A Trapped Intermediate in the Copper(II)-Mediated Template Synthesis of an Amino Acid-Containing Ligand

A transition metal ion-templating reaction that has been widely
exploited for the synthesis of nitrogen macrocycles,
sepulchrates, and linear tetradentate ligands is the template-directed
Mannich condensation of carbon acid and
aldehyde equivalents with amines. In the course of investigating
the copper(II) template-directed synthesis of
linear tetradentate amino acid-containing ligands for the design and
synthesis of double-strand DNA cleavage
agents, we have trapped and characterized an intermediate in the
templating reaction. Condensation of bis(phenylalaninato)copper(II) with formaldehyde and nitroethane
led to a nitro-substituent-bearing precursor complex
that upon reduction is crystallographically characterized as
((2S)-5-amino-2-benzyl-6-hydroxy-5-methyl-3-azahexanoate)copper(II) (space group
P212121, a
= 9.0066(5) Å, b = 11.1040(6) Å,
c = 16.009(2) Å, α = β =
γ = 90.0°, Z = 4, R1 =
0.0265, wR2 = 0.0612). NMR investigation
of the precursor complex and the precursor
and product ligands shows that the templated ligands each contain only
a single phenylalanine unit, not the two
phenylalanine units expected on the basis of similar synthetic
procedures. The structure of the reduced product
confirms this conclusion and provides structural characterization of a
template intermediate trapped during ligand
assembly.

一种被广泛应用于氮杂大环、穴状配体（sepulchrates）与线性四齿配体合成的过渡金属离子模板反应，乃是碳氢酸、醛类等价物与胺类之间的模板导向曼尼希缩合反应。本研究在针对双链DNA切割试剂的设计与合成，开展含氨基酸线性四齿配体的铜(II)模板导向合成研究过程中，捕获并表征了该模板反应中的一个中间体。双(苯丙氨酸根合)铜(II)与甲醛、硝基乙烷发生缩合反应，得到一种带有硝基取代基的前体配合物；该前体经还原后，产物经晶体学表征为((2S)-5-氨基-2-苄基-6-羟基-5-甲基-3-氮杂己酸根)合铜(II)，其空间群为P2₁2₁2₁，晶胞参数a=9.0066(5) Å，b=11.1040(6) Å，c=16.009(2) Å，α=β=γ=90.0°，Z=4，R1因子=0.0265，wR2因子=0.0612。对该前体配合物、前体配体与产物配体的核磁共振波谱（NMR）研究表明，经模板合成的配体仅各含一个苯丙氨酸单元，而非基于类似合成流程预期的两个苯丙氨酸单元。还原产物的晶体结构验证了上述结论，同时为配体组装过程中捕获的模板中间体提供了结构表征依据。