A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I

Abstract

Many polycyclic marine alkaloids are thought to derive from partly reduced macrocyclic alkylpyridine derivatives via a transannular Diels–Alder reaction that forms their common etheno-bridged diaza-decaline core (“Baldwin–Whitehead hypothesis”). Rather than trying to emulate this biosynthesis pathway, a route to these natural products following purely chemical logic was pursued. Specifically, a Michael/Michael addition cascade provided rapid access to this conspicuous tricyclic scaffold and allowed different handles to be introduced at the bridgehead quarternary center. This flexibility opened opportunities for the formation of the enveloping medium-sized and macrocyclic rings. Ring closing alkyne metathesis (RCAM) proved most reliable and became a recurrent theme en route to keramaphidin B, ingenamine, xestocyclamine A, and nominal njaoamine I (the structure of which had to be corrected in the aftermath of the synthesis). Best results were obtained with molybdenum alkylidyne catalysts endowed with (tripodal) silanolate ligands, which proved fully operative in the presence of tertiary amines, quinoline, and other Lewis basic sites. RCAM was successfully interlinked with macrolactamization, an intricate hydroboration/protonation/alkyl-Suzuki coupling sequence, or ring closing olefin metathesis (RCM) for the closure of the second lateral ring; the use of RCM for the formation of an 11-membered cycle is particularly noteworthy. Equally rare are RCM reactions that leave a pre-existing triple bond untouched, as the standard ruthenium catalysts are usually indiscriminative vis-à-vis the different π-bonds. Of arguably highest significance, however, is the use of two consecutive or even concurrent RCAM reactions en route to nominal njaoamine I as the arguably most complex of the chosen targets.

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

“…Under this proviso, we opted for ring closing alkyne metathesis (RCAM) followed by semi‐reduction of the triple bond for the formation of the other macrocycle, [27–29] since molybdenum alkylidynes endowed with silanolate ligands are remarkably tolerant towards many different donor sites, [13, 30–32] most notably complexes with a tripodal silanolate ligand framework (“canopy catalysts”) [33–36] . The projected current application provides a stringent test for this notion [2, 37] …”

“…Of them, the “Baldwin‐Whitehead postulate” became particularly famous, which centers upon a transannular Diels–Alder cycloaddition of an intermediate of type A with formation of iminium ion B in the first place (Scheme 1). [1] Simple reduction connects B to a prominent class of pentacyclic products such as keramaphidine and congeners, [2] whereas isomerization to the new iminium species C followed by hydrolysis opens entry into the manzamine series. Moreover, cleavage of the C−C bond at one of the bridgeheads of B via a retro‐Mannich‐type reaction gives D and explains the formation of the large set of tetracyclic alkaloids of the halicyclamine class [3, 4] .…”

Madangamine alkaloids: Madness and tranquility

“…The Fürstner group recently implemented an alkyne tether into the bridged core via a double Michael addition (literally a Diels-Alder reaction), which eventually led to the complete synthesis and validation of the absolute configuration of keramaphidin B. [34] The preinstalled stereogenic centre at C11 in 52 controlled the stereochemical outcome of the critical ring construction (Scheme 4c). The following transformations produced bisalkyne 54, which was appropriate for ring-closing alkyne metathesis (RCAM) by the novel Mo-catalyst to afford macrocycle 55 in 83% yield.…”

The Ascent of Alkyne Metathesis to Strategy-Level Status

“…75 Their compatibility with numerous Lewis-basic groups is equally astounding if one considers that the operative metal alkylidyne comprises an early transition metal in its highest oxidation state: the finish of a total synthesis of nominal njaoamine I proves that complex 31 (R = Me) remains fully operative even in the presence of two different tertiary amines and a quinoline (Scheme 8). 96 To properly assess this result, it may suffice to say that a single tertiary amine sufficed to quench the activity of first and second generation Grubbs-type catalysts in a very closely related RCM-setting en route to the sibling alkaloid ingenamine. 96 For this promising application profile, the canopy catalysts have already been subject to intense experimental and computational scrutiny.…”

“…96 To properly assess this result, it may suffice to say that a single tertiary amine sufficed to quench the activity of first and second generation Grubbs-type catalysts in a very closely related RCM-setting en route to the sibling alkaloid ingenamine. 96 For this promising application profile, the canopy catalysts have already been subject to intense experimental and computational scrutiny. 69,75,77,95 Since a comprehensive discussion is beyond the scope of this Perspective, a portrait in "al fresco" style must suffice.…”