Access to unnatural glycosyl amino acid building blocks via a one-pot Ritter reaction

Article abstract of DOI:10.1055/s-2004-837204

α-D-Galacto-2-deoxy-oct-3-ulopyranosonic acids, α-D-gluco-2- deoxy-oct-3-ulopyranosonic acids and α-L-galacto-2,8-dideoxy-oct-3- ulopyranosonic acids can be converted into unnatural glycosyl amino acids via a one-pot intramolecular Ritter reaction. Initia

Full text of DOI:10.1055/s-2004-837204

212
LETTER
Access to Unnatural Glycosyl Amino Acid Building Blocks via a One-Pot
Ritter Reaction
Access to
Unnatural
G
a
lycosyl
A
m
r
inoAcid
l
Build
i
ingBlo
n
cks Penner, David Taylor, Danielle Desautels, Kirk Marat, Frank Schweizer*
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
Fax +1(204)4747608; E-mail: schweize@ms.umanitoba.ca
Received 22 September 2004
(glucose, galactose and fucose, Figure 1). The resulting
Abstract: a-D-Galacto-2-deoxy-oct-3-ulopyranosonic acids, a-D-
gluco-2-deoxy-oct-3-ulopyranosonic acids and a-L-galacto-2,8-
dideoxy-oct-3-ulopyranosonic acids can be converted into unnatu-
ral glycosyl amino acids via a one-pot intramolecular Ritter reac-
glycosyl amino acid building blocks can be used in solid-
phase peptide synthesis to provide unnaturally glycosylat-
ed peptides. It is noteworthy that side-chain-modified
tion. Initially, a ketopyranoside-based acid condenses under Lewis lysine glyco-conjugates incorporated into the RGD tri-
acid-promoted conditions with a nitrile (benzonitrile or acetonitrile)
and a partially protected diamino ester (Boc-DAB-Ot-Bu, Boc-Orn-
Ot-Bu) to form unnatural glycosyl amino esters. The resulting gly-
kinetic properties of RGD peptides.6 Similar approaches
cosyl amino esters are useful building blocks for solid-phase glyco-
peptide synthesis. For example, the glycosyl amino acid derived by
condensation of a-D-galacto-2-deoxy-oct-3-ulopyranosonic acid
with benzonitrile and DAB was used to replace serine in the potent
opioid peptide sequence H2N-Tyr-D-Thr-Gly-Phe-Leu-Ser-
CONH2.
peptide pharmacophore have previously been shown to
improve receptor-subtype selectivity and pharmaco-
may also be applicable to other peptides but require access
to unnatural glycosyl amino acids.
O
O
NH
PO
O
NHBoc
n
Key words: carbohydrates, glycopeptides, combinatorial chemis-
try, glycosyl amino acids, peptides
NH
R
O
O
n = 1, 2
R = C6H5, CH3
Glycosylation of peptides and proteins is a posttransla-
tional event which affects protein folding, intra- and inter-
cellular trafficking, receptor binding and signalling.1,2 In
addition, glycopeptides often show enhanced thermal sta-
bility,3 increased resistance toward proteolytic cleavage4,5
and improved pharmacokinetic properties6 when com-
pared to non-glycosylated peptides which makes them
ideal targets for pharmaceutical exploitation. Oligosac-
charide chains in natural glycopeptides are attached to the
peptide backbone via a N-glycoside linkage between the
reducing terminal sugar and the amide group of aspar-
agine, or an O-glycoside linkage between the sugar and a
hydroxy group of an amino acid. Other naturally occur-
ring linkages include the S-glycoside linkage to cysteine7
and C-glycoside linkage to tryptophan.8 However, O- and
N-linked glycopeptides are metabolically unstable to-
wards glycosidases, an inherent limitation of these mate-
rials as potential drugs. To overcome some of these
drawbacks access to artificial glycopeptide linkages9 such
as C-glycosyl amino acids,9 glycopeptoids,10 retro
amides11 and oxime-linked glycosyl amino acids12 have
appeared.
Figure 1 Unnatural glycosyl amino acids containing a b-amide
linkage between carbohydrate and the side chain of diamino butyric
acid and ornithine; P = OBn.
Previous work14,15 has shown that a-D-galacto-2-deoxy-
oct-3-ulopyranosonic acid (6) can be converted into ga-
lactose-configured b-amides13 with high stereoselectivity
via a one-pot intramolecular Ritter reaction. Initially, acid
6 was condensed with a mono-functionalized nitrile (aro-
matic and aliphatic) under Lewis acid-promoted condi-
tions to form a cyclic imino anhydride.14 Subsequent
exposure of the imino anhydride to a simple amine formed
galactosyl-b-amides.14,15 Based on these results we now
became interested in expanding this three-component
condensation to D-gluco-, D-manno, L-fuco-, and L-rham-
no-based ulosonic acids as well as polyfunctionalized
amino acids and nitriles. An intermolecular version of this
Ritter reaction has previously been reported and was used
to generate natural glycosyl amino esters.29
The known ulosonic esters 1–516 were prepared by reac-
tion of tert-butylacetate enolate with the corresponding
sugar lactone as previously described14 and isolated in
high yields (>84%). To demonstrate the use of polyfunc-
tionalized amine components in this three-component
condensation, we selected side-chain deprotected a,g-di-
aminobutyric tert-butylester (Boc-DAB-Ot-Bu) and orni-
thine (Boc-Orn-Ot-Bu). Removal of the tert-butyl group
of the galactose-based ulosonic ester 1 with trifluoroacetic
acid generated 6 in situ. Treatment of 6 with trimethyl-
silyltrifluoromethanesulfonate (TMSOTf) and excess
In this paper we report the synthesis of unnatural glycosyl
amino acids in which the amino function is contained in
the side chain of DAB (diaminobutyric acid) and ornithine
is conjugated via an b-amide linkage to a monosaccharide
SYNLETT 2005, No. 2, pp 0212–0216
0
1.
0
2.
2
0
0
5
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837204; Art ID: S09104ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Access to Unnatural Glycosyl Amino Acid Building Blocks
213
benzonitrile (PhCN) for 2 hours followed by quenching amino esters 12–14 in 95%, 79% and 55% yield, respec-
the reaction with excess diisopropylethylamine (DIEA) tively (Scheme 1).17 By comparison, TMSOTf-promoted
and addition of Boc-Dab-Ot-Bu or Boc-Orn-Ot-Bu pro- condensation of D-manno-based ulosonic acid 8 with ben-
duced the protected galactose-configured amino esters 9 zonitrile and Boc-Orn-Ot-Bu afforded only trace amounts
and 10 as single stereoisomers in 75% and 64% yield (<3%)18 of the corresponding mannose-configured amino
(Scheme 1).17 Replacement of PhCN by acetonitrile ester.26 Next, we explored the chemistry of L-fucose and
(MeCN) and exposure to Boc-Orn-Ot-Bu provided the L-rhamno-based acids 15 and 16 (Scheme 1). Thus, Ritter
galactose-configured amino ester 11 in 61% yield.
reaction of the L-fucose-based ulosonic acid 15 with
PhCN and trapping of the intermediate imino anhydride
with propylamine and Boc-Dab-Ot-Bu provided the fu-
cose-configured amide 17 and fucosyl amino acid 18 in
40% and 18% yield, respectively. This is in contrast to the
reaction of L-rhamno-based acid 16 which provided only
traces (<3%)18 of the corresponding glycosyl amino es-
ter.26 The absolute stereochemistry of the protected
glycosyl amino esters 9–14, 17, 18, and 29 was assigned
based on interproton effects of H-7 (>0.6% NOE) mea-
sured relative to the singlet amide resonance signal. For
instance, subjection of the singlet amide signal in 9 to a
Once we had demonstrated the compatibility of polyfunc-
tionalized amines in this three-component reaction, we
then explored the one-pot Ritter-based condensation us-
ing the glucose-based ulosonic acid 7. TMSOTf-promot-
ed condensation of 7 with PhCN and subsequent
quenching with excess benzylamine afforded the glyco-
syl-b-amide 29 in 65% yield (Scheme 2). Encouraged by
these results we then subjected the ulosonic acid 7 to the
same reaction conditions previously applied to acid 6 us-
ing two nitriles (PhCN and MeCN) and two amines (Boc-
Dab-Ot-Bu, Boc-Orn-Ot-Bu) and isolated the glucosyl
OBn
R4
R2
O
OH
R1
BnO
O
O
Ot-Bu
R1
R3
Ot-Bu
OBn
R4
R3
R2
OH
O
4
5
R1 = H, R2 = OBn, R3 = OBn, R4 = H
1
2
3
R1 = H, R2 = OBn, R3 = OBn, R4 = H
R1 = OBn, R2 = H, R3 = OBn, R4 = H
R
1 = OBn, R2 = H, R3 = H, R4 = OBn
R
1 = OBn, R2 = H, R3 = H, R4 = OBn
a
a
OBn
O
R2
OH
R4
O
OH
R1
R1
O
R3
OH
BnO
OBn
R4
R2
R3
OH
O
15 R1 = H, R2 = OBn, R3 = OBn, R4 = H
6
R1 = H, R2 = OBn, R3 = OBn, R4 = H
1 = OBn, R2 = H, R3 = OBn, R4 = H
R1 = OBn, R2 = H, R3 = H, R4 = OBn
16
R
1 = OBn, R2 = H, R3 = H, R4 = OBn
7
8
R
b
b
OBn
R2
R4
O
O
7
R1
BnO
O
R1
1
O
NH
NH
Ot-Bu
NHBoc
3
7
5
R2
R3 NH
n
1
O
NH
O
OBn
O
4
OBn
R5
BnO
17
9
R
1 = H, R2 = OBn, R3 = OBn, R4 = H, R5 = Ph; n = 1;
17 R1, R2 = H
18 R1 = COOt-butyl, R2 = NHBoc
10 R1 = H, R2 = OBn, R3 = OBn, R4 = H, R5 = Ph; n = 2;
11 R1 = H, R2 = OBn, R3 = OBn, R4 = H, R5 = Me; n = 2;
12
13
14
R
R
R
1 = OBn, R2 = H, R3 = OBn, R4 = H, R5 = Ph; n = 1;
1 = OBn, R2 = H, R3 = OBn, R4 = H, R5 = Ph; n = 2;
1 = OBn, R2 = H, R3 = OBn, R4 = H, R5 = Me; n = 2;
Scheme 1 Ritter-based synthesis of glycoysl amino acids 9–14, 17 and 18. Reagents and conditions: a) 50% TFA in CH2Cl2, 2 h; b) sugar
(4 equiv), TMSOTf (12 equiv), nitrile (MeCN or PhCN, 16 equiv), CH2Cl2, 2 h, 0 °C then DIEA (15 equiv), amino acid (1 equiv), 0 °C to r.t.,
12 h, 55–95%.
Synlett 2005, No. 2, 212–216 © Thieme Stuttgart · New York

214
M. Penner et al.
LETTER
one-dimensional GOESY21 experiment showed inter-
proton effect to H-7 (0.8% NOE28 measured relative to the
singlet amide signal). This is only compatible with an
axial orientation of the anomeric amide group (Figure 2).
O
NH2
O
19
d
OBn
c
O
BnO
BnO
7
NH
e
BnO NH
O
O
OBn
O
BnO
COOH
NH
BnO
29
BnO
O
NH
O
Scheme 2 Ritter-based synthesis of glucosyl-b-amide 29. Reagents
and conditions: c) TMSOTf (3.5 equiv), PhCN (10 equiv), CH2Cl2,
0 °C, 2 h, then C6H5CH2NH2 (10 equiv), 0 °C to r.t., 12 h, 65%.
OBn
BnO
20
O
Scheme 3 Ritter-based synthesis of galactosyl-b-amide 20 on the
solid phase. Reagents and conditions: d) sugar (4 equiv), TMSOTf
(12 equiv), nitrile (MeCN or PhCN, 16 equiv), CH2Cl2, 2 h, 0 °C then
DIEA (15 equiv) and 19 (1 equiv), 0 °C to r.t., 12 h; e) 1% TFA in
CH2Cl2, 30 min, 52%.
O
1
NH
BnO
Ot-Bu
3
BnO
O
O
NHBoc
H-7
N
H
3J H-4,H-5 = 9.6 Hz
3J H-5,H-6 = 2.0 Hz
improved blood brain barrier penetration.24 In order to
study the effect of unnatural glycosylation we replaced the
terminal serine by the unnatural glycosyl amino acid 21.
The synthesis of glycopeptide 22 is outlined in Scheme 4.
Initially, we immobilized the galactose-configured amino
acid 21 onto a deprotected FMOC-Rink resin and per-
formed standard solid-phase glycopeptide synthesis using
Fmoc-protected amino acids [Fmoc-Leu-OH, Fmoc-Phe-
OH, Fmoc-Gly-OH, Fmoc-D-Thr(t-Bu)-OH, Fmoc-Tyr(t-
Bu)-OH] and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetra-
methyluronium tetrafluoroborate (TBTU) as coupling re-
agent in DMF. On-resin removal of the terminal Fmoc-
protecting group and subsequent exposure to hydrazine in
methanol19 (acetate removal), followed by standard resin
cleavage, produced glycopeptide 22 in 40% yield.20
3
Figure 2 Conformationally relevant NOE interactions and JH-4,H-5
and 3JH-5,H-6 coupling constants observed for 9. Similar NOE interac-
tions were observed for glycosyl amino acid derivatives 10–14, 17,
18, 20 and 29.
In order to facilitate isolation and purification of the
sugar-amino acid conjugates we also explored the use of
immobilized amines in this three-component condensa-
tion. For instance, exposure of resin (2-chlorotrityl)-
bound amino acid 19 to a mixture containing acid 6,
PhCN and TMSOTf (quenched with DIEA) provided the
acid 20 in 52% yield after resin cleavage (Scheme 3).
To convert the glycosyl amino ester 9 into a building
block suitable for solid-phase glycopeptide synthesis we
applied a four-step deprotecting–protecting protocol
(Scheme 4). First, the O-benzyl protecting groups on the
galactose-moiety were removed by catalytic hydrogena-
tion followed by acetylation of the free hydroxyl groups.
Then the tert-butylcarbamate and the tert-butyl ester pro-
tecting groups were cleaved by treatment with TFA before
selective deprotection of the amino function using 9-fluo-
renylmethyl pentafluorophenyl carbonate (FmocOPfp)
produced the Fmoc-protected galactose-based amino acid
21 in 76% overall yield (Scheme 4).
Finally, we explored the use of polyfunctionalized
nitriles30 in this condensation reaction and subjected the
acid 7 under TMSOTf-promoted reaction conditions to
the nitriles 23, 2422 and 2523 followed by work-up with
DIEA and propylamine (Scheme 5). While reaction with
nitriles 23 and 24 provided only trace amounts of the cor-
responding glycosyl amides (yield <3%), we were en-
couraged to find that the reaction of 7 with nitrile 25
provided the glycosyl-b-peptide 26 in 23% yield. It is
noteworthy that addition of amine 27 instead of propyl-
amine produced the glyco-b-tripeptide 28 in 20% yield as
a single stereoisomer.25 Work to explore the full scope of
this Ritter-based condensation for the synthesis of glyco-
b-peptides using polyfunctionalized nitriles is in progress.
With Fmoc-protected galactose-configured amino acid 21
in hand we then studied the use of this building block in
solid-phase glycopeptide synthesis. We selected the po-
tent opioid peptide sequence H2N-Tyr-D-Thr-Gly-Phe-
Leu-Ser-CONH2 as our initial target. Previous studies
have shown that O-glycosylation of this peptide sequence
The present ‘Ritter’-based method allows fast access to
glycosyl amino acids bearing an b-amide linkage between
glucose, galactose and fucose and the side chain of
19
Synlett 2005, No. 2, 212–216 © Thieme Stuttgart · New York

LETTER
Access to Unnatural Glycosyl Amino Acid Building Blocks
215
OBn
O
OAc
AcO
BnO
O
O
g
O
h
f
NH
BnO
NH
Ot-Bu
AcO
OH
BnO NH
O
O
NHBoc
AcO NH
O
O
NHFmoc
9
21
i
HO
j
O
O
O
H
N
H
N
H
N
H3N
N
H
N
H
NH2
O
O
O
k
OH
NH
22
O
H
N
OH
O
HO
HO
O
HO
Scheme 4 Deprotection of glycosyl amino acid 9 and solid-phase peptide synthesis of 22. Reagents and conditions: f) Pd(OH)2, MeOH, H2
then Ac2O–C5H5N, 20 h, 90%; g) 50% TFA in CH2Cl2, 0 °C to r.t., 8 h; h), THF–H2O (2:1), Fmoc-OPfp (2 equiv), NaHCO3, 12 h, 84%; i) Rink
amide resin (MBHA, deprotected 0.64 mmol/g), TBTU, DMF, DIEA, 12 h then morpholine–DMF 1:1 (2 × 30 min); j) standard solid-phase
peptide synthesis, amino acids: Fmoc-Leu-OH, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-D-Thr(t-Bu)-OH, Fmoc-Tyr(t-Bu)-OH, TBTU, DMF,
DIEA; k) acetate deprotection: 80% NH2NH2 in MeOH (2 × 30 min + 1 × 60 min) then resin cleavage 95% TFA in CH2Cl2, 40%.
OBn
O
ornithine and diamino butyric acid. The resulting glycosyl
amino acids can be incorporated into unnatural glycopep-
tides using solid-phase glycopeptide synthesis. The com-
mercial availability of large numbers of nitriles and amino
acids suggests that the methodology presented here
should be attractive for the preparation of unnatural
glycosyl amino acid libraries and artificial glycopeptide
libraries.27
BnO
BnO
OH
BnO
O
OH
7
l
OBn
O
BnO
NH
R1
Analytical Data for 9, 21 and 22:
BnO
Compound 9: 1H NMR (300 MHz, CDCl3, r.t., TMS): d = 1.44 (s, 9
H), 1.46 (s, 9 H), 1.51–1.65 (m, 1 H), 1.70–1.85 (m, 1 H), 2.74 (d,
J = 15.3 Hz, 1 H), 2.84–3.01 (m, 1 H), 3.03–3.24 (m, 1 H), 3.64–
3.81 (m, 4 H), 3.86–3.94 (m, 1 H), 3.96–4.07 (m, 1 H), 4.11 (dd,
J = 2.0, <1 Hz, 1 H), 4.21 (d, J = 9.6 Hz, 1 H), 4.41–5.09 (m, 8 H
and 1 × NH), 6.86 (s, 1 × NH), 7.01 (t, J = 5.3 Hz, 1 × NH), 7.22–
7.66 (m, 25 H). 13C NMR (75 MHz, CDCl3, r.t.): d = 28.0, 28.4,
31.2, 36.1, 43.0, 52.3, 67.8, 71.0, 72.1, 72.8, 73.6, 74.7, 76.1, 77.0,
79.6, 80.7, 81.8, 87.0, 126.9–128.7, 131.9, 134.6, 137.8 (2×), 138.3,
155.5, 166.7, 169.0, 171.5. MS (ES): m/z calcd [M + H]+: 958.48;
found: 958.98.
BnO
O
NH
O
NHFmoc
26 R1 = CH2CH2CH3
28 R1 = CH2CH2COOt-Bu
NC
NC
CN
MeOOC
NHFmoc
Compound 21: 1H NMR (300 MHz, DMSO-d6, r.t.): d = 1.58–1.87
(m, 2 H), 1.89 (s, 3 H), 1.96 (s, 3 H), 1.99 (s, 3 H), 2.12 (s, 3 H), 2.81
(d, J = 14.6 Hz, 1 H), 2.87–3.20 (m, 3 H), 3.59–3.72 (m, 2 H), 3.97–
4.10 (m, 4 H), 4.14–4.29 (m, 1 H), 4.34 (t, J = 6.6 Hz, 1 H), 5.31 (d,
J = 10.3 Hz, 1 H), 5.34 (d, J = 3.8 Hz, 1 H), 5.83 (dd, J = 10.3, 3.7
Hz, 1 H), 6.58–6.77 (m, 1 × NH), 7.26–7.92 (m, 13 H), 7.92–8.06
(m, 1 × NH), 8.60 (s, 1 × NH). MS (ES): m/z calcd [M + H]+:
832.29; found: 832.80.
23
24
COOt-Bu
27
CN
FmocHN
H2N
25
Scheme 5 Synthesis of glycosyl-b-peptides 26 and 28. Reagents
and conditions: l) sugar (1 equiv), TMSOTf (4 equiv), nitrile (8
equiv), CH2Cl2, 2 h, 0 °C then DIEA (8 equiv) then amine (4 equiv),
0 °C to r.t., 12 h, 20–23%.
Synlett 2005, No. 2, 212–216 © Thieme Stuttgart · New York

216
M. Penner et al.
LETTER
1
Compound 22: characteristic data H NMR (600 MHz, CD3OD,
r.t.): d = 3.93 (dd, J = 3.03 Hz, J < 1 Hz, H-6Gal), 4.02 (d, J = 9.8 Hz,
H-4Gal). MS (ES): m/z calcd [M + H]+: 1022.48; found: 1022.65.
(13) It is noteworthy that these b-galactosyl amides are not
accessible via acylation of the corresponding galactosyl-
amine.14
(14) Schweizer, F.; Lohse, A.; Otter, A.; Hindsgaul, O. Synlett
2001, 1434.
(15) Lohse, A.; Schweizer, F.; Hindsgaul, O. Comb. Chem. High
Typical Procedure for the One-Pot Synthesis of Protected
Glycosyl Amino Esters.
Ketol 1 (4.3 mmol) was dissolved in 1:1 mixture containing TFA
and CH2Cl2 (30 mL) at 0 °C for 2 h. The solvent was removed under
reduced pressure and co-destilled with toluene (3 × 10 mL) to dry-
ness. The oily residue was redissolved in CH2Cl2 (15 mL), PhCN
(17.2 mmol) and TMSOTf (12.9 mmol) were added at 0 °C. After 2
h, the reaction was quenched with DIEA (16.12 mmol) and the ami-
no acid (Boc-DAB-Ot-Bu × HCl, 1 mmol) dissolved in a 1:1 mix-
ture of CH2Cl2 and DIEA (4 mL) was added. Aqueous work up after
12 h followed by chromatographic purification afforded the protect-
ed glycosylamino ester 9 in 75% yield.
Throughput Screening 2002, 5, 389.
(16) Orsini, F.; Di Teodoro, E. Tetrahedron: Asymmetry 2003,
14, 2521.
(17) Yield calculation is based on the addition of the partially
protected diamino ester.
(18) Products were identified by MS.
(19) Bilsky, E. J.; Egleton, R. D.; Mitchell, S. A.; Palian, M. M.;
Daid, P.; Huber, J. D.; Jones, H.; Yamamura, H. I.; Janders,
H.; Davis, T. P.; Porreca, F.; Hruby, V. J.; Polt, R. J. Med.
Chem. 2000, 43, 2586.
(20) Yields are based on isolated amount after reverse phase
HPLC purification. Characteristic data for 22: 1H NMR (600
MHz, CD3OD, r.t.): d = 3.93 (dd, J = 3.03 Hz, J < 1 Hz, H-
Acknowledgment
6Gal), 4.02 (d, J = 9.8 Hz, H-4Gal), 6.80 (d, J = 8.4 Hz, 2 H),
The authors thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for financial support.
7.15 (d, J = 8.4 Hz, 2 H), 7.20–7.35 (m, 4 H), 7.45–7.53 (m,
2 H), 7.55–7.62 (m, 2 H), 7.82 (d, J = 7.10 Hz, 2 H). MS
(ES): m/z calcd [M + H]+: 1022.48; found: 1022.65.
(21) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A.
J. J. Am. Chem. Soc. 1995, 117, 4199.
(22) Elmore, D. T.; Guthrie, D. J. S.; Kay, G.; Williams, C. H. J.
Chem. Soc., Perkin Trans. 1 1988, 1051.
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(25) The stereochemistry at the anomeric center in 28 has not yet
been determined.
(26) We speculate that the axial substituent at the C-4 position in
mannose-configurated ulosonic acid 8 and rhamnose-
configurated ulosonic acid 16 destabilizes the cyclic form
and favors the open ketone form resulting in low yields of
the corresponding unnatural glycosyl amino acids
(Scheme 6).
(7) Weiss, J. B.; Lote, C. J.; Bobinski, H. Nature (London) New
Biol. 1971, 234, 25.
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(10) (a) Saha, U. K.; Roy, R. Tetrahedron Lett. 1995, 36, 3635.
(b) Saha, U.; Roy, R. Tetrahedron Lett. 1997, 38, 7697.
(c) Kim, J. M.; Roy, R. Tetrahedron Lett. 1997, 38, 3487.
(d) Kim, J. M.; Roy, R. Carbohydr. Res. 1997, 298, 173.
(11) (a) Hoffmann, M.; Burkhart, F.; Hessler, G.; Kessler, H.
Helv. Chim. Acta 1996, 79, 1519. (b) Frey, O.; Hoffmann,
M.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2026.
(12) (a) Marcaurelle, L. A.; Rodriguez, E. C.; Bertozzi, C. R.
Tetrahedron Lett. 1998, 39, 8417. (b) Peri, F.; Cipolla, L.;
Rescigno, M.; La Ferla, B.; Nicotra, F. Bioconjugate Chem.
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Peri, F.; La Ferla, B.; Nicotra, F. Bioorg. Med. Chem. Lett.
2002, 10, 1639.
Scheme 6
(27) Arya, P.; Barkley, A.; Randell, K. J. Comb. Chem. 2002, 4,
193.
(28) A 40 ms gaussian pulse with a 560 ms mixing time was used.
(29) Handlon, A. L.; Fraser-Reid, B. J. Am. Chem. Soc. 1993,
115, 3796.
(30) Cyanoalanine and nitriles with branching at the b-position
have previously been used without success in an
intermolecular Ritter reaction (see ref. 29).
Synlett 2005, No. 2, 212–216 © Thieme Stuttgart · New York