Ilane, NPY Y5 receptor Antagonist list furnishing a silyl enol ether and the catalytically active Cu-hydride species. The silyl enol ether is inert to protonation by tert-butanol, and thus the competing secondary cycle will result in a decreased yield of reduction solution. This reasoning prompted us to run the reaction in toluene without the need of any protic co-solvent, which ought to exclusively cause the silyl enol ether, and add TBAF as a desilylating agent following comprehensive consumption of theTable 1: Optimization of conditions for CM of ten and methyl vinyl ketone (8).aentry 1 2b 3 4 five 6caGeneralcatalyst (mol ) A (2.0) A (five.0) A (0.5) A (1.0) B (two.0) B (two.0) B (five.0)solvent CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene toluene CH2ClT 40 40 40 40 80 80 40yield of 11 76 51 67 85 61 78 93conditions: 8.0 equiv of 8, initial substrate concentration: c = 0.5 M; bformation of (E)-hex-3-ene-2,5-dione observed inside the 1H NMR spectrum with the crude reaction mixture. cWith phenol (0.5 equiv) as additive.Beilstein J. Org. Chem. 2013, 9, 2544555.Table 2: Optimization of Cu -catalysed reduction of 16.entry 1 2 three 4aaTBAFCu(OAc)two 2O (mol ) 5 five 1BDP (mol ) 1 1 0.5PMHS (equiv) 2 two 1.2solvent toluene/δ Opioid Receptor/DOR Agonist Compound t-BuOH (five:1) toluene/t-BuOH (2:1) toluene/t-BuOH (two:1) tolueneyield of 14 72 78 67 87(two equiv) added soon after full consumption of starting material.starting material. The decreased solution 14 was isolated under these conditions in 87 yield (Table 2, entry four). With ketone 14 in hands, we decided to establish the necessary configuration at C9 within the subsequent step. To this end, a CBS reduction [45,46] catalysed by the oxazaborolidine 17 was tested first (Table three).Table 3: Investigation of CBS reduction of ketone 14.in the RCM/base-induced ring-opening sequence. However, the expected macrolactonization precursor 19 was not obtained, but an inseparable mixture of items. To access the intended substrate for the resolution, secondary alcohol 19, we investigated an inverted sequence of methods: ketone 14 was initially converted towards the 9-oxodienoic acid 20 below RCM/ring-opening circumstances, followed by a reduction of the ketone with DIBAl-H to furnish 19. Regrettably, the yields obtained via this twostep sequence were only moderate and probably to low to provide adequate amounts of material for an efficient resolution (Scheme 4). These unsuccessful attempts to establish the appropriate configuration at C9 led to a revision in the synthetic method. We decided to investigate a dynamic kinetic resolution (DKR) method at an earlier stage with the synthesis and identified the secondary alcohol 21 as a promising beginning point for this approach (Scheme five). Compound 21 was obtained via two alternate routes, either by reduction of ketone 13 (Scheme three) with NaBH4 or from ester 25 by means of one-flask reduction to the corresponding aldehyde and addition of methylmagnesium chloride. Ester 25 was in turn synthesized in three measures from monoprotected dienediol 10 by means of cross metathesis with methyl acrylate (22) [47] using a comparatively low loading of phosphine-free catalyst A, followed by MOM protection and Stryker ipshutz reduction of 24. Notably the latter step proceeds substantially a lot more effective in a toluene/tertbutanol solvent mixture than the analogous enone reductions outlined in Scheme three and Table 2. Compared to these reactions, the saturated ester 25 was obtained in a nearly quantitative yield working with half the volume of Cu precatalyst and BDP ligand. So that you can receive enantiomerically pure 21, an enzy.