Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols

Abstract

The discovery of catalysts that can be used to synthesize complex organic compounds by enantioselective transformations is central to advances in the life sciences; for this reason, many chemists aim to discover catalysts that allow for preparation of chiral molecules as predominantly one mirror-image isomer. The ideal catalyst should not contain precious elements and should bring reactions to completion in a few hours through operationally simple procedures. Here we introduce a set of small organic molecules that can catalyse reactions of unsaturated organoboron reagents with imines and carbonyls; the products of the reactions are enantiomerically pure amines and alcohols, which might serve as intermediates in the preparation of biologically active molecules. A distinguishing feature of this catalyst class is the presence of a 'key' proton embedded within their structure. Catalysts are derived from the abundant amino acid valine and are prepared in large quantities in four steps with inexpensive reagents. Reactions are scalable, do not demand stringent conditions, and can be performed with as little as 0.25 mole per cent catalyst in less than six hours at room temperature to generate products in more than 85 per cent yield and ≥97:3 enantiomeric ratio. The efficiency, selectivity and operational simplicity of the transformations and the range of boron-based reagents are expected to render this advance important for future progress in syntheses of amines and alcohols, which are useful in chemistry, biology and medicine.

Figure 1. The significance of homoallylic amines and alcohols; three approaches to their catalytic enantioselective synthesis

a, Biologically active natural products synthesized via homoallylic amines and alcohols. b, With a metal-containing catalyst, high rates are achieved through facile ligand exchange. c, In a metal-free system, the catalyst must be reassembled prior to each cycle. d, A catalyst might be designed with an internal H-bond promoting fast reaction rates and high enantioselectivities. Catalytic cycles deliver net α addition (C₁–B→C₁–C) resulting from two γ-selective processes (G→B and D→F). Facile catalyst regeneration may occur through allylation of G via H. PG = protecting group.

Figure 2. Examination of chiral amino alcohols as candidates for catalyst precursors

The lack of activity shown by catalysts derived from 2b and 2c is consistent with the mechanistic scenario outlined in Fig. 1d, as the requisite chiral allylboron species cannot be generated. Also consistent is the low activity and enantioselectivity by ester-containing 2e, underscoring the pivotal role of the catalyst’s Lewis basic C-terminus in establishing an H-bond. Reactions were carried out in toluene under an atmosphere of nitrogen gas; ND = not determined. § Conversion to the desired product as measured by analysis of 400 MHz ₁H NMR spectra of unpurified mixtures versus an internal standard of 9-methylanthracene; the variance of values is estimated to be <±2%. † Enantiomeric ratios were determined by HPLC analysis; the variance of values is estimated to be <±2%. See the Supplementary Information for details.

Figure 3. Efficient and enantioselective catalytic allyl additions to aldimines

Aryl-, alkenyl-, alkynyl- and alkylimines can be used to generate homoallylic amides with high efficiency and enantioselectivity (Tables 2–3). Mechanistic models account for the observed enantioselectivity and involve H-bonding interactions that bring the reaction components together, promote high enantiotopic face differentiation by enforcing an organized transition structure, and facilitate bond formation by minimizing electron–electron repulsion caused by the converging heteroatoms; this model is supported by the X-ray crystal structures of 2g and its HCl salt, which contain a proton-bridge connecting the amine and carbonyl units (see the Supplementary Information). Reactions were carried out in toluene under an atmosphere of nitrogen gas. §Conversion to the desired product as measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures versus an internal standard of 9-methylanthracene; the variance of values is estimated to be <±2%. §§Yield of isolated product after purification; the variance of values is estimated to be ±2%. †Enantiomeric ratios were determined by HPLC analysis; the variance of values is estimated to be <±2%. See the Supplementary Information for details.

Figure 4. Practical, scaleable and highly α-selective catalytic enantioselective allyl additions to imines

a, Amino alcohol 2g is prepared in multi-gram quantities inexpensively by simple procedures; additions are easily performed on gram scale. b, Deuterium-labeling experiments support the preference for high α selectivity. c, Various attributes of the chiral catalyst allow access to homoallylamides with an additional tertiary or quaternary carbon stereogenic center with high α- diastereo- and enantioselectivity. d, The stereochemical outcome with substituted allylboron reagents support the proposed mechanism and shed light on the efficient and stereoselective allyl transfer phase of the catalytic cycle (catalyst regeneration/product release). H-bonding in VII stimulates enhanced Lewis acidity at the chiral catalyst’s boron center, favoring donation by the π bond of the organoboron reagent 12 (cf. VIII), facilitating stereoselective generation of IX. Conversions and diastereomeric ratios were measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; the variance of values estimated to be <±2%. Yields correspond to isolated and purified products (±2%). Enantiomeric ratios were determined by HPLC analysis (±2%). See the Supplementary Information for experimental details and spectroscopic analyses.

Figure 5. Catalytic enantioselective additions to isatins and reactions with an allenylboron reagent

a, Enantioselective allyl additions to isatins afford homoallylic alcohols. b, A stereochemical model proposed to account for the enantioselectivities. c, Broad applicability is illustrated by enantioselective allene additions to isatins, performed with commercially available organoboron reagent 19. All reactions were carried out in toluene under an atmosphere of nitrogen gas. Conversions measured by analysis of 400 MHz ¹H NMR spectra of unpurified mixtures; the variance of values estimated to be <±2%. Yields correspond to isolated and purified products (±2%). Enantiomeric ratios were determined by HPLC analysis (±2%). See the Supplementary Information for details. TBS = t-butyldimethylsilyl; Bn = benzyl; PMB = p-methoxybenzyl; SEM = 2-(trimethylsilyl)ethoxymethyl.