Cyclopentane-based synthesis

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. 

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. 

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 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. 

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... 

A hydrosilylation/cyclization process forming a vinylsilane product need not begin with a diyne, and other unsaturation has been examined in a similar reaction. Alkynyl olefins and dienes have been employed,97 and since unlike diynes, enyne substrates generally produce a chiral center, these substrates have recently proved amenable to asymmetric synthesis (Scheme 27). The BINAP-based catalyst employed in the diyne work did not function in enyne systems, but the close relative 6,6 -dimethylbiphenyl-2,2 -diyl-bis(diphenylphosphine) (BIPHEMP) afforded modest yields of enantio-enriched methylene cyclopentane products.104 Other reported catalysts for silylative cyclization include cationic palladium complexes.105 10511 A report has also appeared employing cobalt-rhodium nanoparticles for a similar reaction to produce racemic product.46... 

The vinylcyclopropane rearrangement is particularly valuable for cyclopentane synthesis. Aphidicolin (187), a most unusual antitumor agent, yields nicely to an analysis based on the concept of cyclopentanone annulation as outlined in Scheme 9... 

Cyclopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcyclopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsuccinate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic add or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

P. Chand, P. L. Kotian, A. Dehghani, Y. El-Kattan, T. H. Lin, T. L. Hutchison, Y. S. Babu, S. Bantia, A. J. Elliott, and J. A. Montgomery, Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity, J. Med. Chem., 44 (2001) 4379-4392. 

An intramolecular radical cyclization on carbohydrate derivatives was the method developed by Lundt and Homeman in a highly stereocontrolled synthesis of functionalized cyclopentanes [9]. Due to the neutral conditions required for the cyclization step, which prevented competing side reactions such as P-elimination and base-promoted epimerization, the potential of the employed radical intramolecular reaction versus the classical carbanionic carbon-carbon bond forming reactions was demonstrated. 

Ring closure to cyclobutanes and cyclopentane-s The synthesis of cyclo-propanones by elimination of lithium thiophenoxicMe with this base has been extended to similar syntheses of functionalized cyclob tanes and cyclopentanes, as shown in equations (I) and (II), When extended to synthesis of a cyclohexane derivative, this method resulted in a very low yield. One possible mechanism is formation of a dianion followed by loss of thiophenoxid e ion to give a carbene-anion, which cyclizes with loss of the second thiophenoxide ion. 

Functionalized substituted cyclopentanes and spirocyclopentanes were easily accessed by intramolecular photocycloaddition of dihydrofuran based dienes catalyzed by Cu(i) salts. Thus, tricyclic compound 39 was synthesized in 60% yield starting from 38 (Scheme 2.22). Notably, 39 can be easily transformed upon treatment with triflic acid into substituted cyclopentanones, which are important building blocks in the total synthesis of natural products. ... 

Hashimoto and coworkers have reported a highly diastereo- and enantioselective synthesis of 1,2-disubstituted cyclopentanes 53 that also avoids competing 1,2 hydride migration with appropriate choice of catalyst (Fig. 4) [68], Phthalimide-based Rh2(5-PTTL)4 (29a) was found to be the optimal catalyst for insertion into the benzylic position of the precursors to 53, and was effective for both electron poor and electron rich systems. The diastereoselectivity for the 1,2 cis product was excellent as long as the reaction was conducted at -78 °C, and enantioselectivities of up to 95% were achieved. An additional example demonstrated that insertion into a fully aliphatic position could also proceed with high ee (94%), but the resulting product was the trans diastereomer. 

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