Ring-forming strategies

For lactone synthesis there is no need for special ester linker requirements. It can be performed using an ester activating reagent like TEA that enhances intramolecular nucleophilic attack by an alkoxy fimctionality. The distance between the ester group and the alkoxy functionality determines the resulting ring-size and therefore whether y- or 5-lactone-derivatives are released [134]. 

Matthews et al. described a synthetic route to hydantoins as well as thio-hydantoins on solid-supported esters in 1997 [136,137]. The hydantoin or thiohydantoin skeleton is synthesized on Wang resin by addition of an amino acid and following reductive alkylation. For the release of hydantoins, acylation with an isocyanate to urea derivatives with following base promoted cleavage takes place. For the preparation of thiohydantoins, isothiocyanates have to be reacted with the corresponding precursors these intermediates cyclize without additional treatment with bases to the corresponding thiohydantoins. 

Applications for this lactone formation chemistry are manifold. Kobayashi et al. for example found a method to synthesize monosaccharide derivatives via cleavage of thioester linkers [139]. The resulting lactones had to be reduced with DIBAL-H to get glucose derivatives. 

Thioesters in their function as activated derivatives of carboxylic esters are also important for lactam formation as shown in a synthesis published by Vlattas et al. in 1997 [90]. 

---

The numerous methods which are available for the synthesis of substituted fi-lactams involve a variety of ring-forming strategies. Two categories only are selected and exemplified below to illustrate some of the interesting chemistry involved Cyclisation reactions and Cycloaddition reactions. 

The preparation of substituted five- and six-membered lactones served as a model system to examine the feasibility of this novel ring-forming strategy. A hydroxythioamide (168) was allowed to react with chloroacetyl chloride, and the resulting a-chloro ester (169) was treated with sodium iodide and the Eschenmoser dual base-thiophile reagent (28) to afford the cyclic enamino lactone (170) in high yield (Scheme 35). No epimerization of the lactone was observed. Likewise, the five-membered enamino lactone (172) resulted from reaction of the hydroxythioamide (171) with chloroacetyl chloride followed by sulfide contraction. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

The preparation of C-1 glycals has been largely addressed by synthetic modifications on cyclic carbohydrate derivatives, although strategies that rely on ring forming reactions from acyclic derivatives have recently emerged (Fig. 1). 

As in the five-membered heterocyclic section the discussion of the relevant ring-forming reaction is related, as appropriate, to an overall strategy of skeletal assembly, and to a more rigorous retrosynthetic analysis. The reactions are conveniently discussed in relation to the synthesis of compounds belonging to the following groups of heterocycles. 

---