Mannich-type synthesis

Figure 10. Mannich type synthesis of glutathione conjugates of arylamlnes.

SCHEME 13.2 A one step Mannich-type synthesis is nsed to prepare Salan ligand precursors. 

Macrolides, synthesis of 632 Mannich-type reactions 641 Mass spectrometry... 

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]. 

Moedritzer, K. and Irani, R.R., The direct synthesis of a-aminomethylphos-phonic acids. Mannich-type reactions with orthophosphorous acid, /. Org. Chem., 31, 1603, 1966. 

Zirconium enolates of various carbonyl compounds have also been investigated for Mannich-type reactions with different electrophiles. According to Shibasaki s method,148 the coupling reaction between a 3-acetoxy-4-alkyl-/3-lactam and the in r(/ -generated zirconium enolate 96 of a cyclohexanone derivative was realized as a key step during the total synthesis of an anitibiotic (Scheme 42).117,149... 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

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. 

S. Kobayashi, T. Busujima, S. Nagayama, Ln(OTf)3- or Cu(OTf)2-Catalyzed Mannich-Type Readions of Aldehydes, Amines, and Silyl Enolates in Micellar Systems. Facile Synthesis of (5-Amino Ketones and Esters in Water Synlett. 1999,545-546. 

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

Mannich reactions, or a close 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 mode of biosynthesis, i.e., biogenetic-type synthesis. The earliest example of the use of the Mannich reaction in this way was the successful synthesis of tropinone, a derivative of the alkaloid tropine, by Sir Robert Robinson in 1917. 

The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

Bischler-Napieralski reactions, 4, 279 carboline synthesis from, 4, 516 Mannich-type reactions, 4, 279 sulfur isosteres, biological activity, 4, 913 synthesis, 4, 337, 913 Tryptophan biosynthesis, 1, 264 carboline synthesis from, 4, 516 molecular structure, 4, 162 Tryptophan hydroxylase in serotonin biosynthesis, 1, 261 Tryptophan oxygenase... 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

An intramolecular Mannich-type cyclization of l,3-dimethyl-6-(2-aminophenylthio)uracil (120) has been utilized for the synthesis of 5, 6-dihydropyrimido[4,5-b][ 1,5]benzothiazepine-2,4( 1H,3//)-diones (121) this synthesis was realized by reaction of 120 with an excess of formaldehyde, benzaldehyde, or p-nitro- or p-methoxybenzaldehyde in chloroform in the presence of a catalytic amount of p-toluenesulfonic acid under reflux for 4-10 hours. The thiazepine cyclization using aliphatic aldehydes other than formaldehyde did not give satisfactory results. In these cases the reaction resulted in the formation of a dimeric product that probably... 

In another study by Dondoni et al. [17] the synthesis of C-glycosyl-/ -aminoesters as single diastereomers is achieved via a Mannich-type three-component reaction of /Minked C-galactosyl or C-ribosyl formaldehyde, p-methoxybenzyl amine and ketene silyl acetals using catalytic amounts of InCfi (Scheme 9.8). 

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-... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

A more general and highly diastereoselective Mannich-type reaction was developed by Ohshima and Shibasaki. The tartrate-derived diammonium salt 43c possessing 4-fluorophenyl substituents was identified as an optimal catalyst for the reaction of 28 with various N-Boc imines under solid (Cs2CC>3)-liquid (fluoroben-zene) phase-transfer conditions, as exemplified in Scheme 4.24 [64]. The usefulness of the Mannich adduct 67b was further demonstrated by the straightforward synthesis of the optically pure tripeptide 68. 

---