Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transformation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine.     

New natural products in the discorhabdin A- and B-series from New Zealand-sourced Latrunculia spp. sponges

A survey of the secondary metabolite chemistry profiles of New Zealand sponges of the genus Latrunculia has yielded new members of the discorhabdin A- and B-type families. The structure elucidation of (+)-(6R,8S)-1-thiomethyldiscorhabdin G^∗/I (5) and both enantiomers of 16a,17a-dehydrodiscorhabdin W (6) are reported. Absolute configurations were assigned by comparison with a dataset of recently reported electronic circular dichroism spectra of discorhabdin alkaloids. A stereochemical correction of the recently reported natural product (+)-3-dihydrodiscorhabdin A from (3S,5R,6S,8S)-(7) to the C3-epimeric (+)-(3R,5R,6S,8S)-(8) and assignment of absolute configuration is also presented. Semi-synthesis of (+)-(3S,5R,6S,8S)-(7) from (+)-discorhabdin A provided further evidence for this structure revision. Cytotoxicity data is reported for 5-8.     

Stereospecific synthesis and hydrolysis of optically active diaryl(acylamino)(acyloxy)spiro-λ4-sulfanes and related cyclic diaryl(acylamino)sulfonium salts

The stereospecific synthesis of diaryl(acylamino)(acyloxy)spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5, (S)-(+)-8, and their conversion into related diaryl(acylamino)sulfonium tetrafluoroborates (R)-(+)-3, (S)-(+)-6, (R)-(+)-9, respectively, is described. The enantiomers of spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5 and (S)-(+)-8 were prepared by dehydration of the corresponding optically active sulfoxide–carboxylic acids (R)-(+)-1, (R)-(−)-4 and (S)-(+)-7, respectively, which were obtained from the racemic forms by diastereoisomeric salt separation with homochiral organic bases. The stereomechanism of the hydrolysis reaction of spiro-λ⁴-sulfanes and sulfonium tetrafluoroborates that depends on pH, the nature of the axial heteroatom, the size of the spiro rings and carboxyl neighbouring group participation is also discussed.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones

A synthesis of the enamine (−)-(1′S)-5-ethyl-1-(1′-phenylethyl)-1,2,3,4-tetrahydropyridine 4 and its application in a synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones 5 and 6 is described. In addition, an X-ray study of 6 is reported. Finally, the preparation of (+)-(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one 7 is described.     

Absolute configuration of gomadalactones A, B and C, the components of the contact sex pheromone of Anoplophora malasiaca

Absolute configuration of gomadalactones A (1), B (2) and C (3), the pheromone components of the white-spotted longicorn beetle (Anoplophora malasiaca) was assigned as (1S,4R,5S)-1, (1R,4R,5R)-2 and (1S,4R,5S,8S)-3 by comparing their published CD spectra with those of (1R,5R)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]oct-7-ene-2,6-dione (4) and (1S,5R,8S)-(+)-4,4,8-trimethyl-3-oxabicyclo[3.3.0]octane-2,6-dione (5) prepared from (R)-(−)-carvone (6).     

Vibrational circular dichroism study for natural bioactive schizandrin and reassignment of its absolute configuration

Bioactive natural product (+)-schizandrin was assigned as (7S,8S) using NMR. Recently, we obtained (+)-schizandrin from TCM Schisandra sphenanthera Rehd. et Wils. Its planar structure was well established using NMR and HR-MS including the reported references. Its absolute configuration is assigned using vibrational circular dichroism (VCD). By careful VCD investigation of (7S,8S) and (7S,8R) using B3LYP/6-311+G(d) methods, absolute configuration of (+)-schizandrin is assigned as (7S,8R). Electronic circular dichroism (ECD) was used for the discussion too and it gave the same conclusion.     

Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin

A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin from l-ascorbic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM deprotection and bicyclic ketal formation was carried under Pd/C, H₂ followed by acid treatment.     

A novel and versatile method for the enantioselective syntheses of tropane alkaloids

A full account of the novel and flexible approach to hydroxylated 8-azabicyclo[3,2,1]octan-3-ones and 9-azabicyclo[3,3,1]nonan-3-ones is presented.Using keto-lactams as the starting materials,this two-step method consists of silyl enol ether formation with TBDMSOTf,lactam activation with Tf2O/DTBMP,and halide-promoted cyclization.Radical dechlorination of the resulting 1-halotropan-3-ones led to the corresponding hydroxylated tropan-3-ones,which can be hydrogenated to yield3,6-dihydroxytropanes.Starting from optically active keto-lactams,the method has been applied to the enantioselective syntheses of(+)-(1S,3S,5R,6S)-pervilleine C(6),(+)-(1S,3R,5S,6R)-valeroidine(3),(+)-(1S,3S,5R,6S)-dibenzoyloxytropane(8),and(+)-(1S,3S,5R,6S)-merredissine(9).     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

Absolute configuration of (-)-biflora-4,10(19),15-triene,a diterpene from a termite soldier,as determined by the synthesis of its (1R, 6S, 7S, 11R)-(+)-isomer

(1R, 6S, 7S, 11R)-(+)-Biflora-4, 10(19),15-triene was synthesized starting from (r)-(+)-citronellic acid. This enabled us to assign (1S), 6R, 7R, (11S)-stereochemistry to the naturally occurring (-)-enantiomer isolated from soldiers of the termite species Cubitermes umbratus.     

Asymmetric Phase-Transfer Catalysis by Quaternary Ammonium Ions Derived from Cinchona-Alkaloid Analogs Containing 1,1′-Binaphthalene Moieties

The synthesis and catalytic properties of a new type of enantioselective phase-transfer catalysts, incorporating both the quinuclidinemethanol fragment of Cinchona alkaloids and a 1,1′-binaphthalene moiety, are described. Catalyst (+)-(aS,3R,4S,8R,9S)- 4 with the quinuclidine fragment attached to C(7′) in the major groove of the 1,1′-binaphthalene residue was predicted by computer modeling to be an efficient enantioselective catalyst for the unsymmetric alkylation of 6,7-dichloro-5-methoxy-2-phenylindanone ( 1 ; Scheme 1, Fig. 1). Its synthesis involved the selective oxidative cross-coupling of two differently substituted naphthalen-2-ols to afford the asymmetrically substituted 1,1′-binaphthalene derivative (±)- 17 in high yield (Scheme 3). Chromatographic optical resolution via formation of diastereoisomeric camphorsulfonyl esters and functional-group manipulation gave access to the 7-bromo-1,1′-binaphthalene derivative (−)-(aS)- 11 (Scheme 4). Nucleophilic addition of lithiated (−)-(aS)- 11 to the quinuclidine Weinreb amide (+)-(3R,4S,8R)- 8 afforded the two ketones (aS,3R,4S,8R)- 27 and (aS,3R,4S,8S)- 28 as an inseparable mixture of diastereoisomers (Scheme 6). Stereoselective reduction of this mixture with DIBAL-H (diisobutylaluminum hydride; preferred formation of the C(8)−C(9) erythro-pair of diastereoisomers with 18% de) or with NaBH₄ (preferred formation of the threo-pair of diastereoisomers with 50% de) afforded the four separable diastereoisomers (+)-(aS,3R,4S,8S,9S)- 29 , (+)-(aS,3R,4S,8R,9R)- 30 , (−)-(aS,3R,4S,8S,9R)- 31 , and (+)-(aS,3R,4S,8R,9S)- 32 (Scheme 6). A detailed conformational analysis, combining ¹H-NMR spectroscopy and molecular-mechanics computations, revealed that the four diastereoisomers displayed distinctly different conformational preferences (Figs. 2 and 3). These novel Cinchona-alkaloid analogs were quaternized to give (+)-(aS,3R,4S,8R,9S)- 4 , (+)-(aS,3R,4S,8S,9S)- 5 , (+)-(aS,3R,4S,8R,9R)- 6 , and (−)-(aS,3R,4S,8S,9R)- 7 (Scheme 7) which were tested as phase-transfer agents in the asymmetric allylation of phenylindanone 1 . Without any optimization work, (+)-(aS,3R,4S,8R,9S)- 4 was found to catalyze the allylation of 1 yielding the predicted enantiomer (+)-(S)- 3b in 32% ee. The three diastereoisomeric catalysts (+)- 5 , (+)- 6 , and (−)- 7 gave access to lower enantioselectivities (6 to 22% ee's), which could be rationalized by computer modeling (Fig. 4).     

Total synthesis of natural (+)-hyacinthacine A6 and non-natural (+)-7a-epi-hyacinthacine A1 and (+)-5,7a-diepi-hyacinthacine A6

Naturally occurring (1S,2R,3R,5R,7aR)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-hyacinthacine A₆, 2] together with unnatural (1S,2R,3R,7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine [(+)-7a-epi-hyacinthacine A₁, 3] and (1S,2R,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine [(+)-5,7a-diepi-hyacinthacine A₆, 4] have been synthesized from a DALDP derivative [5, (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine], as the homochiral starting material. The synthetic process employed took advantages of Wittig methodology followed by internal lactamization, in the case of (+)-7a-epi-hyacinthacine A₁ (3), and reductive amination for (+)-hyacinthacine A₆ (2) and (+)-5,7a-diepi-hyacinthacine A₆ (4).     

Determination of the absolute structure of albaconol

The concise synthesis of (8aR)-(−)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthetic (8aR)-(−)-albaconol (1) and natural (+)-albaconol (1), the absolute structure of natural (+)-1 was determined to be 1R,2R,4aS,8aS configuration.     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Unexpected retro-Michael reaction of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1-phenylethyl)octahydroquinolin-7-ones

An unexpected retro-Michael reaction of (−)-(1′S,4aS,8aR)-and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)octahydroquinolin-7-ones 1 and 2 is described. In addition, a diastereospecific intramolecular Michael reaction of 3·HCl and 4·HCl is reported.     

Synthesis of (+)-1,3,5,7 -tetrakis[2-(1S,3S,5R,6S,8R,10R)-D3-trishomocubanylbuta-1,3-diynyl]adamantane : The first optically active organic molecule with t symmetry and of known absolute configuration

(-)-(1S,3S,5R,6S,8R,10R)-Trishomocubanethanoic acid (5) of known absolute configuration and absolute rotation was converted into (+)-(1S,3S,5S,6S,8R,10R)-2-bromoethynyl-D₃-trishomocubane (27) of C₃ symmetry. 1,3,5,7-Tetraethynyladamantane (22), with Td symmetry, was prepared from 1,3,5,7-tetrakis(hydroxymethyl)adamantane(13). Coupling of the C₃-component 27 with the Td component 22 was successfully accomplished by Chodkiewicz and Cadiot's procedure providing (+)-1,3,5,7-tetrakis[2-(1S,3S,5R,6S,8R,10R)-D₃-trishomocubanylbuta-1,3-diynyl]adamantane(4) whose highest attainable static and time-averaged dynamic symmetry are T and (C₃)⁴ XXX T,respectively.     

New asymmetric strategy for the total synthesis of naturally occurring (+)-alexine and (−)-7-epi-alexine

A novel and highly convenient process is described for the asymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, (+)-alexine [(1R,2R,3R,7S,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine] and (−)-7-epi-alexine [(1R,2R,3R,7R,7aS)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine], as the potent glycosidase inhibitors by featuring the efficient and stereodefined elaboration of the functionalized pyrrolidine derivatives, which were, in turn, prepared via stereoselective manipulation of the homochiral allyl alcohol precursors derived from l-xylose.     

Arylacetic acid derivatization of 2,3- and internal erythro-squalene diols. Separation and absolute configuration determination

We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6S,7S)-6,7-SO, and (10R,11R)- and (10S,11S)-10,11-SO. Monoderivatization of the corresponding racemic squalene diol intermediates with pure stereoisomers of (S)-(+)-methoxyphenyl acetic acid ((S)-(+)-MPA), (S)-(+)-9-anthrylmethoxyacetic acid ((S)-(+)-9-AMA) and (S)-(+)-acetoxyphenylacetic acid ((S)-(+)-APA) afforded the diastereomeric esters which could be easily separated by column flash chromatography with silica gel. In addition, the absolute configuration for these diastereoisomers of the derivatized diols was advantageously inferred from ¹H NMR data according to the models depicted for these derivatizing chiral agents. In order to demonstrate the absolute configuration assignment of the different stereoisomers, (S)-(+)-AMA showed the larger Δδ by ¹H NMR, however, (S)-(+)-MPA esters were much more stable derivatives.