A racemic synthesis of an AB-ring system of hexacyclinic acid

Article abstract of DOI:10.1021/ol051633r

(Chemical Equation Presented) An AB-ring system of the polyketide natural product hexacyclinic acid has been synthesized in racemic form. The key steps were an intramolecular Diels-Alder cyclization of an ester tethered 1,3-nonadiene-8-yne, which generate

Full text of DOI:10.1021/ol051633r

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4221-4224
A Racemic Synthesis of an AB-Ring
System of Hexacyclinic Acid
Paul A. Clarke* and Andrew P. Cridland
School of Chemistry, UniVersity of Nottingham,
UniVersity Park, Nottingham, NG7 2RD, United Kingdom
paul.clarke@nottingham.ac.uk
Received July 12, 2005
ABSTRACT
An AB-ring system of the polyketide natural product hexacyclinic acid has been synthesized in racemic form. The key steps were an intramolecular
Diels Alder cyclization of an ester tethered 1,3-nonadiene-8-yne, which generated the B-ring, and a samarium diiodide mediated reductive
−
annulation, which was used to form the A-ring.
Recently, the structure of hexacyclinic acid 1, a new poly-
ketide natural product was reported (Figure 1).1 This com-
pound was isolated from Streptomyces cellulosae subsp.
griseorubiginosus (strain S1013) and was shown to have
some cytotoxic activity when tested in three cell lines
(HM02, HEPG2, and MCF7). A similar compound, also with
cytotoxic activity, FR182877 (Figure 1), has also been
reported.2-4 FR182877 differs from hexacyclinic acid in the
relative stereochemical configurations around the six-
membered B-ring and that a bridgehead double bond exists
where the cyclic hemiketal is in hexacyclinic acid. The B-ring
of hexacyclinic acid is functionalized by a carboxylic acid
residue, whereas this is a methyl group in FR182877. The
main other difference is in the acylation of the C9 hydroxyl
in hexacyclinic acid.
Figure 1. Structures of hexacyclinic acid and FR182877.
syntheses.5a,b Despite the similarities between hexacyclinic
acid and FR182877, there have been fewer reported routes
toward the hexacyclinic acid ring systems.5h,6
Our strategy for the synthesis of the ABC-rings of 1 was
to employ an ester tethered intramolecular Diels-Alder
The unique structural features and challenging nature of
these molecules have attracted the attention of several groups
across the world. This has led to the realization of several
strategies toward the FR182877 ring systems5 and two total
(5) (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem.
Soc. 2002, 124, 4552. (b) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed.
2002, 41, 1787. (c) Armstrong, A.; Goldberg, F. W.; Sandham, D. A.
Tetrahedron Lett. 2001, 42, 4585. (d) Suzuki, T.; Nakada, M. Tetrahedron
Lett. 2002, 43, 3263. (e) Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5,
4223. (f) Funel, J.-A.; Prunet, J. J. Org. Chem. 2004, 69, 4555. (g) Clarke,
P. A.; Grist, M.; Ebden, M. Tetrahedron Lett. 2004, 45, 927. (h) Clarke, P.
A.; Grist, M.; Ebden, M.; Wilson, C., Blake, A. J. Tetrahedron 2005, 61,
353. (i) Clarke, P. A.; Davie, R.; Peace, S. Tetrahedron 2005, 61, 2335.
(1) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000, 39,
3258.
(2) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.; Hino,
M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123.
(3) Sato, B.; Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano,
H. J. Antibiot. 2000, 53, 204.
(4) Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J.
Antibiot. 2000, 53, 615.
10.1021/ol051633r CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/23/2005

reaction to form the B-ring 5 with control of the newly
formed chiral centers. The inclusion of a bromine atom on
the B-ring would enable its conversion to either the car-
boxylic acid group of hexacyclinic acid or the methyl group
of FR182877, and thus, in theory, provide access to the
B-ring of either natural product. Introduction of the appropri-
ate functionality would then allow for the synthesis of the
A- and C-rings via a reductive annulation protocol. Such a
route would install the desired stereochemical triad of the
A-ring 3 and form the C-ring 2 with functionality suitable
to allow the homologation of a DEF-ring precursor (Scheme
1). We now wish to report the success of this strategy for
Scheme 2. Synthesis of Lactone 5
Scheme 1. Retrosynthetic Analysis of the ABC-Rings of 1
AB-rings of hexacyclinic acid.6b With this in mind 9 was
subjected to a Mitsunobu esterification, which generated 6
in 86% yield. Heating 6-propiolyl-1,3-nonadiene-8-yne 6
under reflux in toluene provided the Diels-Alder adduct 10
in good yield (80%). Copper(I) bromide catalyzed conjugate
addition of vinylmagnesium bromide to the unsaturated
γ-lactone yielded 5 in 89% yield (Scheme 2). The relative
1
stereochemistry of 5 was confirmed by H NMR coupling
constants and gradient nOe experiments.
Installation of the second vinyl group, which was required
for formation of the A-ring via a reductive annulation
protocol, was achieved by the series of transformations
detailed in Scheme 3.
Reduction of lactone 5 to the corresponding lactol with
Dibal-H (73% yield) was followed by formation of the
dithiolane 11. Oxidation of the primary alcohol to aldehyde
12 allowed for the addition of vinylmagnesium bromide to
yield allylic alcohol 13 as a 30:1 mixture of diastereomers.
We postulated that the major diastereomer would be the one
needed for continuation of the synthesis of the A-ring, as
the desired diastereomeric product would result from a
Felkin-Ahn controlled addition to the least hindered face of
the carbonyl group (Figure 2).
the construction of a functionalized AB-ring system 3 of
hexacyclinic acid.
To this end, vinyl dibromide 77 and boronic acid 88 were
coupled by use of a Suzuki reaction, under conditions
previously reported to generate the desired diene geometry.5b,9
This furnished diene 9 in 77% yield (Scheme 2). As we have
recently shown that intramolecular Diels-Alder cyclizations
of 6-fumaryl-1,3,8-nonatrienes generate cyclohexene prod-
ucts in which the major diastereomer formed is the one
required for the synthesis of FR182877,5i we opted to
investigate the intramolecular Diels-Alder cyclization of
6-propiolyl-1,3-nonadiene-8-yne 6. We rationalized that
conjugate addition of an appropriate nucleophile would
generate the diastereomer required for the synthesis of the
(6) (a) Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C. Chem. Commun.
2003, 1560. (b) Stellfeld, T.; Bhatt, U.; Kalesse, M. Org. Lett. 2004, 6,
3889.
(7) Spectroscopic data in agreement with: Sauer, D. R.; Schneller, S.
W.; Gabrielsen, B. Carbohydr. Res. 1993, 241, 71. Prepared in accordance
with: Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(8) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Tetrahedron Lett.
1996, 37, 8989.
(9) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157.
Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503.
Figure 2. Rationale for the diastereoselectivity in the addition of
vinylmagnesium bromide to aldehyde 12.
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Org. Lett., Vol. 7, No. 19, 2005

system 3 was the only isolable product obtained from this
reaction.
Scheme 3. Synthesis of Lactol 14
Scheme 4. Synthesis of AB-Rings 3
As it was not possible to determine which major diastereo-
mer had resulted from the addition reaction, the crude
reaction mixture was subjected to dithiolane removal by the
action of ethyl iodide and calcium carbonate in aqueous
acetonitrile. This resulted in the formation of two lactol
diastereomers, which were separated by flash column chro-
matography. The major one was shown to be 14 by 1H NMR
and gradient nOe experiments (Figure 3).
The anti arrangement of the two newly formed stereo-
centers was predicted due to the repulsion of the anionic
oxygen and carbon atoms in the transition state. The
stereochemical relationship of the newly formed stereotriad
with the preexisting stereocenters was determined by H
NMR and nOe experiments (Figure 4).
1
Figure 3. Diagnostic nOe data for lactol 14.
Figure 4. Diagnostic nOe data for AB-ring 3.
Knowing that we had synthesized the desired diastereomer
of 13, we continued our synthesis of the AB-ring system
3 by silylating the allylic alcohol in 13 with TBSOTf
in pyridine to obtain silyl ether 15 in 71% yield. Reduc-
tive annulation precursor 4 was revealed (81% yield) by
removal of the dithiolane with ethyl iodide and calcium
carbonate in aqueous acetonitrile. Formation of the AB-ring
system 3 was achieved in 46% yield when 4 was treated
with samarium diiodide in THF/HMPA, with butanol as
an external proton source (Scheme 4).10 The AB-ring
In summary, we have executed a stereocontrolled
racemic synthesis of an AB-ring system of hexacyclinic acid.
The key steps were a Diels-Alder cyclization of a 6-pro-
piolyl-1,3-nonadiene-8-yne and a reductive annulation
reaction promoted by samarium diiodide. Currently, we
are attempting to use Diels-Alder chemistry presented
in a recent report by Sherburn to develop an enantio-
(10) Grove´, J. J. C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron
Lett. 1996, 37, 1305 and 5817.
Org. Lett., Vol. 7, No. 19, 2005
4223

selective synthesis11 of the AB-ring system. In addition we
are also focusing on a way to annulate the C-ring onto the
AB-ring system in such a manner as to allow for the
formation of the DEF-rings via our iodocyclization
protocol.6a
AstraZeneca for unrestricted funding (P.A.C.), and the
EPSRC National Mass Spectrometry Service, Swansea for
accurate mass determination.
Supporting Information Available: Experimental pro-
cedures for the preparation of and spectroscopic data for all
new compounds is available as well as copies of nOe
spectroscopic data for 14 and 3. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the EPSRC and the Uni-
versity of Nottingham for a DTA studentship award (A.P.C.),
(11) Lilly, M. J.; Miller, N. A.; Edwards, A. J.; Willis, A. C.; Turner,
P.; Paddon-Row, M. N.; Sherburn, M. S. Chem. Eur. J. 2005, 11, 2525.
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