Synthesis of the bridging framework of phragmalin-type limonoids

Article abstract of DOI:10.1021/ol300647k

An efficient synthesis of the octahydro-1H-2,4-methanoindene core of phragmalin-type limonoids, such as xyloccensins O and P, is reported. The success of the synthetic route is predicated on the use of network analysis in the retrosynthetic analysis and a

Full text of DOI:10.1021/ol300647k

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2110–2113
Synthesis of the Bridging Framework of
Phragmalin-Type Limonoids
Terry P. Lebold, Gary M. Gallego, Christopher J. Marth, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
rsarpong@berkeley.edu
Received March 13, 2012
ABSTRACT
An efficient synthesis of the octahydro-1H-2,4-methanoindene core of phragmalin-type limonoids, such as xyloccensins O and P, is reported. The
success of the synthetic route is predicated on the use of network analysis in the retrosynthetic analysis and a DielsÀAlder reaction for the
synthesis of a key hydrindanone derivative.
The phragmalin-type limonoids (e.g., xyloccensin O and
P, 2 and 3, and trichagmalin A and C, 4 and 5, Figure 1)1
are highly oxygenated triterpenoid derivatives of daunting
molecular complexity that, to date, have not succumbed to
total synthesis. The intricate polycyclic and highly oxyge-
nated nature of these compounds constitutes a significant
challenge for modern chemical synthesis.2 Central among
thechallengesassociatedwiththe chemicalsynthesisof this
subset of limonoids is identifying effective approaches to
the unusual octahydro-1H-2,4-methanoindene frame-
work (highlighted in Figure 1). We reasoned that a
synthetic endeavor aimed at this unique carbon skeleton
would lead to the discovery of novel strategies and
tactics applicable to the synthesis of a variety of phrag-
malin-type limonoids. An efficient synthetic route could
enable further investigation into the already diverse
bioactivities of the limonoid family (e.g., anticancer,3
anti-HIV,4 antibiotic, anti-inflammatory,5 and antifeedent6
properties) and, potentially, improvement of their pharma-
cological profiles by derivitization.
(1) Wu, J.; Xiao, Q.; Huang, J.; Xiao, Z.; Qi, S.; Li, Q.; Zhang, S. Org.
Lett. 2004, 6, 1841–1844.
(2) For a recent review of limonoids, see: Heasley, B. H. Eur. J. Org.
Chem. 2011, 19–46.
(3) (a) Brandt, G. E.; Schmidt, M. D.; Prisinzano, T. E.; Blagg, B. S.
J. Med. Chem. 2008, 51, 6495–6502. (b) Luo, J.; Wang, J.-S.; Wang,
X.-B.; Luo, J.-G.; Kong, L.-Y. Chem. Pharm. Bull. 2011, 59, 225–230.
(c) Cui, J.; Deng, Z.; Xu, M.; Proksch, P.; Li, Q.; Lin, W. Helv. Chim.
Acta 2009, 92, 139–150.
(4) Kuo, R.-Y.; Qian, K.; Morris-Natschke, S. L.; Lee, K.-H. Nat.
Prod. Rep. 2009, 26, 1321–1344.
Figure 1. Selected limonoid natural products.
r
10.1021/ol300647k
Published on Web 04/03/2012
2012 American Chemical Society

Biosynthetically, the phragmalin-type limonoids likely
arise from the related mexicanolide-type natural products
(e.g., 7, Scheme 1). A possible biogenetic connection
between the mexicanolide-type (7) and corresponding
phragmalin derivatives (e.g., 9), proposed by Hao and
co-workers,7 is outlined in Scheme 1. This process may
begin with a photoinitiated Norrish type II reaction to
afford the strained octahydro-1H-2,4-methanoindene frame-
work. Given that the Norrish type II product (9) likely
represents the photostationary state, highly strained sys-
tems of this type may be accessed.
skeleton was to apply the method of network analysis.9
To forge the caged methanoindene polycycle (see 6 in
Figure 1), a disconnection of any of the bonds shown
in red would realize the main goal of network analysis,
namely, the simplification of the complex caged structure
to a fused ring system.8b Despite the powerful reduction in
complexity in the retrosynthetic sense that this approach
offers, we were cognizant of the significant challenge that
the forward CÀC bond construction posed due to the
accompanying increase in strain.10
In this communication, we report the successful imple-
mentation of network analysis guidelines for forming
functionalized octahydro-1H-2,4-methanoindene frame-
works (14 and 26, Scheme 2 and 6, respectively), which
serve as models for the challenging phragmalin-type caged
architecture (e.g., in xyloccensin O, 2).
Scheme 1. Proposed Biogenetic Connection between Mexica-
nolide-Type and Phragmalin-Type Limonoids
Initial studies focused on the construction of 14. This
undertaking would demonstrate the feasibility of the in-
tramolecular cylization by using an irreversible alkylation
before attempting the bond construction using a
potentially reversible Michael addition (vide infra). We
envisioned that 14 could arise from conformer 13A of
hydrindanone derivative 13 by an alkylative CÀC bond
formation. Although conformations of hydrindane and
hydrindanone systems have been studied,11 there are no
reports that describe these dynamics in highly functiona-
lized systems. Despite preliminary computations suggest-
ing conformer 13B to be lower in energy, the irreversibility
of the alkylation step arising from conformer 13A was
expected to lead to productive formation of 14.12 Hydrin-
danone derivative 13 could in turn arise from a
DielsÀAlder cycloaddition between cyclopentenone 11
and diene 12.
Biomimetic syntheses can often bring an unprecedented
level of simplication to a challenging synthetic target;8
however, the unique environ of an enzyme, should one
be required, is not easily emulated by synthetic chemists.
For the phragmalin-type limonoids in particular, the strict
conformational requirements regarding the proximity of
reacting partners in photoreactions, including the Norrish
type II process, makes it unclear how high yielding the
conversion of 7 to 9 would be outside of a biological
context. As such, we decided to pursue alternative, more
robust, strategies for the formation of the caged phragma-
lin framework.
Given that 2-methoxycarbonylcyclopent-2-enone (11) is
readily available in multigram quantities,13 our synthesis of
13 commenced with the preparation of diene 12 (Scheme 3).
(9) (a) Corey, E. J.; Ohno, M.; Vatakencherry, P. A.; Mitra, R. B. J.
Am. Chem. Soc. 1961, 83, 1251–1253. (b) Corey, E. J.; Ohno, M.; Mitra,
R. B.; Vatakencherry, P. A. J. Am. Chem. Soc. 1964, 86, 478–485. (c)
Corey, E. J.; Howe, W. J.; Orf, H. W.; Pensak, D. A.; Petersson, P. G. J.
Am. Chem. Soc. 1975, 97, 6116–6124. (d) Corey, E. J. Angew. Chem., Int.
Ed. 1991, 30, 455–465.
(10) For example, the following homodesmotic calculation
(Gaussian DFT; basis set B3LYP/6-31G(d,p); see the Supporting In-
formation for details) indicates that formation of the tricycle from the
bicycle is uphill by 10.36 kcal/mol. For a discussion on homodesmotic
calculations, see: Wheeler, S. E.; Houk, K. N.; Schleyer, P. v. R.; Allen,
W. D. J. Am. Chem. Soc. 2009, 131, 2547–2560.
Foremost among our considerations as to how to access
the architecturally intricate phragmalin-type tricyclic
(5) (a) Ravangpai, W.; Sommit, D.; Teerawatananond, T.; Sinpranee,
N.; Palaga, T.; Pengpreecha, S.; Muangsin, N.; Pudhom, K. Bioorg. Med.
Chem. Lett. 2011, 21, 4485–4489. (b) Luo, J.; Wang, J.-S.; Luo, J.-G.;
Wang, X.-B.; Kong, L.-Y. Tetrahedron 2011, 67, 2942–2948.
(6) Wu, J.; Xiao, Q.; Zhang, S.; Li, X.; Xiao, Z.; Ding, H.; Li, Q.
Tetrahedron 2005, 61, 8382–8389.
(7) Zhang, Q.; Di, Y.-T.; He, H.-P.; Fang, X.; Chen, D.-L.; Yan,
X.-H.; Zhu, F.; Yang, T.-Q.; Liu, L.-L.; Hao, X.-J. J. Nat. Prod. 2011, 74,
152–157. For other proposed biosynthetic pathways for more highly
oxygenated limonoids, see: (a) Taylor, D. A. H. Phytochemistry 1983, 22,
1297–1299. (b) Abdelgaleil, S. A. M.; Okamura, H.; Iwagawa, T.; Sato, A.;
Miyahara, I.; Doe, M.; Nakatani, M. Tetrahedron 2001, 57, 119–126.
(8) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Com-
mun. 2003, 551–564. (b) Heathcock, C. H. Angew. Chem., Int. Ed. 1992,
31, 665–681.
(11) (a) Sokolova, I. M.; Petrov, A. A. Neftekhimiya 1977, 17, 498;
Chem. Abstr. 87, 184059b. (b) Lo cicero, B.; Weisbuch, F.; Dana, G. J.
Org. Chem. 1981, 46, 914–919. (c) Schneider, H.-J.; Nguyen-Ba, N. Org.
Magn. Reson. 1982, 18, 38. (d) Moniz, W. B.; Dixon, J. A. J. Am. Chem.
Soc. 1961, 83, 1671–1675. (e) Lack, R. E.; Roberts, J. D. J. Am. Chem.
Soc. 1968, 90, 6997–7001.
(12) Our preliminary conformational search of 13 using Macromodel
minimization/Monte Carlo search parameters has identified compound
13B as more energetically stable than compound 13A.
(13) Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1998,
54, 8355–8370.
Org. Lett., Vol. 14, No. 8, 2012
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Scheme 2. Retrosynthetic Analysis of 14
Scheme 4. Synthesis of Hydrindanone Derivative 13
Building on precedents from d’Angelo14 and Grierson,15
we began with the Ley oxidation16 of allylic alcohol 15
(prepared from ethyl propiolate),17 affording aldehyde 16
in 66% yield. Wittig olefination using carbomethoxy-
methylidene phosphorane gave diene ester 17 in 81% yield
as a separable 7:1 mixture of E,E and E,Z isomers. Sub-
sequent reduction of the ester group (LiAlH4) and silyla-
tion using TBSCl and imidazole provided the desired diene
(12) in 69% yield over the two steps.
adduct 18 (Scheme 4) in 89% combined yield (>10:1 endo/
exo ratio).18,19 Reduction of the double bond in18could be
accomplished under carefully monitored hydrogenation
conditions, which proceeded without hydrogenolytic clea-
vage of the benzyl ether. Treatment of the crude hydro-
genation product (19) with 1% HCl in MeOH furnished
alcohol 20, which was sulfonated to produce keto-benze-
nesulfonate 13 in 82% yield over the three steps.
With keto-benzenesulfonate 13 in hand, the stage was
set for the key alkylation reaction to build the tricyclic
framework of the phragmalin-type limonoids. As shown in
Table 1, several conditions were explored with varying
levels of success. While excess KHMDS (Table 1, entry 1)
led only to decomposition, the use of 1.1 equiv of KHMDS
gave the desired octahydro-1H-2,4-methanoindene frame-
work(entry 2). However, the yields were found tobehighly
variable, with significant amounts of hydrindene 21 often
being formed. Ultimately, a 74% yield of 14 could be
consistently obtained under carefully controlled condi-
tions using KHMDS (1.1 equiv) as the base in the presence
of triethylamine and tetrabutylammonium iodide (TBAI;
1 equiv) in THF at À78 °C with warming to room
temperature over 20 min (entry 3). The structure of 14 was
unambigously confirmed by X-ray crystallographic analy-
sis of the corresponding p-bromobenzoate derivative 22
(Figure 2).20
Scheme 3. Synthesis of Diene 12
With diene 12 and dienophile 11 in hand, we next
pursued the DielsÀAlder cycloaddition. Heating a mixture
of diene 12 and freshly prepared 11 (1.45 equiv) provided
Table 1. Optimization of Alkylation Conditions
(14) Maddaluno, J.; d’Angelo, J. Tetrahedron Lett. 1983, 24, 895–
898.
(15) Prabhakaran, J.; Lhermitte, H.; Das, J.; Sasi-Kumar, T. K.;
Grierson, D. S. Synlett 2000, 5, 658–662.
(16) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625–1627. (b) Hinzen, B.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 1997, 1907–1908.
(17) (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T.
€
Tetrahedron Lett. 2005, 46, 3465–3468. (b) Tellam, J. P.; Kociok-Kohn,
G.; Carbery, D. R. Org. Lett. 2008, 10, 5199–5202.
(18) The endo and exo diastereomers could be easily separated by
column chromatography.
(19) Of note, the double bond in 18 could provide a functional handle
for the annulation of the remainder of the phragmalin framework.
2112
Org. Lett., Vol. 14, No. 8, 2012

Scheme 6. Michael Addition
Figure 2. ORTEP representation of 22.
The fragmentation product (i.e., hydrindene 21) likely
arises through a retro-Claisen reaction (Scheme 5) where
initial nucleophilic attack on the ketone moiety by trace
alkoxide generates tetrahedral intermediate 23, which can
collapse to form 21 via ester enolate 24 (E1cB type
process).21,22
To this end, alcohol 20 was converted to enoate 25 through
sequential oxidation and Wittig olefination in 49% yield
over two steps (Scheme 6). Gratifyingly, treating enone 25
with catalytic amounts of KOt-Bu in THF (À78 - 0 °C) led
to the desired 1,4-adduct (26) as a single diastereomer in
79% yield.24 Having accomplished the intramolecular 1,4-
conjugate addition, we are currently focused on the pre-
paration of more highly functionalized caged frameworks.
In conclusion, we have developed a rapid and efficient
route to the octahydro-1H-2,4-methanoindene core of the
phragmalin-type limonoids. Key to the success of this
route was the synthesis of the highly substituted hydrinda-
none system 18, which, in turn, provided access to intra-
molecular cyclization precursors 13 and 25. This work
illustrates the utility of network analysis in defining a rapid
path to architecturally complex frameworks such as the
octahydro-1H-2,4-methanoindene core of the highly com-
plex phragmalin-type limonoids.
Scheme 5. Fragmentation Pathway of 14
Acknowledgment. The authors are grateful to the NIH
(NIGMS RO1 084906) and American Cancer Society
(RSG-09-017-01 CDD) for support of this work. T.P.L.
thanks the NSERC (Canada) for a postdoctoral fellow-
ship. Kathleen A. Durkin (UC Berkeley) is also thanked
for computational assistance (NSF CHE-0233882 and
CHE-0840505).
After the success of the intramolecular alkylative cycli-
zation, we next investigated the potentially more challen-
ging Michael addition, which would incorporate the
required methylene ester present in the natural products.23
(20) Ortep-3 for Windows: Farrugia, L. J. J. Appl. Crystallogr. 1997,
30, 565.
(21) Support for this hypothesis is found by treatment of 14 with
KOBn which results in clean conversion to 21.
(22) Interestingly, fragmentation of the polycyclic framework is not
observed upon reduction of the carbonyl group of 14 with NaBH4. For
more information, see the Supporting Information.
(23) The success of this cyclization illustrates the potential for further
elaboration of this core towards the phragmalin-type limonoids.
(24) Stereochemistry of 26 predicated on A1,3 considerations.
Supporting Information Available. Experimental de-
tails and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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