Synthesis of C6-substituted 3,4-dideoxy furanoid sugar amino acids

Article abstract of DOI:10.1016/j.tetasy.2004.11.058

A variety of chiral 3,4-dideoxy furanoid sugar amino acids have been synthesized, which were substituted at C6 with different alkyl groups, such as methyl, benzyl, isopropyl and hydroxymethyl synthesized from their corresponding N,N-dibenzylaminoaldehydes

Full text of DOI:10.1016/j.tetasy.2004.11.058

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 7–9
Synthesis of C6-substituted 3,4-dideoxy furanoid sugar amino acids
Tushar Kanti Chakraborty* and Gangarajula Sudhakar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 17 September 2004; accepted 23 November 2004
Available online 22 December 2004
Abstract—A variety of chiral 3,4-dideoxy furanoid sugar amino acids have been synthesized, which were substituted at C6 with
different alkyl groups, such as methyl, benzyl, isopropyl and hydroxymethyl synthesized from their corresponding N,N-dibenz-
ylaminoaldehydes.
Ó 2004 Elsevier Ltd. All rights reserved.
Introduction of a stereogenic centre at the C6 position
of the amino terminus of furanoid amino acids gives rise
to an additional combinatorial site in these multifunc-
tional building blocks 1 that will not only help to induce
desired secondary structure in peptides, but will also
allow to mimic the side chains of natural amino acids
influencing the hydrophobicity/hydrophilicity of the
resulting peptidomimetic molecules.1 Development of a
robust synthetic strategy to construct these molecules
in enantiomerically pure form will allow their applica-
tion as dipeptide isosteres in peptidomimetic studies.
C7-Substituted pyranoid sugar amino acids based on a
tetrahydropyran framework have already been devel-
oped.2 Compounds with a methyl at C6 of 3,4-dideoxy
furanoid sugar amino acids have also been synthesized
and used in peptidomimetic studies by Koert et al.3
However, the reported procedures suffer from poor dia-
stereoselectivity leading to mixtures of isomers. Herein,
we describe an alternate method for the synthesis of
C6-substituted furanoid sugar amino acids. The process,
which uses chiral N,N-dibenzylaminoaldehydes and
glyceraldehyde acetonide as starting materials, is applied
to the synthesis of a variety C6-substituted 3,4-dideoxy
furanoid sugar amino acids, (2R,5R,6S)-6-amino-2,5-
anhydro-3,4,6-trideoxy-aldonic acids 2 with 6-methyl
(a), 6-benzyl (b), 6-isopropyl (c) and 6-(CH2OBn) (d)
substituents.
The synthesis is outlined in Scheme 1. One of the start-
ing materials in this scheme was the commercially avail-
able (S)-N,N-dibenzylaminoaldehyde4 3a (R = Me) that
could also be prepared from L-Ala.5 The second starting
material used was 3,4-O-isopropylidene-1,1-dibromo-
but-1-en-3,4-diol 46 prepared from (R)-glyceraldehyde
acetonide, which could be made easily in large quantities
by oxidative cleavage of 1,2:5,6-di-O-isopropylidene-D-
mannitol using NaIO4.7 Treatment of 3a at ꢀ78 °C with
the Li-acetylide, prepared in situ by reacting 4 with n-
BuLi in dry THF at ꢀ78 °C for 30min and subsequently
at room temperature for an additional 30min, gave the
expected adduct 5a8 as the major product in 81% yield
with excellent diastereoselectivity and, as expected, with
a 5R stereochemistry.4a,9
Hydrogenation of 5a 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,10 which
was reprotected using Boc2O to furnish 6a in 85% yield.8
(OR3)n
R1HN
OR4
1
5
2
R
6
R
BocHN
CO2Me
1
Treatment of 6a with acid deprotected the acetonide
moiety giving the triol 7a in 95% yield. Selective sulfonyl-
ation of the primary hydroxyl group of 7a using 2,4,6-
triisopropylbenzenesulfonyl chloride (TrisCl) gave a
sulfonate intermediate that was treated with anhydrous
K2CO3 to carry out a facile intramolecular ring closure
reaction via an epoxide intermediate to get the tetrahy-
drofuran framework of 8a in 72% yield in two steps.11
Finally, a two-step oxidation process converted the
6
2
O
S
5
O
R2
O
R
1
2
R1, R3, R4 = protective groups;
a: R = Me; b: R = CH2Ph
c: R = CHMe2; d: R = CH2OBn
R2 = alkyl or aryl substituents; n = 0-2
*
Corresponding author. Fax: +91 40 27193108/27160387; e-mail :
chakraborty@iict.res.in
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.058

8
T. K. Chakraborty, G. Sudhakar / Tetrahedron: Asymmetry 16 (2005) 7–9
OH
Br
O
Bn2N
O
5
1. H2, Pd(OH)2-C, MeOH
Bn2N
CHO
OH
Br
4
O
R
O
R
3
2. Boc2O, Et3N, MeOH
85-92% (ref.10)
n-BuLi, THF
78-93%
5
OH
1. TrisCl, Py, CH2Cl2
BocHN
CSA, MeOH
85-95%
BocHN
O
OH
2. K2CO3, MeOH
R
O
R
OH
72-88%
6
7
1. SO3-py, Et3N, DMSO, CH2Cl2
BocHN
BocHN
OH
CO2Me
O
O
2. NaClO2, Na H PO4,
2
R
R
2-methyl-2-butene, tBuOH
8
2
3. CH2N2, Et2O
84-88%
[a: R = Me; b: R = CH2Ph; c: R = CHMe2; d: R = CH2OBn]
Scheme 1.
4. (a) Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162; (b)
Reetz, M. T.; Drewes, M. W.; Schwickardi, R. Org. Synth.
1998, 76, 110–115.
5. (a) Chakraborty, T. K.; Dutta, S. Synth. Commun. 1997,
27, 4163–4172; (b) OÕBrien, P.; Warren, S. Tetrahedron
Lett. 1996, 37, 4271–4274; (c) Beaulieu, P.; Wernic, D.
J. Org. Chem. 1996, 61, 3635–3645.
primary hydroxyl group of 8a into an acid that was
treated with an excess of diazomethane in ether to get
the final product 2a12 in 84% yield.
Similarly, starting with N,N-dibenzylphenylalaninal 3b,
N,N-dibenzylvalinal 3c and N,N,O-tribenzylserinal 3d
compounds 2b, 2c and 2d, respectively, were synthesized
following Scheme 1.12
6. Gung, B. W.; Kumi, G. J. Org. Chem. 2003, 68, 5956–
5960.
7. (a) Schmid, C. R.; Bryant, J. D. J. Org. Chem. 1991, 56,
4056–4058; (b) Schmid, C. R.; Bryant, J. D.; Dowlatzedah,
M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.; Sear, N.
L.; Vianco, C. S. J. Org. Chem. 1991, 56, 4056–4058.
Acknowledgements
We thank CSIR, New Delhi for research fellowship
(G.S.) and DST, New Delhi for financial assistance.
8. All new compounds were characterized by IR, 1H and 13
NMR and mass spectroscopic studies.
C
9. For recent reports on the diastereoselective nucleophilic
addition to N,N-dibenzylaminoaldehydes see: (a) Fuku-
zawa, S.; Miura, M.; Saitoh, T. J. Org. Chem. 2003, 68,
2042–2044; (b) Goff, N. L. C.; Audin, P.; Paris, J.; Cazes,
B. Tetrahedron Lett. 2002, 43, 6325–6328.
10. During the hydrogenation of 5d, selective deprotection of
NBn2 could be achieved by carefully monitoring the
reaction and allowing it to run for a shorter period of time
than other substrates. The rate of deprotection of NBn2
was found to be much faster than that of OBn group
giving a modest 58% yield of 6d.
References
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.;
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.
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.
11. Maezaki, N.; Kojima, N.; Asai, M.; Tominaga, H.;
Tanaka, T. Org. Lett. 2002, 4, 2977–2980.
12. Selected physical data of 2a (R = Me): Rf = 0.4 (silica gel,
27
30% EtOAc in petroleum ether); ½aꢁD = ꢀ9.1 (c 0.98,
1
CHCl3); IR (neat) mmax 3438, 3385, 1700 cmꢀ1; H NMR
(CDCl3, 200 MHz): d 4.67 (d, J = 6.6 Hz, 1H, NH) 4.54
(dd, J = 5.2, 8.1 Hz, 1H, C2H), 4.15 (m, 1H, C5H), 3.74 (s,
3H, CO2Me), 3.71 (m, 1H, C6H), 2.28 (m, 1H), 2.03 (m,
1H), 1.72 (m, 2H), 1.44 (s, 9H, Boc), 1.14 (d, J = 6.6 Hz,
3H, CH3); 13C (CDCl3, 75 MHz): d 173.56, 155.35, 83.48,
79.22, 76.57, 51.92, 49.27, 29.84, 28.34, 27.43, 16.04; MS
(LSIMS) m/z (%) 274 (24) [M+H]+. Selected physical data
of 2b (R = Bn): Rf = 0.45 (silica gel, 30% EtOAc in
3. (a) Vescovi, A.; Knoll, A.; Koert, U. Org. Biomol. Chem.
2003, 2983–2997; (b) Schrey, A.; Vescovi, A.; Knoll, A.;
Rickert, C.; Koert, U. Angew. Chem., Int. Ed. 2000, 39,
900–902; (c) Schrey, A.; Osterkamp, F.; Straudi, A.;
Rickert, C.; Wagner, H.; Koert, U.; Herrschaft, B.;
Harms, K. Eur. J. Org. Chem. 1999, 2977–2990.
27
petroleum ether); ½aꢁD = +4.6 (c 0.98, CHCl3); IR (KBr)
mmax 3369, 1831, 1669, 1508 cmꢀ1 1H NMR (CDCl3
;
200 MHz): d 7.26 (m, 5H, Ph), 4.6 (m, 1H), 4.38 (br s, 1H,

T. K. Chakraborty, G. Sudhakar / Tetrahedron: Asymmetry 16 (2005) 7–9
9
NH), 4.07 (m, 1H), 3.87 (m, 1H), 3.75 (s, 3H, CO2Me),
2.99 (m, 1H), 2.99 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H),
2.02 (m, 2H), 1.83 (m, 1H), 1.34 (s, 9H, Boc); 13C (CDCl3,
75 MHz): d 173.53, 155.36, 137.52, 129.55, 128.19, 126.18,
81.74, 79.18, 76.56, 54.1, 51.8, 37.02, 29.67, 28.16, 27.81;
MS (LSIMS) m/z (%) 350(16) [M+H] +.Selected physical
data of 2c (R = CHMe2): Rf = 0.45 (silica gel, 30% EtOAc
2 Me); 13C (CDCl3, 75 MHz): d 173.71, 156.11, 80.78,
79.14, 76.58, 57.87, 51.79, 29.52, 28.31, 28.16, 19.97, 15.66;
MS (LSIMS) m/z (%) 302 (34) [M+H]+. Selected physical
data of 2d (R = OBn): Rf = 0.4 (silica gel, 30% EtOAc
27
in petroleum ether); ½aꢁD = ꢀ40.4 (c 0.67, CHCl3); IR
(neat) mmax3119, 1401 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 7.28 (m, 5H, Ph), 4.96 (br s, 1H, NH), 4.49 (m, 3H), 4.27
(m, 1H), 3.7 (m, 5H), 3.54 (m, 1H), 2.27 (m, 1H), 2.04–1.86
(m, 3H), 1.4 (s, 9H, Boc); 13C (CDCl3, 75 MHz): d 173.54,
155.63, 138.18, 128.26, 127.5, 79.93, 79.36, 76.56, 73.23,
27
in petroleum ether); ½aꢁD = ꢀ11.0( c 0.68, CHCl3); IR
(neat) mmax 1523, 1354 cmꢀ1; 1H NMR (CDCl3, 200 MHz):
d 4.51 (m, 1H), 4.3 (d, J = 10.2 Hz, 1H, NH), 4.03 (m, 1H),
3.72 (s, 3H, CO2Me), 3.46 (m, 1H, C5H), 2.4–1.7 (m, 5H,
C3H, C4H and C7H), 1.43 (s, 9H, Boc), 0.97–0.83 (m, 6H,
63.43, 53.25, 51.81, 30.05, 29.64, 28.3, 27.63; MS (LSIMS)
m/z (%) 380(32) [M+H]
+
.