Orthogonally Protected Furanoid Sugar Diamino Acids for Solid-Phase Synthesis of Oligosaccharide Mimetics

Article abstract of DOI:10.1021/acs.joc.5b01049

Sugar diamino acids (SDAs), which differ from the widely used sugar amino acids in the presence of a second amino group connected to the carbohydrate core, share structural features of both amino acids and carbohydrates. They can be used for the preparati

Full text of DOI:10.1021/acs.joc.5b01049

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The Journal of Organic Chemistry
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Orthogonally Protected Furanoid Sugar Diamino Acids
for SolidꢀPhase Synthesis of Oligosaccharide Mimetics
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†
,‡
*,†
Franklin John and Valentin Wittmann
†
Fachbereich Chemie and Konstanz Research School Chemical Biology (KoRSꢀCB), Universität
Konstanz, 78457 Konstanz, Germany
‡
New affiliation: Department of Chemistry, Sacred Heart College (M. G. University), Kochi 682013,
India
*Eꢀmail: mail@valentinꢀwittmann.de
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SDA building blocks Amide-linked oligosaccharide mimetic
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O
H
O
N
NH2
BocHN
COOH
FmocHN
COOH
H N
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O
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FmocHN OMOM
FmocHN
BocHN OMOM
NH OH H N OH
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H N
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COOH
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NH OH
H N
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N3 OMOM
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H N OH
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ABSTRACT: Sugar diamino acids (SDAs), which differ from the widely used sugar amino acids
SAAs) in the presence of a second amino group connected to the carbohydrate core, share structural
(
features of both amino acids and carbohydrates. They can be used for the preparation of linear and
branched amideꢀlinked oligosaccharide mimetics. Such oligomers carry free amino groups, which are
positively charged at neutral pH, in a spatially defined way and, thus, represent a potential class of
aminoglycoside mimetics. We report here the first examples of orthogonally protected furanoid SDAs
and their use in solidꢀphase synthesis. Starting from Dꢀglucose, we developed a divergent synthetic
route to three derivatives of 3,5ꢀdiaminoꢀ3,5ꢀdideoxyꢀDꢀribofuranose. These building blocks are
compatible with solidꢀphase peptide synthesis following the 9ꢀfluorenylmethoxycarbonyl (Fmoc)
strategy which we demonstrate by the synthesis of an SDA tetramer.
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Introduction
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Carbohydrates are involved in a myriad of biological processes including cellꢀcell recognition,
1
modulation of protein function, and many important biosynthetic pathways. Structurally, carbohydrates
represent highly diverse molecular scaffolds that offer several attachment points for introducing
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diversity making them ideal templates for combinatorial synthesis and drug discovery. The application
of carbohydrates for the presentation of pharmacophores in a defined spatial arrangement was
3
demonstrated in seminal studies by Hirschmann et al. Sugar amino acids (SAAs) are special examples
of carbohydrateꢀderived scaffolds that also have been used for the generation of pharmacophoreꢀ
4
mapping combinatorial libraries. SAAs are carbohydrate derivatives comprising at least one amino and
5
one carboxy group connected to the carbohydrate core. In nature, SAAs occur for example as cellꢀwall
components in the form of neuraminic acid and muramic acid and as substructures of nucleoside
6
7
8
9
antibiotics (e.g. ezomycin A, gougerotin, aspiculamycin ), and of herbicides (e.g. hydantocidin ).
Sharing structural features of both amino acids and carbohydrates, SAAs can bridge the two classes of
biopolymers formed from these building blocks. As such, SAAs have been applied for the preparation
of peptidomimetics as well as amideꢀlinked oligosaccharide mimetics. For example, SAAs can function
1
0
as secondaryꢀstructureꢀinducing elements and have been incorporated as turn mimetics in analogues of
1
0b,11
12
biologically active peptides, such as Leuꢀenkephalin,
RGDꢀcontaining integrin antagonists,
11,13
14
somatostatin,
and gramicidin S. Linear and cyclic SAA oligomers can adopt defined threeꢀ
1
5
16
dimensional structures and, thus, belong to the family of the soꢀcalled foldamers.
An attractive application of SAAs is the preparation of oligosaccharide mimetics in which the
15d,17
glycosidic linkages are replaced by amide bonds.
Taking advantage of the wellꢀdeveloped protocols
for automated solidꢀphase peptide synthesis, such oligomers can be efficiently synthesized without the
challenge to selectively form new stereo centers as it is required in oligosaccharide synthesis during
every glycosylation step. Previously, we introduced a new class of pyranoid SAAs with an additional
1
8
amino group, termed sugar diamino acids (SDAs). We employed orthogonally protected SDA building
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blocks for the preparation of linear and branched oligosaccharide mimetics. Besides the opportunity to
form branched structures, the additional amino groups can also be exploited for ligandꢀtarget
interactions. In the case of the aminoglycoside antibiotics, the presentation of positive charges in a
spatially defined way has been shown to be a key feature to achieve selectivity for certain RNA targets
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due to electrostatic complementarity. Thus, oligomeric SDAs with their additional free amino groups
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represent a potential class of aminoglycoside mimetics. Such new antibiotics may give options to
20
overcome the worldwide emergence of antibiotic resistance.
The major hurdle in the preparation of SDAs is the incorporation of one or both amino groups and
their orthogonal protection to allow selective derivatization during oligomer synthesis. So far, only a
1
8,21
few examples of SDAs, all featuring a pyranose ring, have been published.
We now report the first
examples of furanoid SDAs and their use in solidꢀphase synthesis. Starting from Dꢀglucose, we
developed a divergent synthetic route to three derivatives of 3,5ꢀdiaminoꢀ3,5ꢀdideoxyꢀDꢀribofuranose.
These building blocks are compatible with solidꢀphase peptide synthesis following the 9ꢀ
fluorenylmethoxycarbonyl (Fmoc) strategy which we demonstrate by the synthesis of an SDA tetramer.
Results and discussion
General synthetic considerations. Chart 1 depicts the three SDA building blocks 1–3 designed for
use in solidꢀphase synthesis of oligosaccharide mimetics as well as tetramer 4 that we exemplarily
synthesized. Using Fmoc groups as temporary amine protection, SDAs 1 and 2 allow the synthesis of
2
2
oligomers connected via the amino group in position 3 and 5, respectively. Methoxymethyl (MOM)
groups were chosen as permanent hydroxy protection. They can be easily removed under acidic
1
8
conditions together with tertꢀbutyloxycarbonyl (Boc) groups which were used as permanent protection
of the second amino functionality. In addition, MOM groups show only low interference with the
reactivity of adjacent nucleophilic centers. They are less electronꢀwithdrawing than ester protecting
groups, such as acetyl and benzoyl residues, and they cannot undergo an irreversible O→N acyl shift.
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Furthermore, they are much smaller than benzyl ethers that have been shown to hinder acylation of
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adjacent amino groups in some cases. Building block 3 can be used for the synthesis of branched
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oligomers because the azide and the Fmoc group function as orthogonal protection of the amines in 3ꢀ
and 5ꢀposition. Whereas azides are stable in presence of piperidine, which is commonly used for Fmoc
cleavage, they are readily reduced to amines in the presence of Fmoc groups under neutral Staudinger
reaction conditions.
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Chart 1. Structure of SDA building blocks 1, 2, and 3 and oligosaccharide mimetic 4.
For the synthesis of the three SDA building blocks 1, 2 and 3 we developed a divergent route depicted
in Scheme 1. Key intermediate for the synthesis of all three SDAs was Cꢀfuranoside 15 that was
1
5c
obtained from known isopropylideneꢀprotected 3ꢀazidoꢀαꢀDꢀallofuranose 5. Further functional group
manipulation led to protected SDA 18 that served as branching point of the synthesis to access building
blocks 1 and 3 the latter of which was subsequently transformed to building block 2. In this way the
majority of synthetic steps was the same for all three compounds.
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Scheme 1. General synthetic strategy for SDA building blocks 1, 2 and 3.
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Synthesis of Cꢀglycosyl cyanide 15. The synthesis of Cꢀglycoside 15 started from literatureꢀknown
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ꢀazidoꢀαꢀDꢀallofuranose 5 in which the first amino function within the ribofuranose core structure was
already present as an azido group. In a first attempt we aimed to introduce the second amino group by
reductive amination (Scheme 2). Diol 5 was oxidatively cleaved under mild conditions with sodium
periodate and the resultant aldehyde 6 was reacted with ammonium acetate and sodium cyano
2
4
borohydride. The expected amine 7, however, was not formed under these conditions; instead the
reaction resulted in the formation of secondary amine 8 likely via reaction of initially formed amine 7
with either aldehyde 6 or the iminium ion formed thereof. Attempts to trap intermediately formed amine
7
by FmocꢀCl gave only low yields (up to 12 % from 5) of the Fmocꢀprotected derivative of 7.
Scheme 2. Reductive amination of intermediate aldehyde 6.
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Since the reductive amination did not provide primary amine 7, we turned our attention to the Gabriel
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synthesis as an alternative method. Periodate cleavage of diol 5 followed by reduction with sodium
borohydride afforded alcohol 9 in a yield of 77 % over both steps (Scheme 3). The azido group was not
affected under these conditions. Subsequently, 9 was converted to the corresponding tosylate 10 which
was treated with potassium phthalimide to give protected diamino ribose derivative 11.
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A critical step of the synthesis was the Cꢀglycosylation reaction to introduce an anomeric cyano group
as precursor for the carboxylic acid. We decided to use an ester protecting group in the 2ꢀposition of the
diamino ribose to control the stereochemistry of this step by neighboring group participation. However,
it had been reported that furanoses with an acetyl group in 2ꢀposition can lead to the formation of 1,2ꢀOꢀ
2
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cyanoethylidene derivatives. Indeed, attempts to employ 1,2ꢀdiꢀOꢀacetylꢀ3ꢀazidoꢀ3,5ꢀdideoxyꢀ5ꢀ
phthalimidoꢀ ꢀribofuranose, that was obtained in two steps from 11, in a Cꢀglycosylation reaction
TMSꢀCN, SnCl , CH Cl ) failed and gave predominantly the corresponding 1,2ꢀOꢀcyanoethylidene
D
(
4
2
2
derivative (data not shown). Since the formation of cyanoethylidene derivatives can be suppressed by
26c,f,27
the use of benzoyl groups in the 2ꢀposition,
we prepared 1ꢀOꢀacetylꢀ2ꢀOꢀbenzoyl derivative 14 as
2
7ꢀ28
precursor for the Cꢀglycosylation reaction. Acidꢀcatalyzed methanolysis
of acetonide 11 resulted in
methyl glycoside 12 in a yield of 72 %. Benzoylation of 11 in pyridine afforded ribofuranoside 13 that
was further converted into glycosyl acetate 14 by acetolysis in excellent yield over both steps. Cꢀ
Glycosylation of 14 was achieved with TMSꢀCN employing SnCl as Lewis acid catalyst and
4
dichloromethane as solvent to give 15 in a yield of 46 %. Formation of the 1,2ꢀOꢀcyanobenzylidene
.
derivative was not observed. Other catalysts, such as BF OEt or SnCl , were also attempted for this
3
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conversion but resulted in lower yields.
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Scheme 3. Synthesis of ribofuranosyl cyanide 15.
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Synthesis of SDA building blocks 1–3. For the synthesis of common intermediate 18, glycosyl
cyanide 15 was hydrolyzed at 60 °C under acidic conditions resulting in the formation of carboxylic
acid 16 in a yield of 88 % without affecting any other functional groups (Scheme 4). Removal of the
phthaloyl group with preservation of the azide, however, was challenging. Hydrazine hydrate could not
2
9
be used due to a known side reaction of the azide most probably caused by contaminating diimine.
Also ethylenediamine, which had been developed as an alternative reagent for phthalimide cleavage that
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is compatible with azides,
could not be employed because it resulted in decomposition of the
starting material. We achieved the removal of the phthalimide group under mild conditions following a
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1
twoꢀstep oneꢀflask procedure comprising NaBH and subsequent acetic acid treatment. The resulting
4
primary amine was directly treated without any purification with Na CO , resulting in concomitant
2
3
hydrolysis of the benzoic ester, and Nꢀ(9ꢀfluorenylmethoxycarbonyloxy) succinimide (FmocꢀOSu) to
furnish Fmocꢀprotected 17 in a yield of 60 % over three steps. The acidꢀlabile MOM group was
introduced by treatment with dimethoxymethane in presence of P O (avoiding the use of toxic MOMꢀ
2
5
32
Cl) resulting in the formation of MOM ester derivative 18 in 55 % yield. Subsequent ester hydrolysis
of 18 under basic conditions and reꢀprotection of the amine with FmocꢀOSu resulted in SDA 3 in 70 %
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yield. A part of SDA 3 served as starting material for the preparation of SDA building block 2. For the
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reduction of the azide in presence of the hydrogenolytically labile Fmoc group we employed Staudinger
conditions. Thus, treatment of 3 with trimethyl phosphine in THF/H O followed by protection of the
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free amine with diꢀtertꢀbutyldicarbonate (Boc O) afforded 2 in an overall yield of 51 %.
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Scheme 4. Synthesis of SDA building blocks 2 and 3.
The synthesis of SDA building block 1, finally, started from the common intermediate 18 (Scheme 5).
Saponification of 18 resulted in ester hydrolysis and Fmoc removal to generate the free amine in 5ꢀ
position which was subsequently Boc protected to yield intermediate compound 19. Without further
purification, crude 19 was subjected to hydrogenation with Pd/C catalyst to reduce the azide to the free
amine. Subsequent protection of the amine with FmocꢀOSu resulted in the formation of orthogonally
protected SDA building block 1 in 39 % yield starting from 18.
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Scheme 5. Synthesis of SDA building block 1.
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Solidꢀphase synthesis of pseudo oligosaccharide 4. To illustrate the application of the new SDA
building blocks in solidꢀphase synthesis of amideꢀlinked oligosaccharide mimetics following the
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standard Fmoc protocol, we synthesized oligomer 4. Rink amide AM (RAM) resin 20 which is
commonly used in peptide synthesis served as solid support (Scheme 6). After removal of the Fmoc
group with piperidine, SDA 3 was coupled as the first building block to give loaded resin 21. Unreacted
amino groups were capped by acetylation. SDA 3 is suited to synthesize branched oligomers. Although
its use is not required for the synthesis of linear oligomer 4, we employed 3 to demonstrate that the
azido group is stable under the conditions of the solidꢀphase synthesis. Resin 21 then was stepwise
elongated with building block 1 and Oꢀ(7ꢀazabenzotriazoleꢀ1ꢀyl)ꢀ1,1,3,3ꢀtetramethyluronium
35
hexafluorophosphate (HATU) and 1ꢀhydroxyꢀ7ꢀazaꢀ1Hꢀbenzotriazole (HOAt) as coupling reagents to
give resinꢀbound tetramer 22 in six steps (Scheme 7). The azide group was reduced under Staudinger
conditions using trimethyl phosphine in aqueous dioxane. After Fmoc deprotection with piperidine, the
oligomer was cleaved from the resin with concomitant removal of the acidꢀlabile Boc and MOM groups
using a mixture of trifluoroacetic acid (TFA), triisopropyl silane (TIS) and water. Purification by RPꢀ
3
6
HPLC with addition of ionꢀpairing reagent pentafluoropropionic acid (PFPA) to increase its otherwise
low retention time gave 4 in a yield of 22 % starting from loaded resin 21 as pentakis(PFPA) salt in
1
13
>90 % purity. Oligomer 4 was thoroughly characterized by oneꢀ and twoꢀdimensional H and C NMR
1
13
spectroscopy to confirm its structure. Figure 1 shows the DQFꢀCOSY spectrum, and H and C NMR
chemical shifts are listed in Table 1.
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a
Schene 6. Synthesis of resinꢀloaded SDA building block 21.
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
DIEA = diisopropyl ethyl amine, Nle = norleucine
Scheme 7. Solidꢀphase synthesis of oligomer 4.
21
1
2
3
. piperidine, DMF
. 1, HOAt, HATU, DIEA
. piperidine, DMF
4. 1, HOAt, HATU, DIEA
5. piperidine, DMF
6
. 1, HOAt, HATU, DIEA
O
H
O
H
N
N
BocHN
RAM
O
O
O
O
NH OMOM N3 OMOM
BocHN
O
O
NH OMOM
BocHN
2
2
FmocHN OMOM
1
2
3
4
. PMe , H O, dioxane
. piperidine, DMF
3
2
. TFA/H O/TIS (95/2.5/2.5)
2
. RP-HPLC purification
O
H
O
N
NH2
H N
2
O
O
C
D
O
NH OH H N OH
2
H N
2
O
B
O
5
NH OH
H N
2
O
A
4
1
4 (x 5 PFPA)
3
2
2
2 % (from 21)
H N OH
2
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. DQFꢀCOSY spectrum (600 MHz, D O) of oligomer 4. Proton assignments of rings A and D
2
are exemplarily shown. For full assignments of peaks see Table 1. For definition of rings A–D see
Scheme 7.
1
13
a
Table 1. H and C NMR chemical shifts of oligomer 4.
b
Ring
C(1)ꢀH
C(2)ꢀH
C(3)ꢀH
C(4)ꢀH
C(5)ꢀH
2
3
.55 (dd, J = 13.5, 2.9)
4.59 (d, J ≈ 3.4)
4.67 (dd, J = 6.3, 4.3)
71.9
3.82 (‘t’, J = 6.7)
53.0
4.53 (m, overl.)
76.6
A
3.32 (m, overl.)
40.6
8
3.8 or 83.0
c
B
3.47ꢀ3.43 (m, overl.)
4
8
.59 (d, J ≈ 3.4)
3.0 or 83.8
4.49 (m, overl.)
72.7
4.24 (dd, J = 5.7, 9.2)
52.9
4.34ꢀ4.29 (m, overl.)
76.9
3
4
.32ꢀ3.28 (m, overl.)
0.9 or 40.7
c
C
3.47ꢀ3.43 (m, overl.)
.32ꢀ3.28 (m, overl.)
40.7 or 40.9
4
8
.54 (d, J ≈ 2.7)
4.1
4.51 (m, overl.)
72.7
4.22 (dd, J = 5.8, 9.3)
52.9
4.34ꢀ4.29 (m, overl.)
76.9
3
D
4.47 (d, J = 3.5)
2.8
4.64 (dd, J = 5.9, 3.6)
72.0
3.69 (m, overl.)
52.5
4.41 (ddd, J = 7.8, 6.0, 3.8)
78.9
3.71ꢀ3.66 (m, 2H, overl.)
40.2
8
A–D
δC of amides: 173.8, 172.1, 171.8, 171.2
a
1
13
3
Determined in D O at 600 MHz ( H) and 150 MHz ( C), respectively. J coupling constants given
2
H,H
b
in Hz. Some signals could not be unambiguously assigned due to signal overlap (overl.). For definition
of rings A–D see Scheme 7. Rings B and C cannot be clearly distinguished and might be exchanged.
c
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1
2
3
4
5
Conclusion
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, we have presented a divergent synthesis of orthogonally protected SDA building blocks
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
, 2, and 3 which are the first examples of furanoid SDAs. The protecting group strategy adopted here
allows the facile assembly of these derivatives on solid support by standard peptide coupling
methodology. This has been demonstrated by the synthesis of amideꢀlinked oligosaccharide 4. The wide
1
8
variety of possibilities in connecting these and previously published SDAs to yield linear as well as
branched structures makes them ideal building blocks for the combinatorial synthesis of oligosaccharide
mimetics. Since oligomers made of SDAs represent a potential class of aminoglycoside mimetics, their
synthesis opens new avenues for the development of new ligands to target RNA. Indeed, the synthesis
of a library of SDA oligomers and their investigation as RNA ligands has been successfully carried out
in our laboratory and will be published in due course.
Experimental Section
General Experimental Methods: Solvents for moisture sensitive reactions were distilled and dried
according to standard procedures prior to use. All solvents for silica gel flash chromatography (FC)
were distilled. 3ꢀAzidoꢀ3ꢀdeoxyꢀ1,2ꢀOꢀisopropylideneꢀαꢀDꢀallofuranose 5, was prepared according to a
1
5c
published procedure. Rink amide AM (RAM) resin 20 was obtained from Novabiochem (product No.
855120). Thin layer chromatography (TLC) was performed on Merck Silica Gel 60 F254 aluminum
sheets. For developing plates, ceric ammonium molybdate, KMnO , orcine or ninhydrin was used. Flash
4
column chromatography (FC) was performed on Macherey-Nagel Silica Gel 60 (0.04ꢀ0.063 mm; 230ꢀ
4
00 mesh). NMR spectra were recorded at 298 K. Chemical shifts are referenced to the solvent signal
CDCl3: δH = 7.26 δC = 77.0, DMSOꢀd6: δH = 2.5, δC = 39.5). Optical rotations were determined at 25
°C with a 1 dm cell. Melting points are uncorrected.
(
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3
ꢀAzidoꢀ3ꢀdeoxyꢀ1,2ꢀOꢀisopropylideneꢀαꢀ
D
ꢀribofuranose (9). To a stirred solution of 3ꢀazidoꢀ3ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
deoxyꢀ1,2ꢀOꢀisopropylideneꢀαꢀ
Dꢀallofuranose 5 (493 mg, 2.01 mmol) in MeOH (7 mL) and H O (10
2
mL), NaIO (516 mg, 2.4 mmol) was gradually added at 0 °C and kept stirring for 4 h. The reaction
4
mixture was diluted with MeOH (8 mL), the inorganic salts were filtered off, and the filtrate was
evaporated to obtain light yellow syrup. The crude product was dissolved in MeOH (5 mL) and THF (2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mL). NaBH (86 mg, 2.22 mmol) was added and the reaction mixture stirred for 3 h at 0 °C and filtered.
4
The solvent was evaporated and the residue purified by FC (petroleum ether/ethyl acetate, 1:2) to give 9
(334 mg, 1.55 mmol, 77%) as white solid. mp 54ꢀ56 °C; R = 0.39 (petroleum ether/ethyl acetate, 1:2);
f
25
1
[
α]D + 58.0 (c 0.5, CHCl ); H NMR (250 MHz, CDCl ) δ = 5.77 (d, 1H, J = 3.7 Hz), 4.72 (t, 1H, J =
3 3
4.2 Hz), 4.10 (m, 1H), 4.00 (dd, 1H, J = 12.3, 2.2 Hz), 3.70 (dd, 1H, J = 12.5, 2.7 Hz), 3.52 (dd, 1H, J =
13
9
.4, 4.5 Hz) 1.56 (s, 3H), 1.35 (s, 3H); C NMR (62.5 MHz, CDCl )
δ
= 113.3, 104.2, 80.2, 78.2, 60.3,
3
+
5
9.5, 26.4; ESIꢀMS m/z: [M + H] Calcd for C H N O 216.1; Found 215.0. Anal. Calcd for
8
14
3
4
C H N O : C, 44.65; H, 6.09; N, 19.53. Found: C, 44.74; H, 6.13; N, 19.34.
8
13
3
4
3
ꢀAzidoꢀ3ꢀdeoxyꢀ1,2ꢀOꢀisopropylideneꢀ5ꢀOꢀtosylꢀαꢀDꢀribofuranose (10). To a solution of 9 (333
mg, 1.55 mmol) in dry pyridine (4 mL) tosyl chloride (413 mg, 2.17 mmol) was added at 0 °C, and the
mixture was stirred overnight. The reaction mixture was quenched with water and the solvent
evaporated. The crude product was purified by FC (petroleum ether/ethyl acetate, 2:1) to give 10 (342
mg, 0.93 mmol, 60%) as white crystals. mp 71ꢀ73 °C; R = 0.44 (petroleum ether/ethyl acetate, 2:1);
f
25
1
[
α]D + 42.8 (c 0.5, CHCl ); H NMR (250 MHz, CDCl ) δ = 7.78 (m, 2H), 7.35 (m, 2H), 5.72 (d, 1H, J
3 3
= 3.6 Hz) , 4.69 (t, 1H, J = 4.3 Hz), 4.31ꢀ4.10 (m, 3H), 3.49 (dd, 1H, J = 9.3, 4.5 Hz), 2.42 (s, 3H), 1.50
13
(
3, 3H), 1.41 (3, 3H); C NMR (62.5 MHz, CDCl )
δ
= 145.2, 132.6, 130.3, 127.9, 113.4, 104.2, 79.8,
3
+
7
5.7, 67.0, 60.3, 26.4, 21.6; MALDIꢀMS m/z: [M + Na] Calcd for C H N NaO S 392.1; Found 392.8.
15 19
3
6
Anal. Calcd for C H N O S: C, 48.77; H, 5.18; N, 11.38. Found: C, 48.61; H, 5.19; N, 11.34.
1
5
19
3
6
3
ꢀAzidoꢀ3,5ꢀdideoxyꢀ1,2ꢀOꢀisopropylideneꢀ5ꢀphthalimidoꢀαꢀDꢀribofuranose (11). A solution of 10
(2.5 g, 6.77 mmol) and potassium phthalimide (1.5 g, 8.12 mmol) in dry DMF (20 mL) was stirred at
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The Journal of Organic Chemistry
7
5
0 °C for 24 h. After addition of H O (30 mL), the reaction mixture was extracted with CH Cl (2 ×
2 2 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0 mL). The organic layer was successively washed with 5% aq NaOH (20 mL) and brine and dried
over Na SO , and the solvent was evaporated. The crude product was purified by FC (petroleum
2
4
ether/ethyl acetate, 1:1) to yield 11 (1.4 g, 4.07 mmol, 60%) as a white solid. mp 148ꢀ151 °C; R = 0.5
f
2
5
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(petroleum ether/ethyl acetate, 1:1); [α]D + 47.8 (c 0.5, CHCl ); H NMR (250 MHz, CDCl )
3
3
δ
= 7.87
(m, 2H), 7.74 (m, 2H), 5.80 (d, 1H, J = 3.7 Hz), 4.72 (t, 1H, J = 4.3 Hz), 4.30 (m, 1H), 3.98 (m, 2H),
13
3
.32 (dd, 1H, J = 9.7, 4.7 Hz), 1.52 (3, 3H), 1.31 (3, 3H); C NMR (62.5 MHz, CDCl3) δ = 168.1,
+
1
34.1, 132.0, 123.5, 113.3, 104.2, 80.1, 74.9, 63.4, 39.0, 26.5; MALDIꢀMS m/z: [M + Na] Calcd for
C H N O Na 367.1; Found 366.7. Anal. Calcd for C H N O : C, 55.81; H, 4.68; N, 16.27. Found: C,
16
16
4
5
16 16
4
5
55.95; H, 4.94; N, 16.55.
Methyl 3ꢀAzidoꢀ3ꢀ5ꢀdideoxyꢀ5ꢀphthalimidoꢀDꢀribofuranoside (12). To a stirred solution of 11 (1.7
g, 4.94 mmol) in MeOH (15 mL), acetyl chloride (0.2 mL) was added at room temperature and the
mixture stirred for 5 h. The solution was neutralized with pyridine (3 mL) and the solvent evaporated.
The crude product was purified by FC (petroleum ether/ethyl acetate, 2:1) to give 12 (1.13 g, 3.55
1
mmol, 72%, α:β ≈ 1:12) as a white foam. R = 0.21 (petroleum ether/ethyl acetate, 2:1); H NMR (600
f
MHz, CDCl3)
δ = 7.86 (m, 2H), 7.72 (m, 2H), 4.89 (d, 1H, J = 4.6 Hz, α isomer), 4.79 (s, 1H, β isomer),
4
.30 (m, 1H, β isomer), 4.14 (d, 1H, J = 4.3 Hz, β isomer), 4.06 (dd, 1H, J = 7.9, 4.4 Hz, β isomer), 3.98
13
(m, 2H, β isomer), 3.44 (s, 3H, αꢀisomer), 3.29 (s, 3H, β isomer); C NMR (150 MHz, CDCl )
δ
(β
3
+
isomer) = 168.2, 134.2, 131.9, 123.6, 108.0, 78.3, 75.6, 64.4, 55.3, 40.7; MALDIꢀMS m/z: [M + Na]
Calcd for C H N O Na 341.1; Found 341.7. Anal. Calcd for C H N O : C, 52.83; H, 4.43; N; 17.60.
1
4
14
4
5
14 14
4
5
Found: C, 53.05; H, 4.76; N, 7.68.
Methyl 3ꢀAzidoꢀ2ꢀOꢀbenzoylꢀ3ꢀ5ꢀdideoxyꢀ5ꢀphthalimidoꢀDꢀribofuranoside (13). To a solution of
1
2 (8.3 g, 26.1 mmol) in pyridine (60 mL), benzoyl chloride (15 mL, 130 mmol) was added dropwise at
room temperature and the reaction mixture was stirred for 3 h. The solvent was evaporated and the
residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (2 ×),
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dried (Na SO ), filtered, and evaporated. The crude product was purified by FC (petroleum ether/ethyl
2
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
acetate, 2:1) to give 13 (10.5 g, 24.85 mmol, 95%, α:β ≈ 1:4) as a colorless gum. R = 0.4 (petroleum
f
1
ether/ethyl acetate, 2:1); H NMR (600 MHz, CDCl )
δ = 8.11 (m, 1H), 8.04 (m, 1H), 7.89 (m, 2H),
3
7
.75 (m, 2H), 7.59 (m, 1H), 7.46 (m, 2H), 5.44 (d, 1H, J = 4.6 Hz, β isomer), 5.24 (d, 1H, J = 4.3 Hz, α
isomer), 5.19 (dd, 1H, J = 7.9, 4.4 Hz, α isomer), 4.95 (s, 1H, β isomer), 4.41 (m, 1H, β isomer), 4.30
m, 1H, α isomer), 4.24 (dd, 1H, J = 8.3, 4.6 Hz, β isomer), 4.17 (m, 1H, α isomer), 4.04 (m, 2H, β
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1
3
isomer), 3.41 (s, 3H, α isomer), 3.36 (s, 3H, β isomer); C NMR (150 MHz, CDCl )
δ
(β isomer) =
3
1
68.3, 165.4, 134.3, 133.7, 130.1, 129.0, 128.6, 128.5, 123.5, 106.1, 78.4, 76.6, 62.7, 55.4, 40.7;
+
MALDIꢀMS m/z: [M + Na] Calcd for C H N O Na 445.1; Found 445.6. Anal. Calcd for C H N O :
21 18
4
6
21 18
4
6
C, 59.71; H, 4.30; N, 13.26. Found: C, 59.83; H, 4.48; N, 12.38.
ꢀOꢀAcetylꢀ3ꢀazidoꢀ2ꢀOꢀbenzoylꢀ3,5ꢀdideoxyꢀ5ꢀphthalimidoꢀ
18.2 g, 43.09 mmol) was dissolved in acetic acid (172 mL). Acetic anhydride (40.5 mL, 431.2 mmol)
and conc. H SO (11.5 mL, 215 mmol) were added to the solution followed by stirring for 1 h. The
1
Dꢀribofuranose (14). Compound 13
(
2
4
reaction mixture was poured into sat. NaHCO solution and extracted with CH Cl (2 × 100 mL). The
3
2
2
combined organic layers were washed with brine, dried over Na SO , filtered and evaporated. The
2
4
residue was purified by FC (petroleum ether/ethyl acetate, 2:1) to give 14 (17.47 g, 38.8 mmol, 90%,
1
α:β ≈ 16:1) as a white solid. R = 0.3 (petroleum ether/ethyl acetate, 2:1); H NMR (250 MHz, CDCl )
δ
f
3
=
8.03 (m, 2H), 7.87 (m, 2H), 7.73 (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 6.55 (d, 1H, J = 4.5 Hz, α
isomer), 6.24 (s, 1H, β isomer), 5.55 (d, 1H, J = 4.5 Hz, β isomer), 5.49 (dd, 1H, J = 7.5, 4.3 Hz, α
isomer), 4.49 (m, 1H, α isomer), 4.19 (m, 1H, α isomer), 4.08ꢀ3.91 (m, 2H, α isomer), 2.07 (s, 3H, α
13
isomer), 1.91 (s, 3H, β isomer); C NMR (62.5 MHz, CDCl )
δ
(α isomer) = 169.1, 168.1, 165.5, 134.3,
3
+
1
33.5, 131.7, 129.9, 128.9, 128.7, 123.8, 94.1, 80.4, 72.3, 60.4, 39.6, 20.7; MALDIꢀMS m/z: [M + Na]
Calcd for C H NaN O 473.1; Found 472.7. Anal. Calcd for C H N O : C, 58.67; H, 4.03; N, 12.44.
2
2
18
4
7
22 18
4
7
Found: C, 58.85; H, 4.12; N, 12.41.
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3
ꢀAzidoꢀ2ꢀOꢀbenzoylꢀ1ꢀcyanoꢀ5ꢀphthalimidoꢀ1,3,5ꢀtrideoxyꢀβꢀDꢀribofuranose (15). To a solution
1
2
of 14 (15 g, 33.3 mmol) and TMSꢀCN (25 mL, 200 mmol) in anhydrous CH Cl (150 mL), a 1 M
2
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
solution of SnCl in CH Cl (40 mL) was added dropwise at room temperature. The reaction mixture
4
2
2
was refluxed for 5 h and poured into sat. NaHCO solution. The mixture was extracted with CH Cl (4 ×
3
2
2
2
00 mL). The combined organic layers were washed with brine, dried (Na SO ), filtered and evaporated
2 4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to get crude residue. It was purified by FC (petroleum ether/ethyl acetate, 2:1) to yield 15 (6.39 g, 15.32
25
mmol, 46%) as a pale yellow solid. mp 168ꢀ170 °C; R = 0.4 (petroleum ether/ethyl acetate, 2:1); [α]D
f
1
+ 44.8 (c 0.5, CHCl ); H NMR (600 MHz, CDCl )
δ = 8.05 (m, 2H), 7.91 (m, 2H), 7.76 (m, 2H), 7.63
3
3
(m, 1H), 7.48 (m, 2H), 5.77 (m, 1H), 4.78 (d, 1H, J = 2.2 Hz), 4.37 (m, 1H), 4.29 (m, 1H), 4.16ꢀ4.08 (m,
1
3
2H); C NMR (150 MHz, CDCl )
δ
= 168.2, 164.7, 134.4, 134.1, 131.7, 130.0, 128.7, 128.0, 123.6,
3
+
1
4
15.4, 79.8, 75.8, 69.8, 63.0, 38.5; MALDIꢀMS m/z: [M + Na] Calcd for C H NaN O 440.1; Found
21
15
5
5
40.1. Anal. Calcd for C H N O : C, 60.43; H, 3.62; N, 16.78. Found: C, 60.43; H, 3.62; N, 16.69.
2
1
15
5
5
3
ꢀAzidoꢀ2ꢀOꢀbenzoylꢀ5ꢀphthalimidoꢀ1,3,5ꢀtrideoxyꢀβꢀDꢀribofuranoseꢀ1ꢀcarboxylic Acid (16). To
a solution of 15 (10.60 g, 25.4 mmol) in dioxane/water (10:1, 110 mL), HCl (4 M in dioxane, 100 mL)
was added, and the mixture was heated to 60 °C for 24 h and the solvent was evaporated. The residue
was dissolved in 1 N HCl and extracted with CH Cl (4 × 100 mL). The combined organic layers were
2
2
dried over Na SO , filtered, and dried. The crude residue was purified by FC (CH Cl /MeOH, 9:1) to
2
4
2
2
25
D
yield 16 (9.79 g, 22.4 mmol, 88%) as pale yellow foam. R = 0.3 (CH Cl /MeOH, 9:1); [α] + 44.8 (c
f
2
2
1
0
.5, CHCl ); H NMR (250 MHz, DMSOꢀd ) δ = 7.99ꢀ7.96 (m, 2H), 7.89ꢀ7.82 (m, 4H), 7.71ꢀ7.64 (m,
3 6
1H), 7.56ꢀ7.50 (m, 2H), 5.70 (m, 1H) , 4.36 (d, J = 1.8 Hz, 1H), 4.28 (dd, J = 8.3, 4.8 Hz, 1H), 4.11ꢀ
13
4
.03 (m, 3H); C NMR (62.5 MHz, DMSOꢀd6)
δ
= 171.3, 167.8, 164.7, 134.3, 133.6, 131.5, 129.2,
+
1
28.8, 128.7, 122.9, 82.3, 77.3, 76.6, 63.4, 39.8; MALDIꢀMS m/z: [M + H] Calcd for C H N O
21 17
4
7
4
37.1; Found 437.1. Anal. Calcd for C H N O : C, 57.80; H, 3.70; N, 12.84. Found: C, 57.98; H, 3.68;
21 16 4 7
N, 12.81.
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3
ꢀAzidoꢀ5ꢀ(9ꢀfluorenylmethoxycarbonylamino)ꢀ1,3,5ꢀtrideoxyꢀβꢀDꢀribofuranoseꢀ1ꢀcarboxylic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Acid (17). To a stirred solution of 16 (2.1 g, 6.7 mmol) in 2ꢀpropanol (62 mL) and H O (10 mL),
2
NaBH (1.27 g, 33.5 mmol) was added and the solution was kept stirring for 24 h. TLC indicated
4
complete consumption of starting material. Glacial acetic acid (7.2 mL) was added carefully to adjust
the pH to 4.8, and when the foaming subsided, the reaction mixture was stirred at 80 °C for 15 h. The
solvent was evaporated and the crude residue was used in the next step without any purification. The
crude amine was dissolved in acetone/H O (1:1, 6 mL). 1 M Na CO solution (2.8 mL) was added and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
3
the mixture was stirred for 5 h to hydrolyze the benzoyl ester. To this solution, FmocꢀOSu (950 mg,
.83 mmol), dissolved in acetone (5 mL), was added, and the solution was stirred for 8 h. Acetone was
2
evaporated and the reaction mixture was acidified to pH = 3 with 1 N HCl. The reaction mixture was
extracted with ethyl acetate (5 × 30 mL). The combined organic phases were washed twice with H O,
2
dried over Na SO , and the solvent was evaporated. The crude residue was purified by FC
2
4
(
CH Cl /MeOH, 9:1) to yield 17 (1.6 g, 3.8 mmol, 60%) as a white solid. mp 140ꢀ142 °C; R = 0.3
2
2
f
25
D
1
(
CH Cl /MeOH, 9:1); [α] + 41.7 (c 0.5, CHCl ); H NMR (600 MHz, DMSOꢀd )
δ
= 8.35 (m, 2H),
2
2
3
6
8
.20 (m, 2H), 7.86 (m, 2H), 7.78 (m, 2H), 7.20 (br s, 1H), 5.18 (m, 1H), 4.81ꢀ4.6 (m, 4H), 4.25 (m, 2H),
1
3
3.78 (m, 2H); C NMR (150 MHz, DMSOꢀd6)
δ
= 182.5, 168.1, 153.5, 152.0, 138.5, 138.2, 137.1,
+
1
32.5, 94.8, 91.3, 88.2, 78.0, 73.1, 58.1, 52.3; ESIꢀMS m/z:
[
M + H] C H N O Calcd for 425.2;
2
1
21
4
6
Found 425.4. Anal. Calcd for C H N O : C 59.43; H, 4.75; N, 13.20. Found: C, 59.41; H, 4.73; N,
2
1
20
4
6
,
1
2.82.
ꢀAzidoꢀ5ꢀ(9ꢀfluorenylmethoxycarbonylamino)ꢀ2ꢀOꢀmethoxymethylꢀ1,3,5ꢀtrideoxyꢀβꢀDꢀ
3
ribofuranoseꢀ1ꢀcarboxylic Acid Methoxymethyl Ester (18). To a stirred solution of 17 (2.4 g, 5.66
mmol) in formaldehyde dimethyl acetal (120 mL) and THF (5 mL), P O (1.2 g) was added in portions
2
5
and stirred for 3 h and then transferred to a flask. The remaining solids were taken up in Na CO (1 M,
2
3
30 mL) and the aqueous layer was then extracted with CH Cl (2 × 20 mL). The combined organic
2
2
layers were washed with sat. NaHCO solution and H O. After drying over Na SO and evaporation, the
3
2
2
4
crude product was purified by FC (petroleum ether/ethyl acetate, 1:1) to give 18 (1.595 g, 3.1 mmol,
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2
5
1
5
5%) as a colorless gum. R = 0.35 (petroleum ether/ethyl acetate, 1:1); [α]D –0.7 (c 0.5, CHCl ); H
f 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (600 MHz, CDCl3)
δ = 7.77 (d, 2H, J = 6.0 Hz), 7.65ꢀ7.60 (m, 2H), 7.41ꢀ7.39 (m, 2H), 7.33ꢀ7.31
(m, 2H), 5.85 (br. m, 1H), 5.36ꢀ5.26 (m, 2H), 4.83ꢀ4.78 (m, 2H), 4.58 (d, J = 1.8 Hz, 1H), 4.46ꢀ 4.41
1
3
(m, 3H), 4.27ꢀ4.23 (m, 2H), 3.65ꢀ3.43 (m, 9H); C NMR (150 MHz, CDCl ):
δ
= 157.8, 143.8, 141.3,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
27.7, 127.1, 125.2, 124.8, 119.9, 96.2, 91.6, 81.1, 80.2, 79.8, 66.8, 60.4, 58.1, 56.1, 47.3, 41.4; HRMS
+
+
(
ESIꢀTOF) m/z: [M + H] Calcd for C H N O 513.1980; Found 513.1994.
25 29 4 8
3ꢀAzidoꢀ5ꢀ(9ꢀfluorenylmethoxycarbonylamino)ꢀ2ꢀOꢀmethoxymethylꢀ1,3,5ꢀtrideoxyꢀβꢀDꢀ
ribofuranoseꢀ1ꢀcarboxylic Acid (3). A solution of 18 (2 g, 3.9 mmol) in MeOH (10 mL) was stirred
with 1 N NaOH (11.7 mL) for 2 h. The reaction mixture was neutralized with 1 N HCl (12 mL) and the
solvent was evaporated in vacuum to give the crude amino acid. The crude product was dissolved in
acetone/H O (1:2, 8 mL) and 1 M Na CO solution (3 mL) was added. To this solution FmocꢀOSu
2
2
3
(950 mg, 2.83 mmol) in acetone (5 mL) was added and the mixture stirred for 8 h. Acetone was
evaporated and the reaction mixture was acidified to pH 3 with 1 N HCl. The reaction mixture was
extracted with ethyl acetate (5 × 30 mL). The combined organic phases were washed with H O (2 ×),
2
dried over Na SO and the solvent was evaporated under vacuum. The crude residue was purified by FC
2
4
(
CH Cl /MeOH, 9:1) to yield 3 (1.26 g, 2.7 mmol, 70%) as a white solid. R = 0.25 (CH Cl /MeOH,
2
2
f
2
2
25
1
9
:1); mp 78ꢀ80 °C; [α]D + 15.4 (c 1.0, CHCl ); H NMR (600 MHz, DMSOꢀd ) δ = 8.3 (br s, 1H), 7.86
3 6
(m, 2 H), 7.69 (m, 2H), 7.39 (m, 2H), 7.31 (m, 2H), 4.83 (d, J = 6.6 Hz, 1H), 4.70 (d, J = 6 Hz, 1H),
13
4
.39 (m, 1H), 4.23ꢀ4.21 (m, 4H), 4.07ꢀ4.00 (m, 2H), 3.76 (m, 1H), 3.34 (m, 4H); C NMR (150 MHz,
DMSOꢀd6):
δ
= 173.3, 156.5, 143.8, 140.6, 127.5, 127.0, 125.2, 120.0, 94.8, 82.6, 79.9, 78.4, 65.7, 61.0,
+
5
5.1, 46.6, 42.3; MALDIꢀMS m/z: [M + Na] Calcd for C H N O Na 491.1; Found 491.0. Anal. Calcd
2
3
24
4
7
for C H N O : C, 58.97; H, 5.16; N, 11.96. Found: C, 58.91; H, 5.14; N, 11.91.
2
3
24
4
7
3ꢀ(tertꢀButoxycarbonylamino)ꢀ5ꢀ(9ꢀfluorenylmethoxycarbonylamino)ꢀ2ꢀOꢀmethoxymethylꢀ1,3,5ꢀ
trideoxyꢀβꢀ ꢀribofuranoseꢀ1ꢀcarboxylic Acid (2). To a stirred solution of 3 (700 mg, 1.49 mmol) in
D
THF (10 mL), PMe (1 M in THF, 7.5 mL) and H O (15 mL) were added, and the mixture was kept
3
2
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stirring for 5 h. The solvent was evaporated, and toluene was evaporated several times from the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
remainder. The crude amine (500 mg, brownish liquid, R = 0.35 (MeCN/H O, 4:1)) was dissolved in
f
2
H O (10 mL). 1 M Na CO solution (3 mL) and then a solution of Boc O (480 mg, 2.2 mmol) in
2
2
3
2
dioxane (3 mL) were added. After having been stirred for 5 h, the solution was concentrated and
acidified to pH 3 by addition of 1 N HCl. The product was extracted with CHCl (4 × 20 mL), the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
combined organic phases were dried (Na SO ), concentrated, and the crude residue was purified by FC
2
4
(
ethyl acetate/MeOH, 9:1) to give 2 (412 mg, 0.76 mmol, 51%) as a white solid. R = 0.17 (ethyl
f
2
5
1
acetate/MeOH, 9:1); mp 92ꢀ94 °C; [α]D + 15.4 (c 0.5, CHCl ); H NMR (600 MHz, DMSOꢀd )
δ =
3
6
7
.89 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.0 Hz, 2H), 7.45ꢀ7.30 (m, 4H), 7.10 (m, 1H), 4.72 (m, 1H), 4.59
1
3
(
m, 1H), 4.43 (m, 1H), 4.21 (m, 4H), 4.0 (m, 2H), 3.81 (m, 1H), 3.27 (m, 4H), 1.36 (s, 9H); C NMR
(150 MHz, DMSOꢀd6):
δ
= 172.7, 158.4, 144.1, 140.9, 127.9, 127.4, 125.5, 120.3, 95.3, 80.9, 79.4, 78.5,
–
7
7.9, 66.1, 65.7, 55.3, 53.8, 46.9, 28.4; ESIꢀMS m/z: [M – H] Calcd for C H N O 541.2; Found
2
8
33
2
9
541.1. Anal. Calcd for C H N O : C, 61.98; H, 6.32; N, 5.16. Found: C, 61.72; H, 6.31; N, 5.14.
2
8
34
2
9
5
ꢀ(tertꢀButoxycarbonylamino)ꢀ3ꢀ(9ꢀfluorenylmethoxycarbonylamino)ꢀ2ꢀOꢀmethoxymethylꢀ1,3,5ꢀ
trideoxyꢀβꢀ ꢀribofuranoseꢀ1ꢀcarboxylic Acid (1). A solution of 18 (2.3 g, 4.49 mmol) in MeOH
10 mL) was treated with 1 N NaOH (12 mL) and stirred for 2 h at room temperature. The reaction
D
(
mixture was neutralized with 1 N HCl and the solvent was evaporated. The crude amino acid was
dissolved in dioxane/H O (1:4, 10 mL). 1 M Na CO solution (3 mL) and a solution of Boc O (1.18 g,
2
2
3
2
5
.39 mmol) in dioxane (5 mL) were added and the mixture was stirred for 5 h at room temperature. The
reaction mixture was acidified with 1 N HCl to pH 3 and extracted with CHCl (4 × 20 mL). The
3
combined organic phases were dried over Na SO and concentrated to obtain 3ꢀazidoꢀ5ꢀ(tertꢀ
2
4
butoxycarbonylamino)ꢀ2ꢀOꢀmethoxymethylꢀ1,3,5ꢀtrideoxyꢀβꢀ
Dꢀribofuranoseꢀ1ꢀcarboxylic acid (19) as a
white solid (1.09 g, 3.14 mmol, 70%, R = 0.17 (CH Cl /MeOH 4:1)) which was used in the next step
f
2
2
without any purification. Crude 19 (1 g, 2.89 mmol) was dissolved in anhydrous MeOH (15 mL). After
addition of dry 10% palladium on carbon catalyst (2 spatula tips), the reaction mixture was vigorously
stirred under H (1 atm) at room temperature for 40 min. The mixture was filtered through Celite and
2
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the solvent evaporated. The crude oily liquid (0.9 g, 2.81 mmol, R = 0.21 (CH Cl /MeOH, 4:1)), was
f
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dissolved in acetone/H O (1:1, 10 mL). A solution of FmocꢀOSu (1.14 g, 3.37 mmol) in acetone (8 mL)
2
was added, and the mixture was stirred overnight. The reaction mixture was acidified with 1 N HCl to
pH 3 and the product was extracted with CHCl (4 × 20 mL). The combined organic phases were dried
3
over Na SO and concentrated. The obtained crude product was purified by FC (CH Cl /MeOH, 9:1) to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
2
2
25
yield 1 (860 mg, 1.59 mmol, 55%) as a white solid. R = 0.20 (CH Cl /MeOH, 9:1); mp 75ꢀ78 °C; [α]
D
f
2
2
1
+
15.8 (c 0.5, CHCl ); H NMR (600 MHz, DMSOꢀd ) δ = 7.87 (m, 2H), 7.69 (m, 2H), 7.40 (m, 2H),
3
6
7.33 (m, 2H), 4.69 (d, J = 6.6 Hz, 1H), 4.51 (d, J = 6.6 Hz, 1H), 4.27 (m, 2H), 4.19ꢀ4.11 (m, 4H), 4.01
13
(
m, 1H), 3.20ꢀ3.14 (m, 4H), 1.35 (s, 9H); C NMR (150 MHz, DMSOꢀd6):
δ
= 172.9, 156.1, 144.0,
140.8, 127.7, 127.2, 125.3, 120.2, 94.5, 78.8, 77.7, 77.4, 77.2, 65.7, 59.9, 54.9, 46.8, 28.4; ESIꢀMS m/z:
–
[
M – H] Calcd for C H N O 541.2; Found 541.7. Anal. Calcd for C H N O : C 61.98; H, 6.32; N,
28
33
2
9
28 34
2
9
,
5
.16. Found: C, 61.71; H, 6.29; N, 5.14.
SolidꢀPhase Synthesis of Oligomer 4. Solidꢀphase synthesis was carried out in a disposable fritted
33
syringe according to standard Fmoc protocols starting from Rink amideꢀAMꢀresin 20 (152 mg, loading
–
1
density 0.96 mmol g ). Fmoc deprotection. The resin was swollen for 5 min in DMF. The solvent was
removed and the resin shaken with 20% piperidine in DMF (1 mL per 100 mg resin) (1 × 3 min, 1 × 10
min). Loading of resin. After Fmoc deprotection the resin was washed with DMF (10 × 1 min). SDA 3
(137 mg, 0.29 mmol), HOAt (40 mg, 0.29 mmol), HATU (106 mg, 0.28 mmol), and DIEA (100 µL,
0
.59 mmol) were mixed in Nꢀmethylpyrrolidinꢀ2ꢀone (NMP)/CH Cl (3:1 (v/v), 1 mL), taken into the
2 2
syringe and shaken for 3 h. Subsequently, the resin was washed with DMF (10 × 1 min). Capping. The
resin was shaken with Ac O/pyridine (1:3, 0.5 mL per 100 mg resin) for 15 min and then washed with
2
DMF (10 × 1 min). Determination of loading density. The resin was washed with CH Cl (2 × 1 min)
2
2
and dried under vacuum to afford resin bound SDA building block 21 (168 mg). A small amount of dry
resin (4 mg) was taken out and treated with 20% piperidine in DMF (10 mL) for 15 minutes. The UV
absorbance at 301 nm of the cleavage product (piperidineꢀdibenzofulvene adduct) was determined using
–
a 1 cm cuvette and its concentration was calculated using an extinction coefficient of ε301 = 8100 L mol
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1
–1
–1
cm . The loading density of resin 21 was calculated to be 0.39 mmol g . Further coupling steps
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with SDA 1. First, Fmoc deprotection was carried out with piperidine/DMF as described above. Then,
SDA building block 1 (2 equiv relative to resin loading), HOAt (2 equiv), HATU (1.9 equiv) and DIEA
(4 equiv) were mixed in NMP (0.5 – 1 mL), taken into the syringe and shaken for 2 to 3 hours. The resin
3
7
was washed with DMF (10 × 1 min) and capping was carried out as described above. Kaiser test was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
performed with a small resin sample to ensure complete coupling. After three coupling steps with SDA
1
the resin was washed with DMF (10 × 1 min) and CH Cl (2 × 3 min) and dried under vacuum to give
2 2
resinꢀbound oligomer 22. Staudinger reduction on solid phase. To reduce the azido group present in
2, the resin was suspended in a mixture of dioxane (0.4 mL) and water (0.1 mL). PMe (1 M in THF, 6
2
3
equiv) was added and the capped syringe was shaken for 2 hours. The resin was washed with anhydrous
dioxane (5×) to remove the excess PMe . Subsequently, Fmoc deprotection was carried out with
3
piperidine/DMF as described above and the resin was thoroughly washed with DMF and CH Cl .
2
2
Peptide cleavage. The resin was shaken with a freshly prepared mixture of TFA/TIS/water (95:2.5:2.5,
v/v/v) for 6 hours and filtered off. The cleavage solution was added dropwise to a 20 fold excess of ice
cold tertꢀbutylꢀmethyl ether and kept in the freezer overnight to precipitate the SDA oligomer. In
parallel, the resin was washed with 2–3 mL of water and lyophilized. The precipitated crude product
was removed from the cleavage solution by centrifugation (10000 rpm, 20 min). The obtained pellet
was resuspended in cold tertꢀbutylꢀmethyl ether and centrifuged again. The pellet and the lyophilized
product were combined and lyophilized again from water. Purification. The crude product was
dissolved in a solution of 0.13 % PFPA in water and purified by RPꢀHPLC (column: Nucleosil C18
–
1
from Knauer, analytical scale: 250 × 4 mm, flow: 1 mL min ; preparative scale: 250 × 8 mm, flow: 6
–
1
mL min ) using a gradient of 1–50 % B in A over 30 min (A = 0.13 % PFPA in water, B = 0.13 %
PFPA in MeCN). After RPꢀHPLC purification, SDA oligomer 4 was lyophilized to obtain the
1
corresponding pentakis(PFPA) salt (9 mg, 22 % from 21). Analytical RPꢀHPLC: t = 12.5 min. H and
R
1
3
1
13
C NMR data determined in D O at 600 MHz ( H) and 150 MHz ( C), respectively, are given in Table
2
+
1
. ESIꢀMS m/z: [M + H] Calcd for C H N O 650.3; Found 650.3.
2
4
44
9
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Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 579), the German Academic
Exchange Service (DAAD), and the University of Konstanz. We thank Claudia Meßmer for assisting in
the large scale synthesis of compound 5 and Anke Friemel for the measurement of NMR spectra.
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Supporting Information. H and C NMR spectra of newly synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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