Studies directed toward strategies for construction of neodolastane diterpenes have culminated in the total synthesis of trichoaurantianolides C and D. This account describes the most challenging aspects of the proposed lines of inquiry, and unanticipated results, encountered in the pursuit of these ideas. Methodology development defined new knowledge of reactivity and stereoselectivity for advancements in organic synthesis. Efforts explore issues of stereocontrol in the formation of highly substituted cycloheptane ring systems. Regioselective oxidation reactions are also described. Several cyclization processes are examined in the course of the study.
The hexadehydro Diels–Alder (HDDA) reaction has recently emerged as a powerful tool for aryne formation, thereby giving access to highly functionalized aromatic skeletons. In this chapter, we describe an HDDA-based approach to the total synthesis of selaginpulvilins C and D, which relies on generation of an aryne intermediate in situ. The isolation, structural elucidation and biological activities of selaginpulvilins as well as other related alkynyl phenols are discussed, and various synthetic approaches to total synthesis of these natural products are reviewed.
The highly potent anticancer natural products, the Amaryllidaceae isocarbostyril alkaloids, have been a desirable target for total synthesis over the past few decades. However, while many elegant approaches have been reported previously, scalable access to these important medicinal compounds has remained unrealized. Here, we describe our efforts toward these antineoplastic agents in detail, including failed routes and how we overcame them. The brevity and scalability of our synthesis was due to the development of the nickel-catalyzed asymmetric dearomative carboamination reaction, allowing for olefin difunctionalization reactions to install the contiguous stereocenters of the cyclitol core. Upon completion of our synthesis, we synthesized a series of analogs, some of which displayed equipotent activity and increased aqueous solubility, a major inhibitor of these alkaloids' preclinical evaluation. We then synthesized isotopologs of the natural products to identify the potential sites of metabolism, leading to increased stability over the parent compounds. With this synthetic blueprint, we hope to enable the preclinical evaluation of these important cytotoxic natural products.
The first total synthesis of (±)-gelsenicine is described. The strategy centers on a pivotal metal-catalyzed cycloisomerization–Cope rearrangement sequence to construct the central core of the Gelsemium alkaloid. The study provided a stimulating forum for analyzing the cycloisomerization reaction in detail, where we uncovered many subtle effects related to the substrates and catalytic conditions that guided our optimization. Ultimately, we were able to forge the core architecture of the molecule in good yield through this complexity-building transformation, which enabled a highly streamlined synthesis of the natural product. This chapter will highlight our cycloisomerization studies and how they influenced the evolution of our methods-focused strategy toward gelsenicine.
The first stereoselective synthesis of the dimeric naphthoquinonopyrano-γ-lactone (−)-crisamicin A is described (13 steps, 5% overall yield). 1,4,5-Trimethoxynaphthalene, reached in five known steps, was brominated at C3. This allowed for appending a trans-configured CH=CH–CH2–CO2R side-chain (R = Me, Bn, t-Bu) by Heck couplings. An asymmetric Sharpless dihydroxylation followed. It gave a β-hydroxy-γ-lactone (R = Me or Bn disappearing) or a β,γ-dihydroxyester (R = t-Bu staying), both with >99.9% ee. Either compound underwent an oxa-Pictet–Spengler reaction (“cyclization”) with acetaldehyde and BF3-etherate; in parallel, the tert-butylester lactonized. This established the trisubstituted dihydropyran ring with perfect diastereoselectivity. The “monomer” thus obtained was subjected to a dimerization unprecedented in natural product synthesis: It combined a meta-selective C–H borylation under Ir-catalysis and an autoxidative coupling of the resulting boronate under Pd-catalysis in tandem. The emerging bi(naphthohydroquinonyl) was advanced to totally synthetic crisamicin A by double quinone formation and double ether cleavage.
This chapter is a personal account on the Murelli laboratory's inspiration and efforts on the synthesis of highly oxygenated troponoids, and the advances in oxidopyrylium [5 + 2] cycloaddition chemistry that have resulted from these studies. As part of this discussion, this chapter also provides a minireview describing the history of oxidopyrylium [5 + 2] cycloaddition routes to troponoids more generally.
The tetrapetalones were pursued for well over a decade by numerous research groups. Herein, we detail our motivations and findings, which we imagine are very different from the many others who tackled this extremely challenging problem. In this chapter, we explain how our many failures caused us to revise our strategy eight times. Although we failed to reach the genuine natural product, we hope the reader will conclude that we nevertheless developed several valuable methods and that we gained important strategic insights from our trials and tribulations. At the very least, we can emphatically state that we developed a great appreciation of the wonderful ways in which our chemistry community is interconnected, and the great benefit we all enjoy from one another's achievements.
The chemoenzymatic dihydroxylation of arenes by microbial organisms represents a unique reaction found in nature. The reaction is highly stereo-, regio-, and enantioselective and yields versatile metabolites that have been exploited in the synthesis of countless natural products and useful homochiral building blocks. This chapter provides a brief history of the discovery and development of the microbial diol metabolites, their synthetic utility, and evolving applications in total synthesis. An extensive table is included to depict the many natural products and related synthetic targets attained through syntheses starting from cis-dihydrocatechols. The authors hope to highlight the utility of these chiral synthons in the assembly of natural products and to demonstrate the importance of incorporating biological methods into enantioselective synthesis.
An approach for the syntheses of herqulines B and C is reported that takes advantage of an l-tyrosine-derived diketopiperazine, a mycocyclosin analogue, as a synthetic precursor. The strategy relies on a series of consecutive reductions to adjust the mycocyclosin oxidation state to that observed in the herquline class of natural products. The strained and distorted l-tyrosine-based biaryl system characteristic for mycocyclosin is selectively converted to the 1,4-diketone structural motif common to the herqulines via initial hypervalent iodine-mediated dearomatization and a subsequent directed Birch reduction, enabled by an intramolecular H-source. Additionally, the piperazine oxidation state is accessible via an iron-catalyzed reduction of a diketopiperazine intermediate.
This chapter describes the development of novel trithiols for use as bifunctional chelators for no-carrier-added arsenic radioisotopes. A model trithiol (2-ethyl-2-(mercaptomethyl)propane) was synthesized with thiocyanate protecting groups, and the radioarsenic chemistry was developed. Conversion of the model trithiol into a bifunctional trithiol chelator that was amenable to peptide or antibody conjugation proved to be challenging. The first analogue involved using Cu(II)-mediated click chemistry to add a carboxylic acid moiety for peptide conjugation resulted in a very lipophilic radioarsenic bioconjugate. Synthesis of a hydrophilic trithiol conjugate involved redesign of the synthetic scheme, including changing the starting material (isophthalic acid rather than 1,1,1-tris(hydroxymethyl)propane), the thiol protecting groups (trityl rather than thiocyanate), and the leaving groups (bromide rather than tosyl) utilized.
Enantioselective total syntheses of the prenylated indole alkaloids, (−)-α-cyclopiazonic acid and (+)-iso-α-cyclopiazonic, have been achieved in nine steps (longest linear sequence, 13 steps in total). The molecules were assembled using a combination of three key methodologies: (1) an asymmetric aziridination of an activated imine with a chiral sulfur ylide; (2) a bioinspired intramolecular aziridine-alkene formal cycloaddition; and (3) an unprecedented carbonylation/N–O bond reduction cascade to install the challenging tetramic acid. A key lesson learned was that new technologies can enable routes previously discarded as nonviable, with the final synthesis much further from the original proposal in time than in design.
Cephalotane-type diterpenoids represent an important type of natural products among the metabolites of the Cephalotaxaceae family, which are intriguing due to their complex molecular architecture, significant bioactivities, as well as the potential correlation of mutual structural interconversions. Herein, the first synthetic work on the total syntheses of two members of the cephalotane-type diterpenoids, cephanolides B and C, is described in detail. Central to our synthetic route was a palladium-catalyzed cascade cyclization reaction, which allowed us to rapidly and efficiently obtain copious amounts of the 6-5-6 cis-fused tricyclic ring system found in the entire family of Cephalotaxus diterpenoids. Meanwhile, it also represented a novel synthetic methodology for the construction of complex architectures contained in natural products. Additionally, a programmed site-selective late-stage sp3 C–H bond oxidation not only provided a shortcut to access cephanolide C but also further demonstrated the efficiency and utility of our divergent synthetic strategy.
In this chapter, we discuss the original inspiration of a target-oriented total synthesis for a supply problem. Lasonolide A is a marine antitumor polyketide featuring two stereochemically rich tetrahydropyran rings and two polyene linkages. Prior to our synthetic work, five total syntheses and several synthetic studies had been released with innovative approaches. Based on method development on hydroboration–allylation and iterative hydroboration–oxidation of an α-allenic alcohol in this laboratory, we devised a streamlined, highly convergent synthesis of lasonolide A. This synthetic route aims to provide a practical solution to the derivatization of target molecules for future drug development.
Astellatol is a synthetically highly challenging sesterterpenoid that possesses a congested pentacyclic ring system, which contains 10 stereocenters, a unique bicyclo[4.1.1]octane motif, a cyclobutane moiety that possesses two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif. Herein, we describe the full account of our synthesis of astellatol, including two generations of synthetic design and corresponding experimental attempts. The key transformations of our synthetic strategy include a facile construction of 5/7-bicyclic motif, an intramolecular Pauson–Khand reaction that quickly constructed the hydrindane scaffold, a SmI2-induced reductive radical 1,6-addition that successfully forged the cyclobutane ring, and a key strategic late-stage reduction of a fully substituted olefin that produced the critical trans-hydrindane moiety of astellatol.
The putative common precursor to siphonarin B, baconipyrone A, baconipyrone C, and caloundrin B was prepared by an enantioselective total synthesis featuring our thiopyran route to polypropionates strategy. In the presence of imidazole, the precursor undergoes ring–chain tautomerism to afford siphonarin B that, upon treatment with alumina in hot ethanol, rearranges to baconipyrone A and baconipyrone C via a retro-Claisen reaction. The presence of caloundrin B was not detected in these (or many other) isomerization experiments. Caloundrin B was prepared by a total synthesis featuring a novel aldol coupling of enantiopure and racemic fragments and rearranges to siphonarin B in the presence of imidazole. Consequently, caloundrin B cannot be an isolation artifact and must be considered a plausible biosynthetic product from which the in vitro formation of siphonarin B, baconipyrone A, baconipyrone C can be readily explained.
