Synthesis of the spiroketal fragment of bistramide A via an exocyclic enol ether

Article abstract of DOI:10.1016/j.tetlet.2010.06.006

An efficient synthesis of the spirocyclic fragment 1 of bistramides is reported. An olefination reaction of lactone 4 with sulfone 5 gave the enol ether 3, which upon cyclization in acidic media provided the spiroketal ring system. This compound was then converted into the C19-C36 fragment of the bistramides via successive Julia-Kocienski and Horner-Emmons olefinations.

Full text of DOI:10.1016/j.tetlet.2010.06.006

Tetrahedron Letters 51 (2010) 4599–4601
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the spiroketal fragment of bistramide A via an exocyclic enol ether
*
*
Loïc Tomas, David Gueyrard , Peter G. Goekjian
Université de Lyon, Laboratoire Chimie Organique 2, ICBMS—UMR 5246, Université Claude Bernard Lyon 1, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of the spirocyclic fragment 1 of bistramides is reported. An olefination reaction of
lactone 4 with sulfone 5 gave the enol ether 3, which upon cyclization in acidic media provided the spi-
roketal ring system. This compound was then converted into the C19–C36 fragment of the bistramides
via successive Julia–Kocienski and Horner–Emmons olefinations.
Received 11 May 2010
Revised 28 May 2010
Accepted 1 June 2010
Available online 15 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bistramide
Bisatratene
Enol ethers
Spiroketal
Lactone
Julia–Kocienski reagents
Natural product synthesis
Thebistramidesaremarinemetabolitesisolated from Lissoclinum
bistratum by Verbist in 1988 in the case of bistramide A (bistratene A,
Fig. 1),1 and in 1994 for the four additional members of the family
(bistramide B–D and K).2 These molecules lead to growth arrest, dif-
ferentiation, and apoptosis and have thus emerged as potential anti-
inflammatory and anti-tumor agents.
The first total synthesis of bistramide A was reported by Kozmin
and co-workers in 2004.3 Crimmins et al.,4 Panek and co-workers5
and Yadav et al.6 later also performed total syntheses of the natural
compound. Each of these prepared the spiroketal by spirocycliza-
tion of a dihydroxyketone or equivalent, which they approached
via a double crossed metathesis, addition of an acetylene anion
to a lactone, and by Wittig reaction or double TosMIC alkylation,
respectively. Bistramide C has been synthesized by Wipf7 who
used a hypervalent iodine-mediated C–H insertion to form the
spiroketal. We report herein the synthesis of the spiroketal frag-
ment of the bistramides using a new route to enol ethers,8 which
could eventually provide access to novel analogs, such as those
substituted at the C28 position.9
vanced intermediate 1 described by Crimmins et al.4 (Fig. 2).
The spiroketal 2 in turn can be prepared through the enol ether
3 by coupling the lactone 4 with the benzothiazolyl sulfone 5.
Fragment 4 and 5 can be prepared from a common mannitol-
derived precursor 6.
The synthesis of both lactone 4 and sulfone 5 are shown in
Scheme 1. The ester 611 was deprotected to the diol, which was dif-
ferentially protected with a silyl and tetrahydropyranyl ether to
provide the compound 7 in 77% overall yield. The methyl group
was introduced based on the Hanessian’s procedure by the addi-
tion of lithium dimethylcuprate to the unsaturated ester 8 in the
presence of trimethylsilyl chloride.12 Homologation of the ester
by Dibal-H reduction and Wittig reaction furnished the enol ether
9. Finally, acidic hydrolysis and oxidation of the lactol intermediate
provided the lactone 4.
For the synthesis of the Julia–Kocienski reagent 5, ester 6 was
converted into the tosylate derivative 10, which provided the sul-
fone upon substitution with 2-mercaptobenzothiazole and sulfur
oxidation using ammonium molybdate and hydrogen peroxide.13
The key step of the synthesis is the construction of the spirok-
etal subunit by the coupling of lactone 4 and the Julia–Kocienski
We recently reported the synthesis of functionalized exo-gly-
cals from sugar-derived lactones using Julia–Kocienski olefination
reagents, and their conversion into spiroketals.10 This approach is
extended here to the synthesis of enol ethers from non-carbohy-
drate lactones under newly optimized conditions. Thus, the
C19–C40 fragment of bistramides can be obtained via the ad-
Me Me
Me
Me
Me
O
O
40
H
N
O
1
O
36
N
H
O
13
19
OH
28
O
OH
* Corresponding authors. Tel.: +33 04 72 44 81 83; fax: +33 04 72 43 27 52.
E-mail addresses: gueyrard@univ-lyon1.fr (D. Gueyrard), goekjian@univ-lyon1.fr
(P.G. Goekjian).
Bistramide A
Figure 1. Structure of bistramide A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.006

4600
L. Tomas et al. / Tetrahedron Letters 51 (2010) 4599–4601
1) LiHMDS,
BF3.Et2O
THF, -78ºC
2) DBU, THF, rt
Julia-Kocienski
O
O
O
TBDPSO
TBDPSO
O
O
O
TBDPSO
OTBDPS
Bistramide A
OH
O
4
3
+
1
O
S
N
O
Horner-Emmons
O
p-TsOH
CH2Cl2
69% over
two steps
O
S
5
O
O
HO
OTBDPS
O
O
O
O
HO
OTBDPS
O
O
3
2
2
Scheme 2. Spiroketal synthesis.
O
S
N
O
O
OTBDPS
+
O
O
S
(COCl)2, DMSO
Et3N, CH2Cl2
4
5
O
O
OTBDPS
O
HO
OTBDPS
O
O
-78ºC to rt
86%
2
11
Dicyclohexilidene-
D
-mannitol
LiHMDS,12, THF
-78ºC then 60ºC
Figure 2. Retrosynthetic analysis of the C19–C36 fragment.
85%
SO2Btz
BnO
12
TBAF, THF, rt
90%
BnO
O
BnO
O
OTBDPS
O
CO2Et
O
O
1) (COCl)2
,
DMSO, Et3N
OEt
O
14
THF, -78ºC to rt
13
1) AcOH/H2O (8/2), 80ºC
2) TBDPSCl, imidazole, DMAP,
DMF, 0ºC to rt
3) DHP, PPTS, CH2Cl2
73%
2) (EtO)2POCH2CO2Et
1) H2, Pd/C, MeOH, rt
2) LiAlH4 THF, TBDPSCl, 0ºC to rt
3) TsCl, Et3N, CH2Cl2
77%
O
NaH, THF, 0ºC to rt
6
,
H2, Pd/C, EtOH
76%
81%
E/Z 96/4
, 0ºC to rt
, rt
1) TBDPSCl,
Imidazole,
THPO
TBDPSO
DMAP, DMF,
0ºC to rt
TBDPSO
O
HO
O
OEt
OH
O
O
CO2Et
O
2) LiAlH4, THF,
0ºC to rt
O
OTs
O
7
15
1
97%
10
ref. 4
MeLi, CuI, TMSCl,
THF, -78ºC
84%
1) NaH, BtzSH, DMF,
0ºC to rt
O
NPht
2) H2O2
,
(NH4)6Mo7O24
,
4H2O,
O
OH
EtOH, 0ºC to rt
THPO
TBDPSO
71%
16
OEt
O
anti/syn 4/1
Me
Scheme 3. Functionalization of the spiroketal 2.
8
S
N
O
O
O
S
1) Dibal-H, CH2Cl2, -78ºC
2) ClPh3PCH2OMe, NaHMDS,
THF, -78ºC to rt
The completion of the C19–C36 fragment synthesis was per-
formed as illustrated in Scheme 3. Functionalization of the spirok-
etal 2 was started by Swern oxidation providing the aldehyde 11
which was subjected to a Julia–Kocienski reaction17 with sulfone
12. This reaction gave surprisingly poor results under the various
reported experimental conditions: neither the order of addition
(Barbier or premetalation), the solvent (THF or DMF), nor the
choice of base (LiHMDS or KHMDS) significantly improved the
yields, which ranged from 13% to 34%. However, running the reac-
tion at ꢀ10 °C, then warming to 40 °C increased the yield to 69%.
Finally, the best results were obtained by performing the coupling
step at ꢀ78 °C and then heating directly to 60 °C, instead of warm-
ing progressively.18 The resulting spiroketal 13 was thus obtained
in 85% yield.
O
5
76%
O
O
THPO
TBDPSO
TBDPSO
Me
OMe
1) PPTS, dioxane/H2O (9/1)
70ºC
2) PCC, CH2Cl2
73%
Me
4
9
, rt
Scheme 1. Synthesis of the lactone 4 and benzothiazolyl sulfone 5.
reagent 5, followed by elimination in the presence of DBU, to afford
the intermediate enol ether 3. Under previously reported condi-
tions,10,14 the reaction gave virtually none of the desired products
(5–10% yield). As the enol ether was found to be more sensitive to
chromatography than its carbohydrate counterparts, it was
cyclized directly under thermodynamic conditions to provide the
differentially protected spiroketal 2 (Scheme 2). However, the
yields remained disappointing. After investigating a number of
conditions, we found that the addition of a Lewis acid, such as
BF3–etherate, along with the lithiated Julia–Kocienski reagent to
the lactone improved the reaction considerably.15 The spiroketal
2 was thus obtained in 69% yield over the two steps on gram scale
as a single stereoisomer.16 The expected thermodynamically fa-
vored, bis-anomeric stereochemistry at the spiroketal center was
ultimately confirmed by correlation to the Crimmins’ structure.
The silyl group of compound 13 was deprotected to the corre-
sponding spiroketal alcohol, which was then oxidized to undergo
a Horner–Emmons olefination with triethylphosphonoacetate pro-
viding the a,b-unsaturated ester 14 in good yield. Finally, the latter
product was treated by palladium on charcoal under hydrogen
atmosphere to furnish the compound 15. The alcohol was subse-
quently protected as a silyl ether using TBDPSCl and submitted
to reduction of the ester function to obtain compound 1 which
was previously described by Crimmins et al.4 The structure was
confirmed by correlation with the NMR data.
In conclusion, we demonstrated a new access to the C19–C36
fragment of the bistramides using an original enol ether synthesis.

L. Tomas et al. / Tetrahedron Letters 51 (2010) 4599–4601
4601
11. Sharma, A.; Iyer, P.; Gamre, S.; Chattopadhyay, S. Synthesis 2004, 1037–
Such an approach may eventually allow for the preparation of no-
vel analogs, for example those substituted at the C28 position. The
basic spiroketal subunit 2 can be obtained in 22% overall yield on
1040.
12. Hanessian, S.; Sumi, K. Synthesis 1991, 1083–1089.
13. Blakemore, P. R.; Ho, D. K. H.; Mieke Nap, W. Org. Biomol. Chem. 2005, 3, 1365–
1368.
14. Gueyrard, D.; Haddoub, R.; Salem, A.; Said Bacar, N.; Goekjian, P. G. Synlett
2005, 520–522.
gram scale from dicyclohexylidene-D-mannitol. This key interme-
diate was converted on to Crimmins’ C19–C36 fragment 1 with
sequential olefination reactions. The total synthesis of bistramide
A will be reported in due course.
15. A more detailed report of the Lewis acid-catalyzed enol ether synthesis will
appear in due course.
16. Procedure for spiroketal
2 is as follows: To a solution of compound 4
(3.2 mmol, 1 equiv) in tetrahydrofuran (5.3 mL) was added boron trifluoride
etherate (3.16 mmol, 1 equiv) and benzothiazolylsulfone 5 (1.37 g, 3.8 mmol,
1.2 equiv). The mixture was cooled to ꢀ78 °C and lithium hexamethyldisilazide
(1 M in tetrahydrofuran, 6.3 mmol, 2 equiv) was added dropwise. The reaction
was stirred at -78 °C for 30 min, quenched at ꢀ78 °C with acetic acid
(9.48 mmol, 3 equiv), stirred at room temperature for 15 min, and extracted
with ethyl acetate. The organic layers were combined, washed with brine and
dried over anhydrous sodium sulfate. After filtration and evaporation in vacuo,
the residue was dissolved in tetrahydrofuran (30 mL) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (3.32 mmol, 2 equiv) was added over 5 min.
The reaction was stirred at room temperature for 30 min, quenched by an
aqueous NH4Cl solution and diluted with ethyl acetate. The mixture was
extracted with ethyl acetate. The organic layers were combined, washed with
brine and dried over anhydrous sodium sulfate. Filtration and evaporation in
vacuo, provided a mixture of geometrical isomers. The crude mixture was
dissolved in methylene chloride (45 mL), para-toluenesulfonic acid (300 mg,
1.6 mmol) was added and the reaction mixture was stirred at room
temperature for 25 min, hydrolyzed with an aqueous NaHCO3 solution and
extracted with ethyl acetate. The organic layers were combined and washed
with brine, dried over anhydrous magnesium sulfate and filtered. The solvent
was evaporated in vacuo and the crude product was purified by flash
chromatography over silica gel (85:15 petroleum ether/ethyl acetate) to
Acknowledgments
Financial support from the European Commission (Contract No.
LSHB-CT-2004-503467) and from the Ministère de la Recherche et
de la Technologie (Research Fellowship for L.T.) is gratefully
acknowledged. Marine Bayeux is thanked for her technical assis-
tance. We also thank Professor Crimmins for kindly providing
copies of NMR spectra.
Supplementary data
Supplementary data (analytic data and spectra (1H and 13C) for
compound 1) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.06.006.
References and notes
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ꢁ
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