Lactone synthesis intramolecular cyclization

S. Velazquez, S. Huss, and M.-J. Camarasa, Stereoselective synthesis of [3.3.0] fused lactones (y-butyrolactones) of sugars and nucleosides by free radical intramolecular cyclization, J. Chem. Soc. Chem. Commun. p. 1263 (1991). 

Lithium enolates of phenyl esters (28) react with aldehydes or ketones to give O-lithiated phenyl 3-hydroxyalkanoates (29) which undergo spontaneous intramolecular cyclization to P-lactones (30) (95JOC758), Also, lithium enolates are used in the synthesis of 3-[l-(dialkylamino)alkyl]()-lactoncs (94JOC7994), which are precursors for a-oxo-P-lactones. 

Formation of p-Lactams, Peptides and Oligonucleotides. The intramolecular cyclization technology to form /8-lactams using DCC in the condensation reaction was used by Sheehan and Henery-Logan in the total synthesis of penicilline in 1957. They also found that N-trityl penicilloates are cyclized with diisopropylcarbodiimides. Other p-lactames, such as cephalothin lactone and (—)-thienamicin are similarly constructed. The latter synthesis proceeds in a stereospecific manner and DCC is used in combination with triethylamine to give a 93 % yield of the /3-lactam 661. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Taber, D. F., Nakajima, K., Xu, M., Rheingold, A. L. Lactone-Directed Intramolecular Diels-Alder Cyclization Synthesis of trans-Dihydroconfertifolin. J. Org. Chem. 2002, 67, 4501 504. 

Kuroda, C., Shimizu, S., Haishima, T., and Satoh, J.Y, Synthesis of a stereoisomer of frullanolide utilizing the intramolecular cyclization of co-formyl-2-alkenylsilane. Bull. Chem. Soc.. Jpn., 66, 2298, 1993. Kuroda, C., Inoue, S., Kato, S., and Satoh, J.Y, Synthesis of a-methylene-y-lactones fused to a perhydro azulene carbon framework through intramolecular cyclization of allylsilanes, 7. Chem. Res. (M), 458, 1993. 

Kuroda, C., and Anzai, S., Synthesis of a-methylene-y-lactone fused to seven, eight, and fourteenmembered carbocycle through intramolecular cyclization of functionalized allylsilane with acid chloride. Chem. Lett.. 875, 1998. 

Figure 7.3 summarizes our synthesis of all three stereoisomers of auxin-glutaric acid (167).3 Commercially available (.S )-2-methyl-l -butanol (A) and L-isoleucine (B) were converted to (.S)-3-mclhylpcntanoic acid (C), which was previously employed by Kogl and Erxleben to synthesize auxin-glutaric acid. Then, C was converted to bromo ester E, whose intramolecular cyclization to give 5-lactone F was the key step. Chromic-acid oxidation of F furnished a stereoisomeric mixture of auxin-glutaric acid (167). 

Synthesis from o-isoascorbic acid Syntheses of 2 and its antipode 37 from the commercially available D-isoascorbic acid have been reported by conversion to the enantiomerically pure acetonide lactone 29 on a large scale in 75% yield (Scheme 5). Lactone 29 was treated with amino vinylsilane 30 to give the amide 31 in 82% yield, which was used in two different ways. Mitsunobu conditions were not successful to convert 31 to 32. However, the conversion has been achieved in 88% yield by mesylation and then subjection to intramolecular cyclization. Treatment of 32 with Lawesson s reagent afforded the respective thioamide, which was treated with BFj OEtj followed by direct reduction with LiBEtjH to provide the 2-(ethylthio)pyrrolidine 35. Cyclization of 35 afforded the single stereoisomeric tetrahydroindolizine 36. Catalytic hydrogenation of 36 followed by deprotection provided 2-cp/-lentiginosine (2). 

Further elaboration of these molybdenum-7i-cyclohexadiene cations for stereoselective synthesis of cyclohexene compounds was achieved. Addition of NaBH, RMgBr, and LiCH(COOMe)2 to diene 107 gives the Ti -4,6-cw-disubstituted cyclohexadienyl compounds 110 a-d. After conversion of 110b to its acid form 111, a NOBp4-promoted intramolecular cyclization of this monoacid compound delivers bicyclic lactone 112 with a 50% yield. 

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]. 

The carbonylative cyclization of 2-iodophenols with norbornadiene or norbornene was also carried out. In 1989, Catellani s group studied the annulation of 2-iodophenol with norbornadiene to coumarin (Scheme 3.11a). ° In this method, the elimination of cyclopentadiene via retro-Diels-Alder reaction was involved in the formation of the terminal product. Fiaud and co-workers reported the palladium-catalyzed carbonylative cyclization of 2-iodophenol with norbornene in 1997 (Scheme 3.11b). They reported that the selectivity for the production of the two regioisomers can be controlled. Catellani and co-workers studied the intramolecular cyclization of ort/zo-iodophenyl 3-butenoate to 4-methylcoumarin with a palladium catalyst. 85% of 4-methylcoumarin was produced in the presence of benzonitrile and carbon monoxide, which is compulsory (Scheme 3.12a). Silva, Costa and their co-workers reported a tandem process for the synthesis of coumarins from 2-iodophenols and enoates with the assistance of a palladium catalyst (Scheme 3.12b). The general scope of this Heck-lactonization involves E- and Z-enoates as substrates. It was shown that this reaction is sensitive to steric hindrance around the double bound in... 

Taber DF, Nakajima K, Xu M et al (2002) Lactone-directed intramolecular Diels-Alder cyclization synthesis of trans-dihydroconfertifolin. J Org Chem 67 4501-4504... 

To redirect hydroxyvalerate production from PHA synthesis, they investigated the use of a Pseudomonas strain with systems for a removal of the CoA carriers from the hydroxy acids. Wild-type Pseudomonas overexpressing the gene of a recombinant thioesterase from E. coli yielded 14 g L 4-hydroxyvalerate and 5 g L 3-hydroxyvalerate as by-products (Fig. 12). They used minimal medium which was supplemented with glucose and levulinic acid (Martin and Prather 2009). Regarding the production of y-VL, they faced the problem that the intramolecular cyclization of 4-hydroxyvaleric acid is pH dependent and that the equilibrium at pH 7.5 in the cytosol is unfavorable for lactonization. By using a variant of human paraoxonase I, they achieved a substantial increase in y-VL production. 

---