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

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

clor2.ch.man.ac.uk
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04.11.2014 Views

Chapter 3 – Oxazoline synthesis & removal Ph Ph AD mix α, Me 2 SO 2 NH 2 t-BuOH/H 2 O, 0 °C 2 d O Ph Ph CDI, CH 2 Cl 2 O O HO OH rt 16 hr 98% Ph Ph 176 177 100% NaN 3 , DMF Ph Ph H 2 , Pd/C Ph Ph 110 °C 2 d HO 178 N 3 HCl/EtOH HO 174 NH 2 82% (2 steps) >99:1 e.r. Scheme 3.10 – modified Sharpless synthesis of amino alcohol 174 Aziridine 173 was made from the products of this synthesis either by intramolecular Mitsunobu reaction of amino alcohol 174, or treatment of azide 178 with triphenylphosphine. 64 phosphazide. Ph HO 178 Ph N 3 The latter reaction presumably proceeding via a Staudinger-type PPh 3 , Et 2 O rt 2 hr HN Ph 173 Ph 64% (from carbonate) Ph HO 174 Ph NH 2 Ph PPh 3 , DIAD HN Et 3 N, THF Ph rt 18 hr 92% 173 Scheme 3.11 – aziridine synthesis The asymmetric synthesis of amino alcohol 175 is not trivial since most obvious intermediates such as cis-stilbene oxide, 179, are meso. It should be possible to invert the alcoholic centre of 174 by Mitsunobu reaction after deactivating the amine as the carbamate, by the method of Lipshutz. 127 However this is presently deemed unnecessary since the racemic amino alcohol can be quickly synthesised (Table 3.1). 101

3.1 – Oxazoline synthesis mCPBA O NH 4 OH, MeOH Ph Ph Ph Ph CH 2 Cl 2 Ph Ph Conditions 90% 179 HO NH 2 ± 175 Entry NH 4 OH:MeOH Temp / °C Time 175 (SM) / % a 1:1 100 Δ 24 hr 55 (25) b 3:1 120 µω 2 min 15 (85) c 3:1 140 µω 20 min 93 (5) Table 3.1 – synthesis of racemic amino alcohol The improvement seen under microwave conditions is believed to be due to the use of a sealed vessel increasing the partial pressure of ammonia, but is also assisted by a particularly easy isolation which only requires filtration of the cool reaction mixture. The synthesis of ±175 would be made particularly atom efficient if an oxidant such as dimethyldioxirane or hydrogen peroxide were used for the epoxidation. 128 3.1.4 Oxazoline synthesis The availability of only two of the three amines in near optical purity meant that the amide and aziridine methods (Scheme 3.9) are the remaining viable routes to the synthesis of enantiomerically pure diphenyl oxazolines. It is important to note that the amine syntheses above allow either enantiomer to be synthesised. The third method is still presented below, since it allows the synthesis of racemic diphenyl oxazoline as well as most of the other oxazolines studied in the previous chapter. 102

Chapter 3 – Oxazoline synthesis & removal<br />

Ph<br />

Ph<br />

AD mix α, Me 2 SO 2 NH 2<br />

t-BuOH/H 2 O, 0 °C 2 d<br />

O<br />

Ph Ph CDI, CH 2 Cl 2<br />

O O<br />

HO OH rt 16 hr<br />

98%<br />

Ph Ph<br />

176 177 100%<br />

NaN 3 , DMF<br />

Ph<br />

Ph<br />

H 2 , Pd/C<br />

Ph<br />

Ph<br />

110 °C 2 d<br />

HO<br />

178<br />

N 3<br />

HCl/EtOH<br />

HO<br />

174<br />

NH 2<br />

82% (2 steps)<br />

>99:1 e.r.<br />

Scheme 3.10 – modified Sharpless synthesis of amino alcohol 174<br />

Aziridine 173 was made from the products of this synthesis either by intramolecular<br />

Mitsunobu reaction of amino alcohol 174, or treatment of azide 178 with<br />

triphenylphosphine. 64<br />

phosphazide.<br />

Ph<br />

HO<br />

178<br />

Ph<br />

N 3<br />

<strong>The</strong> latter reaction presumably proceeding via a Staudinger-type<br />

PPh 3 , Et 2 O<br />

rt 2 hr<br />

HN<br />

Ph<br />

173<br />

Ph<br />

64%<br />

(from carbonate)<br />

Ph<br />

HO<br />

174<br />

Ph<br />

NH 2<br />

Ph<br />

PPh 3 , DIAD<br />

HN<br />

Et 3 N, THF<br />

Ph<br />

rt 18 hr 92%<br />

173<br />

Scheme 3.11 – aziridine synthesis<br />

<strong>The</strong> asymmetric synthesis of amino alcohol 175 is not trivial since most obvious<br />

intermediates such as cis-stilbene oxide, 179, are meso. It should be possible <strong>to</strong> invert<br />

the alcoholic centre of 174 by Mitsunobu reaction after deactivating the amine as the<br />

carbamate, by the method of Lipshutz. 127 However this is presently deemed<br />

unnecessary since the racemic amino alcohol can be quickly synthesised (Table 3.1).<br />

101

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