Step sequence were only moderate and probably to low to
Step sequence have been only moderate and most likely to low to provide adequate amounts of material for an efficient resolution (Scheme four). These unsuccessful attempts to establish the right configuration at C9 led to a revision on the synthetic approach. We decided to investigate a dynamic kinetic resolution (DKR) strategy at an earlier stage of the synthesis and identified the secondary alcohol 21 as a promising beginning point for this method (Scheme five). Compound 21 was obtained by means of two alternate routes, either by reduction of ketone 13 (Scheme three) with NaBH4 or from ester 25 by way of one-flask reduction for the corresponding aldehyde and addition of methylmagnesium chloride. Ester 25 was in turn synthesized in three actions from monoprotected dienediol ten through cross metathesis with methyl acrylate (22) [47] making use of a comparatively low loading of phosphine-free catalyst A, followed by MOM protection and Stryker ipshutz reduction of 24. Notably the latter step proceeds significantly much more efficient in a toluenetertbutanol solvent mixture than the analogous enone reductions outlined in Scheme 3 and Table 2. When compared with these reactions, the saturated ester 25 was obtained in a almost quantitative yield applying half the volume of Cu precatalyst and BDP ligand. To be able to acquire enantiomerically pure 21, an enzymetransition metal-catalysed approach was investigated [48,49]. In this regard, the mixture of Ru complexes which include Shvo’s catalyst (C) [50], the amino-Cp catalyst D [51], or [Ru(CO)2Cl(5C5Ph5)] [52], along with the lipase novozym 435 has Caspase 6 Formulation emerged as especially useful [53,54]. We tested Ru catalysts C and D under various conditions (Table 4). Within the absence of a Ru catalyst, a kinetic resolution happens and 26 andentry catalyst reducing agent (mol ) 1 2 3 four 17 (10) 17 (20) 17 (20) 17 (20) H3B Me2 H3B HF H3B HF catechol boraneT dra-78 20 -50 -78no conversion complicated mixture 1:1 three:aDeterminedfrom 1H NMR spectra from the crude reaction mixtures.With borane imethylsulfide complicated as the reductant and 10 mol of catalyst, no conversion was observed at -78 (Table 3, entry 1), whereas attempted reduction at ambient temperature (Table three, entry 2) resulted in the formation of a complex mixture, presumably on account of competing hydroboration in the alkenes. With borane HF at -50 the reduction proceeded to completion, but gave a 1:1 mixture of diastereomers (Table three, entry 3). With catechol borane at -78 conversion was once again full, however the diastereoselectivity was far from getting synthetically useful (Table 3, entry four). On account of these rather discouraging ALK1 Storage & Stability benefits we did not pursue enantioselective reduction methods additional to establish the essential 9R-configuration, but deemed a resolution strategy. Ketone 14 was initially reduced with NaBH4 for the expected diastereomeric mixture of alcohols 18, which had been then subjected towards the conditionsBeilstein J. Org. Chem. 2013, 9, 2544555.Scheme four: Synthesis of a substrate 19 for “late stage” resolution.Scheme five: Synthesis of substrate 21 for “early stage” resolution.Beilstein J. Org. Chem. 2013, 9, 2544555.Table 4: Optimization of conditions for Ru ipase-catalysed DKR of 21.entry conditionsa 1d 2d 3d 4d 5d 6d 7e 8faiPPA:26 49 17 30 50 50 67 76 80(2S)-21b,c 13c 44 n. d. n. d. 38 n. i. 31 20 n. i. n. d. 65 30 n. d. n. d. n. d. n. d. n. d.Novozym 435, iPPA (1.0 equiv), toluene, 20 , 24 h C (2 mol ), Novozym 435, iPPA (ten.0 equiv), toluene, 70 , 72 h C (1 mol ), Novozym 435, iPPA (10.0 equiv),.
