Benzamides 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. 

Birch reduction of the chiral benzamide 5 generates the amide enolate 6 (Scheme 4). This enolate has been characterized by NMR spectroscopy and by an extensive examination of the effects of changes in alkali metal, solvent, reaction... 

It is important to perform both the Birch reduction of 5 and the alkylation of enolate 6 at —78 °C. Enolate 6 obtained directly from 5 at low temperatures is considered to be a kinetic enolate . A thermodynamic enolate obtained from 6 by equilibration techniques has been shown to give an opposite sense of stereoselection on alkylation. Although a comprehensive study of this modification has not been carried out, diastereoselectivities for formation of 8 were found to be greater than 99 1 for alkylations with Mel, EtI, and PhCH2Br. Thus, it should be possible to obtain both enantiomers of a target structure by utilization of a single chiral benzamide. SE... 

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

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... 

Birch reduction-methylation of the 2,3-dialkyl substituted benzamide 85 (Scheme 19) provided the cyclohexa-1,4-diene 86 with diastereoselectivity comparable to that observed with the 2-alkylbenzamides illustrated in Scheme 4. Cyclohexadiene 86 was converted to iodolactone 87 and reduction of 87 with BusSnH occurred with exclusive equatorial delivery of hydrogen to give the axial methoxyethyl derivative 88. Lactone 88 was converted to the Caribbean fruit fly pheromone (+)-epia-nastrephin 90 (> 98% ee) in 9.5% overall yield from the chiral benzamide 85. °... 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Birch reduction of enantiomcrieally pure benzamides followed by alkylation of the amide enolate was used with remarkable success to obtain chiral cyclohexadiene derivatives22. In this case the chiral auxiliary was located in the benzamide moiety. 

The reversed sense of diastereoselectivity is also observed in the direct Birch reduction alkylation of a number of ort/w-alkylated benzamides of 2-(methoxymethyl)pyrrolidine [i.e., l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines, 8] which also give high diastereoselectivities of a-methylated products (see Table 6)33. Diastereomeric ratios (TR/TS) for the different R groups range from 5 95 for R = ethyl to 2 98 for R = 2-(tm-butyldimethylsilyloxy)ethyl33. 

Birch reductive alkylation of benzamide (24) was optimized to give the corresponding cyclohexa-1,4-diene products in 66-78% isolated yield and with high diastereo- (g) selectivity.386... 

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a >100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

Birch reduction of chiral benzamide (181) followed by oxidation of the resulting enolate with (+)-(114) afforded dienol (182) in 86% de, but in only 16% yield <92JOC2973>. The yield improves to 57%, (80% based on recovered starting material) if ammonia is removed prior to the oxidation (Scheme 33). Asymmetric hydroxylation of the prochiral enolate derived from the Birch reduction of methyl 2-methoxybenzoate with ( + )-(114) gave the corresponding dienol in 50-60% yield and 30% ee. 

Stereoselective Birch reduction is possible and a number of examples have been reported, particularly for selective alkylation of the intermediate enolate anion. For example, reduction of the chiral benzamide 69 with potassium in ammonia, followed by alkylation with ethyl iodide gave essentially a single diastereomer of the cyclohexadiene 70, which was used in a synthesis of (-l-)-apovincamine (7.50). 

N-Methyl groups in amides may be monochlorinated by irradiation in the presence of chlorine. Some studies on the Birch reduction of benzamides have revealed reactant-reagent ratios that are preferable to those previously recorded in the literature. 

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