Synthesis on novel Tamoxifen derivatives

Article abstract of DOI:10.1016/j.tet.2012.08.089

The design and synthesis of derivatives of 4-hydroxy-Tamoxifen as potential antagonists of the nuclear receptor LRH-1 are described. Stereoselective McMurry coupling was used to generate the desired internal alkene and a novel method for the synthesis of

Full text of DOI:10.1016/j.tet.2012.08.089

Tetrahedron 68 (2012) 9211e9217
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis on novel Tamoxifen derivatives
,
Jullien Reya, Haipeng Hu b, James P. Snyder b, Anthony G.M. Barrett a
*
a Department of Chemistry, Imperial College London, England SW7 2AZ, UK
b Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2012
Received in revised form 9 August 2012
Accepted 28 August 2012
Available online 1 September 2012
The design and synthesis of derivatives of 4-hydroxy-Tamoxifen as potential antagonists of the nuclear
receptor LRH-1 are described. Stereoselective McMurry coupling was used to generate the desired in-
ternal alkene and a novel method for the synthesis of tetrasubstituted cyclopropane analogues was also
developed.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Antagonist
Computer assisted drug design
Tamoxifen
Cyclopropanation
1. Introduction
Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor
(NR) from the superfamily of transcription factors that control
a range actions fundamental to human physiology.1 Of particular
interest is the implication of LRH-1 in the control of aromatase
expression2 and its ability to act as a key regulator of ER expression
in breast cancer cells.3 In the light of these considerations, the
identification and development of small molecule antagonists of
LRH-1 could provide a new approach for potential therapies against
breast cancer.
Fig. 1. In silico modifications of 4-hydroxy-Tamoxifen (1).
To date, there is only one example of agonists of LRH-1 but no
antagonists of this NR have yet been reported.4 We have recently
examined the design and synthesis of novel ring A and D func-
tionalized steroids as potential antagonists but none of these
compounds were significantly active in modulating the effects of
LRH-1.5 Using computational methods and the crystal structure of
the LRH-1 ligand-binding domain (LBD, PDB ID code 1YOK),6 we
have now designed structures of novel derivatives of Tamoxifen
(2e4), which we believe could be effective as antagonists of LRH-1
(Fig. 1).
helix 12 (H12) displacement, we designed compounds capable of
generating an inactive conformation of H12 by inducing steric
clashes between the amino acid residue Leu532 and an antagonist
(Fig. 2). Generating an inactive conformation of LRH-1 could pos-
sibly prevent co-activator recruitment and subsequent stimulation
of gene expression.8
2. Results and discussion
Docking studies were initiated with 4-hydroxy-Tamoxifen (1)7
whose structure was modified to generate three virtual antago-
nists capable of binding to the LRH-1 LBD by hydrophobic in-
teractions. Based on the fact that anti-estrogens, such as 4-hydroxy-
Tamoxifen can induce a conformational change in the NR LBD by
The synthesis of these three virtual LRH-1 antagonists was un-
dertaken to test the validity of our computational studies. Many
academic groups and pharmaceutical companies have been in-
terested in the synthesis of Tamoxifen and structurally related
analogues. While many syntheses have been reported in the liter-
ature, few are geometrically selective in the construction of the
central alkene unit.9,10 Synthesis of the hydroxytriphenylethylene
motif has been extremely challenging especially in a stereoselective
manner. Another challenge in the preparation of compounds
* Corresponding author. E-mail address: agm.barrett@imperial.ac.uk (A.G.M.
Barrett).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.089

9212
J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
Scheme 2. Cross-coupling to access ketone 12.
Fig. 2. Molecular modeling of analogues 2 (blue structure), 3 (yellow structure) and 4
(cyan structure) in the LBD of LRH-1 (PDB ID code 1YOK) depict a steric conflict with
the key amino acid residue Leu532 on H12 highlighted in red.
bearing this motif was to avoid isomerization of the olefin sub-
sequent to its elaboration.
Scheme 3. Syntheses of ketones 18 and 19.
Gauthier’s procedure10b for the stereoselective synthesis of 4-
hydroxy-Tamoxifen (1) appeared to be the method of choice to
synthesize the computer assisted drug design (CADD) analogues.
We believed that the targets 2e4 should be available by depro-
tection of the phenolic pivaloyl groups and subsequent nucleophilic
substitution of free phenol 5. The desired (E)-olefin 5 would be
stereoselectively synthesized using McMurry intermolecular cou-
pling between ketones 6 and 7. Finally, depending on the nature of
the R-group, ketone 7 could be either obtained by copper-catalyzed
cross-coupling from chloroketone 8 (R¼Cl) or by Grignard addition
Reaction of ketones 12, 18 and 19 with the benzophenone 6
under McMurry conditions stereoselectively gave the correspond-
ing (E)-alkenes (E/Z >10:1) (Scheme 4). This geometric selectivity is
possibly the result of intramolecular
p-stacking between both the
phenyl and the more electron-rich phenol ring during the forma-
tion of the initial diol titanium complex. Attempted re-
crystallization of the crude mixtures from a wide range of solvent
mixtures was examined. Several triturations and recrystallization
from ethanol gave the (E)-alkene 21 in moderate yield. Re-
crystallization of alkenes 22 and 23 was unsuccessful and these
intermediates, slightly contaminated with their undesired (Z)-iso-
mers, were used in the next step with no further purification. The
desired (E)-geometry of the product alkenes 21 to 23 was con-
firmed by nOe experiments in which crucially selective irradiation
of the signal due to H-1 showed spatial relationship with H-2. The
alkenes 21 to 23 were then carefully alkylated with 2-(dimethyla-
mino)ethyl chloride (24) to avoid trans-esterification and the pure
(E)-alkenes 25 to 27 were formed in moderate yields. Finally, the
pivaloyl groups were deprotected using methyllithium at ꢀ78 ꢁC
and Tamoxifen analogues 2e4 were isolated as white solids after
repeated trituration with ethanol. The low overall yields obtained
for the whole sequence resulted from the need to purify every in-
termediate to avoid isomerization of the central tetrasubstituted
i
to aldehyde 9 (R¼Et, Pr) followed by subsequent oxidation of the
resultant secondary alcohol (Scheme 1).
Scheme 1. Retrosynthetic analysis.
Since chloroketone 8 is commercially available, its reactivity
toward copper-catalyzed cross-coupling reaction conditions, in
presence of an organozinc halide was investigated.11 Reaction of
chloroketone 8 with cyclohexylmagnesium bromide (10) in the
presence of copper(II) acetate and zinc(II) chloride gave ketone 12
in 77% yield (Scheme 2).
A two-step procedure was developed for the synthesis of the
McMurry coupling precursors 18 and 19. Aldehydes 13 and 14 were
allowed to react with (cyclohexylmethyl)magnesium bromide (15)
to generate the corresponding racemic secondary alcohols 16 and
17 in good yields. The latter were subsequently oxidized under
ParikheDoering conditions, to give ketones 18 and 19 in 64% and
70% yields, respectively (Scheme 3).12
Scheme 4. Syntheses of 4-hydroxy-Tamoxifen derivatives by McMurry coupling.

J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
9213
alkene. Yields of each of the isolated intermediates 25 to 27 and
final products referred to single geometric isomers (>95:5) as
shown by their respective 1H NMR spectra and LCMS analysis.
From CADD, the most favorable energetically docking poses
were obtained for compounds 2e4 displaying a steric clash with
H12 via their 2-(dimethylamino)ethyl side chains. With this in
mind, it was believed that replacement of the dimethyl amino tail
by a bulkier functionality could eventually generate compounds
with a better probability of showing antagonistic activities and,
therefore, docking studies were carried out with compounds
bearing cyclic amine side chains. The best result was obtained for
analogue 30 that took the desired antagonistic docking pose with
the piperidine ring inducing additional steric hindrance around
H12. Alkylation of phenol 22 with N-(2-chloroethyl)-piperidine
(28) gave the Tamoxifen analogue 29 as a single geometric isomer
in 62% yield (Scheme 5). Deprotection of the pivaloate ester with
methyllithium, trituration of the crude product with ethanol and
recrystallization from dichloromethane and methanol gave solely
the (Z)-isomer 30 in 41% yield.
cyclopropanate alkene 2 to generate the corresponding racemic
cyclopropane 31. Unfortunately, reaction of alkenes 2 and 25 under
SimmonseSmith cyclopropanation conditions14 did not provide
the desired products even when trifluoroacetic acid was added to
generate a more active carbenoid15 (Scheme 6). The lack of re-
activity was presumably the result of steric hindrance with these
tetrasubstituted alkenes.
Scheme 6. Direct cyclopropanation of internal olefin.
Cyclopropanation of olefins with diazoalkanes in the presence
of transition metal catalysis appeared to be a possible alternative
for the synthesis of these analogues. Many metals, such as Cu, Rh
and Pd have been reported as excellent catalysts for carbenoid
formation followed by cyclopropanation with an alkene.16 We
considered that cyclopropane 32 could be obtained from diazo
intermediate 34 and alkene 35 (Scheme 7) either via metal car-
benoid 36 formation followed by cyclopropanation (Scheme 7,
path A) or, without addition of catalyst, via 1,3-dipolar cycload-
dition to form pyrazoline intermediate 37, which under thermal
conditions could react to form the cyclopropane 32 (Scheme 7,
path B).
Scheme 5. Synthesis of piperidine analogue 30.
The major issue in synthesizing and handling these analogues
was their instability even under slightly acidic conditions. For in-
stance, if chloroform-d1 was used as an NMR solvent, the Tamoxifen
analogues underwent facile acid catalyzed E/Z isomerization to
a mixture of isomers. In the solid state, the geometrically pure (Z)-
analogues proved to be stable for months when stored at low
temperature, but we harbored doubts as to their geometric stability
when used in solution for biological evaluation. In order to over-
come this isomerization problem, we sought to replace the acid-
sensitive alkene by a cyclopropane. Further CADD docking studies
led to the design of analogues 31 and 32 (Fig. 3). Introduction of
a cyclopropane ring did not seem to alter the antagonistic binding
pose of these new compounds.
Scheme 7. Metal carbenoid and pyrazoline pathways to cyclopropane 32.
Monomethylation of 4,40-dihydroxybenzophenone (20) with
iodomethane and subsequent condensation under basic conditions
with 2-(dimethylamino)ethyl chloride (24) gave ketone 39 in 62%
yield. This was converted to a mixture of isomeric hydrazones 40
using hydrazine hydrate in ethanol at reflux. Finally, by following
Miller’s work on the preparation of crystalline diphenyldiazo-
methane,17 40 was oxidized with yellow mercury(II) oxide and
ethanolic potassium hydroxide as catalyst. In this reaction, strictly
anhydrous conditions were essential to prevent decomposition of
the sensitive diazoalkane 34, which was isolated as a purple solid
(Scheme 8).
Fig. 3. Cyclopropane analogues 31 and 32.
Many methods for efficient diastereoselective and enantiose-
lective cyclopropanations have been reported in the literature in-
cluding the use of chiral auxiliaries, chiral ligands in stoichiometric
quantities and chiral catalysts.13 We initially sought to directly

9214
J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
techniques 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 chroma-
tography (TLC) was performed using pre-coated aluminum plates
(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 Merck 9385 Kieselgel 60 (230e400 mesh)
under a positive pressure of nitrogen. Melting points (mp) were
determined using a hot-stage microscope and are uncorrected.
Infrared (IR) spectra were recorded with ATR technique, monitoring
from 4000e700 cmꢀ1. NMR spectra were recorded using an in-
ternal deuterium lock at ambient probe temperatures (1H NMR
recorded at 400 or 500 MHz and 13C NMR recorded at 100 or
Scheme 8. Synthesis of diazo intermediate 34.
Alkene 35 was prepared quantitatively by Wittig reaction be-
tween ketone 12 and methylenetriphenylphosphorane (41)
(Scheme 9).18
125 MHz). Chemical shifts (d) are quoted in parts per million (ppm)
and are referenced to a residual solvent peak.
4.1. Computational details
The crystal structure of LRH-1 LBD (PDB code: 1YOK) and the
Schrodinger Suite 201019 were used to perform 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 522e538) in
LRH-1 LBD were removed from the protein structure in the CADD
analysis. All analogues were generated using LigPrep 2.3 and were
docked into LRH-1 LBD crystal structure using Glide 5.5. A Prime
2.1 MM-GBSA rescoring was performed to predict LRH-1 binding
affinities of the potential antagonists.
Scheme 9. Wittig reaction to access alkene 35.
The cyclopropanation reaction between diazoalkane 34 and al-
kene 35 via metal carbenoid formation was investigated. Un-
fortunately, reaction of diazoalkane 34 with dirhodium(II)
tetraoctanoate, palladium(II) diacetate or copper(II) triflate in
presence of alkene 35 did not provide the desired cyclopropane 32.
Heating diazoalkane 34 and alkene 35 in THF at reflux only led to
formation of unidentified byproducts. However, when diazoalkane
34 was added to the neat pre-heated alkene 35, cyclopropane 32
was isolated as a 1:1 mixture of diastereoisomers in 27% yield over
two steps (Scheme 10). Variation of the number of alkene equiva-
lents and/or temperature did not improve the yield of the reaction.
All of our attempts to selectively deprotect the methoxy group of
cyclopropane 32 failed, and the only product that could be isolated
was the di-phenol with cleavage of both the methyl and 2-(dime-
thylamino)ethyl groups.
4.2. Experimental details
4.2.1. Synthesis of (12). Cyclohexylmagnesium chloride (10)
(4.00 mL, 7.95 mmol, 1.5 equiv, 2 M in Et2O) was added to ZnCl2
(1.08 g, 7.95 mmol,1.5 equiv) in Et2O (40.0 mL) and the mixture was
stirred vigorously at 0 ꢁC for 30 min. The resulting white suspen-
sion was added to chloroketone 8 (1.00 g, 5.30 mmol, 1.0 equiv) and
Cu(OAc)2 (48.5 mg, 0.265 mmol, 0.05 equiv) in THF (10.6 mL) at
room temperature. The mixture was stirred at room temperature
for 17 h, diluted with Et2O and quenched by addition of saturated
aqueous NH4Cl. The aqueous phase was extracted with Et2O (ꢂ1)
and the combined organic extracts were dried (MgSO4), filtered,
concentrated and chromatographed (97:3 hexanes/Et2O) to yield
ketone 12 (960 mg, 77%) as a white solid: mp¼55e60 ꢁC (hexanes);
Rf (3% Et2O/hexanes) 0.35; IR (neat) 1686, 1583, 1398, 1284, 1217,
1088, 818 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼8.8 Hz, 2H),
7.42 (d, J¼8.8 Hz, 2H), 2.78 (d, J¼6.9 Hz, 2H), 2.00e1.90 (m, 1H),
1.76e1.64 (m, 5H), 1.33e0.96 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3)
d 199.0, 139.3, 135.7, 129.6, 128.8, 46.2, 34.5, 33.4, 26.2,
ꢃ ꢃ
26.1 ppm; MS (EI) m/z¼236 [M (35Cl)]þ , 238 [M (37Cl)]þ ; HRMS (EI)
Scheme 10. Synthesis of cyclopropane analogue 32.
ꢃ
calcd for C14H1735ClO [M]þ 236.0968, found: 236.0961.
3. Conclusion
4.2.2. Synthesis of (16). (Cyclohexyl)methylmagnesium bromide
(15) (44.8 mL, 22.4 mmol, 3 equiv, 0.5 M in THF) was added drop-
wise with stirring to aldehyde 13 (1.03 mL, 7.45 mmol, 1 equiv) in
THF (53 mL) at 0 ꢁC. The mixture was stirred at 0 ꢁC for 3 h and
quenched with 1 M aqueous HCl. The aqueous phase was extracted
with Et2O (ꢂ3) and the combined organic extracts were dried
(MgSO4), filtered, concentrated and chromatographed (9:1 to 7:3
hexanes/Et2O) to yield alcohol 16 (1.37 g, 79%) as a colorless oil: Rf
(20% Et2O/hexanes) 0.25; IR (neat) 3295, 1463, 1447, 1343, 1089,
Computational studies led to the design of novel analogues of
Taxoxifen 2e4 and 30 that were stereoselectively synthesized by
McMurry coupling to generate the desired tetrasubstituted alkene.
These alkenes proved to be sensitive under acidic conditions and
replacement of the alkene by a cyclopropane was successfully
achieved via 1,3-dipolar cycloaddition between an alkene and
a diazoalkane. The analogues were of insufficient solubility in polar
media, which precluded meaningful assay against LRH-1.
1064, 1045, 992, 827 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.27 (d,
J¼7.8 Hz, 2H), 7.18 (d, J¼7.8 Hz, 2H), 4.78e4.74 (m, 1H), 2.65 (q,
J¼7.3 Hz, 2H), 1.85e1.79 (m, 1H), 1.74e1.63 (m, 6H), 1.55e1.48 (m,
1H), 1.47e1.38 (m, 1H), 1.24 (t, J¼7.3 Hz, 3H), 1.26e1.14 (m, 3H),
4. Experimental section
General remarks: All chemicals were used as received, or purified
1.02e0.88 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 143.5, 142.6,
using standard procedures. Solvents were dried by standard
127.9, 125.8, 71.9, 46.9, 34.2, 33.9, 32.9, 28.5, 26.6, 26.3, 26.1,

J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
9215
ꢃ
15.6 ppm; MS (CI) m/z¼232 [M]þ ; HRMS (CI) calcd for C16H28NO
organic extracts were dried (MgSO4), filtered and concentrated. The
resulting solid was purified by trituration and recrystallization.
[MþNH4]þ. 250.2171, found: 250.2173.
4.2.3. Synthesis of (17). (Cyclohexyl)methylmagnesium bromide
(15) (50.0 mL, 25.0 mmol, 3 equiv, 0.5 M in THF) was added drop-
wise with stirring to aldehyde 14 (1.26 mL, 8.33 mmol, 1 equiv) in
THF (60 mL) at 0 ꢁC. The mixture was stirred at 0 ꢁC for 3 h and
quenched with 1 M aqueous HCl. The aqueous phase was extracted
with Et2O (ꢂ3) and the combined organic extracts were dried
(MgSO4), filtered, concentrated and chromatographed (85:15 to 7:3
hexanes/Et2O) to yield alcohol 17 (1.61 g, 79%) as a colorless oil: Rf
(20% Et2O/hexanes) 0.32; IR (neat) 3293,1461,1447,1415,1048, 990,
4.3.1. Synthesis of (21). Ketones 6 (1.05 g, 3.50 mmol, 1 equiv) and
12 (2.50 g, 10.6 mmol, 3 equiv) were subjected to general procedure
1. The crude product was purified by trituration (EtOH, 20 mL) and
recrystallization (EtOH) providing olefin 21 (480 mg, 27%) as a light
yellow solid: IR (neat) 3403, 1723, 1611, 1512, 1267, 1196, 1163, 1015,
903, 827 cmꢀ1 1H NMR (400 MHz, (CD3)2SO)
; d 9.23 (s, 1H),
7.25e7.20 (m, 4H), 7.12e7.09 (m, 4H), 6.65 (d, J¼8.8 Hz, 2H), 6.44 (d,
J¼8.8 Hz, 2H), 2.25 (d, J¼6.9 Hz, 2H), 1.59e1.49 (m, 5H), 1.30 (s, 9H),
1.08e0.94 (m, 4H), 0.78e0.69 (m, 2H) ppm; 13C NMR (100 MHz,
(CD3)2SO) d 176.2, 155.3, 149.1, 140.9, 140.5, 139.4, 137.0, 132.9, 131.0,
130.9, 130.4, 129.9, 127.7, 121.3, 114.4, 41.8, 38.4, 35.5, 32.7, 26.7,
25.8, 25.7 ppm.
827 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.31 (d, J¼8.3 Hz, 2H), 7.24
(d, J¼8.3 Hz, 2H), 4.81e4.78 (m, 1H), 2.99e2.89 (app-m, 1H),
1.88e185 (m, 1H), 1.79e1.67 (m, 6H), 1.58e1.45 (m, 2H), 1.29e1.23
(m, 9H), 1.06e0.91 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 148.1,
142.8, 126.5, 125.8, 71.9, 46.9, 34.2, 34.0, 33.8, 32.9, 26.6, 26.3, 26.1,
4.3.2. Synthesis of (22). Ketones 6 (320 mg, 1.07 mmol, 1 equiv)
and 18 (740 mg, 3.21 mmol, 3 equiv) were subjected to general
procedure 1. The crude solid was triturated with EtOH (6.0 mL)
and collected by filtration. Recrystallization was unsuccessful and
olefin 22 (245 mg, 46%) (slightly contaminated with (Z)-isomer)
was isolated as a white solid. This material was used without
further purification: IR (neat) 3456, 1726, 1615, 1513, 1265, 1213,
ꢃ
24.0 ppm; MS (CI) m/z¼246 [M]þ ; HRMS (CI) calcd for C17H30NO
[MþNH4]þ. 264.2327, found: 264.2333.
4.2.4. Synthesis of (18). DMSO (9.0 mL) and SO3$pyridine (5.33 g,
15.1 mmol, 3.5 equiv, 45% purity) were added to alcohol 16 (1.00 g,
4.30 mmol, 1.0 equiv) and Et3N (2.95 mL, 21.1 mmol, 4.9 equiv) in
CH2Cl2 (35 mL) at 0 ꢁC. The mixture was stirred at room tempera-
ture for 1 h and diluted with EtOAc. The resulting solution was
washed successively with H2O (ꢂ3), saturated aqueous NaHCO3
(ꢂ1) and brine (ꢂ1). The organic phase was dried (MgSO4), filtered,
concentrated and chromatographed (98:2 to 95:5 hexanes/Et2O) to
yield ketone 18 (635 mg, 64%) as a colorless oil: Rf (5% Et2O/hex-
anes) 0.35; IR (neat) 1679, 1606, 1447, 1410, 1223, 1004, 959,
1135, 833 cmꢀ1 1H NMR (400 MHz, (CD3)2SO)
; d 9.19 (s, 1H), 7.22
(d, J¼8.3 Hz, 2H), 7.10 (d, J¼8.3 Hz, 2H), 7.03 (app-s, 4H), 6.66 (d,
J¼8.3 Hz, 2H), 6.42 (d, J¼8.3 Hz, 2H), 2.56 (q, J¼7.3 Hz, 2H), 2.25
(d, J¼6.8 Hz, 2H), 1.62e1.50 (m, 5H), 1.31 (s, 9H), 1.15 (t, J¼7.3 Hz,
3H), 1.13e1.12 (m, 1H), 0.97e0.94 (m, 3H), 0.77e0.69 (m,
2H) ppm.
817 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼8.3 Hz, 2H), 7.28
4.3.3. Synthesis of (23). Ketones 6 (407 mg, 1.36 mmol, 1 equiv)
and 19 (1.00 g, 4.09 mmol, 3 equiv) were subjected to general
procedure 1. The crude solid was triturated with EtOH (4.0 mL) and
collected by filtration. Recrystallization was unsuccessful and olefin
23 (115 mg, 17%) (contaminated with (Z)-isomer) was isolated as
a white solid. This material was used without further purification:
(d, J¼8.3 Hz, 2H), 2.80 (d, J¼6.9 Hz, 2H), 2.71 (q, J¼7.3 Hz, 2H),
2.02e1.91 (m, 1H), 1.77e1.64 (m, 5H), 1.26 (t, J¼7.3 Hz, 3H),
1.28e1.14 (m, 3H), 1.06e0.96 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3)
d 200.0, 149.7, 135.2, 128.4, 128.0, 46.1, 34.7, 33.5, 28.9, 26.3,
26.2, 15.2 ppm; MS (ESI) m/z¼231 [MþH]þ; HRMS (ESI) calcd for
C16H23O [MþH]þ 231.1749, found: 231.1740.
IR (neat) 3453, 1726, 1614, 1512, 1268, 1212, 1196, 1136, 836 cmꢀ1
;
1H NMR (400 MHz, (CD3)2SO)
d
9.17 (s, 1H), 7.20 (d, J¼8.3 Hz, 2H),
4.2.5. Synthesis of (19). DMSO (13 mL) and SO3$pyridine (7.54 g,
21.3 mmol, 3.5 equiv, 45% purity) were added to alcohol 17 (1.50 g,
6.09 mmol, 1.0 equiv) and Et3N (4.16 mL, 29.8 mmol, 4.9 equiv) in
CH2Cl2 (50 mL) at 0 ꢁC. The mixture was stirred at room tempera-
ture for 1 h and diluted with EtOAc. The resulting solution was
washed successively with H2O (ꢂ3), saturated aqueous NaHCO3
(ꢂ1) and brine (ꢂ1). The organic phase was dried (MgSO4), filtered,
concentrated and chromatographed (98:2 to 95:5 hexanes/Et2O) to
yield ketone 19 (1.03 g, 70%) as a colorless oil: Rf (5% Et2O/hexanes)
7.10e7.00 (m, 6H), 6.64 (d, J¼8.3 Hz, 2H), 6.40 (d, J¼8.3 Hz, 2H),
2.84e2.77 (app-m, 1H), 2.23 (d, J¼6.8 Hz, 2H), 1.61e1.49 (m, 5H),
1.30 (s, 9H), 1.16 (d, J¼6.8 Hz, 6H), 1.09e1.03 (m, 1H), 0.96e0.92 (m,
3H), 0.76e0.70 (m, 2H) ppm.
4.4. General procedure 2: introduction of the 2-(dimethyla-
mino)ethyl side chain
K2CO3 (3.3 equiv) was added to phenol (1.0 equiv) and hydro-
chloride salt of 2-(dimethylamino)ethyl chloride (24) (2.0 equiv) in
acetone (13 mL/mmol) and H2O (0.80 mL/mmol). The mixture was
heated to reflux in the dark for 5 h. The solution was cooled to room
temperature, dried (MgSO4), filtered, concentrated and chromato-
graphed to yield the corresponding amine.
0.38; IR (neat) 1677, 1604, 1405, 1222, 1058, 1000, 820 cmꢀ1
NMR (400 MHz, CDCl3)
;
1H
d
7.89 (d, J¼8.3 Hz, 2H), 7.30 (d, J¼8.3 Hz,
2H), 3.00e2.91 (app-m, 1H), 2.80 (d, J¼6.8 Hz, 2H), 2.02e1.92 (m,
1H), 1.77e1.60 (m, 5H), 1.33e1.10 (m, 9H), 1.06e0.96 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3)
d 199.9, 154.3, 135.4, 128.4, 126.6, 46.1,
34.6, 34.2, 33.5, 26.3, 26.2, 23.7 ppm; MS (ESI) m/z¼245 [MþH]þ;
HRMS (ESI) calcd for C17H25O [MþH]þ 245.1905, found: 245.1911.
4.4.1. Synthesis of (25). Phenol 21 (350 mg, 0.689 mmol, 1 equiv)
was subjected to general procedure 2. The crude product was
chromatographed (98:2 to 95:5 CH2Cl2/MeOH) to yield amine 25
(185 mg, 46%) as a colorless oil: Rf (5% MeOH/CH2Cl2) 0.35; IR (neat)
4.3. General procedure 1: formation of olefin via McMurry
coupling
1744, 1608, 1506, 1241, 1199, 1116, 832 cmꢀ1
CDCl3)
J¼8.3 Hz), 7.02 (d, 2H, J¼8.3 Hz), 6.74 (d, J¼8.8 Hz, 2H), 6.57 (d,
J¼8.8 Hz, 2H), 3.94 (t, J¼5.9 Hz, 2H), 2.67 (t, J¼5.9 Hz, 2H), 2.30
(app-s, 8H), 1.60e1.54 (m, 5H), 1.36 (s, 9H), 1.18e1.11 (m, 1H),
1.04e1.00 (m, 3H), 0.84e0.76 (m, 2H) ppm; 13C NMR (100 MHz,
;
1H NMR (400 MHz,
7.22 (d, 2H, J¼8.3 Hz), 7.13 (d, 2H, J¼8.3 Hz), 7.05 (d, 2H,
TiCl4 (4 equiv) was added dropwise with stirring to a suspension
of zinc (8 equiv) in THF (8.7 mL/mmol) under N2 and the mixture
was stirred at reflux for 2 h. Ketone 6 (1 equiv) and ketone (3 equiv)
in dry THF (14 mL/mmol) was added and the reflux was continued
for 5 h. The mixture was cooled to room temperature and poured
onto 10% aqueous K2CO3 and EtOAc. The resulting black suspension
was filtered through a short pad of Celite, the layers separated and
the aqueous phase extracted with EtOAc (ꢂ2). The combined
d
CDCl3)
d 177.0, 156.8, 149.6, 141.0, 140.7, 139.4, 138.1, 135.1, 131.5,
130.8, 130.5, 128.0, 121.0, 113.5, 65.6, 58.2, 45.8, 42.5, 39.1, 36.1, 33.2
(two carbons), 27.1, 26.3 ppm (one quaternary carbon obscured);

9216
J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
MS (ESI) m/z¼574 [M (35Cl)þH]þ, 576 [M (37Cl)þH]þ; HRMS (ESI)
calcd for C36H4535ClNO3 [MþH]þ 574.3088, found: 574.3083.
829 cmꢀ1; 1H NMR (400 MHz, CD3OD)
d
7.01 (d, J¼8.8 Hz, 2H), 6.98
(app-s, 4H), 6.78e6.75 (m, 4H), 6.56 (d, J¼8.8 Hz, 2H), 3.95 (t,
J¼5.4 Hz, 2H), 2.68 (t, J¼5.4 Hz, 2H), 2.56 (q, J¼7.3 Hz, 2H), 2.33 (d,
J¼7.3 Hz, 2H), 2.29 (s, 6H), 1.65e1.55 (m, 5H), 1.19 (t, J¼7.3 Hz, 3H),
1.19e1.17 (m, 1H), 1.07e1.01 (m, 3H), 0.86e0.78 (m, 2H) ppm; 13C
4.4.2. Synthesis of (26). Phenol 22 (200 mg, 0.403 mmol, 1 equiv)
was subjected to general procedure 2. The crude product was
chromatographed (98:2 to 95:5 CH2Cl2/MeOH) to yield amine 26
(83.5 mg, 34%) as a colorless oil: Rf (5% MeOH/CH2Cl2) 0.39; IR
(CHCl3) 1753, 1608, 1608, 1507, 1279, 1242, 1198, 1115, 1031,
NMR (100 MHz, CD3OD)
d 157.9, 157.1, 143.0, 141.6, 140.7, 139.9,
137.9, 136.5, 132.8, 131.8, 130.8, 128.3, 115.8, 114.4, 66.4, 59.2, 45.9,
43.8, 37.6, 34.7, 29.5, 27.7, 27.6, 16.0 ppm; MS (ESI) m/z¼484
[MþH]þ; HRMS (ESI) calcd for C33H42NO2 [MþH]þ 484.3216, found:
484.3200.
833 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼8.8 Hz, 2H), 7.04 (d,
J¼8.8 Hz, 2H), 6.98 (app-s, 4H, CH¼C), 6.74 (d, J¼8.8 Hz, 2H), 6.53 (d,
J¼8.8 Hz, 2H), 3.96 (t, J¼5.9 Hz, 2H), 2.70 (t, J¼5.9 Hz, 2H), 2.58 (q,
J¼7.4 Hz, 2H), 2.33 (s, 6H), 2.29 (d, J¼7.4 Hz, 2H), 1.63e1.54 (m, 5H),
1.36 (s, 9H), 1.20 (t, J¼7.3 Hz, 3H), 1.19e1.17 (m, 1H), 1.07e0.98 (m,
4.5.3. Synthesis of (4). Ester 27 (100 mg, 0.172 mmol, 1 equiv) was
subjected to general procedure 3. The crude solid was triturated
with EtOH (1.8 mL) and collected by filtration. The latter was then
recrystallized from EtOH to yield phenol 4 (23.5 mg, 27%) as a white
solid: mp¼168e170 ꢁC (EtOH); IR (neat) 1606, 1508, 1449, 1275,
3H), 0.84e0.78 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 177.1,
156.4,149.4,141.7,141.3,139.5,139.4,138.2,135.8,131.6,130.7,129.3,
127.2, 121.0, 113.3, 65.4, 58.1, 45.7, 42.8, 39.1, 36.0, 33.4, 28.4, 27.2,
26.4, 26.3, 15.3 ppm; MS (ESI) m/z¼568 [MþH]þ; HRMS (ESI) calcd
for C38H50NO3 [MþH]þ 568.3791, found: 568.3771.
1243, 1166, 1096, 1068, 1049, 969, 835, 829 cmꢀ1
;
1H NMR
(400 MHz, CD3OD) d 7.03e7.00 (m, 6H), 6.77e6.75 (m, 4H), 6.56 (d,
J¼8.8 Hz, 2H), 3.95 (t, J¼5.4 Hz, 2H), 2.83e2.78 (app-m, 1H), 2.68 (t,
J¼5.4 Hz, 2H), 2.33 (d, J¼6.8 Hz, 2H), 2.29 (s, 6H), 1.66e1.55 (m, 5H),
1.20 (d, J¼6.8 Hz, 6H), 1.19e1.18 (m, 1H), 1.08e0.99 (m, 3H),
4.4.3. Synthesis of (27). Phenol 23 (110 mg, 0.216 mmol, 1 equiv)
was subjected to general procedure 2. The crude product was
chromatographed (98:2 to 95:5 CH2Cl2/MeOH) to yield amine 27
(28.4 mg, 23%) as a colorless oil: Rf (5% MeOH/CH2Cl2) 0.41; IR
(CHCl3) 1754, 1608, 1508, 1483, 1280, 1242, 1198, 1164, 1117, 1032,
0.86e0.80 (m, 2H) ppm; 13C NMR (100 MHz, CD3OD)
d 157.9, 157.0,
147.7, 141.7, 140.8, 139.9, 137.9, 136.6, 132.8, 131.9, 130.8, 126.8, 115.8,
114.4, 66.4, 59.2, 45.9, 43.8, 37.6, 35.0, 34.7, 27.7, 27.6, 24.5 ppm; MS
(ESI) m/z¼498 [MþH]þ; HRMS (ESI) calcd for C34H44NO2 [MþH]þ
498.3372, found: 498.3379.
834 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼8.3 Hz, 2H), 7.04
(d, J¼8.3 Hz, 2H), 6.99 (app-s, 4H), 6.73 (d, J¼8.3 Hz, 2H), 6.52 (d,
J¼8.3 Hz, 2H), 3.93 (t, J¼5.9 Hz, 2H), 2.86e2.79 (app-m, 1H), 2.66 (t,
J¼5.9 Hz, 2H), 2.30 (app-s, 8H), 1.64e1.54 (m, 5H), 1.36 (s, 9H),
1.30e1.26 (m, 1H), 1.21 (d, J¼6.8 Hz, 6H), 1.06e1.00 (m, 3H),
4.5.4. Synthesis of (29). K2CO3 (147 mg, 1.06 mmol, 3.3 equiv) was
added to phenol 22 (160 mg, 0.321 mmol, 1.0 equiv) and hydro-
chloride salt of N-(2-chloroethyl)-piperidine (28) (119 mg,
0.643 mmol, 2.0 equiv) in acetone (4.1 mL) and H2O (0.30 mL). The
mixture was heated to reflux in the dark for 5 h. The solution was
cooled to room temperature, dried (MgSO4), filtered, concentrated
and chromatographed (98:2 to 95:5 CH2Cl2/MeOH) to yield amine 29
(120 mg, 62%) as a colorless oil: Rf (5% MeOH/CH2Cl2) 0.40; IR (CHCl3)
0.84e0.78 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 177.1, 156.5,
149.4,146.4,141.3,139.7,139.5,138.2,135.7,131.6,130.7,129.3,125.7,
120.9, 113.3, 65.6, 58.2, 45.8, 42.8, 39.1, 36.0, 33.6, 33.4, 27.1, 26.4,
26.3, 23.9 ppm; MS (ESI) m/z¼582 [MþH]þ; HRMS (ESI) calcd for
C39H52NO3 [MþH]þ 582.3947, found: 582.3958.
4.5. General procedure 3: pivaloyl protecting group
deprotection
1753, 1507, 1279, 1242, 1198, 1164, 1115, 1031, 833 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.23 (d, J¼8.3 Hz, 2H), 7.04 (d, J¼8.3 Hz, 2H), 6.98
(app-s, 4H), 6.74 (d, J¼8.8 Hz, 2H), 6.52 (d, J¼8.8 Hz, 2H), 4.00 (t,
J¼5.9 Hz, 2H), 2.74 (t, J¼5.9 Hz, 2H), 2.58 (q, J¼7.3 Hz, 2H), 2.52 (app-
br s, 4H), 2.29 (d, J¼7.3 Hz, 2H),1.63e1.54 (m, 9H),1.46e1.42 (m, 2H),
1.36(s, 9H),1.20 (t, J¼7.3 Hz, 3H),1.19e1.17 (m,1H),1.05e1.00 (m, 3H),
MeLi (3 equiv, 1.6 M in Et2O) was added to the pivaloyl ester
(1 equiv) in THF (21 mL/mmol) at ꢀ78 ꢁC. The mixture was stirred
at this temperature for 2 h and quenched with saturated aqueous
NH4Cl (10 mL/mmol). The mixture was allowed to warm to room
temperature and then extracted with EtOAc (ꢂ4). The combined
organic extracts were dried (MgSO4), filtered and concentrated. The
crude solid was triturated to yield the corresponding phenol.
0.81e0.78 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d 177.1, 156.4,
149.4, 141.7, 141.3, 139.5, 139.4, 138.2, 135.8, 131.6, 130.7, 129.3, 127.2,
121.0,113.4, 65.3, 57.7, 54.9, 42.8, 39.1, 36.0, 33.4, 28.4, 27.2, 26.4, 25.5,
26.3, 23.9, 15.3 ppm; MS (ESI) m/z¼608 [MþH]þ; HRMS (ESI) calcd
for C41H54NO3 [MþH]þ 608.4104, found: 608.4095.
4.5.1. Synthesis of (2). Ester 25 (110 mg, 0.191 mmol, 1 equiv) was
subjected to general procedure 3. The crude solid was triturated
with EtOH (1.2 mL) and collected by filtration to yield phenol 2
(52.5 mg, 56%) as a white solid: mp¼161e162 ꢁC (EtOH); IR (neat)
1611,1507,1447,1278,1238,1168,1092,1014, 839, 833, 781 cmꢀ1; 1H
4.5.5. Synthesis of (30). Ester 29 (100 mg, 0.172 mmol, 1 equiv) was
subjected to general procedure 3. The crude solid was triturated
with EtOH (1.5 mL) and collected by filtration. The latter was then
recrystallized from CH2Cl2/MeOH (95:5) to yield phenol 30
(35.0 mg, 41%) as a white solid: mp¼188e189 ꢁC (CH2Cl2/MeOH);
NMR (500 MHz, CD3OD)
d
7.13 (d, J¼8.3 Hz, 2H), 7.07 (d, J¼8.3 Hz,
2H), 7.02 (d, J¼8.8 Hz, 2H), 6.79e6.75 (m, 4H), 6.61 (d, J¼8.8 Hz, 2H),
3.97 (t, J¼5.4 Hz, 2H), 2.69 (t, J¼5.4 Hz, 2H), 2.36 (d, J¼7.3 Hz, 2H),
2.29 (s, 6H),1.65e1.56 (m, 5H),1.19e1.14 (m, 1H),1.08e0.98 (m, 3H),
IR (neat) 1607, 1509, 1448, 1240, 1171, 1038, 834 cmꢀ1 1H NMR
;
(400 MHz, mixture CD2Cl2/CD3OD)
d
7.04 (d, J¼8.8 Hz, 2H), 6.99
(app-s, 4H), 6.80e6.76 (m, 4H), 6.54 (d, J¼8.8 Hz, 2H), 3.96 (t,
J¼5.4 Hz, 2H), 2.67 (t, J¼5.4 Hz, 2H), 2.56 (q, J¼7.8 Hz, 2H), 2.47
(app-br s, 4H), 2.30 (d, J¼6.8 Hz, 2H), 1.63e1.53 (m, 9H), 1.46e1.41
(m, 2H), 1.18 (t, J¼7.8 Hz, 3H), 1.17e1.15 (m, 1H), 1.05e1.00 (m, 3H),
0.83e0.78 (m, 2H) ppm; 13C NMR (100 MHz, mixture CD2Cl2/
0.88e0.79 (m, 2H) ppm; 13C NMR (125 MHz, CD3OD)
d 158.3, 157.3,
143.2,142.0,138.7,137.4,136.0,132.8,132.6,132.5,131.7,128.9,115.9,
114.6, 66.5, 59.2, 45.9, 43.6, 37.7, 34.7, 27.6, 27.5 ppm; MS (ESI) m/
z¼490 [M (35Cl)þH]þ, 492 [M (37Cl)þH]þ; HRMS (ESI) calcd for
C31H3735ClNO2 [MþH]þ 490.2513, found: 490.2526.
CD3OD)
d 157.1, 156.1, 142.4, 140.9, 139.8, 139.5, 137.4, 136.1, 132.2,
131.3, 130.2, 127.7, 115.4, 113.9, 65.7, 58.4, 55.4, 43.4, 36.8, 34.1, 29.0,
27.1, 27.0, 26.0, 24.5, 15.6 ppm; MS (ESI) m/z¼524 [MþH]þ; HRMS
(ESI) calcd for C36H46NO2 [MþH]þ 524.3529, found: 524.3552.
4.5.2. Synthesis of (3). Ester 26 (65 mg, 0.12 mmol, 1 equiv) was
subjected to general procedure 3. The crude solid was triturated
with EtOH (1.2 mL) and collected by filtration to yield phenol 3
(27 mg, 49%) as a white solid: mp¼157e159 ꢁC (EtOH); IR (neat)
1606, 1508, 1449, 1275, 1243, 1166, 1096, 1068, 1049, 967, 835,
4.5.6. Synthesis of (39). K2CO3 (6.51 g, 47.1 mmol, 5 equiv) was
added to phenol 38 (2.15 g, 9.42 mmol, 1 equiv) and hydrochloride

J. Rey et al. / Tetrahedron 68 (2012) 9211e9217
9217
salt of 2-(dimethylamino)ethyl chloride (24) (4.07 g, 28.3 mmol,
3 equiv) in DMF (19 mL). The mixture was heated at 110 ꢁC for 5 h,
cooled to room temperature, diluted with EtOAc and quenched by
addition of H2O. The aqueous layer was extracted with EtOAc (ꢂ4)
and the combined organic extracts were dried (MgSO4), filtered,
concentrated and chromatographed (99:1 to 9:1 CH2Cl2/MeOH) to
yield amine 39 (1.74 g, 62%) as an amorphous light brown solid: Rf
(5% MeOH/CH2Cl2) 0.25; IR (neat) 1640, 1603, 1505, 1418, 1252,
chromatographed (96:4 CH2Cl2/MeOH) to yield cyclopropane 32
(45.4 mg, 27% over two steps) (1:1 mixture of diastereoisomers) as
a light yellow oil: Rf (4% MeOH/CH2Cl2) 0.25; IR (neat) 1608, 1510,
1493, 1450, 1244, 1174, 1034, 839 cmꢀ1; 1:1 mixture of isomer (A)þ
isomer (B): 1H NMR (400 MHz, CDCl3)
d
7.37e7.34 (m, 4H, AþB),
7.10e7.08 (m, 8H, AþB), 6.93e6.89 (m, 4H, AþB), 6.87e6.83 (m, 4H,
AþB), 6.51e6.47 (m, 4H, AþB), 4.06 (t, J¼5.9 Hz, 2H, A), 3.89 (t,
J¼5.9 Hz, 2H, B), 3.78 (s, 3H), 3.62 (s, 3H), 2.75 (t, J¼5.9 Hz, 2H, A),
2.64 (t, J¼5.9 Hz, 2H, B), 2.36 (s, 6H), 2.29 (s, 6H), 2.19e2.16 (m, 4H),
1.91e1.88 (m, 2H), 1.57e1.49 (m, 8H), 1.20e1.17 (m, 2H), 1.09e0.97
(m, 8H), 0.90e0.85 (m, 4H), 0.83e0.79 (m, 2H) ppm; 13C NMR
1152, 1031, 853, 769 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.79e7.76
(m, 4H), 6.98e6.94 (m, 4H), 4.15 (t, J¼5.9 Hz, 2H), 3.88 (s, 3H), 2.77
(t, J¼5.9 Hz, 2H), 2.36 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3)
d
194.4, 162.8, 162.1, 132.2 (two carbons), 130.9, 130.8, 114.0, 113.5,
(100 MHz, CDCl3) d 157.8, 157.0, 156.1, 140.3, 136.2, 136.0, 135.6,
66.2, 58.1, 55.5, 45.9 ppm; MS (ESI) m/z¼300 [MþH]þ; HRMS (ESI)
135.4, 130.9 and 130.8 (AþB), 130.4 (AþB), 130.3 and 130.2 (AþB),
127.8 (AþB), 114.3 (AþB), 113.7 (AþB), 113.0, 65.7 (A), 65.4 (B), 58.2
(A), 58.1 (B), 55.2, 54.9, 46.0, 45.7, 45.6, 39.3, 36.3, 35.4, 34.5, 32.4,
26.5, 26.2, 26.0, 24.3 ppm; MS (ESI) m/z¼518 [M (35Cl)þH]þ, 520 [M
calcd for C18H22NO3 [MþH]þ 300.1600, found: 300.1602.
4.5.7. Synthesis of (40). Hydrazine monohydrate (5.20 mL,
107 mmol, 20 equiv) was added to ketone 39 (1.60 g, 5.34 mmol,
1.0 equiv) in absolute EtOH (22 mL). The mixture was heated to
reflux for 24 h and cooled to room temperature. Filtration of the
crude mixture gave pure hydrazone 40 (1.34 g, 80%) as a 1:1.4
mixture of geometric isomers: IR (neat) 3325, 3152, 1605, 1507,
1457, 1243, 1165, 1035, 953, 839 cmꢀ1; Mixture of major isomer (A)þ
(
37Cl)þH]þ; HRMS (ESI) calcd for C33H4135ClNO2 [MþH]þ 518.2826,
found: 518.2838.
Acknowledgements
We are grateful to Cancer Research U.K. (CRUK) for financial
support of this research and to Dennis Liotta (Emory University) for
partial support of the work.
minor isomer (B): 1H NMR (400 MHz, CDCl3)
d 7.39e7.37 (m, 4H,
AþB), 7.23e7.19 (m, 4H, AþB), 7.04e7.02 (m, 4H, AþB), 6.84e6.80
(m, 4H, AþB), 5.32 (br s, 4H, AþB), 4.11 (t, J¼5.9 Hz, 2H, B), 4.05 (t,
J¼5.9 Hz, 2H, A), 3.86 (s, 3H, A), 3.79 (s, 3H, B), 2.76 (t, J¼5.9 Hz, 2H,
B), 2.71 (t, J¼5.9 Hz, 2H, A), 2.36 (s, 6H, B), 2.32 (s, 6H, A) ppm; 13C
Supplementary data
NMR (100 MHz, CDCl3) d 159.8, 159.7, 159.1, 159.0, 149.3, 131.7, 130.2
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.08.089.
(AþB), 127.8 (AþB), 125.1, 125.0, 115.3, 114.7 (AþB), 114.1 (AþB),
113.5, 66.1 (B), 66.0 (A), 58.3 (AþB), 55.3 (AþB), 45.9 (AþB) ppm;
MS (ESI) m/z¼314 [MþH]þ; HRMS (ESI) calcd for C18H24N3O2
[MþH]þ 314.1869, found: 314.1883.
References and notes
1. Fayard, E.; Auwerx, J.; Schoonjans, K. Trends Cell Biol. 2004, 14, 250e260.
2. Clyne, C. D.; Speed, C. J.; Zhou, J.; Simpson, E. R. J. Biol. Chem. 2002, 277,
20591e20597.
3. Thiruchelvam, P. T. R.; Lai, C.-F.; Hua, H.; Thomas, R. S.; Hurtado, A.; Hudson, W.;
Bayly, A. R.; Kyle, F. J.; Periyasamy, M.; Photiou, A.; Spivey, A. C.; Ortlund, E. A.;
Whitby, R. J.; Carroll, J. S.; Coombes, C. R.; Buluwela, L.; Ali, S. Breast Cancer Res.
Treat. 2011, 127, 385e396.
4. (a) Whitby, R. J.; Dixon, S.; Maloney, P. R.; Delerive, P.; Goodwin, B. J.; Parks, D.
J.; Willson, T. M. J. Med. Chem. 2006, 49, 6652e6655; (b) Whitby, R. J.; Stec, J.;
Blind, R. D.; Dixon, S.; Leesnitzer, L. M.; Orband-Miller, L. A.; Williams, S. P.;
Willson, T. M.; Xu, R.; Zuercher, W. J.; Cai, F.; Ingraham, H. A. J. Med. Chem. 2011,
54, 2266e2281.
4.5.8. Synthesis of (34). Anhydrous Na2SO4 (73.4 mg, 0.510 mmol,
1.6 equiv), two drops of 10% ethanolic KOH and yellow mercuric(II)
oxide (166 mg, 0.763 mmol, 2.4 equiv) were successively added to
a suspension of hydrazone 40 (100 mg, 0.318 mmol, 1.0 equiv) in
dry Et2O (1.0 mL). The mixture was stirred at room temperature in
the dark for 1 h. The solid was filtered off, washed with dry Et2O
and dried under a N2 flow to give diazoalkane 34 as a purple solid.
The compound was used without further purification: IR (neat)
2030, 1608, 1510, 1245, 1179, 1033, 830 cmꢀ1
.
5. Rey, J.; O’Riordan, T. J. C.; Hu, H.; Snyder, J. P.; White, A. J. P.; Barrett, A. G. M. Eur.
J. Org. Chem. 2012, 20, 3781e3794.
6. Krylova, I. N.; Sablin, E. P.; Moore, J.; Xu, R. X.; Waitt, G. M.; MacKay, J. A.;
Juzumiene, D.; Bynum, J. M.; Madauss, K.; Montana, V.; Lebedeva, L.; Suzawa,
M.; Williams, J. D.; Williams, S. P.; Guy, R. K.; Thornton, J. W.; Fletterick, R. J.;
Willson, T. M.; Ingraham, H. A. Cell 2005, 120, 343e355.
4.5.9. Synthesis of (35). Potassium tert-butoxide (850 mg,
7.60 mmol, 2 equiv) was added to triphenylmethylphosphonium
bromide (2.72 g, 7.60 mmol, 2 equiv) in dry Et2O (9.0 mL) at room
temperature. The mixture was vigorously stirred for 30 min and
ketone 12 (900 mg, 3.80 mmol, 1 equiv) in dry Et2O (9.0 mL) was
added dropwise. The yellow suspension was stirred at room tem-
perature for 4 h, filtered through Celite and the solid washed with
Et2O. The solvent was concentrated in vacuo and the residue was
chromatographed (hexanes) to yield alkene 35 (880 mg, 99%) as
a colorless oil: Rf (hexanes) 0.75; IR (neat) 1490, 1448, 1090, 1014,
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Calogeropoulou, T. J. Org. Chem. 2002, 67, 4608e4611; (b) Gauthier, S.; Mailhot,
J.; Labrie, F. J. Org. Chem. 1996, 61, 3890e3893; (c) Shimizu, M.; Nakamaki, C.;
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834 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.33e7.27 (m, 4H), 5.25 (s,
1H), 5.02 (s,1H), 2.36 (d, J¼6.9 Hz, 2H),1.68e1.60 (m, 5H),1.33e1.25
(m, 1H), 1.15e1.10 (m, 3H), 0.93e0.86 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) d 146.1, 139.9, 132.9, 128.4, 127.6, 114.0, 43.6, 35.8,
ꢃ ꢃ
33.2, 26.5, 26.2 ppm; MS (EI) m/z¼234 [M (35Cl)]þ , 236 [M (37Cl)]þ
;
ꢃ
HRMS (EI) calcd for C15H1935Cl [M]þ 234.1175, found: 234.1177.
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4.5.10. Synthesis of (32). Alkene 35 (375 mg, 1.60 mmol, 5 equiv)
was heated at 72 ꢁC for 15 min and crude diazoalkane 34
(0.320 mmol, 1 equiv) was added in one portion. The neat mixture
was stirred at 72 ꢁC for 3.5 h, until the purple color had completely
disappeared. The mixture was cooled to room temperature and
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€
19. Schrodinger, Inc., 120 West 45th Street, 29th Floor, New York, NY 10036-4041;
http://www.schrodinger.com/products/14/12/ (accessed Aug 2011).