Abbreviated synthesis of the C3-C14 (substituted 1,7-dioxaspiro[5.5]undec-3-ene) system of okadaic acid.

Article abstract of DOI:10.1021/ol9906615

[formula: see text] Described is a novel, concise, and flexible synthesis of the C3-C14 portion of okadaic acid. A substituted valerolactone (C3-C8) was prepared in three steps and alpha-hydroxylated using Davis' oxaziridine. Conjugate addition of dimethy

Full text of DOI:10.1021/ol9906615

ORGANIC
LETTERS
1999
Vol. 1, No. 3
451-453
Abbreviated Synthesis of the C3−C14
(Substituted
1,7-Dioxaspiro[5.5]undec-3-ene) System
of Okadaic Acid
Amy B. Dounay and Craig J. Forsyth*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
forsyth@chem.umn.edu
Received May 12, 1999
ABSTRACT
Described is a novel, concise, and flexible synthesis of the C3−C14 portion of okadaic acid. A substituted valerolactone (C3−C8) was prepared
in three steps and r-hydroxylated using Davis’ oxaziridine. Conjugate addition of dimethylcuprate upon ynones derived from the C3−C8
lactones followed by intramolecular ketalization provided the C3−C14 fragment and revealed a significant role of the C7 r′-ketone substituent
upon the efficiency of spiroketalization.
Okadaic acid (1) is a notorious marine natural product that
has been the focus of a resurgence of synthetic interest.1-7
We recently described a total synthesis of 1 that relied upon
the convergent coupling of three separate polyether-bearing
fragments.2,3
in the original synthesis of 1,1 enone 5 was obtained from
lactone 8 and alkyne 12.3 This involved acetylide anion
addition to the lactone, followed by installation of the C10
methyl group by 1,4-addition of dimethylcuprate8 to the
derived ynone. Subsequent treatment of the resultant latent
δ,δ′-dihydroxy enone under acidic conditions provided the
(8R)-spiroketal (2), but in only modest yields.3,9 Furthermore,
synthetic access to lactone 8 proved cumbersome,10 reductive
debenzylation in the final step of the published total syntheses
of 1 has been problematic,1,3,4 and C7 variants would be
(4) Ley, S. V.; Humphries, A. C.; Eick, H.; Downham, R.; Ross, A. R.;
Boyce, R. J.; Pavey, J. B. J.; Pietruszka J. J. Chem. Soc., Perkin Trans. 1
1998, 3907.
(5) Marko, I. E.; Dobbs, A. P.; Scheirmann, V.; Chelle, F.; Bayston, D.
J. Tetrahedron Lett. 1997, 38, 2899.
(6) Marko, I. E.; Chelle, F. Tetrahedron Lett. 1997, 38, 2895.
(7) Dankwardt, S. M.; Dankwardt, J.; Schlessinger, R. H. Tetrahedron
Lett. 1998, 39, 4983 and preceding papers in that issue.
(8) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
1851.
The C1-C14 fragment was elaborated from spiroketal 2,
which in turn was prepared by intramolecular ketalization
of enone 5 (Scheme 1).3 In an approach similar to that used
(1) Isobe, M.; Ichikawa, Y.; Goto, T. Tetrahedron Lett. 1986, 27, 963.
(2) Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J. J. Am. Chem. Soc. 1998,
120, 2523.
(9) Ichikawa, Y.; Isobe, M.; Bai, D.-L.; Goto, T. Tetrahedron 1987, 43,
4737.
(3) Sabes, S. F.; Urbanek, R. A.; Forsyth, C. J. J. Am. Chem. Soc. 1998,
120, 2534.
(10) Lactone 8 was prepared previously in eight steps from D-2-
acetoxytriacetylglucal.3
10.1021/ol9906615 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/22/1999

then provided diol 16. Oxidation of 16 with PCC (CH2Cl2,
4 Å MS, rt) conveniently delivered lactone 11, as well as
minor amounts of the corresponding keto-aldehyde. Diaste-
reoselective R-hydroxylation of 11 was effected with Davis’
chiral oxaziridine 17.13 Treatment of the lithium enolate of
lactone 11 with 17 in the presence of TMEDA followed by
careful quench with CSA gave R-hydroxy lactone 10 in
moderate yield. The hydroxyl group could be benzylated
under nonbasic conditions14 to yield the known okadaic acid
intermediate 8 via this dramatically abbreviated route.10
However, the C7 hydroxyl group was alternatively masked
as a TBS ether (9) at this stage to facilitate final deprotection.
To determine the utility of the C7 variants for formation
of spiroketals 3 and 4, ynones 18 and 19 were prepared from
alkyne 123 and the corresponding lactones 9 and 11 (Scheme
3).15 Conjugate addition of dimethylcuprate to 18 or 19
Scheme 1. Retrosynthesis of the C3-C14 Domain
Scheme 3. Synthesis of C3-C14 Spiroketals
useful for biological studies. Hence, a new concise and
flexible synthesis of the C3-C8 lactone was developed and
used to prepare C7-functionalized derivatives of the (8R)-
1,7-dioxaspiro[5.5]undec-3-ene system of 1.
Lactone 1111 was prepared in three steps from benzyl
propargyl ether (13) and silylated glycidol 14 (Scheme 2).
Opening of epoxide 14 with the acetylide anion derived from
13 under Yamaguchi conditions12 gave 15. Hydrogenation
provided nearly quantitative yields of enones 6 or 7,
respectively, each as an approximate 1:1 mixture of (E,Z)-
isomers.16 TsOH-induced spiroketalization of the (E,Z)-
mixture of 6 generated (8R)-spiroketal 3 in 31% yield,
comparable to the yield obtained for the conversion of 5 to
2 in the total synthesis of 1.3 Similar yields of 3 were
obtained from chromatographically separated samples of
(E)-6 and (Z)-6 upon subjection of each to the ketalization
conditions. However, treatment of the (E,Z)-mixture of 7
under the same conditions remarkably generated (8R)-
spiroketal 4 in higher yield (76%). Because the starting enone
configuration has little impact on the overall efficiency of
the bicyclodehydration, the limited yield of spiroketal 3
obtained via the conjugate addition-spiroketalization se-
quence may largely be attributable to the presence of the
substituent at C7. Spiroketalization may be initiated by a
relatively unencumbered attack of the C4 oxygen upon the
central C8 ketone (path a, Scheme 4), followed by capture
of an oxocarbenium intermediate by an impeded C12 oxygen.
Scheme 2. Synthesis of C3-C8 Lactone
(11) All new compounds gave characterization data that are fully
consistent with the structures assigned.
(12) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(13) Davis, F. A.; Kumar, A. J. Org. Chem. 1992, 57, 3337.
(14) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(15) Chabala, J. C.; Vincent, J. E. Tetrahedron Lett. 1978, 937.
(16) The ratios of (E,Z)-isomers of 6 and 7 were assigned by integration
of the vinylic proton and methyl resonances in the 1H NMR spectra of the
crude conjugate addition products.
452
Org. Lett., Vol. 1, No. 3, 1999

the spirocycle by the C4 oxygen. In either path, attack of
the C12 oxygen upon an sp2-hybridized carbon at C8 is
expected to be sterically hindered by the substituent at C7.17
This study defines improved synthetic access to two key
okadaic acid intermediates, differentially protected lactone
9 and spiroketal 3. Although the yield of the spiroketalization
step to form the bis-silyl ether 3 is comparable to that for
the formation of 2,3 the use of a fluoride-labile protecting
group for the C7 hydroxyl obviates the necessity for an
ultimate reductive deprotection.18 Combined, these findings
will contribute to further syntheses of okadaic acid. More-
over, omission of C7 functionalization altogether facilitates
dramatically the key spiroketalization process, which will
support the generation of analogues of okadaic acid lacking
the C7 hydroxyl group.
Scheme 4. C7 Substituent Effect on Spiroketalization
Acknowledgment. Financial support of this research from
an American Chemical Society Division of Medicinal
Chemistry Graduate Fellowship sponsored by Parke-Davis
and a University of Minnesota Graduate School Fellowship
(A.B.D.) as well as a University of Minnesota McKnight
Land-Grant Professorship, a Zeneca Pharmaceuticals Excel-
lence in Chemistry Award, and the NIH (CA62195) (C.J.F.)
is gratefully acknowledged. We also thank Drs. S.F. Sabes
(Shionogi BioResearch Corp.) and R.A. Urbanek (Astra-
Zeneca) for helpful discussions.
OL9906615
(17) This problem is nicely avoided in the recently reported synthesis
of 1 by Ley et al.4
(18) The primary TBDPS ether of 3 could be cleaved selectively in the
presence of the secondary TBS ether using TBAF to generate the
synthetically viable3 primary alcohol in 61% yield.
Alternatively, a sterically disfavored initial addition of the
C12 oxygen to C8 (path b) would be followed by closure of
Org. Lett., Vol. 1, No. 3, 1999
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