Mannich reaction natural products

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The condensation reaction of a CH-acidic compound—e.g. a ketone 3—with formaldehyde 1 and ammonia 2 is called the Mannich reaction, the reaction products 4 are called Mannich bases. The latter are versatile building blocks in organic synthesis, and of particular importance in natural products synthesis. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

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. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

The condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

Compounds in which two donor atoms are linked by a three-carbon chain undergo C-C bond cleavage readily. Well-known reactions are the retro-aldolization, retro Claisen, retro-Michael, and retro-Mannich reactions. Significant application of such processes to synthesis of complex natural products include approaches to caryophyllene [80], nootkatone [81], trihydroxydecipiadiene [82], hybridalactone [83], and mesembrine [84],... 

The Mannich reaction is an important biosynthetic route to natural products, mainly alkaloids, and some of these routes have been duplicated in the laboratory. A classic example is the synthesis of tropinone (17) by Robinson in 1917. Robinson synthesized tropinone by a Mannich reaction involving succindialdehyde, methylamine, and acetone 183... 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

The first example of the application of the Mannich reaction to natural product synthesis is attributed to Robinson in his synthesis of tropinone R. Robinson, J. Chem. Soc. 1917, 762. 

Cyclic ketone with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Mannich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enoUtes such as that derived from ethyl acetoacetate. This starting material wias prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

Racemization of the Mannich ba.se may be caused by intrinsic instability " of the optically active final product, or it may occur during the synthesis or the optical resolution. The former case is fiequently observed in the preparation of cyclic derivatives of natural products and concerns Mannich reactions of different types, including the tandem aza-Cope-Mannich rearrangement, which affords more or less extensively ra-cemized products starting from optically active materials. -" -" - This finding is explained on the basis of the equilibrium involved in the 3,3-reanangement leading to ketones 201 (Fig. 72), key intermediates for the synthesis of alkaloids. 

The chemistry of Mannich bases is implied in important spontaneous reactions involving natural products such as the alkaloids,- where a Mannich-type condensation is a key reaction leading to the biogenesis of the final product, as well as in interesting synthetic methods adopted in the laboratory preparation of natural molecules or of structurally related models. The chemical modification of natural compounds and the synthesis of labeled derivatives for biological studies also constitute relevant applications connected with chemistry of Mannich bases. 

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