Enantioselective Total Synthesis of (−)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones

Abstract

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio-and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate-and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a β-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/ allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Tertiary Arsine Ligands for Pd-Catalyzed Direct Arylation

“…Palladium­(II) acetate (Pd­(OAc) 2 ), triphenylarsine ( L4 ), and 2,3-benzofuran were purchased from Sigma-Aldrich. Dichloromethane (CH 2 Cl 2 ), ethyl acetate (EtOAc), 2-thiophenecarboxaldehyde, magnesium turnings, and concentrated ammonia solution (28% NH 3aq ) were purchased from Nacalai Tesque, Inc. Tetrahydrofurane (THF, anhydrous), N , N -dimethylacetamide anhydrous (DMA), diethyl ether (ether), hexane, magnesium sulfate anhydrous (MgSO 4 ), ammonium chloride (NH 4 Cl), copper­(I) iodide (CuI), pivalic acid (PivOH), and potassium carbonate (K 2 CO 3 ) were purchased from FUJIFILM Wako Pure Chemical Industry, Ltd. 1,3,5-Trimethoxybenzene, mesityl bromide, 2-bromotoluene, 4-bromotoluene, 2-bromoanisole, bromobenzene, 2-bromobenzotrifluoride, 4-bromobenzotrifluoride, 4-chlorobenzotrifluoride, 4-bromofluorobenzene, 2-propylthiophene, 2-methoxythiophene, methyl 2-thiophenecarboxylate, 2-phenylthiophene, 2-chlorothiophene, benzo­[ b ]­thiophene, 2-acetylthiophene, 2-isobutylthiazole, benzothiazole, 1-methyl-2-pyrrolecarboxaldehyde, furfural, 4-bromoanisole, 4-iodobenzotrifluoride, and tri­( o -tolyl)­phosphine were purchased from Tokyo Chemical Industry Co., Ltd. Arsenic ligands L1 - L2 , L7 - L9 , L11 , L3 , L5 - L6 , L12 - L13 , L10 , L14 , L16 - L20 , 2-(benzodithiaarsolyl)-2′,6′-dimethoxybiphenyl, L15 , 2-propylthiophene- d , 2-methoxythiophene- d , 2-dodecylthiophene, tris­(o-trifluorotolyl)­phosphine, and tris­( p -trifluorotolyl)­phosphine were prepared according to literature procedures.…”

Asymmetric C–H Dehydrogenative Alkenylation via a Photo-induced Chiral α‑Imino Radical Intermediate

“…The catalytic asymmetric α -alkenylation of carbonyls is a strategic C-C bond-forming transformation that grants access to chiral α -vinyl carbonyls as versatile frameworks and synthons 1 , 2 . There have been major advances along this line to enable stereoselective α -alkenylation via enolate or enamine intermediates by means of transition metal or organic catalysis 3 – 13 . However, most of these processes necessitate the use of pre-functionalized vinyl precursors, which require activating functional groups such as halides 3 – 7 , hypervalent iodinium 8 , 9 or borate 10 – 13 (Fig.…”

Synthesis of a fused N-bridged [3.3.1]nonadiquinoline multicyclic skeleton via a metal-free formal [4 + 2] cycloaddition/Mannich/dearomatization domino reaction

“…Alkaloid skeletons have become hot synthetic targets in modern organic synthesis. 1 Azabicyclo [3.3.1]nonanes are one of the most important classes of polycyclic alkaloids 2 that are ubiquitous in complex bioactive natural products 3 and pharmaceuticals, such as ajmaline, 4 granisetron, 5 and sarpagine, 6 used as an antiarrhythmic agent, to prevent nausea and vomiting, and as an anti-inflammatory agent, respectively (Fig. 1).…”