Reduction of Aminals and Hemiaminals

As demonstrated with acetals and ketals, aminals are also readily reduced with silanes under acid catalysis. The Et3SiH/BF3 OEt2 combination reduces 

O-Aminomethyl lactones are reduced to amino acids with the Et3SiH/TFA combination (Eq. 321).528 

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TABLE 21. ORGANOSILANE REDUCTION OF AMINALS AND HEMIAMINALS (Continued)... 

Supplemental Reference for Table 21. Organosilane Reduction of Aminals and Hemiaminals... 

Several characterized NRPSs utilize alternative methods for chain termination. In some synthetases, the TE domain of the final module is replaced by an NAD(P)H-dependent reductase domain. Reduction of a peptidyl-S-PCP substrate through a two-electron reaction leads to the formation of a transient aldehyde, which is subsequently converted into a cyclic imine or hemiaminal through intramolecular cyclization. This two-electron reaction is utilized in the biosynthesis of nostocyclopeptides, the saframycins, ° and anthramycin. Alternatively, a four-electron reduction to the primary alcohol is observed in the biosynthesis of mycobacterial peptidolipids, linear gramicidin," " the myxalamides, lyngbyatoxin, " and myxochelin A 75,76 alternative four-electron reduction pathway involving aldehyde formation, transamination, and reduction to a primary amine occurs in the biosynthesis of myxochelin B. ... 

Reductive amination is historically defined as the combination of a Brpnsted acid, a ketone, an amine, and a coexisting reductant. The recent evolution of titanium (IV) alkoxides, as mild Lewis acid replacements for Brpnsted acids, owes its genesis to a clever modification of titanium amide chemistry demonstrated by Mattson et al. in 1990. By prestirring a ketone, amine, and Ti(OiPr)4 (neat), followed by the addition of EtOH and NaBH3CN, the desired reductive amination product was afforded (Scheme 8.8). The same authors suggested that these reductive aminations proceeded through a hemiaminal titanate intermediate, based on IR spectroscopy before addition of the reductant. 

The (reversible) transformation of an a-ketocarboxyhc acid in presence of ammonia and one equivalent of NAD(P)H furnishes the corresponding a-amino acid and is catalyzed by amino acid dehydrogenases [EC 1.4.1.X] [962]. Despite major differences in its mechanism, this reaction bears a strong resemblance to carbonyl group reduction and it formally respresents a reductive amination (Scheme 2.133). As deduced for L-Leu-dehydrogenase [963], the a-ketoacid substrate is positioned in the active site between two Lys-residues. Nucleophihc attack by NH3 leads to a hemiaminal intermediate, which eliminates H2O to form an iminium species. The latter is reduced by a hydride from nicotinamide forming the L-amino acid. Since this mechanism is highly tuned for a-keto/a-amino acids, it is clear that a neutral Schiff base cannot be accepted as substrate. 

Their reaction setup requires the conversion of aldehyde 122 and aromatic amine 123 into the imine prior to treatment with catalyst 99c (a phosphoric acid) and enecarbamate (and a final reduction of the hemiaminal intermediate 125). This three-component reaction can thus be classified as a sequential reaction. Notably, the authors also used aliphatic aldehydes successfully. Using substituted enecarbamates gave 1,2-disubstituted 1,3-diamines 126 with excellent anti-selectivity. They proposed a transition state in which the chiral phosphoric acid activates not only the imine as a Bronsted acid, but also the (i )-enecarbamate as Bronsted base, resulting in a pseudo-intramolecular Si-face attack to the imine [69]. 

Aggarwal and Bi proposed the synthesis of 8a-epi-swainsonine (222) from hemiaminal 218 which was prepared from the protected amine 217 in the aza-Achmatowicz reaction as shown in Scheme 42/ The heterocyclic derivative 218 was, under the acidic conditions, transformed into the acetal the carbonyl group was then reduced, under the Luche conditions, providing derivative 219 as practically single isomer. Reduction of the double bond with simultaneous removal of the Cbz group and cleavage of the N,0-acetal afforded piperidine 220 which was easily transformed, via 221, into 8a-epi-swainsonine 222. 

In 2006, Fukuyama and coworkers reported their independent synthesis of yatakemycin (150) [64]. The preparation of the left-hand fragment 165 started with dimethoxybenzene derivative 161. Dibromination of 161 in the presence of FeCls, removal of the TFA group, and oxidation provided a dihydroisoquinoline. Treatment with NsCl to form the hemiaminal, and reductive opening using NaBIl, gave cycUzatiOTi precursor 162. Amination using Cul to give the desired indoline. 

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