Fragmentation and Cyclization

Along the same lines, Prevost and Shipman have developed an intramolecular radical rearrangement of 2-methyleneaziridines providing piperidines, decahydroquinolines, and octahydroindohzines [85], 

Bacque et al. have reported new approaches to cycloheptenes based on pathway a [86]. 

The same authors have proposed a similar approach for the total syntheses of serofendic acids [90] using tin-free conditions with the NaBH3CN/ZnCl2 reduction of a tosylhydrazone [91]. 

Also related to pathway b, Hodgson et al. were able to obtain 2-aza-bicyclo[2.2.1]hept-5-enes from 7-azabicyclo[2.2.1]heptadienes by a tandem featuring a thiyl intermolecular addition followed by a homoallylic radical rearrangement [92]. 

Mascarenas appUed a strategy related to type c with an alkoxy radical to the chemistry of oxabicyclic systems (see 89 90). He uncovered a very 

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Other radicals undergo rearrangement in competition with bimolecular processes. An example is the 5-hexenyl radical (5). The 6-heptenoyloxy radical (4) undergoes sequential fragmentation and cyclization (Scheme 3.8).1S... 

For example, cis- and trans- 1,4-cyclohexanediols yield essentially identical El spectra. In Cl, the trans isomer yields an (M + H-H20)+ peak that is relatively more intense than that for the cis isomer [8], a phenomenon which allows one isomer to be distinguished from the other. The difference is ascribed to the possibility of forming a hydrogen bond in the case of the cis isomer and to the assisted fragmentation and cyclization in the case of the trans isomer ... 

Abstract This review provides an overview of some of the more recent work directed to exploit radical-based chemistry for the modification of some of Natures most important biomolecules, such as amino acids, peptides, and carbohydrates. Radical reactions are particularly advantageous for carrying out a variety of structural modifications on biomolecules as the reaction conditions are typically compatible with a wide variety of functional groups and solvents. An array of effective synthetic transformations will he discussed including selective side chain and backbone modifications of amino acids and peptides, along with methods for the transformation of carbohydrate substituents, as well as fragmentation and cyclizations reactions for the preparation of either structurally modified carbohydrates or chiral building blocks. 

Other workers have also used variations of the Kuehne biomimetic approach in the synthesis of ibophyllidine. Das and collaborators (338) prepared the secodine precursor 730 by an obvious modification of the route used in the synthesis of vincadifformine. Acid hydrolysis of 730, followed by quaternization, fragmentation, and cyclization, then gave the ibophyllidine ring system. Use of the racemic aminoacetal (/ 5-731) in the first essential stage in Scheme 109 was reported ultimately to give ibophyllidine (672) and 20-epi-ibophyllidine (673), whereas the simpler aminoacetal 732 gave desethyl-ibophyllidine (674). Subsequent repetition of this synthesis (394), using the chiral 5-aminoacetal (S-731) resulted in an enantioselective synthesis of (-f)-20-epi-ibophyllidine [(-(-)-673]. Similarly, the enantiomeric H-acetal (/ -731) was converted into (-)-20-epi-ibophyllidine [(-)-673]. Contrary to the earlier report, it now appears that no ibophyllidine is produced in these syntheses. 

Treatment of this intermediate with BFa-OEta then induced a domino fragmentation and cyclization cascade The cleavage of the oxabicyclic ring produced the intermediate A -acyl iminium ion 114, which was trapped by the pendant t-butyl ester carbonyl, followed by the loss of isobutene, to give the advanced intermediate 116 in 94% yield (Scheme 29). This compound, which contains the complete polycyclic framework of aspidophytine (117), was then further elaborated to produce the natural product in subsequent steps. 

The most studied reaction in liquid crystalline solvents is the NorishA ang type II reaction of alkyl and aryl alkyl ketones (Scheme 1). This reaction has been used extensively, mainly by Weiss and coworkers, to probe the properties of liquid crystals, since the distribution of fragmentation and cyclization products and the distribution of stereoisomeric trans- and cw-cyclobutanols are sensitive to the dynamics and conformational equilibria of the 1,4-biradical intermediate produced in the primary photochemical decay process of the ketone [352, 353, 360, 368-376]. Generally, in liquid crystals there is a preference for fragmentation over cyclization of the biradical, due to a preference for the biradical conformer that can only react by fragmentation. When cy-... 

Oxasteroids arising from tandem P-fragmentation and cyclization are products in the photolysis of the hypoiodites generated from 3-hydroxy-A -steroids and lead tetraacetate-iodine, as outlined in Scheme 84. The path of the formation of the oxasteroids is outlined in Scheme 85 one-electron oxidation of the intermediate radicals arising from the cyclization of allylic radicals generates the oxonium ions, which trap acetic acid to give the products. 

Total syntheses have been reported by E.J. Corey (1978B, 1979). We outline only the stereoselective synthesis of a protected fragment (A) which contains carbon atoms 1—9. This fragment was combined with fragment (B) by a Grignard reaction and cyclized by one of the methods typical for macrolide formation (see p. 146). 

Annelation of carbocycle to heterocycle and cyclizations with simultaneous formation of carbo- and heterocyclic fragments 98JCS(P1)983. 

The following syntheses of five-membered carbocyclic systems involve radical-induced epoxide fragmentation with radical translocation and cyclization. The resulting bicyclic alcohols are formed as a mixture of two epimeric esters with cw-fused rings.[71]... 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

The reduction of polymers can be carried out by using a diimide, generated in situ. The precursor for diimide can be p-toluenesulfonyl hydrazide (TSH), the reaction temperature is between 110-160 °C and the solvents are high boiling aromatic compounds. Possible side-reactions are cis-trans isomerization of 1,4-dienes, attachment of hydrazide fragments to the polymer, degradation and cyclization of the polymer. 

Different nucleophiles such as methanol, allylsilanes, silyl enol ethers, trimethylsilyl-cyanide, and arenes can be used in this process [62]. When the sulfide itself contains an unsaturated or aromatic fragment and the process is carried out in the absence of a nucleophile, an intramolecular anodic sub-stitution/cyclization might occur [61-63]. Methyl esters of 2-benzothiazolyl-2-alkyl or aryl-acetic acid, oxidized in MeOH/Et4 NCIO4 or H2SO4 in the presence of CUCI2, form 2,2-dimethoxy products (Eq. 7) [64]. 

An interesting application of photoinduced electron transfer involving fragmentation and subsequent cyclization reactions is reported by Kirschberg and... 

An El report deals with the tautomerism of unsubstituted and the differentiation of substituted pyrimidin-4(3//)- and -4(l//)-ones (90OMS115). Another publication on 2-alkyl (Et, Pr) or 2-arylmethyl-substituted derivatives shows that the substituent decisively influences their fragmentation and that, especially in the case of 2-arylmethyl substituents, an intramolecular cyclization in the formation of the ion again becomes very... 

R. E. Gawley, The Beckmann reactions Rearrangements, elimination-additions, fragmentations, and rearrangement-cyclizations , in Organic Reactions, Vol. 35 (Ed. A. S. Kende), Wdey-Intersdence, London, 1988, pp. 1-415. 

Avalos et al. (223,224) also found that simpler 2-aminothioisomiinchnones react with nitroalkenes to give dihydrothiophenes and other products, work that includes detailed MO calculations that rationalize both the reactivity of the thioisomilnch-nones and the observed regioselectivity (224). These same thioisomtinchnones (324) react with aryl aldehydes to provide p-lactams 325 following fragmentation and subsequent cyclization of the primary cycloadducts (225). Novel 1,2,4-triazines are produced when 324 is exposed to diethyl azodicarboxylate (226), and detailed synthetic and mechanistic studies have been reported for the reactions of 324 with alkynes (227) and chiral 1,2-diaza-l,3-butadienes (228). 

Since nicotine is the major precursor to NNN in tobacco and tobacco smoke, the reaction of nicotine with sodium nitrite was studied to provide information on formation of other tobacco specific nitrosamines, especially NNK and NNA, which could arise by oxidative cleavage of the l -2 bonds or l -5 bond of nicotine followed by nitrosation (26). The reaction was investigated under a variety of conditions as summarized in Table I. All three nitrosamines were formed when the reaction was done under relatively mild conditions (17 hrs, 20 ). The yields are typical of the formation of nitrosamines from tertiary amines (27). At 90 , with a five fold excess of nitrite, only NNN and NNK were detected. Under these conditions, both NNK and NNA gave secondary products. NNK was nitrosated a to the carbonyl to yield 4-(N-methyl-N-nitrosamino)-2-oximino-l-(3-pyridyl)-1-butanone while NNA underwent cyclization followed by oxidation, decarboxylation and dehydration to give l-methyl-5-(3-pyridyl)pyrazole, as shown in Figure 4. Extensive fragmentation and oxidation of the pyrrolidine ring was also observed under these conditions. The products of the reaction of nicotine and nitrite at 90 are summarized in Table II. 

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