Enantioselective Synthesis of Tropanes: Brønsted Acid Catalyzed Pseudotransannular Desymmetrization

Abstract

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1‐aminocyclohept‐4‐ene‐derived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8‐azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products (−)‐α‐tropanol and (+)‐ferruginine.

Testing enabling techniques for olefin metathesis reactions of lipophilic substrates in water as a diluent

“…2, 131.6, 130.7, 128.1, 126.5, 74.9, 48.5, 38.5, 23.0. Presented analytical data are consistent with literature (Rodriguez et al, 2020;Toh et al, 2021). 2, 136.2, 125.9, 125.8, 124.7, 124.2, 123.2, 122.3, 111.6, 54.0, 53.4; melting point: 216 C. Presented analytical data are consistent with literature (Nienałtowski et al, 2020b).…”

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…In the proposed transition state (65-A), the catalyst interacted with the bromide via hydrogen bonds and with the oxetane via Lewis basic functionality to induce the enantioselectivity. Aside from oxetanes, epoxides and aziridines are other prevailing building blocks and recent studies have been performed by Vicario and Adamo, respectively (Figure 5E,F) [83,84]. Furthermore, some impressive investigations on the azetidines and azetidiniums have been performed successfully [85][86][87].…”

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…Starting from the scaffold 453 , they also synthesized (+)‐ferruginine ( 460 ) via a multistep sequence that included oxidation, alkynylation, Rupe rearrangement, and detosylation/ N ‐methylation (Scheme 49). [96] …”

“…[95] In 2020, Uria, Merino, Vicario, and co-workers reported an enantioselective total synthesis of (À )-α-tropanol (455) and (+)-ferruginine (460, Scheme 49). [96] They first realized an asymmetric pseudotransannular ring-opening of epoxycycloheptylamines using a chiral phosphoric acid 452 as the catalyst. Then they applied the method for the total synthesis of two natural products from the tropane family.…”

“…Starting from the scaffold 453, they also synthesized (+)-ferruginine (460) via a multistep sequence that included oxidation, alkynylation, Rupe rearrangement, and detosylation/N-methylation (Scheme 49). [96] In 2016, Yang, Yao, and co-workers reported an enantioselective total synthesis of lycoposerramine-Z (469, Scheme 50). [97] To obtain the key intermediate 463, they carried out an asymmetric intramolecular Michael addition of α,β-unsaturated ketone 461 using chiral phosphoric acid 462 as the catalyst.…”