Oxidative free-radical cyclization

Removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a silyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. 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 Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. 

Improved yields of products have been achieved from oxidative free-radical cyclization of deuteriated substrates459, The reaction of CH2=CMeCH2CH2COCD(COOMe)CH2 CH=CH2 (387) with Mn(OAc)3 afforded 65% 388 (R R2 = H, Me) whereas 387 of natural isotopic composition provided only 22% of 388 under the same conditions. Large... 

Deuterium tracer and isotope effect study of Mn(lll)-based oxidative free-radical cyclizations... 

Oxidative Free-Radical Cyclizations and Additions with Mono and / -Dicarbonyl Compounds... 

The reaction of /3-dicarbonyl compounds and simple ketones with Mn(OAc)3 or ceric ammonium nitrate is a general and effective method for C-H activation that has been extensively reviewed [1-6]. The oxidative free-radical cyclizations of la... 

Under oxidative conditions, treatment of chiral menthyl (3-ketoesters (55) with Mn(OAc)3/Yb(OTf)3 (Lewis acid) in CF3CH2OH generates the corresponding cyclized products with high diastereoselectivity. Eq. 10.26 shows the treatment of chiral menthyl (3-keto esters (55) with Mn(OAc)3-mediated oxidative free radical cyclization to form a single isomer (56a) predominantly. This method can be applied to the enantioselective synthesis of (+)-triptophenolide with 90%e.e., which is a biologically active natural product. 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

In their enantioselective total synthesis of (+)-triptocallol (3-79), a naturally occurring terpenoid, Yang and coworkers made use of a concise Mn(OAc)rmediated and chiral auxiliary-assisted oxidative free-radical cyclization [39]. Reaction of 3-77, bearing a (R)-pulegone-based chiral auxiliary, with Mn(OAc)3 and Yb(OTf)3 yielded tricyclic 3-78 in a twofold ring closure in 60% yield and a diastereomeric ratio of 9.2 1 (Scheme 3.20). A further two steps led to (-i-)-triptocallol (3-79). For the interpretation of the stereochemical outcome, the authors proposed the hypothetical transition state TS-3-80, in which chelation of the (3-keto ester moiety with Yb(OTf)3 locks the two carbonyl groups in a syn orientation. The attack of the Mn -oxidation-generated radical onto the proximate double bond is then restricted to the more accessible (si)-face, as the (re)-face is effectively shielded by the 8-naphthyl moiety. 

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). 

DCP as a Chiral Controller in Oxidative Free Radical Cyclizations. As a chiral auxiliary, DCP (1) is also reported to induce modest diastereoselection (60% de) in Mn(III)-based oxidative free-radical cyclizations of p-keto esters (eq 12). Chiral p-keto ester 25 was prepared by transesterification reaction with methyl ester 23, 1, and 0.3 equiv of DMAP (catalyst) in anhydrous toluene at reflux for 3-5 d as described by Taber. Oxidative cyclization of a 0.1 M solution of 24 in AcOH with 2 equiv of Mn(OAc)3-2HzO and 1 equiv of Cu(OAc)3 HzO provided bicyclo[3.2.1]octan-2-one (25). 

The Liu synthesis of Aa-methyl-A18-isokoumidine (137) (214) starts from L-tryptophan (138), which was transformed to intermediate 139 in six steps. The Dieckmann condensation of 139 afforded the /3-ketoester 140. Oxidative free radical cyclization of /3-ketoester 140, initiated with Mn(0Ac)3, H20/Cu/(0Ac)2 H2O, followed by the removal of the Na-protecting group, led almost quantitatively to 141. Hydrolysis and decarboxylation using the Barton method afforded, via compound 142, intermediate 143. Treatment of 143 with (CH3)2S = CH2/dimethyl sulfoxide (DMSO) THF yielded the epoxy derivative 144, which was reduced with A1H2C1 in THF to the, not yet naturally found, jVa-methyl-A18-isokoumidine (137) (Scheme 12). 

Manganese(III)-mediated radical reactions have become a valuable method for the formation of carbon-carbon bonds over the past thirty years since the oxidative addition of acetic acid (1) to alkenes to give y-butyrolactones 6 (Scheme 1) was first reported by Heiba and Dessau [1] and Bush and Finkbeiner [2] in 1968. This method differs from most radical reactions in that it is carried out under oxidative, rather than reductive, conditions leading to more highly functionalized products from simple precursors. Mn(III)-based oxidative free-radical cyclizations have been extensively developed since they were first reported in 1984-1985 [3-5] and extended to tandem, triple and quadruple cyclizations. Since these additions and cyclizations have been exhaustively reviewed recently [6-11], this chapter will present an overview with an emphasis on the recent literature. 

Mn (III)-Mediated Electrochemical Oxidative Free-Radical Cyclizations... 

SNIDER McCarthy Mn Mediated Oxidative Free-Radical Cyclizations 85... 

We have been interested in developing oxidative free-radical cyclizations using Mn(OAc)3 (26-49). These reactions have the potential to prepare complex, highly functiondized, polycyclic molecules from simple precursors. They also pose a more stringent challenge for the method than oxidative additions of simple substrates, like acetic acid or acetone, to alkenes. Acetic acid and acetone are used in excess as solvent and the yield is based on the oxidant consumed. Further oxidation of the product is not generally a problem since the starting material is present in vast excess. In oxidative cyclizations, the substrate is too complex and expensive to use in excess. Further oxidation of the product is a major concern and common side reaction. 

At the current level of development, Mn(III)-based oxidative free-radical cyclization is a very attractive procedure. Simple substrates are converted readily to highly functionalized and versatile products. The preferred solvent, acetic acid, is relatively safe since it becomes vinegar on dilution with water. Cu(OAc)2 is used in catalytic quantities. However, 2 equivalents of Mn(OAc)3 must be used. The amount of Mn(n) waste would be significantly decreased if Mn(OAc)3 could be used in catalytic quantities and regenerated by in situ reoxidation of the Mn(II) produced in the reaction. From the pollution point of view, electrochemical oxidation would be an effective way to regenerate Mn(ni). Oxidative free-radical cyclization using Mn(III) and Cu(n) as catalysts in an electrochemical oxidation would minimize the production of toxic chemicals and the resulting pollution. 

Mn(in)-based oxidative free-radical cyclization is an attractive alternative to tin hydride based procedures both in terms of chemical efficiency and pollution prevention potential since toxic tin byproducts are not produced and Mn(H) can be reoxidized to Mn(III) by KMn04. Mn(III)-mediated electrochemical oxidative cyclization has significant potential for pollution prevention since only catalytic amounts of Mn(III) are needed. Our results indicate that each case must be examined in detail. Some substrates are oxidized in high yield under the electrochemical conditions others give very low yields of products. Further work is needed to understand these differences and develop more general catalytic conditions. 

Snider BB, Merritt JE, Dombroski MA, Buckman, BO. Solvent effects on manganese(III)-based oxidative free-radical cyclizations ethanol and acetic acid. J. Org. Chem. 1991 56 (19) 5544-5553. 

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