Cyclopentane-based

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...

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. 

A new stereoselective synthesis of 1,2,3-trisubstituted cyclopentanes based on the Wag-ner-Meerwein rearrangement of a 7-oxabicyclo[2.2.1]heptyl 2-cation starts with the Diels-Alder product of maleic anhydride and a furan (78TL2165, 79TL1691). The cycloadduct was hydrogenated and subjected to methanolysis. The half acid ester (47) was then electrolyzed at 0 °C to generate a cationic intermediate via the abnormal Kolbe reaction (Hofer-Moest reaction). Work-up under the usual conditions provided the 2-oxabicyclo[2.2.1]heptane (48) in 83% yield. Treatment of this compound in turn with perchloric acid effected hydrolysis of the ketal with formation of the trisubstituted cyclopentane (49) in nearly quantitative yield (Scheme 11). Cyclopentanes available from this route constitute useful... 

Enynes in which three or four atoms separate the double and triple bonds cyclize upon complexation to Co2(CO)g and subsequent heating to give bicyclic enones (equation 52). With the exception of slightly elevated temperatures the conditions required are no different than those of the stoichiometric procedure described earlier for reactive substrates in intermolecular Pauson-Khand reactions. The intramolecular cycloaddition cannot in general be carried out under catalytic conditions. Hex-l-en-5-yne, which would give a four-membered ring upon intramolecular cycloaddition, instead undergoes alkyne trimerization exclusively.3 The most extensively studied systems are those derived from hept-l-en-6-yne, as the products, bicyclo[3.3.0]oct-l-en-3-ones, are useful in the synthesis of numerous cyclopentane-based polycy-clics. 

A thiol handle can, in principle, be introduced through an auxiliary group [123] or by direct attachment to a side-chain. While auxiliaries can be anchored either to the backbone or to a side-chain, each approach involves inherent limitations (Fig. 2). When an auxiliary is attached to the backbone, the subsequent coupling to this residue is typically slow, which limits its utility to less hindered junctions. Nevertheless, successful examples have been reported by Kent [124, 125], Botti [126], Dawson [127], Danishefsky [128], and others [123, 129]. Use of a side-chain auxiliary circumvents the above difficulty but requires an appropriate side-chain anchoring site. This method has been successfully demonstrated by Wong et al. with carbohydrate-based auxiliaries at the side-chains of Ser or Thr [130, 131] and Brik et al. with cyclohexane or cyclopentane-based auxiliaries on the side-chains of Asp, Glu, Ser, or Thr [132,133],... 

The cyclopentane-based phosphate 79, designed as a mimic for myo-inositol 1,4,5-trisphosphate, has been synthesized by two different routes. The cyclitol ring was formed firstly by a Cp2Zr induced ring contraction of a hept-6-enose derivative, essentially as previously reported (Vol. 29, p. 238, ref. 94) secondly by a samarium diiodide promoted pinacol-like coupling of a 1,6-dialdehyde derived from methyl 2-0-benzyl-3,4-bis-(p-methoxybenzyl)-a-D-g/wco-hexodialdopyrano-side. ... 

Table 4.6. Examples of contributions of substitutions of a methyl group with one hydrogen on the methane and cyclopentane bases...

The cyclopentane-based inhibitor 8 was hcensed to Johnson Johnson for clinical development under the generic name peramivir. While data had suggested that peramivir (8) could be delivered for therapy by oral administration (e.g.,... 

General Methods.—Trost and his co-workers have extended their earlier studies of the synthesis of cyclopentanes based on thermolysis of vinylcyclopropanes, and shown that it is expedient to use the recently developed 1-lithiocyclopropyl phenyl sulphide (32) for the preparation of the appropriate vinylcyclopropane precursor. Thus addition of (32) to ketone (33), followed by dehydration of the intermediate hydroxy-sulphide with SOCI2, led to (34), which on thermolysis in the vapour phase at 350 °C, then hydrolysis, gave the cyclopentenone (35). An identical approach to cyclopentane annelation has been used by Miller in a synthesis of (36) from cyclopent-2-enone. 

The scope provided by the method of synthesis of cyclopentanes based on thermal conrotatory ring closure of a chloropentadienyl cation, followed by hydrolysis, has been expanded with new approaches to the formation of the requisite carbonium intermediates (Scheme... 

Allosamidin has been converted to its demethyl and didemethyl analogues by treatment with methylamine and ammonia respectively, and 6- and 6"-0-acyl derivatives were also prepared. A study of the biosynthesis of allosamidin suggests that one A -methyl group is introduced before cyclization of the oxazoline ring. A synthesis of the cyclopentane-based (-)-allosamizoline moiety of allosamidin is mentioned in Chapter 18. 

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