Formation of Macrocycles

Large rings are often encountered in natural product synthesis and there are, to date, relatively few methods to prepare them in adequate yields. One tool regularly employed is the 

This example of a macrocyclization proves once again the high flexibility and tolerance towards a wide range of functional groups of the Mizoroki-Heck reaction. 

The synthesis of heterocycles via intramolecular Mizoroki-Heck reaction is still an expanding field of current research due to the signiflcant importance of heterocycles, thereby engendering the need for reliable, specific and high-yielding preparation methods. The Mizoroki-Heck reaction is one of the chemist s synthetic tools matching best these criteria and has only begun to reveal its full synthetic potential in this specific domain. 

and de Meijere, A. (2004) Cross coupling of organic hahdes with alkenes the Heck reaction, in Metal-Catalyzed Cross-Coupling Reactions, Vol. 1 (eds A. de Meijere and F. Diederich), Wiley-VCH Verlag GmbH, Weinheim, pp. 217-315. 

and de Meijere, A. (2002) Background, mHandbookofOrgano-Palladium Chemistry (ed. E.-i. Negishi), John WUey Sons Inc., New York, pp. 1123-32. 

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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). 

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. 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

The first reaction is the initiation step and the other two form the propagation sequence. This sequence leads to the formation of macrocyclic compounds, which can be decomplexed by an exchange reaction of the following type ... 

The results obtained with the various metathesis substrates depicted in Scheme 44 demonstrate the lack of a stereopredictive model for the RCM-based formation of macrocycles, not only by the strong influence that may be exhibited by remote substituents, but also by the fact that the use of more reactive second-generation catalysts may be unfavorable for the stereochemical outcome of the reaction. Dienes 212a-f illustrate the influence of the substitution pattern. All reactions were performed with Grubbs first-generation catalyst A... 

A. Miyake, H. Kondo, M. Nishino, and S. Tokizane Catalytic formation of macrocyclic polyenes from butadiene, pp. 201-211 (13). 

Wasserman, H. H. (1987). New methods in the formation of macrocyclic lactams and lactones of biological interest. Aldrichimica Acta 20, 63—74. 

Chelate ring formation may be rate-limiting for polydentate (and especially macrocyclic) ligand complexes. Further, the rates of formation of macrocyclic complexes are sometimes somewhat slower than occur for related open-chain polydentate ligand systems. The additional steric constraints in the cyclic ligand case may restrict the mechanistic pathways available relative to the open-chain case and may even alter the location of the rate-determining step. Indeed, the rate-determining step is not necessarily restricted to the formation of the first or second metal-macrocycle bond but may occur later in the coordination sequence. 

As will be discussed later, ammonium salts have also been used as hydrogen bond-donor templates to favour the formation of macrocycles (yielding pseu-dorotaxanes and rotaxanes). 

Brunelle, D. J., Boden, E. P. and Shannon, T. G., Remarkably selective formation of macrocyclic aromatic carbonates versatile new intermediates for the synthesis of aromatic polycarbonates, J. Am. Chem. Soc., 112,569 (1990). 

The intervention of a metal ion in the stoichiometry of a reaction has been illustrated several times previously. Reaction is forced to completion in ester hydrolysis since the carboxylate grouping forms a more stable complex than the ester moiety does. A similar driving force underlies the formation of macrocycles and the completion of transamination by formation of the metal-Schiff base complex. The latter is particularly relevant in dilute solution and at low pH. For example, the extent of aldimine formation between pyridoxal and alanine is undetectable at the physiological pH but occurs to the extent of = 10% in the presence of zinc... 

The formation of macrocycles through ring-enlargement reactions via bicyclic tetrahedral intermediates—i.e., the cyclols of general type 89 or 92 (the ionized forms are shown), which are mostly unstable and can be... 

Scheme 4 Formation of macrocyclic biaryl bond through oxidation of arylcopper intermediate...

The first successful attempt involved diisonitrile 110. Ugi reaction of 110 with succinic acid, isopropylamine, and isobutyraldehyde led to the formation of macrocycle 111 (Scheme 19) and its head-to-head coupled isomer 112 (not shown). All of the obtained disteroid macrocycles were mixtures of... 

ROMP is generally an irreversible process, and relief of ring strain is the driving force for the forward reaction. Reversibility (with the formation of macrocyclic oligomers) is possible for less strained cycloalkenes like cyclooctene when the lifetimes for propagating chains are high. 

Finally, it has to be considered that also the formation of macrocyclic oligomers and polymers cannot be fully neglected. For example, by use of mass spectrometry, the existence of ring-shaped polycondensates is definitely elucidated in all types of polycondensates. 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

Alkyl halides possessing / -hydrogens are usually poor substrates for carbonylative cross-coupling due to competitive / -hydride elimination/ Allyl chlorides can be used in carbonylative cross-coupling with allylstannanes/ phenyl-, 3-furyl, or vinylstannanes " to afford allylketones in modest to good yields. Divinylketones can be accessed through the reaction of vinylstannanes with vinyl iodides or vinyl triflates, with the latter requiring the addition of LiCl. Synthetic potential of this method has been proved in the formation of macrocyclic ketone jatrophone. In the reaction of vinyl triflates with tetramethyltin or aryltrimethylstannanes the additional activation by ZnCle is required. 

The highest flexibility for a variation of the functional group and the chains X and Y (i.e. the size of the rim of the lamp shade) will be realiad when the synthesis of 3 is convergent and modular (Scheme 1). Amide bonds can easily be formed in macrocyclizations [13], therefore macrocyclic diamines 7 and diacyl dichlorides 8 had to be prepared. For the synthesis of macrocyclic diamines 7, also a large number of reactions are known. However, in this case a reduction of a macrocyclic diamide could not be achieved [11]. Therefore, another route was used the formation of macrocyclic diimines 6 (bis-Schiff bases) followed by NaBH4 reduction to the macrocyclic diamines 7. This approach has the advantage that for the construction of macrocyclic diimines 6, the metal ion template effect [14] may be exploited. 

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... 

A logical extension of the condensation reactions which yield multidentate nitrogen donors is the formation of macrocyclic ligands. The preference of palladium for square planar coordination makes it an ideal metal for the formation of complexes of these ligands. Thus palladium porphyrins are very stable and resistant to demetallation.281 Both 14- and 16-atom macrocycles have been used to form complexes. The ligand l,8-dihydro-5,7,12,14-tetramethyl-dibenzo[b,i][l,4,8,ll]tetraaza[14]annulene reacts with [PdCl2(PhCN)2] to yield the complex (46). 

With cyclic olefins as the reactants, disproportionation results in ring enlargement leading to the formation of macrocyclics and, ultimately, polymeric materials, i.e., polyalkenamers (Reaction 3). 

ZIEGLER METHOD. Cydization of dinitriles at high dilution in dialkyl ether in the presence of ether-soluble metal alkylamlide and hydrolysis of the resultant imino-nitril with formation of macrocyclic ketones in good yields. 

Pyridine-2,6-dicarbaldehyde and 2,6-diacetylpyridine have been widely used in the template synthesis of imine chelates ranging in complexity from linear tridentates, such as (17),38 39 to macrocyclic structures with a range of ring sizes, such as (18).40-42 The in situ formation of macrocyclic ligands of this type depends upon the ring size and the strength of complexation of the triamine by the metal ion at the pH of the reaction. Related complexes with an additional donor atom attached to R2 have been synthesized also.43 44... 

In many of the above examples, especially those resulting in the formation of macrocyclic complexes, the metal-free macrocycles can be obtained as hydroperchlorate salts by combination of the amino and carbonyl fragments in the presence of perchloric acid. Such a procedure has resulted in the formation of an even wider range of macrocyclic complexes than is available by metal template methods. The two approaches are complementary, as different geometrical isomers and stereoisomers can be formed by the different methods in some cases. 

The application of ring closing metathesis for the synthesis of Friedinger lactams was studied by Piscopio et al.4S (Fig. 15), as well as other groups,46 while the formation of macrocycles was accomplished by Blechert s group.47... 

Scheme 2.71. Formation of macrocyclic ethers via coupling Ugi-4CR/SNAr.

One of the simplest and widely used methods of forming C-S bonds involves nucleophilic attack of a thiolate on a suitable C-centred electrophile such as an alkyl halide (Fig. 5-74). Co-ordinated thiolate ligands behave as nucleophiles in exactly the same manner, and the method has been extensively used for the preparation of thioethers and their metal complexes. The method has been particularly commonly utilised in the formation of macrocyclic ligands in templated syntheses (see Chapter 6). 

There are also potential disadvantages associated with the use of template methodology for the formation of macrocyclic ligands. Perhaps the most important is the observation that not all metal ions can act as templates for the specific cyclisation reactions of interest. In many cases it may not be trivial to find an appropriate template ion (if indeed... 

The formation of macrocyclic ligands by template reactions frequently involves the reaction of two difunctionalised precursors, and we have tacitly assumed that they react in a 1 1 stoichiometry to form cyclic products, or other stoichiometries to yield polymeric open-chain products. This is certainly the case in the reactions that we have presented in Figs 6-8, 6-9, 6-10, 6-12 and 6-13. However, it is also possible for the difunctionalised species to react in other stoichiometries to yield discrete cyclic products, and it is not necessary to limit the cyclisation to the formal reaction of just one or two components. This is represented schematically in Fig. 6-19 and we have already observed chemical examples in Figs 6-4, 6-11 and 6-18. We have already noted the condensation of two molecules of 1,2-diaminoethane with four molecules of acetone in the presence of nickel(n) to give a tetraaza-macrocycle. Why does this particular combination of reagents work Again, why are cyclic products obtained in relatively good yield from these multi-component reactions, rather than the (perhaps) expected acyclic complexes We will try to answer these questions shortly. 

What should we do to observe a three-dimensional template effect First, we should choose a reaction type that we know to be effective for the formation of macrocyclic ligands and extend the methodology to a kinetically inert cP or d6 metal centre. Let us reconsider the reaction, that we first encountered in Fig. 6-11. In this reaction, a dioximato complex reacted with BF3 to give the nickel(n) complex of a dianionic macrocycle (Fig. 7-1). 

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