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.     

Chemoenzymatic resolution of epimeric cis 3-carboxycyclopentylglycine derivatives

Epimeric 3-carboxycyclopentylglycines (+)-10/(−)-10 and (+)-11/(−)-11 were efficiently prepared by the way of a sequence of Diels-Alder and retro-Claisen reactions. The synthesis incorporates a concise and inexpensive chemoenzymatic resolution of racemic compounds 4,5a, the N,O-protected derivatives of amino acids 10,11. Systematic screening with different enzymes and microorganisms was performed to select a very efficient catalyst for the separation of the racemic mixtures. The reaction conditions allowing deprotection of both ester and amino functions and to avoiding epimerization processes were studied. Enantiomers (i.e., (+)-10/(−)-10 and (+)-11/(−)-11) were obtained in high enantiopurity. The absolute configuration of all stereocenters was unequivocally assigned.     

Molecular structures and ab initio molecular orbital calculations of the optically active derivatives of 1-aminocyclopropane-1-carboxylic acid

The novel optically active derivatives of 2,2′-disubstituted-1-aminocyclopropane-1-carboxylic acid (−)-2 and (+)-3 were synthesised from the spiro-azlactone (+)-1. Oxidation of the diol moiety of (+)-3 gave by ring enlargement the racemic mixture of 2,3-dihydrofuran derivative (±)-6. This conversion is explained by stepwise rearrangement of the initially formed tetrasubstituted cyclopropanecarbaldehyde 4 through zwitterionic's reactive intermediate 5. The formation of (±)-6 is preferred energetically as established by ab initio calculations of the ground states and possible intermediates for that rearrangement. The crystal structure and absolute configuration of the compounds (+)-1, (−)-2, (+)-3 and (−)-7 were determined by single-crystal X-ray diffraction method. All four compounds possess Z-configuration of the cyclopropane ring. The dioxolane ring in the structures (+)-1 and (−)-2 adopts half-chair conformation, while the cyclopropane ring and geminally substituted groups in the structures (−)-2, (+)-3 and (−)-7 possess the anticlinal conformation. The molecules of the compound (+)-1 are connected by very weak intermolecular hydrogen bond of C-H?O type. In the compounds (−)-2, (+)-3 and (−)-7inter- and intramolecular hydrogen bonds of N-H?O type were observed. The spiro-compound (+)-1 exhibited a more pronounced inhibitory activity against the proliferation of murine leukemia and human T-lymphocytes cells than other type of tumor cell lines and normal human fibroblast cells.     

Total syntheses of the sesquiterpenoids (+)-trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Sesquiterpenoids (+)-trans-dracuncuflifoliol (1) and (+)-4-hydroxyoppositan-7-one (2) were prepared stereoselectively from enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((−)-6), whose synthesis was described herein. Conjugate addition of the organocopper (I) reagent 10 to (−)-6, followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral centers of both natural products.     

An efficient approach to 2-substituted N-tosylpiperdines: asymmetric synthesis of 2-(2-hydroxy substituted)piperidine alkaloids

We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral α-substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinylethanol 15 and ent-15, was achieved from l- and d-aspartic acids, respectively in few steps. Piperidine 15 was converted into 2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline (R,R)-2a, (+)- and (−)-sedamine 2b, (+)- and (−)-allosedamine 2c, (+)- and (−)-sedridine 2d, (+)- and (−)-allosedridine 2e, (+)-tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted via Mitsunobu inversion in excellent yields.     

Asymmetric synthesis of the 6-cyanoindole derivatives as non-steroidal glucocorticoid receptor modulators using (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate

We have successfully synthesized enantiomerically pure (+)- and (−)-tert-butyl 6-cyano-3-[3-ethoxy-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl]-1H-indole-1-carboxylate (+)-1 and (−)-1, which are key intermediates of non-steroidal glucocorticoid receptor modulators, by employing a cinchona alkaloid catalyzed addition of 6-cyanoindole to ethyl trifluoropyruvate. The optimized method can be applied to large-scale synthesis. Furthermore, using the key intermediates (+)-1 and (−)-1, enantiomerically pure glucocorticoid receptor modulators (+)-3 and (−)-3 can be synthesized (>99% ee for both compounds). The glucocorticoid receptor binding affinity was influenced by the stereogenic center at the trifluoromethyl alcohol moiety; compound (−)-3 showed a higher binding affinity compared to (+)-3.     

A non-catalytic regioselective approach to the synthesis of (E)-stilbenes from suitably functionalized 2H-pyran-2-ones

Highly functionalized (E)-stilbenes 3a-m and 4-aryl-6-styryl-pyran-2-ylidineacetonitriles 4a-b have been prepared and delineated through the ring transformation of 6-aryl-3,4-disubstituted-2H-pyran-2-ones 1 with commercially available (E/Z)-4-phenyl-3-buten-2-one 2 without the use of any catalyst.     

Enantioselective synthesis of axially chiral 1-(1-naphthyl)isoquinolines and 2-(1-naphthyl)pyridines through sulfoxide ligand coupling reactions

Racemic 1-(1′-isoquinolinyl)-2-naphthalenemethanol rac-12 was prepared through a ligand coupling reaction of racemic 1-(tert-butylsulfinyl)isoquinoline rac-7 with the 1-naphthyl Grignard reagent 10. Resolution of rac-12 was achieved through chromatographic separation of the Noe-lactol derivatives 14 and 15, providing (R)-(−)-12 of >99% ee and (S)-(+)-12 of 90% ee. The ligand coupling reaction of optically enriched sulfoxide (S)-(−)-7 (62% ee) with Grignard reagent 10 furnished rac-12, with the absence of stereoinduction resulting from competing rapid racemisation of the sulfoxide 7. Reaction of optically enriched (S)-(−)-7 with 2-methoxy-1-naphthylmagnesium bromide was also accompanied by racemisation of the sulfoxide 7, and furnished optically active (+)-1-(2′-methoxy-1′-naphthyl)isoquinoline (+)-3b in low enantiomeric purity (14% ee). The absolute configuration of (+)-3b was assigned as R using circular dichroism spectroscopy, correcting an earlier assignment based on the Bijvoet method, but in the absence of heavy atoms. Optically active 2-pyridyl sulfoxides were found not to undergo racemisation analogous to the 1-isoquinolinyl sulfoxide 7, with the ligand coupling reactions of (R)-(+)- and (S)-(−)-2-[(4′-methylphenyl)sulfinyl]-3-methylpyridines, (R)-(+)-17 and (S)-(−)-17, with 2-methoxy-1-naphthylmagnesium bromide providing (−)- and (+)-2-(2′-methoxy-1′-naphthyl)-3-methylpyridines, (−)-18 and (+)-18, in 53 and 60% ee, respectively. The free energy barriers to internal rotation in 3b and 18 have been determined, and the isoquinoline (R)-(−)-12 examined as a ligand in the enantioselectively catalysed addition of diethylzinc to benzaldehyde; (R)-(−)-12 was also converted to (R)-(−)-N,N-dimethyl-1-(1′-isoquinolinyl)-2-naphthalenemethanamine (R)-(−)-19, and this examined as a ligand in the enantioselective Pd-catalysed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate.     

Donnazoles A and B from Axinella donnani sponge: very close derivatives from the postulated intermediate ‘pre-axinellamine’

Two novel dimeric pyrrole-aminoimidazole (PAI) alkaloids (−) donnazoles A-B (1-2) were isolated from the marine sponge Axinella donnani collected off the Mauritius Island. Their structures were elucidated mainly by 2D NMR. Both compounds bear the crucial substituted cyclopentane of ‘pre-axinellamine’, the hypothetical common intermediate of all dimeric PAIs. Additionally, the essential trans-6,7 ring junction of palau′amine’s congeners is already established in 1 and 2. The absolute configurations of 1 and 2 were deduced via NOE correlations in combination with the comparison of their circular dichroism data with the one of (−) sceptrin. The absolute configuration of (−) donnazoles A (1) and B (2) is coherent with the absolute configuration of the known dimeric members of PAI alkaloids.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

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.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Stereoselective total syntheses of (+)-exo- and (−)-exo-brevicomins, (+)-endo- and (−)-endo-brevicomins, (+)- and (−)-cardiobutanolides, (+)-goniofufurone

Stereoselective total syntheses of aggregation pheromones (+)-exo-brevicomin (9a), (−)-exo-brevicomin (9b), (+)-endo-brevicomin (9c), (−)-endo-brevicomin (9d) and styryllactones (+)-cardiobutanolide (14a), (−)-cardiobutanolide (14b), and (+)-goniofufurone (19a) were achieved in good yields from enantiomerically pure highly functionalized furanoid glycal building blocks (1a-d) involving similar synthetic strategies, thus making these furanoid glycals highly useful building blocks in diversity-oriented synthesis (DOS).     

A divergent approach for the total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids

The divergent total syntheses of cernuane-type and quinolizidine-type Lycopodium alkaloids are described. A common intermediate 5 for the two types of alkaloids was assembled practically from (+)-citronellal via organocatalytic α-amination, followed by the construction of oxazolidinone that was used for diastereoselective allylation. Key compound 5 was converted into cermizine C (3), and this in turn was converted into senepodine G (4) by the regioselective Polonovsky-Potier reaction. The total synthesis of representative cernuane-type alkaloids, (−)-cernuine (1) as well as (+)-cermizine D (2), was also accomplished from 5 by utilizing asymmetric transfer aminoallylation as a key step.     

Structural and stereochemical investigations into bromotyrosine-derived metabolites from southern Australian marine sponges, Pseudoceratina spp.

Chemical investigation of a southern Australian sponge, Pseudoceratina sp., resulted in the isolation of twelve bromotyrosine-derived alkaloids, comprising four new metabolites, aplysamine-7 (1), (−)-purealin B (2), purealin C (3) and purealin D (4); two new spiroisoxazole enantiomers, (−)-purealidin R (5) and (−)-aerophobin-2 (6); five known metabolites (−)-pseudoceratinine A (7), (−)-aeroplysinin-1 (8), aplysamine-2 (9), purpuramine G (10) and purpuramine J (11); and an artifact 12 derived from ethanolysis of 5. Structures for 1-12 were assigned on the basis of detailed spectroscopic analysis. A second southern Australian Pseudoceratina sp. afforded the first recorded account of a racemic bromotyrosine-derived spiroisoxazole, (±)-purealin (13b), together with the known achiral precursor purealidin A (15). A literature review of marine bromotyrosine-derived spiroisoxazoles reaffirmed the published dominance of (+)-spiroisoxazoles, acknowledging several accounts of (−)-spiroisoxazoles, while also revealing a wide range of chiroptical measurements suggestive of variable optical purity. The Pseudoceratina sp. metabolites 1-12, 13b and 15 were assessed for antibiotic properties, with the new metabolites 3 and 13b exhibiting broad spectrum activity against several Gram-positive bacteria.     

Senepodines B-E, new C22N2 alkaloids from Lycopodium chinense

Four new C₂₂N₂Lycopodium alkaloids, senepodines B-E (2-5), consisting of an octahydroquinoline ring and a quinolizidine ring have been isolated together with senepodine A (1) from the club moss Lycopodium chinense. The relative and absolute stereochemistry of 2-5 were determined by combination of NOESY correlations and chemical transformation, while the absolute configuration of 1 was assigned by exciton chirality method.     

Neat total synthesis of six monoterpenic alkaloids of the actinidine series

A concise enantiopure synthesis of six monoterpenic alkaloids of the actinidine series possessing a cyclopenta[c]pyridine skeleton, (+)-deoxyrhexifoline (4), (+)-boschniakinic acid (5), (+)-boschniakine (6), (−)-plantagonine (7), (−)-indicaine (8) and (−)-tecostidine (9) is reported starting with the chiral precursor 3-bromo-5-((4R)-phenyloxazolin-2-yl)pyridine (10). It involves a C-4 regioselective connection of a butene appendice and an intramolecular 5-exo-trig Heck annulation sequence followed by hydrogenation of the exocyclic alkene. Mixture of (3R)- and (3S)-7-((4R)-phenyloxazolin-2-yl)cyclopenta[c]pyridines was separated by HPLC before being transformed into enantiopure natural products (4-9) by modification of the oxazoline group.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

Total synthesis of marine bisindole alkaloids, (+)-hamacanthins A, B and (−)-antipode of cis-dihydrohamacanthin B

The total synthesis of the marine bisindole alkaloids, (+)-hamacanthins A (2a) and B (2b), and (−)-antipode of cis-dihydrohamacanthin B (2e) was achieved by transamidation-cyclization of N-(2-aminoethyl)-2-oxoethanamide 18 derived from (S)-indolylglycinol 10.     

Dopamine derivatives from the insect Polyrhachis dives as inhibitors of ROCK1/2 and stimulators of neural stem cell proliferation

Polyrhachis dives is consumed as an insect food in some regions of China. In this study, new dopamine derivatives, (+)-polyrhadopamine A (1a) and (−)-polyrhadopamine A (1b), (+)-polyrhadopamine B (2a) and (−)-polyrhadopamine B (2b), and polyrhadopamines C–E (3–5), were isolated from this species. The structures and stereochemistry of these substances were assigned by using spectroscopic and computational methods. Compounds 1a, 1b, 2a, and 2b are dimeric N-acetyldopamine derivatives, 3 is a dopamine analog containing an unusual sulfone group, and 4 and 5 possess a rare benzo[d]thiazole moiety. The functions of these substances as ROCK1/2 inhibitors, neural stem cell (NSCs) proliferation stimulators, immunosuppressive, and anti-inflammatory agents were determined.