Efficient Palladium(II)-mediated Construction of Functionalized Plakortone Cores

Article abstract of DOI:10.1021/ol991055c

(Matrix Presented) Appropriate enediols experience a one-pot palladium(II)-mediated hydroxycyclization-carbonylation-lactonization sequence to provide side-chain-functionalized 2,6-dioxabicyclo[3.3.0]octan-3-ones, the core structures of the plakortones, a

Full text of DOI:10.1021/ol991055c

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1905-1907
Efficient Palladium(II)-Mediated
Construction of Functionalized
Plakortone Cores
Gregory C. Paddon-Jones, Natasha L. Hungerford, Patricia Hayes, and
William Kitching*
Department of Chemistry, The UniVersity of Queensland,
Brisbane, Queensland, Australia 4072
kitching@chemistry.uq.edu.au
Received September 16, 1999
ABSTRACT
Appropriate enediols experience a one-pot palladium(II)-mediated hydroxycyclization−carbonylation−lactonization sequence to provide side-
chain-functionalized 2,6-dioxabicyclo[3.3.0]octan-3-ones, the core structures of the plakortones, a novel class of activators of cardiac SR-
Ca2+-pumping ATPase, from the sponge Plakortis halichondrioides.
Recently we reported efficient syntheses of the bicyclic
lactones 1 and 2 in both racemic and enantiomeric forms
and confirmed their presence in the lactone-rich Hagen’s
glands of certain species of parasitic wasps.1 Our approach
to 1 and 2 utilized a palladium (II)-catalyzed hydroxy-
cyclization-carbonylation-lactonization sequence in a “one-
pot” conversion of appropriate enediols (Scheme 1a). Previ-
ous stereochemical assignments for 1 and 21,2 have now been
confirmed by directed syntheses of either the cis or trans
lactones from enediols of appropriate relative stereochem-
istry. Kinetic aldol product 3, on reduction with NaBH4 in
benzene, afforded predominantly syn-1,3 diol 4 whereas use
of NaBH(OAc)3 in benzene or HOAc-CH3CN (-40 °C)3
provided mainly anti-diol 5 on the basis of 13C chemical
shifts4 of the acetonide CH3 groups (DEPT spectra). (Ac-
etonide of 4 showed CH3 shifts at δ 19.7 and 30.1 and of 5
at 25.3 and 24.6 ppm.) Diol regeneration and Pd(II) cycliza-
tion cleanly afforded the lactones 1 and 2 (R ) nC6H13) from
syn- and anti-diols respectively, in agreement with earlier
conclusions1,2 (Scheme 1a). The cyclizations now described
proceeded in good yields (≈ 80%, see Supporting Informa-
tion), and when diastereomeric mixtures of enediols were
employed, this was reflected in the ratio of isomeric lactones.
Because this bicyclic lactone system occurs in other natural
systems,5 we now describe further developments of this
sequence6 and in particular apply it for acquisition of systems
capable of side-chain elongation to the plakortones 6a-d
(Scheme 1b), recently isolated from the sponge Plakortis
halichondrioides.7 The plakortones are micromolar activators
of Ca2+ pumping in cardiac muscle sarcoplasmic reticulum
(SR) and are relevant to correction of relaxation abnormali-
ties.
(5) See, for example: Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick,
P. E.; McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655, Fang,
X. P.; Anderson, J. E.; Chang, C. J.; McLaughlin, J. L. J. Nat. Prod. 1991,
54, 1034.
(1) Paddon-Jones, G. C.; Moore, C. J.; Brecknell, D. J.; Ko¨nig, W. A.;
Kitching, W. Tetrahedron Lett. 1997, 38, 3479.
(2) Paddon-Jones, G. C. Ph.D. Thesis, The University of Queensland,
November, 1998.
(6) For a palladium(II)-based route to (-)goniofufurone,2 see: Gracza,
T.; Ja¨ger, V. Synlett 1992, 191.
(3) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(4) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett, 1990, 31, 945.
(7) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley, J. W.;
Johnson, R. K. Tetrahedron 1996, 52, 377.
10.1021/ol991055c CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/18/1999

Scheme 1
Scheme 2
relative stereochemistry was assigned by NMR methods. The
absence of a signal for H6a was notable, with a prominent
ion for (M - C6H13) in the GC-MS, and spectral comparisons
indicated that the introduction of the ethyl group at C-6a
had minimal impact on ring geometries2 (Scheme 3).
Formation of the actual plakortone core with ethyl attach-
ment at both C-6a and C-5 can be envisaged by cyclization
of the protected triol 15, and this delivered the readily
Our approach to the plakortone system7 was based on
proximate (side chain) double bond disconnection for either
plakortone A or B, 6a or 6b. Consequently, efficient access
to the plakortones was dependent on the ability of the
Pd(II)-mediated process to deliver tertiary centers in the
presence of the additional functionality necessary for chain
extension (Scheme 1b). Introduction of the hydroxymethyl
group at C-5 would require the cyclization to proceed with
a 1,2,4-triol arrangement, and use of unprotected triol 7
yielded acetate 8 as the isolated product. For provision of a
suitably protected lactone derivative, benzyl-protected triol
systems 9 and 10 were obtained as shown below (Scheme
2). These were successfully cyclized under the normal
conditions to 11 and finally deprotected to yield desired
hydroxy lactone 12.8
1
separated lactones 16 and 17. Their H NMR spectra were
remarkably similar, and this is reflected in the calculated
geometries and observed and calculated coupling constants.2
NOE-based relative stereochemistry, and comparisons with
the data for plakortone D, indicate that cis-isomer 16
probably corresponds to the plakortone structure.7
An alternative cyclization precursor, 19, was accessible
in principle by double addition of vinylmagnesium bromide
to heptane-3,5-dione (Scheme 3), and ozonolysis of 20 would
then provide the aldehyde for planned Wittig extension.
Despite the potential for side reactions, the simplicity of this
process was attractive, and a two-step procedure via 18 was
developed for the provision of diol 19 which was im-
mediately cyclized. Flash chromatography provided an
isomer of 20, and this procedure is being optimized.
With respect to ethyl group introduction, tert-allylic
alcohol 13 (as a diastereomeric mixture) was transformed
to lactone mixture 14 which was separated (HPLC), and the
(8) Hydroxylactone 12 was efficiently oxidized by Dess-Martin perio-
dinane to the corresponding aldehyde (δCHO 9.6, d, 1.4 Hz), but Swern
conditions, as employed in the acquisition of 21 (Scheme 3), are a better
practical approach for these systems.
1906
Org. Lett., Vol. 1, No. 12, 1999

Scheme 3
With respect to chain extension, aldehyde 21 (δCHO 9.76,
Acknowledgment. The authors are grateful to the Aus-
tralian Research Council for financial support.
br s m/z 183, M+ - CHO) was treated with a slight excess
of stabilized ylide 22 and afforded enoate 23 as an E-Z
(12:1) mixture, suggesting that this general approach would
be applicable to side-chain attachment necessary for acquisi-
tion of the plakortones.9 A full report of this work will appear
at a later date.
Supporting Information Available: Illustrative proce-
dure for Pd(II)-mediated hydroxycyclization-carbonylation-
1
lactonization. Characterization data including H and 13C
NMR data for compounds 8, 11, 12, 14, 16, 17, 20, and 23.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Recently the synthesis of a lactone analogous to 16 but with an
nbutyl side chain in place of the hydroxymethyl group was reported. Bittner,
C.; Burgo, A.; Murphy, P. J.; Sung, C. H.; Thornhill, A. J. Tetrahedron
Lett. 1999, 40, 3455.
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Org. Lett., Vol. 1, No. 12, 1999
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