Employment of a cyclobutene ring-opening metathesis reaction towards a concise synthesis of (±)-sporochnol A

Article abstract of DOI:10.1016/S0040-4039(01)02007-X

A concise formal synthesis of (±)-sporochnol A 1, a naturally occurring feeding deterrent towards herbivorous fish, is described. The target compound was prepared by the employment of a Ru-catalysed cyclobutene ring-opening metathesis reaction with gaseou

Full text of DOI:10.1016/S0040-4039(01)02007-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9055–9057
Employment of a cyclobutene ring-opening metathesis reaction
towards a concise synthesis of ( )-sporochnol A
Martin J. Bassindale,a Peter Hamleyb and Joseph P. A. Harritya,*
aDepartment of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
bDepartment of Medicinal Chemistry, AstraZeneca Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Received 7 September 2001; revised 9 October 2001; accepted 19 October 2001
Abstract—A concise formal synthesis of ( )-sporochnol A 1, a naturally occurring feeding deterrent towards herbivorous fish, is
described. The target compound was prepared by the employment of a Ru-catalysed cyclobutene ring-opening metathesis reaction
with gaseous ethylene followed by a site selective hydroboration reaction as the key steps. The optimisation of the metathesis
process regarding the Ru-catalyst and reaction conditions is also delineated. © 2001 Elsevier Science Ltd. All rights reserved.
The development of efficient techniques for the con-
struction of quaternary centres remains a significant
challenge in organic chemistry, particularly when con-
trol of absolute stereochemistry is required.1 In this
context, we have recently initiated studies towards the
development of a new approach to quaternary centre
containing synthetic intermediates through the
employment of desymmetrisation of meso-ketones2
followed by a ring-opening metathesis (ROM) reac-
tion, the general strategy is illustrated in Scheme 1.
As well as the key ring-opening metathesis process,
the differentiation of the two newly formed alkene
units is pivotal to the independent and two directional
elaboration of the resulting diene intermediate. We
wish to report herein our initial observations regard-
ing the ring-opening metathesis of 3,3-disubstituted
cyclobutenes with ethylene and the differentiation of
the olefin units through a site selective hydroboration
reaction. Additionally, the application of this method
to the short formal synthesis of ( )-sporochnol A 1, a
naturally occurring compound isolated from the
Caribbean marine alga Sporochnus bolleanus, which
exhibits significant feeding deterrence toward herbivo-
rous fish, is described.3,4
Scheme 1.
Keywords: cyclobutenes; ring-opening metathesis; hydroboration; sporochnol A.
* Corresponding author. E-mail: j.harrity@sheffield.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02007-X

9056
M. J. Bassindale et al. / Tetrahedron Letters 42 (2001) 9055–9057
We began our studies with the preparation of
cyclobutene 4 which we anticipated would be a suitable
substrate to examine the ROM reaction as well as
providing an appropriate substrate for the synthesis of
sporochnol A. Cyclobutene 4 was prepared in a five-
step sequence starting from commercially available 4-
methoxyphenyl methyl ketone 2, as outlined in Scheme
2. Accordingly, methylenation of 2 proceeded efficiently
and the resulting alkene underwent clean a,a-dichloro-
cyclobutanone formation with trichloroacetyl chloride
in the presence of a freshly prepared Zn–Cu couple.
Subsequent dechlorination with Zn powder and NH4Cl
provided ketone 3 in 70% yield over the two steps.5 We
investigated two approaches for the conversion of 3 to
the desired cyclobutene. Firstly, we hoped to employ a
two-step approach using a Shapiro reaction.6 There-
fore, we prepared the p-toluenesulfonyl hydrazone of 3
and subjected this to 3 equiv. of n-BuLi. In the event,
the reaction was very slow and was found to proceed
only after heating the THF solution at reflux for over 2
h. Nonetheless, the cyclobutene could be isolated in
74% yield after chromatographic purification. Our sec-
ond approach employed the sodium borohydride reduc-
tion of ketone 3, which proceeded in excellent yield to
give the corresponding alcohol as a 1:1 mixture of
diastereoisomers. Subsequent tosylation followed by
base-induced elimination furnished 4 in 59% overall
yield over the three steps.
With cyclobutene 4 in hand, we turned our attention to
the ROM step. The ROM of cyclobutenes has been
studied extensively by Snapper and co-workers and
provided firm precedent for successful incorporation of
ethylene towards the desired diene.7 Surprisingly, how-
ever, the metathesis of 4 with ethylene in the presence
of 10 mol% of commercially available Grubbs’ catalyst
Cl2(Cy3P)2RuꢀCHPh I8 proved to be very sluggish and
low conversion of 4 (<30%) to diene 5 was observed
over a period of 16 h. Moreover, 5 could not be readily
separated from the starting cyclobutene 4. In an effort
to force the ROM reaction to higher conversion, we
examined the effects of reaction temperature and cata-
lyst loading. As outlined in Table 1, complete conver-
sion of 4 to diene 5 was only achieved using 45 mol% I,
which had to be added to the reaction mixture in 5–10
mol% portions over 5 days. The unacceptably high
catalyst loadings and reaction times required to com-
plete the ROM reaction prompted us to examine the
recently developed and more active 4,5-dihydroimida-
zol-2-ylidene-Ru catalyst II8 for this conversion. Grati-
fyingly, as outlined in entry 4 of Table 1, much higher
conversions were achieved with lower catalyst loadings
over a significantly shorter time period. Unfortunately,
however, the desired diene was contaminated with the
product of olefin isomerisation 6.9 Since 6 must result
from diene 5, this observation suggested that the ROM
reaction had proceeded to significant conversion well
Scheme 2. Reagents and conditions: (a) Ph3PMeBr, KOBu-t,
THF–toluene, 25°C, 99%. (b) (i) Cl3CCOCl, Zn–Cu, Et2O,
25°C, (ii) Zn, NH4Cl, MeOH, 70%. (c) TsNHNH2, MeOH,
84%. (d) BuLi (3 equiv.), THF, −78 to 70°C, 74%. (e) NaBH4,
MeOH, 96%. (f) TsCl, pyr., 95%. (g) KOBu-t, DMSO, 70°C,
65%.
Table 1. Ethylene-mediated ROM reaction of cyclobutene 4

M. J. Bassindale et al. / Tetrahedron Letters 42 (2001) 9055–9057
9057
Acknowledgements
The authors gratefully acknowledge financial support
from the EPSRC and AstraZeneca.
References
Scheme 3. Reagents and conditions: (a) (i) 9-BBN, THF,
25°C, (ii) H2O2, 6 M NaOH, 50%. (b) Dess–Martin periodi-
nane, 77%. (c) Me2CꢀPPh3, toluene, 59%.
1. Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 389.
2. (a) Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron:
Asymmetry 1993, 4, 1475; (b) Honda, T.; Kimura, N.
Chem. Commun. 1994, 77; (c) for a review, see: O’Brien,
P. J. Chem. Soc. Perkin Trans. 1 1998, 1439.
within the 48 h time period employed. Indeed, we were
pleased to find that the reaction was in fact complete
within 3 h at 60°C and allowed us to isolate 5 with <5%
6 present in the reaction mixture (as judged by 250
3. Isolation studies: Shen, Y. C.; Tsai, P. I.; Fenical, W.;
Hay, M. E. Phytochemistry 1992, 32, 71.
1
MHz H NMR). Having achieved efficient consump-
4. For previous approaches to sporochnol A, see: (a) Taka-
hashi, M.; Shioura, Y.; Murakami, T.; Ogasawara, K.
Tetrahedron: Asymmetry 1997, 8, 1235; (b) Kamikubo,
T.; Shimizu, M.; Ogasawara, K. Enantiomer 1997, 2, 297;
(c) Fadel, A.; Vandromme, L. Tetrahedron: Asymmetry
1999, 10, 1153; (d) Li, Y.; Yuan, H.; Lu, B.; Li, Y.; Teng,
D. J. Chem. Res., Synop. 2000, 530; (e) Luchaco-Cullis,
C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2001, 40, 1456.
tion of cyclobutene 4 and circumvented alkene isomeri-
sation, we were disappointed to find that the diene 5
was only returned in 52% yield. The remainder of the
mass balance comprised of dimer 7, which was charac-
terised on the basis of its 1H NMR and mass spec-
trum.10 Accordingly, the metathesis process was carried
out under more dilute conditions, which provided 5 in
73% yield albeit over a longer reaction time.
5. The preparation of 3,3-disubstituted cyclobutanones by
this method has been previously described: Greene, A. E.;
Lansard, J.-P.; Luche, J.-L.; Petrier, C. J. Org. Chem.
1983, 48, 4763.
6. For an excellent overview of the Shapiro reaction, see:
Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res.
1983, 16, 55.
7. (a) Randall, M. L.; Tallarico, J. A.; Snapper, M. L. J.
Am. Chem. Soc. 1995, 117, 9610; (b) Snapper, M. L.;
Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997,
119, 1478; (c) Tallarico, J. A.; Bonitatebus, Jr., P. J.;
Snapper, M. L. J. Am. Chem. Soc. 1997, 119, 7157; (d)
Tallarico, J. A.; Randall, M. L.; Snapper, M. L. Tetra-
hedron 1997, 53, 16511; (e) Limanto, J.; Snapper, M. L. J.
Am. Chem. Soc. 2000, 122, 8071.
8. For a recent account of the mechanism and activity of
Ru-based alkene metathesis catalysts, see: Sanford, M. S.;
Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
6543.
9. For an example of alkene isomerisation using Ru-cata-
lysts bearing imidazol-2-ylidene ligands, see: Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.
J. Org. Chem. 2000, 65, 2204.
10. Subjection of the dimer 7 to 5 mol% II under an ethylene
atmosphere at 60°C in DCE for 48 h resulted in 17%
conversion to 5. This suggests that dimer formation is
reversible in the presence of ethylene and II and that
isomerisation (5“6) highlighted in entry 4, Table 1 pre-
vents significant quantities of dimerised product from
being isolated in this case.
Having demonstrated the effectiveness of the ROM
methodology, it remained only to differentiate the
alkene units of the diene product. We anticipated that
the different steric environments around the alkenes
would allow ready differentiation upon treatment with
a bulky reagent. Indeed, treatment of 5 with 9-BBN
proceeded smoothly to provide alcohol 8 in 50% iso-
lated yield (60% based on recovered starting material)
after oxidation. We were pleased to find that products
of hydroboration of the more hindered alkene were not
observed under these conditions.11 We envisage that the
ease of independent manipulation of the alkene and
alcohol units in 8 will permit a two directional elabora-
tion of this and related systems and this concept is
currently under investigation. Nonetheless, the formal
synthesis of sporochnol A was completed upon oxida-
tion of 8 followed by Wittig olefination to provide
diene 9, which showed analytical and spectroscopic
data in accordance with those previously reported
(Scheme 3).4a
In conclusion, we have demonstrated that the ROM of
3,3-disubstituted cyclobutenes with ethylene proceeds
efficiently with recently reported and highly active Ru-
catalyst II and that the olefin units of the resulting
diene can be readily differentiated by site selective
hydroboration. Studies towards developing efficient
enantioselective routes to 3,3-disubstituted cyclobutenes
from the appropriate meso-ketones with a view to
controlling the stereochemistry of chiral quaternary
centre containing intermediates are underway and will
be reported in due course.
11. The employment of excess 9-BBN resulted in hydrobora-
tion of the remaining alkene moiety.