The key to the general and efficient palladium‐catalyzed formylation of aryl and heteroaryl bromides is the use of the di‐1‐adamantyl‐n‐butylphosphane (cataCXium A) as ligand. Low pressure of the synthesis gas and appropriate choice of the base are also important for high yields (up to 99 %) of a broad range of (hetero)aromatic aldehydes at unprecedented low catalyst concentrations (see scheme; TMEDA= N,N,N′,N′‐tetramethylethylenediamine).
The acid-catalyzed condensation chemistry of simple amides and aldehydes provides a highly prolific source of diverse reactants for irreversible follow-up reactions. Amide-aldehyde mixtures have been successfully employed in multicomponent syntheses of N-acyl alpha-amino acids (via palladium-catalyzed amidocarbonylation) and various cyclohexene, cyclohexadiene, and benzene derivatives (via the amide-aldehyde-dienophile (AAD) reaction).
Primary alcohols with an unfunctionalized stereogenic center in the b-position undergo an enzyme-and metal-catalyzed dynamic kinetic resolution (DKR). The in situ racemization of the primary alcohol, required for the DKR, takes place via: (i) ruthenium-catalyzed dehydrogenation of the alcohol, (ii) enolization of the aldehyde formed, and (iii) ruthenium-catalyzed readdition of hydrogen to the aldehyde. The present method widens the scope of metal-and enzyme-catalyzed DKR, which has so far been limited to a-chiral alcohol and amine derivatives.Keywords: dynamic kinetic resolution; enzyme catalysis; metal catalysis; primary alcohols The development of efficient protocols for the synthesis of optically active compounds has attracted major attention in organic chemistry, because of the increasing demand for such compounds as building blocks in the pharmaceutical or agrochemical industry.[1] The most common way to prepare enantiomerically pure compounds in the chemical industry is still via resolution and separation of enantiomers from racemic mixtures.[2] In this respect, enzymatic resolution plays an important and dominant role [3] and a number of multi-ton industrial processes are based on enzymatic resolution.[4] A drawback with these kinetic resolutions (KR) is the maximum theoretical yield of 50 % leading to waste of half of the material. A solution to this problem is dynamic kinetic resolution (DKR), [5] which takes advantage of an in situ racemization of the remaining substrate enantiomer (Scheme 1). In this way a yield of up to 100 % of enantiopure material can be achieved.During the past decade, various DKR methods based on the combination of an enzyme and an additional racemization catalyst have been developed. [5d,6] In particular, the combination of an enzyme and a transition metal catalyst has proven to be useful for DKR of secondary alcohols.[5d] In the first efficient system developed, [7] Shvos ruthenium catalyst 1 (Scheme 2) was employed, and this catalyst requires a slightly elevated temperature. This procedure has been successfully applied to the DKR of various substituted secondary alcohols including diols [8] and allylic alcohols.[9] The method was recently extended to amines. [10] Further developments have led to room temperature procedures for DKR of secondary alcohols that employ a new type of racemization catalyst together with an enzyme. [11][12][13] In all these applications, the metal catalyst can be compared with the dehydrogenase/hydrogenase activity by enzymes having NAD(P)/ NAD(P)H as cofactor.All of the protocols for chemoenzymatic DKR of alcohols and amines described to date have been limited to substrates that are chiral at the a-carbon (A, Figure 1). An extension of chemoenzymatic DKR to alcohols and amines with a non-functionalized chiral carbon, for example, B (Figure 1) would significantly broaden the scope of the method.
Scheme 1. Principle of a dynamic kinetic resolution (DKR).Adv. Synth. Catal. 2007, 349, 1577 -1581 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim...
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