Radical intermediates stereoselective synthesis

The wide variety of methods available for the synthesis of orga-noselenides,36 and the observation that the carbon-selenium bond can be easily cleaved homolytically to give a carbon-centered radical creates interesting possibilities in organic synthesis. For example, Burke and coworkers have shown that phenylselenolactone 86 (see Scheme 16), produced by phenylselenolactonization of y,S-unsaturated acid 85, can be converted to free radical intermediate 87 with triphenyltin hydride. In the presence of excess methyl acrylate, 87 is trapped stereoselectively, affording compound 88 in 70% yield 37 it is noteworthy that the intramolecular carbon-carbon bond forming event takes place on the less hindered convex face of bicyclic radical 87. 

Indolines and indoles were prepared by a direct electrochemical reduction of arenediazonium salts. As a result, radical intermediates were generated from which 3,4-disubstituted tetrahydrofuran skeleta were constructed <02OL2735>. A short and stereoselective total synthesis of furano lignans was realized by radical cyclization of epoxides using a transition-metal radical source <02JOC3242>. Other preparations of tetrahydrofurans using radical cyclization include the synthesis of novel amino acids L-bis-... 

The results can be rationalized as follows the first cyclization of substrate 68 gave a mixture of a-sulfonyl radical intermediates 71 and 72 (Scheme 19). These then underwent a second fully stereoselective cyclization to give the cis- and franr-fused bicyclic products 69 and 70, respectively, as single isomers. Such sequential transformations, in which two carbon-carbon bonds are formed in a single step, are attractive methods for enhancing the efficiency of organic synthesis. As y-hydroxy-a,P-unsaturated phenyl sulfones can be prepared in enantiomerically pure form,48 this procedure should be readily applied to the synthesis of enantiomerically pure bicyclic products. 

The preparation of a-selenoketones, esters, nitriles and related compounds can easily be performed via alkylation of the corresponding enolates or stabilized carbanions [21]. These compounds have found many synthetic applications in radical chemistry. In Eq. (9), a typical example involving a ketone is depicted [22]. The stability of a-selenoketones such as 41 is remarkable. Similar reactions with lactones have been performed. For instance, this approach has been applied to the stereoselective synthesis of oxygen-containing rings to either faces of a bicyclic structure [23]. The approach based on a-selenenylation/radical allyla-tion compares favorably with classical enolate allylation procedures, which usually leads to mixture of mono- and diallylated compounds. Furthermore, this strategy is excellent for the preparation of quaternary carbon centers [24] as shown by the conversion of 43 to 45, a key intermediate for the synthesis of fredericamycin A, [Eq. (10)] [25]. Similar reactions with sulfoxides [26] and phosphonates [27] have also been reported. 

A much more stereoselective synthesis of vinylcyclopentanes was obtained when l,l-dihalo-2-vinylcyclopropanes 40 were reacted with electron-deficient alkenes in a process catalyzed by diphenyl disulfide. Cyclization of the intermediate-adduct radicals occurred to give 4-sub-stituted l,l-dihalo-3-vinylcyclopentanes 41 in good yields with excellent diastereoselectivity for the 3,4-CM-isomer. 

A further example of the stereoselective synthesis of /ran.v-subsiituted tetrahydropyrans is the radical cyclization of ethyl (4R)-(Z)-4-(2-bromo-l-ethoxyethoxymethyl)-2-hexenoate3" The radical cyclization is performed by heating the bromoacetal in the presence of tributyltin hydride and AIBN in benzene. A mixture of two diastereomers is formed in 97% yield. Reduction, benzylation, hydrolysis and oxidation gives the /ran.v-substituted ( + )-(4S,57 )-4-(2-benzyloxyethyl)-5-ethyltetrahydro-2//-pyran-2-one (5), which is a potential synthetic intermediate for (—)-emetine35. The highly selective formation of the tram-substituted pyrans is rationalized by an allylic strain effect that destabilizes the transition state leading to the cis- isomers. 

Vinylogous sulfonates are valuable radical acceptors for the stereoselective synthesis of cyclic ethers [48]. Evans used the Z-vinylogous sulfonate 73 for preparation of the intermediate 74, which will be used in the synthesis of mucocin [49] (Scheme 26). More recently, an intermediate in the synthesis of garsubellin A was prepared via E -vinylogous sulfonate radical cyclization by Nicolaou [50]. 

Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxoeene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachi-bana employed the same reaction sequence in the partial synthesis of ciguatoxin ]128]. 

An alkylation/reductive decyanation method was developed for the efficient synthesis of xjn-l,3-diols [9, 10]. Cyanohydrin acetonides are rapidly deprotonated by amide bases and alkylated with suitably reactive electrophiles to yield diaste-reomerically pure coupled products. Subsequent exposure to Li/NHa affords exclusively xy -l,3-diol acetonides (see above). Although the alkylation itself is stereoselective, it is noteworthy that the, 2>-syn stereochemistry is ultimately set in the reductive decyanation by virtue of the anomeric axial radical intermediate. This methodology was effectively applied in the total synthesis of the polyene macrolide roflamycoin (Scheme 15) [23]. Noteworthy is the formation of the entire protected polyol segment of roflamycoin by treatment of a late-stage intermediate with Li/ NHa to effect a simultaneous decyanation/debenzylation. 

The control of anomeric stereochemistry continues to fuel the investigation into the synthetic utility of (x-oxygenated radical intermediates. Moreover, it has proven to be a valuable tool in organic synthesis, especially in the stereoselective synthesis of various substituted tetrahydropyrans, y>>n-l,3-dioxanes, and carbohydrate derivatives. The recent discovery of non-equilibrium radical reactions and conformation-induced self-regeneration of stereocenters should provide new opportunities in the ever-expanding field of a-oxygenated radical chemistry. 

The extention of radical cyclization of (bromomethyl)dimethylsilyl allyl ethers to propargyl analogs 17 has been studied by Malacria and coworkers. The intermediate exocyclic vinyl radical 18 can be either trapped by the hydrogen atom to give, after simple chemical transformations, the trisubstituted alkene 19 (equation 25) or can be added intramolecularly to give cyclic products when suitably located double bonds are present (equations 26 and 27). An attempt to apply this methodology to the stereoselective synthesis of angular and linear triquinane has also been performed. When = t rt-butyl,... 

The applications in stereoselective synthesis of monocyclic and bicydic products with up to four contiguous stereogenic centers have been reported, as shown in Scheme 5.15 in which 63 reacts with the borane 59 to give 64 [26]. In these processes, the addition of the radical to the enone is followed by trapping of the enolate radical 60 with an organoborane and the formation of an intermediate... 

Condensation of silylimine of (5)-lactic aldehyde with lithium enolate of t-butyl isovalerate affords the -lactam in 80% chemical yield and in a 97 3 diastereomeric ratio. The mixture was desilylated and treated with lead tetracetate to give, in one step, through a radical fragmentation reaction, the 4-acetoxy derivative as a 1 1 4(R) 4(S) imeric mixture. The lack oi stereospecificity is not easy to rationalize expecially if one considers that the analogous lead tetraacetate induced oxidative decarboxylation is completely trans stereoselective. Both reactions should have the same radical intermediate. However, this lack of stereospecificity is not important for the success of the synthesis since the mixture of diastereoisomers exclusively affords the trans 4-substituted azetidinone by the subsequent Merck procedure (Scheme 9). 

Two unselective approaches to the two alkaloids are illustrated in Scheme 50. A straightforward synthesis by King relied on acid-induced intramolecular Mannich reaction of ammoketone 396, prepared from 5-aminopentanal diethyl acetal and pent-3-en-2-one, to give a mixture of ( )-394 (55%) and ( )-395 (20%) (367). The synthesis by Pilli et at. involved a one-pot trimethylsilyl triflate-catalyzed condensation between pent-3-en-2-one and the acyliminium ion derived fium JV-Boc-2-ethoxypiperidine (397) (368,369). Under the reaction conditions, the intermediate 398 underwent spontaneous V-deprotection and cyclization to give a 5.5 1 mixture of ( )-394 and ( )-395 (67%). In the same Scheme is also shown the much shorter stereoselective synthesis of ( )-394 by Beckwith et al, who used a radical-mediated cyclization on the V-acylated 2,3-dihydropyridin-4-one 399 to give the bicyclic product 400 as the sole diastereomer (91%) (370). Compound 400 was readily converted into the target alkaloid by reduction of both carbonyl groups with lithium aluminum hydride followed by reoxidation of the secondary alcohol at C-2. 

The aim of this chapter is to provide an overview of the utility of radical synthetic methods for constructing valuable intermediates in target-oriented synthesis of natural products. The chapter is organized according to the methods used in carbon-carbon, bond-forming radical reactions. Representative examples of the successful implementation of radical-promoted stereoselective carbon-carbon formation published since 1991 are presented, most of which, as will become apparent, involve substrate-controlled diaster-eoselective radical cyclizations. ... 

Radical Coupling and Cyclization Reactions. Phenyl thionocarbonate esters derived from alcohols serve as efficient precursors for the generation of radical intermediates which can be used for the formation of new carbon-carbon bonds. For example, a 4-thionocarbonate ester derived from L-lyxose undergoes a stereoselective allylation upon photolysis in toluene in the presence of 2.0equiv ofAllyltributylstannane (eq 6). Photoehemical initiation is preferable to chemical initiation using Azobisisobu-tyronitrile which results in the formation of side products at the expense of the desired product. The allylation produet was used further in a total synthesis of pseudomic acid C. 

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