Studies on chromium(0)-promoted higher-order cycloaddition-based benzannulation. Total synthesis of (+)-estradiol

Article abstract of DOI:10.1021/ja991016w

A benzannulation sequence featuring [6π + 4π] cycloaddition of (η⁶- thiepin 1,1-dioxide)tricarbonylchromium(0) complexes with highly substituted dienes followed by Ramberg-Backlund rearrangement has been developed. Enantiomerically pure (+)-estradiol (estra-1,3,5(10)-triene-3,17β-diol) has been synthesized by employing a higher-order cycloaddition between an appropriately substituted thiepin dioxide chromium(0) complex and a diene panner derived from an enantiomerically pure indandione precursor as the key ring construction event. Subsequent Ramberg-Backlund rearrangement of this cycloadduct and routine functional group interchanges afforded the steroid target.

Full text of DOI:10.1021/ja991016w

J. Am. Chem. Soc. 1999, 121, 8237-8245
8237
Studies on Chromium(0)-Promoted Higher-Order Cycloaddition-Based
Benzannulation. Total Synthesis of (+)-Estradiol
James H. Rigby,* Namal C. Warshakoon, and Anne J. Payen
Contribution from the Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
ReceiVed March 29, 1999
Abstract: A benzannulation sequence featuring [6π + 4π] cycloaddition of (η6-thiepin 1,1-dioxide)-
tricarbonylchromium(0) complexes with highly substituted dienes followed by Ramberg-Ba¨cklund rearrange-
ment has been developed. Enantiomerically pure (+)-estradiol (estra-1,3,5(10)-triene-3,17â-diol) has been
synthesized by employing a higher-order cycloaddition between an appropriately substituted thiepin dioxide
chromium(0) complex and a diene partner derived from an enantiomerically pure indandione precursor as the
key ring construction event. Subsequent Ramberg-Ba¨cklund rearrangement of this cycloadduct and routine
functional group interchanges afforded the steroid target.
In recent years, higher-order cycloaddition reactions have
been shown to be powerful methods for the rapid construction
of stereochemically rich and structurally elaborate polycyclic
systems in a variety of contexts.1,2 Certainly, one of the most
versatile 6π partners for applications to natural product synthesis
is the thiepin dioxide ligand system. Complex 1 has been shown
to undergo smooth cycloaddition with a range of 4π partners
to afford cycloadducts that are amenable to various postcy-
cloaddition heteroatom extrusion protocols.3
Scheme 1
Ten-membered carbocycles, for example, can be quickly
accessed via a cycloaddition-cheletropic extrusion sequence 1
f 2 f 3 (Scheme 1). A particularly powerful and comple-
mentary application of this cycloaddition-heteroatom extrusion
technology is the net benzannulation sequence 1 f 2 f 4
(Scheme 1), wherein SO2 excision occurs as part of a Ramberg-
Ba¨cklund rearrangement process.4 Noteworthy features of this
protocol include the simultaneous formation of two rings, rather
than the usual one, and that all six of the carbon atoms
comprising the incipient benzo ring are delivered by the thiepin
dioxide triene moiety.
determining whether structurally elaborate diene partners can,
in fact, participate in the process in an efficient fashion (eq 1).
While these sequences are quite attractive and show much
promise in relatively simple applications, several critical issues
must be addressed in more complex environments if this
methodology is to become a generally useful addition to the
synthetic repertoire. Among the most important of these is
establishing the regioselectivity profile of the cycloaddition step
when unsymmetrically substituted trienes are employed, and
We wish to report that these questions have now been answered
within the setting of a total synthesis of enantiomerically pure
(+)-estradiol (8), one of the most potent estrogens, in which
the higher-order cycloaddition-Ramberg-Ba¨cklund protocol
serves as the key strategy level transformation.
Construction of the tetracyclic steroid nucleus has long served
as an important forum for illustrating the scope and limitations
of new synthetic methods,5 and developing a novel approach
into the estrone ring system was viewed as an excellent
opportunity for evaluating several critical aspects of our
cycloaddition benzannulation protocol. The salient features of
the synthesis strategy are outlined in Scheme 2. In terms of the
(1) For general reviews, see: (a) Rigby, J. H. Acc. Chem. Res. 1993,
26, 579. (b) Rigby, J. H. In AdVances in Metal-Organic Chemistry;
Liebeskind, L. S., Ed.; JAI Press: Greenwich, CT, 1995; Vol. 4, pp 89-
127. (c) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (d)
Rigby, J. H. Org. React. 1997, 49, 331.
(2) For some representative applications of Cr(0)-mediated cycloaddi-
tions, see: (a) Rigby, J. H.; Sugathapala, P.; Heeg, M. J. J. Am. Chem.
Soc. 1995, 117, 8851. (b) Rigby, J. H.; Niyaz, N. M.; Short, K.; Heeg, M.
J. J. Org. Chem. 1995, 60, 7720. (c) Rigby, J. H.; Pigge, F. C. J. Org.
Chem. 1995, 60, 7392. (d) Rigby, J. H.; Warshakoon, N. C.; Heeg, M. J.
J. Am. Chem. Soc. 1996, 118, 6094. (e) Rigby, J. H.; Niyaz, N. M.;
Sugathapala, P. J. Am. Chem. Soc. 1996, 118, 8178. (f) Rigby, J. H.; Kirova-
Snover, M. Tetrahedron Lett. 1997, 38, 8153. (g) Rigby, J. H.; Hu, J.; Heeg,
M. J. Tetrahedron Lett. 1998, 39, 2265.
(3) (a) Rigby, J. H.; Ateeq, H. S.; Krueger, A. C. Tetrahedron Lett. 1992,
33, 5873. (b) Rigby, J. H.; Krueger, A. C. Synlett, 1993, 829.
(4) Rigby, J. H.; Warshakoon, N. C. J. Org. Chem. 1996, 61, 7644.
(5) For an overview of some recent advances in the synthesis of estrone
steroids, see: (a) Zeelen, F. J. Nat. Prod. Rep. 1994, 11, 607. (b) Tietze,
L. F.; No¨bel, T.; Spescha, M. J. Am. Chem. Soc. 1998, 120, 8971.
10.1021/ja991016w CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/31/1999

8238 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Rigby et al.
Scheme 2
synthesis end-game, it was envisioned that the ∆7,8-intermediate
9 derived directly from Ramberg-Ba¨cklund rearrangement of
key cycloadduct 10 could be processed without much difficulty
to deliver the requisite trans-BC fusion in 8. However, at the
outset of this investigation crucial questions remained regarding
regiocontrol during the cycloaddition between 4-substituted thie-
pin dioxide complex 11 and the structurally complex diene 12.
A key feature of the synthesis was the expectation that diene
12 could be easily prepared from the enantiomerically pure in-
dandione 13,6 which is readily available from microbial degra-
dation of the abundant soya sterols sitosterol and campesterol.7
With a viable strategy delineated, attention was initially
directed toward establishing the regiochemical preferences for
the photocycloaddition of substituted thiepin dioxide complexes
with various dienes. This aspect of the strategy design was a
source of some concern, since earlier studies in our laboratory
on the regioselectivity of metal-mediated [6π + 4π] cycload-
ditions with substituted cycloheptatriene complexes revealed a
mixed set of results in which no clear selectivity trends could
be discerned when electronic effects were considered.8 This
situation is in stark contrast to the Diels-Alder and other
cycloaddition reactions in which electronic effects strongly and
predictably influence the regiochemical course of reaction. On
the basis of our view of the mechanistic pathway followed by
Cr(0)-promoted cycloadditions,8 it was reasoned that properly
designed and positioned substituents of sufficient steric hin-
drance might offer a reliable regiocontrol strategy. Silicon-based
substituents were selected for initial study since they are
frequently effective steric control elements, and there exists a
number of methods by which they can be transformed, after
cycloaddition, into oxygen substituents as required in the steroid
target molecule.9,10 A search for preparative methods for these
complexes was then initiated.
As studies on making substituted thiepin dioxide ligands
moved forward, it became clear that convenient access to these
6π partners was quite difficult, if not impossible to achieve,
using conventional preparative methods. However, an intriguing
and somewhat obscure report a number of years ago by Khand
and Pauson11 on a cobalt-mediated cycloaddition between phen-
ylacetylene and divinyl sulfone to give 4-phenyldihydrothiepin
dioxide presented a possible solution to our problem, if the
reaction could be successfully extended to include bulkier sili-
con-substituted alkynes. Thus, the corresponding trimethylsi-
lylacetylenedicobalt hexacarbonyl complex was prepared and
exposed to divinyl sulfone in refluxing toluene. To our delight,
this afforded the heterocycle 14 in modest, but serviceable
yields. Although the yield was relatively low, the reaction proved
to be amenable to scale-up so sufficient quantities of material
could be secured in this fashion. Subsequent oxidation to the
triene via the usual halogenation-dehydrohalogenation protocol
and metalation under standard conditions provided the well-
behaved complex 16 in good yield.
A brief examination of this unusual Co-mediated cycload-
dition process to assess its generality for preparing a range of
substituted dihydrothiepin dioxides revealed that bis(trimeth-
(7) (a) Biggs, C. B.; Pyke, T. R.; Wovcha, M. G. U.S. Patent 4,062,729,
1977; Chem. Abstr. 1978, 88, P188129t. (b) Cooper, G. F.; Van Horn, A.
R. Tetrahedron Lett. 1981, 22, 1479.
(8) Rigby, J. H.; Ateeq, H. S.; Charles, N. R.; Cuisiat, S. V.; Ferguson,
M. D.; Henshilwood, J. A.; Krueger, A. C.; Ogbu, C. O.; Short, K. M.;
Heeg, M. J. J. Am. Chem. Soc. 1993, 115, 1382.
(9) (a) Partch, R. E. J. Am. Chem. Soc. 1967, 89, 3662. (b) Kalman, J.
R.; Pinhey, J. T.; Sternhell, S. Tetrahedron Lett. 1972, 5369.
(10) (a) Kumada, M.; Tamao, K.; Yoshida, J. J. Organomet. Chem. 1982,
239, 115. (b) Fleming, I. In Organosilicon and Bioorganosilicon Chemistry;
Sakurai, H., Ed.; Ellis Horwood: Chichester, 1985; p 197.
(11) Khand, I. U.; Pauson, P. L. Heterocycles 1978, 11, 59.
(6) We are grateful to Pharmacia & Upjohn for providing very generous
supplies of this compound for our studies.

Total Synthesis of (+)-Estradiol
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8239
ylsilyl)acetylene did not undergo cycloaddition under these
conditions, although diphenylacetylene did. A thorough appraisal
of this reaction is now underway in our laboratory.
With the key TMS-substituted complex 16 in hand, attention
turned to exploring its cycloaddition chemistry to evaluate
regioselection trends. Thus, irradiating 16 in the presence of
piperylene afforded cycloadduct 17 as a single stereo- and
regioisomer. As anticipated, the reaction proceeded through an
endo transition state and the diene approached the triene from
what would appear to be the least hindered orientation. A more
revealing result was obtained by reacting complex 16 with the
structurally elaborate diene 18,12 which provided tetracyclic
adduct 19 in nearly quantitative yield, once again, as a single
isomer. It was gratifying that both cycloaddition events pro-
ceeded with high regioselectivity in the sense required for the
projected synthesis of estradiol.
In an effort to install functionality that would preclude the
undesired isomerization process, 13 was efficiently converted
by a series of routine reactions into the protected hydroxy
lactone 24 as a mixture of isomers (eq 6). This material was
then further transformed into iodoformate 25 via treatment of
the corresponding lactol with iodobenzene diacetate (IBDA) and
I2.16 It was anticipated that dehydrohalogenation to the vinyl
group could be achieved in 25 without concomitant isomeriza-
tion, since the ethylidene isomer would no longer benefit from
conjugation with a carbonyl group.
The success of this trial cleavage prompted a more detailed
examination of the preparation of the lactol precursor in an effort
to effectively control the stereochemistry of the ketone reduction
step. To our delight, it was found that L-Selectride (Aldrich) at
-78 °C converted diketo ester 22 directly into keto lactol 26 in
excellent yield with complete control of stereochemistry. It is
noteworthy that reduction of the cyclopentanone did not occur
under these conditions. This material was then subjected to the
IBDA/I2 fragmentation conditions, which afforded the stereo-
chemically homogeneous iodoformate 27 in good yield. Un-
fortunately, attempted dehydrohalogenation of this material
using a variety of bases gave the desired vinyl formate in no
better than 30% yield (eq 8). Clearly, an alternative entry into
the diene was required.
Based on our own earlier experience with oxidative decar-
boxylation using Pb(OAc)4/Cu(OAc)2 and recognizing that
related lactol cleavages can be effected with FeSO417 and Mn-
(OAc)2,18 both in the presence of catalytic Cu(OAc)2, we elected
to explore modified cleavage conditions that incorporated Cu-
(OAc)2 as an electron-transfer agent. It was hoped that these
modified reaction conditions could produce the requisite alkene
directly during the ring-opening step. In the event, we were most
With the successful synthesis and cycloaddition chemistry
of complex 16 established, construction of enantiomerically pure
diene 12 from indandione 13 became our principal focus (see
Scheme 2). Compound 13 is, in principle, a very attractive
steroid CD ring building block and has been employed for that
purpose on several previous occasions;7a,13 however, it had never
been modified in a fashion that provided useful precedent to
support our projected processing into the diene. Initially, it was
envisioned that oxidative decarboxylation of the proprionate side
chain in 13 using one of several Pb(IV)- or I(III)-based methods
should lead to vinyl dione 20, which could then be further
converted to the desired diene 12 in straightforward fashion.
Unfortunately, subjecting the dione acid to either Pb(OAc)4/
Cu(OAc)214 or PhI(OAc)2/Cu(OAc)215 led only to the conjugated
enone 21 as a mixture of isomers in modest yields.
(14) (a) Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 279. (b)
Kochi, J. K. J. Am. Chem. Soc. 1965, 87, 1811. (c) Kochi, J. K.; Bacha, J.
D.; Bethea, T. W. J. Am. Chem. Soc. 1967, 89, 6538. (d) Kochi, J. K.;
Bacha, J. D. J. Org. Chem. 1968, 33, 2746. (e) Ogibin, Y. N.; Katzin, M.
I.; Nikishin, G. I. Synthesis 1974, 889.
(15) Concepcion, J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
(16) Francisco, C. G.; Freire, R.; Rodriguez, M. S.; Suarez, E. Tetrahe-
dron Lett. 1987, 28, 3397.
(17) Schreiber, S. L.; Hulin, B.; Liew, W. F. Tetrahedron 1986, 42, 2945.
(18) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524.
(12) Woski, S. A.; Koreeda, M. J. Org. Chem. 1992, 57, 5736.
(13) (a) Guarna, A.; Occhiato, E. G.; Machetti, F.; Scarpi, D. J. Org.
Chem. 1998, 63, 4111. (b) Stork, G.; Clark, G.; Weller, T. Tetrahedron
Lett. 1984, 25, 5367. (c) Stork, G.; Clark, G.; Shiner, C. S. J. Am. Chem.
Soc. 1981, 103, 4948.

8240 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Rigby et al.
cycloaddition studies in our laboratory that suggested the pro-
jected Cr(0)-promoted [6π + 4π] cycloaddition would proceed
more efficiently and with greater selectivity if the ketone in 31
was reduced to the â-oriented alcohol and protected.19 Therefore,
31 was reduced to the corresponding â-alcohol as a single
isomer with KBH4 and protected as the TBS ether in excellent
overall yield for the two steps.
pleased to find that irradiating lactol 26 with a mixture of IBDA/
cat. Cu(OAc)2 and pyridine in cyclohexane afforded 28 in 70%
yield. Even more encouraging for our purposes, a Pb(OAc)4/
Cu(OAc)2 combination provided 82% of the desired vinyl
formate 28. It appears that these novel fragmentation conditions
offer certain advantages over existing methods, and a detailed
study of their scope and limitations is currently underway in
our laboratory.
The stage was now set to carry out the crucial higher-order
cycloaddition step to assemble the tetracyclic target system, and
based on the preliminary studies described above, it was
expected that this operation would proceed as required. In the
event, a mixture of complex 16 and excess diene 34 were
irradiated through a uranium glass filter20 for several hours at
which time the original 1,2-dichloroethane solvent was replaced
with MeOH and the solution stirred under a blanket of CO for
15 h.21 As anticipated, a single regio- and stereoisomer was
isolated from this reaction. The previous model studies with
complex 16 (vide supra) correctly predicted the regiochemical
outcome of the current reaction, and the normal endo-selective
cycloaddition pathway once again prevailed to deliver compound
35 in quite good yield. At this stage of the synthesis, it becomes
important to note that the endo transition state that dominates
these reactions delivers an adduct possessing the unnatural
stereogenicity at C-9 (steroid numbering). We were, of course,
well aware of this situation from the outset of this investigation,
but assumed that subsequent manipulations of the substrate
would afford the natural stereochemistry at this center as
precedented in the steroid literature.
With a new and reliable fragmentation protocol at our
disposal, the next task in this segment of the synthesis became
the completion of the diene preparation via a trans-diaxial
elimination of the alcohol resulting from the aforementioned
cleavage process. Routine saponification of 28 yielded 29, which
was treated with Ms2O/TEA to give the corresponding mesylate.
Subsequent exposure of this compound to t-BuOK in THF at 0
°C gave a 60% yield of an inseparable mixture of the desired
diene 31 and a regioisomeric diene 32 in a 1:2 ratio. This was
a disappointing result, but it suggested that subtle modification
of the reaction conditions could shift the product ratio in a more
favorable direction.
Toward this end, a second attempt to control this elimination
process was carried out. Thus, alcohol 29 was converted to the
tosylate 33 and again treated with t-BuOK/THF. Unfortunately,
these conditions provided only the undesired diene 32 in 65%
yield. We were quite pleased, however, when it was found that
by performing the elimination in DMSO instead of THF the
desired diene 31 was produced exclusively in a very respectable
78% yield. One final manipulation of this substrate was required
prior to attempting the key cycloaddition step. The need for
this particular operation was prompted by results from previous
(19) Rigby, J. H.; Ateeq, H. S. J. Am. Chem. Soc. 1990, 112, 6442.
(20) It has been determined that cycloadditions involving thiepin dioxide
complexes proceed best when irradiated through a uranium glass filter: ref
3a.
(21) Stirring under CO often enhances yields by collapsing intermediates
and facilitating decomplexation: Rigby, J. H.; Krueger, A. C. In AdVances
in Detailed Reaction Mechanisms; Coxon, J. M., Ed.; JAI: Greenwich, CT,
1995; Vol. 4, pp 1-40.

Total Synthesis of (+)-Estradiol
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8241
The projected end-game of the synthesis involved Ramberg-
Ba¨cklund conversion of 35 into the benzo-fused tetracycle.22
Following the sequence of steps that had proven most effective
during previous studies,4 35 was treated sequentially with
t-BuOK/THF at -105 °C, then excess NIS, and, finally, a
second equivalent of t-BuOK/THF at -105 °C. This set of steps
afforded a 65% yield of a mixture of the desired tetracycle 36
and an overoxidized, equilenin-type product, 37. It was reasoned
that the presence of excess NIS was responsible for the oxidation
to 37, so the reaction conditions were modified accordingly.
Employing only 1 equiv of NIS did indeed suppress the for-
mation of 37, but it also had the undesired effect of depressing
the yield of 36 to only 30%. After considerable experimentation
it was found that the cleanest conversion to 36 could be achieved
using 1 equiv of NCS as the halogen source (eq 15). It is
interesting to note that in previous studies on this type of
rearrangement, NCS was often the least effective electrophilic
reagent.4
alcohols were then exposed to Et3SiH/TFA in benzene25a,b to
provide the requisite trans-fused tetracycle 39 in 45% yield. The
synthesis of (+)-estradiol was completed by transforming the
trimethylsilyl substituent on the arene ring into the corresponding
phenol using the well-known Pb(OTFA)4/TFA procedure.26 The
resultant synthetic sample was shown to be identical in all
regards with authentic (+)-estradiol.
This study has revealed a number of important attributes of
thiepin dioxide as a 6π participant in the Cr(0)-promoted higher-
order cycloaddition process. Structurally elaborate dienes react
with good efficiency and high levels of regiocontrol are
frequently obtained when sterically hindered substituents are
present on the triene. These capabilities have been illustrated
in an efficiently total synthesis of (+)-estradiol, and the success
in this endeavor points to the utility of this chemistry in
evermore challenging syntheses. In addition, a novel radical-
based lactol fragmentation has been developed in conjunction
with these studies, which may provide advantages over existing
technology in this area.
With 36 in hand, the final assault on the estrogen target
required only reduction to the trans-fused tetracycle. To set the
stage for this reduction, it was assumed that equilibration of
the ∆7,8 unsaturation into conjugation with the A ring would
be routine. Indeed, in the natural series, it is quite difficult to
avoid this migration.23 However, as pointed out above, com-
pound 36 is epimeric to the natural series at C9, and as it turned
out, this minor difference contributed significantly to the
difficulties experienced in trying to move this alkene into
conjugation with the A-ring. For example, no reaction occurred
when 36 was treated with t-BuOK at room temperature in
various solvents, and decomposition ensued under more forcing
conditions. A number of other conditions were explored to no
avail. Finally, potassium 3-aminopropylamide (KAPA), an
exceptional base for effecting prototropic reactions, was exam-
ined.24 To our disappointment, exposing 36 to KAPA in
3-aminopropylamine (APA) under standard conditions reported
in the literature resulted only in recovered starting material.
Replacing APA with THF, however, resulted in the disappear-
ance of 36 to give an inseparable mixture of two new tetracycles
tentatively assigned structures 37 and 38 in 71% yield. The
replacement of the vinylic signal at δ 5.67 in the starting material
with a new signal at δ 5.44 confirmed the complete disappear-
ance of 36 and the appearance of a new isomer during this
reaction. Both of the new compounds were considered to be
useful for subsequent reduction to the requisite trans BC ring
fusion.25
Experimental Section27
General Procedure for the Preparation of Alkynecobalt Com-
plexes. Dicobalt octacarbonyl (5.0 g, 14.62 mmol) was dissolved in
CH2Cl2 (20 mL), and to this mixture was added a neat solution of the
alkyne (1.2 equiv) at room temperature. A rapid evolution of CO gas
resulted, and the color of the solution changed from purple to dark
red. At the completion of the reaction as indicated by TLC analysis
(10-15 min), the solvent was removed in vacuo and the crude residue
was chromatographed on silica gel with 100% hexane as the eluant to
afford the corresponding alkynecobalt complexes as viscous oils or
solids.
4-Trimethylsilyl-2,7-dihydrothiepin-1,1-dioxide (14). A mixture
of trimethylsilylacetylene complex (1.56 g, 4.77 mmol) and divinyl
sulfone (0.77 mL, 6.96 mmol) was heated in dry toluene (100 mL) at
reflux until the completion of the reaction as indicated by TLC analysis.
At this time, the mixture was filtered through a thin pad of Celite, the
filtrate was concentrated, and the residue was purified by column
chromatography (silica gel; 1:6 ethyl acetate/hexane) to afford sulfone
14, 0.30 g (30%), as a yellow oil: IR (neat) ν 3023, 2956, 1408, 1309,
1
1249, 1126, 1068 cm-1; H NMR (500 MHz, CDCl3) δ 0.14 (s, 9H),
3.60 (d, J ) 7.0 Hz, 2H), 3.72 (d, J ) 6.5 Hz, 2H), 5.97 (m, 1H), 6.18
(23) (a) Zderic, J. A.; Bowers, A.; Carpio, H.; Djerassi, C. J. Am. Chem.
Soc. 1958, 80, 2596. (b) Amorosa, M.; Caglioti, L.; Cainelli, G.; Immer,
H.; Keller, J.; Wehrli, H.; Mihailovic, M. L.; Schaffner, K.; Arigoni, D.;
Jeger, O. HelV. Chem. Acta 1962, 45, 2674.
(24) (a) Brown, C. A. Synthesis 1978, 754. (b) Brown, C. A.; Jadhav, P.
K. Org. Synth. 1987, 65, 224.
(25) (a) Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 1996, 37, 7403.
(b) Posner, G. H.; Switzer, C. J. Am. Chem. Soc. 1986, 108, 1239. (c)
Douglas, G. H.; Graves, J. M. H.; Hartley, D.; Hughes, G. A.; McLoughlin,
B. J.; Siddall, J.; Smith, H. S. J. Chem. Soc. 1963, 5072.
(26) (a) Kalman, J. R.; Pinhey, J. T.; Sternhell, S. Tetrahedron Lett. 1972,
5369. (b) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1979, 101,
215.
(27) For general experimental procedures used in this investigation,
see: ref 8.
(28) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck: Whitehouse
Station, NJ, 1996; p 630.
The mixture of 37 and 38 was first treated with HF/MeCN
to remove the hydroxyl group protection, and the resultant
(22) For a review of the Ramberg-Ba¨cklund reaction, see: (a) Paquette,
L. A. Org. React. 1977, 25, 1. For recent applications, see: (b) Grumann,
A.; Marley, H.; Taylor, R. J. K. Tetrahedron Lett. 1995, 36, 7767. (c)
Doomes, E.; McKnight, A. A. J. Heterocycl. Chem. 1995, 32, 1467. (d)
Alvarez, E.; Diaz, M. T.; Hanxing, L.; Martin, J. D. J. Am. Chem. Soc.
1995, 117, 1437.

8242 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Rigby et al.
(t, J ) 6.5 Hz, 1H), 6.62 (d, J ) 9.5 Hz, 1H): 13C NMR (125 MHz,
CDCl3) δ -2.3, 56.8, 55.1, 120.1, 127.9, 137.3, 150.4; MS m/e (rel
int) 137 (38), 78 (22), 77 (20), 73 (100), 59 (23); HRMS calcd for
C9H16SO2Si (M+) 216.0640, found 216.0639.
3110, 2667, 2550, 1260, 1120 cm-1; H NMR (500 MHz, CDCl3) δ
0.12 (s, 9H), 1.24 (m, 1H), 1.57 (m, 1H), 2.28 (m, 1H), 2.48 (m, 1H),
2.61 (m, 1H), 2.84 (m, 1H), 3.06-3.14 (m, 1H), 3.70 (m, 1H), 3.78 (s,
3H), 3.93 (m, 1H), 5.38 (m, 1H), 5.75 (d, J ) 12.5 Hz, 1H), 5.89 (m,
2H), 6.62 (bs, H1), 6.68 (m, 1H), 7.10 (d, J ) 14 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ -1.8, 27.4, 29.5, 37.2, 55.2, 65.4, 69.3, 112.0,
112.4, 119.4, 122.4, 125.9, 129.6, 130.1, 130.3, 139.7, 140.7, 141.1,
159.0; MS m/e (rel int) 335 (31), 336 (24), 263 (22), 210 (32), 187
(16); HRMS calcd for C22H28SO3Si (M+) 400.1528, found 400.1526.
(3aS,7aS)-4-Ethylidene-5,6,7,7a-tetrahydro-7a-methylindan-1,5-
dione. Oxidative Decarboxylation of Diketo Acid 13 (Kochi’s
Procedure).14a Lead tetraacetate (3.0 g, 6.72 mmol) was added to a
solution of diketo acid 13 (1.0 g, 4.20 mmol), Cu(OAc)2 (0.14 g, 0.76
mmol), and pyridine (0.40 mL, 5.04 mmol) in benzene (120 mL). The
mixture was flushed with nitrogen and carefully warmed to avoid rapid
and uncontrollable liberation of CO2. After the initial evolution of gases
had subsided, the reaction was refluxed for an additional 2 h. Ethylene
glycol and water were then added, and the layers were separated. The
organic layer was then washed sequentially with 10% aqueous HNO3
solution and H2O. The organic layer was dried (Na2SO4), and the solvent
was removed in vacuo. The residue was then chromatographed (silica
gel; 1:7 ethyl acetate/hexane) to afford enone 21, 0.30 g (38%), as a
colorless oil: IR (neat) ν 2134, 1660, 1655, 1460, 1240 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.92 (s, 3H), 1.81 (m, 2H), 1.95-2.06 (m, 5H),
2.31 (m, 1H), 2.44-2.61 (m, 3H), 2.71 (m, 1H), 5.74 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 13.8, 15.3, 20.6, 28.9, 36.3, 37.6, 47.8, 49.9,
81.5, 133.3, 136.9, 202.1, 218.5; MS m/e (rel int) 192 (100), 149 (28),
136 (28), 107(30), 93 (31); HRMS calcd for C12H16O2 (M+) 192.1150,
found 192.1149.
1
4-Trimethylsilylthiepin-1,1-dioxide (15). A solution of sulfone 14
(0.20 g, 0.92 mmol) in CH2Cl2 (5 mL) was treated with a solution of
Br2 (0.056 mL, 1.08 mmol), in CH2Cl2 (1 mL) at room temperature.
The progress of the reaction was monitored by TLC, and at the
completion of the reaction, the solvent and excess bromine were
removed in vacuo to afford a viscous oil. Methylene chloride (10 mL)
was added, the mixture was cooled to 0 °C, and triethylamine (0.28
mL, 2.01 mmol) was added dropwise. At the completion of the reaction
as indicated by TLC, the solvent was removed in vacuo to afford a
solid residue. This material was dissolved in EtOAc (20 mL), filtered,
and concentrated in vacuo, and the residue was purified via column
chromatography (silica gel; 4:1 hexane/ethyl acetate) to afford sulfone
15, 0.14 g (70%), as a white solid: mp 132-133 °C (CH2Cl2); IR
(CH2Cl2) ν 3943, 3756, 3692, 3067, 2975, 2685, 2410 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.25 (s, 9H), 6.65 (t, J ) 8.5 Hz, 2H), 6.89 (m,
2H), 6.97 (d, J ) 10.5 Hz, 1H); 13C NMR (125 Hz, CDCl3) δ -1.8,
132.4, 132.5, 133.5, 135.8, 138.8, 150.6; MS m/e (rel int) 136 (14),
135 (100), 73 (37); HRMS calcd for C9H14SO2Si (M+) 214.0483, found
214.0478. Anal. Calcd For C9H14SO2Si: C, 50.45; H, 6.50. Found: C,
49.93; H, 6.50.
(η6-4-Trimethylsilylthiepin-1,1-dioxide)tricarbonylchromium-
(0) (16). A mixture of tris(acetonitrile)tricarbonylchromium(0) [from
Cr(CO)6 (2.0 g, 9.08 mmol)] and 4-trimethylsilylthiepin-1,1-dioxide
15 (0.97 g, 4.54 mmol) was stirred in dry THF (20 mL) under argon
atmosphere for 15 min. At this time, the solvent was removed in vacuo,
and the crude residue was dissolved in CH2Cl2, filtered through Celite,
and concentrated in vacuo. The residue was dissolved in a small amount
of CH2Cl2 and charged onto a column of silica gel. The yellow
intermediate complex was removed by continuous washing with
hexanes and subsequent elution with 100% CH2Cl2 to afford the
complex 1.34 g (85%) as a red solid: mp 188-189 °C (CH2Cl2/
Oxidative Decarboxylation of Diketo Acid 13 (Ogibin’s Modi-
fication of Kochi’s Procedure).14e Solid Pb(OAc)4 was gradually added
over 3 h to a vigorously stirred, refluxing mixture of diketo acid 13
(2.0 g, 8.40 mmol), Cu(OAc)2 (0.17 g, 0.84 mmol), and pyridine (0.70
mL, 8.40 mmol) in benzene (120 mL). Stirring and refluxing was
continued for 1 h, and the reaction mixture was then allowed to cool
to room temperature. The resultant precipitate of Pb(OAc)4 was removed
by filtration and extracted with ether. The combined ethereal extracts
and the benzene solution were washed with 10% HCl, dried (Na2SO4),
and concentrated in vacuo. Purification of the residue via column
chromatography (silica gel; 1:7 ethyl acetate/hexane) afforded enone
21, 0.56 g (35%).
Oxidative Decarboxylation of Diketoacid 13 with Iodobenzene
Diacetate/Cu(OAc)2.16 A solution of diketo acid 13 (0.30 g, 1.25 mmol)
in dry benzene (40 mL) containing Cu(OAc)2 (0.045 g, 0.20 mmol)
and pyridine (0.070 mL, 0.87 mmol) was stirred for 15 min under argon.
Iodobenzene diacetate (2.01 g, 6.25 mmol) was added to this solution
in portions (1 mmol every 90 min), and the mixture was then refluxed
for 8 h. The reaction mixture was cooled and washed with 5% aqueous
hydrochloric acid solution and water. The aqueous layer was extracted
with EtOAc (3 × 10 mL); the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated. The residue was subjected
to column chromatography (silica gel; 1:7 ethyl acetate/hexane) to afford
enone 21, 0.097 g (40%).
(3aS,7aS)-1,5-Dioxo-4r-methylpropionic-3ar,4,5,6,7,7a-hexahy-
dro-7a-methylindan (22). A mixture of diketo acid 13 (2.0 g, 8.39
mmol) and p-toluenesulfonic acid (0.015 g, 0.083 mmol) in methanol
was heated at reflux for 2 h. After 2 h, the reaction mixture was cooled
to room temperature and diluted with EtOAc (20 mL). The organic
phase was washed with saturated aqueous NaHCO3 solution, water,
and brine. The combined organic extracts were dried (Na2SO4),
concentrated, and filtered through a silica gel plug to afford 1.90 g
(90%) of diketo ester 22 as a colorless oil: IR (neat) ν 3220, 2956,
2800, 1680, 1646, 1200 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.16 (s,
3H), 1.63 (m, 1H), 1.79 (m, 4H), 1.97 (m, 1H), 2.05 (m, 1H), 2.23 (m,
1H), 2.36 (m, 1H), 2.42-2.59 (m, 5H), 3.65 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 13.4, 21.3, 22.2, 30.3, 31.5, 36.0, 37.3, 48.9, 49.4,
51.5, 173.9, 210.3, 219.1; MS m/e (rel int) 219 (48), 218 (95), 190
(84), 162 (66), 126 (45), 94 (74), 55 (100); HRMS calcd for C14H20O4
(M+) 252.1361, found 252.1360. Anal. Calcd for C14H20O4: C, 65.63;
H, 7.99. Found: C, 65.98; H, 8.07.
hexanes); IR (Nujol) ν 3035, 2020, 1974, 1920, 1280, 1164, 1120 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.42 (s, 9H), 4.88 (m, 1H), 5.08 (m,
1H), 5.33 (m, 2H), 6.03 (d, J ) 7.8 Hz, 1H): 13C NMR (75 MHz,
CDCl3) δ -1.3, 94.6, 95.9, 104.3, 216.1; MS m/e (rel int) 202 (15),
135 (67); HRMS calcd for C12H14SO5SiCr (M+) 349.9736, found
349.9738. Anal. Calcd for C12H14SO5SiCr: C, 41.14; H, 4.03. Found:
C, 41.35; H, 4.15.
[1Hâ,6Ηâ]-7r-Methyl-3-trimethylsilyl-11-thiabicyclo[4.4.1]undeca-
2,4,8-triene-11,11-dioxide (17). A mixture of chromium complex 16
(0.20 g, 0.57 mmol) and piperylene (0.22 mL, 2.28 mmol) in
1,2-dichloroethane (20 mL) was irradiated under standard photochem-
ical conditions (medium-pressure Hg lamp, uranium glass filter) until
disappearance of the starting materials as indicated by TLC analy-
sis. The solvent was removed in vacuo and the residue dissolved in
MeOH and stirred under a blanket of CO gas (balloon) for 12 h. The
solvent was removed, and the residue was purified via column
chromatography (silica gel; 6:1 hexanes/ethyl acetate) to afford
cycloadduct 17, 0.14 g (85%), as a white solid: mp 142-143 °C
(CH2Cl2/pentane); IR (CH2Cl2) ν 3154, 3007, 1726, 1291, 1120 cm-1
;
1H NMR (500 MHz, CDCl3) δ 0.10 (s, 9H), 1.32 (d, J ) 7.5 Hz, 3H),
2.61 (m, 1H), 2.94-2.98 (m, 1H), 3.30 (m, 1H), 3.63 (m, 1H), 3.89
(m, 1H), 5.45 (m, 1H), 5.55 (dd, J ) 13, 8 Hz, 1H), 5.66 (m, 2H),
6.04 (d, J ) 12.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ -1.8, 20.6,
26.5, 32.1, 66.06, 71.0, 119.7, 127.8, 129.4, 130.4, 138.1, 141.3; MS
m/e (rel int) 145 913), 144 (19), 135 (12), 73 (100); HRMS calcd for
C14H22SO2Si (M+) 282.1109, found 282.1107.
[1Hâ,14Hâ]-13(S)-8-Methoxy-17-trimethylsilyl-19-thiatetracyclo-
[12.4.1.0.4,1305,10]nonadeca-3,5,7,9,15,17-hexaene-19,19-dioxide (19).
A mixture of chromium complex 16 9.20 g, 0.57 mmol) and diene
1812 (0.42 g, 2.28 mmol) in 1,2-dichloroethane (20 mL) was irradiated
under standard photochemical conditions (medium-pressure Hg lamp,
uranium glass filter) until the disappearance of the starting materials
as indicated by TLC analysis. Standard workup procedure (see above)
followed by purification via column chromatography (silica gel 6:1
hexanes/ethyl acetate) afforded cycloadduct 120, 0.21 g (95%), as a
white solid: mp 165-166 °C (CH2Cl2/pentane); IR (CH2Cl2) ν 3147,
(3aS,7aS)-1,5-Dihydroxy-4r-â-propionolactone-31,4,5,6,7,7a-

Total Synthesis of (+)-Estradiol
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8243
hexahydro-7a-methylindan (23). To a solution of diketoester 22 (0.50
gm, 1.98 mmol) in methanol at 0 °C was added solid potassium
borohydride (0.16 g, 2.98 mmol), and the mixture was allowed to stir
at that temperature for a further 30 min. The solvent was removed in
vacuo, the residue was dissolved in EtOAc and washed with water,
and the aqueous layer was washed with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel; 1:2 ethyl acetate/hexane) to afford 23, 0.38 g (85%),
as a white solid: mp 121-122 °C (CH2Cl2/pentane); IR (NaCl, CH2-
was removed in vacuo, and the residue was purified by column
chromatography (silica gel; 1:3 ethyl acetate/hexane) to afford lactol
26, 0.38 g (86%), as a white solid: mp 87-88 °C (CH2Cl2/hexane);
1
IR (NaCl, CH2Cl2) ν 3408, 2940, 1735, 1453 cm-1; H NMR (400
MHz, CDCl3) δ 0.87 (s, 3H), 1.43-2.25 (m, 12H), 2.46 (m, 2H), 3.75
(m, 1H), 4.74 (m, 1H), 5.27 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ
12.6, 21.2, 23.5, 26.8, 27.3, 27.6, 33.4, 35.4, 39.7, 73.9, 91.7, 96.8,
220.6; MS m/e (rel int) 150 (16), 86 (65), 84 (100); HRMS calcd For
C13H20O3 (M+) 224.1412, found 224.1416. Anal. Calcd for C13H20O3:
C, 67.60; H, 8.99. Found: C, 67.88; H, 9.07.
1
Cl2) ν 3220, 2890, 1660, 1220 cm-1; H NMR (500 MHz, CDCl3) δ
(3aS,7aS)-5-Formyloxy-4r-(2′-iodoethyl)-1-oxo-3a,4,5,6,7,7a-
hexahydro-7a-methylindan (27). A mixture of lactol 26 (0.38 g, 1.76
mmol), iodobenzene diacetate (0.68 g, 2.12 mmol), and iodine (0.22
g, 1.76) in cyclohexane (20 mL) was photolyzed with a 150 W tungsten
lamp. The reaction was stopped when the violet color disappeared from
the reaction mixture. No starting material was detected in the mixture
at this time. The reaction was diluted with CH2Cl2 (20 mL) and filtered
through a thin pad of Celite. The filtrate was concentrated, and the
residue was purified by column chromatography (silica gel; 1:5 ethyl
acetate/hexane) to afford iodo formate 22, 0.47 g (78%), as a colorless
0.90 (s, 3H), 1.06-2.17 (m, 13H), 2.47-2.58 (m, 1H), 2.66-2.72 (m,
1H), 3.68 (t, J ) 8.5 Hz, 1H), 3.86 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 11.1, 22.2, 24.0, 27.8, 29.5, 30.7, 33.7, 37.2, 43.5, 47.7, 80.7,
84.0, 171.3; MS m/e (rel int) 224 (30), 206 (28), 180 (85), 165 (50),
147 (60), 133 (59), 107 (100); HRMS calcd for C13H20O3 (M+)
224.1412, found 224.1412.
(3aS,7aS)-5-Hydroxy-4r-â-propionolactone-1-[(tert-butyldimeth-
ylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-7a-methylindan (24). A mixture
of hydroxy lactone 23 (0.50 g, 2.23 mmol), imidazole (0.40 g, 5.89
mmol), and tert-butyldimethylsilyl chloride (0.47 g, 3.14 mmol) in
dimethylformamide (2 mL) was stirred for 18 h at room temperature.
Water (10 mL) was added, and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed thoroughly
with water (5 × 10 mL) and brine, and dried (Na2SO4). The solvent
was removed in vacuo, and the residue was purified by column
chromatography (silica gel; 1:10 ethyl acetate/hexane) to afford 24,
0.64 g (85%), as a colorless oil: IR (neat) ν 3000, 2986, 1680, 1223
oil: [R]25 ) +89.0 (c ) 1, CHCl3); IR (neat) ν 2940, 2882, 1735,
D
1
1456, 1265, 1028 cm-1; H NMR (500 MHz, CDCl3) δ 0.93 (s, 3H),
1.49-1.99 (m, 8H), 2.12 (m, 2H), 2.46 (m, 1H), 3.11 (m, 1H), 3.22
(m, 1H), 3.22 (m, 1H), 5.27 (m, 1H), 8.06 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 3.6, 2.9, 21.8, 26.4, 26.5, 31.9, 35.2, 39.9, 43.2, 47.8,
69.0, 160.3, 219.4; MS m/e (rel int) 305 (25), 225 (12), 177 (82), 149
(100), 105 (55), 93 (88); HRMS calcd for C13H19O3I (M+) 350.0377,
found 350.0375.
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.001 (s, 3H), 0.006 (s, 3H),
(3aS,7aS)-4r-Ethenyl-5r-formyloxy-1-oxo-3,4,5,6,7,7a-hexahydro-
7a-methylindan (28). To a solution of iodo formate 27 (0.20 g, 0.57
mmol) in benzene (1.0 mL) was added a solution of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (0.10 mL, 0.68 mmol) in benzene (1 mL). The
resultant mixture was heated at reflux while the progress of the reaction
was monitored by TLC analysis. At the completion of the reaction as
indicated by TLC analysis, the reaction was allowed to cool to room
temperature. Water (2.0 mL) was added, and the mixture was extracted
with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by the column chromatography (silica gel; 1:6 ethyl acetate/
hexane) to afford formate 28, 0.04 g (30%), as a thick, viscous oil:
[R]25D ) 78.2° (c ) 1, CHCl3); IR (neat) ν 2945, 1721, 1171 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.93 (s, 3H), 1.45-2.16 (m, 8H), 2.43 (m,
2H), 5.10-5.20 (m, 3H), 5.67 (m, 1H), 8.05 (s, 1H): 13C NMR (75
MHz, CDCl3) δ 12.7, 22.1, 26.3, 26.4, 35.1, 42.5, 44.7, 72.5, 117.6,
135.9, 160.3, 219.6; MS m/e (rel int) 176 (68), 148 (22), 133 (45), 119
(67), 105 (83), 79 (100); HRMS calcd for C13H18O3 (M+) 222.0932,
found 222.1259.
Attempted Oxidative Fragmentation of Lactol 26 with Iodoben-
zene Diacetate/Copper Acetate Mixture. An oven-dried flask equipped
with a water reflux condenser was charged with a mixture of lactol 26
(0.95 g, 4.30 mmol), iodobenzene diacetate (1.66 g, 5.16 mmol), and
copper acetate (1.20 g, 6.45 mmol) in cyclohexane (20.0 mL) and
photolyzed with 150 W tungsten lamp, while the progress of the reaction
was monitored by TLC. At the completion of the reaction, the mixture
was filtered through a thin pad of Celite, the filtrate was concentrated,
and the residue was purified by column chromatography (silica gel;
1:10 ethyl acetate/hexane) to afford formate 28, 0.66 g (70%).
Oxidative Fragmentation of Lactol 26 with Lead Tetracetate/
Copper Acetate. A mixture of lactol 26 (0.55 g, 2.48 mmol), lead
tetraacetate (1.76 g, 3.97 mmol), copper acetate (0.08 g, 0.45 mmol),
and pyridine (0.24 mL, 2.97 mmol) in benzene (20.0 mL) was heated
at reflux while the progress of the reaction was monitored by TLC. At
the completion of the reaction as indicated by TLC, the reaction was
cooled to room temperature. The mixture was filtered through a thin
pad of Celite, the filtrate was concentrated, and the residue was
chromatographed (silica gel, 1:10 ethyl acetate/hexane) to afford formate
28, 0.45 g (82%).
0.86 (s, 3H), 0.87 (s, 9H), 1.33-1.99 (m, 12H), 2.50-2.57 (m, 1H),
2.65-2.71 (m, 1H), 3.58 (t, J ) 8.5 Hz, 1H), 3.84 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ -4.9, -4.5, 11.4, 18.0, 21.7, 22.4, 24.0, 25.7,
25.8, 27.9, 29.5, 31.1, 34.1, 37.3, 47.3, 80.6, 84.4, 141.3; MS m/e (rel
int) 281 (100), 205 (22), 147 (28), 75 (65); HRMS calcd for C19H34O3-
Si (M+) 338.2277, found 338.2270.
(3aS,7aS)-5-Formyloxy-4r-(2′-iodoethylene-1-[tert-(butyldimeth-
yl)silyloxy]-3a,4,5,6,7,7a-hexahydro-7a-methylindan (25). To a solu-
tion of lactone 24 (0.88 g, 2.56 mmol) in dry CH2Cl2 (40 mL) at -78
°C was added a solution of diisobutylaluminum hydride (DIBALH)
(1.0 M soln in hexane, 2.84 mL, 2.84 mmol). The mixture was stirred
at -78 °C for 1 h and then quenched by addition of MeOH (8 mL).
Water (20 mL) was added, and the mixture was diluted with CH2Cl2
(80 mL). The layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 40 mL). The solvent was removed in vacuo, and the
residue was purified by column chromatography (silica gel; 1:8 ethyl
acetate/hexane) to afford 0.6 g (70%) of the corresponding hemiacetal.
A mixture of this lactol (0.50 g, 1.47 mmol), iodobenzene diacetate
(0.52 g, 1.62 mmol), and iodine (0.38 g, 1.47 mmol) in cyclohexane
(10 mL) was photolyzed with a 150 W tungsten lamp. The reaction
was stopped when the purple color of the solution had disappeared. At
this time, no starting material remained in the reaction mixture. The
mixture was diluted with CH2Cl2 (20 mL) and filtered through a thin
pad of Celite. The filtrate was concentrated, and the residue was
chromatographed (silica gel; 1:10 ethyl acetate/hexane) to afford iodo
formate 25, 0.53 g (75%), as a colorless oil: IR (neat) ν 2929, 2856,
1
1724, 1462, 1250, 1175 cm-1; H NMR (500 MHz, CDCl3) δ -0.01
(s, 6H), 0.80 (s, 3H), 0.86 (s, 9H), 1.06-1.95 (m, 12H), 3.15 (m, 2H),
3.54 (t, J ) 8 Hz, 1H), 4.62 (m, 1H), 8.08 (s, 1H); 13C NMR (125
MHz, CDCl3) δ -4.9, -4.5, 10.4, 11.1, 23.6, 25.7, 27.5, 30.9, 34.3,
35.2, 42.0, 46.8, 76.6, 80.7, 160.8; MS m/e (rel int) 409 (23), 341 (22),
297 (16), 161 (28); HRMS calcd for C19H35O3I (M+) 466.1398, found
(M+ - 57) 409.0701.
Preparation of Ketolactol 26. To a solution of diketo ester 22 (0.50
g, 1.98 mmol) in dry THF at -78 °C was added a solution of
L-Selectride (1.0 M soln in THF, 4.00 mL, 4.00 mmol). The solution
was stirred at -78 °C for an additional 30 min, and then a solution of
5% aqueous hydrochloric acid solution (10 mL) was added. EtOAc
(20 mL) was added, and the resultant mixture was allowed to stir at
room temperature for 2 h. The aqueous layer was extracted with EtOAc
(3 × 20 mL), washed with brine, dried (Na2SO4), and passed through
a plug of silica gel to remove the inorganic byproducts. The solvent
(3aS,7aS)-4r-Ethenyl-5r-hydroxy-1-oxo-3a,4,5,6,7,7a-hexahydro-
7a-methylindan (29). To a solution of formate 28 (0.20 g, 0.90 mmol)
in methanol (5 mL) was added potassium carbonate (K2CO3) (0.14 g,
0.99 mmol) at room temperature. The resultant mixture was allowed

8244 J. Am. Chem. Soc., Vol. 121, No. 36, 1999
Rigby et al.
to stir while the progress of the reaction was monitored by TLC. At
the completion of the reaction, the solvent was removed, and the residue
was dissolved in water (10 mL) and acidified with 5% aqueous
hydrochloric acid solution. The resultant mixture was extracted with
EtOAc (3 × 10 mL), washed with brine, and dried (Na2SO4). The
solvent was removed in vacuo, and the residue was purified by column
chromatography (silica gel; 1:6 ethyl acetate/hexane) to afford alcohol
29, 0.15 g (85%), as a white solid: [R]25D ) +6.5 (c ) 1, CHCl3); mp
81-82 °C (EtOAc/hexane); IR (NaCl, CH2Cl2) ν 3471, 2939, 1731
cm-1; 1H NMR (500 MHz, CDCl3) δ 0.87 (s, 3H), 1.42-1.89 (m, 7H),
2.06 (m, 2H), 2.39 (m, 1H), 2.39 (m, 1H), 3.89 (m, 1H), 5.16 (m, 2H),
5.88 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 12.7, 22.1, 25.8, 28.6,
35.2, 40.8, 45.9, 69.3, 116.9, 137.6, 220.5; MS m/e (rel int) 194 (49),
139 (44), 109 (73), 97 (100), 81 (74), 79 (91); HRMS calcd For
C12H18O2 (M+) 194.1306, found 194.1303. Anal. Calcd For C12H18O2:
C, 74.18; H, 9.34. Found: C, 73.97; H, 9.31.
in vacuo, and the residue was dissolved in EtOAc (20 mL). The mixture
was washed with water (2 × 10 mL), dried (Na2SO4), and concentrated.
The resultant crude alcohol was dissolved in dimethylformamide (DMF)
(1.0 mL), tert-butyldimethylsilyl chloride (0.29 g, 1.90 mmol) and
imidazole (0.24 g, 3.56 mmol) were added at room temperature, and
the resultant mixture was stirred at room temperature for 18 h. At this
time, a saturated solution of NaHCO3 was added, and the mixture was
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were washed with water (5 × 10 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (silica gel;
hexanes) to afford diene 34, 0.50 g (80%): [R]25 ) +36.1° (c ) 1,
D
1
CHCl3); IR (neat) ν 2928, 2857, 1462, 1361, 1256, 1112 cm-1; H
NMR (500 MHz, CDCl3) δ 0.04 (s, 6H), 0.88 (s, 3H), 0.90 (s, 9H),
1.25 (m, 1H), 1.58 (m, 2H), 1.74 (m, 1H), 1.98 (m, 2H), 2.22 (m,
3H), 3.68 (t, J ) 8.5 Hz, 1H), 4.85 (d, J ) 11.5 Hz, 1H), 5.17 (d,
J ) 18.0 Hz, 1H), 5.66 (m, 1H), 6.22 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ -4.8, -4.5, 10.9, 18.1, 23.8, 24.5, 25.7, 25.8, 31.2, 33.3,
43.6, 43.7, 80.0, 111.5, 126.8, 137.8, 138.7; MS m/e (rel int) 235 (55),
159 (32), 117 (51); HRMS calcd For C18H32OSi (M+) 292.222, found
292.2220.
(3aS,7aS)-4r-Ethenyl-5r-methanesulfonyl-1-oxo-3a,4,5,6,7,7a-
hexahydro-7a-methylindan (30). To a solution of alcohol 29 (0.20 g,
1.03 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.20 mL,
1.44 mmol) followed by methanesulfonic anhydride (0.25 g, 1.44 mmol)
at 0 °C. The resultant mixture was stirred at 0 °C for 2 h and then
quenched by the addition of water (2.0 mL). The mixture was extracted
by CH2Cl2 (3 × 10 mL), dried (Na2SO4), and concentrated. The residue
was purified by column chromatography (silica gel; 1:6 ethyl acetate/
hexane) to afford mesylate 30, 0.18 g (65%), as a colorless oil: IR
(1S,2S,5S,9S,13S)-6-[(tert-Butyldimethylsilyl)oxy]-5-methyl-15-tri-
methylsilyl-18-thiatetracyclo[11.4.1.02,1005,9]-10,14,16-triene-18,18-
dioxide (35). A mixture of (η6-4-trimethylsilylthiepin-1,1-dioxide)-
chromium(0) complex 16 (0.25 g, 0.72 mmol) and the diene 34 (0.83
g, 2.88 mmol) in 1,2-dichloroethane was irradiated under standard
conditions (medium-pressure mercury lamp, uranium glass filter) until
the disappearance of the starting material as indicated by the TLC
analysis. At the completion of the reaction, the solvent was removed
in vacuo, and the residue was dissolved in methanol (20 mL) and stirred
under a blanket of CO overnight. The mixture was concentrated, and
the residue was purified by column chromatography (silica gel; 1:7
ethyl acetate/hexane) to afford cycloadduct 35, 0.25 g (70%), as white
1
(neat ν 2930, 2846, 1465, 1221 cm-1; H NMR (300 MHz, CDCl3) δ
0.89 (s, 3H), 1.00 (m, 1H), 1.47 (m, 1H), 1.65 (m, 1H), 1.82 (m, 2H),
1.94 (m, 2H), 2.08 (m, 1H), 2.16-2.21 (m, 2H), 2.97 (s, 3H), 4.82 (m,
1H), 5.20 (m, 2H), 5.76 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 12.7,
21.9, 25.9, 27.5, 31.5, 35.0, 38.5, 41.9, 43.1, 45.4, 47.0, 82.2, 118.3,
135.6; MS m/e (rel int) 256 (67), 155 (45), 73 (100); HRMS calcd for
C13H20SO4 (M+) 272.1028, found 272.1023.
solid: [R]25 ) +245.4° (c ) 1, CHCl3); mp 175-176 °C (EtOAc/
(3aS,7aS)-4r-Ethenyl-1-oxo-5-(4′-methylbenzenesulfonyl)-
3a,4,5,6,7,7a-hexahydro-7a-methylindan (33). A solution of alcohol
29 (0.79 g, 4.08 mmol), p-toluenesulfonyl chloride (2.40 g, 12.25
mmol), and 4-(dimethylamino)pyridine (4.50 mg, 0.04 mmol) was
stirred at room temperature for 3 days. At this time, a solution of 5%
aqueous hydrochloric acid solution was added, and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers were
washed thoroughly with water (3 × 10 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel; 1:10 ethyl acetate/hexane) to afford tosylate 33,
D
hexane); IR (NaCl, CH2Cl2) ν 3081, 3002, 2987, 1464, 1220, 1087
1
cm-1; H NMR (500 MHz, CDCl3) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.09
(s, 9H), 0.58 (s, 3H), 0.88 (s, 9H), 1.39-1.62 (m, 6H), 1.73 (m, 1H),
1.98 (m, 1H), 2.06 (m, 1H), 2.61 (m, 1H), 3.02-3.07 (m, 1H), 3.46 (t,
J ) 7.0 Hz, 1H), 3.58 (m, 1H), 3.73 (m, 1H), 3.95 (m, 1H), 5.11 (m,
1H), 5.57 (m, 2H), 6.03 (d, J ) 12.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ -4.8, -4.4, -1.8, 1.0, 13.6, 18.0, 21.8, 25.8, 26.5, 28.2,
30.7, 34.6, 34.8, 43.0, 47.8, 66.8, 72.3, 81.5, 94.0, 120.5, 129.3, 129.9,
140.6, 144.8; MS m/e (rel int) 507 (100), 442 (57), 441 (46), 73 (69);
HRMS calcd for C27H46SO3Si2 (M+) 506.2706, found (M+ - 64)
442.3090. Anal. Calcd for C27H46SO3Si2: C, 63.99; H, 9.16. Found:
C, 63.12; H, 9.06.
1.10 g (78%), as a white solid: [R]25 ) +78.1° (c ) 1, CHCl3); mp
D
146-147 °C (EtOAc/hexane); IR (NaCl, CH2Cl2) ν 3079, 2685, 2410,
2305, 1737 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.85 (s, 3H), 1.37-
2.37 (m, 10H), 2.43 (s, 3H), 4.72 (m, 1H), 4.89-5.04 (m, 2H), 5.53
(m, 1H), 7.30 (d, J ) 8.1 Hz, 2H), 7.74 (d, J ) 8.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 12.8, 21.5, 22.0, 26.0, 27.0, 35.0, 41.9, 45.7, 47.0,
82.2, 117.5, 127.7, 129.7, 134.3, 135.4, 144.6, 219.1; MS m/e (rel int)
176 (49), 105 (25), 91 (100), 79 (29); HRMS calcd for C19H24SO4 (M+)
348.1395, found 348.1395. Anal. Calcd for C19H24SO4: C, 65.59; H,
6.95. Found: C, 65.59; H, 7.07.
1-[(tert-Butyldimethylsilyl)oxy]-3-trimethylsilyl-9Hâ-estra-1,3,5-
(10),7-tetraene (36). A solution of the cycloadduct 35 (0.02 g, 0.039
mmol) in dry, degassed THF (5.0 mL) was cooled to -105 °C, and a
solution of potassium tert-butoxide (1.0 M solution in THF, 0.04 mL,
0.043 mmol) was added dropwise using a syringe. The mixture was
allowed to stir at -105 °C for a further 15 min with vigorous stirring.
At this time, a solution of N-chlorosuccinimide (NCS) (10.0 mg, 0.075
mmol) in THF (2 mL) was added to the reaction via a cannula. The
resultant mixture was allowed to stir for 1 h, while the temperature
was allowed to warm to 25 °C. The mixture was cooled to -105 °C
again, and a second equivalent of potassium tert-butoxide (1.0 M
solution in THF, 0.04 mL, 0.04 mmol) was added. The resultant mixture
was allowed to warm to room temperature over a period of 4 h. Water
(2 mL) was added, and the mixture was extracted with pentane (3 ×
20 mL). The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography on silica gel (100% hexane) to afford 10.4 mg (60%)
(3aS,7aS)-4-Ethenyl-1-[(tert-butyldimethylsilyl)oxy]-3a-methyl-
3a,6,7,7a-tetrahydro-4-indene (34). To a solution of tosylate 33 (1 g,
2.8 mmol) in DMSO (15 mL) was added a solution of potassium tert-
butoxide (1.0 M soln in THF, 6.0 mL, 5.9 mmol) at 0 °C. The solution
was stirred at 0 °C for 1 h and quenched by addition of water (20 mL).
The solution was extracted with CH2Cl2 (3 × 50 mL). The combined
organic extracts were washed thoroughly with water (3 × 50 mL), dried
(Na2SO4), and concentrated. The residue was purified (silica gel; 1:20
ethyl acetate/hexane) to afford diene 31, 0.40 g (78%) as a colorless
oil: [R]25 ) +54.2 (c ) 1, CHCl3); IR (neat) ν 2933, 1739, 1625,
D
1
1458, 1369, 1249 cm-1; H NMR (300 MHz, CDCl3) δ 0.90 (s, 3H),
of the rearranged product 36 as a white solid: [R]25 ) +53.4° (c )
D
1.10-2.75 (m, 9H), 4.84 (m, 1H), 5.16 (m, 1H), 5.64 (m, 1H), 6.21
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2, 22.1, 22.8, 28.2, 33.3,
35.7, 46.5, 115.5, 125.8, 129.5, 139.7, 221.4; MS m/e 155 (45), 100
(43), 99 (100), 73 (55); HRMS calcd for C12H16O (M+) 176.1201, found
176.1109. This diene (0.38 g, 2.18 mmol) was dissolved in methanol
(5.0 mL) and cooled to 0 °C. To this was added solid potassium
borohydride (0.09 g, 1.74 mmol), and the resultant mixture was stirred
at 0 °C for 1 h. Acetone (1.0 mL) was added, the solvent was removed
2, CHCl3); mp 112-113 °C (CH2Cl2/pentane); IR (NaCl, CH2Cl2) ν
1
2955, 2929, 2857, 1471, 1249, 1099, 837 cm-1; H NMR (500 MHz,
CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.27 (s, 9H), 0.82 (s, 3H), 0.92 (s,
9H), 1.49-1.80 (m, 5H), 1.92 (m, 1H), 2.01 (m, 1H), 2.32 (m, 1H),
2.44 (m, 1H), 3.22 (m, 2H), 3.35 (m, 1H), 3.86 (t, J ) 8.0 Hz, 1H),
5.67 (m, 1H), 7.26-7.38 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
-4.7, -4.3, -1.0, 17.4, 18.1, 22.4, 23.3, 25.8, 31.4, 31.4, 33.7, 37.1,
43.0, 43.9, 83.0, 118.0, 123.4, 130.8, 132.2, 136.9, 137.1, 141.6, 146.2;

Total Synthesis of (+)-Estradiol
J. Am. Chem. Soc., Vol. 121, No. 36, 1999 8245
MS m/e (rel int) 147 (14), 75 (41), 73 (100); HRMS calcd for C27H44-
OSi2 (M+) 440.2903, found 440.2930.
for 15 h. The mixture was then added to a saturated solution of NaHCO3
(5 mL) at 0 °C, and the resultant mixture was extracted with CH2Cl2
(2 × 10 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo, and the residue was purified
by column chromatography (silica gel; 1:10 ethyl acetate/hexane) to
Attempted Migration of the ∆7,8 Double Bond in 36 to the ∆9,11
Position with Potassium 3-Aminopropylamide (KAPA). A dry, 25
mL tube was charged with 25% potassium hydride in oil (0.57 g, 3.55
mmol). The oil was removed by washing with dry pentane (3 × 8
mL). After removal of the residual pentane, 3-aminopropylamine (3.50
mL) was injected in a stream of argon; formation of KAPA was
complete in 1 h. Concurrently, a 10 mL flask suitable for vigorous
stirring was charged with compound 36 (0.03 g, 0.061 mmol) in dry
THF (1 mL). With vigorous stirring a small amount of KAPA stock
solution was injected (3 drops). The resultant mixture was allowed to
stir at room temperature for 15 h. At this time, the reaction mixture
was quenched by addition of water. The resultant mixture was extracted
with pentane (3 × 10 mL), dried (Na2SO4), and concentrated. The
residue was purified by column chromatography on silica gel (100%
hexane) to afford the 0.02 g (71%) of compounds 37 and 38 as an
inseparable mixture: 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 3H), 0.98
(s, 3H), 0.30 (s, 9H), 0.76 (s, 3H), 0.94 (s, 9H), 1.74-2.81 (m, 12H),
3.78 (t, J ) 7 Hz, 1H), 5.44 (m, 0.60H), 7.23-7.40 (m, 3H).
afford compound 39, 4.52 mg (45%), as a colorless oil: [R]25
)
;
D
+68.0° (c ) 1, CHCl3); IR (neat) 3054, 2857, 1654, 1222, 870 cm-1
1H NMR (500 MHz, CDCl3) δ 0.24 (s, 9H), 0.81 (s, 3H), 1.12-3.90
(m, 16H), 3.85 (t, J ) 7.5 Hz, 1H), 7.12 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ -1.1, 11.8, 24.1, 27.7, 28.7, 30.8, 38.1, 40.7, 44.5, 45.5,
48.5, 48.7, 51.4, 82.6, 124.8, 130.8, 134.3, 135.8, 137.6, 14.04; MS
m/e (rel int) 328 (45), 255 (67), 73 (100); HRMS calcd for C21H32OSi
(M+) 328.2222, found 328.2220.
Preparation of Estra-1,3,5(10)-triene-3,17â-diol (8). To a solution
of alcohol 39 (6.0 mg, 0.018 mmol) in trifluoroacetic acid (1 mL) was
added lead tetrakistrifluoroacetate (17 mg, 0.03 mmol) at room
temperature. Within 5 min, the solid oxidant turned black and became
gummy. The stirring was continued for 30 min, and the mixture was
treated with an equal volume of aqueous NaOH solution with stirring
and after neutralization was made basic again with NaHCO3. The phases
were separated, and the aqueous phase was extracted with CH2Cl2 (2
× 10 mL). The organic solutions were combined, dried over Na2SO4,
and concentrated, and the residue was purified (silica gel; 1:10 ethyl
acetate/hexane) to afford â-estradiol, 3.98 mg (80%), as a white solid,
1â-Hydroxy-3-trimethylsilylestra-1,3,5(10)-triene (39). A mixture
of 37 and 38 (27 mg, 0.061 mmol) was dissolved in acetonitrile (2
mL), and a 48% solution of HF (2 drops) was added at room
temperature. The mixture was allowed to stir at room temperature while
the progress of the reaction was monitored by TLC. At the completion
of the reaction, the solvent was removed in vacuo, and the residue was
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were washed with a saturated solution of NaHCO3 and water and dried
(Na2SO4). The solvent was removed in vacuo, and the residue was
purified by column chromatography (silica gel; 1:10 ethyl acetate/
hexane) to afford 17 mg (85%) of alcohols as an inseparable
mixture.This mixture of crude alcohols (10 mg, 0.03 mmol) was
dissolved in anhydrous benzene (1 mL) and treated with a mixture of
trifluoroacetic acid (46 µL, 0.60 mmol) and triethylsilane (48 µL, 0.30
mmol). The reaction mixture was allowed to stir at room temperature
1
the H NMR and 13C NMR of which were identical with those of an
authentic sample: mp 175-176 °C (lit.28 mp 178-179 °C); [R]25
D
+78.8° (c ) 1, dioxane) [lit.28 [R]25 +80.4° (c ) 1, dioxane)].
D
Acknowledgment. The authors thank the National Institutes
of Health (GM-30771) for their generous support of this
research. They also thank Dr. Bruce A. Pearlman of Pharmacia
& Upjohn for a very generous supply of indandione 13.
JA991016W