Synthesis of enantiopure estrone via a double heck reaction

Article abstract of DOI:10.1021/ja981539o

A novel efficient catalytic approach to steroids by a double Heck reaction of the vinyl bromides 2 and the CD-building block 3 is presented. The new estrogen analogues 1a and 1b are formed via 23a and 23b in a highly regio- and stereoselective manner in g

Full text of DOI:10.1021/ja981539o

J. Am. Chem. Soc. 1998, 120, 8971-8977
8971
Synthesis of Enantiopure Estrone via a Double Heck Reaction
Lutz F. Tietze,* Thomas No1bel, and Maurus Spescha
Contribution from the Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t, Tammannstrasse 2,
D-37077 Go¨ttingen, Germany
ReceiVed May 4, 1998
Abstract: An novel efficient catalytic approach to steroids by a double Heck reaction of the vinyl bromides
2 and the CD-building block 3 is presented. The new estrogen analogues 1a and 1b are formed via 23a and
23b in a highly regio- and stereoselective manner in good yields. They contain a cis-BC ring junction and
two double bonds in the 6,7- and the 11,12-positions which can be functionalized in a selective way. Inter
alia, homogeneous hydrogenation with (PPh3)3RhCl to give 28 followed by hydrogenation with 1,4-
cyclohexadiene in the presence of palladium affords the known estradiol derivative 29a in 76% yield which
can easily be transformed into estrone 31.
The total synthesis of steroids represents an attractive research
area due to their high biological activity and broad pharmaco-
logical applications.1 Thus, several of the most applied
pharmaceutical drugs in the United States contain estrogens2
and millions of women use estradiol in oral contraceptives.3 In
past decades, several elegant approaches to steroids were
developed employing new synthetic methodologies;4 among
them are the cationic polyolefinic cyclization,5 the more recent
transition metal mediated reactions of polyenynes,6 and the
thermally induced radical cyclization of enyne-allenes.7 They
all allow the construction of the steroidal skeleton in one step.
However, the number of total syntheses of steroids is rather
limited compared to the nearly numberless publications which
deal with the partial synthesis of steroids and selective func-
tionalizations of mostly every position of the steroidal tetra-
cycle.8
Scheme 1. Retrosynthetic Analysis of Estrone
In recent years, palladium-catalyzed bond forming processes
have evolved as very powerful tools for constructing complex
natural compounds.9 The syntheses of morphine, calcitriol, CC-
1065, paclitaxel, camptothecin, and cephalotaxine employing
the Heck reaction demonstrate their broad potential.10
Here we describe a highly efficient total synthesis of
enantiopure estrone 31 using two successive Heck reactions as
key steps for constructing the steroidal skeleton (Scheme 1). In
addition, new estradiol derivatives with the unusual cis-ring
junction of the rings B and C containing ∆6,7- and ∆11,12-double
bonds have been prepared.11 The novel compounds might be
of great interest for investigations of structure-binding affinity
relationships with the estrone receptor.
The key intermediate in our synthesis of estrone 31 is the
tetracycle 1b which was further transformed by selective
(1) For biological properties, see: Anstead, G. M.; Carlson, K. E.;
Katzenellenbogen, J. A. Steroids 1997, 62, 268-303.
(2) Simonsen, L. L. P. Pharm. Times 1994, April, 18-32.
(3) Djerassi, C. Science 1989, 245, 356-361.
(9) (a) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic
Press: London, 1985. (b) Tsuji, J. Palladium Reagents and Catalyst -
InnoVations in Organic Synthesis; Wiley: Chichester, 1995. (c) Shibasaki,
M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371-7395. (d)
Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. ReV. 1996, 96,
365-393. (e) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7. (f)
Meijere, A. de; Meyer, F. E. Angew. Chem. 1994, 106, 2473-2506; Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379-2411.
(4) For the total syntheses of steroids, see: (a) Zeelen, F. J. Nat. Prod.
Rep. 1994, 11, 607-612. (b) Groen, M. B.; Zeelen, F. J. Recl. TraV. Chim.
Pays-Bas 1986, 105, 465-487.
(5) (a) Corey, E. J.; Virgil, S. C.; Cheng, H.; Baker, C. H.; Matsuda, S.
P. T.; Singh, V.; Sarshar, S. J. Am. Chem. Soc. 1995, 117, 11819-11820.
(b) Johnson, W. S.; Fletcher, V. R.; Chenera, B.; Bartlett, W. R.; Tham, F.
S.; Kullnig, R. K. J. Am. Chem. Soc. 1993, 115, 497-504.
(6) (a) Grigg, R.; Rasul, R.; Savic, V. Tetrahedron Lett. 1997, 38, 1825-
1828. (b) Bao, J.; Dragisich, V.; Wenglowsky, S.; Wulff, W. D. J. Am.
Chem. Soc. 1991, 113, 9873-9875. (c) Zhang, Y.; Wu, G.; Agnel, G.;
Negishi, E. J. Am. Chem. Soc. 1990, 112, 8590-8592. (d) Vollhardt, K. P.
C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539-555; Angew. Chem. 1984,
96, 525-541. (e) Gauthier, V.; Cazes, B.; Gore, J. Tetrahedron Lett. 1991,
32, 915-918.
(10) (a) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993,
115, 11028-11029. (b) Trost, B. M.; Dumas, M. V. J. Am. Chem. Soc. 1992,
114, 9836-9845. (c) Tietze, L. F.; Grote, T. J. Org. Chem. 1994, 59, 192-
196. (d) Tietze, L. F.; Buhr, W. Angew. Chem. 1995, 107, 1485-1487;
Angew. Chem., Int. Ed. Engl. 1995, 34, 1366-1368. (e) Comins, D. L.;
Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10971-10972. (f)
Tietze, L. F.; Schirock, H. Angew. Chem. 1997, 109, 1159-1160; Angew.
Chem., Int. Ed. Engl. 1997, 36, 1124-1125.
(7) Andemichael, Y. W.; Huang, Y.; Wang, K. K. J. Org. Chem. 1993,
58, 1651-1652.
(8) Hanson, J. R. Steroids 1996, 13, 373-386.
(11) Tietze, L. F.; No¨bel, T.; Spescha, M. Angew. Chem. 1996, 108,
2385-2386; Angew. Chem., Int. Ed. Engl. 1996, 35, 2259-2261.
S0002-7863(98)01539-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/07/1998

8972 J. Am. Chem. Soc., Vol. 120, No. 35, 1998
Scheme 2. Products of Arylation of 3 with 4
Tietze et al.
Scheme 3. Products of Arylation and Vinylation of 3 with
10, 15, and 16
hydrogenation. The retrosynthetic analysis of 1b consists of a
disconnection of the 7,8- and the 9,10-C-C bond in the steroid
skeleton to give the doubly functionalized arene 2 and the chiral
hydrindene 3 as potential starting material for the two successive
Heck reactions. In this approach the steroid skeleton is derived
from a ring A and a CD-building block which so far has not
been used for the total synthesis of steroids.
However, several problems had to be faced in this project:
(1) Cyclohexenes have already been used quite often in inter-
and intramolecular Heck reactions, but they usually react rather
sluggishly.12 (2) In Heck reactions, the C-C bond formation
usually takes place at the less-hindered position; thus, for the
reaction of hydrinden 3 the formation of a mixture of regio-
isomers had to be expected. (3) The shielding of the upper
face of 3 by the angular methyl group would clearly allow a
stereoselective addition from the lower face. (4) A further
problem on which we had to focus is the usually low selectivity
of the formation of the double bond in Heck reactions. Thus,
an isomerization of the primarily formed double bond is
encountered quite often under Heck conditions. (5) Finally,
nothing was known about the difference in reactivity of a vinyl
halide and an aryl halide functionality being in the same
molecule.
For the investigations on the rate as well as the diastereo-
and regioselectivity of the Heck reaction with 3, we performed
several transformations with mono-functionalized iodo arenes
(Scheme 2). The Heck reaction of 3 and iodo benzene 4 was
performed under modified Jeffery conditions13 to quantitatively
provide a mixture of the four arylated compounds 5, 6, 7, and
8 in a ratio of 2.4:1.7:1.3:1 which could be separated by
crystallization and column chromatography. As expected, the
reaction takes place with a low regioselectivity at C-4 and C-5,
however with complete stereocontrol anti to the angular methyl
group of 3. The formation of the double bond isomers 6 and 8
can be explained by a readdition-elimination process of a
H-PdII-I species to 5 and 7. The reaction was also performed
in the presence of silver carbonate to suppress the isomerization
of the double bond;14 however, we observed a similiar ratio of
isomeric products. In addition, a small amount of the biphe-
nylated compound 9 was formed probably due to the higher
reactivity of an intermediate L2Pd+ species [5 (37%), 6 (26%),
7 (8%), 8 (8%), 9 (4%)]. The phenyl group at C-5 in 9 is
introduced syn to the angular methyl group due to the stronger
directing properties of the phenyl group at C-4 which is
introduced first.
Rather unexpectedly, the Heck reaction of the sterically highly
hindered 3-iodotetramethylbenzene (10) with 3 under modified
Jeffery conditions gave exclusively attack at C-4 with the
formation of the two isomers 11 and 12 in a 1:1 ratio in 90%
yield; the diastereoselectivity of this reaction again was >98%
(Scheme 3). Also in this transformation, the use of a silver
salt did not prevent the isomerization of the initially formed
double bond. Thus, in the presence of silver phosphate 11 and
12 were obtained in a ratio of 1:2 and a yield of 74%.15
Next we performed Heck reactions of 3 with the halovinyl-
arenes 13 or 14,16 to allow the introduction of two additional
carbons to give 15 or 16 with selective C-C-bond formation
at C-4 in 46% and 39% yield, respectively. Approximately 50%
of 3 was recovered in each case and in addition 4% of 17 was
isolated in the reaction of 14 and 3. The lower yield in these
transformations is probably due to the higher sensitivity of 15
and 16 compared to 4 and 10 (Scheme 3).
For the formation of ring B of the steroidal skeleton, a doubly
functionalized arene with different reactivity of the two functions
(14) Conditions: 10 mol % Pd(OAc)2, 22 mol % PPh3, 2.5 equiv of
Ag2CO3, 2.0 equiv of 4, DMF, 110 °C, 60 h.
(15) Conditions: 5 mol % Pd(OAc)2, 2.0 equiv of Ag3PO4, 2.0 equiv of
10, DMF, 90 °C, 64 h.
(12) (a) Larock, R. C.; Gong, W. H. J. Org. Chem. 1989, 54, 2047-
2050. (b) Larock, R. C.; Baker, B. E. Tetrahedron Lett. 1988, 29, 905-
908.
(13) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667-2670.
(16) Albrecht, K.; de Meijere, A. Chem. Ber. 1994, 127, 2539-2541.

Enantiopure Estrone Via a Double Heck Reaction
Scheme 4. Synthesis of Bromo Arenes
J. Am. Chem. Soc., Vol. 120, No. 35, 1998 8973
This type of a Pd-catalyzed Ullmann coupling process was also
performed with Zn as reducing agent, but formation of the
butadienes could not be detected.20 Using a 2-fold excess of
3, the isolated yield of 23b could be increased to 61%. Under
these conditions, 24b was also formed only in traces. The
relative configuration of 23b was determined by X-ray analy-
sis.21
Interestingly, the transformations are highly sensitive toward
the ratio of palladium and triphenylphosphane; with a ratio of
1:3 and higher, the Heck reaction is completely suppressed. Also
noteworthy, the vinyl bromides 2a and 2b do not react until
the alkene 3 is added to the mixture22 and addition of water
(10%) strongly accelerates the coupling.23
The highly selective formation of 23a and 23b needs some
comment. The high stereoselectivity can easily be explained
by shielding of the upper face of 3 by the angular methyl group,
and the absence of double bond isomerization compared to the
reaction with iodobenzene may be due to the milder reaction
conditions. However, the high regioselectivity in the C-C-
bond formation is difficult to understand. We assume that this
might be due to a stereoelectronic effect which forces the attack
of the palladium at C-5 from the R-face to allow a chair-like
transition state with subsequent syn addition of the vinyl group
at C-4 (structure 26).24
Scheme 5. Synthesis of Iodo Arenes
A variety of different catalyst systems was employed for the
intramolecular Heck reaction of 23a and 23b to give the estradiol
derivatives 1a and 1b (Table 2). The best results were obtained
using the recently described palladacycle 25 providing 1a and
1b in quantitative yield as single diastereomers with a cis-
junction of the rings B and C as well as a ∆6,7- and a
∆
11,12-C-C double bond. Also in this case, the addition of water
leads to a increase of the reaction rate.24 Compared to the
transformation with Pd(OAc)2 and PPh3, the reaction is much
cleaner in the presence of 25 and needs a shorter reaction time.
The formation of 1b from 3 and 2b was also carried out as
a domino reaction without isolation of 23b using catalyst 25.25
However, so far the yield (35%) is slightly lower than found
for the two-step transformation.26
For the synthesis of estrone it was necessary to hydrogenate
the two olefinic double bonds and isomerize the stereogenic
center C-9 in 1b to provide a trans-ring junction of the rings B
and C (Scheme 7).27 Hydrogenation of 1b using Pd/C in acetic
acid under a hydrogen atmosphere of 3 bar provided a separable
mixture of 29a and 29b in a ratio of 1:2, obtained in almost
quatitative yield. The formation of 29a might be explained by
an intermediate isomerization of the ∆11,12- to the ∆9,11-double
had to be used. We therefore prepared the five halogenated
halovinylarenes 2a-e according to Schemes 4 and 5. Com-
pounds 2a and 2b were obtained in two steps from 18a and
18b by a Corey-Fuchs reaction17 and a selective Pd-catalyzed
replacement of one Br atom with n-Bu3SnH in excellent yield.18
The (Z)-configuration of the double bond in 2a-e was
confirmed by a coupling constant of J ) 8.0-8.3 Hz by the
1
signals of the two vinylic hydrogens in the H NMR spectra.
The Heck reactions of 3 with the doubly functionalized
compounds 2a-e revealed that in general, vinyl iodides and
vinyl bromides are more reactive than the bromo and iodo
arenes. However, the difference in reactivity between the two
functions in 2d and 2e proved to be insufficient to allow a highly
chemoselective reaction. Furthermore, in the presence of silver
salts, we observed an I/Br exchange at the arene moiety. On
the other hand, the vinyl iodide 2c appeared to be rather unstable
in palladium-catalyzed reactions. Therefore, we used 2a and
2b in the double Heck reaction with 3 which proceeded in an
astoundingly selective fashion with the nearly exclusive forma-
tion of 23a and 23b, respectively (Table 1, Scheme 6). Thus,
no diastereomer, regioisomer, or double bond isomer of 23a or
23b was found. Under optimized conditions 23a was obtained
in 66% yield and 23b in a slightly lower yield of 50% after
chromatographic purification. In both cases approximately 30%
of 3 could be recovered. Thus, on the basis of transformed 3,
the reaction of 2a is nearly quantitative and that of 2b shows a
yield of about 80%. As byproducts in the different reactions,
the butadiene 24a was obtained in traces and the butadiene 24b
was isolated in variable yields of 5-10% being formed by a
Pd-catalyzed homocoupling process of 2a and 2b, respectively.19
(19) (a) Jutand, A.; Mosleh, A. J. Org. Chem. 1997, 62, 261-274. (b)
Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988, 44, 2049-2054.
(20) Jutand, A.; Mosleh, A. Synlett 1993, 568-570.
(21) Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication nos. CCDC-101100
(25b) and CCDC-101054 (27). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax (+44) 1223 336-033; e-mail deposit@ccdc.cam. ac.uk).
(22) Herrmann, W. A.; Brossmer, Ch.; O¨ fele, K.; Reisinger, C. P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem. 1995, 107, 1989-
1992; Angew. Chem., Int. Ed. Engl. 1995, 34, 1844-1846; Chem. Eur. J.
1997, 3, 1357-1364.
(23) Jeffery, T. Tetrahedron Lett. 1994, 35, 3051-3054.
(24) Whiting, D. A. J. Chem. Soc., Chem. Commun. 1987, 510-511.
(25) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (b) Tietze, L. F.;
Beifuss, U. Angew. Chem. 1993, 105, 137-170; Angew. Chem., Int. Ed.
Engl. 1993, 32, 131-163.
(26) Conditions: 2.5 mol % trans-di-(µ-acetato)bis[o-(di-o-tolylphos-
phino)benzyl]dipalladium(II), 2.5 equiv of n-Bu4NOAc, DMF/CH3CN/H2O
(1:1:0.2), 168 h, 60 °C, 30% of 2 could be recovered.
(27) Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. ReV.
1985, 85, 129-170.
(17) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(18) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem.
1996, 61, 5716-5717.

8974 J. Am. Chem. Soc., Vol. 120, No. 35, 1998
Table 1. Conditions for Heck Reaction of 2a-e and 3
Tietze et al.
entry substrate
catalyst
solvent
additive
product yield [%]
1
2
3
4
5
6
2a
2b
2b
2c
2d
2e
10 mol % Pd(OAc)2, 22 mol % PPh3, 60 °C, 60 h DMF/CH3CN
n-Bu4NOAc; 2.0 equiv of 2a
66
50
61
<5
36
33
10 mol % Pd(OAc)2, 25 mol % PPh3, 75 °C, 7 h
10 mol % Pd(OAc)2, 20 mol % PPh3, 80 °C, 7 h
10 mol % Pd(OAc)2, 70 °C, 4 h
DMF/CH3CN/H2O n-Bu4NOAc
DMF/CH3CN/H2O n-Bu4NOAc; 2.0 equiv of 3
DMF/CH3CN/H2O n-Bu4NOAc
DMF
DMF
5 mol % Pd[PPh3]4, 120 °C, 69 h
Ag3PO4
Ag3PO4
5 mol % Pd[PPh3]4, 80 °C, 68 h
Scheme 6. Products of Coupling Reactions of 2a-e with 3
hydrogen pressure and room temperature for 4 h the alkene 28
was obtained in 94% yield. The reaction takes place without
changing the configuration at C-8 and C-9 which was confirmed
by an X-ray analysis of 28.21 The ∆11,12-double bond is much
less reactive under homogeneous catalysis; thus, even under 55
bar of hydrogen pressure for 4 h only 30% of 29b together with
70% of 28 was obtained. Estradiol derivatives with a ∆11,12
-
double bond have been isolated from the urine of pregnant
women.28
The synthesis of the known estradiol derivative 29a which
can easily be transformed into estrone 31 using known
procedures was finally accomplished in good yield by hydro-
genation of 28 in the presence of palladium and a large excess
of 1,4-cyclohexadiene as a source of a hydrogen. Using 0.6
equiv of palladium in ethanol for 48 h at 100 °C, 29a was
obtained in 76% yield. In addition 24% of the equilenin
derivative 30 was found. Using a smaller concentration of
palladium (0.07 equiv), 24% of 29a and 68% of 30 were
isolated. The formation of 30 results from an aromatization of
the B-ring by migration of the double bond and dehydrogenation
due to the low concentration of active hydrogen.29 The
formation of 29a from 28 can be explained as already mentioned
by an isomerization of the ∆11,12- to the ∆9,11-double bond
followed by hydrogenation. All spectroscopic properties of 29a
were identical with those reported.30
bond which is known to give a trans-B/C-ring junction on
hydrogenation to provide the thermodynamically more stable
all-trans configuration of the steroidal skeleton. Using Pd/C
without any source of hydrogen 1b is transformed into the
unsaturated equilenin derivative 27 in excellent yield.
The diene 1b, however, could also be transformed highly
selectively into 29b in 97% yield using platinum as catalyst in
the hydrogenation. As expected, no isomerization was observed.
The homogeneous hydrogenation employing the Wilkinson
catalyst allowed the selective hydrogenation of the more
accessible ∆6,7-double bond of 1b; thus, in the presence of 10
mol % (PPh3)3RhCl in methanol/ethyl acetate at ambient
Conclusion
A novel highly efficient strategy for the preparation of new
types of estrogen derivatives has been developed with two
stereoselective Heck reactions as the key steps which provide
a general and selective access to the steroidal skeleton.
Furthermore, the obtained products 1a and 1b with two double
bonds in the 6,7- and the 11,12-positions might be used as
starting materials for the synthesis of numerous novel highly
functionalized steroids. Hydrogenation of 1b allows the selec-
tive formation of the known estradiol derivative 29a which can
be transformed into estrone 31.30d
Scheme 7. Selective Hydrogenation and Dehydrogenation of 1b

Enantiopure Estrone Via a Double Heck Reaction
J. Am. Chem. Soc., Vol. 120, No. 35, 1998 8975
Table 2. Conditions for Intramolecular Heck Reactions to 1a,b
entry
substrate
catalyst
solvent
additive
product yield [%]
1
2
3
4
5
23a
23a
23a
23b
23b
16 mol % Pd(OAc)2, 34 mol % PPh3, 60 °C, 60 h
12 mol % Pd(OAc)2, 24 mol % PPh3, 115 °C, 60 h
2.5 mol % 25, 115 °C, 4.5 h
13 mol % Pd(OAc)2, 27 mol % PPh3, 115 °C, 60 h
2.5 mol % 25, 115 °C, 4.5 h
DMF/CH3CN/H2O
DMF
DMF/CH3CN/H2O
DMF
n-Bu4NOAc
Ag3PO4
n-Bu4NOAc
Ag3PO4
68%
85%
99%
63%
99%
DMF/CH3CN/H2O
n-Bu4NOAc
UV (CH3CN) λmax (log ꢀ) 206.5 (4.284), 247.0 (3.924); IR (film) 3070,
1618; H NMR (300 MHz, CDCl3) δ 6.75 (d, J ) 8.0 Hz, 1 H), 7.17
Experimental Section
1
Instrumentation. Multiplicities of 13C NMR peaks were determined
with the APT pulse sequence. Mass spectra were measured at 70 eV.
UV/vis spectra [λmax, nm, log ꢀ) were taken in CH3CN. IR spectra
were recorded as KBr pellets or as films. Melting points are corrected.
Materials. All reactions were performed in oven-dried glassware
in an atmosphere of nitrogen or argon unless otherwise noted. Solvents
were dried and distilled prior to use and degassed by pump and freeze
methodology. TLC chromatography was performed on precoated silica
gel SIL G/UV254 plates (Machery, Nagel & Co.), and silica gel 32-63
(0.032-0.064 mm) (Machery, Nagel & Co.) was used for column
chromatography.
The starting materials 3-tert-butoxy-3a-methyl-2,3,3a,4,5,7a-hexahy-
dro-1H-indene (3),31 3-iodotetramethylbenzene (10),32 ((E)-(2-iodo-
ethenyl)benzene (13),33 ((Z)-(2-bromoethenyl)benzene (14),34 and 2-bro-
mo-5-methoxybenzaldehyde (18b)35 were prepared according to pub-
lished procedures.
(dt, J ) 7.5, 1.5 Hz, 1 H), 7.20 (d, J ) 8.0 Hz, 1 H), 7.33 (dt, J ) 7.5,
1.5 Hz, 1 H), 7.59 (dd, J ) 8.0, 1.5 Hz, 1 H), 7.76 (dd, J ) 7.5, 1.5
Hz, 1 H); 13C NMR (50 MHz, CDCl3) δ 109.3, 123.7, 126.8, 129.6,
130.5, 132.3, 132.6, 135.1; MS (70 eV, EI) m/z (%) 259.9 (28) [M+],
181.0 (100) [M+ - HBr], 102.0 (78) [M+ - HBr - Br]; EI HRMS
m/e 259.8836, C8H6Br2 requires 259.8836.
2-(2,2′-Dibromoethenyl)-4-methoxybromobenzene (19b). To a
suspension of CBr4 (99.50 g, 300 mmol) and Zn (19.62 g, 300 mmol)
in CH2Cl2 (1000 mL) was added a solution of PPh3 (78.69 g, 300 mmol)
in CH2Cl2 (200 mL) at room temperature. After 30 min, a solution of
18b (32.24 g, 150 mmol) in CH2Cl2 (150 mL) was added, and the
mixture was stirred for 1.5 h. The mixture was diluted with petroleum
ether (2000 mL), filtered, and concentrated under reduced pressure.
Purification by column filtration (petroleum ether) afforded 19b (54.10
g, 97%) as white solid: mp 46.9 °C (MeOH); UV (CH3CN) λmax (log
ꢀ) 202.0 (4.335), 294.0 (3.392); IR (KBr) 3020, 2962, 2832, 1594; 1H
NMR (200 MHz, CDCl3) δ 3.80 (s, 3 H), 6.77 (dd, J ) 8.8, 3.2 Hz, 1
H), 7.15 (d, J ) 3.2 Hz, 1 H), 7.45 (d, J ) 8.8 Hz, 1 H), 7.48 (s, 1 H);
13C NMR (50 MHz, CDCl3) δ 55.54, 92.84, 113.4, 115.6, 115.9, 133.1,
136.4, 136.5, 158.4; MS (70 eV, EI) m/z (%) 370.0 (100) [M+], 291.0
(25) [M+ - Br], 210.1 (75) [M+ - 2 × Br]. Anal. Calcd for C9H7-
OBr3 (370.7): C, 29.13; H, 1.88; Br, 64.66. Found: C, 29.53; H, 1.89;
Br, 64.32.
(Z)-1-Bromo-2-(2-bromovinyl)-4-methoxybenzene (2b).36 To a
degassed solution of 19b (2.68 g, 7.23 mmol) in anhydrous toluene
(40 mL) and Pd(PPh3)4 (4 mol %, 334 mg) was added n-Bu3SnH (7.59
mmol, 2.21 g, 2.04 mL), and the mixture was stirred for 1 h at room
temperature. The reaction mixture was poured in petroleum ether (100
mL), washed with water (30 mL) and brine (50 mL), and dried over
MgSO4. Concentration in vacuo and purification by column chroma-
tography provided 2b (2.06 g, 98%) as yellow oil: Rf 0.05 (pentane);
bp 78 °C (0.01 mbar); UV (CH3CN) λmax (log ꢀ) 202.5 (4.295), 297.0
(3.279); IR (film) 3002, 2932, 2832, 1590; 1H NMR (200 MHz, CDCl3)
δ 3.81 (s, 3 H), 6.57 (d, J ) 8.1 Hz, 1 H), 6.76 (dd, J ) 8.7, 3.0 Hz,
1 H), 7.18 (d, J ) 8.1 Hz, 1 H), 7.36 (d, J ) 3.0 Hz, 1 H), 7.47 (d, J
) 8.7 Hz, 1 H); 13C NMR (50 MHz, CDCl3) δ 55.50, 109.2, 114.2,
115.6, 115.8, 132.1, 133.1, 135.6, 158.2; MS (70 eV, EI) m/z (%) 292.1
(100) [M+], 211.1 (62) [M+ - HBr], 132.1 (84) [M+ - HBr - Br].
Anal. Calcd for C9H8OBr2 (291.8): C, 37.01; H, 2.74. Found: C,
37.05; H, 2.81.
1-Bromo-2-(2,2-dibromovinyl)benzene (19a). To a solution of
CBr4 (3.58 g, 10.8 mmol) in CH2Cl2 (20 mL) was added a solution of
PPh3 (5.67 g, 21.6 mmol) in CH2Cl2 (20 mL) at 0 °C. The mixture
was stirred for 30 min, and then a solution of 18a (1.00 g, 5.40 mmol)
in CH2Cl2 (20 mL) was added. The reaction mixture was allowed to
warm to room temperature with continued stirring. After 2 h the
mixture was poured in petroleum ether (200 mL), filtered, and
concentrated in vacuo. Purification by column chomatography provided
19a (1.57 g, 4.61 mmol, 85%) as yellow oil: Rf 0.57 (petroleum ether);
UV (CH3CN) λmax (log ꢀ) 206.0 (4.314), 250.5 (3.942); IR (film) 3060,
1
1604; H NMR (200 MHz, CDCl3) δ 7.21 (dt, J ) 7.4, 1.2 Hz, 1 H),
7.34 (dt, J ) 7.4, 1.2 Hz, 1 H), 7.51 (s, 1 H), 7.59 (dd, J ) 8.0, 1.2
Hz, 1 H), 7.59 (dd, J ) 8.0, 1.2 Hz, 1 H); 13C NMR (50 MHz, CDCl3)
δ 92.83, 123.0, 127.1, 129.8, 130.3, 132.5, 136.0, 136.6; MS (70 eV,
EI) m/z (%) 339.9 (72) [M+], 261.0 (100) [M+ - HBr], 180.0 (87)
[M+ - HBr - Br], 101.1 (46) [M+ - HBr - Br - Br]; EI HRMS m/e
337.7941, C8H5Br3 requires 337.7940.
(Z)-1-Bromo-2-(2-bromovinyl)benzene (2a). To a degassed solu-
tion of 19a (868 mg, 2.55 mmol) in anhydrous toluene (15 mL) and
Pd(PPh3)4 (4 mol %, 118 mg) was added n-Bu3SnH (778 mg, 2.67
mmol, 0.72 mL), and the mixture was stirred for 1 h at room
temperature. The reaction mixture was poured in petroleum ether (100
mL), washed with water (30 mL), brine (30 mL), and dried over MgSO4.
Concentration in vacuo and purification by column chromatography
provided 2a (661 mg, 99%) as yellow oil: Rf 0.44 (petroleum ether);
(3R,3aS,7S,7aS)-(-)-3-tert-Butoxy-3a-methyl-7-(Z)-[2-(2-bromophe-
nyl)vinyl]-2,3,3a,4,7,7a-hexahydro-1H-indene (23a). To a degassed
solution of 3 (208 mg, 1.0 mmol) and 2a (524 mg, 2.0 mmol) in DMF
(5 mL) were added Pd(OAc)2 (10 mol %, 23 mg), PPh3 (20 mol %, 52
mg), and silver phosphate (836 mg, 2.0 mmol). The mixture was stirred
for 60 h at 120 °C. The mixture was then cooled to room temperature
and diluted with ether (20 mL) and water (20 mL). The organic layer
was washed with brine (15 mL), dried (MgSO4), and concentrated in
vacuo. Purification by column chromatography afforded 257 mg of
23a (66%) as colorless oil: Rf 0.23 (petroleum ether/CH2Cl2 ) 10:1);
[R] -23.3 (c ) 0.45, CHCl3); UV (CH3CN) λmax (log ꢀ) 195.5 (4.395);
(28) Luukainnen, T.; Adlercreutz, H. Biochim. Biophys. Acta 1965, 107,
579-592.
(29) (a) Hoyer, G. A.; Junghans, K.; Cleve, G. Chem. Ber. 1974, 107,
363-366. (b) Hilscher, J. C. Chem. Ber. 1975, 108, 727-729.
(30) (a) Eder, U.; Gibian, H.; Haffer, G.; Neef, G.; Sauer, G.; Wiechert,
R. Chem. Ber. 1976, 109, 2948-2953. (b) Groth, U.; Ko¨hler, T.; Taapken,
T. Tetrahedron 1991, 47, 7583-7592. (c) Cohen, N.; Banner, B. L.; Eichel,
W. F.; Parrish, P. R.; Sausy, G. J. Org. Chem. 1975, 40, 681-685. (d)
Quinkert, G.; Del Grosso, M.; Doring, A.; Do¨ring, W.; Schenkel, R. I.;
Bauch, M.; Dambacher, G. T.; Bats, Y. W.; Zimmerman, G.; Du¨rner, G.
HelV. Chim. AVta 1995, 78, 1345-1391.
(31) (a) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem.
1992, 57, 6090-6092. Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J.
Tetrahedron 1993, 49, 5483-5493. (b) Tietze, L. F.; Subba Rao, P. S. V.
Synlett 1993, 291-292.
(32) (a) Toehl, A. Chem. Ber. 1892, 25, 1521-1526. (b) Janssen, D. E.;
Wilson, C. V. Org. Synth. 1963, 4, 547-549.
(33) Zweifel, G.; White, C. C. J. Am. Chem. Soc. 1967, 89, 2753-2754.
(34) Cristol, S. J.; Norris, W. P. J. Am. Chem. Soc. 1953, 75, 2645-
2646.
1
IR (film) 3052, 2970; H NMR (300 MHz, CDCl3) δ 0.63 (s, 3 H),
(36) Reimer, M.; Kamerling, H. H. J. Am. Chem. Soc. 1933, 55, 4643-
4648.
(37) Acheson, R. M.; Lee, G. C. M. J. Chem. Soc., Perkin Trans. I 1987,
2321-2332.
(38) Akgun, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J. Org. Chem.
1981, 46, 2730-2734.
(35) Morrow, G. W.; Marks, T. M.; Sear, D. L. Tetrahedron 1995, 51,
10115-10124.
(39) Horne, S.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1992, 164-
166.

8976 J. Am. Chem. Soc., Vol. 120, No. 35, 1998
Tietze et al.
1.13 (s, 9 H), 1.15-1.20 (m, 1 H), 1.22-1.40 (m, 2 H), 1.52-1.70
(m, 1 H), 1.76-1.88 (mc, 2 H), 1.98 (dddd, J ) 17.3, 4.9, 1.9, 1.7 Hz,
1 H), 2.82-3.00 (m, 1 H), 3.48 (dd, J ) 8.5, 8.1 Hz, 1 H), 5.46 (dd,
J ) 11.0, 10.7 Hz, 1 H), 5.40-5.50 (m, 1 H), 5.69 (dddd, J ) 9.5, 4.6,
2.4, 2.2 Hz, 1 H), 6.47 (d, J ) 11.0 Hz, 1 H), 7.04-7.20 (m, 1 H),
7.22-7.34 (m, 2 H), 7.57 (d, J ) 7.8 Hz, 1 H); 13C NMR (50 MHz,
CDCl3) δ 11.48, 24.71, 28.75, 30.44, 38.74, 38.76, 41.21, 46.31, 72.23,
80.63, 123.9, 126.9, 127.4, 128.3, 128.9, 129.3, 130.6, 132.5, 136.3,
57.1 (41) [C4H9+], 41.1 (15) [C3H5+]; EI HRMS m/e 308.2140, C22H28O
requires 308.2140.
(-)-17â-tert-Butoxy-3-methoxy-9â-estra-1,3,5(10),6,11(12)-pen-
taene (1b). To a carefully degassed solution of 23b (182 mg, 0.43
mmol) and n-Bu4NOAc (327 mg, 1.09 mmol) in DMF/CH3CN/H2O
(1:1:0.2, 5 mL) was added trans-di-(µ-acetato)bis[o-di-o-tolylphosphi-
no)benzyl]dipalladium(II) (25) (8.1 mg, 2.0 mol %) at 50 °C. The
mixture was stirred for 4.5 h at 115 °C. After cooling to room
temperature, the mixture was diluted with ether (100 mL) and washed
with water (30 mL) and brine (30 mL), dried (MgSO4), and concentrated
in vacuo. Purification by column chromatography afforded 1b (145
mg, 99%) as a colorless solid: Rf 0.28 (petroleum ether/ CH2Cl2 )
3:1); mp 65.4 °C (MeOH); [R] -149.0 (c ) 0.5, CHCl3); UV (CH3-
CN) λmax (log ꢀ) 228.5 (4.425), 256.0 (3.699), 265.5 (3.734), 275.5
(3.654), 302.5 (3.405), 313.0 (3.353); IR (KBr) 3032, 3014, 2972, 2834,
1390; 1H NMR (500 MHz, CDCl3) δ 0.87 (s, 3 H), 1.11 (s, 9 H), 1.35-
1.50 (m, 3 H), 1.65-1.75 (m, 1 H), 1.81-1.92 (m, 1 H), 2.64 (ddd, J
) 11.7, 6.7, 6.4 Hz, 1 H), 3.46 (dd, J ) 6.5, 6.4 Hz, 1 H), 3.67 (dd,
J ) 6.4, 4.5 Hz, 1 H), 3.77 (s, 3 H), 5.90 (dd, J ) 9.8, 6.7 Hz, 1 H),
6.03 (d, J ) 9.9 Hz, 1 H), 6.11 (dd, J ) 9.9, 4.5 Hz, 1 H), 6.32 (d, J
) 9.8 Hz, 1 H), 6.54 (d, J ) 2.8 Hz, 1 H), 6.68 (dd, J ) 8.3, 2.8 Hz,
1 H), 7.17 (d, J ) 8.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 14.93,
22.80, 28.71, 31.82, 34.00, 37.15, 41.46, 44.80, 55.21, 72.35, 76.29,
112.05, 112.12, 125.5, 126.7, 127.7, 129.5, 131.0, 134.0, 135.9, 158.0;
MS (70 eV, EI) m/z (%) 338.4 (25) [M+], 281.0 (50) [M+ - C4H9+],
137.8; MS (70 eV, EI) m/z (%) 388.0 (5) [M+], 210.1 (46) [M+
-
+
C4H9 - Br - C3H5+], 105.1 (32) [C8H9+], 91.0 (46) [C7H7+], 57.0
(100) [C4H9+], 41.0 (19) [C3H5+]. Anal. Calcd for C22H29OBr (389.4):
C, 68.05; H, 7.21. Found: C, 68.20; H, 7.25.
(1S,3aS,4S,7aS)-(-)-4-[2-(2-Bromo-5-methoxyphenyl)vinyl]-1-
tert-butoxy-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene (23b). To
a degassed solution of 3 (208 mg, 1.0 mmol), 2b (292 mg, 1.0 mmol),
and n-Bu4NOAc (2.5 mmol, 754 mg) in DMF/CH3CN/H2O (1:1:0.2,
10 mL) were added at 50 °C Pd(OAc)2 (10 mol %, 23 mg) and PPh3
(25 mol %, 66 mg). The mixture was stirred for 8 h at 70 °C. The
mixture was then cooled to room temperature and diluted with ether
(50 mL) and water (50 mL). The organic layer was washed with water
(2 × 50 mL) and brine (30 mL), dried (MgSO4), and concentrated in
vacuo. Purification by column chromatography afforded 23b (210 mg,
50%) as colorless oil. Recrystallization from methanol yielded white
needles: Rf 0.27 (petroleum ether/CH2Cl2 ) 3:1); mp 85.4 °C (MeOH);
[R] -60.4 (c ) 0.5, CHCl3); UV (CH3CN) λmax (log ꢀ) 201.0 (4.403),
289.0 (3.422); IR (KBr) 3012, 2970, 2836; 1H NMR (500 MHz, CDCl3)
δ 0.66 (s, 3 H), 1.13 (s, 9 H), 1.15-1.22 (m, 1 H), 1.30-1.44 (m, 2
H), 1.63-1.71 (m, 1 H), 1.80-1.90 (m, 2 H), 2.00 (dddd, J ) 17.1,
5.4, 1.8, 1.8 Hz, 1 H), 2.97 (mc, 1 H), 3.49 (t, J ) 8.4 Hz, 1 H), 3.78
(s, 3 H), 5.45 (dd, J ) 11.2, 10.7 Hz, 1 H), 5.45 (mc, 1 H), 5.69 (dddd,
J ) 9.8, 4.6, 2.3, 2.3 Hz, 1 H), 6.45 (d, J ) 11.2 Hz, 1 H), 6.69 (dd,
J ) 8.7, 3.0 Hz, 1 H), 6.82 (d, J ) 3.0 Hz, 1 H), 7.45 (d, J ) 8.7 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 11.45, 24.78, 28.73, 30.49, 38.77,
41.22, 46.31, 55.42, 72.22, 80.60, 114.4, 114.5, 115.9, 127.5, 128.8,
129.3, 133.0, 136.4, 138.5, 158.4; MS (70 eV, EI) m/z (%) 418.1 (32)
263.0 (100) [M+ - C4H9 - H2O], 57.1 (41) [C4H9+], 41.0 (16)
+
[C3H5+]. Anal. Calcd for C23H30O2 (338.5): C, 81.61; H, 8.93.
Found: C, 81.52; H, 8.93.
(+)-17â-tert-Butoxy-3-methoxyestra-1,3,5(10),6,8(9),11-hexaene
(27). A suspension of Pd/C (5%) and 1b (75 mg, 0.22 mmol) in ethanol
(4 mL) was stirred under a inert atmosphere at 80 °C for 3.5 d. After
cooling, the reaction mixture was diluted with ether (10 mL). The
catalyst was removed by filtration through a short pad of silica gel.
Evaporation of the solvent and purification by column chromatography
afforded 72 mg (97%) of 27 as colorless solid: Rf 0.26 (petroleum
ether/CH2Cl2 ) 3:1); mp 98.0 °C (EtOH); [R] +43.4 (c ) 0.5, CHCl3);
UV (CH3CN) λmax (log ꢀ) 201.0 (4.307), 239.5 (4.650), 286.5 (3.649),
300.0 (3.737), 313.0 (3.777), 338.5 (3.451), 354.0 (3.456); IR (KBr)
2968, 2874, 1626, 1556, 1382, 1360, 1086; 1H NMR (500 MHz, CDCl3)
δ 0.66 (s, 3 H), 1.26 (s, 9 H), 1.70-1.78 (mc, 1 H), 1.82-2.10 (m, 2
H), 2.20-2.30 (mc, 1 H), 3.00 (dd, J ) 12.0, 8.0 Hz, 1 H), 3.92 (s, 3
H), 3.98 (dd, J ) 7.6, 7.5 Hz, 1 H), 6.46 (d, J ) 10.0 Hz, 1 H), 7.10-
7.14 (mc, 2 H), 7.16 (dd, J ) 8.5, 3.0 Hz, 1 H), 7.23 (d, J ) 10.0 Hz,
1 H), 7.62 (d, J ) 9.5 Hz, 1 H), 8.02 (d, J ) 9.5 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 10.53, 21.75, 28.82, 32.45, 44.91, 46.00, 55.24,
72.58, 75.63, 106.3, 118.7, 122.1, 124.2, 124.24, 125.1, 125.9, 129.5,
133.5, 133.7, 139.4, 156.6; MS (70 eV, EI) m/z (%) 336.4 (50) [M+],
261.3 (86) [M+ - C4H9+ - H2O], 91.1 (12) [C7H7+], 57.0 (18) [C4H9+];
EI HRMS m/e 336.2089, C23H28O2 requires 336.2089.
[M+], 265.1 (100) [M+ - OC4H9 - Br], 105.0 (43) [C8H9+], 91.0
+
(20) [C7H7+], 57.0 (92) [C4H9+]. Anal. Calcd for C23H31O2Br
(419.4): C, 65.87; H, 7.45; Br, 19.05. Found: C, 65.95; H, 7.45; Br,
18.95.
1,4-Bis[2-bromo-5-methoxyphenyl]-1,3-butadiene (24b). Rf 0.28
(petroleum ether/CH2Cl2 ) 3:1); mp 157.0 °C (ether); UV (CH3CN)
λmax (log ꢀ) 192.5 (4.404), 222.0 (4.339), 332.0 (4.136); IR (KBr) 2934;
1H NMR (500 MHz, CDCl3) δ 3.84 (s, 6 H), 6.71 (dd, J ) 8.8, 3.3
Hz, 2 H), 7.00 (mc, A2B2-signal, 4 H), 7.16 (d, J ) 3.3 Hz, 2 H), 7.45
(d, J ) 8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 55.53, 111.2,
114.8, 115.6, 131.5, 132.4, 133.7, 137.3, 159.0; MS (70 eV, EI) m/z
(%) 423.9 (29) [M+], 343.0 (21) [M+ - Br], 264.1 (100) [M+ - 2 ×
Br], 249.1 (12) [M+ - 2 × Br - CH3]. Anal. Calcd for C18H16O2Br2
(424.13): C, 50.97; H, 3.80. Found: C, 51.21; H, 3.98.
(-)-17â-tert-Butoxy-9â-estra-1,3,5(10),6,11(12)-pentaene (1a). To
a carefully degassed solution of 23a (157 mg, 0.40 mmol) and n-Bu4-
NOAc (302 mg, 1.00 mmol) in DMF/CH3CN/H2O (1:1:0.2, 5 mL) was
added trans-di-(µ-acetato)bis[o-di-o-tolylphosphino)benzyl]dipalladium-
(II) (25) (7.5 mg, 2.0 mol %) at 50 °C. The mixture was stirred for
4.5 h at 115 °C. After cooling to room temperature, the mixture was
diluted with ether (100 mL) and washed with water (30 mL) and brine
(30 mL), dried (MgSO4), and concentrated in vacuo. Purification by
column chromatography afforded 1a (123 mg, 99%) as colorless oil:
Rf 0.29 (petroleum ether/CH2Cl2 ) 10:1); [R] -173.4 (c ) 0.5, CHCl3);
UV (CH3CN) λmax (log ꢀ) 213.0 (4.362), 219.0 (4.351), 225.5 (4.221),
264.0 (3.866), 271.5 (3.846); IR (film) 2970, 1082; 1H NMR (500 MHz,
CDCl3) δ 0.90 (s, 3 H), 1.13 (s, 9 H), 1.39-1.58 (m, 3 H), 1.78 (ddd,
J ) 12.1, 11.9, 6.6 Hz, 1 H), 1.83-1.91 (m, 1 H), 2.69 (ddd, J ) 11.9,
6.6, 6.1 Hz, 1 H), 3.48 (dd, J ) 6.7, 6.6 Hz, 1 H), 3.77 (dd, J ) 6.6,
5.0 Hz, 1 H), 5.90 (dd, J ) 9.6, 6.1 Hz, 1 H), 6.09 (d, J ) 10.1 Hz, 1
H), 6.17 (dd, J ) 10.1, 5.0 Hz, 1 H), 6.40 (d, J ) 9.6 Hz, 1 H), 6.99
(dd, J ) 7.1, 1.6 Hz, 1 H), 7.11-7.19 (m, 2 H), 7.30 (d, J ) 7.4 Hz,
1 H); 13C NMR (125 MHz, CDCl3) δ 14.87, 22.75, 28.65, 31.74, 33.75,
37.92, 41.45, 44.73, 72.30, 76.21, 125.2, 126.1, 126.6, 126.67, 126.69,
127.2, 130.0, 132.8, 136.1, 137.3; MS (70 eV, EI) m/z (%) 308.2 (7)
(-)-17â-tert-Butoxy-3-methoxy-9â-estra-1,3,5(10),11(12)-tet-
raene (28). A solution of 1b (100 mg, 0.30 mmol) and (PPh3)3RhCl
(10 mol %, 27 mg) in methanol/ethyl acetate (1:1, 8 mL) was shaken
at room temperature for 4 h under H2 atmosphere (3 bar). The mixture
was filtered and concentrated in vacuo. Purification by column
chromatography afforded 95 mg of 28 (94%) as colorless solid: Rf
0.28 (petroleum ether/CH2Cl2 ) 3:1); mp 60.9 °C (MeOH); [R] -37.8
(c ) 0.5, CHCl3); UV (CH3CN) λmax (log ꢀ) 200.5 (4.585), 272.5
1
(3.685); IR (KBr): 2972, 2870, 1608; H NMR (500 MHz, CDCl3) δ
0.87 (s, 3 H), 1.11 (s, 9 H), 1.41 (ddd, J ) 23.6, 10.7, 5.7 Hz, 1 H),
1.46-1.54 (m, 2 H), 1.62 (dddd, J ) 8.6, 8.6, 5.7, 2.0 Hz, 1 H), 1.70
(dddd, J ) 8.8, 8.6, 4.4, 4.3 Hz, 1 H), 1.81 (tdd, J ) 13.4, 4.8, 4.6 Hz,
1 H), 1.93 (dddd, J ) 13.5, 9.4, 9.4, 6.2 Hz, 1 H), 2.34 (mc, 1 H), 2.53
(ddd, J ) 16.0, 4.4, 4.3 Hz, 1 H), 2.75 (ddd, J ) 16.0, 11.7, 4.3 Hz,
1 H), 3.47 (mc, 1 H), 3.47 (dd, J ) 7.4, 7.1 Hz, 1 H), 3.77 (s, 3 H),
5.94 (dd, J ) 9.9, 3.7 Hz, 1 H), 5.98 (dd, J ) 9.9, 0.9 Hz, 1 H), 6.61
(d, J ) 2.8 Hz, 1 H), 6.74 (dd, J ) 8.6, 2.8 Hz, 1 H), 7.22 (d, J ) 8.6
Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.94, 22.91, 25.29, 26.20,
28.71, 31.48, 31.86, 38.67, 42.30, 44.53, 55.15, 72.30, 76.76, 112.1,
113.3, 128.6, 129.0, 131.5, 135.4, 138.6, 157.0; MS (70 eV, EI) m/z
[M+], 251.2 (43) [M+ - C4H9+], 233.1 (100) [M+ - C4H9 - H2O],
(%) 340.4 (56) [M+], 283.3 (69) [M+ - C4H9+], 265.3 (51) [M+
-
+

Enantiopure Estrone Via a Double Heck Reaction
J. Am. Chem. Soc., Vol. 120, No. 35, 1998 8977
C4H9+ - H2O], 57.1 (41) [C4H9+], 41.0 (9) [C3H5+]. Anal. Calcd for
1 H), 6.73 (dd, J ) 8.5, 2.8 Hz, 1 H), 7.28 (d, J ) 8.5 Hz, 1 H); 13C
NMR (125 MHz, CDCl3) δ 11.23, 23.54, 24.59, 25.41, 26.04, 28.72,
30.64, 32.90, 34.04, 37.37, 41.38, 42.73, 55.08, 72.12, 80.90, 111.8,
113.7, 127.4, 130.7, 139.0, 157.0; MS (70 eV, EI) m/z (%) 342.3 (79)
C23H32O2 (340.5): C, 81.13; H, 9.47. Found: C, 80.86; H, 9.17.
(+)-17â-tert-Butoxy-3-methoxyestra-1,3,5(10)-triene (29a).
A
suspension of 28 (51 mg, 0.15 mmol), 1,4-cyclohexadien (15 mmol,
1.41 mL), and Pd/C (5%, 0.60 equiv of Pd, 191 mg) in ethanol (8.0
mL) was stirred for 48 h at 100 °C. After cooling, the reaction mixture
was diluted with ether (10 mL). The catalyst was removed by filtration
through a short pad of silica gel. Evaporation of the solvent and
purification by column chromatography afforded 39 mg (76%) of 29a
as colorless solid and 9 mg of 30: Rf 0.32 (petroleum ether/tert-butyl
methyl ether ) 40:1); mp 92.6 °C (MeOH); (lit.30d 90-92 °C); [R]
+59.2 (c ) 0.5, CHCl3; lit:30d + 62.2 c ) 1.0, CHCl3); UV (CH3CN)
[M+], 286.2 (100) [M+ - C4H9+], 267.2 (56) [M+ - C4H9 - H2O],
+
57.1 (29) [C4H9+]; EI HRMS m/e 342.2558, C23H34O2 requires
342.2559.
(+)-17â-tert-Butoxy-3-methoxyestra-1,3,5(10),6,8(9)-pentaene (30).
A suspension of 28 (41 mg, 0.12 mmol), 1,4-cyclohexadiene (12 mmol,
1.13 mL), and Pd/C (5%, 7 mol % Pd, 18 mg) in ethanol (4.0 mL) was
stirred for 48 h at 100 °C. After cooling, the reaction mixture was
diluted with ether (10 mL). The catalyst was removed by filtration
through a short pad of silica gel. Evaporation of the solvent and
purification by column chromatography afforded 28 mg (68%) of 30
as colorless solid and 10 mg (24%) of 29a: Rf 0.28 (petroleum ether/
tert-butyl methyl ether ) 40:1); [R] +5.4 (c ) 0.5, CHCl3); UV (CH3-
CN) λmax (log ꢀ) 229.5 (4.667), 259.0 (3.728), 277.5 (3.651), 288.0
(3.487), 302.5 (2.986), 323.0 (3.181), 338.0 (3.262); IR (KBr) 2964,
λmax (log ꢀ) 200.0 (4.645), 279.0 (3.314), 286.5 (3.277); IR (KBr) 2972,
2864; 1H NMR (500 MHz, CDCl3) δ 0.76 (s, 3 H), 1.16 (s, 9 H), 1.16-
1.43 (m, 5 H), 1.45-1.54 (m, 2 H), 1.63-1.69 (m, 1 H), 1.86-1.97
(m, 3 H), 2.18 (ddd, J ) 11.5, 11.5, 4.0 Hz, 1 H), 2.25-2.30 (mc, 1
H), 2.85 (dd, J ) 8.0, 7.5 Hz, 2 H), 3.45 (t, J ) 7.9 Hz, 1 H), 3.78 (s,
3 H), 6.63 (d, J ) 2.7 Hz, 1 H), 6.71 (dd, J ) 8.6, 2.7 Hz, 1 H), 7.22
(d, J ) 8.6 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 11.61, 23.51,
26.41, 27.29, 28.77, 29.90, 31.24, 37.27, 38.77, 42.78, 44.14, 50.05,
55.19, 72.18, 80.86, 111.4, 113.8, 126.3, 132.9, 138.1, 157.4; MS (70
eV, EI) m/z (%) 342.3 (100) [M+], 286.2 (74) [M+ - C4H9+], 267.2
(29) [M+ - C4H9+ - H2O], 57.1 (25) [C4H9+]; EI HRMS m/e 342.2558,
C23H34O2 requires 342.2559.
1
1624, 1084; H NMR (200 MHz, CDCl3) δ 0.70 (s, 3 H), 1.20 (s, 9
H), 1.50-1.82 (m, 4 H), 2.08-2.23 (m, 2 H), 2.65-2.80 (mc, 1 H),
3.23 (t, J ) 8.2 Hz, 2 H), 3.64 (t, J ) 7.5 Hz, 1 H), 3.90 (s, 3 H),
7.08-7.22 (m, 3 H), 7.57 (d, J ) 8.3 Hz, 1 H), 7.88 (d, J ) 8.5 Hz,
1 H); 13C NMR (50.3 MHz, CDCl3) δ 10.78, 23.90, 24.51, 28.76, 31.90,
34.35, 42.42, 46.25, 55.23, 72.34, 79.92, 106.5, 118.2, 124.8, 124.9,
125.3, 127.4, 130.8, 133.1, 134.4, 156.5; MS (70 eV, EI) m/z (%) 338.2
(-)-17â-tert-Butoxy-3-methoxy-9â-estra-1,3,5(10)-triene (29b). A
suspension of 1b (30 mg, 0.09 mmol) and PtO2 (10 mol %, 20.4 mg)
in ethyl acetate (5 mL) was subjected to 55 bar of hydrogen pressure
at room temperature for 12 h. The catalyst was removed by filtration
through a short pad of silica gel. Evaporation of the solvent gave 29b
(30 mg, 97%) as colorless oil: Rf 0.35 (petroleum ether/tert-butyl methyl
ether ) 40:1); [R] -10.6 (c ) 0.5, CHCl3); UV (CH3CN) λmax (log ꢀ)
200.5 nm (4.610), 279.5 (3.318), 287.0 (3.291); IR (KBr) 2972, 2872;
1H NMR (500 MHz, CDCl3) δ 0.83 (s, 3 H), 0.93 (ddd, J ) 12.8, 5.0,
3.7 Hz, 1 H), 1.07 (s, 9 H), 1.22-1.26 (m, 1 H), 1.29-1.35 (m, 1 H),
1.36-1.45 (mc, 1 H), 1.51 (dt, J ) 12.8, 3.4 Hz, 1 H), 1.55-1.62 (mc,
1 H), 1.74-1.84 (mc, 3 H), 1.93 (ddt, J ) 14.6, 5.0, 3.8 Hz, 1 H), 2.04
(ddd, J ) 11.9, 8.1, 3.8 Hz, 1 H), 2.29 (ddd, J ) 14.6, 5.6, 3.1 Hz, 1
H), 2.63 (dt, J ) 8.5, 3.6 Hz, 1 H), 2.75-2.82 (mc, 1 H), 2.94 (sbr, 1
H), 3.25 (dd, J ) 8.8, 7.4 Hz, 1 H), 3.79 (s, 3 H), 6.63 (d, J ) 2.8 Hz,
(100) [M+], 281.1 (41) [M+ - C4H9+], 263.1 (61) [M+ - C4H9
-H2O]; EI HRMS m/e 338.2245, C23H30O2 requires 338.2246.
+
Acknowledgment. We thank the Deutsche Forschungsge-
meinschaft (SFB 416), the Schering AG, and the Fonds der
Chemischen Industrie for generous support.
Supporting Information Available: Experimental proce-
dures with NMR assignments for the compounds 5-9, 11-12,
15-17, 20-22, and 2c-e (12 pages, print/PDF). See any
current masthead page for ordering information and Web access
instructions.
JA981539O