Cembradienes from the Caribbean sea whip Eunicea sp.

A new cembradiene diterpenoid 1, together with the known antiplasmodial cembradiene 2, was isolated from the sea whip Eunicea sp. collected from Santa Marta Bay on the Colombian Caribbean sea. The structures and absolute stereochemistry of 1-2 were determined by extensive spectroscopic analysis, chemical transformation of 2 to the new diterpenoid 3, and by using modified Mosher’s method. This is the first known report regarding the determination of the absolute configuration of 2.     

New bioactive cyclic peroxides from the Caribbean marine sponge Plakortis zyggompha

The new plakortide Q (1) has been isolated from the little studied marine sponge Plakortis zyggompha, together with the six new cyclic peroxide analogues 2-7 in their methyl ester forms 2a-7a. Their structure was fully elucidated through NMR and MS analyses and the relative stereochemistry of the 1,2-dioxane ring was established after interpretation of the coupling constant values and the NOESY data. The carboxylic acid function of these compounds was proved to be very reactive and methylation was found to take place during the purification process. The non-esterified peroxides exhibited more cytotoxic activity against human tumor cell lines than their corresponding methyl esters.     

Conformational analysis and absolute stereochemistry of ‘spongian’-related metabolites

New degraded and rearranged diterpenoids, 5-8, have been isolated from the Antarctic sponge Dendrilla membranosa. The structure and relative stereochemistry of these compounds were determined by spectroscopic data. The absolute stereochemistry of 5 was determined by spectroscopic data using a chiral reagent. Conformational studies allowed us to assign also the absolute stereochemistry of 6-8, as well as those previously isolated spongian-derived metabolites with known relative stereochemistries.     

On the relative stereochemistry of atomaric acid and related compounds

The stereochemistry at C-3 of the known compounds atomaric acid 2a, 5′a-desmethyl-5′-acetylatomaric acid 4a, and stypoquinonic acid 5a is revised to 2, 4, and 5 on the basis of a careful study of 2D NOESY experiments and also from comparison of their ¹H and ¹³C chemical shifts with those of the related metabolites 6 and 7 isolated from Stypopodium zonale. Compound 7 is a novel unusually functionalized 1-keto-5′a-desmethyl atomaric acid derivative whose structure and stereochemistry were determined by spectroscopic means.     

Synthesis and conformational analysis of 3-hydroxypipecolic acid analogs via CSI-mediated stereoselective amination

A short and efficient stereoselective synthetic approach toward substituted piperidines, involving (2S,3S)-3-hydroxypipecolic acid 1, (2R,3S)-3-hydroxypipecolic acid 3, and their acid-reduced analogs 2 and 4, has been developed. The requisite anti- and syn-1,2-amino alcohols 11 and 12 for the preparation of title four piperidine analogs 1-4 were synthesized via the regioselective and diastereoselective amination of anti- and syn-1,2-dibenzyl ethers 13 and 14 using chlorosulfonyl isocyanate (CSI). As a result, reaction of anti-1,2-dibenzyl ether 13 with CSI afforded exclusively the anti-1,2-amino alcohol 11 with the diastereoselectivity of 49:1 in toluene at −78 °C and syn-isomer 14 gave the syn-1,2-amino alcohol 12 as the major product with the diastereoselectivity of 12:1 in hexane at −78 °C. The result of these reactions could be explained by the neighboring group effect leading to retention of stereochemistry. In addition, conformational changes of trans-piperidine intermediate 9 in terms of the nature of N-protecting groups are described. The conformations of 9 and 24-28 were confirmed by ¹H NMR analysis and NOE correlation. Furthermore, the conformations of piperidines 18 and 23 with hydroxyl methyl substituent at C-2 were investigated by NMR spectroscopy.     

Stereochemical challenges in characterizing nitrogenous spiro-axane sesquiterpenes from the Indo-Pacific sponges Amorphinopsis and Axinyssa

An investigation was conducted to identify the structures and bioactive properties of five compounds isolated from the Halichondrida sponges Amorphinopsis foetida and Axinyssa aplysinoides. All compounds possessed the spiro-axane sesquiterpene core and all were substituted at C-2 with nitrogen containing functionality. The stereochemistry of one known compound has been revised to (2R,5R,10S)-2-formamido-6-axene (3). It exhibited mild selective solid tumor and mild antibacterial activity and was found from Axinyssa. A second known substance whose stereochemistry has also been revised, (2R,5R,10S)-2-isothiocyanato-6-axene (4) plus its undescribed diastereomer (5) were isolated from Amorphinopsis. Both sponges were the source of two new N-phenethyl-2-formamido-6-axene diastereomeric compounds 6 and 7. No solid tumor or antibacterial activity was found for 4-7.     

Daphnezomines P, Q, R and S, new alkaloids from Daphniphyllum humile

Four new alkaloids, daphnezomines P-S (1-4), have been isolated from the fruits of Daphniphyllum humile, and the structures and the stereochemistry were elucidated on the basis of spectroscopic data including 2D NMR and MS/MS spectra, and chemical correlations. Daphnezomines P (1) and Q (2) were the first Daphniphyllum alkaloids with an iridoid glycoside moiety.     

Synthesis and structural determination of the C33-C42 fragment of symbiodinolide

Symbiodinolide (1) is a polyol macrolide with a molecular weight of 2859 mu. As one of the degradation reactions, cross-metathesis of 2, which is a methyl ester of 1, with ethylene was performed to give the C33-C42 degraded fragment 4. The absolute configuration of 4 was estimated to be (36S,40S) by Mosher method. Stereoselective synthesis of 4 was achieved in 14 steps from l-aspartic acid. Synthetic bis-(S)- and (R)-MTPA esters exhibited the spectroscopic data identical with those of bis-(S)- and (R)-MTPA esters derived from the degraded fragment 4. Thus, the absolute stereochemistry of 4 was elucidated to be (36S,40S).     

Thermal rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates. Synthesis of 3H-imidazol-1-ium ylides and their silver derivatives

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD undergo rearrangement to 3,4-dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 3, which spontaneously undergo elimination to give 3H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 5 or 1H-imidazoles 6 when heated in toluene at reflux. The presence of the aromatic ring at C-6 decelerated the conversion and enhanced the yield of 5. Solvents more polar than toluene (e.g., DMSO) provided quantitative conversion of 2 into 6 in mild conditions, while in less polar solvents such as CCl₄, the reaction rate was lowered and the yield of 5 enhanced. C-2 unsubstituted ylides 5 were treated with Ag₂O or AgNO₃ in the presence of Et₃N at room temperature to give C-2 metallated derivatives 9 in excellent yields.     

Novel reactions of lycoctonine analogs: unusual pyrolysis of C4-COOH and hydrogenolysis of N-C6 bond

Pyrolysis of carboxylic acid group at C-4 of 2, an oxidation product from the C₁₉-diterpenoid alkaloid lycoctonine 1, generated an unexpected but novel rearranged product 13 (37%). The structure of 13 was confirmed by its 2D NMR data and its single crystal X-ray crystallographic analysis. In addition, hydrogenolysis of 13 in the presence of acetic acid yielded the N-C6 bond fission products 16 and 17, which represents the first hydrogenolysis involving the breakage of the N-C6 bond of the diterpenoid alkaloids. Some new observations on the oxidation of lycoctonine 1 were described as well.     

Carbenoid induced irreversible ring opening of naphthopyrans

Contrary to expectation rhodium carbenoids do not undergo cycloaddition to the 2H-pyran unit of the isomeric naphthopyrans 3 and 5. With 3, a naphtho[2,1-b]pyran-8-ylacetate, 4 is formed and a novel merocyanine dye 6 results from a cycloaddition across the C-5-C-6 double bond of the naphtho[1,2-b]pyran 5. Tethering the carbenoid to the naphtho[1,2-b]pyran system 5, as in 10, results in a similar mode of addition and affords the intensely coloured tetracycle 11.     

An unexpected reaction of pyridine with acetyl chloride to give dihydropyridine and piperidine derivatives

An unexpected reaction of pyridine with acetyl chloride to give N-acetyl-1,2 and 1,4-dihydropyridyl acetic acid (1, 2) in high yield and regioselectivity has been reported. The key step is the formation of a zwitterionic pyridinium ketene enolate. The effect of different activating agents on the reaction yield and selectivity has been studied. Platinum(IV) mediated hydrogenation of the corresponding methyl esters (7, 8) gave piperidine derivatives (9, 10).     

Caminatal, an aldehyde sesterterpene with a novel carbon skeleton from the Antarctic sponge Suberites caminatus

A new sesterterpene, caminatal 1, containing a bicyclic terpenoid moiety with an aldehyde appendage in combination with an isolated isoprenic aromatic ring leading to a novel carbon skeleton has been obtained from the Antarctic sponge Suberites caminatus. Its structure and relative stereochemistry were established by spectroscopic evidence and biogenetic considerations.     

Synthesis and characterization of boronates derived from non-symmetric amino-bis-phenols

The condensation of 2-[[(2-hydroxyphenyl)amino]methyl]-phenols (1a-1e) with different arylboronic acids led to 12 new monomeric boronates of the type 2-aryl-dibenzo[d,h]-6-aza-1,3-dioxa-2-boracyclononene (2a-2l). The boronates were characterized by ¹H-, ¹³C-, ¹¹B- and 2D-NMR experiments, FT infrared, mass spectra and elemental analyses. The stereochemistry of the H-N → B-Ph fusion is always cis, as established through the NMR spectra, as well as the X-ray structures of four boronates (2a, 2e, 2f and 2l). Hydrogen bonds between the amine proton and the oxygen ester of the five- membered ring are present in three X-ray structures (2a, 2e and 2f), while the supramolecular structure in the derivative possessing a primary amine (2l) is built up through the protons present in this moiety instead of the proton from the H-N → B-Ph fragment.     

Two novel 3,4-seco-trinorlanostane triterpenoids isolated from Ganoderma fornicatum

Two novel 3,4-seco-25,26,27-trinorlanostane triterpeniod compounds, fornicatins A and B (1 and 2) have been isolated from the fruiting body of G. fornicatum. The structural elucidation of 1 and 2 were accomplished by extensive NMR analysis. The relative stereochemistry of 2 was established by single crystal X-ray crystallography, which also confirmed the novel carbon skeleton of the new triterpenoid. An ether linkage of C-4 with C-7 in 1 is unprecedented in natural triterpenoids. Both compounds were tested for their inhibitory effects on rabbit platelet aggregation induced by PAF, ADP, or AA.     

(+)-Cystothiazole G: isolation and structural elucidation

Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpent-4-yne-1,2-diol (6) derived from (2R,3S)-epoxybutanoate 5 followed by methylation gave the tetrahydro-2-furylidene acetate (−)-7, which was converted to the left-half aldehyde (+)-3. A Wittig reaction between (+)-3 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 4 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazole G (2), whose spectral data were identical with those of the natural product (+)-2. Thus, the stereochemistry of cystothiazole G (2) was proved to be (4R,5S,6(E)).     

Synthesis and conformational analysis of tetrahydroisoquinoline- and piperidine-fused 1,3,4,2-oxadiazaphosphinanes, new ring systems

Through cyclization of tetrahydroisoquinoline and piperidine 1,2-hydrazino alcohols with phenylphosphonic dichloride and phenyl dichlorophosphate, P-epimeric diastereomers of 1,6,7,11b-tetrahydro-4H-1,3,4,2-oxadiazaphosphino[5,4-a]isoquinoline-3-oxides (13 and 14), 1,6,11,11a-tetrahydro-4H-1,3,4,2-oxadiazaphosphino[4,5-b]isoquinoline-3-oxides (15 and 16) and 1,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d][1,3,4,2]oxadiazaphosphinane-3-oxides (17 and 18), the first representatives of these ring systems, were prepared. NMR and X-ray diffraction studies revealed that, independently of the P-substituent and the relative configuration of the phosphorus atom, 13, 14, 17 and 18 could be characterized by trans-connected hetero rings and the chair conformation of the 1,3,4,2-oxadiazaphosphinane moiety, while the stereochemistry of the connection of the hetero rings in the 1,3,4,2-oxadiazaphosphinanes linearly fused to tetrahydroisoquinoline (15 and 16) was found to be dependent on the P-configuration relative to that of the carbon at the annelation.     

Synthesis and reactivity of new functionalized Pd(II) cyclometallated complexes with boronic esters

Treatment of the functionalized Schiff base ligands with boronic esters 1a, 1b, 1c and 1d with palladium (II) acetate in toluene gave the polynuclear cyclometallated complexes 2a, 2b, 2c and 2d, respectively, as air-stable solids, with the ligand as a terdentate [C,N,O] moiety after deprotonation of the -OH group. Reaction of 1j with palladium (II) acetate in toluene gave the dinuclear cyclometallated complex 5j. Reaction of the cyclometallated complexes with triphenylphosphine gave the mononuclear species 3a, 3b, 3c, 3d and 6j with cleavage of the polynuclear structure. Treatment of 2c with the diphosphine Ph₂PC₅H₄FeC₅H₄PPh₂ (dppf) in 1:2 molar ratio gave the dinuclear cyclometallated complex 4c as an air-stable solid.Deprotection of the boronic ester can be easily achieved; thus, by stirring the cyclometallated complex 3a in a mixture of acetone/water, 3e is obtained in good yield. Reaction of the tetrameric complex 2a with cis-1,2-cyclopentanediol in chloroform gave complex 2c after a transesterification reaction. Under similar conditions complexes 3a and 3d behaved similarly: with cis-1,2-cyclopentanediol, pinacol or diethanolamine complexes 3c, 3b, 3g and 3f, were obtained. The pinacol derivatives 3b and 3g experiment the Petasis reaction with glyoxylic acid and morpholine in dichloromethane to give complexes 3h, and 3i, respectively.     

Steric course of some cyclopropanation reactions of L-threo-hex-4-enopyranosides

Completely protected 4-deoxy-α-L-threo-hex-4-enopyranosides 1c,d undergo the dichlorocarbene addition affording exclusively diastereomeric adducts 5c,d with the cyclopropane ring anti to the C-3 alkyloxy substituent, while the reaction with 3-unprotected derivatives 1a,b affords a mixture of syn and anti derivatives. Under the Simmons-Smith cyclopropanation adducts 2a-d with a syn stereochemistry are obtained. Starting from 5b, the cyclopropanated sugar 3b is obtained by reduction with LiAlH₄, thus the two diastereomers 2b and 3b can be stereoselectively obtained through the two different pathways. For a useful comparison, 4-deoxy-β-L-threo-hex-4-enopyranoside 1e was also subjected to the above two cyclopropanation methods affording the expected cycloadduct 2e and a diastereomeric mixture of dichlorocycloadducts 4e and 5e (4e/5e=2.8:1).     

Dopamine derivatives from the insect Polyrhachis dives as inhibitors of ROCK1/2 and stimulators of neural stem cell proliferation

Polyrhachis dives is consumed as an insect food in some regions of China. In this study, new dopamine derivatives, (+)-polyrhadopamine A (1a) and (−)-polyrhadopamine A (1b), (+)-polyrhadopamine B (2a) and (−)-polyrhadopamine B (2b), and polyrhadopamines C–E (3–5), were isolated from this species. The structures and stereochemistry of these substances were assigned by using spectroscopic and computational methods. Compounds 1a, 1b, 2a, and 2b are dimeric N-acetyldopamine derivatives, 3 is a dopamine analog containing an unusual sulfone group, and 4 and 5 possess a rare benzo[d]thiazole moiety. The functions of these substances as ROCK1/2 inhibitors, neural stem cell (NSCs) proliferation stimulators, immunosuppressive, and anti-inflammatory agents were determined.