Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis : Novel ...

NITRONE REACTIONS 243
EtAlCl2, TiCl4, and ZnBr2) were used. The highest optical purity of hydroxylamines
(320) was obtained by using 0.5 equiv ZnBr2 and D-glucose diacetonide
(A9) (558).
Stereoselective synthesis of pseudo C2-symmetrical 1,3-dibenzyldiamino
alcohol (S,S) (323) a core unit of HIV protease inhibitors, and the two mesostereoisomers
(323a) and (323b) was achieved by stereocontrolled addition of
benzylmagnesium chloride to nitrones (63a) and (63b) (Scheme 2.137). The yield
of (S,S)-(323), based on N -Boc-L-phenylalaninal, accounts for 23% (Scheme
2.137) (211).
Sugar-derived nitrones are widely and effectively used as substrates in reactions
with Grignard reagents and as starting materials in the synthesis of many
biologically interesting compounds, including amino acids, amino alcohols, and
nucleoside analogs (2). The reactions of nitrones derived from sugars with
α-alkoxyalkyl (or β-alkoxy) groups, can be fully stereocontrolled by using appropriate
Lewis acids as pre-complexing agents. Examples of these reactions are
shown in Scheme 2.138, Table 2.10, and Fig. 2.23. They lead to β,γ-dialkoxyhydroxylamines
(324–326) which can be further transformed into syn- andanti-
3-amino-1,2-diols (327–329) andtoα-hydroxy-β-amino acid esters (330–332).
Stereocontrol of the nucleophilic additions requires ZnBr2 or Et2AlCl as precomplexing
agents (559–561).
A similar strategy was used in the synthesis of 1,4-diaminobutanediol derivatives
(335) starting from dinitrone (333) (Scheme 2.139) (562, 563).
Stereoselectivity of nucleophilic addition of Grignard reagents can be improved
by using trimethylsilyl trißate (207).
Table 2.10 Stereoselective additions of Grignard reagents to nitrone 292 a
Lewis Isolated
Entry RMgBr b Solvent acid c Hydroxylamine syn/anti d Yield (%) e Yield (%) f
1 PhMgBr THF none 324 80:20 84 67 (syn)
2 PhMgBr Et2O ZnBr2 324 90:10 86 77 (syn)
3 PhMgBr Et2O Et2AlCl 324 5:95 72 68 (anti)
4 MeMgBr THF none 325 76:24 81 62 (syn)
5 MeMgBr Et2O ZnBr2 325 91:9 82 75 (syn)
6 EtMgBr Et2O Et2AlCl 325 18:82 77 63 (anti)
7 EtMgBr THF none 326 75:25 74 56 (syn)
8 EtMgBr Et2O ZnBr2 326 78:22 72 56 (syn)
9 EtMgBr Et2O Et2AlCl 326 30:70 81 57 (anti)
a All reactions were carried out at −60 ◦ C for 6 h.
b 1.5 equiv. were used.
c 1.0 equiv. were used.
d Measured from the intensities of 1 H NMR signals.
e Determined on isolated mixture of diastereomers.
f After puriÞcation by column chromatography.