Development of a method for the preparation of α-azido-masked acyl cyanides, synthetic equivalents of N-protected-C-activated α-amino acids

Article abstract of DOI:10.1016/S0040-4020(00)00040-5

A method for the preparation of α-azido-masked acyl cyanides as synthetic equivalents of N-protected-C-activated α-amino acids was developed using carbon-carbon bond formation between aldehydes and the Masked Acyl Cyanide Reagents, followed by sulfonylati

Full text of DOI:10.1016/S0040-4020(00)00040-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1463–1468
Development of a Method for the Preparation of a-Azido-Masked
Acyl Cyanides, Synthetic Equivalents of N-Protected–C-Activated
a-Amino Acids
*
Hisao Nemoto, Rujian Ma, Touru Ibaragi, Ichiro Suzuki and Masayuki Shibuya
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan
Received 8 December 1999; accepted 11 January 2000
Abstract—A method for the preparation of a-azido-masked acyl cyanides as synthetic equivalents of N-protected–C-activated a-amino
acids was developed using carbon–carbon bond formation between aldehydes and the Masked Acyl Cyanide Reagents, followed by
sulfonylation and substitution by azide anion. This method was applied to the synthesis of d-threonine and l -allo-threonine derivatives.
᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
two problems should be solved to extend the efficiency of
our method.
To prepare peptides, an N-protected–C-activated a-amino
acid is one of the most useful synthetic intermediates.
Thus we have developed a method for the synthesis of
N-sulfonyl-a-amino-alkoxymalononitrile 3 as a synthetic
equivalent of the acyl cyanides 51 using MAC2 reagents 1
and the N-sulfonylimines 2 (PGySO2R) (Scheme 1). Since
both the carbonyl group of 3 is masked and the unmasking
steps from 3 to 5 via 4 can be carried under very mild
conditions,3 the epimerization of a-position of carbonyl
group of 5 can be theoretically inhibited. However, the
verification has not been carried out enough.4 Furthermore
aliphatic derivatives of 3 have not been prepared by using
our method since it is difficult to prepare aliphatic aldimines
2 having electron-withdrawing groups on nitrogen. These
Results and Discussion
We report a new method for the preparation of the a-azido-
MAC 9 (Scheme 2) as a synthetic equivalent of 3 and
demonstrate the synthesis of optically active threonine deri-
vatives from them without epimerization.
Prior to the examination of the one-pot reaction directly
from the aldehyde 6 to the triflates 8, step from 6 to 7 was
optimized by using 6a (a: Rˆ2-phenylethyl) since 7a is the
most stable adducts of all we examined. Some of the adducts
7 were not isolated as a stable form. From 6a and 1A,5 the
Scheme 1.
Scheme 2.
Keywords: cyanides; threonine; acyl anion; azides; amino acids and peptides.
* Corresponding author. Tel ϩ81-88-633-7284; fax: ϩ81-88-633-9549; e-mail: nem@ph2.tokushima-u.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00040-5

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H. Nemoto et al. / Tetrahedron 56 (2000) 1463–1468
Table 1. Reaction of aldehydes 6 with 1A
Entry
RCHO (6)
1A (equiv.)
Catalyst (mol%)
Time (h) for 6 to 7
Yield (%) of 8 from 6
1
2
3
4
5
6
7
8
C6H5CH2CH2CHO (6a)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
Pd(dppe)2 (5)
Py (10)
Et3N (10)
None
Py (10)
Et3N (10)
Py (10)
Et3N (10)
Py (10)
Py (10)
Et3N (10)
None
pd(dppe)2 (5)
Et3N (10)
Py (10)
5
5
5
24
5
5
5
5
5
5
87
94
79
94
90
74
88
80
55
61
35
78
20
46
49
52
0
6a
6a
6a
CH3(CH3)8CHO (6b)
6b
(CH3)2CHCH2CHO (6c)
6c
9
cyclo-C6H11CHO (6d)
10
11
12
13
14
15
16
17
18
19
6d
6d
6d
5
24
72
8
24
24
Ͼ72
Ͼ72
Ͼ72
(CH3)2CHCHO (6e)
6e
6e
6e
Py (10)
a
(CH3)3CCHO (6f)
C6H5CHyCHCHO (6g)
p-CH3C6H4CHO (6h)
a
a
0
0
a All the reaction conditions carried out in entries 1–16 were attempted.
adduct 7a was produced in excellent yields for 5 h with
various catalysts such as Pd(dppe)2,6 pyridine (Py), or
triethylamine (Et3N). It is noteworthy that the reaction
also proceeded with no catalyst7 in excellent yield although
it took 24 h to convert 6a to 7a. According to these pre-
liminary examinations, we carried out the one-pot reaction
directly from 6a to the triflate 8a by the addition of trifluoro-
methanesulfonic anhydride (Tf2O)8 and Py after 6a was
sufficiently transformed to 7a. The results are shown in
entries 1–4 of Table 1. The aldehydes without bulky sub-
stituents were also transformed to the desired triflates 8 in
excellent yields (entries 5–8). When the reaction of 6d and
1A was carried out under the similar conditions as entries 2,
5 and 7, 8d was obtained in moderate yield (entry 9).
Although 3 equiv. of 1A was used, yield of 8d was not
increased very much (entry 10). When the reaction of 6d
is prolonged with Py or Et3N, both MAC reagent 1A and the
adduct 7d were gradually decreased probably due to the
decomposition of 7d and 1A (entries 10 and 11). Finally
we found that 8d was obtained in 78% yield when the
reaction of 6d was carried out without catalyst (entry 12).
In contrast, no reaction occurred when 6e was examined
without catalyst. Therefore we carefully optimized the
reaction conditions using the catalysts, and the yield of 8e
was optimized to 52% (entries 13–16). The aldehyde 6f was
not converted to 8f under the various conditions that we
have mentioned above (entry 17). In entry 18, 8g was not
obtained although the adduct 7g was observed in the crude
reaction mixture by thin layer chromatography and 1H
NMR. Presumably the rate of the reverse reaction9
(7g!6gϩ1A) is extremely high even under the weak
basic conditions with Py. In entry 19, 8h10 was not obtained,
again probably due to similar reasons. All the obtained
triflates 8 were subsequently converted to the corresponding
azides 9 in excellent yields (Table 2).
Using 9a as a representative example, we demonstrated the
transformation of the a-azido-MAC derivatives 9 into the
corresponding amides via the in situ generated acyl cyanide
(Scheme 3). The MOM group of 9a was deprotected with
trifluoroacetic acid (TFA)–water–tetrahydrofuran (THF)
(v/v/vˆ4:1:1) for 24 h at rt. The resulting crude product
10 was transformed into the butylamide 11 with 1.2 equiv.
of butylamine in 77% overall yield based on 9a. Conversion
of the glycine methyl ester to the dipeptide derivative 12
proceeded in 53% yield from 9a.
Next we examined the epimerization at the a-position to the
carbonyl group by synthesizing BocNH-d-Thr(Bn)-
NHC4H9 (18) and BocNH-l -allo-Thr(Bn)-NHC4H9 (19)
(Scheme 4). The key substrates 14 and 15 were prepared
starting from 2S-2-benzyloxypropionaldehyde (13).11 The
aldehyde 13 was reacted with 3 equiv. of 1A in CH2Cl2
and the resulting adducts (the ratio of the diastereomers is
ϳ2:1) were converted to 14 and 15 in 48 and 24% overall
yields, respectively, based on conversion of 13, 40% of
which was recovered.
The carefully purified product 14 was transformed in 47%
yield into the corresponding butylamide 16, the stereo-
chemistry of which was determined by analysis of the
1
300 MHz H NMR of the crude product. The amide 16
Table 2. Reaction of 8 to 9
Entry
8
Yield of 9 (%)
1
2
3
4
5
8a
8b
8c
8d
8e
90
91
84
91
82
Scheme 3.

H. Nemoto et al. / Tetrahedron 56 (2000) 1463–1468
1465
Scheme 4.
was converted to 18 in 96% yield by the reduction of the
azide,12 followed by protection using tert-butyl pyrocarbo-
nate (Boc2O). The diastereomer 15 was also transformed
into 19 (via 17) in 54% overall yield under similar con-
ditions.
calcium hydride. Tetrahydrofuran (THF), benzene and
diethyl ether were distilled over sodium/benzophenone.
All the reactions were carried out under nitrogen atmos-
phere unless otherwise noted.
(^)-(1-Hydroxy-3-phenylpropyl)(methoxymethoxy)me-
thane-1,1-dicarbonitrile (7a). A mixture of 3-phenylpro-
panal (6a) (134 mg, 1 mmol), (methoxymethoxy)methane-
1,1-dicarbonitrile (H-MAC-MOM) (1A) (252 mg, 2 mmol)
and a catalyst (or no additive) in CH2Cl2 (2 mL) was stirred
for 5 h (or 24 h) at rt, and was purified by silica gel column
chromatography eluted with hexane–ethyl acetate (5:1) to
give 7a as a colorless oil (260 mg, 1 mmol, 100% yield). FT-
IR (in CHCl3): 3337, 1167, 1110, 1041, 945 cmϪ1. 1H NMR
(400 MHz): 7.48–7.28 (m, 2H), 7.28–7.17 (m, 3H), 5.06 (d,
Jˆ7.1 Hz, 1H), 5.04 (d, Jˆ7.1 Hz, 1H), 3.99 (dd, Jˆ10.0,
1.0 Hz, 1H), 3.52 (s, 3H), 3.00 (ddd, Jˆ13.7, 9.0, 4.8 Hz,
1H), 2.99 (m, 1H –OH), 2.78 (dt, Jˆ13.7, 8.1 Hz, 1H),
2.24–2.11 (m, 1H), 2.11–1.98 (m, 1H). 13C NMR
(100 MHz): 140.0, 128.7, 128.5, 126.5, 112.1, 112.0, 96.5,
75.0, 70.5, 57.5, 32.3, 31.3. HRMS Calcd for C14H16N2O3
(Mϩ): 260.1161. Found 260.1158.
Analysis of the crude products 16 and 17 by 1H NMR indi-
cated that no epimerization (14!17 or 15!16) occurred.
An authentic sample of 18 was prepared in 93% yield by
condensation of commercially available Boc-NH-l -Thr(Bn)
and butylamine using 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt).
Measurement of the [a]d20 proved that the synthetic 18
was the d-isomer (synthetic: [a]2d0ˆϪ39.22Њ. authentic
sample: [a]2d0ˆϩ37.23Њ). Compound 19 was therefore
determined to be an l -allo-threonine derivative.
Conclusions
We have developed a new alternative method for the syn-
thesis of N-protected–C-activated a-amino acids and have
demonstrated that no epimerization occurs using optically
active a-azido-MAC derivatives during the amide bond
formation. By this method, aliphatic a-amino acids can be
efficiently synthesized. Further studies using MAC reagents
are now in progress.
(^)-1-[Dicyano(methoxymethoxy)methyl]-3-phenylpro-
pyl (trifluoromethyl)-sulfonate (8a) from 6a. A mixture of
6a (46.2 mg, 0.35 mmol), 1A (90.0 mg, 0.71 mmol) and
catalyst (or no additive) in CH2Cl2 (0.8 mL) was stirred
for 2–24 h at rt, then a solution of Py (163 mg, 2.1 mmol)
in CH2Cl2 (3.5 mL) was added at 0ЊC. To the resulting
mixture was added Tf2O (292 mg, 1.04 mmol) dropwise
slowly at 0ЊC. After stirred for 30 min at 0ЊC, the reaction
mixture was concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
hexane–ethyl acetate (15:1) to give 8a as a colorless oil
(127.2 mg, 0.32 mmol, 94% yield). FT-IR (in CHCl3):
Experimental
The spectra were measured with the following equipments
and conditions unless otherwise noted. IR spectra were
measured with Perkin–Elmer 1720 Infrared Fourier Trans-
1
fer Spectrometer indicating with cmϪ1. H and 13C NMR
1
1421, 1212, 1206, 1140 cmϪ1. H NMR (400 MHz): 7.37–
spectra were measured with JEOL JMN-AL300 Spec-
trometer at 300 and 75 MHz, respectively, or with JEOL
GSX400 Spectrometer at 400 and 100 MHz, respectively,
in chloroform-d and indicated as d value. High Resolution
Mass Spectra (HRMS) were measured with JEOL JMS-
DX303. Pyridine (Py) and triethylamine (Et3N) were
distilled over potassium hydroxide. Dichloromethane
(CH2Cl2) was distilled over phosphorous pentoxide. Aceto-
nitrile and dimethylformamide (DMF) were distilled over
7.31 (m, 2H), 7.30–7.19 (m, 3H), 5.14 (d, Jˆ7.2 Hz, 1H),
5.10 (dd, Jˆ6.8, 5.5 Hz, 1H), 5.09 (d, Jˆ7.2 Hz, 1H), 3.57
(s, 3H), 3.00 (ddd, Jˆ14.2, 7.1, 7.1 Hz 1H), 2.78 (dt,
Jˆ14.2, 8.2 Hz, 1H), 2.47–2.39 (m, 2H). 13C NMR
(100 MHz): 138.0, 129.0, 128.4, 127.2, 118.4 (q, JC–F
ˆ
319.9 Hz), 110.6, 109.5, 97.0, 85.0, 67.7, 57.9, 31.8, 30.6.
HRMS Calcd for C15H15F3N2O5S1(Mϩ): 392.0654. Found
392.0653.

1466
H. Nemoto et al. / Tetrahedron 56 (2000) 1463–1468
(^)-(1-Azido-3-phenylpropyl)(methoxymethoxy)methane-
1,1-dicarbonitrile (9a) from 8a. A mixture of 8a (158 mg,
0.40 mmol) and sodium azide (60 mg, 0.92 mmol) in DMF
(2 mL) was stirred at 0ЊC for 10 min. The resulting reaction
mixture was directly charged into silica gel column chroma-
tography eluted with hexane–ethyl acetate (15:1) to give 9a
as a colorless oil (103.5 mg, 0.36 mmol, 90% yield). FT-IR
1.48–1.04 (m, 5H). 13C NMR (100 MHz): 111.8, 111.6,
96.4, 72.7, 68.9, 39.2, 31.3, 29.7, 27.2, 26.0, 25.6, 25.6.
Anal. Calcd for C12H17N5O2: C, 54.74; H, 6.51; N, 26.60.
Found C, 54.80; H, 6.60; N, 26.47.
(^)-(1-Azido-2-methylpropyl)(methoxymethoxy)methane-
1,1-dicarbonitrile (9e). FT-IR (in CHCl3): 2973, 2115,
(in CHCl3): 2109, 1250, 1168, 1113, 1045 cmϪ1. H NMR
1168, 1021 cmϪ1
;
1H NMR (400 MHz): 5.16 (d,
1
(400 MHz): 7.48–7.41 (m, 2H), 7.28–7.18 (m, 3H), 5.10 (d,
Jˆ7.2 Hz, 1H), 5.07 (d, Jˆ7.2 Hz, 1H), 3.73 (dd, Jˆ11.2,
2.4 Hz, 1H), 3.55 (s, 3H), 3.02 (ddd, Jˆ14.1, 8.3, 4.5 Hz,
1H), 2.77 (dt, Jˆ14.1, 8.3 Hz, 1H), 2.27–2.16 (m, 1H),
2.07–1.94 (m, 1H). 13C NMR (100 MHz): 139.0, 129.0,
128.5, 126.8, 111.6, 111.3, 96.7, 69.9, 66.4, 57.7, 31.7,
30.6. HRMS Calcd for C12H10N3O1(MϩϪN2ϪCH2OCH3):
212.0824. Found 212.0854. Anal. Calcd for C14H15N5O2: C,
58.94; H, 5.30; N, 24.55. Found C, 58.89; H, 5.30; N, 24.43.
Jˆ6.8 Hz, 1H), 5.10 (d, Jˆ6.8 Hz, 1H), 3.77 (d,
Jˆ4.0 Hz, 1H), 3.58 (s, 3H), 2.40–2.28 (m, 1H), 1.18 (d,
Jˆ6.8 Hz, 3H), 1.12 (d, Jˆ6.8 Hz, 3H). 13C NMR
(100 MHz): 111.8, 111.6, 96.4, 72.8, 69.1, 57.7, 29.7,
21.5, 16.7. Anal. Calcd for C9H13N5O2: C, 48.42; H, 5.87;
N, 31.37. Found C, 48.58; H, 5.96; N, 31.15.
(^)-2-Azido-N-butyl-4-phenylbutanamide (11). A solu-
tion of 9a (285 mg, 1 mmol) in TFA–THF–water (4:1:1)
(6 mL) was stirred for 24 h at rt. The reaction mixture was
concentrated in vacuo to remove the solvent. The residue
was dissolved in CH2Cl2 (2 mL), and then butylamine
(365 mg, 5 mmol) was added. The mixture was stirred for
15 min at rt, and concentrated in vacuo. The residue was
purified by silica gel column chromatography eluted with
hexane–ethyl acetate (5:1) to give 11 as a colorless oil
(200 mg, 0.77 mmol, 77% yield). FT-IR (in CHCl3): 3422,
2111, 1673 cmϪ1. 1H NMR (400 MHz): 7.33–7.27 (m. 2H),
7.25–7.17 (m, 3H), 6.34 (br, 1H, –NH), 3.95 (dd, Jˆ7.6,
4.8 Hz, 1H), 3.35–3.20 (m, 2H), 2.82–2.67 (m, 2H), 2.30–
2.18 (m, 1H), 2.17–2.06 (m, 1H), 1.56–1.44 (m, 2H), 1.40–
1.38 (m, 2H), 0.93 (t, Jˆ7.2 Hz, 3H). 13C NMR (100 MHz):
169.0, 140.3, 128.6, 128.5, 126.3, 63.8, 39.2, 33.9, 31.5,
31.5, 20.0, 13.7. EI-HRMS Calcd for C14H21N4O (Mϩϩ1):
261.1715. Found 261.1716.
General procedures for 9 from 6
A mixture of 6 (1 mmol), 1A (252 mg, 2 mmol), and a cata-
lyst (or no catalyst) in CH2Cl2 (2 mL) was stirred for 5–24 h
at rt. The resulting solution was diluted with CH2Cl2 (5 mL),
cooled to 0ЊC, and Py (6 mmol) was added. Then a solution
of Tf2O (3 mmol) in CH2Cl2 (2 mL) was slowly added drop-
wise. The reaction mixture was stirred for 30 min at 0ЊC.
The residue was briefly purified by short silica gel column
chromatography eluted with hexane–ethyl acetate (15:1) to
give 8, which was used in the next reaction without further
purification. A mixture of 9 (1 mmol) and sodium azide
(195 mg, 3 mmol) in DMF (5 mL) was stirred at 0ЊC for
10 min. The resulting reaction mixture was directly charged
into silica gel column chromatography eluted with hexane–
ethyl acetate (15:1) to give 9 as a colorless oil.
(^)-Methyl 2-(2-azido-4-phenylbutanoylamino)acetate
(12). A solution of 9a (285 mg, 1 mmol) in TFA–THF–
water (4:1:1) (6 mL) was stirred for 24 h at rt. The reaction
mixture was concentrated in vacuo to remove the solvent.
To the residue in CH2Cl2 (2 mL) were added Et3N
(505.5 mg, 5 mmol) and glycine methyl ester hydrochloride
(151 mg, 1.2 mmol). The mixture was stirred for 2 h at rt,
and concentrated in vacuo. The residue was purified by
silica gel column chromatography eluted with hexane–
ethyl acetate (4:1) to give 12 as a colorless oil (150 mg,
0.53 mmol, 53% yield). FT-IR (in CHCl3): 3417, 2113,
(^)-(Azidodecyl)(methoxymethoxy)methane-1,1-dicarbo-
nitrile (9b). FT-IR (in CHCl3): 2929, 2116, 1168, 1040,
1
937 cmϪ1; H NMR (400 MHz): 5.13 (d, Jˆ7.2 Hz, 1H),
5.10 (d, Jˆ7.2 Hz, 1H), 3.78 (dd, Jˆ10.4, 2.8 Hz, 1H),
3.58 (s, 3H), 1.94–1.83 (m, 1H), 1.78–1.60 (m, 3H),
1.53–1.20 (m, 12H), 0.89 (t, Jˆ6.8 Hz, 3H). 13C NMR
(100 MHz): 111.7, 111.4, 96.7, 70.0, 67.5, 57.6, 31.9,
29.4, 29.3, 29.2, 29.1, 29.0, 26.0, 22.7, 14.1. Anal. Calcd
for C15H25N5O2: C, 58.61; H, 8.20; N, 22.78. Found C,
58.85; H, 8.24; N, 22.61.
1749, 1685 cmϪ1 1H NMR (400 MHz): 7.32–7.19 (m,
;
5H), 6.82 (brt, Jˆ5.2 Hz, 1H), 4.06 (d, Jˆ5.2 Hz, 2H),
4.01 (dd, Jˆ7.2, 5.2 Hz, 1H), 3.78 (s, 3H), 2.85–2.70 (m,
2H), 2.32–2.09 (m, 2H). 13C NMR (100 MHz): 169.8,
169.5, 140.2, 128.6, 128.5, 126.3, 63.4, 52.5, 41.1, 33.7,
31.3; EI-HRMS Calcd for C13H17N4O3(Mϩϩ1): 277.1301.
Found 277.1299.
(^)-(1-Azido-3-methylbutyl)(methoxymethoxy)methane-
1,1-dicarbonitrile (9c). FT-IR (in CHCl3): 2964, 2120,
1
1469, 1251, 1168, 1057, 1036, 970, 928 cmϪ1; H NMR
(400 MHz): 5.13 (d, Jˆ7.2 Hz, 1H), 5.10 (d, Jˆ7.2 Hz,
1H), 3.85 (dd, Jˆ11.4, 2.4 Hz, 1H), 3.58 (s, 3H), 1.98–
1.87 (m, 1H), 1.75 (ddd, Jˆ13.8, 11.4, 3.9 Hz, 1H), 1.61
(ddd, Jˆ13.8, 10.0, 2.4 Hz, 1H), 1.04 (d, Jˆ6.4 Hz, 3H),
1.00 (d, Jˆ6.4 Hz, 3H). 13C NMR (100 MHz): 111.8, 111.4,
96.7, 70.2, 65.9, 57.6, 37.6, 25.0, 23.3, 21.0. Anal. Calcd for
C10H15N5O2: C, 50.62; H, 6.37; N, 29.52. Found C, 50.82;
H, 6.48; N, 29.43.
1S,2R-(14) and 1R,2R-[1-Azido-2-(phenylmethoxy)pro-
pyl](methoxymethoxy)methane-1,1-dicarbonitrile (15).
A mixture of 13 (62.0 mg, 0.376 mmol) and 1A (142 mg,
1.128 mmol) in CH2Cl2 (0.5 mL) was stirred for 2 h at rt.
The resulting mixture was concentrated in vacuo and the
residue was treated by silica gel short column chroma-
tography to remove the remaining 13 (25.0 mg, 0.152 mmol,
40% recovered) and 1A. The eluent was concentrated and
dissolved in CH2Cl2 (0.5 mL). To the solution was added Py
(261 mg, 3.3 mmol) at 0ЊC, then was added Tf2O (0.1 mL,
(^)-(Azidocyclohexylmethyl)(methoxymethoxy)methane-
1,1-dicarbonitrile (9d). FT-IR (in CHCl3): 2937, 2113,
1168, 1015, 928 cmϪ1 1H NMR (400 MHz): 5.15 (d,
;
Jˆ7.2 Hz, 1H), 5.10 (d, Jˆ7.2 Hz, 1H), 3.73 (d,
Jˆ4.0 Hz, 1H), 2.02–1.89 (m, 2H), 1.89–1.64 (m, 4H),

H. Nemoto et al. / Tetrahedron 56 (2000) 1463–1468
1467
dˆ1.487, 0.621 mmol), and the resulting mixture was
stirred for 10 min at 0ЊC. The mixture was directly poured
into silica gel column chromatography to give a mixture of
diastereomers (67:33, briefly 68.0 mg, 0.161 mmol, 72%
yield based on conversion of 13), which was used in the
next step without further purification.
of C6H5CH2O–), 4.09 (dq, Jˆ3.0, 6.0 Hz, 1H, CH3CH-
(OBn)–), 3.91 (d, Jˆ3.0 Hz, 1H, –CH(OBn)CHN3–), 3.27
(dt, Jˆ6.5, 6.5 Hz, –NHCH2–), 1.34 (d, Jˆ6.0 Hz, 3H,
CH3CH(OBn)–), 1.64–1.23 (m, 4H, –NHCH2(CH2)2CH3),
0.90 (t, Jˆ7.0 Hz, 3H, –NH(CH2)3CH3). 13C NMR: 167.7
(–CyO), 137.7 (C of C6H5–), 128.4 (two CH of C6H5–),
127.8 (one CH of C6H5–), 127.8 (two CH of C6H5–), 75.7
(–CH–OBn), 71.9 (C6H5–CH2O–), 68.6 (–CH–N3), 39.3
(–NHCH2–), 31.5 (–CH2–), 20.0 (–CH2–), 16.7
(CH3CH(OBn)–), 13.7 (–NH(CH2)3CH3). HRMS: m/z
calcd. for C15H22N4O2: 290.1743, Found: 290.1776.
To the crude mixture of diastereomers in DMF (5 mL) was
added sodium azide (31.4 mg, 0.483 mmol), and the
mixture was stirred for 40 min at rt. The resulting mixture
was poured into water and extracted with three portions of
ethyl acetate. The combined organic layers were washed
with brine, dried over magnesium sulfate, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography eluted with hexane–ethyl acetate (3:1) to
give 14 (34.1 mg, 0.108 mmol, 48% yield based on con-
version of 13) and 15 as colorless oils (16.8 mg,
0.053 mmol, 24% yield), respectively.
2R,3R-2-Azido-N-butyl-3-(phenylmethoxy)butanamide
(17). A solution of 15 (11.7 mg, 0.037 mmol) in TFA–
water–THF (4:1:1, 0.5 mL) was stirred for 10 h at rt. The
resulting mixture was concentrated in vacuo and the residue
was dissolved in CH2Cl2 (1 mL). To the solution, butyl-
amine (0.02 mL, dˆ0.740, 0.222 mmol) in CH2Cl2 (1 mL)
was added, and the mixture was stirred for 10 min at rt. The
resulting solution was concentrated in vacuo and the residue
was purified by silica gel column chromatography eluted
with hexane–ethyl acetate (3:1) to give 17 as a colorless
oil (6.0 mg, 0.021 mmol, 56% yield). [a]2d0 Ϫ5.76 (cˆ0.31,
14: [a]2d0Ϫ5.28 (cˆ0.11, CHCl3). IR (neat): 2925, 2360,
1
2114 cmϪ1. H NMR: 7.40–7.30 (m, 5H, C6H5–), 5.14 (d,
Jˆ7.0 Hz, 1H, one of –OCH2O–), 5.08 (d, Jˆ7.0 Hz, 1H,
one of –OCH2O–), 4.65 (d, Jˆ11.5 Hz, 1H, one of
C6H5CH2O–), 4.56 (d, Jˆ11.5 Hz, 1H, one of
C6H5CH2O–), 3.96 (d, Jˆ7.5 Hz, 1H, –CH(OBn)CHN3–),
3.77 (dq, Jˆ7.5, 6.0 Hz, 1H, CH3CH(OBn)–), 3.56 (s, 3H, –
OCH3), 1.42 (d, Jˆ6.0 Hz, 3H, CH3CH(OBn)–). 13C NMR:
136.8 (C of C6H5–), 128.6 (two CH of C6H5), 128.5 (two
CH of C6H5), 128.3 (one CH of C6H5–), 111.6 (CN), 111.3
(CN), 96.3 (–OCH2O–), 72.0 (–CH–OBn), 71.5 (C6H5–
CH2O–), 70.8 (–CH–N3), 68.0 (–C(CN)2OMOM), 57.6
(–OCH3), 16.3 (CH3CH(OBn)–). HRMS: m/z calcd for
C15H17N5O3: 315.1331, Found: 315.1365.
CHCl3): R (neat): 2933, 2360, 1658 cmϪ1 1H NMR:
.
7.40–7.25 (m, 5H, C6H5–), 6.48 (brt, Jˆ6.5 Hz, 1H,
–NH–), 6.43 (d, Jˆ12.0 Hz, one of C6H5CH2O–), 4.60
(d, Jˆ12.0 Hz, one of C6H5CH2O–), 4.34 (d, Jˆ3.0 Hz,
1H, –CH(OBn)CHN3–), 4.23 (dq, Jˆ3.0, 6.5 Hz, 1H,
CH3CH(OBn)–), 3.27 (dt, Jˆ6.5, 6.5 Hz, 2H, –NHCH2–),
1.18 (d, Jˆ6.5 Hz, 3H, CH3CH(OBn)–), 1.64–1.23 (m,
4H, –NHCH2(CH2)2CH3), 0.92 (t, Jˆ7.0 Hz, 3H,
–NH(CH2)3CH3). 13C NMR: 167.1 (–CyO), 138.1 (C of
C6H5–), 129.1 (two CH of C6H5), 127.9 (one CH of
C6H5), 127.8 (two CH of C6H5), 76.6 (–CH–OBn), 71.3
(C6H5CH2O–), 66.5 (–CH–N3), 39.3 (–NHCH2–), 31.6
(–CH2–), 20.1 (–CH2–), 14.6 (CH3CH(OBn)–), 13.8
(–NH(CH2)3CH3). HRMS: m/z calcd for C15H22N4O2:
290.1743, Found: 290.1774.
15: [a]2d0 Ϫ3.97 (cˆ0.25, CHCl3): R (neat): 2925, 2360,
1
2114 cmϪ1. H NMR: 7.40–7.30 (m, 5H, C6H5–), 5.11 (d,
Jˆ7.0 Hz, 1H, one of –OCH2O–), 5.03 (d, Jˆ7.0 Hz, 1H,
one of –OCH2O–), 4.68 (d, Jˆ10.0 Hz, 1H, one of
C6H5CH2O–), 4.53 (d, Jˆ10.0 Hz, 1H, one of C6H5CH2O–),
4.16 (dq, Jˆ3.0, 6.0 Hz, 1H, CH3CH(OBn)–), 3.74 (d,
Jˆ3.0 Hz, 1H, –CH(OBn)CHN3–), 3.54 (s, 3H, –OCH3),
1.41 (d, Jˆ6.0 Hz, 3H, CH3CH(OBn)–). 13C NMR: 136.7
(C of C6H5–), 128.5 (two CH of C6H5–), 128.2 (two CH of
C6H5–), 128.1 (one CH of C6H5–), 111.6 (CN), 111.4 (CN),
96.3 (–OCH2O–), 73.7 (–CH–OBn), 71.7 (C6H5–CH2O–),
70.7 (–CH–N3), 67.6 (–C(CN)2OMOM), 57.6 (–OCH3),
16.7 (CH3CH(OBn)–). HRMS: m/z calcd for C15H17N5O3:
315.1331, Found: 315.1365.
2S,3R-2-[(tert-Butoxy)carbonylamino]-N-butyl-3-(phenyl-
methoxy)-butanamide ((Ϫ)-18). To a solution of 16
(2.9 mg, 0.010 mmol) in THF–water (20:1, 1.05 mL) was
added triphenylphosphine (10.9 mg, 0.041 mmol) and the
mixture was stirred for 10 h at rt. The mixture was concen-
trated in vacuo and the residue was dissolved in CH2Cl2
(0.5 mL). To the solution, Boc2O (7.0 mg, 0.032 mmol)
was added. The mixture was stirred for 10 h at rt, poured
into water, extracted with ethyl acetate and washed with
brine. The extract was concentrated in vacuo and the residue
was purified by silica gel column chromatography eluted
with hexane–ethyl acetate (3:1) to give 18 as a colorless
oil (3.5 mg, 0.0096 mmol, 96% yield). [a]2d0 Ϫ39.22
(cˆ0.056, CHCl3). FT-IR (neat) 3326, 1652, 765,
2S,3R-2-Azido-N-butyl-3-(phenylmethoxy)butanamide
(16). A solution of 14 (6.6 mg, 0.021 mmol) in TFA–
water–THF (4:1:1, 1 mL) was stirred for 10 h at rt. The
resulting mixture was concentrated in vacuo and the residue
was dissolved in CH2Cl2 (1 mL). To the solution, butyl-
amine (0.02 mL, dˆ0.740, 0.222 mmol) was added, and
the mixture was stirred for 10 min at rt. The resulting solu-
tion was concentrated in vacuo and the residue was purified
by silica gel column chromatography eluted with hexane–
ethyl acetate (3:1) to give 16 as a colorless oil (3.1 mg,
0.0107 mmol, 47% yield). [a]2d0 Ϫ1.41 (cˆ0.43, CHCl3):
1
696 cmϪ1. H NMR: 7.40–7.25 (m, 5H, C6H5–), 6.48 (brt,
Jˆ6.5 Hz, 1H, –NHCH2–), 5.51 (brd, Jˆ5.5 Hz, 1H,
–NHBoc–), 4.61 (d, Jˆ11.0 Hz, 1H, one of C6H5CH2O–),
4.56 (d, Jˆ11.0 Hz, 1H, one of C6H5CH2O–), 4.24 (brd,
Jˆ5.5 Hz, 1H, –CHNHBoc–), 4.18 (dq, Jˆ3.0, 6.0 Hz,
1H, CH3CH(OBn)–), 3.26 (m, 2H, –NHCH2–), 1.52–1.20
(m, 4H, –NHCH2(CH2)2–), 1.45 (s, 9H, –C(CH3)3), 1.17 (d,
Jˆ6.0 Hz, 3H, CH3CH(OBn)–), 0.88 (t, Jˆ7.0 Hz,
–NH(CH2)2CH3). 13C NMR: 169.7 (–CˆO of the amide),
155.9 (–CyO of the carbamate), 138.2 (C of C6H5–), 128.5
1
R (neat): 3326, 1652, 735, 696 cmϪ1. H NMR: 7.40–7.25
(m, 5H, C6H5–), 6.46 (brt, Jˆ6.5 Hz, 1H, –NH–), 4.60 (d,
Jˆ11.5 Hz, one of C6H5CH2O–), 4.47 (d, Jˆ11.5 Hz, one

1468
H. Nemoto et al. / Tetrahedron 56 (2000) 1463–1468
(two CH of C6H5–), 127.9 (one CH of C6H5–), 127.9 (two
CH of C6H5–), 80.1 (–C(CH3)3), 75.0 (CH3CH(OBn)–),
Science) for the foreign student scholarship awarded to
R. Ma.
71.7
(C6H5CH2O–),
57.6
(–CHNHBoc–),
39.3
(–NHCH2–), 31.6 (–CH2–), 28.4 (–C(CH3)3), 20.1
(–CH2–), 15.6 (CH3CH(OBn)–), 13.8 (–NH(CH2)3CH3).
HRMS: m/z calcd for C20H32N2O4: 364.2362, Found:
364.2378.
References
1. (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990,
55, 4515–4516. (b) Yamamoto, Y.; Kubota, Y.; Honda, Y.; Fukui,
H.; Asao, N.; Nemoto, H. J. Am. Chem. Soc. 1994, 116, 3161–
3162. (c) Nemoto, H.; Kubota, Y.; Sasaki, N.; Yamamoto, Y.
Synlett 1993, 465–466. (d) Nemoto, H. J. Syn. Org. Chem., Jpn.
1994, 52, 1044–1052.
2. MAC is an abbreviation of –[C(CN)2O]–. ‘MAC reagent’
means ‘H–[C(CN)2O]–R’. Nemoto, H.; Ibaragi, T.; Kido, M.;
Bando, M.; Shibuya, M. Tetrahedron Lett. 1999, 40, 1319–1322.
3. Some unstable carbonyl compounds have been effectively
synthesized using the transformation from HO–C–CN to –CyO.
For example, b-hydroxycyclopentanone: (a) Stork, G.; Takahashi,
T.; Kawamoto, I.; Suzuki, T. J. Am. Chem. Soc. 1978, 100, 8272–
8273.; b,g-unsaturated ketone: (b) Takahashi, T.; Nemoto, H.;
Kanda, Y.; Tsuji, J.; Fukazawa, Y.; Okajima, T.; Fujise, Y. Tetra-
hedron 1987, 43, 5499–5520.
4. Although we have demonstrated the suppression of epimeriza-
tion, the synthesized compound is not an a-amino acid derivative.2
5. By using the MAC reagent 1B (R0ˆ1-ethoxyethyl) instead of
1A, 6a was also converted to the desired adduct in high yield.
However, the adduct cannot be used in further steps since the
corresponding sulfonates were not obtained in reproducible yields.
NMR analysis of the crude product indicated that the 1-ethoxyethyl
moiety of the adduct was lost. Thus we focused on using 1A for
further optimization.
6. We previously reported the preparation of acylated derivatives
of 7 using aldehydes 6 and 1A with Pd(dppe)2. Nemoto, H.;
Kubota, Y.; Yamamoto, Y. J. Chem. Soc., Chem. Commun.
1994, 1665–1666.
2R,3R-2-[(tert-Butoxy)carbonylamino]-N-butyl-3-(phenyl-
methoxy)butanamide ((ϩ)-19). To a solution of 17
(6.0 mg, 0.021 mmol) in THF–water (20:1, 1.05 mL) was
added triphenylphosphine (10.9 mg, 0.041 mmol) and the
mixture was stirred for 10 h at rt. The mixture was concen-
trated in vacuo and the residue was dissolved in CH2Cl2
(0.5 mL). To the solution, Boc2O (7.0 mg, 0.032 mmol)
was added. The mixture was stirred for 10 h at rt, poured
into water, extracted with ethyl acetate, washed with brine
and dried over magnesium sulfate. The extract was concen-
trated in vacuo and the residue was purified by silica gel
column chromatography eluted with hexane–ethyl acetate
(3:1) to give 18 as a colorless oil (7.3 mg, 0.020 mmol, 97%
yield). [a]2d0ϩ12.80 (cˆ0.063, CHCl3). FT-IR (neat) 3328,
1650, 667, 606 cmϪ1. 1H NMR: 7.40–7.25 (m, 5H, C6H5–),
6.10 (brt, Jˆ6.5 Hz, 1H, –NHCH2–), 5.14 (brd, Jˆ6.0 Hz,
1H, –NHBoc–), 4.59 (d, Jˆ11.5 Hz, 1H, one of
C6H5CH2O–), 4.47 (d, Jˆ11.5 Hz, 1H, one of
C6H5CH2O–), 4.18 (t, Jˆ6.0 Hz, 1H, –CHNHBoc–), 3.82
(dq, Jˆ6.0, 6.0 Hz, 1H, CH3CH(OBn)–), 3.25 (quintet,
Jˆ6.0 Hz 2H, –NHCH2–), 1.50–1.20 (m, 4H,
–NHCH2(CH2)2–), 1.45 (s, 9H, –C(CH3)3), 1.25 (d,
Jˆ6.0 Hz, 3H, CH3CH(OBn)–), 0.89 (t, Jˆ7.0 Hz,
–NH(CH2)2CH3). 13C NMR: 169.7 (CyO of the amide),
155.9 (CyO of the carbamate), 138.2 (C of C6H5–), 128.5
(two CH of C6H5–), 127.9 (one CH of C6H5–), 127.8 (two
CH of C6H5–), 80.1 (–C(CH3)3), 76.8 (CH3CH(OBn)–),
75.0
(C6H5CH2O–),
57.6
(–CHNHBoc–),
39.3
(–NHCH2–), 31.6 (–CH2–), 28.4 (–C(CH3)3), 20.1
(–CH2–), 15.5 (CH3CH(OBn)–), 13.8 (–NH(CH2)3CH3).
HRMS: m/z calcd for C20H32N2O4: 364.2362, Found:
364.2338.
7. Ionic carbon–carbon bond formation between malononitrile
and benzaldehyde has been reported without the use of any
additive. Corson, B. B.; Stoughton, R. W. J. Am. Chem. Soc.
1928, 50, 2825–2837.
8. Although sulfonylation reactions of 7a were also attempted
using p-toluenesulfonyl chloride, p-toluenesulfonic anhydride,
methanesulfonyl chloride, and methanesulfonic anhydride, Tf2O
gave the best results.
Preparation of authentic sample for (2R,3S-2-[(tert-
butoxy)carbonyl- amino]-N-butyl-3-(phenylmeth-
oxy)butanamide) ((ϩ)-18)
A mixture of 2R,3S-2-[(tert-butyloxy)carbonylamino]-3-
phenylmethoxybutanoic acid (Boc-l -Thr(OBn)) (200 mg,
0.646 mmol), butylamine (0.06 mL, 0.647 mmol), HOBt
(198 mg, 1.293 mmol), EDC (186 mg, 0.907 mmol) in
CH2Cl2 (5 mL) was stirred for 20 min at rt, poured into
water, extracted with CH2Cl2, washed with brine and
dried over magnesium sulfate. The extract was concentrated
in vacuo and the residue was purified by silica gel column
chromatography eluted with hexane–ethyl acetate (1:1) to
give (ϩ)-18 as a colorless oil (220 mg, 0.604 mmol, 93%
yield). [a]2d0 ϩ37.23 (cˆ0.059, CHCl3).
9. The fact that the reverse reaction occurs is supported by the
kinetics of the hydrolysis of benzylidenemalononitrile. Bernasconi,
C. F.; Howard, K. A.; Kanavarioti, A. J. Am. Chem. Soc. 1984, 106,
6827–6835.
10. In contrast to 7g, 7h was not observed at all by either 1H NMR
or TLC presumably because the reverse reaction is extremely fast
t
even under neutral conditions. However, when H-MAC-SiMe2 Bu
t
is used instead of 1A, migration of the SiMe2 Bu prevents the
reverse reaction. Therefore, all the aldehyde 6h was consumed
and a product was isolated after a short period. This result will
be published after further optimization.
11. Massad, S. K.; Hawkins, L. D.; Baker, D. J. J. Org. Chem.
1983, 48, 5180–5182.
Acknowledgements
12. Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763–764.
We thank the JSPS (Japan Society for the Promotion of