A tandem Petasis-Ugi multi component condensation reaction: Solution phase synthesis of six dimensional libraries

Article abstract of DOI:10.1016/S0040-4039(02)02619-9

Amino acids with three points of diversity generated from the Petasis boronic acid-Mannich reaction can be used as one of the four components of the Ugi condensation to prepare six dimensional libraries of dipeptide amides.

Full text of DOI:10.1016/S0040-4039(02)02619-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 603–605
A tandem Petasis–Ugi multi component condensation reaction:
solution phase synthesis of six dimensional libraries
David E. Portlock,a,* Ryszard Ostaszewski,b Dinabandhu Naskarc and Laura Westa
aCombinatorial Chemistry Section, Procter & Gamble Pharmaceuticals Health Care Research Center,
8700 Mason Montgomery Road, Mason, OH 45040, USA
bWarsaw University of Technology, Noakowskiego 3, Warsaw 00-664, Poland
cChembiotek Research International, Block BN, Sector-V, Salt Lake City, Calcutta 700 091, India
Received 14 October 2002; accepted 6 November 2002
Abstract—Amino acids with three points of diversity generated from the Petasis boronic acid–Mannich reaction can be used as
one of the four components of the Ugi condensation to prepare six dimensional libraries of dipeptide amides. © 2002 Published
by Elsevier Science Ltd.
The rapid, automated synthesis of molecular diversity
to fuel high throughput biological screening for lead
generation as well as the synthesis of directed libraries
for subsequent lead optimization has evolved into an
effective strategy to accelerate drug discovery.1 Indeed,
during the past decade combinatorial chemistry has
provided access to greatly expanded chemical collec-
tions of drug-like compounds using practical synthetic
methods, which proceed in high yields and product
purities.2 Among the most useful methods, which have
emerged to meet this synthetic challenge, are the multi
component condensations (MCC),3 due to their ability
to efficiently generate large numbers of compounds in
one or two synthetic steps. Examples of MCC reactions
include the Ugi,4 Passerini,5 Biginelli,6 and the Petasis
boronic acid–Mannich reaction.7 Most of these as well
as other MCC have been used to generate combinato-
rial libraries useful for pharmaceutical discovery.8
Following a strategy in which two MCCs are used in
tandem can lead to even greater diversity compared
with either MCC alone. For example, if ten building
blocks are used in a three-component condensation,
1000 distinct compounds are produced, but if a three
component and a four-component condensation are
used in tandem (producing in effect a six component
Scheme 1. Tandem Petasis–Ugi multi component condensation.
* Corresponding author. E-mail: portlock.de@pg.com
0040-4039/03/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02619-9

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D. E. Portlock et al. / Tetrahedron Letters 44 (2003) 603–605
tandem Pt-U6CC by using commercially available N,N-
dimethylglycine (1a, R1=R2=CH3; R3=H) as a model
Petasis amino acid substrate for the Ugi reaction. In
spite of our concerns, that the tertiary amine present in
1a could retard formation of the protonated imine
necessary for the success of the Ugi reaction,4 the
desired product 2a (Table 1) was obtained in 42% yield
after purification. Encouraged by this result, 1b was
subsequently prepared via standard experimental
conditions7 (1 equiv. of each reaction component in
DCM, room temperature, 48 h). After removal of
DCM, crude 1b was dissolved in MeOH and treated
with the Ugi reaction components. Stirring for 24 h at
condensation), the number of distinct compounds
increases to 1,000,000. In this context, we hypothesized
that the Petasis boronic acid–Mannich reaction could
be used to prepare carboxylic acids containing three
points of diversity, and that these products could in
turn be employed as one of the components of the Ugi
reaction, subsequently leading to six dimensional
libraries (Scheme 1).
Although there is precedent for combinations of
MCC,3,9 to our knowledge a tandem Petasis–Ugi MCC
reaction (Pt3CC+U4CC=Pt-U6CC) has not been
reported.10 We first examined the practicality of a
Table 1. Tandem Petasis–Ugi multi component condensation reaction

D. E. Portlock et al. / Tetrahedron Letters 44 (2003) 603–605
605
room temperature, produced the tandem Pt-U6CC
product (2b) in 54% yield after purification. As
expected, the product consisted of a 50:50 mixture of
racemic diastereomers (LC-MS). The yield could be
improved by using excess of all components relative to
the isonitrile; e.g. 2f was obtained in 73% yield by
limiting 2,6-dimethylphenylisonitrile to 0.8 equiv.11 In
this example, the racemic diastereomers (1:1) were sepa-
rated by preparative RP-HPLC and characterized by
H, C NMR, and HRMS. Remarkably, isomer A (tR=
8.4 min) is a low melting solid (mp 49–50) and exists in
CDCl3 as a 1:1 mixture of rotamers, but isomer B
(tR=9.6 min) is a crystalline solid (mp 144–145) and
exists in CDCl3 as a single rotamer. Using an optically
active amine for the Petasis boronic acid–Mannich
reaction gave 1g as a 70:30 mixture of diastereomers.
Subsequent Ugi condensation provided 2g in 32% yield
and the same isomeric ratio. Hydrazines can also par-
ticipate in the tandem Pt-U6CC (2h), which is consis-
tent with our earlier observations.10b
7. (a) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetra-
hedron 1997, 53, 16463; (b) Jiang, B.; Yang, C.-G.; Gu,
X.-H. Tetrahedron Lett. 2001, 42, 2545.
8. Obrecht, D.; Villalgordo, J. M. Solid-Supported Combina-
torial and Parallel Synthesis of Small-Molecular-Weight
Compound Libraries; Tetrahedron Organic Chemistry
Series, Pergamon: New York, 1998; Chapters 1 and 4.
9. (a) Constabel, F.; Ugi, I. Tetrahedron 2001, 57, 5785; (b)
Domling, A.; Herdtweck, E.; Ugi, I. Acta Chem. Scand.
1998, 52, 107.
10. The concept of a tandem Petasis–Ugi multi-component
condensation has been disclosed by us previously, see: (a)
CHIs Seventh Annual High Throughput Organic Synthesis
Symposium, Portlock, D. E. ‘Synthesis of Thematic
Libraries for a Platform Target-Based Approach to Drug
Discovery’, 13–15 Feb 2002, San Diego, CA; (b) Portlock,
D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett. 2002,
43, 6845.
11. General procedure: To a stirred mixture of glyoxylic acid
monohydrate (0.582 g, 6.32 mmol) in CH2Cl2 (33 mL) was
added heptamethylenimine (0.715 g, 6.32 mmol) followed
by 4-methoxyphenylboronic acid (0.96 g, 6.32 mmol). The
resulting mixture was stirred at ambient temperature for
48 h and after this time, the solvent was removed under
reduced pressure. The crude product 1f was dissolved in
MeOH (9 mL) and to this solution was added 2-
methoxyethylamine (0.475 g, 6.32 mmol) and isovaleralde-
hyde (0.544 g, 6.32 mmol). This solution was allowed to
stir at ambient temperature for 10 min and then 2,6-
dimethylphenylisocyanide (0.328 g, 5.0 mmol) was added.
The resulting mixture was stirred at ambient temperature
for 24 h and after this time, the MeOH was removed under
reduced pressure. The residue was purified by column
chromatography (silica gel, 40% EtOAc:hexanes) to give
2.021 g (73%) of 2f as a 1:1 mixture of racemic
diastereomers, which were separated by preparative HPLC
(Inertsil ODS3, 8 microns, 5.0×25 cm, mobile phase 65%
MeOH, 35% H2O, 0.1% TFA, flow rate 50 mL/min;
tR=8.4 min (isomer A) and tR=9.6 min (isomer B). 2f (A):
Rf=0.62 (50% EtOAc:hexanes); white solid, mp 49–50°C
(uncorrected); H NMR (CDCl3, 300 MHz): l=0.38–2.05
(m, 13H), 0.72–0.78 and 0.97–0.99 (rotamers 1 and 2, 2m,
6H), 2.05 and 2.22 (rotamers 1 and 2, 2s, 6H), 3.01–4.18
(m, 8H), 3.33 and 3.43 (rotamers 1 and 2, 2s, 3H), 3.81 and
3.88 (rotamers 1 and 2, 2s, 3H), 4.60–4.80 (m, 1H), 5.96
(s, 1H), 6.94–7.96 (m, 8H); C NMR (CDCl3, 75 MHz):
18.6, 21.7, 22.7, 23.1, 23.8, 24.0, 24.4, 24.6, 25.1, 25.2, 25.5,
25.6, 26.3, 37.9, 39.2, 43.2, 52.6, 55.6, 55.8, 55.9, 58.2, 59.1,
59.5, 69.3, 69.9, 71.6, 115.8, 120.0, 120.7, 127.4, 127.7,
128.4, 128.5, 131.9, 133.8, 134.3, 135.5, 162.1, 165.72,
166.43; LCMS (ELSD): 552 (M+H+); HRMS: 552.378545
[calcd for C33H49N3O4 552.380133 (M+H)+]. 2f (B): Rf=
0.76 (50% EtOAc:hexanes); white solid, mp 144–145°C
(uncorrected); H NMR (CDCl3, 300 MHz): l=0.88–0.92
(m, 6H), 1.2–2.1 (m, 13H), 2.2 (s, 6H), 3.0–3.7 (m, 8H), 3.3
(s, 3H), 3.8 (s, 3H), 5.02 (t, 1H), 5.9 (s, 1H), 7.0 (d, 2H),
7.0–7.1 (m, 3H), 7.59 (d, 2H), 8.3 (s, 1H); C NMR (CDCl3,
75 MHz): 18.4, 18.6, 21.5, 22.5, 23.1, 23.6, 24.4, 24.8, 25.3,
25.7, 37.8, 44.34, 50.7, 54.0, 55.9, 57.7, 59.1, 70.3, 70.5,
115.8, 120.1, 127.9, 128.7, 131.8, 133.7, 135.5, 162.1, 169.6,
170.4; LCMS (ELSD): 552 (M+H+); HRMS: 552.377520
[calcd for C33H49N3O4 552.380133 (M+H)+].
In summary, we have demonstrated that the Petasis
boronic acid–Mannich (three-component) condensation
can be performed in tandem with the Ugi (four-compo-
nent) condensation to provide access to six dimensional
libraries using practical reaction conditions. This
method expands considerably the synthetic versatility
of multi-component condensations for the preparation
of large, diversity-driven libraries for drug discovery.
Application of this methodology to the preparation of
low molecular weight heterocyclic scaffolds10 will be
reported in due course.
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