Exploring biosynthetic relationships among furanocembranoids: Synthesis of (-)-bipinnatin J, (H-)-intricarene, (+)-rubifolide, and (+)-isoepilophodione B

Article abstract of DOI:10.1021/ol062581o

(Diagram presented) The asymmetric total synthesis of (-)-bipinnatin J and its conversion into (+)-intricarene through a transannular 1,3-dipolar cycloaddition is described. In addition, the conversion of (-)-bipinnatin J into (+)-rubifolide and (+)-isoepilophodione B is reported. Biosynthetic relationships among furanocembranoids and the possible role of 1,3-dipolar cycloadditions in biosynthesis are discussed.

Full text of DOI:10.1021/ol062581o

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5901-5904
Exploring Biosynthetic Relationships
among Furanocembranoids:
Synthesis of (
−
)-Bipinnatin J,
)-Intricarene, ( )-Rubifolide, and
)-Isoepilophodione B
(
+
+
(
+
Paul A. Roethle, Paul T. Hernandez, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
trauner@berkeley.edu
Received October 19, 2006
ABSTRACT
The asymmetric total synthesis of (
described. In addition, the conversion of (
among furanocembranoids and the possible role of 1,3-dipolar cycloadditions in biosynthesis are discussed.
−)-bipinnatin J and its conversion into (
+
)-intricarene through a transannular 1,3-dipolar cycloaddition is
−
)-bipinnatin J into ( )-rubifolide and (
+
+
)-isoepilophodione B is reported. Biosynthetic relationships
Cycloadditions are now firmly established in the canon of
biosynthetic reactions.1 It is therefore surprising that an
important subclass of these reactions, namely 1,3-dipolar
cycloadditions, appear to play a very minor role in biosyn-
thesis.2 Despite the fact that several 1,3-dipoles have been
identified as natural products,3 their participation in a
cycloaddition has not been demonstrated. Numerous naturally
occurring nitrones, for instance, have been isolated but only
one isoxazolidine has been suspected to arise through a
biosynthetic [3+2]-cycloaddition.4 Similarly, diazo com-
pounds are known as natural products, but pyrazolidines have
not been isolated.3a Azomethine ylides could be readily
formed from R-amino acid derivatives, yet no genuine
example of a biosynthetic cycloaddition involving these
interesting 1,3-dipoles appears to have been reported.
In light of this apparent lack of biosynthetic 1,3-dipolar
cycloadditions, we became very interested in the recently
disclosed natural product intricarene (5).5a Intricarene is one
of a series of furanocembranoid diterpenes isolated from
Caribbean gorgonian corals, mostly by Rodr´ıguez and co-
workers (Figure 1).5 The simpler members of this series,
rubifolide (1) and bipinnatin J (2), show the traditional
macrocyclic makeup of the furanocembranoid family. Kallolide
(1) Stocking, E. M.; Williams, R. M. Angew. Chem., Int. Ed. 2003, 42,
3078-3115.
(2) (a) Padwa, A.; Schoffshall, A. M. AdV. Cycloadd. 1990, 2, 1-89.
(b) Padwa, A.; Pearson, W. H., Eds. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Wiley: Hoboken, NJ, 2003. (c) Mulzer, J. Org. Synth. Highlights 1991,
77-95.
(4) Irlapati, N. R.; Baldwin, J. E.; Adlington, R. M.; Pritchard, G. J.;
Cowley, A. R. Tetrahedron 2005, 61, 1773-1784.
(3) (a) He, H.; Ding, W.-D.; Bernan, V. S.; Richardson, A. D.; Ireland,
C. M.; Greenstein, M.; Ellestad, G. A.; Carter, G. T. J. Am. Chem. Soc.
2001, 123, 5362-5363. (b) Qian-Cutrone, J.; Huang, S.; Shu, Y.-Z.; Vyas,
D.; Fairchild, C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.;
Gao, Q. J. Am. Chem. Soc. 2002, 124, 14556-14557. (c) Fenical, W.;
Jensen, P. R.; Cheng, X. C. Avrainvillamide, a Cytotoxic Marine Natural
Product, and Derivatives thereof. U.S. Patent 6,066,635, 2000.
(5) (a) Marrero, J.; Rodr´ıguez, A. D.; Barnes, C. L. Org. Lett. 2005, 7,
1877-1880. (b) Rodr´ıguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem.
1998, 63, 4425-4432. (c) Marrero, J.; Rodr´ıguez, A. D.; Baran, P.; Raptis,
R. G.; Sa´nchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6,
1661-1664. (d) Rodr´ıguez, A. D.; Shi, Y.-P. J. Org. Chem. 2000, 65, 5839-
5842. (e) Williams, D.; Andersen, R. J.; Van Duyne, G. D.; Clardy, J. J.
Org. Chem. 1987, 52, 332-335.
10.1021/ol062581o CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/09/2006

Scheme 1. Proposed Biosynthetic Origin of Intricarene
Figure 1. Furanocembranoids isolated from Gorgonian corals.
oxygen across the furan to yield ozonide 10, followed by
reduction or hydrolysis to yield dienedione 11 (Scheme 2).
A (4) is a photochemically rearranged derivative of 2, which
still retains its furan moiety. By contrast, only remnants of
this ring can be found in isoepilophodione B (3), intricarene
(5), and bielschowskysin (6). The unique frameworks of 5
and 6 are distinguished from the furanocembranoid skeleton
through additional, transannular C,C-bonds.
Scheme 2. Formation of Intricarene through Singlet-Oxygen
Addition
Apart from their intriguing structural characteristics, many
of the furanocembranoids exhibit promising biological activi-
ties. Bielschowskysin stands out due to its strong antimalarial
activity and significant cytotoxicity against lung and renal
cancer cell lines.5c With too little material in hand to
comprehensively evaluate the compound, intricarene has thus
far only shown modest biological activities.5a
Retrosynthetic analysis of intricarene (5) suggests that it
could be formed from bipinnatin J (2) through a 1,3-dipolar
cycloaddition of possible biosynthetic relevance (Scheme 1).
Epoxidation of the furan moiety, for instance by a monooxy-
genase, could afford an unstable spiroepoxide (7) whose
rearrangement affords hydroxypyranone 8. Overall, this
transformation would correspond to the well-known Ach-
matowicz oxidation of hydroxyfurans.6 Subsequent 1,3-
elimination of water yields an oxidopyrylium species 9,
which undergoes a transannular 1,3-dipolar cycloaddition to
yield intricarene. Achmatowicz oxidations and subsequent
1,3-dipolar cycloadditions of oxidopyrylium dipoles have
been employed in the total synthesis of natural products, but
never in a biomimetic context.7
Rearrangement of this compound would again afford hy-
droxypyrone 8. This second entry to oxidopyrylium species
has indeed been utilized in synthesis.7b,c
Intrigued by these possible biosynthetic relationships,
several laboratories have undertaken the challenge of syn-
thesizing bipinnatin J and converting it into intricarene,
including Rawal’s8 and Pattenden’s.9 We have previously
reported a very efficient, 9-step synthesis of racemic bipin-
natin J, which put us in a position to thoroughly investigate
biosynthetic relationships between the furanocembranoids.10
In parallel to our racemic synthesis, we have developed
an asymmetric approach to (-)-bipinnatin J (Scheme 3). It
In an alternative pathway, the hydroxypyranone intermedi-
ate 8 could be formed though [4+2]-cycloaddition of singlet
(6) Szechner, B.; Achmatowicz, O. Pol. J. Chem. 1994, 68, 1149-1160.
(7) (a) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc.
1997, 119, 7897-7898. (b) Magnus, P.; Shen, L. Tetrahedron 1999, 55,
3553-3560. (c) Bauta, W. E.; Booth, J.; Bos, M. E.; DeLuca, M.; Diorazio,
L.; Donohoe, T. J.; Frost, C.; Magnus, N.; Magnus, P.; Mendoza, J.; Pye,
P.; Tarrant, J. G.; Thom, S.; Ujjainwalla, F. Tetrahedron 1996, 52, 14081-
14102. (d) Lee, H.-Y.; Sohn, J.-H.; Kim, H. Y. Tetrahedron Lett. 2001,
42, 1695-1698.
(8) Huang, Q.; Rawal, V. H. Org. Lett. 2006, 8, 543-545.
(9) Tang, B.; Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47,
6401-6404.
(10) Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345-347.
5902
Org. Lett., Vol. 8, No. 25, 2006

Scheme 3. Asymmetric Synthesis of Bipinnatin J
starts with oxidation of alcohol 12,11 followed by addition
enantiomerically enriched (-)-bipinnatin J (2) in good yield.
Chiral HPLC showed that our optically active material had
retained 88% ee (see the Supporting Information). Therefore,
the Stille-coupling as well as the Appel and NHK reactions
proceeded without further racemization.
With ample supplies of racemic and enantiomerically pure
bipinnatin J in hand, we were in a good position to explore
synthetic and biosynthetic relationships among furanocem-
branoids.
of lithiated TMS-acetylene and reoxidation. Asymmetric re-
duction of the resulting ynone 13 with Midland’s (S)-Alpine
borane12 gave propargylic alcohol 14 in 92% ee. A series of
high-yielding standard transformations was used to convert
this material into enantiomerically enriched propargylic
alcohol 15, which had been used in racemic form in our
previous synthesis. Unfortunately, we were unable to obtain
(S)-15 directly by enantioselective reduction of the corre-
sponding ynone or asymmetric propargylate additions to the
aldehyde obtained from 12.
Rubifolide was obtained from 2 through SN1-deoxygen-
ation (Scheme 4). Treatment of bipinnatin J with triethylsi-
The remainder of our asymmetric synthesis closely follows
the racemic one, keeping in mind that only one stereocenter,
which is at risk to be racemized, is present until bipinnatin
J is reached. Gratifyingly, the ruthenium-catalyzed Alder ene
reaction proceeded without incident, as reported by Trost,13
to afford 16 in 92% ee. In the subsequent Wittig olefination
step, however, we had to divert from our previous synthesis,10
since reaction of 16 with Ph3PdC(Me)CHO (17a) resulted
in complete racemization. Use of the more reactive reagent
Ph3PdC(Me)COOEt (17b) largely retained the stereochem-
ical integrity of the olefination product 18 (88% ee) but
required two extra steps to distinguish between the ester and
butenolide moiety. Careful reduction of 18 with DIBAl-H
gave a very sensitive lactol 19. Oxidation with PDC, followed
by chemoselective reduction with sodium borohydride gave
allylic alcohol 20. Stille-coupling with stannane 21 afforded
allylic alcohol 22, which was converted into allylic bromide
23 through Appel reaction.14 A highly diastereoselective
Nozaki-Hiyama-Kishi (NHK)15 macrocyclization then gave
Scheme 4. Synthesis of (+)-Rubifolide and
(+)-Isoepilophodione B
lane and trifluoroacetic acid gave (+)-rubifolide (1) in
essentially quantitative yield.16,17 Oxidation of this natural
product with mCPBA cleaved the furan nucleus to yield
(11) Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784-785.
(12) Midland, M. M.; Tramontano, A.; Kazubski, A.; Graham, R. S.;
Tsai, D. J. S.; Cardin, D. B. Tetrahedron 1984, 40, 1371-1380.
(13) Trost, B. M.; Mu¨ller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995,
117, 1888-1899.
(14) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801-811.
(15) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
Org. Lett., Vol. 8, No. 25, 2006
5903

(+)-isoepilophodione B (3) in 88% yield. Selective addition
of singlet oxygen to the furan moiety of 1, followed by re-
duction also gave 3, shedding light on the potential biosyn-
thetic origin of this natural product (see the Supporting
Information).
While these synthetic studies were ongoing, we also
investigated the crucial biomimetic conversion of bipinnatin
J to intricarene. Both the Achmatowicz strategy shown in
Scheme 1 and the singlet-oxygen route shown in Scheme 2
were explored. Oxidation of bipinnatin J with mCPBA
proved to be most favorable and proceeded cleanly to afford
the sensitive hydroxypyranone 8, apparently as a single
stereoisomer (Scheme 5). Acetylation gave acetate 24, which
After expending ca. 1 g of synthetic bipinnatin J, we finally
found conditions that reliably yielded intricarene. Dissolution
of 24 in DMSO, followed by addition of 2,2,6,6-tetrameth-
ylpiperidine (TMP) and heating to 150 °C in a sealed tube
afforded intricarene in 26% yield. Thus it appears that the
combination of a very hindered secondary amine base with
high temperatures and a polar solvent is most effective in
achieving the desired conversion. The oxidative transforma-
tion starting from (-)-bipinnatin J, which resulted in an
asymmetric total synthesis of (+)-intricarene, gave spectra,
optical rotation, and MS data that matched the published data.
It is interesting to speculate how relevant our work is for
establishing the biosynthetic relationship between bipinnatin
J and intricarene. Temperatures in excess of 150 °C certainly
cannot be deemed “biomimetic”. On the other hand, the
requirement for high temperatures opens the fascinating
possibility that, in Nature, an enzyme could mediate the
reaction. This enzyme, possibly the very monooxygenase that
performs the initial oxidation, could catalyze the formation
of the high-energy species 9 or conformationally preorganize
9 toward the cycloaddition. It could also stabilize 9 against
nonproductive pathways such as dimerization. In light of our
results it seems unlikely that the formation of intricarene
proceeds spontaneously from an oxidation product of bipin-
natin J (e.g., compound 8).
Scheme 5. Conversion of Bipinnatin J into Intricarene
Future investigations will be directed at exploring other
connections between bipinnatin J and its furanocembranoid
congeners, e.g., bielschowskysin. With significant quantities
of several furanocembranoids, including intricarene, in hand,
we intend to fully evaluate their biological activities. Results
of these screenings will be reported in due course.
exists at room temperature as a mixture of isomers. Variable-
temperature NMR spectroscopy showed that these isomers
were not two diastereomers with respect to the newly formed
acetal stereocenter but two conformers, whose NMR-spectra
coalesce above 10 °C (see the Supporting Information).
The elimination of water from 8 or acetic acid from 24
followed by 1,3-dipolar cycloaddition, however, turned out
to be a surprisingly difficult task. For instance, treatment of
hydroxypyranone 8 with a wide array of acids or dehydrating
agents gave little if any intricarene. 1,3-Elimination of acetic
acid from 24 under standard conditions, e.g., Et3N or DBU
in MeCN, gave 5 in very low yields (see the Supporting
Information for an extensive list of conditions tried).18
Acknowledgment. This work was supported by a gener-
ous grant from the Alfred P. Sloan Foundation. We thank
Dr. Frederick J. Hollander and Dr. Alan G. Oliver (UC
Berkeley) for crystal structure determinations. We also thank
Professor Abimael Rodr´ıguez (U. of Puerto Rico) for an
authentic sample of intricarene.
Supporting Information Available: Spectoscopic data
and experimental procedures for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062581O
(16) McCombie, S. W.; Shankar, B. B.; Ganguly, A. K. Tetrahedron
Lett. 1987, 28, 4123-4126.
(17) For previous synthesis of (-)-rubifolide see: Marshall, J. A.; Sehon,
C. A. J. Org. Chem. 1997, 62, 4313-4320.
(18) In Pattenden’s work (ref 9), intricarene was obtained from 24 in
10% yield under the DBU/MeCN conditions. However, this was not
optimized due to the relative dearth of bipinnatin J available.
5904
Org. Lett., Vol. 8, No. 25, 2006