Synthesis of a protected δ-glyco-amino acid building block for incorporation into peptide chains

Article abstract of DOI:10.1055/s-2007-965942

The synthesis of a suitably protected sugar amino acid (δ-glyco-amino acid) as a building block to be incorporated into the peptide chain (N-terminus) of bioactive peptide analogues is described. Its efficient coupling reactions with pilot amino acids as

Full text of DOI:10.1055/s-2007-965942

PAPER
845
Synthesis of a Protected d-Glyco-amino Acid Building Block for Incorporation
into Peptide Chains
Synthesis of
a
Prot
e
ected
d
-Gly
o
co-amino A
r
cid Build
g
ing Block e Paloumbis,a Christos C. Petrou,a Berthold Nock,b Theodosia Maina,b George Pairas,a Petros G. Tsoungas,c
Paul Cordopatis*a
a
Department of Pharmacy, University of Patras, 26504 Patras, Greece
Fax +30(2610)997714; E-mail: pacord@upatras.gr
Institute of Radioisotopes – Radiodiagnostic Products, National Centre for Scientific Research ‘Demokritos’, Agia Paraskevi Attikis,
b
15310 Athens, Greece
c
Ministry of Development, Department of Research and Technology, 14–18 Messogion Ave, 11510 Athens, Greece
Received 11 October 2006; revised 15 November 2006
O
O
Abstract: The synthesis of a suitably protected sugar amino acid
(d-glyco-amino acid) as a building block to be incorporated into the
peptide chain (N-terminus) of bioactive peptide analogues is de-
scribed. Its efficient coupling reactions with pilot amino acids as
well as dipeptides have been accomplished by standard peptide
chemistry.
OMe
O
O
R2
HO
NHR1
R2
NHR1
OH
O
HO
OH
O
OH
O
O
NHR1
OH
Key words: carbohydrates, d-glyco-amino acid, glycosylation,
glycopeptides, radiolabelling
R2
NHR1
R2
HO
HO
HO
OH
OH
Carbohydrates represent an attractive source of readily
available stereodefined scaffolds, as they carry easily con-
vertible substituents on a rigid pyran or a more flexible fu-
ran ring.1–4 Their molecular diversity provides a valuable
tool for drug discovery. Derivatives bearing an amine and
a carboxyl group are non-natural amino acid analogues
known as glyco-amino acids or sugar amino acids
(SAAs).5 SAAs attached to peptides give rise to peptido-
mimetics, hybrid structures with folded conformations.5–8
Synthetic peptide analogues are widely recognized as im-
portant lead compounds for development of new
materials9 and generation of therapeutic agents.5,10
Figure 1 Building blocks of sugar amino acids
properties arising from the incorporation of the carbohy-
drate structure into the peptide skeleton.
Peptidomimetics incorporating SAAs (Figure 1) have
been reported first by Kessler et al.14 It was demonstrated
that the SAA entity triggered constrains on local confor-
mations of the peptide backbone. Furanoid SAAs to be in-
corporated into peptide side chains have been prepared by
other groups.15–17 Unlike their a-, b-, and g-peptide-based
foldamers, d-counterparts are somewhat less explored,
probably due to their increased backbone flexibility.8,18
Several studies have shown that peptide glycosylation can
be used to enhance their resistance to proteolysis and rap-
id excretion, hence improving their transport across mem-
branes.11 An example is the incorporation of carbohydrate
groups into enkephalin peptides; this influences receptor
binding and enhances peptide delivery to the brain or the
spinal cord.12
As part of an ongoing research programme on the study of
somatostatin peptidomimetic frameworks, we have em-
barked on the synthesis of suitably protected d-glyco-
amino acids such as A (Scheme 1).
SAA A, if incorporated into a peptide sequence, will lead
to peptide structure B (Scheme 1), which can be selective-
ly deprotected at the N-terminus (base-labile protection)
without the other acid-labile protecting groups of the sug-
ar being affected. The released amine can then be coupled
with a suitable chelator, e.g. a tetraamine, to further stably
bind a metallic radionuclide such as 99mTc, affording the
diagnostic radiopeptide C (Scheme 1). Chelator–peptide
conjugates labelled with 99mTc and other radiometals,
such as 111In, 68Ga, 90Y, and 64Cu, have been proposed for
the scintigraphic imaging or radiotherapy of tumours ex-
pressing the corresponding peptide receptors in high den-
sity.19–21
Synthetic glycopeptides can be obtained in preparative
quantities and can be linked to complex biological carrier
molecules. Albert et al.13 described the synthesis of chem-
ically stable glycated derivatives to produce somatostatin
analogues by the Amadori reaction. The in vitro activity
of these glycated molecules was shown to be similar to
that of the nonglycated parent octreotide. Nonetheless,
some of the Amadori products were found to have en-
hanced bioavailability compared to octreotide. This was
thought to be the result of changes in physicochemical
We report herein the synthesis of A as the key building
block for our objectives.
SYNTHESIS 2007, No. 6, pp 0845–0852
Advanced online publication: 20.02.2007
DOI: 10.1055/s-2007-965942; Art ID: P12006SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

846
G. Paloumbis et al.
PAPER
O
P1
P1
P1
+1
O
O
peptide
O
O
O
O
NH
CO2H
O
HN
HN
O
99Tc
O
H2N
H2N
O
peptide
NH
O
NH
P1
P1
O
O
NH
NH
P2
O
P2
O
O
P1
P1
P1
P1
A
B
C
Scheme 1 Strategy for synthetic targets (P1 = acid-labile protection; P2 = base-labile protection)
It is obvious that the key transformations in the synthesis access to the C-4 position. Benzylidene acetals are most
of a molecule such as A would be the introduction of the suitable in this respect, since they form a six-membered
carboxylic acid at C-1 and the amino function at C-4. ring with the hydroxy groups at C-4 and C-6. Subsequent
From a retrosynthetic point of view, the carboxy group reductive cleavage leaves a free hydroxy group at either
can be obtained from the hydrolysis of a nitrile, which in position, depending on the conditions used.25 Our original
turn can be obtained by a nucleophilic displacement at the approach involved benzylidenation of the hydroxy groups
anomeric centre with a suitable cyanide reagent. Similar- at C-4 and C-6 with benzaldehyde dimethyl acetal fol-
ly, the amino group could come from the reduction of an lowed by benzylation of the remaining hydroxy groups
azide derived from a nucleophilic displacement at C-4. with benzyl bromide. Reductive opening of the ben-
Our synthesis was based on a method recently reported by zylidene group with hydrogen chloride–sodium cyano-
Ichikawa et al.,22 in which glucose-type amino acids were borohydride afforded the C-4-unprotected hydroxy group,
prepared and combined to form homo-oligomers.
which was further functionalised. However, a few steps
later we realized that our molecule was unstable to the cat-
alytic hydrogenation conditions used for the removal of
the benzyl groups. For this reason we decided to use acid-
labile protecting groups on the hydroxy functions from the
beginning of our synthesis to avoid this problem.
To this end we chose to use the commercially available
penta-O-acetyl-b-D-galactopyranose (1) as our starting
galactopyranoside molecule (Scheme 2). This was chosen
because the introduction of the amino functionality at C-4
involves an SN2 displacement of a triflate group by a met-
al azide, which results in inversion of stereochemistry (see As before, but now using the p-methoxybenzylidene ace-
Scheme 4), thus giving the desired glucose configuration. tal, we prepared the C-4- to C-6-protected diol 4 in 79%
Furthermore, the transformation into the nitrile intermedi- yield (Scheme 3). Attempts to protect the remaining hy-
ate 2 is higher-yielding (77%) than when the a-isomer droxy functions (at C-2 and C-3) also with the p-methoxy-
(60%) or the a- and b-glucopyranose derivatives (12% benzyl group (PMBCl, KI, K2CO3) were unsuccessful,
and 15% respectively) are used.23
and we never managed to obtain the fully protected sugar.
As an alternative, the tert-butyldimethylsilyl group was
used, since the formation of the Si–O bond is much more
favourable, and can be readily cleaved under acidic con-
ditions. The a-oxymethyl (formacetal) group (ROCH2O-)
is equally effective, hence an efficient surrogate of tert-
butyldimethylsilyl.26 The fully protected galactose deriv-
ative 5 was obtained in 80% yield (Scheme 3). Regiose-
lective reduction with sodium cyanoborohydride and
trifluoroacetic acid afforded the hydroxy ether 6 in 64%
yield after chromatography.
In our case the displacement of the acetoxy group at C-1
with trimethylsilyl cyanide proceeded smoothly, giving
nitrile 2 in 70% yield after recrystallisation. Direct hydro-
lysis of nitrile 2 to the methyl ester derivative 3 with con-
comitant deprotection of the hydroxy groups can be
efficiently effected with either the boron trifluoride–
ethanol or –methanol complex24 or with acetyl chloride/
methanol. The latter combination led to a quantitative
yield of ester 3. The assignment of the b-configuration at
C-1 was on the basis of the large coupling constant
(J = 10.1 Hz) between H-1 (axial) and H-2 (axial) in the With the hydroxy group at C-4 exposed, its triflate ana-
1H NMR spectrum.
logue was prepared to allow its displacement by the azide
group, a commonly used sequence of transformations in
glyco-amino acids.27
The next set of experiments involved the protection of the
free hydroxy functionalities with groups that would allow
OAc
OAc
O
H O
HO
CN
OAc
OAc
O
O
O
a
b
O
OAc
AcO
OH
AcO
OAc
OAc
HO
1
2
3
Scheme 2 Reagents and conditions: (a) TMSCN, BF3·OEt2, MeNO2, r.t., 23 h, 70%; (b) AcCl, MeOH, 0 °C (15 min) then 60–65 °C (3 d), 100%.
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

PAPER
Synthesis of a Protected d-Glyco-amino Acid Building Block
847
OH
O
O
O
O
OMe
OH
O
OMe
OH
a
b
HO
O
OH
OH
MeO
3
4
O
O
O
O
OMe
O
O
HO
OMe
O
OTBDMS
OTBDMS
c
MeO
MeO
OTBDMS
OTBDMS
6
5
Scheme 3 Reagents and conditions: (a) PMPCH(OMe)2, TsOH, MeCN, 2 h, r.t., then Et3N, 79%; (b) TBDMSCl, imidazole, DMAP, DMF,
65 °C, 24 h, 80%; (c) NaBH3CN, TFA, 4-Å MS, CH2Cl2, THF, r.t., 24 h, 64%.
The crude triflate derivative 7 (Scheme 4) was treated such as H-b-Ala-Ot-Bu, to give 11, as well as with the
with ten equivalents of sodium azide in N,N-dimethyl- dipeptide H-Ala-Ala-Ot-Bu, to give 12 (Scheme 5). The
formamide to give glucose derivative 8 in 89% yield after coupling reaction was performed by a protocol involving
chromatography. The azide was reduced to the secondary N,N-diisopropylethylamine combined with O-(7-azaben-
amine 9 by the Staudinger reaction (PPh3/THF/H2O), and zotriazol-1-yl)-N,N,N¢,N¢-tetramethyluronium hexafluo-
the ester was hydrolysed in ‘one pot’ by the addition of rophosphate (HATU); this afforded the desired products
lithium hydroxide or sodium hydroxide to the mixture. Fi- cleanly and relatively quickly (0.5–1 h) (Scheme 5).
nally, the amino terminus was protected with the Fmoc
Table 1 and Table 2 show the correlations between the
group by treatment of compound 9 with Fmoc-OSu; this
protons and carbons of compound 10 and 12, respectively,
gave target molecule 10 in 63% yield.
which helped in the assignment of the spectra.
The penultimate step of our synthetic scheme has been re-
In summary, we have synthesised a highly functionalised
peated a few times to optimise the conditions. While the
building block, in good overall yield (73%), with orthog-
formation of the phosphazene and its hydrolysis to the
onal protecting groups suitable for Fmoc/t-Bu peptide
synthesis. We decided to introduce acid-labile protecting
free amine seems to work well, prolonged treatment with
lithium hydroxide or sodium hydroxide to facilitate ester
groups on the free hydroxy functions and a base-labile
hydrolysis sometimes leads to byproducts and reduces the
(Fmoc) protecting group on the free amine (N-terminus).
yield.
The free carboxy group was successfully coupled with a
Finally, to test and establish the conditions of coupling of single non-natural amino acid (b-Ala) as well as a dipep-
our glyco-amino acid 10 with bionucleophiles, 10 suc- tide (Ala-Ala) by use of standard peptide coupling reac-
cessfully reacted at the N-terminus of a single amino acid tions (HATU/DIPEA protocol).
OPMB
O
OPMB
OPMB
O
O
O
O
O
a
OMe
OMe
b
OMe
OTBDMS
OTBDMS
HO
TfO
N3
OTBDMS
OTBDMS
OTBDMS
OTBDMS
c
6
7
8
OPMB
O
OPMB
O
O
O
OH
O
O–
OTBDMS
d
O
N
OTBDMS
OTBDMS
H
+H3N
OTBDMS
10
9
Scheme 4 Reagents and conditions: (a) Tf2O, py, CH2Cl2, r.t., 35 h, 87%; (b) NaN3, DMF, r.t., 2.5 h, 89%; (c) PPh3, THF, H2O, r.t., 45 min,
then 50 °C for 1.25 h, then LiOH or NaOH, 16–40%; (d) Fmoc-OSu, MeCN, H2O, Et3N, r.t., 17 h, 84%.
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

848
G. Paloumbis et al.
PAPER
Table 2 HMQC Correlations for Compound 12
Table 1 HMQC Correlations for Compound 10
No. of hydrogens
dH (ppm)
–0.002 to 0.21
0.78
dC (ppm)
No. of hydrogens
dH (ppm)
0.07–0.20
0.85
dC (ppm)
–5.27, –4.95, –4.84
25.72
12
9
–5.36, –4.98, –4.83
25.66, 25.88
25.66, 25.88
18.0, 18.56
27.98
12
9
9
2
2
3
1
1
1
1
2
2
2
4
2
2
2
9
0.93
0.93
25.93
6
1.38
3.63
70.63
9
1.47
3.72
72.78
7
3.63–3.72
51.99, 55.18, 71.8,
71.92, 73.22, 77.23
3.74
51.07
3.86
76.21
1
1
5
4.13
47.24
80.72
4.16
47.37
4.19
4.29
78.04
4.29–4.44
48.76, 48.80, 66.67,
71.8
4.31
71.91
4.42
66.83
2
2
5
2
3
2
4.54
6.83
7.29
7.38
7.50
7.75
74.02
4.50
73.35
113.80
6.84
114.01
127.15, 129.70
127.87
125.04
120.18
127.02, 129.4
127.69
7.25–7.31
7.40
125.03
7.54
120.0
7.76
some cases, receptor-specific analogues, but, more impor-
tantly, assist in tracing the probable conformation of these
molecules.
Future work will involve the coupling of the protected
glyco-amino acid with peptide analogues, introduction of
a chelator at the amino terminus of the sugar, and binding
with a radionuclide to obtain a radiopeptide which will be
used for further studies.
The diversity of sugar molecules can be exploited to cre-
ate a combinatorial library of sugar-amino-acid-based
molecular frameworks predisposed to fold into architec-
turally beautiful structures, which may also have interest-
ing properties. The protected/unprotected hydroxy groups
of sugar rings can also influence the hydrophobic/hydro-
philic nature of such molecular assemblies.
This work has demonstrated how the incorporation of pyr-
anoid sugar amino acid based building blocks, in peptides
and natural biopolymers, has tapped into new aspects of
drug design. Their incorporation into biologically active
compounds may directly give rise to highly active and, in
O
PMBO
O
O
O
N
H
a
FmocHN
OTBDMS
11
PMBO
O
OTBDMS
O
OH
PMBO
OTBDMS
FmocHN
O
O
H
b
OTBDMS
O
N
N
H
O
10
O
12
FmocHN
OTBDMS
OTBDMS
Scheme 5 Coupling of SAA 10 with H-b-Ala-Ot-Bu and H-Ala-Ala-Ot-Bu. Reagents and conditions: (a) H-b-Ala-Ot-Bu, HATU/DIPEA,
CDCl3–DCE, r.t., 30 min, 85%; (b) H-Ala-Ala-Ot-Bu, HATU/DIPEA, CDCl3–DCE, r.t., 30 min, 80%.
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

PAPER
Synthesis of a Protected d-Glyco-amino Acid Building Block
849
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Bruker DPX400 spectrometer. For samples in CDCl3, CD2Cl2, and
DMSO-d6, TMS was used as an internal reference (d = 0.00), and
for samples in D2O, the sodium salt of 3-(trimethylsilyl)propionic-
2,2,3,3-d4 acid was used as an internal reference (d = 0.00), unless
otherwise stated. IR spectra were recorded either at NIMS on a
Nicolet Avatar 360 FT-IR spectrometer as a film (neat), or by Ana-
lytical Services at Novartis Pharma, Basel on a Bruker IFS 66 FT-
IR spectrometer, as neat films. Liquid chromatography–mass spec-
trometetry (LC-MS) was recorded on a Micromass Platform liquid
chromatograph with a Gilson LC system [column: CHROMOLITH
SpeedROD RP-18e; 50 × 4.6 mm; gradient elution: 5% MeCN in
H2O (with 0.08% formic acid), held for 1 min, then to 100% MeCN
over 4 min, and held at 100% MeCN for 1 min at 3.0 mL/min]. An-
alytical TLC was performed on either Merck or Whatman 0.25-mm
silica gel 60-F plates. Flash column chromatography was performed
on Biotage FLASH 12i or 40i systems or the Jones Chromatography
Personal Flashmaster with Isolute Flash Si SPE cartridges. All reac-
tion mixtures were stirred by a magnetic hotplate and were kept un-
der an atmosphere of either anhyd N2 or anhyd Ar at r.t., unless
otherwise stated.
Methyl 2,6-Anhydro-5,7-O-(4-methoxybenzylidene)-D-glycero-
L-manno-hepturonate (4)
To a soln of 3 (1.21 g, 5.40 mmol) in anhyd MeCN (35 mL) at r.t.
was added PMPCH(OMe)2 (2.5 equiv, 2.32 mL, 13.61 mmol) fol-
lowed by cat. TsOH·H2O (78 mg, 0.41 mmol). The resulting mix-
ture was stirred at r.t. for 1.67 h, then quenched with Et3N (0.35 mL,
2.51 mmol), and stirred for a further 10 min. The volatiles were
evaporated and the crude product was purified by flash chromatog-
raphy (silica gel, EtOAc–n-hexane, 0:1 to 1:0, 1 h). Evaporation of
the desired fractions gave a white solid.
Yield: 1.45 g (79%); Rf = 0.5 (CH2Cl2–MeOH, 10:1).
IR: 3429 (br, OH), 1740 (C=O), 1614, 1518 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.43, 6.87 (2 d, J = 8.7 Hz, 4 H,
ArH), 5.47 (s, 1 H, CHPh), 4.30 (dd, J = 1.3, 12.7 Hz, 1 H, H-1),
4.18 (d, J = 3.3 Hz, 1 H, H-3), 4.07 (td, J = 2.6, 9.5 Hz, 1 H, H-6),
4.01 (dd, J = 1.7, 12.7 Hz, 1 H, H-2), 3.82–3.79 (m, 7 H, 2 × OCH3,
H-6¢), 3.68 (td, J = 3.7, 9 Hz, 1 H, H-4), 2.94 (d, J = 8.7 Hz, 1 H, H-
5).
13C NMR (400 MHz, CDCl3): d = 169.9 (CO2CH3), 160.3 (CAr-
OMe), 130.1 (CAr), 113.6 (CAr), 101.3 [ArCH(OR)2], 77.9 (C-4),
75.3 (C-5), 73.4 (C-1), 71.2 (C-2), 70.3 (C-3), 69.1 (C-6), 55.3
(ArOCH3), 52.7 (CO2CH3).
3,4,5,7-Tetra-O-acetyl-2,6-anhydro-D-glycero-L-manno-hepto-
nitrile (2)
LC-MS: m/z [MH+] = 341.03; tR = 2.61 min (6 min run).
To a stirred soln of 1 (30 g, 76.86 mmol) and TMSCN (2 equiv,
15.26 g, 153.72 mmol) in MeNO2 (250 mL) under argon at r.t. was
added BF3·OEt2 (1 equiv, 10 mL, 76.85 mmol) over 5 min. The re-
sulting bright yellow soln was allowed to stir at r.t. for 23 h. The
soln was concentrated under reduced pressure. The residue was di-
luted with CHCl3 (600 mL) and washed with chilled H2O (4 × 150
mL). The organic layer was dried (MgSO4), filtered, and concen-
trated under reduced pressure; this gave a yellow oil, which solidi-
fied in vacuo. Recrystallisation of this from CH2Cl2–Et2O (1:1)
gave 2.
Methyl 2,6-Anhydro-3,4-bis(O-tert-butyldimethylsilyl)-5,7-O-
(4-methoxybenzylidene)-D-glycero-L-manno-hepturonate (5)
To a stirred soln of 4 (511 mg, 1.50 mmol) in anhyd DMF (25 mL)
was added TBDMSCl (4 equiv, 905 mg, 6.01 mmol), imidazole (8
equiv, 818 mg, 12.01 mmol), and DMAP (15 mol%, 28 mg, 0.23
mmol) at r.t. The mixture was then placed in an oil bath and heated
at 65 °C for 24 h. It was then allowed to cool down to r.t., and dilut-
ed with EtOAc (150 mL). The organic phase was washed with H2O
(3 × 150 mL) and brine (100 mL), dried (MgSO4), filtered, and
evaporated under reduced pressure. The yellow oil that was ob-
tained was purified by flash chromatography (silica gel, cyclohex-
ane–EtOAc, 1:0 to 4:1).
Yield: 19.22 g (70%); white crystals.
IR: 2361 (C≡N), 1731 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01 (s, 3 H, CH3CO), 2.06 (s, 3
H, CH3CO), 2.12 (s, 3 H, CH3CO), 2.19 (s, 3 H, CH3CO), 3.90 (t, 1
H, H-5), 4.10 (d, J = 6.4 Hz, 2 H, H-6, H-6¢), 4.29 (d, J = 10.2 Hz,
1 H, H-4), 5.0 (dd, J = 3.3, 10.2 Hz, 1 H, H-2), 5.4 (dd, J = 0.82, 3.2
Hz, 1 H, H-1), 5.52 (t, J = 10.1 Hz, 1 H, H-3).
13C NMR (400 MHz, CDCl3): d = 107.7 (CH3CO), 170.4 (CH3CO),
170.2 (CH3CO), 169.2 (CH3CO), 116.1 (C≡N), 75.8 (C-5), 71.2 (C-
3), 67.2 (C-4), 66.4 (C-2), 61.6 (C-6), 21.7 (CH3CO), 21.0
(CH3CO), 20.9 (CH3CO), 20.3 (CH3CO), 20.0 (CH3CO).
Yield: 683 mg (80%); colourless oil; Rf = 0.4 (cyclohexane–EtOAc,
4:1).
IR: 1749 (C=O), 1612, 1518 (C=C), 833, 775 (Si–O) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47, 6.91 (2 d, J = 8.7 Hz, 4 H,
ArH), 5.40 (s, 1 H, H-7), 4.29 (dd, J = 1.3, 12.5 Hz, 1 H, H-1), 4.18
(t, J = 9 Hz, 1 H, H-4), 4.08 (d, J = 2.8 Hz, 1 H, H-6), 3.97 (dd, J =
1.65, 12.5 Hz, 1 H, H-2), 3.81–3.73 (m, 8 H, p-CH3O, CO2CH3, H-
3, H-6¢), 3.4 (d, J = 0.8 Hz, 1 H, H-5), 0.92 (s, 9 H, SiCMe3), 0.85
(s, 9 H, SiCMe3), –0.01 to 0.12 (m, 12 H, 2 × SiMe2).
13C NMR (400 MHz, CDCl3): d = 169.2 (CO2CH3), 160.1 (CAr-
OMe), 130.8 (CAr), 127.7 (CAr), 113.9 (CAr), 113.6 (CAr), 101.3
[ArCH(OR)2], 81.1 (C-4), 80.7 (C-1), 75.8 (C-5), 70.6 (C-3), 69.7
(C-6), 69.2 (C-2), 55.4 (p-CH3OAr), 52.3 (CO2CH3), 27.0
[SiC(CH3)3], 26.5 [SiC(CH3)3], 26.2 [SiC(CH3)3], 25.9
[SiC(CH3)3], 18.8 [SiC(CH3)3], 18.4 [SiC(CH3)3], –2.97 [Si(CH3)2],
–3.0 [Si(CH3)2], –3.7 [Si(CH3)2], –4.9 [Si(CH3)2].
Methyl 2,6-Anhydro-D-glycero-L-manno-hepturonate (3)
A soln of 2 (11.05 g, 30.93 mmol) in an HCl–MeOH mixture [pre-
pared by the slow addition of AcCl (8.4 mL) to anhyd MeOH (50
mL) at 0 °C] was heated to 60–65 °C for 3 d. After the mixture had
been allowed to cool to r.t., all the volatiles were removed under re-
duced pressure; this yielded crude 3 as a white foam. 1H NMR spec-
troscopy showed that a single clean product was obtained. The
compound was used without further purification in the next step.
LC-MS: m/z [MH+] = 586.93; tR = 5.73 min (6 min run).
Yield: 6.87 g (100%).
IR: 3108 (OH), 1742 (C=O) cm–1.
Methyl 2,6-Anhydro-3,4-bis(O-tert-butyldimethylsilyl)-7-O-(4-
methoxybenzyl)-D-glycero-L-manno-hepturonate (6)
1H NMR (400 MHz, D2O): d = 4.05 (d, J = 10.1 Hz, 1 H, H-1), 4.0
(m, 1 H, H-2), 3.89 (s, 3 H, OCH3), 3.87–3.70 (m, 5 H, H-3, H-4, H-
5, H-6, 6¢).
13C NMR (400 MHz, D2O): d = 171.1 (CO2CH3), 80.1 (C-5), 77.9
(C-1), 76.0 (C-3), 72.5 (C-2), 70.1 (C-4), 60.7 (C-6), 49.8
(CO2CH3).
A soln of 5 (1.20 g, 2.11 mmol) and NaBH3CN (10 equiv, 1.33 g,
21.1 mmol) in anhyd CH2Cl2 (30 mL) and anhyd THF (5 mL) was
cooled to 0 °C, and 4-Å activated powder MS (9.8 g) were added.
The resulting mixture was allowed to stir at 0 °C for 40 min and then
a soln of TFA (20 equiv, 3.13 mL, 42.19 mmol) in anhyd CH2Cl2 (5
mL) was added dropwise over 20 min. The ice bath was removed
and the mixture was stirred for 24 h. It was then diluted with EtOAc
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

850
G. Paloumbis et al.
PAPER
(150 mL), neutralised with sat. aq NaHCO3 (200 mL), and filtered
through a sintered-glass funnel. The layers were separated and the
organic phase was washed with more sat. aq NaHCO3 (100 mL) and
brine (100 mL), dried (MgSO4), filtered, and evaporated under re-
duced pressure. The yellow syrup thus obtained was purified by
flash chromatography (silica gel, EtOAc–n-hexane, 0:1 to 4:1, 50
min).
LC-MS: m/z [MH+] = 613.94; tR = 6.06 min (7 min run).
5-Amino-2,6-anhydro-3,4-bis(O-tert-butyldimethylsilyl)-7-O-
(4-methoxybenzyl)-5-deoxy-D-glycero-L-gulo-heptonic Acid (9)
To a soln of 8 (87 mg, 0.15 mmol) in anhyd THF (1 mL) and H2O
(1 mL) at r.t. was added PPh3 (42 mg, 0.16 mmol). The resulting
mixture was stirred for 45 min and then heated at 50 °C for 1.25 h.
LiOH (2.1 equiv, 12.9 mg, 0.31 mmol) was then added and stirring
continued for another 2 h at 50 °C. The mixture was allowed to cool
to r.t. and was then acidified with citric acid. The aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined extracts were
washed with brine (30 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure. The white solid thus obtained was triturated
with n-hexane, filtered, and dried under suction.
Yield: 770 mg (64%); colourless oil; Rf = 0.39 (cyclohexane–
EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 7.26, 6.87 (2 d, J = 8.7 Hz, 4 H,
ArH), 4.48 (m, 2 H, MeOPhCH2), 4.02 (t, J = 8.8 Hz, 1 H, H-4), 3.86
(m, 1 H, H-1), 3.80 (s, 3 H, PhOCH3), 3.74 (s, 1 H, CO2CH3), 3.71–
3.62 (m, 5 H, H-6, H-6¢, H-2, H-3, H-5), 2.44 (s, 1 H, OH), 0.94 (s,
9 H, SiCMe3), 0.86 (s, 9 H, SiCMe3), 0.16 (s, 3 H, SiMe), 0.13 (s, 3
H, SiMe), 0.08 (s, 3 H, SiMe), –0.05 (s, 3 H, SiMe).
Yield: 12.9 mg (16%).
1H NMR (400 MHz, CDCl3): d = 7.28, 6.89 (2 d, J = 8.7 Hz, 4 H,
ArH), 4.53 (s, 2 H, ArCH2), 4.29 (s, 1 H, H-6), 4.27 (d, J = 4.0 Hz,
1 H, H-1), 3.82 (m, 1 H, H-3), 3.81 (s, 3 H, ArOCH3), 3.74 (d, J =
4.1 Hz, 1 H, H-2), 3.65 (m, 2 H, H-5, H-6¢), 2.74 (d, J = 8.9 Hz, 1
H, H-4), 0.91 (s, 9 H, SiCMe3), 0.86 (s, 9 H, SiCMe3), 0.18 (s, 3 H,
SiMe2), 0.14 (s, 3 H, SiMe2), 0.07 (s, 3 H, SiMe2), 0.06 (s, 3 H,
SiMe2).
13C NMR (400 MHz, CDCl3): d = 169.8 (CO2CH3), 159.4 (CAr-
OMe), 130.0 (CAr), 129.3 (CAr), 129.1 (CAr), 113.7 (CAr), 81.1 (C-
5), 79.2 (C-1), 76.0 (PMPCH2), 73.1 (C-3), 71.0 (C-6), 67.6 (C-2),
55.9 (ArOCH3), 53.8 (C-4), 52.7 (CO2CH3), 27.2 [SiC(CH3)3], 26.1
[SiC(CH3)3], 26.0 [SiC(CH3)3], 25.7 [SiC(CH3)3], 18.4
[SiC(CH3)3], 18.2 [SiC(CH3)3], –2.57 [Si(CH3)2], –3.1 [Si(CH3)2],
–3.5 [Si(CH3)2], –4.8 [Si(CH3)2].
13C NMR (400 MHz, CDCl3): d = 169.3 (CO2CH3), 159.4 (CAr-
OMe), 130.2 (CAr), 129.6 (CAr), 114 (CAr), 80.9 (C-3), 77 (C-1),
73.4 (ArCH2), 70.3 (C-5), 70.1 (C-4), 69.2 (C-6), 55.4 (ArOCH3),
52.3 (CO2CH3), 26.5 [SiC(CH3)3], 26.1 [SiC(CH3)3], 18.5
[SiC(CH3)3], 18.2 [SiC(CH3)3], –2.8 [Si(CH3)2], –3.3 [Si(CH3)2],
–3.9 [Si(CH3)2], –4.9 [Si(CH3)2].
LC-MS: m/z [MH+] = 571.86; tR = 5.55 min (6 min run).
Methyl 2,6-Anhydro-5-azido-3,4-bis(O-tert-butyldimethylsilyl)-
7-O-(4-methoxybenzyl)-5-deoxy-D-glycero-L-gulo-hepturonate
(8)
A soln of 6 (752 mg, 1.32 mmol) in anhyd CH2Cl2 (20 mL) was
cooled to 0°C (ice bath). Py (4 equiv, 427 mL, 5.27 mmol) was add-
ed, followed by slow addition of Tf2O (2 equiv, 445 mL, 2.63 mmol)
and DMAP (2 crystals). The mixture was allowed to warm to r.t.
and was stirred for 35 h. It was then diluted with H2O (200 mL) and
the aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were dried (MgSO4), filtered, and evap-
orated under reduced pressure. The residue was purified by flash
chromatography (silica gel, EtOAc–n-hexane, 0:1 to 4:1, 1.5 h); this
gave 7 as a colourless oil, which was dried under high vacuum.
LC-MS: m/z [MH+] = 556.84; tR = 3.54 min (7 min run).
2,6-Anhydro-3,4-bis(O-tert-butyldimethylsilyl)-5-[(9-fluorenyl-
methoxy)carbonylamido]-7-O-(4-methoxybenzyl)-5-deoxy-D-
glycero-L-gulo-heptonic Acid (10)
To a soln of 9 (12.9 mg, 0.023 mmol) in MeCN (1 mL) and H2O (1
mL) at r.t., Fmoc-OSu (1.1 equiv, 8.5 mg, 0.025 mmol) was added,
followed by Et3N (2.2 equiv, 8 mL, 0.051 mmol). The mixture was
stirred at r.t. for 17 h. The aqueous phase was extracted with EtOAc
(3 × 20 mL) and the combined extracts were washed with brine (10
mL), dried (MgSO4), filtered, and evaporated under reduced pres-
sure. Flash chromatography (silica gel, EtOAc–n-hexane, 0:1 to
1:0, 1.5 h) gave pure 10.
Yield: 805 mg (87%).
LC-MS: m/z [MH+] = 703.44; tR = 5.92 min (7 min run).
Compound 7 (740 mg, 1.05 mmol) was dissolved in anhyd DMF
(14 mL) at r.t., and NaN3 (10 equiv, 685 mg, 10.53 mmol) was add-
ed in one portion. The mixture was stirred at r.t. for 2.5 h, and was
then quenched with H2O (150 mL). The aqueous phase was extract-
ed with EtOAc (3 × 60 mL) and the combined extracts were washed
with H2O (50 mL) and brine (60 mL). The organic phase was dried
(MgSO4), filtered, and evaporated; this gave a yellow oil which was
purified by flash chromatography (silica gel, EtOAc–n-hexane, 0:1
to 7:3, 1 h). Azide derivative 8 was obtained as a colourless oil.
Yield: 15.1 mg (84%); Rf = 0.47 (CH2Cl2–MeOH, 10:1).
IR: 3480 (OH), 1724 (C=O), 1612, 1512 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 9.5 (v br, 1 H, CO2H), 7.77 (d, J =
7.5 Hz, 2 H, ArH), 7.55 (m, 2 H, ArH), 7.42 (t, J = 7.3 Hz, 2 H,
ArH), 7.27 (m, 4 H, ArH), 6.85 (d, J = 8.7 Hz, 2 H, ArH), 5.25 (d,
J = 10.3 Hz, 1 H, NH), 4.50 (d, J = 1.6 Hz, 2 H, H-6¢, FmocCH),
4.42 (m, 2 H, PMPCH2), 4.31 (m, 2 H, H-6, H-1), 4.16 (m, 1 H, H-
4), 3.86 (m, 1 H, H-5), 3.75–3.71 (m, 5 H, -OCH3, H-2, H-3), 3.63
(d, J = 5.0 Hz, 2 H, FmocCH2), 0.93 (s, 9 H, SiCMe3), 0.85 (s, 9 H,
SiCMe3), 0.20 (s, 3 H, SiMe2), 0.13 (s, 3 H, SiMe2), 0.083 (s, 3 H,
SiMe2), 0.082 (s, 3 H, SiMe2).
13C NMR (400 MHz, CDCl3): d = 170.3 (CO2H), 159.6 (CArOMe),
155.5 (NHCO), 144.0 (CAr), 143.9 (CAr), 141.5 (CAr), 129.8 (CAr),
129.7 (CAr), 127.9 (CAr), 127.2 (CAr), 127.1 (CAr), 120.2 (CAr), 115.3
(CAr), 114.0 (CAr), 113.2 (CAr), 78.0 (C-1), 76.2 (C-5), 73.3 (C-2),
72.8 (C-3), 71.9 (C-6), 70.6 (FmocCH2), 66.8 (PMPCH2), 55.4
(FmocCH), 51.1 (CH3O), 47.4 (C-4), 25.9 [SiC(CH3)3], 25.7
[SiC(CH3)3], 18.1 [SiC(CH3)3], 17.9 [SiC(CH3)3], –4.8 [Si(CH3)2],
–4.9 [Si(CH3)2], –5.3 [Si(CH3)2].
Yield: 557 mg (89%).
IR: 2108 (N3), 1754 (C=O), 1613, 1513 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30, 6.89 (2 d, J = 8.7 Hz, 4 H,
ArH), 4.55 (m, 2 H, ArCH2), 4.09 (d, J = 5.0 Hz, 1 H, H-1), 4.04 (t,
J = 5.2 Hz, 1 H, H-6), 3.80 (s, 3 H, ArOCH3), 3.73 (s, 3 H, CO2CH3),
3.70 (m, 4 H, H-2, H-4, H-5, H-6¢), 3.50 (m, 1 H, H-3), 0.90 (s, 9 H,
SiCMe3), 0.89 (s, 9 H, SiCMe3), 0.15 (s, 3 H, SiMe2), 0.13 (s, 3 H,
SiMe2), 0.10 (s, 3 H, SiMe2), 0.05 (s, 3 H, SiMe2).
13C NMR (400 MHz, CDCl3): d = 169.8 (CO2CH3), 159.2 (CAr-
OMe), 130.0 (CAr), 129.6 (CAr), 113.7 (CAr), 113.6 (CAr), 79.4 (C-
1), 75.8 (C-5), 75.4 (ArCH2), 73.2 (C-6), 69.7 (C-3), 63.0 (C-2),
55.2 (ArOCH3), 52.2 (CO2CH3), 31.6 (C-4), 26 [SiC(CH3)3], 25.9
[SiC(CH3)3], 25.8 [SiC(CH3)3], 22.7 [SiC(CH3)3], 18.1
[SiC(CH3)3], 18.0 [SiC(CH3)3], 14.1, –3.5 [Si(CH3)2], –3.7
[Si(CH3)2], –4.1 [Si(CH3)2], –4.6 [Si(CH3)2].
LC-MS: m/z [MH+] = 779; tR = 5.79 min (7 min run).
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

PAPER
Synthesis of a Protected d-Glyco-amino Acid Building Block
851
{3,4-Bis(O-tert-butyldimethylsilyl)-4-[(9-fluorenylmethoxy)car-
bonylamido]-6-O-(4-methoxybenzyl)-4-deoxy-b-D-glucopyra-
nosyl}-C-carboxamido-N-b-alanine tert-Butyl Ester (11)
To a stirred soln of 10 (15.1 mg, 0.019 mmol) in CDCl3 (1 mL) and
DCE (0.5 mL) at r.t., HATU (1.1 equiv, 8.12 mg, 0.021 mmol), DI-
PEA (2.1 equiv, 7.1 mL, 0.041 mmol), and H-b-Ala-Ot-Bu (1.05
equiv, 0.02 mmol, 2.90 mg) were added. The resulting mixture was
stirred at r.t. for 30 min. It was then diluted with CH2Cl2 (10 mL),
and the organic phase was washed with sat. aq NaHCO3 (10 mL)
and brine (10 mL). The organic phase was dried (MgSO4), filtered,
and evaporated under reduced pressure. This yielded a brown oil,
which was purified by column chromatography (silica gel, EtOAc–
n-hexane, 0:1 to 3:17, 1 h).
(CAr), 127.0 (CAr), 114.0 (CAr), 113.8 (CAr), 82.2 [CO2C(CH3)3],
80.7 (C-5), 74.0 (PMPCH2), 73.2 (C-1), 71.9 (C-3), 71.8 (C-6), 66.7
(C-2), 55.2 (OCH3), 55.0 (Fmoc-CH), 52.0 (C-4), 48.8
(NHCHCH3-Ala), 48.7 (NHCHCH3-Ala), 28.5 [C(CH3)3], 26.9
[SiC(CH3)3], 25.9 [SiC(CH3)3], 25.7 [SiC(CH3)3], 19.3, 18.6
[SiC(CH3)3], 18.0 [SiC(CH3)3], 17.8 (NHCHCH3-Ala), –4.8
[Si(CH3)2], –5.0 [Si(CH3)2], –5.1 [Si(CH3)2].
LC-MS: m/z [MH+] = 977.6; tR = 10.95 min (12 min run).
Acknowledgment
Dr. A. J. Culshaw and Dr. G. A. Hughes are thanked for allowing
G.P. to use the facilities of Novartis Institutes for Biomedical Re-
search in London.
Yield: 14.9 mg (85%); colourless oil; Rf = 0.83 (CH2Cl2–MeOH,
10:1).
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 7.5 Hz, 2 H, ArH),
7.57 (m, 2 H, ArH), 7.40 (m, 2 H, ArH), 7.30 (m, 4 H, ArH), 7.01
(m, 1 H, peptide NH), 6.83 (d, J = 8.6 Hz, 2 H, ArH), 5.16 (d, J =
10.4 Hz, 1 H, -NH-Fmoc), 4.50 (m, 2 H, H-6¢, FmocCH), 4.38 (m,
3 H, PMPCH2, H-1), 4.18 (m, 2 H, FmocCH, H-4), 3.73 (s, 3 H,
OCH3), 3.71–3.51 (m, 5 H, FmocCH2, H-2, H-3, H-6), 3.15 (m, 1
H, CH2NHCO), 2.45 (t, J = 6.5 Hz, 2 H, CH2CO2t-Bu), 1.44 (s, 9 H,
OCMe3), 0.93 (s, 9 H, SiCMe3), 0.83 (s, 9 H, SiCMe3), 0.21 (s, 3 H,
SiMe2), 0.14 (s, 3 H, SiMe2), 0.07 (s, 3 H, SiMe2), 0.02 (s, 3 H,
SiMe2).
References
(1) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E.
M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.;
Shakespeare, W. C.; Sprengler, P. A.; Hamley, P.; Smith, A.
B. III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.;
Vale, W.; Freidinger, E. M.; Cascieri, M. A.; Strader, C. D.
J. Am. Chem. Soc. 1993, 115, 12550.
(2) Bols, M. Carbohydrate Building Blocks; Wiley: New York,
1996.
13C NMR (400 MHz, CDCl3): d = 173.4 (CO2t-Bu), 172.1 (CONH-
peptide), 159.7 (CArOMe), 155.8 (FmocCONH), 144.1 (CAr), 143.6
(CAr), 141.1 (CAr), 130 (CAr), 129.4 (CAr), 128.2 (CAr), 126.8 (CAr),
125.7 (CAr), 114.2 (CAr), 114.1 (CAr), 82.2 (CO2CMe3), 79.1 (C-5),
75.4 (PMPCH2), 75.2 (C-1), 71.0 (C-3), 70.4 (C-6), 67.7 (C-2), 67.3
(FmocCH2), 55.8 (OCH3), 53 (FmocCH), 52.2 (C-4), 38.6
(CH2NHCO), 38.3 (CH2CO2t-Bu), 28.7 [C(CH3)3], 28.5 [C(CH3)3],
25.9 [SiC(CH3)3], 25.7 [SiC(CH3)3], 19.3 [SiC(CH3)3], 18.6
[SiC(CH3)3], 18.2 [SiC(CH3)3], 17.8 [SiC(CH3)3], –4.8 [Si(CH3)2],
–5.0 [Si(CH3)2], –5.1 [Si(CH3)2].
(3) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.;
Kunz, H. Angew. Chem. Int. Ed. 1998, 37, 2503.
(4) Scgweuzer, F.; Gubdsgayk, O. Curr. Opin. Chem. Biol.
1999, 3, 291.
(5) (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H.
Chem. Rev. 2002, 102, 491; and references cited therein.
(b) van Well, R. M.; Marinelli, L.; Altona, C.; Erkelens, K.;
Siegal, G.; van Raaij, M.; Llamas-Saiz, A. L.; Kessler, H.;
Novellino, E.; Lavecchia, A.; van Boom, J. H.; Overhard, M.
J. Am. Chem. Soc. 2003, 125, 10822. (c) Chakraborty, T.
K.; Srinivasu, P.; Bikshapathy, E.; Nagaraj, R.; Vairamani,
M. J.; Kumar, S. K.; Kunwar, A. C. J. Org. Chem. 2003, 68,
6257. (d) Grotenbreg, G. M.; Timmer, M. S. M.; Llamas-
Saiz, A. L.; Verdoes, M.; van der Marel, G. A.; van Raaij, M.
J.; Overkleeft, H. S.; Overhand, M. J. Am. Chem. Soc. 2004,
126, 3444.
LC-MS: m/z [MH+] = 905.8; tR = 11.22 min (12 min run).
{3,4-Bis(O-tert-butyldimethylsilyl)-4-[(9-fluorenylmethoxy)car-
bonylamido]-6-O-(4-methoxybenzyl)-4-deoxy-b-D-glucopyra-
nosyl}-C-carboxamido-N-alanine-alanine tert-Butyl Ester (12)
To a stirred soln of 10 (27.8 mg, 0.036 mmol) in CDCl3 (0.5 mL)
and DCE (1 mL) at r.t. was added HATU (1.1 equiv, 14.9 mg, 0.039
mmol), DIPEA (2.1 equiv, 13.1 mL, 0.075 mmol), and H-Ala-Ala-
Ot-Bu (1.05 equiv, 8.17 mg, 0.038 mmol). After 30 min, TLC
(CH2Cl2–MeOH, 10:1) showed that the reaction had gone to com-
pletion. The mixture was diluted with CH2Cl2 (18 mL) and the or-
ganic phase was washed with sat. aq NaHCO3 (20 mL) and brine
(15 mL), then dried (MgSO4), filtered, and evaporated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy (silica gel, EtOAc–n-hexane, 0:1 to 1:9, 1 h).
(6) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S. Comb. Chem.
High Throughput Screening 2002, 5, 373.
(7) Wormald, M. R.; Petrescu, A. J.; Pao, Y.-L.; Glithero, A.;
Elliott, T.; Dwek, R. A. Chem. Rev. 2002, 102, 371; and
references cited therein.
(8) Zhao, X.; Jia, M.-X.; Jiang, X.-K.; Wu, L.-Z.; Li, Z.-T.;
Chen, G.-J. J. Org. Chem. 2004, 69, 270.
(9) (a) Kieber-Emmons, T.; Murali, R.; Greene, M. I. Curr.
Opin. Biotechnol. 1997, 8, 435. (b) Kee, S.; Jois, S. D. S.
Curr. Pharm. Des. 2003, 9, 1209.
(10) (a) Schweizer, F. Angew. Chem. Int. Ed. 2002, 41, 230.
(b) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S. Curr.
Med. Chem. 2002, 9, 421. (c) Geervay-Hague, J.; Weathers,
T. M. J. Carbohydr. Chem. 2002, 21, 867; and references
cited therein.
(11) Schottelius, M.; Wester, H. J.; Reubi, J. C.; Senekowitsch-
Schmidtke, R.; Schwaiger, M. Bioconjugate Chem. 2002,
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Davis, P.; Huber, J. D.; Jones, H.; Yamamura, H. I.; Janders,
J.; Davis, T. P.; Porrera, F.; Hruby, V. J.; Polt, R. J. Med.
Chem. 2000, 43, 2586.
Yield: 28 mg (80%); colourless oil; Rf = 0.95 (CH2Cl2–MeOH,
10:1).
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 7.5 Hz, 2 H, ArH),
7.56 (m, 2 H, ArH), 7.51 (d, J = 6.6 Hz, 1 H, NH-Ala), 7.41 (m, 2
H, ArH), 7.31–7.26 (m, 4 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH),
6.22 (d, J = 7.2 Hz, 1 H, NH-Ala), 5.18 (d, J = 10.3 Hz, 1 H, Fmoc-
NH), 4.54 (m, 2 H, PMPCH2), 4.48–4.21 (m, 5 H, H-1, FmocCH2,
2 × H-Ala), 4.19–4.05 (m, 2 H, Fmoc-CH, H-5), 3.72–3.60 (m, 8 H,
OCH3, H-2, H-3, H-4, H-6, H-6¢), 1.47 (s, 9 H, CO2t-Bu), 1.43–1.36
(m, 6 H, 2 × CH3-Ala), 0.93 (s, 9 H, SiCMe3), 0.78 (s, 9 H, SiCMe3),
0.21 (s, 3 H, SiMe2), 0.14 (s, 3 H, SiMe2), 0.05 (s, 3 H, SiMe2), 0.01
(s, 3 H, SiMe2).
(13) Albert, R.; Marbach, P.; Bauer, W.; Briner, U.; Fricker, G.;
Bruns, C.; Pless, J. Life Sci. 1993, 53, 517.
13C NMR (400 MHz, CDCl3): d = 171.9 (sugar-CONH), 170.9 (Ala-
CO-Ala), 169.5 (CO2t-Bu), 159.2 (CArOMe), 155.4 (Fmoc-CONH),
144.0 (CAr), 143.8 (CAr), 141.4 (CAr), 130.2 (CAr), 130.0 (CAr), 127.7
Synthesis 2007, No. 6, 845–852 © Thieme Stuttgart · New York

852
G. Paloumbis et al.
PAPER
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