Synthesis and Structure Revision of Dichrocephones A and B

Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B.     

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.     

Annulation Approach to Doubly Linked (A‐type) Oligocatechins: Syntheses of (+)‐Procyanidin A2 and (+)‐Cinnamtannin B1

The first stereoselective syntheses of doubly linked (A‐type) oligocatechins, (+)‐procyanidin A₂ and (+)‐cinnamtannin B₁, have been achieved. Ethylenedioxy‐bridged flavans served as excellent platforms, thus allowing annulation with nucleophilic catechin units in a stereoselective manner. An additional key was the new synthetic approach to selectively protected nucleophilic catechin, thus enabling regioselective construction of the key dioxabicyclo skeleton of the A‐type oligocatechins.     

Enantioselective Biomimetic Total Syntheses of Kuwanons I and J and Brosimones A and B

The first enantioselective total syntheses of prenylflavonoid Diels–Alder natural products (?)‐kuwanon I, (+)‐kuwanon J, (?)‐brosimone A, and (?)‐brosimone B have been accomplished from a common intermediate based on a concise synthetic strategy. Key elements of the synthesis include a biosynthesis‐inspired asymmetric Diels–Alder cycloaddition mediated by a chiral ligand/boron Lewis acid, as well as a process involving regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable tandem inter‐/intramolecular asymmetric Diels–Alder cycloaddition process was applied for the synthesis of (?)‐brosimone A.     

Conformation‐Enabled Total Syntheses of Ohmyungsamycins A and B and Structural Revision of Ohmyungsamycin B

The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycin A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N‐methyl amides and non‐proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycin B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.     

Enantioselective Syntheses of the Proposed Structures of Kopeolin and Kopeolone

The first total syntheses of the proposed structures of kopeolin ( 1 ) and kopeolone ( 3 ) have been achieved from a common enantiopure chiral building block obtained by a chemoenzymatic enantioconvergent methodology. The syntheses feature two key steps: a one‐pot reduction/diastereoselective protonation followed by a highly diastereoselective addition of an organocerate. The synthetic structures were fully characterized and all stereocenters were confirmed. The results show that the two previously reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two revised structures, 1′ for kopeolin and 3′ for kopeolone, are proposed.     

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.     

Total Syntheses of Sesterterpenoid Ansellones A and B,and Phorbadione

Ansellane‐type sesterterpenoids including, ansellones A‐G and (+)‐phorbadione are structurally novel marine secondary metabolites which exhibit anticancer and anti‐HIV activity. The first, asymmetric total syntheses of three structurally representative members, (−)‐ansellones A and B and (+)‐phorbadione, were accomplished in 16–23 steps from (+)‐sclareolide. The route features the first regioselective cyclization of vinyl epoxides with internal alcohol nucleophiles in a 1,4‐addition manner (S_N2′). Additionally, the allylic C−H oxidation was exploited at a late stage of the synthesis of (−)‐ansellone A and (+)‐phorbadione. This strategy is expected to be applicable to the synthesis of other ansellane sesterterpenoids.     

A Domino Approach to the Enantioselective Total Syntheses of Blennolide C and Gonytolide C

The first enantioselective total syntheses of the tetrahydroxanthenone (?)‐blennolide C (ent‐ 4 ) and related γ‐lactonyl chromanone (?)‐gonytolide C (ent‐ 3 ) are reported. Key to the syntheses is an enantioselective domino‐Wacker/carbonylation/methoxylation reaction to set up the stereocentre at C‐4a. Various chiral BOXAX ligands were investigated, including novel (S,S)‐iBu‐BOXAX, and allowed access to chromane 8 in an excellent enantioselectivity of 99 %. The second stereocentre at C‐4 was established employing a diastereoselective Sharpless dihydroxylation. An extensive survey of (DHQ)‐ and (DHQD)‐based ligands enabled the preparation of both the anti‐isomer 14 a and the syn‐isomer 14 b in very good to reasonable selectivities of 13.7:1 and 1:3.7, respectively. While 14 a was further converted to ent‐ 3 and ent‐ 4 , 14 b was elaborated to syn‐acid 25 and 2′‐epi‐gonytolide C 28 .     

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.     

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin,and (−)‐Pavidolide B: A Divergent Approach

A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (?)‐3‐oxochatancin, and (?)‐pavidolide B, has been developed, and it also led to the structural revision of (?)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.     

Total Synthesis of the Putative Structure of Xylarinol B

The total synthesis of the putative structure of xylarinol B is described and the need to revise its structure is demonstrated. The central benzoxepine skeleton was constructed by employing a cobalt‐mediated bimolecular [2+2+2] Reppe–Vollhardt alkyne cycloaddition reaction.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

Total Syntheses of Linear Polythiazole/Oxazole Plantazolicin A and Its Biosynthetic Precursor Plantazolicin B

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4‐concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.     

Enantioselective Total Synthesis of (−)‐Lansai B and (+)‐Nocardioazines A and B

The concise total syntheses of the bis(pyrroloindolines) (?)‐lansai B and (+)‐ nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)‐nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation.     

Total Synthesis and Complete Stereostructure of a Marine Macrolide Glycoside, (−)‐Lyngbyaloside B

We have described in detail the total synthesis of both the proposed and correct structures of (?)‐lyngbyaloside B, which facilitated the elucidation of the complete stereostructure of this natural product. Our study began with the total synthesis of 13‐demethyllyngbyaloside B, in which an esterification/ring‐closing metathesis (RCM) strategy was successfully used for the efficient construction of the macrocycle. We also established reliable methods for the introduction of the conjugated diene side chain and the l ‐rhamnose residue onto the macrocyclic framework. However, the esterification/RCM strategy proved ineffective for the parent natural product because of the difficulties in acylating the sterically encumbered C‐13 tertiary alcohol; macrolactionization of a seco‐acid was also extensively investigated under various conditions without success. We finally completed the total synthesis of the proposed structure of (?)‐lyngbyaloside B by means of a macrolactonization that involves an acyl ketene as the reactive species. However, the NMR spectroscopic data of our synthetic material did not match those of the authentic material, which indicated that the proposed structure must be re‐examined. Inspection of the NMR spectroscopic data of the natural product and molecular mechanics calculations led us to postulate that the configuration of the C‐10, C‐11, and C‐13 stereogenic centers had been incorrectly assigned in the proposed structure. Finally, our revised structure of (?)‐lyngbyaloside B was unambiguously verified through total synthesis.