Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine

Abstract

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis -hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.

Catalytic Asymmetric Total Syntheses of (−)-Galanthamine and (−)-Lycoramine

“…(4aS,6R,8aR)-6-Hydroxy- 3-methoxy-11-methyl-4a,5,7,8,11,12hexahydro-6H-benzo[2,3]benzofuro [4,3-cd]azepin-10(9H)-one (16). To a stirred solution of 15 (157 mg, 0.388 mmol, 1 equiv) in dry DCE (15 mL), paraformaldehyde (47 mg, 1.55 mmol, 4 equiv) and CF 3 CO 2 H (434 μL, 5.82 mmol, 15 equiv) were added sequentially at room temperature.…”

“…The D ring of target molecules 1a and 1b could be installed by an intramolecular Pictet−Spengler cyclization of intermediate I, whereas the amide moiety in I would be introduced from the common advanced building block II by a subsequent selective debenzylation/oxidation/radical-induced amidation procedure. We expected that intermediate II could be prepared via a series of functional group conversions from α,β-unsaturated ketone 2, which can be easily accessed from compound 3 via our newly developed SPD-catalyzed asymmetric Robinson annulation 16 with an excellent enantioselectivity (>99% ee). Similarly, following the above-mentioned research results, the enone precursor 3 can also be efficiently synthesized from commercially available 4 and 5 at a gram scale in just four steps.…”

“…Our synthetic route commenced with the preparation of 9 on a gram scale from the optically pure tricyclic compound 2 (>99% ee), which was readily available from 3-butyn-1-ol 5 through our recently reported six-step protocol featuring a Pdcatalyzed Suzuki coupling reaction and an SPD-catalyzed asymmetric Robinson annulation 16 (Scheme 3). To this end, the first key issues that needed to be addressed were the construction of the C2 stereocenter and adjustments of the enone group in compound 2.…”

“…Very recently, as a continuation of our ongoing project centered on the exploration of novel chiral ligands or catalysts based on SPD (spirocyclic pyrrolidine) and SPA (spirocyclic amide) backbones, we developed a novel SPD-catalyzed enantioselective Robinson annulation to rapidly construct a cis -hydrodibenzofuran skeleton. We achieved the asymmetric total syntheses of (−)-codeine and (−)-morphine with high efficiency (Scheme b). Considering the existence of the common cis- hydrodibenzofuran core in these two categories of alkaloids and conducting further investigations into diversity-oriented synthetic applications of the SPD-catalyzed Robinson annulation, herein, we present our research results of the asymmetric total syntheses of (−)-galanthamine ( 1a ) and (−)-lycoramine ( 1b ) (Scheme c).…”

Bioinspired Scalable Total Synthesis of Opioids

“…Second, synthetic biologists have recently achieved the complete biosynthesis of thebaine and derivatives in yeast, which, however, is far from practical application. Moreover, synthetic chemists have developed over 30 total syntheses of morphine and congeners, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but none of these de novo approaches, especially those to oxycodone (3) [18][19][20][21][22] and related derivatives 4-7, are competitive in cost with the current farming/isolation/semisynthesis protocol. An important solution to the practical synthesis of opioids would be to mimic the methods employed by the Mother Nature.…”