A Versatile Synthesis of α-Amino Acid Derivatives via the Ugi Four-Component Condensation with a Novel Convertible Isonitrile

Article abstract of DOI:10.1055/s-2003-43355

The Ugi four-component condensation (4CC) reaction with the carbonate-type isonitrile 9 proceeded smoothly, and subsequent base treatment of the Ugi products 10 provided the N-acyloxazolidinones 11 in high yield. The N-acyloxazolidinones derivatives can be reacted with several hetero-nucleophiles, namely, reaction of 11 with thiolates gave thiol ester derivatives 16 efficiently.

Full text of DOI:10.1055/s-2003-43355

LETTER
41
A Versatile Synthesis of a-Amino Acid Derivatives via the Ugi Four-
Component Condensation with a Novel Convertible Isonitrile
Versatile
S
ynthesis
e
of
a
-Amin
n
o
A
cid
D
eriv
t
a
tive
s
aro Rikimaru, Arata Yanagisawa, Toshiyuki Kan, Tohru Fukuyama*
Graduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 10 October 2003
(Figure 1). In the case of Armstrong’s 1-cyclohexenyl iso-
cyanide (2),5 the nucleophilic addition to the amide bond
of the Ugi products was readily carried out under acidic
conditions. On the other hand, the condensation product
Abstract: The Ugi four-component condensation (4CC) reaction
with the carbonate-type isonitrile 9 proceeded smoothly, and subse-
quent base treatment of the Ugi products 10 provided the N-acylox-
azolidinones 11 in high yield. The N-acyloxazolidinones
derivatives can be reacted with several hetero-nucleophiles, name- derived from the isocyanoalkyl alkyl carbonates 3 report-
ly, reaction of 11 with thiolates gave thiol ester derivatives 16 effi-
ed by Ugi was converted to the corresponding a-amino es-
ter derivatives 6 by treatment with base.6 As shown in
ciently.
Key words: Ugi four-component condensation (4CC), a-amino
acid derivatives, convertible isonitrile, N-acyloxazolidinones, thiol
esters
Scheme 2, this reaction would take place via the forma-
tion of the N-acyloxazolidinones 5 by cyclization of the
amide anion onto the carbonate of 4 followed by addition
of the alkoxide (–OR) and elimination of the oxazolidino-
ne. Thus, using an isonitrile 9 similar to the Ugi convert-
ible isonitrile 3, we expected to obtain the N-
acyloxazolidinones from the Ugi products. Since the C–N
bond in the N-acyloxazolidinones can be cleaved by sev-
eral nucleophiles under mild conditions, this protocol
would allow the production of numerous analogues.
Multi-component reactions (MCRs) have attracted much
attention because of their use in the construction of com-
binatorial libraries.1 In particular, the Ugi four-component
condensation (Ugi’s 4CC)2 has been widely employed
since it provides various a-amino amide derivatives 1 by
a simple experimental procedure under mild conditions.1b
These products possess a drug-like structure and could be
responsible for a variety of important biological activities.
Moreover, the great facility of the condensation to form
amide bonds also permits the efficient total synthesis of
complex natural products.3
Here we describe the Ugi 4CC reaction with the novel
isonitrile 9 and a convenient procedure for conversion of
the Ugi products by cleavage of the C-terminal amide
bond.
Although numerous reports of the Ugi 4CC reaction have
been published, inherent problems in the stereoselective
construction of the a-position4 and cleavage of the C-ter-
minal amide still need to be solved. Due to the limited va-
riety of isonitriles available in comparison with the other
components, incorporation of other diverse functional
groups at the C-terminal amide (R-groups) has been re-
quired for the generation of these libraries (Scheme 1).5–11
Figure 1 Convertible Isonitriles
Recently, the 4CC reaction with the convertible isonitriles
2 and 3 was reported by Armstrong and Ugi, respectively
Scheme 2 Ugi approach
Scheme 1 Ugi 4CC and its limitations
Our working hypothesis for the isonitrile 9 is based on the
theory that the phenoxide anion would not attack the N-
acyloxazolidinone of 5, because of its weak nucleophilic-
ity (pKa = 10). Preparation of the isonitrile 9 was per-
formed according to the Ugi protocol.6,12 Upon treatment
SYNLETT 2004, No. 1, pp 0041–0044
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43355; Art ID: U21003ST
© Georg Thieme Verlag Stuttgart · New York

42
K. Rikimaru et al.
LETTER
Table 2 Formation of Oxazolidinone Rings15
of 4,4-dimethyloxazoline (7)13 with n-BuLi, smooth
deprotonation and elimination gave the b-isocyanoalkox-
ide 8. Subsequent protection of the alkoxide intermediate
by phenyl chloroformate afforded the isonitrile 9
(Scheme 3). The isonitrile 9 has the advantage of being
odorless and stable under silica gel chromatographic puri-
fication.
Entry
X
Y
Z
Temp Time
Yield (%)
(°C)
(min)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
0
10
83 (11a)
85 (11b)
90 (11c)
89 (11d)
95 (11e)
82 (11f)
86 (11g)
0
10
Me
Ph
0
10
0
10
i-Pr
i-Pr
Ph
0
10
Scheme 3 Preparation of isonitrile 912
0
10
With the requisite isonitrile 9 in hand, the Ugi 4CC reac-
tion of the combined aromatic and/or aliphatic amines, al-
dehydes and carboxylic acids was carried out.14 As shown
in Table 1, the 4CC proceeded smoothly to give the de-
sired a-amino amide derivatives 10a–g in almost quanti-
tative yields. In the case of entry 7, a relatively higher
temperature was needed for the completion of the reac-
tion. Next, we turned our attention to the transformation
of the Ugi products 10a–g to the N-acyloxazolidinones
11a–g.15 After several attempts at cyclization, treatment
with t-BuOK in THF in the presence of molecular sieves
4 Å (MS 4 Å) gave the best results. As shown in Table 2,
the desired cyclization proceeded smoothly to afford the
N-acyloxazolidinones 11a–g in more than 80% yield. As
expected, the nucleophilic attack of the phenoxide anion
on the N-acyloxazolidinones did not occur. Furthermore,
MS 4 Å play a key role in preventing hydrolysis of the
starting materials and/or products by moisture.16
0
10
Since the C–N bond in N-acyloxazolidinones is activated
by two carbonyl groups, cleavage of the amide bonds was
accomplished readily by addition of a hetero-nucleophile
or via LiBH4 reduction, similar to the Evans
oxazolidinones17–19 (Scheme 4). Among the possible nu-
cleophiles, thiol groups would be attractive, since the thiol
esters could be converted into the corresponding
aldehydes20a or ketones20b in the presence of a palladium
catalyst. The Pd-mediated reduction by triethylsilane and
alkylation with zinc reagents of the thiol esters were de-
veloped by our group. The conversion of the N-protected
a-amino carbonyl compounds proceeded readily under
neutral conditions. Recently, we also reported that thiol
esters, derived from odorless n-dodecanethiol,21 could be
applicable to the Pd-mediated reaction instead of
ethanethiol.22 Thus, upon treatment of the N-acyloxazoli-
dinones 11a–g with lithium thiolate generated from n-
BuLi and n-dodecanethiol, the conversion proceeded
smoothly to give the n-dodecanethiol esters 16a–g
(Table 3).23,24
Table 1 Ugi 4CC Reaction with Isonitrile 914
Entry
X
Y
Z
Temp Time
Yield (%)
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
70
(min)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
60
91 (10a)
88a (10b)
83 (10c)
88 (10d)
98 (10e)
99 (10f)
89 (10g)
10
Me
Ph
10
60b
60
Scheme 4 Transformation from N-acyloxazolidinones
i-Pr
i-Pr
Ph
In conclusion, we have developed a highly efficient, ver-
satile synthetic method for a-amino acid derivatives by
means of the Ugi 4CC reaction with a newly developed
isonitrile 9. As summarized in Scheme 5, the choice of
the appropriate components, acids (X), amines (Y) and
aldehydes (Z) and/or nucleophiles (R) for the N-acyl-
10
60b
a Small amounts of inseparable impurities were detected by 1H NMR;
b The starting material remained
Synlett 2004, No. 1, 41–44 © Thieme Stuttgart · New York

LETTER
Versatile Synthesis of a-Amino Acid Derivatives
43
Table 3 Formation of Thiol Esters23
was reported, see: Denmark, S. E.; Fan, Y. J. Am. Chem. Soc.
2003, 125, 7825.
(5) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1996, 118, 2574. (b) Strocker, A. M.; Keating, T. A.;
Tempest, P. A.; Armstrong, R. W. Tetrahedron Lett. 1996,
37, 1149.
(6) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411.
(7) Geller, J.; Ugi, I. Chem. Scr. 1983, 22, 85.
(8) Mjalli, A. M. M.; Sarshar, S.; Baiga, T. J. Tetrahedron Lett.
1996, 37, 2943.
Entry
X
Y
Z
Temp Time
Yield (%)
(°C)
(min)
(9) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem.
1999, 64, 336.
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Ph
Ph
i-Pr
H
0
10
83 (16a)
79 (16b)
75 (16c)
66 (16d)
78 (16e)
86 (16f)
68 (16g)
(10) (a) For the use of N-tert-butoxycarbonylation to activate
amides, see: Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org.
Chem. 1983, 48, 2425. (b) For its application to the Ugi 4CC
reaction, see: Hulme, C.; Ma, L.; Cherrier, M.-P.; Romano,
J. J.; Morton, G. Tetrahedron Lett. 2000, 41, 1883.
(11) For the use of N-nitrosation to activate amides, see:
(a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011.
(b) Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J.
C.; Katz, J. I.; Kung, D. W. Tetrahedron Lett. 1997, 38,
4535. (c) Berenguer, R.; Garcia, J.; Vilarrasa, J. Synthesis
1989, 305. (d) For its applications to the Ugi 4CC reaction,
see: Isenring, H. P.; Hofheinz, W. Synthesis 1981, 385.
(e) Also see: Isenring, H. P.; Hofheinz, W. Tetrahedron
1983, 39, 2591.
0
10
Me
Ph
0
10
0
10
i-Pr
i-Pr
Ph
0
10
0
10
0
10
oxazolidinones and thiol esters would allow us to synthe-
(12) Synthesis of Isonitrile 9: To a stirred solution of 4,4-
dimethyloxazoline (0.997 g, 10.1 mmol) in THF (10 mL)
under Ar atmosphere at –78 °C, was added dropwise n-BuLi
(1.1 M solution in hexane, 9.60 mL, 10.6 mmol) in a
duration of 5 min and stirred at same temperature for 1 h
followed by dropwise addition of phenyl chloroformate
(1.40 mL, 10.7 mmol). After stirring for 5 min, the reaction
mixture was warmed to ambient temperature and diluted
with Et2O, and water was added to the mixture. The organic
layer was separated and washed with brine, dried over
Na2SO4 and filtered. The solvent was removed under
reduced pressure, the resulting residue was purified by silica
gel chromatography (EtOAc–hexane = 1:9–1:4) to afford
1.10 g of 9 (49.7%). IR (film): 2991, 2136, 1767, 1592,
1496, 1457, 1401, 1378, 1258, 1074, 1024, 970, 879, 835,
775, 735 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.45–7.19
(m, 5 H), 4.21 (s, 2 H), 1.53 (s, 6 H). 13C NMR (100 MHz,
CDCl3): d = 156.1, 153.1, 150.8, 129.4, 126.1, 120.8, 72.9,
56.1, 25.6. HRMS (FAB): m/z calcd for C12H13NO3:
219.0895; found: 219.0900.
size a variety of N-acylamino acid derivatives.
Further applications of this methodology to the syntheses
of a range of peptidomimetic derivatives and/or natural
products are under investigation in our laboratories.
Scheme 5
(13) Meyers, A. I.; Collington, E. W. J. Am. Chem. Soc. 1970, 92,
6676.
References
(14) General Procedure for the Ugi 4CC with Isonitrile 9,
Synthesis of 10a: To a stirred solution of isonitrile 9 (223
mg, 1.02 mmol), isobutylaldehyde (0.310 mL, 3.40 mmol),
and benzoic acid (128 mg, 1.05 mmol) in MeOH (3.5 mL,
0.19 M) was added dropwise benzylamine (74 mL, 0.68
mmol) within 2 min at ambient temperature. After stirring
for 60 min, the solvent was removed under reduced pressure.
The resultant crude mixture was purified by silica gel
chromatography (EtOAc–hexane = 1:9–1:2) to afford 310
mg of 10a (91%) as a pale yellow foam. IR (film): 3301,
3063, 2968, 1764, 1680, 1620, 1545, 1496, 1457, 1367,
1263, 1211, 1066, 963, 918, 774, 734 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.60–7.05 (m, 15 H), 4.67 (d, J = 16 Hz,
1 H), 4.45 (m, 2 H), 4.29 (d, J = 11 Hz, 2 H), 2.80 (m, 1 H),
1.36 (m, 6 H), 1.02 (m, 1 H). 13C NMR (100 MHz, CDCl3):
d = 174.0, 170.2, 153.6, 151.1, 136.6, 136.5, 129.8, 129.5,
128.5, 128.4, 127.8, 127.7, 126.7, 126.0, 121.0, 76.7, 72.1,
54.0, 52.8, 27.2, 24.3, 23.8, 19.8, 19.5. HRMS (FAB): m/z
calcd for C30H34N2O5: 502.2468; found: 502.2485.
(1) For reviews of multicomponent reactions with isonitriles,
see: (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
51. (b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (c) Gokel, G.; Lüdke, G.; Ugi, I. In Isonitrile
Chemistry; Ugi, I., Ed.; Academic: New York, 1971, 145–
199.
(2) (a) Ugi, I.; Myer, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I.; Steinbrückner, C. Angew.
Chem. 1960, 72, 267.
(3) (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552.
(b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3200.
(4) (a) For a recent example of the stereoselective Ugi 4CC
reaction using a chiral amine component, see: Ross, G. F.;
Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127; and
references therein. (b) Recently, the first example of
catalytic asymmetric a-addition of isonitrile to an aldehyde
Synlett 2004, No. 1, 41–44 © Thieme Stuttgart · New York

44
K. Rikimaru et al.
LETTER
(20) (a) Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.;
(15) General Procedure for the Synthesis of N-Acyloxazol-
idinones, Synthesis of 11a: To a stirred solution of 10a (220
mg, 0.44 mmol) in anhyd THF (2.0 mL, 0.22 M) at 0 °C was
added freshly activated MS 4 Å (powder, 280 mg), and
stirred for 10 min, followed by dropwise addition of 1.0 M
t-BuOK in t-BuOH (0.45 mL, 0.45 mmol) in a duration of
2 min. After stirring for 5 min, 10% aq citric acid was added
and the mixture was extracted with EtOAc. The combined
organic layer was washed with brine, dried over MgSO4 and
filtered. The solvent was removed under reduced pressure,
the resultant crude mixture was purified by silica gel
chromatography (EtOAc–hexane = 1:9–1:2) to afford 11a
(149 mg, 83%) as a pale yellow foam. IR (film): 2968, 2360,
1779, 1701, 1646, 1496, 1374, 1305, 1231, 1173, 1089,
1031, 761, 734 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.36–
7.19 (m, 10 H), 5.63 (m, 1 H), 4.88 (m, 2 H), 3.94 (m, 2 H),
2.43 (m, 1 H), 1.49 (s, 3 H), 1.33 (s, 3 H), 0.93 (d, J = 15 Hz,
6 H). 13C NMR (100 MHz, CDCl3): d = 175.8, 173.9, 172.3,
152.9, 138.7, 136.7, 129.6, 128.6, 128.3, 128.2, 127.4,
126.8, 126.3, 75.1, 61.0, 29.5, 24.3, 23.8, 19.4, 18.6. HRMS
(FAB): m/z calcd for C24H28N2O4: 408.2049; found:
408.2033.
Fukuyama, T. Synthesis 2002, 1121. (b) Tokuyama, H.;
Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 3189.
(21) (a) Nishide, K.; Ohsugi, S.; Shiraki, H.; Tamakita, H.; Node,
M. Org. Lett. 2001, 3, 3121. (b) Node, M.; Kumar, K.;
Nishide, K.; Ohsugi, S.; Miyamoto, T. Tetrahedron Lett.
2001, 42, 9207.
(22) Tokuyama, H.; Miyazaki, T.; Yokoshima, S.; Fukuyama, T.
Synlett 2003, 1512.
(23) General Procedure for the Synthesis of Thiolesters,
Synthesis of 16a: To a solution of n-dodecanethiol (0.26
mL, 1.08 mmol) in anhyd THF (2.5 mL) at 0 °C was added
dropwise n-BuLi (1.0 M solution in hexane, 0.40 mL, 0.40
mmol) for 2 min. After stirring for 5 min, the resulting white
suspension was added to a solution of N-acyloxazolidinone
11a (93 mg, 0.23 mmol) in THF (1.5 mL) at 0 °C. After
stirring for 10 min, 10% aq citric acid was added and the
mixture was extracted with EtOAc. The combined organic
layer was washed with brine, dried over MgSO4 and filtered.
The solvent was removed under reduced pressure, the
resultant crude mixture was purified by silica gel
(16) In the absence of MS 4 Å, the reaction resulted in low yields,
accompanied by the N-acylamino alcohols 12 and/or
carboxylic acid 13 (Figure 2).
chromatography (EtOAc–hexane = 1:9–1:2) to afford 16a
(94 mg, 83%) as a white solid. IR(film): 2915, 2854, 1684,
1653, 1457, 1300, 1129, 731 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.58–6.98 (m, 10 H), 4.88 (d, J = 14 Hz, 1 H),
4.65 (d, J = 15 Hz, 1 H), 4.10 (d, J = 7.3 Hz, 1 H), 2.77 (t,
J = 15 Hz, 2 H), 2.43 (m, 1 H), 1.30–1.00 (m, 20 H), 0.88 (t,
J = 14 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 196.8,
173.5, 138.1, 136.2, 129.7, 128.5, 128.3, 128.1, 127.8,
127.5, 126.8, 73.5, 62.7, 50.3, 45.8, 31.9, 29.6, 29.5, 29.4,
29.1, 29.0, 22.7, 19.5, 19.1, 14.1. HRMS (FAB): m/z calcd
for C24H28N2O4: 495.3171; found: 495.3169.
Figure 2
(24) In order to avoid the thiolate addition to the carbonyl group
on the oxazolidinone ring, the reaction should be carried out
at a temperature lower than 0 °C. Reactions at higher
temperature often provided the undesired N-acylamino
alcohols 12. This tendency was notably observed in
compounds possessing a bulky substituent at the Z-position.
(17) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127.
(18) For recent examples, see: Orita, A.; Nagano, Y.; Hirano, J.;
Otera, J. Synlett 2001, 637; and the detailed references cited
therein.
(19) For C–N bond cleavage in N-acyl-4,4-dimethyl-2-
oxazolidinones, see: (a) MeOMgBr: Chevliakov, M. V.;
Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139.
(b) Me(OMe)2: Kanemasa, S.; Kanai, T. J. Am. Chem. Soc.
2000, 122, 10710. (c) Sm(OTf)3–MeOH: Sibi, M. P.;
Gorikunti, U.; Liu, M. Tetrahedron 2002, 58, 8357.
(d) NaOH–t-BuOH: Ito, Y.; Terashima, S. Tetrahedron
1991, 47, 2821.
Synlett 2004, No. 1, 41–44 © Thieme Stuttgart · New York