A practical synthesis of α-amino ketones via aryllithium addition to N-Boc-α-amino acids

Article abstract of DOI:10.1055/s-2003-40875

The reaction of N-Boc-α-amino acids with aryllithium reagents followed by removal of the nitrogen protecting group provides enantiomerically pure α-amino aryl ketones as their corresponding HCl salts. This practical two-step sequence gives rapid access to a pharmaceutically interesting class of compounds from commercially available starting materials.

Full text of DOI:10.1055/s-2003-40875

PAPER
1653
A Practical Synthesis of -Amino Ketones via Aryllithium Addition to N-Boc-
Amino Acids
-
A
P
ractica
l
Synthe
l
sis of
a
-Amino Ke
n
tones S. Florjancic,* George S. Sheppard
Abbott Laboratories, Global Pharmaceutical Products Research and Development, R4PM AP10, 100 Abbott Park Road, Abbott Park,
IL 60064, USA
Fax +1(847)9355466; E-mail: alan.florjancic@abbott.com
Received 7 May 2003
To the memory of Professor Henry Rapoport for his insight and advice while conducting this research.
boxylate prior to the aryl addition reaction (acid
Abstract: The reaction of N-Boc- -amino acids with aryllithium
2
c,d,5
6
7
chloride,
morpholine amide, imidazolide, hemi-ace-
reagents followed by removal of the nitrogen protecting group pro-
vides enantiomerically pure -amino aryl ketones as their corre-
sponding HCl salts. This practical two-step sequence gives rapid
8
9
10
tal, isoxazolidide, Weinreb amide, etc.). Due to the in-
stability of tert-butyl carbamates in the presence of highly
11
access to a pharmaceutically interesting class of compounds from nucleophilic bases, very little has been described utiliz-
commercially available starting materials.
ing the large number of commercially available N-Boc- -
Key words: arylations, amino acids, lithiation, ketones, nucleo- amino acids as precursors to -amino ketones. Work done
2
d
12
philic additions
by Rapoport in the early 80’s and Pace and Kabalka, in
the mid-90’s did show that this transformation was feasi-
ble, but still largely unexplored. Taking the precedent
In drug discovery research, practicality and ease of syn- from these early examples, we sought a way to develop
thesis are often important factors in the initial chemical the chemistry into a rapid and efficient way of obtaining a
design and SAR development of a project. With increased unique set of pharmaceutically interesting precursors.
pressure to produce larger numbers of unique analogues in
a shorter time-frame, finding chemistry amenable to rapid
diversification and scalability can be crucial to the success
of a medicinal chemistry project. It was during the course
of investigation of a series of matrix metalloprotienase in-
hibitors, that we discovered that the terminal N-methyl
amide of L-phenylalanine could effectively be replaced by
the corresponding phenyl ketone (Figure 1).1
Initial experiments began with the slow addition of 4
equivalents of cold (–78 °C) phenyllithium in diethyl
ether to a solution of N-Boc-L-phenylalanine at –78 °C in
THF, and warming to room temperature overnight
(
Equation 1). The purified N-Boc-amine of 1 was then
deprotected to give an initial 7% yield of 1. It was ob-
served that when using THF as solvent or co-solvent,
yields were consistently lower. Incorporating a combina-
tion of anhydrous diethyl ether as the lone solvent, care-
fully controlling the reaction times (1–2 h) and
temperatures (–78 °C, then warming to 0 °C) a greatly im-
proved 57% yield of 1 could be obtained, after deprotec-
tion, with minimal racemization.1 Presumably, the
presence of the adjacent negative charge on the carbamate
O
O
O
O
H
N
H
N
HO
HO
N
N
N
H
H
H
R
O
R
O
Ph
Ph
Figure 1 Structures showing terminal N-methyl amide group and its nitrogen under the reaction conditions blocks potential
replacement with aryl ketone
enolization of the -center, protecting the stereochemical
integrity of the amino ketone.2d
Since -amino ketones serve as useful precursors to a
wide variety of natural products and pharmaceutically rel-
evant compounds, a fairly large body of work exists de-
1
.) 4 eq PhLi
THF/Et2O, 16h
O
O
H
O
N
HCl•H N
2
2
,3
OH
tailing their synthesis. N-Protected -amino acids and
their derivatives have been used as starting materials in
the synthesis of -amino ketones by addition of alkyl- and
aryllithium anions, Grignard reagents, and via Friedel–
2.) 4N HCl/dioxane
O
1
Equation 1
2
Crafts chemistry. All of these approaches require protec-
tion of the amine by a variety of groups (benzyloxy and
2
b,d,4
5
From a practical standpoint, this chemistry requires no
special precautions, and can be run on multi-gram scale.
The isolation of the intermediate N-Boc-amino ketone is
accomplished via silica plug or quick column chromatog-
raphy, and treating the resulting material with 4 N HCl/di-
oxane for several hours. The amino ketone 1, as its
methoxycarbonyl,
nyl, etc.), and most require fuctionalization of the car-
phenylfluorenyl, phenylsulfo-
2
a
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1653,1656,ftx,en;C02603SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York

1
654
A. S. Florjancic, G. S. Sheppard
PAPER
corresponding HCl salt, was precipitated out of solution Table 2 Preparation of Phenyl Ketones from N-Boc-Amino Acids
with diethyl ether, filtered and dried as a white solid.
1.) 4 eq PhLi
Et2O, 1-2h
O
O
H
With the reaction conditions made more efficient and
higher yielding, we sought to explore the scope of the re-
action with regard to substitution on aryllithium as well as
the generality of the amino acid partner. A survey of a va-
riety of substitutions on the aryllithium showed that both
electron-releasing and -withdrawing groups in the para
position are well tolerated and seem to have only a minor
effect on the overall yield of the reaction with N-Boc-L-
phenylalanine (Table 1).
HCl•H2N
O
N
OH
2.) 4N HCl/dioxane
R
O
R
1
, 7-13
Product
R
Yield (%)
ee (%)
>99
>99
>99
>99
>99
>99
>99
>99
1
CH Ph
57
60
63
63
58
39
30
12
2
CH PhOBu-ta
2
7
8
Me
Table 1 Formation of Aryl Ketones from N-Boc-L-phenylalanine
9
Et
1
.) 4 eq ArLi
Et2O, 1-2h
O
O
H
10
CH C H
11
2
6
O
N
HCl•H2N
Ar
OH
2
.) 4N HCl/dioxane
1
1
CH CHMe
2 2
O
1-6
12
CH(Me)CH Me
2
1
3
t-Bu
Product
Ar
Yield (%)
ee (%)
>99
a
Isolated as the free phenol.
1
57
HPLC analysis,14 and all were found to be in excellent
enantiomeric excess.
2
3
55
>99
>99
54
O
OH
O
O
R
O
4
5
6
50
42
47
>99
>99
>99
Figure 2 Structure of an enantiopure succinic acid
SMe
F
We feel that we have demonstrated that a series of phar-
maceutically useful precursors can be quickly and effi-
ciently synthesized, from commercially available
materials, in multi-gram quantity, with excellent enantio-
meric purity.
CF3
Aryl Ketones from N-Boc-Amino Acids; General Procedure
To further explore the scope of the chemistry, a variety of To a 0 °C solution of n-BuLi (4 equiv, 20 mmol, 2.5 M/hexanes) in
N-Boc-amino acids were reacted with phenyllithium un- Et
der the standard reaction conditions. Not surprisingly, it
was found that with increasing size at the -position, es-
O (15 mL), was added neat aryl bromide (4.1equiv, 20.5 mmol)
over 2–3 min. The solution was allowed to stir at 0 °C for 25 min
and added, via cannula, to a cold –78 °C solution of N-Boc-amino
2
acid (5 mmol) in Et O (100 mL). The resulting solution was held at
2
pecially with respect to -branching (products 11–13), a
dramatic drop in yield of the corresponding phenyl ketone
was observed (Table 2).
–
78 °C for 25 min, then warmed to 0 °C over 1–2 h, then quenched
with H O. The aqueous layer was extracted with Et O (3 × 25 mL)
2
2
and the combined organic layers were washed with brine (25mL),
dried (MgSO ) and concentrated in vacuo. The N-Boc-amino ke-
All reactions were run on a 500 mg to one gram scale, and
4
tone was isolated by flash chromatography or silica plug (typically
:1 hexane–EtOAc), which was immediately treated with 4 N HCl/
in the case of 7, the reaction was scaled up to provide 30
9
1
3
g in 55% yield.
dioxane for 2–8h, then diluted with Et O. The corresponding HCl
2
During the course of our medicinal chemistry research, salt was collected via filtration and dried in high vacuum for 16 h.
most of the amino ketones were coupled directly to a va-
(
S)-2-Amino-1,3-diphenylpropan-1-one Hydrochloride (1)
riety of enantiopure succinic acids (Figure 2). NMR anal-
ysis of the corresponding amide products did not provide
evidence of diastereomer formation. The stereochemical
integrity of the amino ketones was also verified by chiral
Yield: 2.55 g (57%); white solid.
1
H NMR (DMSO-d ): = 8.58 (br s, 2 H), 7.99–7.95 (d, 1 H, J = 8.7
6
Hz), 7.73–7.66 (t, 1 H, J = 8.6 Hz), 7.55–7.47 (t, 1 H, J = 8.7 Hz),
Synthesis 2003, No. 11, 1653–1656 © Thieme Stuttgart · New York

PAPER
.30–7.09 (m, 5 H), 5.44–5.37 (t, 1 H, J = 7.5 Hz), 3.20–3.15 (d, 2
A Practical Synthesis of -Amino Ketones
1655
7
(S)-2-Amino-3-(4-hydroxyphenyl)-1-phenylpropan-1-one Hy-
drochloride (7)
H, J = 7.5 Hz).
Yield: 1.5 g (60%); white solid.
1H NMR (DMSO-d6): = 9.4 (s, 1 H), 8.42 (s, 2 H), 7.99–7.97 (d,
MS (ESI): m/z = 226 (M + H).
Anal. Calcd for C H ClNO: C, 68.84; H, 6.01; N, 5.37. Found C,
15
16
2
H, J = 8.5 Hz), 7.72–7.68 (t, 1 H, J = 7.5 Hz), 7.57–7.52 9 (t, 2 H,
6
8.83; H, 6.16; N, 5.35.
J = 7.8 Hz), 6.91–6.89 (d, 2 H, J = 8.4 Hz), 6.63–6.60 (d, 2 H,
J = 8.5 Hz), 5.33–5.50 (t, 1 H, J = 7.4 Hz) 3.07–3.02 (m, 2 H).
(
S)-2-Amino-1-(4-tert-butylphenyl)-3-phenylpropan-1-one Hy-
drochloride (2)
MS (ESI): m/z = 242 (M + H), 240 (M – H).
Yield: 0.98 g (55%); white solid.
1H NMR (DMSO-d6): = 8.43 (s, 2 H), 7.94–7.91 (d, 2 H, J = 8.5
Hz), 7.57–7.54 (d, 2 H, J = 8.5 Hz), 7.32–7.12 (m, 5 H), 5.40–5.32
Anal. Calcd for C H ClNO : C, 64.86; H, 5.80; N, 5.04. Found: C,
64.75; H, 5.74; N, 4.99.
1
5
16
2
(
t, 1 H, J = 7.4 Hz), 3.20–3.11 (m, 2 H), 1.32 (s, 9 H).
(S)-2-Amino-1-phenylpropan-1-one Hydrochloride (8)
Yield: 0.62 g (63%); white solid.
1H NMR (DMSO-d6): = 8.43 (s, 2 H), 8.08–8.04 (d, 2 H, J = 7.4
Hz), 7.77–7.72 (t, 1 H, J = 7.8 Hz), 7.63–7.58 (t, 2 H, J = 7.6 Hz),
MS (ESI): m/z = 282 (M + H).
Anal. Calcd for C H ClNO: C, 70.68; H, 7.90; N, 4.57. Found: C,
1
8
24
7
0.60; H, 7.79; N, 4.50.
5
.20–5.10 (q, 1 H, J = 7.5, 7.6 Hz), 1.43–1.41 (d, 3 H, J = 7.1 Hz).
(
S)-2-Amino-1-(4-methoxyphenyl)-3-phenylpropan-1-one Hy-
MS (ESI): m/z = 150 (M + H).
drochloride (3)
Yield: 0.76 g (54%); white solid.
1H NMR (DMSO-d6): = 8.56 (s, 2 H), 7.97–7.94 (d, 2 H, J = 9.2
Hz), 7.26–7.19 (m, 3 H), 7.14–7.12 (m, 2 H), 7.05–7.02 (d, 2 H,
J = 8.1 Hz), 5.36–5.31 (t, 1 H, J = 6.1 Hz), 3.85 (s, 3 H), 3.19–3.16
Anal. Calcd for C H ClNO: C, 58.22; H, 6.51; N, 7.54. Found: C,
9
12
5
8.12; H, 6.50; N, 7.48.
(S)-2-Amino-1-phenylbutan-1-one Hydrochloride (9)
Yield: 0.93 g (63%); white solid.
(
d, 2 H, J = 6.4 Hz).
1H NMR (DMSO-d6): = 8.56 (s, 2 H), 8.08–8.05 (d, 2 H, J = 7.1
Hz), 7.77–7.71 (t, 1 H, J = 7.5 Hz), 7.62–7.57 (t, 2 H, J = 7.0 Hz),
MS (ESI): m/z = 256 (M + H).
5
7
.13–5.10 (m, 1 H), 2.10–1.78 (m, 2 H), 0.88–0.83 (t, 3 H, J = 7.4,
.5 Hz).
Anal. Calcd for C H ClNO : C, 65.86; H, 6.21; N, 4.80. Found: C,
16
18
2
6
5.62; H, 6.19; N, 4.67.
MS (ESI): m/z = 164 (M + H).
(
S)-2-Amino-1-(4-methylsulfanylphenyl)-3-phenylpropan-1-
Anal. Calcd for C H ClNO: C, 60.15; H, 7.06; N, 7.01. Found: C,
1
0
14
one Hydrochloride (4)
Yield: 0.52 g (50%); off-white solid.
6
0.11; H, 7.12; N, 6.88.
1H NMR (DMSO-d6): = 8.35 (s, 2 H), 7.91–7.81 (m, 2 H), 7.41–
(S)-2-Amino-3-cyclohexyl-1-phenylpropan-1-one Hydrochlo-
ride (10)
7
.35 (m, 2 H), 7.30–7.19 (m, 3 H), 7.18–7.06 (m, 2 H), 5.42–5.35
(
m, 1 H), 3.21–3.05 (m, 2 H), 2.60–2.42 (m, 3 H).
Yield: 0.83 g (58%); white solid.
MS (ESI): m/z = 272 (M + H).
1H NMR (DMSO-d6): = 8.44 (s, 2 H), 7.99–7.97 (d, 2 H, J = 7.6
Hz), 7.77–7.72 (t, 1 H, J = 7.4 Hz), 7.64–7.59 (t, 2 H, J = 7.7 Hz),
Anal. Calcd for C H ClNO: C, 62.43; H, 5.89; N, 4.55. Found: C,
1
6
18
5
.16 (m, 1 H), 2.00–1.96 (m, 1 H), 1.65–1.50 (m, 7 H), 1.20–0.84
6
2.21; H, 5.89; N, 4.37.
(
m, 5 H).
(
S)-2-Amino-1-(4-fluorophenyl)-3-phenylpropan-1-one Hydro-
MS (ESI): m/z = 232 (M + H).
chloride (5)
Yield: 0.66 g (42%); white solid.
1H NMR (DMSO-d6): = 8.47 (s, 2 H), 8.06–8.01 (m, 2 H), 7.37–
Anal. Calcd for C H ClNO: C, 67.27; H, 8.28; N, 5.23. Found: C,
1
5
22
6
7.24; H, 8.20; N, 5.20.
7
.31 (t, 2 H, J = 7 Hz), 7.23–7.11 (m, 5 H), 5.41–5.35 (t, 1 H, J = 7.4
(S)-2-Amino-4-methyl-1-phenylpentan-1-one Hydrochloride
Hz), 3.15–3.12 (m, 2 H).
(11)
Yield: 0.57 g (39%); white solid.
MS (ESI): m/z = 244 (M + H).
1H NMR (DMSO-d6): = 8.49 (s, 2 H), 8.01–7.92 (d, 2 H, J = 7.6
Hz), 7.77–7.73 (t, 1 H, 7.6 Hz), 7.64& ndash;7.59 (t, 2 H, J = 7.5
Hz), 5.13–5.08 (m, 1 H), 1.82–1.54 (m, 3 H), 1.00–0.98 (d, 3 H,
J = 6.4 Hz), 0.83–0.81 (d, 3 H, J = 6.6Hz)
Anal. Calcd for C H ClFNO: C, 64.40; H, 5.40, N, 5.00. Found:
C, 64.33; H, 5.33; N, 5.02.
1
5
15
(
S)-2-Amino-3-phenyl-1-(4-trifluoromethylphenyl)propan-1-
one Hydrochloride (6)
MS (ESI): m/z = 192 (M + H).
Yield: 0.94 g (47%); white solid.
1H NMR (DMSO-d6): = 8.71 (s, 2 H), 8.13–8.10 (d, 2 H, J = 8.4
Hz), 7.87–7.84 (d, 2 H, J = 8.5 Hz), 7.23–7.10 (m, 5 H), 5.50–5.46
Anal. Calcd for C H ClNO: C, 63.28; H, 7.96; N, 6.15. Found: C,
63.10; H, 7.85; N, 5.99.
1
2
18
(
t, 1 H, J = 7.6 Hz), 3.27–3.11 (m, 2 H).
(S)-2-Amino-3-methyl-1-phenylpentan-1-one Hydrochloride
(
12)
MS (ESI): m/z = 294 (M + H).
Yield: 0.3 g (30%); off-white solid.
1H NMR (DMSO-d6): = 8.32 (s, 2 H), 8.06–8.03 (d, 2 H, J = 7.3
Hz), 7.75–7.71 (t, 1 H, J = 7.4 Hz), 7.63–7.58 (t, 2 H, J = 7.5 Hz),
Anal. Calcd for C H ClF NO: C, 58.27; H, 4.58; N, 4.24. Found:
C, 58.14; H, 4.60; N, 4.02.
16
15
3
5
0
.12–5.10 (m, 1 H), 1.99–1.85 (m, 1 H), 2.3–2.05 (m, 1 H), 0.98–
.96 (d, 3 H, J = 6.7 Hz), 0.78–0.73 (t, 2 H, J = 7.5 Hz).
MS (ESI): m/z = 192 (M + H).
Synthesis 2003, No. 11, 1653–1656 © Thieme Stuttgart · New York

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A. S. Florjancic, G. S. Sheppard
PAPER
(2) (a) Maurer, P. J.; Knudsen, C. G.; Palkowicz, A. D.;
Anal. Calcd for C H ClNO: C, 63.28; H, 7.96; N, 6.15. Found: C,
1
2
18
6
3.21; H, 7.90; N, 6.12.
Rapoport, H. J. Org. Chem. 1985, 50, 325. (b) Cupps, T. L.;
Boutin, R. H.; Rapoport, H. J.Org.Chem. 1985, 50, 3972.
(c) Knudsen, C. G.; Rapoport, H. J. Org. Chem. 1983, 48,
2260. (d) Buckley, T. F.; Rapoport, H. J. Am. Chem. Soc.
1981, 103, 6157. (e) Luca, L.; Giamcomelli, G.; Porcheddu,
A. Org.Lett. 2001, 3, 1519.
(
S)-2-Amino-3,3-dimethyl-1-phenylbutan-1-one Hydrochlo-
ride (13)
Yield: 0.1 g (12%); off-white solid.
1H NMR (DMSO-d6): = 8.32 (s, 2 H), 8.10–8.08 (d, 2 H, J = 7.7
Hz), 7.81–7.74 (t, 1 H, J = 7.6 Hz), 7.61–7.59 (t, 2 H, J = 7.5 Hz),
5
(
3) (a) Klix, R. C.; Chamberlin, S. A.; Bhatia, A. V.; Debroah,
D. A.; Hayes, T. K.; Rojas, F. G.; Koops, R. W. Tetrahedron
Lett. 1995, 36, 1791. (b) Takahashi, Y.; Ishiwata, H.;
Deushi, T.; Nakayama, M.; Shiratsuchi, M. Tetrahedron
Lett. 1991, 32, 1067.
.04 (s, 1 H), 0.93 (s, 9 H).
MS (ESI): m/z = 192 (M + H).
Anal. Calcd for C H ClNO: C, 63.28; H, 7.96; N, 6.15. Found: C,
6
1
2
18
(
(
(
(
4) McClure, D. E.; Arison, B. H.; Jones, J. H.; Baldwin, J. J. J.
3.27; H, 7.91; N, 6.09.
Org. Chem. 1981, 46, 2431.
5) Paleo, M. R.; Sardina, F. J. Tetrahedron Lett. 1996, 37,
3403.
Acknowledgment
6) Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999,
Thanks to Professor Peter Beak, Dr. Michael Curtin and the late
Professor Henry Rapoport for helpful discussions regarding this re-
search, and Mark Mullaly of the High-Throughput Purification
group for most of our chiral HPLC analysis.
40, 4107.
7) (a) Bonini, B. F.; Franchini-Comes, M.; Fochi, M.;
Mazzanti, G.; Ricci, A.; Varchi, G. Synlett 1998, 1013.
(
b) Giordano, A.; Monica, C.; Landi, F.; Spinella, A.;
Sodano, G. Tetrahedron Lett. 2000, 41, 3979.
8) Mattson, M. N.; Rapoport, H. J. Org. Chem. 1996, 61, 6071.
9) Berree, F.; Chang, K.; Cobas, A.; Rapoport, H. J. Org.
Chem. 1996, 61, 715.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(11) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991.
(
(
References
(
1) Sheppard, G. S.; Florjancic, A. S.; Giesler, J. R.; Xu, L.;
Guo, Y.; Davidsen, S. K.; Marcotte, P. A.; Elmore, I.; Albert,
D. H.; Magoc, T. J.; Bouska, J. J.; Goodfellow, C. L.;
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(12) Pace, R. D.; Kabalka, G. W. J. Org. Chem. 1995, 60, 4838.
(
(
13) Florjancic, A.; Curtin, M., unpublished results.
14) HPLC analysis with ChiralPak AD 4.6 × 250 mm column
from Chiral Technologies. Solvent system: 25–40% EtOH in
hexanes.
Synthesis 2003, No. 11, 1653–1656 © Thieme Stuttgart · New York