An asymmetric approach to 5-O-carbamoyl-2-epi-polyoxamic acid and the total synthesis of 2′′-epi-polyoxin J

Article abstract of DOI:10.1016/j.tetasy.2009.03.033

A stereospecific synthetic approach to 5-O-carbamoyl-2-epi-polyoxamic acid has been developed. The asymmetric nucleophilic addition of 2-lithiofuran to a tert-butanesulfinyl imine was employed as the key step to construct the C-2 stereocenter and 2′′-epi-

Full text of DOI:10.1016/j.tetasy.2009.03.033

Tetrahedron: Asymmetry 20 (2009) 1174–1180
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An asymmetric approach to 5-O-carbamoyl-2-epi-polyoxamic acid
and the total synthesis of 200-epi-polyoxin J
*
Yong-Chun Luo, Huan-Huan Zhang, Yao-Zong Liu, Rui-Ling Cheng, Peng-Fei Xu
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereospecific synthetic approach to 5-O-carbamoyl-2-epi-polyoxamic acid has been developed. The
asymmetric nucleophilic addition of 2-lithiofuran to a tert-butanesulfinyl imine was employed as the
key step to construct the C-2 stereocenter and 200-epi-polyoxin J has been synthesized for the first time.
Significantly, the synthesis provides a facile method for the large scale and stereoselective preparation of
5-O-carbamoyl-2-epi-polyoxamic acid and some related diastereoisomers of polyoxins and its analogues
because of its simple operation, excellent yield, and high stereoselectivity. This will be convenient for
research of the polyoxins’ structure–activity relationship and to search for more potent and effective anti-
candidal agents.
Received 3 March 2009
Accepted 10 March 2009
Available online 6 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
OH
1. Introduction
O
O
4
2
H2N
O
OH
1
5
3
The polyoxins are an important group of nucleoside peptide
antibiotics which have been isolated from the fermentation broth
of Streptomyces cacaoi var. asoensis and are characterized by Isono
et al.1 Quite interestingly, their structure showed the presence of
OH
NH2
5-O-carbamoyl polyoxamic acid
R
unique 1-(50-amino-50-deoxy-b-
D-allofuranuronosyl)pyrimidines
4
6'
6
O
OH
COOH
5'
5
2
O
O
that constitute the common skeleton of all the members of polyoxin
families. For example, polyoxin J and polyoxin L (Fig. 1) comprised
of 5-O-carbamoyl polyoxamic acid and two different nucleoside
amino acids, respectively. The unique difference between them is
the substituent on the pyrimidine bases.
N
1
NH
3
4''
2''
4'
O
1'
2'
H2N
O
N
H
1''
5''
3''
O
3'
OH
NH2
OH OH
Polyoxin J R=CH3
Polyoxin L R=H
Polyoxins are known as antifungal agents that selectively inhi-
bit membrane bound enzyme chitin synthase from yeast and other
fungi,2 including Candida albicans, a fungal pathogen which affects
immunocompromised humans. In addition polyoxins are ineffec-
tive against other microorganisms, plants, or animals.2e Because
of their biological activities, the synthesis of the polyoxins and
their analogues has received considerable attention from synthetic
chemists. Several groups have described total synthesis of polyoxin
J.3 Akita et al. have reported an elegant convergent approach to
both polyoxins J and L.3f,g According to the characteristic structural
features of polyoxins and the products of their hydrolytic cleavage,
most of these syntheses are based on the previous construction of
Figure 1. Structures of polyoxin J and polyoxin L.
The different biological activities against the enzyme (chitin
synthase) and C. albicans in culture between polyoxins and the clo-
sely related nikkomycins5 suggested that analogues of the polyox-
ins could be more effective as anticandidal agents. In this regard,
some attention has been paid to the synthesis of structural ana-
logues of the polyoxins,5b,6 but there is no report concerning the
preparation of diastereoisomers of the polyoxins or nikkomycins.
In order to make convenient to search for more potent and safer
anticandidal agents related to the polyoxins, it is necessary to
develop some stereospecific synthetic methods.
In our laboratory an ongoing program aimed at using enantio-
merically pure tert-butanesulfinamide as a chiral auxiliary for
the efficient synthesis of the biologically interesting polyoxin and
nikkomycin antibiotics is in progress. After we achieved the
facile synthesis of polyoxin C and its analogues with different
pyrimidine bases (Fig. 2),7 we endeavored to synthesize some
the 1-(50-amino-50-deoxy-b-
D-allofuranuronosyl)pyrimidine unit.
Therefore, considerable synthetic efforts have been directed to-
ward the construction of the nucleoside skeleton.4
* Corresponding author. Tel.: +86 931 8912281; fax: +86 931 8915557.
E-mail address: xupf@lzu.edu.cn (P.-F. Xu).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.033

Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
1175
COOMe
O
high yield and with excellent diastereoselectivity. Followed by
some classic functional group conversion, we obtained protected
5-O-carbamoyl-2-epi-polyoxamic acid 9 for coupling with the
O
S
B
OMe
O
H2N
N
D-ribose
1-(50-amino-50-deoxy-b-
D-allofuranuronosyl)pyrimidine unit. The
O
O
AcO
OAc
synthesis provides a facile method for the large-scale preparation
of 5-O-carbamoyl-2-epi-polyoxamic acid because of the simple
operation, excellent yield and high stereoselectivity.
B = thymine, uracil, 5-fluorouracil
Figure 2. New approach to polyoxin Cs.
diastereoisomers of other complex members of the polyoxins.
Many members of the polyoxin family and related classes of com-
pounds feature the 5-O-carbamoyl polyoxamic acid as a common
side chain. In view of this, we started our synthesis from the prep-
aration of 5-O-carbamoyl-2-epi-polyoxamic acid. Although some
synthetic approaches to this component have been reported,8,3f it
was often obtained as by-product. There has been no report con-
cerning a diastereoselective synthesis. Davis9 has reported a stere-
oselective synthesis of polyoxamic acid lactone and its 2-epi-
diastereoisomer but the total yield is low and the procedure is
not suitable for preparation on a large scale. We considered that
both the protected
5-O-carbamoyl-2-epi-polyoxamic acid 9 and the core structure 12
could be obtained by our own method using tert-butanesulfina-
mide as a chiral auxiliary and the furan as a masked carboxylic acid
d1-synthon. Thus, the diastereoselective nucleophilic addition of
2-lithiofuran to the tert-butanesulfinyl imine without any Lewis
acid additive was employed to construct the C-2 stereocenter in
2. Results and discussion
Our synthesis began with the direct condensation of (R)-(+)-
tert-butanesulfinamide and aldehyde 1 (Scheme 1) derived from
L
-ascorbic acid.10 In an attempt to improve the yield of the conden-
sation, we carried out a series of reactions according to the re-
ported methods11 and found that the addition of 1.0 equiv of
PPTS in the presence of anhydrous CuSO4 could dramatically pro-
mote the reaction affording the tert-butanesulfinyl imine 2 in
92% yield. The aldehyde 1 was chosen as our starting material be-
cause we hoped the chirality of the aldehyde unit and the chiral
tert-butanesulfinyl group could work as a matched combination
during the nucleophilic addition. With tert-butanesulfinyl imine
2 in hand, the stereocontrolled installation of a potential carboxyl
group was crucial to successful synthesis and it could be easily
achieved by the addition of 2-lithiofuran to the tert-butanesulfinyl
imine 2 in THF at ꢀ78 °C without any additive to give the adduct
product 3 in 92% yield with excellent diastereoselectivity (dr
O
S
O
H2N
O
O
2-lithiofuran, THF
-78 ºC, 4h, 92%
O
O
CHO
OTBS
S
N
CuSO4, PPTS,
r.t., 36h, 92%
dr >12/1
OTBS
1
2
O
O
1. HCl, MeOH,
Dioxane, r.t., 5h
HO
O
O
S
O
HO
2. Boc2O, Et3N,
NHBoc
N
MeOH, r.t., 12h,
H
84% (2 steps)
OH
TBSO
3
4
Scheme 1.
O
O
TBDPSCl, Et3N,
HO
HO
DMAP, r.t., 12h, 92%
TBDPSO
HO
NHBoc
NHBoc
OH
OH
5
4
O
TBAF, THF, 0 ºC
10h, 93%
O
2,2-dimethoxypropane
CSA, r.t., 12h, 88%
TBDPSO
NHBoc
O
6
O
O
O
1. ClCOO-Ph-NO2 (p),
O
CH2Cl2, pyridine, 0 ºC, 10h
H2N
O
HO
NHBoc
NHBoc
2. NH4OH, THF, 0 ºC
0.5h, 83% (2 steps)
O
O
O
8
7
Scheme 2.

1176
Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
O
O
COOH
NHBoc
O
NaIO4, RuCl3,
H2N
O
CCl4/H2O/CH3CN
H2N
O
NHBoc
r.t., 2h, 79%
O
O
O
O
9
8
O
COOMe
NHBoc
CH2N2, Et2O, r.t.
0.5 h, quant.
H2N
O
O
O
10
O
COOH
NHBoc
CF3COOH, MeOH,
r.t., 3h
OH
COOH
NH2
H2N
O
H2N
O
propylene oxide,
EtOH, 62%
O
O
OH
O
5-O-carbamoyl-2-epi-polyoxamic acid
11
9
Scheme 3.
>12:1). Subsequently, the tert-butanesulfinyl group and other hy-
droxy protecting groups were removed simultaneously with HCl
and the desired N-Boc derivative 4 was obtained successively in
84% yield in a two-step sequence.
lectivity observed during the addition should be attributed to the
matched combination of the six-membered cyclic transition state
and the chirality of the protected triol unit. This matched combina-
tion was also confirmed by the decreased stereoselectivity in the
nucleophilic addition when (S)-(ꢀ)-tert-butanesulfinamide was
used as a chiral auxiliary.
When we furnished triol 4, selective carbamoylation of the pri-
mary hydroxy (Scheme 2) was necessary. First of all, protection of
the primary hydroxy with TBDPSCl selectively gave the diol 5 in
high yield (92%) and the resulting diol 5 was transformed to 6 in
88% yield using 2,2-dimethoxypropane in the presence of CSA at
room temperature. Then, removal of the silyl group of protected
triol 6 with TBAF in THF at 0 °C for 10 h released the primary hy-
droxyl group in 93% yield. With the primary alcohol 7 in hand,
the carbamoylation could be achieved in a two-step sequence:
(1) esterification of the primary hydroxyl group with p-nitrophenyl
chloroformate, (2) selective ammonolysis to furnish the resulting
ester 8 in 83% yield over two steps after chromatography.
Next, we considered the release of the carboxylic acid function
from the furan ring (Scheme 3), a crucial operation for the comple-
tion of the synthetic plan. Thus, the oxidative cleavage of the furan
ring was achieved using catalytic RuCl3 in the presence of an excess
of NaIO4 to give compound 9 in 79% yield. This conversion can also
be achieved by ozonization in methanol in good yield. In order to
determine the stereochemistry of C-2 generated in the nucleophilic
addition, compound 9 was converted into the corresponding
methyl ester 10 by treatment with a solution of CH2N2 in ethyl
ether in quantitative yield. Comparison of the physical properties
and spectroscopy of 10 with the data8,3f reported previously dem-
onstrated that the stereochemistry of C-2 was the expected (R)-
configuration required for the continuation of the synthesis of
200-epi-polyoxin J and suggested the nucleophilic addition of 2-lith-
iofuran took place from the Si face of tert-butanesulfinyl imine 2.
Subsequently, the facile deprotection of 9 with trifluoroacetic acid
in methanol furnished 5-O-carbamoyl-2-epi-polyoxamic acid 11 in
moderate yield.
M
S
O
Nu-
N
O
Si
O
O
Figure 3. Proposed transition state for the nucleophilic addition.
After we achieved the synthesis of 11, we turned our attention
to furnish 200-epi-polyoxin J (Scheme 4). According to our previous
O
COOMe
BOP, i-Pr2NEt,
DMF, r.t., 18h, 52%
N
NH
O
H2N
H2N
H2N
+
9
O
AcO
OAc
12
O
COOMe
O
1. LiOH, THF/H2O, 0 ºC
2.TFA, 0 ºC
O
O
O
N
NH
O
O
N
O
O
H
O
NHBoc
AcO
OAc
A highly organized transition state model as depicted in Figure
3 may explain the high degree of diastereoselection associated
with the nucleophilic addition of 2-lithiofuran to tert-butanesulfi-
nyl imine 2. In this model, a six-membered cyclic transition state
with lithium coordinated to the sulfinyl oxygen was formed. Obvi-
ously, the bulky tert-butyl group and the protected triol unit occu-
pied the less hindered equatorial position resulting in preferential
attack from the Si face of the tert-butanesulfinyl imine for this
addition. Furthermore, the hindrance of the protected triol unit
also favors the addition from the Si face. So, the excellent stereose-
13
O
COOH
O
OH
O
O
N
NH
N
H
OH NH2
HO
OH
2''-epi-polyoxin J
14
Scheme 4.

Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
1177
work7 protected thymine polyoxin C 12 was easily prepared from
-ribose on a large scale. Coupling of protected 2-epi-polyoxamic
cally pure tert-butanesulfinyl imine, we found that PPTS could
promote the condensation of tert-butanesulfinamide and the ali-
phatic aldehyde with large substituent. This discovery simplified
the preparation of the tert-butanesulfinyl imine. As our previous
work, the nucleophilic addition of 2-lithiofuran to a tert-butanesul-
finyl imine was employed as a key step to construct the stereo-
D
acids 9 and 12 in the presence of BOP furnished the protected
200-epi-polyoxin J 13. Then, the deprotection procedure reported
by Ghosh3c was employed to remove the protecting groups of 13.
However, the purification of the final product 14 was difficult.
In order to resolve this problem, we thought that the protecting
groups of 12 should be removed before coupling. Thus, 12 was con-
verted into the corresponding N-Cbz derivative 15 in quantitative
yield. Subsequently, compound 15 was transformed into thymine
polyoxin C 16 by the standard deprotection sequence (Scheme 5).
Having obtained compound 16, we saw that what remained to
complete the synthesis of 200-epi-polyoxin J was the coupling of 9
and 16 via an amide bond as follows (Scheme 6). Treatment of 9
with N,N-dicyclohexylcarbodiimide-N-hydroxysuccinimide gave
the active ester 17 which was then condensed with thymine poly-
oxin C to afford the dipeptide 18 in 77% yield. Removal of the N-Boc
and O-isopropylidene protecting groups upon acid hydrolysis pro-
vided 200-epi-polyoxin J 14 in 85% yield.
chemistry at C-2 of an
a-amino acid successfully. Combined with
our previous work on the synthesis of polyoxin C, 200-epi-polyoxin
J was synthesized by a convergent strategy for the first time.
4. Experimental
Unless noted otherwise, reagents available commercially were
used without further purification. Solvents were dried by heating
at reflux for at least 12 h over P2O5 (dichloromethane) or so-
dium/benzophenone (toluene, THF, and n-hexane), and were
freshly distilled prior to use. Flash chromatography was carried
out utilizing silica gel 200–300 mesh. 1H NMR spectra were re-
corded on a Bruker AM-400 (400 MHz) spectrometer, and are re-
ported in ppm using a solvent as an internal standard (CDCl3 at
7.26 ppm). J values are recorded in hertz and abbreviations used
are s—singlet, d—doublet, m—multiplet, br—broad. Proton-decou-
O
O
COOMe
O
COOMe
O
CbzCl, NaHCO3,
dioxane, H2O,
r.t., 12h, quant.
pled 13C NMR spectra were recorded on
a Bruker AM-400
N
NH
N
NH
(100 MHz) spectrometer, and are reported in ppm using solvent
as an internal standard (CDCl3 at 77.0 ppm). Optical rotations were
measured on the Perkin Elmer 341 polarimeter. Melting points
were determined on an XT-4 melting point apparatus, and are
uncorrected. HRMS were performed on Bruker Apex II mass instru-
ment (ESI). For chiral diastereomeric products, the diastereomeric
ratios were determined by integration of suitable sets of peaks
on the 1H NMR (Bruker-400 MHz). 1H NMR, and 13C NMR data
are those of the major diastereomer unless otherwise noted.
CbzHN
H2N
O
O
AcO
OAc
AcO
OAc
15
12
O
COOH
1. LiOH, THF, H2O,
0 ºC,
N
NH
O
H2N
O
2. Pd/C, H2 ,MeOH
r.t., 10h, 54%
HO
OH
thymine polyoxin C
4.1. (SR,2S,3S)-(ꢀ)-N-(2-tert-Butyldimethylsilyloxy-3,4-isopro-
pylidenedioxy)butylidine-tert-butanesulfinamide (2)
16
Scheme 5.
To a 0.5 M solution of R-(+)-tert-butanesulfinamide (484 mg,
4.0 mmol) in dry dichloromethane were added anhydrous CuSO4
(1.4 g, 8.8 mmol) and PPTS (1.0 g, 4.0 mmol) followed by the alde-
hyde 1 (1.2 g, 4.4 mmol). The mixture was stirred at room temper-
ature for 36 h. The reaction mixture was filtered through a pad of
Celite, and the filter cake was washed well with dichloromethane.
The organic phase was combined and washed with brine, dried
over Na2SO4. Evaporation of the solvent gave a residue which
was chromatographed over silica gel to afford the tert-butanesulfi-
O
O
O
O
N-hydroxysuccinimide,
DCC, EtOAc, 0 ºC,8 h
H2N
O
N
O
9
O
NHBoc
O
17
COOH
O
nyl imine 2 (1.39 g, 92%) as a colorless oil. ½a D20
ꢁ
¼ ꢀ129 (c 1.37,
16, DMSO, i-Pr2NEt,
r.t., 24h, 77%
O
O
O
N
NH
O
CHCl3); IR (KBr): 2965, 2932, 2892, 2858, 1626, 1469, 1368,
1254, 1152, 1089 cmꢀ1 1H NMR (400 MHz, CDCl3) d (ppm) 7.99
;
H2N
O
N
O
H
O
NHBoc
(d, J = 3.6 Hz, 1H), 4.48 (dd, J = 3.6 Hz, 5.6 Hz, 1H), 4.25 (dd,
J = 5.6 Hz, 12.4 Hz, 1H), 3.99 (dd, J = 6.8 Hz, 8.4 Hz, 1H), 3.86 (dd,
J = 5.6 Hz, 8.8 Hz, 1H), 1.37 (s, 3H), 1.28 (s, 3H), 1.17 (s, 9H), 0.86
(s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) d
(ppm) 168.4, 109.9, 75.0, 65.2, 57.0, 26.1, 25.7, 25.0, 22.5, 18.2,
ꢀ4.6, ꢀ5.0; HRMS (calcd for C17H35NO4SSiNa) 400.1948, found
400.1944 (M+Na+).
HO
OH
18
O
COOH
O
O
OH
TFA, H2O, 0 ºC,
3h, 85%
N
NH
O
H2N
O
N
H
O
OH NH2
HO
OH
2''-epi-polyoxin J
4.2. (SR,1R,2S,3S)-(+)-N-(2-tert-Butyldimethylsilyloxy-1-(2-
furyl)-3,4-isopropylidenedioxy)butyl-tert-butanesulfin-amide 3
14
Scheme 6.
To a solution of n-BuLi (2.164 M in hexane, 3.0 mmol) at ꢀ78 °C
was added furan (245 mg, 3.6 mmol) in THF (5 mL), which was
stirred at room temperature for 3 h. The mixture was then cooled
to ꢀ78 °C, to which was added 0.5 M solution of tert-butanesulfinyl
imine 2 (754 mg, 2.0 mmol) in anhydrous THF via syringe over
10 min. The mixture was stirred at ꢀ78 °C for 3 h and quenched
3. Conclusions
In conclusion, a stereospecific synthesis of 5-O-carbamoyl-2-
epi-polyoxamic acid has been developed in high yield and with
excellent stereoselectivity. During the preparation of enantiomeri-
with
a saturated NH4Cl solution (2 mL). The solvent was

1178
Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
evaporated under reduced pressure and the residue was dissolved
in water (10 mL), then extracted with EtOAc, dried with Na2SO4
and concentrated. Flash chromatography (petroleum ether/ethyl
acetate, 6:1), afforded compound 3 (820 mg, 92%) as an oil.
thoxypropane (13 mL/mmol) was added camphor sulfonic acid
(2.5 g, 1.05 mmol). The solution was stirred at room temperature
for 24 h and then hydrolyzed with a saturated aqueous solution
of NaHCO3. The mixture was concentrated and water (20 mL)
was added. The aqueous phase was extracted with EtOAc thrice.
The combined organic layers were successively washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 8:1) to give
½
a 2D0
ꢁ
¼ þ11 (c 1.13, CHCl3); IR (KBr): 3337, 3221, 2982, 2955,
2931, 2897, 2858, 1469, 1371, 1253, 1218, 1148, 1071 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d (ppm) 7.31 (d, J = 0.8 Hz, 1H), 6.45 (d,
J = 3.2 Hz, 1H), 6.34 (dd, J = 2.0 Hz, 3.2 Hz, 1H), 4.44 (d, J = 9.6 Hz,
1H), 4.39 (dd, J = 3.2 Hz, 5.6 Hz, 1H), 4.03 (dd, J = 4.8 Hz, 8.4 Hz,
1H), 3.91–3.99 (m, 2H), 3.69 (t, J = 6.8 Hz, 1H), 1.40 (s, 3H), 1.30
(s, 3H), 1.22 (s, 9H), 0.91 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13C
NMR (100 MHz, CDCl3) d (ppm) 152.9, 141.9, 110.6, 109.3, 108.9,
76.7, 74.7, 65.6, 58.5, 58.1, 26.4, 25.9, 25.5, 22.6, 18.3, ꢀ4.4, ꢀ4.5;
HRMS (calcd for C21H40NO5SSi) 446.2391, found 446.2382 (M+H+).
compound 6 (560 mg, 98%). ½a D20
¼ ꢀ3 (c 0.76, CHCl3); IR (KBr):
ꢁ
3448, 3342, 3071, 2980, 2932, 2859, 1715, 1496, 1368, 1246,
1167, 1109 cmꢀ1 1H NMR (400 MHz, CDCl3) d (ppm) 7.70 (dd,
;
J = 7.2 Hz, 13.6 Hz, 4H), 7.35–7.47 (m, 7H), 6.34 (dd, J = 2.0 Hz,
3.2 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 5.05 (d, J = 9.2 Hz, 1H), 4.97
(br, 1H), 4.32 (t, J = 6.0 Hz, 1H), 4.04 (s, 1H), 3.78 (dd, J = 3.6 Hz,
10.8 Hz, 1H), 3.68 (dd, J = 4.0 Hz, 10.8 Hz, 1H), 1.42 (s, 9H), 1.40
(s, 3H), 1.30 (s, 3H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3) d
(ppm) 155.0, 141.9, 135.7, 133.2, 129.8, 129.7, 127.7, 127.6,
110.3, 109.8, 107.7, 63.9, 28.3, 27.3, 27.0, 26.9, 19.2; HRMS (calcd
for C32H44NO6Si) 566.2932, found 566.2936 (M+H+).
4.3. tert-Butyl (1R,2S,3S)-1-(2-furyl)-2,3,4-trihydroxybutyl-
carbamate 4
The product 3 (445 mg, 1.0 mmol) was dissolved in methanol
(10 mL), to which was added 4 M HCl (5 mL) in 1,4-dioxane
(20 mmol). The mixture was stirred for 5 h at room temperature
and then concentrated. The residue was dissolved in methanol
(5 mL) and then Boc2O (262 mg, 1.2 mmol) and Et3N (0.3 mL,
2.5 mmol) were added into the solution successively. The mixture
was stirred for 12 h at room temperature and concentrated. Flash
chromatography (petroleum ether/ethyl acetate, 1.5:1), afforded
compound 4 (241 mg, 84% from 3) as a white solid. Mp: 118–
4.6. tert-Butyl (1R,2S,3S)-1-(2-furyl)-2,3-isopropylidenedioxy-4-
hydroxybutylcarbamate 7
To a solution of 6 (735 mg, 1.3 mmol) in THF (5 mL) was added a
1 M solution of TBAF in THF (2.6 mL, 2.6 mmol, 2 equiv). The
resulting solution was stirred for 10 h at 0 °C, quenched with satu-
rated NH4Cl (2 mL) and diluted with water (10 mL), extracted with
Et2O. The combined organic phases were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The oily residue was purified by flash chromatography on silica
gel (petroleum ether/EtOAc, 5:1) to give 7 (396 mg, 93%) as a col-
120 °C; ½a 2D0
ꢁ
¼ þ63 (c 0.82, MeOH); IR (KBr): 3530, 3400, 3352,
3006, 2976, 2924, 1677, 1521, 1276, 1233, 1166, 1004 cmꢀ1
;
1H
NMR (400 MHz, CDCl3) d (ppm) 7.39 (d, J = 0.8 Hz, 1H), 6.37 (d,
J = 3.2 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.33 (d, J = 7.6 Hz, 1H),
4.82 (t, J = 8.0 Hz, 1H), 3.73–3.84 (m, 5H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) d (ppm) 156.6, 151.5, 142.4, 110.5, 108.2, 80.9,
73.1, 69.9, 64.3, 51.3, 28.3; HRMS (calcd for C13H22NO6)
288.1442, found 288.1443 (M+H+).
orless oil. ½a 2D0
ꢁ
¼ þ12 (c 1.14, CHCl3); IR (KBr): 3449, 3334, 2982,
2934, 2250, 1701, 1504, 1370, 1248, 1167 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d (ppm) 7.37 (dd, J = 0.8 Hz, 1.6 Hz, 1H), 6.34
(dd, J = 2.0 Hz, 3.2 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H), 5.23 (d,
J = 8.0 Hz, 1H), 4.96 (br s, 1H), 4.19 (dd, J = 6.0 Hz, 8.0 Hz, 1H),
4.05 (t, J = 3.6 Hz, 1H), 3.77 (d, J = 12 Hz, 1H), 3.61 (dd, J = 5.6 Hz,
11.6 Hz, 1H), 2.31 (s, 1H), 1.43 (s, 9H), 1.40 (s, 3H), 1.29 (s, 3H);
13C NMR (100 MHz, CDCl3) d (ppm) 155.1, 151.5, 142.0, 110.4,
109.7, 107.8, 80.2, 78.6, 78.2, 62.3, 50.5, 28.3, 28.0, 27.3, 26.7;
HRMS (calcd for C16H25NO6Na) 350.1574, found 350.1574 (M+Na+).
4.4. tert-Butyl (1R,2S,3S)-4-tert-butyldiphenylsilyloxy-1-(2-
furyl)-2,3-dihydroxybutylcarbamate 5
To a solution of N-Boc-aminotriol 4 (574 mg, 2.0 mmol) in
CH2Cl2 (20 mL) were added tert-butyldiphenylsilyl chloride
(0.57 mL, 2.2 mmol), freshly distilled Et3N (0.31 mL, 2.0 mmol)
and DMAP (10 mg, 0.06 mmol). The mixture was stirred at room
temperature for 20 h. The mixture was then concentrated and
water (20 mL) was added. The aqueous phase was extracted thrice
with CH2Cl2 and twice with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (petroleum ether/
EtOAc, 4:1) to give the monosilylated compound 5 (920 mg, 88%)
4.7. (1R)-4-O-(Aminocarbonyl)-1-((tert-butoxycarbonyl)amino)-
1-deoxy-1-(2-furyl)-2,3-O-isopropylidene-D-threitol 8
Compound 7 (196 mg, 0.6 mmol) was dissolved in CH2C12
(3 mL). Pyridine (0.5 mL) followed by p-nitrophenylchloroformate
(305 mg, 1.51 mmol) was added at 0 °C. The resulting mixture
was stirred at 0 °C for 10 h. The reaction mixture was diluted with
CH2C12 and washed with saturated aqueous NaHCO3, brine, and
dried over anhydrous Na2SO4. Evaporation of the solvent gave a
pale yellow solid which was dissolved in THF (3 mL). The resulting
mixture was cooled to 0 °C, and aqueous ammonia (0.5 mL) was
added. After stirring for 30 min at 0 °C, the mixture was diluted
with EtOAc, washed with saturated aqueous NaHCO3 and brine,
and dried over anhydrous Na2SO4. The solvent was evaporated un-
der reduced pressure, and the residue was purified by column
chromatography (petroleum ether/EtOAc, 5:1) to give pure 8
as a colorless oil. ½a D20
¼ þ20 (c 1.31, CHCl3); IR (KBr): 3410,
ꢁ
2958, 2933, 2858, 2250, 1694, 1590, 1501, 1367, 1249, 1167,
; d (ppm) 7.67 (dd,
1111 cmꢀ1 1H NMR (400 MHz, CDCl3)
J = 1.6 Hz, 5.6 Hz, 4H), 7.37–7.47 (m, 7H), 6.35 (dd, J = 2.0 Hz,
3.2 Hz, 1H), 6.28 (d, J = 2.8 Hz, 1H), 5.47 (d, J = 6.4 Hz, 1H), 4.88
(t, J = 8.0 Hz, 1H), 3.95 (d, J = 6.8 Hz, 1H), 3.78 (br s, 3H), 1.46 (s,
9H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) d (ppm) 142.1,
135.6, 135.5, 133.1, 133.0, 129.8, 127.8, 110.4, 107.6, 80.3, 71.7,
70.2, 65.1, 51.7, 28.3, 26.8, 19.2; HRMS (calcd for C29H40NO6Si)
526.2619, found 526.2621 (M+H+).
(184 mg, 83%) as an oil. ½a D20
¼ þ5 (c 1.13, CHCl3); IR (KBr): 3447,
ꢁ
3352, 2983, 2934, 2252, 1713, 1602, 1503, 1370, 1333, 1250,
4.5. tert-Butyl (1R,2S,3S)-4-tert-butyldiphenylsilyloxy-1-(2-
1167 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d (ppm) 7.37 (dd,
furyl)-2,3-isopropylidenedioxybutylcarbamate (6)
J = 0.4 Hz, 1.6 Hz, 1H), 6.34 (dd, J = 2.0 Hz, 3.2 Hz, 1H), 6.29 (d,
J = 3.2 Hz, 1H), 5.23 (d, J = 11.2 Hz, 1H), 4.99 (br, 3H), 4.09–4.21
(m, 4H), 1.44 (s, 9H), 1.40 (s, 3H), 1.29 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 256.5, 155.1, 151.3, 142.1, 110.4,
Under an inert atmosphere, to a solution of the monosilylated
compound 5 (525 mg, 1.0 mmol) in freshly distilled 2,2-dime-

Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
1179
110.3, 107.8, 80.2, 79.3, 76.3, 65.2, 50.5, 29.6, 28.3, 28.2, 27.0, 26.7;
HRMS (calcd for C17H27N2O7) 371.1813, found 371.1810 (M+H+).
(200 mg, 0.48 mmol) and diisopropylethylamine (0.13 mL,
0.75 mmol). The resulting mixture was stirred at 23 °C for 18 h.
The solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography on silica gel (chloro-
form/methanol, 30:1) to furnish the coupling product 13 (115 mg,
4.8. (3S,4S)-5-((Aminocarbonyl)oxy)-N-((1,1-dimethylethoxy)
carbonyl)-3,4-((1-methylethylidene)dioxy)-norvaline 9 and
methyl ester 10
63%) as a white foam. Mp: 124–125 °C; ½a D20
ꢁ
¼ þ7 (c 0.84, CHCl3);
IR (KBr): 3301, 2983, 1748, 1697, 1373, 1243, 756 cmꢀ1
;
1H NMR
To a well-stirred solution of NaIO4 (0.351 g, 1.65 mmol) in
H2O–CCl4–CH3CN (3:2:3, 7.4 mL) was added RuCl3 (2.8 mg,
0.013 mmol). After stirring for 15 min, the 2-furyl derivative 8
(0.1 g, 0.27 mmol) in CH3CN (0.5 mL) was added. The color of the
solution turned instantaneously from yellowish to black. Then en-
ough NaIO4 was added to restore the yellowish color. After 5 min,
the mixture was diluted with water (5 mL) and extracted with
EtOAc (3 ꢂ 10 mL). The combined organic extracts were washed
successively with 20% aqueous NaHSO3 until colorless and brine
and dried over magnesium sulfate, and the solvent was evaporated
under reduced pressure. This residue was taken up with saturated
aqueous K2CO3 (10 mL), the solution was stirred for 10 min
and then washed with EtOAc (2 ꢂ 15 mL). Acidification (pH 2) of
the aqueous layer by addition of 2 M HCl, extracted with CH2Cl2
(3 ꢂ 20 mL), dried over magnesium sulfate, and evaporation of
the solvent under reduced pressure gave pure 9 (82 mg, 87%) as
(400 MHz, CDCl3) d (ppm) 9.38 (br s, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.13 (s, 1H), 5.84 (d, J = 7.2 Hz, 1H), 5.58 (d, J = 7.6 Hz, 1H), 5.48
(s, 1H), 5.30 (d, J = 5.2 Hz, 1H), 5.12 (br s, 3H), 4.40–4.47 (m, 2H),
4.34 (br s, 1H), 4.30 (d, J = 12 Hz, 1H), 4.08–4.13 (m, 1H), 4.03 (t,
J = 7.2 Hz, 1H), 3.78 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 1.91 (s, 3H),
1.43 (s, 12H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) d (ppm)
171.1, 169.7, 169.6, 168.8, 163.6, 156.7, 155.8, 150.4, 136.1,
111.8, 110.3, 88.0, 81.5, 80.7, 72.4, 69.2, 64.5, 60.4, 56.2, 53.1,
52.9, 28.2, 26.8, 26.7, 21.0, 20.4, 14.2, 12.4; HRMS (calcd for
C30H44N5O16) 730.2778, found: 730.2789 (M+H+).
4.11. Methyl 5-((Benzyloxycarbonyl)amino)-5-deoxy-1,2,3-tri-
O-acetyl-D-allo-hexofuranuronate 15
The crude amine 12 (400 mg, 1.0 mmol) was dissolved in diox-
ane (10 mL) and the solution was treated with 7% aqueous NaHCO3
(5 mL). After stirring for 20 min at 0 °C, the reaction mixture was
treated with benzyl chloroformate (0.16 mL, 1.1 mmol) and
was stirred for 12 h at ambient temperature. Then water (15 mL)
was added, and the mixture was extracted with CH2Cl2. The com-
bined organic extracts were dried over magnesium sulfate, and the
solvent was removed in vacuo. The residue was purified by column
chromatography (petroleum ether/ethyl acetate, 1:2.5) to give
an oil. ½a 2D0
ꢁ
¼ ꢀ23 (c 0.64, acetone); IR (KBr): 3382, 3205, 3060,
2957, 1747, 1700, 1458, 1377, 1242, 1095, 1053 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d (ppm) 5.49 (d, J = 8.4 Hz, 1H), 5.35–5.48 (br s,
3H), 4.67 (d, J = 4.4 Hz, 1H), 4.35 (s, 1H), 4.23 (d, J = 4.8 Hz, 2H),
4.14 (dd, J = 4.4 Hz, 12.4 Hz, 1H), 1.46 (s, 9H), 1.42 (s, 6H); 1H
NMR (400 MHz, DMSO)
d (ppm) 12.90 (br s, 1H), 7.34 (d,
J = 9.2 Hz, 1H), 6.45–6.67 (br d, 2H), 3.98–4.22 (m, 4H), 3.79 (dd,
J = 7.2 Hz, 11.6 Hz, 1H), 1.34 (s, 9H), 1.31 (s, 3H), 1.29 (s, 3H); 13C
NMR (100 MHz, DMSO) d (ppm) 171.8, 156.4, 155.4, 109.2, 78.5,
76.4, 76.3, 64.3, 55.4, 28.1, 27.2, 26.9; HRMS (calcd for C14H24N2O8-
Na) 371.1425, found 371.1429 (M+Na+).
pure 15 (530 mg, quantitative) as colorless oil. ½a D20
ꢁ
¼ þ16 (c
0.85, CH2Cl2); IR (KBr): 3299, 3065, 1750, 1696, 1239 cmꢀ1
;
1H
NMR (400 MHz, CDCl3) d (ppm) 9.14 (br s, 1H), 7.27–7.37 (m,
5H), 7.03 (s, 1H), 5.92 (d, J = 5.6 Hz, 2H), 5.51 (t, J = 5.6 Hz, 1H),
5.26 (t, J = 6.0 Hz, 1H), 5.10 (s, 2H), 4.82 (d, J = 3.9 Hz, 1H), 4.38
(t, J = 4.4 Hz, 1H), 3.78 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.86 (s,
3H); 13C NMR (100 MHz, CDCl3) d (ppm) 169.6, 169.5, 169.3,
163.3, 156.0, 135.8, 135.5, 128.5, 128.3, 128.1, 112.0, 87.5, 81.9,
77.2, 72.3, 69.7, 67.4, 60.3, 55.1, 52.9, 20.3, 12.4; HRMS (calcd for
C24H31N4O11) 551.1989, found 551.1984 (M+NH4+).
The acid 9 was dissolved in diethyl ether and treated with an
ethereal solution of diazomethane to give the ester 10 (78 mg,
100%) as an oil. ½a D20
ꢁ
¼ ꢀ28 (c 0.8, CH2Cl2); IR (KBr): 3438, 3369,
2987, 1750, 1690, 1615, 1527, 1429, 1375 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d (ppm) 5.43 (d, J = 7.2 Hz, 1H), 4.95 (br s, 2H),
4.61 (d, J = 5.6 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H), 4.24–4.28 (m, 1H),
4.16 (dd, J = 5.2 Hz, 11.2 Hz, 1H), 4.03 (dd, J = 4.0 Hz, 8.0 Hz, 1H),
3.79 (s, 3H), 1.45 (s, 9H), 1.40 (s, 3H), 1.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 170.0, 156.2, 155.1, 110.5, 80.4, 79.8,
75.7, 64.9, 55.1, 52.5, 28.3, 27.0, 26.8; HRMS (calcd for C15H26N2O8-
Na) 385.1581, found 385.1582 (M+Na+).
4.12. Thymine polyoxin C 16
To a solution of 15 (88.7 mg, 0.166 mmol) in THF (8 mL) and
H2O (1.5 mL) at 0 °C was added solid LiOHꢃH2O (24 mg,
0.57 mmol). The resulting yellow solution was stirred at 0 °C until
the TLC (5:4:1 CHC13/MeOH/H2O) showed the starting material
disappeared. The mixture was diluted with H2O (10 mL) and ex-
tracted with CH2C12 (3 ꢂ 20 mL) to remove any nonacidic material,
and the resulting basic solution was cooled to 0 °C and acidified to
pH 2–3 with 1 N HC1. This mixture was extracted with EtOAc
(6 ꢂ 20 mL), and all organic layers were combined, dried over
Na2SO4, filtered, and concentrated in vacuo to give a yellow solid.
The solid was dissolved in MeOH (4.5 mL) and 5% Pd/C (33 mg)
was added to the solution. The black suspension was stirred under
H2 atm for 4 h when the TLC (5:4:1 CHC13/MeOH/H2O) showed
complete consume of starting material (Rf, 0.51). The reaction mix-
ture was filtered through a pad of Celite bed eluting with hot H2O
(3 ꢂ 10 mL), and the filtrate was concentrated in vacuo to give 16
4.9. 5-O-Carbamoyl-2-epi-polyoxamic acid 11
Compound 9 (150 mg, 0.43 mmol) was dissolved in 3 mL of
cold MeOH–trifluoroacetic acid (v/v, 1:10) and the solution was
stirred for 1.5 h at room temperature. Then the solvent was evap-
orated under reduced pressure below 30 °C. The residue was dis-
solved in 1 mL of EtOH and propylene oxide (5 mL) was added
slowly. The white solid started to precipitate, which was collected
by filtration to give 11 in the yield of 62%. Mp: 78–82 °C;
½
a 2D0
ꢁ
¼ þ0:7 (c 0.64, H2O); 1H NMR (400 MHz, D2O) d (ppm) 4.13
(s, 1H), 4.06–4.08 (m, 2H), 3.95–3.99 (m, 2H); 1H NMR (400 MHz,
DMSO) d (ppm) 7.49 (br s, 2H), 6.48 (br s, 2H), 3.89 (d, J = 6.0 Hz,
1H), 3.74–3.78 (m, 1H), 3.42 (d, J = 6.0 Hz, 1H); 13C NMR
(100 MHz, DMSO) d (ppm) 157.2, 69.6, 69.2, 65.3, 56.9; HRMS
(calcd for C6H13N2O6) 209.0768, found 209.0733 (M+H+).
as
½ ꢁ
a
yellow solid (20.8 mg, 54% yield). Mp: 184–186 °C;
¼ þ9 (c 0.47, H2O); IR (KBr): 3579, 3419, 3336, 1712, 1681,
1674, 1609 cmꢀ1 1H NMR (400 MHz, D2O) d (ppm) 7.43 (s, 1H),
a 2D0
;
4.10. Peptide derivative 13
5.77 (d, J = 5.2 Hz, 1H), 4.55 (t, J = 5.6 Hz, 1H), 4.26–4.31 (m, 2H),
4.05 (dd, J = 2.4 Hz, 5.6 Hz, 1H), 1.85 (s, 3H); 13C NMR (100 MHz,
D2O) d (ppm) 168.5, 156.0, 150.2, 137.0, 110.7, 88.5, 80.6, 71.8,
68.0, 54.3, 11.5.
To a stirred solution of 9 (90 mg, 0.26 mmol) and 12 (100 mg,
0.25 mmol) in DMF (3 mL) were sequentially added BOP reagent

1180
Y.-C. Luo et al. / Tetrahedron: Asymmetry 20 (2009) 1174–1180
4.13. Peptide derivative 18
Program for NCET-05-0880 and the Fund (02079) from the Minis-
try of Education, PR China.
To a cooled (0 °C) solution of 9 (20.7 mg, 0.059 mmol) in EtOAc
(7 mL) were added DCC (11.7 mg, 0.059 mmol) and N-hydroxy-
succinimide (6.85 mg, 0.059 mmol). The mixture was stirred at
0 °C for 8 h and then the solvent was evaporated under reduced
pressure. The crude 17 was dissolved in DMSO (3 mL), and the
solution was treated with 16 (18 mg, 0.06 mmol) and diisopropyl-
ethylamine (0.01 mL, 0.06 mmol). The reaction mixture was stirred
at ambient temperature for 24 h. The mixture was directly chro-
matographed on silica gel (CHCl3/MeOH/H2O, 5:2:0.5) to give the
product 18 (21 mg, 58%) as a white solid.
References
1. (a) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333; (b) Isono, K.; Asahi, K.;
Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490.
2. (a) Zhang, D.; Miller, M. J. Curr. Pharmaceut. Des. 1999, 5, 73; (b) Gooday, G. W.
In Biochemistry of Cell Walls and Membranes in Funghi; Kuhnm, P. J., Trinci, A. P.,
Jung, M. J., Goosey, M. W., Copping, L. G., Eds.; Springer: Berlin, 1990; p 61; (c)
Muzzerelli, R. A. A. Chitin; Pergamon Press: Oxford, 1977; (d) Isono, K.
J. Antibiot. 1988, 41, 1711; (e) Misato, M.; Kakiki, K. In Antifungal Compounds;
Siegel, M., Sisler, H. D., Eds.; Dekker: New York, 1977; p 277.
3. (a) Dondoni, A.; Franco, S.; Junquera, F.; Merchán, F. L.; Merino, P.; Tejero, T.
J. Org. Chem. 1997, 62, 5497; (b) Dondoni, A.; Junquera, F.; Merchán, F. L.;
Merino, P.; Tejero, T. Chem. Commun. 1995, 2127; (c) Ghosh, A. K.; Wang, Y.
J. Org. Chem. 1999, 64, 2789; (d) Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.;
Ogawa, S. Chem. Commun. 1994, 111; (e) Tabusa, F.; Yamada, T.; Suzuki, K.;
Mukaiyama, T. Chem. Lett. 1984, 405; (f) Uchida, K.; Kato, K.; Akita, H. Synthesis
1999, 1678; (g) Akita, H.; Uchida, K.; Kato, K. Heterocycles 1998, 47, 157; (h)
Akita, H. Heterocycles 2009, 77, 67.
4. (a) Kato, K.; Chen, C. Y.; Akita, H. Synthesis 1998, 1527; (b) Ghosh, A. K.; Wang,
Y. J. Org. Chem. 1998, 63, 6735; (c) Evina, C. M.; Guillerm, G. Tetrahedron Lett.
1996, 37, 163; (d) Dondoni, A.; Junquera, F.; Merchán, F. L.; Merino, P.; Tejero, T.
Tetrahedron Lett. 1994, 35, 9439; (e) Chen, A.; Savage, I.; Thomas, E. J.; Wilson, P.
D. Tetrahedron Lett. 1993, 34, 6769; (f) Barrett, A. G. M.; Lebold, S. A. J. Org.
Chem. 1990, 55, 3853; (g) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55, 3772; (h)
Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265; (i)
Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019; (j) Damodaran, N. P.; Jones,
G. H.; Moffatt, J. G. J. Am. Chem. Soc. 1971, 93, 3812; (k) Ohrui, H.; Kuzuhara, H.;
Emoto, S. Tetrahedron Lett. 1971, 12, 4267; (l) Akita, H.; Uchida, K.; Chen, C.-Y.
Heterocycles 1997, 46, 87; (m) Akita, H.; Uchida, K.; Chen, C.-Y.; Kato, K. Chem.
Pharm. Bull. 1998, 46, 1034; (n) Gethin, D. M.; Simpkins, N. S. Tetrahedron 1997,
53, 14417; (o) Chen, A.; Thomas, E. J.; Wilson, P. D. J. Chem. Soc., Perkin Trans. 1.
1999, 3305.
Mp: 195–200 °C; ½a D20
¼ ꢀ0:6 (c 0.71, MeOH); IR (KBr): 3437,
ꢁ
1700, 1523 cmꢀ1
;
1H NMR (400 MHz, D2O) d (ppm) 7.47 (d,
J = 0.8 Hz, 1H), 5.85 (d, J = 6.4 Hz, 1H), 4.57 (d, J = 3.2 Hz, 1H),
4.43 (br s, 1H), 4.25–4.33 (m, 4H), 4.15–4.19 (m, 2H), 4.06 (d,
J = 12.4 Hz, 1H), 1.88 (s, 3H), 1.39 (s, 3H), 1.38 (s, 9H), 1.34 (s,
3H); 13C NMR (100 MHz, D2O) d (ppm) 173.4, 170.4, 166.3, 158.7,
157.0, 151.9, 137.4, 111.5, 110.8, 87.2, 85.1, 81.8, 76.9, 75.9, 73.1,
69.4, 63.9, 62.5, 56.1, 48.8, 27.4, 25.9, 25.7, 11.7; HRMS (calcd for
C25H38N5O14) 632.2410, found: 632.2403 (M+H+).
4.14. 200-Epi-polyoxin J 14
A solution of 18 (13 mg, 0.022 mmol) in 2:1 trifluoroacetic acid–
water (3 mL) was stirred at 0 °C for 2 h. The solvent was evaporated
under reducedpressure below 40 °C. Thebrownishsolid residue was
purified by column chromatography (CHCl3/MeOH/H2O, 5:4:1) to
give pure 200-epi-polyoxin J 14 (8 mg, 80%) as a white solid.
5. (a) Krainer, E.; Becker, J. M.; Naider, F. J. Med. Chem. 1991, 34, 174; (b) Bohem, J.
C.; Kingsbury, W. D. J. Org. Chem. 1986, 51, 2307.
Mp: 165–170 °C; ½a D20
¼ þ1:1 (c 0.61, H2O); IR (KBr): 3431,
ꢁ
6. (a) Rosenthal, A.; Cliff, B. L. Carbohydr. Res. 1980, 79, 63; (b) Fiandor, J.;
Garciá-López, M.-T.; DelasHeras, F. G.; Méndez- Castrillón, P. P. Synthesis
1987, 978; (c) Ward, S. E.; Holmes, A. B.; McCague, R. Chem. Commun.
1997, 2085; (d) Zhang, D.; Miller, M. J. J. Org. Chem. 1998, 63, 755; (e)
Aggarwal, V. K.; Monteiro, N. J. Chem. Soc., Perkin Trans. 1 1997, 2531; (f)
Dehoux, C.; Fontaine, E.; Escudier, J.-M.; Baltas, M.; Gorrichon, L. J. Org.
Chem. 1998, 63, 2601; (g) Merino, P.; Franco, S.; Merchán, F. L.; Tejero, T.
J. Org. Chem. 2000, 65, 5575.
7. Luo, Y.-C.; Zhang, H.-H.; Xu, P.-F. Synlett 2009, 833.
8. Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Ganguly, A. K.; McPhail, A. T.
J. Org. Chem. 1986, 51, 5024.
9. Davis, F. A.; Prasad, K. R.; Carroll, P. J. J. Org. Chem. 2002, 67, 7802.
10. Lilly, M. J.; Miller, N. A.; Edwards, A. J.; Willis, A. C.; Turner, P.; Paddon-Row, M.
N.; Sherburn, M. S. Chem. Eur. J. 2005, 11, 2525.
11. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
64, 1278; (b) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403; (c) Huang, Z.-Y.; Zhang, M.; Wang, Y.;
Qin, Y. Synlett 2005, 1334.
2990, 1710 cmꢀ1
;
1H NMR (400 MHz, D2O) d (ppm) 7.51 (d,
J = 0.8 Hz, 1H), 5.82 (d, J = 5.6 Hz, 1H), 4.55 (d, J = 3.6 Hz, 1H),
4.47 (t, J = 5.2 Hz, 1H), 4.31 (d, J = 5.6 Hz, 1H), 4.21–4.26 (m, 2H),
4.15 (dd, J = 2.0 Hz, 5.6 Hz, 1H), 4.05–4.09 (m, 2H), 3.92–3.96 (m,
1H), 1.87 (s, 3H); 13C NMR (100 MHz, D2O) d (ppm) 166.5, 166.3,
158.8, 151.8, 137.5, 111.7, 88.5, 83.6, 72.8, 70.9, 68.5, 67.5, 65.2,
62.5, 56.3, 48.8, 11.5; HRMS (calcd for C17H26N5O12) 492.1572,
found: 492.1576 (M+H+).
Acknowledgments
We are grateful for financial support of the National Natural Sci-
ence Foundation of China (NSFC Nos. 20572039, 20772051), the