Synthesis of (S,S)- and (R,R)- 2-amino-3-methylaminobutanoic acid (AMBA)

Article abstract of DOI:10.1055/s-2000-6417

The synthesis and characterization of (S, S)- and (R, R)-2-amino-3-methylaminobutanoic acid starting from tert-butyl crotonate is described.

Full text of DOI:10.1055/s-2000-6417

1310
PAPER
Synthesis of (S,S)- and (R,R)- 2-Amino-3-methylaminobutanoic Acid (AMBA)
D. David Hennings, Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Fax +1(970)4915610; E-Mail: rmw@chem.colostate.edu
Received 18 January 2000; revised 31 March 2000
purpose of preparing the b-N-methylated AMBA analogs,
Abstract: The synthesis and characterization of (S, S)- and (R, R)-
it was envisioned that the asymmetric aminohydroxyla-
tion reaction used by Han and Janda would be ideal for in-
stalling the necessary chirality, giving a substrate that
could be selectively methylated at the 3-amino position.
2-amino-3-methylaminobutanoic acid starting from tert-butyl cro-
tonate is described.
Key words: (S,S)-2-amino-3-methylaminobutanoic acid, (R,R)-2-
amino-3-methylaminobutanoic acid, AMBA, Sharpless asymmetric
As shown in Scheme 1, commercially availalable tert-bu-
tyl crotonate was subjected to the Sharpless aminohydrox-
ylation conditions reported by Han and Janda5h using the
(DHQD)2PHAL ligand giving 2 in 68% yield. Protection
of the alcohol as a TBS ether was accomplished using TB-
SCl and imidazole in DMF affording 3 in 96% yield. The
CBz-carbamate in 3 was methylated using NaH and dim-
ethyl sulfate to give a 90% yield of the desired N-methyl
compound 4 as a colorless oil.
aminohydroxylation, azide displacement
2-Amino-3-methylaminobutanoic acid (AMBA) has been
found to be a component of the peptidyl backbone of a re-
cently discovered family of uridyl peptide antibiotics that
includes the mureidomycins,1 pacidomycins,2 and the
napsamycins.3 The AMBA molecule has also been used
as an aza analog of isoleucine for the purpose of produc-
ing compounds with biologically antagonistic properties4.
Although there have been several reports of syntheses of
2,3-diaminobutanoic acids,5 the preparation of the b-N-
methylated analogs has received little attention.4,6 In fact,
there is only one reported synthesis of AMBA in which
the title compounds are prepared in the syn- and anti-
forms as diastereomeric racemates.4 Since the absolute
and relative configuration of the AMBA fragment in the
uridyl peptide antibiotics have not been rigorously as-
signed, it was deemed necessary to independently prepare
the four diastereomers of AMBA with known stere-
ochemical assignment (Figure). Described herein is the
preparation and characterization of the two anti-isomers
of AMBA.
At this point, the second amino group was introduced.
Deprotection of the TBS ether using HF in acetonitrile
gave a 98% yield of alcohol 5. Conversion of 5 to the cor-
responding mesylate followed by displacement of the me-
sylate with NaN3 in DMF gave the azide 6 in 62% yield
for 2 steps. Finally, the desired AMBA product could be
generated by simultaneous hydrogenolysis of the CBz
protecting group and the azide using H2 and Pd/C fol-
lowed by acidic hydrolysis of the tert-butyl ester with
TFA. The residue was treated with a 1 N solution of HCl
in methanol and concentrated to give (2R, 3R)-1a as an
off-white solid in 82 % yield for the last 2 steps.
(DHQD)2PHAL
K2OsO2(OH)4
O
CBzHN
Me
O
TBSCl
Me
Ot-Bu
Ot-Bu
DMF, im.
96%
OH
2a
CBzNHCl
MeCN, H2O
68%
O
MeHN
Me
O
MeHN
Me
t-butylcrotonate
OH
OH
NH2
Me
NH2
(2S, 3S)-1b
Me
CBzHN
Me
O
CBzN
Me
O
NaH, THF
CBzN
Me
O
(2R, 3R)-1a
5% HF
Ot-Bu
Ot-Bu
Ot-Bu
Me2SO4
90%
O
MeCN
98%
MeHN
Me
OTBS
O
MeHN
Me
OTBS
OH
5a
OH
OH
3a
4a
NH2
Me
O
NH2
(2S, 3R)-1d
Me
NH
O
1. MsCl, Et3N
1. H2Pd-C, MeOH
CBzN
Me
(2R, 3S)-1c
Me
OH
Ot-Bu
2. NaN3, DMF
62%
2. TFA, HCl
82%
NH2
N3
6a
Figure The four stereoisomers of 2-amino-3-methylaminobutanoic
acid (AMBA)
(2R, 3R)-1a
Scheme 1
The reported preparations of 2,3-diaminobutanoic acids
typically employ the use of optically active amino acids as
starting materials. The exceptions are Davies’use of a ho-
mochiral lithium amide equivalent for Michael addition to
a,b-unsaturated esters,5e and the Han/Janda method in
which a Sharpless asymmetric aminohydroxylation7 of
tert-butyl crotonate led to the desired products. For the
The enantiomeric (2S, 3S)-anti-AMBA product 1b, could
be prepared using the same reaction sequence. Substitu-
tion of the (DHQ)2PHAL ligand for the (DHQD)2PHAL
led to the formation of alcohol 2b, the enantiomer of com-
pound 2a. The optical purity of the products 1a and 1b de-
Synthesis 2000, No. 9, 1310–1314 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (S,S)- and (R,R)-2-Amino-3-methylaminobutanoic Acid (AMBA)
1311
CBzHN
O
H
O
CBzHN
Me
O
O2N
CO2H
CBzHN
Me
O
Me
O
Ot-Bu
H
NaOH, MeOH
80%
Ot-Bu
Ot-Bu
DEAD, Ph3P, THF
96%
OH
2b
OH
7
2c
NO2
O
Bn
Me
CBzN
Me
O
MeN
Me
ref. Scheme 1
O
MeN
Me
CBzN
O
H
O
+
+
O
Me
Ot-Bu
Me
Ot-Bu
H
H
CO2t-Bu
CO2t-Bu
N3
6c (trace)
N3
6b (trace)
8
9
Scheme 2
scribed in this report are assumed to be >98:2 er based on and thus, a relatively unencumbered approach vector for
Mosher amide analysis (1H and 19F nmr) of the Mosher azide displacement exists for this stereoisomer.
amides obtained from compound 3.
Two of the four AMBA stereoisomers were prepared from
Attempts to prepare the syn-AMBA products 1c and 1d by tert-butyl crotonate using the Sharpless asymmetric ami-
inversion of stereochemistry of the a-stereogenic center of nohydroxylation reaction followed by stereospecific azi-
2 was attempted but with limited success. Mitsunobu dation. This reaction sequence should be useful for the
reaction8 of 2b with 4-nitrobenzoic acid, triphenylphos- preparation of various protected forms of AMBA for their
phine, and diethylazodicarboxylate (DEAD) led to clean incorporation into the peptide backbones of the uridyl
inversion giving p-nitrobenzoate 7 in 96% yield (Scheme peptide antibiotics and other relevant biologically active
2). Cleavage of the benzoate was accomplished using targets. Studies pertinent to the elucidation of the relative
NaOH in methanol giving an 80% yield of alcohol 2c. All and absolute stereochemistry of the mureidomycins,
attempts to process 2c by the same series of transforma- pacidamycins and napsamycins utilizing these amino acid
tions used in the conversion of 2a/b into the correspond- building blocks are under investigation in these laborato-
ing syn-series (6c/d), yielded a small amount of 6b plus a ries.
cyclic urethane (9) and only a trace of the desired syn-
azide 6c as shown in Scheme 2. The formation of a trace
of 6b from this sequence presumably arises via intramo-
lecular displacement of the azide by the neighboring
N-CBz group forming an incipient oxocarbenium ion 8 or
aziridinium ion, followed by azide displacement yielding
the product of net retention 6b.
Unless otherwise noted materials were obtained from commercially
available sources and used without further purification. Et2O and
THF were distilled from sodium benzophenone ketyl under N2.
CH2Cl2, Et3N, pyridine, MeCN, and MeOH were distilled under N2
from CaH2. DMF was dried over activated 4Å molecular sieves. All
reactions involving hydroscopic substances were conducted with
flame or oven dried glassware under an inert atmosphere (Ar) dried
by passage of atmospheric gases through a column packed with
CaSO4. Filtrations of organic extracts were conducted with a cotton
plug using gravity, and concentration of the resultant filtrate was
performed under reduced pressure (aspirator) using a rotary evapo-
rator. Chromatographic separations were performed with EM Sci-
ence TLC plates (silica gel 60, F254, 20 × 20 cm × 250 mm) or with
EM Science 230-400 mesh silica gel using positive air pressure.
Reactions and chromatographic fractions were monitored and ana-
lyzed with EM Science TLC plates. Visualization on TLC was
achieved with ultraviolet light or heating of TLC plates submerged
in a 5% solution of phosphomolybdic acid in 95% EtOH. Radial
chromatography employed a Chromatotron Model 7954 using 2 or
Attempts to improve the yield of the syn-azide 6c via this
strategy have not been successful thus far. The reluctance
of the mesylate derived from 2c to undergo intermolecular
substitution appears to be a manifestation of the steric hin-
drance imposed by the preferred conformation of the anti-
mesylate 10 (Scheme 3) that displays the mesylate and
urethane in a trans-antiperiplanar disposition thus provid-
ing an inherent tendency to form the cyclic urethane prod-
uct 9. On the other hand, the mesylate derived from 5a/b
does not provide a suitable conformation for the intramo-
lecular displacement as shown in Newman projection 11
N3
Me
H
NCBz
t-BuO2C
OMs
t-BuO2C
H
9
6c
5b
6b
Me
NCBz
Me
H
Me
H
OMs
10
N3
11
Scheme 3
Synthesis 2000, No. 9, 1310–1314 ISSN 0039-7881 © Thieme Stuttgart · New York

1312
D. D. Hennings, R. M. Williams
PAPER
4 mm silica plates as needed. Melting points were determined in
open-ended capillary tubes with a Mel-Temp apparatus and are un-
corrected. IR spectra were recorded on a Perkin-Elmer 1600 series
FTIR as thin films between NaCl plates. Optical rotations were ob-
tained on a Rudolph Research Autopol III automatic polarimeter at
a wave length of 589 nm (sodium "D" line) with a 1.0 dm cell with
a volume of 1 mL at 25 °C. Specific rotations are reported at the
specified concentration (c) given in grams per 100 mL in the speci-
fied solvent. Elemental analyses were performed by M-H-W Labo-
ratories, Phoenix, AZ, and are accurate to within ±0.4% of the
calculated values. HRMS were obtained on a Fisons VG-7070 at
University of California Riverside. NMR spectra were acquired us-
ing a Bruker AC-300 of JS-300 spectrometer.
vacuo, and the mixture partitioned between H2O and CH2Cl2. The
combined organic extracts were dried (MgSO4), filtered, concen-
trated, and purified by flash column chromatography on silica gel
(elution with 20% EtOAc in hexanes) to afford the 2° alcohol 5a
(0.1827 g, 98%) as a pale oil; [a]D +8.1 (c = 0.7, CH2Cl2).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.13 (d, J = 7.3 Hz, 3
H), 1.40 (s, 9 H), 2.82 (s, 3 H), 3.98 (d, J = 6.6 Hz, 1 H), 4.36 (qn,
J = 6.9 Hz, 1 H), 5.05 (1/2Abq, J = 12.5 Hz, 1 H), 5.10 (1/2Abq,
J = 12.8 Hz, 1 H), 7.35 (m, 5 H).
13C NMR (75 MHz, DMSO-d6, 80 °C): d = 13.7, 27.2, 29.3, 52.8,
65.7, 72.8, 80.1, 126.9, 127.2, 127.8, 136.7, 155.2, 171.0.
IR (neat): n = 3448, 1728, 1697, 1157 cm-1.
HRMS (FAB): m/z Calcd for C17H26NO5 [MH+]: 324.1811, found
324.1809.
(2S,3R)-tert-Butyl 2-tert-Butyldimethylsilyloxy-3-(N-benzyloxy-
carbonyl)aminobutanoate (3a)
A solution of 2a (0.557 g, 1.8 mmol) in DMF (4.5 mL) was treated
with imidazole (0.3530 g, 5.18 mmol) followed by TBSCl (0.566 g,
3.8 mmol). The mixture was stirred at 25 °C under argon for 20 h.
The mixture was directly purified by flash column chromatography
on silica gel (elution with 20% EtOAc in hexanes) to afford the
TBS-ether 3a (0.73 g, 96%) as a colorless oil; [a]D -14.6 (c = 0.8,
CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3 H), 0.10 (s, 3 H), 0.92
(s, 9 H), 1.20 (d, J = 7.0 Hz, 3 H), 1.42 (s, 9 H), 4.05 (d, J = 2.2 Hz,
1 H), 4.17 (m, 1 H), 5.06 (s, 2 H), 5.15 (d, J = 9.2 Hz, 1 H, D2O ex-
changeable), 7.34 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = -5.6, -4.7, 18.4, 25.7, 27.9, 50.1,
66.5, 74.7, 81.6, 127.9, 128.0, 128.4, 136.5, 155.4, 170.6.
IR (neat): n = 3442, 3350, 1727, 1503 cm-1.
HRMS (FAB): m/z Calcd for C22H38NO5Si [MH+]: 424.2519, found
(1S,2R)-2(N-Benzyloxycarbonyl-N-methyl)amino-1-(tert-but-
oxycarbonyl)propyl-1-methanesulfonate
A solution of 5a (30 mg, 0.09 mmol) in CH2Cl2 (1 mL) was cooled
to 0 °C, treated with Et3N (28 mL, 0.2 mmol) followed by MsCl
(16 mL, 0.2 mmol). The reaction temperature was allowed to warm
to 25 °C stirred under argon for 1.5 h. The mixture was concentrated
and directly purified by flash column chromatography on silica gel
(elution with 33% EtOAc in hexanes) to afford the desired mesylate
(37.9 mg, quant.) as colorless oil.
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.23 (d, J = 7.0 Hz,
3 H), 1.41 (s, 9 H), 2.82 (s, 3 H), 3.16 (s, 3 H), 4.68 (qn, J = 7.0 Hz,
1 H), 4.97 (d, J = 5.9 Hz, 1 H), 5.07 (1/2Abq, J = 12.5 Hz, 1 H), 5.11
(1/2Abq, J = 12.5 Hz, 1 H), 7.31-7.37 (m, 5 H).
IR (neat): n = 1743, 1700, 1363, 1325, 1161 cm-1.
HRMS (FAB): m/z Calcd for C18H28NO7S [MH+]: 402.1586, found
424.2514.
402.1598.
(2S,3R)-tert-Butyl 2-tert-Butyldimethylsilyloxy-3-(N-benzyloxy-
carbonyl-N-methyl)aminobutanoate (4a)
(2R,3R)-tert-Butyl 2-Azido-3-(N-benzyloxycarbonyl-N-methyl)-
aminobutanoate (6a)
A suspension of NaH (0.26 g of a 60% suspension in oil, 6.5 mmol)
in THF (100 mL) was treated with a THF solution (15 mL) of 3a
(0.56 g, 1.3 mmol). The mixture was allowed to stir until evolution
of H2 ceased. The mixture was then treated with dimethyl sulfate
(1.30 mL, 13.7 mmol) and stirred under argon for 48 h. The mixture
was concentrated in vacuo and the resulting residue was partitioned
between EtOAc and brine. The combined organic extracts were
dried (MgSO4), filtered, concentrated, and purified by flash column
chromatography on silica gel (elution with 9% EtOAc in hexanes)
to afford the N-methylcarbamate 4a (0.5190 g, 90%) as a colorless
oil; [a]D -14.4 (c = 1.0, CH2Cl2).
A solution of (1S,2R)-2-(N-benzyloxycarbonyl-N-methyl)amino-1-
(tert-butoxycarbonyl)propyl-1-methanesulfonate
(41 mg,
0.1 mmol) in DMF (0.65 mL) was treated with a NaN3 (12mg,
0.18 mmol) and stirred at 65 °C for 14 h. The mixture was allowed
to cool to r.t. and directly purified by flash column chromatography
on silica gel (elution with 33% EtOAc in hexanes) to afford the de-
sired azide 6a (21.9 mg, 62%) as a pale oil; [a]D +4.5 (c = 0.8,
CDCl3).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.21 (d, J = 7.0 Hz,
3 H), 1.41 (s, 9 H), 2.82 (s, 3 H), 4.14 (d, J = 8.1 Hz, 1 H), 4.40 (m,
1 H), 5.09 (s, 2 H), 7.37 (m, 5 H).
13C NMR (75 MHz, DMSO-d6, 80 °C): d = 13.7, 27.1, 29.2, 51.8,
64.1, 66.1, 82.1, 127.0, 127.4, 127.9, 136.3, 154.7, 167.1.
IR (neat): n = 2108, 1735, 1702, 1158 cm-1.
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 0.03 (s, 3 H), 0.04 (s,
3 H), 0.89 (s, 9 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.39 (s, 9 H), 2.83 (s,
3 H), 4.17 (d, J = 5.5 Hz, 1 H), 4.43 (m, 1 H), 5.03 (1/2Abq, J = 12.8
Hz, 1 H), 5.07 (1/2Abq, J = 12.8 Hz, 1 H), 7.35 (m, 5 H).
HRMS (FAB): m/z Calcd for C17H25N4O4 [MH+]: 349.1876, found
349.1878.
13C NMR (75 MHz, DMSO-d6, 80 °C): d = -6.0, -5.6, 13.5, 17.2,
25.0, 27.1, 29.4, 53.1, 65.8, 74.7, 80.4, 127.0, 127.2, 127.8, 136.6,
155.0, 169.9.
IR (neat): n = 2933, 1744, 1703, 1460 cm-1.
HRMS (FAB): m/z Calcd for C23H40NO5Si [MH+]: 438.2676, found
(2R,3R)-2-Amino-3-methylaminobutanoic Acid Di-HCl Salt
(1a)
To a solution of 6a (68.0 mg, 0.2 mmol) in MeOH (5.0 mL) was
added 10% Pd/C (67 mg). The mixture was stirred under H2 at 25 °C
for 3 h at which time the starting material had been consumed, as
shown by TLC. The mixture was filtered through Celite and con-
centrated to give a pale yellow solid. This solid was dissolved in
CH2Cl2 (5.0 mL), cooled to 0 °C, and treated with TFA (0.5 mL).
The mixture was stirred under argon at 0 °C for 1 h followed by stir-
ring at 25 °C for 1 h. The mixture was then concentrated to give a
yellow oil which was dissolved in MeOH and treated with a 1 N so-
lution of HCl in MeOH. The solution was concentrated to give the
438.2677.
(2S,3R)-tert-Butyl 2-Hydroxy-3-(N-benzyloxycarbonyl-N-me-
thyl)aminobutanoate (5a)
A solution of 4a (0.254 g, 0.58 mmol) in MeCN (14 mL) was cooled
to 0 °C and treated with a 5% solution of HF in MeCN (6.0 mL). Af-
ter stirring at 0 °C for 30 min the mixture was allowed to warm to
25 °C and stirred for 1 h. The mixture was quenched with aq sat.
NaHCO3 solution, stirred for 10 min, the MeCN was removed in
Synthesis 2000, No. 9, 1310–1314 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (S,S)- and (R,R)-2-Amino-3-methylaminobutanoic Acid (AMBA)
1313
desired di-HCl salt 1a (32.5 mg, 82%) as a crystalline solid;
[a]D -11.7 (c = 0.2, 6 N HCl).
1H NMR (300 MHz, D2O): d = 1.47 (d, J = 7.0 Hz, 3 H), 2.83 (s,
3 H), 3.85 (m, 1 H), 4.24 (d, J = 6.6 Hz, 1 H).
13C NMR (75 MHz, D2O): d = 12.7, 31.4, 54.3, 55.0, 169.8.
Electrospray mass spectrum: m/z Calcd for C5H13N2O2 [MH+]:
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.13 (d, J = 7.0 Hz,
3 H), 1.40 (s, 9 H), 2.82 (s, 3 H), 3.97 (d, J = 6.2 Hz, 1 H), 4.36 (qn,
J = 6.6 Hz, 1 H), 5.05 (1/2Abq, J = 12.8 Hz, 1 H), 5.10 (1/2Abq,
J = 12.8 Hz, 1 H), 7.30-7.37 (m, 5 H).
13C NMR (75 MHz, DMSO-d6, 80 °C): d = 13.6, 27.2, 29.2, 52.8,
65.7, 72.8, 80.1, 126.9, 127.2, 127.8, 136.7, 155.2, 171.0.
IR (neat): n = 3445, 1728, 1698, 1161 cm-1.
HRMS (FAB): m/z Calcd for C17H26NO5 [MH+]: 324.1811, found
133.09, found: 133.1.
324.1802.
(2R,3S)-tert-Butyl 2-tert-Butyldimethylsilyloxy-3-(N-benzylox-
ycarbonyl)aminobutanoate (3b)
A solution of 2b (0.52 g, 1.7 mmol) in DMF (4.0 mL) was treated
with imidazole (0.389 g, 5.7 mmol) followed by TBSCl (0.575 g,
3.8 mmol). The mixture was stirred at 25 °C under argon for 20 h.
The mixture was directly purified by flash column chromatography
on silica gel (elution with 20% EtOAc in hexanes) to afford the
TBS-ether 3b (0.6910 g, 97%) as a colorless oil; [a]D +10.5 (c = 1.2,
CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3 H), 0.10 (s, 3 H), 0.92
(s, 9 H), 1.20 (d, J = 6.6 Hz, 3 H), 1.42 (s, 9 H), 4.05 (d, J = 2.2 Hz,
1 H), 4.17 (m, 1 H), 5.06 (s, 2 H), 5.15 (d, J = 9.5 Hz, 1 H, D2O ex-
changeable), 7.34 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = -5.5, -4.7, 18.4, 25.8, 27.9, 50.1,
66.6, 74.7, 81.6, 128.0, 128.1, 128.4, 136.5, 155.5, 170.7.
IR (neat): n = 3441, 3355, 1726, 1503 cm-1.
HRMS (FAB) m/z Calcd for C22H38NO5Si [MH+]: 424.2519, found
(1R,2S)-2(N-Benzyloxycarbonyl-N-methyl)amino-1-(tert-bu-
toxycarbonyl)propyl-1-methanesulfonate
A solution of 5b (0.576 g, 1.8 mmol) in CH2Cl2 (20 mL) was cooled
to 0 °C, treated with Et3N (0.9 mL, 6.45 mmol) followed by MsCl
(0.47 mL, 6.07 mmol). The reaction temperature was allowed to
warm to 25 °C and the mixture stirred under argon for 2.5 h. The
mixture was concentrated and directly purified by flash column
chromatography on silica gel (elution with 33% EtOAc in hexanes)
to afford the desired mesylate (0.6533 g, 91%) as a colorless oil;
[a]D +8.0 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.23 (d, J = 7.0 Hz,
3 H), 1.41 (s, 9 H), 2.82 (s, 3 H), 3.16 (s, 3 H), 4.68 (m, 1 H), 4.97
(d, J = 5.9 Hz, 1 H), 5.07 (1/2Abq, J = 12.5 Hz, 1 H), 5.11 (1/2Abq,
J = 12.5 Hz, 1 H), 7.31-7.37 (m, 5 H).
IR (neat): n = 1744, 1702, 1367, 1325, 1161 cm-1.
HRMS (FAB): m/z Calcd for C18H28NO7S [MH+]: 402.1586, found
424.2516.
402.1580.
(2R,3S)-tert-Butyl 2-tert-Butyldimethylsilyloxy-3-(N-benzyloxy-
carbonyl-N-methyl)aminobutanoate (4b)
(2S,3S)-tert-Butyl 2-Azido-3-(N-benzyloxycarbonyl-N-meth-
yl)aminobutanoate (6b)
A solution of (1R,2S)-2(N-benzyloxycarbonyl-N-methyl)amino-1-
A suspension of NaH (0.45 g of a 60% suspension in oil,
11.2 mmol) in THF (190 mL) was treated with a THF solution (20
mL) of 3b (0.95 g, 2.23 mmol). The mixture was allowed to stir un-
til evolution of H2 had ceased. The mixture was then treated with
dimethyl sulfate (2.10 mL, 22.2 mmol) and stirred under argon for
44 h. The mixture was then concentrated in vacuo and the resulting
residue was partitioned between EtOAc and brine. The organic ex-
tracts were dried (MgSO4), filtered, concentrated, and purified by
flash column chromatography on silica gel (elution with 9% EtOAc
in hexanes) to afford the N-methylcarbamate 4b (0.88 g, 90%) as a
colorless oil; [a]D +14.3 (c = 0.5, CH2Cl2).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 0.03 (s, 3 H), 0.04 (s,
3 H), 0.88 (s, 9 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.39 (s, 9 H), 2.83 (s,
3 H), 4.17 (d, J = 5.9 Hz, 1 H), 4.43 (m, 1 H), 5.03 (1/2Abq, J = 12.4
Hz, 1 H), 5.07 (1/2Abq, J = 12.4 Hz, 1 H), 7.33-7.36 (m, 5 H).
13C NMR (75 MHz, DMSO-d6, 80 °C): d = -6.0, -5.6, 13.5, 17.2,
25.0, 27.1, 29.4, 53.1, 65.8, 74.7, 80.4, 126.9, 127.2, 127.8, 136.6,
155.0, 169.9.
(tert-butoxycarbonyl)propyl-1-methanesulfonate
(0.65 g,
1.6 mmol) in DMF (7.5 mL) was treated with a NaN3 (0.229 g,
3.5 mmol) and stirred at 75 °C for 19 h. The reaction mixture was
allowed to cool to r.t. and directly purified by flash column chroma-
tography on silica gel (elution with 20% EtOAc in hexanes) to
afford the desired azide 6b (0.3233 g, 57%) as a pale oil; [a]D -6.1
(c = 0.1, CH2Cl2).
1H NMR (300 MHz, DMSO-d6, 80 °C): d = 1.21 (d, J = 7.0 Hz, 3
H), 1.41 (s, 9 H), 2.82 (s, 3 H), 4.14 (d, J = 8.1 Hz, 1 H), 4.40 (m, 1
H), 5.09 (s, 2 H), 7.34-7.37 (m, 5 H).
13C NMR (75 MHz, DMSO-d6, 80 °C): d = 13.7, 27.1, 29.2, 51.8,
64.1, 66.1, 82.1, 127.0, 127.4, 127.9, 136.3, 154.7, 167.1.
IR (neat): n = 2108, 1734, 1700, 1155 cm-1.
HRMS (FAB): m/z Calcd for C17H25N4O4 [MH+]: 349.1876, found
349.1875.
IR (neat): n = 2954, 1747, 1702, 1458 cm-1.
HRMS (FAB): m/z Calcd for C23H40NO5Si [MH+]: 438.2676, found
(2S,3S)-2-Amino-3-methylaminobutanoic Acid Di-HCl Salt
(1b)
To a solution of (2S,3S)-tert-butyl 2-azido-3-(N-benzyloxycarbon-
yl-N-methyl)aminobutanoate (0.121 g, 0.35 mmol) in MeOH (8.0
mL) was added 10% Pd/C (90 mg). The mixture was stirred under
H2 at 25 °C for 3 h at which time starting material was consumed as
detected by TLC. The mixture was filtered through Celite and con-
centrated to give a pale yellow solid. This solid was dissolved in
CH2Cl2 (8.0 mL), cooled to 0 °C, treated with TFA (0.8 mL), and
stirred at 0 °C for 1 h followed by stirring at 25 °C for another 1 h.
The mixture was concentrated to give a yellow oil which was dis-
solved in MeOH and treated with a 1 N soution of HCl in MeOH.
The solution was concentrated to give 54.8 mg (77%) of the desired
di-HCl salt 1b as a crystalline solid; [a]D +12.1 (c = 0.7, 1 N HCl).
438.2677.
(2R,3S)-tert-Butyl 2-Hydroxy-3-(N-benzyloxycarbonyl-N-me-
thyl)aminobutanoate (5b)
A solution of 4b (0.88 g, 2.0 mmol) in MeCN (50 mL) was cooled
to 0 °C and treated with a 5% solution of HF in MeCN (18 mL). Af-
ter stirring at 0 °C for 30 min, the mixture was allowed to warm to
25 °C and stirred for 1h. The mixture was then quenched with aq
sat. NaHCO3 solution, stirred for 10 min, the MeCN was removed
in vacuo, and the mixture partitioned between water and CH2Cl2.
The combined organic extracts were dried (MgSO4), filtered, con-
centrated, and purified by flash column chromatography on silica
gel (elution with 20% EtOAc in hexanes) to afford the 2° alcohol 5b
(0.5760 g, 89%) as a pale oil; [a]D -8.0 (c = 0.5, CH2Cl2).
1H NMR (300 MHz, D2O): d = 1.47 (d, J = 7.0 Hz, 3 H), 2.83 (s, 3
H), 3.85 (m, 1 H), 4.24 (d, J = 7.3 Hz, 1 H).
Synthesis 2000, No. 9, 1310–1314 ISSN 0039-7881 © Thieme Stuttgart · New York

1314
D. D. Hennings, R. M. Williams
PAPER
(b) Isono, F.; Inukai, M.; Takahashi, S.; Haneishi, T. J.
Antibiot. 1989, 42, 667.
(c) Isono, F.; Katayama, T.; Inukai, M.; Haneishi, T. J.
Antibiot. 1989, 42, 674.
13C NMR (75 MHz, D2O): d = 12.7, 31.3, 54.4, 55.1, 170.5.
Electrospray mass spectrum: m/z Calcd for C5H13N2O2 [MH+]:
133.09, found 133.1.
(d)Sakaida, Y.; Takahashi, S.; Kinoshita, T.; Nakamura, T.;
Inukai, M., J. Antibiot. 1993, 46, 1203.
(e) Isono, F.; Inukai, M. Antimicrob. Agents. Chemother.
1991, 35, 234.
(f) Inukai, M.; Isono, F.; Takatsuki, A. Antimicrob. Agents
Chemother. 1993, 37, 980.
(g) Brandish, P. E.; Burnham, M. K.; Lonsdale, J. T.;
Southgate, R.; Inukai, M.; Bugg, T. D. H. J. Biol. Chem. 1996,
271, 7609.
(2S,3S)-tert-Butyl 2-p-Nitrobenzyloxy-3-(N-benzyloxycarbon-
yl)aminobutanoate (7)
To a cold solution (0 °C, ice water bath) of 2b (0.578 g, 1.87 mmol),
Ph3P (1.869 g, 7.25 mmol), and p-nitrobenzoic acid (1.21 g,
7.13 mmol) in THF (20 mL) was added diethylazodicarboxylate
(1.20 mL, 7.62 mmol) via a syringe. The mixture was allowed to
warm to r.t. and stirred under argon for another 16 h. The mixture
was concentrated under reduced pressure and directly purified by
flash column chromatography on silica gel (elution with 20%
EtOAc in hexanes) to afford 0.8207 g (96%) of 7 as a pale yellow
foam; [a]D -30.5 (c = 3.4, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 1.32 (d, J = 7.0 Hz, 3 H), 1.49 (s,
9 H), 4.47 (m, 1 H), 4.99 (d, J = 8.8 Hz, 1 H, D2O exchangeable),
5.10 (s, 2 H), 5.33 (d, J = 3.7 Hz, 1 H), 7.33 (s, 5 H), 8.20 (d, J = 9.1
Hz, 2 H), 8.27 (d, J = 8.8 Hz, 2 H).
(2) (a) Karwowski, J. P.; Jackson, M.; Theriault, R. J.; Chen, R.
H.; Barlow, G. J.; Maus, M. L., J. Antibiot. 1989, 42, 506-511.
(b) Chen, R. H.; Buko, A. M.; Whittern, D. N.; McAlpine, J.
B., J.Antibiot. 1989, 42, 512-520.
Fernandes, P. B.; Swanson, R. N. Hardy, D. J.; Hanson, C. W.;
Coen, L.; Rasmussen, R. R.; Chen, R. H., J. Antibiot. 1989, 42,
521-526.
(3) Chaterjee, S.; Nadkarni, S. R.; Vijayakumar, E. K. S.; Patel,
M. V.; Ganguli, B. N.; Fehlhaber, H.-W.; Vertesy, L., J.
Antibiot. 1994, 47, 595-598.
(4) Paul, P.; Lutz, T. M.; Osborn, C.; Kyosseva, S.; Elbein, A. D.;
Towbin, H.; Radominska, A.; Drake, R. R. J. Biol. Chem.
1993, 268, 12933.
13C NMR (75 MHz, CDCl3): d = 15.9, 28.0, 47.4, 67.0, 75.6, 83.4,
123.5, 128.1, 128.2, 128.5, 130.9, 134.6, 136.0, 150.6, 155.2, 163.8,
166.1.
IR (neat): n = 3332, 1732 cm-1.
HRMS (FAB): m/z Calcd for C23H27N2O8 [MH+]: 459.1767, found
(3) Ohrui, H.; Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1971,
45, 4267.
459.1769.
(4) McCord, T. J.; Foyt, D. C.; Kirkpatrick, J. L.; Davis, A.L., J.
Med. Chem. 1967, 10, 353.
(5) (a) Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, R.
Synthesis 1992, 1201.
(2S,3S)-tert-Butyl 2-Hydroxy-3-(N-benzyloxycarbonyl)amino-
butanoate (2c)
To a solution of 7 (1.30 g, 2.83 mmol) in MeOH (25 mL) was added
a mixture of NaOH (0.90 g, 22.5 mmol) in MeOH (50 mL). The
mixture was stirred at r.t. for 45 min. The reaction was quenched
with H2O (50 mL) and the MeOH removed under reduced pressure.
The resulting mixture was extracted with EtOAc (4 × 75 mL) and
the combined organic extracts were dried (MgSO4). The solution
was filtered, concentrated under reduced pressure, and purified by
flash column chromatography on silica gel (elution with 20%
EtOAc in hexanes) to afford 0.70 g (80%) of 2c as a colorless oil;
[a]D +11.2 (c = 0.8, CH2Cl2).
1H NMR (300 MHz, DMSO-d6, 353 K): d = 1.04 (d, J = 7.0 Hz,
3 H), 1.42 (s, 9 H), 3.78-3.90 (m, 1 H), 3.94 (m, 1 H), 5.03 (s, 2 H),
5.05 (d, J = 5.1 Hz, D2O exchangeable, 1 H), 6.68 (br s, 1 H), 7.36
(m, 5 H).
(b) Nakamura, Y.; Shin, C. Chem. Lett. 1992, 49.
(c) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.;
Shin, C. Bull. Chem. Soc. Jpn. 1995, 1369.
(d) Palomo, C.; Aizpurua, J.M.; Cabre, F.; Cuevas, C.; Munt,
S.; Odriozola, J. M. Tetrahedron Lett. 1994, 35, 2725.
(e) Burke, A. J.; Davies, S. G.; Hedgecock, C. J. R. Synlett
1996, 621.
(f) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Tetrahedron Lett. 1997, 38, 1813.
(g) Kuwano, R.; Okuda, S.; Ito, Y. Tetrahedron: Asymmetry
1998, 9, 2773.
(h) Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63,
2045.
13C NMR (75 MHz, DMSO-d6, 353K): d = 14.8, 27.3, 48.9, 64.9,
72.8, 80.0, 127.1, 127.2, 127.8, 136.8, 154.8, 171.1.
IR (neat): n = 3380, 1720 cm-1.
HRMS (FAB): m/z Calcd for C16H24NO5 [MH+]: 310.1654, found
(6) (a) Lebedeva, Z. I.; Baratova, L. A.; Avaeva, S. M.;
Medvedeva, I. V.; Mirzayanova, M. N.; Khorlin, A. Ya
Bioorg. Khim. 1975, 1, 923; Chem. Abstr. 1976, 84, 105986.
(b) Mirzayanova, M. N.; Medvedeva, I. V.; Fedulova, I. E.;
Egorov, Ts. A.; Khorlin, A. Ya. Izv. Akad. Nauk SSSR, Ser.
Khim. 1976, 1603; Chem. Abstr. 1976, 85, 123293.
(7) (a) Gunther, S.; Sharpless, K. B. In Asymmetric Oxidation
Reactions: A Practical Approach: Katsuki, T., Ed.; Oxford
University Press: London, 1998.
310.1642.
Acknowledgement
(b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2813.
(8) Mitsunobu, O. Synthesis 1981, 1.
This work was supported by the National Science Foundation (CHE
9320010). Mass spectra were obtained on instruments supported by
the National Institutes of Health Shared Instrumentation Grant
GM49631.
Article Identifier:
1437-210X,E;2000,0,09,1310,1314,ftx,en;M03900SS.pdf
References
(1) (a) Inukai, M.; Isono, F.; Takahashi, S.; Enokita, R.; Sakaida,
Y.; Haneishi, T. J. Antibiot. 1989, 42, 662.
Synthesis 2000, No. 9, 1310–1314 ISSN 0039-7881 © Thieme Stuttgart · New York