He secondary alcohol 21 as a promising beginning point for this method (Scheme 5). Compound 21 was obtained through two alternate routes, either by reduction of ketone 13 (Scheme 3) with NaBH4 or from ester 25 through one-flask reduction to the corresponding aldehyde and addition of methylmagnesium chloride. Ester 25 was in turn synthesized in 3 measures from monoprotected dienediol 10 by means of cross metathesis with methyl acrylate (22) [47] employing a comparatively low loading of phosphine-free catalyst A, followed by MOM protection and Stryker ipshutz reduction of 24. Notably the latter step proceeds drastically much more effective inside a toluene/tertbutanol solvent mixture than the analogous enone reductions outlined in Scheme 3 and Table two. In comparison with these reactions, the saturated ester 25 was obtained inside a almost quantitative yield working with half the amount of Cu precatalyst and BDP ligand. To be able to acquire enantiomerically pure 21, an enzyme/transition metal-catalysed approach was investigated [48,49]. Within this regard, the mixture of Ru complexes like 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 especially helpful [53,54]. We tested Ru catalysts C and D under a range of conditions (Table four). In the absence of a Ru catalyst, a kinetic resolution occurs and 26 andentry catalyst lowering agent (mol ) 1 two three four 17 (ten) 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 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 inside the formation of a complex mixture, presumably resulting from competing hydroboration in the alkenes.1211526-53-2 Price With borane HF at -50 the reduction proceeded to completion, but gave a 1:1 mixture of diastereomers (Table 3, entry three).1359656-11-3 web With catechol borane at -78 conversion was again comprehensive, but the diastereoselectivity was far from becoming synthetically beneficial (Table three, entry four).PMID:23509865 On account of these rather discouraging results we didn’t pursue enantioselective reduction techniques additional to establish the required 9R-configuration, but regarded as a resolution strategy. Ketone 14 was initial lowered with NaBH4 towards the expected diastereomeric mixture of alcohols 18, which had been then subjected towards the conditionsBeilstein J. Org. Chem. 2013, 9, 2544?555.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, 2544?555.Table 4: Optimization of situations 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 (two mol ), Novozym 435, iPPA (ten.0 equiv), toluene, 70 , 72 h C (1 mol ), Novozym 435, iPPA (ten.0 equiv), Na2CO3 (1.0 equiv), toluene, 70 , 24 h D (2 mol ), Novozym 435, iPPA (1.five equiv), Na2CO3 (1.0 equiv); t-BuOK (5 mol ), toluene, 20 , 7 d D (2 mol ); Novozym 435, iPPA (1.5 equiv), t-BuOK (five mol ), toluene, 20 , 7 d D (2 mol ), Novozym 435, iPPA (3.0 equiv), Na2CO3 (1.0 equiv), t-BuOK (three mol ), toluene, 30 , 7 d D (five mol ), Novozym 435, iPPA (1.5 equiv), Na2CO3 (.
