Step sequence have been only moderate and most likely to low to
Step sequence had been only moderate and probably to low to supply adequate amounts of material for an efficient resolution (Scheme 4). These unsuccessful attempts to establish the correct configuration at C9 led to a revision from the synthetic approach. We decided to investigate a dynamic kinetic resolution (DKR) strategy at an earlier stage on the synthesis and identified the secondary alcohol 21 as a promising starting point for this Glycopeptide Compound approach (Scheme 5). Compound 21 was obtained via two alternate routes, either by reduction of ketone 13 (Scheme 3) with NaBH4 or from ester 25 by means of one-flask reduction for the corresponding aldehyde and addition of methylmagnesium chloride. Ester 25 was in turn synthesized in 3 actions from monoprotected dienediol ten through cross metathesis with methyl acrylate (22) [47] applying 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 more effective inside a toluenetertbutanol solvent mixture than the analogous enone reductions outlined in Scheme three and Table two. In comparison to these reactions, the saturated ester 25 was obtained in a practically quantitative yield making use of half the amount of Cu precatalyst and BDP ligand. In order to acquire Kinesin-14 MedChemExpress enantiomerically pure 21, an enzymetransition metal-catalysed method was investigated [48,49]. In this regard, the combination 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 emerged as particularly beneficial [53,54]. We tested Ru catalysts C and D beneath a variety of situations (Table 4). Inside the absence of a Ru catalyst, a kinetic resolution happens and 26 andentry catalyst decreasing 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 complex mixture 1:1 three:aDeterminedfrom 1H NMR spectra of the crude reaction mixtures.With borane imethylsulfide complicated because the reductant and ten mol of catalyst, no conversion was observed at -78 (Table three, entry 1), whereas attempted reduction at ambient temperature (Table three, entry 2) resulted within the formation of a complicated mixture, presumably as a consequence of competing hydroboration of the alkenes. With borane HF at -50 the reduction proceeded to completion, but gave a 1:1 mixture of diastereomers (Table three, entry three). With catechol borane at -78 conversion was once again complete, however the diastereoselectivity was far from getting synthetically valuable (Table three, entry 4). As a result of these rather discouraging outcomes we did not pursue enantioselective reduction strategies further to establish the required 9R-configuration, but regarded as a resolution strategy. Ketone 14 was first reduced with NaBH4 to the expected diastereomeric mixture of alcohols 18, which had been then subjected to the conditionsBeilstein J. Org. Chem. 2013, 9, 2544555.Scheme four: Synthesis of a substrate 19 for “late stage” resolution.Scheme 5: Synthesis of substrate 21 for “early stage” resolution.Beilstein J. Org. Chem. 2013, 9, 2544555.Table four: Optimization of circumstances 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 (10.0 equiv), toluene, 70 , 72 h C (1 mol ), Novozym 435, iPPA (ten.0 equiv),.