Guapsidial A and Guadials B and C: Three New Meroterpenoids with Unusual Skeletons from the Leaves of Psidium guajava

A novel sesquiterpene‐based Psidium meroterpenoid, possessing an unusual coupling pattern, and two new monoterpene‐based meroterpenoids with unprecedented skeletons were isolated from the leaves of Psidium guajava. Their structures and absolute configurations were elucidated by spectroscopic, X‐ray diffraction, and computational methods. The plausible biosynthetic pathway of these meroterpenoids as well as their cytotoxicities toward HepG2 and HepG2/ADM cells were also discussed.     

Enantioselective Total Synthesis of Terreumols A and C from the Mushroom Tricholoma terreum

The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring‐closing metathesis to form a trisubstituted Z double bond embedded in the 10‐membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (?)‐Terreumol C was converted into (?)‐terreumol A by diastereoselective epoxidation. Starting from 2‐bromo‐3,5‐dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (?)‐terreumol A. X‐ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration.     

Omaezallene from Red Alga Laurencia sp.: Structure Elucidation,Total Synthesis,and Antifouling Activity

Natural antifouling products have been the subject of considerable attention. We screened marine algae for antifouling activity and discovered omaezallenes, the new bromoallene‐containing natural products isolated from the red alga Laurencia sp. Described is the isolation, structure elucidation, and total syntheses of omaezallenes. The relative and absolute configurations of natural omaezallenes were unambiguously established through total synthesis. The antifouling activities and ecotoxicity of omaezallenes were also evaluated.     

Total Synthesis of Astellatol

A nearly‐30‐year‐old unanswered synthetic puzzle, astellatol, has been solved in an enantiospecific manner. The highly congested pentacyclic skeleton of this rare sesterterpenoid, which possesses a unique bicyclo[4.1.1]octane motif, ten stereocenters, a cyclobutane that contains two quaternary centers, an exo‐methylene group, and a sterically encumbered isopropyl trans‐hydrindane motif, makes astellatol arguably one of the most challenging targets for sesterterpenoid synthesis. An intramolecular Pauson–Khand reaction was exploited to construct the right‐hand side scaffold of this sesterterpenoid. An unprecedented reductive radical 1,6‐addition, mediated by SmI₂, forged the cyclobutane motif. Last, a strategic oxidation/reduction step provided not only the decisive solution for the remarkably challenging late‐stage transformations, but also a highly valuable unravelling of the notorious issue of trans‐hydrindane synthesis. Importantly, the synthesis of astellatol showcases a rapid, scalable strategy to access diverse complex isopropyl trans‐hydrindane sesterterpenoids.     

Asymmetric Total Synthesis of Oxazolomycins B and C

Efforts towards the first total synthesis of (−)-oxazolomycin B and (+)-oxazolomycin C from the intermediate of our previous synthesis of (+)-neoxazolomycin are reported. The syntheses were achieved in a longest linear sequence of 25 steps from the amino acid serine in 3.6 and 2.7 % overall yields, respectively. The efficiency of our approach is derived from silyl triflate-mediated reductive oxazolidine ring-opening and Fürstner's Ru-catalyzed hydrosilylation and protodesilylation reactions. The obtained spectra and optical rotations were in good agreement with those of natural products, thus confirming the structures.     

Total Synthesis of Carthamin,a Traditional Natural Red Pigment

The first total synthesis of carthamin ( 3 ), a historic natural red pigment, has been achieved. The molecular structure was efficiently constructed by assembling two equivalents of the in situ generated lithiated monomers and triisopropyl orthoformate. This synthesis confirms the structure proposed in 1996.     

Total Synthesis of Anti-MRSA Active Diorcinols and Analogues

Diorcinols and related prenylated diaryl ethers were reported to exhibit activity against methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA). Within these lines, we report the first total synthesis of diorcinol D, I, J, the proposed structure of verticilatin and recently isolated antibacterial diaryl ether by using an efficient and highly divergent synthetic strategy. These total syntheses furnish the diaryl ethers in only five to seven steps employing a Pd-catalyzed diaryl ether coupling as the key step. The total synthesis led to the structural revision of the natural product verticilatin, which has been isolated from a plant pathogenic fungus. Furthermore, these structures were tested in order to determine their antibacterial activities against different MRSA strains as well as further Gram-positive and -negative bacteria.     

Total Synthesis of Leucosceptroids A and B

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram‐scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)‐citronellal‐derived aldehyde, a SmI₂‐mediated intramolecular ketyl–olefin radical cyclization, and final‐stage alcohol oxidation.     

Total Synthesis,Stereochemical Revision,and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Mandelalide A and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure 1 as the purported representation of mandelalide A. The sequence involves an iridium‐catalyzed two‐directional Krische allylation and a cobalt‐catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal acetylene metathesis into natural product total synthesis, which is remarkable in that this class of substrates had been beyond the reach of alkyne metathesis for decades. Synthetic 1 , however, proved not to be identical with the natural product. In an attempt to clarify this issue, NMR spectra were simulated for 20 conceivable diastereomers by using DFT followed by DP4 analysis; however, this did not provide a reliable assignment either. The puzzle was ultimately solved by the preparation of three diastereomers, of which compound 6 proved identical with mandelalide A in all analytical and spectroscopic regards. As the entire “northern sector” about the tetrahydrofuran ring in 6 shows the opposite configuration of what had originally been assigned, it is highly likely that the stereostructures of the sister compounds mandelalides B–D must be corrected analogously; we propose that these natural products are accurately represented by structures 68 – 70 . In an attempt to prove this reassignment, an entry into mandelalides C and D was sought by subjecting an advanced intermediate of the synthesis of 6 to a largely unprecedented intramolecular Morita–Baylis–Hillman reaction, which furnished the γ‐lactone derivative 74 as a mixture of diastereomers. Whereas (24R)‐ 74 was amenable to a hydroxyl‐directed dihydroxylation by using OsO₄/TMEDA as the reagent, the sister compound (24S)‐ 74 did not follow a directed path but simply obeyed Kishi’s rule; only this unexpected escape precluded the preparation of mandelalides C and D by this route. A combined spectroscopic and computational (DFT) study showed that the reasons for this strikingly different behavior of the two diastereomers of 74 are rooted in their conformational peculiarities. This aspect apart, our results show that the OsO₄/TMEDA complex reacts preferentially with electron deficient double bonds even if other alkenes are present that are more electron rich and less encumbered. Finally, in a brief biological survey authentic mandelalide A ( 6 ) was found to exhibit appreciable cytotoxicity only against one out of three tested human cancer cell lines and all synthetic congeners were hardly active. No significant fungicidal properties were observed.     

Catalysis‐Based Total Synthesis of Putative Mandelalide A

A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A ( 1 ) is disclosed. Specifically, an iridium‐catalyzed two‐directional Krische allylation and a cobalt‐catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal‐acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11‐epi‐ 1 deviate from those of the natural product, which implies a subtle but deep‐seated error in the original structure assignment.     

Discovery,Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide,a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

A new dimeric macrolide xylopyranoside, cocosolide ( 1 ), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X‐ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide ( 1 ) along with its [α,α]‐anomer ( 26 ) and macrocyclic core ( 28 ), thus leading to the confirmation of the structure of natural 1 . The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α‐selective glycosidation and β‐selective glycosidation. Compounds 1 and 26 potently inhibited IL‐2 production in both T‐cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti‐CD3‐stimulated T‐cells in a dose‐dependent manner.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.     

Total Synthesis and Structure Revision of Didemnaketal B

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV‐1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7–C21 spiroacetal domain by means of a strategy exploiting Suzuki–Miyaura coupling, 2) an Evans syn‐aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1–C7 acyclic domain, and 3) a Nozaki–Hiyama–Kishi reaction for the construction of the C21–C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner’s stereochemical assignment led us to postulate that the absolute configuration of the C10–C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7–C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.     

Total Synthesis and Structural Revision of (+)‐Uprolide G Acetate

The first, asymmetric total synthesis of the proposed structure of (+)‐uprolide G acetate (UGA) is reported, and the spectral properties of the synthetic compound clearly differed from those reported for natural UGA. On the basis of comprehensive analysis of the NMR data, two possible structures for the natural UGA were proposed and their total synthesis achieved, thus leading to the identification and confirmation of the correct structure and absolute configuration of the natural UGA. This synthesis was enabled by development of a novel synthetic strategy, which revolved around three key cyclization reactions: an Achmatowicz rearrangement, Sharpless asymmetric dihydroxylation/lactonization, and ring‐closing metathesis. These synthetic studies pave the way for further studies on this class of structurally unusual cytotoxic cembranolides.     

Structure Elucidation and Total Synthesis of Kulkenon

The impressive biological profile of secondary metabolites isolated from strains of Sorangium cellulosum prompted us to initiate synthetic studies on kulkenon, also isolated from Sorangium cellulosum. The synthesis features a syn‐selective vinylogous Kobayashi aldol reaction, recently developed by us, and a ring‐closing intramolecular Heck reaction as the pivotal transformations. Comparison of the NMR spectra of the authentic and synthetic material revealed that the proposed configuration had to be revised. A combination of molecular modeling and NOE experiments was used to propose the revised configuration, which was confirmed by a new synthesis.