Short Synthesis of Alkaloid (−)-205B

Abstract

The alkaloid (−)-205B has in the past served as a testing ground for novel approaches in nitrogen heterocycle synthesis. We herein report a highly straightforward synthesis of (−)-205B in just six synthetic steps, making it the shortest route currently known. The central steps of our approach are a vinylogous Mukaiyama–Mannich reaction to establish the first two stereogenic centers with excellent diastereo- and enantiocontrol followed by zinc-mediated Barbier allylation to set the third chiral center with high substrate control. Upon cyclization of the Barbier product to lactam and enolate methylation, the third ring is annulated by a one-pot sequence of lactam reduction and aza-Prins cyclization to directly set the final stereogenic center with complete cis-stereoselectivity. As the iminium ion undergoing the aza-Prins cyclization rapidly isomerized to a planar enamine intermediate, the alkaloid was eventually obtained as a 1:1 mixture of C6 diastereomers, which were readily separated by chromatography. Yet, the target natural product was obtained isomerically pure in an overall yield of 12%, which compares favorably with all previous syntheses.

Stereoselective Synthesis of the Decahydroquinoline Alkaloid cis-195J

“…11 Moreover, we recently developed a short and high-yielding synthetic route to alkaloid (−)-205B (3). 12 Building on this experience, we embarked on a total synthesis of the 2,5-disubstituted-DHQ alkaloid cis-195J.…”

“… This process has later been implemented by our group as the key step in syntheses of a broad range of indolizidine- and quinolizidine-based alkaloids 1 and 2 , respectively . Moreover, we recently developed a short and high-yielding synthetic route to alkaloid (−)- 205B ( 3 ) . Building on this experience, we embarked on a total synthesis of the 2,5-disubstituted-DHQ alkaloid cis - 195J .…”

Stereodivergent Synthesis of Alkaloid (±)-223A and (±)-6-epi-223A via Rh-Catalyzed Hydroformylation Double Cyclization

“…Simple treatment with a slight excess of LDA (1.1 equiv) followed by addition of EtI (1.5 equiv) led primarily to recovered starting material 7a (entry 1). The addition of more LDA (2.0 equiv) and EtI (2.0 equiv) resulted in the formation of two diastereomeric monoalkylated products, 7b and epi - 7b , 18 as well as the recovery of starting material 7a (entry 2). The switch to LiHMDS (2.0 equiv) gave results similar to those of entry 2 (entry 3).…”

Chiral Spirophosphoric-Acid-Catalyzed Divergent Vinylogous Mannich and aza-Friedel–Crafts Reactions of 2-Methoxyfuran

“…The deliverables have garnered significant attention due to their applicability in the synthesis of valuable biologically active compounds . The VMR has been extensively studied in the last two decades, with much emphasis on asymmetric variations under metal and metal-free catalysis. , The five-membered γ-butenolide and isoxazoline heterocycles are widespread and exhibit remarkable pharmacological activities (Scheme a). , A new scaffold that is combined with these pharmacophores would be anticipated to have reinforced biological properties as compared to their parent heterocyclic derivatives. The synthetic methods involving isoxazolines and butenolides have attracted a great deal of attention in recent years. , …”