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

3.1 – Oxazoline synthesis
3.1.1.a Hydroxyamides – alcohol activation
O
R
X
H 2 N
OH
O
R
H
N
OH
SOCl 2 , Na 2 CO 3
O N
Δ
R
c. 70%
116
Scheme 3.1 – unfunctionalised oxazolines via amides
Oxazolines are traditionally made by condensation of β-amino alcohol with carboxylic
acids or derivatives, before cyclisation by azeotropic reflux or treatment with excess
thionyl chloride (Scheme 3.2). 117
This method works well for generating oxazolines
without a C5 stereocentre, although significant amounts of the intermediate chloramide
is often isolated, diminishing the yield. A number of milder methods for activating the
amido alcohol have been developed, which are compatible with more sensitive
functional groups.
Ph
Ph
Ph
O
N
H
165a
Ph
O
N
H
166
OH
Ph
OH
Me
DIC 1 eq
Cu(OTf) 2 5%,
dioxane, Δ 6 hr
DIC 1 eq
Cu(OTf) 2 5%,
THF, μω 5 min
Ph
Ph
O
N
Ph
101a
O
Ph
110
N
Ph
Me
78%
> 95:5 dr
88%
> 95:5 dr
R
O
N
H
i-Pr
NH
O
N i-Pr
R
167
61-98%
16 examples
Scheme 3.2 – cyclisation of amides by the method of Linclau 118
Linclau recently developed a method using the coupling agent diisopropylcarbodiimide
(DIC) to promote displacement of the newly activated alcohol. 118
Catalytic copper
triflate is added to promote in situ formation of isoureas 167 and is shown not to affect
the cyclisation step which proceeds exclusively in an S N 2 manner for the examples
shown. This method is particularly appropriate since they make not only diphenyl
oxazoline 101a, but also the norephedrine-derived oxazoline 110 studied in the
previous chapter.
96