Tetrahedron Letters
Synthesis of enantiopure b-amino amides via a practical reductive
amination of the corresponding b-keto amides
⇑
Dalila Mtat, Ridha Touati , Béchir Ben Hassine
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (UR11ES56), Faculté des Sciences de Monastir, Avenue de l’Environnement, 5019 Monastir, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2014
Revised 28 August 2014
Accepted 24 September 2014
Available online 2 October 2014
A convenient and efficient reductive amination for the preparation of chiral b-amino amides is developed
utilizing microwave heating. A variety of chiral b-keto amides react with ammonium acetate and sodium
cyanoborohydride to afford the desired functionalized amines in good yields. This improved procedure
takes advantage of microwave heating to significantly accelerate the reaction and offers a convenient
and effective method to access some interesting molecules containing primary amine functionalities.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
b-Keto esters
b-Keto amides
Reductive amination
b-Amino amides
Microwave
Amino- and amido-functionalized organic compounds are very
common in Nature. Their biological importance1 has led to exten-
sive studies of their structural and physicochemical properties.
In addition to their relevance in biochemistry and pharmaceuti-
cal chemistry, amines and amides are attractive building blocks in
supramolecular chemistry.2 Depending on the solution pH, amine-
based ligands can act as both cation and anion chelators.3
Amide-containing receptors also exhibit dual cation/anion
binding properties. They have emerged as attractive building
blocks for a variety of anion receptors due to their relatively strong
hydrogen bond donor N–H groups.3 In addition, they contain
oxygen and nitrogen heteroatoms that can coordinate with metal
ions.4
On the other hand, b-amino amide subunits are found in
numerous pharmaceuticals and are often found as constituents of
important building blocks of many natural products that express
potent biological activity.5
Prominent examples of amino amides have recently emerged,
underscoring their importance in medicinal chemistry.6 Among
them are saxagliptin and compounds 2a and 2b7 (Fig. 1). Further-
more, a series of b-amino amides bearing triazolopiperazines has
been prepared and evaluated as potent, selective, orally active
dipeptidyl peptidase IV (DPP-4) inhibitors for the treatment of type
Bestatin (3) is a prototypical member of a growing family of
peptidyl -hydroxy-b-amino amide natural products isolated from
a
bacterial cultures that demonstrate potent inhibition of aminopep-
tidases and prolyl endopeptidases.9
Due to their roles in various key industries, useful synthetic
approaches have been reported10 for the synthesis of this class of
compounds. Most have involved coupling of tetrahydrotriazolo-
pyrazine with b-amino acids,11 acylation of amines with (3R)-
N-Boc-b-amino acids using a coupling reagent such as TsCl with
N-methylimidazole,6b or acid-catalysed hydrolysis of the resulting
F
F
O
NH2
H
O
NH2
N
H
N
N
N
H
CO2H
. H3PO4
N
F
H
H
OH
CF3
1 JanuviaTM (sitagliptin phosphate)
3 bestatin
OH
F
X
NH
O
F
NC
N
H
O
H
NH2
H
H
N
2
diabetes, with Januvia™ (sitagliptin phosphate) (1) as an
H2N
example)6a,8 (Fig. 1).
H
H
F
2a X= CO; 2b X= SO2
4 saxagliptin (BMS477778)
⇑
Corresponding author. Tel./fax: +216 73 682 190.
Figure 1. Representative examples of biologically active
derivatives.
a- and b-amino amide
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.