Stereoselective Synthesis of meso-2,6-Diaminopimelic Acid and Its Selectively Protected Derivatives

Four synthetic routes to selectively protected derivatives and isomers of meso -diaminopimelic acid (DAP) ( 1a ), a key constituent of bacterial peptidoglycan, were investigated. N -( tert -butyloxycarbonyl)- d -allylglycine ( 2 ) and N -(benzyloxycarbonyl)- l -allylglycine ( 4 ) were esterified to ethylene glycol and cyclized via olefin metathesis to a protected derivative 7 of 2,7-diaminosuberic acid. Analogous linking of propane-1,3-diol with 2 and potential precursors of N -(benzyloxycarbonyl)- l -vinylglycine moieties, such as N -(benzyloxycarbonyl)- l -glutamate or N -(benzyloxycarbonyl)- l -methionine sulfoxide, gave 12 or 15, both of which produced the α,β-unsaturated ester 14 upon attempted generation of the vinylglycine precursor for olefin metathesis to DAP derivatives. An alternative route, based on SnCl 4 -catalyzed ene reaction of methyl N -(benzyloxycarbonyl)- l -allylglycinate ( 18 ) with glyoxylate esters of phenylcyclohexanol isomers as chiral auxiliaries, gave ca. 85:15 ratios of diastereomeric alcohols ( 19 or 20 ). These could be transformed to DAP derivatives in a series of steps employing azide displacement of corresponding mesylates to introduce the second nitrogen. A third method, involving reduction of pure dimethyl ( 6S )-2-keto-6-[ N -(benzyloxycarbonyl)amino]pimelate ( 32 ) to the corresponding alcohol 33 with ( S )-binaphthol−ruthenium catalyst as the key step, gives a 79:21 isomeric ratio. The fourth route employs the bis(oxazoline)−copper complex 41 as a chiral catalyst for the ene reaction of methyl ( S )-4-(phenylthio)allylglycinate ( 39 ) and methyl glyoxylate to afford 42 in 94:6 isomeric ratio. Nickel boride removal of sulfur and the double bond in the presence of the Cbz group gives the desired alcohol, dimethyl (2 S,6 S )-6-[ N -(benzyloxycarbonyl)amino]-2-hydroxyheptane-1,7-dioate ( 33 ). The required selectively protected second nitrogen is introduced using Mitsunobu inversion with N - tert -butyl [[2-(trimethylsilyl)ethyl]sulfonyl]carbamate ( 34 ) as a key step.