Abstract
We report on an improved strategy for the preparation of artificial molecular machines that can pick up and assemble reactive groups in sequence by traveling along a track. In the new approach a preformed rotaxane synthon is attached to the end of an otherwise fully formed strand of building blocks. This "rotaxane-capping" protocol is significantly more efficient than the "final-step-threading" method employed previously and enables the synthesis of threaded molecular machines that operate on extended oligomer, and potentially polymer, tracks. The methodology is exemplified through the preparation of a machine that adds four amino acid building blocks from a strand in sequence, featuring up to 20-membered ring native chemical ligation transition states.
Highlights
Many biological molecular machines responsible for sequencespecific synthesis, including the ribosome[1] and various DNA polymerases,[2] travel along tracks in order to assemble reactive building blocks in a precise order.[3]
We report on a molecular peptide synthesizer containing four amino acids loaded onto the building block strand, prepared using a “rotaxane-capping” strategy (Schemes 1b)
Synthesis and Operation of Four-Barrier Molecular Machine 8a aReagents and conditions: (i) TentaGel-TBTA/Cu(CH3CN)4·PF6 (0.5 equiv), 4:1 CH2Cl2/t-BuOH, RT, 48 h, 70%. (ii) PhNH2, BocGlyGlyCys(S-Trt)NHN CHC6H4OCH3 (7) in 3:1 dimethyl sulfoxide: 2-(N-morpholino)ethanesulfonic acid aqueous buffer, 60 °C, 2 days, 90%. (iii) CF3CO2H (20% in CH2Cl2), RT, 2 h. (iv) ((CH3)2CH)2NEt, (HO2CCH2CH2)3P in 3:1 CH3CN:(CH3)2NCOH, 60 °C, microwave, 48 h, 9 (80%) and 10 (53%)
Summary
Many biological molecular machines responsible for sequencespecific synthesis, including the ribosome[1] and various DNA polymerases,[2] travel along tracks in order to assemble reactive building blocks in a precise order.[3]. The key reaction to form the interlocked machine architecture involves threading of the ring onto the full strand of building blocks (Scheme 1a).[5] the active template[8,9] reaction employed to do this is low yielding and comes as the last step of a long synthetic route, limiting the utility of this approach for longer tracks. The low efficiency of the threading is probably due to the number of amide groups on the completed track that can sequester the Cu(I) catalyst from the pyridine group of the macrocycle used to promote the active template threading reaction.9a In order to produce machines that can operate on extended strands with more. Assembling Threaded Molecular Machines for Sequence-Specific Synthesis building blocks it is clearly necessary to find a more efficient strategy to assemble such machine-track conjugates.
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