Total Synthesis of (±)-Jiadifenin, a Non-peptidyl

Neurotrophic Modulator

David Carcache,1 Young Shin Cho,1 Zihao Hua,1 Yuan Tian,2 Yue-Ming Li,2 Samuel J. Danishefsky1,3,*

1
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New
York, New York 10021
2
Laboratory of Biochemistry and Pharmacology, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue,
New York, New York 10021
3
Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027

Supporting Information

O
O a. LHMDS, MeI
b. KOH, HCHO O
O
O
O
5 OH

To a solution of LHMDS (1.0 M in THF, 89.5 mL, 1.0 equiv) in THF (250 mL) at -78 oC was added a
solution of ketone 5 (13.90 g, 89.00 mmol) in THF (40 mL) slowly over 15 min and the resulting mixture
was stirred at -78 oC for 34 min. Iodomethane (6.5 mL, 1.2 equiv) was added to the reaction mixture and
the resulting solution was stirred at -78 oC for 20 min and at room temperature for 2 h. The reaction
mixture was quenched by addition of saturated NH4Cl (250 mL) and extracted with ether (3 x 250 mL).
Combined extracts were dried (MgSO4), filtered, and concentreated in vacuo. Flash chromatography
(pentane-ether 4:1 → 3:1 → 2:1) afforded α-methylcyclohexanone (11.16 g, 74% yield). The
spectroscopic data of the product were in accord with the published data1.

1
Pfau, M.; Jabin, I.; Revial, G. J. Chem. Soc., Perkin Trans. 1, 1993, 1935.
S1
 To a yellow solution of α-methylcyclohexanone (1.871 g, 10.67 mmol) in 10% KOH in MeOH (10 g)
at 0 oC was added a solution of 37% aqueous formaldehyde (0.80 mL, 1.0 equiv) in MeOH (0.80 mL)
dropwise over 30 min. The reaction mixture was stirred at 0 oC for 15 min. The reaction mixture was
quenched by addition of 1 N aqueous HCl (18 mL), diluted with saturated NH4Cl (20 mL), and extracted
with CH2Cl2 (4 x 100 mL). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo.
Flash chromatography (hexanes-ether 1.5:1 → 1:1 →1:2 → 1:3) gave alcohol product (1.508 g, 71% yield,
89% based on recovered starting material): IR (neat) 3475 (m, br), 2959 (m), 2933 (m), 2883 (m), 1706 (s),
1457 (w), 1432 (w), 1362 (w), 1308 (w), 1275 (w), 1151 (w), 1113 (m), 1078 (m), 1038 (m), 995 (w), 948
(m) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.07-3.93 (m, 4 H), 3.58 (dd, J = 7.4, 11.3 Hz, 1 H), 3.37 (dd, J =
6.6, 11.4 Hz, 1 H), 2.75 (ddd, J = 6.1, 11.1, 15.0 Hz, 1 H), 2.59 (t, J = 7.0 Hz, 1 H), 2.40 (td, J = 5.5, 15.0
Hz, 1 H), 2.16 (d, J = 14.1 Hz, 1 H), 2.06-1.93 (m, 2 H), 1.74 (dd, J = 2.6, 14.1 Hz, 1 H), 1.55 (s, 1 H),
1.20 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 215.1, 107.3, 68.5, 64.4, 64.1, 49.4, 42.1, 36.2, 34.0, 21.4;
HRMS m/z 223.0943 [(M+Na)+; calcd for C10H16O4Na: 223.0946].

O O
TBSOTf or
O TBDPS-Cl O
O O

OH OR
11: R = TBS
17: R = TBDPS

TBS ether 11. A solution of the alcohol (2.80 g, 14 mmol) in CH2Cl2 (150 mL) was cooled to 0 oC,
treated with 2,6-lutidine (4.0 mL, 2.5 equiv) and TBSOTf (3.7 mL, 1.1 equiv) and stirred at 0 oC for 15
min. The reaction mixture was quenched with saturated NH4Cl (175 mL) and extracted with CH2Cl2 (3 x
150 mL). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Flash
chromatography (hexanes-ether 4:1 → 3:1 → 2:1) gave TBS ether 11 (4.73 g, 97% yield): IR (neat) 2955
(s), 2930 (s), 2884 (s), 2859 (s), 1716 (s), 1472 (m), 1463 (m), 1433 (w), 1387 (w), 1361 (m), 1307 (w),
1255 (m), 1101 (m, br), 1035 (w), 1005 (w), 949 (w), 837 (m, br) cm-1; 1H NMR (400 MHz, CDCl3) δ 3.98
(m, 4 H), 3.73 (d, J = 9.4 Hz, 1 H), 3.46 (d, J = 9.4 Hz, 1 H), 2.52 (tdd, J = 6.8, 15.6, 37.8 Hz, 2 H), 2.25
(d, J = 14.2 Hz, 1 H), 1.97 (t, J = 7.1 Hz, 2 H), 1.72 (d, J = 14.0 Hz, 1 H), 1.10 (s, 3 H), 0.84 (s, 9 H), 0.01
(s, 6 H); 13C NMR (125 MHz, CDCl3) δ 213.2, 107.9, 68.3, 64.4, 64.3, 49.9, 41.6, 36.3, 33.9, 25.8, 21.8,
18.2, -5.58, -5.59; HRMS m/z 337.1808 [(M+Na)+; calcd for C16H30O4NaSi: 337.1811].
TBDPS ether 17: A solution of the alcohol (436 mg, 2.18 mmol) in dry DMF (2.4 ml) was treated with
imidazole (445 mg, 6.54 mmol) and TBDPS-Cl (1.43 ml, 5.45 mmol) and the resulting pale yellow
solution was stirred for 4 h at room temperature. The mixture was then poured into H2O (20 ml) and
extracted with Et2O (3 x 30 mL). The combined organic layers were then washed with H2O (1 x 80 mL),
brine (1 x 80 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (SiO2, Pentane/Et2O 3:1) provided TBDPS ether 17 (762 mg, 80% yield) as a colorless
liquid: IR (neat) 2929 (m), 1710 (s), 1426 (m), 1111 (s), 823 (m), 741 (w), 701 (s), 614 (w) cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.70-7.62 (m, 4 H), 7.46-7.35 (m, 6 H), 4.02-3.93 (m, 4 H), 3.84 (d, J = 9.7, 1 H),
3.55 (d, J = 9.7, 1 H), 2.62-2.44 (m, 2 H), 2.37 (d, J = 14.2, 1 H), 2.01 (d, J = 7.5, 1 H), 1.99 (d, J = 6.5, 1
H), 1.80 (d, J = 13.8, 1 H), 1.15 (s, 3 H), 1.03 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 212.8, 135.7 (2x),
135.7 (2x), 133.4, 133.3, 129.6 (2x), 127.6 (2x), 127.6 (2x), 107.8, 68.8, 64.4, 64.3, 50.1, 41.9, 36.3, 34.0,
26.8 (3x), 21.9, 19.3; HRMS (ESI) calcd. for C26H35O4Si [M+H]+ 439.2305, found 439.2319.
S2
 O O

O LHMDS O
allyl bromide
O O

OR OR
11: R = TBS 14: R = TBS
17: R = TBDPS 18: R = TBDPS

Ketone 14. To a solution of TBS ether 11 (1.389 g, 4.42 mmol) in THF (45 mL) at -78 oC was added
LHMDS (1.0 M in THF, 4.40 mL, 1.0 equiv) dropwise and the resulting mixture was stirred at -78 oC for
23 min. The reaction mixture was treated with allyl bromide (0.57 mL, 1.5 equiv) and warmed to room
temperature over 4 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted
with ether (3 X 100 mL). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo.
Flash chromatography (hexanes-ether 10:1 → 3:1) afforded a mixture (less polar compound:more polar
compound = 1:1.3) of α-allylcyclohexanone 14 (1.147 g, 73% yield, 99% based on recovered starting
material); IR (neat) 2954 (s), 2929 (s), 2884 (s), 2857 (s), 1716 (s), 1641 (w), 1472 (m), 1463 (m), 1387
(w), 1361 (m), 1297 (w), 1257 (m), 1202 (w), 1177 (w), 1095 (s, br), 1031 (w), 1006 (w), 948 (w), 913
(w), 836 (m, br) cm-1; less polar compound 1H NMR (500 MHz, CDCl3) δ 5.73 (m, 1 H), 5.01 (m, 2 H),
4.05 (m, 2 H), 3.96 (m, 2 H), 3.80 (d, J = 9.5 Hz, 1 H), 3.27 (d, J = 9.5 Hz, 1 H), 2.83 (m, 1 H), 2.51 (td, J
= 6.2, 14.4 Hz, 1 H), 2.24 (d, J = 14.1 Hz, 1 H), 2.08-1.98 (m, 2 H), 1.81 (dd, J = 3.6, 14.1 Hz, 1 H), 1.65
(t, J = 13.6 Hz, 1 H), 1.19 (s, 3 H), 0.86 (s, 9 H), 0.03 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ 213.5,
136.1, 116.6, 107.9, 68.3, 64.7, 64.0, 49.6, 43.1, 41.8, 39.3, 33.2, 25.8, 22.5, 18.2, -5.5, -5.6; more polar
compound 1H NMR (500 MHz, CDCl3) δ 5.76 (m, 1 H), 5.00 (m, 2 H), 4.02 (m, 2 H), 3.92 (t, J = 6.2 Hz,
2 H), 3.89 (d, J = 9.4 Hz, 1 H), 3.61 (d, J = 9.5 Hz, 1 H), 2.81 (m, 1 H), 2.51 (td, J = 6.1, 14.1 Hz, 1 H),
2.21 (dd, J = 2.8, 14.4 Hz, 1 H), 2.13 (ddd, J = 3.0, 5.4, 13.6 Hz, 1 H), 1.96 (td, J = 7.3, 14.4 Hz, 1 H), 1.68
(d, J = 14.3 Hz, 1 H), 1.65 (t, J = 13.7 Hz, 1 H), 1.06 (s, 3 H), 0.85 (s, 9 H), 0.01 (s, 6 H); 13C NMR (125
MHz, CDCl3) δ 213.3, 136.2, 116.5, 107.6, 68.8, 64.6, 64.1, 50.0, 43.6, 42.7, 40.5, 33.4, 25.7, 21.0, 18.1, -
5.61, -5.64; HRMS m/z 377.2113 [(M+Na)+; calcd for C19H34O4NaSi: 377.2124].

Ketone 18. A solution of LHMDS (1.0 M in THF, 1.06 mL) was diluted with dry THF (8 mL) and cooled
to –78 °C. It was then treated with a solution of TBDPS ether 17 (524 mg, 1.19 mmol) in dry THF (4 mL)
and this mixture was stirred for 30 min at –78 °C. Allyl bromide (0.31 mL, 3.57 mmol) was then added
and the mixture was stirred for another 10 min at –78 °C. The cooling bath was then removed and the
mixture was allowed to warm to r.t. After 16 h, the mixture was poured into sat. aq. NH4Cl (40 mL) and
extracted with Et2O (3 x 60 mL). The combined organic phases were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (SiO2, Pentane/ Et2O 9:1) gave ketone 18
(290 mg, 51% yield) as a colorless oil. IR (neat) 2930 (m), 1715 (s), 1428 (m), 1112 (s), 824 (w), 740 (w),
702 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ less polar diast. 7.73-7.61 (m, 4 H), 7.45-7.36 (m, 6 H), 5.77
(ddt, J = 17.1, 10.1, 7.0, 1 H), 5.04 (d, J = 17.3, 1 H), 5.02 (d, J = 9.6, 1 H), 4.09-3.95 (m, 4 H), 3.92 (d, J
= 9.7, 1 H), 3.32 (d, J = 9.7, 1 H), 2.89 (ddt, J = 13.5, 8.0, 5.3, 1 H), 2.57-2.50 (m, 1 H), 2.42 (d, J = 14.0,
1 H), 2.13-2.04 (m, 2 H), 1.91 (dd, J = 14.0, 3.6, 1 H), 1.72 (t, J = 13.6, 1 H), 1.21 (s, 3 H), 1.04 (s, 9 H);
more polar diast. 7.66-7.61 (m, 4 H), 7.46-7.36 (m, 6 H), 5.79-5.68 (m, 1 H), 5.06-4.99 (m, 2 H), 4.00 (d,
J = 9.8, 1 H), 3.96-3.87 (m, 4 H), 3.70 (d, J = 9.8, 1 H), 2.77 (ddt, J = 13.6, 7.8, 5.5, 1 H), 2.55-2.49 (m, 1

S3
 H), 2.23 (dd, J = 14.4, 3.0, 1 H), 2.10 (ddd, J = 13.6, 5.3, 3.1, 1 H), 2.03-1.95 (m, 1 H), 1.74 (d, J =
14.3, 1 H), 1.64 (t, J = 13.7, 1 H), 1.14 (s, 3 H), 1.04 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ less polar
diast. 213.0, 136.1, 135.7 (2x), 135.6 (2x), 133.5, 133.3, 129.6 (2x), 127.6 (4x), 116.7, 107.9, 68.8, 64.7,
64.0, 49.9, 43.0, 42.1, 39.3, 33.3, 26.8 (3x), 22.6, 19.3; more polar diast. 213.1, 136.2, 135.6 (4x), 133.3,
133.2, 129.7, 129.6, 127.6 (2x), 127.6 (2x), 116.6, 107.4, 69.4, 64.5, 64.1, 50.2, 43.5, 43.1, 40.3; 33.4, 26.8
(3x), 21.2, 19.3; HRMS (ESI) calcd. for C29H39O4Si [M+H]+ 479.2618, found 479.2617.

O O O
LDA; HMPA EtO2C O EtO2C O
O
BrCH2CO2Et +
O O O

OR OR OR
14: R = TBS 15: R = TBS 16: R = TBS
18: R = TBDPS 19: R = TBDPS 20: R = TBDPS

Esters 15 and 16. To a solution of LDA (1.1 equiv.) in THF (30 mL) at -78 oC was added a solution of α-
allylcyclohexanone 14 (3.036 g, 8.562 mmol) in THF (6 mL) dropwise and the resulting mixture was
warmed to -20 oC over 2 h. The reaction mixture was cooled to –78 oC and treated with a mixture of ethyl
bromoacetate (2.0 mL, 2.1 equiv.) and HMPA (1.5 mL, 1.1 equiv.). The resultant mixture was stirred at -
78 oC for 21 h. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with
ether (3 x 250 mL). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Flash
chromatography (hexanes-ether 10:1 → 6:1 → 3:1) afforded esters 15 (2.754 g, 73% yield) and 16 (0.905
g, 24% yield).
15: IR (neat) 2955 (s), 2929 (s), 2883 (s), 2857 (s), 1733 (s), 1710 (s), 1638 (w), 1472 (m), 1463 (m), 1407
(m), 1388 (m), 1370 (m), 1344 (m), 1254 (m), 1190 (m), 1155 (m), 1098 (m, br), 1033 (m), 984 (m), 947
(m), 917 (m), 839 (m,br) cm-1; 1H NMR (400 MHz, CDCl3) δ 5.65 (m, 1 H), 5.06 (m, 2 H), 4.04 (q, J = 7.2
Hz, 2 H), 4.00-3.88 (m, 4 H), 3.96 (d, J = 8.9 Hz, 1 H), 3.13 (d, J = 9.1 Hz, 1 H), 2.89 (d, J = 16.6 Hz, 1
H), 2.58 (d, J = 14.6 Hz, 1 H), 2.45 (dd, J = 7.5, 13.8 Hz, 1 H), 2.43 (d, J = 14.4 Hz, 1 H), 2.20 (d, J = 16.7
Hz, 1 H), 2.16 (dd, J = 7.3, 13.8 Hz, 1 H), 1.95 (d, J = 14.5 Hz, 1 H), 1.81 (d, J = 15.4 Hz, 1 H), 1.19 (t, J
= 7.1 Hz, 3 H), 1.13 (s, 3 H), 0.84 (s, 9 H), 0.00 (s, 3H), -0.01 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
214.9, 171.5, 133.0, 119.2, 107.8, 68.4, 64.0, 63.8, 60.3, 49.5, 48.3, 41.2, 40.6, 39.6, 39.4, 25.8, 22.8, 18.2,
14.2, -5.6, -5.7; HRMS m/z 463.2478 [(M+Na)+; calcd for C23H40O6NaSi: 463.2492].
16: IR (neat) 2929 (s, br), 2883 (s), 2858 (s), 1732 (s), 1698 (s), 1638 (m), 1474 (m), 1408 (w), 1389 (w),
1370 (m), 1341 (m), 1304 (w), 1252 (m), 1187 (m), 1152 (m), 1094 (m), 1033 (m), 1013 (m), 972 (m), 948
(m), 918 (m), 836 (m, br) cm-1; 1H NMR (400 MHz, CDCl3) δ 5.61 (m, 1 H), 5.06 (m, 2 H), 4.03 (q, J =
7.1 Hz, 2 H), 4.01-3.95 (m, 2 H), 3.90 (m, 2 H), 3.71 (d, J = 9.3 Hz, 1 H), 3.47 (d, J = 9.3 Hz, 1 H), 2.82
(d, J = 16.7 Hz, 1 H), 2.55 (dd, J = 7.6, 13.8 Hz, 1 H), 2.38 (dd, J = 7.2, 13.8 Hz, 1 H), 2.29 (d, J = 14.4
Hz, 1 H), 2.22 (d, J = 14.2 Hz, 1 H), 2.21 (d, J = 16.7 Hz, 1 H), 1.97 (dd, J = 2.6, 14.2 Hz, 1 H), 1.85 (dd, J
= 2.6, 14.4 Hz, 1 H), 1.193 (s, 3 H), 1.185 (t, J = 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.004 (s, 3 H), -0.002 (s, 3 H);
13
C NMR (100 MHz, CDCl3) δ 215.9, 171.8, 133.7, 119.6, 108.2, 69.8, 65.0, 63.8, 60.7, 49.6, 49.5, 42.3,
41.6, 40.8, 39.9, 26.3, 23.4, 18.7, 14.6, -5.1, -5.2; HRMS m/z 463.2487 [(M+Na)+; calcd for
C23H40O6NaSi: 463.2492].

S4
 Esters 19 and 20. A solution of LDA (0.451 mmol) in dry THF (1.2 mL) at –78 °C was treated with
a solution of ketone 18 (188 mg, 0.392 mmol) in dry THF (0.5 mL). This mixture was allowed to warm to
–35 °C over 3 h, and was then cooled again to –78 °C. HMPA (65 µL, 0.392 mmol) and ethyl
bromoacetate (87 µl, 0.784 mmol) were then added and the flask was placed in the freezer at –78 °C. After
40 h, the reaction was quenched by adding sat. aq. NH4Cl (20 ml) and this mixture was extracted with
AcOEt (3 x 40 mL). The combined organic layers were dried voer MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography (SiO2, Pentane/Et2O 5:1) afforded esters 19/20 (187 mg, 85%
yield, 19/20 = 6.8:1) as a mixture of diastereoisomers.

O O
a. LHMDS
O allyl bromide O
O b. TBAF O

14 OTBS 12 OH

Alcohol 12. To a solution of 14 (0.509 g, 1.43 mmol) in THF (40 mL) at –78 oC was added LHMDS (2.4
mL, 1.0 M in THF) dropwise. The resulting mixture was stirred at –78 oC for 30 min. Allyl bromide (0.30
mL, 3.5 mmol) was added and the reaction mixture was warmed to room temperature slowly and stirred at
room temperature overnight. The reaction was quenched with sat. NH4Cl and then extracted with Et2O
(100 mL x 3). Combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo.
Flash chromatography (hexanes-ether 15:1 → 6:1) afforded diallyl product (0.566 g, 95% yield). The
diallyl compound (2.833 g, 7.18 mmol) was dissolved in THF (150 mL) and to this solution was added
TBAF (1.0 M in THF, 10.5 mL), the resulting mixture was stirred at room temperature overnight. The
reaction was quenched with sat. NH4Cl and then extracted with EtOAc (200 mL x 4). Combined extracts
were dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography (hexanes-
ether 15:1 → 3:1 → 2:1 → 1:1 → 1:2 → 1:4 → ether) afforded alcohol 12 (1.544 g, 76% yield): IR (neat)
3501 (s, br), 3076 (m), 2934 (s, br), 1843 (w), 1699 (s), 1636 (m), 1456 (s), 1362 (m), 1262 (m), 1150 (m),
1079 (m), 920 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 5.60 (m, 2 H), 5.05 (m, 4 H), 3.95 (m, 4 H), 3.63
(dd, J = 7.6, 11.1 Hz, 1 H), 3.29 (dd, J = 6.0, 11.1 Hz, 1 H), 2.44 (m, 3 H), 2.27 (dd, J = 7.8, 13.9 Hz, 1 H),
2.23 (d, J = 14.6 Hz, 1 H), 2.14 (dd, J = 8.1, 13.9 Hz, 1 H), 2.02 (m, 2 H), 1.81 (d, J = 14.7 Hz, 1 H), 1.15
(s, 3 H); 13C NMR (125 MHz, CDCl3) δ 218.2, 133.5, 133.4, 119.0, 118.9, 107.6, 69.5, 64.3, 63.8, 50.6,
48.7, 41.4, 41.1, 40.9, 39.6, 21.9; HRMS 281.1739 [M+; calcd for C16H25O4: 281.1753].

Br
O O
Me
NBS H O
O O
H
O O
Br HO
12 OH 13

Bromoether 13. The alcohol 12 (22.6 mg, 0.0806 mmol) was azeotroped with anhydrous toluene (3 x 10
mL) and placed under high vacuum for 1 h. Then 12 was dissolved in THF (3 mL), cooled to -45 oC, and
treated with N-bromosuccinimde (34.6 mg, 2.4 equiv.) in one portion. The resulting mixture was stirred at

S5
 -40 ~ -45 oC for 20 min. The reaction mixture was quenched by addition of saturated NaHCO3 (30
mL) and extracted with ether (3 x 40 mL). Combined extracts were dried (MgSO4), filtered and
concentrated in vacuo. Flash chromatography (hexanes-ether 3:1 → 1:1 → 1:2 → 1:4 → ether) afforded
bromoether 13 (24.3 mg, 66% yield) and a mixture of other isomers (8.8 mg, 24% yield). IR (neat) 3543
(m, br), 2962 (s), 2879 (s), 1709 (m), 1458 (m), 1419 (m), 1361 (m), 1317 (w), 1223 (m), 1096 (s), 1017
(s), 880 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 4.38 (m, 2 H), 3.90-3.83 (m, 4 H), 3.58 (dd, J = 5.0, 11.7
Hz, 1 H), 3.49-3.43 (m, 4 H), 3.37 (dd, J = 6.2, 10.4 Hz, 1 H), 2.60 (t, J = 6.7 Hz, 1 H), 2.18-2.02 (m, 5 H),
1.96 (m, 1 H), 1.92 (d, J = 15.0 Hz, 1 H), 1.64 (d, J = 15.1 Hz, 1 H), 1.06 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 119.2, 108.7, 77.4, 77.1, 68.1, 63.9, 63.8, 52.7, 46.1, 45.3, 44.0, 41.9, 40.2, 34.4, 34.3, 20.1;
HRMS 455.0073 [M+; calcd for C16H25O5Br2: 455.0069].

O
O
LiCH2P(O)(OMe)2 (MeO)2(O)P O
EtO2C O O
O
O
OTBS
15 OTBS

To a solution of dimethyl methylphosphonate (0.51 mL, 20 equiv) in THF (3.0 mL) at -78 oC was added a
solution of n-BuLi (1.6 M in hexanes, 2.80 mL, 19 equiv.) dropwise and the resulting cloudy mixture was
stirred at -78 oC for 22 min. A solution of ester 15 (104 mg, 0.237 mmol) in THF (1.0 mL) was added
dropwise to the reaction mixture and the resulting mixture was stirred at –78 oC for 1 h. The reaction
mixture was quenched by water (40 mL) and extracted with EtOAc (3 x 45 mL). Combined extracts were
dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 3:1 → 1:1)
gave phosphonate (100 mg, 81% yield, 99% based on recovered starting material): IR (neat) 2954 (s), 2929
(s), 2856 (m), 1709 (s), 1462 (m), 1389 (w), 1361 (m), 1257 (s), 1182 (w), 1099 (m), 1030 (s), 983 (w),
948 (w), 917 (w), 838 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 5.64 (m, 1 H), 5.07 (m, 2 H), 4.02-3.84 (m,
5 H), 3.733 (d, J = 11.3 Hz, 3 H), 3.726 (d, J = 11.3 Hz, 3 H), 3.15 (m, 2 H), 3.09 (dd, J = 13.8, 22.4 Hz, 1
H), 2.89 (dd, J = 13.8, 22.7 Hz, 1 H), 2.56 (d, J = 18.6 Hz, 1 H), 2.54 (d, J = 14.6 Hz, 1 H), 2.41 (dd, J =
7.9, 13.9 Hz, 1 H), 2.35 (d, J = 14.5 Hz, 1 H), 2.16 (dd, J = 7.2, 13.9 Hz, 1 H), 1.87 (d, J = 14.5 Hz, 1 H),
1.81 (d, J = 14.7 Hz, 1 H), 1.15 (s, 3 H), 0.83 (s, 9 H), -0.01 (s, 3 H), -0.02 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 215.2, 199.6 (d, J = 6.1 Hz), 133.0, 119.2, 107.7, 68.0, 64.1, 63.6, 53.1 (d, J = 6.8 Hz), 52.9 (d, J
= 6.1 Hz), 51.1, 49.6, 48.2, 42.2, 40.9, 40.4, 39.2 (d, J = 16.5 Hz), 25.8, 23.0, 18.2, -5.6, -5.7; HRMS m/z
541.2355 [(M+Na)+; calcd for C24H43O8NaSiP: 541.2363].

O O
NaH
(MeO)2(O)P O O
O
O
O

OTBS 22 OTBS

Cyclopentenone 22. To a solution of phophonate (71.4 mg, 0.136 mmol) in THF (12 mL) was added NaH
(60%, 28.7 mg, 5.2 equiv.) in one portion and the resulting mixture was stirred at room temperature for 5
S6
 min until gas evolution ceased. The reaction mixture was heated at 60 oC for 2 h. The reaction
mixture was quenched with saturated NH4Cl (55 mL) and extracted with ether (3 x 65 mL). Combined
extracts were dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc
1:1) afforded cyclopentenone 22 (48.9 mg, 91% yield): IR (neat) 2955 (s), 2928 (s), 2884 (s), 2856 (s),
1733 (m), 1716 (s), 1699 (s), 1604 (m), 1471 (m), 1418 (w), 1388 (w), 1361 (m), 1257 (m), 1202 (w), 1158
(w), 1098 (m, br), 1057 (w), 1026 (w), 1006 (w), 989 (w), 946 (w), 916 (w), 838 (m, br) cm-1; 1H NMR
(400 MHz, CDCl3) δ 6.00 (s, 1 H), 5.63 (m, 1 H), 5.01 (m, 2 H), 3.99 (m, 2 H), 3.89 (d, J = 9.6 Hz, 1 H),
3.85 (m, 2 H), 3.62 (d, J = 9.6 Hz, 1 H), 2.64 (dd, J = 6.0, 14.0 Hz, 1 H), 2.48 (d, J = 17.7 Hz, 1 H), 2.47
(dd, J = 6.6, 14.0 Hz, 1 H), 2.15 (dd, J = 2.3, 13.8 Hz, 1 H), 2.06 (d, J = 17.9 Hz, 1 H), 2.00 (dd, J = 2.3,
14.3 Hz, 1 H), 1.67 (d, J = 13.8 Hz, 1 H), 1.51 (d, J = 14.3 Hz, 1 H), 1.20 (s, 3 H), 0.85 (s, 9 H), 0.01 (s, 3
H), -0.005 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 206.9, 186.5, 134.3, 131.5, 118.7, 107.9, 67.6, 65.0,
63.3, 51.7, 47.5, 44.9, 43.0, 42.8, 42.5, 26.7, 25.7, 18.1, -5.6, -5.7; HRMS m/z 393.2469 [(M+H)+; calcd
for C22H37O4Si: 393.2461].

O
O
O 2N HCl
O O

OTBS OH
22

A mixture of cyclopentenone 22 (1.87 g, 4.77 mmol) and 2 N aqueous HCl (13 mL) in THF (20 mL) was
stirred at room temperature for 3 d. The reaction mixture was poured into ice (60 mL)-saturated NaHCO3
(100 mL) and extracted with EtOAc (3 x 200 mL, 2 x 130 mL). Combined extracts were dried (MgSO4),
filtered and concentrated in vacuo to give alcohol product (1.05 g, 95% yield): IR (neat) 3413 (m, br), 2969
(m), 2925 (m), 2873 (m), 1687 (s), 1602 (m), 1455 (w), 1414 (m), 1385 (w), 1315 (w), 1279 (m), 1212
(m), 1176 (w), 1058 (m), 1008 (w), 934 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 6.21 (s, 1 H), 5.69-5.58
(m, 1 H), 5.18-5.10 (m, 2 H), 3.71 (dd, J = 5.8, 11.8 Hz, 1 H), 3.64 (dd, J = 5.7, 10.8 Hz, 1 H), 2.88 (d, J =
16.6 Hz, 1 H), 2.80 (d, J = 16.3 Hz, 1 H), 2.63 (d, J = 18.0 Hz, 1 H), 2.45 (d, J = 16.2 Hz, 1 H), 2.49-2.43
(m, 1 H), 2.40-2.35 (m, 1 H), 2.34 (d, J = 16.5 Hz, 1 H), 2.28 (d, J = 18.0 Hz, 1 H), 1.61 (t, J = 5.8 Hz, 1
H), 1.30 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 207.9, 205.6, 184.4, 132.5, 131.1, 120.3, 69.5, 53.4, 50.9,
50.0, 48.1, 47.5, 43.1, 27.6; HRMS m/z 257.1140 [(M+Na)+; calcd for C14H18O3Na: 257.1154].

O O
ClCO2Et
O O

OCO2Et
OH 8

Ethyl carbonate 8. To a solution of alcohol (1.05 g, 4.50 mmol) in CH2Cl2 (90 mL) at 0 oC were added
DMAP (11 mg, 0.02 equiv.), pyridine (8.5 mL, 23 equiv.) and ethyl chloroformate (5.2 mL, 12 equiv.) and
the resulting mixture was stirred at room temperature for 21 h. Another 2.6 mL of ethyl chloroformate was
added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was quenched
S7
 with 2N aqueous HCl (200 mL) and extracted with EtOAc (3 x 200 mL). Combined extracts were
dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1:1 →
1:2 → 1:5) gave ethyl carbonate 8 (1.32 g, 93% yield): IR (neat) 2979 (m), 2937 (w), 1746 (s), 1712 (s),
1606 (w), 1466 (w), 1399 (w), 1375 (m), 1255 (s), 1206 (m), 1180 (w), 1090 (w), 1007 (m), 962 (w), 927
(w), 873 (w) cm-1; 1H NMR (400 MHz, CDCl3) δ 6.21 (s, 1 H), 5.58 (m, 1 H), 5.13 (m, 2 H), 4.22 (d, J =
10.9 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.07 (d, J = 10.9 Hz, 1 H), 2.87 (d, J = 16.8 Hz, 1 H), 2.81 (d, J =
16.9 Hz, 1 H), 2.60 (d, J = 18.0 Hz, 1 H), 2.40 (dd, J = 6.9, 14.3 Hz, 1 H), 2.38 (t, J = 16.3 Hz, 2 H), 2.32
(dd, J = 6.3, 14.4 Hz, 1 H), 2.21 (d, J = 17.9 Hz, 1 H), 1.32 (s, 3 H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 206.7, 205.2, 182.7, 154.7, 131.8, 131.2, 120.6, 72.5, 64.4, 49.6, 49.3, 47.8, 47.1,
43.0, 40.3, 28.1, 14.1; HRMS m/z 329.1362 [(M+Na)+; calcd for C17H22O5Na: 329.1365].

O O
NaH
O O
O
OCO2Et O
8 9

Lactone 9. To a solution of ethyl carbonate 8 (1.29 g, 4.20 mmol) in THF (250 mL) was added NaH
(60%, 1.99 g, 12 equiv.) in one portion and the resulting mixture was heated to reflux for 12 h. The
reaction mixture was quenched with saturated NH4Cl (150 mL) and 4 N aqueous HCl (75 mL), and after
separation, further extracted with EtOAc (3 x 250 mL). Combined extracts were dried (MgSO4), filtered
and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1:1 → 1:3 → CH2Cl2-MeOH
20:1 → 10:1) gave lactone 9 (1.02 g, 94% yield): IR (neat) 2976 (m), 2917 (m), 1791 (s), 1716 (s, br),
1609 (m), 1455 (m), 1418 (m), 1391 (m), 1365 (m), 1337 (w), 1264 (m), 1164 (m), 1101 (w), 1024 (m),
992 (w), 929 (w), 889 (w), 862 (w) cm-1; 1H NMR (500 MHz, CD3COCD3) δ 6.40 (s, 1 H), 5.57 (m, 1 H),
5.13 (m, 2 H), 4.45 (d, J = 9.5 Hz, 1 H), 4.25 (d, J = 9.5 Hz, 1 H), 3.63 (s, 1 H), 2.96 (d, J = 14.3 Hz, 1 H),
2.78 (d, J = 14.3 Hz, 1 H), 2.54 (d, J = 17.9 Hz, 1 H), 2.413 (d, J = 18.0 Hz, 1 H), 2.410 (dd, J = 7.4, 14.5
Hz, 1 H), 2.29 (dd, J = 6.5, 14.4 Hz, 1 H), 1.68 (s, 3 H); 13C NMR (125 MHz, CD3COCD3) δ 204.9, 200.3,
179.7, 171.3, 133.9, 133.4, 121.0, 76.6, 61.5, 51.5, 50.4, 49.9, 46.0, 43.5, 27.9; HRMS m/z 283.0935
[(M+Na)+; calcd for C15H16O4Na: 283.0946].

O m-CPBA O
O O OH
O O
O O
9

To a solution of lactone 9 (78.1 mg, 0.300 mmol) in CH2Cl2 (10 mL) was added m-CPBA (~100%, 51.0
mg, 0.99 equiv) and the resulting mixture was stirred at room temperature for 15 min. The reaction
mixture was quenched with a mixture of saturated Na2S2O3 (35 mL)-water (35 mL)-saturated NaHCO3 (35
mL) and extracted with EtOAc (3 X 150 mL). Combined extracts were dried (MgSO4), filtered and

S8
 concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1:1) afforded α-hydroxy lactone
product (74.4 mg, 90% yield): IR (film) 3340 (m, br), 2976 (w), 2923 (w), 1793 (s), 1715 (s), 1688 (s),
1604 (w), 1392 (w), 1364 (w), 1291 (w), 1250 (w), 1206 (w), 1159 (m), 1108 (m), 1021 (w), 1001 (m),
934 (w) cm-1; 1H NMR (400 MHz, CD3OD) δ 6.39 (s, 1H), 5.47 (m, 1 H), 5.13 (m, 2 H), 4.42 (d, J= 9.9
Hz, 1 H), 4.16 (d, J = 10.0 Hz, 1 H), 3.36 (d, J = 12.3 Hz, 1 H), 2.62 (d, J = 12.3 Hz, 1 H), 2.56 (d, J = 3.1
Hz, 2 H), 2.43 (d, J = 7.2 Hz, 2 H), 1.47 (s, 3 H); 13C NMR (100 MHz, CD3OD) δ 207.1, 205.1, 178.1,
174.2, 136.3, 132.9, 121.0, 85.3, 72.5, 51.82, 51.75, 51.73, 48.2, 43.7, 19.9; HRMS m/z 299.0891
[(M+Na)+; calcd for C15H16O5Na: 299.0895].

OH
O
NaBH4 O OH
O OH
O
O
O
O 25

Diol 25. To a solution α-hydroxy lactone (1.16 g, 4.20 mmol) in THF-MeOH (180 mL, 1:1) at -78 oC was
added NaBH4 (179 mg, 1.1 equiv.) in one portion and the resulting mixture was stirred for 1 min. The
reaction mixture was quenched with brine (175 mL) and extracted with EtOAc (3 x 300 mL). Combined
extracts were dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc
2:1) gave diol 25 (1.08 g, 93 % yield): IR (film) 3342 (m, br), 2919 (w), 1754 (s), 1678 (s), 1590 (w), 1449
(w), 1408 (w), 1361 (w), 1261 (w), 1226 (w), 1161 (m), 1114 (m), 1079 (m), 1020 (m), 991 (m) cm-1; 1H
NMR (400 MHz, CD3OD) δ 6.23 (s, 1 H), 5.58 (m, 1 H), 5.06 (m, 2 H), 4.87 (d, J = 8.5 Hz, 1 H), 3.99 (d,
J = 8.4 Hz, 1 H), 3.32 (m, 1 H), 3.12 (dd, J = 7.0, 14.1 Hz, 1 H), 2.67 (dd, J = 7.8, 14.1 Hz, 1 H), 2.53 (d, J
= 18.0 Hz, 1 H), 2.23 (dd, J = 2.8, 14.4 Hz, 1 H), 2.21 (d, J = 18.0 Hz, 1 H), 1.97 (dd, J = 3.0, 14.5 Hz, 1
H), 1.39 (s, 3 H); 13C NMR (100 MHz, CD3OD) δ 209.2, 183.8, 179.5, 135.2, 134.9, 119.5, 83.7, 73.7,
72.8, 53.8, 48.3, 47.7, 45.5, 39.9, 22.0; HRMS m/z 279.1232 [(M+H)+; calcd for C15H19O5: 279.1232].

OH OH
LDA; MeI
O OH O OH
O O
O O
25

To a solution of LDA (3.5 equiv.) in THF (20 mL) at -45 oC was added a solution of diol 25 (153 mg,
0.548 mmol) in THF (2.5 mL) and the resulting mixture was warmed to -15 oC over 55 min. The reaction
mixture was cooled to -40 oC, treated with a mixture of iodomethane (40 µL, 1.2 equiv.) and HMPA (90
µL, 1.0 equiv.), and stirred at -35 oC for 18 h. The reaction mixture was quenched with saturated NH4Cl
(125 mL) and extracted with EtOAc (3 x 150 mL). Combined extracts were dried (MgSO4), filtered and
concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1:1 → CH2Cl2-MeOH 10:1) gave a
methyl cyclopentenone (103 mg, 64% yield, 77% based on recovered starting material): IR (film) 3382 (m,
br), 3265 (m, br), 1762 (s), 1686 (s), 1600 (m), 1456 (w), 1401 (w), 1371 (w), 1260 (w), 1164 (m), 1115

S9
 (m), 1056 (w), 1023 (w), 989 (m) cm-1; 1H NMR (400 MHz, CD3OD) δ 6.18 (s, 1 H), 5.62 (m, 1 H),
5.06 (m, 2 H), 4.87 (d, J = 8.5 Hz, 1 H), 4.12 (t, J = 3.0 Hz, 1 H), 4.00 (d, J = 8.4 Hz, 1 H), 2.99 (dd, J =
6.9, 14.0 Hz, 1 H), 2.80 (dd, J = 7.8, 14.0 Hz, 1 H), 2.42 (q, J = 7.6 Hz, 1 H), 1.96 (dq, J = 3.0, 14.0 HZ, 2
H), 1.39 (s, 3 H), 1.01 (d, J = 7.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 213.5, 183.5, 179.6, 135.3,
132.7, 119.7, 83.7, 73.9, 73.0, 54.1, 50.1, 48.3, 46.7, 33.5, 22.0, 13.9; HRMS m/z 293.1395 [(M+H)+;
calcd for C16H21O5: 293.1389].

O
OH a. O3; Me2S
b. Jones' reagent O OH
O OH
O O
O O
10

Lactone 10. A red solution of the methyl cyclopentenone (10 mg, 0.034 mmol) and Sudan Red 7B (trace)
in CH2Cl2 (1.8 mL)-EtOH (1.8 mL) was cooled to -78 oC and a flow of ozone was bubbled through the
solution until a red color turned into a yellow/orange. Argon was bubbled through the reaction mixture for
10 min. The mixture was treated with Me2S (0.02 mL), warmed to room temperature, and concentrated in
vacuo to give a mixture of lactols. The residue was diluted with acetone (1.7 mL), cooled to 0 oC, and
treated with Jones reagent (2.6 M, 0.25 mL, 19 equiv.). The reaction mixture was stirred at 0 oC for 7 min
and quenched by addition of EtOH (1.5 mL). The resulting green mixture was diluted with EtOAc (20
mL) and washed with saturated NaHCO3 (20 mL). The aqueous phase was combined with green solid
residue and further extracted with EtOAc (3 x 20 mL). Combined extracts were dried (MgSO4), filtered
and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 2:1 → 1:1 → 1:3) afforded lactone 10
(9 mg, 90% yield): IR (film) 3334 (m, br), 2975 (m), 2877 (m), 1784 (s), 1748 (s), 1710 (s), 1609 (m),
1491 (w), 1456 (m), 1367 (m), 1348 (w), 1327 (w), 1286 (w), 1251 (m), 1200 (m), 1159 (m), 1119 (m),
1063 (m), 1027 (m), 996 (m), 976 (w), 948 (w), 888 (w) cm-1; 1H NMR (400 MHz, CD3OD) δ 6.27 (s, 1
H), 4.79 (dd, J = 1.8, 4.1 Hz, 1 H), 4.14 (d, J = 10.5 Hz, 1 H), 4.05 (d, J = 10.6 Hz, 1 H), 3.10 (d, J = 19.1
Hz, 1 H), 2.81 (dd, J = 2.7, 19.1 Hz, 1 H), 2.30 (dd, J = 4.1, 14.0 Hz, 1 H), 2.25 (q, J = 7.7 Hz, 1 H), 2.19
(td, J = 2.3, 14.4 Hz, 1 H), 1.44 (s, 3 H), 1.13 (d, J = 7.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 207.3,
176.7, 175.9, 167.6, 131.9, 78.7, 78.4, 73.7, 52.4, 44.3, 43.2, 42.6, 27.7, 22.1, 11.6; HRMS: m/z 293.1013
[(M+H)+; calcd for C15H17O6: 293.1025].

O O

O O
NaBH4
CeCl3.7H2O
O OH HO OH
O O
O O
10 26

Alcohol 26. A solution of lactone 10 (40 mg, 0.0137 mmol) and CeCl3.7H2O (153 mg, 3.0 equiv) in THF
(8.2 mL)-MeOH (2.8 mL) was cooled to -60 oC and treated with a solution of NaBH4 (0.82 mL, 3.0 equiv)
in 2-methoxyethyl ether (0.5 M). The resulting mixture was stirred at -55~-50 oC for 35 min. The reaction
mixture was quenched with 1N aqueous HCl (0.23 mL), diluted with brine (50 mL), and extracted with
S10
 EtOAc (5 X 100 mL). Combined extracts were dried (MgSO4), filtered and concentrated in vacuo.
Flash chromatography (hexanes-EtOAc 1:1 → CH2Cl2-MeOH 40:1) gave alcohol 26 (35 mg, 88% yield):
IR (neat) 3384 (s, br), 2972 (s), 2935 (s), 2876 (m), 1784 (s), 1749 (s), 1456 (m), 1368 (m), 1325 (w), 1226
(m), 1162 (m), 1117 (m), 1087 (m), 1064 (m), 1028 (m), 999 (m), 969 (w), 913 (w), 888 (w) cm-1; 1H
NMR (400 MHz, CD3OD) δ 5.80 (d, J = 1.3 Hz, 1 H), 4.89 (dd, J = 1.3, 6.6 Hz, 1H), 4.72 (dd, J = 1.3, 4.3
Hz, 1 H), 4.00 (d, J = 10.1 Hz, 1 H), 3.80 (d, J = 10.1 Hz, 1 H), 2.85 (d, J = 18.8 Hz, 1 H), 2.67 (dd, J =
2.6, 18.9 Hz, 1 H), 2.17 (m, 2 H), 1.93 (dd, J = 4.4, 14.0 Hz, 1 H), 1.35 (s, 3 H), 0.92 (d, J = 7.3 Hz, 3 H);
13
C NMR (100 MHz, CD3OD) δ 178.6, 172.0, 147.5, 133.6, 81.4, 78.7, 76.6, 76.0, 50.3, 48.0, 44.4, 43.7,
28.3, 22.5, 9.1; HRMS m/z 295.1184 [(M+H)+; calcd for C15H19O6: 295.1182].

O O
HO
O O
NaHMDS
HO OH O HO OH
O PhSO2N CHPh O
O O
26 27

α-Hydroxy Lactone 27. Alcohol 26 (69.5 mg, 0.236 mmol) was azeotroped with anhydrous benzene (3 x
80 mL) and placed under high vacuum for 1 h. Then the alcohol was dissolved in THF (80 mL), cooled to
-78 oC, and treated with a solution of NaHMDS (0.93 mL, 3.9 equiv) in THF (1.0 M). The resultant
mixture was stirred at -78 oC for 6 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (248
mg, 4.0 equiv) in THF (1.0 mL) was added to the reaction mixture and the resulting mixture was stirred at
-78 oC for 3 min. The reaction mixture was quenched with saturated NH4Cl (5.0 mL), diluted with EtOAc
(500 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (hexanes-EtOAc 1:1
→ CH2Cl2-MeOH 30:1 → 20:1 → 10:1) gave the unreacted alcohol starting material 26 (51.2 mg, 73%
recovered) and α-hydroxy lactone 27 [19.1 mg, 26% yield, 99% based on recovered starting material, 6:1
at C(10)]. Recovered starting material (51.2 mg, 0.174 mmol) was engaged in a second hydroxylation
reaction followed by flash chromatography to provide the unreacted starting material 26 (28.3 mg, 56%
recovered, total recovery: 41%) and α-hydroxy lactone 27 (11.3 mg, 21% yield, 42% overall yield): IR
(neat) 3337 (m, br), 2975 (m), 2877 (m), 1783 (s), 1456 (m), 1369 (m), 1343 (w), 1228 (m), 1171 (m),
1111 (m), 1085 (m), 1051 (m), 1024 (m), 997 (m), 966 (w), 890 (w) cm-1; 1H NMR (400 MHz, CD3OD)
δ 5.89 (s, 1 H), 5.00* [dd, J = 1.6, 7.1 Hz, 1 H, minor diastereomer at C(10)], 4.94 (dd, J = 1.3, 6.6 Hz, 1
H), 4.70 (dd, J = 1.2, 4.7 Hz, 1 H), 4.62* (dd, J = 1.7, 4.2 Hz, 1 H), 3.99 (d, J = 10.0 Hz, 1 H), 3.79 (d, J =
1.6 Hz, 1 H), 3.64 (d, J = 10.1 Hz, 1 H), 2.91 (quintet, J = 7.1 Hz, 1 H), 2.49* (quintet, J = 7.3 Hz, 1 H),
2.23 (dd, J = 4.7, 14.1 Hz, 1 H), 2.03 (td, J = 1.4, 14.0 Hz, 1 H), 1.36* (s, 3 H), 1.35 (s, 3 H), 0.91* (d, J =
7.5 Hz, 3 H), 0.85 (d, J = 7.3 Hz, 3 H); 13C NMR (100 MHz, CD3OD) δ 178.8, 172.4, 144.3, 136.0, 81.3,
77.5, 76.6, 76.5, 73.3, 54.2, 44.6, 42.8, 23.2, 21.4, 9.5; HRMS: m/z 333.0953 [(M+Na)+; calcd for
C15H18O7Na: 333.0950].

S11
 O O
HO HO HO CO2Me
O Jones' reagent, O O
acetone; MeOH
HO OH O OH + O OH
O O O

O O O

27 28 1

(1R∗,10S∗)-2-Oxo-3,4-dehydroneomajucin (28) and (±)-Jiadifenin (1). To a solution of α-hydroxy

lactone 27 (19.1 mg, 0.0615 mmol) in acetone (8.0 mL) was added Jones reagent (2.6 M, 1.0 mL, 42
equiv.) and the resulting mixture was stirred at room temperature for 19 min. The reaction mixture was
treated with MeOH (3.5 mL) and stirred at room temperature for 10 min. The reaction mixture was placed
into an ice bath, quenched with saturated NaHCO3 (7 mL), diluted with EtOAc (450 m), dried (MgSO4),
filtered and concentrated in vacuo. Preparative TLC (250 µm x 20 cm x 20 cm, CH2Cl2-MeOH 25:1)
afforded (1R∗,10S∗)-2-oxo-3,4-dehydroneomajucin (28) (5.6 mg, 29% yield) and (±)-jiadifenin (1) (8.5 mg,
40% yield).
(1R∗,10S∗)-2-Oxo-3,4-dehydroneomajucin (28): IR (film) 3392 (m, br), 2933 (m), 1785 (s), 1751 (s),
1710 (s), 1608 (w), 1558 (w), 1456 (w), 1368 (w), 1289 (w), 1226 (w), 1158 (w), 1114 (m), 1065 (m), 996
(m), 967 (w), 853 (w) cm-1; 1H NMR (500 MHz, C5D5N-TMS) δ 6.57 (s, 1 H), 5.29 (m, 1 H), 4.40 (brs, 1
H), 4.38 (d, J = 10.5 Hz, 1 H), 4.26 (d, J = 10.5 Hz, 1 H), 3.28 (q, J = 7.7 Hz, 1 H), 2.88 (dd, J = 4.3, 14.0
Hz, 1 H), 2.46 (d, J = 14.0 Hz, 1 H), 1.65 (brs, 3 H), 1.31 (d, J = 7.7 Hz, 3 H); 13C NMR (125 MHz,
C5D5N-TMS) δ 208.6, 177.1, 176.1, 170.6, 133.6, 79.8, 79.4, 73.7, 73.4, 51.3, 49.0, 44.8, 23.0, 22.6, 13.1;
HRMS m/z 331.0784 [(M+Na)+; calcd for C15H16O7Na: 331.0794].
(±)-Jiadifenin (1): IR (film) 3402 (m, br), 2957 (m), 2876 (w), 1778 (s), 1746 (s), 1710 (s), 1610 (w),
1456 (w), 1398 (w), 1374 (w), 1257 (m), 1224 (w), 1192 (m), 1165 (w), 1104 (w), 1052 (m), 1036 (m),
998 (w), 938 (w), 895 (w) cm-1; 1H NMR (500 MHz, C5D5N-TMS) δ 6.57 (s, 1 H), 6.50* [s, 1 H, minor
diastereomer at C(10)], 5.87 (d, J = 8.5 Hz, 1 H), 5.12* (d, J = 6.2 Hz, 1 H), 5.05 (d, J = 6.2 Hz, 1 H),
4.43* (d, J = 9.0 Hz, 1 H), 4.20 (d, J = 8.4 Hz, 1 H), 4.16* (d, J = 9.0 Hz, 1 H), 3.68 (s, 3 H), 3.56* (s, 3
H), 3.51* (q, J = 7.7 Hz, 1 H), 3.17* (dd, J = 6.3, 11.8 Hz, 1 H), 3.03 (dd, J = 6.2, 12.4 Hz, 1 H), 2.95 (q, J
= 7.6 Hz, 1 H), 2.62* (d, J = 11.8 Hz, 1 H), 2.53 (d, J = 12.4 Hz, 1 H), 1.69 (s, 3 H), 1.64* (s, 3 H), 1.38*
(d, J = 7.7 Hz, 3 H), 1.24 (d, J = 7.7 Hz, 3 H); 13C NMR (125 MHz, C5D5N-TMS) δ 209.6*, 208.7, 180.0,
178.8, 178.6*, 177.2*, 171.4, 169.0*, 131.1*, 130.5, 105.8, 103.9*, 80.8, 80.4, 80.2*, 79.3*, 75.9, 75.2*,
61.3*, 60.1, 52.6, 51.9*, 45.1, 44.7*, 44.6*, 42.8, 31.5*, 31.3, 23.1, 23.0*, 14.4*, 12.9; HRMS m/z
339.1072 [M+; calcd for C16H19O8: 339.1080].

S12
 CO2Et
O O
O LDA O
BrCH2CO2Et
O O

OR OR
11: R = TBS 21: R = TBS
17: R = TBDPS 31: R = TBDPS

Ester 21. A solution of LDA (2.79 mmol) in dry THF (5 mL) at –78 °C was treated with a solution of
TBS ether 11 (878 mg, 2.79 mmol) in dry THF (5 mL) and this mixture was allowed to warm slowly to –
20 °C over 90 min. It was then cooled again to –78 °C and a solution of ethyl bromoacetate (0.34 mL, 3.07
mmol) in dry THF (1 mL) was added. The mixture was stirred at –78 °C for another 10 min and the
cooling bath was then removed. After 16 h, the mixture was poured into sat. aq. NH4Cl (40 mL) and
extracted with Et2O (4 x 50 mL). The combined org. layers were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (SiO2, Pentane/Et2O 4:1) provided ester 21
(716 mg, 64% yield) as a colorless oil: IR (neat) 2928 (m), 1736 (s), 1710 (s), 1462 (w), 1251 (m), 1178
(m), 1095 (s), 1035 (m), 1000 (m), 836 (s), 777 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ less polar diast.
4.12 (q, J = 7.1, 2 H), 4.10-3.90 (m, 4 H), 3.76 (d, J = 9,6, 1 H), 3.42-3.34 (m, 1 H), 3.31 (d, J = 9.6, 1 H),
2.73 (dd, J = 16.6, 7.1, 1 H), 2.21 (d, J = 14.1, 1 H), 2.14-2.04 (m, 2 H), 1.85 (dd, J = 14.1, 3.6, 1 H), 1.76-
1.69 (m, 1 H), 1.24 (t, J = 7.1, 3 H), 1.23 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); more polar
diast. 4.17-3.91 (m, 6 H), 3.76 (s, 2 H), 3.33-3.25 (m, 1 H), 2.72 (dd, J = 16.5, 6.3, 1 H), 2.28 (dd, J =
14.3, 3.0, 1 H), 2.21-2.12 (m, 2 H), 1.83-1.76 (m 1 H), 1.68 (d, J = 14.3, 1 H), 1.25 (t, J = 7.1, 3 H), 1.07
(s, 3 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.03 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ less polar diast. 212.4,
172.2, 107.5, 68.1, 64.7, 64.0, 60.4, 49.3, 42.1, 40.5, 39.9, 34.0, 25.8 (3x), 22.2, 18.2, 14.2, –5.6, –5.6;
more polar diast. 212.4, 172.1, 107.2, 68.2, 64.7, 64.2, 60.4, 50.1, 42.2, 41.3, 40.6, 34.2, 25.8 (3x), 21.0,
18.2, 14.2, –5.6 (2x); HRMS (ESI) calcd. for C20H37O6Si [M+H]+ 401.2359, found 401.2367.

Ester 31. A solution of LDA (9.12 mmol) in dry THF (26 mL) at –78 °C was treated dropwise with a
solution of TBDPS ether 17 (4.00 g, 9.12 mmol) in dry THF (26 mL) and this mixture was allowed to
warm slowly to –35 °C over 3 h. It was then cooled again to –78 °C and a solution of ethyl bromoacetate
(1.11 mL, 10.03 mmol) in dry THF (5 mL) was added. The mixture was stirred for 10 min. at –78 °C and
then allowed to warm to r.t. After 3 h, the mixture was poured into sat. aq. NH4Cl (100 mL) and extracted
with Et2O (4 x 100 mL). The combined org. phases were then dried over MgSO4, filtered, and concentrated
in vacuo. Purification by flash chromatography (SiO2, Pentane/Et2O 4:1→3:2) ester 31 (3.88 g, 81% yield)
as an inseparable mixture of the two diastereoisomers: IR (neat) 2930 (m), 1734 (s), 1714 (s), 1428 (w),
1179 (m), 1112 (s), 1034 (w), 824 (w), 703 (s) cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.72-7.63 (m, 4 HA, 4
HB), 7.44-7.35 (m, 6 HA, 6 HB), 4.19-3.81 (m, 7 HA, 8 HB), 3.48 (m, 1 HA), 3.39 (d, J = 9.8, 1 HA), 3.31-
3.22 (m, 1 HB), 2.79 (dd, J = 16.6, 7.0, 1 HA), 2.72 (dd, J = 16.5, 6.0, 1 HB), 2.39 (d, J = 14.0, 1 HA), 2.35
(dd, J = 14.4, 3.0, 1 HB), 2.26-2.10 (m, 2 HA, 2 HB), 1.98 (dd, J = 14.0, 3.5, 1 HA), 1.85-1.77 (m, 1 HA, 1
HB), 1.75 (d, J = 14.2, 1 HB), 1.29 (s, 3 HA), 1.26 (t, J = 7.2, 3 HB), 1.24 (t, J = 7.2, 3 HA), 1.15 (s, 3 HB),
1.06 (s, 9 HA), 1.05 (s, 9 HB); 13C-NMR (100 MHz, CDCl3) δ 212.0, 211.9, 172.2, 171.9, 135.7 (4x), 135.6
(4x), 133.4, 133.3, 133.2, 133.1, 129.6 (2x), 129.5 (2x), 127.6 (4x), 127.5 (4x), 107.4, 107.0, 68.7, 68.6,
64.7, 64.6, 64.1, 64.0, 60.4, 60.3, 50.2, 49.6, 42.6, 42.3, 41.2, 40.5, 40.4, 39.9, 34.1, 34.0, 26.8 (3x), 26.8
(3x), 22.2, 21.2, 19.3, 19.3, 14.1, 14.1; HRMS (ESI) calcd. for C30H41O6Si [M+H]+ 525.2672, found
525.2670.
S13
 CO2Et CO2Et
O O
t-BuOK O
O allyl chloroformate O
O O O

OR OR
21: R = TBS 29: R = TBS
31: R = TBDPS 30: R = TBDPS

Carbonate 29. A solution of t-BuOK (1.0 M in THF, 0.83 mL, 0.831 mmol) was diluted with dry THF (4
mL), and cooled to –78 °C. A solution of ester 21 (333 mg, 0.831 mmol) in dry THF (2.5 mL) was added
and the yellow mixture was allowed to warm to –40 °C over 2.5 h. It was then cooled again to –78 °C and
allyl chloroformate (97 µL, 0.914 mmol) was added. After 20 min, the mixture was poured into sat aq.
NH4Cl (25 mL) and extracted with Et2O (4 x 30 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, Pentane/Et2O
2:1) afforded carbonate 29 (322 mg, 80% yield) as a colorless oil. IR (neat) 2954 (m), 2929 (m), 1762 (s),
1735 (s), 1472 (w), 1368 (m), 1247 (s), 1097 (s), 1021 (m), 946 (w), 836 (m), 776 (m) cm-1; 1H NMR (400
MHz, CDCl3) δ 5.95 (ddt, J = 17.0, 10.6, 5.6, 1 H), 5.39 (dd, J = 17.2, 1.3, 1 H), 5.29 (d, J = 10.5, 1 H),
4.64 (d, J = 5.8, 2 H), 4.12 (q, J = 7.1, 2 H), 3.95 (s, 4 H), 3.74 (d, J = 9.1, 1 H), 3.22 (d, J = 9.1, 1 H), 2.93
(s, 2 H), 2.58 (d, J = 17.1, 1 H), 2.46 (d, J = 17.0, 1 H), 2.24 (d, J = 13.7, 1 H), 1.57 (d, J = 13.7, 1 H), 1.24
(t, J = 7.1, 3 H), 1.10 (s, 3 H), 0.87 (s, 9 H), 0.02 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 169.9, 152.7,
146.9, 131.3, 119.0, 118.1, 107.0, 68.8, 67.3, 64.2, 64.1, 60.5, 42.6, 39.2, 39.1, 36.0, 25.7 (3x), 21.5, 18.1,
14.0, –5.7 (2x); HRMS (ESI) calcd. for C24H41O8Si [M+H]+ 485.2571, found 485.2571.

Carbonate 30. A solution of t-BuOK (1.0 M in THF, 6.90 mL) was diluted with dry THF (33.5 mL) and
cooled to – 78 °C. It was then treated dropwise with a solution of ester 31 in dry THF (26.5 mL) and
allowed to warm to –30 °C over 2 h. The mixture was then cooled again to –78 °C and allyl chloroformate
was added. The mixture was stirred for 20 min and then poured into sat. aq. NH4Cl (80 mL), extracted with
Et2O (4 x 80 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in
vacuo to give a pale yellow oil that showed to be pure carbonate 30 (4.2 g, quant. yield): IR (neat) 2931
(m), 1761 (s), 1735 (s), 1427 (w), 1368 (m), 1242 (s), 1111(s), 1021 (m), 824 (w), 703 (s) cm-1. 1H-NMR
(400 MHz, CDCl3) δ 7.70-7.63 (m, 4 H);, 7.43-7.35 (m, 6 H), 5.89 (ddt, J = 17.1, 10.5, 5.7, 1 H), 5.34 (dd,
J = 17.2, 1.4, 1 H), 5.25 (dd, J = 10.4, 1.1, 1 H), 4.58 (d, J = 4.8, 2 H), 4.10 (q, J = 7.1, 2 H), 3.99-3.89 (m,
4 H), 3.84 (d, J = 9.4, 1 H), 3.35 (d, J = 9.4, 1 H), 2.94 (d, J = 3.4, 2 H), 2.59 (d, J = 17.1, 1 H), 2.50 (d, J =
17.1, 1 H), 2.44 (d, J = 13.6, 1 H), 1.64 (d, J = 13.5, 1 H), 1.22 (t, J = 7.2, 3 H), 1.12 (s, 3 H), 1.04 (s, 9 H);
13
C-NMR (100 MHz, CDCl3) δ 170.0, 152.7, 146.7, 135.7 (2x), 135.6 (2x), 133.6, 133.5, 131.3, 129.5
(2x), 127.6 (2x), 127.5 (2x), 118.9, 118.3, 107.1, 68.8, 68.0, 64.3 (2x), 60.6, 43.0, 39.8, 39.0, 36.1, 26.8
(3x), 21.6, 19.3, 14.1; HRMS (ESI) calcd. for C34H45O8Si [M+H]+ 609.2884, found 609.2899.

S14
 CO2Et O O
O
O Pd(PPh3)4 EtO2C O EtO2C O
O
+
O O O O

OR OR OR
29: R = TBS 15: R = TBS 16: R = TBS
30: R = TBDPS 19: R = TBDPS 20: R = TBDPS

Esters 15/16. A solution of carbonate 29 (250 mg, 0.516 mmol) in dry THF (7 mL) was treated with
Pd(PPh3)4 (30 mg, 0.026 mmol) and the mixture was stirred at r.t. for 20 min. The mixture was then
filtered through a short pad of celite and the filter was rinsed with THF (30 mL). The filtrate was
concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, Pentane/Et2O
4:1) affording esters 15/16 (142 mg, 62% yield, 1:5.6) as a mixture of diastereoisomers.

Esters 19/20. A solution of carbonate 30 (355 mg, 0.583 mmol) in dry THF (7 mL) was cooled to –40 °C
and then treated with Pd(PPh3)4 (45 mg, 0.039 mmol). The mixture was stirred at –40 °C for 7 h and then
concentrated in vacuo. Purification by flash chromatography (SiO2, Pentane/Et2O 7:1) afforded esters
19/20 (213 mg, 65% yield, 1:8.7): IR (neat) 3071 (w), 2931 (m), 1857 (m), 1732 (s), 1697 (m), 1741 (w),
1427 (m), 1370 (m), 1342 (m), 1188 (m), 1155 (m), 1112 (s), 1031 (m), 1013 (m), 996 (m), 822 (m), 741
(m), 703 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 20 (syn) 7.70-7.65 (m, 4 H), 7.44-7.35 (m, 6 H), 5.65
(ddt, J = 17.0, 10.0, 7.3, 1 H), 5.11 (d, J = 10.8, 1 H), 5.08 (d, J = 16.8, 1 H), 4.09-3.91 (m, 4 H), 3.99 (q, J
= 7.2, 2 H), 3.89 (d, J = 9.5, 1 H), 3.52 (d, J = 9.5, 1 H), 2.83 (d, J = 16.6, 1 H), 2.60 (dd, J = 13.9, 7.6, 1
H), 2.52 (d, J = 14.1, 1 H), 2.44 (dd, J = 13.9, 7.2, 1 H), 2.30 (d, J = 14.0, 1 H), 2.27 (d, J = 16.5, 1 H),
2.06-1.97 (m, 2 H), 1.26 (s, 3 H), 1.15 (t, J = 7.2, 3 H), 1.07 (s, 9 H); 19 (anti) 7.70-7.63 (m, 4 H), 7.43-
7.35 (m, 6 H), 5.70 (ddt, J = 17.1, 10.0, 7.4, 1 H), 5.09 (d, J = 10.2, 1 H), 5.05 (d, J = 17.2, 1 H), 4.10-3.88
(m, 4 H), 4.09 (d, J = 8.6, 1 H), 4.07 (q, J = 7.2, 2 H), 3.20 (d, J = 9.3, 1 H), 2.96 (d, J = 16.7, 1 H), 2.75
(d, J = 14.7, 1 H), 2.54 (dd, J = 13.7, 7.6, 1 H), 2.47 (d, J = 14.6, 1 H), 2.25 (d, J = 16.7, 1 H), 2.20 (dd, J =
14.0, 7.5, 1 H), 2.00 (d, J = 14.6, 1 H), 1.87 (d, J = 14.7, 1 H), 1.22 (t, J = 7.1, 3 H), 1.18 (s, 3 H), 1.03 (s,
9 H); 13C NMR (100 MHz, CDCl3) δ 20 (syn) 214.8, 171.2, 135.71 (2x), 135.69 (2x), 133.5, 133.5, 133.3,
129.5, 129.5, 127.6 (2x), 127.6 (2x), 119.2, 107.8, 69.9, 64.6, 63.4, 60.3; 49.5, 49.1, 41.9, 41.1, 40.6, 39.5,
26.9 (3x), 23.0, 19.4, 14.1; 19 (anti) 215.0, 171.9, 136.1 (4x), 133.7, 133.7, 133.3, 130.0, 130.0, 128.0 (4x),
119.8, 108.2, 69.1, 64.4, 64.3, 60.8, 50.1, 48.8, 41.7, 41.2, 40.6, 39.6, 27.2 (3x), 23.3, 19.7, 14.6; HRMS
(ESI) calcd. for C33H45O6Si [M+H]+ 565.2985, found 565.2978.

CO2Et
O O O
PdCl2, O2
EtO2C Cu(OAc)2
O O
O O

OTBDPS OTBDPS
20 34

Ketone 34. A solution of ester 20 (706 mg, 1.29 mmol) in DMA (8.2 mL) and H2O (1 mL) was treated
with PdCl2 and Cu(OAc)2 and this mixture was stirred at room temperature under an O2 atmosphere. After
S15
 90 h, the mixture was poured into H2O (30 mL) and extracted with Et2O (5 x 40 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (SiO2, Pentane/Et2O 4:1) provided methyl ketone 34 (516 mg, 69% yield) as a colorless
oil. IR (neat) 2931 (m), 1730 (s), 1712 (s), 1697 (s), 1428 (m), 1362 (m), 1110 (s), 823 (w), 703 (s) cm-1;
1
H NMR (400 MHz, CDCl3) δ 7.70-7.63 (m, 4 H), 7.44-7.34 (m, 6 H), 4.05 (q, J = 7.1, 2 H), 4.02 (d, J =
9.3, 1 H), 3.99-3.88 (m, 4 H), 3.31 (d, J = 9.2, 1 H), 3.28 (d, J = 18.4, 1 H), 2.85 (d, J = 18.4, 1 H), 2.79 (d,
J = 15.6, 1 H), 2.63 (dd, J = 14.5, 1.5, 1 H), 2.37 (d, J = 14.4, 1 H), 2.32 (d, J = 15.7, 1 H), 2.20 (dd, J =
14.3, 1.5, 1 H), 2.09 (s, 3 H), 2.02 (d, J = 14.5, 1 H), 1.30 (s, 3 H), 1.18 (t, J = 7.1, 3 H), 1.06 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 214.5, 206.3, 170.8, 135.6 (4x), 133.4, 133.3, 129.6, 129.5,127.6 (2x), 127.5
(2x), 107.5, 68.7, 64.0, 63.9, 60.3, 50.7, 50.3, 46.8, 40.0, 39.8, 38.0, 30.2, 26.8 (3x), 23.6, 19.3, 14.1;
HRMS (ESI) calcd. for C33H45O7Si [M+H]+ 581.2935, found 581.2936.

CO2Et CO2H
O O O
t-BuOK O
O O
O

OTBDPS OTBDPS
34 36

Cyclopentenone 36. A solution of ketone 34 (110 mg, 0.189 mmol) in dry THF (14 mL) was cooled to 0
°C and then treated with a solution of t-BuOK (1.0 M in THF, 1.9 mL). The orange mixture was stirred for
30 min at 0 °C and the reaction was then quenched by adding 3 mL of sat. aq. NH4Cl. After further
dilution with AcOEt (200 mL), this org. phase was dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (SiO2, Hex/AcOEt/AcOH 6:3:0.2) gave cyclopentenone 36 (62 mg,
61% yield) as a colorless oil: IR (neat) 2959 (br, m), 1857 (m), 1730 (s), 1700 (s), 1603 (w), 1472 (w),
1427 (m), 1186 (m), 1112 (s), 1029 (w), 823 (w), 703 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.66-7.61
(m, 4 H), 7.46-7.36 (m, 6 H), 6.12 (s, 1 H), 3.94 (d, J = 10.2, 1 H), 3.94-3.80 (m, 4 H), 3.69 (d, J = 10.1, 1
H), 3.23 (d, J = 16.1, 1 H), 2.72 (d, J = 18.5, 1 H), 2.59 (dd, J = 14.1, 2.1, 1 H), 2.39 (d, J = 16.2, 1 H),
2.30 (d, J = 18.6, 1 H), 2.02 (dd, J = 14.4, 2.3, 1 H), 1.60 (d, J = 14.1, 1 H), 1.55 (d, J = 14.4, 1 H), 1.28 (s,
3 H), 1.06 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 206.5, 186.0, 176.3, 135.7 (2x), 135.7 (2x), 133.1,
133.0, 131.9, 129.8, 129.8, 127.7 (2x), 127.7 (2x), 107.6, 68.3, 65.0, 63.5, 51.9, 45.6, 43.4, 42.9, 42.8,
41.3, 27.2, 26.9 (3x), 19.4; HRMS (ESI) calcd. for C31H39O6Si [M+H]+ 535.2516, found 535.2524.

CO2H O SEt
O O
EtSH, DMAP
O O EDCI.HCl O
O

OTBDPS OTBDPS
36

A solution of cyclopentenone 36 (54 mg, 0.101 mmol) in dry CH2Cl2 (2 mL) was treated with DMAP ( 0.6
mg, 0.005 mmol) and ethane thiol (30 µL, 0.404 mmol) and this mixture was cooled to 0 °C. It was then
treated with EDCI⋅HCl (29 mg, 0.152 mmol) and the mixture was stirred for 10 min at 0 °C. the cooling
S16
 bath was then removed and the mixture was allowed to warm to r.t. After 2 h, the mixture was diluted
with CH2Cl2 (50 mL) and washed with sat. aq. NH4Cl (1 x 40 mL), H2O (1 x 40 mL), dried over MgSO4,
filtered, and concentrated in vacuo, to give pure thioester (56 mg, 95% yield) as a pale yellow oil. IR (neat)
2930 (m), 1716 (m), 1698 (s), 1606 (w), 1472 (w), 1427 (m), 1265 (w), 1112 (s), 1030 (m), 822 (m), 702
(s) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67-7.62 (m, 4 H), 7.46-7.37 (m, 6 H), 6.11 (s, 1 H), 3.97-3.78
(m, 5 H), 3.94 (d, J = 9.8, 1 H), 3.68 (d, J = 10.0, 1 H), 3.48 (d, J = 15.8, 1 H), 2.82 (dq, J = 7.4, 2.5, 2 H),
2.78 (d, J = 18.2, 1 H), 2.60 (dd, J = 12.1, 2.4, 1 H), 2.58 (d, J = 16.0, 1 H), 2.25 (d, J = 18.6, 1 H), 2.00
(dd, J = 14.3, 2.5, 1 H), 1.54 (d, J = 14.2, 1 H), 1.29 (s, 3 H), 1.21 (t, J = 7.5, 3 H), 1.07 (s, 9 H); 13C NMR
(100 MHz, CDCl3) δ 206.7, 198.0, 186.5, 136.2 (2x), 136.1 (2x), 133.5 (2x), 132.3, 130.2 (2x), 128.2 (2x),
128.1 (2x), 108.1, 68.7, 65.5, 63.9, 51.9, 50.4, 47.1, 43.9, 43.4, 43.2, 27.6, 27.3 (3x), 23.8, 19.8, 15.1;
HRMS (ESI) calcd. for C33H43O5SSi [M+H]+ 579.2601, found 579.2613.

O SEt
CHO
O O
Et3SiH
O O Pd/C O
O

OTBDPS OTBDPS

A solution of thioester (48 mg, 0.083 mmol) and Et3SiH (40 µL, 0.249 mmol) in dry CH2Cl2 (0.8 mL) was
treated with Pd/C (10%, 4.4 mg, 0.0042 mmol) and the mixture was stirred at r.t. After 45 min, the mixture
was filtered through a short pad of celite and the filter was washed with CH2Cl2. The filtrate was
concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, Hex/AcOEt 3:1)
providing aldehyde (29 mg, 67% yield) as a pale yellow oil: IR (neat) 2930 (m), 1720 (s), 1698 (s), 1605
(w), 1427 (m), 1111 (s), 823 (m), 742 (m), 703 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1 H), 7.65-
7.61 (m, 4 H), 7.47-7.36 (m, 6 H), 6.12 (s, 1 H), 4.03 (d, J = 10.0, 1 H), 3.91-3.80 (m, 4 H), 3.68 (d, J =
10.0, 1 H), 3.10 (d, J = 17.8, 1 H), 2.52 (d, J = 18.5, 1 H), 2.44 (dd, J = 14.0, 2.4, 1 H), 2.35 (d, J = 17.7, 1
H), 2.34 (d, J = 18.5, 1 H), 1.97 (dd, J = 14.5, 2.5, 1 H), 1.60 (d, J = 14.1, 1 H), 1.55 (d, J = 14.4, 1 H),
1.30 (s, 3 H), 1.07 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 205.9, 200.4, 186.0, 135.8 (4x), 133.1, 133.0,
132.0, 129.9, 129.8, 127.7 (2x), 127.7 (2x), 107.7, 68.4, 64.9, 63.5, 51.9, 50.7, 45.1, 43.6, 43.0, 42.7, 27.2,
26.9 (3x), 19.3; HRMS (ESI) calcd. for C31H39O5Si [M+H]+ 519.2567, found 519.2565.

CHO
O O
O H2C=PPh3 O
O O

OTBDPS OTBDPS
37

A suspension of MePPh3Br (23 mg, 0.064 mmol) in dry THF (0.5 mL) was treated with a solution of
NaHMDS (1.0 M in THF, 64 µL) and this bright yellow mixture was stirred for 15 min at r.t. A solution of
aldehyde (29 mg, 0.056 mmol) in dry THF (0.7 mL) was then added. After 1 h, the mixture was
concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, Hex/AcOEt 4:1)
affording ketone 37 (21 mg, 72% yield) as a colorless oil: IR (neat) 2930 (m), 1697 (s), 1602 (w), 1427
S17
 (m), 1105 (s), 822 (w), 742 (w), 702 (s) cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.67-7.61 (m, 4 H), 7.46-
7.35 (m, 6 H), 6.08 (s, 1 H), 5.57 (ddt, J = 17.1, 10.0, 7.2, 1 H), 4.98 (d, J = 10.2, 1 H), 4.90 (d, J = 16.9, 1
H), 3.96-3.82 (m, 4 H), 3.88 (d, J = 9.8, 1 H), 3.80 (d, J = 9.8, 1 H), 2.52 (d, J = 17.7, 1 H), 2.47 (d, J =
7.3, 2 H), 2.16 (dd, J = 13.8, 2.2, 1 H), 2.10 (d, J = 17.8, 1 H), 2.09 (dd, J = 14.3, 2.6, 1 H), 1.66 (d, J =
13.8, 1 H), 1.53 (d, J = 14.2, 1 H), 1.28 (s, 3 H), 1.07 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 206.9,
186.7, 135.8 (2x), 135.7 (2x), 134.1, 133.3, 133.2, 131.6, 129.7 (2x), 127.6 (4x), 118.9, 107.9, 68.2, 65.0,
63.4, 51.8, 47.6, 44.7, 43.1, 42.8 (2x), 26.9 (4x), 19.4; HRMS (ESI) calcd. for C32H41O4Si [M+H]+
517.2774, found 517.2784.

D DD O D D D

D O O D
D D

d10-Diallyl carbonate. A flame-dried flask was charged with CDI (334 mg, 2.06 mmol), d5-allyl alcohol
(0.7 mL, 10.30 mmol) and DMF (5.25 mL) and this mixture was treated with EtONa (4 mg, 0.059 mmol)
and stirred at r.t. for 5 h. The mixture was then poured into sat. aq. NH4Cl (30 mL) and extracted with Et2O
(3 x 40 mL). The combined organic layers were then washed with H2O (3 x 50 mL), dried over MgSO4,
filtered, and carefully concentrated in vacuo, to give pure d10-diallyl carbonate (298 mg, 95% yield): 13C
NMR (100 MHz, CDCl3) δ 154.8, 130.9 (t, 2 x), 118.3 (quint., 2 x), 67.7 (quint., 2 x).

D D
D
CO2Et D DD O D D D D DO
O O
D O O D EtO2C EtO2C O
O O O
D D +
19 + d5 -19 + O O
O O
Pd(PPh3)4
OTBDPS OTBDPS
OTBDPS
30 20 d5 -20

A solution of carbonate 30 (90 mg, 0.148 mmol) and d10-diallyl carbonate (225 mg, 1.48 mmol) in dry
THF (2.2 mL) was treated with Pd(PPh3)4 (12 mg, 0.01 mmol) and the mixture was stirred at r.t. for 15
min. It was then concentrated in vacuo and the crude product was purifed by flash chromatography (SiO2,
Pentane/Et2O 7:1) affording a mixture of esters 19/20 (76 mg, 90% yield, 1:6.6): 1H-NMR (400 MHz,
CDCl3) δ 7.69-7.62 (m, 4 H), 7.43-7.34 (m, 6 H), 5.67-5.60 (m, 0.33 H), 5.12-5.05 (m, 0.67 H), 4.09-3.91
(m, 4 H), 3.98 (q, J = 7.1, 2 H), 3.88 (d, J = 9.5, 1 H), 3.50 (d, J = 9.5, 1 H), 2.85-2.80 (m, 1 H), 2.59 (dd, J
= 13.8, 7.5, 0.33 H), 2.51 (d, J = 14.1, 1 H), 2.44 (dd, J = 13.9, 7.2, 0.33 H), 2.05-1.97 (m, 2 H), 1.25 (s, 3
H), 1.14 (t, J = 7.2, 3 H), 1.06 (s, 9 H). About 67% of esters 19/20 have an incorporated deuterated allyl
group.

S18
 O
OH 1) OsO4, NaIO4 O
tBuOH-H2O
O OH O OH
O 2) Jones reagent, O
acetone
O O
25

To a solution of 25 (266 mg, 0.956 mmol) in tBuOH-H2O (45 mL, 2:1), were added OsO4 (2.5 wt%, 0.11
mL) and NaIO4 (922 mg, 4.31 mmol). The resulting mixture was stirred at room temperature overnight and
quenched with brine (130 mL). The mixture was extracted with EtOAc (0.2 L x 6) and the combined
extracts were washed with brine and dried over anhydrous MgSO4. The solvent was evaporated under
reduced pressure to give crude lactol (345 mg), which was used for next step without further purification.
To a solution of crude lactol (345 mg) in acetone (60 mL) at 0 oC was added Jones reagent (3.2 mL). The
resulting mixture was stirred at 0 oC for 5 min before being treated with EtOH (4.5 mL). The mixture was
diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3. The aqueous phase was
extracted with EtOAc (200 mL x 5) and the combined organic layers were dried over anhydrous MgSO4.
The solvent was removed under reduced pressure and the crude product was purified with flash
chromatography on silica gel (CH2Cl2-MeOH, 10:1) to afford the lactone product (140 mg, 53% for 2
steps): IR (neat) 3299 (m, br), 2975 (m), 2875 (m), 1785 (s), 1749 (s), 1698 (s), 1610 (m), 1456 (w), 1406
(w), 1367 (m), 1326 (w), 1290 (w), 1248 (w), 1225 (m), 1209 (m), 1160 (m), 1112 (m), 1046 (m), 1027
(w), 1005 (m), 987 (w), 965 (w), 885 (w) cm-1; 1H NMR (400 MHz, CD3OD) δ 6.29 (s, 1H), 4.77 (dd, J =
1.7, 4.1 Hz, 1H), 4.14 (d, J = 10.5 Hz), 4.02 (d, J = 10.6 Hz, 1H), 3.11 (d, J = 19.1 Hz, 1H), 2.85 (dd, J =
2.6, 19.1 Hz, 1H), 2.63 (d, J = 18.6 Hz, 1H), 2.42 (dd, J = 4.1, 14.1 Hz, 1H), 2.39 (d, J = 18.5 Hz, 1H), 2.31
(td, J = 2.1, 14.2 Hz, 1H), 1.45 (s, 3H); 13C NMR (125 MHz, acetone-d6) δ 204.1, 178.9, 175.9, 168.2,
133.4, 79.3, 79.0, 73.5, 67.8, 50.7, 42.8, 31.5, 25.9, 22.1; HRMS (ESI) calcd. for C14H14O6 [M+H]+
279.0869, found 279.0863.

O O

O NaBH4 O
CeCl3.7H2O
O OH HO OH
THF-MeOH O
O
O O

A mixture of lactone (140 mg, 0.504 mmol) and CeCl3.7H2O (574 mg, 3.0 equiv) in THF-MeOH (40 mL,
3:1) was cooled to -60 oC, to this solution was added a solution of NaBH4 in 2-methoxyethyl ether (0.5 M,
3.0 mL). The resulting mixture was stirred at -55 ~ -50 oC for 7 minutes. The reaction mixture was
quenched with 1N aqueous HCl (0.5 mL), diluted with brine (75 mL), and extracted with EtOAc (150 mL
x 6). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Flash
chromatography (CH2Cl2-MeOH 30:1 → 20:1 → 10:1) gave alcohol product (114 mg, 81% and 88%
brsm) and recovered lactone (11.2 mg, 8.0%): IR (neat) 3310 (m, br), 2930 (w), 1799 (s), 1748 (m), 1718
(m), 1652 (w), 1456 (w), 1367 (m), 1339 (w), 1250 (w), 1224 (m), 1205 (m), 1164 (m), 1108 (m), 1066
(m), 1021 (w), 1001 (m) cm-1; 1H NMR (400 MHz, acetone-d6) δ 5.91 (s, 1H), 4.98 (t, J = 7.1 Hz, 1H),
4.69 (dd, J = 1.3, 3.5 Hz, 1H), 3.84 (brs, 1H), 3.77 (d, J = 10.0 Hz, 1H), 3.62 (t, J = 6.3 Hz, 1H), 2.88 (d, J
= 18.7 Hz, 1H), 2.65 (dd, J =2.4, 18.7 Hz, 1H), 2.27 (dd, J = 6.7, 12.6 Hz, 1H), 2.18 (m, 2H), 1.76 (dd, J =
S19
 7.7, 12.7 Hz, 1H), 1.37 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 177.0, 169.0, 146.9, 135.4, 79.9,
77.8, 74.9, 74.2, 51.0, 44.3, 44.1, 42.6, 32.2, 22.2; HRMS (ESI) calcd. for C14H16O6 [M+H]+ 281.1025,
found 281.1021.

O O
HO
O O
NaHMDS, THF;
HO OH HO OH
O O
O
PhSO2N CHPh
O O

Alcohol (113.8 mg, 0.406 mmol) was azeotroped with anhydrous benzene (60 mL x 3) and placed under
high vacuum for 1 h. Then the alcohol was dissolved in THF (110 mL) and cooled to -78 oC. To this
solution was added a solution of NaHMDS in THF (1.0 M, 0.93 mL). The resultant mixture was stirred at -
78 oC for 6 minutes. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (318 mg, 1.470 mmol) in
THF (1.0 mL) was added to this mixture and the resulting mixture was stirred at -78 oC for 3 minutes. The
reaction was quenched with saturated NH4Cl (8.0 mL) and then diluted with EtOAc (700 mL). The
solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography
(hexanes-EtOAc 1:1 → CH2Cl2-MeOH 30:1 → 20:1 → 10:1) gave the unreacted alcohol starting material
(71.5 mg, 63% recovered) and α-hydroxy lactone (37.3 mg, 31% and 83% brsm): IR (neat) 3316 (s, br),
2976 (m), 2933 (m), 2876 (m), 1783 (s), 1749 (s), 1490 (w), 1453 (w), 1368 (m), 1341 (w), 1222 (m), 1170
(m), 1140 (w), 1109 (m), 1050 (m), 1000 (m), 965 (w), 925 (w), 889 (w), 847 (w) cm-1; 1H NMR (400
MHz, CD3OD) δ 6.01 (s, 1H), 4.88 (d, J = 6.9 Hz, 1H), 4.66 (dd, J = 0.9, 3.9 Hz, 1H), 3.98 (d, J = 10.1 Hz,
1H), 3.77 (d, J = 1.3 Hz, 1H), 3.66 (d, J = 10.1 Hz, 1H), 2.90 (dd, J = 6.7, 12.8 Hz, 1H), 2.47 (dd, J = 4.5,
14.1 Hz, 1H), 1.93 (d, J = 14.1 Hz, 1H), 1.43 (dd, J = 8.1, 12.8 Hz, 1H), 1.36 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 178.7, 172.2, 146.3, 138.0, 81.1, 77.8, 76.1, 74.7, 73.4, 51.0, 45.5, 43.1, 26.9, 13.2; HRMS
(ESI) calcd. for C14H16O7 [M+H]+ 297.0974, found 297.0960.

O
O
HO CO2Me HO
HO O O
O Jones reagent
acetone;
O OH + O OH
HO OH
MeOH O O
O
O O
O
38 39

Normethyl Jiadifenin (38) and Normethyl dehydroneomajucin (39) To a solution of α-hydroxy

lactone (32.0 mg, 0.108 mmol) in acetone (10 mL) was added Jones reagent (2.6 M, 1.5 mL) and the
resulting mixture was stirred at room temperature for 19 minutes. The reaction was quenched by addition
of MeOH (5 mL). The mixture was placed into an ice bath before being stirred at room temperature for 10
minutes and then treated with saturated NaHCO3 (10 mL). The mixture was diluted with EtOAc (1 L),
dried over anhydrous MgSO4, filtered and concentrated in vacuo. Preparative TLC (250 µm, 20 cm x 20
cm, 3:1 MeOH-EtOAc as eluant) afforded normethyl dehydroneomajucin 39 (9.1 mg, 25% yield,
decomposed in NMR solvent) and normethyl jiadifenin 38 (14.4 mg, 36% yield, ~ 3:2 mixture of
diastereomers at C(10)).
S20
 Normethyl jiadifenin (38): IR (neat) 3354 (m, br), 2957 (m), 2936 (m), 2877 (m), 1778 (s), 1747 (s),
1721 (s), 1688 (s), 1609 (m), 1456 (m), 1437 (w), 1403 (w), 1374 (w), 1275 (m), 1258 (m), 1228 (m), 1167
(m), 1103 (m), 1044 (s), 1016 (m), 968 (w), 934 9w), 901 (m) cm-1; 1H NMR (400 MHz, C5D3N-TMS)
δ 6.57 (s, 1H), 6.51* [s, 1H, minor diastereomer at C(10)], 5.82 (d, J = 8.5 Hz, 1H), 5.07 (d, J = 6.1 Hz,
1H), 4.44* (d, J = 9.0 Hz, 1H), 4.20 (d, J = 8.4 Hz, 1H), 4.16* (d, J = 9.0 Hz, 1H), 3.65 (s, 3H), 3.57* (s,
3H), 3.52* (d, J = 18.5 Hz, 1H), 3.23* (dd, J = 6.2, 11.8 Hz,, 1H), 3.09 (dd, J = 6.0, 12.3 Hz, 1H), 3.06 (d, J
= 18.6 Hz, 1H), 2.78* (d, J = 18.5 Hz, 1H), 2.69 ( d, J = 19.0 Hz, 1H), 2.62* (d, J = 12.4 Hz, 1H), 1.69 (s,
3H), 1.63* (s, 3H); 13C NMR (125 MHz, C5D3N-TMS) δ 205.9, 205.5*, 180.6, 178.9*, 178.7*, 177.7, 171.5,
169.1*, 132.8*, 132.0, 105.8, 103.5*, 80.6, 80.3*, 80.1, 79.3*, 76.1, 75.4*, 57.4*, 56.1, 52.6, 52.0*, 45.0,
44.6*, 42.0*, 40.1, 34.9*, 34.7, 23.2, 23.1*; LRMS (ESI) calcd. for C15H16O8Na [M+Na]+ 347.1, found
347.2.
Normethyl dehydroneomajucin (39): IR (neat) 3359 (m, br), 2977 (m), 2937 (m), 2877 (m), 1784
(s), 1749 (s), 1733 (s), 1715 (s), 1698 (s), 1607 (m), 1456 (w), 1394 (w), 1369 (m), 1342 (w), 1320 (w),
1293 (w), 1244 (m), 1227 (m), 1210 (m), 1162 (m), 1109 (m), 1084 (m), 1048 (m), 1024 (m), 999 (m), 979
(w), 954 (w), 913 (w); 1H NMR (400 MHz, CD3OD) δ 6.37 (s, 1H), 4.74 (dd, J = 1.2, 3.4 Hz, 1H), 4.10 (d,
J = 8.7 Hz, 1H), 3.92 (d, J = 1.4 Hz, 1H), 3.89 (d, J = 8.7 Hz, 1H), 3.00 (d, J = 15.2 Hz, 1H), 2.69 (dd, J =
3.4, 11.4 Hz, 1H), 2.37 (d, J = 15.2 Hz, 1H), 2.16 (td, J = 1.2, 11.4 Hz, 1H), 1.45 (s, 3H); LRMS (ESI)
calcd. for C14H14O7Na [M+Na]+ 317.1, found 316.8.

S21