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

Abstract

A new method for the synthesis of enantiopure α-substituted piperazines via direct functionalization of the intact piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an α-methylbenzyl-functionalized N-Boc piperazine using s-BuLi/(-)-sparteine or (+)-sparteine surrogate and provides access to a range of piperazines (as single stereoisomers). Optimization of the new methodology required a detailed mechanistic study. Surprisingly, it was found that the main culprits affecting the yield and enantioselectivity were the electrophile (the last reagent to be added to the reaction flask) and the distal N-substituent. The mechanistic studies included optimization of lithiation times using in situ IR spectroscopy, identification of a ring-fragmentation of the lithiated piperazines (that could be minimized with sterically hindered N-alkyl groups), and use of a novel "diamine switch" strategy to improve enantioselectivity with certain electrophiles. The methodology was showcased with the preparation of an intermediate for Indinavir synthesis and the stereoselective synthesis of 2,5-trans- and 2,6-trans-piperazines.

General Procedures for the Lithiation/Trapping of N-Boc Piperazines

“…Since we were unsuccessful in our attempts to cleave the N-tert-butyl group we focused mostly on cumyl protected piperazine 16 as it can be removed by hydrogenolysis. 13 Silylated, stannylated and methylated piperazines 18a, 18b and 18c were isolated in 98%, 80% and 95% yield respectively. Transmetallation to copper followed by trapping with allyl bromide 15a,17 gave α-allyl piperazine 18d in 80% yield.…”

“…Initial in situ IR studies with the previously reported 14, piperazine 12 showed that diamine-free lithiation was much slower than with N-Boc-N'-benzyl piperazine 1. 13 Upon addition of s-BuLi to 12 in THF at -78 °C (ν C=O 1694 cm -1 ), lithiation proceeded to give lithiated intermediate 13 (ν C=O 1645 cm -1 ). However, after 2 h the reaction was incomplete (Scheme 6).…”

A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

“…It is well known that the presence of proline in peptide chain is crucial for protein structural and dynamic properties; thence, cyclic amino acids attract increasing attention in medicinal chemistry, and thus, structurally variable six‐membered‐ring heterocyclic amino acids have been introduced as building blocks for the preparation of bioactive compounds . Thus, intensive research efforts have been dedicated to their preparation, particularly pipecolic acid 1 , piperazine‐2‐carboxylic acid 2 , morpholine‐3‐carboxylic acid 3 , and thiomorpholine‐3‐carboxylic acid 4 . Additionally, these cyclic amino acids have also been used as precursors for the preparation of more complex scaffolds exhibiting pharmacological activities or acting as organocatalysts .…”

Synthesis of N‐alkyl‐N′‐aryl or Alkenylpiperazines: A Copper‐Catalyzed C–N Cross‐Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

“…Several piperazine‐containing drugs are within the top 100 best‐selling pharmaceutical products. The high value of the piperazine motif is reflected in the myriad strategies for its construction, the majority of which involve stepwise synthesis . These studies are very well recapitulated in a review written by Dai .…”