Supporting Information for
Gross,
and
Stoltz
S
1
Convenient Access to a Strained Bicyclic Enone:
A Concise and Improved Formal Synthesis of Ineleganolide
Benjamin M. Gross, and Brian M. Stoltz
*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division
of
Chemistry and Chemical Engineering, California Institute of Technology,
MC 101
-
20,
Pasadena, California 91125
, United States
stoltz@caltech.edu
Table of Contents:
Materials and Methods
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................................
....................
2
List of Abbreviations
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2
Experimental Procedures
................................
................................
................................
................................
................
3
References
................................
................................
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................................
.....
11
Spectral Data
................................
................................
................................
................................
................................
.
12
Supporting Information for
Gross,
and
Stoltz
S
2
Materials and Methods
Unless otherwise stated, reactions were performed in flame
-
dried glassware under an argon or
nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through
an activated alumina column under argon.
1
Reaction progress was monitored by thin
-
layer
chromatography (TLC). TLC was performed using E. Merck silica gel 60 F254 precoated glass
plates (0.25 mm) and visualized by UV fluorescence quenching
, p
-
anisaldehyde, or
KMnO
4
staining.
Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40
–
63 μm) was used for
flash chromatography.
1
H NMR spectra were recorded on Varian Inova 500 MHz and 600 MHz
and Bruker 400 MHz spectrometers and are reported relative to residual CHCl
3
(δ 7.26 ppm), C
6
D
6
(δ 7.16 ppm) or CD
3
OD (δ 3.31 ppm).
13
C NMR spectra were recorded on a Varian Inova 500
MHz spectrometer (125 MHz) and Bruker 400 MHz spectrometers (100 MHz) and are reported
relative to CHCl
3
(δ 77.16 ppm),
C
6
D
6
(δ 128.06 ppm) or CD
3
OD (δ 49.01 ppm). Data for
1
H
NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz),
integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,
p = pentet, sept = septuplet, m = multiplet, br s = broad
singlet, br d = broad doublet. Data for
13
C
NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin
Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited
on NaCl plates and
reported in frequency of absorption (cm
-
1
).
High resolution mass spectra
(HRMS) were obtained using an Agilent 6200 Series TOF with an Agilent G1978A Multimode
source in electrospray ionization (ESI+)
mode
.
List of Abbreviations
DMAP
–
4
-
Dimethylaminopyridine, HPLC
–
High performance liquid chromatography
.
Supporting Information for
Gross,
and
Stoltz
S
3
Experimental Procedures
Cyclopentenone 6
:
Prepared according to
a known
literature procedure
.
2
Deionized water (509
mL, 0.4M), furfuryl alcohol (20 g, 203.8 mmol, 1.0 equiv
.
) and 6.25 g of KH
2
PO
4
were placed in
a round bottom flask equipped with a reflux condenser. The pH was measured with a handheld
pH
-
Meter and H
3
PO
4
was added until the pH was measured to be ~4.1. The solution was placed
under inert atmosphere and was degassed by bubbling argon through the solution for 1 hour.
Subsequently the reaction mixture was heated to
reflux for 72 hours and complete consumption of
starting material was observed by GC
-
MS. The reaction mixture was cooled to room temperature
and washed once with EtOAc. The aq
ueous layer was evaporated under reduced pressure, diluted
with EtOAc and the salts filtered off. The organic layer was evaporated under reduced pressure to
yield product
7
(6.9 g, 70.3 mmol, 35% yield) as a colorless oil
.
1
H NMR (
3
00 MHz, CDCl
3
) δ
7.57 (dd,
J
= 5.7, 2.3 Hz, 1H)
,
6.22 (dd,
J
= 5.7, 1.3 Hz, 1H)
,
5.05
(dtd,
J
= 6.0, 2.3, 1.3 Hz, 1H)
, 3.44 (br s, 1H),
2.78 (dd,
J
= 18.5, 6.1 Hz, 1H)
,
2.28 (dd,
J
= 18.5,
2.2 Hz, 1H)
.
The spectroscopic data matches those previously reported.
2
O
OH
6
Furfuryl alcohol
O
OH
KH
2
PO
4
/H
3
PO
4
pH ~ 4.1
H
2
O, reflux
Supporting Information for
Gross,
and
Stoltz
S
4
Silyl Ether
7
:
Prepared according to a
known
literature procedure.
3
Allylic alcohol
6
(7.0 g, 71
mmol, 1.0 equiv.) was placed in a round bottom flask and dissolved in dichloromethane (355 mL,
0.2 M). Imidazole (9.6 g, 142 mmol, 2.0 equiv.), TBSCl (16 g, 107 mmol, 1.5 equiv.) and DMAP
(1.7 g, 14.2 mmol, 0.2 equiv.) were added and the reacti
on mixture stirred at 20
°C
for 6 hours.
After complete consumption of starting material, water was added to the reaction mixture and the
aqueous phase extracted with Et
2
O (3x). The combined organic layers were washed with brine,
dried over Na
2
SO
4
and the solvent evaporated under reduced pressure. The crude
product
was
purified by flash chromatography on silica gel (0
→
1
0% EtOAc/Hexanes) to yield product
7
(
13.5
g, 64 mmol,
90% yield)
as a colorless oil.
1
H NMR (
3
00 MHz, CDCl
3
) δ
7.45 (ddd,
J
= 5.7, 2.3, 0.7 Hz, 1H)
,
6.18 (ddd,
J
= 5.6, 1.3, 0.7 Hz,
1H)
,
4.98 (dd,
J
= 3.7, 1.6 Hz, 1H)
,
2.70 (ddd,
J
= 18.2, 5.9, 0.7 Hz, 1H)
,
2.24 (ddd,
J
= 18.2, 2.2,
0.7 Hz, 1H)
, 0.90 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H).
The spectroscopic data matches those previously reported.
3
O
OH
6
O
OTBS
TBSCl (1.5 equiv)
imidazole (2.0 equiv)
DMAP (0.2 equiv)
CH
2
Cl
2
7
Supporting Information for
Gross,
and
Stoltz
S
5
Vinyl iodide 8
:
Prepared according to a
known
literature procedure.
4
Starting material
7
(1.0 g,
4.7 mmol, 1.0 equiv.) was dissolved in a mixture of dichloromethane/pyridine (8 mL/8 mL) and
cooled to 0
°C
in an ice bath. A solution of iodine (2.0 g, 8.0 mmol, 1.7 equiv.) in a mixture of
dichloromethane/pyridine (9.5 mL/9.5 mL) was added dropwise over the course of 1 h.
The
mixture was then allowed to warm to room temperature and stirred for another hour. Upon
complete consumption of starting material as determined by TLC, aqueous HCl (1M) was added
and the aqueous layer extracted with CH
2
Cl
2
(
2x). The combined organic layers were washed with
a sat. aqueous solution of Na
2
S
2
O
3
, brine and dried over Na
2
SO
4
. The crude product was purified
by flash column chromatography on silica gel (
0
→
10% EtOAc
/Hexanes) to yield the product as
a
yellow
oil (1.28 g, 3.8 mmol, 8
0
% yield).
1
H NMR (
6
00 MHz, CDCl
3
) δ
7.80 (d,
J
= 2.5 Hz, 1H)
,
4.95 (d,
J
= 6.1 Hz, 1H)
,
2.86 (dd,
J
=
18.2, 6.0 Hz, 1H)
,
2.35 (ddd,
J
= 18.2, 2.2, 0.7 Hz, 1H)
, 0.91 (s, 9H), 0.14 (s,
3H), 0.13 (s, 3H).
The spectroscopic data matches those previously reported.
4
O
OTBS
I
O
OTBS
I
2
(1.7 equiv)
pyridine:CH
2
Cl
2
(1:1)
7
8
Supporting Information for
Gross,
and
Stoltz
S
6
Alcohol 9
:
Vinyl iodide
8
(300 mg, 0.88 mmol, 1.0 equiv.) was placed in a vial equipped with a
stir bar, sealed, evacuated, and backfilled with N
2
(3x). The starting material was dissolved in THF
(8.8 mL, 0.1 M) and cooled to
–
78 °C
in a dry ice/acetone bath. MeMgBr (3M in Et
2
O, 0.35 mL,
1.05 mmol, 1.2 equiv) was added dropwise over the course of 5 min and the reaction mixture
warmed and kept at temperature between
–
40
°C
and
–
30
°C
. After 1 h
,
another equivalent of
MeMgBr (3M in Et
2
O, 0.3 mL) was added and the reaction stirred for another hour at the same
temperature. After full consumption of SM as indicated by TLC, a solution of sat. aq. NH
4
Cl was
added, and the reaction mixture warmed to room temperature. The aqueous layer was extracted
with EtOAc (3x) and the combined organic layers dried over Na
2
SO
4
.
The crude product was
purified by flash column chromatography on silica gel (
0
→
15% EtOAc/Hexanes) to yield the
product
9
as
a yellow oil (22
5 mg, 0.64 mmol, 72% yield).
1
H NMR (
4
00 MHz, CDCl
3
) δ
6.16 (d,
J
= 2.2 Hz, 1H)
,
4.60 (ddd,
J
= 6.6, 4.4, 2.1 Hz, 1H)
,
2.48
(dd,
J
= 13.3, 6.8 Hz, 1H)
, 2.17 (s, 1H),
1.91 (dd,
J
= 13.3, 4.4 Hz, 1H)
, 1.24 (s, 3H), 0.88 (s, 9H),
0.07 (s, 6H)
;
13
C
NMR (1
25
MHz, CDCl
3
)
δ
143.2, 113.8, 82.7, 75.6, 48.2, 27.4, 25.9, 18.2,
-
4.6,
-
4.6
;
IR (
n
eat
f
ilm, NaCl
)
3423, 2954, 2929, 2856, 1743, 1604, 1471, 1359, 1255, 1087, 960, 824,
776, 681, 651
cm
–
1
;
HRMS (
ESI+
):
m/z
calc’d for C
12
H
22
Si
O
I
[M
–
O
H
]
+
:
337
.
0480
, found
3
37
.
0482
.
O
OTBS
OTBS
I
HO
I
MeMgBr (2.2 equiv)
THF, –78 ºC to –30 ºC
16:1 d.r.
8
9
Supporting Information for
Gross,
and
Stoltz
S
7
Methyl Ester
1
0
:
Starting material
9
(183 mg, 0.516 mmol, 1.0 equiv.) was placed in a vial and
dissolved in THF (3.4 mL, 0.15 M). Sodium hydride (60% in mineral oil, 103 mg, 2.58 mmol, 5.0
equiv.) was added and the reaction stirred for 10 minutes at room temperature. Methyl
chloroacetate (0.
135 mL, 1.55 mmol, 3.0 equiv.) was added dropwise and the reaction mixture
heated to 60
°C
for 3 hours. The reaction mixture was cooled to room temperature and quenched
with a sat. aq. solution of NaHCO
3
. The aqueous layer was extracted with Et
2
O (3x), the
combined
organic layers dried over
Na
2
SO
4,
and the solvent evaporated under reduced pressure.
The crude
product was purified by flash column chromatography on silica gel (
0
→
10% EtOAc/Hexanes)
to yield the product
10
as a colorless oil (44.5 mg, 0.11 mmol, 21% yield) along with reisolated
starting material
9
(
126 mg, 0.35 mmol,
69% yield).
1
H NMR (
6
00 MHz, CDCl
3
) δ
6.31 (dd,
J
= 2.3, 0.5 Hz, 1H)
,
4.75
–
4.31 (m, 1H)
,
4.12 (d,
J
=
16.4 Hz, 1H)
,
3.99 (d,
J
= 16.4 Hz, 1H)
,
3.73 (s, 3H)
,
2.35 (dd,
J
= 14.7, 7.5 Hz, 1H)
,
1.92 (dd,
J
= 14.7, 3.0 Hz, 1H)
,
1.34 (s, 3H)
, 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H)
;
13
C
NMR (1
25
MHz,
CDCl
3
)
δ
171.3, 146.1, 109.7, 88.9, 75.1, 61.9, 51.9, 42.3, 28.1, 25.9, 18.2,
-
4.6,
-
4.7
;
IR (
n
eat
f
ilm, NaCl
)
2955, 2928, 2856, 1741, 1648, 1462, 1361, 1257, 1103, 1035, 837, 778
cm
–
1
;
HRMS
(
ESI+
):
m/z
calc’d for
C
12
H
22
Si
O
I
[M
–
OCH
2
COOMe
]
+
:
337.0480
, found
337
.
0488.
OTBS
OTBS
NaH (5.0 equiv)
O
OMe
Cl
HO
I
O
OMe
O
I
(3.0 equiv)
THF, 60 ºC
9
10
Supporting Information for
Gross,
and
Stoltz
S
8
Enone
11
:
Starting material
10
(20 mg, 0.048 mmol, 1.0 equiv.) was placed in a vial, capped,
equipped with a stir bar, evacuated, and backfilled with N
2
(3x). Et
2
O (4.8 mL, 0.01 M) was added,
and the reaction mixture cooled to
–
78
°C
in a dry ice/acetone bath. A solution of
t
-
BuLi
(1.7M in
pentane, 0.072 mmol, 0.042 mL)
was added dropwise to the reaction mixture and the solution
stirred for 30 minutes
, before
t
he reaction was quenched with a sat. aq. solution of NaHCO
3
and
subsequently warmed to room temperature.
The aqueous layer was extracted with Et
2
O (3x
),
and
the combined organic layers dried over Na
2
SO
4
. The solvent was evaporated under reduced
pressure and the crude product purified by
flash column chromatography on silica gel (
0
→
10%
EtOAc/Hexanes) to yield the product
11
a
s a colorless oil (10.2 mg, 0.038 mmol,
79
% yield).
1
H NMR (
6
00 MHz, CDCl
3
) δ
6.48 (s, 1H),
5.18 (t,
J
= 6.6 Hz, 1H)
,
4.26 (d,
J
= 17.1 Hz, 1H)
,
4.2
1
(d,
J
= 17.1 Hz, 1H)
,
2.64 (dd,
J
= 11.8, 5.6 Hz, 1H)
,
2.27 (dd,
J
= 11.9, 8.0 Hz, 1H)
, 1.39 (s,
3H),
0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H
).
The spectroscopic data matches those previously reported.
5
OTBS
OTBS
O
O
OMe
O
I
O
t
-BuLi (1.5 equiv)
Et
2
O, –78 ºC
10
11
Supporting Information for
Gross,
and
Stoltz
S
9
Alcohol 14
:
Vinyl bromide
13
(500 mg, 1.71 mmol, 1.0 equiv.) was placed in a round bottom flask
with a stir bar, sealed, evacuated, and backfilled with N
2
(3x). The starting material was dissolved
in Et
2
O (17 mL, 0.1 M) and cooled to
–
78 °C
in a dry ice/acetone bath. MeMgBr (3M in Et
2
O,
0.85 mL, 2.56 mmol, 1.5 equiv) was added dropwise over the course of 5 min and the reaction
mixture warmed and kept at temperature between
–
40
°C
and
–
30
°C
. After 1 h another equivalent
of MeMgBr (3M in Et
2
O, 0.3 mL) was added and the reaction stirred for another hour at the same
temperature. After full consumption of SM as indicated by TLC, a solution of sat. aq. NH
4
Cl was
added, and the reaction mixture warmed to room temperature. The aqueous layer was extr
acted
with EtOAc (3x) and the combined organic layers dried over Na
2
SO
4
.
The crude product was
purified by flash column chromatography on silica gel (
0
→
15% EtOAc/Hexanes) to yield the
product
14
as
a yellow oil (363 mg, 1.18 mmol, 69% yield).
1
H NMR (
4
00 MHz, CDCl
3
) δ
5.94 (d,
J
= 2.2 Hz, 1H)
,
4.60 (ddd,
J
= 6.5, 3.9, 2.2 Hz, 1H)
,
2.49
(dd,
J
= 13.4, 6.8 Hz, 1H)
,
1.95 (dd,
J
= 13.4, 4.0 Hz, 1H)
, 1.32 (s, 3H), 0.88 (s, 9H), 0.08 (s, 6H)
;
13
C
NMR (1
25
MHz, CDCl
3
)
δ
134.9, 81.1, 73.2, 49.6, 26.2,
25.9, 18.2,
-
4.6,
-
4.6
;
IR (
n
eat
f
ilm,
NaCl
)
3423, 2954, 2930, 2857, 1618, 1358, 1254, 1087, 970, 901, 820, 777
cm
–
1
;
HRMS (
ESI+
):
m/z
calc’d for C
12
H
22
Si
O
Br
[M
–
OH
]
+
:
291
.0
598
, found
291.0605
.
O
OTBS
OTBS
Br
HO
Br
MeMgBr (2.5 equiv)
THF, –78 ºC to –30 ºC
10:1 d.r.
13
14
Supporting Information for
Gross,
and
Stoltz
S
10
Methyl Ester 10
:
Starting material
14
(
220
mg, 0.
714
mmol, 1.0 equiv.) was placed in a vial and
dissolved in THF (
7
mL, 0.1 M). Sodium hydride (60% in mineral oil,
142
mg,
3.57
mmol, 5.0
equiv.) was added and the reaction stirred for 10 minutes at room temperature. Methyl
chloroacetate (0.
183
mL,
2
.
1
mmol, 3.0 equiv.) was added dropwise and the reaction mixture
heated to 60
°C
for 3 hours. The reaction mixture was cooled to room temperature and quenched
with a sat. aq. solution of NaHCO
3
. The aqueous layer was
extracted with Et
2
O (3x), the combined
organic layers dried over Na
2
SO
4,
and the solvent evaporated under reduced pressure.
The crude
product was purified by flash column chromatography on silica gel (
0
→
10% EtOAc/Hexanes)
to yield the product
10
as a colorless oil (
67
mg, 0.1
8
mmol,
25
% yield) along with reisolated
starting material
9
(
132
mg, 0.
43
mmol, 6
0
% yield).
1
H NMR (
6
00 MHz, CDCl
3
) δ
6.08 (dd,
J
= 2.4, 0.6 Hz, 1H)
,
4.56 (d,
J
= 7.3 Hz, 1H)
,
4.15 (d,
J
= 16.3 Hz, 1H)
,
4.00 (d,
J
= 16.3 Hz, 1H)
, 3.73 (s, 3H),
2.38 (dd,
J
= 14.8, 7.4 Hz, 1H)
,
1.97 (dd,
J
= 14.8, 2.7 Hz, 1H)
, 1.41 (s, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H)
;
13
C
NMR (1
25
MHz,
CDCl
3
)
δ
171.3, 137.9, 131.5, 87.3, 72.5, 62.0, 52.0, 44.0, 26.8, 25.9, 18.1,
-
4.6,
-
4.7
;
IR (
n
eat
f
ilm, NaCl
)
3503, 2954, 2857, 1740, 1619, 1471, 1359, 1251, 1118, 1060, 1036, 972, 900, 840,
777
cm
–
1
;
HRMS (
ESI+
):
m/z
calc’d for C
12
H
22
Si
O
Br
[M
–
OCH
2
COOMe
]
+
:
291.0598
, found
291.0602
.
OTBS
OTBS
NaH (5.0 equiv)
O
OMe
Cl
HO
Br
O
OMe
O
Br
(3.0 equiv)
THF, 60 ºC
14
12
Supporting Information for
Gross,
and
Stoltz
S
11
References
1)
Watson
A. M.;
Giardello,
M. A.;
Grubbs,
R. H.;
Rosen,
R. K.
;
Timmers,
F. J.
Safe and
Convenient Procedure for Solvent Purification
.
Organometallics
1996
,
15
, 1518
–
1520.
2)
Watson, T. J. N. et al.
Development of the Carbocyclic Nucleoside MDL 201449A: A
Tumor Necrosis Factor
-
α
Inhibitor.
Org. Proc. Res. Dev.
1998
,
6,
357
–
365.
3)
Jacobo, S. H. et al. Total Synthesis of 8,12
-
iso
-
iPF
3α
-
VI, an EPA
-
Derived Isoprostane:
Stereoselective
Introduction of the Fifth Asymmetric Center
.
J. Org. Chem.
2006
,
71
,
1370
–
1
379.
4)
Kimbrough, J. R. et al. Synthesis of tetranor
-
PGE
1
: A urinary metabolite of
prostaglandins E
1
and E
2
,
Tetrahedron Lett.
2020
,
61
, 151922.
5)
Gross, B. M. et al. A
Convergent Total Synthesis of (+)
-
Ineleganolide
,
J. Am. Chem. Soc.
2023
,
145
,
7763
–
7767.
Supporting Information for
Gross
, and Stoltz
S
12
0
1
2
3
4
5
6
7
8
p
p
m
1
.
0
0
1
.
0
2
1
.
0
3
1
.
0
7
3
.
0
2
9
.
0
0
6
.
3
2
0
.
9
6
0
.
0
7
0
.
8
8
1
.
2
4
1
.
8
9
1
.
9
0
1
.
9
2
1
.
9
3
2
.
1
7
2
.
4
6
2
.
4
7
2
.
4
9
2
.
5
1
4
.
5
9
4
.
5
9
4
.
6
0
4
.
6
0
4
.
6
1
4
.
6
2
4
.
6
2
6
.
1
6
6
.
1
6
1
H NMR (
600
MHz, CDCl
3
) of compound
9
.
OTBS
HO
I
Supporting Information for
Gross
, and Stoltz
S
13
0
5
0
1
0
0
1
5
0
2
0
0
p
p
m
-
4
.
6
-
4
.
6
1
8
.
2
2
5
.
9
2
7
.
4
4
8
.
2
7
5
.
6
8
2
.
7
1
1
3
.
8
1
4
3
.
2
0.0
Infrared spectrum (Thin Film, NaCl) of compound
9
.
13
C NMR (100 MHz, CDCl
3
) of compound
9
.