Akuammiline Alkaloids (−)-Strictamine and (−)-Rhazinoline

Development of the Type II Radical Cascade Reaction

Having secured the intra-/intramolecular (type I) radical cascade, we next explored an intra-/intermolecular (type II) cascade process using sulfonamide 37 and an external radical acceptor as reaction partners. Pleasingly, reactions of 37 with various acceptors (39−42) took place under the same photocatalytic conditions as those applied to the type I reaction, providing corresponding tetrahydrocarbolinones 38a−l in moderate to high yields (Figure 4). Of note, this protocol proved to be useful for generating tetrahydrocarbolinone products with versatile functional groups. For instance,
products 38k and 38l bearing a methylene group α and β to C3 were obtained by employing 41 and 42 as the external radical acceptors, respectively. Again, the stereochemical outcomes of the newly formed stereocenters (C2 and C3) were excellently controlled in all of the products.

Total Synthesis of the Akuammiline Alkaloids (−)-Strictamine and (−)-Rhazinoline
Strictamine and its associated akuammiline alkaloids (43−45, Figure 5) are structurally unique natural products possessing a characteristic methanoquinolizidine motif (CDE rings) as well as differentiated stereochemistries at the C16 position.23 These fascinating molecules have attracted considerable attention of synthetic chemists for decades.24,25 We envisioned that taking advantage of the photoredox type II radical cascade strategy would facilitate the total synthesis of strictamine and related alkaloids. Retrosynthetically, the C ring and E ring in (−)-strictamine and (−)-rhazinoline were expected to be
assembled from advanced intermediates 46a and 46b at a late stage. The critical C7−C16 bond in 46a and 46b would be established from 47 via a Tsuji−Trost allylation.26 The latter could be synthetically traced back to the tricyclic compound 48, which was envisioned to be synthesized through a type II radical cascade reaction between 49 and acrolein (50).

 

In the forward synthesis, the radical cascade reaction between 49 and acrolein (50) was conducted using Ir-(dtbbpy)(ppy)2PF6 (0.5 mol %) and KHCO3 in degassed THF by irradiation with blue LEDs (Scheme 5). Without workup, upon sequentially adding vinylmagnesium bromide (51) and Na/naphthalene to the reaction mixture, the allylic alcohol 52 was obtained as a pair of inseparable diastereomers
(1.2:1 dr at C16) in 47% yield in one pot. The readily accessed tetrahydrocarbolinone 52 was converted to enal 53 in 8 steps.

 

After further functional group manipulations of 53 to yield enoate 54 possessing a vinyl iodide side chain, the stage was set for E ring formation. The palladium-catalyzed reductive Heck cyclization of 54 occurred effectively in the presence of Pd2(dba)3/PPh3/HCO2Na (dba = dibenzylideneacetone), was determined via nuclear Overhauser effect (NOE) experiments. Assembly of the remaining C ring (55 to 56) was realized in three additional steps, providing 16-epi-strictramine (56). Finally, conversion of the C16 ester to corresponding aldehyde enabled the first synthesis of (−)-rhazinoline [(−)-44]. On the other hand, unsuccessful attempts to directly epimerize the C16 stereocenter in 16-epi-strictramine (56) prompted us to seek an alternative approach to (−)-strictamine [(−)-43].16 In this context, allylic alcohol 57 containing a vinyl iodide chain tethered to N4 was prepared via four steps starting from the advanced intermediate 53. A nickel-mediated cyclization of 57 followed by intramolecular N4-alkylation
(with 2-fluoropyridine and Tf2O) allowed the E and C rings to be successively established. Notably, selective hydroboration−oxidation of the resultant exocyclic terminal alkene was achieved by employing 9-BBN followed by treatment with NaBO3·4H2O, which afforded the primary alcohol 58 and secured the anticipated C16 configuration. Further functionality manipulations via three steps provided the target alkaloid (−)-strictamine [(−)-43].

 

With both C16-epimers of strictamine (56 and 43) in hand, we again investigated the direct interconversion between them, which was experimentally verified to be unsuccessful (Scheme 6). Presumably, H16 is located at the sterically hindered concave face in 56, and thus, deprotonation of H16 (in 56) to yield anion 59 would be hampered, preventing its further transformation to 43 (via 60). On the other hand,
deprotonation of the convex H16 in (−)-strictamine [(−)-43] would occur to produce 61. After enolization (61 to 60), selective protonation at the sterically less hindered convex face could regenerate 43.

 

Consequently, these naturally occurring C16 diastereomers in the strictamine akuammiline alkaloid family would be most likely generated during construction of the C7−C16 bond from the corynanthe
intermediates in the biosynthetic processes. 

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