Supporting Information

Enantioselective Total Synthesis of (+)-Wortmannin

Yinliang Guo,†,§ Tianfei Quan,‡,§ Yandong Lu,† Tuoping Luo*,†,‡

†
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and
Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular
Engineering, Peking University, Beijing 100871, China
‡
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies,
Peking University, Beijing 100871, China

§These authors contributed equally.

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Table of Contents
I. Supplementary Figures and Tables………………………………………………..…S3

Figure S1. The Deprioritized Approach for Connecting Hajos-Parrish Ketone Derivative 16
to the Furan Moiety……………………………………………………………………………..S3

Figure S2. Proposed Mechanism for the Pd-catalyzed Cascade Reaction Leading to
Compound (+)-15………………………………………………………………………………..S3

Table S1. Optimization of the Pd-catalyzed Cascade Reaction for Synthesizing Compound
(+)-15……………………………………………………………………………………………..S4

Table S2. Scope of the Pd-catalyzed Cascade Reaction for the Synthesis of Substituted
Furans…………………………………………………..………………………………………..S4

Table S3. Optimization of the Intramolecular Friedel-Crafts Reaction for Synthesizing

Compound (−)-20…………………………………………………………………………….....S5

Scheme S1. Total Synthesis of (+)-Wortmannin (1)…………………….……………………S6

II. Experimental Procedures and Spectroscopic Data …………….…………………...S7

General Information……………………………………………………………..…..…………S7

The Pd-catalyzed Cascade Reaction for Synthesizing Substituted Furans…….…………...S8

Total Synthesis of (+)-Wortmannin……………………………..……………………….……S16

Table S4. Comparison of the 1H NMR for Synthetic 17-β-Hydroxy-wortmannin with

Literature Data………………………….……………………………………………………...S37

Table S5. Comparison of the 1H NMR for Synthetic 11-O-Desacetyl-wortmannin with

Literature Data…………………………..……………………………………….…………….S38

Table S6. Comparison of the 1H and 13

C NMR for Synthetic Wortmannin and Literature
Data……………………………………….…………………………………………...………..S39

III. Evaluation of Wortmannin and Analogs by In Vitro Kinase Assays…….………...S40

Table S7. “Kd (nM)” of Wortmannin and Analogs towards Kinases….................................S40

Table S8. In vitro Kinase Assay Measurements of IC50 (nM) Values for (+)-24 and (−)-25 Using
SelectScreen (Invitrogen)...........................................................................................................S40

Figure S3. KinomeScan Profile of (+)-24 and (−)-25 against 468 Kinases………..……......S41

IV. 1H and 13C NMR Spectra of Compounds………………….......................................S42

V. References………………………………..………...…................................................S83

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I. Supplementary Figures and Tables

Figure S1. The Deprioritized Approach for Connecting Hajos-Parrish Ketone

Derivative 16 to the Furan Moiety

Figure S2. Proposed Mechanism for the Pd-catalyzed Cascade Reaction Leading to
Compound (+)-15
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Table S1. Optimization of the Pd-catalyzed Cascade Reaction for Synthesizing
Compound (+)-15

Table S2. Scope of the Pd-catalyzed Cascade Reaction for the Synthesis of
Substituted Furans

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Table S3. Optimization of the Intramolecular Friedel-Crafts Reaction for
Synthesizing Compound (−)-20

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Scheme S1. Total Synthesis of (+)-Wortmannin (1)a

aReagents and conditions: (a) 14 (1.05 equiv), Pd2(dba)3 (0.02 equiv), dppf (0.08 equiv), DIPEA (2.4 equiv), PhCl, 130 °C, 1.5 h; 15, 42%;
16, 33%; (b) TBSCl (1.1 equiv), imidazole (1.3 equiv), DMF, 1.5 h, 0 °C to RT, 85%; (c) NiCl2·6H2O (5.0 equiv), NaBH4 (15.0 equiv),
MeOH, −90 °C to −60 °C; 9, 69%; S19, 17%; (d) PCC (2.4 equiv), NaOAc (6 equiv), DCM, rt, 70%; (e) LHMDS (2.0 equiv), PhNTf2 (1.8
equiv), THF, −78 °C to 0 °C, 98%; (f) 10 (1.3 equiv), Pd2(dba)3 (0.04 equiv), AsPh3 (0.24 equiv), NMP, 70 °C , 6 h, 69%; (g) TBHP (2.0
equiv), (−)-DIPT (0.5 equiv), Ti(OiPr)4 (0.4 equiv), 4Å MS, DCM, −40 °C, 5 h, 68% ; (h) NaH (2.5 equiv), MeI (2.0 equiv), DMF, −10 °C
to rt, 91%; (i) Ph4PBF4 (3 equiv), DCM:HFIP (4:1), −15 °C, 65 h; 19, 11%; (j) TBAF·3H2O, rt, 1 h; 20, 47% (2 steps); (k) TEMPO (0.3
equiv), PhI(OAc)2 (1.5 equiv), DCM, rt, 20 h, 93%; (l) NaClO2 (5.0 equiv), NaH2PO4·2H2O (5.0 equiv), 2-methyl-2-butene (30.0 equiv),
tBuOH:THF:H O (3: 2: 1), rt, 1.5 h; (m) CMPI (6.0 equiv), Et N (8.0 equiv), DCM, rt, 12 h, 75% (2 steps); (n) Urea hydrogen peroxide
2 3
(4.0 equiv), TFAA (1.5 equiv), Na2CO3 (6.0 equiv), DCM, 0 °C, 1.5 h, 69% (85% brsm); (o) NBS (1.5 equiv), AIBN (0.3 equiv), CCl 4,
reflux, 1.5 h; then AgBF4 (1.2 equiv), Et3N (2.0 equiv), DMSO, rt, 65%; (p) Et2NH (2.0 equiv), DCM, rt, 20 min; then DBN (4.0 equiv),
DCM, 35°C, 6 h; then HCl, THF, 35°C, 15 h, 25% (40% brsm); (q) Ac2O (15 equiv), pyridine, rt, 12 h; then 3HF·Et3N, THF, 45 °C, 76%;
(r) DMP (1.5 equiv), DCM, 0 °C to rt, 2.5 h, 85%; (s) 3HF·Et3N, THF, 45 °C, 17 h, 95%; (t) DMP (2.0 equiv), DCM, 0 °C to rt, 1.5 h, 89%;
(u) Et2NH (2.0 equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35°C, 4 h; then HCl, THF, 35°C, 12 h, 54% (62% brsm); (v) Ac2O
(12 equiv), pyridine, rt, 12 h, 84%.

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II. Experimental Procedures and Spectroscopic Data
General Information
Unless otherwise mentioned, all reactions were carried out under a nitrogen
atmosphere with dry solvents under anhydrous conditions. All the chemicals were
purchased commercially, and used without further purification. Anhydrous THF was
distilled from sodium-benzophenone, toluene was distilled from sodium,
dichloroethane and dichloromethane were distilled from calcium hydride. Yields refer
to chromatographically. Reagents were purchased at the highest commercial quality and
used without further purification, unless otherwise stated.
Reactions were monitored by Thin Layer Chromatography on plates (HSGF254)
supplied by Yantai Chemicals (China). If not specially mentioned, flash column
chromatography uses silica gel (200-300 mesh) supplied by Tsingtao Haiyang
Chemicals (China).
NMR spectra were recorded on Brüker Advance 400 (1H 400 MHz, 13C 100 MHz)
or Brüker Advance 500 (1H 500 MHz, 13
C 125 MHz). TMS was used as internal
standard for 1H NMR (0.00 ppm), and solvent signal was used as reference for 13C
NMR (CDCl3, 77.0 ppm). The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
Mass spectrometric data were obtained using Brüker Apex IV FTMS using ESI
(electrospray ionization) and Waters GCT (GC-MS) using EI (electron impact
ionization). Infrared spectra were recorded on a Thermo Nicolet iS5 spectrometer.
Optical rotations were measured on a Perkin-Elmer 341LC digital polarimeter with a
sodium lamp at ambient temperature and are reported as follows: [α]λ (c g/100mL).

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The Pd-catalyzed Cascade Reaction for Synthesizing Substituted Furans

Preparation of Carbonates：
Synthesis of compound 14

To a solution of the S243 (56 g, 360 mmol) in THF (240 mL) was added LDA (2.0
M, 165 mL) at −78 °C. The resulting solution was stirred for 1 h at this temperature
prior to slow addition of S234 (39 g, 300 mmol) in THF (10 mL) and the resulting
reaction mixture was warmed up to room temperature. After stirring for an additional 1
h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with
EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated
in vacuo, and the residue was purified by flash column chromatography on silica gel
(EtOAc/PE = 1/4 to 1/2) to afford compound S25 as a yellow oil (67 g, 234 mmol) in
78% yield; Rf = 0.25 (EtOAc/PE = 1/4); 1H NMR (400 MHz, CDCl3) δ 4.70 (s, 2H),
4.02 (d, J = 11.3 Hz, 2H), 3.75 (d, J = 11.3 Hz, 2H), 3.31 (s, 1H), 1.49 (s, 9H), 1.47 (s,
3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.62, 98.55, 83.57, 83.16, 80.83,
68.30, 63.27, 54.38, 28.41, 27.69, 18.18; IR (neat, cm-1): 3442, 2982, 1742, 1370, 1274,
1251, 1149, 1091, 852, 828, 521; HRMS-ESI (m/z) calc. for C14H22NaO6 [M + Na+]:
309.1309; Found: 309.1311.
The mixture of S25 (50 g, 175 mmol) in 90% acetic acid (90%, 250 mL) was
stirred at 90 °C for 15 min. The reaction mixture was concentrated in vacuo and the
resulting residue was purified by flash column chromatography on silica gel (EtOAc/PE
= 1/1 to 5/1) to afford compound 14 as an orange oil (39 g, 158 mmol) in 91% yield; Rf
= 0.10 (EtOAc/PE = 1/1); 1H NMR (400 MHz, CDCl3) δ 4.69 (s, 2H), 4.13 (br s, 1H),
3.72 (s, 4H), 3.36 (br s, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.87, 86.03,
83.37, 80.13, 71.55, 66.60, 54.66, 27.69; IR (neat, cm-1): 3365, 2980, 1740, 1369, 1274,
1252, 1152, 1047, 848, 730; HRMS-ESI (m/z) calc. for C11H18NaO6 [M + Na+]:
269.0996; Found: 269.0993.
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Synthesis of compounds S27 and S28

To a solution of the S26 (327 mg, 1.92 mmol) in THF (1.0 mL) was added LDA
(2.0 M, 1.1 mL) at −78 °C. The resulting solution was stirred for 1 h at this temperature
prior to slow addition of S234 (208 mg, 1.60 mmol) in THF (1.0 mL) and the resulting
reaction mixture was warmed up to room temperature. After stirring for an additional 1
h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with
EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated
in vacuo, and the residue was purified by flash column chromatography on silica gel
(EtOAc/PE = 1/4 to 1/2) to afford compound S27 as a yellow oil (210 mg, 0.70 mmol)
in 44% yield; Rf = 0.30 (EtOAc/PE = 1/4); 1H NMR (400 MHz, CDCl3) δ 5.35-5.24 (m,
1H), 3.99 (d, J = 11.4 Hz, 2H), 3.73 (d, J = 12.0 Hz, 2H), 3.30 (s, 1H), 1.50 (d, J = 6.7
Hz, 3H), 1.48 (s, 9H), 1.45 (s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.28,
98.51, 85.13, 82.87, 81.56, 68.38, 68.36, 63.19, 62.88, 28.54, 27.73, 21.28, 18.07; IR
(neat, cm-1): 3444, 2986, 2938, 1739, 1370, 1251, 1151, 1094, 829, 791, 521; HRMS-
ESI (m/z) calc. for C15H28NO6 [M + NH4+]: 318.1911; Found: 318.1912.
The mixture of S27 (200 mg, 0.66 mmol) in 90% acetic acid (90%, 1.5 mL) was
stirred at 90 °C for 15 min. The reaction mixture was concentrated in vacuo and the
resulting residue was purified by flash column chromatography on silica gel (EtOAc/PE
= 1/1 to 5/1) to afford compound S28 as a yellow oil (127 mg, 0.49 mmol) in 74% yield;
Rf = 0.10 (EtOAc/PE = 1/1); 1H NMR (400 MHz, CDCl3) δ 5.23 (q, J = 6.7 Hz, 1H),
3.78 (br s, 1H), 3.71 (s, 4H), 2.99 (br s, 2H), 1.51 (d, J = 6.7 Hz, 3H), 1.48 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 152.63, 84.65, 84.11, 83.18, 71.55, 66.77, 66.75, 63.23,
27.73, 21.04; IR (neat, cm-1): 3371, 2981, 2936, 1738, 1253, 1156, 1093, 1042, 831,
792, 756; HRMS-ESI (m/z) calc. for C12H20NaO6 [M + Na+]: 283.1152; Found:
283.1151.

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Synthesis of compound S30

The mixture of S29 (40 g, 147 mmol) in 90% acetic acid (90%, 200 mL) was
stirred at 90 °C for 15 min. The reaction mixture was concentrated in vacuo and the
resulting residue was purified by flash column chromatography on silica gel (EtOAc/PE
= 1/1 to 5/1) to afford compound S30 as an orange oil (25 g, 108 mmol) in 73% yield;
Rf = 0.10 (EtOAc/PE = 1/1); 1H NMR (400 MHz, CDCl3) δ 4.94-4.76 (m, 1H), 4.74 (s,
2H), 4.51 (br s, 1H), 3.81 (br s, 2H), 3.71 (s, 4H), 1.29 (s, 3H), 1.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 154.17, 86.31, 79.76, 73.00, 71.54, 66.40, 55.25, 21.69; IR (neat,
cm-1): 3357, 2983, 1730, 1378, 1255, 1089, 1047, 926, 907, 830, 789; HRMS-ESI (m/z)
calc. for C10H20NO6 [M + NH4+]: 250.1285; Found: 250.1281.

General Procedure of Condition A:

To a stirred solution of substrate (1 equiv), propargyl carbonate (1.2 equiv), dppf
(0.20 equiv) in dioxane was added DIPEA (2.4 equiv) and Pd2(dba)3 (0.05 equiv) in a
round flask at room temperature. After degassing, the reaction mixture was heated to
70 °C and stirred continuously for 5 h. After evaporation of the solvent in vacuo, the
residue was purified by flash column chromatography on silica gel.

General Procedure of Condition B:

To a stirred solution of substrate (1 equiv), propargyl carbonate (1.2 equiv), dppf
(0.20 equiv) in PhCl was added DIPEA (2.4 equiv) and Pd2(dba)3 (0.05 equiv) in a
round flask at room temperature. After degassing, the reaction mixture was heated to
130 °C and stirred continuously for 1.5 h. After evaporation of the solvent in vacuo,
the residue was purified by flash column chromatography on silica gel.

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Synthesis of compound (+)-S13

To a solution of 132 (800 mg, 2.45 mmol) in benzene (12 mL) and methanol (3
mL) was added trimethylsilyl diazomethane (1.6 mL, 3.19 mmol, 1.2 M in hexane) at
room temperature. After stirring for 30 min, the reaction mixture was concentrated in
vacuo. The residue was purified by flash column chromatography on silica gel
(EtOAc/PE = 1/10 to 1/4) to afford compound (+)-S31 as a yellow solid (766 mg, 2.25
mmol) in 91% yield; Rf = 0.44 (EtOAc/PE = 1/4); [α]25D = +53 (c = 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 3.86-3.72 (m, 4H), 2.84 (ddd, J = 20.8, 11.1, 1.9 Hz, 1H),
2.64-2.41 (m, 3H), 2.00 (m, 2H), 1.89-1.68 (m, 2H), 1.13 (s, 3H), 0.89 (s, 10H), 0.05
(s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.54, 176.69, 166.00, 128.52,
80.28, 51.97, 46.36, 33.42, 33.14, 29.61, 26.54, 25.72, 18.00, 15.31, −4.47, −4.91；IR
(neat, cm-1): 2953, 2929, 2856, 2029, 1736, 1676, 1249, 1118, 872, 838, 777; HRMS-
ESI (m/z) calc. for C18H31O4Si [M + H+]: 339.1986; Found: 339.1992.

The General Procedure of Condition A was followed employing (+)-S31 (900 mg,
2.65 mmol), S30 (800 mg, 3.18 mmol), Pd2(dba)3 (121 mg, 0.132 mmol), dppf (295 mg,
0.53 mmol), DIPEA (1.0 mL, 6.40 mmol), dioxane (20 mL). (+)-S31 was completely
consumed as indicated by TLC analysis, and the reaction mixture was concentrated in
vacuo. To the solution of the residue in CHCl3（20mL）was added p-TsOH∙H2O (46
mg, 0.26 mmol). After stirring for 5 min, the reaction mixture was concentrated in
vacuo. the residue was purified by flash column chromatography on silica gel
(EtOAc/PE = 1/15 to 1/3) to afford compound (+)-S13 as a yellow oil (820 mg, 1.82
mmol) in 69% yield; Rf = 0.70 (EtOAc/PE = 1/1); 1H NMR (400 MHz, CDCl3) δ 7.21
(s, 2H), 6.04 (s, 1H), 6.02 (s, 1H), 5.65 (dd, J = 3.3, 1.8 Hz, 1H), 5.54 (dd, J = 3.3, 1.7
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Hz, 1H), 4.46 (s, 2H), 4.44 (s, 2H), 3.92 (dd, J = 8.9, 7.5 Hz, 1H), 3.76 (dd, J = 8.9, 7.5
Hz, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 3.56 (d, J = 14.6 Hz, 1H), 3.46 (d, J = 14.9 Hz, 1H),
3.26 (dd, J = 29.8, 14.7 Hz, 2H), 2.82-2.69 (m, 1H), 2.65-2.56 (m, 1H), 2.47-2.21 (m,
6H), 1.85-1.70 (m, 3H), 1.18-1.09 (m, 1H), 1.07 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.45
(s, 3H), 0.03 (s, 6H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 208.03,
207.63, 171.03, 152.13, 152.02, 138.51, 138.29, 126.17, 126.12, 124.86, 124.20,
109.43, 108.81, 82.07, 81.74, 62.00, 61.80, 56.80, 52.96, 52.82, 46.95, 46.75, 38.50,
38.28, 36.40, 35.55, 34.66, 33.68, 33.18, 32.41, 25.75, 18.03, 18.01, 15.94, 14.13, −4.48,
−4.89, −4.92; IR (neat, cm-1): 3412, 2953, 2930, 2856, 1744, 1713, 1250, 1129, 837,
776, 671; HRMS-ESI (m/z) calc. for C24H37O6Si [M + H+]: 449.2354; Found: 449.2359.

Synthesis of compound S14

The General Procedure of Condition A was followed employing S32 (28 μL, 0.172
mmol), S30 (48 mg, 0.206 mmol), Pd2(dba)3 (8 mg, 9 μmol), dppf (19 mg, 0.034 mmol),
DIPEA (68 μL, 0.413 mmol), dioxane (1.7 mL). Purification by flash column
chromatography on silica gel (EtOAc/PE = 1/10 to 1/3) afforded compound S14 as a
yellow oil (30 mg, 0.107 mmol) in 62% yield; Rf = 0.60 (EtOAc/PE = 1/1); 1H NMR
(400 MHz, CDCl3) δ 7.26 (s, 1H), 6.11 (s, 1H), 4.48 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H),
3.26 (d, J = 15.1 Hz, 1H), 2.93 (d, J = 15.1 Hz, 1H), 2.54-2.38 (m, 3H), 2.05-1.99 (m,
1H), 1.78-1.71 (m, 2H), 1.69-1.62 (m, 1H), 1.51-1.42 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H);
C NMR (100 MHz, CDCl3) δ 206.77, 170.84, 152.20, 138.84, 125.99, 108.66, 61.53,
13

60.98, 56.86, 40.96, 35.64, 33.18, 27.47, 22.35, 14.05; IR (neat, cm-1): 3366, 2922,
2850, 1708, 1439, 1205, 1119, 1094, 1018, 800, 729, 603; HRMS-ESI (m/z) calc. for
C15H21O5 [M + H+]: 281.1384; Found: 281.1388.

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Synthesis of compound S15

The General Procedure of Condition B was followed employing S33 (32 μL, 0.220
mmol), 14 (65 mg, 0.264 mmol), Pd2(dba)3 (10.0 mg, 0.011 mmol), dppf (24.0 mg,
0.044 mmol), DIPEA (87 μL, 0.528 mmol), PhCl (2.2 mL). Purification by flash
column chromatography on silica gel (EtOAc/PE = 1/10 to 1/3) afforded compound
S15 as a yellow oil (38.4 mg, 0.144 mmol) in 66% yield; Rf = 0.43 (EtOAc/PE = 1/1);
1
H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 6.11 (s, 1H), 4.48 (s, 2H), 4.18 (q, J = 7.1
Hz, 2H), 3.22 (d, J = 15.1 Hz, 1H), 3.08 (d, J = 15.1 Hz, 1H), 2.53-2.35 (m, 2H), 2.26-
2.12 (m, 1H), 2.07-1.91 (m, 2H), 1.72-1.62 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 214.49, 170.67, 152.19, 138.95, 126.08, 108.53, 61.70, 59.87,
56.71, 38.06, 32.34, 31.93, 19.45, 14.05; IR (neat, cm-1): 3357, 2961, 2918, 2849, 1748,
1718, 1260, 1093, 1020, 799, 598; HRMS-ESI (m/z) calc. for C14H19O5 [M + H+]:
267.1227; Found: 267.1227.

Synthesis of compound S16

The General Procedure of Condition B was followed employing S345 (29 mg,
0.142 mmol), 14 (42 mg, 0.171 mmol), Pd2(dba)3 (6.5 mg, 7 μmol), dppf (16 mg, 0.028
mmol), DIPEA (56 μL, 0.341 mmol), PhCl (1.4 mL). Purification by flash column
chromatography on silica gel (EtOAc/PE = 1/10 to 1/3) afforded compound S16 as a
yellow oil (35.6 mg, 0.113 mmol) in 80% yield; Rf = 0.43 (EtOAc/PE = 1/1); 1H NMR
(400 MHz, CDCl3) δ 7.32 (s, 1H), 7.30-7.20 (m, 3H), 7.18-7.08 (m, 2H), 6.16 (s, 1H),
4.51 (s, 2H), 3.73 (s, 3H), 3.28-3.09 (m, 4H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 203.92, 171.60, 151.56, 139.24, 135.94, 130.05, 128.40, 127.06, 126.02, 108.84,
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64.60, 56.73, 52.50, 37.63, 30.47, 27.31; IR (neat, cm-1): 3408, 3037, 2952, 2924, 1748,
1710, 1434, 1177, 1018, 814, 730, 702, 599, 519; HRMS-ESI (m/z) calc. for C18H21O5
[M + H+]: 317.1384; Found: 317.1385.

Synthesis of compound S17

The General Procedure of Condition B was followed employing S35 (21.6 mg,
0.172 mmol), S36 (48 mg, 0.206 mmol), Pd2(dba)3 (8 mg, 9 μmol), dppf (19 mg, 0.034
mmol), DIPEA (68 μL, 0.413 mmol), PhCl (1.7 mL). Purification by flash column
chromatography on silica gel (EtOAc/PE = 1/10 to 1/5) afforded compound S17 as a
yellow oil (27 mg, 0.123 mmol) in 69% yield; Rf = 0.80 (EtOAc/PE = 1/1); 1H NMR
(400 MHz, CDCl3) δ 6.98 (s, 1H), 5.85 (s, 1H), 3.11 (s, 2H), 2.67-2.54 (m, 4H), 1.93
(d, J = 1.2 Hz, 3H), 1.91-1.75 (m, 2H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
210.09, 150.90, 137.88, 120.63, 110.37, 63.59, 38.23, 35.28, 21.61, 17.10, 9.57; IR
(neat, cm-1):2960, 2925, 1725, 1693, 1453, 1320, 1108, 1023, 806, 605, 555; HRMS-
EI (m/z) calc. for C13H16O3 [M+]: 220.1089; Found: 220.1094.

Synthesis of compound S18

The General Procedure of Condition B was followed employing S37 (18 mg, 0.16
mmol), S28 (50 mg, 0.19 mmol), Pd2(dba)3 (7.3 mg, 8 μmol), dppf (17.7 mg, 0.032
mmol), DIPEA (63 μL, 0.38 mmol), PhCl (1.6 mL). Purification by flash column
chromatography on silica gel (EtOAc/PE = 1/10 to 1/5) afforded compound S18 as a
yellow oil (25.6 mg, 0.115 mmol) in 73% yield; Rf = 0.31 (EtOAc/PE = 1/1); 1H NMR
(400 MHz, CDCl3) δ 7.24 (s, 1H), 6.08 (s, 1H), 4.48 (s, 2H), 3.23 (q, J = 7.2 Hz, 1H),
S14 / 83
2.67-2.33 (m, 4H), 1.77 (s, 1H), 1.37 (d, J = 7.2 Hz, 3H), 1.15 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 216.84, 216.17, 156.09, 138.47, 126.27, 106.86, 57.77, 56.65, 39.25,
35.44, 35.18, 17.53, 13.09; IR (neat, cm-1): 3675, 3418, 2967, 2921, 1760, 1715, 1417,
1257, 1026, 929, 819, 728, 599; HRMS-ESI (m/z) calc. for C13H17O4 [M + H+]:
237.1121; Found: 237.1126.

S15 / 83
Total Synthesis of (+)-Wortmannin

Synthesis of compound S36

To a solution of furfuryl alcohol (1.14 g, 11.6 mmol) in dry ether (40 mL) was
added PBr3 (1.1 mL, 11.6 mmol) at room temperature. The mixture was stirred for 1 h
at this temperature. The resulting solution was treated with H2O and extracted with
Et2O three times. The combined organic layer was washed with saturated, aqueous
NaCl solution, dried over Na2SO4 and filtered. The filtrate was added with THF (350
mL) and Et2O was removed under reduced pressure on a rotary evaporator (0 oC) to
obtain a solution of 2-(bromomethyl)furan (S3) in THF (0.3 M), which was identified
by GC-MS.

Synthesis of compounds (+)-S4 and (−)-S57

A suspension of NaH (60% in mineral oil, 21.2 mg, 0.53 mmol) in DMSO (1 mL)
was stirred for 2 h at 55 oC. To the resulting mixture were successively added THF (2
mL) and compound (+)-16 (124 mg, 0.44 mmol) in DMSO (1 mL) at 0 °C. The mixture
was allowed to warm to room temperature and stirred for 2 h. A solution of bromide
S3 (1.8 mL, 0.53 mmol, 0.3 M in THF) was added and the mixture was stirred for 3 h
at room temperature. The resulting solution was treated with saturated aqueous NH4Cl
and extracted with EtOAc three times. The combined organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/PE = 1/30 to 1/10) to afford the compound (+)-
S4 as a colorless oil (43.8 mg, 0.12 mmol) in 28% yield, compound (−)-S5 as a colorless

S16 / 83
oil (65.8 mg, 0.15 mmol) in 34% yield and recovery of (+)-16 (19.3 mg, 16%).
Compound (+)-S4: Rf = 0.42 (EtOAc/PE = 1/8); [α]20D = +24.0 (c = 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ7.25 (d, J = 4, 1.9 Hz, 1H), 6.23 (dd, J = 3.1, 1.9 Hz, 1H),
5.90 (dd, J = 3.1, 1.0 Hz, 1H), 3.75 (dd, J = 10.3, 7.3 Hz, 1H), 3.52 (s, 2H), 2.71-2.33
(m, 4H), 2.05-1.92 (m, 2H), 1.87-1.62 (m, 4H), 1.10 (s, 3H), 0.90 (s, 9H), 0.05 (s, 3H),
0.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.45 , 170.48 , 153.39 , 140.81 , 129.39 ,
110.13 , 105.24 , 80.87 , 45.81 , 33.97 , 33.34 , 29.88 , 25.72 , 25.38 , 23.92 , 17.99 ,
15.49 , –4.46 , –4.90; IR (neat, cm-1): 2954, 2928, 2856, 1664, 1504, 1471, 1418, 1377,
1353, 1250, 1120, 901, 858, 836, 776, 725; HRMS-ESI (m/z) calc. for C21H33O3Si [M
+ H+]: 361.2193; Found: 361.2189. Compound (−)-S5: Rf = 0.52 (EtOAc/PE = 1/8);
[α]20D = −16.0 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 1.4 Hz, 1H),
7.23 (dd, J = 1.8, 0.8 Hz, 1H), 6.23 (td, J = 3.5, 1.9 Hz, 2H), 5.96 (d, J = 3.2 Hz, 1H),
5.88 (d, J = 3.1 Hz, 1H), 5.24 (dd, J = 3.6, 1.8 Hz, 1H), 3.70 (dd, J = 9.0, 7.4 Hz, 1H),
3.24 (dd, J = 14.4, 5.5 Hz, 2H), 2.87 (dd, J = 14.4, 12.9 Hz, 2H), 2.42-2.21 (m, 4H),
1.64-1.58 (m, 1H), 1.02-0.91 (m, 1H), 0.86 (s, 9H), 0.66 (s, 3H), 0.00 (s, 3H), –0.02 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 213.71, 152.05, 151.78, 147.80, 141.20, 140.88,
122.92, 110.24, 110.22, 108.68, 107.92, 81.84, 55.83, 46.80, 38.76, 38.25, 38.21, 35.93,
31.81, 25.74, 18.00, 15.12, –4.51, –4.98; IR (neat, cm-1): 2954, 2928, 2855, 1707, 1502,
1461, 1360, 1250, 1147, 1127, 1102, 1009, 898, 837, 775, 730; HRMS-ESI (m/z) calc.
for C26H37O4Si [M + H+]: 441.2456; Found: 441.2460.

Synthesis of compound (+)-15

1 g scale:
To a stirred solution of 13 (1.18 g, 3.62 mmol), 14 (0.94 g, 3.82 mmol), and dppf
(161 mg, 0.29 mmol) in PhCl (36 mL) was added DIPEA (1.5 mL, 8.74 mmol) and

S17 / 83
Pd2(dba)3 (67 mg, 0.07 mmol) in a round flask at room temperature. After degassing
with nitrogen, the reaction mixture was heated to 130 °C and stirring was continued for
1.5 h. Then the solvent was removed in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/PE = 1/15 to 1/3 to 1/1) to afford compound (+)-
16 as a yellow oil (271 mg, 0.97 mmol) in 26% yield; Rf = 0.90 (EtOAc/PE = 1/1) and
compound (+)-15 as a yellow oil (570 mg, 1.47 mmol) in 41% yield and compound (−)-
S12 as a yellow oil (253 mg, 0.51 mmol) in 14% yield. Compound (+)-15: Rf = 0.70
(EtOAc/PE = 1/1); [α]25D = +18.2 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.22
(s, 1H), 5.93 (s, 1H), 4.45 (s, 2H), 3.75 (dd, J = 10.3, 7.3 Hz, 1H), 3.48 (s, 2H), 2.69-
2.37 (m, 4H), 1.98 (m, 2H), 1.87-1.63 (m, 4H), 1.10 (s, 3H), 0.90 (s, 10H), 0.05 (s, 3H),
0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.53, 170.74, 154.39, 138.18, 129.19,
125.81, 105.57, 80.87, 56.87, 45.87, 33.98, 33.36, 29.90, 25.75, 25.46, 24.12, 18.02,
15.55, −4.43, −4.86; IR (neat, cm-1): 3419, 2953, 2928, 2856, 1664, 1471, 1250, 1119,
1029, 837, 776, 670; HRMS-ESI (m/z) calc. for C22H35O4Si [M + H+]: 391.2299; Found:
391.2289. Compound (−)-S12: Rf = 0.30 (EtOAc/PE = 1/1); [α] 25D = −9.0 (c = 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.22 (s, 1H), 6.03 (s, 1H), 5.95 (s,
1H), 5.28 (dd, J = 3.5, 1.8 Hz, 1H), 4.47 (d, J = 2.5 Hz, 4H), 3.74 (dd, J = 9.0, 7.4 Hz,
1H), 3.19 (dd, J = 14.5, 2.4 Hz, 2H), 2.85 (dd, J = 14.5, 12.1 Hz, 2H), 2.47-2.20 (m,
4H), 1.69-1.64 (m, 4H), 1.13-1.05 (m, 1H), 0.87 (s, 10H), 0.72 (s, 3H), 0.02 (s, 3H),
0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 213.34, 152.98, 152.72, 147.99, 138.54,
138.22, 126.00, 125.98, 123.01, 108.97, 108.27, 81.87, 56.81, 56.79, 55.72, 46.89,
38.50, 38.30, 38.01, 35.81, 32.06, 25.77, 18.03, 15.41, −4.45, −4.93; IR (neat, cm-1):
3370, 2926, 2854, 1702, 1429, 1250, 1124, 1021, 835, 774, 669, 598; HRMS-ESI (m/z)
calc. for C28H41O6Si [M + H+]: 501.2667; Found: 501.2676.

8 g Scale:
To a stirred solution of 13 (8.2 g, 25.2 mmol), 14 (6.5 g, 26.5 mmol), and dppf
(1.118 g, 2.02 mmol) in PhCl (250 mL) was added DIPEA (10 mL, 60.5 mmol) and
Pd2(dba)3 (462 mg, 0.50 mol) in a round flask at room temperature. After degassing

S18 / 83
with nitrogen, the reaction mixture was heated to 130 °C and stirring was continued for
1.5 h. Then the solvent was removed in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/PE = 1/15 to 1/3 to 1/1) to afford compound (+)-
16 as a yellow oil (2.3 g, 8.2 mmol) in 33% yield; Rf = 0.90 (EtOAc/PE = 1/1) and
compound (+)-15 as a yellow oil (4.2 g, 10.8 mmol) in 42% yield.

Synthesis of compound (+)-17

To a stirred solution of (+)-15 (20.0 g, 51.3 mmol) in DMF (150 mL) at 0 °C was
added imidazole (4.5 g, 66.6 mmol) and TBSCl (8.5 g, 56.52 mmol). The solution was
warmed to room temperature slowly. After stirring for 1.5 h, the reaction was quenched
with saturated aqueous NH4Cl and extracted with Et2O three times. The combined
organic layers were washed with saturated aqueous NaCl for three times, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/PE = 1/50) to afford compound (+)-17 as a
colorless oil (22.0 g, 43.6 mmol) in 85% yield; Rf = 0.80 (EtOAc/PE = 1/4); [α]25D =
+18.6 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 5.87 (s, 1H), 4.50
(s, 2H), 3.74 (dd, J = 10.3, 7.3 Hz, 1H), 3.48 (s, 2H), 2.67-2.38 (m, 4H), 2.04-1.92 (m,
13
2H), 1.85-1.66 (m, 2H), 1.09 (s, 3H), 0.90 (s, 9H), 0.89 (s, 10H), 0.05 (s, 13H); C
NMR (100 MHz, CDCl3) δ 197.39, 170.43, 153.90, 137.54, 129.41, 105.48, 80.92,
57.60, 45.83, 34.02, 33.36, 29.90, 25.92, 25.75, 25.40, 24.03, 18.02, 15.49, −4.43,
−4.87, −5.20; IR (neat, cm-1): 2955, 2929, 2856, 1972, 1775, 1667, 1252, 1122, 837,
776; HRMS-ESI (m/z) calc. for C28H49O4Si2 [M + H+]: 505.3164; Found: 505.3166.

S19 / 83
Synthesis of compound (+)-9

To a solution of (+)-17 (2.52 g, 5.0 mmol) and NiCl2∙6H2O (5.94 g, 25.0 mmol) in
MeOH (100 mL) at −90 °C was added NaBH4 (2.84 g, 75.0 mmol). The resulting
mixture was stirred for 20 min at the same temperature, and allowed to warm to −60 °C
over 40 min. Then the reaction mixture was quenched with saturated aqueous NH4Cl,
and extracted with EtOAc three times. The organic layer was washed with saturated
aqueous NaCl, dried over Na2SO4 and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (EtOAc/PE = 1/30 to 1/5) to afford
compound (+)-9 as a colorless oil (1.741 g, 3.43 mmol) in 69% yield and compound
(−)-S19 as a colorless oil (0.433 g, 0.85mmol) in 17% yield. Compound (+)-9: Rf = 0.6
(EtOAc/PE = 1/10); [α]25D = +28.2 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.16
(s, 1H), 5.97 (s, 1H), 4.52 (s, 2H), 3.60 (t, J = 8.3 Hz, 1H), 2.90 (dd, J = 15.2, 6.2 Hz,
1H), 2.74 (dd, J = 15.3, 4.6 Hz, 1H), 2.67 (dd, J = 12.4, 5.5 Hz, 1H), 2.57-2.42 (m, 1H),
2.35 (ddd, J = 15.8, 5.5, 1.8 Hz, 1H), 2.03-1.85 (m, 2H), 1.67-1.29 (m, 6H), 1.01 (s,
4H), 0.90 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.00 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 211.34, 154.80, 137.27, 126.40, 106.68, 80.32, 57.63, 50.31, 48.89, 43.67, 37.58,
35.39, 31.47, 25.93, 25.80, 25.37, 24.04, 18.04, 10.91, −4.49, −4.90, −5.19; IR (neat,
cm-1): 2954, 2908, 2856, 1711, 1471, 1255, 1135, 1079, 836, 776, 670; HRMS-ESI
(m/z) calc. for C28H51O4Si2 [M + H+]: 507.3320; Found: 507.3329. Compound (−)-S19:
Rf = 0.2 (EtOAc/PE = 1/10); [α]25D = −9.6 (c = 0.5, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 7.20 (s, 1H), 5.95 (s, 1H), 4.53 (s, 2H), 4.14 (t, J = 7.7 Hz, 1H), 3.54 (dd, J = 10.0,
7.6 Hz, 1H), 3.46 (d, J = 15.7 Hz, 1H), 3.30 (d, J = 15.6 Hz, 1H), 2.39-2.23 (m, 2H),
2.06 (m, 1H), 1.90-1.82 (m, 1H), 1.73-1.66 (m, 3H), 1.59 (br s, 1H), 1.27-1.21 (m, 1H),
0.98 (s, 3H), 0.91 (s, 10H), 0.89 (s, 9H), 0.07 (s, 6H), 0.03 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 154.72, 144.93, 137.74, 128.35, 126.31, 105.66, 81.34, 69.96, 57.59, 44.62,
33.90, 29.95, 29.86, 27.45, 25.93, 25.81, 23.78, 18.40, 18.05, 17.26, −4.40, −4.81,

S20 / 83
−5.18; IR (neat, cm-1): 3339, 2953, 2927, 2855, 1462, 1250, 1110, 1077, 996, 833, 772,
668, 596; HRMS-ESI (m/z) calc. for C28H54NO4Si2 [M + NH4+]: 524.3586; Found:
524.3572.

Oxidation of (−)-S19 to compound (+)-17

To a stirred solution of (−)-S19 (3.3 g, 6.5 mmol) in DCM (300 mL) was added
NaOAc (3.2 g, 39.0 mmol) and PCC (3.4 g, 15.6 mmol) at room temperature. The
reaction was stirred at this temperature for 4 h. Then the reaction mixture was filtered
through a short column of silica gel and the column was washed with EtOAc. The
filtrate was concentrated in vacuo and purified by flash column chromatography on
silica gel (EtOAc/PE = 1/50) to afford compound (+)-17 as a colorless oil (2.3 g, 4.6
mmol) in 70% yield, Rf = 0.80 (EtOAc/PE = 1/4).

Synthesis of compound (−)-S20

To solution of (+)-9 (5.5 g, 10.8 mmol) in anhydrous THF (80 mL) was added
LiHMDS (16.7 mL, 1.3 M in THF) at −78 °C. After 1 h at −78 °C under nitrogen
atmosphere, a solution of PhNTf2 (7.0 g, 19.5 mmol) in anhydrous THF (10 mL) was
slowly added to the mixture at −78 °C. Then, the reaction mixture was allowed to warm
to 0 °C and stirred for additional 0.5 h. After the completion of the reaction, the resulting
solution was treated with saturated aqueous NH4Cl and extracted with Et2O three times.
The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (EtOAc/PE = 1/200)
to afford the compound (−)-S20 as a pale yellow oil (6.9 g, 10.6 mmol) in 98% yield;
S21 / 83
Rf = 0.8 (EtOAc/PE = 1/10); [α]25D = −12.0 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.21 (s, 1H), 6.03 (s, 1H), 5.74 (dd, J = 4.1, 2.0 Hz, 1H), 4.54 (s, 2H), 3.62 (t, J = 8.6
Hz, 1H), 2.96 (dd, J = 15.4, 5.3 Hz, 1H), 2.82 (dd, J = 15.4, 4.1 Hz, 1H), 2.71-2.60 (m,
1H), 2.11-2.00 (m, 1H), 1.96-1.79 (m, 2H), 1.73-1.60 (m, 1H), 1.57-1.39 (m, 2H), 1.39-
1.24 (m, 1H), 0.90 (s, 9H), 0.87 (s, 9H), 0.83 (s, 3H), 0.07 (s, 6H), 0.00 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 151.50, 136.97, 125.45, 119.04, 117.57 (q, J = 320.4 Hz),
106.52, 79.36, 56.52, 43.99, 41.67, 40.38, 34.94, 30.15, 25.90, 24.86, 24.75, 22.49,
17.31, 16.99, 9.81, −5.50, −5.92, −6.21; IR (neat, cm-1): 2954, 2929, 2857, 1418, 1247,
1212, 1144, 867, 837, 775; HRMS-ESI (m/z) calc. for C29H50F3O6SSi2 [M + H+]:
639.2813; Found: 639.2808.

Synthesis of compound (−)-18

A solution of Pd2(dba)3 (483 mg, 0.53 mmol) in anhydrous and oxygen-free NMP
(50 mL) was treated with AsPh3 (969 mg, 3.17 mmol); after 5 min, a solution of (−)-
S20 (8.43 g, 13.19 mmol) in anhydrous and oxygen-free NMP (16 mL) was added.
After the solution was stirred for 10 min, a solution of stannane 108 (6.19 g, 17.15 mmol)
in NMP (16 mL) was added. Then, the resulting solution was heated to 70 °C. After
stirring for 6 h, saturated aqueous KF solution (50 mL) was added. The reaction mixture
was stirred for 30 min and extracted with Et2O three times. The combined organic layer
was washed with saturated aqueous NaCl and saturated aqueous KF solution, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (EtOAc/PE = 1/200 to 1/4) to afford compound (−)-18 as
a pale yellow oil (5.12 g, 9.12 mmol) in 69% yield; Rf = 0.4 (EtOAc/PE = 1/4); [α]25D
= −48.2 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 5.90 (s, 1H), 5.61
(dt, J = 6.3, 2.0 Hz, 1H), 5.53 (td, J = 6.9, 1.6 Hz, 1H), 4.52 (s, 2H), 4.25-4.16 (m, 2H),
3.61 (t, J = 8.5 Hz, 1H), 2.77-2.63 (m, 2H), 2.60-2.49 (m, 1H), 2.00 (ddd, J = 17.0, 6.2,

S22 / 83
1.7 Hz, 1H), 1.88-1.79 (m, 2H), 1.76 (d, J = 1.2 Hz, 3H), 1.58 (m, 1H), 1.49-1.32 (m,
3H), 1.30-1.19 (m, 1H), 0.90 (s, 9H), 0.87 (s, 9H), 0.72 (s, 3H), 0.07 (s, 6H), 0.01 (s,
3H), 0.00 (s, 3H); 13
C NMR (100 MHz, CDCl3) δ 155.16, 143.54, 139.75, 137.16,
124.46, 124.41, 106.58, 81.44, 59.54, 57.57, 45.21, 42.56, 39.08, 38.56, 30.89, 30.11,
25.92, 25.85, 24.58, 18.37, 18.09, 15.87, 10.82, −4.47, −4.80, −5.15; IR (neat, cm-1):
3339, 2953, 2928, 2856, 1471, 1254, 1082, 836, 814, 775, 667; HRMS-ESI (m/z) calc.
for C32H56NaO4Si2 [M + Na+]: 583.3609; Found: 583.3598.

Synthesis of compound (−)-S21

To a suspension of D-(−)-DIPT (459 mg, 1.96 mmol) and activated 4 Å MS (6.6

g) in dry DCM (70 mL) was stirred at −40 °C under nitrogen atmosphere, then Ti(OiPr)4
(464 μL, 1.57 mmol) was added to the reaction mixture. After stirring for 30 min, (−)-
18 (2.2 g, 3.92 mmol) in DCM (8 mL) and TBHP (1.42 mL, 5.5 M in decane) were
added to the reaction mixture at −40 °C under nitrogen atmosphere. After stirring for 5
h, the suspension was quenched with saturated aqueous Na2S2O3 (20 mL) and stirred at
−40 °C for 5 min. The reaction mixture was filtered through a short pad of celite and
washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was
purified by flash column chromatography on silica gel (EtOAc/PE = 1/20 to 1/10) to
afford the compound (−)-S21 as a pale yellow oil (1.53 g, 2.66 mmol) in 68% yield; Rf
= 0.5 (EtOAc/PE = 1/4); [α]25D = −7.0 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.19 (s, 1H), 5.99 (s, 1H), 5.77 (dt, J = 6.3, 2.0 Hz, 1H), 4.52 (s, 2H), 3.81 (dd, J = 12.1,
4.5 Hz, 1H), 3.70 (dd, J = 12.1, 6.4 Hz, 1H), 3.59 (t, J = 8.4 Hz, 1H), 2.97-2.85 (m, 2H),
2.61 (dd, J = 15.4, 6.9 Hz, 1H), 2.42 (br s, 1H), 2.09-1.86 (m, 2H), 1.84-1.72 (m, 2H),
1.48-1.32 (m, 6H), 1.26-1.11 (m, 2H), 0.90 (s, 10H), 0.87 (s, 9H), 0.71 (s, 3H), 0.07 (s,
7H), 0.00 (s, 3H), −0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.60, 139.59, 137.32,
126.42, 121.64, 106.84, 81.24, 65.51, 61.75, 61.13, 57.50, 45.67, 42.81, 39.08, 37.58,

S23 / 83
30.83, 30.08, 25.90, 25.83, 24.36, 18.37, 18.07, 17.25, 10.73, −4.48, −4.82, −5.17,
−5.18; IR (neat, cm-1): 3434, 2953, 2928, 2856, 1471, 1251, 1130, 1082, 836, 775, 667;
HRMS-ESI (m/z) calc. for C32H57O5Si2 [M + H+]: 577.3739; Found: 577.3731.

Synthesis of compound (+)-S38

To a suspension of L-(+)-DIPT (11.7 mg, 0.05 mmol) and activated 4 Å MS (168

mg) in dry DCM (1 mL) was stirred at −40 °C under nitrogen atmosphere, then
Ti(OiPr)4 (12 μL, 0.04 mmol) was added to the reaction mixture. After stirring for 30
min, (−)-18 (56 mg, 0.1 mmol) in DCM (1 mL) and TBHP (36 μL, 5.5 M in decane)
were added to the reaction mixture at −40 °C under nitrogen atmosphere. After stirring
for 5 h, the suspension was quenched with saturated aqueous Na2S2O3 (1 mL) and
stirred at −40 °C for 5 min. The reaction mixture was filtered through a short pad of
celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue
was purified by flash column chromatography on silica gel (EtOAc/PE = 1/20 to 1/10)
to afford the compound (+)-S38 as a colorless oil (30 mg, 0.05 mmol) in 52% yield and
recovery of (−)-18 (24.1 mg, 43 %). Compound (+)-S38: Rf = 0.45 (EtOAc/PE = 1/4);
[α]20D = +10.8 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.19-7.18 (m, 1H), 6.00
(d, J = 0.9 Hz, 1H), 5.78 (dt, J = 6.1, 2.0 Hz, 1H), 4.53 (d, J = 1.1 Hz, 2H), 3.91-3.81
(m, 1H), 3.77-3.71 (m, 1H), 3.57 (t, J = 8.5 Hz, 1H), 3.25 (dd, J = 6.4, 4.6 Hz, 1H),
3.04 (dd, J = 15.4, 4.6 Hz, 1H), 2.74 (dd, J = 15.3, 6.6 Hz, 1H), 2.60-2.49 (m, 1H), 1.97
(ddd, J = 17.1, 6.1, 1.9 Hz, 1H), 1.84-1.81 (m, 1H), 1.79-1.73 (m, 2H), 1.56-1.47 (m,
1H), 1.41 (s, 3H), 1.35-1.25 (m, 2H), 1.19 (td, J = 11.7, 5.3 Hz, 1H), 0.90 (s, 9H), 0.87
(s, 9H), 0.68 (s, 3H), 0.07 (s, 6H), −0.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ155.14,
139.56, 137.09, 127.62, 126.41, 106.67, 81.18, 63.62, 61.28, 60.98, 57.63, 45.39, 42.61,
39.26, 37.96, 30.76, 29.66, 25.89, 25.81, 24.13, 18.35, 18.32, 18.05, 10.87, −4.49,
−4.85, −5.17, −5.20; IR (neat, cm-1): 3422, 2953, 2927, 2856, 1471, 1251, 1128, 1080,

S24 / 83
836, 774, 668; HRMS-ESI (m/z) calc. for C32H60NO5Si2 [M + NH4+]: 594.4005; Found:
594.4014.

Synthesis of compound (+)-8

To a solution of (−)-S21 (5.3 g, 9.18 mmol) in DMF (50 mL) was added NaH
(60%, 918 mg, 22.96 mmol) at -10 °C. After stirring for 20 min, MeI (1.14 mL, 18.36
mmol) was added and the reaction mixture was was warmed to room temperature. After
stirring for 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl (5
mL) and the mixture was extracted with Et2O three times. The combined organic layer
was washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash column chromatography on silica gel
(EtOAc/PE = 1/50) to afford compound (+)-8 as a pale yellow oil (4.94 g, 8.35 mmol)
in 91% yield; Rf = 0.7 (EtOAc/PE = 1/10); [α]25D = +3.8 (c = 0.5, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.19 (s, 1H), 5.98 (s, 1H), 5.78 (dt, J = 6.3, 1.9 Hz, 1H), 4.53 (s, 2H),
3.65 (dd, J = 11.2, 4.2 Hz, 1H), 3.58 (t, J = 8.6 Hz, 1H), 3.43 (dd, J = 11.2, 6.3 Hz, 1H),
3.38 (s, 3H), 2.99 -2.89 (m, 2H), 2.55 (dd, J = 15.3, 7.5 Hz, 1H), 2.47-2.37 (m, 1H),
1.98 (ddd, J = 16.9, 6.3, 1.7 Hz, 1H), 1.84-1.67 (m, 2H), 1.46-1.24 (m, 7H), 0.90 (s,
9H), 0.86 (s, 9H), 0.70 (s, 3H), 0.07 (s, 6H), −0.01 (s, 3H), −0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 154.77, 139.74, 137.33, 126.38, 121.59, 106.72, 81.21, 71.17,
63.79, 60.48, 59.12, 57.53, 45.84, 42.86, 39.12, 37.57, 30.85, 30.33, 25.90, 25.84, 24.37,
18.36, 18.07, 17.31, 10.74, −4.48, −4.82, −5.16, −5.18; IR (neat, cm-1): 2954, 2988,
2856, 1471, 1252, 1131, 1080, 837, 774, 756, 668; HRMS-ESI (m/z) calc. for
C33H59O5Si2 [M + H+]: 591.3896; Found: 591.3881.

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Synthesis of compound (−)-20

To a solution of Ph4PBF4 (2.216 g, 5.20 mmol) in HFIP/DCM (v:v = 1:3.3, 296

mL) was added a solution of (+)-8 (1.025 g, 1.73 mmol) in DCM (50 mL) dropwise at
−15 °C within 10 min through a syringe. After stirring for 65 h, EtOAc (500 mL) was
added to the above mixture and stirred for 5 min, during which time Ph4PBF4 was
precipitated out as a white powder. After filtration, the liquid phase was concentrated
in vacuo. The crude product was added EtOAc (100 mL) and the residual Ph4PBF4 was
precipitated out (Ph4PBF4 could be recycled for new reaction) and removed by filtration.
The filtrate was concentrated in vacuo and the crude residue was purified by flash
column chromatography on silica gel (EtOAc/PE = 1/50 to 1/5) to afford compound
(−)-19 as a pale yellow oil (110mg, 0.186 mmol) in 11% yield and partially purified 7
(710 mg) as a yellow oil; Rf = 0.4 (EtOAc/PE = 1/10). Compound (−)-19: Rf = 0.25
(EtOAc/PE = 1/10); [α]20D = −31 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.17
(s, 1H), 5.94 (s, 1H), 5.65 (dt, J =6.3, 2.0 Hz, 1H), 5.30 (t, J = 1.8 Hz, 1H), 5.08 (s, 1.0
Hz, 1H), 4.51 (s, 2H), 4.39 (d, J = 7.9 Hz, 1H), 3.61 (t, J = 8.5 Hz, 1H), 3.44 (dd, J =
9.9, 2.6 Hz, 1H), 3.37 (s, 3H), 3.16 (dd, J = 9.9, 8.2 Hz, 1H), 2.80 (dd, J = 15.2, 4.7 Hz,
1H), 2.58 (dd, J = 15.2, 6.3 Hz, 1H), 2.49-2.42 (m, 1H), 2.07-1.97 (m, 1H), 1.89-1.76
(m, 2H), 1.68-1.48 (m, 2H), 1.48-1.38 (m, 1H), 1.31 (dd, J = 10.6, 7.2 Hz, 1H), 1.26-
1.18 (m, 1H), 0.90 (s, 10H), 0.87 (s, 9H), 0.72 (s, 3H), 0.07 (s, 6H), 0.00 (s, 3H), −0.01
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.99, 149.54, 140.49, 137.26, 126.38, 111.35,
106.81, 81.29, 76.47, 70.46, 59.00, 57.52, 45.50, 42.66, 39.23, 38.55, 30.80, 30.62,
25.92, 25.83, 24.48, 18.37, 18.07, 11.12, −4.47, −4.83, −5.17, −5.17; IR (neat, cm-1):
2953, 2928, 2856, 1471, 1252, 1124, 1084, 835, 774, 668; HRMS-ESI (m/z) calc. for
C33H59O5Si2 [M + H+]: 591.3896; Found: 591.3879.

S26 / 83
 A solution of partially purified 7 (710 mg) in THF (60 mL) was added TBAF∙3H2O
(450 mg) at room temperature. The reaction mixture was stirred at this temperature for
1 h. The solvent was concentrated in vacuo and the residue was purified by flash
chromatography on silica gel (EtOAc/PE = 1/10 to 1/1) to afford compound (−)-20 as
a white solid (389 mg, 0.82 mmol) in 47% yield (2 steps); Rf = 0.40 (EtOAc/PE = 1/1);
m.p. 140-143 oC; [α]25D = −5.6 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.26 (s,
1H), 5.80 (dt, J = 5.5, 2.2 Hz, 1H), 4.59 (d, J = 12.6 Hz, 1H), 4.37 (d, J = 12.6 Hz, 1H),
4.14 (dd, J = 9.3, 2.0 Hz, 1H), 3.72 (t, J = 8.5 Hz, 1H), 3.36-3.30 (m, 1H), 3.24 (s, 3H),
2.81-2.68 (m, 2H), 2.19 (d, J = 11.9 Hz, 1H), 2.15-1.91 (m, 4H), 1.77-1.71 (m, 1H),
1.58 (s, 3H), 1.54-1.48 (m, 1H), 1.44-1.32 (m, 2H), 0.89 (s, 10H), 0.71 (s, 3H), 0.04 (s,
3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.71, 142.85, 140.04, 125.28,
123.05, 117.28, 81.62, 78.83, 74.14, 58.94, 55.89, 46.96, 44.03, 41.97, 38.98, 38.14,
30.87, 27.35, 27.29, 25.83, 24.08, 18.09, 11.04, −4.50, −4.80; IR (neat, cm-1): 3317,
2952, 2927, 2853, 1471, 1250, 1109, 1087, 837, 775; HRMS-ESI (m/z) calc. for
C27H44NaO5Si [M + Na+]: 499.2850; Found: 499.2856.

Synthesis of compound (−)-S22

To a solution of (−)-20 (85 mg, 0.18 mmol) in DCM (18 mL) was added
(diacetoxyiodo)benzene (86 mg, 0.27 mmol) and 2,2,6,6-tetramethylpiperidinooxy (8.4
mg, 54 μmol) at room temperature. The mixture, protected from direct light, was stirred
for 20 h. The reaction was quenched with saturated aqueous Na2S2O3 (50 mL), and
extracted with DCM three times. The combined organic layer was dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash column chromatography
on silica gel (PE/EtOAc = 10/1) to afford compound (−)-S22 (80 mg, 0.17 mmol) as a
colorless oil in 93% yield; Rf = 0.79 (EtOAc/PE = 1/1); [α]20D = −26.9 (c = 0.5, CHCl3);
1
H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.92 (s, 1H), 5.85 (dd, J = 5.6, 2.8 Hz, 1H),

S27 / 83
4.26 (d, J = 8.8 Hz, 1H), 3.72 (t, J = 8.5 Hz, 1H), 3.57 (d, J = 3.2 Hz, 1H), 3.30 (dd, J
= 9.4, 2.4 Hz, 1H), 3.22 (s, 3H), 2.81 (dd, J = 15.4, 5.3 Hz, 1H), 2.61 (t, J = 9.2 Hz,
1H), 2.27 (s, 1H), 2.19-2.03 (m, 2H), 2.00-1.93 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.59
(m, 3H), 1.59-1.48 (m, 2H), 1.46-1.34 (m, 2H), 0.89 (s, 10H), 0.72 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 188.29, 153.45, 150.31, 141.63, 128.59,
123.29, 117.49, 81.54, 76.83, 74.62, 58.93, 46.90, 44.11, 42.01, 38.89, 37.49, 30.84,
29.42, 27.10, 25.84, 24.13, 18.11, 10.97, −4.48, −4.80; IR (neat, cm-1): 3430, 2957,
2927, 2851, 1679, 1529, 1087, 897, 837, 776; HRMS-ESI (m/z) calc. for C27H43O5Si
[M + H+]: 475.2874; Found: 475.2881.

Synthesis of compound (−)-6

To a solution of (−)-S22 (350 mg, 0.74 mmol) in t-BuOH/THF (v:v = 3:2, 74 mL)
was added 2-methylbut-2-ene (2.3 mL, 22 mmol), then a solution of NaClO2 (417 mg,
3.7 mmol), and NaH2PO4∙2H2O (576 mg, 3.7 mmol) in water (14.8 mL) at room
temperature. The reaction mixture was stirred at this temperature for 1.5 h, then poured
into water, and extracted with EtOAc six times. The combined organic layer was dried
over Na2SO4, and concentrated in vacuo. To a solution of the residue in DCM (44 mL)
was added trimethylamine (0.82 mL, 5.9 mmol), 2-chloro-1-methylpyridinium iodide
(CMPI) (1.1 g, 4.4 mmol) at room temperature. The reaction mixture was stirred at this
temperature for 12 h, then concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (EtOAc/PE = 1/20 to 1/10) to afford compound
(−)-6 (265 mg, 0.56 mmol) as a colorless oil in 75% yield; Rf = 0.69 (EtOAc/PE =
1/2); [α]20D = −10 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 5.52 (dt,
J = 6.3, 2.2 Hz, 1H), 4.84 (dd, J = 7.8, 2.3 Hz, 1H), 3.73-3.65 (m, 2H), 3.25 (s, 3H),
2.99-2.91 (m, 2H), 2.64 (s, 1H), 2.21 (dd, J = 16.5, 9.9 Hz, 1H), 2.09 (ddd, J = 17.0,
6.2, 1.8 Hz, 1H), 1.99-1.88 (m, 2H), 1.82-1.77 (m, 1H), 1.51 (m, 4H), 1.47-1.40 (m,

S28 / 83
2H), 0.88 (s, 10H), 0.76 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 160.62, 148.96, 145.02, 137.88, 123.60, 121.96, 113.20, 89.30, 81.34, 72.13, 59.19,
47.63, 42.58, 38.31, 37.66, 36.10, 30.61, 29.66, 28.55, 25.82, 24.35, 18.08, 10.85, −4.47,
−4.83; IR (neat, cm-1): 2953, 2927, 2855, 1746, 1552, 1252, 1135, 1088, 1006, 858,
837, 776; HRMS-ESI (m/z) calc. for C27H41O5Si [M + H+]: 473.2718; Found: 473.2717.

Synthesis of compound (+)-21

To a flame-dried flask was added urea hydrogen peroxide (94 mg, 1.0 mmol) and
sodium carbonate (158 mg, 1.5 mmol) and dried under vacuum conditions for 10 min.
Then, DCM (25 mL) was added to the mixture under a nitrogen atmosphere, followed
by the addition of compound (−)-6 (118 mg, 0.25 mmol) at 0 °C. Trifluoroacetic
anhydride (52 μL, 0.37 mmol) was added in a dropwise manner, and the mixture was
stirred for 1.5 h at 0 °C. Saturated aqueous Na2S2O3 (10 mL) was added, and stirring
continuously for 5 min at an ice-cold temperature. The mixture was filtrated through a
Celite pad, and washed with EtOAc. The filtrate was concentrated in vacuo and the
residue was purified by flash column chromatography on silica gel (EtOAc/PE = 1/10
to 1/5) to afford (+)-21 (84.3 mg, 0.17 mmol) as a colorless oil in 69% yield and
recovery of (−)-6 (22.3 mg, 19%). Compound (+)-21: Rf = 0.30 (EtOAc/PE = 1/4);
[α]20D = +3 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 4.40 (dd, J =
8.3, 3.4 Hz, 1H), 3.73 (dd, J = 11.6, 3.4 Hz, 1H), 3.60 (t, J = 8.3 Hz, 1H), 3.23 (s, 3H),
3.16 (d, J = 5.3 Hz, 1H), 3.10 (dd, J = 11.6, 8.4 Hz, 1H), 2.84 (dd, J = 14.9, 4.4 Hz,
1H), 2.53-2.37 (m, 2H), 2.01-1.86 (m, 2H), 1.69-1.62 (m, 5H), 1.52-1.36 (m, 3H), 0.88
(s, 9H), 0.81 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.51,
148.83, 144.80, 121.93, 113.53, 87.30, 81.23, 72.22, 64.87, 59.13, 54.59, 42.16, 40.62,
36.94, 36.57, 35.75, 30.47, 26.13, 25.79, 25.67, 23.31, 18.03, 12.89, −4.45, −4.88; IR
(neat, cm-1): 2953, 2928, 2855, 1744, 1463, 1255, 1141, 1098, 1018, 837, 776; HRMS-

S29 / 83
ESI (m/z) calc. for C27H41O6Si [M + H+]: 489.2667; Found: 489.2678.

Synthesis of compound (−)-5

To a solution of compound (+)-21 (165 mg, 0.34 mmol) in CCl4 (33 mL) at room
temperature under N2 was added NBS (90 mg, 0.51 mmol) and AIBN (17 mg, 0.10
mmol), and was degassed for 15 min under N2 balloon. The mixture was heated to
reflux for 1 h, then cooled to room temperature, and concentrated in vacuo. To a solution
of the residue in dry DMSO (20 mL) was added a solution of AgBF4 (79 mg, 0.40 mmol)
in dry DMSO (13 mL) dropwise at room tempeture, after which AgBr precipitated
immediately. The resulting suspension was stirred for 30 min, after which time Et3N
(0.1 mL, 0.67 mmol) was added and the reaction mixture was stirred for an additional
2 h. Then the mixture was filtered through a short column of silica gel and the column
was washed with EtOAc. The filtrate was poured into water and extracted with EtOAc
three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel (EtOAc/PE = 1/10)
to afford compound (−)-5 (111 mg, 0.22 mmol) as a white solid in 65% yield; Rf = 0.3
(EtOAc/PE = 1/4); m.p. 203-205 oC; [α]20D = −30.4 (c = 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.12 (s, 1H), 4.45 (dd, J = 5.7, 3.2 Hz, 1H), 3.68-3.57 (m, 2H), 3.38 (dd, J =
11.4, 5.7 Hz, 1H), 3.23-3.09 (m, 5H), 2.44-2.33 (m, 1H), 1.95 (dt, J = 11.2, 4.2 Hz, 2H),
1.86-1.79 (m, 4H), 1.59 (s, 1H), 1.52-1.38 (m, 2H), 0.88 (s, 9H), 0.84 (s, 3H), 0.02 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 184.20, 158.83, 149.28, 144.21, 141.30, 115.02,
86.67, 80.56, 72.09, 69.76, 59.07, 54.55, 50.15, 42.62, 37.93, 35.92, 35.71, 30.68, 25.79,
25.10, 23.54, 18.03, 12.96, −4.40, −4.90; IR (neat, cm-1): 2952, 2928, 2855, 2359, 1752,
1694, 1539, 1465, 1250, 1137, 1098, 837, 774, 668; HRMS-ESI (m/z) calc. for
C27H42NO7Si [M + NH4+]: 520.2725; Found: 520.2732.

S30 / 83
Synthesis of compound (+)-23

To a stirred solution of (−)-5 (12.2 mg, 24 μmol) in DCM (0.5 mL) was added
Et2NH (5 μL, 49 μmol) at room temperature. The reaction mixture was stirred at this
temperature for 20 min, then concentrated in vacuo. To a solution of the residue in DCM
(0.5 ml) was added DBN (12 μL, 96 μmol) at 35 oC. The reaction mixture was stirred
at this temperature for 6 h, then concentrated in vacuo. To a solution of the residue in
THF (0.6 ml) was added 3 N aqueous HCl solution (0.3 mL) at 35 oC. The reaction
mixture was stirred at this temperature for 15 h, then poured into water, and extracted
with EtOAc three times. The combined organic layer was dried over Na 2SO4, and
concentrated in vacuo. The residue was purified by preparative thin layer
chromatography (EtOAc/PE = 1/2) to afford compound (+)-23 (3.0 mg, 6 μmol) as a
colorless oil in 25% yield, compound (+)-S39 (1.1 mg, 2.9 μmol) as a colorless oil in
12% yield, compound (–)-25 (0.5 mg, 1.2 μmol) as a colorless oil in 5% yield and
recovery of (−)-5 (4.5 mg, 37%). Compound (+)-23: Rf = 0.59 (EtOAc); m.p. 115-120
C; [α]20D = +92 (c = 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 5.64 (dd,
o

J = 9.2, 4.0 Hz, 1H), 4.88-4.81 (m, 1H), 3.76 (dd, J = 9.0, 7.2 Hz, 1H), 3.47 (dd, J =
9.6, 4.0 Hz, 1H), 3.26 (d, J = 12.0 Hz, 1H), 3.15 (s, 3H), 2.81 (t, J = 9.4 Hz, 1H), 2.76-
2.66 (m, 1H), 2.42-2.32 (m, 2H), 2.08-1.97 (m, 1H), 1.79 (s, 3H), 1.70 (dd, J = 12.4,
6.1 Hz, 1H), 1.28-1.21 (m, 1H), 0.90 (s, 9H), 0.79 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H);
13
C NMR (100 MHz, CDCl3) δ 173.94, 157.93, 154.57, 149.51, 146.53, 141.72, 137.95,
113.39, 86.03, 79.22, 71.16, 69.53, 59.33, 45.66, 45.00, 44.25, 41.08, 30.98, 25.81,
25.40, 25.07, 18.07, 12.58, −4.40, −4.85; IR (neat, cm-1): 3438, 2953, 2929, 2856, 1754,
1675, 1466, 1250, 1133, 1104, 836, 776; HRMS-ESI (m/z) calc. for C27H39O7Si [M +
H+]: 503.2460; Found: 503.2459. Compound (+)-S39: Rf = 0.26 (EtOAc); [α]28D = +90.5
(c = 0.2, CHCl3); 1H NMR (800 MHz, CDCl3) δ 8.21 (s, 1H), 5.63 (dd, J = 9.1, 4.0 Hz,
1H), 4.87–4.84 (m, 1H), 3.87 (dd, J = 9.2, 7.6 Hz, 1H), 3.47 (dd, J = 9.7, 4.0 Hz, 1H),

S31 / 83
3.15 (s, 3H), 2.83 (t, J = 9.4 Hz, 1H), 2.79–2.72 (m, 1H), 2.47–2.41 (m, 2H), 2.24–2.19
(m, 1H), 1.80 (s, 3H), 1.75–1.70 (m, 1H), 1.58–1.53 (m, 1H), 1.33 (t, J = 11.3 Hz, 1H),
0.84 (s, 3H); 13C NMR (200 MHz, CDCl3) δ 173.77, 157.82, 154.52, 149.55, 146.44,
141.76, 137.66, 113.40, 85.98, 79.21, 71.16, 69.33, 59.32, 45.26, 44.65, 44.62, 41.09,
30.70, 25.44, 24.89, 12.22; IR (neat, cm-1): 3433, 2924, 1748, 1673, 1540, 1467, 1364,
1139, 1099, 870, 731; HRMS-ESI (m/z) calc. for C21H25O7 [M + H+]: 389.1595; Found:
389.1594.

Synthesis of compound (+)-24 (17-β-hydroxy-Wortmannin)

To a stirred solution of (+)-23 (5.2 mg, 10 μmol) in pyridine (1.0 mL) was added
Ac2O (15 μL, 0.15 mol) at room temperature. The reaction mixture was stirred at this
temperature for 12 h and concentrated in vacuo. To a stirred solution of the residue in
THF (0.6 mL) was added 3HF∙Et3N (0.3 mL) at room temperature. The reaction mixture
was heated to 45 °C and stirred for 12 h. Then silica gel and EtOAc was added to the
reaction mixture. After stirring for additional 10 min, the reaction mixture was filtrated
through a short column of silica gel and the column was washed with EtOAc. The
filtrate was concentrated in vacuo. The residue was purified by preparative thin layer
chromatography (EtOAc/PE = 1/1) to afford compound (+)-24 (3.4 mg, 7.6 μmol) as a
white solid in 76% yield; Rf = 0.33 (EtOAc/PE = 1/1); m.p. 212-214 oC [ Lit9: m.p. 209-
213 oC]; [α]17D = +58 (c = 0.56, EtOH); [ Lit9: [α]28D = +55 (c = 0.12, EtOH), [α]26D = +60
(c = 0.56, EtOH)]; 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 6.12 (ddd, J = 10.1, 7.3,
3.1 Hz, 1H), 4.77 (dd, J = 7.3, 1.9 Hz, 1H), 3.87 (t, J = 8.5 Hz, 1H), 3.46 (dd, J = 11.1,
1.8 Hz, 1H), 3.19 (s, 3H), 2.97 (dd, J = 11.1, 7.3 Hz, 1H), 2.81-2.71 (m, 1H), 2.62 (dd,
J = 12.0, 7.2 Hz, 1H), 2.53 (ddd, J = 12.4, 7.2, 3.1 Hz, 1H), 2.28-2.17 (m, 1H), 2.15 (s,
3H), 1.77-1.66 (m, 1H), 1.74 (s, 3H), 1.60-1.51 (m, 1H), 1.46 (br s, 1H), 1.43-1.38 (m,
1H), 0.86 (s, 3H); C NMR (125 MHz, CDCl3) δ 173.00, 169.63, 157.73, 149.75,
13

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148.45, 145.05, 142.68, 141.99, 114.24, 88.98, 77.01, 72.92, 70.76, 59.43, 45.27, 44.19,
40.70, 40.10, 30.57, 26.57, 24.67, 21.14, 11.82; IR (neat, cm-1): 3473, 2915, 2848, 1740,
1676, 1541, 1466, 1372, 1220, 1097, 1025, 907, 729, 562; HRMS-ESI (m/z) calc. for
C23H27O8 [M + H+]: 431.1700; Found: 431.1701.

Synthesis of compound (−)-25

To a stirred solution of (−)-5 (57.9 mg, 0.12 mmol) in THF (2 mL) was added
3HF∙Et3N (1 mL) at room temperature. The reaction mixture was stirred at 45 °C for
17 h, then silica gel and EtOAc was added to the reaction mixture at 0 oC. After stirring
for 10 min, the reaction mixture was filtrated through a short column of silica gel and
the column was washed with EtOAc. The filtrate was concentrated in vacuo. The
residue was purified by preparative thin layer chromatography (EtOAc) to afford
compound (−)-25 (42.5 mg, 0.11 mmol) as a colorless oil in 95% yield; Rf = 0.64
(EtOAc); [α]20D = −29.5 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H),
4.47 (dd, J = 5.6, 3.2 Hz, 1H), 3.73 (t, J = 8.6 Hz, 1H), 3.65 (dd, J = 11.4, 3.2 Hz, 1H),
3.40 (dd, J = 11.4, 5.7 Hz, 1H), 3.21 (d, J = 11.0 Hz, 1H), 3.15 (d, J = 4.7 Hz, 4H),
2.49-2.38 (m, 1H), 2.18-2.01 (m, 2H), 1.87 (s, 4H), 1.68 (d, J = 15.2 Hz, 1H), 1.41-1.58
(m, 2H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.01, 158.82, 149.38, 144.13,
141.39, 115.05, 86.62, 80.51, 72.07, 69.65, 59.07, 54.41, 49.98, 42.23, 37.92, 36.41,
35.40, 30.57, 24.96, 23.54, 12.66; IR (neat, cm-1): 3675, 2990, 2971, 2900, 1967, 1746,
1696, 1394, 1231, 1066, 899, 755; HRMS-ESI (m/z) calc. for C21H24NaO7 [M + Na+]:
411.1414; Found: 411.1422.

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Synthesis of compound (+)-26

To a stirred solution of (−)-25 (17.3 mg, 44 μmol) in DCM (3 mL) was added Dess-
Martin periodinane (DMP) (38 mg, 89 μmol) at 0 oC. The reaction mixture was stirred
at this temperature for 1 h, and then warmed to room temperature. After stirring for 30
min, the reaction mixture was concentrated in vacuo. The residue was purified by
preparative thin layer chromatography (EtOAc) to afford compound (+)-26 as a white
solid (15.2 mg, 44 μmol) in 89% yield; Rf = 0.64 (EtOAc); m.p. 215-218 oC; [α]20D =
+17.3 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 4.46 (dd, J = 5.3,
3.2 Hz, 1H), 3.64 (dd, J = 11.3, 3.2 Hz, 1H), 3.43 (dd, J = 11.4, 5.3 Hz, 1H), 3.35 (d, J
= 11.0 Hz, 1H), 3.19 (d, J = 5.2 Hz, 1H), 3.15 (s, 3H), 2.85-2.93 (m, 1H), 2.48 (dd, J =
19.8, 9.28 Hz, 1H), 2.31-2.16 (m, 2H), 2.04 (dd, J = 15.5, 5.3 Hz, 1H), 1.90-1.86 (m,
4H), 1.83-1.77 (m, 1H), 1.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 219.08, 183.23,
158.60, 149.60, 143.89, 141.65, 115.17, 86.43, 72.07, 69.72, 59.08, 53.99, 48.65, 46.18,
37.85, 37.31, 36.07, 30.74, 23.67, 16.56; IR (neat, cm-1): 2972, 2922, 1739, 1694, 1538,
1454, 1226, 1133, 1040, 1000, 933, 753, 552; HRMS-ESI (m/z) calc. for C21H26NO7
[M + NH4+]: 404.1704; Found: 404.1704.

Synthesis of compound (+)-27 (11-O-Desacetyl-wortmannin)

To a stirred solution of (+)-26 (17.3 mg, 45 μmol) in DCM (1.5 mL) was added
Et2NH (9.2 μL, 89 μmol) at room temperature. The reaction mixture was stirred at this
temperature for 20 min, then concentrated in vacuo. To a solution of the residue in DCM
(1.5 mL) was added DBN (22 μL, 180 μmol) at 35 oC. The reaction mixture was stirred
at this temperature for 4 h, then concentrated in vacuo. To a solution of the residue in
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THF (1.8 mL) was added 3 N aqueous HCl solution (1 mL) at 35 oC. The reaction
mixture was stirred at this temperature for 12 h, then poured into water, and extracted
with EtOAc three times. The combined organic layer was dried over Na 2SO4, and
concentrated in vacuo. The residue was purified by preparative thin layer
chromatography (EtOAc) to afford compound (+)-27 (9.3 mg, 24 μmol) as a colorless
oil in 54% yield with the recovery of (+)-26 (2.4 mg, 14%). Compound (+)-27: Rf =
0.59 (EtOAc); [α]20D = +126.2 (c = 0.5, CHCl3); [Lit9: [α]20D = +144 (c = 0.90, CHCl3)];
1
H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 5.61 (dd, J = 9.3, 3.9 Hz, 1H), 4.87-4.94
(m, 1H), 3.51 (dd, J = 9.6, 3.9 Hz, 1H), 3.47 (d, J = 9.8 Hz, 1H), 3.20-3.13 (m, 1H),
3.18 (s, 3H), 2.87 (t, J = 9.5 Hz, 1H), 2.85-2.78 (m, 1H), 2.59 (dd, J = 19.4, 8.7 Hz,
1H), 2.45 (dd, J = 12.7, 6.5 Hz, 1H), 2.23 (dt, J = 19.4, 8.9 Hz, 1H), 2.12-1.99 (m, 1H),
1.80 (s, 3H), 1.54 (dd, J = 12.6, 10.1 Hz, 1H), 0.96 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 216.80, 173.44, 157.58, 155.68, 149.80, 146.18, 141.85, 135.95, 113.39, 85.74, 71.12,
69.17, 59.41, 49.28, 44.55, 41.16, 39.86, 35.75, 25.43, 23.08, 14.75; IR (neat, cm-1):
3444, 3130, 2933, 1742, 1675, 1644, 1541, 1467, 1373, 1141, 1105, 994, 759, 663, 570,
547; HRMS-ESI (m/z) calc. for C21H23O7 [M + H+]: 387.1438; Found: 387.1441.

Synthesis of (+)-Wortmannin (1)

The first approach：

To a stirred solution of (+)-24 (3.3 mg, 7.7 μmol) in DCM (0.8 mL) was added
Dess-Martin periodinane (DMP) (5.0 mg, 12.0 μmol) at 0 oC. The reaction mixture was
stirred at this temperature for 2 h, and then warmed to room temperature. After stirring
for 30 min, the reaction mixture was concentrated in vacuo. The residue was purified
by preparative thin layer chromatography (EtOAc/PE = 1/1) to afford compound (+)-
Wortmannin (1) (2.8 mg, 6.5 μmol) as a white solid in 85% yield.

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The second approach：

To a stirred solution of (+)-27 (9 mg, 23 μmol) in pyridine (1.8 mL) was added
Ac2O (25 μL, 0.27 mmol) at room temperature. The reaction mixture was stirred at this
temperature for 12 h, and concentrated in vacuo. The residue was purified by
preparative thin layer chromatography (EtOAc/PE = 1/1) to afford compound (+)-
Wortmannin (1) (8.4 mg, 20 μmol) as a white solid in 84% yield; Rf = 0.85 (EtOAc);
m.p. 238-240 oC [ Lit10,11: m.p. 240 oC, 238-239 oC]; [α]20D = +86.5 (c = 0.17, CHCl3),
[α]18D = +86.4 (c = 1.1, CHCl3); [Lit11,12: [α]28D = +88 (c = 0.17, CHCl3), [α]26D = +89 (c =
1.1, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 6.16 (ddd, J = 8.8, 7.5, 2.8
Hz, 1H), 4.76 (dd, J = 7.0, 1.9 Hz, 1H), 3.46 (dd, J = 11.2, 1.9 Hz, 1H), 3.21-3.14 (m,
1H), 3.19 (s, 3H), 3.01 (dd, J = 11.2, 7.0 Hz, 1H), 2.89 (ddd, J = 12.7, 6.0, 2.7 Hz, 1H),
2.66-2.53 (m, 2H), 2.30-2.21 (m, 1H), 2.14 (s, 3H), 2.12-2.01 (m, 1H), 1.74 (s, 3H),
1.60 (dd, J = 13.3, 8.3 Hz, 1H), 0.97 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 216.11,
172.62, 169.47, 157.56, 149.97, 149.56, 144.80, 142.86, 140.39, 114.30, 88.52, 72.89,
70.08, 59.45, 49.20, 44.10, 40.78, 36.19, 35.73, 26.51, 22.95, 21.04, 14.60; IR (neat,
cm-1): 3126, 2982, 2930, 1745, 1678, 1542, 1468, 1372, 1228, 1211, 1142, 1032, 993,
793, 762, 594; HRMS-ESI (m/z) calc. for C23H25O8 [M + H+]: 429.1544; Found:
429.1544.

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Table S4. Comparison of the 1H NMR for Synthetic 17-β-Hydroxy-wortmannin
and Literature Data

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Table S5. Comparison of the 1H NMR for Synthetic 11-O-Desacetyl-wortmannin
and Literature Data

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Table S6. Comparison of the 1H and 13C NMR for Synthetic Wortmannin and
Literature Data

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III. Evaluation of Wortmannin and Analogs by In Vitro Kinase

Assays

Table S7. “Kd (nM)” of Wortmannin and Analogs towards Kinasesa

Kinases (+)-1 (−)-4 (+)-24 (−)-25
p110α 8.0 ±2.2 >100000 2.8 ±0.6 420 ±127
p110β 12.2 ±1.7 N.D. 2.8 ±0.5 74 ±19
p110δ 21 ±6.0 N.D. 10.1 ±5.0 495 ±173
p110γ 10.2 ±2.1 N.D. 10.8 ±5.7 215 ±35
VPS34 14.2 ±3.3 N.D. 7.7 ±1.1 87 ±12
p110α (E545K) N.D. N.D. 2.4 ±0.6 384 ±121
p110α (H1047L) N.D. N.D. 3.6 ±0.5 172 ±43
PI3K-C2β N.D. N.D. 39 ±11 429 ±194
PI4Kβ N.D. N.D. 99 ±15 >10000
PLK1 N.D. N.D. 74 ±35 N.D.
PIP5K1A N.D. N.D. >10000 >10000
CLK1 N.D. N.D. >10000 N.D.
CSNK1E N.D. N.D. >10000 N.D.
CSNK1G3 N.D. N.D. >10000 N.D.
EGFR (G719C) N.D. N.D. >10000 >10000
EGFR (L861Q) N.D. N.D. N.D. >10000
MST1 N.D. N.D. >10000 N.D.
a K ± SEM (nM) values were measured using KdELECT (DiscoverX).
d

Table S8. In vitro Kinase Assay Measurements of IC50 (nM) Values for (+)-24 and
(−)-25 Using SelectScreen (Invitrogen)a
Kinases (+)-24 (−)-25
PI3Kα 1.1 ±0.2 1406 ±317
PI3Kβ 8.5 ±0.7 1227 ±160
PI3Kδ 1.0 ±0.2 886 ±92
PI3Kγ 6.2 ±0.8 1731 ±1419
VPS34 3.1 ±0.2 390 ±110
PI3Kα (E545K) 2.2 ±0.3 2268 ±291
PI4Kβ 125 ±19 >10000
PI3K-C2α 416 ±48 >10000
PI3K-C2β 6.2 ±0.5 2684 ±479
DNA-PK 111 ±12 >10000
PLK1 34 ±13 >10000
EGFR (L861Q) >10000 >10000
a IC ± SEM
50 (nM) were determined at Km(ATP).

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Figure S3 (related to Table S9). KinomeScan Profile of (+)-24 and (−)-25 against 468
Kinases. The dendrograms were generated with DiscoverX TREEspotTM software.
Targets retaining less than 35% residual activity (red circles) or more than 35% (green
circles) (compared with DMSO controls) after (+)-24 (1 μM) or (−)-25 (5 μM)
treatment. Circle size is proportional to binding affinity. Blue circles represent false
positives that have been identified using KdELECT (Table S7).

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 1
IV. H, and 13C NMR Spectra of Compounds

1
H NMR of compound (+)-S31

13
C NMR of compound (+)-S31
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1
H NMR of compound S25

13
C NMR of Compound S25

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1
H NMR of Compound S27

13
C NMR of Compound S27

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1
H NMR of compound S30

13
C NMR of compound S30

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1
H NMR of Compound 14

13
C NMR of Compound 14

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1
H NMR of Compound S28

13
C NMR of Compound S28

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1
H NMR of compound (+)-S13

13
C NMR of compound (+)-S13

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1
H NMR of compound S14

13
C NMR of compound S14

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1
H NMR of compound S15

13
C NMR of compound S15

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1
H NMR of compound S16

13
C NMR of compound S16

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1
H NMR of compound S17

13
C NMR of compound S17

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1
H NMR of compound S18

13
C NMR of compound S18

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1
H NMR of compound (+)-S4

13
C NMR of compound (+)-S4

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1
H NMR of compound (−)-S5

13
C NMR of compound (−)-S5

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1
H NMR of compound (+)-15

13
C NMR of compound (+)-15

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1
H NMR of compound (−)-S12

13
C NMR of compound (−)-S12

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1
H NMR of compound (+)-17

13
C NMR of compound (+)-17

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1
H NMR of compound (+)-9

13
C NMR of compound (+)-9

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HSQC of compound (+)-9

COSEY of compound (+)-9

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NOSEY of compound (+)-9

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1
H NMR of compound (−)-S19

13
C NMR of compound (−)-S19

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HSQC of compound (−)-S19

COSEY of compound (−)-S19

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NOSEY of compound (−)-S19

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1
H NMR of compound (−)-S20

13
C NMR of compound (−)-S20

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1
H NMR of compound (−)-18

13
C NMR of compound (−)-18

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1
H NMR of compound (−)-S21

13
C NMR of compound (−)-S21

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1
H NMR of compound (+)-S38

13
C NMR of compound (+)-S38

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1
H NMR of compound (+)-8

13
C NMR of compound (+)-8

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1
H NMR of compound (−)-19

13
C NMR of compound (−)-19

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1
H NMR of compound (−)-20

13
C NMR of compound (−)-20

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1
H NMR of compound (−)-S22

13
C NMR of compound (−)-S22

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1
H NMR of compound (−)-6

13
C NMR of compound (−)-6

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1
H NMR of compound (+)-21

13
C NMR of compound (+)-21

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1
H NMR of compound (−)-5

13
C NMR of compound (−)-5

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1
H NMR of compound (+)-23

13
C NMR of compound (+)-23

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1
H NMR of compound (+)-S39

13
C NMR of compound (+)-S39

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1
H NMR of compound (+)-24

13
C NMR of compound (+)-24

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1
H NMR of compound (−)-25

13
C NMR of compound (−)-25

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1
H NMR of compound (+)-26

13
C NMR of compound (+)-26

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1
H NMR of compound (+)-27

13
C NMR of compound (+)-27

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1
H NMR of compound (+)-Wortmannin (1)

13
C NMR of compound (+)-Wortmannin (1)

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 V. References

1. (a) Nieman, J. A.; Keay, B. A. Tetrahedron Lett. 1994, 35, 5335-5338. (b) Bures,
E.; Nieman, J. A.; Yu, S.; Spinazzé, P. G.; Bontront, J.-L. J.; Hunt, I. R.; Rauk, A.;
Keay, B. A. J. Org. Chem. 1997, 62, 8750-8759.
2. a) Isaacs, R. C.; Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938-
3941; b) Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11, 5394-5397.
3. Hussein, M.; Dine, A. N.; Fares, F.; Dorcet, V.; Hachem, A.; Gree, R. Tetrahedron
Lett. 2016, 57, 1990-1993.
4. Gonzalezgarcia, E. M.; Grognux, J.; Wahler, D.; Reymond, J. Helv. Chim. Acta.
2003, 86, 2458-2470.
5. Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834-
8837.
6. Cai, Z. R.; Jabri, S. Y.; Jin, H.; Lansdown, R. A.; Metobo, S. E.; Mish, M. L.; Pastor,
R. PCT Int. Appl. WO 2007136714 A2, 2007.
7. (a) Sugimura, T.; Paquette, L. A. J. Am. Chem. Soc. 1987, 109, 3017-3024. (b)
Yamashita, S.; Iso, K.; Kitajima, K.; Himuro, M.; Hirama, M. J. Org. Chem. 2011,
76, 2408-2425.
8. Hoecker, J.; Gademann, K. Org. Lett. 2013, 15, 670-673.
9. Haefliger, W.; Kis, Z.; Hauser, D. Helv. Chim. Acta 1975, 58, 1620-1628.
10. Brian, P.W.; Curtis, P. J.; Hemming, H. G.; Norris, G. F. L. Trans. Br. Mycol. Soc.
1957, 40, 365-368.
11. MacMillan, J.; Vanstone, A. E.; Yeboah, S. K. J. Chem. Soc. Perkin Trans. 1 1972,
22, 2898-2903.
12. Sato, S.; Nakada, M.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 6141-6144.
13. Creemer, L. C.; Kirst, H. A.; Vlahos, C. J.; Schultz, R. M. J. Med. Chem. 1996, 39,
5021-5024.
14. Simpson, T. J.; Lunnon, M. W.; MacMillan, J. J. Chem. Soc. Perkin Trans. 1 1979,
4, 931-934.
15. Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002,
41, 4680-4682.

Complete ref 28 in the manuscript:

Ref. 28: (a) Fabian, M. A.; Biggs III, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.;
Carter, T. A.; Ciceri, P.; Edden, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard,
S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lélias, J.-M.; Mehta, S. A.; Milanov, Z. V.; Velsasco, A. M.; Modicka,
L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. Nat. Biotech. 2005, 23, 329-336. (b) Karaman, M. W.; Herrgard,
S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P.
T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.;
Pritchard, S.; Wodicka, L. M.; Zarrinkar, P. P. Nat. Biotech. 2008, 26, 127-132.

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