UPDATES
in hand, formation of Schiff base 1 b by condensation
with salicylaldehyde derivative 7 proceeded in quan-
titative yield with no detectable byproducts. Catalyst
were separated. The organic layer was washed with a 20%
aqueous solution of sodium carbonate (250 mL). The com-
bined aqueous layers were washed with chloroform
(3 ´ 150 mL). All organic phases were combined, dried over
1
b was tested in a representative Strecker reaction
sodium sulfate and concentrated to afford a mixture of 4
and tetramethylurea as a white solid (4.71 g, 21.4 mmol,
of an aldimine, and the corresponding Strecker ad-
duct was isolated in 96% ee and 97% yield (Equa-
9
9% yield of 4 over two steps based on crude mass and
[9]
tion 2).
1
H NMR analysis). The mixture was carried on to the next
step without further purification.
Carbamate and Urea Formation (4 ® 5 ® 6)
A 500-mL, round-bottomed flask equipped with a stirbar
was flame-dried and charged with the entire amount of
crude 4 obtained from the previous step (4.71 g, 21.4 mmol
of 4) dissolved in freshly distilled dichloromethane (50 mL).
Freshly distilled pyridine (3.49 mL, 2 equiv.) was added via
syringe to the stirred solution; after 2 minutes, 4-nitrophenyl
chloroformate (4.44 g, 1.02 equiv.) was added in one portion.
After the reaction was stirred for 10 minutes, (S,S)-1,2-dia-
minocyclohexane (7.40 g, 3 equiv.) was added in one por-
tion, followed by addition of DIPEA (4.2 mL, 1.1 equiv.) via
syringe, and the reaction mixture was stirred for an addi-
tional 10 minutes. The resulting mixture was then combined
with dichloromethane (500 mL) and 0.5 M sodium hydro-
xide solution (120 mL). The organic layer was separated,
washed with another portion of 0.5 M sodium hydroxide so-
lution (120 mL), and dried over sodium sulfate. The organic
layer was concentrated by rotary evaporation to afford a vis-
cous oil which was suspended in hexanes (500 mL). The re-
sulting mixture was allowed to stand for 30 minutes, and
then filtered, with the collected solids then washed with
In summary, we have developed an optimized proce-
dure for the synthesis of 1 b in 5 steps from commer-
cially available Boc-tert-leucine and in 80±83% over-
all yield (Scheme 2). We have found that a first-time
practitioner can execute the entire synthesis within
one day and in the indicated yield range. The im-
proved route should make possible the synthesis of
1
b on a commercial scale. In light of the considerable
synthetic utility of this Strecker catalyst, we hope this
will open the door to its broad application in asym-
metric synthesis.
Experimental Section
(
(
6
3 ´ 125 mL) hexanes. The white powder thus obtained
6.25 g, 17.3 mmol, 82% yield over 2 steps) was identified as
General
1
with no impurities detectable by H NMR analysis: IR (thin
±1
1
All commercial reagents were used as received unless noted
otherwise. Boc-l-tert-leucine was purchased from Fluka;
HBTU and diisopropylethylamine from Advanced Chem-
Tech; and 4-nitrophenyl chloroformate and benzylamine
from Aldrich. (S,S)-1,2-Diaminocyclohexane was resolved
film): n = 3284, 2934, 2858, 1631, 1555 cm ; H NMR
(400 MHz, CDCl ): d = 7.28 (m, 5 H), 7.08 (s, 1 H), 6.11 (s,
1 H), 5.31 (s, 1 H), 4.48 (dd, J = 14.9 Hz, J = 6.1 Hz, 1 H),
4.26 (dd, J = 14.9 Hz, J = 5.1 Hz, 1 H), 4.20 (d, J = 8.8 Hz,
3
1
2
1
2
1 H), 3.20 (m, 1 H), 2.31 (m, 1 H), 1.98 (d, J = 11.7 Hz, 1 H),
1.85 (m, 2 H), 1.68 (d, J = 11.2 Hz, 2 H), 1.16 (m, 5 H), 1.03 (s,
[
10]
by literature methods.
Aldehyde 7 was synthesized ac-
[
2]
13
1
cording to our published procedure.
9 H); C NMR { H} (400 MHz, CDCl
1
3
): d = 172.7, 159.0, 138.5,
28.5, 127.5, 127.1, 61.3, 57.0, 55.1, 43.1, 35.0, 34.7, 33.4, 27.1,
Coupling of Boc-l-tert-leucine with Benzylamine
Followed by Deprotection (2 b ® 3 b ® 4)
25.3, 25.1.
A 1000-mL, round-bottomed flask equipped with a stirbar
was charged with 5.00 g (21.6 mmol) of Boc-l-tert-leucine
Schiff Base Formation (6 ® 1 b)
A 1000-mL, round-bottomed flask equipped with a stirbar
was charged with 6.25 g of 6 and anhydrous methanol
(40 mL) was added with stirring. Once the solution became
homogeneous, sodium sulfate (10 g) was added. In a sepa-
rate flask, aldehyde 7 (4.73 g, 0.98 equiv.) was dissolved in
anhydrous methanol (40 mL), then transferred to the reac-
tion mixture. An additional 30 mL of methanol was used to
effect quantitative transfer of aldehyde 7 into the reaction
mixture. The reaction mixture was stirred for 90 minutes,
then concentrated under reduced pressure with the sodium
sulfate still present. The resulting mixture was combined
with hexanes (250 mL) and filtered through a Buchner fun-
nel, and the solids were rinsed with hexanes (250 mL). The
filtrate was concentrated under reduced pressure to yield
10.55 g of 1 b as a yellow solid (17.0 mmol, 98% yield, 80%
overall yield from 2 b) with spectral and physical properties
(
1
(
2 b). Dichloromethane (170 mL) and HBTU (8.21 g,
.0 equiv.) were added with stirring. After 2 minutes, DIPEA
7.55 ml, 2 equiv.) and benzylamine (2.37 mL, 1.0 equiv.)
were added sequentially and the reaction was stirred for
0 minutes. The mixture was combined with dichloro-
9
methane (250 mL) and water (250 mL) and the organic
layer was separated, washed three times with 1 M hydro-
chloric acid (250 mL), and dried over sodium sulfate. Sol-
vents were removed in vacuo to afford crude 3 b as a color-
less oil. The oil was dissolved in dichloromethane
(110 mL); then trifluoroacetic acid (25 mL, 15 equiv.) was
added in one portion and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was then
cooled to 0 °C and a 20% aqueous solution of sodium carbo-
nate (250 mL) was added slowly. The resulting biphasic
mixture was transferred to a separatory funnel, diluted with
chloroform (140 mL), and the organic and aqueous layers
[1,2]
identical to those reported previously.
Adv. Synth. Catal. 2001, 343, 197±200
199
Su, Julius T.
