A Convergent Synthesis of (±)-α- and β-Himachalenes

(±)-α and β-Himachalene, 5 and 6 , have been synthesized in a convergent manner from 3,3-dimethylacrolein ( 9 ), the ester enolate 10 and the silyloxypentadienyllithium 7 . The key steps are the regioselective γ-addition of the dienal 13 to 7 and the intramolecular Diels-Alder addition 15 → 16 . Hydrogenolysis of the diethylphosphate group and functionalization at C (5) completed the synthesis of 5 and 6 .     

The Terpenoids of Maytenus boaria MOL. (Celastraceae)

The known triterpenoids β-amyrin (= olean-12-en-3β-ol; 22 ), lupeol (= lup-20(29)-en-3β-ol; 17 ), betulin (= lup-20(29)-ene-3β,28-diol; 18 ), lup-20(29)-ene-3β,30-diol ( 20 ), oleanolic acid (= 3β-hydroxyolean-12-en-28-oic acid; 21 ), and betulonic acid (= 3-oxolup-20(29)-en-28-oic acid; 19 ), together with epicatechol (= cis-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol; 23 ), 5′-O-methylgallocatechol (= trans-2-(3,4-dihydroxy-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol; 24 ), and 4-hydroxybenzaldehyde were isolated from the aerial parts of Maytenus boaria (MOL. ). Additonally, the eight 4,C⁴-dihydro-β-agarofuran sesquiterpenoids 1–8 , one of them a diol with a (4R)-configuration, and compound 9 were present in the extract. The structures of these compounds were established by spectroscopic and chemical means.     

New Triterpenes from the Heartwood of Melaleuca leucadendron L.

Fourteen chemical constituents were isolated from the CHCl₃ soluble portion of the heartwood of Melaleuca leucadendron L. These compounds include β-sitosterol (1) , β-sitostenone (2) , 6-hydroxy-4,6-dimethyl-3-hepten-2-one (3) , naphthalene (4) , squalene (5) , 2α3β-dihydroxyurs-12-en-28-oic acid (6) , 3β-hydroxylup-20(29)-en-27,28-dioic acid (7) , 2α,3β-dihydroxyolean-12-en-28-oic acid (8) , 3β,23-dihydroxyolean-12-en-28-oic acid (9) , 2α,3β,23-trihydroxyolean-12-en-28-oic acid (10) , 3β-trans-p-coumaroyloxy-2α,23-dihydroxyolean-12-en-28-oic acid (11) , and three novel oleanane derivatives 23-trans-p-coumaroyloxy-2α,3β-dihydroxyotean-12-en-28-oic acid (12), 3β-trans-caffeoyloxy-2α,23-dihydroxyolean-12-en-28-oic acid (13) , and its isomer 3β-cis-caffeoyloxy-2α,23-dihydroxyolean-12-en-28-oic acid (14) , The three novel compounds were characterized as the two and three O-methylated derivatives, respectively.     

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3, 3-Amino Acid Esters

Mukaiyama–Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama–Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β^{3, 3}-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.     

The Reaction of Patchoulol with Lead Tetraacetate,a Regiospecific Fragmentation

Patchoulol (1) forms 2,2,6,8-tetramethylbicyclo [5.3.1]undec-7-en-3-one (5) with lead tetraacetate. This ketone undergoes acid-catalyzed cyclization to 2,6,6,10-tetramethyltricyclo [5.3.1.0^1,5]undec-9-en-5-ol (10) , and is reduced to 2 stereoisomeric alcohols with lithium aluminium hydride. One of these alcohols 8 is readily dehydrated with cyclization to 2,6,6,10-tetramethyltricyclo [5.3.1.0^1,5]undec-9-ene (12) and a double bond isomer 13 , longer treatment with acid resulting in a Wagner-Meerwein rearrangement to a mixture of two 1,3,7,7-tetramethyltricyclo [6.2.1.0^2,6]-undecenes ( 19 and 20 ), isomeric with β-patchoulene ( 23 ). The other alcohol 7 with p-toluenesulfonic acid forms the cyclic ether, 1,3,7,7-tetramethyl-11-oxatricyclo-[4.4.1.1^2,8]dodecane ( 15 ).     

Identification de stérols à chaîne latérale oxygénée dans une éponge de l'espèce Hyrtios

Thirty-two sterols are identified in the sponge Hyrtios sp. In addition to fourteen monohydroxylated compounds, the sterol fraction contains eight functionalized sidechain sterols, three of them new: 3 β-hydroxy-24-norchol-5-en-23-al (19) , (22-trans)-3 β-hydroxycholest-5, 22-dien-24-one (20) and (22R, 23R, 24S) or (22S, 23S, 24S)- 22,23-epoxy-24-methylchoest-5-en-3 β-ol (24). The probable biological origin, rather than artifact production, of these undescribed components is discussed.     

Identification de stérols à chaînes latérales courtes dans l′éponge Damiriana hawaiiana

Identification of short side chain sterols in the sponge Damiriana hawaiiana The steroidal composition of the sponge Damiriana hawaiiana is examined. Twenty-seven components are identified. In addition to the C₂₆-C₂₉, Δ⁵-mono and diunsaturated sterols, the sponge contains sterols without side-chain: androsta-5, 16-dien-3β-ol( 1 ), androst-5-en-3β-ol( 2 ); sterols with a non-functionalized side-chain consisting of two, three, four, five and six carbon atoms: pregna-5, 20-dien-3β-ol( 5 ), pregn-5-en-3β-ol( 6 ), 23, 24-bisnor-chola-5, 20-dien-3β-ol( 7 ), 23, 24-bisnor-chol-5-en-3β-ol( 8 ), 24-nor-chol-5-en-3β-ol( 10 ), chol-5-en-3β-ol( 11 ), 26, 27-bisnor-cholest-5-en-3β-ol( 12 ), and sterols possessing a short oxygenated side-chain such as 3β-hydroxy-androst-5-en-17-one( 3 ), androst-5-en-3β, 17β-diol( 4 ) and 3β-hydroxy-26, 27-bisnor-22-trans-cholesta-5, 22-dien-24-one( 14 ). The probable biological or dietary origin rather than artifact production of these hitherto undescribed components from marine sources is supported by their relatively high concentration and their relative proportions, both very different from those expected for autoxidation.     

Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and their use as building blocks for the solid-phase synthesis of β-peptides

N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β³-amino acids β³: side chain and NH₂ at C(3)(= C(β)) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β²- Amino acids (β² side chain at C(2), NH₂ at C(3)(= C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β³-heptapeptides 5–8 , a β³- pentadecapeptide 9 and a β²-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β³-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12 ). The CD spectra of the β²- and β³-peptides 5 , 9 , and 10 show the typical pattern previously assigned to an (M) 3₁ helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5 , this corresponds to a 2.5 fold increase in the molar ellipticity per residue!     

The Deoxygenation and Isomerization of Artemisinin and Artemether and Their Relevance to Antimalarial Action

The treatment of artemisinin ( 1 ) and β-artemether ( 6 ) with Zn dissolving in AcOH for a few hours results in mono-deoxygenation giving deoxyartemisinin ( 5 ) and deoxy-β-artemether ( 7 ), respectively, as the sole product. In contrast, submission of 1 to FeCl₂ · 4 H₂O in MeCN at room temperature for 15 min causes only isomerization, (3aS,4R,6aS,7R,10S,10aR)-octahydro-4,7-dimethyl-8-oxo-2H-10H-furo[3,2-i] benzopyran-10-yl acetate ( 8 ) and (3R)-3-hydroxydeoxyartemisinin ( 9 ) being produced in 78 and 17% yield, respectively. The action of FeCl₂ · 4 H₂O in MeCN on 6 is similar. Under the same conditions, 6 gives products analogous to 8 and 9 accompanied by an epimeric mixture of 2-[4-methyl-2-oxo-3-(3-oxobutyl)cyclohexyl]propanaldehyde in yields of 32, 23, and 16%, respectively. No epoxide is formed on repeating the last two experiments in the presence of cyclohexene. The deoxygenation of 1 and 6 by Zn is rationalized in terms of its oxophilic nature. The catalyzed isomerization of 1 and 6 by Fe²⁺ is attributed to the redox properties of the Fe²⁺/Fe³⁺ system.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 10. Reactions with ester enolates. Synthesis of 4-hydroxy-1-methyl-3-prenyl-2(1H)-quinolinones,Crucial intermediates in the synthesis of quinoline alkaloids

N-Methylisatoic anhydride reacts with the lithium enolates of esters to produce β-ketoesters 4 in nearly quantitative yield. Thermal cyclization of these relatively unstable intermediates afford the corresponding 3-substituted-4-hydroxy-1-methyl-2(1H)-quinolinones (5) in good yields. The reaction of the lithium enolate of 5-methyl-4-hexenoic acid ethyl ester ( 14 ) with various nuclear substituted isatoic anhydrides gives 4-hydroxyl-methyl-3-prenyl-2(1H)-quinolinones 8, 9 , and 18 which are highly desirable intermediates in the synthesis of a variety of quinoline alkaloids. Treatment of 18 with DDQ furnishes oricine in 73% yield.     

Photochemische Reaktionen. 109. Mitteilung [1]. Zur Photochemie konjugierter δ-Keto-enone und β,γ,δ,ϵ-ungesättigter Ketone

Photochemistry of Conjugated δ-Keto-enones and β,γ,δ,?-Unsaturated Ketones On ¹π,π*-excitation the δ-keto-enones 5–8 are isomerized to compounds B ( 18 , 22 , 26 , 28 ) via 1,3-acyl shift and to compounds C ( 19 , 23 , 27 , 29 ) via 1,2-acyl shift, whereas the β,γ,δ,?-unsaturated ketone 9 gives the isomers 32 and 33 by 1,2-and 1,5-acyl shift, respectively. Furthermore, isomerization of 6 to 24 , dimerization of 8 to 30 and addition of methanol to 8 ( 8 → 31 ) is observed. Unlike 7 and 8 the acyclic ketones 5 , 6 and 9 undergo photodecarbonylation on ¹π,π*-excitation ( 5 → 20 , 21 ; 6 → 20 , 25 ; (E)- 9 → 35–38 ). Evidence is given, that the conversion to B as well as the photodecarbonylation of 5,6 and 9 arise from an excited singulet state, but the conversion to C as well as the dimerization of 8 from the T₁-state.     

Heterotricyclodecane XXVII. Ein weiterer Zugang zu 2,6-Dioxatricyclo [3.3.2.03,7]decan

A Further Approach to 2,6-Dioxatricyclo[3.3.2.0^3,7]decane A further synthesis of 2,6-dioxatricyclo[3.3.2.0^3,7]decane ( 10 ) is described by bridging the 9-oxabicyclo[4.2.1]non-7-en-3endo-ol ( 9 ). The latter compound was prepared by ring expansion starting from the known 8-oxabicyclo[3.2.1]oct-6-en-3-on ( 1 ).     

O-(α-D-Glucopyranosyl)trichloroacetimidate as a Glucosyl Donor

Model reactions of 0-(α-D-glucopyranosyl)trichloroacetimidate 2α with methanol and choTesterol under various conditions demon-strated that stereocontrolled glucosyl transfer with inversion of configuration at the anomeric center is best carried out in di-chloromethane at low temperatures with boron trifluoride-ether as a catalyst. Under these conditions β-glucoside 4β and β-disaccha-rides 5β- 9β were obtained in good to excellent yields.

With Brtosnsted acids, fast glucosyl transfer to the acid anion was mainly observed and required no further acidic catalysis. With strong acids formation of the thermodynamically more stable product dominated. However, with the weaker carboxylic acids highly diastereoselective inversion of configuration at the anomeric center led, for instance, to β-1-O-acyl derivatives 11β - 18β, revealing a convenient method for the synthesis of O-glycosyl-carb-oxylates. This method was also applied to resolution of racemic carboxylic acids.

Similar results were obtained with N-nucleophiles. Hydrazoic acid gave exclusively α-azide 19a. Nitrogen heterocycles gave with boron trifluoride-ether catalysis mainly β-nucleosides 20β - 23β. Reaction of trichloroacetimidate 2α with O-nucleophiles in aceto-nitrile as solvent led to different products due to competition     

Synthesis of β -Cyperone via Fungal Hydroxylation of thujone-derived tricyclic cyclopropanes

Synthesis of optically active sesquiterpenes with a eudesmane C-skeleton from the chiral starting material thujone involves transformation of a tricyclic intermediate (1R,2R,4S)-1,7-dimethyl-4-(1-methylethyl)tricyclo[4.4.0.0^2,4]dec-6-en-8-one ( 2 ) into the bicyclic compound β -cyperone ( 5 ). Hydroxylation of 2 at C(5) or C(11) permits subsequent opening of the cyclopropane ring and rearrangement to β -cyperone. In this publication, studies involving hydroxylation of 2 by fungal cultures are presented. The resultant products are useful intermediates in efficient synthesis of eudesmane sesquiterpenes. Of five fungi tested, Rhizopus oryzae ATCC 11145 proved most versatile. It hydroxylates at the exocyclic C(11) position in high yield (70%) and, to a lesser extent, at C(5) (5%). Enzymatic activity appears at the end of growth phase and at least 2.2 g of 2 per liter can be metabolized without significant loss of product yield. A second fungus, Cunninghamella echinulata ATCC 9244, proved most useful for hydroxylation of derivatives of 2 for the preparation of derivatives of β -cyperone, although product yields were low (2–20%), some derivatives were nonreactive, and hydroxylation at C(9) occurred. The relationship between precursor structure and enzyme affinity is discussed.     

Intercalating Nucleic Acids with Insertion of 5‐[(Pyren‐1‐yl)methylidene]hydantoin‐Substituted Butane‐1,2‐diol

Isopropylidene‐protected (S)‐4‐O‐(methylsulfonyl)butane‐1,2,4‐triol was used for alkylation of 5‐[(pyren‐3‐yl)methylidene]hydantoin to give the N³‐monoalkylated product 4 in 29% yield together with a dialkylated product 5 in 12% yield. After deprotection, compound 4 was transformed into a dimethoxytrityl (DMT)‐protected phosphoramidite building block 9 for standard DNA synthesis. When inserted as a bulge in the triplex‐forming oligomer, compound 6 stabilizes a DNA triplex, whereas the corresponding DNA/DNA and DNA/RNA duplexes are slightly destabilized. For the triplex, fluorescence enhancement was observed at 500 nm.     

Photochemical reactivity of α,β-unsaturated δ-lactams: Synthesis of seco-steroids. Photochemical reactions. XIII [1]

The UV. irradiation of 17 β-hydroxy-2-aza-4-androsten-3-one (1) , N-methyl-17 β-hydroxy-2-aza-4-androsten-3-one (3) , 17 β-hydroxy-4-aza-5 β-androst-1-en-3-one (2) and N-methyl-17 β-hydroxy-4-aza-5 β-androst-1-en-3-one (4) , gives rise to 1,10-seco (from 1 and 3 ) and 5, 10-seco (from 2 and 4 ) steroids.     

Steroidal analogues of unnatural configuration—VII : Total synthesis of 17β-hydroxy-9-methyl-9β, 10α-oestr-4-en-3-one,a novel retrotestosterone isomer

Conjugate methylation of 17β-hydroxy-des-a-oestr-9-en-5-one (1) and the derived 4,5-seco-steroid (6b) afforded the respective 9β-methyl compounds. Base-catalysed alkylation of 17β-hydroxy-9-methyl-des-a-9/gb-oestran-5-one (3a) resulted in attack at C(6); this result was used to prepare the anthrasteroid (5). Ring closure of the 9β-methyl-4,5-seco-steroid (8) derived from 6b afforded 17β-hydroxy-9-methyl-9β,10α-oestr-4-en-3-one (9a). Conjugate methylation of 17β-hydroxyoestra-4,9-dien-3-one (11) resulted in 1,4-addition to the dienone system.     

Synthese von Pyrano[3,2-b][1]benzopyranen aus 1-Nitroglycalen

Synthesis of Pyranol [3,2-b][1]benzopyrans from 1-Nitroglycals A synthesis of pyrano[3,2-b][l]benzopyrans β-addition of salicylic aldehyde to 1-nitroglycals, followed by a Henry reaction, is described. This sequence gave the cis-annelated pyranobenzopyranes 9 and 11 from 5 in 54 and 9% yield, respectively, demonstrating the pronounced diastereoselectivity of the β-addition. Reductive denitration of the crude product mixture yielded 14 (75%), 15 (15%), and 16 (7%), which were oxidized to the aryl ketones 20 and 21 , respectively. Reduction of 20 (NaBH₄) gave exclusively 15 . The ketone 20 was deprotected to 22 and 23 .     

Bildung von 4-, 5- und 6gliedrigen Heterocyclen durch ambidoselektive Ringschlüsse von Enolat-Ionen

Formation of 4-, 5- and 6-membered heterocycles by ambidoselective cyclization of enolate anions N-Acylmethyl-N-chloracetyl-2,6-dimethylanilines 4 were cyclized with base to 4-, 5- or 6-membered ring compounds, depending on the substituent R² (Scheme 2). All products can be rationalized as derived from the intermediate enolate anions a and b . The enolate anion a reacts by intramolecular alkylation to yield either 1, 4-oxazines 5 or azetidines 6 (Schemes 1, 3 and 7). The regioselectivity observed is expected on the basis of the allopolarization principle. The enolate anion b reacts only with formation of a new C? C bond (Scheme 5). Comparison with the behaviour of the 2, 6-unsubstituted anilines 9, 1a and 12 , shows a strong dependence not only on electronic but also on steric factors (Scheme 4 and 6).     

A Versatile Approach for Synthesis of 2,3-Dimethyl Chroman-4-ones,Intermediate for Calanolide Anti-HIV Agents,VIA Aldol/Mitsunobu Reactions

Combined aldol/Mitsunobu reactions have been employed for the first time for synthesis of 2,3-dimethyl chroman-4-ones, intermediates for calanolide anti-HIV agents. Thus, the lithium enolate of chromene 1 reacted with acetaldehyde at -78°C to afford the aldol products 4 and 5. Under Mitsunobu conditions (Ph₃P/DEAD), the syn aldol product 4 led to the formation of trans-2,3-dimethyl chroman-4-one 2 while the anti aldol product 5 yielded both trans and cis derivatives (2 and 3). The use of other phosphorous and azo compounds in this reaction has also been investigated.