Total Synthesis of (±)-Flustramines A and C, (±)-Flustramide A, and (−)- and (+)-Debromoflustramines A

Abstract

Here we describe the efficient total synthesis of the three title hexahydropyrrolo[2,3-b]indole alkaloids and debromo derivative from readily available indolin-3-ones using key domino reactions, olefination-isomerization-Claisen rearrangement (OIC), and reductive cyclization (RC). (+/-)-Flustramine C (5) was synthesized in five steps from 6-bromoindolin-3-one 9 via a key intermediate 13a. (+/-)-Flustramine A (1) has been obtained by reduction of flustramide A (6), which has been prepared in five steps from 13a. (+/-)-Debromoflustramine A (19) was provided in a similar manner from 13b. The (-)- and (+)-enantiomers of 19 were synthesized through optical resolution of (+/-)-carboxylic acid 17b using (R)-4-phenyloxazolidin-2-one.

Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3‐b]indole

“…[196] While studying nucleophilic substitution in indoles, the Somei group reacted N-methoxyindole derivatives with alkoxides to obtain useful route for the synthesis of (AE )-debromoflustramine B (69). [197] Further studies of the same authors conducted to the synthesis of 3a-oxygenated HPIC [198,199] by a rearrangement of the 1-benzoyloxy group of tryptamine 179 followed by cyclization to give the tricyclic system 181 (F, Scheme 5).…”

Development of the Regiodivergent Asymmetric Prenylation of 3‐Substituted Oxindoles

“…[23] Reductive cyclization with alane-dimethylethylamine complex (Scheme 6) was carriedo ut on (+ +)-13 (prepared using (R,R)-L 2 )a nd (+ +)-22 (prepared using (S,S)-L 1 )t o obtain the unnatural (+ +)-isomers of all four natural products, spectrald ata of which was in agreement with literature reports. [24] Meanwhile, the use of (À)-22 (prepared using (R,R)-L 1 ) in the same sequence led to the formation of the naturally occurring (À)-isomers of flustramideBand flustramine B. This allowed us to assign the absolute stereochemistry forp renylation products 13 and 22,a nd the absolutes tereochemistry in the reverse and linear prenylation of other oxindole substrates in this paper was assigned by analogy with these results.…”

Formal synthesis of (−)-flustramine B and its absolute configuration assignment by vibrational circular dichroism exciton chirality

“…16 We were able to obtain single crystals of (S)-14 which provided the X-ray structure shown in Figure 10 (top). The absolute configuration structure was established by taking advantage of the heavy atom at C6 by evaluation of the Flack 17a [À0.002 (7), (R)-enantiomer 1.015 (16)] and the Hooft 17b parameters [0.006(2), (R)-enantiomer 1.008 (2)]. As can also be seen in Figure 9 (bottom), in the solid state a clockwise twist is evident for the (À)-(3S)-14 isomer with a C2@O, C9@O distance of 3.2 Å.…”