Macrocyclic isomers

Macrocyclization. Trost and Warner17 have effected efficient cyclization to ten-and fifteen-membered rings by use of Pd(0) supported on a polystyrene bearing phosphine ligands. Precursors with an epoxy vinyl terminal group proved particularly suitable. Thus, 1 in the presence of such a Pd(0) catalyst cyclizes to 2 and 3 in 71% yield. The products are isomeric at the double bond, since both are oxidized to the ketone 4. The same catalyst system converted 1 (n = 9) into two macrocyclic isomers in 66% yield. Both cyclizations are concentration dependent. The temperature is also critical, the reaction being particularly clean at 65°. 

In theory, each macrocyclic isomer could be formed as a mixture of diastereoisomers, depending on how the EtOCO residues at the two methano bridge C-atoms are oriented with respect to each other in-in, in-out, and out-out stereoisomerism) [69]. However, with the exception of the in-out isomer ( )-49 (Scheme 7-8), out-out stereoisomers have been obtained exclusively until now. The out- out geometry of cis-2 bis-adduct 42 with an o-xylylene tether was proven by X-ray crystallography [59]. 

Figure 5 Structures of macrocycle isomers with nitrogen donors at different positions. (Reproduced from Ref. 14. Wiley-VCH, 1998.)...

Quite recently, Ciampolini and coworkers have reported the synthesis of two isomeric mked oxygen-phosphorus macrocycles and the crystal structures of their cobalt complexes. Synthesis of macrocycle 27 was accomplished by condensation of 1,2-bis-(phenylphosphino)ethane dianion with 2,2 -dichlorodiethyl ether in THE. The two isomers of 27 were isolated in 1.5% and 2% yield. The synthesis is formulated in Eq. (6.17), below. 

The preparations of chlorins described so far by attack of different reagents at a peripheral C — C double bond of the porphyrin macrocycle are all restricted to highly symmetric porphyrins because otherwise complex mixtures of constitutional isomers can be formed. The problem of... 

The approach makes use of a bipyrroledicarbaldehyde 54 and a tripyrranedicarboxylic acid 55 which are condensed with subsequent decarboxylation in the presence of acid and oxygen. The presence of oxygen, as in many other syntheses of porphinoid macrocycles, is necessary to adjust the oxidation level of the chromophore which is in sapphyrins a 2271-aromatic cyclically conjugated system. Many sapphyrins 56 with different substitution patterns have been synthesized according to this general scheme. As in all McDonald-type condensations at least one of the components has to be symmetric because otherwise mixtures of constitutional isomers would be formed. 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

In macrocycle [5b] the difference between log Ki and log K2 is 3.6, reflecting the strong Coulomb repulsion between two neighbouring positive charges. When the nitrogen atoms have a larger separation as in the isomer [5c] the difference is smaller (1.1), and if the sulfur atoms are replaced by oxygen atoms it is even lower (0.7 in [5d]). 

The 14-membered macrocycle 1,4,8,11-tetraazacyclotetradecane (cyclam or [14]aneN4), unlike cyclen, is capable of encircling most transition metal ions and in the case of Co111 the trans configuration is much preferred by comparison with the folded cis isomer. Electrochemical reduction of A,v-[Co(cyclam)(OI I)2]+ in 3M NaOH leads to rapid isomerization to the trans form, and the relative stabilities of the trans and cis isomers of the di- and trivalent complexes were determined from a thermodynamic cycle.702 This preference for trans orientation of the non-macrocyclic donors has enabled the isolation and investigation of many Co complexes without the complications of isomerization. Some novel examples include /r[Pg.61]

In a comparative study, the semiempirical PM3(tm) method was shown to be less effective than molecular mechanics for modeling the structures of Ni11 complexes with tetraaza macrocycles.398 In contrast, local DFT calculations (VWN5 method), coupled with appropriately large basis sets, accurately describes the geometries of the isomers of [Ni(cyclam]2+. 

In the case of the smaller macrocycle [13]aneN4, six configurational isomers exist for [Ni([13]aneN4)]2+ due to the orientation of the N—H protons above or below the plane of the macrocycle. X-ray crystallography and NMR spectroscopy, respectively, revealed that the R,iS,7 ,iS -[Ni([13]aneN4)]2+ form (trans- ) is the preferred one both in aqueous solution and in the solid state.1 43... 

The zinc complex of the saturated macrocycle (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20,21,22-docosahydrodibenzo-[B,I][l,4,8,l 1] tetra-azacyclotetradecine), which is a 14[ane]N4 (cyclam) ring incorporating two cyclohexyl rings into the macrocycle, has been prepared and characterized.688 Two isomers of the ligand were separately complexed with zinc and characterized by NMR. 

Because of its flexibility, macrocycle (44) (Black McLean, 1968) has the choice of three possible coordination modes (46)-(48) around an octahedral metal ion nevertheless, for a given metal, all isomers will not be of equal energy and hence all three may not be observed experimentally. In contrast, the macrocycle (45) is partially constrained since each set of three donor atoms (S-N-S) is incorporated in a fully conjugated section of the ligand s backbone (Lindoy Busch, 1969). These two conjugated sections will tend to remain planar such that only a configuration corresponding to (46) can occur around an octahedral metal ion if all donor atoms remain coordinated. 

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