Improved and scalable synthetic route to the synthon 17-β-(2- Carboxyethyl)-1,3,5(10)-estratriene: An important intermediate in the synthesis of bone-targeting estrogens

Article abstract of DOI:10.1080/00397910903013796

An improved, highly scalable methodology for the multigram-scale preparation of an important synthon, 17-β-(2-carboxyethyl)-1,3,5(10)- estratriene, is described. Previous approaches have failed to provide useful quantities of the analytically pure product because of facile retro-Michael breakdown of the-alkoxy carbonyl precursors during workup and isolation operations. The synthetic approach described herein has been designed specifically to sidestep this problematic breakdown process. This new scalable method of preparation overcomes a major hurdle in the exploration of structure-activity relationships centered around novel estradiol derivatives with bone-targeting properties and also provides a scalable process for subsequent developmental work.

Full text of DOI:10.1080/00397910903013796

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Improved and Scalable Synthetic
Route to the Synthon 17-β-(2-
Carboxyethyl)-1,3,5(10)-estratriene: An
Important Intermediate in the Synthesis
of Bone-Targeting Estrogens
Shama Nasim a , Ashish P. Vartak a , William M. Pierce Jr. b c , K.
Grant Taylor c & Peter A. Crooks a
a Department of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, Kentucky, USA
b Department of Pharmacology and Toxicology, School of Medicine,
University of Louisville, Louisville, Kentucky, USA
c Department of Chemistry, University of Louisville, Louisville,
Kentucky, USA
Version of record first published: 04 Feb 2010.
To cite this article: Shama Nasim , Ashish P. Vartak , William M. Pierce Jr. , K. Grant Taylor & Peter A.
Crooks (2010): Improved and Scalable Synthetic Route to the Synthon 17-β-(2-Carboxyethyl)-1,3,5(10)-
estratriene: An Important Intermediate in the Synthesis of Bone-Targeting Estrogens, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:5, 772-781
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Synthetic Communications1, 40: 772–781, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903013796
IMPROVED AND SCALABLE SYNTHETIC ROUTE TO
THE SYNTHON 17-b-(2-CARBOXYETHYL)-1,3,5(10)-
ESTRATRIENE: AN IMPORTANT INTERMEDIATE IN
THE SYNTHESIS OF BONE-TARGETING ESTROGENS
Shama Nasim,1 Ashish P. Vartak,1 William M. Pierce Jr.,2,3
K. Grant Taylor,3 and Peter A. Crooks1
1Department of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, Kentucky, USA
2Department of Pharmacology and Toxicology, School of Medicine,
University of Louisville, Louisville, Kentucky, USA
3Department of Chemistry, University of Louisville, Louisville,
Kentucky, USA
An improved, highly scalable methodology for the multigram-scale preparation of an
important synthon, 17-b-(2-carboxyethyl)-1,3,5(10)-estratriene, is described. Previous
approaches have failed to provide useful quantities of the analytically pure product because
of facile retro-Michael breakdown of the b-alkoxy carbonyl precursors during workup and
isolation operations. The synthetic approach described herein has been designed specifically
to sidestep this problematic breakdown process. This new scalable method of preparation
overcomes a major hurdle in the exploration of structure–activity relationships centered
around novel estradiol derivatives with bone-targeting properties and also provides a
scalable process for subsequent developmental work.
Keywords: Bone-targeting; estradiol; retro-Michael addition
INTRODUCTION
Disorders arising from bone resorption constitute a major health concern in
the United States and elsewhere in the world. A third of all postmenopausal cauca-
sian women have osteoporosis, and 54% have osteopenia.[1] One of the potentially
useful pharmacological actions of the anabolic steroid estradiol (1) and its deriva-
tives is that they inhibit the bone resorption that occurs in such disorders. The utility
of these steroids is limited, however, because of their nonspecific effects on a number
of other physiological systems.
Received March 28, 2009.
Address correspondence to Peter A. Crooks, Department of Pharmaceutical Sciences, College of
Pharmacy, University of Kentucky, 501A, 725 Rose Street, Lexington, KY 40536, USA. E-mail:
pcrooks@email.uky.edu
772

17-b-(2-CARBOXYETHYL)-1,3,5(10)-ESTRATRIENE
773
RESULTS AND DISCUSSION
A few years ago, we explored a prodrug strategy utilizing 1 to selectively target
bone tissue.[2] This strategy consisted of conjugating calcium-chelating small mole-
cules, such as the salicylamide derivative 2, to the 17-b-hydroxy functionality of 1.
Salicylamide derivatives are known to possess a strong affinity for divalent calcium
ions.[3] In our previous studies, we have described the interaction of compounds such
as 2 with hydroxyapatite in bone tissue, which is advantageous, because large con-
centrations of hydroxyapatite are usually found in locations of bone tissues that
are in the process of undergoing resorption. Two classes of compounds were synthe-
sized: compound 3, which incorporates succinoyl linker units, and compound 4, with
carboxyethyl linker units (Fig. 1). 17-b-ester-linked compounds such as 3 were found
to possess poor hydrolytic stability in vivo, and were cleaved prior to their arrival at
the site of action.
It was found that when the labile succinoyl ester bond of 3 was replaced with a
carboethoxy linker (as in 4), the resulting compounds retained targeting and ana-
bolic properties. Additionally, the carboethoxy linker was found to possess high
stability toward in vivo hydrolysis. Thus, 4 was chosen as a lead compound for
further structure–activity relationship studies.
Synthesis of a library of compounds structurally related to 4 mandated the
development of a methodology for the preparation of the key intermediate 17-b-
(2-carboxyethyl)-estra-1,3,5(10)-triene (5). Analytically pure samples of 5 were
required for several studies, including pharmacological testing, toxicity analysis,
Figure 1. Structures of estradiol (1), the calcium chelator 3-amino-6-methoxysalicylamide 2, and estradiol
derivatives 3–5.

774
S. NASIM ET AL.
Scheme 1. Synthesis of 7.
and pharmacokinetic-pharmacodynamic (PK-PD) studies, because 5 is a possible
metabolic breakdown product of the final bone-targeting agents.
The b-alkoxy acid functionality of 5 combined with the hindered secondary
alcohol at C-17 introduces synthetic challenges, which arise primarily from the
Scheme 2. Acidic hydrolysis of 7.

17-b-(2-CARBOXYETHYL)-1,3,5(10)-ESTRATRIENE
775
Scheme 3. DIBAL-H reduction of 7.
tendency of this group to undergo a retro-Michael addition under both acidic and
basic conditions. Our initial subgram-scale preparation of this compound involved
addition of the 17-b-alkoxide of 6 to acrylonitrile to afford a b-alkoxynitrile that
Scheme 4. Synthesis and hydrogenolysis of 13.

776
S. NASIM ET AL.
Scheme 5. Synthesis and hydrogenolysis of 13.
could be hydrolyzed to the carboxylic acid. We decided to attempt the utilization of
this synthetic route for the preparation of multigram quantities of 5.
Benzylation of the 3-OH function of 1 was carried out with benzyl bromide in
acetone=K2CO3.[4] This transformation could be carried out on a 30-g scale in
93–95% yields.
Excess benzyl bromide was removed from the product 6 by triturating with
hexanes followed by crystallization of the resulting residue from EtOAc=hexanes.
On smaller scales, the product 6 was purified by chromatography. Scale-up of the
Michael addition of 6 with acrylonitrile proved to be difficult. This transformation
was initially carried out with 5 equiv. of Triton B as the base in CH2Cl2, employing
a large excess (typically 40-fold molar excess) of acrylonitrile, which was necessary to
ensure completion of the reaction. It was noticed that acrylonitrile undergoes exten-
sive degradation when treated with Triton B alone; thus, we attempted to lower the
quantity of this base. After several trials, the reaction proceeded to completion with
just 4 equiv. of acrylonitrile, provided the quantity of Triton B was no more than
1.0 equiv. Column chromatography could be avoided by triturating the resulting
brown-black residue with diethyl ether, followed by precipitation of the product
from cold MeOH, to afford an analytically pure sample of the b-alkoxynitrile deriva-
tive, 7. The isolated yields of 7, however, varied widely (50–80%).
Unfortunately, concomitant deprotection of the 3-O-benzyl function and
nitrile hydrolysis did not result in the formation of appreciable amounts of 5. Heat-
ing a mixture of 7 in AcOH and conc. HCl resulted in varied and complex product
mixtures across several runs. One prominent side product was 1 itself, which likely
arises from retro-Michael breakdown of the b-alkoxynitrile derivative. Absence of
the 3-benzylated 6 in the product mixture indicated that benzyl deprotection is the
first step during the acid-mediated breakdown of 7. Other side products observed
were 17-acetyl estradiol (9) and a significant quantity of the debenzylated product
8, which was significant especially when shorter reaction times were utilized.

17-b-(2-CARBOXYETHYL)-1,3,5(10)-ESTRATRIENE
777
Attempts to precipitate 8 from the reaction mixture by partial evaporation of the
solvent followed by addition of MeOH resulted in rapid esterification of 5 (present
in small quantities) to the methyl ester, 10. Treatment of 7 with anhydrous HCl in
MeOH resulted in the formation of the 3-O-debenzylated derivative 8, but no further
reaction was observed, even when the reaction mixture was heated. Stirring 7 in
AcOH and conc. HCl at ambient temperature also led to 8 as the sole product.
Attempts to oxidize nitrile 7 to the corresponding carboxylic acid with sodium
peroxides with alcoholic potassium hydroxide (KOH)[5] failed because of immediate
retro-Michael breakdown of 7. Therefore, we concluded that intermediate 7 is
unstable in the harsh acidic or basic conditions that are generally required for nitrile
hydrolysis.
In a final attempt at utilizing nitrile 7, we carried out a diisobutylaluminum
hydride (DIBAL-H) reduction at ꢀ78 ꢁC in CH2Cl2.[6] Although an aldehyde inter-
mediate was seen transiently by thin-layer chromatographic (TLC) monitoring of
the reaction, we could not obtain this product after quenching the reaction mixture
with Rochelle’s salt. Instead, 3-O-benzylated estradiol 6 was isolated in nearly quan-
titative yields after removal of a brown polymeric material. This indicated that, as
with 7, the b-alkoxy aldehyde 11, or imine 12 is likely susceptible to retro-Michael
breakdown.
In all of these cases, it was not possible to obtain an analytically pure sample of
the required acid 5, even in small quantities. Among the aforementioned side pro-
ducts, the methyl ester 10 could be isolated in an analytically pure form. A carefully
controlled basic hydrolysis with one equiv. of LiOH in 4:1 THF=H2O, followed by
acidic workup, was found to yield pure 5. We therefore focused our efforts at obtain-
ing 10 through a synthetic route that avoided harsh acidic or basic conditions.
Michael addition of 6 to methyl, ethyl, or t-butyl acrylate was attempted, under
base, dimethylaminopyridine (DMAP), or Ph3P catalysis. Unfortunately, we did not
see any evidence of a desired product in these reactions. In all cases, a polymeric
material was obtained, which formed even in the absence of 6. It was therefore con-
cluded that this Michael addition reaction is either not possible under these reaction
conditions or is slower than the rate of base-catalyzed degradation of alkyl acrylates.
In fact, Christain and Hixon[7] reported that hindered secondary alcohols are poor
substrates for reaction with alkyl acrylates because of facile base-catalyzed retro-
Michael reactions.
One way of overcoming the reversibility of this reaction is to replace the enone
electrophile by an alkyne (i.e., by employing an alkyl=aryl propiolate),[8] because the
elimination of alcohols from enol-ethers is not as facile as that in a b-alkoxy ester.
Benzyl propiolate was prepared by the alkylation of propiolic acid with benzyl
bromide in acetone=K2CO3.[9] Addition of 6 to benzyl propiolate and N-methyl
morpholine in CH2Cl2 proceeded without event to yield 13 in 80% yield after chro-
matography. Unfortunately, we were unable to achieve an efficient and clean
concomitant hydrogenolysis of the two benzyl groups and reduction of the alkene
moiety of 13. The longer reaction times necessary for complete consumption of 13
resulted in the formation of large amounts of 1, which could not be completely
removed from the product mixture.
We finally attempted the utilization of methyl propiolate instead of benzyl pro-
piolate. Treatment of 6 with methyl propiolate and N-methyl morpholine in CH2Cl2

778
S. NASIM ET AL.
resulted in complete consumption of the starting material within 24 h, affording the
enol ether 14 in 83–96% yield. This reaction was reproducible when carried out on a
30-g scale. Although initially isolated by chromatography, 14 could be purified by
filtering the reaction mixture through a short silica plug, evaporating to dryness,
and crystallizing the resulting residue from hot methanol (MeOH). An attempted
catalytic hydrogenation of 14 with Pd(OH)2 under H2 was found to be too slow
to be of any practical value. We therefore attempted a catalytic-transfer hydrogen-
ation with ammonium formate as the hydrogen source. This reaction proceeded to
completion within 24 h, with 10 equiv. of ammonium formate and 10% w=w of cata-
lyst (Pd=C) loading. Surprisingly, traces of 1 were observed in the crude product mix-
ture, indicating that even a weak acid–base catalyst such as ammonium formate is
capable of mediating breakdown of the product, 10. Methyl ester 10 could be ren-
dered free from traces of 1 by suspension in hexanes and filtering, followed by recrys-
tallization from hot hexanes. LiOH hydrolysis then afforded the desired acid 5,
which could then be purified by crystallization from CH2Cl2 and hexanes.
CONCLUSIONS
We have thus accomplished the development of a scalable and reliable syn-
thetic route for the preparation of 5 in an analytically pure form. During the course
of these studies, an alternative sequence for the conversion of a hindered secondary
alcohol to a b-alkoxy ester that bypasses intermediates labile toward retro-Michael
breakdown was developed.
EXPERIMENTAL
Tetrahydrofuran (THF) and ether were distilled over THF=benzophenone
ketyl. Dichloromethane was distilled from calcium hydride. Chloroform was distilled
from potassium hydroxide (KOH) pellets and stored over KOH. Hexanes were used
˚
as received. All other chemicals were used without purification. Silica gel (60 A ICN
Silica Tech) was used for flash chromatography. NMR spectra were recorded (in
CDCl3) on a Varian 300-MHz instrument, and chemical shifts are reported in parts
per million (ppm). Gas chromatography–mass spectrometry (GC-MS) were recorded
on an Agilent 6890 GC incorporating an Agilent 7683 autosampler and an Agilent
5973 MSD. Elemental analysis was performed by Atlantic Micro Labs. Compounds
6 and b (Scheme 4) were prepared according to previously reported method.[4,9]
3-Benzyloxy-17-b-1-(2-carboxybenzyloxyethylenyl)-
1,3,5(10)-estratriene (13)
N-Methyl morpholine (3.62 mL, 2.0 equiv.) was added dropwise to a solution
of 3-benzyloxy-17-b-hydroxy-estra-1,3,5-triene (6.0 g, 16.57 mmol) and benzyl pro-
piolate (5.30 g, 2.0 equiv) in CH2Cl2 (80 mL). The resulting amber solution was stir-
red at ambient temperature overnight (24 h) before being filtered through a plug of
silica. The plug was washed with EtOAc (3 ꢂ 100 mL), and the combined filtrates
were evaporated to afford a brown solid, which was dissolved in CHCl3 (ca.
2 mL) and loaded on a silica-gel plug (20 g, packed with hexanes). The plug was

17-b-(2-CARBOXYETHYL)-1,3,5(10)-ESTRATRIENE
779
eluted with hexanes=diethyl ether (24:1, 12:1, 6:1, ca. 200 mL of each). The product
was isolated in the last 200 mL of eluent, evaporation of which furnished pure 13 as a
white solid (1.60 g, 79.7%); Rf ¼ 0.52 (diethyl ether=hexanes; 9:13); 1H NMR
(300 MHz, CDCl3) d 7.62 (d, J ¼ 12.6 Hz, 1H), 7.46ꢀ7.31 (m, 10H), 7.19 (d,
J ¼ 8.4 Hz, 1H), 6.79 (dd, J ¼ 8.4 and 2.7 Hz, 1H), 6.72 (d, J ¼ 2.7 Hz, 1H), 5.32
(d, J ¼ 12.6 Hz, 1H), 5.17 (s, 2H), 5.04 (s, 2H), 3.97 (t, J ¼ 8.4 Hz, 1H), 2.86 (m,
2H), 2.24 (m, 3H), 2.00ꢀ1.22 (m, 10H), 0.83 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3) d 168.1, 165.9, 163.2, 157.8, 156.9, 138.0, 137.4, 136.7, 132.6, 128.8, 128.7,
128.6, 128.3, 128.2, 127.6, 126.5, 115.0, 112.5, 104.3, 97.1, 91.5, 70.2, 66.6, 65.8,
50.0, 44.1, 44.0, 38.8, 37.4, 30.1, 27.9, 27.5, 26.4, 23.6, 12.2 ppm. EI-MS m=z 522.
Elemental analysis (13) calculated for C35H38O4: C, 80.43%; H, 7.33%. Found: C,
80.40%; H, 7.12%.
3-Benzyloxy-17-b-1-(2-carboxymethylethylenyl)-1,3,5(10)-
estratriene (14)
N-Methyl morpholine (3.62 mL, 2.0 equiv.) was added dropwise to a solution
of 3-benzyloxy-17-b-hydroxy-estra-1,3,5-triene (6, 6.0 g, 16.57 mmol) and methyl
propiolate (2.76 mL, 2.0 equiv) in CH2Cl2 (80 mL). The resulting amber solution
was stirred at ambient temperature overnight before being filtered through a plug
of silica; the plug was then washed with EtOAc (3 ꢂ 100 mL). The combined filtrates
were evaporated to afford a brown solid, which was suspended in 400 mL of meth-
anol; this mixture was boiled for 15 min. Cooling of the resulting solution afforded
white needles, which were removed by filtration and washed with chilled MeOH
(2 ꢂ 50 mL) before being dried in air (7.10 g, 96%). Mp 125–127 ꢁC; Rf ¼ 0.45 (pet-
1
roleum ether [bp 35–60 ꢁC]=diethyl ether; 7:3); H NMR (300 MHz, CDCl3) d 7.61
(d, J ¼ 12.3 Hz, 1H), 7.48–7.35 (m, 5H), 7.24 (d, J ¼ 8.4 Hz, 1H), 6.82 (dd, J ¼ 8.4
and 2.4 Hz, 1H), 6.76 (d, J ¼ 2.4 Hz, 1H), 5.32 (d, J ¼ 12.3 Hz, 1H), 5.06 (s, 2H),
3.99 (t, J ¼ 8.4 Hz, 1H), 3.74 (s, 3H), 2.89 (m, 2H), 2.36ꢀ2.08 (m, 3H), 2.02ꢀ1.22
(m, 10H), 0.87 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) d 168.7, 162.9, 156.9,
138.0, 137.4, 132.6, 128.7, 128.0, 127.6, 126.5, 115.0, 112.4, 97.0, 91.5, 70.0, 51.2,
49.8, 43.9, 43.8, 38.6, 37.2, 29.8, 27.7, 27.3, 26.2, 23.3, 11.9 ppm. EI-MS m=z 446.
Elemental analysis (14) calculated for C29H34O4: C, 78.00%; H, 7.67%. Found: C,
78.03%; H, 7.70%. Subsequent runs of this reaction of 6 produced yields ranging
from 83 to 96%.
3-Hydroxy-17-b-1-(2-carboxymethylethyl)-1,3,5(10)-estratriene (10)
Pd(OH)2 (20% on carbon, 50% wet, 0.25 g, 10%w=w) and ammonium formate
(5.00 g, excess) were added to a solution of 14 (2.50 g, 5.60 mmol) in THF=MeOH
(1:2, 70 mL). The reaction was stirred at 60 ꢁC for 12 h before being filtered through
celite and evaporated to afford a white solid residue, which was mostly 10 (98% by
GC analysis) with traces of estradiol (1). This residue was dissolved in CHCl3 (ca.
2 mL) and loaded onto a silica-gel plug (20 g, packed with hexanes). The plug was
eluted with hexanes=EtOAc (24:1 ! 12:1 ! 6:1, ca. 200 mL of each). The product
was eluted in the last 200 mL of eluent, evaporation of which furnished pure 10 as
a white solid (1.60 g, 80%). With larger scale runs (20 g) the reaction mixture was

780
S. NASIM ET AL.
filtered through celite, evaporated, and the residue was suspended in hot hexanes.
Filtration of this mixture followed by cooling led to the crystallization of pure 10.
Rf ¼ 0.55 (diethyl ether=hexanes; 9:13); 1H NMR (300 MHz, CDCl3) d 7.14 (d,
J ¼ 8.4 Hz, 1H), 6.65 (dd, J ¼ 8.4 and 2.7 Hz, 1H), 6.58 (d, J ¼ 2.7 Hz, 1H),
3.86ꢀ3.71 (m, 2H), 3.73 (s, 3H), 3.42 (t, J ¼ 8.7 Hz, 1H), 2.81 (m, 2H), 2.60 (t,
J ¼ 6.6 Hz, 2H), 2.29ꢀ1.13 (m, 14H), 0.77 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3)
d 172.9, 153.7, 138.3, 132.5, 126.6, 115.4, 112.8, 89.6, 65.6, 51.9, 50.3, 44.0, 43.4, 38.7,
38.0, 35.5, 29.8, 28.1, 27.3, 26.6, 23.2, 11.7 ppm. GC-MS m=z 358. Elemental analysis
(10) calculated for C22H30O4: C, 73.71%; H, 8.44%. Found: C, 73.53%; H, 8.32%.
3-Hydroxy-17-b-1-(2-carboxyethyl)-1,3,5(10)-estratriene (5)
A solution of LiOH (150 mg, 2.1 equiv.) in water (10 mL) was added slowly to a
stirred solution of 10 (1.32 g, 2.95 mmol) in THF (20 mL). The resulting pale pink
solution was heated to reflux for 1 h before being cooled to ambient temperature
and neutralized with conc. HCl. The THF was removed under reduced pressure,
and the aqueous layer (pH ¼ 1) was extracted with EtOAc (3 ꢂ 30 mL). The com-
bined organic extracts were dried (Na2SO4) and evaporated to afford a white solid.
This white solid was dissolved in hot chloroform (ca. 20 mL), and hot hexanes (ca.
20 mL) were added portionwise to the chloroform solution until a slight turbidity
persisted. A few drops of chloroform were then added to clarify the solution, and
the solution was allowed to cool to ambient temperature, during which time large
white crystals were formed. The mixture was chilled in the freezer and then filtered.
The filter cake was washed with chilled CHCl3=hexanes (1:1) 2 ꢂ 20 mL. Drying in
air yielded 5 as a white solid (1.13 g, 90%). Mp ¼ 151–152 ꢁC; Rf ¼ 0.40 (CHCl3=
1
MeOH; 19:1); H NMR (300 MHz, CDCl3) d 7.13 (d, J ¼ 8.7 Hz, 1H), 6.63 (dd,
J ¼ 8.7 and 2.7 Hz, 1H), 6.57 (d, J ¼ 2.7 Hz, 1H), 3.78 (m, 2H), 3.45 (t, J ¼ 8.0 Hz,
1H), 2.81 (m, 2H), 2.65 (t, J ¼ 8.0 Hz, 2H), 2.28–2.00 (m, 5H), 1.87ꢀ1.13 (m,
10H), 0.78 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) d 176.9, 153.4, 138.4, 132.7,
126.7, 115.5, 112.8, 89.9, 65.3, 50.3, 44.1, 43.5, 38.7, 38.0, 35.4, 29.8, 28.1, 27.4,
26.6, 23.3, 11.9 ppm. EI-MS m=z 344. Elemental analysis (5) calculated for
C21H28O4. 0.33 H2O: C, 71.97%; H, 8.24%. Found: C, 72.23%; H, 8.09%.
ACKNOWLEDGMENTS
Financial support from Pradama, Inc. and the Kentucky Science and
Technology Corporation is gratefully acknowledged. W.M.P., K.G.T., and P.A.C.
have a financial interest in Pradama Inc.
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