A proof
of concept for the combination of an asymmetric organocatalytic
reaction with a biotransformation toward a “one-pot like”
process for 1,3-diols based on immobilized organo- and biocatalysts,
which are utilized in different compartments, is demonstrated. This
process which runs completely in organic media consists of an initial
proline-derivative-catalyzed aldol reaction and a subsequent reduction
of the aldol adduct catalyzed by an alcohol dehydrogenase (ADH) without
the need for intermediate isolation. Economically attractive superabsorber-based
coimmobilization for the ADH and its cofactor NAD+ turned
out to give a highly efficient biocatalyst with excellent reusability
and simple product separation from the immobilizate under avoidance
of any tedious extraction steps during the overall process.
Recent developments in the field of (enantioselective) organocatalysis have established it as a broadly applicable and efficient synthetic tool for the preparation of many types of enantiomerically enriched and enantiomerically pure molecules.[1] In these syntheses, organocatalysts are typically used in amounts of 1 to 20 mol %. [1,2] In general it is assumed that the enantioselective reactions proceed under kinetic control when the amount of catalyst used is within this range. Accordingly, the applied amount of catalyst indicates the degree of catalyst activity, and the catalyst amount can be adjusted in order to optimize the reaction rate and the overall conversion. Although organocatalytic reactions are in general assumed to be kinetically controlled within this range of catalyst loadings, it is in principle possible to switch from a kinetically controlled to a thermodynamically controlled regime even within this narrow range of catalyst loadings and within typical reaction times. Herein we report such an example in which the switch from kinetic to thermodynamic control occurs through a variation of catalyst loading in a narrow range between 0.5 and 10 mol %. Since the transformations reported here can be carried out in water, this also allows new efficient applications for chemoenzymatic one-pot multistep syntheses in aqueous reaction media. [3] As a model reaction we chose the aldol reaction of acetone (2) with 3-chlorobenzaldehyde (1) in the presence of the organocatalyst 3, which was developed by Singh et al. [4] In previous work, we conducted such reactions at room temperature as we had aimed at a combination with enzymatic syntheses, and in this connection we used a loading of 5 mol % of the organocatalyst 3.[5] Under these reaction conditions the aldol reaction of 2 (9 equiv) with 1 proceeded with an enantioselectivity of 70 % ee (Scheme 1). [6] With a view toward chemoenzymatic one-pot syntheses in aqueous medium we also have been interested in conducting the aldol reaction in this reaction medium. Accordingly we tested this transformation in aqueous NaCl. We observed that with the same catalyst amount (5 mol %), the reaction gave significantly lower enantioselectivity after 48 h, leading to the formation of the desired product (S)-4 with only 47 % ee (Figure 1). An even more surprising result was obtained in an experiment with 10 mol % of the organocatalyst (R,R)-3, which led to a complete loss of enantioselectivity (0 % ee). To determine the reasons for this drastic decrease of enantioselectivity, we first studied the effect of lower catalyst amounts. Interestingly, when the catalyst amount was lowered to 1.0 mol %, the enantioselectivity of the reaction continuously improved (Figure 1). For example, in the presence of 1.0 mol % of the catalyst a high, greatly improved enantioselectivity of 91 % ee was achieved at a product-based conversion of 90 % (95 % overall conversion). A further increase of the enantioselectivity up to 93 % ee at a product-based conversion of 92 % (95 % overall conversion) was...
Aldol reactions with trifluoroacetophenones as acceptors yield chiral α-aryl, α-trifluoromethyl tertiary alcohols, valuable intermediates in organic synthesis. Of the various organocatalysts examined, Singh's catalyst [(2S)-N-[(1S)-1-hydroxydiphenylmethyl-3-methylbutyl]-2-pyrrolidinecarboxamide] was found to efficiently promote this organocatalytic transformation in a highly enantioselective manner. Detailed reaction monitoring ((19)F-NMR, HPLC) showed that, up to full conversion, the catalytic transformation proceeds under kinetic control and affords up to 95% ee in a time-independent manner. At longer reaction times, the catalyst effects racemization. For the product aldols, even weak acids (such as ammonium chloride) or protic solvents, can induce racemization, too. Thus, acid-free workup, at carefully chosen reaction time, is crucial for the isolation of the aldols in high (and stable) enantiomeric purity. As evidenced by (19)F-NMR, X-ray structural analysis, and independent synthesis of a stable intramolecular variant, Singh's catalyst reversibly forms a catalytically inactive ("parasitic") intermediate, namely a N,O-hemiacetal with trifluoroacetophenones. X-ray crystallography also allowed the determination of the product aldols' absolute configuration (S).
A suitable “process window” was identified for the combination of an asymmetric organocatalytic aldol reaction and subsequent biocatalytic reduction in aqueous medium, which thus enabled the enantio‐ and diastereoselective synthesis of 1,3‐diols in a tandem‐type, one‐pot process. A key feature of this one‐pot synthesis is the high 500 mm loading of the aldehyde substrate used as a starting material.
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