Dilactone synthesis

A short enandoselecdve synthesis of f- -f/f,/f -pytenophorin, a naturaUy occurring and-fun-giil 16-membered macrohde dilactone, is prepared from fS -5-nitropentan-2-ol via the Michael addidon and Nef reacdon fScheme 4.23. The choice of base Is important to get the E-alkene in the Michael addidon, for other bases give a rruxture of and Z-alkenes. The reqidslte chiriil fS -5-nitropentan-2-ol Is prepared by enandoselecdve redncdon of 5-nitropentan-2-one v/ith baker s yeast. ... 

Perhydropyrido[l,2-A][l,2]oxazines have been utilized as key intermediates in a stereospecific total syntheses of (—)-pumiliotoxin C and 5-< />z-pumiliotoxin C <1996J(P1)1113>, and the marine alkaloids (—)-lepadins A, B, and C and macrocyclic dilactones, (+)-azimine and (+)carpaine <20000L2955, 2001JOC3338, 2003OL3839>. In the total synthesis of the marine alkaloids ( )-fasicularin and ( )-lepadiformine, perhydro[l,2]oxazino[3,2 /]quinolines were used to control the stereochemistry <2000JA4583, 2000TL1205>. 

Macrodilactonization. The final steps in a synthesis of the 12-membered dilactone intergerrimine 31 involve selective cleavage of the (trimethylsilyl)ethyl... 

This method of cyclization has been used successfully for synthesis of four 11-membered dilactone pyrrolizidine alkaloids,2 but it does not appear to be useful for cyclization to simple macrolides. 

L-Mannitol has been prepared by the reduction of L-mannosaccharo-dilactone or L-mannose. By far the most convenient procedure is that used by Baer and Fischer for their preparation of L-glyceraldehyde by the oxidative cleavage of l,2 5,6-diisopropylidene-L-mannitol with lead tetraacetate. L-Arabinose was converted to L-mannonolactone by the cyanohydrin synthesis and this was hydrogenated over platinum oxide to the desired L-mannitol. High hydrogen pressures, rather than low as usually employed with this catalyst, were used. 

As indicated in the section describing the structures of natural dilactones, wentilactone B was wrongly assigned when the structure of 30-hydroxy-13,14,15,16-tetranorlabda-7,9(ll)-dien-(19,6(J),(12,17)-diolide was isolated. Our synthesis of this compound allows the reassignment of the structure of wentilactone B. Thus, the hydroxyl group of this natural podolactone should be relocated at C-2 with an a- configuration [87]. Two double cyclization steps were employed in this synthesis. The first involves the construction of the bicyclic skeleton via a Mn(III)-mediated... 

Total synthesis of nagilactone F, a biologically active norditerpenoid dilactone isolated from Podocarpus nagi. Hayashi, Y. Matsumoto, T. Nishizawa, M. Togami, M. Hyono, T. Nishikawa, N. Uemura, M. J. Org. Chem. 1982, 47, 3428-3433. 

Pateamine (606), a potent cytotoxin containing a dilactone functionality, was isolated from a New Zealand species of Mycale and identified by analysis of spectral data [480]. Total synthesis of pateamine A (606) involved a (3-lactam based macrocyclisation [481,482], while another total synthesis of pateamine employed a concise and convergent route [483]. 

A very short and elegant synthesis of the 16-rtiembered dilactone ( )-pyrenophorin (515) has been accomplished by the dipolar cycloaddition reaction of a trialkylsilyl nitronate (81TL735). Nitromethane was added to 3-buten-2-one and the carbonyl group of the product reduced with sodium borohydride. The nitro alcohol (511) was converted to the acrylate (512) which was then subjected to a dimerization-cyclization reaction by treatment with chlorotrimethylsilane and triethylamine in dry benzene. Hydrogenation of the mixture of isoxazoline products (513) over palladium on charcoal followed by double dehydration of the intermediate bis-/3-hydroxyketone (514) led to ( )- and meso-pyrenophorin (Scheme... 

Knust H, Hoffmann RW (2003) Synthesis and Conformational Analysis of Macrocyclic Dilactones Mimicking the Pharmacophore of Aplysiatoxin. Helv Chim Acta 86 1871... 

After these pioneering works, several reviews cover the enormous number of papers published in this field [3-7]. The synthesis of oxetanes can have a great importance in the development of compounds with relevant biological properties oxetane ring is present in the skeleton of taxol (1), an important drug used in the treatment of ovarian cancer [8] in merrilactone A (2), a new sesquiterpene dilactone with neurotrophic activity [9] and in several antiviral oxetanes, such as 3, 4, and 5, which have been described in literature (Scheme 3.2) [10-12],... 

Furfural (18) was oxidized to give the butenolide 19, which on Michael condensation with diethyl ethylmalonate afforded lactone 20. Hydrolysis of 20 yielded the dilactone 21. This was treated with ethanol in the presence of sulfuric acid. The isomer mixture obtained was separated by preparative thin-layer chromatography, yielding 4-ethoxy-3-ethoxycarbonylmethyl-2-ethyl-4-butanolide (22). Elimination of ethanol, with the aid of p-amino-benzenesulfonic acid, gave 2-(3//)-furanone 23 the 2-(5//)-furanone isomer 24 was obtained with the aid of orthophosphoric acid. Both isomeric esters gave the acid 25 after hydrolysis, which on catalytic hydrogenation afforded m-3-carboxymethyl-2-ethyl-4-butanolide 26, identical to homopilopic acid. This synthesis of homopilopic acid differs from earlier syntheses because the less stable cw-2,3-disubstituted butanolide (26) is formed in the last step. 

This reaction provides a short synthesis of thi tetracyclic dilactone 5 from 4 (equation 1). 

An alternative ester synthesis, the reaction of a carboxylate anion with an alkyl halide, was used by Madejewski [62] for the preparation of ( , )-l,9-dioxacy-clohexadeca-3,1 l-dien-2,10-dione (76) under dilution conditions. This 16-membe-red dilactone represents a precursor for the synthetic norpyrenophorin 77 a, the physiological activity of which corresponds to the one of the natural products pyrenophorin 77b and vermiculin 77c. The lactone 76 can be obtained in 77% yield by dimerization of ( )-7-bromo-2-heptenic acid (75) in DMF in the presence of potassium carbonate. 

Another useful reagent for macrolactonization via mixed phosphoric anhydride is N,N- bis(2-oxo-3-oxazolidinyl)phosphordiamidic chloride (BOP-Cl, 64), which was used by Corey and coworkers [41] in the first synthesis of aplasmomycin (67), a novel boron-containing macrocyclic antibiotic. As shown in Scheme 21, the linear precursor 65 was treated with 3 equiv of BOP-Cl (64) and 7 equiv of triethylamine in dichloromethane at 23 °C for 6 h to give the dilactone 66 in 71% yield. 

In the first synthesis of the dilactonic antibiotic pyrenophorin 89) by Raphael and coworkers [53], imidazole ester was used to achieve cyclization. As shown in Scheme 29, the linear precursor 87 was converted to the imidazolide by the action of diimidazol-l-yl ketone (ImjCO) and foDowed by l,5-diazabicyclo[4.3.0]non-5-ene (DBN) induced cyclization to give the dilactone 88 in 60% yield. 

During the total synthesis of the pentacyclic sesquiterpene dilactone (+)-merrilactone A by S.J. Danishefsky et al., a two-carbon unit was introduced at C9 by a Johnson-Claisen rearrangement. This high yielding transformation was carried out in the presence of catalytic 2,2-dimethyl propanoic acid at 135 °C using mesitylene as the solvent. A mixture of diastereomeric esters were formed, which were later hydrolyzed and subjected to iodolactonization to form the second lactone ring present in merrilactone A. The natural product was synthesized in 20 steps with an overall yield of 10.7%. 

S.J. Danishefsky and co-workers reported the total synthesis of pentacyclic sesquiterpene dilactone, merrilactone A. ° In their approach, they utilized Keck s radical allylation method to achieve the required chain extension. This sidechain was later used to construct one of the cyclopentane rings of the natural product. 

The reaction of olefins with lead tetraacetate has not been a useful method in organic synthesis, because reactions such as addition of an oxygen functional group to the double bond, substitution of hydrogen at the allylic position, and C-C bond cleavage can occur to give complex mixtures of products. With some specific alkenes, however, reaction with lead tetraacetate can afford synthetically important compounds cleanly. For instance, reaction of the diacid with 6 equiv. lead tetraacetate in acetonitrile gave the dilactone in excellent yield (Scheme 13.36) [59]. 

A synthesis of pyrenophorin using dithian shows how it works. The target 23 is a macrocyclic (16-membered ring) dilactone and disconnection of the ester linkages reveals two identical halves 24 pyrenophorin has C2 symmetry.7... 

Cathedulins -K17, -K19, and -K20 have been isolated from C. edulis, and their structures determined using FABMS, and one- and two-dimensional and NMR [169]. Cathedulins -K17 and -K19 each contain edulinic acid (B) as the acid component of the macrocyclic dilactone. The absolute configuration of B derived from cathedulin -K19 was established by synthesis of the (5)-dialcohol C from methyl (R)-3-hydroxy-2-methylpropionate. The product (C) was identical to the compound produced by UAIH4 reduction of cathedulin -K19, in sign of optical rotation, IR, H and NMR spectra [170]. 

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