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...

One‐of‐a‐kind. A bromine‐induced rearrangement has been designed for the formation of the spiro‐β‐lactam ring present in the structurally unique chartelline alkaloids (see picture of chartelline A). This method is used in combination with others to provide rapid access to the carbocyclic skeletons of the chartelline, securine, and securamine alkaloids.

We have previously reported the discovery of potent and selective inhibitors of 6-phosphogluconate dehydrogenase, the third enzyme of the phosphate pentose pathway, from Trypanosoma brucei, the causative organism of human African trypanosomiasis. These inhibitors were charged phosphate derivatives with restricted capacity to enter cells. Herein, we report the synthesis of five different classes of prodrugs: phosphoramidate; bis-S-acyl thioethyl esters (bis-SATE); bis-pivaloxymethyl (bis-POM); CycloSaligenyl; and phenyl, S-acyl thioethyl mixed phosphate esters (mix-SATE). Prodrugs were studied for stability and activity against the intact parasites. Most prodrugs caused inhibition of the growth of the parasites. The activity of the prodrugs against the parasites appeared to be related to their stability in aqueous buffer.

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...

S-Malic acid is an important chiral building block which has found wide application in the enantioselective synthesis of chiral compounds. 1 Manipulation of this polyfunctional synthon requires the selective protection of the different functionalities and the distinction of the two carboxyl groups present. The O-protected hydroxysuccinic anhydrides (I) derived from malic acid offer a unique way to achieve both these tasks. These anhydrides react regioselectively at the C-2 site with oxygen and nitrogen nucleophiles providing malic acid monoesters 2 and monoamides, 3 respectively. However, no report has appeared concerning similar behavior toward carbon nucleophiles.