Spirocyclic derivatives, formation

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. 

The metal-catalyzed formation of 2,3-dihydrothiophene derivatives via a 1,5-dipolar electrocyclization has been reported by Hamaguchi et al. (124). For example, the Rh2(OAc)4-catalyzed reaction of vinyldiazo compound 159 (R = Ph) with xanthione (160) produced the spirocyclic dihydrothiophene 161. In contrast, when 159 containing a methyl group (R = Me) was used, thiirane 162 was the sole product (Scheme 5.48). This result was rationalized by the selective formation of an intermediate thiocarbonyl ylide 163 with (Z)- and (E)-configuration, respectively. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

The reaction of A,iV -bis(trimethylsilyl)ureas with phenylsulfenyl chlorides furnished iV-arylthioureas. The treatment of the latter with various organodichlorophosphines led to the formation of l,3,2-diazaphosphetidin-4-one derivatives (Table 4) <1995ZFA2001>. A similar [3+1] cyclocondensation reaction of iV-arylselenourea with dichloromethyl-and dichlorophenylphosphines has been carried out <1996ZFA1250>. The reaction of chloromethyldichlorophos-phine with A,iV -dimethyl-iV,iV -bis(trimethylsilyl)urea led to the spirocyclic P(lll)-P(v) diphosphorus compound 59 (Scheme 37) <1997ZFA1325>. 

Holmes and his coworkers described a number of pentacoordinated anionic germanium complexes containing a spirocyclic framework with methyl, phenyl, halogen or hydroxyl ligand at the acyclic site307,332,333. Reaction of an organogermanium trichloride with a catechol or thiocatechol derivative in the presence of triethylamine, followed by a metathetical exchange, led to desired products as illustrated by the formation of the phenyl-substituted derivatives 90 and 91 (equation 16)333. 

As depicted in the following scheme, a homoallyl alcohol derived from a norbomyl a-diketone underwent a lead(IV) acetate reaction in MeOH, resulting in the formation of a novel methoxy substituted spirocyclic tetrahydrofuran <07CC4239>. It is believed that the addition of the methoxylead(IV) acetate species across the alkene from the less sterically hindered side to form a plumbonium cation leads to the major product after subsequent cyclization and reductive elimination. Moreover, construction of tetrahydrofurans by a Pd(II)/Pd(IV)-catalyzed aminooxygenation of homoallyl alcohols was also reported <07AGE5737>. 

Equation 69 illustrates the formation of spirocyclic double stannocanes 403-405 from Sn(II) derivatives . ... 

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. 

Polyfluorinated aliphatic aldehydes reacted with 1-phenyl-3-methylpyrazol-5-one, l-phenyl-3-methyl-5-amino (N,N-dimethylaminomethylenamino)pyrazole, and l-phenyl-3-aminopyrazol-5-one at room temperature in the absence of catalyst with formation of 4-(l-hydroxypolyfluoroalkyl)pyrazoles <2000JFC(101)111>. Dehydration of the 4-(l-hydroxypolyfluoroalkyOpyrazoles with morpholinosulfur trifluoride generated 4-polyfluoroalkylidenepyrazoles, which were active dienophiles and reacted with 2,3-dimethylbutadiene and cyclopentadiene forming spirocyclic pyrazole derivatives. 

Intramolecnlar alkenylation at a furan a- or P-position by an alkyne occurs, with the formation of bicycUc derivatives, when promoted by mercury(II) acetate (or Hg(OAc)(OTf), generated in situ from mercuric acetate and scandinm triflate). In the case of closure onto a p-position, a spirocyclic intermediate from preferred attack at the a-position, may be involved, as shown. 

If the carbon chain containing the nucleophile is not attached to nitrogen, the preference for six-mem-bered ring formation is less pronounced. This is apparent from the spirocyclizations utilized for the synthesis of perhydrohistrionicotoxin (equation 71). The tertiary Af-acyliminium ion derived from (108) cyclizes to a mixture of (109) and (110). Surprisingly, the amount of five-membered ring product (110)... 

The other key step in the synthetic approaches to FR901483 is the elaboration of the quaternary spirocenter at C(l) (Scheme 4). Sorensen, Ciufolini, and Wardrop all use an oxidative spirocyclization of nitrogen tethered phenol derivatives, employing hypervalent iodine reagents, to generate the spirocenter at C(l). In contrast, in the other approaches the formation of the quaternary stereocenter does not coincide with the... 

As far as the reaction mechanism is concerned, we assume that the sequence conunences with the addition of the Lewis add to the carbon atom of the phosphaalkyne (9 - 69), in accord with the polarization of the PsC bond [10b]. The addition of fluorosulfonic acid to 9 a in liquid SO2 also begins with C-protonation [63]. The resultant, activated phosphaal-kenes undergo [2 -1- 2]-cycloaddition with a second equivalent of 9 to furnish the adducts 70. A subsequent [2 -I-1]-cycloaddition with a third equivalent of 9 is then responsible for the formation of the spirocyclic phosphorus derivatives (- 71). 

---