The stereoselective birch reduction of pyrroles

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C-2 position. Using either 8- phenylmenthol or trans-2-(α-cumyl)cyclohexanol (TCC) as auxiliaries, high levels of stereoselectivity were obtained. Moreover, the auxiliary could be removed using a high-yielding three-step sequence to furnish substituted dehydroproline derivatives with high enantiomeric purity. By choosing either (-)-8-phenylmenthol or (+)-TCC as an auxiliary either enantiomer of the dehydroproline product could be obtained

Reduction of electron-deficient pyrroles using group I and II metals in ammonia

The preparation and Birch reduction of a series of electron-deficient pyrroles is described. This methodology allows the synthesis of a variety of C-2 substituted 3-pyrrolines in good to excellent yields. The role of various activating groups (amide, ester, carbamate and urea) has been examined with regard to both stability under the Birch conditions and ease of deprotection after reduction. In addition, we discovered that the 3-pyrroline skeleton can be oxidised at C-5 with chromium trioxide-3,5-dimethylpyrazole to form the 3-pyrrolin-2-one nucleus. The identity of the Birch reduced products and also of the oxidised 3-pyrrolin-2-ones has been confirmed by X-ray crystallography on two derivatives

The birch reduction of 3-substituted pyrroles

The Birch reduction of electron-deficient 3-substituted pyrroles is described. Use of a reductive alkylation procedure involving sodium metal in liquid ammonia gave good yields of 4-alkyl-2-pyrrolines. The identity of these products was proven by an X-ray structure of a crystalline derivative. Moreover, the pyrroles used in this study could be readily prepared by reaction of TOSMIC with acrylic amides and esters and, once the reduction was complete, the ester activating group could be easily removed to yield the corresponding N-protected β-proline derivatives

Reductive aldol reactions on aromatic heterocycles

The Birch reduction of both pyrroles and furans can be quenched with an aldehyde electrophile, thus constituting a reductive aldol reaction. Although the reaction was not stereoselective, the pyrrolines derived from reduction of pyrroles could be oxidised and then reduced with NaBH4 to provide syn- aldol adducts with high levels of stereoselectivity. The relative stereochemistry of two adducts was proven by X-ray crystallography. (C) 2000 Elsevier Science Ltd

Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20s proteasome inhibitor, clasto-lactacystin beta-lactone.

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound