Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC(50) values of 31 and 2.4 microM, respectively. Diol (+)-5 inhibited CETP activity with an IC(50) value of 16 microM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8alpha,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates.     

A Synthesis of (+)-Oblongolide

The absolute configuration of natural oblongolide is reassigned as (3aS,5aR,7S,9aS,9bS)-3a,5a,6,7,8,9,9a,9b-octahydro-7,9b-dimethylnaphtho[1,2-c]furan-1(3H)-one 2 by a 7-stage synthesis of its enantiomer 1 from (+)-citronellol involving a regioselective reduction and an intramolecular Diels-Alder reaction (IMDA) as the key steps. (+)-Citronellol was converted into methyl (2E,4E,10E)-(S)-(+)-11-tert-butoxycarbonyl-7-methyl-undeca-2,4,10-trienoate 7 by sequential Lemieux-Johnson oxidation, Wittig reaction, pyridinium chlorochromate oxidation, and Wadsworth-Emmons-Homer alkenation. A regioselective reduction of the methoxycarbonyl group in 7 afforded tert-butyl (2.E,8E,10E)-(S)-(+)-2,6-dimethyl-12-hydroxy-dodeca-2,8,10-trienoate 8 from which (+)-oblongolide was readily obtained via an IMDA reaction.     

Stereoselective synthesis of (+/-)-rocaglaol analogues

An intramolecular hydroxy epoxide opening was used to access the cyclopenta[b]benzofuran ring system of the natural product rocaglaol (2). Our route allowed the stereocontrolled preparation of the rocaglaol derivative (+/-)-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the (+/-)-(3R*)-epimer of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring. [reaction: see text]     

Synthesis of nucleoside analogues bearing the five naturally occurring nucleic acid bases built on a 2-oxabicylo[3.1.0]hexane scaffold

Hitherto unknown nucleoside analogues incorporating the five naturally occurring nucleic acid bases built on a 2-oxabicyclo[3.1.0]hexane template were synthesized. The synthesis of these new conformationally restricted nucleoside analogues involved the preparation of a suitable sugar precursor bearing the 2-oxabicyclo[3.1.0]hexane scaffold. This sugar was readily obtained from [(3aS,6aS)-2,2-dimethyl-3a,6a-dihydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether (4) following a Simons-Smith-type cyclopropanation reaction. Finally, glycosylation reactions and deprotection provided the nucleoside analogues. Using nucleoside 14 bearing thymine base as a model, we found that the conformation of such nucleoside analogue was restricted toward a (0)T(1) conformation.     

Application of a stereospecific RhCl(PPh3)3 decarbonylation reaction for the total synthesis of 7-(±)-deoxypancratistatin

A highly efficient total synthesis of 7-deoxypancratistatin is described. The synthesis features the ready preparation of the phenanthridone skeleton by a Stille-IMDAF cycloaddition cascade. The resulting cycloadduct is converted into a key aldehydic intermediate, which is then induced to undergo a stereospecific decarbonylation reaction using Wilkinson’s catalyst to set the trans B-C ring junction of the target molecule.     

Cyclopropane-annelated azaoligoheterocycles by Ti-mediated intramolecular reductive cyclopropanation of cyclic amino Acid amides

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.     

Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (+/-)-Lycoricidine and (+/-)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels-Alder cycloaddition cascade to construct the core skeleton. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 degrees C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required pi-bond in the C-ring of (+/-)-lycoricidine, and (2) conversion of the initially formed Diels-Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B-C ring junction of (+/-)-7-deoxypancratistatin.     

Novel Diels-Alder reaction of 4-nitro-1(2H)-isoquinolones

A novel Diels-Alder (DA) reaction with 4-nitro-1(2H)-isoquinolones acting as the dienophile afforded 5(6H)-phenanthridone derivatives. The DA reaction of 4-nitro-1(2H)-isoquinolone with 1-methoxy-1,3-butadiene gave biologically active 5(6H)-phenanthridone possessing in a high yield. Regioselectivity of 4-nitro-1(2H)-isoquinolones with 1-methoxy-3-silyloxy-1,3-butadiene was calculated using molecular orbital (MO) calculations.     

Inhibition of (+)-aristolochene synthase with iminium salts resembling eudesmane cation

Trigonal iminium halides of (4aS,7S)-1,4a-dimethyl- and (4aS,7S)-4a-methyl-7-(prop-1-en-2-yl)-2,3,4,4a,5,6,7,8-octahydroquinolinium ions, aimed to mimic transition states associated with the aristolochene synthase-catalyzed cyclization of (-)-germacrene A to eudesmane cation, were evaluated under standard kinetic steady-state conditions. In the presence of inorganic diphosphate, these analogues were shown to competitively inhibit the enzyme, suggesting a stabilizing role for the diphosphate leaving group in this apparently endothermic transformation.     

Characteristic features of reduction with i-Bu2AlH of products of ring opening with (?)-α-methylbenzylamine of (3aS,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-epoxy-2-benzofuran-1,3-dione

A special procedure of synthesis was developed for amidoaminals of atypical topology through a reduction with i-Bu₂AlH of primary products of thermodynamical opening of (3aS,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-epoxy-2-benzofuran-1,3-dione at treating with (−)-α-methylbenzylamine. Characteristic spectral criteria are described for assignment of diastereomeric compounds; possible routes of reaction stages are considered.     

Mercuric triflate-catalyzed tandem cyclization leading to polycarbocycles

[reaction: see text] We developed Hg(OTf)2-catalyzed cyclization of (E)-1,3-dimethoxy-5-(4-methyl-3-nonen-7-ynyl)benzene leading to the formation of (4aS,10aS)-3,4,4a,9,10,10a-hexahydro-5,7-dimethoxy-1,4a-dimethylphenanthrene in 98% yield with up to 100 catalytic turnovers. This is the first mercuric salt-catalyzed biomimetic tandem cyclization.     

A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin

A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin has been achieved from readily available starting materials via unified strategy employing Sharpless asymmetric dihydroxylation, ring closing metathesis, Overman rearrangement, hydrogenolysis and Bischler–Napieralski reaction in 15 purification steps with 15% overall yield.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

The enantioselective synthesis of tetracyclic methyllycaconitine analogues

A new enantioselective synthesis of ABEF ring analogues of methyllycaconitine has been developed using a chiral cobalt(III) salen-catalyzed Diels-Alder reaction to form the B ring. Subsequent elaboration to form the A, E and F rings was achieved by sequential Dieckmann, Mannich and Wacker-type cyclizations to afford tetracyclic analogues in 97.5% ee.     

Cytotoxic alkaloids and a flavan from the bulbs of Crinum asiaticum var. japonicum

A new pyrrolophenanthridone alkaloid, criasiaticidine A (1), was isolated from the bulbs of Crinum asiaticum var. japonicum, together with pratorimine (2), lycorine (3) and 4'-hydroxy-7-methoxyflavan (4). The structure of the new alkaloid was determined to be 4,5-etheno-9,10-dihydroxy-6-phenanthridone by spectroscopic means. The cytotoxicity of the isolated compounds 1-4 was evaluated in vitro against Meth-A (mouse sarcoma) and Lewis lung carcinoma (mouse lung carcinoma) tumor cell lines. Furthermore, 3 was examined for in vivo antitumor activity with LLC tumor cells.     

An intra/intermolecular suzuki sequence to benzopyridyloxepines containing geometrically pure exocyclic tetrasubstituted alkenes

A route to enable the preparation of 5-benzylidenyl-benzopyridyloxepine analogues was developed to continue our research in the field of nuclear hormone receptor modulators. The key steps are 1) a syn-stereoselective diboration of a tethered aryl alkyne; 2) an intramolecular Suzuki cross-coupling reaction, which forms in a stereo- and regiocontrolled fashion, the 5-exoalkylidenyl 7-membered ring imbedded within the core of the scaffold and; 3) an intermolecular Suzuki to furnish the final tetra-substituted olefinic benzopyridyloxepines.     

1，2，4－三嗪类化合物研究（XXIV）──吡唑并－（5，4－e）－1，2，4－三嗪衍生物的合成

先合成１，２，４－三嗪环，然后并接吡唑环，对标题化合物进行了合成研究。对１，２，４－三嗪环上的硫化反应进行了改进，解决了３个反应活性相近部位的选择性肼解问题；并发现了肼基与乙酸乙酯于室温下反应生成１，３，４－　二唑环的新反应。     

Reaction of ninhydrin with enamino amides of the 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline series and drotaverine

“Push–pull” enamines of the 1,2,3,4-tetrahydroisoquinoline series, 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin- 1-ylidene)acetamides, reacted as 1,3-binucleophiles with ninhydrin to form tricyclic tetrahydroindeno[1,2-b]pyrrole system. The nucleophilic centers in the enamines were the amide NH₂ group and ß-carbon atom of the enamine fragment. The reaction of ninhydrin with 2-[2,2-dimethyl-2,3-dihydrobenzo[f]-isoquinolin-1(4H)-ylidene]-1-(pyrrolidin-1-yl)ethanone involved only addition to the ß-carbon atom of the enamine fragment. The different reaction directions were rationalized by steric effect of two methyl groups in position 3 of the isoquinoline ring. The Knoevenagel condensation product was obtained by the reaction of ninhydrin with drotaverine (base). The structure of the 1,3-addition product, (3aS,8bS,Z)-{2,2-dimethyl-2,3- dihydrobenzo[f]isoquinolin-4(1H)-ylidene}-3a,8b-dihydroxy-1,3,3a,8b-tetrahydroindeno[1,2-b]pyrrole-2,4-dione, was confirmed by X-ray analysis.     

1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecanes: novel spirofused bis-trioxane peroxides

A set of new bis-spirofused 1,2,4-trioxanes 4a-d was obtained from the reaction of cyclohexane-1,4-dione with allylic hydroperoxides 2a-d, bearing an additional hydroxy group in the homoallylic position, by diastereoselective photooxygenation of allylic alcohols 1a-d and subsequent BF(3)-catalyzed peroxyacetalization with the diketone. From the reaction of a monoprotected cyclohexane-1,4-dione 5 with the allylic hydroperoxide 6 derived from the singlet oxygenation of methyl hydroxytiglate, one monospiro compound was obtained, the 1,2,4-trioxane ketone 7, as well as a mixture of the diastereoisomeric syn- and anti bis-1,2,4-trioxanes 8. The structures of bis-1,2,4-trioxanes were examined theoretically by DFT methods and compared with X-ray structural data in order to evaluate the preferential trioxane ring conformational orientation.     

A simple and efficient approach for the synthesis of fluorinated and nonfluorinated octaethylporphyrin-based benzochlorins with variable lipophilicity, their in vivo tumor uptake, and the preliminary in vitro photosensitizing efficacy

Starting from commercially available Ni(II)octaethylporphyrin (OEP), an efficient approach for the preparation of a series of fluorinated and nonfluorinated benzochlorins with variable lipophicity has been developed. Their spectroscopic properties, preliminary in vitro photosensitizing efficacy, and tumor selectivity were determined. Our methodology provides a facile approach for the preparation of the free-base and the related Zn(II) benzochlorins containing alkyl and alkyl ether side chains with variable carbon units. For the preparation of benzochlorins containing alkyl groups attached to the exocyclic phenyl ring, the Ni(II) meso-(2-formylvinyl)octaethyl porphyrin 2 was reacted with various reagents such as (trifluoromethyl)trimethylsilane (TMS-CF3) or the Grignard reagents of various fluorinated or nonfluorinated alkyl halides. The corresponding intermediates 3, 6a-6e, and 8 obtained via intramolecular cyclization under acidic conditions afforded the related benzochlorins 5, 7a-d, and 9 in good yields except for 7e which was obtained in poor yield (11.4%). The alcohol 10 obtained by reacting porphyrin 2 with ethynylmagnesium chloride did not produce the expected acetylenic benzochlorin; instead the corresponding acetyl derivative 11 was obtained as a major product, which under appropriate reaction conditions was converted into a series of alkyl ether derivatives 13a-13d. To obtain a benzochlorin bearing an ester functionality (15), porphyrin 2 was first reacted with ethyl acetate/LDA and the intermediate alcohol 14 was then cyclized with sulfuric acid. Unlike most of the natural and synthetic chlorins, the Zn(II) complexes of the benzochlorin analogues exhibited a significant bathochromic shift ( approximately 10 nm) in the electronic absorption spectra, and the long wavelength absorptions were observed in the range 671-677 nm (epsilon: 43270-50360). For investigating the in vitro efficacy of these analogues, Molt-4 cells were used. At a concentration of 2.5 microM, and a light dose of 4 J/cm2, all benzochlorins produced significant photosensitizing efficacy. The tumor (RIF) and muscle uptake in C3H mice of these photosensitizers was determined by in vivo reflectance spectroscopy. These results indicate that in this series increasing the length of the alkyl or alkyl ether carbon chains at the fused phenyl ring system produced a significant increase in tumor uptake.