Improved Methodology for the Preparation of Chiral Amines

compound by the auxiliary. The auxiliary is later deattached from the final product. Despite
the breadth of functionality available from nature, limited examples are available in optically
pure form on a large scale. This means that incorporation of a “chiral pool” material into a
synthesis can result in a multistep sequence. However, with the recent advances in synthetic
methods which added new compounds to the chiral pool they are still limited.
Typically chiral pool material should be available on large scale in a reasonable price. One
example is L-aspartic acid, where the chiral material can be cheaper than the racemate. An
example of the application of chiral pool for synthesis of pharmaceutical drugs is the
synthesis of (S)-Vigabatrin, a potent GABA-T inhibitor from (R)-methionine by Knaus and
Wei in 96% yield and >98% ee as shown in scheme 1.5. [33]
S
COO
NH 3
1 S COOMe
NHCOOR 1
2 S
NHCOOR 1
COOR 2
a) R 1 =PhCH 2
b) R 1 =Me
3
a) R 1 =PhCH 2 ,R 2 =Et
b) R 1 =PhCH 2 ,R 2 =Me
c) R 1 =Me, R 2 =Et
d) R 1 =Me, R 2 =Me
NH 3
COO
5
O
N
H
4
O
N
H
SMe
1. i)MeOH/SOCl 2 . ii) NaHCO 3 /ClCO 2 R 1 . yield 82%-86%; 2. (R 2 O)P(O)CH 2 CO 2 R 2 /tBuLi/DiBAL-H,62-78% yield;
3. Mg/MeOH. 92-95% yield; 4. i) NaIO 4 . ii)190 °C. 56%yield; 5) KOH/iPrOH/H 2 O. 96% yield. 98% ee.
Scheme 1.5. Synthesis of (S)-vigabatrin from (R)-methionine, chiral pool approach.
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