Bicyclic ring systems, alkylative

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

The final option available to a u-alkylpalladium intermediate from Heck alkylation occurs if another alkene or alkyne function is situated properly to participate in a further Heck-type carbopalladation (equation 161)318,319. In properly constructed systems, more than one further carbopalladation is feasible, and many examples of these cascade car-bopalladations have been reported. Several have been quite spectacular (equation 162)320. Fused, spirocyclic and bridged bicyclic ring systems have been prepared in this manner. The process may also create as many as five rings in one step, with five-,six- and three-membered rings321 being the most suitable for preparation (equation 163). Alternatively, the proper orientation of double and triple bonds allows cyclotrimerization to highly functionalized arenes or fulvenes (equation 164)322,279. 

Stereoselective Michael addition of lunctionalized zinc-copper reagents to cycloheptatrienone iron tricarbonyl complexes is observed (Scheme 146). A pendant nitrile can participate in an alkylation reaction of the intermediate enolate forming a fused bicyclic ring system (Scheme 147). Addition in a 1,2- or 1,4-fashion depends on the nucleophile. Harder nucleophiles tend to form 1,2-adducts (Scheme 148). 

In 2009, the Magnus group disclosed the synthesis of racemic codeine [50]. In their synthesis (1) an intramolecular phenol alkylation generating an A-C bicyclic ring system with a quaternary carbon, (2) a stereo-controlled, one-pot formation of a B-ring by way of the combination of Henry reaction and Michael addition of nitromethane with a cyclohexadienone-aldehyde, and (3) an introduction of the requisite functionalities in the C-ring by the epoxide-mediated selenylation followed by oxidation, were employed as the key transformations. 

When the acetonide and the bicyclic ring system are removed, as in the substrate triene 33, it becomes apparent that the origin of the stereoselectivity lies in the influence of the remote alkyl substituents. Cyclization of the hexatriene 33 (R1 = Et R2 = CH3), a substrate that retains the substitution pattern of those described previously (i.e., 27 and 30), affords the same sense and degree of selectivity [d.r. (34/35) 4 1]. The isomeric substrate 33 (R1 = CH3 R2 = Et). a substrate in which the alkyl substituents are reversed, affords a 1 1 mixture of diastereomers. 

Bicyclic rings can also be constructed from enamines using bifunctional reagents. The bromoester 7, for example, reacts by both an Sn2 alkylation and a Michael addition, giving the bicyclic ring system 8 ° ... 

In general, enolates of cis-fused 5,6 bicyclic ring systems display strong tendencies to undergo alkylation from the less hindered convex side [15]. An example demonstrating this trend was reported by Marshall, who obtained lactone 35 in 91 % yield as the only observed diastereomer in the methylation of 34 (Equation 6) [48], For trans-fused bicyclic systems, prediction of the stereochemical outcome becomes more complicated, as the inherent stereogenic centers may exhibit mutually opposing biases consequently, the situation has to be carefully evaluated for each particular enolate. The diastereomeric trans-lactone 36 (Equation 7) thus furnished methylated product 37 in 97 % yield and dr >97 3 [49]. 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

With 0,-y-unsaturated a -diazo ketones, the resulting [2.1.0]-bicyclic systems (40) were quite unstable and underwent a [2 + 2] cycloreversion to generate ketenes (41), which were then trapped by nucleophiles (Scheme 7). The overall scheme has been named a vinylogous Wolff rearrangement and offers a novel entry to products usually derived from a Claisen rearrangement.102 A recent report describes its application for functionalized angular alkylation in fused ring systems.103 In contrast, the intramolecular re-... 

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