Total asymmetric synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin a and of the authentic natural sclerophytins A and B.

An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structure assigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequential Tebbe-Claisen rearrangement of lactones 29 and 30, which originated from the Diels-Alder cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introduced into the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methyl group to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. The superfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means of oxymercuration chemistry. Only then was the exocyclic methylene group unmasked via elimination. An alternative approach to the alpha-carbinol diastereomer proceeds by initial alpha-oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerization at C10. Through deployment of oxymercuration chemistry, it was again possible to elaborate the dual oxygen-bridge network of the target ring system. Oxidation of the organomercurial products with O(2) in the presence of sodium borohydride furnished 72, which was readily separated from its isomer 73 after oxidation to 61. Hydride attack on this ketone proceeded with high selectivity from the beta-direction to deliver (-)-60. Comparison of the high-field (1)H and (13)C NMR properties and polarity of synthetic 5 with natural material required that structural revision be made. Following a complete spectral reassessment of the structural assignments to many sclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytin B was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absolute configurations were properly determined. Key elements of the strategy include dihydroxylation of a medium-ring double bond, oxidation of the secondary hydroxyl in the two resulting diols, unmasking of an exocyclic methylene group at C-11, and stereocontrolled 1,2-reduction of the alpha-hydroxy ketone functionality made available earlier.

Revised constitution of sclerophytins A and B.

[structure: see text] Spectroscopic reevaluation of sclerophytin B, the acetate of sclerophytin A, has demonstrated unequivocally that these coral metabolites are not composed of two ether bridges.

Longiberine and O-methyllongiberine, dimeric protoberberine-benzyl tetrahydroisoquinoline alkaloids from Thalictrum longistylum(1).

Two benzyltetrahydroisoquinoline-protoberberine dimers, longiberine (1) and O-methyllongiberine (2), were isolated from the roots of Thalictrum longistylum and represent a new class of dimeric alkaloids. The structure of longiberine (1) was established by spectral and chemical methods. Reductive cleavage of O-ethyllongiberine (4) with Na/liquid NH(3) yielded (+)-(S)-N-methylcoclaurine (5), which determined one-half of the dimer, and 1D and 2D NMR studies arranged the substituents on the protoberberine nucleus. Chemical conversion of thalidezine (6) to 1 via the O-acetyl N,N-didemethyl derivative 9, which was methylenated in the Mannich reaction and N-methylated by the Eschweiler-Clarke procedure, established the second asymmetric center as S and confirmed the ring size and the order of the substituents for 1. Methylation of 1 with diazomethane formed the O-methyl derivative 2, identical with the natural product.

Four dimeric aporphine-containing alkaloids from Thalictrum fauriei.

Four dimeric alkaloids (1-4) containing an aporphine unit and representing unique structural features were obtained from Thalictrum fauriei and were characterized by spectral and chemical methods. Fauripavine (1), with a munitagine pavine unit, is the first such dimer with an aporphine C-1 diphenyl ether connection; although fauridine (2), also the first of its class, has codamine, a benzyl tetrahydroisoquinoline, linked at the same position. Faurithaline (3) and its 3-methoxy analogue 4, both with reticuline, a benzyl tetrahydroisoquinoline as the second unit, are the first dimers with the diphenyl ether linkage at C-8 of an aporphine oxygenated at C-10 and C-11. Oconovine (8) was converted to 8-hydroxy-O-methyloconovine (12) to determine the effect of oxygenation at C-8 on the proton chemical shift of the C-7 hydrogens in a study to support the C-8 ether linkage of alkaloids 3 and 4. All the alkaloids have the S-configuration at their asymmetric centers as established from their CD spectra when compared with those of model compounds.

Faurine and O-methylfaurine, two novel benzyl-aporphine dimers from Thalictrum fauriei.

Two new benzyl-aporphine dimers, faurine (1) and its O-methyl ether (2), were obtained from Thalictrum fauriei and their structures determined by spectral and chemical methods. Faurine (1), the first dimer with the diphenyl ether connection at C-1 of the aporphine, did not undergo a Hofmann degradation, yet formed a chiral phenanthrene product (6) with cyanogen bromide. Two nondimeric chiral aporphine alkaloids, O-acetylisocorydine and O-methylisocorydine, gave the corresponding phenanthrene products 7 and 8, respectively, under the same conditions, but only compound 7 was optically active.

Cis-clerodane diterpene lactones from Amphiachyris dracunculoides. 3.

Five cis-clerodane lactones, amphiacrolides J (1), K (2), L (3), M (4), and N (5), were isolated from the aerial parts of the composite Amphiachyris dracunculoides. The first four are new compounds, and the fifth was previously reported from another source. All compounds were assigned stereochemical structures based upon spectral and chemical data, including high-field 1D and 2D NMR for complete assignment of 1H- and 13C-NMR spectra. Amphiacrolide N (5) was converted to amphiacrolide J (1) by treatment with MeOH and TFA, and amphiacrolide L (3) was prepared from amphiacrolide B (9) by CrO3 oxidation to ketone 10 followed by its reduction with NaBH4.

Amoenolide K and amoenolide K 19-acetate, two grindelane peroxides from Amphiachyris amoena. Isolation, structure determination, and preparation of amoenolide K from amoenolide A by photochemical oxygenation.

Two new 9,13-diepoxy labdane diterpenes, amoenolide K [1] and its 19-acetate [2], were isolated from the aerial parts of the composite Amphiachyris amoena and their structures were established by spectral methods, especially high-field nmr spectroscopy. Amoenolide K [1] was prepared from amoenolide A [3] by singlet oxygen addition via the ene reaction. A study was made of the ene reaction products with amoenolide K triacetate [5] which showed them to arise from stereospecific oxygen addition to the 8,9-double bond, with the exception of the sterically hindered beta-side at C-9, for which no products were isolated.

Modified labdane diterpenes from Amphiachyris amoena.

Two new modified labdane diterpenes, amoenolide L [1] and amoenolide M [2] with a 3-(p-hydroxyphenyl)propionate ester unit, were isolated from the above-ground parts of Amphiachyris amoena. Their stereochemical structures were assigned by spectral methods including uv, ir, fabms, and one- and two-dimensional high field 1H- and 13C-nmr. Properties of their acetate derivatives are also recorded.

New labdane diterpene glycosides from Amphiachyris amoena.

Five new labdane diterpene glycosides, amoenolide A 19-beta-D-glucopyranoside [1], and amoenolides E [3], F [4], G [6], and H [8] were isolated from the above-ground parts of Amphiachyris amoena. Amoenolide F is a 19-beta-D-glucopyranoside, while the others are 6-alpha-L-arabinopyranosides. Their structures were established by chemical and spectral methods, especially high-field nmr techniques, and complete 1H- and 13C-nmr assignments are given.

Five new labdane diterpenes from Amphiachyris amoena.

Five new labdane diterpenes, amoenolide A 19-aldehyde [2], and amoenolides B [3], C [4], D [5], and J [6] were isolated from the above-ground parts of Amphiachyris amoena, and their structures determined by spectral methods, in particular high-field nmr, and selective chemical studies. Amoenolide J [6] had its carbon skeleton established by the INADEQUATE 13C-13C connectivity nmr experiment.

Amoenolide A and related acetylated labdane diterpenes from Amphiachyris amoena.

Four new labdane diterpenes, amoenolide A [1] and its 19-acetate [2], 6-acetate [3], and 6,19-diacetate [4], were isolated from the above-ground parts of Amphiachyris amoena and their structures established by spectral and chemical methods. High-field 1H- and 13C-nmr assignments were made for each compound using 1D and 2D nmr techniques including 1H single-frequency spin-coupling and nOe difference experiments, one-bond and long-range carbon-hydrogen correlations, and the INADEQUATE carbon-carbon connectivity experiment. The absolute stereochemistry was established by the Horeau partial-resolution chemical method with amoenolide A and racemic 2-phenylbutyric anhydride, and by the cd exciton splitting physical method on the synthetic amoenolide A 2-acetate 6,19-dibenzoate [9].

Chlorosilphanol A and silphanepoxol, labdane diterpenes from Silphium perfoliatum.

Two carterochaetols, chlorosilphanol A and silphanepoxol, isolated from the leaves of Silphium perfoliatum were assigned structures 1 and 3, respectively, from spectral studies and with absolute stereochemistry established by X-ray crystallography of 1. Complete 1H- and 13C-nmr assignments for the parent compounds and their acetates 2 and 4 were made at high-field using 1D and 2D methods, and chlorosilphanol A was chemically converted via its acetate to silphanepoxol. Revision of structure for related carterochaetols in the literature is required, in particular with respect to the stereochemistry at C-12 and that of the side-chain.

cis-clerodane diterpene lactones from Amphiachyris dracunculoides.

Four cis-ent-neoclerodane lactones, amphiacrolide A [2], amphiacrolide B [3], amphiacrolide C [4] and amphiacrolide D [5] were isolated from the aerial parts of Amphiachyris dracunculoides, and their structures established by physical and chemical methods. High field 1H- and 13C-nmr assignments were made for each compound and some of their derivatives by using one- and two-dimensional nmr techniques including nOe difference, COSY, and CH-correlation of one-bond and multiple bond (COLOC) relationships. A chemical correlation of the amphiacrolides to gutierolide [1], a compound with absolute stereochemistry determined by X-ray analysis, established the stereochemistry for the group. Consequently, a compound having reported properties identical with amphiacrolide D [5] must have its structure revised to contain the beta-faced epoxide. Amphiacrolide A [2] had not been reported previously.

High field 1H- and 13C-nmr assignments of grayanotoxins I, IV, and XIV isolated from Kalmia angustifolia.

Grayanotoxins I [2], IV [3], and XIV [4] were isolated from Kalmia angustifolia var. caroliniana, a North American member of the Ericaceae. Their structures were established from physical and spectral data (mp, ir, [alpha]D, uv, cd, ms, 1H and 13C nmr). High field 1H- and 13C-nmr assignments were made for each compound using 1D and 2D nmr techniques including extensive 1H single-frequency spin-decoupling and nOe difference experiments, one-bond and long-range (COLOC) carbon-hydrogen correlations, and the INADEQUATE carbon-carbon correlation experiment. This is the first report of the presence of grayanotoxins IV and XIV in this source, of complete high field (500 MHz) 1H-nmr assignments for any grayanoid, and of 13C-nmr assignments for grayanotoxins IV and XIV. For grayanotoxin I, ambiguities in the literature 13C-nmr assignments have been removed by definitive assignments made through the use of the INADEQUATE experiment.

Inhibition of human platelet aggregation and secretion by ant venom and a compound isolated from venom.

Venom from the tropical ant, Pseudomyrmex triplarinus, has activity against rheumatoid arthritis. Since platelets are involved in inflammatory responses, they were employed to study the effects of venom on prostaglandin-dependent human platelet aggregation and secretion. The assay is very sensitive and uses microliter volumes, which makes it useful as a screen during isolation and characterization of venom components. Whole venom inhibited arachidonic acid- and U46619-induced platelet aggregation with IC50s of 45 and 39 micrograms/ml, respectively. This suggested that venom prevented the action of prostaglandins. Pure venom was fractionated by gel filtration and at least three materials with antiplatelet activity were detected. The smallest component (factor F) was most active and was purified by additional molecular filtration and characterized by UV absorbance, thin-layer chromatography, nuclear magnetic resonance spectra, and activity to platelets. Factor F was identified as adenosine, which is known to stimulate platelet adenylate cyclase and has not been previously reported to be a component of insect venom.

Alkaloids of Thalictrum XXVI. New hypotensive and other alkaloids from Thalictrum minus race B.

The roots of T. minus race B have yielded 9 alkaloids, thalirabine (1), thaliracebine (13), thalfine (19), thalfinine (20), thalrugosaminine (22), thalidasine (13), obaberine (24), thaliglucinone (25) and (S)-reticuline (26). The first two, possessing marked hypotensive activity, were assigned complete structures by physical and chemical methods. Thalfine (19) was given S-configuration at its one asymmetric center and was converted to thalfinine (20) and epithalfinine (21), thus the stereochemistry was established at one of the two optically active positions. The other alkaloids were identified by direct comparison with known samples. Antimicrobial testing showed thalirabine, thaliracebine, thalfine, and thalfinine to be active against Mycobacterium smegmatis.

Alkaloids of Thalictrum XXVII. New hypotensive aporphine-benzylisoquinoline derived dimeric alkaloids from Thalictrum minus race B.

The roots of T. minus race B have yielded, in addition to adiantifoline (1) previously isolated from this source, two new related alkaloids, thaliadine (2) and thaliadanine (5). Both were assigned complete structures by spectral methods and by chemical interconversion to adiantifoline or its product. O-Desmethyladiantifoline should have structure 14, rather than the previously reported 5. All three isolated alkaloids show hypotensive activity in rabbits, and thaliadanine (5) has antimicrobial activity against Mycobacterium smegmatis.

Alkaloids of Thalictrum. XXII. Isolation of alkaloids with hypotensive and antimicrobial activity from Thalictrum revolutum.

Sixteen alkaloids were characterized from Thalictrum revolutum DC., namely; thalidasine, O-methylthalmethine, O-methylthalicberine, thalrugosaminine, thalicarpine, thalmelatine, pennsylvanine, palmatine, berberine, thalifendine, columbamine, jatrorrhizine, deoxythalidastine, thalphenine and magnoflorine. The structure of thairugosaminine (1) a bisbenzylisoquinoline type which was previously proposed on partial data was completely established, including the absolute configuration as S,S. Thalphenine, thalidasine, O-methylthalicberine, thalicarpine, thalrugosaminine and thaliglucinone were found to possess hypotensive activity in rabbits. Thalrugosaminine, thalicarpine, thalmelatine, O-methylthalmethine, pennsylvanine and thalphenine were found to be active against Mycobacterium smegmatis.