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ABSTRACT 
 
 
 
Biomimetic Synthesis of Chiral Cyanogenic Glycosides 
 
 
 
 
Anthony Dookieram 
 
A mixture of α- and β- glycosides of 2,3,4,6-tetra-O-benzyl-α,β-D-
glucopyranosylmandelonitrile 19.1 was successfully synthesized from 2,3,4,6-
tetra-O-benzyl-1-O-1,3,2-dioxaphosphacyclohexane-α,β-D-glucopyranosyl-2-
oxide 16.6 and O-(trimethylsilyl)mandelonitrile 18.3 in 73% yield, where the 
O-(trimethylsilyl)mandelonitrile 18.3 was synthesized by Kobayashi’s17 
procedure from benzaldehyde 18.1 and trimethylsilyl cyanide 18.2. 
 
 
Having synthesized a mixture of α- and β- cyanogenic glycoside 19.1 
we were then successful in synthesizing R-2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosylmandelonitrile 21.5, a chiral cyanogenic glycoside from 
2,3,4,6-tetra-O-acetyl-1-O-1,3,2-dioxaphosphacyclohexane-α,β-D-
glucopyranosyl-2-oxide 21.3 and the chiral cyanohydrin, mandelonitrile 21.4 
in a yield of 72%.  
 
 
The use of 1,3-diylphosphate activation of the glucose ring for the 
glycosylation reaction allowing the desired β-glycoside where the acetyl 
protecting group is used, provides an alternative means for the synthesis of 
these cyanogenic glycosides. 
 
 
Having successfully synthesized a chiral cyanogenic mono-glycoside 
the synthesis of a cyanogenic di-glycoside, amygdalin 24.6 was next 
envisioned. Acetyl 2,3,4-tri-O-benzyl-β-D-glucopyranoside-(1→6)-2,3,4,6-
tetra-O-acetyl-β-D-glucopyranoside 23.3 was synthesized from acetyl 2,3,4-
tri-O-benzyl-β-D-glucopyranoside 23.2 and 2,3,4,6-tetra-O-acetyl-1-O-1,3,2-
dioxaphosphacyclohexane-β-D-glucopyranosyl-2-oxide 21.3 in 53% yield. 
The synthesis of this protected gentiobiose disaccharide 23.3 will ultimately 
lead to the synthesis of amygdalin 24.6. 
 
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A chiral cyanogenic di-glycoside, R-2,3,4,6-tetra-O-acetyl-β-D-
galactopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl-
mandelonitrile 24.5, was also synthesized from its precursor sugar, 2,3,4,6-
tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-2,3,6-tri-O-acetyl-1-O-1,3,2-
dioxaphosphacyclohexane-β-D-glucopyranoside 24.4, in an overall yield of 
41%. The use of 1,3-diylphosphate activation of the lactose ring for the 
glycosylation reaction allowing the desired β-di-glycoside was also utilized in 
this synthesis.  
 
 
Future work involves the completion of the synthesis of amygdalin 
(Scheme 24) and the synthesis of a chiral catalyst that would enable the 
synthesis of a wide variety of chiral cyanohydrins resulting in the synthesis of 
different chiral cyanogenic glycosides. The catalyst that would be chosen is 
the Jacobsen’s22 catalyst 25.3 which is synthesized from 2-isothiocyanato-3,3-
N-trimethyl-butyramide 25.1 and N,N-diisopropyl-cyclohexane-1,2-diamine 
25.2.  
 
Keywords: Chiral cyanohydrin; Mandelonitrile; 1,3-diylphosphate activation 
of the glucose ring; Amygdalin; Jacobsen’s catalyst.