Cyclizations on solid supports

The recent impact of solid-phase synthesis on medicinally relevant benzoaime-lated nitrogen heterocycles has been recently reviewed [16], therefore in this section only recent publications are included. Benzoannelated heterocycles can be prepared efficiently through cyclization on solid supports employing classical heterocycle forming reactions such as the Fischer [425], the Bischler-Napieralski [426], Tsuge [427], Nenitzescu [428], and Richter [140] reactions. In addition, the... 

Ricl994b Richter, L.S., Tom, J.Y.K. and Bumier, J.P., Peptide-Cyclizations on Solid Support A Fast and Efficient Route to Small Cyclopeptides, Tetrahedron Lett., 35 (1994) 5547-5550. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Varma and coworkers have explored the use of hypervalent iodine compounds on solid support for the first time and developed a facile oxidative procedure that rapidly converts alcohols to the corresponding carbonyl compounds using alumina-sup-ported IBD under solvent-free conditions and MW irradiation in almost quantitative yields [108]. The use of alumina as a support improved the yields markedly as compared to neat IBD (Scheme 6.33). 1,2-Benzenedimethanol, under these conditions, undergoes cyclization to afford l(3H)-isobenzofuranone. 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

The choice of protecting groups and of the type of resin-anchor required for synthesis of cyclic peptides on solid supports not only depends upon the particular amino add sequence of the target molecule, but decisively upon the mode of cyclization, particularly whether the C-terminal carboxy group should act as bridgehead or not. Correspondingly, the synthetic routes can be subdivided into two main classes either based on the attachment of the C-terminus to the solid support by suitable anchors or where side-chain functionalities are exploited for this purpose. 

The majority of cyclic peptides synthesized on solid support are cyclized in the head-to-side-chain or side-chain-to-side-chain mode. For this purpose the amino acids involved in cyclization must be side-chain protected in a manner that allows for an additional level of orthogonal deprotection. Thus, upon assembly of the fully protected linear precursor on-resin, deprotection of the functionalities involved in the lactam ring formation is performed, followed by regio-selective cyclization by amide bond formation, and finally by the resin-cleavage/deprotection step as outlined in Scheme 16. In Table 8, examples of syntheses of such cyclic peptides are listed with the relevant information regarding protection scheme, resin anchor, and mode of cyclization. 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

For the synthesis of dihydrothiazole-containing cyclic peptides alternative synthetic routes are presently available.1514570 In one of these approaches suitably protected 2-(aminoal-kyl)dihydrothiazole-4-carboxylic acids are prepared and then used as building units for the assembly of the target peptides by standard synthesis on solid supports 519 539 561 571 572 or more frequently in solution, 539571 followed by cyclization again by standard protocols. 552 564 However, great care has to be taken in all these synthetic steps because of the facile race-mization at both chiral centers of the dihydrothiazole building blocks (see Scheme... 

In the final example of the Heck reaction on solid support, a Chiron group54 55 used a palladium-catalyzed cyclization step to prepare heterocycles. An example of their work, the production of l-(2H)-isoquinolinones, is shown in Scheme 22. 

Until now, the chemistry of radicals on solid supports has been investigated mostly in respect to intramolecular radical cyclizations and radical chain reactions. One reason for refraining from free radical transformations is the chemical nature of the polystyrene with its abundance of benzylic positions that are prone to H-radical abstraction and oxidation. 

Non-oligomeric and air- or moisture-sensitive chemistries such as cycloadditions, cyclizations, and carbanion condensations have already been successfully enabled on solid support, and some recent examples are discussed below. It is anticipated that these studies will be further extended in combinatorial formats and libraries subjected to HTS in the near future. 

Other methods of preparing imidazoles on solid-supports have been reported. Solid-supported amino acid 71 underwent sequential reductive amination with aldehydes, benzotriazole-mediated cyclizations and acidic cleavage to give 1,2,5-trisubstituted-4-... 

Scheme 10 Potential Cyclization Reactions in the N-to-C Peptide Synthesis in Solution and on Solid Supports Oxazol-5(4/()-one (Path a) and Piperazine-2,5-dione Formation (Path b)...

Uronium/guanidinium salt mediated cyclizations may also be performed on solid supports, However, in contrast to the case involving phosphonium salts... 

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