Retro-Mannich

Finally, in the last step, the chelating auxiliary had to be removed Ideally, one would like to convert 4.54 into ketone 4.55 via a retro Mannich reaction. Unfortunately, repeated attempts to accomplish this failed. These attempts included refluxing in aqueous ethanol under acidic and basic conditions and refluxing in a 1 1 acetone - water mixture in the presence of excess paraformaldehyde under acidic conditions, in order to trap any liberated diamine. Tliese procedures were repeated under neutral conditions in the presence of copper(II)nitrate, but without success. 

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

Hydroxyprotoberberine 59a and ( )-corytencine (98) led to 13-acetoxy compounds 104,105, and 107 moreover, the 2,3,9,10,12-pentaoxy-genated protoberberine 108 was also obtained from 98 via the p-quinol acetate 106 through a retro-Mannich reaction followed by recyclization (74,75). Oxidation in dichloromethane instead of acetic acid proceeded differently, namely, 97 and 98 led to pentaoxygenated protoberberines 103 and 109 by introduction of an acetoxyl group at C-4 and C-12, respectively, via o-quinol acetates (76). 

More recently in 2001, Winkler and Kwak reported methodology designed to access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2], retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2] cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44 via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then effected a Mannich reaction, resulting in pyrrolidine 45. 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

The above assumption has been supported by in vitro transformation of 4,21-didehydrogeissoschizine (32) to 5,6-dihydroflavopereirine (3) (108). Treatment of 32 with base supplied dienamine 149, which loses the (3-aldehydo ester unit attached to C-15 in a retro-Mannich reaction. Finally, two subsequent [1,5]-sigmatropic hydrogen migrations led to 5,6-dihydroflavopereirine (3), isolated as the perchlorate salt. 

The intramolecular photochemistry of the vinylogous amide 173 in terf-butyl alcohol yielded a retro-Mannich type reaction product 174 (equation 114)170. 

The recognition of consonant bifunctional relationships in the target molecule allows their disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition [equivalent, according to Corey s formalisation, to the application of the corresponding transforms (= operators) to the appropriate retrons]. 

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

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],... 

Assembly of the indolazepine intermediate for synthesis of vincadifformine [92] encompasses a 1,2-rearrangement-retro Mannich-Mannich reaction sequence. Need-... 

Iminium salts (182) were starting materials in reactions with enamines (93CB133 94CB1437), which proceed by two different pathways with the formation of bicyclic ketones (183) and with the formation of substituted pyridines. The authors assume that the reaction takes place by a double electrophilic attack of the salt (182) in the /3-positions of the enamine and the resulting immonium cations undergo a retro-Mannich type of reaction with the opening of one of the piperidine rings. 

Hydrogenation of 4-formyl spiro-p-lactams like 180, Scheme 55, accessible from cyclic amino acids and chiral imines, resulted in the formation of bicyclic system like 181, which was reduced to piperazine 182 [139]. The reductive rearrangement leading to 181 proceeds in high yield and the scission of the C3-C4 bond is rationalized in terms of a retro-Mannich process. Unfortunately, however, isomerization occurs during rearrangement, leading to racemic products. 

Here again, loss of Y = H would result in rearomatization and formation of 12, but in the case of Y = Me, this cannot occur. However, assistance by the amine nitrogen lone pair can aid the rearomatization process, producing the copper-bound phenol product and an imininm salt. Hydrolysis during the workup procedure could release the 2-meth-ylphenol product and result in a retro-Mannich reaction to give the observed secondary amine (PY2) and formaldehyde. A small amount (<10%) of N—Me—PY2 is often observed as a byproduct and its yield is at the expense of the PY2 and formaldehyde thus, it appears to be derived from direct reduction of the intermediate iminium salt [167],... 

Scheme3.3. Retro-Diels-Alder [9], retro-aldol [10] and retro-Mannich reaction [11] of strained substrates.

Under certain circumstances, the conjugate addition and cycloaddition reaction pathways overlap for a,P-unsaturated electrophiles. For example, when the 2,5-dimethylpyrrole complex 22 is combined with 1 equiv of MVK in acetonitrile, a 1 1 ratio of the p-alkylated 3//-pyrrole complex 96 and the a-alkylated 2Z/-pyrrole complex 98 is isolated (Figure 18). When the reaction is monitored by H NMR in CD3CN, an intermediate 7-azabicyclo[2.2.1]heptene complex (97) is observed at early reaction times, and eventually converts (tm 1 h) to compound 98 via a retro-Mannich reaction followed by proton transfer. 

With Q = N, a similar fragmentation reaction is possible (retro-Mannich reaction), which leads to an imine or an iminium ion [57]. Fragmentations of this type have been frequently used for substrates of type A3 but can also be found for substrate class A2, A5, and A6 (vide infra). 

Furthermore, the vintage observation [32] of retro-Mannich reactivity of gramines has allowed the development of a new route to 3,4-disubstituted indoles, especially dihalogenated derivatives 52 —> 53 —> 54 (Scheme 18) [33]. In order to open the door to DoM reactivity studies in the benzo ring component of indoles, the 5-O-carbamate 56 has recently been systematically studied (Scheme 19) [34]. The absence or presence of 3-substitution, no matter what size, allows, respectively, 4- (55) and 6- (57) derivatization of indoles, including tryptophols and tryptamines [35]. 

Scheme 18. 3,4-Substituted indoles via DoM-retro Mannich sequence.

Spiropiperidine Alkaloids.—The spirocyclic keto-base (18), which possesses a histrionicotoxin skeleton, undergoes an acid-catalysed retro-Mannich reaction, followed by re-condensation, to afford the unsaturated imine (19), with a pumiliotoxin skeleton. A mechanism for the transformation has been proposed.29... 

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