Mannich reaction in synthesis

Robinson synthesis of tropinone (example of Mannich reaction in synthesis)... 

Heathcock and co-workers have now published full details of their synthetic work amongst lycopodium alkaloids which demonstrates further the powerful use of the intramolecular Mannich reaction in synthesis. ... 

Mannich reactions, or a mechanistic analog, are important in the biosynthesis of many nitrogen-containing natural products. As a result, the Mannich reaction has played an important role in the synthesis of such compounds, especially in syntheses patterned after the biosynthesis, i.e., biomimetic synthesis. The earliest example of the use of the Mannich reaction in this way was Sir Robert Robinson s successful synthesis of tropinone, a derivative of the alkaloid tropine, in 1917. 

Tropinone is a structural component of several alkaloids, including atropine. The synthesis is based on a double Mannich process with iminium ions as intermediates. The Mannich reaction in itself is a three-component domino process, which is one of the first domino reactions developed by humankind. 

Unexpected Course of a Mannich Reaction in Alkaloid Synthesis... 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

H. Heaney, The Bimolecular Aromatic Mannich Reaction, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 2, 953, Peigamon Press, Oxford, 1991. 

Deng and Overman employed the aza-Cope-Mannich reaction in the enantios-elective total synthesis of (+)-preussin (21), a potent antifungal agent possessing a pyrrolidine skeleton8 (Scheme 1.6h). Conversion of the amino alcohol 22 to the oxazolidine derivative 23 was readily accomplished by reacting with decanal in hot benzene with removal of water using a Dean-Stark trap. Treatment of... 

The process, which includes the simultaneous separation and synthesis of vitamin E (a-tocopherol) (F ig, 181), appears particularly interesting aminomethylation at the phenolic ring of type 489 compounds allows the separation from the aminomethylated material of any vitamin E that may be present and that is unable to undergo Mannich reaction. In a second step, further amounts of vitamin E are provided by hydrogenolysis of the aminomethylated product to the corresponding methyl derivative. ... 

Activation of a substrate involves a modification in the reactive center in order to enhance its nucleophilic character and make possible, or favor, the attack by the ami-nomethylating reagent. This is more frequently required by aliphatic carbonyl and carboxyl derivatives (ketones, aldehydes, and, respectively, esters, and lactones). The latter compounds, in particular, would not even be able to give a Mannich reaction in the absence of any activation, as the ester group, unlike the keto group, usually docs not render the hydrogen atom in the a position sufficiently acidic. Activation of aliphatic ketones, on the other hand, is carried out mainly when chemo- or regioselective reactions are involved in Mannich synthesis. 

The steroid skeleton is usually subjected to Mannich reaction in order to obtain derivatives possessing basic functionalities. Steroidal aminomethyl compounds arc used mostly for the synthesis of compounds having pharmacological activity. 

Modified Mannich reaction. In a synthesis of some diaza steroids, Taylor and Shvo1 found that the allylic protons at CI9 of the diaza steroid (1) have considerable active methylene character. Thus treatment of (1) with bis(dimethylamino)... 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Unfortunately, due to the low solubility of melamine in oxazolidine, reaction 15.39 takes place slowly, needs a long reaction time and unreacted melamine frequently remains. The best method for the synthesis of melamine Mannich base is the Mannich reaction in the presence of aqueous formaldehyde. 

Tan and coworkers reported the decarbojgrlative Mannich reaction between imine and a malonic half-ester (Scheme 23.9). ° Nagasawa and coworkers reported the synthesis of the same p-amino acid by an enantiodivergent Mannich reaction in which both stereoisomers could be obtained by a switch of solvent between m-)q lene and acetonitrile (Scheme 23.9). ... 

Scheme 26 Mannich reaction in the synthesis of (+)-polyoxamic acid (112)...

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