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In-Depth Information
CO
2
H
CO
2
H
CO
2
H
neutral Al
2
O
3
I
2
2
BocHN
S
S
-
I
+
H
3
N
NHBoc
NH
3
+
I
-
S
S
600 rpm, 30 min.
6 balls, 10 mm O
solvent-free
HS
NHR
HO
2
C
HO
2
C
(
R
,
R
)-Boc-
1
, 96%
(
R
)-
1
(
R
,
R
)-
1
, 100%
R = Boc
R = H
Scheme 6.4
Solid-state oxidation to organo-disulfides.
6.2.3 Asymmetric Synthesis of Amino Acids
Ball milling was also successfully applied to the preparation of amino acid
derivatives in their chiral form, which remains an ongoing challenge for
organic chemists.
20
For example, the metal-free aminohalogenation
21,22
of
electron-deficient olefins was described from cinnamate (R
2
¼
OMe) and
cinnamide (R
2
¼
NEt
2
) 12, promoted by (diacetoxyiodo)benzene [PhI(OAc)
2
],
with high regio- and diastereo-selectivity (Scheme 6.5).
Commercially available and inexpensive chloramine-T trihydrate
(TsNClNa
3H
2
O) or tosylamide/N-bromosuccinimide (TsNH
2
/NBS)
23
system
were used as nitrogen and halogen sources, respectively. Although the re-
action mechanism is not yet known, it was proposed that the oxidation of
chloro- 13 or bromo-derivative 14 by PhI(OAc)
2
led to a similar intermediate
N-acetoxy-N-halogen-p-toluenesulfonamide B, via intermediate A after
releasing iodobenzene. The electrophilic attack of B on a,b-unsaturated
enones 12 afforded the highly reactive aziridinium intermediate C that
underwent fast ring opening via S
N
2 attack of the more electrophilic
b-position by the in situ formed nearby halogen anion. High regio- and
diastereoselectivity (up to anti/syn499 : 1) characterized the formation of
intermediate D-(
), which reacted with the suitable halogeno-derivative (13
or 14) to afford the final product, regenerating the intermediate B. The
mechanism involving the formation of a bridged halogenium ion inter-
mediate (instead of aziridinium) was excluded because a reversed regio-
stereoselectivity would have been observed (dominant formation of the
syn-diastereoisomer).
Chiral amino esters were also prepared by an asymmetric alkylation
reaction starting from the Schiff base of glycine in the presence of chiral
ammonium phase-transfer catalyst
(PTC) 20 under basic conditions
24
(Scheme 6.6).
The transamination reaction between benzophenone imine (17) and
stoichiometric quantities of glycine tert-butyl ester hydrochloride (18) led to
Schiff base 19 in nearly quantitative yield (and up to two-gram scale), after
washing the milling powder with water to eliminate ammonium chloride
salt. The reaction time was shorter compared to the synthesis in solution
(overnight) and no chlorinated solvent was needed. For the enantioselective
reaction, the first step was a solid-state deprotonation occurring at the
interface of the Schiff base and KOH - performed best among the various
bases explored with M
2
CO
3
or MOH (M
¼
Na, K, Cs) - and leading to a
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