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
(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.
Org. Lett., Vol. XX, No. XX, XXXX
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