NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones.

The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a (+)-carene-derived amino alkoxide (ROLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(ROLi) mixed tetramer, a C(2)-symmetric and asymmetric (RCCLi)(2)(ROLi)(2) mixed tetramer, and a C(3)-symmetric (RCCLi)(ROLi)(3) mixed tetramer. Analogous mixtures of RCCLi/ROLi in Et(2)O and Me(2)NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C(2)-symmetric (RCCLi)(2)(ROLi)(2) mixed tetramer is formed in Et(2)O, whereas the asymmetric isomer is formed in Me(2)NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-ROLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me(2)NEt.

Efficient pyridinylmethyl functionalization: synthesis of 10, 10-Bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (DMP 543), an acetylcholine release enhancing agent.

2-Fluoro-4-methylpyridine (3) is efficiently functionalized by chlorination, hydrolysis and methanesulfonylation into the novel alkylating agent 7. This mesylate is used for the bisalkylation of anthrone under carefully defined conditions to prepare the cognition enhancer drug candidate 1. This process proceeds in up to 37% overall yield and is adaptable for large scale synthesis.

An efficient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.