A Scalable Total Synthesis of (−)-Nakadomarin A

Abstract

The convergent total synthesis of the manzamine alkaloid (-)-nakadomarin A (1) is described. The retrosynthetic analysis recognized spirocycle 3, assembled via an organocatalyst-promoted Michael addition/cyclization between bicyclic lactam 4 and furan aldehyde 5, both accessible from achiral starting materials and on a multigram scale. Lactam 4 is assembled through an S2'/reduction/Staudinger/retro-aza-Claisen sequence on scale. After spirocyclization, the synthesis of nakadomarin is completed in only six steps.

Molybdenum Alkylidyne Complexes with Tripodal Silanolate Ligands: The Next Generation of Alkyne Metathesis Catalysts

“…[4][5][6] This auspicious profile is manifest, inter alia, in the high-yielding formation of numerous polyfunctionalized targets;t he examples shown in Figure 1a re representative. [7][8][9][10][11][12][13][14] Even protic groups were found to be compatible in favorable cases,although important limitations still remain: [15] the polarization of the operative [Mo CR] unit, which is inherently nucleophilic and basic at carbon, constitutes apotential Achilles heel of any Schrock alkylidyne in ap rotic environment. [16,17] Moreover,s ubstrates able to entail ligand exchange will eventually bring productive alkyne metathesis to ahold since catalyst 1 and congeners draw their excellent performance from a( largely) intact siloxide ligand sphere.Inconsideration thereof,itmay not come as asurprise that the attempted metathesis reaction of as ubstrate as simple as 8 containing an unhindered primary alcohol basically met with failure (Scheme 1).…”

Recent Advances in Total Synthesis of Alkaloids from α,β‐Unsaturated Aldehydes

“…In 2016, Boeckman et al proposed new approach to build DE rings of (-)-nakadomarin A (36). [27] First, the authors synthesized achiral designer substrates -the bicyclic lactam 37 and β-furyl aldehyde 38 on a multigram scale. Then organocatalytic Michael addition/spirocyclization between lactam 37 and furan aldehyde 38 to provide spirocycle 40 and further via seven stages unique core of (-)-nakadomarin A (36) is formed in 3 % overall yield (Scheme 6).…”

Molybdenum Alkylidyne Complexes with Tripodal Silanolate Ligands: The Next Generation of Alkyne Metathesis Catalysts

“…[1][2][3] Catalysts such as 1 or the derived bench-stable adduct 2 combine excellent activity with user-friendliness;m ost importantly,t hey are distinguished by aremarkable and so far unrivaled functional group tolerance. [7][8][9][10][11][12][13][14] Even protic groups were found to be compatible in favorable cases,although important limitations still remain: [15] the polarization of the operative [Mo CR] unit, which is inherently nucleophilic and basic at carbon, constitutes apotential Achilles heel of any Schrock alkylidyne in ap rotic environment. [7][8][9][10][11][12][13][14] Even protic groups were found to be compatible in favorable cases,although important limitations still remain: [15] the polarization of the operative [Mo CR] unit, which is inherently nucleophilic and basic at carbon, constitutes apotential Achilles heel of any Schrock alkylidyne in ap rotic environment.…”

“…Catalysts such as 1 or the derived bench‐stable adduct 2 combine excellent activity with user‐friendliness; most importantly, they are distinguished by a remarkable and so far unrivaled functional group tolerance . This auspicious profile is manifest, inter alia, in the high‐yielding formation of numerous poly‐functionalized targets; the examples shown in Figure are representative . Even protic groups were found to be compatible in favorable cases, although important limitations still remain: the polarization of the operative [Mo≡CR] unit, which is inherently nucleophilic and basic at carbon, constitutes a potential Achilles heel of any Schrock alkylidyne in a protic environment .…”