Combined solid phase and solution synthesis of a library of α,α-disubstituted-α-acylaminoketones

Article abstract of DOI:10.1016/S0040-4039(02)01804-X

Preparation of a demonstration library of α,α-disubstituted-α-acylaminoketones, of interest as ecdysone agonists, is described. The five-step synthetic sequence employed α,α-disubstituted amino acids, Grignard reagents and carboxylic acids as building blocks in a strategic combination of solid phase and solution steps.

Full text of DOI:10.1016/S0040-4039(02)01804-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7495–7498
Combined solid phase and solution synthesis of a library of
a,a-disubstituted-a-acylaminoketones
a,b
a
a,
b, ,†
Javier Garcia, Ernesto Nicol a` s, Fernando Albericio, * Enrique L. Michelotti * and
c
Colin M. Tice
a
Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
b
Rohm and Haas Company, PO Box 904, 727 Norristown Road, Spring House, PA 19477-0904, USA
c
RHeoGene Inc., PO Box 949, 727 Norristown Road, Spring House, PA 19477-0949, USA
Received 12 August 2002; revised 23 August 2002; accepted 26 August 2002
Abstract—Preparation of a demonstration library of a,a-disubstituted-a-acylaminoketones, of interest as ecdysone agonists, is
described. The five-step synthetic sequence employed a,a-disubstituted amino acids, Grignard reagents and carboxylic acids as
building blocks in a strategic combination of solid phase and solution steps. © 2002 Elsevier Science Ltd. All rights reserved.
a,a-Disubstituted-a-acylaminoketones of general struc-
range of target compounds 1, we explored the alterna-
tive approaches described here and achieved success
with a combined solid phase and solution route.
1
2,3
ture 1 have been reported as antibiotics, fungicides
4
and pesticides. We became interested in this class of
1
1a
compounds, particularly those in which R and R are
2
3
alkyl groups and R and R are aromatic rings, as
potential bioisosteres of diacylhydrazine ecdysone ago-
Initially we explored a purely solution strategy starting
with Boc-Aib-OH (3a) (Fig. 2) which was coupled with
N,O-dimethylhydroxylamine using DCC to afford Boc
protected Weinreb amide 4a (Scheme 1). Treatment of
5
nists e.g. 2 (Fig. 1). In the preceding paper, we
reported on a solid phase approach in which the inter6-
mediates were linked to the resin via a Weinreb amide.
This approach afforded the desired products 1 in cer-
tain cases but was of limited utility due to a lack of
generality in the building blocks that could be used and
poor product purity. In an attempt to access a broader
4
a with excess ethylmagnesium bromide (5a) in solution
at room temperature under an inert atmosphere did not
give the expected Boc protected a-aminoketone 6 but
rather a mixture of the a-aminoketone 7a and the
symmetrical a-acylaminoketone 8. Presumably 7a and 8
arise from nucleophilic addition of the Grignard
reagent to the carbonyl of the Boc group of 6, followed
by loss of either the anion of 7a or t-butoxide anion to
afford 8.
Although a-aminoketones 7 can readily be acylated to
afford the desired a-acylaminoketones 1, the need to
purify every intermediate at this stage was unattractive.
In addition, we anticipated that when higher molecular
weight substituted aromatic Grignard reagents were
employed, the crude a-aminoketones 7 would be even
less pure due to the presence of biphenyls that are often
a byproduct of aromatic Grignard preparation and of
non-volatile aromatic compounds from quenching the
excess Grignard reagent. Performing the Grignard reac-
tion on an intermediate that remained bound to a solid
support would allow removal of these impurities by
simple filtration and we thus chose to explore attach-
ment of the Weinreb amide intermediate to a solid
Figure 1. a,a-Disubstituted-a-acylaminoketones 1 and diacyl-
hydrazine 2
Abbreviations: Aib, a-aminoisobutyric acid; Boc, tert-butoxycarbonyl;
DCC, N,N%-dicyclohexylcarbodiimide; DIC, N,N%-diisopropylcar-
bodiimide; DMAP, 4-(dimethylamino)pyridine; DMF, N,N-dimethyl-
formamide; HOAc, acetic acid; i-Pr NEt, N,N-diisopropyl-
2
ethylamine; NMM, N-methylmorpholine; NMP, N-methylpyrrolidin-
2
-one; PAS-FTIR, photoacoustic Fourier transform infrared spec-
troscopy; TFA, trifluoroacetic acid.
*
Corresponding authors.
Current address: Locus Discovery Inc., Four Valley Square, 512
Township Line Road, Blue Bell, PA 19422, USA.
†
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01804-X

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J. Garcia et al. / Tetrahedron Letters 43 (2002) 7495–7498
3
Scheme 3. (a) R CO H (14, 5 equiv.), DIC (5 equiv.), DMAP
2
(
1 equiv.), DMF/CH Cl (1:1).
2
2
8
1
6
0, which was incubated with excess 9a in NMP at
0°C in the presence of i-Pr NEt to afford resin bound
2
Weinreb amide 12a. Alternatively 12a could be pre-
pared by reaction of 9a with (N-succinimidyl)carbonate
9
resin 11 at room temperature. Treatment of resin 12a
with a large excess of ethylmagnesium bromide (5a) in
dry THF afforded resin bound ketone 13a. In contrast
to the analogous solution phase reaction of 4a with 5a,
the reaction of 12a proceeded without disruption of the
carbamate linker. Resin bound intermediates 10, 12a
and 13a were characterized by PAS-FTIR. The reso-
nances in the carbonyl region were diagnostic. Cleavage
of 13a with wet TFA gave a-aminoketone 7a as its
TFA salt in 82% yield based on the initial functional-
ization of polymeric support 11. The purity of 7a was
Figure 2. Reagents 3, 5 and 14 used for production of demon-
stration library.
1
estimated at 85% based on H NMR. The major impu-
rity was 9a which presumably resulted from cleavage of
unreacted 12a from the resin. To facilitate the purifica-
tion of the products obtained in final coupling step, the
polymer supported active ester 16a was prepared from
benzoic acid 14a, supported HOBt and DIC (Scheme
10
Scheme 1. (a) MeNHOMe·HCl (1.2 equiv.), DMAP (1.2
equiv.), i-Pr NEt (1.2 equiv.), DCC (1.2 equiv.), CH Cl ,
3). Thus, excess DIC, the corresponding urea and
unreacted benzoic acid were removed by simple filtra-
tion and washings. The final conversion of 7a to 1a was
accomplished using 1.5 equiv. of resin 16a. LC MS
indicated that the main impurities in the crude product
were aminoketone 7a and carboxylic acid 14a. These
were readily removed by treatment of the crude product
with a weakly basic ion exchange resin followed by
passage through a short column of silica gel to afford
2
2
2
25°C, 5 days; (b) EtMgBr 5a (5 equiv.), THF, 25°C, 5 h.
7
support via its amino group, and posterior acylation in
solution after cleavage of the free aminoketone from
the resin.
Thus, Boc protected Weinreb amide 4a was deprotected
with TFA to provide a-aminoamide 9a as its TFA salt
in 80% yield (Scheme 2). Wang resin was treated with
p-nitrophenyl chloroformate and NMM in CH Cl to
11
12
1a in 87% yield and 83% purity by HPLC.
Encouraged by these results, we embarked on produc-
tion of the remaining members of a 25-compound
2
2
produce the activated p-nitrophenyl carbonate resin
2
Scheme 2. (a) TFA/CH Cl (1:1), 25°C, 20 min; (b) 9 (5 equiv.), i-Pr NEt (15 equiv.), NMP, 60°C, 16 h; (c) R MgBr (5, 15
2
2
2
equiv.), THF, 25°C, 4 h followed by HOAc/CH Cl (9:1); (d) TFA/H O (95:5); (e) 16 (1.5 equiv.), i-Pr NEt (1.5 equiv.), CH Cl .
2
2
2
2
2
2

J. Garcia et al. / Tetrahedron Letters 43 (2002) 7495–7498
7497
demonstration library using the reagents shown in Fig.
. Firstly, resin bound Weinreb amide 12a was reacted
References
2
with 3,5-dimethylphenylmagnesium bromide to afford a
second a-aminoketone 7b after cleavage. Secondly,
cyclic amino acid 3b was converted to resin bound
Weinreb amide 12b which was successfully reacted with
the three Grignard reagents 5a–c to afford the expected
a-aminoketones 7c–e. The yields and purities of all five
a-aminoketone intermediates are shown in Table 1.
Finally, the four additional library members 1b–e were
prepared from aminoketone 7a by reaction with acti-
vated carboxylic acid resins 16b–e and the completely
enumerated library of the 20 compounds 1f–y derived
from reaction of 7b–e with the resins 16a–e was pre-
1. JP 4,8018,222 (Chem. Abstr. 79:78590).
2. US 5,304,572 (Chem. Abstr. 121:76155).
3. Young, D. H.; Slawecki, R. A. Pestic. Biochem. Physiol.
2001, 69, 100–111.
4. WO 2001/60783 (Chem. Abstr. 135:195424).
5. Wing, K. D.; Slawecki, R. A.; Carlson, G. R. Science
1988, 241, 470–472.
6. Tice, C. M.; Michelotti, E. L.; Mata, E.; Nicol a` s, E.;
Garcia, J.; Albericio, F. Tetrahedron Lett. 2002, 43, 7491–
7494.
7. Porco, J. A., Jr.; Deegan, T.; Devenport, W.; Gooding,
O. W.; Heisler, K.; Labadie, J. W.; Newcomb, B.;
Nguyen, C.; van Eikeren, P.; Wong, J.; Wright, P. Mol.
Diversity 1997, 2, 197–206.
1
pared. All library compounds were characterized by H
NMR and LC MS. The yields and purities of the
library compounds are shown in Table 2. The yields
ranged from 61 to 92%. On average the yields were
better when the aromatic Grignard reagents 5b and 5c
were employed and when the benzoic acid 14 did not
have an ortho substituent. Purities ranged between 82
and 97% with no obvious trends correlated with the
reagents employed.
8. Dixit, D. M.; Smith, H.; Leznoff, C. C. J. Chem. Soc.,
Chem. Commun. 1977, 798–799.
9. Alsina, J.; Rabanal, F.; Chiva, C.; Giralt, E.; Albericio,
F. Tetrahedron 1998, 54, 10125–10152.
10. Pop, I. E.; D e´ prez, B. P.; Tartar, A. L. J. Org. Chem.
1997, 62, 2594–2603.
11. Granger, R.; T e´ cher, H.; Massiau, A. C.R. Hebd. Seances
Acad. Sci. 1960, 250, 4378–4380.
In conclusion, we have described the synthesis of a
demonstration library of 25 a-acylamino-a,a-disubsti-
tuted ketones 1 taking strategic advantage of the fea-
tures of solid phase chemistry and solution chemistry in
conjunction with polymer bound reagents.
12. The following experimental procedure is representative.
Preparation of 9a. To a stirred mixture of Boc-Aib-OH
(3a, 5 g, 24.61 mmol, 1 equiv.), MeNHOMe·HCl (2.88 g,
29.53 mmol, 1.2 equiv.), DMAP (3.61 g, 29.53 mmol, 1.2
equiv.), i-Pr NEt (5.02 mL, 29.53 mmol, 1.2 equiv.) and
2
CH Cl (100 mL) was added DCC (6.09 g, 29.53 mmol,
2
2
1.2 equiv.). The mixture was stirred at room temperature
for 5 days. The mixture was filtered to remove precipi-
tated N,N%-dicyclohexylurea and the filtrate was evapo-
rated under reduced pressure. The residue was dissolved
in ethyl acetate (200 mL), washed with 10% aqueous
citric acid (3×200 mL), 10% aqueous NaHCO3 (3×200
mL) and saturated aqueous sodium chloride (3×200 mL),
a
Table 1. Yields and purities of a-aminoketones 7
1
1a
R2
Yieldb
Cmpd
R , R
Purity of 7
% recovered 9)
c
(
7
7
7
7
7
a
b
c
d
e
Me, Me
Me, Me
Et
82
76
80
86
94
85 (9)
89 (9)
and dried over MgSO . Removal of solvent gave the
4
d
3,5-diMe-Ph
Et
3,5-diMe-Ph
Ph
crude product which was purified by column chromato-
graphy (hexane/ethyl acetate 60:40) to afford 4a (4.85 g,
ꢀ(CH ) ꢀ
80 (12)
2
4
d
ꢀ(CH ) ꢀ
94 (5)
1
2
4
80%) as a white solid. H NMR (200 MHz, CDCl ): l
3
d
ꢀ(CH ) ꢀ
92 (3)
2
4
1
.43 (s, 6H), 1.58 (s, 9H), 3.22 (s, 3H), 3.69 (s, 3H), 6.95
+
(
bs, 1H). MS (ESI, +ve ion): m/z 247.2 (M+1) . The Boc
protected Weinreb amide 4a (1.1 g, 4.47 mmol) was taken
up in TFA/CH Cl (1:1, 50 mL) and stirred for 20 min.
a
Isolated as trifluoroacetate salts.
Yield was calculated based on the initial functionalization of the
resin.
Purity was calculated by integration of appropriate peaks in the H
NMR.
b
2
2
c
1
Removal of the solvent left 9a (1.15 g, 99%, quantitative
1
yield) as its TFA salt. H NMR (200 MHz, CD OD): l
3
d
Purity confirmed by integration of the HPLC trace at 220 nm.
1.63 (s, 6H), 3.25 (s, 3H), 3.78 (s, 3H). MS (ESI, positive
Table 2. Yields and purities of library compounds of general structure 1
a
3
b
3
3
3
3
a-Aminoketone used
R =Ph 14a
R =2-Me-Ph 14b
R =3-MeO-Ph 14c
R =4-Et-Ph 14d
R =3,4-OCH O-Ph 14e
2
1a 87 (83)e
1f 90 (95)
1k 82 (96)
1p 89 (94)
1u 76 (95)
c
d
1b 61 (82)
1g 76 (90)
1l 65 (87)
1q 80 (92)
1v 74 (92)
1c 78 (89)
1h 80 (85)
1m 70 (88)
1r 87 (95)
1w 83 (92)
1d 76 (82)
1i 92 (92)
1n 69 (92)
1s 88 (96)
1x 84 (84)
1e 83 (91)
1j 81 (86)
1o 73 (87)
1t 84 (97)
1y 77 (82)
7a
7b
7c
7d
7e
a
b
c
See Table 1 for R , R1a and R2 substituent definitions.
Carboxylic acid building block used. See Fig. 2 and Scheme 3.
Product compound number.
1
d
e
Yields were calculated based on starting a-aminoketone TFA salt.
Purities were calculated based on integration of the HPLC trace at 220 nm.

7
498
J. Garcia et al. / Tetrahedron Letters 43 (2002) 7495–7498
+
ion): m/z 147.3 (M+1) . Preparation of 12a. To a suspen-
Hydroxybenzotriazole resin 15 (0.107 g, 0.196 mmol) was
treated with benzoic acid (0.12 g, 0.982 mmol, 5 equiv.),
DIC (0.152 mL, 0.982 mmol, 5 equiv.) and DMAP (0.024
g, 0.196 mmol, 1 equiv.) in DMF/CH Cl (1:1) and
sion of resin 10 (1 g, 0.86 mmol) in i-Pr NEt (2.2 mL,
2
1
(
6
2.9 mmol, 15 equiv.) and NMP (5 mL) was added 9a
1.15 g, 4.42 mmol, 5 equiv.). The mixture was heated at
0°C for 16 h, cooled and washed with NMP (5×10 mL),
DMF (5×10 mL), CH Cl (5×10 mL), and dried in vacuo
2
2
shaken for 5 h. The mixture was filtered and the resin was
washed with DMF (10×5 mL) and CH Cl (10×5 mL) to
2
2
2
2
overnight to leave 12a. PAS-FTIR carbamate CꢁO
give 16a. To a suspension of 16a (0.196 mmol, 1.5 equiv.)
in CH Cl (2 mL) were added i-Pr NEt (0.033 mL, 0.196
−
1
−1
stretch: 1727 cm , amide CꢁO stretch: 1646 cm . Prepa-
ration of 7a. To a suspension of 12a (0.86 mmol) in dry
THF (5 mL) under argon was added ethylmagnesium
bromide solution (1 M in THF, 12.9 mL, 12.9 mmol, 15
equiv.). The mixture was stirred for 4 h and the resin was
2
2
2
mmol, 1.5 equiv.) and 7a (0.03 g, 0.131 mmol, 1 equiv.).
The mixture was agitated for 16 h and filtered. The
filtrate was shaken for with a weakly basic ion exchange
−
1
resin Amberlite IRA-95 (1 g, 4.7 mmol g , 25 equiv.) for
6 h to remove benzoic acid present in the solution and
washed with THF (5×10 mL), DMF/H O (5×10 mL),
CH Cl (5×10 mL), followed by HOAc/CH Cl (9:1), and
2
1
2
2
2
2
filtered. The filtrate was eluted through a short column of
silica gel (hexane/ethyl acetate 50:50) to remove the unre-
CH Cl (5×10 mL) to afford 13a. PAS-FTIR carbamate
2
2
−
1
−1
CꢁO stretch: 1734 cm , ketone CꢁO stretch: 1718 cm .
acted amine. The organic solvent was evaporated to leave
The resin was treated with 5 mL of TFA/H O (90:10) for
2
1
1
a (0.03 g, 87%) as a white solid. H NMR (200 MHz,
2
h. The mixture was filtered and the filtrate was evapo-
rated to afford 7a (0.19 g, 82%) as its TFA salt. H NMR
200 MHz, (CD ) CO): l 1.04 (t, J=6.8 Hz, 3H), 1.71 (s,
H), 2.77 (q, J=7 Hz, 2H), 8.97 (bs, 1H). MS (ESI,
1
CDCl ): l 1.14 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.63 (q,
3
J=7 Hz, 2H), 7.21 (bs, 1H), 7.38–7.56 (aromatic H’s,
(
3 2
3
H), 7.79 (dd, J=8, 1.8 Hz, 2H). MS (ESI, positive ion):
6
+
+
positive ion): m/z 115.89 (M+1) . Preparation of 1a.
m/z 220.2 (M+1) .