3-Lactones azide synthesis

A lactone-based synthesis converted keto-alkyne 6.245 to carboxylic acid 6.246 in four steps. Formation of lactone 6.247 was followed by conversion to azide 6.248. Reaction with butylamine and hydrogenation gave N-butyl 5-amino-6-cycIohexyI-2-isopropylhexanamide, 6.249. This amino acid product is considered to an hydroxy-ethylene dipeptide isostere. 115,143 jn the case of 6.249, the term isostere essentially refers to replacing one group in a molecule with another that will give similar chemical or physiological properties. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

The installation of the amine functionality at C5 is accomplished by mesylation of 41 followed by azide displacement to give 44 (71% yield over four steps). The P-aminopropanamide 13 is then introduced directly to the lactone under 2-hydroxypyridine catalysis to give the penultimate intermediate 45. Reduction of the azide and isolation as the hemifumarate salt provides aliskiren hemifiimarate (l).37 Based on the information disclosed to date, the synthesis of aliskiren is accomplished with an overall yield of 14% from iso vanillin 14 with a longest linear sequence of 15 steps. Given the complexity of aliskiren, this is a remarkably efficient process, and it should be noted that this analysis likely only establishes a lower limit of efficiency, as further optimization of the route on a manufacturing scale is expected. 

Nitta, Hatanaka and Ishimura11 started their synthesis of cephalosporin precursors from L-aspartic acid. The key intermediate is the lactone 1. The azidation resembles the general preparation procedure given for open-chain imide enolates in Section 7.1.1. The main differences are the generation of a dianion with lithium diisopropylamide and the application of tosyl azide. 

Azides (175 X = OH) were resolved through microbial reduction of p-keto esters (181) with baker s yeast and provided the azido dienes (182) and (183) in about 70% ee in an approach to enantiocontrolled synthesis of pyrrolizidines (equation 55). In this series extensive racemization toc place prior to or during the vinylaziridine formation. A conversion of chlorobenzenediol (184) to lactone (185) and elaboration of this material to either enantiomer of trihydroxyheliotridane (187) constituted a fully enantiocontrolled approach to both enantiomeric series of highly oxygenated pyrrolizidine alkaloids (Scheme 41).2 ... 

A versatile stereoselective synthesis of endo,exo-furofuranones was accomplished by R.C.D. Brown and coworkers. One of the key steps was a Rh(ll)-catalyzed C-H insertion reaction and the required diazo lactone was prepared via the Regitz diazo transfer reaction. The 2-acetyl substituted lactone substrate proved to be recalcitrant toward the deacylative diazo transfer under standard conditions. Eventually the authors decided to use the very reactive triflyl azide (TfNs), which was generated in situ under phase-transfer conditions to afford the desired a-diazo lactone. The C-H insertion product was then converted to (+)-methylxanthoxylol. 

A further use of Barton esters has been described as a path to enol ether radicals. The reaction involves the photochemical decomposition at 355 nm of the derivative (85). As part of an approach to the synthesis of a series of Kopsia alkaloids, the reductive decarboxylation of the derivative (86) was carried out. This involved irradiation of the Barton ester (86a) in the presence of t-BuSH. This affords the product (86b). The photochemical decomposition of the Barton ester (87) provides a path to the silyl derivatives (88). The nature of the trapping agent X is dependent on the conditions under which the reaction is carried out. Thus a variety of derivatives can be obtained using alcohols to afford ethers, or using ethanesulfonyl azide to give azides. The Barton esters (89) undergo the usual photochemical decarboxylation to afford ethenoyloxy radicals. Cyclization within these, in the presence of tributylstannane yields the lactones (90). ... 

Synthesis fromo-glucoronolactone A synthesis of the dihydroxyproline 76 from the lactone 74 has been reported (Scheme 10). ° ° The lactone 74 was converted into the azide 75 in four steps. Hydrogenation of 75 in water in the presence of palladium black afforded 76 in 12% overall yield from the lactone 74. 

Synthesis from o-xylonolactone A synthesis of (25, 3-, 4A)-3,4-dihydroxy-proline (2) from 2,5-dibromo-2,5-dideoxy-D-xylono-l,4-lactone (77) has been reported (Scheme 11). ° Compound77 was reacted with sodium azide to give a 5 1 mixture of azides 78 and 79 in 95% yield. Hydrogenation of 78 afforded 2-amino-5-bromo-2,5-dideoxy-D-lyxono-1,4-lactone (80), which upon treatment with aqueous Ba(OH)2 led to spontaneous cyclization of the amino acid 81 to afford 2 in 60% yield. 

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