Letters in Organic Chemistry - Volume 6, Issue 2, 2009

The synthesis of C2-symmetric glycophanes incorporating two triazole linkers has been achieved in seven steps from 3,4,6-tri-O-acetyl-D-glucal in good overall yields. The intermolecular Cu(I)-mediated Huisgen reaction was used for the ring closure key-step to give almost exclusively 24-, 26-, and 32-membered chiral macrocycles without significant polymerization. Target compounds however had low solubility in water, precluding investigation of their recognition behaviour in this medium.

The Henry reaction between the nitroalkanes 6-11 and (R)-(+)-glyceraldehyde acetonide (1), was investigated in respect to the variation of the base, temperature and reaction time. Nitroalcohols 5a-f were obtained in good yields (70- 85%) and moderate to good anti-selectivities (50-79%). The transformation of the nitroalcohol 5a,b in title γ-lactone 2, a potential precursor of bioactive β-aminoacids, was also investigated.

Synthesis of alkyl β-glucosides such as p-anisyl β-D-glucopyranoside, phenethyl β-D-glucopyranoside, salidroside, cinnamyl β-D-glucopyranoside, citrusin D, 3-methylbutyl β-D-glucopyranoside, 3-methyl-2-butenyl β-Dglucopyranoside, geranyl β-D-glucopyranoside, perilloside A, and cyclohexyl β-D-glucopyranoside was accomplished in moderate yields by transglucosylation using hyperthermostable Pyrococcus furiosus β-glucosidase immobilized onto gelatin gel. Recovered immobilisate was reusable on successive runs in transglucosylation.

Circular dichroism calculations and conformational analyses of 2,2'-binaphthyl esters derived from primary alcohols with a chiral center in the β-position of the hydroxy group were performed using the time-dependent density functional theory (TD-DFT) method, suggesting that the TD-DFT is highly effective for determining the absolute configuration of the binaphthyl esters.

By means of microwave irradiation, the rearrangement from 12β-tosylate and 12β-alcohol of hecogenin derivatives into C-nor-D-homo-Δ17a(18)-olefin (2) and the Δ13(17a)-isomer (3) was achieved. With this method, the controlled solvolysis in anhydrous pyridine gave total conversion to desired exocyclic-olefin which is expected to be a building block of isosteroidal alkaloids.

An analogue of Tipranavir was designed by replacing the dihydropyrone core with a 1,3-cyclohexanedione ring. The thio-alkyl group was used as a temporary protection group for α, β-unsaturated cyclohexane-1,3-diketone derivative, and the resulting compound was reacted with an ethyl-organometallic reagent to form the desired Michael addition product. By using this strategy, a more stable analogue of Tipranavir was synthesized and exhibited excellent HIV protease inhibition (12 nM Ki).

The key intermediates 5-benzyl-2-phenylpyrimidin-4(3H)-ones or (E)-5-benzylidene-2-phenyl- 5,6-dihydropyrimidin- 4(3H)-ones were obtained conveniently by cyclization of the acetates of Baylis-Hillman adducts and benzamidine hydrochloride in the presence of sodium ethoxide at room temperature. Chlorination of pyrimidinones with phosphorus oxychloride and subsequent treatment with morpholine and demethylation yielded PI3K inhibitors.

Synthesis of new cap analogs containing 2'-OH modifications on both guanosine and m7guanosine moieties such as m2 7,2'OG[5']ppp[5']m2'OG and 2'-OH modifications on both m7guanosine moieties such as m2 7,2'OG[5']ppp[5'] m2 7,2'OG are reported. Structures were confirmed by 1H and 31P NMR and mass spectral data.

A new series of 4-alkyl(aryl)-4-tetramethylenesulfoximide-1,1,1-trifluoroalk-3-en-2-ones has been prepared from the O,N-exchange reactions of 4-alkyl(aryl)-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with the cyclic S,Stetramethylenesulfoximide in absence of solvent, in good yields. Subsequently, the easy preparation of a new series of a fused heterocyclic system of 3-aryl-5-trifluoromethyl-7,8-dihydro-6H-thieno[2,1-f][1,2]thiazine 1-oxide derivatives (60- 85% yields) from intramolecular cyclization reactions of sulfoximide enones employing potassium t-butoxide in diethyl ether at reflux is also reported.

A mild aza-Michael protocol has been developed using ZrCl4 as catalyst on α, β-unsaturated esters and nitriles. The aromatic amines were found to give the products with ease. The ZrCl4 mediated route was compatible with acid sensitive carbohydrate esters and provided an efficient method to prepare C-linked carbo β3-amino acids (β3-Caa).

An effective method to prepare racemic α-amino acids was developed. The key reactions involve nitrosation of malonate under basic conditions and reduction of α-hydroxyimino ester derivatives with zinc powder in the presence of acetic anhydride.

A novel one-pot fisher indole synthesis approach has been developed by using bismuth nitrate as a catalyst. Yields around 90-95% were obtained after reaction in methanol at reflux temperature in 20-40 min. Apart from the mild reaction conditions of the process and its excellent results, the simplicity of product isolation and the possibility to recycle the bismuth nitrate offers a significant advantage.

The reaction of 2-imino-3-(2-propynyl)-1,3-benzothiazole with various aryl iodides, catalyzed by Pd-Cu, in the presence of sodium lauryl sulfate as the surfactant and potassium carbonate as the base, in water, leads to the formation of 2-substituted imidazo[2,1-b][1,3]benzothiazoles.

A series of 4-bromo-5-halo and 4-bromo-5-organometal-2-anilinothiazole derivatives were prepared via the halogen dance (HD) reaction. Subsequent Pd-catalyzed Stille and Suzuki-Miyaura cross-coupling reactions were performed in a sequential manner to obtain novel 4,5-diarylated-2-anilinothiazoles.

Aliphatic and aromatic nitriles are converted to corresponding amides in a single step via hydrolysis with basic H2O2 in aqueous solution of the surfactant Cetyltrimethylammonium methanesulfonate (CTAOMs). The method has several advantages: use and recycle of water as reaction medium, use of environmentally benign oxidant H2O2, easy product isolation, short reaction time, high yields and selectivity, mild conditions.

Racemic P-acetoxy-P-chloro phenylphosphonite reacts with prochiral 3-acylcoumarins yielding (2R,3R)/(2S,3S)-coumarino-3,4-c-2-oxo-2-phenyl-1,2-3H-oxaphospholes with >99% regio- and diastereoselectivity. The stereoselectivity is governed by the presence of phophonite phenyl group and oxaphosphole ring formation. The product has suitable conformation providing stereoselective route to (R,S)/(S,R) phosphino-substituted coumarins, normally inaccessible by the Phospha-Michael reaction employing achiral reagents.