Synthesis of the sponge-derived plakortone series of bioactive compounds

Article abstract of DOI:10.1021/jo101224w

The Caribbean sponges of the genus Plakortis, P. halichondrioides, and P. simplex have provided a series of biologically active furanolactones the plakortones A-D (1-4) from the former sponge and B-F (2-6) from the latter. The defining motif of the plakortones is a sterically congested 2,6-dioxabicyclo[3. 3.0]octan-3-one moiety, the emblematic furanolactone core. This core is efficiently accessed by a palladium(II) mediated hydroxycyclization- carbonylation-lactonization cascade with an appropriate ene-1,3-diol. Total syntheses of plakortones C (3) and F (6) are now described which settle constitutional and stereochemical features in this group of secondary metabolites. Acquisition of plakortone D (4), the most effective activator of SR-Ca²⁺-pumping ATPase, utilized stereodefined lactone cores that resulted from asymmetric dihydroxylation of protected homoallylic alcohol 29. A derived lactone aldehyde was then coupled with an independently generated, sulfone-activated side chain unit, 57. The 11,12-E-double bond, carried through the sequence as a protected, stereodefined diol, was released therefrom by stereospecific syn-elimination via an orthoester derivative. In this way, plakortone D (4) was demonstrated to possess the (3S,4S,6S,10R,11E) configuration. Racemic plakortone E (5) was also acquired by using the Pd(II) induced sequence, but in this case, the required, complete acyclic system 52 was assembled first. Plakortone C (3) resulted from a sequence commencing with (R)-(+)-3-hydroxy-2-methylpropionate, with a derived iodide 76 alkylating the enolate of the butyramide 77 generated from (1S,2S)-(+)-pseudoephedrine. The liberated primary alcohol 79 was converted by standard procedures to key enediol 89 which, with the Pd(II) protocol, afforded the major separable plakortones 90 and 91, with the former being identical with natural plakortone C (3). Very mild hydrogenation of 90 afforded a saturated plakortone, identical with natural plakortone F (6), thus establishing its structure and absolute stereochemistry. Available information on the stereoselective routes to plakortones E (5) and B (2) are also outlined, so that the constitution and absolute stereochemistry of plakortones B-F are now established.

Full text of DOI:10.1021/jo101224w

pubs.acs.org/joc
Synthesis of the Sponge-Derived Plakortone Series
of Bioactive Compounds
Patricia Y. Hayes, Sharon Chow, Fredrik Rahm, Paul V. Bernhardt,
James J. De Voss, and William Kitching*
School of Chemistry and Molecular Biosciences (SCMB), The University of Queensland,
Brisbane, 4072, Australia
w.kitching@uq.edu.au
Received June 23, 2010
The Caribbean sponges of the genus Plakortis, P. halichondrioides, and P. simplex have provided a
series of biologically active furanolactones the plakortones A-D (1-4) from the former sponge
;
and B-F (2-6) from the latter. The defining motif of the plakortones is a sterically congested 2,6-
dioxabicyclo[3.3.0]octan-3-one moiety, the emblematic furanolactone core. This core is efficiently
accessed by a palladium(II) mediated hydroxycyclization-carbonylation-lactonization cascade
with an appropriate ene-1,3-diol. Total syntheses of plakortones C (3) and F (6) are now described
which settle constitutional and stereochemical features in this group of secondary metabolites.
Acquisition of plakortone D (4), the most effective activator of SR-Ca2þ-pumping ATPase, utilized
stereodefined lactone cores that resulted from asymmetric dihydroxylation of protected homoallylic
alcohol 29. A derived lactone aldehyde was then coupled with an independently generated, sulfone-
activated side chain unit, 57. The 11,12-E-double bond, carried through the sequence as a protected,
stereodefined diol, was released therefrom by stereospecific syn-elimination via an orthoester
derivative. In this way, plakortone D (4) was demonstrated to possess the (3S,4S,6S,10R,11E)
configuration. Racemic plakortone E (5) was also acquired by using the Pd(II) induced sequence, but
in this case, the required, complete acyclic system 52 was assembled first. Plakortone C (3) resulted
from a sequence commencing with (R)-(þ)-3-hydroxy-2-methylpropionate, with a derived iodide 76
alkylating the enolate of the butyramide 77 generated from (1S,2S)-(þ)-pseudoephedrine. The
liberated primary alcohol 79 was converted by standard procedures to key enediol 89 which, with the
Pd(II) protocol, afforded the major separable plakortones 90 and 91, with the former being identical
with natural plakortone C (3). Very mild hydrogenation of 90 afforded a saturated plakortone,
identical with natural plakortone F (6), thus establishing its structure and absolute stereochemistry.
Available information on the stereoselective routes to plakortones E (5) and B (2) are also outlined, so
that the constitution and absolute stereochemistry of plakortones B-F are now established.
Introduction
peroxides and lactones are especially prominent.1 The
Caribbean species P. halichondrioides and P. simplex are
prolific in this regard, and have provided a fascinating series
Sponges of the genus Plakortis are adept in the production
of biologically active secondary metabolites, among which
(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) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Rosa, M.;
Ianaro, A. Tetrahedron 1999, 55, 13831.
*To whom correspondence should be addressed. Fax: þ61 (7) 3365 4299.
Phone: þ61 (7) 3365 3795.
(1) Rahm, F.; Hayes, P. Y.; Kitching, W. Heterocycles 2004, 64, 523.
DOI: 10.1021/jo101224w
r
Published on Web 09/02/2010
J. Org. Chem. 2010, 75, 6489–6501 6489
2010 American Chemical Society

Hayes et al.
JOCArticle
FIGURE 2. Structure and absolute stereochemistry of plakortone
D (4).
constitutional and stereochemical definition for the known
plakortone congeners.
General Approach
Early contributions11-14 focused on construction of the
emblematic structural motif of the plakortones viz. the 2,6-
dioxabicyclo[3.3.0]octan-3-one, a cis-fused tetrahydrofura-
nolactone moiety. We considered an economical and flexible
route might be based on metal ion induced ring closure of a
suitable hydroxy alkene that would deliver the tetrahydro-
furan unit, bearing a pendant primary carbon-metal bond.
Carbonylation, well-known for Pd(II) systems, would pro-
vide the additional carbon at the appropriate oxidation level
and then intramolecular lactonization, with formal expulsion
of (reoxidizable) Pd(0), would consummate the sequence. This
retrosynthesis is shown below in Scheme 1. Early work of
FIGURE 1. Structures of plakortones A-G (1-7) and plakortide
F (8).
Semmelhack15 and later reports by Jager16 with carbohydrate-
€
of furanolactones the plakortones A-F (1-6),2-4 with
based enepolyols indicated that ene-1,3-diols would respond
to these conditions, and some stereochemical aspects of this
transformation were established by Yoshida.17 The practicality
of this “one-pot” conversion of appropriate enediols was
demonstrated by our synthesis of the novel bicyclic lactones
present in the Hagen’s glands of certain parasitic wasps.18
;
A-D (1-4)2 from the former sponge and B-F (2-6)3 from
the latter. Plakortone G (7),5 from the Jamaican sponge
Plakortis sp., is simpler in structure, probably biosynthe-
tically related to the peroxide, plakortide F (8),6 and stereo-
chemically relevant to the plakortones A-F (1-6).
Plakortones A-D (1-4) constitute a new group of acti-
vators of the cardiac SR-Ca2þ-pumping ATPase and are of
interest with respect to correction of cardiac muscle relaxa-
tion irregularities. Plakortone D (4) is the most active in this
connection and overall the plakortones represent a new family
of pharmacological importance. The structures deduced by
Patil and co-workers,2 and subsequently by Fattorusso,3 are
portrayed in Figure 1 with the partial relative stereochemistry
based on NOE difference data. The absolute stereochemistry
was not determined for any of the plakortone congeners.
The pharmacological properties associated with these un-
usual metabolites generated interest in their synthesis and our
acquisition of plakortone D (4)7 confirmed its constitution and
established its absolute stereochemistry (Figure 2).
SCHEME 1. Likely Component Steps of the Pd(II)-Cascade
Importantly, the sterically congested furanolactone moiety of
the plakortones is also efficiently accessed by this Pd(II)-mediated
cascade, and furthermore it was tolerant of the additional
These strategies then guided us to plakortones E (5),8 C
(3), and F (6), and established the absolute stereochemistry
of the latter two. Others have subsequently reported synthe-
ses of plakortones E (5)9 and B (2).10 We now report in full
our syntheses of plakortones D (4),7 C (3), and F (6), which
along with data for plakortones E (5)9 and B (2),10 provide
(11) Bittner, C.; Burgo, A.; Murphy, P. J.; Sung, C. H.; Thornhill, A. J.
Tetrahedron Lett. 1999, 40, 3455.
(12) Semmelhack, M. F.; Shanmugam, P. Tetrahedron Lett. 2000, 41,
3567.
(13) Hui, C. W.; Lee, H. K.; Wong, H. N. C. Tetrahedron Lett. 2001, 43,
123.
(4) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro, A. Tetra-
hedron 1999, 53, 7045.
(5) Gochfeld, D. J.; Hamann, M. T. J. Nat. Prod. 2001, 64, 1477.
(6) Patil, A. D.; Freyer, A. J.; Carte, B.; Johnson, R. K.; Lahouratate, P.
J. Nat. Prod. 1996, 59, 219.
(7) Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718.
(8) Hayes, P. Y.; Kitching, W. Heterocycles 2004, 62, 173.
(9) Akiyama, M.; Isoda, Y.; Nishimoto, M.; Narazaki, M.; Oka, H.;
Kuboki, A.; Ohira, S. Tetrahedron Lett. 2006, 47, 2287.
(10) Semmelhack, M. F.; Hooley, R. J.; Kraml, K. M. Org. Lett. 2006, 8,
5203.
(14) Lee, H. K.; Wong, H. N. C. Chem. Commun. 2002, 2114.
(15) (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106,
1496. (b) Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.;
Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035.
€
€
(16) Gracza, T.; Hasenohrl, T.; Stahl, U.; Jager, V. Synthesis 1991, 1108.
(17) Tamara, Y.; Kobayashi, T.; Kawamura, S.-i.; Ochiai, H.; Hojo, M.;
Yoshida, Z.-i. Tetrahedron Lett. 1985, 26, 3207.
€
(18) (a) Paddon-Jones, G. C.; Moore, C. J.; Brecknell, D. J.; Konig,
W. A.; Kitching, W. Tetrahedron Lett. 1997, 38, 3479. (b) Paddon-Jones,
€
G. C.; McErlean, C. S. P.; Hayes, P.; Moore, C. J.; Konig, W. A.; Kitching,
W. J. Org. Chem. 2001, 66, 7487.
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JOCArticle
SCHEME 2. Synthesis of Functionalized Plakortone Cores
FIGURE 3. The naturally occurring bicyclic lactones 23 and 2418b
and trans-25.
SCHEME 4. Synthesis of Bicyclic Lactones cis-(3R,4R,6R)-36
and trans-(3S,4S,6R)-36a
SCHEME 3. Retrosynthesis of Plakortone D (4)
aReagents and conditions: (a) DEAD, PPh3, 4-methoxyphenol, 60%;
(b) bromo-9-BBN, CH2Cl2, rt, 1 h, 68%; (c) EtMgBr, 3% Fe(acac)3,
THF-NMP, -5 °C, 15 min, 84%; (d) AD mix β, H2O, tBuOH, 0 °C, 24 h,
81%; (e) (S)-Mosher acid, DCC, DMAP, CH2Cl2, Δ, 12 h, 66%,
(f ) Me2C(OMe)2, PTSA then CAN, 54%; (g) TPAP/NMO, 91%;
(h) EtMgBr, THF, -78 °C, 74%; (i) TPAP, NMO, 73%; (j) THF,
-78 °C, CH2dCHMgBr, 95%; (k) Dowex 50, MeOH, 61%; (l) PdCl2,
CuCl2, CO, NaOAc, AcOH; (m) MeOH, K2CO3, 60% (2 steps).
functionality necessary for strategic chain extension as shown
in Scheme 2.12,19 (For convenience, trans and cis refer through-
out to the orientation of the ethyl groups at C4 and C6 on the
tetrahydrofuran ring.)
Results and Discussion: Synthesis of Plakortone Congeners
Plakortone D. Because of its bioactivity, plakortone D (4)2
was targeted initially and its synthesis navigated us to plak-
ortones E (5), C (3), and F (6). The chemistry summarized in
Scheme 2 led to the disconnection that unveils the accessible
lactone II and the side chain moiety I.7 The latter would
require stereocontrol at C10, and incorporate a C11-C12
E-double bond or a precursor to it (Scheme 3).
Bicyclic Lactone Core. The relative stereochemistry
around the lactone core of the plakortones has been
settled,2,3 but not the relationship with side-chain centers,
for example at C10 in plakortone D (4). Regarding the likely
enantiomeric system for synthetic pursuit, some guidance
emerges from our review of the Plakortis metabolites.1 The
plakortones A-F (1-6) are all levo-rotatory and assuming
that the furanolactone moiety predominately regulates the
molecular rotation20 and remembering that in simpler lac-
tone series, levo-enantiomers manifest the sense of chirality
shown below in Figure 3, then our initial quest was for
arrangement trans-25.
Furanolactone II should be delivered by subjecting an
ene-triol, incorporating both an allylic and nonallylic tert-
alcohols, to the Pd(II)-mediated cascade. Asymmetry was to
be installed using dihydroxylation, as developed by Sharp-
less. These procedures are now described.
Inexpensive 3-butyn-1-ol (26), after protection as the PMP
ether 27, was treated with bromo-9-BBN to give the 2-bromo-
21
1-alkene 28, which in the presence of Fe(acac)3 and ethyl
magnesium bromide yielded the protected homoallylic alcohol
29, ready for asymmetric dihydroxylation. Reaction with
AD-mix β provided protected triol 30 of >95% ee, by exami-
nation of its Mosher ester 31, and predicted to be R-configured
by the Sharpless mnemonic (Scheme 4).22 This was confirmed
by its levo rotation, as the 2-methyl (lower) homologue, of
known absolute configuration, is also levo-rotatory.23 Pro-
tected triol 30 was then processed to afford sensitive triol 35
(21) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
(22) Kolb, H. C.; VanNievwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(23) Corey, E. J.; Angel Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805.
(19) Paddon-Jones, G. C.; Hungerford, N. L.; Hayes, P.; Kitching, W.
Org. Lett. 1999, 1, 1905.
(20) Capon, R. J.; Macleod, J. K. Tetrahedron 1985, 41, 3391.
J. Org. Chem. Vol. 75, No. 19, 2010 6491

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SCHEME 5. Degradative Study of Methyl Ester 37 from
P. halichondroides
SCHEME 6. Synthesis of Sulfones 46 and 47a
as a mixture of diastereomers, which were subjected to
the Pd(II)-lactone forming cascade. Two readily separated
furanolactones 36 were formed in good yield (overall 78%) in
the ratio 63:37, and NOESY spectra7 with the benzyl deriv-
atives confirmed that the major lactone possessed the de-
sired trans-configuration with the absolute stereochemistry
portrayed in Scheme 4. With this lactone available, attention
then turned to construction of the side chain, and its linkage
to this core.
The C8-C14 Side Chain24 and Considerations of C10 Chir-
ality. With respect to the likely configuration at C10 in
plakortone D (4), there was information based on degra-
dative studies with natural methyl ester 37 and synthetic deri-
vative 38 that ethyl bearing C8 was likely to be R-configured25
(Scheme 5).
aReagents and conditions: (a) EtMgBr, Et2O, 0 °C, 88%; (b) CH3C-
(OEt)3, Hþ, Δ, 68%; (c) AD-mix R, CH3SO2NH2, tBuOH, H2O, 0 °C, 48
h, 90%; (d) LiAlH4, Et2O; (e) Me2C(OMe)2, PTSA; (f) 1-phenyl-1H-
tetrazole-5-thiol, DEAD, PPh3; (g) (NH4)6Mo7O24 4H2O, H2O2.
3
On the basis that C8 in these compounds has a likely
biosynthetic nexus with C10 in plakortone D (4), the 10R
configuration would be likewise favored, although we con-
veniently acquired both C10 enantiomers of I (see Scheme 3)
for linkage to the lactone core.
The γ,δ-unsaturated ester 41 (obtained from enol 40 by the
Johnson variant of the enolate Claisen rearrangement) on
treatment with AD-mix R provided a separable mixture of
two lactones, 42 and 43. NOESY spectra and the X-ray
crystal structure of the p-nitrobenzoate of 42, when consid-
ered with the mnemonic for predicting the sense of induction
in these reactions, led to the absolute stereochemistry shown
in Scheme 6.
SCHEME 7. Synthesis of Diols 50 and 51 and Plakortone D (4)a
In confirmation of these conclusions, (S,S)-hydroxylactones
of this type are dextrorotatory and 42 and 43 have [R]D
of þ38.6 and þ20.3, respectively.26 The separated lac-
tones were then reduced (LiAlH4) to the 1,4,5-triols, with
the 4,5-diol subunit then protected as the acetonide, to afford
44 and 45, epimeric at the center destined to become C10 in
plakortone D (4). The modified sulfones 46 and 47, gener-
ated from the sulfides (with 1-phenyl-1H-tetrazole-5-thiol)
by oxidation with peroxide and molybdate,27 were selected
as carbanionic precursors for coupling with the furanol-
actone aldehyde (3S,4S,6R)-48.
aReagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -40 °C,
60%; (b) KHMDS/THF, -78 °C, 46, 54%; (c) MeOH, PTSA, 82%;
(d) H2, PdC, hexane, 83%; (e) HC(OEt)3, Δ, 60%.
Lactone-Side Chain Coupling. The hydroxymethyl trans-
lactone (3S,4S,6R)-36 was oxidized (Swern) to the aldehyde
48, which was immediately coupled with the anion of sulfone
46, generated with KHMDS in THF. After workup, flash
chromatography afforded pure lactone 49. Acetonide removal
liberated the (C7-C8)-unsaturated 11,12-diol and mild
hydrogenation furnished key diol 50 with [R]D -26.3. Sul-
fone 47, the epimer of 46, was likewise coupled with the same
aldehyde (3S,4S,6R)-48, to provide diol 51, with [R]D -25.5
(Scheme 7).
Diols of this constitution, presciently from our point of
view, were prepared by Patil and co-workers2 from their
natural plakortone D (4) with both AD-mix R and AD-mix
β, in the hope that increased polarity in the side-chain would
enhance activity and hydrophilicity. Regrettably, the diols,
unlike plakortone D (4) itself, showed no effect on SR-Ca2þ
uptake. However, these conversions of natural plakortone D
(24) The racemic C8-C14 side chain was constructed from ester 41,
converted to its phosphorane, and coupled with the aldehyde acquired from
trans-(3S,4S,6R)-36 to yield 7,8-dehydroplakortone D. Attempts at regio-
selective reduction of the 7,8-double bond were not successful. This informa-
tion is presented in the Supporting Information.
(25) Schmidt, E. W.; Faulkner, D. J. Tetrahedron Lett. 1996, 37, 6681.
(26) Wang, Z.-M.; Zhang, X.-L; Sharpless, K. B.; Sinha, S. C.; Sinha-
Bagchi, A.; Ehud Keinan, E. Tetrahedron Lett. 1992, 33, 6407.
~
(27) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
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TABLE 1. NMR Data (CDCl3) for Synthesized 50 and 51 and Diol Derived from Natural Plakortone D (4)
(S,S) diol derived from natural 42
50 ([R]D -26.3)
H [J in Hz]
51 ([R]D -25.5)
H [J in Hz]
position
δ
H [J in Hz]
δC
δ
δC
δ
δC
1
2
175.6
37.4
175.4
37.4
175.5
37.5
2.71, dd, 4.5, 18.3
2.64, dd, 1.0, 18.3
4.34, dd, 1.1, 4.5
2.69, dd, 4.7, 18.3
2.63, brd, 18.3
4.33, dd, 0.7, 4.6
2.69, dd, 4.6, 18.3
2.63, dd, 0.8, 18.3
4.33, dd, 1.1, 4.5
3
4
5
80.6
97.8
45.2
80.6
97.7
45.2
80.6
97.7
45.1
2.29, d, 14.4
1.89, d, 14.4
2.28, d, 14.4
1.87, d, 14.4
2.27, d, 14.4
1.87, d, 14.4
6
7
87.4
38.9
87.4
38.8
87.4
38.9
1.48, m
1.47, m
1.28, m
1.35, m
1.51, m
1.41, m
1.40, m
8
9
1.42, ma
21.4
30.2
21.4
30.2
23.0
28.9
1.28, ma
1.42, ma
1.43, m
1.28, m
1.39, m
3.37, t, 4.5
3.53, dt, 4.9, 8.1
1.55, m
1.28, ma
1.40, m
10
11
12
13
41.3
75.3
73.4
26.8
1.41, m
41.2
75.3
73.4
26.8
41.4
75.0
73.3
26.8
3.37, dd, 4.2, 5.2
3.54, dt, 4.2, 6.8
1.56, m
3.37, dd, 4.2, 4.6
3.54, dt, 4.6, 8.1
1.55, m
1.42, m
0.98, t, 7.4
1.56, m
0.85, t, 7.4
1.74, m
1.42, m
0.97, t, 7.4
1.57, m
0.83, t, 7.4
1.74, m
1.02, t, 7.4
1.47, m
1.32, m
1.44, m
0.97, t, 7.4
1.57, m
0.83, t, 7.4
1.73, m
14
15
16
17
18
19
9.9
31.3
8.5
30.4
8.6
9.9
31.2
8.5
30.4
8.6
9.9
31.3
8.5
30.4
8.6
1.01, t, 7.4
1.42, m
1.00, t, 7.4
1.27, m
21.1
21.1
21.6
20
0.90, t, 7.4
11.6
0.89, t, 7.4
11.6
0.88, t, 7.4
11.3
aIncorrectly assigned chemical shifts.
TABLE 2. NMR Data (CDCl3) for Synthesized and Natural Plakortone
D (4)
(4) to diols, with [R]D -27.3 from AD-mix R and [R]D -9.8
from AD-mix β, and assigned as the R (R,R) and β (S,S)
stereoisomers, respectively,2 assist stereochemical assign-
ments in our synthetic systems. However, correct application
of the Sharpless mnemonic22 requires Patil’s assignments to
be reversed, so that the AD-mix R-derived diol with [R]D
-27.3 is (S,S). Our diol 50, necessarily constrained to be
(S,S) configured by the manner of its construction, exhibited
natural plakortone D (4)2
synthetic plakortone D (4)
position
δ
H [J in Hz]
δC
δH [J in Hz]
δC
1
2
175.5
175.6
37.4
2.70, dd, 4.4, 18.3
2.63, dd, 1.3, 18.3
4.33, dd, 1.3, 4.4
37.4 2.68, dd, 4.4, 18.3
2.62, dd, 1.3, 18.3
80.5 4.32, dd, 1.3, 4.4
97.8
3
4
5
80.6
97.8
45.0
[R]D -26.3, in good agreement. As shown in Table 1, the 13
C
2.26, d, 14.4
1.89, d, 14.4
45.0 2.24, d, 14.4
1.87, d, 14.4
87.5
NMR data for our synthesized diol 50 matched with high
precision that for the (S,S)-diol (using AD-mix R) from
natural plakortone D (4), but clearly less well for epimeric
(at C10) diol 51, e.g. C8, C9, C19, and C20. Therefore, the C10
ethyl bearing center in plakortone D (4) is R-configured, as con-
sidered likely25 from the data for the natural methyl ester 37.
Manipulation of diol 50 by stereospecific syn removal of
the 1,2-diol unit and creation thereby of the E-double bond
would yield plakortone D (4). An attractive procedure for
such a manouevre was reported by Crank and Eastwood in
their early pyrolytic studies.28 In the prescribed manner,28
diol 50 was reacted with triethyl orthoformate at 150 °C for
3 h, with removal of ethanol, and the resulting crude ortho
compound was heated at 180 °C for 1 h. (Elimination to pro-
vide the desired alkene occurred under GC-MS conditions.)
The pure alkene (60%) was obtained after flash chromato-
6
7
87.5
38.4
1.53, m
1.35, m
1.21, m
1.16, m
1.32, m
1.18, m
1.76, m
38.4 1.51, m
1.35, m
8
9
21.5 1.17-1.24, m
21.5
35.4
44.3
35.4 1.30, m
1.17, m
44.3 1.76, m
10
11
12
13
14
15
16
17
18
19
5.07, ddt,1.5, 8.9,15.3 133.2 5.05, ddt, 1.5, 8.9, 15.3 133.2
5.38, dt, 6.4, 15.3
2.00, m
132.3 5.39, dt, 6.3, 15.3
25.6 1.99, m
14.2 0.95, t, 7.4
31.4 1.55, m
8.4 0.83, t, 7.4
30.3 1.73, m
8.6 1.00, t, 7.4
28.3 1.34, m
1.17, m
132.3
25.7
14.3
31.5
8.4
0.97, t, 7.4
1.55, m
0.84, t, 7.4
1.74, m
30.4
8.6
1.02, t, 7.4
1.35, m
1.18, m
28.3
1
graphy and the H and 13C NMR (see Table 2) and mass
spectra matched those for authentic plakortone D (4).29,30
The specific rotation, [R]D -24.5, for synthetic material was
20
0.82, t, 7.4
11.7 0.80, t, 7.4
11.7
also in good agreement with that of isolated 4 ([R]D -26.3).2
Consequently, plakortone D (4) has the structure and abso-
lute stereochemistry portrayed in Figure 2 and its acquisition
demonstrated (1) the likely utility of the Pd(II)-induced cascade
in the synthesis of other plakortones and (2) stereochemical
(28) Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1392.
(29) Copies of spectra of plakortone D and the derived C11,12 diols were
kindly provided by Drs. Patil and Freyer of Glaxo-Smith-Kline.
(30) 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).
J. Org. Chem. Vol. 75, No. 19, 2010 6493

Hayes et al.
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TABLE 3. 1H NMR Spectral Data (CDCl3) of Natural Plakortone E (5) and Synthetic Diastereomers 53-56
53
53 or 55 (I)
53 or 55 (II)
54 or 56 (III)
54 or 56 (IV)
2
2.70, dd, 18.0, 4.8
2.63, bd, 18.0
4.31, bd, 4.8
2.18, d, 14.6
1.97, d, 14.6
1.62, m
1.45, dd, 13.2, 9.0
1.92, m
5.09, dd, 15.3, 9.0
5.38, dt, 15.3, 6.2
2.00, m
0.97, t, 7.6
1.63, m
1.57, m
0.85, t, 7.6
1.76, dq, 15.3, 6.9
1.70, dq, 15.3, 6.9
1.00, t, 6.9
1.40, dq, 13.9, 6.9
1.21, dq, 13.9, 6.9
0.82, t, 6.9
2.67, dd, 18.0, 4.8
2.60, bd, 18.0
4.33, dd, 4.7, 0.6
2.21, d, 14.5
2.04, d, 14.5
1.58, m
1.57, dd, 14.3, 9.0
1.91, m
5.13, ddt, 15.3, 9.0, 1.4
5.35, dt, 15.3, 6.3
1.98, dqd, 7.5, 7.5, 1.5
0.94, t, 7.4
1.59, m
1.54, m
0.82, t, 7.4
1.73, dq, 14.2, 7.4
1.67, dq, 14.2,7.4
0.98, t, 7.4
1.35, m
1.24, m
0.80, t, 7.4
2.66, dd, 18.2, 5.0
2.61, bd, 18.2
4.30, dd, 5.0,0.8
2.15, d, 14.5
1.95, d, 14.5
1.59, m
1.43, dd, 14.2, 9.2
1.89, m
5.07, ddt, 15.3, 9.3, 1.5
5.38, dt, 15.3, 7.0
2.00, dqd, 7.3, 7.3, 1.0
0.94, t, 7.5
2.67, dd, 18.2, 4.6
2.62, dd, 18.2, 1.0
4.27, dd, 4.6,1.2
2.37, d, 14.3
2.67, dd, 18.3, 4.7
2.61, bd, 18.3, 0.5
4.23, dd, 4.7, 0.95
2.27, d, 14.5
3
5
1.85, d, 14.3
1.79, d, 14.5
7
1.61, dd, 14.3, 7.9
1.48, m
1.86, m
5.10, ddt, 15.3, 9.0, 1.5
5.35, dt, 15.3, 6.3
1.98, dqd, 7.5, 7.5, 1.4
0.94, t, 7.5
1.55, dd, 14.3, 7.2
1.62, m
1.85, m
5.07, ddt, 15.3, 9.3, 1.4
5.33, dt, 15.3, 6.3
2.00, m
8
9
10
11
12
13
0.94, t, 7.5
1.41-1.55, m
1.50-1.64, m
1.46-1.54, m
14
15
0.82, t, 7.5
1.65-1.77, m
0.82, t, 7.5
0.83, t, 7.4
1.63-1.76, m
1.74, dq, 14.3, 7.2
1.70, dq, 14.3, 7.4
0.99, t, 7.5
1.36, m
1.17, m
0.78, t, 7.5
16
17
0.98, t, 7.5
1.38, m
1.21, m
0.97, t, 7.4
1.34, m
1.19, m
18
0.80, t, 7.5
0.79, t, 7.4
TABLE 4. 13C NMR spectral data (CDCl3) of NaturalPlakortone E (5)
and Synthetic Diastereomers 53-56
53
53 or 55 (I) 53 or 55 (II) 54 or 56 (III) 54 or 56 (IV)
1
2
3
4
5
6
7
8
9
175.5
37.5
80.2
98.0
46.2
88.2
43.6
40.7
133.1
175.6
37.6
80.8
97.9
44.6
87.7
43.4
40.5
134.3
131.7
25.5
13.9
32.8
8.5
175.6
37.5
80.0
97.9
46.0
87.7
43.5
40.8
133.8
131.8
25.5
13.9
31.7
8.3
175.5
37.3
79.9
97.9
45.4
87.5
43.0
40.6
134.2
131.6
25.5
13.9
31.4
8.1
175.6
37.4
79.5
98.1
47.2
87.3
43.7
41.1
134.0
131.8
25.5
13.9
30.5
7.9
FIGURE 4. Structure of plakortone E (5).
10 132.0
11 25.5
12 13.9
13 31.7
14 8.4
15 30.5
16 8.5
30.2
8.6
30.4
8.6
30.5
8.5
30.4
8.5
17 29.6
18 11.7
30.0
11.6
29.7
11.6
29.9
11.6
29.7
11.6
The required diene-diol 52 was acquired as a stereoisomeric
mixture,8 and the key cyclization-carbonylation steps pro-
ceeded satisfactorily with this sensitive enediol to afford HPLC-
separable diastereomers 53-56 (Figure 5), all as racemates.
Detailed NMR studies (NOESY spectra) permitted the four
isomers to be grouped8 into two sets of two, on the basis of the
trans or cis relationship of ethyl groups at C4 and C6. These
subsets, with defining NOE’s, are shown below, with the
relative stereochemistry at C8 again not established.
FIGURE 5. Selective NOE correlations for the diastereomers
53-56 of plakortone E (5).
guidance for them, assuming a similar biosynthetic pedigree.
We were therefore encouraged to extend synthetic work to
other members of the family.
Plakortone E. Plakortone E (5) (Figure 4) is a lower bis-
homologue of plakortone D (4) and among the series B-F
(2-6), which are all cytotoxic,3 this plakortone is the most
active. The relative stereochemistry about the bicyclic core
was based on a 2D ROESY spectrum, but was not related to
the C8 configuration. The determination for plakortone D (4),
however, would suggest C8 to be R-configured.
The sequence employed for acquisition of the four racemic
diastereomers of plakortone E (5)8 again utilizes the Pd(II)-
based cascade but unlike the approach to plakortone D (4), the
complete acyclic carbon skeleton was assembled first and then
subjected to the Pd(II) conditions. This was partly because we
believed stereodefined acyclic precursors of this type could be
acquired and thence deliver enantiomers of plakortone E (5).
1
A full listing of the H and 13C NMR spectral data is
shown in Tables 3 and 4. Careful comparisons of these data
confirm that the second eluting isomer (II) under our HPLC
conditions is spectroscopically identical with the natural
compound, which therefore is one of the two trans-systems,
53 or 55. The most noticeable difference in NMR shifts
between 53 and 55 concerned C5 and H7 (Table 3 and 4). The
reported3 shift for C8 (45 ppm) in natural plakortone E (5)
has been corrected to δ 40.7, on the basis of the HSQC spec-
trum kindly provided by Professor Fattorusso.
The demonstrated configuration of plakortone D (4)
indicates that an enantioselective synthesis of plakortone E
(5) would result from the transformation in Scheme 8, which
6494 J. Org. Chem. Vol. 75, No. 19, 2010

Hayes et al.
JOCArticle
SCHEME 8. Retrosynthetic Analysis of Plakortone E (5)
and 59). The derived Barton ester 67 (from sodium N-hydroxy-
thiopyridone) on photolysis in the presence of iodoform
provided the required iodide R-58. Iodide-lithium exchange
with tert-butyllithium in ether-pentane provided primary
lithium species 68, which on addition to protected ketodiol
59, afforded the protected, oily triol 69 as a 1:1.4 mixture of
diastereomers, in reasonable yield (59%). Deprotection relea-
sed the triol 70, which was converted to mesylate 71 and then
to the primary bromide 72.
β-Elimination from either 71 or 72 would provide epi-57, a
system already demonstrated8 in the racemic series to re-
spond well to the Pd(II)-promoted cascade to afford the
plakortone E (5) system.
Although we were not unmindful that the tert-center, γ to
the bromo or mesyloxy leaving group, would be retardative
to basic β-elimination, it was surprising that not one of a
variety of procedures for basic elimination (also via the
selenoxide) provided any significant alkene formation. Start-
ing material was generally recovered. Interestingly, an ana-
logous elimination proceeded (with t-BuOK in refluxing
t-BuOH) in a β,γ,γ-trisubstituted primary iodide to yield
the terpenoid (þ)-amiteol.31
would deliver two separable stereoisomers, configuration-
ally defined at the C8 position, and with NMR assessable
ring stereochemistry. One by our reckoning would be natural
plakortone E (5).
For reasons of convenience, we sought to acquire an epimer of
57 by utilizing the available R-58 rather than S-58 shown in
Scheme 8. The protected ketodiol 59 was acquired from 30 (see
Scheme 4) as shown in Scheme 9, with asymmetry introduced by
asymmetric dihydroxylation of a p-methoxyphenyl ether.
Primary iodide R-58 was accessed with configuration
control at the ethyl-bearing center, by a sequence originating
with (E)-hept-4-en-3-ol (40). Asymmetric epoxidation based
kinetic resolution of the racemic enol furnished S-64, which
was then chain extended with the Johnson-Claisen rearrange-
ment to carboxylic acid 66 (notice there is 1,3-chirality trans-
fer in the 64 to 65 conversion, and a descriptor change at the
ethyl-bearing center accompanying coupling of fragments 58
An altered approach with earlier introduction of the
terminal double bond was required but coincidentally Ohira
reported9 a conceptually very different synthesis of plakor-
tone E (5) and after comparison with our spectral data of 53
and 55, settled its absolute stereochemistry as (3S,4S,6S,8R)
(shown in Scheme 9) as suggested by us.8 With the absolute
configuration of 5 settled, we turned to the more complex
congeners, plakortones C (3) and F (6).
Plakortone C. Plakortone C (3) resembles plakortone
D (4) but incorporates methyl substitution at C8, presumably
SCHEME 9. Synthesis of Bromide 72a
aReagents and conditions: (a) MsCl, Et3N, CH2Cl2; (b) K2CO3, MeOH, H2O (91% over 2 steps); (c) 2-ethyl-1,3-dithiane, nBuLi, Et2O, 0 °C, 5 h, 92%;
(d) TBDMSOTf, Et3N, CH2Cl2; (e) Storke’s reagent [(CF3CO2)2IPh], CaCO3, MeOH:H2O 9:1, 86% over 2 steps; (f) (-)-DIPT, TBHP, Ti(iOPr)4,
CH2Cl2, 61%; (g) CH3C(OEt)3, propionic acid, Δ; (h) NaOH, MeOH, H2O, 59% over 2 steps; (i) (COCl)2, CH2Cl2, sodium 2-thioxopyridin-1(2H)-
olate, 98%; (j) CHI3, hν, CCl4, 86%; (k) nBuLi, -78 °C, pentane:Et2O 3:2; (l) Et2O, 59, 59%; (m) CAN, MeOH, 71%; (n) MsCl, Et3N, 0 °C, CH2Cl2;
(o) LiBr, THF, Δ, 64% over 2 steps.
J. Org. Chem. Vol. 75, No. 19, 2010 6495

Hayes et al.
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SCHEME 10. Synthesis of Plakortone C (90) and epi-Plakortone C (91)a
aReagents and conditions: (a) TBDPSCl, imidazole, DMF, 0 °C to rt, 5 h; (b) DIBAL, toluene, -78 °C to rt, 2 h (89% two steps); (c) PPh3, imidazole,
I2, CH2Cl2, 0 °C to rt, 2 h (88%); (d) LDA, LiCl, THF, 0 °C to rt, 24 h (85%); (e) LiH2NBH3, THF, 0 °C to rt, 8 h (97%, de >95%); (f) (COCl)2, CH2Cl2,
DMSO, -78 °C; Et3N, -78 °C to rt (75%); (g) C2H5CH2SO2Ph, n-BuLi, THF, -78 °C; (h) Ac2O, Et3N, DMAP; (i) Mg, HgCl2, EtOH, rt, 42% three
steps, E:Z 11:1; (j) TBAF, THF, rt, 92%; (k) I2, PPh3, imidazole, toluene, rt, 100%; (l) NaCN, DMF, rt, 79%; (m) DIBAL, Et2O, -78 to 0 °C,
(n) EtMgBr, THF, -78 °C, 73%; (o) (COCl)2, CH2Cl2, DMSO, Et3N, -40 °C, 70%; (p) LDA, THF, -78 °C, CH3 C(NNMe2)CH2CH3; (q) CuCl2,
THF-H2O, 41% over 2 steps; (r) Et2O, -78 °C, CeCl3, CH2dCHMgBr, 90%; (s) 10% PdCl2, CuCl2, NaOAc, 1 atm CO, AcOH, rt, 24 h, 33%.
biosynthetic similarities,1 we considered the likely stereochemis-
try in the side chain of plakortone C (3) to be (8S,10R).
The synthetic strategy was to generate this chirality as part
of a diene-diol that on experiencing the Pd(II)-induced
cascade, would deliver isomers of plakortone C (3) of
determinable stereochemistry for comparison with the nat-
ural compound.
The key elements of the synthesis are summarized in
Scheme 10. (R)-(þ)-3-Hydroxy-2-methylpropionate (75)
was protected, reduced, and then converted to primary
iodide 76, which alkylated the lithium enolate of the butyr-
amide 77 generated from (1S,2S)-(þ)-pseudoephedrine, to
afford the dialkyl-substituted amide 78. Reduction liberated
FIGURE 6. Structures of plakortones C (3), D (4), and related
the (2R,4S) primary alcohol 79, the aldehyde 80 from which,
with the anion of phenyl propyl sulfone, followed by alcohol
deprotection, provided primary alcohol 82. Derived iodide,
(5R,7S,E)-83, was chain extended to the nitrile 84, the
aldehyde 85 from which, on reaction with ethylmagnesium
bromide yielded the secondary alcohol 86 as a 60/40 diastereo-
meric mixture. Swern oxidation provided ketone 87, which
with the (kinetic) lithium anion of 2-butanone N,N-dimethyl-
hydrazone provided a moderate yield of the ketone (7S,9R,E)-
88. This ketone, with CeCl3-vinylmagnesium bromide
afforded, in apparently good yield, ostensibly the diene-diol
89, which was immediately subjected to the Pd(II)-promoted
sequence with CO. The resulting furanolactones, 90-93
(GC-MS) on flash chromatography, provided two fractions:
a mixture (50 mg) of the major isomers 90 and 91 and a
mixture (15 mg) of the four possible isomers, 90-93. Part of
the former mixture was subjected to HPLC separation and
provided pure samples of the two major lactones. These two
lactones were characterized by NMR methods and both had
a trans-arrangement of ethyl groups about the cis-fused bicyclic
cyclic peroxides 73 and 74.
reflecting propionate incorporation, rather than acetate, during
its biosynthesis. In planning our approach, we examined the
report of Yao and Steliou,32 which described synthetic studies
of a cyclic peroxide 73 (Figure 6) isolated from the Caribbean
sponge Plakortis angulospiculatus (Family Plakinidae), and co-
occurring with an 11,12-dihydro relative 74.33 These authors,
on the basis of partial asymmetric synthesis, diastereomer
separation following syn-enforced singlet oxygen addition to
the appropriately functionalized diene, and NMR comparisons
with the natural compound, concluded that the natural per-
oxide possessed (3S,6R,8S,10R) stereochemistry, as shown in
Figure 6. (This stereochemistry would reasonably apply to
dihydro-relative 74 as well.) With this intelligence, and assumed
(31) Kesselmans, R. P. W.; Wijnberg, J. B. P. A.; Minnaard, A. J.;
Walinga, R. E.; De Groot, A. J. Org. Chem. 1991, 56, 7237.
(32) Yao, G.; Steliou, K. Org. Lett. 2002, 4, 485.
(33) Gunasekera, S. P.; Gunasekera, M.; Gunawardana, G. P.;
McCarthy, P.; Burres, N. J. Nat. Prod. 1990, 53, 669.
6496 J. Org. Chem. Vol. 75, No. 19, 2010

Hayes et al.
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FIGURE 7. Selected NOE correlations for synthetic plakortone C (90) and epi-plakortone C (91) and corresponding 3D structures (Chemdraw).
TABLE 5. 1H and 13C NMR Data (CDCl3) of Plakortone C (3) and Synthetic Diastereomers 90 and 91
natural plakortone C (3)2
synthetic plakortone C (90)
epi-plakortone C (91)
δ
H [J in Hz]
δC
δH [J in Hz]
δC
δ
H [J in Hz]
δC
1
2
175.5
37.4
175.6
37.5
175.6
37.6
2.69, dd, 18.2, 4.8
2.61, dd, 18.2, 1.0
4.34, dd, 4.8, 1.0
2.67, dd, 18.3, 4.7
2.61, brd, 18.2
4.32, brd, 4.7
2.68, brd, 18.0
2.61, brd, 18.0
4.31, dd, 4.8, 0.7
3
4
5
80.2
97.6
45.9
80.3
97.7
46.0
80.4
97.8
45.9
2.28, d, 14.5
1.83, d, 14.5
2.28, d, 14.4
1.83, d, 14.4
2.27, d, 14.5
1.86, d, 14.5
6
7
88.0
45.9
88.1
46.0
88.1
46.2
1.38, d, 5.7
1.36, d, 5.7
1.45, dd, 15.0, 5.0
1.31, dd, 15.0, 6.3
1.55, m
1.30, m
1.06, m
1.82, m
5.00, ddt, 15.1, 9.0, 1.4
5.38, dt, 15.1, 6.2
1.98, m
0.94, t, 7.5
1.56, m
0.82, t, 7.4
1.71, m
0.99, t, 7.4
1.28 m
1.16, m
8
9
1.57, m
1.20, m
1.10, m
1.85, m
4.99, ddt, 15.3, 9.0, 1.5
5.39, dt, 15.3, 6.4
1.99, m
0.95, t, 7.4
1.60, m
0.82, t, 7.4
1.74, m
1.00, t, 7.4
1.30, m
1.17, m
26.3
44.7
1.55, m
1.16, m
1.09, m
1.82, m
4.98, ddt, 15.3, 9.1, 1.4
5.38, dt, 15.3, 6.3
1.99, m
0.95, t, 7.5
1.58, m
0.81, t, 7.4
1.72, m
0.99, t, 7.4
1.28, m
1.16, m
26.4
44.7
26.4
44.0
10
11
12
13
14
15
16
17
18
19
42.1
133.2
132.5
25.6
14.1
31.6
8.6
30.3
8.5
28.9
42.1
133.2
132.4
25.6
14.2
31.6
8.7
30.4
8.6
29.0
42.3
133.2
132.3
25.6
14.2
32.0
8.6
30.3
8.6
29.0
20
21
0.81, t, 7.4
0.89, t, 6.5
11.7
20.7
0.80, t, 7.4
0.88, t, 6.5
11.7
20.8
0.80, t, 7.4
0.85, t, 6.3
11.8
21.0
system, and were therefore 90 and 91 (see Figure 7 for the
important NOE’s). The former has [R]D -29.3 and the latter
[R]D þ11.5, which are consistent with our determinations for
plakortone D (4) allowing identification of 90 and 91.
Plakortone C (3) has a reported2 [R]D -24.9. A full listing of
the NMR assignments for natural plakortone C (3) and our syn-
thesized products is located in Table 5. It is seen that the data for
synthesized 90 with (3S,4S,6S,8S,10R)-stereochemistry match
those for natural plakortone C (3), thereby establishing its
absolute stereochemistry. epi-Plakortone C (91) differs from
90 in the chemical shift, and appearance of one H7, one H9,
and C9. A long-range NOE effect between H3 and the C8
methyl group was much more pronounced in 90 than in 91,
consistent with the calculated preferred geometries for these
stereoisomers, as shown in Figure 7.
Spectroscopic data supported its formulation as the 11,12-
dihydro derivative of plakortone C (3) and confirmed the
same relative stereochemistry about the lactone core. The
reported optical rotations for plakortones C (3) and F (6) are
[R]D -24.9 and [R]D -11, respectively, suggesting likely coinci-
dence of absolute stereochemistry (Figure 8).
Plakortone F. Fattorusso and his group3 isolated plakor-
tone F (6) from the Caribbean sponge Plakortis simplex.
FIGURE 8. Structures of plakortones C (3) and F (6).
J. Org. Chem. Vol. 75, No. 19, 2010 6497

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TABLE 6. NMR Spectral Data (CDCl3) of Natural Plakortone F (6) and Synthetic Plakortone F (94) and epi-Plakortone F (95)
natural plakortone F (6)3
synthetic plakortone F (94)
epi-plakortone F (95)
position
δH [J in Hz]
δC
δ
H [J in Hz]
δC
δH [J in Hz]
δC
1
2
176.0
37.2
175.6
37.3
175.6
37.5
2.71, dd, 18.3, 5.1
2.64, dd, 18.3, 0.8
4.35, bd, 5.1
2.68, dd, 18.3, 4.5
2.62, brd, 18.3
4.33, dd, 5.1, 0.8
2.68, dd, 18.3, 5.1
2.62, brd, 18.3
4.32, dd, 5.1, 0.8
3
4
5
80.5
97.9
46.2
80.1
97.6
46.4
80.3
97.8
46.0
2.32, d, 14.7
1.83, d, 14.7
2.30, d, 14.6
1.82, d, 14.6
2.29, d, 14.7
1.88, d, 14.7
6
7
88.0
45.3
88.0
45.4
88.0
46.0
1.41, dd, 14.0, 8.0a
1.34, dd, 14.0, 3.7a
1.60, m
1.12, m
1.06, m
1.39, dd, 14.3, 3.2
1.33, dd, 14.3, 7.5
1.56, m
1.52, dd, 14.1, 4.1
1.27, dd, 14.1, 7.0
1.56, m
1.02, m
1.20, m
8
9
31.0b
43.1
26.4
43.4
26.4
43.1
1.03-1.08, m
10
11
12
13
14
15
1.28, m
1.24, m
1.26, m
1.29, m
0.88, t, 7.3
1.29, m
1.22, m
29.7c
32.3
28.5
22.8
13.4
26.6
1.25, m
36.1
32.5
28.5
23.2
14.2
26.5
1.22, m
1.20, m
1.20, m
1.26, m
0.87, t, 7.0
1.24, m
36.3
32.5
28.5
23.2
14.2
26.5
1.17-1.24, m
1.22, m
1.29, m
0.87, t, 7.0
1.31, m
1.19, m
16
17
18
0.83, t, 6.6
0.93, d, 6.6
1.62, m
10.7
21.8
26.8b
0.81, t, 7.2
0.91, d, 6.5
1.63, m
10.8
21.5
31.1
0.81, t, 7.2
0.88, d, 6.5
1.56, m
10.9
21.9
31.9
1.58, m
1.56, m
19
20
0.87, t, 7.3
1.77, m
1.74, m
8.7
30.3
0.84, t, 7.6
1.70, m
1.79, m
8.7
30.5
0.84, t, 7.6
1.71, m
8.5
30.4
21
1.02, t, 7.3
8.3
1.00, t, 7.6
8.6
1.00, t, 7.6
8.6
aH-7a and H-7b coupling constants have been interchanged in the original paper. bThe chemical shifts of C8 and C18 have been interchanged in the
original paper. cIncorrect chemical shift.
SCHEME 11. Synthesis of Plakortone F (94) and epi-Plakortone
F (95)
Having established the structure and absolute stereochemis-
try of plakortone C (3), the truth of the deduction2 that
plakortone F (6) is its 11,12-dihydro relative is open to
testing. Mild reduction of pure plakortone C (H2, Pd-C,
hexane, 1 h) provided a single dihydro derivative 94 that was
spectroscopically identical (1H NMR, see Table 6) with natural
plakortone F (6), thus confirming its constitution and absolute
stereochemistry.34 Our measured optical rotation, [R]D -24.0,
differs somewhat from that reported for the natural compound,
[R]D -11, but this could be ascribed to the difficulty of working
with the low concentration available from the natural source.35
(Our synthesized plakortone C (3) has [R]D -29.3, with that
reported for the natural compound as [R]D -24.9.)
A sample of epi-plakortone C 91 ([R]D þ11.5) (with
alternate disposition of the trans ethyl groups compared
with plakortone C (3)) was similarly hydrogenated to pro-
vide epi-plakortone F, 95 ([R]D þ3.4). These conversions are
shown in Scheme 11.
SCHEME 12. Final Step in Semmelhack’s Synthesis10 of
Plakortone B (2)
Conclusions and Future Prospects. Our exploration of the
plakortone E (5) synthesis had been driven by the hypothesis
that acquisition of an essentially complete, stereochemically
pure, carbon framework of a plakortone which incorporated
the enediol for Pd(II)-induced furanolactone formation would
allow direct access to these interesting natural products.
This hypothesis was validated in 2006 by Semmelhack’s10
(34) This assumes there was no stereochemical compromise, e.g., at the
allylic ethyl bearing position during the mild hydrogenation, consistent with
the formation of a single dihydro derivative.
(35) Communication from Professor Fattorusso, January 2010: The
small discrepancies in the absolute values can be explained by the fact that
we have registered our optical rotation on a very small amount (about 1 mg)
of a not absolutely pure substance.
synthesis of plakortone B (2) in which a trienediol that
represented the complete carbon framework of 2 was acquired
and subsequently underwent Pd(II)-mediated formation of
the bicyclic furanolactone core and spectroscopic compari-
sons with natural plakortone B (2) and stereochemical
6498 J. Org. Chem. Vol. 75, No. 19, 2010

Hayes et al.
JOCArticle
SCHEME 13. Possible Natural Precursor of Plakortone A (1)
(0.1 equiv) was added, and stirring was continued. After refilling
the balloon with CO, the reaction was stirred overnight at room
temperature. This resulted in a color change from bright green to a
dull brown. After discharging the carbon monoxide, water (20 mL)
was added and the solution turned black. This solution was
neutralized with solid NaHCO3 until effervescence ceased. Extrac-
tion of the neutralized solution with EtOAc (3 ꢀ 20 mL), followed
by removal of the solvent gave the crude bicyclic lactones.
Synthesis of 93-102 from (R)-(þ)-3-Hydroxy-2-methylpro-
pionate (75). Compounds 76-85 were synthesized following
literature procedures for the synthesized stereoisomer.32
(2R)-3-tert-Butyldiphenylsilyloxy-2-methylpropyl Iodide (76).
This compound was synthesized in 88% yield. Spectroscopic
data of 76 matched those of the previously known (S)-enan-
tiomer5 [R]22D -3.3 (c 0.6, CHCl3) (reported32 for the (S)-enan-
tiomer: [R]23D þ3.18 (c 7.0, CHCl3)).
precedent,7 defined the stereochemistry of plakortone B (2) as
shown in Scheme 12.36
Finally, it is germane to consider whether the isolated plakor-
tones may be artifacts resulting from acid-induced furanol-
actonization of suitable unsaturated dihydroxy acids. This no-
tion is encouraged by the work of Rudi and Kashman,37 who
characterized C8 alkylated (methyl, ethyl) acids such as 4,6-
dihydroxy-4,6,8,10-tetraethyltetradec-2,7,11-trienoic acid
97, but no plakortones from P. halichondrioides. As shown in
Scheme 13, acid-promoted furanolactonization is feasible,
and this particular acid could yield plakortone A (1), with no
stereochemistry implied.
Syntheses of plakortones D, C, F, and (racemic) E are
described and with other information for plakortones B and E
establish the constitutions and absolute stereochemistries of
these five sponge-derived biologically active secondary metabo-
lites. A palladium(II) triggered furanolactonization, in the
presence of carbon monoxide, has been exploited to deliver
the fused, bicyclic, sterically congested emblematic “core” or
“structural motif” of the series. The possibility that some or all
of the known plakortones are artifacts, resulting from acid-
induced furanolactonization of natural alkyl-substituted, di-
hydroxy, unsaturated fatty acids is briefly considered.
(2R,4S)-5-(tert-Butyldiphenylsilyloxy)-2-ethyl-N-((1R,2R)-1-
hydroxy-1-phenylpropan-2-yl)-N,4-dimethylpentanamide (78): Yield
85%. [R]22D þ31.7 (c 0.6, CHCl3). 1H NMR (400 MHz, C6D6) δ
0.80 (t, J=7.4 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H), 0.99 (d, J=6.87
Hz, 3H), 1.06-1.13 (m, 1H), 1.16-1.21 (s and m, 11H), 1.26-1.36
(m, 1H), 1.55-1.71 (m, 2H), 1.91-1.98 (m, 1H), 2.31 (s, 3H),
2.31-2.33 (m, 1H), 3.46 (dd, J=6.5, 9.8 Hz, 1H), 3.57 (dd, J=5.2,
9.8 Hz, 1H), 4.52 (t, J=6.2 Hz, 1H), 7.05-7.11 (m, 1H), 7.21-7.32
(m, 10H), 7.77-7.81 (m, 1H). 13C NMR (100 MHz, C6D6) δ 11.9,
14.5, 17.2, 19.6, 26.8, 27.2, 33.8, 36.5, 41.1, 60.0, 69.5, 76.4, 126.7,
127.3, 128.3, 129.9, 134.30, 134.34, 136.0, 143.9, 177.8. Anal. Calcd
for C34H48NO3Si: C 74.82, H 8.68, N 2.57. Found: C 74.55, H 9.03,
N 2.43.
(2R,4S)-5-(tert-Butyldiphenylsilyloxy)-2-ethyl-4-methylpentan-
1-ol (79): Yield 97%. [R]22D -9.6 (c 0.42, CHCl3). 1H NMR (400
MHz, CDCl3) δ 0.85 (d, J=7.4 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H),
1.04 (s, 9H), 1.16-1.56 (m, 5H), 1.68-1.73 (m, 1H), 3.40-3.53 (m,
4H), 7.33-7.42 (m, 6H), 7.63-7.66 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 11.1, 17.4, 19.3, 24.2, 26.9, 33.4, 34.4, 39.4, 65.2, 69.2,
127.6, 134.0, 135.6. HR-MS m/z calcd [MþNa]þ for C24H37O2SiNa
407.2382, found 407.2377.
(2R,4S)-5-(tert-Butyldiphenylsilyloxy)-2-ethyl-4-methylpentanal
1
(80): Yield 75%. [R]22 -7.71 (c 0.97, CHCl3). H NMR (400
D
Experimental Section
MHz, CDCl3) δ 0.87 (d, J = 7.4 Hz, 3H), 0.89 (d, J = 6.7 Hz,
3H), 1.04 (s, 9H), 1.16 (ddd, J=14.2, 9.0, 4.7 Hz, 1H), 1.52-1.69
(m, 3H), 1.88 (ddd, J = 14.2, 9.1, 4.9 Hz, 1H), 2.18-2.25 (m,
1H), 3.44 (d, J=5.3 Hz, 2H), 7.33-7.43 (m, 6H), 7.61-7.64 (m,
4H), 9.47 (d, J = 3.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
11.4, 16.7, 19.3, 22.6, 26.8, 32.4, 33.5, 51.0, 68.8, 127.6, 129.6,
133.8, 135.6, 205.6. HR-MS m/z calcd [MþNa]þ for C24H35O2-
SiNa 405.2226, found 405.2220.
General Methods. Optical rotations were measured at 25 °C,
using a 1 mL cell with a 10 cm path length. NMR spectra were
recorded on 500 or 400 MHz spectrometers. 1H and 13C signals
were recorded in parts per million (ppm) on the δ scale, with the
residual solvent peaks (CDCl3: δH 7.24 and δC 77.0; C6D6: δH
7.15 and δC 128.0) as internal references. HRESIMS were
recorded on a MicrOTof-Q spectrometer (ESI mode). ESIMS
were recorded on an ion trap spectrometer (ESI mode). HPLC
purification was carried out on a HPLC system equipped with a
RI detector and a Luna Silica (2) column (250 ꢀ 4.6 mm, 100)
with 5% ethyl acetate in hexane as an eluent, at a flow rate of
2 mL/min. Flash chromatography separations were performed
with silica gel (Silica gel 60, 0.04-0.06 mm, 230-400 mesh ASTM).
Melting points were performed on a melting-point apparatus
(Dr. Tottoli) and are uncorrected.
General Procedure: Hydroxycyclization-Carbonylation-
Lactonization Sequence. NaOAc (3 equiv) and CuCl2 (3 equiv)
were added to a dry three-necked flask containing glacial acetic
acid (4.5 mL). The solution was stirred until the solid dissolved,
and then the unsaturated diol (0.6 mmol) in acetic acid (1 mL)
was added. While the contents were stirred vigorously, the flask
was purged several times with nitrogen initially and then car-
bon monoxide through a balloon. A catalytic amount of PdCl2
tert-Butyl((2S,4R,E)-4-ethyl-2-methyloct-5-enyloxy)diphenyl-
silane (81): Yield 42% over 3 steps. [R]22D þ11.0 (c 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3) δ 0.80 (t, J=7.3 Hz, 3H), 0.84 (d, J=6.6
Hz, 3H), 0.94 (d, J=7.4 Hz, 3H), 1.02 (s, 9H), 1.11-1.20 (m, 1H),
1.22-1.35 (m, 3H), 1.62-1.71 (m, 1H), 1.80-1.88 (m, 1H), 1.94-
2.20 (m, 2H), 3.40 (dd, 9.8, 6.3 Hz, 1H), 3.45 (dd, J= 9.8, 6.2 Hz,
1H), 4.99 (ddt, J=15.2, 8.9, 1.5 Hz, 1H), 5.36 (dt, J=15.2, 6.3 Hz,
1H), 7.33-7.41 (m, 6H), 7.63-7.65 (m, 4H). 13C NMR (125 MHz,
CDCl3) δ 11.7, 14.2, 16.3, 19.3, 25.6, 26.9, 29.0, 33.3, 38.8, 41.9, 69.7,
127.5, 129.4, 132.0, 133.4, 134.2, 135.6. HR-MS m/zcalcd [MþNa]þ
for C27H40OSiNa 431.2746, found 431.2741.
(2S,4R,E)-4-Ethyl-2-methyloct-5-en-1-ol (82): Yield 92%.
1
[R]22 -21.1 (c 0.5, CHCl3). H NMR (500 MHz, CDCl3) δ
D
0.84 (t, J=7.5 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H), 0.94 (d, J=7.3
Hz, 3H), 1.08-1.02 (m, 1H), 1.08-1.41 (m, 4H), 1.60-1.66 (m,
1H), 1.84-1.91 (m, 1H), 1.95-2.01 (m, 2H), 3.38 (dd, J=10.4,
6.5 Hz, 1H), 3.44 (dd, J = 10.4, 6.0 Hz, 1H), 5.00 (ddt, J=15.2,
9.0, 1.4 Hz, 1H), 5.39 (dt, J = 15.2, 6.3 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 11.7, 14.2, 16.0, 25.6, 29.1, 33.4, 38.8, 42.0,
69.1, 132.5, 133.1. HR-MS m/z calcd [MþNa]þ for C11H22ONa
193.1568, found 193.1554.
(36) Unfortunately, no optical rotation was reported for synthesized
plakortone B, in ref 10.
(37) Rudi, A.; Kashman, Y. J. Nat. Prod. 1993, 56, 1827.
J. Org. Chem. Vol. 75, No. 19, 2010 6499

Hayes et al.
JOCArticle
(5R,7S,E)-5-Ethyl-8-iodo-7-methyloct-3-ene (83): Yield 100%.
[R]22D þ2.3 (c 0.65, CHCl3). 1H NMR (500 MHz, CDCl3) δ 0.81
(t, J= 7.3 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H), 0.95 (t, J=7.3 Hz,
3H), 1.12-1.22 (m, 2H), 1.26-1.36 (m, 2H), 1.45-1.53 (m, 1H),
1.70-1.87 (m, 1H), 1.95-2.02 (m, 2H), 3.11 (dd, J=9.5, 6.1 Hz,
1H), 3.17 (dd, J = 9.5, 5.1 Hz, 1H), 5.00 (ddt, J=15.2, 9.2, 1.8 Hz,
1H), 5.39 (dt, J = 15.3, 6.4 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 12.0, 14.4, 19.3, 20.2, 25.9, 29.1, 32.8, 42.5, 42.6,
133.0, 133.1. HR-MS (EI) m/z calcd for C11H21I 280.0688,
found 280.0684.
(3S,5R,E)-5-Ethyl-3-methylnon-6-enenitrile (84): Yield 79%.
[R]22D þ7.4 (c 0.7, CHCl3). 1H NMR (500 MHz, CDCl3) δ 0.81
(t, J=7.6 Hz, 3H), 0.94 (t, J=7.6 Hz, 3H), 0.98 (d, J=6.7 Hz,
3H), 1.12-1.38 (m, 4H), 1.80-1.90 (m, 2H), 1.95-2.01 (m, 2H),
2.19 (dd, J=16.5, 6.7 Hz, 1H), 2.25 (dd, J=16.5, 6.1 Hz, 1H),
4.98 (ddt, J =15.1, 9.1, 1.4 Hz, 1H), 5.40 (dt, J= 15.1, 6.3 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 11.6, 14.1, 18.8, 25.5, 25.6,
28.2, 28.9, 30.9, 41.5, 42.2, 132.3, 133.2. HR-MS m/z calcd [Mþ
Na] for C12H21NNa 202.1572, found 202.1566.
(5S,7R,E)-7-Ethyl-5-methylundec-8-en-3-ol (86). The previ-
ous cyanide 84 was converted to the corresponding aldehyde
following a literature procedure for a diastereomer32 and the
crude aldehyde was used for the next step without purification.
To a cooled (-78 °C) solution of EtMgBr (3.0 M in ether, 4 mL)
in dry THF (15 mL) was added dropwise a solution of crude
aldehyde 85 (600 mg, 3.3 mmol) in THF (5 mL). Once the
addition was completed, the solution was warmed gradually to
rt and stirring was continued for another hour. After recooling
to -10 °C, the solution was quenched by addition of saturated
NH4Cl. The aqueous layer was separated and extracted with
DCM, followed by washing the combined organic extracts with
brine and water. Drying (MgSO4) and removal of the solvent
afforded a crude residue, which was purified by flash chromato-
graphy (ether/hexane 1:4) to give 510 mg of the pure alcohol 86
(73%) as a diastereomeric mixture (40/60). 1H NMR (500 MHz,
CDCl3) δ 0.80 (t, J=7.4 Hz, 3H), 0.81 (t, J=7.3 Hz, 3H), 0.83
(d, J=6.7 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H), 0.91 (t, J=7.5 Hz,
3H), 0.92 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 0.95 (t, J=
7.3 Hz, 3H), 0.98-1.69 (m, 20H), 1.83-1.98 (m, 2H), 1.94-2.04
(m, 4H), 3.56-3.62 (m, 2H), 4.98-5.03 (m, 2H), 5.34-5.41 (m,
2H). 13C NMR (125 MHz, CDCl3) δ major isomer: 9.9, 11.7,
14.2, 18.8, 25.6, 26.7, 28.9, 30.8, 42.2, 43.6, 45.4, 71.0, 132.2,
133.3; minor isomer: 9.8, 11.8, 14.3, 20.2, 25.6, 26.9, 29.1, 30.4,
42.0, 43.6, 45.5, 71.0, 132.5, 133.3. HR-MS m/z calcd [MþNa]þ
for C14H28ONa 235.2038, found 235.2032.
(7S,9R,E)-5,9-Diethyl-5-hydroxy-7-methyltridec-10-en-3-one
(88). At -78 °C, BuLi (1.8 M in hexane, 2.2 mL) was added
n
dropwise to 2-butanone N,N-dimethylhydrazone (537 mg, 4.7
mmol) in dry THF (25 mL) over 5 min under a nitrogen
atmosphere. The reaction was stirred at -78 °C for 2 h, during
which a white solid formed. Ketone 87 (330 mg, 1.57 mmol) in
dry THF (4 mL) was then added dropwise and the solution was
allowed to warm to room temperature and stirred overnight.
The reaction was quenched by the addition of 10% HCl (10 mL)
and the aqueous layer was extracted with DCM (3 ꢀ 30 mL).
The combined organic extracts were washed with brine (20 mL),
dried (MgSO4), and concentrated in vacuo. The crude product
was dissolved in THF (20 mL) and then added to CuCl2 2H2O
3
(0.75 g, 4.4 mmol) in water (10 mL) and pH 7 phosphate buffer
(5 mL). This mixture was stirred overnight at room temperature.
The reaction was then quenched by the addition of aqueous
NaCl-NaOH (pH 8, 20 mL) and was then extracted with DCM.
The combined organic extracts were dried (MgSO4) and con-
centrated under reduced pressure. The residue was purified by
column chromatography (ether/hexane 1:19) to afford the
desired product 88 (184 mg, 41%) as a colorless liquid. 1H
NMR (400 MHz, CDCl3) δ 0.79 (t, J=7.4 Hz, 3H), 0.80 (t, J=
7.5 Hz, 3H), 0.821 (t, J=7.6 Hz, 3H), 0.825 (t, J=7.6 Hz, 3H),
0.85 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.5 Hz, 3H), 0.95 (t, J=7.4
Hz, 6H), 1.02 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H),
1.05-1.20 (m, 20H), 1.78-1.87 (m, 2H), 1.95-2.02 (m, 2H),
2.40-2.45 (m, 4H), 2.52-2.54 (m, 4H), 4.96-5.05 (m, 2H), 5.38
(dt, J = 15.2, 6.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 7.4
(2C), 8.3, 8.4, 11.7, 11.8, 14.23, 14.3, 21.1, 21.2, 25.6 (2C), 26.0
(2C), 28.98, 29.02, 32.1, 32.4, 37.9 (2C), 42.2, 42.3, 44.3, 44.7,
46.3, 46.4, 49.1, 49.2, 74.7, 74.8, 132.2, 132.3, 133.3, 133.4,
214.16, 214.20. HR-MS m/z calcd [M þ Na]þ for C18H34O2Na
305.2456, found 305.2451.
Plakortone C (90) and epi-Plakortone C (91). To a solution of
hydroxy ketone 88 (184 mg, 0.65 mmol) in dry THF (10 mL) was
added anhydrous CeCl3 (690 mg, 3.15 mmol), and the mixture
was stirred for 20 min. Vinylmagnesium bromide (1.65 M in
THF, 1.90 mL) was added at room temperature and left to react
for 1 h. AcOH (10%, 5 mL) was then added, and the solution
was extracted with ether (3 ꢀ 15 mL). The combined organic
extracts were washed with saturated NaHCO3 (10 mL) and
brine (10 mL), dried (MgSO4), and evaporated to afford 180 mg
of a colorless oil (90%). The crude 89 was immediately subjec-
ted to the hydroxycyclization-carbonylation-lactonization se-
quence following the general procedure, to give after workup the
crude bicyclic lactones 90-93 in a 3:3:1:1 ratio. Flash chromato-
graphic purification (ether/hexane 1:4) resulted in two frac-
tions: 50 mg of a mixture of the major isomers 90 and 91 and
15 mg of a mixture of the 4 isomers 90-93 (33% in total over
2 steps). A fraction of the mixture of the major isomers (1:1)
was subjected to HPLC (5% ethyl acetate in hexane, refractive
index detector) for separation of the isomeric lactones and
NMR analysis.
(5S,7R,E)-7-Ethyl-5-methylundec-8-en-3-one (87). To a solu-
tion of oxalyl chloride (0.45 mL, 5.3 mmol) in DCM (8 mL)
at -78 °C was added dropwise DMSO (0.72 mL, 10.1 mmol).
The resulting mixture was stirred at -78 °C for a further 5 min
before adding dropwise a solution of alcohol 86 (0.5 g,
2.3 mmol) in DCM (5 mL). After the mixture was stirred at
-78 °C for 1 h, an excess of triethylamine (2.2 mL, 15.6 mmol)
was added and the solution was stirred for another 15 min. The
solution was warmed to 0 °C for 20 min, followed by dilution
with ether and washed with brine. After drying (MgSO4),
filtration, and concentration, the crude material was purified
by flash chromatography (ether/hexane 1:9) to afford 345 mg
Synthetic plakortone C (90), identical to natural plakortone C
(3). First eluted isomer, Rt 38 min. [R]22D -29.3 (c 0.47, CHCl3).
Reported2 [R]22D -24.9 (c 1.23, CHCl3). See Table 5 for 1H NMR
(500 MHz, CDCl3) and 13C NMR (125 MHz, CDCl3). HR-MS
m/z calcd [M þ Na]þ for C21H36NaO3 359.2562, found 359.2557.
of the pure ketone 87 (70%) as a colorless oil. [R]22 -10.0
D
(c 0.67, CHCl3). 1H NMR (500 MHz, CDCl3) δ 0.79 (t, J=7.3
Hz, 3H), 0.82 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.7 Hz, 3H), 1.02
(t, J = 7.3 Hz, 3H), 1.05-1.18 (m, 3H), 1.22-1.33 (m, 1H),
1.87-1.80 (m, 1H), 1.93-2.03 (m, 3H), 2.21 (dd, J=15.5, 7.5
Hz, 1H), 2.29 (dd, J=15.5, 6.5 Hz, 1H), 2.36 (dq, J=7.1, 1.0
Hz, 2H), 5.01 (ddt, J=15.1, 9.2, 1.5 Hz, 1H), 5.38 (dt, J=15.1,
6.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 7.8, 11.7, 14.2,
19.4, 25.6, 27.0, 28.9, 36.3, 42.1, 42.5, 50.9, 132.5, 132.9, 211.7.
HR-MS m/z calcd [MþNa]þ for C14H26ONa 233.1881, found
233.1876.
epi-Plakortone C (91). Second eluted isomer, Rt 40 min. [R]22
D
þ11.5 (c 0.7, CHCl3). See Table 5 for 1H NMR (500 MHz,
CDCl3) and 13C NMR (125 MHz, CDCl3). HR-MS m/z calcd
[M þ Na]þ for C21H36O3 Na 359.2562, found 359.2558.
Plakortone F (94). A solution of synthetic plakortone C (90)
(4.7 mg, 0.014 mmol) in hexane (2 mL) was stirred under a hydro-
gen atmosphere (1 atm) in the presence of a catalytic amount of
Pd/C for 1 h. After filtration and concentration, the fully hydro-
genated product, plakortone F (94), was obtained (4.2 mg, 90%)
as a colorless oil. [R]22D -24.0 (c 0.40, CHCl3). Reported3 [R]22
D
6500 J. Org. Chem. Vol. 75, No. 19, 2010

Hayes et al.
JOCArticle
1
-11.0 (c 0.001, CHCl3). See Table 6 for H NMR (500 MHz,
CDCl3) and 13C NMR (125 MHz, CDCl3). HR-MS m/z calcd
[M þNa]þ for C21H38O3 Na 361.2719, found 361.2713.
epi-plakortone F (95). Following an identical procedure to
that for 94, epi-plakortone F (95) was obtained (4.8 mg, 80%)
Products, University of Naples, for kind provision of copies
of spectra of natural plakortones and some derivatives. This
research was supported by the Australian Research Council,
to whom we are grateful.
from epi-plakortone C (91) (6.0 mg, 0.015 mmol). [R]22 þ3.4
D
1
(c 0.48, CHCl3). See Table 6 for H NMR (500 MHz, CDCl3)
Supporting Information Available: Full experimental details
for the synthesis of plakortones D (4) and E (5) as well as for (()-
dehydroplakortones D 105 and 106 and (()-dihydroplakortone
D 107, copies of NMR spectra (1H and 13C) of new compounds
and for 53-56, 90, 91, 94, and 95, and crystallographic informa-
tion files (CIF, ORTEP plot and crystal data) of the p-nitro-
benzoate derivative of compound 42. This material is available
free of charge via the Internet at http://pubs.acs.org.
and 13C NMR (125 MHz, CDCl3). HR-MS m/z calcd [MþNa]þ
for C21H38O3 Na 361.2719, found 361.2714.
Acknowledgment. The authors are grateful to Drs. Patil
and Freyer of Glaxo-Smith-Kline, Pennsylvania, and to
Professor Fattorusso, Department of Chemistry of Natural
J. Org. Chem. Vol. 75, No. 19, 2010 6501