Lactones intramolecular nucleophilic

The existence of n-complex intermediates can be inferred from experiments in which they are trapped by nucleophiles under special circumstances. For example, treatment of the acid 1 with bromine gives the cyclohexadienyl lactone 2. This product results from capture of the n-complex by intramolecular nucleophilic attack by the carboxylate group ... 

The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>. 

Treatment of carboxyaldehydes 252 with hydrazine hydrate in ethanolic KOH under refluxing conditions provides an easy entry to the novel imidazo[2,l-4][l,3]thiazole fused diazepinones 253 via lactone ring opening by intramolecular nucleophilic attack of the amino group of the intermediate hydrazone which could not be isolated (Equation 31) <2006TL2811>. 

The pyrrolidine derivative 314, a skeletal analog of the antitumor antibiotic anisomycin, was synthesized from the acetal derivative 16b. The 5-OH group of 16b was tosylated and then substituted with sodium azide. Reduction (sodium borohydride) of the lactone group afforded an open-chain derivative, which was selectively protected to give 313. Hydrogenation of the azide function, followed by p-toluenesulfonylation, led to 314 by an intramolecular nucleophilic displacement (284). 

Fig. 10.16. Comparison of the metabolism of A4-valproic acid (10.54), a metabolite of valproic acid, with that of ethyl A4-valproate (10.57), a synthetic analogue. Both compounds undergo cytochrome P450 catalyzed oxygenation to form the corresponding epoxides (10.55 and 10.58, respectively). The former reacts intramolecularly to form the lactone 10.56 and is not detectably a substrate for epoxide hydrolase. Epoxide 10.58, in contrast, is a substrate for epoxide hydrolase, forming the diol 10.59, which, in turn, carries out an intramolecular nucleophilic attack to form lactone 10.56 [136],...

Mass spectroscopic analysis of the gas phase revealed that 53 is formed with the concomitant generation of H2. Based on the proposed catalytic cycle for silyUbrmylation (Scheme 6.12), the formation of 53 and 54 can be explained by the intervention of 55 (n=2), which plays a pivotal role in the differentiation between intramolecular nucleophilic attack of the hydroxy group and reductive elimination of 54. Thus, the addition of base is believed to accelerate the conversion of 55 to the rhodate anion 56. This notation is supported by the fact that the introduction of a strong base such as DBU is advantageous for the selective formation of a lactone framework. 

Intramolecular nucleophilic displacements, such as those in lactone formation, have faster reaction rates than intermolecular S,42 reactions because the latter require two species to collide. The neighboring participant is said to furnish anchimeric assistance. 

Although it is reported that the U-5C-4CR can work well with nucleophiles other than methanol, such as primary or secondary amines, the only examples reported in the literature are those where trifunctional a-aminoacids such as lysine [67] or homoserine [66] or bifunctional aldehydes such as glycolaldehyde [65] are employed. In these cases, the side-chain amino or hydroxy group acts as the nucleophile and opens the cyclic intermediate generating the corresponding lactams or lactones. A less nucleophilic solvent such as trifluoroethanol is usually employed, in order to maximize the intramolecular attack. The observed stereoselectivities are, apart from a few examples [66], usually not very high this could be due to different factors (a) the side chains of the a-amino acids are not very bulky (b) the intramolecular nucleophilic attack could be faster than the methanol attack and the cyclic intermediate could not equilibrate to the thermodynamically favored isomer (c) the intramolecular nucleophilic attack on the more stable diastereoiso-meric cyclic intermediate could be kinetically less favored. 

It is worthy of note that the type of reaction shown in Scheme 6.39, Eq. (1) was reported only recently [102]. In 2001, Romo and co-workers described an intramolecular, nucleophile-catalyzed aldol-lactonization (NCAL) process which contains... 

Homopropargylic alcohols (but-3-ynols) as well as propargylic epoxides are suitable products to form cyclic ruthenium alcoxycarbenes upon intramolecular nucleophilic addition of the OH group to the electrophilic a-carbon of ruthenium vinylidene species. The recovery of the organic ligand as a lactone... 

An interesting intermolecular version of this reaction has likewise been put forward for the preparation of seven-, eight-, and nine-mem-bered carbocycle, as illustrated with a sole example in Scheme 3 [7]. In contrast to the above, these reactions begin with a carbonyl addition reaction of chloroiodoalkanes to cyclic or acyclic keto esters leading to the formation of an intermediate lactone. An intramolecular nucleophilic acyl substitution then terminates the sequence. The example in Scheme 3 represents a simple method for the construction of the 5 8 5 tricyclic ring system. 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

Homopropargylic alcohols as well as propargylic epoxides and pentynols readily form cyclic ruthenium alkoxycarbenes upon intramolecular nucleophilic addition of the OH group to the electrophilic a-carbon of ruthenium-vinylidene species. Their oxidation in the presence of N-hydroxysuccinimide leads to the formation of penta-lactones. The best catalytic system reported until now for this transformation of but-3-ynols is based on RuCl(C5H5)(cod), tris(2-furyl)phosphine, NaHCOs as a base, in the presence of nBu4NBr or nBu4NPp6, and N-hydroxysuccinimide as the oxidant in DMF-water at 95 °C (Scheme 8.11) [22]. 

Structures I and II differ only in the lactonic C-O bond. This seemingly simple transformation conceals complications derived from the oxidative process involved in the formation of this bond. Necessarily, the oxidant must be an external agent since the enone II does not show the traces (reduced fragments) that are always produced during any intramolecular redox operation. This oxidizing agent in all probability is bromine. In fact, one could predict, in the absence of any further evidence, that the reaction mechanism must proceed by way of an allylic bromination at the 7 carbon of enone I, which would provide the required functionalization for an intramolecular nucleophilic displacement of bromide by the carboxylate anion in a second step. This is shown in structure... 

The normal primary deuterium isotope effect in the first part shows that an OH bond is being broken in tile rate-detertnining step. Imidazole is loo weak a base to remove the OH proton completely so its role must be as general base catalyst. Attack on the carbonyl is the slow step with (aster breakdown of the tetrahedral intermediate arid hydrolysis of the lactone. Lactones arc hydroly,sed faster than esters because they lack anomeric stabilization (p. 1134). [ he role ttf the OH group is intramolecular nucleophilic catalyst. 

The ABC ring system of the carbocyclic skeleton of variecolin, a sesterterpenoid natural product was accomplished by G.A. Molander and co-workers. In their approach, they utilized two samarium diiodide mediated processes. First, a primary alkyl iodide was reacted with a ketone substrate in the presence of two equivalents of samarium diiodide and catalytic nickel(ll) iodide under samarium Grignard conditions. Subsequent oxidation and lactone formation provided the chlorolactone substrate. As alkyl chlorides are less reactive than alkyl bromides and iodides, the second samarium diiodide mediated process, an intramolecular nucleophilic acyl substitution, required visible light irradiation. 

The key steps in the first total synthesis of (+)-momilactone A by P. Deslongchamps et al. were a highly diastereoselective transannular DIels-Alder cycloadditlon and the Prdvost reaction The 3-ketolactone moiety was installed by first treating the tricyclic alkene with A/-bromo acetamide and silver acetate to obtain the trans bromoacetate with excellent diastereoselectivlty. The cIs stereochemistry of the lactone was achieved a few steps later by the intramolecular nucleophilic displacement of the bromide with the carboxylate ion on the adjacent six-membered ring. 

Molander, G. A., McKie, J. A. Intramolecular nucleophilic acyl substitution reactions of halo-substituted esters and lactones. New applications of organosamarium reagents. J. Org. Chem. 1993, 58, 7216-7227. 

Low-valent titanium alkoxide complexes have proved to be particularly useful in intramolecular nucleophilic acyl substitution (INAS) reactions. Addition of propargyl alcohol derivatives to 236 has been used as an efficient and practical method for the synthesis of allenyltitanium compounds (Scheme 43).197 Performing the reaction with a homopropargylic carbonate provides access to an alkenyltitanium compound with a lactone moiety.198 This methodology has since been extended to include olefinic carbonates and, through trapping with appropriate electrophiles such as aldehydes and iodine, affords substituted lactones.199... 

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

Many other heterocycles have been prepared following intramolecular nucleophilic cleavage strategies, like pyrazolones [102,103], benzimidazoles [104], indoles [105], quinazoline-2,4-diones [106], quinolinones [107], tetramic acids [108], oxa-zolidinones [82] and lactones [109, 110]. 

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