Stereoselective synthesis of the various isomers of 3,4-dideoxy furanoid sugar amino acids with methyl substitution at the C6 position

Article abstract of DOI:10.1016/j.tetlet.2005.04.094

Various isomers of C6-methyl-containing chiral 3,4-dideoxy furanoid sugar amino acids were synthesized following a common strategy, in which the C2 and C6 chiral centres were derived from the chiralities of the two starting materials, glyceraldehyde aceto

Full text of DOI:10.1016/j.tetlet.2005.04.094

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4287–4290
Stereoselective synthesis of the various isomers of
3,4-dideoxy furanoid sugar amino acids with methyl
substitution at the C6 positionI
Tushar Kanti Chakraborty* and Gangarajula Sudhakar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 March 2005; revised 19 April 2005; accepted 26 April 2005
Abstract—Various isomers of C6-methyl-containing chiral 3,4-dideoxy furanoid sugar amino acids were synthesized following a
common strategy, in which the C2 and C6 chiral centres were derived from the chiralities of the two starting materials, glyceralde-
hyde acetonide and N,N-dibenzylalaninal, respectively, and the C5 centre was fixed by standard diastereoselective transformations.
Ó 2005 Elsevier Ltd. All rights reserved.
The advantage of sugar amino acids as potential combi-
natorial building blocks stems from the structural diver-
sity of carbohydrate molecules.1 Introduction of an
additional combinatorial site in the C6 position can raise
many fold the diversity of furanoid sugar amino acid-
based molecular libraries.2 Recently, we reported an effi-
cient synthesis of C6-substituted furanoid sugar amino
acids using chiral N,N-dibenzylaminoaldehydes and
glyceraldehyde acetonide as starting materials.3 The
method was applied for the synthesis of a variety of
3,4-dideoxy furanoid sugar amino acids with 6-methyl,
6-benzyl, 6-isopropyl and 6-(CH2OBn) substituents. It
was envisaged that the method had the potential to lead
to the synthesis of all the possible isomers of such C6-
substituted furanoid sugar amino acids. To demonstrate
the versatility of the method, we employed it successfully
for the synthesis of six isomers of 3,4-dideoxy furanoid
sugar amino acids with methyl substitution at the C6 po-
sition (1–6),4 the results of which are presented in this
communication. While the chiralities of the C2 and C6
centres were derived from the two chiral starting materi-
als, glyceraldehyde acetonide and N,N-dibenzylalaninal,
respectively, the third chiral centre at C5 position was
fixed by standard stereoselective transformations. Dia-
stereoselective addition of the acetylide derived from
glyceraldehyde acetonide to the chiral amino aldehyde
directly induced the requisite chirality in the C5 posi-
tions of 1, 3, 5 and 6, which was inverted by an oxida-
tion–reduction sequence to synthesize the other
isomers 2 and 4.
The outlines of the synthetic protocol for the first two
compounds 1–2, which were obtained from the L-ala-
nine-derived amino aldehyde are shown in Scheme 1.
Synthesis of compound 1 has already been reported by
us.3 The intermediate 9 from that synthesis constituted
R
R
S
R
R
S
S
S
BocHN
BocHN
BocHN
BocHN
6
6
6
6
CO2Me
1
CO2Me
1
CO2Me
1
CO2Me
1
2
2
2
2
S
5
Me
S
5
Me
S
5
Me
S
5
Me
O
O
O
O
1
2
3
4
S
S
S
6
R
BocHN
BocHN
6
CO2Me
1
CO2Me
1
2
2
R
5
Me
R
5
O
O
Me
5
6
Keywords: Sugar amino acids; Amino acids; Peptidomimetics; Dipeptide isosteres.
q IICT Communication No. 050319.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/27160387; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.094

4288
T. K. Chakraborty, G. Sudhakar / Tetrahedron Letters 46 (2005) 4287–4290
R
5
Me
S
5
Me
R
2
R
2
BocHN
BocHN
6
6
L-alanine
CO2Me
1
CO2Me
1
O
O
S
S
2
1
D-mannitol
(ref. 3)
OH
(ref. 3)
Br
O
OH
O
Bn2N
Bn2N
Br
1. Oxd.
2. Red.
Bn2N
CHO
8
O
Me
O
Me
O
O
Me
n-BuLi
9
10
7
Scheme 1. Reagents and conditions for the conversion of 9 to 10: (1) oxidation: SO3-py, Et3N, DMSO, CH2Cl2; (2) reduction: K-selectride, THF,
ꢀ78 °C.
the starting material for the synthesis of isomer 2. The
stereochemistry of the C5 hydroxyl group of 9 was in-
verted by subjecting it to an oxidation–reduction se-
quence to give the isomeric product 10.
Hydrogenation of 10 using 20% Pd(OH)2–C as a cata-
lyst in MeOH reduced the triple bond and at the same
time also deprotected NBn2 to give a free amine, which
was protected using Boc2O to furnish 11 in 85% yield.6
Treatment of 11 with acid deprotected the acetonide
moiety giving the triol 12 in 95% yield. Selective sulfonyl-
ation of the primary hydroxyl group of 12 using 2,4,6-
triisopropylbenzenesulfonyl chloride (TrisCl) gave a
sulfonate intermediate that was treated with anhydrous
K2CO3 to carry out an efficient intramolecular ring
closure reaction via an epoxide intermediate to give
the tetrahydrofuran 13 in 80% yield in two steps.7 Finally,
a two-step oxidation process converted the primary hy-
droxyl group of 13 into an acid that was treated with an
excess of CH2N2 in ether to produce the final product 28
in 88% yield.
Oxidation of 9 using SO3-py was immediately followed
by the diastereoselective hydride reduction of the result-
ing unstable keto intermediate using K-selectride5 to
give compound 106 with >98% diastereoselectivity and
no trace of the other diastereomer. Compound 10 was
then transformed into the furanoid 3,4-dideoxy sugar
amino acid (2R,5S,6S)-2 following the reported proce-
dure (Scheme 2).3
OH
1. H2, Pd(OH)2-C, MeOH
BocHN
10
O
For the synthesis of compounds 3–4, as shown in
Scheme 3, the same L-alanine-derived N,N-dibenzyl-
amino aldehyde 7, used in Scheme 1, was reacted with
the Li-acetylide prepared from isomeric 3,4-O-isopropyl-
idene-1,1-dibromobut-1-en-3,4-diol 14. Compound 14,
an enantiomer of 8, was prepared by known methods
from L-ascorbic acid.9 The adduct 15 was formed in
89% yield exclusively with no trace of the other diaste-
reomer. Its C5-isomer, compound 16, was next prepared
in 82% yield from 15 by the same oxidation–reduction
sequence used for the synthesis of 10. The selectivity in
this case was 90:10 in favour of the required isomer
and the minor isomer could be separated easily by stan-
dard silica gel column chromatography after the cyclo-
etherification step. Compounds 15 and 16 were next
converted into (2S,5R,6S)-310 (51% overall yield from
15) and (2S,5S,6S)-411 (52% overall yield from 16),
respectively, following the methods used in Scheme 2.
2. Boc2O, Et3N, MeOH
85%
Me
11
O
OH
1. TrisCl, Py, CH2Cl2
CSA, MeOH
95%
BocHN
OH
2. K2CO3, MeOH
80%
Me
OH
12
1. SO3-py, Et3N, DMSO,
CH2Cl2
BocHN
Me
OH
2
O
2. NaClO2, NaH2PO4,
2-methyl-2-butene, tBuOH
3. CH2N2, Et2O
13
88%
Scheme 2. Conversion of 10 to 2.3
R
5
Me
S
5
Me
S
2
S
2
BocHN
BocHN
6
6
L-alanine
CO2Me
1
CO2Me
1
O
O
S
S
4
3
L-ascorbic acid
(Scheme 2)
(Scheme 2)
Br
O
OH
OH
O
Bn2N
Bn2N
Br
Bn2N
CHO
Me
7
1. Oxd.
14
n-BuLi
O
O
O
Me
Me
O
2. Red.
16
15
Scheme 3. Synthesis of 3 and 4: Reagents and conditions for the conversion of 15 to 16: (1) oxidation: SO3-py, Et3N, DMSO, CH2Cl2; (2) reduction:
K-selectride, THF, ꢀ78 °C.

T. K. Chakraborty, G. Sudhakar / Tetrahedron Letters 46 (2005) 4287–4290
4289
Jayaprakash, S.; Ghosh, S. Comb. Chem. High Throughput
Screening 2002, 5, 373–387; (e) Schweizer, F. Angew.
Chem., Int. Ed. 2002, 41, 230–253; (f) Peri, F.; Cipolla, L.;
Forni, E.; La Ferla, B.; Nicotra, F. Chemtracts Org.
Chem. 2001, 14, 481–499.
same as in
BocHN
+
+
D-alanine
D-alanine
14
8
CO2Me
CO2Me
O
Schemes 1-3
Me
Me
5
2. (a) Raunkjær, M.; El Oualid, F.; van der Marel, G. A.;
Overkleeft, H. S.; Overhand, M. Org. Lett. 2004, 6, 3167–
3170; (b) Mazur, A. W.; Kulesza, A.; Mishra, R. A.;
Cross-Doersen, D.; Russell, A. F.; Ebetino, F. H. Bioorg.
Med. Chem. 2003, 11, 3053–3063; (c) Kulesza, A.; Ebetino,
F. H.; Mishra, R. K.; Cross-Doersen, D.; Mazur, A. W.
Org. Lett. 2003, 5, 1163–1166; (d) Vescovi, A.; Knoll, A.;
Koert, U. Org. Biomol. Chem. 2003, 2983–2997; (e)
Schrey, A.; Vescovi, A.; Knoll, A.; Rickert, C.; Koert,
U. Angew. Chem., Int. Ed. 2000, 39, 900–902; (f) Schrey,
A.; Osterkamp, F.; Straudi, A.; Rickert, C.; Wagner, H.;
Koert, U.; Herrschaft, B.; Harms, K. Eur. J. Org. Chem.
1999, 2977–2990.
same as in
BocHN
O
Schemes 1-3
6
Scheme 4. Synthesis of 5 and 6.
Similarly, starting from D-alanine and following the
methods outlined in Schemes 1–3, the two other isomers
of this C6-substituted 3,4-dideoxy furanoid sugar amino
acid 512 and 613 were prepared as shown in Scheme 4.
3. Chakraborty, T. K.; Sudhakar, G. Tetrahedron: Asymme-
try 2005, 16, 7–9.
4. Synthesis of 1 is already reported in Ref. 3.
5. Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron Lett.
1985, 26, 5139–5142.
Compounds 5 and 6 are enantiomers of 1 and 3, respec-
tively, having identical spectral data. The enantiomeric
purities of these substrates were verified by measuring
their specific rotations. In addition to the specific rota-
tions of the final esters, they were also compared at
the alcohol stage. Thus the intermediate 17 from 9,
en route to 1, had a specific rotation equal, but opposite
to that of intermediate 19 obtained during the synthesis
of 5. Similarly, the alcohol 18 prepared from 15,
en route to 3, had an equal and opposite specific
rotation to that of 20, the precursor of 6.
6. All new compounds were characterized by standard
spectroscopic methods.
7. Maezaki, N.; Kojima, N.; Asai, M.; Tominaga, H.;
Tanaka, T. Org. Lett. 2002, 4, 2977–2980.
8. Selected physical data of 2: Rf = 0.4 (silica gel, 30% EtOAc
28
in petroleum ether); ½aꢁD ꢀ8.25 (c 0.54, CHCl3); IR (neat)
m
max 3365, 2974, 2927, 1743, 1711 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 5.88 (d, J = 8.3 Hz, 1H, NH), 4.46 (dd,
J = 3.2, 9.0 Hz, 1H, C2H), 4.01 (m, 1H, C5H), 3.77 (s, 3H,
CO2Me), 3.72 (m, 1H, C6H), 2.26 (m, 1H), 2.11 (m, 1H),
1.88 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H, Boc), 1.26 (d,
J = 6.7 Hz, 3H, CH3); 13C (CDCl3, 75 MHz): d 174.29,
156.16, 84.39, 78.74, 76.57, 52.13, 48.01, 30.89, 28.45,
27.18, 19.75; MS (LSIMS) m/z (%) 273 (4) [M]+, 174 (20)
[M+HꢀBoc]+.
R
R
R
6
S
BocHN
BocHN
6
OH
OH
2
2
S
S
5
Me
5
Me
O
O
1
1
17
18
[ ]26D =—27.8 (c 0.39, CHCl3)3
25
α
—
[
α
]
=
11.7 (c 2.25, CHCl3)
D
9. (a) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H.
K.; Mikkilineni, A. B.; Wu, D. C.-J.; Saibaba, R.; Panzica,
R. B. J. Org. Chem. 1988, 53, 2598–2602; (b) Hubschw-
erlen, C. Synthesis 1986, 962–964; (c) Takano, S.; Numata,
H.; Ogasawara, K. Heterocycles 1982, 19, 327–328; (d)
Jackson, D. Y. Synth. Commun. 1988, 18, 337–341.
10. Selected physical data of 3: Rf = 0.4 (silica gel, 30% EtOAc
S
S
S
R
BocHN
BocHN
6
6
OH
OH
2
2
R
5
Me
R
5
Me
O
O
1
1
19
20
[ ]26D = —+27.6 (c 1.6, CHCl3)
[ ] D = +12.5 (c 5.44, CHCl3)
α 25
α
Thus, the present method, as depicted in Scheme 1–3,
was employed successfully for the synthesis of various
isomers of C6-substituted 3,4-dideoxyfuranoid sugar
amino acids 1–6 in pure enantiomeric forms simply by
altering the chiralities of the starting amino aldehydes
and glyceraldehyde acetonides, but essentially following
a common strategy.
29
in petroleum ether); ½aꢁD ꢀ20.1 (c 1.07, CHCl3); IR (neat)
m
max 3350, 2977, 1745, 1709, 1172 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 5.01 (d, J = 5.2 Hz, 1H, NH), 4.42 (dd,
J = 4.7, 8.3 Hz, 1H, C2H), 3.93 (m, 1H, C5H), 3.75 (m,
1H, C6H), 3.73 (s, 3H, CO2Me), 2.21 (m, 1H), 2.07 (m,
1H), 1.93 (m, 1H), 1.81 (m, 1H), 1.43 (s, 9H, Boc), 1.19 (d,
J = 6.6 Hz, 3H, CH3); 13C (CDCl3, 75 MHz): d 173.49,
155.72, 84.09, 79.07, 76.57, 51.99, 48.89, 30.23, 28.41,
26.99, 16.27; MS (LSIMS) m/z (%) 274 (10) [M+H]+, 174
(91) [M+HꢀBoc]+.
Acknowledgements
11. Selected physical data of 4: Rf = 0.4 (silica gel, 30% EtOAc
in petroleum ether); IR (neat) mmax 3395, 2975, 2928, 1712,
We thank CSIR, New Delhi, for research fellowship
(G.S.) and DST, New Delhi, for financial assistance.
1171 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): d 5.0 (d,
J = 4.5 Hz, 1H, NH), 4.5 (dd, J = 4.5, 7.8 Hz, 1H, C2H),
4.1 (m, 1H, C5H), 3.94 (m, 1H, C6H), 3.74 (s, 3H,
CO2Me), 2.22 (m, 1H), 2.02 (m, 2H), 1.78 (m, 1H), 1.43 (s,
9H, Boc), 1.2 (d, J = 6.8 Hz, 3H, CH3); MS (EI) m/z (%)
173 (5) [MꢀBoc]+.
References and notes
1. For reviews on sugar amino acids see: (a) Chakraborty, T.
K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. J. Chem. Sci.
2004, 116, 187–207; (b) Gruner, S. A. W.; Locardi, E.;
Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491–514; (c)
Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S. Curr.
Med. Chem. 2002, 9, 421–435; (d) Chakraborty, T. K.;
12. Selected physical data of 5: Rf = 0.4 (silica gel, 30% EtOAc
29
in petroleum ether); ½aꢁD +9.9 (c 1.01, CHCl3); IR (neat)
m
max 3371, 2976, 1745, 1709, 1170 cmꢀ1; 1H NMR (CDCl3,
300 MHz): d 4.63 (d, J = 7.9 Hz, 1H, NH), 4.49 (dd,
J = 4.9, 8.0 Hz, 1H, C2H), 4.1 (m, 1H, C5H), 3.72 (s, 3H,
CO2Me), 3.65 (m, 1H, C6H), 2.25 (m, 1H), 2.01 (m, 2H),

4290
T. K. Chakraborty, G. Sudhakar / Tetrahedron Letters 46 (2005) 4287–4290
1.75 (m, 1H), 1.42 (s, 9H, Boc), 1.12 (d, J = 6.6 Hz,
300 MHz): d 5.01 (d, J = 3.7 Hz, 1H, NH), 4.42 (dd,
J = 4.7, 8.3 Hz, 1H, C2H), 3.94 (m, 1H, C5H), 3.75 (m,
1H, C6H), 3.74 (s, 3H, CO2Me), 2.22 (m, 1H), 2.07 (m,
1H), 1.93 (m, 1H), 1.81 (m, 1H), 1.43 (s, 9H, Boc), 1.19 (d,
J = 6.6 Hz, 3H, CH3); 13C (CDCl3, 75 MHz): d 173.49,
155.72, 84.09, 79.09, 76.57, 52, 48.92, 30.23, 28.41, 27,
16.28; MS (LSIMS) m/z (%) 296 (8) [M+Na]+, 274 (14)
[M+H]+, 174 (98) [M+HꢀBoc]+.
3H, CH3); 13C (CDCl3, 75 MHz); d 173.61, 155.36,
83.52, 79.28, 76.57, 51.99, 49.29, 29.9, 28.38, 27.48,
16.05; MS (LSIMS) m/z (%) 274 (7) [M+H]+, 174 (42)
[M+HꢀBoc]+.
13. Selected physical data of 6: Rf = 0.4 (silica gel, 30% EtOAc
29
in petroleum ether); ½aꢁD +20.7 (c 1.2, CHCl3); IR (neat)
m
max 3350, 2977, 1745, 1709, 1172 cmꢀ1; 1H NMR (CDCl3,