Cross-metathesis of C-glycosides and peptides

Article abstract of DOI:10.1080/00397910701481146

Peptides bearing an acryloyl residue at their N-terminus were coupled with various C-glycosides in an equimolar ratio via cross-metathesis. The newly formed olefin was obtained with high E/Z selectivity in satisfying to high yields with low homodimerizati

Full text of DOI:10.1080/00397910701481146

This article was downloaded by: [George Mason University]
On: 24 December 2014, At: 08:52
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Cross‐metathesis of C‐Glycosides and
Peptides
Peter Brüchner a , David Koch a , Ulrike Voigtmann b & Siegfried Blechert a
a Institut für Organische Chemie, Technische Universitaet Berlin , Berlin,
Germany
b Schering AG , Berlin, Germany
Published online: 14 Aug 2007.
To cite this article: Peter Brüchner , David Koch , Ulrike Voigtmann & Siegfried Blechert (2007)
Cross‐metathesis of C‐Glycosides and Peptides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:16, 2757-2769, DOI: 10.1080/00397910701481146
To link to this article: http://dx.doi.org/10.1080/00397910701481146
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 2757–2769, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701481146
Cross-metathesis of C-Glycosides
and Peptides
Peter Bru¨chner and David Koch
Institut fu¨r Organische Chemie, Technische Universitaet Berlin, Berlin,
Germany
Ulrike Voigtmann
Schering AG, Berlin, Germany
Siegfried Blechert
Institut fu¨r Organische Chemie, Technische Universitaet Berlin, Berlin,
Germany
Abstract: Peptides bearing an acryloyl residue at their N-terminus were coupled with
various C-glycosides in an equimolar ratio via cross-metathesis. The newly formed
olefin was obtained with high E/Z selectivity in satisfying to high yields with low
homodimerization of the starting materials. The posttranslational cross-metathesis
approach was shown to be suitable for the combinatorial synthesis of a small library
of C-glycopeptides.
Keywords: C-glycopeptides, cross-metathesis, posttranslational synthesis
Carbohydrates play a pivotal role in a variety of diseases, such as cancer,
inflammation, and autoimmune diseases, as well as microbial infections and
graft rejection.[1] Inhibition of carbohydrate-processing enzymes involved in
the synthesis, transport, and cleavage of oligosacharides is of great interest,
Received in the U.K. August 4, 2006
Address correspondence to Siegfried Blechert, Institut fu¨r Organische Chemie,
Sekr. C3, Technische Universitaet Berlin, Strasse des 17. Juni 135, 10623 Berlin,
Germany. E-mail: blechert@chem.tu-berlin.de
2757

2758
P. Bru¨chner et al.
highlighting the importance of carbohydrate-based inhibitors. These may find
applications as novel therapeutic agents or as tools for studying their biologi-
cal targets. Hence, there is a rising need for rapid and broadly applicable
synthetic routes to stable, well-defined glycopeptide analogues.
A large number of synthetic investigations have been made into the
synthesis of C-glycoside amino acids and peptides because of their particular
stability against hydrolysis.[2] The synthesis of glycoamino acids by cross-
metathesis[3] has been achieved by a number of research groups.[4–7] Most
of these approaches can be classified as cotranslational, that is, the cross-
metathesis linkage between the sugar and an amino acid is installed first,
while the actual peptide assembly is carried out at a later stage. Normally,
derivatized vinyl-and allylglycine have been employed, together with vinyl-
and allyl-C-glycosides as coupling partners, using (PPh3)2Cl2Ru ¼ Ph 1 as
the (pre)catalyst. Common drawbacks in these examples are the formation
of E/Z-isomeric mixtures of the newly formed olefin, the use of high
catalyst loadings (20 mol%), and the occasional use of harsh conditions. In
addition, homodimerization of both coupling partners is generally observed.[8]
The more convergent posttranslational route (i.e., the cross-metathesis of
peptides bearing an olefin moiety with vinyl- or allyl-C-glycosides) has
notable advantages, mainly better suitability for solid-phase synthesis.[5]
However, the challenge of this approach lies in the unpredictable behavior
of peptides caused by conformational features, solubility issues, as well as
the array of different functional groups that might affect the metathesis
catalyst. As far as we know, there are only two reports on a cross-metathesis
between sugar and peptide. The first gives account of an glycylglycine ester
that became alkenylated at the N-terminus and coupled with protected
O- and C-allyl glycosides of N-acetylglucosamine, galactose, and mannose,
yielding four glycopeptoides in the range of 40 to 52%, besides homodimer
side products.[7] The second account showed the cross-metathesis of alanyl-
allylglycinyl-phenylalanyl methylester with three C-glycosides, one of them
being a disaccharide, giving yields between 39 and 68%.[5]
With the advent of the second-generation Grubbs catalyst 2 in the late
1990s,[9] new variations in cross-metathesis became available for synthetic
chemistry (i.e., the coupling of electron-poor olefins with electron-rich
olefins). These problems in cross-metathesis are minimal in the cases of
a,b-unsaturated carbonyl compounds, which react efficiently with alkylated
nonconjugated olefins.[10,11] We were interested in combining the advantages
of this CM-variation with the posttranslational approach to C-glycopeptide
synthesis and to explore the limits of this route. In general, the strategy
involves acylation at the N-terminus of various peptides with acryloyl
chloride, followed by cross-metathesis with several sugar derivatives (Fig. 1).
(Pre)catalysts 2 and 3[12] are known to promote the cross-metathesis of
acrylamide derivatives unlike 1 or several molybdenum catalysts. Hence, these
two were compared to each other in a series of reactions (Fig. 2). Thus
N-acryloyl-glycinyl-prolinyl methylester 7 was coupled with C-glycosides

Cross-metathesis of C-Glycosides and Peptides
2759
Figure 1. Acylation and cross-metathesis of a peptide ester.
4, 5, and 6 to give C-glycopeptides 8, 9, and 10. The results (Fig. 2) show that
(pre)catalyst 3 clearly performed better[13] than 2 and was therefore used in all
further cross-metathesis reactions. It is noteworthy that for the more challenging
substrates such as the completely unprotected 5 or the sterically encumbered
vinyl-glycoside 6, (pre)catalyst 3 gave a yield increase of more than 25% of
the products 9 and 10 when compared to reaction with (pre)catalyst 2.
In a further step, stoichiometry of the two cross partners was optimized.
Known C-allyl glycoside 11[14] and peptide 11 were reacted with each other in
varying ratios (Table 1).
Reaction of sugar 11 with 1 equivalent of peptide 12, using 5 mol% of 3,
1
gave the heterocoupled product 13 in 65% yield (Table 1), and H NMR
analysis of the crude mixture showed the presence of 15% of the sugar
dimer 14 (entry 1). Raising the amount of 12 to 1.5 equivalents (entry 2)
Figure 2. Comparison between (pre)catalysts 2 and 3.

2760
P. Bru¨chner et al.
Table 1. Cross-metathesis of sugar 11 with peptide 12
Entry
11:12
14 (%)a
13 (%)b
1
2
3
1:1
15
7
65
69
76
1:1.5
1:2
9
aDetermined by NMR.
bIsolated yield.
and finally to 2 equivalents (entry 3) gave at best only an 11% yield increase of
13. Therefore, the chemoselectivity of the reaction was considered to be suffi-
cient with an equimolar ratio of sugar and peptide. We proceeded to test the
general applicability of the reaction and the tolerance of the catalyst toward
functional groups. Thus, cross-metathesis with sugar 11 was attempted
using peptides with a broad range of functionality, in the presence of (pre)ca-
talyst 3 (Table 2).
Good to satisfying yields were obtained with a wide range of functional
groups. Even in the presence of a thioether (entry 8), cross-metathesis
resulted in a satisfying yield of 58%. Basic and/or coordinating functionality
can deactivate metathesis catalysts.[15] Hence, the results with the peptides
containing histidine (entry 2), where no desired product was obtained, and
tryptophan[16] (entry 10), which gave a 17% yield, are consistent with this
observation. In addition, utilization of 5 mol% precatalyst 3 gives comparable
yields to the previously-mentioned cross-metathesis examples where up to
20 mol% (pre)catalyst 1 or 2 have been used.[4,6]
With these encouraging results in hand, we investigated the synthesis of a
small library of glycopeptides. Cross-metathesis was attempted using five
fucose derivatives and eight acylated peptides (Table 3).
The use of peptides with an unprotected C-terminus failed either because of
chelation to the catalyst by the carboxylic acid or insolubility of the peptide in
DCM (entry 1). In contrast, esterified peptides gave good yields (entries 2–8).
Benzyl- and acetyl-protected allyl-sugars 4 and 32 were consistently good
coupling partners and gave yields of 60–90%. In all cases except for 33,

Cross-metathesis of C-Glycosides and Peptides
Table 2. Scope of (pre)catalyst 3 in cross-metathesis
2761
Entry
Peptide
AlaPheOMe 12
AlaHisOMe 14
Producta
1
65% 13
ncb
3% 17
2
3
AlaTyrOMe 16
PheSerOMe 18
4
43% 19
62% 21
46% 23
62% 25
58% 27
62% 29
17% 31
5
Lys(N-Cbz)PheOMe 20
AlaGlnOMe 22
6
7
AlaGlu(b-OMe)OMe 24
GlyMetGlyOMe 26
PheGlyGlyOMe 28
GlyGlyTrpOMe 30
8
9
10
aIsolated yields.
bNo conversion observed.
the E/Z ratios of the crossed products were higher throughout than 19:1. The
completely unprotected glycoside 5 gave variable yields but with consistently
high E/Z ratios. Considering that 5 provides numerous potential chelates for
catalyst deactivation, the good yields obtained (entries 2, 3, 5, and 7) are
delightful. The acetal protected 33 gave consistently good yields. In
contrast to the completely protected glycosides 4 and 32, the E/Z ratios
with 33 as cross-partner were distinctively lower. Engelhardt et al. reported
that E/Z ratios are affected by chelation of the catalyst.[17] Therefore, it
seems logical to suggest that chelation by the free hydroxyl group in 33
would account for the observed lower ratios. The low yields obtained with
vinylic 6 are likely due to the steric bulk of the a,b-branched olefin. A remark-
able exception is in entry 2 with the proline-containing peptide. It is possible
that rotamers may be playing a role here, but more evidence would be needed
to support this.
In summary, a small library of glycopeptides has been built, employing
cross-metathesis in a posttranslational manner as a synthetic method for con-
necting sugar and peptide moieties.
(Pre)catalyst 3 was shown to outperform catalyst 2 for our substrates. In
contrast to most reported examples, synthesis of C-glycoside peptides was
performed under very mild conditions, employing peptide and sugar in an

Table 3. Synthesis of a glycopeptide library
Entrya
Peptide
GlyGlyOH 34
GlyProOMe 7
4
32
33
5
6
1
2
3
4
5
6
7
8
15% 35
88% 8
—
—
—
65% 9
—
77% 36
65% 40
66% 46
74% 52
58% 58
49% 64
62% 69
88% (8:1) 37
71% (5:1) 41
66% 47
65% 10
30% 43
35% 49
29% 55
33% 61
nce
GlyGlyOMe 38
AlaAlaOMe 44
85% 39
79% 45
68% 51
70% 57
65% 63
53% 68
72% 42
15%b,c 48
60%d 54
36% 60
72% 66
40% 71
Asp(b-OMe)PheOMe 50
GlyGlyAlaOMe 56
AlaGlyGlyOMe 62
LeuAlaProOMe 67
75% (3:1) 53
72% (4:1) 59
88% (4:1) 65
72% (4:1) 70
17% 72
aIn all cases, E/Z ratio was .19:1. For glycopeptideseries 33, E/Z ratios are given in brackets.
bThe product was not isolated.
cYield was estimated from isolated starting material and the NMR.
dYield estimated by NMR.
eNo conversion observed.

Cross-metathesis of C-Glycosides and Peptides
2763
equimolar ratio with low homodimerization. Furthermore, the reaction was
shown to have a remarkable scope with (pre)catalyst 3 tolerating a wide
range of functionality and therefore allowing access to structurally diverse
molecules with an array of different functional groups. The simple preparation
of the metathesis precursors and the satisfying to high yields obtained provide
scope for transposition to solid-phase synthesis with rapid construction of
large glycopeptide libraries. Further results from these studies will be
presented in due course.
EXPERIMENTAL
Data for selected samples only. For complete spectra and characterization
data, please contact the authors. All reagents were obtained commercially
and were used without further purification. All reactions were carried out
under an inert atmosphere (N2) unless otherwise indicated. 1H and 13C
spectra were recorded at 500.0 and 125.8 MHz or 400.0 and 100.6 MHz,
respectively. Chemical shifts are expressed in parts per million (ppm)
upfield relative to the internal solvent peak. Mass spectra were obtained at
an ionizing potential of 70 eV. Melting points are uncorrected. (Pre)catalysts
2 and 3 were prepared according to literature procedures.[9,12] C-glycosides 4,
5, 6, 32, and 33 were provided by Schering AG.
General Procedure for Esterification and Acylation of the Peptides
Aqueous HCl (3 ml, 36%) was added to a suspension of the peptide
(4.3 mmol) in 43 ml of freshly distilled dimethoxypropane and left stirring
at ambient temperature for 24 to 48 h. The resulting blackened mixture was
concentrated in vacuo, and the residue was taken up in 14 ml of MeOH.
After addition of 93 ml of diethylether, the precipitate was filtrated and
dissolved in 6 ml of DMF and 1.3 g of triethylamine (12.8 mmol, 3 equiv.).
The solution was cooled in a 2108C (NaCl-saturated) ice bath. Acryloyl
chloride (7.7 mmol, 1.8 equiv.) was added dropwise over 30 min. After the
addition was complete, the reaction was warmed to room temperature and
stirred for 5 h. Water (20 ml) was added. Extraction with ethylacetate
failed. Therefore, the mixture was lyophilized, and the residue was purified
by chromatography and recrystallization (MeOH/EtOAc/pentane) to yield
a colorless solid. Spectral details, yields, and solvents for chromatography
are given for each compound separately.
General Procedure for Cross-metathesis
(Pre)catalyst 2 or 3 (0.0023 mmol, 5 mol%) was added to a solution of
0.047 mmol of C-glycoside (1 equiv.) and 0.047 mmol of acylated peptide

2764
P. Bru¨chner et al.
(1 equiv.) in 1 ml of dry DCM at 408C. After 18 h, the mixture was concen-
trated in vacuo, and the residue was purified by chromatography (SiO2,
solvents given separately). Yields are given in Tables 2 and 3.
Data
N-Acryloyl-glycinyl-prolinyl methylester 7. Yield 49% (SiO2, EtOH/DCM
1/4) 1H NMR (200.0 MHz, MeOD): d 6.34–6.20 (m, 2H), 5.66 (dd, J ¼ 1.4,
10.3 Hz, 1H), 4.45–4.43 (m, 1H), 4.20–4.02 (m, 2H), 3.82–3.53 (m, 2H),
3.68 (s, 3H), 2.34–1.82 (m, 4H). 13C NMR (50.0 MHz, MeOD): d 176.6
(Cq), 171.7, 170.6 (Cq), 134.1 (CH), 129.6 (CH2), 62.9 (CH), 55.2 (CH3),
49.8 (CH2), 45.0 (CH2), 32.4 (CH2), 28.1 (CH2); MS (EI, 1108C): m/z (%)
241 (2) [Mþ], 240 (4), 128 (70), 84 (16), 70 (100), 55 (34); HRMS
(C11H16N2O4): calcd. 240.1110; found 240.1115; mp 97–988C.
Glycopeptide 13. (SiO2, hexanes/EtOAc 1/1) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 7.07 (d J ¼ 7.0 Hz, 2H), 6.80 (m, 1H), 6.68 (br d,
J ¼ 8.0 Hz), 5.91 (br d, J ¼ 8.0 Hz, 1H), 5.78 (d, J ¼ 16.0 Hz, 1H), 4.40–
4.59 (m, 10H), 3.95–4.15 (m, 3H), 3.85 (m, 1H), 3.74 (m, 5H), 3.65
(m, 1H), 3.12 (dd, J ¼ 14.0, 6.0 Hz, 1H), 3.02 (dd, J ¼ 14.0, 6.0 Hz, 1H)
2.53 (m, H), 2.44 (m, 1H), 1.30 (d, J ¼ 7.0 Hz, 3H); 13C NMR (126 MHz,
CDCl3): d 171.8 (Cq), 171.7 (Cq), 166.5 (Cq), 141.8 (CH), 138.5 (2 Cq),
138.3 (Cq), 138.2 (Cq), 135.8 (Cq), 129.3 (CH), 128.7 (CH), 128.5 (2CH),
128.4 (2 CH), 128.1 (CH), 128.0 (CH), 127.9 (2 CH), 127.7 (3 CH), 127.6
(CH), 127.2 (CH), 125.0 (CH), 76.3 (CH), 74.1 (CH), 73.3 (2 CH2),
73.1 (CH), 67.1 (CH2), 53.4 (CH2), 52.4 (CH), 48.6 (CH), 37.9 (CH2), 30.7
(CH2), 30.6 (CH2), 29.8 (CH2), 18.0 (CH3); MS (EI): m/z (%) ¼ 840 (Mþ,
,1), 270 (4), 264 (8), 201 (36), 181 (12), 130 (24), 91 (100). HRMS
(C51H56N2O9): calcd. 840.3986; found 840.3989.
Glycopeptide 17. (SiO2, hexanes/EtOAc 1/2) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 6.80 (d, J ¼ 7.0 Hz, 2H), 6.70 (d, J ¼ 7.0 Hz, 1H) 5.74
(m, 2H), 4.40–4.85 (m, 10H), 3.90–4.25 (m, 4H), 3.74 (m, 4H), 3.66 (m, 2H),
3.09 (dd, J ¼ 14.0, 5.0 Hz, 1H), 2.81 (dd, J ¼ 14.0, 8.0 Hz, 1H), 2.60 (m, 1H),
2.32 (m, 1H), 1.25 (d, J ¼ 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3): d 172.0
(Cq), 171.6 (Cq), 165.3 (Cq), 155.6 (Cq), 142.2 (CH), 138.4 (CH), 138.2 (CH),
137.9 (2 CH), 130.5 (CH), 130.4 (CH), 128.6 (CH), 128.5 (2 CH), 128.3
(CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8 (2 CH)
127.7 (CH), 127.6 (2 CH), 126.6 (Cq), 125.2 (CH), 115.8 (CH), 76.7 (CH),
74.1 (CH), 73.3 (3 CH2), 66.8 (CH2), 53.3 (CH3), 52.5 (CH), 48.3 (CH),
36.9 (CH2), 29.8 (CH2), 17.3 (CH3); MS (EI): m/z (%) ¼ 856 (Mþ, ,1),
181 (6), 107 (10), 91 (100), 77 (5); HRMS (C51H56N2O10): calcd. 856.3935;
found 856.3954.

Cross-metathesis of C-Glycosides and Peptides
2765
Glycopeptide 19. (SiO2, hexanes/EtOAc 1/3) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 7.02 (br d, J ¼ 8.0 Hz, 1H), 6.74 (m, 1H), 6.21 (br d,
J ¼ 8.0 Hz, 1H), 5.79 (d, J ¼ 15.0 Hz, 1H), 4.40–4.75 (m, 10H), 3.95–4.15
(m, 3H), 3.85 (m, 3H), 3.71 (m, 5H), 3.63 (m, 1H), 3.15 (dd, J ¼ 13.0,
7.0 Hz, 1H), 3.03 (dd, J ¼ 14.0, 7.0 1H), 2.49 (m, 1H), 2.39 (m, 1H). 13C
NMR (126 MHz, CDCl3): d 71.1 (Cq), 170.5 (Cq), 166.1 (Cq), 142.5 (CH),
138.5 (Cq), 138.4 (Cq), 138.3 (Cq), 138.1 (Cq), 136.4 (Cq), 129.4 (CH),
128.9 (CH), 128.7 (CH), 128.5 (3 CH), 128.4 (CH), 128.1 (CH), 127.9
(2 CH), 127.7 (2 CH), 127.6 (CH), 127.1 (CH), 124.7 (CH), 76.5 (CH),
74.1 (CH), 73.2 (CH2), 73.1 (CH2), 67.0 (CH2), 62.6 (CH2), 55.0 (CH3),
54.8 (CH), 52.7 (CH), 38.0 (CH2), 29.8 (CH2); MS (EI): m/z (%) ¼ 856
(Mþ, ,1), 210 (4), 181 (11), 97 (7), 91 (100), 57 (9); HRMS
(C51H56N2O10): calcd. 856.3935; found 856.3949.
Glycopeptide 21. (SiO2, hexanes/EtOAc 2/3) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 7.07 (d J ¼ 7.0 Hz, 1H), 6.80 (m, 1H), 6.61 (br d,
J ¼ 8.0 Hz, 1H), 6.09 (br d, J ¼ 8.0 Hz, 1H), 5.83 (d, J ¼ 15.0 Hz), 5.06
(m, 2H), 4.99 (m, 1H), 4.35–4.85 (m, 10H), 3.95–4.15 (m, 3H), 3.85
(m, 1H), 3.73 (m, 2H), 3.66 (m, 4H), 2.95–3.20 (m, 4H), 2.54 (m, 1H),
2.42 (m, 1H), 1.79 (m, 1H), 1.25–1.63 (m, 7H); 13C NMR (126 MHz,
CDCl3): d 171.9 (Cq), 171.3 (Cq), 165.7 (Cq), 156.7 (Cq), 141.9 (CH), 138.5
(2 Cq), 138.4 (Cq), 138.2 (Cq), 136.7 (Cq), 135.7 (Cq), 129.3 (CH), 128.7
(CH), 128.6 (CH), 128.5 (2 CH), 128.4 (CH), 128.1 (2 CH), 127.9 (2 CH),
127.7 (2 CH), 127.6 (CH), 127.2 (CH), 125.0 (CH), 76.5 (CH), 74.2 (CH),
73.3 (CH2), 73.2 (CH2), 73.1 (CH2), 67.2 (CH2), 66.7 (CH2), 53.3 (CH3),
52.8 (CH), 52.5 (CH), 40.4 (CH2), 37.8 (CH2), 31.7 (CH2), 29.4 (CH2),
22.2 (CH2); MS (EI): m/z (%) ¼ 1031 (Mþ, ,1), 368 (6), 201 (4), 181
(7), 156 (13), 122 (7), 91 (100), 68 (20).
1
Glycopeptide 23. (SiO2, EtOAc) H NMR (500 MHz, CDCl3): d 7.15–7.40
(m, 20H), 6.79 (m, 1H), 6.33 (m, 1H), 5.89 (d, J ¼ 15.0 Hz, 1H), 5.69
(m, 1H), 4.40–4.70 (m, 10H), 4.05 (m, 2H), 3.98 (br s, 1H), 3.89 (m, 1H),
3.55–3.70 (m, 6H), 2.54 (m, 1H), 2.34 (m, 1H), 2.05–2.30 (m, 5H), 1.93
(m, 1H), 1.34 (d, J ¼ 7 Hz, 3H); 13C NMR (126 MHz, CDCl3): d 174.7
(Cq), 172.6 (Cq), 172.1 (Cq), 165.8 (Cq), 142.1 (CH), 38.4 (Cq), 138.3 (Cq),
138.2 (Cq), 138.0 (Cq), 128.5 (2 CH), 128.4 (CH), 128.1 (CH), 128.0
(2 CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 125.2 (CH), 76.6
(CH), 74.1 (CH), 73.2 (CH2), 73.0 (CH2), 67.0 (CH2), 52.5 (CH3), 52.0
(CH), 49.0 (CH), 31.3 (CH2), 27.2 (CH2), 17.8 (CH3); MS (EI): m/z
(%) ¼ 789 (Mþ, ,1), 181 (8), 91 (100), 84 (2); HRMS (C46H51N3O9):
calcd. 789.3625; found 789.3633.
Glycopeptide 25. (SiO2, hexanes/EtOAc 1/2) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 6.97 (br d, J ¼ 8.0 Hz, 1H), 6.79 (m, 1H), 6.06 (br d,
J ¼ 8.0 Hz, 1H), 5.82 (d, J ¼ 15.0 Hz, 1H), 4.40–4.75 (m, 10H), 4.06

2766
P. Bru¨chner et al.
(m, 2H), 4.01 (br s, 1H), 3.85 (m, 1H), 3.73 (m, 5H), 3.64 (m, 4H), 2.52
(m, 1H), 2.25–2.45 (m, 3H), 2.20 (m, 1H), 2.01 (m, 1H), 1.36
(d, J ¼ 7.0 Hz); 13C NMR (100 MHz, CDCl3): d 173.2 (Cq), 172.2 (Cq),
171.9 (Cq), 165.4 (Cq), 141.6 (CH), 138.4 (Cq), 138.3 (Cq), 138.1 (Cq),
128.4 (2 CH), 128.3 (CH), 128.0 (CH), 127.8 (2 CH), 127.6 (CH), 127.5
(CH), 125.0 (CH), 76.4 (CH), 74.1 (CH), 73.2 (CH2), 73.0 (CH2), 52.5
(CH3), 51.8 (2 CH), 48.7 (CH), 29.9 (CH2), 27.0 (CH2), 18.2 (CH3); MS
(EI): m/z (%) ¼ 836 (Mþ, ,1), 181 (10), 105 (4), 91 (100), 84 (8), 57 (4).
HRMS (C48H56N2O11): calcd. 836.3884; found 836.3881.
Glycopeptide 27. (SiO2, hexanes/EtOAc 1/10) 1H NMR (500 MHz, CDCl3):
d 7.15–7.40 (m, 20H), 7.16 (m, 2H), 6.79 (m, 1H), 6.09 (br s, 1H), 5.95
(d, J ¼ 15.0 Hz, 1H), 4.40–4.75 (m, 10H), 4.08 (m, 2H), 3.90–4.05
(m, 4H), 3.81 (m, 2H), 3.55–3.75 (m, 6H), 2.56 (m, 3H), 2.35 (m, 1H),
1.94–2.15 (m, 5H); 13C NMR (100 MHz, CDCl3): d 171.4 (Cq), 170.2 (Cq),
169.3 (Cq), 166.8 (Cq), 142.2 (CH), 138.4 (2 CH), 138.1 (CH), 128.6 (CH),
128.5 (2 CH), 128.4 (CH), 128.1 (CH), 127.9 (2 CH), 127.8 (2 CH), 127.1
(CH), 124.6 (CH), 76.7 (CH), 74.2 (CH), 73.2 (CH2), 67.5 (CH2), 52.4
(CH3), 52.3 (CH), 43.7 (CH2), 41.2 (CH2), 30.7 (CH2), 30.1 (CH2), 29.8
(CH2), 15.3 (CH3); MS (EI): m/z (%) ¼ 867 (Mþ, ,1), 181 (8), 105 (4),
91 (100), 61 (5); HRMS (C48H57N3O10S): calcd. 867.3765; found 867.3741.
Glycopeptide 29. (SiO2, hexanes/EtOAc 1/9) 1H NMR (500 MHz, CDCl3):
d 7.10–7.40 (m, 23H), 6.96 (m, 2H), 6.78 (m, 1H), 6.29 (br d, J ¼ 8.0 Hz,
1H), 5.85 (d, J ¼ 15.0 Hz, 1H), 4.40–4.70 (m, 10H), 3.55–4.15 (m, 16H),
3.09 (dd, J ¼ 15.0, 7.0 Hz, 1H), 3.02 (dd, J ¼ 14.0, 7.0 Hz, 1H), 2.52
(m, 1H), 2.38 (m, 1H); 13C NMR (100 MHz, CDCl3): d 171.6 (Cq), 170.3
(Cq), 169.1 (Cq), 166.2 (Cq), 142.4 (CH), 138.4 (2 Cq), 138.3 (Cq), 138.1
(Cq), 136.5 (Cq), 129.3 (CH), 128.8 (CH), 128.5 (3 CH), 128.4 (CH), 128.1
(CH), 128.0 (CH), 127.9 (CH), 127.8 (2 CH), 127.7 (CH), 127.6 (CH),
127.5 (CH), 127.1 (CH), 124.8 (CH), 76.6 (CH), 74.1 (CH), 73.2 (CH2),
63.1 (CH2), 67.1 (CH2), 55.1 (CH3), 52.4 (CH), 43.0 (CH2), 41.1 (CH2),
37.8 (CH2); MS (EI): m/z (%) ¼ 883 (Mþ, ,1), 368 (6), 317 (4), 256 (4),
213 (3), 181 (9), 130 (9), 98 (22), 91 (100), 55 (12).
Glycopeptide 31. (SiO2, EtOAc/MeOH 20/1) 1H NMR (500 MHz, CDCl3):
d 8.82 (s, 1H), 7.46 (d J ¼ 8.0 Hz, 1H), 7.20–7.40 (m, 22H), 7.09 (m, 2H),
6.93 (br s, 1H), 6.74–6.88 (m, 3H), 5.88 (m, 2H), 4.84 (m, 1H), 4.44–4.73
(m, 8H), 4.10 (m, 1H), 4.00 (m, 2H), 3.59–3.83 (m, 10H), 3.28 (m, 1H),
2.54 (m, 1H), 2.33 (m, 1H); 13C NMR (100 MHz, CDCl3): d 172.3 (Cq),
169.7 (Cq), 168.7 (Cq), 166.7 (Cq), 142.3 (CH), 138.4 (Cq), 138.3 (Cq),
138.2 (Cq), 138.0 (Cq), 136.2 (Cq), 128.6 (CH), 128.5 (2 CH), 128.4 (CH),
128.1 (CH), 128.0 (CH), 127.9 (2 CH), 127.8 (2 CH), 127.6 (CH), 127.5
(CH), 124.5 (CH), 123.6 (CH), 122.0 (CH), 119.5 (CH), 118.4 (CH), 111.6

Cross-metathesis of C-Glycosides and Peptides
2767
(Cq), 109.3 (CH), 74.2 (CH), 73.2 (CH), 73.1 (CH2), 67.4 (CH2), 52.6 (CH3),
52.5 (CH), 43.3 (CH2), 43.0 (CH2), 27.3 (CH2); MS (EI): m/z (%) ¼ 922
(Mþ, ,1), 368 (2), 328 (2), 284 (4), 256 (7), 201 (11), 181 (15), 162 (8),
130 (23), 91 (100), 77 (6).
1
Glycopeptide 8. (SiO2, EtOAc) H NMR (500 MHz, CDCl3): d 7.39–7.25
(m, 15H, Ar-H), 6.89–6.84 (m, 1H), 6.42 (s, 1H, NH), 5.86 (d, J ¼ 15.6 Hz,
1H), 4.98–4.95 (m, 2H), 4.77–4.62 (m, 4H), 4.53–4.51 (m, 1H), 4.16–4.03
(m, 2H), 3.76–3.48 (m, 5H), 3.74 (s, 3H), 3.42–3.40 (m, 1H), 3.30–3.26
(m, 1H), 2.70–2.65, 2.38–2.31 (m, 2H), 2.27–2.00 (m, 4H), 1.13
(d, J ¼ 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 172.1 (Cq), 167.0 (Cq),
165.6 (Cq), 141.5 (CH), 138.5, 138.2, 138.2 (Cq), 128.3, 128.3, 128.2, 128.0,
127.9, 127.6, 127.5, 127.4 (CH), 124.7 (CH), 85.1 (CH), 78.4 (CH), 78.3
(CH), 76.7 (CH), 75.2 (CH2), 74.4 (CH2), 74.1 (CH), 72.2 (CH2), 58.8 (CH),
52.2 (CH3), 45.8 CH2), 41.9 (CH2), 34.3 (CH2), 28.9 (C-16), 24.5 (CH2),
17.1 CH3); MS (EI, 2508C): m/z (%) ¼ 670 (,1) [M], 517 (1), 181 (6), 154
(7), 130 (15), 111 (7), 91 (100), 70 (10); HRMS (C39H46N2O8): calcd.
670.3254; found 670.3250.
1
Glycopeptide 36. (SiO2, EtOAc) H NMR (500 MHz, CDCl3/MeOD): d
6.78–6.73 (m, 1H), 5.97 (d, J ¼ 15.4 Hz, 1H), 5.29–5.25 (m, 1H), 5.21 (br
s, 1H), 5.17–5.13 (m), 4.48–4.45 (m, 1H), 4.28–4.25 (m, 1H), 4.17–4.02
(m, 2H), 3.97–3.92 (m, 1H), 3.73–3.69 (m, 1H), 3.70 (s, 3H), 2.64–2.57,
2.40–2.35 (m, 2H), 2.26–1.85 (m, 4H), 2.11, 2.02, 1.97 (s, each 3H), 1.10
(d, J ¼ 6.0 Hz, 3H); 13C NMR (50 MHz, CDCl3): d 72.2 (Cq, 170.5, 170.1,
169.8 (Cq), 167.0 (Cq, 165.1 (Cq), 139.9 (CH), 125.5 (CH), 71.4 (CH), 70.4
(CH), 68.4 (CH), 68.1 (CH), 66.0 (CH), 58.9 (CH), 52.4 (CH3), 46.0 (CH2),
42.0 (CH2), 29.0 (CH2), 28.9 (CH2), 24.6 (CH2), 20.7, 20.7, 20.6 (CH3)
15.9 (CH3); MS (EI, 2708C): m/z (%) ¼ 526 (16) [M], 398 (15), 341 (10),
273 (22), 171 (10), 153 (38), 128 (90), 111 (37), 83 (11), 70 (100); HRMS
(C24H34N2O11): calcd. 526.2163; found 526.2163.
Glycopeptide 37. (SiO2, EtOAc/MeOH 10/1) 1H NMR (500 MHz, CDCl3):
d 7.22 (s, 1H, NH), 6.81–6.75 (m, 1H), 5.98 (d, J ¼ 15.4 Hz, 1H), 4.54–4.52
(m, 1H), 4.32–4.27, 3.95–3.91 (m, 2H), 4.29–4.27 (m, 1H), 4.12–4.05
(m, 3H), 3.78–3.56 (m, 3H), 3.73 (s, 3H), 3.08 (d, J ¼ 4.1 Hz, 1H, OH),
2.56–2.52, 2.47–2.43 (m, 2H), 2.27–2.00 (m, 4H), 1.48 (s, 3H), 1.32
(s, 3H), 1.24 (d, J ¼ 6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3): d 172.4
(Cq, 167.7 (Cq), 166.3 (Cq), 140.6 (CH), 125.6 (CH), 109.3 (Cq), 75.4 (CH),
74.9 (CH), 70.2 (CH), 68.0 (CH), 65.6 (CH), 59.1 (CH), 52.5 (CH3), 46.3
(CH2), 41.9 (CH2), 33.8 (CH2), 29.1 (CH2), 27.0 (CH2), 24.7 (CH3), 24.6
(CH3), 17.7 (CH3); MS (EI, 2008C): m/z (%) ¼ 440 [M], 364 (6), 312 (5),
254 (9), 228 (16), 187 (19), 130 (100), 70 (68), 59 (7). HRMS
(C21H32N2O8): calcd. 440.2159; found 440.2161.

2768
P. Bru¨chner et al.
1
Glycopeptide 9. (SiO2, EtOAc/MeOH 10/1) H NMR (500 MHz, CDCl3/
MeOD): d 7.39–7.25 (m, 15H), 6.83–6.78 (m, 1H), 6.03 (d, J ¼ 15.4 Hz,
1H), 4.47–4.45 (m, 1H), 4.21–3.99 (m, 3H), 3.90–3.87 (m, 1H), 3.78–3.55
(m, 5H), 3.7 (s, 3H), 2.60–2.51 (m, 2H), 2.23–2.00 (m, 4H), 1.19
(d, J ¼ 6.5 Hz, 3H); 13C NMR (126 MHz, CDCl3/MeOD): d 172.4 (Cq),
167.3 (Cq, 166.4 (Cq), 141.8 (CH), 124.2 (CH), 73.8 (CH), 70.8 (CH), 70.4
(CH), 67.9 (CH), 67.0 (CH), 58.7 (CH), 51.7 (CH3), 45.8 (CH2), 41.2
(CH2), 28.5 (CH2), 27.5 (CH2), 24.1 (CH2), 17.3 (CH3); MS (EI, 2808C):
m/z (%) ¼ 400 (6) [M], 228 (20), 187 (14), 154 (30), 130 (52), 111 (38),
83 (46), 69 (100). HRMS (C18H28N2O8): calcd. 400.1845; found 400.1852.
1
Glycopeptide 10. (SiO2, EtOAc) H NMR (500 MHz, CDCl3): d 7.39–7.25
(m, 15H), 7.04 (dd, J ¼ 4.3, 15.4 Hz, 1H), 6.51 (s, 1H, NH), 6.24
(d, J ¼ 15.4 Hz, 1H), 4.99, 4.85, 4.76, 4.71, 4.62 (m, 6H), 4.55–4.53
(m, 1H), 4.17–4.07 (m, 2H), 3.88–3.85 (m, 1H), 3.76–3.70 (m, 1H), 3.74
(s, 3H), 3.64–3.62 (m, 3H), 3.53–3.48 (m, 2H), 2.27–2.00 (m, 4H), 1.19
(d, J ¼ 6.4 Hz, 3H); 13C NMR (126 MHz, CDCl3): d 172.3 (Cq, 167.0 (Cq),
165.4 (Cq), 140.6 (CH), 138.7, 138.5, 138.1 (Cq), 128.5, 128.5, 128.4,
128.3, 128.3, 127.8, 127.6, 127.8, 127.6 (CH), 124.1 (CH), 84.9 (CH), 78.8
(CH), 78.8 (CH), 76.6 (CH), 75.6 (CH2), 74.6 (CH2), 74.3 (CH), 72.8
(CH2), 59.0 (CH), 52.5 (CH3), 46.0 (CH2), 42.2 (CH2), 29.1 (CH), 24.7
(CH2), 17.3 (CH3); MS (EI, 2508C): m/z (%) ¼ 656 (2) [M], 565 (6), 436
(5), 251 (12), 181 (7), 130 (5), 91 (100), 70 (7). HRMS (C38H44N2O8):
calcd. 656.3098; found 656.3079.
ACKNOWLEDGMENT
U.V. thanks Oliver von Ahsen for conducting biological assays on some of the
glycopeptides.
REFERENCES
1. (a) Varki, A. Glycobiology 1993, 3, 97–130; (b) Dwek, R. A. Chem. Rev. 1996, 3,
683–720; (c) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek, R. A.
Science 2001, 291, 2370–2376; (d) Bertozzi, C. R.; Kiessling, L. L. Science
2002, 291, 2357–2364; (e) Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C.
Bioorg. Med. Chem. Lett. 2005, 105, 425–448.
2. (a) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395–4422;
(b) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron Asymmetry
2005, 16, 45–55; (c) Chaulagain, M. R.; Postema, M. H. D.; Valerioteb, F.;
Pietraszkewicz, H. Tetrahedron Lett. 2004, 45, 7791–7794.
3. (a) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900–1923;
(b) Vernall, A. J.; Abell, A. D. Adrichim. Acta 2003, 36, 93–105;
(c) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360–11370.

Cross-metathesis of C-Glycosides and Peptides
2769
4. Vernall, A. J.; Abell, A. D. Org. Biomol. Chem. 2004, 2, 2555–2557.
5. Garvey, G. J.; Benedum, T. E.; Schmidtmann, F. W. Org. Lett. 2002, 4,
3591–3594.
6. (a) Wan, Q.; Cho, Y. S.; Lambert, T. H.; Danishefsky, S. J. J. Carbohydr. Chem.
2005, 24, 425–440; (b) Dondoni, A.; Giovannini, P. P.; Perone, D. J. Org. Chem.
2005, 70, 5508–5518; (c) Nolen, E. G.; Kurish, A. J.; Potter, J. M.;
Donahue, L. A.; Orlando, M. D. Org. Lett. 2005, 7, 3383–3386;
(d) Schmidtmann, F. W.; Benedum, T. E.; McGarvey, G. J. Tetrahedron Lett.
2005, 46, 4677–4681; (e) Liu, S.; Ben, R. N. Org. Lett. 2005, 7, 2385–2388;
(f) Postema, M. H. D. Org. Lett. 2003, 5, 1721–1723; (g) Nolen, E. G.;
Kurish, A. J.; Wong, K. A.; Orlando, M. D. Tetrahedron Lett. 2003, 44,
2449–2453; (h) Godin, G.; Compain, P.; Martin, O. R. Org. Lett. 2003, 5,
3269–3272; (i) Biswas, K.; Coltart, D. M.; Danyshefsky, S. Tetrahedron Lett.
2002, 43, 6107–6110; (k) Dondoni, A.; Giovannini, P. P.; Marra, A. J. Chem.
Soc., Perkin Trans. 1 2001, 19, 2380–2388; (l) Dominique, R.; Liu, B.; Das, S.;
Roy, R. Synthesis 2000, 862–868.
7. Hu, Y. J.; Roy, R. Tetrahedron Lett. 1999, 40, 3305–3308.
8. Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc., Perkin Trans. 1 1998,
2485–2500.
9. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
10. (a) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Syn. Lett. 2001, 430–432;
(b) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001, 634,
216–222; (c) Cossy, J.; BouzBouz, S. Org. Lett. 2001, 3, 1451–1454;
(d) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783–3784.
11. Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12, 1873–1876.
12. (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179; (b) Gesslar, S.; Blechert, S. Tetrahedron Lett. 2000, 41,
9973–9976.
13. (a) Imhof, S.; Randl, S.; Blechert, S. Chem. Commun. 2001, 1692–1693;
(b) Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun. 2001, 1796–1797.
14. Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976–4978.
15. Grubbs, R. H. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH, 2003.
16. For coordination of Trp moieties to transition metals, see Kaminskaia, N. V.;
Ullmann, G. M.; Fulton, D. B.; Kostic, N. M. Inorg. Chem. 2000, 39, 5004–5013.
17. Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209–2212.