Transannular Cyclization Research Articles

Enantioselective Synthesis of Sealutomicin C.

The sealutomicins are a family of anthraquinone antibiotics featuring an enediyne (sealutomicin A) or Bergman-cyclized aromatic ring (sealutomicins B-D). Herein we report the development of an enantioselective organocatalytic method for the synthesis of dihydroquinolines and the use of the developed method in the total synthesis of sealutomicin C which features a transannular cyclization of an aryllithium onto a γ-lactone as a second key step.

A Biomimetic Approach to Premyrsinane-Type Diterpenoids: Exploring Microbial Transformation to Enhance Their Chemical Diversity.

Premyrsinane-type diterpenoids have been considered to originate from the cyclization of a suitable 5,6- or 6,17-epoxylathyrane precursor. Their biological activities have not been sufficiently explored to date, so the development of synthetic or microbial approaches for the preparation of new derivatives would be desirable. Epoxyboetirane A (4) is an 6,17-epoxylathyrane isolated from Euphorbia boetica in a large enough amount to be used in semi-synthesis. Transannular cyclization of 4 mediated by Cp2TiIIICl afforded premyrsinane 5 in good yield as an only diasteroisomer. To enhance the structural diversity of premyrsinanes so their potential use in neurodegenerative disorders could be explored, compound 5 was biotransformed by Mucor circinelloides NRRL3631 to give rise to hydroxylated derivatives at non-activated carbons (6-7), all of which were reported here for the first time. The structures and absolute configurations of all compounds were determined through extensive NMR and HRESIMS spectroscopic studies.

Total synthesis of (–)-deglycocadambine

The first total synthesis of (–)-deglycocadambine is achieved from (+)-genipin, wherein the well-designed cascade annulation and the late-stage transannular oxidative cyclization clearly unveil the bond-forming logic in this synthetic route.

Synthesis of a Halicyclamine-Type Macrocyclic Scaffold via Biomimetic Transannular Cyclization

Previous attempts for biomimetic transannular reactions between two dihydropyrdine (DHP) rings incorporated in macrocycle frameworks relevant to manzamine alkaloids have been unsuccessful. Herein, we report an efficient regiocontrolled transannular cyclization of C2-symmetric macrocyclic precursor with rational modifications of the 3 and 6 positions of the DHP rings to synthesize a halicyclamine-type scaffold. The cis-double bonds installed in the macrocyclic alkyl loops played a crucial role in achieving the biomimetic transannular cyclization.

Design and Synthesis of Nitro Cage Heterocycles as Energetic Materials Derived from Pentacycloundecane (PCUD) Systems

AbstractA variety of pentacycloundecane (PCUD) based cage compounds containing nitro groups were synthesized via a simple synthetic method starting with cage diones. Eight PCUDs were used for nitro functionalization. These cage diones were prepared starting with easily accessible starting materials such as 2,3‐dimethylhydroquinone, 1,4‐dihydroxybenzene, and cyclopentadiene. Here, we have used Diels‐Alder (DA) reaction, [2+2] photocycloaddition, and Henry reaction as key steps. Transannular cyclization plays an important role to generate a nitro substituted cage heterocycles via base promoted reaction using nitromethane as a reagent. Some of these oxa‐cage structures have been further supported by single‐crystal X‐ray diffraction studies. Energetic performance of the title compounds was evaluated using DFT based calculations. These bis(nitromethyl)octahydro‐1H‐1,3,4,6(epiethane‐[1,1,2,2]tetrayl)‐pentaleno[1,6‐bc]furan analogues (11 b–18 b) owned the densities in the range of 1.37–1.60 g/cm3. All the studied compounds possess high positive enthalpy of formation (33.68–230.48 kJ/mol, except compound with dimethyl groups (16 b, −11.38 kJ/mol) and very good thermal (Tm=99–147 °C) and kinetic stabilities. Ammonium perchlorate based various propulsion formulations suggests that these compounds could be excellent candidates in the solid rocket propulsion.

Diastereoselective Synthesis of Camptothecin‐like Scaffolds: Construction of a New Class of Pseudo‐natural Products

AbstractThe discovery of novel small molecules endowed with high 3D‐content remains a powerful tool for interrogating underrepresented biological space. To this end, the pseudo‐natural products (pseudo‐NP) strategy has become one of the most important tools to deliver biologically significant chemical probes. In this article, we describe the development of a new class of pseudo‐NP collection, through connecting tryptamines with a furanose derivative followed by subjecting the product from this operation to a ring distortion strategy that led to diastereoselective synthesis of camptothecin‐like compounds. This process is driven by a cascade that unites Pictet–Spengler reaction with Michael addition reaction, followed by oxidative‐ring enlargement and subsequent transannular aldol cyclization delivering camptothecin‐like architectures. The obtained diastereoselectivity was verified using density functional theory (DFT) calculations.

Four-Step Synthesis of (-)-4-epi-Presilphiperfolan-8α-ol by Intramolecular Iron Hydride Atom Transfer-Mediated Ketone-Alkene Coupling and Studies to Access trans-Hydrindanols with a Botryane Scaffold.

From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (-)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent FeIII -mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds.

Mechanistic Investigations on N-Cα Bond Cleavages in Dibasic Peptides Containing Internal Lys and Arg Residues.

The model nonapeptide AAARAAKAG* (* indicates amide) is used to explore N-Cα bond fragmentation under CID-MS conditions. Neighboring group participation and the effect of positioning of Lys and Arg residues on N-Cα bond cleavage is established using a library of synthetic peptide analogues. The importance of the Arg residue at position 4 and the i to i+3 spacing between Arg and Lys residues in determining the formation of the N-Cα bond cleaved product ions (cn) is demonstrated by a comparative MS study of positional variants in analogue peptides. The effect of shortening of the Lys side chain has been established using ornithine (Orn) and diaminobutyric acid (Dab) analogues. The involvement of the Lys residue in mediating the N-Cα bond cleavage is further probed using Nε-dimethyl and isotopically labeled 15Nα,ε lysine residues. MSn experiments reveal that the c6 ion originates from a doubly charged dehydrated b8 ion [b8-18]2+. The mechanism of this unusual fragmentation process has been probed by using position 8 analogues (Gly, Ala, and Aib). A plausible mechanism is proposed for the origin of the c6 ion, which involves C-terminus lactam formation followed by transannular cyclization and dehydration. The results presented in this study highlight the role of reactive side chain functionalities in promoting noncanonical fragmentation pathways.

Annulation Tactics of cis-syn-cis Triquinanes by Allylsilanes: Application of Hosomi-Sakurai Reaction Conditions.

A stereoselective [3+2] cycloaddition approach to functionalized pentaquinanes starting from cis-syn-cis triquinanes, derived from Cookson's diones, is reported. This transformation involves generation of six new stereocenters in a single step leading to cis-anti-cis-syn-cis-anti-cis polyquinane systems. Our method prevents transannular cyclizations which are prevalent in these moieties. The structure and stereochemistry of target molecules are well-characterized based on NMR data and X-ray diffraction studies.

Collective Total Syntheses of Five Lycopodium Alkaloids.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Collective Total Syntheses of Five Lycopodium Alkaloids

AbstractIt is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold‐catalyzed enamide–alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting‐group‐free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten‐membered lactam system in phlegmariurine B; 3) a Fukuyama one‐pot protocol for the construction of the 2‐pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Exploring the Acid-Catalyzed Reactions of 10,11-Epoxy-Dibenzo[a,d]cycloheptan-5-ol as the Synthetic Modules toward Polycyclic Aromatic Scaffolds.

The structural diversity of polycyclic aromatic hydrocarbons (PAHs) offers exciting opportunities for their applications. Yet, selective synthesis of such conjugated networks poses a formidable challenge. Compared to the prominence of transition-metal-catalyzed cross-coupling and oxidative Scholl reactions, cationic rearrangement in the synthesis of polycyclic aromatic hydrocarbon is an underexplored subject. In this study, we reveal that cationic intermediate generated from epoxy dibenzocycloheptanol can be transformed into acenes, azulene-embedded PAHs, and dibenzocycloheptanone derivatives. Reactive patterns, including Meinwald rearrangement, Nazarov cyclization, transannular aryl migration, and transannular Friedel–Crafts cyclization were identified. Both substrate structures and reaction temperature affect the reaction pathways in predictable and manageable manners. A mechanistic scheme was postulated as the working model to guide the reactivity for further application. Substrates containing heterocyclic and ferrocenyl groups exhibit similar reactivity profiles. The inquiry culminates in the selective synthesis of 5, 7, 12, 14-tetrasubstituted C2h and C2v pentacene derivatives. Our results demonstrate that polycyclic aromatic hydrocarbons can be selectively prepared with this cation-initiated strategy by methodically tuning the reactivity.

Synthesis and DFT conformational analysis of trimethyl-functionalized [2.2]metacyclophanes and their Lewis-acid assisted reactions

The synthesis of the strained trimethyled anti-[2.2]metacyclophanes 5a and 5b is reported. They were synthesized by ring contraction of the corresponding unstrained cyclic precursors 2,11-dithia[3.3]metacyclophane-2,2,11,11-tetraoxides, 4a and 4b by the vacuum-pyrolysis elimination of sulfur dioxide ("sulfone pyrolysis‘).Tetraoxides 4a and 4b were generated by the oxidation of their respective dithia[3.3]metacyclophane precursors 3a and 3b. The macrocyclic coupling reactions which formed 3a and 3b also produced both anti- and syn-conformational isomers which could be separated from their respective reaction mixtures and whose structures were confirmed by 1H-NMR spectroscopy. Single-crystal X-ray analyses confirmed the anti conformation of anti-3b in the solid state and that the corresponding oxidized tetraoxide, syn-4b adopts a syn conformation. The Lewis acid (TiCl4/AlCl3-MeNO2)-catalyzed reactions of anti-5b under various conditions led to transannular cyclization to afford tetrahydropyrene 7, pyrene derivative 8 and/or de-tert-butylated anti-5a. A DFT (Density Functional Theory) computational study was conducted to determine the stabilities of the different conformational isomers of the target compounds.

4b-Aryltetrahydroindeno[1,2-a]indenes by Acid-Catalyzed Trans­annular Cyclization of Benzannulated Cyclooctene Alcohols

AbstractBy starting from two simple building blocks, benzannulated cyclooctenones were obtained in three steps. Subsequent Grignard/aryl lithium addition to the ketone yielded the corresponding tertiary alcohols that underwent stereoselective acid-catalyzed transannular cyclization to provide a cis-fused 5/5 bicyclic indanylindane framework exclusively. Subsequent stereoselective nucleophilic addition to the indanyl cation by hydride, water, or electron-rich aromatics furnished the 4b-aryltetrahydroindano[1,2-a]indenes in good to excellent yields (up to 92%) in the trans-C9–C9a form in up to a >99:1 diastereomeric ratio.

Six-Step Total Synthesis of Isohirsut-4-ene through [5+2+1] Cycloaddition and Transannular Epoxide-Alkene Cyclization.

A six-step total synthesis of isohirsut-4-ene with a 5/5/5 tricyclic core has been achieved. The synthesis features a Rh(I)-catalyzed [5+2+1] cycloaddition, a Corey-Chaykovsky reaction, and a transannular epoxide-alkene cyclization that afford the skeleton of the target molecule. This three-step strategy was further utilized to synthesize more 5/5/5 tricyclic analogues with one or two bridgehead quaternary centers.

Cage‐Opened C60 Isomers with Different Reactivities

AbstractWe synthesized two cage‐opened C60 isomers with different arrangement of an imine moiety on their orifices and investigated reactivities of them toward nucleophiles. Both isomers underwent the enlargement of the opening by the reaction with N‐methylmorpholine N‐oxide in comparable yields while the reaction with MeOH caused an orifice contraction via a transannular cyclization resulting in obviously different yields. The products in the latter reaction have a new hexagonal or heptagonal ring on their skeletons. The observed difference in reactivity could be explained by the greater thermodynamic stabilization in the hexagon‐containing isomer compared with the other.

Total syntheses of seven stemoamide-type Stemona alkaloids

Six Stemona alkaloids were synthesized racemically using stemoamide, obtained via a cascade cyclization or our reported transannular cyclization of parvistemoamide, as the common intermediate.

Transition Metal/Lewis Acid Catalyzed Reactions of Zerumbone for Diverse Molecular Motifs.

Zerumbone is a naturally occurring humulene type sesquiterpene, isolated from the rhizomes of Zingiber zerumbet (L.) Smith with excellent therapeutic potential and is recognized as a valuable synthon for the construction of diverse array of natural product motifs. In this review, we intended to highlight our achievements in utilizing abundant natural product zerumbone and its derivatives for the development of pharmacologically relevant molecular scaffolds. We provided an account of the transition-metal catalyzed 1,4-conjugate addition reactions of zerumbone and its derivatives along with palladium-catalyzed cross-couplings, transition metal-based Lewis acid promoted interrupted Nazarov cyclisation reaction with substituted indoles and transannular cyclizations, photo-induced transformations of zerumbone and its epoxide.

Stereoselective Synthesis of Hydrindane and Hydroazulene Derivatives by Transannular Cyclization of Nine- and Ten-Membered Carbocycles.

Treatment of cis-fused bicyclic diene dicarboxylates with Li/naphthalene triggers a tandem ring-opening and transannular cyclization process that stereoselectively yields hydroazulenes and hydrindanes derivatives. Cyclononadienyl diesters, which can be isolated after the ring-opening step by judicious choice of the reaction conditions, undergo a tandem conjugate addition/intramolecular Michael addition upon treatment with chiral lithium amides to give bicyclic β-amino esters in a process where 4 contiguous stereocenters are formed with high diastereocontrol. A concise route toward the highly enantioenriched AEF ring core of the aconitine-type alkaloids has been developed as an application of this methodology. The starting cis-fused bicyclic dicarboxylates are easily prepared in one step by reductive alkylation of diisopropyl phthalate (Na/THF, followed by the appropriate bis-electrophiles).

Synthesis of the Proposed Structures of Parvistemoamide and Their Transformations to Stemoamide Derivatives.

The proposed structures of parvistemoamide have been achieved by macrolactamization, but none of the characterization data of synthetic samples matched with those of the natural sample. The transformation of the highly strained 10-membered lactam ring in parvistemoamide into the pyrrolo[1,2-a]-azepine nucleus in stemoamide is accomplished for the first time by either transannular cyclization or Pilli's transformation. This research may promote the total synthesis of other more complex stemoamide-type or medium-sized-ring-containing Stemona alkaloids.