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

Chapter 3 – Oxazoline synthesis & removal
Hydrolysis of oxazolidine 222 was considerably slower than Meyers’ oxazolines,
which are reported hydrolyse in 15 to 20 hours. Comparative hydrolysis of recovered
oxazolidine and a crude mixture confirmed that the slow reaction rate was not due to
thermodynamic resolution of the possible diastereomers. Treatment of enol ether 102b
proceeded in a similar manner, although significant amounts of hydrolysis was
observed during the alkylation, and the ratio was the same whether bench or dry
methanol were used. Interestingly the hydrolysis of the mixed oxazolidines took
considerably longer than of 222 alone (vide infra).
Ph
O
N
Ph
MeOTf
15 hr
then NaBH 4
Ph
O
Ph
NMe
+
Ph
O
Ph
NMe
i) (CO 2 H) 2 , rt 10 d
THF/H 2 O
ii) NaBH 4 , MeOH
HO
OMe
102b
O
224
OH
222
OH
225
55%
Crude ratio
224 : 222
3 : 2
Scheme 3.35 – alkylation-hydrolysis of enol ether 102b
Alkylation of the oxazoline is reported by Meyers to proceed within 1-4 hours by TLC
analysis, however in these studies complete conversion of starting material to baseline
salts was never observed and reaction times are often longer than necessary. Later
experiments indicate that alkylation was complete within 2-3 hours. Whilst the
neopentyl aldehydes were stable to chromatography and for weeks under atmospheric
conditions, they were unstable to purification by acid resin (SCX) with rapid
decomposition observed. The oxazolidines were largely stable to chromatography,
although it was observed that purification of this intermediate reduced the overall yield
of auxiliary removal.
During the synthesis of carbasugars (section 4.2.7), oxazolidine 226 was also found to
hydrolyse very slowly (Table 3.12).
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