High-dilution macrocyclization

A series of benzomolybdacrowns, prepared by the high-dilution macrocyclization of 1,2-,... 

Various 14-member P2X2ring systems were prepared from 1,2-bis(phen-ylphosphino)benzene. A high-dilution macrocyclization technique gave these species as colorless crystal materials in yields ranging from 18 to 45% [47, 86]. 

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

Macrocyclic peptides and depsipeptides ( macrocyciic peptides with amide and ester linkages) are important natural compounds. They have been synthesized in low yield from open-chain precursors by DCC treatment at high dilution (E. SchrSder, 1963 M.M. Shemyakin,... 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

I E G L E R Macrocyclic synthesis Synthesis ol macrocyclic ketones from dinitnles using high dilution... 

In the course of experiments directed at the synthesis of open-chained equivalents of macrocyclic polyethers (see Chap. 7), Rasshofer and Vogtle found that 9 or its derivatives were formed rather than the desired compounds . Although the yields obtained by this method are modest, the facts that the reaction is conducted without the use of high dilution and in one-pot recommend it. 

At about the same time Pedersen s work was underway, Bradshaw and his coworkers had undertaken the systematic preparation of numerous mono- and polysulfur macrocycles The syntheses were carried out in a fashion similar to that shown in Eq. (6.3). The two principal sources of sulfur in the first paper from this groupwere sodium sulfide and 1,2-ethanedithiol. The latter was utilized in the presence of sodium hydroxide base. Ethanol was generally used as solvent and the reactions were conducted at high dilution. Products were purified either by vacuum distillation or recrystallization as appropriate. The yields were generally in the 5—30% range. 

Although the first all-sulfur macrocycles were prepared many years ago " the first systematic study of such compounds was initiated by Busch and his coworkers , who were interested in the cation binding properties of such ligands. A sequential synthesis was utilized to produce 1,4,8,11-tetrathiacyclotetradecane [tetrathia-14-crown-4 (70)] . In the first step, 1,3-propanedithiol is metallated using sodium and alkylated with 2-chloroethanol. The diol was then treated with thiourea to form the dimercapto-dithioether compound 9. The latter was once again metallated with sodium and allowed to react with 1,3-dibromopropane. The yield of 70 in the ring closure step, conducted at high dilution in absolute ethanol, was 7.5% after recrystallization. The entire sequence is illustrated in Eq. (6.8) . ... 

Kyba and eoworkers prepared the similar, but not identical compound, 26, using quite a different approach. In this synthesis, pentaphenylcyclopentaphosphine (22) is converted into benzotriphosphole (23) by reduction with potassium metal in THF, followed by treatment with o "t/20-dichlorobenzene. Lithium aluminum hydride reduction of 23 affords l,2-i>/s(phenylphosphino)benzene, 24. The secondary phosphine may be deprotonated with n-butyllithium and alkylated with 3-chlorobromopropane. The twoarmed bis-phosphine (25) which results may be treated with the dianion of 24 at high dilution to yield macrocycle 26. The overall yield of 26 is about 4%. The synthetic approach is illustrated in Eq. (6.16), below. 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

Rossa, L., Vogtle, F. Synthesis of Medio- and Macrocyclic Compounds by High Dilution Principle Techniques, 113, 1-86 (1983). 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Trost and coworkers137 have reported the polymer-supported palladium catalyzed cyclization of 1, l-bis(phenylsulfonyl)epoxyalkene 235 which gives cycloalkanes 236 and 237 in a 2 1 ratio (equation 143). This method has proven useful for the synthesis of macrocyclic compounds under neutral conditions without using high dilution technique. Temperature and concentrations are critical. The best results are achieved if a reaction mixture of 0.1-0.5 m is added to a preheated (at 65 °C) suspension of the catalyst. 

Diene 265, substituted by a bulky silyl ether to prevent cycloaddition before the metathesis process, produced in the presence of catalyst C the undesired furanophane 266 with a (Z) double bond as the sole reaction product in high yield. The same compound was obtained with Schrock s molybdenum catalyst B, while first-generation catalyst A led even under very high dilution only to an isomeric mixture of dimerized products. The (Z)-configured furanophane 266 after desilylation did not, in accordance with earlier observations, produce any TADA product. On the other hand, dienone 267 furnished the desired macrocycle (E)-268, though as minor component in a 2 1 isomeric mixture with (Z)-268. Alcohol 269 derived from E-268 then underwent the projected TADA reaction selectively to produce cycloadduct 270 (70% conversion) in a reversible process after 3 days. The final Lewis acid-mediated conversion to 272 however did not occur, delivering anhydrochatancin 271 instead. 

When disodium (Z)-l,2-dicyanoethene-l,2-dithiolate and 1,3-dibromopropane are cyclized under high dilution conditions, the desired 14-membered macrocyclic tetrathioether was isolated <96LA1005>. 

Condensation of dicesium 2-thioxo-l,3-dithiole-4,5-diselenolate with fo/s-alkylating polythioethers under high dilution conditions afforded the TTF-containing macrocycles possessing soft donor sites and 12-, 15-, and 18-membered rings <%JCS(P1)1995>. 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

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