Pyran lactone

The oxidative carbonylation of hydroxy-substituted alkenes can lead to synthetically interesting tetrahydrofurans and pyrans." As early as 1984, Semmelhack and his group developed a methodology for the synthesis of furans and pyrans using a palladium-catalyzed oxidative carbonylation of hydroxyalkenes. In the presence of CUCI2 (3 equiv), PdCl2 (0.1 equiv) and CO (1.1 bar) at 25 °C, the heterocycles were isolated in good yields (Scheme 8.9) [50]. In another study, they performed the carbonylative synthesis of tetrahydrofurans [51, 52], and this procedure was applied to the synthesis of pyran-lactones [53], racemic frenolicin [54], and also plakortones [55-58]. 

Semmelhack MF, Bodurow C, Baum M. Direct s3mthesis of pyran-lactones related to naphtoquinone antibiotics. Tetrahedron Lett. 1984 25 3171-3174. 

Synthesis of cyclopenta[d]pyran skeleton of natural lactones 97T14507. 

The addition of the lithium enolates of various acetic add esters to (S)-3-(4-methylphcnyl-sulfmyl)-2(5//)-liiranone and (,S)-5,6-dihydro-3-(4-methylphenylsulfinyl)-2//-pyran-2-one gives, after desulfurization with Raney nickel, 4-substituted dihydro-2(3//)-furanoncs and 4-substituted tetrahydro-2//-pyran-2-ones, respectively, in good to quantitative enantiomeric excess. Addition of the enolate occurs via the nonchelate mode. The enolate of methyl (phenylthio)acetatc is best overall in regards to chemical yields and enantiomeric purity of the final lactone product13. 

Elaboration of triol 88b to bryostatin 7 requires chemoselective hydrolysis of the Cl methyl ester in the presence of the C7 and C20 acetates, macrolide formation, installation of the C13 and C21 methyl enoates, and, finally, global deprotection. The sequencing of these transformations is critical, as attempts to introduce the C21 methyl enoate to form the fully functionalized C-ring pyran in advance of macrolide formation resulted in lactonization onto the C23 hydroxyl. In the event, trimethyltin hydroxide promoted hydrolysis [73] of the Cl carboxylate of triol 88b, and subsequent trie thy lsilylation of the C3 and C26 hydroxyls each occurs in a selective fashion, thus providing the seco-acid 89. Yamaguchi macrolacto-nization [39] proceeds uneventfully to provide the macrolide 67 in 66 % yield (Scheme 5.14). 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

The pyran-2-one ring system 174 (Scheme 68) is a potentially aromatic species, due to the contribution of the pyrylium-2-olate structure 174b, but facile cleavage of the ring by nucleophiles makes it most likely a lactone rather than an aromatic system. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

Table 3.20 lists examples of the preparation of oxygen-containing heterocycles by RCM. Further examples, including lactones [895], pyrans [896,897], chromenes [839], tetrahydrofurans [838], phosphonates [898], and oxepines [856,899-902], have been reported. For references to macrocyclizations see Scope and Limitations in this section. 

The rhodium-catalyzed asymmetric conjugate addition is applicable to a,yS-unsaturated esters (Scheme 3.8). Hayashi reported [20] that the reachon of 5,6-dihydro-2H-pyran-2-one 19a with phenylboronic acid gave a 94% yield of phenylated lactone (S)-20am with 98% enanhomeric excess. For the linear enoates, organoboronic acids did not give... 

B. 1,3-Dimethyl-6H-benzo[b]naphtho[1,2-d]pyran-6-one (4). Under an argon atmosphere, a 250-mL, oven-dried, round-bottomed flask, equipped with a reflux condenser, is charged with freshly distilled N,N-dimethylacetamide (DMA, 130 mL), 3,5-dimethylphenyl 1-bromo-2-naphthoate (3, 3.24 g, 9.12 mmol), palladium(ll) acetate (205 mg, 0.913 mmol), triphenylphosphine (481 mg, 1.83 mmol), and sodium acetate (1.50 g, 18.3 mmol) (Notes 4 and 5). The orange suspension is degassed three times, placed in a preheated (130°C) oil bath (Note 5), and stirred at 130°C for 12 hr (Note 6). Removal of the solvent at 40°C (0.1 mbar, 0.075 mm) gives a black oily residue, which is Chromatographed (5 x 40 cm column, silica gel 0.063 - 0.2 mm, 170 g, 1 cm of charcoal at the top of the column eluent hexane / diethyl ether 5 1), to yield 2.00 g (80%) of the lactone 4 as a slightly yellow solid. Recrystallization from diethyl ether / hexane delivers 1.63 g (65%) of colorless or pale yellow crystals (Note 7). 

Although the valence bond description of pyran-2-one could include a zwitterionic contribution involving the carbonyl group, thus making the ring aromatic, there is little evidence to support this. For example, the IR carbonyl frequency (1740 cm ) is typical of an unsaturated lactone, and the chemical shifts of the ring protons in the H NMR spectrum indicate that there is no ring current. 

The lactonic property of pyran-2-ones is apparent in their reactions with nucleophiles, which normally lead to ring opening. However, this may not be simply direct attack of the reagent at the carbonyl carbon. 

Some representatives of this group occur as natural products, including kojic acid (4.1), which can be isolated from the Aspergillus mould used in the manufacture of sake from rice. Like pyran-2-ones, these compounds show little aromatic character and are best considered as vinylogous lactones (Scheme 4.9), rather than as unsaturated ketones. 

Alkyl bromides have been shown to add to 5-trifluoroacetyl-3,4-dihydro-2/7-pyrans in the presence of zinc powder (Scheme 31). When BrCH2C02Me is employed as the alkyl bromide, after the initial addition, the ester may easily be cleaved under acidic conditions and the product undergoes spontaneous cyclization to afford a bicyclic lactone <1999JEC141>. 

Similarly, the structure of a nitro-PAH lactone found in ambient aerosols and also formed in laboratory irradiations of phenathrene-NO -air mixtures, 2-nitro-6//-dibenzo[h,rf]pyran-6-one, which is a powerful, direct-acting bacterial mutagen and potent human cell mutagen, is commonly shown as (XI) (Helmig et al., 1992a Arey et al., 1992 Sasaki et al., 1995, 1997b Arey, personal communication). 

In the early 1990s, several nitro-polycyclic aromatic compounds that are powerful direct mutagens were identified in ambient particulate matter, including the nitrophenanthrene lactones 2- and 4-nitro-6//-dibenzo[6,r/]pyran-6-one, whose mutagenicities are given in Table 10.20. The 2-isomer (XI) is not only very... 

Obviously, conversion of an acyclic diastereomer into a compound with known configuration is another secure method. For example, conversion of ester 3 into the ethenyl lactone324 which was hydrogenated to the known lactone (3.S,4A)-3-ethyltetrahydro-3,4-dimcthyl-2//-pyran-2-one... 

Particularly important is the influence of the metal countercation e.g., cleavage of the achiral lactone l,3-dimethyl-6//-benzo[ ,]naphtho[1.2-d]pyran-6-one in toluene at — 40 CC, using different metal alkoxides, e.g., (+)-menthol as inexpensive chiral 0-nucleophiles, gives atropisomer ratios of 81 19 for lithium, 66 34 for sodium, and 63 37 for potassium. In other solvents (e.g., THF), this selectivity order may be reversed14. 

Each desired enantiomer of 3-substituted dihydro-2(3.//)-furanones and 3-substituted tetrahydro-2//-pyran-2-ones was prepared starting either from 4,5-dihydro-2-(m-trimethylsilyloxy)oxazoles and alkylating with the corresponding alkyl halide, or by reversing the order of alkyl group introduction. Upon hydrolysis with dilute hydrochloric or sulfuric acid, 2-substituted cyclic lactones were obtained in 40-75% overall yield and 60-86% enantiomeric excess20. 

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