Total synthesis and absolute stereochemistry of plakortone D

Article abstract of DOI:10.1021/ja026728s

The first total synthesis of plakortone D is described and thereby establishes the structure and absolute stereochemistry of the most biologically active member of the marine-derived plakortone family. The sterically congested bicyclic lactone core result

Full text of DOI:10.1021/ja026728s

Published on Web 07/27/2002
Total Synthesis and Absolute Stereochemistry of Plakortone D
Patricia Y. Hayes and William Kitching*
Department of Chemistry, The UniVersity of Queensland, Brisbane 4072, Australia
Received April 30, 2002
Scheme 1
Sponges of the genus Plakortis are prolific in their production
of biologically active secondary metabolites, and peroxides and
lactones are especially favored.1 A particularly interesting group
of such compounds comprises the plakortones A-F2-5 (Figure 1)
from the Caribbean sponges, Plakortis halichondrioides and P.
simplex.
Plakortones A-D2 constitute a new class of activators of cardiac
SR-Ca2+-pumping ATPase, and are relevant to correction of cardiac
relaxation irregularities.2 Plakortone D is the most active in this
respect. Plakortones B-F3 exhibit in vitro cytotoxic activity on a
murine fibrosarcoma cell line, so that overall, the plakortones
represent a new family of drugs of substantial pharmacological
interest. The structures were deduced by NMR methods, and nOe
difference data provided the relative stereochemistry portrayed in
Figure 1; however, that at C10 was undetermined. The absolute
rotation and recognizing that in a simpler lactone series,7c levo-
enantiomers 3 manifest the sense of chirality shown, our initial quest
was for the system 2.
Figure 1.
stereochemistry in the series was unknown. We now report the total
synthesis of plakortone D,6 which not only clarifies uncertain
structural and stereochemical features but also enables acquisition
of other plakortones and analogues, in the correct stereochemical
series.
The constant structural motif in the plakortone series is the 2,6-
dioxabicyclo[3.3.0]octan-3-one moiety, incorporating quaternary
centers at C4 and C6 (numbering as in Figure 1, following the
system of Patil2). We have demonstrated6a that these sterically
congested bicyclic lactones are efficiently accessed by a palladium-
(II)-mediated-hydroxy-cyclization-carbonylation-lactonization cas-
cade,7 so that the key disconnection in our approach to plakortone
D was scission at C7-C8. This provides, along with the lactone 2,
the side chain unit 1 (C8-C14), that requires control at C10 and
eventually an E-double bond (C11-C12).
For the side chain unit 1 (C8-C14), we felt it prudent to acquire
both C10 enantiomers for linkage to 2, although there was an
indication that one was more likely.8
Synthesis of the Bicyclic Lactone 2. Inexpensive 3-butyn-1-ol
was protected and converted to alkene 5, the substrate for
asymmetric dihydroxylation. Reaction with AD mix-â provided diol
6 of >95% ee (Mosher’s ester) and predicted9 6 to be (R)-
configured. This was confirmed by its levo-rotation.10 Deprotection,
oxidation, and addition steps provided sensitive triol 10 as a mixture
of diastereomers. This was subjected to the Pd(II)-mediated lactone-
forming cascade,7c which provided readily separated 11 and the
required 2 (absolute stereochemistry determined by NOESY experi-
ment of the benzyl derivatives of 2 and 11, see Supporting
Information)6a (Scheme 1).
Synthesis of the (C8-C14) Side Chain, 16a,b. γ,δ-Unsaturated
ester 13 resulting from the Johnson variant of the enolate Claisen
rearrangement,11 with AD mix-R, provided in excellent yield (90%)
a mixture of only two lactones, 14a and 14b.12 NOESY spectra
and X-ray crystal structure of the p-nitrobenzoate of 14b established
their relative stereochemistry, and on the basis of the Sharpless
mnemonic and optical rotation data,13 their absolute stereochemistry
is as shown. Reduction of 14b provided a triol, which as the
acetonide 15b was converted to the modified sulfone 16b14 ready
The plakortones A-F are all levorotatory.2,3 Presuming that the
bicyclic lactone moiety is the dominant contributor to the molecular
* To whom correspondence should be addressed. E-mail: Kitching@
chemistry.uq.edu.au.
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J. AM. CHEM. SOC. 2002, 124, 9718-9719
10.1021/ja026728s CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Finally, creation of the C11-C12 E-double bond requires
stereospecific syn removal of the 1,2-diol unit. Reaction of 19b
with triethylorthoformate16 afforded an ortho compound which was
isolated in crude form and then heated at ∼180 °C for 1 h to provide
cleanly the alkene 20b. The 1H and 13C NMR and mass spectra of
20b matched those of authentic plakortone D. The specific rotations
were also in good agreement. Therefore plakortone D has structure
20b.17
This work confirms the structure and absolute stereochemistry
of plakortone D and almost certainly for this entire series of
biosynthetically related lactones. Adaptation of the described route
will provide other plakortones and analogues. This work will be
reported at a later date.
Acknowledgment. We are grateful to the Australian Research
Council for support and to Drs. Patil and Freyer (GlaxoSmithKline)
for kindly providing copies of spectra of authentic plakortone D
and the derived C11,12 diols. We thank Dr. P. Bernhardt for the
X-ray structure of the p-nitrobenzoate of 14b.
Supporting Information Available: Full experimental details for
18a,b, 19a,b, and 20b, spectral data for compounds 2, 6-9, 11, 14a,b,
16a,b, 18a,b, 19a,b, and 20b and copies of the 1H and 13C spectra for
7-9, 14a,b, 18a,b, 19a,b, and 20b, NOESY spectra for the benzyl
derivatives of 2 and 11, and crystal structure (ORTEP figure) of the
p-nitrobenzoate derivative of 14b (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Scheme 3
References
(1) See for example Stierle, D. B.; Faulkner, D. J. J. Org. Chem. 1980, 45,
3396.
(2) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley, J. W.;
Johnson, R. K.; Lahouratate, P. Tetrahedron 1996, 52, 377.
(3) Caffierei, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Rosa, M.; Ianaro,
A. Tetrahedron 1999, 55, 13831.
(4) Caffierei, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro, A. Tetrahedron
1999, 53, 7045.
(5) Gochfeld, D. J.; Hamann, M. T. J. Nat. Prod. 2001, 64(11), 1477.
(6) For reported substructure syntheses, approaches, or comments, see: (a)
Paddon-Jones, G. P.; Hungerford, N. L.; Hayes, P.; Kitching W. Org.
Lett. 1999, 1, 1905. (b) Bittner, C.; Burgo, A.; Murphy, P. J.; Sung, C.
H.; Thornhill, A. J. Tetrahedron Lett. 1999, 40, 3455. (c) Semmelhack,
M. F.; Shaunnugam, P. Tetrahedron Lett. 2000, 41, 3567. (d) Hui, C.
W.; Lee, M. K.; Wong, H. N. C. Tetrahedron Lett. 2002, 43, 123.
(7) (a) Semmelhack, M. F.; Bodurow, C. J. J. Am. Chem. Soc. 1984, 106,
1496. (b) Gracza, T.; Haseno¨hvl, J.; Stahl, V.; Ja¨ger, V. Synthesis 1991,
1108. (c) Paddon-Jones, G. C.; McErlean, C. S. P.; Hayes, P.; Moore, C.
J.; Ko¨nig, W.; Kitching, W. J. Org. Chem. 2001, 66, 7487 and reference
therein.
for coupling. Similar processing of the lactone 14a provided the
epimeric sulfone 16a (Scheme 2).
(8) Degradation of plakortin1,4 and application of NMR methods for deter-
mination of absolute stereochemistry indicated that C8 in this peroxide
metabolite was likely to be (R)-configured. C8 in plakortin has likely nexus
with C10 in plakortone D.
Lactone Side-Chain Coupling. Hydroxymethyl lactone 2 was
oxidized (TPAP/NMO) to aldehyde 17, (Scheme 3) which was
immediately coupled with the anion of the sulfone 16b to afford
the elongated lactone 18b. Acetonide removal and hydrogenation
afforded the key diol 19b. Most conveniently, Patil and co-workers2
had treated (natural) plakortone D with both AD mix-R and AD
mix-â to generate the 11,12-diols, with [R]D of -27.3 and -9.8,
and assigned as the R (R,R)- and â (S,S)-diols, respectively.
However, correct application of the Sharpless mnemonic9 requires
a reversal of these assignments, so that the AD mix-R-derived diol
with [R]D -27.3 is (S,S)-configured. Our diol 19b exhibited [R]D
-26.3, in good agreement.
Sulfone diol 16a, epimeric at C10, was similarly coupled with
the same lactone system 2, to afford diol 19a, [R]D -25.5 (c, 0.27,
CHCl3). The 13C NMR spectrum of the natural plakortone-D-derived
(S,S)-diol (from AD mix R) matched with high precision the data
for our synthesized diol 19b but less well with the data for epimeric
diol 19a.15 Consequently, the C10-ethyl-bearing center in plakortone
D is (R)-configured, consistent with the result for the peroxide,
plakortin.8
(9) Kold, H. C.; VanNievwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(10) The 2-methyl (lower) homologue of 6, of known absolute stereochemistry
(see: Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc,
1995, 117, 10805) has [R]D -7.7 (c, 2.8, CHCl3), compared with [R]D
-9.3 (c, 1.0, CHCl3) for 6.
(11) Our original approach was based on initial kinetic resolution (asymmetric
epoxidation) of the allylic alcohol 12 prior to the Claisen rearrangement.
Paddon-Jones, G. C. Ph.D. Thesis, The University of Queensland, 1998,
160.
(12) See: Wang, Z.-M.; Zhang, X.-L, Sharpless, K. B. Tetrahedron Lett. 1992,
33, 6407.
(13) For 14a and 14b, [R]D + 38.6 and + 20.3, respectively. (S,S)-lactones of
this type are dextrorotatory.12
(14) Blakemore, P. R.; Cole, W. J.; Kocien˜ski, P. J.; Morley, A. Synlett 1998,
26.
(15) As anticipated, the most significant differences in the 13C chemical shifts
occurred in the immediate structural vicinity of C10, as 19a and 19b are
epimeric at this position.
(16) Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1392.
(17) (Lit. [R]D -26.3 (c, 1.27, CHCl3))2. Measured [R]D -24.5 (c, 0.2, CHCl3).
Pr. J. Boukouvalas (Laval University) has presented a synthesis of
plakortone D (see abstract OE9, 38th IUPAC Congress Frontiers in
Chemistry, Word Chemistry Congress 2001, Brisbane).
JA026728S
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J. AM. CHEM. SOC. VOL. 124, NO. 33, 2002 9719