Improved Methodology for the Preparation of Chiral Amines

3.3.2. Reductive Amination Utilizing Chiral Auxiliary.
Ellman was the first to introduce the use of t-butylsulfinylamide as a chiral auxiliary for the
asymmetric reductive amination (Scheme 3.13). [47] The imine was generated in situ with
Ti(OEt) 4 at 60-70 °C which was then reduced with NaBH 4 at -48 °C. Ti(OEt) 4 serves as a
desiccant, facilitates imine formation and even helps to improve the yield and
diastereoselectivity of the t-butylsulfinyl protected-amines. He demonstrated that his
methodology is applicable for both aryl-alkyl and alkyl-alkyl ketones in 66-86% yield and
80-94% de. Deprotection step is carried out under acidic conditions to obtain the primary
amine without any compromise in the yield or ee. In his attempt to broaden the scope of the
reaction he tested L-Selectride as a hydride donor under similar conditions. The opposite
enantiomer of the primary amine was obtained. The aliphatic ketone substrates gave similar
yield and de of the protected amine but benzocyclic ketones showed an improved de with
similar yields. [48]
O
S NH2
O
R 1 R 2
NaBH 4
THF
-48 °C
O R 1
S N R 2
O R 1
S NH R 2
Ti(OEt) 4
THF
L-Selectride
O
R 1
S NH R 2
THF
-48 °C
Scheme 3.13. Reductive Amination of Ketones using tert-butylsulfinylamide as Auxiliary.
Pannecoucke used the chiral auxiliary developed by Ellman for the reductive amination of α-
fluoro α,β-unsaturated ketones. He reported mediocre to good yields (46-86%) and high des
(96-99%) for aryl, aliphatic and sterically aliphatic substrates. The imine was prepared in situ
through combining Ti(OEt) 4 (2.0 equiv), (S)- tert-butylsulfinylamine (2.0 equiv), and 2-
fluoroenone (1.0 equiv) in dry THF under argon and heated to reflux for 2 h. The mixture
was allowed to cool to room temperature and then cooled to -78 °C. DIBAL-H (1M in
toluene, 4.0 equiv) was then added dropwise, and the mixture was stirred for 1 h and the
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