Spirocyclic ketone

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]. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Nucleophilic addition to the spirocyclic ketone also proceeds with high stereoselectivity. ... 

It is interesting to discern the different migratory aptitudes displayed by spirocyclic ketones on exposure to hydrogen peroxide [252] (Eq. 226,227). Although participation of the selenium atom to direct the attack of the peroxide has been formulated, the results are also consistent with an electronic explanation. Thus, the rapid formation of selenoxide renders the spirocyclic center acceptor-like through polarity alternation, and the migration of the methylene group becomes more favorable. 

Spirocyclic 2-alkylidenecyclobutanones can be prepared from vinylidenecycloalkane additions with dimethylketene (see Tabic 1). Alternatively, cycloaddition of cycloalkylidenemethanone to allenes permits synthesis of spirocyclic cyclobutanones. This latter route is more attractive because of the greater availability of simple allcnes as compared with the alkylidenecycloalka-nes. The in situ generation of cyclohexylidenemethanone in the presence of excess tetramethyl-allcnc produced the spirocyclic ketone 9 in reasonable yield.5... 

Kulagowski, J. J. (Merck, Sharp Dohme) Spirocyclic ketones and their use as tachykinin antagonists, WO 0047562. 

A stereoselective, Lewis acid-mediated cyclization of l-substituted-2-naphthols (41) has been reported to produce spirocyclic ketones (43). Evidence has been presented for the involvement of the cyclic aluminium intermediate (42).50... 

In fact Corey8 chose strategy a using the pinacol dimerisation to make the diol 44 and the pinacol rearrangement to make the spirocyclic ketone 42. 

A new spirocyclic ketone 225 was proposed for the asymmetric epoxidation of olefins <02JOC2435>... 

Revision elements. Suggest two syntheses of this spirocyclic ketone from the starting materials shown. Neither starting material is available. 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cycloaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the l-oxa-1,3-butadiene moiety in 2-816. The formed spirocyclic ketones 2-818/2-819 can be used in natural products synthesis and in medicinal chemistry [410]. They have also been used in the preparation of exotic amino acids these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

In a third category of cyclic 3, y-enones of synthetic potential, the chromophore moieties are linked by a spiro carbon typical examples are a 3, y-unsaturated 8-diketone and 3, y 8,e-unsaturated spirocyclic ketones. " A representative of the latter category is (53), which upon triplet sensitization with Mich-ler s ketone affords the isomers (54) and (55) in a ratio of about 2 1 and a total yield of 82% (Scheme... 

Tandem fragmentation-cyclization of bicyclic ketones connected to unsaturated side chains have been used to construct hi-, tri-, and spirocyclic ketones [334], Cossy et al. have shown that depending upon the substitution pattern, ketyl radical anions obtained from photochemically induced electron transfer from amines to cyclopropylketones lead either to the formation of 3-substituted cycloalkanones or to ring expanded products (Scheme 78) [335],... 

Another variety of enolizable 1,3-dicarbonyl compounds and related structures were shown to undergo the same type of reaction with this (cyclopropyl)triphenylphosphonium salt. ° When 2-formylcycloalkanones were applied as 1,3-dicarbonyl compounds, the corresponding spirocyclic ketones were obtained due to the participation of the formyl group in the intramolecular Wittig reaction. 

The selenium version of this reaction offers the advantages that over-oxidation is no problem and that the elimination of the selenoxides occurs at room temperature or below so that the oxidation and elimination normally occur as a single step.23 A simple example is the preparation of another starting material 158 for a dienone-phenol rearrangement.24 The lithium enolate of spirocyclic ketone 155 reacts with PhSeCl to give 156 and oxidation with H202 gives the dienone 158 directly, with the selenoxide 157 as an intermediate. The overall yield is 83%. 

A similar high diastereoselectivity is obtained in the catalytic hydrogenation of spirocyclic ketone 7. Delivery of hydrogen proceeds exclusively from the face of the double bond opposite the isopropyl group19. 

A further extension of the cyclopropyl fragmentation method involves entrapment of the initially formed radical by a suitable radical acceptor [100]. This radical cascade has facilitated the efficient synthesis of spirocyclic ketones (Eq. 90). 

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