A convenient synthesis of a N-protected l-carbamoylpolyoxamic acid derivative: Total synthesis of (+)-polyoxin J and (+)-polyoxin L1

Article abstract of DOI:10.1055/s-1999-3563

A convenient synthesis of the N-protected L-carbamoylpolyoxamic acid derivative 7 from 4-O-tert-butyldiphenylsilyl-2,3-isopropylidene-L-threose (8) using vinylmagnesium bromide and its application to the total syntheses of the peptidyl nucleoside antibiotics, polyoxins J (1) and L (2), are described.

Full text of DOI:10.1055/s-1999-3563

1678
PAPER
A Convenient Synthesis of a N-Protected L-carbamoylpolyoxamic Acid
Derivative: Total Synthesis of (+)-Polyoxin J and (+)-Polyoxin L1
Kimio Uchida, Keisuke Kato, Hiroyuki Akita*
School of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510, Japan
Fax +81(474)721825; E-mail: akita@phar.toho-u.ac.jp
Received 11 March 1999; revised 21 April 1999
R
Abstract: A convenient synthesis of the N-protected L-carbam-
O
oylpolyoxamic acid derivative 7 from 4-O-tert-butyldiphenylsilyl-
2,3-isopropylidene-L-threose (8) using vinylmagnesium bromide
and its application to the total syntheses of the peptidyl nucleoside
antibiotics, polyoxins J (1) and L (2), are described.
O
OH
O
COOH
O
N
NH
H2N
O
N
H
OH NH2
O
OH
HO
Key words: total synthesis, diastereoselective vinylation, polyox-
amic acid, polyoxin J, polyoxin L
1
2
R=Me
R=H
R
O
O
Polyoxins J (1) and L (2) are a class of peptidyl nucleoside
antibiotics isolated from the culture broths of Streptomy-
ces cacaoi var asoensis.2 All members of the polyoxin
family possess the 1-(5’-amino-5’-deoxy-b-D-allofuranu-
ronosyl)pyrimidines such as thymine polyoxin C (3) and
uracil polyoxin C (4) as a basic component. The biological
activity of the polyoxins are very characteristic because of
their specific action against phytopathogenic fungi and
the human fungal pathogen (e.g. Candida albicans), and
lack of activity against other microorganisms, plants, fish,
and mammals.2b The site of action of the polyoxins was
reported to be responsible for cell wall chitin biosynthe-
sis.3 Based on the structure of polyoxins, the appearance
of biological activity was reported to be due to the gross
structural similarity of the polyoxins to UDP-N-acetylglu-
cosamine, a substrate for chitin synthetase, which is the
polymerizing enzyme responsible for the synthesis of
chitin, a polysaccharide corresponding to the b-1,4-poly-
N-acetylglucosamine.2b In the preceeding paper, 4 we re-
ported a short path synthesis of ethyl (methyl-2,3-O-iso-
propylidene-a-L-talofuranoside)uronate from methyl 2,3-
O-isopropylidene-dialdo-D-ribofuranoside using 1-ethox-
yvinyllithium and its application to the total syntheses of
thymine polyoxin C (3) and uracil polyoxin C (4). Four to-
tal syntheses5 of 1 have been reported, these methods in-
volving coupling of the congener of polyoxamic acid 5
with thymine polyoxin C (3).5b,5d,6 A variety of chemical
syntheses 5-O-carbamoyl-polyoxamic acid derivatives
have been reported over years,7,5d one of the most impor-
tant intermediate for the general synthesis of them ap-
peared to be (2R)-hydroxy ester such as 6. We now
describe a convenient synthesis of the N-protected L-car-
bamoylpolyoxamic acid derivative 7 via 6 from 4-O-tert-
butyldiphenylsilyl-2,3-isopropylidene-L-threose (8) de-
rived from dimethyl L-tartrate and its application to the to-
tal syntheses of polyoxins J (1) and L (2) (Scheme 1). The
key reaction step is the addition of vinylmagnesium bro-
mide to 8.
COOH
O
OH
O
N
NH
COOH
+
H2N
H2N
O
OH NH2
5
OH
HO
R=Me
R=H
3
4
O
O
O
COOMe
COOH
2S
2R
TBDPSO
H2N
O
O
OH
O
NHBoc
6
7
Scheme 1
In seeking a practical route to 7, use of dimethyl L-tartrate
with its inherent C-2 axis symmetry appeared to be the
most promising. A useful synthesis of 5 utilizing L-tartaric
acid has been described by Mukaiyama et al.,7f the crucial
step being the stereoselective addition of titanium sily-
lacetylide species to 4-O-benzyl-2,3-isopropylidene-L-
threose (9). Our own strategy for the introduction of the a-
hydroxy ester functionality involves the addition of vinyl-
magnesium bromide to 4-O-tert-butyldiphenylsilyl-2,3-
isopropylidene-L-threose (8) followed by oxidative cleav-
age of the terminal double bond as key steps. Reduction of
the commercially available acetonide 10 with NaBH4
gave the diol 11 (92%), which was treated with t-
BuPh2SiCl (TBDPSCl) in the presence of NaH8 to afford
the monosilyl ether 12 (95%). Swern oxidation of 12 pro-
vided the aldehyde 8 (96%) which reacted with vinylmag-
nesium bromide followed by acetylation to give a 53:47
diastereomeric mixture of the acetates 13 in 73% overall
yield. Ozonolysis of 13 followed by treatment with Jones
reagent and CH2N2 afforded a diastereomeric mixture of
a-acetoxy esters 14 in 59% overall yield. This mixture
was hydrolysed to the diastereomeric mixture of a-hy-
droxy esters 15 and 6, which were separated to the less po-
lar alcohol (2S)-15 {45%, [a]D +4.0 (c = 0.80, CHCl3)}
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-Polyoxin J and (+)-Polyoxin L
1679
and the more polar one (2R)-6 {54%, [a]D –21.3 (c = 0.95, the (2S)-N-Boc ester 19 {81% overall yield, [a]D+1.4
CHCl3)}. Conversion of (2S)-15 into (2R)-6 was effected (c = 0.51, CHCl3)}. Desilylation of 19 with HF in pyri-
by treating 15 with trifluoromethanesulfonic anhydride dine gave the alcohol 20 {94%, [a]D+15.3 (c = 1.0,
(Tf2O) to form first the triflate 16 (90%). Reaction of tri- CHCl3)} which was subjected to carbamoylation by the
flate 16 with cesium acetate provided the (2R)-acetoxy es- reported procedure9 to furnish the desired N-protected
ter-14 {93%, [a]D –15.2 (c = 1.34, CHCl3)}. Hydrolysis carbamoylpolyoxamic acid ester 17 (Scheme 3) {97%
of (2R)-14 gave the inverted (2R)-hydroxy ester (6) {87%, overall yield, [a]D –2.7 (c = 1.05, CH2Cl2)}. Physical data
[a]D –21.8 (c = 1.25, CHCl3)} which is consistent with the ([a]D and NMR) of the prepared 17 were identical with
above mentioned (2R)-hydroxy ester 6 (Scheme 2).
those {[a]D –3.6 (c = 1.5, CH2Cl2) and NMR} of the re-
ported (2S,3S,4S)-17.7c
O
O
NaBH4
O
MeOOC
OH
COOMe
HO
1) Tf2O, pyridine
COOMe
2S
N3
MeOH
92%
6
TBDPSO
O
O
10
11
2) NaN3, DMF
98%
O
O
18
TBDPSCl, NaH
OH
TBDPSO
THF
95%
O
O
1) H2, 20% Pd(OH)2
2S COOMe
NHBoc
12
TBDPSO
2) Boc2O, Et3N, dioxane
81%
O
O
19
1) DMSO, (COCl)2
CHO
RO
O
2) Et3N
96%
O
HF, pyridine
94%
2S COOMe
NHBoc
HO
R=TBDPS 8
R=PhCH2
O
9
20
O
O
1) vinylmagnesium bromide
4
3
O
O
1) ClCOO-Ph-NO2 (p),
8
TBDPSO
pyridine, Et3N
2S COOMe
NHBoc
2) Ac2O, pyridine
73%
O
OAc
H2N
O
2) NH3, MeOH
97%
13
O
1) O3, CH2Cl2, -78°C
17
K2CO3
2) Me2S
COOMe
TBDPSO
Scheme 3
3) CrO3, H2SO4
MeOH
O
OAc
4) CH2N2
59%
14
O
O
The stereochemistry of 15 was also confirmed by compar-
ison with the reported N-protected 5-O-carbamoyl-(2R)-
polyoxamic acid derivative 24.7c Triflation of 15 followed
by treatment with NaN3 afforded the diastereomerically
pure (2R)-azide ester 21 {87% overall yield, [a]D –21.4
(c = 0.98, CHCl3)} which was subjected to hydrogenation
and subsequent N-Boc derivatization to provide the (2R)-
N-Boc ester 22 {62% overall yield, [a]D –26.2 (c = 1.02,
CHCl3)}. Desilylation of of 22 with HF in pyridine gave
the alcohol 23 {69%, [a]D –40.9 (c = 0.75, CHCl3)} which
was subjected to carbamoylation to afford the N-protected
carbamoylpolyoxamic acid ester 24 (Scheme 4) {67%
overall yield, [a]D –28.8 (c = 0.55, CH2Cl2)}. Physical
data ([a]D and NMR) of the 24 prepared were identical
with those {[a]D –26.5 (c = 1.8, CH2Cl2) and NMR} of the
reported (2R,3S,4S)-24.7c Thus, the configurations of the
newly generated chiral centers of a-hydroxy esters 6 and
15 were found to be R and S, respectively.
COOMe
2S
2R COOMe
OH
+
TBDPSO
TBDPSO
O
OH
O
15 (45%)
6 (54%)
O
Tf2O, pyridine
90%
COOMe
OTf
15
TBDPSO
O
16
O
K2CO3
AcOCs
2R COOMe
OAc
TBDPSO
6
DMF
93%
MeOH
87%
O
anti-14
Scheme 2
In order to determine the stereochemistry, the a-hydroxy
ester 6 was converted to the reported N-protected 5-O-car-
bamoyl-(2S)-polyoxamic acid derivative 17.7c Triflation
of 6 followed by treatment with NaN3 afforded the diaste-
reomerically pure (2S)-azide ester 18 {98% overall yield,
[a]D –16.2 (c = 1.02, CHCl3)} which was subjected to hy-
drogenation and subsequent N-Boc derivation to provide
In the nucleophilic addition of vinylmagnesium bromide
to the aldehyde 8, a low diastereoselectivity (53:47) was
observed. For the purpose of improving the diastereose-
lectivity, effect of coexisting metal halides in addition to
8 was examined (Scheme 5) and the results are shown in
the Table. The anti-selective addition of a nucleophile to
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

1680
K. Uchida et al.
PAPER
tiveness (diastereoselectivity and conversion yield), the
present synthetic route to the desired a-azide ester (2S)-18
by way of (2S)-15 and (2R)-6 seemed to be useful because
both (2S)-15 and (2R)-6 were finally converted to the im-
portant intermediate 18 for the synthesis of N-protected L-
carbamoyl-polyoxamic acid derivative 7.
O
1) Tf2O, pyridine
2R COOMe
N3
15
TBDPSO
2) NaN3, DMF
87%
O
21
O
1) H2, 20% Pd(OH)2
2R COOMe
NHBoc
TBDPSO
M
2) Boc2O, Et3N, dioxane
62%
H
O
O
22
Me
Me
TBDPSO
O
O
H
HF, pyridine
69%
2R COOMe
NHBoc
HO
O
O
Nu
23
O
Fig I
O
O
1) ClCOO-Ph-NO2 (p),
Figure Felkin–Anh model for the anti-selective addition of a nu-
cleophile to 8
pyridine, Et3N
2R COOMe
NHBoc
H2N
O
2) NH3, MeOH
67%
24
For the conversion of ester group in 17 to carboxylic acid
under mild conditions, it was transesterified with benzyl
alcohol into the benzyl ester 25 {[a]D –16.4 (c = 1.01,
CHCl3)} in the presence of Ti(OPr-i)4 in 82% yield. Cat-
alytic deprotection of benzyl group in 25 gave the desired
N-protected (2S)-carbamoylpolyoxamic acid derivative 7
{[a]D +1.03 (c = 0.775, acetone)} in quantitative yield,
which is consistent with the reported values.7c Successful
coupling of thymine polyoxin C (3)4 with the desired N-
protected (2S)-7 was carried out by the N,N-dicyclohexy-
Scheme 4
8 is explainable by the Felkin–Anh model10 as depicted in
the Figure. The b-chelation of metal ion enhances the Fel-
kin selectivity. The addition of nucleophile to 8 may be
controlled by the above mentioned reason since the
TBDPSOCH2-group is located trans to the reacting
formyl group on the dioxolane ring. The addition of vinyl
magnesium bromide to 8 in the presence of ZnBr2 fol-
lowed by acetylation raised anti-selectivity and afforded
(3,4)-anti-13 (Table, Entries 4, 5 and 6). When this reac-
tion was carried out at –78 °C, ratio of anti/syn was en-
hanced up to 8:1. On the contrary, without ZnBr2 the
addition was non-selective to give a 53:47 mixture of
(3,4)-anti- and (3,4)-syn-13 (Table, Entry 1). For large
scale preparation of (2R)-6, the 5:1 mixture of (3,4)-anti-
13 (Table, Entry 6) was converted to 6 [52% overall yield
from (3,4)-anti-13] as the main product by the same way
as stated above. From the point view of synthetic effec-
lcarbodiimide-N-hydroxysuccinimide (DCC-HOSu) ac-
5a
tive ester method
in DMSO and N,N-
diisopropylethylamine as the base. Thus, the treatment of
polyoxamic acid derivative 7 with DCC-HOSu gave the
active ester 26 which was condensed with 3 to afford the
dipeptide 27 (82% from 7). Removal of the N-Boc and O-
isopropylidene protecting groups upon acid hydrolysis
provided polyoxin J (1) (Scheme 6) {mp 195–200 °C
(dec), [a]D +35.7 (c = 0.68, H2O)} in 86% yield. The
physical properties of the 1 prepared were identical with
those of synthetic polyoxin J (1) {[a]D +33.0 (c = 0.75,
O
O
MgBr / additive
1)
4
4
3
3
+
8
TBDPSO
TBDPSO
2) Ac2O, pyridine
O
OAc
O
OAc
(3,4)-anti-13
(3,4)-syn-13
Table Reaction of 8 and Vinylmagnesium Bromide in the Presence of Additive
Entry
Substrate 8 (g)
Additive
Reaction Conditions
Yield of 13 (%)
Ratio of anti/syna
1
2
3
4
5
6
9.53
0.4
0.4
0.4
2
none
Et2AlCl
TiCl4/Ti(OPr-i)4 (1:1)
ZnBr2
ZnBr2
0°C, 2 h
–40 to 0°C, 3 h
0°C, 2 h
–40 to 0°C, 2 h
–78 to 0°C, 2 h
–78 to 0°C, 4 h
73
50
69
80
50
70
53:47
2:1
4:3
5:1
8:1
12
ZnBr2
5:1
a The anti/syn ratio was determined by NMR analysis of an integral value based on acetoxy groups [d = 2.05 (s), 2.07 (s)].
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-Polyoxin J and (+)-Polyoxin L
1681
H2O),5a mp 200–210 °C(dec.),5b [a]D +35.0 (c = 0.8,
H2O),5b and NMR,5b mp 200 °C(dec.),5c [a]D +30.3 (c =
0.10, H2O)5c}.
sured on a Jeol EX-400 spectrometer and spectra were taken as 5-
10% (w/v) solutions in CDCl3 with TMS as an internal reference. IR
spectra were measured on a Jasco FT/IR-300 spectrometer. FAB-
MS were obtained with a Jeol JMS-DX 303 instrument [matrix:
DDT/NBA; a 1:1 (v/v) mixture of dithiothreitol (DTT) and m-ni-
trobenzyl alcohol (NBA)12]. Optical rotations were measured on a
JASCO DIP-370 digital polarimeter. A11 the reactions were carried
out in an atmosphere of argon. A11 evaporations were performed
under reduced pressure.
O
O
PhCH2OH,
Ti(O-i-Pr)4
H2, 10% Pd-C
>99%
2S
COOCH2Ph
17
H2N
O
benzene
reflux
O
NHBoc
82%
25
(+)-2,3-O-Isopropyridene-L-threitol (11)
O
O
To a solution of 10 (12.61 g, 57.8 mmol) in MeOH (100 ml) was
added NaBH4 (4.72 g, 126 mmol) at 0 °C and the mixture was
stirred for 30 min. The mixture was diluted with H2O (500 mL), ex-
tracted with EtOAc (3 × 300 mL) and dried (MgSO4). Evaporation
of organic solvent gave an oily product which was chromato-
graphed on silica gel (300 g) with hexane/EtOAc (1:1) as eluent to
11 as a colorless oil; yield:8.64 g (92%); [a]D +3.8 (c = 2.1,
EtOH).
IR (neat): n = 3410 cm-1.
dicyclohexylcarbodiimide ,
(DCC)
2S
COOH
H2N
O
N-hydroxysuccinimide
AcOEt
O
NHBoc
7
O
25
O
O
thymine polyoxin C 3,
(i-Pr)2NEt
COO
N
H2N
O
O
DMSO
O
NHBoc
O
1H NMR: d = 1.43 (s, 6 H), 2.40 (br s, 2 H), 3.66–3.73 (m, 2 H),
3.76–3.83 (m, 2 H), 3.98–4.02 (m, 2 H).
MS (FAB): m/z = 163 (M++1).
26
Me
O
O
O
COOH
O
N
NH
N
H2N
O
H
4-O-tert-Butyldiphenylsilyl-2,3-O-Isopropyridene-L-threitol
(12)
O
NHBoc
O
OH
HO
To a solution of 11 (19.14 g, 118 mmol) in THF (200 mL) was add-
ed a 50% suspension of NaH in mineral oil (5.66 g, 118 mmol) at
0 °C and the mixture was stirred for 30 min. tert-Butyldiphenylsilyl
chloride (33.1 g, 118 mmol) was then added and the mixture was
stirred for 10 min. The mixture was diluted with H2O (300 mL), ex-
tracted with EtOAc (3 × 300 mL) and dried (MgSO4). Evaporation
of organic solvent gave an oily product which was chromato-
graphed on silica gel (200 g) using hexane/EtOAc (4:1) as eluent to
27 (82% from 7)
CF3COOH, MeOH-H2O (2:1)
86%
polyoxin J (1)
Scheme 5
24
12 as a colorless oil; yield: 44.96 g (95%); [a]D –0.09 (c = 1.1,
Likewise, condensation of the active ester 26 with uracil
polyoxin C (4) afforded the dipeptide 28 (74% from 7)
which was converted to polyoxin L (2) (Scheme 7) {mp
180–183°C (dec), ([a]D +35.0 (c = 1.215, H2O)} in 94%
yield. The physical properties of the 2 prepared were in
good agreement with the literature of natural polyoxin L
(2)11 {[a]D +34.4 (c = 1, H2O)} and constitutes its first to-
tal synthesis. The work described herein can be applicable
to the synthesis of other components of polyoxin fami-
lies.1a
CHCl3).
Anal. calcd for C23H32SiO4 (400.6): C, 68.96; H, 8.05. Found C,
68.73; H, 8.07.
IR (neat): n = 3464 cm-1.
1H NMR: d = 1.06 (s, 9 H), 1.39 (s, 3 H), 1.41 (s, 3 H), 3.65 (dd, 1
H, J = 4.5, 12 Hz), 3.74 (dd, 1 H, J = 6, 10.5 Hz), 3.80 (dd, 1 H, 4,
12 Hz), 3.82 (dd, 1 H, J = 4, 10.5 Hz), 3.97 (ddd, 1 H, J = 4, 6, 8
Hz), 4.07 (dt, 1 H, J = 4, 8 Hz), 7.37–7.46 (m, 6 H), 7.65–7.68 (m,
4 H).
MS (FAB): m/z = 401 (M++1).
All melting points were measured on a Yanaco MP-S3 micro melt-
ing point apparatus and are uncorrected. NMR spectra were mea-
4-O-tert-butyldiphenylsilyl-2,3-isopropylidene-L-threose (8)
To a solution of DMSO (7.09 mL, 100 mmol) in CH2Cl2 (80 mL)
was added oxalyl chloride (4.23 mL, 50 mmol) at –78 °C and the
mixture was stirred for 30 min. A solution of 12 (10 g, 25 mmol) in
CH2Cl2 (20 ml) was the added and the mixture was stirred for 50
min. Et3N (27.67 mL, 200 mmol) was added and the mixture was
stirred at r.t., for 15 min. The mixture was diluted with H2O (300
mL), extracted with EtOAc (3 × 300 mL) and dried (MgSO4). Evap-
oration of organic solvent gave an oily product which was chro-
matographed on silica gel (100 g) with hexane/EtOAc (9:1) as
eluent to give 8 as a colorless oil; yield: 9.53 g (96%); [a]D24 –2.89
(c = 1.07, CHCl3).
uracil polyoxin C 4,
(i-Pr)2NEt
dicyclohexylcarbodiimide ,
(DCC)
7
26
N-hydroxysuccinimide
AcOEt
DMSO
O
NH
O
O
O
COOH
O
N
N
H2N
O
H
O
NHBoc
O
OH
HO
1H NMR: d = 1.06 (s, 9 H), 1.42 (s, 3 H), 1.49 (s, 3 H), 3.81 (dd, 1
H, J = 4.5, 11 Hz), 3.86 (dd, 1 H, J = 4.5, 11 Hz), 4.18 (dt, 1 H,
J = 4.5, 7 Hz), 4.43 (dd, 1 H, J = 1.5, 7 Hz), 7.37–7.47 (m, 6 H),
7.66–7.71 (m, 4 H), 9.79 (d, 1 H, J = 1.5 Hz).
28 (74% from 7)
CF3COOH, MeOH-H2O (2:1)
94%
polyoxin L (2)
MS (FAB): m/z = 399 (M++1).
Scheme 6
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

1682
K. Uchida et al.
PAPER
Reaction of 8 and Vinylmagnesium Bromide (Table, Entry 1)
To a solution of 8 (9.53 g, 23.9 mmol) in THF (90 mL) at 0 °C was
added vinylmagnesium bromide (1 M in THF, 95.6 mL (95.6
mmol)). The mixture was stirred at 0 °C for 2 h, diluted with 1 M aq
HCl (150 mL) and extracted with EtOAc (2 × 300 mL). The extract
was washed with brine (100 mL), dried (MgSO4) and concentrated.
To a solution of the crude product in pyridine (60 mL, 742 mmol)
at 0 °C was added Ac2O (27 mL, 286 mmol). The mixture was
stirred for 12 h, diluted with H2O (200 mL) and extracted with
EtOAc (2 × 300 mL). The organic layer was washed with 10% aq
HCl (100 mL), brine (100 mL), dried (MgSO4) and evaporated. The
residue was chromatographed on silica gel (200 g) with hexane/
EtOAc (9:1) as eluent to give a mixture of (3,4)-anti-13 and (3,4)-
syn-13 (anti/syn = 53:47) as a colorless oil; yield: 8.16 g (73%).
diluted with H2O (100 mL) and extracted with Et2O (2 × 100 mL).
The organic layer was dried (MgSO4) and evaporated. The residue
was chromatographed on silica gel (100 g) with hexane/EtOAc
(14:1) as eluent to afford 15 (1.07 g, 45%) and 6 (1.26 g, 54%) as
colorless oils.
15
[a]D23 +4.0 (c = 0.8, CHCl3).
Anal.calcd for C25H34SiO6•5 H2O (467.6): C, 64.21; H, 7.54. Found
C, 64.39; H, 7.43.
IR (neat): n = 3501, 1748 cm-1.
1H NMR: d = 1.07 (s, 9 H), 1.38 (s, 3 H), 1.42 (s, 3 H), 3.02 (d, 1 H,
J = 9 Hz), 3.77 (dd, 1 H, J = 4, 10.5 Hz), 3.85 (s, 3 H), 3.88 (dd, 1
H, J = 6, 10.5 Hz), 4.26 (dd, 1 H, J = 1, 9 Hz), 4.30 (ddd, 1 H, J = 4,
6, 8 Hz), 4.32 (dd, 1 H, J = 1, 8 Hz), 7.37–7.47 (m, 6 H), 7.66–7.72
(m, 4H).
Anal. calcd for C27H37SiO6 (468.7): C, 69.20; H, 7.74. Found C,
69.04; H, 8.11.
IR (neat): n = 1747 cm-1.
MS (FAB): m/z = 443 (M+ – CH3).
1H NMR: d = 1.07 (s, 18 H), 1.42 (s, 12 H), 2.05 (s, 3 H), 2.07 (s, 3
H), 3.70 (dd, 1 H, J = 4, 11 Hz), 3.72 (dd, 1 H, J = 4, 11 Hz), 3.81
(dd, 1 H, J = 4, 11 Hz), 3.82 (dd, 1 H, J = 4, 11 Hz), 3.95 (dt, 1 H,
J = 4, 8 Hz), 3.98 (dt, 1 H, J = 4, 8 Hz), 4.18 (dd, 1 H, J = 6.5, 8 Hz),
4.20 (dd, 1 H, J = 4, 8 Hz), 5.24 (dd, 1 H, J = 1, 10.5 Hz), 5.28 (dd,
1 H, J = 1, 10.5 Hz), 5.30 (dd, 2 H, J = 1, 17 Hz), 5.38 (dd, 1 H,
J = 5.5, 6.5 Hz), 5.45 (dd, 1 H, J = 4, 6.5 Hz), 5.75 (ddd, 1 H,
J = 5.5, 10.5, 17 Hz), 5.83 (ddd, 1 H, J = 6.5, 10.5, 17 Hz), 7.36–
7.45 (m, 12 H), 7.66–7.71 (m, 8 H).
6
[a]D24 –21.3 (c = 0.95, CHCl3).
Anal. calcd for C25H34SiO6•0.5 H2O (467.6): C, 64.21; H, H, 7.54.
Found C, 64.71; H, 7.54.
IR (neat): n = 3464, 1744 cm-1.
1H NMR: d = 1.07 (s, 9 H), 1.40 (s, 3 H), 1.41 (s, 3 H), 3.06 (d, 1 H,
J = 6 Hz), 3.70 (dd, 1 H, J = 4, 11 Hz), 3.75 (s, 3 H), 3.80 (dt, 1 H,
J = 4.5, 11 Hz), 4.23 (ddd, 1 H, J = 4, 4.5, 8 Hz), 4.31 (dd, 1 H,
J = 4, 8 Hz), 4.39 (dd, 1 H, J = 4, 6 Hz), 7.36–7.47 (m, 6 H), 7.66–
7.71 (m, 4 H).
MS (FAB): m/z = 453 (M+ – CH3).
Ozonolysis of a Mixture of (3,4)-anti-13 and (3,4)-syn-13
Ozone was passed through a solution of a mixture of (3,4)-anti-13
and (3,4)-syn-13 (anti : syn = 53:47, 8.16 g, 17.4 mmol) in CH2Cl2
(80 mL) at –78°C for 4.5 h followed by the addition of Me2S (16
mL, 188 mmol). The mixture was stirred at r.t. for 30 min and evap-
orated. The residue was dissolved in acetone (80 mL) and Jones re-
agent (8.16 mL, 26.1 mmol) was added at –20 °C. The mixture was
stirred for 30 min at the same temperature and treated with isopro-
pyl alcohol (5 mL). The mixture was diluted with H2O (100 mL)
and extracted with Et2O (3 × 200 ml). After evaporation, the residue
was chromatographed on silica gel (200 g) with CHCl3/MeOH (4:1)
as eluent to give an amorphous product (7.54 g). A solution of the
amorphous product in Et2O (50 mL) was treated with an excess of
CH2N2 in Et2O at 0°C. The mixture was stirred at r.t. for 30 min and
evaporated. The residue was chromatographed on silica gel (200 g)
using hexane/EtOAc (14:1) as eluent to give a mixture of (2R)-14
and (2S)-14 as a colorless oil; yield: 5.13 g (59%).
MS (FAB): m/z = 443 (M+ – CH3).
Conversion of 15 into (2R)-14
To a solution of 15 (371 mg, 0.81 mmol) in CH2Cl2 (4 mL) at 0 °C
was added pyridine (0.65 mL, 8.1 mmol) and Tf2O (0.2 mL, 1.21
mmol) and the mixture was stirred for 20 min. It was then diluted
with H2O (20 mL), extracted with Et2O (2 × 20 mL). The organic
layer was washed with 1 M aq HCl (10 mL), brine and dried
(MgSO4). After evaporation, the residue was chromatographed on
silica gel (20 g) with hexane/EtOAc (19:1) as eluent to afford 16
(428 mg, 90%) as a colorless oil. To a solution of a part of 16 (124
mg, 0.21 mmol) in DMF (1 mL) was added CsOAc (81 mg, 0.42
mmol) and the mixture was stirred for 1 h. It was diluted with H2O
(20 mL), extracted with Et2O (2 × 20 mL). The organic layer was
washed with brine and dried (MgSO4). After evaporation, the resi-
due was chromatographed on silica gel (20 g) with hexane/EtOAc
(19:1) as eluent to afford (2R)-14 (97 mg, 81% overall yield from
15) as a colorless oil; [a]D24 –15.2 (c = 1.34, CHCl3).
Anal. calcd for C27H36SiO7 (500.7): C, 64.77; H, 7.25. Found C,
64.77; H, 7.35.
IR (neat): n = 1754 cm-1.
Anal. clcd for C27H36SiO7·H2O (518.7): C, 62.52; H, 7.38. Found C,
1H NMR: d = 1.06 (s, 9 H), 1.07 (s, 9 H), 1.38(s, 3 H), 1.40 (s, 3 H),
1.43 (s, 3 H), 1.44 (s, 3 H), 2.15 (s, 3 H), 2.18 (s, 3 H), 3.70–3.80
(m, 2 H), 3.71 (s, 3 H), 3.72 (dd, 1H, J = 4, 11 Hz), 3.78 (s, 3 H),
3.81 (dd, 1 H, J = 4, 11 Hz), 4.08 (ddd, 1 H, J = 4.5, 5.5, 7.5 Hz),
4.34 (dt, 1 H, J = 4, 8 Hz), 4.42 (dd, 1 H, J = 3, 8 Hz), 4.52 (dd, 1
H, J = 3, 8 Hz), 5.18 (d, 1 H, J = 3 Hz),. 5.25 (d, 1 H, J = 3 Hz),
7.37–7.46 (m, 12 H), 7.66–7.7 (m, 8 H).
62.55; H, 7.32.
IR (neat):n = 1754 cm-1.
1H NMR: d = 1.06 (s, 9 H), 1.38 (s, 3 H), 1.43 (s, 3 H), 2.15 (s, 3 H),
3.71 (s, 3 H), 3.72 (dd, 1 H, J = 4, 11 Hz), 3.81 (dd, 1 H, J = 4, 11
Hz) 4.34 (dt, 1 H, J = 4, 8 Hz),4.42 (dd, 1 H, J = 3, 8 Hz), 5.25 (d,
1 H, J = 3 Hz), 7.37–7.46 (m, 6 H), 7.66–7.70 (m, 4 H).
MS (FAB): m/z = 485 (M+ – CH3).
Methyl 5-O-tert-Butyldiphenysilyl-3,4-O-isopropylidene-L-lyx-
onate (6)
Methyl 5-O-tert-Butyldiphenysilyl-3,4-O-isopropylidene-L-xy-
lonate (15)
and Methyl 5-O-tert-Butyldiphenysilyl-3,4-O-isopropylidene-L-
lyxonate (6)
To a solution of a mixture of (2R)-14 and (2S)-14 (2.57 g, 5.13
mmol) in MeOH (20 mL) was added K2CO3 (0.78 g, 5.64 mmol) at
0 °C and the mixture was stirred for 40 min at 0 °C. The mixture was
To a solution of 14 (91 mg, 0.18 mmol) in MeOH (2 mL) was added
K2CO3 (0.78 g, 5.64 mmol) at 0 °C and the mixtutre was stirred for
1 h. The mixture was diluted with H2O (10 mL) and extracted with
Et2O (2 × 20 mL). The organic layer was dried (MgSO4) and evap-
orated. The residue was chromatographed on silica gel (30 g) with
hexane/EtOAc (9:1) as eluent to afford 6 (72 mg, 87%) as a color-
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-Polyoxin J and (+)-Polyoxin L
1683
less oil; [a]D21 –21.8 (c = 1.25, CHCl3). Pyhsical data (IR and NMR)
were identical with those of the above mentioned 6.
4.36 (dd, 1 H, J = 2, 8.5 Hz), 4.45 (dd, 1 H, J = 2, 9 Hz), 5.39 (d, 1
H, J = 9 Hz).
MS (FAB): m/z = 320 (M++1).
Methyl 2-Azido-5-O-tert-butyldiphenysilyl-2-deoxy-3,4-O-iso-
propylidene-L-xylonate (18)
Methyl 5-O-(Aminocarbonyl)-2-(tert-butoxycarbonyl)amino-2-
deoxy-3,4-O-isopropylidene-L-xylonate (17):
To a solution of 6 (395 mg, 0.86 mmol) in CH2Cl2 (4 mL) at 0 °C
was added pyridine (0.7 mL, 8.6 mmol) and Tf2O (0.21 mL, 1.29
mmol) and the mixture was stirred for 20 min. It was diluted with
H2O (20 mL), extracted with Et2O (2 × 20 mL). The organic layer
was washed with 1 M aq HCl (10 mL), brine, dried (MgSO4) and
concentrated. To a solution of the crude product in DMF (4 mL) was
added NaN3 (84 mg, 1.29 mmol) at 0 °C and the mixture was stirred
at r.t. for 30 min. It was diluted with H2O (30 mL) and extracted
with Et2O (2 × 20 mL). The organic layer was dried (MgSO4) and
evaporated. The residue was chromatographed on silica gel (25 g)
with hexane/EtOAc (19:1) as eluent to give 18 as a colorless oil;
yield 409 mg (98%); [a]D24 –16.2 (c = 1.02, CHCl3).
To a solution of 20 (176 mg, 0.55 mmol) in THF (0.6 mL)/Et2O (1.5
mL) at –20 °C was added pyridine (0.29 mL, 3.58 mmol), Et3N (0.1
mL, 0.72 mmol) and 4-nitrophenyl chloroformate (167 mg, 0.825
mmol) and the mixture was stirred for 1 h at the same temperature.
After the mixture was stored in a refrigerator for 3 days, it was
diluted with H2O (50 mL), extracted with EtOAc (2 × 20 mL). The
organic layer was washed with 1 M aq HCl (10 ml), 7% aq NaHCO3
solution, dried (MgSO4) and concentrated. To a solution of the
crude residue in MeOH (8 mL) was added an cxcess of 8% NH3 in
MeOH at 0 °C and the mixture was stirred for 30 min. The mixture
was evaporated to give the crude product, which was chromato-
graphed on silica gel (20 g) with hexane/EtOAc (3:1) as eluent to
Anal. calcd for C25H33N3O5Si•0.5 H2O (492.7): C, 60.95; H, 6.96;
N, 8.53. Found C, 60.88; H, 6.68; N, 8.35.
IR (neat): n = 2118, 1752 cm-1.
1H NMR: d = 1.06 (s, 9 H), 1.38 (s, 3 H), 1.49 (s, 3 H), 3.74 (dd, 1
H, J = 6.5, 10.5 Hz), 3.82 (d, 1 H, J = 2 Hz), 3.86 (dd, 1 H, J = 4,
10.5 Hz), 3.87 (s, 3 H), 4.24 (ddd, 1 H, J = 4, 6.5 8 Hz), 4.52 (dd, 1
H, J = 2, 8 Hz), 7.37–7.47 (m, 6 H), 7.64–7.68 (m, 4 H).
22
affod 17 as a colorless oil; yield: 194 mg (97%); [a]D –2.7
(c = 1.05, CH2Cl2).
Anal. calcd for C15H26N2O8 (362.4): C, 49.72; H, 7.23; N, 7.73.
Found C, 50.26; H, 7.57; N, 7.84.
IR (KBr): n = 3455, 2984,1727, 1609 cm-1.
1H NMR: d = 1.38 (s, 3 H), 1.42 (s, 3 H), 1.45 (s, 9 H), 3.79 (s, 3 H),
4.02 (dt, 1 H, J = 5, 8 Hz), 4.23–4.30 (m, 3 H), 4.50 (dd, 1 H,
J = 1.5, 9.5 Hz), 4.80 (br s, 2 H), 5.25 (d, 1 H, J = 9.5 Hz).
MS (FAB): m/z = 484 (M++1).
MS (FAB): m/z = 363 (M++1).
Methyl 5-O-tert-Butyldiphenysilyl-2-(tert-butoxycarbonyl)ami-
no-2-deoxy-3,4-O-isopropylidene-L-xylonate (19)
A mixture of 18 (561 mg, 1.16 mmol) and 20% Pd(OH)2 on carbon
(81 mg) in MeOH (6 mL) was subjected to catalytic hydrogenation
at r.t. for 12 h and the mixture was filtered with the aid of Celite. The
filtrate was evaporated to give the crude product. To a solution of
the crude product in dioxane (6 mL) was added Et3N (0.24 g, 2.32
mmol) and di-tert-butyl dicarbonate (0.39 g, 1.74 mmol) at r.t. and
the mixture was stirred for 75 min. The mixture was diluted with
H2O (10 mL), extracted with Et2O (50 mL), dried (MgSO4) and con-
centrated. The residue was chromatographed on silica gel (30g)
with hexane/EtOAc (19:1) as eluent to provide 19 as a colorless oil;
yield: 521 mg (81%); [a]D26 +1.4 (c = 0.51, CHCl3).
Methyl 2-Azido-5-O-tert-butyldiphenysilyl-2-deoxy-3,4-O-iso-
propylidene-L-lyxonate (21)
To a solution of 15 (381 mg, 0.83 mmol) in CH2Cl2 (4 mL) at 0 °C
was added pyridine (0.67 mL, 8.3 mmol) and Tf2O (0.21 mL, 1.25
mmol) and the mixture was stirred for 20 min. It was diluted with
H2O (20 mL), extracted with Et2O (2 × 20 mL). The organic layer
was washed with 1 M aq HCl (10 mL), brine, dried (MgSO4) and
concentrated. To a solution of the crude product in DMF (2 mL) was
added NaN3 (81 mg, 1.25 mmol) at 0 °C and the mixture was stirred
at r.t. for 20 min. It was diluted with H2O (30 mL) and extracted
with Et2O (2 × 20 mL). The organic layer was dried (MgSO4) and
evaporated. The residue was chromatographed on silica gel (25 g)
with hexane/EtOAc (19:1) as eluent to give 21 as a colorless oil;
yield 348 mg (87%); [a]D23 –21.4 (c = 0.98, CHCl3).
Anal. calcd for C30H43NO7Si (557.8): C, 64.60; H, 7.77; N, 2.51.
Found C, 64.31; H, 8.15; N, 2.89.
IR (KBr): n = 3446, 2937, 2864, 1750, 1720 cm-1.
1H NMR: d = 1.07 (s, 9 H), 1.38 (s, 3 H), 1.42 (s, 3 H), 1.45 (s, 9 H),
3.80 (s, 3 H), 3.77–3.86 (m, 2 H), 3.96 (dt, 1 H, J = 4, 8 Hz), 4.48
(d, 1 H, J = 10 Hz), 4.59 (d, 1 H, J = 8 Hz), 5.31 (d, 1 H, J = 10 Hz),
7.36–7.46 (m, 6 H), 7.68–7.73 (m, 4 H).
Anal. calcd for C25H33N3O5Si (483.6): C, 62.09; H, 6.88; N, 8.69.
Found C, 62.07; H, 6.85; N, 8.50.
IR (neat): n = 2112, 1749 cm-1.
1H NMR: d = 1.08 (s, 9 H), 1.43 (s, 6 H), 3.68 (dd, 1 H, J = 4, 11
Hz), 3.75 (s, 3 H), 3.83 (dd, 1 H, J = 4, 11 Hz), 4.21 (d, 1 H, J = 4.5
Hz), 4.24 (ddd, 1 H, J = 4, 4, 7.5 Hz), 4.46 (dd, 1 H, J = 4.5, 7.5 Hz),
7.37–7.46 (m, 6 H), 7.67–7.71 (m, 4 H).
MS (FAB): m/z = 558 (M++1).
Methyl 2-(tert-Butoxycarbonyl)amino-2-deoxy-3,4-O-isopropy-
lidene-L-xylonate (20)
MS (FAB): m/z = 484 (M++1).
To a solution of 19 (1.15 g, 2.06 mmol) in pyridine (10 mL) at 0 °C
was added aq 48% HF (2 mL) and the mixture was stirred at r.t. for
3 h. It was diluted with H2O (50 mL), extracted with EtOAc
(2 x 100 mL). The organic layer was washed with 1 M aq HCl (10
mL), 7% aq NaHCO3 solution, dried (MgSO4) and concentrated.
The residue was chromatographed on silica gel (30 g) with hexane/
EtOAc (3:1) as eluent to give 20 as a colorless oil; yield: 620 mg
(94%); [a]D24 +15.3 (c = 1.0, CHCl3).
Methyl 5-O-tert-Butyldiphenysilyl-2-(tert-butoxycarbonyl)ami-
no-2-deoxy-3,4-O-isopropylidene-L-lyxonate (22)
A mixture of 21 (354 mg, 0.73 mmol) and 20% Pd(OH)2 on carbon
(51 mg) in MeOH (4 mL) was subjected to catalytic hydrogenation
at r.t. for 12 h and the mixture was filtered with the aid of Celite. The
filtrate was evaporated to give the crude product. To a solution of
the crude product in dioxane (4 mL) was added Et3N (0.20 g, 1.47
mmol) and di-tert-butyldicarbonate (0.26 g, 1.1 mmol) at r.t. and the
mixture was stirred for 75 min. The mixture was diluted with H2O
(10 mL), extracted with Et2O (50 mL), dried (MgSO4) and concen-
trated. The residue was chromatographed on silica gel (30g) with
Anal. calcd for C14H25NO7 (319.4): C, 52.66; H, 7.89; N, 4.39.
Found C, 52.23; H, 8.36; N, 4.28.
IR (neat): n = 3448, 2984, 2936, 1749, 1712 cm-1.
1H NMR: d = 1.39 (s, 3 H), 1.40 (s, 3 H), 1.45 (s, 9 H), 2.33 (t, 1 H,
J = 6 Hz), 3.79 (s, 3 H), 3.80 (m, 2 H), 3.90 (dt, 1 H, J = 4, 8.5 Hz),
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

1684
K. Uchida et al.
PAPER
hexane/EtOAc (14:1) as eluent to provide 22 as a colorless oil;
yield: 253 mg (62%); [a]D27 –26.2 (c = 1.02, CHCl3).
The extract was washed with brine (20 mL), dried (MgSO4) and
concentrated. To a solution of the crude product in pyridine (1 mL,
12.9 mmol) at 0 °C was added Ac2O (0.5 mL, 5.3 mmol). The mix-
ture was stirred at r.t. for 6 h, diluted with H2O (50 mL) and extract-
ed with EtOAc (30 mL). The organic layer was washed with brine
(20 mL), dried (MgSO4) and evaporated. The residue was chro-
matographed on silica gel (20 g) with hexane/EtOAc (9:1) as eluent
to give a mixture of (3,4)-anti-13 and (3,4)-syn-13 (anti : syn = 2:1)
as a colorless oil; yield: 233 mg (50%).
Anal. calcd for C30H43NO7Si (557.8): C, 64.60; H, 7.77; N, 2.51.
Found C, 64.44; H, 8.09; N, 2.57.
IR(KBr): n = 3436, 2930, 1746, 1713 cm-1.
1H NMR: d = 1.07 (s, 9 H), 1.36 (s, 3 H), 1.38 (s, 3 H), 1.42 (s, 9 H),
3.68–3.73 (m, 1 H), 3.73 (s, 3 H), 3.76–3.82 (m, 1 H), 4.21–4.28 (m,
2 H), 4.45–4.51 (m, 1 H), 5.29 (br s, 1 H), 7.36–7.49 (m, 6 H), 7.68–
7.72(m, 4 H).
Reaction of 8 and Vinylmagnesium Bromide in the Presence of
TiCl4 and Ti(O-i-Pr)4 (Table, Entry 3)
MS (FAB): m/z = 558 (M++1).
To a solution TiCl4 (0.22 mL, 2 mmol) and Ti(OPr-i)4 (0.59 mL, 2
mmol) in THF (10 mL) at –40 °Cwas added vinylmagnesium bro-
mide (1 M in THF, 2 mL, 2 mmol), and the mixture was stirred at –
40 °Cfor 10 min. A solution of 8 (400 mg, 1 mmol) in THF (4 mL)
was added to the above mixture at 0 °C, and the mixture was stirred
at –40 °Cfor 10 min and stirred at 0 °C for 2 h. The mixture was di-
luted with H2O (50 mL) and extracted with EtOAc (3 × 30 mL). The
extract was washed with brine (20 mL), dried (MgSO4) and concen-
trated. To a solution of crude product in pyridine (1 mL, 12.9 mmol)
at 0 °Cwas added Ac2O (0.5 mL, 5.3 mmol). The mixture was
stirred at room temperature for 6 h, diluted with H2O (50 mL) and
extracted with EtOAc (30 mL). The organic layer was washed with
brine (20 mL), dried (MgSO4) and evaporated. The residue was
chromatographed on silica gel (20 g) with hexane/EtOAc (9:1) as
eluent to give a mixture of (3,4)-anti-13 and (3,4)-syn-13 (anti :
syn = 4:3) as a colorless oil; yield: 322 mg (69%).
Methyl 2-(tert-Butoxycarbonyl)amino-2-deoxy-3,4-O-isopropy-
lidene-L-lyxonate (23)
To a solution of 22 (133 mg, 0.24 mmol) in pyridine (2 mL) at 0 °C
was added aq 48% HF (0.6 mL) and the mixture was stirred for 4 h.
It was diluted with H2O (10 mL), extracted with EtOAc (2 x 20
mL). The organic layer was washed with 1 M aq HCl (10 mL), 7%
aq NaHCO3 solution, dried (MgSO4) and concentrated. The residue
was chromatographed on silica gel (20 g) with hexane/EtOAc (2:1)
26
as eluent to give 23 as a colorless oil; yield: 52 mg (69%); [a]D
40.9 (c = 0.75, CHCl3).
–
Anal. calcd for C14H25NO7•H2O (337.4): C, 49.84; H, 8.07; N, 4.15.
Found C, 49.53; H, 7.84; N, 4.10.
IR (neat): n = 3443, 2984, 2936, 1714, 1518 cm-1.
1H NMR: d = 1.36 (s, 3 H), 1.39 (s, 3 H), 1.44 (s, 9 H), 2.40 (br s,,
1 H), 3.78 (s, 3 H), 3.68–3.84 (m, 2 H), 4.08 (dd, 1 H, J = 4, 8 Hz),
4.23 (dt, 1 H, J = 4, 8 Hz), 4.51 (br s, 1 H), 5.44 (br s, 1 H).
Reaction of 8 and Vinylmagnesium Bromide in the Presence of
ZnBr2 (Table, Entry 4)
MS (FAB): m/z = 320 (M++1).
To a mixture of ZnBr2 (450 mg, 2 mmol) in THF (5 mL) at –40
°Cwas added vinylmagnesium bromide (1 M in THF, 2 mL, 2
mmol), and the mixture was stirred at –40 °C for 10 min. A solution
of 8 (400 mg, 1 mmol) in THF (4 mL) was added to be above mix-
ture at –40 °C, and the mixture was stirred at –40 °C for 10 min and
stirred at 0 °C for 2 h. The mixture was diluted with H2O (50 mL)
and extracted with EtOAc (3 × 30 mL). The extract was washed
with brine (20 mL), dried (MgSO4) and concentrated. To a solution
of the crude product in pyridine (1 mL, 12.9 mmol) at 0 °C was add-
ed Ac2O (0.5 mL, 5.3 mmol). The mixture was stirred at r.t. for 6 h,
diluted with H2O (50 mL) and extracted with EtOAc (30 mL). The
organic layer was washed with brine (20 mL), dried (MgSO4) and
evaporated. The residue was chromatographed on silica gel (20 g)
with hexane/EtOAc (9:1) as eluent to give a mixture of (3,4)-anti-
13 and (3,4)-syn-13 (anti : syn = 5:1) as a colorless oil; yield: 375
mg (80%).
Methyl 5-O-(Aminocarbonyl)-2-(tert-butoxycarbonyl)amino-2-
deoxy-3,4-O-isopropylidene-L-lyxonate (24)
To a solution of 23 (38 mg, 0.12 mmol) in THF (0.4 mL)/Et2O (1
mL) at –20 °C was added pyridine (0.063 mL, 0.78 mmol), Et3N
(0.034 mL, 0.24 mmol) and 4-nitrophenyl chloroformate (36 mg,
0.18 mmol) and the mixture was stirred for 1 h at the same temper-
ature. After the mixture was stored in a refrigerator for 3 days, it was
diluted with H2O (10 mL), extracted with EtOAc (2 × 20 mL). The
organic layer was washed with 1 M aq HCl (1 mL), 7% aq NaHCO3
solution, dried (MgSO4) and concentrated. To a solution of the
crude residue in MeOH (1 mL) was added an cxcess of 8% NH3 in
MeOH at 0 °C and the mixture was stirred for 30 min. The mixture
was evaporated to give the crude product, which was chromato-
graphed on silica gel (20 g) with hexane/EtOAc (2:1) as eluent to
26
affod 24 as a colorless oil; yield: 29 mg (67%); [a]D –28.8
(c = 0.55, CH2Cl2).
Major product; (3,4)-anti-13
1H NMR: d = 1.07 (s, 9 H), 1.40 (s, 3 H), 1.42 (s, 3 H), 2.05 (s, 3 H),
3.72 (dd, 1 H, J = 4, 11 Hz), 3.82 (dd, 1 H, J = 4, 11 Hz), 3.98 (dt,
1 H, J = 4, 8 Hz), 4.20 (dd, 1 H, J = 4, 8 Hz), 5.28 (dd, 1 H, J = 1,
10.5 Hz), 5.30 (dd, 1 H, J = 1, 17 Hz), 5.45 (dd, 1 H, J = 4, 6.5 Hz),
5.83 (ddd, 1 H, J = 6.5, 10.5, 17 Hz), 7.37–7.43 (m, 6 H), 7.67–7.71
(m, 4 H).
Anal. calcd for C15H26N2O8 (362.4): C, 49.72; H, 7.23; N, 7.73.
Found C, 50.04; H, 7.53; N, 7.34.
IR (KBr): n = 3440, 3363, 2927,1749, 1690, 1523, 1431 cm-1.
1H NMR: d = 1.36 (s, 3 H), 1.38 (s, 3 H), 1.43 (s, 9 H), 3.78 (s, 3 H),
4.02 (dd, 1 H, J = 4, 8 Hz), 4.15 (dd, 1 H, J = 5, 11 Hz), 4.24 (dd, 1
H, J = 5.5, 11 Hz), 4.34 (m, 1 H), 4.60 (dd, 1 H, J = 4, 9 Hz), 4.94
(br s, 2 H), 5.43 (d, 1 H, J = 9 Hz).
Reaction of 8 and Vinylmagnesium Bromide in the Presence of
ZnBr2 (Table, Entry 5)
MS (FAB): m/z = 363 (M++1).
To a mixture of ZnBr2 (2.25 g, 10 mmol) in THF (40 mL) at –78 °C
was added vinylmagnesium bromide (1 M in THF, 11 mL, 11
mmol), and the mixture was stirred at –78°C for 30 min. A solution
of 8 (2.0 g, 5 mmol) in THF (10 mL) was added to the above mix-
ture at –78 °C, and the mixture was stirred at –78 °C for 10 min and
stirred at 0 °Cfor 2 h. The mixture was diluted with H2O (100 mL)
and extracted with EtOAc (100 mL). The extract was washed with
brine (50 mL), dried (MgSO4) and concentrated. The crude product
was dissolved in pyridine (4 mL, 49.5 mmol) at 0 °C and treated
Reaction of 8 and Vinylmagnesium Bromide in the Presence of
Et2AlCl (Table, Entry 2)
To a solution of Et2AlCl [1.08 M in hexane. 1.85 mL (2.0 mmol)]
was added vinylmagnesium bromide (1 M in THF, 2 mL, 2 mmol),
and the mixture was stirred at –78 °C for 10 min. A solution of 8
(400 mg, 1 mmol) in THF (4 mL) was added to the above mixture
at 0 °C, and the mixture was stirred at 0 °C for 3 h. The mixture was
diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL).
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (+)-Polyoxin J and (+)-Polyoxin L
1685
with Ac2O (3 mL, 31.8 mmol). The mixture was stirred at r.t. for 12
h, diluted with H2O (50 mL) and extracted with EtOAc (100 mL).
The organic layer was washed with brine (20 mL), dried (MgSO4)
and evaporated. The residue was chromatographed on silica gel (50
g) with hexane/EtOAc (9:1) as eluent to give a mixture of (3,4)-anti-
13 and (3,4)-syn-13 (anti : syn = 8:1) as a colorless oil; yield:1.18 g
(50%).
(br s, 2 H), 5.16 (d, 1 H, J = 12.5 Hz), 5.29 (d, 1 H, J = 12.5 Hz),
5.30 (d, 1 H, J = 10 Hz), 7.35 (m, 5 H).
13C NMR (CDCl3) : d = 26.7, 26.8, 28.2, 53.1, 64.0, 67.4, 74.8, 78.2,
109.9, 128.0, 128.3, 128.5, 135.2, 155.8, 156.2, 170.0.
MS (FAB): m/z = 439 (M++1).
5-O-(Aminocarbonyl)-2-(tert-butoxycarbonyl)amino-2-deoxy-
3,4-O-isopropylidene-L-xylonic acid (7)
Reaction of 8 and Vinylmagnesium Bromide in the Presence of
ZnBr2 (Table, Entry 6)
A mixture of 25 (86 mg, 0.196 mmol) and 10% Pd/C (50 mg) in
MeOH (6 mL) was subjected to catalytic hydrogenation at r.t. for 30
min and the mixture was filtered with the aid of Celite. The filtrate
was evaporated to give 7 as a colorless oil; yield: 68 mg (>99%);
[a]D28 +1.03 (c = 0.775, acetone).
i) To a mixture of ZnBr2 (10 g, 44.4 mmol) in THF (200 mL) at
–78 °C was added vinylmagnesium bromide (1 M in THF, 45 mL,
45 mmol), and the mixture was stirred at –78°C for 30 min. A solu-
tion of 8 (12 g, 30.1 mmol) in THF (30 mL) was added at –78 °C,
and the mixture was stirred at –78 °C for 1 h and stirred at 0 °C for
3 h. The mixture was diluted with H2O (300 mL) and extracted with
EtOAc (3 × 300 mL). The extract was washed with brine (200 mL),
dried (MgSO4) and concentrated. To a solution of the crude product
in pyridine (5 mL, 63.3 mmol) at 0 °C was added Ac2O (5 mL, 49
mmol). The mixture was stirred at r.t. for 6 h, diluted with H2O (200
mL) and extracted with EtOAc (3 × 100 mL). The organic layer was
washed with brine (200 mL), dried (MgSO4) and evaporated. The
residue was chromatographed on silica gel (200 g) with hexane/
EtOAc (15:1) as eluent to give a mixture of (3,4)-anti-13 and (3,4)-
syn-13 (anti : syn = 5:1) as a colorless oil; yield: 9.9 g (70%).
IR (KBr): n = 3445, 3367, 2929, 1724, 1602 cm-1.
1H NMR: d = 1.40 (s, 3 H), 1.42 (s, 3 H), 1.45 (s, 9 H), 4.02 (dt, 1
H, J = 5, 8 Hz), 4.26 (dd, 1 H, J = 5, 11.5 Hz), 4.31 (dd, 1 H, J = 5,
11.5 Hz), 4.36 (d, 1 H, J = 8 Hz), 4.52 (d, 1 H, J = 9.5 Hz), 5.35 (d,
1 H, J = 9.5 Hz), 5.39 (br s, 2 H).
MS (FAB): m/z = 349 (M+ + 1).
13C NMR data of 7 were already given in Ref. 5d.
Coupling Between 7 and Thymine Polyoxin C (3)
A mixture of 7 (68 mg, 0.196 mmol), N-hydroxysuccinimide (23
mg, 0.196 mmol), N,N-dicyclohexylcarbodiimide (41 mg, 0.196
mmol) in EtOAc (2 mL) was stirred at 0 °Cfor 1 h. The mixture was
evaporated to give a crude residue which was dissolved in DMSO
(1 mL). A solution of thymine polyoxin C 3 (59 mg, 0.196 mmol)
and i-Pr2NEt (0.034 mL, 0.196 mmol) in DMSO (2 mL) was added
to the above DMSO Solution and the mixture was stirred for 24 h at
r.t. The mixture was directly chromatographed on silica gel (10 g)
with CHCl3/MeOH (4:1) as eluent to give 27 as a colorless amor-
ii) Ozone was passed through a solution of a mixture of (3,4)-anti-
13 and (3,4)-syn-13 (anti : syn = 5:1, 9.9 g, 21.2 mmol) in CH2Cl2
(50 mL) at –78 °C for 3 h followed by the addition of Me2S (4 mL,
47 mmol). The mixture was stirred at r.t. for 1 h and evaporated. The
residue was dissolved in acetone (20 mL) and Jones reagent (22
mL) was added at –20 °C. The mixture was stirred for 2 h at the
same temperature and treated with isopropyl alcohol (10 mL). The
mixture was diluted with H2O (100 mL) and extracted with Et2O (3
× 200 mL). After evaporation, the residue was dissolved in Et2O (50
mL) and treated with an excess of CH2N2 in Et2O at 0 °C. The mix-
ture was stirred at r.t. for 2 h and evaporated. The crude residue of
(2R)-14 and (2S)-14) was dissolved in MeOH (30 mL), K2CO3 (2.9
g, 21 mmol) was added at 0 °C and the mixture was stirred for 30
min at r.t. The mixture was diluted with brine (100 mL) and extract-
ed with EtOAc (3 × 100 mL). The organic layer was dried (MgSO4)
and evaporated. The residue was chromatographed on silica gel
(200 g) with hexane/EtOAc (10:1) as eluent to afford 15 [0.98 g,
overall yield 10% from (3,4)-syn-13] and 6 [5.1 g, overall yield 52%
from (3,4)-anti-13] as colorless oils. NMR spectra of both 15 and 6
were identical with those of the above mentioned (2S)-15 and (2R)-
6, respectively.
25
phous product; yield: 101 mg (82%); mp 170–172 ° C (dec.); [a]D
–7.7 (c = 0.505, MeOH).
IR (KBr): n = 3433, 1701, 1512 cm-1.
1H NMR (CD3OD/D2O): d = 1.36 (s, 3 H), 1.41 (s, 3 H), 1.45 (s, 9
H), 1.91 (d, 3 H, J = 1 Hz), 4.05 (m 1 H), 4.18 (m, 1 H), 4.24–4.35
(m, 5 H), 4.42 (m, 1 H), 4.64 (d, 1 H, J = 3.5 Hz), 5.73 (d, 1 H, J = 6
Hz), 7.52 (d, 1 H, J = 1 Hz).
MS (FAB): m/z = 632 (M+ + 1), 654 (M+ + Na), 670 (M+ + K).
13C NMR data of 27 were already given Ref. 5d.
Polyoxin J (1)
To a solution of 27 (170 mg, 0.27 mmol) in MeOH (6 mL) and H2O
(3 mL) at 0 °Cwas added CF3SO3H (3 mL) and the mixture was
stirred for 24 h at r.t. The mixture was evaporated to give a residue,
which was chromatographed on silica gel (10 g) with CHCl3/MeOH
(2:1) as eluent to give an amorphous product. It was dissolved in
H2O (2 mL) and filtered with the aid of Celite (100 mg) and activat-
ed carbon (50 mg). The filtrate was evaporated to afford 1 as an
amorphous product; yield: 113 mg (86%); mp 195–200 °C(dec.);
[a]D28 +35.7 (c = 0.68, H2O).
Benzyl 5-O-(Aminocarbonyl)-2-(tert-butoxycarbonyl)amino-2-
deoxy-3,4-O-isopropylidene-L-xylonate (25)
A mixture of 17 (1.217 g, 3.36 mmol), benzyl alcohol (7.26 g, 67
mmol) and and Ti(OPr-i)4 (0.473 mL, 1.68 mmol) in benzene (40
mL) was refluxed with stirring for 12 h. The mixture was diluted
with H2O (10 mL), extracted with EtOAc (2 × 20 mL). The organic
layer was washed with 1 M aq HCl (1 mL), 7% aq NaHCO3 solu-
tion, dried (MgSO4) and concentrated. The residue was chromato-
graphed on silica gel (50 g) with hexane/EtOAc (2:1) as eluent to
IR (KBr): n = 3433, 2985, 1701, 1515 cm-1.
28
give 25 as a colorless oil; yield: 1.205 g (82%); [a]D –16.4
1H NMR (D2O): d = 1.77 (d, 3 H, J = 1 Hz), 3.94–4.02 (m, 3 H),
4.08 (m, 1 H), 4.10–4.16 (m, 2 H), 4.20 (t, 1 H, J = 5 Hz), 4.37 (t, 1
H, J = 5 Hz), 4.45 (d, 1 H, J = 3 Hz), 5.71 (d, 1 H, J = 5 Hz), 7.41
(d, 1 H, J = 1 Hz).
(c = 1.01, CHCl3).
Anal. calcd for C21H30N2O8 (438.5): C, 57.52; H, 6.90; N, 6.29.
Found C, 57.76; H, 7.34; N, 6.47.
IR (KBr): n = 3452, 3377, 2983,1721, 1604, 1503 cm-1.
MS (FAB): m/z = 492 (M+ + 1), 514 (M+ + Na), 530 (M+ + K).
1H NMR: d = 1.36 (s, 3 H), 1.41 (s, 3 H), 1.44 (s, 9 H), 4.02 (dt, 1
H, J = 5, 8 Hz), 4.20 (dd, 1 H, J = 5, 11 Hz), 4.27 (dd, 1 H, J = 5, 11
Hz), 4.30 (dd, 1 H, J = 2, 8 Hz), 4.56 (dd, 1 H, J = 2, 10 Hz), 4.83
HRMS (FAB, matrix: glycerol): m/z calcd for C17H26N5O12 (M+ + 1)
492.1578; found 492.1575.
13C NMR data of 1 were already given Ref. 5d.
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York

1686
K. Uchida et al.
PAPER
(3) Sasaki, S.; Ohta, N.; Yamaguchi, I.; Kuroda, S.; Misato, T.
Coupling Between 7 and Uracil Polyoxin C (4)
A mixture of 7 (160 mg, 0.46 mmol), N-hydroxysuccinimide (53
mg, 0.46 mmol), N,N-dicyclohexylcarbodiimide (95 mg, 0.46
mmol) in EtOAc (4 mL) was stirred at 0 °C for 1 h. The mixture was
evaporated and the crude residue was dissolved in DMSO (1 mL).
A solution of uracil polyoxin C 4 (132 mg, 0.46 mmol) and i-Pr2NEt
(0.081 mL, 0.46 mmol) in DMSO (2 mL) was added to the above
DMSO Solution and the mixture was stirred for 24 h at r.t. The mix-
ture was directly chromatographed on silica gel (10 g) with CHCl3/
MeOH (4:1) as eluent to give 28 as a colorless amorphous product;
yield: 209 mg (74%); mp 176–178 °C (dec.); [a]D25 –3.2 (c = 1.22,
MeOH).
Nippon Nogei Kagaku Kaishi 1968, 42, 633; Chem. Abstr.
1969, 70, 35349.
(4) (a) Akita, H.; Uchida, K.; Cheng, Yu Chen Heterocycles 1997,
46, 87.
(b) Akita, H.; Uchida, K.; Cheng, Yu Chen; Kato, K; Chem.
Pharm. Bull. 1998, 46,1034.
(5) (a) Kuzuhara, H.; Ohrui, H.; Emoto, S. Tetrahedron Lett.
1973, 5055.
(b) Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa
S. J. Chem. Soc., Chem. Commun. 1994, 111.
(c) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T. J. Chem. Soc., Chem. Commun. 1995, 2127.
(d) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.;
Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497
(6) (a) Ohrui, H.; Kuzuhara, H.; Emoto, S. Tetrahedron Lett.
1971, 4267.
IR (KBr): n = 3423, 2985, 1701, 1507 cm-1.
1H NMR (CD3OD): d = 1.26 (s, 3 H), 1.30 (s, 3 H), 1.35 (s, 9 H),
3.95 (m 1 H), 4.05 (m, 1 H), 4.12–4.24 (m, 4 H), 4.35 (m, 2 H), 4.58
(m, 1 H), 5.68 (d, 1 H, J = 8 Hz), 5.76 (d, 1 H, J = 5 Hz), 7.55 (d, 1
H, J = 8 Hz).
(b) Garner, P.; Park, J. M. Tetrahedron Lett. 1989, 30, 5065.
(c) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55, 3772.
(d) Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019.
(e) Chen, A.; Savage, I.; Thomas, E. J.; Wilson, P. D.
Tetrahedron Lett. 1993, 34, 6769.
MS (FAB): m/z = 618 (M+ + 1), 640 (M+ + Na), 656 (M+ + K).
Polyoxin L (2)
To a solution of 28 (157 mg, 0.254 mmol) in MeOH (6 mL) and
H2O (3 mL) at 0 °Cwas added CF3SO3H (3 mL) and the mixture was
stirred for 24 h at r.t. The mixture was evaporated to give a residue,
which was chromatographed on silica gel (10 g) with CHCl3/MeOH
(2:1) as eluent to give an amorphous product. It was dissolved in
H2O (2 mL) and filtered with the aid of Celite (100 mg) and activat-
ed carbon (50 mg). The filtrate was evaporated to afford 2 as an
amorphous product; yield: 113 mg (94%); mp 180–183°C (dec.);
[a]D22 +35.0 (c = 1.215, H2O).
(f) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1994, 35, 9439.
(7) (a) Kuzuhara, H.; Ohrui, H.; Emoto, S. Agr. Biol. Chem. 1973,
37, 949.
(b) Kuzuhara, H.; Emoto, S.Tetrahedrn Lett. 1973, 5051.
(c) Saksena, A. K.; Lovey, R. G.; Girijavallabham, V. M.;
Ganguly, A. K. J. Org. Chem. 1986, 51, 5024.
(d) Garner, P; Park, J. M. J. Org. Chem. 1988, 53, 2979.
(e) Savage, I.; Thomas, E. J. J. Chem. Soc. Chem. Commun.
1989, 717.
IR (KBr): n = 3348, 1685, 1617, 1469 cm-1.
1H NMR (D2O): d = 3.96–4.04 (m, 3 H), 4.08 (d, 1 H, J = 5 Hz),
4.15 (t, 1 H, J = 3.5 Hz), 4.17 (d, 1 H, J = 5 Hz), 4.21 (t, 1 H, J = 5.5
Hz), 4.37 (t, 1 H, J = 5.5 Hz), 4.52 (d, 1 H, J = 3.5 Hz), 5.69 (t, 1 H,
J = 5.5 Hz), 5.76 (d, 1 H, J = 8 Hz), 7.52 (d, 1 H, J = 8 Hz).
(f) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265.
(g) Dureault, A.; Carreaux, F.; Depezay, J. C. Synthesis 1991,
150.
(h) Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1993, 34, 5479.
(i) Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem.
1994, 59, 5139.
(j) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1994, 35, 733.
(k) Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J.; Clegg,
W.; Elsegood, M. R. J. J. Org. Chem. 1995, 60, 6431.
(l) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J.
Am. Chem. Soc. 1996, 118, 6520.
13C NMR (D2O) : d = 55.9, 64.8, 68.0, 69.0, 69.3, 69.6, 72.4, 83.6,
88.9, 102.1, 141.7, 151.2, 158.5, 165.5, 166.8, 169.5.
MS (FAB): m/z = 478 (M+ + 1).
HRMS (FAB, matrix: glycerol): m/z calcd for C16H24N5O12 (M+ + 1)
478.1421; found 478.1418.
Acknowledgement
The authors are grateful to Professor S. Ogawa, Keio University, Ja-
pan for generously providing the spectral data of synthetic polyoxin
J (1) and to Dr. N. Nakayama of Nippon Roche Co. LTD., Japan for
measurement of high resolution mass spectra (FAB-MS) of synthe-
tic polyoxins J (1) and L (2). This work was supported by a grant for
the "Biodesign Research Program" from Riken (The Institute of
Physical and Chemical Research) to H. A.
(8) McDougal, P. G.; Rico, J. G.; Oh, Y. -I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
(9) Tabusa, F.; Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem.
Lett. 1984, 405
(10) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199.
(11) Isono, K.; Kobinata, K.; Suzuki, S. Agr. Biol. Chem. 1968, 32,
792.
(12) Takayama, M., Kataoka, H., Katagi, T., Horiyama, S.,
Yamaki, M., Hasegawa, F., Abliz, Z. J. Mass Spectrom. Soc.
Jpn. 1998, 46, 143.
References
(1) A part of this work was published as a preliminary
communication: Akita, H.; Uchida, K.; Kato, K.
Heterocycles 1998, 47, 157. The title of this paper has an error
and should be revised as: Total Syntheses of (+)-Polyoxin J
and (+)-Polyoxin L.
Article Identifier:
1437-210X,E;1999,0,09,1678,1686,ftx,en;F11899SS.pdf
(2) (a) Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969,
91, 7490.
(b) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
Synthesis 1999, No. 9, 1678–1686 ISSN 0039-7881 © Thieme Stuttgart · New York