A convenient conversion of α-aminoacids into NH-Boc protected α-aminoketones via imidazolides

Article abstract of DOI:10.1055/s-1998-1831

Imidazolides obtained from natural α-aminoacids react with a twofold excess of Grignard reagents to afford in satisfactory to good yields the corresponding NH-Boc protected α-aminoketones. Under optimized conditions the reaction with phenyl- and n-pentylm

Full text of DOI:10.1055/s-1998-1831

September 1998
SYNLETT
1013
A Convenient Conversion of α-Aminoacids into NH-Boc Protected α-Aminoketones via
Imidazolides
Bianca F. Bonini, Mauro Comes-Franchini, Mariafrancesca Fochi, Germana Mazzanti, Alfredo Ricci*, Greta Varchi
Dipartimento di Chimica Organica "A. Mangini", Università di Bologna, Viale Risorgimento 4, I- 40124-Bologna (Italy)
Fax +39 51 6443654; E-mail: ricci@ms.fci.unibo.it
Dedicated to the memory of Prof. Antonino Fava (deceased December 19, 1997) Professore Emerito of the University of Bologna
Received 5 June 1998
Abstract: Imidazolides obtained from natural α-aminoacids react with a
twofold excess of Grignard reagents to afford in satisfactory to good
yields the corresponding NH-Boc protected α-aminoketones. Under
optimized conditions the reaction with phenyl- and n-pentylmagnesium
bromide required the addition of catalytic amounts of Cu(I)-salt which
turned out to be unnecessary in the case of Buchi’s Grignard.
butoxycarbonylamino)-1-imidazol-1-yl-3-phenyl-propan-1-one (4) was
treated with two equivalents17 of freshly prepared C H11MgBr the (2S)-
5
1-phenyl-2-(t-butoxycarbonylamino)octan-3-one (7) was isolated in
yields never exceeding 15-20% even after a prolonged reaction time.
Furthermore the presence of extensive amounts of degradation products
was observed. Addition of a catalytic amount (6%) of CuI to the
Grignard reagent led to a sizeable enhancement of the yields. Usually
after 2-3 h at 0°C the reactions were complete and the α-aminoketones
were isolated in satisfactory yields after chromatography on silica gel
and characterized.18 (Scheme 2 and Table 1)
Enantiomerically pure N-protected α-aminoketones are of great
importance in preparative organic chemistry of biologically active
substances. Moreover they are interesting intermediates in natural
1
product synthesis and valuable starting materials for N-containing
2
heterocycles, diamines and aminoalcohols. Several methods for the
3
synthesis of α-aminoketones have been reported. A number of them
makes use of α-aminoacids as precursors since they are generally
inexpensive compounds and readily available in enantiomerically pure
form.
To date, several protecting groups have been used for the preparation of
α-aminoketones starting from α-aminoacids. Besides N-
phenylsulfonyl, N-(9-phenylfluoren-9-yl), N,N-dibenzyl6 and N-
4
5
Scheme 2
7
4c,d,8
9
phthaloyl also carbamates (Boc
conditions have been utilized.
and Cbz ) removable under mild
1
0
NH-Boc α-aminoketones have been previously obtained1
a,8d,e
Unexpectedly in the case of α-aminoketones 9, 12 and 15 the addition of
a catalytic amount of CuI to Buchi’s Grignard reagent19 led to slightly
lower yields with respect to those obtained in the uncatalyzed reaction.
We infer that the addition of Cu(I) salts might reverse the Schlenk
equilibrium of intramolecular solvolysis reported for this Grignard
reagent20 which leads to a soft carbon nucleophile mimicking the
reactivity of an organocopper reagent. The three dioxolane derivatives 9,
by
reaction between Grignard or organolithium reagents and amino acid-
1
1
derived Weinreb amides in which the N-methoxy-N-methylamide
moiety acts as a leaving group. This route, though well established,
suffers from drawbacks since the starting amide needs to be purified by
chromatography on silica gel and in all the cases reported so far a large
excess of the organometallic reagent has to be used.
1
2 and 15 appear as new promising and versatile building blocks due to
We describe herein an alternative approach toward the synthesis of
homochiral NH-Boc protected α-aminoketones via the reaction of
imidazolides with Grignard reagents under Cu(I) catalysis.
Imidazolides are readily obtained12 in nearly quantitative yields from
NH-Boc protected α-aminoacids and N,N-carbonyldiimidazole in THF
at room temperature for 30 min. Purification of the crude reaction
products is not needed since they are sufficiently pure to be used in the
next step. By this route the α-aminoacids 1-3 have been converted into
imidazolides 4-6 (Scheme 1).
the presence of the masked carbonyl group. Moreover from compounds
1
3-15, derivatives containing the 2-amino-1,3-propanediol subunit,
2
1
which is present in an extensive array of antibiotics, can be obtained.
Key features of this protocol which leads in satisfactory to good yields
to the desired α-aminoketones are the mildness of the reaction
2
2
conditions and, due to the high reactivity of acylimidazoles, the
reduced amount of the organometallic reagent. The assumption that this
latter condition would prevent the occurrence of an even partial
racemization of the homochiral aminoketones is supported by the
observation that in the case of the synthesis of 10-15, diastereomeric
1
13
mixtures have never been detected by H and C NMR analyses.
In summary a careful tuning of the leaving group ability in the activated
form of the aminoacids and of the nature of the organometallic reagent,
allows to envisage a useful approach to the synthesis of a range of
homochiral NH-Boc-protected α-aminoketones, which complements
and favorably compares to those previously reported.
Further work involving the use of products 7-15 as building blocks for
asymmetric transformations is being actively pursued in this laboratory
and will be reported in due course.
Scheme 1
To date, the reaction of Grignard reagents with imidazolides has been
1
3
applied to the synthesis of alkyl and aryl ketones, symmetrical diaryl-
1
4
15
1
,2-diketones , α-ketoesters and acids and, under FeCl activation, of
3
16
steroidal carbonyl compounds.
However, when the (2S)-(t-

1
014
LETTERS
SYNLETT
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48, 2260.
(
(
5) Palev, M. R.; Sardina, F. J. Tetrahedron Lett. 1996, 37, 3403.
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2
533.
(8) a) Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.; Wang, Z.;
Thottathil, J.; Barrish, J. C.; Polniaszek, R. P. Tetrahedron Lett.
1
997, 38, 3175. b) Gramble, M. P.; Giblin, G. M.; Montana, J. G.;
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1
996, 37, 7457. c) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996,
6
1, 4999. d) Dufour, M. N.; Jauin, P.; Poncet, J.; Pantaloni, A.;
Castro, B. J. Chem. Soc. Perkin Trans. I 1986, 1895. e) Sawamura,
M.; Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem. 1995, 60, 1727.
(
(
(
9) McClure, D. E.; Arison, B. H.; Jones, J. H.; Baldwin, J. A. J. Org.
Chem. 1981, 46, 2433.
10) Kocienski, P. J. in Protecting Groups, Georg Thieme Verlag,
Stuttgart-New York 1994.
11) a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 39, 3815.
b) Levin, I. J.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
1
2, 989.
(12) Anderson, G. W.; Paul, R. J. Org. Chem. 1962, 27, 2094.
Anderson, G. W.; Paul, R. J. Am. Chem. Soc. 1960, 82, 4596.
(
(
(
(
13) Staab, H. A.; Jost, E. Liebigs Ann. Chem. 1962, 655, 90.
14) Mitchell, R. H.; Iyer, V. S. Tetrahedron Lett. 1993, 34, 3683.
15) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211.
16) Bhattacharya, A.; Williams, J. M.; Amato, J. S.; Dolling, U. H.;
Grabowski, E. J. J. Synth. Commun. 1990, 2683.
(
(
17) Two equivalents of Grignard reagent were used on the assumption
of proton abstraction from the carbamate.
18) Typical procedure for the synthesis of α-amino ketones:
(
2S)-1-phenyl-2-(t-butoxycarbonylamino)octan-3-one (7): A
Acknowledgments: This work has been supported by Progetto
Strategico “Tecnologie Chimiche Innovative” (CNR, Italy) and by
University of Bologna (Funds for Selected Research Topics, A. A. 1995-
solution of 568 mg (1.8 mmol) 4 in THF (7.0 mL) was slowly
added under Ar to a slurry containing pentyl magnesium bromide
(2.0 mL, 3.6 mmol) and CuI (20 mg, 0.1 mmol) at 0°C. After
being stirred for 2-3 h the reaction mixture was hydrolyzed with
97).
NH Cl and extracted three times with diethyl ether. The solution
4
was dried over MgSO4 and the solvent evaporated.
References and Notes:
Chromatography (SiO ), eluting with diethyl ether:petroleum
2
ether 1:2 gave 7 (325 mg, 56%) as a yellow oil. [α] = 41.0° (c 3,
(
1) a) Angle, S. R.; Boyle, J. P. Tetrahedron Lett. 1995, 36, 6185.
b) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721.
c) Wesson, B. K.; Gibson, W. K.; Stuart, R. S.; Williams, H. W.
R.; Yates, C. H. J. Med. Chem. 1972, 15, 651. d) Marrow, D. F.;
Johnson, P. C.; Tonabi, H.; Williams, D.; Wedding, D. L.; Craig, J.
W.; Majewski, R. F.; Braselton, J. P.; Gallo, D. G. J. Med. Chem.
D
-1
+
CHCl ). IR (CCl ) 3435, 1712 cm . M.S (m/e): 319 (M ), 263,
3
4
1
2
46, 219, 163, 120. H NMR (CDCl ) δ: 0.80 (t, 3H, J=7.5 Hz),
3
1
.10-1.50 (m, 15H), 2.30 (m, 2H), 2.95 (m, 2H), 4.45 (dq, 1H,
13
J=6.7 Hz), 5.10 (d, 1H, J=6.7 Hz), 7.05 7.30 (m, 5H) ppm.
C
NMR δ: 13.80, 22.28, 22.89, 28.21, 31.17, 37.88, 40.73, 58.89,
9.70, 126.86, 128.52, 129.17, 136.23, 154.83, 209.30 ppm. Anal.
7
1973, 16, 736.
Calcd for C19H29NO : C 71.44, H 9.15, N 4.38. Found: C 71.22,
3
(2) a) Tramontini, M. Synthesis 1982, 605. b) Reetz, M. T.; Angew.
Chem. Int. Ed. Engl. 1991, 30, 1531.
H 9.10, N 4.36.
Illustrative spectroscopic data for compounds 8-15.
(2S)-(t-butoxycarbonylamino)-1,3-diphenyl-propan-1-one (8):
(3) Mayer, D. in Houben-Weyl, Methoden der Organischen Chemie,
-1
4th Edit., E. Müller Ed., Vol. 7, 2c Thieme Verlag, Stuttgart, 1977,
[α] =59.8° (c 1.65, CHCl ). IR (CCl ) 3440, 1710, 1690 cm .
D 3 4
+
1
pp 2253. b) Fischer, L. E.; Muchowski, J. M.; Org. Prep. Proced.
M.S (m/e): 325 (M ), 220. H NMR (CDCl ) δ: 1.40 (s, 9H), 2.96
3

September 1998
SYNLETT
1015
(dd, 1H, J=13.7, 6.3 Hz), 3.26 (dd, 1H, J=13.7, 6.3 Hz), 5.38 5.62
C16H29NO : C 60.91, H 9.27, N 4.44. Found: C 60.78, H 9.25, N
5
(
m, 2H), 7.05 (m, 2H), 7.20 (m, 3H), 7.40 7.65 (m, 3H), 7.95 (m,
4.42. (2R,3S)-3-(t-butoxycarbonylamino)-2-benzyloxy-nonan-
1
3
2
1
1
7
H) ppm. C NMR (CDCl ) δ: 28.28, 39.03, 55.92, 79.62,
4-one (13): [α] =31.0° (c 2.60, CHCl ). IR (CCl ) 3435, 3100-
D 3 4
3
-1
+
1
26.78, 128.27, 128.60, 128.78, 129.46, 133.59, 134.70, 135.73,
2860, 1710 cm . M.S (m/e): 363 (M ), 319, 308, 264, 164. H
54.77, 197.97 ppm. Anal. Calcd for C20H23NO : C 73.81, H
NMR (CDCl ) δ: 0.85 (t, J07.0 Hz, 3H), 1.15-1.35 (m, 7H), 1.40-
3
3
.13, N 4.31. Found: C 73.40, H 7.11, N 4.31. (2S)-(t-
1.60 (s+m, 11H), 2.45 (t, J=7.5 Hz, 2H), 4.00-4.15 (m, 1H), 4.25
(dd, 1H, J=9.2, 2.5 Hz), 4.40 (d, 1H, J=11.6 Hz), 4.57 (d, 1H,
butoxycarbonylamino)-5-[1,3]dioxolan-2-yl-1-phenyl-pentan-
3
1
1
3
-one (9): [α] =37.0° (c 4.12, CHCl ). IR (CCl ) 3450, 1727,
J=11.6 Hz), 5.45 (d, 1H, J=9.2 Hz), 7.20-7.40 (m, 5H). C NMR
D
3
4
-1
+
t
1
717 cm . M.S (m/e): 292 (M -Bu ), 276, 221, 134, 120.
H
(CDCl ) δ: 13.83, 15.92, 22.34, 22.81, 28.24, 31.22, 40.09, 63.54,
3
NMR (CDCl ) δ: 1.40 (s, 9H),1.95-2.05 (m, 2H), 2.50-2.55 (m,
70.73, 74.23, 79.66, 127.69, 128.29, 137.74, 155.92, 208.79 ppm.
3
2
3
H), 2.90 (dd, 1H, J=14.0, 6.1 Hz), 3.15 (dd, 1H, J=14.0, 6.1 Hz),
.80-3.95 (m, 4H),4.50-4.55 (m, 1H), 4.78-4.85 (m, 1H), 5.15 (d,
Anal. Calcd for C21H33NO : C 69.38, H 9.16, N 3.86. Found: C
68.93, H 9.14, N 3.84. (2S,3R)-2-(t-butoxycarbonylamino)-3-
4
13
J=8.0 Hz, 1H), 7.10-7.30 (m, 5H) ppm. C NMR (CDCl ) δ:
2
1
benzyloxy-1-phenyl-butan-1-one (14): [α] =19.4° (c 5.28)
D
3
-
1
+
7.07, 28.03, 33.96 37.32, 59.92, 64.65, 79.40, 102.75, 126.61,
28.29, 129.01, 136.19, 154.95, 208.04 ppm. Anal. Calcd for
CHCl . IR (CCl ) 3440, 1730, 1680 cm . M.S (m/e): 369 (M ),
3 4
1
164, 134. H NMR (CDCl ) δ: 1.30 (d, J=7.0 Hz, 3H), 1.45 (s,
3
C19H27NO : C 65.29, H 7.79, N 4.01. Found: C 65.09, H 7.77, N
9H), 3.98-4.05 (m, 1H), 4.20 (d, 1H, J=11.5 Hz), 4.40 (d, 1H,
J=11.5), 5.20-5.25 (m, 1H), 5.72 (d, 1H, J=8.5 Hz), 7.00-7.65 (m,
5
4
.00. (3S,4S)-4-(t-butoxycarbonylamino)-3-methyl-decan-5-
one (10): [α] =47.6° (c 2.25, CHCl ). IR (CCl ): 3440, 1740,
8H), 7.85 ( d, 2H, J=7.5 Hz) ppm. 13C NMR (CDCl ) δ: 18.23,
D
3
4
3
+
t
1
1
0
1
710. M.S (m/e): 228 (M -Bu ), 186. H NMR (CDCl ) δ: 0.75-
28.14, 60.01, 70.55, 74.34, 79.50, 127.35, 127.77, 128.00, 128.30,
128.47, 133.06, 135.26, 137.40, 155.96, 197.55 ppm. Anal. Calcd
3
.95 (m, 9H), 1.15 1.30 (m, 6H), 1.37 (s, 9H), 1.45-1.60 (m, 2H),
.70-1.90 (m, 1H), 2.40 (t, J=7.5 Hz, 2H), 4.10-4.20 (m, 1H), 5.05
for C22H27NO : C 71.51, H 7.37, N 3.79. Found: C 71.43, H 7.35,
4
1
3
(
d, 1H, J=8.7 Hz) ppm. C NMR (CDCl ) δ: 11.63, 13.86, 16.16,
N
3.77. (4S,5R)-4-(t-butoxycarbonylamino)-5-benzyloxy-1-
[1,3]dioxolan-2-yl-hexan-3-one (15): [α] =27.1° (c 6.00)
3
2
1
1
2.39, 23.15, 24.10, 28.29, 31.33, 37.08, 41.03, 63.77, 79.53,
D
-1
+
55.85, 210.04 ppm. Anal. Calcd for C16H31NO : C 67.31, H
CHCl . IR (CCl ) 3440, 1730, 1710 cm . M.S (m/e): 393 (M ),
3 4
264, 129, 91. H NMR (CDCl ) δ: 1.15 (d, 3H, J=6.8 Hz), 1.40 (s,
3
1
0.95, N 4.91. Found: C 66.89, H 10.87, N 4.91. (2S,3S)-2-(t-
3
butoxycarbonylamino)-3-methyl-1-phenyl-pentan-1-one (11):
9H), 1.90 (m, 2H), 2.50 (t, 2H, J=7.3 Hz), 3.65-3.85 (m, 4H),
3.95-4.00 (m, 1H), 4.20 (dd, 1H, J=8.8, 2.4 Hz), 4.35 (d, 1H,
J=11.3 Hz), 4.45 (d, 1H, J=11.3 Hz), 4.80-4.85 (m, 1H), 5.45 (d,
+
t
[
α] =82.7° (c 4.16, CHCl ). M.S (m/e): 218 (M -OBu ), 186,
D 3
30, 105. IR (CCl ) 3435, 1715 cm . H NMR (CDCl ) δ: 0.70 (t,
4 3
-1 1
1
3
5
2
5
H), 0.95 (d, 3H), 1.10-1.40 (s+m, 11H), 1.70-1.90 (m, 1H), 5.05-
.20 (m, 1H), 5.40 (d, 1H, J=9.0 Hz), 7.35-7.57 (m, 3H), 7.90 (m,
1H, J=8.8 Hz), 7.10-7.35 (m, 5H) ppm. 13C NMR (CDCl ) δ:
3
15.70, 27.06, 28.04, 33.84, 63.45, 64.62, 70.51, 73.99, 79.42,
102.84, 127.46, 128.10, 137.58, 155.70, 207.58 ppm. Anal. Calcd
1
3
H) ppm. C NMR (CDCl ) δ: 11.40, 16.18, 23.64, 28.23, 38.22,
3
9.25, 79.44, 128.45, 128.67, 133.39, 135.50, 155.58, 199.85
for C21H31NO : C 64.10, H 7.94, N 3.56. Found: C 63.89, H 7.92,
6
ppm. Anal. Calcd for C17H25NO : C 70.06, H 8.65, N 4.81.
N 3.55.
3
Found:
C
69.77,
H
8.64,
N
4.78. (4S,5S)-4-(t-
(
19) Buchi, G.; Wuest, H. J. Org. Chem. 1969, 34, 1122.
20) Swarin, M.; Neumann, W. L. Tetrahedron Lett. 1987, 28, 3217.
butoxycarbonylamino)-1-[1,3]dioxolan-2-yl-5-methyl-hepten-
(
3
-one (12): [α] = 38.2° (c 4.22, CHCl ). IR (CCl ) 3450, 1750,
D 3 4
-
1
+
t
1
(21) Choi, S.-K.; Lee, J.-S.; Kim, J.-H.; Lee, W. K. J. Org. Chem. 1997,
2, 743 and references cited therein.
1720 cm . M.S (m/e): 258 (M -Bu ), 242, 186, 130. H NMR
6
(
CDCl ) δ: 0.70-0.90 (m, 6H), 1.10 (m, 2H), 1.30 (s, 9H), 1.75 (m,
3
1
4
H), 1.80-1.95 (m, 2H), 2.50 (t, 2H, J=7.5 Hz), 3.70-3.95 (m, 4H),
.15 (m, 1H), 4.70-4.85 (m, 1H), 5.10 (d, J=9.0 Hz, 1H) ppm. 13
(22) The reaction of N-(tert-butoxycarbonyl)-L-phenylalanine-N’-
C
methoxy-N’-methylamide with two equivalents of C H11MgBr in
6
NMR (CDCl ) δ: 11.44, 15.92, 23.82, 27.14, 28.08, 34.41, 36.75,
the presence of CuI (6% mol), led after 48 h at rt to 15% of 7 and
3
64.58, 64.72, 78.78, 102.83, 155.58, 208.57 ppm. Anal. Calcd for
to recovery of about 80% of the starting amide.