Synthesis of (S)-jamaicamide C carboxylic acid

Article abstract of DOI:10.1021/ol9021222

"Chemical Equation Presented" The jamaicamides are natural product sodium channel blockers derived from the cyanobacterium Lyngbya majuscula. The carboxylic acid fragment of jamaicamide C contains a methyl stereocenter and a trisubstituted E chloroolefin.

Full text of DOI:10.1021/ol9021222

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5382-5385
Synthesis of (S)-Jamaicamide C
Carboxylic Acid
Kristin M. Graf,† Martin G. Tabor,‡ Milton L. Brown,‡ and Mikell Paige*,‡
Drug DiscoVery Program, Georgetown UniVersity Medical Center, 3970 ReserVoir RD,
NW, NRB EP15A, Washington D.C., 20057, and Department of Chemistry, UniVersity
of Virginia, McCormick Road, CharlottesVille, Virginia 22901
map65@georgetown.edu
Received September 14, 2009
ABSTRACT
The jamaicamides are natural product sodium channel blockers derived from the cyanobacterium Lyngbya majuscula. The carboxylic acid
fragment of jamaicamide C contains a methyl stereocenter and a trisubstituted E chloroolefin. Herein, we present the nonracemic synthesis
of the aliphatic chain of jamaicamide C. The methyl stereocenter was installed using Evans’ oxazolidinone methodology, and the trisubstituted
chloroolefin was set by silylstannylation of a triple bond.
Jamaicamides A, B, and C make up a family of lipopeptidic
natural products isolated from a dark green strain of Lyngbya
majuscula, a cyanobacterium from Hector’s bay, Jamaica.
The jamaicamides differ in structure only at the terminal end
of their polyketide aliphatic chain (Figure 1).1 Jamaicamides
were found to block the sodium channel in a cell-based
screen developed by Manger and co-workers, which involved
Figure 1. Structure of jamaicamides A, B, and C.
measuring the end point of mitochondrial dehydrogenase
activity in neuroblastoma cells.2
Sodium channel blockers are an important class of drugs,3
and novel molecules that block this channel may provide
new structures with clinical potential. To date, the jamaica-
mides and kalkitoxin are the only polyketide-peptides
reported to be sodium channel blockers and, as such,
represent a new template for the design of novel sodium
channel ligands. Kalkitoxin was synthesized by White’s
group in 2003;4 this was followed by a second total synthesis
by the Shioiri group in 2004.5 However, to the best of our
knowledge, the total synthesis of jamaicamide has not been
accomplished.
In our efforts toward the total synthesis of jamaicamide
C, construction of the appended vinyl chloride substituent
at C-9 proved to be a considerable synthetic challenge.
In this report, we describe a strategy to stereoselectively
set this E trisubstituted olefin, which led to the nonracemic
synthesis of the polyketide aliphatic chain of jamai-
camide C.
† University of Virginia.
‡ Georgetown University.
(1) Edwards, D. J.; Marquez, B. L.; Nogle, L. M.; McPhail, K.; Goeger,
D. E.; Roberts, M. A.; Gerwick, W. H. Chem. Biol. 2004, 11, 817–833.
(2) Manger, R. L.; Leja, L. S.; Lee, S. Y.; Hungerford, J. M.; Hokama,
Y.; Dickey, R. W.; Granade, H. R.; Lewis, R.; Yasumoto, T.; Wekell, M. M.
J. AOAC Int. 1995, 78, 521–527.
Initially, we envisioned setting the trisubstituted chlo-
roolefin by suitable functionalization of a terminal acetylene,
chlorination, and alkyl homologation, which together would
(3) Anger, T.; Madge, D. J.; Mulla, M.; Riddall, D. J. Med. Chem. 2001,
44, 115–137.
(5) Yokokawa, F.; Asano, T.; Okino, T.; Gerwick, W. H.; Shioiri, T.
Tetrahedron 2004, 60, 6859–6880.
(4) White, J. D.; Lee, C.-S.; Xu, Q. Chem. Commun. 2003, 2012–2013.
10.1021/ol9021222 CCC: $xxxx
Published on Web 11/11/2009
 2009 American Chemical Society

give a general route to unsymmetrical bisalkyl vinyl chlo-
rides. Silylstannylation of terminal acetylenes is a convenient
way of accessing a dimetalated olefin of defined stereochem-
istry and differential reactivity. We therefore decided to
incorporate such a reaction in our strategy for the synthesis
of the carboxylic acid polyketide of jamaicamide C as shown
in Scheme 1.
subsequent Negishi coupling to append the 5-pentenyl group
was accomplished in high yield as outlined in Scheme 2.
Scheme 2. Iodination Followed by Negishi Coupling
Scheme 1. Strategy for Polyketide 1
Desilylchlorination was required to install the trisubstituted
vinyl chloride motif. As outlined in Table 2, a series of
conditions were screened to convert the trimethylsilyl group
to a chloride.7 The optimized conditions resulted from the
use of 2 equiv of NCS in DMF for 72 h at 50 °C (Table 2,
entry 7).
We began our studies with TBS-protected butyn-1-ol as
our model substrate. As outlined in Table 1, treatment with
trimethylsilyltributylstannane under conditions reported by
Mitchell and co-workers6 provided the silylstannylated
product as a single isomer. Optimization of the silylstanny-
lation reaction was accomplished under microwave condi-
tions to give the product in 1 h as compared to 15 h at reflux
in THF (Table 1, entries 3 and 1, respectively). Increasing
catalyst loading resulted in a modest increase in yield.
Although the yields for the thermally induced reactions were
comparable to those obtained by microwave irradiation, the
product obtained under microwave conditions was formed
more rapidly and was more readily purified.
Table 2. Optimization of the Desilylchlorination Reactiona
entry solvent time temp.
Cl+
results
1
2
3
4
5
6
7
DMSO 24 h 50 °C 2 equiv NCS desilylation
DMF
DMF
DMF
DMF
24 h 50 °C 2 equiv NCS incomplete conv.
24 h 50 °C 5 equiv NCS incomplete conv.
5 h 75 °C 2 equiv NCS decomposition
2 h 50 °C 2 equiv HxCb multiple impurities
CH3CN 24 h 50 °C 2 equiv NCS multiple impurities
DMF 72 h 50 °C 2 equiv NCS complete, 80% yield
a Yields determined by GCMS. b HxC ) 2,3,4,4,5,6-hexachlorocy-
Table 1. Optimization of the Silylstannylation Reaction
clohexa-2,5-dien-1-one.
With the synthetic conditions devised for our model
trisubstituted chloroolefin system, we commenced our
synthesis of the polyketide region of the jamaicamides as
shown in Scheme 3. From the known amide 2,8 lithium
amidoborane reduction of the chiral auxiliary provided
the primary alcohol 3. TPAP-catalyzed oxidation of
alcohol 3 to the aldehyde followed by treatment with
vinylmagnesium bromide gave allylic alcohol 4 as a
mixture of diastereomers (∼1:1 mixture). Johnson-Claisen
rearrangement to enoate 5 was followed by TBAF-
mediated deprotection of the DPS protecting group and
oxidation of the resulting alcohol to aldehyde 6. One-
carbonalkynylationwasaccomplishedunderOhira-Bestmann
conditions to yield the target alkyne 7.
entry
conditions
time
yield (%)
1
2
3
reflux, 2 mol % Pd(PPh3)4
reflux, 4 mol % Pd(PPh3)4
microwave 150 W,
95 °C, 2 mol % Pd(PPh3)4
microwave 150 W,
15 h
24 h
1 h
64%
71%
61%
4
1 h
75%
95 °C, 4 mol % Pd(PPh3)4
The silylstannylated product of methyl 5-hexynoate was
synthesized as a model substrate for elaboration to the
terminal end of jamaicamide C. Selective conversion of the
tributylstannane group to the vinyl iodide followed by
Silylstannylation of alkyne 7 produced the functionalized
olefin 8 as expected. However, elaboration of stannane 8 to
the vinyl iodide under the conditions worked out in Scheme
2 resulted in desilylated vinyl iodide 9a. Buffering the
reaction with triethylamine allowed for synthesis of vinyl
iodide 9b with the silyl group intact. Unfortunately, Negishi
coupling under the conditions devised for our model system
(6) Mitchell, T. N.; Killing, H.; Dicke, R.; Wickenkamp, R. Chem.
Commun. 1985, 354–355.
(7) Initial conditions were derived from Kigoshi’s synthesis of hateru-
malide NA, which contains a trisubstituted chloroolefin with a different
substitution pattern than found in the jamaicamides. See: Kigoshi, H.; Kita,
M.; Ogawa, S.; Itoh, M.; Uemura, D. Org. Lett. 2003, 5, 957–960.
(8) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720–
14721.
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On the basis of our hypothesis that the remote double bond
is problematic for the Negishi coupling, we developed a
revised route that involves installation of the internal E olefin
late in the synthesis as outlined in Scheme 5.
Scheme 3. Synthesis of Alkyne 7
Scheme 5. Synthesis of Carboxylic Acid 1
resulted in desilylation. The homologated substrate 10 was
isolated with a considerable amount of starting material
(Scheme 4).
Scheme 4. Failed Approach to Jamaicamide C Carboxylic Acid
Palladium-mediated silylstannylation of oxazolidinone 11
under microwave irradiation conditions provided vinylstan-
nane 12 in 69% yield. Iodination gave vinyl iodide 13 in
99% yield, which then underwent Negishi coupling to give
the homologated product 14 in 84% yield. Generation of the
enolate of oxazolidinone 14 followed by methylation resulted
in compound 15 in 80% yield as a single product.11
Conversion of the vinylsilane to the vinyl chloride was
accomplished by treatment with NCS in DMF to give the
product in 42% yield. Removal of the oxazolidinone was
accomplished by treatment with lithium aluminum hydride
and gave alcohol 17. Oxidation to the aldehyde under
Dess-Martin conditions followed by addition of vinylmag-
nesium bromide afforded allylic alcohol 18 in 50% yield over
the two steps as a mixture of diastereomers (∼1:1 mixture).
Johnson-Claisen rearrangement gave methyl ester 19 in 83%
yield, which was saponified to give the nonracemic jamai-
camide C carboxylic acid (1) in 11 steps from commercially
available 5-hexynoic acid.
The reasons for the problems faced with the iodination
followed by Negishi coupling of substrate 8 are not clear.
The main difference between substrate 8 and the model
system is a methyl stereocenter and the presence of an ester
with a carbon-carbon double bond. Danishefsky reported a
remote olefin-directed aldol facial selectivity presumably due
to electron donation of the olefin into a carbonyl group.9
Smith reported that the acidity of a dithiane was reduced
due to πfσ* donation of a remote olefin into an unfilled
orbital on the dithiane sulfur atom.10 It remains unclear
whether a πfπ* event between the remote olefin and the
silylstannylated olefin plays a role in the facile desilylation
of our substrate.
According to Tamao and co-workers, vinylsilanes react
with electrophilic halides to give a stabilized carbocation ꢀ
(9) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K. A.; Danishefsky,
S. J. Tetrahedron Lett. 1999, 40, 2267–2270.
(10) Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull,
K. G.; Iwashima, M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-
W. J. Am. Chem. Soc. 1999, 121, 10468–10477.
(11) Kalesse, M.; Quitschalle, M.; Claus, E.; Gerlach, K.; Pahl, A.;
Meyer, H. H. Eur. J. Org. Chem. 1999, 2817–2833.
5384
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to the silyl group.12 For E disubstituted vinylsilanes, inversion
of configuration with respect to the position of the starting
silane was observed when the reaction was carried out in
DMF. Following Tamao’s analysis, conditions for conversion
of our trisubstituted vinylsilane to the vinyl chloride in DMF
were predicted to give inversion of configuration. However,
Chou and co-workers reported the conversion of a trisub-
stituted vinylsilane (with a similar substitution pattern to ours)
to the corresponding vinyl halide with retention of config-
uration.13 In Chou’s case, (E)-2-ethyl-1-(trimethylsilyl)-1-
hexene was treated with iodine monochloride in carbon
tetrachloride to give the corresponding (E)-vinyl iodide. On
the basis of these reports, it was necessary for us to determine
whether our reaction resulted in inversion or retention of
configuration (Figure 2).
Figure 3. 400 MHz 2D-NOESY of jamaicamide C carboxylic acid
(CDCl3).
of jamaicamide C that can be applied toward the total
synthesis of the jamaicamide family of natural products. We
have also reported a new strategy for setting unsymmetrical
trisubstituted chloroolefins with complete stereocontrol. Also
noteworthy are optimization of the silylstannylation reaction
and the Negishi coupling under microwave irradiation.
Finally, we report optimized conditions for the conversion
of a vinylsilane to the chloroolefin and show by 2D-NOESY
NMR experiments that the reaction gives retention of
configuration.
Figure 2. Stereochemical results of desilylhalogenation reactions.
For the structure elucidation of the jamaicamides, the
configuration of the chloroolefin was determined by HSQM-
BC experiment, which allowed for measurement of the
coupling constants between the chloroolefin vinylic proton
and each adjacent allylic carbon atom.1,14 We employed 400
MHz 2D-NOESY analysis to determine the configuration of
the chloroolefin. As shown in Figure 3, there was an intense
NOE signal between δ 5.77 and δ 2.00 ppm suggesting that
the configuration of the double bond was E.
Acknowledgment. We would like to thank the George-
town University Drug Discovery Program and the Lombardi
Comprehensive Cancer Center (LCCC) for support. We
thank Dr. James A. Marshall at the University of Virginia
for suggesting a thorough analysis of the stereochemistry of
the desilylchlorination reaction, and we acknowledge LCCC
Proteomics & Metabolomics Shared Resource (PMSR) for
mass spectrometry analysis.
In summary, the synthetic sequence presented above is
an efficient route for the synthesis of the polyketide fragment
(12) Tamao, K.; Akita, M.; Maeda, K.; Kumada, M. J. Org. Chem. 1987,
52, 1100–1106.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Chou, S. -S. P.; Kuo, H.-L.; Wang, C.-J.; Tsai, C.-Y.; Sun, C.H-
M. J. Org. Chem. 1989, 54, 868–872.
(14) Williamson, R. T.; Marquez, B. L.; Gerwick, W. H.; Kover, K. E.
Magn. Reson. Chem. 2000, 38, 265–273
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