Application of isocyanides derived from α-amino acids as substrates for the Ugi reaction

Article abstract of DOI:10.1080/00397910802222787

A systematic study on the influence of Lewis acid, solvent, and temperature on the stereochemical course of the Ugi reaction was performed to find conditions in which the isocyanides derived from enantiopure α-amino acids do not racemize. After a series o

Full text of DOI:10.1080/00397910802222787

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Application of Isocyanides
Derived from α-Amino Acids as
Substrates for the Ugi Reaction
Stanisław Berłożecki a , Wiktor Szymański a
&
Ryszard Ostaszewski a
a Institute of Organic Chemistry, Polish Academy of
Sciences, Warsaw, Poland
Published online: 25 Aug 2010.
To cite this article: Stanisaw Beroecki , Wiktor Szymaski & Ryszard Ostaszewski
(2008) Application of Isocyanides Derived from α-Amino Acids as Substrates
for the Ugi Reaction, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:16, 2714-2721, DOI:
10.1080/00397910802222787
To link to this article: http://dx.doi.org/10.1080/00397910802222787
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Synthetic Communications1, 38: 2714–2721, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802222787
Application of Isocyanides Derived from a-Amino
Acids as Substrates for the Ugi Reaction
´
Stanisław Berłoz˙ecki, Wiktor Szymanski, and Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland
Abstract: A systematic study on the influence of Lewis acid, solvent, and
temperature on the stereochemical course of the Ugi reaction was performed to
find conditions in which the isocyanides derived from enantiopure a-amino acids
do not racemize. After a series of experiments, dichloromethane was used as a
solvent and BF3ꢀOEt2 as a Lewis acid catalyst. This combination allowed us to
obtain a product in a model reaction with 99% diastereoisomeric ratio (dr), with
the structure motif of a group of cathepsin K inhibitors.
Keywords: Isocyanides, racemization, Ugi reaction
Ugi multicomponent reaction (U-MCR, Fig. 1) is a powerful tool in the
synthesis of diverse small peptides and their analogs.[1] Isocyanides
derived from enantiopure a-amino acids could serve as ideal substrates
for Ugi reactions, because they are readily availiable in enantiopure form.
However, their applicability is limited by fast racemization under the con-
ditions of Ugi reaction.[2] This leads to the formation of a mixture of dia-
stereoisomers, which decreases the yield of the target compound and
makes the purification process very difficult or sometimes impossible.
Therefore, the synthetic procedure for the synthesis of product A,
without the racemization of optically pure isocyanides derived from
a-amino acids, is of great importance. Proper selection of solvent and
catalyst may decrease the racemization rate of isocyanide. For the
systematic model study, we have chosen a reaction (Fig. 2) between
Received in the U.K. May 30, 2007
Address correspondence to Ryszard Ostaszewski, Institute of Organic Chemis-
try, Polish Academy of Sciences, Kasprzaka 44=52, 01-224 Warasaw, Poland.
Fax: þ48 22 6326681. E-mail: rysza@icho.edu.pl
2714

Isocyanides as Substrates in Ugi Reaction
2715
Figure 1. Ugi reaction with isocyanides derived from a-amino acids.
Figure 2. Model Ugi reaction with isocyanides derived from a-amino acids.
Figure 3. Cathepsin K inhibitors.
isocyanide derived from the methyl ester of (S)-phenylalanine (1), acetic
acid (2), enantiopure (R)-1-phenyl-ethylamine (3), and cyclohexanone (4).
To avoid the potential formation of four diastereisomers, cyclic
ketone 4 was used. Our choice was also influenced by the fact that the
scaffold is widely encountered in structures of medicinal importance,
such as cathepsin K inhibitors A and B (Fig. 3), potentially useful in
the treatment of osteoporosis.[3,4]
Prior to the optimization study, a method for the preparation of the iso-
cyanide 1 had to be established that would not affect the enantiopurity of the
starting a-amino acid, which is a common problem in the synthesis of this
type of compounds. A systematic study on the conditions of formamide 7
dehydratation (Fig. 4) was performed. The results are presented in Table 1.
Figure 4. Synthesis of isocyanide 1.

´
S. Berłoz˙ecki, W. Szymanski, and R. Ostaszewski
2716
Table 1. Conditions of isocyanide 1 synthesisa
Reaction conditions
Isocyanide 1b
T (ꢂC)
Dehydrating agent
[a]D
Mp (ꢂC)
c
Solvent
Amine
20
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CHCl3
TEA
TEA
TEA
TEA
NMM
NMM
ꢃ50
ꢃ50
ꢃ50
ꢃ50
ꢃ35
ꢃ40
Mesyl chloride
POCl3
Oxalyl chloride
POCl3
Diphosgene
Diphosgene
0
47
nd
nd
nd
nd
65–66
ꢃ4.7
ꢃ1.7
ꢃ1.3
ꢃ10.8
ꢃ16.5
CH2Cl2
aAbbreviations used: TEA—triethylamine, NMM—4-methylmorpholine.
bPublished data[5]: [a]D ¼ ꢃ13.2 (c ¼ 1.3, benzene), mp ¼ 58–59 ꢂC.
20
cBenzene used as a solvent, c ¼ 1.3.
The results in Table 1 clearly show the problem of isocyanide racemi-
zation during the reaction course, as most of commonly used dehydra-
tation conditions (Table 1, entries 1–4) fail to yield compounds of high
enantiopurity. The use of 4-methylmorpholine (entries 5 and 6),
especially when dichloromethane was used as solvent, proved to be the
best combination, and it was used in further studies.
To investigate the compositions of model Ugi reactions (Fig. 2), ana-
lytical high pressure liquid chromatography (HPLC) was used. However,
it should be stated that first a series of five experiments was performed,
where results obtained from analytical HPLC were compared with those
obtained from preparative (HPLC). The data were consistent within the
statistical error of ꢀ1%.
First, the influence of temperature and Lewis acid catalyst on the
product distribution was studied. It is already known that the addition
of such catalysts sometimes improves the stereochemical outcome of
Ugi reactions.[5] Results obtained after 6 h of reaction in CH2Cl2 are
presented in Table 2.
The reaction carried out at room temperature without catalyst
(Table 2, entry 1) proceeded in good yield, but two dioastereoizomers
were formed in an almost 1:1 ratio. Surprisingly, the lowering of tempera-
ture resulted in significant increase of diastereoisomeric ratio (entry 2),
although the yield decreased from 61 to 31.5% (entries 3 and 4). Most
of the Lewis acid catalysts failed to improve this ratio. However, the
use of boron trifluoride ethyl eterate (entry 5) proved to be promising.
In the next step, the influence of the solvent was examined. The
model reaction was performed in previously established conditions
(BF3ꢁOEt2 as catalyst, 0 ꢂC, 6 h) with the alteration of solvent. The results
are presented in Table 3.

Isocyanides as Substrates in Ugi Reaction
2717
Table 2. Influence of temperature and Lewis acid (CH2Cl2, 6 h)
T (ꢂC)
Lewis acid
Yield (5 þ 6)
Dr
20
0
0
0
0
—
—
ZnCl2
LiCl
61a
31.5
3.6
13.8
16.5
25.1
55.0:45.0
91.5:8.5
63.8:37.2
73.5:26.5
98.5:1.5
BF3ꢁOEt2
0
Mg(ClO4)2
84.7:15.3
aReaction time prolonged to 210 h.
A strong influence of solvent on the outcome of model reaction is vis-
ible. In alcohols (Table 3, entries 1 and 2), the reaction proceeds with
moderate yields, and a good diastereoisomeric ratio of the product is
obtained. Out of examined ethers (Table 3, entries 3–5), tetrahydrofuran
used as a solvent leads to improvement of the yield, with the dr being the
same as in alcohols.
The best yield was obtained in the case of acetonitrile (Table 3, entry
6), however, at the cost of almost complete loss of diastereoselectivity.
When one of the reagents (cyclohexanone, Table 3, entry 7) was used
Table 3. Influence of solvent (cat. BF3ꢁOEt2, 0 ꢂC, 6 h)
Solvent
Time (h)
Yield (5 þ 6) %
Dr
Methanol
6
6
6
6
6
17.4
17.7
2.4
22.3
4.2
93:7
92:8
91.4:8.6
92.5:7.5
58:42
Iso-propanol
Ethyl ether
Tetrahydrofurane
Dioxane
Acetonitrile
Cyclohexanonea
Benzene
Toluene
Xylene
CH2Cl2
Chloroform
Carbon tetrachloride
Toluene
Xylene
CH2Cl2
6
6
6
6
6
6
6
6
39.2
22.1
14.2
16.3
12.5
16.5
12.1
9.9
55.5:44.5
96.7:3.3
91.5:8.5
89.9:10.1
93:7
98.5:1.5
92.3:7.7
85:15
42
42
42
37.3
31.6
34.2
89.2:9.8
93:7
88.7:11.3
aExcess of reagent used as solvent.

´
S. Berłoz˙ecki, W. Szymanski, and R. Ostaszewski
2718
Table 4. Final results (CH2Cl2, cat. BF3ꢁOEt2, 0ꢂC, 6 h)
Substrates
Product’s dr
R-(þ)-Amine, S-(ꢃ)-isocyanide
R-(þ)-Amine, R-(þ)-isocyanide
S-(ꢃ)-Amine, S-(ꢃ)-isocyanide
S-(ꢃ)-Amine, R-(þ)-isocyanide
98.5:1.5
3:97
2:98
97.5:2.5
as a solvent, the product was obtained in moderate yield, with good dia-
stereoisomeric excess. Out of aromatic solvents (Table 3, entries 8–10),
xylene proved to be the best in terms of dr preservation; however, the
yield was the lowest. In chlorinated solvents (Table 3, entries 11–13), a
trend is visible: the increase in the number of chlorine atoms leads to
the loss of both yield and dr.
For aromatic solvents, the elongation of reaction time to 42 h (Table
3, entries 14 and 15) led to the increase of yield, with no loss of diaster-
eoisomeric excess. Unfortunately, in case of dichloromethane (Table 3,
entry 16), the purity of the product was severely diminished after 42 h,
although the yield was significantly higher. Nevertheless, dichloro-
methane was finally chosen as a solvent and BF3ꢁOEt2 as a catalyst,
and the reaction temperature was optimized as 0 ꢂC (as in entry 11).
Finally, to verify if the optimized parameters are set correctly, we
decided to run four reactions with all the combinations of isocyanide 1
and amine 3 enantiomers. Obtained results are presented in Table 4.
The data proved to be consistent within statistical error, and the use of
the optimized procedure allowed the formation of all four diastereoi-
somers with high selectivity.
In this article, we have described our systematic study on the influ-
ence of solvent and Lewis acid catalyst on the stereochemical outcome
of Ugi reaction, which uses isocyanide derived from enantiopure a-amino
acid. A set of parameters was found that enables the synthesis of small
peptides and their analogs in the Ugi reaction without the loss of enantio-
purity of isocyanide component. However, it is accomplished at the cost
of a lower reaction yield.
The utility of established procedure was further visualized by multi-
component synthesis of an enantiopure compound bearing a structure
motif of a group of cathepsin K inhibitors.
Studies on the broadening of the scope of Ugi reaction seem worth-
while because of the wide applicability of tripeptides and their analogues
readily obtained from it. We believe that these results will lead to a recon-
sideration of the views on the use of isocyanides derived from a-amino
acids as substrates for the Ugi reaction.

Isocyanides as Substrates in Ugi Reaction
2719
EXPERIMENTAL
Equipment
Semipreparative HPLC: three columns (30 ꢄ 0.8 cm, connected rankly)
filled with 10 mm of Lichrosorb with isocratic mixture 1:1 (v=v) hexa-
ne=ethyl acetate as eluent (20 ml=min). Shimadzu RID-6A RI detector
and Shimadzu LC-8A preparative liquid chromatograph were used.
Analytical HPLC: Pump: Merck Hitashi L-6000A. Column:
(250 ꢄ 4,6 mm), filled with 5 mm of Kromasil. Detector: Merck Hitashi
UV detector L-7400, k ¼ 254 nm. Eluent: isocratic mixture 98:2 v=v
CH2Cl2=isopropanol (flow 1 ml=min).
Procedures
Methyl (S)-2-isocyano-3-phenylpropionate was prepared by
a
modification of a method published by Seebach and coworkers.[6]
N-Formyl-(S)-phenylalanine methyl ester (1 eq, 0.8 M solution in
dichloromethane), stirred under argon, was cooled to ꢃ10 ꢂC, and
N-methylmorpholine (2 eq) was added via syringe through septum. The
mixture was further cooled to ꢃ50 ꢂC, and a 2.4 M solution of trichloro-
methyl chloroformate (0.5 eq) was added via dropping funnel at such a
rate that the temperature did not exceed ꢃ45 ꢂC. The resulting suspension
was stirred for 2 h at this temperature, and then it was allowed to warm
up to ꢃ15 ꢂC. Then it was poured into ice-cooled water and extracted
three times with dichloromethane. Collected organic layers were passed
through a layer of MgSO4 and silica gel (100–200 Mesh) and eluted with
CH2Cl2 under reduced pressure. The product was obtained in the form of
red-orange crystals, as stated by the authors of cited article. However,
purification on semipreparative HPLC with isocratic mixture 9:1 (v=v)
of hexane=ethyl acetate as eluent yielded white, rectangular-shaped plates
with data shown in Table 1, entry 6. Yield after HPLC purification: 72%.
Methyl (R)-2-isocyano-3-phenylpropionate was prepared by the
same procedure as before, using N-formyl-(R)-phenylalanine methyl ester
as substrate. Yield after HPLC purification: 53%.
Typical Experimental Procedure for the Optimized Ugi Reaction
Acetic acid (0.5 mmol), cyclohexanone (0.5 mmol), and 1-phenylethyla-
mine (0.5 mmol) were stirred in 1.0 ml of CH2Cl2 at 0 ꢂC. A catalytic
amount of freshly distilled of BF3ꢁEt2O (25 ml) was added, followed
after 5 min by methyl 2-isocyano-3-phenylpropionate (0.5 mmol). After
6 h the product was purified by column chromatography (30) ꢄ 1.3 cm

´
S. Berłoz˙ecki, W. Szymanski, and R. Ostaszewski
2720
packed with 7 g of silica gel 60). Elution was carried with 25 ml
of CH2Cl2 followed by 50 ml of methanol. Methanol fractions were
collected, and products were separated via semipreparative HPLC.
An analytical HPLC procedure was used to determine the diastereo-
isomeric ratio.
Data
Compound 5: [a]D ¼ 18.4 (c ¼ 1.1, benzene). Anal. C27H34N2O4
20
requires C, 71.97%; H, 7.61%; N, 6.22%; found: C, 72.11%; H,
1
7.55%; N, 6.19%: H NMR (CDCl3, 200 MHz) d: 1.63–1.86 (m, 13H,
c-hex, CH3CO), 2.30–2.44 (m, 1H, PhCH2), 2.60–2.75 (m, 1H, PhCH2),
3.23 (d, 3H, J ¼ 6.0 Hz, CH3CHPh), 3.76 (s, 3H, CH3O), 4.98 (q, 1H,
J ¼ 7.0 Hz, PhCHCH3), 5.17–5.25 (m, 1H, CHCH2Ph), 6.69–6.79 (m,
1H, NH), 7.30–7.42 (m, 10H, ArH); 13C NMR (CDCl3, 50 MHz) d:
20.7, 23.1, 25.8, 26.1, 33.8, 34.2, 38.4, 52.4, 53.5, 67.4, 126.4, 127.1,
127.2, 128.8, 129.0, 129.7, 136.7, 143.3, 172.6, 173.5, 173.8; HRMS
(ESI, [M þ Na]þ) 473.2420 (C27H34N2O4Na: 473.2411).
Compound 6: [a]D ¼ 55.2 (c ¼ 1.1, benzene); 1H NMR (CDCl3,
20
200 MHz) d: 1.63–1.86 (m, 13H, c-hex, CH3CO), 2.10–2.32 (m, 1H,
PhCH2), 2.66–2.82 (m, 1H, PhCH2), 3.19 (d, 3H, J ¼ 6.0 Hz, CH3CHPh),
3.80 (s, 3H, CH3O), 4.98 (q, 1H, J ¼ 7.2 Hz, PhCHCH3), 5.17–5.25 (m,
1H, CHCH2Ph), 6.69–6.79 (m, 1H, NH), 7.18–7.51 (m, 10H, ArH); 13C
NMR (CDCl3, 50 MHz) d: 20.0, 22.8, 23.0, 25.4, 25.6, 33.3, 34.0, 38.2,
52.1, 53.2, 67.1, 126.0, 126.8, 128.3, 128.7, 129.3, 136.3, 142.8, 172.4,
173.6; HRMS (ESI, [M þ Na]þ ) 473.2421 (C27H34N2O4Na: 473.2411).
ACKNOWLEDGMENT
This work was financially supported by Polish State Committee for
Scientific Research, Grant N405 007 31=0544.
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Isocyanides as Substrates in Ugi Reaction
2721
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