Cysteine Isocyanide in Multicomponent Reaction: Synthesis of Peptido-Mimetic 1,3-Azoles

Article abstract of DOI:10.1021/acs.joc.7b01615

An alternative approach toward the simple and robust synthesis of highly substituted peptidic thiazole derivatives using Ugi-multicomponent reaction (U-MCR) is described. Thus, we introduced the enantiopure (R)-2-methyl-2-isocyano-3-(tritylthio)propanoate as a novel class of isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of bis-heterocyclic rings were also synthesized through the proper choice of the aldehyde component in the U-4CR. The method opens a wide range of applications toward the synthesis of nonribosomal natural products and other bioactive compounds.

Full text of DOI:10.1021/acs.joc.7b01615

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Article
Cysteine isocyanide in multicomponent reaction:
Synthesis of peptido-mimetic 1,3-azoles
Thimmalapura M. Vishwanatha, Katarzyna Kurpiewska, Justyna Kalinowska-T#u#cik, and Alexander Dömling
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01615 • Publication Date (Web): 17 Aug 2017
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Cysteine isocyanide in multicomponent reaction: Synthesis of peptido-mimetic
1
,3-azoles
a
b
b
Thimmalapura M. Vishwanatha, Katarzyna Kurpiewska, Justyna KalinowskaꢀTłuścik and
a
Alexander Dömling *
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a
b
University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Jagiellonian University, Department of Crystal Chemistry and Crystal Physics, Ingardena 3, 30ꢀ060 Karkow,
Poland.
Email a.s.s.domling@rug.nl
Abstract
An alternative approach towards the simple and robust synthesis of highly substituted peptidic
thiazole derivatives by using Ugiꢀmulticomponent reaction (UꢀMCR) is described. Thus, we
introduced the enantiopure (R)ꢀ2ꢀmethylꢀ2ꢀisocyanoꢀ3ꢀ(tritylthio)propanoate as novel class of
isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to
afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of
bisꢀheterocyclic rings were also synthesized through the proper choice of the aldehyde
component in the Uꢀ4CR. The method opens a wide range of applications towards the synthesis
of nonꢀribosomal natural product and other bioactive compounds.
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Introduction
Cysteine (Cys, C) possessing peptides and proteins have attracted widespread attention in
1,2
medicinal chemistry as well as chemical biology. It has been the most prominent target
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in protein chemical synthesis and postꢀtranslational modifications. One such
modification involves the biosynthetic incorporation of thiazole onto the growing peptide
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through enzymatic cyclization (Figure 1). The thiazole moiety has been commonly found
6,7
in a variety of natural products with associated interesting biological activities.
Plantazolicin is a structurally impressive natural product containing multiple oxazole and
thiazole moieties in which three and four heterocyclic rings are connected in a
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consecutive fashion. A large number of synthetic drugs also comprises thiazole ring as
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active part in the molecule. Due to the broad spectrum of pharmacological activities of
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1,3ꢀazoles numerous methods for their preparation have been described. Commonly
available synthetic methods mostly involve conventional peptide synthesis bearing
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Cys/Ser/Thr amides followed by cylcodehydration and oxidation. However, the classical
peptide synthesis is sequential, time consuming and costly. On the other hand, the Ugi
multicomponent reaction (UꢀMCR) is an alternative approach for the synthesis of short
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peptide sequences. It produces αꢀaminoꢀamides from isocyanides which allows an easy
and simple way for the synthesis of libraries of small molecules, peptides,
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peptidomimetics and macrocycles. Additionally, postꢀcondensation modification of
isocyanideꢀbased MCRs allow for a simple and fast entry to medicinal chemistry
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applications.
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Figure 1. Biosynthesis of 1,3ꢀazoles from Cys and Ser peptides
Focusing on the synthesis of thiazole derivatives through UꢀMCR, we have previously
developed a oneꢀpot thiazole synthesis through the Ugi reaction of thioacids and
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Schöllkopf isocyanide (Figure 2A, route 1). The reaction was used in the total synthesis
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of tubulysin derivatives. Similarly, the Kazmaier group employed a twoꢀstep synthesis
involving UꢀMCR of thioacid and isocyanodimethylacetal and the resulting
endothiopeptidic derivatives were cyclized to yield terminal thiazole peptide analogues
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(
Figure 2A, route 2). Although, the methods offer a variety of advantages but still they
deserve improvement due to the limited availability of thioacids and the rather low yields
due to the air sensitive nature of the thioacids. To overcome these issues, we were
interested in an alternative MCR strategy for the synthesis of 1,3ꢀazole derivatives. In this
context, synthesis of isocyanide derived from cysteine amino acid would be an ideal
choice. Moreover, dipeptide isocyanide bearing cysteine derivatives with an Sꢀethyl
carbamate protecting group have been recently described for the synthesis of
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polyisocyanides. In another report, (R)ꢀmethyl 3ꢀ(benzythio)ꢀ2ꢀisocyanopropanoate was
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described for the synthesis of corresponding isoselenocyanate. However, benzyl
protection for thiol is not promising for many postꢀmodifications on sulfur. Very recently,
we have synthesized the stable and enantiomerically pure chiral isocyanide derived from
Sꢀtrityl protected cysteine and employed it for the preparation of disulfide bridged
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macrocycles. Herein we describe another important application of isocyanide
MCR to access peptidic thiazole derivatives in short (Figure 2B).
4 in Uꢀ
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A
COOR
R1
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(1 step)
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COOR
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R NH
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Domling 2000
+
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R CHO
+
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R COSH
R3 R2
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NC
O
N
O
N
R1
TMSCl, NaI (2 step)
S
Kazmaier 2003
B
this work
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COOR
STrt
R NH2
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N
+
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R3
CN
S
R CHO
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. Tf O, Ph SO,Py,MnO
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+
O
R2
N
COOR
3
R COOH
(2 step)
Figure 2. (a) Previous works on thiazole synthesis using Ugi multicomponent reaction and (b)
this work
Results and discussion
We synthesized isocyanide
. The esterification of with thionyl chloride yielded
was subjected to formylation with methylformate to afford formyl protected Cys(Trt)ꢀ
OMe in 95% yield. Next, we examined the enantiopure preparation of isocyanide
Commonly employed dehydrating conditions such as POCl /TEA, POCl /NMM,
4
from readily available Cys(Trt)ꢀOH
1 according to Scheme
1
1
2
in quantitative yield. The latter
3
4.
3
3
diphosgene/NMM at ꢀ78 °C resulted in considerable racemization and also affords low
22,14b
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yields.
Burgess reagent and phosgene derivatives have been commonly employed
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for the epimerizationꢀfree synthesis of amino acid isocyanides. We carried out the
dehydration of in the presence of triphosgene (0.35 eq.) and NMM (2.0 eq.) at ꢀ78 °C
for 3 h and in fact isocyanide was obtained in 85% yield and high enantiopurity as
shown by chiral HPLC (SI). The synthesis of has also been performed on a 30 g scale.
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Scheme 1. Synthesis of chiral Cys(Trt)ꢀisocyano methyl ester 4
To demonstrate the usefulness of the novel isocyanide
4
, we tested its competency in
peptide synthesis involving UꢀMCR. The most straightforward approach would involve
ammonia as an amine component. However, the Ugi reaction using ammonia is often
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described as complex and low yielding, or no product formation is observed at all. To
overcome these issues, cleavable amine components or ammonium salts of carboxylic
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acid have been developed. However, cleavable amine or aldehyde components require
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additional steps and racemization is possible. In principle, ammonium salts of
carboxylates could be ideal components in the UꢀMCR due to their general and simple
preparation while maintaining a neutral pH during the Ugi reactions thus avoiding
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racemization during the peptide synthesis. Therefore we have synthesized ammonium
salt of carboxylates derived from ꢀprotected amino acids (1.0 eq.) by the treatment of
ammonium bicarbonate in a mixture of CH CN:H O. The ammonium salts were easy to
N
3
2
isolate by filtration. In a general Ugi reaction the aldehyde component was added to the
ammonium salt of carboxylate in trifluoroethanol (TFE, 0.1 M) at 0 °C. After 15 minutes
isocyanide
4 was added and allowed to stir at r.t. for 24 h (Table 1). Aldehyde such as
paraformaldehyde and isovaleraldehyde produced the Ugi adducts 5a-c in moderate
yields. Next, with the aim to access oxazoles, we focused on the incorporation of serine
side chains into peptides using glycolaldehyde dimer (Table 1, entries 5d-f).
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Table 1. Synthesis of Ugi products 5 using isocyanide 4
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Isolated yields are given; diastereomeric ratios are given according to H NMR analysis; enantiomeric excess determined by
chiral SFCꢀHPLC
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In these cases, the Ugi products were obtained in moderate yields without detection of
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any byproducts such as Passerini or Ugiꢀ5Cꢀ3CR products as previously observed. The
synthesis of selenopeptidic derivatives through UꢀMCR reaction have been well
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described. However, similar incorporation of sulfur is less common through UꢀMCR,
for example, spiro derivatives of thiazolines were employed as components in UꢀMCR for
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the assembly of constrained analogues of peptides. In an effort to introduce Cys moieties
into glutathione derivatives, benzylthio aldehdyes and ketones were used in the Ugi
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reaction. The benzyl protecting group for thiol, however, is not compatible for a
straightforward postꢀmodification strategy. The simple and scalable preparation of trityl
protected mercaptoacetaldehyde as a component in Uꢀ4CR is therefore a viable
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alternative to other procedures. Interestingly, trityl protected mercaptoacetaldehyde
reacted with the ammonium salts of Nꢀprotected acids and isocyanide at r.t. The
4
reaction indeed worked well and the respective Ugi products were obtained in moderate
yields (Table 1, entries 5g-i). These examples demonstrate that sequential Cys(Trt)
derivatives can be incorporated into the peptide backbone through the UꢀMCR. To
demonstrate the general utility of the isocyanide
4
in the classical Uꢀ4CR, simple primary
ꢀalkylated Ugi products
amines, acids and aldehydes were also employed. The resulting
N
were obtained in excellent yields (Table 1, entries 5j-l). The diastereoselectivity of the
Ugi products varied from 1:0.5 to 1:0.8. Compounds 5a and 5b were obtained as single
crystals analysis confirmed their structures (Figure 3). As shown in table 1, the yields of
Ugi products 5a-5i are low when compare to the Ugi products 5j-5l. The moderate yields
for 5a-5i is due to slow reactivity of the aldehydes with ammonium salt of carboxylates as
evidenced by the LCꢀMS analysis of the crude reaction mixtures which showed only
desired product and unreacted staring materials.
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Figure 3. ORTEP pictures of Ugi products 5a and 5b
The retention of the optical purity of the isocyanide or the carboxylic acid was accessed
by using model Ugi products 5m and 5n (Figure 4) The excellent enantioselectivities
.
observed in Ugi products 5a and 5m revealed that retention of chirality is maintained in
the isocyanide part. An additional set of Ugi products 5a and 5n also showed that
negligible epimerization was observed even at the Nꢀprotected amino acids. No
racemization observed here, we speculate, is due to the neutral conditions in the Ugi
28d
reaction. This is also supported by the work of others.
STrt
STrt
O
O
H
H
N
N
FmocHN
N
H
COOMe FmocHN
N
H
COOMe
O
O
a
b
5m 51%, ee 99%
5n 45%, ee 97%
a
b
(
D)ꢀenantiomer of the isocyanide 4 is used in Uꢀ4CR; Fmocꢀ(D)ꢀValꢀOH is used as acid component; isolated yields are given;
enantiomeric excess determined by chiral SFCꢀHPLC
Figure 4 Racemization test for Uꢀ4CR
Having Cys(Trt) containing Ugi products at hand, we next elaborated the
cyclodehydration towards thiazoles. We envisioned a cascade cyclization of Ser/Cys(Trt)
or Cys(Trt)/Cys(Trt) amides fallowed by oxidation of resulting azolines to azoles in oneꢀ
pot to avoid tedious isolations and purifications of intermediates. Activated MnO has
2
been commonly used oxidant for the conversion of azolines to azoles and it is highly
compatible for many organic solvents. We speculated that direct treatment of MnO after
2
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the cyclodehydration could access to thiaozles in oneꢀpot. Consequently, various known
cyclodehydrating fallowed by MnO oxidation procedures were examined by using 5d as
2
a model substrate (Table 2). Literature reported reagents such as TiCl (Table 2, entries
4
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a,b), diethylaminosulfur trifluoride (DAST) (Table 2, entries c, d) and tosyl chloride
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(TsꢀCl) (Table 2, entries e,f) were tested under various conditions from equimolar
amounts to large excess.
a
Table 2. Optimization studies for the synthesis of 6d
Entry
A
Reagent
Conditions
0 °C to r.t.
r.t.
ꢀ78 °C to 0 °C
ꢀ78 °C to 0 °C
60 °C
Time (h)
Yield of 6d (%)
TiCl (6 eq.)
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24
24
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8
10
ꢀ
12
15
ꢀ
4
B
C
D
E
F
G
TiCl (6 eq.)
4
DAST (5 eq.)
DAST (10 eq.)
TsꢀCl (10 eq.)
TsꢀCl (20 eq.)
Tf O/PPh O
60 °C
ꢀ78 °C
ꢀ
18
2
3
(
3.0 eq./6 eq.)
H
I
Tf O/PPh O
(3.0 eq./6 eq.)
ꢀ20 °C
ꢀ78 °C
8
5
28
62
2
3
Tf O/Ph SO/ Py
2
2
(
3.0 eq./6.0 eq./
0.0 eq.)
1
a
All reactions were conducted at 1.0 mmol scale; time refers to the formation of thiazoline. Activated MnO (10 eq.)
2
was added to the crude thiazoline flowed by refluxed at 80 ºC for 3 h in CHCl ; isolated yields are given
3
All these reagents afforded complex product mixtures and often in low yields. Finally, we
employed Tf O (3.0 eq.)/PPh O (6 eq.) at ꢀ78 °C (Table 2, entry g) and 6d was obtained
2
3
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in 18% yield. When the reaction was carried out at ꢀ20 °C (Table 2, entry h) resulted in
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8% of 6d. Further optimization by increasing the amount of reagents and time did not
gave improved results. Encouragingly, changing the additive to Ph SO (6 eq.) and by
2
using pyridine (10 eq.) as base in the presence of Tf O at ꢀ78 °C afforded 62% of 6d after
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MnO oxidation (Table 2, entry i). As shown in table 3, the optimized conditions
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worked well for bisꢀ as well as monoꢀcyclodehydration of Cys(Trt)ꢀamides (Table 3, 6a-
6l).
a
Table 3. List of thiazole derivatives synthesized.
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Isolated yields are given
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5
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5
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5
5
5
6
In order to examine the racemization of the intermediate thiazolines, two peptide
thiazolines 7a and 7b were isolated in moderate yield and were obtained in good
enantioselectivity, indicating low epimerization (Figure 5).
0
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Isolated yields are given; enatiomeric excess determined by chiral SFCꢀHPLC.
Figure 5. Thiazolines isolated for racemization test
Conclusions
In summary, we have introduced the cysteineꢀderived chiral isocyanide
4 as a versatile
component for the short synthesis of thiazole and bisꢀoxazole/thiazole derivatives via
UgiꢀMCR and subsequent cyclodehydration strategy. We believe the methodology will
prove for the formation of oxazole and thiazole fragments in natural product synthesis and
their unnatural derivatives as well as in the synthesis of heterocyclic libraries to enrich
40
screening decks, for example the European Lead Factory. Additionally, the described
novel isocyanide has wide synthetic applications in multicomponent reactions beyond
thiazole formation, as we will communicate shortly.
Experimental Section
General methods
All N–protected amino acids, reagents and solvents were purchased from Sigma Aldrich. The
enantiomers of the Cys(Trt)–OH were purchased from abcr GmbH company were used as
received. All reaction mixtures were stirred magnetically and were monitored by thin–layer
chromatography using silica gel precoated glass plates, which were visualized with UV light and
then, developed using iodine. Flash chromatography was performed on a Teledyne ISCO
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Combiflash Rf , using RediSep Rf Normal–phase Silica Flash Columns (Silica Gel 60 Å, 230 –
400 mesh). Cyclodehydration was carried under nitrogen atmosphere. Nuclear magnetic
1
resonance spectra were recorded on a Bruker Avance 500 spectrometer { H NMR (500 MHz),
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1
C NMR (125 MHz)). Chemical shifts for H NMR were reported as δ values and coupling
1
13
constants were in hertz (Hz). H and C NMR values are given for major diastereomeric Ugi
product. Mass spectra were measured on a Waters Investigator Supercritical Fluid
Chromatograph with a 3100 MS Detector (ESI) using a solvent system of methanol and CO on
2
either a Viridis 2ꢀethyl pyridine column (4.6 × 250 mm, 5 µm particle size) or a Viridis silica gel
column (4.6 × 250 mm, 5 µm particle size) and reported as (m/z). The specifications of chiral
SFCꢀHPLC details are given on respective spectra. Optical rotations were measured using a 1
mL cell with a 10 mm path length on an Pꢀ2000 JASCO digital polarimeter.
Methyl S–trityl–L–cysteinate, 2
This compound was synthesized according to the procedure of Graham et al. and the analytical
[
41]
data were compared.
To a stirred solution of S–trityl–L–cysteine (1.0 g, 2.76 mmol) in 50 mL of methanol at 0 ˚C
was added thionyl chloride (1.50 mL, 0.206 mmol) in a dropwise fashion. The solution was
allowed to warm up to r.t. and then refluxed at 80 °C for 5 h. The solvent was removed under
reduced pressure and the crude product was extracted with ethyl acetate and washed with
saturated sodium bicarbonate for several times. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated to give ester 2 as a pale yellow gum.
2
0
f
yield = 85% (0.865 g), yellow gum, R 0.41 (PE/EtOAc, 1:1), [α]D = +31.5 (C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.47 – 7.14 (m, 15H), 6.73– 6.78 (br, m, 2H), 3.62 (s, 3H), 3.20
3
(m, 1H), 2.58 (dd, J = 12.4, 4.9 Hz, 1H), 2.47 (dd, J = 12.5, 7.7 Hz, 1H).
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13
C NMR (126 MHz, CDCl ) δ 174.1, 144.4, 129.7, 129.5, 128.0, 127.9, 127.7, 126.8, 126.7,
3
66.8, 53.7, 52.1, 36.8.
+
MS (ESI) m/z: [M + Na] Calcd for C H NO SNa 400.13; Found 400.10.
2
3
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Methyl N–formyl–S–trityl–L–cysteinate, 3
Amine 2 (1.0 g, 2.65 mmol) was dissolved in methyl formate (10 mL, solvent) and the solution
was allowed to reflux at 60 °C until TLC showed complete consumption of the starting material
(
usually 24 h). The solvent was evaporated and the product was purified through column
chromatography to yield formyl ester 3 as a white solid.
yield = 95% (1.03 g), white solid, mp: 132–133 °C, R 0.50 (PE/EtOAc, 1:1), [α]D = +19.1
20
f
(
C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.95 (s, 1H), 7.50 – 7.11 (m, 15H), 6.14 (d, J = 8.1 Hz, 1H), 4.64
3
(dt, J = 8.2, 5.2 Hz, 1H), 3.68 (s, 3H), 2.77 (dd, J = 12.7, 5.8 Hz, 1H), 2.69 (dd, J = 12.9, 6.5 Hz,
1H).
1
3
C NMR (126 MHz, CDCl ) δ 170.3, 160.4, 144.1, 129.4, 128.0, 128.0, 126.9, 126.8, 67.0, 52.6,
3
49.7, 33.5.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO S 406.1471; Found 406.1477.
24
24
3
Methyl (R)–2–isocyano–3–(tritylthio)propanoate, 4
To a solution of N–formyl Cys(Trt)–methyl ester 3 (30.0 g, 74.0 mmol) in CH Cl (150.0 mL) at
2
2
–78 °C, N–methylmorpholine (2.0 eq. 16.5 mL) was added. After 5 min triphosgene (7.6 g, 0.35
eq.) in CH Cl (50.0 mL) was added dropwise and the reaction mixture was stirred for 3h at –78
2
2
o
C (TLC analysis). Saturated NaHCO solution (10 mL) was added at same temperature and
3
allowed to warm to r.t. The reaction mixture was extracted with CH Cl , the organic extracts
2
2
were separated, dried over anhydrous Na SO , filtered, and concentrated. The solution was
2
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diluted with diethyl ether (10 mL) and stored at –15 °C for 5 h which resulted pure solid of
isocyanide 4 which was collected by filtration.
20
yield = 85% (24.3 g), white solid, mp: 96 –97 °C, R 0.42 (EtOAc/ PE, 10:90), [α]D = +32.8
f
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60
(
C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.57 – 7.06 (m, 15H), 3.70 (s, 3H), 3.34 (dd, J = 7.7, 5.8, Hz, 1H),
3
2
.89 – 2.63 (m, 2H).
1
3
C NMR (126 MHz, CDCl ) δ 165.6, 160.9, 143.9, 129.4, 129.2, 128.2, 128.0, 128.0, 127.9,
3
127.1, 67.5, 55.3, 53.4, 34.2.
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO S 388.1365; Found 388.1363.
+
2
4
22
2
Methyl S–trityl–R–cysteinate, 2b
This compound was synthesized according to general procedure for the preparation of 2 by using
S–trityl–R–cysteine 1b (1.0 g, 2.76 mmol)
2
0
f
yield = 80% (0.830 g), yellow gum; R 0.41 (PE/EtOAc, 1:1), [α]D = ꢀ31.1 (C1, CHCl3)
1
H NMR (500 MHz, CDCl ) δ 7.50 – 7.18 (m, 15H), 6.72 – 6.75 (br, m, 2H) 3.61 (s, 3H), 3.24
3
(dd, J = 7.9, 4.8 Hz, 1H), 2.56 (dd, J = 12.5, 4.7 Hz, 1H), 2.48 (dd, J = 12.5, 7.8 Hz, 1H).
1
3
C NMR (126 MHz, CDCl ) δ 174.2, 144.5, 130.1, 129.6, 128.3, 128.0, 66.9, 53.8, 52.2, 36.9.
3
+
MS (ESI) m/z: [M + Na] Calcd for C H NO SNa 400.13; Found 400.04.
2
3
23
2
Methyl N–formyl–S–trityl–R–cysteinate, 3b
This compound was synthesized according to general procedure for the preparation of 3 by using
methyl S–trityl–R–cysteinate, 2b (1.0 g, 2.65 mmol)
2
0
yield = 78 % (0.837 mg), white solid, mp: 135–137 °C, R 0.50 (PE/EtOAc, 1:1), [α]D = ꢀ18.8
f
(C1, CHCl3).
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H NMR (500 MHz, CDCl ) δ 7.98 (s, 1H), 7.52 – 7.12 (m, 15H), 6.15 (d, J = 12.6 Hz, 1H), 4.69
3
(dt, J = 8.1, 5.2 Hz, 1H), 3.65 (s, 3H), 2.82 (dd, J = 12.7, 5.8 Hz, 1H), 2.67 (dd, J = 12.7, 4.7 Hz,
1
H).
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13
C NMR (126 MHz, CDCl ) δ 170.5, 160.6, 144.3, 129.6, 129.5, 128.2, 128.1, 127.1, 67.0, 52.8,
3
49.8, 33.7.
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO S 406.1477; Found 406.1477.
+
24
24
3
Methyl (S)–2–isocyano–3–(tritylthio)propanoate, 4b
This compound was synthesized according to general procedure for the preparation of 4 by using
methyl N–formyl–S–trityl–R–cysteinate, 3b (2.0 g, 5.0 mmol)
20
yield = 76% (20.9 g), white solid, mp: 101 –103 °C, R 0.42 (EtOAc/ PE, 10:90), [α]D = ꢀ32.9
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.56 – 7.26 (m, 15H), 3.71 (s, 3H), 3.36 (dd, J = 7.9, 5.8 Hz, 1H),
3
2
.89 – 2.60 (m, 2H).
1
3
C NMR (126 MHz, CDCl ) δ 165.6, 160.9, 143.9, 130.7, 129.5, 128.3, 128.0, 128.0, 127.7,
3
1
27.3, 127.2, 127.1, 67.6, 55.4, 53.4, 34.2.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO S 388.1365; Found 388.1363.
24
22
2
Trityl thioacetic acid
This compound was synthesized according to the procedure of Tam et al. and the analytical data
[
42]
were compared.
To a mixture of mercaptoacetic acid (3.48 mL, 50.0 mmol) and triphenylmethanol (13.0 g, 50.0
mmol) in 50 mL of chloroform was added trifluoroacetic acid (10 mL) in 5 min. After stirring at
r.t. for 1 h, the volatiles were removed in vacuo. The crude product was purified by
recrystallization (CH Cl /Hexane; 1/2) to give trityl thioacetic acid.
2
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yield = 98% (16.3 g), white solid, mp: 159–161 °C, R 0.38 (EtOAc/ PE/ AcOH, 30:70:1.0),
f
1
H NMR (500 MHz, CDCl ) δ 7.56 – 7.15 (m, 15H), 3.06 (s, 2H).
3
1
3
C NMR (126 MHz, CDCl ) δ 175.5, 143.9, 129.5, 128.1, 127.9, 127.0, 67.3, 34.5.
3
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+
MS (ESI) m/z: [M + Na] Calcd for C H O SNa 357.09; Found 357.21.
2
1
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2
N–methoxy–N–methyl–2–(tritylthio)acetamide
To a solution of acid (20.0 mmol), PyBOP (1.1 equiv.) and TEA (2.5 equiv.) in CH Cl (50 mL)
2
2
was added N,O–dimethylhydroxylamine hydrochloride (1.2 equiv.) and the solution was allowed
to stir at r.t. overnight. The solution was then diluted with excess CH Cl and washed
2
2
consecutively with 1 M HCl solution (3 x 10 mL), saturated aq. NaHCO (3 x 10 mL), and water
3
(
1 x 10 mL). The organic phase was dried over MgSO , filtered and concentrated in vacuo. The
4
residue was purified by flash chromatography on silica gel to afford the desired Weinreb amide.
yield = 95% (7.1 g), white solid, mp: 125–127 °C, R 0.32 (EtOAc/ PE, 30:70)
f
1
H NMR (500 MHz, CDCl ) δ 7.52 – 7.44 (m, 7H), 7.32–7.31 (m, 8H), 3.49 (s, 3H), 3.14 (s,
3
3H), 3.11 (s, 2H).
13
C NMR (126 MHz, CDCl ) δ 172.0, 144.3, 129.6, 128.0, 127.8, 126.8, 66.9, 61.4, 33.7.
3
+
MS (ESI) m/z: [M + Na] Calcd for C H NO SNa 400.13; Found 400.25.
2
3
23
2
2
–(tritylthio)acetaldehyde
A stirred solution of Weinreb amide (10.0 mmol) in dry THF (50 mL) was cooled to 0 °C.
Lithium aluminium hydride (LAH, 11.0 mmol) was added in portions and after 30 minutes 0.2 M
KHSO (30 mL) was added. The organic compounds were extracted with diethyl ether (3x 30
4
mL). The combined organic phases were washed with 1 M HCl (3x 10 mL), brine (3x 10 mL)
and dried (MgSO ). The solvent was evaporated under reduced pressure and the crude colorless
4
oil was used immediately in the Ugi reaction (analysis was done only by TLC).
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yield = 88% (2.7 g), pale yellow oil, R 0.25 (EtOAc/ PE, 10:90)
f
Preparation of Ammonium salt of carboxylate
Ammonium bicarbonate (1.3 mmol) was added to a solution of Nꢀprotected amino acid (1.0
mmol) in acetonitrile (10.0 mL) followed by dropwise addition of water (1.0 mL) with rapid
stirring. The ammonium salt of carboxylate was precipitated out in 5 min. The stirring is
continued for another 5 min and the precipitate was filtered, dried and used for Ugi reaction.
General Procedure for Ugi 4CR. Preparation of Ugi products 5
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Aldehyde component (1.3 mmol, 1.3 eq.) was added to a solution of ammonium salt of
carboxylate (1.2 eq.) in trifluoroethanol (10 mL) at 0 °C. After stirring for 30 min, isocyanide 4
(387 mg, 1.0 mmol, 1.0 eq.) was added. Small amount of THF (1.0 mL) was added to get a
homogeneous solution. The mixture was allowed to stir r.t. for 24 h, the solution was diluted
with CH Cl (30 mL) and washed with 1 N KHSO and sat. NaHCO solution. The organic layer
2
2
4
3
was dried over Na SO and the solvent was evaporated in vacuo. The crude product was purified
2
4
by flash column chromatography to afford Ugi products.
1N KHSO solution necessary to decolorize the reaction mixture from dark yellow color to pale
“
4
yellow and also helps to separate the CH Cl layer from the aqueous layer”.
2
2
Spectroscopic data for compounds 5a–l
Methyl N–(((9H–fluoren–9–yl)methoxy)carbonyl)–L–valylglycyl–S–trityl–L–
cysteinate, 5a
25
D
yield = 48% (0.360 g), white solid, mp: 132–133 °C, R 0.32 (EtOAc/ PE, 50:50), [α] = +21.5
f
(
C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.79 – 7.19 (m, 23H), 6.52 (br, s, 1H), 6.36 (d, J = 8.3 Hz, 1H),
3
5.38 (br, s, 1H), 4.58 – 4.50 (m, 1H), 4.43 (d, J = 7.5 Hz, 2H), 4.23 (t, J = 12.5 Hz, 1H), 4.04
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(
dd, J = 7.8, 15.6 Hz, 1H), 3.95 (s, 2H), 3.71 (s, 3H), 2.75 (dd, J = 12.1, 9.2 Hz, 1H), 2.69 (dd, J
=
12.6, 6.3 Hz, 1H), 2.23 – 2.20 (m, 1H), 0.99 (d, J = 8.6 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) δ 172.0, 171.0, 170.1, 155.8, 144.0, 142.1, 140.7, 129.3, 127.8,
3
10
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1
27.5, 126.9, 126.7, 124.9, 119.8, 66.9, 60.8, 56.5, 51.1, 47.0, 42.5, 33.3, 26.2, 18.9, 18.1.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 756.3101; Found 756.3100.
45
46
3
6
Methyl N–((benzyloxy)carbonyl)–L–alanylglycyl–S–trityl–L–cysteinate, 5b
25
yield = 55% (0.351 g), white solid, mp: 115–116 °C, R 0.41 (EtOAc/ PE, 50:50), [α]D = +62.5
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.54 – 7.18 (m, 20H), 6.73 (br, s, 1H), 6.44 (br, s, 1H), 5.30 (d, J
3
=
7.2 Hz, 1H), 5.15 (s, 2H), 4.51 (ddd, J = 7.9, 6.3, 4.7 Hz, 1H), 4.34 – 4.22 (m, 1H), 3.98 (s,
2H), 3.71 (s, 3H), 2.75 (dd, J = 12.7, 6.3 Hz, 1H), 2.65 (dd, J = 12.6, 4.7 Hz, 1H), 1.40 (d, J =
.0 Hz, 3H).
7
1
3
C NMR (126 MHz, CDCl ) δ 172.5, 170.7, 168.9, 155.3, 144.2, 136.0, 129.5, 128.6, 128.3,
3
128.2, 128.1, 127.0, 67.2, 64.1, 52.7, 51.3, 42.8, 28.3, 18.4.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 640.2475; Found 640.2472.
36
38
3
6
Methyl N–((benzyloxy)carbonyl)glycylleucyl–S–trityl–L–cysteinate, 5c
25
yield = 60% (0.400 g), gummy solid, R 0.45 (EtOAc/ PE, 50:50), [α]D = +139.1 (C1, CHCl3)
f
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.48 – 7.17 (m, 20H), 6.55 (d, J = 8.5 Hz,
3
1H), 5.95 (d, J = 7.9 Hz, 1H), 5.42 (br, s, 1H), 5.13 (s, 2H), 4.64 (dt, J = 7.9, 5.2 Hz, 1H), 4.49 –
4.47 (m, 1H), 3.74 (s, 3H), 3.70 (s, 2H), 2.69 – 2.60 (m, 2H), 1.82 – 1.75 (m, 2H), 1.53 – 1.49
(m, 1H), 0.93 (d, J = 7.9, Hz, 6H).
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C NMR (126 MHz, CDCl ) (major diastereomer) δ 171.5, 171.0, 168.9, 156.6, 144.3, 144.2,
3
136.1, 129.5, 128.6, 128.2, 128.1, 128.1, 128.1, 128.0, 128.0, 127.0, 127.0, 126.9, 126.9, 67.3,
67.0, 57.4, 57.1, 51.1, 44.6, 40.9, 29.1, 24.5, 23.1, 22.2.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 682.2945; Found 682.2945.
39
44
3
6
Methyl N–((benzyloxy)carbonyl)–L–phenylalanylseryl–S–trityl–L–cysteinate, 5d
2
5
yield = 53% (0.39 g), white solid, mp: 129–132 °C, R 0.32 (EtOAc/ PE, 70:30), [α]D
=
f
+179.5 (C1, CHCl3).
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.44 – 7.37 (m, 6H), 7.36 – 7.12 (m, 19H),
3
7.10 (d, J = 6.6 Hz, 1H), 6.98 – 6.92 (m, br, 1H), 5.59 (d, J = 7.7 Hz, 1H), 5.03 (s, 2H), 4.51 –
4.31 (m, 3H), 3.90 – 3.80 (br, m, 1H), 3.68 (s, 3H), 3.67 – 3.59 (m, 1H), 3.45 – 3.30 (m, 2H),
3.15 – 2.95 (m, 2H), 2.70 – 2.60 (m, 2H).
13
C NMR (126 MHz, CDCl ) (major diastereomer) δ 171.6, 170.8, 169.9, 156.2, 144.5, 136.9,
3
136.2, 129.5, 129.3, 129.2, 128.7, 128.5, 128.2, 128.1, 128.0, 127.1, 127.0, 126.9, 67.7, 67.1,
62.7, 56.2, 54.0, 52.8, 51.8, 38.5, 33.1.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 746.2894; Found 746.2897.
4
3
44
3
7
Methyl N–((benzyloxy)carbonyl)–L–alanylseryl–S–trityl–L–cysteinate, 5e
yield = 60% (0.41 g), white solid, mp: 141–144 °C, R 0.35 (EtOAc/ PE, 70:30), [α]D = +75.6
2
5
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.43 – 7.14 (m, 20H), 7.11 (d, J = 7.8 Hz,
3
1H), 6.78 (d, J = 7.8 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 5.13 (s, 2H), 5.05 (d, J = 11.8 Hz, 1H),
4.51 – 4.36 (m, 1H), 4.30 – 4.23 (m, 1H), 4.06 (Br, s, 1H), 3.69 (s, 3H), 3.35 (dd, J = 8.3, 5.6 Hz,
2H), 2.75 – 2.70 (m, 1H), 2.65 – 2.61 (m, 1H), 1.40 (d, J = 3.1 Hz, 3H).
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C NMR (126 MHz, CDCl ) (major diastereomer) δ 170.8, 170.7, 156.2, 144.2, 136.2, 129.5,
3
128.5, 128.1, 128.0, 127.1, 126.8, 67.0, 62.4, 56.3, 54.5, 54.4, 52.6, 50.7, 26.3, 18.1.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 670.2581; Found 670.2581.
37
40
3
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl N–((benzyloxy)carbonyl)–L–valylseryl–S–trityl–L–cysteinate, 5f
yield = 52% (0.36 g), white solid, mp: 125–127 °C, R 0.41 (EtOAc/ PE, 70:30), [α]D = +155.5
25
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.49 – 7.18 (m, 20H), 6.81 (d, J = 7.8 Hz,
3
1H), 6.78 (d, J = 8.8 Hz, 1H), 5.46 (d, J = 8.2 Hz, 1H), 5.16 (s, 2H), 4.74 – 4.63 (m, 1H), 4.49 –
4.33 (m, 2H), 4.23 – 4.16 (m, 1H), 4.15 – 3.88 (m, 1H), 3.71 (s, 3H),3.24 (br, m, 1H), 2.87 –
2.76 (m, 1H), 2.68–2.57 (m, 1H), 2.16 – 2.03 (m, 1H), 0.92 (d, J = 11.8, Hz, 3H), 0.85 (d, J =
6.8, Hz, 3H).
13
C NMR (126 MHz, CDCl ) (major diastereomer) δ 174.6, 173.5, 170.4, 156.7, 144.2, 136.8,
3
129.5, 128.5, 128.1, 128.0, 127.8, 126.9, 68.1, 66.4, 64.2, 60.4, 56.8, 53.7, 51.7, 33.0, 27.3, 19.7,
17.9.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 698.2894; Found 698.2894.
39
44
3
7
Methyl
N–(N–(((benzyloxy)carbonyl)–L–phenylalanyl)–S–tritylcysteinyl)–S–trityl–L–
cysteinate, 5g
2
5
yield = 45% (0.45 g), yellow gum, R 0.38 (EtOAc/ PE, 30:70), [α]D = +155.9 (C1, CHCl3).
f
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.50 – 7.07 (m, 41H), 6.42 (d, J = 18.2 Hz,
3
1
H), 6.18 (d, J = 6.4 Hz, 1H), 5.04 (s, 2H), 4.38 (dt, J = 7.5, 5.6 Hz, 1H), 4.20 (dd, J = 7.1, 2.7
Hz, 1H), 4.10 – 4.03 (m, 1H), 3.65 (s, 3H), 3.15 – 2.98 (m, 2H), 2.67 – 2.62 (m, 2H), 2.59 – 2.25
m, 2H).
(
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
C NMR (126 MHz, CDCl ) (major diastereomer) δ 172.4, 170.5, 155.7, 145.3, 144.2, 136.8,
3
136.4, 129.6, 129.5, 129.3, 128.9, 128.7, 128.5, 128.3, 128.2, 128.1, 128.0, 126.9, 126.8, 69.0,
67.0, 66.3, 65.8, 53.1, 52.0, 50.6, 38.3, 34.8, 28.7.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 1004.3761; Found 1004.3761.
62
58
3
6 2
Methyl
N–(N–((((9H–fluoren–9–yl)methoxy)carbonyl)–L–valyl)–S–tritylcysteinyl)–S–
trityl–L–cysteinate, 5h
2
5
yield = 48% (0.50 g), pale yellow solid, m.p: 113 –116 °C, R 0.44 (EtOAc/ PE, 30:70), [α]D
=
f
ꢀ89.3 (C1, CHCl3).
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.95 – 7.00 (m, 38H), 6.72 (d, J = 7.6 Hz,
3
1H), 6.33 (d, J = 7.5 Hz, 1H), 5.59 (d, J = 8.5 Hz, 1H), 4.58 – 4.44 (m, 1H), 4.43 (t, J = 6.8 Hz,
1H), 4.25 – 4.19 (m, 1H), 4.17 – 4.08 (m, 3H), 3.62 (s, 3H), 2.77 – 2.68 (m, 1H), 2.66 – 2.55 (m,
3H), 2.54 – 2.48 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 12.2 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) (major diastereomer) δ 171.2, 170.1, 169.3, 156.3, 144.5, 144.2,
3
143.9, 141.2, 129.5, 129.4, 129.3, 128.1, 128.0, 127.9, 127.6, 127.0, 126.9, 126.7, 125.1, 119.9,
67.8, 66.9, 66.6, 60.3, 60.2, 59.8, 51.4, 47.0, 33.7, 33.3, 31.3, 19.2, 17.7.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 1044.4074; Found 1044.4075.
65
62
3
6 2
Methyl N–(N–((((9H–fluoren–9–yl)methoxy)carbonyl)–L–isoleucyl)–S–tritylcysteinyl)–S–
trityl–L–cysteinate, 5i
2
5
yield = 39% (0.41 g), yellow gum, R 0.41 (EtOAc/ PE, 30:70), [α]D = +166.9 (C1, CHCl3).
f
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.87 – 7.08 (m, 39H), 6.35 (d, J = 7.7 Hz,
3
1H), 6.17 (d, J = 9.4 Hz, 1H), 4.48 – 4.40 (m, 1H), 4.39 – 4.33 (m, 2H), 4.25 (t, J = 6.9 Hz, 1H),
4.18 – 4.10 (m, 1H), 4.08 – 3.96 (m, 1H), 3.62 (s, 3H), 2.70 – 2.65 (m, 2H), 2.64 – 2.53 (m, 2H),
1.81 – 1.73 (m, 1H), 1.50 – 1.33 (m, 2H), 0.96 (d, J = 12.4 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H).
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C NMR (126 MHz, CDCl ) (major diastereomer) δ 170.1, 170.0, 169.2, 156.0, 144.2, 143.7,
3
141.3, 129.5, 129.5, 128.1, 128.0, 127.7, 127.1, 126.9, 125.1, 120.0, 67.2, 66.7, 59.7, 52.5, 51.5,
47.1, 37.0, 33.6, 24.7, 15.5, 11.4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 1058.4231; Found 1058.4233.
66
64
3
6 2
Methyl N–(N–benzoyl–N–benzylglycyl)–S–trityl–L–cysteinateCompound, 5J
yield = 88% (0.55 g), white solid, mp: 97 – 98 °C, R 0.52 (EtOAc/ PE, 30:70).
f
1
H NMR (500 MHz, CDCl ) (major rotamer) δ 7.81 – 7.20 (m, 25H), 5.82 (br, s, 1H), 4.96 –
3
4.90 (m, 1H), 4.73 (s, 2H)), 4.16 (s, 2H), 3.68 (s, 3H), 2.88 – 2.79 (m, 1H), 2.77 – 2.50 (m, 1H).
13
C NMR (126 MHz, CDCl ) (major rotamer) δ 170.5, 170.1, 169.1, 144.7, 136.4, 130.6, 129.9,
3
1
27.7, 126.8, 126.5, 126.1, 125.7, 67.3, 59.8, 57.1, 52.5, 51.2, 30.3, 29.4.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 629.2468; Found 629.2467.
39
37
2
4
Methyl N–(N–benzyl–N–(3–phenylpropanoyl)glycyl)–S–trityl–L–cysteinate, 5k
yield = 91% (0.59 g), white solid, mp: 74–75 °C, R 0.35 (EtOAc/ PE, 30:70).
f
1
H NMR (500 MHz, CDCl ) (major rotamer) δ 7.51 – 7.11 (m, 25H), 6.81 (d, J = 8.8 Hz, 1H),
3
4
.66 (s, 2H), 4.59 – 4.50 (m, 1H), 4.11 (s, 2H), 3.69 (s, 3H), 3.22 – 3.88 (m, 2H), 2.68 (t, J =
12.8 Hz, 2H), 2.57 (t, J = 18.6 Hz, 2H).
1
3
C NMR (126 MHz, CDCl ) (major rotamer) δ 171.1, 170.5, 168.4, 144.2, 140.9, 135.6, 129.7,
3
1
29.5, 129.4, 129.0, 128.8, 128.5, 128.1, 127.9, 126.9, 126.2, 66.8, 52.6, 51.9, 51.2, 49.4, 34.9,
33.3, 31.2.
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 657.2781; Found 657.2784.
+
41
41
2
4
Methyl N–(N–(4–chlorobenzyl)–N–(4–phenylbutanoyl)leucyl)–S–trityl–L–cysteinate, 5l
2
5
yield = 89% (0.67 g), yellow gum, R 0.46 (EtOAc/ PE, 30:70), [α]D = +79.4 (C1, CHCl3).
f
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2
2
2
2
2
2
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3
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3
3
3
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
1
H NMR (500 MHz, CDCl ) (major diastereomer) δ 7.51 – 6.83 (m, 25H), 5.24 – 5.21 (m, 1H),
3
4
2
1
.48 (s, 2H), 4.30 – 4.25 (m, 1H), 3.69 (s, 3H), 2.80 – 2.74 (m, 2H), 2.69 – 2.50 (m, 2H), 2.20 –
.14 (m, 2H), 1.98 – 1.85 (m, 3H), 1.55 – 1.48 (m, 1H), 0.92 (d, J = 9.6 Hz, 3H), 0.87 (d, J =
2.8 Hz, 3H).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
C NMR (126 MHz, CDCl ) (major diastereomer) δ 175.5, 170.8, 170.4, 144.2, 141.2, 136.2,
3
1
32.9, 129.5, 128.5, 128.4, 128.0, 127.8, 127.2, 126.8, 126.0, 66.9, 55.4, 52.5, 51.2, 47.8, 36.8,
3
5.0, 32.9, 26.6, 26.5, 25.1, 22.4, 22.3.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H ClN O S 761.3174; Found 761.3171.
46
50
2
4
Methyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valylglycyl-S-trityl-D-cysteinate, 5m
2
5
f
yield = 51% (0.57 g), yellow gum, R 0.32 (EtOAc/ PE, 50:50), [α]D = ꢀ22.0 (C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 7.77 (dd, J = 7.7, 3.3 Hz, 2H), 7.59 (dd, J = 13.4, 7.5 Hz, 2H),
3
7
5
1
.46 – 7.35 (m, 5H), 7.35 – 7.02 (m, 14H), 6.48 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 16.0 Hz, 1H),
.42 (d, J = 12.2 Hz, 1H), 4.52 (d, J = 6.4 Hz, 2H), 4.41 (dd, J = 10.6, 7.4 Hz, 1H), 4.31 (d, J =
0.6, 1H), 4.18 (dt, J = 15.8, 7.1 Hz, 1H), 4.09 (br, s, 2H), 3.62 (s, 3H), 2.73 (dd, J = 12.6, 6.6
Hz, 1H), 2.65 (dd, J = 12.6, 4.9 Hz, 1H), 2.20 – 2.11 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.89 (d, J
= 12.0 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) δ 172.2, 170.6, 168.6, 156.7, 144.2, 143.9, 143.8, 141.3, 129.5,
3
1
28.2, 127.8, 127.7, 127.1, 126.9, 125.2, 120.0, 119.9, 67.2, 67.0, 60.5, 52.6, 51.5, 47.1, 42.8,
33.6, 31.1, 19.3, 18.0.
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 756.3101; Found 756.3100.
+
45
51
3
6
Methyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-D-valylglycyl-S-trityl-L-cysteinate, 5n
2
5
yield = 45% (0.49 g), yellow gum, R 0.33 (EtOAc/ PE, 50:50), [α]D = ꢀ36.4 (C1, CHCl3).
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H NMR (500 MHz, CDCl ) δ 7.78 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 13.5 Hz, 2H), 7.47 – 7.37
3
(m, 10H), 7.28 – 7.17 (m, 9H), 6.88 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 14.2 Hz, 1H), 5.72 (d, J =
8
.5 Hz, 1H), 4.51 (d, J = 6.4 Hz, 2H), 4.34 (dd, J = 10.7, 6.9 Hz, 1H), 4.30 (t, J = 7.1 Hz, 1H),
.17 – 4.11 (m, 1H), 4.00 (br, s, 2H), 3.65 (s, 3H), 2.76 (dd, J = 12.5, 6.8 Hz, 1H), 2.67 (dd, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
9.5, 3.2 Hz, 1H), 2.17 – 2.10 (m, 1H), 0.96 (d, J = 13.9, 3H), 0.88 (d, J = 6.7 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) δ 172.0, 170.5, 168.5, 156.6, 144.2, 143.8, 141.2, 129.5, 128.5,
3
128.2, 127.7, 127.1, 126.9, 126.6, 125.1, 120.0, 67.1, 66.8, 60.5, 52.7, 51.5, 47.2, 42.8, 33.5,
31.0, 19.3, 17.9.
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 756.3101; Found 756.3100.
+
45
52
3
6
Procedure for entries a-f in Table 2
A solution of Ugi product 5d (1.0 mmol), in 10 mL of CH Cl was maintained at the temperature
2
2
indicated in the table. After 5 min, the corresponding reagents were added slowly. The reaction
mixture was allowed to stir until the starting material was completely consumed (TLC analysis,).
The solution was quenched with saturated NaHCO and the solution was extracted with CH Cl
2
3
2
(
2 X 10 mL) and the organic layer was separated, dried over MgSO , filtered and evaporated.
4
The crude product in CHCl (10 mL) was treated with activated MnO (10 mmol) and the
3
2
reaction mixture was refluxed for 3h at 80 °C. The crude reaction mixture was analyzed with
SFCꢀMS.
Procedure for entries g-i in Table 2
A solution of PPh O or Ph SO (6.0 mmol) in 10 mL of CH Cl was cooled to –78 °C, triflic
3
2
2
2
anhydride (3.0 mmol) was added dropwise and stirred at same temperature for 30 min. Pyridine
6.0 mmol) was added to the reaction mixture. A solution of Cys(Trt) amide (1.0 mmol) in 5 mL
of CH Cl was added and stirred at the indicated temperature in the table. After complete
(
2
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6
consumption of the reactant (TLC analysis) the reaction mixture was warmed to r.t. and
quenched with saturated solution of NaHCO . The solution was extracted with CH Cl (2 X 10
3
2
2
mL) and the organic layer was separated, dried over MgSO , filtered and evaporated. The crude
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
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9
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9
0
1
2
3
4
5
6
7
8
9
0
product in CHCl (10 mL) was treated with activated MnO (10 mmol) and the reaction mixture
3
2
was refluxed for 3h at 80 °C. The reaction mixture was cooled to r.t. and filtered through a pad of
Cellite®. After evaporation of the solvent, the residue was purified by flash chromatography
(silica gel, PE/EtOAc) and gave the corresponding azoles.
General Procedure for the optimized synthesis of 1,3 azoles 6a–c and 6j–l
A solution of diphenyl sulfoxide (3.0 mmol) in 10 mL of CH Cl cooled to –78 °C, triflic
2
2
anhydride (1.5 mmol) was added dropwise and stirred at the same temperature for 30 minutes
and pyridine (3.0 mmol) was added to the reaction mixture. A solution of Cys(Trt) amide (1.0
mmol) in 5 mL of CH Cl was added and stirred for 5h at –78 °C. After complete consumption
2
2
of the reactant (TLC analysis) the reaction mixture was warmed to r.t. and quenched with
saturated solution of NaHCO . The solution was extracted with CH Cl (2 X 10 mL) and the
3
2
2
organic layer was separated, dried over MgSO , filtered and evaporated. The crude product in
4
CHCl (10 mL) was treated with activated MnO (10 mmol) and the reaction mixture was
3
2
refluxed for 3h at 80 °C. The reaction mixture was cool to r.t. and filtered through a pad of
Cellite®. After evaporation of the solvent, the residue was purified by flash chromatography
(Silica gel, PE/EtOAc) and gave the corresponding azoles.
General Procedure for the synthesis of 6d–i
A solution of diphenyl sulfoxide (6.0 mmol) in 15 mL of CH Cl cooled to –78 °C, triflic
2
2
anhydride (3.5 mmol) was added dropwise and stirred at same temperature for 30 min. Pyridine
(6.0 mmol) was added to the reaction mixture. A solution of Cys(Trt) amide (1.0 mmol) in 5 mL
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of CH Cl was added dropwise and the reaction mixture was stirred for 6 h at –78 °C. After
2
2
completion of the reaction (TLC analysis) a saturated solution of NaHCO was added and
3
extracted with CH Cl (2 X 10 mL). The organic layer was separated, dried over MgSO , filtered
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4
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and evaporated. The crude product in CHCl (10 mL) was treated with activated MnO (10.0
3
2
mmol) and the reaction mixture was refluxed for 3h at 80 °C. The reaction mixture was cool to
r.t. and filtered through a pad of Cellite®. After evaporation of the solvent, the residue was
purified by flash chromatography (Silica gel, PE/EtOAc) and gave the corresponding azoles.
Methyl
(S)–2–((2–((((9H–fluoren–9–yl)methoxy)carbonyl)amino)–3–
methylbutanamido)methyl)thiazole–4–carboxylate, 6a
25
yield = 71% (0.35 g), white solid, mp: 98 – 99 °C, R 0.51 (EtOAc/ PE, 40:60), [α]D = +7.2
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 8.21 (s, 1H), 7.78 –7.11 (m, 8H), 5.80 (d, J = 12.6 Hz, 1H), 5.72
3
(
d, J = 6.0 Hz, 1H), 4.42 (d, J = 8.6 Hz, 2H), 4.23 (t, J = 12.4, 1H), 4.20 – 4.14 (m, 1H), 4.00
br, s, 2H), 3.77 (s, 3H), 2.61 – 2.49 (m, 1H), 0.99 (d, J = 12.1 Hz, 3H), 0.96 (d, J = 3.8 Hz, 3H).
(
13
C NMR (126 MHz, CDCl ) δ 169.5, 164.1, 160.2, 156.4, 143.9, 143.7, 141.3, 127.8, 127.1,
3
126.3, 125.1, 124.3, 123.7, 120.0, 67.1, 65.4, 51.8, 47.2, 37.4, 31.0, 19.1, 17.5.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 494.1744; Found 494.1747.
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Methyl
(S)–2–((2–(((benzyloxy)carbonyl)amino)propanamido)methyl)thiazole–4–
carboxylate, 6b
25
yield = 80% (0.30 g), white solid, mp: 75 – 76 °C, R 0.51 (EtOAc/ PE, 40:60), [α]D = +15.5
f
(
C1, CHCl3).
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6
1
H NMR (500 MHz, CDCl ) δ 8.16 (s, 1H), 7.48–7.15 (m, 5H), 6.28 (d, J = 12.2 Hz, 1H), 5.81
3
(
d, J = 6.8 Hz, 1H), 5.12 (s, 2H), 4.31 (dd, J = 3.4, 12.8 Hz, 1H), 4.15 (d, J = 8.1 Hz, 2H), 3.78
s, 3H), 1.40 (d, J = 9.1 Hz, 3H).
(
0
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8
9
0
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0
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0
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4
5
6
7
8
9
0
13
C NMR (126 MHz, CDCl ) δ 169.0, 163.7, 160.6, 156.5, 144.2, 136.1, 129.5, 128.5, 128.2,
3
128.1, 128.0, 126.9, 67.1, 54.1, 52.7, 43.1, 18.4.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 378.1118; found 378.1118.
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Methyl
2–(1–(2–(((benzyloxy)carbonyl)amino)acetamido)–3–methylbutyl)thiazole–4–
carboxylate, 6c
yield = 65% (0.27 g), yellow solid, mp: 69–71 °C, R 0.43 (EtOAc/ PE, 50:50).
f
1
H NMR (500 MHz, CDCl ) δ 8.24 (s, 1H), 7.31 –7.49 (m, 5H), 6.73 (d, J = 3.5 Hz, 1H), 6.08
3
(d, J = 5.6 Hz, 1H), 5.15 (s, 2H), 4.10–4.18 (m, 1H), 3.81 (d, J = 7.6 Hz, 2H), 3.68 (s, 3H), 1.72
(dt, J = 11.6, 5.4, 1.3 Hz, 2H), 1.11–1.25 (m, 1H), 0.92 (d, J = 11.4 Hz, 3H), 0.86 (d, J = 5.7 Hz,
3
H).
1
3
C NMR (126 MHz, CDCl ) δ 170.0, 169.3, 160.8, 155.6, 148.6, 136.4, 130.6, 128.1, 127.9,
3
1
27.6, 127.0, 126.6, 66.3, 52.5, 50.0, 43.1, 40.4, 24.3, 22.7, 21.1.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 420.1587; Found 420.1583.
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Methyl (S)–2–(2–(1–(((benzyloxy)carbonyl)amino)–2–phenylethyl)oxazol–4–yl)thiazole–4–
carboxylate, 6d
25
yield = 45% (0.20 g), white solid, mp: 111–112 °C, R 0.33 (EtOAc/ PE, 60:40), [α]D = +13.7
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 8.50 (s, 1H), 7.99 (s, 1H), 7.61–7.32 (m, 1H), 6.91 (br, s, 1H),
3
5
.28 (s, 2H), 5.11–5.03 (m, 1H), 3.79 (s, 3H), 2.65 (dd, J = 15.1, 8.6 Hz, 1H), 2.48 (dd, J = 22.4,
6
.5 Hz, 1H).
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C NMR (126 MHz, CDCl ) δ 168.2, 167.9, 167.5, 156.9, 145.7, 140.6, 136.0, 135.7, 129.5,
3
129.4, 128.7, 128.6, 128.5, 128.3, 128.3, 128.2, 128.0, 127.7, 127.2, 123.8, 121.5, 67.8, 54.8,
50.5, 38.6.
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+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 464.1274; Found 464.1272.
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Methyl
(S)–2–(2–(1–(((benzyloxy)carbonyl)amino)ethyl)oxazol–4–yl)thiazole–4–
carboxylate, 6e
2
5
yield = 62% (0.24 g), white solid, mp: 85 – 86 °C, R 0.33 (EtOAc/ PE, 60:40), [α]D = +24.6
f
(C1, CHCl3)
1
H NMR (500 MHz, CDCl ) δ 8.26 (s, 1H), 7.70 (s, 1H), 7.32– 7.28 (m, 5H), 6.48 (d, J = 5.8 Hz,
3
1
H), 5.18 (s, 2H), 4.50–4.46 (m, 1H), 3.80 (s, 3H), 1.48 (d, J = 12.6 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) δ 164.6, 160.8, 159.0, 155.8, 144.9, 141.1, 136.0, 128.6, 128.3,
3
1
28.2, 128.0, 122.3, 120.7, 67.6, 53.2, 49.5, 18.4.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 388.0961; Found 388.0965.
18 18
3
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Methyl (S)–2–(2–(1–(((benzyloxy)carbonyl)amino)–2–methylpropyl)oxazol–4–yl)thiazole–
–carboxylate, 6f
yield = 55% (0.22 g), white solid, mp: 69–70 °C, R 0.33 (EtOAc/ PE, 60:40), [α]D = +32.5
4
25
f
(C1, CHCl3).
1
H NMR (500 MHz, CDCl ) δ 8.26 (s, 1H), 7.79 (s, 1H), 7.51–7.20 (m, 5H), 6.23 (br, s, 1H),
3
5.15 (s, 2H), 4.48 (dd, J = 12.8, 6.5 Hz, 1H), 3.78 (s, 3H), 2.30 – 2.28 (m, 1H), 1.12 (d, J = 12.5
Hz, 3H), 0.98 (d, J = 5.6 Hz, 3H).
1
3
C NMR (126 MHz, CDCl ) δ 161.6, 160.7, 159.5, 153.8, 144.8, 140.6, 136.2, 128.6, 128.5,
3
1
28.4, 128.2, 128.1, 127.9, 127.1, 123.8, 122.9, 67.2, 63.8, 50.8, 31.1, 19.1, 19.0, 17.4.
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O S 416.1274; Found 416.1272.
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22
3
5
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