A concise approach towards the synthesis of steganone analogues

Article abstract of DOI:10.1039/a900743a

The cobalt-mediated [2+2+2] cycloaddition of a tethered deca-1,9-diyne is used as a key step in a highly convergent route to steganone analogues.

Full text of DOI:10.1039/a900743a

A concise approach towards the synthesis of steganone analogues
Adrian Bradley,a William B. Motherwell*a and Feroze Ujjainwallab
a Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London,
UK WC1H 0AJ. E-mail: w.b.motherwell@ucl.ac.uk
b Department of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, UK
SW7 2AY
Received (in Cambridge, UK) 27th January 1999, Accepted 12th April 1999
The cobalt-mediated [2+2+2] cycloaddition of a tethered
deca-1,9-diyne is used as a key step in a highly convergent
route to steganone analogues.
quantities of the required diyne 2. Thus, the protected lactone 3
was readily prepared from racemic paraconic acid 5 via
palladium-catalysed coupling of the derived acid chloride with
Me3SiC·CSnMe3 followed by ketalisation of the resultant
ynone 6, whilst the known benzylic alcohol7 7 was available
from 3,4,5-trimethoxybenzaldehyde via a straightforward se-
quence involving iodination, borohydride reduction, and a
second palladium catalysed coupling reaction of the resultant
iodoarene with Me3SiC·CH. The transformation to the corre-
sponding bromide 4 was then acheived using the PPh3–CBr4
protocol. The coupling reaction of the two fragments proceeded
smoothly through prior generation of the lithium enolate of
lactone 3 with LDA at 278 °C followed by alkylation with the
benzylic bromide 4 at 235 °C to give 8 as a single diastereoi-
somer. Deprotection of the acetylenic groups then furnished the
parent diyne 2.
Steganone 1 is one member of the family of four bisbenzocy-
clooctadiene lignan lactones isolated from the Ethiopean shrub
Steganotaenia araliciae Hochst and characterised by Kupchan1
O
O
O
O
MeO
O
MeO
OMe
Our attention then focused on the crucial CpCo(CO)2-
mediated [2+2+2] cycloaddition step using diyne 2, Me3-
SiC·CSiMe3 as the third acetylenic component, and the
standard irradiation conditions developed by Vollhardt.5 To our
consternation, initial experiments failed to yield any significant
amounts of the desired biaryl 9, and the beautifully crystalline
orange material which could be isolated as a single diastereo-
isomer in up to 57% yield was shown by X-ray crystallography
to be the cobaltacyclobutadiene complex 10 (Scheme 3).
Although the formation of similar complexes has been pre-
viously observed9 and is generally considered to arise when
either co-ordination or insertion of the third alkyne component
is problematic, it was nevertheless encouraging to note that the
structure 10 confirmed both the viability of the eight-membered
ring closure and also the trans stereochemistry around the g-
lactone. Gratifyingly however, whether via the intermediacy of
the putative metallocyclopentadiene precursor to 10 or one of
the other two possible candidates from reaction with Me3-
1
in 1973. These compounds have displayed significant activity in
vivo against P-388 leukemia in mice and in vitro against cells
derived from human carcinoma of the nasopharynx (KB). They
act as spindle poisons and function by stabilising dimeric
tubulin and thereby inhibiting formation of microtubules.2
These intriguing structures, comprising an eight-membered ring
fused to a biaryl moiety, are composed of three stereochemical
elements, two deriving from the trans-fused g-lactone, whilst
the third is the stereogenic axis of the atropisomeric biaryl unit.
Since its discovery, steganone 1 has proven to be a favoured
target for sustained synthetic effort, and for more than two
decades a wide variety of synthetic strategies have culminated
in a number of total/formal syntheses.3 Careful scrutiny of these
approaches reveals striking parallels in retrosynthetic analysis,
with no less than ten of the syntheses requiring a late stage
installation of the trans-fused g-lactone. Moreover, in every
single instance to date some variant of a biaryl coupling reaction
is used to forge the crucial carbon–carbon bond between the two
aromatic rings.
Since the properties of steganone 1 itself are well known, our
own objective in this area was to develop a highly convergent
route which would be potentially amenable to the syntheses of
a wide variety of differentially substituted aromatic analogues
for use in structure–activity studies. To the best of our
knowledge, only a single analogue of this type has thus far been
reported.4 As shown in Scheme 1, the key element of the present
strategy involves the use of the tethered diyne 2 in a cobalt
mediated [2+2+2] cycloaddition,5 thereby enabling closure of
the eight-membered carbocyclic ring with concomitant con-
struction of a usefully functionalised northern aryl unit for
further elaboration. We also envisaged that the required trans
stereochemistry round the g-lactone 2 would be derived by
alkylation of the lactone enolate from 3 with the benzylic
bromide 4 or congeners thereof which would allow yet further
variation in aromatic functionality to be introduced at an
antepenultimate stage.
X
X
X
X
O
O
O
[2+2+2]
Cycloaddition
O
O
MeO
MeO
MeO
MeO
O
O
OMe
OMe
2
SiMe3
O
O
MeO
MeO
Br
+
O
Me3Si
OMe
O
3
4
In the event, as outlined in Scheme 2, it was possible to
develop a concise and highly efficient route to multigram
Scheme 1
Chem. Commun., 1999, 917–918
917

SiMe3
H
O
Me3Si
MeO
MeO
CpCo
O
O
O
O O
HO
O
•
i, ii
+
O
O
2
O
OMe
MeO
MeO
MeO
5
O
O
iv–vi
i, ii
MeO
OMe
OMe
SiMe3
10
9
O
H+
MeO
MeO
OH
O
Me3Si
X
Y
O
O
6
OMe
Yield
10
7
Conditions
9
O
MeO
MeO
vii
iii
i
ii
57 5–10
37 19
O
4
3
OMe
viii
11 X = Y = SiMe3
12 X = SiMe3, Y = H
13 X = Y = H
Z
Z
O
O
Scheme 3 Reagents and conditions: i, Me3SiC·CSiMe3, CpCo(CO)2,
50–65 °C, reflux, hn, addition of 2 in THF over 9 h; ii, Me3SiC·CSiMe3,
MeCN, reflux, hn, addition of 2 in THF over 9 h.
O
MeO
MeO
O
acknowledge his personal debt of gratitude to the late Professor
R. A. Raphael FRS, whose mastery of the Art of Organic
Synthesis was matched only by his ability to encourage and to
instil his love and enthusiasm for the subject in others.
OMe
8 Z = SiMe3
2 Z = H
ix
Notes and references
1 S. M. Kupchan, R. W. Britton, M. F. Ziegler, C. J. Gilmore, R. J. Restivo
and R. Bryan, J. Am. Chem. Soc., 1973, 95, 1335
2 R. W. J. Wang, L. I. Rebbun and M. S. Kupchan, Cancer Res., 1977, 37,
3071.
Scheme 2 Reagents and conditions: i, (COCl)2, CH2Cl2, DMF (cat), room
temp., 1 h; ii, Me3SiC·CSnMe3, Pd(PPh3)2Cl2, ClCH2CH2Cl, 50 °C, 16 h,
67% over 2 steps; iii, HOCH2CH2OH, PhH, PPTS (cat), reflux, 12 h, 87%;
iv, I2, AgO2CCF3, CH2Cl2, 20 °C, 12 h, quant.; v, NaBH4, MeOH, 25 °C,
30 min, quant.; vi, Me3SiC·CH, Pd(PPh3)2Cl2, CuI, Et2NH, 50 °C, 2 h,
92%; vii, CBr4, PPh3, Et2O, 24 h, 92%; viii, 4, LDA, THF, 278 °C, 1 h, then
add 3, 235 °C, 1 h, 80%; ix, K2CO3, MeOH, 20 °C, 15 h, 95%.
3 N. S. Narasimhan and I. R. Aiden, Tetrahedron Lett., 1988, 29, 2987;
N. S. Narasimhan and I. R. Aiden, Indian J. Chem., Sect. B., 1993, 32B,
211; A. I. Meyers, J. R. Flisak and R. A. Aitken, J. Am. Chem. Soc.,
1987, 109, 5446; P. Magnus, J. Schultz and T. Gallagher, J. Am. Chem.
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1983, 39, 2787; M. Mervic, Y. Ben-David and E. Ghera, Tetrahedron
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J. Chem. Soc., Chem. Commun., 1995, 1943.
SiC·CSiMe3, further variation in experimental conditions gave
the desired biaryl 9 possessing the carbocyclic steganone core in
20% yield.
The structure of the indicated atropisomer of the biaryl 9,
which corresponds to the natural series, was established both by
NOE experiments and also by deprotection of the ketal using
wet formic acid which furnished the parent ketone 11 (nmax
1674 cm21) in 54% yield (Scheme 3). Deprotection accom-
panied by selective mono- or di-protodesilylation could also be
achieved in a single step by treatment of 9 with TFA either at
room temperature or at reflux to afford the further steganone
analogues 12 and 13 in 73 and 51% yield, respectively.
In summary, these preliminary results demonstrate the
viability of using a tethered deca-1,9-diyne in a cobalt-mediated
[2+2+2] cyclobenzannulation strategy for the construction of
steganone analogues in a highly convergent manner. Within this
framework, current studies are directed towards the use of
further 2p addends and additional metal-based cyclotrimerisa-
tion reactions both for aromatic and heteroaromatic rings in
order to further enhance the flexibility of this approach.
We thank the EPSRC and Zeneca Agrochemicals for the
award of a CASE studentship to F. U., and University College
London for the provision of a Provosts’ studentship to A. B. We
are also indebted to Professor D. Williams and Dr A. M. Z.
Slawin for X-ray structural determination and the University of
London Intercollegiate Research School (ULIRS) for mass
spectral measurements. Finally, one of us (W. B. M.) wishes to
4 D. Becker, L. R. Hughes and R. A. Raphael, J. Chem. Soc., Chem.
Commun., 1974, 430.
5 K. P. C.Vollhardt, Angew. Chem., Int. Ed. Engl., 1984, 28, 539.
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8 F. Ujjainwalla, PhD thesis, University of London, 1993. We are grateful
to Drs D. Williams and A. M. Z. Slawin for the crystal structure
determination, which will be discussed in the full paper.
9 R. Gleiter, D. Kratz, M. L. Ziegler and B. Nuber, Tetrahedron Lett.,
1990, 31, 6175; C.-A. Chang, J. A. King Jr. and K. P. C. Vollhardt,
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Vollhardt, in Organic Synthesis Today and Tomorrow, ed. B. M. Trost
and C. R. Hutchinson, Pergamon, New York, 1981, 71; P. Phanasavath,
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Chem. Commun., 1999, 917–918