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).     

Preparation of a new 1,2,3-trithiolane, trans-9,10,11-trithiabicyclo[6.3.0]undecane, and its oxidation reactions

The reaction of trans-cyclooctene with S₈O yielded a novel bicyclic 1,2,3-trithiolane and trans-9,10,11-trithiabicyclo[6.3.0]undecane (7). Oxidation of the trithiolane with dimethyldioxirane yielded three monoxides, which are assigned to two isomeric 9-oxides, rel-(1R,8R,9S)-9-oxide (15) and rel-(1R,8R,9R)-9-oxide (16), and 10-oxide (17). Further oxidation of rel-(1R,8R,9S)-9-oxide (15) provided rel-(1R,8R,9S,11S)-9,11-dioxide (18) and rel-(1R,8R,9R,11S)-9,11-dioxide (19), while that of rel-(1R,8R,9R)-9-oxide (16) gave rel-(1R,8R,9R,11S)-9,11-dioxide (19) and rel-(1R,8R,9R,11R)-9,11-dioxide (20). The structures of 18 and 19 were determined by X-ray crystallography. The structures of other oxides were elucidated by the spectroscopic data and results of further chemical transformations. Two isomers, 15 and 16, isomerized to one another. A 9,11-dioxide 20 isomerized to 19, which is in equilibrium with 18, where 18 is thermodynamically the most stable isomer.     

Synthesis of the ABC-ring models of goniodomin A: preference for the unnatural configuration at C11 of the BC-ring in a non-macrocyclic model system

To confirm the natural relative stereochemistry of the ABC-ring of goniodomin A (1), the corresponding three stereoisomeric compounds, (2R,5S,6S,7S,9S,11R,15S)-, (2R,5S,6S,7R,9R,11S,15R)-, and (2R,5S,6S,7R,9R,11R,15S)-isomers (2, 3, and 5, respectively), were stereoselectively synthesized using a Nozaki-Hiyama-Kishi reaction as a key step. It was also found that a (2R,5S,6S,7R,9R,11S,15S)-isomer (4), corresponding to the absolute configuration of 1 recently proposed by Sasaki, was not detected during the formation of 5 from a common ketodiol substrate under acid-catalyzed spiroacetalization conditions. This would be attributable to the absence of a macrocyclic framework.     

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.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Synthesis of ‘thianthrene dimer’ by the coupling reaction of stannylthianthrenes in the presence of copper catalysts

The coupling reaction of 1-tributylstannylthianthrene (5) and 2-tributylstannylthianthrene (7) in the presence of copper catalysts at rt afforded the thianthrene dimer 1,1′-bithianthrene (3), 2,2′-bithianthrene (8), and 1,2′-dithianthrene (9) in high yields. Also we obtained thianthrene oxide dimer (R,R) (S,S)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (12) and (R,S) (S,R)-1-(10-S-monoxythianthrene-1-yl)thianthrene-10-S-monoxide (13) from 1-tributylstannyl-10-S-monoxythianthrene (10) under the same reaction condition. The final structural conformation of 3, 8, 9, and 12 was performed by X-ray crystallographic analysis. Further, the solvent effects in the coupling reactions were also examined.     

Regioselective rearrangement of 7-azabicyclo[2.2.1]hept-2-aminyl radicals: first synthesis of 2,8-diazabicyclo[3.2.1]oct-2-enes and their conversion into 5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidines, new inhibitors of α-mannosidases

Enantiomerically pure 2,8-diazabicyclo[3.2.1]oct-2-ene derivatives (+)-5 and (−)-5 have been obtained from 2-azido-3-tosyl-7-azabicyclo[2.2.1]heptanes (+)-1 and (−)-2 and their enantiomers, by ring expansion under radical conditions. Compounds (+)-5 and (−)-5 were transformed into hemiaminals 9 ((3S,4R,5R)- and 10 ((3R,4S,5S)-5-(2-aminoethyl)-2,3,4-trihydroxypyrrolidine) that are good inhibitors of α-mannosidases.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.     

Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes

Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2S, 5R)-3a-6a and (2R, 5R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G^∗ level of conformational inter-conversion for (2S, 5R)-D5a and (2R, 5R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2S, 5R)-D5a while conformer K2 is more stable in the case of (2R, 5R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (−) and (+) epoxides in the case of ketones 3e-6e.     

A structure and an absolute configuration of (+)-alternamin, a new coumarin from Murraya alternans having antidote activity against snake venom

(+)-Alternamin (1), a new dihydrofuranocoumarin, was isolated from the aerial parts of Murraya alternans (Kurz) Swingle. The analysis 2-D NMR correlation of (+)-1 led to either of linear dihydrofuranocoumarin (2A, 2C) or angular one (2B). An IR and a vibrational circular dichroism (VCD) studies were conducted to distinguish the structure and to assign the absolute configuration. By comparison of the observed spectra with the calculated spectra for (S)-2A, (S)-2B, and (R)-2C, the molecular structure of (+)-1 was determined to be (S)-(+)-5,8-dimethoxymarmesin. The compound exhibited antidote activity against snake venom from Trimeresurus flavoviridis, affording experimental support for the pharmacological use of M. alternans.     

Gold catalysis in stereoselective natural product synthesis: (+)-linalool oxide, (−)-isocyclocapitelline, and (−)-isochrysotricine

A stereoselective synthesis of the tetrahydrofuran-containing natural products (2S,5R)-(+)-linalool oxide (1), (−)-isocyclocapitelline (2), and (−)-isochrysotricine (3) is reported. Key steps are the copper-mediated S_N2′-substitution of propargyl oxiranes 7 and the gold-catalyzed cycloisomerization of dihydroxyallenes 8/17, resulting in a highly efficient center-to-axis-to-center chirality transfer. The enantioselective total synthesis of (−)-isocyclocapitelline (2) and (−)-isochrysotricine (3) allowed the elucidation of the absolute configuration of these β-carboline natural products.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Oxazolidinone cross-alkylation during Evans’ asymmetric alkylation reaction

Starting from Evans’ imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of a CH(CH₃)CO fragment. The stereochemistry of 3 was established by NMR spectroscopy, mainly NOE experiments, as expected, the new center has an S configuration, the compound being thus S,R. The structure of compound 5 was determined by X-ray crystallography. A mechanism of formation of 5 was proposed.     

Short, convergent, stereoselective syntheses of enantiopure 2-benzopyran-5,8-quinones related to the aphid insect pigments, the protoaphins

The enantiopure (1S,3S,4R)-, (1R,3S,4S)- and (1S,3S,4S)-3,4-dihydro-1,3-dimethyl-4-hydroxy-2-benzopyrans 16, 25 and 26 are prepared in two related reaction sequences, each in eight steps and good overall yield. The starting materials are 4-methoxyphenol 6 and (2S,1′R and 2S,1′S)-1′ ethoxyethoxypropanal 9, the latter providing the source of asymmetry from the chiral pool. The three key reactions involved in each sequence are either highly or completely diastereoselective.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Studies on Wittig rearrangement of furfuryl ethers in steroidal side chain synthesis

Wittig rearrangement of 17(20)-ethylidene-16-furfuryloxy steroids 5-8 was examined. Reaction of 17E(20)-ethylidene-16α-furfuryloxy steroid 5 with t-BuLi in THF afforded (20S,22S)- and (20S,22R)-22-hydroxy steroids 9, 10 and 17Z(20)-ethylidene-16α-(2-furyl)hydroxymethyl steroid 11 in 61, 28, and 9% yields, respectively. Base treatment of 17E(20)-ethylidene-16β-furfuryloxy steroid 7 gave (20R,22R)-22-hydroxy steroid 13 and 17Z(20)-ethylidene-16β-(2-furyl) hydroxymethyl steroid 14 in 60 and 17% yields. In contrast, 17Z(20)-ethylidene-16-furfuryloxy steroids 6, 8 led to the corresponding 2,3-rearranged products in low yields (25% for (20R,22S)-22-hydroxy steroid 12; 31% for (20S,22R)-22-hydroxy steroid 10). Both (20S,22S)- and (20S,22R)-22-hydroxy steroids 9, 10 were converted by catalytic hydrogenation into known compounds 16, 17, key intermediates for the synthesis of biologically active steroids.     

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.