Total synthesis of topopyrones B and D

Article abstract of DOI:10.1021/ol0617291

(Chemical Equation Presented) We describe a straightforward synthesis of topopyrones B and D, which are potent and selective inhibitors of topoisomerase I. The chemistry should be suitable for additional structure-activity relationship (SAR) work.

Full text of DOI:10.1021/ol0617291

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4771-4774
Total Synthesis of Topopyrones B and D
Jason Samuel Tan and Marco A. Ciufolini*
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
Received July 14, 2006
ABSTRACT
We describe a straightforward synthesis of topopyrones B and D, which are potent and selective inhibitors of topoisomerase I. The chemistry
should be suitable for additional structure activity relationship (SAR) work.
−
Topoisomerases I and II (topo-I and topo-II) are nuclear
enzymes that relax superhelical tension in DNA during
replication, transcription, and repair events.1 These enzymes
operate by reversibly breaking one (topo-I) or both (topo-
II) DNA strands and by unwinding the severed strand(s),
thereby avoiding buildup of torsional energy. Interestingly,
cancerous cells tend to overexpress topoisomerases, inhibition
of which is fatal to the cell. Consequently, topoisomerase
inhibitors have emerged as important antineoplastic agents.2
A number of antitumor drugs target topo-II.3 Selective
intervention at the level of topo-I constitutes an equally
desirable strategy in cancer therapy. The prototype of all
selective topo-I inhibitors is camptothecin,4 derivatives of
which are currently marketed for the treatment of various
neoplastic conditions. Other natural products that behave as
selective topo-I poisons include the fungal metabolite,
hypoxyxylerone,5 certain marine alkaloids,6 and a family of
recently discovered substances, which have been christened
the “topopyrones” (Figure 1).7 These compounds are based
Figure 1. Structures of topopyrones A-D.
on an anthraquinone framework that carries an angularly
(topopyrones A, 1, and C, 2) or linearly (topopyrones B, 3,
and D, 4) fused γ-pyrone ring. Bioactivity is especially
pronounced in topopyrone B, the potency of which toward
topo-I is comparable to that of camptothecin.8
(1) Recent review: Champoux, J. J. Annu. ReV. Biochem. 2001, 70, 369.
(2) Denny, W. A. Expert Opin. Emerging Drugs 2004, 9, 105. (b)
AdVances in Pharmacology; Liu, L. F., Ed.; Academic Press: San Diego,
CA, 1994; Vol. 29B.
(3) Recent review: Kellner, U.; Sehested, M.; Jensen, P. B.; Gieseler,
F.; Rudolph, P. Lancet Oncol. 2002, 3, 235.
To our knowledge, no synthetic work toward 1-4 has been
detailed in the peer-reviewed literature as of this writing,
(4) Reviews: (a) Rothenberg, M. L. Ann. Oncol. 1997, 8, 837. (b)
Versace, R. W. Expert Opin. Ther. Pat. 2003, 13, 1.
(6) Review: Dias, N.; Vezin, H.; Lansiaux, H.; Lansiaux, A.; Bailly, C.
Top. Curr. Chem. 2005, 253, 89.
(7) (a) Kanai, Y.; Ishiyama, D.; Senda, H.; Iwatani, W.; Takahaski, H.;
Konno, H.; Tokumasu, S.; Kanazawa, S. J. Antibiot. 2000, 53, 863. (b)
Ishiyama, D.; Kanai, Y.; Senda, H.; Iwatani, W.; Takahashi, H.; Konno,
H.; Kanazawa, S. J. Antibiot. 2000, 53, 873.
(5) Isolation: (a) Edwards, R. L.; Fawcett, V.; Maitland, D. J.; Nettleton,
R.; Shields, L.; Whalley, A. J. S. J. Chem. Soc., Chem. Commun. 1991,
1009. Bioactivity: (b) Gimbert, Y.; Chevenier, E.; Greene, A. E.; Mas-
sardier, C.; Piettre, A. EP 01 402 551 4, 2001. Synthetic work: (c) Piettre,
A.; Chevenier, E.; Massardier, C.; Gimbert, Y.; Greene, A. E. Org. Lett.
2002, 4, 3139. (d) Chevenier, E.; Lucatelli, C.; Pandya, U.; Wang, W.;
Gimbert, Y.; Greene, A. E. Synlett 2004, 2693.
(8) Reported activity (ref 7): IC50 ) 0.15 ng/mL for 3 vs 0.10 ng/mL
for camptothecin.
10.1021/ol0617291 CCC: $33.50
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Published on Web 09/15/2006

1
although synthetic studies toward these substances have been
recorded in a dissertation.9 In this paper, we describe a
straightforward avenue to topopyrones that should be suitable
for congener synthesis and structure-activity relationship
(SAR) studies.
Exposure to alkali promotes facile rearrangement of
angularly fused 1 and 2 to the corresponding linearly fused
3 and 4.7 This observation indicates that topopyrones B and
D are thermodynamically favored relative to topopyrones A
and C. Our avenue to 3 and 4 therefore relies on the
cyclization of intermediate 5 under thermodynamically
controlled conditions (Figure 2). Drawing upon the work of
It is noteworthy that the H and 13C NMR spectra of
compounds 13, 14, and 8 indicated that these substances exist
as mixtures of diastereomeric atropisomers. This was also
the case for later intermediates incorporating fragment 8 and
retaining the TIPS protecting group present therein. Atro-
pisomerism disappeared upon release of the TIPS unit. A
qualitative appreciation for these phenomena may be readily
garnered through an inspection of molecular models of
compounds 13, 14, and 8: the bulky TIPS group greatly
hampers rotation about the σ-bond connecting the benzylic
carbon to the aryl segment.
No experiments were carried out to determine the coa-
lescence temperature for atropisomer interconversion, let
alone to measure conformational activation parameters.
However, a rough estimate of the energy barrier for internal
rotation in TIPS-protected intermediates was generated
through a molecular mechanics study of model structure 15.
The optimized conformation of 15 is depicted in Figure 3
Figure 2. Retrosynthetic plan for topopyrones.
Snieckus,10 we chose to assemble the anthraquinone core of
the target molecules through the merger of fragments 6-8,
a transformation that may be achieved through a one-pot,
three-step sequence.
Figure 3. Computed conformational properties of model compound
15.
The preparation of the “eastern” moiety 8, which is
common to all topopyrones, commenced with halogen-metal
exchange of 911 and addition of the resulting organometallic
to aldehyde 10 (Scheme 1).12 O-Silylation of the emerging
as 15a. The dihedral angle θ between the benzylic hydrogen
and the ortho-aryl carbon atom is equal to approximately
-9°. When θ was set to 90° and the remainder of the
molecule was allowed to relax in the MM+ force field,13
a
conformer 15b containing 17.3 kcal/mol of excess energy
resulted. We regard this as the lower limit for the rotational
barrier in such TIPS-protected molecules.14
Scheme 1. Preparation of Fragment 8
The union of segment 8 with fragments 6 and 7 was
achieved as outlined in Scheme 2. Thus, the Snieckus-type
anion obtained upon directed metalation of benzamides 6
and 7 added to aldehyde 8 to form an intermediate presumed
to be 16. Treatment in situ with additional tert-BuLi
presumably induced bromine-lithium exchange, thereby
triggering cyclization of 16 to the corresponding dihydroan-
thraquinone. Exposure to air finally afforded the desired 17
and 18 in a yield of 17 and 20%, respectively, for the one-
pot, three-step process (after purification).15 In either case,
debrominated compounds 19 and 20 were the major products
(60-70% chromatographed).
11 furnished 12. Aromatic bromination followed by selective
deprotection of the primary benzylic alcohol afforded 14,
which, upon Swern oxidation, yielded subtarget 8.
(12) Langer, P.; Freifeld, I. Synlett 2001, 4, 523.
(13) Calculations were performed with the Hyperchem package, available
from Hypercube, Inc.
(14) The computed value is a lower limit for the rotational energy barrier
(which is notoriously difficult to calculate with precision) because there
is no actual eclipsing between the aryl carbons and the alkyl or OTIPS
residues.
(9) Qi, L. Dissertation; Brown University: Providence, RI, 2003: Diss.
Abstr. Int., B 2003, 64, 1737.
(10) (a) Wang, X.; Snieckus, V. Synlett 1990, 313. See also: (b) De
Silva, S. O.; Watanabe, M.; Snieckus, V. J. Org. Chem. 1979, 44, 4802.
(11) The preparation of this material is described in the Supporting
Information.
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Org. Lett., Vol. 8, No. 21, 2006

significantly more efficient, providing recrystallized product
in 40% yield (Scheme 3, the crude yield of 23 was at least
Scheme 2. Anthraquinone Assembly
Scheme 3. Synthesis of Anthraquinone 20
Several comments are in order at this juncture. First,
deprotonation of 6 occurred rapidly with the standard sec-
BuLi/TMEDA combination (1.05 equiv, 3 h, -78 °C).16 By
contrast, chlorinated benzamide 711 proved to be remarkably
resistant to deprotonation under the same conditions, even
when exposed to the action of a 5-fold molar excess of the
sec-BuLi/TMEDA complex (no incorporation of deuterium
upon quenching with CD3OD). Ultimately, deprotonation was
effected by the use of the more basic tert-BuLi/TMEDA
system (1 equiv, 3 h, -78 °C; essentially complete deutera-
tion upon a CD3OD quench). The reason(s) for such
difficulties remain unclear. A number of chlorinated benza-
mides undergo deprotonation in a normal fashion,12 signaling
that the behavior of 7 cannot be attributed to the chloro
substituent per se. It is likewise difficult to impute the
foregoing problems to sequestration of the base through
coordination/chelation17 effects involving the chlorine atom
because amide 7 resisted deprotonation even in the presence
of excess base and because, e.g., 2,3,4-trimethoxybenzamide
(an analogue of 7 wherein a methoxy group replaces the
chloro substituent) undergoes directed ortho metalation
without incident,18 even though the triad of adjacent methoxy
groups undoubtedly can coordinate/chelate/sequester organo-
lithium species at least as effectively as the 2,4-dimethoxy-
3-chloro arrangement present in 7.
60%). We therefore suspect that parasitic proton-transfer
events, perhaps from one of the benzylic positions of the
presumed aryllithium derivative of 16, consume transient
organometallic species, resulting in the formation of 19
and 20 while eroding the overall yield of the targets 17 and
18.
Conversion of 17 and 18 to topopyrones D and B entailed
desilylation and IBX oxidation of the resulting alcohol,19
followed by exposure of ketones 24 and 25 to 48% aqueous
HBr solution (Scheme 4). Topopyrone D was characterized
Scheme 4. Synthesis of Topopyrones B and D
Second, the genesis of products 19 and 20 is not attri-
butable to an insufficient time allotted to the cyclization
step. To wit, the yield and the ratio of desired 17 and 18
to undesired 19 and 20 remained essentially unchanged
when, following addition of tert-BuLi to the solution
containing 16, the mixture was allowed to stir for a period
ranging from 3 to 12 h. Moreover, the construction of 1,3,6,8-
tetramethoxy-anthraquinone 23 by the same method was
as such.20 However, the isolation paper7 provides no spectral
properties for free 3 and 4, which were instead characterized
as the respective triacetate and trimethyl derivatives. This is
probably a consequence of the poor solubility of topopyrones
in common organic solvents. Accordingly, fully synthetic 3
and 4 were converted to trimethyl ether 27 and triacetate
26, respectively. These derivatives produced spectra that were
in complete accord with the data reported for their naturally
derived counterparts.7
(15) These yields are somewhat disappointing. However, the one-pot
process of Scheme 2 permits a high degree of convergency, and it involves
three distinct, sequential reactions (nucleophilic addition of the lithiated
benzamide to 8, halogen-metal exchange, and intramolecular addition of
the aryllithium derivative of 16 to the amide carbonyl). An overall yield of
20% thus corresponds to an average 58% yield per step.
(16) Snieckus, V. Chem. ReV. 1990, 90, 879.
In summary, we have devised a straightforward avenue
to topopyrones that should be suitable for congener synthesis
and SAR studies. This would entail the use of suitably
(17) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206.
(18) Sibi, M. P.; Jalil Miah, M. A.; Snieckus, V. J. Org. Chem. 1984,
49, 737.
(19) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(20) See Supporting Information for pertinent data.
Org. Lett., Vol. 8, No. 21, 2006
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modified fragments 6-8 in the sequence outlined in Scheme
2. Improved variants of the approach described herein are
under development, and additional results in this area will
be described in due course.
Research Chair Program, and MerckFrosst Canada for
financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and spectra of all the com-
pounds described herein. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Prof. V. Snieckus, of
Queen’s University, Kingston, ON, for helpful discussion
and the University of British Columbia, NSERC, the Canada
OL0617291
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