Synthesis of nicotine derivatives via reductive disilylation of (S)-nicotine.

[reaction: see text] A variety of novel nicotine derivatives were prepared via reductive disilylation of (S)-nicotine. Treatment of nicotine with lithium powder and chlorotrimethylsilane afforded 1,4-bis(trimethylsilyl)-1,4-dihydronicotine in high yield. Addition of various carbonyl electrophiles and a catalytic amount of TBAF provided either C-5 substituted nicotines or 1,4-dihydronicotine derivatives.

Regioselective C-2 and C-6 substitution of (S)-nicotine and nicotine derivatives.

[reaction: see text] Regioselective deprotonations of (S)-nicotine and derivatives at the C-2 and C-6 positions of the pyridine ring were performed in good to excellent yields. These methodologies allow the direct introduction of a plethora of functional groups onto the pyridine ring of nicotine.

Synthesis of C-4 substituted nicotine derivatives via an N-acylpyridinium salt of (S)-nicotine.

[reaction: see text] A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield. Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.

Diels-Alder reactions of N-acyl-2-alkyl(aryl)-5-vinyl-2,3-dihydro-4-pyridones.

Readily available N-acyl-5-vinyl-2,3-dihydro-4-pyridones undergo Diels-Alder cyclization with various dienophiles to afford novel octahydroquinolines containing synthetically useful functionality. With dihydropyridone 5 and cis-disubstituted dienophiles, the resulting cycloadducts were obtained as single diastereomers in good to excellent yield. The corresponding reaction of 5 with methyl acrylate, acrylonitrile, and phenyl vinyl sulfone showed modest preference for the endo adducts. The effect of the dihydropyridone C-2 and C-4 substituents on the degree of diastereofacial control was examined. By using this methodology, the core decahydroquinoline skeleton of gephyrotoxin was prepared in a stereocontrolled fashion. Interesting reactivity was observed with certain dienophiles leading to ring-opening of the initially formed cycloadducts. This tandem reaction provides a route to uniquely substituted beta-aminoketones, alcohols, and unnatural amino acids.