A Synthetic Route to Highly Substituted 1,2,3,4‐Tetrahydroisoquinolines via Yb(OTf)₃‐Catalyzed Diastereoselective Ring Opening of Bridged Oxazolidines: Asymmetric Synthesis of 2‐Azapodophyllotoxin

Abstract

We herein report a robust and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs) from Garner aldehyde. We utilized the inherent chirality of Garner aldehyde through 1,2- and 1,3-/1,4-asymmetric inductions iteratively to obtain 1,2,3,4-tetrasubstitued THIQs using rigid and isolable bridged oxazolidines without any external chiral sources. All possible stereoisomers of bridged oxazoliodines were efficiently synthesized from L- and D-Garner aldehydes and transformed into fully functionalized THIQs via diastereoselective ring opening with various nucleophiles in the presence of Yb(OTf)(3). This methodology furnished four out of eight possible diastereomers of 1,2,3,4-tetrasubstituted THIQs despite the electronic nature of substituents on the aryl rings. Finally, the enantioselective synthesis of 2-azapodophyllotoxin was achieved with an overall yield of 35.4% (eight steps) from D-Garner aldehyde using this synthetic route.

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

“…Deprotection of the triisopropylsilyl (TIPS) group from 1f provided an alcohol product, that was readily converted to the desired bridged oxazolidines 14f , 15f and 16f (scaffold VI ) in good to excellent yields upon treatment with various N -modifying agents such as Boc anhydride (Boc 2 O), benzyl isocyanate and 3-nitrobenzene sulfonyl chloride ( m -NsCl) through iminium formation and subsequent intramolecular nucleophilic addition of the hydroxyl moiety31. The structure of bridged oxazolidine 16f was confirmed by X-ray crystallographic analysis (Supplementary Fig.…”

Stereoselective synthesis of functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) via highly diastereoselective Ugi three-component reactions (U3CRs) with chiral 3,4-dihydroisoquinolines (DHIQs)

“…Though 1,3-cis configuration is most common in naturally occurring THIQ containing alkaloids, 19 epimers of naturally occurring counterparts such as 3-epi-Jorumycin; V and 3-epi-Renieramycin G; VI have been of significant synthetic interest to explore the role of stereochemistry in their pharmaceutical properties. 23 This method offered an excellent method to obtain C-1 functionalized THIQs, however substitutions at N-2 were limited and required protection-deprotection operations for further applications in total synthesis. 23 In order to develop efficient synthesis of THIQ containing alkaloids, various functionalizations at N-2 are required with diastereoselective derivatization at C-1.…”

“…22 Recently, we have developed a novel method to synthesize 1,2,3,4-THIQ 3 from 3,4-dihydroisoquinoline 1 via a bridged oxazolidine intermediate 2 by employing Lewis acid catalyzed diastereoselective nucleophilic substitution reactions (eqn (1)). 23 This offered an excellent method to obtain C-1 functionalized THIQs, however substitutions at N-2 were limited and required protection-deprotection operations for further applications for the total synthesis. 23 (1) (2) In order to develop an efficient synthesis of THIQ containing alkaloids, various functionalizations at N-2 are required with diastereoselective derivatization at C-1.…”

Diversity-Oriented Synthesis of Functionalized Polyheterocycles from Garner Aldehyde

“…8 As a continuation of our efforts on the construction of novel molecular frameworks, we reported a robust and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines 3, a privileged structural motif that is frequently found in bioactive natural products and therapeutic agents. 9 As shown in Scheme 1 (Path A), a series of enantiopure bridged oxazolidine intermediates 2 were synthesized from Garner aldehyde 1 and its inherent chirality was utilized via 1,2-and 1,3-/1,4-asymmetric inductions iteratively to obtain 1,2,3,4-tetrasubstituted 1,2,3,4-tetrahydroisoquinolines 3 through ytterbium(III) triflate catalyzed diastereoselective nucleophilic additions. We also accomplished the first enantioselective total synthesis of 2-azapodophyllotoxin (4) with an overall yield of 35% (8 steps) from D-Garner aldehyde 1 for the validation of this synthetic methodology.…”

“…We also observed the formation of enantiopure bridged oxazolidine 7 and the corresponding 3,4-dihydroisoquinoline 21 through sequential deprotection of 20 using different hydrochloric acid concentrations such as 3 M and 6 M hydrochloric acid in tetrahydrofuran, respectively. 9 Due to the existing synthetic utility and biological importance of chiral 1,3-dihydroisobenzofurans, several asymmetric synthetic routes have been reported: alkylation of arenechromium tricarbonyl, 14 benzylic deprotonative lithiation followed by alkylation, 15 tandem addition/ cyclization of organozinc reagents to alk-2-ynyl aldehydes, 16 and cyclization of ortho-lithiated chiral aryloxiranes. 17 Functionalized 1,3-dihydroisobenzofurans serve as important intermediates for the generation of important natural products and natural-product-like molecules.…”