A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11), in ten steps and 11% overall yield from isatin, is reported. In addition, the ETP natural product (+)-gliocladine C (6) is prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of (+)-gliocladine C (6) constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.

A common strategy for preparing tryptophan-derived epidithiodioxopiperazine (ETP) natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter is reported. This strategy is exemplified by enantioselective total syntheses of four heptacyclic ETP natural products — gliocladine C (6), leptosin D (7), T988C (8), and bionectin A (9)—starting with the di-(tertbutoxycarbonyl) derivative 17 of the trioxopiperazine natural product gliocladin C, which is readily available by enantioselective chemical synthesis. In addition, total syntheses of the enantiomer of gliocladine C (ent-6) and gliocladin A (11), the di(methylthio) congener of bionectin A, are reported. These syntheses illustrate a synthetic strategy wherein diversity in the dioxopiperazine unit of ETP natural products is introduced at a late stage in a synthetic sequence. In vitro cytotoxicity of compounds in this series against invasive human prostrate (DU145) and melanoma (A2058) cancer cell lines is described and compared to that of chaetocin A (4).

Pteridines substituted with a 1,1‐, 1,2‐, or 1,1,3‐substituted alkenyl group (mostly (E)‐configured) at C(6) were synthesized in high yields by the intramolecular nitroso‐ene reaction of 4‐(alkenoylamino)‐2‐amino‐6‐benzyloxy‐5‐nitroso‐ and 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidines. Thus, the N‐alkenoyl nitrosopyrimidines 4 and 5 provided the pteridines 6 and 7, respectively, characterized by a 1,2‐disubstituted (E)‐alkenyl substituent, the C(4)‐(E)‐geranoyl amide 13 led regio‐ and stereoselectively to the (E)‐1,1,2‐trisubstituted alkenyl‐pteridine 16, and the C(4)‐(Z) isomer 14 led to 17 possessing a 1,1‐disubstituted alkenyl group. The trifluoromethylated butenoyl amide 15 possessing a less highly nucleophilic alkenoyl group reacted more slowly to give the trifluoromethylated vinylpteridine 18. Also the 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidine 20 reacted more slowly than 4 and 5, and provided the pteridines 23; introduction of additional N‐acyl groups as in 21 and 22 led to a considerably faster ene reaction.The X‐ray crystal structure analysis of the nitroso amide 15 shows eight symmetrically independent molecules in the unit cell. In the crystalline state, the N,N‐dimethylformamidine derivative 9 of 6 forms a centrosymmetric dimer with the 7,8‐lactam group connected by intermolecular hydrogen bonds.

Then-octanol/water partition coefficient (log KOW) is a useful parameter for the assessment of the environmental fate and impact of xenobiotic trace contaminants. Quantitative structure-activity relationship (QSAR) model for log KOWof polychlorinated biphenyls (PCBs) was analyzed by using the density functional theory at B3LYP/6-31G(d) level and the partial least squares (PLS) method with an optimizing procedure. A PLS model with reasonably good coefficient (R2=0.992) and cross-validation test (Q2cum=0.988) values was obtained. All the predicted values are within the range of±0.3log unit from the observed values. The log KOWvalues of 7 PCBs in the test set predicted by the model are very close to those observed, indicating that this model has high fitting precision and good predictability. The PLS analysis showed that PCBs with larger electronic spatial extent and lower molecular total energy values tend to be more hydrophobic and lipophilic.

New spirocyclic heterocycles 8, 16, 19/20, 25, 27, and 30 derived from pyrimido [4,5-b][1,4]diazepin]-8'(9'H)-one were synthesised by a tandem nitroso-ene/Diels -Alder reaction of 4-(alkenoylamino)-5-nitrosopyrimides. The crystal structure of 16 was established by X-ray analysis. It is characterised by four pairs of intermolecular H-bonds linking every two molecules in the unit cell. Sequential imine reduction and intramolecular condensation of the C(4')-(acylamino)-pyrimido [4,5-b] Introduction. -The nitroso-ene reaction of 4-(alkenoylamino)-5-nitrosopyrimidines 1 generates allylic hydroxylamines, and is followed by in situ elimination of H 2 O, leading in high yield to C(6)-substituted pteridinones 2 [1]. We wondered about the ene reaction of the 4-(acylamino)-5-nitrosopyrimidines I (Scheme 1), possessing an Nalkenoyl group substituted at C(2) rather than at C(3). The ene reaction of I may lead either to 6,6-disubstituted pteridinones II, via the reacting conformer Ia, or to pyrimido [4,5-b][1,4]diazepines IV, via conformer Ib. Dehydration of the initial ene products should generate the quinonoid III and/or lead to pyrimido [4,5-b][1,4]diazepines V. The expected high reactivity of the intermediates and products suggested intercepting them. We planned to do so by combining the nitroso-ene reaction with a cycloaddition. The cycloaddition of V to 2,3-dimethylbuta-1,3-diene is expected to lead to spiropyrimidodiazepines VI. This imine, or the presumably more stable amine VII, should facilitate the analysis of the regioselectivity of the ene reaction, and lead to a new ring system. No issue of regioselectivity is expected for the ene raction of 4-(alkenoylamino)-5-nitrosopyrimidines I that lack the CH 2 R 4 substituent. Their tandem ene/Diels -Alder reaction was thought to lead exclusively to pyrimido [4,5-b]