Synthesis of a platform to access bistramides and their analogues

Article abstract of DOI:10.1021/ol202483u

The platform C14-C40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%. Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the versatility of the synthesis of the C14-C40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.

Full text of DOI:10.1021/ol202483u

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6018–6021
Synthesis of a Platform To Access
Bistramides and Their Analogues
Malgorzata Commandeur, Claude Commandeur, and Janine Cossy*
ꢀ
Laboratoire de Chimie Organique Associe au CNRS, ESPCI ParisTech,
10, rue Vauquelin, 75231 Paris Cedex 05, France
Janine.cossy@espci.fr
Received September 13, 2011
ABSTRACT
The platform C14ꢀC40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%.
Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the
versatility of the synthesis of the C14ꢀC40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.
1
2
3
ꢀ
Bistramides AꢀD, K, and L belong to a family of
natural products isolated from an ascidian, Lissoclinum
bistratum, which was collected in New Caledonia
(Noumea). Since their isolation in 1988 and 1994, a
new member of this family, 39-oxobistramide K, has
been isolated in 2009 from Trididemnum cyclops in Ma-
dagascar (Scheme 1).4 Bistramides have shown to exhibit
numerous biological properties such as antiparasitic,5
immunomodulatory,6 neurotoxic,1 antiproliferative,7 and
cytotoxic activities.8 Due to the biological properties and
the challenging molecular structure of bistramides, it is not
surprising that bistramides have elicited considerable in-
terest from the synthetic community.9
ꢁ
(1) Gouiffes, D.; Juge, M.; Grimaud, N.; Welin, L.; Sauviat, M. P.;
Barbin, Y.; Laurent, D.; Roussakis, C.; Henichart, J. P.; Verbist, J. F.
ꢀ
ꢀ
Toxicon 1988, 26, 1129–1136.
(2) (a) For isolation of bistramide A, see: Gouiffes, D.; Moreau, S.;
ꢁ
Helbecque, N.; Bernier, J. L.; Henichart, J. P.; Barbin, Y.; Laurent, D.;
ꢀ
Verbist, J. F. Tetrahedron 1988, 44, 451–459 and cited references. (b) For
isolation of bistratenes, which were deduced to be identical with bistra-
mides, see: Degnan, B. M.; Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.;
Parry, D. L.; Watters, D. J. J. Med. Chem. 1989, 32, 1354–1359.
Herein, we report a convergent approach to a plat-
form that could allow the synthesis of all bistramides
and their analogues. In considering a retrosynthetic
scheme for the bistramides, the C14ꢀC40 spiroketalic
subunit A could be considered as a common fragment
to all bistramides and, accordingly, was selected as our
target molecule (Scheme 2).
Recently, we have shown that a spiroketal of type II
can be formed in good yield and diastereoselectivity from
an ω-unsaturated lactol of type I when treated with FeCl3
(Scheme 3).10
(3) (a) For isolation of bistramides AꢀD and K: Biard, J. F.;
ꢁ
Roussakis, C.; Komprobst, J. M.; Gouiffes-Barbin, D.; Verbist, J. F.;
Cotelle, P.; Foster, M. P.; Ireland, C. M.; Debitus, C. J. Nat. Prod. 1994,
57, 1336–1345. (b) For isolation of bistramides D, K, and L: Biard, J. F.;
Cortadellas, D.; Debitus, C.; Laurent, D.; Roussakis, C.; Verbist, J. F.
WO 9420503 A1, 1994.
(4) Murphy, B. T.; Cao, S.; Brodie, P.; Maharavo, J.; Andriamanan-
toanina, H; Ravelonandro, P.; Kingston, D. G. J. Nat. Prod. 2009, 72,
1338–40.
(5) (a) Gautret, P.; Le Pape, P.; Biard, J. F.; Menard, D.; Verbist,
J. F.; Marjolet, M. Acta Parasitol. 1998, 43, 50–53. (b) See ref 3b.
(6) (a) Pusset, J.; Maillere, B.; Debitus, C. J. Nat. Toxins 1996, 5, 1–6.
(b) See also ref 5a.
(7) (a) See ref 3a. (b) Rizvi, S. A.; Liu, S.; Chen, Z.; Skau, C.; Pytynia,
M.; Kovar, D. R.; Chmura, S. J.; Kozmin, S. A. J. Am. Chem. Soc. 2010,
132, 7288–7290. (c) Kozmin, S. A.; Rizvi, S. US 20100217019 A1, 2010.
(d) Rizvi, S. A.; Courson, D. S.; Keller, V. A.; Rock, R. S.; Kozmin, S. A.
Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 4088–4092. (e) Rivzi, S. A.;
Tereshko, V.; Kossiakoff, A. A.; Kozmin, S. A. J. Am. Chem. Soc. 2006,
128, 3882–3883. (f) Statsuk, A. V.; Bai, R.; Baryza, J. L.; Verma, V. A.;
Hamel, E.; Wender, P. A.; Kozmin, S. A. Nat. Chem. Biol. 2005, 1, 383–
388. (g) Johnson, W. E. B.; Watters, D. J.; Suniara, R. K.; Brown, G.;
Bunce, C. M. Biochem. Biophys. Res. Commun. 1999, 260, 80–88.
(8) (a) Riou, D.; Roussakis, C.; Biard, J. F.; Verbist, J. F. Anticancer
Res. 1993, 13, 2331–2334. (b) Liscia, E.; Riou, D.; Siavoshian, S.; Boesch,
S.; Lebert, V.; Tomasoni, C.; Dabouis, G.; Biard, J. F.; Roussakis, C.
Anticancer Res. 1996, 16, 1209–1212. (c) Siavoshian, S.; Jacquot, C.;
Biard, J. F.; Briand, G.; Roussakis, C. Anticancer Res. 1999, 19, 5361–
5365. (d) see also ref 7.
r
10.1021/ol202483u
Published on Web 10/17/2011
2011 American Chemical Society

Scheme 1. Bistramides AꢀD, K, L and 39-Oxobistramide K
Scheme 4. Retrosynthetic Approach towards A
4-DMAP, CH3CN, rt then 60 °C) to obtain the corre-
sponding bis-carbamate 2 (70% yield).12 After ozonolysis
(O3, CH2Cl2, ꢀ78 °C then Me2S), aldehyde 3 (80% yield)12
was treated with the highly face-selective titanium complex
(S,S)-Ti-I (Et2O, ꢀ78 °C, 18 h),11 leading to the corre-
sponding homoallylic alcohol in good diastereoselectivity
and enantioselectivity (dr >95/5; ee >95%). In order to
transform the latter to the corresponding carboxylic acid 5,
the hydroxyl group was protected (TESCl, imid.) and the
resulting silyl ether 4 was oxidatively cleaved (NaIO4,
RuCl3, CCl4/MeCN/H2O, rt, 16h).9n Afteradeprotection/
protection sequence, the Fmoc-protected amino acid 6 was
isolated in 71% yield over three steps (Scheme 5). Thereby,
fragment C14ꢀC18 was synthesized in an overall yield of
34% yield over seven steps which, according to our knowl-
edge, is the most efficient synthesis for compound 6.9j,n
The synthesis of spiroketal 20 was next under-
taken (Schemes 6, 7) from the commercially available
1,4-butanediol (7). The first step entailed monoprotec-
tion of one of the primary hydroxyl groups as a tert-
Scheme 2. Retrosynthetic Approach to All Bistramides from A
Scheme 3. Fecl3-Catalyzed Spiroketalization of Unsaturated
Lactol
(9) (a) Bauder, C. Eur. J. Org. Chem. 2010, 6207–6216. (b) Tomas, L.;
Gueyrard, D.; Goekjian, P. G. Tetrahedron Lett. 2010, 51, 4599–4601.
(c) Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron Lett. 2010, 51, 5091–
5093. (d) Wrona, I. E.; Lowe, J. T.; Turbyville, T. J.; Johnson, T. R.;
Beignet, J.; Beutler, J. A.; Panek, J. S. J. Org. Chem. 2009, 74, 1897–1916.
(e) Hiebel, M.-A.; Pelotier, B.; Lhoste, P.; Piva, O. Synlett 2008, 1202–
1204. (f) Lowe, J. T.; Wrona, I. E.; Panek, J. S. Org. Lett. 2007, 9, 327–
330. (g) Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587–4589. (h)
Kiyota, H. Top. Heterocycl. Chem. 2006, 5, 65–95. (i) Bauder, C.; Biard,
With the aim of developing a convergent route to A, an
appropriate disconnection point appeared to be at the
C18ꢀC19 bond which led to two fragments B and C.
Our strategy for fragment C would rely on four key
reactions, a HornerꢀWadsworthꢀEmmons (HWE) reac-
tion to introduce the unsaturation at C36ꢀC37, a Wittig
reaction to form the C32ꢀC33 bond, a spiroketalization of
an unsaturated lactol of type D, and a cross-metathesis to
introduce the unsaturation in lactol D. Lactol D would be
synthesized from lactone E whose stereogenic centers
would be controlled by enantioselective crotyltitanation.11
Lactone E would itself be available from the cheap com-
mercially available 1,4-butanediol (7) (Scheme 4).
ꢀ
J. F.; Solladie, G. Org. Biomol. Chem. 2006, 4, 1860–1862. (j) Crimmins,
M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128, 4936–4937. (k)
Zuber, G.; Goldsmith, M. R.; Hopkins, T. D.; Beratan, D. N.; Wipf, P.
Org. Lett. 2005, 7, 5269–5272. (l) Lowe, J. T.; Panek, J. S. Org. Lett.
2005, 7, 3231–3234. (m) Wipf, P.; Hopkins, T. D. Chem. Commun. 2005,
3421–3423. (n) Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc.
2004, 126, 9546–9547. (o) Wipf, P.; Uto, Y.; Yoshimura, S. Chem.;Eur.
J. 2002, 8, 1670–1681. (p) Gallagher, P. O.; McErlean, C. S. P.; Jacobs,
M. F.; Watters, D. J.; Kitching, W. Tetrahedron Lett. 2002, 43, 531–535.
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(q) Solladie, G.; Bauder, C.; Biard, J. F. Tetrahedron Lett. 2000, 41,
7747–7750. (r) Foster, M. P.; Mayne, C. L.; Dunkel, R.; Pugmire, R. J.;
Grant, D. M.; Kornprobst, J. M.; Verbist, J. F.; Biard, J. F.; Ireland,
C. M. J. Am. Chem. Soc. 1992, 114, 1110–1111.
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(10) Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808–1811.
(11) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rhote-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321–2336.
(b) Cossy, J.; Bouzbouz, S.; Pradaux, F.; Willis, C.; Bellosta., V. Synlett
2002, 1595–1606.
The C14ꢀC18 region of the target represented by
amino acid 6 was synthesized from allylamine 1. The
first step consisted of a bis-protection of the amine (Boc2O,
(12) Varney, M. D.; Romines, W. H.; Palmer, C. L. U.S. Patent
5,594,139, 1997, 20 pp.
Org. Lett., Vol. 13, No. 22, 2011
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Scheme 5. Synthesis of C14ꢀC18 Fragment 6
Scheme 6. Synthesis of Intermediate 14
butyldiphenylsilyl ether (TBDPS) (Scheme 6).13 Oxidation
of the second primary hydroxyl group to aldehyde 8
was performed by using a Swern oxidation under stan-
dard conditions [(COCl)2, DMSO, CH2Cl2, ꢀ78 °C, then
Et3N]. This oxidation was followed by a diastereo-
selective crotyltitanation using the highly face-selective
titanium complex (R,R)-[Ti]-I (Et2O, ꢀ78 °C);11 it led
to the corresponding homoallylic alcohol 9 (97% over
two steps, dr >95/5, ee >95%, [R]D20 = þ4.5 (c = 6.4,
EtOH)).14
In order to access the six-membered ring lactone 11,
homoallylic alcohol 9 was first converted to the unsatu-
rated ester 10 in 83% yield, by performing a cross-meta-
thesis with an excess of methyl acrylate in the presence of
the GrubbsꢀHoveyda second generation catalyst (HG-II,
5ꢀ8 mol %)15 under microwave irradiation, for 2 h. After
hydrogenation [H2, (1 atm), Pd/C (10 mol %), EtOAc, 2 h]
and treatment under acidic conditions (cat. CSA, CH2Cl2,
rt, 2 h), lactone 11 was isolated in quantitative yield. Lac-
tone 11 was then transformed to lactol 14 in three steps.
The first step involved the addition of 4-pentenyl magne-
sium bromide to 11 (Et2O, ꢀ20 °C), and lactol 12 was
produced in 93% yield. This latter was then condensed
with allyl acetate 1316 utilizing the GrubbsꢀHoveyda
second generation catalyst15 (HG-II, 10 mol %, micro-
wave irradiation, CH2Cl2, 2 h) to furnish a mixture of two
products: lactol 14 and its glycal derivative. Upon treat-
ment with a catalytic amount of CSA in wet THF, the
crude mixture gave the functionalized lactol 14 (88%), the
precursor of spiroketal 15.
with O3 (ꢀ78 °C, CH2Cl2, then Me2S), to produce the
corresponding aldehyde which was directly used for a
Wittig reaction with phosphonium salt 1617 (n-BuLi,
THF, 0 °C) to generate alkene 17 in 79% yield (two steps).
In order to install the amino group at C19, the silyl ether
was cleaved (TBAF, THF, 93%) and the resulting hydro-
xyl group was transformed to a phthalimido group under
Mitsunobuconditions(phthalimide, PPh3, DIAD). A two-
step one-pot hydrogenation/deprotection sequence (1 atm
of H2, Pd/C) led to hydroxyl-phthalimido spiroketal 18
which was isolated in 87% yield. Oxidation of 18 (TPAP,
˚
NMO, MS 4 A, CH2Cl2) to the corresponding aldehyde
and a HWE reaction, using activated Ba(OH)2 8H2O as a
3
base, afforded enone 19 in 75% yield, when the phthali-
mido group had been cleaved.
The formation of this amido carboxylic acid was not a
dramatic issue as the treatment of 19 with DCC (CH2Cl2,
0 °C, 30 min then rt, 1 h) and then with N-methylhy-
drazine (THF, ꢀ10 °C, 10 min) produced the desired
amino group at C19.18 The resulting amine was then
coupled with the previously synthesized amino acid 6,
using PyBOP (iPr2NEt, DMF, rt), to afford com-
pound 20 which can give access to bistramide C and
39-oxobistramide K after Fmoc removal9n and immedi-
ate peptide coupling with the appropriate C1ꢀC1319
lateral chain of bistramides.
Following treatment of 14 with FeCl3 6H2O (5 mol %,
CH2Cl2, rt)10 the desired spiroketal 15 was isolated in
59% yield (Scheme 7). Spiroketal 15 was then cleaved
3
(13) Freeman, F.; Kim, D. S. H. L.; Rodriguez, E. J. Org. Chem.
1992, 57, 1722–1727.
(17) Compound 16 was prepared according to the following synthetic
sequence: (a) (Benzylation) Widmer, U. Synthesis 1987, 568–570. (b)
(Ester reduction) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57,
5292–5300. (c) (Bromination) Boons, G.-J.; Clase, J. A.; Lennon, J. C.;
Ley, S. V.; Staunton, J. Tetrahedron 1995, 51, 5417–5446. (d) (Preparation
of phosphonium salt) See ref 9f.
(14) Due to the very small value of optical rotation for compound 9,
when the analysis was performed in aprotic solvent, [R]D20 = ꢀ0.2 (c = 1,
CHCl3); measurement was done in protic solvent at higher concentra-
tion to obtain a stable value ([R]D20 = þ4.5 (c = 6.4, EtOH).
(15) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956. (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–8179.
(16) Marion, N.; Gealageas, R.; Nolan, S. P. Org. Lett. 2007, 9,
2653–2656.
(18) Stocksdale, M. G.; Ramurthy, S.; Miller, M. J. J. Org. Chem.
1998, 63, 1221–1225.
(19) See ref 9a, 9cꢀ9h, 9j, 9lꢀ9o.
(20) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986–2012.
6020
Org. Lett., Vol. 13, No. 22, 2011

Scheme 7. Synthesis of Spiroketal 20
Scheme 8. Chemoselective Reduction of the Enone of 19
peptide coupling with the appropriate C1ꢀC13 chain], can
potentially lead to bistramides A, B, D, K, and L.
In summary, compound 20 was synthesized in 19 steps
with an overall yield of 6.2% and can be utilized to
synthesize bistramide C and 39-oxobistramide K by realiz-
ing a peptide coupling with the appropriate carboxylic acid
C1ꢀC13.19 On the other hand, 21 can be the precursor
of bistramides A, B, D, K, and L. Based on recent SAR
studies,7b,d showing that the biological activity of bistra-
mide derivatives is strongly dependent on the C14ꢀC40
subunit, our platform offers a straightforward access to a
range of analogues. Furthermore, due to the versatility of
allyl metals for controlling the stereogenic centers at
C15ꢀC16 and at C22ꢀC23, a great diversity of stereoi-
somers can, in principle, be easily reached.
ꢀ
Acknowledgment. Dr. Serge Sable (Sanofi-Aventis,
Vitry-sur-Seine, France) is acknowledged for his contribu-
tion for the structural determinations.
It is worth noting that enone 19 was reduced to alcohol
21 using (R)-CBS and catechol borane20 in 64% yield
over three steps, starting from 18, with good diastereo-
selectivity (dr >95:5) (Scheme 8). Alcohol 21, through
the sequence described previously [phthalimide removal,
peptide coupling with 6 (Scheme 7), Fmoc removal, and
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 22, 2011
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