Regio‐ and Stereoselective Homologation of 1,2‐Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3‐Diols and Sch 725674

Abstract 1,2‐Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3‐bis(boronic esters), which can be subsequently oxidized to the corresponding secondary‐secondary and secondary‐tertiary 1,3‐diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14‐membered macrolactone, Sch 725674. The nine‐step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high‐yielding late‐stage cross‐metathesis and Yamaguchi macrolactonization reactions.

. The Fawcett Flaskcustom glassware for the addition of solutions at cryogenic temperatures to a second solution at the same temperature.
Operation: After flame-drying the flask is attach to a Schlenk manifold, and the two groundglass joints are stoppered with suba-seals, before applying a high vacuum until the glassware has cooled to ambient temperature. The necessary reagents and solvents are then added into the appropriate sides of the flask (we typically add the reagents as a solution to the receiving flask a few minutes prior to transfer as it can be difficult to control the stirring in both halves when the flask is clamped into position). The flask can then be comfortably lowered into a cooling bath for the required reaction time. To perform the inverse-addition procedure the flask needs to be unclamped (we have found that the flask can sit happily in a cooling bath without the need for clamping for short periods of time) and held at an angle to allow proper stirring in both halves. Simple tipping of the flask, without removing either side from the cooling bath, will allow the solution in the delivering half to pour across into the receiving half. We have found that it is easy to control the rate of addition, so that it is comparable to dropwise or small portion-wise addition. To pour the final few drops across it is necessary to close the Schlenk tap on the side of the receiving flask and insert a needle into the suba-seal of the receiving flask. A finger over the end of the needle is sufficient to control the rate of addition of these final few drops. IR (neat) νmax: 2956,2928,2856,1334,1252,1146,1084,834 and 773 cm 1
The collected data was identical to that described above.

Entry 2 -Diamine-free homologation:
n-BuLi (1.6 M, 0.34 mL, 0.54 mmol, 1.0 eq.) was added dropwise to a solution of (R)-3-(4methoxyphenyl)-1-(tributylstannyl)propyl diisopropylcarbamate (317 mg, 0.54 mmol, 1.0 eq.) in Et2O (2.72 mL) at -78 °C (dry ice/acetone). After 1 h a solution of 2 (199 mg, 0.54 mmol, 1.0 eq.) in Et2O (0.54 mL) was added rapidly and the resulting solution was allowed to stir at the same temperature for 1 h. The solution was warmed to ambient temperature and then heated at 35 °C (oil bath) for 16 h. After cooling to ambient temperature, the solution was cooled to 0 °C (ice/water) before adding a 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL), which was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. The mixture was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The broad regions containing products A, and B and C, were collected by purification of the crude residue by flash column chromatography (SiO2; 40:60 EtOAc:pentane) to yield A as a 1:2.27 mixture with pinacol (97 mg, 43% A) as a colorless viscous oil, and a 1:2.13 mixture of B and C (117 mg, 17% B, 37% C) as a colorless viscous oil.

Entry 3 -TMEDA-ligated carbenoid homologation:
sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) was added dropwise to a solution of 1a (168 mg, 0.57 mmol, 1.05 eq.) and TMEDA (0.09 mL, 0.57 mmol, 1.05 eq.) in anhydrous Et2O (2.87 mL) at 78 °C (dry ice/acetone). After 2 h and solution of rac-2 (200 mg, 0.55 mmol, 1.00 eq.) in anhydrous Et2O (0.55 mL) was added dropwise and the resulting solution was S19 allowed to react for a further 1 h. The solution was warmed to ambient temperature and then heated at 35 °C (oil bath) for 16 h. After cooling to ambient temperature, the solution was cooled to 0 °C (ice/water) before adding a 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL), which was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. The mixture was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The broad regions containing products A, and B, C and D, were collected by purification of the crude residue by flash column chromatography (SiO2; 40:60 EtOAc:CH2Cl2) to yield A (70 mg, 47%) as a colorless viscous oil, and a mixture of rearranged carbamate (65 mg), B and D (27 mg, 5% B; 46 mg, 19% D) as a colorless viscous oil. No presence of C was detected.

Entry 4 -TMS-diazomethane homologation:
According to a modified literature procedure, 2 (100 mg, 0.27 mmol, 1.00 eq.) was dissolved in anhydrous toluene (1.00 mL) and trimethylsilyldiazomethane (0.55 mL, 2.0 m solution in hexanes, 1.09 mmol, 4.00 eq.) was added. The resulting solution was heated for 8 h at 80 °C (oil bath) before cooling to ambient temperature, adding another portion of trimethylsilyldiazomethane (0.55 mL, 2.0 m solution in hexanes, 1.09 mmol, 4.00 eq.) and heating at 80 °C (oil bath) for 16 h. After cooling to ambient temperature a few drops of acetic acid were added to quench any unreacted trimethylsilyldiazomethane. Analysis of the crude reaction mixture by GC-MS only showed the starting 1,2-bis(boronic ester) (2) and no other compounds, even in trace amounts. and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and

Regioselective Homologation of 1,2-bis(boronic ester) development
30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react S21 for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (97 mg, 60%) as a gummy white solid and 3b (6 mg, 3%) as a colorless oil.

Entry 3:
3-(4-Methoxyphenyl)propyl diisopropylcarbamate (337 mg, 1.15 mmol, 1.05 eq.), (+)-sparteine (0.26 mL, 1.15 mmol, 1.05 eq.) and anhydrous Et2O (5.75 mL) were added to the left-hand side of a flame-dried Fawcett Flask (see Figure 1) purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.85 mL, 1.28 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (400 mg, 1.09 mmol, 1.00 eq.) was dissolved in anhydrous Et2O (1.10 mL) in the right-hand flask and allowed to cool to -78 °C over 5 min. The solution of lithiated carbamate was added dropwise to the boronic ester solution over 5 min before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the flask was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (5.75 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). to the left-hand side of a flame-dried Fawcett Flask (see Figure 1) purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.85 mL, 1.28 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (400 mg, 1.09 mmol, 1.00 eq.) was dissolved in anhydrous Et2O (1.10 mL) in the right-hand flask and allowed to cool to -78 °C over 5 min. The solution of lithiated benzoate was added dropwise to the boronic ester solution over 5 min before leaving to react for a further 1 hr at the same temperature. The flask was allowed to warm to ambient temperature before adding THF (5.75 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (8 mL) and 30% aqueous H2O2 (4 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (20 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×40 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (183 mg, 57%) as a gummy white solid and 3b (11 mg, 2%) as a colorless oil. eq.), (+)-sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (242 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. The flask was allowed to warm to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (111 mg, 69%) as a gummy white solid.

S25
Entry 9: 3-(4-Methoxyphenyl)propyl 2,4,6-triisopropylbenzoate (226 mg, 0.57 mmol, 1.05 eq.), (+)-sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (242 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A 1 M solution of MgBr2 in MeOH (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. THF (2.85 mL) and one crystal of BHT were added, and the mixture was subsequently cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL).
Entry 10: 3-(4-Methoxyphenyl)propyl diisopropylcarbamate (167 mg, 0.57 mmol, 1.05 eq.), (+)-sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (242 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the Et2O was carefully removed under reduced pressure and replaced with anhydrous CHCl3 (4.0 mL) before sealing the Schlenk-tube and heating at 65 °C (oil bath) for 2 hr. The flask was allowed to cool to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction S26 mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (101 mg, 62%) as a gummy white solid.
Entry 11: 3-(4-Methoxyphenyl)propyl diisopropylcarbamate (167 mg, 0.57 mmol, 1.05 eq.), (+)-sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to -78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (R)-2 (242 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A freshly prepared 1 M solution of MgBr2 in Et2O (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. At this stage 11 B NMR showed no ate-complex and TLC showed no formation of single or doubly homologated products. min and leaving to react for 2 hr at this temperature. (R)-2 (200 mg, 0.55 mmol, 1.00 eq.) was dissolved in anhydrous Et2O (0.55 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. MeOH (0.1 mL) was added dropwise before allowing the flask to warm to ambient temperature. THF (3.40 mL) and one crystal of BHT were added, before cooling to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (107 mg, 66%) as a gummy white solid. leaving to react for 2 hr at this temperature. (R)-2 (200 mg, 0.55 mmol, 1.00 eq.) was dissolved in anhydrous Et2O (0.55 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. Anhydrous methanol (0.1 mL) was added dropwise and the reaction was left for a further 2 min. After warming to ambient temperature the Schlenk-tube was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (3.40 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (S,S)-3 (102 mg, 63%) as a gummy white solid and 3b (5 mg, 2%) as a colorless oil.
3-(4-Methoxyphenyl)propyl diisopropylcarbamate (167 mg, 0.57 mmol, 1.05 eq.), ()sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flamedried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 2 hr at this temperature. (S)-2 (242 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the Schlenk-tube was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 75:25 petroleum ether 40/60:EtOAc) to yield (R,R)-3 (105 mg, 65%) as a gummy white solid.
This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was analysed by 13 C NMR and found to contain a 81:19 ratio of A:B.

Experiment B:
sec-BuLi (0.27 mL, 1.30 M, 0.35 mmol, 1.00 eq.) was added dropwise to a solution of 1a (108 mg, 0.37 mmol, 1.05 eq.) and (+)-sparteine (0.08 mL, 0.37 mmol, 1.05 eq.) in anhydrous Et2O (1.84 mL) at 78 °C (dry ice/acetone). After 2 h, a 1:1 mixture of 39 (99 mg, 0.35 mmol, 1.00 eq.) and rac-2 (129 mg, 0.35 mmol, 1.00 eq.) in anhydrous Et2O (0.35 mL) was quickly added and the resulting solution was left to react for a further 1 h. After warming to ambient temperature the solution was heated at 35 °C (oil bath) for 16 h. The flask was allowed to cool to ambient temperature before adding THF (2 mL), and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (2 mL) and 30% aqueous H2O2 (1 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (5 mL) was carefully added and the reaction mixture was extracted with EtOAc (3 × 10 mL).
The combined organic fractions were dried over Na2SO4, filtered and concentrated under S36 reduced pressure. The crude residue was analysed by 13 C NMR and found to contain a 54:46 ratio of A:C.
The collected data was identical to that described above.

S40
Aliquots of the reaction mixtures were oxidised and protected as acetonides 6 for analysis of enantiomeric purity by chiral-GC. The collected data was identical to that described above.  rac-56 was synthesised using the following procedure:
The collected data was identical to that described above.
Aliquots of the reaction mixtures were oxidised and protected as acetonides 6 for analysis of enantiomeric purity by chiral-GC. (1.85 g, 7.30 mmol, 1.05 eq.) were added to a flame-dried Schlenk-tube purged with N2. THF S46 (7.00 mL) was added before sealing the flask and heating at 80 °C (oil bath) for 30 mins. After cooling to ambient temperature 4,4-dimethyl-1-pentene (1.00 mL, 6.96 mmol, 1.00 eq.) was added before re-sealing and heating for 3 hr at 60 °C (oil bath). The solution was then cooled to ambient temperature and concentrated under reduced pressure. The crude residue was directly purified by flash column chromatography (SiO2; 95:5 pentane:Et2O) to yield 57 ( The collected data was identical to that described above. (1.64 g, 6.47 mmol, 1.05 eq.) were added to a flame-dried Schlenk-tube purged with N2. THF (6.16 mL) was added before sealing the flask and heating at 80 °C (oil bath) for 30 mins. After cooling to ambient temperature 43 (2.00 g, 6.16 mmol, 1.00 eq.) was added before re-sealing and heating for 3 hr at 60 °C (oil bath). The solution was then cooled to ambient temperature and concentrated under reduced pressure. The crude residue was directly purified by flash column chromatography (SiO2; 95:5 pentane:Et2O) to yield 58 (

Carbenoid Scope (3R,5R)-2-Methylundecane-3,5-diol (4):
Isobutyl 2,4,6-triisopropylbenzoate (32) (175 mg, 0.57 mmol, 1.05 eq.), ()-sparteine (0.13 mL, 0.57 mmol, 1.05 eq.) and anhydrous Et2O (2.85 mL) were added to a flame-dried Schlenktube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.42 mL, 1.30 M, 0.55 mmol, 1.00 eq.) dropwise over 5 min and leaving to react for 3 hr at this temperature. (S)-2 (240 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. After warming the solution to ambient temperature THF (2.85 mL) and one crystal of BHT was added, and then it cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 90:10 pentane:EtOAc) to yield 4 (86 mg, 78%) as a viscous colorless oil. mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the Schlenk-tube was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL).  before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the Schlenk-tube was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and

TLC:
30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.50 mL, 1.30 M, 0.66 mmol, 1.20 eq.) dropwise over 5 min and leaving to react for 5 hr at this temperature. (S)-2 (242 mg, 0.55 mmol, 1.00 eq.) was dissolved in anhydrous Et2O (0.55 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. After warming to ambient temperature the Schlenk-tube was sealed and heated at 35 °C (oil bath) for 16 hr. The flask was allowed to cool to ambient temperature before adding THF (2.85 mL) and one crystal of BHT, and was then cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL  (S,E)-Pent-3-en-2-yl diisopropylcarbamate (47)   (S)-4-Phenyl-2-(trimethylstannyl)butan-2-yl 2,4,6-triisopropylbenzoate (48) (300 mg, 0.55 mmol, 1.00 eq.) TMEDA (0.09 mL, 0.61 mmol, 1.10 eq.) and anhydrous Et2O (2.76 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding n-BuLi (0.38 mL, 1.60 M, 0.61 mmol, 1.10 eq.) dropwise over 10 min and leaving to react for 2 hr at this temperature. (S)-2 (243 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min S60 before leaving to react for a further 1 hr at the same temperature. After warming the solution to ambient temperature THF (2.85 mL) and one crystal of BHT was added, and then it cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0.61 mL, 0.61 mmol, 1.10 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 80:20 pentane:EtOAc) to yield 10 (150 mg, 94%) as a viscous colorless oil. (S)-1-Phenylethyl diisopropylcarbamate (50) (138 mg, 0.55 mmol, 1.00 eq.) and anhydrous Et2O (2.77 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.48 mL, 1.30 M, 0.62 mmol, 1.12 eq.) dropwise over 5 min and leaving to react for 15 min at this temperature. (S)-2 (243 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature.
A 1 M solution of MgBr2 in MeOH (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc S63 (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2; 80:20 pentane:EtOAc) to yield 11 (101 mg, 73%) as a viscous colorless oil. (S)-1-(4-Fluorophenyl)ethyl diisopropylcarbamate (51) (146 mg, 0.55 mmol, 1.00 eq.) and

TLC
anhydrous Et2O (2.73 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.47 mL, 1.30 M, 0.62 mmol, 1.12 eq.) dropwise over 5 min and leaving to react for 15 min at this temperature. (S)-2 (240 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A 1 M solution of MgBr2 in MeOH (0.82 mL, 0.82 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, S64 followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. 2 M aqueous HCl (10 mL) was carefully added and the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were dried over Na2SO4, filtered and IR (neat) νmax: 3344, 2928, 2857, 1602, 1509, 1416, 11375, 1225, 1159, 1088 and 834 cm 1 [ ] : +16.0 (c = 1.0, CHCl3) S65

tert-Butyl (6S,8R)-6,8-dihydroxy-8-phenylnonanoate (13):
(S)-1-Phenylethyl diisopropylcarbamate (50) (138 mg, 0.55 mmol, 1.00 eq.) and anhydrous Et2O (2.77 mL) were added to a flame-dried Schlenk-tube purged with N2. The solution was cooled to 78 °C (dry ice/acetone) before adding sec-BuLi (0.48 mL, 1.30 M, 0.62 mmol, 1.12 eq.) dropwise over 5 min and leaving to react for 15 min at this temperature. 54 (291 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A 1 M solution of MgBr2 in MeOH (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water). A 2:1 v:v mixture of 3 M aqueous NaOH (4 mL) and 30% aqueous H2O2 (2 mL) was prepared at 0 °C (ice/water) and degassed by gently bubbling N2 through the solution. This aqueous solution was added dropwise to the vigorously stirred reaction mixture, which was subsequently warmed to ambient temperature and allowed to react for 1 hr. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×20 mL). The eq.) dropwise over 5 min and leaving to react for 15 min at this temperature. 55 (258 mg, 0.66 mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A 1 M solution of MgBr2 in MeOH (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water).    mmol, 1.20 eq.) was dissolved in anhydrous Et2O (0.66 mL) and added dropwise to the reaction mixture over 1 min before leaving to react for a further 1 hr at the same temperature. A 1 M solution of MgBr2 in MeOH (0.83 mL, 0.83 mmol, 1.50 eq.) was added dropwise over 2 min and the mixture was allowed to react for a further 2 min before warming to ambient temperature. Water (10 mL) was added and the organic phase was collected, followed by extraction of the aqueous phase (3×15 mL Et2O). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (6 mL) and one crystal of BHT was added, then the mixture was subsequently cooled to 0 °C (ice/water). [ ] :  (c = 1.0, CHCl3)