8-amino-5,6,7,8-tetrahydroquinolin

In 2007, Crawford et al. observed a spontaneous enzymatically mediated DKR of 8-amino-5,6,7,8-tetrahydroquinoline in the presence of Candida antarctica lipase B, in which a >60% yield of the expected enantiopure (R)-acetamide was isolated from the racemic amine. " The spontaneous formation of 5,6,7,8-tetrahydroquinolin-8-one as a side product, followed by a con-densation/hydrolysis sequence with the remaining (5)-8-amino-5,6,7,8-tetra-hydroquinoline via the corresponding enamine, provided the necessary racemisation pathway (Scheme 3.52). 

Crawford JB, Skerlj RT, Bridger GJ. Spontaneous enzymatically mediated dynamic kinetic resolution of 8-amino-5,6,7,8-tetrahydroquinoline. J. Org. Chem. 2007 72 669 71. 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

The ring closure of N-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)amino-methylenemalonate (705) by heating in polyphosphoric acid at 140°C for 30 min gave 1,7-phenanthrolinecarboxylate (706) in good yield [80JAP(K)69582],... 

The reaction between 1,1-diphenylethene and l-imino-l,2,3,4-tetrahy-droquinolinium ion, obtained by electrochemical oxidation of 1-amino-1,2,3,4-tetrahydroquinoline, furnished 3,3-diphenyl-l,2,3,7,8,9-hexahydro-pyrido[3,2,l-y]cinnoIine (66TL2583). 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

Treatment of 2-amino-3-cyano-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroquinoline 575 with CS2 and KOH in DMF led to the dithioxopyrimido[4,5- ]quinoline derivative 576 (Equation 45) <1994MI203>. The dioxopyri-... 

Fmoc-amino acids used as building blocks of testing compounds are as follows Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Met-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Ile-OH, Fmoc-His(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc)-OH, Fmoc-D-Ala-OH, Fmoc-D-Arg(Pmc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(OtBu)-OH, Fmoc-D-His(Trt)-OH, Fmoc-D-Gln(Trt)-OH, Fmoc-D-Leu-OH, Fmoc-D-Met-OH, Fmoc-D-Pro-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-D-Lys(Boc)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-D-Asn(Trt)-OH, Fmoc-3-(4-pyridyl)alanine, Fmoc-D-3-(3-pyridyl)alanine, Fmoc-4-tert-butoxyproline, Fmoc-3-chlorophenylalanine, Fmoc-norleucine, Fmoc-2-cyclohexylglycine, Fmoc-2-aminoisobutyric acid, Fmoc-tranexamic acid, Fmoc-(i ,S)-3-amino-3-(2-furyl)propionic acid, Fmoc-(i ,S)-(6,7-di-methoxy)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, Fmoc- (R, S)-3-amino-3-(4-hydroxyphenyl)propionic acid, Fmoc-(i ,S)-3-aminovaleric acid, Fmoc-(i ,5 )-3-amino-3-(3,4-dichlorophenyl)propionic acid, Fmoc-isonipecotic acid, Fmoc-(i ,S)-3-amino-3-(3,4-methylenedioxyphenyl)... 

Reaction of 4-amino-l,2,3,4-tetrahydroquinoline-8-carboxamide and 2H-chromene-3-carbaldehydes in MeOH in the presence of pTsOH H20 at room temperature for 20 min then heating for 2 h afforded racemic... 

Methoxy-2,3,4,4fl,5,6-hexahydro-lH-pyrazino[l,2-fl]quinoline was prepared by the cyclization of 8-methoxy-2-[(2-hydroxyethyl)amino-methyl]-l,2,3,4-tetrahydroquinoline, on the action of P205 in boiling xylene overnight (07MIP2). 

Figure 15.23 Tetrahydroquinoline-based p-amino acids synthesized by an asymmetric hetero-Michael approach.

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