General Strategy for Synthesis of C-19 Methyl-Substituted Sarpagine/Macroline/Ajmaline Indole Alkaloids Including Total Synthesis of 19(S),20(R)-Dihydroperaksine, 19(S),20(R)-Dihydroperaksine-17-al, and Peraksine

Abstract

A detailed account of the development of a general strategy for synthesis of the C-19 methyl-substituted alkaloids including total synthesis of 19(S),20(R)-dihydroperaksine-17-al (1), 19(S),20(R)-dihydroperaksine (2), and peraksine (6) is presented. Efforts directed toward the total synthesis of macrosalhine chloride (5) are also reported. Important to success is the sequence of chemical reactions which include a critical haloboration reaction, regioselective hydroboration, and controlled oxidation (to provide sensitive enolizable aldehydes at C-20). In addition, the all-important Pd-catalyzed α-vinylation reaction has been extended to a chiral C-19 alkyl-substituted substrate for the first time. Synthesis of the advanced intermediate 64 completes an improved formal total synthesis of talcarpine (26) and provides a starting point for synthesis of macroline-related alkaloids 27–31. Similarly, extension of this synthetic strategy in the ring A oxygenated series should provide easy access to the northern hemisphere 32b of the bisindoles angustricraline, alstocraline, and foliacraline (Figure 4).

Total Synthesis of Macrocarpines D and E via an Enolate-Driven Copper-Mediated Cross-Coupling Process: Replacement of Catalytic Palladium with Copper Iodide

“…All of the vinyl iodide intermediates ( 16 , 18 , 20 and, 22 ) were prepared according to the previously reported procedures 21 (Scheme 2) beginning from the tetracyclic ketones 24 / 25 which had been prepared in the standard two pot process on 300 gram scale. 23 As depicted in Scheme 2, the N b alkylation via S N 2 substitution of the chiral tosylates ( 26 / 27 ) in CH 3 CN with K 2 CO 3 and subsequent deprotection of the TIPS protecting group with wet TBAF in THF furnished the N b -alkylated terminal alkynes ( 28 – 31 ) in excellent yields.…”

“…23 As depicted in Scheme 2, the N b alkylation via S N 2 substitution of the chiral tosylates ( 26 / 27 ) in CH 3 CN with K 2 CO 3 and subsequent deprotection of the TIPS protecting group with wet TBAF in THF furnished the N b -alkylated terminal alkynes ( 28 – 31 ) in excellent yields. Haloboration 21 of the terminal alkynes with I-B(Cy) 2 in DCM followed by protodeboronation with HOAc, resulted in the vinyl iodides ( 16 , 18 , 20 , and, 22 ) in 74–79% yield with complete regioselectivity.…”

Sarpagine and Related Alkaloids

“…140,141 In order to install the C-19 methyl functionality in the tetracyclic ketone 164 , 142 the N b -H group was alkylated with the optically active R- tosylate 224 (which was in turn obtained from the R propargylic alcohol via a 2-step sequence) in acetonitrile/K 2 CO 3 , followed by treatment with tetrabutylammonium fluoride hydrate to obtain the acetylenic ketone 225 in 96% yield. The terminal alkyne in 225 was converted into the iodo-olefin functionality by treating with dicyclohexyliodoborane [I-B(Cy) 2 ], followed by protonolysis.…”

“…Upon heating the mono-alcohol 233 under acidic conditions the hemiacetal ring was formed intramolecularly to obtain peraksine ( 223 ) as an epimeric mixture at C-17 in 52% yield. 141 …”

Total Synthesis of Sarpagine‐Related Bioactive Indole Alkaloids

“…[7b, 9] This diastereospecific cyclization reaction sets the requireds tereochemistry at the C-3 positionf or the target natural products, beginningw ith commerciallya vailable d-(+ +)-tryptophan. [10] In the strategy developedb yE dwankare tal., [10] the N b -alkyl tethered functionality was introduced after accessing the bicyclo[3.3.1]nonane system in 11.D espite the robustness of this strategy (Scheme1a), it was deemed useful to reduce the number of steps by avoiding some earlier transformations while retaining compatibility with various conditions necessary for accessing the desired system in high enantiomeric (ee)a nd diastereomeric excess( de). The N b -alkylated compounds( see 12,S cheme 1) are key intermedi- ates that have been used in the total synthesis of several sarpagine andm acroline relatedi ndole alkaloids, which contain a stereogenic methyl function att he C-19 position of the core structure.…”