Birch reductive alkylation, asymmetric

Companion reactions that serve to expand the scope of the asymmetric Birch reduction-alkylation strategy... 

The development of facial selective addition reactions of cyclohexa-1,4-dienes 7 and 14 has greatly extended the value of the asymmetric Birch reduction-alkylation. For example, amide directed hydrogenation of 15 with the Crabtree catalyst system occurs with outstanding facial selectivity iyw to the amide carbonyl group to give 16 (Scheme 5)."... 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

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. 

What truly distinguishes the asymmetric Birch reduction-alkylation protocol from other methods for preparation of non-... 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

For the first report of an asymmetric Birch reduction-alkylation, see A. G. Schultz and P. Sundararaman, Tetrahedron Lett., 1984, 25, 4591. 

Schultz AG, Pettus L. Desymmetrization of benzoic acid in the context of the asymmetric birch reduction-alkylation protocol. Asymmetric total syntheses of (—)-ebumamonine and (—)-aspidospermidine. J. Org. Chem. 1997 62 (20) 6855-6861. 

Asymmetric Birch reduction and reduction-alkylation in synthesis of natural products 99CC1263. 

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... 

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. 

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. 

Schultz, A. G. The asymmetric Birch reduction and reduction-alkylation strategies for synthesis of natural products. Chem. Common. 1999, 1263-1271. 

Phenylmenthol is the auxiliary in an asymmetric Birch reduction of pyrroles by Donohoe37 Lithium in ammonia does the reduction and the enolate is trapped with various alkyl halides. Hydrolysis of the esters 227 releases the enantiomerically enriched (78-90% ee) dihydropyrroles 228 in good yield. Furans give similar products with a C2 symmetric amine as auxiliary. This should become a general route to a variety of heterocycles. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

Asymmetric Birch reductions and reductive alkylations using 2-substituted benz-amides and pyrrolobenzodiazepine-5,ll-diones with an (X)-prolinyl chiral auxiliary have provided routes for the synthesis of a wide variety of natural products and related compounds. ... 

Asymmetric versions of the Birch reduction are now appearing (chapter 28) and a C2 auxiliary attached to the furoic acid 141 allows Birch reduction and alkylation between the ring oxygen atom and the carbonyl group to give, after hydrolysis, enantiomerically pure acids39 144. 

The normal Birch reduction is most interesting when applied to aromatic ethers 209 or acids 213. The addition of two electrons may make a dianion in which the charges keep away from the ether 210 but conjugate with the acid 214. Protonation of 210 gives the enol ether 211 and hence the non-conjugated enone 212. The dianion 214 has a proton which transfers to the less stable anion leaving the enolate 215 that can be alkylated to give 216. None of these compounds is chiral and there appears to be little scope for asymmetric induction. 

In addition to the classical reactions, this book covers many techniques and reactions that have more recently gained wide use among practicing chemists. Molecular-orbital theory is introduced early and used to explain electronic effects in conjugated and aromatic systems, pericyclic reactions, and ultraviolet spectroscopy. Carbon-13 NMR spectroscopy is treated as the routine tool it has become in most research laboratories, and the DEPT technique is introduced in this edition. Many of the newer synthetic techniques are also included, such as asymmetric hydrogenation and epoxidation, use of sodium triacetoxyborohydride, Birch reduction, Swern oxidations, alkylation of 1,3-dithianes, and oxidations using pyridinium chlorochromate. 

Another interesting synthetic application of the Birch reduction is the capture of the in itfM-generated carbanion with a carbon electrophile (usually an alkyl halide) forming a new carbon-carbon bond [9] this process has also been studied in an asymmetric manner [10]. 

One-carbon Homologations. SEM-Cl can be used as a formaldehyde equivalent, which upon alkylation affords, directly, a protected hydroxyl. SEM-Cl does not suffer from some of the handling liabilities of formaldehyde (e.g., the need for cracking or the use of aqueous solutions) and as such has shown specific promise in the area of asymmetric alkylations. Asymmetric alkylations of enolates have been accomplished via the employment of chiral auxiliaries including oxazolidinones (eq 26) and RAMP/SAMP hydrazones. Furthermore, Schultz and co-workers have utilized SEM-Cl to trap chiral enolates derived from Birch reductions (eq 27). ... 

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