Lactone synthesis oxidative addition

The synthesis of 7-lactones by oxidative addition of acetic acid to alkenes in the presence of Mn(0Ac)2 has been documented for some... 

Therefore, taking into account the potentialities of such lactones as carbohydrate delivery synthons (vide infra), several routes leading to carboxymethyl glycosides (and thus subsequently to the lactones) were investigated, in order to get as many structural variations as possible for widening the scope of their use in synthesis. In addition to the isomaltulose oxidation method (route a), the oxidation of allyl glycosides (route b), and the anomeric alkylation with tert-butylbromoacetate (route c) were studied (Scheme 11). These three methods are detailed in the following sections. 

One of the earliest examples of the synthetic promise of radical reactions for preparing polycyclic products was provided by Corey s y-lactone synthesis. This approach was actually based on a well-known reaction of a-carbonyl radicals, generated by manganese(iii) oxidation of carboxylic acids, with unsaturated substrates. The mechanism of the basic steps shown for the preparation of lactone 418 (Scheme 2.140) involves initial addition of the a-carbonyl radical 419 to the double bond of styrene, followed by oxidation of the radical intermediate 419a to carbocation 419b, and subsequent intramolecular reaction with the carboxyl nucleophile to yield the lactone product. 

The first synthesis of this compound to be completed was the result of studies by Smith and co-workers in 1982. The readily available flavor constituent cyclotene (368) (Scheme 2.28) was reduced and isomerized to 2-methyl-2-cyclopenten-l-one (369) in 64% yield. Addition of dimethyl cuprate followed by isomerization and Baeyer-Villiger oxidation gave the racemic 8-lactone 370 (86%). Addition of allyl Grignard reagent followed by formation of the methyl ketal provided a 71% yield of 371, which possesses the expected axial methoxy group. Conversion of the terminal olefin into the functionalized isoxazoline 373 was accomplished in 68% by the 1,3 dipolar cycloaddition of nitrile oxide 372. 

Mori and Shibasaki s group described the use of a special titanium-isocyanate complex for a novel one-step synthesis of isoindolinones and quinazolinones starting from o-halophenyl alkyl ketones [260]. As shown in Scheme 2.35, this reaction proceeds through the oxidative addition of the enol lactone, generated by palladium-catalyzed carbonylation of o-halophenyl alkyl ketones, to the titanium-isocyanate complex A. 

Transition metal catalyzed insertion of CO has proven to be an excellent method for the synthesis of lactones [6-8]. Access to lactones via this approach typically involves Pd(0) catalysis via (i) oxidative addition of a C—X bond, (ii) insertion of CO, (iii) intramolecular addition of 0-based nucleophiles, and (iv) reductive elimination (Scheme 2.2). 

Surprisingly, methyl esters are also suitable substrates whereby intramolecular cyclization occurs with concomitant loss of methyl iodide. Larock used internal alkynes as coupling partners for lactone synthesis (Scheme 2.33) [74]. The proposed mechanism involves oxidative addition of Pd(0) to the aryl iodide, followed by addition across the alkyne and cyclization of the carbonyl O of the ester to form an oxonium ion. Reductive elimination followed by loss of the methyl group then yields the product [74]. Shen and coworkers also reported a variant utilizing o-2,2-dibromovinylbenzoates (Scheme 2.34) [79]. 

Palladium-catalyzed lactonization with CO insertion is a useful method that has been developed over the years to become an important tool in organic synthesis. The most straightforward approach consists of an oxidative addition of Pd(0) to a vinyl/aryl halide or a pseudohalide (e.g., triflate) followed by insertion of carbon monoxide and subsequent intramolecular attack of the oxygen nucleophile onto the carbonyl, with regeneration of the Pd(0) catalyst. An appropriate base is necessary to trap the acid released during the reaction (Scheme 1). 

In 2004, Cheng and co-workers reported a nickel-catalyzed cyclization of 2-haloesters with aldehydes to phthalides. Here, hy using Ni(n) as the catalyst, phthalide derivatives were produced in excellent yields with high chemoselectivily under mild conditions (Scheme 2.162a). In addition to five-memhered products, this methodology can he further applied to the synthesis of six-memhered lactones. The reaction of methyl 2-(2-bromophenyl)-acetate with henzaldehyde under similar reaction conditions afforded a six-membered lactone in a 68% yield. A possible catalytic mechanism for this cyclization was also proposed. Reduction of nickel(ii) to nickel(O) hy using zinc powder is likely to initiate the catalytic reaction. Oxidative addition of atyl iodide to the nickel(O) species yields the nickel(ii) intermediate. 

A novel Y-lactone synthesis (Figure 9) uses the high Sjj1 reactivity of p-methoxybenzyl chloride to give 1 1 addition products with a variety of alkenes. The oxidative degradation of the aromatic ring and lactoni-sation are achieved in a one pot reaction, and preliminary experiments indicate that a-substituted Y-lactones are also accessible by this method. ... 

Ishii et al. also found that phthalimide N-oxyl 94 generated by cocatalyzed oxidation of N-hydroxyphthalimide under O2 atmosphere abstracts a hydrogen atom of C-H moiety in secondary alcohol. They also expanded Ms reaction to y-lactone synthesis through this radical generation from cyclopentanol 92 followed by radical addition to acrylates (Scheme 42) [65]. 

Similarly, Schlecht and Kim have reported a substituent-directed oxidation method for the synthesis of 8-lactones by oxidative cyclization of hydroxyalkenes [80] (Scheme 36). Addition of alkenyl Grignard reagent to ketones 184 afforded hydroxyalkene 185, which upon treatment with chromium trioxide in acetic acid and acetic anhydride provided spiro-8-lactone 186. 

Formation o/p- and a-Lactones from Vinyhxiranes. An oxidative addition of vinyloxiranes (22) to iron(O) complexes provides the most usual synthesis of ferralactone complexes (21) (eq 16). ... 

Alkynes undergo stoichiometric oxidative reactions with Pd(II). A useful reaction is oxidative carboiiyiation. Two types of the oxidative carbonyla-tion of alkynes are known. The first is a synthesis of the alkynic carbox-ylates 524 by oxidative carbonylation of terminal alkynes using PdCN and CuCh in the presence of a base[469], Dropwise addition of alkynes is recommended as a preparative-scale procedure of this reation in order to minimize the oxidative dimerization of alkynes as a competitive reaction[470]. Also efficient carbonylation of terminal alkynes using PdCU, CuCI and LiCi under CO-O2 (1 I) was reported[471]. The reaction has been applied to the synthesis of the carbapenem intermediate 525[472], The steroidal acetylenic ester 526 formed by this reaction undergoes the hydroarylalion of the triple bond (see Chapter 4, Section 1) with aryl iodide and formic acid to give the lactone 527(473],... 

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

The low yield in this reaction might be caused by a number of reasons. First, the overall reaction is only rapid for readily enolizable compounds. 1,3-Dicarbonyl compounds will therefore be a better choice as compared to acetic acid. Second, to prevent oxidation of radical 54, it is advantageous to work with excess diene and therefore speed up trapping of 54 through diene addition. Finally, lactone 55 can, as an enolizable compound itself, also be oxidized by manganese(III) acetate and form various oxidation products. Shorter reaction time and the use of understoichiometric amounts of oxidant might therefore benefit the overall result. All these factors have been taken into account in the synthesis of bicyclic /-lactone 56, which has been obtained from cyanoacetic acid and 1,3-cyclohexadiene in 78% yield within 15 min reaction time (equation 25)60,88. 

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