De novo asymmetric synthesis of protected 5-O-carbamoylpolyoxamic acid

Article abstract of DOI:10.1055/s-2000-7114

The synthesis of 5-O-carbamoylpolyoxamic acid from a non carbohydrate precursor was achieved in 12 steps and 7% yield starting from chiral α,β-epoxyaldehyde readily available from cis-2-butene-1,4-diol. The main steps concern the Sharpless asymmetric epoxidation of a suitable chosen allylic alcohol, the use of thiazolyl group for carbon homologation, the stereo- and regioselective opening of the epoxide and the transformation of the primary alcohol to the acid functionality of the final product.

Full text of DOI:10.1055/s-2000-7114

PAPER
1409
De Novo Asymmetric Synthesis of Protected 5-O-Carbamoylpolyoxamic Acid
Cécile Dehoux, Céline Monthieu, Michel Baltas,* Liliane Gorrichon
Laboratoire de Synthèse et Physicochimique de Molécules d’Intérêt Biologique, UMR 5068 Associée au CNRS, Université Paul Sabatier,
118 route de Narbonne, 31062 Toulouse Cedex 04, France
Tel. 330(5)61556293; Fax 330(5)61556011; E-mail: baltas@iris.ups-tlse.fr
Received 23 March 2000; revised 23 May 2000
O
Abstract: The synthesis of 5-O-carbamoylpolyoxamic acid from a
R3
R2O2C
non carbohydrate precursor was achieved in 12 steps and 7% yield
starting from chiral a,b-epoxyaldehyde readily available from cis-
2-butene-1,4-diol. The main steps concern the Sharpless asymmet-
ric epoxidation of a suitable chosen allylic alcohol, the use of thia-
zolyl group for carbon homologation, the stereo- and regioselective
opening of the epoxide and the transformation of the primary alco-
hol to the acid functionality of the final product.
NH
O
N
N
O
O
H2N
H
R1
HO OH
HO
O
H2N
Key words: amino acids, antifungal agents, asymmetric synthesis,
epoxide, azide
O
R1 = OH, H
R2
=
N
OH
COOH
R3 = CH2OH, COOH, CH3, H
Polyoxins form an important class of antifungal antibiot-
ics isolated from the culture broths of Streptomyces cacoi
var. asoensis by Isono and coworkers.1,2 They act as com-
petitive inhibitors of the enzyme chitin synthase
(E.C.2.4.1.16). This enzyme catalyses the production of
chitin, a linear b-1,4-N-acetyl glucosamine polymer that
constitutes one of the major structural components of the
fungal cell walls.3 Among these compounds, polyoxin D
is used as an agricultural antifungal agent to treat rice
sheath blight and pear black spot.4 Polyoxins are peptido-
nucleosides comprising a nucleosidic aminoacid moiety
connected by a peptide linkage to an unusual hydroxylat-
ed aminoacid, the 5-O-carbamoylpolyoxamic acid (ex-
cept for polyoxins E and G) (Figure). As a consequence of
the potent antifungal activity associated with this type of
peptidyl nucleosides, a variety of chemical syntheses of
the nucleosidic5 and polyoxamic parts6 have been report-
ed over the years, most of them based on carbohydrate
templates as starting materials. A number of polyoxamic
acid syntheses have been reported utilising L-tartric acid.
A very useful strategy towards the synthesis of the nucle-
osidic part (thymine polyoxin C) and 5-O-carbamoylpoly-
oxamic acid have been developed from D-serinal by
Garner and Park.5c,6c Only Trost and co-workers have de-
scribed a de novo asymmetric synthesis of polyoxamic
acid using a Pd-based opening of a vinyl epoxide by phta-
lamide, in the presence of a chiral ligand.6l
OH
HOOC
R = H
OR
NH2 OH
polyoxamic acid
carbamoylpolyoxamic acid
R = C(O)NH2
Figure
b) homologation of the epoxyaldehyde, c) stereo- and re-
gioselective opening of the oxirane and, d) epimerisation
of the C2 carbon on the aldehyde.
The (2R,3R)-4-(tertbutyldiphenylsilyloxy)-2,3-epoxybu-
tan-1-al (1) is obtained in three steps and 56% yield after
monoprotection, Sharpless asymmetric epoxidation8 us-
ing (-)DET as chiral agent (ee = 84%) and Doering
oxidation9 of the corresponding epoxyalcohol. Condensa-
tion of compound 1 with 2-trimethylsilylthiazole10 and
deprotection of the silylated intermediate 2 leads exclu-
sively to the anti-2,3-epoxythiazolyl compound 3a in 86%
yield after silica gel purification. The stereochemical as-
signment of the aldol product 3a was established by con-
version to the six membered acetonide (Scheme 2).
Reduction of compound 3a in the presence of RedAl in
THF and treatment of the 1,3-diol 4 formed with
2,2-dimethoxypropane with p-toluenesulfonic acid (cata-
We have recently described the synthesis of a thymine
2¢-deoxypolyoxin C analogue7 from a non carbohydrate
precursor. It was achieved in ten steps and 9% yield, start-
ing from a chiral g,d-epoxy-b-hydroxyester readily avail-
able from cis-2-butene-1,4-diol. Herein, we would like to
report a de novo stereocontrolled access to the protected
5-O-carbamoylpolyoxamic acid starting from the same
achiral precursor. Our methodology is based on four key
steps (Scheme 1): a) Sharpless asymmetric epoxidation,
1
lytic) leads to the six membered acetonide 5. H NMR
analysis of the coupling constants and 13C NMR shifts of
the acetal carbons11 correspond to a syn configuration of
compound 5 and thus an anti configuration for compound
3a. The diastereoselectivity observed is in agreement with
the results concerning addition of 2-trimethylsilylthiazole
on a,b-alkoxy aldehydes.10a
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1410
C. Dehoux et al.
PAPER
OH
N3
Th
Th
TBDPSO
+
O
O
N3
OH
OH
a
c
TBDPSO
H
TBDPSO
Th
7a
HO
OH
O
OR
R = SiMe3
3a R = H
1
TBDPSO
2
b
OH
7b
O
O
O
d
e
Th
CHO
CHO
f
7a
TBDPSO
TBDPSO
TBDPSO
N3
N3
N3
O
O
O
8
9
10
g, h, i
O
O
O
O
O
j
k, i
HOOC
BocHN
CH2OH
RO
BocHN
TBDPSO
O
O
NH2
NH2
X
O
O
O
16
14 R = TBDPS
15 R = H
11 X = N3
12 X = NH2
13 X = NHBoc
Reagents and conditions: (a) 1.5 equiv 2-trimethylsilylthiazole, CH2Cl2, -30 °C to r.t.; (b) Amberlite IR 120, MeOH (86% from 1); (c) 5 equiv
NaN3, 2.5 equiv NH4Cl, reflux (93%); (d) (CH3)2C(OCH3)2, p-toluenesulfonic acid, PhCH3, 30 min, reflux (93%); (e) i) 1.2 equiv TMSTf,
CH3CN, molecular sieves 4 Å, ii) 2 equiv NaBH4, MeOH, iii) HgCl2, MeCN/H2O (10:1); (f) K2CO3, MeOH, 0 °C, 12 h; (g) NaBH4, MeOH
(36% from 5); (h) H2, Pd/C (10%), EtOH/H2O (9:1); (i) Boc2O, CH2Cl2 (87%); (j) p-nitrophenylchloroformate, pyridine, 30 min then NH3, Me-
OH, 1 h, 0 °C (70%); (k) HF/pyridine, THF/pyridine (100%); (l) BAIB, TEMPO, CH3CN/H2O (48%)
Scheme 1
Considering the absolute configuration of the final poly- the diol 7a in the presence of 2,2-dimethoxypropane gives
oxamic acid, we have to reverse the configuration of the acetonide 8 in 93% yield that was followed by demasking
carbon atom C1 of compound 3a. Oxidation of compound of the thiazolyl group to the corresponding aldehyde 9.
3a in the presence of dimethylsulfoxide and acetic anhy- The thiazol to formyl protocol consists of a three reaction
dride gives the corresponding ketone 6 in 94% yield sequence (N-methylation, reduction, and metal assisted
(Scheme 3). Reduction of the ketone 6 in presence of so- hydrolysis), each step taking place under almost neutral or
dium borohydride or K-selectride (Table), gives as the non oxidative conditions.10a,d This one pot transformation
major or sole compound the adduct 3a. syn-Adduct 3b affords the aldehyde 9 in 89% yield which is further trans-
was only obtained in 20% yield when operating with two formed without any purification. Treatment of the alde-
equivalents of NaBH4 at -78 °C. It is noteworthy that this hyde under basic conditions (K2CO3, MeOH) allows the
result is in contrast with that obtained from reduction of epimerisation of the C2 carbon of the aldehyde and leads
a,b-alkoxythiazolyl ketones which are reported to give exclusively to the more stable epimer 10. Reduction of al-
the syn-adducts under the same experimental condi- dehyde with sodium borohydride affords alcohol 11,
tions.10a
which is obtained in 36% yield starting from compound 8
after silica gel purification. Reduction of the azido func-
tionality (H2, Pd/C) followed by tert-butyloxycarbonyl
protection of the amino derivative 12 yields compound 13
(87% for the two steps). The primary alcohol is then car-
bamoylated via a two steps procedure using p-nitrophe-
nylchloroformate in pyridine and treatment of the
In order to circumvent this problem, a different approach
was investigated. Stereo- and regioselective opening of
the oxirane under non-chelating conditions with sodium
azide and ammonium chloride12 gives a mixture of regio-
isomers 7a and 7b (7a/7b = 90/10) easily separated by sil-
ica gel chromatography (93% global yield). Protection of
(Me)2C(OMe)2
PTSA, PhCH3
OH
O
O
OH
O
RedAl, THF
16%
TBDPSO
TBDPSO
TBDPSO
Th
Th
Th
91%
4
5
OH
Scheme 2
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
De Novo Asymmetric Synthesis of Protected 5-O-Carbamoylpolyoxamic Acid
1411
O
O
O
O
reducing
agent
DMSO
Ac2O
TBDPSO
Th
TBDPSO
Th
TBDPSO
Th
TBDPSO
Th
+
94%
OH
O
OH
OH
3a
6
3a
3b
Scheme 3
due was chromatographed on silica gel with petroleum ether/Et2O,
5:5 (Rf = 0.22) to give compound 3a; yield: 4.5 g (86%).
[a]D24 = +24.6° (c 0.92, CHCl3).
IR (CHCl3): n = 3466, 3133, 1050 cm-1.
1H NMR (CDCl3): d = 7.78 (d, 1H, J = 3.0 Hz, CH thiazole), 7.73-
7.68 (m, 4H, phenyl), 7.47-7.35 (m, 7H, phenyl and CH thiazole),
4.90 (d, 1H, J = 7.3 Hz, H1), 4.04 (dd, 1H, J = 5.5, 11.0 Hz, H4),
3.95 (dd, 1H, J = 5.3, 11.0 Hz, H4), 3.37 (dd, 1H, J = 4.1, 7.3 Hz,
H2), 3.35 (ddd, 1H, J = 4.1, 5.3, 5.5 Hz, H3), 1.08 (s, 9H, TBDPS).
13C NMR (CDCl3): d = 170.4 (Cq thiazole), 142.4 (CHN thiazole),
135.9, 135.8, 135.8, 132.6, 130.1, 127.9 (phenyl), 119.8 (CHS thia-
zole), 89.9 (C1), 62.5 (C4), 58.3, 56.8 (C3 and C2), 28.8 (Me TB-
DPS), 19.2 (Cq TBDPS).
carbamate intermediate at 0 °C with methanolic
ammonia10c to give compound 14 in 70% yield. The tert-
butyldiphenylsilyl group is then removed quantitatively
with HF/pyridine and the primary alcohol 15 was oxidised
to the corresponding acid 16 in 48% yield through one
step oxidation using BAIB (bis-acetoxyiodobenzene)
with a catalytic amount of TEMPO13 (2,2,6,6-tetramethyl-
1-piperidinyloxy) free radical. Acid 16 shows spectral
properties (1H, 13C) identical to those of literature.10c,6m
In conclusion this methodology, based on the use of suit-
ably chosen epoxyalcohol, can lead to the protected 5-O-
carbamoylpolyoxamic acid 16 obtained in 12 steps and
7.0% overall yield from epoxyaldehyde 1. It compares
with that of the only group6l which realised the de novo
synthesis of polyoxamic acid. An advantage of the meth-
odology resides also in the possibility of creating any
epimer of this optically active aminoacid compound. Fur-
ther work dealing with construction of the nucleoside
moiety and applications of these results to the total syn-
thesis of polyoxin J is currently underway.
MS (DCI, NH3): m/z = 426 (MH+, 100%).
Anal. Calcd for C23H27NO3SSi: C, 64.90; H, 6.39; N, 3.29. Found:
C, 64.90; H, 6.35; N, 3.23.
(1S,3R)-4-tert-Butyldiphenylsilyloxy-1,3-dihydroxy-1-(thiazol-
2-yl)-butane (4)
At 0 °C, a solution of RedAl (3.5 M, 121 mL, 0.70 mmol) in toluene
was added to a solution of 3a (60 mg, 0,14 mmol) in THF (1.7 mL).
The mixture was stirred for 3 h at r.t. After dilution with Et2O, the
mixture was slowly hydrolysed with H2O (2.3 mL). After stirring
for 1 h, the aqueous phase was extracted with Et2O. The combined
organic layers were dried (Na2SO4) and concentrated. The residue
was chromatographed on silica gel with CH2Cl2/EtOAc, 8:2
(Rf = 0.28) to give 10 mg of compound 4 (16%).
1H NMR (CDCl3): d = 7.70-7.63 (m, 5H, phenyl and CHN), 7.42-
7.26 (m, 7H, phenyl and CHS), 5.28 (dd, 1H, J = 2.8, 9.5 Hz, H1),
4.17 (m, 1H, H3), 3.66 (dd, 1H, J = 3.6, 10.2 Hz, H4), 3.53 (dd, 1H,
J = 7.0, 10.2 Hz, H4), 2,10 (m, 2H, H2), 1,07 (s, 9H, Me TBDPS).
All chemicals were obtained from commercial suppliers. Solvents
were distilled prior to use. THF, Et2O were distilled over Na;
CH2Cl2 was distilled over CaH2; and pyridine over KOH. TLC was
performed on silica gel 60-coated aluminium sheets (Merck) with
detection UV at 254 nm. Products were purified by medium pres-
sure liquid chromatography. The following spectrometers were
used to record physical data. NMR: Bruker 250 MHz (250 MHz for
1H and 62.9 MHz for 13C using CDCl3 with internal TMS as refer-
ence). IR: Perkin-Elmer 1725X. MS: Nermag R10-10. Optical ro-
tations were recorded on a Perkin-Elmer 241 polarimeter.
(1S,3R)-1,3-Dioxyisopropylidene-4-tert-butyldiphenylsilyloxy-
1-(thiazol-2-yl)-butane (5)
(1S,2R,3S)-4-tert-Butyldiphenylsilyloxy-2,3-epoxy-1-(thiazol-2-
yl)butanol (3a)
A mixture of compound 4 (10 mg, 0.023 mmol), dimethoxypropane
(500 mL) and p-tolunesulfonic acid (0.5 mg) in anhyd toluene
(2 mL) was refluxed for 15 min. At r.t., the mixture was hydrolysed
with sat. NaHCO3, and the aqueous phase was extracted with tolu-
ene. The combined organic layers were dried (MgSO4) and concen-
trated. The residue was chromatographed with petroleum ether/
CH2Cl2/EtOAc, 7:24:6 (Rf = 0.22) to give 10 mg of compound 5
(91%).
1H NMR (CDCl3): d = 7.78-7.64 (m, 5H, phenyl and CHN), 7.39-
7.26 (m, 7H, phenyl and CHS), 5.28 (dd, 1H, J = 2.9, 11.8 Hz, H1),
4.13 (m, 1H, H3), 3.74 (dd, 1H, J = 5.2, 10.4 Hz, H4), 3.58 (dd, 1H,
J = 6.0, 10.4 Hz, H4), 2.16 (m, 2H, H2), 1.53 (s, 3H, acetonide),
1.48 (s, 3H, acetonide), 1.05 (s, 9H, TBDPS).
At -30 °C, to a solution of epoxyaldehyde 1 (4.2 g, 12.5 mmol) in
CH2Cl2 (58 mL) was added slowly a solution of 2-trimethylsilylth-
iazole (3 mL, 18.7 mmol) in CH2Cl2 (40 mL).The mixture was
stirred for 20 minutes at -30 °C and 12 h at r.t. CH2Cl2 was evapo-
rated to give the compound 2. To a solution of the crude product in
MeOH (58 mL) was added Amberlite IR120 (2 g), and the mixture
was stirred for 6 h at r.t. After filtration and concentration, the resi-
Table
Reducing agent Conditions
3a/3b
Yield %
99
13C NMR (CDCl3): d = 172.4 (Cq thiazole), 142.2 (CHN), 135.7,
133.8, 132.4, 129.6, 127.6 (phenyl), 119.0 (CHS), 97.7 (Cq ace-
tonide), 70.0, 69.5 (C1 and C3), 67.2 (C4), 34.9 (C2), 29.8 (Me ac-
etonide), 26.8 (Me TBDPS), 19.8 (Me acetonide), 19.1 (Cq
TBDPS).
NaBH4
2 equiv MeOH,
80/20
−78°C
NaBH4
2 equiv MeOH,
0°C to r.t.
80/20
100/0
70
62
K-selectride
2 equiv THF,
−78°C
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1412
C. Dehoux et al.
PAPER
(2S,3S)-4-tert-Butyldiphenylsilyloxy-2,3-epoxy-1-(thiazol-2-yl)-
butan-1-one (6)
(1S,2S,3R)-3-Azido-4-tert-butyldiphenylsilyloxy-2-hydroxy-1-
(thiazol-2-yl)-butanol (7a)
To a solution of compound 3a (124 mg, 0.28 mmol) in dimethylsul-
foxide (1.4 mL) was slowly added freshly distilled acetic anhydride
(630 mL). After stirring for 12 h at r.t., sat. NaHCO3 (10 mL) was
added, and stirring was maintained for 5 min. The aqueous layer
was extracted with Et2O and the combined organic layers were
washed with H2O, dried (Na2SO4) and concentrated. The residue
was chromatographed with petroleum ether/Et2O, 6:4 (Rf = 0.30) to
give 111 mg of compound 6 (94%).
[a]D24 = -16.0° (c 0.58, CHCl3).
IR (CHCl3): n = 3607, 3453, 3074, 2114, 1058 cm-1.
1H NMR (CDCl3): d = 7.75-7.61 (m, 5H, phenyl and CHN), 7.46-
7.31 (m, 7H, phenyl and CHS), 4.99 (d, 1H, J = 7.3 Hz, H1), 4.07-
3.77 (m, 4H, H2, H3 and H4), 1.08 (s, 9H, Me TBDPS).
13C NMR (CDCl3): d = 172.4 (Cq thiazole), 142.1 (CHN), 135.6,
132.7, 129.9, 127.9 (phenyl), 119.7 (CHS thiazole), 73.7 (C1), 71.7
(C2), 64.8 (C4), 62.9 (C3), 26.8 (Me TBDPS), 19.1 (Cq TBDPS).
[a]D24 = +9.1° (c 0.55, CHCl3).
IR (CHCl3): n = 1696 (C=O), 1111 cm-1.
MS (DCI, NH3): m/z = 469 (MH+, 100%).
1H NMR (CDCl3): d = 8.08 (d, 1H, J = 3.0 Hz, CHN), 7.75 (d, 1H,
J = 3.0 Hz, CHS), 7.60-7.52 (m, 4H, phenyl), 7.42-7.26 (m, 6H,
phenyl), 4.82 (d, 1H, J = 4.3 Hz, H2), 3.96 (dd, 1H, J = 7.0, 13.5
Hz, H4), 3.70 (dd, 1H, J = 5.7, 13.5 Hz, H4), 3.70 (ddd, 1H, J = 4.3,
5.7, 7.0 Hz, H3), 0.92 (s, 9H, TBDPS).
13C NMR (CDCl3): d = 186.1 (C1), 165.2 (Cq thiazole), 145.3
(CHN thiazole), 135.5, 135.4, 132.9, 129.8, 127.8, 127.7 (phenyl),
126.8 (CHS thiazole), 60.8 (C4), 59.1, 55.5 (C2 and C3), 26.6 (Me
TBDPS), 19.1 (Cq TBDPS).
Anal. Calcd for C23H28N4O3SSi: C, 58.95; H, 6.02; N, 11.95. Found:
C, 59.01; H, 5.91; N, 11.66.
(1S,2R,3S)-2-Azido-4-tert-butyldiphenylsilyloxy-3-hydroxy-1-
(thiazol-2-yl)-butanol (7b)
IR (film): n = 3665, 3072, 2110 cm-1.
1H NMR (CDCl3): d = 7.75-7.61 (m, 5H, phenyl and CHN), 7.46-
7.31 (m, 7H, phenyl and CHS), 5.35 (d, 1H, J = 3.6 Hz, H1), 4.06
(m, 1H, H3), 3.96 (t, 1H, J = 3.6 Hz, H2), 3.82-3.77 (m, 2H, H4),
1.08 (s, 9H, TBDPS).
13C NMR (CDCl3): d = 172.0 (Cq thiazole), 142.4 (CHN thiazole),
135.9, 132.9, 129.9, 127.9 (phenyl), 119.9 (CHS thiazole), 73.7
(C1), 72.9 (C2), 66.6 (C3), 64.8 (C4), 26.9 (Me TBDPS), 19.2 (Cq
TBDPS).
MS (DCI, NH3): m/z (%) = 299 (100), 424 (MH+, 25,), 441 (MNH4 ,
+
2.6)
Anal. Calcd for C23H25NO3SSi: C, 65.25; H, 5.95; N, 3.31. Found:
C, 64.55; H, 6.07; N, 3.36.
MS (DCI, NH3): m/z = 469 (MH+, 100%).
Reduction with K-selectride
At -78 °C, to a solution of compound 6 (160 mg, 0.380 mmol) in
THF (25 mL) was slowly added a solution 1 M of K-selectride
(760 mL) in THF. The mixture was stirred for 1 h at -78 °C and then
hydrolysed at 0 °C with H2O (1 mL). THF was evaporated, and the
residue was dissolved in CH2Cl2 and H2O. The organic layer was
dried (MgSO4), concentrated and the resulting crude product was
chromatographed with petroleum ether/Et2O, 5:5 (Rf = 0.22) to
yield 100 mg of 3a (62%).
Anal. Calcd for C23H28N4O3SSi: C, 58.95; H, 6.02; N, 11.95. Found:
C, 59.10; H, 6.05; N, 11.80.
(1S,2S,3R)-3-Azido-1,2-dioxyisopropylidene-4-tert-butyldiphe-
nylsilyloxy-(1-thiazol-2-yl)-butane (8)
To a solution of compound 7a (936 mg, 2.0 mmol) in anhyd toluene
(30 mL) were added dimethoxypropane (7.5 mL) and p-toluene-
sulfonic acid (38 mg, 0.2 mmol), and the mixture was refluxed for
20 min. It was then diluted with toluene and hydrolysed with sat.
NaHCO3. The organic phase was washed with H2O, dried (MgSO4)
and concentrated. The residue was chromatographed on silica gel
with petroleum ether/CH2Cl2/EtOAc, 8:16:2 (Rf = 0.30) to afford
945 mg of compound 8 (93%).
Reduction with NaBH4
At 0 °C (or at -78 °C), NaBH4 (20 mg, 0.522 mmol) was added to
compound 6 (110 mg, 0.261 mmol) in MeOH (10 mL). After stir-
ring for 1 h at r.t.(or -78 °C), acetone (1 mL) was added. The mix-
ture was concentrated and the residue was dissolved in EtOAc and
washed with H2O. The organic phase was dried (Na2SO4) and the
solvent evaporated. The residue was chromatographed with petro-
leum ether/CH2Cl2/EtOAc, 30:56:17 (Rf3a = 0.27, Rf3b = 0.20) to
yield 60 mg of compound 3a, 12 mg of 3b and 7 mg of ketone 6
(70%).
[a]D24 = -7.9° (c 0.66, CHCl3).
IR (CHCl3): n = 3100, 2125, 1054 cm-1.
1H NMR (CDCl3): d = 7.76 (d, 1H, J = 3.2 Hz, CHN), 7.70-7.45
(m, 4H, phenyl), 7.45-7.35 (m, 6H, phenyl), 5.45 (d, 1H, J = 7.2
Hz, H1), 4.62 (dd, 1H, J = 4.0, 7.2 Hz, H2), 3.88 (dd, 1H, J = 5.6,
10.0 Hz, H4), 3.77 (dd, 1H, J = 6.5, 10.0 Hz, H4), 3.46 (ddd; 1H,
J = 4.0, 5.6, 6.5 Hz, H3), 1.70 and 1.44 (2s, 6H, acetonide), 1.05 (s,
9H, TBDPS).
13C NMR (CDCl3): d = 170.1 (Cq thiazole), 143.0 (CHN thiazole),
135.7, 132.9, 129.9, 127.8 (phenyl), 119.8 (CHS thiazole), 110.4
(Cq acetonide), 77.1 (C1), 76.7 (C2), 64.3 (C4), 61.1 (C3), 26.7 (Me
TBDPS), 26.6, 24.8 (Me acetonide), 19.0 (Cq TBDPS).
(1R,2R,3S)-4-tert-Butyldiphenylsilyloxy)-2,3-epoxy-1-(thiazol-
2-yl)-butan-1-ol (3b)
IR (film): n = 3349, 1110 (C-O) cm-1.
1H NMR (CDCl3): d = 7.78 (d, 1H, J = 3.2 Hz, CHN), 7.70-7.62
(m, 4H, phenyl), 7.47-7.35 (m, 7H, phenyl and CHS), 4.35 (dd, 1H,
J = 2.0, 9.2 Hz, H1), 3.88 (m, 1H, H2), 3.85-3.81 (m, 2H, H4), 3.37
(m, 1H, H3), 2.52 (d, 1H, J = 9.2 Hz, OH), 1,08 (s, 9H, TBDPS).
MS (DCI, NH3): m/z = 509 (MH+, 100%).
Anal. Calcd for C26H32N4O3SSi: C, 61.39; H, 6.34; N, 11.01. Found:
C, 61.28; H, 6.22; N, 10.80.
Reaction of 3a with NaN3/NH4Cl
A mixture of compound 3a (4.5 g, 10.6 mmol), NaN3 (3.44 g,
5 equiv) and NH4Cl (2.5 equiv) in MeOH/H2O, 8:1 (100 mL) was
refluxed for 44 h. The MeOH was evaporated and the aqueous layer
was extracted with Et2O. The combined organic layers were dried
(Na2SO4) and concentrated. The residue was chromatographed on
silica gel with petroleum ether/CH2Cl2/EtOAc (3:56:14) to give
4.2 g of compound 7a (Rf = 0.30) and 400 mg of compound 7b
(Rf = 0.18) (global yield = 93%).
(2S,3S,4R)-4-Azido-2,3-dioxyisopropylidene-5-tert-butyldiphe-
nylsilyloxy-pentanol (11)
A mixture of compound 8 (960 mg, 1.89 mmol) and activated mo-
lecular sieves 4 Å (4 g) in anhyd MeCN (20 mL) was stirred for
10 min. at r.t., and then methyltriflate (267 mL, 2.27 mmol) was add-
ed. The suspension was stirred for 35 min. at r.t. and concentrated
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
De Novo Asymmetric Synthesis of Protected 5-O-Carbamoylpolyoxamic Acid
1413
to dryness. The residue was diluted in MeOH (20 mL), cooled to
0 °C, treated with NaBH4 (142 mg, 3.80 mmol), and stirred for 40
min. Acetone (2 mL) was added and the mixture was stirred for 1 h.
The suspension was filtered through Celite and concentrated. The
crude product was then dissolved in MeCN/H2O, 10:1 (20 mL) and
the solution treated with HgCl2 (500 mg) in 2 mL of the same sol-
vent mixture. The mixture was stirred for 30 min., filtered through
Celite and concentrated. The crude product was dissolved in CH2Cl2
and washed with 10% aqueous KI. The aqueous layer was extracted
with CH2Cl2 and the combined organic layers were dried (Na2SO4)
and concentrated. The residue was dissolved in Et2O and quickly
filtered through a pad of Fluorisil. After concentration, aldehyde 9
(760 mg) was obtained as a clear yellow syrup (89%).
13C NMR (CDCl3): d = 135.7, 132.8, 130.0, 129.7, 127.9 (phenyl),
109.9 (Cq acetonide), 77.8, 76.2 (C2 and C3), 64.3 (C5), 62.6 (C4),
61.7 (C1), 27.2 (Me acetonide), 26.8 (Me TBDPS), 26.7 (Me ace-
tonide), 19.2 (Cq TBDPS).
+
MS (DCI, NH3): m/z = 473 (MNH4 , 100%).
Anal. Calcd for C26H33N4O3SSi: C, 63.27; H, 7.30; N, 9.22. Found:
C, 63.30; H, 7.00; N, 9.10.
(2S,3S,4R)-4-(tert-Butyloxycarbonylamino)-2,3-dioxyisopropy-
lidene-5-tert-butyldiphenylsilyloxy-pentanol (13)
A suspension of alcohol 11 (300 mg, 0.66 mmol) and 10% Pd/C
(74 mg) in EtOH/H2O. 9:1l (8.3 mL) was degassed and then pres-
surised with H2. After stirring for 4 h, the suspension was filtered on
Celite and then concentrated in vacuo to give 256 mg of compound
12 (90%).
Compound 9
IR (CHCl3): n = 3074, 2959, 2111, 1729 cm-1.
1H NMR (CDCl3): d = 9.80 (d, 1H, J = 2.0 Hz, H1), 7.70-7.65 (m,
4H, phenyl), 7.46-7.26 (m, 6H, phenyl), 4.52 (dd, 1H, J = 2.0, 8.3
Hz, H2), 4.35 (dd, 1H, J = 2.0, 8.3 Hz, H3), 3.95 (dd, 1H, J = 7.7,
10.4 Hz, H5), 3.87 (dd, 1H, J = 5.6, 10.4 Hz, H5), 3.46 (ddd, 1H,
J = 2.0, 5.6, 7.7 Hz, H4), 1.70 and 1.44 (2s, 6H, acetonide), 1.05 (s,
9H, TBDPS).
13C NMR (CDCl3): d = 202.4 (C1), 135.6, 132.8, 130.0, 129.7,
128.2, 127.9 (phenyl), 111.2 (Cq acetonide), 80.4, 78.4 (C2 and
C3), 63.6 (C5), 59.9 (C4), 26.7 (Me TBDPS), 26.9, 24.5 (Me ace-
tonide), 19.2 (Cq TBDPS).
Compound 12
1H NMR (CDCl3): d = 7.87-7.25 (m, 10H, phenyl), 4.01 (dt, 1H,
J = 4.6, 8.4 Hz, H2), 3.87 (dd, 1H, J = 3.7, 8.4 Hz, H3), 3.77 (dd,
1H, J = 4.9, 10.1 Hz, H5), 3.60 (dd, 1H, J = 7.5, 10.1 Hz, H5), 3.63
(d, 2H, J = 4.6 Hz, H1), 3.07 (ddd, 1H, J = 3.7, 4.9, 7.5 Hz, H4),
2.24 (m, 3H, OH and NH2), 1.36 and 1.33 (2s, 6H, acetonide), 1.06
(s, 9H, TBDPS).
13C NMR (CDCl3): d = 135.6, 133.3, 133.2, 129.9, 127.8 (phenyl),
108.7 (Cq acetonide), 79.0, 77.4 (C2 and C3), 65.8 (C5), 62.3 (C1),
53.1 (C4), 27.1, 26.9 (Me acetonide), 26.7 (Me TBDPS), 19.3 (Cq
TBDPS).
A mixture of aldehyde 9 (760 mg, 1.68 mmol) and K2CO3 (232 mg,
1.68 mmol) in MeOH (20 mL) was stirred for 12 h at 0 °C. After di-
lution with H2O, MeOH was evaporated. The aqueous phase was
extracted with Et2O and the combined organic layers were washed
with sat. NaCl and dried (Na2SO4). Concentration afforded 760 mg
of the epimer 10 (100%).
A
mixture of compound 12 (256 mg, 0.60 mmol) and Boc2O
(130 mg, 0.60 mmol) in CH2Cl2 (12 mL) was stirred for 12 h at r.t.
After concentration, the residue was chromatographed on silica gel
with petroleum ether/CH2Cl2/EtOAc (5:4:1) to afford 300 mg of
compound 13 (95%).
Compound 10
Compound 13
IR (CHCl3): n = 3073, 2934, 2111, 1733 cm-1.
IR (CHCl3): n = 3607, 3445, 1708, 1109 cm-1.
1H NMR (CDCl3): d = 9.76 (d, 1H, J = 1.6 Hz, H1), 7.70-7.65 (m,
4H, phenyl), 7.46-7.26 (m, 6H, phenyl), 4.34 (dd, 1H, J = 1.6, 7.0
Hz, H2), 4.18 (dd, 1H, J = 3.4, 7.0 Hz, H3), 3.91-3.85 (m, 2H, H5),
3.47 (m, 1H, H4), 1.49 and 1.39 (2s, 6H, acetonide), 1.06 (s, 9H,
TBDPS).
13C NMR (CDCl3): d = 201.3 (C1), 135.6, 132.8, 130.0, 129.7,
127.9, 127.8 (phenyl), 111.9 (Cq acetonide), 81.5, 76.2 (C2 and
C3), 63.8 (C5), 62.6 (C4), 26.7 (Me TBDPS), 26.4, 26.1 (Me ace-
tonide), 19.1 (Cq TBDPS).
1H NMR (CDCl3): d = 7.69-7.63 (m, 4H, phenyl), 7.43-7.33 (m,
6H, phenyl), 4.76 (d, 1H, J = 9.5 Hz, NH), 4.18 (dd, 1H, J = 1.0, 8.5
Hz, H3), 3.90 (dd, 1H, J = 5.0, 10.0 Hz, H5), 3.87 (dd, 1H, J = 5.5,
10.0 Hz, H5), 3.82 (dddd, 1H, J = 1.0, 5.0, 5.5, 9.5 Hz, H4), 3.71 (m,
3H, H1+H2), 2.14 (br s, 1H, OH), 1.53 (s, 9H, Boc), 1.45 and 1.42
(2s, 6H, acetonide), 1.04 (s, 9H, TBDPS).
13C NMR (CDCl3): d = 156.0 (C=O Boc), 135.6, 133.3, 129.8,
127.8, 127.7 (phenyl), 109.0 (Cq acetonide), 79.7 (Cq Boc), 77.1,
76.2 (C2 and C3), 64.1 (C5), 61.6 (C1), 51.0 (C4), 28.4 (Me Boc),
27.4, 27.0 (Me acetonide), 26.8 (Me TBDPS), 19.2 (Cq TBDPS).
To a solution of aldehyde 10 (750 mg, 1.65 mmol) in MeOH
(40 mL) was added NaBH4 (63 mg, 1.65 mmol) at 0 °C. The mix-
ture was stirred for 10 min. at 0 °C, and 3 h at r.t. Acetone was then
added (6 mL) and the mixture was stirred for 15 min. The solvents
were evaporated and the residue was dissolved with CH2Cl2 and sat.
NaCl. The aqueous phase was extracted with CH2Cl2, dried
(Na2SO4) and concentrated. The crude product was chromato-
graphed on silica gel with petroleum ether/CH2Cl2/EtOAc, 70:24:6
(Rf = 0.17) to afford 310 mg of compound 11 (41%).
MS (DCI, NH3): m/z (%) = 530 (MH+, 100), 547 (MNH4 , 7).
+
Anal. Calcd for C29H43NO6Si: C, 65.75; H, 8.18; N, 2.64. Found: C,
65.70; H, 8.24; N, 2.60.
(2S,3S,4R)-4-(tert-Butyloxycarbonylamino)-1-O-carbamoyl-
2,3-dioxyisopropylidene-5-tert-butyldiphenylsilyloxy-pentanol
(14)
To compound 13 (60 mg, 0.113 mmol) in pyridine (500 mL) was
added p-nitrophenylchloroformate (34 mg, 0.169 mmol). After be-
ing stirred for 30 min., the mixture was diluted with EtOAc, washed
with sat. NaHCO3 and then with sat. NaCl. The organic phase was
dried (Na2SO4) and concentrated. The carbonate intermediate was
dissolved in MeOH (1.5 mL) and a 7 N solution of NH3 in MeOH
(600 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 h
and MeOH was evaporated. The residue was chromatographed on
silica gel with petroleum ether/CH2Cl2/EtOAc, 3:56:14 (Rf = 0.19)
to afford 45 mg of compound 14 (70%).
Compound 11
IR (CHCl3): n = 3679 (OH), 3055 (CH arom.), 2112 (N3), 1111
(C-O) cm-1.
1H NMR (CDCl3): d = 7.69-7.40 (m, 10H, phenyl), 4.09 (ddd, 1H,
J = 3.6, 4.4, 8.3 Hz, H2), 3.98 (dd, 1H, J = 3.3, 8.3 Hz, H3), 3.90
(dd, 1H, J = 7.5, 10.0 Hz, H5), 3.82 (dd, 1H, J = 4.9, 10.0 Hz, H5),
3.76 (dd, 1H, J = 3.6, 12.1 Hz, H1), 3.59 (dd, 1H, J = 4.4, 12.1 Hz,
H1), 3.37 (ddd, 1H, J = 3.3, 4.9, 7.5 Hz, H4), 1.85 (br s, 1H, OH),
1.42 and 1.38 (2s, 6H, acetonide), 1.07 (s, 9H, TBDPS).
IR (CHCl3): n = 3546, 3436, 3074, 2961, 1731, 1711, 1112 cm-1.
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York

1414
C. Dehoux et al.
PAPER
1H NMR (CDCl3): d = 7.69-7.65 (m, 4H, phenyl), 7.43-7.34 (m,
6H, phenyl), 4.87-4.76 (d and large s, 3H, J = 9.8 Hz, NHBoc and
NH2), 4.22 (d, 2H, J = 5.1 Hz, H1), 4.19 (dd, 1H, J = 8.0, 1.5 Hz,
H3), 4.00 (td, 1H, J = 5.1, 8.0 Hz, H2), 3.98 (dddd, 1H, J = 1.5, 5.8,
8.3, 9.8 Hz, H4), 3.72 (dd, 1H, J = 5.8, 9.9 Hz, H5), 3.65 (dd, 1H,
J = 8.3, 9.9 Hz, H5), 1.42 (s, 9H, Boc), 1.41 and 1.39 (2s, 6H, ace-
tonide), 1.05 (s, 9H, TBDPS).
13C NMR (CDCl3): d = 156.3, 155.7 (C=O), 135.6, 133.2, 129.7,
127.7, 127.6 (phenyl), 109.4 (Cq acetonide), 79.7 (Cq acetonide),
76.6, 75.0 (C2 and C3), 64.5, 63.8 (C1 and C5), 50.8 (C4), 28.3 (Me
Boc), 26.9, 26.8 (Me acetonide), 19.2 (Cq TBDPS).
References
(1) Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91,
7490.
(2) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
(3) Hori, M.; Kakiki, K.; Misato, T. Agric. Biol. Chem. 1974, 38,
691.
(4) Ko, K. In Pesticide Chemistry: Human Welfare and the
Environment; Miyamato, J., Ed.; Pergamon Press: Elmsford,
NY, 1983; p 247.
(5) a) Damadaran, N. P.; Jones, G. H.; Mofatt, J. G. J. Am. Chem.
Soc. 1971, 93, 3812.
+
MS (DCI, NH3): m/z (%) = 573 (MH+, 100), 590 (MNH4 , 26.5).
b) Tabusa, F.; Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem.
Lett. 1984, 405.
Anal. Calcd for C30H44O7N2Si: C, 62.91; H, 7.74; N, 4.89. Found:
C, 62.83; H, 7.68; N, 4.89.
c) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55, 3853.
d) Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019.
e) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1994, 35, 9439.
f) Ghosh, A. K.; Wang, Y. J. Org. Chem. 1998, 63, 6735.
(6) a) Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1973, 50, 5051.
b) Saksena, A. K.; Lovey, R. G.; Girijavallabham, V. M.;
Guanguly, A. K. J. Org. Chem. 1986, 51, 5024.
c) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979.
d) Savage, I., Thomas, E. J. J. Chem. Soc., Chem. Commun.
1989, 717.
(2R,3S,4S)-2-(tert-Butyloxycarbonylamino)-5-O-carbamoyle-
3,4-dioxyisopropylidene-pentanol (15)
To a solution of 14 (34 mg, 0.059 mmol) in a mixture of THF/pyri-
dine (300 mL/150 mL) was added HF/pyridine (120 mL), and the re-
action mixture was stirred for 8 h at r.t. It was then diluted with
EtOAc and hydrolysed with sat. NaHCO3. The aqueous phase was
extracted with EtOAc and the combined organic layers were dried
(Na2SO4) and concentrated. The residue was chromatographed on
silica gel with CH2Cl2/EtOAc (8:2) to give 20 mg of alcohol 15
(100%).
e) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F.
Tetrahedron 1990, 46, 265.
f) Dureault, A.; Carreaux, F.; Depezay, J. C. Synthesis 1991,
150.
g) Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1993, 34, 5479.
h) Chida, N.; Koisumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa,
S. J. Chem. Soc., Chem. Commun. 1994, 111.
i) Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem.
1994, 59, 5139.
j) Matsuura, F.; Hamada, Y.; Shiori, 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.
IR (CHCl3): n = 3621, 3507, 3438, 3054, 2978, 1729, 1708 cm-1.
1H NMR (CDCl3): d = 5.12 (d and large s, 3H, J = 10 Hz, NHBoc
and NH2), 4.25 (dd, 1H, J = 5.0, 11.5 Hz, H1), 4.20 (dd, 1H, J = 4.5,
11.5 Hz, H1), 4.06 (dd, 1H, J = 1.0, 8.5 Hz, H3), 3.98 (td, 1H,
J = 5.0, 8.5 Hz, H2), 3.84 (dddd, 1H, J = 1.0, 4.7, 6.3, 10.0 Hz, H4),
3.74 (dd, 1H, J = 4.7, 11.0 Hz, H5), 3.64 (dd, 1H, J = 6.3, 11.0 Hz,
H5), 3.30 (large s, 1H, OH), 1.43 (s, 9H, Boc), 1.42 and 1.38 (2s,
6H, acetonide).
13C NMR (CDCl3): d = 156.6, 156.3 (C=O), 109.8 (Cq acetonide),
80.1 (Cq Boc), 78.3, 75.5 (C2 and C3), 68.0 (C5), 64.3 (C1), 50.7
(C4), 28.3 (Me Boc), 26.9 (Me acetonide).
+
MS (DCI, NH3): m/z (%) = 335 (MH+, 100), 352 (MNH4 , 54.8).
Anal. Calcd for C14H26N2O7: C, 50.29; H, 7.84; N, 8.38; Found C,
50.30; H, 7.78; N, 8.30.
m) Ghosh, A. K.; Wang, Y. J. Org. Chem. 1999, 64, 2789.
n) Uchida, K.; Kato, K.; Akita, H. Synthesis 1999, 9, 1541.
(7) Dehoux, C.; Fontaine, E.; Escudier, J. -M.; Baltas, M.;
Gorrichon, L. J. Org. Chem. 1998, 63, 2601.
(8) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
Chong, J. M.; Wong, S. J. Org. Chem. 1987, 52, 2596.
(9) Parikh, J. R.; Von, E.; Doering, W. J. Am. Chem. Soc. 1967,
89, 5505.
(10) a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1989, 54, 693. Dondoni, A.; Fantin,
G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J. Org. Chem.
1989, 54, 702.
(2S,3S,4S) 2-(tert-Butyloxycarbonylamino)-5-O-carbamoyle-
3,4-dioxyisopropylidene pentanoic Acid (16)
To a solution of compound 15 (32 mg, 0.096 mmol) in CH3CN/H2O
(300 mL/300 mL) were added TEMPO (3 mg, 0.019 mmol) and
BAIB (67 mg, 0.21 mmol). The mixture was stirred for 5 h at r.t. and
then concentrated. The residue was chromatographed with a gradi-
ent from CH2Cl2/EtOAc (7:3) to EtOAc to give 16 mg of compound
16 (48%); mp: 60 °C.
IR (CHCl3): n = 3674-3000, 3510, 3436, 3054, 2978, 1729, 1708
cm-1.
b) Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995,
60, 8074.
c) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.;
Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497.
d) Dondoni, A. Synthesis 1998, 1681.
1H NMR (CDCl3): d = 9.64 (s, 1H, COOH), 5.37-5.30 (d and large
s, 3H, J = 8.4 Hz, NHBoc and NH2), 4.52 (d, 1H, J = 8.4 Hz, H2),
4.38 (m, 1H, H3), 4.30 (m, 2H, H5), 4.00 (m, 1H, H4), 1.46 (s, 9H,
Boc), 1.43 and 1.40 (2s, 6H, acetonide).
13C NMR (CDCl3): d = 173.1, 157.1, 156.2 (C=O), 110.2 (Cq ace-
tonide), 80.7 (Cq Boc), 78.5, 75.0 (C2 and C3), 64.0 (C5), 52.9
(C2), 28.3 (Me Boc), 26.9 (Me acetonide).
(11) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511.
(12) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
(13) De Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
1996, 1153.
MS (DCI, NH3): m/z (%) = 158 (100), 349 (MH+, 12.5), 366
+
Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293.
(MNH4 , 13.9).
Article Identifier:
1437-210X,E;2000,0,10,1409,1414,ftx,en;P02800SS.pdf
Synthesis 2000, No. 10, 1409–1414 ISSN 0039-7881 © Thieme Stuttgart · New York