Cyclization cyclobutane synthesis

Cyclobutane synthesis allows introduction of substituents on the cyclobutane ring in various patterns (Scheme 8.24) [55], Allyl bromide with boron trichloride and tri-ethylsilane yields the alkyldichloroborane 103, which is converted into pinacol (3-bro-mopropyl)boronate (104) and on to the cyano derivative 105 by standard methods. Transesterification of 105 and reaction with LiCHClj was used to make 100. However, 105 can be deprotonated and monoalkylated efficiently, and transesterification then yields 106. Transesterification with DICHED and asymmetric insertion of the CHCl group furnishes 107, which cyclizes to 108 or 109 with about the same 20 1 di-astereoselection as seen with the unsubstituted intermediate 100. The pattern of substitution shown by 111 was achieved via reaction of pinacol (bromomethyl)boronate (63) with lithioacetonitrile to form 110, which underwent chain extension and substitution in the usual manner. It was necessary to construct 110 in this way because substitution of a (p-haloalkyl)boronic acid is not possible. With R = H or CH3, substituents included Me, Bu, and OBn [55]. 

The aryl groups of the styryl systems need not be unsubstituted, as has been illustrated before for the cyclizations encountered in the synthesis of naphthalenophanes from 120. Indeed cyclization to afford a cyclobutane derivative where methoxy groups are on the adjacent ring position to the vinyl moieties has also been studied. The irradiation of 138 affords the m-cyclophanes 139 and 14065. Further study has sought to evaluate the steric effect of o-methoxy groups in such molecules66. 

It has been shown that the cyclization step of 3-halopropylmalonic esters to give cyclobutane-1,1-dicarboxylatcs, e.g. 3. is rate-determining.4 A convenient synthesis of cyclobutyl derivatives via hydroboration has been reported.5 In this case, 4-tosyloxybut-1-yne was bishydroborated with 9-borabicyclo[3.3.1]nonane (9-BBN), and this was followed by treatment with methyllithi-um to give 9-cyclobutyl-9-BBN 4 in 65% yield.5 24... 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

The six-membered ring 85 is obtained from the allylamine 84 [31]. The sulfur-containing ring 87 was obtained from 86 using the Mo catalyst. The Ru catalyst is not active for this reaction [32]. The (S, f )-chromene derivative 89 was obtained in 97% yield by the Mo-catalysed intramolecular metathesis of (S,f )-cycloheptenyl styrenyl ether 88 under an atmosphere of ethylene. In the absence of ethylene, 89 and its dimer were obtained. The enantioselective total synthesis of (.S, / ,/ , / )-ncbivoIoI (90) has been carried out from 89 [33]. No cyclization of the cyclopentene 91 was observed, because the highly strained cyclobutane intermediate 92 is difficult to form. 

Stork, G. Cohen, J. F. Ring size in epoxynitrile cyclization. A general synthesis of functionally substituted cyclobutanes. Application to ( )-grandisol. /. Am. Chem. Soc. 1974, 96, 5270-5272. 

Reductive dehalogenation is an efficient method of synthesis of cyclopropanes spiroannulated to five- and higher-membered carbocycles (i.e. compounds in which spiroannulation does not result in accumulation of extra strain) . The required gem-(dihalomethyl)cycloalkanes are usually prepared by halogenation of the precursor diols (equation 1). The cyclization is most efficiently accomplished in the Zn-alcohol-water system . For example, spiro[2.5]octane 7 was prepared in 91% yield using this procedure. This method is useful even for a one-step preparation of bis-spirocyclopropyl compounds as exemplified in equation 2. However, the application of the reductive dehalogenation method to the synthesis of more strained SPC (i.e. spirohexane or spiropentane) often leads to rearranged products. For example, methylenecyclopentane was the only product obtained from bis(bromomethyl)cyclobutane (equation 3) ... 

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. 

A regiospecific synthesis of A -substituted (aminopyridinyl)imidazole 1286 started with ketone 1282 (cf. Section 4.02.9.2(i)). a-Oximination of ketone 1282 with isoamyl nitrite under basic condition provides oxime isomers 1283. Both as- and /ra t-oximes 1283 participate in the cyclization process when treated with l,3,5-trimethyl-l,3,5-triazinane, leading to imidazole iV-oxide 1284 that is then reduced with 2,2,4,4-treta-methyl-cyclobutane-l,3-dithione to give 1285 (Scheme 326) <2003JOC4527, 1999JME2180> (see also Section 4.02.9.3(i)). 

An intramolecular alkylation of a-thionitrile (58) leads to a macrocycle, an intermediate for the synthesis of the sesquiterpene (-)-dihydrogermacrene D (Scheme 29). Alkylation of an a-cyanosulfone followed by reduction gave a-substituted acetonitriles. Cyclization of a 1,3-dibromoalkane with (methylthio)acetonitrile yields a l-cyano-l-(methylthio)cyclobutane, a precursor for the synthesis of cyclopentanones. Reaction of a-(arylthio)nitriles with aryl halides in the presence of LDA and BusP at -78 C affords cyanostilbenes. ... 

More modern studies have made use of copper(I) triflate (CuOTf) as the reagent. This compound is well known to form complexes with dienes and it provides a template on which cycloadditions can be effected. Several examples of this type of cyclization have been reported and cycloadditions based on this approach provide a useful route to cyclobutane derivatives. Thus, a new stereochemical synthesis of grandisol has been developed using the copper(I)-catalysed cycloaddition of the dienol 95 to afford the isomeric bicyclo-heptenols 96 exo endo ratio in this cyclization is solvent-dependent. The racemic... 

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