Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr. These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation). Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.

We describe the total synthesis of (+)- and (-)-galbulimima alkaloid 13. The absolute stereochemistry of natural (-)-galbulimima alkaloid 13 is revised to 2S. Sequential use of catalytic cross-coupling and cross-metathesis reactions followed by an intramolecular Diels-Alder reaction provided the required trans-decalin AB-ring system and masked the C16 carbonyl as an N-vinyl carbamate for late-stage unveiling in the form of the necessary C16 enone. A vinyl radical cyclization secured the C-ring, while successful execution of our strategy for introduction of the CDE-ring system in complex galbulimima alkaloids provided the target pentacycle with complete diastereoselection.

We have developed a method for the rapid and unambiguous identification of sequences of hit compounds from one-bead-one-compound combinatorial libraries of peptide and peptoid ligands. The approach uses a cleavable linker that is hydrophilic to help reduce nonspecific binding to biological samples and allows for the attachment of a halogen tag, which greatly facilitates post-screening sequencing by tandem mass spectrometry (MS/MS). The linker is based on a tartaric acid unit, which, upon cleavage from resin, generates a C-terminal aldehyde. This aldehyde can then be derivatized with a bromine-containing amino-oxy compound that serves as an isotope tag for subsequent MS/MS analysis of y-ion fragments. We have applied this linker and method to the syntheses of a number of peptoids that vary in sequence and length and have also demonstrated single-bead sequencing of a peptoid pentamer. The linker is also shown to have very low levels of nonspecific binding to proteins.

We describe the first total synthesis of (−)-himandrine, a member of the class II galbulimima alkaloids. Noteworthy features of this chemistry include a diastereoselective Diels-Alder reaction in the rapid synthesis of the tricycle ABC-ring system in enantiomerically enriched form, the use of a formal [3+3] annulation strategy to secure the CDE-ring system with complete diastereoselection, and successful implementation of our biogenetically inspired oxidative spirocyclization of an advanced intermediate. The successful and direct late-stage formation of the F-ring in the hexacyclic movassag@mit.edu. Supporting Information Available: Experimental procedures, spectroscopic data, copies of 1 H and 13 C NMR spectra, and X-ray structure of (−)-1. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 July 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript core of himandrine drew on the power of biogenetic considerations and fully utilized the inherent chemistry of a plausible biosynthetic intermediate.The galbulimima alkaloid (−)-himandrine (1) is a topologically fascinating compound isolated from the bark of Galbulimima belgraveana, a tree indigenous to Papua New Guinea and northern Australia. 1 The promise that natural and synthetic derivatives of galbulimima alkaloids have shown for treatment of human ailments 2 has resulted in substantial attention in both academia and industry. We previously reported the first enantioselective total synthesis of (−)-galbulimima alkaloid 13 (class III) 3 and revised the absolute stereochemical assignment of the class II and III derivatives. 4 While there have been several outstanding syntheses of class I 5 and III 6 galbulimima alkaloids, no total synthesis of the class II 7 galbulimima alkaloids possessing the unique N-C9 spirofused polycyclic framework has been reported. Herein we describe our total synthesis of class II alkaloid 1 guided by our previously disclosed hypothesis for its biogenesis, 3b featuring a final stage oxidative spirocyclization to secure the BCF ring juncture.Inspired by Mander, Ritchie and Taylor's 1967 proposal relating all galbulimima alkaloids to a single polyacetate precursor, 1d and consistent with our specific hypothesis for the biogenesis of class II and III galbulimima alkaloids, 3b we identified aminoketoester 3 (Scheme 1) as a plausible point of divergence en route to more complex alkaloids. Our retrosynthetic analysis of (−)-1 follows this hypothesis, 3b in which the N-C9 bond is introduced by a late stage oxidative spirocyclization of the pentacyclic aminoketoester 3. We envisioned that oxidation of 3, potentially facilitated by dienol formation, would afford allylic alcohol 2, which is poised for the critical condensative spirocyclization. We expected that application of our annulation methodology 8 to enone 4 and iminium chloride 5 would convergently assemble a pentacycle primed for our...

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