Stereoselective synthesis of N-aryl proline amides by biotransformation- Ugi-Smiles sequence

Article abstract of DOI:10.1039/c1ob06699d

An efficient combination of MAO-N-catalyzed desymmetrization of cyclic meso-amines with Ugi-Smiles multicomponent chemistry produced optically pure N-aryl proline amides. This method represents the first report of a fully asymmetric Ugi-Smiles process.

Full text of DOI:10.1039/c1ob06699d

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Stereoselective synthesis of N-aryl proline amides by
biotransformation–Ugi-Smiles sequence†‡
Anass Znabet,a Sara Blanken,a Elwin Janssen,a Frans J. J. de Kanter,a Madeleine Helliwell,b
Nicholas J. Turner,c Eelco Ruijter*a and Romano V. A. Orru*a
Received 7th October 2011, Accepted 10th November 2011
DOI: 10.1039/c1ob06699d
An efficient combination of MAO-N-catalyzed desym-
metrization of cyclic meso-amines with Ugi-Smiles multi-
component chemistry produced optically pure N-aryl proline
amides. This method represents the first report of a fully
asymmetric Ugi-Smiles process.
The synthesis of complex and challenging target molecules re-
quires sophisticated synthetic concepts and methodologies. Owing
to their high flexibility, selectivity, and convergence, multicompo-
nent reactions (MCRs)1 have emerged as powerful tools in the syn-
thesis of complex, biologically relevant molecules.2 Undoubtedly
the most widely used MCR is the Ugi four-component reaction
(U-4CR). This reaction between amines, aldehydes, carboxylic
acids and isocyanides affords a wide range of peptidic and pep-
tidomimetic products. However, no catalytic asymmetric version
of the U-4CR has been described to date and, as many MCRs,
it typically suffers from very poor diastereoselectivity.3 Recently,
we developed a highly stereoselective synthesis of substituted
prolyl peptides 5 by combining the biocatalytic desymmetrization
of 3,4-cis-substituted meso-pyrrolidines 1 using an engineered
monoamine oxidase N (MAO-N) from Aspergillus niger4 and
an Ugi-type three-component reaction (MAO-N oxidation–MCR
sequence, Scheme 1).5 These prolyl peptides are of considerable
interest in organocatalysis. This method has also proven very
efficient in the synthesis oꢀf alkaloid-type compounds6 and the
hepatitis C drug TelaprevirC (IncivekTM).7
Scheme 1 Asymmetric synthesis of prolyl peptides by MAO-N oxidation
and Ugi-type 3CR.5
of the Ugi reaction in which the carboxylic acid component
is substituted by an electron-deficient phenol derivative (or a
heteroaromatic analog),8 is a promising candidate for combination
with our biocatalytic oxidation due to its mechanistic similarity
with the Ugi reaction. Recently, El Ka¨ım and coworkers described
a three-component Ugi-Smiles coupling of five- and six-membered
(racemic) cyclic imines.9
Because the optically active 1-pyrrolines generated by MAO-N
oxidation are versatile building blocks for a diverse set of MCRs,
we envisioned that combining these substituted 1-pyrrolines
We then decided to investigate the possibility of extending this
methodology to other MCRs. The Ugi-Smiles reaction, a variation
aDepartment of Chemistry & Pharmaceutical Sciences and Amsterdam
Institute of Molecules, Medicines and Systems, VU University Amsterdam,
De Boelelaan 1083, 1081 HV Amsterdam, the Netherlands. E-mail: r.v.a.
orru@vu.nl;e.ruijter@vu.nl; Fax: +31 20 5987488; Tel: +31 20 5987447
bSchool of Chemistry, University of Manchester, Brunswick Street, Manch-
ester, M13 9PL, UK
cSchool of Chemistry, University of Manchester, Manchester Interdisci-
plinary Biocentre, 131 Princess Street, Manchester, M1 7DN, UK
† This work was financially supported by the Netherlands Organization
for Scientific Research (NWO) by means of a Mosaic Fellowship to A. Z.
We thank Dr M. T. Smoluch (VU University) for HRMS measurements.
‡ Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of 1H and 13C NMR spectra
for all new compounds. CCDC reference number 844264. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06699d
Scheme 2 Asymmetric synthesis of N-aryl proline amides by MAO-N
oxidation and Ugi-Smiles 3CR.
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Table 1 Optimization of the Ugi-Smiles 3CR of bridged imine 8, 2-nitrophenol (9) and tert-butyl isocyanide (10)
Entry
Solvent
T/◦C
Reaction Time
Additives
8) : 9 : 10a
Yield (%)
1
2
3
4
5
6
7
8
MeOH
Toluene
MeOH
Toluene
MeOH
MeOH
MeOH
MeOH
TFE
MeOH
MeOH
MeOH
MeOH
MeOH
60
80
60
80
RT
40
125
150
135
RT
60
RT
40
60
24 h
24 h
48 h
48 h
72 h
24 h
—
—
—
—
—
—
—
—
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
1.0 : 1.3 : 1.3
2.0 : 1.3 : 1.5
2.0 : 1.0 : 1.5
2.0 : 1.0 : 1.5
53b
26b
55b
25b
39b
43b
40c
40c
<10c
34b
24b
33b
73b
44b
30 mind
30 mind
30 mind
24 h
9
—
Sc(OTf)3
Sc(OTf)3
10
11
12
13
14
24 h
24 h
24 h
24 h
—
—
a Molar ratios of the reactants; b Isolated yield; c Yield estimated by HPLC analysis; d Microwave irradiation in closed vessel; TFE = 2,2,2-trifluoroethanol.
with the Ugi-Smiles MCR would generate highly functionalized,
optically pure 3,4-substituted N-aryl proline amides (Scheme 2).
Similar compounds have been reported to be potent VLA-4
antagonists.10 These antagonists may be useful in the treatment
of diseases like asthma, atherosclerosis, rheumatoid arthritis,
inflammatory bowel disease, and multiple sclerosis.11
We started our investigation by finding the most suitable
conditions for the Ugi-Smiles MCR. The reaction of bridged
imine 8, 2-nitrophenol (9) and tert-butyl isocyanide (10) was
designated as a benchmark reaction (Table 1). We began by using
the conditions reported by El Ka¨ım et al.12 Unfortunately, these
conditions afforded 11 in moderate yield at best (entries 1 and
2, Table 1). Therefore, we opted to extend the reaction time and
raise the temperature. However, this did not have any effect and
the isolated yield remained more or less the same (entries 3–6,
Table 1). Neither microwave irradiation of the reaction mixture
(entries 7–9, Table 1) nor the use of Sc(OTf)3 as Lewis acid additive
(entries 10 and 11, Table 1) led to an improved yield. In a final
attempt to improve the yield we used a two-fold excess of the
imine. Performing the reaction at room temperature afforded the
product in low yield (entry 12, Table 1). To our delight the yield
increased to a satisfactory 73% when the temperature was raised
Fig. 1 Scope of Ugi-Smiles 3CR using optically pure 8. Reagents and conditions: imine 8 (2.0 equiv.), (hetero)aromatic alcohol (1.0 equiv.), isocyanide
(1.5 equiv.), MeOH, 40 ◦C, 24 h.
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◦
to 40 C (entry 13, Table 1). Further raising the temperature to
◦
60 C led to a significant drop in yield, probably due to stability
issues of the imine (entry 14, Table 1).13
With this procedure in hand we turned our attention to the
synthesis of a small set of Ugi-Smiles products. Starting from
bridged imine 8, various phenols and isocyanides were employed
to generate the corresponding Ugi-Smiles products 11–21 (Fig.1).
Using ortho-nitrophenol and para-nitrophenol with different
isocyanides gave the desired Ugi-Smiles products in moderate to
good yields as single diastereomers (11–15, Fig. 1). 3-Nitro-2-
pyridinol and 2-mercaptopyrimidine were tolerated as inputs and
gave the desired products in moderate to good yields as single
diastereomers (16–19, Fig. 1).
2-Pyridylmethyl isocyanide was also tolerated as the isocyanide
input, affording the corresponding Ugi-Smiles product 20 in
fair yield (Fig. 1). In addition, the use of an optically pure
chiral isocyanide input [(R)-a-methyl-benzyl isocyanide] led to
the formation of a single diastereomer with a 2,3-trans config-
uration, confirming that the starting chiral imine is responsible
for the diastereoselectivity of the reaction (21, Fig. 1). X-
Ray crystallographic analysis of 11 (see Fig. 2)‡ unequivocally
established the absolute configuration at C2 as (S) since the
absolute stereochemistry at C3 and C4 positions, resulting from
the biotransformation, has been reported previously.4 Next, the
sterically less demanding enantiomerically enriched (1S,4R)-3-
azabicyclo[3.3.0]oct-2-ene (32)4 was used in a series of Ugi-Smiles
3CRs (22–31, Fig. 3). Very good diastereomeric ratios were
obtained for compounds 22–31 and considerably higher yields
were observed compared to reactions using the bulky bridged
imine 8 as an input (cf. Fig. 2). This observation can be rationalized
by steric considerations or by the difference in stability between
the cyclic imines used.13
Fig. 2 Single-crystal structure of 11. Displacement ellipsoids are drawn
at the 50% probability level. Most hydrogen atoms are omitted for clarity.
or azide–alkyne cycloaddition16) or Pd-catalyzed cross-coupling
reactions17,18 to provide rapid access to highly complex scaffolds
with pharmaceutically interesting properties.
We chose to introduce an azide and allyl functionality into
our Ugi-Smiles products by using 2-azidoethyl isocyanide19 and
commercially available allyl isocyanide as an input. The presence
of the azide or allyl functionality in the final adduct allows
interesting applications to heterocycle synthesis. The desired azide
compound 33 was obtained in good yield and diastereoselectivity
(72%, d.r. = 88 : 12). Next, we secured Ugi-Smiles adducts 34 (55%,
d.r. = 89 : 11) and 35 (34%, d.r. >99 : 1) with the desired allyl
functionality. In the latter case, we used the saturated bridged imine
364 as the double bond in 8 could possibly interfere in subsequent
follow-up reactions.
Remarkably, Ugi-Smiles products derived from 2-nitrophenol
or 3-nitro-2-pyridinol as inputs showed unusually high aD values
(see the ESI‡). For example, compound 11 has a specific rotation
of -1043.1◦, the highest specific rotation ever reported for a
Subsequently, we synthesized a set of Ugi-Smiles products (Fig.
4) that can undergo additional complexity-generating reactions,
e.g. olefin metathesis,14 cycloaddition reactions (Diels–Alder15
Fig. 3 Scope of Ugi-Smiles 3CR using enantiomerically enriched 32. Reagents and conditions: (1S,4R)-3-azabicyclo-[3.3.0]oct-2-ene (32, 2.0 equiv.),
(hetero)aromatic alcohol (1.0 equiv.), isocyanide (1.5 equiv.), MeOH, 40 ◦C, 24 h. Diastereomeric ratios were determined by 1H NMR.
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combinatorial libraries (e.g. better coverage of chemical space)
of highly functionalized heterocyclic small molecules for the
pharmaceutical industry.
Notes and references
1 (a) R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471–1499; (b) J. Zhu
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4 V. Ko¨hler, K. R. Bailey, A. Znabet, J. Raftery, M. Helliwell and N. J.
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Fig. 4 Ugi-Smiles products with reactivity handles. Reagents and condi-
tions: chiral cyclic imine (32 or 36, 2.0 equiv.), (hetero)aromatic alcohol
(1.0 equiv.), isocyanide (1.5 equiv.), MeOH, 40 ◦C, 24 h. Diastereomeric
ratios were determined by 1H NMR.
multicomponent product. This phenomenon was only observed
for compounds with the nitro substituent in a position ortho
to the newly formed N-aryl bond. These compounds are likely
highly rigid due to restricted rotation of the N-aryl bond. Further
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specific rotations is ongoing.
12 L. El Ka¨ım, M. Gizolme, L. Grimaud and J. Oble, Org. Lett., 2006, 8,
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Conclusions
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reaction. We experimentally observed that 8 partially decomposed
during the reaction, especially at elevated temperature.
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We have developed an efficient combination of MAO-N-catalyzed
desymmetrization of cyclic meso-amines with Ugi-Smiles mul-
ticomponent chemistry to generate optically pure N-aryl pro-
line amides. This method represents the first report of a fully
asymmetric Ugi-Smiles process. The simple procedure, broad
substrate scope and the presence of diverse (heterocyclic) ring
systems make these compounds highly attractive. Especially the
possibility to add more diversity and complexity to these N-aryl
proline amides by introducing strategic functional groups would
make these products appealing for the design of synthesis of
19 F. E. Hahn, V. Langenhahn and T. Pape, Chem. Commun., 2005, 5390–
5392.
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