Synthetic Study of Matrine-Type Alkaloids: Stereoselective Construction of the AB Rings of the Quinolizidine Skeleton

Abstract

A new method has been developed for the stereoselective construction of the AB rings of the quinolizidine skeleton of matrine-type alkaloids with a cis-cis stereochemistry. The key features of this method involve: (i) the construction of the quinolizidine by the reduction of an acylpyridinium cation; and (ii) the late stage introduction of methoxypyridine by sequential Stille coupling and diastereoselective hydrogenation reactions.

Quinolizidine-Type Alkaloids: Chemodiversity, Occurrence, and Bioactivity

“…95 So far, almost 40 lupanine-like QAs have been reported, comprising a chemical diversification illustrated by compounds 55−93 (Figure 6, Figure S2). The central structural core agrees with the alkaloid lupanine (levo or dextrorotatory, i.e., 56 or 61, respectively), which is mostly substituted in rings A and D. 85 ylupanine (63) but also ester moieties such as angeloyl (91), tigloyl (75), cinnamoyl (70), or pyrroyl (90). Common unsaturations are also present at positions Δ 5(6) (55) or Δ 7 (17) (77), forming dehydrolupanines.…”

“…In addition, the matrine-type QAs are sometimes found in the N -oxide form (e.g., 1 , 2 , 17 , 18 , and 37 ), with N-1 being the most common point for such oxidation. The matrine-type QAs 1 – 54 differ mainly in their substitution patterns and stereochemistry . They contain structural variations associated with double bonds (specifically in the D-ring) and α- or β-oriented substitutions around each tetracycle, such as hydroxyl (e.g., 1 , 3 , 4 , 8 , 18 , 19 , 21 , 29 , 30 – 43 , 45 , 47 , 49 , 50 , 53 , and 54 ), acetyl (e.g., 33 , 35 , 39 , 51 , and 52 ), epoxy (e.g., 40 and 41 ), (methylthio)­methoxy (e.g., 34 and 36 ), methoxy (e.g., 38 ), and indolyl (e.g., 22 ) groups .…”

“…The matrine-type QAs 1 – 54 differ mainly in their substitution patterns and stereochemistry. 70 They contain structural variations associated with double bonds (specifically in the D-ring) and α- or β-oriented substitutions around each tetracycle, such as hydroxyl (e.g., 1 , 3 , 4 , 8 , 18 , 19 , 21 , 29 , 30 – 43 , 45 , 47 , 49 , 50 , 53 , and 54 ), acetyl (e.g., 33 , 35 , 39 , 51 , and 52 ), epoxy (e.g., 40 and 41 ), (methylthio)methoxy (e.g., 34 and 36 ), methoxy (e.g., 38 ), and indolyl (e.g., 22 ) groups. 71 Thus, nine different positions for matrine substitutions (R 1 to R 9 ) were evidenced, the structural distribution of which is outlined in Figure 5 .…”