Total Syntheses of (−) Epilupinine and (−)-Tashiromine Using Imino-Aldol Reactions

Abstract

Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ∼13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.

Novel stereocontrolled syntheses of tashiromine and epitashiromine

“…The stereochemistry of (±)- 6 was unequivocally assigned by NMR data, which were consistent with those reported [35–37]. …”

“…Reduction of the ester group of (±)- 5 with an excess of LiAlH 4 in THF at 20 °C gave the corresponding tashiromine (±)- 6 [35–37], which was isolated in 48% yield after purification by column chromatography (Scheme 2). The stereochemistry of (±)- 6 was unequivocally assigned by NMR data, which were consistent with those reported [35–37].…”

“…(−)-Tashiromine has been accessed through the ring closure of difunctionalized acyclic chiral sulfonamide-based β-amino acids [35], the cyclization of pyrrole derivatives with a chiral side-chain [36], or the enantioselective arylation of pyrrole, followed by saturation [37]. The transformation of chiral functionalized pyrrole or pyrrolidine derivatives has served as the basis of the construction of (−)-epitashiromine [38–39] (Fig.…”

Total Synthesis and Full Histone Deacetylase Inhibitory Profiling of Azumamides A–E as Well as β2- epi-Azumamide E and β3-epi-Azumamide E

“…This indicates that the pathway leading to our major isomer did not proceed through the six-membered Zimmerman− Traxler-type transition state, 22 which has been proposed to be responsible for the diastereoselectivity with similar substrates. 20,23 By using HMPA as an additive instead of a Lewis acid, this reaction has previously been shown to proceed through a different transition state, 20 and indeed we saw the same product distribution when using HMPA and TiCl(O i Pr) 3 as additives with our substrates (entries 5 and 6). This indicates that the six-membered transition state, where coordination of titanium is crucial, is highly unlikely to play a significant role in the formation of our major isomer.…”

Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base

“…Lemieux–Johnson oxidation 15 of ent - 2 , 16 followed by a global reduction gave (−)-tashiromine in 90% yield over two steps. 17 The same two-step sequence from 10 afforded (+)-epi-lupinine in 72% yield. 18 …”