Two-Carbon Annulation

Bravetti et al. have devised a very simple regio- and stereo-specific synthesis of the noraphidicolane (64) and norstemadone (65) ring systems from the common bicyclo[2.2.2]octane intermediate (59) (Scheme 5). The intermediate (59) was prepared by the Wiesner two-carbon annulation sequence involving (i) photocycloaddition of allene to the cyclohexenone (57), (ii) conversion of this into the masked aldol (58), and (iii) retro-aldolization. After conversion into the mesylates (60) and (62), acetolysis gave the respective bicyclo[3.2.1]octane derivatives (61) and (63), which were elaborated to (64) and (65) respectively. 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Ketone enolate 51 could also serve as a two-carbon component in [3 + 2] annulation when reacted with -heteroatom-substituted a,/ -unsaturated acylsilane 52345 Ppj. tjjg enolate of 3-methyl-2-butanone 51 (R = /-Pr) reacts with... 

Some representative examples of the [3+2] annulatlon are listed in Table 1. Both cyclic and acyclic allenophiles participate in the reaction, a-Alkylidene ketones undergo annulation to provide access to spiro-fused systems, and acetylenic allenophiles react to form cyclopentadiene derivatives. The reactions of (E)- and (Z)-3-methy1-3-penten-2-one illustrate the stereochemical course of the annulation, which proceeds with a strong preference for the suprafacial addition of the allene to the two-carbon allenophile. The high stereoselectivity displayed by the reaction permits the stereocontrol led synthesis of a variety of mono- and polycyclic systems. 

Srikrishna and co-workers have described cyclopentannulation of allyl alcohols by radical cyclizations as, protocols for the synthesis of sesquiterpenes. The total synthesis of 4-epibakkenolide-A 98 wherein two radical annulations were used for key carbon-carbon bond formations is illustrated [95CC469]. Radical cyclizations based on the 5-exo-dig pathway have been used as the key step in the total synthesis of sporothriolide and 4-epi-ethisolide [95TL2661] and in an approach to eriolanin skeleton [95TL2067],... 

Steroid-type molecules, e.g., 48, were generated from (l-alkynyl)carbene complex 11 by [4+2] cycloaddition of a TBSO butadiene to the C2-C3 triple bond of lk and subsequent two-alkyne annulation to the M = C bond (Scheme 17).75 Other polycyclic compounds have been obtained similarly by insertion of several alkyne units tethered by a carbon chain.76,77 It should be noted that an annulation of an aromatic ring instead of a 1,4-cycIohexa-diene is achieved if the diene component contains a potential leaving group, as shown in Schemes 16 and 17. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

In summary then, the oxyanion-accelerated rearrangement of 2-vinylcyclobutanol derivatives is now established as an attractive method for achieving two-carbon ring expansion under relatively mild conditions. In conjunction with the efficient synthetic routes to vinylcyclobutanones outlined in Scheme 21, this version of the VCB rearrangement provides several strategically novel annulation methods for the construction of six-membered carbocycles. ... 

Alkoxy iron complexes of the type (316) will also react with alkynes to give six-membered ring products that, like the two-alkyne annulation, are formally the result of a [2 -i- 2 -i- 1 + 1] cycloaddition. The formation of these pyrone complexes (317) have only been reported from the reactions of alkynes with iron-carbene complexes. These pyrones are also the only product from the reaction of an alkyne with any carbene complex which incorporates one alkyne, two carbon monoxides and the carbene ligand. 

The classical methods of constructing six-membered rings are the Diels-Alder reaction or the Robinson annulation, which consist of the union of two fragments, one with two carbon atoms and the other with four carbons. A conceptually different method from the above involves the condensation of two three-carbon units, one with two nucleophilic sites and the other containing two electrophilic sites. Furthermore, the regiochemistry of the reaction is controlled by the differential reactivities of these sites. 

By far the most cominon annulalion reactions of enamines lead to the formation of six-membered rings. Depending on the nature of the electrophilic reagent, the same enamine can act as either a two-carbon or a three-carbon component in the annulation process (Scheme 124). Furthermore, the same enamine and the same electrophilic reagent can give completely different products depending on the experimental conditions employed (Scheme 125). 

A useful reaction for the synthesis of unsaturated seven-membered heterocycles is the (2 + 2)-cycloaddition of heteroaromatic compounds, e.g., 1 //-pyrrole, furan, or thiophene derivatives, with acetylenes. In combination with a subsequent intramolecular (2 + 2)-cycloreversion (Section IV,B,2) of the annulated cyclobutene moiety, ring enlargement with two carbon atoms can be achieved. 1-Heterocycloheptatrienes, such as benzol6]azepines,26,27,65,66 benzo[fc]oxepins,67,68 benzo[6]-thiepins,69,70 and thiepins,18,71 have been successfully prepared in this way other routes are either nonexistent or laborious.72 In these compounds the reacting carbon-carbon double bond constitutes part of a (4n + 2)7r-electron system and in the (2 + 2)-cycloaddition the resonance energy of the aromatic nucleus is lost. Just like the nonaromatic heterocycles, heteroaromatic compounds have been reported to undergo (2 + 2)-cycloaddition reactions both with electron-deficient and with electron-rich acetylenes. 

We have seen that Michael reactions and aldol additions both form new carbon-carbon bonds. The Robinson annulation is a reaction that puts these two carbon-carbon bond-forming reactions together in order to form an a,j8-unsaturated cychc ketone. Annulation comes from annulus, Latin for ring, so an annulation reaction is a ring-forming reaction. The Robinson annulation makes it possible to synthesize many complicated organic molecules. 

In a related study, the annulation is combined with a ring expansion reaction. The reaction utilizes a -keto sulfone as the two-carbon component along with an allylic mesylate as the bifunctional reagent. The alkylation/cyclization process is outlined in eq 4. The subsequent ring expansion appears to be a general process except for cases involving fused six- and seven-membered ring systems (eq 5). 

Cyclocontraction-Spiroannulation. The mesylate derivative of 2-hydroxymethyl-3-triinethylsilylpropene participates in an interesting annulation reaction involving a -keto sulfone as the two-carbon component (eq 9). 

Scheme 8.1 Ring-closure reaction (Pathway A), annulation of one carbon chain and one carbon atom (Pathway B), and annulation of two-carbon chain subunits (Pathway C).

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