Macrocyclic 1,4-diketone

Macrocyclic 1,4-diketones (71), generated by hydrolysis of the furan ring in (27) (77H(7)8l), have been transformed into mixed heterophanes (72) by treatment with an amine (73TL4017, 74CC119). 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

Application of this ring enlargement and oxidation procedure to 2-alkoxy-l-siloxycyclopropanes incorporated in a large ring provides macrocyclic diketones which act as potent chelating agents for metal cations [50]. 

Macrocyclic diketones can undergo transannular aldol cyclization reactions, giving bicyclic aldols. A representative example is seen in the cyclization of 1,6-cyclodecanedione to the corresponding hy-droazulenone (equation 142). Aldolization of the related cyclodecadienedione (120) has also been examined under mildly basic conditions aldols (121) and (122) are the main products, being formed in a ratio of 1 4 (equation 143). Control experiments with the pure aldols showed that this is the thermodynamic ratio of isomers. 

Seven-membered and larger rings can be prepared by this method and the yields can often be satisfactory. Carefully controlled nonequilibrium conditions and high dilution techniques are often required. Medium rings (9-12) are either not formed, or formed in low yield, a combination of a Claisen condensation followed by a Dieckmann reaction giving macrocyclic diketones. The conformational energies of the linear precursor influences ring closure. Examples are illustrated in Scheme 19. 

This reaction was first reported by Blomquist in 1947. It is the reaction to form intermediate to macrocyclic ketones via the process of intramolecular condensation of aliphatic diketenes at diluted concentration followed by hydrolysis and decarboxylation of cyclic ketene derivatives. The intermolecular condensation of diketenes will form even larger macrocyclic diketones, which can be converted into simple macrocyclic diketones." The ketene can be easily obtained by the treatment of acyl chloride of dicarboxylic acid with tertiary amines, of which triethylamine gives the best result. Although some polyketene products also form in this process, they can be easily removed. Other methods for preparing macrocyclic ketones include the Ziegler, Hunsdiecker, Ruzicka, and Glinski reactions. 

Knopff O, Kuhne J, Fehr C. Enantioselective intramolecular aldol addition/dehydration reaction of a macrocyclic diketone synthesis of the musk odorants (/f)-muscone and (R,Z)-5-muscone. Augew. Chem. Int. Ed. 2007 46 1307-1310. 

Ibers used the Paal-Knorr furan synthesis to prepare a key intermediate for the synthesis of novel porphyrin-like aromatic macrocycles. Bis yrolyljfuran 27 was available in good yield via the acid catalyzed condensation of diketone 26. ... 

A number of oxepin derivatives with alkano bridges across the 3- and 6-positions and across the central C-C double bond have been oxidized with ruthenium(VIII) oxide. Usually, all of the double bonds of the heterocycle are cleaved and a macrocycle 5 is formed that contains two 1,2-diketone functions.142,199... 

The present procedure for ring expansion has also been applied to l,2-bis(trimethylsilyloxy)bicyclo[n.l.0]alkanes, which are prepared by cyclopropanation of l,2-bis(silyloxy)cycloalkenes. The latter are readily available from acyloin condensations in the presence of chlorotrimethylsilane. " This reaction provides a new route to cyclic 1,3-diketones and macrocyclic compounds containing two 1,3-diketone units in the ring. 

Macrocycle Synthesis Cyfclic Ketones, Ketoalkenes, Diketones and Dienes of Ring Size C21 to C26, Forbes. M.D.E. Dang, Y. Org. Prep, Proceed, Int, 1993, 25, 309... 

Macrocycles containing intra-annular carboxylic acids Macrocycles containing intra-annular sulfinic or sulfonic acids Intra-annular phenols 1,3-Diketones... 

Dicarbonyl functions have been built into macrocyclic structures, and pKa values for the resulting macrocycles [60] have been determined (Alberts and Cram, 1979). When the open-chain model [62] is compared with the macrocycles [60], identical first pK values were found (pKa = 8.6). Thus for the diketones [60], no macrocyclic effect is noticeable. But for the dissociation of a second proton from the mono-aniorts of [60] much higher pKa values are found. To a certain extent. Coulomb repulsions (see Section 2) are probably the reason for this behaviour, but the large difference in the pKa values (ApKa = 2.9, see Table 26) argues for a special stabilization of the mono-anion. Again hydrogen bonds are not unreasonable. 

Bis(ethylenediamine)gold(III) chloride reacts with a variety of -diketonates in aqueous base, via Schiff base condensation, to form 14-membered tetraaza 12jt macrocyclic species [78[. The parent member of the series [AuL ]" being 22 (where H2L = 5,7,12,14-tetramethy]-l,4,8,ll-tetraazacydotetradeca-4,6,ll,13-tetra-ene) (Figure 2.15). The X-ray structure shows the cation to be nearly planar. 

Bis(ethylenediamine)gold(III) chloride reacts with /3-diketonates in aqueous base via Schiff base condensation to form complexes of gold(III) with a 14-membered macrocyclic tetraaza ligand such as (292).1711-1713 The X-ray structure showed the cation to be nearly planar. Delocalization of -electrons within the six-membered /3-diketonate rings was indicated by the observed pattern of C—C and C—N distances. Open-chain tetraaza ligand complexes in which condensation of only one /3-diketonate has occurred, can be isolated as intermediates in this reaction. They may be used for further condensation with a different /3-diketonate. Oxidation of this complex with trityl tetrafluoroborate introduces a double bond in position C2C3.1712,1714... 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

With the bulky metallo-organic Pd(II) catalyst 98, on the other hand, selective formation of 99 was possible here functional groups are tolerated that would react with an Ag(I) catalyst (for example, terminal alkynes, alkyl chlorides, alkyl bromides and alkyl iodides) [59]. With l,n-diallenyl diketones (100), easily accessible by a bidirectional synthesis, up to 52-membered macrocycles (101) could be prepared in an end-group differentiating intramolecular reaction (Scheme 15.26) [60], For ring sizes lager than 12 only the E-diastereomer is formed overall yields of the macrocydes varied between 17 and 38%. Only with tethers shorter than 11 carbon atoms could the Z-diastereomer of the products be observed, a stereoisomer unknown from the intermolecular dimerization reactions of 96. 

Anionic units have not only been attached to macrocyclic polyethers via flexible arms but have also been incorporated into the cycle itself. Alberts and Cram (1976, 1977) have studied the ion-binding properties of crown ethers containing / -diketone units, such as [72] and [73]. 

Substitution of the terminal amine with ligating groups, such as catecholate, hydrox-amate or diketonate, lead to the formation of A-cis chiral complexes. In these structures the chiral information content is located in the amino acid bridges, instead of the macrocyclic peptide ring structure used in ferrichrome. It should be emphasized... 

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