Antimalarial Chemotherapy: Artemisinin-Derived Dimer Carbonates and

Thiocarbonates

Jennifer R. Mazzonea, Ryan C. Conyersa, Abhai K. Tripathib,c, David J. Sullivanb,c, and Gary H.

Posnera,c,*

a Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street,

Baltimore, Maryland, 21218, United Statesb W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health,

The Johns Hopkins University, Baltimore, Maryland, 21205, United Statesc The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, The Johns Hopkins University,

Baltimore, Maryland 21205, United States

* Corresponding author. ghp@jhu.edu (G.H. Posner)

Supplementary Data

Contents:Chemistry experimental details S-2 Stereoselective synthesis of dimer alcohol 12b S-3Synthesis of dimer carbonates 14 and thiocarbonates 15 S-4

Carbonate 14a S-4Carbonate 14b S-5Carbonate 14c S-6Carbonate 14d S-7Carbonate 14e S-7Carbonate 14f S-8Carbonate 14g S-9Carbonate 14h S-10Carbonate 14i S-10Carbonate 14j S-11Carbonate 14k S-12Carbonate 14l S-13

Thiocarbonate 15a S-13Thiocarbonate 15b S-14Thiocarbonate 15c S-15

S-1

Chemistry experiment details

All dimers were >95% pure based on HPLC data. HPLC data were acquired using

a Varian ProStar 210 two-pump system with a ProStar 325 dual wavelength detector set

at 215 and 254 nm. All reactions were performed under argon in oven-dried or flame-

dried glassware. Dichloromethane and tetrahydrofuran were dispensed from an LC

Technology Solutions SPBT-1 benchtop solvent purification system. All commercially

available reagents were purchased from Sigma Aldrich and used as received. Artemether

was purchased from TCI America, with purity >98.0%. All experiments were monitored

by analytical thin layer chromatography (TLC) performed on Silicycle silica gel 60 Å

glass supported plates with 0.25 mm thickness. All reactions were purified via automated

purification on a Teledyne Isco CombiFlash Rf purification system using Teledyne

RediSep Rf Gold High Performance prepacked silica columns. Yields are not optimized.

Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer. Nuclear

magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 MHz FT-

NMR spectrometer (400 MHz for 1H, 100 MHz for 13C) or a Bruker Avance 300 MHz

FT-NMR spectrometer (300 MHz for 1H, 75 MHz for 13C). The following abbreviations

are used in the experimental section for the description of 1H NMR spectra: singlet (s),

doublet (d), triplet (t), quartet (q), multiplet (m), broad singlet (bs), doublet of doublets

(dd), doublet of triplets (dt), and doublet of quartets (dq). High-resolution mass spectra

from fast atom bombardment (HRMS-FAB) were obtained using a VG70SE double

focusing magnetic sector mass spectrometer (VG Analytical, Manchester, U.K., now

Micromass/Waters) equipped with a Cs+ ion gun (28 kV at 2 μA), an off-axis multiplier,

and a MSS data system (MasCom, Bremen, Germany). The resolution of the instrument

was set at 10,000 (100 ppm peak width). Samples were mixed with m-nitrobenzyl alcohol

matrix deposited on the target of a direct insertion probe for introduction into the source.

For accurate mass measurements, a mass scan range was employed with the matrix

containing 10% polyethylene glycol (PEG) or polyethylene glycol monomethyl ether

(PEGMME) mass calibrant.

S-2

Stereoselective synthesis dimer alcohol 12b:

To a 1-dram vial, equipped with magnetic stir bar and argon gas inlet needle, were

added dimer ketone 10 (40 mg, 0.07 mmol, 1.0 eq) and anhydrous THF (0.5 mL). The

stirring solution was cooled to 0 oC, and (R)-(+)-2-methyl-CBS oxazaborolidine (1.0 M in

THF, 0.01 mL, 1.2 eq) and borane (BH3, 1.0 M in THF, 0.01 mL, 1.2 eq) were added.

The reaction mixture was warmed to rt and quenched with H2O after 1 h. The product

was extracted with EtOAc (3 x 0.5 mL), and the organic layers were dried over Na2SO4,

vacuum filtered, and concentrated under reduced pressure. The residue was purified

directly on the silica gel; gradient elution (0-40% EtOAc in hexanes) afforded the desired

dimer alcohol 12b as a colorless amorphous solid: 35.2 mg, 91% yield.1,2

1H NMR (300 MHz, CDCl3) δ 5.54 (s, 1H), 5.40 (s, 1H), 4.40 (ddd, J = 11.21, 6.13, 1.42

Hz, 1H), 4.24 (dd, J = 6.73, 3.63 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.29 (d, J = 1.64 Hz,

1H), 2.76-2.65 (m, 1H), 2.66-2.55 (m, 1H), 2.38-2.24 (m, 2H), 2.09-1.98 (m, 3H), 1.97-

1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.72-1.65 (m, 2H), 1.65-1.62 (m, 2H), 1.62-1.54 (m,

4H), 1.54-1.42 (m, 2H), 1.42-1.35 (m, 8H), 1.35-1.28 (m, 2H), 1.28-1.19 (m, 4H), 0.97

(d, J = 7.64 Hz, 3H), 0.95 (d, J = 6.19 Hz, 7H), 0.86 (d, J = 7.52 Hz, 4H);

13C NMR (100 MHz, CDCl3) δ 103.3, 102.4, 90.9, 88.8, 81.3, 81.0, 75.6, 74.4, 71.2, 52.3,

51.8, 44.3, 43.7, 37.3, 37.2, 36.6, 36.5, 34.4, 34.3, 34.2, 30.3, 30.1, 25.9, 24.8, 24.6, 24.1,

20.2, 20.0, 13.2, 13.0;

ESI-HRMS m/z (M + Na)+ for C32H50NaO9 calc. 601.3347, found = 601.3344;

1 For the synthesis of 2C ketone dimer 10 see: Mott, B. T.; Tripathi, A.; Siegler, M. A.; Moore, C. D.; Sullivan, D. J.; Posner, G. H. J. Med. Chem. 2013, 56, 2630.2 For a detailed description of the stereochemical assignment of 12b see: Conyers, R. C.; Mazzone, J. R.; Siegler, M. A.; Tripathi, A. K.; Sullivan, D. J.; Mott, B. T.; Posner, G. H. Bioorg. Med. Chem. Lett. 2014, 24, 1285.

S-3

FT-IR (cm-1) 3477, 2955, 2923, 2872, 2850, 1541, 1455, 1376, 1275, 1112, 1095, 1043,

1010, 946, 881, 849;

[a]D25 = +68.89 (c = 0.115, CHCl3).

General experimental protocol for synthesis of dimer carbonates 14 or

thiocarbonates 15: To a 2-dram vial equipped with magnetic stir bar and argon gas inlet

needle was added 2C-dimer alcohol 12b (0.012 mmol, 1.0 equiv) in dichloromethane

(200 μL). 4-Dimethylaminopyridine (0.012 mmol, 1.0 equiv), pyridine (0.036 mmol, 3.0

equiv), and the commercial chloroformate (0.036 mmol, 3.0 equiv) were added in that

order to the stirring solution. The reaction was stirred at room temperature until evidence

for product formation was observed by TLC analysis (typically 16-18 h).3,4 The reaction

was quenched with water (ca. 0.5 mL) and extracted with dichloromethane (3 x 1 mL).

The organic layers were pooled, dried with Na2SO4, vacuum filtered, and concentrated

under rotary evaporation. The crude residue was purified directly on silica (CombiFlash

Rf Isco) using a gradient mobile phase (0-30% EtOAc in hexanes), which afforded the

desired carbonate as a colorless, amorphous solid.

Carbonate 14a: 7.2 mg, 94% yield;

1H NMR (400 MHz, CDCl3) δ 5.44 (s, 1H), 5.42 (s, 1H), 5.13 (ddd, J = 7.8, 5.3, 2.6 Hz,

1H), 4.73 (qd, J = 15.5, 2.5 Hz, 2H), 4.63 (dd, J = 7.1, 2.6 Hz, 1H), 4.33 (dq, J = 10.4,

3 After 18 h, if a mixture of both 2C dimer alcohol 12b and desired carbonate were observed by TLC analysis, 4-dimethylaminopyridine (1 equiv), pyridine (3 equiv), and chloroformate (3 equiv) were added.4 In a few cases the reaction was sluggish, resulting in a mixture of 2C dimer alcohol 12b starting material and the desired carbonate after prolonged reaction times of 48h; thus the reaction was quenched and 12b was recovered.

S-4

5.4, 4.9 Hz, 1H), 2.74-2.56 (m, 2H), 2.46 (t, J = 2.4 Hz, 1H), 2.30 (tdd, J = 13.6, 7.9, 3.8

Hz, 2H), 2.08-1.82 (m, 5H), 1.82-1.54 (m, 6H), 1.52-1.17 (m, including singlets at 1.42

and 1.38 ppm, 15H), 0.98-0.94 (m, 10H), 0.94-0.87 (m, 1H) 0.86 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 154.2, 103.2, 102.3, 91.0, 88.9, 81.1, 80.9, 75.1, 72.1,

69.7, 55.1, 52.5, 51.6, 44.5, 43.7, 37.4, 37.3, 36.6, 34.6, 34.2, 31.9, 31.2, 30.4, 30.1, 26.1,

25.9, 24.9, 24.6, 24.4, 22.7, 22.7, 20.2, 19.9, 14.1, 13.2, 12.7;

FAB-HRMS m/z (M + H)+ for C36H53O11 calc. = 661.3588, found = 661.3582;

FT-IR (cm-1) 3356, 2958-2849, 2364, 1746, 1658, 1460, 1376, 1259, 1098, 1056, 1011,

942, 909, 881;

[a]D25 = +23.94 (c = 0.19, CHCl3).

Carbonate 14b: 3.7 mg, 47% yield;

1H NMR (400 MHz, CDCl3) δ 5.93 (ddt, J = 16.4, 10.8, 5.6 Hz, 1H), 5.45 (s, 1H), 5.43 (s,

1H), 5.33 (dq, J = 17.3, 1.5 Hz, 1H), 5.25-5.17 (m, 1H), 5.12 (td, J = 6.8, 2.4 Hz, 1H),

4.72-4.56 (m, 3H), 4.34 (q, J = 7.0 Hz, 1H), 2.72-2.57 (m, 2H), 2.38-2.20 (m, 2H), 2.06-

1.86 (m, 5H), 1.80-1.56 (m, 6H), 1.52-1.19 (m, including singlets at 1.42 and 1.38 ppm,

15H), 0.96-0.94 (m, 10H), 0.94-0.87 (m, 1H), 0.86 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 154.6, 132.1, 118.0, 117.3, 103.1, 102.3, 91.0, 88.9, 81.2,

81.0, 77.2, 76.0, 71.9, 69.6, 68.1, 52.5, 51.6, 44.5, 43.8, 37.4, 36.7, 34.6, 31.3, 30.4, 30.1,

29.7, 26.1, 25.9, 24.9, 24.7, 24.4, 20.5, 19.9, 13.1, 12.8;

FAB-HRMS m/z (M + H)+ for C36H55O11 calc. = 663.3744, found = 663.3702;

FT-IR (cm-1) 2959 – 2852, 1742, 1461, 1376, 1259, 1013, 945;

S-5

[a]D25 = +8.8 (c = 0.16, CHCl3).

Carbonate 14c: 7.3 mg, 79% yield;

1H NMR (400 MHz, CDCl3) δ 5.45 (s, 1H), 5.41 (s, 1H), 5.14-5.10 (m, 1H), 4.68-4.62

(m, 2H), 4.56-4.53 (m, 1H), 4.33-4.40 (m, 1H), 4.38-4.32 (m, 2H), 2.72-2.67 (m, 1H),

2.62-2.56 (m, 1H), 2.35-2.31 (m, 2H), 2.04-1.93 (m, 4H), 1.91-1.84 (m, 1H), 1.80-1.71

(m, 3H), 1.70-1.60 (m, 3H), 1.59-1.55 (m, 2H), 1.48-1.21 (m, including singlets at 1.41

and 1.38 ppm, 13H), 0.96-0.93 (m, 10H), 0.91-0.89 (m, 1H), 0.87 (d, J = 7.2 Hz, 3H);

13C NMR (101 MHz, CDCl3) δ 154.6, 103.2, 102.3, 91.0, 88.3, 82.0, 81.1, 81.0, 80.3,

76.6, 72.3, 69.9, 66.5, 66.3, 52.5, 51.6, 44.5, 43.7, 37.4, 37.3, 36.7, 34.5, 34.2, 31.2, 30.4,

30.1, 29.7, 26.1, 25.9, 24.9, 24.6, 24.5, 20.2, 20.0, 14.1, 13.2, 12.6;

FAB-HRMS m/z (M + H)+ for C35H54FO11 calc. = 669.3645, found = 669.3652;

FT-IR (cm-1) 2956, 2925, 2852, 2363, 2333, 1744, 1457, 1377, 1265, 1099, 1058, 1012,

945, 880;

[a]D25 +25.48 (c = 0.21, CHCl3).

S-6

Carbonate 14d: 6.5 mg, 81% yield;

1H NMR (400 MHz, CDCl3) δ 5.81 (d, J = 6 Hz, 1H), 5.66 (d, J = 6 Hz, 1H), 5.44, (s,

1H), 5.40 (s, 1H), 5.19-5.15 (m, 1H), 4.66 (dd, J = 7.2, 2.8 Hz, 1H), 4.38-4.32 (m, 1H),

2.72-2.67 (m, 1H), 2.63-2.57 (m, 1H), 2.35-2.65 (m, 2H), 2.03-1.97 (m, 3 H), 1.95-1.86

(m, 2 H), 1.80-1.71 (m, 2H), 1.70-1.62 (m, 2H), 1.61-1.55 (m, 3H), 1.52-1.19 (m,

including singlets at 1.41 and 1.38 ppm, 14H), 0.96-0.94 (m, 10H), 0.92-0.88 (m, 1H),

0.87 (d, J = 7.6 Hz, 3H);

13C NMR (101 MHz, CDCl3) δ 153.0, 103.2, 102.3, 91.0, 88.9, 81.1, 80.9, 77.7, 72.2,

72.1, 69.7, 52.5, 51.5, 44.4, 43.7, 37.4, 37.3, 36.6, 34.5, 34.2, 31.2, 30.4, 30.1, 29.7, 26.0,

25.9, 24.9, 24.6, 24.4, 20.2, 19.9, 14.1, 13.1, 12.6;

FAB-HRMS m/z (M + H)+ for C34H52ClO11 calc. = 671.3193, found = 671.3209;

FT-IR (cm-1) 2923, 2851, 2597, 2363, 2332, 1759, 1459, 1378, 1342, 1252, 1149, 1118,

1090, 1003, 948, 906, 879, 843;

[a]D25 +25.48 (c = 0.21, CHCl3).

Carbonate 14e: 8.0 mg, 84% yield;

1H NMR (400 MHz, CDCl3) δ 5.44 (s, 1H), 5.40 (s, 1H), 5.13-5.09 (m, 1H), 4.62 (dd, J =

7.2, 3.2 Hz, 1H), 4.40-4.31 (m, 3H), 3.68 (t, J = 6 Hz, 2H), 2.71-2.66 (m, 1H), 2.61-2.55

S-7

(m, 1H), 2.34-2.29 (m, 2H), 2.02-1.85 (m, 6H), 1.79-1.69 (m, 3H), 1.67-1.56 (m, 3H),

1.51-1.19 (m, including singlets at 1.40 and 1.38 ppm, 14H), 0.96-0.92 (m, 10H), 0.91-

0.88 (m, 1H), 0.86 (d, J = 7.6 Hz, 3H);

13C NMR (101 MHz, CDCl3) δ 154.4, 103.2, 102.3, 91.0, 88.9, 81.1, 81.0, 76.7, 72.4,

70.0, 66.8, 52.5, 51.6, 44.5, 43.7, 41.2, 37.4, 37.3, 36.7, 34.7, 34.5, 34.2, 31.3, 30.4, 30.1,

26.1, 25.9, 24.9, 24.7, 24.5, 20.2, 20.0, 13.2, 12.6;

FAB-HRMS m/z (M + H)+ for C35H54ClO11 calc. = 685.3349, found = 685.3343;

FT-IR (cm-1) 2958, 2925, 2851, 2364, 2334, 1756, 1679, 1459, 1378, 1276, 1253, 1098,

1057, 1012, 944, 881;

[a]D25 +25.48 (c = 0.21, CHCl3).

Carbonate 14f: 4.0 mg, 48% yield;

1H NMR (300 MHz, CDCl3) δ 7.42 – 7.27 (m, 5H), 5.45 (s, 1H), 5.44 (s, 1H), 5.22-5.12

(m, including ABq, 3H), 4.62 (dd, J = 6.8, 2.4 Hz, 1H), 4.36-4.30 (m, 1H), 2.73-2.56 (m,

2H), 2.38 – 2.23 (m, 3H), 2.06 – 1.95 (m, 5H), 1.80 – 1.56 (m, 5H), 1.47-1.18 (m,

including singlets at 1.41 and 1.37 ppm, 15H), 0.96-0.88 (m, 11H) 0.86 (d, J = 7.2 Hz,

3H);

13C NMR (100 MHz, CDCl3) δ 155.1, 103.3, 102.5, 91.0, 88.9, 81.3, 81.0, 75.8, 74.5,

71.3, 69.7, 52.4, 51.9, 44.4, 43.8, 37.4, 36.7, 36.5, 34.5, 34.4, 34.3, 30.4, 30.2, 29.7, 26.1,

26.0, 24.9, 24.7, 24.1, 20.2, 20.1, 13.2, 13.1;

FAB-HRMS m/z (M + H)+ for C40H57O11 calc. = 713.3901, found = 713.3886;

S-8

FT-IR (cm-1) 2958-2850, 1746, 1458, 1374, 1263, 1096, 1011, 947, 910, 881;

[a]D25 = +39.0 (c = 0.10, CHCl3).

Carbonate 14g: 4.3 mg, 59% yield;

1H NMR (400 MHz, CDCl3) δ 8.24 – 8.16 (m, 2H), 7.60 – 7.50 (m, 2H), 5.43 (s, 1H),

5.39 (s, 1H), 5.34-5.21 (ABq, 2H), 5.13 (td, J = 6.2, 3.9 Hz, 1H), 4.65 (dd, J = 6.7, 3.9

Hz, 1H), 4.38 (ddd, J = 11.5, 6.2, 2.9 Hz, 1H), 2.71-2.53 (m, 2H), 2.30 (ddt, J = 14.4,

13.1, 4.5 Hz, 2H), 2.08-1.84 (m, 6H), 1.79-1.71 (m, 3H), 1.65 – 1.54 (m, 2H), 1.49 – 1.19

(m, including singlets at 1.38 and 1.37 ppm, 15H), 0.96-0.91 (m, 11H), 0.86 (d, J = 7.6

Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 154.6, 128.5, 128.0, 123.9, 123.6, 103.1, 102.5, 91.0,

89.0, 81.0, 81.0, 75.7, 72.4, 70.2, 68.4, 52.5, 51.9, 44.4, 44.4, 43.8, 37.3, 36.7, 36.6, 34.5,

34.4, 30.3, 30.2, 29.7, 26.0, 25.8, 24.9, 24.7, 24.1, 20.2, 19.9, 13.2, 13.1;

FAB-HRMS m/z (M + H)+ for C40H56NO13 calc. = 758.3752, found = 758.3732;

FT-IR (cm-1) 2958-2851, 1748, 1606, 1525, 1460, 1379, 1347, 1265, 1104, 1058, 1011,

945, 851;

[a]D25 = +33.51 (c = 0.36, CHCl3).

S-9

Carbonate 14h: 6.4 mg, 66% yield;

1H NMR (400 MHz, CDCl3) δ 7.38 – 7.32 (m, 2H), 7.25 – 7.15 (m, 3H), 5.46 (d, J = 11.3

Hz, 1H), 5.41 (s, 1H), 5.19 (td, J = 6.3, 5.5, 3.3 Hz, 1H), 4.69 (dd, J = 7.0, 3.3 Hz, 1H),

4.40 (ddd, J = 11.6, 6.2, 2.7 Hz, 1H), 2.75-2.60 (m, 2H), 2.31 (td, J = 13.8, 3.8 Hz, 2H),

2.08 – 1.91 (m, 5H), 1.91 – 1.53 (m, 6H), 1.51 – 1.16 (m, including singlets at 1.40 and

1.39 ppm, 15H), 0.98-0.93 (m, 11H), 0.88 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 153.2, 151.4, 129.2, 125.6, 121.3, 103.2, 102.4, 91.0,

88.9, 81.1, 81.0, 72.3, 70.0, 52.5, 51.6, 44.5, 43.8, 37.5, 37.3, 36.7, 34.5, 34.3, 31.1, 30.4,

30.1, 26.1, 25.9, 24.9, 24.6, 24.5, 20.2, 20.0, 13.2, 12.7;

FAB-HRMS m/z (M + H)+ for C39H55O11 calc. = 699.3744, found = 699.3733;

FT-IR (cm-1) 2953-2850, 1759, 1593, 1492, 1457, 1378, 1258, 1211, 1098, 1051, 1011,

945, 881, 824;

[a]D25 = +25.43 (c = 0.32, CHCl3).

Carbonate 14i: 8.2 mg, 98% yield;

1H NMR (400 MHz, CDCl3) δ 7.17-7.06 (m, 4H), 5.47 (s, 1H), 5.41 (s, 1H), 5.18 (ddd, J

= 8.1, 5.3, 2.9 Hz, 1H), 4.69 (dd, J = 7.0, 3.1 Hz, 1H), 4.39 (ddd, J = 11.7, 6.3, 2.7 Hz,

1H), 2.68 (dp, J = 35.6, 7.4 Hz, 2H), 2.38 – 2.24 (m, including singlet at 2.33 ppm, 5H),

S-10

2.17 – 1.91 (m, 5H), 1.91 – 1.53 (m, 6H), 1.52 – 1.16 (m, including singlets at 1.40 and

1.39 ppm, 15H), 1.01 (d, J = 7.6 Hz, 3H), 0.97-0.92 (m, 8H), 0.88 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 153.3, 149.2, 135.2, 129.6, 121.1, 103.2, 102.3, 90.9,

88.8, 81.0, 80.9, 72.3, 69.9, 52.5, 51.5, 44.5, 43.8, 37.4, 37.2, 36.7, 34.5, 34.2, 31.0, 30.1,

26.1, 25.9, 24.9, 24.9, 24.6, 24.5, 20.8, 20.2, 20.0, 13.2, 12.7;

FAB-HRMS m/z (M + H)+ for C40H57O11 calc. = 713.3901, found = 713.3899;

FT-IR (cm-1) 2958 – 2851, 1759, 1509, 1459, 1377, 1258, 1204, 1099, 1012, 946, 881,

823;

[a]D25 = +41.27 (c = 0.28, CHCl3).

Carbonate 14j: 8.5 mg, 85% yield;

1H NMR (400 MHz, CDCl3) δ 7.26 – 7.15 (m, 2H), 7.07 – 6.96 (m, 2H), 5.46 (s, 1H),

5.40 (s, 1H), 5.16 (td, J = 6.1, 3.7 Hz, 1H), 4.68 (dd, J = 6.8, 3.9 Hz, 1H), 4.41 (ddd, J =

11.6, 6.2, 2.5 Hz, 1H), 2.71 (h, J = 7.2 Hz, 1H), 2.76-2.56 (m, 2H), 2.35-2.26 (m, 2H),

2.14 – 1.85 (m, 6H), 1.80-1.54 (m, 6H), 1.46-1.22 (m, including singlets at 1.40 and 1.38

ppm, 15H), 0.99 (d, J = 7.6 Hz, 3H), 0.97-0.93 (m, 8H), 0.88 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 161.3, 158.9, 153.2, 147.4, 122.9, 122.8, 115.8, 115.6,

103.2, 102.3, 91.0, 89.0, 81.1, 80.9, 77.7, 72.6, 72.6, 70.3, 52.5, 51.6, 44.4, 43.7, 37.5,

37.3, 36.7, 34.5, 34.2, 31.1, 30.3, 30.2, 29.7, 26.0, 25.8, 24.9, 24.9, 24.7, 24.6, 20.2, 20.0,

13.2, 12.5;

FAB-HRMS m/z (M + H)+ for C39H54FO11 calc. = 717.3650, found = 717.3662;

S-11

FT-IR (cm-1) 2956-2849, 1761, 1505, 1458, 1377, 1259, 1197, 1149, 1098, 1051, 1012,

946, 881, 844;

[a]D25 = +24.98 (c = 0.43, CHCl3).

Carbonate 14k: 7.3 mg, 85% yield;

1H NMR (400 MHz, CDCl3) δ 7.42 (m, 1H), 7.31-7.26 (m, 2H), 7.18 (m, 1H), 5.49 (s,

1H), 5.44 (s, 1H), 5.22 (ddd, J = 7.8, 5.0, 2.5 Hz, 1H), 4.71 (dd, J = 7.1, 2.5 Hz, 1H), 4.36

(ddd, J = 10.5, 6.2, 3.6 Hz, 1H), 2.68 (dp, J = 34.9, 7.6, 7.2 Hz, 2H), 2.35-2.27 (m, 2H),

2.14-1.94 (m, 5H), 1.89-1.56 (m, 6H), 1.50-1.18 (m, including singlets at 1.40 and 1.39

ppm, 15H), 1.05 (d, J = 7.6 Hz, 3H) 0.97-0.93 (m, 8H), 0.89 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ151.6, 130.3, 127.6, 127.0, 124.8, 123.8, 103.2, 102.4,

91.0, 90.4, 88.9, 81.1, 81.0, 77.6, 72.1, 69.5, 68.5, 53.4, 52.6, 51.6, 44.5, 43.8, 37.5, 37.2,

36.7, 34.2, 31.1, 30.4, 30.0, 29.7, 26.1, 25.9, 25.0, 24.6, 24.5, 20.2, 20.0, 13.2, 12.9;

FAB-HRMS m/z (M + H)+ for C39H54ClO11 calc. = 733.3555, found = 753.3348;

FT-IR (cm-1) 2954-2852, 1765, 1455, 1377, 1253, 1222, 1098, 1059, 1012, 946;

[a]D25 = +26.48 (c = 0.19, CHCl3).

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Carbonate 14l: 8.3 mg, 96% yield;

1H NMR (400 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 7.22 – 7.16 (m, 2H), 5.45 (s, 1H),

5.39 (s, 1H), 5.16 (td, J = 6.1, 3.8 Hz, 1H), 4.68 (dd, J = 6.8, 4.0 Hz, 1H), 4.40 (ddd, J =

11.6, 6.2, 2.5 Hz, 1H), 2.76-2.56 (m, 2H), 2.37 – 2.17 (m, 2H), 2.16 – 1.86 (m, 6H), 1.80-

1.72 (m, 2H), 1.69-1.56 (m, 4H), 1.56 – 1.20 (m, including singlets at 1.39 and 1.37 ppm,

15H), 1.00-0.93 (m, 10H), 0.88 (d, J = 7.6 Hz, 3H);

13C NMR (100 MHz, CDCl3) δ 152.9, 150.0, 129.2, 122.8, 106.0, 103.2, 102.3, 91.0,

88.9, 81.1, 80.9, 77.8, 72.7, 70.3, 52.5, 51.6, 44.4, 43.6, 37.5, 37.3, 36.7, 34.5, 34.2, 31.0,

30.3, 30.2, 26.1, 25.8, 24.9, 24.9, 24.6, 20.2, 20.0, 13.2, 12.5;

FAB-HRMS m/z (M + H)+ for C39H54ClO11 calc. = 733.3355, found = 733.3341;

FT-IR (cm-1) 2960 – 2849, 1760, 1667, 1489, 1457, 1376, 1257, 1218, 1093, 1052, 1012,

945, 911, 823;

[a]D25 = +31.44 (c = 0.3, CHCl3).

Thiocarbonate 15a: 7.1 mg, 74% yield;

1H NMR (400 MHz, CDCl3) δ 5.45 (s, 1H), 5.42 (s, 1H), 5.38-5.35 (m, 1H), 4.64 (dd, J =

7.2, 2 Hz, 1H), 4.36-4.32 (m, 1H), 2.91-2.84 (m, 2H), 2.69-2.60 (m, 2H), 2.34-2.26 (m,

2H), 2.04-1.86 (m, 6H), 1.79-1.71 (m, 2H), 1.69-1.62 (m, 3H), 1.52-1.21 (m, including

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singlets at 1.42 and 1.39 ppm, 18H), 0.96-0.93 (m, 10H), 0.92-0.89 (m, 1H), 0.87 (d, J =

7.6 Hz, 3H);

13C NMR (101 MHz, CDCl3) δ 170.6, 103.1, 102.4, 91.0, 89.1, 81.0, 74.9, 71.2, 69.5,

52.5, 51.6, 44.4, 43.9, 37.42, 37.36, 36.69, 36.66, 34.6, 34.3, 31.5, 30.3, 30.1, 29.7, 26.1,

25.9, 25.4, 24.9, 24.7, 24.3, 22.7, 20.2, 20.0, 15.1, 14.1, 13.0;

FAB-HRMS m/z (M + H)+ for C35H54O10S calc. = 667.3510, found = 667.3501;

FT-IR (cm-1) 2963, 2925, 2850, 2361, 1706, 1460, 1377, 1258, 1163, 1099, 1057, 1012,

942, 881;

[a]D25 +25.48 (c = 0.21, CHCl3).

Thiocarbonate 15b: 7.0 mg, 71% yield;

1H NMR (400 MHz, CDCl3) δ 5.44 (s, 1H), 5.43 (s, 1H), 5.36-5.33 (m, 1H), 4.63 (d, J =

7.2 Hz, 1 H), 4.39-4.34 (m, 1 H), 2.64-2.60 (m, 2 H), 2.33-2.26 (m, 2H), 2.03-1.98 (m,

3H), 1.95-1.85 (m, 3 H), 1.79-1.56 (m, 7 H), 1.47-1.21 (m, including singlets at 1.47,

1.41, and 1.38 ppm, 22 H), 0.97-0.93 (m, 10 H), 0.91-0.88 (m, 1 H), 0.86 (d, J = 7.6 Hz,

3 H);

13C NMR (101 MHz, CDCl3) δ 169.5, 103.0, 102.4, 91.0, 89.3, 81.0, 80.9, 73.8, 70.8,

69.5, 52.5, 51.6, 47.1, 44.4, 43.9, 37.4, 36.72, 36.67, 34.6, 34.3, 31.8, 30.4, 30.2, 30.1,

26.1, 25.9, 24.9, 24.7, 24.3, 20.2, 20.0, 12.94, 12.90;

FAB-HRMS m/z (M + H)+ for C37H58O10S calc. = 695.3823, found = 695.3813;

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FT-IR (cm-1) 2965, 2925, 2850, 2363, 1705, 1460, 1374, 1258, 1225, 1145, 1100, 1056,

1013, 942, 880;

[a]D25 +25.48 (c = 0.21, CHCl3).

Thiocarbonate 15c: 7.9 mg, 80% yield;

1H NMR (400 MHz, CDCl3) δ 7.57-7.54 (m, 2 H), 7.37-7.36 (m, 3 H), 5.43 (s, 1 H), 5.37-

5.34 (m, 2 H), 4.65 (dd, J = 7.2, 2.4 Hz, 1 H), 4.39-4.34 (m, 1 H), 2.68-2.58 (m, 2 H),

2.30 (td, J = 3.6, 13.6 Hz, 2 H), 2.04-1.93 (m, 4 H), 1.90-1.84 (m, 1 H), 1.79-1.58 (m, 6

H), 1.51-1.19 (m, including singlet at 1.39 ppm, 15 H), 0.97-0.93 (m, 10 H), 0.88-0.83

(m, 4 H);

13C NMR (101 MHz, CDCl3) δ 168.9, 134.8, 129.2, 128.9, 128.4, 103.1, 102.4, 90.9,

89.1, 81.0, 80.9, 76.1, 71.3, 69.6, 52.4, 51.6, 44.4, 43.8, 37.4, 37.3, 36.69, 36.66, 34.5,

34.3, 31.5, 30.3, 30.1, 29.7, 26.0, 25.9, 25.0, 24.9, 24.7, 24.3, 20.2, 20.0, 13.0, 12.8;

FAB-HRMS m/z (M + H)+ for C39H54O10S calc. = 715.3510, found = 715.3515;

FT-IR (cm-1) 2961, 2926, 2852, 2362, 2332, 1728, 1461, 1377, 1257, 1157, 1096, 1057,

1013, 942;

[a]D25 +25.48 (c = 0.21, CHCl3).

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