Step sequence have been only moderate and probably to low to
Step sequence were only moderate and most likely to low to provide sufficient amounts of material for an effective resolution (Scheme four). These unsuccessful attempts to establish the appropriate configuration at C9 led to a revision in the synthetic strategy. We decided to investigate a dynamic kinetic resolution (DKR) approach at an earlier stage in the synthesis and identified the secondary alcohol 21 as a promising starting point for this approach (Scheme 5). Compound 21 was obtained through two alternate routes, either by reduction of ketone 13 (Scheme three) with NaBH4 or from ester 25 via one-flask reduction to 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] utilizing a comparatively low loading of CXCR4 Accession phosphine-free catalyst A, followed by MOM protection and CK1 Biological Activity Stryker ipshutz reduction of 24. Notably the latter step proceeds drastically much more effective within a toluenetertbutanol solvent mixture than the analogous enone reductions outlined in Scheme 3 and Table two. Compared to these reactions, the saturated ester 25 was obtained in a almost quantitative yield making use of half the volume of Cu precatalyst and BDP ligand. To be able to get enantiomerically pure 21, an enzymetransition metal-catalysed method was investigated [48,49]. In this regard, the mixture of Ru complexes such as Shvo’s catalyst (C) [50], the amino-Cp catalyst D [51], or [Ru(CO)2Cl(5C5Ph5)] [52], and also the lipase novozym 435 has emerged as specifically beneficial [53,54]. We tested Ru catalysts C and D beneath a variety of conditions (Table four). Within the absence of a Ru catalyst, a kinetic resolution occurs and 26 andentry catalyst lowering agent (mol ) 1 two three 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 in 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 as a result of competing hydroboration on the alkenes. With borane HF at -50 the reduction proceeded to completion, but gave a 1:1 mixture of diastereomers (Table 3, entry three). With catechol borane at -78 conversion was again complete, however the diastereoselectivity was far from becoming synthetically helpful (Table three, entry 4). As a result of these rather discouraging final results we didn’t pursue enantioselective reduction techniques additional to establish the required 9R-configuration, but considered a resolution method. Ketone 14 was 1st lowered with NaBH4 towards the anticipated diastereomeric mixture of alcohols 18, which had been then subjected for the conditionsBeilstein J. Org. Chem. 2013, 9, 2544555.Scheme 4: 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 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 (ten.0 equiv), toluene, 70 , 72 h C (1 mol ), Novozym 435, iPPA (10.0 equiv),.
