Accessing the structural diversity of pyridone alkaloids: Concise total synthesis of rac-citridone A

Article abstract of DOI:10.1021/ol2017802

A unique route to the structural diversity of pyridone alkaloids is described based on the concept of a common synthetic strategy. Three different core structure analogues corresponding to akanthomycin, septoriamycin A, and citridone A have been prepared by using a highly selective and novel carbocyclization reaction.

Full text of DOI:10.1021/ol2017802

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4592–4595
Accessing the Structural Diversity of
Pyridone Alkaloids: Concise Total
Synthesis of Rac-Citridone A
Anna D. Fotiadou and Alexandros L. Zografos*
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of
Thessaloniki, University Campus, 54124, Thessaloniki, Greece
alzograf@chem.auth.gr
Received July 4, 2011
ABSTRACT
A unique route to the structural diversity of pyridone alkaloids is described based on the concept of a common synthetic strategy. Three different
core structure analogues corresponding to akanthomycin, septoriamycin A, and citridone A have been prepared by using a highly selective and
novel carbocyclization reaction.
4-Hydroxy-2-pyridone alkaloids constitute a family of
natural products that is extremely wealthy in diverse biolo-
gical activity and pharmaceutical applications.1 Despite the
increasing knowledge provided by the large number of
isolated compounds of their family, numerous unanswered
questions remain concerning their biosynthesis, unknown
congeners, and most importantly their biological targets.
Seeking to uncover missing biosynthetic links between
apparently unrelated natural compounds, our interest
focused on three pyridone alkaloids, namely akanthomy-
cin, citridone A, and septoriamycin A.2
Akanthomycin (1) was isolated from the entomopatho-
genic fungus Akanthomyces gracilis ARS 2910 as a mixture
of atropoisomers with restricted rotation around the
C-6ÀC-7 bond.3 Biosynthetic akanthomycin is believed
to derive from cordypyridone AÀB atropoisomers (2)
(1) Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27, 1168–1185.
(2) Since there is no name assigned in the literature until now,
compound 4 was named septoriamycin A for purpose of clarity:
Kumarihamy, M.; Fronczek, F. R.; Ferreira, D.; Jacob, M.; Khan,
S. I.; Nanayakkara, N. P. D. J. Nat. Prod. 2010, 73, 1250–1253.
(3) Wagenaar, M. M.; Gibson, D. M.; Clardy, J. Org. Lett. 2002, 4,
671–673.
r
10.1021/ol2017802
Published on Web 08/05/2011
2011 American Chemical Society

through a cationic ring expansion, which along with cordy-
pyridone C (3) represents its hexacyclic congener, isolated
from pathogenic fungus Cordyceps nipponica BCC 1389.3,4
Septoriamycin A (4) was isolated from a culture medium of
Septoria pistaciarum.2 It possesses moderate activity against
both methicillin-sensitive and methicillin-resistant strains of
Staphylococcus aureous, antimalarial activity against chloro-
quine-sensitive, and chloroquine resistant strains of Plasmo-
dium falciparum as well as cytotoxic activity against Vero cells.
Interestingly, the structurally unrelated compound citri-
doneA (5) can alsobe envisionedtoderive from a potential
synthetic precursor of akanthomycin or septoriamycin
prior to its carbocyclization. Citridone A is produced by
Penicillium sp. FKI-1938 and was found to possess mico-
nazole activity against Candida albicans.5
yield of 3.2%, indicating the difficulty of the synthetic task.6
Meanwhile, in an elegant study by Snider, a biomimetic
approach of Knoevenagel-DielsÀAlder sequence was used
to construct several members of pyridone alkaloids, including
pyridoxatin, leporin, and analogues.7 Although his strategy
surely follows our logic of disconnection, it fails to give any
result in the case of the cordypyridones and akanthomycin
cores. On the other hand a different strategy was used by the
Williams group to approach 3-alkoxy pyridones, funicolosin
and sambutoxin, based on the late formation of the pyridone
core.8 Recently, Jones et al. also reported a well-designed
synthesis of cordypyridones A and B and their epimers, but
yet without answering if the biosynthetic hypothesis correlat-
ing cordypyridones and akanthomycin is correct.9
Our synthetic plan commenced with the construction of
the requisite advance intermediate 26 (Scheme 2), starting
from ethyl tiglate 9. As shown in Scheme 1, reduction of 9
with LAH provided us with alcohol 10, which was either
iodinated following a known protocol10 or oxidized with
PDC to give compounds 11 and 12 respectively. Reaction
of 11 was achieved using the Evans reaction11 with (R)-4-
benzyl-3-propionyloxazolidin-2-one12 under standard basic
The rich biological profile of 1, 4, and 5 along with their
highly functionalized carbocyclic structures led us to in-
vestigate a potentially unified strategy to access the pre-
sented molecular diversity. Thus, compounds 1, 4, and 5
were envisioned to derive from common synthetic inter-
mediates 6 and 7 as shown in retrosynthetic Figure 1.
Scheme 1. Synthesis of Polypropionate Intermediates 23 and 25
Figure 1. Selected pyridone natural products and disconnection of
their molecular complexity to common synthetic intermediate 7.
In this communication, we report the convergent route to
three highly substituted pyridone-2 structures, representing
the cores for akanthomycin, citridone A, and septoriamycin
A natural compounds, from a common synthetic strategy.
Despite the interesting biological profiles of these alkaloids,
only the synthesis of citridone A has been recently reported.
This total synthesis consists of 24 steps and has an overall
(6) Miyagaya, T.; Nagai, K.; Yamada, A.; Sugihara, Y.; Fukuda, T.;
Fukuda, T.; Uchida, R.; Tomoda, H.; Omura, S.; Nagamitsu, T. Org.
Lett. 2011, 13, 1158–1161.
(7) (a) Snider, B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065–8070. (b)
Snider, B. B. Synth. Commun. 2001, 31, 2667–2679. (c) Snider, B. B.; Lu,
Q. Tetrahedron Lett. 1994, 35, 531–534. (d) Snider, B. B.; Lu, Q. J. Org.
Chem. 1996, 61, 2839–2844.
(8) (a) Williams, D. R.; Lowder, P. D.; Gu, Y. ÀG. Tetrahedron Lett.
1997, 38, 327–330. (b) Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2,
3217–3220.
(9) Jones, I. L.; Moore, F. K.; Chai, C. L. L. Org. Lett. 2009, 11,
5526–5529.
(4) Isaka, M.; Tanticharoen, M. J. Org. Chem. 2001, 66, 4803–4808.
(5) Fukuda, T.; Tomoda, H.; Omura, S. J. Antibiot. 2005, 58, 315–
321.
Org. Lett., Vol. 13, No. 17, 2011
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conditions providing the enantiopure compound 13 in 72%
yield. An alternative procedure utilizing of MgBr2 OEt was
3
Scheme 2. Synthesis of Advanced Intermediates 29À31 and
Failed Plan to Synthesize Key Products 27 and 28
used to synthesize anti-compound 14 in excellent diaster-
eoselectivity (dr =28:1).13 Compound 14 was protected
with TBS-group and then both 13 and 15 were reduced to
16 and 17 respectively using lithium borohydride. Iodina-
tion of alcohol 16 followed by SAMP-hydrazone14 alkyla-
tion and subsequent acid catalyzed hydrolysis led to the
enantioselective construction of (2S,4R) aldehyde 23 in
moderate yield but in high enantioselectivity (93% ee).
Several conditions were tried to couple (2S,4R) aldehyde
23 to 2,4-dihydroxy pyridine, without any success, due to
the epimerization of the sensitive R-positioned methyl
group. This setback led us to modify our strategy to target
the more easily accessible R-methyl diasteromeric mixture
of 23 as the coupling partner of the 2,4-dihydroxy pyridine
compound. Asa result, oxidation of16and 17to19and 20,
respectively, followed by HornerÀEmmons reaction with
triethyl-2-phosphonopropionate afforded the desired
alkenes,15 which were selectively reduced to 22 and 24 by
using nickel chloride and sodium borohydride.16 Further
reduction using DIBAL gave the monounsaturated alco-
hols, which were directly oxidized to the desired diaster-
eomeric aldehydes 23 and 25 by PDC oxidation.
The best conditions found for the coupling reaction
between 2,4-dihydroxy pyridine and 23 or 25 involved
heating both components using microwave irradiation in
the presence of piperidine as a base at 160 °C for 10 min as
shown in Scheme 2. Under these conditions none of the
cyclized products 27 and 28 were obtained, as reported for
the total synthesis of pyridoxatin and leporin.7 Instead, the
only isolable products were diasteroisomeric mixtures of
compounds 29 and 30 along with unreacted 2,4-dihydroxy
pyridine and dimerized products.17
these results, we assumed that the steric constraints imposed
by intermediate 26 play the most important role in its inability
to undergo an intramolecular DielsÀAlder reaction.
With compounds 29 and 30 in hand, the stage was set for
developing appropriate selective CÀC reactions in order to
access the structural diversity of the pyridone family. In the
beginning, we tested the possibility of an inverse 1,5-hydride
shift that would lead to the key intermediate quinone 26
which, probably under different reaction conditions, may
lead to 27 or 28. Interestingly, when compound 29 was
heated at 160 °C for several hours in the presence or absence
of base, only a dimeric pyridone compound19 was isolated
along with extented decomposed byproducts.
In an effort to explain the inability of aldehyde 23 to
undergo an intramolecular DielsÀAlder reaction, we pre-
pared aldehydes 32 and 33.18 Interestingly, these compounds
reacted cleanly to give cyclized products 34 and 35 in a 4:1 and
3.2:1 syn:anti mixture of diastereoisomers. On the basis of
Our explanation for the latter was a retro-Knoevenagel
reaction leading to an excess of 2,4-dihydroxy pyridine in
the reaction solution. A closer look reveals a retro-1,5-
hydride shift to form intermediate 26, which then reacted
with the formed 2,4-dihydroxy pyridine.
We hypothesized that this process could be advantageous
if an internal nucleophile was used to capture the formed
intermediate. Thus, when compound 31 was heated to
110 °C for 2 days in benzene, compound 37 was isolated
as a sole product in 66% yield (Scheme 3). Compound 37
represents the core structure of septoriamycin A.
(10) Boeckman, K., Jr.; Pero, J. E.; Boehmler, D. J. J. Am. Chem.
Soc. 2006, 128, 11032–11033.
(11) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R.
J. Am. Chem. Soc. 1990, 112, 5290–5313.
(12) Cage, J. R.; Evans, D. A. Org. Syn. 1990, 68, 83–85.
(13) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2002, 124, 392–393. (b) Diastereomeric ratio determined
by GLC. (c) For reason of comparison, syn-aldol products have also
been obtained by reacting aldehyde 12 with (R)-oxazolidinone propio-
nate and dibutylborontriflate. See Supporting Information for spectral
data.
After extended experimentation it was found that com-
pound 30, bearing the protected hydroxy group can also be
(14) SAMP (S-1-amino-2(methoxymethyl)pyrrolidine: Enders, D.;
€
Nubling, C.; Schubert, H. Liebigs Ann. 1997, 1089–1100.
(15) A 1.5:1 E,Z mixture of alkenes was obtained from compound 19
in contrast with the E-selective formation when compound 20 was used.
See Supporting Information for more details.
(19) The isolation of dimeric product 44 was persistent in every
conditions used in the coupling reaction.
(16) Several other conditions were tried leading either to isomeriza-
tion of the remaining double bond or to unreacted starting material.
Nickel chloride and sodium borohydride reduction according to: Ha-
nessian, S.; Grillo, A. T. J. Org. Chem. 1998, 63, 1049–1057.
(17) Several conditions concerning different bases or acids were
examined under various temperatures. The same products were always
obtained varying from 30 to 55% yield. Heating under regular condi-
tions provided extented decomposition.
(18) For more experimental details, please see the Supporting In-
formation provided.
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Org. Lett., Vol. 13, No. 17, 2011

substances. These building blocks can be easily transformed
either to a plethora of “privileged structures” or to the
corresponding natural compounds. As an example of such
modification, the dephenyl analogue of septoriamycin A
and the total synthesis citridone A are presented (Scheme 4).
Compound 37 was hydrogenated with 10% Pd/C to
provide compound 43 as a 1.5:1 mixture of isomers with
the major component being the one possessing the wrong
stereochemistry with respect to the natural compound.
Finally, the developed methodology using bismuth
triflate can easily be modified leading to citridone A. The
use of aldehyde 20 in coupling with 4-hydroxy-5-phenyl
pyridone-222 provides a complex mixture of isomers 42.
Subsequent treatment with bismuth triflate promotes the
carbocyclization providing citridone A in 40% yield.
Scheme 3. Core Structure Synthesis of Septoriamycin and
Analogues of Citridone and Akanthomycin
Scheme 4. (A) Completion of the Total Synthesis for rac-Citridone
A (5) and (B) Core Structure Synthesis of Septoriamycin A 43
cyclized to the different carbocyclic core 38 when treated with
the appropriate Lewis acids. Bismuth triflate was the reagent
of choice to avoid decomposition, providing 38 in 54%
yield.20 The mechanism is believed to incorporate a cycloi-
somerization reaction triggered by the formation of a bis-
muthÀamide complex (intermediate A), which activates the
distal allylic acetate position. Internal etherification quenches
the formed cation to produce compound 38.21
Meanwhile, when compound 29, bearing no substituent
(R1 = H), was reacted with bismuth triflate, no reaction
was observed. The use of copper(II) acetate instead, how-
ever, promoted a completely different pathway leading this
time to what we believe to be a radical 7-endo-dig reaction
forming compound 40, which represents a close related
analogue of akanthomycin natural product.
In summary, we have described a unique route to the
structural diversity presented in pyridone alkaloids by using
the concept of common synthetic intermediates. The success
of this process depended on the development of (a) a highly
selective CÀC bond formation using a novel bismuth pro-
moted cationic etherocarbocyclization reaction, (b) a copper
mediated etherocarbocyclization, and (c) a unique intramo-
lecular Michael reaction to tetrahydro-pyrane core of septor-
iamycin. The total synthesis of citridone A was also presented
as evidence of the practicality of the described method in
providing readily biologically active scaffolds.
A large array of natural and synthetic compounds were
prepared using these concepts and are currently being
tested for their biological profile. These results will be
published in due course.
Consequently, by modifying the reaction conditions, ad-
vanced intermediate compounds 29À31 can generate highly
diversified building blocks that are closely related to natural
Supporting Information Available. Experimental proce-
dures and characterization data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(20) Isomeric compound 45 (aprox. 12%) was isolated from the
reaction mixture. Lewis-acid is crucial on the amound of 38 formed.
When indium (III) chloride is used, 45 was isolated as the major product
in 42% yield.
(21) The described reaction is highly stereoselective. A test reaction
using an eight compound diastereomeric mixture led only to the
described compound.
(22) 5-Phenyl-4-hydroxy pyridone-2 was prepared according to pre-
viously described method, see ref 7d.
Org. Lett., Vol. 13, No. 17, 2011
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