Synthesis of methylene isosteres of α- And β-D-galactopyranosyl-L-serine

Article abstract of DOI:10.1039/a800571k

The BF₃·Et₂O promoted coupling of tetra-O-benzyl-α-D-galactopyranosyl trichloroacetimidate with a silyl enol ether carrying an oxazolidine ring leads to the α-C-glycosylmethyl ketone (32%, 95% ds) that is converted into the title α-C

Full text of DOI:10.1039/a800571k

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Synthesis of methylene isosteres of a- and b-
D-galactopyranosyl-
L-serine
Alessandro Dondoni,*† Alberto Marra and Alessandro Massi
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università, 44100-Ferrara, Italy
The BF3·Et2O promoted coupling of tetra-O-benzyl-a- -
D
NHBoc
CO2Me
galactopyranosyl trichloroacetimidate with a silyl enol ether
carrying an oxazolidine ring leads to the a-C-glycosylmethyl
ketone (32%, 95% ds) that is converted into the title a-C-
glycosyl amino acid by carbonyl oxygen removal (Barton–
McCombie) and oxidative cleavage (Jones) of the hetero-
cyclic ring, and into the b-isomer by anomerization and the
same two-step sequence.
BocN
OH
i–iv
O
63%
OH
4
5
v
94%
BocN
vi
Towards a better understanding and control of the function of
sugars in natural glycopeptides,1 the synthesis of their ana-
logues in which the sugar moieties are linked to the peptide
backbone by an all-carbon chain that is resistant to chemical and
enzymatic degradation is a topic of increasing importance in
glycobiology and medicinal chemistry. Therefore carbon-
linked glycosyl amino acids as precursors to glycopeptide
mimetics are current synthetic targets in various laboratories.2
Different syntheses of methylene isosteres of O-glycosyl
serines have been reported2a–c,f–h since these sugar amino acids
are the most common constituents of natural glycoproteins. The
C-glycosylation of a suitable a-amino acid equivalent2c appears
to be the most direct route to these compounds.3 Therefore we
describe here the synthesis of a- and b-C-galactosyl serine 1
3
O
82%
O
6
Scheme 1 Reagents and conditions: i, TBDMSOTf (1.2 equiv.), Et3N,
DMAP, DMF, 0 °C to room temp., 1.5 h; ii, LiAlH4 (4 equiv.), THF, 250
°C, 50 min; iii, 2-methoxypropene, CSA, CH2Cl2, 0 °C to room temp., 1.5
h; iv, Bu4NF, THF, room temp., 6 h; v, PCC (5 equiv.), CH2Cl2, 4 Å MS,
room temp., 20 min; vi, TMSOTf (1.4 equiv.), Et3N (1.6 equiv.), CH2Cl2,
215 °C, 1 h
stereocenter of the silyl enol ether 3 was unaffected under the
glycosylation conditions. Towards the target C-glycosyl amino
acid, the deoxygenation of the sugar ketone 8 was first carried
out through the classical Barton–McCombie reduction-elimina-
tion sequence8 affording 9 in 60% yield. Treatment of 9 with the
Jones reagent induced the cleavage of the oxazolidine ring and
oxidation of the alcohol in a single step to give the a-linked
(Gal-CH2-Ser), i.e. the methylene isosteres of
D-galactose a-
and b-linked to -serine (Gal-O-Ser, 2), employing the silyl enol
L
ether 3 as a novel homoalanine carbanion equivalent. To the
best of our knowledge this is the first approach to a pair of a-
and b-isomer C-glycosyl amino acids via a single synthetic
scheme.
tetra-O-benzyl-C-galactosyl- -serine 1a in 96% isolated yield.
L
This compound proved to be contaminated by ca. 5% (1H NMR
analysis) of the corresponding a-amino alcohol. Therefore, the
amino acid 1a was fully characterized through its methyl
ester.
HO
OH
O
NH2
CO2H
BocN
HO
–
*
X
CO2H
NH2
O
HO
Guided by earlier work regarding the base-catalyzed equili-
bration of a-C-glycosides bearing a carbonyl group in the side
chain,9 the anomerization of the a-C-glycosylmethyl ketone 8
was carried out upon treatment with ButLi in Et2O (Scheme 3).
Under these conditions a mixture of 8 and the b-anomer 10 in a
OSiMe3
1 X = CH2
2 X = O
3
The multigram scale synthesis of 3 started from the known4
methyl -threoninate 4 which was transformed by a sequence of
BnO
OBn
O
L
BnO
BnO
OBn
O
high yielding reactions into the ketone 6 (Scheme 1).‡ The
enantiomeric purity of this key intermediate was established by
reduction to the alcohol 5 with sodium borohydride (75% ds)
and conversion of the latter into its Mosher ester. Silylation of
the oxazolidinyl ketone 6 was readily effected using TMSOTf
and Et3N5 furnishing exclusively the kinetic trimethylsilyl enol
ether 3 in 82% yield.§
i
BnO
BocN
BnO
32%
O
BnO
OC NH
CCl3
O
8
7
ii 60%
The glycosylation of the silyl enol ether 3 was carried out
with the readily available electrophilic sugar tetra-O-benzyl
BnO
8
BnO
BnO
BnO
10
7
OBn
OBn
O
9
O
6
a-
-galactopyranosyl trichloroacetimidate6 7 (Scheme 2). Un-
D
iii
96%
5
NHBoc
BocN
optimized conditions involved the addition via syringe pumping
of an Et2O solution of 7 (2 equiv.) to silyl enol ether 3 and
BF3·Et2O (1 equiv.) in Et2O at 215 °C. The expected7 major
product, a-C-glycoside 8, and the b-anomer 10 were isolated by
column chromatography in 32% overall yield and 19:1 ratio.¶
Also isolated was the ketone 6 (45%) arising from the
hydrolysis of unreacted 3, and a mixture of anomeric galactosyl
trichloroacetamides (70%). The recovery of the enantiomer-
ically pure ketone 6 demonstrated that the configuration at the
BnO
BnO
O
4
2
CO2H
3
1
1a
9
Scheme 2 Reagents and conditions: i, 3 (0.5 equiv.), BF3·Et2O (0.5 equiv.),
Et2O, 215 °C, 2 h; ii, NaBH4, MeOH–Et2O, 220 °C, 1 h, then
1,1A-thiocarbonyldiimidazole (10 equiv.), DMAP (15 equiv.), THF, reflux,
6 h, then Bu3SnH (10 equiv.), AIBN (0.1 equiv.), toluene, 85 °C, 2 h; iii, 1
Jones reagent (3 mol per mol of reactant), acetone, 0 °C to room temp.,
3.5 h
M
Chem. Commun., 1998
1741

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H, J4b,5 4.5, H-4b). For 9: [a]D +37.1 (c 0.8); dH([2H6]DMSO, 160 °C)
4.02–3.73 (m, 8 H), 3.69 (dd, 1 H, J 4.2, 11.3), 3.65 (dd, 1 H, J 2.2, 8.1),
1.76–1.50 (m, 4 H). For 1a: dH(CDCl3) 5.29 (br d, 1 H, J2,NH 6.5, NH),
4.30–4.24 (m, 1 H, H-2), 1.99–1.84, 1.80–1.51 (2 m, 4 H, 2 H-3, 2 H-4);
dC(CDCl3) 176.3 (CO2H), 155.8 (CO2But), 53.5 (C-2), 28.3 (CH3). For 1a
Me ester: [a]D +29.0 (c 1.0); dH([2H6]DMSO, 120 °C) 6.53 (br d, 1 H, J2,NH
7.5, NH), 4.06–3.84 (m, 5 H), 3.79–3.72 (m, 2 H), 3.65 (dd, 1 H, J9,10b 4.4,
BnO
BnO
OBn
O
BocN
O
i
8
O
O
63%
BnO
10
ii 60%
J
10a,10b 10.8, H-10b), 3.61 (s, 3 H, OMe), 1.92–1.57 (m, 4 H). For 10: [a]D
+22.4 (c 0.4); dH([2H6]DMSO, 120 °C) 4.47 (dd, 1 H, J1a,2 7.8, J1b,2 3.8,
H-2), 4.07 (dd, 1 H, J7,8 2.8, J8,9 ca. 0.5, H-8), 4.05 (dd, 1 H, J1a,1b 9.0,
H-1a), 3.81 (dd, 1 H, H-1b), 3.76 (dd, 1 H, J6,7 9.1, H-7), 3.74 (ddd, 1 H,
BnO
BnO
BnO
BnO
OBn
OBn
O
iii
NHBoc
CO2H
BocN
O
95%
J
4a,5 2.5, J4b,5 8.8, J5,6 9.2, H-5), 3.69 (ddd, 1 H, J9,10a 6.0, J9,10b 6.5, H-9),
3.57 (dd, 1 H, J10a,10b 10.0, H-10a), 3.51 (dd, 1 H, H-10b), 2.82 (dd, 1 H,
J4a,4b 16.1, H-4a), 2.63 (dd, 1 H, H-4b). [a]D Values were measured in
CHCl3 at 20 ± 2 °C; 1H and 13C NMR spectra were recorded at 300 and 75
MHz, respectively).
BnO
BnO
1b
11
Scheme 3 Reagents and conditions: i, ButLi (1.2 equiv.), Et2O, 278 to 220
°C, 2 h, then room temp., 2 h; ii, NaBH4, MeOH–Et2O, 220 °C, 1 h, then
1,1A-thiocarbonyldiimidazole (10 equiv.), DMAP (15 equiv.), THF, reflux,
6 h, then Bu3SnH (10 equiv.), AIBN (0.1 equiv.), toluene, 85 °C, 2 h; iii, 1
§ TMSOTf and Et3N were added in three portions to the cooled (-15 °C)
CH2Cl2 solution of 6 in order to avoid extensive removal of the protecting
groups.
M
Jones reagent (3 mol per mol of reactant), acetone, 0 °C to room temp.,
¶ The a- and b-D
-configuration of C-glycosides 7 and 10 was proved by 1H
3.5 h
NMR analysis of the corresponding tetra-O-acetyl derivatives (J5,6 4.7 and
9.8, respectively, in [2H6]DMSO at 120 °C).
3:7 ratio and 90% overall yield was obtained. The isolated b-C-
glycosylmethyl ketone 10 was subjected to the radical deoxy-
genation as described above for 8 to give the b-C-alkyl
glycoside2h 11 (60% isolated yield). The conversion of the
oxazolidine ring of this compound into the a-amino acid moiety
1 H. Kunz, Angew. Chem., Int. Ed. Engl., 1987, 26, 294; Pure Appl. Chem.,
1993, 65, 1223; Y. C. Lee and R. T. Lee, Acc. Chem. Res., 1995, 28, 321;
R. A. Dwek, Chem. Rev., 1996, 96, 683; G. Arsequell and G. Valencia,
Tetrahedron: Asymmetry, 1997, 8, 2839.
by treatment with the Jones reagent gave the known2b,h b-
-
D
2 (a) L. Petrus and J. N. BeMiller, Carbohydr. Res., 1992, 230, 197; (b)
C. R. Bertozzi, D. G. Cook, W. R. Kobertz, F. Gonzales-Scarano and M.
D. Bednarski, J. Am. Chem. Soc., 1992, 114, 10 639; (c) B. J. Dorgan and
R. F. W. Jackson, Synlett, 1996, 859; (d) T. F. Herpin, W. B. Motherwell
and J.-M. Weibel, Chem. Commun., 1997, 923; (e) F. Burkhart, M.
Hoffmann and H. Kessler, Angew. Chem., Int. Ed. Engl., 1997, 36, 1191;
(f) L. Lay, M. Meldal, F. Nicotra, L. Panza and G. Russo, Chem.
Commun., 1997, 1469; (g) S. D. Debenham, J. S. Debenham, M. J. Burk
and E. J. Toone, J. Am. Chem. Soc., 1997, 119, 9897; (h) A. Dondoni, A.
Marra and A. Massi, Tetrahedron, 1998, 54, 2827; (i) T. Fuchss and R. R.
Schmidt, Synthesis, 1988, 753.
3 After the submission of this paper and during the editorial processing, a
paper appeared dealing with the SmI2-promoted glycosylation of a
homoalanine equivalent. See: D. Urban, T. Skrydstrup and J.-M. Beau,
Chem. Commun., 1998, 955.
4 P. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361.
5 L. Rossi and A. Pecunioso, Tetrahedron Lett., 1994, 35, 5285.
6 R. R. Schmidt, J. Michel and M. Roos, Liebigs Ann., 1984, 1343.
7 Axial C-glycosides are usually formed by coupling electrophilic sugars
with various carbon nucleophiles; see D. E. Levy and C. Thang, The
Chemistry of C-Glycosides, Pergamon, Oxford, 1995; M. H. D. Postema,
C-Glycoside Synthesis, CRC Press, Boca Raton, 1995.
linked tetra-O-benzyl-C-galactosyl- -serine 1b (95%). The
L
synthesis of 1b highlights the use of the silyl enol ether 3 as the
homoalanine carbanion equivalent since a similar approach
cannot be developed by using amino acid equivalents2c,3
lacking the carbonyl group.
In conclusion, the synthesis of 1a and 1b demonstrates the
viability of a new approach to a- and b-linked C-glycosyl amino
acids starting from a single carbohydrate precursor. The
protected hydroxy and amino groups (as O-benzyl and N-Boc
derivatives) and, by contrast, the free carboxylic group
constitute a synthetically convenient structure for the incorpora-
tion of these C-glycosyl amino acids into a peptide chain. The
application of this method for the preparation of pairs of amino
acids by glycosylation of the silyl enol ether 3 with other sugars
is now of interest.
Notes and References
† E-mail: adn@dns.unife.it
‡ Selected data for 3: [a]D +23.4 (c 0.6); dH(C2D2Cl4, 120 °C) 4.26 (d, 1 H,
J 1.5), 4.24 (dd, 1 H, J 3.5, 7.0), 4.21 (d, 1 H, J 1.5), 4.04 (dd, 1 H, J 7.0,
8.5), 3.95 (dd, 1 H, J 3.5, 8.5), 1.63, 1.58 (2 s, 6 H), 1.46 (s, 9 H), 0.30 (s,
9 H). For 5: mp 87–88 °C (from cyclohexane); [a]D +24.2 (c 0.7);
dH(CDCl3) 4.18–4.11, 4.00–3.77 (2 m, 4 H), 1.58 (s, 3 H), 1.50 (s, 12 H),
1.18 (d, 3 H, J 6.5). For 6: [a]D +56.9 (c 2.1); dH(C2D2Cl4, 120 °C) 4.36 (dd,
1 H, J 3.1, 7.2), 4.15 (dd, 1 H, J 7.2, 9.0), 3.95 (dd, 1 H, J 3.1, 9.0), 2.20 (s,
3H), 1.70, 1.57 (2 s, 6 H), 1.51 (s, 9 H). For 8: [a]D +53.3 (c 0.9);
dH([2H6]DMSO, 120 °C) 4.09 (dd, 1 H, J1a,1b 9.0, J1a,2 7.2, H-1a), 3.86 (dd,
1 H, J1b,2 3.2, H-1b), 2.91 (dd, 1 H, J4a,4b 17.0, J4a,5 8.2, H-4a), 2.68 (dd, 1
8 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1,
1975, 1574.
9 H. Ohrui, G. H. Jones, J. G. Moffatt, M. L. Maddox, A. T. Christensen
and S. K. Byram, J. Am. Chem. Soc., 1975, 97, 4602; P. Allevi, M.
Anastasia, P. Ciuffreda, A. Fiecchi and A. Scala, J. Chem. Soc., Perkin
Trans. 1, 1989, 1275; A. Dondoni and A. Marra, Tetrahedron Lett., 1993,
34, 7327.
Received in Liverpool, UK, 20th January 1998; 8/00571K
1742
Chem. Commun., 1998