Synthesis of the Leu - Trp Component of the Celogentin Family of Cyclic Peptides Through a C - H Activation - Cross-Coupling Strategy

Abstract

A bioinspired approach to the central leucine(C3)-tryptophan(C6) cross-linked moiety present in the celogentin family of cyclic peptide natural products was achieved. The key transformation was enabled through a palladium-catalyzed C-H activation-cross-coupling of leucine quinoline amide and 6-iodotryptophan derivatives. X-Ray crystallographic analysis of a β-(indol-6-yl)-leucine derivative confirms the stereochemistry of the cross-linked adduct matches that of the natural products. The method enables the preparation of the Leu-Trp adduct as a single stereoisomer from l-leucine and l-tryptophan.

A Guide to Directing Group Removal: 8‐Aminoquinoline

“…Not many examples exist of N ‐Boc activation and hydrolysis of simple aromatic AQ‐amides as acid/base hydrolysis or oxidative removal of the MQ directing group (Section 2.2) usually afford similar yields. The method's strength lies in its transformation of sterically hindered substrates such as ortho ‐substituted (hetero)aromatics ( 163 – 164 , Scheme 26) [52, 115] (though no examples have been found of ortho , ortho ‐substituted aromatic AQ‐amides) and alpha ‐substituted aliphatic AQ‐amides ( 167 – 174 ), [29, 116–124] though increased bulk around the amide bond decreases the efficiency of the N ‐Boc activation step which may require a large excess of Boc anhydride ( 165 – 167 ), high reaction temperatures ( 165 – 168 ) and long reaction times ( 169 – 171 , 174 ). Bulky alpha ‐phthaloyl groups are tolerated in some cases ( 169 – 171 ) but can require transformation to a smaller azide if a beta ‐substituent is also present ( 78 , 172 ).…”

Study on the synthesis of the cyclopenta[f]indole core of raputindole A

“…Regarding the investigation of 6-acryloylindoles, we aimed at the synthesis of methyl-branched di(indol-6-yl)pentenones from the beginning, which already included the second indole moiety of raputindole A ( 1 ). Boc protection of 6-iodoindole ( 2 ) [ 35 ], Sonogashira reaction of 3 with TMS-acetylene, and desilylation gave the N-protected alkynylindole 4 in excellent yield ( Scheme 2 ). Boc-iodoindole 3 was also the precursor of the coupling partner, ketone 6 , which was synthesized via Heck reaction with but-3-en-2-ol ( 5 , 89%) in the presence of LiCl, inspired by a procedure by Camp and coworkers [ 36 ].…”

Transition-Metal-Catalyzed Arylation of Unactivated C(sp3)—H Bonds Assisted by Bidentate Directing Groups

“…最 终 , 他 们 以 总 共 23 步 完 成 了 Celogentin C 的全合成. 同年, Hutton 等 [28] 采用相同的 策略, 完成了 Celogentin 家族中 Leu-Trp 片段的合成.…”

“…同时, 该课题组还对 8-氨基喹啉导向的环己基甲酰胺进行 β-C-H 键芳基化, 发现该反应活性较高, 以顺式双芳基取代产物为主 (Scheme 3b). 该研究为后续以环状烷烃为底物的 β-芳基 化反应 [29,30,14～16] 及合成应用 [27,28] 奠定了前期基础. 该反 应也存在一定的局限性, 例如反应温度较高, 且采用无 溶剂体系, 需要过量的芳基碘试剂, 一定程度上阻碍了 其合成应用.…”