Spirocycles, formation

In contrast to intermolecular photoaldols, which can be manipulated with facility, intramolecular cycloadducts undergo retro-[2 + 2] cycloaddition when subjected to hydrolytic conditions. In an alternative protocol, oxymercuration of (229) afforded a-mercurio ketone (230 42%) which was acetylated under standard conditions to provide 1,4-diketone (231) quantitatively. Similarly, epoxidation of (229) provided functionalized photoaldol (232), which was hydrolyzed and acetylated to form a-acetoxy derivative (233). Finally, hydrolysis of (234) (4 1 THF/0.1 N HCl) gave lactol (235) in nearly quantitative yield, illustrating the utility of the intramolecular furan carbonyl photocycloaddition in spirocycle formation. 

A rhenium oxide-catalyzed methodology has been developed for stereoselective polycyclic ether synthesis (Scheme 41). For example, the epoxide (192) reacts to provide the spirocyclic product (193) as the only stereoisomer formed. It is suggested that the ketone acts as a stereochemical conduit to relay the chirality of the epoxide through the cascade reaction. The initial cyclization provides the carboxonium ion (194) and then ion (195) precedes spirocycle formation. 

The alkylpalladium intermediate 198 cyclizes on to an aromatic ring, rather than forming a three-membered ring by alkene insertion[161], Spirocyclic compounds are easily prepared[l62]. Various spiroindolines such as 200 were prepared. In this synthesis, the second ring formation involves attack of an alkylpalladium species 199 on an aromatic ring, including electron-rich or -poor heteroaromatic rings[l6.5]. 

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

Another approach to a donor adduct of the methylene phosphenium cation is the addition of a phosphonium cation to the phosphaalkyne. The reaction of the protic cation [HPPhal + lCFaSOa] with CjoHuCP produced a white powder which was identified as the P-phosphonio-substituted phosphaalkene [74]. Alternatively to the elimination reaction the phosphaalkynes were protonated. C-protonation of adamantylphosphaacetylene and ferf-butylphosphaacetylene occurred in superacid media under formation of phosphavinyl cations. From these spirocyclic betaines by reaction of l-Ad-C=P (Ad = adamantyl) withB(OTf)3 a phosphavinyl cation could be detected [75]. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

Most aromatic difunctional reagents react with N3P3Cl6 to afford spirocyclic products (20,176,180,181,189,190). With catechol, the trispiro product is observed (190). This product was shown to function as a host in the formation of several inclusion adducts, including polymers (191). Ring degradation of the cyclophosphazene ring occurs in the reaction with o-amino phenol as well as in the reaction with catechol in the presence of a triethylamine (192). 

Fig. 20. Thermodynamic (A) vs. supramolecular effect (B) in the formation of spirocyclic and ansa products.

Catalyst 70 is very effective for the reaction of terminal alkenes, however 1,1-disubstituted olefins provide hydrosilylation products presumably, this is due to steric hindrance [45]. When a catalyst with an open geometry (78 or 79) is employed, 1,1-disubstituted alkenes are inserted into C-Y bonds to give quaternary carbon centers with high diastereoselectivities (Scheme 18). As before, initial insertion into the less hindered alkene is followed by cyclic insertion into the more hindered alkene (entry 1) [45]. Catalyst 79 is more active than is 78, operating with shorter reaction times (entries 2 and 3) and reduced temperatures. Transannular cyclization was possible in moderate yield (entry 4), as was formation of spirocyclic or propellane products... 

Addition of hexafluoroacetone to compound 30 leads to cleavage of the P-P bond and formation of spirocyclic 29, containing two four-membered rings (Equation 5) <1997ZFA1325>. 

The epimerization likely occurs through an enamine retro-aAAol reaction after formation of the initial cyclized product (92) (Scheme 6.16) [47]. First, a ring opening of 92 forms the enamine-aldehyde (93a). Rotation about the C-C a-bond in 93a provides intermediate 93b in which enamine addition to the aldehyde to reclose the ring would give 93c. After protonation of the enolate, 91 would result with an overall epimerization of the spirocyclic carbon. In addition to the 2D NMR data, we also planned a complement of experiments to support the epimerization assignment. 

If the side chain with the nucleophile is situated in the 1-position of the conjugated diene, a palladium-catalyzed spirocyclization occurs. In this case stereoselective oxa-spirocyclizations were obtained from the diene alcohols 59 and 60 (equation 23 -25)58. The reaction worked well for the formation of a tetrahydrofuran and tetrahydropyran in the spirocyclization. In the absence of chloride ions 59 gave high yields of the acetoxy oxaspirocyclic compound 61 via a 1,4-anti addition across the diene (equation 23). In the presence of stoichiometric amounts of LiCl a 1,4-syn oxychlorination took place and allylic chloride 62 was obtained (equation 24). Under chloride-free conditions, cyclohep-tadiene alcohol 60 afforded oxaspirocyclic acetate 63 (equation 25). 

The reaction of [H2C(SiMe3)2C]2Si 180 with cyclopropylmethyl chloride proceeds via ring opening and formation of product 192 containing a spirocyclic Si atom, whose formation can be attributed to a radical-reaction pathway... 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

By using the same catalytic system, alkylations of 1,3-dimethylbarbituric acid with alcohols were also accomplished (Scheme 5.31) [68]. The Cp lr-catalyzed alkylation using 2-iodobenzyl alcohol, followed by palladium-catalyzed carbon-carbon bond formation with allene, gave spirocyclic barbituric acid derivatives in a one-pot process. 

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