An unexpected rearrangement of the benzofurobenzazepine skeleton of galanthamine-type alkaloids

Attempted cyclisation of N-methylated spiro benzazepine-cyclohexenone (5) into the corresponding N-methyl tetracyclic unit of galanthamine-type alkaloids (6) instead gave an unexpected rearrangement to yield a cyclopentanoisoquinolinone derivative (7). Methylation of the tetrahydrobenzofurobenzazepine tetracycle resulted in the expected N-methyl derivative 6, and the anomalous product 8, with structure similar to that of 7.     

Stereocontrolled total synthesis of (±)-pisiferol and (±)-pisiferal

The stereoselective total synthesis of (±)-pisiferol (1) and (±)-pisiferal (2) has been successfully accomplished using the trans-octahydrophenanthrene derivative 20 as a key intermediate. Intramolecular cyclisation of the diazoketone 15 followed by catalytic hydrogenation provided, stereoselectively, the keto-ester 17 which was converted into the acetate 20 through the intermediates 18 and 19.     

Oxidation of natural targets by dioxiranes. Part 6: on the direct regio- and site-selective oxyfunctionalization of estrone and of 5α-androstane steroid derivatives

Using methyl(trifluoromethyl)dioxirane (1b), 3β,6α,17β-triacetoxy-5α-androstane (6) could be selectively transformed into its C-14 hydroxy derivative (7) and into the valuable C-12 ketone steroid (8), in high yields under mild reaction conditions. Similarly, the oxidation of 3α-estrone acetate (4) with 1b was carried out to yield selectively the steroid C-9 hydroxy derivative (5). The high regio- and site-selectivity attained demonstrates that the powerful dioxirane 1b is the reagent of choice to synthesize valuable oxyfunctionalized steroid derivatives.     

Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine

(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.     

RCAI-56, a carbocyclic analogue of KRN7000: its synthesis and potent activity for natural killer (NK) T cells to preferentially produce interferon-γ

RCAI-56 (3), a carbocyclic analogue of KRN7000 (1) was synthesized through an efficient coupling of a carba-α-d-galactose derivative 11 with cyclic sulfamidate derivative 13 of phytosphingosine to give 15. Carbasugar derivative 11 was prepared by starting from methyl α-d-galactopyranoside (4), employing Pd(II)-catalyzed Ferrier rearrangement as the key step. RCAI-56 (3) is a potent stimulant of NKT cells in vivo to induce the production of Th1 biased cytokines such as interferon-γ in mice. According to the docking model of CD1d-3 complex, its stabilization energy is approximately at the same level as that of the CD1d-1 complex.     

Lipase-mediated synthesis of enantiomeric 2,5,6-trideoxy-2,5-iminohexitols

Syntheses of 2,5,6-trideoxy-2,5-imino-d-alditol (2, 6-deoxy-DADP) and its enantiomer (3) from tri-orthogonally protected derivatives of DADP have been developed employing lipase-mediated kinetic desymmetrization and protecting group manipulations. Thus, and as an example, the starting DADP derivative (4) was transformed into a new symmetrical 2,5-bis(hydroxymethyl)pyrrolidine (6) by sequential N-protection and bis-O-desilylation. The lipase-mediated desymmetrization of 6 was best carried out under acetylation conditions to give (2R)-acetyloxymethyl derivative 7. The absolute configuration and ee of 7 were unambiguously established by chemical correlation with a homochiral sample. Compound 7 was straightforwardly transformed into the target 2,5,6-trideoxy-2,5-iminohexitol 3.     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

Synthesis and novel reactivities of several 1,9-dithiaalkane-bridged thianthrene 10-oxides

The irreversible photolytic axial to equatorial change (3ax-4ax→3eq-4eq) and the irreversible thermal equatorial to axial change (3eq-4eq→3ax-4ax) of the S-O configuration were first observed. Meanwhile, the shorter 1,9-bridged derivative (2ax) exhibited the interesting photolytic degradation, affording 1,9-dithiadibenzothiophene (5) by the elimination of SO and ethylene.     

Synthetic studies of kampanols, novel p21 farnesyltransferase inhibitors: an efficient synthesis of the tetracyclic ABCD ring system of kampanols

An enantioselective synthesis of the tetracyclic ABCD ring system (4) of kampanols, novel Ras farnesyltransferase inhibitors from a microorganism, was efficiently achieved for the first time starting from the known trans-decalone derivative 9. The synthetic method involves the following two key steps: (i) a conjugate addition reaction between the α-methylene ketone 6 and the Grignard reagent (7) of the ortho-disubstituted bromobenzene derivative 8 to deliver the coupling product 21 with stereoselectivity at the C9 position and (ii) a phenylselenium-mediated cyclization reaction of the phenol derivative 5 to stereoselectively construct the requisite tetracyclic intermediate 25 possessing the cis-fused connectivity of the B/C rings.     

Stereoisomeric bis(phenylglycinol)malonamide gelators: rare examples of gelling meso-compounds

Gelation of malonamides was investigated for the first time. Bis(phenylglycinol)malonamide 1, and methyl-, dimethyl-, ethyl-, diethyl- and isopropylmalonamides 2, 3, 4, 5 and 6, respectively, exhibited profoundly different gelling properties. Monoalkyl malonamides are efficient organogelators, and their gelling properties strongly depend on their stereochemistry. In contrast, symmetrically substituted dialkymalonamides, that is, (R,R)-dimethylmalonamide 3 and (R,R)-diethylmalonamide 5 as well as the unsubstituted 1 lack any gelation ability. Methyl derivative (R,R)-2 is an excellent, and its ethyl analogue (R,R)-4 a moderate gelator of toluene, p-xylene and tetralin while the isopropyl derivative (R,R)-6 shows only very weak gelation of tetralin and some more polar solvents. Meso diastereoisomers (R,r,S)-2 and (R,s,S)-2, as well as (R,r,S)-4 and (R,s,S)-4), each possessing a pseudoasymmetric centre represent very rare examples of gelling meso-compounds. The racemate 4 (rac-4) showed more efficient gelation of some solvents than the pure enantiomer (R,R)-4, while rac-2 failed to gel any of the solvents which were efficiently gelled by (R,R)-2.     

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane with enol ethers of cyclic ketones

Sodium dithionite initiated reactions of 1-bromo-1-chloro-2,2,2-trifluoroethane (1) with methyl and trimethylsilyl ethers of cyclopentanone and cyclohexanone enols (2a-d) in a MeCN/H₂O system were investigated. 2-(2,2,2-Trifluoroethylidene)cyclopentanone (4a) and 2-(2,2,2-trifluoroethylidene)-cyclohexanone (4b), respectively, were obtained as the main products and isolated in reasonable yields. The reaction with a 1:1 mixture of 5- and 3-methyl substituted 1-methoxycyclohexenes, 2e and 2f, revealed strong influence of steric hindrance on the reaction rate; a mixture of 2-(2,2,2-trifluoroethylidene)-5-methylcyclohexanone (6) and 2-(2,2,2-trifluoroethylidene)-3-methylcyclohexanone (7) in a 9:1 ratio was formed. Ketones 4a and 4b were reduced to the corresponding alcohols 8 and 9 and the reaction of 4b with hydrazine gave an indazole derivative 10.     

Syntheses of metabolites of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603)

Convenient and efficient syntheses of ethyl 4-(3-hydroxy-4-methoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (1d) and 10-(3,4-dimethoxyphenyl)-7,8-dimethoxy-2H-pyridazino[4,5-b]quinolin-1-one (1e), metabolites of TAK-603 (1), have been achieved. Use of the methanesulfonyl as a protective group of the phenolic hydroxy for Friedel-Crafts reaction enabled a new simpler synthetic route of 1d in high yield. Chloromethyl derivative (23) was converted to formyl derivative (32) using the Kröhnke reaction, followed by cyclization with hydrazine, which formed a novel compound 1e.     

1,4,5-Thiadiazepines—II : A novel ring contraction giving 1,4-thiazine derivatives

Cyclization of methyl (phenacylsulphonyl)acetate (3a) and methyl 2-(phenacylsulphonyl)-propionate (3b) with hydrazine gave 6-phenyl-2,3,4,7-tetrahydro-1,4,5-thiadiazepin-3-one 1,1-dioxide (4a) and its 2-methyl derivative (4b), respectively. The new thiadiazepines, unlike previously described derivatives, did not undergo desulphonylation when heated in various solvents. Brief reflux of 4a in acetic anhydride gave the O-acetyl derivative (6), while prolonged reflux resulted in extrusion of one nitrogen atom from the 7-membered ring. The mechanism of the ring contraction is discussed in terms of a bicyclic diaziridine intermediate (13).     

Asymmetric synthesis of aerothionin, a marine dimeric spiroisoxazoline natural product, employing optically active spiroisoxazoline derivative

Successful first synthesis of optically pure (+)- and (−)-aerothionins (1) from the racemic spiroisoxazoline derivative 8 has been accomplished. The absolute configuration of natural (+)-1 was determined by comparison of (+)- and (−)-8 with related derivatives.     

Synthesis of all the six components of the female-produced contact sex pheromone of the German cockroach, Blattella germanica (L.)

All of the following six components of the female sex pheromone of the German cockroach, Blattella germanica (L.) were synthesized: (3S,11S)-3,11-dimethyl-2-nonacosanone (1), its 29-hydroxy derivative 2, its 29-oxo derivative 3, (3S,11S)-3,11-dimethyl-2-heptacosanone (4), its 27-hydroxy derivative 5, and its 27-oxo derivative 6. Both the enantiomers of citronellal were employed as the chiral sources and Wacker oxidation was employed for the introduction of the carbonyl group at C-2.     

Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was also possible for the O-isopropylidene-protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (±)-7a-epi-hyacinthacine A₁ (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and 14% overall yield. Enzymatic resolution of pyrrolidine (±)-36 provided a formal total synthesis to both enantiomers of 7.     

New olefinic centred binuclear clamshell type phthalocyanines: Design, synthesis, structural characterisation, the stability and the change in the electron cloud at olefine-based symmetrical diphthalonitrile fragment by the combined application of UV–Vis electronic structure and theoretical methods

The olefinic centred Schiff base (3) was obtained from the condensation of substituted dialdehyde (1) with 2-amino-4-methylphenol (2) in a 1:2 ratio. The diphthalonitrile derivative (5) was prepared by the reaction of 4-nitrophthalonitrile (4) and compound (3) in dry dimethylformamide/potassium carbonate. The key product (5) was obtained by nucleophilic substitution of an activated nitro group into an aromatic ring. The cyclotetramerization of compound (5) with phthalonitrile (6) in 1:6.15 ratio gave the expected metal-free phthalocyanine of clamshell type (7), and with metal salts of Zn(II), Ni(II), Co(II) and Cu(II) gave metallophthalocyanines of clamshell types (8-11), respectively in dimethylaminoethanol/1,8-diazabycyclo[5.4.0]undec-7-ene system. The products were purified by several techniques such as crystallization and preparative thin layer chromatography. The newly prepared compounds were characterised by a combination of elemental analyses, IR, ¹H/¹³C NMR, MS and UV-Vis spectroscopy.     

Synthesis of 4′-benzoyloxycordycepin from adenosine

With an aim to synthesize 4′-substituted cordycepins, the 4′-benzoyloxy precursor (9) was prepared from adenosine through an electrophilic addition (iodo-benzoyloxylation) to the 4′,5′-unsaturated derivative (5) and subsequent radical-mediated removal of the 3′-iodine atom of the resulting adducts (6). Usefulness of 9 was briefly verified by synthesizing the 4′-allyl (12) and 4′-cyano (13) analogues of cordycepin.     

Synthesis and application of monoterpene-based chiral aminodiols

Primary, secondary and tertiary aminodiols were synthetized regio- and stereoselectively from (−)-α-pinene 1 via α-pinene oxide 2, (−)-trans-pinocarveol 3 and key intermediate epoxy alcohol 4. N-Benzyl derivative 5 was transformed to spiro-fused oxazolidine 13 in a highly regioselective ring closure. Aminodiols and their derivatives 5-13 were applied as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde, resulting in chiral 1-phenyl-1-propanol. The substituent effect on the nitrogen was studied in detail and the best enantioselectivity was observed in the case of N-methyl-N-benzyl-substituted derivative 8. The phenomenon was interpreted by using molecular modelling at an ab initio level.     

Novel alkaloids, paxdaphnines A and B with unprecedented skeletons from the seeds of Daphniphyllum paxianum

Two novel Daphniphyllum alkaloids with unprecedented skeletons, namely paxdaphnines A (1) and B (2), have been isolated from the seeds of Daphniphyllum paxianum. Paxdaphnine A (1) is a 19-nor-Daphniphyllum alkaloid with highly caged skeleton, and paxdaphnine B (2) is the first 1,19-bisnor-Daphniphyllum alkaloid. The relative structures of 1 and 2 were elucidated by spectral methods, and their unique biosynthetic pathway postulated. The absolute structure of 1 was determined by X-ray diffraction of the iodide derivative (1a) of 1, and the absolute stereochemistry of 2 was proposed by correlation with the biosynthetic pathway for 1.