A synthesis of (+)-FR182877, featuring tandem transannular Diels-Alder reactions inspired by a postulated biogenesis

Article abstract of DOI:10.1021/ja025885o

An efficient biomimetic synthesis of the reported structure of the hexacyclic, cytotoxic secondary metabolite FR182877 is described. The successful route features the synthesis of a 19-membered ring carbocycle using two π-allyl palladium(II)-mediated C-C

Full text of DOI:10.1021/ja025885o

Published on Web 04/02/2002
A Synthesis of (+)-FR182877, Featuring Tandem Transannular Diels-Alder
Reactions Inspired by a Postulated Biogenesis
David A. Vosburg, Christopher D. Vanderwal, and Erik J. Sorensen*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received February 9, 2002
Scheme 1. A Variant of Our Original Biogenetic Model
In the course of designing a synthesis for a complex natural
product, it can be profitable to consider how its structure may have
arisen in nature.1 “Biogenetic-type” syntheses are those that imitate
established or presumed biosynthetic pathways1a and can uncover
distinctly direct pathways for creating complex molecular archi-
tectures. The application of potentially natural reaction channels
to the chemical synthesis of structurally complex, bioactive natural
products has been a theme of previous studies from our laboratory,2
and we contemplated the structural origin of the cytotoxic, bacterial-
derived natural product FR182877 (1) (Scheme 1). The unique,
hexacyclic architecture of this natural product, a substance formerly
known as WS9885B, was described by scientists from the Fujisawa
Pharmaceutical Company.3 FR182877 (1) is a member of a growing
family of secondary metabolites that bind and stabilize cellular
microtubules and exhibits a potency comparable to that of the anti-
cancer drug Taxol.4 While the biosynthesis of 1 has not yet been
reported, this natural product is a close structural relative of the
polyketide hexacyclinic acid5 and can be reduced to the same
alternating sequence of six acetate and four propionate units.6
With a complex hexacyclic ring system comprising 12 stereo-
centers and a strained bridgehead alkene, FR182877 (1) is an
intimidating objective for research in organic synthesis. In prior
publications, we proposed that the structure of compound 1 could
arise from a significantly less complex polyunsaturated compound
of type 2 (Scheme 1) by a cascade of intramolecular reactions.6,7
In evaluating the potential of FR182877 (1) for a constitutional
self-assembly, we found that a variant of our original biogenetic
postulate in which the structure of 1 would form from a polyun-
saturated macrocycle of type 3 by successive transannular Diels-
Alder reactions is chemically feasible (see 3 f 4 f 1).8 The first
synthesis of the published structure for FR182877 (1) based on
this concept is the subject of this communication.
When compound 6, the trimethylsilyl ether of the recently
described alcohol 5, was reacted with known dienylstannane 7 under
previously reported conditions,6 a smooth union occurred, and
compound 8 was isolated in 85% yield (Scheme 2). The efficiency
of this Stille coupling,9 which occurs via a π-allyl palladium(II)
intermediate, prompted us to consider the feasibility of achieving
a bond formation between carbons 1 and 19 of 9 by a charge-
driven, intramolecular attack of a deprotonated â-keto ester on an
electrophilic π-allyl Pd(II) intermediate.10,11 Toward this end,
C-acylation of lithium tert-butyl acetate by the Weinreb amide
moiety of 812,13 afforded the expected â-keto ester, which was
smoothly converted to the key macrocyclization substrate 9 by the
following sequence: (1) selective cleavage of the C-1 and C-16
silyl ethers with n-Bu4NF, (2) conversion of the primary hydroxyl
group to the corresponding mixed carbonate with methyl chloro-
formate, and (3) resilylation of the C-16 secondary hydroxyl group.
To our delight, the critical C1-C19 ring closure was achieved in
80% yield by exposure of a dilute (5 mM) solution of 9 in THF to
Pd2dba3 (10 mol %) at 40 °C.10,11 The efficient formation of
carbocycle 10 by this method stands in sharp contrast to unsuc-
cessful early efforts to achieve ring-forming Knoevenagel conden-
sations of compounds related to 2 (Scheme 1).
To evaluate the hypothesis outlined in Scheme 1, we needed
only to introduce unsaturation between the two carbonyl functions.
Reaction of the stabilized enolate derived from 10 with phenyl-
selenenyl bromide afforded a ca. 3:1 mixture of inseparable
diastereomers. When this mixture of organoselenides was treated
with mCPBA in CH2Cl2 at -78 °C, a protected version of
compound 3 (Scheme 1) and its geometrical isomer were efficiently
formed.14 Remarkably, when a solution of these geometrically
isomeric macrocycles in chloroform was warmed to 40 °C,
compound 11 was produced in an isolated yield of 40%;15 these
tandem transannular Diels-Alder reactions16 transformed a 19-
membered ring carbocycle to a complex pentacycle with seven new
contiguous stereocenters. Moreover, this process is diastereoselec-
tive and yields a pentacyclic compound with relative stereochemical
relationships that are reflected in FR182877 (1). To the best of our
knowledge, this is the first example of a double transannular Diels-
Alder reaction.
From compound 11, the final ascent to 1 was straightforward.
Solvolysis of the three silyl ethers and cleavage of the tert-butyl
ester function in 11 were best achieved with PPTS/MeOH and
trifluoroacetic acid, respectively. Finally, an EDC-mediated lac-
tonization of triol carboxylic acid 12 afforded (+)-FR182877
[(+)-1].17 The spectroscopic data that was accumulated for this
substance matched the published spectra for FR1828773 in every
detail; however, the sign of the [R]D for our synthetic sample
indicates that the compound shown as 1 in Schemes 1 and 2 is the
* To whom correspondence should be addressed. E-mail: sorensen@
scripps.edu.
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J. AM. CHEM. SOC. 2002, 124, 4552-4553
10.1021/ja025885o CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
a Key: (a) TMSCl, imidazole, CH2Cl2, 96%; (b) Pd2dba3 (0.1 equiv), LiCl, i-Pr2NEt, NMP, 40 °C, 80 min, 85%; (c) LDA, t-BuOAc, Et2O, -78 °C f
rt, 81%; (d) TBAF (2 equiv), THF, -40 f 0 °C, 86%; (e) MeOCOCl, pyridine, CH2Cl2, 93%; (f) TMSCl, imidazole, CH2Cl2, 95%; (g) Pd2dba3 (0.1 equiv),
THF, 40 °C, 12 h, 80%; (h) KHMDS, PhSeBr, THF, -10 °C, 91%; (i) mCPBA, CH2Cl2, -78 °C; then CHCl3, 40 °C, 4 h, 40%; (j) PPTS, MeOH; (k)
TFA/CH2Cl2 (1:9), 0 °C f rt; (l) EDC, DMAP, CH2Cl2, 62% from 11.
enantiomer of naturally occurring FR182877.18 This finding is of
much interest from a biosynthetic perspective because it suggests
Reminiscences and Afterthoughts. In The Biosynthesis of the Tetrapyrrole
Pigments; Ciba Foundation Symposium 180, Wiley: Chichester, 1994; p
309. (j) Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14323.
(2) (a) (-)-Hispidospermidin: Tamiya, J.; Sorensen, E. J. J. Am. Chem. Soc.
2000, 122, 9556. (b) FR901483: Scheffler, G.; Seike, H.; Sorensen, E. J.
Angew. Chem., Int. Ed. 2000, 39, 4593.
(3) (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.; Hino,
M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123. (b) Sato, B.;
Nakajima, H.; Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J. Antibiot.
2000, 53, 204. (c) Yoshimura, S.; Sato, B.; Kinoshita, T.; Takase, S.;
Terano, H. J. Antibiot. 2000, 53, 615.
(4) (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15. (b) Kingston, D. G. I. Chem. Commun. 2001, 867.
(5) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000, 39, 3258.
(6) Vanderwal, C. D.; Vosburg, D. A.; Sorensen, E. J. Org. Lett. 2001, 3,
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(7) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Org. Lett.
1999, 1, 645.
that FR182877 and hexacyclinic acid are closely related with respect
to constitution and absolute stereochemistry.5,6
The asymmetric synthesis of (+)-FR182877 described herein
issued from the following question: Can the unique architecture
of 1 arise spontaneously from a polyunsaturated precursor by a
cascade of cyclizations? In our effort to address this question
experimentally, we found that two π-allyl Pd(II)-mediated bond
forming reactions facilitated a synthesis of a polyunsaturated
macrocycle that can indeed undergo a remarkable sequence of
complexity-generating reactions with minimal instigation. The
diastereoselectivity observed for this polycyclization process is
apparently intrinsic to structures of type 3 and does not result from
the influence of an external asymmetric catalyst. This synthesis of
FR182877 validates our biogenetic proposal and provides a
chemical rationalization of its structure.
(8) The transformations shown in Scheme 1 are generalized and are not meant
to preclude other possible orderings of events.
(9) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(10) (a) For an example of a palladium-mediated macrocyclization, see: Trost,
B. M.; Brickner, S. J. J. Am. Chem. Soc. 1983, 105, 568. (b) For a review,
see: Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(11) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron Lett. 1982,
23, 4809. (b) For a review, see: Tsuji, J. Tetrahedron 1986, 42, 4361.
(12) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171.
(b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989.
(13) Turner, J. A.; Jacks, W. S. J. Org. Chem. 1989, 54, 4229.
(14) (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697. (b)
Reich, H. J.; Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1973, 95, 5813.
(c) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products Synthesis;
CIS, Inc.: Philadelphia, 1984. The oxidative deselenylation gives a ca.
1:1 E/Z ratio of inseparable pentaenes of type 3, isomeric at the newly
formed C1-C19 olefin. Studies to form this olefin with greater E-
selectivity are in progress.
(15) Pentacycle 11 constitutes g50% of the product mass balance and represents
ca. 80% yield based on the unisolable E-pentaene. The minor reaction
products include a diastereomer of 11 and two diastereomeric derivatives
of 4. At room temperature the tandem cycloadditions require ca. 24 h.
Further studies of this process will be reported in due course.
(16) (a) For an excellent review by the pioneer in the development of the
transannular Diels-Alder strategy in organic synthesis, see: Marsault,
E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243.
(b) For a recent and elegant biomimetic natural product synthesis featuring
intermolecular and transannular Diels-Alder reactions, see: Layton, M.
E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773.
(17) The longest linear sequence of 20 steps proceeds in 5% overall yield (86%
yield/step) from (E)-4-tert-butyldimethylsilyloxy-but-2-enal (see ref 6).
(18) Our finding is corroborated in a recent revision of the absolute stereo-
chemistry of FR182877 by Fujisawa scientists (see: J. Antibiot. 2002,
55, C1). We thank Dr. Seiji Yoshimura from Fujisawa Pharmaceutical
Co. for providing us with this information.
Acknowledgment. This paper is dedicated with respect and
affection to Professor Roger C. Hahn on the occasion of his 70th
birthday. Our work was supported by The Skaggs Institute for
Chemical Biology at TSRI, NIH/NCI Grant CA85526, the Beckman
Foundation, a Camille-Dreyfus Teacher-Scholar Award, Astra-
Zeneca, Eli Lilly, Merck, and predoctoral fellowships from the
NSERC of Canada (C.D.V.), Hoffmann-La Roche (C.D.V.), the
Skaggs Institute (C.D.V.), NSF (D.A.V.), and ACS/AstraZeneca
(D.A.V.). We thank Dr. Sven Weiler (now at Novartis) for early
contributions to this project.
Supporting Information Available: Characterization data for 8,
10, 11, and 1 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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