Rearrangement reactions rings

The fully conjugated tetrazine nucleus in principle cannot undergo rearrangement reactions. Ring transformations of dihydro, tetrahydro, and hexahydro 1,2,4,5-tetrazines under acidic and basic conditions (partial hydrolysis) are well known and were competently and extensively treated by NeunhoefiFer <84CHEC-I(3)53i>. Short surveys can be found in Sections 6.21.6 and 6.21.9. No new aspects seem to be worthy of discussion here. 

Figure 4.6 The bifunctional enzyme PRA-isomerase (PRAI) IGP-synthase (IGPS) catalyzes two sequential reactions in the biosynthesis of tryptophan. In the first reaction (top half), which is catalyzed by the C-terminal PRAI domain of the enzyme, the substrate N-(5 -phosphoribosyl) anthranilate (PRA) is converted to l-(o-carboxyphenylamino)-l-deoxyribulose 5-phosphate (CdRP) by a rearrangement reaction. The succeeding step (bottom half), a ring closure reaction from CdRP to indole-3-glycerol phosphate (IGP), is catalyzed by the N-terminal IGPS domain.

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

In a formal synthesis of fasicularin, the critical spirocyclic ketone intermediate 183 was obtained by use of the rearrangement reaction of the silyloxy epoxide 182, derived from the unsaturated alcohol 180. Alkene 180 was epoxidized with DMDO to produce epoxy alcohol 181 as a single diastereoisomer, which was transformed into the trimethyl silyl ether derivative 182. Treatment of 182 with HCU resulted in smooth ring-expansion to produce spiro compound 183, which was subsequently elaborated to the desired natural product (Scheme 8.46) [88]. 

It is claimed that the limiting value of k bs, 2.81 x 10" sec-1, represents the rate coefficient for the rearrangement reaction above (k,). The ring deuterium isotope effect kH kD was re-determined for this individual rate coefficient for rearrangement by finding the limiting value in the presence of added N-methylaniline and was found to be 2.4 at two different acidities, as compared with 1.7 for the ratio of the observed composite rate coefficients, as expected, since no isotope effect would be predicted for the de-nitrosation step. 

Fig. la—d Typical alkene metathesis reactions ring-closing (RCM) and ring-opening (ROM) metathesis (a), diene cross metathesis (CM, b), ROM-RCM (c), and ROM-double RCM (d) sequences (ring-rearrangement reactions, RRM)... 

Scheme 10.14 gives some other examples of Wolff rearrangement reactions. Entries 1 and 2 are reactions carried out under the classical silver ion catalysis conditions. Entry 3 is an example of a thermolysis. Entries 4 to 7 are ring contractions done under photolytic conditions. Entry 8, done using a silver catalyst, was a step in the synthesis of macbecin, an antitumor antibiotic. Entry 9, a step in the synthesis of a drug candidate, illustrates direct formation of an amide by trapping the ketene intermediate with an amine. 

Reinhoudt et al.53) have reported the first synthesis of a monocyclic thiepin stabilized by electronic effects of the substituents. This synthesis utilizes the idea described in Section 2.3.3. 3-Methyl-4-pyrrolidinothiophene (85a) was treated in deuteriochloroform at —30 °C with dimethyl acetylenedicarboxylate. H-NMR monitoring of the reaction indicated that a [2 + 2]cycloaddition proceeded slowly at this temperature giving the 2-thiabicyclo[3.2.0]heptadiene (86a) which rearranged via ring opening of the cyclobutene moiety to the 4-pyrrolydinylthiepin (87a). At the... 

Ring expansion.1 The adducts (2) of cycloalkanones with 1 on reaction with methyllithium or wc-butyllithium at 0° rearrange to ring-expanded a-phenylthio ketones. 

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