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Various bicyclic and tricyclic heterocycles are synthesized by condensation and ring-closing reactions, e.g. Knoevenagel and lactonization reaction.

During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10–100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED 50 values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4-quinolylmethyl derivative 4A showed ED 50 values of 3.4 and 2.4 μM and TD 50 values of >200 and 96.4 μM, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents.

1-(9-Hydroxyfluoren-9-yl)-2,2-dimethyl-1-propanone, C18H18O2, M(r) = 266.34, orthorhombic, Pbcn, a = 18.917 (10), b = 11.843 (8), c = 13.177 (7) A, V = 2952 (5) A3, Z = 8, Dx = 1.198 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.72 cm-1, F(000) = 1136, T = 296 K, R = 0.044 for 1042 unique observed reflections. Conversion of ap-9-pivaloylfluorene, ap-(I), into lithiated (I)-9-anion followed by the addition of MeOH, then H2O, led to unexpected hydroxylation to provide 20-40% of sp-9-hydroxy-9-pivaloyfluorene, sp-(II), and 60-80% recovery of ap-(I). The singular sp conformation of (II) in solution suggested by NMR was confirmed in the crystalline state by X-ray diffraction which showed the O(1)-C(9)-C(10)-O(2) torsion angle approximately 0 degrees and the C(10) = O(2)...H(9)-O(1) non-bonding distance 1.95 (4) A, suggesting strong intramolecular hydrogen bonding in this conformation.

C18H19O3P, M(r) = 314.32, monoclinic, P2(1)/n, a = 5.726 (6), b = 14.234 (7), c = 20.08 (1) A, beta = 92.54 (7) degrees, V = 1635 (4) A3, Z = 4, Dx = 1.277 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 1.71 cm-1, F(000) = 664, T = 296 K, R = 0.042, 1813 unique observed reflections. The X-ray structure determination of the title compound shows that the dioxaphosphorinane ring has a chair conformation in which the phosphoryl O atom (P=O) is equatorial, which explains the absence of substantial NMR deshielding by its P=O group on H(4) and H(6), which are axial.

2,2-Disubstituted 2,5-dihydro-4-methyloxazoles (1) were synthesized from 2-aminopropanol in three steps. 3-Oxazolines 1 can be converted into various α-sulfinyl ketimines such as (SS)-{(4-methylphenyl)sulfinylmethyl}-2,2-diethyl-2,5-dihydrooxazole (5) which was stereoselectively reduced with Dibal-H to give 3-hydroxy-2-aminopropyl sulfoxide 7.

(SR)-(−)-N-[1-(Triethoxymethyl)ethylidene]-p-toluenesulfinamide (2) was synthesized from the addition reaction of triethoxyacetonitrile with MeLi followed by (+)-(R)-d-menthyl p-toluenesulfinate (1R). Sulfinimine 2 underwent complete stereoselective reduction with 9-BBN and addition reaction with allylmagnesium bromide. Optically pure α-amino acids were synthesized from these adducts by simple hydrolysis.

A remarkable asymmetric induction was observed in the one-pot condensation reaction of (S)-(-)-perillaldehyde with 4-hydroxy-6-methyl-2-pyrone in the presence of L-proline which provided the title compound, C 16 H 18 O 3 , a tricyclic pyrone, as a single diastereomer in 78% yield. As the configuration of the cyclohexane C atom holding the isopropenyl group is the same as that in the (S)-aldehyde substrate, the total absolute stereochemistry could be elucidated from its X-ray structure. The cyclohexane ring has a chair conformation in which the juncture H atom (H5a) is axially oriented and the isopropenyl substituent is equatorial.

Enantiopure 1 -t- butylsulfinyl-2-subsituted ferrocenes were synthesized in reactions of (SR,1S,2R)-1-t-butylsulfinyl-2-lithioferrocene (11) with various electrophiles in good yields. (SR,1S,2R)-1-t-Butylsulfinyl-2-formylferrocene (19), prepared this way, underwent complete stereoselective addition reactions with Grignard reagents under chelation controlled conditions with titanium tetraisopropoxide. 1,4-Addition reactions of selected α,β-unsaturated esters with cuprate reagents gave mixtures of two diastereomers. The lack of stereoselectivity in these 1,4-addition reactions is due presumably to the remote reactive site (C-3′) and the flexibility of the side chain of the ester. A stereoselective cationic displacement reaction of (1S,2R,1′S)-1-(t-butylsulfonyl)-2-[α-(2-propenoyl)oxybenzyl]ferrocene (44) with 1-acetoxy-1,3-butadiene was found to produce (1S,2R,1′S)-1-(t-butylsulfonyl)-2-(5′-oxo-1′-phenyl-3′-pentenyl)ferrocene (45).

Most alkyl phenyl sulfones are readily α-chlorinated with CCl4 and α-brominated with CBrCl3 in KOH−t-BuOH via radical−anion radical pair (RARP) reactions. While isopropyl mesityl sulfone (4) is easily α-chlorinated with CCl4, it was completely recovered when treated with the more reactive CBrCl3. Subsequent investigations showed the latter result to be due to the poor acidity of 4 together with the rapid depletion of CBrCl3 and KOH by their reaction with each other, and led to a variety of other important results. 4-Hydroxyphenyl isopropyl sulfone (6) is unreactive with either CCl4 or CBrCl3 in KOH−t-BuOH, its phenoxide anion strongly reducing the electronegativity of the sulfonyl group, thereby inhibiting α-anion formation. This effect is reversed by the electron-withdrawing influence of two α-phenyls, so that benzhydryl 4-hydroxyphenyl sulfone (8) is readily α-halogenated in KOH−t-BuOH with CCl4 or CBrCl3. On further contact with KOH−t-BuOH the α-halogenated sulfones from 8 are decomposed into benzophen...

(R)-Carvone was used as a chiral building block. Regio- and stereoselective alkylations at C6 and C2 of (R)-carvone and (R)-5-isopropyl-2-methyl-2-cyclohexenone [derived from the hydrogenation of (R)-carvone] followed by palladium-mediated ring closures afforded various enantiopure bicyclic and tricyclic alkenones. Hence, cyclization of (5S,6S)-2,6-dimethyl-6-(cis-3-iodo-2-propenyl)-5-isopropenyl-2-cyclohexenone (3) gave (4aS,5S,8aS)-1,4,4a,5,8,8a-hexahydro-5-(methoxycarbonylmethyl)-2,5,8a-trimethylnaphthalen-1-one (7) as the major product, cyclization of (5S,6S)-2,6-dimethyl-6-(cis-3-iodo-2-propenyl)-5-isopropyl-2-cyclohexenone (22) produced (1S,5R,6S)-1,5-dimethyl-6-isopropyltricyclo[3.3.1.02,8]-3-nonen-9-one (23), and cyclization of (2R,5S,6S)-2,6-dimethyl-2-(cis-3-iodo-2-propenyl)-5-isopropenyl-3-cyclohexen-1-one (25) afforded (3aR,6S,7aR)-6,7a-dimethyl-5-isopropenyl-3a,6,7,7a-tetrahydro-1H-inden-7-one (26). A 1,2-rearrangement reaction of bromide 16 gave hexahydro-1H-benzocycloheptene 17.

L'addition de composes organiques du lithium ou du magnesium avec la benzylidene-3 pyrroline-1 suivie d'une cyclisation conduit a des pyrrolizidines