Synthesis of N,N‘-Orthogonally Protected (S)-Piperazine-2-carboxylic Acid

Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent

“…Of note, no ring-fragmentation products were observed in these reactions, due to the presence of the sterically hindered N -alkyl group. The α-methylbenzyl in ( S , S )- 39 could be readily removed upon treatment with Pd/C and H 2 for further functionalization; Cbz protection and ester hydrolysis gave a known piperazine, confirming the configuration.…”

“…The cumyl group could be readily removed using transfer hydrogenolysis: reaction of ( S )- 28 with Pd­(OH) 2 /C and NH 4 + HCO 2 – gave the free amine (97% yield). Subsequent Cbz protection and ester hydrolysis then gave a known compound, and this allowed the absolute configuration to be confirmed (see Supporting Information). Thus, elucidation of a mechanism for piperazine ring-fragmentation highlighted a key role for the distal N -alkyl group.…”

α,β-Diamino Acids: Biological Significance and Synthetic Approaches

“…and to ensure a reasonable yield of α,β-diamino acid derivative. ,38b On the other hand, the group of Vederas has found that, when Mitsunobu conditions are applied to N -protected l -serine in the absence of an external nucleophile, ( S )-3-[( tert -butoxycarbonyl)amino]oxetan-2-one 183 is readily formed without epimerization . This enantiopure intermediate has been useful in the synthesis of natural β-amino alanines such as β-pyrazol-1-yl- l -alanine 151 and analogues of willardine,9b and in the synthesis of enantiopure 2-carboxypiperazine derivatives, such as a constrained Leu−enkephalin analogue . A key step in this synthesis was the one-pot opening of β-lactone 183 with secondary amine 184 followed by coupling of the resulting free acid with a dipeptide.…”

Synthetic Approaches to α,β‐Diamino Acids

“…However, a suitable combination of protecting groups at the acid, the a-nitrogen as well as the newly introduced b-nitrogen should be chosen to prevent undesired side-reactions such as b-elimination, aziridine formation, and so on, and to ensure a reasonable yield of the a,b-diamino acid derivative [75]. The synthesis of b-pyrazol-1-yl-L-alanine [ of willardine [77] as well as enantiopure 2-carboxypiperazine derivatives [78] have been addressed using Mitsunobu protocols. In contrast, the direct nucleophilic substitution on suitably protected b-tosyl serine [79] and threonine [80] derivatives or even on b-chloroalanine [81] is less documented.…”