1. Methyl malonic acid (96%) was purchased from Acros and used as received.
2. Diethyl ether was purchased from Pharmaco-AAper (Reagent Grade ACS Anhydrous) and used without purification.
3. DMAP (4-(Dimethylamino)pyridine, ReagentPlus®, ≥99%) was purchased from Aldrich and used as received.
4. tert-Butyl alcohol (99.5%, extra pure) was purchased from Acros and used as received.
5. Di-tert-butyl dicarbonate (97%) was purchased from Acros and used as received.
6. Silica gel was purchased from Silicylce, Inc. (SiliaFlash P60 (230-400 mesh)) and used as received.
7. Physical characteristics of di-tert-butyl-2-methylmalonate (2): colorless liquid with >99% purity as determined by quantitative 1H NMR using dimethyl fumarate as the internal standard; 1H NMR pdf(500 MHz, CDCl3) δ: 1.32 (d, J = 7.4 Hz, 3H), 1.46 (s, 18H), 3.24 (q, J = 7.5 Hz, 1H); 13C NMR pdf(126 MHz, CDCl3) δ: 13.4, 27.9, 48.1, 81.1, 169.6; IR (neat) cm-1 2978, 1725, 1136, 848; HRMS (C12H22O4, ESI): calculated 253.1415 [M+Na]+1, found 253.1423;
8. A second run produced 21.3 g of the product 2 as colorless oil, 95% yield, >99% purity.
9. THF (tetrahydrofuran, minimum 99%, inhibited with <0.025% butlylated hydroxytoluene) was purchased from Acros and distilled under Ar over benzophenone and sodium.
10. Sodium hydride (60% dispersion in mineral oil in soluble bags, in resealable cans) was purchased from Acros and used as received.
11. 2-Bromoethyl acetate (97%) was purchased from Acros and used without further purification.
12. TLC analysis was performed on silica gel with 10:1 hexanes-EtOAc as eluent and visualization with p-anisaldehyde. The starting material has Rf = 0.38 (blue) and the product has Rf = 0.22 (blue). TLC plates were purchased from Silicycle, Inc. (Glass Backed TLC Extra Hard Layer, 60Å).
13. Anhydrous methanol (anhydrous, 99.8%, AcroSeal (TM)) was purchased from Acros and used received.
14. Saturated NaCl solution/ice bath was used by the submitting authors. The checkers observed that temperature is difficult to be kept under -5 °C using this cooling bath at this scale after addition of base K2CO3.
15. Anhydrous potassium carbonate (Certified ACS Granular Powder) was purchased from Fisher and used as received.
16. NMR spectra and purity of the first batch and second batch of di-tert-butyl 2-(2-hydroxyethyl)-2-methylmalonate (3a) are the same: white crystalline solid with 98% purity as determined by quantitative 1H NMR using dimethyl fumarate as an internal standard; mp = 38-39 °C; 1H NMR pdf(500 MHz CDCl3) δ: 1.40 (s, 3H), 1.48 (s, 18H), 2.09 (t, J = 6.3 Hz, 2H), 2.13 (br s, 1H), 3.75 (t, J = 6.3 Hz, 2H); 13C NMR pdf(126 MHz, CDCl3) δ: 20.2, 27.8, 38.2, 53.7, 59.0, 81.5, 172.0; IR (neat) cm-1 3446, 2977, 1710, 1367, 1154, 1112, 1019, 844 ; HRMS (C14H26O5, ESI): calculated 297.1672 [M+Na]+1, found 297.1665;
17. A second run produced 12.4 g of product 3a, 69% yield, 98% purity.
18. Toluene was purchased from Innovative Technology and passed through a Pure Solv MD 5 Solvent Purification System. The checkers used toluene purchased from Aldrich and distilled over CaH2.
19. (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-1,1'-binapthyl-2,2'-diyl hydrogen phosphate (4) was purchased from Corvinus Chemicals (currently Ark Chemicals) and used as received.
20. TLC analysis was performed on silica gel with 30% EtOAc-hexanes as eluent and visualization with p-anisaldehyde. The starting material has Rf = 0.37 (blue) and the product has Rf = 0.58 (blue). TLC plates were purchased from Silicycle, Inc. (Glass Backed TLC Extra Hard Layer, 60Å).
21. Column diameter: 3.8 cm, silica: 84.0 g (Silicycle Inc., silica 60 (230-400 mesh), eluant: 500 mL 4:1 EtOAc:hexane), fraction size: 20 mL (16 x 150 mm test tubes), product typically found in factions 6-20.
22. Physical characteristics of (S)-tert-butyl 3-methyl-2-oxotetrahydrofuran-3-carboxylate (5a): white solid with 99% purity, as determined by quantitative 1H NMR using dimethyl fumarate as an internal standard; mp = 49-50 °C; [α]D24.5 = +7.08° (c = 1.08, CHCl3); 1H NMR pdf(400 MHz, CDCl3) δ: 1.49 (s, 12 H), 2.18 (m, 1H), 2.71 (m, 1H), 4.35 (m, 2H); 13C NMR pdf(100 MHz, CDCl3) : 20.1, 27.8, 35.1, 50.5, 65.8, 82.8, 169.4, 176.3; IR (neat) cm-1 2980, 1763, 1730, 1426, 1370, 1227, 1132, 1025, 845; HRMS (C10H20NO4, ESI): calculated 218.13868 [M+NH4]+1, found 218.1385;
23. Enantiomeric purity was assessed at 98% ee by chiral HPLC: Chiralcel OJ-3, 4.6 x 150 mm, 3 micro; isocratic: 1% of IPA in heptane; eluent Rate: 1.3 mL/ min; Temperature 5 °C; UV detector 220 nm; RTmajor = 10.2 min, RTminor = 11.2 min.
24. A second run produced 5.97 g of product 5a, 96% yield, 99% purity, 98% ee.