Exploitation of cyclopropane ring-cleavage reactions for the rapid assembly of tetracyclic frameworks related to gibberellins

Article abstract of DOI:10.1021/ol062224d

The readily available hexahydrofluorene 5 has been elaborated over six steps, including three involving cyclopropane ring-cleavage reactions, into compound 12 which incorporates the carbocyclic framework associated with gibberellins.

Full text of DOI:10.1021/ol062224d

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5341-5344
Exploitation of Cyclopropane
Ring-Cleavage Reactions for the Rapid
Assembly of Tetracyclic Frameworks
Related to Gibberellins
Martin G. Banwell,* Andrew T. Phillis, and Anthony C. Willis
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received September 7, 2006
ABSTRACT
The readily available hexahydrofluorene 5 has been elaborated over six steps, including three involving cyclopropane ring-cleavage reactions,
into compound 12 which incorporates the carbocyclic framework associated with gibberellins.
The gibberellins (GAs) are a large and seemingly continu-
ously expanding class of structurally complex diterpenoids
many members of which exhibit extraordinarily potent plant-
growth-regulating properties.1 Indeed, some such compounds
(therefore) commercial significance.1e,3 Not surprisingly, then,
there have been major activities directed toward the total
synthesis of gibberellins1a-d,f and spectacular successes have
been reported by, inter alia, Mori,4 Nagata,5 Corey,6
Mander,1b-d,f De Clercq,7 Yamada,8 and Ihara.9 Notwith-
(3) The inhibition of GA biosynthesis is also very important. Thus, for
example, the semidwarf (sd-1) “green revolution” rice contains a defective
gibberellin 20-oxidase gene that retards in vivo production of the relevant
GAs - see: (a) Sasaki, A.; Ashikari, M.; Ueguchi-Tanaka, M.; Itoh, H.;
Nishimura, A.; Swapan, D.; Ishiyama, K.; Saito, T.; Kobayashi, M.; Khush,
G. S.; Kitano, H.; Matsuoka, M. Nature 2002, 416, 701. (b) Spielmeyer,
W.; Ellis, M. H.; Chandler, P. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
9043.
(4) (a) Mori, K.; Shiozaki, M.; Itaya, N.; Matsui, M.; Sumiki, Y.
Tetrahedron 1969, 25, 1293. (b) Mori, K.; Takemoto, I.; Matsui, M.
Tetrahedron 1976, 32, 1497 and references cited therein.
(5) Nagata, W.; Wakabayashi, T.; Narisada, M.; Hayase, Y.; Kamata,
S. J. Am. Chem. Soc. 1971, 93, 5740.
exert these types of effects at near femtomolar (10-15 M)
levels.1f,2 As a consequence, certain GAs, including gibber-
ellic acid (1, aka GA3), are of considerable agricultural and
(1) For comprehensive reviews on the isolation, structural elucidation,
biogenesis, chemical properties, and/or synthesis of GAs, see: (a) Fujita,
E.; Node, M. Heterocycles 1977, 7, 709. (b) Mander, L. N. Acc. Chem.
Res. 1983, 16, 48. (c) Mander, L. N. Nat. Prod. Rep. 1988, 5, 541. (d)
Mander, L. N. Chem. ReV. 1992, 92, 573. (e) MacMillan, J. Nat. Prod.
Rep. 1997, 14, 221. (f) Mander, L. N. Nat. Prod. Rep. 2003, 20, 49.
(2) (a) Takeno, K.; Yamane, H.; Yamauchi, T.; Takahashi, N.; Furber,
M.; Mander, L. N. Plant Cell Physiol. 1989, 30, 201. (b) Wynne, G. M.;
Mander, L. N.; Oyama, N.; Murofushi, N.; Yamane, H. Phytochemistry
1998, 47, 1177.
(6) (a) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck,
G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031. (b) Corey, E. J.;
Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.; Gopalan, B.; Larsen, S.
D.; Siret, P.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8034. (c) Corey, E.
J.; Munroe, J. E. J. Am. Chem. Soc. 1982, 104, 6129. (d) Corey, E. J.;
Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116, 3611 and
references cited therein.
(7) Grootaert, W. M.; De Clercq, P. J. Tetrahedron Lett. 1986, 27, 1731.
(8) Nagaoka, H.; Shimano, M.; Yamada, Y. Tetrahedron Lett. 1989, 30,
971.
10.1021/ol062224d CCC: $33.50
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standing the remarkable effort involved, the lengthy nature
of the reaction sequences required to complete such work
has meant that essentially all research concerned with
exploring structure-activity relationships within the class
has relied on carrying out chemical modifications of GA3
which is readily accessible in tonne quantities through
fermentation processes.1b-f Accordingly, biological studies
on these diterpenoids could benefit significantly from the
development of simple protocols for the assembly of the
gibberellin and related scaffolds, especially ones that possess
novel functionality and/or frameworks not likely to be readily
accessible through manipulation of GA3. Such objectives
would seem all the more important given the recent
identification of the first gibberellin receptor, GID1,10 and
the accompanying development of a proposed mechanism
for GA signaling. As a consequence, there now appear to
be good prospects for establishing a complete understanding
of the molecular basis of action of the GAs and, therefore,
an attendant capacity to engage in the rational design of
synthetic plant-growth-regulating substances. On this basis,
we describe herein a novel and especially concise reaction
sequence that enables the rapid assembly of tetracyclic
frameworks related to the gibberellins. The key features of
the present work are the exploitation of two cyclopropanation
and three successive cyclopropane ring-cleavage steps in the
elaboration of the methoxy-substituted aromatic ring associ-
ated with the hexahydrofluorene 5 into the bicyclo[3.2.1]-
octane substructure corresponding to the C- and D-rings of
GAs.11
Scheme 1
The route employed for the purposes of elaborating
compound 5 into the title frameworks is shown in Scheme
2 and commences with a Birch reduction step that leads to
the corresponding dihydro-derivative 6 (91%). Reaction of
this diene with excess dichlorocarbene generated from
chloroform under phase-transfer conditions13 afforded a
chromatographically separable mixture of the isomeric
compounds 714 (27%) and 814 (45%). The former product
most likely arises from dichlorocarbene addition to the
slightly less congested R-face of the methoxy-substituted and,
therefore, more nucleophilic double bond within substrate
6. The steric congestion at both faces of the double bond
within the resulting monoadduct inhibits addition of a second
equivalent of dichlorocarbene such that a C-H insertion
process occurs in preference thus affording the dichlorom-
ethylated product 7. In contrast, when dichlorocarbene adds
to the â-face of the methoxy-substituted double bond within
substrate 6 the R-face of the remaining alkene remains
accessible to a second equivalent of this divalent species and
so allowing formation of the desired bis-adduct 8. Treatment
of compound 8 with potassium tert-butoxide in THF at 0 °C
resulted in elimination of the elements of HCl and the
efficient formation (96%) of the cyclopropane ring-cleavage
product 9 now incorporating a chlorinated double bond that
will become the exocyclic alkene attached to the D-ring of
the target GA framework. While the pathway followed during
the conversion 8 f 9 remains to be established, other work
conducted in these laboratories has demonstrated that the
process can be applied within a variety of frameworks.15
Heating of compound 9 in 2,6-lutidine for 4.5 h results in a
smooth vinylcyclopropane to cyclopentene rearrangement16
and the formation of the annulated and crystalline norbornene
1014 in 89% yield. Compound 10 represents an interesting
acquisition because it incorporates a hitherto unreported
C-norGA framework and might, therefore, represent a useful
scaffold for the development of GA agonists and/or inhibitors
of GA biosynthesis. Furthermore, since it is known that the
The synthesis of the previously unreported cis-ring fused
fluorene derivative 5 was readily achieved using the two-
step reaction sequence shown in Scheme 1. This starts with
the commercially available compounds 2 and 3 and engages
them in a PPA-mediated Friedel-Crafts acylation/Nazarov-
type cyclization sequence so generating the known fluoren-
9-one 412 in 65% yield. Subjection of the last compound to
a one-pot hydrogenation/hydrogenolysis sequence, using
dihydrogen in the presence of Pd on C and p-toluenesulfonic
acid, afforded compound 5 in 94% yield.
(9) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc.
2000, 122, 9036.
(10) Ueguchi-Tanaka, M.; Ashikari, M.; Nakajima, M.; Itoh, H.; Katoh,
E.; Kobayashi, M.; Chow, T.-y.; Hsing, Y.-i. C.; Kitano, H.; Yamaguchi,
I.; Matsuoka, M. Nature 2005, 437, 693.
(11) This work was undertaken as part of a program within our group to
exploit gem-dihalogenocyclopropanes as building blocks for chemical
synthesis. For representative publications, see: (a) Banwell, M. G.; Gable,
R. W.; Peters, S. C.; Phyland, J. R. J. Chem. Soc., Chem. Commun. 1995,
1395. (b) Banwell, M.; Edwards, A.; Harvey, J.; Hockless, D.; Willis, A.
J. Chem. Soc., Perkin Trans. 1 2000, 2175. (c) Banwell, M. G.; Harvey, J.
E.; Hockless, D. C. R.; Wu, A. W. J. Org. Chem. 2000, 65, 4241. (d)
Banwell, M. G.; Ebenbeck, W.; Edwards, A. J. J. Chem. Soc., Perkin Trans.
1 2001, 114. (e) Banwell, M. G.; Harvey, J. E.; Jolliffe, K. A. J. Chem.
Soc., Perkin Trans. 1 2001, 2002. (f) Banwell, M. G.; Edwards, A. J.;
Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-Pinard, P. Org. Biomol.
Chem. 2003, 1, 296. (g) Taylor, R. M. Aust. J. Chem. 2003, 56, 631. (h)
Banwell, M. G.; Sydnes, M. O. Aust. J. Chem. 2004, 57, 537. (i)
Stanislawski, P. C.; Willis, A. C.; Banwell, M. G. Org. Lett. 2006, 8, 2143.
(j) Foot, J. S.; Phillis, A. T.; Sharp, P. P.; Willis, A. C.; Banwell, M. G.
Tetrahedron Lett. 2006, 47, 6817. (k) Banwell, M. G.; Vogt, F.; Wu, A.
W. Aust. J. Chem. 2006, 59, 415. For a review of certain aspects of our
work in this area, see: (l) Banwell, M. G.; Beck, D. A. S.; Stanislawski, P.
C.; Sydnes, M. O.; Taylor, R. M. Curr. Org. Chem. 2005, 9, 1589.
(12) Ramana, M. M. V.; Potnis, P. V. Synth. Commun. 1995, 25, 1751.
(13) Ma¸kosza, M.; Wawrzyniewicz, M. Tetrahedron Lett. 1969, 4659.
(14) The structure of this compound has been established by single-crystal
X-ray analysis. Details are provided in the Supporting Information.
(15) (a) Banwell, M. G.; Gable, R. W.; Halton, B.; Phyland, J. R. Aust.
J. Chem. 1994, 47, 1879. (b) Banwell, M. G.; Phillis, A. T. Unpublished
observations.
(16) For a comprehensive review of this type of process see: Hudlicky,
T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247.
5342
Org. Lett., Vol. 8, No. 23, 2006

Scheme 2
gem-dihalocyclopropanes derived from dihalocarbene addi-
methylated product 13 clearly arises from dichlorocarbene
insertion into the allylic C-H bond within substrate 11 and
this event then precludes, through steric effects, addition of
the same carbene to the norbornenyl double bond. Rather,
such addition takes place at the exo-cyclic and chlorinated
alkene, thus forming the third reaction product, namely
compound 14.
tion to norbornenes {bicyclo[2.2.1]heptenes} generally en-
gage in spontaneous electrocyclic ring-opening to the
corresponding bicyclo[3.2.1]octane,17 it was thought that
dihalocarbene addition to compound 10 might provide a
means for its homologation to the GA framework proper. In
the event, all efforts to add dichlorocarbene to compound
10 or the corresponding C10-mono-chlorinated derivatives
failed. As a result compound 10 was treated with zinc in
ethanol in the presence of traces of acetic acid thus forming
the doubly dechlorinated compound 11 in 88% yield. The
latter compound proved reactive toward dichlorocarbene
generated under phase transfer conditions with accompanying
ultrasonication18 and the products 1214 (27%), 13 (25%), and
1414 (19%) so-formed were readily separated from one
another by flash chromatographic methods. The structures
of the first and third of these products were confirmed by
single-crystal X-ray analysis. Compound 12, which embodies
the tetracyclic GA framework, undoubtedly arises by the
anticipated pathway, namely addition of dichlorocarbene to
the norbornenyl framework within substrate 11 and so
forming the cyclopropane 15 which does not survive but
immediately undergoes ring-expansion to form the corre-
sponding bicyclo[3.2.1]octane (viz. 12). The R-orientation
of the allylic chlorine within this last compound reflects the
exo-face selectivity associated with the carbene addition
reaction leading to the intermediate adduct 15. The dichloro-
The acquisition of compound 12 as described above
represents a six-step method for the assembly of the
tetracyclic framework associated with GAs. Furthermore,
comparison of the structure of product 12 with that of GA109
methyl ester (16), a gibberellin-like antheridigen from
gametophytes of the fern Lygodium circinnatum,2a reveals
that the synthetic material incorporates functionality highly
relevant to the assembly of certain biologically active GA-
type natural products. Accordingly, we are now adapting the
abovementioned protocols so as to introduce relevant func-
tionalities into the A- and B-rings within these tetracyclic
frameworks. In particular, we anticipate incorporating a
carbonyl group at C4 and a carboxy unit at C6. The former
group would provide the means for inverting stereochemistry
at C5, and thus establishing the required trans-fusion of the
A- and B-rings, as well as a platform for introducing the
methyl and carboxy residues at C4. It is also worth noting
(17) See, for example: (a) Jefford, C. W.; Mahajan, S.; Waslyn, J.;
Waegell, B. J. Am. Chem. Soc. 1965, 87, 2183. (b) Sasaki, T.; Eguchi, S.;
Kiriyama, T. J. Org. Chem. 1973, 38, 2230. (c) Kraus, W.; Klein, G.; Sadlo,
H.; Rothenwo¨hrer, W. Synthesis 1972, 485.
(18) Xu, L.; Brinker, U. H. In Synthetic Organic Sonochemistry; Luche,
J.-L., Ed.; Plenum Press: New York, 1998; pp 344-345.
Org. Lett., Vol. 8, No. 23, 2006
5343

that compound 13 embodies a C-norGA framework bearing
an angular (and functionalized) methyl group at the junction
between the A- and B-rings and thus representing a lower
homologue of the so-called C20 GAs.
are now underway in our laboratories. Results will be
reported in due course.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for generous
financial support. Stimulating discussions with our colleague
Professor Lew Mander (Australian National University) are
warmly acknowledged.
Supporting Information Available: Preparation and
characterization of compounds 4-14 and 1H and 13C NMR
spectra of compounds 4-14 together with the ORTEP and
certain other material derived from the single-crystal X-ray
analyses for 7, 8, 10, 12, and 14 (CCDC nos. 615227-
615231, respectively). This material is available free of
charge via the Internet at http://pubs.acs.org.
Work directed toward exploiting the abovementioned
observations for the purposes of preparing biologically active
analogues of GAs as well as the natural products themselves
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