Stereoselectivity during cyclization

The relative proportions of the separated diastereoisomers 40a and 40b (Ri = N02, R2 = CH3), the only bis-TB derivatives prepared via both synthetic pathways (Scheme 8), were not identical in each of the methods. The step-by-step synthetic approach (01JOC1607) afforded a 4 1 mixture of isomers 40a and 40b. However, in the case of the simultaneous strategy (04EJ01097), a 1 1 mixture of isomers 40a and 40b was formed under reaction conditions nearly identical to those of the cyclization method. Only the anti diastereoisomer 40b was isolated when the reaction temperature was reduced from 90 to 50°C. This difference in stereoselectivity during the formation of 40 (R3 = N02, R2 = CH3) via similar reactions can only be explained by stereoinduction of by-products, because in the reaction mixture the diastereoisomers 40a and 40b are in thermodynamic equilibrium due to the ready interconversion (racemization) of the methanodiazocine bridges in acidic media. 

The oxidative cyclization of the 5-iodoketone 312 is achieved with high stereoselectivity during the synthesis of 6-oxa-5a-pregnane 313 (Equation 135) <1996JOC6673>. 

In the first approach shown in Scheme 9, ketoester 77 was alkylated successively with 4-bromobutene and 1,3-dibromopropene. After decarboxylation, 78 was converted into iV-aziridinylimine 79 in good yield. The pivotal radical cyclization reaction proceeded smoothly to produce a mixture of isomeric propellane compounds 80, which was purified after the epoxidation step. For the synthesis of modhephene, the mixture of epoxides was rearranged into the corresponding allylic alcohols 81 and then the allylic alcohols were oxidized, giving a separable mixture of unsaturated ketones 82a and 82b. The major product 82a possessed the correct stereochemistry of the methyl group of modhephene. Since 82a had already been converted into modhephene, a formal total synthesis of dZ-modhephene has thus been completed. The isomeric ratio of 80 reflects the stereoselectivity during the radical cyclization reaction. The selectivity was very close to the ratio reported by Sha in his radical cyclization reaction. ... 

Presumably, the allylic side of the radical center places more steric demand than the methylene side of the radical center, leading to the observed stereoselectivity. We envisioned that increasing steric demand on the allylic side would impose the better stereoselectivity during the radical cyclization. 

There are different approaches for stereocontrol for the Robinson annulation the control can either arise fi-om the inherent nature of the starting ketone and/or the vinyl ketones substituents in combination with the reaction conditions, or by the use of a chiral catalyst. In the first case, an example is the stereoselective aldol cyclization to give the ketol intermediate 50. In this case the cyclization is kinetically controlled under protic basic conditions of sodium ethoxide and ethanol as it gives the cw-fused adduct rather than the more stable trans-fased ketol, which is not detected at any time during the reaction. 

An example of a surprisingly facile and stereoselective formation of an eight-membered lactone from an acyclic precursor diene ester was observed during the total synthesis of the antitumor agent octalactin A (148) (Scheme 27) [81]. The dense substitution pattern in cyclization substrate 146 presumably imposes... 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

A new metabolite from Streptomyces olivaceus has been shown to be (2S)-1-oxo-2,3-dihydropyrrolizine-3-carboxylic acid (15b) by total synthesis. The pyrrolizine ring was formed from the pyrrole (14) by stereoselective cyclization with phosphorus pentoxide in toluene in 37% yield. Partial racemization occurred during the hydrolysis of ester 15a.21... 

The use of isopropylidine acetals (112) as tethers in the intramolecular Diels-Alder reactions of dienes with alkenes facilitates the formation of civ-fused cycloadducts (113) from an endo transition state (Scheme 41).218 The intramolecular Diels-Alder reaction of 4-[tris-(2-mcthylcthyl)silyl]oxy-2//-thiopyran derivatives with potential dienophiles tethered at C(2), C(3), C(5), and C(6) positions yielded cycloadducts when the dienophiles were activated with a carbomethoxy group.219 By the substitution of a phenylsulfonyl group on the dienophile of 2-benzopyran-3-ones, it is possible to enhance exo addition during intramolecular Diels-Alder cyclizations to yield a predominance of trans-fused hexaphenanthrenes related to natural products.220 The intramolecular Diels-Alder reaction of 2-furfuryl fumarates has been investigated by molecular mechanics (SIBFA)/continuum reaction field computations.221 The intramolecular 4 + 2-photo-cycloaddition of A-benzylcinnamamides (114) in the presence of C(,H6 gives 3-azatricyclo[5.2.2.01,5]undeca-8,10-dien-4-ones (115) with high stereoselectivity (Scheme 42).222... 

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