Syntheses in the cinchona alkaloid series

The Quest for Quinine: Those Who Won the Battles and Those Who Won the War

“…A previous sequence published in 1970 by Gates et al [155] (which was disclosed simultaneously with that of Gutzwiller and Uskokovic [153] ), also entailed the preparation of olefin 44 b; however, in this case phosphorane 43, which is derived from meroquinene alcohol, [156] and aromatic aldehyde 42 were employed in a Wittig reaction and the cis/trans mixture of olefins so obtained equilibrated with acetic acid to afford exclusively the more stable trans alkene (Scheme 13). Gates et al did not devise a protocol for the required construction of the alicyclic moiety, and considered his route explicitly as a partial synthesis of quinine.…”

“…The C8ÀN strategies devised by Uskokovic and coworkers, [91, 147a] Taylor and Martin, [154] and Gates et al [155] in the 1960s and 1970s for the formation of quinuclidine relied on conjugate addition of an amine to a vinylquinoline or the related epoxide or chloroepoxide. The first of these transformations produced diastereomeric mixtures, because of the unselective addition of the amine to the olefin.…”

“…[153b, 154,155] Formation of the critical CÀC double bond leading to 86 through the use of organophosphorous reagents is the key step for joining the known alicyclic fragment 88 to the aromatic moiety 87. The synthesis of 88 [160] employs the readily available 1R enantiomer of monoacetate 89, [188] which contains all of the five carbon atoms required to build the piperidine ring of 88.…”

Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions

“…Oxidation of the indoline ring of 21 with (PhSeO) 2 Oyielded gram quantities of the intermediate 22,w hich was the C5lactam form of the corynanthe-type alkaloid corynantheol. Conversion of 22 into (+ +)-corynantheol, an enantiomer of the natural product, [33] could be realized using LiAlH 4 ,a nd confirmed the stereochemistry of the corresponding synthetic intermediates (18)(19)(20)(21)(22). [32] With the corynanthe-type tetracycle 22 in hand, we focused on the preparation of an indolyl acetaldehyde precursor to explore the biomimetic indole to quinoline transformation (Scheme 3).…”

“…Thecinchona alkaloids have attracted considerable attention from the synthetic community since their antimalarial activity was recognized. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Despite the advances,a ne fficient and bioinspired synthesis of the cinchona alkaloids via the biosynthetic corynanthe-type indole alkaloid intermediate has not yet been achieved. [29] Logically,s uch as ynthesis would require not only efficient access to the corresponding indole alkaloid core but also apractical biomimetic indole to quinoline transformation.…”