Spiroannulation

An illustrative example of the potency of the second-generation Ru catalyst C is found in Paquette s highly efficient total synthesis of the natural products teubrevin G (122) and teubrevin H (123), which feature a cyclooctane core fused and spiroannulated to smaller oxygen-containing rings [76]. In the retrosyn-thetic analysis, the viability of an RCM step for annulation of a cyclooctenone ring to the furan played a central role. 

A highlight in the application of RCM methodology in natural product synthesis is Hirama s total synthesis of ciguatoxin CTX3C (183) [90], including the more recent improved protective group strategy, as depicted in Scheme 34 [90b]. The structure of 183 spans more than 3 nm and is characterized by 12 six- to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-... 

When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions <06CC194>, as exemplified below. The formation of the kinetic products is the result of the higher nucleophilicity of the furan C2-position. 

Trimethylsilyloxyfurans were employed as C5-dianion equivalents in the spiroannulation with bi-functional ortho-esters to provide spirobutenolide derivatives <060L3705>. When the second step was performed under radical conditions, instead of using base, r is-fused bicyclo[3.n.0]lactones were formed <06CC1200>. An interesting example is... 

As can be seen below, another route for the preparation of spiroannulated 1,3-dihydrobenzo[c]furans (vide supra) was reported by Hotha, who made use of an AuCl, promoted intramolecular Diels-Alder reaction <06TL3307>. 

Beckmann like rearrangements have not been extensively explored but should translate this spiroannulation into a y-butyrolactam synthesis108). 

Indeed, exposure of the vinylcyclobutanone 67 to acid produces the perhydro-azulene skeleton 68 as summarized in Eq. 78 112). With more ready access to the types of substituted cyclobutanones required for this lateral cyclopentannulation (see substitutive spiroannulation), milder conditions and thus better processes will probably ultimately be developed. 

The sequences of spiroannulation-secobromination or, better, spiroannulation-secosulfenylation offer great versatility for geminal alkylation as summarized in Eq. 123. The fact that spiroannulation of carbonyl compounds proceeds with stereocontrol converts these transformations into stereocontrolled carbonyl group elaborations. 

This same concept applies to spiroannulations of six membered rings and is illustrated in a synthesis of acorenone B 155 as outlined in Scheme 547). The notion of alkylative carbonyl transposition permits the spiro enone 156 to become a logical intermediate. The standard analysis by a retro-aldol process translates the spiro ring system of acorenone B into a geminal alkylation problem as revealed by... 

At this time, we can focus on the creation of the butenolide. Sulfur based methodoly allows simplification to the simple butanolide as in 170. While cyclobutanone spiroannulation of 171 followed by a Baeyer-Villiger reaction would create 170,... 

In a projected synthesis of verrucarol in which the tetrahydropyranone 175 is envisioned to play a role, the lactone 176 can serve as a viable intermediate (Scheme 6)7S>. Using cyclobutanone annulation methodology, 177 becomes the required intermediate. The geminal substitution of 177 can also be recognized to derive from a spiroannulation approach as previously analyzed. 

A. Roy, B. Achari, and S. B. Mandal, An easy access to spiroannulated glyco-oxetane, -thietane and -azetane rings Synthesis of spironucleosides, Tetrahedron Lett., 47 (2006) 3875—3879. 

The spiroannulation of cyclic a-epoxy ketones proceeded stereospecifically, but with acyclic a-epoxy ketones the stereospecificity was lost during the oxaspiropentane-forming step, e.g. formation of cyclic a-epoxy ketones 11a, b and acyclic a-epoxy ketones 12/12. 69... 

Spiroannulations with diphenylsulfonium cyclopropanide have also been performed with polycyclic systems. Optically active 4-methyladamantan-2-one (21b),7 and the all-ds configurated tetraquinanes 23,72 73 and 2574 reacted stereoselectively with formation of syn- and endo,enclo-configurated cyclobutanones 22b, 24 and 26, respectively. The last two products 24 and 26 have been further elaborated in a successful75 and a prospective74 synthesis of dodecahcdrane. 

Better yields of cyclobutanones were obtained with steroidal ketones.85 86 In the reaction of 5a-cholestan-3-one (5) with diazocyclopropane, spiroannulation to give 6 (30%) dominated insertion to give 7 (24%), and with 3/ -acetoxy-5a-pregnane-l 1,20-dione (8) only spiroannulation to give 9 (60%) was observed.85 A comparable high yield (78%) of a spiroannulation product 11 was obtained with trispiro[2.0.2.0.2.1]decan-10-one (10).84 It is apparent that efficient formation of oxaspiropentanes as direct precursors of cyclobutanones only takes place with sterically hindered ketones. 

Substitutive spiroannulation of 1-donor-substituted vinylcyclopropanes initiated by electrophiles gives access to a wide range of spirobicyclic and spirotricyclic systems. Generally, the electrophile undergoes addition from the sterically less demanding face and the rearrangement proceeds through back-side attack. The net result is a turns addition. 

Table 9. Cyclobutanones by Cycloalkylativc Spiroannulation of 1-Trimethyl-siloxy-l-vinylcyclopro panesl06,107...

The synthesis of higher spiroannulated cyclobutanones 21 poses no problems. They can be effectively produced by osmium(VUI) oxide oxidalion of cyclopropylidenecycloalkanes followed by treatment with acid.119... 

Interestingly, Lewis acid catalyzed rearrangement of 6-methyltricyclo[8.2.0.0, 6]dodecan-9-one gave the spiroannulated triquinane ketone (l/ , 5/ )-l-methylspiro[bicyclo[3.3.0]octane-2,lf-cyclopentane]-6-one as the major product (70%).85... 

The cyclopropanated furanone 32 was found to behave as a Diels-Alder diene. Thus, 32 reacts with maleic anhydride (33) to give a tetracyclic adduct 34 which is formed endoselectively (Scheme 9) (93SL415). The latter adduct is a spiroannulated butenolide related to naturally occurring sesquiterpenes [85AG(E)94 85TL5453],... 

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