Cyclizative cleavage

In a similar fashion, oxazoHdiones were prepared on a solid support via a cydizative cleavage. The oxazoHdinone scaffold can be found in antibacterial agents and MAO inhibitors. As in the previous example, epoxide ring opening was used to generate a 

CHEMO- AND REGIOSELECTIVITY ENHANCEMENT IN SOLID-SUPPORTED REACTIONS 

As observed in the previous examples, many cyclizative cleavage reactions rely upon a nucleophilic attack onto a carbonyl group however, several alternative methods exist to accomplish a cyclizative cleavage. Many of these have been previously discussed in 

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Furman B, Thurmer R, Kahuza Z, Voelter W, Chmielewski M. A new acetal resin valuable for the solid-phase synthesis of 1-oxacephams via a cyclization/cleavage step. Tetrahedron Lett 1999 40 5909-5912. 

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. 

Several syntheses of l,3-dioxoperhydropyrrolo[l,2-c]imidazoles have been developed using different strategies. a-Substituted bicyclic proline hydantoins were prepared by alkylation of aldimines 135 of resin-bound amino acids with a,tu-dihaloalkanes and intramolecular displacement of the halide to generate cr-substituted prolines 136 and homologs (Scheme 18). After formation of resin-bound ureas 137 by reaction of these sterically hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products <2005TL3131>. 

An experimentally simple synthesis of 2,4(l//,3//)-quinazoline-diones is described1 that uses a thermal cyclization/cleavage as... 

Along with a very wide synthetic application the Cope rearrangement continues to be a subject of intense debates. The key mechanistic question is whether the rearrangement of 1,5-hexadiene derivatives is concerted and passes via a six-electron aromatic transition state, or whether it involves the formation of a diradical intermediate, i.e. a cyclization-cleavage mechanism. In the former case, bond making and bond breaking occur synchronously (a survey of this question has been published210). 

McKay and co-workers determined the X-ray crystallographic structure of a hammerhead RNA-DNA ribozyme complex at 2.6-A resolution in 1994, deposited in the Protein Databank (PDB) as IHMH. The substrate DNA strand ensured that the complex would remain in the ground state since the DNA 2 -deoxy position could not undergo the cyclization/cleavage reaction. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

An especially attractive strategy is simultaneous cyclization/cleavage by RCM [42, 43]. This concept was first introduced by van Maarseveen in the synthesis of seven-membered lactams [44] and subsequently employed by many groups. Recently, this strategy was employed in the solid phase synthesis of epothilone A [45, 46] and dysidiohde analogues [47,48]. 

An elegant cyclization-cleavage strategy has been devised for the removal of resin-bound 1,3-amino alcohol derivatives 392 as l,3-oxazin-2-ones 393 upon treatment with lithium hexamethyldisilazide (LiHMDS) (Equation 42) <20010L3177>. 

Numerous examples of different variants of this cyclization/cleavage protocol have been reported. Diketopiperazine formation (Section 15.22.1), an unwanted side reaction in solid-phase peptide synthesis, is also an example of this type of compound release. Because intramolecular processes generally take place more readily than the corresponding intermolecular reactions, cyclization/cleavage can occur with alkyl... 

P rez, R., Beryozkina, T., Zbruyev, O.I., Haas, W. and Kappe, C.O., Traceless solid phase synthesis of bi-cyclic dihydropyrimidones using multidirectional cyclization cleavage, /. Comb. Chem., 2002,4, 501-510 and references cited therein. 

Oxetanes have also been synthesized by the immobilization of 2,2 -disubstituted 1,3-diols with polymer-bound sulfonyl chloride, followed by intramolecular cyclization/cleavage from the solid support (Scheme 17) <2005TL643>. One percent divinylbenzene (DVB) cross-linked polystyrene and polyethylene glycol (PEG) (average Mn 3400) were used as polymer support in this reaction, and in both cases the properties of the polymer support allowed rapid purification of the intermediate. Intermediates on the insoluble cross-linked polystyrene support could be washed with a range of organic solvents to remove insoluble impurities, whereas the soluble PEG supported products could be purified by recrystallization from isopropanol. This is thought to represent the first reported polymer-supported synthesis of oxetanes. 

Internal hydrogen-bonding in the biradicals from 17 and 18 increases overall quantum yields for product formation by impeding disproportionation. Likewise most polar solvents enhance quantum yields but lower the cyclization/cleavage ratio, presumably because H-bonding of solvent to the hydroxyl group increases steric hindrance to bond rotations. 

Dressman BA, Spangle LA, Kaldor SW, Solid phase synthesis of hydantoins using a carbamate linker and a novel cyclization/cleavage step, Tetrahedron Lett., 37 937-940, 1996. 

A robust catch, cyclize, and release preparation of 3-thioalkyl-1,2,4-triazoles mediated by the polymer-bound base P-BEMP has been described <02TL5305>. Reaction of solid-supported hydrazides 103 with isocyanates or isothiocyanates followed by base-induced cyclization/cleavage afforded 1,2,4-trisubstituted urazoles and thiourazoles 104 <02JCO491, 02TL3899>. Polymer-supported V-acyl-1 //-benzotriazole- 1-carboximidamides 105 reacted with hydrazines followed by acidic cyclizative release to give 3-alkylamino-l,2,4-triazoles 106 <02OL1751>. 

Typical procedure for a cyclization/cleavage reaction The resin 97 (0.3 mmol) was swollen in CH2CI2 (4 mL), and BF3 OEt2 (0.3 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then EtsN (0.1 mL) was added and stirring was continued for 10 min. The resin was then filtered off and the filtrate was collected. The resin was washed several times with CH2CI2, and the combined filtrate and washings were concentrated. The oily residue was dried in vacuo and purified by chromatography on silica gel to afford 98 (67% de). 

Sulfonyl resins (23) have been developed to prepare indoles via a palladium-catalyzed cyclization. Cleavage was carried out with TBAF with excellent yields and purities (85-100%) [78]. Likewise, a library of bivalent ligands (including guanidine, pyridinium and carboxylic and sulfonic acids constituents) for a protein receptor was prepared on nitrobenzenesulfonamide resin 24. Cleavage was achieved with sodium sulfide [79]. 

Cyclization to an organomagnesium compound sufficiently less stable to be present only in small amounts at equilibrium, however, can lead to rearrangement. The organomagnesium-halide reagent either at the left or at the right in Eq. (u) forms a ca. 1 8 mixture of these reagents, by cyclization-cleavage. 

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