A Route to Carbasugar Analogues - Jonathan Clayden - The ...

Chapter 4 – Synthesis of carbasugars
4.4.1 Route A
Route A is the same as the first synthesis but excludes the two protecting groups steps.
Intermediate 213 had been previously synthesised in 64% in three steps from the
anisole derivative.
Entry Conditions
Ox*
OH
213
OH
OsO 4 , conditions
no
reaction
a CH 2 Cl 2, NMO.H 2 O nr
b t-BuOH/H 2 O, NMO nr
c
quinuclidine,
K 3 Fe(CN) 6 , K 2 CO 3
nr
Table 4.5 – dihydroxylation of allylic alcohol (route A)
Surprisingly, no reaction was seen for this dihydroxylation under a range of conditions.
No reaction had occurred after 4 weeks under the Poli conditions (entry a, Table 4.5),
whilst standard Upjohn conditions failed, as did the modified AD conditions of
Warren, 176 the racemic dihydroxylation, RD (entry c). In light of the close precedent
in the previous synthesis this is especially disappointing, however the remaining routes
are both one step shorter than route A.
4.4.2 Route B or C: a model dihydroxylation
Routes B and C involve the same number of synthetic steps, but differ in the execution
of the key dihydroxylation step. In the previous synthesis it was assumed that the
matched “Kishi” stereoelectronics and the encumbrance afforded by the axial
oxazoline were responsible for the high diastereoselectivity. However this was not
tested, and is only now important since two different routes are being considered.
Whilst it may seem clear that route B would afford greater stereoselectivity, it is also
possible that the internal amine will complex osmium, shutting down the catalytic
cycle; dihydroxylation in route C would not face this problem.
In a model study, the dihydroxylation of allylic alcohol 225 was undertaken, also
serving to assign the relative stereochemistry of C4 (Scheme 4.37). As expected, the
anti-diol was favoured by Kishi selectivity (vide supra), however the selectivity was
significantly worse than in the previous synthesis, when it was matched by the
encumbrance of the oxazoline. In light of this, it seemed likely that route C would
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