Organic Syntheses, CV 6, 203
Submitted by Ulf Ragnarsson
1, Sune M. Karlsson, Bengt E. Sandberg, and Lars-Eric Larsson.
Checked by S. Wang and A. Brossi.
1. Procedure
A
1-l. Erlenmeyer flask (Note
1) equipped with a
magnetic stirrer, and a
thermometer is charged with
115 g. (1.00 mole) of L-proline (Note
2) and
500 ml. of dimethyl sulfoxide (Note
3). To the stirred suspension are added simultaneously, over 5 minutes,
115 g. (1.00 mole) of 1,1,3,3-tetramethylguanidine (Note
4) and
214 g. (1.10 moles) of tert-butyl phenyl carbonate (Note
5). The
proline dissolves completely within a few minutes in an exothermic reaction, the temperature of which reaches a maximum of 50–52° after 10–15 minutes. After stirring for 3 hours, the clear reaction mixture is transferred to a
6-l. separatory funnel and shaken with 2.2 l. of water and
1.8 l. of diethyl ether (Note
6). The aqueous layer, after being washed with
500 ml. of ether, is acidified to pH 3.0 by the addition of
10% sulfuric acid (Note
7), which generally causes partial crystallization of the product. The acidic solution, including the solid, is extracted with three
600-ml. portions of a mixture of equal volumes of ethyl acetate and ether. The combined extracts are washed with three 25-ml. portions of water, dried over
magnesium sulfate, filtered, and evaporated with a
rotary evaporator at a bath temperature not exceeding 40°. After drying in a vacuum
oven at 50°, the crude product weighs
202 g., m.p.
129–132°. It is recrystallized from
300 ml. of hot ethyl acetate, and clarified by filtration and the addition of
1 l. of petroleum ether (40–60°), yielding, after drying under vacuum at 50°,
179–193 g. (
83–90%) of
tert-butoxycarbonyl-L-proline, m.p.
132–134°,
[α]D25 −59.84° to −61.6° (
c = 1, glacial
acetic acid) (Note
8),(Note
9), and (Note
10).
2. Notes
1. A
three-necked flask equipped with a U-tube may also be used for the reaction.
2. The submitters used
L-proline obtained from Tanabe Seiyaku Company, Ltd., Osaka, Japan, and checked its purity by the method of Manning and Moore.
2 The
L-proline used by the checkers was obtained from Ajinomoto Company, New York.
4.
1,1,3,3-Tetramethylguanidine, b.p.
159–160°, was used without further purification. The submitters obtained their material from Schuchardt, Munich, Germany, and the checkers obtained theirs from Pfaltz and Bauer, New York.
5.
tert-Butyl phenyl carbonate furnished by Ega-Chemie KG, Steinheim, Germany, was used by the submitters. The checkers used material obtained from Aldrich Chemical Company, Inc.
6. The pH of the aqueous layer was 7.2. If the pH, as measured with a pH meter, is not between 7 and 8, it should be adjusted to within these limits by the addition of either
10% sulfuric acid or
1,1,3,3-tetramethylguanidine. The submitters worked up the reaction by the following alternate, but less convenient, method. The reaction mixture was poured into
1.25 l. of 1 M sodium hydrogen carbonate solution,
500 ml. of ether, and sufficient water (
ca. 1 l.) to give two clear phases. The pH, which was 8.9, was adjusted to 8.0 by the addition, with stirring, of solid
potassium hydrogen sulfate.
8. An additional
5 g. of product, m.p.
127–129°, may be obtained from the mother liquor
9. Some reported yields, melting points, and rotations are:
55%,
136–137°, and
[α]D25 −60.2° (2.011 in
acetic acid)
3;
96%,
134–136°,
[α]57818–25 −68.5° (
c = 1,
acetic acid)
4;
95%,
132–134°,
[α]578 −62.5° (
acetic acid)
5;
90%,
133–135°,
[α]D25 −60.4° (
c = 2.2 in
acetic acid)
6;
93%,
134–135°, no rotation reported.
7
10.
1H NMR (dimethyl sulfoxide-
d6): δ 1.38 (s, 9H, 3C
H3), 1.92 (m, 4H, 2C
H2), 3.31 (t, 2H, C
H2N), 4.05 (t, 1H, C
HN), 12.3 (s, 1H, CO
2H). Analysis calculated for C
10H
17NO
4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.81; H, 7.95; N, 6.44.
3. Discussion
Since their introduction by McKay and Albertson,
8 and Anderson and McGregor,
3 tert-butoxycarbonyl amino acids have been prepared by several different methods. The simplest procedure
6 requires working with large quantities of
phosgene. Another very good method,
5 but one that has not found wide application, involves the use of
tert-butoxycarbonylfluoride, which is not commercially available. At the present the most useful reagent has been
tert-butoxycarbonylazide, for which good procedures
9,10 are available; the excellent method of Schnabel
4 and one more recently reported
7 are based on this reagent. Of the procedures for the preparation of
tert-butoxycarbonylazide, one,
9 which is readily adaptable for large-scale operations, involves three steps and the other,
10 a two-step process, is more suitable for small-scale work.
Proline dissolves readily in
dimethyl sulfoxide. Some other amino which are less soluble require longer reaction times and, in some instances, other solvents.
11 These details and the scope of the reaction are illustrated in Table I.
TABLE I
OTHER BOCa AMINO ACIDS SYNTHESIZED BY THIS PROCEDURE
|
Compound |
Solvent |
Temperature, ° |
Time, Hr. |
Yield, % |
Remarks |
|
Boc-Alab |
DMSOc |
25 |
40 |
58 |
|
Boc-Alab |
DMSOc |
40 |
40 |
79 |
|
Boc-Asnd |
DMSOc |
25 |
66 |
70 |
2 equiv. TMGe |
Boc-Aspf |
DMSOc |
25 |
18 |
89 |
2 equiv. TMG |
Boc-Cys(Bzl)g |
DMSOc |
25 |
40 |
62 |
CHA salth |
Boc-Cys (Bzl)g |
DMSOc |
40 |
40 |
78 |
CHA salt |
Boc-Glni |
DMSOc |
50 |
48 |
62 |
2 equiv. TMG, DCHA salt,j continuous extraction with ethyl acetate |
Boc-Gluk |
DMSOc |
25 |
2.5 |
80 |
2 equiv. TMG |
Boc-Ilel |
DMSOc |
40 |
72 |
72 |
|
Boc-Leum |
DMSOc |
25 |
48 |
73 |
Calc. as hemihydrate |
Boc-Metn |
DMSOc |
25 |
24 |
86 |
81% solid +5% DCHA salt |
Boc-Pheo |
DMSOc |
25 |
40 |
81 |
DCHA salt |
Boc-Pheo |
DMSOc |
25 |
96 |
88 |
DCHA salt |
Boc-Pheo |
DMSOc |
40 |
18 |
81 |
DCHA salt |
Boc-Pheo |
DMSOc |
25 |
48 |
59 |
DCHA salt |
Boc-Pheo |
D—Wq |
25 |
48 |
5 |
DCHA salt |
Boc-Pror |
DMSOc |
25 |
2.5 |
90 |
|
Boc-Pror |
DMFp |
25 |
2.5 |
92 |
|
Boc-Pror |
D—Wq |
25 |
21 |
84 |
|
Boc-Thrs |
DMSOc |
25 |
67 |
66 |
DCHA salt |
Boc-Valt |
DMSOc |
25 |
71 |
77 |
2 equiv. TMG, 65% solid +12% DCHA salt |
|
|
This preparation is referenced from:
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
sulfuric acid (7664-93-9)
acetic acid (64-19-7)
ethyl acetate (141-78-6)
ether,
diethyl ether (60-29-7)
sodium hydrogen carbonate (144-55-8)
alanine (56-41-7)
potassium hydrogen sulfate (7646-93-7)
phosgene (75-44-5)
Glutamic Acid (56-86-0)
magnesium sulfate (7487-88-9)
Methionine (63-68-3)
phenylalanine (63-91-2)
proline,
L-proline (147-85-3)
isoleucine (73-32-5)
leucine (61-90-5)
threonine (72-19-5)
valine (72-18-4)
aspartic acid (56-84-8)
dimethyl sulfoxide (67-68-5)
cysteine (52-90-4)
1,1,3,3-tetramethylguanidine (80-70-6)
Butoxycarbonyl
Glutamine
tert-butoxycarbonylazide (1070-19-5)
2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (58632-95-4)
tert-Butyl phenyl carbonate (6627-89-0)
Di-tert-butyl dicarbonate (24424-99-5)
1,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (S)-,
tert-Butoxycarbonyl-L-proline (15761-39-4)
tert-butoxycarbonylfluoride
tert-butyl-4,6-dimethylpyrimidyl-2-thiol carbonate
tert-butyl α-methoxyvinyl carbonate
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