Absolute stereochemistry of amphidinolide C: synthesis of C-1-C-10 and C-17-C-29 segments

Two of each diastereomers of the C-1-C-10 and C-17-C-29 segments of amphidinolide C (1) were synthesized. Comparing the ¹H NMR chemical shifts of its MTPA esters with those of linear methyl ester of 1, the absolute configurations at C-7, C-8, C-20, C-23, and C-24 in amphidinolide C (1) were confirmed to be all R.     

Meroterpenoids with diverse ring systems and dioxolanone-type secondary metabolites from Phyllosticta capitalensis and their phytotoxic activity

Twenty meroterpenoids with diverse ring systems including five new ones (1, 2, 5, 6, and 15), together with two new (23 and 24) and two known dioxolanone-type secondary metabolites were isolated from Phyllosticta capitalensis, an endophytic fungus from Cephalotaxus fortunei Hook. Compound 1 was the first example with a 9,14-seco ring A and a five-membered ring B in guignardone derivatives. Compound 2 represented a novel guignardone derivative possessing a 5/7/6/5 ring system with CH₂-7 attached to C-4 rather than C-6 in ring D. The structures of all new compounds were elucidated using spectroscopic data analyses and electronic circular dichroism comparison. The phytotoxic effects of compounds 1–24 on Lactuca sativa and Lolium perenne were evaluated. Compound 22 showed inhibition activity on the shoots growth of L. sativa and L. perenne, as well as the roots growth of L. perenne.     

Cabralea eichleriana dc. (meliaceae)—I structure and stereochemistry of wood extractives

From Cabralea eichleriana DC. (Meliaceae) nine compounds having a dammarane skeleton have been isolated and identified. They are cabraleone 2, ocotillone 3, cabraleadiol 4a, cabralealactone 5, cabraleahydroxylactone 6a, eichlerianic acid 7a, shoreic acid 8a, dammarenolic acid 9a and eichlerialactone 10a. The only limonoid present is fissinolide1. Compounds 7a and 10a are hereby reported for the first time as occurring in Nature. Configurations of ocotillone and cabraleone are revised and have been assigned 20S, 24S and 20S, 24R respectively.     

Chemistry of ayurvedic crude drugs—V : Guggulu (resin from commiphora mukul)—5 some new steroidal components and,stereochemistry of guggulsterol-I at C-20 and C-22

20α-hydroxy-4-pregnen-3-one (5), 20β-hydroxy-4-pregnen-3-one (6), 16β-hydroxy-4,17(20)Z-pregnadien-3-one (4) and 16α-hydroxy-4-prenen-3-one (10) have been isolated as new steroidal components of the gum-resin from Commiphora mukul. A simple procedure for the synthesis of 4 is described. Chirality at C-20, C-22 in guggulsterol-I (3) has been clarified.     

Further chemical studies on the Antarctic nudibranch Austrodoris kerguelenensis: new terpenoid acylglycerols and revision of the previous stereochemistry

The diterpenoid acylglycerol fraction from an extract of the mantle of a new collection of the Antarctic dorid gastropod mollusc Austrodoris kerguelenensis has been chemically analysed. Two novel 2-monoacylglycerols 9 and 12, along with known 1,2-diacyl glyceryl esters 5 and 6, now reassigned as 7 and 8, have been isolated. The linkage of a diterpenoid moiety at C-2 of glycerol characterizes all the compounds. Because the R absolute stereochemistry at C-2 of glycerol has been established for the corresponding 1,3-glyceryl esters 1 and 2, derived from 7 and 8 by acyl-migration of the terpenoid moiety from C-2 to C-3, our finding implies that 1,2-derivatives from Antarctic nudibranchs have the same S stereochemistry as all 1,2-sn-diacylglycerols from the other dorids.     

Combined biotransformations of 4(20),11-taxadienes

Taxuyunnanine C (1) and its analogs (2 and 3), the C-14 oxygenated 4(20), 11-taxadienes from callus cultures of Taxus sp., were regio- and stereo-selectively hydroxylated at the 7β position by a fungus, Abisidia coerulea IFO 4011, and it was interesting that the longer the alkyl chain of the acyloxyl group at C-14 became, the higher the yield of 7β-hydroxylated product was. Besides the three 7β-hydroxylated products (5, 9, 17), other nine new products (7, 11, 12, 14, 15, 16, 18, 20 and 21) and six known products (4, 6, 8, 10, 13 and 19) were obtained. Subsequently, the acetylated derivatives (24 and 27) of 7β-and 9α-hydroxylated products of 1 were regio- and stereo-specifically hydroxylated at the 9α position by Ginkgo cells and 7β position by A. coerulea, respectively. Thus, the two specific oxidations have been combined. These bioconversions would provide not only valuable intermediates for the semi-synthesis of paclitaxel or other bioactive taxoids from 1 and its analogs, but also some useful hints for the biosynthetic pathway of taxoid in the natural Taxus plant.     

Biogenetically significant triterpenes in a species of meliaceae: Cabralea polytricha A.Juss.

Four triterpenes have been isolated from the fruits of Cabralea polytricha A.Juss. (Meliaceae). Two of them are new C₃₀ compounds whose structures have been established as the C-3, C-24 epimer of ocotillol-II and the C-24 epimer of ocotillone-II: 20S, 24S-epoxy-dammarane-3α,25-diol (IIa) and the corresponding 3-keto compound (IVa).     

Structures of cyclootochilone and otochilone,two novel steroidal ketones of the orchids otochilusporecta and otochilusfusca

Cyclootochilone and otochilone, two novel steroidal ketones of the orchids Otochilusporecta were shown to have the structures 1a and 2, respectively, from spectral and chemical evidence, 1a alone has also been obtained from the taxonomically related orchid Otochilusfusca. The significance of these compounds in the biogenetic transformation of lanosterol to steroids and the biogenetic sequence of the origin of 9,19- cyclopropane ring present in some terpenoids and steroids, as well as the mechanism of incorporation of two methyl groups at C-24 of some of these compounds were discussed.     

A model for triterpene side-chain synthesis. 2

A bicyclic model for 17-keto derivatives of triterpenes, trans -1,6-dimethyl-2-methoxybicyclo[4.3.0] nonan-7-one (1), was used to explore side-chain construction concurrent with oxidation at C-8 (triterpene C-16). Oxidation of methylene derivative 2 with selenium dioxide gave β alcohol 14, and borohydride reduction of the corresponding ketone (15) led to the α epimer 16. Each allylic alcohol (14 and 16) reacted stereospecifically with phenylsulfenyl chloride to give, respectively, diastereoisomeric sulfoxides 20 and 19. The latter yielded a conjugate base that was methylated selectively to give sulfoxide 21. Desulfuration of 21 with trimethylphosphite generated the ethylidene α alcohol 22, and following PDC oxidation, E enone 25.This enone was a minor product from an alternative synthesis beginning with ethylidene derivative 3. Treatment of 3 with selenium dioxide followed by PDC gave the isomeric Z enone 24 as the major product. Reaction of 24 with lithium bis-4-methyl-3-pentenylcuprate proceeded by a facial-selective conjugate addition to the euphane CD model 26. The E isomer 25, under similar conditions, gave only an unresolved mixture. These results are compared with similar steroid reactions reported by Trost and Schmuff¹¹.     

Studies on the construction of abutasterone-type and 24-epi-abutasterone-type side chains employing asymmetric dihydroxylation of (E)-20(22),24-cholestadiene

The synthesis of abutasterone-type side chain, (20R,22R,24S)-20,22,24,25-tetrahydroxy-6β-methoxy-3α,5-cyclo-5α-cholestane 4, and 24-epi-abutasterone-type side chain, (20R,22R,24R)-20,22,24,25-tetrahydroxy-6β-methoxy-3α,5-cyclo-5α-cholestane 6, by means of Sharpless asymmetric dihydroxylation of (E)-20(22),24-cholestadiene 1 is described. Construction of abutasterone-type side chain 4 was carried out by selective mono-dihydroxylation of diene 1 with (DHQ)₂AQN, followed by dihydroxylation of the corresponding (24S)-hydroxy-20(22)-cholestene 2 with (DHQD)₂AQN. In contrast, bis-dihydroxylation of 1 with either (DHQD)₂PHAL or (DHQD)₂AQN preferentially occurs to produce 24-epi-abutasterone-type side chain 6.     

Stereocontrolled synthesis of gibberellin A19 from gibberellic acid

The biosynthetically important C-20 gibberellin, gibberellin A₁₉5, has been prepared from the readily obtained C-19 gibberellin, gibberellic acid 8, by means of an efficient stereocontrolled ten step sequence.     

Formal enantioselective synthesis of (+)-vincamine. The first enantioselective route to (+)-3,14-epivincamine and its enantiomer

A formal synthesis of (+)-vincamine (1) from (S)-(+)-2-ethyl-2-(2-methoxycarbonylethyl) cyclopentanone (6a) is described. This intermediate had previously been obtained by our research group in 90% ee through d'Angelo's deracemizing alkylation of the chiral imine 7, easily prepared from (R)-(+)-α-methylbenzylamine and 2-ethyl cyclopentanone with methyl acrylate. A potencial advanced intermediate for the synthesis of (+)-4, an epimer of (+)-1 at positions C-3 and C-14, has also been prepared from 6a.     

An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.     

Chiral ligands derived from abrine. Part 7: Effect of O,S, N in aromatic ring substituents at C-1 on enantioselectivity induced by tetrahydro-β-carboline ligands in diethylzinc addition to aldehydes

The effect of O, S and N atoms in aromatic ring substituents at C-1 position of tetrahydro-β-carboline ligands on the enantioselectivity of diethylzinc additions to benzaldehyde was studied when esters or tertiary alcohol functions were present at C-3. A mechanism is proposed to explain why the ester ligands 2c and 2d, in which the pyridyl N atom is at C′-2 in 2c and at C′-3 in 2d, catalyzed the addition of diethylzinc to benzaldehyde to form the (R)- and (S)-enantiomers of 1-phenyl-1-propanol, respectively. An explanation was also proposed for the moderate enantioselectivity induced by tert-alcohol 3c versus the very small enantioselectivity induced by 3d, containing a 3-pyridyl function at C-1, during diethylzinc additions. A -CH₂-t-Bu substituent at C-1 leads to very high enantioselectivities.     

Enantiospecific synthesis of the sugar amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid

An enantiospecific synthesis of the tetrahydrofuran amino acid (2S,5S)-5-(aminomethyl)-tetrahydrofuran-2-carboxylic acid 1 is reported. The sugar enone 2-(S)-octyl 6-O-acetyl-3,4-dideoxy-α-d-glycero-hex-3-enopyranosid-2-ulose 2a, derived from galactose, was employed as a chiral precursor. The enone 2a was converted by chemical manipulation of the functional groups into the 6-azido-2-O-tosyl-3,4,6-trideoxy-d-erythro-hexono-1,5-lactone 9 as key intermediate. Methanolysis of 9 induced the opening of the lactone and the attack of the hydroxyl group at C-5 to C-2 with the displacement of the tosylate. This reaction led to the formation of the tetrahydrofuran ring of methyl (2S,5S)-5-(azidomethyl)-tetrahydrofuran-2-carboxylate 10, which was readily converted into 1. The overall yield of the sequence was 35%, and all the intermediates and the final product have been fully characterized. In addition, the preferential conformations in solution of lactone 9 and target molecule 1 have been established.     

Preparation of 2,2′-anhydronucleosides: regio- and stereoselective modifications of the base and sugar moieties

2′-Deoxy-2′-iodonucleosides 4–9, obtained from suitably protected furanoid glycals 1 and 2 with different silylated pyrimidine bases, were transformed into the corresponding 2,2′-anhydronucleosides 10–15 with inversion of the configuration at C-2′, by heating in DMF with n-dibutyltin oxide. Regio- and stereospecific opening at C-2′ of the 2,2′-ring in compounds 10, 11, and 12 with sodium azide afforded the related 2′-azido-2′-deoxynucleosides 16, 17 and 18, respectively. Action of sodium hydroxide on 12 caused the regioselective opening of the above-mentioned ring at C-2 with retention of the configuration at C-2′ giving 19. Compound 19 could be transformed straightforwardly into 18 by well-established methodology. On the other hand, compound 15 could be transformed into the related 2′,3′-anhydronucleoside 23 by a regio- and stereoselective addition at N-3–C-2′ of allyl bromide concomitant with 2,2′-ring opening and inversion of the configuration at C-2′ to afford the intermediate 2′-bromo-2′-deoxynucleoside 21, which was subsequently treated with sodium methoxide giving 23.     

Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-tetrahydropyrano[2,3-b]indole derivatives

The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole 20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, respectively, was performed starting from the racemic spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared as key intermediates for the synthesis of enantiopure compounds (−)-19 and (−)-20. Since the amino acid 14 is the common intermediate for the chemoselective preparation of derivatives 19 and 20, experimental and computational studies were performed in order to selectively obtain these compounds and to provide a mechanistic rationalization for their formation.     

Chemical studies of british columbia nudibranchs

The chemical constituents of the skin extracts of several nudibranchs have been examined. Extracts of Archidoris montereyensis contain the diterpenoic acid glyceride 20, its two monoacetates 24 and 25, the drimane sesquiterpenoic acid glyceride 26, the monoacetate 28, the monocyclofarnesic acid glyceride 30 and the glyceryl ether 31. Glyceride 20 has also been isolated from extracts of Archidoris odhneri. The odoriferous principle of Amsodoris nobilis extracts was shown to be the degraded sesquiterpenoid 33. Polycera tricolor extracts contain triophamine (19) as their major constituent. ¹⁴C labelled mevalonic acid is incorporated into the diterpenoic add glyceride 20 and the sesquiterpenoic acid glyceride 26 by A. montereyensis, and into the famesic add glyceride 12 by A. odhneri. The drimenoic add glyceride 26 and the glyceryl ether 31 show antifeedant activity against the tide pool sculpin Oligocottus maculosus.     

System oriented design of triquinanes: stereocontrolled synthesis of pentalenic acid and pentalenene

Pentalenic acid, 5, and pentalenene, 4, and their C-9 epimers 5a and 4a, respectively, were synthesized using [4+1] and [2+3] cyclopentene annulation methodology. The key steps involved internal cyc1opropanation of dienes 23 or cyc1opropanation of enone 25 followed by the thermolytic rearrangements of cyclopropanes 24, 39, 42, 45, and 48 to furnish triquinanes 26 and 40. An investigation of electronic effects affecting the diradical cleavage of viny1cyclopropanes was performed. The triquinanes 26 or 40 were transformed to the title compounds by reductive operations at C-9. The equilibration of esters 60 at C-9 was briefly addressed in the context of molecular mechanics predictions regarding the thermodynamic stabilities of conformations at C-9 in the natural vs. the epi series. The stereoselectivities in approaches to natural hydrocarbons and their C-9 epimers were evaluated as better than 9:1 in each series.     

Synthetic disaccharide analogs as potential substrates and inhibitors of a mycobacterial polyprenol monophosphomannose-dependent α-(1→6)-mannosyltransferase

Analogs of the α-d-Manp-(1→6)-α-d-Manp-O(CH₂)₇CH₃ disaccharide 4, a known substrate for a polyprenol monophosphomannose-dependent α-(1→6)-mannosyltransferase involved in mycobacterial LAM biosynthesis, have been synthesized and screened as potential substrates and inhibitors of the enzyme. In the disaccharides synthesized, the hydroxyl groups at C-2 and C-6 on the reducing end residue have been replaced by combinations of amino, fluoro, and methoxy functionalities 9–14. In addition, a disaccharide in which the nonreducing mannopyranose residue was replaced with a 3,6-anhydromannopyranose residue 34 was synthesized from a byproduct formed during one of the reactions leading to 14. When tested against the enzyme, none were active as substrates, as would be expected as all lack the C-6′ hydroxyl group to which an additional sugar residue would be transferred. Evaluation of these compounds as inhibitors of the enzyme revealed that only three, 11, 12, and 13, all of which contain one or more amino groups, inhibited the enzyme. The most potent inhibitor was the diamino-disaccharide, 11.