Improved Methodology for the Preparation of Chiral Amines

It is estimated that 3000 tonnes (after new expansion) of menthol are produced (in 94% ee)
by Takasago International Co., using Noyori's method every year. The key step was the
asymmetric isomerization of geranyldiethylamine, promoted by an (S)-BINAP-Rh complex
in THF and forming (R)-citronellal enamine, which upon hydrolysis gives (R)-citronellal in
96-99% ee. This enantiopurity is higher than naturally available product (ee 80%) obtained
from rose oil (scheme 1.8).
Li, (C 2 H 5 ) 2 NH
H R
Hs
myrcene
diethylgeranylamine
N(C 2 H 5 ) 2
[Rh(S)-BINAP] +
CHO
H 3 O +
Hs
H R
(R)-citronellal
ZnBr 2
N(C 2 H 5 ) 2
(R)-citronellal enamine 96-99% ee
OH
OH
H 2 ,Nicat
isopulegol
(-)-menthol
Scheme 1.8 Rhodium-BINAP in Synthesis of Menthol.
Noyori BINAP system was applied successfully in the synthesis of many important
pharmaceutical drugs as the anti-inflammatory drug, naproxen, in 97% ee from α-aryl-acrylic
acid. [38] and the antibacterial levofloxacin obtained from hydroxyacetone through asymmetric
hydrogenation of (R)-1,2-Propanediol. [39,40]
Third major breakthrough in the field of asymmetric synthesis was introduced by Barry
Sharpless. [41] He developed a highly enantioselective epoxidation of allylic alcohols. His
successful result was obtained by the use of a titanium-tartrate complex as the catalyst and
water in a ratio of 1:2:1. For the process to be catalytically useful only a slight modification
was required. Before catalyst formation 4 Å molecular sieves had to be added. The molecular
sieves act as a moisture scavenger and, therefore, control the amount of water present in the
reaction mixture. In addition, the formation of other, undesired titanium species which lead to
17