Total Synthesis of (±)-Sceptrin

A four-step synthesis of the dimeric pyrrole–imidazole alkaloid sceptrin is reported. The brevity of the route is based on a simple solution developed for selective assembly of the cyclobutane core of the natural product. The photochemical intermolecular [2 + 2] dimerization of a useful hymenidin surrogate enables direct entry to this enigmatic class of biologically active marine secondary metabolites.

a hymenidin derivative because it is intuitive and direct. We pondered the holistic value in re-evaluating a biomimetic synthesis of 3 through such a cycloaddition, although the operative mechanism by which the key transformation would proceed was uncertain. 6 Specifically, photochemical [2 + 2] dimerizations have been largely dismissed since A. sceptrum is isolated at oceanic depths with insufficient light (−20 to −30 m) and attempts involving irradiation of 2 in either solution or the solid state were reportedly fruitless. 1,2a We found inspiration in pioneering studies on "dark photochemistry" conducted by Cilento, White, Lamola, and co-workers in the late 1970s, in which strained endoperoxides 7 were shown to produce upon scission long-lived, high-energy triplet carbonyls capable of energy transfer. 8 Exemplary "photoproducts" accessed without light included lumisantonin, lumicolchicines, and cyclobutane pyrimidine and thymine dimers. 9 These data are conceptually interesting as they allude to nonobvious roles of electronically excited intermediates in secondary metabolite distributions where light is scarce. 9a,10 We reasoned that successful interpretation of this unusual biosynthetic hypothesis in the laboratory employing recent advancements in photochemical methods would yield concise entry to 3 and its congeners.
Carbon−carbon bond-forming reactions promoted by actinic sensitization of alkene substrates are not new. In the historical framework of the sceptrins, both the Baran 2d and Al-Mourabit 11 groups have explored the utility of cyclobutane dimers derived from α,β-unsaturated carbonyl starting materials, a notably privileged structural motif within this class of photochemical transformations. 12 However, to the best of our knowledge, none of these cycloadducts have been successfully advanced to structures like 3. Along these lines, our own experimentation reaffirmed the poor strategic efficiency of late-stage 2-aminoimidazole formation and the potential of the imidazopyrimidine heterocycle as a powerful 2aminoimidazole mask. 13 We designed the new hymenidin surrogate 9 (Scheme 1) possessing the same oxidation state as the native monomers and whereby the polar primary amine "head" and basic 2aminoimidazole "tail" could be revealed with orthogonality.
Although the intermolecular [2 + 2] dimerization of primary allylic amines possessed no precedent, we were motivated by the observation of photochemical alkene isomerization while scouting available aminoimidazolyl propeneamine derivatives 14 since it intimated the intermediacy of a critical diradical intermediate required for cycloaddition. Furthermore, we were enthused by an opportunity to solve a considerable synthetic challenge in the preparation of complex cyclobutanes. 15 Building block 9 was prepared by initial hydroboration of commercially available N-Boc-propargylamine (6) with dicyclohexylborane (Cy 2 BH) and pinacolborane (HBpin) to give the known vinylboronic pinacol ester 7. 16 A tandem Suzuki−Miyaura cross-coupling 17 was executed by reaction with aqueous potassium carbonate (K 2 CO 3 ), 3-bromoimidazopyrimidine (8), and bis(triphenylphosphine)palladium(II) dichloride (5 mol %) in refluxing tetrahydrofuran (THF) to deliver monomer 9 in 63% yield (one pot). The key dimerization was best accomplished by irradiating a methanolic solution of 9 with blue LEDs (440−450 nm) in the presence of catalytic Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (1.8 mol %). 18 The C 2symmetric dimer 10 was isolated after flash column chromatography in 41% yield (57% based on recovered 9, 3.36 g scale) as a single regioisomer and diastereomer. The relative stereochemical configuration of 10 was subsequently confirmed by the total synthesis of 3.
Completion of the synthesis of 3 required exact choreography in order to install pendent acyl 3-bromopyrrole groups and unveil neighboring 2-aminoimidazoles. Optimally, this was conducted in a single flask by tert-butylcarbamate (Boc) cleavage followed by concentration to afford the diamine trifluoroacetic acid (TFA) salt 11. This crude mixture was subsequently exposed to bromopyrrole 12 19 and Hunig's base in acetonitrile (MeCN), after which "protected sceptrin" 13 precipitated from solution. The polar guanidine functionality of 3 was revealed last 13,14d by direct addition of hydrazine (H 2 NNH 2 ) in dimethylformamide (DMF) and warming of the resulting suspension until complete dissolution. Concentration and purification by flash column chromatography on aminefunctionalized silica gel provided free-base 3 in 34% overall yield from 6. Synthetic 3 prepared as described matched Scheme 1. Four-Step Total Synthesis of (±)-Sceptrin from N-Boc-propargylamine  6 as a promoter for the cycloaddition is noteworthy and in line with recent reports of its potency as a visible-light photosensitizer. 21 The selectivity of the transformation is equally impressive. Since 10 regio-and stereochemical permutations of the racemic dimer are statistically possible, we find the selective formation of a single isomer (10) in 57% yield (brsm) with a relative configuration matching the natural series remarkable given that its synthesis occurred in batch solvent and in the absence of any apparent templating phenomenon. 12,22 An evaluation of reaction parameters as shown in Table 1 points to a working hypothesis based on catalytic energy transfer from an excited triplet state iridium complex to 9, which subsequently combines with a ground-state monomer from its excited triplet state. 21a Use of MeOH as the solvent gave the cleanest reaction mixtures, although the reaction yield was not critically dependent on the solvent identity (entries 1− 5), which is consistent with an energy transfer mechanism. Furthermore, Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 is not sufficiently oxidizing in the excited state (+0.89 V) 18 to generate a radical cation from 9, for which the peak oxidation potential was found to be +1.25 V vs SCE. 20 Evaluation of other catalysts, including photooxidants capable of oxidizing 10 from their respective excited states (Ru(bpz) 3 2+ and Mes-Acr-Ph + , entries 6 and 11) in addition to other heteroleptic polypyridyl iridium complexes did not provide any 10. Sensitizers with triplet energies greater than that of Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 but requiring irradiation with purple light (390 nm) 23 were not productive in this case. Finally, control experiments excluding any catalyst revealed that trace amounts of dimer 10 can be isolated following irradiation of 9 with purple light, 24 providing further support for a mechanism based on electronic excitation rather than a redox manifold.
In summary, a blend of biosynthetic logic and modern advances in catalytic photochemistry has enabled a four-step entry to the sceptrin alkaloids. Although the biogenesis of 3 is still a matter of conjecture and awaits experimental confirmation, the precision by which we arrived at the target structure demonstrates the utility of an energy transfer process in their de novo assembly. We have prepared multiple grams of the natural product to date and are currently studying its biological activity and potential interconversion to other dimeric pyrrole−imidazole alkaloids 2d,5 and exploring the utility of new hymenidin surrogates in biomimetic total synthesis.  ■ REFERENCES