Total synthesis of (±)-bipinnatin J

Article abstract of DOI:10.1021/ol053054s

The total synthesis of (±)-bipinnatin J was achieved through a concise route that features the use of a silver ion promoted S_N1-type γ-alkylation of a siloxyfuran and a diastereoselective Cr(II)-mediated macrocyclization to provide bipinnatin J

Full text of DOI:10.1021/ol053054s

ORGANIC
LETTERS
2006
Vol. 8, No. 3
543-545
Total Synthesis of (±)-Bipinnatin J
Qinhua Huang and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received December 16, 2005
ABSTRACT
The total synthesis of (±)-bipinnatin J was achieved through a concise route that features the use of a silver ion promoted SN1-type γ-alkylation
of a siloxyfuran and a diastereoselective Cr(II)-mediated macrocyclization to provide bipinnatin J (1), wherein the remote furanone stereocenter
at C10 induced the relative stereochemistry of the two additional stereocenters.
Marine invertebrates have yielded a plethora of structurally
diverse natural products possessing a range of interesting
biological activities.1 In particular, gorgonian octocorals of
the genus Pseudopterogorgia have proven to be particularly
fertile producers of diterpenes having the cembrane or
pseudopterane skeleta. Members of the first group are
characterized by the presence of a 14-membered ring carbon
framework and include compounds such as lophotoxin and
bipinnatin B, whereas the latter group has a contracted, 12-
membered ring framework, as seen in kallolide A and
pinnatin A (Figure 1).2 Several of these secondary metabo-
lites exhibit promising pharmacological properties.1-3 For
example, bipinnatins A, B, and D display in vitro activity
against the P388 murine tumor cell line, with IC50’s of 0.9,
3.2, and 1.5 µg/mL, respectively.2f Additionally, lophotoxin
and bipinnatin B are potent neurotoxins that irreversibly
block nicotinic acetylcholine receptors.3f Bipinatin I possesses
strong cytotoxic action, eliciting significant differential
responses at the GI50 level for all colon and melanoma cancer
cell lines at concentrations of 10-6 M.2h
(1) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48 and references therein.
(2) For isolation and bioactivities, see. Lophotoxin: (a) Fenical, W.;
Okuda, R. K.; Bandurraga, M. M.; Culver, P.; Jacobs, R. S. Science 1981,
212, 1512-1514. Kallolides: (b) Look, S. A.; Burch, M. T.; Fenical, W.;
Zheng, Q.; Clardy, J. J. Org. Chem. 1985, 50, 5741-5746. (c) Rodr´ıguez,
A. D.; Shi, J.-G.; Shi, Y.-P. J. Org. Chem. 2000, 65, 3192-3199.
Pinnatins: (d) Rodr´ıguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem.
1998, 63, 4425-4432. (e) Rodr´ıguez, A. D.; Shi, J.-G. Org. Lett. 1999, 1,
337-340. Bipinnatins: (f) Wright, A. E.; Burres, N. S.; Schulte, G. K.
Tetrahedron Lett. 1989, 30, 3491-3494. (g) Rodr´ıguez, A. D.; Shi, J.-G.
J. Org. Chem. 1998, 63, 420-421. (h) Rodr´ıguez, A. D.; Shi, J.-G.; Huang,
S. D. J. Nat. Prod. 1999, 62, 1228-1237. (i) Rodrguez, A. D.; Shi, Y.-P.
J. Nat. Prod. 2000, 63, 1548-1550.
(3) (a) Culver, P.; Jacobs, R. S. Toxicon 1981, 19, 825-830. (b) Langdon,
R. B.; Jacobs, R. S. Life Sci. 1983, 32, 1223-1228. (c) Sorenson, E. M.;
Culver, P.; Chiappinelli, V. A. Neuroscience 1987, 20, 875-884. (d) Groebe,
D. R.; Abramson, S. N. J. Biol. Chem. 1995, 270, 281-286. (e) Hyde, E.
G.; Boyer, A.; Tang, P.; Xu, Y.; Abramson, S. N. J. Med. Chem. 1995, 38,
2231-2238. (f) Tornoe, C.; Holden-Dye, L.; Garland, C.; Abramson, S.
N.; Fleming, J. T.; Sattelle, D. B. J. Exp. Biol. 1996, 199, 2161-2168.
Figure 1. Structures of Pseudopterogorgia metabolites.
10.1021/ol053054s CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/13/2006

In connection with our interest in the secondary metabo-
lites of gorgonian corals, and their biosynthetic interrelation-
ships,4 we became interested in the furanocembrane bipin-
natin J (1).5-9 Possessing the less common Z-olefin in its
macrocyclic ring, this compound may well be a precursor
to several more oxidized congeners of the Pseudopterogor-
gia-derived cembranes. Of special interest is the structural
relationship between bipinnatin J and the recently reported
pentacyclic diterpene intricarene (2).10 Isolated from Pseudo-
pterogorgia kallos, this aptly named compound may very
well arise from bipinnatin J, through oxidation of the furan
moiety followed by an oxydopyrylium ion based transannular
[5+2] cycloaddition reaction.11 In this letter, we report a
simple, convergent route to furanocembranes culminating in
the total synthesis of bipinnatin J (1).
away. A highly convergent route was devised for the
synthesis of the macrocyclization precursor.
The synthesis of bipinnatin J commenced with the
preparation of the substituted butyrolactone unit (Scheme 2).
Scheme 2. Synthesis of Fragment 10
Our strategy to bipinnatin J (1) can be seen through the
retrosynthetic analysis presented in Scheme 1. The plan was
Scheme 1. Retrosynthetic Analysis of Bipinnatin J (1)
Allylic oxidation of commercially available 5-bromo-2-
methylpent-2-ene (5) with SeO2 and t-BuOOH proceeded
regioselectively to afford trans-allylic alcohol 6 in 67%
isolated yield.12 The hydroxyl group was protected as the
MOM ether to afford compound 7a in 91% yield. The cross-
coupling of 7a with 3-bromofuran-2(5H)-one to yield the
desired alkylated furanone (10) proved low yielding, so a
less direct route was utilized. The reaction of γ-butyrolactone
enolate with bromide 7a gave the desired alkylation product
(8), but in a low yield. The major product was a conjugated
diene, presumably arising from E2 elimination of 7a. To
favor alkylation over elimination, the bromide was exchanged
for an iodide. The modified alkylating agent performed as
desired and provided the alkylated γ-butyrolactone (8) in
72% yield, along with ∼10% of the diene side-product. The
required olefin was introduced through a two-step, phenylse-
lenation/selenoxide elimination sequence. The selenoxide
elimination proceeded with good regioselectivity and yielded
primarily the endocyclic olefin-containing product, 10 (17:1
ratio).
to construct the 14-membered carbon core of 1 through a
metal-promoted macrocyclization of intermediate 3. An
analysis of molecular models indicated that the relative
stereochemistry at C1 and C2 would be controlled by the
sole stereocenter in the furanone unit, located five carbons
(4) Waizumi, N.; Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc.
2003, 125, 13022-13023.
The elaboration of compound 10 to the desired cyclization
precursor, 3, necessitated alkylation at the γ-position of the
unsaturated lactone. This transform was achieved through
the intermediacy of the corresponding siloxyfuran 11,
prepared in quantitative yield by silation of the enolate of
10 (Scheme 3). The desired γ-alkylation was accomplished
under SN1 conditions. Treatment of siloxyfuran 11 with the
requisite allylic bromide in the presence of Ag(OCOCF3)2
(5) For isolation of bipinnatin J, see ref 2g.
(6) For the synthetic studies toward bipinnatin J, see: Tsubuki, M.;
Takahashi, K.; Sakata, K.; Honda, T. Heterocycles 2005, 65, 531-540.
While this manuscript was being readied for publication, we became aware
of a completed synthesis of bipinnatin J: Trauner, D., private communica-
tion. See: Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345-348.
(7) For total synthesis of furanocembranolides, see for example: (a)
Rayner, C. M.; Astles, P. C.; Paquette, L. A. J. Am. Chem. Soc. 1992, 114,
3926-3936. (b) Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58,
165-169.
(8) For total synthesis of pseudopterolides, see: (a) Marshall, J. A.;
Bartley, G. S.; Wallace, E. M. J. Org. Chem. 1996, 61, 5729-5735. (b)
Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962-5970. (c) Marshall,
J. A.; Van Devender, E. A. J. Org. Chem. 2001, 66, 8037-8041.
(9) Other synthetic studies: (a) Marshall, J. A.; Wang, X.-J. J. Org. Chem.
1992, 57, 3387-3396. (b) Marshall, J. A.; McNulty, L. M.; Zou, D. J.
Org. Chem. 1999, 64, 5193-5200. (c) Tsubuki, M.; Takahashi, K.; Honda,
T. J. Org. Chem. 2003, 68, 10183-10186.
(10) For isolation, see: Marrero, J.; Rodr´ıguez, A. D.; Barnes, C. L.
Org. Lett. 2005, 7, 1877-1880.
(11) Reviews of [5+2] cycloaddition: (a) Mascarenas, J. L. AdV.
Cycloaddit. 1999, 6, 1-54. (b) Harmata, M.; Rashatasakhon, P. Tetrahedron
2003, 59, 2371-2395.
(12) Andresen, G.; Eriksen, A.; Dalhus, A. B.; Gundersen, L.-L.; Rise,
F. J. Chem. Soc., Perkin Trans. 1 2001, 1662-1672.
544
Org. Lett., Vol. 8, No. 3, 2006

reaction conditions (0.429 mmol of 3, 20.6 equiv of CrCl2,
2.0 g of activated, powdered 4 Å molecular sieves, 300 mL
of THF) to minimize intermolecular reactions. The reaction
went to completion after 16 h and, to our delight, gave
bipinnatin J (1), a white solid (mp 176-178 °C, lit.2g mp
141-142 °C dec), as the major product in 73% isolated yield.
Scheme 3. Synthesis of the Macrocyclization Precursor, 3
1
The H and 13C NMR spectra of the synthetic sample are
identical with that reported for the natural product.2g Also
isolated from the macrocyclization reaction were two disas-
teroisomeric cyclization products, 15 and 16, in 12.7% and
5.6% yields, respectively. The structures assigned to these
minor products are based on the NMR data and are
considered tentative. We are examining the effect of reaction
parameters on the diastereoselectivity of the cyclization
reaction. The high diastereoselectivity observed in the
macrocyclization can be understood by considering the likely
transition state for the Nozaki-Hiyama reaction,7,16-18
wherein the remote furanone stereocenter at C10 induces
relative stereochemistry of the two new stereocenters. In
Scheme 4. Macrocyclization to Yield Bipinnatin J (1)
afforded the desired alkylation product (12) in 60% yield.13,14
The required 3-methylfurfural piece was then appended
through the Negishi cross-coupling protocol. The reaction
of iodide 12 and organozinc compound 13, which was
generated in situ by treatment of dioxolane protected
3-methylfurfural with 1.0 equiv of t-BuLi and 1.2 equiv of
ZnCl2 in THF at -78 °C, was catalyzed with PdCl2dppf and
yielded the coupled product (4) in quantitative yield. Treat-
ment of compound 4 with PPTS in refluxing t-BuOH
removed the dioxolane and MOM ether protecting groups
to provide aldehyde 14 in 81% isolated yield. It is noteworthy
that the same reaction when carried out in MeOH or iPrOH
led to decomposition of the starting material, with only trace
1
amounts of the desired product present by H NMR. The
direct, palladium-mediated reductive cyclization of allylic
summary, we have completed an efficient, convergent total
synthesis of bipinnatin J. The longest linear sequence requires
12 steps from the commercially available 5-bromo-2-
methylpent-2-ene. The synthesis features the use of a silver
ion promoted SN1-type γ-alkylation of a siloxyfuran and a
diastereoselective Cr(II)-mediated macrocyclization, which
provides bipinnatin J as the major product. Current efforts
are directed toward the asymmetric synthesis of bipinnatin
J as well as the biomimetic tranformation of this compound
to other Pseudopterogorgia-derived diterpenes, including
intricarene (2).
alcohol 14 was examined, but without success.15
The Nozaki-Hiyama reaction presented a good alternative
for the desired reductive cyclization.16-18 In preparation for
this reaction, the hydroxyl group was converted to the
bromide with use of PPh3 and CBr4. The Nozaki-Hiyama
macrocyclization of bromide 3 was carried out under dilute
(13) Jefford, C. W.; Sledeski, A. W.; Boukouvalas, J. J. Chem. Soc.,
Chem. Commun. 1988, 364-365.
(14) Preparation of 3-bromo-1-iodo-2-methylpropene: Larock, R. C.;
Han, X. J. Org. Chem. 1999, 64, 1875-1887.
(15) For examples of palladium promoted reductive coupling of allylic
alcohols with aldehydes, see: (a) Takahara, J. P.; Masuyama, Y.; Kurusu,
Y. J. Am. Chem. Soc. 1992, 114, 2577-2586. (b) Kimura, M.; Tomizawa,
T.; Horino, Y.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 3627-
3629.
Acknowledgment. We are grateful to the National
Institutes of Health (R01 GM69990) for financial support
of this work.
(16) Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1045.
(17) For the Cr-promoted macrocyclization of allylic bromides, see: (a)
Still W. C.; Mobilio, D. J. Org. Chem. 1983, 48, 4785-4786. (b) Wender,
P. A.; Mckinney, J. A.; Muka, C. J. Am. Chem. Soc. 1990, 112, 5369-
5370. (c) Wender, P. A.; Grissom, J. W.; Hoffmann, U.; Mah, R.
Tetrahedron Lett. 1990, 31, 6605-6608;
Supporting Information Available: General experimen-
tal procedures and characterization data for all key interme-
diates and bipinnatin J. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) In Paquette’s synthesis of gorgiacerone, the Nozaki-Hiyama
reaction was utilized to produce the pseudopterane skeleton (25% yield,
see ref 7a). Paquette has also utilized this process for construction of the
furanocembrane skeleton (20% yield, see ref 7b).
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