Attempts to improve the overall stereoselectivity of the Ireland-Claisen rearrangement

Article abstract of DOI:10.1021/ol8027225

(Chemical Equation Presented) With focus on the steric effects present in the transition states for the [3,3]-sigmatropic rearrangement, the substrate 5 has been designed to improve the overall stereoselectivity of the Ireland-Claisen rearrangement. Exper

Full text of DOI:10.1021/ol8027225

SUPPORTING INFORMATION FOR
Attempts to Improve the Overall Stereoselectivity of Ireland-Claisen
Rearrangement
Chi-Li Chen, Kosuke Namba and Yoshito Kishi*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138
CONTENTS:
General Experimental Practices ……………………………………………………... S2
Experimental Details for the Synthesis Outlined in Scheme 5 and Scheme 6……….. S3
Experimental Details for the Synthesis Outlined in Scheme 7………………….……. S8
Experimental Details for the Synthesis Outlined in Scheme 8…………………..….. S12
1
13
H NMR and C NMR Spectrum of All New Compounds ……………..………….. S18
S1

General Experimental Practices
Tetrahydrofuran, dimethylformamide, and toluene were dried according to the
1
procedure described by Grubbs. All solvents were determined to contain less than 50
ppm H O by Karl Fischer coulometric moisture analysis. Reagents are commercial grade
2
and were used as supplied. Reactions involving air or moisture sensitive reagents or
intermediates were performed under an inert atmosphere of nitrogen or argon in
glassware that was flame dried. LHMDS was purchased from Sigma-Aldrich (225770-
1
00mL), and it was used within two months when the bottle was opened (Good quality is
significant important for silyl ketene acetal formation). Analytical thin layer
chromatography (TLC) was performed with E. Merck precoated TLC plates, silica gel
6
0F-254, layer thickness 0.25 mm. TLC plates were visualized by staining with AMCAN
(
ammonium molybdate/cerium ammonium nitrate), potassium permagnate, or p-
anisaldehyde. Flash chromatography separations were performed on E. Merck kieselgel
1
6
0 (230-400) mesh silica gel. H NMR spectra were recorded on a Varian Inova 600 or
Varian Inova 500. Chemical shifts were reported in parts per million (ppm). The residual
solvent peak was used as an internal reference. Coupling constants (J) are reported in Hz
and the splitting abbreviations used are: s, singlet; d, doublet; t, triplet; app t, apparent
1
3
triplet; q, quartet; m, multiplet; comp, complex multiplet; br, broad. C NMR spectra
were recorded at 125 MHz. Fast atom bombardment (FAB) mass spectra were obtained
with 3-nitrobenzyl alcohol or glycerol as the matrix. Sodium iodide was added when
indicated. Chemical ionization (CI) mass spectra were obtained with ammonia as the
reagent gas. Electrospray ionization experiments were performed on Micromass Inc.,
Platform II Atmospheric Pressure Ionization Mass Spectrometer.
1
Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
S2

Experimental Details for the Synthesis Outlined in Scheme 5 and Scheme 6
(
a) Preparation of Propionate 5:
O
O
O
O
HO
O
O
(
t-Bu) SiOTf , py t-Bu
DMAP, (EtCO) O
t-Bu
2
2
2
Si
Si
O
O
HO
t-Bu
Et N, 50 oC
3
t-Bu
OH
OH
91% over 2 steps
Me
15
16
5
O
(
4aR,8R,8aR)-2,2-Di-tert-butyl-4,4a,8,8a-tetrahydropyrano[3,2-
d][1,3,2]dioxasilin-8-yl propionate (5). A solution of (t-Bu) SiOTf (26.7 mL, 73.2
2
2
mmol) in CH Cl (133 mL) was added dropwise to a solution of D-galactal 15 (10.0 g,
2
2
6
8.4 mmol, from Carbosynth Limited in UK) in DMF (342 mL) at -45 °C over 40 min.
After stirring at -45 °C for 1 h, freshly distilled pyridine (20.3 mL, 205 mmol) was added.
The reaction was allowed to warm to 0 °C and stirred at 0 °C for 1 h. The mixture was
quenched by addition of saturated NaHCO (50 mL) and diluted with hexanes/EtOAc
3
(
(
5:1, 2.5 L). The organic layer was washed with brine (1 x 500 mL, 4 x 200 mL), dried
1
13
MgSO ) and concentrated to give crude allylic alcohol 16 whose H and C NMR
4
2
spectral data were consistent with those reported.
A solution of crude alcohol 16, propionic anhydride (21.9 mL, 171 mmol), and
DMAP (835 mg, 6.8 mmol) in Et N (456 mL) was stirred at 50 °C for 13 h. The mixture
3
was concentrated and then diluted with hexanes/EtOAc (10:1, 0.8 L). The organic layer
was washed with water (4 x 100 mL) and brine (100 mL), dried (Na SO ) and
2
4
concentrated. The residue was purified by flash chromatography on silica gel, eluting
with hexanes/EtOAc (40:1 to 10:1) to afford 21.2 g (91% over 2 steps from 15) of
2
5
1
propionate 5 as a white solid; mp 86 °C; [α] +117 (c 1.00, CHCl ); H NMR (600
D
3
MHz, CDCl ; see the spectrum on page S18) δ 6.41 (dd, J = 6.6, 1.8 Hz, 1 H), 5.26-5.23
3
(
m, 1 H), 4.80 (d, J = 4.8 Hz, 1 H), 4.64 (dd, J = 6.6, 1.8 Hz, 1 H), 4.26 (dd, J = 13.0, 1.8
Hz, 1 H), 4.22 (dd, J = 13.0, 1.8 Hz, 1 H), 3.87 (br, 1 H), 2.37 (dq, J = 7.6, 1.8 Hz, 2 H),
2
Abdel-Rahman, A. A.-H.; Winterfeld, G. A.; Takhi, M.; Schmidt, R. R. Eur. J. Org.
Chem. 2002, 713.
S3

1
3
1
.16 (t, J = 7.6 Hz, 3 H), 1.00 (s, 9 H), 0.99 (s, 9 H); C NMR (125 MHz, CDCl ; see the
3
spectrum on page S19) δ 174.6, 145.9, 98.8, 73.3, 67.6, 67.5, 65.2, 28.0. 27.8, 27.2, 23.5,
1.1, 9.6; mass spectrum (ESI) m/z 365.1742 [C H O SiNa (M+Na) requires 365.1760].
2
17
30
5
(
b) Ireland-Claisen Rearrangement for One Day, and The Yield was Determined at
Lactone Stage:
O
O
O
Me
O
O
H
t-Bu
LHMDS, TBSCl
t-Bu
Benzene
O
OTBS
Si
Si
O
t-Bu
O
O
t-Bu
THF, HMPA, -78 o
t-Bu
80 o
C
Si
O
C
O
O
t-Bu
Me
Me 26 h
OTBS
(Z/E = 7.3:1)
7
5
O
6
Me
Me
H
H
H
O
O
I2, KI, NaHCO3
n-Bu3SnH, Et3B
O
O
t-Bu
O
t-Bu
O
Si
Si
O
O
O
O
84% from 5
t-Bu
t-Bu
H
I
1
9
7
Iodolactone 17. A solution of LHMDS (91.5 mL of a 1.0 M solution in THF, 91.5
mmol) was added dropwise to a solution of TBSCl (15.9 g, 106 mmol) in THF (240 mL)
and HMPA (fresh distilled, 120 mL) at -78 °C. Once addition was complete, the reaction
mixture was stirred at -78 °C for 10 min, warmed to 0 °C and stirred at 0 °C for 10 min,
and then cooled to -78 °C. A solution of propionate 5 (12.0 g, 35 mmol) in THF (60 mL)
was added dropwise over 40 min. The mixture was stirred at -78 °C for 1 h, warmed to 0
°
C over 30 min, and stirred at 0 °C for 20 min. The mixture was poured onto cold
o
hexanes (-15 C, 3 L). The organic layer was washed with water (5 x 600 mL) and brine
(
2 x 600 mL), dried (Na SO ), and concentrated to afford silyl ketene acetal 6 (Z/E =
2 4
1
7
.3:1, H NMR, C D ; see the spectrum on page S20).
6 6
A solution of silyl ketene acetal 6 in benzene (500 mL) was stirred at 80 °C for 26 h
under nitrogen and then concentrated under reduce pressure. The residue was dried under
vacuum for 18 h at room temperature to give crude carboxylate 7 together with
propionate 5 and silyl ketene acetal E-6 in a ca. 12% combined yield. Without
purification, carboxylate 7 was submitted to iodolactonization condition.
S4

Saturated sodium bicarbonate solution (350 mL) was added to a solution of
carboxylate 7 in THF (700 mL), and the mixture was stirred at room temperature for 2 h.
Potassium iodide (23.2 g, 140 mmol), iodine (35.4 g, 140 mmol), and sodium bicarbonate
(
11.8 g, 140 mmol) were added. The mixture was stirred for 69 h, quenched with
saturated Na S O (200 mL), and diluted with hexanes/EtOAc (1:1, 2 L). The organic
2
2
3
layer was washed with brine (3 x 500 mL), dried (Na SO ) and concentrated to give crude
2
4
iodolactone 17, which was subjected to the following reduction condition (n-Bu SnH,
3
Et B) without purification. The crude iodolactone 17 can be purified by flash
3
chromatography on silica gel, eluting with hexanes/EtOAc (15:1 to 10:1) to afford a
2
5
1
white solid; mp 143 °C; [α] -18.2 (c 0.61, CHCl ); H NMR (600 MHz, CDCl ; see the
D
3
3
spectrum on page S22) δ 4.73 (s, 1 H), 4.68-4.64 (m, 1 H), 4.53-4.51 (m, 1 H), 4.32 (d, J
=
=
9
2.4 Hz, 1 H), 4.24 (dd, J = 12.9, 2.4 Hz, 1 H), 4.21 (dd, J = 12.9, 1.2 Hz, 1 H), 3.99 (t, J
3.0 Hz, 1 H), 2.75 (q, J = 8.2 Hz, 1 H), 1.26 (d, J = 8.2 Hz, 3 H), 1.01 (s, 9 H), 0.96 (s,
13
H); C NMR (125 MHz, CDCl ; see the spectrum on page S23) δ 177.7, 77.6, 76.7,
3
7
4
1.9, 69.3, 67.8, 44.2, 27.5, 27.0, 25.5, 23.3, 20.3, 12.4; mass spectrum (ESI) m/z
69.0884 [C H IO Si (M+H) requires 469.0907].
17
30
5
Lactone 9. Triethylborane (1.75 mL, 1.0 M solution in hexanes, 1.75 mmol) was
added to a solution of crude iodolactone 17 and n-Bu SnH (14 mL, 52.5 mmol) in toluene
3
(
233 mL) under nitrogen. The mixture was stirred for 1.5 h and then concentrated under
reduced pressure. The residue was purified by flash chromatography on silica gel, eluting
with hexanes/EtOAc (4:1 to 1:1) to afford 10.1 g (84% from propionate 5) of lactone 9 as
2
5
1
a white solid; mp 102 °C; [α] -40.5 (c 0.95, CHCl ); H NMR (600 MHz, CDCl ; see
D
3
3
the spectrum on page S24) δ 4.42-4.39 (m, 1 H), 4.31-4.29 (m, 1 H), 4.24 (dd, J = 12.3,
.4 Hz, 1 H), 4.16 (dd, J = 12.3, 1.5 Hz, 1 H), 3.96 (d, J = 3.0 Hz, 1 H), 3.31-3.28 (m, 1
H), 2.73 (q, J = 7.9 Hz, 1 H), 2.58 (d, J = 15.9 Hz, 1 H), 1.94 (ddd, J = 15.9, 5.2, 4.2 Hz,
2
1
3
1
H), 1.27 (d, J = 7.9 Hz, 3 H), 1.02 (s, 9 H), 0.97 (s, 9 H); C NMR (125 MHz, CDCl ;
3
see the spectrum on page S25) δ 178.7, 79.8, 73.8, 72.4, 67.6, 65.7, 44.1, 32.2, 27.5, 27.0,
2
3
3.2, 20.1, 12.6; mass spectrum (ESI) m/z 343.1933 [C H O Si (M+H) requires
17 31 5
43.1941].
(
c) Ireland-Claisen Rearrangement for Three Days:
S5

Iodolactone 17. A solution of LHMDS (38.0 mL of a 1.0 M solution in THF, 38.0
mmol) was added dropwise to a solution of TBSCl (6.60 g, 43.8 mmol) in THF (100 mL)
and HMPA (fresh distilled, 50 mL) at -78 °C. Once addition was complete, the reaction
mixture was stirred at -78 °C for 10 min, warmed to 0 °C and stirred at 0 °C for 10 min,
and then cooled to -78 °C. A solution of propionate 5 (5.0 g, 14.6 mmol) in THF (25 mL)
was added dropwise over 40 min. The mixture was stirred at -78 °C for 1 h, warmed to 0
°
C over 30 min, and stirred at 0 °C for 30 min. The mixture was poured onto cold
o
hexanes (-15 C, 1.5 L). The organic layer was washed with water (5 x 300 mL) and brine
(
2 x 300 mL), dried (Na SO ), and concentrated to afford silyl ketene acetal 6 (Z/E =
2 4
1
6
.5:1, H NMR, C D ).
6 6
A solution of silyl ketene acetal 6 in benzene (210 mL) was stirred at 80 °C for 72 h
under nitrogen and then concentrated under reduce pressure. The residue was dried under
vacuum for 14 h at room temperature to give crude carboxylate 7 together with 2%
1
propionate 5 (All silyl ketene acetals were consumed; For H NMR, see the spectrum on
page S21). Without purification, carboxylate 7 was submitted to iodolactonization
condition.
Saturated sodium bicarbonate solution (73 mL) was added to a solution of
carboxylate 7 in THF (146 mL), and the mixture was stirred at room temperature for 2 h.
Potassium iodide (9.70 g, 58.4 mmol), iodine (14.8 g, 58.4 mmol), and sodium
bicarbonate (4.90 g, 58.4 mmol) were added. The mixture was stirred for 72 h, quenched
with saturated Na S O (90 mL), and diluted with hexanes/EtOAc (1:1, 1 L). The organic
2
2
3
layer was washed with brine (3 x 200 mL), dried (Na SO ) and concentrated to give crude
2
4
iodolactone 17, which was subjected to the following reduction condition (n-Bu SnH,
3
Et B) without purification.
3
Lactone 9. Triethylborane (0.73 mL, 1.0 M solution in hexanes, 0.73 mmol) was
added to a solution of crude iodolactone 17 and n-Bu SnH (5.87 mL, 21.9 mmol) in
3
toluene (97 mL) under nitrogen. The mixture was stirred for 1.5 h and then concentrated
under reduced pressure. The residue was purified by flash chromatography on silica gel,
eluting with hexanes/EtOAc (4:1 to 1:1) to afford 4.72 g (94% from propionate 5) of
lactone 9 as a white solid.
S6

(
d) Epimerization of Lactone 9:
Me
Me
H
H
H
H
O
O
TBSOTf, Et N;
O
O
3
t-Bu
O
t-Bu
O
Si
Si
O
O
NH Cl, THF, H O
O
O
4
2
t-Bu
t-Bu
95%
10
9
Epimer 10. TBSOTf (805 µL, 3.50 mmol) was added dropwise to a solution of
lactone 9 (100 mg, 0.29 mmol) and Et N (813 µL, 5.84 mmol) in CH Cl (4.1 mL) at 0
3
2
2
°
C. The mixture was stirred at room temperature for 2 h, diluted with EtOAc (30 mL),
washed with NaHCO (3 x 5 mL), dried (Na SO ) and concentrated. The residue was
3
2
4
o
dissolved in THF/H O/NH Cl(sat, aq) (10:1:1, 6 mL). The mixture was stirred at 50 C
2
4
for 14 h, and then diluted with EtOAc (30 mL). The organic layer was washed with brine
2 x 4 mL), dried (Na SO ) and concentrated. The residue was purified by flash
(
2
4
chromatography on silica gel, eluting with hexanes/EtOAc (4:1 to 1:1) to afford 95 mg
2
5
1
(
(
95%) of lactone 10 as a white solid; mp 146 °C; [α] -24.1 (c 0.75, CHCl ); H NMR
D 3
600 MHz, CDCl ; see the spectrum on page S26) δ 4.30 (ddd, J = 4.8, 2.4, 1.8 Hz, 1 H),
3
4
.27 (dd, J = 12.3, 2.7 Hz, 1 H), 4.23-4.21 (m, 1 H), 4.19 (dd, J = 12.3, 1.8 Hz, 1 H), 4.13
dd, J = 4.2, 2.7 Hz, 1 H), 3.30-3.28 (m, 1 H), 2.70 (dq, J = 7.2, 4.8 Hz, 1 H), 2.57 (dt, J =
5.6, 1.8 Hz, 1 H), 1.94 (ddd, J = 15.6, 4.8, 4.2 Hz, 1 H), 1.28 (d, J = 7.2 Hz, 3 H), 1.01
(
1
1
3
(
s, 9 H), 0.96 (s, 9 H); C NMR (125 MHz, CDCl ; see the spectrum on page S27) δ
3
1
77.9, 76.4, 74.1, 72.7, 67.7, 65.7, 42.2, 32.6, 27.7, 27.1, 23.3, 20.2, 7.8; mass spectrum
(
ESI) m/z 343.1945 [C H O Si (M+H) requires 343.1941].
1
7
31
5
(
e) Reduction of Lactone 9 to Diol i:
Me
H
Me
OH
H
H
O
O
O
OH
LiBH
93%
4
O
t-Bu
O
t-Bu
Si
Si
O
O
O
t-Bu
t-Bu
H
i
9
S7

(
4aR,6S,7S,8aR)-2,2-di-tert-butyl-hexahydro-6-((R)-1-hydroxypropan-2-
yl)pyrano[3,2-d][1,3,2]dioxasilin-7-ol (i). Lithium borohydride (1.40 g, 64.3 mmol) was
added slowly to a solution of lactone 9 (2.20 g, 6.42 mmol) in THF (64 mL) at 0 °C.
After stirring for 2 h, methanol (0.64 mL) was added. The mixture was stirred at 0 °C for
1
2 h and then room temperature for another 12 h. The reaction was quenched at 0 °C by
carefully addition of EtOAc (20 mL), followed by saturated sodium bicarbonate (40 mL).
The mixture was stirred at 0 °C until all bubbles disappeared. Hexanes (60 mL) was
added, and organic layer was separated. The aqueous layer was extracted with
hexanes/Et O (1:1, 4 x 80 mL). All organic layers were combined, dried (Na SO ) and
2
2
4
concentrated. The residue was purified by flash chromatography on silica gel, eluting
with hexanes/EtOAc (4:1 to 1:1) to afford 2.08 g (93%) of diol i as a white solid; mp 143
2
5
1
°
C; [α] +2.9 (c 0.48, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page
D 3 3
S28) δ 4.43 (t, J = 3.0 Hz, 1 H), 4.26 (dd, J = 12.6, 3.0 Hz, 1 H), 4.20 (d, J = 12.6 Hz, 1
H), 4.07 (d, J = 10.2 Hz, 1 H), 3.85-3.81 (m, 1 H), 3.76 (ddd, J = 11.4, 5.1, 2.7 Hz, 1 H),
3
.50 (dt, J = 11.4, 6.3 Hz, 1 H), 3.38-3.36 (m, 1 H), 3.22 (d, J = 7.2 Hz, 1 H), 3.00 (dd, J
6.3, 5.1 Hz, 1 H), 2.32 (dt, J = 14.7, 3.0 Hz, 1 H), 2.09 (dq, J = 6.8, 2.7 Hz, 1 H), 1.77
=
1
3
(
dt, J = 14.7, 3.0 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.04 (s, 9 H), 1.03 (s, 9 H); C
NMR (125 MHz, CDCl ; see the spectrum on page S29) δ 84.0, 76.9, 69.3, 68.6, 64.4,
3
6
3.5, 37.9, 36.6, 27.7, 27.1, 23.1, 20.2, 13.9; mass spectrum (ESI) m/z 369.2072
[
C H O SiNa (M+Na) requires 369.2073]. (For X-ray analysis, see the attached cif file.)
1
7
34
5
Experimental Details for the Synthesis Outlined in Scheme 7
(
a) Synthesis of Propionate 11:
O
O
O
TIPSO
BnO
O
TIPSO
BnO
HO
BnO
TIPSOTf, py, CH2Cl2
38%
DMAP, (EtCO)2O, Et3N
75%
OH
OH
1
9
O
18
11
S8

3
Alcohol 19. TIPSOTf (0.84 mL, 3.14 mmol) was added to a solution of diol 18
o
(
730 mg, 3.14 mmol) and pyridine (0.76 mL, 9.42 mmol) in CH Cl (16 mL) at -50 C.
2 2
o
o
The reaction was slowly warm up to 0 C over 90 min, and then stirred at 0 C for 1 h. A
solution of EtOAc (30 mL) and hexanes (30 mL) was added. The organic layer was
washed with H O (15 mL), NaHCO (15 mL) and brine (15 mL), dried (Na SO ), and
2
3
2
4
concentrated. The residue was purified by flash chromatography on silica gel, eluting
with hexanes/EtOAc (40:1 to 10:1) to afford 463 mg (38%) of alcohol 19 as a colorless
2
5
1
oil; [α] -7.8 (c 0.49, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page
D
3
3
S30) δ 7.37-7.27 (comp, 5 H), 6.30 (dd, J = 6.0, 1.2 Hz, 1 H), 4.81 (d, J = 11.7 Hz, 1 H),
4
3
.74 (d, J = 11.7 Hz, 1 H), 4.69 (ddd, J = 6.0, 2.7, 1.2 Hz, 1 H), 4.35-4.31 (m, 1 H), 4.02-
.98 (comp, 2 H), 3.96 (dd, J = 10.2, 5.4 Hz, 1 H), 3.89 (dd, J = 10.2, 7.2 Hz, 1 H), 2.44
1
3
(
d, J = 10.2 Hz, 1 H), 1.16-1.03 (comp, 21 H); C NMR (125 MHz, CDCl ; see the
3
spectrum on page S31) δ 144.2, 138.0, 128.6, 128.0, 127.9, 103.2, 76.7, 74.5, 72.6, 63.0,
6
4
1.3, 18.0, 11.9; mass spectrum (ESI) m/z 415.2264 [C H O SiNa (M+Na) requires
22 36 4
15.2281].
Propionate 11. A solution of alcohol 19 (463 mg, 1.18 mmol), propionic anhydride
0.38 mL, 2.95 mmol), DMAP (58 mg, 0.47 mmol) in Et N (11.8 mL) was stirred at 50
(
3
o
C for 12 h. The mixture was concentrated and diluted with EtOAc (50 mL). The organic
layer was washed with water (10 mL) and brine (10 mL), dried (Na SO ) and
2
4
concentrated. The residue was purified by flash chromatography on silica gel, eluting
with hexanes/EtOAc (40:1 to 30:1) to afford 395 mg (75%) of propionate 11 as a
2
5
1
colorless oil; [α] -25.1 (c 0.62, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum
D
3
3
on page S32) δ 7.34-7.23 (comp, 5 H), 6.39 (dd, J = 6.0, 1.8 Hz, 1 H), 5.49 (ddd, J = 6.0,
.0, 1.2 Hz, 1 H), 4.74 (d, J = 11.7 Hz, 1 H), 4.71 (ddd, J = 6.0, 3.0, 0.9 Hz, 1 H), 4.59 (d,
3
J = 11.7 Hz, 1 H), 4.10 (t, J = 6.0 Hz, 1 H), 4.08-4.05 (m, 1 H), 3.94 (dd, J = 10.8, 4.8
Hz, 1 H), 3.87 (dd, J = 10.8, 6.0 Hz, 1 H), 2.35-2.22 (m, 2 H), 1.11 (t, J = 7.8 Hz, 3 H),
1
3
1
.09-1.02 (comp, 21 H); C NMR (125 MHz, CDCl ; see the spectrum on page S33) δ
3
3
Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola,
P. M. Tetrahedron Lett. 1992, 33, 1549.
S9

1
1
74.1, 145.5, 138.1, 128.3, 127.8, 127.7, 98.7, 77.4, 73.7, 70.7, 65.5, 61.0, 27.7, 17.9,
1.9, 9.0; mass spectrum (ESI) m/z 471.2565 [C H O SiNa (M+Na) requires 471.2543].
25
40
5
(
b) Ireland-Claisen Rearrangement of TBS Silyl Ketene Acetal 20a and
Characterization at Acid 21:
Me
H
O
O
O
OTBS
TIPSO
BnO
TIPSO
BnO
!
TIPSO
BnO
LHMDS, TBSCl
Benzene
80 o
O
THF, HMPA, -78 o
Z/E = 13:1
C
C
O
O
12a
dr = 11:1
O
OTBS
0a
11
2
Me
H
O
OH
TIPSO
BnO
!
THF, H O
2
O
8
2% from 11
21
Acid 21. A solution of LHMDS (0.10 mL of a 1.0 M solution in THF, 0.10 mmol)
was added dropwise to a solution of TBSCl (17 mg, 113 µmol) in THF (0.66 mL) and
HMPA (fresh distilled, 0.33 mL) at -78 °C. Once addition was complete, the reaction
mixture was stirred at -78 °C for 5 min, warmed to 0 °C and stirred at 0 °C for 5 min, and
then cooled to -78 °C. A solution of propionate 11 (17 mg, 38 µmol) in THF (0.2 mL)
was added dropwise over 2 min. The mixture was stirred at -78 °C for 45 min, warmed to
0
°C, and stirred at 0 °C for 15 min. The mixture was poured onto hexanes (15 mL). The
organic layer was washed with water (4 x 2 mL) and brine (2 mL), dried (Na SO ), and
2
4
1
concentrated to afford silyl ketene acetal 20a (Z/E = 13:1, H NMR, C D ; see the
6
6
spectrum on page S34).
A solution of silyl ketene acetal 20a in benzene (1 mL) was stirred at 80 °C for 16 h
under nitrogen and then concentrated under reduce pressure. The residue was dried under
1
vacuum for 2 h at room temperature to give crude carboxylate 12a (dr = 11:1, H NMR,
C D ; see the spectrum on page S35), in which TBS group tended to fall off during flash
6
6
chromatography on silica gel.
For compound characterization, TBS group was removed to give acid 21. H O (0.5
2
mL) was added to a solution of crude carboxylate 12a in THF (5 mL) at room
temperature, and the reaction was stirred for 14 h. The mixture was concentrated under
S10

reduced pressure. The residue was purified by chromatography on silica gel, eluting with
2
5
hexanes/EtOAc (4:1 to 1:1) to afford 14 mg (82%) of 21 as a colorless oil; [α] -77.5 (c
D
1
0
.67, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S36) δ 7.32-7.23
3
3
(
comp, 5 H), 6.14 (ddd, J = 10.5, 5.4, 1.8 Hz, 1 H), 5.92 (d, J = 10.5 Hz, 1 H), 4.66 (d, J
12.0 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.38 (app d, J = 2.4 Hz, 1 H), 3.94 (dd, J =
0.2, 6.3 Hz, 1 H), 3.88 (dd, J = 10.2, 5.4 Hz, 1 H), 3.87-3.83 (m, 1 H), 3.69 (t, J = 6.0
=
1
13
Hz, 1 H), 2.82-2.75 (m, 1 H), 1.25 (d, J = 7.2 Hz, 3 H), 1.16-0.97 (comp, 21 H); C
NMR (125 MHz, CDCl ; see the spectrum on page S37) δ 175.1, 138.5, 130.4, 128.3,
3
1
27.7, 127.6, 127.1, 79.2, 76.2, 70.7, 67.3, 62.5, 43.4, 18.0, 12.2, 12.0, 11.9; mass
spectrum (ESI) m/z 471.2550 [C H O SiNa (M+Na) requires 471.2543].
2
5
40
5
(
c) General Procedure of Ireland-Claisen Rearrangement of TIPS Silyl Ketene
Acetal 20b:
O
O
Me
TIPSO
BnO
TIPSO
BnO
H
LHMDS, TIPSCl
O
OTIPS
Benzene
87%
TIPSO
BnO
!
THF, HMPA, -78 o
C
O
O
O
Z/E = 13:1
O
OTIPS
12b
1
1
20b
(
(
1) 80 oC, 1 days: dr = 14 : 1, no SKA left
2) 40 oC, 1 day: SKA: P = 45% (Z/E = 8:1): 55% (dr = 30:1)
4
4
0 oC, 2 day: SKA: P = 20% (Z/E = 5:1): 80% (dr = 23:1)
o
0
C, 4 day: SKA: P = 4% (Z/E = 2:1): 96% (dr = 19:1)
A solution of LHMDS (0.10 mL of a 1.0 M solution in THF, 0.10 mmol) was added
dropwise to a solution of TIPSCl (24 µL, 113 µmol) in THF (0.66 mL) and HMPA (fresh
distilled, 0.33 mL) at -78 °C. Once addition was complete, the reaction mixture was
stirred at -78 °C for 5 min, warmed to 0 °C and stirred at 0 °C for 5 min, and then cooled
to -78 °C. A solution of propionate 11 (17 mg, 38 µmol) in THF (0.2 mL) was added
dropwise over 2 min. The mixture was stirred at -78 °C for 45 min, warmed to 0 °C, and
stirred at 0 °C for 25 min. The mixture was poured onto hexanes (15 mL). The organic
layer was washed with water (5 x 3 mL) and brine (3 mL), dried (Na SO ), and
2
4
1
concentrated to afford silyl ketene acetal 20b (Z/E = 13:1, H NMR, C D ; see the
6
6
spectrum on page S38).
S11

A solution of silyl ketene acetal 20b in C D (2 mL) was stirred at 40 °C for 4 days
6
6
under nitrogen and then concentrated under the reduced pressure. The dr of crude
1
carboxylate 12b was 19:1 ( H NMR, C D ; see the spectrum on page S39), and 4% of
6
6
1
silyl ketene acetal 20b (Z/E = 2:1, H NMR) remained in the mixture. Carboxylate 12b
can be purified by flash chromatography on silica gel, eluting with hexanes/EtOAc (40:1
2
5
to 10:1) to afford 20 mg (87% from 11) of carboxylate 12b as a colorless oil; [α] -78.6
D
1
(
(
(
c 1.10, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S40) δ 7.34-7.22
3
3
comp, 5 H), 6.00 (ddd, J = 10.2, 5.4, 2.4 Hz, 1 H), 5.89 (dd, J = 10.2, 1.2 Hz, 1 H), 4.65
d, J = 12.0 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.44-4.40 (m, 1 H), 3.98 (dd, J = 9.6, 8.4
Hz, 1 H), 3.86 (app dt, J = 2.4, 2.4 Hz, 1 H), 3.76 (dd, J = 9.6, 5.4 Hz, 1 H), 3.62-3.57
(
m, 1 H), 2.58 (dq, J = 6.8, 1.2 Hz, 1 H), 1.32-1.26 (comp, 3 H), 1.21 (d, J = 6.8 Hz, 3 H),
1
3
1
.10-1.01 (comp, 39 H); C NMR (125 MHz, CDCl ; see the spectrum on page S41) δ
3
1
74.0, 139.3, 133.1, 128.2, 127.6, 127.3, 125.9, 78.4, 76.1, 70.9, 67.6, 62.1, 45.5, 18.0,
1
8.0, 17.8, 12.0, 11.9; mass spectrum (ESI) m/z 627.3888 [C H O Si Na (M+Na)
34
60
5
2
requires 627.3877].
Experimental details for the synthesis outlined in Scheme 8
(
a) Synthesis of Propionate 13:
O
O
O
BnO
HO
BnO
BnO
PivCl, py
TIPSOTf, py
TIPSO
HO
OPiv
OPiv
24
OH
23
2
2
O
O
BnO
TIPSO
BnO
DMAP, (EtCO) O, Et N
DIBAL
2
3
TIPSO
46% over 4 steps
O
OH
25
O
13
4
Glucal 23. PivCl (0.52 mL, 3.38 mmol) was added to a solution of diol 22 (400
mg, 1.69 mmol), DMAP (4.1 mg, 0.34 mmol) and pyridine (1.10 mL, 13.5 mmol) in
DCM (11.3 mL), and the reaction was stirred at room temperature for 15 h. The mixture
4
Bussolo, V. D.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett. 2003, 5, 2173.
S12

was diluted with EtOAc (50 mL). The organic layer was washed with saturated sodium
carbonate (2 x 10 mL), water (10 mL) and brine (10 mL), dried (Na SO ), and
2
4
concentrated. The residue was purified by chromatography on silica gel, eluting with
25
hexanes/EtOAc (10:1 to 7:1) to afford 343 mg (63%) of glucal 23 as a colorless oil; [α]
D
1
+
1.5 (c 0.64, CHCl ); H NMR (500 MHz, CDCl ; see the spectrum on page S42) δ 7.36-
3
3
7
.25 (comp, 5 H), 6.45 (dd, J = 6.2, 1.5 Hz, 1 H), 5.20 (dt, J = 6.0, 2.0 Hz, 1 H), 4.66 (dd,
J = 6.2, 2.5 Hz, 1 H), 4.62 (d, J = 7.2 Hz, 1 H), 4.58 (d, J = 7.2 Hz, 1 H), 4.00-3.95 (m, 1
H), 3.92 (ddd, J = 9.0, 6.0, 3.0 Hz, 1 H), 3.82-3.77 (comp, 2 H), 3.34 (d, J = 3.0 Hz, 1 H),
1
3
1
1
.19 (s, 9 H); C NMR (125 MHz, CDCl ; see the spectrum on page S43) δ 180.0, 146.1,
3
37.7, 128.4, 127.7, 127.7, 98.9, 77.3, 73.6, 73.0, 68.7, 68.1, 38.8, 27.0; mass spectrum
(
ESI) m/z 343.1530 [C H O Na (M+Na) requires 343.1521].
18 24 5
Glucal 24. TIPSOTf (0.56 mL, 2.14 mmol) was added to a solution of glucal 23
(
343 mg, 1.07 mmol) and pyridine (1.04 mL, 12.8 mmol) in DCM (10.7 mL), and the
reaction was stirred at room temperature for 6 h. The mixture was diluted with
hexanes/EtOAc (4:1, 40 mL). The organic layer was washed with saturated sodium
carbonate (2 x 10 mL), water (10 mL) and brine (10 mL), dried (Na SO ), and
2
4
concentrated. The residue was purified by chromatography on silica gel, eluting with
hexanes/EtOAc (40:1 to 10:1) to afford 510 mg (100%) of glucal 24 as a colorless oil;
2
5
1
[
α] -52.9 (c 0.64, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S44)
D 3 3
δ 7.34-7.24 (comp, 5 H), 6.44 (d, J = 5.7 Hz, 1 H), 4.97 (app t, J = 3.9 Hz, 1 H), 4.77
ddd, J = 5.7, 4.8, 1.2 Hz, 1 H), 4.59 (d, J = 6.0 Hz, 1 H), 4.53 (d, J = 6.0 Hz, 1 H), 4.27-
(
4
.23 (m, 1 H), 4.07 (dt, J = 4.2, 1.2 Hz, 1 H), 3.74 (dd, J = 10.2, 7.5 Hz, 1 H), 3.59 (dd, J
1
3
=
10.2, 3.9 Hz, 1 H), 1.12 (s, 9 H), 1.08-1.00 (comp, 21 H); C NMR (125 MHz, CDCl ;
3
see the spectrum on page S45) δ 177.6, 145.5, 137.9, 128.4, 127.7, 127.7, 97.2, 78.0,
3.4, 68.6, 68.0, 67.5, 38.7, 27.1, 26.5, 18.0, 12.5; mass spectrum (ESI) m/z 499.2862
C H O SiNa (M+Na) requires 499.2856].
7
[
2
7
44
5
Alcohol 25. A solution of DIBAL (3.75 mL of a 1.0 M solution in hexanes, 3.75
mmol) was added dropwise to a solution of glucal 24 (510 mg, 1.07 mmol) in CH Cl (11
2
2
o
mL) at -78 C over 4 min. Once the addition was complete, the reaction was stirred at -78
o
C for 40 min and then quenched with saturated sodium potassium tartrate solution (4
mL). The mixture was stirred at room temperature for 2 h and then diluted with
S13

hexanes/EtOAc (1:1, 30 mL). The organic layer was washed with brine (5 x 3 mL), dried
Na SO ) and concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel, eluting with hexanes/EtOAc (15:1 to 7:1) to afford 352 mg
(
2
4
2
5
1
(
84%) of 25 as a colorless oil; [α] +13.2 (c 0.64, CHCl ); H NMR (600 MHz, CDCl ;
D 3 3
see the spectrum on page S46) δ 7.34-7.25 (comp, 5 H), 6.41 (dd, J = 6.0, 1.2 Hz, 1 H),
.74 (ddd, J = 6.0, 3.6, 0.6 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1
4
H), 4.06-4.01 (comp, 2 H), 3.93 (dd, J = 6.0, 4.8 Hz, 1 H), 3.78 (dd, J = 10.2, 3.0 Hz, 1
H), 3.73 (dd, J = 10.2, 5.4 Hz, 1 H), 2.12 (d, J = 1.2 Hz, 1 H), 1.13-1.00 (comp, 21 H);
1
3
C NMR (125 MHz, CDCl ; see the spectrum on page S47) δ 144.4, 137.6, 128.4, 127.8,
3
1
27.7, 101.8, 78.0, 73.6, 71.9, 69.5, 68.1, 18.1, 12.6; mass spectrum (ESI) m/z 415.2268
[
C H O SiNa (M+Na) requires 415.2281].
22 36 4
Propionate 13. A solution of alcohol 25 (352 mg, 0.90 mmol), propionic anhydride
o
(
0.29 mL, 2.24 mmol), DMAP (11 mg, 0.09 mmol) in Et N (9 mL) was stirred at 50 C
3
for 2 h. The mixture was concentrated and then diluted with hexanes/EtOAc (3:1, 30
mL). The organic layer was washed with saturated sodium bicarbonate solution (10 mL),
water (2 x 10 mL) and brine (10 mL), dried (Na SO ) and concentrated. The residue was
2
4
purified by flash chromatography on silica gel, eluting with hexanes/EtOAc (80:1 to
2
5
4
0:1) to afford 350 mg (87%) of propionate 13 as a colorless oil; [α] -45.7 (c 0.64,
D
1
CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S48) δ 7.34-7.24 (comp, 5
3
3
H), 6.42 (dd, J = 6.3, 0.6 Hz, 1 H), 5.08 (dt, J = 3.6, 1.2 Hz, 1 H), 4.76 (dd, J = 6.3, 3.6
Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.16-4.10 (comp, 2 H),
3
.74 (dd, J = 10.5, 6.0 Hz, 1 H), 3.70 (dd, J = 10.5, 3.6 Hz, 1 H), 2.31-2.20 (m, 2 H), 1.08
1
3
(
t, J = 7.8 Hz, 3 H), 1.07-0.98 (comp, 21 H); C NMR (125 MHz, CDCl ; see the
3
spectrum on page S49) δ 173.7, 145.5, 137.8, 128.3, 127.6, 127.6, 98.0, 78.0, 73.4, 70.9,
8.2, 67.5, 27.7, 18.0, 17.9, 12.6, 8.9; mass spectrum (ESI) m/z 471.2553 [C H O SiNa
6
25
40
5
(
M+Na) requires 471.2543].
(
b) Ireland-Claisen Rearrangement of TBS Silyl Ketene Acetal and
Characterization at Acid 26:
S14

Me
*
O
O
Me
*
H
BnO
H
O
OH
O
OTBS
THF, H O
BnO
1
. LHMDS, TBSCl BnO
2
TIPSO
O
O
THF, HMPA, -78 o
C
TIPSO
TIPSO
80% from 13
2
6
2. Bezene, rt
14a
O
1
3
dr = 14:1
Acid 26. A solution of LHMDS (87 µL of a 1.0 M solution in THF, 87 µmol) was
added dropwise to a solution of TBSCl (15 mg, 0.10 mmol) in THF (0.66 mL) and
HMPA (fresh distilled, 0.33 mL) at -78 °C. Once addition was complete, the reaction
mixture was stirred at -78 °C for 10 min, warmed to 0 °C and stirred at 0 °C for 5 min,
and then cooled to -78 °C. A solution of propionate 13 (15 mg, 33 µmol) in THF (0.2
mL) was added dropwise over 2 min. The mixture was stirred at -78 °C for 40 min,
warmed to 0 °C, and stirred at 0 °C for 15 min. The mixture was poured onto hexanes (15
mL). The organic layer was washed with water (5 x 3 mL) and brine (3 mL), dried
(
Na SO ), and concentrated (The Z/E ratio was not reliably estimated since the Ireland-
2 4
Claisen rearrangement occurred at RT).
The residue in benzene (2 mL) was stirred at room temperature for 24 h under
nitrogen and then concentrated under reduce pressure. The residue was dried under
1
vacuum for 2 h at room temperature to give crude carboxylate 14a (dr = 14:1, H NMR,
C D ; see the spectrum on page S50), in which TBS group tended to fall off during flash
6
6
chromatography on silica gel.
For compound characterization, TBS group was removed to give acid 26. H O (0.5
2
mL) was added to a solution of crude carboxylate 14a in THF (5 mL) at room
temperature, and the reaction was stirred for 24 h. The mixture was concentrated under
reduced pressure. The residue was purified by chromatography on silica gel, eluting with
2
5
hexanes/EtOAc (5:1 to 1:1) to afford 12 mg (80%) of 26 as a colorless oil; [α] +95.1 (c
D
1
0
.67, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S51) δ 7.35-7.22
3
3
(
comp, 5 H), 5.91 (d, J = 10.5 Hz, 1 H), 5.67 (d, J = 10.5 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1
H), 4.53 (d, J = 12.0 Hz, 1 H), 4.46-4.40 (comp, 2 H), 3.75 (dd, J = 10.3, 1.8 Hz, 1 H),
.69 (dd, J = 10.3, 5.1 Hz, 1 H), 3.58-3.52 (m, 1 H), 2.73 (dq, J = 6.6, 2.4 Hz, 1 H), 1.19
3
1
3
(
d, J = 6.6 Hz, 3 H), 1.04-0.98 (comp, 21 H); C NMR (125 MHz, CDCl ; see the
3
spectrum on page S52) δ 175.0, 138.1, 132.6, 128.4, 127.6, 127.6, 125.4, 79.3, 75.2, 73.3,
S15

6
9.0, 63.9, 43.6, 18.1, 18.0, 12.6, 11.6; mass spectrum (ESI) m/z 471.2533 [C H O SiNa
25 40 5
(
M+Na) requires 471.2543].
(
c) General Procedure of Ireland-Claisen Rearrangement of TIPS Silyl Ketene
Acetal:
O
O
Me
*
BnO
H
1
. LHMDS, TIPSCl
THF, HMPA, -78 o
. Bezene,
O
OTIPS
BnO
TIPSO
C
O
TIPSO
2
14b
O
13
(1) RT, 1D, dr = 26:1
2) 0 oC, 3D, dr = 47:1
(
94%
Carboxylate 14b. A solution of LHMDS (580 µL of a 1.0 M solution in THF, 0.58
mmol) was added dropwise to a solution of TIPSCl (143 µg, 0.67 mmol) in THF (4.4
mL) and HMPA (fresh distilled, 2.2 mL) at -78 °C. Once addition was complete, the
reaction mixture was stirred at -78 °C for 5 min, warmed to 0 °C and stirred at 0 °C for 5
min, and cooled to -78 °C. A solution of propionate 13 (100 mg, 0.22 mmol) in THF (1.3
mL) was added dropwise over 10 min. The mixture was stirred at -78 °C for 45 min,
warmed to 0 °C over 30 min, and stirred at 0 °C for 25 min. The mixture was poured onto
o
hexanes (80 mL, -10 C). The organic layer was washed with cold water (5 x 20 mL, 0
o
o
C) and brine (30 mL, 0 C) (The Z/E ratio was not reliably estimated since the Ireland-
o
Claisen rearrangement occurred slowly at 0 C).
o
The mixture was stored at 0 C for 3 days, dried (Na SO ), and concentrated under
2
4
reduced pressure. The residue was dried under vacuum for 2 h at room temperature to
1
give crude carboxylate 14b (dr = 43:1, H NMR, C D ; see the spectrum on page S53),
6
6
which was purified by flash chromatography on silica gel, eluting with hexanes/EtOAc
(
[
40:1 to 10:1) to afford 123 mg (91% from 13) of carboxylate 14b as a colorless oil;
2
5
1
α] +63.2 (c 1.01, CHCl ); H NMR (600 MHz, CDCl ; see the spectrum on page S54)
D
3
3
δ 7.33-7.22 (comp, 5 H), 5.82 (dt, J = 10.5, 2.4 Hz, 1 H), 5.69 (dt, J = 10.5, 1.8 Hz, 1 H),
.59 (d, J = 12.0 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.77-4.44 (m, 1 H), 4.35-4.31 (m, 1
H), 3.71 (dd, J = 11.1, 1.8 Hz, 1 H), 3.65 (dd, J = 11.1, 5.4 Hz, 1 H), 3.46 (dq, J = 5.4,
4
1
.8 Hz, 1 H), 2.57 (dq, J = 7.2, 1.2 Hz, 1 H), 1.31-1.25 (comp, 3 H), 1.19 (d, J = 7.2 Hz, 3
S16

13
H), 1.08-0.98 (comp, 39 H); C NMR (125 MHz, CDCl ; see the spectrum on page S55)
3
δ 173.9, 138.7, 131.2, 128.7, 128.2, 127.6, 127.3, 79.8, 75.7, 73.4, 69.8, 64.5, 45.9, 18.1,
1
8.1, 17.9, 17.8, 12.7, 12.1, 11.9; mass spectrum (ESI) m/z 627.3891 [C H O Si Na
34 60 5 2
(
M+Na) requires 627.3877].
S17

O
O
O
t-Bu
Si
O
t-Bu
Me
O
5
1H NMR Spectrum
600 MHz, CDCl3)
(
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S18

O
O
O
t-Bu
Si
O
t-Bu
Me
O
5
13C NMR Spectrum
125 MHz, CDCl3)
(
180
160
140
120
100
80
60
40
20
0
S19

(
a)
(a)
(a)
(a)
(a)
(a)
(a)
(b)
(b)
(b)
(b)
(b)
6
.0
5.5
5.0
4.5
4.0
3.5
3.0
O
O
O
O
O
t-Bu
t-Bu
Si
Si
Me
O
+
O
t-Bu
t-Bu
O
Me
OTBS
Z-6
a)
OTBS
E-6
(b)
(
7.3:1
Crude unstable intermediates, without purification
1H NMR Spectrum
(
600 MHz, C D )
6
6
(
a)
(b)
(
b) (a)
(b) (a)
(a)
(a)
(a)
(a)
(b) (a)
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S20

Me
H
O
OTBS
O
t-Bu
Si
O
O
t-Bu
7
Crude material, without purification
1H NMR Spectrum
(
600 MHz, C D )
6 6
7
.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S21

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
I
17
1H NMR Spectrum
(600 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S22

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
I
17
13C NMR Spectrum
(125 MHz, CDCl3)
180
160
140
120
100
80
60
40
20
0
S23

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
9
1H NMR spectrum
600 MHz, CDCl3)
(
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S24

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
9
13C NMR Spectrum
125 MHz, CDCl3)
(
180
160
140
120
100
80
60
40
20
0
S25

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
10
1H NMR Spectrum
(
600 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S26

Me
H
H
O
O
t-Bu
O
Si
O
O
t-Bu
10
13C NMR Spectrum
(125 MHz, CDCl3)
180
160
140
120
100
80
60
40
20
0
S27

Me
OH
H
H
O
OH
O
t-Bu
Si
O
t-Bu
i
1H NMR Spectrum
600 MHz, CDCl3)
(
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S28

Me
OH
H
H
O
OH
O
t-Bu
Si
O
t-Bu
i
13C NMR Spectrum
(
125 MHz, CDCl3)
180
160
140
120
100
80
60
40
20
0
S29

O
TIPSO
BnO
OH
19
1H NMR Spectrum
(600 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
S30