Über Alkaloide aus Laurelia novae-zelandiae A. CUNN. 5. Mitteilung über natürliche und synthetische Isochinolinderivate

From an extract of Laurelia novae-zelandiae A. CUNN . the aporphine alkaloids (?)-pukateine (I), (?)-pukateine methyl ether (II), (?)-roemerine (IV), (?)-mecambroline (V), (+)-boldine (VII), (+)-isoboldine (VIII), (+)-laurolitsine (IX), and the proaporphine alkaloid (+)-stepharine (X) were isolated. Compounds II and V were up to now not described as natural alkaloids. These and the alkaloids IV, VII, VIII, IX and X are new for L. novae-zelandiae.     

Indolalkaloide aus den Blättern von Hedranthera barteri (Hook. f.) Pichon. 146. Mitteilung über Alkaloide

From the leaves of the West African plant (Apocynaceae Hedranthera barteri) has been isolated the phenolic (?)-desmethyl-vobtusine ( 3 ), alongside the already known bisindole alkaloids (?)-goziline ( 1 ) and (?)-vobtusine ( 2 ). The new alkaloid 3 has been spectroscopically characterised and correlated with (?)-vobtusine ( 2 ). Furthermore, the ‘monomeric’ alkaloids (?)-hedrantherine ( 4 ) and (?)-17-hydroxy-hedran-therine ( 5 ) were found in the leaves of H. barteri. Both of these alkaloids contain a cyclic semiacetal group. These bases and their derivatives possessing an unchanged β-anilinoacrylester group show, in the mass spectrometer, the same characteristic fragmentation as vincadifformine ( 11 ), whilst their 2,3-dihydroderivatives bear more of a resemblance to aspidospermine. From the strongly negative Cotton effect of 4 and 22 at 300–350 nm follows the absolute configuration in these bases of centre 12. Hedrantherine ( 4 ) represents the lower half of the bisindole type of vobtusine bases. The upper half has previously been encountered in form of the alkaloid beninine in the rootbark of H. barteri.     

Über die Stereoselektivität der α-Alkylierung von (1R, 2S) (+)-cis-2-hydroxy-cyclohexancarbonsäureäthylester

The Stereoselectivity of the α-Alkylation of (+)-(1R, 2S)-cis-Ethyl-2-hydroxy-cyclohexanecarboxylate In continuation of our work on the stereoselectivity of the α-alkylation of β-hydroxyesters [1] [2], we studied this reaction with the title compound (+)- 2 . The latter was prepared through reduction of 1 with baker's yeast. Alkylation of the dianion of (+)- 2 furnished (?)- 4 in 72% chemical yield (Scheme 1) and with a stereoselectivity of 95%. Analogously, (?)- 7 was prepared with similar yields. Oxidation of (?)- 4 and (?)- 7 respectively furnished the ketones (?)- 6 (Scheme 3) and (?)- 8 (Scheme 4) respectively, each with about 76% enantiomeric excess (NMR.). It is noteworthy that yeast reduction of rac- 6 (Scheme 3) is completely enantioselective with respect to substrate and product and gives optically pure (?)- 4 in 10% yield, which was converted into optically pure (?)- 6 (Scheme 3). The alkylation of the dianionic intermediate shows a higher stereoselectivity (95%) from the pseudoequatorial side than that of 1-acetyl- or 1-cyano-4-t-butyl-cyclohexane (71% and 85%) [9] or that of ethyl 2-methyl-cyclohexanecarboxylate (82%). The stereochemical outcome of the above alkylation is comparable with that found in open chain examples [1] [2]. Finally (+)-(1R, 2S)- 2 was also alkylated with Wichterle's reagent to give (?)-(1S, 2S)- 9 in 64% yield. The latter was transformed into (?)-(S)- 10 and further into (?)-(S)- 11 (Scheme 5). (?)-(S)- 10 and (?)-(S)- 11 showed an e.e. of 76–78% (see also [11]). Comparison of these results with those in [11] confirmed our former stereochemical assignment concerning the alkylation step.     

Stereoselective Conversion of Campholene- to Necrodane-Type Monoterpenes. Novel Access to (−)-(R,R)- and (R,S)-α-Necrodol and the Enantiomeric γ-Necrodols

Naturally occurring (?)-(R,R)-α-necrodol ((?)- 1 ) and its C(4)-epimer (?)- 2 are obtained in 84 and 44% yields, respectively, by lithium ethylenediamide (LEDA) treatment of the corresponding β-necrodols (?)- 3 and (?)- 4 (Scheme 1, Table), both readily available from (?)-campholenyl acetate ((?)- i ) by an efficient stereoselective synthesis. The thermodynamically preferred (?)-(R)-γ-necrodol ((?)- 5 ) becomes the major product (≥ 80% yield) after either prolonged treatment with LEDA or exposure of α- and β-necrodols to BF₃·Et₂O. In an alternative route, (+)- 5 is prepared starting from (+)-campholenal ((+)- ii ) via Pd-catalysed decarbonylation to (?)-(S)-1,4,5,5-tetramethylcyclopent-l-ene ((?)- 6 ) and subsequent application of an acid-catalysed CH₂O-addition/rearrangement sequence (Scheme 2).     

1‐Phenyl‐1,2‐cyclohexadiene: Astoundingly High Enantioselectivities on Generation in a Doering–Moore–Skattebøl Reaction and Interception by Activated Olefins

The resolution of (1α,5α,6α)‐6‐bromo‐6‐fluoro‐1‐phenylbicyclo[3.1.0]hexane (rac‐ 5) provided the enantiomerically pure precursors (?)‐ 5 and (+)‐ 5 of 1‐phenyl‐1,2‐cyclohexadiene. On treatment of (?)‐ 5 with methyllithium in the presence of 2,5‐dimethylfuran, the pure (?)‐enantiomer of the [4+2] cycloadduct of 2,5‐dimethylfuran onto 1‐phenyl‐1,2‐cyclohexadiene was obtained exclusively. From this result, it is concluded that pure (M)‐1‐phenyl‐1,2‐cyclohexadiene ((M)‐ 7 ) emerged from (?)‐ 5 and was enantiospecifically intercepted to give the product. In the case of indene as trap for (M)‐ 7 , the (?)‐ and the (+)‐enantiomer of the [2+2] cycloadduct were formed in the ratio of 95:5. Highly surprising, remarkable enantioselectivities were also observed, when (M)‐ 7 was trapped with styrene to furnish two diastereomeric [2+2] cycloadducts. Hence, the achiral conformation of the diradical conceivable as intermediate cannot play a decisive part. The enantioselective generation of (M)‐ and (P)‐ 7 by the β‐elimination route was tested as well. Accordingly, 1‐bromo‐2‐phenylcyclohexene was exposed to the potassium salt of (?)‐menthol in the presence of 2,5‐dimethylfuran, and the enantiomeric [4+2] cycloadducts of the latter onto (M)‐ and (P)‐ 7 were produced in the ratio of 55:45.     

Preparation and Absolute Configuration of (−)-(E)-α-trans-Bergamotenone

The synthesis, absolute configuration, and olfactive evaluation of (?)-(E)-α-trans-bergamotenone (= (?)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (?)- 1 ), as well as its homologue (?)- 19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (?)-α-trans-bergamotene (= (?)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (?)- 2 ), together with those of the structurally related aldehydes (?)- 3a,b and alcohols (?)- 4a,b , have been rigorously assigned.     

Totalsynthese und absolute Konfiguration von natürlichem Multifloramin

The diphenol 1 was resolved into its antipodes and their absolute configuration was established. The levorotatory isomer R-(?)- 1 was oxidized to the dienone R-(?)- 6 , which was rearranged to afford natural (?)-multifloramine (R-(?)- 7 ), thus establishing that the latter has the R-configuration. By the same reaction sequences, the enantiomeric diphenol S-(+)- 1 was transformed to provide (+)-multifloramine (S-(+)- 7 ) of the S-configuration.     

Isolierung von (−)-Dunnion aus Calceolaria integrifolia MURR. (Scrophulariaceae)

Isolation of (?)-dunnione from the leaves of Calceolaria integrifolia, MURR . (fam. Scrophulariaceae) From the leaves of Calceolaria integrifolia, a plant often used in horticulture. partially racemic (?)-dunnione (1) has been isolated. This seems to be the first record of its occurrence outside the family Gesneriaceae, where it previously has been found in two species as the (+)-enantiomer.     

Concise Syntheses of bis‐Strychnos Alkaloids (−)‐Sungucine, (−)‐Isosungucine,and (−)‐Strychnogucine B from (−)‐Strychnine

The first chemical syntheses of complex, bis‐Strychnos alkaloids (?)‐sungucine ( 1 ), (?)‐isosungucine ( 2 ), and (?)‐strychnogucine B ( 3 ) from (?)‐strychnine ( 4 ) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N‐oxide; (2) a biomimetic Mannich coupling to forge the signature C23?C5′ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH₃CN‐mediated reduction to fashion the ethylidene moieties in 1 – 3 . DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.     

Thermische Umlagerung von 2-Oxa-bicyclo [3.3.1]-non-7-en-3-on; eine neuartige Lactonumlagerung. Vorläufige Mitteilung

Thermal Rearrangement of 2-Oxa-bicyclo [3.3.1]-non-7-en-3-ones; a Novel Lactone Rearrangement Lactone (+)- 2 was prepared by iodolactonisation and subsequent elimination in 51% yield from the known acid (+)- 1 (Scheme 1). Alkylation of (+)- 2 furnished (+)- 3a , (+)- 3b and (+)- 3c , respectively (Scheme 2). Heating of (+)- 3a in boiling DMF racemized the compound ((+)- 3a ? (?)- 4a ). Heating of (+)- 3b and (+)- 3c , respectively, equilibrated them with (?)- 4b and (?)- 4c , respectively. This results are interpreted as a [3.3]-sigmatropic rearrangement with a transition state as depicted in a .     

Macrocarpamin,ein neues Bisindolalkaloid aus Alstonia macrophylla WALL. 167. Mittelung über organische Naturstoffe

Macrocarpamine, a new bisindole alkaloid from Alstonia macrophylla WALL . A new bisindole alkaloid give the name (?)-macrocarpamine ( 3 ) was isolated from the bark of Alstonia macrophylla WALL . Under pyrolytic conditions 3 is cleaved into the two known bases (+)-pleiocarpamine ( 2 ) and (?)-anhydro macrosalhin-methin ( 5 ) (Scheme 1). The structure of 3 (including relative configuration) was deduced on the basis of chemical evidence and from its UV.-, IR.-, NMR.- and mass spectroscopic data.     

Analogues of α‐Campholenal (= (1R)‐2,2,3‐Trimethylcyclopent‐3‐ene‐1‐acetaldehyde) as Building Blocks for (+)‐β‐Necrodol (= (1S,3S)‐2,2,3‐Trimethyl‐4‐methylenecyclopentanemethanol) and Sandalwood‐like Alcohols

To complete our panorama in structure–activity relationships (SARs) of sandalwood‐like alcohols derived from analogues of α‐campholenal (= (1R)‐2,2,3‐trimethylcyclopent‐3‐ene‐1‐acetaldehyde), we isomerized the epoxy‐isopropyl‐apopinene (?)‐ 2d to the corresponding unreported α‐campholenal analogue (+)‐ 4d (Scheme 1). Derived from the known 3‐demethyl‐α‐campholenal (+)‐ 4a , we prepared the saturated analogue (+)‐ 5a by hydrogenation, while the heterocyclic aldehyde (+)‐ 5b was obtained via a Bayer‐Villiger reaction from the known methyl ketone (+)‐ 6 . Oxidative hydroboration of the known α‐campholenal acetal (?)‐ 8b allowed, after subsequent oxidation of alcohol (+)‐ 9b to ketone (+)‐ 10 , and appropriate alkyl Grignard reaction, access to the 3,4‐disubstituted analogues (+)‐ 4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)‐ 4b or its methyl ketone (+)‐ 4h , afforded stereoselectively the trans‐epoxy derivatives 11a,b , while the minor cis‐stereoisomer (+)‐ 12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans‐epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans‐epoxy aldehyde (+)‐ 11a or by stereoselective epoxidation of the α‐campholenol (+)‐ 15a or of its acetate (?)‐ 15b , respectively. Their cis‐analogues were prepared starting from (+)‐ 12a . Either (+)‐ 4h or (?)‐ 11b , was submitted to a Bayer‐Villiger oxidation to afford acetate (?)‐ 16a . Since isomerizations of (?)‐ 16 lead preferentially to β‐campholene isomers, we followed a known procedure for the isomerization of (?)‐epoxyverbenone (?)‐ 2e to the norcampholenal analogue (+)‐ 19a . Reduction and subsequent protection afforded the silyl ether (?)‐ 19c , which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)‐ 20c . Further oxidation and epimerization furnished the trans‐ketone (?)‐ 17a , a known intermediate of either (+)‐β‐necrodol (= (+)‐(1S,3S)‐2,2,3‐trimethyl‐4‐methylenecyclopentanemethanol; 17c ) or (+)‐(Z)‐lancifolol (= (1S,3R,4Z)‐2,2,3‐trimethyl‐4‐(4‐methylpent‐3‐enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)‐ 4b gave the saturated cis‐aldehyde (+)‐ 21 , readily reduced to its corresponding alcohol (+)‐ 22a . Similarly, hydrogenation of β‐campholenol (= 2,3,3‐trimethylcyclopent‐1‐ene‐1‐ethanol) gave access via the cis‐alcohol rac‐ 23a , to the cis‐aldehyde rac‐ 24 .     

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

A new approach for synthesis of fawcettimine‐type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels–Alder reaction followed by redox‐controlled elaboration. Eventually, (?)‐8‐deoxyserratinine, (+)‐fawcettimine, (?)‐lycopoclavamine‐A, (?)‐serratine, (?)‐lycopoclavamine‐B and (?)‐serratanidine were successfully accessed.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)‐Epiglobulol and (−)‐4β,7α‐ and (−)‐4α,7α‐Aromadendranediols

Three natural aromadendrane sesquiterpenes, (?)‐epiglobulol, (?)‐4β,7α‐aromadendranediol, and (?)‐4α,7α‐aromadendranediol, have been synthesized in only seven steps in 12, 15, and 17 % overall yields, respectively, from (E,E)‐farnesol by a stereodivergent gold(I)‐catalyzed cascade reaction which forms the tricyclic aromadendrane core in a single step. These are the shortest total syntheses of these natural compounds.     

Enantioselective Access to (−)‐Ambrox® Starting from β‐Farnesene

Starting from inexpensive (E)‐β‐farnesene ( 1 ), an eight‐step enantioselective synthesis of the olfactively precious Ambrox^® ((?)‐ 2a ) has been performed. The crucial step is the catalytic asymmetric isomerization of (2E,6E)‐N,N‐diethylfarnesylamine ( 3 ) to the corresponding enamine (?)‐(R,E)‐ 4a , applying Takasago's well‐known industrial methodology. The resulting dihydrofarnesal ((+)‐(R)‐ 5 ) (90% yield, 96% ee), obtained after in situ hydrolysis (AcOH, H₂O), was then cyclized under catalytic SnCl₄ conditions, via its corresponding unreported enol acetate (?)‐(R)‐ 4b , to afford trans‐decalenic aldehyde (+)‐ 6a . Subsequent transformations furnished bicyclic ketone (?)‐ 8a and unsaturated nitrile (+)‐ 11 , both reported as intermediates to access to (?)‐ 2a .     

The Absolute Configuration of β-Bisabolol

From bergamot oil (Citrus bergamia RISSO), (?)-(4S, 8R)-8-epi-α-bisabolol ( 2 ) and (?)-(4R, 8S)-4-epi-β-bisabolol ( 3 ) were isolated. The absolute configuration of their stereoisomers 4 and 5 was established by an enantioselective synthesis starting from (?)-(S)-p-mentha-1,8-dien-4-ol.     

Indole‐Diterpene Synthetic Studies: Total Synthesis of (−)‐21‐Isopentenylpaxilline

An efficient, stereocontrolled total synthesis of the complex indole‐diterpene alkaloid (?)‐21‐isopentenylpaxilline ( 1 ) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (?)‐ 68 , involving a highly efficient union of the eastern and western fragments (?)‐ 68 and 5 exploiting our 2‐substituted indole synthesis, application of the Negishi π cycloalkylation tactic as a new, potentially general protocol for the construction of ring C, and the fragmentation of a β,γ‐epoxy ketone to introduce the tertiary OH group at C(13) in the indole diterpene skeleton.     

Asymmetrische Synthese von L-γ-Carboxyglutaminsäure-Derivaten

Asymmetric synthesis of L -γ-carboxyglutamic acid derivatives A modified Strecker synthesis according to Patel & Worsley was used to prepare γ,γ′-di-t-butyl L (?)-N-phthaloyl-γ-carboxyglutamate with almost 100% optical purity and an overall yield of about 10% relative to di-t-butyl malonate, or 20% relative to (?)-α-methyl-benzylamine (s. Scheme).     

Le (−)-(2S)-2-Hydroxyhexanedioate de diéthyle,nouveau bloc chiral pour la synthèse énantiospécifique

The (?)-(2S)-Diethyl 2-Hydroxyhexanedioate, a New Chiral Building Block for Enantioselective Synthesis (?)-(2S)-Diethyl 2-hydroxyhexanedioate ((2S)-3) has been obtained by enantioselective reduction of diethyl 2-oxohexanedioate ( 1 ) with baker's yeast. The key intermediate (?)-(5S)-ethyl 5,6-dihydroxyhexanoate ((5S)- 5 ) is proved to be a useful synthon for the synthesis of chiral δ-lactones and a precursor of leukotriene LTB₄ ((5S)- 13 ).