Polycyclic -y-lactones

Combined biotechnological and synthetic methods for preparation of polycyclic y-lactones, clinically important compounds 98PAC2093. 

Polycyclic y-lactones. An intramolecular v. .rsion of the formation of y-lactones by reaction of an alkene with acetic acid and mangane, e(lll) acetate (1) (6, 355-356) provides a general route to polycyclic y-lactones. Thus th unsaturated -keto acid 2 cyclizes to the r/.v-bicyclic y-lactone 3 when warmed in acei c acid with 1 (1.3 cquiv.) ... 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

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. 

This paper presents data on isolation and identification of the following types of geolipids from the Aleksinac oil shale, a Miocene lake sediment n-al-kanes, iso- and/or anteiso-alkanes, aliphatic iso-prenoid alkanes, polycyclic isoprenoid alkanes, aromatic hydrocarbons, saturated unbranched, aliphatic isoprenoid, hopanoic, and aromatic mono- and poly-carboxylic acids, fatty acid methyl esters, aliphatic y- and 6-lactones, cyclic y-lactones, aliphatic methyl- and isoprenoid ketones, and the triterpenoid ketone adiantone. Possible origin of the identified compound classes is discussed, particularly of those which had not been identified previously as geolipids. 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

Chiral ( )-crotylsilanes give tetrahydrofurans, cyclohexanones lead to spiro[4,51decane through a-(silylmethyl)divinyl ketone substitution, P-(alkoxycatbonyl)allylsilanes with epoxides give a-methylene-y-lactones fused to carbocycles, benzyl cations add to give tetrahydronaphthalenes or dihydro(lf/)indenes while tricyclic -2-phenyl-4H-1,3,2-benzodioxaborins with allylSiMes give polycyclic chromans l. 

Chlorine DBPs of the polycyclic musks 6-acetyl-1,1,2,4,4,7-hexamethy 1-tetraline (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-y-2-benzopyran (HHCB), which are widely used fragrances in cosmetics, daily care products, and cleaning products for household and industry, were investigated by Kuhlich et al. [123]. This study evidenced chlorination of HHCB as a potential new source of HHCB-lactone in the environment, other than biological transformation. 

The first asymmetric total synthesis of the macrocyclic lactone metabolite (+)-pyrenolide D was accomplished in the laboratory of D.Y. Gin. The natural product has a densely functionalized polycyclic structure and its absolute configuration had to be established. The key step of the synthesis was a stereoselective oxidative ring-contraction of a 6-deoxy-D-gulal, which was prepared from anomeric allylic sulfoxide via the Mislow-Evans rearrangement. 

In 2013, the Chi group developed the NHC-catalysed activation of the y-carbon atom of a-branched indole-3-carboxaldehydes to generate ortho-quinodimethane intermediates, which further reacted with trifluoromethyl ketones and isatins to give polycyclic and spirocyclic lactones 117 and 118, respectively, in good to excellent yields and over 90% enantiomeric excess (Scheme 20.50). ... 

These compounds will be described in the order of y- and J-lactones, cyanogenic glycosides, cyclohexane epoxides, cyclohexane diols, polycyclic compounds, and miscellaneous. 

Although the Diels-Alder reaction of furan-2(5H)-one itself 140b and its derivatives has been used to synthesize structurally complex polycyclic lactones, lower reactivity of such lactone dienophiles compared to the acyclic dieno-philes sometimes is problematic. Therefore, more reactive synthetic equivalents of y-butenolides were developed [114]. In addition, due to relatively strong Lewis basicity of the lactones, the reaction often requires the use of a stoichiometric amoxmt of Lewis acids [115]. As a recent elegant example of the catalytic Diels-Alder reaction, Corey demonstrated that chiral cationic oxazaborolidine 172 works as one of the effective asymmetric Lewis acid catalysts for the reaction of 140b with cyclopentadiene (Scheme 68) [116]. 

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