Asymmetric total syntheses of (-)-penicipyrone and (-)-tenuipyrone via biomimetic cascade intermolecular michael addition/cycloketalization

Article abstract of DOI:10.1021/ol303071t

The first total syntheses of (-)-penicipyrone and (-)-tenuipyrone were accomplished enantioselectively in 12 steps with an 11% yield and 6 steps with a 28% yield from the known 4-((tert-butyldimethylsilyl)oxy)-cyclopent-2-enone, respectively, by developing a biomimetic bimolecular cascade cyclization featuring an intermolecular Michael addition/cyclo-(spiro-)ketalization sequence. The relative, absolute stereochemistry and carbon connectivity of penicipyrone was further confirmed by X-ray crystallographic analysis and comparison of optical rotations.

Full text of DOI:10.1021/ol303071t

ORGANIC
LETTERS
2013
Vol. 15, No. 1
6–9
Asymmetric Total Syntheses of
(ꢀ)-Penicipyrone and (ꢀ)-Tenuipyrone
via Biomimetic Cascade Intermolecular
Michael Addition/Cycloketalization
Liyan Song, Hongliang Yao, Liangyu Zhu, and Rongbiao Tong*
Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong, China
rtong@ust.hk
Received October 9, 2012
ABSTRACT
The first total syntheses of (ꢀ)-penicipyrone and (ꢀ)-tenuipyrone were accomplished enantioselectively in 12 steps with an 11% yield and 6 steps
with a 28% yield from the known 4-((tert-butyldimethylsilyl)oxy)-cyclopent-2-enone, respectively, by developing a biomimetic bimolecular cascade
cyclization featuring an intermolecular Michael addition/cyclo-(spiro-)ketalization sequence. The relative, absolute stereochemistry and carbon
connectivity of penicipyrone was further confirmed by X-ray crystallographic analysis and comparison of optical rotations.
Recently, two newly isolated polycyclic 4-hydroxy-2-pyrones
(Figure 1) penicipyrone (1)1 and tenuipyrone (2)2 have
attracted our attention because of their unprecedented
polycyclic skeletons and unexplored biological activities,
which might be due to the inadequate supply from natural
sources. Penicipyrone (1), a novel cis-fused tricyclic 6,6,
5-pyrone with three contiguous chiral centers, was isolated
in 2009 with only 1.2 mg out of 15 L of culture broth of
Fungus Penicillium sp. PSU-F44, which exhibited anti-
bacterial activity. Tenuipyrone (2) was isolated by Asai
and Oshima in 2012 with 1.2 mg from 6.9 L of culture
medium of entomopathogenic fungus, Isaria tenuipes,
in the presence of the epigenetic modifying agents his-
tone deacetylase inhibitor and DNA methyltransferase
Figure 1. Tenuipyrone and penicipyrone and biosynthetic hy-
inhibitor. Structurally, tenuipyrone represents a rare
pothesis of tenuipyrone.
tetracyclic 6,6,5,5-pyrone bearing a spiroketal moiety
with four contiguous stereocenters.2 The biogenesis of
tenuipyrone was proposed to involve intermolecular
cephalosporolide B (4), followed by Dieckmann conden-
sation and spiroketalization (Figure 1). To the best of our
knowledge, neither total syntheses nor synthetic studies
of penicipyrone and tenuipyrone have been reported.
Herein, we report the first, asymmetric total syntheses
of (ꢀ)-penicipyrone (ent-1) and (ꢀ)-tenuipyrone (2) by devel-
oping a novel biomimetic cascade cyclization featuring an
Michael addition of 4-hydroxy-6-methyl-2-pyrone (3) to
(1) Trisuwan, K.; Rukachaisirikul, V.; Sukpondma, Y.; Phongpaichit,
S.; Preedanon, S.; Sakayaroj, J. Chem. Pharm. Bull. 2009, 57, 1100.
(2) Asai, T.; Chung, Y.-M.; Sakurai, H.; Ozeki, T.; Chang, F.-R.;
Yamashita, K.; Oshima, Y. Org. Lett. 2012, 14, 513.
r
10.1021/ol303071t
Published on Web 12/18/2012
2012 American Chemical Society

intermolecular Michael addition/cycloketalization.3 This
cascade cyclization may also provide quick and efficient
access to other cis-fused polycyclic pyrones for potential
medicinal applications.
silyloxy substituent. Ketone 6 could be readily synthesized
via R-methylenation and methyllithium opening of
γ-butyrolactone 7.6 The 1,3-diketone 8 could be prepared
by oxidation of MoritaꢀBaylisꢀHillman7 adducts of 4-
((tert-butyldimethylsilyl)oxy)-cyclopent-2-enone (9)8 and
optically pure aldehyde 10. At the outset of our synthetic
studies, it is not clear whether 4-hydroxy-6-methyl-2-pyrone
would undergo 1,4-addition to R,β-unsaturated ketones
since it has been well established that it readily reacts
with R,β-unsaturated aldehyde in a 1,2-addition fashion
in the presence of secondary amine or other catalysts.9 There-
fore, we wished to determine if 1,4-addition of 4-hydroxy-
6-methyl-2-pyrone to R,β-unsaturated ketones would occur
followed by cycloketalization. To this end, three racemic
R-methylene lactones (11aꢀ11c) were prepared as model
compounds for the cascade intermolecular Michael addi-
tion/cycloketalization processes (Scheme 2).
Our synthetic strategy (Scheme 1) was primarily inspired
by the biosynthetic hypothesis of tenuipyrone. Although
the corresponding biosynthesis of penicipyrone (1) has not
been proposed yet, we believe that a similar cascade
intermolecular Michael addition/cycloketalization could
be applied to build up the tricyclic pyrone. Therefore, as
outlined in Scheme 1, we envisioned that cascade inter-
molecular Michael addition of 4-hydroxy-6-methyl-2-pyr-
one (3),4 followed by cycloketalization (or spiroketaliza-
tion),5 would provide the tricyclic and tetracyclic pyrones
found in penicipyrone and tenuipyrone, respectively, when
R,β-unsaturated ketones 6 and 8 were employed as the
corresponding Michael acceptors. The relative stereoche-
mistry of the newly formed chiral centers in penicipyrone
might arise by stereoinduction from ketone 6 through
formation of thermodynamically more stable cis-fused
tricyclic 6,6,5-ketal with the central pyran ring form-
ing anti- to the propenyl side chain to minimize the steric
hindrance. A similar stereoinduction might operate for the
new chiral centers in the cascade intermolecular Michael
Scheme 2. Amberlyst-15 Promoted Cascade Intermolecular
Michael Addition/Cycloketalization
Scheme 1. Retrosynthetic Analyses
As shown in Scheme 2, treatment of the R-methylene
lactone with methyllithium afforded the cascade cycliza-
tion precursors: γ-(or δ-) hydroxyl-R,β-unsaturated ke-
tones, in good yields (50ꢀ71%), which were unconseque-
ntially in equilibrium with the less favored lactol as in-
1
dicated by H NMR. The key cascade intermolecular
Michael addition/cycloketalization process was then expl-
ored by addition of the individual ketone to the 4-hydroxy-
6-methyl-2-pyrone (3) in the presence of Amberlyst-15. To
our delight, the cascade cyclization proceeded smoothly
to give cis-fused tricyclic ketals (12aꢀ12c), correspond-
ing to the penicipyrone core structure, in excellent yields
(72ꢀ88%) with exclusive regioselectivity. The relative
addition/spiroketalization for the total synthesis of tenuipyrone
(2), with addition of 4-hydroxy-2-pyrone anti- to the
(6) Parsons, P. J.; Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem.
Commun. 1995, 437.
(7) For a review, see: Basavaiah, D.; Reddy, B. S.; Badsara, S. S.
(3) For recent advances in the biomimetic total synthesis of natural
products, see: (a) Biomimetic Organic Synthesis; Poupon, E., Nay, B.,
Eds.; Wiley-VCH Verlag & Co. KGaA: Weinheim, Germany, 2011. (b) De la
Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed. 2004, 43, 160. (c)
Bulger, P. G.; Bagal, S. K.; Marquez, R. Nat. Prod. Rep. 2008, 25, 254.
For cascade reactions involving Michael addition in the total synthesis
of natural products, see selected reviews: (d) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (e) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
Chem. Rev. 2010, 110, 5447.
(8) (a) Paquette, L. A.; Heidelbaugh, T. M. Org. Synth. 1996, 73, 44.
(b) Curran, T. T.; Hay, D. A.; Koegel, C. P.; Evans, J. C. Tetrahedron
1997, 53, 1983.
(9) (a) Ikawa, M.; Stahmann, M. A.; Link, K. P. J. Am. Chem. Soc.
~
1944, 66, 902. (b) de March, P.; Roca, J. L.; Moreno-Manas, M.;
Pleixats, R. J. Heterocycl. Chem. 1984, 21, 1369. (c) de March, P.;
~
Moreno-Manas, M.; Casado, J.; Pleixats, R.; Roca, J. L.; Trius, A.
(4) For representative Michael addition of 1,3-dicarbonyl com-
pounds, see: (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 4955. (b) Halland, N.; Aburel, P. S.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2004, 43, 1272. (c) Rueping, M.; Merino,
E.; Sugiono, E. Adv. Synth. Catal. 2008, 350, 2127.
(5) For a representative review, see: Perron, F.; Albizati, K. F. Chem.
Rev. 1989, 89, 1617.
J. Heterocycl. Chem. 1984, 21, 85. (d) Hsung, R. P.; Shen, H. C.;
Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem.
1999, 64, 690. (e) Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.;
Morgan, C. D.; Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.;
Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Wei, L.-L.; Sklenicka, H. M.;
Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68, 1729. (f) Hsung,
R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
Org. Lett., Vol. 15, No. 1, 2013
7

stereochemistry and carbon skeleton of 12c were further
verified by X-ray diffraction analysis.10
methyllithium. With a reliable supply of ketone 6 in hand,
we reached the key cascade intermolecuar Michael addi-
tion/cycloketalization. Gratifyingly, treatment of ketone 6
and 4-hydroxy-6-methyl-2-pyrone (3) with Amberlyst-15
in DCM promoted the cascade cyclization efficiently and
completed the first, asymmetric total synthesis of (ꢀ)-
penicipyrone (ent-1) in 84% yield with exclusive diaster-
eoselectivity (for spectra comparison, see Supporting
Information).10 All aspects of spectroscopic data were in
good agreement withthose ofthe natural product,14 except
the optical rotation. The optical rotation of our synthetic
penicipyrone has an opposite sign (synthetic: [R]D ꢀ52.8,
lit. þ51),1,10 verifying the empirical assignment of the abso-
lute stereochemistry of natural penicipyrone. Moreover,
a single crystal of racemic synthetic penicipyrone was
obtained for the first time for X-ray diffraction analysis,
which further confirmed the constitutional structure and
its relative stereochemistry of the synthetic penicipyrone.
Next, our attention turned to the total synthesis of the
more complex tenuipyrone (2). As outlined in Scheme 4,
our synthetic venture commenced with the synthesis of the
known nonracemic 4-((tert-butyldimethylsilyl)oxy)-cyclo-
pent-2-enone (9a),8 a widely used chiral building block in
prostaglandin synthesis,15 which can be prepared in gram
scales in five steps from furfuryl alcohol.10 The other
coupling partner, aldehyde 10, was readily obtained in
two steps with excellent yield.10 The union of these two
fragments 9a and 10 was very challenging. Considerable
efforts to unite enone 9a with aldehyde 10 through the
obvious MoritaꢀBaylisꢀHillman coupling proved fruit-
less. Alternatively, NozakiꢀHiyamaꢀKishi16 coupling of
9b and 10 gave the desired β-keto alcohol 19 but with poor
reproducibility in 0ꢀ20% yields. Finally, it was found that
the coupling of organoselenium 18 derived from 9a with
aldehyde 10 could be achieved efficiently in 48ꢀ65% yields
as a single diastereomer using the method developed by
Toru.17 Mechanistically, it involved 1,4-addition of tribu-
tylstannyllithium to enone 18 to generate enolate, followed
by aldol reaction of enolate with aldehyde 10 and sponta-
neousdestannylselenenylation. Dess-Martin periodinane18
oxidation of the alcohol 19 gave the β-keto-enone 8 (95%
yield) for the key cascade cyclization. To our delight, under
the identical cascade cyclization conditions for the synth-
eses of penicipyrone and tricyclic pyrrones 12aꢀc, β-keto-
enone 8 underwent Amberlyst-15 promoted cascade
Encouraged by this newly established bimolecular cas-
cade cyclization process, we set out to undertake the
asymmetric total synthesis of penicipyrone. As depicted
in Scheme 3, the commercially available chiral building
block (ꢀ)-methyl lactate (13), which was expected to give
the enantiomer of natural penicipyrone, was protected as
the tert-butyldimethylsilyl (TBS) ether and then reduced to
aldehyde 14. A two-carbon extension was achieved by
HornerꢀWadsworthꢀEmmons (HWE)11 olefination of
14. Reduction of HWE adducts with DIBAL-H and
protective group adjustments afforded the enantiomeri-
cally pure allylic alcohol 15. Note that the racemic 15 was
Scheme 3. Total Synthesis of (ꢀ)-Penicipyrone
initially obtained in high yield at large scale from cis-2-
butene-1,4-diol in three steps (>80% yield, TBS mono-
protection, ParikhꢀDoering oxidation, and MeMgCl
addition). The optically active alcohol 15 was subjected
to JohnsonꢀClaisen rearrangement12 to afford trans-
alkene 16 in 79% yield with excellent stereochemistry trans-
fer. Acid-mediated lactonization of16cleanly delivered the
γ-butyrolactone 7,6 which was converted to γ-hydroxyl-
R,β-unsaturated ketone 6, the precursor for the cascade
cyclization, through a three-step reaction sequence: Clai-
sen condensation with ethyl formate, aldol addition with
paraformaldehyde,13 and γ-butyrolactone opening by
(14) Personal email communication and discussion with professor
Rukachaisirikul: the 165.2 ppm signal in the 13C NMR was barely
observed in the original spectrum due to weak signals, and 160.6 ppm
might be misassigned for the carbon with a resonance of 165.2 ppm. As
for 1H NMR, the only difference between the synthetic (2.12 ppm) and
natural (2.18 ppm) product may arise from use of a combination of
CDCl3 and CD3OD (minor) solvents for recording the 1H NMR
spectrum of the natural penicipyrone. See Supporting Information for
more details.
(10) See Supporting Information for details.
(11) For a selected review, see: Maryanoff, B. E.; Reitz, A. B. Chem.
Rev. 1989, 89, 863.
(12) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970,
92, 741.
(15) For a selected review, see: Noyori, R.; Suzuki, M. Angew.
Chem., Int. Ed. 1984, 23, 847.
(16) (a) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7,
5417. (b) Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7,
€
5421. For a representative review, see: (c) Furstner, A. Chem. Rev. 1999,
99, 991.
(17) Kusuda, S.; Ueno, Y.; Toru, T. Bull. Chem. Soc. Jpn. 1993, 66,
2720.
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(13) (a) Murray, A. W.; Reid, R. G. Synthesis 1985, 35. (b) Jenkins,
S. M.; Wadsworth, H. J.; Bromidge, S.; Orlek, B. S.; Wyman, P. A.;
Riley, G. J.; Hawkins, J. J. Med. Chem. 1992, 35, 2392.
8
Org. Lett., Vol. 15, No. 1, 2013

intermolecular Michael addition/spiroketalization with
4-hydroxy-6-methyl-2-pyrone (3) to afford the (ꢀ)-teuni-
pyrone (2) although it was obtained as a minor compo-
nent of the product mixture with the major component
tentatively assigned as a potential diastereomer 22, pos-
sibly a kinetically favored product. Noteworthy was the
unexpected removal of both TES and TBS during the
cascade reactions.
group to provide (ꢀ)-tenuipyrone (2) in 47% combined
yield over two steps. Mechanistically, this novel cascade
intermolecular Michael addition/spiroketalization is dif-
ferent from the well established formal [3 þ 3] cycloaddi-
tion of R,β-unsaturated aldehyde and 4-hydroxy-6-
methyl-2-pyrone involving Knoevenagel condensation
and 6π-electron electrocyclization.9 We proposed that
intermolecular Michael addition of 3 to 8 was initiated
by a Brønsted acid, followed by enolization of β-ketolac-
tone 20 and spiroketalization to provide the kinetically
favored spiroketal 22, which was further isomerized under
acidic conditions to afford the thermodynamically favored
spiroketal of (ꢀ)-tenuipyrone (2). All spectroscopic data of
our synthetic sample were identical to the reported data of
natural (ꢀ)-tenuipyrone (2).2,10
Scheme 4. Total Synthesis of (ꢀ)-Tenuipyrone (2)
In summary, we have accomplished the first, concise
asymmetric total syntheses of (ꢀ)-penicipyrone (ent-1) and
(ꢀ)-tenuipyrone (2) in 12 steps with an 11% yield from
(ꢀ)-methyl-lactate (13) and 6 steps with a 28% yield from
the known 4-((tert-butyldimethylsilyl)oxy)-cyclopent-2-
enone (9a) (11steps with3.5%yield from furfurylalcohol),
respectively, by developing a biomimetic cascade cycliza-
tion featuring an intermolecular Michael addition/cyclo-
ketalization (spiroketalization). We have further con-
firmed the relative and absolute configuration of penici-
pyrone with X-ray diffraction analysis and comparison of
optical rotations. The new biomimetic cascade polycycli-
zation has provided chemical evidence for the potential
biosynthetic pathway of tenuipyrone and has demon-
strated its viability and efficiency for different γ-(or δ-)
hydroxy-R,β-unsaturated ketone substrates. Further
explorations and exploitations of the cascade intermole-
cular Michael addition/cycloketalization are ongoing in
our laboratory.
Acknowledgment. This research was supported by
startup funding (R9309) from The Hong Kong University
of Science and Technology (HKUST) and a Direct Alloca-
tion Grant (DAG12CS03) from the Research Grant
Council of Hong Kong. A postdoctoral matching fund
(HKUST) for Dr. Song is greatly acknowledged. The
authors are also grateful to Prof. Dr. Ian Williams
(HKUST) for the single crystal X-ray diffraction analysis
and Prof. Dr. V. Rukachaisirikul (Prince of Songkla
University) for providing copies of NMR spectra of
penicipyrone and discussions.
Further efforts to improve the yield of the desired
tenuipyrone in the cascade cyclization revealed that (1)
tenuipyrone may not be stable under strong acid/base
conditions because it decomposed when treated with tetra-
butylammonium fluoride or in CDCl3 solution in the
NMR tube over 7 h while recording 13C NMR spectra
and (2) the diastereomer 22 was initially formed as the only
product based on TLC and then converted slowly into the
tenuipyrone by Amberlyst-15. Based on these findings and
extensive experimentation, we could improve the cascade
cyclization by employing the two-step sequence: (a) Am-
berlyst-15in dryDCM triggeringthe cascade cyclization of
4-hydroxy-6-methyl-2-pyrone (3) and 8 within 30 min to
afford the tetracyclic tenuipyrone (2, 16% yield) and its
TBS ether diastereomer 22 (60% yield) and (b) subjecting
22 to isomerization mediated by Amberlyst-15 in wet
DCM with concomitant removal of the TBS protecting
Supporting Information Available. Detailed experimen-
1
tal procedures, characterizations, and copies of H and
13C NMR spectra of new compounds, and crystallo-
graphic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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