Short, Enantioselective Total Synthesis of Sceptrin and Ageliferin by Programmed Oxaquadricyclane Fragmentation

Abstract

Dedicated to Professor David I. Schuster on the occasion of his 70th birthday.The marine-derived dimeric pyrrole-imidazole alkaloids sceptrin (1) and ageliferin (2) are endowed with intriguing molecular architectures and a range of useful bioactivities (Scheme 1).[1] The enantioselective synthesis of a dimeric pyrrole-imidazole alkaloid has yet to be reported, partly because of the intrinsic difficulty associated with handling multiply charged nitrogen-containing intermediates.[2]We recently described practical syntheses of both 1 and 2 in their racemic form [3,4] by the use of an oxaquadricyclane fragmentation to generate the cyclobutane core of 1. Since the mechanism of this reaction remained ill-defined, [5] it was unclear how, or even if, stereochemical information in an oxaquadricyclane could be transferred to the product cyclobutane. Indeed, preliminary screens using numerous enantioenriched oxaquadricyclanes (3, Scheme 2) under a variety of acidic conditions led to cyclobutanes which were either racemic or showed a considerable loss of optical activity. Racemic oxaquadricyclanes were also evaluated with chiral acids and auxiliaries, but to no avail. Further investigation was warranted because of the lack of viable alternatives for the enantioselective synthesis of tetrasubstituted cyclobutanes. [6] Herein, we report the details of a unique method for the enantioselective synthesis of tetrasubstituted cyclobutanes by programmed fragmentation of an oxaquadricyclane, and the application of this method to the first asymmetric synthesis of both enantiomers of sceptrin and ageliferin.The synthesis commenced with the enzymatic desymmetrization [7] of meso-diester 4[3a] using pig liver esterase (PLE) to provide monoester 5 in quantitative yield and 75 % ee (Scheme 3). The ee value was determined by 1 H NMR spectroscopic analysis of the amide derived from (S)-amethylbenzylamine (absolute configuration determined by X-ray analysis of the ammonium salt derived from the same amine and 5). Formation of a benzylamide using DMT-MM [8] afforded the monobenzylamide 6 in 92 % yield. Remarkably, cis,trans,trans-cyclobutane 10 was formed in 50 % overall yield and 75 % ee when amide 6 was irradiated to form oxaquadricyclane 7 and directly treated with H 2 SO 4 in THF/ MeOH (1:1). Amide (À)-10 is nearly enantiopure (> 95 % ee) after a single recrystallization. The use of a benzylamide was critical to achieve complete transfer of chirality. A mild and chemoselective debenzylation/esterification of the robust secondary amide in 10 and epimerization to the all-trans stereochemistry were necessary to access (À)-13. Treatment of 10 with TsOH and MeOH in toluene at 105 8C [9] accomplished all three tasks in a single pot to afford (À)-13 in 90 % yield. The ease with which this amide is hydrolyzed is likely due to assistance by the nearby cis-methyl ketone, as depicted in structure 12 (simple secondary amides are not converted into methyl esters under these conditions).Scheme 1. The structures of sceptrin (1) and ageliferin (2). TF...

Cascade Reactions in Total Synthesis

“…Indeed, initial attempts to prepare non‐racemic cyclobutanes from enantiomerically enriched chiral 3‐oxaquadricyclanes resulted in significant loss of enantiopurity. However, by employing monobenzylamide 193 , prepared in situ by irradiation of non‐racemic diene 192 , Baran et al were able to access tetrasubstituted cyclobutane 196 with clean transfer of chirality (Scheme 29) 103. They proposed a mechanism involving initial cleavage of the oxygen bridge to give cyclopropyl carbocation 194 .…”

“… The total synthesis of (−)‐sceptrin ( 197 ) and (−)‐ageliferin ( 202 ) by a controlled quadricyclane fragmentation and cationic ring expansion (Baran et al, 2006) 103…”

Photochemische Reaktionen als Schlüsselschritte in der Naturstoffsynthese

“…[274] (S)-Valinol wurde als Auxiliar genutzt, um (À)-Grandisol (ent-73) über das Intermediat ent-202 herzustellen. [275] Durch die Verwendung von (R)-Valinol würde man konsequenterweise über 202 (+)-Grandisol (73) [279,280] oder durch Verwendung eines Auxiliars [279] [286] Die Cyclobutan-Anellierung von bereits existierenden Ringsystemen finden an einem Olefin häufig durch dessen Photocycloaddition an Ethen oder an Surrogaten für Ethen (z. B.…”

Letter 2: The role of primary repair for colonic injuries in wartime (Br J Surg 2004; 92: 643-647)

“…The inherent danger in the incorrect assignment of the absolute configuration through reliance on optical rotation alone is well known but may be compounded further by variables in measurement of α , especially highly charged or polar compounds. For example, the [ α ] D of sceptrin, a pyrrole‐aminoimidazole alkaloid from several different Agelas spp., was shown to be highly variable and dependent – both in sign and magnitude – on concentration and, particularly, on the nature of the counterion 16…”