A stereocontrolled approach to (±)-nonactic acid

Article abstract of DOI:10.1016/j.tetlet.2008.06.100

Racemic nonactic acid was efficiently constructed in a convergent, stereocontrolled fashion (7 steps, 27%). The present synthesis features a stereocontrolled 1,3-dione reduction with NaBH₄/Et₂B(OMe) and an acid-promoted stereospecifi

Full text of DOI:10.1016/j.tetlet.2008.06.100

Tetrahedron Letters 49 (2008) 5271–5272
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Tetrahedron Letters
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A stereocontrolled approach to (± ±)nonactꢀc acꢀd
Yuedong Zhou a,b, Qiongfeng Xu a,c, Hongbin Zhai a,b,c,
*
a
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Road, Beijing 100083, China
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Racemic nonactic acid was efficiently constructed in a convergent, stereocontrolled fashion (7 steps, 27%).
Received 27 April 2008
Revised 16 June 2008
Accepted 24 June 2008
Available online 26 June 2008
4 2
The present synthesis features a stereocontrolled 1,3-dione reduction with NaBH /Et B(OMe) and an
acid-promoted stereospecific cyclization in the formation of 7.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Convergent
Nonactic acid
Racemic
Stereocontrolled
Synthesis
Nonactin (1),1 a 32-membered macrocycle, conceptually con-
tains two molecules of (À)-nonactic acid and two molecules of
report a concise and convergent synthesis of (±)-nonactic acid
((±)-2) that contains four stereogenic centers.
As delineated in Scheme 1, the current synthesis commenced
from (E)-methyl 3-methoxy-2-methyl-2-butenoate (3)12 which is
a known intermediate easily available from methyl acetylacetate
(
+)-nonactic acid arranged in an alternating order with four ester
linkages, and represents the simplest member of a large group of
ionophore antibiotics available from a variety of Streptomyces cul-
2
tures. These macrotetrolides (or polynactins) exhibit pronounced
through methylation at C-2 (MeI, K
from the subsequent enol ether formation (HC(OMe)
MeOH, reflux). Free radical reaction of 3 with NBS (100 mol %) in
2
CO
3
, MeCOMe, reflux) and
antibacterial, insecticidal,4 antitumoral,5 and immunosuppres-
3
, H SO ,
3
2
4
6
sive bioactivities. Due to its impressive pharmacological profile
and novel and challenging structural characteristics, nonactin has
been an alluring target molecule for the synthetic community.
the presence of a catalytic amount of Bz
2
O
2
in refluxing CCl
4
7
Imaginably, extensive endeavors have been devoted to construct-
LDA;
2,4-pentanedione;
then 4
7a,e,8
2a,7a,e,8d,e
ing monomeric nonactic acid (in all forms: (+)-,
(À)-,
NBS
OMe
OMe
9
2a,7,8b,c,10
2 2
Bz O
and (±-) ) and its derivatives.
In asymmetric assembly of
Br
nonactic acid, either one2
a,7b,e,f,8c–e
or two
7a,c,8a,b
chiral segments
61%
79%
CO
2
Me
2
CO Me
could be accommodated into the final molecule. In contrast, the
synthesis of the racemic form has to start with a single stereogenic
center and must be fully stereocontrolled.11 Herein, we wish to
3
4
OMe
2
Et B(OMe)
NaBH4
OMe
O
94%
O
O
CO
2
Me
OH OH
2
CO Me
5
6
O
O
O
O
O
O
O
OH
H
H
H
H
H
H
H
H
O
O
CO H
2
O
a) H , Rh/Al O , 98%
2 2 3
b) PhCO H, DIAD, PPh
O
H
H
2
3
(
±)-2: (±)-nonactic acid
OH
HCl
c) NaOH
O
CO
2
Me
(+)-2
1
: nonactin
79%
O
75%
H
7
*
Corresponding author. Tel.: +86 21 54925163; fax: +86 21 64166128.
E-mail address: zhaih@mail.sioc.ac.cn (H. Zhai).
Scheme 1.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.100

5
272
Y. Zhou et al. / Tetrahedron Letters 49 (2008) 5271–5272
afforded bromide 4 in 61% yield. Double deprotonation of 2,4-penta-
dione with LDA (200 mol %) at À78 °C followed by alkylation with
4. (a) Shopotova, L. P.; Shenin, Y. D. Zh. Prikl. Khim. 1993, 66, 1334–1338; (b) See
also: Chem. Abstr. 1994, 120, 158329; (c) Oishi, H.; Sugawa, T.; Okutomi, T.;
Suzuki, K.; Hayashi, T.; Sawada, M.; Ando, K. J. Antibiot. 1970, 23, 105–106.
4
furnished the coupling product 5, which was present in solution
5.
Borrel, M. N.; Pereira, E.; Fiallo, M.; Garnier-Suillerot, A. Eur. J. Biochem. 1994,
223, 125–133.
as a mixture of dione and ketoenol (in a ratio of ca. 1:4). Treatment
B(OMe)13 stereoselectively formed syn-diol
6.
(a) Callewaert, D. M.; Radcliff, G.; Tanouchi, Y.; Shichi, H. Immunopharmacology
of 5 with NaBH and Et
in excellent yield (94%) via two successive reduction steps. The
second reduction proceeded in a highly stereocontrolled manner
because of the complexation effect of Et B(OMe). Exposure of 6
4
2
1988, 16, 25–32; (b) Tanouchi, Y.; Shichi, H. Immunology 1988, 63, 471–475.
6
7.
(a) Wu, Y. K.; Sun, Y. P. Org. Lett. 2006, 8, 2831–2834; (b) Fleming, I.; Ghosh, S.
K. J. Chem. Soc., Perkin Trans. 1 1998, 2733–2747; (c) Lee, J. Y.; Kim, B. H.
Tetrahedron 1996, 52, 571–588; (d) Schmidt, U.; Werner, J. Synthesis 1986, 986–
2
9
5
92; (e) Bartlett, P. A.; Meadows, J. D.; Ottow, E. J. Am. Chem. Soc. 1984, 106,
304–5311; (f) Schmidt, U.; Gombos, J.; Haslinger, E.; Zak, H. Chem. Ber. 1976,
to 5% HCl in methanol at room temperature effected the desired
cyclization to stereospecifically produce the thermodynamically
109, 2628–2644; (g) Gerlach, H.; Oertle, K.; Thalmann, A.; Servi, S. Helv. Chim.
Acta 1975, 58, 2036–2043.
1
1,14
favored product 7,
in which the (E) configuration of the
8
.
.
(a) Fraser, B.; Perlmutter, P. J. Chem. Soc. Perkin Trans. 1 2002, 2896–2899; (b)
Ahmar, M.; Duyck, C.; Fleming, I. J. Chem. Soc., Perkin Trans. 1 1998, 2721–2732;
(c) Solladie, G.; Dominguezt, C. J. Org. Chem. 1994, 59, 3898–3901; (d) Ireland, R.
E.; Vevert, J. P. Can. J. Chem. 1981, 59, 572–583; (e) John, J. F.; Gschwend, H. W. J.
Org. Chem. 1980, 45, 4259–4260.
carbon–carbon double bond allows maximum conjugation. The
generation of 7 presumably involved hydrolysis, hemi-acetal
formation, and dehydration. By three known transformations
7
e
described previously (i.e., stereoselective hydrogenation,
9
Arco, M. J.; Trammell, M. H.; White, J. D. J. Org. Chem. 1976, 41, 2075–
2083.
8
a
Mitsunobu benzoylation, and saponification of both ester group-
8
a
s
), 7 was smoothly converted to (±)-2 in 75% overall yield. The
10. (a) Kim, W. H.; Jung, J. H.; Sung, L. T.; Lim, S. M.; Lee, E. Org. Lett. 2005, 7, 1085–
1087; (b) Fischer, P.; Segovia, A.; Gruner, M.; Metz, P. Angew. Chem., Int. Ed.
8
a,15
structure of (±)-2 was confirmed by spectroscopic analysis.
2005, 44, 6231–6234; (c) Kim, W. H.; Jung, J. H.; Lee, E. J. Org. Chem. 2005, 70,
In summary, racemic nonactic acid was efficiently constructed
in a convergent, stereocontrolled fashion (7 steps, 27%). The pres-
ent synthesis features a stereocontrolled 1,3-dione reduction with
NaBH /Et B(OMe) and an acid-promoted stereospecific cyclization
4 2
in the formation of 7.
8190–8192; (d) Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.; Lee, E. . J. Am.
Chem. Soc. 2002, 124, 14655–14662; (e) Germay, O.; Kumar, N.; Thomas, E. J.
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1127–1128; (g) Meiners, U.; Cramer, E.; Fröhlich, R.; Wibbeling, B.; Metz, P. Eur.
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Acknowledgement
(
k) Kim, B. H.; Lee, J. Y. Tetrahedron Lett. 1992, 33, 2557–2560.
1
1
1
1. Bartlett, P. A.; Jernstedt, K. K. Tetrahedron Lett. 1980, 21, 1607–1610.
2. Taskinen, E.; Mukkala, V. M. Tetrahedron 1982, 38, 613–616.
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K. M.; Hardtmann, G. E.; Prasad, K.; Repi cˇ , O.; Shapiro, M. J. Tetrahedron Lett.
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The financial support was provided by the grants from NSFC
90713007; 20772141; 20625204; and 20632030) and MOST_863
2006AA09Z405).
(
(
1
4. Compound 7, a pale yellow oil: 1H NMR (300 MHz, CDCl
3
) d 1.23 (d, J = 6.3 Hz,
H), 1.69–1.87 (m, 3H), 1.76 (s, 3H), 2.17–2.28 (m, 1H), 2.49 (s, 1H, OH), 2.81–
.94 (m, 1H), 3.18–3.27 (m, 1H), 3.67 (s, 3H), 3.97–4.08 (m, 1H), 4.45–4.54 (m,
H); 13C NMR (75 MHz, CDCl
) d 11.2, 23.2, 30.3, 30.6, 43.7, 50.8, 66.1, 82.1,
7.2, 169.6, 169.8. ESI-MS 451 (2M+Na), 269 (M+Na+MeOH), 215 (M+H). ESI-
+Na 237.1103; found: 237.1097.
3
2
1
9
References and notes
3
1
.
.
Gerlach, H.; Hutter, R.; Keller-Schlierlein, W.; Seibl, J.; Zahner, H. Helv. Chim.
Acta 1967, 50, 1782–1793.
(a) Takatori, K.; Tanaka, K.; Matsuoka, K.; Morishita, K.; Kajiwara, M. Synlett
18 4
HRMS calcd for C11H O
2
5. Compound (±)-2: 1H NMR (300 MHz, CDCl
) d 1.16 (d, J = 6.9 Hz, 3H), 1.22 (d,
J = 6.6 Hz, 3H), 1.58–1.74 (m, 4H), 1.97–2.11 (m, 2H), 2.46–2.56 (m, 1H), 3.98–
1
3
1
997, 159–160; (b) Corbaz, R.; Ettinger, L.; Gaumann, E.; Keller-Schlierlein, W.;
Kradolfer, F.; Kyburz, E.; Neipp, L.; Prelog, V.; Zahner, H. Helv. Chim. Acta 1955,
8, 1445–1448.
(a) Nefelova, M. V.; Sverdlova, A. N. Antibiot. Med. Biotechnol. 1985, 30, 261–
64; (b) See also: Chem. Abstr. 1985, 102, 201065.
13
4
2
.23 (m, 3H), 5.89 (br s, 2H, CO
8.6, 30.5, 43.1, 45.2, 64.9, 76.8, 80.8, 178.0. ESI-MS 225 (M+Na), 203 (M+H).
+Na 225.1103; found: 225.1097.
2 3
H & OH); C NMR (75 MHz, CDCl ) d 13.4, 22.9,
3
3
.
18 4
ESI-HRMS calcd for C10H O
2