Formation reactions Macrocycles

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 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... 

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... 

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. 

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. 

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). 

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... 

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. 

In terms of template reactions, this combination of kinetic and thermodynamic stability usually means that the metal ion remains co-ordinated to the macrocyclic ligand and the isolation of the metal complex of the macrocycle provides strong circumstantial evidence for the existence of a metal-directed process. This is particularly easy to establish if the incorporation of the metal ion into the macrocyclic ligand can be shown to be slower than the metal-directed formation reaction. 

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). 

The iminium salts of 2,3-dihydropyridines are far more stable than the free bases and have been used extensively in the synthesis of alkaloids. N-Benzyl iminium salt 26, formed from the Polonovski-Potier reaction of V-oxide 25, was transformed into enol ether 27, which is a synthon for the unstable AT-benzvl-l, 2-dihvdropyridine 28 (Scheme 5) <2004LOC168>. The same transformation on a similar iminium salt has been used in the formation of macrocyclic marine alkaloids <1995TL2059>. Carbon nucleophiles, such as the silylenol ethers of esters, have been shown to undergo 1,2-addition rather than 1,4-addition to 2,3-dihydropyridinium salts <1999T14995>. 

Free radical reactions have been used in organic synthesis not only for ring expansion, but also for formation of macrocyclic ketones [48] [51]. 

The role of the metal ions in promoting cyclization was not understood until much later when Hurley et al. 74) isolated a series of intermediates in the reaction between 1,3-diiminoisoindoline with nickel chloride. The widespread utilization of metal ions in the synthesis of macrocycles was developed largely through the work of the group led by Busch. The formation of macrocycles using Ni(II) ions (136) and complexes (138), e.g.,... 

To confirm the possible formation of macrocycles, otherwise saying the absence of chain-ends, - Si NMR was carried after the end of reaction. The spectrum (Fig. 11) shows signals for D and M (hybrid segment) units and arising from L H self-condensation. Neither methoxy nor silanol end-groups could be traced on this spectrum, nor remaining L H at -5.2 ppm or precursor M, around 15 ppm (see for instance [20]). The residual peak at 4-2.5 ppm could not be ascribed. 

Besides, the hybrid silicones synthesized nsing the method in Scheme 3 produced scattered linear lines, whereas those obtained from precursor M mostly overlap on a single line, with a y intercept lower than 0.2 units compared to the PDMS one. This difference is typical of the theoretical lower hydrodynamic volumes for cyclic structures, compared to linear ones [21, 22]. From this analysis, it is reasonable to conclude that the formation of macrocycles prevents high molar masses to be reached, since the hybrid silicones are not capable of ring scission through redistribution reactions within the macromolecular chains, unless PDMS chains. 

Reaction b is a chain transfer to polymer it may involve heteroatom of the foreign or its own macromolecule. In the later case it leads to formation of macrocycle ... 

Condensation reactions between carbonyl compounds and primary amines have played a central role in the synthesis of new macrocyclic ligands [28-34]. Usually, though not in all cases, such reactions are conducted in the presence of metal ions which can serve to direct the condensation preferentially to cyclic rather than oligomeric/polymeric products and to stabilize the macrocycle once formed. The relative atomic radius of the templating ion has a considerable effect on the size of the macrocycle formed. For instance, in what is now classic work, cations such as Mg(Il) (r = 0.72 A) were found to stabilize the formation of macrocycles such as 60 from 1 1 condensations [35], while larger cations such as Sr(II)... 

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. 

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