Stereocontrolled Total Synthesis of (+)‐trans‐Dihydronarciclasine

Abstract

A highly stereoselective and efficient total synthesis of trans-dihydronarciclasine from a readily available chiral starting material was developed. The synthesis defines two of the five stereogenic centers of the natural product by an amino acid ester-enolate Claisen rearrangement. The other three stereogenic centers are created in a highly stereocontrolled fashion via a six-ring vinylogous ester intermediate, which is generated from the γ,δ-unsaturated ester functional group of the Claisen rearrangement product in an efficient three-step sequence. This concise total synthesis exemplifies the use of a highly regioselective Friedel-Crafts-type cyclization to form the B ring via an isocyanate intermediate derived from an N-Boc group, which is superior to the conventional method using an imino triflate intermediate. This same N-Boc group is employed to give high selectivity in the Claisen rearrangement earlier in the sequence.

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives

“…The resulting cycloadduct 198 was then subjected to reductive NÀOb ond cleavage,f ollowed by ad iastereoselective dihydroxylation and persilylation to afford compound 199. [136] This functionality also serves to generate an isocyanate intermediate in an electrophilic aromatic substitution reaction, used to furnish ring B. In this synthesis the author makes excellent use of aBocprotected amino functionality to direct the stereochemistry of the key Ireland-Claisen rearrangement.…”

“…Carbamoylation of the secondary amine in 199 was followed by cleavage of the pyridyl moiety through quaternization and basic hydrolysis.R emoval of the silyl protecting groups and acetylation of the resulting hydroxy moieties afforded triacetate 200.Inorder to effect the final cyclization to create the B ring of trans-dihydronarciclasine,aBanwell-modified Bischler-Napieralski reaction [31] was utilized, as previously demonstrated by Cho. [134][135][136] Thes ubstrate for the key Ireland-Claisen rearrangement was generated by the reaction of allylic alcohol 202,p reviously utilized in Kims synthesis of pancratistatin, [17b] with N-Boc glycine to afford amino acid ester 203 (Scheme 40). [136] This functionality also serves to generate an isocyanate intermediate in an electrophilic aromatic substitution reaction, used to furnish ring B.…”

“…[134,135] In an attempt to circumvent this problem, Kim took advantage of Scheme 39. [136] Angewandte Chemie Reviews the N-Boc functionality to generate an isocyanate intermediate,a so pposed to the imino-triflate intermediate of the Banwell-modified Bischler-Napieralski reaction. [135] Figure 3.…”

“…[110] Asimilar strategy was employed in the synthesis of (+ +)-trans-dihydronarciclasine,wherein chiral ligand 123 was utilized to control the stereochemistry in the key asymmetric Michael addition. [136] Scheme 41. The coupled product was shown to be produced in aratio of 95:5, cis:trans.Epimerization to the desired trans configuration was accomplished with concurrent ester hydrolysis to afford key intermediate 209.Conversion of the carboxylic acid moiety to the corresponding isocyanate was accomplished through aC urtius rearrangement.…”

“…[134,135] Kim employed ak ey Ireland-Claisen rearrangement to set the C-4a/C-10b stereochemistry in an enantioselective synthesis [136] while Tomioka utilized an asymmetric Michael addition to set the stereochemistry at these positions. [134,135] Kim employed ak ey Ireland-Claisen rearrangement to set the C-4a/C-10b stereochemistry in an enantioselective synthesis [136] while Tomioka utilized an asymmetric Michael addition to set the stereochemistry at these positions.…”