No abstract

A novel and efficient reduction of various prochiral ketones such as acetopehones, alpha-azido aryl ketones, beta-ketoesters, and aliphatic acyclic and cyclic ketones to the corresponding optically acive secondary alcohols with moderate to excellent chemical yield was achieved by using Daucus carota, root plant cells under extremely mild and environmentally benign conditions in aqueous medium, has been described. Many of these optically active alcohols are the potential chiral building blocks for the synthesis of pharmaceutically important molecules and asymmetric chiral ligands. Hence, this biocatalytic approach is found to be the most suitable for the preparation of a wide range of chiral alcohols and gave inspiration for the development of a new biotechnological process.

With growing interest in the use of small molecules [1] for dissecting protein-protein interactions [2] and for understanding signaling pathways, the need for developing combinatorial methods to obtain small molecules that have stereochemical and skeletal diversity has also grown. [3,4] Owing to their structural complexity and the diversity of their functional groups, natural products are a source of bioactive lead compounds, and it is highly likely that libraries of small molecules that also display these features would serve as valuable tools. [5] We initiated a combinatorial chemistry program that is aimed at providing indoline-alkaloid-like complex polycyclic compounds in a high-throughput manner. [6] Indole and indoline alkaloids belong to an important family of bioactive natural products, and several of these derivatives (1-3, see Figure 1) exhibit various biological responses. An important milestone in our approach is the development of a practical, enantioselective synthesis of a functionalized aminoindoline scaffold, 4, that could be further utilized in introducing skeletal diversity. [7] This scaffold is highly unique and comprises four orthogonal protecting groups. Our plan was to utilize the phenolic hydroxyl group as an immobilization site in solid-phase synthesis. The remaining three functional groups could further be used in complexity-generating, diversity-oriented reactions. As shown in Scheme 1, aminoindoline 4 could be easily converted into 5, which comprises a conjugated carboxylate ester. Following the immobilization of 5 through the phenolic hydroxyl group on a solid support to give 6 and upon selective removal of the indoline protecting group, the substrate could then be coupled to an amino acid to give 7. A key step in our approach is the formation of a six-membered ring by a stereoselective, conjugate hetero (e.g. aza)-Michael reaction. This could provide the indoline-alkaloid-like tricyclic derivative 8, in which the diversity could easily be introduced at four sites. A six-membered ring-closure strategy that involves the trapping of the primary amine by a conjugated carboxylic ester could also provide a general method to the synthesis of cyclic b-amino acids. [8] The enantioselective synthesis of aminoindoline derivative 13 is shown in Scheme 2. 5-Hydroxy-2-nitro-benzaldehyde (9) was converted into 10 in two steps that involve protection of the phenol and elongation of the carbon chain. Compound 10 was then subjected to an asymmetric aminohydroxylation reaction to give compound 11 in 79 % yield (> 92 % ee).[9] The aminoindoline 12 was obtained from 11 in several steps that involved 1) reduction of the carboxylate ester (70 %), 2) benzoyl-protection of the primary alcohol (OBz, 88 %), 3) tosylation of the secondary alcohol (OTs, 87 %), 4) selective reduction of the nitro group, and 5) cyclization under mild basic conditions (75 % for two steps). Finally, compound 13 was obtained from 12 in three steps by which the indoline nitrogen was protected (Teoc, 98 %), the Cbz protecting group wa...