Keto cyclopentane

The result of the double C-N disconnection in the heterocyclic ring is the two target molecules of the next generation, a-keto-cyclopentane carboxylic acid TM 7.1a and N-cyclohexylurea TM 7.1b. On refra-Dieckmann disconnection, TM 7.1a leads to diethyl adipate (Sect. 4.3.3, Scheme 4.23) and TM 7.1b affords the isocyanate anion and cyclohexylamine. 

I eplanocins. Neplanocins A—D and E (37—41) are carbocycHc nucleoside antibiotic products oi Ampullariella regularis (1,4) that are stmcturaHy related to (36) in that they contain either a cyclopentene or epoxy cyclopentane ring (121,122). The chemical syntheses of (37—41) and the 3-deazaneplanocins have been reported (123—126). Compound (37), which is converted to its 5 -triphosphate, has potent antitumor and antiviral activities (127—129). It strongly inhibits SAM in ceUs and vimses (128—131) and is converted to the 3 -keto derivative by A-adenosyUiomocysteine hydrolase (132,133). 

Sml2 also effects an intramolecular reductive coupling of certain unsaturated (3-keto esters or amides to cyclopentanes with good stereochemical control at three centers (equation II).5... 

We initially observed [4, 5] that an a-diazo / -keto ester 5 would, on exposure to a catalytic amount of Rh2(OAc)4, undergo smooth cyclization to the cyclopentane derivative 6 (Scheme 16.2). The a-diazo / -keto ester 5 is readily prepared by diazo transfer [6] from... 

The presence of an alkene in the seven-membered ring of (—)-reiswigin A provides an immediate disconnection point for this target. Kim and coworkers capitalised on this fact and retrosynthetically cleaved this ring to obtain keto-phosphonate 1 (Scheme 12.1).3 A further clearance and protection of the reactive functionality within 1 then led to cyclopentane 2. 

Bornane monoterpenes are exemplified by camphene (2,2-dimethyl-3-methylene-bicyclo[2,2,1]heptane), a structure in which two fused cyclopentane rings share three Cs. We can simply represent the camphene skeleton as a cyclohexane with a methylene (—CH2—) cross-link (G6(-CH2—)). The keto derivative camphor (camphor smell), the ether eucalyptol (eucalyptus smell) and the simple bornene a-pinene (pine smell) are familiar examples. 

These compounds with the structure of cyclic acetals or cyclic carbonates have been synthesized by I. T. Harrison and V. R. Fletcher117. The compounds represent prostanoids in which oxygen heteroatoms replace hydroxymethine or keto groups in the cyclopentane ring. 

With respect to the mechanism just discussed, the statement of Cowley et al. [25] that merely Z-isomeric [2,2-dimethyl-l-(trimethylsiloxy)propylidene]trimethylsilylphosphane can eliminate hexamethyldisiloxane, does need further verification. From our point of view the E- and Z-isomer of the mesomeric enolate anion are readily interconverted by a rotation around the P-C bond of the keto form (Eq. 6) which is supposed to be an easily accessible transition state. At any rate, we were not able to confirm their results as the reaction of lithium bis(trimethylsilyl)phosphanide with 2,2-dimethylpropionyl chloride at -78 °C in cyclopentane solution gives exclusively the -isomeric phosphaalkene, whereas at room temperature the Z-isomer prevails. 

As with other intramolecular ene reactions, this reaction is best suited to the preparation of cyclopentanes, but can also be used for the preparation of cyclohexanes. The reaction cannot be used for the formation of cyclopropanes or cyclobutanes since the unsaturated carbonyl compound is more stable than the ene adduct. 8,e-Unsaturated ketones (167) do not give cyclobutanes (171) by enolization to give (170) followed by a type I reaction but instead give cyclohexanones (169) by enolization to give (168) followed by a type II reaction. Alkynes can replace alkenes as the enophile. Enols can be prepared from pyrolysis of enol esters, enol ethers and acetals and from -keto esters and 1,3-dicaibonyl compounds. Tlie reaction is well suited to the preparation of fused or bridged bicyclic and spirocyclic compounds. Tandem ene reactions in which two rings are formed in one pot from dienones have also been described. The examples discussed below 2-i63 restricted to those published since Conia and Le Perchec s 1975... 

Cyclic p-kcio esters and )9-diketones (596) smoothly effect ring-opening of 1,1-bis(benzenesulphonyl)cyclopropane (412) under basic conditions. Reductive cleavage of the resulting sulphones (597) by lithium arylides provides routes to 598 and 599 (equation 210) The bis-benzenesulphonyl compound appears to fulfil the requirements for a propylene 1,3-dipole. The fact that the sulphones can be sequentially removed permits selective introduction of from one to three electrophiles (E) (equation 211). In the case of )5-keto esters, such versatility created a novel three carbon insertion between the ester group and the ketone or a cyclopentane annulation. ... 

A more versatile reducing agent is samarium diiodide, which promotes chemoselective cyclizations of functionalized keto aldehydes in a stereodefined manner to form 2,3-dihydrocyclopentane carboxylate derivatives in good yields and with diastereoselectivities of up to 200 1 (equation 38)7 The reaction proceeds via selective one-electron reduction of the aldehyde component and subsequent nucleophilic attack on the ketone moiety. Stereochemical control is established by chelation of the developing diol (19) with Sm " " which thereby selectively furnishes cis diols (equation 39). The stereoselective M/-cyclization of 1,5-diketones to cis cyclopentane-1,2-diols using TiCU/Zn has been used to prepare stereodefined sterically hindered acyclic 1,2-diols when a removable heteroatom, such as sulfur or selenium, is included in the linking chain (equation 40). 

Concurrently, Noels had reported that rhodium carboxylates smoothly catalyze the intermolecular C—H insertion of ethyl diazoacetate into alkanes. Following up on this report, Taber demonstrated that the open chain a-diazo 3-keto ester (60) cyclizes smoothly under rhodium acetate catalysis to give the corresponding cyclopentane (61 equation 24). In contrast to the copper-mediated cyclization cited above (equation 22), the six-membered ring product is not observed. The insertion shows significant electronic selectivity. Although there is a 3 1 statistical preference for methyl C—H, only the methylene C—H insertion product (61) is observed (equation 24). 

Trehazolamine. Chiara has described a synthesis of trehazolamine, the aglycon of trehazolin, a powerful inhibitor of trehalase, wherein a pinacol cyclization provided the necessary cyclopentane framework (Eq. 3.2) [17]. Thus, treatment of the tetrabenzyl-protected keto aldehyde, derived from D-glucose, with Sml2 furnished the two cis diols exclusively as a 1 1 mixture of isomers in excellent yield (>90%) [18]. Previous studies of five-membered ring formation mediated by SmE have also reported good cis/trans selectivity, presumably due to the intervention of a samarium chelate. 

Also used as a spectral comparison model for the elucidation of the B and G aflato-xinsss this compound was prepared in a multi-step synthesis. The von Pechmann condensation of phloroglucinol dimethyl ether (59)133 with diethyl cyclopentane-4,5-dione-l, 3-dicarboxylate (41) in acidic solution afforded the /J-ketoester (42), which readily underwent decarboalkoxylation, in a seperate step, to give the keto-coumarin (5). The beauty of this methodology is illustrated by the use of the symmetrical diketoester (41), which of course, only allows for the formation of a single coumarin (von Pechmann) product (42). The regiochemistry of the final product, however, was demonstrated to be the incorrect isomer insofar as the aflatoxin structures were concerned. 

Beginning with 3-oxycyclopentane methylcarboxylate some natural products have also been synthesized. The key intermediate for the preparation of dihydro-jasmone240), cis-jasmone240), (Eq. 123) and sarkomycin241) (Eq. 124) is a keto-lactone, which is obtained from 3-oxo-cyclopentane methylcarboxylate (Eq. 122) 239a>... 

The mechanism of cyclopentane ring formation of allosamizoline may take place via pathway A or B during inositol biosynthesis, whereas via pathway C during shikimic acid biosynthesis (Scheme 1). This was based on a study using [3- H]-, [4- H]-, [5- H]-and [6- H2]-D-glucosamine feeding in experiments which indicated that the cyclization to form the cyclopentanoid moiety of allosamizoline is presumed to proceed via a 4-keto or... 

The cytotoxicity of these compounds is due to a very reactive centre in the molecule, the exocyclic ot.-methylene-/ -lacton group which may easily add to sulfhydryl groups of enzymes or other proteins (32, 34, 35). Therefore, cystein applied immediately has been shown to be a useful antidot in hamsters (34). Tenulin, which is less toxic than the other compounds lacks this methylenelacton group it possesses an ac,6-unsaturated keto group in the cyclopentane ring, as is found in many toxins and carcinogens. 

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