A new total synthesis of (±)-oestrone

Article abstract of DOI:10.1016/j.tetlet.2004.03.166

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2, via 10, 15, 16 and 17, leading to the intermediate trans,anti,trans-oestradiol derivative 11 in one step, is described. Oxidation of 11, followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1.

Full text of DOI:10.1016/j.tetlet.2004.03.166

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4027–4030
A new total synthesis of ( )-oestrone
Gerald Pattenden,* L. Krishnakanth Reddy and Affo Walter
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
Received 12 March 2004; accepted 26 March 2004
Abstract—A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl
vinylcyclopropane 2, via 10, 15, 16 and 17, leading to the intermediate trans,anti,trans-oestradiol derivative 11 in one step, is
described. Oxidation of 11, followed by demethylation of the resulting aryl methyl ether 18 then gives ( )-oestrone 1.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The female sex hormone oestrone 1 occupies a special
place in the history of natural products and in the
development of modern medicinal chemistry. It was the
first natural steroid hormone to be obtained in pure
form (1929) and it was the first ‘real’ steroid1 to be
synthesised totally (1948).2 Furthermore, oestrone
served as an invaluable precursor to the commercially
important 19-norsteroids, which were first offered as
oral contraceptives over 50 years ago. Since these early
beginnings a variety of strategies have been developed
for the total synthesis of oestrone and nonaromatic
steroids. Prominent amongst these methods have been
those based on the ubiquitous Diels–Alder reaction3 and
on biomimetic electrophilic polyene cyclisations.4
and successive transannulation reactions from a substi-
tuted aryl vinylcyclopropane precursor, viz. 2.
Thus, building on earlier investigations7 and model
studies,8 the iodovinylcyclopropane 2 was synthesised
starting from 2-iodo-4-methoxy benzaldehyde 39 as
summarised in Scheme 1. A Wadsworth–Emmons
reaction between 3 and the appropriate phosphonate
carbanion first led to the E-iodocinnamate 4, which was
then converted into the substituted arylpropanal 5 using
a Heck reaction with prop-2-en-1-ol, in 87% yield. A
Wittig reaction between 5 and triphenyl(tert-butylsilyl-
oxy)propyltriphenylphosphonium iodide in the presence
of potassium bis-(trimethylsilyl)amide at )78 ꢁC was
stereo-selective and next gave the Z-alkene 6a in 92%
yield. Reduction of 6a using DIBAL-H, followed by
Simmons–Smith cyclopropanation of the resulting
allylic alcohol 6b then gave the trans cyclopropylmeth-
anol 7 in 70% yield. Oxidation of 7 with PDC led to the
O
OMe
I
H
H
H
corresponding aldehyde 8a in which
a two-step
HO
MeO
sequence, was converted into the trans cyclopropyl-
methyl ketone 8b. Treatment of 8b with the carbanion
derived from methoxymethyldiphenylphosphine oxide
and LDA at )78 ꢁC proceeded smoothly and gave the
enol ether 9 as a 1:1 mixture of Z- and E-isomers in 90%
yield. Finally, deprotection of the silyl ether 9 and
iodination of the resulting alcohol gave the iodovinyl-
cyclopropane 2.
1
2
Over several years we have examined the scope for a
range of cascade radical-mediated reactions in the syn-
thesis of polycyclic ring systems,5 including steroids.6
We have now extended these investigations and exam-
ined a conceptually new synthetic approach to oestrone
1 in which the B/C/D ring system in the steroid is pro-
duced in a cascade radical-mediated macrocyclisation
When a solution of the iodovinylcyclopropane 2 in dry
degassed toluene was heated under reflux and treated
with Bu3SnH–AIBN via syringe pump over 8 h, a
remarkable regio- and stereo-selective sequence of radi-
cal cyclisations ensued, leading to the trans,anti,trans-
oestradiol derivative 11 in 12–15% yield. The steroid
was obtained as a mixture of C17–OMe epimers and
* Corresponding author. Tel.: +44-115-951-3530; fax: +44-115-951-
3535; e-mail: gp@nottingham.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.166

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G. Pattenden et al. / Tetrahedron Letters 45 (2004) 4027–4030
COOEt
COOEt
CHO
i
ii
CHO
I
MeO
I
MeO
MeO
iii
4
3
5
OH
R
v
OTBS
OTBS
MeO
MeO
6
7
a, R = COOEt
iv
b, R = CH2OH
OMe
OTBS
R
O
vi
viii
ix, x
2
OTBS
MeO
MeO
8
9
a, R = H
vii
b, R = Me
Scheme 1. Reagents and conditions: (i) EtO2CCH2PO(OEt)2, BuLi, THF, 72%; (ii) CH2@CHCH2OH, Pd(OAc)2, n-Bu4nCl, DMF, 87%; (iii)
IPh3P(CH2)3OTBS, KHMDS, THF, 92%; (iv) DIBAL-H, DCM, 82%; (v) Et2Zn, CH2I2, 70%; (vi) PDC, 84%; (vii) MeMgBr followed by Dess–
Martin periodinane, 86%; (viii) MeOCH2POPh2, LDA, THF; then NaH, THF, 90%; (ix) TBAF, THF, 98%; (x) I2, imidazole, PPh3, 80%.
crystallisation from acetonitrile–hexane gave colourless
crystals of the known b-OMe epimer 11a, mp 160–
161 ꢁC (lit.10 mp 161–163 ꢁC) whose NMR spectroscopic
data were identical with those described in the literature.
The major product obtained from treatment of 2 with
Bu3SnH–AIBN was 14a (52%), which results from direct
reduction of the carbon-to-iodide in the starting mate-
rial. In contemporaneous studies, the iodovinylcyclo-
propane 12 lacking a terminal (enol ether) methoxy
substituent was shown to undergo an identical sequence
of regio- and stereo-selective radical cyclisations, when
treated with Bu3SnH–AIBN in refluxing benzene, lead-
ing to the oestrane 13 (15%), together with the reduction
product 14b (20%). The trans,anti,trans oestrane 13
showed 13C NMR spectroscopic data which were iden-
tical with those reported in the literature for this com-
pound.11
Several attempts were made to increase the yield of the
oestradiol derivative 11 using alternative radical forming
reagents and conditions, including Bu3GeH–AIBN,
SmI2–DMPU (Bu3Sn)2-hm, (Me3Si)3SiH–AIBN, vitamin
B12 and other Co(III) compounds with Zn or NaHg, in
different solvents under varying thermal conditions.
However, in none of these cases were we able to increase
the yield of 11 beyond 15%, and the major product was
always 14a (40–50%).12 The cascade of radical reactions
between 2 and 11 involves four successive C fi C bond
forming reactions, that is (i) a 12-endo trig macrocycli-
sation of 10 leading to 15; (ii) cyclopropylmethyl to
OMe
OMe
Bu3SnH
.
radical
H
2
cascade
AIBN
H
H
MeO
MeO
10
11
a = β-OMe
b = α-OMe
R
I
H
Bu3SnH
AIBN
H
H
MeO
MeO
MeO
12
13
14
a R = OMe
b R = H

G. Pattenden et al. / Tetrahedron Letters 45 (2004) 4027–4030
4029
dron 1999, 55, 13037–13050; Quinkert, G.; Del Grosso,
but-2-enyl carbon radical equilibration of 15 to 16; (iii)
6-exo trig transannulation to 17; (iv) 5-exo trig trans-
annulation of 17, followed by H-quench to 11. Since the
product of reduction of 2, that is 14a, is obtained in 52%
yield, each of the radical reactions between 2 and 11
therefore proceeds in an average yield of ca. 65%.
Whether or not the radical intermediate 10 becomes
quenched by H-abstraction in an intramolecular sense
or as a consequence of stereo-electronic features peculiar
to the substrate 2, or combinations of these possibilities,
is unclear at this time.
€
M.; Doring, A.; Doring, W.; Schenkel, R. I.; Bauch, M.;
Dambacher, G. T.; Bats, J. W.; Zimmermann, G.; Durner,
€
€
G. Helv. Chim. Acta 1995, 78, 1345–1391; Sugahara, T.;
Ogasawara, K. Tetrahedron Lett. 1996, 37, 7403–7406;
Vollhardt, P. C. Pure Appl. Chem. 1985, 57, 1819–1826;
Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am.
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4. See for example: Corey, E. J.; Lin, S. J. Am. Chem. Soc.
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6150–6152, and references cited therein.
OMe
OMe
OMe
.
H
.
.
10
H
MeO
MeO
MeO
15
16
17
O
H
CrO3
94%
BBr3
79%
11
( )-Oestrone (1)
H
H
MeO
18
5. Boehm, H. M.; Handa, S.; Pattenden, G.; Roberts, L.;
Blake, A. J.; Li, W.-S. J. Chem. Soc., Perkin Trans. 1
2000, 3522–3538; Handa, S.; Nair, P. S.; Pattenden, G.
Helv. Chim. Acta 2000, 83, 2629–2643; Handa, S.;
Pattenden, G. Contemp. Org. Synth. 1997, 4, 196–215;
See also: Curran, D. P.; Rakiewicz, D. M. Tetrahe-
dron 1985, 41, 3943–3958; Curran, D. P.; Jahn, U.
Terahedron Lett. 1995, 36, 8921–8924; Fang, H.; Ribeiro,
A. A.; Zoretic, P. A. J. Org. Chem. 1998, 63, 7213–7217;
Doi, T.; Takahashi, T.; Tomida, S. Tetrahedron
Lett. 1999, 40, 2363–2366; Ihara, M.; Katsumata, A.;
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dron Lett. 1994, 35, 8601–8604, and references cited
therein.
The synthesis of oestrone 1 from the methyl ether 11 was
smoothly accomplished by oxidation to 18 (94%) using
chromium trioxide in acetone, followed by demethyl-
ation of 18 with BBr3 in THF (79%). The synthetic ( )-
oestrone 1 showed physical and spectroscopic properties
identical with those described in the literature.13
Acknowledgements
We thank Paul Wiedenau and Stuart McCulloch for
their earlier contributions to this study, and AstraZen-
eca for financial support.
6. Batsanov, A.; Chen, L.; Gill, G. B.; Pattenden, G.
J. Chem. Soc., Perkin Trans. 1 1996, 45–55, and references
cited therein; Handa, S.; Pattenden, G.; Li, W.-S. Chem.
Commun. 1998, 311–312.
References and notes
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12. We also synthesised the (+)-menthyl enol ether corre-
sponding to 2, in an attempt to induce chirality in the
ꢀ
9100; Lavoie, R.; Toro, A.; Deslongchamps, P. Tetrahe-

4030
G. Pattenden et al. / Tetrahedron Letters 45 (2004) 4027–4030
product 11 during the cascade radical reaction. However,
13. Johnson, W. S.; Christiansen, R. G.; Ireland, R. E. J. Am.
Chem. Soc. 1957, 79, 1995–2005; Ciuffreda, P.; Ferrabo-
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the only compound we were able to detect by NMR
amongst the mixture of products was reduced material,
that is 14, R ¼ menthyl.