Organic Chemistry of Drug Synthesis. Volume 7

establishment of the chiral locus that will dictate the remaining asymmetric
centers. Oxazolidone ( 20 ), derived from valine serves as the chiral auxili-
ary for that step. Condensation of the mixed-anhydride ( 19 ) from pipero-
nalacetic acid, with the anion from auxiliary 20 , give the corresponding
amide ( 21 ). Treatment of this intermediate with strong base followed by
tert-butyl bromoacetate leads to the alkylation product 22 as virtually a
single isomer. The auxiliary heterocycle is then removed by means of
lithium hydroperoxide to afford the half ester ( 23 ). Reaction of 23 with
diborane selectively reduces the free acid to give the esteralcohol ( 24 ).
The hydroxyl group is then activated by conversion to its tosylate ( 25 ).
Treatment of that intermediate with anisyl hydroxylamine ( 26 ) in the pre-
sence of cesium carbonate affords theO-alkylated derivative 27. The ester
grouping is then exchanged with methylorthoformate to afford the methyl
ester ( 28 ). Reaction of this last intermediate with trimethylsilyl triflate and
butylamine in the presence of 1,2-dichloroethane presumably forms an
anion-like species on the carbon adjacent to the ester. This then adds
internally to the oxime carbon atom to yield a 1,2-oxazine. This product
( 29 ) predominates over the diastereomer in a 9 : 1 ratio.

O

O OCOtBu

19

+HN O

O

20

O

O N O

O O

21

O Br CO

2 tBu

O

O N O

O O

tBuO 2 C

22

O

O OH

O

23

LiOOH

CO 2 tBu

BH 3

O

O

24

CO 2 tBu

OH

BuLi

NaHMDS

O

O

CO 2 tBu

OSO 2 C 6 H 4 CH 3

25

OCH 3

Cs 2 CO (^3) HON
CO 2 CH 3
O
O
CO 2 R
OCH 3
ON
26
2728 ; R = ; R = CHtBU
3
Cl Cl
TMSOTf
ONH
O
O
OCH 3
29
Catalytic hydrogenation of 29 over palladium on charcoal results in
scission of the weak N 22 O bond and formation of aminoalcohol 30.
This compound is converted to a pyrrolidine by an internal alkylation
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