Design and diastereoselective synthesis of C-2,C-20-diaryl steroidal derivatives

Article abstract of DOI:10.1002/ejoc.201200190

A novel and efficient synthetic strategy to access unique C-2 substituted steroid analogues 3 and 4 is described. The unusual C-2 aryl ether analogues 3 were shown to act as virtual antagonists of LRH-1 and were prepared as single diastereoisomers, employing a fifteen-step sequence from pregnenolone (9). The key steps include the stereoconvergent nucleophilic displacement of an epimeric mixture of 3-keto 2-bromo steroids, chemoselective carbonylation of an enol triflate and conversion of a thiopyridyl ester into an aryl ketone. The related C-2 benzyl analogues 4 were prepared in a similar manner. Starting from pregnenolone, a diastereoselective fifteen-step synthesis was developed to access novel C-2-substituted steroid analogues. A range of C-2 benzyl and aryl ether analogues were prepared to probe their efficacy as antagonists of the nuclear receptor LRH-1. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full text of DOI:10.1002/ejoc.201200190

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FULL PAPER
DOI: 10.1002/ejoc.201200190
Design and Diastereoselective Synthesis of C-2,C-20-Diaryl Steroidal
Derivatives
Jullien Rey,[a] Timothy J. C. O’Riordan,[a] Haipeng Hu,[b] James P. Snyder,[b]
Andrew J. P. White,[a] and Anthony G. M. Barrett*[a]
Dedicated to Professor Philip Parsons on the occasion of his 60th birthday
Keywords: Medicinal chemistry / Synthesis design / Drug design / Steroids / Diastereoselectivity / Carbonylation
A novel and efficient synthetic strategy to access unique C-
2 substituted steroid analogues 3 and 4 is described. The un-
usual C-2 aryl ether analogues 3 were shown to act as virtual
antagonists of LRH-1 and were prepared as single diastereo-
isomers, employing a fifteen-step sequence from pregneno-
lone (9). The key steps include the stereoconvergent nucleo-
philic displacement of an epimeric mixture of 3-keto 2-bromo
steroids, chemoselective carbonylation of an enol triflate and
conversion of a thiopyridyl ester into an aryl ketone. The re-
lated C-2 benzyl analogues 4 were prepared in a similar
manner.
therapies in breast cancer treatment. To date, the only re-
ported modulators of LRH-1 are the potent agonists based
on the diene GSK8470 1 (Figure 1).[5,6]
Although, when we started this work, there were no
known antagonists of LRH-1, several steroid-based com-
pounds have demonstrated antagonistic properties towards
a variety of nuclear receptors (Figure 2).[7]
Introduction
Nuclear receptors (NRs) are a large family of mamma-
lian transcription factors that have the particularity of bind-
ing directly to DNA and regulating the expression of adja-
cent genes. Over the years, NRs have frequently been inves-
tigated as targets in drug discovery.[1]
The liver receptor homolog-1 (LRH-1) enzyme is an or-
phan NR (no known natural ligand), which plays an impor-
tant role in human biology as well as being implicated in
the regulation of estrogen biosynthesis.[2,3] More import-
antly, LRH-1 has recently been identified as a key regulator
of estrogen receptor (ER) expression in breast cancer
cells.[4] As such the identification of small molecule antago-
nists of LRH-1 may allow for the development of novel
Figure 1. The LRH-1 agonist GSK8470 1.
Figure 2. Examples of steroid-based nuclear receptor antagonists.
[a] Department of Chemistry, Imperial College London,
SW7 2AZ, England
The LRH-1 ligand-binding domain (LBD)[8] was iden-
tified by computational methods as containing mainly
hydrophobic residues and it was postulated that steroid-
based compounds could be designed as virtual antagonists
of LRH-1. Docking studies were initiated with the farne-
soid X receptor agonist MFA-1 (2),[9] which has the advan-
Fax: +44-207-594-5805
E-mail: agm.barrett@imperial.ac.uk
[b] Department of Chemistry, Emory University,
1515 Dickey Drive, Atlanta, GA 30322, USA
Fax: +1-404-727-6689
E-mail: jsnyder@emory.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200190.
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A. G. M. Barrett et al.
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tage of only being substituted at C-3 and C-17, leaving the
remainder of the core free for in silico manipulation (Fig-
ure 3).
Figure 3. MFA-1 (2) and the virtual LRH-1 antagonists 3 and 4.
It was found that compounds bearing substituents at C-
2 would bind within the LRH-1 LBD and alter its confor-
mational rigidity, generating an inactive conformation of
helix 12 (H12) by inducing steric clashes with the amino
acid residue Leu532 (Figure 4). In particular, compounds 3
containing an aryl ether moiety at C-2 displayed preferen-
tial MM-GBSA[10] scores.
Scheme 1. Retrosynthetic analysis of targets 3 and 4.
The C-2 benzylic side chain R in 5 should be available
through alkylation of the kinetic enolate of enone 7. Alter-
natively, bromination of 7 at C-2, followed by nucleophilic
displacement with a phenol would allow access to the aryl
ether analogues 3 (R = aryl-O). The tert-butyl ester 7
should be available via esterification of the known acid 8,[11]
a derivative of pregnenolone (9).
Results and Discussion
Enone 7 was synthesized in four steps from pregnenolone
(9).[11,12] Methanolysis of the pyridinium iodide derived
from 9 provided methyl ester 10 in 83% yield over two steps
(Scheme 2). Oppenauer oxidation of homoallylic alcohol 10
Figure 4. Molecular modeling (docking poses) of steroids 3a (X =
O, Y = Cl, grey structure) and 3b (X = O, Y = H, yellow structure)
in the LBD of LRH-1 (PDB code: 1YOK). H12 and key amino
acid residue Leu532 highlighted in red.
In addition to the aryl ethers 3, we decided to undertake
the synthesis of the methylene-linked series 4 in parallel to
probe the importance and stability of the arene–steroid
ether linkage.
Retrosynthetic analysis of 3 and 4 revealed that they
could be obtained from commercially available pregnen-
olone (9) (Scheme 1). It was envisaged that the aryl ketone
group could be introduced by the addition of an organome-
tallic reagent to an activated ester. The dienyl acid moiety
could be installed by palladium-catalyzed carbonylation of
the corresponding triflate 5, itself derived from enone 6.
Scheme 2. Formation of ester 7. Reagents and conditions: (a) pyr-
idine, I2, reflux; (b) NaOMe, MeOH, reflux, 83% (2 steps); (c)
Al(OiPr)3, cyclohexanone, toluene, reflux, 61%; (d) KOH, MeOH,
H2O, reflux, 89%; (e) isobutylene, H2SO4, CH2Cl2, –78 to 25 °C,
88%.
2
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C-2,C-20-Diaryl Steroid Analogues
with concomitant olefin migration gave acid 8 after hydrol-
ysis of the C-17 methyl ester. The key tert-butyl ester 7 was
prepared by esterification of 8 with isobutylene under acidic
conditions.
With enone 7 in hand, introduction of the C-2 substitu-
ent was investigated. Generation of the kinetic enolate of
enone 7 followed by addition of iodomethane gave the de-
sired C-2 methylated enone 11 in a moderate 40% yield, as
a single regioisomer and as a 1:1 (α/β) mixture of C-2 epi-
mers. It was subsequently found that treatment of the enol-
ate with hexamethylphosphoramide (HMPA) before the ad-
dition of iodomethane gave methyl ketones 11 in a much
improved 87% yield, again as a 1:1 (α/β) mixture of C-2
epimers (Scheme 3).
Figure 5. X-ray crystallographic analysis of enone 11.
With conditions for C-2 alkylation in hand, addition of
benzylic substituents required for the targets 4 was investi-
gated. Formation of the kinetic enolate of 7, as described
previously, followed by alkylation with benzyl bromide gave
enone 12, this time as a 12:1 (α/β) mixture of C-2 epimers,
negating the need for a separate equilibration step (Table 2,
entry 1). Recrystallization of the crude material from eth-
anol provided ketone 12 as essentially a single epimer.
Pleasingly these reaction conditions were applicable to a
variety of para-substituted benzyl bromides providing ana-
logues 13–15 with good to excellent diastereoisomeric ratios
(Table 2, entries 2–4).
Scheme 3. Alkylation of enone 7. Reagents and conditions: (a)
LiN(SiMe3)2, THF, –78 °C, 30 min; HMPA, 20 min; MeI, –78 to
25 °C, 87%.
In order to obtain 2-methyl-substituted steroid 11 as a
single diastereoisomer, an investigation into the equilibra-
tion of the C-2 epimers was undertaken. Reaction with
methanolic potassium hydroxide either at ambient or ele-
vated temperatures resulted in only a minor change in the
ratio of epimers (Table 1, entries 1–2). It was subsequently
discovered that the ratio of C-2 epimers could be increased
to 8:1 (α/β) by the use of DBU in toluene at reflux (Table 1,
entry 4).
Table 2. Formation of C-2 alkyl analogues.
Table 1. Isomerization of the 2-methyl-substituted steroidal
ketones.
Entry
R
Product
Yield/%
C-2 dr (α/β)[a]
1
2
3
4
H
Cl
tBu
CF3
12
13
14
15
52
61
83
75
50:1[b]
Ͼ 50:1[c]
13:1[d]
16:1[d]
[a] As determined by integration of the 1H NMR spectrum. [b]
After recrystallization from EtOH, crude ratio 12:1 (α/β). [c] After
recrystallization from EtOAc, crude ratio 12:1 (α/β). [d] After col-
umn chromatography.
Entry
Conditions
C-2 dr (α/β)[a]
1
2
3
4
KOH, H2O, MeOH, 8 h, 25 °C
KOH, H2O, MeOH, 8 h, reflux
DBU, toluene, 8 h, 80 °C
1.1:1.0
1.9:1.0
2.1:1.0
8.0:1.0
DBU, toluene, 16 h, reflux
Single crystals of chlorobenzyl ketone 13 were grown
from ethyl acetate and X-ray crystallographic analysis once
more clearly demonstrated the desired α-C-2 stereochemis-
1
[a] As determined by integration of the H NMR spectrum.
Since enone 11 was a solid, attempted recrystallization try (Figure 6).
from a range of solvent mixtures was examined. Recrystalli-
To introduce the C-2 aryl ether functionality, enone 7
zation of the 8:1 (α/β) C-2 epimeric mixture from ethyl acet- was first transformed into bromide 17 by reaction of silyl
ate resulted in an enhancement of the epimeric purity of enol ether 16, derived from enone 7, with N-bromosuc-
enone 11 to 12:1 (α/β). Single crystals of sufficient quality cinimide (Scheme 4). This sequence provided 17 as an in-
for X-ray analysis were obtained and the crystal structure of separable 2:3 (α/β) mixture of C-2 epimers and attempts to
enone 11 demonstrated the required α-C-2 stereochemistry alter the diastereoisomeric ratio by epimerization with lith-
(Figure 5).
ium bromide or recrystallization were unsuccessful. How-
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stants of 13.7 Hz (ax-ax) and 4.9 Hz (ax-eq) suggested that
the aryl ether side chain assumed a pseudo-equatorial posi-
tion. This was subsequently confirmed by X-ray analysis of
ether 20 (Figure 7).
Figure 6. X-ray crystallographic analysis of chloride 13.
ever, addition of the bromide epimers 17 to an excess of
sodium 4-chlorophenoxide led, after recrystallization of the
crude product from ethyl acetate, to the isolation of α-ether
20 as a single diastereoisomer in 75% yield.
Figure 7. X-ray crystallographic analysis of ether 20.
Next our attention was directed towards the introduction
of the dienyl methyl ester moiety via a palladium-catalyzed
carbonylation reaction.[13,14] Enones 11–15 and 20–21 were
initially allowed to react with 2,6-di-tert-butyl-4-methylpyr-
idine (22) and triflic anhydride to generate the correspond-
ing thermodynamic dienyl triflates (Table 3). These were
subsequently allowed to react with carbon monoxide and
Table 3. Introduction of the dienyl ester functionality.
Scheme 4. Introduction of the C-2 aryl ether functionality. Rea-
gents and conditions: (a) LiN(SiMe3)2, THF, –78 °C, 30 min;
HMPA, 30 min; Me3SiCl, –78 °C, 1 h; 0 °C, 30 min; (b) NBS, THF,
0 °C, 30 min, 67% (2 steps); (c) for 20: 18, NaH, THF, 0 °C; 17, 0
to 25 °C, 3 h, 75%; for 21: 19, NaH, THF, 0 °C; 17, 0 to 25 °C,
3 h, 79%.
Interestingly, under these reaction conditions, the desired
α-epimer 20 was formed preferentially. Presumably after re-
action with the mixture of bromide epimers 17, an equili-
bration of the initial mixture of aryl ether epimers occurred.
Either an equilibration of the C-2 proton in the basic condi-
tions or displacement of the undesired β-epimer corre-
sponding to 20 with excess sodium 4-chlorophenolate led
to the formation of the more stable α-epimer 20 in which
the C-2 ether side chain adopts a pseudo-equatorial confor-
mation. An equivalent reaction using sodium phenolate
gave the α-ether 21 in 79% yield from 17.
The relative stereochemistry of ether 20 was initially de-
1
termined by H NMR spectroscopy. A doublet of doublets
at δ = 4.78 ppm corresponding to H-2 with coupling con- [a] Carbonylation carried out at 40 °C. [b] Yield over two steps.
4
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C-2,C-20-Diaryl Steroid Analogues
methanol catalysed by bis(triphenylphosphane)palladium both the alkyl (Table 5, entry 1) and benzylic (Table 5, en-
diacetate thereby giving dienyl methyl esters 23–29. Gratify- tries 2–5) as well as the C-2 aryl ether analogues (Table 5,
ingly, these methoxycarbonylation reactions could be car- entries 6 and 7).[17]
ried out in the presence of aryl chlorides (Table 3, entries 3
and 6) without any complications.
Table 5. Formation of the C-17 activated esters.
Selective deprotection of the tert-butyl ester in the pres-
ence of the methyl ester was achieved under acidic condi-
tions (Table 4).[15] Subjecting the tert-butyl esters 23–27 to
trifluoroacetic acid in the presence of triethylsilane gave the
corresponding carboxylic acids in excellent yield for both
alkyl (Table 4, entry 1) and benzyl (Table 4, entries 2–5) an-
alogues. However, subjecting ethers 28 and 29 to the same
reaction conditions resulted in the formation of a mixture
of by-products where the C-2 aryl ether side chain had been
cleaved, demonstrating the high sensitivity of the ether link-
age to acidic conditions. It was subsequently found that
by employing trimethylsilyl trifluoromethanesulfonate
(TMSOTf) and an excess of triethylamine, the esters 28 and
29 could be selectively cleaved to the corresponding carbox-
ylic acids in good to excellent yield (Table 4, entries 6 and
7).[16]
Table 4. Selective deprotection of the C-17 tert-butyl ester group.
[a] Isolated yield.
It was found that the C-17-aroyl steroid functionality
could be introduced by addition of a Grignard reagent to
the thiopyridine esters (Table 6). By employing the commer-
cially available Grignard reagent 45, followed by THP de-
protection, the corresponding phenols were isolated in good
yield (Table 6, entries 2–4). Our concerns about the stability
of the aryl ether functionality to the acidic deprotection
conditions led us to investigate an alternative approach for
these substrates. Aryl iodide 46 was first allowed to react
with isopropylmagnesium chloride and the resulting Grig-
nard reagent was added to thiopyridine ester in THF at
–50 °C, affording the protected phenol.[18,19] Deprotection
of the silyl ether using tetrabutylammonium fluoride pro-
vided the target phenols (Table 6, entries 1, 5 and 6).
Finally, hydrolysis of the methyl esters under basic condi-
tions at elevated temperatures provided the carboxylic acid
analogues 4a and 4b in the benzylic series (Table 7, entries
1–2).
[a] Reagents and conditions: A: CF3CO2H, Et3SiH, CH2Cl2, 25 °C;
B: TMSOTf, Et3N, CH2Cl2, 0 to 25 °C.
Reaction of the carboxylic acids with triphenylphos-
Subjecting the aryl ether analogues 51 and 52 to the same
phane and 2,2Ј-dithiodipyridine (37) gave the correspond- reaction conditions resulted in the formation of a mixture
ing thiopyridyl esters ready for the installation of the C-20 of unidentified by-products. However, prolonged exposure
phenolic moiety. This transformation was applicable to of methyl esters 51 and 52 to an excess of lithium hydroxide
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Table 6. Formation of the aryl ketone.
eluent systems led to partial C-2 ether cleavage. Pleasingly,
purification of these analogues by preparative TLC gave the
target steroids 3a and 3b.
Scheme 5. Hydrolysis of the C-3 methyl group. Reagents and condi-
tions: (a) LiOH·H2O, H2O, MeOH, 25 °C, 48–96 h.
Conclusions
A number of novel steroids bearing either a para-func-
tionalized C-2 benzylic or aryloxy substituent have been de-
signed and prepared in 14 and 15 steps respectively from
pregnenolone (9). In addition, docking studies performed
on analogues 3a and 3b showed that these two compounds
could act as virtual LRH-1 antagonists by generating an
inactive conformation of this NR. Unfortunately these
novel steroid compounds did not show a significant modu-
lation of LRH-1 activity (less than 50% inhibition at 10 μm)
suggesting that these analogues do not bind LRH-1 as pre-
dicted by our original docking studies.
Computational Details
The crystal structure of LRH-1 LBD (PDB code: 1YOK) was pre-
pared using Maestro9.0 for the docking studies. In order to mimic
the inactive state of LRH-1, residues on H12 and the adjacent loop
between H11 and H12 (residues 522–538) in LRH-1 LBD were
removed in the protein preparation. The steroid analogues were
prepared using LigPrep 2.3 and were docked into prepared LRH-
1 LBD crystal structure using Glide5.5. A Prime 2.1 MM-GBSA
rescoring was performed to predict the LRH-1/compounds binding
affinities.
[a] Reagents and conditions: A: 1) 45, THF, –50 °C; 2) TsOH·H2O,
THF, MeOH. B: 1) 46, iPrMgCl, THF, 0 °C; thiopyridine ester,
–50 °C; 2) Bu4NF, THF. [b] Yield over two steps.
Table 7. Hydrolysis of the C-3 methyl ester group.
Experimental Section
General Remarks: All chemicals were used as received, or purified
using standard procedures. Solvents were dried by standard tech-
niques and distilled under nitrogen before use. All experiments were
carried out in oven-dried glassware under an atmosphere of N2 or
Ar, unless otherwise stated. Analytical thin layer chromatography
(TLC) was performed using pre-coated aluminum plates (Merck
Silicagel 60 F254). Visualization was by UV light and/or treatment
with potassium permanganate (KMnO4) or vanillin stains followed
by heating as deemed appropriate. Flash column chromatography
was carried out using silica (Kieselgel 60, 230–400 mesh, Merck no.
9385) under a positive pressure of nitrogen.
[a] Isolated yield.
Specific rotations were measured with a path length of 1 dm, using
a sodium lamp (λ = 589 nm, D-line); concentrations (c) are quoted
in g/100 mL. Melting points (m.p.) were determined using a hot-
stage microscope. Infrared (IR) spectra were recorded with ATR
monohydrate at room temperature gave the desired acids 3a
and 3b (Scheme 5).[20] Purification of 3a and 3b by flash
column chromatography was unsuccessful due to the high
affinity of these acids to silica gel and the use of acidic technique, monitoring from 4000–700 cm–1. NMR spectra were re-
6
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C-2,C-20-Diaryl Steroid Analogues
corded using an internal deuterium lock at ambient probe tempera-
tures (1H NMR recorded at 400 or 500 MHz and 13C NMR re-
corded at 100 or 125 MHz). Chemical shifts (δ) are quoted in parts
per million (ppm) and are referenced to a residual solvent peak.
Acid 8 was synthesized as described previously.[11]
55.4, 54.1, 45.0, 43.6, 39.2, 38.1, 36.9, 35.5, 32.4, 31.8, 28.2, 24.3,
23.2, 20.7, 17.5, 14.7, 13.2 ppm. MS (ESI): m/z (%) = 387 (100) [M
+ H]+. HRMS (ESI): calcd. for C25H39O3 387.2899; found
387.2896. C25H38O3 (386.57): calcd. C 77.68, H 9.91; found C
77.74, H 9.83. [α]2D5 = +126.0 (c = 1.0, CHCl3).
CCDC-865064 (for 11), -865065 (for 13) and -865066 (for 20) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of 12: Ketone 7 (1.05 g, 2.78 mmol) was subjected to ge-
neral procedure 1 employing PhCH2Br as the electrophile. The
crude product was purified by flash column chromatography (elut-
ing with 1:4 Et2O/hexanes) to yield 12 (670 mg, 52%, 9:1 mixture
of C-2 epimers) as a white solid. Ketone 12 was recrystallized from
EtOH to provide 12 (50:1 mixture of C-2 epimers) as a white solid;
Synthesis of 7: Isobutene (32 mL) was condensed at –78 °C and
acid 8 (10.0 g, 31.6 mmol) in CH2Cl2 (250 mL) was added. Concen-
trated H2SO4 (0.30 mL, 6.30 mmol) was added and the mixture was
warmed to room temperature over a period of 16 h. The reaction
was quenched by dropwise addition of saturated aqueous NaHCO3
and the phases separated. The aqueous layer was extracted with
CH2Cl2 (3ϫ50 mL) and the combined organic extracts were
washed with brine, dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was recrystallized from EtOAc to yield
ester 7 (10.4 g, 88%) as a pale yellow solid; m.p. 216–218 °C
m.p. 118–120 °C (EtOH). IR (neat): ν
= 1719, 1657, 1621 cm–1.
˜
max
1H NMR (400 MHz, CDCl3): δ = (major epimer only) 7.30–7.26
(m, 2 H), 7.21–7.15 (m, 3 H), 5.75 (d, JH,H = 1.2 Hz, 1 H), 3.47
(dd, JH,H = 14.0 and 3.8 Hz, 1 H), 2.65–2.56 (m, 1 H), 2.45–2.20
(m, 4 H), 2.12–1.96 (m, 2 H), 1.92 (dd, JH,H = 13.2 and 4.6 Hz, 1
H), 1.86–1.60 (m, 4 H), 1.53–1.46 (m, 1 H), 1.43 [s, 9 H,
CO2C(CH3)3], 1.39–1.18 (m, 4 H), 1.08 (s, 3 H), 1.06–0.96 (m, 2
H), 0.88 (dt, JH,H = 11.5 and 4.0 Hz, 1 H), 0.67 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 200.1, 173.1, 170.0, 140.2, 129.0,
128.3, 125.8, 123.5, 79.7, 55.7, 55.3, 54.0, 43.6, 43.6, 41.3, 39.1,
38.1, 35.5, 35.0, 32.3, 31.8, 28.2, 24.3, 23.1, 20.7, 17.3, 13.1 ppm.
MS (ESI): m/z (%) = 463 (100) [M + H]+. HRMS (ESI): calcd. for
C31H43O3 463.3212; found 463.3204. C31H42O3 (462.67): calcd. C
80.48, H 9.15; found C 80.36, H 9.25. [α]2D5 = +39.0 (c = 1.0,
CHCl3).
(EtOAc). IR (neat): ν
= 1717, 1674, 1620 cm–1. 1H NMR
˜
max
(400 MHz, CDCl3): δ = 5.72 (s, 1 H), 2.46–2.23 (m, 4 H), 2.13–
1.99 (m, 3 H), 1.88–1.49 (m, 7 H), 1.44 (s, 9 H), 1.30–1.20 (m, 3
H), 1.18 (s, 3 H), 1.12–0.92 (m, 3 H), 0.72 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 199.4, 173.1, 171.1, 123.8, 79.8, 55.8, 53.7,
43.7, 38.6, 38.1, 35.6, 33.9, 32.8, 31.9, 28.2, 24.3, 23.2, 20.9, 17.3,
13.2 (one peak obscured at 35.6) ppm. MS (ESI): m/z (%) = 373
(100) [M + H]+. HRMS (ESI): calcd. for C24H37O3 373.2743, found
373.2744. C24H36O3 (372.55): calcd. C 77.38, H 9.74; found C
77.29, H 9.67. [α]2D5 = +134.5 (c = 1.0, CHCl3).
Synthesis of 13: Ketone 7 (1.05 g, 2.78 mmol) was subjected to ge-
neral procedure 1 employing 4-chlorobenzyl bromide as the electro-
phile. The crude product was purified by flash column chromatog-
raphy (eluting with 1:4 Et2O/hexanes) to yield 13 (818 mg, 61%,
12:1 mixture of C-2 epimers) as a white solid. Ketone 13 was recrys-
tallized from EtOAc to yield diastereomerically pure 13 as a white
Alkylation of Ketone 7 at C-2. General Procedure 1: Ketone 7
(1.0 equiv.) in THF (10 mL/mmol) was added dropwise to LiN-
(SiMe3)2 (1.0 m in THF; 1.2 equiv.) in THF (1.0 mL/mmol) at
–78 °C. The mixture was stirred for 30 min and HMPA (1.2 equiv.)
was added and the mixture was stirred for a further 30 min. The
corresponding electrophile (3.0 equiv.) was added and the mixture
was stirred for 2 h at –78 °C and warmed to 0 °C over a period of
1 h. The mixture was poured into aqueous HCl (1.0 m; 5.0 mL/
mmol) and separated. The aqueous layer was extracted with Et2O
(10 mL/mmol) and the combined organic extracts were washed
with brine (2.0 mL/mmol), dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash column
chromatography to yield the corresponding C-2-alkyl ketone.
solid; m.p. 167–169 °C (EtOAc). IR (neat): ν
= 1721, 1654,
˜
max
1616 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.24 (d, JH,H
=
8.4 Hz, 2 H), 7.10 (d, JH,H = 8.3 Hz, 2 H), 5.74 (d, JH,H = 0.9 Hz,
1 H), 3.37 (dd, JH,H = 13.9 and 3.8 Hz, 1 H), 2.61–2.52 (m, 1 H),
2.45 (dd, JH,H = 13.9 and 8.9 Hz, 1 H), 2.39–2.20 (m, 3 H), 2.11–
1.99 (m, 2 H), 1.90–1.80 (m, 2 H), 1.79–1.62 (m, 2 H), 1.57–1.42
(m, 2 H), 1.43 [s, 9 H, CO2C(CH3)3], 1.36–1.18 (m, 4 H), 1.09 (s, 3
H), 1.08–0.97 (m, 2 H), 0.91–0.82 (m, 1 H), 0.67 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 199.7, 173.1, 170.1, 138.6, 131.6,
130.4, 128.4, 123.4, 79.7, 55.7, 55.3, 54.0, 43.5, 41.2, 39.1, 38.0,
35.4, 34.3, 32.3, 31.7, 28.2, 24.3, 23.1, 20.7, 17.3, 13.1 ppm. MS
(ESI): m/z (%) = 497 (100) [M + H]+. HRMS (ESI): calcd. for
C31H42O3Cl 497.2822; found 497.2808. C31H41ClO3 (497.12): calcd.
C 74.9, H 8.31; found C 75.0, H 8.39. [α]2D5 = +27.5 (c = 1.0,
CHCl3).
Synthesis of 11: Ketone 7 (1.15 g, 3.10 mmol) was subjected to ge-
neral procedure 1 employing MeI as the electrophile. The crude
product was purified by flash column chromatography (eluting
with 1:4 Et2O/hexanes) to yield ketone 11 (1.00 g, 87%) as a 1:1
mixture of C-2 epimers. The resulting ketone was dissolved in tolu-
ene (20 mL) and DBU (0.50 mL, 3.29 mmol) was added. The mix-
ture was heated at reflux for 16 h, cooled to room temperature and
diluted with Et2O (50 mL). The mixture was washed with aqueous
HCl (1.0 m; 20 mL), dried (MgSO4), filtered, and concentrated in
vacuo to yield 11 (978 mg, 83%) as an 8:1 mixture of C-2 epimers.
The crude product was recrystallized from EtOAc to yield ketone
11 (782 mg, 66%, 12:1 mixture of C-2 epimers) as a white solid;
Synthesis of 14: Ketone 7 (1.00 g, 2.68 mmol) was subjected to ge-
neral procedure 1 employing 4-tert-butylbenzyl bromide as the elec-
trophile. The crude product was purified by flash column
chromatography (eluting with 1:4 Et2O/hexanes) to yield 14 (1.15 g,
83%, 13:1 mixture of C-2 epimers) as a colorless oil. IR (neat):
1
ν
= 1724, 1672 cm–1. H NMR (400 MHz, CDCl3): δ = (major
˜
max
epimer only) 7.29 (d, JH,H = 8.2 Hz, 2 H), 7.10 (d, JH,H = 8.2 Hz,
= 1716, 1668, 1623, 2 H), 5.75 (d, JH,H = 1.1 Hz, 1 H), 3.44 (dd, JH,H = 14.2 and 3.7 Hz,
m.p. 176–178 °C (EtOH). IR (neat): ν
˜
max
1148 cm–1. H NMR (400 MHz, CDCl3): δ = (major epimer only)
5.70 (d, JH,H = 1.5 Hz, 1 H), 2.49–2.38 (m, 1 H), 2.37–2.32 (m, 1
H), 2.29–2.22 (m, 2 H), 2.13–1.97 (m, 3 H), 1.88–1.80 (m, 1 H),
1.80–1.46 (m, 6 H), 1.45 [s, 9 H, CO2C(CH3)3], 1.40–1.34 (m, 1 H),
1.30–1.22 (m, 2 H), 1.21 (s, 3 H), 1.10 (d, JH,H = 6.6 Hz, 3 H),
1.08–1.02 (m, 1 H), 0.95–0.86 (m, 1 H), 0.71 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 201.6, 173.1, 169.8, 123.4, 79.8, 55.8,
1 H), 2.61 (ddd, JH,H = 13.8, 8.7 and 4.2 Hz, 1 H), 2.42–2.21 (m,
4 H), 2.12–1.96 (m, 1 H), 1.87–1.59 (m, 4 H), 1.54–1.45 (m, 2 H),
1.43 [s, 9 H, CO2C(CH3)3], 1.31 [s, 9 H, ArC(CH3)3], 1.28–1.20 (m,
3 H), 1.11 (s, 3 H), 1.07–1.00 (m, 2 H), 0.94–0.84 (m, 1 H), 0.67 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.3, 173.1, 169.9,
148.5, 137.0, 128.6, 125.1, 123.5, 79.7, 55.7, 55.3, 54.0, 43.6, 43.6,
41.5, 39.1, 38.1, 35.5, 34.4, 34.3, 32.3, 31.8, 31.3, 28.2, 24.3, 23.1,
1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
A. G. M. Barrett et al.
FULL PAPER
20.8, 17.4, 13.1 ppm. MS (ESI) m/z (%) = 519 (100) [M + H]+.
HRMS (ESI) calcd. for C35H51O3 519.3838; found 519.3835. [α]2D5
= +14.3 (c = 1.0, CHCl3).
crude product was purified by flash column chromatography (elut-
ing with 1:1 hexanes/Et2O) and recrystallized from EtOAc to yield
20 (208 mg, 75%) as a white solid; m.p. 204–207 °C (EtOAc). IR
(neat): ν
= 1721, 1687, 1490, 1367, 1245, 1215, 1151, 823,
˜
max
Synthesis of 15: Ketone 7 (1.00 g, 2.68 mmol) was subjected to ge-
neral procedure 1 employing 4-(trifluoromethyl)benzyl bromide as
the electrophile. The crude product was purified by flash column
chromatography (eluting with 1:4 Et2O/hexanes) to yield 15 (1.06 g,
75%, 16:1 mixture of C-2 epimers) as a colorless oil. IR (neat):
733 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.21 (d, JH,H = 8.9 Hz,
2 H), 6.84 (d, JH,H = 8.9 Hz, 2 H), 5.78 (s, 1 H), 4.78 (dd, JH,H
=
13.7 and 4.9 Hz, 1 H), 2.41–2.32 (m, 3 H), 2.26 (t, JH,H = 9.2 Hz,
1 H), 2.12–2.02 (m, 2 H), 1.94–1.85 (m, 2 H), 1.80–1.65 (m, 2 H),
1.61–1.54 (m, 3 H), 1.45 (s, 9 H), 1.33 (s, 3 H), 1.30–1.22 (m, 2 H),
1.14–1.00 (m, 3 H), 0.72 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.7, 173.1, 170.7, 156.9, 129.3, 126.3, 122.0, 117.1,
79.9, 75.8, 55.8, 55.3, 54.3, 43.6, 42.2, 40.7, 38.0, 35.2, 32.3, 31.9,
28.3, 24.3, 23.2, 20.8, 18.2, 13.2 ppm. MS (ESI): m/z (%) = 499
(100) [M + H]+. HRMS (ESI): calcd. for C30H40ClO4 499.2615;
found 499.2612. [α]2D5 = +40.8 (c = 4.2, CHCl3).
ν
= 1721, 1670, 1618 cm–1. 1H NMR (400 MHz, CDCl3): δ =
˜
max
(major epimer only) 7.53 (d, JH,H = 8.0 Hz, 2 H), 7.29 (d, JH,H
=
8.0 Hz, 2 H), 5.75 (d, JH,H = 1.2 Hz, 1 H), 3.47 (dd, JH,H = 13.7
and 3.6 Hz, 1 H), 2.67–2.50 (m, 2 H), 2.40–2.21 (m, 3 H), 2.13–
1.99 (m, 2 H), 1.91–1.63 (m, 4 H), 1.54–1.45 (m, 2 H), 1.43 [s, 9 H,
CO2C(CH3)3], 1.40–1.18 (m, 4 H), 1.10 (s, 3 H), 1.08–0.97 (m, 2
H), 0.94–0.82 (m, 1 H), 0.67 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 199.4, 173.1, 170.2, 144.5, 129.3, 128.3 (q, JC,F
=
Synthesis of 21: NaH (60% dispersion in mineral oil; 316 mg,
7.91 mmol) was added to phenol (19) (719 mg, 7.64 mmol) in THF
(15 mL) at 0 °C and the mixture stirred for 30 min. The bromide
epimers 17 [1.15 g, 2.55 mmol, 2:3 (α/β)] in THF (5.0 mL) was
added and the mixture stirred at 0 °C for 30 min and warmed to
room temperature over 3 h. The mixture was diluted with EtOAc
(10 mL) and quenched by addition of saturated aqueous NH4Cl
(10 mL). The aqueous layer was extracted with EtOAc (3ϫ10 mL)
and the combined organic extracts were washed with 10% aqueous
KOH (2 ϫ10 mL) and brine (10 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography (eluting with 4:1 hexanes/Et2O) to yield
32 Hz, CF3), 125.2, 125.2, 123.3, 79.8, 55.7, 55.3, 53.9, 43.6, 43.4,
41.3, 39.1, 38.0, 35.4, 34.9, 32.4, 31.7, 28.2, 24.3, 23.1, 20.8, 17.3,
13.1 ppm. 19F NMR (376 MHz, CDCl3): δ = –62.2 ppm. MS (ESI):
m/z (%) = 531 (100) [M + H]+. HRMS (ESI): calcd. for
C32H42O3F3 531.3086; found 531.3085. [α]2D5 = +25.7 (c = 1.0,
CHCl3).
Synthesis of 17: Ketone 7 (1.50 g, 4.03 mmol) in THF (40 mL) was
added dropwise to LiN(SiMe3)2 (1.0 m in THF; 4.83 mL,
4.83 mmol) in THF (4.8 mL) at –78 °C. The reaction mixture was
stirred for 30 min and HMPA (840 μL, 4.83 mmol) was added. Af-
ter 30 min at –78 °C, Me3SiCl (3.07 mL, 24.2 mmol) was added and
the mixture stirred at –78 °C for 1 h, warmed to 0 °C and stirred
for a further 30 min. The mixture was rotary evaporated and the
crude silyl enol ether 16 was dissolved in THF (40 mL) and cooled
to 0 °C. N-bromosuccinimide (789 mg, 4.43 mmol) in THF
(9.0 mL) was added dropwise and the reaction mixture stirred for
30 min. The mixture was diluted with Et2O and quenched by ad-
dition of aqueous HCl (1.0 m; 10 mL). The aqueous layer was ex-
tracted with Et2O (3ϫ20 mL) and the combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography (eluting
with 1:4 Et2O/hexanes) to yield bromo-ketone 17 [1.22 g, 67%, 2:3
(α/β) mixture of C-2 epimers] as a white amorphous solid. IR
21 (930 mg, 79%) as a white paste. IR (neat): ν
= 1722, 1688,
˜
max
1598, 1495, 1366, 1243, 1216, 1149, 751 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.28 (t, JH,H = 7.4 Hz, 2 H), 6.98 (t, JH,H = 7.4 Hz, 1
H), 6.93 (d, JH,H = 7.4 Hz, 2 H), 5.81 (s, 1 H), 4.87 (dd, JH,H
=
13.7 and 4.9 Hz, 1 H), 2.44–2.37 (m, 3 H), 2.28 (t, JH,H = 8.8 Hz,
1 H), 2.15–2.05 (m, 2 H), 1.95–1.85 (m, 2 H), 1.83–1.68 (m, 2 H),
1.62–1.54 (m, 2 H), 1.46 (s, 9 H), 1.35 (s, 3 H), 1.34 (m, 1 H), 1.32–
1.24 (m, 2 H), 1.15–1.00 (m, 3 H), 0.74 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 195.9, 173.0, 170.3, 158.1, 129.3, 122.0,
121.3, 115.6, 79.8, 75.3, 55.6, 55.2, 54.2, 43.6, 42.2, 40.7, 37.9, 35.1,
32.2, 31.8, 28.2, 24.2, 23.1, 20.7, 18.1, 13.1 ppm. MS (ESI): m/z (%)
= 465 (100) [M + H]+, 528 (60) [M + Na + MeCN]+. HRMS (ESI):
calcd. for C30H41O4 465.3005; found 465.3008. [α]2D5 = +101.2 (c =
1.0, CHCl3).
(neat): ν
= 1717, 1681, 1623, 1453, 1367, 1222, 1149, 847 cm–1.
˜
max
1H NMR (400 MHz, CDCl3): Selected peaks only as mixture of
isomers; (selected peaks, α-17): δ = 5.82 (s, 1 H), 4.81 (dd, J = 14.5
and 5.1 Hz, 1 H), 1.45 (s, 9 H), 1.28 (s, 3 H), 0.72 (s, 3 H); (selected
peaks, β-17): δ = 5.84 (s, 1 H), 4.54 (dd, J = 6.2 and 5.4 Hz, 1 H),
1.45 (s, 9 H), 1.37 (s, 3 H), 0.72 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 191.4, 190.9, 173.0, 172.5, 171.4, 121.5, 120.6, 79.9,
55.8, 55.3, 54.0, 53.9, 51.1, 48.0, 46.4, 43.9, 43.6, 42.0, 40.1, 38.2,
38.0, 35.4, 35.3, 33.2, 32.5, 31.7, 28.3, 24.3, 23.3 ppm. MS (ESI):
m/z (%) = 451 (97) [M(79Br) + H]+, 453 (100) [M(81Br) + H]+.
HRMS (ESI): calcd. for C24H3679BrO3 [M + H]+ 451.1848; found:
451.1851.
Transformation of Enones Into Dienyl Esters. General Procedure 2:
Triflic anhydride (1.5 equiv.) was added to enone (1.0 equiv.) and
2,6-di-tert-butyl-4-methylpyridine (22) (1.6 equiv.) in CH2Cl2
(10 mL/mmol) at –20 °C and the mixture was stirred for 2 h and
poured into saturated aqueous NH4Cl (10 mL/mmol). The mixture
was separated and the organic layer was washed with saturated
aqueous NaHCO3 (10 mL/mmol), dried (MgSO4), filtered, and
concentrated in vacuo. The crude enol triflate was dissolved in a
1:1 mixture of DMF and MeOH (4.0 mL/mmol). Et3N (2.0 equiv.)
and (PPh3)2Pd(OAc)2 (0.10 equiv.) were added and the mixture was
sparged with CO for 5 min and stirred under an atmosphere of CO
for 16 h. The mixture was diluted with EtOAc (10 mL/mmol) and
washed with aqueous HCl (1.0 m; 5.0 mL/mmol) and brine
(3ϫ5.0 mL/mmol), dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy to yield the corresponding dienyl ester.
Synthesis of 20: NaH (60% dispersion in mineral oil; 68.8 mg,
1.72 mmol) was added to para-chlorophenol (18) (214 mg,
1.66 mmol) in THF (3.4 mL) at 0 °C and the mixture was stirred
for 30 min. The bromide epimers 17 [250 mg, 0.553 mmol, 2:3 (α/
β)] in THF (1.1 mL) was added and the mixture was stirred at 0 °C
for 30 min and warmed to room temperature over 3 h. The mixture
was diluted with EtOAc (10 mL) and the reaction quenched with
saturated aqueous NH4Cl (10 mL). The aqueous layer was ex-
tracted with EtOAc (3ϫ10 mL) and the combined organic extracts
were washed with 10% aqueous KOH (2ϫ10 mL) and brine
(10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The
Synthesis of 23: Enone 11 (400 mg, 1.03 mmol) was subjected to
general procedure 2. The intermediate triflate required heating at
40 °C for 3 h in DMF-MeOH to ensure complete dissolution. The
crude product was purified by flash column chromatography (elut-
ing with 1:19 Et2O/hexanes) to yield diester 23 (192 mg, 56%) as a
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
C-2,C-20-Diaryl Steroid Analogues
white solid; m.p. 104–106 °C. IR (neat): ν
= 1710, 1638 cm–1.
C37H53O4 561.3944; found 561.3964. [α]2D5 = –113.6 (c = 1.0,
˜
max
1H NMR (400 MHz, CDCl3): δ = 6.90 (d, JH,H = 1.6 Hz, 1 H),
5.79–5.75 (m, 1 H), 3.74 (s, 3 H, CO2CH3), 2.68–2.59 (m, 1 H),
2.30–2.22 (m, 2 H), 2.12–2.02 (m, 2 H), 1.96 (dd, JH,H = 13.2 and
5.4 Hz, 1 H), 1.80–1.57 (m, 6 H), 1.45 [s, 9 H, CO2C(CH3)3], 1.41–
1.36 (m, 1 H), 1.33–1.20 (m, 3 H), 1.13 (d, JH,H = 6.7 Hz, 3 H),
1.06–0.98 (m, 1 H), 0.91 (s, 3 H), 0.71 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.2, 168.4, 141.2, 137.6, 131.2, 130.2,
79.7, 56.3, 55.8, 51.2, 48.0, 43.8, 43.7, 38.2, 35.2, 32.1, 31.5, 28.2,
27.5, 24.3, 23.2, 20.9, 20.2, 19.4, 13.2 ppm. MS (ESI): m/z (%) =
429 (100) [M + H]+. HRMS (ESI): calcd. for C27H41O4 429.3005;
found 429.3005. C27H40O4 (428.61): calcd. C 75.66, H 9.41; found
C 75.57, H 9.35. [α]2D5 = –137.2 (c = 1.0, CHCl3).
CHCl3).
Synthesis of 27: Enone 15 (1.03 g, 1.94 mmol) was subjected to ge-
neral procedure 2. The crude product was purified by flash column
chromatography (eluting with 1:9 Et2O/hexanes) to yield diester 27
(813 mg, 73%, 17:1 mixture of C-2 epimers) as a white foam. IR
1
(neat) ν
= 1705 cm–1. H NMR (400 MHz, CDCl3): δ = (major
˜
max
epimer only) 7.52 (d, JH,H = 8.1 Hz, 2 H), 7.28 (d, JH,H = 8.1 Hz,
2 H), 6.99 (d, JH,H = 1.5 Hz, 1 H), 5.80 (dd, JH,H = 4.3 and 3.0 Hz,
1 H), 3.80 (s, 3 H, CO2CH3), 3.47 (dd, JH,H = 13.2 and 2.6 Hz, 1
H), 2.84 (br. s, 1 H), 2.38 (dd, JH,H = 13.2 and 9.8 Hz, 1 H), 2.30–
2.22 (m, 2 H), 2.13–1.97 (m, 2 H), 1.79–1.55 (m, 6 H), 1.43 [s, 9 H,
CO2C(CH3)3], 1.32–0.85 (m, 6 H), 0.83 (s, 3 H), 0.66 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.1, 168.2, 144.7, 140.9, 139.0,
131.2, 129.4, 129.0, 128.1 (q, JC,F = 32.6 Hz, CF3), 125.1, 125.0,
79.7, 56.2, 55.8, 51.4, 47.9, 43.7, 40.2, 40.1, 38.1, 35.0, 34.4, 32.1,
31.5, 28.2, 24.3, 23.2, 20.8, 19.4, 13.1 ppm. [α]2D5 = –114.8 (c = 1.0,
CHCl3).
Synthesis of 24: Ketone 12 (330 mg, 0.713 mmol) was subjected to
general procedure 2. The crude product was purified by flash col-
umn chromatography (eluting with 1:19 Et2O/hexanes) to yield 24
(224 mg, 62%) as a colorless oil. IR (neat): ν
= 1727, 1708,
˜
max
1
1638 cm–1. H NMR (400 MHz, CDCl3): δ = 7.28 (m, 2 H), 7.19
(m, 3 H), 6.96 (d, JH,H = 1.6 Hz, 1 H), 5.78 (dd, JH,H = 4.5 and
3.0 Hz, 1 H), 3.80 (s, 3 H, CO2CH3), 3.40 (dd, JH,H = 13.1 and
3.1 Hz, 1 H), 2.87–2.79 (m, 1 H), 2.32–2.20 (m, 3 H), 2.11–2.04 (m,
1 H), 1.98 (dd, JH,H = 8.8 and 2.6 Hz, 1 H), 1.82–1.56 (m, 5 H),
1.43 [s, 9 H, CO2C(CH3)3], 1.30–1.04 (m, 7 H), 0.83 (s, 3 H), 0.66
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2, 168.5,
141.1, 140.4, 138.6, 130.6, 129.8, 129.2, 128.1, 125.8, 79.7, 56.2,
55.8, 51.4, 47.9, 43.7, 40.5, 40.1, 38.1, 35.0, 34.5, 32.1, 31.5, 28.2,
24.3, 23.2, 20.8, 19.4, 13.1 ppm. MS (ESI): m/z (%) = 505 (80) [M
+ H]+. HRMS (ESI): calcd. for C33H45O4 505.3318; found
505.3320. [α]2D5 = –121.0 (c = 1.0, CHCl3).
Synthesis of 28: Enone 20 (330 mg, 0.660 mmol) was subjected to
general procedure 2. The crude product was purified by flash col-
umn chromatography (eluting with 1:4 Et2O/hexanes) to yield dies-
ter 28 (262 mg, 73%) as a white solid; m.p. 161–163 °C. IR
(CHCl ): νmax = 1709, 1638, 1590, 1487 cm–1. 1H NMR (400 MHz,
˜
3
CDCl3): δ = 7.22 (d, J = 8.8 Hz, 2 H), 7.03 (s, 1 H), 6.92 (d, J =
8.8 Hz, 2 H), 5.95 (m, 1 H), 5.17 (dd, J = 9.2, 6.8 Hz, 1 H), 3.69
(s, 3 H), 2.44 (dd, J = 12.7, 6.4 Hz, 1 H), 2.33–2.24 (m, 2 H), 2.15–
2.03 (m, 2 H), 1.82–1.60 (m, 5 H), 1.44 (s, 9 H), 1.41–1.27 (m, 4
H), 1.17–1.10 (m, 2 H), 0.99 (s, 3 H), 0.70 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.1, 167.0, 157.3, 139.9, 139.8, 133.4,
129.3, 126.4, 125.9, 117.9, 79.8, 72.7, 56.0, 55.7, 51.5, 47.9, 43.7,
40.1, 38.0, 36.5, 32.1, 30.6, 28.2, 24.3, 23.2, 20.9, 19.8, 13.1 ppm.
MS (ESI): m/z (%) = 413 (100) [M – OPhCl]+. HRMS (ESI): calcd.
for C26H37O4 413.2692; found: 413.2701. [α]2D5 = –138.0 (c = 4.2,
CHCl3).
Synthesis of 25: Enone 13 (370 mg, 0.744 mmol) was subjected to
general procedure 2. The crude product was purified by flash col-
umn chromatography (eluting with 1:9 Et2O/hexanes) to yield dies-
ter 25 (344 mg, 86%) as a colorless oil. IR (neat): ν
= 1704,
˜
max
1638 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.24 (d, JH,H
=
Synthesis of 29: Enone 21 (530 mg, 1.14 mmol) was subjected to
general procedure 2. The mixture was diluted with EtOAc and
washed successively with aqueous HCl (1.0 m) and brine. The crude
product was purified by flash column chromatography (eluting
with 1:4 Et2O/hexanes) to yield diester 29 (374 mg, 65%) as a white
8.4 Hz, 2 H), 7.10 (d, JH,H = 8.4 Hz, 2 H), 6.97 (d, JH,H = 1.6 Hz,
1 H), 5.78 (dd, JH,H = 4.5 and 3.0 Hz, 1 H), 3.79 (s, 3 H, CO2CH3),
3.36 (dd, JH,H = 13.2 and 3.1 Hz, 1 H), 2.82–2.72 (m, 1 H), 2.32–
2.21 (m, 3 H), 2.11–1.92 (m, 2 H), 1.79–1.52 (m, 4 H), 1.45–1.43
(m, 1 H), 1.44 [s, 9 H, CO2C(CH3)3], 1.31–1.21 (m, 3 H), 1.09 (ddd,
JH,H = 19.2, 11.8 and 5.6 Hz, 1 H), 0.99–0.82 (m, 2 H), 0.82 (s, 3
H), 0.66 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2,
168.3, 141.0, 138.9, 138.9, 131.5, 131.0, 130.5, 129.3, 128.2, 79.7,
56.2, 55.8, 51.4, 47.9, 43.7, 40.0, 39.7, 38.1, 35.0, 34.4, 32.1, 31.5,
28.2, 24.3, 23.2, 20.8, 19.4, 13.1 ppm. MS (ESI): m/z (%) = 539 (20)
[M + H]+. HRMS (ESI): calcd. for C33H44O4Cl 539.2928; found
539.2944. [α]2D5 = –131.7 (c = 1.0, CHCl3).
paste. IR (CHCl ): ν
= 1721, 1641, 1597, 1492, 1367, 1263,
˜
3
max
1153 cm–1. H NMR (400 MHz, CDCl3): δ = 7.28 (t, J = 7.4 Hz,
2 H), 7.04–6.94 (m, 4 H), 5.95 (m, 1 H), 5.25 (m, 1 H), 3.70 (s, 3
H), 2.50 (dd, J = 12.7, 6.4 Hz, 1 H), 2.35–2.25 (m, 2 H), 2.15–2.03
(m, 2 H), 1.81–1.57 (m, 5 H), 1.45 (s, 9 H), 1.44–1.36 (m, 2 H),
1.31–1.21 (m, 2 H), 1.16–1.09 (m, 2 H), 1.01 (s, 3 H), 0.71 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2, 167.2, 158.7, 139.9,
139.7, 133.0, 129.4, 126.9, 121.1, 116.6, 79.8, 72.1, 56.1, 55.8, 51.5,
47.9, 43.8, 40.2, 38.0, 36.5, 32.1, 30.7, 28.2, 24.3, 23.3, 21.0, 19.8,
13.2 ppm. MS (ESI): m/z = 413 [M – OPh]+, 570 [M + Na +
MeCN]+. HRMS (ESI): calcd. for C34H45O5NNa 570.3195; found:
570.3194. [α]2D5 = –146.6 (c = 1.0, CHCl3).
1
Synthesis of 26: Enone 14 (1.10 g, 2.12 mmol) was subjected to ge-
neral procedure 2. The crude product was purified by flash column
chromatography (eluting with 1:19 Et2O/hexanes) to yield diester
26 (781 mg, 66%, 13:1 mixture of C-2 epimers) as a white foam.
IR (neat): νmax = 1710, 1708 cm–1. 1H NMR (400 MHz, CDCl3): δ
˜
Acidic Hydrolysis of tert-Butyl Esters. General Procedure 3: Tri-
fluoroacetic acid (13 equiv.) was added to tert-butyl ester
(1.0 equiv.) and Et3SiH (2.6 equiv.) in CH2Cl2 (2.0 mL/mmol) and
the reaction mixture was stirred for 3 h. The mixture was concen-
trated in vacuo and the crude product was purified by flash column
chromatography to yield the corresponding acid.
= (major epimer only) 7.29 (d, JH,H = 8.2 Hz, 2 H), 7.10 (d, JH,H
= 8.2 Hz, 2 H), 6.95 (d, JH,H = 1.5 Hz, 1 H), 5.78 (dd, JH,H = 4.5
and 2.9 Hz, 1 H), 3.79 (s, 3 H, CO2CH3), 3.32 (dd, JH,H = 13.3 and
3.0 Hz, 1 H), 2.84 (br. s, 1 H), 2.34–2.22 (m, 3 H), 2.13–1.97 (m, 2
H), 1.87 (dd, JH,H = 13.1 and 5.5 Hz, 1 H), 1.77–1.59 (m, 4 H),
1.43 [s, 9 H, CO2C(CH3)3], 1.32 [s, 9 H, ArC(CH3)3], 1.29–0.89 (m,
7 H), 0.85 (s, 3 H), 0.67 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.2, 168.6, 148.4, 141.2, 138.4, 137.3, 130.4, 130.1,
Synthesis of 30: Diester 23 (170 mg, 0.397 mmol) was subjected to
general procedure 3. The crude product was purified by flash col-
128.7, 125.0, 79.7, 56.3, 55.8, 51.4, 47.9, 43.8, 40.2, 40.0, 38.2, 35.1, umn chromatography (eluting with 3:7 Et2O/hexanes) to yield carb-
34.4, 34.3, 32.1, 31.5, 31.4, 28.2, 24.3, 23.2, 20.8, 19.4, 13.1 ppm.
oxylic acid 30 (136 mg, 92%) as a white solid; m.p. 228–232 °C. IR
MS (ESI): m/z (%) = 561 (100) [M + H]+. HRMS (ESI): calcd. for
(neat) ν
= 3248, 1723, 1712, 1633, 1603, 1261 cm–1. 1H NMR
˜
max
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
A. G. M. Barrett et al.
calcd. for C33H45O4 505.3318; found 505.3327. [α]2D5 = –121.5 (c =
FULL PAPER
(400 MHz, CDCl3): δ = 11.11 (br. s, 1 H, CO2H), 6.90 (d, JH,H
=
1.6 Hz, 1 H), 5.80–5.75 (m, 1 H), 3.74 (s, 3 H, CO2CH3), 2.68–2.60 0.34, CHCl3).
(m, 1 H), 2.41 (t, JH,H = 9.3 Hz, 1 H), 2.28 (dt, JH,H = 18.9 and
Synthesis of 34: Diester 27 (681 mg, 1.19 mmol) was subjected to
4.9 Hz, 1 H), 2.19–2.08 (m, 2 H), 1.97 (dd, JH,H = 13.2 and 5.4 Hz,
2 H), 1.90–1.60 (m, 5 H), 1.49–1.16 (m, 5 H), 1.13 (d, JH,H
general procedure 3. The crude product was purified by flash col-
umn chromatography (eluting with 1:1 Et2O/hexanes) to yield carb-
oxylic acid 34 (576 mg, 94%, 17:1 mixture of C-2 epimers) as a
=
6.6 Hz, 3 H, CHCH3), 1.04 (dt, JH,H = 11.6 and 5.2 Hz, 1 H), 0.92
(s, 3 H), 0.77 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
179.4, 168.4, 141.2, 137.5, 131.3, 130.1, 56.2, 54.9, 51.3, 47.9, 44.1,
43.7, 37.8, 35.2, 32.1, 31.6, 27.5, 24.4, 23.3, 20.8, 20.2, 19.4,
13.2 ppm. MS (ESI): m/z (%) = 330 (100) [M – CO2 + H]+, 373
(40) [M + H]+. HRMS (ESI): calcd. for C23H33O4 373.2379; found
373.2375. C23H32O4 (372.50): calcd. C 74.16, H 8.66; found C
73.99, H 8.69. [α]2D5 = –123.0 (c = 0.86, CHCl3).
white foam. IR (neat): ν
= 1703 cm–1. 1H NMR (400 MHz,
˜
max
CDCl3): δ = (major epimer only) 11.14 (br. s, 1 H, CO2H), 7.53 (d,
JH,H = 8.1 Hz, 2 H), 7.28 (d, JH,H = 8.1 Hz, 2 H), 6.99 (d, JH,H
=
1.5 Hz, 1 H), 5.80 (dd, JH,H = 4.3 and 2.9 Hz, 1 H), 3.80 (s, 3 H,
CO2CH3), 3.42 (dd, JH,H = 13.1 and 2.6 Hz, 1 H), 2.85 (br. s, 1 H),
2.47–2.36 (m, 2 H), 2.27 (td, JH,H = 19.2 and 5.0 Hz, 1 H), 2.14–
2.03 (m, 2 H), 1.87–1.56 (m, 6 H), 1.35–1.10 (m, 5 H), 1.01–0.86
Synthesis of 31: Diester 24 (198 mg, 0.392 mmol) was subjected to (m, 2 H), 0.84 (s, 3 H), 0.71 (s, 3 H) ppm. 13C NMR (100 MHz,
general procedure 3. The crude product was purified by flash col-
umn chromatography (eluting with 3:7 Et2O/hexanes) to yield carb-
CDCl3): δ = 179.4, 168.3, 144.6, 140.9, 139.0, 131.0, 129.4, 129.1,
128.2 (q, JC,F = 32.0 Hz, CF3), 125.7, 125.0, 56.2, 54.9, 51.5, 47.8,
44.1, 40.2, 40.0, 37.7, 35.0, 34.3, 32.1, 31.5, 24.3, 23.3, 20.7, 19.4,
13.1 ppm. MS (ESI): m/z (%) = 517 (100) [M + H]+. HRMS (ESI):
calcd. for C30H36O4F3 517.2566; found 517.2583. [α]2D5 = –105.5 (c
= 1.0, CHCl3).
oxylic acid 31 (167 mg, 95%) as a white foam. IR (neat): ν
=
˜
max
3438, 1697, 1637, 1604 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.35–7.30 (m, 2 H), 7.26–7.21 (m, 3 H), 7.01 (d, JH,H = 1.4 Hz, 1
H), 5.83–7.81 (m, 1 H), 3.85 (s, 3 H, CO2CH3), 3.42 (dd, JH,H
=
13.1 and 3.0 Hz, 1 H), 2.89 (br. s, 1 H), 2.48–2.26 (m, 3 H), 2.20–
2.05 (m, 2 H), 1.90–1.60 (m, 5 H), 1.53–1.47 (m, 1 H), 1.40–1.14
(m, 4 H), 1.10–0.92 (m, 2 H), 0.88 (s, 3 H), 0.76 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 179.5, 168.5, 141.1, 140.4, 138.5,
130.4, 129.9, 129.2, 128.1, 125.8, 56.2, 54.9, 51.4, 47.8, 44.1, 40.4,
40.1, 37.8, 35.1, 34.5, 32.1, 31.5, 24.4, 23.3, 20.7, 19.4, 13.1 ppm.
MS (ESI): m/z (%) = 449 (100) [M + H]+. HRMS (ESI): calcd. for
C29H37O4 449.2692; found 449.2682. [α]2D5 = –125.0 (c = 1.0,
CHCl3).
Synthesis of 35: Et3N (0.93 mL, 6.66 mmol) was added to ester 28
(200 mg, 0.370 mmol) in CH2Cl2 (5.0 mL) at 0 °C. Me3SiOSO2CF3
(0.60 mL, 3.33 mmol) was added and the reaction mixture was
stirred at 0 °C for 2 h and warmed to room temperature and stirred
for an additional 1 h. The solution was diluted with EtOAc (10 mL)
and the reaction quenched by addition of saturated aqueous
NaHCO3 (5.0 mL). The aqueous layer was extracted with EtOAc
(3ϫ10 mL) and the combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
Synthesis of 32: Diester 25 (420 mg, 0.779 mmol) was subjected to was purified by flash column chromatography (eluting with 4:1 hex-
general procedure 3. The crude product was purified by flash col-
umn chromatography (eluting with 1:4 Et2O/hexanes) to yield carb-
anes/EtOAc) to yield carboxylic acid 35 (165 mg, 92%) as a white
foam. IR (neat) ν
= 1699, 1638, 1489, 1240, 1005 cm–1. 1H
˜
max
oxylic acid 32 (366 mg, 97%) as a white foam. IR (neat): ν
=
NMR (400 MHz, CDCl3): δ = 7.23 (d, JH,H = 8.8 Hz, 2 H), 7.04
(s, 1 H), 6.93 (d, JH,H = 8.8 Hz, 2 H), 5.95 (m, 1 H), 5.18 (dd, JH,H
˜
max
1698, 1637 cm–1. H NMR (400 MHz, CDCl3): δ = 10.98 (br. s, 1
1
H, CO2H), 7.24 (d, JH,H = 8.4 Hz, 2 H), 7.10 (d, JH,H = 8.4 Hz, 2 = 8.8 and 6.8 Hz, 1 H), 3.69 (s, 3 H), 2.46–2.38 (m, 2 H), 2.34–2.28
H), 6.97 (d, JH,H = 1.5 Hz, 1 H), 5.78 (dd, JH,H = 4.3 and 3.0 Hz, (dt, JH,H = 20.1 and 4.9 Hz, 1 H), 2.16–2.09 (m, 2 H), 1.90–1.71
1 H), 3.80 (s, 3 H, CO2CH3), 3.32 (dd, JH,H = 13.2 and 3.1 Hz, 1 (m, 3 H), 1.64–1.61 (m, 2 H), 1.48–1.27 (m, 4 H), 1.21–1.10 (m, 2
H), 2.85–2.75 (m, 1 H), 2.41–2.21 (m, 3 H), 2.12–2.01 (m, 2 H),
1.89–1.56 (m, 5 H), 1.50–1.42 (m, 1 H), 1.34–1.21 (m, 3 H), 1.18–
1.10 (m, 1 H), 1.02–0.84 (m, 2 H), 0.83 (s, 3 H), 0.72 (s, 3 H) ppm.
H), 1.00 (s, 3 H), 0.76 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 179.7, 167.0, 157.3, 139.9, 139.8, 133.2, 129.3, 126.5, 126.0,
117.9, 72.7, 56.0, 54.9, 51.6, 47.8, 44.1, 40.1, 37.7, 36.5, 32.1, 30.7,
13C NMR (100 MHz, CDCl3): δ = 179.3, 168.4, 141.0, 138.8, 138.8, 24.4, 23.3, 20.9, 19.8, 13.2 ppm. MS (ESI): m/z (%) = 357 (100)
131.5, 130.8, 130.5, 129.4, 128.2, 56.2, 54.9, 51.5, 47.8, 44.1, 40.0,
39.7, 37.7, 35.0, 34.4, 32.1, 31.5, 24.3, 23.3, 20.7, 19.4, 13.1 ppm.
MS (ESI): m/z (%) = 483 (20) [M + H]+. HRMS (ESI): calcd. for
C29H36O4Cl 483.2302; found 483.2297. C29H35ClO4 (483.05): calcd.
C 72.11, H 7.30; found C 72.18, H 7.36. [α]2D5 = –137.8 (c = 1.0,
CHCl3).
[M – OPhCl]+. HRMS (ESI): calcd. for C22H29O4 357.2066; found
357.2076. [α]2D5 = –98.8 (c = 4.2, CHCl3).
Synthesis of 36: Et3N (1.49 mL, 10.7 mmol) was added to ester 29
(300 mg, 0.594 mmol) in CH2Cl2 (8.0 mL) at 0 °C. Me3SiOSO2CF3
(0.97 mL, 5.33 mmol) was added and the reaction mixture was
stirred at 0 °C for 2 h and warmed to room temperature and stirred
Synthesis of 33: Diester 26 (730 mg, 1.34 mmol) was subjected to for an additional 1 h. The solution was diluted with EtOAc (15 mL)
general procedure 3. The crude product 33 (629 mg, 95%, 13:1 mix-
ture of C-2 epimers) was isolated as a white foam and was used
and the reaction quenched by addition of saturated aqueous
NaHCO3 (8.0 mL). The aqueous layer was extracted with EtOAc
(3ϫ15 mL) and the combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude product
was purified by flash column chromatography (eluting with 9:1 hex-
anes/EtOAc) to yield carboxylic acid 36 (170 mg, 64%) as a white
directly in the next step without further purification. IR (neat): ν
˜
max
= 1698 cm–1. 1H NMR (400 MHz, CDCl3): δ = (major epimer
only) 11.20 (br. s, 1 H, CO2H), 7.29 (d, JH,H = 8.2 Hz, 2 H), 7.10
(d, JH,H = 8.2 Hz, 2 H), 6.95 (d, JH,H = 1.5 Hz, 1 H), 5.77 (dd,
JH,H = 4.2 and 3.0 Hz, 1 H), 3.79 (s, 3 H, CO2CH3), 3.31 (dd, JH,H
= 13.3 and 3.0 Hz, 1 H), 2.84 (br. s, 1 H), 2.41–2.22 (m, 3 H), 2.15–
2.06 (m, 2 H), 1.88–1.46 (m, 7 H), 1.32 [s, 9 H, ArC(CH3)3], 1.22–
1.11 (m, 2 H), 1.03–0.88 (m, 3 H), 0.85 (s, 3 H), 0.72 (s, 3 H) ppm.
foam. IR (neat): ν
= 1699, 1638, 1596, 1491, 1435, 1265, 1239,
˜
max
1038, 754 cm–1. H NMR (400 MHz, CDCl3): δ = 7.29 (t, JH,H
7.4 Hz, 2 H), 7.04–6.96 (m, 4 H), 5.95 (m, 1 H), 5.26 (m, 1 H), 3.70
(s, 3 H), 2.49 (dd, JH,H = 12.7 and 6.4 Hz, 1 H), 2.41 (t, JH,H
=
1
=
13C NMR (100 MHz, CDCl3): δ = 179.5, 168.6, 148.5, 141.2, 138.4, 9.3 Hz, 1 H), 2.32 (dt, JH,H = 19.6 and 5.4 Hz, 1 H), 2.16–2.09 (m,
137.2, 130.2, 130.2, 128.8, 125.0, 56.2, 54.9, 51.4, 47.9, 44.1, 40.2,
40.0, 37.8, 35.1, 34.4, 34.3, 32.1, 31.6, 31.4, 24.4, 23.3, 20.7, 19.4,
13.1 ppm. MS (ESI): m/z (%) = 505 (100) [M + H]+. HRMS (ESI):
2 H), 1.90–1.71 (m, 3 H), 1.65–1.57 (m, 2 H), 1.48–1.26 (m, 4 H),
1.22–1.11 (m, 2 H), 1.02 (s, 3 H), 0.77 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 179.9, 167.2, 158.6, 139.9, 139.6, 132.8,
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
C-2,C-20-Diaryl Steroid Analogues
129.4, 126.9, 121.1, 116.5, 72.0, 56.0, 54.9, 51.5, 47.8, 44.1, 40.2,
37.7, 36.5, 32.1, 30.7, 24.4, 23.3, 20.9, 19.8, 13.2 ppm. MS (ESI):
m/z (%) = 357 (100) [M – OPh]+, 514 (80) [M + Na + MeCN]+.
HRMS (ESI): calcd. for C30H37O5NNa 514.2569; found 514.2560.
[α]2D5 = –130.6 (c = 1.0, CHCl3).
(100 MHz, CDCl3): δ = 196.8, 168.3, 151.8, 150.2, 140.9, 138.8,
137.0, 131.6, 130.6, 130.5, 130.1, 129.4, 128.2, 123.3, 64.6, 56.4,
51.4, 47.8, 45.0, 40.0, 39.6, 38.1, 35.0, 34.4, 32.0, 31.5, 24.5, 24.0,
20.8, 19.4, 13.2 ppm. MS (ESI): m/z (%) = 576 (100) [M + H]+.
HRMS (ESI): calcd. for C34H39NO3SCl 576.2339; found 576.2338.
C34H38ClNO3S (576.19): calcd. C 70.87, H 6.65, N 2.43; found C
70.95, H 6.61, N 2.35. [α]2D5 = –48.2 (c = 1.0, CHCl3).
Preparation of 2-Thiopyridyl Esters. General Procedure 4: Ph3P
(1.6 equiv.) and 2,2Ј-dithiodipyridine (37) (1.6 equiv., recrystallized
from hexane) were added to acid (1.0 equiv.) in PhMe (3.0 mL/
mmol) and the reaction mixture was stirred for 16 h. The mixture
was concentrated in vacuo and the crude product was purified by
flash column chromatography to yield the corresponding 2-thiopy-
ridyl ester.
Synthesis of 41: Acid 33 (565 mg, 1.12 mmol) was subjected to ge-
neral procedure 4. The crude product was purified by flash column
chromatography (eluting with 1:4 EtOAc/hexanes) to yield pyridyl
thioester 41 (624 mg, 93%, 14:1 mixture of C-2 epimers) as a pale
yellow foam. IR (neat): ν
= 1704 cm–1. 1H NMR (400 MHz,
˜
max
CDCl3): δ = (major epimer only) 8.61 (ddd, JH,H = 4.9, 1.8 and
0.8 Hz, 1 H), 7.72 (dt, JH,H = 7.7 and 1.9 Hz, 1 H), 7.59 (d, JH,H
= 7.9 Hz, 1 H), 7.29 (d, JH,H = 8.2 Hz, 2 H), 7.10 (d, JH,H = 8.2 Hz,
2 H), 6.95 (d, JH,H = 1.6 Hz, 1 H), 5.77 (dd, JH,H = 4.4 and 2.8 Hz,
1 H), 3.79 (s, 3 H, CO2CH3), 3.32 (dd, JH,H = 13.2 and 3.1 Hz, 1
H), 2.84 (br. s, 1 H), 2.72 (t, JH,H = 9.2 Hz, 1 H), 2.35–2.21 (m, 4
H), 1.94–1.47 (m, 7 H), 1.41–1.35 (m, 2 H), 1.32 [s, 9 H, ArC-
(CH3)3], 1.26–1.15 (m, 2 H), 1.06–0.89 (m, 2 H), 0.85 (s, 3 H), 0.74
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.8, 168.5,
151.9, 150.3, 148.5, 141.2, 138.3, 137.1, 136.9, 130.2, 130.1, 130.1,
128.8, 125.0, 123.2, 64.6, 56.4, 51.4, 47.9, 45.0, 40.1, 39.9, 38.2,
35.1, 34.4, 34.3, 32.1, 31.5, 31.4, 24.5, 24.0, 20.8, 19.4 ppm [tBu
quaternary obscured]. MS (ESI): m/z (%) = 598 (100) [M + H]+.
HRMS (ESI): calcd. for C38H48NO3S 598.3355; found 598.3367.
[α]2D5 = –19.7 (c = 1.0, CHCl3).
Synthesis of 38: Acid 30 (429 mg, 1.29 mmol) was subjected to ge-
neral procedure 4. The crude product was purified by flash column
chromatography (eluting with 1:4 EtOAc/hexanes) to yield pyridyl
thioester 38 (420 mg, 70%) as a pale yellow foam. IR (neat): ν
˜
max
= 1705 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, JH,H
=
4.9 and 1.0 Hz, 1 H), 7.98 (dt, JH,H = 7.7 and 1.9 Hz, 1 H), 7.86
(d, JH,H = 7.9 Hz, 1 H), 7.53–7.51 (m, 1 H), 7.15 (d, JH,H = 1.5 Hz,
1 H), 6.01 (dd, JH,H = 4.4 and 2.8 Hz, 1 H), 3.99 (s, 3 H, CO2CH3),
2.99 (t, JH,H = 9.2 Hz, 1 H), 2.92–2.84 (m, 1 H), 2.58–2.47 (m, 3
H), 2.25–2.09 (m, 2 H), 2.05–1.90 (m, 4 H), 1.76–1.43 (m, 5 H),
1.38 (d, JH,H = 6.7 Hz, 3 H, CHCH3), 1.34–1.27 (m, 1 H), 1.17 (s,
3 H), 1.03 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.8,
168.4, 151.9, 150.3, 141.2, 137.4, 136.9, 131.3, 130.1, 129.9, 123.3,
64.6, 56.4, 51.2, 47.9, 45.0, 43.7, 38.2, 35.2, 32.1, 31.5, 27.5, 24.5,
24.0, 20.8, 20.2, 19.4, 13.2 ppm. MS (ESI): m/z (%) = 466 (100)
[M + H]+. HRMS (ESI): calcd. for C28H36NO3S 466.2416; found
466.2429. [α]2D5 = –11.3 (c = 1.0, CHCl3).
Synthesis of 42: Acid 34 (533 mg, 1.03 mmol) was subjected to ge-
neral procedure 4. The crude product was purified by flash column
chromatography (eluting with 1:4 EtOAc/hexanes) to yield pyridyl
thioester 42 (518 mg, 83%, 17:1 mixture of C-2 epimers) as a pale
Synthesis of 39: Acid 31 (267 mg, 0.595 mmol) was subjected to
general procedure 4. The crude product was purified by flash col-
umn chromatography (eluting with 1:4 EtOAc/hexanes) to yield
pyridyl thioester 39 (258 mg, 80%, 24:1 mixture of C-2 epimers) as
yellow oil. IR (neat): ν
= 1702 cm–1. 1H NMR (400 MHz,
˜
max
CDCl3): δ = (major epimer only) 8.61 (ddd, JH,H = 4.9, 1.8 and
0.8 Hz, 1 H), 7.72 (dt, JH,H = 7.7 and 1.9 Hz, 1 H), 7.60–7.57 (m,
1 H), 7.53 (d, JH,H = 8.1 Hz, 2 H), 7.30–7.24 (m, 3 H), 6.99 (d,
JH,H = 1.6 Hz, 1 H), 5.80 (dd, JH,H = 4.6 and 2.9 Hz, 1 H), 3.80
(s, 3 H, CO2CH3), 3.42 (dd, JH,H = 13.2 and 2.9 Hz, 1 H), 2.86 (br.
s, 1 H), 2.72 (t, JH,H = 9.2 Hz, 1 H), 2.45 (dd, JH,H = 13.2 and
9.5 Hz, 1 H), 2.31–2.20 (m, 3 H), 1.94–1.60 (m, 5 H), 1.51–1.44 (m,
1 H), 1.37–1.14 (m, 4 H), 1.04–0.87 (m, 2 H), 0.84 (s, 3 H), 0.74 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.8, 168.3, 151.9,
150.3, 144.5, 140.9, 139.0, 136.9, 130.9, 130.1, 129.4, 129.1, 127.9
(q, JC,F = 31.8 Hz), 125.1, 125.1, 123.3, 64.6, 56.4, 51.5, 47.8, 44.9,
40.2, 40.0, 38.1, 35.0, 34.3, 32.1, 31.5, 24.5, 24.0, 20.8, 19.4,
13.2 ppm. MS (ESI): m/z (%) = 610 (100) [M + H]+. HRMS (ESI):
calcd. for C35H39NO3SF3 610.2603; found 610.2593. [α]2D5 = –17.3
(c = 1.0, CHCl3).
a pale yellow foam. IR (neat): ν
= 1704 cm–1. 1H NMR
˜
max
(400 MHz, CDCl3): δ = (major epimer only) 8.70 (ddd, JH,H = 4.8,
1.8 and 0.8 Hz, 1 H), 7.81 (dt, JH,H = 7.8 and 1.9 Hz, 1 H), 7.68
(dd, JH,H = 7.8 and 0.8 Hz, 1 H), 7.39–7.34 (m, 3 H), 7.30–7.26
(m, 3 H), 7.05 (d, JH,H = 1.5 Hz, 1 H), 5.86 (dd, JH,H = 4.4 and
2.9 Hz, 1 H), 3.89 (s, 3 H, CO2CH3), 3.46 (dd, JH,H = 13.1 and
3.2 Hz, 1 H), 2.94 (br. s, 1 H), 2.81 (t, JH,H = 9.2 Hz, 1 H), 2.48–
2.30 (m, 4 H), 2.03–1.70 (m, 5 H), 1.60–1.24 (m, 5 H), 1.13–0.96
(m, 2 H), 0.93 (s, 3 H), 0.83 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 196.9, 168.5, 151.9, 150.3, 141.1, 140.3, 138.5, 136.9,
130.3, 130.1, 130.0, 129.2, 128.1, 125.8, 123.3, 64.6, 56.4, 51.4, 47.9,
45.0, 40.4, 40.1, 38.1, 35.0, 34.5, 32.1, 31.5, 24.5, 24.0, 20.7, 19.4,
13.2 ppm. MS (ESI): m/z (%) = 542 (100) [M + H]+. HRMS (ESI):
calcd. for C34H40NO3S 542.2729; found 542.2728. [α]2D5 = –25.1 (c
= 1.0, CHCl3).
Synthesis of 43: Acid 35 (71 mg, 0.15 mmol) was subjected to gene-
ral procedure 4. The crude product was purified by flash column
chromatography (eluting with 49:1 CH2Cl2/Et2O) to yield pyridyl
Synthesis of 40: Acid 32 (830 mg, 1.73 mmol) was subjected to ge-
neral procedure 4. The crude product was purified by flash column
chromatography (eluting with 3:7 EtOAc/hexanes) to yield pyridyl
thioester 43 (79 mg, 94%) as a colorless oil. IR (neat): νmax = 1713,
˜
thioester 40 (740 mg, 74%) as a yellow solid. IR (neat): ν
=
1640, 1576, 1489, 1264, 1240, 1038, 1005 cm–1. 1H NMR
˜
max
1701, 1572, 1250 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.65 (dd, (400 MHz, CDCl3): δ = 8.61 (dd, JH,H = 4.9 and 1.5 Hz, 1 H), 7.73
JH,H = 4.5 and 1.4 Hz, 1 H), 7.76 (dt, JH,H = 7.8 and 1.9 Hz, 1 H),
7.62 (d, JH,H = 7.8 Hz, 1 H), 7.32–7.25 (m, 3 H), 7.13 (d, JH,H
8.3 Hz, 2 H), 6.99 (d, JH,H = 1.4 Hz, 1 H), 5.81 (dd, JH,H = 4.3
and 3.0 Hz, 1 H), 3.82 (s, 3 H, CO2CH3), 3.34 (dd, JH,H = 13.2 and
(dt, JH,H = 7.8 and 2.0 Hz, 1 H), 7.61 (d, JH,H = 7.8 Hz, 1 H),
7.29–7.22 (m, 3 H), 7.04 (s, 1 H), 6.94 (d, JH,H = 8.8 Hz, 2 H), 5.96
(m, 1 H), 5.18 (dd, JH,H = 9.3 and 6.4 Hz, 1 H), 3.70 (s, 3 H), 2.74
(t, JH,H = 9.3 Hz, 1 H), 2.44 (dd, JH,H = 12.7 and 6.4 Hz, 1 H),
=
3.2 Hz, 1 H), 2.90–2.79 (m, 1 H), 2.75 (t, JH,H = 9.2 Hz, 1 H), 2.40 2.34–2.26 (m, 3 H), 1.97–1.90 (m, 1 H), 1.85–1.61 (m, 4 H), 1.48–
(dd, JH,H = 13.2 and 9.4 Hz, 1 H), 2.32–2.21 (m, 3 H), 1.98–1.88
(m, 1 H), 1.82–1.62 (m, 5 H), 1.56–1.49 (m, 1 H), 1.41–1.18 (m, 3
H), 1.24–1.16 (m, 1 H), 1.04 (m, 1 H), 1.08–0.99 (dd, JH,H = 12.7
and 11.4 Hz, 1 H), 0.86 (s, 3 H), 0.77 (s, 3 H) ppm. 13C NMR
1.27 (m, 4 H), 1.25–1.14 (m, 2 H), 1.00 (s, 3 H), 0.78 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 196.8, 167.0, 157.4, 151.8, 150.2,
139.8, 137.1, 133.1, 130.2, 129.3, 126.5, 126.0, 123.4, 118.0, 72.7,
64.5, 56.2, 51.6, 47.8, 45.0, 40.1, 38.0, 36.5, 32.1, 30.7, 24.5, 24.1,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
A. G. M. Barrett et al.
FULL PAPER
20.9, 19.8, 13.3 ppm [one aromatic quaternary carbon obscured].
MS (ESI): m/z (%) = 578 (100) [M + H]+. HRMS (ESI): calcd. for
C33H37NO4SCl [M + H]+ 578.2132; found 578.2134. [α]2D5 = –17.7
(c = 3.5, CHCl3).
ketone 49 (205 mg, 60%, 14:1 mixture of C-2 epimers) as a white
foam. IR (neat): ν
= 3338, 1705, 1665, 1645, 1601, 1582 cm–1.
˜
max
1H NMR (400 MHz, CDCl3): δ = (major epimer only) 7.83 (d, JH,H
= 8.7 Hz, 2 H), 7.26 (d, JH,H = 8.3 Hz, 2 H), 7.07 (d, JH,H = 8.3 Hz,
2 H), 6.96 (d, JH,H = 1.5 Hz, 1 H), 6.86 (d, JH,H = 8.7 Hz, 2 H),
6.33 (br. s, 1 H, ArOH), 5.79 (dd, JH,H = 4.2 and 3.1 Hz, 1 H),
3.79 (s, 3 H, CO2CH3), 3.46–3.40 (m, 1 H), 3.29 (dd, JH,H = 13.2
and 3.0 Hz, 1 H), 2.80 (br. s, 1 H), 2.44 (dd, JH,H = 19.7 and
11.0 Hz, 1 H), 2.33–2.25 (m, 2 H), 1.82–1.61 (m, 5 H), 1.45–1.31
(m, 4 H), 1.29 [s, 9 H, ArC(CH3)3], 1.25–1.13 (m, 2 H), 1.03–0.85
(m, 2 H), 0.79 (s, 3 H), 0.59 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 200.4, 168.8, 160.0, 148.5, 141.1, 138.5, 137.1, 132.0,
130.8, 130.6, 130.0, 128.7, 125.0, 115.1, 57.4, 56.6, 51.5, 47.9, 45.0,
40.1, 40.0, 39.1, 35.1, 34.3, 34.3, 32.2, 31.6, 31.4, 24.7, 23.9, 20.9,
19.4, 13.4 ppm. MS (ESI): m/z (%) = 580 (100) [M + H]+. HRMS
(ESI): calcd. for C39H49O4 581.3631; found 581.3651. [α]2D5 = –161.9
(c = 1.0, CHCl3).
Synthesis of 44: Acid 36 (155 mg, 0.344 mmol) was subjected to
general procedure 4. The crude product was purified by flash col-
umn chromatography (eluting with 49:1 CH2Cl2/Et2O) to yield pyr-
idyl thioester 44 (160 mg, 86%) as a colorless oil. IR (neat): ν
˜
max
= 1710, 1641, 1596, 1490, 1421, 1262, 1239, 1037, 913, 766,
1
729 cm–1. H NMR (400 MHz, CDCl3): δ = 8.62 (m, 1 H), 7.74–
7.70 (dt, JH,H = 7.8 and 2.0 Hz, 1 H), 7.60 (d, JH,H = 7.8 Hz, 1 H),
7.31–7.25 (m, 3 H), 7.04–6.96 (m, 4 H), 5.95 (m, 1 H), 5.26 (m, 1
H), 3.69 (s, 3 H), 2.73 (t, JH,H = 9.3 Hz, 1 H), 2.49 (dd, JH,H
=
12.7 and 5.9 Hz, 1 H), 2.34–2.23 (m, 3 H), 1.96–1.86 (m, 1 H),
1.83–1.73 (m, 2 H), 1.69–1.59 (m, 2 H), 1.51–1.30 (m, 4 H), 1.25–
1.12 (m, 2 H), 1.01 (s, 3 H), 0.78 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 196.8, 167.1, 158.6, 151.9, 150.3, 139.9,
139.5, 136.9, 132.7, 130.1, 129.4, 127.0, 123.3, 121.1, 116.5, 72.0,
64.5, 56.2, 51.5, 47.8, 44.9, 40.2, 38.0, 36.5, 32.0, 30.6, 24.5, 24.0,
20.9, 19.8, 13.2 ppm. MS (ESI): m/z (%) = 544 (100) [M + H]+.
HRMS (ESI): calcd. for C33H38NO4S 544.2522; found 544.2507.
[α]2D5 = –21.0 (c = 1.7, CHCl3).
Synthesis of 50: Thioester 42 (180 mg, 0.295 mmol) was subjected
to general procedure 5. The crude product was purified by flash
column chromatography (eluting with 3:17 EtOAc/hexanes) to
yield ketone 50 (71 mg, 41%, 16:1 mixture of C-2 epimers) as a
white foam. IR (neat): ν
= 3336, 1704, 1646, 1602, 1582,
˜
max
1324 cm–1. H NMR (400 MHz, CDCl3): δ = (major epimer only)
1
Addition of 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium Brom-
ide to Thiopyridyl Esters Followed by THP Deprotection. General
Procedure 5: 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium
bromide (45) in THF (0.5 m; 2.6 equiv.) was added to thiopyridyl
ester (1.0 equiv.) in THF (5.0 mL/mmol) at –50 °C and the mixture
was stirred for 1 h. The mixture was quenched with saturated aque-
ous NH4Cl (5.0 mL/mmol) and warmed to room temperature. The
mixture was diluted with Et2O (10 mL/mmol), separated and the
aqueous layer was extracted with Et2O (3ϫ10 mL/mmol). The
combined organic extracts were washed with brine (5.0 mL/mmol),
dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was dissolved in THF (5.0 mL/mmol) and MeOH (5.0 mL/
mmol) and TsOH·H2O (1.0 equiv.) was added. The reaction mix-
ture was stirred for 1 h and diluted with EtOAc (10 mL/mmol). The
mixture was washed with saturated aqueous NaHCO3 (5.0 mL/
mmol) and brine (5.0 mL/mmol), dried (MgSO4), filtered, and con-
centrated in vacuo. The crude product was purified by flash column
chromatography to yield the corresponding phenol.
7.81 (d, JH,H = 8.7 Hz, 2 H), 7.48 (d, JH,H = 8.1 Hz, 2 H), 7.24 (d,
JH,H = 8.1 Hz, 2 H), 7.06 (br. s, 1 H, ArOH), 7.00 (d, JH,H
=
1.6 Hz, 1 H), 6.86 (d, JH,H = 8.7 Hz, 2 H), 5.82–5.80 (m, 1 H), 3.81
(s, 3 H, CO2CH3), 3.46–3.41 (m, 2 H), 2.80 (br. s, 1 H), 2.47–2.25
(m, 3 H), 1.83–1.51 (m, 4 H), 1.42–1.12 (m, 6 H), 1.00–0.81 (m, 3
H), 0.75 (s, 3 H), 0.57 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 200.7, 168.7, 160.4, 144.5, 140.7, 139.3, 131.8, 131.4, 130.8,
129.3, 128.2 (q, JC,F = 32.2 Hz), 127.9, 125.6, 125.0, 115.1, 57.3,
56.6, 51.6, 47.8, 45.0, 40.1, 39.9, 39.0, 34.9, 34.1, 32.2, 31.6, 24.7,
23.8, 20.9, 19.3, 13.4 ppm. MS (ESI): m/z (%) = 593 (100)
[M + H]+. HRMS (ESI): calcd. for C36H40O4F3 593.2879; found
593.2880. [α]2D5 = –131.2 (c = 1.0, CHCl3).
Addition
of
{4-[(tert-Butyldimethylsilyl)oxy]phenyl}magnesium
Chloride to 2-Thiopyridyl Esters Followed by Bu4NF Deprotection.
General Procedure 6: Isopropylmagnesium chloride in THF
(1.34 m; 2.6 equiv.) was added dropwise to PhI 46 (2.6 equiv.) in
THF (2.0 mL/mmol) at 0 °C and the mixture was stirred for 2 h.
The resulting solution of Grignard reagent (2.6 equiv.) was added
to thiopyridyl ester (1.0 equiv.) in THF (5.0 mL/mmol) at –50 °C
and the mixture stirred for 1 h. The mixture was quenched with
saturated aqueous NH4Cl (5.0 mL/mmol) and warmed to room
temperature. The mixture was diluted with Et2O (10 mL/mmol),
separated and the aqueous layer was extracted with Et2O
(3ϫ10 mL/mmol). The combined organic extracts were washed
with brine (5.0 mL/mmol), dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by flash column
chromatography to yield the corresponding 4-OTBS acetophenone
intermediate which was dissolved in THF (10 mL/mmol) and co-
oled to 0 °C. AcOH (3.0 equiv.) and Bu4NF in THF (1.0 m;
3.0 equiv.) were added and the mixture was stirred for 2 h. The
reaction was quenched with saturated aqueous NaHCO3 (10 mL/
mmol) and diluted with EtOAc (10 mL/mmol). The mixture was
separated and the aqueous layer was extracted with EtOAc (10 mL/
mmol). The combined organic extracts were dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude product was purified
by flash column chromatography to yield the corresponding phe-
nol.
Synthesis of 48: Thioester 40 (100 mg, 0.174 mmol) was subjected
to general procedure 5. The crude product was purified by gradient
column chromatography (eluting with 1:9 to 1:4 EtOAc/hexanes)
to yield ketone 48 (70 mg, 79%) as a white solid; m.p. 132–136 °C.
IR (neat): ν
= 3418, 1673, 1659, 1644, 1602, 1588 cm–1. 1H
˜
max
NMR (400 MHz, CDCl3): δ = 7.82 (d, JH,H = 8.6 Hz, 2 H), 7.20
(d, JH,H = 8.2 Hz, 2 H), 7.06 (d, JH,H = 8.2 Hz, 2 H), 6.97 (s, 1 H),
6.86 (d, JH,H = 8.6 Hz, 2 H), 6.30 (br. s, 1 H, ArOH), 5.80 (s, 1 H),
3.81 (s, 3 H, CO2CH3), 3.43 (t, JH,H = 8.4 Hz, 1 H), 3.34 (dd, JH,H
= 13.1 and 2.7 Hz, 1 H), 2.74 (br. s, 1 H), 2.49–2.39 (m, 1 H), 2.33–
2.24 (m, 2 H), 1.81–1.59 (m, 4 H), 1.42–1.10 (m, 6 H), 1.00–0.78
(m, 3 H), 0.73 (s, 3 H), 0.57 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 200.2, 168.7, 159.8, 140.9, 139.0, 138.8, 132.1, 131.5,
131.1, 130.8, 130.5, 129.3, 128.2, 115.1, 57.4, 56.7, 51.6, 47.9, 44.9,
40.0, 39.6, 39.1, 34.9, 34.3, 32.2, 31.6, 24.7, 23.8, 20.9, 19.3,
13.4 ppm. MS (ESI): m/z (%) = 559 (100) [M + H]+. HRMS (ESI):
calcd. for C32H40O4Cl 559.2615; found 559.2620. C35H39ClO4
(559.14): calcd. C 75.18, H 7.03; found C 75.23, H 6.95. [α]2D5
–205.5 (c = 0.33, CHCl3).
=
Synthesis of 49: Thioester 41 (350 mg, 0.585 mmol) was subjected
to general procedure 5. The crude product was purified by flash
column chromatography (eluting with 1:4 EtOAc/hexanes) to yield
Synthesis of 47: Thioester 38 (121 mg, 0.261 mmol) was subjected
to general procedure 6. The crude product was purified by flash
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
C-2,C-20-Diaryl Steroid Analogues
column chromatography (eluting with 1:9 Et2O/hexanes) to yield
ketone 47 (32.0 mg, 41%) as a white foam. 1H NMR (400 MHz,
CDCl3): δ = 7.89 (d, JH,H = 8.7 Hz, 2 H), 6.94 (d, JH,H = 1.2 Hz,
1 H), 6.91 (d, JH,H = 8.7 Hz, 2 H), 5.83–5.81 (m, 1 H), 3.79 (s, 3
zation from EtOH to yield carboxylic acid 4a (65.5 mg, 51%) as a
white solid; m.p. 158–160 °C (EtOH). IR (neat): νmax = 3247, 1664,
˜
1600, 1490 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, JH,H
=
8.8 Hz, 2 H), 7.22 (d, JH,H = 8.4 Hz, 2 H), 7.12 (d, JH,H = 8.4 Hz,
H, CO2CH3), 3.50 (t, JH,H = 8.6 Hz, 1 H), 2.65–2.58 (m, 1 H), 2 H), 6.98 (d, JH,H = 1.4 Hz, 1 H), 6.82 (d, JH,H = 8.8 Hz, 2 H),
2.53–2.45 (m, 1 H), 2.34 (td, JH,H = 18.9 and 4.8 Hz, 1 H), 1.93 5.82–5.78 (m, 1 H), 3.55 (t, JH,H = 8.6 Hz, 1 H), 3.36–3.30 (m, 1
(dd, JH,H = 13.0 and 5.4 Hz, 1 H), 1.85–1.20 (m, 9 H), 1.14 (d, H), 2.76 (br. s, 1 H), 2.46–2.24 (m, 3 H), 1.83–1.59 (m, 5 H), 1.41–
JH,H = 6.7 Hz, 3 H, CHCH3), 1.10–1.03 (m, 1 H), 0.95–0.91 (m, 1 1.13 (m, 6 H), 1.00 (dt, JH,H = 11.7 and 4.1 Hz, 1 H), 0.91–0.82
H), 0.88 (s, 3 H), 0.67 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): (m, 1 H), 0.80 (s, 3 H), 0.56 (s, 3 H) ppm. 13C NMR (100 MHz,
δ = 200.4, 168.7, 160.1, 141.1, 137.8, 131.9, 131.1, 130.9, 130.4, CDCl3): δ = 202.5, 171.5, 163.6, 142.4, 140.4, 140.1, 132.8, 132.1,
115.1, 57.5, 56.6, 51.4, 48.0, 45.1, 43.7, 39.2, 35.2, 32.2, 31.6, 27.4, 132.0, 131.9, 131.0, 129.2, 116.0, 58.4, 57.6, 49.4, 46.1, 41.3, 40.4,
24.7, 23.9, 21.0, 20.2, 19.4, 13.5 ppm. MS (ESI): m/z (%) = 449
(100) [M + H]+. HRMS (ESI): calcd. for C29H37O4 449.2692; found
449.2697. [α]2D5 = –101.2 (c = 1.0, CHCl3).
40.2, 36.2, 35.6, 33.3, 33.0, 25.7, 24.9, 22.1, 19.8, 14.0 ppm [one
aromatic quaternary obscured]. MS (ESI): m/z (%) = 545 (100) [M
+ H]+. HRMS (ESI): calcd. for C34H38O4Cl 545.2459; found
545.2461. [α]2D5 = –158.3 (c = 1.0, CHCl3).
Synthesis of 51: Thioester 43 (70.5 mg, 0.121 mmol) was subjected
to general procedure 6. The crude product was purified by flash
column chromatography (eluting with 49:1 CH2Cl2/Et2O) to yield
ketone 51 (35.0 mg, 59%) as a white amorphous solid. IR (neat):
Synthesis of 4b: Ester 49 (100 mg, 0.172 mmol) was subjected to
general procedure 7. The crude product was purified by flash col-
umn chromatography (eluting with 1:9 EtOAc/CH2Cl2) to yield
ν
= 3349, 1715, 1639, 1602, 1488, 1238, 1167, 1007, 827,
˜
max
carboxylic acid 4b (49.0 mg, 50%) as a white foam. IR (neat): ν
˜
max
739 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.83 (d, JH,H = 8.8 Hz,
= 3434, 1672, 1635, 1601, 1582 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.83 (d, JH,H = 8.7 Hz, 2 H), 7.26 (d, JH,H = 8.2 Hz, 2 H), 7.13
(d, JH,H = 1.0 Hz, 1 H), 7.09 (d, JH,H = 8.2 Hz, 2 H), 6.85 (d, JH,H
= 8.7 Hz, 2 H), 5.85–5.83 (m, 1 H), 3.99–3.91 (m, 1 H), 3.66 (dd,
JH,H = 11.1 and 3.1 Hz, 1 H), 3.46–3.42 (m, 3 H), 2.80 (br. s, 1 H),
2.47–2.22 (m, 3 H), 1.90–1.62 (m, 3 H), 1.46–1.28 (m, 5 H), 1.29
[s, 9 H, ArC(CH3)3], 1.04–0.86 (m, 4 H), 0.81 (s, 3 H), 0.59 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.5, 172.7, 160.0,
148.4, 141.2, 140.7, 137.1, 132.0, 131.7, 130.9, 129.1, 128.8, 125.0,
115.1, 57.4, 56.6, 47.9, 45.0, 40.1, 39.8, 39.1, 35.1, 34.3, 34.1, 32.3,
31.6, 31.4, 24.7, 23.9, 20.9, 19.4, 13.5 ppm. MS (ESI): m/z (%) =
567 (100) [M + H]+. HRMS (ESI): calcd. for C38H47O4 567.3474;
found 567.3474.
2 H), 7.20 (d, JH,H = 8.8 Hz, 2 H), 7.05 (s, 1 H), 6.90 (d, JH,H
=
8.8 Hz, 2 H), 6.85 (d, JH,H = 8.8 Hz, 2 H), 6.75 (s, 1 H), 5.98 (m,
1 H), 5.16 (m, 1 H), 3.71 (s, 3 H), 3.46 (t, JH,H = 8.8 Hz, 1 H),
2.49–2.32 (m, 3 H), 1.85–1.77 (m, 3 H), 1.65–1.62 (m, 1 H), 1.55–
1.49 (m, 2 H), 1.42–1.29 (m, 5 H), 1.16–1.10 (m, 1 H), 0.95 (s, 3
H), 0.63 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 200.6,
167.3, 160.3, 157.2, 140.2, 139.7, 133.6, 131.7, 130.9, 129.3, 126.3,
126.0, 117.9, 115.2, 72.6, 57.2, 56.6, 51.7, 47.9, 45.0, 40.1, 39.0,
36.5, 32.2, 30.8, 24.7, 24.0, 21.1, 19.7, 13.5 ppm. MS (ESI): m/z (%)
= 432 (100) [M – OPhCl]+, 561 (40) [M + H]+. HRMS (ESI): calcd.
for C34H38O5Cl 561.2408; found: 561.2418. [α]2D5 = –120.5 (c = 0.83,
CHCl3).
Synthesis of 52: Thioester 44 (144 mg, 0.265 mmol) was subjected
to general procedure 6. The crude oil was purified by flash column
chromatography (eluting with 49:1 CH2Cl2/Et2O) to yield ketone
Synthesis of 3a: Ester 51 (76 mg, 0.14 mmol) was dissolved in a
mixture of MeOH (4.8 mL) and H2O (0.30 mL). LiOH·H2O
(0.11 g, 2.7 mmol) was added and the reaction mixture was stirred
at room temperature for 96 h. The solution was diluted with EtOAc
(10 mL) and quenched with aqueous HCl (1.0 m; 5.0 mL). The
aqueous layer was extracted with EtOAc (4ϫ10 mL) and the com-
bined organic extracts were dried (MgSO4), filtered, and concen-
trated in vacuo. The crude product was purified by preparative
TLC (developed in 9:1 CH2Cl2/Et2O) to yield 3a (38 mg, 51%) as
52 (86.5 mg, 62%) as an amorphous white solid. IR (neat): ν
=
˜
max
3333, 1714, 1641, 1598, 1585, 1491, 1438, 1267, 1236, 1168, 910,
730 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.82 (d, JH,H = 8.8 Hz,
2 H), 7.27–7.23 (m, 2 H), 7.16 (s, 1 H), 7.05 (s, 1 H), 6.98–6.92 (m,
3 H), 6.86 (d, JH,H = 8.8 Hz, 2 H), 5.97 (m, 1 H), 5.23 (m, 1 H),
3.71 (s, 3 H), 3.46 (t, JH,H = 8.8 Hz, 1 H), 2.45 (dd, JH,H = 12.7
and 6.4 Hz, 1 H), 2.37–2.32 (dt, JH,H = 20.0 and 4.9 Hz, 1 H),
1.89–1.75 (m, 3 H), 1.69–1.62 (m, 1 H), 1.55–1.49 (m, 2 H), 1.38–
1.28 (m, 5 H), 1.16–1.11 (m, 1 H), 0.96 (s, 3 H), 0.64 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 200.8, 167.6, 160.6, 158.5, 140.0,
139.8, 133.3, 131.5, 130.9, 129.4, 126.7, 121.2, 116.6, 115.2, 72.0,
57.2, 56.5, 51.7, 47.9, 45.0, 40.2, 39.0, 36.5, 32.2, 30.8, 24.7, 24.0,
21.0, 19.7, 13.5 ppm. MS (ESI): m/z (%) = 433 (100) [M – OPh]+,
549 (40) [M + Na]+. HRMS (ESI): calcd. for C34H38O5Na
549.2617; found 549.2642. [α]2D5 = –126.0 (c = 0.83, CHCl3).
an amorphous white solid. IR (neat): ν
= 3248, 1684, 1637,
˜
max
1601, 1582, 1488, 1423, 1379, 1236, 1166, 1092, 1000, 824 cm–1. 1H
NMR (500 MHz, CD3OD): δ = 7.81 (d, JH,H = 8.8 Hz, 2 H), 7.20
(d, JH,H = 8.8 Hz, 2 H), 7.00 (s, 1 H), 6.94 (d, JH,H = 8.8 Hz, 2 H),
6.80 (d, JH,H = 8.8 Hz, 2 H), 5.97 (m, 1 H), 5.16 (m, 1 H), 3.55 (t,
JH,H = 8.8 Hz, 1 H), 2.45–2.31 (m, 3 H), 1.85–1.73 (m, 3 H), 1.68–
1.61 (m, 1 H), 1.49–1.43 (m, 7 H), 1.15–1.10 (m, 1 H), 0.98 (s, 3
H), 0.59 (s, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 202.5,
170.3, 163.5, 158.9, 141.3, 140.3, 134.2, 132.2, 132.1, 130.3, 128.9,
126.7, 118.9, 116.1, 73.6, 58.2, 57.5, 49.4, 46.1, 41.3, 40.0, 37.7,
33.3, 32.2, 25.8, 24.9, 22.2, 20.1, 14.1 ppm. MS (ESI): m/z (%) =
419 (100) [M – OPhCl]+, 547 (40) [M + H]+. HRMS (ESI): calcd.
for C33H36O5Cl 547.2251; found 547.2249. [α]2D5 = –40.5 (c = 1.0,
CHCl3).
Hydrolysis of Methyl Esters. General Procedure 7: Water (5.0 mL/
mmol) and KOH (3.0 equiv.) were added to ester (1.0 equiv.) in
MeOH (5.0 mL/mmol) and the mixture was stirred at reflux for
4 h. The mixture was cooled to room temperature and acidified to
pH 1 by the dropwise addition of concentrated HCl. The mixture
was diluted with EtOAc (10 mL/mmol) and separated. The aque-
ous layer was extracted with EtOAc (3ϫ10 mL/mmol) and the
combined organic extracts were washed with brine (5.0 mL/mmol)
then dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash column chromatography or by
recrystallization to yield the corresponding acid.
Synthesis of 3b: Ester 52 (75 mg, 0.14 mmol) was dissolved in
MeOH (5.0 mL) and H2O (0.30 mL). LiOH·H2O (0.12 g,
2.9 mmol) was added and the mixture was stirred at room tempera-
ture for 48 h. The solution was diluted with EtOAc (10 mL) and
quenched with aqueous HCl (1.0 m; 5.0 mL). The aqueous layer
was extracted with EtOAc (4ϫ10 mL) and the combined organic
extracts were dried (MgSO4), filtered, and concentrated in vacuo.
Synthesis of 4a: Ester 48 (130 mg, 0.227 mmol) was subjected to
general procedure 7. The crude product was purified by recrystalli-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
A. G. M. Barrett et al.
FULL PAPER
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The crude product was purified by preparative TLC (developed in
41:9 CH2Cl2/Et2O) to yield carboxylic acid 3b (46 mg, 64%) as an
amorphous white solid. IR (neat): ν
= 3249, 1680, 1638, 1597,
˜
max
1490, 1440, 1379, 1233, 1166, 1037, 842 cm–1. 1H NMR (400 MHz,
CD3OD): δ = 7.81 (d, JH,H = 8.8 Hz, 2 H), 7.22 (m, 2 H), 7.00 (s,
1 H), 6.96 (m, 2 H), 6.89 (m, 1 H), 6.80 (d, JH,H = 8.8 Hz, 2 H),
5.98 (m, 1 H), 5.25 (m, 1 H), 3.57 (t, JH,H = 9.0 Hz, 1 H), 2.47 (dd,
JH,H = 12.7 and 6.3 Hz, 1 H), 2.39–2.32 (m, 2 H), 1.88–1.73 (m, 3
H), 1.68–1.61 (m, 1 H), 1.51–1.25 (m, 7 H), 1.20–1.12 (m, 1 H),
0.99 (s, 3 H), 0.60 (s, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ
= 202.6, 170.5, 163.5, 160.1, 141.4, 140.2, 134.0, 132.2, 132.1, 130.4,
129.2, 122.1, 117.5, 116.1, 73.1, 58.2, 57.5, 49.4, 46.1, 41.4, 40.0,
37.8, 33.3, 32.2, 25.8, 24.9, 22.2, 20.1, 14.0 ppm. MS (ESI): m/z (%)
= 419 (100) [M – OPh]+, 513 (40) [M + H]+. HRMS (ESI): calcd.
for C33H37O5 513.2641; found: 513.2632. [α]2D5 = –51.3 (c = 1.0,
CHCl3).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis of acid 8 and iodide
46 as well as copies of 1H and 13C NMR spectra for all compounds.
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Received: February 17, 2012
Published Online: ᭿
14
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20190
/KAP1
Date: 04-06-12 15:29:34
Pages: 15
C-2,C-20-Diaryl Steroid Analogues
Multi-Step Steroid Synthesis
Starting from pregnenolone, a diastereose-
lective fifteen-step synthesis was developed
to access novel C-2-substituted steroid ana-
logues. A range of C-2 benzyl and aryl
ether analogues were prepared to probe
their efficacy as antagonists of the nuclear
receptor LRH-1.
J. Rey, T. J. C. O’Riordan, H. Hu,
J. P. Snyder, A. J. P. White,
A. G. M. Barrett* ........................... 1–15
Design and Diastereoselective Synthesis of
C-2,C-20-Diaryl Steroidal Derivatives
Keywords: Medicinal chemistry / Synthesis
design / Drug design / Steroids / Diastereo-
selectivity / Carbonylation
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15