Dilactones cyclization

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. 

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... 

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... 

The extreme susceptibility of open dilactone 545 to transannular cyclization under both alkaline and acidic conditions has also been established.429,431 Several more notable examples are illustrated in Scheme 81. Such reactivity has been attri-... 

Macrolactonization. The usually difficult lactonization to ll-membcred pyrroli-zidine dilactones can be achieved by use of a trimethylsilylethyl ester (8, 510-511) and activation of the lo-hydroxyl group by mesylation. Thus treatment of 1 with (C4H,)4N F in acetonitrile at 30° liberates the carboxyl group with spontaneous cyclization to the diastereomer 2, the methoxymethyl ether of dZ-crispatine. ... 

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. 

Barton oxidation was the key to form the 1,2-diketone 341 in surprisingly high yield, in order to close the five-membered ring (Scheme 38). The conditions chosen for the deprotection of the aldehyde, mercuric oxide and boron trifluoride etherate, at room temperature, immediately led to aldol 342. After protection of the newly formed secondary alcohol as a benzoate, the diketone was fragmented quantitatively with excess sodium hypochlorite. Cyclization of the generated diacid 343 to the desired dilactone 344 proved very difficult. After a variety of methods failed, the use of lead tetraacetate (203), precedented by work performed within the stmcmre determination of picrotoxinin (1), was spectacularly successful (204). In 99% yield, the simultaneous formation of both lactones was achieved. EIcb reaction with an excess of tertiary amine removed the benzoate of 344 and the double bond formed was epoxidized with peracid affording p-oxirane 104 stereoselectively. Treatment of... 

Phosphonoacetate cycHzation. Intramolecular cyclization of keto phosphonates can be used for construction of macrocyclic a, -unsaturated lactones. Stork s laboratory found that use of lithium isopropoxide or lithium hexamethyidisilazide in THF containing 1% HMPT minimized formation of cyclic dilactones. Use of sodium or potassium counterions was much less satisfactory. An example is shown in equation (I). 

The Diels-Alder adduct (389), on sequential hydrolysis, bromolactonization, and reductive debromination, was converted into the hydroxy-lactone (390), which, on Collins oxidation to (391) and Baeyer-Villiger ring-expansion, afforded the novel dilactone (392). Free-radical cyclization of the bromo-ketone (393), initiated by tri-n-butyltin hydride, gave a 3 2 mixture of the endo- and exo-derivatives (394), which, on separation and homologation, were transformed into the tricyclic sesquiterpenes sativene, endo-(395), and copacamphene, exo-(395). The use of bicyclo-... 

Oxidation of aldoses yields aldonic acids (onic acids), uronic acids, and glycaric acids (sugar dicarboxylic acids, aldaric acids) (Fig. 36). Aldonic acids easily cyclize to the corresponding y-lactones. Glycaric acids may form dilactones. 

The use of iodolactonization in the synthesis of 5-lactones is demonstrated in routes to a prostaglandin endoperoxide analogue, and to the antibiotic malyngolide. The latter compound (164) has also been prepared as a mixture of C-2 epimers by lactonization of the epoxide (163). Stereoselective sul-phenyl-lactonization plays an important role in a synthesis of octahy-droleukotrienes, and cyclization of the cyclopropyl acid (165) leads to the lactone (166). A spirocyclic dilactone has been prepared and undergoes... 

Membered pyrrolizidine dilactones have been synthesized by treating a trimethylsilylethyl ester with TBAF in MeCN to form an anion, which then undergoes cyclization by displacement of the mesylate. 

Corey reported a highly efficient cyclization of unsaturated diacid 239 in the presence of Pb(OAc)4 (Scheme 9.33) [173, 174). The resulting dilactone 240 (99 % yield) was subsequently recruited in the total synthesis of picrotox-inin (241), an antagonist of GABA inhibition at synapses [173]. 

---