Macrocyclic lactones, formation

For an example of use in macrocyclic lactone formation see B. Seuring and D. Seebach, Justus Liebigs Ann. Chem., 2044 (1978), and references therein. 

Scheme IX/6. Macrocyclic lactone formation through sulfide contraction [15]. a) R 3P b) H30+.

Newkome and co-workers have demonstrated the operation of a template effect in the formation of a pyrido-ester-crown. In the reaction shown in Eq. (2.8), they treated 2-clTloronicotinoyl cliloride with either the disodium or dipotassium salt of pentaethylene glycol. TJie two reactions were conducted under identical conditions except for the presence of sodium vs. potassium cations. Since the product is a six-oxygen macrocycle, its formation would be expected to be favored by K" rather than Na" counter ions for the glycolate. In fact, the yields of crown-lactone were 30% and 48% respectively when Na" and K" were the templating cations. 

There is probably no better evidence for a template effect than its application directly in the solution of a synthetic problem. Rastetter and PhiUion have utilized a substituted 19-crown-6 compound (shown below in Eq. 2.9) in the formation of macrocyclic lactones. Although there were certain experimental variations and the the possibility of intermolecular potassium ion complexation, the overall formation of lactone was favorable. 

When 2-chloronicotinoyl chloride is allowed to react with pentaethylene glycol and sodium hydride in benzene solution, acylation followed by nucleophilic aromatic substitution occurs resulting in the formation of a macrocyclic lactone (48% yield) as shown in Eq. (2.8), in Chap. 2. 

From their structures, it appears that the hydrolytic stability of macrocyclic lactones must necessarily be inferior to macrocyclic polyethers. Ease of synthesis of the cyclic esters is therefore one of the aspects which commend them to interest. It is probably for this reason that such lactones have not been made more often by the interesting approach of Kdgel and Schroder . These workers report the ozonolysis of dibenzo-18-crown-6 in a mixture of methanol and dichloromethane at —20°. Reduction of the ozon-ide at —75° using dimethylsulfide followed by warming and addition of acetone led to formation of 6 in 14% yield. The bis-oxalate had mp 164—165° from acetone, very similar to that of the starting crown. The transformation is illustrated below in Eq. (5.9). 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C a-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

In rare cases, lactone formation can also be achieved by nucleophilic displacement with a cesium carboxylate onto an activated leaving group, thus circumventing the polyol-problem [30]. An alternative to the macrocyclic... 

Naturally occurring organoleptically important lactones are mainly saturated and unsaturated 7- and -lactones, and to a lesser extent macrocyclic lactones. The occurrence of these types of lactones reflects their ready formation from natural acyclic precursors. 

Recently, it has been shown that acyl chlorides may be prepared from cyanuric chloride and carboxylic acids (79TL3037). Cyanuric chloride is also valuable for effecting the formation of macrocyclic lactones (Scheme 44) (80TL1893). Similarly, aryl oximes may be converted to... 

The palladium-catalyzed coupling of aryl iodides with vinylstannanes (Stille coupling) leads to the formation of styrenes. With resin-bound vinylstannanes, this reaction can be conducted in such a way that simultaneous detachment from the support of the newly formed styrenes occurs. This has been realized intramolecularly in the preparation of macrocyclic lactones (Entry 4, Table 3.43). The required resin-bound vinylstannanes were prepared either by hydrostannylation of alkynes with a resin-... 

Lipase-catalyzed intermolecular condensation of diacids with diols results in a mixture of macrocyclic lactones and linear oligomers. Interestingly, the reaction temperature has a strong effect on the product distribution. The condensation of a,CO-diacids with a,(0-dialcohols catalyzed by Candida cyiindracea or Pseudomonas sp. lipases leads to macrocyclic lactones at temperatures between 55 and 75°C (91), but at lower temperatures (<45°C) the formation of oligomeric esters predominates. Optically active trimers and pentamers can be produced at room temperature by PPL or Chromobacterium viscosum lipase-catalyzed condensation of bis (2,2,2-trichloroethyl) (+)-3-methyladipate and 1,6-hexanediol (92). 

An effective new method for the synthesis of macrocyclic lactones has been developed by Corey and Nicolau (75). In this method both the hydroxyl and the carboxyl groups have been activated by formation of a 2-pyridin-ethiol ester. Vertaline was obtained in 67% yield when this procedure was applied to the corresponding hydroxyacid (76). 

Scheme VIII/33. Formation of aromatic macrocyclic lactones and the proposed mechanism for the formation of a side product [103].

The efficiency of detergentless microemulsions in promoting the formation of macrocyllc lactones has been studied in our laboratoriesThe two most direct routes to the formation of large macrocyclic lactones are the acid "catalyzed esterification of ii)-hydroxyalkanoic acids and the cyclization of potassium salts of lo-bromoalkanoic acids. In both reactions a competitive pathway yields polymeric material and as a consequence high dilutions are employed with the attendant extended reaction times. 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

Monomer 33 was made to undergo transesterification polymerization using Ti(OC4H9)4, while monomer 34 was appropriate for a Knoevenagel polycondensation. The transesterification polymerization resulted in the formation of an intractable material of unknown structure. Homopolymerization of 34 by the Knoevenagel technique afforded polymer 35 with a low molecular weight (M 6800). A major byproduct in this polymerization was a macrocyclic lactone, formed via an intramolecular Knoevenagel condensation (Scheme 10-14). 

Sirolimus is a macrocyclic lactone produced by the bacteria Streptomyces hygroscopicus. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechaitism of action involves formation of a complex with an immunophilin, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirolimus does not affect calcineurin activity but binds to and inhibits the mammahan kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

Ether linkages in open-chain bolaamphiphiles were obtained in a 20% isolated yield from a,o)-dibromoeicosane with an alcohol in THF containing sodium hydride (Scheme 2.8). The synthesis of macrocyclic tetraethers was unsuccessful. Attempts to reduce macrocyclic lactones with four ester groups via a variety of methods failed. The production of macrocyclic thioacetals from benzaldehyde derivatives and a,to-dithiols was unproblematic and produced quantitative yields (Scheme 2.8). The cyclization of 2,2-thiodiethanol with a,(o-diols in the melt and in the presence of /7-toluenesulfonic acid is an intermediate case. Apolar macrocycles were obtained in 50% yield. 5-(2-hydroxyethyl)thiiranium ions are presumably formed as reactive intermediates during the ether formation steps. The sulphur atom was oxidized to the... 

An exceptional case is the formation of the macrocyclic lactone shown below however, the choice of the catalyst is crucial for the regioselectivity of this cyclopropanation. ... 

The studies of Ban and Wakamatsu culminated in the preparation of three natural compounds from a single synthetic route (Scheme 1.15). The enediol bis silyl ether 63 was converted to the dianion and immediately alkylated with l-iodo-3-butanol to give glycol 64 as a mixture of diastereomers in 87% yield. Diol fragmentation with lead tetraacetate afforded keto lactone 65 in quantitative yield. Formation of the dithioketal and subsequent Raney nickel desulfurization then gave 66 (81%). Macrocyclic lactone 66 is the simple natural product... 

Formation of macrocyclic lactones and oxalactones by metal carbene transformations 01SL1364. 

Oligomycin [63] (Fig. 13) is a 26-membered macrocyclic lactone produced by avermectin-producing Streptomyces avermitilis. The formation of oligomycin backbone requires 16 cycles of condensations. A region encoding polyketide synthase of oligomycin biosynthesis was cloned by transposon-induced mutagenesis. 

With the aid of this reagent, a method has been developed for the synthesis of peptides [76]. It proceeds under mild conditions and largely without racemization. The combination of reagents provides a method for the synthesis of macrolides (macrocyclic lactones) from long-chain co-hydroxycarboxylic acids, as demonstrated by the formation of pentadecanolide from 15-hydroxypentadecanoic acid [77]. 

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