Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type cyclization sequence

Article abstract of DOI:10.1039/c0cc02938f

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc02938f

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Asymmetric synthesis of synthetic alkaloids by a tandem
biocatalysis/Ugi/Pictet–Spengler-type cyclization sequencew
Anass Znabet,a Job Zonneveld,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 31st July 2010, Accepted 7th September 2010
DOI: 10.1039/c0cc02938f
We have combined the biocatalytic desymmetrization of 3,4-cis-
substituted meso-pyrrolidines with an Ugi-type multicomponent
reaction followed in situ by a Pictet–Spengler-type cyclization
reaction sequence for the rapid asymmetric synthesis of alkaloid-
like polycyclic compounds.
accessible through our MAO-N oxidation/MCR sequence.4
Here we report the stereoselective generation of polycyclic
DKP derivatives 5 by a novel MAO-N oxidation/Ugi MCR/
Pictet–Spengler-type cyclization (MUPS) sequence (Scheme 1).
First, suitable conditions for the Pictet–Spengler-type
cyclization in the MUPS sequence towards 5 were developed.
The cyclization of Ugi product 9, synthesized from bridged imine
6, phenylglyoxylic acid 7 and homoveratryl isocyanide 8 was
selected as the benchmark reaction (Table 1). Based on the
standard reaction conditions for the Pictet–Spengler cyclization
reported by El Kaim and coworkers,7 we started the screening of
reaction conditions using 33% TFA in CH2Cl2. Under these
conditions, no reaction was observed after stirring at room
temperature for 3 h (Table 1, entry 1). Also when the reaction
was performed in TFA as the solvent at RT (4 h; entry 2, Table 1)
or under microwave conditions at elevated temperatures
(entries 3 and 4, Table 1) no DKP 10 was observed and the
starting material 9 was recovered. In another attempt, the reaction
mixture was heated to reflux in pure TFA. After 16 h, conversion
to 10 was observed, accompanied by significant side product
formation (entry 5, Table 1). This prompted us to use trimethyl-
silyl triflate (TMSOTf) instead of TFA. With TMSOTf as the
Lewis acid mediator the reaction indeed took place. After 16 h at
10 1C, the DKP 10 could be isolated in 72% yield (entry 6,
Table 1). With this procedure in hand, we prepared a small set of
different DKPs using several a-keto acids, imines, and isocyanides
(Tables 2 and 3). Thus, different carboxylic acids and isocyanides
were used to generate substituted prolyl peptides 14a–d and 18a–c
in good yields and excellent diastereomeric ratios (Tables 2 and 3).
Multicomponent reactions (MCRs) are powerful tools for the
synthesis of complex, biologically relevant molecules. The atom
economy of MCRs, their convergent character, operational
simplicity, and the structural diversity and complexity of the
resulting molecules make this chemistry exceptionally useful for
discovery and optimization processes in the pharmaceutical
industry.1 However, catalytic asymmetric methods to
control the stereochemical outcome of MCRs are scarce.2 We
recently reported a novel method combining the biocatalytic
desymmetrization of 3,4-cis-substituted meso-pyrrolidines3
using engineered monoamine oxidase N (MAO-N) from
Aspergillus niger and an Ugi-type three-component reaction
(MAO-N oxidation/MCR sequence) to generate highly
functionalized and optically pure 3,4-cis-substituted prolyl
peptides.4 These prolyl peptides are of considerable interest in
medicinal chemistry and organocatalysis.5 We realized that
combination of our MCR approach with cyclization reactions6
could further increase the resulting molecular complexity and
diversity considerably.
Recently, El Kaim and coworkers described an interesting
approach that involves an Ugi four-component reaction
(U-4CR) between amines, aldehydes, a-ketocarboxylic acids
and homoveratryl isocyanide to afford the Ugi intermediate
which subsequently undergoes a Pictet–Spengler cyclization to
obtain 2,5-diketopiperazines (DKPs).7 DKPs are found in
several natural products and display a wide variety of biological
activities including antitumor,8 antiviral,9 antifungal10 and
antibacterial.11 We soon realized that this methodology could
present an efficient approach to expand the structural diversity
a Department of Chemistry & Pharmaceutical Sciences,
Vrije Universiteit Amsterdam, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands. E-mail: rva.orru@few.vu.nl,
e.ruijter@few.vu.nl; Fax: +31 20 59 87488; Tel: +31 20 59 87462
b School of Chemistry, University of Manchester, Brunswick Street,
Manchester, UK M13 9PL
c School of Chemistry, University of Manchester, Manchester
Inter-disciplinary Biocentre, 131 Princess Street, Manchester,
UK M1 7DN
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data, and copies of 1H
and 13C NMR spectra. Crystallographic data for compound 14a.
CCDC 786098. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc02938f
Scheme 1 General scheme of MUPS sequence.
c
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Table 1 Optimization of the Pictet–Spengler-type cyclization of Ugi product 9 towards DKP 10a
Entry
Solvent
Additive
T (1C)/Time (min)
Conversion (%)
Isolated yield (%)
1
2
3
4
5
6
TFA/CH2Cl2 (1 : 2)
TFA
TFA
TFA
TFA
CH2Cl2
—
—
—
—
RT/180
RT/240
MW 150/5
MW 200/5
D/960
—
—
—
—
—
—
—
—
—
TMSOTfb
n.d.c,d
100
n.d.c,d
72
10/960
a
b
Reactions were performed with 0.073 mmol of Ugi product 9; 1.1 equivalent of TMSOTf was added in one portion at the appropriate
c
temperature; Not determined; Unidentified side products detected.
d
Table 2 The MUPS sequence using optically pure 11, isocyanides 8 or 13, and a-keto acids 7 or 12
14
Isolated yield (%)a
DKP
Isolated yield (%)a
a-Keto acid
Isocyanide
Product
d.r.b
Product
d.r.b
Entry
1
7
12
7
8
8
13
13
14a
14b
14c
14d
72
77
79
44
>99 : 1
>99 : 1
>99 : 1
>99 : 1
15a
15b
15c
16
72
86
60
42
>99 : 1
65 : 35
>99 : 1
>99 : 1
2
3c
4c
12
a
b
c
Isolated yield; d.r. determined by 1H NMR analysis; Reaction performed with the addition of 1.0 eq. trifluoroacetic anhydride in 50% TFA/
CH2Cl2.
These prolyl peptides were then subjected to the optimized
Pictet–Spengler cyclization conditions to provide, in most cases,
the desired DKPs 15a–b and 19a–c in moderate to excellent yields
and diastereomeric ratios (Tables 2 and 3). The optimized
Pictet–Spengler conditions did not produce 15c and 15d
(Table 2, entries 3 and 4). In these examples the starting Ugi
products 14c and 14d were recovered.
of a proton to give 16 is available as an alternative reaction
pathway for the intermediate N-acyliminium ion.
Interestingly, the use of phenylglyoxylic acid
7 and
homoveratryl isocyanide (8; Table 2, entries 1 and 3) as
components for the Ugi reaction resulted in a diastereoselec-
tive Pictet–Spengler-type cyclization. However, when the
a-keto acid 12 (R1 = iBu) was employed, the corresponding
DKPs were obtained as mixtures of diastereoisomers (Table 2,
entries 2 and 4). The X-ray crystal structure of 15a (Fig. 1)
allowed the relative stereochemistry of the six asymmetric
carbon atoms to be determined. Since the absolute
stereochemistry at C2, C3 and C4 of the substituted proline
residue is known (see ESI, Fig. S1w) and was previously
reported by us,3,4 the absolute configuration of the molecule
could be deduced.
Such 5-membered ring-fused DKPs have rarely been
described in literature,12 which is not surprising since they
result from a disfavored 5-endo-trig cyclization. This explains
why harsher conditions are required to obtain compounds like
15c. Full conversion of 14c was achieved using 1 eq. of
trifluoroacetic anhydride in TFA/CH2Cl2 (1 : 1) allowing
isolation of the desired Pictet–Spengler-type product 15c in
60% yield (Table 2, entry 3). Under identical conditions,
however, reaction of 14d (Table 2, entry 4) gave the condensation
product 16 instead of the desired 15d. In this case, the
disfavored 5-endo-trig cyclization does not occur because loss
Subsequently, the sterically less demanding optically
active 3-azabicyclo-[3,3,0]oct-2-ene (also prepared by MAO-N
catalyzed desymmetrization3) was used as an input for a series
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Table 3 The MUPS sequence using optically enriched 11, isocyanide 17 and a-keto acids
a-Keto acid
18
Isolated yield (%)a
19
Isolated yield (%)a
Entry
R1 =
Product
d.r.b
Product
d.r.b
1
2
3
Ph (7)
2-Furyl
iBu (12)
18a
18b
18c
77
71
48
>99 : 1
>99 : 1
>99 : 1
19a
19b
19c
92
71
90
57 : 43
63 : 37
74 : 26
a
b
Isolated yield; d.r. determined by H NMR analysis.
1
of Pictet–Spengler-type substrates (Fig. 2A). The desired
DKPs 23–25 were obtained in moderate to very good yields
and diastereomeric ratios (Fig. 2B).
We have documented a highly efficient synthesis of fused
DKPs. The combination of MAO-N catalyzed desymmetrization
of meso-pyrrolidines with an Ugi-type 3CR followed by
Pictet–Spengler-type cyclization led to highly complex
structures with high diversity. In addition, the experimental
procedure is simple and very efficient. To the best of our
knowledge, it also constitutes the first example of MCR
chemistry to synthesize 5-membered ring-fused DKPs
making these compounds interesting targets for medicinal
chemistry.
Notes and references
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2 D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602;
´
Fig. 1 Molecular structure of 15a in the crystal. Displacement
ellipsoids are drawn at 50% probability level.
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Biol., 2010, 14, 371.
3 V. Kohler, K. R. Bailey, A. Znabet, J. Raftery, M. Helliwell and
¨
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4 A. Znabet, E. Ruijter, F. J. J. de Kanter, V. Kohler, M. Helliwell,
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(c) T. M. Chapman, C. J. Schofield and B. G. Davis, J. Am. Chem.
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6 For
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Fig. 2 Structures of Ugi products 20–22 and fused tricyclic DKPs 23–25.
7708 Chem. Commun., 2010, 46, 7706–7708
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This journal is The Royal Society of Chemistry 2010