Synthesis of plakortone B and analogs

Article abstract of DOI:10.1021/ol0618656

Use of a palladium-mediated alkoxycarbonylation/lactonization process provides a variable route to analogs of the plakortones. Four different analogs, including natural plakortone B, have been synthesized via this route.

Full text of DOI:10.1021/ol0618656

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5203-5206
Synthesis of Plakortone B and Analogs
M. F. Semmelhack,*,† Richard J. Hooley,† and Christina M. Kraml‡,§
Department of Chemistry, Frick Chemistry Laboratory, Princeton UniVersity,
Princeton, New Jersey 08544, and DiscoVery Analytical Chemistry,
Wyeth Research, CN 8000, Princeton, New Jersey 08543
mfshack@princeton.edu
Received July 27, 2006
ABSTRACT
Use of a palladium-mediated alkoxycarbonylation/lactonization process provides a variable route to analogs of the plakortones. Four different
analogs, including natural plakortone B, have been synthesized via this route.
The plakortones are a family of natural product furanolac-
tones isolated from the Caribbean sponges Plakortis hali-
chondrioides (plakortones A-D)1 and Plakortis simplex
(plakortones B-F; Figure 1).2 Plakortones A-D show
of interest as agents to increase calcium pumping in order
to correct cardiac muscle relaxation abnormalities.3 Diverse
structures such as gingerol and heparin show similar activity;
however, neither has been shown to be clinically effective.4
From the limited published activity data on the plakortones,
a hypothesis was presented that the central core furanolactone
is necessary for function, and the hydrophobic “tail” might
be altered to provide maximum efficacy.1 A synthetic route
that allows for rapid construction of plakortone analogs with
variable side chains is therefore desirable. The configurations
of the plakortone side chains were not confirmed in the initial
isolation. Recent syntheses of D and E established the
configuration at C10 shown in Figure 1.5 However, the C10
configuration in plakortones A-C and F is still undeter-
mined.
A key operation in the retrosynthetic analysis of plakortone
B (1, Scheme 1) is creation of the furanolactone core by
intramolecular alkoxypalladation-lactonization as developed
previously in this laboratory6 and also applied by Kitching.5a
Access to diol 2 (along with other analogs) could be achieved
by a metal-catalyzed sp2-sp3 coupling reaction between 3
Figure 1. The plakortone family.
activity as activators of the cardiac sarcoplasmic reticulum
Ca2+ ATPase (SERCA).1 Molecules with this activity are
† Princeton University.
‡ Wyeth Research.
(3) (a) Hasenfuss, G.; Reinecke, H.; Studer, R.; Meyer, M.; Pieske, B.;
Holtz, J.; Holubarsch, C.; Posival, H.; Just, H.; Drexler, H. Circ. Res. 1994,
75, 434. (b) Arai, M.; Alpert, N. R.; MacLennan, D. H.; Barton, P.;
Periasamy, M. Circ. Res. 1993, 72, 463.
(4) (a) Kobayashi, M.; Shoji, N.; Ohizumi, Y. Biochim. Biophys. Acta
1987, 903, 96. (b) Xu, Z. C.; Kirchberger, M. A. J. Biol. Chem. 1989, 264,
16644.
§ Current address: AccelaPure Corp., Frick Lab Rm 201, Princeton
University, Princeton, NJ 08544.
(1) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley, J. W.;
Johnson, R. K.; Lahouratate, P. Tetrahedron 1996, 52, 377.
(2) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Rosa, M.;
Ianaro, A. Tetrahedron 1999, 55, 13831.
10.1021/ol0618656 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/13/2006

of 7 proved difficult, as the hydroxyl moiety gave essentially
no selectivity using a variety of carbon nucleophiles and
enolization reduced the efficiency of the reaction with certain
carbanions. However, treatment with in situ generated
vinylcerium chloride10 provided the two diastereomers 8 and
9 in high overall yield. Complete separation was effected
by preparative HPLC.
Scheme 1. Retrosynthetic Analysis of Plakortone B
Protection of quaternary diol 9 was not trivial. The
protection must occur under mild conditions for compatibility
with the tertiary allylic alcohol, and the group must be easily
removed later in the synthesis. The benzylidene acetal,
formed by treatment of 9 with catalytic acid and benzalde-
hyde dimethyl acetal, satisfies both criteria. The protection
gave a mixture of epimers at the acetal position in excellent
overall yield. The isomers were easily separable and both
are useful, but the major isomer was carried forward in the
development of the synthesis. Deprotection and oxidation
with pyridinium chlorochromate gave aldehyde 10.11 The
configuration was confirmed by 1D NOE difference experi-
ments (see Supporting Information)
and one of a variety of side chain derivatives (exemplified
here by the borane 4).7 Variation in the structure of 4 would
provide an array of plakortone analogs.
The synthesis of core precursor 10 began with the
Sharpless asymmetric epoxidation8 of alcohol 5 followed by
silylation to give epoxide 6 in good yield and 85% ee
(Scheme 2). Epoxide ring opening with the anion from
Conversion of 10 to the corresponding acetylene using the
acetyldiazophosphonate protocol12 was followed by methy-
lation to provide 11 in excellent yield (Scheme 3). Taking
Scheme 2. Synthesis of the Core Structure of Plakortone B
Scheme 3. Synthesis of the Trisubstituted Olefin
1-ethyl-2,6,-dithiane,9 followed by oxidative deprotection,9b
provided hydroxyketone 7. The diastereoselective vinylation
advantage of hexane as solvent13 for Pd-catalyzed hydrostan-
nylations to minimize competitive stannane dimerization, 11
was converted to 12 regiospecifically, but unexpectedly,
distannane 13 was formed as a byproduct.
Although hydrostannylation of alkenes is common under
radical conditions,14 the palladium-catalyzed variant is rare
and usually occurs only with highly activated olefins.15 Other
(5) (a) Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718.
(b) Hayes, P. Y.; Kitching, W. Heterocycles 2004, 62, 173. (c) Akiyama,
M.; Isoda, Y.; Nishimoto, M.; Narazaki, M.; Oka, H.; Kuboki, A.; Ohira,
S. Tetrahedron Lett. 2006, 47, 2287. (d) Synthesis of related plakortone G:
Kowashi, S.; Ogamino, T.; Kamei, J.; Ishikawa, Y.; Nishiyama, S. Tetrahed-
ron Lett. 2004, 45, 4393. (e) Related metabolite synthesis: Akiyama, A.;
Isoda, Y.; Nishimoto, M.; Kobayashi, A.; Togawa, D.; Hirao, N.; Kuboki,
A.; Ohira, S. Tetrahedron Lett. 2005, 46, 7483. For related studies, see:
(f) Le, H. K.; Chan, K. F.; Hui, C. W.; Yim, X. W.; Wong, H. N. C. Pure
Appl. Chem. 2005, 77, 139-143. (g) Bittner, C.; Brugol, A.; Murphy, P.
J.; Sung, C. H.; Thornhill, A. J. Tetrahedron Lett. 1999, 40, 3455-3456.
(6) See: Semmelhack, M. F.; Shanmugam, P. Tetrahedron Lett. 2000,
41, 3567 and references therein.
(7) (a) Chemler, S.R.; Trauner, D.; Danishefsky, S.J. Angew. Chem., Int.
Ed. 2001, 40, 4544. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(c) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(8) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(9) (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. (b) Grobel,
B. T.; Seebach, D. Synthesis 1977, 357.
(10) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392-4398.
(11) Piancatelli, G.; Scettri, A.; Dauria, M. Synthesis 1982, 245.
(12) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett
1996, 521. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47,
1837.
(13) Semmelhack, M.F.; Hooley, R.J. Tetrahedron Lett. 2003, 44, 5737.
(14) (a) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworths: London, Boston, 1987; p 342. (b) Davies, A. G. Organotin
Chemistry; VCH: Weinheim, New York, 1997; p 327.
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Org. Lett., Vol. 8, No. 23, 2006

more active catalysts such as Pd(OAc)2/PCy3 increased the
amount of byproduct formed. Slow addition of tri(n-butyl)-
tin hydride reduced byproduct formation to a manageable
level, and vinyl iodide 14 was isolated in 48% yield over
two steps.
the olefins. When 22 was treated with a solution of Na/NH3
in the absence of proton source, clean removal of the acetal
was observed, although the major product was not diol 23
but olefin 24. If the cleavage is performed under Birch
reduction conditions in the presence of isopropanol, the yield
of diol 23 was increased to 65%.
For the key step, treatment of 23 with catalytic PdCl2 and
CuCl2 reoxidant in glacial acetic acid buffered with NaOAc
under an atmosphere of carbon monoxide19 furnished pla-
kortone B (1b) in 75% yield. Only one product was observed,
and the trisubstituted olefin was not affected by the cycliza-
tion conditions. The synthesized plakortone B (1) showed
good agreement with the published 1H and 13C NMR spectra
of natural plakortone B.1 On the basis of this good agreement
and the work of Kitching in the syntheses of plakortones D
and E,5 it is reasonable to assign the natural stereochemistry
at C10 of plakortone B as that shown in Scheme 5.
In order to create side chain analogs of the plakortones,
an adaptable synthetic route is required. To illustrate the
viability of our strategy, two different side chains were
created. Swern oxidation of (S)-2-benzyloxymethyl-butanol
1516 furnished aldehyde 16, which was converted into (E)-
1,2-disubstituted olefin 18 in moderate yield and excellent
stereoselectivity by the use of 17 in the modified Julia
reaction.17 From this olefin, two different side chains were
easily accessed by varying the conditions used to remove
the benzyl protecting group. Pd-catalyzed hydrogenation
effected debenzylation along with saturation of the olefin,
giving (S)-2-ethylhexanol, whereas a dissolving metal reduc-
tion removed the benzyl group without affecting the olefin,18
providing E-(S)-2-ethylhexen-3-ol. The alcohols were con-
verted to iodides 19 and 20 in good yield with PPh3/I2/
imidazole. The attachment of the side chains to the core
Scheme 5. Completion of the Synthesis of Plakortone B
Scheme 4. Synthesis of Two Side Chain Analogs
Scheme 6. Synthesis of 11,12-Dihydroplakortone B 26
structure 14 requires an sp3-sp2 coupling process. Using a
modified Suzuki coupling,7a,c iodide 19 was converted to the
corresponding homoallyllithium, which was then treated with
B-methoxybora-bicyclo[3.3.1]nonane to form boronate 21 in
situ. Addition of vinyl iodide 14 in the presence of
PdCl2(dppf) and K3PO4 as base effected coupling to give 22
stereospecifically and in good yield. Mild acidic conditions
for deprotection of 22 gave no reaction, and more vigorous
conditions caused decomposition of the tertiary allylic alcohol
product 23. Hydrogenolysis proved to be incompatible with
(15) (a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100,
3257. (b) Lautens, M.; Kumanovic, S.; Meyer, C. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1329. (c) Four, P.; Guibe, F. Tetrahedron Lett. 1982, 23,
1825. (d) Keinan, E.; Gleize, P. A. Tetrahedron Lett. 1982, 23, 477.
(16) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto, K.
J. Org. Chem. 1996, 61, 677
This methodology was then extended to the synthesis of
three other plakortone analogs. Coupling of side chain 20 to
vinyl iodide 14 as before, followed by reductive deprotection
and cyclization, provided 11,12-dihydro-plakortone B in 25%
yield overall from vinyl iodide 14 (Scheme 6). Because of
(17) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(18) Jaworek, C. H.; Iacobucci, S.; Calias, P.; d’Alarcao, M. Carbohydr.
Res. 2001, 331, 375
(19) Gracza, T.; Hasenohrl, T.; Stahl, U.; Jager, V. Synthesis 1991, 1108
Org. Lett., Vol. 8, No. 23, 2006
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the low selectivity during vinylation of ketone 7, large
amounts of diol 8 were available and could be converted to
epimers of the plakortone family (Scheme 7). Core vinyl
11,12-dihydroplakortone B (33) in 36% and 38% yield,
respectively, from vinyl iodide 29 (Scheme 8).
Scheme 8. Syntheses of 3,4-Epiplakortone B 32 and
3,4-Epi-11,12-dihydroplakortone B 33
Scheme 7. Synthesis of Core Epimer 29
iodide 29 was synthesized using a route parallel to that shown
in Schemes 2 and 3. Only one benzylidene acetal epimer
(leading to 27) was formed for this diastereomer of the diol,
as opposed to the two observed in the protection of diol 9.
Conversion to the methylacetylene 28 proceeded smoothly.
In this case, the rate of hydrostannylation was much faster,
but again competing hydrostannylation of the vinyl group
in 28 was observed. When the reaction was performed at
-35 °C, the optimum yield of the desired monostannane was
achieved. Treatment of the mixture of mono- and distannyl-
ation products with N-iodosuccinimide gave, after purifica-
tion, vinyl iodide 29 as one isomer in 29% yield over two
steps.
In summary, we have established a viable synthetic route
to various analogs of the plakortone family, employing an
efficient palladium-catalyzed alkoxycarbonylation/ lacton-
ization process on complex intermediates.
Acknowledgment. Financial support was provided by the
ACS Petroleum Research Fund (39189-AC).
Supporting Information Available: Experimental pro-
cedures and product characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The core vinyl iodide 29 was converted to the desired
plakortone analogs by coupling with side chain iodides 19
and 20 as before, followed by reductive deprotection and
cyclization to provide 3,4-epiplakortone B (32) and 3,4-epi-
OL0618656
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Org. Lett., Vol. 8, No. 23, 2006