1.2.3- trisubstituted cyclopentanes

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... 

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. 

The reaction of methyl acrylate and acrylonitrile with pentacarbonyl[(iV,iV -di-methylamino)methylene] chromium generates trisubstituted cyclopentanes through a formal [2S+2S+1C] cycloaddition reaction, where two molecules of the olefin and one molecule of the carbene complex have been incorporated into the structure of the cyclopentane [17b] (Scheme 73). The mechanism of this reaction implies a double insertion of two molecules of the olefin into the carbene complex followed by a reductive elimination. 

Secondary alkyl iodides bearing an additional substituent at the allylic position underwent highly diastereoselective Pd-catalyzed carbozincations, as illustrated for 56 which led after allylation with ethyl 2-bromomethylacrylate to the trisubstituted cyclopentane 57 (C1-C2 trans/cis > 99/1, C2-C3 cis/trans = 95/5) (equation 23)39,40. 

Fig. 5. Design strategy for the synthesis of compounds 31-36 (structure I) by replacing the oxyethylene chain of 21 with the trisubstituted cyclopentane unit of 30.

All the olefins prepared this way can be split at the double bond by hydroxylation or ozonization to furnish substituted alicyclic compounds in the case of 355 and 356 and an all-cis trisubstituted cyclopentane in the case of 358. 

When bromoallyl sulfone 50 is converted into its lithio derivative by treatment with lithium diisopropylamide (LDA) at —78°C, it reacts with acrylic esters 51 via Michael-initiated ring closure to provide trisubstituted cyclopentanes 52 with high regio- and stereoselectivity. Thus, 50 can be seen as a trimethylenemethane equivalent (Scheme 22.14). Using enantiomerically pure acrylic esters. 

Cyclopentene derivatives with carboxylic acid side-chains can be stereoselectively hydroxy-lated by the iodolactonization procedure (E.J. Corey, 1969, 1970). To the trisubstituted cyclopentene described on p. 210 a large iodine cation is added stereoselectively to the less hindered -side of the 9,10 double bond. Lactone formation occurs on the intermediate iod-onium ion specifically at C-9ot. Later the iodine is reductively removed with tri-n-butyltin hydride. The cyclopentane ring now bears all oxygen and carbon substituents in the right stereochemistry, and the carbon chains can be built starting from the C-8 and C-12 substit""" ... 

Wiberg and Saegebarth also obtained fair yields of cyclopentane-13-dialddiyde from the oxidation of bicyclo[2.2.1]hept-2-ene under mild conditions (equation 18). However, the oxidation of unsaturated tertiary carbons to the corresponding ketones is much more typical. The reaction depicted in equation (19), where a trisubstituted double bond is cleaved to a ketone and a carboxylic acid, is exertqrlaty of the products that are normaUy produced when alkenes react with aqueous permanganate. ... 

Kibayashi and coworkers described a similar approach to a 2,3,4-trisubstituted cyclopen-tanone (29) in their total synthesis of (—)-incarvilline (30, equation 10) °. The reaction proceeded with all-trans stereo selection with respect to the stereocenters of the cyclopentane ring. 

In 2006, Nair disclosed the synthesis of ( )-tra s-l,3,4-trisubstituted cyclopentenes resulting from the addition of enals to chalcones catalysed by an achiral carbene." " Mechanistically, the addition of the generated homo-enol to enones to give adduct II, followed by intramolecular acylation to afford cyclopentane-fused p-lactone IV. The final cyclopentene 67 was formed by the in situ decarboxylation of the p-lactones (Scheme 20.32). The enantioselective variant of the process to access ds-cyclopentenes was reported by Bode et al. in 2007. ... 

Application of the procednre to 4-methoxycarbonyl-4-benzyloxycarbonylheptadiyne led to cyclization to the corresponding bis(methoxycarbonyhnethylene)cyclopentane, which is a useful precursor of trisubstituted cyclopentadienes. This compound can be... 

From cycloadduct 293, the aldehyde was homologated to 295. The cyclopentane ring of the core of englerin A was secured by means of an intramolecular Heck reaction from enol triilate 296 to furnish triene 297 (Scheme 18.62). The trisubstituted double bond in 297 was the most electron rich, and was chemoselectively and stereoselectively epoxidized from the less hindered a-face [52]. An Sn2 reductive opening of the vinyl epoxide using DIBAL furnished the... 

---