Foldamer‐Mediated Remote Stereocontrol: >1,60 Asymmetric Induction

Abstract

An N-terminal l-a-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac 6 c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46-and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.In a typical stereoselective reaction, existing stereochemistry governs the formation of a new stereogenic center by controlling the direction of attack of a reagent or a catalyst at a reactive site. Close spatial contact between the controlling center and the reaction site is typically required, and 1,2or 1,3-asymmetric induction (where the two sites are separated by one or two bonds) can routinely be expected to give high levels of stereoselectivity. [1] Asymmetric induction over longer distances ("remote asymmetric induction" usually refers to 1,4-asymmetric induction and beyond) is possible, [2] but only if the flexibility of the molecule is limited, usually by the (sometimes temporary) formation of a cyclic structure. [3] Asymmetric induction can be achieved over more than 20 bonds [4] in non-cyclic molecules by using semi-rigid structures in which relayed interactions between a series of polarized groups allow a controlling stereogenic center to influence the local environment of a remote reactive site. [5] Here we present a way to achieve asymmetric induction over much greater distances by using molecules that have inherent helicity, or foldamers. [6,7] The conformational properties of foldamers as structural analogues of biomolecules have been investigated widely, [7][8][9] but their ability to control reactivity remains largely unexplored. [10] By linking an appropriate controller and a reactive site through a molecular fragment strongly disposed to adopt a helical structure, we show that it becomes possible for the controlling center to govern the stereochemical environment at a remote reactive site located several nanometers away.The helical foldameric parts of our molecules were made from oligomers of aminoisobutyric acid (Aib, 1) and 1aminocyclohexanecarboxylic acid (Ac 6 c, 2) (Figure 1 a). Peptide-like oligomers of these achiral quaternary amino acids typically adopt well-defined 3 10 helical structures in solution, [11] but because the individual amino acids each possess a plane of symmetry, their oligomers exist as a rapidly interconverting [12,13] equal mixture of left-and right-handed helices. A bias towards a single screw sense [14] was induced by ligating to the N-terminus of these oligomers one or more residues of the chiral quaternary amino acid l-a-methylvaline (aMv, 3). The structure of l-a-methylvaline is compatible with the 3 10 helical structure of Aib oligomers, [15] ...

Pure Shift NMR Spectroscopy

“…As with real-time BIRD HSQC, BSD can offer signalto-noise ratios that are actually greater than that of the parent experiment, even where in-band couplings mean that only partial decoupling is achieved. 6,30 A different approach is taken in the anti z-COSY experiment, which segments spins between active and passive subsets by means of a pair of small flip angle pulses that replace the Volume 3, 2014 mixing pulse of a COSY experiment. The small flip angle pulses refocus a small proportion of spins while leaving the majority unaffected; adding a nonselective 180 • pulse results in a COSY spectrum in which the diagonal responses are dominated by a line of multiplet components that run at right angles to the main diagonal.…”

Ligand-modulated conformational switching in a fully synthetic membrane-bound receptor

“…26 In this way endto-end transmission of binding information over multi-nanometre distances has been accomplished through Aib foldamers dissolved in organic solvents. 15,27,28 Recently, covalently controlled conformational switching over multi-nanometre distances within membrane-bound Aib foldamers was demonstrated using a light-switchable molecule. 29 The ligand binding pocket was constructed from a cationic metal(II) bis(2-quinolylmethyl)(2-pyridylmethyl)amine (BQPA) complex (Fig.…”

Real-time bilinear rotation decoupling in absorptive mode J-spectroscopy: Detecting low-intensity metabolite peak close to high-intensity metabolite peak with convenience

“…Real-time pure shift methods are very interesting as they refocus the effect of J-couplings during data acquisition imparting great improvement in sensitivity per unit of measurement time [6,7,10,11,17,19]. Broadband approaches such as, BIRD, and ZS pulse-sequence elements, and band selective methods such as BASH or HOBS have been implemented in realtime [8,17,22] or directly detected dimension (F 2 ). PSYCHE [20,21] offers order of magnitude higher sensitivity than ZS or BIRD but is applicable only in indirect (F 1 ) dimensions of multidimensional approach.…”

“…Numerous pure shift methods and their applications have emerged based on BIRD [9][10][11][12][13][14][15], Zangger and Sterk (ZS) pulse-sequence elements [1][2][3][4][5][6], selective methods such as BASH (band-selective homonuclear) or HOBS (homonuclear band-selective) [8,17,22], and PSYCHE (Pure shift yielded by chirp excitation) [23,24]. Real-time pure shift methods are very interesting as they refocus the effect of J-couplings during data acquisition imparting great improvement in sensitivity per unit of measurement time [6,7,10,11,17,19].…”