Cyclization spiro

Two formal total syntheses of calcimycin have been achieved (94-96). They are similar in concept in that the retrosynthetic analyses entail disconnection of the l,7-dioxaspiro[5.5]undecane moiety of 168 to the ketodiol precursor 170 which would readily yield calcimycin on acid-catalyzed cyclization (spiro-ketalization). Further retrosynthetic fragmentation of ketodiol 170 into the pyr-... 

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

Oxindoles can be prepared from Af,p-acylphenylhydrazines by a reaction which is analogous to the Fischer cyclization. This is known as the Brunner reaction. The reaction is typically conducted under strongly basic conditions. For example, heating Af-phenylcyclopentanecarbonylhydrazide with CaO gives a 70% yield of spiro-cyclopentane oxindole[l]. 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

Similar cyclization of 367 leading to low yields (20%) of benzodithiine 368 was observed with triethylamine in DMSO (Eq. 32) (76ZOR844). On the other hand, coumarin derivative 369 treated with 1,2-ethanedithiole in the presence of triethylamine provided relatively stable spiro compound 370 (Eq. 33) (89ZOR669). 

The proposed mechanism for the conversion of the furanone 118 to the spiro-cyclic lactones 119 and 120 involves electron transfer to the a -unsaturated methyl ester electrophore to generate an anion radical 118 which cyclizes on the /3-carbon of the furanone. The resulting radical anion 121 acquires a proton, giving rise to the neutral radical 122, which undergoes successive electron transfer and protonation to afford the lactones 119 and 120 (Scheme 38) (91T383). 

Formation of the six-membered ring on cyclization of the ( )- and (Z)-4-nonenylhydroxylac-tams [E)-4 and (Z)-4 in formic acid, occurs completely stereoselectivcly to afford the 6.6-spiro compounds (7R )-5 and (7S )-5, respectively51,52. The reaction supposedly proceeds via a chair-like transition state, as depicted. Depending on the reaction conditions, however, 0.5 % 2 or about 25%51 of the five-membered ring isomers are also formed. 

The Lewis acid of choice for most of the cyclization reactions is ethylaluminum dichloride, because of its exceptional properties it is a mild Lewis acid, and, as an organometallic compound, can serve as a proton sponge , and thereby inhibit competitive protodesilyla-tion37. The desired precursors reacted smoothly with 1.1 equivalents of ethylaluminum dichloride in toluene or dichloromethane at low temperature to generate diastereoselectively the desired spiro[4.5]decanones38. 

Additions of silylated ketene acetals to lactones such as valerolactone in the presence of triphenylmethyl perchlorate in combination with either allyltrimethylsilane 82, trimethylsilyl cyanide 18, or triethylsilane 84b, to afford substituted cyclic ethers in high yields have already been discussed in Section 4.8. Aldehydes or ketones such as cyclohexanone condense in a modified Sakurai-cyclization with the silylated homoallylic alcohol 640 in the presence of TMSOTf 20, via 641, to give unsaturated cyclic spiro ethers 642 and HMDSO 7, whereas the 0,0-diethyllactone acetal 643 gives, with 640, the spiroacetal 644 and ethoxytrimethylsilane 13b [176-181]... 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin s results (118,119) and established the structure of the cyclized products 196 and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121) obtained the five-membered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 

The strategy employed in studies aiming at the synthesis of the spiro segment of halichlorine (see also Section 12.01.11.4) involved a ring expansion in indolizidine 264. The double bond of this compound was cleaved by ozonolysis yielding compound 265, which was cyclized to quinolizidine derivative 266 in the presence of base (Scheme 56) <2004TL2879>. 

Radical cyclization of the indole thioesters 107 and 110 with tributyltin hydride and 2,2 -azobisisobutyronitrile (AIBN) gives a mixture of products in each case the 6-< Wo-cyclization product (the indolonaphthyridine, 109 or 112) and the 5-f vv-cyclisation product (the spiro compound 108 or 111) are obtained in approximately equal yield (Equations 22 and 23) <20040L759>. 

The formation of a number of spiro compounds by cationic cyclization has been reported. Formic acid transforms the ketal 132 into 133 in 40% yield (equation 67)77 and the alcohol 134 into the formate 135 (35%) (equation 68)78. The alcohols 136 and 138 yield the spiro compounds 137 (45-50%) (equation 69)79 and 139 (25%) (equation 70)80, respectively. Pallescensin A (141) is produced in 84% yield by the twofold cyclization of the furan derivative 140, induced by boron trifluoride (equation 71)81. 

Spiro-2-oxindoles, such as 331, are readily crafted from the Pd-catalyzed reactions of o-haloanilines with vinyl halides and triflates in the presence of CO [428]. The o-iodo enamide is presumed to form initially, followed by Heck cyclization. 

Spiro tricyclic pyrrolizinone 171 was obtained with 65% yield (and almost poor stereoselectivity) by intramolecular radical cyclization of the xanthate 170 upon exposure of the latter to 2equiv of lauroyl peroxide, in a refluxing 3 1 mixture of methanol and 1,2-dichloromethane. The radical generated from the xanthate moiety cyclizes with the... 

Cyclopentenones. 1,3-Dicarbonyl compounds add to enol ethers or esters (terminal) in the presence of Mn30(OAc)7 (excess) to form l-alkoxy-l,2-dihydro-furans. These can be converted to a 1,4-diketone, which undergoes aldol cyclization to fused (or spiro) cyclopentenones.1... 

Intramolecular arylation of alkenes. The intramolecular palladium-catalyzed condensation of aryl halides with an alkene group (Heck arylation5) can actually proceed more readily than the original bimolecular version. These intramolecular cyclizations typically proceed in acetonitrile at room temperature, particularly when catalyzed by Ag2C03, which also inhibits isomerization of the double bond of the product. They can be used to obtain spiro, bridged, and fused systems. Even tetrasubstituted alkenes can participate, with formation of quaternary centers.6... 

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