Enantiospecific Total Synthesis of the Important Biogenetic Intermediates along the Ajmaline Pathway, (+)-Polyneuridine and (+)-Polyneuridine Aldehyde, as well as 16-Epivellosimine and Macusine A

Abstract

The first stereospecific synthesis of polyneuridine aldehyde (6), 16-epi-vellosimine (7), (+)-polyneuridine (8), and (+)-macusine A (9) has been accomplished from commercially available D-(+)-tryptophan methyl ester. D-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material for the synthesis of the common intermediate, (+)-vellosimine (13). This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from D-(+)-trytophan methyl ester (14) via a combination of the asymmetric Pictet-Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. A new process for this stereocontrolled intramolecular cross-coupling has been developed via a copper-mediated process. The initial results of this investigation indicated that an enolate driven palladium-mediated cross-coupling reaction can be accomplished by a copper-mediated process which is less expensive and much easier to work-up. An enantiospecific total synthesis of (+)-polyneuridine aldehyde (6), which has been proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine (2), was then accomplished in an overall yield of 14.1% in 13 reaction vessels from D-(+)-tryptophan methyl ester (14). Aldehyde 13 was protected as the Na-Boc aldehyde 32 and then converted into the prochiral C (16)-quaternary diol 12 via the practical Tollens’ reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection steps to provide a versatile entry into the three alkaloids, polyneuridine aldehyde (6), polyneuridine (8) and macusine A (9) from the quarternary diol 12. The oxidation of the 16-hydroxymethyl group present in the axial position was achieved with the Corey-Kim reagent to provide the desired β-axial aldehydes, polyneuridine aldehyde (6) and 16-epi-vellosimine (7) with 100% diastereoselectivity.

Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine

“…Then 11 could be converted into (AE)-strychnine in four steps according to ak nown procedure. [11e] Thet otal synthesis of (AE)akuammicine was also achieved from the same key intermediate 9.T reatment of 9 with trifluoroacetic acid and thiophenol resulted in the deprotection product, which was further functionalized with the allyl bromide 12, [12] thus delivering the vinyl iodide 13 over two-steps in 61 %yield. A Heck cyclization completed the total synthesis of (AE)akuammicine in 70 %yield.…”

“…(entries 2-8). It is noteworthy that indoles containing various functional groups at the C3-position, like allyl, benzyl, hydroxy,a nd amino groups,w ere also tolerated (entries [9][10][11][12][13][14][15][16][17]. Considering the difficulty of removing the 2,6-dimethylbenzyl group,t he TBSO-substituted cyclobutane 2c was employed, thus delivering the products that were suitable for further transformation (entries 18 and 19).…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…However, under these conditions the racemization of the products was possible [22]. By this methodology, besides the application of Cook's group to the preparation of natural products [18,[23][24][25][26][27][28], a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B was synthesized by Waldmann and co-workers [29].…”

Bis-[2-(diphenylphosphino)phenyl]ether (Dpe-Phos)

“…For example, Dpe-Phos has been employed as a ligand in a Pd-catalyzed intramolecular enolate alkenylation during the total synthesis of (+)-vellosimine. 92 A catalyst composed of NiCl 2 (PPh 3 ) 2 and Dpe-Phos has been used to effect the reductive homocoupling of 4-chloroquinolones. 93 The use of Dpe-Phos in cross-coupling reactions of bromo-and chloromaleimides with organoindium reagents has also been described.…”