Oxygenative cyclization

Fig. 16 Nickel(0)-catalyzed radical cyclization/oxygenation sequence in a formal total synthesis of (-)-methylenolactocin 73...

In a rather comprehensive work aimed at synthesizing diverse carbapentofuranoses, Desire and Prandi [8] exploited a cobalt-catalyzed radical cyclization/oxygenation of a wide number of 6-iodohex-l-enitols to assemble the carbocyclic frame of the targets. As an example, Scheme 4 displays how 4a-carba-a-D-arabinofuranose 27 was prepared by starting with readily available glucopyranoside 24. 

In the event, Mitsunobu-type displacement of the unprotected hydroxyl of 24 delivered the iodinated sugar 25, which was then elaborated into acyclic iodohexenitol 26 via ring opening using activated zinc in refluxing ethanol, followed by reduction, tosylation and iodination. The pivotal radical cyclization/oxygenation of 26 was finally carried out in the presence of a catalytic amount of cobalt(salen) complex in air. This... 

Prandi has improved the previous oxygenation conditions by using only a catalytic amount of cobalt in the presence of two equivalents of sodium borohydride. Radical cyclization/oxygenation has been applied to the syntheses of biologically important carbofuranosides from iodohexenyl carbohydrates (Scheme 7) [16],... 

The transformation of 3 to hydroperoxide 2 proceeds by sequential oxygenation and peroxyl radical cyclization-oxygen entrapment (Scheme 4). The overall cascade accomplishes the formation of three C-O bonds and three stereocenters in a single... 

Several 1,2-dioxolanes [7, 75-76] and polycyclic peroxides [7, 77[ have been obtained in modest yields from unsaturated hydroperoxides by peroxyl radical cyclization-oxygenation pathways under initiation with DBPO or DTBN (cf. Scheme 43) [76a, 77[. In general, there is a strong bias for exo cyclization [7a, 75b], although an exception has been noted [78]. Moreover, when there is a choice, the... 

A short synthesis of the antimalarial peroxide yingzhaosu C, which allowed the relative stereochemistry of the natural product to be assigned as cis, has been achieved by means of tandem peroxyl radical cyclization-oxygen entrapment... 

Beckwith pioneered the use of a Thiol-Oxygen-Co-Oxidation (TOCO) process for the transformation of 1,4-dienes and 1,3,6-trienes to 1,2-dioxolanes [90], As illustrated by the example in Scheme 51 [90a], this process involves phenylthio radical addition to the least substituted double bond, oxygen entrapment, peroxyl radical cyclization, oxygen entrapment and hydrogen atom transfer from the thiol. In accord with the Beckwith-Houk transition state model [91, 92], cyclization provides preferentially the c/s-3,5-disubstituted 1,2-dioxolanes. 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

Phenolic oxygen participates in facile oxypalladation. The intramolecular reaction of 2-hydroxychalcone (105) produces the flavone 106[127]. The ben-zofuran 107 is formed from 2-allyIphenol by exo cyclization with Pd(OAc)2, but benzopyran 108 is obtained by endo cyclization with PdChf S], Normal cyclization takes place to form the furan 109 from 2-(l-phenylethenyl)phe-nol[129]. Benzofuran formation by this method has been utilized in the synthesis of aklavinione (110)[130]. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

The oxygen analogue of the Fischer cyclization requires the formation of 0-vinyl derivatives of iV-arylhydroxylarnines. These are readily converted to indoles but are less readily accessible than the arylhydrazones used for the Fischer cyclization. 

Fig. 5. Chemistry of cyclized mbbei—bis-a2ide negative acting resist, (a) Preparation of cyclized mbber resin from polyisoprene (b) photochemistry of aromatic bis-a2ide sensiti2ers. The primary photoproduct is a highly reactive nitrene which may combine with molecular oxygen to form oxygenated products, or may react with the resin matrix by addition or insertion to form polymer—polymer linkages.

Elfamycins having 4-hydroxy-2-pyridone moieties (1—6,12) readily undergo reversible internal cyclizations by conjugate addition of either oxygen functionahty on the pyridone ring at C-9. These products can be isolated as exemplified by isoefrotomycin (58). 

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

The electrolysis of adamantylideneadamantane solutions affords the radical cation, which can add molecular (triplet) oxygen to give the peroxide radical anion, which can react with adamantylideneadamantane to give the 1,4-diradical and another molecule of adamantylideneadamantane radical cation. The latter reacts with oxygen, to continue the chain of the reaction, while the former cyclizes to the corresponding 1,2-dioxetane (Scheme 18) (81JA2098). 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

A polyfluorinated P,y-unsaturated ketone is formed m situ from tributylamine and 3,4-bis(tnfluoromethyl)-3-(pentafluoroethyl)-5,5,6,6,6-pentafluoro-2-hex-anone. The enol form of the unsaturated ketone cyclizes via an intermolecular addition-elimination reaction that involves exclusive attack by oxygen rather than by carbon. This reaction demonstrates the hardness of a F-C= site toward... 

The use of this cyclization in the synthesis of isooxapenams demonstrates its usefulness in forming oxygen heterocycles [100] (equation 51)... 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Wasserman demonstrated with 0 labeling studies that the amide carbonyl oxygen is incorporated into the oxazole ring upon cyclization... 

Review of oxygenated 2,11-cyclized marine cembranoids, tri- and tetracyclic bioactive 0-heterocycles with cembrane skeleton 98H(49)531. 

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