Mannich reaction biosynthesis

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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. 

Mearsine (336) was isolated as a minor alkaloid of Peripentadenia mearsii [703]. Its structure was determined with elemental analysis of the crystalline picrate, MS, IR, UV, and 13C NMR, diacetylation of the NaBH4 reduction product, and X-ray crystallography [703,704]. The structure was confirmed by synthesis of (+)-336 from (-)-5-methyl-2-cyclohexenone via a Mannich reaction [705]. The structure of 336 suggested its biosynthesis was from acetate via a polyketide pathway [703]. 

For organic synthesis and biosynthesis the Mannich reaction (he most important multicomponent reaction. The Mannich reaction is an a-aminoalkylation (4) -i- (43) + HX <-> (40) -i- X + H2O -> (44) -I- H2O, where the anion X is a carbanion. Ugi was curious to find out whether or not a carbanionlike isocyanide is capable of undergoing a Mannich reaction , and the relevant experiments were conducted by his doctoral student Cornelius Steinbriickner. 

The simple basis for the biosynthesis of alkaloids in the plant cell is that a few common amino acids can be converted simply into reactive intermediates which may then condense spontaneously in variants of the Mannich reaction to yield, virtually at a stroke, the fully elaborated nuclei of the alkaloids. More detailed accounts of the biogenetic concept... 

The Mannich reaction (Scheme 1.8.5.6) involved in the biosynthesis of many alkaloids (e.g. tropane alkaloids, gramine) has been synthetically used in many elegant syntheses of alkaloids... 

Scheme 2.5. Mannich Reaction in the Biosynthesis of Lupine Alkaloids... 

Robert Robinson in 1917. More recently, modern biosynthetic work has provided a great deal of information about alkaloid biosynthesis and many alkaloids have been efficiently synthesized by routes that generally parallel those followed in nature. The case of the lupine alkaloids can be cited as one example of the role of the Mannich reaction in biosynthesis. Scheme 2.5 provides a rough outline of the biosynthesis of this alkaloid system from the amino acid lysine. 

Also, a large number of indole alkaloids are formed by Mannich reactions involving tryptophan or its decarboxylation product tryptamine with various aldehydes. Both the a- and p-position of the indole nucleus are electronegative, and a Mannich reaction with tryptamine can yield a p-carboline derivative or a 3,3-spiroindolenine [30]. A further example is provided by the tropinone biosynthesis (Figure 1.29) [31 ]. 

Figure 1.29 Examples of Mannich reactions, (a) Biosynthesis of alkaloids bearing the 1,2,3,4-tetrahydroisoqumoline ring, (h) biosynthesis of indole alkaloids (P-carboline, 3,3-spiroindolenine), and (c) tropinone biosynthesis.

Another well-known example is the biosynthesis ofatropine within the formation of the central skeleton tropinone. Using a twofold Mannich reaction, tropinone has been prepared in a single process [8] (Scheme 5). 

In this chapter we will focus on alkaloid total synthesis. We will start with several syntheses that rely on the addition of an iminium ion (or imine) to an enol (or enolate). This process is commonly refered to as the Mannich reaction. It is really the nitrogen counterpart of the aldol condensation. The Mannich reaction is important not only in the laboratory synthesis of many alkaloids, but also in the biosynthesis of many alkaloids. The fact that nature assembles alkaloids using this process is clearly what renders it useful in developing synthetic strategies for alkaloid synthesis. 

Porantherine is one member of a family of structurally (and presumably biosynthetically) related alkaloids shown here. One might imagine that a late step in the synthesis (or biosynthesis) of alkaloids 19-21 could also involve capture of an iminium ion by an appropriate nucleophile (to construct the bonds marked a ). Even porantherilidine (18) contains the 1,3-difiinctional relationship needed to develop a synthetic strategy that takes advantage of the Mannich reaction. 

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