Spirocyclization

Intramolecular reactions of electron donor and acceptor sites in cyclic starting materials produce spirocyclic, fused, or bridged polycyclic compounds. 

Alkenes in (alkene)dicarbonyl(T -cyclopentadienyl)iron(l+) cations react with carbon nucleophiles to form new C —C bonds (M. Rosenblum, 1974 A.J. Pearson, 1987). Tricarbon-yi(ri -cycIohexadienyI)iron(l-h) cations, prepared from the T] -l,3-cyclohexadiene complexes by hydride abstraction with tritylium cations, react similarly to give 5-substituted 1,3-cyclo-hexadienes, and neutral tricarbonyl(n -l,3-cyciohexadiene)iron complexes can be coupled with olefins by hydrogen transfer at > 140°C. These reactions proceed regio- and stereospecifically in the successive cyanide addition and spirocyclization at an optically pure N-allyl-N-phenyl-1,3-cyclohexadiene-l-carboxamide iron complex (A.J. Pearson, 1989). 

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]. 

Organic molecules m which one carbon atom is common to two rings are called spirocyclic compounds The simplest spirocyclic hydrocarbon is spiropentane a product... 

Cyclic hydrocarbons can contain more than one ring Spirocyclic hydro carbons are characterized by the presence of a single carbon that is com mon to two rings Bicyclic alkanes contain two rings that share two or more atoms... 

Spirocyclic hydrocarbon (Section 3.14) A hydrocarbon in which a single carbon is common to two rings. 

A redox process also occurs in the reaction of selenium diimides with bis(amino)stannylenes. Eor example, the cyclic stannylene McaSi)//-N Bu)2Su reacts in a 1 1 molar ratio with BuN=Sc=N Bu to give a spirocyclic tin complex, which reacts with a second equivalent of the stannylene to generate a Sn-Sn bond [d(Sn-Sn) = 2.85 A, /( Sn- Sn) = 13,865 Hz)] (Scheme 10.6). ... 

The spirocyclic cyclopenta[g]indole derivatives represented by 31 have also been prepared via the Madelung indole process. ... 

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. ... 

Dehydration of a spirocyclic quaternary salt such as 147 gives rise to a 3,4-dihydro-y-carboline (148). This reaction is not, however, of general applicability since both 149 (R = C2H5) and 149 (R = CH2C6H5) yield the fully aromatic carbolinium salt 150 under the same conditions. 

Stereocontrolled synthesis of spirocyclic compounds with heterocyclic fragments 99T9007. 

The third synthetic scheme is employed when the phenylthio substituent is in the a-position of the lactone function, which interferes with the cyclization (90JOC5894). Acetylenic ketone 194 (95% yield) is readily transformed to the acetal 195 (with potassium carbonate in methanol) however, under the above conditions neither its hydrolysis nor cyclization to the spiroketal occurs. The spirocyclic pyrone 197 is formed in quantitative yield on treatment of 195 with p-toluenesulfonic acid in a 4 1 THF-H2O mixture at reflux for 12 h. 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

The electroreductive cyclization of the furanone 118 (R = -(CH2)4CH=CH— COOMe Scheme 36) using a mercury pool cathode, a platinum anode, a saturated calomel reference electrode, and a degassed solution of dry CH3CN containing -Bu4NBr as the electrolyte, gave the spirocyclic lactones 119 and 120 in a ratio 1.0 1.1 (Scheme 37)(91T383). 

The Simmons-Smith reaction is well suited for the synthesis of spirocyclic compounds. It has for example been applied for the construction of the fifth cyclopropane ring in the last step of a synthesis of the rotane 8 ... 

In this synthesis, a tandem vicinal difunctionalization of enone 18 provides an exceedingly simple solution to the task of synthesizing spirocyclic intermediate 16. When 18 is treated with the or-ganocuprate reagent, t-Bu2Cu(CN)Li2, a smooth 1,4- or Michael ad-... 

Concealed within spirocyclic intermediate 16 are rings B and F of ginkgolide B. Intermediate 16 is readily formed in two steps from a readily available starting material and it contains a strategically placed ketone carbonyl group which provides several options for further advance. A particularly straightforward route to 15 includes the conversion of ketone 16 into enol triflate 21 by means of McMurry s protocol.16 Thus, enolization of 16 with LDA in dimethoxyethane at -78 °C followed by triflation of the enolate oxygen atom with /V-phenyltrifluoromethanesulfonimide furnishes enol triflate 21 in a yield of 80%. 

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

In the synthesis of spirocyclic systems via an intramolecular Sakurai reaction, allylsilanes with an allyl moiety attached to the 3-position of the 2-cyclohexenone are required as starting materials. 

The diastereoselectivity observed can be explained by a synclinal transition state, probably influenced by chelation and/or stereoelectronic effects of the developing cation38. The minor product is formed via an antiperiplanar transition state. All compounds obtained are useful precursors for several spirocyclic natural products, such as terpenes like lubimine or acoradi-ene. 

A cyclization of / -keto sulfone 17 in the presence of a Lewis acid gives a spirocycles via a pinacol-type rearrangement in which the sulfone group serves as a leaving group (equation 10)9. 

Figure 10.32 Applications of bidirectional chain extension for the synthesis of disaccharide mimetics and of annulated and spirocyclic oligosaccharide mimetics using tandem enzymatic aldol additions, including racemate resolution under thermodynamic control.

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