of 64
S
1
Supporting Information
for
Formal total syntheses of classic natural product target
molecules via palladium
-
catalyzed enantioselective
alkylation
Yiyang Liu, Marc Liniger, Ryan M. McFadden, Jenny L. Roizen, Jacquie Malette, Corey M.
Reeves, Douglas C. Beh
enna, Masaki Seto, Jimin Kim, Justin T. Mohr, Scott C. Virgil and Brian
M. Stoltz*
Address: Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology
, 1200 E.
California Boulevard, Pasadena, CA, USA
Email: Brian M. Stoltz*
-
stoltz@caltech.edu
* Corresponding author
Experimental data, NMR spectra and X
-
ray data
Table of Contents
Experimental Procedures
................................
................................
................................
...........
S
2
Materials and Methods
................................
................................
................................
...........................
S
2
Syntheses of Compounds Related to Thujopsene
................................
................................
....................
S
3
Syntheses of Compounds Related to Quinic Acid
................................
................................
...................
S
8
Syntheses of Compounds Related to Dysidioli
de
................................
................................
....................
S
8
Syntheses of Compounds Related to Aspidospermine
................................
................................
..........
S
11
Syntheses of Compounds Related to Rhazinilam
................................
................................
..................
S
14
Syntheses of Compounds Related to Quebrachamine
................................
................................
..........
S
14
Syntheses of Compounds Related to Vincadifformine
................................
................................
..........
S
15
Methods for the Determination of Enantiomeric Excess
................................
................................
......
S
19
1
H and
13
C NMR Spectra
................................
................................
................................
.........
S
21
X
-
Ra
y Structure Determination
................................
................................
..............................
S
47
S
2
Experimental Procedures
Materials and Methods
Unless stated otherwise, reactions were conducted in flame
-
dried glassware under an
atmosphere of nitrogen using anhydrous solvents (either freshly
distilled or passed through
activated alumina columns). Chloroform, stabilized with ethanol, was stored in the dark over
oven
-
dried 4
Å molecular sieves. Absolute ethanol, methanol, and
N,N
-
dimethyl acetamide were
used as purchased. 2,2,6
-
Trimethylcyclohex
anone
(
16
)
was used as received. TMEDA and
i
Pr
2
NH
were distilled from CaH
2
. All other commercially obtained reagents were used as
received unless specified otherwise. (
S
)
-
t
-
Bu
-
PHOX ligand
(
S
)
-
5
was prepared according to
known methods.
1
Reaction temperat
ures were controlled using an IKAmag temperature
modulator. Thin
-
layer chromatography (TLC) was conducted with E. Merck silica gel 60 F254
pre
-
coated plates (0.25 mm) and visualized using UV at 254 nm,
p
-
anisaldehyde, potassium
permanganate, and iodine vap
or over sand. TLC data include
R
f
, eluent, and method of
visualization. ICN silica gel (particle size 0.032
0.063 mm), SilliaFlash P60 Academic silica gel
(0.040
0.063 mm), or Florisil (Aldrich) was used for flash column chromatography. Analytical
chiral
H
PLC analyses were performed with an Agilent 1100 Series HPLC using a chiralcel OD
or AD normal
-
phase column (250
×
4.6 mm) employing 2.0
3.0% ethanol in hexane isocratic
elution and a flow rate of 0.1 mL/min with visualization at 254
nm. Analytical chiral G
C analysis
was performed with an Agilent 6850 GC using a GT
-
A column (0.25
m
×
30.00
m) employing
an 80 °C isotherm and a flow rate of 1.0 mL/min.
1
H NMR spectra were recorded on a Varian
Mercury 300 (at 300 MHz) or a Varian Inova 500 (at 500 MHz) and are re
ported relative to the
residual solvent peak (
7.26 for CDCl
3
and
7.16 for C
6
D
6
). Data for
1
H NMR spectra are
reported as follows: chemical shift (
ppm), multiplicity, coupling constant (Hz),
2
and
S
3
integration.
13
C NMR spectra were recorded on a Varian Mercury 300 (at 75 MHz) or a Varian
Inova 500
(at 125 MHz) and are reported relative the residual solvent peak (
77.2 for CDCl
3
and
128.4 for C
6
D
6
). Data for
13
C NMR spectra are reported in terms of chemical shift, and
integration (where appropriate). IR spectra were recorded on a Perkin Elmer Spec
trum BXII
spectrometer and are reported in frequency of absorption (cm
-
1
). IR samples were thin films
deposited on sodium chloride plates by evaporation from a solvent (usually CDCl
3
), which is
recorded.
Optical rotations were measured with a Jasco P
-
1010
polarimeter, using a 100 mm
path
-
length cell.
High
-
resolution mass spectra were obtained from the California Institute of
Technology Mass Spectral Facility. Melting points were determined on a Thomas
-
Hoover
melting point apparatus and are uncorrected.
S
yntheses of Compounds Related to Thujopsene
Enol Carbonate 17
.
Preparation and characterization of this compound was reported in our
previous publication.
3
S
4
Allyl Ketone (
)
-
18
. A round bottom flask was flame
-
dried under argon and cycled into the
glove
box. It was charged with
[
Pd
2
(dba)
3
]
(242 mg, 0.264 mmol, 6.25 mol%) and (
S
)
-
t
-
Bu
-
PHOX (
(S)
-
5
)(256 mg, 0.661 mmol, 2.5 mol%). Then, THF (317 mL) was introduced. The red
mixture was stirred for 20 min at 25 °C. Then, enol carbonate
17
(2.37 g, 10.57 mmol, 1
.00
equiv) in THF (10 mL) was added. After the reaction was gauged complete using TLC analysis,
it was removed from the glovebox, then concentrated. PhH (~20 mL) was added. After
concentrating a second time, more PhH (~20 mL) was added. The solution was pu
rified by flash
chromatography on silica gel (2:98 Et
2
O/hexane eluent), affording allyl ketone
(
)
-
18
(1.72 g,
94% yield) as a clear oil in 91% ee as determined by chiral HPLC analysis. R
f
0.48 (1:9
EtOAc/hexane), (I
2
/sand, brown spot);
1
H NMR (300 MHz, C
DCl
3
):

(dddd,
J
= 17.1 Hz,
10.5 Hz, 7.7 Hz, 6.9 Hz, 1H), 5.05 (app. ddt,
J
d1
= 6.3 Hz,
J
d2
= 2.2 Hz,
J
t
= 1.1 Hz, 1H), 4.98
(app. ddt,
J
d1
= 13.8 Hz,
J
d2
= 2.5 Hz,
J
t
= 1.4 Hz, 1H), 2.32 (app. ddt,
J
d1
= 13.8 Hz,
J
d2
= 6.9
Hz,
J
t
= 1.4 Hz, 1H), 2.16
(app. ddt,
J
d1
= 13.8 Hz,
J
d2
= 6.9 Hz,
J
t
= 1.4 Hz, 1H) 1.87
1.47 (m,
6H), 1.15 (s, 3H), 1.09 (s, 3H), 1.08 (s, 3H);
13
C NMR (75 MHz, CDCl
3
):
219.8, 134.7, 118.0,
47.7, 44.6, 44.0, 39.9, 37.0, 28.0, 27.3, 25.7, 17.9; IR (NaCl/CDCl
3
): 3077, 2979, 2964,
2933,
2869, 1697, 1463, 1382, 999, 914 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for C
12
H
20
O, 180.1514;
found, 180.1506; [
]
D
24
36.3° (
c
0.140, CHCl
3
), 91% ee.
For literature data see [3,5].
Alcohols 19A
and
19B
. A round
-
bottom flask was charged with a solutio
n of allyl ketone
(
)
-
18
(1.02 g, 5.65 mmol, 1.00 equiv, 91% ee) and THF (55.5 mL). Then, methyl magnesium bromide
S
5
(3.0 M in Et
2
O, 9.25 mL, 27.8 mmol, 5.00 equiv) was gradually introduced at 23 °C. After 24 h,
the reaction was carefully quenched at 0 °C wi
th sat. aq NH
4
Cl (30 mL). Then H
2
O (50 mL) was
added, along with hexanes (50 mL). The biphasic mixture was extracted with Et
2
O (2 x 30 mL).
All organic layers were combined, dried (Na
2
SO
4
), filtered, and concentrated. The wet residue
was taken up in CHCl
3
and dried again with Na
2
SO
4
, then filtered. The filtrate was concentrated,
giving a 1:1 mixture of diastereomeric alcohols
19A
and
19B
(1.04 g, 94% yield) as a colorless
oil. R
f
0.59 (10:90 EtOAc/hexane), (
p
-
Anisaldehyde, violet spot);
1
H NMR (300 MHz, CDC
l
3
)
(both diastereomers):
5.84 (app. dddd,
J
= 19.4 Hz, 14.6 Hz, 7.4 Hz, 7.2 Hz, 2H), 5.01 (app. d,
J
= 11.1 Hz, 2H), 5.00 (app. d,
J
= 14.6 Hz, 2H), 2.44 (app. ddd,
J
= 12.6 Hz, 11.1 Hz, 7.5 Hz,
2H), 2.07 (app. ddd,
J
= 19.4 Hz, 13.6 Hz, 7.7 Hz, 2H), 1.62
1.46 (m, 4H), 1.44
1.36
(m, 4H),
1.28
1.10 (m, 2H), 1.14 (app. s, 6H), 1.07 (s, 3H), 1.06 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H), 0.98
0.86 (m, 2H), 0.97 (s, 3H), 0.95 (s, 3H);
13
C NMR (75 MHz, CDCl
3
) (both diastereomers):
136.8, 136.4, 117.0, 116.8, 78.2, 77.9, 43.8, 42.0, 41.6,
41.2, 39.2, 39.0, 37.2, 36.9, 33.6, 33.0,
28.3, 28.2, 26.6, 25.8, 22.9, 22.2, 18.6, 18.5, 18.3, 18.1; IR (NaCl/CDCl
3
): 3504 (broad), 3074,
2930, 2867, 1638, 1454, 1378, 1305, 1071, 998, 910 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for
C
13
H
24
O, 196.1827; found, 1
96.1803.
Methylene
c
yclohexane (
)
-
20
. A
20 mL
scintillation
vial
containing a mixture of
diastereomeric alcohols
19A
and
19B
(
72
mg, 0.367
mmol, 1.00 equiv, 91% ee) was treated with
a solution of 9
-
b
orabicyclo[3.3.1]nonane
in THF
(
0.5
M,
0.90
mL,
0.45
mmol,
1.23
equiv)
at 23
S
6
°C
. The reaction was stirred for
2.5
h. Then the reaction was cooled to 0 °C, and H
2
O (
1
mL)
was carefully added, followed by NaBO
3
4H
2
O (
219
g,
1.42
mmol,
3.88
equiv). The biphasic
reaction
mixture
was stirred vigorously at 23 °C f
or
2
h
,
diluted with
water
,
and extracted with
CH
2
Cl
2
(4
x
1
mL). All organic layers were combined, dried (Na
2
SO
4
), filtered, and
concentrated.
The residue
was purified by flash chromatography on silica gel (
25
:
75
EtOAc:hexane
33
:
67
EtOAc:hexane
50:50
EtOAc:hexane eluent), giving an oil containing
two diastereomeric products, which was immediately used in the next reaction.
This mixture was transferred to a
20 mL
scintillation
vial.
I
midazole (
39
mg,
0.57
mmol)
,
4
-
dimethylaminopyridine (1 mg, 0.00885 mm
ol), and
anhydrous
CH
2
Cl
2
(1
.0
mL) were
introduced, followed by a solution of TBSCl (
48
mg,
0.314
mmol) in anhydrous
CH
2
Cl
2
(1
.0
mL) at 23 °C.
A white precipitate quickly formed.
After
10 min
, the reaction was diluted with
hexanes
(
4
mL
),
filtered, and con
centrated. The residue was purified by flash chromatography on
silica gel (
5:95
EtOAc:hexane eluent), affording a diastereomeric mixture of silyl ethers. This
composite was carried on to the next reaction without further characterization.
The mixture of si
lyl ethers was transferred to a
20 mL scintillation vial
, which was
charged with pyridine (freshly distilled from CaH
2
,
1.5
mL). After cooling to 0 °C, SOCl
2
(
36
L,
0.50
mmol) was slowly introduced. After
stirring
1 h
at 0 °C and another 1 h at 23 °C
, H
2
O
(
5
mL) was carefully added, followed by Et
2
O (
8
mL). The organic phase was collected, and the
aqueous layer was extracted with Et
2
O (2 x
10
mL). A
ll organic laye
rs were combined and
washed with 1.0 M aq CuSO
4
(
4
x
5 mL). The aqueous washings were back
-
extracted with Et
2
O
(1 x 10 mL).
All organic layers were combined,
dried (Na
2
SO
4
), filtered, and concentrated. The
residue was purified by flash chromatography on si
lica gel (1:99 Et
2
O:hexane
2
:
98
Et
2
O:hexane eluent), giving pure methylene cyclohexane
(
)
-
20
(
48
mg,
42
% yield from
19A
S
7
and
19B
) as a colorless oil. R
f
0.71 (10:90 EtOAc/hexane), (
p
-
Anisaldehyde, blue spot);
1
H
NMR (300 MHz, CDCl
3
):
5.00 (app. s, 1H), 4.79 (app. s, 1H), 3.57 (app. t,
J
= 6.6 Hz, 2H),
1.80
1.64 (m, 2H), 1.62
1.16 (m, 8H), 1.11 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.89 (s, 9H), 0.04
(s, 6H);
13
C NMR (75 MHz, CDCl
3
):
160.5, 108.7, 64.1, 41.8, 40.8, 39.4, 36.6, 36.5,
32.8,
29.9, 29.8, 28.4, 26.2 (3C), 18.7, 18.6, 5.0 (2C); IR (NaCl/CDCl
3
): 3100, 2955, 2929, 2858,
1623, 1472, 1382, 1361, 1255, 1100, 940, 900, 836, 774 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for
C
19
H
38
SiO, 310.2692; found, 310.2689. [
]
D
24
18.8° (
c
1.90, CHCl
3
), 91% ee.
Carboxylic Acid
(
)
-
12
. A vessel containing methylene cyclohexane
(
)
-
20
(
48
mg, 0.
154
mmol) was charged with acetone (ACS grade,
2.5
mL), then treated with Jones reagent (1.0 M
CrO
3
, 4.0 H
2
SO
4
in H
2
O)(1.0 mL, dropwise from a
glass pipet) at
23 °C. After 15
min, the
reaction was carefully quenched with sat. aq Na
2
SO
3
(2 mL). CHCl
3
(
5
mL) was added, followed
by
H
2
O (5 mL) and
6 M aq HCl (
4
mL). After
5
min, the reaction was extracted with CHCl
3
(3 x
10
mL). All organic layers were combined, dr
ied (Na
2
SO
4
), filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (
6:94 Et
2
O
:
CH
2
Cl
2
14:86
Et
2
O:CH
2
Cl
2
eluent), giving carboxylic acid
(
)
-
12
(
21
mg,
65
% yield) as a colorless oil. R
f
0.17
(10:90 EtOAc/hexane), (
p
-
An
isaldehyde, blue spot);
1
H NMR (300 MHz, CDCl
3
):
5.06 (app. s,
1H), 4.80 (app. s, 1H), 2.36
2.04 (m, 3H), 1.82
1.66 (m, 2H), 1.60
1.30 (m, 5H), 1.11 (s, 3H),
1.10 (s, 3H), 1.05 (s, 3H);
13
C NMR (75 MHz, CDCl
3
):
159.3, 109.6, 41.5, 40.6, 39.2, 36.5,
34.7, 32.7, 29.61, 29.56, 18.6; IR (NaCl/CDCl
3
): 300
0 (broad), 2927, 1708, 1462, 1414, 1380,
S
8
1296, 1095, 902 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for C
13
H
22
O, 210.1620; found, 210.1618.
[
]
D
24
27.8° (
c
1.205, CHCl
3
), 91% ee.
Syntheses
of Compounds Related to Quinic Acid
Preparation and characterization of t
hese compounds was reported in
our previous publication.
4
Syntheses of Compounds Related to Dysidiolide
Keto
-
Enone 34
.
5
A vial was charged with allyl ketone
2
(45.2 mg, 0.297 mmol, 1.0 equiv, 98%
ee), followed by a solution of methyl vinyl ketone (61.8
L, 0.743 mmol, 2.5 equiv) in 1,2
-
dichloroethane (1.5 mL). Then, Grubbs 2
nd
generation catalyst (12.6 mg, 14.9
mol, 5 mol%)
was added. The vessel was sealed and warmed to 55 °C for 24 h. The reaction transitioned from
maroon to deep green. The reaction wa
s cooled to 23 °C and concentrated. The residue was
purified by flash chromatography on silica gel (hexane
20:80 EtOAc:hexane eluent), giving
keto
-
enone
34
(35.7 mg, 62% yield) as a pale brown oil. R
f
0.23 (20:80 EtOAc/hexane), (UV,
254 nm);
1
H NMR (300
MHz, CDCl
3
):
6.70 (app. dt,
J
d
= 15.9 Hz,
J
t
= 7.4 Hz, 1H), 6.03 (app.
d,
J
= 15.9 Hz, 1H), 2.50
2.26 (m, 2H), 2.40 (app. d,
J
= 6.9 Hz, 1H), 2.39 (app. d,
J
= 6.9 Hz,
1H), 2.22 (s, 3H), 1.91
1.81 (m, 2H), 1.80
1.60 (m, 4H), 1.12 (s, 3H);
13
C NMR (75 MHz,
CDCl
3
):
2
14.6, 198.4, 144.1, 134.2, 48.7, 41.0, 38.9, 38.7, 27.4, 26.9, 23.1, 21.1; IR
S
9
(NaCl/CDCl
3
): 2935, 2866, 1704, 1672, 1626, 1426, 1361, 1254, 1124, 986 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for C
12
H
18
O
2
, 194.1307; found, 194.1336. [
]
D
22
1.14° (
c
1.415, CHCl
3
),
98% ee.
Diketone 35
.
5
A round
-
bottom flask containing keto
-
enone
34
(28.0 mg, 0.144 mmol, 1.0 equiv)
in EtOAc (3.0 mL) was sparged with argon for 2 min. Pd/C (10% w/w) (30.6 mg, 28.8
mol, 20
mol) was introduced, and the r
eaction was cooled to
78 °C. It was purged/backfilled with
vacuum/H
2
(1 atm) (3 x) and warmed to 23 °C and stirred under H
2
(1 atm) for 12 h. More
EtOAc (5 mL) was added, and the reaction was sparged with argon to remove residual H
2
. The
material was filt
ered through a plug of silica gel with the aide of EtOAc. The filtrate was
concentrated, affording diketone
35
(17.3 mg, 61% yield) as a pale yellow oil. R
f
0.26 (20:80
EtOAc/hexane), (
p
-
Anisaldehyde, peach spot);
1
H NMR (300 MHz, CDCl
3
):
2.40 (app. t,
J
=
6.6 Hz, 2H), 2.36 (app. t,
J
= 5.5 Hz, 2H), 2.11 (s, 3H), 1.90
1.44 (m, 9H), 1.36 (app. d,
J
= 7.7
Hz, 1H), 1.15 (s, 3H);
13
C NMR (75 MHz, CDCl
3
):
216.0, 208.8, 48.6, 44.0, 39.2, 38.9, 37.0,
30.1, 27.6, 22.7, 21.2, 18.2; IR (NaCl/CDCl
3
): 2936, 2865, 1705, 1452, 1360, 1167, 1123, 1099
cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for C
12
H
20
O
2
, 196.1463; found, 196.1469. [
]
D
22
42.3° (
c
0.865, CHCl
3
), 98% ee.
S
10
Keto
-
Olefin 32
. A round
-
bottom flask was charged with methyl triphenyl phosphonium brom
ide
(weighed in glovebox, 260 mg, 0.688 mmol, 5.0 equiv). THF (5.5 mL) was introduced, followed
by
n
-
BuLi (2.5 M in hexane, 165
L, 0.413 mmol, 3.0 equiv) at 23
C. After stirring for 1 h, a
solution of diketone
35
(27.0 mg, 0.138 mmol, 1.0 equiv) in THF (
2.0 mL) was added. 30 min
later, the reaction was quenched with sat. aq NH
4
Cl (4.0 mL). Then, the reaction was diluted
with H
2
O (20 mL) and hexane (15 mL). The biphasic mixture was extracted with EtOAc (4 x 20
mL). All organic layers were combined, dried (
Na
2
SO
4
), filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (hexane
2:98 EtOAc:hexane eluent),
giving keto
-
olefin
32
(17.3 mg, 65% yield) as a colorless oil. R
f
0.75 (20:80 EtOAc/hexane), (
p
-
Anisaldehyde, blue spot
);
1
H NMR (300 MHz, CDCl
3
):
4.70 (app. s, 1H), 4.65 (app. s, 1H),
2.46
2.26 (m, 2H), 1.98 (app. t,
J
= 7.1 Hz, 2H), 1.94
1.84 (m, 1H), 1.82
1.50 (m, 5H), 1.68 (s,
3H), 1.47
1.39 (m, 1H), 1.38 (app. ddd,
J
= 26.4 Hz, 12.6 Hz, 4.1 Hz, 1H), 1.22
1.10 (m, 2H
),
1.14 (s, 3H);
13
C NMR (75 MHz, CDCl
3
):
216.3, 145.7, 110.3, 48.7, 39.6, 39.0, 38.4, 37.2,
27.7, 22.8, 22.5, 21.7, 21.2; IR (NaCl/CDCl
3
): 3074, 2936, 2865, 1707, 1650, 1452, 1376, 1260,
1096, 1020, 886, 804 cm
-
1
; HRMS
-
EI
+
(
m/z
): [M]
+
calc’d for C
13
H
22
O
, 194.1671; found,
194.1680. [
]
D
21
49.8° (
c
0.865, CHCl
3
), 98% ee.
Lit
erature
optical rotation
: [
]
D
25
55.2
° (
c
0.
2
5, CHCl
3
)
.
6
S
11
Syntheses of Compounds Related to Aspidospermine

Ethyl

Allyloxycarbonyl Vinylogous Ester 42
. A round
-
bottom flask was
flamedried
under argon and charged with dry PhMe (320 mL). Then,
i
Pr
2
NH (12.81 mL, 91.3 mmol, 2.05
equiv) was introduced. The reaction was cooled to
78 °C, and
n
-
BuLi (2.5 M in hexane, 35.68
mL, 89.2 mmol, 2.00 equiv) was added slowly. The reaction was w
armed to 0 °C for 15 min,
then promptly cooled back to
78 °C. Then, a solution of vinylogous acid
41
(7.50 g, 44.6
mmol, 1.00 equiv) in PhMe (20 mL) was added at
78 °C over a 5 min period. After 40 min had
passed, the reaction was treated with allyl chl
oroformate (4.97 mL, 46.8 mmol, 1.05 equiv) over
a 5 min timeframe at
78 °C. After 15 min, the reaction was warmed to 23 °C and stirred for 1 h,
during which the reaction went from yellow to orange. Then, 1.0 M aq KHSO
4
(127 mL) was
added with vigorous st
irring, causing the reaction to turn yellow. The organic phase was
collected. The aqueous layer was extracted with Et
2
O (2 x 50 mL). All organic layers were
combined, dried (Na
2
SO
4
), filtered, and concentrated, giving a crude
allyloxycarbonyl
vinylogous ester as an orange oil, which was immediately used in the next reaction.
A round
-
bottom flask containing the crude vinylogous ester was charged with CH
3
CN
(45 mL), followed by iodoethane (14.26 mL, 178.4 mmol, 4.0 equiv relat
ive to
41
)
. Anhydrous
Cs
2
CO
3
(29.06 g, 89.2 mmol, 2.0 equiv relative to
41
) was introduced, and the reaction was
stirred vigorously at 65 °C for 12 h. The reaction was cooled to 23 °C and filtered over glass
frits. The filtrate was concentrated in vacuo, an
d the residue was purified by flash column
chromatography on silica gel (hexane
15:85 EtOAc:hexane eluent), giving semipure
42
. The