Stereoselective synthesis of (+)-polyoxamic acid starting with a chiral aziridine

Article abstract of DOI:10.1055/s-0033-1338545

An efficient and stereoselective synthesis of (+)-polyoxamic acid was developed. The route starts with the commercially available 1-(R)-α- methylbenzylaziridine-2-methanol, a substance that has not been used previously as a starting material for the preparation of this target. The route also features the use of a stereocontrolled Sharpless asymmetric dihydroxylation reaction, promoted by AD-mix-α, which is followed by a regioselective aziridine ring-opening process, to generate the basic skeleton of target natural product. Subsequent oxidation and global deprotection produces (+)-polyoxamic acid. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338545

3276▌
PAPER
paper
Stereoselective Synthesis of (+)-Polyoxamic Acid Starting with a Chiral
Aziridine
Stereoselective Synthesis of (+)-Polyoxamic Acid
Hojong Yoon,a Taebo Sim*a,b
a
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic
of Korea
b
KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea
Fax +82(2)9585189; E-mail: tbsim@kist.re.kr
Received: 27.08.2013; Accepted after revision: 13.09.2013
use chiral substances (e.g., carbohydrates) as starting ma-
terials. One exception to this general trend is found in the
route for the preparation of 1 that utilized an enantioselec-
tive phase-transfer conjugate addition reaction followed
Abstract: An efficient and stereoselective synthesis of (+)-poly-
oxamic acid was developed. The route starts with the commercially
available 1-(R)-α-methylbenzylaziridine-2-methanol, a substance
that has not been used previously as a starting material for the prep-
aration of this target. The route also features the use of a stereocon- by an asymmetric dihydroxylation process.3 In the others,
trolled Sharpless asymmetric dihydroxylation reaction, promoted
by AD-mix-α, which is followed by a regioselective aziridine ring-
the amino group of (+)-polyoxamic acid was introduced
enantioselectively by employing either (1) a palladium-
opening process, to generate the basic skeleton of target natural
assisted allylation reaction using a chiral ligand com-
product. Subsequent oxidation and global deprotection produces
prised of 2-diphenylphosphinobenzoic acid and a chiral
(+)-polyoxamic acid.
diamine,4 (2) an asymmetric organocatalytic Mannich re-
Key words: polyhydroxylated amino acid, (+)-polyoxamic acid,
action,5 (3) a stereoselective [3,3]-sigmatropic rearrange-
natural product synthesis, chiral aziridine, asymmetric dihydroxyl-
ment of an allylic trifluoroacetimidate,6 (4)
a
ation
regioselective iodocyclization reaction of a trichloroacet-
imidate,7 or (5) a stereospecific bromohydration reaction
using a chiral auxiliary.8 In addition, Sharpless asymmet-
ric dihydroxylation reactions of E-allylic alcohol9 and vi-
nyl oxazolidine10 intermediates have been unsuccessfully
explored for stereoselective introduction of the C3/C4 and
C4/C5 diol moieties in 1.9,10
Polyoxins are a family of natural peptidyl nucleosidic an-
tibiotics isolated from Streptomyces cacoi var. aseonsis1
in 1965. Members of this family possess potent biological
activities against the chitin synthetase of Candida albi-
cans, a human fungal pathogen, and of various other phy-
topathogenic fungi. As a result, polyoxins have been
utilized as agricultural fungicides.2 (+)-Polyoxamic acid
(1), a polyhydroxy amino acid derived by mild hydrolysis
of the polyoxins, has received great attention owing to the
fact that it has a unique structural motif that is commonly
found in a variety of polyoxins (Figure 1).
We have now developed an efficient and stereoselective
route for the synthesis of (+)-polyoxamic acid, which be-
gins with a commercially available chiral aziridine that
until now has not been utilized as a starting material for
the preparation of this target. A retrosynthetic analysis
version of the new approach, illustrated in Scheme 1, sug-
gests that the target can be synthesized by oxidation of the
primary alcohol group in the protected polyhydroxyamino
alcohol 2 followed by global deprotection. Employing this
strategy, 2 would be generated through regioselective
acid-catalyzed ring opening of the dihydroxy aziridine 3,
formed stereoselectively employing Sharpless asymmet-
ric dihydroxylation of (E)-3-(aziridin-2-yl)acrylate 4. Fi-
nally, aziridinyl acrylate 4 would be produced from
commercially available 1-(R)-α-methylbenzylaziridine-2-
methanol (5) by using an oxidation-olefination sequence.
R
HO2C
O
OH
O
OH
3
O
O
HO2C
N
O
NH2
2
4
N
OH
H
N
NH2 OH
NH2 OH
OH
H
O
HO
polyoxin
R
(+)-polyoxamic acid (1)
B
D
J
CH2OH
CO2H
Me
L
H
The route for the synthesis of (+)-polyoxamic acid (1)
commences with the preparation of the (E)-3-(aziridin-2-
yl)acrylate 4. This was accomplished through Swern oxi-
dation of the alcohol moiety in 5 and subsequent Horner–
Wadsworth–Emmons olefination of the resulting alde-
hyde using triethyl phosphonoacetate. This sequence pro-
duced 5 in 72% overall yield as chromatographically
(silica gel) separable 98:2 mixture of trans- and cis-iso-
mers. It should be noted that, because it contains five dif-
ferentially functionalized carbons, 4 should serve as a
Figure 1 (+)-Polyoxamic acid (1) and polyoxins
(+)-Polyoxamic acid (1), which is comprised of five car-
bons that are all functionalized, possesses the contiguous
stereogenic centers. A number of routes for the synthesis
of this substance have been described, nearly all of which
SYNTHESIS 2013, 45, 3276–3280
Advanced online publication: 26.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338545; Art ID: SS-2013-F0593-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Synthesis of (+)-Polyoxamic Acid
3277
OBn
Ph
OH
OH
O
HO
Ph
OBn
HO2C
N
OH
NH OBn
OEt
NH2 OH
H
OH
3a
1
2
Ph
Ph
O
N
N
OEt
OH
H
H
4
5
Scheme 1 Retrosynthetic analysis toward (+)-polyoxamic acid (1)
versatile intermediate for the synthesis of various natural droxylation conditions with either the AD-mix-α or AD-
products.
mix-β reagent combinations (Table 1). In a manner that is
similar to an observation we made earlier,13 dihydroxyl-
ation of 4 promoted by osmium tetroxide in the absence of
a chiral ligand took place to form diol 3 as a near equimo-
lar mixture of diastereomers 3a and 3b. In contrast, the re-
action carried out by using AD-mix-α took place at room
temperature with a reasonable level of diastereoselectivity
(dr of 3a/3b = 4:1). Moreover, a higher level of diastere-
oselectivity (dr = 10:1) was achieved by running this reac-
tion at 0 °C for a longer time period (36 h). Thus, this
approach enables ready control of the absolute stereo-
chemistry at the three contiguous chiral centers in the ami-
no-syn-diol moiety and, as such, it could be the key
component of synthetic approaches to several polyhy-
droxylated amine alkaloid natural products.14
Several issues were considered before attempting the
asymmetric dihydroxylation reaction of (E)-3-(aziridin-2-
yl)acrylate 4. Earlier, it was shown that the diastereoselec-
tivities of dihydroxylation reactions of (E)-2-vinylaziridi-
nes, carried out using osmium tetroxide in the absence of
chiral ligands, are low and variable depending on substit-
uents present on the olefin moiety.11 In addition, it has
been reported that (E)-3-(aziridin-2-yl)acrylates, whose
amine moieties are protected by electron-withdrawing
groups, can be diastereoselectively dihydroxylated using
osmium tetroxide in the absence of chiral ligands.12 In re-
cent efforts in our laboratory, we have shown that dihy-
droxylation reaction of N-(R)-1-phenylethyl-protected
aziridin-Z-enoate using osmium tetroxide leads to nondi-
astereoselective (dr = ca. 1:1) production of a diol product Owing to severe difficulties encountered in the separation
but, in contrast, that the process proceeds with a high level of the diastereomers, a mixture of diols 3a and 3b was em-
of diastereoselectivity when the Sharpless AD-mix-β re- ployed in the next step along the route (Scheme 2). Ac-
agent combination is employed.13
cordingly, reduction using LiAlH4 and subsequent benzyl
protection of the alcohol moieties in the intermediate triol
led to generation of tribenzyloxy aziridine 6 in 74% yield
(2 steps). Separation of the stereoisomer mixture to pro-
duce the desired diastereomer 6 was accomplished at this
Based on these early observations, we explored several
methods for the dihydroxylation of (E)-3-(aziridin-2-
yl)acrylate 4, including the use of osmium tetroxide in the
absence of a chiral ligand and Sharpless asymmetric dihy-
Table 1 Dihydroxylation Reactions of (E)-3-(Aziridin-2-yl)acrylate 4
Ph
Ph
Ph
OsO4, NMO, THF–H2O
or
OH
O
OH
O
O
N
N
N
OEt
OEt
OEt
AD-mix, MeSO2NH2
t-BuOH–H2O
H
H
H
OH
OH
4
3a
3b
Reagent
3aa
3ba
Temp
Yield (%)b
Time (h)
OsO4, NMOc
AD-mix-αd
AD-mix-αd
AD-mix-βd
AD-mix-βd
1
4
1
1
r.t. or 0 °C
r.t.
87
78
73
76
69
6
24
36
24
36
10
1
1
0 °C
4
r.t.
1
10
0 °C
a Ratio of 3a/3b was determined by 1H NMR spectroscopy.
b Mixture of 3a and 3b.
c OsO4 (0.05 equiv), NMO (1.2 equiv), THF–H2O = 3: 1 (0.1 M).
d AD-mix (1000% w/w), MeSO2NH2 (1.5 equiv), t-BuOH–H2O = 1: 1 (0.1 M).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3276–3280

3278
H. Yoon, T. Sim
PAPER
1. Swern oxidation
2. (EtO)2P(O)CH2CO2Et
LHMDS, THF, r.t.
AD-mix-α
MeSO2NH2
t-BuOH–H2O, 0 °C
Ph
Ph
N
Ph
OH
O
O
N
N
OEt
OH
72% over 2 steps
OEt
73% (3a/3b = 10:1)
H
H
H
OH
5
4
3
OBn
Ph
1. LiAlH4, THF, 0 °C
2. NaH, BnBr, TBAI
THF, 0 °C
OBn
1. AcOH, CH2Cl2, r.t.
2. KOH, EtOH, r.t.
HO
Ph
OBn
N
NH OBn
OBn
76% over 2 steps
74% over 2 steps
H
OBn
6
2
O
OBn
1. Pd(OH)2, H2 (50 psi), MeOH
2. DOWEX-50WX8
OH
Jones reagent
acetone, 0 °C
HO
Ph
OBn
HO2C
OH
84%
NH OBn
52%
NH2 OH
7
(+)-polyoxamic acid (1)
Scheme 2 Synthesis of (+)-polyoxamic acid (1) starting with the chiral aziridine 5
stage by using flash column chromatography (silica gel), base form of (+)-polyoxamic acid (1) in 84% yield
thus enabling the production of this key intermediate in (Scheme 2). The identity of the synthetic material was
greater than 1 g quantities. Next, regioselective aziridine confirmed by comparing its spectroscopic properties and
23.5
23
ring-opening reaction15 of 6 was successfully carried out optical rotation ([α]D
+2.2 (c 0.17, H2O) {Lit. [α]D
using excess acetic acid in CH2Cl2. This process afforded +2.1 (c 1.0, H2O)}) to those reported earlier for the natural
the monoacetate ester, which without purification was product.22
subjected to treatment with potassium hydroxide in etha-
nol to form the corresponding alcohol 2 in a 76% yield (2
steps).
In conclusion, in the work described above, a route for the
stereoselective and facile synthesis of (+)-polyoxamic
acid (1) has been developed. The sequence involves 9
Several oxidizing agents were explored to carry out the steps, three of which do not require product purification,
transformation of the primary alcohol group in 2 to the and provides the target in a 12.9% overall yield. The strat-
corresponding carboxylic acid in 7. While PDC/DMF16 egy employed in this stereoselective synthesis of (+)-
and CrO3/2·pyridine17 promoted reaction resulted in the polyoxamic acid uniquely utilizes an enantiomerically
formation of substantial amounts of by-products, and pure chiral aziridine as the starting material. Moreover,
while significant levels of substrate decomposition and other interesting features of the approach include the use
sluggish reactivity were accompanied with respective of Sharpless asymmetric dihydroxylation and a regiose-
Dess–Martin periodinane18 and RuCl3/NaIO4 oxida- lective aziridine ring-opening process. This general strat-
19
tions, the conversion of 2 to 7 took place with modest ef- egy has the potential of being applicable to
ficiency (52%) using the Jones reagent (Scheme 2).
enantioselective syntheses of several other polyhydroxyl-
ated amine natural products.
In studies targeted at accomplishing simultaneous deprot-
ection of the O-benzyl and N-phenylethyl protecting
groups in 7, we observed that, contrary to expectations,
the removal of the N-phenylethyl group was sluggish,
even with prolonged reaction times (4 d), when catalytic
amounts of Pd/C or Pd(OH)2 were used under 1 atmo-
sphere of H2. Furthermore, inclusion of catalytic amounts
of several acids (e.g., AcOH, HCl, TFA, HCO2H) as well
as the use of catalytic hydrogen transfer employing am-
monium formate in refluxing MeOH20 failed to bring
about nitrogen deprotection.
Reactions were monitored by TLC with 0.25 mm E. Merck precoat-
ed silica gel plates (60 F254). Reaction progress was monitored by
TLC analysis using a UV lamp, ninhydrin, or p-anisaldehyde stain
for detection purpose. Purification of reaction products was carried
out by flash chromatography using Kieselgel 60 Art. 9385 (230–
400 mesh). The purity of all compounds was over 95% and was an-
alyzed using Waters LCMS system (Waters 2998 Photodiode Array
Detector, Waters 3100 Mass Detector, Waters SFO System Fluidics
Organizer, Water 2545 Binary Gradient Module, Waters Reagent
Manager, Waters 2767 Sample Manager) using SunFireTM C18 col-
umn (4.6 × 50 mm, 5 μm particle size): solvent gradient = 60% (or
95%) A at 0 min, 1% A at 5 min. Solvent A = 0.035% TFA in H2O;
Solvent B = 0.035% TFA in MeOH; flow rate : 3.0 (or 2.5) mL/min.
1H and 13C NMR spectra were obtained using a Bruker 400 MHz
However, we observed that simultaneous O-benzyl and N-
phenylethyl group deprotection can be accomplished by
using excess Pd(OH)2 under a high pressure hydrogen at-
mosphere (50 psi, 12 h).21 The product generated in this
process was subjected to ion-exchange chromatography
on Dowex-50WX8 (H+ form) using 0.6 M aqueous
1
FT-NMR (400 MHz for H, and 100 MHz for 13C) spectrometer.
1
Chemical shifts are reported relative to CHCl3 (δ = 7.26) for H
NMR and CHCl3 (δ = 77.2) for 13C NMR or D2O for 1H (δ = 4.80)
and D2O for 13C NMR. Standard abbreviations are used for denoting
NH4OH as the eluent. This procedure afforded the free the signal multiplicities. High-resolution mass spectra (HRMS)
were recorded on a QTOF mass spectrometer.
Synthesis 2013, 45, 3276–3280
© Georg Thieme Verlag Stuttgart · New York

PAPER
Stereoselective Synthesis of (+)-Polyoxamic Acid
3279
Ethyl 3-{(R)-1-[(R)-1-Phenylethyl]aziridin-2-yl}prop-2-enoate
(4)
sulting alcohol was used in the next step without further purifica-
tion. To a slurry of NaH (471 mg, 11.78 mmol, 60% dispersion in
mineral oil) in THF (12 mL) was added a solution of the resulting
alcohol in THF (12 mL) at 0 °C. After 1 h, BnBr (1.4 mL, 11.78
mmol) and TBAI (442 mg, 1.2 mmol) were added. The reaction
mixture was stirred for 12 h at r.t., diluted with EtOAc (30 mL),
quenched with H2O (10 mL) at 0 °C and extracted with EtOAc
(2 × 30 mL). The combined organic layers were washed with brine
(30 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. The resulting crude product was purified by silica gel flash
chromatography with EtOAc–hexane (1:9) to afford the title prod-
uct 6; yield: 1.29 g (2.64 mmol, 74% over 2 steps); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.25 (m, 20 H), 4.99 (d,
J = 12.0 Hz, 1 H), 4.73 (d, J = 12.4 Hz, 2 H), 4.60 (d, J = 11.6 Hz,
1 H), 4.41 (s, 2 H), 3.65 (m, 3 H), 3.17 (dd, J = 2.8, 8.4 Hz, 1 H),
2.42 (q, J = 6.4 Hz, 1 H), 1.87–1.82 (m, 1 H), 1.50 (d, J = 6.4 Hz, 3
H), 1.42 (d, J = 6.8 Hz, 1 H), 1.06 (d, J = 6.8 Hz, 1 H).
To a solution of (COCl)2 (4.1 mL, 47.73 mmol) in CH2Cl2 (100 mL)
was slowly added DMSO (7 mL, 99.43 mmol) at –78 °C. After 30
min, a solution of 5 (7.05 g, 39.77 mmol) in CH2Cl2 (80 mL)
was added. After 30 min, Et3N (22 mL, 119.3 mmol) was added at
–78 °C and the reaction mixture was stirred for 30 min at 0 °C. The
mixture was quenched with H2O (50 mL) and then extracted with
CH2Cl2 (2 × 200 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The resulting alde-
hyde was used in the next step without further purification. To a so-
lution of the aldehyde in THF (80 mL) was added triethyl
phosphonoacetate at r.t. After 10 min at r.t., LHMDS (47.7 mL, 47.7
mmol, 1 M in THF) was added. The mixture was stirred for 1 h at
r.t., then quenched with H2O (20 mL), and extracted with EtOAc
(2 × 100 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. The resulting crude product was
purified by silica gel flash column chromatography with EtOAc–
hexane (1:6) to afford the title product 4; yield: 7.02 g (28.63 mmol,
72% over 2 steps); yellow oil.
13C NMR (100 MHz, CDCl3): δ = 144.90, 139.13, 138.79, 138.50,
128.57, 128.47, 128.42, 127.87, 127.84, 127.79, 127.71, 127.22,
127.09, 81.71, 79.37, 73.63, 73.41, 73.39, 70.43, 70.40, 41.69,
30.01, 23.61.
HRMS-ESI: m/z [M + H]+ calcd for C34H38NO3: 508.2846; found:
508.2852.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.23 (m, 5 H), 6.76 (dd,
J = 7.6, 15.6 Hz, 1 H), 6.13 (d, J = 15.6 Hz, 1 H), 4.20 (q, J = 7.2
Hz, 2 H), 2.54 (q, J = 6.4 Hz, 1 H), 2.16–2.11 (m, 1 H), 1.80 (d,
J = 3.2 Hz, 1 H), 1.66 (d, J = 6.4 Hz, 1 H), 1.43 (d, J = 6.6 Hz, 3 H),
1.29 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.38, 148.63, 144.28, 128.59,
127.39, 126.95, 122.05, 70.14, 60.51, 39.83, 36.49, 23.42, 14.46.
(2R,3S,4S)-3,4,5-Tri(benzyloxy)-2-{[(R)-1-phenylethyl]ami-
no}pentan-1-ol (2)
To a solution of 6 (340 mg, 0.67 mmol) in CH2Cl2 (2 mL) was added
AcOH (0.38 mL, 6.7 mmol). The reaction mixture was stirred for 18
h at r.t., diluted with CH2Cl2 (20 mL), and quenched with sat. aq
NaHCO3 (100 mL). The aqueous layer was extracted with CH2Cl2
(2 × 200 mL) and the combined organic layers were washed with
brine (100 mL), dried (MgSO4), filtered through a pad of Celite, and
concentrated in vacuo. The resulting acetate was used in the next
step without further purification. To a solution of the acetate in
EtOH (2 mL) was added KOH (113 mg, 2.1 mmol). The reaction
mixture was stirred for 2 h at r.t., diluted with CH2Cl2 (20 mL), and
quenched with H2O (2 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic layers were washed
with brine (50 mL), dried (MgSO4), filtered through a pad of Celite,
and concentrated in vacuo. The resulting crude product was purified
by silica gel flash chromatography with EtOAc–hexane (1:3) to af-
ford the title product 2; yield: 267 mg (0.51 mmol, 76% yield over
2 steps); yellow oil.
HRMS-ESI: m/z [M + H]+ calcd for C15H20NO2: 246.1489; found:
246.1494.
Ethyl 2,3-Dihydroxy-3-{(R)-1-[(R)-1-phenylethyl]aziridin-2-
yl}propanoate (3)
To a solution of 4 (2.7g, 13.3 mmol) in t-BuOH–H2O (55 mL/55
mL) were added AD-mix-α (27 g) and MeSO2NH2 (1.57 g, 16.6
mmol) at 0 °C. The reaction mixture was stirred for 36 h, washed
with sat. aq Na2SO3 (3 × 20 mL), and then partitioned between
CH2Cl2 (300 mL) and H2O (200 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 100 mL) and the combined organic layers
were washed with brine (200 mL), dried (MgSO4), filtered through
a pad of Celite, and concentrated under reduced pressure. The resi-
due was subjected to silica gel column chromatography with EtO-
Ac–hexane (2:3 to 1:1) to afford the diol 3 (diastereomeric mixture,
3a/3b = 10:1); yield: 2.25 g (9.71 mmol, 73%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.24 (m, 20 H), 4.81 (d,
J = 11.6 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 4.69 (d, J = 12.0 Hz,
1 H), 4.58–4.53 (m, 3 H), 3.97 (q, J = 4.8 Hz, 1 H), 3.83 (q, J = 6.4
Hz, 1 H), 3.77–3.73 (m, 3 H), 3.37–3.29 (m, 2 H), 2.85 (q, J = 4.4
Hz, 1 H), 2.22 (br s, 1 H), 1.24 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 138.11, 138.02, 128.53, 128.50,
128.41, 128.38, 128.31, 128.16, 127.94, 127.77, 127.74, 127.72,
127.27, 126.80, 79.35, 78.14, 74.23. 73.44. 72.86, 69.85, 61.47,
56.95, 56.82, 23.78.
The diastereomeric mixture 3 from column chromatography was
further purified by preparative TLC (eluent: EtOAc–hexane, 1:2 to
2:3) to collect small amount of the desired diastereomer 3a.
Diastereomer 3a
1H NMR (400 MHz, CDCl3): δ = 7.36–7.23 (m, 5 H), 4.29–4.23 (m,
3 H), 3.72 (dd, J = 2.4, 6.4 Hz, 1 H), 3.55 (br s, 2 H), 2.61 (q, J = 6.4
Hz, 1 H), 2.05–2.01 (m, 1 H), 1.71 (d, J = 3.2 Hz, 1 H), 1.48 (d,
J = 6.4 Hz, 3 H), 1.40 (d, J = 6.4 Hz, 1 H), 1.29 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.92, 144.37, 128.62, 127.38,
127.00, 73.42, 72.12, 69.43, 62.16, 41.62, 30.87, 23.44, 14.42.
HRMS-ESI: m/z [M + Na]+ calcd for C15H21NO4 + Na: 302.1363;
HRMS-ESI: m/z [M + H]+ calcd for C34H40NO4: 526.2952; found:
526.2962
found: 302.1368.
(2S,3S,4S)-3,4,5-Tri(benzyloxy)-2-{[(R)-1-phenylethyl]ami-
no}pentanoic Acid (7)
(R)-1-[(R)-1-Phenylethyl]-2-[(1S,2S)-1,2,3-tri(benzyloxy)pro-
pyl]aziridine (6)
To a solution of 2 (110 mg, 0.209 mmol) in acetone (2 mL) was add-
ed Jones reagent (0.21 mL, 0.522 mmol, 2.5 M solution in H2O) at
0 °C. The reaction mixture was stirred for 4 h at 0 °C, quenched
with i-PrOH (0.1 mL), and filtered through a pad of Celite, and
washed with CH2Cl2 (20 mL). The reaction mixture was partitioned
between CH2Cl2 (50 mL) and H2O (10 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL) and combined organic layers
were washed with brine, dried (MgSO4), filtered through a pad of
Celite, and concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography with EtOAc–hexane
To a solution of 3 (1 g, 3.57 mmol) in THF (35 mL) was added
LiAlH4 (1.96 mL, 3.93 mmol, 2 M in THF) at 0 °C. The reaction
mixture was stirred for 20 min at 0 °C, diluted with THF (35 mL),
quenched with sat. Rochelle’s solution (70 mL), and stirred for an
additional 12 h at 0 °C. The mixture was filtered through a pad of
Celite and partitioned between EtOAc (300 mL) and H2O (100 mL).
The aqueous layer was extracted with i-PrOH–CHCl3 (1:4;
3 × 100 mL) and the combined organic layers were dried (MgSO4),
filtered through a pad of Celite, and concentrated in vacuo. The re-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3276–3280

3280
H. Yoon, T. Sim
PAPER
(1:2) to CH2Cl2–MeOH (20:1) to afford the title product 7; yield: 59
mg (0.11 mmol, 52%); white solid; mp 121–124 °C.
(2) (a) Naider, F.; Shenbagamurthi, P.; Steinfeld, A. S.; Smith,
H. A.; Boney, C.; Becker, J. M. Antimicrob. Agents
Chemother. 1983, 24, 787. (b) Shenbagamurthi, P.; Smith,
H. A.; Becker, J. M.; Naider, F. J. Med. Chem. 1986, 29, 802.
(3) Lee, Y. J.; Park, Y.; Kim, M. H.; Jew, S. S.; Park, H. G.
J. Org. Chem. 2011, 76, 740.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.19 (m, 18 H), 7.02–7.00
(m, 2 H) 4.70 (dd, J = 10.8, 14.4 Hz, 2 H), 4.56 (dd, J = 1.2, 5.2 Hz,
1 H), 4.50 (dd, J = 1.6, 11.2 Hz, 2 H), 4.46 (s, 2 H), 4.07 (q, J = 6.8
Hz, 1 H), 3.87 (dd, J = 4.0, 9.2 Hz, 1 H), 3.69 (dd, J = 4.4, 10.4 Hz,
1 H), 3.59 (dd, J = 4.4, 10.4 Hz, 1 H), 3.52 (d, J = 1.2 Hz, 1 H), 1.20
(d, J = 6.8 Hz, 3 H).
(4) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J.
J. Am. Chem. Soc. 1996, 118, 6520.
(5) Enders, D.; Vrettou, M. Synthesis 2006, 2155.
(6) (a) Savage, I.; Thomas, E. J. Chem. Soc., Chem. Commun.
1989, 717. (b) Savage, I.; Thomas, E. J.; Wilson, P. D.
J. Chem. Soc., Perkin Trans. 1 1999, 3291.
(7) Kim, K. S.; Lee, Y. J.; Kim, J. H.; Sung, D. K. Chem.
Commun. 2002, 1116.
(8) Raghavan, S.; Joseph, S. C. Tetrahedron Lett. 2003, 44,
6713.
(9) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1994, 35, 733.
(10) Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39, 119.
(11) Yoon, H. J.; Kim, Y. W.; Lee, B. K.; Lee, W. K.; Kim, Y.;
Ha, H. J. Chem. Commun. 2007, 79.
(12) Righi, G.; Mandic', E.; Naponiello, G. C. M.; Bovicelli, P.;
Tirotta, I. Tetrahedron 2012, 68, 2984.
(13) Lee, B. K.; Choi, H. G.; Roh, E. J.; Lee, W. K.; Sim, T.
Tetrahedron Lett. 2013, 54, 553.
(14) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265.
13C NMR (100 MHz, CDCl3): δ = 170.00, 137.37, 136.99, 129.15,
128.95, 128.70, 128.66, 128.43, 128.26, 128.23, 128.09, 128.00,
127.20, 79.36, 77.70, 75.01, 73.73, 72.75, 68.83, 60.29, 57.76,
19.82.
HRMS-ESI: m/z [M + H]+ calcd for C34H38NO5: 540.2744; found:
540.2749.
(+)-Polyoxamic Acid (1)
To a solution of 7 (59 mg, 0.109 mmol) in MeOH (10 mL) was add-
ed Pd(OH)2 (59 mg). The reaction mixture was flushed with H2 and
stirred for 12 h under a H2 atmosphere (50 psi) at r.t. The mixture
was then filtered through a pad of Celite and concentrated in vacuo.
The resulting crude solid was recrystallized from EtOH to give a
white solid, which was subjected to ion-exchange chromatography
on Dowex-50WX8 (H+ form) using 0.6 M aq NH4OH as eluent to
afford (+)-polyoxamic acid (1); yield: 15 mg (0.091 mmol, 84%);
23.5
white solid; mp 168–171 °C; [α]D
+2.2 (c 0.17, H2O) {Lit.22
[α]D23 +2.1 (c 1.0, H2O)}.
1H NMR (400 MHz, D2O): δ = 4.08 (t, J = 2.4 Hz, 1 H), 3.78–3.74
(m, 2 H), 3.57–3.48 (m, 2 H).
13C NMR (100 MHz, D2O): δ = 172.65, 73.12, 68.07, 62.43, 57.95.
HRMS: m/z [M + Na]+ calcd for C5H11NO5 + Na: 188.0529; found:
(15) Choi, S. K.; Lee, J. S.; Kim, J. H.; Lee, W. K. J. Org. Chem.
1997, 62, 743.
(16) Andres, J. M.; de Elena, N.; Pedrosa, R. Tetrahedron 2000,
56, 1523.
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(18) Barfoot, C. W.; Harvey, J. E.; Kenworthy, M. N.; Kilburn, J.
P.; Ahmed, M.; Taylor, R. J. K. Tetrahedron 2005, 61, 3403.
(19) Joo, J. E.; Pham, V. T.; Tian, Y. S.; Chung, Y. S.; Oh, C. Y.;
Lee, K. Y.; Ham, W. H. Org. Biomol. Chem. 2008, 6, 1498.
(20) Dhavale, D. D.; Saha, N. N.; Desai, V. N. J. Org. Chem.
1997, 62, 7482.
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2007, 18, 1585.
188.0535.
Acknowledgment
This research was supported by Korea Institute of Science and
Technology and a grant (NRF-2011-0028676) from the creative/
challenging research program of National Research Foundation of
Korea.
(22) Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.;
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References
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Synthesis 2013, 45, 3276–3280
© Georg Thieme Verlag Stuttgart · New York