Ecursor 14 in pure type in 71 yield. To prevent the formation of
Ecursor 14 in pure type in 71 yield. To avoid the formation of your inseparable byproduct, we investigated a reversed order of measures. To this finish, 12 was 1st desilylated to allyl alcohol 15, which was then converted to butenoate 16, once again via Steglich esterification. For the selective reduction with the enoate 16, the Stryker ipshutz protocol was once again the process of Akt1 manufacturer choice and optimized conditions at some point furnished 14 in 87 yield (Scheme three). For the Stryker ipshutz reduction of 16 slightly distinct conditions were employed than for the reduction of 12. In distinct, tert-butanol was omitted as a co-solvent, and TBAF was added to the reaction mixture right after completed reduction. This modification was the result of an optimization study according to mechanistic considerations (Table two) [44]. The situations previously employed for the reduction of enoate 12 involved the use of tert-butanol as a co-solvent, together with toluene. Below these circumstances, reproducible yields within the range between 67 and 78 were obtained (Table 2, entries 1). The alcohol is believed to protonate the Cu-enolate formed upon conjugate addition, resulting in the ketone along with a Cu-alkoxide, which can be then lowered with silane to regenerate the Cu-hydride. Alternatively, the Cu-enolate might enter a competing catalytic cycle by reacting with silane, furnishing a silyl enol ether along with the catalytically active Cu-hydride species. The silyl enol ether is inert to protonation by tert-butanol, and hence the competing secondary cycle will lead to a decreased yield of reduction product. This reasoning prompted us to run the reaction in toluene with out any protic co-solvent, which ought to exclusively lead to the silyl enol ether, and add TBAF as a desilylating agent soon after comprehensive consumption of theTable 1: Optimization of situations for CM of 10 and methyl vinyl ketone (8).aentry 1 2b 3 four 5 6caGeneralcatalyst (mol ) A (2.0) A (5.0) A (0.5) A (1.0) B (2.0) B (2.0) 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: eight.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 from the crude reaction mixture. cWith phenol (0.five equiv) as additive.Beilstein J. Org. Chem. 2013, 9, 2544555.Table 2: Optimization of Cu -catalysed reduction of 16.entry 1 two 3 4aaTBAFCu(OAc)two 2O (mol ) 5 5 1BDP (mol ) 1 1 0.5PMHS (equiv) 2 two 1.2solvent toluenet-BuOH (5:1) toluenet-BuOH (two:1) toluenet-BuOH (2:1) LPAR2 Species tolueneyield of 14 72 78 67 87(two equiv) added soon after full consumption of beginning material.starting material. The decreased item 14 was isolated below these situations in 87 yield (Table 2, entry 4). With ketone 14 in hands, we decided to establish the essential configuration at C9 inside the next step. To this end, a CBS reduction [45,46] catalysed by the oxazaborolidine 17 was tested initially (Table three).Table three: Investigation of CBS reduction of ketone 14.in the RCMbase-induced ring-opening sequence. Sadly, the expected macrolactonization precursor 19 was not obtained, but an inseparable mixture of goods. To access the intended substrate for the resolution, secondary alcohol 19, we investigated an inverted sequence of actions: ketone 14 was first converted to the 9-oxodienoic acid 20 below RCMring-opening circumstances, followed by a reduction from the ketone with DIBAl-H to furnish 19. Unfortunately, the yields obtained by way of this two.
