Sommer Konrad, Williams Robert M
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523.
Tetrahedron. 2009 Apr 18;65(16):3246-3260. doi: 10.1016/j.tet.2008.08.102.
The stereocontrolled, asymmetric synthesis of triply deuterium-labeled 7-hydroxy-pre-paraherquamide (27) was accomplished, employing a diastereoselective intramolecular S(N)2' cyclization strategy. The deuterium-labeled substrate was interrogated in a precursor incorporation experiment in the paraherquamide-producing organism Penicillium fellutanum. The isolated sample of paraherquamide A revealed incorporation of one of the two geminal deuterons of the CD(2)-group at C-12 exclusively. The lack of signals for the second deuteron of the CD(2)-group at C-12 and for the CH(2)D-group (C-22/C-23) suggests that this substrate suffered an unexpectedly selective catabolic degradation and metabolic re-incorporation of deuterium thus casting doubt on the proposed biosynthetic intermediacy of 27. Consideration of alternative biosynthetic pathways, including oxidation of the indole C-6 position prior to hydroxylation at C-7 or oxidative spiro-contraction of pre-paraherquamide prior to construction of the dioxepin is discussed. The synthesis of 27 also provides for a concise, asymmetric stereocontrolled synthesis of an advanced intermediate that will be potentially useful in the synthesis of paraherquamide E & F.
采用非对映选择性分子内S(N)2'环化策略，完成了三重氘标记的7-羟基前对羟基赫曲霉素（27）的立体控制不对称合成。在产生对羟基赫曲霉素的真菌费氏青霉的前体掺入实验中，对氘标记的底物进行了研究。分离得到的对羟基赫曲霉素A样品显示，仅在C-12处掺入了CD(2)-基团的两个偕二氘中的一个。C-12处CD(2)-基团的第二个氘以及CH(2)D-基团（C-22/C-23）缺乏信号，这表明该底物经历了意外的选择性分解代谢降解和氘的代谢重新掺入，因此对所提出的27的生物合成中间体产生了怀疑。讨论了替代生物合成途径，包括在C-7羟基化之前吲哚C-6位的氧化或在二氧杂环庚烷构建之前前对羟基赫曲霉素的氧化螺环收缩。27的合成还提供了一种简洁的、不对称立体控制的高级中间体合成方法，该中间体可能在对羟基赫曲霉素E和F的合成中有用。
