Asymmetric Total Synthesis of (S)-(+)-Cocaine and the First Synthesis of Cocaine C-1 Analogs from N-Sulfinyl β-Amino Ester Ketals

Abstract

Sulfinimine-derived α,β-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)(3), undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

Six new monoterpenoid indole alkaloids from the aerial part of Gelsemium elegans

“…The downfield shift (þ8.8 ppm) for C-5 in 2 relative to that in gelsedine 6 and the presence of 10 of unsaturation suggested that the oxygen atom was also connected to N 4 , forming an oxaziridine ring. 11 This conclusion was further confirmed by the IR absorption band for oxaziridine ring at 1318 cm À112,13 and by the high intensity fragment ion peak at m/z 327.1709 in HRESIMS, which was formed by eliminating a neutral oxygen atom (calcd 327.1703). 13 A comprehensive analysis of the 1 He 1 H COSY, HSQC, and HMBC spectra allowed the assignment of NMR data of 2 as shown in Tables 1 and 2.…”

Combined heterogeneous metal/organic catalysts for eco-friendly synthesis

“…Thus, the palladium (0)-aminopropyl-mesocellular foam (Pd(0)-AmP-MCF)-catalyzed aerobic oxidation [31] of alcohols 1 was linked in sequence with several chiral amine 4 [61]-catalyzed one-pot cascade transformations and provided a variety of functional molecules (e.g., aziridine 3a [62,63], E-6b [64,65], pyrrolidine 7a [66] and 8d [67]) with high enantiomeric ratios (Scheme 2). Next, these compounds such as E-6b and 8d can be rapidly converted to tropane alkaloids (e.g., cocaine) [64,65] and secologanine tryptamine alkaloids [67], respectively (Scheme 2b and 2d).…”

“…Next, these compounds such as E-6b and 8d can be rapidly converted to tropane alkaloids (e.g., cocaine) [64,65] and secologanine tryptamine alkaloids [67], respectively (Scheme 2b and 2d). An aerobic oxidation/Michael/ carbocyclization cascade sequence employing the combined heterogeneous Pd/chiral amine multiple relay catalysis and molecular oxygen/air as the terminal oxidant was also investigated (Scheme 3).…”

Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine

“…Voltage-gated sodium channel inhibition assays were performed with cultured neocortical neurons obtained from Swiss-Webster mice, as described briefly in the section below and in further detail elsewhere Jabba et al, 2010). All of the C-1 cocaine analogs were synthesized by us (Davis et al, 2010(Davis et al, , 2012. Other reagents were from Thermo Fisher Scientific (Waltham, MA) or Sigma-Aldrich (St. Louis, MO) unless otherwise indicated.…”

“…No cocaine analogs possessing substituents at the C-1 bridge position existed until recently, when we targeted such analogs with our novel sulfinimine (N-sulfinyl-imine) chemistry (Zhou et al, 2004;Senanayake et al, 2005;Davis, 2006;Morton and Stockman, 2006). Our asymmetric synthesis (Davis et al, 2010(Davis et al, , 2012 generated chiral (R)-(Ϫ)-cocaine analogs with various C-1 substituents, including: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6) moieties (structures shown in Fig. 1).…”