Cyclizations Intramolecular Conjugate Addition

Free-radical cyclizations onto P carbons have also been utilized in the formation of the tricyclic core ring stmcture of alkaloids gelsemine and oxogelsemine (Eq. (13.57)) [73]. Tricyclic compound 183 was formed as a single compound in 87% yield. 

Examples of stereoselective cyclizations involving heteroatom radicals are rare. Tandem oxy radical cyclization and diastereoselective hydrogen atom transfer reactions, however, have also been studied (Eq. (13.58)) [74]. These reactions take advantage of chirality at the y carbon to induce anti-/ cycloaddition. Hydrogen 

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The success of intramolecular conjugate additions of carbon-centered radicals in multifunctional contexts is noteworthy. Compound 57 (see Scheme 10), prepared by an interesting sequence starting from meto-toluic acid (54) (see 54 > 55 > 56 > 57), can be converted to the highly functionalized perhydroindane 58 through an intramolecular conjugate addition of a hindered secondary radical.21-22 This radical cyclization actually furnishes a 6 1 mixture of perhydroindane diastereoisomers, epimeric at C-7, in favor of 58 (96 % total yield). It should be noted that a substantially less strained cis-fused bicyclo[4.3.0] substructure is formed in this cyclization. 

It will be recalled that one of the key operations in the synthesis of IJK ring system 86 is the intramolecular conjugate addition reaction (see 90—>89, Scheme 17b) to form ring J. In the context of compound 90, the electrophilic a,/ -unsaturated ester moiety and the potentially nucleophilic tertiary hydroxyl group reside in proximal regions of space, a circumstance that would seem to favor the desired cyclization evept (see Scheme 19). Indeed, exposure of a solution of 90 in THFto sodium hydride (1 equiv.) for one hour at 25 °C results in the formation of compound 89 in 92% yield. In... 

The tandem intramolecular conjugate addition to 99 followed by an intramolecular alkylation reaction leads to a bis-cyclized product in good yield (equation 80)66. 

Intramolecular conjugate addition of carbamates to a,fi-unsaturated esters.3 In the presence of potassium f-butoxide or NaH, allylic carbamate esters 1 cyclize stereoselectively to traws-oxazolidones (2). 

Intramolecular conjugate addition of allylsilanes to enones (12, 25). In an extension to the earlier study, Majetich et al.5 have examined the intramolecular addition of allylsilanes to cyclic enones. The course of cyclization depends markedly on the choice of catalyst and on the size of the ring that is formed. 

The enantioselective synthesis of (-)-sedacryptine, a piperidine alkaloid, has been achieved via the double intramolecular conjugate addition of a carbamate group onto a vinyl sulfone and then an enone (Scheme 30). The first conjugate addition of 108 proceeded in a. syn-1,3 fashion. The successive cyclization of the resulting carbamate anion 110, which was formed from carbanion 109 via proton transfer, gave a mixture of stereoisomeric products 111 and 112. Both of these isomers were converted into the target natural product.76... 

Cryptocaryolone 690c was prepared, in 44% yield, from the triol 718 by cyclization in benzene in the presence of TsOH <20030L1959>. The lactonization of 719, under normal hydrolytic conditions, afforded the expected pyranone 720 along with the dioxocin 690d by way of the intramolecular conjugate addition of the hydroxyl group. The reaction was found to be susceptible to hydrolytic conditions and the dioxocin was obtained in >90% yield with 80% AcOH at 100°C for 12h (Equation 31) <2000TL707>. 

Intramolecular conjugate additions/ This fluoride ion-catalyzed Michael addition is particularly useful for cyclization of suitably substituted allyltrimethylsilanes with a Michael acceptor. In the examples cited, BE, is not useful, because its use results in desilylation or isomerization. 

Intramolecular conjugate additions of unsaturated esters. Reaction of the ester la with n-butyllithium at — 100° results in r-butyl cyclopentylacetate (2a) in 82% yield. The cyclization presumably involves a rapid lithium-iodine exchange to form a nucleophilic center that undergoes an intramolecular conjugate addition to form a cy-... 

Intramolecular conjugate addition naturally results in ring formation. The body of examples of this type of reaction is subdivided into the Sections 4.7.1.1.2.1. Acyclic Acceptors and 4.7.1.1.2.2. Cyclic Acceptors , depending on whether or not the accepting enone/enoate moiety is part of a ring system. In the latter case, the cyclization affords a bi- or oligocyclic product. The steric restrictions thus imposed reduce the number of thermodynamically feasible products. As a consquence, product structures can usually be predicted easily, and high stereoselectivities are observed. 

The intramolecular conjugate addition of in situ, chemoselectively generated amines 2 bearing an electrophilic double bond in the cu-position leads to functionalized pyrrolidines and piperidines 3 under very mild conditions34. The cyclization step occurs smoothly and the piperidine and pyrrolidine derivatives are obtained as a mixture of diastereomers with good diastereose-lection in most cases. The reactions are under kinetic control and the geometry of the starting alkene does not seem to have an influence on the stereochemical outcome of the cyclization step. 

Few reactions of intramolecular conjugate addition of co-amino groups to alkenes with an electron-withdrawing group are known. Both the E- and Z-isomer of 1 cyclize to the same pyrrolidine 2 with a, 2-anti preference, however, more of the. vvn-isomcr is produced from the F-isomer than from the Z-isomer. The product ratio is determined by separately isolated derivatives of the products 268 74. Similar reactions with lower diastereomeric ratios are known75. 

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