Total synthesis of the anti-apoptotic agents Iso- And bongkrekic acids

Article abstract of DOI:10.1021/ol902676t

(Figure presented) The first convergent total synthesis of isobongkrekic acid is reported involving three different stereospecific palladium cross-couplings for the formation of the diene units. Access to bongkrekic acid by this route is also demonstrated. These syntheses involve the formation of several potentially general building blocks.

Full text of DOI:10.1021/ol902676t

ORGANIC
LETTERS
2010
Vol. 12, No. 2
340-343
Total Synthesis of the Anti-Apoptotic
Agents Iso- and Bongkrekic Acids
Antoine Francais, Antonio Leyva, Gorka Etxebarria-Jardi, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, United Kingdom
sVl1000@cam.ac.uk
Received November 20, 2009
ABSTRACT
The first convergent total synthesis of isobongkrekic acid is reported involving three different stereospecific palladium cross-couplings for
the formation of the diene units. Access to bongkrekic acid by this route is also demonstrated. These syntheses involve the formation of
several potentially general building blocks.
Isobongkrekic acid (IBA, 1) is a complex fatty triacid which
was isolated from the fermentation of Pseudomonas cocoV-
enenants in 1976.1 Closely connected to its better known
isomer bongkrekic acid (BA, 2),2 they form a small family
of toxic antibiotics with potent antiapoptotic activity. These
compounds act as inhibitors of adenine nucleotide translocase
(ANT), which mediates the ADP/ATP exchange in mito-
chondria.3 Mentioned in more than 700 publications, they
are most commonly used to probe apoptosis mechanisms and
to elucidate their link with mitochondrial function.4 As a
consequence, these substances attracted the interest of
chemists. In particular, Corey and Tramontano devised a first
very effective synthesis of BA in 1984,5 while a second and
longer total synthesis appeared some 20 years later.6 Dis-
satisfied by this last approach, Shindo and Shishido continued
to work in the area which culminated recently in two greatly
improved second generation syntheses.7 We too became
interested in these molecules owing to the development of
methods in our laboratory, which we deemed to be suitable
to afford certain structural elements within these natural
products.8 In practice, however, while the methods proved
to be unsatisfactory for either IBA and BA syntheses, a new
highly efficient route has emerged leading to IBA (and BA),
which we describe here. We have primarily targeted IBA as
the center of our interest, since no synthesis has been
reported, nor is any detailed biological evaluation currently
available.
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2008, 64, 4711–4717.
10.1021/ol902676t  2010 American Chemical Society
Published on Web 12/16/2009

Retrosynthetically, we opted for the trimethylester of IBA
(IBAMe3) as our main target which could be constructed
via a Sonogashira coupling between the vinyl iodide 3 and
the alkyne 4. In order to provide access to the vinyl iodide
3, we envisioned the sequence of coupling reactions between
stannane 5, vinyl iodide 6, and eventually novel triiodide 7.
Alkyne 4 was expected to arise via a Suzuki reaction and
an asymmetric homopropargylation following anion genera-
tion from propargyl bromide 8 coupling with fragments 9
and 10 (Scheme 1).
The next crucial component of our synthesis plan involved
the preparation of the triiodide 7. This was designed as a
new bidirectional coupling partner that effectively installs
the unsymmetrical hexa-1,5-diene fragment (a common unit
in a number of natural products)11 by exploiting its orthogo-
nal reactivity. Accordingly, pentynol (13) was transformed
in its corresponding E-vinyl iodide, following a literature
procedure (Scheme 3).12 Subsequently, oxidation of the
Scheme 3. Synthesis of gem-Diiodide 7
Scheme 1. Retrosynthetic Analysis
intermediate alcohol with pyridinium chlorochromate gave
optimal results. Formation of the gem-diiodide function was
then achieved by employing a protocol developed by
Sternhell et al.13 While this method is often low yielding, in
this case we were pleased to obtain this new building block
7 in an efficient and highly reproducible fashion.
In order to synthesize the homologated vinyl iodide 3, the
commercially available, chiral diol 14 was monoprotected
at the less hindered hydroxyl group at low temperature
(Scheme 4). However, the oxidation of this product to the
Scheme 4. Synthesis of Vinyl Iodide 3
The preparation of stannane 5 commenced from 3-butyn-
1-ol (11) by a known sequence of silylation, homologation
with methyl chloroformate, and a stereoselective Piers
hydrostannylation reaction9 to initially provide the stannane
12 with yields similar to the literature process (Scheme 2).10
Scheme 2. Synthesis of Stannane 5
intermediate aldehyde was problematic owing to its instabil-
ity. Nevertheless, inspired by our previous observations
describing a sequential tetra-n-propylammonium perruthenate
(9) Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263–4264.
(10) (a) Maguire, R. J.; Munt, S. P.; Thomas, E. J. J. Chem. Soc., Perkin
Trans. 1 1998, 2853–2863. (b) Chaume, G.; Kuligowski, C.; Bezzenine-
Laffole´e, S.; Ricard, L.; Pancrazi, A.; Ardisson, J. Synthesis 2004, 18, 3029–
3036.
Silyl ether 12 was then treated with the Jones reagent to
simultaneously deprotect and oxidize in situ the intermediate
alcohol to the carboxylic acid. Stannane 5 was finally
obtained after a quantitative esterification using trimethyl-
silyldiazomethane. This approach proved to be reproducible
and gave access to multigram quantities of the stannane 5
ready for the Stille coupling (Scheme 2).
(11) For example, see the following: (a) Curacin family: Gerwick, W. H.;
Proteau, P. J.; Nagle, D. G.; Hamel, E.; Blokhin, A.; Slate, D. L. J. Org.
Chem. 1994, 59, 1243–1245. (b) Ajudazols family: Jansen, R.; Kunze, B.;
Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem. 2002, 91, 7–921.
(12) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am.
Chem. Soc. 1986, 108, 7791–7800.
(13) Pross, A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989–1003.
Org. Lett., Vol. 12, No. 2, 2010
341

(TPAP) oxidation/Wittig reaction,14 we investigated use the
TPAP oxidation immediately followed by a Takai reaction,
in one-pot, to give vinyl iodide 6. This proceeded in a
moderate 65% yield but was reproducible on multigram
scale.
Scheme 6. Synthesis of Alkyne 4
Next, the crucial elaboration of the left-hand diene
geometry to distinguish IBA from BA was studied. The
Stille-Migita coupling15 was used for this process and
involved modified conditions16 using a phosphonate salt as
a tin scavenger as this proved to be the most efficient
procedure (60% yield). The deprotection of diene 15 with
HCl in methanol followed by a Dess-Martin oxidation led
to aldehyde 16. Noteworthy in this reaction is that the
absolute S configuration of the intermediate alcohol is not
racemized, and this observation was corroborated by the
formation and analysis of the corresponding Mosher ester
1
(er >95:5 in H and 19F NMR). Finally, aldehyde 16 was
subjected to a Takai olefination17 using an excess of the
triiodide 7. Pleasingly, vinyl iodide 3 was obtained stereo-
selectively as a single E-isomer in good yield (79%).
For fragment 10, its assembly arose from the initial
formation of vinyl iodide 18 from diethyl 2-methylma-
lonate (17) by a known procedure involving a reaction
with iodoform followed by decarboxylation/elimination.18
Subsequently, vinyl iodide 18 was esterified under acidic
conditions and then cross-coupled with the bis(pinacolato)-
diboron 19 to give boronic ester 10 in 84% yield (Scheme
5).19
amounts of fragments 21 and 10 in hand, different conditions
for the key Suzuki-Miyaura coupling21 could then be
examined. As expected, the stereospecific formation of the
Z,E-diene was complicated. Only when modified Kishi
conditions,22 using thallium ethoxide as a base, were
employed did we obtain completely stereospecific coupling,
confirmed by NOE studies, in high yield (91%) on gram
scale. Several alternative less toxic bases were also inves-
tigated without success. These observations are in accord
with other syntheses.23
Scheme 5. Synthesis of Boronic Ester 10
In order to progress the synthesis, diene 22 was deprotected
with TBAF and the resulting free-alcohol oxidized to the
aldehyde 23 using Dess-Martin periodinane. We recognized
that this aldehyde 23 would be prone to isomerization, and
it was therefore used immediately in homopropargylation
studies. The best conditions for this process turned out to
be the use of indium as a metal source since this combines
mildness and efficiency. When linked to its asymmetric
version developed by Singaram,24 excellent coupling was
achieved giving homopropargylic alcohol 24 in good yield
and acceptable enantiomeric ratio (er 82:18). In order to
enhance this er, enzymatic methods were considered, but all
required a further deprotection step. We therefore preferred
a chemical process, with the method of Fu being particularly
attractive.25 The commercial availability of the required iron
Access to multigram quantities of vinyl iodide 21 was
achieved through a silylation of hydroxyacetone 20 followed
by a Wittig-Stork reaction (Scheme 6).20 With significant
(14) MacCoss, R. N.; Balskus, E. P.; Ley, S. V. Tetrahedron Lett. 2003,
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(15) (a) Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 1423–
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C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2873–
2875.
(22) (a) Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am.
Chem. Soc. 1987, 109, 4756–4758. (b) Frank, S. A.; Chen, H.; Kunz, R. K.;
Schnaderbeck, M. J.; Roush, W. R. Org. Lett. 2000, 2, 2691–2694.
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A.; Marnett, L. J.; Sulikowski, G. A. J. Org. Chem. 2008, 73, 4949–4955.
(b) Nicolaou, K. C.; Nold, A. L.; Milburn, R. R.; Schindler, C. S.; Cole,
K. P.; Yamaguchi, J. J. Am. Chem. Soc. 2007, 129, 1760–1768. (c) Shimizu,
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342
Org. Lett., Vol. 12, No. 2, 2010

DMAP catalyst meant that we could rapidly attain an er of
95:5 for the desired enantiomer in a good yield.26 This high
enantioselectivity was sufficient to progress the synthesis.
Finally, after several unsuccessful attempts, the hydroxyl
group was methylated with methyl triflate and a hindered
base to give the desired alkyne 4 (Scheme 6).27
With the two fragments 3 and 4 now available, their union
via a Sonogashira coupling was investigated and successfully
achieved (Scheme 7).28 The use of triethylamine as solvent29
with an olefin, could be achieved using a large excess of
copper/silver activated zinc.31 A separable 4:1 mixture of
IBAMe3 (27) and BAMe3 (28) was obtained in a satisfying
yield of 73% over two steps. Believing that the final
saponification may led inexorably to further isomerization
on the polyene, the two isomers at this stage were purified
only for characterization and comparison with reported data.
The mixture was then forwarded to the next step. Finally,
we dealt with the final and challenging tris-saponification
process. After several unsuccessful attempts, we found that
by using a large excess of potassium hydroxide we could
obtain the two readily separable natural products IBA (1)
and BA (2) (ratio 2:1). In order to prove that no racemisation
occurred during this final step, IBA and BA were individually
re-esterified to their corresponding IBAMe3 and BAMe3 and
both afforded identical analytical data as the original
substrates prior to their saponification.
Scheme 7. Final Steps
In summary, the total synthesis of IBA and a new route
to BA have been completed. The highly convergent route
proved to be especially effective using only 13 steps as the
longest linear path from commercially available material in
a yield of 7.0% and 29 steps overall. This route therefore
compares very favorably to all previous synthesis work in
the area and also constitutes the shortest route so far to BA.32
Highlights of this work include the formation of the three
diene units by three different palladium cross couplings, the
formation of the ether containing stereogenic center by an
asymmetric homopropargylation followed by a chemical
kinetic resolution, and finally access to the new building
blocks 5, 6, and 10 and the new triiodide 7.
realized the optimal conversion with the minimum dimer-
ization of 4 resulting from the Glaser coupling.30 At this
stage, we advanced a mixture of inseparable isomers and
dimers directly in the following reduction reaction. Although
chemoselective hydrogenation with Lindlar catalyst failed,
this regioselective cis-reduction of the alkyne, conjugated
Acknowledgment. We are grateful to EPSRC (to S.V.L.,
A.F., and A.L.), to le ministe`re franc¸ais des affaires e´tran-
ge`res (to A.F.), and to el Ministerio de Ciencia e Innovacion
de España (to G.E.-J.).
Supporting Information Available: Experimental data
and characterization for all compounds provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.;
Fu, G. C. Chem. Commun. 2000, 1009–1010.
1
(26) The er was determined by H and 19F NMR of the corresponding
Mosher ester.
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Res. 1975, 44, C-5–C-7. (b) Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher,
M. J.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5834–5845.
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1975, 50, 4467–4470. (b) Dieck, H. A.; Heck, F. R. J. Organomet. Chem.
1975, 93, 259–263.
OL902676T
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Acta 1987, 70, 1025–1040. (b) Avignon-Tropis, M.; Pougny, J. R.
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(32) Total synthesis in ref 7a: 19 steps as longest linear path from
commercially available material and 41 steps overall. Total synthesis in
ref 7b: 21 steps as longest linear path from commercially available material
and 40 steps overall.
(30) Glaser, C. Ber. 1869, 2, 422–424.
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