D. E. Portlock et al. / Tetrahedron Letters 44 (2003) 5121–5124
5123
6. General procedure for the tandem Petasis–Ugi multi-com-
ponent condensation reaction using a RINK amine compo-
nent (Table 1): To a stirred mixture of glyoxylic acid
monohydrate (0.582 g, 6.32 mmol) in CH2Cl2 (33 mL)
was added heptamethyleneimine (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 CH2Cl2
was removed under reduced pressure. To an oven-dried
solid-phase reaction vessel was added Fmoc protected
RINK resin (1.08 g, 0.76 mmol, ACT, 0.7 mmol/g, 100–
200 mesh) and treated with 25% piperidine/DMF (15
mL, 2×15 min). After this time, the resin was drained
and washed with DMF (3×5 mL), MeOH (3×5 mL),
CH2Cl2 (3×5 mL). The resin was dried under vacuum
for 20–30 min. To this reaction vessel was added
CH2Cl2/MeOH (30 mL, 4:1) followed by 3-phenylpropi-
onaldehyde (0.671 g, 5 mmol), 1g (1.39 g, 5 mmol) and
then 2,6-dimethylphenylisocyanide (0.656 g, 5 mmol).
The reaction vessel was agitated for 24 h. After this
time, the resin was drained and washed with DMF (3×5
mL), MeOH (3×5 mL), DCM (3×5 mL). The product
were now cleaved from the resin with 40%TFA/DCM/
0.5%TIPS (2×15 mL, 2×15 min each) and finally washed
with DCM (2×15 mL). The combined solutions were
removed and dried under reduced pressure. The residue
amine terminus are readily controlled with the Petasis
MCC. Several examples of this concept were explored
and results are summarized in Table 1. In each case
the products obtained after cleavage from the resin
were purified by column chromatography and the
yields were moderate ranging from 22 to 50%. The
method is practical and as described in the general
procedures, the intermediate Petasis amino acid 1 can
be used without purification. Given the large number
of commercially available secondary amines, aryl-
boronic acids, and aldehydes, millions of compounds
are accessible via this method. As expected, a mixture
of diastereomers as obtained in all cases (2b–g). Hav-
ing established the viability of this tandem Pt–U
MCC on a RINK amine solid support, we next
examined the possibility of using a resin linked isoni-
trile component.8 Application of this reagent to the
tandem Pt–U reaction (Table 2) successfully provided
the expected dipeptide primary amides 3. Again, the
yields are only moderate (31–72%) and a mixture of
diasteremers was obtained.
In summary, we have developed a tandem Pt–U
MCC reaction sequence using solid-support amine
and isonitrile components, which provides dipeptide
amides (2 and 3) in moderate yields. Significantly, this
tandem MCC strategy is a practical method, which
can be automated to provide very large, diverse com-
pound collections for drug discovery.
was
purified
by
chromatography
(silica
gel,
EtOAc:hexanes) to give 0.130 g (32%) of 2g as a 50:50
mixture of racemic diastereomers. Analytical HPLC:
Polaris C18 column (4.6×250 mm, 3 mm particle size),
mobile phase 0.1% aqueous phosphoric acid/CH3CN lin-
ear gradient over 30 min, 1 mL/min, two peaks detected
by ELS and UV at 215 nm, tR=13.03 and 13.09 min.
2g: Rf=0.28 (4% MeOH:CH2Cl2); white solid, mp 86–
87°C; 1H NMR (CDCl3, 300 MHz): l=1.18–1.83 (m,
19H), 1.88 (s, 6H), 2.20 (s, 6H), 2.21–2.48 (m, 6H),
2.61–2.86 (m, 5H), 3.15–3.23 (m, 6H), 3.77 (s, 3H), 3.79
(s, 3H), 4.12 (t, 1H), 4.61 (t, 1H), 5.32 (s, 1H), 5.41 (s,
1H), 6.55 (d, 2H), 6.70 (d, 2H), 6.79 (d, 2H), 6.96 (d,
2H), 6.98–7.39 (m, 14H), 7.49 (d, 2H), 8.62 (br., 1H),
10.03 (br., 1H), 10.20 (br., 1H), 10.64 (br., 1H); 13C
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 (11C), 44.34, 50.7, 54.0,
55.9, 57.7, 59.1, 70.3, 70.5 (8C), 115.8, 120.1, 127.9,
128.7, 131.8, 133.7, 135.5, 162.1 (8C), 169.6, 170.4 (2C);
LCMS (ELSD): 542 (M+H+); HRMS: 542.335742 [calcd
for C34H43N3O3 542.338268 (M+H)+].
References
1. For leading references, see: (a) Nicolaou, K. C.; Hanko,
R.; Hartwig, W. Handbook of Combinatorial Chemistry;
Wiley-VCH: Weinheim, 2002; Vols.
1 and 2; (b)
Edwards, P. J.; Morrell, A. I. Curr. Opin. Drug Discov.
Devel. 2002, 5, 594; (c) Dolle, R. E. J. Combi. Chem.
2002, 4, 369.
2. For reviews, see: (a) Golebiowski, A.; Klopfenstein, S.
R.; Portlock, D. E. Curr. Opin. Chem. Biol. 2001, 5, 273
and references cited therein; (b) Wennemers, H. Combin.
Chem. HTS 2001, 4, 273; (c) Dagani, R. Chem. Eng.
News 2001, 27 Aug, 59.
3. (a) Domling, A. Curr. Opin. Chem. Biol. 2002, 6, 306;
(b) Ugi, I.; Heck, S. Combin. Chem. HTS 2001, 4, 1; (c)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168; (d) Bienayme, H.; Hulme, C.; Oddon, G.; Schmidt,
P. Chem. Eur. J. 2000, 6, 3321.
4. (a) Constabel, F.; Ugi, I. Tetrahedron 2001, 57, 5785; (b)
Lee, D. L.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000,
2, 709; (c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168 and references cited therein.
5. The concept of a tandem Petasis–Ugi multi-component
condensation has been disclosed by us previously, see:
(a) CHI’s Seventh Annual High Throughput Organic
Synthesis Symposium, ‘Synthesis of Thematic Libraries
for a Platform Target-Based Approach to Drug Discov-
ery’, 13–15 Feb., 2002, San Diego, CA; (b) Portlock, D.
E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett. 2002,
43, 6845; (c) Portlock, D. E.; Ostaszewski, R.; Naskar,
D.; West, L. Tetrahedron Lett. 2003, 44, 603.
7. General procedure for the tandem Petasis–Ugi multi-com-
ponent condensation reaction using a RINK isonitrile com-
ponent (Table 2): To a solution of amino acid 1a (0.194
g, 0.7 mmol) in methanol was added isobutyl amine
(0.0512 g, 0.7 mmol) followed by the addition of phenyl-
acetaldehyde (0.094 g, 0.7 mmol). To this mixture was
added 4 ml of tetrahydrofuran, the resulting mixture was
then pipetted onto dry RINK isonitrile resin (0.200 g,
0.14 mmol). This mixture was then allowed to react for
12–16 h, after this time the resin was drained and
washed with DMF, methanol, CH2Cl2. The product was
removed from the resin by cleaving with a stock solution
of 15% trifluoroacetic acid, 0.5% triisopropylsilane, in
CH2Cl2 for 15 min. The cleavage mixture was evapo-
rated to dryness then purified by preparative thin layer
chromatography (silica gel, 30% hexanes:EtOAc). 3a: