Efficient α-mannosylation of phenols: The role of carbamates as scavengers for activated glycosyl donors

Article abstract of DOI:10.1055/s-0032-1316820

The boron trifluoride activation of trichloroacetimidate donors was found to be an efficient method for the α-mannosylation of tyrosine-containing acceptors. Most notably, these conditions are compatible with the commonly used carbamate protecting groups, whereas trichloroacetimidate activation with trimethylsilyl triflate or the use of glycosyl sulfoxides led to diminished yields in the presence of carbamates. In these cases, the competing reaction of the activated donors with the carbamate group was identified as a problematic side reaction. Taking advantage of this reactivity, various glycosyl carbamates were generated for the first time under non-acidic glycosylation conditions by reaction of different Boc-protected amino acids and dipeptides with glycosyl sulfoxides under triflic anhydride activation. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316820

FEATURE ARTICLE
▌27
fEeaftufriecariteiclne t α-Mannosylation of Phenols: The Role of Carbamates as Scavengers
for Activated Glycosyl Donors
Tyrosine Mannosylation
Peter Schüler, Sebastian N. Fischer, Michael Marsch, Markus Oberthür*
Department of Chemistry, Philipps University Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax +49(6421)2822021; E-mail: oberthuer@chemie.uni-marburg.de
Received: 26.09.2012; Accepted after revision: 07.11.2012
antibiotics with excellent activity against resistant bacte-
Abstract: The boron trifluoride activation of trichloroacetimidate
rial strains (methicillin resistant Staphylococcus aureus,
donors was found to be an efficient method for the α-mannosylation
MRSA, and vancomycin resistant enterococci, VRE).
of tyrosine-containing acceptors. Most notably, these conditions are
compatible with the commonly used carbamate protecting groups,
whereas trichloroacetimidate activation with trimethylsilyl triflate
or the use of glycosyl sulfoxides led to diminished yields in the pres-
ence of carbamates. In these cases, the competing reaction of the ac-
tivated donors with the carbamate group was identified as a
problematic side reaction. Taking advantage of this reactivity, vari-
ous glycosyl carbamates were generated for the first time under
non-acidic glycosylation conditions by reaction of different Boc-
protected amino acids and dipeptides with glycosyl sulfoxides un-
der triflic anhydride activation.
α-D-Man
O
iVal
HO
OH
O
α-D-Man
O
HO
OH
OH
O
OH
α-D-Man
NH
NH
L-βhEnd
O
HO
OH
O
HO
HO
HN
O
O
OH
O
HO
N
HN
Key words: glycosylation, natural products, phenols, sulfoxides,
trichloroacetimidates
HN
NH HN
O
D-βhEnd
D-Tyr
NH
HN
O
Introduction
HO
NH HN
O
L-Ser
The glycosylation of proteins and natural products is an
efficient means for organisms to add an additional level of
molecular complexity to the initial gene products.1 In the
case of ribosomally encoded proteins, N-linked glycosyl-
ation of asparagine residues and O-glycosylation of serine
and threonine side chains are the most abundant structural
motifs. Phenol glycosylation of tyrosine side chains, on
the other hand, is far less common, and has mainly been
identified in glycogenin, S-layer proteins,2 and most re-
cently in amyloid precursor proteins and β-peptides con-
nected to Alzheimer’s disease.3
(2S,3S)-βmePhe
O
Gly
mannopeptimycin ε
Figure 1 Structure of mannopeptimycin ε, the most active member
of the naturally occurring mannopeptimycin antibiotics; βhEnd = β-
hydroxyenduracididine; βmePhe = β-methylphenylalanine
The mannopeptimycins contain an α-(1→4)-linked
dimannoside that is attached to a D-tyrosine side chain
(Figure 1).7 Like the 4′-O-isovaleroyl derivative manno-
peptimycin ε, the most active member of the group, all
naturally occurring mannopeptimycins with antibiotic ac-
tivity contain a dimannoside that carries the small hydro-
phobic isovaleroyl group at the terminal mannose unit,
whereas the unusual N-linked D-mannose unit attached to
the cyclic guanidine of D-β-hydroxyenduracididine (D-
βhEnd) is not essential for activity.8
In contrast, microorganisms produce a number of second-
ary metabolites that carry a carbohydrate moiety on the
phenolic hydroxy group of tyrosine or hydroxyphenylgly-
cine derivatives, respectively. The glycosylation pattern
of these metabolites is structurally more diverse than on
the protein level and features mono-, di-, and oligo-
saccharides composed of a variety of α- or β-linked L- and
D-sugars attached to the phenolic side chain. Prominent
examples with interesting biological activity are different
glycopeptide antibiotics, e.g. vancomycin, teicoplanin,4
and ramoplanin,5 and the recently discovered group of
anti-HIV cyclopeptides, the mirabamides.6
While no total synthesis of the mannopeptimycins has
been accomplished so far, efforts towards glycosylated
fragments and structural analogues have been reported. A
group at Wyeth described the synthesis of a mannopepti-
mycin derivative that contains a structurally simplified
cyclopeptide portion.9 Because an unmodified dimanno-
side was the initial synthetic target, acyl groups (Ac and
Bz) could be used as temporary protecting groups for the
glycosyl donors that were required for the generation of
an α-(1→4)-dimannosyl tyrosine building block.10 As a
consequence, this synthetic design is not generally appli-
cable for esterified derivatives like mannopeptimycin ε
Our group is specifically interested in the chemical syn-
thesis of the mannopeptimycins, a group of glycopeptide
SYNTHESIS 2013, 45, 0027–0039
Advanced online publication: 07.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316820; Art ID: SS-2012-E0759-FA
© Georg Thieme Verlag Stuttgart · New York

28
P. Schüler et al.
FEATURE ARTICLE
because of difficulties associated with the selective re- attach different sugars to the tyrosine side chain via an α-
moval of such acyl groups in the presence of other lipid linkage. Published synthetic studies on phenol and tyro-
esters. Following a completely different approach, the sine glycosylation, however, have so far mostly been di-
O’Doherty group has used α-pyranone building blocks for rected at the synthesis of β-glycosides of carbohydrates
the iterative construction of a mannopeptimycin ε derived with an equatorial 2-OH group, e.g. glucose and galac-
glycosylated D-tyrosine unit as well as a small set of struc- tose. Accordingly, in these cases glycosyl donors with 2-
tural analogues.11 Although efficient, this ingenious strat- O-acyl groups were used, which ensured good β-selectiv-
egy will be limited in terms of introducing additional ities by taking advantage of neighboring group participa-
structural variations in the carbohydrate portion. Finally, tion.13–16 In principle, the same strategy can be used for the
the synthesis of a mannopeptimycin ε derived dimannosyl syntheses of α-linked mannosides, because, in this case,
N-phenyl trifluoroacetimidate has been reported, but this neighboring group participation of the now axially orient-
donor was so far only used for the glycosylation of the ed 2-O-acyl blocks the β-side. As described above, how-
side chain of a β-lactam acceptor.12
ever, the use of 2-O-acylated donors is problematic for the
synthesis of mannopeptimycin-type dimannosides with a
4′-O-acyl group.
Because of the limitations described above, we were look-
ing for an efficient and flexible methodology to reliably
Biographical Sketches█
Peter Schüler studied the mannopeptimycins in he is a member of the Pre-
chemistry at the Philipps the group of Dr. Markus clinical Target Develop-
University Marburg and the Oberthür, where his main ment Group of Dr. Aubry K.
University of Cambridge, focus was the development Miller at the German Cancer
UK. He obtained his Ph.D. of conditions for the effi- Research Center, Heidel-
in 2012 for his work to- cient glycosylation of phe- berg.
wards the total synthesis of nolic acceptors. Currently,
Sebastian Fischer studied highly substituted N-hy- research is focused on the
chemistry at the Philipps droxyindoles. In April 2010, synthesis of nonproteino-
University Marburg, where he started his Ph.D. research genic amino acids and struc-
he received his Diploma in under the guidance of Dr. turally complex peptides.
2010 after completing a Markus Oberthür and Prof.
thesis on the synthesis of Armin Geyer. His current
Michael Marsch worked During this time, his main at Marburg, working on the
for 21 years in the group of focus was on the X-ray field measurement and X-
Prof. Gernot Boche after structure determination of ray crystal structure deter-
finishing his training as a oxenoid, nitrenoid, and car- mination of small inorganic
chemistry laboratory techni- benoid compounds. He is and organic molecules.
cian at the Philipps Univer- now a member of the De-
sity Marburg in 1979. partment of Crystallography
Markus Oberthür ob- 2005 with Prof. Daniel tion in 2012. His research
tained his Ph.D. in 1999 for Kahne, first at Princeton interests include the chemis-
work on the synthesis of University and then at try and biology of cyclopep-
galacto-oligosaccharides in Harvard University and tides that act as antibiotics
the group of Prof. Frieder Harvard Medical School, he and antifungals as well as
W. Lichtenthaler at the TU moved to Marburg as a the bacterial iron transport
Darmstadt. After postdoc- Junior Group Leader, where mediated by siderophores.
toral studies from 2000– he completed his habilita-
Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
29
The formation of α-glycosylated tyrosine derivatives by as N-protecting group in general.20 A solution to this prob-
using donors that carry non-participating ether protecting lem was ultimately found after screening additional acti-
groups at O2, on the other hand, has not been studied thor- vation conditions for trichloroacetimidate 2. The best
oughly, and only a few examples in which surprisingly results were obtained when donor 2 was activated with
low glycosylation yields were obtained, have been pub- boron trifluoride–diethyl ether complex instead of tri-
lished.14a,17 Nevertheless, this second approach would not methylsilyl triflate, which led to vastly improved yields
only avoid the tedious search for a compatible 2-O-acyl for carbamate-containing acceptors. As exemplified for
group but also simplify the synthesis of the required man- Cbz-protected tyrosine 3a, the yield of mannoside 4a in-
nopeptimycin building blocks (vide infra). Accordingly, creased from 31% to 76% when mannosyl trichloroacet-
we surveyed a number of perbenzylated glycosyl donors imidate 2 was activated with 0.6 equivalents of boron
regarding their performance in the α-mannosylation of trifluoride–diethyl ether complex (Scheme 1) at –30 °C. A
different tyrosine acceptors. Here, we present the results similar increase was obtained for the mannosylation of the
of these studies that concluded in the identification of re- corresponding N-Alloc derivative. Not surprisingly, the
liable glycosylation conditions for structurally complex activation method had no influence on the outcome of gly-
donors and acceptors.
cosylation reactions when acceptors without carbamate
protecting groups were used, e.g. trifluoroacetamide 3b or
azide 3c. In conclusion, our experiments showed that the
glycosylation of phenolic acceptors with highly reactive
glycosyl donors like sulfoxide 1 (activated by Tf2O) or tri-
Results and Discussion
Model glycosylations: In our efforts towards the efficient chloroacetimidate 2 (in combination with TMSOTf) was
and reliable synthesis of α-mannosylated tyrosine units, only successful if no carbamate protecting groups were
we evaluated various ‘classical’ mannosyl donors. These present in the molecule. The activation of trichloroacet-
donors were uniformly protected with benzyl ethers, i.e. imidates with boron trifluoride, on the other hand, proved
protecting groups that are orthogonal to the isovaleroyl to be compatible with carbamates and afforded the glyco-
ester present in the mannopeptimycin dimannosyl unit. sylated tyrosine derivatives in good yields.
Initially, the perbenzylated sulfoxide donor 1 was used, as
glycosyl sulfoxides are known to be efficient donors for
BnO
the glycosylation of phenols.18 Glycosylation of carba-
OBn
O
BnO
BnO
mate (Cbz) protected D-tyrosine methyl ester 3a with sulf-
oxide 1 under triflic anhydride activation led to the α-
mannosyl amino acid 4a, albeit in only a moderate yield
(45% at best). The corresponding Alloc derivative gave
similar results, whereas Boc- and Teoc-protected deriva-
X
1 X = S(O)Ph
2 X = OC(NH)CCl3
O
tives performed even worse (yields <10%). Interestingly,
activation:
the use of acceptors 3b and 3c19 in which the amines are
a) Tf2O (sulfoxide)
OMe
b) TMSOTf (imidate)
protected as amide groups (trifluoroacetyl) or masked as
an azido group, led to much higher yields of the manno-
sylation products 4b and 4c (80% and 75%, respectively).
c) BF3·OEt2 (imidate)
R
HO
3a–c
The same dependence on the N-protecting group was ob-
served when the corresponding trichloroacetimidate do-
nor 2 was activated with trimethylsilyl triflate. Again, the
carbamate-protected tyrosine 3a could be mannosylated
in only 31% yield, whereas trifluoroacetamide derivate 3b
led to mannoside 4b in 76% yield. Similar results were
obtained with other glycosyl donors, e.g. the correspond-
ing glucosyl and galactosyl derivatives. We were also able
to show that the low yield for carbamate-containing ac-
ceptors was directly related to the phenolic glycosylation
site and not to the instability of the carbamate group under
the glycosylation conditions, because sulfoxide 1 could be
used for the efficient glycosylation of the primary alcohol
of Cbz-L-Ser-OMe.
BnO
O
OBn
O
BnO
BnO
OMe
R
O
4a-c
donor
1a
2b
2c
a
b
c
4a
4b
4c
R = NHCbz
R = NHTFA
R = N3
45%
80%
75%
31%
76%
n.d.
76%
79%
76%
yield
Scheme 1 Glycosylation of different D-tyrosine acceptors 3a–c with
mannosyl sulfoxide 1 and trichloroacetimidate donor 2. Reagents and
conditions: (a) Tf2O (1 equiv), DTBP, CH2Cl2, –60 °C to –45 °C; (b)
TMSOTf (0.8 equiv), CH2Cl2, –20 °C to 0 °C; (c) BF3·OEt2 (0.6
equiv), CH2Cl2, –30 °C to 0 °C. DTBP = 2,6-di-tert-butylpyridine,
TFA = trifluoroacetyl.
The incompatibility of carbamate protecting groups with
standard glycosyl donors for the generation of α-glycosyl-
ated phenols would constitute a severe limitation for the
synthesis of structurally complex carbohydrate-contain-
ing compounds because of the great utility of carbamates
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39

30
P. Schüler et al.
FEATURE ARTICLE
Efficient glycosylation of mannopeptimycin precursor good overall yield (66%, 2 steps). Donor 12 was obtained
peptides: The results of our model studies were con- as an anomeric mixture inseparable by flash chromatogra-
firmed during the glycosylation of different mannopepti- phy and was used directly in the glycosylation reactions.
mycin precursor peptides. Towards this end, we
In parallel, we synthesized the Alloc-protected L-βmePhe-
synthesized the dimannosyl trichloroacetimidate donor 12
D-Tyr dipeptide 13. The mannopeptimycin fragment 13
(Scheme 2) starting from the known mannoside 9.21 In ad-
was assembled from a (2S,3S)-β-methylphenylalanine de-
rivative that was obtained conveniently through a newly
developed route that features a diastereoselective Strecker
reaction (see Supporting Information). Dipeptide 13 was
efficiently glycosylated with trichloroacetimidate 12 to
afford dimannosyl dipeptide 14 (60%) when the donor
was activated with boron trifluoride (0.6 equiv; Scheme
3). It should be noted that glycosylation of the carbamate
dition to serving as the glycosyl acceptor, alcohol 9 can
also be converted into an appropriate sulfoxide donor 10
by acylation (iValCl, DMAP, Et3N, CH2Cl2) to the 4-O-
isovaleroyl derivative and subsequent oxidation with 3-
chloroperoxybenzoic acid (MCPBA; 76% over 2 steps).
Glycosylation of the thioglycoside acceptor 9 with sulfox-
ide 10 under triflic anhydride activation was rendered pos-
sible by the addition of 4-allyl-1,2-dimethoxybenzene to
containing 13 with trichloroacetimidates under trimethyl-
silyl triflate activation or sulfoxides under triflic anhy-
dride activation led to a significant decrease in the yields
the reaction mixture,22 which afforded dimannoside 11 in
acceptable yields.23
of the glycosylated dipeptide, similar to the results of our
model studies.
BnO
OBn
O
HO
BnO
O
BnO
BnO
OBn
O
OBn
O
SPh
76%
9
iValO
BnO
O
BnO
OBn
OBn
OBn
O
OH
c
OBn
O
a, b
BnO
O
BnO
O
BnO
52%
donor 12
O
Alloc
HN
BF3·OEt2
OBn
O
OMe
X
(0.6 equiv)
N
O
iValO
BnO
H
11 X = α-SPh
12 X = OC(NH)CCl3
d,e
CH2Cl2
–30 °C
O
Ph
64%
S(O)Ph
O
13
10
AllocHN
OMe
N
H
Scheme 2 Synthesis of dimannosyl building block 12. Reagents and
conditions: (a) iValCl, DMAP, Et3N, CH2Cl2, 0 °C; (b) MCPBA,
CH2Cl2, –70 °C to –20 °C, 76% (2 steps); (c) Tf2O, DTBP, 4-allyl-
1,2-dimethoxybenzene, CH2Cl2, –70 °C to –25 °C, 52%; (d) NBS,
acetone–H2O, 0 °C, 81%; (f) Cl3CCN, DBU, CH2Cl2, 0 °C, 79%.
O
Ph
(60%)
14
Scheme 3 Glycosylation of dipeptide 13 with dimannosyl donor 12
Finally, thioglycoside 11 was transformed to the corre-
sponding trichloroacetimidate donor 12 by hydrolysis of
the thioglycoside (NBS, acetone–H2O) and treatment of
the resulting lactol with trichloroacetonitrile/DBU in
In addition to this dipeptide fragment, we also synthesized
hexapeptide 15 (see Supporting Information), a linear
hexapeptide precursor to the mannopeptimycins (Scheme
4). This acceptor contains two β-hydroxyenduracididine
O
BnO
OBn
O
O
R
O
NBoc
OH
BnO
O
OBn .
OBn
O
Boc
N
1. Pd(PPh3)4
morpholine
THF
O
BnO
OH
O
O
NBoc
O
67%
NH HN
O
O
2. LiOH (aq)
1,4-dioxane
Boc
N
O
O
OH
HO
O
HN
HN
NH
O
O
NH HN
3. DEBPT
NaHCO3
THF, 4 d
BnO
NH
O
OMe
O
Alloc
NH
HN
72% (2 steps)
O
O
BnO
NH HN
donor 12,
BF3·OEt2
(3.5 equiv)
CH2Cl2
15 R = H
O
62%
O
16 R = 4'-O-iVal-Bn6Man2
–30 °C
17
Scheme 4 Glycoslation of hexapeptide 15 and conversion into cyclopeptide 17
Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
31
analogues in which N-Boc-protected N,O-acetals serve as
surrogates for the cyclic guanidine portion of these unusu-
al amino acids.24 Gratifyingly, the structurally complex
peptide 15 could also be efficiently glycosylated to afford
16 in 62% yield (76% brsm) employing only a slight ex-
cess of trichloroacetimidate donor 12 (1.4 equiv). In com-
parison to previous reactions, it was imperative to raise
the amount of boron trifluoride to 3.5 equivalents, pre-
sumably because of the larger number of carbonyl groups
present in this acceptor, which might sequester some part
of the Lewis acid through coordination. Following this
successful glycosylation, the linear hexapeptide 16 could
be deprotected at the C-and N-termini and cyclized to
mannopeptimycin ε precursor cyclopeptide 17 by using 3-
(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
(DEPBT) for activation of the carboxylic acid.
A
BnO
OBn
O
O
BnO
BnO
OMe
O
sulfoxide 1
HN
Teoc- or
O
Boc-D-Tyr-OMe
Tf2O
O
O
BnO
BnO
BnO
(minor side product)
DTBP
CH2Cl2
–45 °C
18
OBn
B
O
sulfoxide 1
O
α-Man(Bn4)
R
R
t-BuO
N
Tf2O
DTBP
CH2Cl2
O
N
H
H
Glycosyl carbamates: Even after the successful identifi-
cation of generally applicable glycosylation conditions,
the question remained why the trimethylsilyl triflate acti-
vation of trichloroacetimidates and sulfoxide activation
with triflic anhydride, respectively, is incompatible with
carbamate groups when very reactive perbenzylated do-
nors are combined with less reactive phenolic acceptors.
In our model studies, the glycosylation products of carba-
mate-protected acceptors were only isolated in yields
below 50% for such combinations, and the only major ad-
ditional reaction products following workup were the
mannosyl lactol and the recovered acceptor. Other prod-
ucts of the glycosylation reaction remained elusive, e.g.
β-anomers or C-glycosides25 as possible alternate glycos-
ylation products, glycals resulting from elimination with-
in the activated donor,26 or phenol triflates as a result of
acceptor triflation. Therefore, the detection of an addition-
al product that was formed in small amounts during the
sulfoxide glycosylation of Boc- or Teoc-protected tyro-
sine methyl ester, the double glycosylation product 18
[Scheme 5 (A)], was extremely helpful for the interpreta-
tion of the observed reaction outcome. Obviously, in ad-
dition to the phenolic hydroxy group, the carbamate can
also react with the activated glycosyl donor, which, after
elimination of the tert-butyl or 2-(trimethylsilyl)ethyl
group, respectively, led to the formation of a glycosyl car-
bamate.
19, 22 and 23
O
O
OH
O
OMe
HN
HN
LiOH
1,4-dioxane
O
O
O
O
O
BnO
BnO
BnO
RO
RO
89%
OBn
OR
OR
19
R = Bn (75%)
64%
20
H2, Pd/C
MeOH
BnO
OBn
O
21
R = H
BnO
BnO
O
O
OMe
HN
O
N
O
O
O
O
BnO
BnO
BnO
H
N
FmocHN
OMe
O
OBn
Phe
23 (44%)
22 (79%)
Scheme 5 Identification of glycosyl carbamates as reaction products.
A: Side product 18 was identified by MS and 1H NMR of crude prod-
uct mixtures when Teoc-protected tyrosine acceptor was used and
was isolated in 25% yield for the glycosylation of Boc-protected ac-
ceptor. B: Glycosyl carbamates 19, 22, and 23 were isolated as main
products when Boc-containing compounds without any nucleophilic
hydroxy groups were reacted with sulfoxide 1 under Tf2O activation.
To further investigate these findings, we submitted Boc-
L-Phe-OMe to exactly the same glycosylation conditions
[Scheme 5 (B)]. This carbamate-protected amino acid is
missing a hydroxy group (alcohol or phenol) as a possible
glycosylation site, and was converted in good yields into
the carbamoyl-O-glycosylated product 19 [75% after op-
timization of the reaction conditions: donor 1 (1.8 equiv),
–25 °C, 18 h]. The presence of a glycosyl carbamate in 19
was unambiguously proven by a crystal structure (Figure
2),27 which also confirmed the α-linkage of the mannose
residue already assigned based on the 3J1,2 and 1JC,H cou-
pling constants28 (1.5 Hz and 177 Hz, respectively) in the
1H and HMBC spectra. Moreover, the fully protected 19
could be converted into the carboxylic acid 20 by treat-
ment with aqueous lithium hydroxide solution in 1,4-di-
oxane, thereby furnishing a potential coupling partner for
ligation to an amino group. We were also able to remove
the benzyl protecting groups of 19 by hydrogenation,
which led to carbamate 21 with an unprotected mannose
moiety.
To explore the scope of the reaction conditions, we tested
additional amino acid substrates. First, we could show that
carbamate-protected secondary amines are also glycosyl-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39

32
P. Schüler et al.
FEATURE ARTICLE
thoesters.35 In the latter cases, the formation of glycosyl
carbamates was also observed serendipitously as a by-
product of an attempted O-glycosylation of a Boc-protect-
ed amino acid acceptor. This outcome was proposed to
evolve through the intermediacy of a carbamic acid gen-
erated via acid-catalyzed removal of the tert-butyl group,
which subsequently serves as a glycosyl acceptor.35 Here,
we observed this alternate reaction pathway for the first
time under basic glycosylation conditions (sulfoxide acti-
vation with triflic anhydride in the presence of a pyridine
base), which should exclude the formation of carbamic
acids as reaction intermediates. Instead, the direct attack
of the activated donor at the carbamate carbonyl group is
most probably involved, which is then followed by elimi-
nation of the tert-butyl group. This reaction pathway is
similar to the conversion of Boc-carbamates into trialkyl-
silyl carbamates when treated with trialkylsilyl triflates.36
Following this reasoning, such an attack of the activated
glycosyl donor could also account for the three reaction
outcomes that were observed when tyrosine acceptors are
used. Firstly, in amide-protected derivatives, e.g. 3b, the
carbonyl oxygen of the amide group is much less nucleo-
philic than the phenolic group, whereas in azide 3c, a pos-
sible second glycosylation site is missing completely.
Accordingly, such acceptors are efficiently glycosylated
at the phenolic hydroxy group with a variety of highly re-
active glycosyl donors, e.g. 1 and 2, under different acti-
vation conditions. Secondly, in carbamate protected
acceptors, e.g. 3a, the carbonyl oxygen of the carbamate
group is only slightly less nucleophilic than the phenolic
hydroxy group. As a result, a significant part of such ac-
ceptors is glycosylated at the carbamate group instead of
the phenol when sulfoxide donors (Tf2O activation) and
trichloroacetimidate donors (TMSOTf activation) are
used, i.e. under conditions that generate glycosyl triflates.
In addition to the desired phenol glycoside 4a, this would
lead to intermediates of type A or their neutral elimination
products B (Scheme 6). These intermediates, which effec-
tively sequester the activated donor and prevent it from
further glycosylating the phenolic group, are then hydro-
lyzed during the aqueous workup, either to the original
carbamate (R = Cbz or Alloc) or towards glycosyl carba-
mates (R = t-Bu or Teoc), i.e. depending on the stability of
the cationic leaving groups liberated from the different
carbamate groups. This interpretation would explain the
Figure 2 The single crystal X-ray structure of glycocarbamate 1927
proves the α-configuration (O2) of the mannosyl carbamate. The ther-
mal ellipsoids correspond to 50% probability.
ated. In the event, mannosylation of Boc-protected L-pro-
line methyl ester with sulfoxide 1 led to glycosyl
carbamate 22 with similar efficiency (79%).29
Next, a chemoselective carbamate glycosylation was ex-
plored. In our model glycosylation reactions, glycosyl
carbamates could only be detected when Boc and Teoc
derivatives were used as acceptors. Because both groups
contain reasonably good cationic leaving groups [the tert-
butyl and 2-(trimethylsilyl)ethyl cation, respectively], we
reasoned that other carbamates, e.g. Fmoc, that contain
less-stabilized groups, could very well be tolerated. In-
deed, we found that a Fmoc- and Boc-containing dipep-
tide [Fmoc-L-Lys(NHBoc)-L-Phe-OMe] could be
converted into the monomannosyl carbamate 23, i.e. gly-
cosylation was only observed in the lysine side chain,
whereas the Fmoc group remained intact.30
Glycosyl carbamates have previously been prepared by
different methods, most notably by the reaction of lactols
with isocyanates,31 the reaction of amines with activated
sugar carbamates32 or carbonates,33 and by the acid-cata-
lyzed glycosylation of carbamate-protected amines with
either glycosyl trichloroacetimidates34 or glycosyl or-
O
O
lactol + starting
(R = Bn, All)
O
OMe
carbamate
OMe
– HX
+ HX
OMe
HN
O
N
O
R
A
R
aqueous
work-up
HN
O
B
R
O
O
carbamate
glycosylation
O
O
O
alcohol + glycosyl
carbamate
X
activated
glycosyl
donor
.
(R = t-Bu)
BnO
BnO
Scheme 6 Glycosylated carbamates of type A and their elimination products B could sequester the activated glycosyl donor. Upon hydrolysis,
the observed reaction mixtures are formed depending on the relative stability of the two possible leaving groups (R vs. sugar).
Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
33
carried out by fluorescence quenching under UV light (λ = 254 nm)
or by staining with 20% H2SO4 or ninhydrin soln followed by heat-
ing to ca. 300 °C. Flash chromatography was performed on silica
gel 60 (0.040–0.063 mm) from Merck KGaA. The petroleum ether
(PE) used was of the fraction boiling in the 40–60 °C range. NMR
spectra were recorded on Bruker AV 300, Bruker DRX 400, AV
500, DRX 500, and DRX 600 spectrometers at the NMR facilities,
Philipps-Universität Marburg referenced to the solvent residual sig-
nal. All coupling constants are JH,H couplings unless indicated oth-
erwise. All signals are described as they appear in the 1D 1H NMR
spectra, i.e. the actual multiplicitiy and not the expected one is given
and the coupling constants of each signal are actual values for each
signal and not averaged ones. Signals were assigned with the aid of
COSY, HMBC and HMQC spectra. Diastereotopic protons are la-
beled according to their chemical shifts: δa< δb. In the NMR data
listings, the β-hydroxyenduracididine precursor amino acids are ab-
breviated L- and D-Hep, respectively. HRMS (ESI) were acquired
with a LTQ-FT mass spectrometer (Thermo Fischer Scientific); the
resolution was set to 100.000. The optical rotation was measured on
a Perkin-Elmer 241 polarimeter.
low yields for the tyrosine glycosylation irrespective of
the type of carbamate group employed, as well as for for-
mation of the minor side product 18 only in cases where
reasonably good cationic leaving groups are present. So
far, we have never observed glycosyl carbamates in the re-
action mixture prior to aqueous workup, which also sup-
ports this view. Thirdly, and most importantly from a
synthetic point of view, the activation of trichloroacetimi-
dates with boron trifluoride is able to revert the reaction
outcome towards predominant phenol glycosylation, irre-
spective of the N-protecting group. The activated donor
that is formed in the presence of boron trifluoride prefer-
entially reacts at the phenolic hydroxy group, possibly be-
cause this species is less reactive than the corresponding
anomeric triflate generated by trimethylsilyl triflate acti-
vation. Further studies to provide additional experimental
data concerning this mechanistic proposal are currently
under way.
Model glycosylations were performed according to General Proce-
dure A or B. The acceptor phenols were prepared according to es-
tablished procedures. For the synthesis of tyrosine derivatives 3a
and 3b, D-Tyr-OMe was acylated with benzyl chloroformate or tri-
fluoroacetic anhydride, respectively. Azido-D-Tyr-OMe (3c) was
prepared from D-Tyr-OMe using imidazole-1-sulfonyl azide.19 The
perbenzylated sulfoxide 1 was prepared by MCPBA oxidation39 of
the corresponding phenyl thioglycoside.40 The known trichloroacet-
imidate donor 2 was synthesized from the corresponding lactol
(DBU, Cl3CCN), which in turn was obtained from the phenyl thio-
glycoside by treatment with NBS/H2O.40 Mannoside 9 was prepared
according to known procedures.21
Conclusion
The glycosylation of phenolic hydroxy groups is wide-
spread among natural products with interesting biological
activity. The chemical glycosylation of such rather unre-
active acceptors is still a challenge, because subtle chang-
es of reaction conditions can have a profound impact on
the efficiency of these transformations.
Experimental details for the synthesis of (2S,3S)-β-methylphenylal-
anine, dipeptide 13, and hexapeptide 15 and copies of NMR spectra
are given in the Supporting Information. Details of the synthesis of
tetrapeptide S8 (see Supporting Information for the structure) will
be described in a separate account.
During our synthetic studies, we found that carbamate
groups within the acceptor molecule have a negative im-
pact on the glycosylation yield when two of the most com-
mon glycosyl donors are used, namely glycosyl
trichloroacetimidates and sulfoxides. The diminished
yields were traced back to a sequestration of the activated
donor by the carbamate group, which in some cases led to
glycosyl carbamates as side products. We were able to de-
termine conditions that circumvent this problem, specifi-
cally the use of trichloroacetimidate donors that are
activated by boron trifluoride. This methodology allows
the efficient glycosylation of structurally complex pep-
tides that contain multiple carbamate groups with mono-
and disaccharide donors, thus highlighting the reliability
of the presented approach.37,38 These results are of impor-
tance for the glycosylation of phenolic acceptors in gener-
al and should be helpful for the proper choice of coupling
partners and protecting group patterns used in future total
synthesis efforts aimed at the generation of compounds
containing glycosylated phenols.
Mannosylation of Phenolic Acceptors with Sulfoxides; General
Procedure A
Sulfoxide 139,40 (1.5 equiv) and DTBP (3.0 equiv) were coevaporat-
ed with toluene (2 ×) and dissolved in CH2Cl2 (5 mL/mmol sulfox-
ide) under argon. After the addition of molecular sieves (4 Å), the
soln was stirred at r.t. (30 min). The soln was cooled to –70 °C and
Tf2O (1.5 equiv) was added. The mixture was stirred for 5 min at
–60 °C, a soln of the acceptor 3 (1 equiv) [previously coevaporated
with toluene (2 ×)] in CH2Cl2 (5 mL/mmol) was added, and the mix-
ture was stirred at –60 °C to –45 °C for 1 h. The reaction was
stopped by the addition of MeOH, diluted with CH2Cl2, and poured
into sat. aq NaHCO3–brine (1:1). The aqueous phase was extracted
with CH2Cl2 (3 ×) and the combined organic phases were dried
(MgSO4), filtered, and evaporated. Purification of the residue by
flash chromatography (PE–EtOAc, 2:1) gave the mannosylated
phenol 4.
Mannosylation of Phenolic Acceptors with Trichloroacetimi-
dates; General Procedure B
To a soln of 2,3,4,6-tetra-O-benzyl-mannose40 (1 equiv) and trichlo-
roacetonitrile (4.5 equiv) in CH2Cl2 (20 mL/mmol lactol) at 0 °C
was added DBU (0.3 equiv). After 30 min at this temperature, the
mixture was evaporated and purified directly by flash chromatogra-
phy (PE–EtOAc, 6:1 to 2:1), which gave trichloroacetimidate 2 as a
colorless oil (85–90%). To a soln of trichloroacetimidate 2 (1.5
equiv) and the acceptor 3 (1 equiv) in CH2Cl2 was added either
TMSOTf (0.8 equiv based on donor 2) at –20 °C or BF3·OEt2 (0.6
equiv based on donor 2) at –30 °C. The mixture was warmed to 0
°C over 1 h and the reaction was stopped by the addition of Et3N.
Evaporation of the mixture and purification of the residue by flash
chromatography (PE–EtOAc, 2:1) gave the mannosylated phenol 4.
In addition, the efficient and chemoselective generation of
glycosyl carbamates under basic conditions using glyco-
syl sulfoxides and Boc-protected amino acids developed
here nicely complements the known acid-mediated proto-
cols for the formation of these glycoconjugates.
All reactions were carried out under an argon atmosphere. All
chemicals were of reagent grade and were used as purchased. Sol-
vents were dried according to established procedures. TLC was per-
formed on silica gel 60 F254 plates (Merck KGaA). Detection was
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39

34
P. Schüler et al.
FEATURE ARTICLE
Benzyloxycarbonyl-D-Tyr-O-(2,3,4,6-tetra-O-benzyl-α-D-man-
nopyranosyl)-OMe (4a)
Mannoside 4a was prepared according to General Procedure A and
B and was obtained as a colorless oil; yields: see Scheme 1; Rf =
0.55 (PE–EtOAc, 2:1).
Phenyl 2,3,6-Tri-O-benzyl-4-O-isovaleroyl-1-thio-α-D-manno-
pyranoside S-Oxide (10)
Thioglycoside 921 (2.16 g, 3.98 mmol) and Et3N (2.49 mL,
17.8 mmol) were dissolved in CH2Cl2 (50 mL). Isovaleroyl chloride
(1.41 mL, 11.9 mmol) and DMAP (30 mg, cat.) were added at 0 °C
and the mixture was stirred for 6 h at 0 °C. The reaction was
quenched by the addition of MeOH (3 mL) and diluted with CH2Cl2
(100 mL). The mixture was washed with 2 M HCl (50 mL) and sat.
aq NaHCO3 (50 mL), and dried (MgSO4); the solvent was evaporat-
ed to afford the crude 4-O-isovaleoryl derivative (2.3 g).
2
3
1H NMR (300 MHz, DMSO-d6): δ = 2.80 (dd, J = 13.6, Jα,βa
=
10.0 Hz, 1 H, β-HaTyr), 2.97 (dd, 2J = 13.6, 3Jα,βb = 5.0 Hz, 1 H, β-
HbTyr), 3.52–3.75 (m, 3 H, H5, 2 H6), 3.61 (s, 3 H, OCH3), 3.87 (t,
3J3,4 = 3J4,5 = 9.2 Hz, 1 H, H4), 3.98 (dd, 3J2,3 = 2.9, 3J3,4 = 9.3 Hz, 1
3
3
H, H3), 4.09 (dd, J1,2 = 2.1, J2,3 = 3.0 Hz, 1 H, H2), 4.19 (ddd,
3Jα,βt = 5.2, 3Jα,NH = 7.9, 3Jα,βh = 10.2 Hz, 1 H, α-HTyr), 4.35–4.81 (m,
8 H, 4 CH2Bn), 4.95 and 5.00 (2 d, 2J = 12.6 Hz, each 1 H, CH2Cbz),
The crude 4-O-isovaleoryl derivative was dissolved in CH2Cl2
(250 mL) and was subsequently treated dropwise with a soln of
MCPBA (70–75%, 1.03 g, 4.2–4.5 mmol) in CH2Cl2 (100 mL) at
–70 °C. The mixture was slowly warmed to –20 °C over a period of
6 h, and then sat. aq NaHCO3 (100 mL) was added. After the addi-
tion of brine (300 mL), the phases were separated, the aqueous
phase was extracted with CH2Cl2 (2 × 200 mL), and the combined
organic phases were dried (MgSO4) and evaporated. Purification of
the residue by flash chromatography (PE–EtOAc, 4:1) afforded the
sulfoxide 10 (3.08 g, 76% over 2 steps) as a colorless amorphous
powder; Rf = 0.35 (PE–EtOAc, 4:1).
5.69 (d, J1,2 = 1.9 Hz, 1 H, H1), 6.93–7.04 (m, 2 H, o-HaromTyr),
3
7.11–7.47 (m, 27 H, Harom), 7.82 (d, 3Jα,NH = 8.2 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 37.4 (C-βTyr), 52.3 (OCH3), 55.6
(C-αTyr), 65.4 (CH2Cbz), 68.8 (C6), 70.8, 71.9 (CH2Bn), 72.0 (C5),
72.2, 74.1 (3 CH2Bn), 74.2 (C2), 74.3 (C4), 79.4 (C3), 96.5 (C1),
116.7, 121.1, 127.4, 127.6, 127.6, 127.7, 127.8, 127.9, 127.9, 128.1,
128.2, 128.2, 128.3, 128.4, 128.5, 128.7, 130.3 (CHarom), 138.2,
138.3, 138.5, 139.5 (Carom), 150.4, 155.0 (CaromTyr, C=OCbz), 169.6
(COOMe).
3
1H NMR (300 MHz, CDCl3): δ = 0.89 and 0.90 (2 d, J = 6.3 Hz,
HRMS (ESI): m/z [M + Na]+ calcd for C52H53NNaO10: 874.3567;
found: 874.3579.
each 3 H, 2 CH3iVal), 1.98–2.12 (m, 3 H, CH2iVal, CHiVal), 3.48–3.62
(m, 2 H, 2 H6), 4.22 (dd, 3J2,3 = 3.0, 3J3,4 = 9.5 Hz, 1 H, H3), 4.23–
4.32 (m, 1 H, H5), 4.33–4.36 (m, 1 H, H2), 4.42–4.56 (m, 6 H, 3
Trifluoroacetyl-D-Tyr-O-(2,3,4,6-tetra-O-benzyl-α-D-manno-
pyranosyl)-OMe (4b)
CH2Bn), 4.58 (d, J1,2 = 2.1 Hz, 1 H, H1), 5.39 (t, J3,4 = J4,5
=
3
3
3
Mannoside 4b was prepared according to General Procedure A and
B and was obtained as a colorless oil; yields: see Scheme 1; Rf =
0.50 (PE–EtOAc, 2:1).
1H NMR (300 MHz, DMSO-d6): δ= 2.96 (dd, 2J = 13.8, 3Jα,βa = 10.6
Hz, 1 H, β-HaTyr), 3.14 (dd, 2J = 13.9, 3Jα,βb = 4.9 Hz, 1 H, β-HbTyr),
3.48–3.57 (m, 1 H, H6a), 3.60–3.71 (m, 5 H, H5, H6b, OCH3), 3.87
(t, 3J3,4 = 3J4,5 = 9.2 Hz, 1 H, H4), 3.98 (dd, 3J2,3 = 3.0, 3J3,4 = 9.2 Hz,
1 H, H3), 4.08–4.13 (m, 1 H, H2), 4.31–4.84 (m, 9 H, 4 CH2Bn, α-
HTyr), 5.72 (d, 3J1,2 = 1.6 Hz, 1 H, H1), 7.01–7.44 (m, 24 H, Harom),
9.92 (d, 3Jα,NH = 8.0 Hz, 1 H, NH).
9.5 Hz, 1 H, H4), 7.12–7.24 (m, 5 H, CHarom), 7.27–7.50 (m, 13 H,
CHarom), 7.54–7.59 (m, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): δ = 22.4 (2 CH3iVal), 25.5 (CHiVal), 43.3
(CH2iVal), 67.6 (C4), 70.0 (C6), 71.0 (C2), 72.6, 72.6, 73.5 (3
CH2Bn), 76.5 (C5), 76.6 (C3), 95.8 (C1), 124.3, 127.7, 127.8, 128.0,
128.3, 128.3, 129.2, 131.2 (CHarom), 137.4, 137.8, 137.9, 141.6
(Carom), 171.9 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C38H42NaO7S: 665.2543;
found: 665.2561.
13C NMR (75 MHz, DMSO-d6): δ= 34.8 (C-βTyr), 52.4 (OCH3), 54.1
(C-αTyr), 68.7 (C6), 70.8, 71.9 (2 CH2Bn), 72.0 (C5), 72.2, 74.1 (2
CH2Bn), 74.1 (C2), 74.2 (C4), 78.9 (C3), 95.6 (C1), 116.7, 127.3,
127.4, 127.5, 127.5, 127.6, 127.7, 127.7, 128.1, 128.2, 128.2, 130.1
(CHarom), 130.5, 138.2, 138.4, 138.5 (Carom), 154.5 (OCarom), 156.3
(q, 3JC,F = 36.8 Hz, C=OTFA), 170.4 (COOMe).
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2′,3′,6′-tri-O-benzyl-4′-O-iso-
valeroyl-α-D-mannopyranosyl)-1-thio-α-D-mannopyranoside
(11)
Acceptor 9 (422 mg, 0.78 mmol, 1.0 equiv), DTBP (0.52 mL,
2.33 mmol, 3.0 equiv), and 4-allyl-1,2-dimethoxybenzene
(0.32 mL, 1.87 mmol, 2.4 equiv) were coevaporated with toluene (2
× 10 mL). The residue was dissolved in CH2Cl2 (10 mL), molecular
sieves (4 Å) were added, and the resulting mixture was stirred at r.t.
for 30 min under argon. The mixture was cooled to –70 °C and then
Tf2O (0.16 mL, 0.93 mmol, 1.2 equiv) was added dropwise, fol-
lowed by a soln of sulfoxide 10 (600 mg, 0.93 mmol, 1.2 equiv) in
CH2Cl2 (4 mL). The mixture was slowly warmed to –25 °C over 1
h, quenched with Et2NH (0.4 mL), diluted with CH2Cl2 (100 mL),
and poured into sat. aq NaHCO3–brine–H2O (1:1:2, 100 mL). The
aqueous phase was extracted with CH2Cl2 (2 × 50 mL) and the com-
bined organic phases were dried (MgSO4) and evaporated. Purifica-
tion of the residue by flash chromatography (PE–EtOAc, 10:1, 8:1,
6:1) afforded disaccharide 11 (427 mg, 52%) as a colorless syrup;
Rf = 0.45 (PE–EtOAc, 4:1).
HRMS (ESI): m/z [M + Na]+ calcd for C46H46F3NNaO9: 836.3022;
found: 836.3020.
Azido-D-Tyr-O-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)-
OMe (4c)
Mannoside 4c was prepared according to General Procedure A and
B and was obtained as a colorless oil; yields: see Scheme 1; Rf =
0.45 (PE–EtOAc, 4:1).
2
3
1H NMR (300 MHz, acetone-d6): δ = 2.96 (dd, J = 14.1, Jα,βa
=
8.5 Hz, 1 H, β-HaTyr), 3.12 (dd, J = 14.1, Jα,βb = 5.4 Hz, 1 H,
β-HbTyr), 3.62–3.88 (m, 3 H, H5, 2 H6), 3.74 (s, 3 H, OCH3), 4.09 (t,
3J3,4 = 3J4,5 = 9.2 Hz, 1 H, H4), 4.09 (dd, 3J2,3 = 2.9, 3J3,4 = 9.3 Hz, 1
2
3
3
3
H, H3), 4.17 (dd, J1,2 = 2.1, J2,3 = 3.0 Hz, 1 H, H2), 4.29 (dd,
3
1H NMR (500 MHz, CDCl3): δ = 0.87 and 0.88 (2d, J = 6.6 Hz,
3Jα,βb = 5.4, Jα,βa = 8.5 Hz, 1 H, α-HTyr), 4.46–4.98 (m, 8 H, 4
3
each 3 H, 2 CH3iVal), 1.97–2.10 (m, 3 H, CHiVal, CH2iVal), 3.47 (dd,
CH2Bn), 5.69 (d, 3J1,2 = 1.9 Hz, 1 H, H1), 7.04–7.11 (m, 2 H, CHarom),
3
2J = 10.6, J5′,6a′ = 2.8 Hz, 1 H, H6′a), 3.53 (dd, 2J = 10.6,
7.16–7.39 (m, 22 H, CHarom).
3J5′,6b′ = 6.2 Hz, 1 H, H6′b), 3.72 (dd, 3J1′,2′ = 2.5, 3J2′,3′ = 2.8 Hz, 1 H,
13C NMR (75 MHz, CDCl3): δ = 37.2 (C-βTyr), 52.8 (OCH3), 63.8
(C-αTyr), 70.3 (C6), 72.5, 73.5, 73.7 (3 CH2Bn), 73.7 (C5), 75.4
(CH2Bn), 75.7 (C4), 76.1 (C2), 80.8 (C3), 97.7 (C1), 116.7 (o-
CHaromTyr), 127.3, 127.4, 127.5, 127.5, 127.6, 127.7, 127.7, 128.1,
128.2, 128.2, 130.1 (CHarom), 130.5, 138.2, 138.4, 138.5 (Carom),
154.5 (OCarom), 170.4 (COOMe).
3
3
H2′), 3.73 (dd, J2,3 = 2.9, J3,4 = 9.2 Hz, 1 H, H3), 3.83 (dd,
3J2′,3 = 2.9, J3′,4′ = 9.6 Hz, 1 H, H3′), 3.83 (dd, 2J = 10.8,
3
3J5,6a = 6.9 Hz, 1 H, H6a), 3.93 (ddd, J5′,6′a = 2.7, J5′,6′b = 6.2,
3
3
3J4′,5′ = 9.7 Hz, 1 H, H5′), 3.96 (dd, 2J = 11.1, J5,6b = 1.9 Hz, 1 H,
3
3
3
3
H6b), 4.00 (dd, J1,2 = 2.0, J2,3 = 3.1 Hz, 1 H, H2), 4.12 (t, J3,4
=
3J4,5 = 9.3 Hz, 1 H, H4), 4.28–4.36 (m, 5 H, H5, 2 CH2Bn), 4.45–4.70
(m, 8 H, 4 CH2Bn), 5.31 (d, J1′,2′ = 2.2 Hz, 1 H, H1′), 5.37 (dd,
3
HRMS (ESI): m/z [M + Na]+ calcd for C44H45N3NaO8: 766.3104;
found: 766.3115.
3J3′,4′ = 9.7, J4′,5′ = 9.8 Hz, 1 H, H4′), 5.61 (d, J1,2 = 1.9 Hz, 1 H,
3
3
H1), 7.15–7.56 (m, 35 H, CHarom).
Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
35
13C NMR (126 MHz, CDCl3): δ = 22.6 (2 CH3iVal), 25.6 (CHiVal),
43.6 (CH2iVal), 68.7 (C4′), 70.3 (C6′), 70.5 (C5′, C6), 71.2 (CH2Bn),
71.8 (C3′), 71.9, 72.3 (2 CH2Bn), 72.5 (C5), 73.1, 73.2, 73.7 (3
CH2Bn), 75.4, 75.4, 75.5 (C2, C4, C2′), 77.0 (C3′), 80.1 (C3), 85.6
(C1), 100.4 (C1′), 127.3, 127.5, 127.5, 127.6, 127.6, 127.6, 127.8,
127.9, 127.9, 128.1, 128.2, 128.3, 128.4, 128.4, 128.5, 128.7, 129.2,
132.2 (CHarom), 134.2, 137.9, 137.9, 138.4, 138.6, 138.6, 138.9
(Carom), 172.0 (C=OiVal).
1H NMR (500 MHz, acetone-d6): δ = 0.86, 0.88 (2 d, J = 6.7 Hz,
3
each 3 H, 2 CH3iVal), 1.14 (d, Jβ,Me = 7.1 Hz, 3 H, CH3mePhe), 1.98
3
(septet, 3J = 6.7 Hz, 1 H, CHiVal), 2.08–2.12 (m, 2 H, CH2iVal), 2.97
(dd, J = 14.0, 3Jα,βa = 9.2 Hz, 1 H, β-HaTyr), 3.09–3.17 (m, 1 H, β-
2
HmePhe), 3.16 (dd, 2J = 14.2, 3Jα,βb = 5.2 Hz, 1 H, β-HbTyr), 3.41–3.48
(m, 2 H, H6′), 3.62–3.71 (m, 2 H, H6), 3.66 (s, 3 H, OCH3), 3.79 (m,
1 H, H5), 3.87 (dd, 3J2′,3′ = 2.9, 3J3′,4′ = 9.8 Hz, 1 H, H3′), 3.90 (m, 1
3
3
H, H5′), 3.94 (dd, J1′,2′ = 2.1, J2′,3′ = 3.1 Hz, 1 H, H2′), 4.10 (dd,
3
3
3J2,3 = 3.1, J3,4 = 9.2 Hz,
1
H, H3), 4.19 (dd, J1,2 = 2.4,
HRMS (ESI): m/z [M + Na]+ calcd for C65H70NaO11S: 1081.4537;
found: 1081.4556.
3
3J2,3 = 3.1 Hz, 1 H, H2), 4.25 (t, J3,4 = 3J4,5 = 9.4 Hz, 1 H, H4),
4.30–4.80 (m, 14 H, 6 × CH2Bn, CH2All), 4.32–4.38 (m, 1 H, α-
HmePhe), 4.64–4.75 (m, 1 H, α-HTyr), 5.05–5.11, 5.13–5.20 (2 m,
each 1 H, =CH2All), 5.38 (t, 3J3′,4′ = 3J4′,5′ = 9.9 Hz, 1 H, H4′), 5.40 (d,
(2,3,6-Tri-O-benzyl-4-O-chloroacetyl-α-D-mannopyranosyl)-
(1→4)-2,3,6-tri-O-benzyl-α-D-mannopyranosyl Trichloroacet-
imidate (12)
3
3J1′,2′ = 1.7 Hz, 1 H, H1′), 5.69 (d, J1,2 = 1.7 Hz, 1 H, H1), 5.77–
3
5.86 (m, 1 H, =CHAll), 5.92 (br d, Jα,NH = 8.9 Hz, 1 H, NHmePhe),
Thioglycoside 11 (620 mg, 0.58 mmol) was dissolved in acetone–
H2O (19:1, 12 mL) and cooled to 0 °C. After the addition of NBS
(313 mg, 1.76 mmol, 3 equiv), the mixture was stirred for 30 min at
0 °C. The reaction was stopped by the addition of 10% aq Na2S2O3
soln (1 mL), diluted with EtOAc (150 mL), and washed with sat. aq
NaHCO3 soln–brine (1:1, 50 mL). The organic phase was dried
(MgSO4), evaporated, and the residue was purified by flash chroma-
tography (PE–EtOAc, 3:1, 2:1) to afford the corresponding lactol
(460 mg, 81%) as a colorless solid; Rf = 0.45 (PE–EtOAc, 4:1).
1H NMR (500 MHz, DMSO-d6): δ= 0.81 and 0.82 (2 d, 3J = 6.6 Hz,
each 3 H, 2 CH3iVal), 1.88 (septet, 3J = 6.7 Hz, 1 H, CHiVal), 2.06 (d,
3J = 6.9 Hz, 2 H, CH2iVal), 3.28 (dd, 2J = 10.9, 3J5′,6′a = 2.8 Hz, 1 H,
H6′a), 3.30–3.33 (m, 1 H, H6′b), 3.62 (dd, 2J = 10.8, 3J5,6a = 5.0 Hz,
1 H, H6a), 3.67 (dd, 2J = 10.7, 3J5,6b = 1.8 Hz, 1 H, H6b), 3.72 (dd,
6.96–7.51 (m, 39 H, Harom), 7.66 (br d, 3Jα,NH = 8.4 Hz, 1 H, NHTyr).
13C NMR (126 MHz, acetone-d6): δ = 19.1 (CH3mePhe), 22.7 (2
CH3iVal), 26.1 (CHiVal), 37.6 (C-βTyr), 42.9 (C-βmePhe), 43.9 (CH2iVal),
52.3 (OCH3), 54.8 (C-αTyr), 60.7 (C-αmePhe), 65.7 (OCH2All), 69.1
(C4′), 70.6 (C6), 70.9 (C6′), 71.7, 72.1 (2 × CH2Bn), 72.2 (C5′), 73.0
(CH2Bn), 73.1 (C5), 73.3, 73.5, 73.9 (4 × CH2Bn), 75.0 (C4), 75.0
(C2), 76.4 (C2′), 78.0 (C3′), 80.7 (C3), 97.3 (C1′), 100.7 (C1), 117.1
(=CH2All), 117.8 (2 m-CHaromTyr), 127.4, 128.0, 128.1, 128.1, 128.2,
128.2, 128.3, 128.3, 128.4, 128.5, 128.5, 128.6, 128.6, 128.6, 128.7,
128.8, 128.9, 128.9, 129.0, 129.0, 129.0, 129.1, 129.2, 129.3, 131.3,
131.3 (CHarom), 131.3 (o-CHaromTyr), 131.9 (i-CaromTyr), 134.3
(=CHAll), 139.4, 139.6, 139.6, 139.6, 139.8, 139.9, 143.4 (i-Carom),
156.5 (p-CaromTyr, C=Ocarbamate), 171.7 (C=Oamide), 172.1 (C=OiVal),
172.5 (COOMe).
3
3
3J2′,3′ = 2.9, J3′,4′ = 9.8 Hz, 1 H, H3′), 3.75 (ddd, J5′,6′a = 3.1,
3
3
3J5′,6′b = 4.6, J4′,5′ = 10.0 Hz, 1 H, H5′), 3.84 (dd, J1′,2′ = 2.2,
3J2′,3′ = 2.9 Hz, 1 H, H2′), 3.85–3.90 (m, 3 H, H5, H2, H3), 3.93 (dd,
3J3,4 = 9.2, 3J4,5 = 9.5 Hz, 1 H, H4), 4.18–4.65 (m, 12 H, 6 CH2Bn),
5.17 (dd, 3J1,2 = 2.2, 3J1,OH = 4.1 Hz, 1 H, H1), 5.19 (dd, 3J3′,4′ = 9.9,
HRMS (ESI): m/z [M + H]+ calcd for C83H93N2O17: 1389.6474;
found: 1389.6472.
Dimannosylated Linear Hexapeptide 16
3J4′,5′ = 10.0 Hz, 1 H, H4′), 5.30 (d, J1′,2′ = 1.9 Hz, 1 H, H1′), 6.73
3
Trichloroacetimidate 12 (160 mg, 144 μmol, 1.4 equiv) and linear
hexapeptide 15 (126 mg, 101 μmol, 1 equiv) were dissolved in
CH2Cl2 (1.5 mL) and cooled to –30 °C. BF3·OEt2 (62 μL, 504 μmol,
3.5 equiv based on donor 12) was added dropwise, and the reaction
was stirred at this temperature for 40 min. The reaction was stopped
by the addition of Et3N (0.2 mL), and the mixture was diluted with
CH2Cl2 (30 mL) and washed with sat. aq NH4Cl–H2O (1:1, 15 mL)
and sat. aq NaHCO3 (15 mL). The organic phase was dried
(MgSO4) and evaporated, and the residue was purified by flash
chromatography (CH2Cl2–MeOH, 60:1, 40:1, 20:1). This afforded
unreacted acceptor 15 (23 mg, 18%) and the glycosylated hexapep-
tide 16 (137 mg, 62%) as a colorless solid; Rf = 0.50 (CH2Cl2–
MeOH, 20:1).
(d, 3J1,OH = 4.3 Hz, 1 H, 1-OH), 7.08–7.38 (m, 30 H, CHarom).
13C NMR (126 MHz, 300 K, DMSO-d6): δ= 22.0, 22.0 (2 CH3iVal),
24.9 (CHiVal), 42.6 (CH2iVal), 67.4 (C4′), 68.9 (C6′), 69.9 (C6), 70.0
(CH2Bn), 70.0 (C5), 70.5 (C5′), 70.5, 71.5, 71.6, 72.2, 72.4 (5
CH2Bn), 73.6 (C4), 74.6 (C2), 74.8 (C2′), 76.4 (C3′), 79.4 (C3), 90.9
(C1), 98.7 (C1′), 127.0, 127.2, 127.3, 127.3, 127.3, 127.3, 127.4,
127.4, 127.4, 127.5, 127.5, 128.0, 128.1, 128.1, 128.1, 128.1, 128.2
(CHarom), 138.1, 138.2, 138.3, 138.3, 138.4, 138.7 (Carom), 171.1
(C=OiVal).
HRMS (ESI): m/z [M + Na]+ calcd for C59H66NaO12: 989.4452;
found: 989.4431.
The lactol (110 mg, 114 μmol) and trichloroacetonitrile (51 μL,
512 μmol, 4.5 equiv) were dissolved in CH2Cl2 (2 mL) under an at-
mosphere of argon. At 0 °C, DBU (5 μL, 34 μmol, 0.3 equiv) was
added. After stirring for 30 min, the solvent was evaporated and the
crude product was purified by flash chromatography (PE–EtOAc,
6:1, 4:1) to afford trichloroacetimidate 12 (100 mg, 79%) as a col-
orless oil, which was used directly in the glycosylation reactions;
Rf = 0.48 (PE–EtOAc, 4:1).
[α]D22 +33.1 (c 1.0, CHCl3).
1H NMR (500 MHz, 350 K, DMSO-d6): δ = 0.84, 0.85 (2 d, 3J = 6.6
Hz, each 3 H, 2 CH3iVal), 0.92 (d, Jβ,Me = 7.1 Hz, 3 H, CH3mePhe),
3
1.38 (br s, 3 H, CH3i-Pr), 1.42 (br s, 9 H, CH3Boc), 1.44 (br s, 12 H,
CH3i-Pr, CH3Boc), 1.49 (br s, 3 H, CH3i-Pr), 1.51 (br s, 3 H, CH3i-Pr),
3
3
1.91 (septet, J = 6.6 Hz, 1 H, CHiVal), 2.07 (d, J = 6.8 Hz, 2 H,
CH2iVal), 2.79 (dd, 2J = 14.0, 3Jα,βa = 9.7 Hz, 1 H, β-HaTyr), 2.90 (dq,
3Jβ,Me = 6.8, 3Jα,β = 7.5 Hz, 1 H, β-HmePhe), 3.11 (dd, 2J = 14.1, 3Jα,βb
=
HRMS (ESI): m/z [M + Na]+ calcd for C61H66Cl3NNaO12:
1132.3543; found: 1132.3522 (correct isotope pattern).
4.3 Hz, 1 H, β-HbTyr), 3.28–3.44 (m, 2 H, H6a, H6′a), 3.51–3.60 (m,
2 H, H6b, H6′b), 3.61 (s, 3 H, OCH3), 3.67–3.72 (m, 2 H, β-H2Ser),
3.71–3.75 (m, 1 H, H5), 3.75–3.80 (m, 3 H, H3′, H5′, δ-HaL-Hep),
Alloc-L-(3S)-βmePhe-D-Tyr-{O-[2,3,6-tri-O-benzyl-4-O-
(2′,3′,6′-tri-O-benzyl-4′-O-isovaleroyl-α-D-mannopyranosyl)-α-
D-mannopyranosyl]}-OMe (14)
3.82–3.87 (m, 2 H, H2′, δ-HaD-Hep), 3.87–3.94 (m, 4 H, γ-HaD-Hep, γ-
HaL-Hep, CH2Gly), 3.97–4.03 (m, 2 H, H3, β-HL-Hep), 4.08 (t, J3,4
=
3
3J4,5 = 9.4 Hz, 1 H, H4), 4.10 (dd, 3J1,2 = 2.4, 3J2,3 = 3.0 Hz, 1 H, H2),
Trichloroacetimidate 12 (100 mg, 90 μmol, 1.3 equiv) and dipeptide
13 (30 mg, 68 μmol, 1 equiv) were dissolved in CH2Cl2 (2 mL). The
mixture was cooled to –30 °C and BF3·OEt2 (7 μL, 54 μmol, 0.6
equiv based on donor 12) was added. After 1 h at this temperature,
the reaction was quenched by the addition of Et3N (0.2 mL) and pu-
rified directly by flash chromatography (PE–EtOAc, 2:1) to afford
the dimannosyl dipeptide 14 (57 mg, 60%) as a colorless amorphous
solid; Rf = 0.20 (PE–EtOAc, 2:1).
4.09–4.13 (m, 2 H, δ-HbD-Hep, δ-HbL-Hep), 4.22 (t, 3J = 9.0 Hz, 1 H, α-
HmePhe), 4.25–4.30 (m, 1 H, β-HD-Hep), 4.26–4.52 (m, 13 H, OCH2
,
All
5.5 OCH2Bn), 4.33–4.37 (m, 1 H, α-HD-Hep), 4.45–4.48 (m, 1 H, α-
H
L-Hep), 4.59 (ddd, 3Jα,βa = 5.7, 3Jα,NH = 7.5, 3Jα,βb = 8.0 Hz, 1 H, α-
HSer), 4.63–4.75 (m, 4 H, 1.5 OCH2Bn, α-HTyr), 4.89 (br d, 3J = 5.7
Hz, 1 H, OHL-Hep), 4.91 (br s, 1 H, OHD-Hep), 5.04–5.16 (m, 2 H,
=CH2All), 5.21 (t, 3J3′,4′ = 3J4′,5′ = 9.8 Hz, 1 H, H4′), 5.29 (d, 3J1′,2′
=
2.2 Hz, 1 H, H1′), 5.60 (d, 3J1,2 = 2.2 Hz, 1 H, H1), 5.73–5.79 (m, 1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39

36
P. Schüler et al.
FEATURE ARTICLE
H, =CHAll), 6.42 (br s, 1 H, NHmePhe), 6.97–7.40 (m, 44 H, Harom),
3J3,4 = 9.0 Hz, 1 H, H3), 4.07–4.14 (m, 4 H, δ-HbD-Hep, δ-HbL-Hep, H2,
H4), 4.25 (br t, 3J = 6.6 Hz, 1 H, β -HD-Hep), 4.28, 4.34 (2 d, each 1
H, OCH2Bn), 4.34–4.41 (m, 1 H, α-HmePhe), 4.26–4.49 (m, 7 H, 3.5
OCH2Bn), 4.49–4.59 (m, 2 H, α-HL-Hep, α-HSer), 4.51, 4.54, 4.69, 4.70
3
7.98 (br s, 1 H, NHSer), 7.99 (br d, Jα,NH = 7.2 Hz, 1 H, NHL-Hep),
8.13 (br t, 3JCH2α,NH = 6.4 Hz, 1 H, NHGly), 8.16 (br s, 1 H, NHD-Hep),
8.19 (br d, 3J = 6.7 Hz, 1 H, NHTyr).
(3 d and 1 s, 5 H, 2.5 OCH2Bn), 4.65–4.78 (m, 3 H, α-HTyr, OHD-Hep
,
=
13C NMR: (126 MHz, 350 K, DMSO-d6): δ = 18.3 (CH3mePhe), 21.6
(2 CH3iVal), 24.1 (2 CH3i-Pr), 24.5 (CHiVal), 26.1 (2 CH3i-Pr), 27.7
(CH3Boc), 27.8 (CH3Boc), 36.6 (C-βTyr), 40.5 (CH2Gly), 41.2 (C-
βmePhe), 42.4 (CH2iVal), 51.1 (OCH3), 52.6 (C-αSer), 54.0 (C-αTyr),
54.9 (C-αL-Hep), 56.6 (C-αD-Hep), 58.1, 58.4 (C-γD-Hep, C-γL-Hep), 59.6
(C-αmePhe), 62.4 (C-δD-Hep), 62.5 (C-δL-Hep), 64.1 (OCH2Allyl), 67.5
(C4′), 69.0 (2 C, C6, C6′), 69.4 (C-βSer), 69.4 (C-βD-Hep), 70.2
(CH2Ph, C-βL-Hep), 70.4 (CH2Ph), 70.5 (C5), 71.4, 71.4, 71.6, 71.9
(CH2Ph), 72.5 (C4), 73.6 (C2), 74.9 (C2′), 76.2 (C5′, C3′), 78.7
(C3), 79.0, 79.1 (CqBoc), 92.7, 92.9 (Cqi-Pr), 95.9 (C1′), 98.6 (C1),
116.4 (=CH2All), 116.4, 125.7, 126.7, 126.7, 126.8, 126.8, 126.9,
126.9, 127.0, 127.1, 127.1, 127.2, 127.2, 127.4, 127.6, 127.6, 127.7,
127.7, 129.7, 127.8, 131.4 (CHarom, Carom), 132.9 (=CHAll), 137.8,
137.9, 137.9, 137.9, 138.0, 138.1, 142.6 (Carom), 151.3, 151.4
(C=OBoc), 154.2 (C=OAlloc), 154.4 (p-CaromTyr), 169.3 (COOMe),
169.4, 170.3, 170.4 (C=Oamide), 170.6 (C=OiVal).
OHL-Hep), 5.20 (t, 3J3′,4′ = 3J4′,5′ = 9.6 Hz, 1 H, H4′), 5.29 (d, 3J1′,2′
2.0 Hz, 1 H, H1′), 5.56 (d, 3J1,2 = 2.1 Hz, 1 H, H1), 7.00–7.40 (m,
45 H, Harom, NHL-Hep), 7.76 (br s, 1 H, NHmePhe), 7.83 (br s, 1 H, NH-
Gly), 8.26 (br s, 1 H, NHSer), 8.42 (br d, 3J = 8.4 Hz, 1 H, NHTyr), 8.58
(br s, 1 H, NHD-Hep).
13C NMR: (126 MHz, 350 K, DMSO-d6): δ = 18.0 (CH3mePhe), 21.3
(2 CH3iVal), 23.5, 23.7 (2 CH3i-Pr), 23.9 (CHiVal), 25.3, 25.6 (2
CH3i-Pr), 27.4 (CH3Boc), 27.5 (CH3Boc), 34.6 (C-βTyr), 39.7 (C-βmePhe),
40.8 (CH2Gly), 42.0 (CH2iVal), 51.2 (C-αSer), 53.1 (C-αTyr), 54.1 (C-
α
L-Hep), 56.7 (C-αmePhe), 57.4 (C-αD-Hep), 57.8 (C-γD-Hep, C-γL-Hep),
62.0 (C-δD-Hep), 62.5 (C-δL-Hep), 67.2 (C4′), 68.0 (C-βL-Hep), 68.5 (C-
βSer), 68.6 (C6, C6′), 69.8, 70.1 (CH2Ph), 70.3 (C-βD-Hep), 70.4 (C5),
71.2 (C5′), 71.3, 71.4, 71.6, 71.8, 71.9 (CH2Ph), 72.8 (C4), 73.1
(C2), 74.3 (C2′), 75.8 (C3′), 78.5 (C3), 78.2, 79.2 (CqBoc), 92.4, 92.7
(Cqi-Pr), 95.7 (C1′), 98.3 (C1), 116.1, 125.5–142.7 (Carom), 154.3 (p-
CaromTyr), 170.5 (C=OiVal).
HRMS (ESI): m/z [M + Na]+ calcd for C121H150N8NaO30:
2219.0389; found: 2219.0402.
HRMS (ESI): m/z [M + H]+ calcd for C116H143N8O27: 2081.0096;
found: 2081.0107.
Dimannosyl Cyclopeptide 17
To a soln of linear hexapeptide 16 (81 mg, 37 μmol, 1 equiv) in THF
(degassed, 0.5 mL) was added morpholine (16 μL, 184 μmol, 5
equiv) and Pd(PPh3)4 (9 mg, 8 μmol, 0.2 equiv), and the mixture
was stirred for 30 min at r.t. After evaporation of the solvent, the
residue was directly purified by flash chromatography (CH2Cl2–
MeOH, 40:1, 20:1, 10:1), which afforded the corresponding termi-
nal amine (52 mg, 67%) as an amorphous solid; Rf = 0.30 (CH2Cl2–
MeOH, 20:1).
Methyl N-(2,3,4,6-Tetra-O-benzyl-α-D-mannopyranosyloxycar-
bonyl)-L-phenylalaninate (19)
Sulfoxide 1 (259 mg, 0.4 mmol, 1.8 equiv) and DTBP (0.15 mL,
0.69 mmol, 3.1 equiv) were coevaporated with toluene (2 × 5 mL).
The residue was dissolved in CH2Cl2 (2 mL), molecular sieves (4 Å)
were added, and the resulting mixture was stirred at r.t. for 30 min
under argon. After cooling the mixture to –70 °C, Tf2O (52 μL,
0.31 mmol, 1.4 equiv) was added dropwise, followed by a soln of
Boc-L-Phe-OMe (56 mg, 0.22 mmol, 1 equiv) in CH2Cl2 (1 mL).
After stirring for 18 h at –25 °C, the reaction was quenched by the
addition of MeOH (0.1 mL), diluted with CH2Cl2 (30 mL), and
poured into a mixture of sat. aq NaHCO3–brine (1:1, 30 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 20 mL) and the com-
bined organic phases were dried (MgSO4) and evaporated. Purifica-
tion of the residue by flash chromatography (PE–EtOAc, 4:1)
afforded glycocarbamate 19 (124 mg, 75%) as a colorless solid.
Crystallization of an analytical sample (PE–THF–Et2O) gave crys-
tals suitable for X-ray analysis.27 Rf = 0.20 (PE–EtOAc, 4:1).
HRMS (ESI): m/z [M + H]+ calcd for C117H147N8O28: 2113.0358;
found: 2113.0375.
The amine (52 mg, 25 μmol) was dissolved in 1,4-dioxane (0.5 mL)
and treated with aq 1 M LiOH (50 μL, 50 μmol, 2 equiv) at 8 °C.
After stirring for 90 min, the reaction was stopped by the addition
of 2 M HCl (38 μL, 75 μmol, 3 equiv), and the solvents were re-
moved under reduced pressure to afford the N- and C-terminally de-
protected hexapeptide.
HRMS (ESI): m/z [M + H]+ calcd for C116H145N8O28: 2099.0202;
1H NMR (400 MHz, acetone-d6): δ = 3.00 (dd, 2J = 13.8, 3Jα,βa = 9.1
Hz, 1 H, β-HaPhe), 3.17 (dd, J = 13.8, 3Jα,βb = 5.3 Hz, 1 H, β-HbPhe),
3.65 (s, 3 H, OCH3), 3.66–3.73 (m, 1 H, H6a), 3.75–3.83 (m, 2 H,
H6b, H5), 3.86–3.94 (m, 2 H, H2, H3), 4.03 (t, 3J = 9.3 Hz, 1 H, H4),
4.43–4.55 (m, 1 H, α-HPhe), 4.51–4.90 (m, 8 H, 4 OCH2Bn), 6.04 (d,
3J1,2 = 1.5 Hz, 1 H, H1), 6.94 (d, 3JNH,α = 8.8 Hz, 1 H, NH), 7.16–
7.46 (m, 25 H, Harom).
13C NMR (100 MHz, acetone-d6): δ = 38.2 (C-βPhe), 52.4 (OCH3),
56.4 (C-αPhe), 70.1 (C6), 72.4, 73.3, 73.8 (3 × CH2Ph), 74.8 (C5),
75.3 (C2, C4), 75.5 (CH2Ph), 80.7 (C3), 93.1 (C1), 127.6, 128.1,
128.2, 128.3, 128.5, 128.6, 128.6, 128.7, 129.0, 129.0, 129.1, 129.1,
129.2, 130.1 (CHarom), 138.1, 139.7, 139.8, 139.8, 139.9 (Carom),
154.8 (C=Ocarbamate), 172.6 (COOMe).
found: 2099.0232.
The crude residue was dissolved in THF (25 mL) and cooled with
an ice-water bath. Following the addition of solid NaHCO3 (8 mg,
100 μmol, 4 equiv) and DEPBT (22 mg, 75 μmol, 3 equiv), the mix-
ture was stirred at r.t. for 4 d. After evaporation of the solvent, the
residue was partitioned between EtOAc (30 mL) and sat. aq
NaHCO3 (20 mL). The organic phase was washed with sat. aq
NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4), and evaporat-
ed. Purification of the residue by flash chromatography (CH2Cl2–
MeOH, 60:1, 40:1, 20:1) afforded cyclopeptide 17 (37 mg, 72%) as
a colorless, amorphous solid; Rf = 0.40 (CH2Cl2–MeOH, 20:1).
[α]D22 +37.7 (c 1.0, CHCl3).
1H NMR (500 MHz, 350 K, DMSO-d6): δ = 0.72 (br s, 3 H,
CH3mePhe), 0.84, 0.85 (2 d, 3J = 6.7 Hz, each 3 H, 2 CH3iVal), 1.30 (br
s, 3 H, CH3i-Pr), 1.41 (br s, 9 H, CH3Boc), 1.42 (br s, 3 H, CH3i-Pr), 1.48
(br s, 9 H, CH3Boc), 1.49 (br s, 3 H, CH3i-Pr), 1.56 (br s, 3 H, CH3i-Pr),
1.91 (septet, 3J = 6.7 Hz, 1 H, CHiVal), 2.04–2.08 (m, 2 H, CH2iVal),
HRMS (ESI): m/z [M + Na]+ calcd for C45H47NNaO9: 745.3251;
found: 745.3257.
N-(2,3,4,6-Tetra-O-benzyl-α-D-mannopyranosyloxycarbonyl)-
L-phenylalanine (20)
2.76 (dd, 2J = 14.0, 3Jα,βa = 10.2 Hz, 1 H, β-HaTyr), 2.90 (dq, 3Jβ,Me
=
To a soln of ester 19 (24 mg, 32 μmol) in 1,4-dioxane (0.4 mL) was
added at 8 °C aq 1 M LiOH soln (64 μL, 64 μmol, 2 equiv). The
mixture was stirred for 3 h at this temperature and then it was dilut-
ed with EtOAc (20 mL), washed with sat. aq NH4Cl–H2O (1:1), and
dried (MgSO4). Evaporation of the solvent gave acid 20 (21 mg,
89%) as a colorless solid; Rf = 0.50 (CH2Cl2–MeOH, 9:1).
6.7, 3Jα,β = 7.1 Hz, 1 H, β-HmePhe), 3.22 (br d, 2J = 13.8 Hz, 1 H, β-
2
3
HbTyr), 3.34 (dd, J = 11.0, J5,6 = 3.0 Hz, 1 H, H6′a), 3.37 (d, 2J =
11.0, 3J5,6 = 4.6 Hz, 1 H, H6′b), 3.42 (br d, 2J = 11.0 Hz, 1 H, CHaGly),
2
3
3.57–3.63 (m, 2 H, 6H), 3.65 (dd, J = 9.5, J = 8.0 Hz, 1 H, β -
CHaSer), 3.73–3.80 (m, 5 H, CHbGly, β -HbSer, H5, H3′, H5′), 3.80–
3.87 (m, 5 H, δ-HaD-Hep, δ-HaL-Hep, γ-HaD-Hep, γ-HaL-Hep, H2′), 3.89 (br
s, 1 H, β -HL-Hep), 3.97 (br s, 1 H, α-HD-Hep), 4.00 (dd, J2,3 = 3.1,
3
Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
37
1H NMR (400 MHz, acetone-d6): δ = 2.96 (dd, 2J = 14.0, 3Jα,βa = 8.4
Hz, 1 H, β-HaPhe), 3.19 (dd, 2J = 14.0, 3Jα,βb = 4.9 Hz, 1 H, β-HbPhe),
3.64 (dd, 2J = 11.0, 3J5,6a = 1.7 Hz, 1 H, H6a), 3.70–3.76 (m, 2 H, H5,
13C NMR (100 MHz, DMSO-d6): δ= 23.1 (trans-C-γPro), 23.7 (cis-
C-γPro), 29.4 (cis-C-βPro), 30.1 (trans-C-βPro), 46.2 (cis-C-δPro), 46.7
(trans-C-δPro), 51.9 (cis-OCH3), 52.0 (trans-OCH3), 58.5 (trans-C-
αPro), 58.7 (cis-C-αPro), 68.7 (C6), 70.7 (CH2Ph), 71.0 (C5), 71.9,
71.9, 72.3, 72.3, 73.3 (C4), 73.4 (C2), 73.6 (CH2Ph), 73.7, 73.8,
73.9, 74.2, 78.2 (cis-C3), 79.6 (trans-C3), 91.9 (C1), 127.3, 127.4,
127.4, 127.4, 127.5, 127.5, 127.5, 127.6, 127.6, 127.7, 127.7, 127.8,
128.1, 128.2, 128.2, 128.2, 139.8, 139.8, 139.9 (Carom), 151.2
(trans-C=Ocarbamate), 151.8 (cis-C=Ocarbamate), 172.3 (cis-COOMe),
172.8 (trans-COOMe).
H6b), 3.74 (dd, 3J1,2 = 2.1, 3J2,3 = 3.2 Hz, 1 H, H2), 3.80 (dd, 3J2,3
=
3.1, 3J3,4 = 9.5 Hz, 1 H, H3), 4.02 (t, 3J3,4 = 3J4,5 = 9.7 Hz, 1 H, H4),
4.44 (dd, 3Jα,βa = 9.0, 3Jα,βb = 5.4 Hz, 1 H, α-HPhe), 4.44–4.84 (m, 8
H, 4 CH2Bn), 6.03 (d, 3J1,2 = 2.0 Hz, 1 H, H1), 7.10–7.39 (m, 25 H,
Harom).
13C NMR (100 MHz, acetone-d6): δ = 38.2 (C-βPhe), 55.9 (C-αPhe),
67.7 (C6), 69.3, 72.7, 73.1 (3 CH2Bn), 74.1 (C5), 74.5 (C2), 74.9
(C4), 75.8 (CH2Bn), 80.0 (C3), 92.9 (C1), 127.4, 128.2, 128.3, 128.4,
128.7, 128.7, 128.9, 129.0 (CHarom), 129.9 (o-CHaromPhe), 137.6
138.5, 138.8 (Carom), 155.1 (C=Ocarbamate), 174.4 (COOH).
HRMS (ESI): m/z [M + Na]+ calcd for C44H45NNaO9: 754.2987;
found: 754.2975.
HRMS (ESI): m/z [M + Na]+ calcd for C41H45NNaO9: 718.2992;
found: 718.2975.
Nα-Fmoc-L-Lys-Nε-(2,3,4,6-tetra-O-benzyl-α-D-mannopyrano-
syloxycarbonyl)-L-Phe-OMe (23)
Perbenzylated sulfoxide 1 (129 mg, 0.2 mmol, 1.5 equiv) and
DTBP (91 μL, 0.41 mmol, 3.1 equiv) were coevaporated with tolu-
ene (2 × 5 mL). The residue was dissolved in CH2Cl2 (4 mL), and
molecular sieves (4 Å) were added. The resulting mixture was
stirred for 30 min under an argon atmosphere. The mixture was
cooled –70 °C and Tf2O (30 μL, 0.2 mmol, 1.5 equiv) was added
dropwise followed by a soln of Fmoc-L-Lys-(Nε-Boc)-L-Phe-OMe
(83 mg, 131 μmol) in CH2Cl2 (5 mL). The mixture was stirred at
–25 °C for 18 h, and the reaction was stopped by the addition of
MeOH (0.3 mL), diluted with CH2Cl2 (30 mL) and poured into sat.
aq NaHCO3–brine–H2O (1:1:2, 30 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3 × 20 mL), and the combined organic phases
were dried (MgSO4) and evaporated. The residue was purified by
flash chromatography (CH2Cl2–MeOH, 100:1, then 80:1), which
afforded mannosyl carbamate 23 (43 mg, 39 μmol, 44%) as a color-
less solid; Rf = 0.30 (CH2Cl2–MeOH, 40:1).
Methyl N-(α-D-Mannopyranosyloxycarbonyl)-L-phenylalani-
nate (21)
Glycocarbamate 19 (24 mg, 32 μmol) was dissolved in MeOH
(0.5 mL), and 10% Pd/C was added (5 mg). The mixture was stirred
at r.t. under an atmosphere of H2 (1 bar) for 12 h, diluted with
CH2Cl2 (2 mL), and purified directly by flash chromatography
(CH2Cl2–MeOH, 6:1), which afforded the tetraol 21 (8 mg, 64%) as
a colorless solid; Rf = 0.25 (CH2Cl2–MeOH, 9:1).
1H NMR (400 MHz, CD3OD): δ = 2.95 (dd, J = 13.8, 3Jα,βa = 9.3 Hz,
1 H, β-HaPhe), 3.16 (dd, J = 13.8, 3Jα,βb = 5.2 Hz, 1 H, β-HbPhe), 3.59–
3.64 (m, 1 H, H5), 3.66–3.74 (m, 3 H, H4, H3, H6a), 3.70 (s, 3 H,
OCH3), 3.74 (dd, 3J1,2 = 1.7, 3J2,3 = 3.2 Hz, 1 H, H2), 3.79 (dd, 2J =
12.1, 3J5,6b = 2.2 Hz, 1 H, H6b), 4.41 (dd, 3Jα,βa = 9.3, 3Jα,βb = 5.3 Hz,
1 H, α-HPhe), 5.80 (d, 3J1,2 = 1.9 Hz, 1 H, H1), 7.18–7.25 (m, 5 H,
CHarom).
13C NMR (100 MHz, CD3OD): δ = 38.5 (C-βPhe), 52.7 (OCH3), 57.0
(C-αPhe), 62.7 (C6), 68.0 (C4), 71.2 (C2), 72.2 (C3), 76.6 (C5), 96.1
(C1), 127.9, 129.5, 130.3, 138.3 (Carom), 156.4 (C=Ocarbamate), 173.6
(COOMe).
1H NMR (500 MHz, acetone-d6): δ = 1.32–1.46 (m, 2 H, 2 γ-HLys),
1.47–1.57 (m, 2 H, 2 δ-HLys), 1.59–1.70 (m, 1 H, β-HaLys), 1.74–1.85
(m, 1 H, β-HbLys), 3.02 (dd, J = 13.8, 3Jα,βa = 7.8 Hz, 1 H, β-HaPhe),
3.09–3.18 (m, 3 H, β-HbPhe, 2 ε-HLys), 3.64 (s, 3 H, OCH3), 3.69 (d,
2J = 10.7 Hz, 1 H, H6a), 3.77 (dd, 2J = 11.2, 3J5,6b= 4.7 Hz, 1 H, H6b),
3.79–3.84 (m, 1 H, H5), 3.91 (dd, 3J2,3 = 3.0, 3J3,4 = 9.5 Hz, 1 H, H3),
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NNaO9: 408.1265;
found: 408.1259.
3.98 (dd, 3J1,2 = 1.7, 3J2,3 = 3.0 Hz, 1 H, H2), 4.04 (t, 3J3,4 = 3J4,5
=
9.3 Hz, 1 H, H4), 4.15–4.21 (m, 1 H, α-HLys), 4.22 (br t, 3J = 7.3 Hz,
1 H, CHFmoc), 4.26–4.39 (m, 2 H, CH2Fmoc), 4.51–4.68 (m, 5 H, 2
CH2Bn, CHaBn), 4.69–4.75 (m, 1 H, α-HPhe), 4.76 (br s, 2 H, CH2Bn),
4.89 (d, 2J = 11.0 Hz, 1 H, CHbBn), 6.14 (d, 3J1,2 = 1.7 Hz, 1 H, H1),
6.52–6.63 (m, 2 H, α-NHLys, ε-NHLys), 7.12–7.46 (m, 29 H, Harom),
7.48 (d, 3JNH,α = 7.8 Hz, 1 H, NHPhe), 7.65–7.73 (m, 2 H, HaromFmoc),
7.82–7.88 (m, 2 H, HaromFmoc).
Methyl N-(2,3,4,6-Tetra-O-benzyl-α-D-mannopyranosyloxycar-
bonyl)-L-prolinate (22)
Boc-L-Pro-OMe (27 mg, 118 μmol, 1 equiv) and DTBP (98 μL,
425 μmol, 3.6 equiv) were coevaporated with toluene (2 × 5 mL).
The residue was dissolved in CH2Cl2 (2 mL), molecular sieves (4 Å)
were added, and the resulting mixture was stirred at r.t. for 30 min
under argon. After cooling the mixture to –70 °C, Tf2O (35 μL,
212 μmol, 1.8 equiv) was added dropwise, followed by a soln of
sulfoxide 1 (138 mg, 212 μmol, 1.8 equiv) in CH2Cl2 (1 mL), and
the mixture was slowly warmed to r.t. over 5 h. The reaction was
quenched by the addition of MeOH (0.1 mL), diluted with CH2Cl2
(30 mL), and poured into a mixture of sat. aq NaHCO3–brine (1:1,
30 mL). The aqueous phase was extracted with CH2Cl2 (3 × 20 mL)
and the combined organic phases were dried (MgSO4) and evapo-
rated. Purification of the residue by flash chromatography (PE–
EtOAc, 4:1, 3:1) afforded glycocarbamate 22 (65 mg, 79%) as a
colorless oil; Rf = 0.40 (PE–EtOAc, 2:1).
13C NMR (125 MHz, acetone-d6): δ = 23.5 (γ-CLys), 30.3 (δ-CLys),
32.6 (β-CLys), 38.4 (β-CPhe), 41.4 (ε-CLys), 48.1 (CFmoc), 52.4
(OCH3), 54.2 (α-CPhe), 56.2 (α-CLys), 67.3 (CH2Fmoc), 70.1 (C6),
72.3, 73.3, 73.8, 75.4 (4 CH2Ph), 74.7 (C5), 75.6 (C4), 75.7 (C2),
80.8 (C3), 92.6 (C1), 120.8 (CHaromFmoc), 126.2, 127.6, 128.1, 128.2,
128.3, 128.5, 128.6, 128.6, 128.6, 129.0, 129.0, 129.1, 129.1, 129.2
(CHarom), 130.1 (o-CHaromPhe), 136.8, 138.1, 139.7, 139.8, 139.8,
139.9 (Carom), 142.1 (CHaromFmoc), 145.0, 145.1 (CaromFmoc), 155.1
(C=OcarbamateMan), 157.0 (C=OcarbamateFmoc), 172.5 (COOMe).
HRMS (ESI): m/z [M + Na]+ calcd for C66H69N3NaO12: 1118.4779;
found: 1118.4799.
1H NMR (400 MHz, DMSO-d6, mixture of cis- and trans-isomers,
ratio 3:2): δ = 1.77–1.96 (m, 3 H, cis- + trans-βPro-Ha, 2 γPro-H),
2.13–2.30 (m, 1 H, cis- + trans-βPro-Hb), 3.28–3.35 (m, 1.2 H, cis-
δPro-CH2), 3.41 (t, 3Jγ,δ = 7.0 Hz, 0.8 H, trans-δPro-CH2), 3.58 (s, 1.2
H, trans-OCH3), 3.60–3.64 (m, 1 H, cis- + trans-H6a), 3.61 (s, 1.8
H, cis-OCH3), 3.65–3.74 (m, 2.4 H, trans-H3, cis- + trans-H4, cis-
+ trans-H6b), 3.79–3.84 (m, 1 H, trans-H2, cis-H3), 3.84–3.93 (m,
1.6 H, cis-H2, cis- + trans-H5), 4.24 (dd, 3Jα,β = 3.9, 3Jα,β = 9.0 Hz,
0.6 H, cis-αPro-CH), 4.35 (dd, 3Jα,β = 4.1, 3Jα,β = 8.5 Hz, 0.4 H, trans-
αPro-CH), 4.43–4.81 (m, 8 H, 4 CH2Ph), 5.95 (d, 3J1,2 = 1.8 Hz, 0.6
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
DFG (Ob-332/1-1 and 1-2). P.S. thanks the Schering Foundation for
a predoctoral fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
3
H, cis-H1), 5.97 (d, J1,2 = 1.8 Hz, 0.4 H, trans-H1), 7.16–7.23,
7.24–7.39 (2 m, 2 H and 18 H, cis- + trans-βHarom).
m
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39

38
P. Schüler et al.
FEATURE ARTICLE
A. I.; Winterfeld, G. A.; Schmidt, R. R. Eur. J. Org. Chem.
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(18) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am.
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(23) Higher yields for the glycosylation reaction were obtained
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Boc-L-Pro-OMe at –70 °C, then addition of sulfoxide 1) and
raising the reaction temperature to r.t. over 5 h proved to be
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(30) The substantially lower yields are a result of an incomplete
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further.
(14) (a) Jensen, K. J.; Meldal, M.; Bock, K. J. Chem. Soc., Perkin
Trans. 1 1993, 2119. (b) Vargas-Berenguel, A.; Meldal, M.;
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Synthesis 2013, 45, 27–39
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Tyrosine Mannosylation
39
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is lacking. The same is true for the studies of the Romersberg
group,13g where donor/activator systems that presumably led
to glycosyl triflates also performed worse than
trichloroacetimidates activated with BF3. Nevertheless, it is
tempting to speculate that carbamate glycosylation could
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TMSOTf activation of the same trichloroacetimidate donor
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catalyzed Diels–Alder reactions, whereas no such data is
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 27–39