Improved Methodology for the Preparation of Chiral Amines

Another methodology for the synthesis of N-Boc-(R)-3-amino-2,3,4,5-tetrahydro-1 H-
[1]benzazepin-2-one, which is an important intermediate for the preparation of an angiotensin
converting enzyme inhibitor, based on asymmetric acyclic enamide hydrogenation has been
reported by Merck (scheme 1.13). [75]
N
H
O
NHBoc
3.4 bar H 2
(S)-BINAP RuCl 2
80% yield
N
H O
82% ee
NHBoc
Scheme 1.13. Merck Based Methodology for Enamide Hydrogenation.
Zhang worked extensively on the enantioselective reduction of N-acetyl enamides. Various
types of chiral ligands were tested with rhodium catalysts showing extremely high
enantioselectivities for aryl-alkyl, benzocyclic and ortho substituted aryl ketones using
acceptable catalyst loading (0.1-1 mol %) (figure 1.8). [76]
P
P
P
P
(R,R)-Binaphane
(R,S,R,S)-MePennPhos
OCH 3
H 3 CO Ph
H 3 CO PPh 2
H 3 CO PPh 2
H 3 CO Ph
OCH 3
Ph 2 P
H
H
PPh 2
(R,R)-BICP
PPh 2
O
O
PPh 2
Phosphine-Phosphoramide ligand
P
R
N R= Et or Me
R
(S)-o-Ph-hexMeO-BIPHEP
Figure 1.8. Chiral Ligands Used by Zhang in Enamide Reduction.
Rhodium catalyst proved to be the catalyst of choice for N-acetyl enamide hydrogenation the
following table summarizes the latest findings in this field (table 1.1). [77]
26