Synthesis and Binding Affinities of Novel Re-Containing 7α-Substituted Estradiol Complexes: Models for Breast Cancer Imaging Agents

Article abstract of DOI:10.1021/jo990641g

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor status in the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing 7α-substituted estradiol complexes. The introduction of the 7α side chain involves the alkylation of tetrahydropyranyloxy-protected 6-keto estradiol. The methods used to introduce the rhenium metal involve "3 + 1" and "4 + 1" mixed ligand complexes (2a-c and 5, respectively), tricarbonyl dithioether complexes (3), and the cyclopentadienyltricarbonylmetal organometallic system (4ab, 6, 7). These complexes showed binding affinities for the estrogen receptor (as high as 45% for the "3 + 1" complex 2c) when compared to the native ligand estradiol. The polarity of some complexes (4ab) was modified to improve biodistribution properties by introducing (poly)ether linkages into the 7α side chain (6, 7). These complexes provide a further refinement of our understanding of ligand structure-binding affinity correlations for the estrogen receptor, and they furnish the synthetic groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor imaging agents.

Full text of DOI:10.1021/jo990641g

8108
J . Org. Chem. 1999, 64, 8108-8121
Syn th esis a n d Bin d in g Affin ities of Novel Re-Con ta in in g
7r-Su bstitu ted Estr a d iol Com p lexes: Mod els for Br ea st Ca n cer
Im a gin g Agen ts
Marc B. Skaddan,† Frank R. Wu¨st,‡ and J ohn A. Katzenellenbogen†
Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, Illinois 61801, and
Institut fu¨r Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf e.V., Dresden, Germany
Received April 19, 1999
The diagnosis and staging of breast cancer could be improved by the development of imaging
radiopharmaceuticals that provide a noninvasive determination of the estrogen receptor status in
the tumor cells. Toward this goal, we have synthesized a number of novel Re-containing
7R-substituted estradiol complexes. The introduction of the 7R side chain involves the alkylation
of tetrahydropyranyloxy-protected 6-keto estradiol. The methods used to introduce the rhenium
metal involve “3 + 1” and “4 + 1” mixed ligand complexes (2a -c and 5, respectively), tricarbonyl
dithioether complexes (3), and the cyclopentadienyltricarbonylmetal organometallic system (4a b,
6, 7). These complexes showed binding affinities for the estrogen receptor (as high as 45% for the
“3 + 1” complex 2c) when compared to the native ligand estradiol. The polarity of some complexes
(4a b) was modified to improve biodistribution properties by introducing (poly)ether linkages into
the 7R side chain (6, 7). These complexes provide a further refinement of our understanding of
ligand structure-binding affinity correlations for the estrogen receptor, and they furnish the synthetic
groundwork for the synthesis of the analogous Tc-99m complexes for evaluation as breast tumor
imaging agents.
In tr od u ction
imaging3-14 or iodine-123 for SPECT imaging,14-19 a large
effort continues to be made toward the use of Tc-99m as
the radionuclide, because of its convenient 6-h half-life
and its wide availability.
Breast cancer is the most prevalent form of diagnosed
cancer of women in the United States and is the second
leading cause of cancer death in women.1 As with most
cancers, early diagnosis is imperative for long-term
survival. In addition to early detection, the ability to
determine the estrogen receptor (ER) content of the
breast tumor is essential for making the most appropriate
choice of treatment for the patient. Tumors with a
relatively high concentration of the ER are termed ER+
tumors and can often be treated successfully with anti-
estrogen hormone therapy.2 Tumors with a relatively low
concentration of the ER are accordingly dubbed ER-.
Such ER- tumors often respond poorly to hormone
therapy and must be treated by more invasive means,
such as surgical removal of the tumor, oophorectomy,
and/or cytotoxic chemotherapy.
One way to determine the ER content of cells would
be to image breast tumors, using positron emission
tomography (PET) or single photon emission computer-
ized tomography (SPECT). These techniques utilize the
emission characteristics of certain radiolabeled receptor-
binding pharmaceuticals that have appropriate distribu-
tion properties to image tissues.
There are two basic paradigms used to incorporate Tc-
99m into steroids, the “integrated” design and the
“pendant” or “conjugated” design. Although progress has
(3) VanBrocklin, H. F.; Rocque, P. A.; Lee, H. V.; Carlson, K. E.;
Katzenellenbogen, J . A.; Welch, M. J . Life Sci. 1993, 53, 811-819.
(4) VanBrocklin, H. F.; Pomper, M. G.; Carlson, K. E.; Welch, M.
J .; Katzenellenbogen, J . A. Int. J . Radiat. Appl. Instrum. B 1992, 19,
363-374.
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Welch, M. J . J . Med. Chem. 1993, 36, 1619-1629.
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lenbogen, J . A. Steroids 1994, 59, 34-45.
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E.; O’Neil, J . P.; Bonasera, T. A.; Welch, M. J .; Katzenellenbogen, J .
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J .; Katzenellenbogen, J . A. J . Med. Chem. 1995, 38, 328-337.
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J . W.; Mathias, C. J . J . Med. Chem. 1988, 31, 1360-1363.
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Appl. Instrum. B 1990, 17, 309-319.
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Wouda, S.; Oosterhuis, J . W.; Vaalburg, W. Cancer Lett. 1991, 59, 125-
132.
In our ongoing effort to develop imaging agents for
ER+ breast cancer, we have focused on the design of
ligands bearing Tc-99m as the radionuclide. Although
considerable advances have been made in the develop-
ment of steroids labeled with either fluorine-18 for PET
(13) Verhagen, A.; Elsinga, P. H.; de Groot, T. J .; Paans, A. M. J .;
deGoeij, C. C. J .; Sluyser, M.; Vaalburg, W. Cancer Res. 1991, 51,
1930-1933.
(14) Cummins, C. H. Steroids 1993, 58, 245.
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117, 2550-2552.
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J .; Naftolin, F.; Schwartz, P. E. Steroids 1985, 46, 775-778.
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* Telephone: (217) 333-6310. FAX: (217) 333-7325. E-mail: jkatzene@
uiuc.edu.
† University of Illinois.
‡ Institut fu¨r Bioanorganische und Radiopharmazeutische Chemie.
(1) Cancer Facts and Figures; American Cancer Society: New York,
1997.
(2) McGuire, W. L. Estrogen Receptors in Human Breast Cancer;
Raven Press: New York, 1975.
10.1021/jo990641g CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/14/1999

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8109
F igu r e 1. Estradiol and Re-containing estradiol complexes.
been made in the synthesis of integrated estrogen mimics
(where part of the steroid is replaced with the requisite
metal chelate),20-24 the resulting chelates have generally
either been too unstable or exhibited low binding affinity
to the ER. In the conjugated design, a metal-containing
moiety is tethered to an existing steroid, such as proges-
terone or estradiol (1).25-33 The binding affinities of these
complexes can remain quite high when attached to an
appropriate position known to tolerate steric bulk.
We report here the synthesis and binding affinity of
nine rhenium-labeled estradiol complexes based on the
conjugated design (Figure 1). Because of the well-known
chemical similarity of Re to Tc, these mimics should be
effective models for Tc-99m-containing imaging agents
for breast cancer. The 7R position of estradiol was chosen
because of the well-known tolerance of the ER for bulky
substituents at this site.34 Three of these complexes (2a -
c) take advantage of the “3 + 1” approach, in which a
tridentate ligand and monodentate ligand stabilize an
oxorhenium(V) core.35 Four others (4a ,b, 6, 7) are based
on the cyclopentadienyltricarbonylmetal (CpTM) orga-
nometallic system for complexing the metal.36 Both the
“3 + 1” and CpTM paradigms were chosen for their well-
established stability, as well as their known facility for
being prepared at the tracer level.35,37 Two other com-
plexes are based on dithioether-carbonyl (3) and “4 + 1”
mixed ligand designs (5).35,38 The dithioether-carbonyl
design utilizes the recently reported low valence Re(I)
carbonyl precursor [M(Hal)3(CO)3]2- 39
In the “4 + 1”
.
system, a tripodal NS3 ligand and an isocyanide ligand
chelate a Re(III) center. The lipophilicities of these
complexes tend to be lower than their “3 + 1” oxorhenium
counterparts, and hence their biological properties are
expected to be different as well.40
Resu lts a n d Discu ssion
Syn th esis of 7r-Su bstitu ted Estr ogen s 2-5. A
number of factors entered into our choice of the type of
“spacer” to be used to bridge the metal-containing moiety
and the steroid in compounds 2-5. It is known that short
chains with bulky substituents at the 7R position attenu-
ate binding affinity, whereas excessively long chains can
detrimentally increase the lipophilicity and molecular
weight of the compound.34 Therefore, a hexyl spacer of
intermediate length was chosen.
The synthesis of the alcohol, amine, and thiol precur-
sors for mimics 2-5 began with tetrahydropyranyloxy-
(THP)-protected estradiol (8, Scheme 1). The 6-keto
functionality was introduced using a previously published
method41 to provide steroid 9 in good yield. The 7R-
substituted alkene 10 was synthesized in 53% yield by
treating the potassium enolate of 9 with 6-iodohexene,
using BEt3 as an additive to help stabilize the enolate
and prevent O-alkylation.42 The yields for introducing
long side chains at the 7R-position using this method are
(20) Hom, R. K.; Chi, D. Y.; Katzenellenbogen, J . A. J . Org. Chem.
1996, 61, 2624-2631.
(21) Hom, R. K.; Katzenellenbogen, J . A. J . Org. Chem. 1997, 62,
6290.
(22) Skaddan, M. B.; Katzenellenbogen, J . A. Bioconjugate Chem.
1999, 10, 119-129.
(23) Sugano, Y.; Katzenellenbogen, J . A. Bioorg. Med. Chem. Lett.
1996, 6, 361.
(24) Chi, D. Y.; O’Neil, J . P.; Anderson, C. J .; Welch, M. J .;
Katzenellenbogen, J . A. J . Med. Chem. 1994, 37, 928.
(25) DiZio, J . P.; Fiaschi, R.; Davison, A.; J ones, A. G.; Katzenel-
lenbogen, J . A. Bioconj. Chem. 1991, 2, 353.
(26) DiZio, J . P.; Anderson, C. J .; Davison, A.; Ehrhardt, G. J .;
Carlson, K. E.; Welch, M. J . J . Nucl. Med. 1992, 33, 558.
(27) O’Neil, J . P.; Carlson, K. E.; Anderson, C. J .; Welch, M. J .;
Katzenellenbogen, J . A. Bioconjugate Chem. 1994, 5, 182.
(28) Top, S.; Vessieres, A.; J aouen, G. J . Chem. Soc., Chem.
Commun. 1994, 453.
(29) Top, S.; El Hafa, H.; Vessieres, A.; Quivy, J .; Vaissermann, J .;
Hughes, D. W.; McGlinchey, M. J .; Mornon, J . P.; Thoreau, E.; J aouen,
G. J . Am. Chem. Soc. 1995, 117, 8372.
(30) Wu¨st, F.; Spies, H.; J ohannsen, B. Bioorg. Med. Chem. Lett.
1996, 6, 2729.
(31) Wu¨st, F.; Spies, H.; J ohannsen, B. Tetrahedron Lett. 1997, 38,
2931.
(32) Wu¨st, F. R.; Carlson, K. E.; Katzenellenbogen, J . A.; Spies, H.;
J ohannsen, B. Steroids 1998, 63, 665-671.
(35) Spies, H.; Fietz, T.; Glaser, M.; Pietzsch, H. J .; J ohannsen, B.
In Technetium and Rhenium in Chemistry and Nuclear Medicine;
Nicolini, M., Bandoli, G., Mazzi, U., Eds.; SGEditoriali: Padova, Italy,
1995; Vol. 4, pp 243-246.
(36) Spradau, T. W.; Katzenellenbogen, J . A. Organometallics 1998,
17, 2009-2017.
(37) Spradau, T. W.; Edwards, W. B.; Anderson, C. J .; Welch, M. J .;
Katzenellenbogen, J . A. Nucl. Med. Biol. 1999, 26, 1-7.
(38) Schibli, R.; Alberto, R.; Abram, U.; Abram, S.; Egli, A.; Schub-
inger, P. A.; Kaden, T. A. Inorg. Chem. 1998, 37, 3509-3516.
(39) Alberto, R.; Schibli, A.; Egli, P. A.; Schubinger, W. A.; Her-
rmann, W. A.; Artus, G. M.; Abram, U.; Kaden, T. A. J . Organomet.
Chem. 1995, 493, 119-127.
(33) Wu¨st, F. R.; Skaddan, M. B.; Leibnitz, P.; Katzenellenbogen,
J . A.; Spies, H.; J ohannsen, B. Biorg. Med. Chem. 1999, 7, 1827-1836.
(34) Anstead, G. M.; Carlson, K. E.; Katzenellenbogen, J . A. Steroids
1997, 62, 268-303.
(40) Wu¨st, F. R., Forschungszentrum RossendorfsTechnische Uni-
versita¨t Dresden, 1998.
(41) Tedesco, R.; Fiaschi, R.; Napolitano, E. Synthesis 1995, 1493-
1495.

8110 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
Sch em e 1
Sch em e 2
generally quite low, but this is one of the highest
uncorrected yields reported for an alkyl substituent of this
size. Yields corrected for recovered 9 were as high as 64%
for this reaction. Deprotection of the THP groups and
deoxygenation of the 6-keto functionality can be ac-
complished simultaneously with BF3‚OEt2/Et3SiH to af-
ford alkene 11, although in later reactions it was found
that deprotecting the 3 and 17 positions first was
necessary to prevent the product from prematurely
precipitating from solution. Reprotection of the free
hydroxyls with tert-butyldimethylsilyl (TBS) groups pro-
vides TBS-protected alkene 12, and subsequent hydrobo-
ration-oxidation gave alcohol 13 in a 27% overall uncor-
rected yield from 8. Thiol 16 can be prepared by converting
alcohol 13 to thiobenzoate 14 using Mitsunobu condi-
tions,43 followed by acidic deprotection to diol 15 and
saponification of the thiobenzoate. We chose HF as the
deprotecting agent at both sites because of the well-
known stability of 17â-silyl groups toward tetrabutylam-
monium fluoride (TBAF).44 Mitsunobu conditions were
also used to convert alcohol 13 into phthalimide 17.
Subsequent hydrazinolysis provided amine 18 in excel-
lent yield.
attached to the metal center.45 The “SOS” complex 2b
was synthesized in good yield by reacting thiol 16 in a
1:1:1 ratio with the tridentate ligand 20 and (Bu4N)-
[ReOCl4]39 as the source of rhenium. The synthesis of the
N-containing “3 + 1” complex 2c required more vigorous
conditions, in which thiol 16, bis(2-mercaptoethyl)methyl-
amine HCl (21),46 rhenium precursor (PPh3)2ReOCl3, and
MeOH are refluxed together in the presence of NaOAc.
Complexes 2a and 2b were isolated as red foams,
Thiol 16 was then used to prepare all three “3 + 1”
mixed ligand complexes (Scheme 2). These complexes
differ only in the nature of the central donor atom on
the tridentate ligand. The “SSS” complex 2a was pre-
pared in good yield by reacting thiol 16 with rhenium
precursor 19 in which the tridentate ligand is already
(42) Negishi, E.-I.; Chatterjee, S. Tetrahedron Lett. 1983, 24, 1342-
1344.
(43) Hughes, D. L. In Organic Reactions; Paquette, L. A., Ed.; J ohn
Wiley and Sons: New York, 1992; Vol. 42, pp 335-656.
(44) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley and Sons: New York, 1991.
(45) Spies, H.; Fietz, T.; Pietzsch, H. J .; J ohannsen, B.; Leibnitz,
P.; Reck, G.; Scheller, D.; Klosterman, K. J . Chem. Soc., Dalton Trans.
1995, 2277.
(46) Mirza, S. A.; Pressler, M. A.; Kumar, M.; Day, R. O.; Maroney,
M. J . Inorg. Chem. 1993, 32, 977-987.

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8111
Sch em e 3
Sch em e 5
Ta ble 1. Rela tive Bin d in g Affin ity (RBA) a n d log P o/w
Sch em e 4
Va lu es of Rh en iu m Com p lexes
complex/ligand
RBA (0 °C)
RBA (25 °C)
log P
1
100
102
48
107
24
11
43
10
12
5
100
26
14
18
28
21
20
45
15
8
3.74
N/A
N/A
N/A
N/A
5.73
5.95
5.52
6.29
7.31
6.88
5.13
R ) CHdCH2
R ) (CH2)2OH
R ) (CH2)2SH
R ) DTEa
2a
2b
2c
3
4a
4b
5
29
14
24
15
a
DTE ) CH2CH2S(CH2)2SCH3.
the complexation step by the in situ dehydration of amide
47
29 with the PPh3/CCl4/NEt3 system. This isocyanide
immediately underwent complexation with the phos-
phine-containing rhenium(III) precursor 3048 to afford
complex 31. Deprotection with HF gave the final “4 + 1”
complex 5 in good yield.
whereas complex 2c was isolated as a green foam. All
complexes were stable in aqueous media and to column
chromatography.
Synthesis of the dithioether-carbonyl complex 3 begins
with the conversion of alcohol 13 to methanesulfonate
(mesylate) 22 (Scheme 3). Mesylate 22 is then displaced
with thiol 23 (readily prepared from 2-(mercaptomethyl)-
ethanol in two steps, see the Experimental Section). The
resulting protected dithioether is then deprotected with
HF, providing dithioether 24 in modest yield. Reaction
of dithioether 24 with Re(I) precursor 25 at room tem-
perature provides the desired dithioether-carbonyl rhe-
nium complex 3 in good yield.
The protected CpTR ester 27 and amide 28 were
prepared by the coupling of cyclopentadienylrheniumtri-
carbonyl carboxylic acid (26)36 with either alcohol 13 or
amine 18, respectively, using 1-(3-dimethylaminopropyl)-
3-ethylamine carbodiimide HCl (EDC) as the coupling
agent (Scheme 4). Deprotection with HF affords the
desired CpTR ester 4a and CpTR amide 4b in good yields.
The “4 + 1” complex 5 requires the synthesis of the
terminal isocyanide from amine 18 (Scheme 5). This can
be easily accomplished by reacting amine 18 with ethyl
formate to produce amide 29 in good yield. The genera-
tion of the required isocyanide was accomplished during
Estr ogen Recep tor Bin d in g Affin ities a n d log P o/w
Mea su r em en ts of 7r-Su bstitu ted Estr ogen s 2-5.
The ER binding affinities and lipophilicities of complexes
2-5, as well as some of the free ligands, were measured
(Table 1). The affinities are expressed as relative-binding
affinity values (RBA), where estradiol has a value of 100.
Most of the binding affinities of the 7R-substituted
compounds are moderate to high, even for extremely
bulky substituents (e.g., tripodal rhenium moiety in 5),
confirming the high tolerance of the ER toward bulky
substituents at this position. Although binding affinity
values determined at 0 °C are reported for the sake of
comparison, the emphasis should be placed on the 25 °C
RBA values, as this is a temperature more representative
of physiological conditions and the one that gives com-
plete equilibration and the most reproducible binding
affinity values for the complexes. Thus, the highest RBA
at 25 °C for the inorganic complexes is that of “SNS”
(47) Appel, R. Angew. Chem. 1975, 87, 863.
(48) Spies, H.; Glaser, M.; Pietzsch, H.-J .; Hahn, F. E.; Lu¨gger, T.
Inorg. Chim. Acta 1995, 240, 465-478.

8112 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
Sch em e 6
complex 2c, with an RBA of 45%. This is also the highest
RBA value reported for a rhenium-labeled estradiol
complex containing no auxiliary functional groups that
promote receptor binding (e.g., 11â CH2Cl).29 The highest
of the organometallic series (4a , 4b) is the CpTR amide
4b, with an RBA of 24%.
probably as a result of their high lipophilicities. Thus,
we extended our effort to synthesize more polar varieties
of these complexes, focusing our efforts on CpTR amide
4b.
Syn th esis of 7r-Su bstitu ted Estr ogen s 6 a n d 7. To
increase the polarity of CpTR amide 4b, we decided to
introduce ether linkages into the side chain (6 and 7).
This modification keeps the steroid backbone intact,
thereby preserving binding affinity. The long-chain ether
6 has the advantage of possessing a lower molecular
weight, whereas the short-chain ether 7 has the advan-
tage of placing the polar polyether farther away from the
steroid backbone.
The synthesis of long-chain ether 6 begins with TBS-
protected alkene 12 (Scheme 6). It became evident to us
that the 3-TBS group was unstable under the basic
Williamson ether-type conditions required for the conver-
sion of alcohol 33 to ether 35. Therefore, the 3-TBS group
was replaced with the base-stable MEM group to give
32 quantitatively. Efforts to attach polyether unit 3450
using the mesylate, tosylate, or tresylate of alcohol 33
failed to give consistent yields above 20%. The use of a
variety of bases and solvents was also unsuccessful. This
step was finally accomplished by using the triflurometh-
anesulfonate (triflate), under conditions similar to those
of Nicolaou and co-workers in the synthesis of â-D-glucose
ethers.51 This resulted in the formation of polyether
steroid 35 in 59% yield. The benzyl group was then
removed by hydrogenolysis to provide alcohol 36 quan-
titatively. The azide functionality was introduced under
Mitsunobu conditions, followed by hydrogenation of the
azide to amine 37 in 60% yield over two steps. Efforts to
introduce the amine in this substrate via the phthalimide
(vide supra) were unsuccessful. The protected CpTR
amide 38 was then formed in good yield by coupling
It is unclear what accounts for the rise in binding
affinity when a nitrogen is added to the 7R side chain in
2c and 4b. For 2c, it is known that the more basic
nitrogen lengthens and hence weakens the RedO bond,
making it more polarized. This is evident from a drop in
IR stretching frequency for this bond (e.g., 961 cm-1 for
2a , 949 cm-1 for 2c). Molecular modeling studies also
suggest that the 7R substitutents of 2c and 4b remain
in the binding pocket of the ER. One could hypothesize
that the ability of this moiety to interact with the amino
acid residues in the 7R pocket of the ER is the reason for
the dramatic jump in binding affinity for 2c. An analo-
gous explanation could be given for the rise in binding
affinity of 4b vs that of 4a . Amides (e.g., 4b) do have more
single bond character in the CdO bond than do esters
(e.g., 4a ), creating a more polarized CdO bond in 4b.
Again, this is evident from the IR stretching frequencies
of the CdO bond (1723 cm-1 for 4a , 1644 cm-1 for 4b).
Amide 4b also possesses more hydrogen bond donating
capability than ester 4a , as well as more restricted
rotation about the N-CO bond, both of which may also
play a role in its greater affinity for the ER than that of
4a .
As expected, the attachment of a lipophilic side chain
increased the respective log Po/w values of the complexes
vs that of estradiol itself (log Po/w ) 3.74). The change is
most dramatic for that of the CpTR complexes 4a and
4b (7.31 and 6.88, respectively) and dithioether carbonyl
3 (6.29). Tissue distribution studies on the Tc-99m
analogues of 2c and 4b have shown that these complexes,
although stable in aqueous media, show rather low target
tissue uptake selectivity and high nonspecific uptake,49
(50) Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945-5948.
(51) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.;
Salvino, J .; Arison, B.; Cichy, M. A.; Sporrs, P. G.; Shakespeare, W.
M.; Sprengeler, P. A.; Hamley, P.; Smith, A. B. I.; Reisine, T.; Raynor,
K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri,
M. R.; Strader, C. D. J . Am. Chem. Soc. 1993, 115, 12550-12568.
(49) Skaddan M.; Wu¨st, F. R.; J onson, S.; Syhre, R.; Welch, M. J .;
Spies, H.; Katzenellenbogen, J . A. Nucl. Med. Biol., in press.

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8113
Sch em e 7
Ta ble 2. RBA a n d log P o/w Va lu es of 6 a n d 7
amine 37 to CpTR acid 26 in the presence of EDC.
Deprotection of the 3 and 17 hydroxyls then leads to the
desired amide 6.
mimic
RBA (0 °C)
RBA (25 °C)
log P
6
7
7
35
23
20
6.94
5.40
The synthesis of short-chain ether 7 begins with THP-
protected estradiol 8 (Scheme 7). The conditions used to
introduce the allyl side chain were analogous to those
used to form 10, except that the higher reactivity of the
allyl iodide erodes the R/â selectivity in the C(7) alkyla-
tion and also increases the amount of dialkylated product.
The erosion of selectivity can be attributed to the
earlier transition state of the allyl iodide alkyation
relative to that of the reaction involving the less reactive
6-iodohexene. Selectivities for endocyclic enolate alkyla-
tions of six-membered rings involving late transition
states depend on the torsional strain of the six-membered
ring as the electophile approaches from the R or â face.52
For this system, an axial approach of the electrophile
from the 7R face involves a less strained chairlike
transition state, whereas an electrophile approaching
axially from the 7â face involves a more strained boatlike
transition state; hence, the R product is preferred for
alkylation with 6-iodohexene. The much more reactive
allyl iodide involves an earlier, more reactant-like transi-
tion state, and therefore the selectivity between faces is
attenuated. The angular 18-CH3 group may also play a
role in increasing the R-selectivity for the more bulky
6-iodohexene.
accomplished by stirring the reaction product with
NaOMe at room temperature for several hours to produce
alkene 39 in good yield.
Deoxygenation, reprotection of the free hydroxyls with
TBS groups, and hydroboration-oxidation generated al-
cohol 42, using conditions similar to those reported for
the synthesis of hexyl-spaced alcohol 13. Also in this case,
the 3-TBS group on alcohol 42 was removed and the
phenol was protected as a benzyl ether prior to etheri-
fication under basic conditions with monobenzylated
ethylene glycol 44,50 providing ether 45 in good yield. The
reaction sequence to produce amide 7 from ether 45
proceeds analogously to that reported for the synthesis
of amide 6 from ether 35. However, protection of the 3
hydroxyl group was necessary prior to the coupling step.
Amide 7 was formed in a 29% six-step yield from ether
45.
Estr ogen Recep tor Bin d in g Affin ities a n d log P o/w
Mea su r em en ts of 7r-Su bstitu ted Estr ogen s 6 a n d
7. The RBA and log Po/w values for amides 6 and 7 were
measured and are shown in Table 2. It is encouraging to
note that the binding affinities at 25 °C for 6 (23%) and
7 (20%) are relatively unchanged from that of the original
amide 4b. As expected, the introduction of ether func-
tionalities in the side chain did change the log Po/w values
relative to that of the amide. Surprisingly, the log Po/w
for the polyether 6 (6.94) is actually higher than that for
the original amide, even though calculations suggested
that there would be a 5-fold decrease in lipophilicity.53
It is possible that the log Po/w predictions might not be
In contrast to the alkylation conditions used for the
formation of alkene 10, BEt3 had little effect on this
reaction. It was found that by lowering the temperature
to -78 °C and using THF as the solvent, we could ensure
that virtually no dialkylated product was formed. Even
though the 7â epimer is produced exclusively in this
reaction, conversion to the 7R epimer product is readily
(52) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds, 1st ed.; Wiley-Interscience: New York, 1994; p
1267.
(53) log Po/w calculations were performed on ChemDraw Ultra using
the benzamide analogues of 4a , 4b, 6, and 7.

8114 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
1H and 13C NMR were obtained at 400 or 500 MHz and are
reported in parts per million relative to tetramethylsilane or
the incomplete deuteration signal of the NMR solvent. The
signals generated from diastereomeric mixtures (due to the
presence of the tetrahydropyranyloxy group) are reported as
two numbers separated by a comma (x, x) and the 1H
multiplicity is indicated as a double signal (e.g., 2d ) two
doublets). Melting points are uncorrected. Elemental analyses
were performed by the Microanalytical Service Laboratory of
the University of Illinois.
3,17â-Bis(2-tetr ah ydr opyr an yloxy)estr a-1,3,5(10)-tr ien e-
6-on e (9). To a -78 °C solution of 1.3 M n-BuLi in hexanes
(56 mL, 72.6 mmol) in THF (100 mL) was added diisopropyl-
amine (10.2 mL, 72.6 mmol), followed by 1 M KOt-Bu in THF
(72.6 mL, 72.6 mmol). After 5 min, a solution of 8 (8.00 g, 18.2
µmol) in THF (40 mL) was slowly added via cannula. The
solution turned a dark red color, and stirring was continued
for 3 h at -78 °C. The dry ice/IPA bath was replaced with an
ice bath, and trimethylborate (27 mL) was slowly added. The
mixture became turbid, and after the reaction was stirred for
an additional 2 h, the stir bar was removed and replaced by a
mechanical stirrer. To this was added 30% H2O2 (50 mL), and
the reaction was stirred for 1 h at room temperature. The
reaction was cooled to 0 °C, and 10% Na2S2O3 (100 mL) was
added. After extraction with EtOAc, drying over Na2SO4/Na2-
CO3, and evaporation in vacuo, a pale yellow foam of the
6-hydroxy compound was obtained (7.70 g, 93%).
The 6-hydroxy compound (6.50 g, 14.2 mmol) was dissolved
in CH2Cl2 (80 mL). At 0 °C, PCC (5.4 g, 24.8 mmol) was added
in portions within 15 min. After 15 min at 0 °C, the mixture
was allowed to warm to room temperature, and after 1.5 h,
the reaction was diluted with ether (80 mL). The black-brown
mixture was filtered through Florisil to remove the chromium
salts. The yellow solution was evaporated in vacuo, and the
residue was purified by flash chromatography (25% EtOAc/
Hex) to yield 9 as a white foam (4.20 g, 65%, 83% when
corrected for recovered SM). IR (KBr): 1685 cm-1 (s, CdO).
1H NMR (CDCl3, 500 MHz): δ 0.80, 0.81 (2s, 3H), 2.32-2.36
(m, 2H), 2.44-2.49 (m, 1H), 2.72 (dd, J ) 16.8, 3.3 Hz, 1H),
3.48-3.51 (m, 1H), 3.58-3.61 (m, 2H), 3.71, 3.74 (2t, J ) 8.4
Hz, 1H), 3.85-3.93 (m, 2H), 4.63-4.68 (m, 1H), 5.46-5.47 (m,
1H), 7.21, 7.22 (2dd, J ) 8.6, 2.7 Hz, 1H), 7.33, 7.34 (2d, J )
7.9 Hz, 1H), 7.70, 7.71 (2d, J ) 3.1 Hz, 1H). 13C NMR (CDCl3,
125 MHz): δ 11.52, 11.54; 18.71; 19.34, 19.73; 22.75, 22.86;
25.10; 25.48, 25.56; 27.07; 28.62; 30.18; 30.98, 31.05; 36.66,
37.19; 39.76, 39.80; 39.86, 39.89; 42.60, 42.90; 42.96, 43.04,
43.07; 43.97, 44.03; 44.06, 44.11; 49.84, 49.98; 61.92, 62.09;
62.12, 62.60; 83.82, 86.25; 96.30, 96.34; 96.70, 99.35; 113.99,
114.02; 122.49, 122.58; 126.45, 126.50; 133.43; 140.47; 155.40;
197.87, 197.94. MS (CI, CH4): m/z 455 (M + H+, 14), 371 (85),
85 (100). HRMS (CI, CH4) calcd for C28H39O5: 455.2898.
Found: 455.2800. Anal. Calcd for C28H38O5: C, 73.98; H, 8.42.
Found: C, 74.00; H, 8.57.
as accurate for compounds like 6 with a very high
molecular weight. The log Po/w for 7 (5.40), however, did
show a 30-fold increase in polarity relative to that of 4b
(6.90). Thus, the log Po/w value for 7 seems to suggest that
we were successful in increasing the polarity of amide
4b by introducing an ether linkage into the side chain.
It should be noted, however, that while the log Po/w for 6
is still quite high, the extra oxygens in the side chain
offer more hydrogen bond accepting sites; as a result, this
compound might be more soluble in aqueous media than
amide 4b. Therefore, the biodistribution experiments of
the Tc-99m analogues of both 6 and 7 are being inves-
tigated.
Con clu sion s
We have described the synthesis of a number of novel
Re-containing 7R-substituted estrogen complexes, and we
have determined their lipophilicities and binding affini-
ties for the ER. To our knowledge, this is the first time
the 7R-position of estradiol has been labeled with rhe-
nium. The highest affinity ligand in the inorganic com-
plex series (2, 3, 5) is the “SNS 3 + 1” complex 2c, with
an RBA of 45%. The highest affinity ligand in the original
organometallic series (4) was that of the amide 4b, with
an RBA of 24%. The lipophilicities of these two complexes
proved to be too high for an acceptable biodistribution
profile.
This prompted us to increase the polarity of these
complexes by modifying the side chain with ether link-
ages. We focused on modifying amide 4b, synthesizing
both the long-chain polyether 6 and short-chain ether 7.
The critical step was the attachment of the poly(ethylene
glycol) moieties. The final CpTR amides 6 and 7 showed
good binding affinity-essentially unchanged from that
of the original amide 4b. Although the log Po/w of 6 was
unexpectedly high, the log Po/w of 7 (an order of magni-
tude lower than that of 4b) demonstrates that we were
successful in lowering the log Po/w of 4b by introducing
an ether linkage in the 7R side chain. Efforts to synthe-
size the Tc-99m analogues of 6 and 7 are currently
underway. A favorable biodistribution would suggest the
usefulness of these compounds as effective imaging
agents for ER+ breast cancer.
Exp er im en ta l Section
Gen er a l. All reagents and solvents were obtained from
Aldrich, Acros, Alfa Aesar, Fisher, Fluka, or Mallinckrodt. All
reactions were performed under a nitrogen atmosphere unless
otherwise indicated. The synthesis of 3,17â-bis(2-tetrahydro-
pyranyloxy)-estra-1,3,5(10)-triene (8) has already been de-
scribed.41 THF and DME were distilled from sodium/benzophe-
none immediately prior to use. Methylene chloride and toluene
were distilled from CaH2 prior to use. Triethylamine was dried
by distillation from CaH2 and stored over KOH. Diisopropyl-
amine was distilled from powdered KOH and stored over KOH
pellets. Dimethylformamide was dried with BaO and distilled
from and stored over 4 Å molecular sieves. MeOH was distilled
from Mg/I2 and stored over 3 Å molecular sieves. Acetone was
distilled from CaSO4 and stored over 4 Å molecular sieves.
Hexanes were distilled from CaSO4 (Drierite) before use in
flash chromatography.
3,17â-Bis(2-t et r a h yd r op yr a n yloxy)-7r-(5-h exen -1-yl)-
estr a -1,3,5(10)-tr ien e-6-on e (10). A 1 M solution of KOt-Bu
in THF (5.80 mL, 5.80 mmol) was added to a solution of ketone
9 (2.40 g, 5.28 mmol) in DME (25 mL). After 10 min, 1 M BEt3
in THF (6.60 mL, 6.60 mmol) was added, and stirring was
continued for 1 h at room temperature. A solution of 6-io-
dohexene (1.33 g, 6.60 mmol, prepared from 6-bromo-1-hexene
and NaI in acetone) in DME (2 mL) was then added to the
enolate. After 30 min an additional equivalent of KOt-Bu was
added, and the mixture was stirred overnight. The reaction
was quenched with water, extracted with CHCl3, and dried
over MgSO4. After evaporation of the solvent in vacuo, the
residue was purified by flash chromatography (10% EtOAc/
Hex) to afford 10 as a white foam (1.50 g, 53%). IR (KBr): 1683
1
(s, CdO). H NMR (CDCl3, 500 MHz): δ 0.79, 0.80 (2s, 3H),
2.35-2.37 (m, 2H). 2.42-2.45 (m, 1H), 2.67-2.71 (m, 1H),
3.48-3.51 (m, 1H), 3.60-3.63 (m, 1H), 3.74, 3.76 (2t, J ) 8.4
Hz, 1H), 3.87-3.93 (m, 2H), 4.63-4.68 (m, 1H), 4.89-4.97 (m,
2H), 5.45-5.47 (m, 1H), 5.76 (2ddt, J ) 17.0, 10.2, 6.7 Hz, 1H),
7.19, 7.22 (2dd, J ) 8.6, 2.7 Hz, 1H), 7.30, 7.32 (2d, J ) 7.7
Hz, 1H), 7.68, 7.69 (2d, J ) 2.7 Hz, 1H). 13C NMR (CDCl3, 125
MHz): δ 11.52; 18.79, 18.88; 19.37, 19.75; 22.19, 22.32;
Reaction progress was monitored by analytical thin-layer
chromatography (Analtech scored 10 cm × 20 cm hard TLC
plates, glass). Silica gel used in flash chromatography was 32-
63 µm. TLC plates were visualized using short wave UV light
(254 nm), potassium permanganate, ninhydrin, or phospho-
molybdic acid.

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8115
23.46, 23.52; 25.16; 25.51, 25.61; 26.61, 26.79, 27.01; 28.60,
28.94; 30.25, 30.30; 31.00, 31.07; 36.95, 37.40; 37.49; 42.23,
42.27; 42.31, 42.36; 42.78, 43.26; 45.25, 45.34; 48.59, 48.67,
48.75; 61.93, 62.18; 62.32, 62.61; 83.89, 86.31; 96.33, 96.49;
96.70, 99.35; 114.36, 114.58, 114.67; 122.37, 127.05; 132.33;
138.85; 139.42, 139.55; 155.50; 200.86. MS (CI, CH4): m/z 537
(M + H+, 73), 453 (100), 85 (57). HRMS (CI, CH4) calcd for
34H49O5: 537.3580. Found: 537.3583. Anal. Calcd for
34H48O5: C, 76.08; H, 9.01. Found: C, 75.84; H, 8.98.
7r-(5-Hexen -1-yl)-estr a -1,3,5(10)-tr ien e-3,17â-d iol (11).
Et3SiH (30 mL) was added to a solution of steroid 10 (1.40 g,
2.60 mmol) in CH2Cl2 (100 mL). The mixture was cooled to 0
°C and BF3‚Et2O (100 mL) was added dropwise. The yellow-
green solution was warmed to room temperature and stirred
overnight. The reaction was carefully hydrolyzed with 10% K2-
CO3 (500 mL) and then passed through a plug of silica. The
aqueous layer was washed with CH2Cl2, and the organic
fractions were then combined and dried over Na2SO4. Follow-
ing evaporation of the CH2Cl2, the residue was purified by flash
chromatography (40% EtOAc/Hex) to give 11 as a white solid
(700 mg, 76%). IR(KBr): 3410 (s, OH), 1639 (s, CdO). 1H NMR
(CDCl3, 400 MHz): δ 0.78 (s, 3H), 2.70 (d, J ) 16.8 Hz, 1H),
2.86 (dd, J ) 16.8, 4.6 Hz, 1H), 3.75 (t, J ) 8.4 Hz, 1H), 4.82
(bs, 1H), 4.90-4.98 (m, 2H), 5.78 (ddtd, J ) 17.1, 10.3, 6.7,
1.5 Hz, 1H), 6.54 (s, 1H), 6.62 (d, J ) 8.3 Hz, 1H), 7.14 (d, J
) 8.3 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 11.07, 22.63,
25.42, 27.24, 27.62, 29.15, 30.52, 33.13, 33.85, 34.53, 36.85,
38.01, 41.91, 43.36, 46.43, 82.03, 112.79, 114.25, 116.10,
127.07, 131.89, 137.12, 139.01, 153.34. MS (EI, 70 eV): m/z
354 (M, 100). HRMS (EI, 70 eV) calcd for C24H34O2: 354.2559.
Found: 354.2564. Anal. Calcd for C24H34O2‚H2O: C, 77.38; H,
9.74. Found: C, 77.60; H, 9.55.
(54). HRMS (EI, 70 eV) calcd for C36H64O3Si2: 600.4394.
Found: 600.4387. Anal. Calcd for C36H64O3Si2‚0.5H2O: C,
70.88; H, 10.74. Found: C, 70.83; H, 11.02.
7r-[6-(S-Ben zoylt h io)-h exa n -1-yl]-3,17â-b is(t-b u t yld i-
m eth ylsila n yloxy)estr a -1,3,5(10)-tr ien e (14). DIAD (98.0
µL, 0.500 mmol) was added to a cooled solution (0 °C) of PPh3
(131 mg, 0.500 mmol) in THF (3 mL). A white precipitate of
the ylide formed, and the solution was stirred for 30 min at 0
°C. A solution of steroid 13 (150 mg, 0.250 mmol) and
thiobenzoic acid (60.0 µL, 0.500 mmol) in THF (1.5 mL) was
then added dropwise to the ylide. The reaction was stirred for
1 h at 0 °C and then overnight at room temperature. The clear
yellow solution was concentrated and then purified by flash
chromatography (10% EtOAc/Hex) to give 14 as yellow oil (181
C
C
1
mg, 100%). IR (CHCl3): 1666 (s, CdO). H NMR (CDCl3, 400
MHz): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.18 (s, 6H), 0.74 (s, 3H),
0.89 (s, 9H), 0.97 (s, 9H), 2.67 (d, J ) 16.7 Hz, 1H), 2.84 (dd,
J ) 16.6, 4.9 Hz, 1H), 3.05 (t, J ) 7.3 Hz, 1H), 3.65 (t, J ) 8.2
Hz, 1H), 6.53 (d, J ) 2.4 Hz, 1H), 6.60 (dd, J ) 8.5, 2.4 Hz,
1H), 7.11 (d, J ) 8.5 Hz, 1H). MS (CI, CH4): m/z 720 (M +
H+, 23), 664 (73), 590 (100). HRMS (CI, CH4) calcd for
C
43H68O3Si2S: 719.4350. Found: 719.4355.
7r-[6-(S-Ben zoylth io)-h exan -1-yl]-estr a-1,3,5(10)-tr ien e-
3,17â-d iol (15). A solution of 40% HF (0.7 mL) was added to
a solution of thiobenzoate 14 (181 mg, 0.252 mmol) in CH3CN
(1 mL) and THF (1 mL) at 60 °C. After 1 min, another 1 mL
of THF was added, and heating was continued for 20 min. The
reaction was quenched with NaHCO3 (1 mL saturated and
then solid until neutral to pH paper), extracted with CH2Cl2
(3 × 7 mL), and dried over Na2SO4. Evaporation of the organic
fractions in vacuo provided 15 as a white foam (123 mg, 99%).
1
IR (KBr): 3427 (s, OH), 1662 (s, CdO). H NMR (CDCl3, 400
3,17â-Bis(t-bu tyld im eth ylsila n yloxy)-7r-(5-h exen -1-yl)-
estr a -1,3,5(10)-tr ien e (12). A solution of TBSCl (841 mg, 5.58
mmol) in DMF (4 mL) was added to a cooled solution (0 °C) of
imidazole (844 mg, 12.4 mmol) in DMF (10 mL). After the
reaction was stirred for 30 min, a solution of steroid 11 (400
mg, 1.24 mmol) in DMF (2 mL) was added all at once. The
reaction was stirred overnight and then hydrolyzed with 0.1%
K2CO3, followed by extraction with CH2Cl2. The extracts were
flushed through a silica plug and then concentrated in vacuo
to give 12 as a colorless oil (700 mg, 98%). IR (CHCl3): 1608
MHz): δ 0.78 (s, 3H), 2.70 (d, J ) 16.6 Hz, 1H), 2.87 (dd, J )
16.6, 5.1 Hz, 1H), 3.05 (t, J ) 7.3 Hz, 2H), 3.75 (t, J ) 8.5 Hz,
1H), 5.05 (bs, 1H), 6.55 (d, J ) 2.5 Hz, 1H), 6.63 (dd, J ) 8.5,
2.5 Hz, 1H), 7.14 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ 10.96, 22.52, 25.36, 27.12, 27.87, 28.83, 28.88, 29.32,
29.41, 30.39, 33.04, 34.42, 36.72, 37.91, 41.81, 43.24, 46.29,
81.90, 112.71, 116.01, 126.93, 127.03, 128.43, 131.62, 133.13,
136.94, 137.06, 153.31, 192.18. MS (EI, 70 eV): m/z 492 (M,
19), 388 (100), 157 (40), 105 (79). HRMS (EI, 70 eV) calcd for
C
31H40O3S: 492.2698. Found: 492.2693. Anal. Calcd for
1
(s, CdC). H NMR (CDCl3, 400 MHz): δ 0.02 (s, 3H), 0.03 (s,
C31H40O3S‚0.5H2O: C, 74.21; H, 8.24. Found: C, 74.28; H, 8.00.
7r-(6-Mer ca p toh exa n -1-yl)-estr a -1,3,5(10)-tr ien e-3,17â-
d iol (16). A 1 M solution of NaOMe in MeOH (0.5 mL) was
added to a solution of diol 15 (78.5 mg, 0.159 mmol) in MeOH
(6 mL). The reaction was stirred at room temperature for 40
min. After the addition of 1 M HCl (5 mL), the mixture was
extracted with CH2Cl2 (3 × 7 mL), and the organic fractions
were dried over Na2SO4. Evaporation of the solvent and flash
chromatography (50% EtOAc/Hex) provided 16 as a white foam
(53.6 mg, 87%). IR (KBr): 2562 (w, SH). 1H NMR (CDCl3, 400
MHz): δ 0.78 (s, 3H), 2.50 (q, J ) 7.3 Hz, 2H), 2.70 (d, J )
16.6 Hz, 1H), 2.86 (dd, J ) 16.6, 5.1 Hz, 1H), 3.76 (t, J ) 8.5
Hz, 1H), 6.55 (d, J ) 2.7 Hz, 1H), 6.63 (dd, J ) 8.5, 2.7 Hz,
1H), 7.14 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ
11.08, 22.63, 24.61, 25.53, 27.23, 28.05, 28.42, 29.38, 30.48,
33.15, 33.98, 34.52, 36.82, 38.01, 41.90, 43.35, 46.41, 82.03,
112.81, 116.10, 127.04, 131.78, 137.05, 153.41. MS (EI, 70
eV): m/z 388 (M, 53), 55(100). HRMS (EI, 70 eV) calcd for
3H), 0.19 (s, 6H), 0.74 (s, 3H), 2.68 (d, J ) 16.6 Hz, 1H), 2.84
(dd, J ) 16.6, 4.9 Hz, 1H), 3.65 (t, J ) 8.0 Hz, 1H), 4.89-4.99
(m, 2H), 5.78 (ddt, J ) 17.0, 10.3, 6.7 Hz, 1H), 6.53 (d, J ) 2.4
Hz, 1H), 6.60 (dd, J ) 8.5, 2.4 Hz, 1H), 7.14 (d, J ) 8.5 Hz,
1H). 13C NMR (CDCl3, 100 MHz): δ -4.78, -4.46, -4.38,
11.39, 18.12, 22.80, 25.37, 25.70, 25.87, 27.29, 27.64, 29.19,
30.94, 33.25, 33.84, 34.61, 37.37, 38.26, 41.94, 43.71, 46.11,
81.86, 114.25, 117.15, 120.81, 126.65, 132.52, 136.79, 139.06,
153.20. MS (EI, 70 eV): m/z 583 (M, 100), 526 (89), 73 (72).
HRMS (EI, 70 eV) calcd for C36H62O2Si2: 582.4288. Found:
582.4285.
3,17â-Bis(t-b u t yld im et h ylsila n yloxy)-7r-(6-h yd r oxy-
h exa n -1-yl)-estr a -1,3,5(10)-tr ien e (13). A solution of 0.5 M
9-BBN in THF (12.0 mL, 6.00 mmol) was added to a solution
of steroid 12 (700 mg, 1.20 mmol) in THF (40 mL). After being
stirred overnight, the reaction was hydrolyzed with 3 M KOH
(5 mL), followed by 30% H2O2 (5 mL) after 5 min. Stirring was
continued for 3 h, followed by the addition of saturated
NaHCO3 (50 mL) and extraction with CH2Cl2. The organic
fractions were dried over Na2SO4 and evaporated in vacuo,
followed by purification by flash chromatography (20% EtOAc/
Hex) to give 13 as a white solid (580 mg, 81%). IR (KBr): 3402
(s, OH). 1H NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H), 0.04 (s,
3H), 0.19 (s, 6H), 0.74 (s, 3H), 0.89 (s, 9H), 0.98 (s, 9H), 2.68
(d, J ) 16.6 Hz, 1H), 2.84 (dd, J ) 16.6, 5.1 Hz, 1H), 3.62 (t,
J ) 6.6 Hz, 1H), 3.65 (t, J ) 8.0 Hz, 1H), 6.53 (d, J ) 2.4 Hz,
1H), 6.61 (dd, J ) 8.5, 2.4 Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H).
13C NMR (CDCl3, 100 MHz): δ -4.79, -4.47, -4.39, 11.38,
18.11, 22.79, 25.50, 25.63, 25.68, 25.79, 25.86, 27.27, 28.17,
29.77, 30.92, 32.78, 33.28, 34.60, 37.37, 38.26, 41.94, 43.70,
46.09, 63.03, 81.83, 117.14, 120.80, 126.66, 132.54, 136.79,
153.18. MS (CI, CH4): m/z 602 (M + H+, 100), 586 (61), 543
C
C
24H36O2S: 388.2436. Found: 388.2436. Anal. Calcd for
24H36O2S: C, 74.18; H, 9.34. Found: C, 73.93; H, 9.03.
3,17â-Bis(t-b u t yld im et h ylsila n yloxy)-7r-[6-(p h t h a li-
m id o)-h exa n -1-yl]-estr a -1,3,5(10)-tr ien e (17). DIAD (327
µL, 1.66 mmol) was added dropwise to a cooled solution (0 °C)
of PPh3 (436 mg, 1.66 mmol) in THF (10 mL). A white
precipitate of the ylide formed, and the reaction was stirred
for 40 min at 0 °C. A solution of alcohol 13 (500 mg, 0.832
mmol) and phthalimide (244 mg, 1.66 mmol) in THF (5 mL)
was then added to the ylide. The reaction was stirred for 1 h
at 0 °C and then at room temperature overnight. The solvent
was evaporated in vacuo, and the residue was purified by flash
chromatography (5% EtOAc/Hex) to give 17 as a yellow oil (589
1
mg, 97%). H NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H), 0.04 (s,
3H), 0.19 (s, 6H), 0.74 (s, 3H), 0.90 (s, 9H), 0.97 (s, 9H), 2.67

8116 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
(d, J ) 16.6 Hz, 1H), 2.83 (dd, J ) 16.6, 4.9 Hz, 1H), 3.66 (t,
J ) 7.3 Hz, 2H), 3.66 (t, J ) 7.3 Hz, 1H), 6.53 (d, J ) 2.6 Hz,
1H), 6.60 (dd, J ) 8.5, 2.6 Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H),
7.70 (dd, J ) 5.4, 3.0 Hz, 2H), 7.84 (dd, J ) 5.4, 3.0 Hz, 2H).
13C NMR (CDCl3, 100 MHz): δ -4.79, -4.47, -4.40, 11.36,
18.10, 22.77, 25.52, 25.67, 25.86, 26.96, 27.27, 28.03, 28.59,
29.57, 30.90, 33.21, 34.53, 37.33, 38.02, 38.22, 41.91, 43.68,
46.05, 81.81, 117.12, 120.79, 123.11, 126.63, 132.14, 132.50,
133.80, 136.75, 153.17, 168.41. MS (EI, 70 eV): m/z 730 (M,
3), 673 (100). HRMS (EI, 70 eV) calcd for C44H67NO4Si2:
729.4609. Found: 729.4597.
a homogeneous dark green-brown color. After evaporation of
the solvent in vacuo, the residue was purified by flash
chromatography (eluted first with 20% EtOAc/Hex and then
with 10% MeOH/CH2Cl2) to give a green foam (51.4 mg, 56%).
1
IR (KBr): 949 (s, RedO). H NMR (CDCl3, 400 MHz): δ 0.77
(s, 3H), 2.29 (m, 2H), 2.61 (m, 2H), 2.71 (d, J ) 16.6 Hz, 1H),
2.84 (dd, J ) 16.6, 5.4 Hz, 1H), 3.15 (m, 4H), 3.34 (s, 3H), 3.53
(m, 2H), 3.76 (t, J ) 8.5 Hz, 1H), 5.04 (bs, 1H), 6.54 (d, J )
2.6 Hz, 1H), 6.62 (dd, J ) 8.4, 2.6 Hz, 1H), 7.13 (d, J ) 8.4 Hz,
1H). HRMS (FAB, 3-NBA) calcd for C29H47NO3S3187Re (M +
H): 740.2276. Found: 740.2274.
7r-(6-Am in oh exa n -1-yl)-3,17â-bis(t-bu tyld im eth ylsila -
n yloxy)estr a -1,3,5(10)-tr ien e (18). Anhydrous hydrazine
(500 µL) was added to a solution of steroid 17 (74.4 mg, 0.102
mmol) in DME (1 mL) and EtOH (1 mL). The mixture was
refluxed for 2 h, during which time a white precipitate formed
on the sides and the solution turned slightly green. The
reaction was cooled, and 5% NaOH (1 mL) was added,
dissolving the precipitate. After 30 min, water (5 mL) was
added, and the solution was extracted with CH2Cl2 (3 × 5 mL),
dried over Na2SO4, and evaporated to give 18 as a white foam
3,17â-Bis(t-bu tyld im eth ylsila n yloxy)-7r-[6-(m eth a n e-
su lfon yloxy)-h exa n -1-yl]-estr a -1,3,5(10)-tr ien e (22). Et3N
(66.0 µL, 0.480 mmol) was added to a cooled solution (0 °C) of
alcohol 13 (130 mg, 0.220 mmol) in THF (25 mL), followed by
the addition of MsCl (37.0 µL, 0.480 mmol). The reaction was
stirred overnight, then diluted with saturated NaHCO3 (50
mL), and extracted with CHCl3. Evaporation of the solvent,
followed by flash chromatography of the residue (10% EtOAc/
Hex) provided 22 as a colorless oil (125 mg, 85%). 1H NMR
(CDCl3, 400 MHz): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.19 (s, 6H),
0.74 (s, 3H), 0.89 (s, 9H), 0.97 (s, 9H), 2.67 (d, J ) 16.6 Hz,
1H), 2.85 (dd, J ) 16.6, 4.9 Hz, 1H), 2.99 (s, 3H), 3.66 (t, J )
8.0 Hz, 1H), 4.20 (t, J ) 6.6 Hz, 2H), 6.53 (s, J ) 2.4 Hz, 1H),
6.61 (dd, J ) 8.3, 2.4 Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ -4.79, -4.47, -4.37, 11.38, 18.10,
22.79, 25.51, 25.68, 25.86, 27.28, 28.02, 29.13, 29.41, 30.92,
33.28, 34.57, 37.35, 38.26, 41.91, 43.71, 46.08, 70.11, 81.81,
117.18, 120.79, 126.69, 132.51, 136.69, 153.20. MS (CI, CH4):
m/z 680 (M + H+, 2), 178 (54), 59 (100). HRMS (CI, CH4) calcd
for C37H67O5Si2S: 679.4247. Found: 679.4238.
1
(52.2 mg, 85%). IR (CHCl3): 3439 (m, NH). H NMR (CDCl3,
400 MHz): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.19 (s, 6H), 0.74 (s,
3H), 0.89 (s, 9H), 0.98 (s, 9H), 2.68 (d, J ) 17.1 Hz, 1H), 2.70
(t, J ) 7.2 Hz, 2H), 2.84 (dd, J ) 17.1, 4.9 Hz, 1H), 2.88 (s,
2H), 3.66 (t, J ) 8.2 Hz, 1H), 6.53 (d, J ) 2.5 Hz, 1H), 6.61
(dd, J ) 8.5, 2.5 Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): δ -4.81, -4.50, -4.42, 11.34, 18.07, 22.76,
25.49, 25.66, 25.83, 26.90, 27.24, 28.15, 29.75, 30.89, 32.71,
33.23, 34.55, 37.32, 38.21, 41.71, 41.90, 43.66, 46.04, 81.79,
117.11, 120.76, 126.62, 132.48, 136.73, 153.15. MS (CI, CH4):
m/z 601 (M + H+, 24), 585 (16), 57 (70). HRMS (EI, 70 eV)
calcd for C36H65NO2Si: 599.4554. Found: 599.4541.
[3-Th ia p en ta n e-1,5-d ith iola to][7r-(6-m er ca p toh exa n -
1-yl)-estr a -1,3,5(10)-tr ien e-3,17â-d iol]oxor h en iu m (V) (2a ).
A solution of thiol 16 (30.0 mg, 77.0 µmol) and Et3N (10.0 µL)
in CH3CN (1.5 mL) was added to a solution of rhenium complex
19 (27.3 mg, 70.0 µmol) in hot CH3CN (1.5 mL). The mixture
was refluxed for 2 h, followed by evaporation of the solvent in
vacuo. The residue was redissolved in CHCl3 and purified by
flash chromatography (5% acetone/CH2Cl2) to afford 2a as a
brown foam (40.0 mg, 77%). IR (KBR): 961 (s, RedO). 1H NMR
(DMSO-d6, 400 MHz): δ 0.65 (s, 3H), 2.21 (m, 2H), 2.60 (d, J
) 16.3 Hz, 1H), 2.74 (dd, J ) 16.3, 4.4 Hz, 1H), 2.99 (td, J )
14.2, 3.9 Hz, 2H), 3.53 (m, 1H), 3.76 (t, J ) 7.3 Hz, 2H), 4.03
(dd, J ) 10.5, 3.2 Hz, 2H), 4.26 (dd, J ) 12.9, 4.4 Hz, 2H),
4.47 (d, J ) 4.6 Hz, 1H), 6.40 (d, J ) 2.4 Hz, 1H), 6.48 (dd, J
) 8.5, 2.7 Hz, 1H), 7.04 (d, J ) 8.5 Hz, 1H), 8.97 (s, 1H). HRMS
(FAB, 3-NBA) calcd for C28H44O3S4Re (M + H): 743.1731.
Found: 743.1731.
2-(Mer ca p t om et h yl)-et h a n e-1-t h iol (23). A catalytic
amount of DMAP was added to a solution of 2-(mercaptom-
ethyl)-ethanol (10.0 mL, 110 mmol) in CHCl3 (100 mL). The
reaction was cooled to 0 °C, and then SOCl2 (14.3 g, 120 mmol)
was added dropwise. After the reaction was stirred for 6 h at
room temperature, the solvent was removed in vacuo, and the
oily residue was redissolved in 95% EtOH (50 mL). Thiourea
(8.40 g, 110 mmol) was added, and the mixture was refluxed
for 3 h. After the mixture cooled to room temperature, 5 M
NaOH (100 mL) was added, and the mixture was refluxed
again for 2 h while a slow stream of N2 was bubbled through
the solution. Following acidification with 2 M HCl, the yellow
layer was separated, and the aqueous layer was extracted with
CHCl3. Subsequent Kugelrohr distillation provided thiol 23
1
as a pungent, colorless oil (5.00 g, 42%). H NMR (CDCl3, 400
MHz): δ 1.66-1.69 (m, 1H), 2.02 (s, 3H), 2.65-2.66 (m, 4H).
13C NMR (CDCl3, 100 MHz): δ 15.12, 23.99, 37.95. MS (EI,
70 eV): m/z 108 (M, 23), 75 (100), 61 (54). HRMS (EI, 70 eV)
calcd for C3H8S2: 108.0067. Found: 108.0071.
[3-Oxa p en ta n e-1,5-d ith iola to][7r-(6-m er ca p toh exa n -1-
yl)-estr a -1,3,5(10)-tr ien e-3,17â-d iol]oxor h en iu m (V) (2b).
A solution of 3-oxapentane-1,5-dithiol (20, 10.4 µL, 87.5 µmol)
and thiol 16 (34.0 mg, 87.5 µmol) in CHCl3 (1 mL) was added
to a cooled solution (0 °C) of (Bu4N)[ReOCl4]39 (51.3 mg, 87.5
µmol) in EtOH (1 mL). The color of the mixture immediately
turned red. Stirring was continued at 0 °C for 2 h and then
overnight at room temperature. The solvent was evaporated
in vacuo, and the residue was redissolved in CHCl3 and
purified by flash chromatography (5% acetone/CH2Cl2) to give
2b as a red, glassy, solid (44.0 mg, 70%). IR (KBr): 968 (s,
RedO). 1H NMR (DMSO-d6, 400 MHz): δ 0.65 (s, 3H), 2.59
(d, J ) 16.6 Hz, 1H), 2.74 (dd, J ) 16.6, 5.1 Hz, 1H), 3.08-
3.15 (m, 2H), 3.52 (m, 1H), 3.71 (bs, 2H), 3.80 (m, 2H), 4.47
(d, J ) 4.4 Hz, 1H), 4.80 (bs, 2H), 6.40 (d, J ) 2.4 Hz, 1H),
6.48 (dd, J ) 8.5, 2.4 Hz, 1H), 7.04 (d, J ) 8.5 Hz, 1H), 8.97
(s, 1H). HRMS (FAB, 3-NBA) calcd for C28H44O4S3187Re (M +
H): 727.1959. Found: 727.1958.
7r-(7,10-Dith ia -u n d eca n -1-yl)-estr a -1,3,5(10)-tr ien e-3,-
17â-d iol (24). KOt-Bu (53.0 mg, 0.480 mmol) was added in
portions to a solution of thiol 23 (51.4 mg, 0.480 mmol) in DMF
(10 mL). After 1 h, a solution of the mesylate 22 (130 mg, 0.190
mmol) in DMF (10 mL) was added dropwise to the thiolate
solution. After being stirred overnight, the reaction was diluted
with water (50 mL) and extracted with CHCl3, and the organic
fractions were evaporated in vacuo. Purification by flash
chromatography (5% EtOAc/Hex) yielded 130 mg of a clear oil,
which was redissolved in CH3CN (25 mL). The solution was
heated to 50 °C, and 40% HF (3 mL) was added. After being
stirred for 1 h, the solution was neutralized with NaHCO3,
extracted with EtOAc, and purified by flash chromatography
(40% EtOAc/Hex) to yield 24 as a white foam (43.0 mg, 49%).
1H NMR (CDCl3, 400 MHz): δ 0.78 (s, 3H), 2.14 (s, 3H), 2.53
(t, J ) 7.5 Hz, 2H), 2.72 (d, J ) 16.4 Hz, 1H), 2.86 (dd, J )
16.4, 4.6 Hz, 1H), 3.76 (t, J ) 8.3 Hz, 1H), 6.54 (d, J ) 2.4 Hz,
1H), 6.63 (dd, J ) 8.5, 2.7 Hz, 1H), 7.14 (d, J ) 8.5 Hz, 1H).
13C NMR (CDCl3, 100 MHz): δ 11.07, 15.54, 22.63, 25.52,
27.22, 28.02, 28.87, 29.51, 29.61, 30.50, 31.57, 32.14, 33.15,
34.15, 34.52, 36.82, 38.02, 41.90, 43.35, 46.41, 82.01, 112.82,
116.10, 127.05, 131.81, 137.05, 153.45. MS (EI, 70 eV): m/z
462 (M, 73), 157 (53), 75(100). HRMS (EI, 70 eV) calcd for
[3-(N-Meth yl)a za p en ta n e-1,5-d ith iola to][7r-(6-m er ca p -
toh exa n -1-yl)-estr a -1,3,5(10)-tr ien e-3,17â-d iol]oxor h en i-
u m (V) (2c). Thiol 16 (53.6 mg, 138 µmol), N-methyl-3-
azapentane-1,5-dithiol HCl46 (21) (23.6 mg, 125 µmol), and
(PPh3)2ReOCl3 (104 mg, 125 µmol) were added to a solution of
1 M NaOAc/MeOH (1.5 mL) and MeOH (5 mL). The mixture
was refluxed for 45 min, during which time the reaction turned
C
C
27H42O2S2: 462.2626. Found: 462.2630. Anal. Calcd for
24H36O2S: C, 74.18; H, 9.34. Found: C, 73.93; H, 9.03.

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8117
Br om o-tr ica r bon yl-{[7r-(7,10-d ith ia -u n d eca n -1-yl)-es-
tr a -1,3,5(10)-tr ien e-3,17â-d iol]}-r h en iu m (III) (3). A solu-
tion of steroid 24 (18.0 mg, 39.0 µmol) in MeOH (1 mL) was
added to a solution of rhenium precursor 2539 (29.0 mg, 39.0
µmol) in MeOH (1 mL). After the reaction was stirred
overnight at room temperature, the solvent was evaporated
in vacuo. Dry THF (2 mL) was added, and the precipitate was
removed by filtration. The filtrate was concentrated, and the
residue was purified by flash chromatography (10% MeOH/
CH2Cl2) to afford 3 as a white foam (25.0 mg, 79%). IR (KBr):
37.33, 38.23, 39.84, 41.91, 43.68, 46.05, 81.80, 84.70, 85.62,
95.31, 117.15, 120.79, 126.67, 132.55, 136.78, 153.16, 162.10,
192.44. MS (FAB, 3-NBA): m/z 961 (M, 5), 904 (100), 363 (46).
HRMS (FAB, 3-NBA) calcd for C45H67NO6Si2187Re: 960.4065.
Found: 950.4066.
Tr ica r bon yl{[6-[estr a -1,3,5(10)-tr ien e-3,17â-d iol-7r-yl]-
h exyla m id o]cyclop en t a d ien yl}r h en iu m (I) (4b ). A 40%
solution of HF (300 µL) was added to a solution of the amide
28 (55.8 mg, 58.1 µmol) in CH3CN (2 mL) at 60 °C, resulting
in a turbid solution which became clear after several seconds.
After 15 min at 60 °C, the reaction was cooled and quenched
with saturated NaHCO3. The mixture was extracted with CH2-
Cl2 (3 × 5 mL) and evaporated in vacuo to a yellow foam. This
was purified by flash chromatography (5% MeOH/CH2Cl2) to
give 4b as an off-white foam (40.9 mg, 96%). IR (KBr): 2026,
1932 (s, CtO), 1644 (s, CdO). Normal phase HPLC [tR ) 9.4
min, 70% EtOAc/Hex, UV detection (λmax ) 232)] showed only
1
2034, 1938, 1903 (s, CO). H NMR (CDCl3, 400 MHz): δ 0.78
(s, 3H), 2.70 (d, J ) 16.8 Hz, 1H), 2.90 (dd, J ) 16.8, 4.4 Hz,
1H), 3.76 (t, J ) 8.4 Hz, 1H), 6.56 (dd, J ) 6.3, 2.2 Hz, 1H),
6.63 (d, J ) 8.5 Hz, 1H), 7.15 (d, J ) 8.5 Hz, 1H). MS (FAB,
3-NBA): m/z 812 (M, 1), 307 (47), 154 (100), 136 (89). HRMS
(FAB, 3-NBA) calcd for C30H42BrO5S2187Re: 812.1215. Found:
812.1217.
1
Tr ica r bon yl{[6-[3,17â-bis(t-bu tyld im eth ylsila n yloxy)-
estr a -1,3,5(10)-tr ien e-7r-yl]-ca r boh exyloxy]cyclop en ta -
d ien yl}r h en iu m (I) (27). A 0 °C solution of alcohol 13 (15.0
mg, 25.7 µmol), CpTR acid 26 (9.80 mg, 25.7 µmol), EDC (5.42
mg, 28.3 µmol), and a catalytic amount of DMAP in CH2Cl2 (1
mL) was stirred for 30 min and then for 2 h at room
temperature. The volume was reduced, and the residue puri-
fied by flash chromatography (10% EtOAc/Hex) to give 27 as
a colorless oil (21.0 mg, 85%). IR (CHCl3): 2031, 1937 (s, Ct
O), 1727 (s, CdO). 1H NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H),
0.04 (s, 3H), 0.19 (s, 6H), 0.74 (s, 3H), 0.89 (s, 9H), 0.98 (s,
9H), 2.67 (d, J ) 16.7 Hz, 1H), 2.84 (dd, J ) 16.7, 4.9 Hz, 1H),
3.66 (t, J ) 8.2 Hz, 1H), 4.18 (t, J ) 6.7 Hz, 2H), 5.35 (app. t,
J ) 2.3 Hz, 2H), 6.00 (m, 2H), 6.53 (d, J ) 2.4 Hz, 1H), 6.61
(dd, J ) 8.4, 2.4 Hz, 1H), 7.11 (d, J ) 8.4 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): δ -4.78, -4.47, -4.39, 11.38, 18.13, 22.79,
25.45, 25.69, 25.86, 25.98, 27.29, 28.08, 28.55, 29.60, 30.93,
33.26, 34.57, 37.35, 38.24, 41.92, 43.70, 46.07, 65.41, 81.83,
84.79, 84.83, 88.47, 95.43, 117.15, 120.79, 126.66, 132.54,
136.77, 153.18, 163.71, 191.96. MS (FAB, 3-NBA): m/z 962
(M, 11), 437(100), 363 (74), 271 (93), 221 (77). HRMS (FAB,
3-NBA) calcd for C45H66O7Si2187Re: 961.3907. Found: 961.3905.
Tr ica r bon yl{[6-[estr a -1,3,5(10)-tr ien e-3,17â-d iol-7r-yl]-
ca r boh exyloxy]cyclop en ta d ien yl}r h en iu m (I) (4a ). A 40%
solution of HF (300 µL) was added to a solution of ester 27
(50.3 mg, 52.3 µmol) in CH3CN (2 mL) at 50 °C. The solution
became turbid, but the cloudiness disappeared after several
minutes. After 20 min at 50 °C, the reaction was cooled and
concentrated, and the residue was purified by flash chroma-
tography (2.5% MeOH/CH2Cl2) to give 4a as a white foam (35.5
one visible peak. H NMR (CDCl3, 400 MHz): δ 0.78 (s, 3H),
2.69 (d, J ) 16.5 Hz, 1H), 2.86 (dd, J ) 16.5, 5.2 Hz, 1H), 3.30
(q, J ) 6.7 Hz, 2H), 3.75 (t, J ) 8.4 Hz, 1H), 5.09 (s, 1H), 5.36
(t, J ) 2.2 Hz, 2H), 5.64 (t, J ) 5.7 Hz, 1H), 5.86 (m, 2H), 6.55
(d, J ) 2.7 Hz, 1H), 6.64 (dd, J ) 8.5, 2.7 Hz, 1H), 7.15 (d, J
) 8.5 Hz, 1H). MS (FAB, 3-NBA): m/z 733 (M, 3), 279 (30),
155 (100), 136 (97). HRMS (FAB, 3-NBA) calcd for C33H40
-
NO6187Re: 733.2413. Found: 733.2415.
3,17â-Bis(t-bu tyld im eth ylsila n yloxy)-7r-[6-(N-for m yl-
a m in o)-h exa n -1-yl]-estr a -1,3,5(10)-tr ien e (29). A solution
of amine 18 (70.0 mg, 0.120 mmol) and ethylformate (10 mL)
was refluxed for 8 h. Following evaporation of the ethyl
formate, the residue was purified by flash chromatography
(2.5% MeOH/CH2Cl2) to afford 29 as a white foam (52.0 mg,
1
71%). IR (KBr): 1667 (s, CdO). H NMR (CDCl3, 400 MHz):
δ 0.02 (s, 3H), 0.03 (s, 3H), 0.19 (s, 6H), 0.74 (s, 3H), 0.89 (s,
9H), 0.97 (s, 9H), 2.66 (d, J ) 16.6 Hz, 1H), 2.85 (dd, J ) 16.6,
4.6 Hz, 1H), 3.27 (q, J ) 6.8 Hz, 2H), 3.67 (t, J ) 8.0 Hz, 1H),
5.44 (bs, 1H), 6.53 (d, J ) 2.4 Hz, 1H), 6.61 (dd, J ) 8.5, 2.4
Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ -4.78, -4.46, -4.39, 11.38, 18.11, 22.79, 25.42, 25.68,
25.86, 26.82, 27.27, 27.99, 29.45, 29.53, 30.92, 33.26, 34.58,
37.35, 38.15, 38.28, 41.92, 43.70, 46.08, 81.82, 117.17, 120.79,
126.70, 132.54, 136.77, 153.18, 161.06. MS (CI, CH4): m/z 629
(M + H+, 25), 571 (67), 497 (100). HRMS (CI, CH4) calcd for
C
37H66NO3Si2: 628.4581. Found: 628.4566.
Tr is(2-th iola toeth yl)a m in e-{3,17â-bis(t-bu tyld im eth yl-
sila n yloxy)-7r-[6-(isocya n id o)-h exa n -1-yl]-estr a -1,3,5(10)-
tr ien e}-r h en iu m (III) (31). A solution of steroid 29 (32.0 mg,
51.0 µmol), Re(NS)3PPhMe2 (30)48 (17.6 mg, 34 µmol), PPh3
(16.0 mg, 61.0 µmol), Et3N (7.00 mL, 51.0 mmol), and CCl4
(5.00 µL, 51.0 µmol) in CH2Cl2 (1 mL) was refluxed for 4 h.
During this time, the green color of the Re(III) precursor
changed to olive-green. Two consecutive separations by flash
chromatography (1. 20% EtOAc/Hex; 2. 2.5% MeOH/CH2Cl2)
yielded the desired complex 31 as an olive-green foam (27.0
mg, 80%). IR (KBr): 2001 (s, NtC). 1H NMR (CDCl3, 400
MHz): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.19 (s, 6H), 0.73 (s, 3H),
0.89 (s, 9H), 0.97 (s, 9H), 2.68 (d, J ) 16.4 Hz, 1H), 2.82 (dd,
J ) 17.0, 5.2 Hz, 1H), 3.02 (br, 12H), 3.65 (t, J ) 8.3 Hz, 1H),
4.76 (t, J ) 6.3 Hz, 2H), 6.53 (d, J ) 2.3 Hz, 1H), 6.60 (dd, J
) 8.4, 2.6 Hz, 1H), 7.10 (d, J ) 8.4 Hz, 1H). MS (FAB,
3-NBA): m/z 991 (M, 24), 154 (100). HRMS (FAB, 3-NBA) calcd
for C43H75N2O2Si2S3187Re: 990.4087. Found: 990.4083.
1
mg, 93%). IR (KBr): 2031, 1932 (s, CtO), 1723 (s, CdO). H
NMR (CDCl3, 400 MHz): δ 0.78 (s, 3H), 2.70 (d, J ) 16.7 Hz,
1H), 2.86 (dd, J ) 16.7, 5.1 Hz, 1H), 3.76 (t, J ) 8.5 Hz, 1H),
5.07 (bs, 1H), 5.35 (app. t, J ) 2.3 Hz, 2H), 6.00 (app. t, J )
2.2 Hz, 2H), 6.55 (d, J ) 2.7 Hz, 1H), 6.63 (dd, J ) 8.5, 2.7 Hz,
1H), 7.15 (d, J ) 8.5 Hz, 1H). MS (FAB, 3-NBA): m/z 734 (M,
2), 307 (47), 154 (100), 136 (86). HRMS (FAB, 3-NBA) calcd
for C33H30O7187Re: 734.2253. Found: 734.2251.
Tr ica r bon yl{[6-[3,17â-bis(t-bu tyld im eth ylsila n yloxy)-
e st r a -1,3,5(10)-t r ie n e -7r-yl]-h e xyla m id o]cyclop e n t a -
d ien yl}r h en iu m (I) (28). A solution of the amine 18 (42.8 mg,
71.4 µmol), CpTR acid 26 (27.1 mg, 71.4 µmol), and DMAP
(catalytic) in CH2Cl2 (2 mL) was stirred at room temperature
until dissolution was complete. The reaction was then cooled
to 0 °C, and EDC (15.1 mg, 78.5 µmol) was added. The reaction
was stirred for 1 h at 0 °C and then 1 h at room temperature.
The reaction was concentrated, and the residue was purified
by flash chromatography (50% EtOAc/Hex) to give 28 as a
viscous yellow oil (61.0 mg, 89%). IR (CHCl3): 2028, 1933 (s,
Tr is(2-th iola toeth yl)a m in e-{7r-[6-(isocya n id o)-h exa n -
1-yl]-estr a -1,3,5(10)-tr ien e-3,17â-d iol}-r h en iu m (III) (5). A
40% solution of HF (120 µL) was added to a solution of complex
31 (23.0 mg, 23.0 µmol) in CH3CN (1 mL) at 50 °C. After 15
min the solution was loaded onto a silica column and eluted
with 5% MeOH/CH2Cl2 to give 5 as an olive-green solid (14.0
mg, 79%). IR (KBr): 2007 (s, NtC). 1H NMR (CDCl3, 400
MHz): δ 0.77 (s, 3H), 2.72 (d, J ) 16.6 Hz), 2.85 (dd, J ) 16.6,
5.1 Hz, 1H), 3.03 (br, 12H), 3.74 (t, J ) 8.5 Hz, 1H), 4.55 (s,
1H), 4.76 (t, J ) 6.3 Hz, 1H), 6.55 (s, 1H), 6.62 (d, J ) 8.1 Hz,
1H), 7.14 (d, J ) 8.5 Hz, 1H). MS (FAB, 3-NBA): m/z 762 (M,
22), 307 (64), 289 (31), 154 (100), 136 (92). HRMS (FAB,
3-NBA)calcd for C31H47N2O2S3187Re: 762.2357.Found: 762.2355.
1
CtO), 1638 (s, CdO). H NMR (CDCl3, 400 MHz): δ 0.03 (s,
3H), 0.04 (s, 3H), 0.19 (s, 6H), 0.74 (s, 3H), 0.89 (s, 9H), 0.98
(s, 9H), 2.67 (d, J ) 16.6 Hz, 1H), 2.84 (dd, J ) 16.6, 5.1 Hz,
1H), 3.31 (q, J ) 6.7 Hz, 2H), 3.66 (t, J ) 8.2 Hz, 1H), 5.35
(app. t, J ) 2.2 Hz, 2H), 5.71 (t, J ) 5.6 Hz, 1H), 5.86 (app. t,
J ) 2.2 Hz, 2H), 6.53 (d, J ) 2.7 Hz, 1H), 6.61 (dd, J ) 8.5,
2.7 Hz, 1H), 7.11 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ -4.80, -4.48, -4.40, 11.37, 18.10, 22.78, 25.53, 25.67,
25.86, 26.93, 27.27, 28.09, 29.51, 29.66, 30.91, 33.25, 34.59,

8118 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
17â-(t-Bu t yld im et h ylsila n yloxy)-7r-(5-h exen -1-yl)-3-
(m eth oxyeth oxym eth oxy)-estr a -1,3,5(10)-tr ien e (32). A 1
M solution of TBAF in THF (2.00 mL, 2.04 mmol) was added
to a cooled solution (0 °C) of alkene 12 (946 mg, 1.62 mmol) in
THF (10 mL). The reaction was stirred at 0 °C for 5 min and
then room temperature for 15 min. A few drops of water were
added, followed by evaporation of the solvent in vacuo.
Purification of the residue by flash chromatography (30%
EtOAc/Hex) yielded the deprotected product as a white foam
(797 mg, >100%). A portion of this (582 mg, 1.24 mmol) was
redissolved in THF (5 mL) and cooled to 0 °C. NaH (95.6 mg,
2.40 mmol) was added, and the reaction was stirred for 25 min
at 0 °C. MEMCl (274 µL, 2.40 mmol) was then added to the
solution, resulting in a white precipitate of NaCl. The reaction
was warmed to room temperature and stirred overnight. The
reaction was quenched with water, and the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography (1.25% MeOH/CH2Cl2) to yield 32 as an oil
2.73 (d, J ) 16.6 Hz, 1H), 2.87 (dd, J ) 16.6, 5.0 Hz, 1H), 3.39
(s, 3H), 3.43 (t, J ) 6.8 Hz, 2H), 3.57 (m, 4H), 3.66 (m, 11H),
3.83 (m, 2H), 4.57 (s, 2H), 5.24 (s, 2H), 6.77 (d, J ) 2.4 Hz,
1H), 6.85 (dd, J ) 8.5, 2.4 Hz, 1H), 7.19 (d, J ) 8.5 Hz, 1H),
7.30 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ -4.82, -4.50,
11.31, 18.08, 22.74, 25.58, 25.83, 26.16, 27.27, 28.17, 29.61,
29.85, 30.88, 33.16, 34.64, 37.27, 38.10, 41.84, 43.63, 46.00,
58.99, 67.44, 69.36, 69.98, 70.58, 70.61, 71.45, 71.58, 73.18,
81.78, 93.52, 113.67, 117.02, 126.83, 127.53, 127.69, 128.30,
133.39, 137.00, 155.08. MS (FAB, 3-NBA): m/z 796 (M - H,
2), 154 (94), 136 (100). HRMS (FAB, 3-NBA) calcd for C47H75O8-
Si: 795.5231. Found: 795.5223.
17â-(t-Bu tyld im eth ylsila n yloxy)-7r-(15-h yd r oxy-7,10,-
13-tr ioxa -p en ta d eca n -1-yl)-3-(m eth oxyeth oxym eth oxy)-
estr a -1,3,5(10)-tr ien e (36). To a solution of steroid 35 (48.4
mg, 60.6 µmol) in EtOH (1 mL) was added 10% Pd/C (10.0
mg, 9.10 µmol). The reaction flask was evacuated of air and
filled to a pressure of 1 atm with H2. The reaction was stirred
under H2 for 5 h, at which time the EtOH was evaporated in
vacuo, and the residue was purified by flash chromatography
(2.5% to 5% MeOH/CH2Cl2) to yield 36 as a slightly turbid oil
1
(697 mg, 100%). H NMR (CDCl3, 400 MHz): δ 0.06 (s, 3H),
0.07 (s, 3H), 0.77 (s, 3H), 0.92 (s, 9H), 2.05 (q, J ) 6.9 Hz,
2H), 2.76 (d, J ) 16.8 Hz, 1H), 2.90 (dd, J ) 16.8, 5.0 Hz),
3.40 (s, 3H), 3.58 (m, 2H), 3.69 (t, J ) 8.2 Hz, 1H), 3.79 (m,
2H), 4.97 (m, 2H), 5.25 (s, 2H), 5.80 (ddt, J ) 17.1, 10.3, 6.7
Hz, 1H), 6.79 (d, J ) 2.6 Hz, 1H), 6.87 (dd, J ) 8.6, 2.6 Hz,
1H), 7.21 (d, J ) 8.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ
-4.84, -4.53, 11.30, 18.03, 22.73, 25.34, 25.81, 27.27, 27.59,
29.11, 30.87, 33.14, 33.79, 34.64, 37.29, 38.13, 41.86, 43.62,
46.03, 58.92, 67.41, 71.58, 81.79, 93.49, 113.71, 114.17, 117.00,
126.78, 133.28, 136.88, 138.89, 155.10. MS (EI, 70 eV): m/z
557 (M, 67), 499 (57), 89(100). HRMS (EI, 70 eV) calcd for
1
(47.6 mg, 100%). H NMR (CDCl3, 400 MHz): δ 0.02 (s, 3H),
0.03 (s, 3H), 0.73 (s, 3H), 0.89 (s, 9H), 2.53 (bs, 1H), 2.72 (d, J
) 16.8 Hz, 1H), 2.86 (dd, J ) 16.8, 4.6 Hz, 1H), 3.38 (s, 3H),
3.43 (t, J ) 6.8 Hz, 2H), 3.55-3.72 (m, 15H), 3.82 (m, 2H),
5.23 (s, 2H), 6.76 (d, J ) 2.4 Hz, 1H), 6.84 (dd, J ) 8.5, 2.4
Hz, 1H), 7.18 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ -4.83, -4.51, 11.29, 18.06, 22.73, 25.57, 25.82, 26.13,
27.26, 28.15, 29.53, 29.82, 30.86, 33.15, 34.62, 37.26, 38.09,
41.83, 43.61, 45.99, 58.97, 61.68, 67.43, 69.92, 70.29, 70.56,
71.46, 71.57, 72.42, 81.77, 93.51, 113.66, 117.00, 126.80,
133.36, 136.98, 155.05. MS (EI, 70 eV): m/z 707 (M, 1), 630
(76), 89 (72), 59 (100). HRMS (EI, 70 eV) calcd for C40H70O8Si:
706.4840. Found: 706.4847.
C
34H56O4Si: 556.3948. Found: 556.3942.
17â-(t-Bu tyld im eth ylsila n yloxy)-7r-(6-h yd r oxyh exa n -
1-yl)-3-(m et h oxyet h oxym et h oxy)-est r a -1,3,5(10)-t r ien e
(33). A solution of 0.5 M 9-BBN in THF (4.00 mL, 2.00 mmol)
was added to a solution of steroid 32 (226 mg, 0.406 mmol) in
THF (5 mL). After being stirred for 24 h, the reaction was
cooled to 0 °C, and to it was added 3 M KOH (1.5 mL), followed
5 min later by 30% H2O2 (1.5 mL). The mixture was stirred
for 3 h, at which time saturated NaHCO3 (7 mL) was added,
and the solution was stirred 30 min longer. The mixture was
extracted with CH2Cl2 (3 × 15 mL), dried over Na2SO4, and
concentrated to a cloudy oil. This was purified by flash
chromatography (40% EtOAc/Hex) to provide 33 as a colorless,
7r-(15-Am in o-7,10,13-t r ioxa -p en t a d eca n -1-yl)-17â-(t-
b u t yld im et h ylsila n yloxy)-3-(m et h oxyet h oxym et h oxy)-
estr a -1,3,5(10)-tr ien e (37). DIAD (25.0 µL, 125 µmol) was
added dropwise to a cooled solution (0 °C) of PPh3 (32.8 mg,
125 µmol) in THF (0.75 mL). After a precipitate of the ylide
formed, the reaction was stirred for 30 min at 0 °C. A solution
of alcohol 36 (44.2 mg, 62.4 µmol) in THF (0.5 mL) was then
added to the ylide, followed by diphenylphosphoryl azide (27.0
µL, 125 µmol). The reaction was stirred for 30 min at 0 °C
and then and then 3.5 h at room temperature. The reaction
was concentrated and purified by flash chromatography (20%
EtOAc/PhH) to give the azide as a yellow oil contaminated with
a PPh3-like impurity (73.1 mg). This oil was redissolved in
EtOH (1 mL), and to it was added 10% Pd/C (10.0 mg, 9.36
µmol). The flask was evacuated of air and filled to an pressure
of 1 atm with H2. The reaction was stirred under H2 for 8.5 h.
The EtOH was evaporated in vacuo, and the residue was
purified by flash chromatography (eluted first with 40%
EtOAc/Hex and then 20% MeOH/CH2Cl2 with 0.5% Et3N) to
1
viscous oil (191 mg, 82%). H NMR (CDCl3, 400 MHz): δ 0.03
(s, 3H), 0.04 (s, 3H), 0.74 (s, 3H), 0.89 (s, 9H), 2.73 (d, J )
16.8 Hz, 1H), 2.87 (dd, J ) 16.8, 5.1 Hz, 1H), 3.38 (s, 3H),
3.56 (m, 2H), 3.60 (t, J ) 6.7 Hz, 2H), 3.66 (t, J ) 8.2 Hz, 1H),
3.82 (m, 2H), 5.23 (s, 2H), 3.76 (d, J ) 2.6 Hz, 1H), 6.84 (dd,
J ) 8.6, 2.6 Hz, 1H), 7.19 (d, J ) 8.6 Hz, 1H). 13C NMR (CDCl3,
100 MHz): δ -4.85, -4.53, 18.04, 22.71, 25.48, 25.75, 25.80,
27.24, 28.12, 29.71, 30.85, 32.71, 33.15, 34.62, 37.25, 38.11,
41.83, 43.61, 45.99, 58.94, 62.85, 67.41, 71.55, 81.76, 93.49,
113.69, 116.99, 126.80, 133.35, 136.93, 155.04. MS (EI, 70
eV): m/z 575 (M, 8), 498 (40), 441 (53), 133 (46), 89 (78). HRMS
(EI, 70 eV) calcd for C34H58O5Si: 574.4054. Found: 574.4045.
7r-(15-Ben zyloxy-7,10,13-tr ioxa -p en ta d eca n -1-yl)-17â-
(t-bu tyld im eth ylsila n yloxy)-3-(m eth oxyeth oxym eth oxy)-
estr a -1,3,5(10)-tr ien e (35). To a cooled solution (0 °C) of
alcohol 33 (63.2 mg, 0.110 mmol) in CH2Cl2 (1 mL) was added
2,6-lutidine (17.0 µL, 0.143 mmol), followed by triflic anhydride
(22.0 µL, 0.132 mmol). After 15 min, the reaction was diluted
with CH2Cl2 (5 mL), and the reaction was poured into brine
(5 mL). The organic layer was removed and dried over Na2-
SO4. After careful removal of the solvent, the triflate was
placed under high vacuum for 10 min. The triflate was
dissolved in CH2Cl2 (2 mL) and added to a flask containing
10-phenyl-3,6,9-trioxa-decan-1-ol (34)50 (53.1 mg, 0.220 mmol)
at 0 °C. NaH (11.0 mg, 0.275 mmol) was then added, and the
reaction bubbled vigorously. After several minutes, 15-crown-5
(1 drop) was added. The ice bath was removed, and the
reaction was stirred for another 30 min, turning to an orange
color. The reaction was quenched with water, concentrated,
and purified by flash chromatography (40% EtOAc/Hex) to
1
give 37 as a yellow oil (26.1 mg, 60%). H NMR (CDCl3, 400
MHz): δ 0.01 (s, 3H), 0.02 (s, 3H), 0.72 (s, 3H), 0.89 (s, 9H),
2.71 (d, J ) 16.8 Hz, 1H), 2.86 (dd, J ) 16.8, 4.6 Hz, 1H), 2.96
(t, J ) 7.3 Hz, 2H), 3.37 (s, 3H), 3.43 (t, J ) 7.0 Hz, 2H), 3.54-
3.66 (m, 13H), 3.81 (m, 2H), 5.22 (s, 2H), 5.39 (bs, 2H), 6.75
(d, J ) 2.4 Hz, 1H), 6.83 (dd, J ) 8.6, 2.4 Hz, 1H), 7.18 (d, J
) 8.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -4.82, -4.50,
11.29, 18.06, 22.73, 25.57, 25.82, 26.13, 27.25, 28.18, 29.53,
29.84, 30.86, 33.15, 34.62, 37.25, 38.08, 41.82, 43.61, 45.72,
45.99, 58.98, 67.43, 69.82, 70.14, 70.40, 70.46, 71.43, 71.57,
81.76, 93.51, 113.66, 117.02, 126.81, 133.38, 136.98, 155.05.
MS (CI, CH4): m/z 707 (M + H+, 100). HRMS (EI, 70 eV) calcd
for C40H71NO7Si: 705.5000. Found: 705.5008.
Tr ica r b on yl{[15-[17â-(t-b u t yld im et h ylsila n yloxy)-3-
(m et h oxyet h oxym et h oxy)-est r a -1,3,5(10)-t r ien e-7r-yl]-
3,6,9-tr ioxa-pen tadecylam ido]cyclopen tadien yl}r h en iu m -
(I) (38). A solution of amine 37 (13.6 mg, 19.3 µmol), CpTR
acid 26 (12.3 mg, 32.4 µmol), and DMAP (catalytic) in CH2Cl2
(2 mL) was stirred at room temperature until just dissolved.
To the solution was added EDC (6.00 mg, 33.8 µmol), and the
reaction was stirred for 45 min at room temperature. The
reaction was concentrated and purified by flash chromatog-
1
afford 35 as a yellow oil (51.5 mg, 59%). H NMR (CDCl3, 400
MHz): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.74 (s, 3H), 0.90 (s, 9H),

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8119
raphy (EtOAc) to give 38 as a viscous colorless oil (17.3 mg,
84%). 1H NMR (CDCl3, 400 MHz): δ 0.02 (s, 3H), 0.03 (s, 3H),
0.73 (s, 3H), 0.89 (s, 9H), 2.72 (d, J ) 16.8 Hz, 1H), 2.87 (dd,
J ) 16.8, 4.6 Hz, 1H), 3.38 (s, 3H), 3.43 (t, J ) 6.8 Hz, 2H),
3.51-3.68 (m, 15H), 3.82 (m, 2H), 5.23 (s, 2H), 5.33 (t, J ) 2.2
Hz, 2H), 5.97 (t, J ) 2.2 Hz, 2H), 6.58 (m, 1H), 6.76 (d, J )
2.6 Hz, 1H), 6.84 (dd, J ) 8.5, 2.6 Hz, 1H), 7.19 (d, J ) 8.5 Hz,
1H). 13C NMR (CDCl3, 100 MHz): δ -4.82, -4.49, 11.31, 18.09,
22.75, 25.60, 25.83, 26.16, 27.27, 28.20, 29.57, 29.85, 30.89,
33.18, 36.64, 37.28, 38.11, 39.73, 41.84, 43.64, 46.01, 59.01,
67.46, 69.61, 69.91, 70.36, 70.47, 70.51, 71.50, 71.58, 81.79,
84.62, 85.99, 93.55, 95.24, 113.70, 117.03, 126.86, 133.40,
136.99, 155.08, 162.05, 192.57. MS (FAB, 3-NBA): m/z 1068
(M, 1), 406 (61), 136 (100). HRMS (FAB, 3-NBA) calcd for
m/z 495 (M + H+, 33), 411 (100), 85 (86). HRMS (CI, CH4)
calcd for C31H43O5: 495.3110. Found: 495.3103.
7r-(2-P r op en -1-yl)-estr a -1,3,5(10)-tr ien e-3,17â-d iol (40).
Acetyl chloride (20 drops) was added to a solution of ketone
39 (1.70 g, 3.43 mmol) in a minimum amount of MeOH. After
1 h, saturated NaHCO3 was added until neutral, and the
MeOH was evaporated in vacuo. The residue was diluted with
CH2Cl2 and EtOAc and then was passed through a plug of
silica and Na2SO4. The filtrate was evaporated in vacuo, and
the residue was dissolved in CH2Cl2 (100 mL). To this solution
was added Et3SiH (15 mL), followed by BF3‚OEt2 (60 mL)
dropwise. After 1 h, a white precipitate was evident. The
reaction was stirred for 2 days, cooled to 0 °C, and quenched
with 10% K2CO3 (100 mL). The heterogeneous solution was
filtered through a short silica plug, and the organic layer
separated. The aqueous layer was extracted two more times
with CH2Cl2 (50 mL each). The organic fractions were com-
bined, dried over Na2SO4, and evaporated in vacuo to a yellow
solid. Purification by flash chromatography (40% EtOAc/Hex)
C
49H75NO11Si187Re: 1068.4667. Found: 1068.4670.
Tr ica r b on yl{[15-(est r a -1,3,5(10)-t r ien e-3,17â-d iol-7r-
yl)-3,6,9-t r ioxa -p e n t a d e cyla m id o]cyclop e n t a d ie n yl}-
r h en iu m (I) (6). A 40% solution of HF (150 µL) was added to
a solution of the amide 38 (12.3 mg, 11.5 µmol) in CH3CN (1
mL) and THF (250 µL) at 60 °C, resulting in a turbid solution
which became clear after several seconds. After 15 min at 60
°C, the reaction was cooled and quenched with NaHCO3 (1 mL
saturated and then solid NaHCO3 until neutral). The mixture
was extracted with CH2Cl2 (3 × 3 mL) and evaporated in
vacuo. The residue was purified by flash chromatography (5%
MeOH/CH2Cl2) to give a clear residue (7.40 mg, 74%). A foam
was obtained by rapid evaporation from an acetone solution.
IR (KBr): 2025, 1926 (s, CtO), 1647 (CdO). 1H NMR (CDCl3,
400 MHz): δ 0.78 (s, 3H), 2.70 (d, J ) 16.6 Hz, 1H), 2.84 (dd,
J ) 16.6, 4.6 Hz, 1H), 3.30-3.71 (m, 14H), 3.74 (t, J ) 8.4 Hz,
1H), 5.32 (t, J ) 2.3 Hz, 2H), 5.99 (m, 2H), 6.37 (bs, 1H), 6.57
(d, J ) 2.4 Hz, 1H), 6.65 (dd, J ) 8.4, 2.4 Hz, 1H), 6.85 (m,
1H), 7.14 (d, J ) 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ
11.12, 22.62, 24.78, 25.35, 27.21, 27.36, 29.08, 29.15, 30.51,
33.30, 34.73, 36.89, 38.30, 39.80, 42.02, 43.38, 46.48, 69.70,
69.76, 70.15, 70.47, 70.52, 71.53, 81.98, 84.66, 84.75, 85.99,
86.20, 95.04, 113.03, 116.22, 127.04, 131.41, 136.93, 153.72,
1
provided 40 as a white foam (587 mg, 83%). H NMR (CDCl3,
400 MHz): δ 0.79 (s, 3H), 2.72 (d, J ) 16.5 Hz, 1H), 2.83 (dd,
J ) 16.5, 5.1 Hz, 1H), 3.76 (t, J ) 8.5 Hz, 1H), 4.93 (dd, J )
16.5, 1.2 Hz, 1H), 4.97 (d, J ) 10.1 Hz, 1H), 5.43 (bs, 1H),
5.78 (dddd, J ) 16.9, 10.1, 8.0, 5.8 Hz, 1H), 6.54 (d, J ) 2.7
Hz, 1H), 6.64 (dd, J ) 8.5, 2.7 Hz, 1H), 7.15 (d, J ) 8.5 Hz,
1H). 13C NMR (CDCl3, 100 MHz): δ 11.09, 22.50, 27.18, 30.32,
30.51, 32.94, 33.87, 36.77, 38.01, 41.51, 43.36, 46.41, 82.01,
112.93, 115.84, 116.13, 126.95, 131.29, 136.65, 137.99, 153.66.
MS (CI, CH4): m/z 313 (M + H+, 100), 295 (69). HRMS (EI,
70 eV) calcd for C21H28O2: 312.2089. Found: 312.2094. Anal.
Calcd for C21H28O2‚0.3H2O: C, 79.35; H, 9.07. Found: C, 79.39;
H, 9.22.
3,17â-Bis(t-b u t yld im et h ylsila n yloxy)-7r-(2-p r op en -1-
yl)-estr a -1,3,5(10)-tr ien e (41). A solution of TBSCl (1.27 g,
8.45 mmol) in DMF (5 mL) was added to a cooled solution (0
°C) of imidazole (1.28 g, 18.8 mmol) in DMF (10 mL). The
reaction was warmed to room temperature for 30 min. A
solution of diol 40 (587 mg, 1.88 mmol) was then added to the
TBSCl mixture, and the reaction was stirred overnight. The
DMF was removed in vacuo, and the residue was diluted with
0.1% K2CO3 (50 mL) and extracted with CH2Cl2 (3 × 50 mL).
The organic fractions were passed through a silica plug and
then evaporated in vacuo to yield 41 as a yellow oil (917 mg,
90%). 1H NMR (CDCl3, 500 MHz): δ 0.03 (s, 3H), 0.04 (s, 3H),
0.18 (s, 6H), 0.75 (s, 3H), 0.89 (s, 9H), 0.97 (s, 9H), 2.70 (d, J
) 16.5 Hz, 1H), 2.81 (dd, J ) 16.5, 5.2 Hz, 1H), 3.65 (t, J )
8.3 Hz, 1H), 4.91 (d, J ) 17.0 Hz, 1H), 4.97 (d, J ) 10.1 Hz,
1H), 5.78 (dddd, J ) 17.0, 10.1, 8.1, 5.8 Hz, 1H), 6.52 (d, J )
2.4 Hz, 1H), 6.61 (dd, J ) 8.4, 2.4 Hz, 1H), 7.11 (d, J ) 8.4 Hz,
1H). 13C NMR (CDCl3, 125 MHz): δ -4.85, -4.54, -4.48,
11.34, 18.05, 18.10, 22.66, 25.61, 25.64, 25.81, 27.23, 30.48,
30.87, 33.02, 33.93, 37.31, 38.29, 41.55, 43.72, 46.12, 81.78,
115.65, 117.27, 120.84, 126.64, 132.30, 136.43, 138.18, 153.28.
MS (EI, 70 eV): m/z 541 (M, 100), 483 (72), 407 (78). HRMS
(EI, 70 eV) calcd for C33H56O2Si2: 540.3818. Found: 540.3814.
3,17â-Bis(t-bu tyldim eth ylsilan yloxy)-7r-(3-h ydr oxypr o-
p a n -1-yl)-estr a -1,3,5(10)-tr ien e (42). A 0.5 M solution of
9-BBN in THF (17.0 mL, 8.50 mmol) was added to a solution
of steroid 41 (917 mg, 1.70 mmol) in THF (20 mL). After 3
days, the reaction was cooled to 0 °C and quenched with 3 M
KOH (10 mL), followed by 30% H2O2 (10 mL) after 5 min. After
the reaction was stirred for 3 h, saturated NaHCO3 (50 mL)
was added, and the mixture was extracted with CH2Cl2 (3 ×
40 mL). The organic fractions were dried over Na2SO4 and
evaporated in vacuo, and the residue was purified by flash
chromatography (20% to 60% EtOAc/Hex) to provide 42 as a
viscous oil (625 mg, 67%). The 3-deprotected compound was
also isolated (169 mg, 0.380 mmol). Corrected yield of 42 is
162.36, 192.60. MS (FAB, 3-NBA): m/z 866 (M + H, 0.5), 154
187
(100), 136 (87). HRMS (FAB, 3-NBA) calcd for C39H53NO9
Re: 866.3278. Found: 866.3280.
-
3,17â-Bis(2-tetr a h yd r op yr a n yloxy)-7r-(2-p r op en -1-yl)-
estr a -1,3,5(10)-tr ien e-6-on e (39). A 1 M solution of KOt-Bu
in THF (3.10 mL, 3.07 mmol) was added to a cooled solution
(0 °C) of ketone 8 (1.27 g, 2.79 mmol) in THF (50 mL). The
reaction was stirred at 0 °C for 40 min and then cooled to -78
°C. Allyl iodide (255 µL, 2.79 mmol) was then added dropwise
to the solution. After 10 min, the reaction was quenched with
water and warmed to room temperature. The solvents were
removed in vacuo, redissolved in ether, and then passed
through a plug of silica. After the solvent was evaporated in
vacuo, the residue was dissolved in MeOH (50 mL), and to
this was added several small pieces of sodium. The mixture
was stirred for 4 h at room temperature. After the reaction
was quenched with water, the MeOH was evaporated, and the
product was extracted from water with ether. The solvents
were evaporated in vacuo, and the residue was purified by
flash chromatography (10% EtOAc/Hex with 1% Et3N) to give
39 as a white foam (230 mg, 8 ) 1.00 g, 77% corrected yield).
This process can be repeated several times to provide 1.70 g
of 39 for subsequent reactions. 1H NMR (CDCl3, 400 MHz): δ
0.77, 0.79 (2s, 3H), 2.30-2.42 (m, 2H), 2.50-2.55 (m, 1H),
2.65-2.72 (m, 1H), 3.43-3.48 (m, 1H), 3.55-3.58 (m, 1H), 3.71,
3.74 (2t, J ) 8.2 Hz, 1H), 3.82-3.90 (m, 2H), 4.60-4.66 (m,
1H), 4.88-4.96 (m, 2H), 5.41-5.44 (m, 1H), 5.70-5.81 (m, 1H),
7.18, 7.19 (2dd, J ) 8.5, 2.7 Hz, 1H), 7.28, 7.30 (2d, J ) 8.5
Hz, 1H), 7.66 (2d, J ) 2.7 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ 11.32, 11.35; 18.63, 18.68; 19.20, 19.57; 22.04, 22.15;
25.00; 25.36, 25.45; 26.45, 26.84; 28.44, 28.67, 28.75; 30.07,
30.12; 30.83, 30.90; 36.74, 37.26; 37.16, 37.23; 41.89, 41.94;
41.98, 42.02; 42.66, 43.14; 45.12, 45.23; 48.77, 48.84, 48.92;
61.73, 61.96; 62.04, 62.40; 83.63, 86.09; 96.04, 96.27; 96.47,
99.15; 114.41, 114.52; 116.24; 122.19, 122.30; 126.83, 126.88,
126.92; 132.12, 132.15; 135.57, 135.60; 139.05, 139.18; 155.33,
155.36, 155.42, 155.44; 199.53, 199.60, 199.64. MS (CI, CH4):
1
86%. H NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H), 0.05 (s, 3H),
0.20 (s, 6H), 0.76 (s, 3H), 0.90 (s, 9H), 0.99 (s, 9H), 2.69 (d, J
) 16.6 Hz, 1H), 2.89 (dd, J ) 16.6, 5.2 Hz, 1H), 3.59 (t, J )
6.6 Hz, 2H), 3.66 (t, J ) 8.3 Hz, 1H), 6.54 (d, J ) 2.4 Hz, 1H),
6.62 (dd, J ) 8.3, 2.4 Hz, 1H), 7.12 (d, J ) 8.3 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ -4.80, -4.48, -4.39, 11.37, 18.10,
18.12, 21.73, 22.77, 25.64, 25.68, 25.86, 27.29, 30.91, 31.36,

8120 J . Org. Chem., Vol. 64, No. 22, 1999
Skaddan et al.
33.22, 34.58, 37.36, 38.26, 41.95, 43.72, 46.08, 63.22, 81.81,
117.27, 120.79, 126.71, 132.39, 136.44, 153.26. MS (EI, 70
eV): m/z 558 (M, 15), 91 (58), 75 (100). HRMS (EI, 70 eV) calcd
for C33H58O3Si2: 558.3924. Found: 558.3923.
MHz): δ -4.82, -4.50, 11.33, 18.06, 21.87, 22.72, 25.82, 27.33,
28.07, 30.86, 33.08, 34.49, 37.24, 38.11, 41.91, 43.68, 46.01,
61.70, 71.52, 71.68, 81.75, 112.94, 116.08, 127.03, 131.57,
136.69, 153.68. MS (CI, CH4): m/z 489 (M + H+, 29), 427 (74),
295 (100). HRMS (EI, 70 eV) calcd for C29H49O4Si: 488.3322.
Found: 488.3316. Anal. Calcd for C29H48O4Si‚H2O: C, 68.73;
H, 9.94. Found: C, 68.82; H, 9.89.
3-(Ben zyloxy)-17â-(t-b u t yld im et h ylsila n yloxy)-7r-(3-
h yd r oxyp r op a n -1-yl)-estr a -1,3,5(10)-tr ien e (43). A 1 M
solution of TBAF in THF (0.910 mL, 0.910 mmol) was added
to a cooled solution (0 °C) of steroid 42 (391 mg, 0.699 mmol)
in THF (10 mL). The yellow solution was stirred for 5 min at
0 °C and then 15 min at room temperature. The THF was
removed in vacuo, and the residue was passed through a silica
plug with 5% MeOH/CH2Cl2. The filtrate was then evaporated
to a yellow foam. The foam was dissolved in acetone (28 mL),
and to it were added BnBr (106 µL, 0.893 mmol), K2CO3 (823
mg, 5.95 mmol), and 18-crown-6 (59.0 mg, 0.223 mmol). The
mixture was refluxed for 16 h, then cooled, and filtered. The
filtrate was concentrated, and the residue was purified by flash
chromatography (20% EtOAc/Hex) to give 43 as a colorless oil
7r-(6-Azid o-4-oxa -h exa n -1-yl)-17â-(t-b u t yld im et h ylsi-
la n yloxy)-estr a -1,3,5(10)-tr ien e-3-ol (47). DIAD (78.0 µL,
0.395 mmol) was added to a cooled solution (0 °C) of PPh3 (104
mg, 0.395 mmol) in THF (1 mL). After the reaction was stirred
for 30 min at 0 °C, a solution of alcohol 46 (77.3 mg, 0.158
mmol) and diphenylphosphoryl azide (85.0 µL, 0.395 mmol)
in THF (1 mL) was added to the ylide. The reaction was stirred
for 1 h at 0 °C and then overnight at room temperature. The
mixture was then concentrated, and the residue was purified
by flash chromatography (2.5% EtOAc/PhH) to yield 47 as a
1
yellow oil (60.2 mg, 74%). H NMR (CDCl3, 400 MHz): δ 0.03
1
(417 mg, 100%). H NMR (CDCl3, 400 MHz): δ 0.06 (s, 3H),
(s, 3H), 0.04 (s, 3H), 0.74 (s, 3H), 0.90 (s, 9H), 2.70 (d, J )
16.8 Hz, 1H), 2.88 (dd, J ) 16.8, 4.9 Hz, 1H), 3.35 (t, J ) 4.9
Hz, 2H), 3.44 (t, J ) 6.6 Hz, 2H), 3.58 (t, J ) 4.9 Hz, 2H), 3.65
(t, J ) 8.2 Hz, 1H), 4.97 (bs, 1H), 6.54 (d, J ) 1.7 Hz, 1H),
6.63 (dd, J ) 8.3, 1.7 Hz, 1H), 7.15 (d, J ) 8.3 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ -4.82, -4.50, 11.32, 18.08, 21.84,
22.71, 25.83, 27.33, 28.09, 30.87, 32.98, 34.44, 37.24, 38.06,
41.90, 43.65, 45.94, 50.70, 69.50, 71.52, 81.77, 112.81, 116.05,
127.08, 132.02, 136.88, 153.28. MS (CI, CH4): m/z 514 (M +
H+, 22), 498 (41), 486 (80), 456 (100). HRMS (EI, 70 eV) calcd
for C29H47N3O3Si: 513.3387. Found: 513.3391.
0.07 (s, 3H), 0.78 (s, 3H), 0.92 (s, 9H), 2.76 (d, J ) 16.6 Hz,
1H), 2.95 (dd, J ) 16.6, 5.1 Hz, 1H), 3.61 (t, J ) 6.5 Hz, 2H),
3.68 (t, J ) 8.3 Hz, 1H), 5.04 (s, 2H), 6.73 (d, J ) 2.6 Hz, 1H),
6.81 (dd, J ) 8.7, 2.6 Hz, 1H), 7.23 (d, J ) 8.7 Hz, 1H), 7.32-
7.46 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ -4.83, -4.51,
11.31, 18.06, 21.71, 22.72, 28.83, 27.30, 30.85, 31.29, 33.14,
34.68, 37.25, 38.10, 41.89, 43.66, 45.98, 63.13, 69.83, 81.75,
113.34, 115.55, 126.89, 127.44, 127.80, 128.47, 132.22, 136.59,
137.23, 156.68. MS (CI, CH4): m/z 534 (M, 46), 91 (100). HRMS
(EI, 70 eV) calcd for C34H50O3Si: 534.3529. Found: 534.3519.
Anal. Calcd for C34H50O3Si‚0.7H2O: C, 74.59; H, 9.46. Found:
C, 74.66; H, 9.61.
7r-(6-Azid o-4-oxa -h exa n -1-yl)-17â-(t-b u t yld im et h ylsi-
la n yloxy)-3-(m e t h oxye t h oxym e t h oxy)-e st r a -1,3,5(10)-
tr ien e (48). NaH (5.07 mg, 127 µmol) was added to a cooled
solution (0 °C) of azide 47 (21.7 mg, 42.2 µmol) in THF (0.8
mL). After the reaction was stirred for 20 min at 0 °C, MEMCl
(10.0 µL, 84.4 µmol) was added to the yellow solution, and the
reaction was gradually warmed to room temperature over the
course of 2.5 h. The yellow color gradually dissipated, and a
white precipitate of NaCl formed. One drop of water was added
to quench excess NaH, then the reaction was concentrated,
and the residue was purified by flash chromatography (1.25%
MeOH/CH2Cl2) to give 48 as a colorless oil (24.4 mg, 96%). 1H
NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H), 0.04 (s, 3H), 0.74 (s,
3H), 0.89 (s, 9H), 2.74 (d, J ) 16.8 Hz, 1H), 2.91 (dd, J ) 16.8,
4.9 Hz, 1H), 3.35 (m, 2H), 3.39 (s, 3H), 3.43 (m, 2H), 3.57 (m,
4H), 3.65 (t, J ) 8.2 Hz, 1H), 3.83 (m, 2H), 5.24 (s, 2H), 6.77
(d, J ) 2.3 Hz, 1H), 6.85 (dd, J ) 8.5, 2.3 Hz, 1H), 7.20 (d, J
) 8.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -4.83, -4.50,
11.30, 18.07, 21.84, 22.70, 25.83, 27.27, 28.12, 30.86, 32.99,
34.54, 37.24, 38.08, 41.83, 43.64, 45.94, 50.72, 59.00, 67.45,
69.51, 71.47, 71.58, 81.76, 93.52, 113.78, 117.01, 126.88,
131.30, 136.72, 155.10. MS (CI, CH4): m/z 601 (M, 46), 574
(45), 498 (100). HRMS (EI, 70 eV) calcd for C33H55N3O5Si:
601.3911. Found: 601.3917.
3-(Ben zyloxy)-7r-(6-b en zyloxy-4-oxa -h exa n -1-yl)-17â-
(t-bu tyld im eth ylsila n yloxy)-estr a -1,3,5(10)-tr ien e (45). To
a cooled solution (0 °C) of alcohol 43 (100 mg, 0.189 mmol) in
CH2Cl2 (2 mL) was added 2,6-lutidine (28.6 µL, 0.246 mmol),
followed by triflic anhydride (38.0 µL, 0.227 mmol). Another
reaction flask using the exact same quantities of reagents was
also run at the same time. After 15 min each reaction was
diluted with CH2Cl2 (5 mL) and poured separately into brine
(5 mL). The organic layer was dried over Na2SO4; the solution
was kept at 0 °C. The CH2Cl2 was carefully evaporated,
followed by drying of both sets of triflates under high vacuum
for 10 min. Each triflate residue was dissolved in CH2Cl2 (1
mL) and added to a flask containing 2-benzyloxyethanol (44)50
(115 mg, 0.756 mmol) at 0 °C. To this solution was added NaH
(45.2 mg, 1.13 mmol), followed by 15-crown-5 (several drops).
The reaction was stirred for 2 h, then quenched with water,
concentrated, and purified by flash chromatography (10%
EtOAc/Hex) to give 45 as a colorless oil (148 mg, 59%). 1H NMR
(CDCl3, 400 MHz): δ 0.05 (s, 3H), 0.06 (s, 3H), 0.77 (s, 3H),
0.92 (s, 9H), 2.77 (d, J ) 16.8 Hz, 1H), 2.94 (dd, J ) 16.8, 5.0
Hz, 1H), 3.45 (m, 2H), 3.61 (m, 4H), 3.66 (t, J ) 8.3 Hz, 1H),
4.58 (s, 2H), 5.04 (s, 2H), 6.72 (d, J ) 2.4 Hz, 1H), 6.80 (dd, J
) 8.6, 2.4 Hz, 1H), 7.22 (d, J ) 8.6 Hz, 1H), 7.27-7.46 (m,
10H). 13C NMR (CDCl3, 100 MHz): δ -4.82, -4.50, 11.32,
18.08, 21.93, 22.70, 25.83, 27.32, 28.12, 30.89, 33.05, 34.67,
37.26, 38.09, 41.90, 43.68, 46.00, 69.27, 69.85, 70.15, 71.57,
73.15, 81.76, 112.36, 115.51, 126.88, 127.46, 127.52, 127.66,
127.80, 128.30, 128.49, 132.26, 136.71, 137.26, 138.24, 156.68.
MS (EI, 70 eV): m/z 669 (M, 3), 577 (36), 91 (100). HRMS (EI,
70 eV) calcd for C43H60O4Si: 668.4247. Found: 668.4254.
17â-(t-Bu tyld im eth ylsila n yloxy)-7r-(6-h yd r oxy-4-oxa -
h exa n -1-yl)-estr a -1,3,5(10)-tr ien e-3-ol (46). To a solution of
steroid 45 (147 mg, 0.220 mmol) in EtOAc (2 mL) and EtOH
(1.5 mL) was added 10% Pd/C (35.0 mg, 33.0 µmol). The flask
was evacuated of air and filled to a pressure of 1 atm with H2.
The reaction was stirred under H2 for 6 h. The solvents were
removed in vacuo, and the residue was purified by flash
chromatography (40% EtOAc/Hex) to give 46 as a white solid
(78.3 mg, 73%). 1H NMR (CDCl3, 400 MHz): δ 0.03 (s, 3H),
0.04 (s, 3H), 0.74 (s, 3H), 0.89 (s, 9H), 2.69 (d, J ) 16.6 Hz,
1H), 2.87 (dd, J ) 16.6, 4.9 Hz, 1H), 3.43 (m, 2H), 3.51 (t, J )
4.5 Hz, 2H), 3.65 (t, J ) 8.2 Hz, 1H), 3.71 (t, J ) 4.5 Hz, 2H),
6.11 (bs, 1H), 6.53 (d, J ) 2.4 Hz, 1H), 6.63 (dd, J ) 8.4, 2.4
Hz, 1H), 7.13 (d, J ) 8.4 Hz, 1H). 13C NMR (CDCl3, 100
7r-(6-Am in o-4-oxa -h exa n -1-yl)-17â-(t-bu tyld im eth ylsi-
la n yloxy)-3-(m e t h oxye t h oxym e t h oxy)-e st r a -1,3,5(10)-
tr ien e (49). To a solution of azide 48 (59.5 mg, 98.9 µmol) in
EtOAc (0.5 mL) and EtOH (1 mL) was added 10% Pd/C (15.8
mg, 14.8 µmol). The flask was evacuated of air and filled to a
pressure of 1 atm with H2. After the reaction was stirred under
H2 overnight, the solvent was evaporated in vacuo, and the
residue was purified by flash chromatography (10% MeOH/
1
CH2Cl2) to provide 49 as a yellow oil (54.7 mg, 96%). H NMR
(CDCl3, 400 MHz): δ 0.01 (s, 3H), 0.02 (s, 3H), 0.72 (s, 3H),
0.88 (s, 9H), 2.71 (d, J ) 16.6 Hz, 1H), 2.85 (t, J ) 7.0 Hz,
2H), 2.89 (dd, J ) 16.6, 4.9 Hz, 1H), 3.37 (s, 3H), 3.39 (m, 4H),
3.55 (m, 2H), 3.64 (t, J ) 8.2 Hz, 1H), 5.22 (s, 2H), 6.75 (s,
1H), 6.83 (d, J ) 8.5 Hz, 1H), 7.17 (d, J ) 8.5 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ -4.83, -4.55, 11.26, 18.01, 21.87,
22.65, 25.77, 27.22, 28.06, 30.82, 32.99, 34.50, 37.19, 38.05,
41.55, 41.77, 43.60, 49.95, 58.92, 67.39, 71.21, 71.51, 72.24,
81.69, 93.44, 113.74, 116.95, 126.83, 133.18, 136.64, 155.05.
MS (CI, CH4): m/z 576 (M + H+, 100), 560 (26), 500 (27).
HRMS (EI, 70 eV) calcd for C33H57NO5Si: 575.4006. Found:
575.3999.

Re-Containing 7R-Substituted Estradiol Complexes
J . Org. Chem., Vol. 64, No. 22, 1999 8121
Tr ica r b on yl{[6-[17â-(t -b u t yld im e t h ylsila n yloxy)-3-
(m eth oxyeth oxym eth oxy)-estr a -1,3,5(10)-tr ien e-7r-yl]-3-
oxa -h exyla m id o]cyclop en ta d ien yl}r h en iu m (I) (50). A so-
lution of the amine 49 (24.6 mg, 42.7 µmol), CpTR acid 26 (16.2
mg, 42.7 µmol), and DMAP (catalytic) in CH2Cl2 (2 mL) was
stirred at room temperature until just dissolved. To the
solution was added EDC (10.6 mg, 55.5 µmol), and the reaction
was stirred overnight at room temperature. The reaction was
concentrated and purified by flash chromatography (50%
EtOAc/Hex) to give 50 as a viscous colorless oil (32.0 mg, 80%).
IR (NaCl, CH2Cl2): 2027, 1941 (s, CtO), 1662 (s, CdO). 1H
NMR (CDCl3, 400 MHz): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.73 (s,
3H), 0.89 (s, 9H), 2.73 (d, J ) 16.8 Hz, 1H), 2.91 (dd, J ) 16.8,
4.9 Hz, 1H), 3.38 (s, 3H), 3.41 (m, 6H), 3.56 (m, 2H), 3.65 (t, J
) 8.1 Hz, 1H), 3.82 (m, 2H), 5.23 (s, 2H), 5.34 (m, 2H), 5.82
(m, 2H), 6.08 (bs, 1H), 6.71 (s, 1H), 6.85 (d, J ) 8.5 Hz, 1H),
7.19 (d, J ) 8.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ -4.47,
11.34, 18.09, 22.11, 22.75, 25.84, 27.30, 28.21, 30.90, 33.19,
34.63, 37.26, 38.14, 39.44, 41.82, 43.70, 46.05, 59.01, 67.51,
68.99, 71.54, 71.58, 81.76, 84.59, 84.86, 85.68, 85.94, 93.55,
94.87, 113.88, 117.05, 126.93, 133.28, 136.72, 155.12, 162.08,
192.39. MS (FAB, 3-NBA): m/z 936 (M + H, 10), 862 (74), 406
determined by reverse-phase HPLC following the method
outlined by Minick.54 A Chromegabond C8 (5 mm, 60 Å, ES
Industries) 15 cm × 4.6 mm column served as the stationary
phase. The organic mobile phase was methanol containing
0.25% (v/v) 1-octanol, and the aqueous phase consisted of
octanol-saturated water containing 0.25% (v/v) M MOPS (3-
morpholinopropanesulfonic acid, Sigma) buffer and 0.15% (v/
v) n-decylamine, adjusted to pH 7.4. The flow rate was 1 mL/
min.
Estr ogen Recep tor Bin d in g Affin ity. Receptor binding
affinity (RBA) values were determined by a competitive
radiometric binding assay, using tritiated estradiol as the
tracer and lamb uterus cytosol as the source of receptor,
according to a previously established method.55
Ack n ow led gm en t. We are grateful for the support
of this research through grants from the Department
of Energy (DE FG02 86ER60401), the National Insti-
tutes of Health (PHS 5 R01 CA25836), and the Deutsche
Forschungsgemeinschaft and Deutscher Akademischer
Austauschdienst. The assistance of Ms. Kathryn E.
Carlson in the receptor binding experiments is appreci-
ated. NMR experiments were performed in the Varian
Oxford Instrument Center for Excellence NMR Labora-
tory (VOICE NMR Lab), in part funded by grants from
the National Institutes of Health (PHS 1 S10 RR1044-
01), the National Science Foundation (NSF CHE 96-
0152), and the Keck Foundation. Mass spectral data
were acquired on spectrometers purchased with funds
in part from the Division of Research Resources, Na-
tional Institutes of Health (RR 01575 and RR 04648),
the National Science Foundation (PCM 8121494), and
the National Institute of General Medical Sciences
(GM27029).
(100), 363 (80), 135 (53). HRMS (FAB, 3-NBA) calcd for C42H59
-
NO9Si185Re: 934.3489. Found: 934.3477.
Tr ica r bon yl{[6-(estr a -1,3,5(10)-tr ien e-3,17â-d iol-7r-yl)-
3-oxa -h exyla m id o]cyclop en ta d ien yl}r h en iu m (I) (7). The
reaction was performed and purified in the same manner as
that for 6, using 13.2 mg (14.1 µmol) of amide 50. The final
product 7 was isolated as a yellow oil (7.60 mg, 73%), which
could be converted into a foam by quickly evaporating a
1
solution of it in acetone. H NMR (CDCl3, 400 MHz): δ 0.78
(s, 3H), 2.71 (d, J ) 16.8 Hz, 1H), 2.90 (dd, J ) 16.8, 4.9 Hz,
1H), 3.40 (m, 6H), 3.73 (t, J ) 8.2 Hz, 1H), 5.35 (s, 2H), 5.59
(bs, 1H), 5.82 (m, 2H), 6.17 (bs, 1H), 6.55 (d, J ) 2.2 Hz, 1H),
6.64 (dd, J ) 8.5, 2.2 Hz, 1H), 7.14 (d, J ) 8.5 Hz, 1H). 13C
NMR (CDCl3, 100 MHz): δ 11.09, 22.16, 22.61, 27.24, 28.16,
30.45, 33.21, 34.53, 36.82, 38.02, 39.44, 41.88, 43.37, 46.41,
69.05, 71.56, 81.92, 84.70, 84.90, 85.78, 85.96, 94.65, 112.97,
116.11, 127.11, 131.54, 136.76, 153.58, 162.26, 192.41. MS
(FAB, 3-NBA): m/z 736 (M + H, 11), 503 (406), 154 (100), 137
(92). HRMS (FAB, 3-NBA) calcd for C32H39NO7187Re: 736.2284.
Found: 736.2280.
J O990641G
(54) Minick, D. J .; Frenz, J . H.; Patrick, M. A.; Brent, D. A. J . Med.
Chem. 1988, 31, 1923.
(55) Katzenellenbogen, J . A.; J ohnson, H. J ., J r.; Myers, H. N.
Biochemistry 1973, 12, 4085.
Mea su r em en t of th e Octa n ol/Wa ter P a r tition Coef-
ficien t. The log Po/w values were estimated from log k′w values