Trans Ring Junction Research Articles

Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation.

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp3)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.

Synthesis of 3-Azidopiperidine Skeleton Employing Ceric Ammonium Nitrate (CAN)-Mediated Regioselective Azidoalkoxylation of Enol Ether: Total Synthesis of D2 Receptor Agonist (±)-Quinagolide.

The total synthesis of (±)-quinagolide, which is a D2 receptor agonist, was accomplished via a ceric ammonium nitrate (CAN)-mediated regioselective azidoalkoxylation of enol ether route. Key features of the synthesis include Claisen rearrangement, PPTS (pyridinium p-toluenesulfonate)-catalyzed one-pot acetal deprotection, followed by a diastereoselective Henry reaction, which enables construction of the required trans ring junction and CAN-mediated regioselective azidoalkoxylation of enol ether. The PPTS-catalyzed intramolecular diastereoselective Henry reaction to fix three contiguous stereocenters on tetrahydronaphthalene and the first-of-its-kind synthesis of the 3-azidopiperidine skeleton, using a CAN-mediated regioselective azidoalkoxylation of enol ether, are important findings of the present work.

ChemInform Abstract: Design and Synthesis of Polycyclic Sulfones via Diels—Alder Reaction and Ring‐Rearrangement Metathesis as Key Steps.

Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available.

Design and synthesis of polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis as key steps.

Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels–Alder reaction and ring-rearrangement metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available.

Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans

Twelve new bufadienolides (1–12), along with fourteen known analogues (13–26) were isolated from the skins of Bufo bufo gargarizans Cantor. Their chemical structures were elucidated on the basis of NMR, HRESIMS and X-ray diffraction analysis. Compound 1 was an unusual bufadienolide with 3,19-epoxy moiety and A/B trans ring junction. Compounds 2–4 were rare bufadienolides possessing 10-H or 10-carboxyl units. All the isolated compounds were tested for their cytotoxic effects on HepG2, A549 and HeLa cells. Six new compounds (2, 3, 5, 6, 10 and 12) displayed significant anti-proliferative activities with IC50 values ranging from 0.049 to 1.856μM. Arenobufagin (24) exhibited the most potent cytotoxic activity with IC50 value 0.011μM. In addition, the present data provided more insight into the structure–activity relationships of bufadienolides.

Synthesis of cis- and trans-α-l-[4.3.0]Bicyclo-DNA Monomers for Antisense Technology: Methods for the Diastereoselective Formation of Bicyclic Nucleosides

Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5' positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.

N,N-Dimethyldehydroabietylammonium chloride ethanol monosolvate

The title compound {systematic name: 1-[(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa­hydro­phenan­thren-1-yl]-N,N-di­methyl­methanaminium chloride ethanol monosolvate}, C22H36N+·Cl−·C2H6O, was synthesized from dehydroabietylamine by N-methyl­ation with formaldehyde/formic acid and transformation into the hydro­chloride. The de­hydro­abietyl moiety exhibits the usual conformation with the two cyclo­hexane rings in chair and half-chair conformations and a trans-ring junction. The crystal structure is built up from columns of the de­hydro­abietyl moieties stacked along the a axis. These columns are held together by the chloride ions via N—H⋯Cl and C—H⋯Cl inter­actions, which establish a two-dimensional network parallel to (010). The ethanol solvent mol­ecules are located between the columns and anchored via O—H⋯Cl hydrogen bonds.

The Asymmetric Formal Hetero‐Diels–Alder Reaction of Methyl (E)‐4‐Aryl‐2‐oxo‐3‐butenoates Catalyzed by [Sc(OTf)3/pybox] Complexes

AbstractThe complex between scandium triflate and pybox is a good enantioselective catalyst for the reaction between methyl (E)‐4‐aryl‐2‐oxo‐3‐butenoates (1) and enol silyl ethers (2). The main products with (4′S)‐isopropyl‐, (4′S)‐phenyl‐, and (4′S,5′S)‐4‐TIPS‐pybox are methyl (4S,4aS,8aS)‐4‐aryl‐8a‐trialkylsiloxy‐hexahydro‐4H‐chromen‐2‐carboxylates (7), which are obtained in good yield and enantioselectivities of more than 95 % ee. Because the reaction gives products with a trans ring junction that cannot derive from a conventional concerted hetero‐Diels–Alder pathway, the mechanism involved in the enantioselective catalytic cycle and the origin of the stereoinduction were investigated. The structures of two desilylated products, 8b and 9b, were determined by X‐ray crystal analysis. Their absolute configuration was then related to that of 7 by stereospecific isomerization and/or desilylation reactions. If aryl‐butenoates 1 are coordinated to the catalyst, forming reacting complexes characterized by the five‐membered structure 11, these rigid reacting intermediates give a face discrimination that is determined by the configuration of the pybox 4′‐substituent. The resulting face‐selective attack of enol silyl ethers to coordinated 1 gives an enantioselective tandem Mukaiyama–Michael addition/intramolecular ring closure reaction, which is an enantioselective formal hetero‐Diels–Alder reaction, which rationalizes the absolute configuration of the reaction products.

Synthesis of the trans-hydrindane core of dictyoxetane

A concise, stereoselective synthesis of the trans-hydrindane core of the marine natural product dictyoxetane is reported, starting from a Robinson annelation derived bicyclic enone. A phosphorane-mediated, pinacol-like rearrangement of a cis-diol, via a formal 1,2-hydride shift, is used to establish the requisite trans ring junction. (31)P NMR supports the formation of the intermediate phosphorane, generated in situ from the reaction of a diol with Ph(3)PCl(2).

(1R,4aS,10aR)-1,4a-Dimethyl-N-[(morpholin-4-yl)carbothioyl]-7-(propan-2-yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide

In the title compound, C25H36N2O2S, the cyclo­hexane and morpholine rings adopt chair conformations. The cyclo­hexene and cyclo­hexane rings form a trans ring junction with the two methyl groups in axial positions. The N—H and C=O bonds in the urea group are anti to each other. The crystal structure is stabilized by inter­molecular N—H⋯O hydrogen bonds.

Methyl 7-oxo-12-propylamino-13-nitrodeisopropyldehydroabietate

In the title compound, C21H28N2O5 (systematic name: methyl 1,4a-dimethyl-7-nitro-9-oxo-6-propyl­amino-1,2,3,4,4a,9,10,10a-octa­hydro­phenanthrene-1-carboxyl­ate) the cyclo­hexane ring (A) and the central cyclo­hexene ring (B) exist at a trans ring junction, with the two methyl groups in the axial positions of the six-membered rings. Ring A has a chair conformation and ring B a half-chair conformation. An intra­molecular N—H⋯O hydrogen bond occurs. The crystal structure is stabilized by inter­molecular C—H⋯O and N—H⋯O inter­actions.

ChemInform Abstract: Stereocontrolled Formation of cis- and trans-Ring Junctions in Hydrindane and Decalin Systems by Palladium-Catalyzed Regioselective and Stereospecific Hydrogenolysis of Allylic Formates.

ChemInform Abstract: Stereocontrolled Formation of cis- and trans-Ring Junctions in Hydrindane and Decalin Systems by Palladium-Catalyzed Regioselective and Stereospecific Hydrogenolysis of Allylic Formates.

ChemInform Abstract: Titanium-Mediated Cyclization of ω-Vinyl Imides in Alkaloid Synthesis: Isoretronecanol, Trachelanthamidine, 5-Epitashiromine, and Tashiromine.

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of ω-vinyl imides is described. The general procedure involves treatment of readily available ω-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium chloride in the presence of ClTi(O-i-Pr)3 (1.1 equiv) and subsequent stereoselective reduction of the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively prepared by catalytic hydrogenation (H2, PtO2, EtOAc) and NaCNBH3 reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1−8 in good yields.

16-Isopropyl-5,9-dimethyltetracyclo[10.2.2.01,10.04,9]hexadec-15-ene-5,13,14-tricarboxylic acid dimethylformamide disolvate

The title compound, C24H34O6·2C3H7NO, which was isolated from fumaric-modified rosin, has four asymmetrically fused six-membered rings and three carboxylic acid substituents. It contains two fused and unbridged cyclo­hexane rings, which form a trans ring junction with a chair conformation. The asymmetric unit includes one fumaropimaric acid and two dimethyl­formamide mol­ecules. The crystal structure is stabilized through inter­molecular O—H⋯O hydrogen bonds between dimethyl­formamide and fumaropimaric acid.

Methyl 12-bromodehydroabietate

The title compound [systematic name: (1R)-methyl 6-bromo-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa­hydro­phen­anthrene-1-carboxyl­ate], C21H29BrO2, was synthesized from N-bromo­succinimide and methyl dehydro­abietate, which was prepared through an esterification reaction using dehydro­abietic acid and methanol as raw materials. The three six-membered rings adopt planar (mean deviation = 0.002 Å) half-chair and chair conformations. The two cyclo­hexane rings form a trans ring junction with the two methyl groups in axial positions. The crystal structure is stabilized by weak inter­molecular C—H⋯O contacts along the b axis.

Rare Casbane Diterpenoids from the Hainan Soft Coral Sinularia depressa

A series of nine casbane diterpenes, compounds 5-13, exhibiting either cis or trans ring junctions were isolated from the Hainan soft coral Sinularia depressa. The structures of this group of compounds, the basic member of which was named depressin (5), were established by detailed spectroscopic analysis. In addition, the absolute configuration of the main metabolite, 10-hydroxydepressin (7), and of its epimer, 1-epi-10-hydroxydepressin (8), was determined by a combination of conformational analysis and the modified Mosher's method. A stereochemical relationship between all isolated molecules was investigated by analyzing their circular dichroism profiles. Antiproliferative and antibacterial activities of the depressins were also evaluated.

Crystal Structure of Unsymmetrically N-nor-dehydroabietyl-N′-isopropyl Urea

The title compound (C46H72N4O2, M r = 713.08) [systematic name: 1-isopropyl-3-((1R,4aS,10aR)-7-isopropyl-1, 4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)urea] is a new derivative of dehydroabietic acid. It crystallized in the orthorhombic system, space group P2121 21 with cell dimensions of a = 9.5950(19) A, b = 18.740(4) A, c = 24.654(5) A, V = 4,433.0(16) A3, Z = 4, D c = 1.068 g/cm3, λ = 0.71073 A, μ = 0.07 mm−1, F(000) = 1,568, final R = 0.0777 and wR = 0.1731 for 2,048 observed reflections with I > 2σ(I). Two crystallorgraphically independent molecules with different conformations co-exist in the structure. Each molecule exhibit classic tricyclic hydrophenanthrene structure, the two cyclohexane rings form a trans ring junction with chair and half-chair conformations, respectively. The crystal is stabilized by intermolecule hydrogen bonds and the molecules are in a head–tail zigzag arrangement. The title compound (C46H72N4O2, M r = 713.08) [systematic name: 1-isopropyl-3-((1R,4aS,10aR)-7-isopropyl-1, 4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)urea] is a new derivative of dehydroabietic acid. It crystallized in the orthorhombic system, space group P2121 21 with cell dimensions of a = 9.5950(19) A, b = 18.740(4) A, c = 24.654(5) A, V = 4,433.0(16) A3, Z = 4, D c = 1.068 g/cm3, λ = 0.71073 A, μ = 0.07 mm−1, F(000) = 1,568, final R = 0.0777 and wR = 0.1731 for 2,048 observed reflections with I > 2σ(I). Two crystallorgraphically independent molecules with different conformations co-exist in the structure. Each molecule exhibit classic tricyclic hydrophenanthrene structure, the two cyclohexane rings form a trans ring junction with chair and half-chair conformations, respectively. The crystal is stabilized by intermolecule hydrogen bonds and the molecules are in a head–tail zigzag arrangement.

15-Hydroxyethyl-19-isopropyl-5,9-dimethyl-14,16-dioxo-15-azapentacyclo[10.5.2.01,10.04,9.013,17]nonadec-18-ene-5-carboxylic acid

The title compound, C26H37NO5, which was synthesized from monoethano­lamine and maleopimaric acid, consists of two fused and unbridged cyclo­hexane rings. They form a trans ring junction with a chair conformation. The two methyl groups are in axial positions. In the crystal, inter­molecular O—H⋯O hydrogen bonds link adjacent mol­ecules into a layer structure. Two C—H⋯O interactions are also present.

Dehydroabietic acid

The title compound [systematic name: (1R,4aS,10aR)-7-iso­prop­yl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octa­hydro­phen­anthrene-1-carboxylic acid], C20H28O2, has been isolated from disproportionated rosin which is obtained by isomerizing gum rosin with a Pd-C catalyst.. Two crystallographically independent mol­ecules exist in the asymmetric unit. In each mol­ecule, there are three six-membered rings, which adopt planar, half-chair and chair conformations. The two cyclo­hexane rings form a trans ring junction with the two methyl groups in axial positions. The crystal structure is stabilized by inter­molecular O—H⋯O hydrogen bonds.

Anent-kaurane diterpenoid fromIsodon japonicavar. glaucocalyx

The title compound, 14β-acet­oxy-7α-hydr­oxy-ent-kaur-16-ene-3,15-dione or glaucocalyxin B, C22H30O5, a natural ent-kaurane diterpenoid, is composed of four rings with the expected cis and trans ring junctions. In the crystal structure, there are two mol­ecules in the asymmetric unit related by a noncrystallographic twofold screw axis, and ring A is disordered [ratio occupancies 0.829 (19):0.171 (19)], such that both chair and boat conformations are present, but with the boat conformation as the major component. In the crystal, mol­ecules are linked by inter­molecular O—H⋯O hydrogen bonds.