Biomimetic total synthesis of ent-penilactone A and penilactone B

Article abstract of DOI:10.1021/ol4017832

The total synthesis of ent-penilactone A and penilactone B has been achieved via biomimetic Michael reactions between tetronic acids and o-quinone methides. A five-component cascade reaction between a tetronic acid, formaldehyde, and a resorcinol derivati

Full text of DOI:10.1021/ol4017832

ORGANIC
LETTERS
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Vol. XX, No. XX
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Biomimetic Total Synthesis of
ent-Penilactone A and Penilactone B
Justin T. J. Spence and Jonathan H. George*
School of Chemistry and Physics, University of Adelaide, Adelaide, SA 5005, Australia
jonathan.george@adelaide.edu.au
Received June 24, 2013
ABSTRACT
The total synthesis of ent-penilactone A and penilactone B has been achieved via biomimetic Michael reactions between tetronic acids and
o-quinone methides. A five-component cascade reaction between a tetronic acid, formaldehyde, and a resorcinol derivative that generates four
carbonꢀcarbon bonds, one carbonꢀoxygen bond, and two stereocenters in a one-pot synthesis of penilactone A is also reported.
Extremophiles (i.e., microorganisms that grow optimally
under extreme conditions of temperature and pressure, or in
an unusual chemical environment) are a valuable source of
structurally diverse natural products.1 In particular, deep
sea microorganisms grow in darkness at low temperature
and high pressure, and have therefore evolved biosynthetic
pathways that produce unique secondary metabolites.2
For example, penilactones A (1) and B (2) (Figure 1) are
two unusual polyketide natural products isolated from
Penicillium crustosum PRB-2, a fungus found in an Ant-
arctic deep sea sediment.3 The structures of 1 and 2 were
elucidatedusingNMR and X-ray studies, revealinga novel
Figure 1. Penilactones A and B.
tricyclic ring system. Furthermore, CD spectra showed that
1 and 2 possess opposite absolute configurations, which
We have previously used biosynthetic speculation as a
guide for the development of biomimetic cascade reactions
that have been applied in very short syntheses of complex
natural products.4 Such an approach can inspire syntheses
that rapidly install the molecular architecture of the nat-
ural product target with minimal protecting group opera-
tions and functional group interconversions.
suggested to us that they might be formed in Nature by
predisposed, nonenzymatic cascade reactions. They are
therefore attractive targets for biomimetic synthesis.
(1) Wilson, Z. E.; Brimble, M. A. Nat. Prod. Rep. 2009, 26, 44–71.
(2) Skropeta, D. Nat. Prod. Rep. 2008, 25, 1131–1166.
(3) Wu, G.; Ma, H.; Zhu, T.; Li, J.; Gu, Q.; Li, D. Tetrahedron 2012,
68, 9745–9749.
(4) (a) George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M.
Org. Lett. 2010, 12, 3532–3535. (b) Pepper, H. P.; Lam, H. C.; Bloch,
W. M.; George, J. H. Org. Lett. 2012, 14, 5162–5164.
(5) For a review on the use of o-quinone methides in organic synthe-
sis, see: (a) Van De Water, R. W.; Pettus, T. R. Tetrahedron 2002, 58,
5367. (b) Pathak, T. P.; Sigman, M. S. J. Org. Chem. 2011, 76, 9210–
9215. (c) Willis, N. J.; Bray, C. D. Chem.;Eur. J. 2012, 18, 9160–9173.
For recent work by our research group in this area, see: (d) Spence,
J. T. J.; George, J. H. Org. Lett. 2011, 13, 5318–5321. (e) Pepper, H. P.;
Kuan, K. K. W.; George, J. H. Org. Lett. 2012, 14, 1524–1527.
As originally proposed by Li et al. in their isolation
paper,3 we believe that the biosynthesis of penilactones
A (1) and B (2) involves reactions between o-quinone
methides5 and tetronic acids. This is supported by the
coisolation of penilactones A and B with an oxidized
(6) Hassal, C. H.; Todd, A. R. J. Chem. Soc. 1947, 611–613.
r
10.1021/ol4017832
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derivative of clavatol (3),6 a possible o-quinone methide
precursor (Figure 2). Tetronic acids such as 4 and 5 are also
common fungal metabolites,7 and they are therefore reason-
able biosynthetic precursors of penilactones A and B. Indeed,
closely related tetronic acids to 4 and 5 have recently been
isolated alongside clavatol (3) fromPenicillium griseoroseum.8
Scheme 1. Proposed Biosynthesis of Penilactone A
Figure 2. Plausible biosynthetic precursors of the penilactones.
A possible mechanism for the biosynthesis of penilactone A
(1) is outlined in Scheme 1. Oxidation of clavatol (3) could
give o-quinone methide 6. A sequence of two Michael addi-
tion reactions between tetronic acid 4 and two molecules of 6
would form ketone 8 via the enol 7, with formation of a
quaternary carbon center at C-3. Ketone 8 could then under-
go intramolecular nucleophilic attack of the C-40 hydroxy
group at the C-4 carbonyl group to form penilactone A (1).
This final cyclization step must be a selective process, since 8
possesses four distinct phenols that could potentially add to
the C-4 ketone. However, the C-20 and C-200 phenolic hydroxy
groups are presumably deactivated by hydrogen bonding to
the adjacent acetate groups, while the C-5 stereocenter might
direct addition of the C-40 phenol rather than that attached to
C-400. A similar mechanism could account for the formation
of penilactone B (2) from tetronic acid 5, with the C-5
stereocenter in this case dictating the formation of a molecule
with the opposite absolute configuration to penilactone A (1).
In order to gain insight into the biosynthetic mechanism
outlined above, we planned to conduct a short biomimetic
synthesis of the enantiomer of penilactone A (ent-1). This
target was chosen, as (S)-5-methyl tetronic acid (ent-4) is
readily synthesized from (S)-lactic acid.9 We also needed
to synthesize a suitable precursor of o-quinone methide 6,
and 2-methyleneacetoxy-4-methyl-6-acetylresorcinol (11)
was targeted, as similar species have been shown to
generate o-quinone methides under thermal conditions
(Scheme 2).10 FriedelꢀCrafts acylation of commercially
available 4-methylresorcinol (9) gave 4-methyl-6-acetylre-
sorcinol 10, which was reacted with HCHO, NaOAc, and
AcOH to give 11 in good yield.11 This compound could
potentially generate two tautomeric o-quinone methides, 6and
12, via thermal elimination of AcOH. Selective formation of
o-quinone methide 6 was expected due to hydrogen bonding
between the C-1 OH and the adjacent C-6 acetate group,
although addition to either o-quinone methide tautomer
should be effective in forming the penilactone target molecules.
Scheme 2. Synthesis of o-Quinone Methide Precursor 11
(7) Boll, P. M.; Sorensen, E.; Balieu, E. Acta Chem. Scand. 1968, 22,
3251.
(8) Da Silva, J. V.; Fill, T. P.; Da Silva, B. F.; Rodrigues-Fo, E. Nat.
Prod. Res. 2013, 27, 9–16.
(9) (S)-5-Methyl tetronic acid was synthesized in two steps from (S)-
ethyl lactate according to: (a) Fryzuk, M. D.; Bosnich, B. J. J. Am.
Chem. Soc. 1978, 100, 5491–5494. (b) Brandange, S.; Flodman, L.;
Norberg, A. J. Org. Chem. 1984, 49, 927–928.
(10) Rodriguez, R.; Adlington, R. M.; Moses, J. E.; Cowley, A.;
Baldwin, J. E. Org. Lett. 2004, 6, 3617–3619.
(11) This reaction presumably proceeds via the o-quinone methide 6.
Indeed, when 11 was heated in toluene in the presence of
(S)-5-methyl tetronic acid (ent-4), ent-penilactone A (ent-1)
was formed as a single stereoisomer in excellent yield
(Scheme 3) by a mechanism that presumably follows the
biosynthetic hypothesis outlined in Scheme 1. This biomi-
metic cascade reaction formed two carbonꢀcarbon bonds,
one carbonꢀoxygen bond, and two stereocenters in one step.
The reaction was highly selective, as the final cyclization of
B
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Scheme 3. Biomimetic Synthesis of ent-Penilactone A
Scheme 4. Synthesis of Penilactone A via a Five-Component
Cascade Reaction
the intermediate ketone 8 must occur by preferential attack
of the C-40 hydroxyl at the C-4 carbonyl group. If the
reaction was stopped prematurely or run with an excess of
the tetronic acid ent-4, the monoadduct 7 could be isolated,
which adds further support to the biosynthetic proposal. The
1H and 13C NMR spectra of ent-1 in DMSO-d6 showed the
existence of a single compound and perfectly matched the
published data of Li et al.3 However, the NMR spectra of
ent-1 in CDCl3 and C6D6 showed a 7:1 mixture of two
species, with the major compound being penilactone A and
the minor compound being an as yet unidentified diastereo-
mer of penilactone A. We believe this shows that the final
cyclizationtoformtheC-4hemiacetal was under equilibrium,
with penilactone A being the exclusively favored compound in
DMSO. NOESY spectra revealed that the major diastereo-
mer in CDCl3 and C6D6 was the same diastereomer ent-1 as in
DMSO-d6 and in the crystal structure of Li et al. Importantly,
the optical rotation of ent-1, [R]2D5 þ37.8 (c 0.98, MeOH),
showed good correlation with the literature value for 1,
[R]2D0 ꢀ45.1 (c 0.1, MeOH), thus confirming the absolute
stereochemical assignment of Li et al.3
Scheme 5. Biomimetic Synthesis of Penilactone B
The synthesis of ent-penilactone A (ent-1) could be
further shortened by combining the conversion of 10 to
11withthesubsequent biomimeticadditiontotetronicacid
ent-4 in a one-pot, five-component cascade reaction12
(Scheme 4). This reaction directly assembles the natural product
with the formation of four carbonꢀcarbon bonds, one carbonꢀ
oxygen bond, and two stereocenters in a single step.
Synthesis of penilactone B (2) required tetronic acid 5,
which was made in two steps (Scheme 5). The first step
was a domino additionꢀWittig reaction of dibenzyl
(S)-2-hydroxysuccinate (13)13 with (triphenylphosphoranylidene)-
ketene, which gave 14 according to the protocol developed
by Schobert.14 This was followed by debenzylation of 14
under standard conditions to give 5. Heating 5 with 11 in
dioxane then gave penilactone B (2) in excellent yield. Again,
the 1H and 13C NMR spectra of 2 in DMSO-d6 showed a
single compound that matched the published NMR data for
penilactone B,3 but alternative NMR solvents indicated a
mixture of two diastereomers. We therefore suggest that both
penilactones A and B can exist as a mixture of diastereomers
due to a solvent-dependent equilibrium of ring opening and
ring closure at the C-4 hemiacetal group. The optical rotation
of synthetic 2, [R]2D5 þ27.1 (c 1.0, MeOH), showed good
agreement with the literature data, [R]2D4 þ29.4 (c0.1, MeOH).3
In conclusion, we have developed a concise synthesis of ent-
penilactone A (ent-1) and penilactone B (2) using a strategy
guided by biosynthetic speculation. We have confirmed their
absolute configurations and shown that the penilactones can
exist as a solvent-dependent mixture of diastereomers due to
ring opening at the C-4 hemiacetal group. This work also
demonstrates the ability of biomimetic synthesis to rapidly
generate complex natural products and gives some insight
into the possible biosynthesis of the penilactones.
Acknowledgment. We thank the Australian Research
Council for financial support in the form of a Discovery Early
Career Researcher Award (DE130100689) awarded to J.H.G.
Supporting Information Available. Synthetic proce-
dures and analytical data for compounds ent-1, 2, 5, 10,
11, and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) For a recent review on multibond forming reactions in organic
synthesis, see: Green, N. J.; Sherburn, M. S. Aust. J. Chem. 2013, 66,
267–283.
(13) Lee, S. S.; Li, Z.-H.; Lee, D. H.; Kim, D. H. J. Chem. Soc., Perkin
Trans. 1 1995, 2877–2882.
(14) Loffler, L.; Schobert, R. J. J. Chem. Soc., Perkin Trans. 1 1996,
2799–2802.
The authors declare no competing financial interest.
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