Efficient asymmetric synthesis of 2,3-diamino-3-phenylpropanoic acid derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00090-4

An efficient, stereoselective synthesis of selectively-protected anti and syn, methyl 2-amino-3-(Boc-amino)-3-phenylpropanoate is described. Preparation of syn β-acetylamino-α-hydroxy ester was from isopropyl cinnamate via an acetamide-based Sharpless ami

Full text of DOI:10.1016/S0040-4020(01)00090-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2139±2145
Ef®cient asymmetric synthesis of 2,3-diamino-3-phenylpropanoic
acid derivatives
Sang-Hyeup Lee,a Juyoung Yoon,b,p Seung-Hwan Chunga and Yoon-Sik Leea,p
aSchool of Chemical Engineering, Seoul National University, Seoul 151-742, South Korea
bDepartment of New Materials Chemistry, Silla University, Pusan 617-736, South Korea
Received 10 October 2000; accepted 15 January 2001
AbstractÐAn ef®cient, stereoselective synthesis of selectively-protected anti and syn, methyl 2-amino-3-(Boc-amino)-3-phenylpropanoate
is described. Preparation of syn b-acetylamino-a-hydroxy ester was from isopropyl cinnamate via an acetamide-based Sharpless amino-
hydroxylation (AA), and its anti isomer was obtained via C-a epimerization of the syn isomer. For the installation of a second amino group,
two different approaches, involving substitution of the b-hydroxyl group with azide, were investigated. The ®rst was a ring-opening reaction
of trans-oxazoline-5-carboxylate with trimethylsilyl azide, which produced anti b-(acetylamino)-a-azido esters, which then transformed into
the anti isomer; whereas the cis-oxazoline-5-carboxylate was found to be unreactive under this reaction condition. The second approach used
the Mitsunobu reaction of syn and anti b-(Boc-amino)-a-hydroxy esters with hydrazoic acid, followed by catalytic hydrogenation, which
gave both anti and syn isomers, respectively. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
amino-b-lactam via acid hydrolysis.3b,11,12 In his method,
b-lactam was obtained from the chiral ketene-imine
[212] cycloaddition process, or chiral lithium ester
enolate-imine cyclocondensation.
The 2,3-diamino acid family constitutes a key structural
component in a variety of antibiotics1 and anti-fungal dipep-
tides2 as well as in other biologically active molecules.3 For
example, 2,3-diaminobutanoic acids are present in peptide
antibiotics such as aspartocin, lavendomycin, etc.,4,5 while
2,3-diamino-4-phenylbutanoic acid is an important struc-
tural element of aminodeoxybestatin.6 2,3-Diamino-3-
phenylpropanoic acid has been used as an alternative to
the side chain of taxol, in order to improve the water solu-
bility of that anticancer drug.7
Merino has reported that the diastereoselective addition of a
Grignard reagent to a-amino nitrones derived from l-serine
may afford both the syn and anti 3-substituted 2,3-diamino
acids as orthogonally protected forms.13 Recently, both
the syn and anti isomers of Boc- and benzoyl-protected
3-phenyl-2,3-diamino acid were synthesized utilizing
oxazolidinone, which was prepared from 1-phenylallyl
alcohol via a Sharpless asymmetric epoxidation.7
Recently, several synthetic routes for 3-substituted 2,3-
diamino acids, including 3-aryl-2,3-diamino acids, have
been reported.8 Harwood, reported that the cycloaddition
reaction of (5S)-phenylmorpholin-2-one with aromatic
imine, produced enantiomerically pure (2S,3R)-3-aryl-2,3-
amino acids in 36±46% yield.9 Lin described an ef®cient
method for the synthesis of (2R,3R)-2,3-diamino-3-phenyl-
propanoic acid from optically active 2-imidazoline.10
However, in both Harwood's and Lin's methods, only syn
or anti 2,3-diamino acid can be prepared, respectively.
A common route to synthesize 2,3-diamino acid, utilizes
a
starting material.14,15
b-hydroxy-a-amino acid as
However, in the cases of b-substituted b-hydroxy-
a-amino esters, the applicability of this protocol has been
hampered by b-elimination, forming dehydro amino
esters.5,8 For example, under similar Mitsunobu conditions,
the Fmoc-threonine methyl ester produced only the elimina-
tion product.5 To solve this elimination problem, the
carboxylic acid of N-protected threonine, was protected as
Boc-hydrazide,5 or masked as TBS ether, or 2,2-dimethyl-
1,3-oxazoline, after reduction to an hydroxyl group.16 Very
recently, b-hydroxy-a-amino acids, which were protected
as a cyclic ortho ester to reduce the acidity of the a-proton,
were converted to diamino acids via the Mitsunobu reaction,
without an elimination reaction.8
On the other hand, Ojima has reported that both syn
and anti 2,3-diamino acids can be synthesized from 3-
Keywords: 2,3-diamino-3-phenylpropanoic acid derivatives; isopropyl
cinnamate; catalytic hydrogenation.
p
Corresponding authors.
Tel.: 151-309-5618; fax: 151-309-5176; e-mail: jyoon@silla.ac.kr;
Tel.: 12-880-7073; fax: 12-888-1604; e-mail:yslee@snu.ac.kr
On the other hand, b-amino-a-hydroxy acid17 is probably a
better starting point for the synthesis of 2,3-diamino acid,
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00090-4

2140
S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
which eliminates the drawbacks found in the previous
syntheses. Of note, is a method reported by Han and
Janda,18 in which tert-butyl crotonate was exploited as the
starting material. A carbamate-based Sharpless asymmetric
aminohydroxylation (AA) reaction and a regioselective ring
opening of the aziridine functionality, were used for the
installation of amino groups.
a-cation in the preparation of anti a-azido species, we could
not obtain any promising results from these candidates.20
While we were probing various reaction conditions, we
found that the anti b-acetylamino-a-hydroxy ester could
be obtained in a high yield from the methanesulfonate 3,
with clean inversion at the a-carbon, when water was used
as a co-solvent. When methanesulfonate 3 was heated to
708C for 20 h in a sealed vial (5:4 acetone/water mix) in
the presence of two equivalents of sodium azide, anti acetyl-
amino alcohol 5 was obtained in a 91% yield (with overall
yield from syn amino alcohol 2 of 85%). In our case, oxa-
zoline formation, hydrolysis, and O!N acyl migration, all
occurred in the one pot under this reaction condition.21
We report here on an ef®cient stereoselective synthesis of
both the syn and anti isomers of selectively protected 2,3-
diamino-3-phenylpropanoic acids utilizing this b-amino-
a-hydroxy ester, which was prepared from isopropyl cinna-
mate via an acetamide-based Sharpless AA reaction. Mitsu-
nobu reaction conditions were applied for the installation of
the second amino group. We also show an ef®cient, and high-
yielding, synthesis of anti b-amino-a-hydroxy ester via C-a
epimerization of its syn isomer. It is known that only (2R,3S)-
or (2S,3R)-amino alcohol (syn isomers) can be obtained from
a Sharpless AA reaction, either by using hydroquinine 1,4-
phthalazinediyl diether [(DHQ)2PHAL], or by using hydro-
quinidine 1,4-phthalazinediyl diether [(DHQD)2PHAL].
In the synthesis of 2,3-diamino acid, we have recently
investigated the ring opening reactions of oxazoline-5-
carboxylate, as another candidate with an equivalent
2. Results and discussion
In our synthesis route, isopropyl cinnamate 1 was ®rst
functionalized to syn acetylamino alcohol 2, using
(DHQ)2PHAL and N-bromoacetamide following
a
published procedure (Scheme 1).17a This Sharpless AA
reaction gave 2 in high regioselectivity and enantioselectivity
(.99% ee after a single crystallization).19
Although, either syn acetylamino alcohol 2, or its methansul-
fonate 3, can be considered as the synthetic equivalent of an
Scheme 1. Synthesis of anti acetylamino alcohol 5 via an oxazoline inter-
mediate 4.
Scheme 2. Syntheses of selectively protected 2,3-diamino esters (10, 11)
through ring-opening reactions of trans-oxazoline-5-carboxylate 6.

S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
2141
tri¯ate (TMSOTf), only unreacted cis-oxazoline 4 was
recovered in the attempt to open this oxazoline ring with
trimethylsilyl azide. After sequential hydrolysis, esteri®-
cation, appropriate N-protection, and catalytic hydrogena-
tion, selectively-protected anti diamino esters (10,11) could
be obtained. As shown in Scheme 2, we could obtain only
anti isomers, and less than 2% epimers were detected. These
epimers were probably produced during heating (908C) in
acidic solution.
To obtain the syn isomer, we attempted a Mitsunobu reac-
tion of anti b-acetylamino-a-hydroxy ester 5, as an a-cation
equivalent, with hydrazoic acid. However, we could not get
the desired syn azide isomer: instead, only trans-oxazoline 6
was obtained under this reaction condition.
So, we employed a rather labile, and useful, N-protecting
group, the Boc group, instead of the acetyl group, in order to
avoid easy oxazoline ring formation under Mitsunobu
conditions. We re-investigated the synthesis of the anti
and syn diamino esters from the corresponding Boc-
protected b-amino-a-hydroxy ester (12, 13) under Mitsu-
nobu reaction conditions (Scheme 3).
The N-acetyl group was removed under relatively mild
conditions, (re¯uxed in 0.5 M methanolic HCl for 10 h
(twice)), and was then protected by a Boc group, using
Boc2O and triethylamine. In this step, concomitant trans-
esteri®cation of the isopropyl ester to the methyl ester also
occurred. Then, the standard Mitsunobu reaction afforded
the anti and syn azide compounds (9,14) with a clean inver-
sion of the con®guration at the a-carbon in 90 and 91%
yields, respectively. Finally, the catalytic hydrogenation
of the azide group gave (2S,3S)- and (2R,3S)-isomers of
methyl 2-amino-3-(Boc-amino)-3-phenylpropanoate (11, 15).
Scheme 3. Syntheses of the anti and syn isomers of selectively protected
2,3-diamino esters (11, 15).
a-cation (Scheme 2).22 Methanesulfonate 3 was success-
fully transformed to cis-oxazoline 4 with a clean inversion
of con®guration at the a-center with potassium bicarbonate
in acetone-water. On the other hand, the DBU-induced
cyclization proceeds via initial epimerization, prior to cycli-
zation. When trimethylsilyl azide was used as an azide
source in the synthesis of the 2,3-diamino acid derivative,
we found that there were huge differences in reactivity
between the trans-, and cis-oxazoline compounds (6,4).
The treatment of trans-oxazoline 6, with trimethylsilyl
azide in methanol at 70±808C, led to the anti azide 7 in
90% yield. However, even at a higher reaction temperature,
or in the presence of an additional Lewis acid, such as boron
tri¯uoride diethyl etherate (Et2O´BF3), or trimethylsilyl
The overall yields of these compounds in our synthesis were
very good (.50%) for both the (2S,3S)-isomer 11 and the
(2R,3S)-isomer 15. These compounds have a free a-amino
group, a Boc-protected b-amino group, and a methyl ester
group, which can be easily derivatized for further uses.
To con®rm the stereochemistry of our products, cis-imida-
zolidinone 16 and trans-imidazolidinone 17 were syn-
thesized from our products (11, 15), using 1,10-
carbonyldiimidazole (CDI), or triphosgene, after removing
1
the protection of the Boc group (Scheme 4). The H NMR
coupling constant between H-4 and H-5 for the cis-imida-
zolidinone 16 was 9.7 Hz, and for the trans-imidazolidinone
17 was 4.6 Hz. These results are consistent with similar
reported results,7,23 and provide supporting evidence for
the stereochemistry of our anti and syn products (11,15).
Although the above chemistry relates to the (2S,3S)- and
(2R,3S)-isomers, our chemistry can be extended in the
same manner to the remaining two enantiomers, the
(2R,3R)- and (2S,3R)-isomers, utilizing (2S,3R)-acetyl-
amino alcohol, which can be obtained from the Sharpless
AA reaction using (DHQD)2PHAL.
3. Conclusions
In conclusion, we have shown a simple and practical synthesis
Scheme 4. Syntheses of cis- and trans-imidazolidinones (16, 17).

2142
S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
route of both enantiomerically pure syn and anti isomers
of selectively-protected 2,3-diamino-3-phenylpropanoic
acid in high yields, which were derived from the readily
available starting material, isopropyl cinnamate. Also, we
have shown a convenient and high-yielding method for the
C-a epimerization of the syn b-amino-a-hydroxy ester.
Furthermore, in principle, our synthetic route can be applied
to the synthesis of other 2,3-diamino acid derivatives by
simply varying the starting ole®n.
Jˆ6.2 Hz, 1H), 5.18 (d, Jˆ2.8 Hz, 1H), 5.81 (dd, Jˆ2.8,
9.4 Hz, 1H), 6.34 (br d, Jˆ9.4 Hz, 1H), 7.20±7.50 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 21.33, 21.56, 22.94, 38.40,
53.41, 70.90, 80.78, 126.60, 128.32, 128.82, 136.91, 166.17,
169.40; HRMS (FAB) m/zˆ344.1175 (M1H)1, calcd for
C15H22N1O6S1ˆ344.1168.
4.1.3. Isopropyl (2S,3S)-3-(acetylamino)-2-hydroxy-3-
phenylpropionate (5). Compound 3 (500 mg, 1.46 mmol)
and NaN3 (190 mg, 2.91 mmol), were dissolved in an
acetone-water mixture (10 ml, 5:4). The resulting mixture
was heated to 708C for 20 h, with occasional swirling. The
reaction mixture was then allowed to cool to room tempera-
ture, and the solvent was evaporated to dryness. The residue
was treated with EtOAc (4£10 ml) and passed through a
short silica gel plug (,5 cm3). The combined ®ltrate was
concentrated under reduced pressure, and puri®cation of the
residue by ¯ash chromatography (EtOAc/hexane, 2:1)
afforded 5 (351 mg, 1.32 mmol, 91%) as a white crystalline
4. Experimental
4.1. General methods
The HN3 in CH2Cl2 solution was prepared according to a
literature procedure,24 and titrated before use. NMR spectra
were recorded using a JEOL JNM-LA 300 spectrometer at
1
300 MHz (for H NMR) and at 75 MHz (for 13C NMR).
18
solid: mp 112.5±113.58C; [a]D ˆ149.48 (cˆ1, CHCl3); IR
Chemical shifts were obtained in ppm, using TMS as an
internal standard. Mass spectra were obtained using a
JEOL JMS AX505WA spectrometer. Melting points were
determined in open capillaries, and are uncorrected. Optical
rotations were determined at the sodium D line using a
JASCO DIP 1000 polarimeter. Infrared spectra were
recorded using a JASCO FT/IR-200 spectrometer. Flash
chromatography was carried out using Merck silica gel 60
(230±400 mesh). Thin layer chromatography was carried
out using Merck 60 F254 plates with a 0.25-mm thickness.
The CHCl3, CH2Cl2, and MeOH were distilled from CaH2,
and THF was distilled from sodium-benzophenone ketyl.
(KBr) 3469, 3358, 1716, 1648, 1534 cm21 1H NMR
;
(CDCl3, 300 MHz) d 1.15 (d, Jˆ6.2 Hz, 3H), 1.22 (d,
Jˆ6.2 Hz, 3H), 2.03 (s, 3H), 3.11 (d, Jˆ6.1 Hz, 1H), 4.53
(dd, Jˆ3.5, 6.1 Hz, 1H), 4.93 (sept, Jˆ6.2 Hz, 1H), 5.41
(dd, Jˆ3.5, 8.8 Hz, 1H), 6.50 (br d, Jˆ8.8 Hz, 1H), 7.20±
7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 21.62, 21.74,
23.40, 54.84, 70.50, 72.81, 127.89, 128.28, 128.41, 136.61,
169.24, 171.31; HRMS (CI) m/zˆ266.1395 (M1H)1, calcd
for C14H20N1O4ˆ266.1392.
4.1.4. (4S,5S)-5-(Isopropoxycarbonyl)-2-methyl-4-phenyl-
2-oxazoline (4). Compound 3 (300 mg, 0.874 mmol) and
KHCO3 (175 mg, 1.75 mmol) were dissolved in a mixture
of acetone (8 ml) and water (3.2 ml). The resulting mixture
was heated to 708C for 20 h, with occasional swirling. The
reaction mixture was then allowed to cool to room tempera-
ture, and the solvent was evaporated to dryness. The residue
was treated with EtOAc (4£10 ml), and passed through a
short silica gel plug (,3 cm3). The combined ®ltrate was
concentrated under reduced pressure, and puri®cation of
the residue by ¯ash chromatography (hexane/EtOAc, 4:3)
afforded 4 (135 mg, 0.546 mmol, 62%) as a colorless oil:
4.1.1. Isopropyl (2R,3S)-3-(acetylamino)-2-hydroxy-3-
phenylpropionate (2). This compound was prepared in
81% yield, according to the reported acetamide-based
Sharpless aminohydroxylation protocol:17a mp 111±
18
1128C; [a]D ˆ128.38(cˆ1, CHCl3); IR (KBr) 3377,
3283, 1715, 1652, 1542 cm21
;
1H NMR (CDCl3,
300 MHz) d 1.29 (d, Jˆ6.2 Hz, 3H), 1.31 (d, Jˆ6.2 Hz,
3H), 2.01 (s, 3H), 3.26 (d, Jˆ3.8 Hz, 1H), 4.48 (dd,
Jˆ2.0, 3.8 Hz, 1H), 5.11 (sept, Jˆ6.2 Hz, 1H), 5.56 (dd,
Jˆ2.0, 9.2 Hz, 1H), 6.30 (br d, Jˆ9.2 Hz, 1H), 7.20±7.40
(m, 5H); 13C NMR (CDCl3, 75 MHz) d 21.48, 21.65, 23.14,
54.31, 70.79, 73.25, 126.86, 127.74, 128.58, 138.88, 169.28,
172.40; HRMS (CI) m/zˆ266.1400 (M1H)1, calcd for
C14H20N1O4ˆ266.1392.
20
[a]D ˆ252.68 (cˆ1, CHCl3); IR (CHCl3) 1746,
1681 cm21
;
1H NMR (CDCl3, 300 MHz) d 0.60 (d,
Jˆ6.4 Hz, 3H), 1.00 (d, Jˆ6.4 Hz, 3H), 2.21 (d, Jˆ
1.5 Hz, 3H), 4.52 (sept, Jˆ6.4 Hz, 1H) 5.13 (d, Jˆ
10.8 Hz, 1H), 5.48 (dd, Jˆ1.5, 10.8 Hz, 1H), 7.20±7.40
(m, 5H); 13C NMR (CDCl3, 75 MHz) d 13.83, 20.70,
21.47, 69.04, 73.13, 80.80, 127.96, 128.05, 128.12,
136.97, 165.77, 167.66; HRMS (FAB) m/zˆ248.1284
(M1H)1, calcd for C14H18N1O3ˆ248.1287.
4.1.2. Isopropyl (2R,3S)-3-(acetylamino)-2-(methane-
sulfonyloxy)-3-phenylpropionate (3). MsCl (645 mg,
5.65 mmol) in CH2Cl2 (5 ml) was added drop-wise to a
stirred solution of 2 (1 g, 3.77 mmol) and Et3N (1.05 ml,
7.54 mmol) in CH2Cl2 (25 ml) at 08C under N2. After
being stirred for 1 h at 08C, the reaction mixture was stirred
for an additional 2 h at room temperature. The reaction
mixture was then passed through a short silica gel plug
(,10 cm3), and further eluted with EtOAc (100 ml). The
combined ®ltrate was then concentrated under reduced
pressure, and the crude product was recrystallized from
EtOAc/hexane to afford 3 (1.2 g, 3.49 mmol, 93%) as a
4.1.5. (4S,5R)-5-(Isopropoxycarbonyl)-2-methyl-4-phenyl-
2-oxazoline (6). DBU (333 mg, 2.18 mmol) was added to a
stirred solution of compound 3 (500 mg, 1.46 mmol) in dry
CHCl3 (15 ml) at room temperature, and the resulting solu-
tion was heated under re¯ux for 1 h. After being cooled to
room temperature, the reaction mixture was then passed
through a short silica gel plug (,5 cm3) and further eluted
with EtOAc (50 ml). The combined ®ltrate was concen-
trated under reduced pressure, and puri®cation of the
residue by ¯ash chromatography (hexane/EtOAc, 3:1)
afforded 6 (274 mg, 1.11 mmol, 76%) as a colorless oil:
18
pale yellow solid: mp 116±1178C; [a]D ˆ15.58 (cˆ1,
1
CHCl3); IR (KBr) 3254, 1735, 1645, 1541 cm21; H NMR
(CDCl3, 300 MHz) d 1.27 (d, Jˆ6.2 Hz, 3H), 1.30 (d,
Jˆ6.2 Hz, 3H), 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (sept,

S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
2143
20
[a]D ˆ2139.38 (cˆ1, CHCl3); IR (CHCl3) 1747,
4.1.8. Methyl (2S,3S)-2-azido-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (9) (Scheme 2). Application
of procedure A to 163 mg (0.561 mmol) of 7, 196 ml of
Et3N (1.41 mmol), and 184 mg of Boc2O (0.842 mmol),
gave 129 mg of 9 (0.403 mmol, 72%) as white needles,
after ¯ash chromatography (hexane/EtOAc, 6:1) and recrys-
1679 cm21
;
1H NMR (CDCl3, 300 MHz) d 1.31 (d,
Jˆ6.2 Hz, 3H), 1.33 (d, Jˆ6.2 Hz, 3H), 2.19 (d,
Jˆ1.5 Hz, 3H), 4.67 (d, Jˆ6.8 Hz, 1H), 5.10±5.25 (m,
2H), 7.20±7.45 (m, 5H); 13C NMR (CDCl3, 75 MHz) d
13.84, 21.70, 69.58, 74.38, 83.12, 126.27, 127.86, 128.75,
141.20, 165.14, 169.69; HRMS (FAB) m/zˆ248.1283
(M1H)1, calcd for C14H18N1O3ˆ248.1287.
20
tallization (hexane): mp 93±948C; [a]D ˆ22.88 (cˆ1,
1
CHCl3); IR (KBr) 3368, 2104, 1743, 1690, 1524 cm21; H
NMR (CDCl3, 300 MHz) d 1.44 (s, 9H), 3.69 (s, 3H), 4.50
(br d,Jˆ4.1 Hz, 1H), 5.23 (br s, 1H), 5.38 (br s, 1H), 7.20±
7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 28.32, 52.66,
55.67, 65.22, 80.42, 127.23, 128.51, 128.75, 136.83, 154.78,
168.48; HRMS (FAB) m/zˆ321.1564 (M1H)1, calcd for
C15H21N4O4ˆ321.1562.
4.1.6. Isopropyl (2S,3S)-3-(acetylamino)-2-azido-3-
phenylpropionate (7). TMS-N3 (0.8 ml) was quickly
added to a solution of 6 (178 mg, 0.720 mmol) in dry
MeOH (0.8 ml) in a 6-ml vial at 08C. The vial was then
closed tightly with a te¯on disk lid, and the reaction mixture
was heated to 708C for 1 day, and then to 808C for 1.5 day,
with occasional swirling. The solvent was then removed
under reduced pressure, and the residue puri®ed by ¯ash
chromatography (hexane/EtOAc, 2:1) to afford 7 (188 mg,
4.1.9. Methyl (2S,3S)-2-amino-3-(benzoylamino)-3-
phenylpropionate (10): Procedure B. A 10% Pd/C catalyst
(20 mg) was added to a stirred solution of 8 (100 mg,
0.303 mmol) in EtOAc (12 ml). The mixture was then
hydrogenated under atmospheric H2 (balloon) at room
temperature for 30 h, and ®ltered through a short silica gel
plug (,3 cm3). After removal of the solvent under reduced
pressure, the residue was puri®ed using ¯ash chroma-
tography (hexane/EtOAc, 1:5) to afford 10 (88 mg,
0.295 mmol, 96%) as a white solid: mp 114.5±1178C;
20
0.648 mmol, 90%) as a colorless oil: [a]D ˆ13.48 (cˆ1,
CHCl3); IR (CHCl3) 3295, 2116, 1734, 1661, 1526 cm21; 1H
NMR (CDCl3, 300 MHz) d 1.06 (d, Jˆ6.2 Hz, 3H), 1.17 (d,
Jˆ6.2 Hz, 3H), 2.05 (s, 3H), 4.49 (d, Jˆ5.0 Hz, 1H), 4.95
(sept, Jˆ6.2 Hz, 1H), 5.53 (dd, Jˆ5.0, 8.4 Hz, 1H), 6.39
(br d, Jˆ8.4 Hz, 1H), 7.20±7.50 (m, 5H); 13C NMR
(CDCl3, 75 MHz) d 21.39, 21.57, 23.35, 53.76, 64.41,
70.30, 127.53, 128.50, 128.69, 136.53, 167.52, 169.41;
HRMS (FAB) m/zˆ291.1462 (M1H)1, calcd for
C14H19N4O3ˆ291.1457.
20
[a]D ˆ240.68 (cˆ1, CHCl3); IR (KBr) 3414, 3372,
3308, 1741, 1649, 1518 cm21
;
1H NMR (CDCl3,
300 MHz) d 1.75 (br s, 2H), 3.70 (s, 3H), 3.94 (d,
Jˆ4.4 Hz, 1H), 5.65 (dd, Jˆ4.4, 8.4 Hz, 1H), 7.20±7.60
(m, 8H), 7.69 (br d, Jˆ8.4 Hz, 1H), 7.80±7.95 (m, 2H);
13C NMR (CDCl3, 75 MHz) d 52.16, 54.76, 58.23,
126.85, 127.07, 128.08, 128.59, 128.62, 131.62, 134.26,
137.46, 166.35, 173.50; HRMS (FAB) m/zˆ299.1392
(M1H)1, calcd for C17H19N2O3ˆ299.1396.
4.1.7. Methyl (2S,3S)-2-azido-3-(benzoylamino)-3-phenyl-
propionate (8): Procedure A. Compound 7 (150 mg,
0.517 mmol) in a 6-ml vial, was treated with a solution of
6 N HCl/dioxane (4.5 ml, 2:1). The vial was closed tightly
with a te¯on disk lid, and the reaction mixture was then
heated to 908C for 12 h, with occasional swirling. The reac-
tion mixture was then transferred into a single-necked round
bottom ¯ask (25 ml), and the solvent was evaporated to
dryness. The resulting white solid was treated with 0.5M
HCl in MeOH (15 ml) and heated under re¯ux for 2.5 h.
After removal of the solvent under reduced pressure, the
residue was redissolved in fresh MeOH (2£15 ml) and
re-evaporated. To this residue, dry CH2Cl2 (15 ml) was
added, and it was cooled to 08C. To this suspension, Et3N
(288 ml, 2.07 mmol) in CH2Cl2 (1 ml) and then BzCl
(80 mg, 0.568 mmol) in CH2Cl2 (1 ml) was added drop-
wise. The reaction mixture was then stirred for 1 h at 08C,
and for a further hour at room temperature. The reaction
mixture was then passed through a short silica gel plug
(,3 cm3), and further eluted with EtOAc (50 ml). The
combined ®ltrate was then concentrated under reduced
pressure, and puri®cation of the residue by ¯ash chroma-
tography (hexane/EtOAc, 3:1) afforded 8 as a white solid.
This was further puri®ed by recrystallization (EtOAc/hex-
ane) yielding 8 (120 mg, 0.370 mmol, 72%) as a white crys-
4.1.10. Methyl (2S,3S)-2-amino-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (11) (Scheme 2). Application
of procedure B to 110 mg of 9 (0.343 mmol) and 22 mg of
10% Pd/C catalyst gave 98 mg of 11 (0.333 mmol, 97%) as
a white solid, after ¯ash chromatography (hexane/EtOAc,
1
1:1): mp 97±988C; H NMR (CDCl3, 300 MHz, 508C) d
1.40 (s, 9H), 1.47 (br s, 2H), 3.66 (s, 3H), 3.81 (d,
Jˆ4.6 Hz, 1H), 5.08 (br s, 1H), 5.76 (br d, Jˆ6.8 Hz, 1H),
7.20±7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 28.29,
51.96, 56.07, 58.51, 79.59, 126.70, 127.80, 128.42, 137.88,
155.01, 173.58; HRMS (FAB) m/zˆ295.1657 (M1H)1,
calcd for C15H23N2O4ˆ295.1658.
4.1.11. Methyl (2R,3S)-3-(tert-butoxycarbonylamino)-
2-hydroxy-3-phenylpropionate (12): Procedure C.
Compound 2 (420 mg, 1.58 mmol) was treated with 0.5 M
HCl in MeOH (42 ml), and heated under re¯ux for 10 h.
After removal of the solvent under reduced pressure, the
residue was again treated with 0.5 M HCl in MeOH
(42 ml) and heated under re¯ux for an additional 10 h.
After removal of the solvent under reduced pressure, the
residue was redissolved in fresh MeOH (2£30 ml) and
re-evaporated. To this residue, dry CH2Cl2 (15 ml) was
added and it was then cooled to 08C. To this suspension,
Et3N (0.53 ml, 3.80 mmol) in CH2Cl2 (2 ml) was added,
followed by Boc2O (518 mg, 2.375 mmol) in CH2Cl2
(2 ml), and the reaction mixture was stirred for 30 min at
08C and then for a day at room temperature. The reaction
20
talline solid: mp 123±1248C; [a]D ˆ211.68 (cˆ1,
1
CHCl3); IR (KBr) 3331, 2104, 1740, 1642, 1531 cm21; H
NMR (CDCl3, 300 MHz) d 3.71 (s, 3H), 4.65 (d, Jˆ4.7 Hz,
1H), 5.75 (dd, Jˆ4.7, 8.2 Hz, 1H), 7.09 (br d, Jˆ8.2 Hz,
1H), 7.28±7.60 (m, 8H), 7.75±7.90 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 52.80, 54.42, 64.61, 127.10, 127.31,
128.65, 128.71, 128.90, 131.94, 133.80, 136.51, 166.82,
168.70; HRMS (FAB) m/zˆ325.1298 (M1H)1, calcd for
C17H17N4O3ˆ325.1301.

2144
S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
mixture was then passed through a short silica gel plug
(,5 cm3), and further eluted with EtOAc (50 ml). The
combined ®ltrate was then concentrated under reduced
pressure, and the residue was recrystallized from hexane
to afford 12 (406 mg, 1.38 mmol, 87%) as a white crystal-
3.70 (d, Jˆ6.2 Hz, 1H), 4.77 (dd, Jˆ6.2, 9.2 Hz, 1H), 6.79
(br d, Jˆ9.2 Hz, 1H), 7.20±7.31 (m, 5H).
4.1.16. Methyl (2R,3S)-2-amino-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (15). Application of pro-
cedure B to 311 mg of 14 (0.971 mmol) and 33 mg of
10% Pd/C catalyst gave 276 mg of 15 (0.938 mmol, 97%)
as a white solid, after ¯ash chromatography (CHCl3/MeOH,
20
line solid: mp 128±1298C; [a]D ˆ27.38 (cˆ1, CHCl3);
1
25IR (KBr) 3508, 3380, 1734, 1690, 1517 cm21; H NMR
(CDCl3, 300 MHz) d 1.42 (s, 9H), 3.20 (d, Jˆ4.4 Hz, 1H),
3.84 (s, 3H), 4.47 (br s, 1H), 5.22 (br d, Jˆ9.3 Hz, 1H), 5.42
(br d, Jˆ9.5 Hz, 1H), 7.20±7.50 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 27.22, 52.05, 55.03, 72.50, 78.91, 125.70,
126.71, 127.59, 138.09, 154.11, 172.39; HRMS (FAB)
m/zˆ296.1499 (M1H)1, calcd for C15H22N1O5ˆ296.1498.
20
20:1): mp 74±758C; [a]D ˆ223.78 (cˆ1, CHCl3); IR
1
(KBr) 3398, 1734, 1689, 1516 cm21; H NMR (DMSO-d6,
300 MHz, 908C) d 1.35 (s, 9H), 1.87 (br s, 2H), 3.53 (s, 3H),
3.67 (d, Jˆ5.5 Hz, 1H), 4.84 (dd, Jˆ5.5, 9.2 Hz, 1H), 6.87
(br d, Jˆ9.2 Hz, 1H), 7.18±7.32 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 28.30, 52.43, 56.36, 58.54, 79.61, 126.39,
127.51, 128.62, 139.94, 155.29, 173.01; HRFABMS
m/zˆ295.1666 (M1H)1, calcd for C15H23N2O4ˆ295.1658.
4.1.12. Methyl (2S,3S)-3-(tert-butoxycarbonylamino)-2-
hydroxy-3-phenylpropionate (13). Application of pro-
cedure C to 360 mg of 5 (1.36 mmol) gave 352 mg of
13 (1.19 mmol, 88%) as a white crystalline solid, after
recrystallization (from hexane): mp 134.5±135.58C;
4.1.17. (4S,5S)-4-(Methoxycarbonyl)-5-phenyl-2-imida-
zolidinone (16). Compound 11 (160 mg, 0.544 mmol) was
treated with 10 ml of TFA±CH2Cl2 (1:1), and the resulting
solution stirred for 1 h at room temperature. After removal
of the solvent under reduced pressure, the residue was
redissolved in fresh CH2Cl2 (3£10 ml) and re-evaporated.
To this residue, dry THF (10 ml) was added, and the mixture
cooled to 08C. To this stirred solution, Et3N (0.758 ml,
5.44 mmol) in THF (1 ml) was added drop-wise, and then
1,10-carbonyldiimidazole (132 mg, 0.815 mmol) in THF
(1 ml). The reaction mixture was then stirred for 30 min at
08C, and for 2 h at room temperature. After removal of the
solvent under reduced pressure, the residue was treated with
EtOAc (3£30 ml) and passed through a short silica gel plug
(,10 cm3). The combined ®ltrate was concentrated under
reduced pressure, and the residue was recrystallized from
EtOAc to afford 16 (72 mg, 0.327 mmol, 60%), as a white
20
[a]D ˆ128.68 (cˆ1, CHCl3); IR (KBr) 3366, 1719,
1695, 1518 cm21 1H NMR (CDCl3, 300 MHz) d 1.43
;
(s, 9H), 2.85 (br s, 1H), 3.71 (s, 3H), 4.61 (br d,
Jˆ2.8 Hz, 1H), 5.11 (br dd, Jˆ3.2, 8.6 Hz, 1H), 5.60 (br
d, Jˆ8.1 Hz, 1H), 7.15±7.40 (m, 5H); 13C NMR (CDCl3,
75 MHz) d 26.85, 51.06, 55.28, 71.86, 78.47, 125.82,
126.66, 126.99, 135.41, 153.54, 170.83; HRMS (FAB)
m/zˆ296.1496 (M1H)1, calcd for C15H22N1O5ˆ296.1498.
4.1.13. Methyl (2S,3S)-2-azido-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (9) (Scheme 3): Procedure
D. Compound 12 (295 mg, 1.00 mmol) and PPh3 (315 mg,
1.20 mmol) were dissolved in dry THF (15 ml), and the
resulting mixture cooled to 08C. To this stirred mixture,
HN3 (1 M solution in CH2Cl2, 2 ml, 2.00 mmol) was
added drop-wise, followed by diethyl azodicarboxylate
(209 mg, 1.20 mmol) in THF (3 ml) via syringe. The reac-
tion mixture was then stirred for 1 h at 08C, and for a further
hour at room temperature. After removal of the solvent
under reduced pressure, the residue was puri®ed by ¯ash
chromatography (hexane/EtOAc, 4:1) to afford 9 (288 mg,
0.899 mmol, 90%) as a white solid.
20
crystalline solid: mp 203±2058C (dec.); [a]D ˆ1123.28
(cˆ1, MeOH); IR (KBr) 3409, 3255, 1707 cm21
;
1H
NMR (CD3OD, 300 MHz) d 3.15 (s, 3H), 4.64 (d,
Jˆ9.7 Hz, 1H), 5.21 (d, Jˆ9.7 Hz, 1H), 7.26±7.34 (m,
5H); 13C NMR (CD3OD, 75 MHz) d 52.02, 60.07, 61.65,
128.28, 129.30, 129.51, 138.89, 166.06, 171.83; HRMS
(FAB) m/zˆ221.0919 (M1H)1, calcd for C11H13N2O3ˆ
221.0926.
4.1.14. Methyl (2R,3S)-2-azido-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (14). Application of pro-
cedure D to 315 mg of 13 (1.07 mmol) gave 311 mg
of 14 (0.971 mmol, 91%) as a white solid after ¯ash
chromatography (hexane/EtOAc, 4:1): mp 133±1348C;
4.1.18. (4R,5S)-4-(Methoxycarbonyl)-5-phenyl-2-imida-
zolidinone (17). Compound 15 (160 mg, 0.544 mmol) was
treated with 10 ml of TFA±CH2Cl2 (1:1), and the resulting
solution stirred for 1 h at room temperature. After removal
of the solvent under reduced pressure, the residue was
redissolved in fresh CH2Cl2 (3£10 ml) and re-evaporated.
To this residue, dry CH2Cl2 (10 ml) was added, and the
mixture cooled to 08C. To this stirred solution Et3N
(0.758 ml, 5.44 mmol) in CH2Cl2 (2 ml) was added drop-
wise, and then bis(trichloromethyl) carbonate (81 mg,
0.273 mmol) in CH2Cl2 (1 ml). The reaction mixture was
then stirred for 1 h at 08C, and for a further hour at room
temperature. After removal of the solvent under reduced
pressure, the residue was treated with EtOAc (4£20 ml),
and passed through a short silica gel plug (,10 cm3). The
combined ®ltrate was concentrated under reduced pressure,
and puri®cation of the residue by ¯ash chromatography
(EtOAc/hexane, 5:1) afford 17 (65 mg, 0.295 mmol,
20
[a]D ˆ116.58 (cˆ1, CHCl3); IR (KBr) 3388, 2094,
1
1741, 1683, 1526 cm21; H NMR (CDCl3, 300 MHz) d
1.42 (s, 9H), 3.81 (s, 3H), 4.38 (br s, 1H), 5.34 (br s, 2H),
7.25±7.50 (m, 5H); 13C NMR (CDCl3, 75 MHz) d 28.19,
52.95, 55.18, 66.71, 80.21, 126.51, 128.09, 128.71, 138.27,
154.78, 168.62; HRMS (FAB) m/zˆ321.1564 (M1H)1,
calcd for C15H21N4O4ˆ321.1562.
4.1.15. Methyl (2S,3S)-2-amino-3-(tert-butoxycarbonyl-
amino)-3-phenylpropionate (11) (Scheme 3). Application
of procedure B to 233 mg of 9 (0.727 mmol) and 23 mg of
10% Pd/C catalyst gave 212 mg of 11 (0.720 mmol, 99%) as
a white solid, after ¯ash chromatography (CHCl3/MeOH,
20
20:1): mp 97±988C; [a]D ˆ126.78 (cˆ1, CHCl3); IR
1
(KBr) 3370, 1725, 1694, 1517 cm21; H NMR (DMSO-d6,
300 MHz, 908C) d 1.34 (s, 9H), 1.77 (br s, 2H), 3.59 (s, 3H),
54%) as
a
off-white solid: mp 206±2098C (dec.);
20
[a]D ˆ2101.78 (cˆ1, MeOH); IR (KBr) 3401, 3246,

S.-H. Lee et al. / Tetrahedron 57 (2001) 2139±2145
2145
1
1715, 1686 cm21; H NMR (CD3OD, 300 MHz) d 3.81
15. Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.;
Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509.
16. (a) Nakamura, Y.; Shin, C. Chem. Lett. 1992, 49.
(b) Nakamura, Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.;
Shin, C. G. Bull. Chem. Soc. Jpn 1995, 68, 1369.
(s, 3H), 4.10 (d, Jˆ4.6 Hz, 1H), 4.87 (d, Jˆ4.6 Hz, 1H),
7.28±7.40 (m, 5H); 13C NMR (CD3OD, 75 MHz) d 53.13,
60.52, 63.83, 126.99, 129.36, 129.95, 143.13, 165.00,
173.30; HRMS (FAB) m/zˆ221.0919 (M1H)1, calcd for
C11H13N2O3ˆ221.0926.
17. Sharpless has investigated a practical method to prepare
protected amino alcohols in good yields and high enanti-
omeric excess from a range of alkene types, of which a,b-
unsaturated esters or their amides are known to be one of
the best substrates. For references see (a) Bruncko, M.,
Schlingloff, G., Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1483. (b) O'Brien, P. Angew. Chem., Int.
Ed. Engl. 1999, 38, 326 and references therein.
Acknowledgements
We wish to thank Dr Jae Uk Jeong, Professor Hyunsoo Han,
and Professor Kim D. Janda for their valuable information
and helpful discussions. Financial support from the Korean
Research Foundation (2000-042-D00044), and from the
Brain Korea 21 Program, is gratefully acknowledged.
18. Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63, 2045.
19. Enantiomeric excess was determined by HPLC using
Chiralcel OD column and isopropyl alcohol/hexane (1:9) as
a mobile phase. The retention time was 37.4 min for (2R,3S)
isomer and 18.7 min for (2S,3R) isomer, repectively.
References
20. anti Azide 7 was accessible from syn acetylamino alcohol 2
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zoic acid). However, the desired product was not easily
separated from diethyl hydrazodicarboxylate by column
chromatography. When methanesulfonate 3 reacted with
sodium azide in anhydrous DMF, an unseparable mixture of
cis-oxazoline 4 and anti azide 7 (1.6±1.8:1, based on 1H
NMR) was produced.
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nearly quantitatively when cis-oxazoline 4 was heated to
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Lau, R. Synthesis 1992, 1201.
Â
6. Palomo, C.; Aizpurua, J. M.; Cabre, F.; Cuevas, C.; Munt, S.;
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10. Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X. Tetrahedron: Asymmetry
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Â
23. Herranz, R.; Vinuesa, S.; Castro-Pichel, J.; Perez, C.; Garcia-
11. (a) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
(b) Ojima, I. Acc. Chem. Res. 1995, 28, 383. (c) Ojima, I.;
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Â
Lopez, M. T. J. Chem. Soc., Perkin Trans. 1992, I, 1825.
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24. Organic Reactions, Wiley: London, 1946; Vol. III, pp. 327.
25. For compound 12, melting point and speci®c rotation are
13. Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1998, 9, 629.
24
reported as 130.5±131.58C and [a]D ˆ278 (cˆ1.2,
CHCl3); Denis, J.-N.; Greene, A. E.; Serra, A. A.; Luche,
M.-J. J. Org. Chem. 1990, 55, 1957.
14. (a) Mitsunobu, O. Synthesis 1981, 1. (b) Loibner, H.; Zbiral, E.
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