A Route to Carbasugar Analogues - Jonathan Clayden - The ...
A Route to Carbasugar Analogues - Jonathan Clayden - The ... A Route to Carbasugar Analogues - Jonathan Clayden - The ...
Chapter 4 – Synthesis of carbasugars Scheme 4.17 – crystal structure of allylic alcohol 213 Diol 213 is highly crystalline but inseparable from the syn-diol 287 by flash column chromatography. Whilst the majority could be isolated by recrystallisation, it could also be separated by the formation of the acetonide of the syn-diol, and subsequent chromatography. DIBAlH has also been used to effect the stereoselective 1,2-reduction of similar enones. 180 Unfortunately only 1,4-reduction was observed (288), with mainly starting material isolated from the reaction. Ox* Ox* DIBAlH, CH 2 Cl 2 OH -78 °C O O 276 288 OH 15% 40% conv Scheme 4.18 – DIBAlH reduction 4.2.5 Protecting group strategy It was anticipated that as the number of polar groups increased in the synthesis isolation and purification would become more difficult and protecting groups would be needed to mask some of the free alcohols. The protecting group would have to withstand strongly alkylating, moderately reducing and moderately acidic reaction conditions; it also should be removed without the need for aqueous workup. In light of these requirements, the benzyl ether protecting group is ideally suited, and there is significant precedent its use in sugar chemistry. 147
4.2 – Carbasugar synthesis Ox* Ox* NaH (4 eq), BnBr (5 eq) OH 213 OH Bu 4 NI (cat), DMF OBn 289 OBn 72% Scheme 4.19 – benzylation The benzylation conditions were adapted from those of Provelenghiou 184 using catalytic tetrabutylammonium iodide, generating benzyl iodide in situ, to assist functionalisation of the secondary alcohols. Dimethylformamide was chosen as solvent as it promotes the nucleophilicity of anionic species through solubilisation of the counter ion. 185 This yield was sufficient to continue the synthesis, however it might be improved by benzylation with benzyltrichloroacetimidate, developed by Bundle for use in sugar chemistry. 186 4.2.6 Oxidation of the allylic alcohol Allylic alcohol 213 is the point of divergence in this synthesis since two complementary stereoselective oxidations exist. 4.2.6.a Epoxidation In 1957 Henbest demonstrated that stereoselective epoxidation of allylic alcohols may be effected through association with the alcohol with an organic peracid. 187 A number of other stereoselective methods exist for the epoxidation of allylic alcohols, the most noteworthy being the seminal work by Sharpless and Katsuki; 188 an entirely reagentcontrolled method using (+) or (–) diethyl tartrate as the source of chirality. Whilst the original studies of Henbest were performed using peracids, these are not always the best reagents. An insightful study into the selectivity of such oxidations was recently authored by Adam 168 comparing both regio and chemo selectivity of different reagents with acyclic allylic alcohols, and making mechanistic inferences from the results. He divided oxidants into two broad groups; hydrogen bonding reagents (such as peracids) and metal-alcoholate binding reagents (typified by the vanadyl acetyl acetoacetonate, VO(acac) 2 system). Prior studies found these reagents to differ in their optimal reaction geometry, specifically the angle, α, between the 148
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Chapter 4 – Synthesis of carbasugars<br />
Scheme 4.17 – crystal structure of allylic alcohol 213<br />
Diol 213 is highly crystalline but inseparable from the syn-diol 287 by flash column<br />
chroma<strong>to</strong>graphy. Whilst the majority could be isolated by recrystallisation, it could<br />
also be separated by the formation of the ace<strong>to</strong>nide of the syn-diol, and subsequent<br />
chroma<strong>to</strong>graphy.<br />
DIBAlH has also been used <strong>to</strong> effect the stereoselective 1,2-reduction of similar<br />
enones. 180 Unfortunately only 1,4-reduction was observed (288), with mainly starting<br />
material isolated from the reaction.<br />
Ox*<br />
Ox*<br />
DIBAlH, CH 2 Cl 2<br />
OH<br />
-78 °C<br />
O<br />
O<br />
276 288<br />
OH<br />
15%<br />
40% conv<br />
Scheme 4.18 – DIBAlH reduction<br />
4.2.5 Protecting group strategy<br />
It was anticipated that as the number of polar groups increased in the synthesis<br />
isolation and purification would become more difficult and protecting groups would be<br />
needed <strong>to</strong> mask some of the free alcohols. <strong>The</strong> protecting group would have <strong>to</strong><br />
withstand strongly alkylating, moderately reducing and moderately acidic reaction<br />
conditions; it also should be removed without the need for aqueous workup. In light of<br />
these requirements, the benzyl ether protecting group is ideally suited, and there is<br />
significant precedent its use in sugar chemistry.<br />
147
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