relative stereochemistry at C-1 and C-5 was not deter-
mined.5 Herein, we propose that 1 and 2 are derived in
nature from 3 via highly selective, predisposed radical
cyclizations. As delineated in Scheme 1, oxidation of the
Δ2,3 enol of 3 would form the stabilized radical 4 that could
undergo a 7-endo-trig cyclization with the pendant lavan-
dulyl side chain to give the tertiary radical 5. A subsequent
5-exo-trig radical cyclization of 5 onto the Δ7,8 enol would
give the diketo radical 6, which could abstract a hydrogen
atom from a suitable donor to form nemorosonol (2).
Alternatively, 6 could undergo a second 5-exo-trig cycliza-
tion onto the Δ17,18 of the C-1 prenyl group to give tertiary
radical 7. Garcibracteatone (1) could then be formed from
7 eithervia anintramoleculararomatic radical substitution
reaction or, alternatively, by single electron oxidation to
give a carbocation that could participate in an intramole-
cular FriedelÀCrafts reaction.
We have previously applied an oxidative radical cylization
approach to the simpler PPAP natural products ialibi-
nones A and B6 using PhI(OAc)2 as the oxidant.7 A similar
synthesis of ialibinones A and B has also been reported by
Simpkins,8 who usedMn(OAc)3 and Cu(OAc)2 asreagents
for the key radical cascade sequence. The Mn(OAc)3/
Cu(OAc)2 system for inducing oxidative radical cycliza-
tions of enolizable carbonyl compounds has been investi-
gated extensively by Snider,9 and it has been specifically
applied in studies toward the synthesis of PPAPs by
Kraus10 and Porco.11 The work of Porco is particularly
relevant to this synthesis of garcibracteatone, as he showed
the potential for forming complex polycyclic ring systems
via cyclizations of dearomatized phloroglucinols.
Our synthesis of garcibracteatone commenced with a
FriedelÀCrafts reaction between anhydrous phloroglucinol
(8) and benzoyl chloride to give 2,4,6-trihydroxybenzophe-
none (9) in 47% yield (Scheme 2).12 Diprenylation of 9 with
prenyl bromide in aqueous KOH then formed 10 in 34%
yield.13 Alkylation of 10 using (()-lavandulyl iodide14 (11)
with NaH in DMF gave 12 as an inseparable mixture of two
diastereomers, with each diastereomer existing as a mixture
of two tautomers. The modest yield for this reaction (29%,
or 50% based on recovered 10) reflects the sterically
crowded nature of the all-carbon quaternary center formed
at C-1, as well as the low SN2 reactivity of the alkyl iodide
(competing E2 elimination was observed). Oxidation of
12 under the standard Mn(OAc)3/Cu(OAc)2 conditions
then furnished a mixture of (()-garcibracteatone (1, 14%
isolated yield) and (()-5-epi-garcibracteatone (13, 8% iso-
lated yield) that was separable by flash chromatography on
silica gel.15
Scheme 1. Proposed Biosynthesis of Garcibracteatone and
Nemorosonol from Weddellianone A
The structures of 1 and 13 were elucidated via 2D NMR
spectroscopy and later confirmed by X-ray studies,16 and
the data for 1 matched those of the previously isolated
natural product. The relative stereochemistry of 1 at C-5
is therefore confirmed to be as shown in Scheme 2. The
formation of a mixture of 1 and 13 is inevitable by this
strategy due to the nondiastereoselective alkylation of 10
(6) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O.
J. Nat. Prod. 2000, 63, 104–108.
(7) George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M.
Org. Lett. 2010, 12, 3532–3535.
(8) Simpkins, N. S.; Weller, M. D. Tetrahedron Lett. 2010, 51, 4823–
4826.
(9) For a review of Mn(OAc)3-mediated oxidative radical cycliza-
tions, see: Snider, B. B. Chem. Rev. 1996, 96, 339–363.
(10) (a) Kraus, G. A.; Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003,
44, 659–661. (b) Kraus, G. A.; Dneprovskaia, E.; Nguyen, T. H.; Jeon, I.
Tetrahedron 2003, 59, 8975–8978.
(11) Mitasev, B.; Porco, J. A., Jr. Org. Lett. 2009, 11, 2285–2288.
(12) Lin, C.-M.; Huang, S.-T.; Lee, F.-W.; Kuo, H.-S.; Lin, M.-H.
Bioorg. Med. Chem. 2006, 14, 4402–4409.
(13) Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 12682–
12683.
(14) See Supporting Information for synthesis of (()-lavandulyl
iodide (11) from (()-lavandulol.
(15) No other products were isolated from the reaction mixture,
perhaps indicating decomposition of the starting material by
overoxidation.
It was our intention to apply the biosynthetic proposal
outlined in Scheme 1 to a concise biomimetic synthesis of
garcibracteatone (1). In addition to providing evidence
for our proposed biosynthetic pathway, such a synthesis
would also demonstrate the ability of radical cyclizations
to rapidly generate complex PPAP natural products.
(16) CCDC 881560 (1) and CCDC 881559 (13) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
(5) Porto, A. L. M.; Machado, S. M. F.; de Oliveira, C. M. A.;
Bittrich, V.; Amaral, M. E.; Marsailoi, A. J. Phytochemistry 2000, 55,
755–768.
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