Photoaffinity-labeled peptoids and depsipeptides by multicomponent reactions

Article abstract of DOI:10.1055/s-0030-1258182

Photoaffinity tags can be incorporated easily into peptoids and congeners by the Ugi and Passerini multicomponent reactions. Products related to photo-methionine and photo-leucine can be accomplished by diazirine-containing building blocks. The same proto

Full text of DOI:10.1055/s-0030-1258182

PAPER
2997
Photoaffinity-Labeled Peptoids and Depsipeptides by Multicomponent
Reactions
Photoaffinity-Labeled
i
P
eptoid
c
s
a
nd Deps
h
ipeptides ael Henze,a Oliver Kreye,a Sebastian Brauch,a Christoph Nitsche,a Kai Naumann,c Ludger A. Wessjohann,a,b
Bernhard Westermann*a,b
a
Leibniz-Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle (Saale), Germany
Fax +49(34)555821309; E-mail: bwesterm@ipb-halle.de
Martin-Luther-University, Institute of Organic Chemistry, Kurt-Mothes-Str. 2, 06120 Halle (Saale), Germany
Leibniz-Institute of Plant Biochemistry, Department of Stress and Developmental Biology, Weinberg 3, 06120 Halle (Saale), Germany
b
c
Received 18 February 2010; revised 17 May 2010
specifically, the incorporation of diazirine and benzophe-
Abstract: Photoaffinity tags can be incorporated easily into pep-
none moieties in different starting materials used for
isonitrile-based MCRs will be discussed. The popularity
of these photoactive moieties stems from the facile gener-
toids and congeners by the Ugi and Passerini multicomponent reac-
tions. Products related to photo-methionine and photo-leucine can
be accomplished by diazirine-containing building blocks. The same
protocols can be used to synthesize derivatives with benzophenone ation of reactive intermediates, namely the formation of
photo cross-linkers.
carbenes from diazirines or radicals from benzophe-
none.10
Key words: photo-methionine, photo-leucine, Ugi reaction,
Passerini reaction, peptoids
R2NH2
Ugi
R1CHO
R3CO2H
R4NC
Passerini
Peptoids (N-substituted glycines) are oligomers that mim-
ic structural and functional features of native peptides.
Assets that make peptoids attractive for biological appli-
cations are enhanced proteolytic stability, increased cellu-
lar permeability, and ease of access by multicomponent
reactions (MCRs).1–3 They have shown promise in regu-
lating a variety of biological phenomena, and can serve as
powerful tools to study biomolecular interactions.4,5
There is currently considerable interest in developing
chemical reagents to manipulate protein–protein interac-
tions as tools for chemical biology or as potential drugs.
To elucidate the mechanisms, for example, involved in the
adhesion to cell surfaces and their biological consequen-
ces, the investigation of the molecular interactions be-
tween recognition domains and their ligands is of high
relevance. For this purpose, photoaffinity-labeling tech-
niques are studied.6,7 For the synthesis of peptoids, several
approaches can be taken; however, the multi-component
approach utilizing the Ugi four-component reaction (Ugi-
4CR) is most successful for creating diversity.8,9 As por-
trayed in Scheme 1, we have applied the Passerini reac-
tion for the synthesis of photoaffinity-labeled a-acyloxy
amides and Ugi reaction for peptoids (Scheme 1). In addi-
tion, we will describe protocols relying on isonitrile-based
MCRs that can be extended to Passerini reactions leading
to depsipeptides.
O
R1
O
R1
H
H
NR4
NR4
R3
N
R2
R3
O
O
O
R1, R2, R3
photoreactive groups
depsipeptides
peptoids
Scheme 1 Passerini and Ugi reactions
The first series of photolabeled products represent diazir-
ine derived Passerini and Ugi products. The diazirine
modification of peptoids was envisaged due to the close
resemblance to photo-methionine 1 and photo-leucine 2.11
In Scheme 2 the synthesis of a-acyloxy amides 6 by the
Passerini reaction is described.
H2N
CO2H
H2N
N
CO2H
1
2
N
N
N
photo-Met
photo-Leu
O
N
N
N
IBX
ref.12
OH
OH
3
4
O
N
NHR2
N
R1CO2H
Isonitrile-based MCRs such as the Ugi reaction start from
an amine, a carbonyl component, a carboxylic acid, and an
isonitrile. If appropriate photoreactive building blocks are
used, the labeled peptoids can be utilized further. More
N
O
R2NC
Table 1
O
6
O
R1
5
Scheme 2 Passerini reaction to diazirine-modified a-acyloxy
amides 6
SYNTHESIS 2010, No. 17, pp 2997–3003
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x.
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x
.
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0
1
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Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258182; Art ID: T04010SS
© Georg Thieme Verlag Stuttgart · New York

2998
M. Henze et al.
PAPER
Diazirine containing alcohol 4 can be synthesized starting particular interest is the Ugi reaction with isonitrile 11
from 3 in a three-step procedure.12 Oxidation of 4 to the (entry 3), the resulting amide bond can be transformed
aldehyde 5 proved to be problematic in our hands; the iso- into an activated amide bond by formation of an indole
lation was always accompanied by decomposition of the amide after acidic cleavage of the acetal. This cleavable
material. According to a protocol by Zhu et al., aldehydes isonitrile-derived amide was developed recently by us and
employed in MCRs can be synthesized in situ and trans- shows high versatility.14 Thus, the complete moiety 10c
formed without further purification.13 Aldehyde 5 was (excluding the activation unit) can be retained on its sub-
formed as intermediate via an IBX-oxidation and convert- sequent treatment with nucleophiles affording a variety of
ed directly to the Passerini products 6 in 52–76% yields carboxylic acid derivatives of interest.14
(Table 1). As can be seen, the Passerini reaction is not
limited to any particular carboxylic acid or isonitrile, lead-
ing to a variety of products in only one step.
In addition, diazirine 9 can be employed as the carboxylic
acid counterpart in Passerini reaction (Scheme 3). The ap-
propriate depsipeptide of this three-component reaction
can be isolated in 88% yield, as exemplified for the syn-
thesis of 12.
Table 1 Depsipeptides by Passerini-3CR
R1CO2H
R4NC
Product
N
N
N N
TsCl, py
NaCN, DMSO
4
0 °C, 24 h
85%
70 °C, 24 h
78%
OTs
CN
N
7
8
N
CbzHN
NC
1
2
PhCO2H
N
H
NHCbz
( )4
NHR3
R2
( )4
PhCO2
R1NH2
R2CHO
R3NC
O
O
O
N
6a 55%
R1
N
N
NaOH (10%)
reflux, 7 h
89%
Table 2
CO2H
N
10
9
N
N
BnCO2H
t-BuNC
N
N
BnCO2
t-Bu
H
BnCHO
t-BuNC
O
N
N
O
O
88%
NHt-Bu
12
6b 52%
O
Bn
N
O
Scheme 3 Ugi reaction to diazirine-modified peptoids 12
N
3
N-Cbz-glycine c-C6H11NC
N
O
NHCbz
c-C6H11
For the synthesis of benzophenone-containing peptoids
and depsipeptides, the same established protocols were
used (Scheme 4). The synthesis of the isonitrile 14 could
be accomplished in two steps by converting amine 13 via
the mixed anhydride method to the corresponding form-
amide followed by dehydration to isonitrile 14. The over-
all yield for this two-step procedure was 90%. In Passerini
and Ugi reactions this isonitrile behaved as expected lead-
ing to the coupled products 15 or 16 in good yields. Func-
O
6c 76%
For diazirine-labeled Ugi products we chose to start from
diazirine-modified acid 9 (Scheme 3). Diazirine 9 can be
achieved in a three step sequence from 4 in an overall
yield of 60%, and can be used subsequently as the carbox-
ylic acid building block (Table 2). The appropriate racem-
ic Ugi products 10a–c were isolated in 47–88% yields. Of
Table 2 Peptoids by Ugi-4CR
R1CHO, R2 NH2
R4NC
Product
O
Bn
N
( )
1
2
i-PrCHO, BnNH2
t-BuNC
2
NHt-Bu
N
N
O
i-Pr
10a 88%
O
O
i-Pr
( )
N
BnCHO, i-PrNH2
i-PrCHO, i-PrNH2
c-C6H11NC
2
NHc-C6H11
N
N
O
Bn
10b 47%
i-Pr
( )
N
2
N
H
CN
3
N
N
O
i-Pr
(MeO)2HC
(MeO)2HC
11
10c 84%
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York

PAPER
Photoaffinity-Labeled Peptoids and Depsipeptides
2999
tionalization, for example, by deprotection of the Cbz- for example, the incorporation in peptides synthesis is
group in 16 allows for further manipulations and facile in- easily possible. Thus the Cbz-protecting group can be re-
corporation into larger assemblies.
moved to give a free amino terminus and the utilization of
the convertible isonitrile 11 allows for cleavage of the C-
terminal amide bond.
O
O
a: HCO2Et
Ac2O
97%
Further syntheses of chemical probes, especially such that
are useful for proteomic studies are currently carried out
and will be reported in due course.
b: POCl3
Et3N
91%
CN
H2N
13
14
O
All chemicals and solvents used are commercially available and
were obtained from Aldrich/Fluka. Petroleum ether (PE) used refers
to the fraction boiling in the range 40–60 °C. Purification of the
crude products by column chromatography was performed on silica
gel 60 (230–400 mesh, 0.040–0.063 mm), Merck, Germany. TLC
identifications of reactants and products were performed on silica
gel coated aluminum foil (silica gel 60 F254 with fluorescence indi-
cator), Merck, Germany. NMR spectra were recorded on a Varian
O
Passerini-3CR
O
Ph
PhCO2H
BnCHO
73%
N
H
Bn
O
15
O
O
Ugi-4CR
Bn
N
1
Mercury 300 spectrometer. All H NMR spectra were reported in
Cbz-GlyOH
BnNH2
i-PrCHO
59%
N
CbzHN
ppm relative to TMS. All 13C NMR spectra are reported in ppm rel-
ative to the central line of the triplet for CDCl3 at 77.00 ppm. IR
spectra were recorded on Nicolet 5700, Thermo Elektron Co. Elec-
trospray ionization mass spectra (ESI-MS) were recorded on an API
150, Applied Biosystems (ionization condition 70 eV). High-reso-
lution mass spectra (HRMS) were recorded on Bruker BioApex 70
eV FT-ICR spectrometer. Determinations of melting points were
accomplished with a Leica DM LS2 microscope (without correc-
H
O
i-Pr
16
Scheme 4 MCRs starting from benzophenone-derived isonitrile 14
Alternatively, the benzophenone-derived carboxylic acid
17, which is commercially available, can be utilized in the
same MCRs (Scheme 5) leading to a modified arrange- tion).
ment of the Ugi starting products.
2-(3-Methyl-3H-diaziren-3-yl)ethanol (4)
4-Hydroxybutan-2-one (3; 11.2 g, 127 mmol) was dissolved in liq-
uid ammonia (200 mL) and stirred for 5 h at reflux temperature. The
solution was then cooled to –60 °C with a dry ice/EtOH bath and a
solution of hydroxylamine O-sulfonic acid (16.0 g, 141 mmol) in
MeOH (100 mL) was added over a 30-min period. The ice bath was
removed and the reaction mixture was stirred at reflux for 1 h. The
ammonia was allowed to evaporate overnight and the resulting slur-
ry was filtered and washed several times with MeOH. The com-
bined organic solutions were evaporated under reduced pressure to
a volume of about 60 mL until no odor of ammonia could be detect-
ed. No further workup was accomplished. The crude methanolic so-
lution of 4 was diluted with MeOH (50 mL) and cooled in an ice
bath. Et3N (12.6 g, 125 mmol) was added keeping the temperature
at 0 °C, upon which solid I2 (19.6 g, 77.4 mmol) was added in small
portions (~1 g/min). The I2 reduction was virtually instantaneous.
After complete addition, the red brown color of excess I2 persisted.
The solution was concentrated to a volume of about 80 mL and
brine (150 mL) was added and extracted with Et2O (4 × 100 mL).
The combined organic solutions were dried (Na2SO4), filtered, and
evaporated under reduced pressure to dryness. The residue was dis-
tilled (70 °C/32 mbar) to obtain 4 as a colorless liquid (5.45 g,
43%).
O
CO2H
17
O
O
Passerini-3CR
t-Bu
O
O
N
H
t-BuNC
BnCHO
66%
Bn
O
O
O
O
19
20
Passerini-3CR
( )
4
CbzHN
CbzHN
N
H
CbzNH(CH4)NC (18)
i-PrCHO
i-Pr
73%
O
O
Ugi-4CR
Bn
( )
N
CbzNH(CH4)NC (18)
BnNH2
4 N
H
i-Pr
O
O
O
O
21
22
i-PrCHO
85%
1H NMR (300 MHz, CDCl3): d = 1.08 (s, 3 H, CH3), 1.64 (t, J = 6.3
Hz, 2 H, CH2), 1.99 (br s, 1 H, OH), 3.54 (t, J = 6.3 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 20.2, 24.2, 36.9, 57.6.
ESI-MS: m/z = 102.0 [M + H]+.
Ugi-4CR
i-Pr
N
11
i-PrNH2
BnCHO
38%
N
H
MeO
Bn
OMe
Phenyl 3-[(4-{[(Benzyloxy)carbonyl]amino}butyl)amino]-2-[(3-
methyl-3H-diaziren-3-yl)methyl]-3-oxopropanoate (6a); Typi-
cal Procedure for the Sequence of IBX-Oxidation/Passerini-
3CR with 2-(3-Methyl-3H-diaziren-3-yl)ethanol (4)
Cbz-4-isocyanobutylamine (0.93 g, 4.00 mmol) and 4 (0.50 g, 4.50
mmol) were dissolved in THF (20 mL) and subsequently, benzoic
acid (0.93 g, 4.50 mmol) and IBX (2.80 g, 10.0 mmol) were added.
The mixture was stirred overnight at 40 °C. After TLC and ESI-MS
Scheme 5 Synthesis of benzophenone-derivatives 19–22
The Passerini products 19 and 20 could be isolated in 66%
and 73% yield, respectively; the appropriate Ugi products
21 and 22 were obtained in yields of 85% and 38%. The
diversity accomplished by the multicomponent reactions
is illustrated by these examples. Further functionalization,
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York

3000
M. Henze et al.
PAPER
monitoring of the formation of the Passerini product, the consumed
IBX was filtered off and the solution was evaporated under reduced
pressure to give the crude oily product. The residue was purified by
column chromatography (EtOAc) to obtain 6a as a light yellow oil
(1.0 g, 55%); Rf = 0.29 (PE–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.08 (s, 3 H, CH3), 1.50–1.52 (m,
4 H, 2 CH2), 1.85, 1.90 (2 d, J = 9.0 Hz, 1 H, CH2), 2.15–2.23 (m, 1
H, CH2), 3.16–3.20 (m, 2 H, CH2), 3.27–3.29 (m, 2 H, CH2), 5.00
(br s, 1 H, NH), 5.04 (s, 2 H, CH2), 5.40–5.44 (m, 1 H, CH), 6.47 (br
s, 1 H, NH), 7.27–7.37 (m, 5 H, 5 CH), 7.42–7.52 (m, 2 H, 2 CH),
7.55–7.65 (m, 1 H, CH), 8.06–8.14 (m, 2 H, 2 CH).
overnight at 4 °C. The mixture was poured into concd HCl (40 mL)
containing ice (150 g). The oily layer was extracted with Et2O
(3 × 100 mL) and the combined Et2O extracts were washed first
with aq 2 M HCl (100 mL), then with aq 2 M NaOH (100 mL), and
finally with brine (100 mL). The organic solution was dried
(Na2SO4), filtered, and evaporated under reduced pressure to obtain
7 as a light yellow oil (4.34 g, 85%); Rf = 0.70 (PE–EtOAc, 1: 1).
1H NMR (300 MHz, CDCl3): d = 1.00 (s, 3 H, CH3), 1.68 (t, J = 6.4
Hz, 2 H, CH2), 2.46 (s, 3 H, CH3), 3.96 (t, J = 6.3 Hz, 2 H, CH2),
7.37 (d, J = 8.1 Hz, 2 H, 2 CH), 7.81 (d, J = 8.2 Hz, 2 H, 2 CH).
13C NMR (75 MHz, CDCl3): d = 19.7, 21.6, 23.3, 34.0, 65.1, 127.9,
129.8, 132.6, 145.0.
ESI-MS: m/z = 277.0 [M + Na]+, 531.1 [2 M + Na]+.
13C NMR (75 MHz, CDCl3): d = 19.9, 23.5, 26.3, 27.1, 37.0, 39.0,
40.4, 66.5, 70.8, 128.0, 128.0, 128.3, 128.4, 128.6, 128.9, 129.9,
129.9, 133.2, 133.8, 136.5, 156.47, 165.4, 168.8.
ESI-MS: m/z = 475.1 [M + Na]+, 927.8, [2 M + Na]+, 451.4 [M –
3-(3-Methyl-3H-diaziren-3-yl)propanenitrile (8)
H]–.
2-(3-Methyl-3H-diaziren-3-yl)ethyl tosylate (7; 4.21 g, 16.6 mmol)
was dissolved in anhyd DMSO (50 mL) and NaCN (1.62 g, 33.1
mmol) was added. The reaction mixture was heated overnight at
60–70 °C, and then H2O (100 mL) was added to the brown solution.
The solution was extracted with Et2O (3 × 50 mL), and the com-
bined Et2O extracts were washed with H2O (2 × 50 mL) and finally
with brine (2 × 50 mL). The Et2O solution was dried (Na2SO4), fil-
tered, and the solvent was evaporated to yield 8 as a light yellow liq-
uid (1.41 g, 78%).
1H NMR (300 MHz, CDCl3): d = 1.12 (s, 3 H, CH3), 1.76 (t, J = 7.5
Hz, 2 H, CH2), 2.26 (t, J = 7.5 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 12.1, 19.2, 24.4, 30.7, 118.4.
ESI-MS: m/z = 109.3 [M + H]+.
HRMS (ESI): m/z calcd for C24H28N4O5 as [M – N2 + Na]+:
439.1957; found: 439.1948.
Benzyl 3-(tert-Butylamino)-2-[(3-methyl-3H-1,2-diaziren-3-
yl)methyl]-3-oxopropanoate (6b)
The IBX-oxidation/Passerini-3CR of 4 (0.50 g, 4.50 mmol), phenyl-
acetic acid (0.61 g, 4.50 mmol), and tert-butyl isonitrile (0.33 g,
4.00 mmol) in the presence of IBX (2.80 g, 10.0 mmol) led to the
formation of diazirine derivative 6b. After purification by column
chromatography (PE–EtOAc, 1:2), 6b was obtained as a yellow oil
(0.66 g, 52%); Rf = 0.83 (PE–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.02 (s, 3 H, CH3), 1.16 (s, 9 H, 3
CH3), 1.60, 1.65 (2 d, J = 8.4 Hz, 2 H, CH2), 3.79 (s, 2 H, CH2),
5.14–5.18 (m, 1 H, CH), 5.52 (br s, 1 H, NH), 7.28–7.37 (m, 5 H, 5
CH).
13C NMR (75 MHz, CDCl3): d = 19.8, 23.4, 28.3, 36.9, 41.6, 51.1,
70.6, 127.5, 128.9, 129.2, 133.3, 167.4, 169.6.
ESI-MS: m/z = 317.9 [M + H]+, 340.2 [M + Na]+, 316.3 [M – H]–.
HRMS (ESI): m/z calcd for C17H23N3O3 + Na [M + Na]+:
3-(3-Methyl-3H-diaziren-3-yl)propanoic Acid (9)
Aq NaOH (10%, 10 mL) was added to 8 (0.68 g, 6.38 mmol). The
mixture was refluxed for 7 h and then Et2O (10 mL) was added. The
aqueous layer was separated and acidified with aq 4 M HCl. Subse-
quently, the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were dried (Na2SO4), filtered, and
evaporated to dryness under reduced pressure to afford 9 as a light
yellow liquid (0.71 g, 89%).
340.16371; found: 340.16296.
1H NMR (300 MHz, CDCl3): d = 1.05 (s, 3 H, CH3), 1.73 (t, J = 7.3
Hz, 2 H, CH2), 2.25 (t, J = 7.7 Hz, 2 H, CH2), 10.98 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 19.6, 25.0, 28.5, 29.3, 178.7.
MS (ESI): m/z = 126.6 [M – H]–.
Benzyl {4-(Cyclohexylamino)-3-[(3-methyl-3H-diaziren-3-
yl)methyl]-2,4-dioxobutyl}carbamate (6c)
The IBX-oxidation/Passerini-3CR of 4 (0.50 g, 4.50 mmol), Cbz-
Gly-OH (0.94 g, 4.50 mmol), and cyclohexyl isonitrile (0.44 g, 4.00
mmol) in the presence of IBX (2.80 g, 10.0 mmol) led to the forma-
tion of 6c. After purification by column chromatography (EtOAc),
6c was obtained as a red-brown oil (1.27 g, 76%); Rf = 0.69
(EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 3 H, CH3), 1.11–1.35 (m,
6 H, 3 CH2), 1.57–1.73 (m, 4 H, 2 CH2), 1.83–1.88 (m, 2 H, CH2),
3.71–3.75 (m, 1 H, CH), 3.98–4.16 (m, 2 H, CH2), 5.11–5.21 (m, 2
H, CH2), 5.25–5.31 (m, 1 H, CH), 5.63 (br s, 1 H, NH), 6.66 (br d,
J = 7.7 Hz, 1 H, NH), 7.31–7.37 (m, 5 H, 5 CH).
Ugi-4CR with 3-(3-Methyl-3H-diaziren-3-yl)propanoic Acid
(9); N2-Benzyl-N-tert-butyl-N2-[3-(3-methyl-3H-diaziren-3-
yl)propanoyl]valinamide (10a); Typical Procedure
BnNH2 (0.08 g, 0.78 mmol) and isobutyraldehyde (0.06 g, 0.78
mmol) were dissolved in MeOH (10 mL) and were stirred for 2 h at
r.t. to preform the imine. Subsequently, 9 (0.10 g, 0.78 mmol) and
tert-butyl isonitrile (0.07 g, 0.78 mmol) were added. The mixture
was stirred for 1 day. When TLC-monitoring and ESI-MS indicated
the formation of the Ugi-4CR product, the mixture was evaporated
to dryness under reduced pressure. The residue was purified by col-
umn chromatography (hexane–EtOAc, 4:1) to obtain 10a as a col-
orless oil (0.26 g, 88%); Rf = 0.65 (hexane–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 0.85 (d, J = 6.8 Hz, 3 H, CH3),
0.91 (s, 3 H, CH3), 0.96 (d, J = 6.6 Hz, 3 H, CH3), 1.30 (s, 9 H, 3
CH3), 1.57–1.78 (m, 2 H, CH2), 1.87–2.12 (m, 2 H, CH2), 2.34–2.42
(m, 1 H, CH), 4.38–4.51 (m, 2 H, CH2), 4.75–4.84 (m, 1 H, CH),
6.26 (br s, 1 H, NH), 7.13–7.20 (m, 2 H, 2 CH), 7.22–7.32 (m, 3 H,
3 CH).
13C NMR (75 MHz, CDCl3): d = 19.8, 24.8, 24.9, 25.4, 32.5, 32.6,
36.8, 43.5, 48.5, 67.3, 71.0, 127.9, 128.3, 128.5, 135.9, 157.1,
167.5, 169.5.
ESI-MS: m/z = 439.0 [M + Na]+, 833.7 [2 M + H]+, 855.1 [2 M +
Na]+.
HRMS (ESI): m/z calcd for C21H28N4O5 as [M – N2 + Na]+:
411.1896; found: 411.1889.
2-(3-Methyl-3H-diaziren-3-yl)ethyl p-Toluenesulfonate (7)15
2-(3-Methyl-3H-diaziren-3-yl)ethanol (4; 2.00 g, 20.0 mmol) was
dissolved in pyridine (20 mL), cooled down with an ice bath and
TsCl (5.71 g, 29.97 mmol) was added in small portions. The reac-
tion mixture was stirred at 0–10 °C for 2 h and allowed to stand
13C NMR (75 MHz; CDCl3): d = 18.9, 19.6, 19.9, 25.3, 27.4, 28.3,
28.5, 29.5, 48.7, 51.3, 65.8, 126.2, 127.2, 128.5, 137.5, 169.1,
173.8.
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York

PAPER
Photoaffinity-Labeled Peptoids and Depsipeptides
3001
ESI-MS: m/z = 372.9 [M + H]+, 395.3 [M + Na]+, 371.1 [M – H]–.
HRMS (ESI): m/z calcd for C21H32N4O2 + Na [M + Na]+:
13C NMR (75 MHz, CDCl3): d = 19.8, 25.1, 28.5, 28.5, 29.0, 37.6,
51.3, 74.8, 126.9, 128.3, 129.6, 135.8, 167.8, 170.8.
395.24230; found: 395.24181.
ESI-MS: m/z = 332.4 [M + H]+, 354.4 [M + Na]+, 330.4 [ M – H]–.
HRMS (ESI): m/z calcd for C18H25N3O3 + Na [M + Na]+:
354.17936; found: 354.17863.
N-Cyclohexyl-Na-[3-(3-methyl-3H-diaziren-3-yl)propanoyl]-
Na-(1-methylethyl)phenylalaninamide (10b)
The Ugi-4CR of 9 (0.09 g, 0.70 mmol), i-PrNH2 (0.04 g, 0.70
mmol), phenylacetaldehyde (0.08 g, 0.70 mmol), and cyclohexyl
isonitrile (0.08 g, 0.70 mmol) led to the formation of the diazirine
derivative 10b. After purification by column chromatography (hex-
anes–EtOAc, 4:1), 10b was obtained as a yellow oil (0.13 g, 47%);
Rf = 0.38 (hexanes–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 0.45 (d, J = 6.6 Hz, 3 H, CH3),
1.09 (s, 3 H, CH3), 1.13 (d, J = 6.6 Hz, 3 H, CH3), 1.16–1.42 (m, 6
H, 3 CH2), 1.54–2.03 (m, 8 H, 4 CH2), 2.07–2.16 (m, 1 H, CH),
3.18–3.24 (m, 1 H, CH), 3.64–3.69 (m, 1 H, CH), 3.72–3.82 (m, 2
H, CH2), 7.14–7.29 (m, 5 H, 5 CH), 7.72 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 19.6, 20.1, 20.9, 24.5, 25.4, 25.5,
28.8, 29.4, 32.5, 32.7, 35.0, 47.9, 49.6, 63.1, 126.6, 128.3, 129.4,
138.3, 171.6, 172.7.
ESI-MS: m/z = 399.4 [M + H]+, 421.3 [M + Na]+, 431.9 [M – H]–.
HRMS (ESI): m/z calcd for C23H34N4O2 + Na [M + Na]+:
N-(4-Benzoyl)phenyl Isocyanide (14)
N-(4-Benzoylphenyl)formamide: A mixture of Ac2O (21.0 mL, 222
mmol) and formic acid (12.0 mL, 318 mmol) was heated at 65 °C
for 3 h. The mixed anhydride was added under reflux to a solution
of 4-aminobenzophenone (13; 4.00 g, 20.3 mmol) and Et3N (9.00
mL, 64.6 mmol) in THF (150 mL). The resulting mixture was re-
fluxed for further 3 h. After cooling to r.t., the solvent was evapo-
rated and the residue was taken up in EtOAc (200 mL) and H2O (50
mL). The solution was neutralized with solid Na2CO3. The organic
phase was separated and washed with sat. aq NaHCO3 (2 × 50 mL)
and brine (2 × 50 mL). After drying (Na2SO4), the organic solvent
was evaporated to yield N-(4-benzoyl)phenylformamide (4.43 g,
97%) as a white solid; mp 85.9–87.5 °C; Rf = 0.41 (hexanes–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 7.23 (m, 2 H, CH), 7.40–7.50 (m,
4 H, CH), 7.52–7.62 (m, 2 H, CH), 7.69–7.87 (m, 10 H), 8.28 (s, 1
H), 8.43 (s, 1 H), 8.89 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 117.1, 119.1, 128.3, 128.4, 129.7,
129.8, 131.6, 132.2, 132.4, 132.5, 133.3, 133.8, 137.4, 137.6, 140.8,
140.9, 159.4, 162.0, 195.5, 195.9.
421.25795; found: 421.25775.
N-[2-(2,2-Dimethoxyethyl)phenyl]-N2-[3-(3-methyl-3H-diaz-
iren-3-yl)propanoyl]-N2-(1-methylethyl)valinamide (10c)
The Ugi-4CR of 9 (0.10 g, 0.78 mmol), i-PrNH2 (0.05 g, 0.78
mmol), isobutyraldehyde (0.06 g, 0.78 mmol), and 2-(2,2-
dimethoxyethyl)phenyl isonitrile (11; 0.15 g, 0.78 mmol) led to the
formation of the diazirine derivative 10c. After purification by col-
umn chromatography (hexanes–EtOAc, 3:1), 10c was obtained as a
colorless oil (0.28 g, 84%); Rf = 0.46 (hexanes–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 0.89 (d, J = 6.4 Hz, 3 H, CH3),
1.06 (s, 3 H, CH3), 1.08 (d, J = 6.4 Hz, 3 H, CH3), 1.10–1.33 (m, 6
H, 2 CH3), 1.70–1.92 (m, 2 H, CH2), 2.12–2.31 (m, 2 H, CH2), 2.84–
2.94 (m, 2 H, CH2), 3.00–3.18 (m, 1 H, CH), 3.33, 3.34 (2 s, 6 H, 2
CH3), 4.05–4.13 (m, 1 H, CH), 4.45–4.54 (m, 2 H, 2 CH), 7.05–7.11
(m, 1 H, CH), 7.19–7.28 (m, 2 H, 2 CH), 7.77–7.81 (m, 1 H, CH),
9.98 (br s, 1 H, NH).
ESI-MS: m/z = 226.4 [M + H]+, 224.4 [M – H]– .
HRMS (ESI): m/z calcd for C14H10NO2 [M – H]–: 224.07115; found:
224.07126.
14: To a solution of N-(4-benzoyl)phenylformamide (2.11 g, 9.37
mmol) and Et3N (12.0 mL, 86.1 mmol) in anhyd THF (200 mL) was
added dropwise POCl3 (2.00 mL, 21.5 mmol) at –65 °C. The result-
ing mixture was allowed to warm to r.t. overnight. The mixture was
poured into ice water (200 mL). The organic phase was separated
and the aqueous phase was extracted with Et2O (3 × 100 mL). The
combined organic layers were dried (Na2SO4) and the organic sol-
vent was evaporated. The residue was purified on silica gel (hex-
anes–EtOAc, 3:1) to yield 14 as a pale yellow solid (1.78 g, 91%);
mp 101.9–103.4 °C; Rf = 0.72 (hexanes–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 7.49–7.53 (m, 4 H), 7.63 (t,
J = 7.3 Hz, 1 H), 7.78 (d, J = 7.0 Hz, 2 H), 7.85 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 126.4, 128.5, 130.0, 131.1, 133.0,
136.6, 138.1, 166.9, 194.9.
13C NMR (75 MHz, CDCl3): d = 20.0, 20.0, 20.3, 20.9, 21.4, 25.3,
26.8, 28.9, 29.5, 35.7, 49.6, 53.4, 53.9, 68.9, 104.8, 123.8, 124.8,
127.1, 128.8, 130.9, 136.4, 171.1, 172.5.
ESI-MS: m/z = 433.4 [M + H]+, 455.2 [M + Na]+, 431.8 [M – H]–.
HRMS (ESI): m/z calcd for C23H36N4O4 + Na [M + Na]+:
EI-MS:
m/z
= 207.2
[M]+,
130.1
[C8H4NO]+, 105.1
455.26343; found: 455.26295.
[C7H5O]+, 102.1 [C7H4N]+, 77.1 [C6H5]+.
1-Benzyl-2-(tert-butylamino)-2-oxoethyl 3-(3-Methyl-3H-diaz-
iren-3-yl)propanoate (12)
2-Oxo-1-benzyl-2-{[4-(phenylcarbonyl)phenyl]amino}ethyl
Benzoate (15)
t-BuNC (0.05 g, 0.55 mmol) and phenylacetaldehyde (0.07 g, 0.55
mmol) were dissolved in CH2Cl2 (4 mL) and subsequently 9 (0.07
g, 0.55 mmol) was added. The mixture was stirred overnight at r.t.
When TLC-monitoring and ESI-MS indicated the formation of the
Passerini-3CR product, the organic layer was washed with aq sat.
NaHCO3 (4 × 4 mL), dried (Na2SO4), filtered, and evaporated under
reduced pressure to give the crude Passerini-3CR product. The res-
idue was purified by column chromatography (PE–EtOAc, 1:2) to
afford (0.16 g, 88%) 12 as a light, yellow oil (0.16 g, 88%);
Rf = 0.85 (EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.00 (s, 3 H, CH3), 1.28 (s, 9 H, 3
CH3), 1.63–1.78 (m, 2 H, CH2), 2.08–2.15 (m, 2 H, CH2), 3.13–3.17
(m, 2 H, CH2), 5.25 (t, J = 7.0 Hz, 1 H, CH), 5.70 (br s, 1 H, NH),
7.16–7.31 (m, 5 H, 5 CH).
To a solution of N-(4-benzoyl)phenyl isocyanide (14; 0.10 g, 0.48
mmol) and phenylacetaldehyde (0.06 g, 0.48 mmol) dissolved in
CH2Cl2 (4 mL) was added benzoic acid (0.06 g, 0.48 mmol). The
mixture was stirred overnight at r.t. When TLC-monitoring and
ESI-MS indicated the formation of the Passerini-3CR product, the
organic layer was washed with sat. aq NaHCO3 (4 × 4 mL), dried
(Na2SO4), filtered, and evaporated under reduced pressure to give
the crude Passerini-3CR product. After purification by column
chromatography (PE–EtOAc, 1:1), 15 was obtained as a brown oil
(0.16 g, 73%); Rf = 0.67 (PE–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 3.41 (d, J = 6.0 Hz, 2 H, CH2),
5.73 (t, J = 6.0 Hz, 1 H, CH), 7.17–7.35 (m, 5 H, 5 CH), 7.43–7.65
(m, 7 H, 7 CH), 7.72–7.77 (m, 4 H, 4 CH), 7.96–8.04 (m, 3 H, 3
CH).
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York

3002
M. Henze et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 37.7, 75.1, 119.3, 127.2, 128.2,
128.6, 128.7, 128.8, 129.6, 129.8, 129.8, 131.4, 132.3, 133.5, 133.9,
135.4, 137.6, 140.6, 165.4, 167.5, 195.5.
1-Benzyl-2-(tert-butylamino)-2-oxoethyl 3-(Phenyl-
carbonyl)benzoate (19)
t-BuNC (0.18 g, 2.21 mmol) and phenylacetaldehyde (0.27 g, 2.21
mmol) were dissolved in CH2Cl2 (10 mL) and subsequently 17
(0.50 g, 2.21 mmol) was added. The mixture was stirred overnight
at r.t. When TLC-monitoring and ESI-MS indicated the formation
of the Passerini-3CR product, the organic layer was washed with
sat. aq NaHCO3 (4 × 4 mL), dried (Na2SO4), filtered, and evaporat-
ed under reduced pressure to give the crude Passerini-3CR product.
After purification by column chromatography (PE–EtOAc, 2:1), 19
was obtained as colorless, amorphous solid (0.63, 66%); Rf = 0.76
(PE–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.24 (s, 9 H, t-C4H9), 3.28 (d,
J = 5.7 Hz, 2 H, CH2), 5.47 (t, J = 5.7 Hz, 1 H, CH), 5.58 (br s, 1 H,
NH), 7.19–7.22 (m, 5 H, 5 CH), 7.49–7.53 (m, 2 H, 2 CH), 7.59–
7.66 (m, 2 H, 2 CH), 7.78–7.81 (m, 2 H, 2 CH), 8.05 (dt, J = 7.7, 1.4
Hz, 1 H, CH), 8.20 (dt, J = 7.9, 1.4 Hz, 1 H, CH), 8.37 (t, J = 1.5 Hz,
1 H, CH).
ESI-MS: m/z = = 450.3 [M + H]+, 472.4 [M + Na]+, 899.8 [2 M +
H]+, 921.5 [2 M + Na]+, 448.1 [M – H]–.
HRMS (ESI): m/z calcd for C29H23NO4 + Na [M + Na]+: 472.15248;
found: 472.15168.
N-[(Benzyloxy)carbonyl]glycyl-N2-benzyl-N-[4-(phenylcarbon-
yl)phenyl]valinamide (16)
BnNH2 (0.05 g, 0.48 mmol) and isobutyraldehyde (0.04 g, 0.48
mmol) were dissolved in MeOH (2 mL) and stirred for 2 h at r.t. to
preform the imine. Subsequently, Cbz-Gly-OH (0.10 g, 0.48 mmol)
and N-(4-benzoyl)phenyl isocyanide (14; 0.10 g, 0.48 mmol) were
added and the mixture was stirred for 1 day. When TLC-monitoring
and ESI-MS indicated the formation of the Ugi-4CR product, the
mixture was evaporated to dryness under reduced pressure. After
purification by column chromatography (PE–EtOAc, 1:3), 16 was
obtained as a light brown, amorphous solid (0.16 g, 59%); Rf = 0.67
(PE–EtOAc, 1:3).
1H NMR (300 MHz, CDCl3): d = 0.88 (d, J = 6.4 Hz, 3 H, CH3),
1.01 (d, J = 6.4 Hz, 3 H, CH3), 2.53–2.67 (m, 1 H, CH), 3.85–3.97,
4.08–4.20 (m, 2 H, CH2), 4.31–4.60 (m, 2 H, CH2), 4.69–4.90 (m, 1
H, CH), 5.09 (s, 2 H, CH2), 5.73 (br s, 1 H, NH), 7.01–7.33 (m, 10
H, 10 CH), 7.42–7.64 (m, 5 H, 5 CH), 7.66–7.76 (m, 4 H, 4 CH),
9.15 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 28.4, 37.7, 51.3, 75.3, 126.9,
128.3, 128.5, 128.9, 129.5, 129.7, 130.0, 130.9, 132.9, 133.2, 134.6,
135.7, 136.8, 138.0, 164.3, 167.5, 195.4.
ESI-MS: m/z = 430.6 [M + H]+, 452.2 [M + Na]+, 859.6 [2 M + H]+,
881.5 [2 M + Na]+.
HRMS (ESI): m/z calcd for C27H27NO4 + Na [M + Na]+: 452.18378;
found: 452.18336.
13C NMR (75 MHz, CDCl3): d = 19.0, 19.7, 26.7, 43.4, 49.4, 67.0,
119.1, 126.3, 127.5, 127.9, 128.0, 128.2, 128.5, 128.6, 129.0, 129.8,
131.4, 132.1, 133.0, 135.3, 136.1, 137.8, 141.6, 156.1, 168.1, 171.4,
195.6.
1-[(4-{[(Benzyloxy)carbonyl]amino}butyl)carbamoyl]-2-meth-
ylethyl 3-(Phenylcarbonyl)benzoate (20)
To a solution of benzyl 4-isocyanobutyl carbamate (18; 0.51 g, 2.21
mmol) and isobutyraldehyde (0.16 g, 2.21 mmol) in CH2Cl2 (10
mL) was added 17 (0.50 g, 2.21 mmol). The mixture was stirred
overnight at r.t. When TLC-monitoring and ESI-MS indicated the
formation of the Passerini-3CR product, the organic layer was
washed with sat. aq NaHCO3 (4 × 4 mL), dried (Na2SO4), filtered,
and evaporated under reduced pressure to give the crude Passerini-
3CR product. After purification by column chromatography (PE–
EtOAc, 1:1), 20 was obtained as a colorless, amorphous solid (0.67
g, 57%); Rf = 0.47 (PE–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.02 (d, J = 6.8 Hz, 3 H, CH3),
1.03 (d, J = 6.8 Hz, 3 H, CH3), 1.42–1.61 (m, 4 H, 2 CH2), 2.41–
2.47 (m, 1 H, CH), 3.17–3.34 (m, 4 H, 2 CH2), 5.03 (s, 2 H, CH2),
5.08 (br s, 1 H, NH), 5.24 (d, J = 4.6 Hz, 1 H, CH), 6.34 (br s, 1 H,
NH), 7.28–7.34 (m, 5 H, 5 CH), 7.47–7.52 (m, 2 H, 2 CH), 7.57–
7.65 (m, 2 H, 2 CH), 7.77–7.81 (m, 2 H, 2 CH), 8.01 (dt, J = 7.9, 1.4
Hz, 1 H, CH), 8.30 (dt, J = 7.9, 1.4 Hz, 1 H, CH), 8.48 (t, J = 1.4 Hz,
1 H, CH).
ESI-MS: m/z = 578.7 [M + H+], 600.4 [M + Na]+, 1177.6 [2 M +
Na]+, 576.8 [M – H]–.
Benzyl 4-Isocyanobutylcarbamate (18)
Benzyl 4-aminobutylcarbamate16 (8.00 g, 36.0 mmol) was dis-
solved in ethyl formate (250 mL). The solution was refluxed for 4
h. After complete conversion of the amine, the solution was evapo-
rated to dryness. Benzyl [3-(formylamino)butyl]carbamate was ob-
tained as a colorless oil (8.90 g, 36.0 mmol, 99%) and was used
without further purification. To a solution of benzyl [4-(formylami-
no)butyl]carbamate (8.90 g, 35.5 mmol) in anhyd CH2Cl2 (200 mL)
was added (i-Pr)2NH (15.7 mL, 112 mmol). The solution was
cooled to 0 °C and POCl3 (3.90 mL, 42.6 mmol) was added slowly
via a syringe. The cooling bath was removed and the solution was
allowed to warm to r.t. The solution was stirred for 2 h at r.t. Aq
Na2CO3 (10%, 100 mL) was then added and the solution was stirred
for additional 30 min. CH2Cl2 (100 mL) and H2O (100 mL) were
added, the organic phase was separated, and the aqueous phase was
extracted with CH2Cl2 (2 × 100 mL). The combined organic phases
were dried (Na2SO4) and the solvent was evaporated. After column
chromatography (CH2Cl2–MeOH, 9:1), 18 was obtained as a brown
oil (13.0 g, 89%); Rf = 0.71 (CH2Cl2–MeOH, 9:1).
13C NMR (75 MHz, CDCl3): d = 17.1, 18.9, 26.5, 27.2, 30.6, 38.8,
40.4, 66.5, 79.1, 128.0, 128.4, 128.4, 128.7, 129.7, 130.0, 131.0,
132.9, 133.3, 134.6, 136.5, 136.7, 138.1, 156.4, 164.8, 169.1, 195.5.
ESI-MS: m/z = 531.3 [M + H]+, 553.4 [M + Na]+, 1083.8 [2 M +
Na]+, 529.5 [M – H]–.
HRMS (ESI): m/z calcd for C31H34N2O6 + Na [M + Na]+:
553.23146; found: 553.23143.
1H NMR (300 MHz, CDCl3): d = 1.66 (br s, 4 H, 2 CH2), 3.22 (m,
2 H, CH2), 3.40 (br s, 2 H, CH2), 4.91–5.04 (m, 1 H, NH), 5.08 (s, 2
H, CH2), 7.28–7.43 (m, 5 H, CH).
13C NMR (75 MHz, CDCl3): d = 26.2, 26.9, 39.9, 41.0, 41.1, 41.2,
66.6, 127.9, 127.9, 128.3, 136.2, 155.7, 155.8, 155.9, 156.2.
ESI-MS: m/z = 255.4 [M + Na]+.
HRMS (ESI): m/z calcd for C13H16N2O2 + Na [M + Na]+:
Benzyl {4-[(N-Benzyl-N-{[3-(phenylcarbonyl)phenyl]carbon-
yl}valyl)amino]butyl}carbamate (21)
BzNH2 (0.24 g, 2.21 mmol) and isobutyraldehyde (0.16 g, 2.21
mmol) in MeOH (8 mL) were stirred for 2 h at r.t. to preform the
imine. Subsequently, 17 (0.50 g, 2.21 mmol) and benzyl 4-isocy-
anobutyl carbamate (18; 0.51 g, 2.21 mmol) were added and the
mixture was stirred for 1 day. When TLC-monitoring and ESI-MS
indicated the formation of the Ugi-4CR product, the mixture was
evaporated to dryness under reduced pressure. After purification by
255.11096; found: 255.11063.
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York

PAPER
Photoaffinity-Labeled Peptoids and Depsipeptides
3003
column chromatography (PE–EtOAc, 1:3), 21 was obtained as a
light brown oil (1.17 g, 85%); Rf = 0.58 (PE–EtOAc, 1:3).
Acknowledgment
Financial support by the Leibniz-Society (PFI-project) is highly ap-
preciated.
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 6.4 Hz, 3 H, CH3),
1.04 (d, J = 6.4 Hz, 3 H, CH3), 1.42–1.58 (m, 4 H, 2 CH2), 2.64–
2.68 (m, 1 H, CH), 3.07–3.32 (m, 4 H, 2 CH2), 4.27 (d, J = 11.0 Hz,
1 H, CH), 4.47–4.52, 4.70–4.75 (m, 2 H, CH2), 5.02 (br s, 1 H, NH),
5.08 (s, 2 H, CH2), 6.88 (br s, 1 H, NH), 7.13–7.23 (m, 5 H, 5 CH),
7.27–7.33 (m, 7 H, 7 CH), 7.39–7.51 (m, 4 H, 4 CH), 7.57–7.66 (m,
3 H, 3 CH), 7.75–7.77 (m, 2 H, 2 CH).
13C NMR (75 MHz, CDCl3): d = 19.2, 19.9, 26.6, 27.0, 27.3, 38.8,
40.5, 51.9, 53.4, 66.5, 67.3, 127.3, 128.0, 128.3, 128.3, 128.4,
129.9, 130.2, 131.1, 132.7, 136.6, 136.8, 137.7, 156.4, 170.0, 173.0,
195.4.
References
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ESI-MS: m/z = 620.6 [M + H]+, 642.4 [M + Na]+, 1262.0 [2 M +
Na]+, 618.9 [M – H]–.
(3) Domling, A. Chem. Rev. 2006, 106, 17; and references cited
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HRMS (ESI): m/z calcd for C38H41N3O5 + Na [M + Na]+:
642.29439; found: 642.29333.
N-[2-(2,2-Dimethoxyethyl)phenyl]-Na-(1-methylethyl)-Na-{[3-
(phenylcarbonyl)phenyl]carbonyl}phenylalaninamide (22)
i-PrNH2 (0.13 g, 2.21 mmol) and phenylacetaldehyde (0.27 g, 2.21
mmol) in MeOH (8 mL) were stirred for 2 h at r.t. to preform the
imine. Subsequently, 17 (0.50 g, 2.21 mmol) and 11 (0.42 g, 2.21
mmol) were added and the mixture was stirred for 1 day. When
TLC-monitoring and ESI-MS indicated the formation of the Ugi-
4CR product, the mixture was evaporated to dryness under reduced
pressure. After purification by column chromatography (PE–
EtOAc, 1:3), 22 was obtained as a light yellow oil (0.38 g, 38%);
Rf = 0.61 (PE–EtOAc, 1:1).
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1H NMR (300 MHz, CDCl3): d = 0.48 (d, J = 6.4 Hz, 3 H, CH3),
1.16 (d, J = 6.4 Hz, 3 H, CH3), 2.99–3.06 (m, 2 H, CH2), 3.31 (s, 3
H, 2 CH3), 3.35 (s, 3 H, 2 CH3), 3.44 (d, J = 8.8 Hz, 2 H, CH2), 3.79
(quint, J = 6.6 Hz, 1 H, CH), 4.05–4.12 (m, 1 H, CH), 4.49 (t,
J = 5.5 Hz, 1 H, CH), 7.10–7.34 (m, 9 H, 9 CH), 7.43–7.65 (m, 5 H,
5 CH), 7.69–7.79 (m, 2 H, 2 CH), 7.84–7.88 (m, 2 H, 2 CH), 9.90
(br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 19.7, 21.1, 34.4, 36.0, 52.2, 54.6,
62.8, 106.4, 124.3, 125.1, 127.0, 127.1, 127.9, 128.3, 128.4, 128.6,
128.9, 129.7, 129.8, 129.9, 130.5, 130.8, 131.1, 132.7, 136.4, 137.0,
137.7, 137.9, 170.6, 172.3, 195.7.
ESI-MS: m/z = 579.8 [M + H]+, 601.7 [M + Na]+, 1179.5 [2 M +
(15) Kuhn, C. S.; Lehmann, J.; Sandhoff, K. Bioconjugate Chem.
1992, 3, 230.
(16) Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Synthesis
2002, 2195.
Na]+, 577.8 [M – H]–.
HRMS (ESI): m/z calcd for C36H38N2O5 + Na [M + Na]+:
601.26784; found: 601.26779.
Synthesis 2010, No. 17, 2997–3003 © Thieme Stuttgart · New York