Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A "visible Light" Approach

Article abstract of DOI:10.1021/acs.joc.7b02807

In our continued effort to address the challenges of selective sp³ C-H fluorination on complex molecules, we report a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensitized approach is mild, simple to set up, and an economical alternative to our previous protocol based on direct excitation using UV light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary evidence for electron-transfer processes are highlighted.

Full text of DOI:10.1021/acs.joc.7b02807

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Sensitized Aliphatic Fluorination Directed by
Terpenoidal Enones: A "Visible Light" Approach
Desta Doro Bume, Stefan Andrew Harry, Cody Ross Pitts, and Thomas Lectka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02807 • Publication Date (Web): 02 Jan 2018
Downloaded from http://pubs.acs.org on January 3, 2018
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The Journal of Organic Chemistry
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Sensitized Aliphatic Fluorination Directed by Terpenoidal Enones: A
"Visible Light" Approach
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Desta Doro Bume, Stefan Andrew Harry, Cody Ross Pitts, and Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, United States
Supporting Information Placeholder
enone-directed fluorination of complex molecules
compatible with continuous-flow conditions
O
F
R
cat.
O
X
O
F
O
Ph
Ph
or
O
Selectfluor
visible light
X = H or CH2R
selectivity for β- and γ-positions
LEDs
ABSTRACT: In our continued effort to address the challenges of selective sp3 C–H fluorination on complex molecules, we report
a sensitized aliphatic fluorination directed by terpenoidal enones using catalytic benzil and visible light (white LEDs). This sensi-
tized approach is mild, simple to set up, and an economical alternative to our earlier protocol based on direct excitation using UV-
light in a specialized apparatus. Additionally, the amenability of this protocol to photochemical flow conditions and preliminary
evidence for electron transfer processes are highlighted.
fluorination,1,7 β-fluorination of amino acid derivatives has
Organic photosensitization can play a powerful role in mak-
ing ultraviolet light-driven synthetic methods amenable to
safe, inexpensive, and more accessible "visible light" proto-
cols. What is more, developing an alternative visible light
approach allows for milder reaction conditions that are often
accompanied by increases in yields and/or selectivity. In our
laboratory, we recently developed a site-selective fluorination
of polycyclic terpenoids directed by enones under 300 nm
irradiation (provided by a Rayonet reactor).1 Although the
selectivity of this sp3 C-H fluorination reaction is remarkable
given the complexity of the substrate scope, the product yields
are moderate (38-72%), and the reaction is only accessible to
laboratories that possess a dedicated ultraviolet light source.
Ostensibly, this protocol could benefit from an alternative
approach in order to make enone-directed fluorination more
widely used. Accordingly, we now report an enone-directed
β- and γ-fluorination of complex terpenoids using visible light
(provided by white LEDs) and a catalytic amount of benzil.
Not only does this protocol avoid the costs and hazards associ-
ated with ultraviolet light, but also it 1) affords significantly
higher product yields (68-94 %), 2) maintains (or, in some
cases, improves) selectivity, 3) allows for easier scalability,
and 4) can be adapted to multiple setups, including a visible
light continuous flow apparatus. Thus, we believe this to be a
more practical approach than our earlier report (Figure 1).
Directed sp3 C–H fluorination methods on complex struc-
tures are still scarce in the literature. While various methods
using transition metal catalysts,2 radical initiators,3 photosensi-
tizers,4 and organic molecules5 have been reported to effect
aliphatic fluorination,6 guiding selective fluorination on com-
plex molecules through functional groups remains a synthetic
challenge. Thus, the few existing methods to date are notable.
Outside of our recent reports on enone- and ketone-directed
also been achieved using chelating auxiliaries and palladium
catalysis.8 Following our initial success with a sensitized ap-
proach to ketone-directed fluorination, we asked if a similar
protocol could be developed for enones.
previous work
ultraviolet irradiation
70% yield
OAc
OAc
Me
Me
Me
H
Me
H
H
H
H
H
H
F
AcO
O
AcO
O
this work
visible light sensitization
94% yield
Figure 1. Direct excitation vs. visible light-sensitized enone-
directed fluorination.
Thus, we screened various photosensitizers that absorb light
above 400 nm9 using white LED lamps (with a sharp absorb-
ance cut-off around 400 nm) on steroidal enone test substrate
1. This wavelength avoids direct excitation of enone sub-
strates that have an absorbance around 365 nm. Although
many photosensitizers effected the reaction, we found that 10
mol % benzil and 2.0 equiv. of Selectfluor in MeCN under N2
atmosphere afforded fluorinated compound 2 in 94% yield in
14 h (Table 1). The yield was not increased with greater sen-
sitizer loadings, and no fluorinated products were observed
upon irradiation without a photosensitizer. Furthermore, ei-
ther higher or lower equivalents of Selectfluor resulted in di-
minished yields, and other N-F reagents (e.g. NFSI and N-
fluoropyridinium tetrafluoroborate) did not furnish desired
fluorinated products. In addition, heating compound 1 and
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Page 2 of 13
Selectfluor in MeCN did not afford 2, only minor unidentified With optimized conditions in hand, we investigated fluori-
1
2
3
4
5
6
secondary fluorinated products.
nation of the easily (synthetically) accessible and important
class of steroidal substrates whereby an enone is poised to
direct fluorination on the C15 position (compounds 2-7)
through a six-membered transition state (Table 2). These
compounds are derivatives of common, biologically-active
steroids (e.g. testosterone, cholesterol,
Table 1. Screening for an optimal visible light sensitizer.
OAc
OAc
Me
Me
Selectfluor (2.0 equiv)
sensitizer (10 mol%)
Me
H
Me
H
7
8
9
progesterone, androsterone, pregnenolone, etc.).10,11 In all
cases, selective fluorination was observed at the predicted site
in high yields, wherein the α-isomer is slightly favored over
the β-counterpart.
white LEDs
MeCN, 14 h
H
H
H
H
F
1
2
AcO
O
AcO
O
19F NMR yield (%)
entry
sensitizer
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11
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-
0
1
2
3
4,4-difluoro benzil
9-fluorenone
67
47
As a testament to the mild nature of this reaction, a second-
ary aliphatic chloride substituent is tolerated on the cholesterol
derivative (compound 3). In another example, the fluorination
is compatible with an amide group, i.e. compound 5 derived
from dehydroepiandrosterone (one of the most abundant ster-
oids in humans12). Notably, electron-withdrawing groups can-
not be placed in close proximity to the fluorination site (less
than 3 carbon atoms away), as the reaction is completely shut
down; we have attributed this previously to the polar effect.13
In order to access the C11 position on the steroidal core, we
synthesized the starting material for compound 8 from 4-
cholesten-3-one (a precursor of 7α-hydroxycholesterol - an
4
5
2-chlorothioxanthone
dibenzosuberenone
73
55
9,10-phenanthrenequinone
6
64
benzil
94
7
8
9
methyl benzoylformate
2,7-dichloro-9-fluorenone
2-bromo-9-fluorenone
89
71
10
43
Substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), and benzil
(0.025 mmol, 10 mol%) were dissolved in MeCN (4.0 mL) and irradiated with cool
white LEDs for 14 h.
Table 2. Substrate scope of enone-directed fluorination in complex terpenoids.
Yield (%)
Yield (%)
Product
d.r.
Product
d.r.
OAc
C8H17
Me
Me
Me
H
Me
H
H
94
1.4:1
75
1.2:1
H
H
H
2
3
F
F
70
[300 nm]
AcO
O
Cl
O
O
AcO
Me
Me
HN
CF3
Me
Me
H
H
Me
Me
H
74a
1.5:1
1.8:1
1:1
87
1.5:1
1.8:1
>10:1
H
H
H
4
F
COMe
5
F
AcO
O
AcO
O
COOMe
Me
Me
Me
H
H
H
H
81
68
51
[300 nm]
H
H
H
H
6
F
7
F
O
O
AcO
O
C8H17
Me
Me Me
COMe
F
Me
O
Me
Ph
74a
Me
Me
H
75
8
9
H
42
[300 nm]
F
68
[gram scale]
H
H
Me
H
O
O
F
O
Me
F
Me
Me
Me
H
H
70
5.5:1
82a
1.6:1
H
H
10
11
60
[300 nm]
72
[300 nm]
H
H
AcO
H
O
Me COOMe
Me Me
Me
H
O
O
F
F
Me
Me
Me
Me
H
COOMe
81a
4.8:1
71
57
[300 nm]
4.9:1
72
[300 nm]
H
Me
H
Me
12
13
AcO
AcO
H
H
Me Me
Me Me
Unless otherwise specified, the substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), and benzil (0.025 mmol 10 mol%) were
stirred in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h. Yields include both diastereomers and were determined by integration
of 19F NMR signals relative to an internal standard and confirmed by isolation of products through column chromatography on silica gel. Major
diastereomer (with respect to C-F bond) depicted where known. aYield based on recovered starting material.
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intermediate in bile acid synthesis14) with the enone positioned
at C1. Gratifyingly, we achieved C11 fluorination in good
yield, regioselectivity, and diastereoselectivity (>10:1 ratio of
α:β).
2). Analogs of these compounds have been tested as potential
anti-HIV,18 anticancer,19 anti-inflammatory,20 and anti-HCV21
agents. Efficient monofluorination of these compounds repre-
sents a significant leap forward in selective, radical-based
aliphatic fluorination chemistry.
1
2
3
4
Beyond enones that target γ-positions, we also explored
enones poised for β-fluorination. We synthesized two candi-
dates that afforded selectively β-fluorinated products in yields
up to 75% (9 and 10). Compound 10 represents a D-ring ex-
panded enone (example of D-homo steroids that have been
studied for various pharmacological activities15) that provides
C12 fluorination in 70% yield with >5:1 ratio of α:β isomers.
In another case, we synthesized C2-functionalized progester-
one to direct benzylic fluorination (9). We observed a compa-
rable yield (68%) on a gram scale, demonstrating the amena-
bility of this procedure to larger scale syntheses. It is worth
noting that ethylbenzene does not fluorinate under identical
conditions, thus accentuating the necessary role of the enone.
As demonstrated on compounds 7 and 9, substrates contain-
ing ketones are compatible. However, substrates whereby
ketones can access either β- or γ-hydrogen atoms (for competi-
tive fluorination) should be avoided. As a case in point, ~10%
yield of fluorinated products at C12 and C16 were detected by
19F NMR analyses of compounds containing C20 exocyclic
ketones (Figure 2). Previously, we established that compound
14 affords C12 and C16 fluorinated products in a 55% total
yield using similar reaction conditions,7 but in compounds 7
and 9, it is clear the more rigid enone is the more effective
director.
Another type of enone we had not previously explored is the
exocyclic enone (e.g. 11, which is also shown to have an anti-
leukemic effect16). Although the diminished rigidity is not
ideal, one can imagine circumstances where an exocyclic
enone could have a regioselectivity advantage over an exocy-
clic ketone. Consider ketone 14 (directing both C12 and C16
fluorination). In comparison, exocyclic enone 11 blocks β-
fluorination at C16, allowing selective fluorination instead at
C12 – the minor isomer when employing the ketone-directed
approach (Figure 2).
In comparison to our 300 nm light protocol, the mild nature
of this reaction reduced the number of minor unidentified by-
products. Consequently, significant improvements in yield
were observed (300 nm yields are highlighted in Table 2). In
addition to being safer and cost-effective, improved chemical
yields (e.g. nearly double the yield for 8) make this protocol
substantially more attractive than the ultraviolet light ap-
proach.
Additionally, we imagined ways to make the reaction ame-
nable to photochemical continuous flow apparatuses that carry
advantages of scalability, simplicity, and time efficiency.
Microflow reactors have a clear advantage over standard
glassware in photochemical reactions due to an immense in-
crease in surface area (more light penetrates the reaction mix-
ture). Using a simple setup, we found that fluorination is read-
ily adaptable to flow conditions. Our reactor required ca. 7.5
m of FEP tubing (ID 1.6 mm, OD 3.2 mm) coiled around a
Pyrex beaker, a chemical resistant Luer lock syringe adapter,
and a syringe pump. When this configuration is surrounded
by six 72-LED work light sources (Designers Edge L1923)
and wrapped with aluminum foil, we found similar yields to
the standard reaction conditions after only 4 h (Figure 3).
Alternatively, this configuration can be placed inside a Ray-
onet reactor for 300 nm irradiation, and similar yields to our
previous protocol are achieved after only 1 h.
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compatible with continuous-flow conditions
(using Rayonet reactor or LEDs)
A
B
compact fluorescent light (CFL)
as alternative "visible light"
source in direct excitation
LEDs
batch, 4h
(300 nm)
flow, 1h
(300 nm)
batch,14 h
(CFL)
batch,14 h
(LEDs)
flow, 4h
(LEDs)
C
product
enone vs. ketone directing groups
O
O
A
2
11
12
13
70%
50%
72%
72%
61%
46%
59%
54%
65%
51%
65%
74%
94%
75%
82%
81%
70%
65%
74%
n.d.
Me
Me
C12
C12
Me
Me
Ph
C16
C16
Me
H
Me
H
C22
C15
H
H
H
H
7
9
O
O
O
Figure 3. (A) Cross section depiction of photochemical flow
reactor. (B) Depiction of reaction using a household fluorescent
light bulb. (C) Comparison of 19F NMR yields of products from
Table 2 using standard glassware (batch) and the continuous flow
protocol (flow) with various light sources.
Me Me
C15:C12+C16 - ~4:1
C16:C12 - ~3.3:1
C22:C12+C16 - ~7:1
C16:C12 - ~3.3:1
O
O
B
Me
Me
C12
C12
Me
Me
On another front, we discovered that a household compact
fluorescent light (CFL) may serve as an economical alternative
to ultraviolet light sources in direct excitation. Although CFLs
are typically regarded as "visible light" sources, there exists a
spectral line in the near-ultraviolet region (ca. 365 nm) that we
have found to be sufficient in effecting the reaction. However,
yields and selectivity are similar to or slightly lower than the
ultraviolet light setup; therefore, we have found the sensitized
approach using LEDs provides the most optimal results to
date.
C16
Me
H
Me
H
H
H
H
H
14
11
O
O
free σ-bond rotation
no σ-bond rotation
C16 favored (3.1:1)
only C12 possible
Figure 2. Comparing reactivity (A) and applications (B) of
enone and ketone directing groups.
At this juncture, we applied our protocol to triterpenoids.
Using glycyrrhetinic and oleanolic acid derivatives 12 and 13 -
accessible pentacyclic triterpenoids17 - selective fluorination
was accomplished at the C1 position in up to 81% yield (Table
As a last point of interest, we conducted preliminary mech-
anistic experiments. Under our reaction conditions, benzil is
the only chromophore above 400 nm. The photochemical
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properties of benzil are well established – for example, it is
Page 4 of 13
spectra were acquired on a 400 MHz NMR spectrometer in
CDCl3, 19F spectra were acquired on a 300 MHz NMR spec-
1
2
3
4
5
6
7
8
reported to undergo fast intersystem crossing upon irradiation,
so we must consider the involvement of its triplet state.22 Alt-
hough the triplet sensitization of enones by benzil may be pro-
posed, the reported triplet energy of benzil (53 kcal/mol23) is
significantly lower than that of steroidal enones (approximate-
ly 70 kcal/mol24). Therefore, triplet-triplet energy transfer in
this case is highly unfavorable,25 and it is unlikely that the
enone triplet state plays a role. What is more, no byproducts
from classical excited enone processes26 such as α-cleavage, β-
elimination, or Norrish-Yang cyclization were detected.
trometer in CD3CN or CDCl3, and 13C NMR spectra were ac-
quired on a 400 MHz NMR spectrometer in CDCl3. The H,
1
13C, and 19F NMR chemical shifts are given in parts per mil-
lion (δ) with respect to an internal tetramethylsilane (TMS, δ =
0.00 ppm) standard and/or 3-chlorobenzotrifluoride (δ = −64.2
ppm relative to CFCl3).30 NMR data are reported in the fol-
lowing format: chemical shift (integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz)). IR data were obtained using an
ATR-IR instrument. Spectral data were processed with
Bruker software. Photochemical reactions were run in front of
a 72-LED work light (Designers Edge L1923). HPLC purifi-
cation (if necessary) was conducted on a Teledyne Isco Com-
biFlash EZ Prep system using a Dynamax-60A SiO2 column
and HPLC grade EtOAc and hexanes. Spectral data match the
literature for compounds 2, 7, 8, 9, 10, 12, and 13.1,3b The
syntheses and characterization of starting materials are report-
ed in the supporting information.
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triethylborane test
OAc
OAc
Me
Me
Selectfluor (2.0 equiv)
BEt3 (0.2 equiv.)
Me
H
Me
H
dark
H
H
H
H
F
MeCN, 14 h
1
2
AcO
O
AcO
O
same products/selectivity reproduced
Figure 4. Nonphotochemical result suggesting that an elec-
tron transfer mechanism is plausible under visible light condi-
tions.
General Fluorination Procedure
Selectfluor (177 mg, 0.50 mmol), benzil (5.0 mg, 0.025
mmol), and the substrate (0.25 mmol) were added to an oven-
dried µω vial equipped with a stir bar; the vial was then sealed
with a cap w/ septum using a crimper and evacuated/refilled
with N2 multiple times. Anhydrous MeCN (4 mL) was added,
and the reaction mixture was irradiated with a cool white LED
work light while stirring. After 14 h, a 0.3 mL aliquot was
taken for 19F NMR yield determination. Then, the reaction
mixture was diluted with EtOAc, filtered through Celite, and
concentrated. The crude reaction mixture was purified via
gradient column chromatography on silica gel eluting with
EtOAc:hexanes.
Building upon these observations, we explored the possibil-
ity of pathways whereby "photochemistry" only plays a role in
reaction initiation. For instance, we revisited the nonphoto-
3b
chemical BEt3 protocol that has been shown to generate the
N-centered radical cation from Selectfluor. In recent studies,
we have found the BEt3 protocol to be a reasonable test for the
involvement of this intermediate in our light-driven fluorina-
tion chemistry.7,27 (However, it is important to note that we
have found a negative result of this test to be less informative,
as this method may not have the same substrate compatibility
or efficiency as the photochemical reaction.28) Using steroidal
substrate 1, we observed a similar product distribution as the
sensitized conditions, albeit in a lower yield (Figure 4). Con-
sidering that the Selectfluor N-centered radical is established
as a powerful oxidant,29 an electron transfer mechanism could
be possible whereby the enone assists in a directed deprotona-
tion.
In all, the visible light-based photosensitized approach to
enone-directed fluorination is a practical and universally ac-
cessible alternative to the ultraviolet light-based approach.
We have observed notable increases in yields and selectivity,
additional functional group compatibility, and better scalabil-
ity using inexpensive, household LEDs. Furthermore, our
assembly and comparative analysis of rudimentary continuous
flow setups (using both the Rayonet reactor and a self-
assembled LED reactor) demonstrate that this chemistry is a
good candidate for microflow applications. For all of these
reasons, we believe this is a very powerful protocol for "late-
stage fluorination" of complex targets. Future studies will
seek to elucidate the reaction mechanism and additional ways
to apply directing groups to the fluorination of large, biologi-
cally-relevant molecules.
Continuous-Flow Fluorination Procedure
Selectfluor (0.21 g, 0.60 mmol) and the substrate (0.30 mmol)
were added to a flame-dried round bottom flask equipped with
a stir bar under N2. Anhydrous CH3CN (14.4 mL) was added,
and 12 mL of the reaction mixture was drawn into a syringe
(0.25 mmol of substrate used in the reaction). The syringe
containing the reaction mixture was attached to the microflow
reactor with a chemical resistant Luer lock syringe adapter and
placed on a syringe pump. (Note that the microflow reactor
consisted of ca. 7.5 m of FEP tubing (ID 1.6 mm, OD 3.2 mm)
coiled around a Pyrex beaker that was surrounded by six 72-
LED work light sources and wrapped with aluminum foil.
The tubing was purged with N2 and anhydrous CH3CN prior to
use.) The flow rate was adjusted to pump the reaction mixture
through the microflow reactor and into a collection flask over
4 h. The tubing was purged with additional CH3CN, and the
contents of the collection flask were concentrated. The crude
residue was either dissolved in a known amount of solvent to
be subjected to 19F NMR analysis with an internal standard or
purified via gradient column chromatography on silica gel
eluting with EtOAc/hexanes followed by HPLC purification.
EXPERIMENTAL SECTION
General Methods
Characterization of Fluorinated Compounds
Unless otherwise stated, all reactions were carried out under
strictly anhydrous conditions and under N2 atmosphere. All
solvents were dried and distilled by standard methods. All 1H
Compound 2: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
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51.6, 50.5, 44.6 (d, J = 5.9 Hz), 43.1, 38.5, 37.8, 37.7, 35.7,
EtOAc/hexanes. Regiochemical assignment was made on the
basis of 1) chemical shift in the 19F NMR spectrum that indi-
35.4 (d, J = 26.9 Hz, C16), 27.3, 21.5, 21.24, 21.18, 19.9,
17.9, 13.4; 19F NMR (282 MHz, CDCl3): δ -161.0 (m, 1F);
υmax (ATR-IR): 1730 (br), 1671 cm-1. HRMS (ESI-FTICR-
MS) m/z: [M + Na]+ Calcd for C25H35FO5Na+: 457.2361,
Found 457.2358.
1
2
3
4
cates a secondary fluoride, 2) JHF-coupling in the H and 19F
NMR spectra that indicates cyclopentane ring fluorination
2
1
2
(52.2 Hz), and 3) identification of JCF-coupling to distin-
guishable peaks in the 13C NMR spectrum, i.e. C14, C16, and
C17 vide infra. Stereochemical assignment was made on the
basis of 1) chemical shift and splitting in the 19F NMR spec-
trum, 2) accord with the calculated 19F NMR shift and 3) com-
parative analysis to compound 7, for which the crystal struc-
ture was previously reported by our laboratory.
5
6
7
8
Compound 5: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical and stereochemical assign-
ments were made by analogy to compound 2.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
White solid (53 mg, 55%); m.p. = 215-216.5 °C. 1H NMR
(400 MHz, CDCl3): 5.80 (d, J = 2.0 Hz, 1H), 5.24 (dm, J =
52.2 Hz, 1H), 4.89 (t, J = 9.1 Hz, 1H), 4.77-4.69 (m, 1H), 2.62
(ddd, J = 14.3, 5.0, 2.2 Hz, 1H), 2.51-2.33 (m, 3H), 2.22-2.08
(m, 1H), 2.07-2.04 (m, 6H), 2.03-1.94 (m, 2H), 177-1.58 (m,
5H), 1.55-1.44 (m, 1H), 1.37-1.23 (m, 2H), 1.17 (s, 3H), 0.83
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 170.7,
170.2, 164.9, 127.1, 92.1 (d, J = 181.0 Hz, C15), 78.5 (d, J =
1.8 Hz, C17), 71.7, 53.4 (d, J = 19.5 Hz, C14), 50.3, 45.1 (d, J
= 5.5 Hz), 43.1, 37.9, 37.7, 36.7 (d, J = 26.2 Hz, C16), 36.0,
35.7, 27.3, 21.2, 21.0, 20.8, 17.9, 13.2; 19F NMR (282 MHz,
Waxy white solid (49 mg, 44%); 1H NMR (400 MHz, CDCl3):
δ 6.06 (d, J = 7.9 Hz, 1H), 5.82 (d, J = 1.8 Hz, 1H), 5.33 (dm,
J = 51.9 Hz, 1H), 4.80-4.67 (m, 1H), 4.31-4.20 (m, 1H), 2.67-
2.59 (m, 1H), 2.53-2.29 (m, 3H), 2.20-1.94 (m, 3H), 2.05 (s,
3H), 1.88-1.61 (m, 5H), 1.54-1.43 (m, 2H), 1.39-1.26 (m, 1H),
1.17 (s, 3H), 0.78 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 197.8, 170.3, 165.5, 157.3 (q, J = 37.2 Hz), 127.0, 115.8 (q,
J = 288.2 Hz), 91.8 (d, J = 181.3 Hz, C15), 71.7, 56.2, 54.9 (d,
J = 19.9 Hz, C14), 50.3, 46.1 (d, J = 5.5 Hz), 43.2, 37.9, 37.7,
37.1 (d, J = 27.3 Hz, C16), 36.1, 35.7, 27.2, 21.2, 20.8, 17.9,
13.0; 19F NMR (282 MHz, CDCl3): δ -75.1 (s, 3F), -162.4 (m,
1F). υmax (ATR-IR): 3350, 1730 (br), 1680 cm-1. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C23H29F4NO4Na
482.1925, Found 482.1923.
CDCl3): δ -162.7 (m, 1F). υmax (ATR-IR): 1733 (br), 1675 cm-
1
.
HRMS (ESI-FTICR-MS) m/z: [M + Na]+ Calcd for
C23H31FO5Na 429.2048, Found 429.2049.
Compound 3: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical and stereochemical assign-
ments were made by analogy to compound 2.
Compound 6: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical and stereochemical assign-
ments were made by analogy to compound 2.
White solid (43 mg, 41%); m.p. = 142-143 °C. 1H NMR (400
MHz, CDCl3): δ 5.78 (d, J = 1.7 Hz, 1H), 5.26 (dm, J = 53.3
Hz, 1H), 3.90-3.82 (m, 1H), 2.79-2.66 (m, 2H), 2.33-1.82 (m,
6H), 1.73-1.42 (m, 6H), 1.40-1.21 (m, 5H), 1.16 (s, 3H), 1.15-
0.98 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H), 0.88-0.84 (m, 1H), 0.86
(d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.72 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 198.6, 164.5, 126.9, 94.0
(d, J = 176.2 Hz, C15), 58.3 (d, J = 18.8 Hz, C14), 57.3, 52.6,
50.6, 45.1 (d, J = 5.9 Hz), 43.2, 42.5, 39.3, 39.1, 37.9 (d, J =
25.4 Hz, C16), 37.7, 37.4, 36.0, 34.8, 32.7, 28.0, 23.7, 22.8,
22.5, 21.2, 18.5, 17.8, 13.0; 19F NMR (282 MHz, CDCl3):
δ -160.8 (m, 1F). υmax (ATR-IR): 1690 cm-1. HRMS (ESI-
FTICR-MS) m/z: [M + Na]+ Calcd for C27H42ClFONa
459.2800, Found 459.2799.
White solid (50 mg, 52%); m.p. = 188-190 °C. 1H NMR (400
MHz, CDCl3): δ 5.80 (d, J = 2.0 Hz, 1H), 5.34 (dm, J = 52.2
Hz, 1H), 4.77-4.69 (m, 1H), 3.69 (s, 3H), 2.76-2.58 (m, 3H),
2.51-2.44 (m, 1H), 2.32 (t, J = 11.3 Hz, 1H), 2.21-2.07 (m,
1H), 2.05 (s, 3H), 2.04-1.94 (m, 3H), 1.79-1.61 (m, 4H), 1.56-
1.38 (m, 2H), 1.33-1.24 (m, 1H), 1.17 (s, 3H), 0.71 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 197.9, 172.9, 170.2,
164.9, 127.1, 93.5 (d, J = 178.4 Hz, C15), 71.7, 57.6 (d, J =
19.5 Hz, C14), 51.9, 51.5, 50.4, 45.8 (d, J = 5.9 Hz), 43.4,
37.9, 37.7, 37.4, 35.7, 33.8 (d, J = 26.5 Hz, C16), 27.3, 21.2,
21.0, 17.8, 14.4; 19F NMR (282 MHz, CDCl3): δ -161.7 (m,
1F). υmax (ATR-IR): 1721 (br), 1685 cm-1. HRMS (ESI-
FTICR-MS) m/z: [M
429.2048, Found 429.2047.
+
Na]+ Calcd for C23H31FO5Na
Compound 4: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical and stereochemical assign-
ments were made by analogy to compound 2.
Compound 7: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical assignment was made on the
basis of 1) chemical shift in the 19F NMR spectrum that indi-
White solid (54 mg, 52%); m.p. = 164-165 °C. 1H NMR (400
MHz, CDCl3): δ 5.80 (d, J = 2.0 Hz, 1H), 5.28 (dm, J = 53.5
Hz, 1H), 4.89-4.82 (m, 1H), 4.77-4.69 (m, 1H), 2.63-2.58 (m,
1H), 2.51-2.44 (m, 1H), 2.31 (t, J = 11.4 Hz, 1H), 2.05 (s, 3H),
2.02 (s, 3H), 1.99-1.85 (m, 4H), 1.84-1.72 (m, 2H), 1.69-1.60
(m, 3H), 1.55-1.44 (m, 1H), 1.41-1.22 (m, 3H), 1.18 (d, J =
6.2 Hz, 3H), 1.15 (s, 3H), 0.70 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 198.2, 170.28, 170.26, 164.8, 127.3, 93.5 (d,
J = 178.0 Hz, C15), 71.8, 71.6, 57.7 (d, J = 19.2 Hz, C14),
2
1
cates a secondary fluoride, 2) JHF-coupling in the H and 19F
NMR spectra that indicates cyclopentane ring fluorination
2
(52.8 Hz), and 3) identification of JCF-coupling to distin-
guishable peaks in the 13C NMR spectrum, i.e. C14 and C16
vide infra. Stereochemical assignment was made on the basis
of 1) chemical shift and splitting in the 19F NMR spectrum and
2) accord with the calculated 19F NMR shift. Assignments
were previously confirmed by X-ray crystallography.1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
White solid (39 mg, 44%); m.p. = 191-192 °C. 1H NMR (400
MHz, CDCl3): δ 6.03 (s, 1H), 5.40 (dm, J = 52.9 Hz, 1H),
2.84-2.66 (m, 2H), 2.64-2.60 (m, 2H), 2.39 (t, J = 11.5 Hz,
1H), 2.16 (s, 3H), 2.15-1.96 (m, 3H), 1.93-1.73 (m, 5H), 1.58-
1.55 (m, 1H), 1.34 (s, 6H), 1.07 (s, 3H), 0.72 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 212.2, 207.7, 198.1, 174.7, 125.0,
93.2 (d, J = 178.0 Hz, C15), 59.7, 58.8 (d, J = 19.9 Hz, C14),
50.3, 49.5, 45.9 (d, J = 6.3 Hz), 42.7, 38.2 (d, J = 22.5 Hz,
C16), 33.5, 33.3, 33.2, 31.5, 30.9, 28.4, 26.3, 21.6, 17.7, 14.3;
19F NMR (282 MHz, CDCl3): δ -162.8 (dm, J = 52.8 Hz, 1F).
υmax (ATR-IR): 1706 (br), 1669 cm-1. HRMS (ESI-FTICR-
MS) m/z: [M + Na]+ Calcd for C23H31FO3Na 397.2149, Found
397.2150.
3H), 1.53-1.44 (m 2H), 1.42-1.29 (m, 2H), 1.27-1.20 (m, 1H),
1
2
3
4
5
6
7
8
1.18-1.11 (m, 1H), 1.08-0.96 (m, 2H), 1.04 (s, 3H), 0.60 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.1, 196.2, 170.7,
138.9 (d, J = 20.3 Hz, C23), 128.31, 128.29, 127.6 (d, J = 1.1
Hz), 124.6, 124.5, 123.7, 90.1 (d, J = 175.8 Hz, C22), 63.3,
55.8, 53.7, 47.9, (d, J = 22.9 Hz, C2), 43.7, 38.5, 38.4, 35.3,
33.6 (d, J = 5.2 Hz, C1), 32.3, 31.6, 31.4, 24.2, 22.7, 20.8,
17.5, 13.2; 19F NMR (282 MHz, CDCl3): δ - 197.3 (dd, J =
45.9, 31.0 Hz, 1F). υmax (ATR-IR): 1710, 1690 cm-1. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C28H35FO2Na
445.2513, Found 445.2511.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 10: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical assignment was made on the
basis of 1) chemical shift in the 19F NMR spectrum that indi-
cates a secondary fluoride on a cyclohexane ring, 2) identifica-
Compound 8: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical assignment was made on the
basis of 1) chemical shift in the 19F NMR spectrum that indi-
cates a secondary fluoride on a cyclohexane ring, 2) identifica-
tion of 3JHF-coupling (10.3 Hz) to the diagnostic C9 Hax signal
4
tion of JHF-coupling to the distinguishable C18 Me hydrogen
1
2
atoms in the H NMR spectrum, and 3) identification of JCF
-
and JCF-coupling to distinguishable peaks in the 13C NMR
spectrum, i.e. C11, C13, C17a, and C18 vide infra. Stereo-
chemical assignment was made on the basis of 1) chemical
shift and splitting in the 19F NMR spectrum that indicates Fax
on a cyclohexane ring and 2) accord with the calculated 19F
NMR shift.1
3
1
(ddd at 2.35) as confirmed by a H{19F} NMR spectrum, and
3) downfield shifts of the C18 (Δδ = 0.11 ppm) and C19 (Δδ =
0.21 ppm) Me signals in the 1H NMR spectrum with respect to
the starting material. Stereochemical assignment was made on
the basis of 1) chemical shift and splitting in the 19F NMR
spectrum that indicates Feq on a cyclohexane ring, 2) identifi-
White solid (51 mg, 59%); m.p. = 135-137 °C. 1H NMR (400
MHz, CDCl3): δ 6.92-6.87 (m, 1H), 5.98-5.95 (m, 1H), 5.17
(dm, J = 46.8 Hz, 1H), 4.72-4.64 (m, 1H), 2.56-2.49 (m, 1H),
2.16-2.09 (m, 1H), 2.05-1.96 (m, 2H), 2.02 (s, 3H), 1.89-1.80
(m, 2H), 1.73-1.63 (m, 2H), 1.58-1.18 (m, 8H), 1.10-0.97 (m,
2H), 0.96 (d, J = 1.1 Hz, 3H), 0.82 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 201.0 (d, J = 0.7 Hz, C17a), 170.6,
148.2, 128.2, 91.0 (d, J = 172.5 Hz, C12), 73.3, 48.3 (d, J =
19.2 Hz, C13), 45.9, 43.9, 39.8, 36.1, 35.2, 34.7, 33.8, 30.1,
28.2, 27.2, 26.3, 25.4 (d, J = 21.4 Hz, C11), 21.4, 14.9 (d, J =
7.0 Hz, C18), 11.9; 19F NMR (282 MHz, CDCl3): δ -185.6 (m,
1F). υmax (ATR-IR): 1734, 1684 cm-1. HRMS (ESI-FTICR-
MS) m/z: [M + Na]+ Calcd for C22H31FO3Na 385.2149, Found
385.2149.
1
cation of antiperiplanar vicinal coupling in the H NMR spec-
trum of Hax at the C11 position to the axial hydrogen atoms at
C9 and C12 (i.e. t, 3JHH = 11.3 Hz), 3) lack of long-range cou-
pling of fluorine to the C18 and C19 Me hydrogen atoms in
1
the H NMR spectrum, and 4) accord with the calculated 19F
NMR shift.1
White solid (67 mg, 67%); m.p. = 120-123 °C. 1H NMR (400
MHz, CDCl3): δ 5.71-5.70 (m, 1H), 4.56 (dtd, J = 48.2, 11.3,
4.2 Hz, 1H), 2.35 (ddd, J = 11.7, 10.3, 4.1 Hz, 1H), 2.21-2.13
(m, 1H), 2.02 (dd, J = 18.9, 4.9 Hz, 1H), 1.96-1.85 (m, 2H),
1.82 (s, 3H), 1.81-1.74 (m, 1H), 1.71-1.58 (m, 3H), 1.56-1.44
(m, 3H), 1.40-1.19 (m, 8H), 1.17 (s, 3H), 1.16-0.94 (m, 5H),
0.92 (d, J = 6.6 Hz, 3H), 0.87-0.85 (m, 6H), 0.74 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 204.6, 152.9, 125.5, 91.3
(d, J = 181.2 Hz, C11), 56.3, 55.9, 49.4, 49.2, 46.6, 46.5, 46.4,
43.4, 43.34, 43.28, 39.4, 36.5, 35.9, 35.7, 34.7, 34.6, 29.7,
28.4, 28.01, 27.97, 23.9, 23.4, 22.8, 22.7, 22.5, 18.4, 13.7,
10.4; 19F NMR (282 MHz, CDCl3): δ -178.3 (dm, J = 48.2 Hz,
1F). υmax (ATR-IR): 1684 cm-1. HRMS (ESI-FTICR-MS)
m/z: [M + Na]+ Calcd for C28H45FONa 439.3346, Found
439.3347.
Compound 11: Fluorination was run according to the general
procedure, and both major and minor diastereomers were iso-
lated via gradient column chromatography on silica gel eluting
with EtOAc/hexanes.
Regiochemical and stereochemical
assignments were made by analogy to compound 10.
Major diastereomer. White solid (39 mg, 50%); m.p. = 182-
184 °C. 1H NMR (400 MHz, CDCl3): δ 6.71 (dd, J = 3.4 Hz,
1.7 Hz, 1H), 5.74 (d, J = 1.5 Hz, 1H), 5.39 (dt, J = 48.7, 2.7
Hz, 1H), 2.44-2.33 (m, 4H), 2.28 (s, 3H), 2.15-2.10 (m, 1H),
2.08-1.86 (m, 5H), 1.83-1.64 (m, 3H), 1.41-1.33 (m, 1H),
1.23-1.15 (m, 1H), 1.19 (s, 3H), 0.94 (d, J = 1.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 196.4, 169.9,
151.5 (d, J = 2.1 Hz, C17), 144.6, 124.3, 91.1 (d, J = 174.7
Hz, C12), 50.2 (d, J = 18.8 Hz, C13), 48.9 (d, J = 0.7 Hz),
46.9 (d, J = 1.5 Hz), 38.2, 35.3, 33.8, 33.5, 32.5, 31.4, 31.3,
26.8, 26.5 (d, J = 22.1 Hz, C11), 17.0, 16.0 (d, J = 7.4 Hz,
C18); 19F NMR (282 MHz, CDCl3): δ -185.5 (td, J = 46.7,
12.4 Hz, 1F). υmax (ATR-IR): 1698, 1667 cm-1. HRMS (ESI-
Compound 9: Fluorination was run according to the general
procedure (a proportional scale up was used for the gram-scale
synthesis), and one diastereomer was isolated via gradient
column chromatography on silica gel eluting with
EtOAc/hexanes. Characterization data are consistent with
previous literature.3b
1
White solid (0.35 g, 34%); m.p. = 150-152 °C. H NMR (400
MHz, CDCl3): δ 7.41-7.35 (m, 2H), 7.32-7.27 (m, 3H), δ 6.48
(dd, J = 46.1, 1.8 Hz, 1H), 5.82 (d, J = 1.4 Hz, 1H), 2.64
(dddd, J = 30.4, 13.5, 5.3, 2.2 Hz, 1H), 2.52 (t, J = 9.0 Hz,
1H), 2.41-2.27 (m, 2H), 2.21-2.13 (m, 1H), 2.10 (s, 3H), 2.01
(dt, J = 12.2, 3.1 Hz, 1H), 1.87-1.79 (m, 2H), 1.74-1.60 (m,
FTICR-MS) m/z: [M + Na]+ Calcd for
353.1887, Found 353.1888.
C21H27FO2Na
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Page 7 of 13
The Journal of Organic Chemistry
(m, 2H), 1.28-1.18 (m, 4H), 1.12 (d, J = 2.1 Hz, 3H), 0.99-
Minor diastereomer. White solid (25 mg, 32%); m.p. = 179-
0.92 (m, 10H), 0.90 (s, 3H), 0.87 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 200.3, 177.5, 170.5, 169.2, 127.6, 95.0 (d, J =
172.5 Hz, C1), 75.1, 52.6 (d, J = 8.1 Hz, C9), 51.9, 47.7, 46.2,
44.8, 44.2, 43.8, 41.6, 41.0, 40.9, 37.9, 33.7, 32.8, 32.2, 31.6,
30.7, 28.3, 28.1, 27.8, 23.5, 23.4, 22.9, 21.2, 19.1, 16.9, 16.4,
16.3; 19F NMR (282 MHz, CDCl3): δ -192.2 (m, 1F). υmax
(ATR-IR): 1734 (br), 1652 cm-1. HRMS (ESI-FTICR-MS)
m/z: [M + Na]+ Calcd for C33H49FO5Na 567.3456, Found
567.3452.
182 °C. 1H NMR (400 MHz, CDCl3): δ 6.66 (dd, J = 3.4, 1.8
Hz, 1H), 5.77-5.75 (m, 1H), 4.57 (ddd, J = 49.5, 15.8, 5.6 Hz,
1H), 2.45-2.38 (m, 3H), 2.36-2.31 (m, 2H), 2.32 (s, 3H), 2.21-
2.13 (m, 1H), 2.05-1.97 (m, 2H), 1.93-1.87 (m, 1H), 1.77-1.64
(m, 3H), 1.39-1.30 (m, 1H), 1.24 (s, 3H), 1.14-1.04 (m, 2H),
1.09 (d, J = 0.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
199.0, 196.7, 169.2, 154.6 (d, J = 2.2 Hz, C17), 143.2, 124.5,
94.1 (d, J = 185 Hz, C12), 52.5, 52.4 (d, J = 3.3 Hz), 51.1 (d, J
= 17.3 Hz, C13), 38.4, 35.5, 33.8, 32.4, 31.3 (d, J = 1.8 Hz),
30.9 (d, J = 1.8 Hz), 28.28, 28.25, 27.9 (d, J = 22.5 Hz, C11),
17.0, 11.9 (d, J = 2.2 Hz, C18); 19F NMR (282 MHz, CDCl3):
δ -170.3 (m, 1F). υmax (ATR-IR): 1695, 1670 cm-1. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C21H27FO2Na
353.1887, Found 353.1887.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Syntheses and characterization of starting materials
Starting
material
for
compound
2
(3β,17β-
Diacetoxyandrost-5-ene-7-one31,32,33): To a flame-dried round
bottom equipped with a stir bar under N2 was added prasterone
(4.0 g, 13.9 mmol) and MeOH (75 mL). The reaction mixture
was treated with NaBH4 (0.53 g, 13.9 mmol) in portions over
10 min, and then stirred for an additional 2 h. The resulting
white precipitate was collected by filtration and dried to pro-
vide 5-androstenediol (3.50 g, 87 %).
Compound 12: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes. Regiochemical assignment was made on the
basis of 1) chemical shift in the 19F NMR spectrum that indi-
cates a secondary fluoride on a cyclohexane ring, 2) disap-
pearance of the diagnostic C1 Heq signal (dt at 2.76 ppm) in
The 5-androstenediol from the previous step (3.1 g, 10.7
mmol), p-TsOH•H2O (60 mg, 0.30 mmol), and acetic anhy-
dride (4.6 mL) were dissolved in pyridine (6.0 mL) under N2.
After stirring for 1 h at rt, the reaction mixture was heated to
95 °C and stirred for an additional 3.5 h. The reaction mixture
was then cooled to rt and diluted with H2O (150 mL). The
white precipitate was collected by filtration, washed with H2O,
and dried to provide androstenediol-3,17-diacetate (3.52 g, 85
%).
1
1
the H NMR spectrum concomitant with appearance of a H
signal with the shift (5.58 ppm) and coupling constant (2JHF
=
47 Hz) that indicate a geminal fluoride, and 3) identification of
3
2JCF- and JCF-coupling to distinguishable peaks in the 13C
NMR spectrum, i.e. C2, C9, C10, and C25 vide infra. Stereo-
chemical assignment was made on the basis of 1) chemical
shift and splitting in the 19F NMR spectrum that indicates Fax
on a cyclohexane ring and 2) accord with the calculated 19F
NMR shift.1
Androstenediol-3,17-diacetate (1.9 g, 5.2 mmol) was dis-
solved in a mixture of acetone (200 mL) and acetic acid (20
mL) in a round-bottom flask equipped with a stir bar and re-
flux condenser under N2. The reaction mixture was treated
with N-hydroxysuccinimide (5.9 g, 52 mmol) and K2Cr2O7
(6.0 g, 21 mmol), and then the reaction mixture was stirred at
40 °C for 48 h. The reaction mixture was cooled to rt,
quenched with aq. 10 % sodium metabisulfite solution, filtered
through Celite, and extracted into Et2O. The combined organ-
ic layers were washed with saturated aq. NaHCO3, brine, dried
with MgSO4, and concentrated. The crude residue was recrys-
tallized in MeOH to provide 3β,17β-diacetoxyandrost-5-ene-
7-one (1.64 g, 82 %) as a white solid; m.p. = 222-223 °C. 1H
NMR (400 MHz, CDCl3): δ 5.70 (d, J = 1.8 Hz, 1H), 4.74-
4.65 (m, 1H), 4.63-4.59 (m, 1H), 2.55 (ddd, J = 14.0, 5.1, 2.2
Hz, 1H), 2.49-2.39 (m, 2H), 2.29-2.14 (m, 2H), 2.03 (s, 3H),
2.02 (s, 3H), 2.00-1.93 (m, 2H), 1.77-1.68 (m, 2H), 1.67-1.57
(m, 2H), 1.54-1.47 (m, 3H), 1.43-1.35 (m, 1H), 1.30-1.25 (m,
1H), 1.20 (s, 3H), 1.18-1.11 (m, 1H), 0.80 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 201.1, 171.1, 170.2, 164.3, 126.5,
81.9, 72.0, 49.7, 45.0, 44.7, 43.0, 38.3, 37.8, 36.0, 35.8, 27.5,
27.3, 25.8, 21.2, 21.1, 20.7, 17.3, 12.0. υmax (CaF2, CHCl3):
1729 (br), 1669 cm-1. λmax (CH3CN): 329 nm. HRMS (ESI-
FTICR-MS) m/z: [M + Na]+ Calcd for C23H32O5Na 411.2142,
Found 411.2144.
White solid (88 mg, 67%); m.p. = 265-265.5 °C. 1H NMR
(400 MHz, CDCl3): δ 5.68 (s, 1H), 5.58 (ddd, J = 46.6, 3.4,
2.2 Hz, 1H), 4.92 (dd, J = 11.9, 5.1 Hz, 1H), 3.69 (s, 3H), 3.13
(s, 1H), 2.12-2.06 (m, 2H), 2.05 (s, 3H), 2.04-1.91 (m, 4H),
1.83 (td, J = 13.6, 4.3 Hz, 1H), 1.71-1.58 (m, 3H), 1.56-1.45
(m, 1H), 1.41-1.36 (m, 2H), 1.39 (s, 3H), 1.32-1.30 (m, 3H),
1.21-1.20 (m, 1H), 1.16 (d, J = 2.0 Hz, 3 H), 1.15 (s, 3H), 1.14
(s, 3H), 1.04-0.98 (m, 1H), 0.91 (s, 3H), 0.88 (s, 3H), 0.80 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.2, 176.9, 170.5,
169.8, 128.3, 94.1 (d, J = 172.9 Hz, C1), 75.1, 52.6 (d, J = 8.1
Hz, C9), 51.8, 48.4, 47.6, 45.2, 44.0, 43.5, 41.1, 40.9, 40.7,
37.9, 37.7, 32.1, 31.8, 31.1, 28.4 (d, J = 25.8 Hz, C2), 28.2 (d,
J = 21.7 Hz, C10), 27.8, 26.5, 26.4, 23.3, 21.2, 18.9, 17.0, 16.5
(d, J = 5.9 Hz, C25), 16.3; 19F NMR (282 MHz, CDCl3): δ -
191.9 (m, 1F). υmax (ATR-IR): 1734 (br), 1653 cm-1. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C33H49FO5Na
567.3456, Found 567.3451.
Compound 13: Fluorination was run according to the general
procedure, and the major diastereomer was isolated via gradi-
ent column chromatography on silica gel eluting with
EtOAc/hexanes followed by silica-based HPLC using
EtOAc/hexanes. Regiochemical and stereochemical assign-
ments were made by analogy to compound 12.
White solid (78 mg, 59%); m.p. = 238-241 °C. 1H NMR (400
MHz, CDCl3): δ 5.65 (s, 1H), 5.62 (dm, J = 46.3 Hz, 1H), 4.92
(dd, J = 12.0, 4.9 Hz, 1H), 3.63 (s, 3H), 3.10 (s, 1H), 3.04-2.99
(m, 1H), 2.12-2.06 (m, 1H), 2.05 (s, 3H), 2.04-2.01 (m, 1H),
1.99-1.86 (m, 1H), 1.77-1.69 (m, 2H), 1.67-1.63 (m, 2H),
1.61-1.58 (m, 2H), 1.51-1.41 (m, 1H), 1.38 (s, 3H), 1.37-1.30
Starting material for compound 3 (7-Keto-cholesteryl
chloride33): Cholesteryl chloride (5.0 g, 12 mmol) was dis-
solved in a mixture of acetone (300 mL) and acetic acid (30
mL) in a round-bottom flask equipped with a stir bar and re-
flux condenser under N2. The reaction mixture was treated
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with N-hydroxysuccinimide (11.2 g, 99 mmol) and K2Cr2O7
FTICR-MS) m/z: [M + Na]+ Calcd for C25H36O5Na 439.2455,
Found 439.2453.
1
2
3
4
5
6
7
8
(14.5 g, 49 mmol), and then the reaction mixture was stirred at
40 °C for 18 h. The reaction mixture was cooled to rt,
quenched with aq. 10 % sodium metabisulfite solution, filtered
through Celite, and extracted into Et2O. The combined organ-
ic layers were washed with saturated aq. NaHCO3, brine, dried
over MgSO4, and concentrated. The crude residue was puri-
fied by gradient column chromatography on silica gel eluting
with EtOAc:hexanes to provide 7-keto-cholesteryl chloride
(4.0 g, 78 %) as a white solid; m.p. = 132-134 °C. 1H NMR
(400 MHz, CDCl3): δ 5.58 (t, J = 1.1 Hz, 1H), 3.88-3.80 (m,
1H), 2.70 (dm, J = 8.2 Hz, 2H), 2.43-2.36 (m, 1H), 2.26-2.14
(m, 2H), 2.06-1.86 (m, 4H), 1.60-1.47 (m, 5H), 1.39-1.29 (m,
4H), 1.28-1.24 (m, 2H), 1.22 (s, 3H), 1.16-1.09 (m, 4H), 1.07-
0.99 (m, 2H), 0.92 (d, J = 6.6 Hz, 3H), 0.86-0.85 (m, 6H), 0.68
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 202.2, 164.1,
126.1, 57.7, 54.7, 49.83, 49.76, 45.4, 43.0, 42.6, 39.4, 38.6,
38.03, 38.00, 36.1, 35.6, 32.7, 28.4, 27.9, 26.2. υmax (ATR-
IR): 1700 cm-1. λmax (CH3CN): 321, 287 nm. HRMS (ESI-
Starting
material
for
compound
5
(17β-
trifluoroacetamido-3β-acetoxyandrost-5-en-7-
one34,35,36,37,38): To a flame-dried three-neck round bottom flask
equipped with a stir bar under N2 was added prasterone (5.0 g,
17 mmol), acetic anhydride (10 mL), and pyridine (10 mL).
The reaction mixture was stirred for 21 h, and then diluted
with CH2Cl2 (20 mL). The organic layer was washed with 1.0
M HCl, saturated aq. NaHCO3, and H2O. The organic layer
was dried over MgSO4, filtered through Celite, and concen-
trated. The crude residue was purified via gradient column
chromatography on silica gel eluting with EtOAc:hexanes to
provide prasterone acetate (5.2 g, 90 %) as a white solid.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Prasterone acetate (5.2 g, 16 mmol) from the previous step
and NH2OH•HCl (4.3 g, 62 mmol) were dissolved in pyridine
(75 mL) under N2. After stirring for 16 h, the reaction mixture
was quenched with H2O, extracted into EtOAc, dried over
MgSO4, filter through Celite, and concentrated. The crude
product (5.1 g, 95 %) was used without further purification.
FTICR-MS) m/z: [M
441.2895, Found 441.2894.
+
Na]+ Calcd for C27H43ClONa
Starting material for compound 4 (3β,20β-Diacetoxy-5α-
pregnen-7-one 31,32,33): To a flame-dried round-bottom flask
equipped with a stir bar under N2 was added pregnenolone (4.0
g, 13 mmol) and MeOH (80 mL). The reaction mixture was
treated with NaBH4 (0.96 g, 25 mmol) in portions over 10
min, and then stirred for an additional 2 h. The resulting white
precipitate was collected by filtration and dried to provide
pregn-5-ene-3β,20α-diol (3.0 g, 75%).
To a flame dried round-bottom flask equipped with a stir bar
was added 3β-acetoxy-androst-5-en-17-one oxime (6.2 g, 18
mmol), MoO3 (5.2 g, 54 mmol), MeOH (250 mL), and THF
(100 mL). The reaction mixture was cooled to 0 °C, and
NaBH4 (6.8 g, 179 mmol) was added portionwise over 30 min.
The reaction mixture slowly warmed to rt and stirred for 30
min. Then, KOH (7.5 g) in H2O (40 mL) was added, and the
flask was stored at 0 °C for 14 h. The crude mixture was fil-
tered through Celite, and the filtrate was concentrated to 50
mL. The mixture was poured into H2O, extracted into CH2Cl2,
dried over MgSO4, and concentrated. The crude residue was
recrystallized in EtOAc and hexanes to provide 17β-
aminoandrost-5-en-3β-ol (2.6 g, 51 %)
The pregn-5-ene-3β,20α-diol from the previous step (2.5 g,
7.9 mmol), p-TsOH•H2O (48 mg, 0.24 mmol), and acetic an-
hydride (4 mL) were dissolved in pyridine (5 mL) under N2.
After stirring for 1 h, the reaction mixture was heated to 95 °C
and stirred for an additional 4 h. The reaction mixture was
then cooled to rt and diluted with H2O (130 mL). The white
precipitate was formed and collected by filtration, washed
with H2O, and dried to provide pregn-5-en-3β,20α-diyl diace-
tate (2.4 g, 76%).
To a flame dried round-bottom flask equipped with a stir bar
was added 17β-aminoandrost-5-en-3β-ol (4.5 g, 16 mmol),
Et3N (2.2 mL, 16 mmol), and MeOH (45 mL). The reaction
mixture stirred for 5 min, and ethyl trifluoroacetate was then
added dropwise (2.4 mL, 20 mmol). After 20 h, the reaction
mixture was concentrated, acidified with 1.0 M HCl, extracted
into CH2Cl2, dried over MgSO4, and concentrated. The crude
residue was recrystallized in EtOAc and hexanes to provide
17β-trifluoroacetamidoandrost-5-en-3β-ol (3.9 g, 60 %).
Pregn-5-en-3β,20α-diyl diacetate (2.4 g, 5.0 mmol) was
dissolved in a mixture of acetone (300 mL) and acetic acid (30
mL) in a round-bottom flask equipped with a stir bar and re-
flux condenser under N2. The reaction mixture was treated
with N-hydroxysuccinimide (6.9 g, 60 mmol) and K2Cr2O7
(7.1 g, 24 mmol), and then the reaction mixture was stirred at
40 °C for 48 h. The reaction mixture was cooled to rt,
quenched with 10% aq. sodium metabisulfite solution, filtered
through Celite, and extracted into Et2O. The combined organ-
ic layers were washed with saturated aq. NaHCO3, brine, dried
over MgSO4, and concentrated. The crude residue was recrys-
tallized in MeOH to provide 3β,20α-diacetoxypregn-5-en-7-
one (1.6 g, 75%) as a white solid; m.p. = 170-171 °C. 1H NMR
(400 MHz, CDCl3): δ 5.71 (s, 1H), 4.89-4.82 (m, 1H), 4.75-
4.67 (m, 1H), 2.58-2.44 (m, 3H), 2.26-2.21 (m, 1H), 2.05 (s,
3H), 2.01 (s, 3H), 1.98-1.94 (m,1H), 1.87-1.67 (m, 3H), 1.62-
1.50 (m, 6H), 1.43-1.34 (m, 1H), 1.33-1.24 (m, 3H), 1.20 (s,
3H), 1.16 (d, J = 6.2 Hz, 3H), 0.65 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 201.5, 170.3, 170.2, 164.1, 126.5, 72.8,
72.1, 53.6, 49.8, 49.3, 45.2, 42.8, 38.3, 38.0, 37.7, 36.0, 27.3,
26.2, 25.7, 21.5, 21.2, 21.0, 19.9, 17.2, 12.4. υmax (ATR-IR):
1730, 1672 cm-1. λmax (CH3CN): 332, 285 nm. HRMS (ESI-
To a flame dried round-bottom flask equipped with a stir bar
was added 17β-trifluoroacetamidoandrost-5-en-3β-ol (2.3 g,
6.0 mmol), acetic anhydride (2 mL), and pyridine (2 mL).
After stirring the reaction mixture for 36 h at rt, CH2Cl2 (20
mL) was added and transferred to a separatory funnel. The
mixture was then washed with 1.0 M HCl, saturated aq. Na-
HCO3, and H2O. The organic layer was dried over MgSO4,
filtered through Celite, and concentrated. The crude residue
was purified via gradient column chromatography on silica gel
eluting with EtOAc:hexanes to provide 3β-acetoxy-17β-
acetylamino-androst-5-ene (2.3 g, 90 %).
To a flame dried round-bottom flask equipped with a stir bar
and reflux condenser was added 3β-acetoxy-17β-acetylamino-
androst-5-ene (1.4 g, 3.1 mmol), CuI (0.41 g, 2.1 mmol),
TBAB (0.12 g, 0.38 mmol), 70% t-BuOOH in H2O (2.8 mL,
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The Journal of Organic Chemistry
denser under N2. The reaction mixture was treated with N-
32 mmol), and CH2Cl2 (15 mL) under N2. The reaction mix-
1
2
3
4
5
6
7
8
ture was heated to reflux for 20 h (additional 70% t-BuOOH in
H2O (2.8 mL, 32 mmol) was added at 1.5 h and 3 h marks).
The reaction mixture was quenched with 1.0 M HCl, washed
with 1.0 M NaHSO4, dried over MgSO4, filtered through
Celite, and concentrated. The crude residue was purified via
gradient column chromatography on silica gel eluting with
EtOAc:hexanes to provide 17β-trifluoroacetamido-3β-
acetoxyandrost-5-en-7-one (0.8 g, 62%) as a white solid; m.p.
= 238-241 °C. 1H NMR (400 MHz, CDCl3): δ 6.01 (d, J = 7.4
Hz, 1H), 5.73 (s, 1H), 4.76-4.68 (m, 1H), 3.93 (q, J = 9.2 Hz,
1H), 2.61-2.44 (m, 3H), 2.29-2.21 (m, 2H), 2.05 (s, 3H), 2.03-
1.96 (m, 2H), 1.75-1.65 (m, 4H), 1.52-1.45 (m, 3H), 1.33-1.26
(m, 3H), 1.22 (s, 3H), 0.75 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 200.8, 170.2, 164.6, 157.2 (q, J = 36.7 Hz), 126.3,
115.6 (q, J = 288.3 Hz), 71.7, 58.6, 49.6, 46.4, 45.2, 44.1,
38.3, 37.7, 35.9, 35.7, 28.1, 27.2, 25.7, 21.2, 20.6, 17.2, 11.9.
υmax (ATR-IR): 3350, 1728, 1682 cm-1. λmax (CH3CN): 322,
280 nm. HRMS (ESI-FTICR-MS) m/z: [M + Na]+ Calcd for
C23H30F3NO4Na 464.2019, Found 464.2017.
hydroxysuccinimide (3.7 g, 32 mmol) and K2Cr2O7 (4.7 g, 16
mmol), and then the reaction mixture was stirred at 40 °C for
48 h. The reaction mixture was cooled to rt, quenched with
10% aq. sodium metabisulfite solution, filtered through Celite,
and extracted into Et2O. The combined organic layers were
washed with saturated aq. NaHCO3, brine, dried over MgSO4,
and concentrated. The crude residue was purified by gradient
column chromatography on silica gel eluting with
EtOAc:hexanes to provide methyl 33β--acetoxy-7-oxo-5-
1
9
etienate (1.2 g, 75%) as white solid; m.p. = 185-186 °C. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (400 MHz, CDCl3): δ 5.71 (d, J = 1.8 Hz, 1H), 4.75-
4.67 (m, 1H), 3.67 (s, 3H), 2.59-2.43 (m, 3H), 2.32 (t, J = 9.5
Hz, 1H), 2.28-2.22 (m, 1H), 2.18-2.08 (m, 1H), 2.05 (s, 3H),
2.05-1.95 (m, 3H), 1.92-1.82 (m, 1H), 1.74-1.63 (m, 2H),
1.60-1.51 (m, 2H), 1.49-1.38 (m, 2H), 1.32-1.24 (m, 2H), 1.21
(s, 3H), 0.68 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
200.7, 174.0, 169.8, 164.0, 126.1, 71.8, 53.7, 50.9, 49.4, 49.1,
45.1, 44.1, 38.1, 37.5, 36.8, 35.7, 27.0, 26.2, 23.7, 20.9, 20.7,
17.0, 13.1. υmax (ATR-IR): 1720 (br), 1686 cm-1. λmax
(CH3CN): 326, 277 nm. HRMS (ESI-FTICR-MS) m/z: [M +
Na]+ Calcd for C23H32O5Na 411.2142, Found 411.2140.
Starting material for compound 6 (Methyl 3β-acetoxy-7-
oxo-5-etienate 39,40,41,33): In a three-neck round bottom flask
equipped with a stir bar, NaOH (8.3 g, 207 mmol) was dis-
solved in H2O (70 mL) and cooled to -5 °C. To this solution,
Br2 (2.7 mL, 52 mmol) was then added slowly. The ice-cold
solution was diluted with 1,4-dioxane (50 mL), and was kept
at 0 °C. Meanwhile, to a three-neck round bottom flask
equipped with a stir bar and thermometer was added 5-
pregnen-3β-ol-20-one (5.0 g, 16 mmol), 1,4-dioxane (220
mL), and H2O (70 mL). The reaction mixture was cooled to 0
°C, and the cold NaOBr solution was added while keeping the
internal temperature below 10 °C. After stirring the reaction
mixture for 3 h, Na2SO4 (3.0 g) in H2O (20 mL) was added,
and the crude mixture was then heated to reflux for 30 min.
The reaction mixture was acidified with concentrated HCl (10
mL) while still hot and was stored at 5 °C for 14 h. The crys-
tallized etienic acid was collected via filtration.
Starting material for compound
7 (4,4-Dimethyl-5-
pregnen-3,7,20-trione42,43): To
a
flame-dried three-neck
round bottom equipped with a stir bar and reflux condenser
under N2 was added progesterone (6.0 g, 19 mmol) and ben-
zene (160 mL). The reaction mixture was stirred and heated to
reflux. A solution of KOtBu (6.4 g, 57 mmol) in t-BuOH (74
mL) was added drop wise, immediately followed by a solution
of Iodomethane (24 mL, 382 mmol) in benzene (120 mL); the
reaction mixture was stirred at reflux for 10 min and then
cooled to rt. The reaction mixture was quenched with H2O
(5.3 mL), diluted with Et2O, filtered through Celite, and con-
centrated. The crude residue was recrystallized from MeOH
three times to provide 4,4-dimethyl-5-pregnen-3,20-dione (3.9
g, 62 %).
To a flame-dried three-neck round bottom equipped with a
stir bar and reflux condenser under N2 was added CrO3 (0.035
g, 0.35 mmol) and CH2Cl2 (55 mL), followed by a 5-6 M solu-
tion of t-BuOOH in decane (9.8 mL, 49 mmol). The product
from the previous step, 4,4-dimethyl-5-pregnen-3,20-dione
(2.4 g, 7.0 mmol), was then added as a solution in CH2Cl2 (25
mL). The reaction mixture was stirred at rt for 14 h, then fil-
tered through neutral alumina and concentrated. The crude
residue was purified via gradient column chromatography
eluting with EtOAc:hexanes to provide 4,4-dimethyl-5-
pregnen-3,7,20-trione (1.4 g, 55 %) as a beige solid; m.p. =
194-198 °C. 1H NMR (400 MHz, CDCl3): δ 5.72 (s, 1H),
2.53-2.38 (m, 2H), 2.36-2.28 (m, 2H), 2.19-2.13 (m, 1H),
2.03-1.90 (m, 3H), 1.96 (s, 3H), 1.72-1.66 (m, 1H), 1.64-1.51
(m, 3H), 1.45-1.35 (m, 1H), 1.33-1.19 (m, 3H), 1.15 (s, 3H),
1.13 (s, 3H), 0.92 (s, 3H), 0.49 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 212.1, 208.8, 200.5, 173.8, 123.9, 61.7, 49.8,
49.0, 48.6, 44.2, 44.0, 38.4, 37.3, 32.7, 31.1, 30.6, 28.6, 26.0,
25.7, 23.2, 21.1, 16.1, 12.9. υmax (CaF2, CHCl3): 1704 (br),
1666 cm-1. λmax (CH3CN): 334, 288 nm. HRMS (ESI-FTICR-
MS) m/z: [M + Na]+ Calcd for C23H32O3Na 379.2244, Found
379.2242.
The etienic acid (4.2 g, 13.2 mmol) from the previous step
and acetic anhydride (60 mL) were added to a round bottom
flask under N2. The reaction mixture was heated to reflux for
3 h, acetic acid (8 mL) and H2O (15 mL) were then added to
the hot mixture. Upon cooling, the precipitate of 3β-
acetoxyetienic acid was collected via filtration, and washed
successively with H2O and minimal amount of Et2O.
To a flame-dried round bottom equipped with a stir bar un-
der N2 was added 3β-acetoxyetienic acid (1.5 g, 4.2 mmol),
K2CO3 (1.0 g, 7.1 mmol), and DMF (20 mL). The reaction
mixture was stirred for 30 min at rt. Iodomethane (0.49 mL,
8.4 mmol) was then added, and the reaction mixture was
stirred for 18 h. At this point, TLC indicated the complete
consumption of the starting material. The reaction mixture was
diluted with CH2Cl2, transferred to separatory funnel, and
washed successively with H2O, 1.0 M HCl, saturated aq.
NH4Cl, and brine. The organic layer was dried over MgSO4,
filtered through Celite, concentrated, and the crude product
(1.5 g, 96 %) was used without a further purification.
The crude product from the previous step was dissolved in a
mixture of acetone (200 mL) and acetic acid (20 mL) in a
round-bottom flask equipped with a stir bar and reflux con-
Starting material for compound 8 (3-Methyl-2-cholesten-1-
one44,45): To a flame-dried three-neck round bottom equipped
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145 °C. 1H NMR (400 MHz, CDCl3): δ 7.30-7.27 (m, 2H),
with a stir bar and reflux condenser under N2 was added
1
2
3
4
5
6
7
8
Pd(TFA)2 (0.42 g, 1.3 mmol), a suspension of 5α-cholestan-3-
one (9.7 g, 25.0 mmol) in AcOH (125 mL), and DMSO (0.18
mL, 2.5 mmol). The reaction mixture was stirred, and the N2
atmosphere was replaced with an O2 balloon. The reaction
mixture was then heated to 80 °C for 16 h. Upon cooling, the
reaction mixture was neutralized with saturated aq. NaHCO3
and extracted into CHCl3. The combined organic layers were
dried with MgSO4, filtered through Celite, and concentrated.
The crude residue was purified via gradient column chroma-
tography eluting with hexanes to 15:85 EtOAc:hexanes to
provide 1-cholesten-3-one (8.7 g, 90 %).
7.22-7.16 (m, 3H), 5.75 (d, J = 1.6 Hz, 1H), 3.46 (dd, J = 14.1,
3.8 Hz, 1H), 2.65-2.57 (m, 1H), 2.53-2.42 (m, 2H), 2.39-2.25
(m, 2H), 2.21-2.12 (m, 1H), 2.1 (s, 3H), 2.03-1.99 (m, 1H),
1.95-1.90 (m, 1H),1.87-1.81 (m, 1H), 1.74-1.62 (m, 2H), 1.55-
1.45 (m, 2H),1.37-1.20 (m, 4H), 1.16-1.10 (m, 1H), 1.09 (2,
3H), 1.05-0.87 (m, 2H), 0.61 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 209.1, 200.0, 169.7, 140.2, 129.0, 128.3,
125.9, 123. 5, 63.4, 55.9, 53.9, 43.8, 43.6, 41.3, 39.0, 38.5,
35.3, 35.0, 32.3, 31.7, 31.4, 24.3, 22.7, 20.8, 17.3, 13.2. υmax
(ATR-IR): 1710, 1686 cm-1. λmax (CH3CN): 293 nm. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C28H36O2Na
427.2608, Found 427.2606.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The product from the previous step, 1-cholesten-3-one
(2.1 g, 5.5 mmol), was added to a flame-dried three-neck
round bottom equipped with a stir bar and reflux condenser
under N2, followed by Et2O (25 mL). The reaction mixture
was stirred and cooled to 0 °C. A 1.6 M solution of methyl-
lithium in Et2O (14 mL, 22 mmol) was added drop wise while
stirring. After addition, the reaction mixture was stirred for 1
h and let gradually warm to rt. The reaction mixture subse-
quently was cooled to 0 °C and quenched with saturated aq.
NH4Cl slowly while stirring. The organic layer was separated
and washed with H2O and brine, then dried with MgSO4, fil-
tered through Celite, and concentrated in a round bottom flask.
To the crude reaction mixture was added a stir bar, pyridinium
dichromate (5.0 g, 13 mmol), and CH2Cl2 (75 mL) under N2.
The reaction mixture was stirred at rt for 16 h, then diluted
with Et2O, filtered through a pad of Celite and silica gel, then
concentrated. The crude residue was purified via gradient
column chromatography eluting with hexanes to 25:75
EtOAc:hexanes to provide 3-methyl-2-cholesten-1-one (1.2 g,
55 %) as a white solid; m.p. = 110-111 °C. 1H NMR (400
MHz, CDCl3): δ 5.57 (s, 1H), 2.44-2.35 (m, 1H), 2.09 (dd, J =
18.8, 11.1 Hz, 1H), 1.98-1.87 (m, 2H), 1.79 (s, 3H), 1.76-1.69
(m, 2H), 1.58-1.35 (m, 5H), 1.32-1.14 (m, 9H), 1.11-0.99 (m,
6H), 0.97-0.92 (m, 1H), 0.96 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H),
0.82 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H), 0.62 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 205.9, 155.9, 125.5, 56.3,
47.4, 45.9, 42.9, 42.4, 40.1, 39.4, 36.6, 36.1, 36.0, 35.7, 30.6,
27.99, 27.97, 27.8, 24.1, 23.8, 23.4, 23.0, 22.7, 22.4, 18.5,
12.2, 10.5. υmax (CaF2, CHCl3): 1663 cm-1. λmax (CH3CN):
331 nm. HRMS (ESI-FTICR-MS) m/z: [M + Na]+ Calcd for
C28H46ONa 421.3441, Found 421.3438.
Starting material for compound 10 (3β-Acetoxy-D-homo-
5α-androst-16-en-17a-one47,48): Prasterone acetate (5.0 g, 15
mmol) was dissolved in EtOH (150 mL) and treated with KCN
(31.5 g, 484 mmol) while stirring. The reaction mixture was
cooled to 0 ºC and AcOH (35 mL) was added drop wise; the
reaction mixture was stirred for 1 h. The reaction mixture was
stirred for an additional 2 h at rt and then quenched with H2O.
The white precipitate was collected by filtration, washed with
H2O, washed with 2 % aq. AcOH, and then dried. The crude
residue (4.8 g, 12 mmol), PtO2 (1.0 g), and AcOH (150 mL)
were shaken under H2 at 40 psi in a Parr apparatus for 48 h.
The solution was filtered through Celite, concentrated, and
diluted with water (80 mL). Neutral impurities were removed
by extracting into Et2O. The aqueous layer was then trans-
ferred to a round bottom flask, along with AcOH (10 mL), and
cooled to 0 ºC. Then, NaNO2 (2.4 g, 35 mmol) dissolved in
water (8 mL) was added to the reaction mixture, which was
then stirred for 2 h at 0 ºC. The reaction mixture was warmed
to rt and stirred for additional 16 h. The precipitated white
solid was collected via filtration, washed with H2O, and dried.
The crude residue was purified via column chromatography
eluting with EtOAc:hexanes to provide 3β-acetoxy-D-homo-
5α-androstan-17a-one (2.4 g, 56 %).
To a flame-dried three-neck round bottom equipped with a
stir bar and reflux condenser under N2 were added 3β-acetoxy-
D-homo-5α-androst-17a-one (1.0 g, 2.9 mmol) and benzene-
seleninic acid anhydride (2.1 g, 5.8 mmol). Anhydrous chlo-
robenzene (12 mL) was added via syringe under N2 atmos-
phere, and the reaction mixture was stirred and heated to re-
flux for 2.5 h. The reaction mixture was quenched with satu-
rated aq. NaHCO3 and transferred to a separatory funnel. The
crude mixture was extracted into EtOAc, and the combined
organic layers were washed with H2O and brine. The crude
mixture was dried with MgSO4, filtered through Celite, and
concentrated. The crude residue was purified via column
chromatography on silica gel eluting with 20:80
EtOAc:hexanes to provide 3β-acetoxy-D-homo-5α-androst-
16-en-17a-one (0.9 g, 90 %) as a white solid; m.p. = 144-146
°C. 1H NMR (400 MHz, CDCl3): δ 6.79-6.75 (m, 1H), 5.82-
5.79 (m, 1H), 4.64-4.55 (m, 1H), 2.36 (dt, J = 19.4, 4.9 Hz,
1H), 1.96-1.83 (m, 2H), 1.93 (s, 3H), 1.80-1.67 (m, 3H), 1.60-
1.52 (m, 2H), 1.50-1.36 (m, 3H), 1.32-1.03 (m, 6H), 0.97-0.89
(m, 1H), 0.92 (s, 3H), 0.85-0.76 (m, 1H), 0.74 (s, 3H), 0.65-
0.59 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.3,
170.3, 147.6, 127.3, 73.2, 52.7, 46.5, 44.3, 43.7, 36.2, 35.30,
35.29, 33.6, 32.0, 30.3, 28.1, 27.10, 27.07, 21.2, 19.8, 15.5,
11.9. υmax (CaF2, CHCl3): 1722, 1667 cm-1. λmax (CH3CN):
Starting
material
for
compound
9
(2-
Benzylprogesterone46): To a flame-dried three-neck round-
bottom flask equipped with a stir bar and reflux condenser
under N2 was added LiBr (1.9 g, 22 mmol), diisopropylamine
(3.2 mL, 23 mmol), and THF (50 mL). The reaction mixture
was cooled to -20 °C, and then slowly treated with n-BuLi
(14.4 mL, 23 mmol, 1.6 M in hexanes) and stirred for 30 min.
The reaction mixture was cooled to -78 °C, and then proges-
terone (6.3 g, 20 mmol) in THF (15 mL) was added dropwise
and stirred for an additional 30 min. Subsequently, benzyl
bromide (4.8 mL, 40 mmol) dissolved in THF (5.0 mL) was
added dropwise, the reaction mixture was slowly warmed to rt,
and stirred for 12 h. Then, the reaction was quenched with 1.0
M HCl, extracted into Et2O (x 3), the combined organic layers
were dried over MgSO4, filtered through Celite, and concen-
trated. The crude residue was purified via column chromatog-
raphy on silica gel eluting with EtOAc:hexanes to provide 2-
benzylprogesterone (6.2 g, 78 %) as a white solid; m.p. = 142-
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
335 nm. HRMS (FTMS) m/z: [M + Na]+ Calcd for
Starting material for compound 13 (Methyl 3β-acetyl-11-
keto-oleanolate41,40,33): To
flame-dried round bottom
1
2
3
4
5
6
7
8
C22H32O3Na 367.2244, Found 367.2241.
Starting material for compound
a
equipped with a stir bar under N2 was added oleanolic acid
(3.0 g, 6.6 mmol), K2CO3 (1.5 g, 11 mmol), and DMF (30
mL). The reaction mixture was stirred for 30 min at rt. Iodo-
methane (0.49 mL, 8.4 mmol) was then added, and the reac-
tion mixture was stirred for 18 h. At this point, TLC indicated
the complete consumption of the starting material. The reac-
tion mixture was diluted with CH2Cl2, transferred to separato-
ry funnel, and washed successively with H2O, 1.0 M HCl,
saturated aq. NH4Cl, and brine. The organic layer was dried
over MgSO4, filtered through Celite, concentrated, and the
product (2.85 g, 92 %) was used without a further purification.
11
(16-
Dehydroprogesterone49): To a flame-dried three-neck round-
bottom flask equipped with a stir bar and reflux condenser
under N2 was added 16α,17-epoxyprogesterone (2.0 g, 6.0
mmol), zinc-copper couple (5.0 g), and EtOH (30 mL). The
reaction mixture was heated to reflux and stirred for 12 h. The
crude mixture was then cooled to rt and filtered. The filtrate
was transferred to a separatory funnel, washed with H2O, 1.0
M HCl, brine, dried over MgSO4, and concentrated. The
crude residue was purified by gradient column chromatog-
raphy on silica gel eluting with EtOAc:hexanes to provide 16-
dehydroprogesterone (1.5 g, 80 %) as a white solid; m.p. =
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Oleanolic acid methyl ester (2.8 g, 6.0 mmol) from the pre-
vious step was dissolved in acetic anhydride, and the reaction
mixture was stirred and heated to reflux for 3 h. Acetic acid (7
mL) and H2O (12 mL) were then added to the hot reaction
mixture, and then the reaction mixture was cooled to rt. The
crystalline precipitate was collected by filtration, washed with
H2O (4 x 15 mL) and Et2O (4 mL), and then dried to provide
methyl 3β-acetyl-oleanolate (2.93 g, 96 %).
1
178-180 °C. H NMR (400 MHz, CDCl3): δ 6.70 (dd, J = 3.4,
1.9 Hz, 1H), 5.74 (brs, 1H), 2.48-2.38 (m, 3H), 2.37-2.35 (m,
1H), 2.33-2.28 (m, 2H), 2.26 (s, 3H), 2.13-2.00 (m, 2H), 1.90-
1.85 (m, 1H), 1.81-1.67 (m, 2H), 1.66-1.58 (m, 2H), 1.56-1.30
(m, 2H), 1.21 (s, 3H), 1.19-1.07 (m, 1H), 1.06-0.97 (m, 1H),
0.94 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.8,
196.1, 170.5, 154.6, 143.9, 123.5, 55.2, 53.7, 45.6, 38.3, 35.1,
34.1, 33.5, 33.4, 32.3, 31.7, 31.4, 26.7, 20.3, 16.8, 15.4. υmax
(ATR-IR): 1700, 1669 cm-1. λmax (CH3CN): 319 nm. HRMS
(ESI-FTICR-MS) m/z: [M + Na]+ Calcd for C21H28O2Na
335.1982, Found 335.1984.
Methyl 3β-acetyloleanolate (2.0 g, 3.9 mmol) from the pre-
vious step was dissolved in a mixture of acetone (200 mL) and
acetic acid (20 mL) in a round-bottom flask equipped with a
stir bar and condenser. The reaction mixture was treated with
N-hydroxysuccinimide (4.49 g, 39 mmol) and K2Cr2O7 (4.6 g,
16 mmol), then stirred at 40 °C for 48 h. The reaction mixture
was cooled to rt, quenched with aq. 10 % sodium metabisulfite
solution, filtered through Celite and extracted into Et2O. The
combined organic layers were washed with saturated aq. Na-
HCO3 and brine, then dried with MgSO4, and concentrated.
The crude residue was recrystallized in MeOH to provide me-
thyl 3β-acetyl-11-keto-oleanolate (1.52 g, 74 %) as a white
solid; m.p. = 235.5-237 °C. 1H NMR (400 MHz, CDCl3):
δ 5.63 (s, 1H), 4.5 (dd, J = 11.6, 4.8 Hz, 1H), 3.62 (s, 3H),
3.02-2.97 (m, 1H), 2.82 (dt, J = 13.7, 3.6 Hz, 1H), 2.33 (s,
1H), 2.08-2.00 (m, 1H), 2.04 (s, 3H), 1.76-1.52 (m, 9H), 1.45-
1.30 (m, 3H), 1.35 (s, 3H), 1.28-1.17 (m, 3H), 1.12 (s, 3H),
1.09-1.01 (m, 1H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H),
0.86 (s, 6H), 0.86-0.76 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 200.0, 177.3, 170.8, 168.5, 127.7, 80.5, 61.5, 54.9,
51.7, 46.1, 44.9, 44.1, 43.3, 41.5, 38.6, 37.9, 37.0, 33.6, 32.74,
32.69, 31.5, 30.5, 27.9, 27.6, 23.43, 23.39, 23.3, 22.8, 21.2,
18.8, 17.2, 16.6, 16.1. υmax (CaF2, CHCl3): 1721 (br), 1651
cm-1. λmax (CH3CN): 332 nm. HRMS (ESI-FTICR-MS) m/z:
[M + Na]+ Calcd for C33H50O5Na 549.3551, Found 549.3545.
Starting material for compound 12 (Methyl 3β-acetoxy-
glycyrrhetinate41,40): To a flame-dried round bottom equipped
with a stir bar under N2 was added 18β-glycyrrhetinic acid
(2.0 g, 4.3 mmol), K2CO3 (1.0 g, 7.2 mmol), and DMF (20
mL). The reaction mixture was stirred for 30 min at rt. Iodo-
methane (0.32 mL, 5.1 mmol) was then added, and the reac-
tion mixture was stirred for 18 h. At this point, TLC indicated
the complete consumption of the starting material. The reac-
tion mixture was diluted with CH2Cl2, transferred to separato-
ry funnel, and washed successively with H2O, 1.0 M HCl,
saturated aq. NH4Cl, and brine. The organic layer was dried
over MgSO4, filtered through Celite, concentrated, and the
product (2.0 g, 92 %) was used without further purification.
Methyl 3β-hydroxyl-glycyrrhetinate (1.8 g, 3.7 mmol) from
the previous step was dissolved in acetic anhydride and heated
to reflux for 3 h. Acetic acid (4 mL) and H2O (8 mL) were
added to the hot reaction mixture, and then the reaction mix-
ture was cooled to rt. The crystalline precipitate was collected
by filtration, washed with H2O (4 x 10 mL), Et2O (3 mL), and
dried to provide methyl 3β-acetoxy-glycyrrhetinate (1.87 g, 96
%) as a white solid; m.p. = 295-296 °C. 1H NMR (400 MHz,
CDCl3): δ 5.62 (s, 1H), 4.47 (dd, J = 11.6, 4.9 Hz, 1H), 3.64
(s, 3H), 2.76 (dt, J = 13.7, 3.6 Hz, 1H), 2.31 (s, 1H), 2.06-2.01
(m, 1H), 2.00 (s, 3H), 1.98-1.93 (m, 2H), 1.91-1.85 (m, 1H),
1.82-1.74 (m, 1H), 1.71-1.51 (m, 5H), 1.48-1.34 (m, 3H), 1.32
(s, 3H), 1.28-1.22 (m, 2H), 1.17-1.14 (m, 1H), 1.11 (s, 3H),
1.10 (s, 3H), 1.08 (s, 3H), 1.05-0.95 (m, 2H), 0.83 (s, 6H),
0.78-0.74 (m, 1H), 0.76 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 199.9, 176.8, 170.8, 169.1, 128.4, 80.5, 61.6, 54.9,
51.6, 48.3, 45.3, 43.9, 43.1, 40.9, 38.7, 37.9, 37.6, 36.8, 32.6,
31.7, 31.0, 28.4, 28.2, 27.9, 26.4, 26.3, 23.4, 23.2, 21.2, 18.6,
17.3, 16.6, 16.3. υmax (CaF2, CHCl3): 1724 (br), 1653 cm-1.
λmax (CH3CN): 336 nm. HRMS (ESI-FTICR-MS) m/z: [M +
Na]+ Calcd for C33H50O5Na 549.3551, Found 549.3545.
ASSOCIATED CONTENT
Supporting Information
NMR spectra, UV-vis spectra, and microflow-reactor setups.
AUTHOR INFORMATION
Corresponding Author
* lectka@jhu.edu
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The Journal of Organic Chemistry
Page 12 of 13
Notes
1
The authors declare no competing financial interest.
2
3
4
5
6
7
8
12
Rutkowski, K.; Sowa, P.; Rutkowska-Talipska, J.; Kuryliszyn-
Moskal, A.; Rutkowski, R. Drugs 2014, 74, 1195-1207.
(a) Walling, C. Free Radicals in Solution; Wiley: New York, NY,
1957. (b) Zavitsas, A. A.; Pinto, J. A. J. Am. Chem. Soc. 1972, 94,
7390-7396. (c) Newhouse, T.; Baran, P. S. Angew. Chem. Int. Ed.
2011, 50, 3362-3374.
ACKNOWLEDGMENT
13
T. L. thanks the National Science Foundation (NSF) (CHE-
1465131) for support. The authors also thank COSMIC Lab at
Old Dominion University.
14 Duane, W. C.; Javitt, N. B. J. Lab. Clin. Med. 2002, 139, 109-115.
9
REFERENCES
15 Wolfling, J. Arkivoc. 2007, 210-230 and references therein.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
Samudio, I.; Konopleva, M.; Safe, S.; McQueen, T.; Andreeff, M.
Mol. Cancer. Ther. 2005, 4, 1982-1992.
17 Kamble, S. M.; Goyal, N. S.; Patil, R. C. RSC. Adv. 2014, 4, 33370-
33382.
18 Cassels, B. K.; Asencio, M. Phyochem. Rev. 2011, 10, 545-564.
1 Pitts, C. R.; Bume, D. D.; Harry, S. A.; Siegler, M. A.; Lectka, T. J.
Am. Chem. Soc. 2017, 139, 2208-2211.
For some examples, see: (a) Bloom, S.; Pitts, C. R.; Miller, D.;
19
Petronelli, A.; Pannitteri, G.; Testa, U. Anti-Cancer Drugs 2009,
20, 880-892.
2
20 Han, N.; Bakovic, M. J. Bioanal. Biomed. 2015, S12, 1-11.
21 Yu, F.; Wang, Q.; Zhang, Z.; Peng, Y.; Qiu, Y.; Shi, Y.; Zheng, Y.;
Xiao, S.; Wang, H.; Huang, X.; Zhu, L.; Chen, K.; Zhao, C.; Zhang,
C.; Yu, M.; Sun, D.; Zhang, L.; Zhou, D. J. Med. Chem. 2013, 56,
4300-4319.
Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem. Int.
Ed. 2012, 51, 10580-10583. (b) Liu, W.; Huang, X.; Cheng, M.;
Nielson, R. J.; Goddard III, W. A.; Groves, J. T. Science 2012, 337,
1322-1325. (c) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.;
Holl, M. G.; Lectka, T. Org. Lett. 2013, 15, 1722-1724. (d) Liu, W.;
Groves, J. T. Angew. Chem. Int. Ed. 2013, 52, 6024−6027. (e) Xia,
J.-B.; Ma, Y.; Chen, C. Org. Chem. Front. 2014, 1, 468−472. (f)
Braun, M.-G.; Doyle, A. J. Am. Chem. Soc. 2013, 135, 12990-12993.
22
Fang, T.-S.; Brown, R. E.; Kwan, C. L.; Singer, L. A. J. Phys.
Chem. 1978, 82, 2489-2496.
23 Evans, T. R.; Leermakers, P. E. J. Am. Chem. Soc. 1967, 89, 4380-
4382.
3
24
(a) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu,
Schuster, D. I.; Dunn, D. A.; Heibel, G. E.; Brown, P. B.; Rao, J.
T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am. Chem. Soc.
2012, 134, 4026-4029. (b) Pitts, C. R.; Ling, B.; Woltornist, R.; Liu,
R.; Lectka, T. J. Org. Chem. 2014, 79, 8895-8899. (c) Zhang, X.;
Guo, S.; Tang, P. Org. Chem. Front. 2015, 2, 806-810.
M.; Woning, J.; Bonneau, R. J. Am. Chem. Soc. 1991, 113, 6245-
6255.
25 For general information on triplet-triplet energy transfer, see: Turro,
N. J. in Modern Molecular Photochemistry, The Benjamin/Cummings
Publishing Company, Inc., Menlo Park, CA, 1978, ch. 9, pp. 296-361.
4
For some examples, see: (a) Xia, J.-B.; Zhu, C.; Chen, C. J. Am.
26
Chem. Soc. 2013, 135, 17494-17500. (b) Bloom, S.; Knippel, J. L.;
Lectka, T. Chem. Sci. 2014, 5, 1175-1178. (c) Kee, C. W.; Chin, K.
F.; Wong, M. W.; Tan, C.-H. Chem. Commun. 2014, 50, 8211-8214.
(d) Halperin, S. D.; Fan, H.; Chang, S.; Martin, R. E.; Britton, R.
Angew. Chem. Int. Ed. 2014, 53, 4690-4693. (e) Xia, J.-B.; Zhu, C.;
Chen, C. Chem. Commun. 2014, 50, 11701-11704. (f) Nodwell, M.
B.; Bagai, A.; Halperin, S. D.; Martin, R. E.; Knust, H.; Britton, R.
Chem. Commun. 2015, 51, 11783–11786. (g) Bume, D. D.; Pitts, C.
R.; Jokhai, R. T.; Lectka, T. Tetrahedron 2016, 72, 6031-6036. (h)
Hua, A. M.; Mai, D. N.; Martinez, R.; Baxter, R. D. Org. Lett. 2017,
19, 2949-2952.
Turro, N. J.; Scaiano, J. C.; Ramamurthy, V. Modern Molecular
Photochemistry of Organic Molecules; University Science
Books:Saulito, CA, 2010.
27
Pitts, C. R.; Ling, B.; Snyder, J. A.; Bragg, A. E.; Lectka, T. J. Am.
Chem. Soc. 2016, 138, 6598-6609.
28 We previously reported one example of a steroidal enone failing the
triethylborane test. However, upon revisiting the reaction with 1
under scrupulous conditions, among other steroidal enones, we were
able to reproduce the selectivity observed in the photochemical reac-
tion (in lower yields, but this protocol is notably more sensitive to O2,
H2O, etc.).
5
29
Amaoka, Y.; Nagamoto, M.; Inoue, M. Org. Lett. 2013, 15, 2160-
(a) Bloom, S.; Bume, D. D.; Pitts, C. R.; Lectka, T. Chem. Eur. J.
2163.
2015, 21, 8060-8063. (b) Pitts, C. R.; Bloom, M. S.; Bume, D. D.;
Zhang, Q. A.; Lectka, T. Chem. Sci. 2015, 6, 5225-5229.
6 (a) Chatalova-Sazepin, C.; Hemelaere, R.; Paquin, J.-F.; Sammis, G.
M. Synthesis 2015, 47, 2554-2569. (b) Champagne, P. A.; Desroches,
J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115,
9073-9174.
30
Naumann, D.; Kischkewitz, J. J. Fluorine Chem. 1990, 47, 283-
299.
31
Liu, X.-K.; Ye, B.-J.; Wu, Y.; Nan, J.-X.; Lin, Z.-H.; Piao, H.-R.
7 Bume, D. D.; Pitts, C. R.; Ghorbani, F.; Harry, S. A.; Capilato, J. N.;
Siegler, M. A.; Lectka, T. Chem. Sci. 2017, 8, 6918-6923.
8 For pioneering examples of palladium catalysis in a directed sp3 C-H
fluorination, see: (a) Hull, K. L.; Anani W. Q.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 7134-7135. (b) McMurtrey, K. B.; Racowski,
J. M.; Sanford, M. S. Org. Lett. 2012, 14, 4094-4097. (c) Zhu, R.-Y.;
Tanaka, K.; Li, G.-C.; He, J.; Fu, H.-Y.; Li, S.-H.; Yu, J.-Q. J. Am.
Chem. Soc. 2015, 137, 7067-7070. (d) Zhang, Q.; Yin, X.-S.; Chen,
K.; Zhang, S.-Q.; Shi, B.-F. J. Am. Chem. Soc. 2015, 137, 8219-8226.
(e) Miao, J.; Yang, K.; Kurek, M.; Ge, H. Org. Lett. 2015, 17, 3738-
3741. (f) Lu, X.; Xiao, B.; Shang, R.; Liu, L. Chin. Chem. Lett. 2016,
27, 305-311.
Chem. Biol. Drug. Des. 2012, 79, 523-529.
32 Zheng, Y.; Li, Y. J. Org. Chem. 2003, 68, 1603-1606.
33
Siewert, B.; Wiemann, J.; Köwitsch, A.; Csuk, R. Eur. J. Med.
Chem. 2014, 72, 84-101.
34 Takatsuto, S.; Ikekawa, N. Chem. Pharm. Bull. 1987, 35, 986-995.
35
Pouzar, V.; Černý, I. Collect. Czech. Chem. Commun. 1995, 60,
137-149.
36 Szendi, Z.; Dombi, G.; Vincze, I. Monatsh. Chem. 1996, 127, 1189-
1196.
37 Curphey, T. J. J. Org. Chem. 1979, 44, 2805-2807.
38 Arsenou. E. S.; Koutsourea, A. I.; Fousteris, M. A.; Nikolaropoulos,
S. S. Steroids, 2003, 68, 407-414.
9 See supporting information for UV-vis spectra of the sensitizers.
39 Staunton, J.; Eisenbraun, E. J. Org. Synth. 1962, 42, 4-7.
40 Beseda, I.; Czollner, L.; Shah, P. S.; Khunt, R.; Gaware, R.; Kosma,
P.; Stanetty, C.; del Ruiz-Ruiz, M. C.; Amer, H.; Mereiter, K.; Da
Cunha, T.; Odermatt, A.; Claben-Houben, D.; Jordis, U. Bioorg. Med.
Chem. 2010, 18, 433-454.
10
For some reviews, see: (a) Shahidi, N. T. Clin. Ther. 2001, 23,
1355-1390. (b) Moses, T.; Papadopoulou, K. K.; Osbourn, A. Crit.
Rev. Biochem. Mol. Bio. 2014, 49, 439-462.
11
(a) Hu, J.; Zhang, Z.; Shen, W.-J.; Azhar, S. Nutr. Metab. 2010, 7,
41 Csuk, R.; Shwarz, S.; Kluge, R.; Ströhl, D. Eur. J. Org. Chem.
2010, 45, 5718-5723.
47 and references therein. (b) Miller, W. L. Mol. Cell. Endocrinol.
2013, 379, 62-73.
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8
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42 Sondheimer, F.; Mazur, Y. J. Am. Chem. Soc. 1957, 79, 2906-2910.
46 Mitsuhashi, K.; Ito, R.; Arai, T.; Yanagisawa, A. Org. Lett. 2006, 8,
43 Muzart, J. Tetrahedron Lett. 1987, 28, 4665-4668.
1721-1724.
44 Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566-14569.
45 Frelek, J.; Szczepek, W. J.; Weiss, H. P.; Reiss, G. J.; Frank, W.;
Brechtel, J.; Schultheis, B.; Kuball, H.-G. J. Am. Chem. Soc. 1998,
120, 7010-7019.
47 Kirk, D. N.; Klyne, W.; Peach, C. M.; Wilson, M. A. J. Chem. Soc.
C 1976, 1454-1460.
48
Barton, D. H. R.; Lester, D. J.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1, 1980, 2209-2212.
49 Shankar, S.; Coates, R. M. J. Org. Chem. 1998, 63, 9177-9182.
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