Chiral auxiliary based approach toward the synthesis of C-glycosylated amino acids.

Article abstract of DOI:10.1021/ol015743j

[reaction in text] In a chiral auxiliary based method C-glycosylated amino acids can be obtained by a 1,3-dipolar cycloaddition of a chiral glycine equivalent and C-1 allyl- or vinyl-derived carbohydrate building blocks as the key step. The products are f

Full text of DOI:10.1021/ol015743j

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1375-1378
Chiral Auxiliary Based Approach Toward
the Synthesis of C-Glycosylated Amino
Acids
,†
Bernhard Westermann,* Armin Walter,† Ulrich Flo1rke,† and
,‡
Hans-Josef Altenbach*
UniVersita¨t Paderborn, Fachbereich fu¨r Chemie und Chemietechnik,
Warburgerstr. 100, 33098 Paderborn, Germany, and Bergische UniVersita¨t Wuppertal,
Gaussstr. 20, 42097 Wuppertal, Germany
bw@fb13n.uni-paderborn.de
Received February 21, 2001
ABSTRACT
In a chiral auxiliary based method C-glycosylated amino acids can be obtained by a 1,3-dipolar cycloaddition of a chiral glycine equivalent and
C-1 allyl- or vinyl-derived carbohydrate building blocks as the key step. The products are formed regio- and diastereoselectively. Reductive
cleavage of the N−O bond of the isoxazolidine and of the chiral auxiliary leads to C-glycosylated amino acids. The use of (−)-menthone to
(+)-menthone as the auxiliary leads to the corresponding diastereomers.
Recently, approaches toward the synthesis of glycopeptide
mimics have gained considerable interest because they
promise to yield biologically active derivatives without the
synthesis of the complex natural derivatives.1 In this context,
much effort has been directed toward the synthesis of
metabolically and chemically stable products. This has been
achieved by incorporating isosteric, retro-isomeric, or peptoid
building blocks as substitutes for the peptide-glycoside
bond.2 Our interest in this field is mainly concerned with
the synthesis of C-glycosylated amino acids.3 For this class
of compounds a number of synthetic strategies have been
described, which in addition to often being lengthy and
complex exhibit limited usefulness for the stereoselective
synthesis of manno-, gluco- and galacto-glycosylated amino
acids.4,5
In this communication we present a very short and efficient
† Universita¨t Paderborn.
(3) Walter, A.; Westermann, B. Synlett 2000, 1682-1684. Westermann,
B.; Walter, A.; Diedrichs, N. Angew. Chem. 1999, 111, 3554-3556; Angew.
Chem., Int. Ed. 1999, 38, 3384-3386. Westermann, B.; Diedrichs, N.;
Gedrath, I.; Walter, A. In Bioorganic Chemistry; Diederichsen, U.,
Lindhorst, T. K., Westermann, B., Wessjohann, L. A., Eds., Wiley-VCH:
Weinheim, 1999.
(4) Reviews: Dondoni, A.; Marra, A. Chem. ReV. 2000, 100, 4395-
4422. Du, Y.; Linhardt, R. J. Tetrahedron 1998, 54, 9913-9959. Taylor,
C. M. Tetrahedron 1998, 54, 11317-11362. Postema, M. H. D. Tetrahedron
1992, 48, 8545-8599.
(5) Selected publications: Wellner, E.; Gustaffsson, T.; Ba¨cklund, J.;
Holmdahl, R.; Kihlberg, J. ChemBioChem 2000, 1, 272-280. Vincent, S.
P.; Schleyer, A.; Wong, C. H. J. Org. Chem. 2000, 65, 4440-4443.
Lundquist, J. J.; Debenham, S. D.; Toone, E. J. J. Org. Chem. 2000, 65,
8245-8250. SanMartin, R.; Tavassoli, B.; Walsh, K. E. Org. Lett. 2000,
2, 4051-4054. Dominique, R.; Liu, B. C.; Das, S. K.; Roy, R. Synthesis
2000, 862-868.
‡ Bergische Universita¨t Wuppertal.
(1) Reviews and concepts: Seitz, O. ChemBioChem 2000, 1, 214-246.
Koeller, K. M.; Wong, C. H. Chem. ReV. 2000, 100, 4465-4494. Herzner,
H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. ReV. 2000, 100, 4495-4538.
Marcaurelle, L. A.; Bertozzi, C. R. Chem. Eur. J. 1999, 5, 1384-1390.
Sears, P.; Wong, C. H. Angew. Chem. 1999, 111, 2446-2471; Angew.
Chem., Int. Ed. 1999, 38, 2300-2324. Davis, B. G. J. Chem. Soc., Perkin
Trans. 1 1999, 3215-3237. Warren, D. G.; Garg, H. G. In Glycopeptides
and Related Compounds; Warren, C. D., Large, D. G., Eds.; Marcel
Dekker: New York, 1997. Bill, R. M.; Flitsch, S. L. Chem. Biol. 1996, 3,
145-149.
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944. Hoffmann, M.; Burkhart, F.; Kessler, H. HelV. Chim. Acta 1996, 79,
1519-1532. Dechantsreiter, M. A.; Burkhart, F.; Kessler, H. Tetrahedron
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3487-3490 and references therein.
10.1021/ol015743j CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/05/2001

approach toward this class of building blocks suitable for
incorporation in glycopeptide mimics. Several prerequisites
were established for the synthesis of C-glycosylated amino
acids: (criterion a) easy and broadly applicable approach to
a large variety of products with different configurations in
the glycosidic and aglycosidic moieties, and (criterion b)
orthogonal protecting group strategies. To meet these criteria,
we designed a chiral auxiliary based approach with a [2 +
3] cycloaddition of appropriate precursors as the key step.
With (-)-menthone-derived chiral nitrone (-)-1 as a glycine
equivalent and allyl-substituted glycosidic building blocks
2 as starting materials, cycloadditions exhibiting a high
degree of regio- and diastereoselectivity should occur
(Scheme 1).
and subsequent oxidation with m-chloro perbenzoic acid.7
It should be mentioned at this point that the chiral auxiliary
menthone can be obtained as its D- and L-isomer; it is thus
possible to synthesize (+)- and (-)-1. Therefore, both
diastereomers of the glycosylated amino acids, exhibiting
different configurations at the stereogenic center of the amino
acid moiety, are accessible (criterion a).
The cycloadditions of (-)-1 and 2 were performed in
toluene under reflux; in all cases the yield was >82% (Table
1). It could be demonstrated that the R- and â-configurated
Table 1. Results of the [2 + 3] Cycloaddition of Nitrone
(-)-1 and Allyl Glycosides 2 To Give 3, Followed by SmI2
Cleavage to 4a
Scheme 1
a (Note 1): in CHCl3.
The C-1-allylated manno-, gluco- and galacto-configured
C-glycosides â-2a and R-2b-e are known products, which
can be obtained easily from common sources (criterion a).6
The protecting groups can be varied; in this study we only
used acetyl- and benzyl-protected derivatives (criterion b).
The nitrone (-)-1 can be obtained in a two-step procedure
by condensation of (-)-menthone and glycine methyl amide
glycosides did not differ in reactivity and selectivity.
Spectroscopic analysis of the products (â-3a, R-3b-e)
revealed that the reaction was completely diastereo- and
regioselective. These stereochemical results were as devised
in our blueprints: nitrones and olefins tend strongly to form
the C-C bond with the lowest substitution count.8,9 In terms
(7) Vogt, A.; Altenbach, H.-J.; Kirschbaum, M.; Hahn, M. G.; Mattha¨us,
M. S. P.; Herrmann, A. R. EP 976721, 2000; Chem. Abstr. 2000, 132,
108296. Altenbach, H.-J.; Hahn, M.; Mattha¨us, M. S. P. N,N-Acetals from
Menthone with R-Aminocarboxylic acid and N-Methylamides. 12th Inter-
national Conference on Organic Synthesis, Venice, Italy, 1998, OC-68.
(8) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909.
Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis; VCH: Weinheim, 1988. Little, R. D. Thermal Cycloadditions.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon Press: New York, 1991, Vol. 5.
(6) â-2a, 6: Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982,
104, 4974-4978. Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53,
752-753. R-2b,d,e: Hosomi, A.; Sakata, Y.; Sakurai, H. Carbohydr. Res.
1987, 171, 223-232. R-2c: Giannis, A.; Sandhoff, K. Tetrahedron Lett.
1985, 26, 1479-1482. R-2f: Horton, D. In Methods in Carbohydrate
Chemistry; Whistler, R. J., BeMiller, J. N., Eds.; Academic Press: New
York, 1972; Vol. 6, pp 282-285. Cui, J.; Horton, D. Carbohydr. Res. 1998,
309, 319-330.
1376
Org. Lett., Vol. 3, No. 9, 2001

of diastereoselectivity, a â-facial/exo-attack can be assumed,
with the isopropyl moiety of the chiral auxiliary determining
the site selectivtiy (Figure 1).10 The absolute configuration
4a-e could not be used because they interfered with the
protecting groups on the glycosidic moiety. Therefore, we
turned our attention to the SmII-mediated cleavage of N-O
bonds, which was described first by Natale.11 In all cases
the cleavage could be obtained in high yields, leading to the
corresponding 1,3-amino alcohols 4. The protecting groups
remained intact.
The N,N-acetal 4 was quantitavely hydrolyzed on being
stirred in 0.6 M aqueous HCl and a small amount of acetic
acid. Cleavage of the amide bond could be achieved with
an equimolar amount of lithium hydroxide. Both hydrolytic
steps were quantitative. Under these conditions, no cleavage
of the acetyl protecting groups in 5 was observed. During
these two steps the presence of the free hydroxy group at
C-4 of the aglycosidic moiety turned out to be crucial,
presumably as a result of some neighboring effect. After
protection (e.g., benzylation) no cleavage occurred.
Figure 1. exo- vs. endo-configurated transition states during the
cycoaddition step of (-)-1 and 2.
To demonstrate the broad applicability of the aglycosidic
building block, the GlcNAc derivative 2f,6 the â-configurated
vinyl derivative 66, and the pseudo-glucal 712 were also
utilized (Scheme 2). In these cases, the same regio- and
at the newly created stereogenic centers could be confirmed
by X-ray crystallography of the crystalline cycloadduct 12
(Figure 2).
Scheme 2
Figure 2. Molecular structure of 12. Displacement ellopsoids
shown at the 50% level; H atoms are omitted for clarity.
diastereoselectivities were observed as in the previous
cycloadditions. As described earlier, the endocyclic double
bond in 7 is not susceptible to cycloaddition reactions;
therefore only the exocyclic double bond underwent reac-
tion.13
Subsequently, classical methods (H2/Pd or Zn/acetic acid)
for the reductive cleavage of the N-O bond in isoxazolidines
During our studies the question arose as to whether the
stereochemical information provided by the glycosidic moiety
alone may account for the observed diastereoselectivity. To
test this, we utilized nitrone 1014 (from proline) in the
cycloaddition with â-2a (Scheme 3). Two diastereomers
11a,b (1:1) were obtained and were, unfortunately, insepa-
(9) Selected publications: Cardona, F.; Valenzy, S.; Goti, A.; Brandi,
A. Eur. J. Org. Chem. 1999, 1319-1323. Cardona, F.; Valenza, S.; Picasso,
S.; Goti, A.; Brandi, A. J. Org. Chem. 1998, 63, 7311-7318. Tamura, O.;
Kuraki, T.; Sakai, Y.; Takizawa, J. I.; Yoshino, J.; Morita, Y.; Mita, N.;
Gotanda, K.; Sakamoto, M. Tetrahedron Lett. 1999, 40, 895-898. Baldwin,
S. W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett. 1998, 39, 6819-
6822. Katagiri, N.; Okada, M.; Morishita, Y.; Kaneko, C. Tetrahedron 1997,
53, 5725-5746.
(10) The determined configuration is in strong correlation to previous
results; see ref 9.
(11) Myers, R. M.; Langston, S. P.; Conway, S. P.; Abell, C. Org. Lett.
2000, 2, 1349-1352. Keck, G. E.; Wager, T. T.; McHardy, S. F.
Tetrahedron 1999, 55, 11755-11772. Natale, N. R. Tetrahedron Lett. 1982,
23, 5009-5012.
Scheme 3
(12) Toshima, K.; Matsuo, G.; Ishizuka, T.; Ushiki, Y.; Nakata, M.;
Matsumura, S. J. Org. Chem. 1998, 63, 2307-2313.
(13) Cardona, F.; Salanski, P.; Chmielewski, M.; Valenza, S.; Goti, A.;
Brandi, A. Synlett 1998, 1444-1446.
(14) Bernotas, R. C.; Sabol, J. S.; Sing, L.; Friedrich, D. Synlett 1999,
653-655.
Org. Lett., Vol. 3, No. 9, 2001
1377

rable. NMR spectroscopy (DEPT-135) revealed, however,
that only the one expected regioisomer was formed. It was
thus proven that a chiral glycine equivalent is necessary to
produce diastereomerically pure cycloaddition products.
Haarmann & Reimer GmbH, Germany, for a gift of D- and
L-menthol.
Supporting Information Available: General experimen-
tal procedures, characterization data for compounds â-3b,
4b and 5b, and X-ray data of 12 to confirm the relative
stereochemistry of cycloadducts. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (We1826/3-1) and the Fonds der
Chemischen Industrie is highly appreciated. We thank
OL015743J
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Org. Lett., Vol. 3, No. 9, 2001