The synthesis of some oligopeptides derived from novel carbohydrate α-amino acids

Article abstract of DOI:10.1071/CH04014

The attempted coupling of a carbohydrate α-azido acid with a carbohydrate α-amino ester in the presence of a diimide, hopefully to produce a dipeptide, yielded only the carboxylic anhydride. However, the combination of 4-toluenesulfonyl chloride in pyridi

Full text of DOI:10.1071/CH04014

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 733–740
The Synthesis of Some Oligopeptides Derived from Novel
Carbohydrate α-Amino Acids
Adrian Scaffidi,A Brian W. Skelton,A Robert V. Stick,A,B and Allan H. WhiteA
A Chemistry, School of Biomedical and Chemical Sciences M313, University of Western Australia,
Crawley WA 6009, Australia.
B Author to whom correspondence should be addressed (e-mail: rvs@chem.uwa.edu.au).
The attempted coupling of a carbohydrate α-azido acid with a carbohydrate α-amino ester in the presence of a
diimide, hopefully to produce a dipeptide, yielded only the carboxylic anhydride. However, the combination of
4-toluenesulfonyl chloride in pyridine was successful, and four carbohydrate dipeptides were separately produced.
One of these dipeptides was further transformed into a tripeptide, and another into a hexapeptide.
A single-crystal X-ray structure is reported for (3S)-3-azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-d-ribo-hexose, amide with (3S)-3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-α-d-ribo-
hexose.
Manuscript received: 22 January 2004.
Final version: 5 March 2004.
Introduction
In our initial investigations we decided to couple the
azido acid 1 with the amino ester 2 (Scheme 2); the logical
reagent was dicyclohexylcarbodiimide (DCC), in combi-
nation with 4-dimethylaminopyridine (DMAP).[2,3] To our
surprise, the reaction did not appear (thin-layer chromato-
graphy, TLC) to give a product with the polarity expected
of a dipeptide. The reaction was repeated with a different
diimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDC) hydrochloride, again in the presence of a base
(ethyldiisopropylamine).[4] The outcome (TLC) appeared to
be the same, even in the presence of 3-hydroxybenzotriazole.
Eventually we isolated the anhydride 3 from both reaction
mixtures, an observation made by others in related systems.[3]
It appears that the anhydride 3, once formed, is too hindered
to acylate the amine 2.
At this stage it was brought to our attention that 4-
toluenesulfonyl (tosyl) chloride in pyridine was an effective
combination for promoting the esterification of (hindered)
alcohols;[5] the method can be modified for the synthesis
of anhydrides and amides. It was somewhat curious to us
that, for the synthesis of amides, the method involved the
addition of just half a mole equivalent of tosyl chloride to
In the preceding paper we described the synthesis of four
suites of precursors to novel carbohydrate α-amino acids
(Scheme 1).[1] It was our next intent to couple some of
these precursors together to form dipeptides and perhaps even
higher oligopeptides. This paper, then, describes our efforts
towards four new dipeptides and the extension of one of them
up to a hexapeptide. Along the way we encountered some
interesting aspects of peptide coupling.
O
O
O
X
Y
O
O
X
Y
O
O
X
Y
O
O
O
N3 CO2Me
N3 CO2H
NH2 CO2Me
X
O
Ph
Ph
O
O
O
O
O
BnO
X
Y
BnO
Y
OMe
OMe
Scheme 1.
O
O
O
O
O
O
O
O
N3
O
NH2
(a)
N3
O
ϩ
O
O
O
HO2C
O
MeO2C
O
OC
O
2
1
2
3
Scheme 2. (a) DCC, DMAP, CH2Cl2 or EDC.HCl, EtPri2N, CH2Cl2.
© CSIRO 2004
10.1071/CH04014
0004-9425/04/080733

734
A. Scaffidi et al.
C(122؅)
C(1؅)
the carboxylic acid, thereby ensuring the formation of the
intermediate carboxylic anhydride, able to acylate the added
amine but wasteful of half of the acid (Scheme 3).A far better
approach seemed to be to add (at least) a full equivalent of
tosyl chloride, so forming a mixed anhydride, capable of acy-
lating the added amine to form the amide (Scheme 4). In the
event, the addition of about two mole equivalents of tosyl
chloride to a mixture of the acid 1 and the amine 2 in pyridine
gave a good yield of the amide 4 (Scheme 5). Apparently, the
conversion of the amine 2 into the 4-toluenesulfonamide is a
slow process in pyridine, and this was indeed found to be the
case when a separate test experiment was conducted (TLC).
The dipeptide 4, fortunately, was crystalline, allowing for
a single-crystal X-ray structure determination (Fig. 1), one
molecule, devoid of crystallographic symmetry, comprising
the asymmetric unit of the structure. The most notable fea-
ture is the transoid nature of the newly formed amide moiety
that provides the only hydrogen atom displaying signifi-
cant interaction with any neighbouring group(s), the nearest
such contact being intramolecular [N,H(3)· · ·O(5ꢀ) 2.907(2),
2.15(3) Å]. In the azide group, the C–N–N angle is 114.1(1)◦,
while N(32ꢀ)–N(31ꢀ,33ꢀ) are 1.241(2), 1.120(3) Å, respec-
tively. The conformations of the two C4O rings are similar,
albeit rather widely divergent, suggestive of some lack of
rigidity; within the C3O2 rings, three of the four are diversely
similar, with the conformation of the fourth the inverse
(Table 1).
O(1؅)
C(2؅)
C(121؅)
O(4؅)
O(2؅)
C(3؅)
C(6؅)
C(4؅)
N(31؅)
C(31؅)
N(32؅)
O(31؅)
N(33؅)
C(5؅)
O(6؅)
C(562)
O(5؅)
C(56؅)
C(6)
N(3)
O(4)
C(2)
C(5)
C(561؅)
C(56)
O(5)
C(1)
C(4)
C(3)
O(6)
O(1)
C(12)
O(31)
C(31)
C(561)
C(121)
O(2)
O(32)
C(32)
C(122)
Fig. 1. Projection of a single molecule of 4, showing 50% probability
amplitude displacement envelopes for C, N, and O, with hydrogen atoms
having arbitrary radii of 0.1 Å.
Table 1. Ring conformational descriptors
Torsion angles (degrees) are given for each of the rings
for the bonds designated, the two values in each entry
being for unprimed, primed atoms, respectively
The tosyl chloride/pyridine method was then applied to
mixtures of the three other azido acids and corresponding
aminoesters, toproducethedipeptides5, 6, and 7(Scheme6).
Our next effort was to attempt the preparation of a higher
oligopeptide by coupling the azido acid dipeptide 8 with the
amino ester dipeptide 9 [both derived from 4], again using
tosyl chloride in pyridine (Scheme 7). Unfortunately, and sur-
prisingly, the only product isolated was the anhydride 10.
Atoms
Angles
C4O rings
C(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–O(4)
O(4)–C(1)
5.6(2), −6.8(2)
15.9(2), 27.4(2)
−32.3(2), −39.2(2)
38.1(2), 37.6(2)
−27.5(2), −19.1(2)
C3O2 rings
(a)
(b)
ϩ
ϩ
RCO2H
2RCO2H
TsCl
(RCO)2O
RCONHRЈ
C(1)–C(2)
C(1)–O(1)
C(2)–O(2)
O(1)–C(12)
O(2)–C(12)
C(5)–C(6)
C(5)–O(5)
C(6)–O(6)
O(5)–C(56)
O(6)–C(56)
5.9(2), −9.7(2)
−21.4(2), −11.5(2)
11.4(2), 27.1(2)
‘Ts’ is 4-MeC6H4SO2
28.8(2), 28.4(2)
Scheme 3. (a) pyridine; (b) RꢀNH2.
−24.5(2), −34.8(2)
−16.7(3), 32.0(2)
−4.3(3), −16.1(2)
31.8(3), −36.7(2)
23.7(3), −5.8(2)
−35.0(3), 27.2(2)
(a)
(b)
ϩ
RCO2H
TsCl
RCO2Ts
RCONHRЈ
Scheme 4. (a) pyridine; (b) RꢀNH2.
O
O
O
N3
O
O
O
O
O
O
N3
O
NH2
(a)
OC
O
O
O
O
ϩ
O
O
O
HO2C
O
MeO2C
O
NH
O
MeO2C
Scheme 5. (a) TsCl, pyridine.

Oligopeptides Derived from Novel Carbohydrate α-Amino Acids
735
The addition of 4-dimethylaminopyridine to the reaction mix-
ture still did not cause any formation of the desired tetra-
peptide. The same problem was encountered when we tried
to couple the azido acid tripeptide 11 with the amino ester
tripeptide 12 (Scheme 8 and below)—only the anhydride 13
was isolated, with no evidence for formation of the desired
hexapeptide.
Although a slight molar excess of acid (8 and 11) over
amine (9 and 12) was employed in both of the above reactions,
it is difficult to comprehend why the carboxylate ion (leading
totheobservedanhydrides10and 13)shouldbemorereactive
than the amine (leading to the desired tetra- and hexa-peptide)
towards the purported mixed anhydride intermediate. With
this frustrating result in hand, we decided to ‘creep up’ on
our target oligopeptides by adding just one amino acid unit
at a time.
So, the amino ester 14 [derived from 6] and the azido
acid 15 were treated with tosyl chloride in pyridine to yield
the azido ester tripeptide 16 in moderate yield (Scheme 9).
Similarly successful was a synthesis of the tripeptide 17 from
the amino ester 9 and the azido acid 1 (Scheme 10). In fact,
we had considerable amounts of the tripeptide 17 and were
able, through an iterative process involving azide reduction
(to the amine) and coupling with the azido acid 1, to access
the azido ester tetra- 18, penta- 19, and hexa-peptides 20
from the corresponding amino ester tri- 21, tetra- 22, and
penta-peptides 23 (Scheme 11).
All of the peptides described in this paper were fully
characterized by elemental analysis (where appropriate),
accurate mass determination, NMR spectroscopy, and IR
spectroscopy. Of particular relevance in the NMR spectra
was the presence of the various α-carbon atoms, certainly
O
N3
OMe
OBn
O
O
Ph
O
O
N3
Ph
O
O
OC
O
O
C
O
BnO
O
NH
O
NH
O
OC
OMe
NH
O
N3
O
Ph
O
O
MeO2C
O
O
O
BnO
CO2Me
O
Ph
BnO
MeO
O
MeO2C
O
OMe
5
6
7
Scheme 6.
O
O
O
O
O
O
O
N3
O
NH2
O
N3
O
O
O
O
O
O
OC
O
O
O
O
OC
OC
O
O
(a)
O
O
O
O
O
O
ϩ
O
O
O
O
NH
NH
NH
MeO2C
HO2C
OC
2
8
9
10
Scheme 7. (a) TsCl, pyridine.
O
O
N3
O
Ph
O
N3
O
Ph
Ph
H2N
O
O
O
O
BnO
BnO
BnO
OC
OC
OC
OMe
OMe
OMe
NH
O
NH
O
O
O
Ph
Ph
Ph
NH
O
O
(a)
O
O
O
ϩ
O
BnO
BnO
BnO
OC
OC
OC
OMe
OMe
OMe
NH
O
O
NH
O
NH
O
O
O
Ph
Ph
Ph
O
O
O
BnO
BnO
BnO
MeO2C
HO2C
OC
OMe
OMe
OMe
2
11
12
Scheme 8. (a) TsCl, pyridine.
13

736
A. Scaffidi et al.
N3
Ph
O
O
O
BnO
O
H2N
Ph
OC
O
OMe
NH
O
O
N3
Ph
O
O
BnO
Ph
O
(a)
O
OC
ϩ
O
OMe
NH
BnO
BnO
HO2C
OC
O
Ph
OMe
OMe
NH
O
O
O
BnO
15
Ph
O
O
BnO
MeO2C
OMe
MeO2C
14
OMe
16
Scheme 9. (a) TsCl, pyridine.
O
O
O
N3
O
O
O
O
O
OC
O
O
O
O
O
O
NH2
O
O
O
N3
OC
O
NH
O
O
(a)
ϩ
O
O
NH
OC
HO2C
O
O
O
O
O
O
1
MeO2C
NH
O
MeO2C
O
9
17
Scheme 10. (a) TsCl, pyridine.
O
O
O
O
O
O
O
O
O
O
O
O
X
X
N3
NH2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OC
OC
OC
OC
O
O
O
O
O
O
O
O
NH
O
NH
NH
NH
O
O
O
O
O
OC
OC
NH
OC
NH
OC
NH
2
3
4
O
O
O
O
O
O
O
O
NH
O
O
O
O
O
MeO2C
O
MeO2C
O
MeO2C
O
MeO2C
O
19 X ϭ N3
NH2
23
20
21
18 X ϭ N3
NH2
22
Scheme 11.
simplifying the 1H spectra and giving a reliable marker in the
13C spectra. As well, the infrared spectra of the higher oligo-
peptides consistently showed one amide carbonyl absorp-
tion at around 1740 cm−1, with the rest at approximately
for example, a Staudinger reaction between an azide and
a carboxylic acid, could generate an amide directly.[6] As
well, we seek to make cyclic oligopeptides, for example,
by cyclization of the reduced (azide to amine) form of the
hexapeptide 20. There are then the exciting possibilities for
these oligomers that are, on the one hand, oligopeptides
and, on the other, molecules that still seem oligosaccharide-
like.
1690 cm−1
.
We have much work left to do in this area. We still
do not fully understand the chemistry involved in the pep-
tide coupling reactions used here; perhaps other approaches,

Oligopeptides Derived from Novel Carbohydrate α-Amino Acids
737
Experimental
[Methyl (3S)-3-Azido-2-O-benzyl-4,6-O-benzylidene-3-C-carboxy-
3-deoxy-α-D-ribo-hexoside, Amide with Methyl (3S)-3-Amino-2-O-
benzyl-4,6-O-benzylidene-3-deoxy-3-C-methoxycarbonyl-α-D-ribo-
hexoside] 7
General experimental procedures have been given previously.[7] For the
1H NMR spectra it was not possible to unambiguously assign any of the
ring hydrogen atoms for the peptides.
Methyl
(3S)-3-azido-2-O-benzyl-4,6-O-benzylidene-3-C-carboxy-
3-deoxy-α-d-ribo-hexoside,[1] methyl (3S)-3-amino-2-O-benzyl-4,6-
O-benzylidene-3-deoxy-3-C-methoxycarbonyl-α-d-ribo-hexoside,[1]
and tosyl chloride in pyridine yielded[8] (flash chromatography,
EtOAc/petrol, 2 : 3) the azido ester dipeptide 7 as a glass (65%), [α]D
−48.4◦. vmax (film)/cm−1 3250 (NH), 2110 (N3), 1735 (OC=O), 1685
(NHC=O). δH (300 MHz) 3.27, 3.35 (6H, 2 s, OCH3), 3.57 (d, J1,2
4.3, H2), 3.60–3.70, 3.85–3.90, 4.22–4.31, 4.38–4.68, 4.70–4.85 (13H,
5 m, H1, H4, H4ꢀ, H5, H5ꢀ, H6, H6ꢀ, CH2Ph), 3.82 (s, CO2CH3), 4.35
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Anhydride with (3S)-3-Azido-3-C-carboxy-
3-deoxy-1,2:5,6-di-O-isopropylidene- α-D-ribo-hexose 1] 3
1,3-Dicyclohexylcarbodiimide (75 mg, 0.36 mmol) was added to the
acid 1[8] (100 mg, 0.30 mmol), the amine 2[8] (80 mg, 0.25 mmol), and
DMAP (5 mg, 0.04 mmol) in CH2Cl2 (10 mL) and the mixture left for
1 h. The standard workup (CH2Cl2) followed by flash chromatography
(EtOAc/petrol, 1 : 5) afforded the anhydride 3 as an oil (72 mg, 74%).
vmax (film)/cm−1 1750, 1780 (C=O), 2120 (N3). δH (300 MHz) 1.32,
1.43, 1.55 (12H, 3 s, CH3), 4.01 (dd, J6,6 8.6, J5,6 4.8, H6), 4.15 (dd,
J5,6 6.3, H6), 4.20–4.26 (m, H5), 4.68 (d, J4,5 7.5, H4), 4.71 (d, J1,2
3.7, H2), 5.96 (d, H1). δC (75.5 MHz) 25.00, 25.90, 26.42, 26.57 (4C,
CH3), 67.08 (C6), 72.91, 81.67, 84.77 (C2, C4, C5), 75.12 (C3), 105.14
(C1), 110.03, 114.01 (2C, OCO), 159.25 (C=O). m/z (FAB) 641.2426,
[M + H]+ requires 641.2419.
(d, J1 ,2 5.3, H2ꢀ), 5.03 (d, H1ꢀ), 5.20, 5.52 (2 H, 2 × s, CHPh), 7.12–
7.30 (20H, m, Ph), 8.81 (br s, NH). δC (75.5 MHz) 53.04 (CO2CH3),
55.49, 55.75 (2C, OCH3), 59.76, 60.20, 74.36, 75.73, 79.07, 83.37
(C2, C2ꢀ, C4, C4ꢀ, C5, C5ꢀ), 67.92, 71.09 (C3, C3ꢀ), 69.42, 69.44 (C6,
C6ꢀ), 73.88, 74.25 (2C, CH2Ph), 97.84, 98.98 (C1, C1ꢀ), 101.40, 101.64
(2C, CHPh), 125.92–138.32 (Ph), 164.86, 168.73 (CO2CH3, NCO). m/z
(FAB) 853.3285, [M + H]+ requires 853.3296.
ꢀ
ꢀ
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-deoxy-
1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
α-D-ribo-hexose 2] 4
The azido acid 1 and the amino ester 2 yielded[8] the azido ester dipep-
tide 4 (Found: C 51.6, H 6.4, N 8.8. C27H40N4O13 requires C 51.6,
H 6.4, N 8.9%).
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-
3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose] 8
Potassium hydroxide (15 mL, 1.2 M in MeOH) was added to the azido
ester dipeptide 4 (100 mg, 0.16 mmol) and the solution stirred at 50◦C
(1 h). Water was added, followed by evaporation of the MeOH and
addition of 1 M HCl until the mixture reached pH 4. A standard
workup (EtOAc) afforded the azido acid dipeptide 8 as an oil (87 mg),
[α]D +73.1◦. δH (300 MHz) 1.25, 1.27, 1.31, 1.33, 1.34, 1.35, 1.47, 1.52
(24H, 8 s, CH3), 3.92–4.35 (7H, m, H4, H5, H5ꢀ, H6, H6ꢀ), 4.70 (d, J1,2
[(3S)-3-Azido-3-C-carboxy-1,2:5,6-di-O-cyclohexylidene-
3-deoxy-α-D-xylo-hexose, Amide with (3S)-3-Amino-
1,2:5,6-di-O-cyclohexylidene-3-deoxy-3-C-methoxycarbonyl-
α-D-xylo-hexose] 5
3.5, H2), 4.75 (d, J4 ,5 7.5, H4ꢀ), 5.20 (d, J1 ,2 3.9, H2ꢀ), 5.83 (d, H1),
6.12 (d, H1ꢀ), 8.11 (br s, OH), 8.20 (br s, NH). δC (75.5 MHz) 25.10,
25.28, 26.00, 26.05, 26.15, 26.43, 26.50, 26.66 (8C, CH3), 66.81, 67.65
(C6, C6ꢀ), 71.74, 73.91, 81.09, 81.77, 84.96, 85.11 (C2, C2ꢀ, C4, C4ꢀ,
C5, C5ꢀ), 72.06, 75.09 (C3, C3ꢀ), 103.79, 106.00 (C1, C1ꢀ), 109.54,
110.62, 112.42, 113.58 (4C, OCO), 165.38, 169.72 (CO2H, NCO). m/z
(FAB) 615.2494, [M + H]+ requires 615.2514.
ꢀ
ꢀ
ꢀ
ꢀ
(3S)-3-Azido-3-C-carboxy-1,2:5,6-di-O-cyclohexylidene-3-deoxy-α-
d-xylo-hexose,[1] (3S)-3-amino-1,2:5,6-di-O-cyclohexylidene-3-deoxy-
3-C-methoxycarbonyl-α-d-xylo-hexose,[1] and tosyl chloride in pyri-
dine afforded[8] (flash chromatography, EtOAc/petrol, 1 : 2) the azido
ester dipeptide 5 as a glass (75%), [α]D +34.9◦. vmax (film)/cm−1 3300
(NH), 2110 (N3), 1740 (OC=O), 1675 (NHC=O). δH (300 MHz) 1.30–
ꢀ
ꢀ
1.94 (40H, m, CH2), 3.55 (dd, J6,6 8.4, J5,6 6.8, H6), 3.64 (dd, J6 ,6 8.4,
[(3S)-3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-deoxy-1,2:5,6-di-
O-isopropylidene-3-C-methoxycarbonyl-α-D-ribo-hexose 2] 9
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J5 ,6 6.7, H6 ), 3.78 (s, CO2CH3), 3.80 (dd, J5,6 6.2, H6), 3.91 (dd, J5 ,6
6.4, H6ꢀ), 4.32(d, J1,2 3.4, H2), 4.34(d, J4,5 9.2, H4), 4.45–4.65(m, H4ꢀ,
ꢀ
ꢀ
H5, H5ꢀ), 4.96 (d, J1 ,2 3.6, H2 ), 5.90 (d, H1), 6.03 (d, H1 ), 8.36 (br s,
NH). δC (75.5 MHz) 23.43–36.60 (CH2), 52.79 (CO2CH3), 64.63, 66.16
(C6, C6ꢀ), 69.08, 72.83 (C3, C3ꢀ), 73.43, 75.12, 83.44, 83.65, 86.19,
86.27 (C2, C2ꢀ, C4, C4ꢀ, C5, C5ꢀ), 104.20, 105.18 (C1, C1ꢀ), 110.18,
110.33, 116.44, 116.99 (4C, OCO), 165.68, 167.46 (CO2CH3, NCO).
m/z (FAB) 789.3876, [M + H]+ requires 789.3922.
ꢀ
ꢀ
Palladium on activated charcoal (20 mg, 10% w/w) was added to the
azido ester dipeptide 4 (200 mg) in MeOH (10 mL) and the mixture
stirred under an atmosphere of hydrogen at room temperature (16 h).
Removal of the solvent gave a black residue that was subjected to
flash chromatography (MeOH/CHCl3, 1 : 19) to afford the amino ester
dipeptide 9 as a powder (188 mg, 98%), mp >230◦C (EtOAc/pentane),
[α]D +62.3◦. δH (300 MHz) 1.20, 1.24, 1.27, 1.29, 1.31, 1.32, 1.48, 1.53
(24H, 8 s, CH3), 1.76 (br s, NH2), 3.75 (s, CO2CH3), 3.90–4.17, 4.37–
4.40 (7H, 2 m, H4, H5, H5ꢀ, H6, H6ꢀꢀ), 4.30 (d, J1,2 3.5, H2), 4.75 (d,
[Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside 15, Amide with Methyl (2S)-2-Amino-3-
O-benzyl-4,6-O-benzylidene-2-deoxy-2-C-methoxycarbonyl-
α-D-arabino-hexoside] 6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J4 ,5 8.0, H4 ), 5.20 (d, J1 ,2 4.0, H2 ), 5.85 (d, H1), 6.18 (d, H1 ), 7.88
(br s, NH). δC (75.5 MHz) 25.11–26.67 (CH3), 52.64 (CO2CH3), 67.10,
67.93 (C6, C6ꢀ), 67.74, 71.58 (C3, C3ꢀ), 72.27, 73.65, 82.36, 83.35,
85.56, 87.41 (C2, C2ꢀ, C4, C4ꢀ, C5, C5ꢀ), 104.68, 106.94 (C1, C1ꢀ),
109.10, 110.12, 111.89, 113.06 (4C, OCO), 168.26, 168.77 (CO2CH3,
NCO). m/z (FAB) 603.2794, [M + H]+ requires 603.2765.
The azido acid 15,[1] methyl (2S)-2-amino-3-O-benzyl-4,6-O-
benzylidene-2-deoxy-2-C-methoxycarbonyl-α-d-arabino-hexoside,[1]
and tosyl chloride in pyridine furnished[8] (flash chromatography,
EtOAc/petrol, 2 : 3) the azido ester dipeptide 6 as a glass (62%), [α]D
−1.1◦. vmax (film)/cm−1 3285 (NH), 2125 (N3), 1750 (OC=O), 1705
(NHC=O). δH (300 MHz) 3.35, 3.42 (6H, 2 s, OCH3), 3.50–3.58, 3.75–
3.98, 4.08–4.33, 4.56–4.65, 4.73–4.96 (14H, 5 m, H3, H3ꢀ, H4, H4ꢀ,
H5, H5ꢀ, H6, H6ꢀ, CH2Ph), 3.73 (s, CO2CH3), 4.59, 5.40, 5.62, 5.83
(4H, 4 s, H1, H1ꢀ, CHPh), 7.05 (br s, NH), 7.20–7.76 (20H, m, Ph).
δC (75.5 MHz) 52.71 (CO2CH3), 55.88, 55.92 (2C, OCH3), 62.49,
63.49, 75.47, 76.87, 80.41, 80.51 (C3, C3ꢀ, C4, C4ꢀ, C5, C5ꢀ), 67.15,
72.58 (C2, C2ꢀ), 68.62, 68.68 (C6, C6ꢀ), 74.93, 75.30 (2C, CH2Ph),
99.00, 101.00 (C1, C1ꢀ), 101.62, 101.66 (2C, CHPh), 125.94–138.43
(Ph), 165.41, 168.35 (CO2CH3, NCO). m/z (FAB) 853.3302, [M + H]+
requires 853.3296.
{[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose] 8, Anhydride with
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose] 8} 10
4-Toluenesulfonyl chloride (100 mg, 0.52 mmol) was added to the azido
acid dipeptide 8 (150 mg, 0.25 mmol) and the amino ester dipeptide 9
(125 mg, 0.21 mmol) in pyridine (10 mL) at 0◦C. The resulting solution

738
A. Scaffidi et al.
was stirred at 25◦C (2 h) before being diluted with saturated NaHCO3
solution. A standard workup (CH2Cl2) followed by flash chromatogra-
phy (EtOAc/petrol, 1 : 4) furnished the anhydride 10 as an oil (110 mg,
75%). δH 1.20, 1.30, 1.34, 1.35, 1.54, 1.65 (24H, 6 s, CH3), 3.94–4.15,
4.25–4.33 (6H, 2 m, H5, H5ꢀ, H6, H6ꢀ), 4.38 (d, J4,5 5.4, H4), 4.40
(9H, 3 s, OCH3), 5.48, 5.50, 5.62 (3 s, H1, H1ꢀ, H1ꢀꢀ), 6.25 (br s, NH+),
requires 1218.4559.
7.07–7.50 (30H, m, Ph). m/z (FAB) 1218.4631; [M − C66H68N5O19
]
(d, J1,2 3.6, H2), 4.61 (d, J4 ,5 7.1, H4ꢀ), 4.65 (d, J1 ,2 3.6, H2ꢀ), 5.95
(d, H1ꢀ), 6.10 (d, H1). δC (75.5 MHz) 24.62, 25.03, 25.94, 26.17, 26.59,
26.67, 26.69, 26.81 (8C, CH3), 66.82, 67.21 (C6, C6ꢀ), 71.13, 75.54
(C3, C3ꢀ), 73.00, 73.29, 80.75, 84.65, 85.20, 85.69 (C2, C2ꢀ, C4, C4ꢀ,
C5, C5ꢀ), 105.11, 106.88 (C1, C1ꢀ), 109.62, 109.77, 113.76, 114.15
ꢀ
ꢀ
ꢀ
ꢀ
[Methyl (2S)-2-Amino-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside, Amide with Methyl (2S)-2-Amino-
3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-C-methoxycarbonyl-
α-D-arabino-hexoside] 14
(4C, OCO), 161.41 (OC=O), 170.75 (NC=O). m/z (FAB) 597.2385,
The azido ester dipeptide 6 in MeOH was treated with hydrogen and
palladium on activated charcoal as for the azide 4 to yield the amino
ester dipeptide 14 as a glass (96%), [α]D +11.7◦. δH (300 MHz) 2.10
(br s, NH2), 3.18, 3.42 (6H, 2 s, OCH3), 3.70–4.10, 4.25–4.37 (8H, 2 m,
H4, H4ꢀ, H5, H5ꢀ, H6, H6ꢀ), 3.74 (s, CO2CH3), 4.51, 5.58, 5.60, 5.64
+
[M − C26H37N4O13
]
requires 597.2408.
[Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside 15, Amide with Methyl (2S)-2-Amino-
3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-
hexoside, Amide with Methyl (2S)-2-Amino-3-O-benzyl-4,6-
O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-
hexoside] 11
(4H, 4 s, H1, H1ꢀ, CHPh), 4.61 (d, J3,4 9.5, H3), 4.74 (d, J3 ,4 9.3,
H3ꢀ), 4.81, 4.90 (AB, J 10.9, CH2Ph), 4.98 (s, CH2Ph), 7.23–7.56 (20H,
m, Ph), 8.40 (br s, NH). δC (75.5 MHz) 52.09 (CO2CH3), 55.40, 55.50
(2C, OCH3), 62.44, 62.66, 75.12, 75.75, 80.32, 80.99 (C3, C3ꢀ, C4, C4ꢀ,
C5, C5ꢀ), 65.38, 65.88 (C2, C2ꢀ), 68.59, 68.61 (C6, C6ꢀ), 74.71, 74.73
(2C, CH2Ph), 100.00, 101.44, 101.50, 102.22 (4C, C1, C1ꢀ, CHPh),
125.79–138.99 (Ph), 168.60, 168.92 (CO2CH3, NCO). m/z (FAB)
827.3376, [M + H]+ requires 827.3391.
ꢀ
ꢀ
The azido ester tripeptide 16 (150 mg) was treated with KOH as for
the ester 4 to afford the azido acid tripeptide 11 as a glass (130 mg),
[α]D +20.5◦. δH (partial, 300 MHz) 3.20, 3.43, 3.45 (9H, 3 s, OCH3),
4.97, 5.35, 5.60, 5.65, 5.66, 6.04 (6H, 6 s, H1, H1ꢀ, H1ꢀꢀ, CHPh),
7.15–7.55 (40H, Ph), 8.00 (br s, OH), 8.72 (br s, NH). δC (75.5 MHz)
55.79, 56.07, 56.08 (3C, OCH3), 62.09, 62.63, 63.40, 74.87, 75.66,
76.18, 80.20, 80.22, 80.38 (C3, C3ꢀ, C3ꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C5, C5ꢀ, C5ꢀꢀ),
67.59, 68.74, 72.44 (C2, C2ꢀ, C2ꢀꢀ), 68.42, 68.60, 68.65 (C6, C6ꢀ, C6ꢀꢀ),
75.19, 75.28, 75.55 (3C, CH2Ph), 96.38, 98.75, 100.86, 101.50, 101.68,
101.83 (6C, C1, C1ꢀ, C1ꢀꢀ, CHPh), 125.82–138.67 (Ph), 169.13, 169.56,
169.81 (3C, CO2H, NCO). m/z (FAB) 1236.4684, [M + H]+ requires
1236.4665.
[Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside 15, Amide with Methyl (2S)-2-Amino-
3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-
hexoside, Amide with Methyl (2S)-2-Amino-3-O-benzyl-4,6-
O-benzylidene-2-deoxy-2-C-methoxycarbonyl-α-D-arabino-
hexoside] 16
The azido acid 15, the amino ester dipeptide 14, and tosyl chloride
in pyridine afforded[8] (flash chromatography, MeOH/CHCl3, 1 : 49)
the azido ester tripeptide 16 as a glass (64%), [α]D +10.6◦. δH (par-
tial, 300 MHz) 3.20, 3.42, 3.50 (9H, 3 s, OCH3), 3.74 (s, CO2CH3),
4.58 (d, J3,4 9.6, H3), 4.63, 5.65, 5.67, 5.68, 6.12 (6H, 5 s, H1, H1ꢀ,
H1ꢀꢀ, CHPh), 7.20–7.58 (40H, Ph), 8.34 (br s, NH). δC (75.5 MHz)
52.08 (CO2CH3), 55.44, 55.57, 55.66 (3C, OCH3), 61.98, 63.06, 63.16,
74.75, 76.26, 76.51, 80.07, 80.36, 80.43 (C3, C3ꢀ, C3ꢀꢀ, C4, C4ꢀ, C4ꢀꢀ,
C5, C5ꢀ, C5ꢀꢀ), 65.58, 68.59, 72.97 (C2, C2ꢀ, C2ꢀꢀ), 68.36, 68.52, 68.56
(C6, C6ꢀ, C6ꢀꢀ), 74.75, 75.01, 75.27 (3C, CH2Ph), 96.40, 100.83, 101.46,
101.55, 101.64, 101.66 (6C, C1, C1ꢀ, C1ꢀꢀ, CHPh), 125.77–139.11 (Ph),
166.16, 168.11, 168.30 (3C, CO2CH3, NCO). m/z (FAB) 1250.4739,
[M + H]+ requires 1250.4822.
[Methyl (2S)-2-Amino-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside, Amide with Methyl (2S)-2-Amino-
3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-
hexoside, Amide with Methyl (2S)-2-Amino-3-O-benzyl-4,6-
O-benzylidene-2-deoxy-2-C-methoxycarbonyl-α-D-arabino-
hexoside] 12
The azido ester tripeptide 16 in MeOH was treated with hydrogen
and palladium on activated charcoal as for the azide 4 to yield the amino
ester 12 as a glass (96%), [α]D +22.6◦. δH (partial, 300 MHz) 3.13, 3.39,
3.46 (9H, 3 s, OCH3), 3.67 (s, CO2CH3), 4.55 (d, J3,4 9.6, H3), 4.58,
4.85, 5.60, 5.64, 5.65, 6.05 (6H, 6 s, H1, H1ꢀ, H1ꢀꢀ, CHPh), 4.79 (dd, J3,4
9.6, J4,5 3.7, H4), 7.22–7.55 (40H, m, Ph), 8.47, 8.55 (2H, 2 br s, NH).
δC (75.5 MHz) 52.16 (CO2CH3), 55.26, 55.43, 55.78 (3C, OCH3),
61.99, 62.76, 63.26, 74.78, 75.26, 76.36, 80.36, 80.57, 81.30 (C3,
C3ꢀ, C3ꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C5, C5ꢀ, C5ꢀꢀ), 65.53, 66.00, 68.55 (C2,
C2ꢀ, C2ꢀꢀ), 68.70, 68.87, 69.10 (C6, C6ꢀ, C6ꢀꢀ), 74.78, 74.90, 75.17
(3C, CH2Ph), 96.47, 101.64, 101.70, 101.75, 101.94, 102.42 (6C, C1,
C1ꢀ, C1ꢀꢀ, CHPh), 125.93–139.55 (Ph), 167.07, 168.54, 172.22 (3C,
CO2CH3, NCO). m/z (FAB) 1224.4967, C67H74N3O19 (M + H)+
requires 1224.4916.
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
α-D-ribo-hexose 2] 17
The azido acid 1, the amino ester dipeptide 9, and tosyl chlo-
ride in pyridine afforded[8] (flash chromatography, MeOH/CHCl3,
1 : 49) the azido ester tripeptide 17 as a glass (86%), [α] +84.7◦.
vmax (film)/cm−1 3250 (NH), 2120 (N3), 1755 (OC=DO), 1745
(NHC=O), 1685 (NHC=O). δH (partial, 300 MHz) 1.27, 1.29, 1.31,
1.32, 1.36, 1.37, 1.39, 1.46, 1.51, 1.54, 1.60 (36H, 11 s, CH3), 3.75 (s,
{[Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-
2-deoxy-α-D-arabino-hexoside 15, Amide with Methyl (2S)-2-Amino-
3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-
hexoside, Amide with Methyl (2S)-2-Amino-3-O-benzyl-4,6-
O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-hexoside] 11,
Anhydride with Methyl (2S)-2-Azido-3-O-benzyl-4,6-O-benzylidene-
2-C-carboxy-2-deoxy-α-D-arabino-hexoside 15, Amide with Methyl
(2S)-2-Amino-3-O-benzyl-4,6-O-benzylidene-2-C-carboxy-2-deoxy-
α-D-arabino-hexoside, Amide with Methyl (2S)-2-Amino-3-O-benzyl-
4,6-O-benzylidene-2-C-carboxy-2-deoxy-α-D-arabino-hexoside 11} 13
ꢀ
ꢀ
CO2CH3), 4.58 (d, J4,5 8.7, H4), 4.62 (d, J1,2 3.8, H2), 4.64 (d, J4 ,5
5.2, H4ꢀ), 4.78 (d, J4 ,5 5.2, H4ꢀꢀ), 4.80 (d, J1 ,2 3.6, H2ꢀ), 5.20 (d,
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
J1 ,2 3.7, H2ꢀꢀ), 5.91 (d, J1 ,2 3.7, H1ꢀ), 6.00 (d, H1ꢀꢀ), 6.04 (d, H1),
8.46, 8.75 (2H, 2 br s, NH). δC (75.5 MHz) 25.08–27.02 (CH3), 52.61
(CO2CH3), 65.78, 66.56, 67.50 (C6, C6ꢀ, C6ꢀꢀ), 70.52, 70.58, 74.77 (C3,
C3ꢀ, C3ꢀꢀ), 72ꢀ.ꢀ58, 73.52, 73.93, 80.36, 82.09, 82.35, 83.03, 85.68, 85.85
(C2, C2ꢀ, C2 , C4, C4ꢀ, C4ꢀꢀ, C5, C5ꢀ, C5ꢀꢀ), 104.92, 105.06, 105.22
(C1, C1ꢀ, C1ꢀꢀ), 108.70, 109.76, 110.11, 112.60, 112.79, 113.81 (6C,
OCO), 165.62, 166.32, 167.31 (3C, CO2CH3, NCO). m/z (FAB)
914.3817, [M + H]+ requires 914.3883.
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
The azido acid tripeptide 11 (100 mg, 0.08 mmol) and the amino ester
tripeptide 12 (80 mg, 0.07 mmol) in pyridine (10 mL) were treated with
tosylchloride (30 mg, 0.16 mmol)asforthe acid 8 andtheamine 9 to fur-
nish the anhydride 13 as an oil (72 mg, 73%). δH (partial) 3.12, 3.25, 3.45

Oligopeptides Derived from Novel Carbohydrate α-Amino Acids
739
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-deoxy-1,2:5,6-di-
O-isopropylidene-3-C-methoxycarbonyl-α-D-ribo-
hexose 2] 18
the azido ester hexapeptide 20 as a fluffy solid (62%), mp >230◦C
(EtOAc/pentane), [α]D +9.7◦. vmax (KBr)/cm−1 3380 (NH), 2120
(N3), 1730 (OC=O), 1705 (NHC=O), 1680 (NHC=O). δH (partial,
500 MHz) 1.22–1.70 (72H, m, CH3), 3.76 (s, CO2CH3), 4.38 (d, J4,5
7.8, H4), 4.40 (d, J4 ,5 8.0, H4ꢀ), 4.43 (d, J4 ,5 7.5, H4ꢀꢀ), 4.48
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
(d, J4
6.9, H4ꢀꢀꢀ), 4.52 (d, J4
8.5, H4ꢀꢀꢀꢀ), 4.64, 5.06, 5.07,
ꢀꢀꢀꢀ,5ꢀꢀꢀꢀ
ꢀꢀꢀ,5ꢀꢀꢀ
5.15, 5.90, 6.17, 6.18, 6.19 (8 d, H1, H1ꢀ, H1ꢀꢀ, H1ꢀꢀꢀ, H2, H2ꢀ, H2ꢀꢀ,
H2ꢀꢀꢀ), 4.77 (d, J4 8.9, H4ꢀꢀꢀꢀꢀ), 5.03 (d, J1 3.6, H2ꢀꢀꢀꢀ), 5.13
ꢀꢀꢀꢀꢀ,5ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀ,2ꢀꢀꢀꢀ
The azido acid 1, the amino ester tripeptide 21, and tosyl chlo-
ride in pyridine afforded[8] (flash chromatography, EtOAc/petrol, 2 : 3)
the azido ester tetrapeptide 18 as a glass (87%), [α]D +71.0◦. vmax
(film)/cm−1 3280 (NH), 2120 (N3), 1755 (OC=O), 1740 (NHC=O),
1695 (NHC=O), 1680 (NHC=O). δH (partial, 300 MHz) 1.21–1.60
(d, J1
3.9, H2ꢀꢀꢀꢀꢀ), 6.10 (d, H1ꢀꢀꢀꢀꢀ), 6.16 (d, H1ꢀꢀꢀꢀ), 7.80, 8.05, 8.13,
ꢀꢀꢀꢀꢀ,2ꢀꢀꢀꢀꢀ
8.25, 8.27 (5H, 5 br s, NH). δC (125.8 MHz) 25.05–26.72 (CH3), 52.66
(CO2CH3), 66.78, 66.80, 67.00, 67.22, 67.42, 67.54 (C6, C6ꢀ, C6ꢀꢀ, C6ꢀꢀꢀ,
C6ꢀꢀꢀꢀ, C6ꢀꢀꢀꢀꢀ), 69.87, 69.90, 69.96, 69.98, 71.99 (C3, C3ꢀ, C3ꢀꢀ, C3ꢀꢀꢀ,
C3ꢀꢀꢀꢀ, C3ꢀꢀꢀꢀꢀ), 72.23, 72.48, 72.74, 72.81, 73.35, 73.67, 74.87, 82.93,
83.09, 83.23, 83.38, 83.41, 83.ꢀ6ꢀꢀ9ꢀꢀ, 83.94, 84.81, 84.94, 85.17, 85.54
ꢀ
ꢀ
(48H, m, CH3), 3.79 (s, CO2CH3), 4.36 (d, J4,5 8.1, H4), 4.53 (d, J4 ,5
8.6, H4ꢀ), 4.58 (d, J4 ,5 5.3, H4ꢀꢀ), 4.62 (d, J1,2 3.7, H2), 4.80 (d,
ꢀꢀ ꢀꢀ
(C2, C2ꢀ, C2ꢀꢀ, C2ꢀꢀꢀ, C2ꢀꢀꢀꢀ, C2 , C4, C4ꢀ, C4ꢀꢀ, C4ꢀꢀꢀ, C4ꢀꢀꢀꢀ, C4ꢀꢀꢀꢀꢀ
,
ꢀꢀꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀꢀ,5ꢀꢀꢀ
J4
8.8, H4 ), 4.94 (d, J1 ,2 3.6, H2 ), 5.17 (d, J1 ,2 3.7, H2 ), 5.28
C5, C5ꢀ, C5ꢀꢀ, C5ꢀꢀꢀ, C5ꢀꢀꢀꢀ, C5ꢀꢀꢀꢀꢀ), 104.91, 106.29, 106.38, 106.83,
107.00, 107.22 (C1, C1ꢀ, C1ꢀꢀ, C1ꢀꢀꢀ, C1ꢀꢀꢀꢀ, C1ꢀꢀꢀꢀꢀ), 109.06, 109.23,
109.38, 109.57, 109.78, 110.04, 111.82, 112.08, 112.21, 112.48, 112.58,
113.76 (12C, OCO), 163.86, 164.63, 164.80, 164.84, 165.09, 168.13
(6C, CO2CH3, NCO). m/z (FAB) 1768.7469, [M + H]+ requires
1768.7441.
4.0, H2ꢀꢀꢀ), 5.90 (d, H1ꢀꢀ), 5.91 (d, H1), 6.02 (d, H1ꢀ), 6.14
ꢀꢀꢀ,2ꢀꢀꢀ
(d, J1
(d, H1ꢀꢀꢀ), 8.06, 8.43, 8.60 (3H, 3 br s, NH). δC (75.5 MHz) 25.24–26.87
(CH3), 52.57 (CO2CH3), 66.51, 67.23, 67.46, 67.51 (C6, C6ꢀ, C6ꢀꢀ,
C6ꢀꢀꢀ), 70.28, 70.44, 72.09, 74.65 (C3, C3ꢀ, C3ꢀꢀ, C3ꢀꢀꢀ), 71.99, 72.51,
73.63, 74.06, 80.97, 82.60, 83.10, 83.21, 83.48, 84.56, 85.37, 85.56 (C2,
C2ꢀ, C2ꢀꢀ, C2ꢀꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C4ꢀꢀꢀ, C5, C5ꢀ, C5ꢀꢀ, C5ꢀꢀꢀ), 104.91, 105.12,
105.46, 107.13 (C1, C1ꢀ, C1ꢀꢀ, C1ꢀꢀꢀ), 109.08, 109.68, 110.04, 110.08,
111.70, 112.62, 112.75, 113.77 (8C, OCO), 164.74, 165.31, 165.77,
168.17 (4C, CO2CH3, NCO). m/z (FAB) 1199.5093, [M + H]+ requires
1199.5095.
[(3S)-3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with
(3S)-3-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-
methoxycarbonyl-α-D-ribo-hexose 2] 21
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-3-
Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-deoxy-3-C-carboxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
α-D-ribo-hexose 2] 19
The azido ester dipeptide 17 in MeOH was treated with hydrogen
and palladium on activated charcoal as for the azide 4 to yield the
amino ester tripeptide 21 as a glass (97%), [α]D +122.8◦. δH (par-
tial, 300 MHz) 1.26–1.28 (15H, m, CH3), 1.33, 1.37, 1.40, 1.48, 1.50,
1.52, 1.57 (21H, 7 s, CH3), 3.73 (s, CO2CH3), 4.24 (d, J1,2 3.7, H2),
4.65 (d, J4,5 8.3, H4), 4.72 (d, J1 ,2 4.0, H2ꢀ), 4.81 (d, J1 ,2 4.4,
H2ꢀꢀ), 5.88 (d, H1ꢀ), 5.91 (d, H1ꢀꢀ), 6.04 (d, H1), 8.82, 9.23 (2H, 2 br
s, NH). δC (75.5 MHz) 25.09–27.25 (CH3), 52.46 (CO2CH3), 65.22,
66.40, 68.04 (C6, C6ꢀ, C6ꢀꢀ), 67.93, 69.99, 70.39 (C3, C3ꢀ, C3ꢀꢀ), 73.30,
73.53, 74.18, 79.09, 81.70, 81.92, 82.15, 86.15, 87.52 (C2, C2ꢀ, C2ꢀꢀ, C4,
C4ꢀ, C4ꢀꢀ, C5, C5ꢀ, C5ꢀꢀ), 104.50, 104.60, 105.07 (C1, C1ꢀ, C1ꢀꢀ), 108.42,
109.67, 109.75, 111.27, 112.74, 113.21 (6C, OCO), 167.10, 167.19,
171.09 (3C, CO2CH3, NCO). m/z (FAB) 888.3983, [M + H]+ requires
888.3977.
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
The azido acid 1, the amino ester tetrapeptide 22, and tosyl chlo-
ride in pyridine afforded[8] (flash chromatography, EtOAc/petrol,
2 : 3) the azido ester pentapeptide 19 as a fluffy solid (73%),
mp >230◦C (EtOAc/pentane), [α]D +26.0◦. vmax (KBr)/cm−1 3380
(NH), 2120 (N3), 1760 (OC=O), 1740 (NHC=O), 1700 (NHC=O),
1685 (NHC=O). δH (partial, 300 MHz) 1.20–1.65 (60H, m, CH3), 3.85
(s, CO2CH3), 4.45 (d, J4,5 7.8, H4), 4.48 (d, J4 ,5 8.6, H4ꢀ), 4.62
ꢀ
ꢀ
(d, J1,2 3.7, H2), 4.74 (d, J4 ,5 8.6, H4ꢀꢀ), 4.99 (d, J1 ,2 3.6, H2ꢀ),
ꢀꢀ ꢀꢀ
ꢀ
ꢀ
5.05 (d, J1 ,2 3.6, H2ꢀꢀ), 5.10 (d, J1
4.0, H2ꢀꢀꢀ), 5.12 (d, J1
ꢀꢀꢀꢀ,2ꢀꢀꢀꢀ
ꢀꢀꢀ,2ꢀꢀꢀ
ꢀꢀ ꢀꢀ
3.5, H2ꢀꢀꢀꢀ), 5.89 (d, H1ꢀꢀ), 6.08 (d, H1ꢀꢀꢀ), 6.11 (d, H1), 6.13 (d, H1ꢀ),
6.14 (d, H1ꢀꢀꢀꢀ), 7.80, 8.10, 8.24, 8.29 (4H, 4 br s, NH). δC (75.5 MHz)
25.08–26.69 (CH3), 52.63 (CO2CH3), 66.68, 66.75, 67.13, 67.40, 67.51
(C6, C6ꢀ, C6ꢀꢀ, C6ꢀꢀꢀ, C6ꢀꢀꢀꢀ), 69.87, 69.91, 69.93, 71.88, 74.84 (C3,
C3ꢀ, C3ꢀꢀ, C3ꢀꢀꢀ, C3ꢀꢀꢀꢀ), 72.28, 72.47, 72.74, 73.41, 73.62, 82.61,
82.91, 83.05, 83.32, 83.45, 83.62, 83.64, 84.98, 85.18, 85.26 (C2,
C2ꢀꢀꢀ,ꢀ C2ꢀꢀ, C2ꢀꢀꢀ, C2ꢀꢀꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C4ꢀꢀꢀ, C4ꢀꢀꢀꢀ, C5, C5ꢀ, C5ꢀꢀ,
C5 , C5ꢀꢀꢀꢀ), 104.90, 106.08, 106.18, 106.75, 107.08 (C1, C1ꢀ, C1ꢀꢀ,
C1ꢀꢀꢀ, C1ꢀꢀꢀꢀ), 109.03, 109.32, 109.60, 109.78, 110.00, 111.83, 112.14,
112.60, 112.67, 113.73 (10C, OCO), 163.99, 164.84, 164.95, 165.18,
168.07 (5C, CO2CH3, NCO). m/z (FAB) 1484.6190, [M + H]+ requires
1484.6307.
[(3S)-3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-deoxy-1,2:5,6-di-
O-isopropylidene-3-C-methoxycarbonyl-α-D-ribo-
hexose 2] 22
The azido ester dipeptide 18 in MeOH was treated with hydrogen
and palladium on activated charcoal as for the azide 4 to yield the
amino ester tetrapeptide 22 as a glass (97%), [α]D +81.6◦. δH (par-
tial, 300 MHz) 1.21–1.58 (48H, m, CH3), 3.75 (s, CO2CH3), 4.56 (d,
J4,5 8.4, H4), 4.67 (d, J4 ,5 5.3, H4ꢀ), 4.81 (d, J4 ,5 8.6, H4ꢀꢀ), 4.92
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
[(3S)-3-Azido-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose 1, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-deoxy-1,2:5,6-di-O-
isopropylidene-3-C-methoxycarbonyl-α-D-ribo-hexose 2] 20
(d, J1,2 3.5, H2), 5.17 (d, J1 ,2 4.0, H2ꢀ), 5.24 (d, J1 ,2 3.7, H2ꢀꢀ),
5.87 (d, H1ꢀꢀ), 5.99 (d, J1 3.4, H1ꢀꢀꢀ), 6.01 (d, H1), 5.17, 6.13 (d,
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀꢀ,2ꢀꢀꢀ
H1ꢀ), 8.15, 8.58, 8.99 (3H, 3 br s, NH). δC (75.5 MHz) 25.28–26.90
(CH3), 52.51 (CO2CH3), 66.61, 67.06, 67.31, 67.93 (C6, C6ꢀ, C6ꢀꢀ,
C6ꢀꢀꢀ), 67.58, 70.36, 70.44, 71.94 (C3, C3ꢀ, C3ꢀꢀ, C3ꢀꢀꢀ), 72.09, 73.01,
73.64, 74.03, 80.83, 82.40, 82.51, 82.65, 83.29, 84.80, 85.69, 87.52 (C2,
C2ꢀ, C2ꢀꢀ, C2ꢀꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C4ꢀꢀꢀ, C5, C5ꢀ, C5ꢀꢀ, C5ꢀꢀꢀ), 104.75, 105.09,
105.44, 106.93 (C1, C1ꢀ, C1ꢀꢀ, C1ꢀꢀꢀ), 109.04, 109.62, 109.83, 110.04,
111.71, 112.62, 112.70, 113.32 (8C, OCO), 165.55, 166.45, 168.08,
169.94 (4C, CO2CH3, NCO). m/z (FAB) 1173.5112, [M + H]+ requires
1173.5190.
The azido acid 1, the amino ester pentapeptide 23, and tosyl chloride
in pyridine afforded[8] (flash chromatography, MeOH/CHCl3, 1 : 49)

740
A. Scaffidi et al.
[(3S)-3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
α-D-ribo-hexose, Amide with (3S)-3-Amino-3-C-carboxy-3-deoxy-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, Amide with (3S)-
3-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methoxycarbonyl-
α-D-ribo-hexose 2] 23
employed; computation was performed using the Xtal 3.7 program
system.[9] The configuration setting adopted was on the basis of the
known chemistry. Pertinent results are given below and in Table 1 and
Fig. 1. Full crystallographic details (excluding structure factor ampli-
tudes) are deposited with the Cambridge Crystallography Data Centre
(CCDC 226182).
Crystal data: C27H40N4O13, M628.6. Monoclinic, space group P21
(C22, no. 4), a 10.3840(6), b 13.1090(7), c 11.3260(6) Å, β 96.921(1)◦,
V 1531 Å3. Dc(Z = 2) 1.364 g cm−3. µMo 0.11 mm−1; specimen:
The azido ester dipeptide 19 in MeOH was treated with hydrogen and
palladium on activated charcoal as for the azide 4 to yield the amino
ester pentapeptide 23 as a glass (95%), mp >230◦C (EtOAc/pentane),
[α]D +42.8◦. δH (partial, 300 MHz) 1.20–1.63 (60H, m, CH3), 3.72
(s, CO2CH3), 4.74 (d, J4,5 7.4, H4), 4.96 (d, J1,2 3.6, H2), 5.07 (d,
0.32 × 0.25 × 0.18 mm3; ‘T’min/max 0.93. |ꢀρmax| 0.36(3) e Å−3
.
Acknowledgment
J1 ,2 3.8, H2ꢀ), 5.09 (d, J1 ,2 4.2, H2ꢀꢀ), 5.17 (d, J1
3.6, H2ꢀꢀꢀ),
We thank Simon Brayshaw for suggesting the tosyl chloride/
pyridine procedure to us.
ꢀ
ꢀ
ꢀꢀ ꢀꢀ
ꢀꢀꢀ,2ꢀꢀꢀ
5.86 (d, J1,2 3.6, H1), 6.06–6.11 (m, H1ꢀ, H1ꢀꢀ, H1ꢀꢀꢀ), 6.13 (d, J1
ꢀꢀꢀꢀ,2ꢀꢀꢀꢀ
3.6, H1ꢀꢀꢀꢀ), 7.85, 8.07, 8.35, 8.68 (4H, 4 br s, NH). δC (75.5 MHz)
25.11–26.75 (CH3), 52.58 (CO2CH3), 66.61, 66.73, 67.01, 67.47, 67.87
(C6, C6ꢀ, C6ꢀꢀ, C6ꢀꢀꢀ, C6ꢀꢀꢀꢀ), 67.63, 69.84, 69.99, 70.03, 71.73 (C3, C3ꢀ,
C3ꢀꢀ, C3ꢀꢀꢀ, C3ꢀꢀꢀꢀ), 72.33, 72.85, 72.99, 73.51, 73.60, 82.41, 82.55, 82.93,
83.23, 83.43, 83.53, 83.70, 84.88, 85.25, 87.45 (C2, C2ꢀ, C2ꢀꢀ, C2ꢀꢀꢀ,
C2ꢀꢀꢀꢀ, C4, C4ꢀ, C4ꢀꢀ, C4ꢀꢀꢀ, C4ꢀꢀꢀꢀ, C5, C5ꢀ, C5ꢀꢀ, C5ꢀꢀꢀ, C5ꢀꢀꢀꢀ), 105.13,
105.91, 106.05, 106.50, 106.89 (C1, C1ꢀ, C1ꢀꢀ, C1ꢀꢀꢀ, C1ꢀꢀꢀꢀ), 109.0,
109.29, 109.51, 109.75, 109.79, 111.86, 112.19, 112.53, 112.69, 113.25
(10C, OCO), 164.93, 165.26, 165.88, 167.98, 169.16 (5C, CO2CH3,
NCO). m/z (FAB) 1458.6376, [M + H]+ requires 1458.6402.
References
[1] A. Scaffidi, B. W. Skelton, R. V. Stick, A. H. White, Aust. J.
Chem. 2004, 57, 723. doi:10.1071/CH04015.
[2] B. Neises, W. Steglich, Angew. Chem., Int. Ed. Engl. 1978, 17,
522. doi:10.1002/ANIE.197805221
[3] A. Hassner, V. Alexanian, Tetrahedron Lett. 1978, 4475.
doi:10.1016/S0040-4039(01)95256-6
[4] N. L. Hungerford, T. D. W. Claridge, M. P. Watterson, R. T. Aplin,
A. Moreno, G. W. J. Fleet, J. Chem. Soc., Perkin Trans. 1 2000,
3666. doi:10.1039/B002996N
Structure Determination of 4
[5] J. H. Brewster, C. J. Ciotti, J. Am. Chem. Soc. 1955, 77, 6214.
[6] O. David, W. J. N. Meester, H. Bieraugel, H. E. Schoemaker,
H. Hiemstra, J. H. van Maarseveen, Angew. Chem., Int. Ed.
2003, 42, 4373. doi:10.1002/ANIE.200351930
[7] J. C. McAuliffe, R. V. Stick, Aust. J. Chem. 1997, 50, 193.
[8] G. S. Forman, A. Scaffidi, R. V. Stick, Aust. J. Chem. 2004, 57,
25. doi:10.1071/CH03214
[9] The Xtal 3.7 System (Eds S. R. Hall, D. J. du Boulay,
R. Olthof-Hazekamp) 2002 (University of Western Australia:
Perth).
A full sphere of CCD area-detector diffractometer data (Bruker AXS
instrument, ω-scans; monochromatic MoKα radiation, λ 0.71073 Å,
2θmax 75◦; T ≈ 153 K) was measured, yielding 31 788 reflections, these
merging after ‘empirical’/multiscan absorption correction (proprietary
software) to 8290 independent (Rint 0.031; ‘Friedel’ data also merged,
there being no non-trivial anomalous scatter), 6410 with F > 4σ(F)
considered ‘observed’ and used in the full-matrix least-squares refine-
ment, refining anisotropic displacement parameter forms for C, N, and
O; (x, y, z, Uiso)H were also refined. Conventional residuals R, Rw at
convergence were both 0.045. Neutral atom scattering factors were