Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides. Additionally, we utilized NMR and IR-spectroscopic methods as well as computations to shed light on the factors responsible for the selectivity. The catalyst system can be readily modified to a multicatalyst by adding other catalytically active amino acids to the peptide backbone, enabling the stereoselective one-pot synthesis of complex molecules from simple starting materials.

The desymmetrization of meso-compounds is a powerful methodology for the synthesis of chiral building blocks.[1] High stereochemical induction for desymmetrizations of meso-1,2-diols 1 utilizing acyl transfer, however, is challenging owing to facile acyl group migration of the monoprotected product 2 (Scheme 1). [2][3][4] Other groups than acyl are less prone to migration; Hoveyda and Snapper could show that 1 can effectively be desymmetrized through silyl group transfer.[5] The challenge here lies in the identification of more active catalysts as typical loadings of 20-30 mol % are required.[5] Here we report an alternative approach that does utilize acyl transfer combined with an in situ oxidation to protect the valuable product from racemization. This procedure directly gives the corresponding aacetoxy ketones (3). While we had shown recently that trans-1,2-cycloalkanediols can be resolved kinetically, [6] the desymmetrization of 1 alone is not sufficient to prepare valuable compounds. As we show here, a newly developed onepot oxidation is a straightforward way to prepare highly enantio-enriched acyloin derivatives.There are only a few enzymatic approaches using stereoselective acyl transfer for the desymmetrization of 1 a. Pseudomonas lipase catalyzes esterification of 1 a with isopropenyl acetate [7] in 81 % yield and 81 % ee; porcine pancreas lipase catalyzes the reaction of 1 a with methyl acetate with 84 % ee (no yields given).[2] To the best of our knowledge, there are no metal-catalytic approaches for the desymmetrization of 1 a via acyl transfer. Organocatalytic methods using isobutyric anhydride as the electrophile and chiral 4-pyrrolidinopyridine (PPY) analogues (65 % ee, 61 % yield) [8] or an N,N-dimethylaminopyridine (DMAP)-based atropisomeric biaryl derivative (77 % ee, 20 % conversion) [9] apparently lack in efficiency. Chiral phosphine catalyzed desymmetrization of 1 a via acyl group transfer leads to maximum ee of 67 % at 66 % conversion. [3] Procedures for the synthesis of enantiomerically enriched a-acetoxy ketones are also rare. An eight-step procedure of Oku et al. [10] leads to an overall low yield while the five-step procedure of Sugimura leads to ee values > 98 % at low overall yield.[11] Enantioselective Shi epoxidation of acylated cyclohexene-1-ol followed by thermal rearrangement gives 3 a in 75 % ee and 99 % yield.[12] An ee of 48 % of 3 a at 68 % conversion could be achieved with Shi's kinetic resolution of the corresponding enol ester epoxide.[13] a-Acetoxy ketone 3 a could also be observed during the hydrolytic enzymatic kinetic resolution of the cyclohexen-1-ol ester epox- Scheme 1. A catalyst for enantioselective acylation followed by one-pot oxidation would render the synthesis of 3 a significantly more efficient.

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One-Pot Desymmetrization of meso-1,2-Hydrocarbon Diols Through Acylation and Oxidation. -Oligopeptide HGCP containing an adamantane amino acid moiety is used to catalyze the desymmetrization of meso-1,2-diols (I) with high enantioselectivities. The acylated products show a tendency to racemization. This process can be avoided by direct oxidation of the monoacylated product providing α-acetoxy ketones such as (IV) and (VII) with high enantioselectivities. -(MUELLER, C. E.; ZELL, D.; SCHREINER*, P. R.; Chem. Eur. J. 15 (2009) 38, 9647-9650; Inst. Org. Chem.,

Lipophilic Oligopeptides for Chemo-and Enantioselective Acyl Transfer Reactions onto Alcohols. -A lipophilic oligopeptide is used as an organocatalyst for the acylative kinetic resolution of racemic cycloalkane-1,2-diols using various acyl donors. It shows an unexpected high activity usually only observed for enzymes or related large molecules. In addition, it is also shown that anhydrides proved to be the most efficient acyl source to achieve high enantioselectivities. -(MUELLER, C. E.; ZELL, D.; HRDINA, R.; WENDE, R. C.; WANKA, L.; SCHULER, S. M. M.; SCHREINER*, P. R.; J. Org. Chem. 78 (2013) 17, 8465-8484, http://dx.