A biomimetic synthetic approach to the frondosins

Article abstract of DOI:10.1071/CH16218

The frondosins are a family of five marine sponge-derived meroterpenoids. We propose that the 6-7 ring system common to each of the frondosins is biosynthesized via ring expansion of a 6-6 ring system. Compelling evidence in favour of this proposal was obtained in the form of a biomimetic synthesis of the frondosin 6-7 ring system, which features a highly stereo- and regio-selective ring expansion cascade reaction as the key step.

Full text of DOI:10.1071/CH16218

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Communication
http://dx.doi.org/10.1071/CH16218
A Biomimetic Synthetic Approach to the Frondosins*
A
A
A B
,
Kevin K. W. Kuan, Aylin M. C. Hirschvogel, and Jonathan H. George
A
Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia.
B
Corresponding author. Email: jonathan.george@adelaide.edu.au
The frondosins are a family of five marine sponge-derived meroterpenoids. We propose that the 6–7 ring system common
to each of the frondosins is biosynthesized via ring expansion of a 6–6 ring system. Compelling evidence in favour of this
proposal was obtained in the form of a biomimetic synthesis of the frondosin 6–7 ring system, which features a highly
stereo- and regio-selective ring expansion cascade reaction as the key step.
Manuscript received: 4 April 2016.
Manuscript accepted: 2 June 2016.
Published online: 20 July 2016.
HO
O
Frondosins A–E (1–5, Fig. 1) are a family of five meroterpenoid
natural products first isolated from Dysidea frondosa in 1997.[1]
The isolation of frondosin A and frondosin D from Euryspongia
sp. was reported shortly afterwards.[2] The frondosins each
possess a 6–7 carbocyclic framework that is either attached or
fused to a hydroquinone, quinone, or benzofuran ring system.
The unusual structures of the frondosins, combined with
their reported inhibition of the binding of interleukin-8 to its
receptor, has inspired significant attention from the synthetic
community.[3] However, a general and divergent synthetic route
to the whole frondosin family has remained elusive.
HO
OH
OH
O
1: frondosin A
2: frondosin B
OH
3: frondosin C
OMe
O
O
O
O
We aimed to use our proposal for the biosynthesis of the
frondosins (Scheme 1) as the blueprint for a unified synthetic
approach.[4] A similar proposal for frondosin biosynthesis has
also been suggested by Pettus.[5] Although it has not yet been
isolated as a natural product, we believe that hydroquinone 6 is a
plausible intermediate in the biosynthesis of the frondosins. We
have previously converted 6 into aureol, a marine sponge
meroterpenoid closely related to the frondosins.[6] The bicyclic
framework of 6 (with its characteristic D5,11-double bond) has
also been formed by acid-catalyzed rearrangement of avarol[7]
(via sequential 1,2-methyl and hydride shifts[8]) and by acid-
catalyzed fragmentation of aureol.[9] Oxidation of hydroquinone
6 could form o-quinone methide 7, via either tautomerization of
an intermediate quinone or direct oxidation at the benzylic C-10
position. We propose that the reactive o-quinone methide
intermediate 7 could then undergo a highly stereo- and regio-
selective ring expansion to form frondosin A (1). Further
oxidation of 1 could form quinone 8, which could undergo
epimerization at C-10 to form 10. The quinone carbonyl group
of 10 could then participate in an intramolecular Paterno`–Bu¨chi
reaction with the neighbouring D9,18-alkene to give a strained
oxetane intermediate 11, which could fragment to give frondo-
sin C (3). Alternatively, deprotonation of 8 at C-10 could form
o-quinone methide 9, which could cyclize via a 6p-electrocyclic
reaction to form 12. Oxidation of 12 could then give frondosins
D and E (4 and 5) via the interception of an intermediate quinone
cation with either H2O or MeOH respectively. Finally, frondosin
4: frondosin D
5: frondosin E
Fig. 1. Frondosins A–E.
B (2) could arise via intramolecular 1,6-conjugate addition of 4
followed by elimination of formaldehyde from 13 by a retro
[4þ2] cycloaddition.
The initial oxidation of frondosin A (1) to quinone 8 is likely
to be a facile process and could occur spontaneously under
aerobic oxidation conditions. As the later rearrangements to
give frondosins B–E (2–5) could be predisposed to occur under
non-enzymatic conditions, it is possible that these compounds
are artefacts of the isolation process. In particular, the use of
MeOH in both extraction and isolation procedures could explain
the presence of the C-17 methoxy group of frondosin E.
Nevertheless, we were attracted by the idea of using the unified
proposal for the biosynthetic origin of the frondosins as outlined
in Scheme 1 to inspire a divergent synthesis of all five family
members.
We have previously investigated our proposal for the bio-
synthetic origin of the frondosin C ring system via a model study
(Scheme 2).[4] Quinone 15 was synthesized in 14 steps from
(þ)-sclareolide (14). Exposure of 15 to sunlight then formed the
liphagal–frondosin C hybrid molecule 18 in 60 % yield, along
*The corresponding author, Jonathan H. George, was awarded the 2015 RACI Athel Beckwith Lectureship.
Journal compilation ꢀ CSIRO 2016
www.publish.csiro.au/journals/ajc

B
K. K. W. Kuan, A. M. C. Hirschvogel, and J. H. George
HO
HO
O
HO
O
H
O
OH
18
Oxidation to quinone,
then tautomerization to
o-quinone methide
10
11
OH
Ring expansion
Oxidation
10
9
5
1: frondosin A
8
6
7
ϪHϩ
Epimerization
at C-10
Ϫ
O
O
O
O
Hϩ
OH
O
O
O
9
10
Fragmentation
[2ϩ2] photocycloaddition
H
Paternò–Büchi reaction
9
3: frondosin C
11
10
6π-electrocyclic
reaction
HO
HO
HO
O
OR
O
17 O
O
O
1,6-conjugate
addition (R ϭ H)
O
Retro [4ϩ2] cycloaddition
ϪCH2O
Oxidation
ϩH2O
or
ϩMeOH
2: frondosin B
13
4: frondosin D (R ϭ H)
5: frondosin E (R ϭ Me)
12
Scheme 1. Proposed biosynthesis of frondosins A–E.
O
synthesis of frondosin A via this strategy would be the selective
installation of the exocyclic D9,18-alkene. The investigation
began with synthesis of aldehyde 19 in eight steps from
(þ)-sclareolide (14) according to our previously published
procedures[6] (Scheme 3). Nucleophilic addition of the aryl-
lithium species generated from aryl bromide 20[11] and t-BuLi
gave alcohol 21 as single diastereomer (although the configura-
tion of the newly formed stereocentre at C-10 was not deter-
mined). Treatment of 21 with p-toluenesulfonic acid (TsOH) in
MeOH then gave the ring-expanded frondosin analogue 24 in
good yield and as a single diastereomer.[12] The structure of 24
was determined via 2D NMR studies (see the Supplementary
Material for a full presentation of NMR data). We propose that
this acid-catalyzed reaction proceeds via two-fold desilylation
followed by dehydration to give o-quinone methide 22 and then
ring expansion to give tertiary carbocation 23.[13] Alternatively,
the reaction could be considered to involve ring expansion of a
stabilized benzylic carbocation. The 1,2-shift is highly selective,
with the vinylic C-9–C-11 bond migrating in preference to the
C-8–C-9 bond. The cascade reaction is terminated by trapping of
the tertiary carbocation 23 by the adjacent phenol to give 24,
rather than deprotonation to form the exocylic alkene of fron-
dosin A (1). However, given that we had efficiently synthesized
the 6–7 ring system common to the frondosins, we sought
methods to convert 24 into some of our natural product targets
by fragmentation of the undesired dihydrobenzofuran ring. Our
first strategy involved oxidative dearomatization of 24 using
PhI(OAc)2 to give hemiacetal 25 (under aqueous conditions) or
acetal 26 (with MeOH as solvent). We then attempted to
fragment 25 and 26 to give quinone 8 under acid catalysis, base
catalysis, and using dehydration reagents such as Martin’s
sulfurane, but without success. This was unfortunate, as quinone
8 has previously been reduced to frondosin A, and it could also
O
O
O
14 steps
ref. [4]
H
H
14
15
[2ϩ2] photocycloaddition hv, CH2CI2, rt
O
O
O
Hϩ
OH
O
O
Fragmentation
9
10
ϩ
H
H
H
H
H
18(60 %)
16
17
(14 %)
liphagal–frondosin C
hybrid
Scheme 2. Previous synthesis of a liphagal–frondosin C hybrid.
with 14 % of the stable oxetane 16. We propose that intramolec-
ular Paterno`–Bu¨chi reaction of 15 forms two diastereomeric
oxetanes, 16 and 17. Oxetane 17 has an antiperiplanar relation-
ship between the C–H bond at C-10 and the C–O bond at C-9,
and therefore undergoes rapid fragmentation to give 18, whereas
oxetane 16 is kinetically stable.
Our primary aim in the present investigation was to synthe-
size the 6–7 ring system of frondosin A via a ring-expansion
cascade reaction of a 6–6 ring system. We have previously
employed a similar strategy in two total syntheses of lipha-
gal.[10] We soon realized that the major challenge in the

A Biomimetic Synthetic Approach to the Frondosins
C
O
H
HO
HO
O
O
8 steps
O
O
H
ϩ
ref. [6]
Phl(O2CCF3)2, HFIP
10
H
60ЊC or rt
14
19
TBSO
24
27
20 ϭ
20, t-BuLi, Et2O
Ϫ78ЊC to rt
88 %
1,2-Me shift
ϪH ϩ
OTBS
Br
rt
60ЊC
HO
TBSO
HO
HO
Hϩ
OTBS
10
O ϩ
O
O
HO
9
TsOH, MeOH, 65ЊC
11
8
22
21
29
28 (70 %)
Ring expansion
Ring contraction
HO
H
HO
HO
HO
OH
O
H
ϩ
ϩ
O
O
ϪH ϩ
81 %
23
24
Phl(OAc)2, MeCN
H2O, 0ЊC (R ϭ H)
Phl(OAc)2, MeOH
0ЊC (R ϭ Me)
30
31 (41 %)
or
Scheme 4. Undesired oxidative rearrangement of dihydrobenzofuran 24.
O
O
OR
O
MeO
14
O
H
ϪH2O (R ϭ H)
H
O
HO
OTBS
or
32, t-BuLi, Et2O
Ϫ78ЊC to rt
ϪMeOH (R ϭ Me)
8
25 (R ϭ H, 87 %)
26 (R ϭ Me, 90 %)
96 %
MeO
19
33
Scheme 3. Ring expansion of alcohol 21.
32 ϭ
TsOH, MeCN
H2O, 80ЊC
82 %
MeO
potentially be used to access frondosins B–E using our biosyn-
thetic hypothesis outlined in Scheme 1.
Br
OTBS
Oxidative dearomatization of 24 using PhI(O2CCF3)2 in
hexafluoroisopropanol (HFIP) gave very different results
(Scheme 4). When the oxidation was conducted at room tem-
perature, diene 28 was formed, presumably via benzylic oxida-
tion at C-10 to give carbocation 27 followed by deprotonation.
Alternatively, heating the reaction at 608C gave the ring-
contracted isomer 31. The formation of 31 presumably proceeds
via a 1,2-methyl shift of carbocation 27 to generate oxonium
ion 29, followed by a ring contraction to give carbocation 30
and finally deprotonation.
MeO
OH
12
O
H
10
NaOt-Pent, DMSO, rt
57 %
35
34
1:1 mixture of atropisomers
Scheme 5. Base-induced fragmentation of dihydrobenzofuran 34.
We also attempted the fragmentation of the dihydrobenzo-
furan ring of 24 under basic conditions. This reaction failed to
proceed, perhaps owing to the presence of the unprotected
phenol at C-14. We therefore synthesized 34 (a dihydrobenzo-
furan substrate with a methoxy group instead of a phenol at
C-14) via the union of aldehyde 19 and aryl bromide 32[14] to
give alcohol 33, followed by acid-catalyzed ring expansion
(Scheme 5). Basic fragmentation of 34 with sodium pentoxide
was possible, but we were unable to control the location of the
newly formed alkene, with the undesired conjugated diene 35
formed as a 1 : 1 mixture of atropisomers (owing to restricted
rotation about the C-10–C-12 bond). Attempts to oxidize 35 to a
quinone, and then to potentially isomerize it to form the
frondosin D and E ring system, were unsuccessful owing to its
instability to even mild oxidants.
In a final study, we investigated the effect of removing the
C-17 substituent altogether. Thus, aldehyde 19 was combined

D
K. K. W. Kuan, A. M. C. Hirschvogel, and J. H. George
TBSO
(g) X. Li, R. E. Kyne, T. V. Ovaska, Org. Lett. 2006, 8, 5153.
doi:10.1021/OL0620848
(h) B. M. Trost, Y. Hu, D. B. Horne, J. Am. Chem. Soc. 2007, 129,
TBSO
HO
36 ϭ
Br
H
11781. doi:10.1021/JA073272B
17
O
(i) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573. doi:10.1021/
OL702844G
(j) X. Li, A. Keon, J. A. Sullivan, T. V. Ovaska, Org. Lett. 2008, 10,
36, t-BuLi, Et2O
Ϫ78ЊC to rt
80 %
3287. doi:10.1021/OL8011343
(k) G. Mehta, N. S. Likhite, Tetrahedron Lett. 2008, 49, 7113.
doi:10.1016/J.TETLET.2008.09.163
37
19
(l) T. V. Ovaska, J. A. Sullivan, S. I. Ovaska, J. B. Winegrad, J. D. Fair,
Org. Lett. 2009, 11, 2715. doi:10.1021/OL900967J
(m) G. Mehta, N. S. Likhite, Tetrahedron Lett. 2009, 50, 5263.
doi:10.1016/J.TETLET.2009.07.021
TsOH, CHCI3
0ЊC to rt
Ring expansion
(n) K.-S. Masters, B. L. Flynn, Org. Biomol. Chem. 2010, 8, 1290.
doi:10.1039/B924542A
(o) M. Reiter, S. Torsell, S. Lee, D. W. C. MacMillan, Chem. Sci. 2010,
HO
HO
17
ϪHϩ
ϩ
1, 37. doi:10.1039/C0SC00204F
35 %
(p) D. Garayalde, K. Kruger, C. Nevado, Angew. Chem. Int. Ed. 2011,
50, 911. doi:10.1002/ANIE.201006105
(q) D. W. Lee, R. K. Pandey, S. Lindeman, W. A. Donaldson, Org.
Biomol. Chem. 2011, 9, 7742. doi:10.1039/C1OB05720K
(r) J. Zhang, L. Li, Y. Wang, W. Wang, J. Xue, Y. Li, Org. Lett. 2012,
14, 4528. doi:10.1021/OL3020013
39
38
Scheme 6. Ring expansion of alcohol 37.
(s) D. R. Laplace, B. Verbraeken, K. Van Hecke, J. M. Winne, Chem. –
Eur. J. 2014, 20, 253. doi:10.1002/CHEM.201303273
(t) E. Z. Oblak, M. D. VanHeyst, J. Li, A. J. Wiemer, D. L. Wright,
J. Am. Chem. Soc. 2014, 136, 4309. doi:10.1021/JA413106T
(u) M. D. VanHeyst, D. L. Wright, Eur. J. Org. Chem. 2015, 1387.
doi:10.1002/EJOC.201403116
with aryl bromide 36[15] to give alcohol 37 (Scheme 6). Acid-
catalyzed ring expansion of 37 presumably generated the
tertiary carbocation 38, which lacked the C-17 phenol and
therefore underwent deprotonation to give diene 39. The
NMR spectra of 39 were very similar to those of 35, except
for the absence of the doubling of signals due to atropisomerism.
In conclusion, we have used a biosynthetically inspired ring-
expansion cascade reaction to construct the 6–7 ring system of
frondosin A. However, the undesired formation of an additional
dihydrobenzofuran ring, and its resistance towards selective
fragmentation, have thwarted attempts to synthesize frondosin
A itself.
[4] H. P. Pepper, K. K. W. Kuan, J. H. George, Org. Lett. 2012, 14, 1524.
doi:10.1021/OL300257V
[5] S. K. Jackson, K.-L. Wu, T. R. R. Pettus, in Biomimetic Organic
Synthesis (Eds E. Poupon, B. Nay) 2011, Vol. 2, Ch. 20, pp. 723–749
(Wiley-VCH: Weinheim).
[6] K. K. W. Kuan, H. P. Pepper, W. M. Bloch, J. H. George, Org. Lett.
2012, 14, 4710. doi:10.1021/OL301715U
[7] L. Minale, R. Riccio, G. Sodano, Tetrahedron Lett. 1974, 15, 3401.
doi:10.1016/S0040-4039(01)91918-5
Supplementary Material
[8] J. H. George, M. McArdle, J. E. Baldwin, R. M. Adlington, Tetrahe-
dron 2010, 66, 6321. doi:10.1016/J.TET.2010.05.052
[9] P. Djura, D. B. Stierle, B. Sullivan, D. J. Faulkner, E. Arnold, J. Clardy,
J. Org. Chem. 1980, 45, 1435. doi:10.1021/JO01296A019
[10] (a) J. H. George, J. E. Baldwin, R. M. Adlington, Org. Lett. 2010, 12,
2394. doi:10.1021/OL100756Z
(b) A. W. Markwell-Heys, K. K. W. Kuan, J. H. George, Org. Lett.
2015, 17, 4228. doi:10.1021/ACS.ORGLETT.5B01973
[11] J. P. Willis, K. A. Z. Gogins, L. L. Miller, J. Org. Chem. 1981, 46,
3215. doi:10.1021/JO00329A013
Experimental procedures and full characterization data for all
new compounds are available on the Journal’s website.
Acknowledgement
We thank the Australian Research Council for financial support in the form
of a Discovery Project (DP160103393).
References
[1] A. D. Patil, A. J. Freyer, L. Killmer, P. Offen, B. Carte, A. J. Jurewicz,
R. K. Johnson, Tetrahedron 1997, 53, 5047. doi:10.1016/S0040-4020
(97)00205-6
[12] For a related ring-expansion reaction, see: M. Zhou, H.-C. Geng, H.-B.
Zhang, K. Dong, W.-G. Wang, X. Du, X.-N. Li, F. He, H.-B. Qin,
Y. Li, J.-X. Pu, H.-D. Sun, Org. Lett. 2013, 15, 314. doi:10.1021/
OL303226C
[2] Y. F. Hallock, J. H. Cardellina, M. R. Boyd, Nat. Prod. Lett. 1998, 11,
153. doi:10.1080/10575639808041212
[13] (a) For reviews of o-quinone methide chemistry, see: R. W. Van De
Water, T. R. R. Pettus, Tetrahedron 2002, 58, 5367. doi:10.1016/
S0040-4020(02)00496-9
[3] (a) M. Inoue, A. J. Frontier, S. J. Danishefsky, Angew. Chem. Int. Ed.
2000, 39, 761. doi:10.1002/(SICI)1521-3773(20000218)39:4,761::
AID-ANIE761.3.0.CO;2-I
(b) T. P. Pathak, M. S. Sigman, J. Org. Chem. 2011, 76, 9210.
doi:10.1021/JO201789K
(c) N. J. Willis, C. D. Bray, Chem. – Eur. J. 2012, 18, 9160.
doi:10.1002/CHEM.201200619
(b) M. Inoue, M. W. Carson, A. J. Frontier, S. J. Danishefsky, J. Am.
Chem. Soc. 2001, 123, 1878. doi:10.1021/JA0021060
(c) C. C. Hughes, D. Trauner, Angew. Chem. Int. Ed. 2002, 41, 1569.
doi:10.1002/1521-3773(20020503)41:9,1569::AID-ANIE1569.3.0.
CO;2-8
(d) D. J. Kerr, A. C. Willis, B. L. Flynn, Org. Lett. 2004, 6, 457.
doi:10.1021/OL035822Q
(e) C. C. Hughes, D. Trauner, Tetrahedron 2004, 60, 9675.
doi:10.1016/J.TET.2004.07.041
(d) W.-J. Bai, J. G. David, Z.-G. Feng, M. G. Weaver, K.-L. Wu, T. R.
R. Pettus, Acc. Chem. Res. 2014, 47, 3655. doi:10.1021/AR500330X
[14] J. Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3854. doi:10.1002/ANIE.
201310280
[15] R. N. Misra, B. R. Brown, W.-C. Han, D. N. Harris, A. Hedberg, M. L.
Webb, S. E. Hall, J. Med. Chem. 1991, 34, 2882. doi:10.1021/
JM00113A030
(f) I. Martinez, P. E. Alford, T. V. Ovaska, Org. Lett. 2005, 7, 1133.
doi:10.1021/OL050144O