Benzoic acid derivatives Birch reduction

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Birch reduction of benzoic acids in the presence of an alcohol (proton donor) furnishes 1,4-dihydrobenzoic acids. The carboxylate salt (-CO2 M ) formed during reduction of benzoic acid derivatives is sufficiently electron rich that it is not reduced. 

Emantioseieetive Birch redmction-atkylation. lire chiral benzoic acid deriv ativc 1. prepared hy ccuidcnsatioit irf o-bydroxybenzcM add with L olinol fob lowed by cycltzation (Mitsunobu reaction), undergoes Birch reduction (K. NHt. HfF, r-butyl aloohot) (oltow cd by alkylation with essentially only 2. 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

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