Late-stage benzenoid-to-troponoid skeletal modification of the cephalotanes exemplified by the total synthesis of harringtonolide.

Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners - representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner-Curtius-Schlotterbeck reaction of a p-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.

Remote C-H Amination and Alkylation of Camphor at C8 through Hydrogen-Atom Abstraction.

Camphor continues to serve as a versatile chiral building block for chemical synthesis. We have developed a novel method to functionalize the camphor skeleton at C8 using an intramolecular hydrogen atom abstraction. The key advance involves the use of a camphor-derived aminonitrile, which is converted to the corresponding nitrogen-centered radical under photoredox conditions to effect the 1,5-hydrogen atom transfer at C8. The resulting carbon-centered radical at C8 was utilized in a C-H amination to access topologically complex proline derivatives. Furthermore, the total synthesis of several sesquiterpenoids was accomplished by engaging the radical generated at C8 in alkylation reactions.

Development of a nitrogen-bound hydrophobic auxiliary: application to solid/hydrophobic-tag relay synthesis of calpinactam.

In the last couple of decades, technologies and strategies for peptide synthesis have advanced rapidly. Although solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS) have contributed significantly to the development of the field, there have been remaining challenges for C-terminal modifications of peptide compounds in SPPS and LPPS. Orthogonal to the current standard approach that relies on installation of a carrier molecule at the C-terminus of amino acids, we developed a new hydrophobic-tag carbonate reagent which facilitated robust preparation of nitrogen-tag-supported peptide compounds. This auxiliary was easily installed on a variety of amino acids including oligopeptides that have a broad range of noncanonical residues, allowing simple purification of the products by crystallization and filtration. We demonstrated a de novo solid/hydrophobic-tag relay synthesis (STRS) strategy using the nitrogen-bound auxiliary for total synthesis of calpinactam.

Chemical Degradation-Inspired Total Synthesis of the Antibiotic Macrodiolide, Luminamicin.

This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol ß-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.

Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides.

Detailed herein are our synthetic studies toward the preparation of the C18- and C19-benzenoid cephalotane-type norditerpenoids. Guided by chemical network analysis, the core structure of this natural product family was constructed in a concise manner using an iterative cross-coupling, followed by a formal inverse-electron-demand [4 + 2] cycloaddition. Initial efforts to functionalize an alkene group in the [4 + 2] cycloadduct using a Mukaiyama hydration and a subsequent olefination led to the complete C18-carbon framework. While effective, this approach proved lengthy and prompted the development of a direct alkene difunctionalization that relies on borocupration to advance the cycloadduct to the natural products. Late-stage peripheral C-H functionalization facilitated access to all of the known cephanolides in 6-10 steps as well as five recently isolated ceforalides in 8-13 steps.

Strategy Evolution in a Skeletal Remodeling and C-H Functionalization-Based Synthesis of the Longiborneol Sesquiterpenoids.

Detailed herein are our synthesis studies of longiborneol and related natural products. Our overarching goals of utilizing a "camphor first" strategy enabled by skeletal remodeling of carvone, and late-stage diversification using C-H functionalizations, led to divergent syntheses of the target natural products. Our initial approach proposed a lithiate addition to unite two fragments followed by a Conia-ene or Pd-mediated cycloalkylation reaction sequence to install the seven-membered ring emblematic of the longibornane core. This approach was unsuccessful and evolved into a revised plan that employed a Wittig coupling and a radical cyclization to establish the core. A reductive radical cyclization, which was explored first, led to a synthesis of copaborneol, a structural isomer of longiborneol. Alternatively, a metal-hydride hydrogen atom transfer-initiated cyclization was effective for a synthesis of longiborneol. Late-stage C-H functionalization of the longibornane core led to a number of hydroxylated longiborneol congeners. The need for significant optimization of the strategies that were employed as well as the methods for C-H functionalization to implement these strategies highlights the ongoing challenges in applying these powerful reactions. Nevertheless, the reported approach enables functionalization of every natural product-relevant C-H bond in the longibornane skeleton.

Total synthesis of nine longiborneol sesquiterpenoids using a functionalized camphor strategy.

Natural product total synthesis inspires the development of synthesis strategies to access important classes of molecules. In the 1960s, Corey and coworkers demonstrated a visionary preparation of the terpenoid longifolene, using 'strategic bond analysis' to craft a synthesis route. This approach proposes that efficient synthesis routes to bridged, polycyclic structures should be formulated to introduce the bulk of the target's topological complexity at a late stage. Subsequently, similar strategies have proved general for the syntheses of a wide variety of bridged, polycyclic molecules. Here, we demonstrate that an orthogonal strategy where topological complexity is introduced at the outset leads to the short synthesis of the longifolene-related terpenoid longiborneol. To implement this strategy, we access a bicyclo[2.2.1] starting material through scaffold remodelling of readily available (S)-carvone. We also employ a variety of late-stage C-H functionalization tactics in divergent syntheses of many longiborneol congeners. Our strategy may prove effective for the preparation of other topologically complex natural products that contain the bicyclo[2.2.1] framework.

Discoveries and Syntheses of Highly Potent Antimalarial Troponoids.

Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.

Total Syntheses and Chemical Biology Studies of Hymeglusin and Fusarilactone A, Novel Circumventors of ß-Lactam Drug Resistance in Methicillin-Resistant Staphylococcus aureus.

Hymeglusin, a previously known eukaryotic hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitor, was identified as circumventing the ß-lactam drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). We describe the concise total syntheses of a series of natural products, which enabled determination of the absolute configuration of fusarilactone A and provided structure-activity relationship information. Based on previous reports, we speculated that the target protein of this circumventing effect may be MRSA bacterial HMG-CoA synthase (mvaS). We found that this enzyme was dose-dependently inhibited by hymeglusin. Furthermore, overexpression of the MRSA mvaS gene and site-directed mutagenesis studies suggested its binding site and the mechanism of action.

Total Synthesis of the Cephalotaxus Norditerpenoids (±)-Cephanolides A-D.

Concise syntheses of the Cephalotaxus norditerpenoids cephanolides A-D (8-14 steps from commercial material) using a common late-stage synthetic intermediate are described. The success of our approach rested on an early decision to apply chemical network analysis to identify the strategic bonds that needed to be forged, as well as the efficient construction of the carbon framework through iterative Csp2-Csp3 cross-coupling, followed by an intramolecular inverse-demand Diels-Alder cycloaddition. Strategic late-stage oxidations facilitated access to all congeners of the benzenoid cephanolides isolated to date.

Synthesis and Evaluation of Antibacterial Activity of Bottromycins.

Total synthesis of bottromycin A2 can be accomplished through a diastereoselective Mannich reaction of a chiral sulfinamide, mercury-mediated intermolecular amidination, and cyclization of a constrained tetracyclic peptide. Exploitation of this process allowed the synthesis of several novel bottromycin analogs. The antimicrobial activity of these analogs was evaluated in vitro against Gram-positive bacteria, such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE). Structure-activity relationships were explored taking into consideration the unique three-dimensional structure of the compounds. Notably, one of the new analogs devoid of a methyl ester, which is known to lower the in vivo efficacy of bottromycin, exhibited antibacterial bioactivity comparable to that of vancomycin.

Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and structure-activity relationship studies.

Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.

A concise total synthesis of puberulic acid, a potent antimalarial agent.

Efficient and practical total synthesis of puberulic acid has been accomplished via 8 steps, with 54% overall yield, and only two C-C bond formations, without the introduction of oxygen atoms into the core skeleton. Construction of the tropolone framework as the key transformation was achieved by multi-tandem oxidation of the aliphatic-triol, from D-(+)-galactose as the starting material.