single-ring stmcture. The low molecular weight naphthenic acids contain alkylated cyclopentane carboxyUc acids, with smaller amounts of cyclohexane derivatives occurring. The carboxyl group is usually attached to a side chain rather than direcdy attached to the cycloalkane. The simplest naphthenic acid is cyclopentane acetic acid [1123-00-8] (1, n = 1). 

In the first of these sequences, often called the Torgov-Smith synthesis, the initial step consists in condensation of a 2-alkyl-cyclopentane-l,3-dione with the allyl alcohol obtained from 6-methoxy-l-tetralone and vinylmagnesium chloride. Although this reaction at first sight resembles a classic SN displacement, the reaction is actually carried out with only a trace of base. 

A general preparation of 2-acetonyl-2,4,6-triaryl-2//-thiopyrans 58 was discovered in the reaction of corresponding 2,4,6-triarylthiopyrylium perchlorates with ethanolic acetone catalyzed with various dialkylammonium salts (86GEP235455, 86JPR573). This preparative procedure was successfully extended to cyclohexane- and cyclopentane- 1,2-diones as the carbonyl components (89JPR853 90GEP280324). The action of bases on thiopyrylium salts may caused their dimerization to thiopyranyl derivatives under suitable conditions (89KGS479). 

A direct application of the ring-opening reaction of an epoxide by a metal enolate amide for the synthesis of a complex molecule can be found in the synthesis of the trisubstituted cyclopentane core of brefeldin A (Scheme 8.35) [68a]. For this purpose, treatment of epoxy amide 137 with excess KH in THF gave a smooth cyclization to amide 138, which was subsequently converted into the natural product. No base/solvent combination that would effect cyclization of the corresponding aldehyde or ester could be found. 

Fig. 8 Superimposition of inhibitors and key active site residues in influenza A virus sialidase cyclopentane-based inhibitor peramivir 34 (brown carbons, PDB - 117f), Neu5Ac2en 4 (green carbons, PDB - lf8b). Note the overlap of the carboxyl and acetamido-methyl groups of the inhibitors, and the alternative conformations of the side-chain of Glu276. To the right is shown peramivir 34 oriented as in the crystal structure...

Chan T-H, Xin Y-C, von Itzstein M (1997) Synthesis of phosphonic add analogs of siaUc acids (Neu5Ac and KDN) as potential sialidase inhibitors. J Org Chem 62 3500-3504 Chand P, Kotian PL, Dehghani A, El-Kattan Y, Lin T-H, Hutchison TL, Babu YS, Bantia S, Elliott AJ, Montgomery JA (2001) Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J Med Chem 44 4379 392... 

Compound 1 was the first cyclopentane-based NK-1 receptor antagonist development candidate at Merck. It contains five stereocenters a central core possessing three contiguous all-trans stereocenters, a pendent bis(trifluoromethyl)-benzyHc ether, and a nipecotic acid moiety (Figure 7.1). Key to the successful preparation of 1 was construction of the trans, trans-cyclopentyl core and installation of the unsymmetrical secondary-secondary (sec-sec) ether. The preparation of 1 is the focus of this chapter. 

The trihuoromethylcycloalkane systems do provide, however, some examples of CF3 bound to a tertiary center, with 1-methyl-1-trihuoro-methylcyclohexane, cyclopentane, and cyclobutane all absorbing at higher fields (-81, -78, and -80ppm, respectively) than the secondary systems mentioned above, as would be expected based on the branching principle. 

C-Chiral diphosphinites based on cyclohexane and cyclopentane rings (31) (cf. structure 17) have been used in 1 1 rhodium complexes at 50 atm H2 in unspecified solvents (259, 260). 

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