Synthesis of (±) [5‐3H] N′‐nitrosoanatabine, a tobacco‐specific nitrosamine

Abstract

AbstractTobacco‐specific N′‐nitrosamines (TSNA) are a unique class of systemic organ‐specific carcinogens. The TSNA are formed by N‐nitrosation of nicotine and of the minor tobacco alkaloids after harvesting of tobacco and during smoking. The N‐nitrosation of anatabine leads to N′‐nitrosoanatabine (NAT; 1‐nitroso‐1,2,3,4‐tetrahydro‐2,3'‐bipyridyl) which requires in‐depth assays in laboratory animals other than the rat. Furthermore, delineation of its tissue distribution and metabolism is needed for structure:activity comparisons with other TSNA and for the assessment of potential human risk from this TSNA. We have, therefore, synthesized (±)[5‐3H]NAT. 5‐Bromo‐3‐pyridine‐carboxaldehyde was condensed with ethyl carbamate prior to Diels–Alder reaction with 1,4‐butadiene to give the racemic anatabine ring system. Hydrolysis, followed by reduction with LiAlT4 and nitrosation, led to (±)[5‐3H]NAT (60% yield, specific activity 266 mCi/mmol, radiochemical purity of >99%). Copyright © 2002 John Wiley & Sons, Ltd.