The total synthesis of epibatidine

Abstract

The synthesis of the potent analgesic alkaloid epibatidine 1, employing as the key step a singlet oxygen reaction with 1 -(2-chloro-5-pyridyl)cyclohexa-2,4-diene 2, is described.

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates

“…19 This approach is applicable to a wide range of substrates as summarized in Scheme 2. When applied towards the cyclopropanation of various vinyl heterocycles, 30,31 the (R)pantolactone-condensed-aryldiazoacetates gave routinely high asymmetric induction (87-98% de) and the process was suitable for the synthesis of a variety of heterocycle-substituted cyclopropanes. In general, reactions involving a para-substituted aryldiazoacetate gave slightly higher asymmetric induction than ortho-substituted analogues (8-11 (97-98% de) vs. 9-16 (87-89% de)).…”

“…22,28,29 Even in the case of successful methodologies, the vast excess of substrate typically used in these reactions raises concerns that vinyl heterocycles, particularly pyridine derivatives, may interfere with the catalyst. 25,33,34 In order to evaluate the inuence of different heterocycles an assortment of vinyl heterocycles (2.32 equiv., see S8-S10 in the ESI † for synthetic details 30,31 ) were reacted with 2,2,2-trichloroethyl 2-(4-bromophenyl)-2-diazoacetate (1.0 equiv.) (Table 1).…”

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues,

“…[13][14][15][16][17][18] Similarly, another well exploited methodology for the synthesis of 1 has employed intramolecular nucleophilic ring closure of 1,4-aminocyclohexane derivatives 7, originally developed for the construction of 7-azanorbornane system, 19 and employs multiple steps even to reach the crucial trans-1,4-aminocyclohexanol derivatives. [20][21][22][23][24][25][26][27] More recently, 28 the elaboration of tropinone skeleton (6) into 1 via Favorskii rearrangement by Bai et al, although elegant, suffers from the poor yield. Moreover, these strategies lack easy adaptability for the synthesis of epibatidine analogues.…”

1-Acetoxy-1,3-butadiene

“…This work was ultimately employed in the total synthesis of epibatidine (eq 16). 41 Another interesting thermal case was reported 42 in which 1-acetoxy-1,3butadiene served as a dienophile and ortho-quinone ketals (4) as dienes (eq 17). This cycloaddition provided the bicyclo[2.2.2]octannoe (5), which underwent a Cope rearrangement to give cis-decalin (6), thereby establishing a stereoselective tandem strategy for the synthesis of highly functionalized cis-decalins.…”