R-α-Phenylglycinol and R-α-phenylglycinamide as novel chiral templates in diastereoselective Ugi reaction

Article abstract of DOI:10.1016/j.mencom.2011.09.004

R-α-Phenylglycinol and R-α-phenylglycinamide as chiral amino components in the Ugi multicomponent reaction provide up to 98% de of S,R-isomer.

Full text of DOI:10.1016/j.mencom.2011.09.004

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 245–246
R-a-Phenylglycinol and R-a-phenylglycinamide as novel
chiral templates in diastereoselective Ugi reaction
Valentine G. Nenajdenko,* Anton V. Gulevich, Konstantin Yu. Chernichenko,
Nadezhda V. Sokolova and Elizabeth S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
DOI: 10.1016/j.mencom.2011.09.004
R-a-Phenylglycinol and R-a-phenylglycinamide as chiral amino components in the Ugi multicomponent reaction provide up to 98% de
of S,R-isomer.
Isocyanide-based multicomponent Passerini and Ugi reactions
are efficient methods allowing formation of set of C–C, and C–O
or C–N bonds in one step.1 These methodologies are extremely
useful for a construction of new amino and hydroxy acid frag-
ments as well as skeleton of peptides and peptide-like molecules,
especially containing artificial a-amino acid.2
gave better results; see Online Supplementary Materials]. We
found that under optimal conditions the product 2a,† having
S-configuration, can be obtained in good yield and 96% de. Note
that the reaction did not proceed without Lewis acid. We also
tried to optimize the structure of chiral template to achieve higher
stereoselectivity. Thus, protection of hydroxy group with Me (1b)
or TBS (1c) group, as expected, leads to the decrease in stereo-
selectivity due to Lewis acid coordination restriction. Insertion
of additional coordinating group SMe (1d) into the ortho-posi-
tion of benzoic ring also gave no positive result (Scheme 1).‡ The
major diastereomer in all cases had S,R configuration according
to the diagnostic chemical shift of But group in NMR spectra.4
However, the main challenge of the Ugi reaction-based syn-
thesis of peptides and amino acids is a formation of new centre in
a stereoselective fashion. Up to days, only chiral amines provided
sufficient stereoselectivity, whereas chiral isocyanide, carbonyl
compounds and carboxylic acids are usually inefficient.3
A variety of chiral amines were tested as chiral auxiliaries for
the Ugi reaction. Commercial (a-phenylethyl)amine4 usually
gives low selectivity. Chiral (+)-(a-ferrocenylethyl)amines were
also used.5 However, high molecular weight, conformational
instability and multistep synthesis of amine templates are dis-
advantageous. In 1987 Kunz et al.6 introduced a-d-galactoamine
derivatives as a chiral template for this purpose. The reaction
proceeds in the presence of Lewis acid (ZnCl2) at low tempe-
ratures (up to –78°C) and provides products in good yields and
stereoselectivity of up to 94% de.7 It was found that this stereo-
selectivity was caused by formation of complex from imine and
Lewis acid.8 Later other amino sugars were tested as chiral
templates for the Ugi reaction.9 Although these templates some-
times had shown good to excellent diastereoselectivity, the
removal of sugar moiety from Ugi products was not simple.
Moreover, all amino sugar-based templates have limitations with
respect to the carbonyl input and relatively high molecular weight
(M at least 350 g mol–1) and, hence, lack principles of atom-
economy. Therefore, development of new efficient and low mole-
cular weight chiral templates is still a great challenge in the Ugi
reaction.
d(H1) ~ 1.37 ppm
d(H1) ~ 1.11 ppm
R
H2N
R2
OR1
O
O
But
Pri
R
But
Pri
S
N
N
H
i
H
+
N
N
OR1
OR1
Ph(O)C
R2
Ph(O)C
1a–d
R
R
R2
+
PriCHO
PhCOOH
ButNC
2a–d
2'a–d
S,R
R,R
major
minor
R1
R2
de
a
b
c
H
H
H
H
SMe
96%
76%
90%
92%
TBS
Me
H
d
Scheme 1 Reagents and conditions: 1 equiv. ZnCl2 (0.1 m solution in THF),
–38°C, 12 h; de was determined by GC-MS and NMR techniques.
Here, we have disclosed employment of a-d-phenylglycinol
and a-d-phenylglycinamide as new chiral amino templates for
Ugi reactions. The suggested auxillaries are commercially available
compounds in both enantiomeric forms.
†
To a stirred solution of isobutyric aldehyde (1 mmol) and R-a-phenyl-
glycinol 1a (1 mmol) in THF (9 ml), ZnCl2 solution in THF (1 mmol in
1 ml) was added at –38°C. After that benzoic acid (1 mmol) and ButNC
(1.2 mmol) were subsequently added. The mixture was stirred at this tem-
perature for ~48 h, evaporated in vacuo and the residue was analyzed by
GC-MS and NMR or purified by column chromatography (hexane–EtOAc,
4:1). Product 2a, yield 70%, was obtained as a white solid, mp 143–145°C.
1H NMR (CDCl3, 400 MHz) d: 0.98 (d, 3H, J 5.0 Hz), 1.07 (d, 3H, J 5.0 Hz),
1.10 (s, 6H), 2.99 (br.s, 1H), 3.27 (d, 1H, J 9.9 Hz), 3.80–4.20 (m, 2H), 5.1
(br.s, 1H), 7.00–7.50 (m, 10H), 8.3 (br.s, 1H). 13C NMR (CDCl3, 100 MHz)
d: 19.9, 20.6, 27.3, 28.3, 50.1, 60.6, 64.1, 71.2, 127.1, 127.8, 128.0, 128.5,
128.6, 129.8, 136.4, 136.9, 170.8, 174.5. [a]2D0 +28.8 (c 0.032, MeOH).
HRMS (ESI), m/z: 419.2355 [M+Na]+ (calc. for C24H32N2O3, 419.2311).
Initially, we supposed that modification of a-phenylethyl amine
molecule with hydroxy group can deliver additional coordination
site for the Lewis acid due to chelation of metal atom. As a result,
addition of isocyanide should occur from less restricted side to
induce a new stereocenter with predictable configuration.
The model Ugi reaction of a-d-phenylglycinol 1a, isobutiric
aldehyde, benzoic acid and tert-butyl isocyanide and a number
of Lewis acids were tested (Scheme 1). Zn salts were found to be
most efficient activators [Yb(OTf)2, BF3·Et2O, NiCl2, Al(OPri)3,
Ti(OPri)4, MgCl2, Zn(OTf)2, ZnBr2 were also tested, but ZnCl2
‡
For synthesis of 1b–d, see Online Supplementary Materials.
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 245–246
R-a-Phenylglycinamide 3 was used several times as a chiral
Ph
Ph
O
auxiliary in different reactions, including step of nucleophilic
addition to imine.10 We propose that R-a-phenylglycinamide 3
having more constrained amide fragment would be even more
efficient in terms of coordination of imine by Lewis acid. For this
purpose, chiral imine 4 having trans-configuration was easily
synthesized from isobutyraldehyde and compound 3.§ We have
found that reaction of imine 4 gave Ugi products 5a,b in good
yield and excellent stereoselectivity (>98%) in the presence of
1 equiv. of ZnCl2 (Scheme 2).§ To verify the absolute configura-
tion, compound 5b was deprotected and hydrolized to known
valine N-tert-butylamide, which was found to be S-enantiomer.
H2N
OH
H2N
NH2
1a
3
ButNC
ButNC
Ph
NH2
Ph
Zn
H
H
N
H
R
H
R
N
O
O
Zn
Cl
Cl
ButNC
t
Cl
Cl
Bu NC
A
B
chelated transitition state
(S)-product 2a, de ~ 96%
(S)-product 5, de > 98%
Scheme 3
Pri
PriCHO
CH2Cl2
CONH2
H2N
CONH2
N
Ph
Ph
3
4, 80%
trans only
This work was supported by the Federal Agency of Education
(grant no. P2063).
O
But
Pri
ButNC
RCOOH
ZnCl2
THF, –38 °C, 48 h
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.09.004.
N
4
H
R
N
CONH2
O
Ph
References
5a R = Ph, yield 70%, de > 98%
5b R = CF3, yield 63%, de > 98%
1 (a) A. Dömling and I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168;
(b) Multicomponent Reactions, eds. J. Zhu and H. Bienamé, Wiley-VCH,
Weinheim, 2005; (c) A. Dömling, Chem. Rev., 2006, 106, 17; (d) A. V.
Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko, Chem.
Rev., 2010, 110, 5235.
2 (a)A.V. Gulevich, N. E. Shevchenko, E. S. Balenkova, G.-V. Röschenthaler
and V. G. Nenajdenko, Synlett, 2009, 403; (b) M. Mroczkiewicz and
R. Ostaszewski, Tetrahedron, 2009, 65, 4025; (c) A. G. Zhdanko, A. V.
Gulevich and V. G. Nenajdenko, Tetrahedron, 2009, 65, 4629; (d) A. V.
Gulevich, I. V. Shpilevaya and V. G. Nenajdenko, Eur. J. Org. Chem.,
2009, 3801; (e) A. G. Zhdanko and V. G. Nenajdenko, J. Org. Chem.,
2009, 74, 884; (f) V. G. Nenajdenko, A. V. Gulevich, N. V. Sokolova,
A. V. Mironov and E. S. Balenkova, Eur. J. Org. Chem., 2010, 1445.
3 (a) G. F. Ross, E. Herdtweck and I. Ugi, Tetrahedron, 2002, 58, 6127;
(b) D. J. Ramon and M. Yus, Angew. Chem. Int. Ed., 2005, 44, 1602;
(c) V. G. Nenajdenko,A. L. Reznichenko and E. S. Balenkova, Tetrahedron,
2007, 63, 3031.
Scheme 2
We proposed that reactions proceed through chelate inter-
mediates A and B displaying restricted approach of isocyanide
from one of the sides (Scheme 3). Slightly higher selectivity in
case of R-a-phenylglycinamide 3 can be caused by more con-
strained amide structure of intermediate B. These models permit
to predict the configuration of major diastereomer in both cases.
The approach of isocyanide from upper face gave S configuration
of new stereocentre formed.
In conclusion, we have tested several derivatives of R-a-phenyl-
glycinol as a chiral auxiliary for Ugi multicomponent reac-
tion and found that under optimized conditions reaction can be
performed in diastereoselectivity up to 96% de. We have also
demonstrated that a-d-phenylglycinamide is more efficient
template for the Ugi reaction and can be employed for prepara-
tion of the products in highly diastereoselective fashion with
de up to 98%. Note that suggested templates are commercially
available in both enantiomeric forms, whereas their residues are
readily removed from the target compounds by hydrogenolysis
(see Online Supplementary Materials).
4 A. V. Gulevich, E. S. Balenkova and V. G. Nenajdenko, J. Org. Chem.,
2007, 72, 7878 and references therein.
5 (a) D. Marquarding, P. Hoffman, H. Heitzer and I. Ugi, J. Am. Chem. Soc.,
1970, 92, 1969; (b) R. Urban, G. Eberle, D. Marquarding, D. Rehn, H. Rehn
and I. Ugi, Angew. Chem., Int. Ed. Engl., 1976, 15, 627; (c) R. Urban,
Tetrahedron, 1979, 35, 1841.
6 H. Kunz and W. Pfrengle, J. Am. Chem. Soc., 1988, 110, 651.
7 (a) H. Kunz, W. Pfrengle and W. Sager, Tetrahedron Lett., 1989, 30, 4109;
(b) R. J. Linderman, S. Binet and S. R. Petrich, J. Org. Chem., 1999, 64,
336; (c) K. Oertel, G. Zech and H. Kunz, Angew. Chem. Int. Ed., 2000,
39, 1431.
8 H. Kunz and W. Pfrengle, Tetrahedron, 1988, 44, 5487.
9 (a) M. Goebel and I. Ugi, Synthesis, 1991, 1095; (b) M. Goebel and
I. Ugi, Tetrahedron Lett., 1995, 36, 6043; (c) C. Lehnhoff, M. Goebel,
R. M. Karl, R. Klösel and I. Ugi, Angew. Chem., Int. Ed. Engl., 1995, 34,
1104; (d) G. Ross and I. Ugi, Can. J. Chem., 2001, 79, 1934; (e) G. Ross,
E. Herdtweck and I. Ugi, Tetrahedron, 2002, 58, 6127.
§
To a stirred solution of 4 (1 mmol) in THF (9 ml), ZnCl2 solution in
THF (1 mmol in 1 ml) was added at –38°C. After that, benzoic acid
(1 mmol) for 5a or trifluoroacetic acid (1 mmol) for 5b and ButNC
(1.2 mmol) were subsequently added. The mixture was then stirred at this
temperature for ~48 h, evaporated in vacuo and the residue was analyzed
by GC-MS and NMR or purified by column chromatography (hexane–
EtOAc, 3:1). Product 5a was obtained as a white solid in 70% yield,
mp 112–116°C. 1H NMR (mixture of rotamers, CDCl3, 400 MHz) d: 0.5
(d, 3H, J 6.1 Hz), 0.66 (d, 3H, J 6.1 Hz), 1.31 (s, 9H), 2.00–2.20 (m, 1H),
3.54–3.76 (m, 1H), 5.30–5.60 (m, 2H), 6.0–6.30 (m, 2H), 7.35–7.40 (m,
9H), 7.60–7.70 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 172.7, 168.4,
166.9, 136.5, 136.4, 129.6, 129.3, 128.8, 128.5, 125.6, 63.4 (m), 60.1,
28.4, 28.1, 20.8, 19.9. [a]D20 +3.3 (c 0.03, MeOH). HRMS (ESI) m/z:
432.2296 (calc. for C24H31N3O3 [M+Na]+, 432.2263).
10 M. Van der Sluis, J. Dalmolen, B. de Lange, B. Kaptein, R. M. Kellogg
and Q. B. Broxterman, Org. Lett., 2001, 3, 3943.
For synthesis and characteristics of imine 4, and characteristics of
product 5b, see Online Suppplementary Materials.
Received: 31st March 2011; Com. 11/3709
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