T-muurolol sesquiterpenes from the marine Streptomyces sp. M491 and revision of the configuration of previously reported amorphanes.

Two new sesquiterpenes, 15-hydroxy-T-muurolol (3d) and 11,15-dihydroxy-T-muurolol (3e), along with the plant cadinenes T-muurolol (3f) and 3alpha-hydroxy-T-muurolol (3g), were isolated from the marine-derived Streptomyces sp. M491. Their absolute configuration was established via NMR spectroscopy and X-ray crystallography of 3-oxo-T-muurolol (3a), which was reisolated from this strain. In addition, the absolute configuration of further sesquiterpenes previously reported from this strain was revised. These products were tested for their cytotoxicity against 37 human tumor cell lines using the MTT method. Only 3d was cytotoxic against a range of human tumor cell lines with a mean IC50 of 6.7 microg/mL.

Computer-aided structure analysis of an epimerized dehydroepiandrosterone derivative and its biological effect in a model of reactive gliosis.

The naturally occurring steroid dehydroepiandrosterone (DHEA) is reported to reduce glial fibrillary acidic protein (GFAP) overexpression in a model of reactive gliosis due to its conversion to estradiol by the enzyme aromatase. In the present study we examined the biological effect of a new epimerized derivative of DHEA, 16alpha-iodomethyl-13alpha-dehydroepiandrosterone derivative (16alpha-iodomethyl-13alpha-DHEAd, 16alpha-iodomethyl-13alpha-androst-5-en-3beta,17beta-diol), using the same model system, and compared the 3D structure of this molecule with that of DHEA and two steroidal type aromatase inhibitors, formestane and exemestane. The synthetic compound, in contrast to the reported effect of DHEA, was able to reduce GFAP overexpression only if the enzyme aromatase was inhibited. Data obtained from computational calculations fortified by X-ray crystallography revealed that contrary to the nearly planar sterane framework of DHEA, the synthetic derivative 16alpha-iodomethyl-13alpha-DHEAd has a bent sterane skeleton, resulting in a 3D structure that is similar to that of formestane or exemestane. Moreover, 16alpha-iodomethyl-13alpha-DHEAd resulted to be metabolically more stable than DHEA. The results suggest that epimerization of the sterane skeleton of DHEA inclines the plane of the D ring, leading to a significantly altered biological activity. The synthetic molecule has a DHEA-like effect on GFAP overexpression when the enzyme aromatase is inhibited and the naturally occurring DHEA is ineffective in this respect. On the other hand, based on their structural similarity it can be hypothesized that 16alpha-iodomethyl-13alpha-DHEAd applied alone might have a biological effect similar to that of formestane or exemestane.

Enantio- and diastereoselective synthesis of duocarmycine-based prodrugs for a selective treatment of cancer by epoxide opening.

For the enantio- und diastereoselective synthesis of the prodrug 2, the N-tert-butyloxycarbonyl-protected amine 7 was alkylated with the enantiopure epoxide 14 to give the amide 10. A regio- and facial-selective metal-mediated cyclisation by using a cuprate led to 17 with an inversion of configuration at C10. Subsequent transformation of the hydroxy group in 17 by using the Appel procedure afforded (1S,10R)-9 with an unusual double inversion owing to neighbouring-group participation of the N-tert-butoxycarbonyl group. (1S,10R)-9 is the key intermediate in the synthesis of the prodrug 2, which has been developed for a selective treatment of cancer based on the antibody-directed enzyme prodrug therapy as an analogue of the natural antibiotic duocarmycine SA (1).

Bullvalene trisepoxide and its stereospecific rearrangement to 2,8,12-trioxahexacyclo[8.3.0.0(3,9)0(4,6)0(5,13)0(7,11)]tridecane: two new C3-symmetrical oligocycles with propeller chirality.

Epoxidation of bullvalene (1) with a neutralized solution of Oxone gave racemic trisepoxide rac-6 in 93 % isolated yield. Its structure was examined by X-ray crystallography. The two enantiomers of 6 were separated by preparative HPLC and exhibited specific rotations of [alpha](25)(D)= +160, [alpha](25)(365)= +567 (c=0.946, CHCl(3)) for the firstly eluted and [alpha](25)(D)= -157, [alpha](25)(365)= -554 (c=0.986, CHCl3) for the secondly eluted enantiomer of 6. The geometry of (+)-6 and the absolute configuration of (-)-6 were determined by X-ray crystal structure analysis and anomalous diffraction, respectively. According to this, (-)-6 possesses (3R,5S,7S,9R,11R,13S)- and (+)-6 has (3S,5R,7R,9S,11S,13R)-configuration. Upon treatment with BF(3)Et(2)O at -78 degrees C, trisepoxide rac-6 rearranges with retention of the skeletal three-membered carbocycle to give the cage trisether rac-8, as proved by X-ray crystal structure analysis, in virtually quantitative yield. Enantiomers of rac-8 were separated by preparative HPLC and exhibited specific rotations of [alpha](25)(D)= +49, [alpha](25)(365)= +170 (c=1.01, CHCl3) (firstly eluting) and [alpha](25)(D)= -46, [alpha](25)(365)= -160 (c=1.02, CHCl(3)) (secondly eluting enantiomer). The absolute configuration of (-)-8 was determined by anomalous diffraction to be (1R,3R,7R,9R,11R,13R). DFT computations at the TD-B3 LYP/6-31+G(d,p)//B3 LYP/6-31+G(d) level of theory for (3R,5S,7S,9R,11R,13S)-6 and (1R,3R,7R,9R,11R,13R)-8 predicted specific rotations of -206.7 and -83.4, respectively. Acid-catalyzed isomerization of the enantiomerically pure (+)-6 proceeded without racemization to give exclusively (-)-8, and (-)-6 provided only (+)-8. Thus, this isomerization occurs with ring opening of the three C--O bonds in the epoxide moieties in the alpha-position relative to the three-membered carbocycle rather than in the beta-position.

Six- and eightfold palladium-catalyzed cross-coupling reactions of hexa- and octabromoarenes.

Palladium-catalyzed sixfold coupling of hexabromobenzene (20) with a variety of alkenylboronates and alkenylstannanes provided hexaalkenylbenzenes 1 in up to 73 % and 16 to 41 % yields, respectively. In some cases pentaalkenylbenzenes 21 were isolated as the main products (up to 75 %). Some functionally substituted hexaalkenylbenzene derivatives containing oxygen or sulfur atoms in each of their six arms have also been prepared (16 to 24 % yield). The sixfold coupling of the less sterically encumbered 2,3,6,7,10,11-hexabromotriphenylene (24) gave the desired hexakis(3,3-dimethyl-1-butenyl)triphenylene (25) in 93 % yield. The first successful cross-coupling reaction of octabromonaphthalene (26) gave octakis-(3,3-dimethyl-1-butenyl)naphthalene (27) in 21 % yield. Crystal structure analyses disclose that, depending on the nature of the substituents, the six arms are positioned either all on the same side of the central benzene ring as in 1 a and 1 i, making them nicely cup-shaped molecules, or alternatingly above and below the central plane as in 1 h and 23. In 27, the four arms at C-1,4,6,7 are down, while the others are up, or vice versa. Upon catalytic hydrogenation, 1 a yielded 89 % of hexakis(tert-butylethyl)benzene (23). Some efficient accesses to alkynes with sterically demanding substituents are also described. Elimination of phosphoric acid from the enol phosphate derived from the corresponding methyl ketones gave 1-ethynyladamantane (3 b, 62 % yield), 1-ethynyl-1-methylcyclohexane (3 c, 85 %) and 3,3-dimethylpentyne (3 e, 65 %). 1-(Trimethylsilyl)ethynylcyclopropane (7) was used to prepare 1-ethynyl-1-methylcyclopropane (3 d) (two steps, 64 % overall yield). The functionally substituted alkynes 3 f-h were synthesized in multistep sequences starting from the propargyl chloride 11, which was prepared in high yields from the dimethylpropargyl alcohol 10 (94 %). The alkenylstannanes 19 were prepared by hydrostannation of the corresponding alkynes in moderate to high yields (42-97 %), and the alkenylboronates 2 and 4 by hydroboration with catecholborane (27-96 % yield) or pinacolborane (26-69 % yield).