Efficient and stereoselective access to the polyol fragment C9-C16 of ansamycin antibiotics

Article abstract of DOI:10.1021/ol901144j

Image Persented Efficient synthesis of the fragment C9-C16 bearing the anti, syn stereotriad of ansamycin antibiotics is described. Key steps for controlling the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction of a β-ketosulfoxide.

Full text of DOI:10.1021/ol901144j

ORGANIC
LETTERS
2
009
Vol. 11, No. 16
542-3545
Efficient and Stereoselective Access to
the Polyol Fragment C9-C16 of
Ansamycin Antibiotics
3
Michel Obringer, Marie Barbarotto, Sabine Choppin, and Fran c¸ oise Colobert*
Laboratoire de st e´ r e´ ochimie associ e´ au CNRS, UMR 7509, UniVersit e´ de Strasbourg,
ECPM, 25 rue Becquerel, 67087 Strasbourg Cedex 2, France
francoise.colobert@unistra.fr
Received June 2, 2009
ABSTRACT
Efficient synthesis of the fragment C9-C16 bearing the anti,syn stereotriad of ansamycin antibiotics is described. Key steps for controlling
the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction
of a ꢀ-ketosulfoxide.
Isolation from microbial sources (Streptomycines generally)
and structure elucidation of an important class of complex
1
macrolactam antibiotics, the ansamycins (mycotrienins), has
been reported in the last two decades. These secondary
metabolites are very attractive because of their powerful
biological activity, for example, antibacterial, antifungal, or
antitumor properties. The ansamycin class of natural products
2
includes mycotrienins (or ansatrienins) I (1a) and II (2a),
3
4
trienomycin A (3a), cytotrienin A (2b), and thiazinotrieno-
(
(
1) Wrona, I. E.; Agouridas, J.; Panek, J.S. C. R. Chimie 2008, 11, 1483.
2) Sugita, M.; Hiramoto, S.; Ando, C.; Sasaki, T.; Furihata, K.; Seto,
H.; Otake, N. J. Antibiot. 1985, 38, 799, and references cited therein.
Figure 1
.
Members of the triene-ansamycins group.
(
3) (a) Nomoto, H.; Katsumata, S.; Takahashi, K.; Funayama, S.;
Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1989, 42, 479. (b)
Blagg, B. S.J.; Peng, W. Org. Synth. 2006, 8, 965.
(
4) (a) Zhang, H. P.; Kakeya, H.; Osada, H. Tetrahedron Lett. 1997,
5
mycin (4a) (Figure 1). More recently, quinotrierixin (1a with
3
8, 1789. (b) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamura,
T.; Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Ang. Chem.,
Int. Ed. 2008, 47, 6657.
3
a SCH on the quinone ring), demethyltrienomycins A and
B, and demethyltrienomycinol (without a methyl at C14)
(5) Hosokawa, N.; Yamamoto, S.; Uehara, Y.; Hori, M.; Tsuchiya, K. S.
J. Antibiot. 1999, 52, 485, and references cited herein.
were isolated from the culture broth of Streptomyces species
10.1021/ol901144j CCC: $40.75
Published on Web 07/22/2009
 2009 American Chemical Society

PAE37 and were found to have cytocidal activity against
HeLa cells. All these compounds are characterized by a 21-
membered cyclic lactam including a (E,E,E)-triene and four
chiral centers. A series of SAR studies were performed to
screen the most active part of the triene ansamycins. These
One synthetic key issue of the ansamycin is the stereocontrol
of the stereotriad C11-C13. Using our Reformatsky-type
reaction between R-bromo-R′-sulfinyl ketone 6 and the
aldehyde 7 as well as the well-established DIBALH or Lewis
acid/DIBALH diastereoselective reduction of the corre-
sponding ꢀ-keto sulfoxide 8, we report a highly stereose-
lective access to the stereotriad (Scheme 1). To facilitate
6
1
6
3
results indicate that the stereotriad C11-C13, the CH group
6
,7
3
at C14, and the OCH group at C3 are essential.
Absolute and relative stereochemistry of the stereogenic
centers of these ansamycins have been determined or
assigned by Smith and co-workers through careful degra-
Scheme 1
.
Retrosynthesis toward the C9-C16 Unit 5 of
8
dative and spectroscopic methods. To date, only Smith,
Ansamycin
Panek, and very recently Hayashi have reported the total
9
10
synthesis of trienomycin, mycotrienin, thiazinotrienomy-
1
1
4b
cin, and cytotrienin A as well as the macrocyclic core
1
2
of cytotrienin. More recently, Kirschning et al. reported a
multigram scale synthesis of the ansatrienol derivative.
1
3
In relation with a program devoted to asymmetric synthesis
1
4
mediated by sulfoxides, we have recently described a
highly stereoselective Reformatsky-type reaction of chiral
non racemic R-bromo-R′-sulfinyl ketones with aldehydes in
1
5
2
the presence of SmI .
In this paper, we describe the synthesis of the C9-C16
unit 5 of ansamycins bearing the anti,syn stereotriad C11-C13.
elucidation of mechanism of action of ansamycins, the
development of a methodology allowing the synthesis of
some stereoisomers of the stereotriad is highly important.
With our methodology, four diastereomers of the stereotriad
could be easily accessible depending on the absolute con-
figuration of the sulfinyl moiety.
(
6) (a) Kawamura, T; Tashiro, E.; Yamamoto, K.; Shindo, K.; Imoto,
M. J. Antibiot. 2008, 61, 303. (b) Kawamura, T; Tashiro, E.; Shindo, K.;
Imoto, M. J. Antibiot. 2008, 61, 312.
(
7) (a) Funayama, S.; Anraku, Y.; Mita, A.; Yang, Z.-B.; Shibata, K.;
Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1988, 41, 1223. (b)
Tashiro, E.; Hironiwa, N.; Mitsuhiro, K.; Futamura, Y.; Suzuki, S.-I.; Nishio,
M.; Masaya, I. J. Antibiot. 2007, 60, 549. (c) Kawamura, T; Tashiro, E.;
Yamamoto, K.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 303. (d)
Kawamura, T; Tashiro, E.; Shindo, K.; Imoto, M. J. Antibiot. 2008, 61,
312.
(
8) (a) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo,
C. J. J. Am. Chem. Soc. 1990, 112, 7425. (b) Smith, A. B., III; Wood,
J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Komiyama, K.;
Omura, S. J. Am. Chem. Soc. 1996, 118, 8308.
Scheme 2
.
Synthesis of the Aldehyde 7
(
9) (a) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am.
Chem. Soc. 1995, 117, 10777. (b) Smith, A. B., III; Barbosa, J.; Wong,
W.; Wood, J. L. J. Am. Chem. Soc. 1996, 118, 8316.
(
10) (a) Panek, J. S.; Masse, C. E. J. Org. Chem. 1997, 62, 8290. (b)
Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am. Chem. Soc. 1998,
20, 4123.
11) (a) Smith, A. B., III; Wan, Z. Org. Lett. 1999, 1, 1491. (b) Smith,
1
(
A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738.
(
(
12) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525.
13) Kashin, D.; Meyer, A.; Wittenberg, R.; Sch o¨ ning, K.-U.; Kamlage,
S.; Kirschning, A. Synthesis 2007, 304.
14) Overviews: (a) Carre n˜ o, M. C. Chem. ReV. 1995, 95, 1717. (b)
Hanquet, G.; Colobert, F.; Lanners, S.; Solladi e´ , G. ARKIVOC 2003, 7,
28. (c) Fernandez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651. Recent work:
c) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem. 2005,
334. (d) Broutin, P.-E.; Colobert, F. Org. Lett. 2005, 7, 3737. (e) Broutin,
(
3
(
3
P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113. (f) Colobert, F.;
Ballesteros-Garrido, R.; Leroux, F. R.; Ballesteros, R.; Abarca, B. Tetra-
hedron Lett. 2007, 48, 6896. (g) Colobert, F.; Choppin, S.; Ferreiro-Mederos,
L.; Obringer, M.; Luengo Arratta, S.; Urbano, A.; Carre n˜ o, M. C. Org.
Lett. 2007, 9, 4451. (h) Carre n˜ o, M. C.; Hernandez-Torres, G.; Urbano,
A.; Colobert, F. Eur. J. Org. Chem. 2008, 12, 2035.
17
The synthesis of the aldehyde 7 depicted in Scheme 2
began with the formation of the diethyl acetal of ethyl
pyruvate in the presence of triethyl orthoformate in concen-
trated sulfuric acid. Reduction of the ester moiety with
(
15) (a) Obringer, M.; Colobert, F.; Neugnot, B.; Solladi e´ , G. Org. Lett.
2
003, 5, 629. (b) Obringer, M.; Colobert, F.; Solladi e´ , G. Eur. J. Org. Chem.
006, 1455.
2
(
16) Early work: (a) Carre n˜ o, M. C.; Garc ´ı a Ruano, J. L.; Mart ´ı n, A.;
4
LiAlH followed by transacetalization in the presence of
Pedregal, C.; Rodr ´ı guez, J. H.; Rubio, A.; S a´ nchez, J.; Solladi e´ , G. J. Org.
Chem. 1990, 55, 2120. Recent examples: (b) Lanners, S.; Hassan, N.-A.;
Salom-Roig, X. J.; Hanquet, G. Angew. Chem. Int. Ed. 2007, 46, 7086. (c)
Raghavan, S.; Krishnaiah, V. Tetrahedron Lett. 2006, 47, 7611. (d)
Cardellicchio, C.; Omar, O. H.; Naso, F.; Capozzi, M. A. M.; Capitellic,
F.; Bertolasi, V. Tetrahedron: Asymmetry 2006, 17, 223. (e) Des Mazery,
R.; Pullez, M.; L o´ pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2005, 127, 9966.
diethylene glycol afforded the dioxolane derivative which
was then submitted to a Moffatt-type oxidation to give the
aldehyde 7 in 52% overall yield.
(17) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996,
37, 3881.
Org. Lett., Vol. 11, No. 16, 2009
3543

2
We applied our SmI -promoted Reformatsky-type reaction
between R-bromo-R′-tert-butylsulfinyl ketone 6 synthesized
15a
Scheme 4. Obtaining the Syn-Anti Stereotriad
as previously reported and the aldehyde 7, and we obtained
the Reformatsky adduct 8 in excellent syn diastereoselec-
1
8
tivity and good yield (Scheme 3).
Scheme 3. Reformatsky-Type Reaction between 6 and 7
aldehyde 11, which was then submitted to a Wittig reaction
with Ph PdCH in THF to give the corresponding olefin 12
in 88% yield. Further regioselective hydroboration of 12 with
2 2
-BBN in THF followed by treatment with NaOH and H O
afforded the alcohol 13 in 90% yield which was protected
as a silylated ether 14 (Scheme 5).
To confirm the absolute configuration of the major
stereoadduct, after chromatographic separation and crystal-
lization, suitable crystals were obtained and the structure
3
2
9
(
3R,4R)-8 was determined by X-ray analysis (Figure 2).
Scheme 5. Synthesis of the Methyl Ketone 16
Figure 2
for clarity.
. ORTEP plot of (3R,4R)-8. Hydrogen atoms are omitted
In order to obtain the (2R,3R,4R,RS) stereotriad of ansamy-
cins, we performed the diastereoselective reduction of 8 with
3
DIBALH in the presence of Yb(OTf) followed by protection
19
of the resulting 1,3-diols by a silylated bridge giving after
flash chromatography the enantiopure (2R,3R,4R,RS)-10
2
0
[
[R]
assignment was controlled by NOESY experiments (Scheme
).
It should be pointed out that the stereoisomer
2S,3R,4R,RS) was easily obtained by reduction with
DIBALH only, and both diastereomers (2R,3S,4S,SS) and
2S,3S,4S,SS) could be efficiently synthesized using the
D
) +34.8 (c 0.45, CHCl
3
)] whose stereochemical
4
(
(
enantiomer (S) of the sulfinyl moiety.
Treatment of the enantiopure compound 10 under Pum-
2
0
merer conditions afforded after flash chromatography the
In order to obtain the methyl ketone 16 which will be
transformed into the vinylic ester 5, we had to perform a
selective deprotection of the dioxolane 14 in the presence
of the silylene bridge. The first attempt using PPTS in acetone
and water afforded only the deprotection of the TBDMS
(
18) Determined by proton NMR analysis of the product on the basis
15
of our previous results.
(
19) (a) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.
b) Toshima, K.; Jyojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.;
Matsumura, S. J. Org. Chem. 2001, 66, 1708.
20) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
(
(
3544
Org. Lett., Vol. 11, No. 16, 2009

ether. Therefore, we tried the deprotection on the free alcohol
3 with PPTS in acetone/water at reflux or with acetic acid/
water at room temperature, but no reaction occurred.
1
Scheme 6. Synthesis of the Z Olefin 5
Nevertheless, more acidic conditions such as p-toluene-
2
1
sulfonic acid in water at room temperature or use of CAN
led to the deprotection of the dioxolane as well as the
deprotection of the silylated bridge. Finally, formic acid in
2
2
presence of CuSO
1/1) afforded the methyl ketone 15 in 65% yield whose
primary alcohol was then silylated to give 16 (Scheme 5).
4
2 2
in a mixture of CH Cl and hexane
(
8
b
Starting from the methyl ketone 16, we used the Smith
procedure to obtain the methyl-substituted double bond with
Z selectivity. The kinetic enolate of 16 was obtained by
treatment with sodium bis(trimethylsilyl)amide and trapped
with diethyl chlorophosphate to give the corresponding enol
phosphate. Elimination induced by t-BuLi provided the
terminal alkyne 17 in 73% yield. Treatment of 17 with t-BuLi
and methyl chloroformiate afforded 18. Finally, methyl
cuprate (Me
2
CuLi) addition was performed in THF at -20
°
C giving in 61% yield the desired Z olefin 5. The
tics. The asymmetric synthesis of C9-C16 fragment 5 has
been achieved in 11 steps and an overall yield of 6%. Total
synthesis of trienomycinol 3 (with R ) H) is currently
underway in our laboratory.
stereochemistry of the double bond was controlled by
NOESY experiments considering the interaction between
H15 and the adjacent methyl group (Scheme 6).
In conclusion, our strategy based on the stereoselective
Reformatsky-type reaction followed by the reduction of
Acknowledgment. This work was supported by the CNRS
and Minist e` re de la Recherche. M.O. and M.B. thank the
Minist e` re de la Recherche for a fellowship.
ꢀ
-ketosulfoxides has been exemplified by the enantiopure
synthesis of the stereotriad C11-C13 of ansamycin antibio-
(
21) (a) Mark o´ , I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.;
Supporting Information Available: Experimental pro-
cedures and data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207. (b)
Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Mark o´ , I.
Tetrahedron Lett. 1999, 40, 1799.
(
22) Aubert, C. Gotteland, J. P. Malacria, M. J. Org. Chem. 1993, 58,
4
298. I would like to thank Corinne Aubert for this excellent suggestion.
OL901144J
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