Metal-templated cyclization

Sb(OEt)3 is highly effective for the metal-templated cyclization of tetramino esters to give macrocyclic spermine alkaloids such as buchnerine, verbacine, verbaskine, and verbascenine (Eq. 3) [9]. The accelerated rates and high regioselectivities suggest a mechanism in which the acyclic tetramino esters are covalently or coordinately attached to the antimony before the final cyclization step. In addition, Sb(OEt)3 is useful as an intermolecular amidation catalyst for reactions between esters or carboxylic acids and amines (Eq. 4) [9]. 

Metal-coordinated phosphines react similarly, as in the metal-templated cyclization of (CO)jMo(PH2CH2CH= 0113)3 in the presence of 2.2 -azobis(isobutyronitrile)(AIBN) ... 

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

Fig. 3a,b. Template cyclization reactions of a crown ethers and b CPOs. The coordination bonds are illustrated by black arrows. In the crown ether synthesis, ethylene glycols coordinate toward the metal acting as the template (normal template reaction) however, the template coordinates to the incorporated metals of porphyrin In CPO synthesis (inverse-template reaction)... 

Other template cyclizations. In another Schiff-base template reaction, 1,3-diaminopropane monohydrochloride was reacted with biacetyl in methanol in the presence of Ni(n) to yield the nickel complex of the corresponding cyclic tetraimine - see [2.16] (Jackels et al., 1972). The success of the procedure illustrated is quite dependent on the reaction conditions employed. Attempts to isolate the metal-free macrocycle were unsuccessful - this once again emphasizes the stabilizing role of the metal... 

Porphyrazines are typically synthesized by a templated cyclization of substituted dinitriles, Fig. 2 (2). The most common divalent metal used as the template for this reaction is Mg2+, usually as the butoxide or propoxide, although other group 1(1 A) and 2(IIA) metals have been reported (41). Mixed cyclizations, which utilize two different dinitriles, Fig. 3, in principal, would give a statistical mixture of six different products or isomers. The truly enabling synthetic foundation for modem pz chemistry is the development of strategies directed toward the synthesis... 

Porphyrin synthesis can be enhanced by metal template methods using several strategies, including tetramerization of pyrrole derivatives (equation 45),251 dimerization of dipyrrolomethenes (equation 46)252 and cyclization of 1,19-dideoxybiladiene-ac derivatives (equation 47).252 These derivatives can also be induced to undergo direct base-catalyzed template cyclization to octa-dehydrocorrins of different chromophores depending on the 1,19-substituents (Scheme 61).253-255 The cationic complex (99) can be transformed by thermal ring expansion processes to porphyrin derivatives (Scheme 62).253... 

Figure 2.22. Strategies for the transition metal-templated synthesis of catenanes. The metal (in) predisposes two fragments as open chelates (A) (strategy I) or as a macrocyclic chelate (E) and an open chelate (strategy II) in intermediates (B) and (F), respectively. Cyclization of these intermediate complexes with the chain fragments (C) provides the [2]-catenate complex (D).

Principally, the same ring closure reactions as for tetraazacycles (Section 14.11.5.3) can be applied for preparation of larger polyazamacrocycles however, mostly tosylamide and peptide-like syntheses are employed. In addition, metal template or cyclization reactions between carbonyl compounds and amines (and reduction of intermediate Schiff base) are often utilized. 

For larger cycles, tosylamide or high-dilution amide condensations were mostly used. In addition, cyclization of amines and aldehydes to get Schiff bases (mostly for [2+2] or [3+3] cyclizations) is convenient. Metal template synthesis is useful only in special cases. Polycycles are conveniently prepared from appropriately protected cycles. 

Hoffman et al. have reported the synthesis of tetrakis-, tris-, and monothiacrown ethers containing a tetra-azaporphyrin unit 139-152. The first porphyradine crown ethers were prepared by the Mgz+ template cyclization of the appropriate crowned derivative of dithiomaleonitrile 32 and 33 to afford 139 and 143, respectively, in ca. 35% yields. Treatment of 139 and 143 with trifluoroacetic acid provided the metal-free porphyrazines 140 and 144, respectively. Subsequent reaction with Ni(OAc)2 or Cu(OAc)2 quantitatively produced 141, 142, 145, and 146 (Scheme 21). 

The cholates 8.117-8.119 were designed for the preparation of dynamic hbraries with different binding affinities for alkah metal ions. The presence of a polyether chain in position 7 of 8.117 provided a recognition element for metal binding that was absent from the disubstituted p-methoxybenzyl substitution pattern of 8.118, while the 7-deoxy derivative 8.119 was even less prone to metal coordination. The three monomers were submitted to transesterification/cyclization protocols, either without metal templates or using different alkali metal salts as templates. The relative abundances of cyclic dimers, trimers, tetramers, and pentamers for each experiment are reported in Table 8.7. 

Curtis and others showed that cyclic condensation also was possible in the absence of a metal template ion, but acid was necessary for those reactions. Possibly, the protonated amines formed an internal hydrogen-bonding network that acted as a template. Cyclization was observed in yields of up to 80% (Curtis and Hay, 1966 Kolinski and Korybut-Daszkiewicz, 1969 Tait and Busch, 1978a, 1978b). The isomers of the formed cyclic Schiff bases were difficult to separate. Reduction of the unsaturated macrocycles gave cyclic polyamines with up to six chiral centers and up to 20 diastereomeric isomers (Hay and Piplani, 1977 Kolinski and Korybut-Daszkiewicz, 1969). 

This reaction is thought to be a stepwise, template-assisted cyclization and worked well when Ni(II) perchlorate or chloride was used. Others found only linear compounds under similar conditions but were able to prepare the macrocycle from primary amines using Ni(II) or Cu(II) as metal template ions (Suh and Kang, 1988). 

Other Oxygen-containing Derivatives. Acetone and furan condense in an acidic medium to form (54). The yield is increased by the addition of metal salts, e.g. IiC104. The increase has been attributed to acidity (pH) effects rather than to effects of metal ion templates. This is the first demonstration of the importance of the effects of pH in metal-assisted cyclizations. Compound (54) is cleaved by m-chloroperoxybenzoic acid to form the novel octaketone (55), with a n s-enedione configuration. The endoperoxide (56) is converted into a bis-epoxide on treatment with catalytic amounts of cobalt(n) 5,10,15,20-tetraphenylporphine at — 10°C, and the epoxide rearranges to (57) at 20... 

Another celebrated example of the template effect is the synthesis of crown ethers by Pedersen [11], but it was Busch who first intentionally used templates in synthesis and who first articulated the concept of the template effect in the 1960s [12]. Busch used the reaction of a nickel(Il) dithiolate complex 7 with l,2-bis(bromomethyl)benzene 8 to illustrate his ideas (Scheme 1-3) [13]. Once one end of the l,2-bis(bromomethyl)ben-zene has reacted with the nickel complex, the nickel template induces the reactive ends of the intermediate 9 to come into close proximity and favors cyclization. The metal template allows the synthesis of a metallated macrocycle 10 the free ligand cannot be prepared by the reaction of l,2-bis(bromomethyl)benzene with the unbound thiol (in the absence of a template other cyclic and acyclic products are formed). 

In generalizing the latter examples one may be tempted to assume that all metal-assisted cyclization and cross coupling reactions are templated processes. This viewpoint, however, not only sets an impractically wide scope for a review, it may even be incorrect. Therefore, the present article does not try to cover all potentially templated ring closure reactions [4], but presents just a very limited and personal selection of metal-assisted or metal-catalyzed cyclizations based on C-C coupling reactions. They are analyzed with the intention to deduce more accurately what the phenomenological effect of tern-plating refers to. 

Scheme 21. Role of the metal template in carbene-alkyne cyclization reactions.

Kern. J.-M. Sauvage, J.-P. Weidemann. J.-L. Multiring interlocked systems via transition metal-templated strategy The single-cyclization synthesis of [3]-catenates. 1. Tetrahedron 8996, 52. 10921-10934. 

Scheme 8 Metal template for anodic cyclization reaction...

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