Nucleophilic addition reaction of 2-trimethylsilyloxyfuran to N-gulosyl-C-alkoxymethylnitrones: synthetic approach to polyoxin C.

Article abstract of DOI:10.1021/ol0200044

[reaction: see text] The stereoselectivity of nucleophilic addition of 2-trimethylsilyloxyfuran to N-gulosyl-C-alkoxymethylnitrones was investigated. It was found that the selectivity was highly dependent on the bulkiness of the C-substituent of the nitrone. The major adducts were elaborated into the key intermediate of polyoxin C.

Full text of DOI:10.1021/ol0200044

ORGANIC
LETTERS
2
002
Vol. 4, No. 7
111-1114
Nucleophilic Addition Reaction of
-Trimethylsilyloxyfuran to
1
2
N-Gulosyl-C-alkoxymethylnitrones:
Synthetic Approach to Polyoxin C
†
,‡
‡
,†
Naka Mita, Osamu Tamura,* Hiroyuki Ishibashi, and Masanori Sakamoto*
Meiji Pharmaceutical UniVersity, Noshio, Kiyose, Tokyo 204-8588, Japan,
and Faculty of Pharmaceutical Sciences, Kanazawa UniVersity, Takaramachi,
Kanazawa 920-0934, Japan
tamura@dbs.p.kanazawa-u.ac.jp
Received January 2, 2002
ABSTRACT
The stereoselectivity of nucleophilic addition of 2-trimethylsilyloxyfuran to N-gulosyl-C-alkoxymethylnitrones was investigated. It was found
that the selectivity was highly dependent on the bulkiness of the C-substituent of the nitrone. The major adducts were elaborated into the key
intermediate of polyoxin C.
4
Polyoxin Cs, the hybrid compounds of nucleosides and
R-amino acids, are important as the C-terminal amino acid
components of nikkomycins, which exhibit antifungal activ-
amino acid framework (indicated in the box in 3), the
essential structure for polyoxin C, by the use of nucleophilic
1
(2) (a) Naka, T.; Hashizume, T.; Nishimura, M. Tetrahedron Lett. 1971,
5-98. (b) Damodaran, N. P.; Jones, G. H.; Moffatt, J. G. J. Am. Chem.
ity. Therefore, the stereoselective synthesis of the unique
9
2
amino acid has been intensively investigated. In connection
Soc. 1971, 93, 3812-3813. (c) Ohrui, H.; Kuzuhara, H.; Emoto, S.
Tetrahedron Lett. 1971, 4267-4270. (d) Tabusa, F.; Yamada, T.; Suzuki,
K.; Mukaiyama, T. Chem. Lett. 1984, 405-408. (e) Mukaiyama, T.; Suzuki,
K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265-276. (f) Garner,
P.; Park, J. M. Tetrahedron Lett. 1989, 30, 5065-5068. (g) Garner, P.;
Park, J. M. J. Org. Chem. 1990, 55, 3772-3787. (h) Barrett, A. G. M.;
Lebold, S. A. J. Org. Chem. 1990, 55, 3853-3857. (i) Auberson, Y.; Vogel,
P. Tetrahedron 1990, 46, 7019-7032. (j) Chen, A.; Savage, I.; Thomas, E.
J.; Wilson, P. D. Tetrahedron Lett. 1993, 34, 6769-6772. (k) Chida, N.;
Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. Chem. Commun. 1994,
with our synthetic program of nikkomycin Bz (1), a novel
route to polyoxin C (3) was sought (Scheme 1). In our
3
previous study of N-terminal amino acid component 2
employing intramolecular cycloaddition of N-(2,3:5,6-O-
dicyclohexylidene-L-gulosyl)-C-(p-methoxycinnamyloxycar-
bonyl)nitrone (A), the protected L-gulosyl group played a
key role of the stereoselection as the chiral auxiliary. We
envisioned stereoselective construction of the ribofuranosyl
1
11-113. (l) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Tetrahedoron Lett. 1994, 35, 9439-9442. (m) Dondoni, A.; Junquera,
F.; Merchan, F. L.; Merino, P.; Tejero, T. Chem. Commun. 1995, 2127-
2
128. (n) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037-3038.
†
Meiji Pharmaceutical University.
Kanazawa University.
(o) Kato, K.; Chen, C. Y.; Akita, H. Synthesis 1998, 1527-1533.
(3) (a) Tamura, O.; Mita, N.; Kusaka, N.; Suzuki, H.; Sakamoto, M.
Tetrahedron Lett. 1997, 38, 429-432. See also: (b) Tamura, O.; Gotanda,
K.; Yoshino, J.; Morita, Y.; Terashima, R.; Kikuchi, M.; Miyawaki, T.;
Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000,
65, 8544-8551.
‡
(1) (a) Hagenmaier, H.; Keckeisen, A.; Z a¨ hner, H.; K o¨ nig, W. A. Liebigs
Ann. Chem. 1979, 1494-1502. (b) K o¨ nig, W. A.; Hahn, H.; Rathmann,
R.; Hass, W.; Keckeisen, A.; Hagenmaier, H.; Bormann, C.; Dehler, W.;
Kurth, R.; Z a¨ hner, H. Liebigs Ann. Chem. 1986, 407-421. (c) Hahn, H.;
Heitsch, H.; Rathmann, R.; Zimmermann, G.; Bormann, C.; Z a¨ hner, H.;
K o¨ nig, W. A. Liebigs Ann. Chem. 1987, 803-807 and references therein.
Krainer, E.; Becker, J. M.; Naider, F. J. Med. Chem. 1991, 34, 174-180
and references therein.
(4) For reviews for synthesis of optically active R-amino acids, see: (a)
Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids; Baldwin, J.
E., Magnus, P. D., Eds.; Pergamon Press: New York, 1989. (b) Duthaler,
R. O. Tetrahedron 1994, 50, 1539-1650.
1
0.1021/ol0200044 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

Scheme 1
Scheme 3
addition of 2-silyloxyfuran to O-silylated N-(L-gulosyl)-
nitrone as the glycine cation equivalent B.4 We present
here the addition reaction of the silyloxyfuran to N-(2,3:5,6-
O-diisopropylidene-L-gulosyl)-C-(alkoxymethyl)nitrone with
high diastereoselectivity and diastereofacial selectivity and
application of the reaction to synthesis of the key intermedi-
ate to polyoxin C.
-8
major products accompanied by the other diastereomers
9-11 after workup with TBAF (Scheme 3). The stereose-
lectivities of the addition reactions were highly dependent
on the bulkiness of C-substituents of nitrones 6 (Table 1).
Four types of (Z)-N-(2,3:5,6-O-diisopropylidene-L-gulo-
syl)-C-(alkoxymethyl)nitrones (6a-d) were prepared by
Table 1. Addition Raction of Nitrones 6a-d with
Silyloxyfuran 7
condensation of 2,3:5,6-O-diisopropylidene-L-gulose oxime
9
(
4) with R-alkoxyaldehydes (5a-d) in chloroform in the
presence of magnesium sulfate (Scheme 2).
Scheme 2
Thus, the reaction of C-benzyloxymethylnitrone 6a produced
a mixture of four diastereomers in a ratio of 76:13:8:3 and
in 84% combined yield (entry 1). More hindered C-
triisopropylsilyloxymethylnitrone 6b gave a mixture of three
(
5) For an excellent review for addition of organometallic reagents to
CdN bonds, see: Bloch, R. Chem. ReV. 1998, 98, 1407-1438.
6) For a review for nucleophilic additions to nitrones, see: Lombardo,
M.; Trombini, C. Synthesis 2000, 759-774. See also: Lombardo, M.;
Trombini, C. Tetrahedron 2000, 56, 323-326.
(
On treatment of nitrones 6 with 2-trimethylsilyloxyfuran
(
7) in the presence of catalytic amounts of TMSOTf in CH
2
-
Cl at -78 °C, a smooth addition reaction took place and
was completed within 15 min to give initially unstable
products C, which afforded stable bicyclic products 8 as
2
(7) For reviews for nucleophilic additions of 2-siloxyfurans, see: (a)
Casiraghi, G.; Rassu, G. Synthesis 1995, 607-626. (b) Rassu, G.; Zanardi,
F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333-1350. (c) Bur, S. K.;
Martin, S. F. Tetrahedron 2001, 57, 3221-3242.
1112
Org. Lett., Vol. 4, No. 7, 2002

diastereomers, and the use of tert-butyldiphenylsilyloxy-
methylnitrone 6c afforded improved selectivity (entries 2 and
The major bicyclic products 8c and 8d were readily
isolated and employed for synthetic studies on C-terminal
amino acids of nikkomycin Bz. Hydrolytic removal of the
sugar auxiliary of 8c gave 12 after protection of the nitrogen
3). Nitrone 6d having a branched substituent derived from
D-glyceraldehyde 5d afforded the single stereoisomer 8d
1
0
(entry 4).
2
atom by treatment with Boc O (Scheme 4). N-Protected
The substituent effect in stereoselectivity may be explained
by taking into account the bulkiness of the initially generated
silyloxyiminium intermediate B (Figure 1). In the case of
Scheme 4
Figure 1.
nitrone 6c or 6d having a bulky C-substituent, silyloxyfuran
7
seems to approach from the vacant region around the
hydrogen atom indicated by a bold arrow, since the other
space may be filled with the substituents. Therefore, transi-
tion state models D and E may be considered (to simplify,
only upper face approaches of silyloxyfuran 7 to silyloxy-
iminium cation B are represented in Figure 1). Transition
states D and E give opposite relative 3,3a-stereochemistries
to each other. Since the 4-position of the furan is apparently
bulkier than the 1-position, the use of a nitrone having a
sterically more demanding C-substituent makes model E
more favored than model D. Transition state E may exhibit
high diastereofacial selectivity because of the closeness
between the 4-position and the chiral auxiliary, whereas both
antipodal transition states would be possible in the case of
D. Accordingly, the use of bulky nitrones having a tendency
to form E shows good diastereoselectivity and diastereofacial
compound 12 was led to alcohol 13 by desilylation under
the mild condition of TBAF-AcOH-THF. Adduct 8d was
treated by HClO
c to afford diol 14. Diol 14 was transformed into 13 by
oxidative cleavage with NaIO and reduction with Zn(BH
Concordant specific rotations of 13 herein obtained, [R]
4 2
followed by Boc O in a similar way for
8
4
4 2
) .
2
1
D
21
3
-23.1 (c 0.96 CHCl ) from 8c; [R]
D
3
-22.1 (c 0.81 CHCl )
from 8d, confirmed that 8c and 8d have the same stereo-
chemistry on the bicyclic systems.
Reductive cleavage of the N-O bond of 13 by heating
with molybdenum hexacarbonyl in acetonitrile-water and
subsequent treatment with 2,2-dimethoxypropane in the
presence of a catalytic amount of PPTS in toluene produced
acetonide 15 (Scheme 5). Treatment of acetonide 15 with
MsCl and triethylamine caused dehydration to give buteno-
lide 16. Finally, dihydroxylation of 12 by the reported
11
selectivity to afford 8.
(8) For nucleophilic additions to N-glycosyl nitrones, see: (a) Huber,
R.; Knierzinger, A.; Obrecht, J.-P.; Vasella, A. HelV. Chim. Acta 1985, 68,
1
730-1747. (b) Mancini, F.; Piazza, M. G.; Trombini, C. J. Org. Chem.
1
991, 56, 4246-4252. (c) Basha, A.; Henry, R.; McLaughlin, M. A.;
2
g
method gave known ribonolactone-amino acid derivative
Ratajczyk, J. D.; Wittenberger, S. J. J. Org. Chem. 1994, 59, 6103-6106.
2
g
21
2g
(d) Rohloff, J. C.; Alfredson, T. V.; Schwartz, M. A. Tetrahedron Lett.
17, [R]
+31.0 (c 0.85, CHCl
), lit. [R] +31.8 (c 0.87,
D
3
D
1
994, 35, 1011-1014. (e) Lantos, I.; Flisak, J.; Liu, L.; Matsuoka, R.;
CHCl ), a key intermediate of polyoxin C.
3
Mendelson, W.; Stevenson, D.; Tubman, K.; Tucker, L.; Zhang, W.-Y.;
Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt, K.; Ross, S. J. Org. Chem.
1
997, 62, 5385-5391.
(11) Trombini et al. reported the reaction of 7 with an N-benzylnitrone
derived from O-benzyl lactate. They proposed a π-π interaction of 7 with
the N-benzyl group, see: Castellari, C.; Lombardo, M.; Pietropaolo, G.;
Trombini, C. Tetrahedron: Asymmetry 1996, 7, 1059-1068. Martin et al.
expanded the Diels-Alder type transition state (DATS) model for the
reaction of silyloxyiminium ion with 7.7c In the present reaction, DATS
giving the major isomer 8 would demand that C(4) carbon of 7 should
occupy a very close position to the R group of iminium ion B. However,
the reaction of nitrone 6 bearing a bulkier R group gave a higher ratio of
8. Consequently, it seems to be reasonable to assume model E for the
formation of 8 instead of DAST.
(
9) The oxime was prepared by a similar method for dicyclohexylidene
congener of 4, see: (a) Iida, H.; Kasahara, K.; Kibayashi, C. J. Am. Chem.
Soc. 1986, 108, 4647-4648. (b) Kasahara, K.; Iida, H.; Kibayashi, C. J.
Org. Chem. 1989, 54, 2225-2233.
(
10) It is known that addition reaction of N-benzyl congener of 6d with
7
in the presence of TMSOTf gives four stereoisomers of adduct with very
low stereoselectivity. The stereoselectivity of the present reaction of 6d,
therefore, may be mainly due to the effect of the sugar auxiliary. See:
Degiorgis, F.; Lombardo, M.; Trombini, C. Tetrahedon 1997, 53, 11721-
1
1730.
Org. Lett., Vol. 4, No. 7, 2002
1113

of the silyloxyfuran-nitrone addition reaction can be con-
trolled by the N-chiral auxiliary of the nitrone. It was also
found that a nitrone having bulkier C-substituent gives
a better stereoselectivity. The products 8c and 8d of the
present reaction could be successfully applied to the synthesis
of the C-terminal amino acid component of nikkomycin
Bz.
Scheme 5
Acknowledgment. The authors wish to acknowledge the
financial support of a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, Culture,
and Technology Japan.
Supporting Information Available: Spectroscopic data
for all new compounds, as well as detailed experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have explored the stereoselective
addition reaction of 2-silyloxyfuran to N-gulosylnitrone.
This is the first example showing that stereoselectivity
OL0200044
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Org. Lett., Vol. 4, No. 7, 2002