Lactone macro

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

Prior to the synthesis of the epothilones, the use of RCM for the preparation of macrolactones had received little attention [5]. In part, this could be attributed to the generally held assumption that only conformational biased precursors would undergo cyclization. Although several examples of macro-RCM had been reported, notably by Pandit [9],Hoveyda [10] andFurstner [11], preparation of the densely functionalized 16-membered lactone core of the epothilones was not a trivial undertaking. Preliminary studies focused on the preparation and cyclization of model substrates in order to assess the viability of the RCM approach and to provide precedent for subsequent, more ambitious, synthetic endeavors. 

Condensation of the two fragments A and B via aldol reaction, followed by macro-lactonization, completes the synthesis as shown in Scheme 7-9. 

The major components are series of homologous trimers, tetramers, and pentamers of the three acids 44-46, along with smaller quantities of dimers, hexamers, and heptamers. Furthermore, the secretion contains several isomers of each oligomer, furnishing a combinatorial library of several hundred macro-cyclic polyamines [51, 52]. Using repeated preparative HPLC fractionation, the most abundant trimeric, tetrameric and pentameric earliest-eluting compounds were isolated. One and two-dimensional H NMR spectroscopic analyses showed that these molecules were the symmetric macrocyclic lactones 48, 49, and 50 (m, n, o, p, q=7) derived from three, four or five units, respectively, of acid 46. Moreover, using preparative HPLC and NMR methods, various amide isomers, such as 53,54, and 55 (Fig. 9) were also isolated and characterized [51,52]. 

Oxygen- and sulfur-assisted methods have been described to synthesize strained macrolactams by ring contraction through attack of the amine on the intermediate macro(thio)lactone [37]. 

RCHiCOOH - RCH=C—0.i Mukaiyama s reagent has been used for macro-lactonization of -hydroxy carboxylic acids (14,117-118). However, reaction of the substrate 2 with 1 and N(C2H5)3 in refluxing CH3CN does not lead to the expected... 

Giraldes JW, Akey DL, Kittendorf JD, Sherman DH, Smith JL, Fe-cik RA. Stmcrnral and mechanistic insights into polyketide macro-lactonization from polyketide-based affinity labels. Nat. Chem. Biol. 2006 2 531-536. 

Bryostatins are naturally occurring antineoplastic macro-cyclic lactones derived from the marine invertebrate Bugula neritina, different varieties being isolated from different populations of the same species. More than 13 structurally related compounds have been isolated (1,2), and there is a variety of synthetic analogues (3). The bryostatins modulate the activity of protein kinase C. 

The 14-membered macrocyclic ring of (-)-galbonolide B was formed utilizing a novel macro-Dieckmann cyclization which was developed in the laboratory of B. Tse. In order to bring about the desired macrolactonization, the secondary acetate was treated with LiHMDS in refluxing THF under high-dilution conditions to afford the desired lactone in 75% yield. It is important to note, however, that the analogous secondary propionate failed to cyclize under identical conditions. 

Macro, K., Baltas, M., Zedde, C, Gorrichon, L., Jaud, J. Lactonization and lactone ether formation of nerol geraniol compounds. Use of C... 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

In their synthetic studies towards lophotoxin and pukalide, Paterson and coworkers explored both intermolecular and intramolecular Stille coupling reactions [108]. The intermolecular approach between vinyl iodide 107 and furylstannane 108 is more successful, giving adduct 109 in 67% yield. The intramolecular version provides the macro-cyclized 14-membered lactone in only 15% yield. Pattenden reported a related investigation towards the synthesis of lophotoxin and observed comparable inter- and intramolecular reactivity in similar Stille reactions [109]. 

It has also been established that consecutive esterification and cross-coupling affords the same macrolide segment (Scheme 12.111) [213]. This tandem cross-coupling procedure is an efficient means of assembly of a C2-C5 diene in (-[-macro-lactone A (Scheme 12.112) [214]. In this reaction a bromoethyne was used as the starting component otherwise a mixture of regioisomers (7 3 P/a) was obtained on hydrostannation. 

Their structures were mainly determined by spectral studies using EI-MS, IR, H-NMR, NOE, and CD spectra (75). They consist of a main spiroether moiety, corresponding to 1-oxaspiro[5. 5]undec-4-ene-8-one ring system, (including seven asymmetric centers and possessing a (Z)-olefin, a mefa-substituted phenol, and a P-ketocarboxylic acid functions) and a P-hydroxy-y-lactone moiety. Oscillatoxin Ds are present as esters of both moieties. On the other hand, aplysiatoxins are present as macro bis-lactones including a spiroacetal. We are interested in the relationship between oscillatoxins and aplysiatoxins from a biosynthetic point of view. 

Gill, M., and Gimenez, A. (1990). Pigments of fungi. 18. The dermocanarins, unique macro-cyclic lactones from the fungus Dermocybe canaria. Tetrahedron Lett. 31, 3505-3508. 

The total synthesis of avermectin B,a (3b) by White et al. was accomplished via Julia coupling of the C9-C28 northern and C1-C8 southern segments, macro-lactonization, deconjugation of the C2-C3 double bond to the C3-C4 position, and glycosidation via the pyridylthio glycoside (Fig. 7). 

Danishefsky s total synthesis of avermectin (3a) was accomplished via an aldol reaction to join the northern and southern segments, intramolecular Nozaki aldol cyclization [138] to construct the southern ring system, Mukaiyama macro-lactonization, deconjugation to the C3-C4 double bond, and NIS-mediated gly-cosidation (Fig. 7). 

The results described herein demonstrate that the )9-fragmentation reaction of alkoxyl radicals generated under oxidative or reductive conditions is well suited for the synthesis of medium-sized and macro ketones and lactones. The system hyper-... 

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