A straightforward approach towards combined ?-amino and ?-hydroxy acids based on Passerini reactions

Article abstract of DOI:10.3762/bjoc.7.151

Complex amino acids with an ?-acyloxycarbonyl functionality in the side chain are easily available through epoxide opening by chelated enolates and subsequent oxidation/Passerini reaction. This protocol works with both, aldehyde and ketone intermediates, as long as the ketones are activated by electron-withdrawing groups. In principle Ugi reactions are also possible, allowing the generation of diamino acid derivatives.

Full text of DOI:10.3762/bjoc.7.151

A straightforward approach towards combined
α-amino and α-hydroxy acids based on
Passerini reactions
Ameer F. Zahoor, Sarah Thies and Uli Kazmaier*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1299–1303.
Institute for Organic Chemistry, Saarland University, P.O. Box
151150, 66041 Saarbrücken, Germany
doi:10.3762/bjoc.7.151
Received: 14 May 2011
Email:
Accepted: 23 August 2011
Published: 19 September 2011
Uli Kazmaier* - u.kazmaier@mx.uni-saarland.de
* Corresponding author
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
Keywords:
amino acids; chelated enolates; epoxides; Passerini reactions; Ugi
reactions
© 2011 Zahoor et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Complex amino acids with an α-acyloxycarbonyl functionality in the side chain are easily available through epoxide opening by
chelated enolates and subsequent oxidation/Passerini reaction. This protocol works with both, aldehyde and ketone intermediates, as
long as the ketones are activated by electron-withdrawing groups. In principle Ugi reactions are also possible, allowing the genera-
tion of diamino acid derivatives.
Introduction
Multicomponent reactions (MCR) are a very popular and Therefore, the Ugi reaction is even more flexible than the
powerful tool in modern organic synthesis [1-4]. Besides a wide Passerini approach, but both reactions together have made the
range of heterocycle syntheses [5] and catalytic cross coupling IMCR highly popular in combinatorial chemistry [7,8].
reactions [6], the isonitrile-based MCRs (IMCR) especially
have developed exceptionally well during the last few decades Our group has been involved in amino acid and peptide syn-
[7,8]. Based on the pioneering work of Passerini, who observed thesis for nearly two decades [12,13], and multicomponent reac-
the first three-component coupling of carbonyls with carboxylic tions are known to play a dominant role [14,15]. In particular,
acids and isonitriles in 1921 [9], the so-called Passerini reac- the Ugi reaction has so far been used for the construction of
tion became a powerful tool for the synthesis of acylated exotic peptides [16-19] and cyclopeptides [20,21]. Herein we
α-hydroxyacid amides [10]. Later on, in 1961, Ugi and describe a straightforward protocol towards combined α-amino
Steinbrückner reported the extension of this protocol by and α-hydroxy acids through Passerini reactions. Suitable
incorporating also a primary amine as a fourth component [11]. amino acid precursors with an oxygen functionality in the side
1299

Beilstein J. Org. Chem. 2011, 7, 1299–1303.
chain can be obtained by chelated enolate Claisen rearrange- sterically least-hindered position [26]. These alcohols can easily
ment [22,23] or transition metal-catalyzed allylic alkylation of be oxidized by Swern-oxidation [27] or with Dess–Martin-
chelated enolates [24] and subsequent oxidative cleavage of the periodinane (DMP) [28], giving rise to the required γ-oxo-
γ–δ-unsaturated amino acids obtained.
amino acids 2 (Table 1). In principle both protocols are suitable
for oxidation, but in general the yields obtained were better with
DMP (82–93%), while under Swern conditions the yields were
Results and Discussion
An alternative approach is based on regioselective ring opening in the range of 75 ± 3%.
of epoxides, followed by oxidation of the hydroxy amino acid
formed. While aryl-substituted epoxides react preferentially at With these γ-oxo-α-amino acids 2 in hand, we investigated the
the benzylic position giving rise to the terminal primary alco- Passerini reactions under neat conditions with acetic acid as the
hols [25], the corresponding alkyl-substituted epoxides provide (liquid) acidic component and isocyano acetates as the reactive
secondary alcohols 1 by nucleophilic attack of the enolate at the component (Table 2). Interestingly, no reaction was observed
Table 1: Synthesis of γ-oxo-amino acids.
Entry
1
R
Yield (%)
2
Yield (%)
Meth. Bb
Meth. Aa
1
2
3
4
5
6
1a [26]
1b [26]
1c [26]
1d
CH3
92
82
86
88
84
83
2a
2b
2c
2d
2e
2f
78
75
76
72
75
74
91
90
93
82
87
84
CH2Cl
CH2OC6H5
CH2O-(p-Cl-C6H4)
CH2O-(o-NO2-C6H4)
CH2O-(p-NO2-C6H4)
1e
1f
aMethod A: Swern oxidation; bMethod B: DMP oxidation.
Table 2: Passerini reactions of γ-oxo-amino acids.
Entry
2
R
R’
3
Yield (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
CH3
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3f
–
CH2Cl
65
57
69
62
69
68
CH2OC6H5
CH2O-(p-Cl-C6H4)
CH2O-(o-NO2-C6H4)
CH2O-(p-NO2-C6H4)
CH2O-(p-Cl-C6H4)
2d
Et
3g
1300

Beilstein J. Org. Chem. 2011, 7, 1299–1303.
with the methyl-substituted oxo acid 2a (entry 1); only the attempts in CH3OH and CH2Cl2 were unsuccessful. While no
starting material was recovered. For this reason, we switched to reaction was observed in CH2Cl2, in CH3OH the only product
activated ketones bearing an electron-withdrawing group at the (besides starting material) was the unsaturated acetal resulting
α-position. With the chlorinated ketone 2b the yield was 65% from a nucleophilic attack of the solvent on the aldehyde group.
(entry 2), and similar results were obtained with a range of Therefore, we decided to run the reaction also under neat condi-
aryloxy-substituted derivatives 2c–2f (entries 3–7). The new tions as reported for the γ-oxo-amino acids. With acetic acid as
stereogenic center was formed without significant selectivity. the acidic component the yield of 6a was comparable to the
previous examples. In principle, other acids such as benzoic
To increase the synthetic potential of this protocol we also acid or Cbz-protected glycine can be used as well. The lower
applied the Pd-catalyzed opening of a vinyl epoxide with our yield obtained in these cases probably results from stirring
chelated enolate (Scheme 1) [29]. In this case an amino acid 4 problems under these solvent-free conditions.
with an allyl alcohol side chain was formed which could be
oxidized to the α,β-unsaturated aldehyde 5. Although these To circumvent the problems caused by the α,β-unsaturated alde-
types of aldehydes are critical candidates in Passerini and Ugi hyde, we hydrogenated 4 before oxidation to obtain the satu-
reactions [30], we were interested to see if we could also obtain rated aldehyde 7. And indeed, under our optimized reaction
unsaturated Passerini adducts by this procedure. Our first conditions the addition product 8 could be obtained in 80%
Scheme 1: Passerini reactions of α,β-unsaturated aldehyde 5.
1301

Beilstein J. Org. Chem. 2011, 7, 1299–1303.
References
yield (Scheme 2). In principle, Ugi reactions are also possible,
as illustrated with the formation of 9, although the yield was
significantly lower in this case and the products are formed as a
1:1 diastereomeric mixture.
1. Ramón, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628–1661.
doi:10.1002/ange.200460548
Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
doi:10.1002/anie.200460548
2. Zhu, J.; Bienaymé, H., Eds. Multicomponent reactions; Wiley:
Weinheim, Germany, 2005.
3. Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.;
Salvino, J. M. J. Comb. Chem. 2006, 8, 597–635.
doi:10.1021/cc060095m
4. Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486.
doi:10.1021/cr800296p
5. Isambert, N.; Lavilla, R. Chem.–Eur. J. 2008, 14, 8444–8454.
doi:10.1002/chem.200800473
6. Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P.
Chem. Rev. 2010, 110, 6169–6193. doi:10.1021/cr100108k
7. Dömling, A. Chem. Rev. 2006, 106, 17–89. doi:10.1021/cr0505728
8. El Kaim, L.; Grimaud, L. Tetrahedron 2009, 65, 2153–2171.
doi:10.1016/j.tet.2008.12.002
9. Passerini, M. Gazz. Chim. Ital. 1921, 51-2, 126–129.
10.Banfi, L.; Riva, R. The Passerini Reaction. Organic Reactions; Wiley:
New Jersey, 2005; Vol. 65, pp 1–140.
doi:10.1002/0471264180.or065.01
11.Ugi, I.; Steinbrückner, C. Chem. Ber. 1961, 94, 734–742.
doi:10.1002/cber.19610940323
12.Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett 2000, 11, 1523–1535.
doi:10.1055/s-2000-7904
13.Deska, J.; Kazmaier, U. Curr. Org. Chem. 2008, 12, 355–385.
doi:10.2174/138527208783743697
Scheme 2: Passerini and Ugi reaction of saturated aldehyde 7.
14.Schmidt, C.; Kazmaier, U. Org. Biomol. Chem. 2008, 6, 4643–4648.
doi:10.1039/b811382c
Conclusion
15.Kazmaier, U.; Schmidt, C. Synlett 2009, 1136–1140.
doi:10.1055/s-0028-1088150
In conclusion, we showed that the ring opening of epoxides,
either directly or Pd-catalyzed, with chelated enolates combined
with Passerini reactions is a suitable tool for the synthesis of
highly functionalized α-hydroxy and α-amino acid derivatives.
These new compounds are interesting building blocks for
peptide-derived drugs. Attempts to improve the yields and to
evaluate the scope and limitations are currently underway.
16.Kazmaier, U.; Hebach, C. Synlett 2003, 1591–1594.
doi:10.1055/s-2003-40987
17.Pick, R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 5,
757–760. doi:10.1055/s-2005-863722
18.Kazmaier, U.; Ackermann, S. Org. Biomol. Chem. 2005, 3, 3184–3187.
doi:10.1039/b507028g
19.Kazmaier, U.; Persch, A. Org. Biomol. Chem. 2010, 8, 5442–5447.
doi:10.1039/c0ob00453g
20.Hebach, C.; Kazmaier, U. J. Chem. Soc., Chem. Commun. 2003,
596–597. doi:10.1039/b210952b
Supporting Information
21.Kazmaier, U.; Hebach, C.; Watzke, A.; Maier, S.; Mues, H.; Huch, V.
Org. Biomol. Chem. 2005, 3, 136–145. doi:10.1039/b411228h
22.Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941–954.
doi:10.1016/0040-4020(95)00946-9
Supporting Information features detailed experimental
procedures, NMR as well as analytical data of all
compounds.
23.Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37, 7945–7946.
doi:10.1016/0040-4039(96)01764-9
Supporting Information File 1
Experimental section.
24.Kazmaier, U. Curr. Org. Chem. 2003, 7, 317–328.
doi:10.2174/1385272033372888
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-151-S1.pdf]
25.Zahoor, A. F.; Kazmaier, U. Synthesis 2011, 7, 1059–1066.
doi:10.1055/s-0030-1258460
26.Kazmaier, U.; Zahoor, A. F. ARKIVOC 2011, IV, 6–16.
27.Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482. doi:10.1021/jo00406a041
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft. A. F. Zahoor thanks the DAAD and HEC (Pakistan) for
a PhD fellowship.
28.Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
doi:10.1021/jo00170a070
29.Thies, S.; Kazmaier, U. Synlett 2010, 1, 137–141.
doi:10.1055/s-0029-1218536
1302

Beilstein J. Org. Chem. 2011, 7, 1299–1303.
30.Baker, R. H.; Schlesinger, A. H. J. Am. Chem. Soc. 1945, 67,
1499–1500. doi:10.1021/ja01225a027
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.151
1303