Synthesis of α-ω-Diamino Acids: An Efficient Preparation of DL-Homolysine and Protected Derivatives

Prior literature contains ample low-yield, multi-step precedents for the preparation of DL-homolysine (2,7-diaminoheptanoic acid). In a modified Albertson and Archer acetamidomalonic ester synthesis,1 diethyl acetamidomalonate was alkylated, in the presence of sodium ethoxide, with 5-benzamido-1-chloropentane,2 itself prepared from N-benzoylpiperidine and PCl5 as described by Harris and Work,3 or from dihydropyran via 5-hydroxyvaleraldehyde4 as described by Wada.5 These multi-step methods have limited synthetic utility, due to low yields of electrophile preparation and of carbon-carbon bond formation, leading to an overall 10% yield of DL-homolysine. Takagi and Hayashi6 explored several approaches to D,L-homolysine. One of these involved a modification of the malonic ester synthesis where ethyl 5-bromocaporate was prepared from cyclohexanone7 and used to alkylate diethyl malonate, giving DL-homolysine, after two steps, in 1396 overall yield. In a second approach, Takagi and Hayashi performed end group transformations on a C-8 backbone, suberic acid, using a Schmidt reaction to prepare DL-homolysine, in 1196 yield after eight steps. More recently Kirret8 improved this method, through the use of a Hunsdiecker reaction, reducing the number of steps to six, giving DL-homolysine in 18% yield. These methods failed to meet our synthetic objectives of greater than 50% yield in a minimum number steps.