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44130-G1
Solid-Supported Cyclotrimerization Reactions
The overall goal of the research project is the development of chemo- and regioselective [2+2+2] cyclotrimerization reactions through the application of a solid-support. Moreover, the developed reactions are then applied to the synthesis of a variety of compound classes (benzenes, pyridines, iminopyridines, pyridones, etc.) and natural products (anthraquinones and indanones).
1) Cyclotrimerization of Immobilized Alkynes – Synthesis of Pyridines. By immobilizing one alkyne reaction partner on a polystyrene resin we resolved the chemoselectivity problem of [2+2+2] cyclotrimerization reactions and we achieved the first chemoselective pyridine formation by a cobalt-catalyzed, solid-supported cyclotrimerization of two different alkynes and a nitrile. The reaction tolerates a variety of substituents, including alkyl groups (Me, Et, Bu), aryl groups (Ph), hydroxy groups, alkoxy groups (MeOCH2, EtO), and carbamates (BocNH) on the reaction partners. The products were obtained in 43-85% yield and with excellent purity (generally >90%, as determined by 1H NMR, GC/MS, and LC/MS). Although 2-3 regiosiomers were obtained in various ratios, 2,4,6-pyridines represent the major product according to NMR data and a generally accepted reaction mechanism described for the formation of homo-pyridines.
2) Cyclotrimerization of Immobilized Diynes – Synthesis of Fused Benzenes. To investigate the assembly of bicyclic structures via solid-supported cyclotrimerizations, 1,6-diyne substrates were immobilized on polystyrene resins. The following conditions were found to be optimal: Wilkinson's catalyst (2×5mol%, 24h each) in CH2Cl2/ethanol (3:1) at 60oC. After 48 hours the resins were filtered, washed, and the cyclotrimerized products were cleaved. Isoindolines were isolated in 70-95% yield (>90% purity by 1H NMR and LC/MS). In these, and all other experiments, a highly chemoselective reaction without dimerization of two immobilized diynes was observed. This high selectivity can be attributed to the spatial separation of diynes on the resin surface, and represents a major improvement over traditional solution-phase cyclotrimerizations. This improved chemoselectivity is especially prevalent in reactions with less reactive, internal alkynes. In solution-phase these alkynes lead almost exclusively to the dimerization of the terminal diyne starting materials, as observed by us and others. Moreover indanes and phthalans were synthesized in 60-95% yield and >90% purity. Due to the presence of an internal triple bond in the phthalan precursor a non-selective formation of regioisomers was observed in the case of Wilkinson's catalyst. This regioselectivity problem was solved by switching the catalyst system to Cp*RuCl(COD), which predominantly (9:1) yielded the shown meta isomer. The same catalyst was used in the synthesis of tetrahydroisoquinolines under microwave irradiation (72-89% yield). In contrast, when these [2+2+2] cyclotrimerization reactions were carried out in solution-phase, complex compound mixtures were obtained and the products were only isolated in diminished yield.
3) Solid-supported Synthesis of Natural Products and Analogs. Prominent examples of indanones we are currently targeting include pterosin P, mukagolactone, and monachosorin A. The solid-supported [2+2+2] cyclotrimerization under Ru-catalysis proceeded smoothly, and a one-pot cleavage/oxidation step afforded pure indanones in 57-78% yield (three steps). However, both regiosiomers were obtained as expected. This regioselectivity problem was solved by installation of a temporary regiodirecting group (TMS), which was removed in a traceless fashion and led to exclusive formation of the meta isomer. We then applied the developed approach to the first synthesis of a recently isolated marine natural product. This compound shows promising activity as a regulator of tumor angiogenesis by inhibiting human VEGF, and our solid-supported cyclotrimerization strategy enables the rapid assembly of analogs for activity improvement
4) Microwave Effects on Cyclotrimerization Reactions. We discovered generally applicable conditions for highly efficient [2+2+2] cyclotrimerizations of a variety of different substrates using microwave irradiation. An initial solution-phase investigation towards fused pyridines was conducted using trityl-protected dipropargylamine and PhCN. The cyclotrimerization was performed with 10mol% CpCo(CO)2 under microwave irradiation (300W, 110oC, toluene, 10min), and after protecting group removal, the product was obtained in 46% yield. Without microwave irradiation, only 9% product formation was observed, even after a prolonged reaction time of 24 hours at 110oC! The modest yield of 46% in the solution-phase cyclotrimerization is a result of the formation of benzene byproducts through starting material di- and trimerization, a common problem in cyclotrimerizations. This chemoselectivity problem was solved via immobilization on a polystyrene resin. In conjunction with microwave heating the immobilized diyne delivered fused pyridines in excellent yields (92-95%) and high purities (>90%) after cleavage from the resin. The implementation of microwave irradiation in conjunction with the solid-support affords a significant increase in yield, extremely reduced reaction times, and the elimination of catalyst activating additives, excessive heating, or light irradiation. Interestingly, the reaction could not be performed under thermal conditions (24h, 110oC, <5% yield). This dramatic improvement through microwave irradiation cannot just be attributed to efficient heating (in fact the reaction temperature is lower than under traditional conditions), but represents one of the most pronounced non-thermal microwave effects. Subsequently, we applied the same advantageous microwave conditions to the solid-supported synthesis of iminopyridines and pyridones.
