Improved Methodology for the Preparation of Chiral Amines

4.1.16. Synthesis of Ritonavir and Lopinavir:
Ritonavir and lopinavir are HIV-protease inhibitors. Their synthesis depends on the synthesis
of chiral aminoalcohols. [11] Titanium isopropoxide with polymethylhydrosiloxane (hydride
source) and p-anisidine were utilized for the synthesis of aminoalcohols under reductive
amination conditions. Aliphatic, cyclic, as well as aromatic and heteroaromatic
hydroxyketones were tested showing good to high yields (76-89%) with good
stereoselectivities (de 72-86%).
R 1
OH O
R 2
NR 3 H 2
Ti(O i Pr) 4
PMHS
R 1
O
N
R 2
H + TiLn
OH NR 3 H
R 1
R 3
R 2
S
N
CH 3
N
O
H
N
O
Ph
NH
OH
Ph
H
N
O
O
S
N
HN
O
N
O
Ph
NH
OH
Ph
H
N
O
O
Ritonavir
Lopinavir
Scheme 4.16. Synthesis of Aminoalcohols the Core of Ritonavir and Lopinavir:
4.1.17. Synthesis of Tetrahydrocarbazoles:
Tetrahydrocarbazoles is an efficient compound for the treatment of human papillomaviruses
(HPVs). [12] HPV infection is considered the most common sexually transmitted disease
throughout the world. There are over 5.5 million new cases of sexually transmitted HPV in
the United States each year, with at least 20 million people currently infected. The chiral
centre in the molecule is the α-chiral amine in which its synthesis represents the key step in
the synthesis of this tetrahydrocarbazoles. In their initial attempts for building this chiral
moiety they tested chemical resolution. The best results were obtained utilizing dibenzoyl-Dtartaric
acid leading to 86% ee with only 13% yield. This low yield encouraged them to shift
to the asymmetric synthesis for building the chiral centre. Noyori catalyst was tested for the
95