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...

Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence

“…1, sceptrin ( 1a ) (22), massadine ( 2a ) (23, 24), and ageliferin ( 3a ) (25, 26) are family members derived from formal [2+2], [3+2], and [4+2] cycloaddition reactions of oroidin ( 4a ), hymenidin ( 4b ), or their congeners. Our previous studies on the de novo synthesis of ageliferins ( 3 ) (4, 14, 15) suggest that the biogenic dimerization of 4 is likely a radical reaction. We now describe the de novo syntheses of sceptrin ( 1a ) and massadine ( 2a ), using oxidative reactions that are suspected to be involved in their biosyntheses.…”

“…The prior synthesis of sceptrin ( 1a ) by Birman (20) and us (2, 4, 5) involved the construction of the cyclobutane ring by forming the C9/C10 and C9′/C10′ bonds using a [2+2] photocycloaddition reaction. The synthesis described herein involves the alternative formation of the C9/C9′ and C10/C10′ bonds (biogenic connection) via a SET-promoted [2+2] cycloaddition reaction (Molinski-Romo hypothesis).…”

Preparation of l -tryptophan imprinted microspheres based on carboxylic acid functionalized polystyrene

“…Chiral synthesis by using asymmetric reactants regarded as the most effective and economic procedure for manufacturing of enantiopure substances. However, this high efficiency was only displayed with limited number of exceptional stereoselective reactions [4][5][6][7].…”

Recent advances of desymmetrization protocol applied in natural product total synthesis

“…24 Baran group reported the first asymmetric synthesis of both enantiomers of Sceptrin 42 and Ageliferin 43 in 2006. 25 Their synthesis commenced with the enzymatic desymmetrization of meso-diester 44 using PLE in buffer and pH 8 to provide monoester (À)-45 in 75% ee. Subsequently, they accomplished the total synthesis of sceptrin 42 and ageliferin 43 with high overall yield (Scheme 13).…”