Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles

The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C2-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.


Supplementary Information
General procedure 1b: Asymmetric allylic alkylation products S5 General procedure 1c: Asymmetric allylic alkylation products with quaternary dicenters S6 General procedure 2: Phosphate reduction and esterification for HPLC dianalysis S7 General procedure 3: Oxidation of diones S8 General procedure 4: Luche reduction of dienones S8 General procedure 5: Phosphorylation of diols via anion approach S9 Experimental Procedures and Characterisation of Compounds S10 Starting Materials S10

General procedure 3: Oxidation of diones
Under Ar dione (15 mmol, 1.0 eq) was dissolved in anhydrous MeOH (100 mL) before addition of CuBr2 (7.37 g, 33.0 mmol, 2.2 eq). The mixture was heated to reflux and stirred for 1 hour. The resulting black mixture was cooled, quenched with dropwise addition of H2O (25 ml) and 1M HCl (50 mL). The mixture was concentrated in vacuo to remove MeOH. The resulting mixture was extracted with EtOAc (3 x 75 mL) and the organic extracts were combined, washed with brine (2 x 50 mL), dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica (eluent specified below) to give the dienone product. NOTE: All examples presented give bright yellow products.

General procedure 5: Phosphorylation of diols via a dianion approach
A solution of diol (10.0 mmol, 1.0 eq.) in THF (60 mL) and TMEDA (15 mL) was cooled to -40 ˚C using a MeCN/CO2 bath before nBuLi (2.5 M in hexane, 8.80 mL, 22.0 mmol, 2.2 eq.) was added dropwise. The resulting solution was left to stir for 10 minutes at -40 ˚C before dialkyl chlorophosphate (25.0 mmol, 2.5 eq.) was added dropwise. The resulting mixture was left to stir at -40 ˚C for 2 hours and then warmed to 0 °C. Brine (10 mL) was added slowly to the mixture which was then poured over H2O (80 mL) and extracted with CH2Cl2 (3 x 80 mL). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo. The crude material was purified on silica (eluent specified below) to give the diphosphate product.

Cis-4-cyclopentene-1,3-diol
Cyclopentadiene (2.00 mL, 24.3 mmol, 1.0 eq.), thiourea (1.84g, 24.3 mmol, 1.0 eq.) and Rose Bengal (50 mg, 0.048 mmol, 0.002 eq.) were added to a round-bottomed flask containing methanol (400 mL). O2 gas was bubbled through the resulting pink solution for 15 mins before being maintained under an atmosphere of O2. The flask was partially submersed in an ice bath and irradiated with a 500 W halogen lamp with stirring for 8 hours (Supplementary Figure 1). The lamp was turned off and the mixture was left to stir in the dark at room temperature for 16 hours. The mixture was evaporated in vacuo to give a viscous pink residue. The residue was dissolved in water (250 mL) and extracted with Et2O (3 x 200 mL). The aqueous layer was evaporated in vacuo to give a pink residue, which was dissolved in methanol (50 mL) and loaded onto Chem Tube-Hydromatrix for purification on silica (1% MeOH in EtOAc) to give cis-4-cyclopentene-1,3-diol as a white solid (1.72 g, 71% yield). 1 H NMR (400 MHz, DMSO-d6) δH/ppm: 5.75 (s, 2H), 4.84 (dd, 2H, J = 7.8, 2.
The diester was dissolved in MeOH (21 mL) before addition of H2O (323 µL, 18.27 mmol, 6.0 eq) and LiOH (437 mg, 18.27 mmol, 6.0 eq). The resulting mixture was left to stir at room temperature for 13 hours. The mixture was evaporated in vacuo and the resulting residue was filtered through a short plug of silica, rinsing with 5% MeOH in CH2Cl2. The filtrate was evaporated in vacuo to give the crude alcohol (290 mg) that was used immediately in the next step.
The mixture was extracted with EtOAc (3 x 50 mL). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4) and evaporated in vacuo to
The product was derivatised according to general procedure 2 for HPLC analysis.
The product was derivatised according to general procedure 2 for HPLC analysis.
SFC was performed on a Waters SFC 15 system equipped with a Waters 2998 PDA (UV) detector and Waters SQD2 mass spectrometer using a Daicel Chiralpak IA column (10 x 250 mm, 5 μm). Mobile phase was 90% CO2 and 10% methanol with 20mM NH3. The flow rate was 10 mL/min, the back pressure was 120 bar, and the column temperature was 40 °C. The PDA detector range was 210 -400 nm.

S89
Mobile phase A was CO2 and mobile phase B was methanol with 20mM NH3. A gradient from 5% to 50% mobile phase B over 3.5 minutes was used, followed by an increase to 60% over 0.05 minutes, a hold at 60% for 0.4 minutes and return to 5%.
The total flow was 2 mL/min, the back pressure was 140 bar, and the column temperature was 40 °C. The PDA detector range was 210 -400 nm.
SFC was performed on a Waters UPC system equipped with a PDA (UV) detector and QDa (MS) detector using a Lux Cellulose 2 column (3.0 x 50 mm, 3 μm). Mobile phase A was CO2 and mobile phase B was IPA with 20mM NH3. A gradient from 5% to 50% mobile phase B over 3.5 minutes was used, followed by an increase to 60% over 0.05 minutes, a hold at 60% for 0.4 minutes and return to 5%. The total flow was 2 mL/min, the back pressure was 140 bar, and the column temperature was 40 °C.
The PDA detector range was 210 -400 nm.
The organic layers were combined, dried (MgSO4) and evaporated in vacuo to give a yellow oil. The yellow oil was purified on silica (30-70% EtOAc in heptane) to give 17 as a yellow oil (107 mg, 75%, 94% ee). Other diastereomer observed in crude NMR at a 4:1 ratio in favour of the isolated product.

S107
SFC was performed on a Waters UPC system equipped with a PDA (UV) detector and QDa (MS) detector using a Daicel Chiralpak IC column (3.0 x 50 mm, 3 μm).
Mobile phase A was CO2 and mobile phase B was methanol with 20mM NH3. A gradient from 5% to 50% mobile phase B over 3.5 minutes was used, followed by an increase to 60% over 0.05 minutes, a hold at 60% for 0.4 minutes and return to 5%.
The total flow was 2 mL/min, the back pressure was 140 bar, and the column temperature was 40 °C. The PDA detector range was 210 -400 nm.