Macrocycle formation

The polymerization of ethyleneimine (16,354—357) is started by a catalyticaHy active reagent (H or a Lewis acid), which converts the ethyleneimine into a highly electrophilic initiator molecule. The initiator then reacts with nitrogen nucleophiles, such as the ethyleneimine monomer and the subsequendy formed oligomers, to produce a branched polymer, which contains primary, secondary, and tertiary nitrogen atoms in random ratios. Termination takes place by intramolecular macrocycle formation. 

Thomas E. J. Cytochalasan Synthesis Macrocycle Formation Via Intramolecular Diels-Alder Reactions Acc. Chem. Res. 1991 24 229 235... 

Fig. 22 Macrocyclisation equilibrium constants for macrocyclic formats [30] in CH2C12 in the presence of Et2OBF3 as a catalyst (V) m = 1 (O) m = 2 (A) m= 3 (U)m = 4. (Reproduced with permission from Yamashita et al., 1980)...

Initial efforts in the ring-dosing metathesis approach were attempted with substrates 34 and 35. However, after employing a variety of catalysts and experimental conditions, no cydized systems (36 or 37) were obtained. Other substrates were prepared to further probe this unexpected failure however, no observable reaction was realized. Model systems later suggested that die dense functionality between C3 and C8 was the culprit for lack of macrocycle formation. Eventually a second generation Cl2-03 RCM (not shown here) approach was developed [26] which yielded mixtures of C12-C13 Z/E isomers that were used in early SAR studies. [26b] However, since the separation of products was so difficult, we did not seriously pursue this route for total synthesis. 

The choice of starter sequences for a nucleation-elongation polymerization is very important. Starter sequences that can combine to form stable macrocycles (64 and 65) will result primarily in macrocycle formation (55), creating... 

Although the metal ions promoted macrocycle formation, in some cases the free macrocycles could be synthesized in non-template conditions of high dilution. The free macrocycles have sometimes been prepared by means of template reactions involving zinc(II) acetate. The dialdehydes (68) were prepared by a sequence of reactions involving a poor initial alkylation step, but a superior approach has been developed (Scheme 26).156-158 Alkylation of isatin compounds can be carried out in high yield and substituted isatins are readily available. 

The construction of suitable dialdehydes for macrocycle formation by metal template methods has more recently been extended to include a range of oxamides. In the first case, the simple 2,2 -(oxalyldiimino)bisbenzaldehyde underwent rather sluggish template reactions but yielded extremely stable macrocyclic complexes (Scheme 31).167 168 These products could be sulfonated in oleum, without destruction of the macrocyclic structure. This general synthetic route has been extended to include reactions of diketones and the formation of complexes of macrocyclic ligands such as (70) and (71). Attempts to incorporate a malonamide fragment in place of the oxamide... 

One of the first examples of metal ions facilitating macrocycle formation was the synthesis of metal phthalocyanines (95) from 1,2-dicyanobenzene or 2-cyanobenzamide (Scheme 53).229-231 This example of macrocycle synthesis has been applied to a very wide range of metal salts of various valencies, and is of great commercial interest. As this area of chemistry has been reviewed frequently and is dealt with in Chapter 21.1, only a brief consideration of the most important template reactions will be presented here. 

ROP of lactones and lactides using lanthanide alkoxide-based initiators is a relatively recent discovery. The first example of lactone polymerization by lanthanide alkoxide complexes was reported in a DuPont patent written by McLain and Drysdale in 1991 [89]. In general, the activity of these catalysts is much higher than that determined for aluminum alkoxides, especially in lactide polymerization [90-92]. Polymers of relatively high molecular weight and narrow MWD are formed. The negative side-reactions such as macrocycle formation, transesterification, and racemization are absent. 

Lanthanide-based initiator systems offer a fourth possibility, permitting the block copolymerization of lactones with compounds such as ethylene,tetrahy-drofuran, l-LA, trimethylene carbonate, and methyl methacrylate. Detrimental side reactions such as macrocyclic formation, transesterification, and racemiza-tion are absent and the reactions are extremely fast. 

The macrocycle formation proceeds via the intermediate compound A that can undergo two different reactions either intramolecular cyclization towards the desired macrocycle M or intermolecular reaction with additional A to produce the... 

Figure 6.1 Schematic description of synthetic strategies for macrocycle formation.

At this juncture, we felt confident that the chemistry was robust enough to explore a series of double cyclizations in this way access to polyvalent structures would be possible. The application of our methodology to the synthesis of P-C-trisaccharides (25) was therefore considered (Scheme 18). In order to attempt the double cyclizations, it became clear that an efficient synthesis of the required diacid was required and that the possibility of macrocycle formation and other competing side reactions had to be considered. 

Fig. 33. Electrospray ionization mass spectrum of a Starburst PAMAM (generation = 4). Note the last significant peak M = 10632 daltons (degree of polymerization = 93), corresponding to the magic number for ideal structure. The remaining labeled species correspond to M — x(l 14) (defects due to missing monomer units) and the unlabeled species which correspond to M — x(60) (defects due to macrocycle formation)...

Re/ro-Michael reactions produce mutant species at [5154 — n (114)] (e.g., 5040, 4925 and 4812 daltons), whereas macrocycle formation gives mutant products at [5154 — n (60)] (e.g., 5094, 4980 and 4865 daltons). Note the perfect structure at 5154 daltons is the predicted magic number for generation = 3. In some cases a mutant defect (i.e., a retro-Michael reaction site) may be repaired in subsequent iteration sequence to give a regressed branch cell. Many of these errors (mutations) are found to be generation dependent. In any case, these errors may be routinely appraised as a function of generation by mass spectroscopy, electrophoresis and... 

When A7-(2-aminoacetyl)-2-pi peri done 49 was dissolved in aprotic or protic solvents, a fast equilibrium, ca. 1 1, between the cyclol form (tetrahedral intermediate) 50 and the bislactam 51 is established (Scheme 1). Dynamic ll NMR has been used to evaluate the exchange between the two forms at different pFI. The rate law for the proposed exchange mechanism between the cyclol form and macrocycle was proposed. Both the macrocycle formation and cyclol formation constants are specific base catalyzed however, the equilibrium constant is independent of pH <2002J(P2)2078>. 

The last few years have seen the synthesis of zwitterions which polymerize by the charge cancellation mechanism foreshadowed by Swarc. To varying degrees these monomers do not exhibit a unique propagation reaction, charge cancellation can occur between monomers, chain and monomer, or chain and chain. However, there can be no doubt about the nature of the chains and one novel reaction predicted for zwitterions, macrocycle formation, has been shown to occur. 

Both Saegusa63 and Schmidt52 have shown that macrocycles are more likely to be formed when charge cancellation polymerizations are carried out in solvents of low dielectric constant. The equilibrium concentration of cyclic ion pairs will increase at the expense of linear ion pairs and free ions if the dielectric constant of the medium falls. Naturally under these circumstances there is a relative increase in the rate of macrocycle formation. 

---