of 33
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
1
Supporting Information for
Some Unusual
Transformations
of a Highly Reactive α
-
Bromocaranone
Adrian E. Samkian,
Zachary P. Sercel
,
Scott C. Virgil,
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:
General
considerations
.............................................................................................................................
....
S2
Synthetic
procedures
and characterization of compounds
......................................................................
S3
S
8
DFT calculations
.............................................................................................................................
.............
S
9
References
...................................................................................
...............................................................
S10
NMR spectra and IR spectra
..............................................................................................................
S11
S
33
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
2
General
considerations
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
(+)
-
3
-
Carene was purchased from TCI
and used as received,
N
-
bromosuccinimide (NBS) was recrystallized from boiling water prior to use, trimethylsilyl chloride
(TMSCl) was distilled under argon prior to use, all other reagents and solvents were purchased from various
commercial suppliers and
used as received. Reaction progress was monitored by thin
-
layer chromatography
(TLC) or Agilent 1290 UHPLC
-
MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass
plates (0.25 mm) and visualized by UV fluorescence quenching or
p
-
anisaldehy
de staining. Silicycle
SiliaFlash® P60 Academic Silica gel (particle size 40
63
μ
m)
or
Sigma
-
Aldrich aluminum oxide
(activated, neutral, Brockmann Activity I)
were
used for flash chromatography.
Preparatory HPLC was
performed on an Agilent
1200 preparatory
HPLC system
using
a
9.4 x 250 mm
Eclipse XDB
-
C18 column
.
A water/MeCN gradient was used as the mobile phase and the compounds were detected at 230.8 nm and
254.4 nm.
Analytical SFC was performed with a Mettler SFC supercritical CO
2
analytical chromatography
system utilizing a Chiralpak AD
-
H column (4.6 mm x 25
cm) obtained from Daicel Chemical Industries,
Ltd.
1
H NMR spectra were recorded on Varian Inova 500 MHz, Varian 400 MHz, and Bruker 400 MHz
spectrometers and are reported relative to residual CHCl
3
(δ 7.26 ppm).
13
C NMR spectra were recorded on
a Varian In
ova 500 MHz spectrometer (125 MHz), a Varian 400 MHz spectrometer (100 MHz), and Bruker
400 MHz spectrometers (100 MHz) and are reported relative to CHCl
3
(δ 77.16 ppm). Data for
1
H NMR
are reported as follows: chemical shift (δ ppm) (multiplicity, couplin
g 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 ch
emical shifts (δ ppm) Some reported spectra include minor solvent impurities of water (δ 1.56ppm),
ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), acetone (δ 2.17 ppm), grease (δ
1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm),
which do not impact product assignments. IR spectra
were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl
plates and reported in frequency of absorption (cm
1
). Optical rotations were measured with a Jasco P
-
2000
polarimeter operating on the sodium D
-
line (589 nm), using a 100 mm path
-
length cell. High
-
resolution
mass spectrometry was performed by the Multi User Mass Spectrometry Laboratory at the California
Institute of Technology
using a JMS
-
T200 GC AccuTOF
GC
-
Alpha mass spectrometer
.
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
3
Synthetic Procedures and Characterization of Compounds
(1R,3R,4R,6S)
-
4,7,7
-
trimethylbicyclo[4.1.0]heptan
-
3
-
ol (
S0
)
.
The
procedure was adapted from the
literature
:
2
To a dried
500
mL
round bottom
flask was added
NaBH
4
(6.94 g, 183 mmol, 1.0 equiv), THF
(60 mL)
,
and (+)
-
3
-
carene (25 g, 180 mmol, 1.0 equiv). The reaction flask was cooled to 0 °C in an ice
bath, and
BF
3
•OEt
2
(26 g, 160 mmol, 1.0 equiv) was added dropwise over 30 min. The reaction was stirred
at this temperature for 4 h, after which the reaction was cooled to
10 °C and aq. NaOH (
3M,
60 mL) was
added dropwise over 40 min. H
2
O
2
(
30 wt %,
100 mL) was then added
dropwise over
1 h, and the reaction
allowed to warm to
20 °C
. The solution was concentrated under reduced pressure to remove THF, and the
aqueous layer was extracted with
CH
2
Cl
2
(3 x 40 mL). The combined organic layers were washed with
water
(100 mL)
and
b
rine
(100 mL)
, dried
over
Na
2
SO
4
,
and filtered
. Concentration under reduced pressure
afforded an oil
that
was distilled under vacuum
(0.5 mmHg, 150 °C)
to afford
S0
(22 g, 78%)
as a colorless
oil
that solidified upon cooling.
1
H NMR
(chloroform
-
d
, 400 MHz): δ =
3.07 (ddd,
J
= 10.3, 9.3, 6.6 Hz,
1H), 2.10 (ddd,
J
= 14.1, 6.6, 0.9 Hz, 1H), 2.01
1.92 (m, 1H), 1.61
1.51 (m, 1H), 1.29
1.17 (m, 1H),
0.97 (s, 3H), 0.93 (d,
J
= 6.4 Hz, 3H), 0.90 (s, 3H), 0.86
0.77 (m, 1H), 0.75
0.67
(m, 2H).
Spectral data
are in agreement with previously reported values.
3
(1R,4R,6S)
-
4,7,7
-
trimethylbicyclo[4.1.0]heptan
-
3
-
one (
2
)
.
A
procedure
from the literature
4
was modified
as follows: To a 1
L
round bottom
flask was added
alcohol
S0
(20 g, 130 mmol, 1
.0
equiv) and Et
2
O (280
mL). The solution
was
cooled in an ice bath, and
Brown
Garg (BG)
reagent
5,6
(70 mL)
was
added dropwise
over 20 min
with vigorous stirring, maintaining
the
reaction
temperature
below 20 °C. The ice bath
was
then re
moved, and the solution stirred for 1 h. Additional BG reagent (70 mL)
was
added
slowly,
and the
reaction
was
left to stir for 18 h.
The organic layer was then separated
,
and the aqueous layer
was
extracted
with
Et
2
O
(2 x 50 mL). The combined organic layers were washed with brine
(100 mL)
, dried
over
Na
2
SO
4
,
filtered,
and concentrated under reduced pressure. The residual oil was
distilled under vacuum
(0.5 mmHg,
130 °C)
to yield
2
(12.8 g, 65%)
as
fragrant,
yellow oil
.
1
H NMR (
chloroform
-
d
,
400 MHz)
:
δ
=
2.52 (ddd,
J
= 18.0, 8.4, 0.9 Hz, 1H), 2.41
2.32 (m, 1H), 2.32
2.25 (m, 2H), 1.31
1.19 (m, 1H), 1.07 (
m
, 1H),
1.04 (s, 3H), 1.02
0.97 (m, 1H), 0.95 (d,
J
= 6.4 Hz, 3H), 0.84 (s, 3H).
Spectral data are in agreement with
previously reported values.
4
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
4
(1R,2R,4R,6S)
-
2
-
bromo
-
4,7,7
-
trimethylbicyclo[4.1.0]heptan
-
3
-
one (
5
)
.
To a
flame
-
dried 250 mL
Schlenk flask was added THF (29 mL) and diisopropylamine (1.59 g, 15.8 mmol, 1.2 equiv). The solution
was cooled to
78 °C and
n
-
butyllithium
(
2.5 M in hexanes,
5.5 mL, 13.8 mmol, 1.05 equiv) was added
dropwise
over 8 min
. After stirring for 3
0 min,
a solution of
ketone
2
(2 g, 13.1 mmol, 1.0 equiv) in THF
(2 mL) was added dropwise
over 5 min
and the
reaction mixture
allowed to stir at
78 °C
for 1.5 h. TMSCl
(2.14 g, 19.7 mmol, 1.5 equiv) was added and the
reaction
was allowed to warm to 0 °C in an ice bath
,
and
further
stirred at
0 °C
for 1 h.
The reaction
flask
was then
wrapped in Al foil to exclude
light and NBS (3.5
g, 19.7 mmol, 1.5 equiv
) was added in
a single
portion. After stirring for a further 30 min
in the dark,
the
reaction
was
quenched
*
with
saturated
aq. NaHCO
3
(50 mL)
and extracted with
Et
2
O
(2 x 20
mL
). The
combined organic layers were washed with water (2 x 40 mL) and
brine
(40 mL)
, dried over Na
2
SO
4
, and
filtered
. The solution was concentrated under reduced pressure
to yield 2.1 g of
residue
. A small amount of
this residue (255 mg) was
purified
via
flash chromatography on neutral alumina
(
hexanes
)
to yield
5
(
173
mg
,
e
xtrapolated to 48
%
overall yield
)
as
an unstable
straw
-
colored
oil which
crystallized when pure.
5
was
used immediately or stored as a frozen solution in
benzene.
1
H NMR (chloroform
-
d
, 400 MHz): δ =
4.37
(d,
J
= 1.2 Hz, 1H), 3.22 (ddq,
J
= 13.0, 7.7, 6.5 Hz, 1H), 2.45 (ddd,
J
= 14.7, 9.7, 7.6 Hz, 1H), 1.52 (dd,
J
= 8.6, 1.3 Hz, 1H), 1.40 (ddd,
J
= 14.8, 13.0, 4.3 Hz, 1H), 1.18 (td,
J
= 8.9, 4.2 Hz, 1H), 1.07 (s, 3H), 1.00
(d,
J
= 6.5 Hz, 3H), 0.84 (s, 3H)
;
13
C{
1
H} NMR (chloroform
-
d, 10
0
MHz): δ =
209.
7
, 48.
2
, 36.2, 33.
7
, 30.7,
28.2, 22.
2
, 20.
5
, 14.7, 14.
1
;
IR (Neat Film, NaCl)
2933, 1719, 1455, 1378, 1162, 848, 776, 622
cm
1
;
HRMS
(FI+):
m/z
calc’d for
C
10
H
15
OBr
[M
]
+
:
230.0301 found, 230.0308
;
[α]
D
22.16
278.99 (c 1.0, CHCl
3
)
.
*Due
to the light
-
sensitivity of the product, it is recommended to
perform the work
-
up in the dark
.
(4R,6R)
-
4
-
isopropyl
-
6
-
methylcyclohex
-
2
-
en
-
1
-
one (
1
0
)
. AIBN (
20
mg,
0.121
mmol, 0.2 equiv) was
loaded into a
20 mL vial with septum cap
.
A solution of
bromide
5
(
140
mg, 0.
606
mmol, 1.0 equiv) and
Bu
3
SnH (
353
mg,
1.21
mmol, 2
.0
equiv) in
anhydrous
benzene (
6
mL) was added. The reaction
mixture
was stirred at 86 °C for
1 h,
after which
the
solvent was removed under reduced pressure. The residue was
purified by flash chromatography on silica (
0
10
% EtOAc in hexanes) to afford
1
0
(
82
mg, 8
9
%)
as a
colorless oil.
The
resulting product
is pure enough for most purposes, but a sample of higher purity
for
analysis was
obtained by distillation.
1
H NMR (chloroform
-
d
, 400 MHz): δ = 6.82 (dt,
J
= 10.2, 2.2 Hz,
1H), 6.01 (dd,
J
= 10.2, 3.0 Hz, 1H), 2.
39
(
m
,
2
H), 1.96 (dtd,
J
= 13.0, 4.5, 2.0 Hz, 1H), 1.80 (pd,
J
= 6.9,
4.8 Hz, 1H), 1.54
1.49 (ddd,
J
= 13.9, 13.0, 11.4 Hz, 1H), 1.15 (d,
J
= 6.6, 3H), 0.96 (d,
J
= 7.1
,
3H), 0.94
(d,
J
= 6.9
,
3H);
13
C{
1
H} NMR (chloroform
-
d, 10
0
MHz): δ = 202.
7
, 153.
5
, 129.
7
, 43.5, 41.7, 34.
2
, 31.
8
,
19.
6
, 19.
3
, 15.2;
IR (Neat Film, NaCl) 2959, 2872, 1684, 1458, 1386, 1219, 803 cm
1
;
HRMS (FI+):
m/z
calc’d for
C
10
H
16
O
[M
]
+
:
152.1196 found
,
152.1198
; [α]
D
22.31
35.30 (c 1.0, CHCl
3
).
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
5
(4S,6R)
-
4
-
(2
-
bromopropan
-
2
-
yl)
-
6
-
methylcyclohex
-
2
-
en
-
1
-
one
(
13
)
.
To a 4 mL vial
was added
bromide
5
(36 mg, 0.156 mmol, 1.0 equiv) in
anhydrous
benzene (1.5 mL). To this
solution
was added allyltributyltin
(21 mg, 0.062 mmol, 0.4 equiv) and AIBN (5 mg, 0.03 mmol, 0.2 equiv). The vial was
sealed
,
and
the
reaction
mixture
stirred at 86 °C for 4 h. The
reaction was then allowed to cool to
20 °C
and
concentrated
under reduced
pressure
.
T
he residue
was
purified
via
flash chromatography
on silica
(
5
10% EtOAc in
hexanes
)
to
afford
1
3
(26 mg, 72%) as a colorless oil.
1
H NMR (chloroform
-
d
, 400 MHz): δ = 7.09 (dt,
J
=
10.3, 2.1 Hz, 1H), 6.09 (dd,
J
= 10.3, 2.8 Hz, 1H), 2.85 (dddd,
J
= 11.4, 4.6, 2.9, 2.0 Hz, 1H), 2.41 (dqd,
J
= 13.4, 6.7, 4.5 Hz, 1H), 2.24 (dtd,
J
= 12.7, 4.4, 2.2 Hz, 1H), 1.89 (s, 3H), 1.74 (s, 3H), 1.67
1.58 (m,
1H), 1.17 (d,
J
= 6.7 Hz, 3H);
13
C{
1
H} NMR (chloroform
-
d, 10
0
MHz):
δ = 201.3, 150.1, 130.2, 68.3, 50.
5
,
41.0, 34.2, 32.
9
, 30.9, 15.1;
IR (Neat Film, NaCl) 2967, 1682, 1455, 1372, 1213, 1125, 803, 644, 601 cm
1
;
HRMS (FI+):
m/z
calc’d for
C
10
H
15
OBr
[M
]
+
:
230.0301
,
found 230.0300
; [α]
D
22.13
62.67 (c 1.0, CHCl
3
).
(4S,6R)
-
6
-
methyl
-
4
-
(2
-
methylpent
-
4
-
en
-
2
-
yl)cyclohex
-
2
-
en
-
1
-
one
(
1
2
)
. To a
20
mL vial was added
bromide
1
3
(
45 mg, 0.195 mmol, 1.0 equiv
) in
anhydrous
benzene (
4
mL). To this was added allyltributyltin
(
390
mg,
1.17
mmol,
6
.0 equiv) and AIBN (
6.4
mg, 0.03
9
mmol, 0.2 equiv). The vial was sealed
,
and the
reaction
mixture
stirred at
86
°C for
48
h.
The solution was concentrated under reduced pressure and
the
residue
purified
via
flash chromatography
on silica
(
5% EtOAc in hexanes
) to afford
1
2
(
24
mg, 63%
) as a
colorless oil. The compound is pure enough for most purposes, but a sample of higher puri
ty for analysis
was obtained by preparatory HPLC
(
60
80% MeCN in H
2
O over 5 min at 12 mL/min
)
.
1
H NMR
(chloroform
-
d
, 400 MHz): δ =
6.96 (dt,
J
= 10.3, 2.1 Hz, 1H), 6.03 (dd,
J
= 10.3, 3.0 Hz, 1H), 5.83 (ddt,
J
= 16.8, 10.2, 7.4 Hz, 1H), 5.13
5.02 (m, 2H),
2.36
(m,
2
H), 2.11
2.06 (m, 2H), 2.03 (ddq,
J
= 11.0, 4.4,
2.2 Hz, 1H), 1.55
1.46 (m, 1H), 1.15 (d,
J
= 6.7 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 3H);
13
C{
1
H} NMR
(chloroform
-
d, 10
0
MHz): δ =
202.4, 151.7, 134
.
7
, 1
30.0
, 118.0, 45.7, 44.5, 41.
8
, 35.
7
, 33.
1
, 24.
9
, 24.6,
15.
3
;
IR (Neat Film, NaCl) 2961, 1683, 1385, 1222, 914, 802 cm
1
;
HRMS (FI+):
m/z
calc’d for
C
13
H
20
O
[M
]
+
:
192.1509
,
found 192.1509
; [α]
D
22.49
25.44 (c 0.25, CHCl
3
).
(S)
-
5
-
(2
-
bromopropan
-
2
-
yl)
-
2
-
methylcyclohex
-
2
-
en
-
1
-
one (
1
4
)
.
To a 4 mL vial was added
bromide
5
(86
mg, 0.372 mmol, 1.0 equiv) in anhydrous benzene (1.6 mL). The vial was sealed
,
and the reaction
mixture
stirred at 86 °C
for 25 min.
The solution was concen
trated under reduced pressure
and
the residue was
purified by flash chromatography
on neutral alumina
(
5% EtOAc in
hexanes)
to afford
1
4
(
63
mg,
73
%) as
a colorless oil.
1
H NMR (chloroform
-
d
, 400 MHz): δ = 6.75 (ddq,
J
= 5.4, 2.8, 1.4 Hz, 1H), 2.74 (ddd,
J
=
16.0, 3.7, 1.8 Hz, 1H), 2.59 (dddt,
J
= 18.2, 6.2, 4.6, 1.5 Hz, 1H), 2.41 (
m
,
2
H), 2.05 (dddd,
J
= 13.5, 11.1,
4.6, 3.7 Hz, 1H), 1.79 (m, 3H), 1.79 (s, 3H), 1.77 (s, 3H)
;
13
C{
1
H} NMR (chloroform
-
d, 10
0
MHz): δ =
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
6
199.2, 144.3, 135.4, 70.1, 48.3, 41.2, 32.
5
, 32.
2
, 29.
2
, 15.7
;
IR (Neat Film, NaCl)
2972, 1674, 1451, 1370,
1254, 1103, 1062, 904, 690
cm
1
;
HRMS (FI+):
m/z
calc’d for
C
10
H
15
OBr
[M
]
+
:
230.0301
,
found 230.0302
.
14
was determined to be racemic by chiral SFC analysis (AD
-
H, EtOH/CO
2
=
5
/95, flow rate =
3.5
mL/min,
= 210 nm) t
R
= 3.39, 3.95.
Procedure for the Ag
I
mediated fragmentation of bromide
5
.
To a solution of the indicated silver salt (0.182 mmol, 2.1 equiv) in THF (0.6 mL) was added a solution of
bromoketone
5
(20 mg, 0.0865 mmol, 1.0 equiv) in THF (0.3 mL, 0.1 M total concentration) dropwise
over
1
min
with stirring at 2
0
°C. In all cases, a
thick precipitate immediately formed. Stirring was continued for
an additional 20 min, after which the reaction mixture was quenched with saturated aq. NaHCO
3
(1 mL)
and filtered through
a plug of
celite with EtOAc. The layers were
separated
and the organi
c layer was dried
with Na
2
SO
4
,
filtered
,
and
concentrated
under reduced pressure to provide a crude product that was purified
by silica gel flash chromatography
(5% EtOAc
in
hexanes)
.
(R)
-
6
-
methyl
-
4
-
(propan
-
2
-
ylidene)cyclohex
-
2
-
en
-
1
-
one
(
7
)
.
8.
7
mg (67
%
)
yield with AgClO
4
;
7.1 mg
(
55%
)
yield with AgOTf;
1
H NMR (
chloroform
-
d, 400 MHz
)
:
δ
=
7.42 (dd,
J
= 10.1, 0.9 Hz, 1H), 5.80 (d,
J
= 10.0 Hz, 1H), 2.84 (dd,
J
= 14.6, 5.4 Hz, 1H), 2.48 (dqd,
J
= 10.9, 6.8, 5.4 Hz, 1H), 2.39
2.27 (m,
1H), 1.93 (dd,
J
= 1.6, 0.8 Hz, 3H), 1.90 (s, 3H), 1.
14 (d,
J
= 6.8 Hz, 3H);
13
C
{
1
H}
NMR (
chloroform
-
d,
100 MHz
)
:
δ
=
203.0, 143.1, 139.4, 126.7, 124.0, 40.9, 34.1, 21.9, 20.8, 15.9
;
IR (Neat Film, NaCl) 2927,
1672, 1623, 1453, 1216, 812 cm
1
;
HRMS (F
I
+):
m/z
calc’d for C
10
H
1
4
O [M]
+
:
150.1039
, found
150.1039
;
[α]
D
21.95
+137.36 (c 0.5, CHCl
3
).
(4S,6R)
-
6
-
methyl
-
4
-
(prop
-
1
-
en
-
2
-
yl)cyclohex
-
2
-
en
-
1
-
one (
3
)
.
Isopropenyl enone
3
was observed in trace
quantities in the Ag
I
-
mediated fragmentation of bromide
5
. 0.7 mg (5% yield) with AgBF
4
.
A sample
suitable
for characterization, albeit containing a minor impurity,
could be obtained by automated silica gel
flash chromatography
(Teledyne ISCO, 0→10% EtOAc in hexanes)
on a 100 mg scale.
1
H NMR
Supporting Information for Samkian, Sercel,
Virgil
,
and Stoltz
S
7
(
chloroform
-
d, 400 MHz
): δ = 6.81 (dt,
J
= 10.1, 2.0 Hz, 1H
), 6.03 (dd,
J
= 10.1, 3.0 Hz, 1H), 4.86 (p,
J
=
1.5 Hz, 1H), 4.81 (dq,
J
= 1.6, 0.8 Hz, 1H), 3.21
3.12 (m, 1H), 2.42 (dqd,
J
= 13.5, 6.7, 4.5 Hz, 1H), 2.13
(dtd,
J
= 13.0, 4.5, 2.0 Hz, 1H), 1.77 (dd,
J
= 1.4, 0.9 Hz, 3H), 1.72
1.61 (m, 1H), 1.15 (d,
J
= 6.6 Hz,
3H);
13
C{
1
H} NMR (
chloroform
-
d, 100 MHz
): δ = 202.0, 152.5, 146.9, 129.6, 112.0, 45.2, 41.8, 37.7, 20.8,
15.1
;
IR (Neat Film, NaCl) 2964, 2934, 2862, 1683, 1649, 1454, 1376, 1215, 1188, 1118, 895, 804 cm
1
;
HRMS (FI+):
m/z
calc’d for C
10
H
1
4
O [M]
+
:
150.1039
, found
150.1030
;
[α]
D
21.23
92.59 (c 0.33, CHCl
3
).
(4S,6R)
-
4
-
(2
-
fluoropropan
-
2
-
yl)
-
6
-
methylcyclohex
-
2
-
en
-
1
-
one (
9
)
.
6.6 mg of a 3.4:1 (
w/w
) mixture of
fluoride
9
and dienone
7
was isolated, corresponding to a 35% yield of fluoride
9
. While this mixture was
inseparable by silica gel flash chromatography, an analytical sample of
9
was isolated by reverse
-
phase
preparative HPLC
(
50
70% MeCN in H
2
O over 3.5 min at 10 mL/min
)
;
1
H
NMR (
chloroform
-
d, 400 MHz
)
:
δ
=
6.96 (dt,
J
= 10.3, 2.0 Hz, 1H), 6.09 (dd,
J
= 10.3, 3.0 Hz, 1H), 2.88
2.75 (m, 1H), 2.41 (dqd,
J
= 13.5,
6.7, 4.6 Hz, 1H), 2.08 (dtdd,
J
= 12.8, 4.5, 2.1, 0.9 Hz, 1H), 1.53
1.45 (m, 1H), 1.42 (d,
J
= 22.0 Hz, 3H),
1.32
(d,
J
= 22.0 Hz, 3H), 1.16 (d,
J
= 6.7 Hz, 3H);
13
C
{
1
H}
NMR (
chloroform
-
d, 100 MHz
)
:
δ
=
201.6,
148.
9
, 148.8, 130.
5
, 97.3, 95.6, 47.
4
, 47.
2
, 41.3, 33.4, 33.
4
, 25.6, 25.
4
, 23.
7
, 23.4, 15.1
;
IR (Neat Film,
NaCl) 2930, 1682, 1453, 1376, 1219, 878, 812, 522 cm
1
;
HRMS (FI+):
m/z
calc’d for C
10
H
15
FO [M]
+
:
170.1101, found 170.1099;
[α]
D
21.82
37.10 (c 0.167, CHCl
3
).
(1R,6S)
-
4,4,7,7
-
tetramethylbicyclo[4.1.0]heptan
-
3
-
one
(
16
)
.
To a rapidly stirr
ed
suspension of NaH
(60% dispersion in mineral oil, 289 mg, 7.23 mmol, 1.1 equiv) in THF (
5
.6 mL, 1 M
final
substrate
concentration) in a 50 mL 2
-
neck flask equipped with a reflux condenser
was added ketone
2
(1.00 g, 6.57
mmol, 1.0 equiv) through the top o
f the condenser. Additional THF (1 mL) was used to rinse the ketone
into the reaction mixture. The suspension was then heated to reflux in an oil bath and stirred for 1.5 h. Then,
HMDS (0.21 mL, 0.986 mmol, 0.15 equiv) was added through the top of the cond
enser and the reaction
mixture was stirred under reflux for an additional 25 min. The flask was then cooled to 0 °C in an ice bath,
and the reflux condenser was replaced with a
septum.
MeI (0.45 mL, 7.23 mmol, 1.1 equiv) was added
dropwise, after which the
ice bath was
removed.
After stirring
at 20 °C for 17 h
, the reaction mixture was
quenched with H
2
O (20 mL), the layers were separated, and the aqueous layer was extracted with Et
2
O
(4x10 mL). The combined organic layers were dried over MgSO
4
, concentrated
under reduced pressure,
and purified
via
silica gel flash chromatography (10% Et
2
O in hexanes). The resulting oil was purified again
by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc in hexanes) to provide
dimethyl ketone
1
6
(361 mg
, 29% yield desired isomer
) as a fragrant,
co
lorless oil containing 1
1
% of an
inseparable
isomeric impurity
;
1
H NMR (
chloroform
-
d
, 400 MHz
)
:
δ
=
2.65
2.52 (m, 1H), 2.19
2.07
(m, 1H), 1.94 (ddt,
J
= 14.9, 9.3, 1.4 Hz, 1H), 1.39 (ddt,
J
= 14.9, 6.2, 0.9 Hz, 1H), 1.22 (s, 3H), 1.11
1.06
(m, 1H), 1.04 (s,
3
H), 0.94 (s,
3
H), 0.90
0.80 (m, 4H)
;
13
C
{
1
H}
NMR (
chloroform
-
d, 100 MHz
)
:
δ
=