Cyclization cyclopentane synthesis

Cyclization of Aliphatic Precursors. This strategy consists of assembling the key functional groups in an aUphatic format, cyclizing to a cyclopentane intermediate, and completing the synthesis by further elaboration of the side chains. One appHcation of this strategy is as follows ... 

The use of radical cyclizations to make five-membered rings has become a very important tool for synthetic chemists Although there has been a virtual explosion of reports in the literature regarding the cyclization of 5-hexenyl radicals to cyclopentyl carbinyl radicals in all types of hydrocarbon systems [55], the use of this cyclization for the synthesis of fluorme-containing cyclopentanes has been largely ignored... 

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. 

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... 

Hydrosilylation of 1,6-dienes accompanied by cyclization giving a five-membered ring system is emerging as a potential route to the synthesis of functionalized carbocycles.81,81a,81b 82 As its asymmetric version, diallylmalonates 86 were treated with trialkylsilane in the presence of a cationic palladium catalyst 88, which is coordinated with a chiral pyridine-oxazoline ligand. As the cyclization-hydrosilylation products, //ww-disubstituted cyclopentanes 87 were obtained with high diastereoselectivity (>95%), whose enantioselectivity ranged between 87% and 90% (Scheme 25).83 83a... 

Shibata and co-workers have reported an effective protocol for the cyclization/hydrosilylation of functionalized eneallenes catalyzed by mononuclear rhodium carbonyl complexes.For example, reaction of tosylamide 13 (X = NTs, R = Me) with triethoxysilane catalyzed by Rh(acac)(GO)2 in toluene at 60 °G gave protected pyrrolidine 14 in 82% yield with >20 1 diastereoselectivity and with exclusive delivery of the silane to the G=G bond of the eneallene (Equation (10)). Whereas trimethoxysilane gave results comparable to those obtained with triethoxysilane, employment of dimethylphenylsilane or a trialkylsilane led to significantly diminished yields of 14. Although effective rhodium-catalyzed cyclization/hydrosilylation was restricted to eneallenes that possessed terminal disubstitution of the allene moiety, the protocol tolerated both alkyl and aryl substitution on the terminal alkyne carbon atom and was applicable to the synthesis of cyclopentanes, pyrrolidines, and tetrahydrofurans (Equation (10)). 

Mori has independently developed a procedure for the cyclization/stannylsilylation of enynes similar to that developed by Lautens. As an example of Mori s procedure, reaction of dimethyl allylpropargylmalonate with trimethylsilyltributylstannane catalyzed by Pearlman s catalyst [Pd(OH)2/C] in THF at room temperature for 20 h formed cyclopentane 94 [X = C(C02Me)2] in 90% yield (Equation (61)). The transformation was compatible with a number of functional groups, tolerated limited substitution of the G=C bond, and was applicable to the synthesis of nitrogen heterocycles. In a notable example, reaction of the benzhydryl-protected allylpropargylamine 95 with MesSiSnBus catalyzed by Pd(OH)2/C formed the bis(functionalized) octahydroindole 96 in 66% yield as a single diastereomer (Equation (62)). 

This stereochemical control in hex-5-enyl radical cyclizations can be used for the synthesis of highly functionalized cyclopentanes with vicinal trans- or cis-dialkyl-substituents. The synthesis of a versatile prostaglandin intermediate, Corey lactone 12, from the intermediate 6a (Y = OMe) has been described [14]. 

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). 

A. M. Horeman and I. Lundt, Highly functionalised cyclopentanes by cyclization of unsaturated bromolactones. 2. A facile synthesis of the first carbaaldohexo-furanoses and their conversion to carbapentofuranoses, J. Org. Chem., 63 (1998) 1919-1928. 

A palladium(0)-catalysed cascade cyclization-Suzuki coupling reaction of various 1,6-enynes (72) with ArB(OH)2 has been developed as a new approach to the synthesis of stereodefined a-arylmethylene-y-butyrolactones, lactams, multifunctional tetrahy-drofurans, pyrrolidines, and cyclopentanes (73) (X = O, H2, Y = O, CH2, NR3). A 7r-allylpalladium intermediate and a chair-like transition state were suggested to account for the stereochemistry of this reaction.86... 

Radical methods are useful for the synthesis of highly functionalized enantiomerically pure cyclopentane derivatives [95SL918]. Reductive cyclization of the arabinolactone 88 furnished the eir-lactone 89 in quantitative yield. Exhaustive reduction with borane-dimethylsulfide gave the functionalized cyclopentane 90. 

Several routes to cycloalkanes have been developed (Fig. 4). Bolton [29] described the synthesis of azabicyclo[4.3, 0]nonen-8-ones using an intramolecular Pauson-Khand cycliza-tion. The relative stereochemistry was controlled in this cyclization step which proceeded in good yield regardless of whether the nitrogen atom bore an allyl (shown) or propargyl (not shown) substituent. The ene reaction was employed in a route to trans-substituted cyclopentane and cyclohexanes [30], Reductive cleavage from the resin with LiBFL, provided the diol or, alternatively, cleavage with Ti(OEt)4 produced the diester. 

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. 

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