Synthesis of a liphagal-frondosin c hybrid and speculation on the biosynthesis of the frondosins

Article abstract of DOI:10.1021/ol300257v

A hypothesis for the biosynthesis of the frondosins A-E is presented. Synthesis of a liphagal-frondosin C hybrid molecule has been achieved, with the frondosin C 6-7-5-6 ring system being constructed by a photochemical process that follows an intramolecul

Full text of DOI:10.1021/ol300257v

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1524–1527
Synthesis of a LiphagalꢀFrondosin C
Hybrid and Speculation on the
Biosynthesis of the Frondosins
Henry P. Pepper, Kevin K. W. Kuan, and Jonathan H. George*
School of Chemistry & Physics, University of Adelaide, North Terrace, Adelaide SA
5005, Australia
jonathan.george@adelaide.edu.au
Received February 1, 2012
ABSTRACT
A hypothesis for the biosynthesis of the frondosins AꢀE is presented. Synthesis of a liphagalꢀfrondosin C hybrid molecule has been achieved,
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with the frondosin C 6ꢀ7ꢀ5ꢀ6 ring system being constructed by a photochemical process that follows an intramolecular PaternoꢀBuchi
reaction/fragmentation pathway.
Marine sponges provide a rich source of natural pro-
ducts with unusual molecular structures and potentially
useful biological activities.1 Liphagal (1)2 and frondosins
AꢀE (2ꢀ6)3 are marine sponge-derived meroterpenoids
with 6ꢀ7 carbocyclic ring systems that are fused or
attached to benzofuran, hydroquinone, or quinone groups
(Figure 1). Liphagal was isolated in 2006 by Andersen from
Aka coralliphaga, and it was found to be a potent inhibitor
of the PI3K cell signaling pathway.2 We recently synthesized
liphagal via a biomimetic ring-expansion strategy,4 and
routes to the compound have also been published by the
groups of Andersen,1 Mehta,5 Alvarez-Manzaneda,6 and
Stoltz.7 The frondosins have also attracted significant
attention from the synthetic community since their initial
isolation in 1997 from Dysidea frondosa and their re-
ported inhibition of the binding of interleukin-8 to its
receptor in the low micromolar range.8
Despite the close similarity between the structures of the
frondosins AꢀE, there has been no synthetic work on the
biosynthetic relationships between these compounds. As
part of our continuing interest in biomimetic reactions of
o-quinone methides,9 we were interested in investigating
the formation of some of the unusual frondosin quinone
systems using a 6ꢀ7 carbocyclic scaffold generated during
(8) (a) Inoue, M.; Frontier, A. J.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 761. (b) Inoue, M.; Carson, M. W.; Frontier, A. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 1878. (c) Hughes, C. C.;
Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569. (d) Kerr, D. J.; Willis,
A. C.; Flynn, B. L. Org. Lett. 2004, 6, 457. (e) Hughes, C. C.; Trauner, D.
Tetrahedron 2004, 60, 9675. (f) Martinez, I.; Alford, P. E.; Ovaska, T. V.
Org. Lett. 2005, 7, 1133. (g) Li, X.; Kyne, R. E.; Ovaska, T. V. Org. Lett.
2006, 8, 5153. (h) Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc.
2007, 129, 11781. (i) Olson, J. P.; Davies, H. M. L. Org. Lett. 2008, 10,
573. (j) Li, X.; Keon, A.; Sullivan, J.; Ovaska, T. V. Org. Lett. 2008, 10,
3287. (k) Mehta, G.; Likhite, N. S. Tetrahedron Lett. 2008, 49, 7113. (l)
Ovaska, T. V.; Sullivan, J. A.; Ovaska, S. I.; Winegrad, J. B.; Fair, J. D.
Org. Lett. 2009, 11, 2715. (m) Mehta, G.; Likhite, N. S. Tetrahedron Lett.
2009, 50, 5263. (n) Masters, K.-S.; Flynn, B. L. Org. Biomol. Chem. 2010,
8, 1290. (o) Reiter, M.; Torsell, S.; Lee, S.; MacMillan, D. W. C. Chem.
Sci. 2010, 1, 37. (p) Garayalde, D.; Kruger, K.; Nevado, C. Angew.
Chem., Int. Ed. 2011, 50, 911.
(1) For a recent review of drug development from marine natural
products, see: Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes,
J. P. Nat. Rev. Drug Discov. 2009, 8, 69.
(2) Marion, F.; Williams, D. E.; Patrick, B. O.; Hollander, I.; Mallon,
R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest, R.; Andersen, R. J.
Org. Lett. 2006, 8, 321.
(3) (a) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.;
Jurewicz, A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047. (b) Hallock,
Y. F.; Cardellina, J. H.; Boyd, M. R. Nat. Prod. Lett. 1998, 11, 153.
(4) George, J. H.; Baldwin, J. E.; Adlington, R. M. Org. Lett. 2010,
12, 2394.
(5) Mehta, G.; Likhite, N. S.; Kumar, C. S. A. Tetrahedron Lett.
2009, 50, 5260.
(6) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Cano, M. J.;
Haidour, A.; Alvarez-Manzaneda, R. Org. Lett. 2010, 12, 4450.
(7) Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva,
J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 6814.
(9) (a) George, J. H.; Hesse, M. D.; Baldwin, J. E.; Adlington, R. M.
Org. Lett. 2010, 12, 3532. (b) Spence, J. T. J.; George, J. H. Org. Lett.
2011, 13, 5318.
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10.1021/ol300257v
Published on Web 02/24/2012
2012 American Chemical Society

our previous liphagal work.4 This would give insight into
the biosynthesis of the frondosins, as well as generating
liphagalꢀfrondosin hybrid molecules for further biologi-
cal evaluation.
Scheme 1. Proposed Biosynthesis of Frondosin A via an Intra-
molecular Vinylogous Aldol Reaction
Figure 1. Liphagal and the frondosins.
Frondosin A is presumably derived from initial union of
farnesyl pyrophosphate and hydroquinone to give the
polyene 7, which could cyclize to give the drimane carbo-
cation 8 (Scheme 1). Rearrangement of carbocation 8 via
sequential 1,2-hydride and methyl shifts would then form
9.10 The hydroquinone moiety of 9 could readily undergo
oxidation to give the quinone 10. Tautomerization of
quinone 10could then form o-quinone methide11 11, which
might undergo a ring-expansion to generate the 6,7-ring
system of frondosin A (2), with concomitant reformation
of the aromatic hydroquinone ring as the reaction driving
force. This reaction may possess a degree of synchronicity
which ensures the formation of the exocyclic Δ9,18 methy-
lene group, as the mechanism drawn in Scheme 1 suggests.
We propose that quinones and o-quinone methide inter-
mediates are further involved in the biosynthetic conver-
sion of frondosin A into frondosins BꢀE (similar ideas
have been presented by Pettus12 in a recent book chapter).
Oxidation of the hydroquinone of frondosin A would give
quinone 12, which would possess a relatively acidic proton
at C-10 (Scheme 2).
obvious fate for the o-quinone methide 13 might be a 6π-
electrocyclic reaction to form 14.13 A third and final
oxidation in the biosynthetic sequence would then give a
quinone cation that could be trapped by water at C-17 to
give frondosin D (5) or by methanol to give frondosin E
(6). Finally, the biosynthesis of frondosin B (3) requires a
one-carbon dehomologation, which could occur from
frondosin D (5) via an intramolecular 1,6-conjugate addi-
tion to give 15, followed by deformylation by a retro [4 þ 2]
cycloaddition mechanism.12
Our intention was to model some of the biosynthetic
processes outlined in Schemes 1 and 2 using a readily
accessible liphagal-type scaffold. As such, the known
aldehyde 1714 was obtained from (þ)-sclareolide15 (16) in
eight steps (Scheme 3). Addition of 2,5-dimethoxymagne-
sium bromide to 17 generated 18 in 87% yield, which was
treated with LiAlH4 to give diol 19. Pinacol rearrangement
of 19 by treatment with TFA then gave the ring-expanded
product 20 as a single diastereoisomer in 61% yield over
two steps, presumably via a benzylic carbocation. The
relative stereochemistry of 20 was assigned by analysis of
Deprotonation at C-10 would generate the o-quinone
methide 13, which could perhaps undergo an intramole-
cular vinylogous aldol reaction to give frondosin C (4),
although stereoelectronic considerations might appear to
disfavor such a transformation. Later experiments in this
paper will indicate that an alternative mechanism is more
likely for the biogenetic origin of frondosin C. A more
(13) For a review of biomimetic and biosynthetic electrocyclic reac-
tions, see: (a) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev.
2005, 105, 4757. (b) Burnley, J.; Ralph, M.; Sharma, P.; Moses, J. E. In
Biomimetic Organic Synthesis; Poupon, E., Nay, B., Eds.; Wiley-VCH:
New York, 2011; Vol. 2, pp 591ꢀ635.
(10) George, J. H.; McArdle, M.; Baldwin, J. E.; Adlington, R. M.
Tetrahedron 2010, 66, 6321.
(11) For a review of o-quinone methide chemistry, see: Van De
Water, R. W.; Pettus, T. R. Tetrahedron 2002, 58, 5367.
(12) Jackson, S. K.; Wu, K.-L.; Pettus, T. R. R. In Biomimetic
Organic Synthesis; Poupon, E., Nay, B., Eds.; Wiley-VCH: New York,
2011; Vol. 2, pp 723ꢀ749.
(14) Kulcitki, V.; Ungur, N.; Gavagnin, M.; Carbone, M.; Cimino,
G. Eur. J. Org. Chem. 2005, 1816.
(15) For a review of the use of (þ)-sclareolide in the synthesis of
terpenoid natural products, see: Frija, L. M. T.; Frade, R. F. M.;
Afonso, C. A. M. Chem. Rev. 2011, 111, 4418.
Org. Lett., Vol. 14, No. 6, 2012
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Scheme 2. Proposed Biosynthesis of Frondosins BꢀE via o-
Scheme 3. Synthesis of Quinone 23
Quinone Methide Rearrangements
a NOESY NMR spectrum. Attempts to directly methyle-
nate ketone 20 under a variety of conditions failed to give
more than trace quantities of alkene 22, so a two step
strategy was employed instead. Stereoselective addition of
methylmagnesium iodide to 20 gave tertiary alcohol 21 as a
single diastereoisomer. Screening of a variety of reaction
conditions initially failed to selectively dehydrate 21 to 22,
with a mixture of tetra-substituted alkenes generally
being formed. However, the use of pTSA in MeOH gave
exocyclic alkene 22 as the sole reaction product in 92%
yield; we are unable to explain this unusual selectivity.
Oxidation of 22withCAN thengavequinone23, albeitin a
modest isolated yield of 40% due to significant decom-
position of the starting material under the reaction
conditions.
Scheme 4. Synthesis of LiphagalꢀFrondosin C Hybrid 26 via an
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Intramolecular PaternoꢀBuchi Reaction
A sample of quinone 23 in CDCl3 was found to undergo
slow conversion into two new products, 26 and 24, in a 5:1
ratio as observed by 1H NMR, with the reaction taking 10
days to reach completion (Scheme 4). Compound 26 was
immediately recognized as having a frondosin C-type
carbocyclic framework, and 24 was later characterized as
possessing a highly strained bicyclic oxetane ring system.
Attempts to speed up the formation of 26 using acid or
base catalysis failed, but exposure of a CH2Cl2 solution of
23 to sunlight resulted in a complete reaction in 30 min, as
observed by TLC analysis. The optimized final procedure
involved exposure of a solution of quinone 23 to a 500W
lamp for 2 h. Presumably a photochemical [2 þ 2] cycload-
dition between the exocylic alkene and the adjacent qui-
initially gives a mixture of diastereomeric oxetanes 24 and
25 with unusual 6-oxabicyclo[2.2.1]hexane ring systems.
Bicyclic oxetane 24 is stable under the reaction conditions
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none carbonyl group of 23 (a PaternoꢀBuchi reaction)
1526
Org. Lett., Vol. 14, No. 6, 2012

(and is indeed stable at elevated temperatures), but the
presumed intermediate 25 could readily undergo frag-
mentation to give 26 due to the antiperiplanar relationship
between the proton at C(10) and the C(9)-O bond that is
broken. The relative stereochemistry of 24 was deter-
mined by NOE spectroscopy. The configuration of the
C-17 stereocenter of 26 was also determined by NOE
spectroscopy.
C-9 and C-10 for a stereoelectronically favorable fragmen-
tation to occur to give 4.
Scheme 6. Revised Biosynthesis of Frondosin C via an Intra-
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molecular PaternoꢀBuchi Reaction
Attempts to form an o-quinone methide intermediate
from 23, and thus give 26 via a vinylogous aldol reaction,
or 28 via a 6π-electrocyclization, failed under a variety of
conditions (Scheme 5).
Scheme 5. Attempted o-Quinone Methide Formation from 23
In conclusion, we have developed an efficient synthesis
of the 6ꢀ7ꢀ5ꢀ6 ring system of frondosin C via an
intramolecular [2 þ 2] cycloaddition/fragmentation strategy.
It is probable that this reaction sequence mirrors the bio-
synthesis of frondosin C. Furthermore, we have presented a
biosynthetic origin for the whole frondosin family. Efforts
to mimic these reactions in a synthesis of all the frondosins
are underway and will be reported in due course.
Acknowledgment. We thank Mr. Phil Clements (Univer-
sity of Adelaide) for assistance with NMR studies.
The ease of the photochemical transformation of 23 into
26 suggests that a similar process might occur in the
biosynthesis of frondosin C (4). Epimerization at C-10 of
the reactive quinone 12 might first be required to give 29,
Supporting Information Available. Experimental proce-
dures and spectral data for compounds 18ꢀ24 and 26. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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which could undergo an intramolecular PaternoꢀBuchi
reaction to give the 6-oxabicyclo[2.2.1]hexane ring system
of 30 (Scheme 6). The bicyclic oxetane ring system of 30
would then possess the correct relative stereochemistry at
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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