Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals

Article abstract of DOI:10.1021/ja201249c

Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for S_N2 versus S_N1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S_N2 or S_N2-like mechanism (ρ = -1.3 vs ρ = -5.1 for corresponding S_N1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH, and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the side-chain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products.

Full text of DOI:10.1021/ja201249c

Wurst, Liu, and Tan
Supporting Information
Page S1
Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the
Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides
to Form Spiroketals
†
‡
†,‡
Jacqueline M. Wurst, Guodong Liu, and Derek S. Tan
†
Tri-Institutional Training Program in Chemical Biology,
‡
Molecular Pharmacology and Chemistry Program,
and Tri-Institutional Research Program, Memorial Sloan–Kettering Cancer Center,
1
275 York Avenue, Box 422, New York, New York 10065
Supporting Information
A. Materials and methods
S2
B. General procedure for epoxidation and spontaneous spirocyclization
C. General procedure for epoxidation and MeOH-induced spirocyclization
D. General procedure for temperature dependent spirocyclization
E. Kinetic studies
S3
S4
S5
S6
F. Synthesis of sidechain precursors (S1–S25)
S19
S30
S39
S48
G. Synthesis of substituted C1-aryl glycal substrates (S26, 5–7)
H. C1-aryl spiroketal products with retention of configuration (11–13)
I. C1-aryl spiroketal products with inversion of configuration (8–10)
J. MeOH-induced spirocyclization of C1-aryl cyclohexene oxide (S27–S30, 26–28) S54
K. Synthesis of TBS-protected methyl glycoside (29–30)
L. NMR spectra of new compounds
S58
S60

Wurst, Liu, and Tan
Supporting Information
Page S2
A. MATERIALS AND METHODS
Reagents were obtained from Aldrich Chemical (www.sigma-aldrich.com), Strem
www.strem.com), or Acros Organics (www.fishersci.com) and used without further purification
(
unless otherwise indicated. Solvents (Optima or HPLC grade) were obtained from Fisher
Scientific (www.fishersci.com), degassed with Ar, and purified on a solvent drying system as
1
described unless otherwise indicated. Reactions were performed in flame-dried glassware under
positive Ar pressure with magnetic stirring. Cold baths were generated as follows: 0 °C, wet
ice/water; –20 °C, dry ice/ CCl ; –44 °C, dry ice/CH CN; –63 °C, dry ice/chloroform; –78 °C,
4
3
dry ice/acetone.
TLC was performed on 0.25 mm E. Merck silica gel 60 F254 plates and visualized under UV
light (254 nm) or by staining with potassium permanganate (KMnO ), cerium ammonium
4
molybdenate (CAM). Silica flash chromatography was performed on E. Merck 230–400 mesh
silica gel 60. Optical rotations were recorded on a JASCO model PTC-103T digital polarimeter.
IR spectra were recorded on a Bruker Optics Tensor 27 FTIR spectrometer with peaks reported
–
1
in cm . NMR spectra were recorded on Bruker UltraShield Plus 500 MHz instruments at 24 °C
1
in CDCl unless otherwise indicated. Chemical shifts are expressed in ppm relative to TMS ( H,
3
1
3
1
13
0
ppm) or solvent signals: CDCl ( C, 77.0 ppm), C D ( H, 7.16 ppm; C, 128.0 ppm), CD Cl
3 6 6 2 2
13 1 13 13
H, 5.31 ppm; C, 53.5 ppm), CD OD ( H, 3.31 ppm; C, 63.1 ppm) or acetone-d ( C,
1
(
3
6
2
06.2 ppm); coupling constants are expressed in Hz. Mass spectra were obtained at the MSKCC
Analytical Core Facility on a Waters Acquity TM mass spectrometer by electrospray (ESI)
ionization or atmospheric pressure chemical ionization (AP-CI). Curve fits were carried out
using GraphPad Prism version 5.0a (GraphPad Software, Inc, La Jolla, CA).
N.B.: Atom numbering in IUPAC compound names herein does not correspond to conventional
carbohydrate nomenclature and is used for naming purposes only. Atom numbering in the text
and paper corresponds to conventional carbohydrate nomenclature. Compounds not cited in the
paper are numbered herein S1–S30.
1
Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15,
1
518–1520.

Wurst, Liu, and Tan
Supporting Information
Page S3
B. GENERAL PROCEDURE FOR EPOXIDATION AND SPONTANEOUS
SPIROCYCLIZATION (TABLE 1 OF MANUSCRIPT)
Glycal alcohols 5–7 (1.0 equiv) were dissolved in CH Cl (final ratio 6:1 CH Cl /acetone) and
2
2
2
2
cooled to –78 °C. DMDO (0.073 M in acetone, 1.2 equiv) was added via syringe and the
mixture was stirred at –78 °C for 10 min. The reaction was warmed to rt and concentrated by
1
rotary evaporation. The crude reaction mixtures were analyzed by H-NMR to determine the
ratios listed in Table 1 of the manuscript. Spiroketal retention products 11–13 were purified
from product mixtures by silica flash chromatography (20:1–10:1 hexanes/EtOAc with 0.5%
Et N).
3

Wurst, Liu, and Tan
Supporting Information
Page S4
C. GENERAL PROCEDURE FOR EPOXIDATION AND MEOH-INDUCED
SPIROCYCLIZATION (TABLE 2 OF MANUSCRIPT)
The glycal alcohol 5–7 (1.0 equiv) was dissolved in 5:1 MeOH/CH Cl (final ratio after DMDO
2
2
addition = 5:1:1 MeOH/CH Cl /acetone) and cooled to –63 °C. DMDO (0.073 M in acetone,
2
2
1
.2 equiv) was added via syringe, and the reaction mixture was stirred at –63 °C for 3 h. The
reaction was warmed to rt and concentrated by rotary evaporation. The crude reaction mixtures
1
were analyzed by H-NMR to determine the ratios listed in Table 2 of the manuscript. Silica
flash chromatography (20:1–10:1 hexanes/EtOAc with 0.5% Et N) of product mixtures provided
3
contrathermodynamic spiroketals 8–10.

Wurst, Liu, and Tan
Supporting Information
Page S5
D. GENERAL PROCEDURE FOR TEMPERATURE DEPENDENT SPIROCYCLIZATION
TABLE 3 OF MANUSCRIPT)
The glycal substrate (1.0 equiv) was added as a solution in CDCl to an oven-dried, Ar-flushed
(
3
5
mm NMR tube. The tube was capped with a rubber septum. The appropriate amount of
additional deuterated solvent (CD OD, CDCl ) was added, followed by brief mixing and cooling
3
3
to −78 °C. DMDO (0.073 M in acetone, 1.2 equiv), removed from a −80 °C freezer and used
immediately, was added and the tube was shaken vigorously for 3 s, then warmed to −44 °C
(except for entry 1, where the epoxide was kept at −78 °C). The tube was transferred quickly to
the NMR instrument which was precooled to −40 °C (or −63 °C for entry 1). The sample was
locked and shimmed and the NMR was tuned (3 min), then the sample was warmed to the
temperature indicated in the table to initiate the spirocyclization reaction. Reactions were run to
1
completion over 2 h and crude H-NMR spectra were analyzed. Integration of the C2 proton of
spiroketal 18 (δ 3.22) and methyl glycoside 20 (δ 3.33) gave the ratio shown in entry 2.
Integration of the benzylic protons of spiroketal 9c (δ 2.90, 2H) and spiroketal 12c (δ 2.52,
3
.12, 2H) gave the ratio shown in entry 6. Integration of a benzylic proton of spiroketal 13c
(
δ 2.44) and methyl glycoside 16c (δ 2.66) gave the ratio shown in entry 7.

Wurst, Liu, and Tan
Supporting Information
Page S6
E. KINETIC STUDIES
1
. NMR ANALYSIS OF TOSIC ACID EPIMERIZATION OF CONTRATHERMODYNAMIC SPIROKETALS
Contrathermodynamic spiroketals 8b–f (1.0 equiv) were added as a solution in CDCl (0.011 M)
3
to an oven-dried, Ar-flushed 5 mm NMR tube. To each of the CDCl solutions was added tosic
3
acid monohydrate (0.1 equiv) as a stock solution in THF-d (0.026 M) for a final tosic acid
8
concentration of 0.0012 M. The tubes were shaken vigorously for 5 s and a timer was started.
Conversion of 8b–f to 11b–f was recorded over time by NMR integration of the benzylic proton
signals (5.00–5.30 ppm) (Table S1, Figure S1). The observed rates of epimerization were
2
calculated based on the method of initial rates (Table S2). For spiroketal 8f (R = NO ), no
2
equilibration to spiroketal 11f was observed under these conditions over >72 h.
Following the above procedure, contrathermodynamic spiroketal 8a (1.0 equiv) was prepared as
a solution in CDCl (0.011 M), except in a flame-dried 4 mL vial. To the CDCl solution was
3
3
added tosic acid monohydrate (0.1 equiv) as a stock solution in THF-d (0.026 M) for a final
8
tosic acid concentration of 0.0012 M. At the indicated times in Table S1, the reaction was
quenched by the immediate addition of 5 vol. satd aq NaHCO and extracted with EtOAc. The
3
organic layer was dried over MgSO , filtered, and concentrated by rotary evaporation. The
4
product ratio of 8a to 11a was determined by NMR as described above.
Table S1. Sample of kinetic data for tosic acid equilibration at room temperature using NMR for each
a
substituted spiroketal 8a–f (Figure 3b of manuscript).
R
R
TsO
TBDPSO
R
1
0 mol%
TsOH
TBDPSO
O
O
TBDPSO
O
O
O
CDCl3
OH
OH OH
OTIPS
OH
OTIPS
OTIPS
contrathermodynamic
oxocarbenium
intermediate
thermodynamic
(C1-retention)
(
C1-inversion)
a–f
8
21a–f
11a–f
R = OMe
R = Me
R = H
R = Cl
R = CF
3
time
time
(min)
time
(min)
time
(min)
time
(min)
%
11a
% 11b
% 11c
% 11d
% 11e
(
min)
0
0
0
0
0
6.25
9.0
0
7.4
0
6.0
0
0
1440
3413
0
4.0
8.0
0
0
0
.083
31
57
69
3.25
5.25
7.0
8
0.5
2.0
21.8
35.4
42.8
51.6
57.6
62.5
1.5
4.3
5.7
7.4
9.1
9.9
.33
.58
9.9
15.75
26.0
36.25
46.5
56.75
12.0
15.0
18.0
21.5
12.2
13.7
16.6
19.3
.75
1
1
a
Spiroketal 8f did not convert to spiroketal 11f at this concentration of TsOH over >72 h.
2
Ansyln, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books: Sausalito,
California, 2006; Chapter 7; p 389.

Wurst, Liu, and Tan
Supporting Information
Page S7
Me
Me
1
0 mol %
TsOH
t = 3.25 min
1
4
14
Ha
Ha
TBDPSO
O
TBDPSO
O
t = 5.25 min
t = 7.0 min
t = 8.75 min
t = 10.5 min
t = 12.0 min
O
H
b
O
H
b
CDCl3
OH
OH
OTIPS
contrathermodynamic
C1-inversion)
OTIPS
thermodynamic
(C1-retention)
(
8b
11b
b
C14-H of 8b
a
C14-H of 11b
b
C14-H of 11b
a
C14-H of 8b
Figure S1. Example of kinetic measurements made by NMR. Contrathermodynamic spiroketal 8b
epimerizes to thermodynamic spiroketal 11b with 10 mol % TsOH (Figure 3b of manuscript).
Table S2. Observed initial rates from two tosic acid equilibration experiments for each substituent
(
Figure 3c of manuscript).
–
1
k
obs (min )
R = OMe
R = Me
R = H
R = Cl
R = CF
3
experiment 1
experiment 2
157
161
6.0
6.7
0.93
0.91
0.13
0.18
0.013
0.0028

Wurst, Liu, and Tan
Supporting Information
Page S8
2
. GENERAL PROCEDURE FOR NMR ANALYSIS OF GLYCAL EPOXIDE SPIROCYCLIZATIONS
Each glycal substrate (1.0 equiv) was added as a solution in CDCl to an oven-dried, Ar-flushed
3
5
mm NMR tube. The tube was capped with a rubber septum. The appropriate amount of
additional deuterated solvent (CD OD, CDCl , and C D O) was added, followed by brief mixing
3
3
3
6
and cooling to –78 °C. Dimethyldioxirane (DMDO) solution (1.2 equiv, 0.073 M in acetone),
taken from a –80 °C freezer and used immediately, was added and the tube was shaken
vigorously for 3 s and then warmed to –44 °C. The tube was transferred quickly to the NMR
instrument which was precooled to –40 °C. The sample was locked and shimmed and the NMR
was tuned (3 min), then the sample was warmed to –35 °C to initiate the spirocyclization
reaction. When the probe temperature remained constant (2–3 min), conversion of the glycal
epoxide intermediate to the spiroketal inversion product was measured by integration of the C3
1
proton signals at various time intervals (respective H-NMR shifts noted below). Reactions were
2
run to ≥10–20% conversion and the method of initial rates was used. Conversion at t = 0 was
extrapolated from the linear fits derived from the initial rates data.
3
. METHANOL-INDUCED GLYCAL EPOXIDE SPIROCYCLIZATION WITH VARYING SUBSTITUENTS
Following the general procedure above, the appropriate glycal 5a–f (1.0 equiv, 0.008 mmol) was
dissolved in CDCl (300 µL) and CD OD (400 µL, 11.9 M final concentration), then cooled to
3
3
−
78 °C and epoxidized with DMDO (1.2 equiv, 130 µL, 0.073 M in acetone). Conversion was
measured by integration of the C3 protons of glycal epoxide intermediates 22a–e (4.30–4.40
ppm) and spiroketal inversion products 8a–e (4.50–4.60 ppm) (Table S3, Figure S2). In the case
of glycal epoxide 22f (R = NO ), no reaction occurred under these conditions and epoxide
2
persisted for the duration of the experiment (approx. 1 h).
Table S3. Sample of kinetic data collected using NMR for inversion product formation in the presence of
1
3
1.9 M CD OD at –35 °C for substituted glycals 5a–e (Figure 4b of manuscript).
R
R
R
DMDO
TBDPSO
O
TBDPSO
O
TBDPSO
O
O
O
1
1.9 M CD OD
3
HO
OTIPS
OH
OH
CDCl , acetone
3
OTIPS
–35 °C
OTIPS
C1-inversion
8a–e
glycal epoxide intermediate
5a–e
22a–e
R = OMe
time
R = Me
time
R = H
R = Cl
R = CF
3
time
(min)
time
(min)
time
%
8a
% 8b
% 8c
% 8d
% 8e
(
min)
(min)
(min)
0
2
4
9
3.5
5.75
8.0
0
4.6
0
4.25
6.5
8.75
11.0
13.25
17.75
0
6.3
0
6.25
9.5
12.75
16.0
19.25
22.5
0
7.4
0
7.0
0
3.6
6.3
7.5
10.1
12.8
13.4
0
0
4.0
6.1
8.8
10.9
12.0
13.6
.25
.5
.0
14.75
27.25
33.5
39.75
46.0
11.1
23.9
32.3
38.5
43.9
10.3
14.1
15.7
19.5
25.8
11.0
14.8
18.2
22.5
25.7
13.5
16.75
20.0
23.25
29.75
1
1
1
52.25

Wurst, Liu, and Tan
Supporting Information
Page S9
Me
Me
t = 0
R
5 O
3
time course
R
5
O
t = 6.50 min
t = 11.00 min
t = 13.25 min
t = 17.75 min
O
O
1
1.9 M CD OD
3
3
OH
OH
CDCl , acetone
3
OTIPS
glycal epoxide intermediate
2b
OTIPS
–35 °C
C1-inversion
2
8b
C3 of 22b
C5 of 22b
C5 of 8b
C3 of 8b
Figure S2. Example of kinetic measurements made by NMR. Glycal epoxide 22b spirocyclizes to
spiroketal inversion product 8b in 11.9 M CD OD at −35 °C (Figure 4b of manuscript).
3
Table S4. Observed initial rates for three spirocyclization experiments (Figure 4c of manuscript).
–
1
k
obs (min )
R = OMe
R = Me
R = H
R = Cl
R = CF
3
experiment 1
experiment 2
experiment 3
0.0248
0.0260
0.0154
0.0141
0.0163
0.0124
0.0116
0.0112
0.0110
0.0058
0.0066
0.0031
0.0027
0.0013
0.0016
4
. HAMMETT ANALYSES OF EPIMERIZATION AND SPIROCYCLIZATION REACTIONS
Observed rates for both the tosic acid epimerization (Table S2) and methanol-induced
spirocyclization with inversion of configuration (Table S4) gave access to two distinct Hammett
plots as a means to compare the same substrates under two different reaction conditions
(
Figure 3c vs. 4c of manuscript). For the tosic acid epimerization data, the logarithm of the ratio
–1
of observed rates of isomerization for each spiroketal 8a–e (k [min ]) divided by the observed
rate of isomerization for 8c (R = H; k [min ]) was plotted against known sigma values
obs
–
1
0
3
(Figure 3c of manuscript). For the methanol-induced epoxide opening spirocyclization, the
logarithm of the ratio of observed spirocyclization rate for each glycal epoxide 22a–e
–
1
–1
(
k [min ]) divided by the observed rate of spirocyclization for 22c (R = H; k [min ]) was
obs 0
plotted against known sigma values (Figure 4c of manuscript).
3
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.

Wurst, Liu, and Tan
Supporting Information
Page S10
Table S5. Data for Hammett plot analysis of TsOH epimerization, where k
isomerization to spiroketal 11c (R = H) (Figure 3c of manuscript).
0
is observed rate for
3
a
(
σ)
k
0
log (kobs/k )
obs
expt 1
157
expt 2
161
6.7
expt 1
expt 2
R = OMe
R = Me
R = H
–0.28
–0.14
0.00
0.24
0.53
2.23
0.81
0.0
–0.86
–1.9
2.24
0.87
0.0
–0.70
–2.5
6.0
0.93
0.13
0.013
0.91
0.18
0.0028
R = Cl
R = CF
3
a
Values obtained from Table S2.
Table S6. Data for Hammett plot analysis of methanol-induced spirocyclization, where k
for the formation of 8c (R = H) (Figure 4c of manuscript).
0
is observed rate
3
a
(
σ)
kobs
log (kobs/k0)
expt 2
expt 1
expt 2
expt 3
expt 1
expt 3
R = OMe
R = Me
R = H
–0.28
–0.14
0.00
0.24
0.53
0.025
0.014
0.012
0.0058
0.0027
0.026
0.016
0.011
0.0066
0.0013
0.015
0.012
0.011
0.0031
0.0016
0.33
0.085
0.0
–0.30
–0.63
0.24
0.042
0.0
–0.35
–1.1
0.14
0.044
0.0
–0.56
–0.85
R = Cl
R = CF
3
a
Values obtained from Table S4.
5
. DETERMINATION OF KINETIC ORDER OF METHANOL IN GLYCAL EPOXIDE SPIRO-
CYCLIZATION
Following the general procedure above, glycal 5c (1.0 equiv, 0.008 mmol) was dissolved in
varying amounts of CDCl (100–500 µL) and CD OD (200–600 µL, 5.9–17.8 M final
3
3
concentrations), then cooled to –78 °C and epoxidized with DMDO (1.2 equiv, 130 µL, 0.073 M
in acetone). Percent conversion at – 35 °C was measured by integration of the C3 proton of
glycal epoxide intermediate 22c (4.35–4.40 ppm) and spiroketal inversion product 8c (4.55–4.60
ppm) (Table S7, Figure S3–S4). Initial rates were then calculated for the varying concentrations
of CD OD (Table S8) and these observed rates were plotted against their respective
3
concentrations of CD OD yielding a polynomial curve (Figure 5a of manuscript). In the absence
3
of CD OD, no spirocyclization was observed at – 35 °C and the epoxide intermediate persisted
3
for the duration of the experiment (approx. 1 h). The initial rates data in Table S8 was then
n
–5
subjected to a non-linear least squares fit to the equation f(x) = c[CD OD] , yielding c = 6.1×10
3
and n = 2.1, which is consistent with two molecules of MeOH in the transition state leading to
epoxide opening spirocyclization with inversion of configuration. To confirm this fit, a plot of
2
2
observed rate as a function of [CD OD] gave a linear fit with r = 0.95 (Figure 5b of
3
manuscript).

Wurst, Liu, and Tan
Supporting Information
Page S11
Table S7. Sample of kinetic data collected using NMR for spirocyclization in the presence of varying
concentrations of CD OD at –35 °C (Figure 5a of manuscript).
3
DMDO
TBDPSO
O
TBDPSO
O
TBDPSO
O
O
O
CD OD
3
HO
OTIPS
OH
OH
CDCl , acetone
3
OTIPS
–
35 °C
OTIPS
C1-inversion
8c
glycal epoxide intermediate
5
c
22c
1
7. 8 M
14.8 M
time
11.9 M
8.9 M
5.9 M
time
min)
time
(min)
time
(min)
time
(min)
%
8c
% 8c
% 8c
% 8c
% 8c
(
(min)
0
0
0
0
0
0
0
0
0
0
3
7
0.25
3.5
6.75
0.0
.75
.0
10.1
20.2
28.4
36.8
44.4
50.3
4.0
7.5
10.75
14.0
17.25
20.5
7.2
6.5
7.4
22.5
26.75
31.0
35.25
39.5
43.75
11.5
13.2
14.6
17.7
19.5
21.9
29.5
34.75
40.0
50.5
61.0
71.5
5.3
6.2
6.6
7.3
9.7
12.6
15.1
20.2
25.4
32.8
36.5
9.75
13.0
16.25
19.5
22.75
11.0
14.8
18.2
22.5
25.7
1
1
1
2
t = 0
R
5 O
time course
1.9 M CD OD
R
5
O
t = 6.5 min
t = 13.0 min
t = 19.5 min
t = 26.0 min
O
O
3
1
3
3
OH
OH
CDCl , acetone
3
OTIPS
glycal epoxide intermediate
2c
OTIPS
–35 °C
C1-inversion
2
8c
C5 of 22c
C3 of 22c
C3 of 8c
C5 of 8c
Figure S3. Example of kinetic measurements taken by NMR. Glycal epoxide 22c spirocyclizes to
spiroketal inversion product 8c in 11.9 M CD OD at −35 °C (Figure 5a of manuscript).
3

Wurst, Liu, and Tan
Supporting Information
Page S12
Figure S4. Plot of raw data in Table S7.
Table S8. Observed initial rates for each concentration CD
3
OD for two spirocyclization experiments
(
Figure 5a of manuscript).
–
1
17.8 M
CD OD]
14.8 M
11.9 M
8.9 M
5.9 M
k
obs (min )
[
3
[CD
3
OD]
[CD
3
OD]
[CD
3
OD]
[CD
3
OD]
experiment 1
experiment 2
0.0272
0.0198
0.0178
0.0177
0.0115
0.0105
0.0051
0.0047
0.0018
0.0022
6
. DETERMINATION OF KINETIC ORDER OF METHANOL IN CYCLOHEXENE OXIDE SPIRO-
CYCLIZATION
Epoxide 27 (2 mg, 0.005 mmol) as a solution in toluene-d (100 µL) was added to an oven-dried
8
Ar-flushed 5 mm NMR tube and the tube was capped with a rubber septum. Varying amounts of
additional toluene-d (0–300 µL) and CD OD (300–700 µL, 10.5–24.6 M final concentrations)
8
3
were added, followed by shaking for 5 s. (For experiments run in neat CD OD (24.6 M), the
3
substrate was loaded in toluene-d as described above then concentrated in vacuo before the
8
addition of 700 µL CD OD.) The tubes were inserted into a foam tube holder to the depth of the
3
solvent volume, then floated in a 60 °C oil bath for 30 min intervals. At each time point, the
tubes were removed from the bath and washed in a hexanes bath at rt to cool the reactions
quickly and halt spirocyclization. Although no reaction occurred at rt, the NMR spectra were
taken within 15 min before heating was resumed at 60 °C. Percent conversion was measured by
integration of the C3 protons of epoxide 27 (4.10 ppm) and the C2 protons of spiroether 28
(
3.50 ppm) (Table S9, Figure S5–S6) and initial rates were determined (Table S10). In the
absence of CD OD (neat toluene-d ), there was no conversion of epoxide 27 to spirocycle 28
3
8
over 24 h at 60 °C.

Wurst, Liu, and Tan
Supporting Information
Page S13
Table S9. Sample of kinetic data collected using NMR for spiroether formation in the presence of varying
concentrations of CD OD at 60 °C (Figure 8b of manuscript).
3
CD OD
3
toluene-d8
1
O
O
OH
60 °C
OH
OTIPS
OTIPS
C1-inversion
28
27
2
4.6 M
21.1 M
time
17.6 M
14.1 M
10.5 M
time
time
% 28
% 28
time
% 28
time
% 28
% 28
(
min)
(min)
(min)
(min)
(min)
0
0
0
0
20
50
80
0
5.6
7.8
12.0
14.0
20.2
21.4
0
30
60
90
120
150
180
0
4.2
8.3
10.9
14.0
17.5
20.3
0
30
60
90
120
150
180
0
4.1
6.3
9.7
11.9
15.8
18.0
0
30
60
90
120
150
180
0
2.9
6.6
7.5
10.5
12.8
15.4
0
30
60
90
120
150
180
0
3
6
9
3.5
5.4
7.8
9.8
12.4
13.4
1
1
1
t = 30 min
t = 60 min
t = 90 min
t = 120 min
t = 150 min
t = 180 min
C3 of 27
time course
21.1 M CD OD
O
O
2
3
OH
3
OH
6
0 °C
OTIPS
OTIPS
2
7
28
C2 of 28
C3 of 28
Figure S5. Example of kinetic measurements taken by NMR. Epoxide 27 spirocyclizes to 28 in 21.1 M
CD OD at 60 °C (Figure 8b of manuscript).
3

Wurst, Liu, and Tan
Supporting Information
Page S14
Figure S6. Plot of raw data in Table S9.
Table S10. Observed initial rates for two experiments at each concentration of CD
3
OD (Figure 8b of
manuscript).
–
1
24.6 M
CD OD]
21.1 M
17.6 M
14.1 M
10.5 M
k
obs (min )
[
3
[CD
3
OD]
[CD
3
OD]
[CD
3
OD]
[CD
3
OD]
experiment 1
experiment 2
0.1186
0.1161
0.1110
0.1042
0.0988
0.0965
0.0832
0.0815
0.0743
0.0706
7
. DETERMINATION OF KINETIC ORDER OF ACETONE IN GLYCAL EPOXIDE SPIROCYCLIZATION
Following the general procedure above, glycal 5c (1.0 equiv, 0.008 mmol) was dissolved in
varying amounts of CDCl (0–300 µL), acetone-d (0–300 µL, 2.1–7.0 M final concentration
3
6
acetone including acetone added from DMDO stock), and CD OD (400 µL, 11.9 M) before a
3
brief mixing and cooling to –78 °C and epoxidizing with DMDO (1.2 equiv, 130 µL, 0.073 M in
acetone). Percent conversion at –35 °C was measured by integration of the C3 proton of glycal
epoxide intermediate 22c (4.40–4.45 ppm) and inversion spiroketal product 8c (4.60–4.65 ppm)
(Table S11, Figure S7–S8). Initial rates were then calculated for the varying concentrations of
acetone (Table S12) and these observed rates were plotted against their respective concentrations
of acetone yielding an inhibition curve (Figure 9a of manuscript). This data was then subjected
n
–2
to a non-linear least squares fit to the equation f(x) = c[acetone] , yielding c = 2.2×10 and
n = –1.0, which is consistent with first-order inhibition. To confirm this fit, a plot of observed
–
1
2
rate as a function of [acetone] gave a linear fit with r = 0.98 (Figure 9b of manuscript).

Wurst, Liu, and Tan
Supporting Information
Page S15
Table S11. Sample of kinetic data collected using NMR for spirocyclization in the presence of varying
concentrations of acetone (acetone-d
6
+ acetone from DMDO) at –35 °C (Figure 9a of manuscript).
R
R
R
DMDO
TBDPSO
O
TBDPSO
O
TBDPSO
O
O
O
1
1.9M CD OD
acetone-d6
3
HO
OTIPS
OH
OH
OTIPS
CDCl3
OTIPS
C1-inversion
–
35 °C
glycal epoxide intermediate
5
c
22c
8c
2
.1 M
3.8 M
5.4 M
time
7.0 M
time
time
min)
time
(min)
%
8c
% 8c
% 8c
% 8c
(
(min)
(min)
0
6
9
2.5
5.75
9.0
0
6.7
8.6
11.6
17.3
20.2
24.0
0
8.5
0
0
0
0
0
.0
.25
4.6
7.4
8.2
8.7
11.7
13.6
12.5
16.75
21.0
25.25
29.50
38.0
5.0
6.2
7.9
8.6
10.5
13.9
15.25
21.5
27.75
34.0
40.25
46.5
4.9
6.4
7.3
9.7
12.5
14.2
11.75
15.0
18.25
21.5
24.75
1
1
1
2
2.25
t = 0
R
5 O
time course
R
5
O
t = 8.5 min
t = 15.0 min
t = 21.5 min
t = 28.0 min
O
O
3
1
3
1.9 M CD OD
.8 M acetone
3
OH
3
OH
OTIPS
glycal epoxide intermediate
2c
OTIPS
CDCl3
–35 °C
C1-inversion
2
8c
C3 of 22c
C5 of 22c
C3 of 8c
C5 of 8c
Figure S7. Example of kinetic measurements taken by NMR. Glycal epoxide 22c opens to spiroketal
inversion product 8c in 3.8 M acetone at −35 °C (Figure 9a of manuscript).

Wurst, Liu, and Tan
Supporting Information
Page S16
Figure S8. Plot of raw data in Table S11.
Table S12. Observed initial rates for two spirocyclization experiments at different concentrations of
acetone (Figure 9a of manuscript).
–
1
2.1 M
acetone]
3.8 M
[acetone]
5.4 M
[acetone]
7.0 M
[acetone]
k
obs (min )
[
experiment 1
experiment 2
0.0112
0.0105
0.0054
0.0059
0.0040
0.0045
0.0032
0.0038
8
. DETERMINATION OF KINETIC ORDER OF METHANOL IN METHYL GLYCOSIDE FORMATION
TBS-protected glycal 29 (1.0 equiv, 0.008 mmol) as a solution in CDCl (100 µL) was added to
3
an oven-dried, Ar-flushed 5 mm NMR tube. The tube was capped with a rubber septum.
Varying amounts of additional CDCl (0–400 µL) and CD OD (200–600 µL, 5.9–17.8 M final
3
3
concentrations) were added, followed by brief mixing and cooling to –78 °C. DMDO solution
1.2 equiv, 130 µL, 0.073 M in acetone), taken from a –80 °C freezer and used immediately, was
(
added and the tube was shaken vigorously for 3 s then warmed to 0 °C. The tube was transferred
quickly into the NMR instrument which was precooled to 15 °C. The sample was locked and
shimmed and the NMR was tuned (3 min). When the probe temperature remained constant
(
2–3 min), conversion of epoxide 31 to methyl glycoside 30 was measured by integration of the
C3 protons of glycal epoxide intermediate 31 (4.30–4.40 ppm) and methyl glycoside product 30
4.15–4.25 ppm) (Table S13, Figure S9–S10). Reactions were run to at least 20% conversion
(
2
and initial rates were determined (Table S14). Conversion at t = 0 was extrapolated from the
linear fits derived from the initial rates data. These observed rates were plotted against their
respective concentrations of methanol, yielding a linear fit with r = 0.98 (Figure 10b of
2
manuscript).

Wurst, Liu, and Tan
Supporting Information
Page S17
Table S13. Sample of kinetic data collected using NMR for methyl glycoside formation in the presence of
varying concentrations of CD
3
OD at 15 °C (Figure 10b of manuscript).
DMDO
OTBS
TBDPSO
O
TBDPSO
O
TBDPSO
O
O
OCD3
CD OD
CDCl3
acetone
3
OTBS
OTBS
OH
OTIPS
OTIPS
OTIPS
1
5 °C
glycal epoxide intermediate
methyl glycoside
2
9
31
30
1
7. 8 M
14.8 M
time
11.9 M
8.9 M
5.9 M
time
% 30
% 30
time
% 30
time
% 30
time
% 30
(
min)
(min)
(min)
(min)
(min)
0
0
0
0
0
0
0
0
0
0
4
6
9
1.25
3.5
.5
.75
.0
11.0
17.3
23.6
27.2
32.9
37.6
4.5
6.75
9.0
11.25
13.5
15.75
8.9
5.75
7.0
9.25
11.5
13.75
16.0
8.8
7.75
10.0
12.25
14.5
16.75
19.0
9.3
18.5
10.2
11.5
12.9
14.1
16.7
19.8
14.3
18.4
23.5
27.0
30.8
13.5
16.2
19.0
22.3
26.0
13.6
14.6
17.4
21.3
23.1
20.75
25.25
27.50
29.75
35.25
1
1
1
5.75
t = 0
t = 4.5 min
t = 9.0 min
t = 13.5 min
t = 18.0 min
OTBS
R
O
time course
7. 8 M CD OD
R
O
O
OCD3
OH
OTIPS
3
3
1
3
OTBS
CDCl , acetone
3
OTIPS
glycal epoxide intermediate
15 °C
methyl glycoside
31
30
C3 of 31
C3 of 30
Figure S9. Example of kinetic measurements taken by NMR. Intermediate epoxide 31 forms methyl
glycoside 30 in 17.8 M CD OD at 15 °C (Figure 10b of manuscript).
3

Wurst, Liu, and Tan
Supporting Information
Page S18
Figure S10. Plot of raw data in Table S13.
Table S14. Observed initial rates for two experiments at each concentration of CD
3
OD (Figure 10b of
manuscript).
–
1
17.8 M
CD OD]
14.8 M
11.9 M
8.9 M
5.9 M
[CD OD]
3
k
obs (min )
[
3
[CD
3
OD]
[CD
3
OD]
[CD
3
OD]
experiment 1
experiment 2
0.0244
0.0201
0.0193
0.0190
0.0154
0.0148
0.0118
0.0128
0.0055
0.0078

Wurst, Liu, and Tan
Supporting Information
Page S19
F. SYNTHESIS OF SIDECHAIN PRECURSORS (S1–S25)
Ac O
O
2
Et N
DMAP
3
O
R
Br
S1–S5
HO
CO H
2
B
C
CH Cl2
2
Br BH •SMe
Br
3
2
O
THF
R
R
DMP
Br
0
°C to rt
A
2
CH Cl2
S6–S10
R
Figure S11. Synthesis of aryl side-chains for 5-membered ring spiroketals and substituted
benzaldehydes used for the synthesis of aryl side-chains for 6- and 7-membered ring spiroketals.
4
1
. GENERAL PROCEDURE A FOR REDUCTION OF ARYL ACIDS
A solution of the commercially available aryl acid (1.0 equiv) was dissolved in THF (0.15 M)
and cooled to 0 °C. Borane dimethyl sulfide (1.0 M CH Cl , 3.0 equiv) was added dropwise at a
2
2
rate of 0.5 mL/min. After stirring for 3 h at 0 °C, the mixture was warmed to rt for 12 h, then
quenched slowly with 1 N aq HCl. The aqueous layer was separated and extracted with Et O.
2
The combined organic extracts were washed with brine, dried (MgSO ), filtered, and
4
concentrated by rotary evaporation. The crude products were acetylated according General
Procedure B or oxidized according to General Procedure C below.
2
. GENERAL PROCEDURE B FOR ACETYLATION OF ALCOHOLS (S1–S5, S11–S15, S21–S25)
To a solution of alcohol (1.0 equiv) in CH Cl (0.1 M) was added triethylamine (2.0 equiv),
2
2
4
-dimethylaminopyridine (0.2 equiv), and acetic anhydride (2.0 equiv). After stirring for 2 h at
rt, the mixture was washed with satd aq NH Cl and the aqueous layer was separated and
4
extracted with Et O. The combined organic extracts were washed with brine, dried (MgSO ),
2
4
filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography
95:5–90:10 hexanes/EtOAc with 0.5% Et N) provided S1–S5.
(
3
3
. GENERAL PROCEDURE C FOR OXIDATION OF BENZYL ALCOHOLS (S6–S10)
To a solution of alcohol (1.0 equiv) in CH Cl (0.2 M) was added Dess–Martin periodinane
2
2
(
1.1 equiv) and the mixture was stirred for 1 h at rt. The reaction was washed with 10% aq
Na S O and the aqueous layer was separated and extracted with Et O. The combined organic
2
2
3
2
extracts were washed with brine, dried (MgSO ), filtered, and concentrated by rotary
4
evaporation. Purification by silica flash chromatography (9:1 hexanes/EtOAc with 0.5% Et N)
3
provided S6–S10.
4
Lane, C. F.; Myatt, H. L.; Daniels, J.; Hopps, H. B. J. Org. Chem. 2002, 39, 3052–3054.

Wurst, Liu, and Tan
Supporting Information
Page S20
O
O
O
Br
2
-Bromo-5-methoxybenzyl acetate (S1). White solid (46 mg, 81%, 2 steps). TLC: R
f
0.50
(
1
4:1 hexanes/EtOAc). mp: 34.2–34.7°C. IR (NaCl, film): 1740 (C=O st), 1699, 1653, 1575,
540, 1521, 1507, 1473, 1248 (C–O st), 1165, 1048, 1023, 868, 807. H-NMR (500 MHz):
1
δ 7.45 (d, 1H, J = 8.8 Hz), 6.96 (d, 1H, J = 3.0 Hz), 6.74 (dd, 1H, J = 8.8, 3.1 Hz), 5.15 (s, 2H),
1
3
3
1
.80 (s, 3H), 2.14 (s, 3H). C-NMR (125 MHz): δ 170.6, 159.1, 136.2, 133.5, 115.7, 115.0,
+
13.5, 65.8, 55.4, 20.8. ESI-MS m/z (rel int): (pos) 280.8 ([M+Na] , 95).
O
O
Br
2
f
-Bromo-5-methylbenzyl acetate (S2). White solid (42 mg, 75%, 2 steps). TLC: R 0.60 (4:1
hexanes/EtOAc). mp: 51.3–51.8 °C. IR (NaCl, film): 1741 (C=O st), 1699, 1635, 1558, 1473,
1
1
1
457, 1376, 1240 (C–O st), 1024, 810. H-NMR (500 MHz): δ 7.44 (d, 1H, J = 8.0 Hz), 7.21 (d,
H, J = 1.8 Hz), 7.00 (dd, 1H, J = 8.1, 2.1 Hz), 5.15 (s, 2H), 2.31 (s, 3H), 2.14 (s, 3H).
1
3
C-NMR (125 MHz): δ 170.7, 137.5, 134.8, 132.6, 130.8, 130.6, 120.2, 65.9, 21.0 (2). ESI-MS
m/z (rel int): (pos) 264.8 ([M+Na] , 100).
+
O
O
Br
Cl
2
-Bromo-5-chlorobenzyl acetate (S3). White solid (41 mg, 74%, 2 steps). TLC: R
f
0.68 (4:1
hexanes/EtOAc). mp: 65.4–66.4 °C. IR (NaCl, film): 1740 (C=O st), 1461, 1378, 1361, 1248
1
(
C–O st), 1052, 876, 821. H-NMR (500 MHz): δ 7.49 (d, 1H, J = 8.5 Hz), 7.39 (d, 1H, J = 2.5
1
3
Hz), 7.17 (dd, 1H, J = 8.5, 2.6 Hz), 5.14 (s, 2H), 2.17 (s, 3H). C-NMR (125 MHz): δ 170.4,
37.1, 134.0, 133.7, 129.7, 129.2, 120.7, 65.1, 21.0. ESI-MS m/z (rel int): (pos) 286.8
1
+
([M+Na] , 40).
O
O
Br
O N
2
2
-Bromo-5-nitrobenzyl acetate (S4). White solid (43 mg, 78%, 2 steps). TLC: R
f
0.38 (4:1
hexanes/EtOAc). mp: 106.9–107.9 °C. IR (NaCl, film): 1730 (C=O st), 1559, 1527, 1340
1
(
N–O st), 1232 (C–O st), 1053, 921, 824, 811, 740. H-NMR (500 MHz): δ 8.27 (d, 1H, J = 2.7
Hz), 8.05 (dd, 1H, J = 8.7, 2.7 Hz), 7.77 (d, 1H, J = 8.7 Hz), 5.24 (s, 2H), 2.21 (s, 3H).
1
3
C-NMR (125 MHz): δ 170.3, 147.3, 137.6, 133.9, 129.8, 124.1, 123.7, 64.8, 20.9. ESI-MS
+
m/z (rel int): (pos) 296.0 ([M+Na] , 100).

Wurst, Liu, and Tan
Supporting Information
Page S21
O
O c
Br
b
F3C
a
d
2
-Bromo-5-(trifluoromethyl)benzyl acetate (S5). White solid (1.16 g, 99%, 1 step from
commercially available benzyl OH). TLC: R 0.75 (4:1 hexanes/EtOAc). mp: 42.0–43.0 °C. IR
NaCl, film): 1749 (C=O st), 1653, 1558, 1507, 1418, 1329, 1224 (C–O st), 1169, 1127, 1082,
f
(
1
1
1
1
027, 827. H-NMR (500 MHz): δ 7.71 (d, 1H, J = 8.3 Hz), 7.66 (d, 1H, J = 1.2 Hz), 7.45 (dd,
1
3
H, J = 8.5, 1.3 Hz), 5.22 (s, 2H), 2.18 (s, 3H). C-NMR (125 MHz): δ 170.1, 136.6, 133.3,
29.9 (1C , q, J = 33.1 Hz), 126.7, 126.0 (1C , q, J = 3.7 Hz), 125.8 (1C , q, J = 3.7 Hz), 123.7
b
c
d
+
(
1C
a
, q, J = 272.1 Hz), 64.9, 20.5. ESI-MS m/z (rel int): (pos) 319.1 ([M+Na] , 30).
O
Br
2
f
-Bromo-5-methylbenzaldehyde (S6). White solid (81 mg, 98%, 2 steps). TLC: R 0.67 (4:1
hexanes/EtOAc). mp: 42.5–43.0 °C. IR (NaCl, film): 1697 (C=O st), 1593, 1466, 1386, 1271,
1
1
1
225, 1153, 1026, 936, 816, 743, 657. H-NMR (500 MHz): δ 10.25 (s, 1H), 7.63–7.63 (m,
1
3
H), 7.44 (d, 1H, J = 8.2 Hz), 7.21–7.19 (ddt, 1H, J = 8.2, 2.3, 0.6 Hz), 2.31 (s, 3H). C-NMR
(
1
125 MHz): δ 191.6, 138.0, 136.2, 133.5, 133.0, 130.0, 123.8, 20.7. ESI-MS m/z (rel int): (neg)
96.9 ([M–H] , 20).
–
O
Br
O N
2
2
f
-Bromo-5-nitrobenzaldehyde (S7). White solid (169 mg, 91%, 2 steps). TLC: R 0.45 (4:1
hexanes/EtOAc). mp: 103.5–104.5 °C. IR (NaCl, film): 1685 (C=O st), 1604, 1573, 1524, 1451,
1
1
1
350 (N–O st), 1185, 1036, 930, 845, 816, 735. H-NMR (500 MHz): δ 10.35 (s, 1H), 8.66 (d,
1
3
H, J = 2.6 Hz), 8.27 (dd, 1H, J = 8.7, 2.7 Hz), 7.88 (d, 1H, J = 8.7 Hz). C-NMR (125 MHz):
δ 189.4, 147.7, 135.4, 134.4, 133.0, 128.8, 124.6. ESI-MS m/z (rel int): (neg) 227.9 ([M–H] ,
–
6
0).
O
Br
c
b
F3C
a
d
2
-Bromo-5-(trifluoromethyl)benzaldehyde (S8). Light yellow oil (986 mg, 99%, 1 step from
0.67 (4:1 hexanes/EtOAc). IR (NaCl, film): 1700
commercially available benzyl OH). TLC: R
f
1
(C=O st), 1653, 1606, 1558, 1327, 1253, 1176, 1131, 1078, 1031, 913, 834. H-NMR
(
8
500 MHz): δ 10.38 (s, 1H), 8.17 (d, 1H, J = 1.8 Hz), 7.82 (d, 1H, J = 8.4 Hz), 7.70 (dd, 1H, J =
.4, 2.0 Hz). C-NMR (125 MHz): δ 190.2, 134.7, 133.9, 131.4 (1C , q, J = 3.7 Hz), 130.8
c
1
3

Wurst, Liu, and Tan
Supporting Information
Page S22
(
1C
b
, q, J = 33.8 Hz), 130.4, 126.8 (1C
d
, q, J = 3.7 Hz), 123.2 (1C
a
, q, J = 272.2 Hz). ESI-MS
+
m/z (rel int): (pos) 253.1 ([M+H] , 60).
O
Br
O
5
2
2
-Bromo-5-methoxybenzaldehyde (S9). Previously reported.
O
Br
Cl
5
-Bromo-5-chlorobenzaldehyde (S10). Previously reported.
O
O
O
OH
1
2
. MeOCH PPh Cl
KHMDS
0 °C to rt
Ac O
2
3
2
O
Et N
3
Br
Br NaBH
4
Br
DMAP
Br
. 1.5 N HCl aq., THF
reflux
MeOH
0 °C to rt
CH Cl2
R
R
R
2
R
S6–S10
D
E
B
S11–S15
Figure S12. Synthesis of aryl side-chains for 6-membered ring spiroketals from substituted
benzaldehydes S6–S10.
4
. GENERAL PROCEDURE D FOR ONE CARBON HOMOLOGATION OF SUBSTITUTED
BENZALDEHYDES
To a solution of methoxymethyl triphenyl phosphonium chloride (1.6 equiv) in toluene (0.25 M),
cooled to 0 °C was added potassium bis(trimethylsilyl) amide (0.5 M in toluene, 2.0 equiv)
dropwise at a rate of 0.5 mL/min. The solution was allowed to warm to rt over 1 h, then cooled
back to 0 °C for the addition of benzaldehyde (S6–S10) (0.3 M in toluene, 1.0 equiv) at a rate of
0
.5 mL/min. The solution was warmed to rt over 7 h, then quenched with satd aq NH Cl. The
4
aqueous layer was separated and extracted with Et O. The combined organic extracts were
2
washed with brine, dried (MgSO ), filtered, and concentrated by rotary evaporation to afford the
4
crude enol ether product, which was used without further purification.
The crude enol ether was redissolved in THF (0.1 M), and 1.5 N aq HCl (3 vol) was added. The
solution was refluxed for 12 h. The reaction was washed with sat aq NaHCO and the aqueous
3
layer was separated and extracted with Et O. The combined organic extracts were washed with
2
brine, dried (MgSO ), filtered, and concentrated by rotary evaporation to afford the crude aryl
4
acetaldehyde product, which was used without further purification below.
5
Spring, D. R.; Krishnan, S.; Blackwell, H. E.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 1354–1363.

Wurst, Liu, and Tan
Supporting Information
Page S23
5
. GENERAL PROCEDURE E FOR REDUCTION OF ARYL ACETALDEHYDES
To a solution of aryl acetaldehyde (1.0 equiv) in methanol (0.1 M) cooled to 0 °C was added
sodium borohydride (10.0 equiv) in several portions over 10 min. After an additional 15 min,
the reaction was warmed to rt. Upon complete conversion as judged by TLC analysis (90 min),
the reaction was cooled back to 0 °C and quenched with satd aq NH Cl. The aqueous layer was
4
separated and extracted with Et O. The combined organic extracts were washed with brine, dried
2
with (MgSO ), filtered, and concentrated by rotary evaporation to afford the crude alcohol
4
product, which was acetylated without further purification according to the General Procedure B
above.
O
O
Br
O
2
-Bromo-5-methoxyphenethyl acetate (S11). Yellow oil (641 mg, 66%, 3 steps from S9).
TLC: R 0.44 (4:1 hexanes/EtOAc). IR (NaCl, film): 1738 (C=O st), 1595, 1572, 1473, 1363,
f
1
1
1
239 (C–O st), 1163, 1036, 852, 809. H-NMR (500 MHz): δ 7.41 (d, 1H, J = 8.8 Hz), 6.79 (d,
H, J = 3.0 Hz), 6.66 (dd, 1H, J = 8.8, 3.0 Hz), 4.29 (t, 2H, J = 7.0 Hz), 3.76 (s, 3H), 3.03 (t, 2H,
1
3
J = 7.0 Hz), 2.03 (d, 3H, J = 6.1 Hz). C-NMR (125 MHz): δ 170.9, 159.0, 138.1, 133.4, 116.7,
1
+
15.0, 113.9, 63.3, 55.4, 35.5, 20.9. ESI-MS m/z (rel int): (pos) 294.9 ([M+Na] , 100).
O
O
Br
2
-Bromo-5-methylphenethyl acetate (S12). Light yellow oil (492 mg, 89%, 3 steps from S6).
TLC: R
C–O st), 1035, 808. H-NMR (500 MHz): δ 7.41 (d, 1H, J = 8.1 Hz), 7.07 (s, 1H), 6.90 (d, 1H,
J = 8.1 Hz), 4.31 (t, 2H, J = 7.1 Hz), 3.06 (t, 2H, J = 7.1 Hz), 2.29 (s, 3H), 2.04 (s, 3H).
f
0.64 (4:1 hexanes/EtOAc). IR (NaCl, film): 1740 (C=O st), 1473, 1383, 1363, 1239
1
(
1
3
C-NMR (125 MHz): δ 170.8, 137.4, 136.8, 132.6, 131.8, 129.3, 128.4, 121.3, 63.5, 35.2, 20.9.
+
ESI-MS m/z (rel int): (pos) 278.9 ([M+Na] , 100).

Wurst, Liu, and Tan
Supporting Information
Page S24
O
O
Br
Cl
2
-Bromo-5-chlorophenethyl acetate (S13). Yellow oil (437 mg, 66%, 3 steps from S10).
f
TLC: R 0.51 (4:1 hexanes/EtOAc). IR (NaCl, film): 1740 (C=O st), 1558, 1462, 1363, 1234
1
(
C–O st), 1098, 1037, 810. H-NMR (500 MHz): δ 7.47 (d, 1H, J = 8.5 Hz), 7.24 (d, 1H, J = 2.5
Hz), 7.09 (dd, 1H, J = 8.5, 2.6 Hz), 4.30 (t, 2H, J = 6.8 Hz), 3.05 (t, 2H, J = 6.8 Hz), 2.05 (s,
1
3
3
H). C-NMR (125 MHz): δ 170.9, 139.1, 133.9, 133.4, 130.9, 128.5, 122.5, 62.9, 35.2, 21.0.
+
ESI-MS m/z (rel int): (pos) 298.9 ([M+Na] , 70).
O
O
Br
O N
2
2
R
1
2
2
1
-Bromo-5-nitrophenethyl acetate (S14). Orange solid (62 mg, 50%, 3 steps from S7). TLC:
0.58 (4:1 hexanes/EtOAc). mp: 47.5–48.5 °C. IR (NaCl, film): 1735 (C=O st), 1653, 1558,
f
1
522, 1457, 1345 (N–O st), 1232 (C–O st), 1037, 740. H-NMR (500 MHz): δ 8.10 (d, 1H, J =
.7 Hz), 7.94 (dd, 1H, J = 8.7, 2.7 Hz), 7.72 (d, 1H, J = 8.7 Hz), 4.33 (t, 2H, J = 6.6 Hz), 3.17 (t,
1
3
H, J = 6.6 Hz), 2.01 (s, 3H). C-NMR (125 MHz): δ 170.8, 147.2, 139.5, 133.9, 131.9, 125.6,
+
23.0, 62.4, 35.3, 20.8. ESI-MS m/z (rel int): (pos) 309.9 ([M+Na] , 60).
O
O
Br
c
b
F3C
a
d
2
-Bromo-5-(trifluoromethyl)phenethyl acetate (S15). Yellow oil (880 mg, 57%, 3 steps from
0.62 (4:1 hexanes/EtOAc). IR (NaCl, film): 1743 (C=O st), 1605, 1365, 1327,
S8). TLC: R
236, 1169, 1128 (C–O st), 1084, 1040, 896. H-NMR (500 MHz): δ 7.69 (dd, 1H, J = 8.3, 3.6
Hz), 7.50 (s, 1H), 7.38–7.36 (m, 1H), 4.33 (td, 2H, J = 6.7, 4.4 Hz), 3.15 (td, 2H, J = 6.7, 4.1
f
1
1
1
3
Hz), 2.04–2.03 (m, 3H). C-NMR (125 MHz): δ 170.9, 138.5, 133.5, 130.0 (1C
H), 128.5, 127.8 (1C , q, J = 3.7 Hz), 125.1 (1C , q, J = 3.7 Hz), 123.8 (1C , q, J = 272.2 Hz),
2.7, 35.3, 20.9. ESI-MS m/z (rel int): (neg) 333.0 ([M+Na] , 60).
b
, q, J = 33.0
c
d
a
+
6

Wurst, Liu, and Tan
Supporting Information
Page S25
O
O
O
R
O
O
(
EtO) P(O)CH CO Et
TsNHNH2
NaOAc
2
2
2
Br
NaH
Br
Br
THF
°C to rt
THF/H O
2
R
R
0
(1:1)
reflux
G
S6–S10
F
S16–S20
Figure S13. Synthesis of ester precurors of aryl side-chains for 7-membered ring spiroketals from
substituted benzaldehydes S6–S10.
6
. GENERAL PROCEDURE F FOR HORNER–WADSWORTH–EMMONS OLEFINATION OF SUBSTI-
TUTED BENZALDEHYDES
To a solution of NaH (1.1 equiv) in THF (0.2 M) cooled to 0 °C was added triethyl phosphono-
acetate (1.2 equiv) dropwise at a rate of 0.25 mL/min. After addition the solution was warmed to
rt over 25 min. The reaction was cooled back to 0 °C and benzaldehyde (S6–10) (0.2 M, 1.0
equiv) was added. The reaction was warmed to rt and stirred for 30 min. The mixture was
washed with satd aq NH
4
Cl and the aqueous layer was separated and extracted with Et
2
O. The
combined organic extracts were washed with brine, dried (MgSO
4
), filtered, and concentrated by
rotary evaporation to afford the crude ethyl enoate, which was used without further purification
below.
7
. GENERAL PROCEDURE G FOR TOSYL HYDRAZIDE REDUCTION (S16–S20)
To a solution of ethyl enoate (1.0 equiv) in mixture of THF/H O (1:1, final concentration
2
0
.15 M) was added tosyl hydrazide (2.0 equiv) and NaOAc (3.0 equiv). The reaction was
refluxed over 20 h. The solution was washed with H O and aqueous layer was separated and
2
extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4),
filtered, and concentrated by rotary evaporation. Purification by silica flash chromatography (9:1
hexanes/EtOAc with 0.5% Et N) provided S16–S20.
3
O
O
O
Br
Ethyl 3-(2-bromo-5-methoxyphenyl)propanoate (S16). Light yellow oil (277 mg, 96%,
2
1
steps from S9). TLC: R
596, 1574, 1474, 1374, 1279, 1243, 1164 (C–O st), 1058, 1022, 857, 806.
f
0.54 (4:1 hexanes/EtOAc). IR (NaCl, film): 2981, 1733 (C=O st),
1
H-NMR
(500 MHz): δ 7.35 (d, 1H, J = 8.7 Hz), 6.78 (d, 1H, J = 2.9 Hz), 6.60 (dd, 1H, J = 8.7, 3.0 Hz),
4
3
5
.11 (q, 2H, J = 7.1 Hz), 3.72 (s, 3H), 2.99 (t, 2H, J = 7.8 Hz), 2.60 (t, 2H, J = 7.8 Hz), 1.22 (t,
1
3
H, J = 7.1 Hz). C-NMR (125 MHz): δ 172.4, 159.0, 140.8, 133.3, 116.1, 114.6, 113.6, 60.4,
+
5.3, 34.1, 31.6, 14.2. ESI-MS m/z (rel int): (pos) 308.9 ([M+Na] , 100).

Wurst, Liu, and Tan
Supporting Information
Page S26
O
O
Br
Ethyl 3-(2-bromo-5-methylphenyl)propanoate (S17). Yellow oil (201 mg, 74%, 2 steps from
S6). TLC: R 0.42 (4:1 hexanes/EtOAc). IR (NaCl, film): 2926, 1735 (C=O st), 1474, 1372,
f
1
1
6
7
300, 1181 (C–O st), 1127, 1026, 879, 807. H-NMR (500 MHz): δ 7.28 (d, 1H, J = 8.1 Hz),
.96 (d, 1H, J = 1.6 Hz), 6.78 (dd, 1H, J = 8.1, 1.6 Hz), 4.04 (q, 2H, J = 7.1 Hz), 2.92 (t, 2H, J =
.8 Hz), 2.52 (t, 2H, J = 7.7 Hz), 2.17 (s, 3H), 1.15 (t, 3H, J = 7.1 Hz). C-NMR (125 MHz):
1
3
δ 172.7, 139.4, 137.4, 132.6, 131.3, 128.9, 120.9, 60.5, 34.3, 31.4, 20.8, 14.2. ESI-MS m/z (rel
+
int): (pos) 293.1 ([M+Na] , 100).
O
O
Br
Cl
Ethyl 3-(2-bromo-5-chlorophenyl)propanoate (S18). Yellow oil (215 mg, 74%, 2 steps from
S10). TLC: R 0.46 (4:1 hexanes/EtOAc). IR (NaCl, film): 2981, 1734 (C=O st), 1462, 1373,
f
1
1
7
7
1
349, 1184 (C–O st), 1097, 1030, 873, 809. H-NMR (500 MHz): δ 7.36 (d, 1H, J = 8.5 Hz),
.16 (d, 1H, J = 2.5 Hz), 6.97 (dd, 1H, J = 8.5, 2.5 Hz), 4.06 (q, 2H, J = 7.1 Hz), 2.94 (t, 2H, J =
1
3
.7 Hz), 2.54 (t, 2H, J = 7.7 Hz), 1.16 (t, 3H, J = 7.1 Hz). C-NMR (125 MHz): δ 172.3, 141.6,
33.9, 130.4, 129.9, 128.1, 122.2, 60.7, 33.8, 31.3, 14.2. ESI-MS m/z (rel int): (pos) 313.1
+
–
([M+Na] , 80); (neg) 325.3 ([M+Cl] , 100).
O
O
Br
O N
2
Ethyl 3-(2-bromo-5-nitrophenyl)propanoate (S19). Yellow–orange oil (128 mg, 83%, 2 steps
from S7). TLC: R 0.50 (4:1 hexanes/EtOAc). IR (NaCl, film): 2981, 1732 (C=O st), 1569,
526, 1346 (N–O st), 1295, 1268, 1187 (C–O st), 1032, 893, 826, 793, 740. H-NMR
500 MHz): δ 8.07 (d, 1H, J = 2.5 Hz), 7.86 (dd, 1H, J = 8.7, 2.6 Hz), 7.65 (d, 1H, J = 8.7 Hz),
.08 (q, 2H, J = 7.1 Hz), 3.09 (t, 2H, J = 7.6 Hz), 2.63 (t, 2H, J = 7.6 Hz), 1.18 (t, 3H, J = 7.1
f
1
1
(
4

Wurst, Liu, and Tan
Supporting Information
Page S27
1
3
Hz). C-NMR (125 MHz): δ 171.9, 141.8, 133.8, 131.7, 129.9, 125.0, 122.7, 60.9, 33.4, 31.4,
+
1
4.2. ESI-MS m/z (rel int): (pos) 324.0 ([M+Na] , 100).
O
O
Br
c
b
F3C
a
d
Ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)propanoate (S20). Clear oil (117 mg, 61%,
2
1
steps from S8). TLC: R
410, 1374, 1329, 1277, 1168, 1128 (C–O st), 1082, 1030, 902, 824. H-NMR (500 MHz):
f
0.66 (4:1 hexanes/EtOAc). IR (NaCl, film): 2983, 1734 (C=O st),
1
δ 7.66 (d, 1H, J = 8.3 Hz), 7.51 (d, 1H, J = 1.8 Hz), 7.34 (dd, 1H, J = 8.3, 1.8 Hz), 4.14 (qd, 2H,
J = 7.1, 0.9 Hz), 3.12 (t, 2H, J = 7.7 Hz), 2.67 (t, 2H, J = 7.8 Hz), 1.24 (td, 3H, J = 7.1, 0.9 Hz).
1
3
C-NMR (125 MHz): δ 172.1, 140.9, 133.5, 130.0 (1C
3.5 Hz), 124.8 (1C , q, J = 3.7 Hz), 123.8 (1C , q, J = 272.1 Hz), 60.7, 33.7, 31.4, 14.2.
ESI-MS m/z (rel int): (pos) 346.8 ([M+Na] , 60); 325.0 ([M+H] , 10).
b c
, q, J = 33.0 Hz), 128.3, 127.2 (1C , q, J
=
d
a
+
+
O
R
O
HO
O
Ac O
2
O
DIBAL-H
toluene
Et N
3
Br
Br
DMAP
Br
–
78 °C to rt
CH Cl2
R
2
R
S16–S20
H
B
S21–S25
Figure S14. Synthesis of the aryl side-chains S21–S25 for 7-membered ring spiroketals from substituted
ethyl esters S16–S20.
8
. GENERAL PROCEDURE H FOR DIBAL REDUCTION OF ETHYL ESTERS
To a solution of ethyl ester (1.0 equiv) in toluene (0.15 M) cooled to –78 °C was added DIBAL
1.2 M in toluene, 3.0 equiv) dropwise at a rate of 0.5 mL/min. The reaction was allowed to
(
warm to rt over 30 min. The reaction was quenched with 1 N HCl and the aqueous layer was
separated and extracted with Et O. The combined extracts were washed with brine, dried
2
(
MgSO ), filtered, and concentrated by rotary evaporation. The crude product was used without
4
further purification and was acetylated according to General Procedure B.

Wurst, Liu, and Tan
Supporting Information
Page S28
O
O
Br
O
3
-(2-Bromo-5-methoxyphenyl)propyl acetate (S21). Yellow oil (145 mg, 97%, 2 steps).
f
TLC: R 0.48 (4:1 hexanes/EtOAc). IR (NaCl, film): 2958, 1737 (C=O st), 1595, 1572, 1472,
1
1
365, 1241 (C–O st), 1162, 1041, 1014, 850, 803. H-NMR (500 MHz): δ 7.39 (d, 1H, J = 8.7
Hz), 6.76 (d, 1H, J = 3.0 Hz), 6.62 (dd, 1H, J = 8.6, 3.1 Hz), 4.10 (t, 2H, J = 6.5 Hz), 3.76 (s,
1
3
3
1
3
H), 2.76 (t, 2H, J = 7.7 Hz), 2.06 (s, 3H), 1.98–1.92 (m, 2H). C-NMR (125 MHz): δ 171.1,
59.0, 141.5, 133.4, 116.1, 114.8, 113.3, 63.7, 55.4, 32.8, 28.7, 21.0. ESI-MS m/z (rel int): (pos)
09.2 ([M+Na] , 90).
+
O
O
Br
3
-(2-Bromo-5-methylphenyl)propyl acetate (S22). Clear oil (152 mg, 76%, 2 steps). TLC:
f
R 0.58 (4:1 hexanes/EtOAc). IR (NaCl, film): 2955, 1738 (C=O st), 1472, 1364, 1237 (C–O st),
1
1
8
(
023, 807, 668. H-NMR (500 MHz): δ 7.39 (d, 1H, J = 8.1 Hz), 7.02 (s, 1H), 6.86 (d, 1H, J =
.0 Hz), 4.11 (t, 2H, J = 6.5 Hz), 2.76 (t, 2H, J = 7.8 Hz), 2.27 (s, 3H), 2.06 (s, 3H), 1.95
1
3
quintet, 2H, J = 7.3 Hz). C-NMR (125 MHz): δ 171.1, 140.2, 137.3, 132.6, 131.2, 128.6,
21.0, 63.8, 32.5, 28.8, 21.0 (2). ESI-MS m/z (rel int): (pos) 293.1 ([M+Na] , 100).
+
1
O
O
Br
Cl
3
-(2-Bromo-5-chlorophenyl)propyl acetate (S23). Clear oil (190 mg, 88%, 2 steps). TLC:
f
R 0.61 (4:1 hexanes/EtOAc). IR (NaCl, film): 2957, 1740 (C=O st), 1463, 1389, 1367, 1239
1
(
C–O st), 1100, 1029, 888, 811, 670. H-NMR (500 MHz): δ 7.43 (d, 1H, J = 8.5 Hz), 7.20 (d,
1
2
1
H, J = 2.4 Hz), 7.04 (dd, 1H, J = 8.5, 2.5 Hz), 4.11 (t, 2H, J = 6.4 Hz), 2.77 (t, 2H, J = 7.8 Hz),
1
3
.06 (s, 3H), 1.94 (quintet, 2H, J = 6.5 Hz). C-NMR (125 MHz): δ 171.0, 142.4, 133.9, 133.4,
+
30.2, 127.9, 122.2, 63.5, 32.6, 28.5, 20.9. ESI-MS m/z (rel int): (pos) 313.1 ([M+Na] , 60);
–
(neg) 325.3 ([M+Cl] , 35).

Wurst, Liu, and Tan
Supporting Information
Page S29
O
O
Br
O N
2
3
-(2-Bromo-5-nitrophenyl)propyl acetate (S24). Orange oil (75 mg, 58%, 2 steps). TLC:
R
f
0.44 (4:1 hexanes/EtOAc). IR (NaCl, film): 2959, 1737 (C=O st), 1569, 1525, 1462, 1345
1
(N–O st), 1237 (C–O st), 1028, 906, 829, 810, 740. H-NMR (500 MHz): δ 8.10 (d, 1H, J = 2.7
Hz), 7.93 (dd, 1H, J = 8.7, 2.7 Hz), 7.72 (d, 1H, J = 8.7 Hz), 4.14 (t, 2H, J = 6.3 Hz), 2.92 (dd,
1
3
2
1
H, J = 8.8, 7.0 Hz), 2.08 (s, 3H), 2.04–1.98 (m, 2H). C-NMR (125 MHz): δ 171.0, 147.3,
42.6, 133.9, 131.7, 124.8, 122.5, 63.3, 32.8, 28.3, 20.9. ESI-MS m/z (rel int): (pos) 324.1
+
([M+Na] , 100).
O
O
Br
c
b
F3C
a
d
3
-(2-Bromo-5-(trifluoromethyl)phenyl)propyl acetate (S25). Clear oil (574 mg, 93%, 2
f
steps). TLC: R 0.53 (4:1 hexanes/EtOAc). IR (NaCl, film): 2960, 1741 (C=O st), 1604, 1410,
1
1
1
2
1
1
1
367, 1330, 1240, 1168, 1126 (C–O st), 1084, 1025, 903, 824. H-NMR (500 MHz): δ 7.66 (d,
H, J = 8.3 Hz), 7.47 (s, 1H), 7.33 (d, 1H, J = 8.2 Hz), 4.13 (td, 2H, J = 6.4, 1.8 Hz), 2.88 (td,
1
3
H, J = 7.8, 1.6 Hz), 2.07 (s, 3H), 2.02–1.96 (m, 2H). C-NMR (125 MHz): δ 171.1, 141.7,
33.5, 130.0 (1C , q, J = 32.6 Hz), 128.3, 126.9 (1C , q, J = 3.7 Hz), 124.5 (1C , q, J = 3.5 Hz),
, q, J = 272.0 Hz), 63.6, 32.8, 28.5, 21.0. ESI-MS m/z (rel int): (pos) 347.1 ([M+Na] ,
b
c
d
+
23.8 (1C
00).
a

Wurst, Liu, and Tan
Supporting Information
Page S30
G. SYNTHESIS OF SUBSTITUTED C1-ARYL GLYCAL SUBSTRATES (S26, 5–7)
Br
R
R
AcO
R
O
O
TBDPSO
O
SnBu3
n
K CO
3
S1–S25
2
n
OAc
n
OH
Pd(PPh3)
toluene, reflux
n = 1–3
4
THF, MeOH
OTIPS
OTIPS
OTIPS
S26
5–7
R = OMe, Me, H, Cl, CF , NO
3
2
Figure S15. Synthesis of glycals 5–7 from glycal stannane S26 by Stille cross coupling of aryl bromides,
followed by K CO deacetylation.
2
3
6
GENERAL PROCEDURE FOR STILLE COUPLING OF ARYL BROMIDES
7
To a solution of glycal stannane S26 (1.0 equiv), prepared as previously described, in degassed
toluene (0.1 M) was added the appropriate aryl bromide sidechain S1–S25 (1.2 equiv) and
8
Pd(PPh ) (0.2 equiv). The yellow solution was shielded from light with aluminum foil and
3
4
heated to reflux for 6–8 h, then cooled to rt and concentrated by rotary evaporation. Passage
over a short silica plug yielded the intermediate O-acetyl C1-aryl glycals. These protected
glycals were dissolved in THF/MeOH (1:1, final concentration 0.1 M) and K CO (2.0 equiv)
2
3
6
was added. After stirring for 3–4 h, the mixture was diluted with Et O, filtered through a plug
2
of celite, dried (MgSO ), and concentrated by rotary evaporation. Purification by silica flash
4
chromatography (20:1–10:1 hexanes/EtOAc with 1% Et N) afforded 5–7.
3
O
O
O
O
Si
OH
Si
(
2
–)-(2-((2R,4S)-2-(2-(tert-Butyldiphenylsilyloxy)ethyl)-4-(triisopropylsilyloxy)-3,4-dihydro-
H-pyran-6-yl)-5-methoxyphenyl)methanol (5a). Clear oil (352 mg, 86%, 2 steps). TLC:
1
9
R 0.33 (4:1 hexanes/EtOAc). [α] : –4.5° (c 1.0, CHCl ). IR (NaCl, film): 3446 (O–H st),
f
D
3
3
7
070, 2941, 2864, 1653, 1697, 1572, 1485, 1463, 1427, 1388, 1272, 1095 (C–O st), 882, 822,
37, 702. H-NMR (500 MHz): δ 7.68–7.65 (m, 4H), 7.44–7.32 (m, 6H), 7.31 (d, 1H, J = 8.4
1
Hz), 6.98 (d, 1H, J = 2.7 Hz), 6.80 (dd, 1H, J = 8.4, 2.7 Hz), 4.93 (t, 1H, J = 2.1 Hz), 4.69 (ddd,
1
1
H, J = 8.8, 6.6, 2.2 Hz), 4.59 (d, 2H, J = 6.1 Hz), 4.43–4.38 (m, 1H), 3.88–3.78 (m, 5H), 2.35 (t,
H, J = 6.5 Hz), 2.21–2.17 (m, 1H), 2.05–1.98 (m, 1H), 1.92–1.87 (m, 1H), 1.85–1.78 (m, 1H),
6
(
a) Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 2572–2574. (b) Beau, J.; Dubois, E. Carbohydr. Res.
992, 228, 103–120. (c) Liu, G.; Wurst, J. M.; Tan, D. S. Org. Lett. 2009, 11, 3670–3673.
a) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796–13797. (b) Moilanen, S. B.;
Tan, D. S. Org. Biomol. Chem. 2005, 3, 798–803.
1
7
8
(
Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Kapdi, A.; Taylor, R. J. K.; Whitwood, A. C. Tetrahedron 2005,
1, 9736–9751.
6