An efficient total synthesis of okadaic acid

Full text of DOI:10.1021/ja9715206

J. Am. Chem. Soc. 1997, 119, 8381-8382
8381
maximal functionality into each fragment and the use of direct
and chemoselective coupling methods to minimize the number
of post-coupling transformations.
An Efficient Total Synthesis of Okadaic Acid
Craig J. Forsyth,* Steven F. Sabes, and Rebecca A. Urbanek
The synthesis of the C1-C14 portion of 1 combined an
established spiroketalization approach17 with Seebach's lactate
enolate alkylation methodology.18 Addition of the lithium
acetylide of 219 to lactone 3,20 followed by trimethylsilylation
gave ynone 4 (Scheme 1). Conjugate addition of lithium
dimethyl cuprate to 4 provided predominately the (Z)-enone
5,17,21 which upon treatment with acid generated spiroketal 622
in 31% overall yield from 3. Attempts to incorporate the C1-
C2 moiety of 1 by alkylation of metal enolates of lactate
pivalidene 718 with primary tosylate, triflate, or halides obtained
from 6 were unproductive. In contrast, the lithium enolate of
7 added smoothly to the aldehyde derived from 6. The major
resultant alcohol 8 was deoxygenated23 without incident to give
9 (70% yield from 6). Removal of the p-methoxybenzyl (PMB)
protecting group24 at C14 followed by oxidation with Dess-
Martin periodinane25 gave aldehyde 10, to complete the
synthesis of the C1-C14 intermediate in 11 steps and ca. 20%
overall yield from lactone 3.
The synthesis of the central C16-C27 fragment of 1 began
with Gray’s one-pot C-glycosidation26 of altropyranoside 1127
(Scheme 2). Subsequent formation of the anisylidene acetal
aided purification and provided R-propenyl-C-glycoside 12.
Treatment of the derived aldehyde 13 with organolithium 1428
followed by oxidation25 installed carbons 16-19 with C19 at
the ketone oxidation state required for 1. The ketone was
masked as a mixed acetal en route to secondary alcohol 15 (45%
yield from 13). Installation of the C24 exocyclic methylene29
and the C27 aldehyde were then accomplished routinely to give
16 (ca. 20% yield from 11).
Department of Chemistry, UniVersity of Minnesota
Minneapolis, Minnesota 55455
ReceiVed May 12, 1997
Okadaic acid (1)1 is the archetypal member of a class of
structurally diverse natural products that inhibit the protein
serine/threonine phosphatases 1 (PP1) and 2A.2 As such, 1 has
become a widely used tool to study the roles of these ubiquitous
enzymes.3-5 Other members of the okadaic acid class of
phosphatase inhibitors, including calyculin A,6 tautomycin,7
microcystin-LR,8 motuporin,9 and cantharidin,10 have drawn
considerable synthetic attention recently. However, little syn-
thetic activity toward 1 or its analogs has been reported since
Isobe’s original total synthesis in 1986.11,12 Although several
of okadaic acid’s structural features have been implicated to be
important for phosphatase inhibition13-15 and an X-ray structure
of microcystin covalently bound to PP1 has been determined
recently,16 the structural basis of phosphatase inhibition by 1
remains largely undefined. Practical synthetic access to ratio-
nally designed, non-natural analogs of 1 will facilitate further
studies aimed at fully defining the structural requirements for
phosphatase binding and inhibition. Toward this end, we have
developed an efficient and flexible total synthesis of okadaic
acid.
The sensitive â,γ-unsaturated aldehyde 16 was coupled
directly with an intermediate representing the C28-C38 portion
of 1. Addition of freshly prepared 16 to an excess of thermally
unstable organolithium 1730 yielded the epimeric secondary
alcohols 18 and 1931 nonstereoselectively and in low yield.
Preliminary attempts to enhance the coupling diastereoselectivity
With 17 stereogenic carbons and three separate polyether
domains, 1 presents a substantial challenge for efficient as-
sembly. This challenge was met by the synthesis and sequential
coupling of three fragments, representing C1-C14, C16-C27,
and C28-C38 of the natural product. Although disconnections
similar to those used in the original synthesis11 of 1 were
employed, the present strategy relied upon the incorporation of
(17) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Goto, T. Tetrahedron Lett. 1985,
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(18) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313-
1324.
(19) Alkyne 2 was prepared from (2R,3R)-3-methyl-1,2,4-butanetriol
[Mori, K.; Iwasawa, H. Tetrahedron 1980, 36, 87-90.] as follows: (i)
3-pentanone/TsOH, (ii) PMBCl/NaH, (iii) TsOH/MeOH, (iv) N-TsIm/NaH
[Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122-8123.], (v)
TMSCCLi, (vi) TBAF, and (vii) TMSCl.
(1) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Engen, D.
V.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981, 103,
2469-2471.
(20) Lactone 3 was prepared from isopropyl 4,5-dideoxy-R-D-glucopy-
ranoside [Isobe, M.; Ichikawa, Y.; Goto, T. Tetrahedron Lett. 1985, 26,
5199-5202.] as follows: (i) TBDPSCl/Et3N, (ii) BnBr/NaH, (iii) PhSH/
BF3‚OEt2, (iv) I2/aqueous NaHCO3, and (v) PCC.
(2) Bialojan, C.; Takai, A. Biochem. J. 1988, 256, 283-290.
(3) Fujiki, H. Molecular Carcinogenesis 1992, 5, 91-94.
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(21) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
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(5) Schonthal, A. New Biol. 1992, 4, 16-21.
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Kato, Y.; Fusetani, N.; Watabe, S.; Hashimoto, K. Biochem. Biophys. Res.
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(22) Spiroketal 6 was formed as the major isomer of a ca. 2.2:1 ratio of
diastereomers.
(23) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
I 1975, 1574-1585.
(7) MacKintosh, C.; Klumpp, S. FEBS Lett. 1990, 277, 137-140.
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Tetrahedron 1986, 42, 3021-3028.
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C. F. B.; Allen, T. M. Tetrahedron Lett. 1992, 33, 1561-1564.
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7287.
(26) Bennek, J. A.; Gray, G. R. J. Org. Chem. 1987, 52, 892-897.
(27) Compound 11 was obtained by hydrolysis of the known benzylidene
derivative: Kunz, H.; Weissmueller, J. Liebigs Ann. Chem. 1984, 66-77.
(28) Compound 14 was prepared from 1,3-propanediol as follows: (i)
anisaldehyde/TsOH, (ii) AlCl3/LiAlH4/Et2O, (iii) CBr4/Ph3P, and (iv) t-BuLi/
Et2O.
(11) Isobe, M.; Ichikawa, Y.; Goto, T. Tetrahedron Lett. 1986, 27, 963-
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(12) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Masaki, H.; Goto, T. Tetra-
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Matsushima, R.; Iida, Y.; Ojika, M.; Yamada, K.; Uemura, D.; Yasumoto,
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Chem. 1989, 53, 525-529.
(29) Miljkovic, M.; Glisin, D. J. Org. Chem. 1975, 40, 3357-3359.
(30) Compound 17 was obtained from the corresponding bromide (t-
BuLi/THF/-78 °C), which in turn was prepared in 10 steps and 35% overall
yield from methyl (S)-(+)-3-hydroxy-2-methylpropionate as follows: (i)
TBSCl/Im, (ii) Dibal/CH2Cl2, (iii) tri-n-butylcrotylstannane/BF3‚OEt2 [Keck,
G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883-1886.], (iv) TBAF/
THF, (v) BnBr/NaH, (vi) O3/Ph3P, (vii) dimethyl (2-oxo-6-benzyloxy)hexyl
phosphonate/LiCl/i-Pr2NEt, (viii) H2/Pd(OH)2 (spontaneous spiroketalization
occurred), (ix) TsCl/Et3N, and (x) LiBr/CH3CN.
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Yasumoto, T. Biochem. J. 1992, 284, 539-544.
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S0002-7863(97)01520-5 CCC: $14.00 © 1997 American Chemical Society

8382 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Communications to the Editor
Scheme 1
Scheme 2
and purification. Thus, the convergent assembly of okadaic acid
was accomplished in 26 steps and ca. 3% overall yield in the
longest linear sequence from altropyranoside 11.41
In addition to providing an alternative source of 1, the direct
and modular nature of this synthesis makes it amenable to the
facile construction of new compounds based upon the okadaic
acid architecture. The preparation and exploration of such
compounds for selective ligand modulation of protein serine/
threonine phosphatase activity is currently underway in our
laboratory.
using other organometallics derived from 17 were only margin-
ally successful.32 However, useful yields of coupled products
18 and 19 (2.5:1, 55% yield combined) could be obtained
reproducibly using the less basic reagent generated from CeCl3
and 17 in THF at -78 °C. Neither appreciable epimerization
at C26 nor conjugation of the alkene occurred under these
conditions. A simple two-step oxidation-reduction sequence33
gave 19 in a 9:1 ratio (19:18) from 18. Removal of the PMB
group from 19 was accomplished using DDQ in a buffered (pH
7) suspension to avoid premature and irretrievable C16-C19
spiroketalization. Thereafter, the C15-C38 ketophosphonate
20 was obtained uneventfully and in 21 steps and ca. 5% overall
yield from altropyranoside 11.
The complete carbon skeleton of 1 was assembled by joining
10 and 20 (86% yield) under standard conditions.34 Only four
steps were required to convert the resultant enone 21 into
okadaic acid. Diastereoselective reduction of 21 using Corey’s
(S)-CBS/BH3 system (22),35 followed by acid-induced spiroket-
alization gave 23 (81% yield from 21).36 Final deprotection
involving LiOH-promoted removal of the pivalidene group and
carefully optimized reductive debenzylation37 using LiDBB in
THF38,39 delivered 140 (ca. 70% yield from 23) after workup
Acknowledgment. This work was dedicated to Professor Yoshito
Kishi on the occasion of his 60th birthday. We thank Prof. D. Uemura
for providing an authentic sample of 1 isolated from Halichondria
okadai. Financial support from the NIH (CA62195) and a University
of Minnesota McKnight Land-Grant Professorship (C.J.F.) is gratefully
acknowledged.
Supporting Information Available: Physical and spectral data for
compounds 1-6, 8-13, 15, 16, 18-21, and 23 and comparison of 1H
NMR spectra of natural and synthetic 1 (50 pages). See any current
masthead page for ordering and Internet access instructions.
JA9715206
(37) As noted previously11 (Ichikawa, Y.; Isobe, M.; Goto, T. Agric Biol.
Chem. 1988, 4, 975-981), over reduction occurs readily upon debenzylation
of 7,24,27-tri-O-benzylokadaic acid using Li/NH3/EtOH; however, overre-
duction was avoided here using LiDBB in THF at -78 °C.38,39
(38) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930.
(31) The C27 carbinol configuration of 19 was assigned at this stage by
Mosher ester analysis.
(32) Use of the following in conjunction with 17 gave low de’s and/or
low yields: MgBr2, CuBr.DMS, CuCN, 2-thienyl-CuCNLi, or CrCl3‚THF.
(33) Ichikawa, Y.; Isobe, M.; Goto, T. Tetrahedron Lett. 1984, 25, 5049-
5052.
(34) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(35) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925-7926.
(36) The ratio of diastereomeric spiroketal products was ca. 5:1; the
configurations at C16 and C19 of the minor diastereomer were not
determined.
(39) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854-
860.
(40) Synthetic 1 matched (1H NMR, [R]D, HRMS, and TLC; see
Supporting Information) an authentic sample of the natural product isolated
from H. okadai that was kindly provided by Prof. D. Uemura.
(41) Although this total synthesis has not been optimized, it compares
favorably in length and efficiency with the original synthesis of 1,11,12 which
reportedly spanned 54 steps and ca. 0.01% overall yield for the longest
linear sequence.