Efficient Synthesis of the Peptide Fragment of the Natural Depsipeptides Jaspamide and Chondramide

Article abstract of DOI:10.1002/ejoc.201800992

A new method for the synthesis of the tripeptide part of the jaspamide and chondramide alkaloids using a Ugi reaction was developed. The reported approach is considerably shorter than all literature syntheses of the peptide parts of these natural products. A family of peptides with different substituents at the 2-position of the indole moiety was prepared to open up access to analogues of these natural products.

Full text of DOI:10.1002/ejoc.201800992

A Journal of
Accepted Article
Title: Efficient Synthesis of Peptide Fragment of Natural Depsipeptides
Jaspamide and Chondramide
Authors: Valentine G. Nenajdenko, Danil Zarezin, Olga Shmatova, and
Adil Kabylda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800992
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800992
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
Efficient Synthesis of Peptide Fragment of Natural Depsipeptides
Jaspamide and Chondramide
Danil P. Zarezin,a Olga I. Shmatova,a Adil M. Kabyldaa and Valentine G. Nenajdenko*a
a Department of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia.
Key words: Alkaloids, Multicomponent reactions, Peptides, Chiral pool, Amino acids
Abstract: A novel method for the synthesis of the tripeptide part of Jaspamide and
Chondramide alkaloids using Ugi reaction was elaborated. The proposed approach is
considerably shorter than all literature syntheses of peptide parts of these natural products. A
family of peptides having different substituents at 2-nd position of indole was prepared to open
access to synthesis of analogues of these natural products.
Introduction
Marine sponges are one of the most important sources of various biologically active
compounds including linear peptides, depsipeptides, macrocyclic and bicyclic peptides. Great
amount of intriguing substances with high therapeutic potential have been isolated from marine
sponges.1 For example, cytarabine, spongothymidine, manoalide, dysidotronic acid,
spongouridine, geodiamolides, seragamides, jasplakinolides, neosiphoniamolides and etc. Such
compounds possess diverse bioactivity: antibacterial, antiviral, antifungal, antimalarial,
antitumor, immunosuppressive, and cardiovascular activity.2
Natural depsipeptides of kind of Jasplakinolides isolated from marine sponges Jaspis
splendens are of special interest for modern medicinal chemistry as novel anti-cancer drugs and
antibiotics.3 Many types of jasplakinolides have been discovered in sponges but none of these
compounds has been commercialized due to their low concentrations of the desired substances in
sponges. Past years a significant amount of articles has been devoted to the synthesis of
jasplakinolides, however, these alkaloids are still hardly available.4 It should be noted that
another type of natural depsipeptides Chondromides isolated from waste of myxobacteria
Chondromyces crocatus have a peptide part similar or identical to Jaspamides (Fig. 1).5
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
OH
OH
β
-Tyr
β
-Tyr
O
O
D- -Me-Trp
N
D- -Me-Trp
N
HN
O
O
HN
X
X
O
O
O
O
HN
HN
MeN
MeN
O
NH
N
H
Ala
Ala
O
X = Br: Jaspamide
X = H: Jaspamide Q
X = H: Chondramide C
X = Cl: Chondramide D
Figure 1. Some alkaloids of Jaspamide and Chondramide types.
Looking on the structures of Jaspamide and Chondramide one can see that both natural
products contain very similar tripeptide part. This fragment consists of three amino acids: L-
alanine, beta3-L-tyrosine and N-methyl-D-tryptophan bearing hydrogen or different halogens (Cl
or Br) at 2nd position of indole ring. All previous syntheses of these natural depsipeptides
included classic peptide synthesis with stepwise elongation for the preparation of peptide part of
Chondramides and Jaspamides (Fig. 2). However, such approach has significant disadvantages
such as multistage procedure and expensive starting materials. Moreover, two of three amino
acids are not natural and beta3- L-tyrosine is not easily available.
Previous works: Peptide Synthesis
O
OPg
Target fragment
HN
OPg
OH
multistep
OH
+
+
NHPg
O
O
X
O
N
H2N
OR
Pg
HN
OR
This work: Ugi Reaction
OBn
O
O
MeN
X
N
O
Pg
1 step
O
+
NHPg
X = H, Cl, Br
+
X
BocHN
N
OH
CN
Boc
MeNH2
O
OMe
Figure 2. Comparison of synthetic methods for preparing of target tripeptide at previous
works and at this one.
This study is focused on to the synthesis of tripeptide parts of Jaspamide and
Chondramide using multicomponent Ugi reaction. It is well known that isocyanide based Ugi
and Passerini reactions are suitable for one step construction of complex molecules of various
nature. This chemistry is especially powerful to construct peptides and peptidomimetics.6
According to the structure of Jaspamide and Chondromide, peptide part of these
compounds can be easily prepared using the Ugi reaction with methylamine, alanine, indole-3-
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
acetaldehyde and 3-(4-hydroxyphenyl)-3-isocyanopropanoic acid (Fig. 2). However, availability
of chiral beta3-isocyanopropionates is most crucial moment to perform Ugi approach to these
peptides.
Results and Discussion
Therefore, first aim of our study was to elaborate short and efficient synthesis of key
isocyanide derived from beta3-isocyanopropionic acid in enantiomerically pure form. It was
decided to start this study from the synthesis of model isocyanide derived from 3-(4-
hydroxyphenyl)-3-isocyanopropanoic acid. This homologue of target isocyanide can be prepared
from inexpensive natural L-tyrosine as a starting material. N-formyl-L-tyrosine 1a was prepared
by formylation of L-tyrosine. Our synthesis of chiral β3-isocyanopropanoic acid derivative 4a
included three steps: Arndt-Eistert reaction with N-formyl-L-tyrosine 1a, Wolff rearrangement of
prepared chiral diazoketone 2a in methanol to form the corresponding methyl ester 3a, finally
dehydration of 3a resulted in isocyanide 4a in enantiomerically pure form (Scheme 1).
CbzO
CbzO
PhCOOAg
MeOH
POCl3, Et3N
CH2Cl2
Cbz-Type
n
n
CbzO
CN
HN
HO
3a
n=1, , 92%
3b
n=0, , 85%
O
1) CbzCl, THF,
dioxane, Et3N
O
OMe
O
OMe
n
O
n=1, 4a, 93%
4b
n=0, , 87%
n
HN
O
2) CH2N2, Et2O
OBn
HN
OBn
CHN2
O
OH
O
n=1, 2a, 85%
n=0, 2b, 70%
1a
1b
n=1,
n=0,
Bn-Type
1) PhCOOAg, Et3N,
MeOH
POCl3, Et3N
CH2Cl2
HN
CN
2) BnBr, K2CO3
DMF
O
O
3c
OMe
, 76%
O
OMe
4c, 88%
Scheme 1. Synthesis of isocyanides 4a-c
The reaction conditions for each step of the synthesis of target compounds were
optimized. Arndt-Eistert reaction in different solvents and their combinations (THF, dioxane,
DME) using various bases (Et3N, DIPEA, N-methylmorpholine, pyridine, 2,6-lutidine),
temperature and the reagents ratio was screened. In this stage benzyl chloroformate played
double role: first - to protect phenolic hydroxyl group, second - to form mixed anhydride with N-
formyl amino acid 1a. Screening of conditions for this step finally shown that a mixture of THF
and dioxane in ratio 4:1 as a reaction media and triethylamine as a base gave the best results.
Target product 2a can be isolated in high yield (85%) using abovementioned conditions. Next,
the Wolff rearrangement was investigated. The reaction proceeds very efficiently in methanol in
the presence of silver benzoate to give desired product 3a in 92% isolated yield. Finally,
isocyanide 4a was prepared using standard procedure with phosphoryl chloride - triethylamine
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
dehydrating system. Having elaborated the synthesis of 4a, the method was successfully used for
the synthesis of isocyanide 4b derived from chiral N-formyl α-4-hydroxy-phenylglycine
(Scheme 1, Cbz-Type).
Having in hand chiral isocyanides 4a,b we explored Ugi reaction with methylamine.
However, it was found that very complex reaction mixture is formed using various conditions.
We proposed that isonitriles 4a,b gave undesired byproducts in Ugi reaction conditions because
Cbz-protective group is labile and can react with highly nucleophilic methylamine. Therefore, it
was necessary to use alternative protective group on phenolic oxygen of isocyanide. Benzyl
group was chosen for this aim (Scheme 1, Bn-derivatives 3c, 4c). To our delight, when the Wolff
rearrangement was performed in methanol in the presence of triethylamine the reaction resulted
in formation of the corresponding methyl ester 3c with simultaneous removal of Cbz-group from
phenolic oxygen. Subsequent alkylation of hydroxyl group with benzyl bromide gave target N-
formamide 3c in good isolated yield (76%). In a similar manner 3-(4-hydroxyphenyl)-3-
isocyanopropanoic acid derivative 4c was prepared in 88% yield. Isocyanide 4c demonstrated
much better behavior in model Ugi reaction with methylamine.
Having prepared key isocyanides, next goal of this study was the synthesis of family of 2-
substituted indole-3-acetaldehydes with and without protecting group at indole nitrogen (Scheme
2). An attempt to obtain indole-3-acetaldehyde 6a in one step by oxidation of commercially
available L-tryptophan with NaOCl resulted in poor yield. As alternative approach
straightforward reduction of methyl indolylacetic ester 5a with DIBAL-H was studied. However,
a more reliable approach was found for the transformation of 5a into the corresponding aldehyde
6a included two steps: reduction of 5a with lithium aluminiumhydride (96%) followed by
oxidation of isolated alcohol to aldehyde 6a using IBX in DMSO (87%). As a result, target
aldehyde 6a can be prepared very efficiently in multigram scale.
NH-Type
COOH
NH2
5a, X = H
D, E or F
COOMe
X
O
C
1) A, 96%;
2) B, 87%
~10%
N
N
H
5b-d
H
N
H
X = Cl, Br, CF3
5a-d
6a
N-protected-Type
COOMe
R = Boc, X = H, 8a
R = Boc, X = Cl, 8b
R = Boc, X = Br, 8c
R = Boc, X = CF3, 8d
O
I
G, 94-98%
X
X
N
H
or , 57%
N
71-97%
8a-e
R
R
8e
R = Me, X =H,
7a-e
A
F
B
- LiAlH4;THF; - IBX, DMSO; - NaOCl; - X = Cl, NCS, CCl4, 85%; - X = Br, NBS, CCl4, 88%;
C
D
E
G
- X = CF3, reagent Togni, Cu(OAc)2, MeOH, 60% ; - Boc2O, DMAP, THF, X = H, Cl, Br, CF3;
H
I
- MeI, NaH, THF, R = Me, X = H; - DIBAL-H, toluene.
Scheme 2. One-step methods of synthesis of indole-3-acetaldehydes.
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
Next, a small family of N-protected indole-3-acetaldehydes 8a-e was prepared. Target
tripeptide units of Jaspamide and Chondramide contain N-methyl-D-tryptophan with halogens in
the position 2 of indole. Therefore, 2-chloro- 5b and 2-bromo substituted 5c methyl
indolylacetates were prepared using halogenation with NCS and NBS respectively7 (D and E,
Scheme 2). The corresponding esters were isolated in 85-88% yields. Moreover, 2-
trifluoromethyl substituted derivative 5d was also synthesized8 because of importance of CF3-
group as an attractive pharmacophore.9 Trifluoromethylation of 5a with Togni I reagent in the
presence of copper acetate provided the corresponding ester 7d in reasonably high yield (60%).
We also decided to synthesize N-protected indole derivatives having Boc-group (G, Scheme 2)
or methyl substituent (H, Scheme 2) on the indole nitrogen.10 Finally, a number of N-protected
indole-3-acetaldehydes 8 was synthesized in one step by reduction of indole-3-acetates 7 with
DIBAL-H (I, Scheme 2) to give target carbonyls in high isolated yields (71-97%).
It was discovered that all aldehydes 8 have limited stability and should be stored in
refrigerator. Most probably such behavior can be explained by their tendency for enolization and
self condensation due to highly acidic methylene moiety in the structure. All these aldehydes
should be used immediately after the isolation, otherwise, yields of the Ugi reaction (see below)
are dropped significantly.
Scheme 3. Synthesis of the target tripeptides.
Our attempts to use NH- and N-methyl-indole-3-acetaldehydes 6a, 8e the Ugi reaction
were unsuccessful. It was found that complex mixture of products is formed in both cases. To
our delight the Ugi reaction with O-benzyl protected isonitrile 4c, methylamine, N-Boc-protected
alanine and Boc-protected indole-3-acetaldehyde 8a proceeded cleanly to give tripeptide 9a in
reasonably high isolated yield (50%). Probably Boc-protected aldehyde has lower propensity to
undergo enolization to increase the yield of the target reaction product. Tripeptide 9a was formed
as a separable mixture of two diastereomers in almost 1/1 ratio which is usual for Ugi reaction.11
Conventional column chromatography was found applicable for the separation. Such approach
can be even more productive for subsequent investigation of biological activity of both
diastereomers of natural products. In all cases peptides 9a-d were isolated as a mixture of two
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
diastereomers in up to 81% yield. It was demonstrated that both diastereomers can be isolated in
pure form using tripeptide 9b as an example (Scheme 3). We must remind our readers that the
synthesis of jasplakinolides and chondramide from obtained tripeptides 9 was described in
previous papers.4
Conclusions
In summary, a novel short and efficient synthesis of peptide parts of natural depsipeptides
of the families of Chondramide and Jasplakinolides was elaborated using the Ugi reaction. Key
building blocks - chiral isocyanides derived from β-amino acids can be prepared in 3 steps from
natural amino acids.
Experimental Section
1D NMR (1H, 13C, and F) spectra were obtained on 400 MHz spectrometers. Chemical
19
shifts are reported in parts per million downfield from TMS. Deuterated solvent peaks were used
19
as internal references: deuterochloroform at 7.27 and 77.00 ppm. Chemical shifts for F NMR
data are referenced to CFCl3 (0.0 ppm) or PhCF3 (−63.90 ppm). High-resolution mass
spectrometry (HRMS) was performed using a MicroTOF-Q instrument. Electrospray ionization
(ESI) mass spectrometry (MS) was performed using dichloromethane or methanol solutions.
Melting points are uncorrected. The silica gel used for flash chromatography was 230−400 mesh.
General procedure for preparation of diazoketones 2a-b. To a solution of an
°
appropriate N-formyl amino acid (2 mmol) in 4:1 THF (120 ml) and dioxane (30 ml) at -20 C
were consequentially added benzyl chloroformate (2.2 eq., 4.4 mmol, 0.63 ml) then
triethylamine (2.2 eq., 4.4 mmol, 0.62 ml). The resulting solution was stirred at this temperature
1-2 hours (TLC control). Then to the reaction mixture ether solution of diazomethane (100 ml,
obtained from 0.98 g (9 mmol, 4.5 eq.) of N-nitroso-N-methylurea) was added. The solution was
stirred for 8-9 hours (TLC control) at the room temperature. The reaction mixture was then
filtered from the precipitate and the solvent was removed in vacuo (unheated water bath) to
afford the desired diazoketone. The resulting crude yellow oil was purified via column
chromatography (CH2Cl2/methanol 50:1).
(S)-Benzyl (4-(4-diazo-2-formamido-3-oxobutyl)phenyl) carbonate (2a), 623 mg, 85%,
yellow oil; 1H NMR (400 MHz, CDCl3): δ 3.07 (d, J = 6.7 Hz, 2H), 4.77 – 4.82 (m, 1H), 5.20 (s,
13
1H), 5.27 (s, 2H), 6.35 (bs, 1H), 7.12 – 7.22 (m, 4H), 7.37 – 7.45 (m, 5H), 8.15 (s, 1H). C
NMR (100 MHz, CDCl3): δ 37.5, 55.3 (d, J = 30.6 Hz), 65.3, 70.4, 121.3, 126.9, 127.6, 128.5,
128.7, 128.8, 130.4, 150.2, 153.6, 160.6, 191.4. IR (nujol, cm-1): 1640, 1670, 1760, 2160, 2950,
3340. HRMS (ESI): calcd. for C19H18NO5 [M-N2+H]+ 340.1179, found 340.1184. [α]20D=+19.0º
(c 1.0, CH2Cl2).
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
((S)-Benzyl (4-(3-diazo-1-formamido-2-oxopropyl)phenyl) carbonate (2b), 494 mg, 70%,
yellowish solid m.p. 121 – 123ºC; 1H NMR (400 MHz, CDCl3): δ 5.25 (s, 1H), 5.27 (s, 2H), 5.52
– 5.53 (m, 1H), 7.10 (d, J = 6.3 Hz, 1H), 7.18 – 7.45 (m, 9H), 8.21 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 55.4, 58.2, 70.5, 121.8, 128.5, 128.6, 128.8, 128.9, 134.5, 151.2, 153.3, 160.3, 189.4.
IR (nujol, cm-1): 1620, 1675, 1760, 2150, 2940, 3330. HRMS (ESI): calcd. for C18H16NO5 [M-
N2+H]+ 326.1023, found 326.1027. [α]20D=+217.2º (c 1.0, CH2Cl2).
General procedure for preparation of methyl ester of N-formyl β-amino acids 3a-b (Cbz-
Type). The appropriate N-formyl diazoketone 2a-b (1 mmol) was dissolved in methanol (70 ml).
Silver benzoate (0.1 mmol, 22 mg) was added to the solution. The reaction mixture was stirred
for several hours (TLC control). Then the solvent was evaporated in vacuo and the compound
was purified via column chromatography (eluent - CH2Cl2:MeOH).
(S)-Methyl 4-(4-(((benzyloxy)carbonyl)oxy)phenyl)-3-formamidobutanoate (3a), 341 mg,
92%, coloreless oil, two rotomers in ratio – 10:1 (signals of minor rotomer in brackets) 1H NMR
(400 MHz, CDCl3): δ 2.50 – 2.56 (m, 2H), 2.86 – 2.99 (m, 2H), 3.70 (s, 3H), 4.51 – 4.57 (m,
1H), 5.27 (s, 2H), 6.42 (bd, J = 8.41 Hz, 1H), 7.11 – 7.19 (m, 4H), 7.39 – 7.46 (m, 5H), 8.08 (s,
13
1H). C NMR (100 MHz, CDCl3): δ 36.6, 38.9, 46.1, 51.8, 70.4, 121.2 (121.4), 128.5, 128.7,
128.8, 130.2 (130.4), 135.1 (134.7), 149.9, 153.6, 160.7, 171.9. IR (nujol, cm-1): 1675, 1734,
+
1751, 2935, 3335. HRMS (ESI): calcd. for C20H22NO6 [M+H] 372.1442, found 372.1442.
[α]20D=+7.0º (c 1.0, CH2Cl2).
(R)-Methyl 3-(4-(((benzyloxy)carbonyl)oxy)phenyl)-3-formamidopropanoate (3b), 303
1
mg, 85%, coloreless oil, two rotomers in ratio – 4:1 (signals of minor rotomer in brackets) H
NMR (400 MHz, CDCl3): δ 2.75 – 2.90 (m, 2H), 3.58 (3.62) (s, 3H), 5.23 (s, 2H), 5.45 – 5.48
13
(m, 1H), 7.09 – 7.42 (m + bs, 10H), 8.03 (8.10) (s, 1H). C NMR (100 MHz, CDCl3): δ 39.5,
(40.9), 47.6, 51.7, (51.8), (52.1), 70.2, (70.3), 121.1, (121.3), (121.9), (127.1), 127.4, 128.3,
(128.4), (128.4), 128.5, 128.6, (129.1), 134.4, 137.9, (138.0), 150.2, (150.4), 153.3 (153.3),
160.5, (164.4), (170.4), 170.9. IR (ZnSe, cm-1): 1638, 1735, 1754, 3219. HRMS (ESI): calcd. for
C20H22NO6 [M+H] + 358.1285, found 358.1287. [α]20D=-9.8º (c 1.0, CH2Cl2).
Procedure for preparation of methyl ester of N-formyl β-amino acids 3c (Bn-Type). The N-
formyl diazoketone 2b (3 mmol, 1.1 g) was dissolved in methanol (100 ml). Silver benzoate
(0.10 mmol, 68 mg) and triethylamine (4.5 eq., 13.5 mmol, 1.9 ml) were added to the solution.
The reaction mixture was stirred for several hours (TLC control). Then the reaction mixture was
filtered through Celite, washed with methanol and concentrated under reduce pressure. Residue
was dissolved in DMF (25 ml). Benzyl bromide (1.5 eq., 4.5 mmol, 0.54 ml) and large excess of
potassium carbonate (5 eq., 15 mmol, 2 g) were added to the solution. The reaction mixture was
stirred for 24 hours (TLC control). Then reaction mixture was filtered, diluted by
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
dichloromethane and washed with water. The organic layer was separated and the aqueous layer
was extracted three times with dichloromethane (3 x 50 ml). Then the solvent was evaporated in
vacuo and the compound was purified via column chromatography (CH2Cl2/MeOH).
((R)-Methyl 3-(4-(benzyloxy)phenyl)-3-formamidopropanoate (3c), 714 mg, 76%,
1
colorless oil; two rotomers in ratio – 6:1 (signals of minor rotomer in brackets). H NMR (400
MHz, CDCl3): δ 2.78 – 2.95 (m, 2H), 3.62 (3.66) (s, 3H), 5.03 (5.05) (s, 2H), 5.43 – 5.48 (5.59 –
5.60) (m 1H), 6.92 – 6.97 (m, 3H), 7.17 – 7.43. (m, 7H), 8.14 (8.16) (s, 1H). 13C NMR (100
MHz, CDCl3): δ 39.7, (41.3), 47.7, 51.7, (52.3), (54.4), 69.8, 114.9, (115.1), (127.2), 127.3,
127.4, 127.9, (127.9), 128.4, 132.3, 136.7, 158.1, (158.3), 160.4 (164.3), 170.7 (171.3). IR
(ZnSe, cm-1): 1664, 1731, 2988, 3280. HRMS (ESI): calcd. for C20H22NO6 [M+H]+ 314.1387,
found 314.1391. [α]20D=-5.2º (c 1.0, CH2Cl2).
General procedure for preparation of isonitriles 4a-b (Cbz-type). The appropriate N-formyl
amino ester 3a-b (2 mmol) and triethylamine (7.5 eq., 15 mmol, 2.1 ml) was dissolved in
absolute dichloromethane (50 ml). POCl3 (1.1 eq. 2.2 mmol, 0.21 ml) was added by dropping
funnel to stirred solution at 0ºC. The reaction mixture was stirred for an additional one hour, a
small amount of POCl3 was added for complete conversion (TLC control). After this, the
reaction mixture was filtered through short column chromatography. Evaporation of the solvent
gave isocyanides.
(S)-Methyl 4-(4-(((benzyloxy)carbonyl)oxy)phenyl)-3-isocyanobutanoate (4a), 657 mg,
1
93%, brown oil; H NMR (400 MHz, CDCl3): δ 2.56 – 2.71 (m, 2H), 2.92 – 2.94 (m, 2H), 3.71
13
(s, 3H), 4.16 – 4.19 (m, 1H), 5.27 (s, 2H), 7.15 – 7.26 ( m, 4H), 7.38 – 7.46 (m, 5H). C NMR
(100 MHz, CDCl3): δ 38.6, 39.6, 51.9, 70.0, 121.0, 128.2, 128.4, 128.5, 130.2, 132.9, 134.4 ,
150.2, 153.2 , 158.4, 169.3. IR (nujol, cm-1): 1740, 1765, 2165, 2970. HRMS (ESI): calcd. for
C20H19NO5Na [M+Na]+ 376.1155, found 376.1157. [α]20D=-6.5º (c 1.0, CH2Cl2).
(R)-Methyl 3-(4-(((benzyloxy)carbonyl)oxy)phenyl)-3-isocyanopropanoate (4b), 590 mg,
87%, yellowish solid m.p. 67 – 69ºC; 1H NMR (400 MHz, CDCl3): δ 2.80 – 2.85 (m, 1H), 2.99 –
3.05 (m, 1H), 3.74 (s, 3H), 5.18 – 5.22 (m, 1H), 5.29 (s, 2H), 7.23 – 7.25 ( m, 2H), 7.38 – 7.47
(m, 7H). 13C NMR (100 MHz, CDCl3): δ 43.0, 52.2, 53.9, 70.4, 121.6, 127.2, 128.5, 128.6,
128.7, 133.6 , 134.4, 151.2 , 153.2, 158.6, 169.0. IR (nujol, cm-1): 1736, 1751, 2152, 2952.
HRMS (ESI): calcd. for C19H17NO5Na [M+Na]+ 362.0999, found 362.1002. [α]20D=+23.2º
(c 1.0, CH2Cl2).
Procedure for preparation of isonitrile 4c (Bn-Type). The N-formyl amino ester 3c (2 mmol,
630 mg) and triethylamine (2.5 eq., 5 mmol, 0.7 ml) was dissolved in absolute dichloromethane
(50 ml). POCl3 (1.1 eq. 2.2 mmol, 0.21 ml) was added by dropping funnel to stirred solution at
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
0ºC. The reaction mixture was stirred for an additional one hour, a small amount of POCl3 was
added for complete conversion (TLC control). After this, the reaction mixture was poured into a
solution of 10 equiv of K2CO3 in water and stirred for 30 min. The organic phase was separated,
dried over K2CO3 and evaporated. The residue was diluted in dichloromethane and filtered
through short column chromatography. Evaporation of the solvent gave isocyanides.
(R)-Methyl 3-(4-(benzyloxy)phenyl)-3-isocyanopropanoate (4c), 519 mg, 88%, yellowish
solid, m.p. 79 – 81ºC; 1H NMR (400 MHz, CDCl3): δ 2.79 – 2.84 ( m, 1H), 2.99 – 3.06 (m, 1H),
13
3.74 (s, 3H), 5.08 (s, 2H), 5.13 – 5.15 (m, 1H), 6.99 – 7.01 (m, 2H), 7.29 – 7.45 (m, 7H). C
NMR (100 MHz, CDCl3): δ 43.3, 52.2, 54.2, 70.1, 115.3, 127.3, 127.4, 128.1, 128.3, 128.6,
136.5, 144.2, 159.1, 169.3. IR (ZnSe, cm-1): 1734, 2140, 2962. HRMS (ESI): calcd. for
C18H17NO5Na [M+H]+ 318.1101, found 318.1102. [α]20D=+16.0º (c 1.0, CH2Cl2).
Procedure for preparation of 5b-c. To a solution of an indol-3-yl acetates 5a (2 mmol,
378 mg) in CCl4 (10 ml) were added freshly recrystallized NBS or NCS (1.5 eq., 3 mmol, 533
mg for NBS or 400 mg for NCS). The solution was stirred for one day (TLC control) at the room
temperature. After reaction was completed the solvent was removed under reduced pressure.
Product was purified via column chromatography (CH2Cl2/Hexane 3/1).
Methyl 2-(2-chloro-1H-indol-3-yl) acetate (5b), 379 mg, 85 %. Spectra data matched
literature data.7
Methyl 2-(2-bromo-1H-indol-3-yl) acetate (5c), 470 mg, 88 %. Spectra data matched
literature data.7
Procedure for preparation of 5d. To a solution of methyl indol-3-yl acetates 5a (2
mmol, 378 mg) in MeOH (10 ml) were added reagent Togni (1.2 eq., 2.4 mmol, 758 mg) and
copper (II) acetate (0.15 eq., 0.3 mmol, 54 mg). The solution was stirred for one day (TLC
control). After reaction was completed the solvent was removed under reduced pressure. Product
was purified via column chromatography (CH2Cl2/Hexane 3/1).
Methyl 2-(2-(trifluoromethyl) -1H-indol-3-yl) acetate (5d), 308 mg, 60 %. Spectra data
matched literature data.8
Procedure for preparation of 7e. To a solution of methyl indol-3-yl acetates 5a (2
mmol, 378 mg) in THF (10 ml) were added sodium hydride (1 eq., 2 mmol, 48 mg) and methyl
iodide (1 eq., 2 mmol, 0.12 mg). The solution was stirred for one day (TLC control). After
reaction was completed the solvent was removed under reduced pressure. Product was purified
via column chromatography (CH2Cl2/Hexane 3/1).
Methyl 2-(1-methyl-1H-indol-3-yl) acetate (7e), 203 mg, 50 %. Spectra data matched
literature data.10
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
General procedure for preparation of N-Boc-indol-3-yl acetates 7b-d. To a solution
of an appropriate indol-3-yl acetates 5b-d (2 mmol) in THF (10 ml) were added consequently di-
tert-butyl dicarbonate (1 eq., 2 mmol, 436 mg) and DMAP (1 eq., 2 mmol, 244 mg). The solution
was stirred at the room temperature for one day (TLC control). After reaction was completed
the solvent was removed under reduced pressure. Product was purified via column
chromatography (CH2Cl2/Hexane).
tert-Butyl 3-((methoxycarbonyl)methyl)-1H-indole-1-carboxylate (7a), 560 mg, 97 %.
Spectra data matched literature data.11,12
tert-Butyl 3-((methoxycarbonyl)methyl)-2-chloro-1H-indole-1-carboxylate (7b), 620 mg,
96%, yellowish oil; 1H NMR (400 MHz, CDCl3): δ 1.70 (s, 9H), 3.71 (s, 3H), 3.77 (s, 2H), 7.24
– 7.34 (m, 2H), 7.45 – 7.47 (m, 1H), 8.09 – 8.11 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 28.1,
29.9, 52.2, 84.9, 112.4, 115.2, 118.1, 123.1, 123.6, 124.6, 127.7, 135.1, 148.8, 170.5. IR (ZnSe,
cm-1): 1635, 1734, 2979. El. analisys: calcd. for C16H18ClNO4 C 59.35; H 5.60; N 4.33 found C
59.27; H 5.61; N 4.19
tert-Butyl 3-((methoxycarbonyl)methyl)-2-bromo-1H-indole-1-carboxylate (7c), 690 mg,
94%, yellowish oil; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 9H), 3.71 (s, 3H), 3.79 (s, 2H), 7.23
– 7.37 (m, 2H), 7.47 – 7.49 (m, 1H), 8.09 – 8.11 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 28.2,
31.4, 52.2, 85.1, 110.9, 115.4, 116.2, 118.2, 123.1, 124.6,128.4, 136.4, 149.0, 170.5. IR (ZnSe,
cm-1): 1644, 1733, 2981. El. analisys: calcd. for C16H18BrNO4 C 52.19; H 4.93; N 3..80 found C
51.94; H 5.08; N 3.74.
tert-Butyl
3-((methoxycarbonyl)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate
1
(7d), 700 mg, 98 %, yellowish oil; H NMR (400 MHz, CDCl3): δ 1.67 (s, 9H), 3.71 (s, 3H),
3.95 (s, 2H), 7.28 – 7.32 (m, 1H), 7.43 – 7.47 (m, 1H), 7.56 – 7.58 (m, 1H), 8.21 – 8.23 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 27.6, 30.0, 52.1, 85.4, 115.5, 118.9 (d, J = 2.67 Hz), 119.5,
121.4 (q, J = 268.3 Hz), 123.3, 127.3, 127.5, 136.6, 148.6, 170.2. 19F NMR (376.5 MHz,
CDCl3): δ -54.67 (CF3). IR (ZnSe, cm-1): 1663, 1745, 2985. HRMS (ESI): calcd. for
C12H11F3NO2 [M+H-Boc]+ 258.0736, found 258.0742.
General procedure for preparation of indol-3-yl acetaldehydes 8a-e. A solution of an
appropriate indol-3-yl acetate 7a-e (1 mmol) in dry toluene (100 mL) was cooled under an
atmosphere of argon to -78°C. A 20% solution of DIBAL-H in hexane (1.5 eq., 1.6 ml) was
added. The reaction was stirred for 2 hours at -78°C, before being quenched by the dropwise
addition 50 ml mixture of methanol and water (4:1). The solution was stirred for 15 minutes,
after which time it settled to two clear phases. The organic layer was separated, and the aqueous
layer was extracted three times with diethyl ether. The combined organics phases were dried
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
over magnesium sulfate. Then the solvent was evaporated in vacuo and the compound was
purified via column chromatography (CH2Cl2/Hexane).
tert-Butyl 3-(formylmethyl)-1H-indole-1-carboxylate (8a), 251 mg, 97%, yellowish oil;
1H NMR (400 MHz, CDCl3): δ 1.67 (s, 9H), 3.75 (d, J = 1.58 Hz, 2H), 7.23 – 7.27 (m, 1H), 7.32
– 7.36 (m, 1H), 7.44 – 7.46 (m, 1H), 7.57 (s, 1H), 8.14 – 8.16 (m, 1H), 9.77 (t, J = 2.11 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 28.2, 40.0, 83.9, 115.4, 118.7, 122.8, 124.7, 124.8, 127.1, 128.3,
132.4 149.5, 198.5. IR (ZnSe, cm-1): 1655, 1722, 2977. El. analisys: calcd. for C15H17NO3 C
69.48; H 6.61; N 5.40 found C 69.26; H 6.77; N 5.31
tert-Butyl 2-chloro-3-(formylmethyl)-1H-indole-1-carboxylate (8b), 270 mg, 92%,
yellowish oil; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 9H), 3.76 (d, J = 1.9 Hz, 2H), 7.22 – 7.31
(m, 1H), 7.33 – 7.36 (m, 2H), 8.11 – 8.14 (m, 1H), 9.69 (t, J = 1.9 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 27.9, 38.9, 84.9, 110.4, 115.2, 117.7, 123.1, 123.7, 124.7, 127.5, 135.1 145.5, 197.1.
IR (ZnSe, cm-1): 1675, 1738, 2980. HRMS (ESI): calcd. for C10H9ClNO [M-Boc+H]+ 194.0367,
found 194.0364.
tert-Butyl 2-bromo-3-(formylmethyl)-1H-indole-1-carboxylate (8c), 300 mg, 89%,
yellowish oil; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 9H), 3.80 (d, J = 2.1 Hz, 2H), 7.24 – 7.28
(m, 1H), 7.32 – 7.38 (m, 2H), 8.10 – 8.12 (m, 1H), 9.71 (t, J = 2.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 28.1, 39.2, 85.2, 108.8, 115.4, 117.8, 123.3, 124.0, 124.9, 127.8, 135.3, 148.8, 197.5.
IR (ZnSe, cm-1): 1652, 1735, 2979. HRMS (ESI): calcd. for C10H9BrNO [M-Boc+H]+ 237.9862,
found 237.9854.
tert-Butyl 2-(trifluoromethyl)-3-(formylmethyl)-1H-indole-1-carboxylate (8d), 301 mg,
1
92%, white solid, m.p. 72 – 74ºC; H NMR (400 MHz, CDCl3): δ 1.69 (s, 9H), 4.00 – 4.01 (m,
13
2H), 7.31 – 7.34 (m, 1H), 7.47 – 7.54 (m, 2H), 8.23 – 8.26 (m, 1H), 9.75 (bs, 1H). C NMR
(100 MHz, CDCl3): δ 27.7, 39.6 (d, J = 2.05Hz), 85.7, 115.7, 117.1 (d, J = 2.2 Hz), 119.5, 121.4
19
(d, J = 268.1Hz), 123.5, 127.5, 127.6, 136.8, 148.5, 196.7. F NMR (376.5 MHz, CDCl3): δ -
54.20 (CF3). IR (ZnSe, cm-1): 1644, 1736, 2888. HRMS (ESI): calcd. for C16H17F3NO3 [M+H]+
328.1155, found 328.1155.
1
2-(1-Methyl-1H-indol-3-yl)acetaldehyde (8e), 121 mg, 71%, brown oil; H NMR (400
MHz, CDCl3): δ 3.80 (s, 3H), 3.81 – 3.82 (m, 2H), 7.03 (s, 1H), 7.16 – 7.20 (m, 1H), 7.28 – 7.36
13
(m, 2H), 7.56 – 7.58 (m, 1H), 9.77 (t, J = 2.5 Hz, 1H). C NMR (100 MHz, CDCl3): δ 32.7,
40.2, 104.2, 109.4, 118.5, 119.4, 122.0, 127.8, 128.0, 137.0, 199.4. IR (ZnSe, cm-1): 1731, 2967,
HRMS (ESI): calcd. for C11H12NO [M+H]+ 174.0913, found 174.0912.
General procedure for the Ugi reactions. The freshly obtained aldehyde (0.2 mmol) was
dissolved in MeOH (5 mL). The 3M solution of methylamine in methanol (1.05 eq., 0.21 mmol,
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
70 µl), Boc-alanine (1.05 eq., 0.21 mmol, 40 mg) and isocyanide 4c (1.0 eq., 0.2 mmol, 59 mg)
were added, and the solution was kept for one day (TLC control) at the room temperature. When
the reaction was completed, solvent was evaporated and the product was purified via column
chromatography (dichloromethane/methanol).
tert-Butyl
3-(3-(((R)-1-(4-(benzyloxy)phenyl)-3-methoxy-3-oxopropyl)amino)-2-((S)-2-
((tert-butoxycarbonyl)amino)-N-methylpropanamido)-3-oxopropyl)-1H-indole-1-carboxylate
(9a), 76 mg, 50%, brown oil; mixture of two diastereomers and several rotomers (signals of 2nd
diastereomer and rotomers in brecket) 1H NMR (400 MHz, CDCl3): δ 0.26 – 1.17 (m, 3H), 1.37
– 1.47 (m, 9H), 1.64 – 1.77 (m, 9H), 2.67 – 3.13 (m, 6H), 3.37 – 3.66 (m, 4H), 4.08 – 4.55 (m,
1H), 4.88 – 5.48 (m, 4H), 6.87 – 7.60 (m, 15H), 8.09 – 8.44 (m, 1H)..13C NMR (100 MHz,
CDCl3): δ 16.4 (18.5), 23.3, 28.1 (28.2), 28.2 (28.3), 31 (28.8), 40.7 (39.9), 45.0 (46.7), 50.0
(49.1), 51.7, 60.0, 69.9, 80.5, 83.3, 114.9 (114.9), 115.2 (115.1), 115.5 (115.8), 118.2 (117.9),
118.8 (119.8), 122.9 (122.6), 123.7, 124.5 (124.7), 127.4 (127.3), 127.5 (127.6), 127.9 (128.0),
128.5, 129.9, 133.9 (132.9), 136.8 (136.9), 148.7 (149.4), 156.2, 158.1 (158.1), 168.2 (168.4),
171.1 (170.9), 174.0 (173.8). IR (ZnSe, cm-1): 1660, 1680, 1731, 2978, 2933, 3311, 3324.
HRMS (ESI): calcd. for C42H53N4O9 [M+H]+ 757.3807, found 757.3812.
tert-Butyl
3-(3-(((R)-1-(4-(benzyloxy)phenyl)-3-methoxy-3-oxopropyl)amino)-2-((S)-2-
((tert-butoxycarbonyl)amino)-N-methylpropanamido)-3-oxopropyl)-2-chloro-1H-indole-1-
carboxylate (9b), 128 mg, 81%, both diastereomers in ration – 1:1;
1st diastereomer – yellowish oil, several rotomers (signals of minor rotomers in bracket)
1H NMR (400 MHz, CDCl3): δ 0.32 (1.12) (d, J = 6.7 (6.7) Hz, 3H), 1.39 (1.35, 1.36, 1.42) (s (s,
s, d, J = 2.5 Hz), 9H), 1.67 (1.69) (s, 9H), 2.69 – 3.31 (m, 6H), 3.65 (3.50, 3.59) (s, 3H), 4.07 –
4.14 (4.28 – 4.34, 4.47 – 4.51) (m, 1H), 4.87 – 5.67 (m, 5H), 6.86 – 7.60 (m, 14H), 8.07 (8.41)
13
(d, J = 7.5 (8.1) Hz, 1H). C NMR (100 MHz, CDCl3): δ 16.6 (18.3), 23.1, 28.1, 28.3 (28.3),
29.3, 40.7, 44.7, 50.0, 51.7 (51.7), 59.1, 69.9, 80.5, 85.1, 110.0, 114.9 (115.1). 115.4, 117.7,
123.5 (123.3), 124.9 (124.5), 127.3, 127.5 (127.4), 127.6, 127.7, 127.9, 128.5, 133.8, 135.2,
136.9 (136.8), 148.7, 158.1, 158.1 (158.1), 168.1 (168.4), 170.8, 173.9. IR (ZnSe, cm-1): 1637,
1676, 1735, 2933, 2978, 3301, 3320. HRMS (ESI): calcd. for C42H52ClN4O9 [M+H]+ 791.3423,
found 791.3429. [α]20D=-33.6º (c 0.83, CH2Cl2).
2nd diastereomer – yellowish oil, several rotomers (signals of minor rotomers in
1
bracket) H NMR (400 MHz, CDCl3): δ 0.82 (d, J = 6.9 Hz, 3H), 1.36 (1.39, 1.41, 1.42) (s (s, s,
s), 9H), 1.67 (1.69, 1.71) (s (s, s), 9H), 2.69 – 3.43 (m, 7H), 3.64 (3.60, 3.65, 3.66) (s (s, s, s),
3H), 4.29 – 4.35 (4.11 – 4.16) (m, 1H), 5.01 – 5.04 (m, 3H), 5.38 – 5.68 (m, 2H), 6.89 – 6.94 (m,
3H), 7.18 – 7.50 (m, 10H), 8.02 (d, J = 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 16.6, 22.4,
28.1, 28.3, 31.5, 40.4, 46.4, 49.6, 51.8, 55.7m 70.0, 79.8, 84.8, 109.6, 115.0, 115.0, 118.3, 122.7,
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
123.0, 124.5, 127.4, 127.6, 127.8, 128.0, 128.6, 133.0, 135.2, 136.9, 148.9, 155.7, 158.2, 168.8,
171.1, 174.2. IR (ZnSe, cm-1): 1637, 1676, 1735, 2933, 2978, 3301, 3320. HRMS (ESI): calcd.
for C42H52ClN4O9 [M+H]+ 791.3423, found 791.3429. [α]20D=-2.2º (c 0.18, CH2Cl2).
tert-Butyl
3-(3-(((R)-1-(4-(benzyloxy)phenyl)-3-methoxy-3-oxopropyl)amino)-2-((S)-2-
((tert-butoxycarbonyl)amino)-N-methylpropanamido)-3-oxopropyl)-2-bromo-1H-indole-1-
carboxylate (9c), 107 mg, 64%, brown oil; mixture of two diastereomers and several rotomers
(signals of 2nd diastereomer and rotomers in brecket) 1H NMR (400 MHz, CDCl3): δ 0.31 – 1.29
(m, 3H), 1.38 – 1.74 (m, 18H), 2.55 – 4.35 (m, 11H), 4.94 – 5.65 (m, 4H), 6.88 – 7.50 (m, 14H),
8.01 – 8.42 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 16.5, 24.3 (23.7), 28.1 (28.2), 31.9 (29.8),
40.4 (40.7), 46.4 (44.7), 49.6 (49.9), 51.7, 59.1, 55.9, 69.9, 80.5 (79.7), 85.3 (84.9), 110.4, 114.9
(114.9), 115.1 (115.5), 118.3 (117.7), 118.5 (119.0), 122.8 (123.0), 123.4, 124.5 (124.8), 127.4
(127.5), 127.5 (127.6), 127.9, 128.5, 133.0 (133.7), 136.4 (136.4), 136.9, 148.9 (148.8), 155.6
(156.1), 158.1 (158.1), 168.8 (168.1), 171.1, 174.2 (174.0). IR (ZnSe, cm-1): 1654, 1682, 1716,
1733, 2933, 2978, 3301, 3307. HRMS (ESI): calcd. for C42H52BrN4O7 [M+H]+ 835.2918, found
835.2924.
tert-Butyl
3-(3-(((R)-1-(4-(benzyloxy)phenyl)-3-methoxy-3-oxopropyl)amino)-2-((S)-2-
((tert-butoxycarbonyl)amino)-N-methylpropanamido)-3-oxopropyl)-2-(trifluoromethyl)-1H-
indole-1-carboxylate (9d), 109 mg, 66%, yellow oil; mixture of two diastereomers and several
1
rotomers (signals of 2nd diastereomer and rotomers in brecket) H NMR (400 MHz, CDCl3): δ
0.30 – 1.12 (m, 3H), 1.26 – 1.42 (m, 9H), 1.60 – 1.67 (m, 9H), 2.67 – 3.02 (m, 5H), 3.31 – 3.76
(m, 5H), 3.99 – 4.50 (m, 1H), 4.84 – 5.55 (m, 5H), 6.87 – 7.77 (m, 13H), 8.12 – 8.39 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 16.4 (18.2), 22.5 (23.4), 27.7 (27.7), 28.2, 31.5 (29.5), 40.8
(40.4), 46.3 (44.6), 50.0 (49.7), 51.7 (51.7), 57.6 (61.0), 70.0, 79.8 (80.6), 85.7 (85.2), 111.1,
114.9 (114.9), 115.4 (115.6), 119.3 (q, JCF = 256.2 Hz), 120.2 (119.6), 123.3 (123.4), 123.9,
127.3 (127.3), 127.4, 127.5 (127.5), 127.6, 127.8 (127.7), 127.9, 128.6, 133.1 (133.7), 136.7
(136.9), 148.7, 156.1 (155.7), 158.1 (158.1), 168.4 (167.8), 171.1 (170.8), 174.3 (173.9). 19F
NMR (376.5 MHz, CDCl3): δ -54.0 (-54.3, -54.4) (CF3). IR (ZnSe, cm-1): 1655, 1668, 1716,
1740, 2931, 2979, 3307, 3317. HRMS (ESI): calcd. for C43H52F3N4O9 [M+H]+ 825.3681, found
825.3786.
Acknowledgment
This study was supported by program of Leading Scientific Schools (Grant N
4687.2018.3 and RFBR (Russian Foundation for Basic Research) (Grant N 16-33-60012
mol_a_dk). The authors acknowledge Thermo Fisher Scientific Inc., MS Analytica (Moscow,
Russia), and personally to Prof. A.Makarov for providing mass spectrometry equipment for this
work.
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10.1002/ejoc.201800992
European Journal of Organic Chemistry
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