Stereoselective synthesis of the C1-C13 fragment of bistramide A

Article abstract of DOI:10.1016/j.tetlet.2010.07.119

The C1-C13 fragment of bistramide A was prepared from 5-hexenoic acid in 15 linear steps and in 16% overall yield. The core 2,6-trans-tetrahydropyran ring was obtained via a kinetically controlled oxa- Michael cyclization from the corresponding chiral α,β

Full text of DOI:10.1016/j.tetlet.2010.07.119

Tetrahedron Letters 51 (2010) 5091–5093
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the C1–C13 fragment of bistramide A
a,b,c,
Marie-Aude Hiebel a,b,c, Béatrice Pelotier a,b,c, , Olivier Piva
*
*
a Université Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Equipe Surcoof, 43 boulevard du 11 novembre 1918, Villeurbanne F-69622, France
b CNRS, UMR5246, Villeurbanne F-69622, France
c Université de Lyon, Lyon F-69622, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The C1–C13 fragment of bistramide A was prepared from 5-hexenoic acid in 15 linear steps and in 16%
overall yield. The core 2,6-trans-tetrahydropyran ring was obtained via a kinetically controlled oxa-
Michael cyclization from the corresponding chiral a,b-unsaturated hydroxyester. This precursor was pre-
pared by using a diastereoselective alkylation reaction using Davies Superquat auxiliary and a diastereo-
selective Roush’s allylboration as key steps.
Received 21 June 2010
Revised 13 July 2010
Accepted 21 July 2010
Available online 25 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bistramide
Tetrahydropyrans
Intramolecular oxa-Michael addition
Cyclization
Bistramide A is a member of a family of bioactive cyclic polye-
thers isolated from the marine ascidian Lissoclinum bistratum near
New Caledonia.1,2 This macrolide induces sodium channel inhibi-
tion3 and has immunomodulating properties.4 In addition, bistra-
mide A exhibits high cytotoxicity and has significant effects on
cell cycle regulation,2,5 in particular a potent antiproliferative pro-
file.6 The mode of action of bistramide A to explain this antiprolif-
erative activity was initially attributed to a highly selective
activation of protein kinase C isotope d.7 More recent studies have
identified actin as the primary cellular receptor of bistramide A
establishing this marine metabolite as a potential lead for a new
class of anticancer agents.8–10
in these cases obtained by lactonization of an appropriate hydroxy-
ester precursor. Panek and co-workers have described the synthe-
sis of the C1–C13 fragment through a [4 + 2]-annulation utilizing a
chiral syn-(Z)-crotylsilane reagent.13,15 Depending on the crotylsi-
lane stereochemistry, this methodology enabled the access to all
eight possible stereoisomers of the tetrahydropyran subunit, which
allowed the recently published synthesis and screening of a 35-
member analog library of bistramide A.16 As a part of a program
devoted to the discovery of new modulators of protein kinases,
we were interested in the total synthesis of bistramide A and ana-
logs. In parallel to our work on the formation of tetrahydropyran
analogs of the C1–C13 subunit,17,18 our objective was to design a
novel diastereoselective synthesis of this fragment, which we dis-
close herein.
The disconnection of bistramide A amide linkages leads to three
fragments: a central c-aminoacid residue connected to a tetrahy-
dropyran subunit (C1–C13 fragment Fig. 1) and a spiroketal sub-
unit. All syntheses of this target macrolide reported so far have
been designed on this convergent approach.11–14 In the first total
synthesis of bistramide A by Kozmin et al. providing the full struc-
tural and stereochemical assignment of this complex molecule, the
construction of the C1–C13 fragment was based on a ring-closing
metathesis reaction to form an intermediate unsaturated d-lac-
tone. After hydrogenation, this compound was then transformed
into the tetrahydropyran ring via a key C-glycosidation to intro-
duce the C1–C4 enone fragment.11 The same strategy to access
the tetrahydropyran subunit from the saturated d-lactone was ap-
plied in two other syntheses.12,14 The intermediate d-lactone was
O
O
H
N
1
O
N
13 H
OH O
bistramide A
O
O
OH
O
O
1
O
13 OEt
1
* Corresponding authors. Fax: +33 472448136 (B.P.).
E-mail addresses: beatrice.pelotier@univ-lyon1.fr (B. Pelotier), olivier.piva@u-
niv-lyon1.fr (O. Piva).
Figure 1. Fragment C1–C13 of bistramide A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.119

5092
M.-A. Hiebel et al. / Tetrahedron Letters 51 (2010) 5091–5093
The retrosynthetic analysis is shown in Scheme 1. The enone
alcohol was thus obtained in high yield as a 4:1 mixture of diaste-
reoisomers, from which the desired isomer 9 could be isolated in
73% yield. A TBS protection of the resulting secondary alcohol, fol-
lowed by PMB deprotection of 10, afforded primary alcohol 11,
which was oxidized in the presence of Dess–Martin periodinane.22
A Wittig reaction between aldehyde 12 and commercially available
(carbethoxymethylene) triphenylphosphorane provided the geo-
metric (E)-isomer 13 in 94% yield. Removal of the TBS-protecting
group under acidic conditions23 provided the target Michael accep-
tor 3 in quantitative yield.
The key transformation of this synthesis was the intramolecular
oxa-Michael cyclization and its stereochemical outcome from
functionalized Michael acceptor 3. Previous studies on nor-methyl
derivatives have shown that NaH-promoted conjugate addition
(ꢀ78 °C to rt) could afford 2,6-trans disubstituted tetrahydropy-
rans as the major stereoisomer.18,24,25 Preliminary attempts26 in
the presence of NaH or t-BuOK indicated that cyclization occurred
very rapidly at ꢀ78 °C while t-BuOK gave a higher ratio in favor of
the desired isomer than NaH. Therefore less basic t-BuOK was used
instead of NaH. Treatment of 3 for 25 min at ꢀ78 °C in the presence
of 1.1 equiv of t-BuOK provided a 3:1 mixture of cyclization prod-
ucts in favor of the 2,6-trans isomer in 96% yield (Scheme 4).27 The
reaction had to be carried out under kinetic conditions (low tem-
perature, short reaction time) in order to avoid the formation of
the thermodynamic cycloadduct epi-2. Indeed, when the reaction
was allowed to warm up to rt or when cycloadduct epi-2 was
resubmitted under the reaction conditions, this starting material
was recovered unchanged in both cases. The diastereomers were
separable by column chromatography and tetrahydropyran 2 could
be isolated in 72% yield. The relative 2,6-trans relationship of the
protons adjacent to the oxygen in THP 2 was attributed on the ba-
sis of the values of the chemical shifts of these protons (4.30 and
3.64 ppm) which are higher for the trans-isomer than for the cis-
isomer epi-2 (3.42 and 3.32 ppm).
moiety is accessible in a straightforward manner from allyl-substi-
tuted tetrahydropyran 2. This substrate may be constructed
through a Wittig reaction and a diastereoselective allylation reac-
tion on aldehyde 4, which can be derived from 5-hexenoic acid.
The synthesis of aldehyde 4 depicted in Scheme 2 was achieved
from 5-hexenoic acid, which is commercially available but can also
be prepared on a large scale in one step from inexpensive cyclo-
hexanone.19 This acid was converted into chiral N-acyl compound
5 with Davies’ 4-isopropyl-5,5-dimethyl Superquat auxiliary.20 The
asymmetric alkylation of N-acyl enolate derived from 5 with
methyl iodide furnished methylated product 6 which could be iso-
lated as a single diastereoisomer in 86% yield after recrystalliza-
tion. Rapid treatment of 6 with LiAlH4 yielded alcohol 7 and the
recovery of the chiral auxiliary. A PMB protection of 7 followed
by an oxidative cleavage of olefin 8 delivered aldehyde 4 in high
yield.
Aldehyde 4 was next subjected to a diastereoselective allylation
reaction with chiral diisopropyl tartrate allylboronate according to
Roush’s methodology (Scheme 3).21 The corresponding homoallylic
O
O
O
2
O
1
13 OEt
1
CO2Et
OH
3
O
OPMB
CO2Et
4
Scheme 1. Retrosynthetic analysis.
i. (COCl)2, DMF cat.
ii. L, BuLi, -78°C to rt
The completion of the C1–C13 fragment was achieved in three
steps from 2 according to a sequence previously reported by Kit-
ching and co-workers (Scheme 5).28 Oxidative cleavage of the ter-
minal olefin afforded the corresponding intermediate aldehyde,
which was directly subjected to an allylation reaction with zinc
powder and allyl bromide under biphasic conditions.29 Homoal-
lylic alcohol 14 was thus obtained in 92% yield over two steps
and subjected to oxidation under Swern conditions.30 Use of excess
O
5
N
O
OH
90%
O
O
86% (after
recrystallisation)
O
O
LDA, MeI
0°C to rt
L =
HN
LiAlH4, Et2O
rt, 20 min
O
6
N
OH
91%
7
O
O
PMB-trichloroacetimidate
CSA cat., 0°C to rt
94%
tBuOK (1.1 eq)
THF, -78°C, 25 min
+
i. NMO, OsO4
ii. NaIO4
O
2
O
epi-
OH
3
96%
CO2Et
CO2Et
2
CO2Et
O
OPMB
OPMB
94%
8
4
3 / 1
Scheme 2. Synthesis of aldehyde 4.
Scheme 4. Oxa-Michael cyclization.
CO2iPr
CO2iPr
O
TBSCl
B
imidazole, DMAP
CH2Cl2, rt
O
toluene, -78°C
OPMB
DDQ
O
OPMB
OH OPMB
OTBS
91%
94%
4
9
10
CH2Cl2, H2O
96%
dr = 4/1
(73% isolated)
CO2Et
Ph3P
Dess-Martin
CH2Cl2, 0°C to rt
periodinane
CSA cat.
CH2Cl2, MeOH
OH
O
OTBS
OTBS
OTBS
CO2Et
94%
83%
11
13
quant.
12
OH
3
CO2Et
Scheme 3. Synthesis of Michael acceptor 3.

M.-A. Hiebel et al. / Tetrahedron Letters 51 (2010) 5091–5093
15. Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231–3234.
5093
16. 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.
17. Hiebel, M.-A.; Pelotier, B.; Goekjian, P.; Piva, O. Eur. J. Org. Chem. 2008, 713–
720.
O
2
CO2Et
1) i. NMO, OsO4 cat.
18. Hiebel, M.-A.; Pelotier, B.; Lhoste, P.; Piva, O. Synlett 2008, 1202–1204.
19. Ogibin, Y. N.; Starostin, E. K.; Aleksandrov, A. V.; Pivnitsky, K. K.; Nikishin, G. I.
Synthesis 1994, 901–903.
20. Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1
1999, 387–398.
ii. NaIO4
92% (2 steps)
2) allylbromide, Zn
THF/NH4Cl aq
OH
21. (a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186–
8190; (b) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. C. J. Org. Chem.
1990, 55, 4109–4117.
CO2Et
77%
O
14
22. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
23. Treatment of
x-silyloxy-a,b-unsaturated esters under basic conditions (TBAF)
(COCl)2, DMSO, Et3N
CH2Cl2, -78°C to rt
is known to yield tetrahydropyrans by a tandem deprotection/cyclization
process. See, for example: (a) Horita, K.; Hachiya, S.; Nagasawa, M.; Hikota, M.;
Yonemitsu, O. Synlett 1994, 38–40; (b) Noda, A.; Aoyagi, S.; Machinaga, N.;
Kibayashi, C. Tetrahedron Lett. 1994, 35, 8235–8240.
O
CO2Et
24. Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. J. Chem. Soc., Perkin
Trans. 1 1996, 967–969.
25. Bates, R. W.; Palani, K. Tetrahedron Lett. 2008, 49, 2832–2834.
O
1
26. Preliminary experiments on
a 1/1 diastereomeric mixture of alcohols 3
Scheme 5. Completion of the fragment C1–C13.
performed at ꢀ78 °C with NaH and t-BuOK, respectively, showed that higher
amounts of the desired isomer was obtained in the presence of t-BuOK.
27. To a solution of alcohol 3 (0.27 mmol, 60 mg) in THF (2 mL) at ꢀ78 °C was
added t-BuOK (0.29 mmol, 33 mg). After 25 min stirring at ꢀ78 °C, a saturated
solution of NH4Cl (3 mL) was added and the mixture warmed up to rt.
Extraction was carried out with Et2O (3 ꢁ 3 mL). The organic phase was dried
over MgSO4, filtered, and was concentrated in vacuo. The purification of the
residue was done by flash column chromatography (hexanes/EtOAc, 98:2)
furnished cycloadduct 2 in 72% yield (0.19 mmol, 43 mg) as a colorless oil.
Rf = 0.7 (hexanes/EtOAc, 90:10). 1H NMR d 0.81 (d, J = 7.0 Hz, 3H), 1.26 (t,
J = 7.1 Hz, 3H), 1.27–1.40 (m, 2H), 1.61–1.67 (m, 2H), 1.86–1.98 (m, 1H), 2.07–
2.26 (m, 2H), 2.31 (dd, JAB = 14.0 Hz, J = 4.5 Hz, 1H), 2.71 (dd, JAB = 14.0 Hz,
J = 10.6 Hz, 1H), 3.60–3.68 (m, 1H), 4.14 (qt, J = 7.1, 1.1 Hz, 2H), 4.30 (dt,
J = 10.7, 4.7 Hz, 1H), 4.98 (br d, J = 10.4 Hz, 1H), 5.03 (br d, J = 17.5 Hz, 1H), 5.78
(ddt, J = 17.1, 10.2, 7.0 Hz, 1H). 13C NMR d 14.3, 16.7, 26.7, 30.3, 32.9, 33.2, 40.2,
triethylamine in this last step enabled the in situ isomerization of
the resulting
a,b-unsaturated ketone into conjugation to provide
target enone 1 in 77% yield.31
In conclusion, a diastereoselective synthesis of the C1–C13 frag-
ment of bistramide A has been achieved in 15 steps with a 16%
overall yield. The core-trisubstituted tetrahydropyran was ac-
cessed through a key oxa-Michael cyclization under kinetic condi-
tions to control its 2,6-trans relative stereochemistry.
60.5, 69.2, 74.2, 116.4, 135.3, 172.1. IR (film)
1438, 1370, 1285, 1191, 1711, 1037, 911 cmꢀ1
13H22O3Na+ [M+Na+] 249.1467, found 249.1468. a 2D5
½ ꢂ
m
3071, 2976, 2952, 2932, 1737,
HRMS (ESI) calcd for
¼ ꢀ60:4 (c = 0.98,
Acknowledgments
.
C
The authors are grateful to the European Community for fund-
ing this work (European Union FP6 Integrated Project No. LSHB-CT-
2004-503467 on protein kinases). We also thank CNRS and Univer-
sity Lyon1 for the financial support.
CHCl3). Isomer epi-2: isolated as a colorless oil (0.059 mmol, 13 mg, 22%).
Rf = 0.5 (hexanes/EtOAc, 95:5). 1H NMR d 0.82 (d, J = 6.4 Hz, 3H), 1.25 (t,
J = 7.1 Hz, 3H), 1.20–1.40 (m, 3H), 1.58–1.78 (m, 2H), 2.10 (dd, JAB = 14.2 Hz,
J = 6.4 Hz, 1H), 2.25 (dd, JAB = 14.2 Hz, J = 7.2 Hz, 1H), 2.35 (dd, JAB = 14.5 Hz,
J = 9.5 Hz, 1H), 2.60 (dd, JAB = 14.5 Hz, J = 3.5 Hz, 1H), 3.28–3.36 (m, 1H), 3.42
(td, J = 9.5, 3.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.96–5.06 (m, 2H), 5.78 (ddt,
J = 17.1, 10.2, 6.8 Hz, 1H).
References and notes
28. Gallagher, P. O.; McErlean, C. S. P.; Jacobs, M. F.; Watters, D. J.; Kitching, W.
Tetrahedron Lett. 2002, 43, 531–535.
29. Marton, D.; Stivanello, D.; Tagliavini, G. J. Org. Chem. 1996, 61, 2731–2737.
30. Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 4537–4538.
1. Gouiffes, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.; Henichard, J. P.; Barbin, Y.;
Laurent, D.; Verbist, J. F. Tetrahedron 1988, 44, 451–459.
2. Biard, J. F.; Roussakis, C.; Kornprobst, 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.
31. To a solution of freshly distilled oxalyl chloride (0.09 mmol, 8
l
L) in dry DCM
(1.2 mL) cooled at ꢀ78 °C was added dry DMSO (0.19 mmol, 13
lL). After
15 min of stirring, a solution of alcohol 14 (0.078 mmol, 21 mg) in dry DCM
(0.8 mL) was added at ꢀ78 °C. The mixture was stirred for a further 20 min at
that temperature before adding dropwise a solution of freshly distilled Et3N
3. Sauviat, M. P.; Gouiffes-Barbin, D.; Ecault, E.; Verbist, J. F. Biochim. Biophys. Acta
1992, 1103, 109–114.
4. Pusset, J.; Maillere, B.; Debitus, C. J. Nat. Toxins 1996, 5, 1–6.
5. 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.
6. Riou, D.; Roussakis, C.; Robillard, N.; Biard, J. F.; Verbist, J. F. Biol. Cell 1993, 77,
261–264.
7. Griffiths, G.; Garrone, B.; Deacon, E.; Owen, P.; Pongracz, J.; Mead, G.; Bradwell,
A.; Watters, D.; Lord, J. Biochem. Biophys. Res. Commun. 1996, 222, 802–808.
8. 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.
9. Rizvi, S. A.; Tereshko, V.; Kossiakoff, A. A.; Kozmin, S. A. J. Am. Chem. Soc. 2006,
128, 3882–3883.
10. 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.
(4 mmol, 550 lL) in DCM (2 mL). The reaction mixture was allowed to warm
up to rt and stirred for 24 h. The mixture was then diluted with DCM (10 mL)
and washed with saturated aqueous solutions of NaHCO3 (10 mL), NH4Cl
(10 mL), and NaCl (5 mL). The organic layer was dried over MgSO4, filtered, and
was concentrated in vacuo. The crude residue was purified by flash column
chromatography on silica gel (hexanes/EtOAc, 85:15) to yield enone
1
(0.060 mmol, 16 mg) as a colorless oil in 77% yield. Rf = 0.5 (hexanes/EtOAc,
80/20). 1H NMR d 0.81 (d, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.27–1.43 (m,
2H), 1.59–1.78 (m, 2H), 1.87–1.95 (m, 1H), 1.89 (dd, J = 7.0, 1.7 Hz, 3H), 2.34
(dd, JAB = 14.5 Hz, J = 4.7 Hz, 1H), 2.51 (dd, JAB = 15.2 Hz, J = 6.2 Hz, 1H), 2.71
(dd, JAB = 14.5 Hz, J = 10.0 Hz, 1H), 2.78 (dd, JAB = 15.2 Hz, J = 6.4 Hz, 1H), 4.05–
4.32 (m, 3H), 4.28 (br dt, J = 9.8, 4.9 Hz, 1H), 6.11 (dq, J = 15.7, 1.7 Hz, 1H), 6.83
(dq, J = 15.7, 6.8 Hz, 1H). 13C NMR d 14.3, 16.7, 18.4, 26.6, 30.6, 32.8, 33.1, 45.9,
60.6, 66.7, 74.3, 132.6, 143.3, 172.0, 198.4. HRMS (ESI) calcd for C15H24O4Na+
11. Statsuk, A. V.; Liu, D.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 9546–9547.
12. Crimmins, M. T.; DeBaillie, A. C. J. Am. Chem. Soc. 2006, 128, 4936–4937.
13. Lowe, J. T.; Wrona, I. E.; Panek, J. S. Org. Lett. 2007, 9, 327–330.
14. Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587–4589.
[M+Na+] 291.1572, found 291.1572. ½a 2D5
¼ ꢀ50:0 (c = 0.4, CHCl3). Literature:
ꢂ
½
a 2D5
ꢂ
¼ ꢀ54:0 (c = 0.1, CHCl3) for the acid derivative.16