Synthesis of the Proposed Structures of Parvistemoamide and Their Transformations to Stemoamide Derivatives

Abstract

The proposed structures of parvistemoamide have been achieved by macrolactamization, but none of the characterization data of synthetic samples matched with those of the natural sample. The transformation of the highly strained 10-membered lactam ring in parvistemoamide into the pyrrolo­[1,2-a]-azepine nucleus in stemoamide is accomplished for the first time by either transannular cyclization or Pilli’s transformation. This research may promote the total synthesis of other more complex stemoamide-type or medium-sized-ring-containing Stemona alkaloids.

Formal Syntheses of (±)‐Tuberostemospiroline and (±)‐Stemona‐lactam R and Total Synthesis of (±)‐Stemoamide

“…Recently, Wang and coworkers used a macrolactamization approach to prepare the racemic forms of 4 a and its stereoisomers displaying a trans ring fusion of the butenolide‐lactam ring junction, just to find that none of them matched the spectroscopic data available for the putative (+)‐parvistemoamide. In this work, the authors also validated our biomimetic proposal and converted one of the stereoisomers of the structure proposed for parvistemoamide (the C‐9a epimer of macrolactam 4 a ) to (±)‐stemoamide ( 1 ) either by carrying out C‐9a oxidation, followed by an intramolecular reductive amidation sequence, or by mesylation of the hydroxyl group at C‐9a, followed by an intramolecular displacement [4g] …”

“…After these results appeared, we carried out a careful analysis of the data provided by Xu and coworkers, particularly the 13 C NMR and mass spectrometry data of the natural product which had its structure assigned both as 4 a and 4 b by these authors. It became clear to us that those data could not be reconciled with neither of the proposed structures as a single carbinolic carbon was present in the 13 C‐NMR spectrum of the isolated compound and assigned to C‐8 (77.6 ppm), while structures 4 a and 4 b would require another carbinolic signal around 70 ppm, as observed by Wang and coworkers for the four synthetic stereoisomers (68.4–73.1 ppm) [4g] . Additionally, the mass spectrometry data does not show the molecular ion peak expected for 4 a and 4 b ( m/z 241) but a peak at m/z 223 instead, tentatively assigned to the loss of water from the molecular ion for 4 a or 4 b [3a]…”

“…Our attempts to synthesize the Stemona alkaloid isolated by Xu and coworkers [3] from S. parviflora and named as parvistemoamide (structures 4 a or 4 b ), in conjunction with the results recently disclosed by Wang and coworkers, [4g] allowed us to question the existence of such secondary metabolite. In addition, a stereoselective formal synthesis of racemic 10‐norstemoamide 27 (31 % yield, 7 : 1 mixture of epimers) was implemented as well as of racemic stemoamide ( 1 ) in 5 steps, 12 % overall yield as a 5 : 1 mixture of epimers via a very concise approach.…”

“…We also surmised that the incorporation of a bromine substituent at C‐5 would promote nucleophilic addition via C‐2 due to the resonance effect imparted by the presence of the bromine atom which would stabilize the Wheland intermediate involved in the formation of the spiro tricyclic system shown in Scheme 1d, despite being a deactivating group for electrophilic aromatic substitutions. Finally, inspired by the work of Wang and coworkers., [4g] we revisited our early attempts to obtain 4 a , one of the putative structures proposed by Xu and coworkers for parvistemoamide, [3] just to find that hydrogenation of trisubstituted γ‐butyrolactone shown in Scheme 1e leads directly to (±)‐stemoamide ( 1 ).…”

Ir-Catalyzed Asymmetric Total Syntheses of Bisdehydrotuberostemonine D, Putative Bisdehydrotuberostemonine E and Structural Revision of the Latter

“…The Stemona alkaloids are a large category of natural products, possessing a plenitude of complex stereochemistry as well as potent biological activities; such features make them attractive targets to synthetic chemists. Despite the long-standing popularity of these alkaloids in synthetic community, studies focusing on the synthesis of pyrrole Stemona alkaloids (Figure ) remain sparse. To the best of our knowledge, only in 2018 did the first report on this topic appear in the literature (Dai’s racemic syntheses of 1 and 2 ).…”