New approach to carbamoyl-polyoxamic acid derivatives through an oxazolidinone synthon

Article abstract of DOI:10.1016/j.tetasy.2007.06.002

A key oxazolidinone synthon was obtained through condensation of vinyl magnesium with an epoxyimine, followed by a carbonation/cyclisation reaction in the presence of ammonium carbonate. Oxidative ozonolysis after protection and carbamolylation (optional)

Full text of DOI:10.1016/j.tetasy.2007.06.002

Tetrahedron: Asymmetry 18 (2007) 1320–1329
New approach to carbamoyl-polyoxamic acid derivatives
through an oxazolidinone synthon
*
´
Magalie Collet, Yves Genisson and Michel Baltas
`
´ ´ ˆ
Laboratoire de Synthese et Physicochimie des Molecules d’Interet Biologique, SPCMIB, UMR-CNRS 5068, Universite Paul Sabatier,
118 route de Narbonne, 31062 Toulouse, France
´
Received 5 April 2007; accepted 4 June 2007
Abstract—A key oxazolidinone synthon was obtained through condensation of vinyl magnesium with an epoxyimine, followed by a car-
bonation/cyclisation reaction in the presence of ammonium carbonate. Oxidative ozonolysis after protection and carbamolylation
(optional) afforded the (5-O-carbamoyl-)polyoxamic derivatives in 9% (or 14%) total yield in six (or four) steps.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
other fungi.5 Polyoxin D is used as an antifungal agent
to treat rice sheath blight and pear black spot with no side
effects.6 They are also therapeutically useful against Can-
dida albicans, a fungal pathogen that affects humans. How-
ever, polyoxins are only weakly active against whole cells
of pathogenic fungi as presumably due to their hydrolytic
instability and/or inefficient transport into the cell.7 All
members of the polyoxin family comprise a nucleosidic
aminoacid moiety connected by a peptide linkage to the
unnatural aminoacid 5-O-carbamoyl polyoxamic acid
(except for polyoxins E and G, Fig. 1).
Fungal infections of humans range from superficial to inva-
sive and often lethal ones. Over the past two decades, the
number of life threatening infections has increased dramat-
ically.1 Factors contributing to these phenomena include
the growth of immunocompromised populations of pa-
tients with AIDS, more aggressive medical procedures
and treatment with broad spectrum antibiotics creating
resistance.2 Therapy for systemic mycoses began with the
discovery of amphotericin B and 5-fluorocytosine in the
1950s, followed by azoles in the 1960s and lipopeptides in
the 1970s. Resistance against many of these compounds
is still emerging.
Polyoxamic acid 1 and its 5-O-carbamoyl derivative 2
(Fig. 2) have been the subject of many synthetic studies
and a variety of chemical syntheses have been reported,
most of which are based on carbohydrate chemistry or
on the use of chiral auxiliaries.8 Conversely, a very few
number of de novo asymmetric syntheses have been
reported. Trost et al.9 have described one using a Pd-based
opening of a vinyl epoxide by phthalamide in the presence
of a chiral ligand. More recently, Pepper et al.10 used a
stereoselective cycloaddition of acyl nitroso compounds
to cyclic dienes followed by an oxidative ring cleavage of
the cycloadducts as a new approach to the synthesis of
polyoxamic acid.
The fungal cell wall is a structure, that is, both essential for
the fungus and absent from the mammalian host, conse-
quently it presents an attractive target for pharmaceutical
(but also agricultural) pathogen management. Chitin and
glucan are two main components of the cell wall unique
to the fungi and thus a priori good drug target.3
Polyoxins form an important class of peptidyl nucleosidic
antibiotics isolated from the culture broths of Streptomyces
cacoi var. asoensis by Isono et al.4 They are known anti-
fungal agents that selectively and competitively inhibit
membrane-bound enzyme chitin synthase from yeasts and
Over the course of our ongoing research program directed
towards the use of a,b-epoxyaldehydes for the elaboration
of natural products and analogues possessing a 1,2,3-pol-
yol or aminodiol pattern, we have described the convergent
synthesis of thymine polyoxin11 C and the 5-O-carbamoyl
*
Corresponding author. Tel.: +33 0 561556292; fax: +33 0 561556011;
e-mail: baltas@chimie.ups-tlse.fr
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.002

M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
1321
O
Polyoxines
R1
R2
R3
R1
HN
A
B
D
E
F
G
H
J
CH2OH
CH2OH
COOH
COOH
COOH
CH2OH
CH3
X
HO
HO
HO
X
HO
HO
HO
H
R2OC
COHN
H2NHC
O
O
N
R3HC
HO
OH
HO
H
HOHC
HO
X
CH2OCONH2
HO
HO
HO
HO
CH3
HO
X
COOH
N
K
L
H
X=
H
HO
Figure 1. List of polyoxins from A to L.
in Figure 3. The suitably chosen epoxyimine 4 is reacted
under conditions inspired by Procter’s methodology14 with
vinylmagnesium bromide in the presence of the Lewis acid
chelator Et2OÆBF3, to afford compound 5. Its stereochem-
ical assignment has already been established by chemical
correlation.15
O
OH
OH
COOH
COOH
H2N
O
HO
OH NH2
OH NH2
2
1
Figure 2. Polyoxamic acid 1 and its 5-O-carbamoyl polyoxamic derivative
2.
Compound 5 possesses the right C-2 and C-4 stereogenic
centres of the polyoxamic acid and a reverse one at the
C-3 position. Opening of the oxirane moiety at the C-3
position was then accomplished by our recently elaborated
intramolecular cyclisation sequence16 affording oxazolidi-
none 6 as the sole product of the reaction in 90% yield after
silica-gel purification.
polyoxamic acid.12 In the latter case, our methodology
was based on four steps, that is (a) Sharpless asymmetric
epoxidation; (b) homologation of the epoxyaldehyde; (c)
stereo- and regioselective opening of the oxirane; and (d)
epimerisation of the C-2 carbon atom.
We have recently developed13 a flexible and stereoselective
approach to 1,2,3-aminodiol systems possessing a terminal
vinyl group and made use for the synthesis of various imi-
nosugars. Herein we report the use of this methodology for
a new access to 5-O-carbamoyl polyoxamic derivatives.
Having in hand oxazolidinone 6, we explored two path-
ways for the synthesis of 5-O-carbamoyl polyoxamic acid
derivatives (Fig. 4). The first resides on cleavage of the oxa-
zolidinone moiety prior to further group manipulations,
while the second maintains the oxazolidinone moiety until
the end of the synthetic pathway.
Cleavage of the cyclic carbamate was performed via a
saponification reaction (Fig. 5). Compound 6, when treated
with lithium hydroxide under reflux conditions, afforded
aminotriol 7 in 65% yield after silica gel purification. The
2. Results and discussion
The key synthon of the methodology presented here is
vinylic oxazolidinone 6, the synthesis of which is presented
3 steps
O
O
a
HO
OH
TBDPSO
H
TBDPSO
H
90%
3
O
NBn
4
cis-but-2-ene1,4 diol
b
64%
OH
TBDPSO
2
O
2
c
3
TBDPSO
4R
4
3
O
90%
NBn
NHBn
5
O
6
˚
Figure 3. Reagents and conditions: (a) PhCH2NH2, MS 4 A, Et2O, rt, 3 h; (b) Et2OÆBF3, C2H3MgBr, Et2O, ꢀ78 °C, 64%; (c) (NH4)2CO3, THF/H2O (4/1),
rt, 90%.

1322
M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
O
O
N
O
N
H2N
O
TBDPSO
COOH
Bn
O
O
path a
Boc
Boc
Bn
O
OH
COOH
NH2
H2N
O
OH
TBDPSO
HO
O
5-
O
-carbamoyl polyoxamic acid
NBn
O
path b
O
OBn
COOH
NBn
OBn
NBn
H2N
O
TBDPSO
O
O
O
O
Figure 4. Retrosynthetic pathways.
OH
OH
TBDPSO
O
4
4
2
2
2
HO
HO
b, c
TBDPSO
a
2
3
3
3
4
3
O
4
65%
85%
O
NBn
NHBn
NHBn
O
6
7
8
d
89%
O
O
O
HO
TBDPSO
O
2
2
f,g
H2N
e
O
3
3
2
4
4
3
O
O
Boc
4
65%
O
N
N
Bn
Bn
Boc
N
Bn
Boc
10
9
11
h
35%
O
O
O
O
H2N
H2N
O
O
2
2
3
3
COOH
Bn
COOH
Bn
4
4
O
O
1/1
N
N
Boc
Boc
12
12'
Figure 5. Reagents and conditions: (a) LiOHÆH2O, dioxane/H2O (3/1), reflux, 4 h, 65%; (b) TBDPSCl, Et3N, DMAP (cat), CH2Cl2, rt, 20 h, 85%; (c) CSA,
dimethoxypropane, rt, 24 h, quant.; (d) Boc2O, Et3N, CH2Cl2, rt, 48 h, 89%; (e) TBAF/SiO2, THF, rt, 20 h, 85%; (f) p-nitrophenylchloroformate, pyridine,
rt 30 min; (g) NH3 in MeOH (7 N), 0 °C, 1 h, 77%; (h) O3, AcOEt, ꢀ78 °C, then H2O2 (30% in H2O), 50 °C, 5 min, 35%.
tert-butyldiphenyl silyl group had also been eliminated.
Other basic conditions reactions used gave the same result.
Protection of the aminotriol at the primary position, and
subsequent formation of the five membered acetonide
yielded compound 8 in 85% yield for the two steps
sequence. tert-Butyloxy carbonyl protection of the secondary
amine afforded the completely protected aminopolyol 9.
Elimination of the silyl group was followed by carbamo-
ylation of primary alcohol 10 via a two-step procedure
using p-nitrophenylchloroformate in pyridine and treat-
ment of the primary carbamate intermediate at 0 °C with
methanolic ammonia. The 5-O-carbamoyl moiety was thus
installed in 65% yield (three steps). An ozonolysis reaction
at low temperature followed by the immediate treatment

M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
1323
of the ozonide with hydrogen peroxide for 5 min at 50 °C
afforded the protected 5-O-carbamoyl polyoxamic acid 12
and its aminoacid epimer 120 in 35% yield and in a 1:1 ratio.
Concerning the 13C NMR spectra, two C@O chemical
shifts were observed at d = 160.1 ppm (COOH) and at
d = 156.9 (NCOO), the latter being in agreement with the
literature data.18 Finally, the IR spectra showed two car-
bonyl absorption bands at 1775 m cmꢀ1 (NCOO) and
1727 cmꢀ1 (COOH).
With regards to the second pathway, the ozonolysis
reaction of the vinylic group (Fig. 6) was also explored.
Protection of the secondary hydroxyl group (NaH, BnBr,
n-Bu4NI) led to oxazolidinone 13 in 70% yield.
The reaction mixture of the ozonolysis reaction on com-
pound 13 was also allowed to react at 80 °C for 5 min.
After quenching, extraction and silica-gel purification, a
sole product could be obtained different from compounds
15 and 16. It is noteworthy that the same new compound
was also obtained when the H2O2 treatment was conducted
at 50 °C for 40 h. After a careful analysis of its spectro-
scopic characteristics (1H, 13C, HSQC, HMBC, IR), we
assigned the structure to compound 14, obtained in 35%
yield. Some marked differences appear between compounds
14 and 15. First, the N–CH2–Ph AB system in 14 has a
different chemical shift and is much less split
(DdHA ꢀ HB = 69 Hz, vs 148 Hz), suggesting a less con-
strained environment for the corresponding methylene.
The H-4 chemical shift has moved downfield for compound
14, d = 5.01 versus d = 5.90 for compound 15, while the
coupling constants remain small. Concerning the 13C
NMR spectra, we observed only one chemical shift for
the C@O functions (d = 157.9 ppm) and in the IR spectra
a unique carbonyl band absorption at m = 1739 cmꢀ1. Rel-
ative data are scarce in the literature. It is noteworthy that
an unsubstituted analogous compound reported recently
by Martin19 shows a sole 13C carbonyl chemical shift.
Since the oxidative ozonolysis reaction at rt gave a mixture
of non-acid compounds (not characterised), we studied the
reaction conditions at different temperatures. In all cases,
the ozonolysis reaction started at ꢀ78 °C in ethylacetate,
after which the reaction mixture was dropped in a 30%
aqueous H2O2 solution heated at two different tempera-
tures, 50 °C and 80 °C.
When the reaction mixture was heated for 30 min at 50 °C,
two compounds were isolated after quenching, extraction
and silica-gel purification. They were identified to be deriv-
atives 15 and 16 (35% yield, 3:2 ratio of 15:16). The latter
was obtained through an additional oxidative process of
the benzyloxy group. Primary methyl ethers (RCH2OCH3)
have already been reported as latent carbomethoxy groups
in ruthenium tetraoxide catalysed oxidations.17 To the best
of our knowledge, this is the first time that this transforma-
tion has occurred in such functionalised systems.
One dimensional (1H, 13C) and two dimensional (HSQC,
HMBC) NMR spectroscopy was performed for compound
15. Concerning the 1H NMR spectra, we can find a
straightforwad AB system for the N–CH2–Ph hydrogen
atoms (DdHA ꢀ dHB = 148 Hz) and small coupling con-
stants for JH3ꢀH2 and JH3ꢀH4 (both equal to J = 1.8 Hz).
These small values are indicative of a trans relationship
of the oxazolidinone system. Analogous coupling values
and chemical shifts have been reported in the literature.18
A mechanism for this transformation is tentatively pre-
sented below (Fig. 7). The process might be initiated from
intermediate 15 by the reversible intramolecular attack of
the carboxylate onto the oxazolidinone carbonyl. The
unstable cyclic entity thus formed might then rapidly
evolve, either through cleavage of the C–N or the C–O
OBn
O O
OH
OBn
TBDPSO
TBDPSO
TBDPSO
2
2
2
a
b
3
3
3
O
4
4
4
O
O
O
70%
13a
NBn
NBn
NBn
6
13
O
O
O
d
c
35%
O
Ph
OBn
O
OBn
TBDPSO
TBDPSO
2
2
TBDPSO
2
3
3
3
COOH
COOH
4
4
NHBn
4
O
O
O
NBn
NBn
15
16
14
O
O
O
O
O
5 min.
30 min.
R=35%
R=35%
15
15/16 (3/2)
Figure 6. Reagents and conditions: (a) NaH, BnBr, n-Bu4NI, THF, rt, 70%; (b) O3, AcOEt, ꢀ78 °C, 20 mn; (c) H2O2 (30% in H2O), 80 °C, 5 min, 35%; (d)
H2O2 (30% in H2O), 50 °C, 5 or 30 min.

1324
M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
OBn
TBDPSO
OBn
OH
2
O
OBn
O
TBDPSO
2
a
TBDPSO
a
2
3
4
3
HO
3
4
O
O
O
O
O
O
4
BnN
NBn
NBn
O
b
OH
b
15
OBn
TBDPSO
O
2
3
4
NHBn
HO
O
O
3
4
BnO
2
O
O
O
O
TBDPSO
14
N
Bn
Figure 7. Proposed mechanism for the formation of cyclic mixed anhydride 14.
bond. The former possibility would lead to the formation
of an N-carboxyanhydride that can be ruled out on the
basis of the characterisation of compound 14. On the other
hand, in the latter case, an intramolecular mixed anhydride
would be generated. Such a structure would be in agree-
ment with the spectral data of derivative 14.
ly, the protected 5-O-carbamoyl-polyoxamic acid deriva-
tive 19 was obtained in 15.8% yield (from 6) and 9%
from 3 (six steps).
4. Experimental
In order to proceed with the synthesis of the carbamoylated
derivatives, oxazolidinone 13 was desilylated smoothly
(TBAF/SiO2, THF rt 83%) and the carbamoylation was
conducted as previously to afford compound 18 in 90%
yield (Fig. 8). The oxidative (5 min, 50 °C) ozonolysis reac-
tion performed as before yielded the corresponding acid 19
in 30% yield.
4.1. General methods
Dry solvents were distilled prior to use: CH2Cl2, Et3N and
DMSO from CaH2, and THF from sodium/benzophenone.
Chromatographic purifications were performed by Med-
ium-pressure liquid chromatography with a Jobin-Yvon
apparatus using Merck 15–40 lm silica gel, flash column
chromatography was carried out with SDS 35–70 lm silica
gel, and preparative HPLC column chromatography was
carried out using Merck 12 lm silica gel. H NMR, 13C
1
3. Conclusion
NMR and 19F NMR spectra were recorded on Brucker
AC 250 and AC400 spectrometers at 20 °C, using CDCl3
as a solvent and tetramethylsilane as an internal standard.
Infrared (IR) spectra were recorded on a Perkin–Elmer FT-
IR 883 spectrometer using NaCl plates. Mass spectrometry
(MS) data were obtained on a NERMAG R10-10 spec-
trometer. Optical rotations were measured on a Perkin–El-
mer model 141 polarimeter. High resolution mass spectra
(HRMS) were performed on a ThermoFinnigan MAT 95
XL spectrometer (DCI). Enantiomeric excesses were deter-
mined by HPLC using a chiral analytic column CHIRA-
CEL OD.
In conclusion, based on the use of a suitably chosen epoxy-
alcohol, our methodology on the region- and stereo-
controlled opening of the oxirane ring of the vinylic
epoxyamines and on the direct oxidative ozonolyses reac-
tions can lead to the formal synthesis of 5-O-carbamoyl
polyoxamic acid and its protected derivatives.
Following the first methodology, the carbamoylated ethyl-
enic intermediate 11 was obtained in eight steps starting
from epoxyaldehyde 3 and 18.4% total yield. Nevertheless,
the transformation of the ethylenic functionality to the acid
remains problematic under ozonolysis conditions due
essentially to low yield and epimerisation.
4.2. (4R,5S)-3-Benzyl-5-((1S)-2-tert-butyldiphenylsilyloxy-
1-hydroxyethyl)-4-vinyl-1,3-oxazolan-2-one 6
Following the second approach, protected polyoxamic acid
15 was obtained in 24.5% total yield from oxazolidinone 6
and 14.1% yield from epoxyaldehyde 3 (four steps). Final-
To a solution of epoxyamine 5 (3.73 g, 8.16 mmol) in a
mixture of THF/H2O 4:1 (20 mL/mmol) was added ammo-
O
O
OBn
OBn
OBn
OBn
HO
2
H2N
b,c
90%
O
2
TBDPSO
H2N
O
2
2
3
3
d, e
30%
a
4
3
3
4
COOH
NBn
19
O
4
4
O
O
O
83%
NBn
NBn
NBn
O
O
O
O
17
18
13
Figure 8. Reagents and conditions: (a) TBAF/SiO2, THF, rt, 20 h, 83%; (b) p-nitrophenylchloroformate, pyridine, rt 30 mn; (c) NH3 in MeOH (7 M),
0 °C, 1 h, 90%; (d) O3, AcOEt, ꢀ78 °C, 20 min; (e) H2O2 (30% in H2O), 50 °C, 5 min, 30%.

M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
1325
nium carbonate (6.30 g, 65.30 mmol). After 24 h, the mix-
ture was concentrated and 150 mL of water was added.
The aqueous phase was extracted three times with Et2O,
and the combined organic layers were successively washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was then puri-
fied by medium-pressure chromatography on silica gel
(petroleum ether/EtOAc 85:15) to give starting materials
5 (0.25 g, 0.55 mmol), which has not reacted, and 6
(CH arom.), 118.6 (C6), 74.0 (C3), 72.3 (C2), 65.4 (C1),
63.7 (C4), 50.5 (NCH2Ph); MS (DCI, NH3): m/z = 238
[M+H]+ (100); HRMS (DCI, NH3) calcd. for
C13H20NO3 [M+H]+ 238.1443. Found: 238.1449.
4.4. (2S,3S,4R)-4-Benzylamino-1-tert-butyldiphenylsilyloxy-
2,3-dioxyisopropylidene-hex-5-en 8
To a solution of aminotriol 7 (0.14 g, 0.60 mmol) in
CH2Cl2 (10 mL/mmol) were added tert-butyldiphenylsilyl
chloride (0.17 mL, 0.66 mmol), freshly distilled Et3N
(92 lL, 0.66 mmol) and DMAP (3 mg, 0.02 mmol). The
mixture was stirred at rt for 20 h. The mixture was then
concentrated and 10 mL of water was added. The aqueous
phase was extracted three times with CH2Cl2 and twice
with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified
by medium-pressure column chromatography on silica gel
(petroleum ether/EtOAc 9:1) to give the monosilylated
(3.68 g, 7.34 mmol, 90% yield): Rf = 0.11 (petroleum
25
ether/EtOAc 85:15); ½aꢁD ¼ þ30:2 (c 1.06, CHCl3); IR
(film) 3405, 3074, 1726, 1426, 1064 cmꢀ1 1H NMR d
;
ppm (400 MHz, CDCl3) 7.65–7.60 (4H, m, phenyl), 7.46–
7.39 (6H, m, phenyl), 7.32–7.26 (5H, m, phenyl), 5.68
(1H, ddd, 3JH5/H4 = 9.2 Hz, 3JH5/H6a = 10.4 Hz and
3JH5/H6b = 17.0 Hz, H5), 5.35 (1H, d, 3JH6a/H5 =
10.4 Hz, H6a), 5.24 (1H, d, 3JH6b/H5 = 17.0 Hz, H6b),
4.77 and 4.05 (2H, AB part of an ABX system,
2
DdHa ꢀ dHb = 288 Hz, Jgem = 15.2 Hz, NCH2Ph), 4.27
(1H, dd, 3JH3/H2 = 2.4 Hz and 3JH3/H4 = 7.2 Hz, H3),
4.07 (1H, dd, 3JH4/H3 = 7.2 Hz and 3JH4/H5 = 9.2 Hz,
H4), 3.77 and 3.72 (2H, AB part of an ABX system,
DdHa ꢀ dHb = 21 Hz, 3JH1a/H2 = 7.0 Hz, 3JH1b/H2 =
compound (0.24 g, 0.51 mmol, 85% yield): Rf = 0.16
25
(petroleum ether/EtOAc 9:1); ½aꢁD ¼ þ7:3 (c 0.79, CHCl3);
1
IR (film) 3415, 2929, 2856, 1636, 1111 cmꢀ1; H NMR d
2
3
5.8 Hz, JH1a/H1b = 10.2 Hz, H1), 3.65 (1H, ddd, JH2/
H1a = 7.0 Hz, 3JH2/H1b = 5.8 Hz and 3JH2/H3 = 2.4 Hz,
H2), 2.39–2.21 (1H, m, OH), 1,06 (9H, s, CH3 tBuPh2Si);
13C NMR d ppm (100 MHz, CDCl3) 157.5 (C@O), 135.6
(Cq arom.), 135.5 (CH arom.), 134.6 (C5), 132.8 (Cq
arom.), 129.9, 128.7, 128.3, 127.8 (CH arom.), 121.8 (C6),
78.1 (C3), 70.8 (C2), 64.1 (C1), 60.0 (C4), 46.0 (NCH2Ph),
26.8 (CH3 tBuPh2Si), 19.2 (Cq tBuPh2Si); MS (DCI, NH3):
m/z = 519 [M+NH4]+ (100), 502 [M+H]+ (15); HRMS
(DCI, NH3) calcd. for C30H36NO4Si [M+H]+ 502.2414.
Found: 502.2415.
ppm (400 MHz, CDCl3) 7.73–7.67 (4H, m, phenyl), 7.45–
3
7.34 (11H, m, phenyl), 5.80 (1H, ddd, JH5/H4 = 8.4 Hz,
3JH5/H6a = 10.4 Hz and 3JH5/H6b = 17.2 Hz, H5), 5.35
(1H, dd, 3JH6a/H5 = 10.4 Hz and 2JH6a/H6b = 1.6 Hz,
H6a), 5.24 (1H, dd, 3JH6b/H5 = 17.2 Hz and 2JH6a/
H6b = 1.6 Hz, H6b), 3.92 and 3.65 (2H, AB part of
2
an ABX system, DdHa ꢀ dHb = 108 Hz, Jgem = 12.8 Hz,
NCH2Ph), 3.82–3.75 (2H, m, H1), 3.78–3.75 (1H, m, H2),
3.73 (1H, dd, 3JH3/H2 = 1.4 Hz and 3JH3/H4 = 4.8 Hz,
H3), 3.21 (1H, dd, 3JH4/H3 = 4.8 Hz and 3JH4/
H5 = 8.4 Hz, H4), 1.08 (9H, s, CH3 tBuPh2Si); 13C NMR
d ppm (100 MHz, CDCl3) 139.5 (Cq arom.), 136.6 (C5),
135.6 (CH arom.), 133.1, 132.9 (Cq arom.), 129.8, 128.5,
128.4, 127.8, 127.2 (CH arom.), 118.4 (C6), 72.6 (C2),
72.4 (C3), 66.3 (C1), 64.0 (C4), 50.6 (NCH2Ph), 26.9
(CH3 tBuPh2Si), 19.2 (Cq tBuPh2Si); MS (DCI, NH3): m/
z = 476 [M+H]+ (100); HRMS (DCI, NH3) calcd. for
C29H38NO3Si [M+H]+ 476.2621. Found: 476.2624. Under
an inert atmosphere, to a solution of this monosilylated
compound (0.9 g, 0.19 mmol) in freshly distilled 2,2-
dimethoxypropane (13 mL/mmol) was added camphor sul-
fonic acid (0.5 g, 0.21 mmol). The solution was stirred at rt
for 24 h and then hydrolysed with a saturated aqueous
solution of NaHCO3. The mixture was then concentrated,
10 mL of water added, and the aqueous phase extracted
three times with EtOAc. The combined organic layers were
successively washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. Compound 8
(97 mg, 0.19 mmol, quant.) was obtained as a pure product
4.3. (2S,3S,4R)-4-Benzylamino-1,2,3-triol-hex-5-en 7
To a solution of oxazolidinone 6 (0.99 g, 1.97 mmol) in a
mixture of dioxane/H2O 3:1 (10 mL/mmol) was added
monohydrated lithium hydroxide (0.49 g, 11.80 mmol).
The mixture was heated at reflux for 4 h, after which the
mixture was concentrated. Water was then added
(20 mL), and the aqueous phase extracted three times with
CH2Cl2. The combined organic layers were successively
washed with brine, dried over MgSO4, filtered and concen-
trated under reduced pressure. The crude product was then
purified by medium-pressure column chromatography on
silica gel (EtOAc with 0.25% Et3N) to give 7 (0.30 g,
1.28 mmol, 65% yield): Rf = 0.11 (EtOAc with 0.25%
25
Et3N); [aꢁD ¼ ꢀ20:0 (c 2.75, CHCl3); IR (film) 3453,
1
2931, 2858, 1638, 1066 cmꢀ1; H NMR d ppm (400 MHz,
3
CDCl3) 7.36–7.28 (5H, m, phenyl), 5.79 (1H, ddd, JH5/
H4 = 8.8 Hz, 3JH5/H6a = 10.4 Hz and 3JH5/H6b
=
without purification: Rf = 0.33 (petroleum ether/EtOAc
25
17.2 Hz, H5), 5.36 (1H, dd, 3JH6a/H5 = 10.4 Hz and
2JH6a/H6b = 1.6 Hz, H6a), 5.25 (1H, dd, 3JH6b/H5 =
17.2 Hz and 2JH6a/H6b = 1.6 Hz, H6b), 3.91 and 3.64
(2H, AB part of an ABX system, DdHa ꢀ dHb = 107 Hz,
2Jgem = 12.8 Hz, NCH2Ph), 3.78–3.73 (2H, m, H1), 3.75–
3.72 (1H, m, H2), 3.62 (1H, dd, 3JH3/H2 = 1.8 Hz and
3JH33/H4 = 4.8 Hz, H3), 3.24 (1H, dd, 3JH4/H3 = 4.8 Hz
and JH4/H5 = 8.8 Hz, H4); 13C NMR d ppm (100 MHz,
CDCl3) 139.1 (Cq arom.), 136.2 (C5), 128.6, 128.4, 127.4
85:15 with 0.25% Et3N); ½aꢁD ¼ ꢀ81:6 (c 1.20, CHCl3);
1
IR (film) 3331, 2930, 2858, 1494, 1111 cmꢀ1; H NMR d
ppm (400 MHz, CDCl3) 7.70–7.67 (4H, m, phenyl), 7.44–
7.28 (11H, m, phenyl), 5.61 (1H, dd, 3JH5/H4 = 8.8 Hz
3
and JH5/H6b = 6.2 Hz, H5), 5.22 (1H, s, H6a), 5.19 (1H,
d, 3JH6b/H5 = 6.2 Hz, H6b), 4.09 (1H, td, 3JH2/
H3 = 5.6 Hz and 3JH2/H1a = 3JH2/H1a = 4.0 Hz, H2),
4.07 (1H, dd, 3JH3/H2 = 5.6 Hz and 3JH3/H4 = 6.4 Hz,
H3), 3.90 and 3.63 (2H, AB part of an ABX system,

1326
M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
2
1
DdHa ꢀ dHb = 108 Hz, Jgem = 13.6 Hz, NCH2Ph), 3.78
IR (film) 3453, 2930, 1690, 1111 cmꢀ1; H NMR d ppm
and 3.67 (2H, AB part of an ABX system, DdHa ꢀ dHb =
(400 MHz, CDCl3) 7.32–7.24 (5H, m, phenyl), 6.02–5.88
(1H, m, H5), 5.37–5.32 (1H, m, H6a), 5.28–5.14 (1H, m,
H6b), 4.77–4.64 (1H, m, H4), 4.57 (2H, s, NCH2Ph),
4.32–4.21 (1H, m, H3), 3.93–3.82 (1H, m, H2), 3.82–3.76
(2H, m, H1), 1.52 and 1.33 (6H, 2s, H8 and H9), 1.42
(9H, s, CH3 Boc); 13C NMR d ppm (100 MHz, CDCl3)
156.1 (C@O Boc), 135.6 (Cq arom.), 133.9 (C5), 128.3,
127.0 (CH arom.), 120.3 (C6), 109.3 (C7), 79.5 (C3), 78.8
(C2), 62.8 (C1), 62.2 (C4), 50.4 (NCH2Ph), 28.4 (C8 and
C9), 27.4 (CH3 Boc); MS (DCI, NH3): m/z = 378
[M+H]+ (100); HRMS (DCI, NH3) calcd. for
C21H32NO5 [M+H]+ 378.2280. Found: 378.2279. The
para-nitrophenyl chloroformate was purified by sublima-
tion. Under inert atmosphere, to a solution of deprotected
compound (69 mg, 0.18 mmol) in anhydrous pyridine
(5 mL/mmol) was added p-nitrophenyl chloroformate
(55 mg, 0.28 mmol). After 30 min at rt, the mixture was
diluted with EtOAc, and washed successively with a
saturated aqueous solution of NaHCO3 and brine. The
organic phase was dried over MgSO4, filtered and concen-
trated under reduced pressure to give a red oil. This inter-
mediate was then solubilised in MeOH (15 mL/mmol), and
a 7 M solution of ammonia in MeOH (5 mL/mmol) was
added at 0 °C. The mixture was stirred for 1 h at 0 °C
and then methanol was evaporated. The crude product
was purified by medium-pressure column chromatography
on silica gel (petroleum ether/EtOAc 7:3) to give 11 (59 mg,
44 Hz,
3JH1a/H2 = 3JH1b/H2 = 4.0 Hz
and
3JH1a/
3
H1b = 10.8 Hz, H1), 3.16 (1H, dd, JH4/H3 = 6.4 Hz and
3JH4/H5 = 8.8 Hz, H4), 1.41 and 1.37 (6H, 2s, H8 and
H9), 1.06 (9H, s, CH3 tBuPh2Si); 13C NMR d ppm
(100 MHz, CDCl3) 140.4 (Cq arom.), 137.2 (C5), 135.7
(CH arom.), 133.3 (Cq arom.), 129.6, 128.3, 128.1, 127.7,
126.8 (CH arom.), 118.8 (C6), 109.3 (C7), 79.7 (C3), 79.1
(C2), 64.3 (C1), 63.7 (C4), 50.7 (NCH2Ph), 27.5 (C8 and
C9), 26.8 (CH3 tBuPh2Si), 19.2 (Cq tBuPh2Si); MS
(DCI, NH3): m/z = 516 [M+H]+ (100); HRMS (DCI,
NH3) calcd. for C32H42NO3Si [M+H]+ 516.2934. Found:
516.2938.
4.5. (2S,3S,4R)-4-Benzylamino-1-tert-butyldiphenylsilyloxy-
4-tert-butyloxycarbonylamino-2,3-dioxyisopropylidene-
hex-5-en 9
To a solution of compound 8 (0.24 g, 0.47 mmol) and Et3N
(0.13 mL, 0.94 mmol) in CH2Cl2 (15 mL/mmol of com-
pound 8) slowly was added, at 0 °C, Boc2O (0.11 g,
0.52 mmol). The mixture was then stirred at rt for 48 h
and then, hydrolysed with 20 mL of water. The aqueous
phase was extracted three times with EtOAc, and the com-
bined organic layers were successively washed with brine,
dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by medium-pres-
sure column chromatography on silica gel (petroleum
0.14 mmol, 77% yield): Rf = 0.24 (petroleum ether/EtOAc
25
ether/EtOAc 95:5) to give 9 (0.26 g, 0.42 mmol, 89%):
7:3); ½aꢁD ¼ ꢀ3:5 (c 1.26, CHCl3); IR (film) 3359, 2932,
25
Rf = 0.17 (petroleum ether/EtOAc 95:5); ½aꢁD ¼ þ3:1 (c
1729, 1692, 1067 cmꢀ1 1H NMR d ppm (400 MHz,
;
1.47, CHCl3); IR (film) 2931, 2858, 1695, 1428,
CDCl3) 7.32–7.25 (5H, m, phenyl), 6.04–5.78 (1H, m,
H5), 5.32 (1H, s, H6a), 5.27–5.17 (1H, m, H6b), 5.29
(2H, m, NH2), 4.88–4.69 (1H, m, H4), 4.69–4.48 (2H, m,
NCH2Ph), 4.36–4.08 (2H, m, H1), 4.21 (1H, t, 3JH3/
H2 = 3JH3/H4 = 7.4 Hz, H3), 4.08–3.92 (1H, m, H2), 1.53
and 1.34 (6H, 2s, H8 and H9), 1.41 (9H, s, CH3 Boc);
13C NMR d ppm (100 MHz, CDCl3) 156.5 (C@O Boc),
155.9 (C@O carbamoyl), 135.4 (Cq arom.), 133.6 (C5),
128.3, 127.1, 126.8 (CH arom.), 120.2 (C6), 109.9 (C7),
79.1 (C3), 76.4 (C2), 65.3 (C1), 61.3 (C4), 50.4 (NCH2Ph),
28.4 (C8 and C9), 27.2 (CH3 Boc); MS (DCI, NH3): m/
z = 421 [M+H]+ (100); HRMS (DCI, NH3) calcd. for
C22H33N2O6 [M+H]+ 421.2339. Found: 421.2331.
1058 cmꢀ1 1H NMR d ppm (400 MHz, CDCl3) 7.75–
;
7.71 (4H, m, phenyl), 7.46–7.38 (5H, m, phenyl), 7.32–
7.24 (6H, m, phenyl), 5.85–5.69 (1H, m, H5), 5.32–5.28
(1H, m, H6a), 5.13–5.06 (1H, m, H6b), 4.71–4.65 (1H, m,
H4), 4.66–4.57 (2H, m, NCH2Ph), 4.47 (1H, t, 3JH3/
H2 = 3JH3/H4 = 7.2 Hz, H3), 3.97–3.93 (1H, m, H2),
3.94–3.67 (2H, m, H1), 1.51 and 1.34 (6H, 2s, H8 and
H9), 1.46 (9H, s, CH3 Boc), 1.10 (9H, s, CH3 tBuPh2Si);
13C NMR d ppm (100 MHz, CDCl3) 156.0 (C@O Boc),
135.9 (CH arom.), 134.2 (C5), 133.6 (Cq arom.), 129.9,
128.3, 127.9 (CH arom.), 119.7 (C6), 109.5 (C7), 79.9
(C2), 77.1 (C3), 63.7 (C1), 60.7 (C4), 49.7 (NCH2Ph),
28.5 (C8 and C9), 27.6 (CH3 Boc), 27.0 (CH3 tBuPh2Si),
19.5 (Cq tBuPh2Si); MS (DCI, NH3): m/z = 616 [M+H]+
(100); HRMS (DCI, NH3) calcd. for C37H50NO5Si
[M+H]+ 616.3458. Found: 616.3459.
4.7. (2S,3S,4S)-4-Benzylamino-4-tert-butyloxycarbonyl-
amino-1-O-carbamoyl-2,3-dioxyisopropyliden-pentano¨ıc
acid 12 and (2S,3S,4R)-4-benzylamino-4-tert-butyloxy-
carbonylamino-1-O-carbamoyl-2,3-dioxyisopropyliden-
pentano¨ıc acid 120
4.6. (2S,3S,4R)-4-Benzylamino-4-tert-butyloxycarbonyl-
amino-1-O-carbamoyl-2,3-dioxyisopropylidene-hex-5-en 11
In a solution of alkene 10 (31 mg, 73 lmol) in EtOAc
(10 mL/mmol), at ꢀ78 °C, O3 was bubbled until the solu-
tion became blue. The ozonide formed was then decom-
posed by dropping the mixture in 130 lL of a 30%
aqueous solution of hydrogen peroxide heated at 50 °C,
and stirring it at 50 °C for 5 min. The mixture was then
cooled to 0 °C and basified with 2 mL of a saturated aque-
ous solution of K2CO3 and extracted with Et2O. The aque-
ous phase was then acidified until pH 4 with a 1 M
hydrochloric acid aqueous solution saturated in NaCl,
and extracted with Et2O. The organic layers were succes-
To a solution of compound 9 (0.14 g, 0.23 mmol) in anhy-
drous THF (35 mL/mmol) was added TBAF supported on
silica (0.27 g, 0.27 mmol). The mixture was stirred over-
night at rt after which it was concentrated. The residue
was suspended in EtOAc and filtered. Then, the solvent
was evaporated under reduced pressure. The crude product
was purified by medium-pressure column chromatography
on silica gel (petroleum ether/EtOAc 8:2) to give the depro-
tected product 10 (72 mg, 0.19 mmol, 85% yield): Rf = 0.13
25
(petroleum ether/EtOAc 8:2); ½aꢁD ¼ þ3:6 (c 0.73, CHCl3);

M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
1327
sively washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product
was purified by medium-pressure column chromatography
on silica gel (CH2Cl2/EtOAc 7:3) to give a mixture 1:1 of 12
and 120 (12 mg, 26 lmol, 35% yield): Rf = 0.08 (CH2Cl2/
(CH3 tBuPh2Si), 19.1 (Cq tBuPh2Si); MS (DCI, NH3):
m/z = 609 [M+NH4]+ (100), 592 [M+H]+ (25); Anal.
Calcd for C37H41NO4Si: C, 74.09; H, 6.98; N, 2.37. Found:
C, 74.97; H, 7.08; N, 2.45.
EtOAc 7:3); IR (film) 3359, 2978, 1729, 1692, 1068 cmꢀ1
;
4.9. (5S,6S,10S)-5-Benzylamino-6-(1-benzyloxy-2-tert-
butyldiphenylsilyloxy)ethyl-1,3-dioxane-2,4-dione 14
1
Compound 12: H NMR d ppm (400 MHz, CDCl3) 9.27
(1H, m, H5), 7.34–7.29 (5H, m, phenyl), 4.70 (2H, d,
J = 12.0 Hz, NH2), 4.68–4.56 (1H, d, 3JH4/H3 = 7.2 Hz,
H4), 4.47 and 4.37 (2H, AB part of an ABX system,
In a solution of alkene 13 (53 mg, 90 lmol) in EtOAc
(8 mL/mmol), at ꢀ78 °C, O3 was bubbled until the solution
became blue. The ozonide formed was then decomposed by
dropping it in a solution of 150 lL of a 30% aqueous solu-
tion of hydrogen peroxide heated at 80 °C, and stirring the
mixture at 80 °C for 5 min. The mixture was then cooled to
0 °C and basified with 2 mL of a saturated aqueous solu-
tion of K2CO3 and extracted with Et2O. The aqueous
phase was then acidified until pH 4 with a 1 M hydrochlo-
ric acid aqueous solution saturated in NaCl, and extracted
with Et2O. The organic layers were successively washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified
by medium-pressure column chromatography on silica gel
2
DdHa ꢀ dHb = 40 Hz, Jgem = 15.6 Hz, NCH2Ph), 4.42–
4.34 (1H, m, H3), 4.25–4.17 (2H, m, H1), 4.14–4.08 (1H,
m, H2), 1.46 (9H, s, CH3 Boc), 1.43 and 1.40 (6H, 2s, H8
and H9); Compound 120: 1H NMR d ppm (400 MHz,
CDCl3) 9.39 (1H, m, H5), 7.34–7.29 (5H, m, phenyl),
5.29 (2H, d, J = 12.0 Hz, NH2), 4.55–4.53 (1H, m, H4),
4.47 and 4.37 (2H, AB part of an ABX system,
2
DdHa ꢀ dHb = 40 Hz, Jgem = 15.6 Hz, NCH2Ph), 4.42–
4.34 (1H, m, H3), 4.25–4.17 (2H, m, H1), 4.08–4.01 (1H,
m, H2), 1.46 (9H, s, CH3 Boc), 1.43 and 1.40 (6H, 2s, H8
and H9); MS (DCI, NH3): m/z = 456 [M+NH4]+ (15),
393 [MꢀCO2H] (68), 218 (100%).
(petroleum ether/EtOAc 9:1) to give 14 (19 mg, 32 lmol,
25
4.8. (4R,5S)-3-Benzyl-5-((1S)-2-tert-butyldiphenylsilyloxy-
1-benzyloxyethyl)-4-vinyl-1,3-oxazolan-2-one 13
35% yield): Rf = 0.08 (petroleum ether/EtOAc 9:1); ½aꢁD ¼
þ64:8 (c 1.20, CHCl3); IR (film) 2931, 2858, 1739, 1428,
1
1114 cmꢀ1; H NMR d ppm (400 MHz, CDCl3) 7.98 (1H,
Under an inert atmosphere, to a solution of oxazolidinone
6 (0.60 g, 1.2 mmol) in anhydrous THF (20 mL/mmol) at
0 °C was added 60% sodium hydride in oil (72 mg,
1.8 mmol). After 5 min, the mixture was warmed up to rt
and tetrabutylammonium iodide (22 mg, 0.06 mmol) was
added. After 5 min of stirring, benzyl bromide (214 lL,
1.8 mmol) was added. The mixture was stirred at rt for
3.5 h, and was then hydrolysed with a saturated aqueous
solution of NaHCO3. THF was evaporated and the resid-
ual aqueous phase extracted three times with DCM. The
combined organic layers were washed successively with
water and brine, dried over MgSO4, filtered and concen-
trated under reduced pressure. The crude product was puri-
fied by medium-pressure column chromatography on silica
gel (petroleum ether/EtOAc 9:1) to give 13 (0.50 g,
s, H acid), 7.68–7.63 (5H, m, phenyl), 7.47–7.41 (7H, m,
phenyl), 7.29–7.26 (6H, m, phenyl), 6.98–6.96 (2H, m,
3
phenyl), 5.01 (1H, d, JH4/H3 = 2.5 Hz, H4), 4.83 (1H, t,
3JH3/H2 = 3JH3/H4 = 2.5 Hz, H3), 4.60 and 4.43 (2H,
AB part of an ABX system, DdHa ꢀ dHb = 69 Hz,
2Jgem = 16.8 Hz, NCH2Ph), 4.51 and 4.29 (2H, AB part
of an ABX system, DdHa ꢀ dHb = 88 Hz, 2Jgem = 12.1 Hz,
OCH2Ph), 3.90 and 3.84 (2H, AB part of an ABX system,
DdHa ꢀ dHb = 23 Hz, 3JH1a/H2 = 7.3 Hz, 3JH1b/H2 =
5.4 Hz and 3JH1a/H1b = 10.5 Hz, H1), 3.53 (1H, ddd,
3JH2/H1a = 7.3 Hz,
3JH2/H1b = 5.4 Hz
and
3JH2/
H3 = 2.5 Hz, H2), 1.06 (9H, s, CH3 tBuPh2Si); 13C NMR
d ppm (100 MHz, CDCl3) 157.9 (C5 and C6), 137.5 (Cq
arom. OBn), 136.2 (Cq arom. NBn), 135.7 (CH arom.),
133.3, 133.0 (Cq arom.), 130.1, 129.1, 128.6, 128.1 (CH
arom.), 92.1 (C4), 77.4 (C2), 76.4 (C3), 72.3 (OCH2Ph),
61.7 (C1), 46.0 (NCH2Ph), 27.0 (CH3 tBuPh2Si), 19.3 (Cq
tBuPh2Si); MS (DCI, NH3): m/z = 627 [M+NH4]+ (100),
564 [MꢀCO2H] (27); Anal. Calcd for C36H39NO6Si: C,
70.91; H, 6.45; N, 2.30. Found: C, 71.02; H, 6.54; N, 2.38.
0.84 mmol, 70% yield): Rf = 0.25 (petroleum ether/EtOAc
25
9:1); ½aꢁD ¼ þ84:5 (c 1.90, CHCl3); IR (film) 3405, 3074,
1755, 1589, 1064 cmꢀ1 1H NMR d ppm (400 MHz,
;
CDCl3) 7.65–7.60 (4H, m, phenyl), 7.46–7.39 (6H, m,
3
phenyl), 7.32–7.26 (5H, m, phenyl), 5.63 (1H, td, JH5/
H4 = 3JH5/H6a = 9.0 Hz and 3JH5/H6b = 17.0 Hz, H5),
3
5.20 (1H, d, JH6a/H5 = 9.0 Hz, H6a), 4.82 and 3.91 (2H,
4.10. (2S,3S,4S)-2-Benzyloxy-3-O,4-N-benzylcarbamate-1-
tert-butyldiphenylsilyloxy-pentano¨ıc acid 15
AB part of an ABX system, DdHa ꢀ dHb = 228 Hz,
2Jgem = 15.0 Hz, NCH2Ph), 4.73 (1H, d, 3JH6b/H5 =
17.0 Hz, H6b), 4.56 and 4.29 (2H, AB part of an ABX
system, DdHa ꢀ dHb = 68 Hz, 2Jgem = 12.8 Hz, OCH2Ph),
4.35 (1H, dd, 3JH3/H2 = 2.6 Hz and 3JH3/H4 = 7.2 Hz,
H3), 3.88 and 3.87 (2H, 2d, 3JH1a/H2 = 3JH1b/
H2 = 6.0 Hz, H1), 3.74 (1H, dd, 3JH4/H3 = 7.2 Hz and
3JH4/H5 = 9.0 Hz, H4), 3.34 (1H, td, 3JH2/H1a = 3JH2/
H1b = 6.0 Hz and 3JH2/H3 = 2.6 Hz, H2), 1.06 (9H, s,
CH3 tBuPh2Si); 13C NMR d ppm (100 MHz, CDCl3)
157.6 (C@O), 137.4, 135.8 (Cq arom.), 135.6 (CH arom.),
134.8 (C5), 133.2, 132.9 (Cq arom.), 129.9, 128.6, 128.4,
127.8 (CH arom.), 121.4 (C6), 77.8 (C3), 76.1 (C2), 72.4
(OCH2Ph), 62.0 (C1), 59.3 (C4), 45.8 (NCH2Ph), 26.8
In a solution of alkene 13 (53 mg, 90 lmol) in EtOAc
(8 mL/mmol), at ꢀ78 °C, O3 was bubbled until the solution
became blue. The ozonide formed was then decomposed by
dropping it in 150 lL of a 30% aqueous solution of hydro-
gen peroxide heated at 50 °C, and then stirring the mixture
at 50 °C for 5 min. The mixture was then cooled to 0 °C
and basified with 2 mL of a saturated aqueous solution
of K2CO3 and extracted with Et2O. The aqueous phase
was then acidified until pH 4 with a 1 N hydrochloric acid
aqueous solution saturated in NaCl, and extracted with
Et2O. The organic layers were successively washed with
brine, dried over MgSO4, filtered and concentrated under

1328
M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
reduced pressure. The crude product was purified by med-
ium-pressure column chromatography on silica gel (petro-
DdHa ꢀ dHb = 20 Hz, 3JH1a/H2 = 7.6 Hz, 3JH1b/H2 =
3
6.1 Hz and JH1a/H1b = 10.4 Hz, H1), 1.03 (9H, s, CH3
leum ether/EtOAc 8:2) to give 15 (17.5 mg, 31.5 lmol, 35%
tBuPh2Si); 13C NMR d ppm (100 MHz, CDCl3) 165.0
(C7), 159.8 (C5), 156.6 (C6), 135.4 (CH arom.), 134.3
(Cq arom.), 133.6 (CH arom.), 132.6, 132.5 (Cq arom.),
130.0, 128.6, 128.3, 128.10, 127.9 (CH arom.), 82.6 (C4),
77.7 (C3), 71.9 (C2), 60.9 (C1), 45.9 (NCH2Ph), 26.7
(CH3 tBuPh2Si), 19.1 (Cq tBuPh2Si); MS (DCI, NH3): m/
z = 641 [M+NH4]+ (100), 578 [MꢀCO2H] (24); Anal.
Calcd for C36H37NO7Si: C, 69.32; H, 5.98; N, 2.25. Found:
C, 69.43; H, 6.07; N, 2.36.
25
yield): Rf = 0.10 (petroleum ether/EtOAc 8:2); ½aꢁD
¼
þ22:4 (c 0.75, CHCl3); IR (film) 2931, 2858, 1775, 1727,
1428, 1114 cmꢀ1 1H NMR d ppm (400 MHz, CDCl3)
;
8.02 (1H, s, H acid), 7.66–7.61 (4H, m, phenyl), 7.45–7.38
(6H, m, phenyl), 7.28–7.18 (8H, m, phenyl), 6.93–6.89
(2H, m, phenyl), 5.90 (1H, d, 3JH4/H3 = 1.8 Hz, H4),
4.75 and 4.16 (2H, AB part of an ABX system,
2
DdHa ꢀ dHb = 148 Hz, Jgem = 15.2 Hz, NCH2Ph), 4.66
3
(1H, t, JH3/H2 = 3JH3/H4 = 1.8 Hz, H3), 4.38 and 4.20
(2H, AB part of an ABX system, DdHa ꢀ dHb = 45 Hz,
2Jgem = 11.9 Hz, OCH2Ph), 3.85 and 3.76 (2H, AB part
of an ABX system, DdHa ꢀ dHb = 23 Hz, 3JH1a/H2 =
8.2 Hz, 3JH1b/H2 = 5.1 Hz and 3JH1a/H1b = 10.4 Hz,
H1), 3.66 (1H, ddd, 3JH2/H1a = 8.2 Hz, 3JH2/
H1b = 5.1 Hz and 3JH2/H3 = 1.8 Hz, H2), 1.03 (9H, s,
CH3 tBuPh2Si); 13C NMR d ppm (100 MHz, CDCl3)
160.1 (C5), 156.9 (C6), 137.2 (Cq arom. OBn), 135.5 (Cq
arom.), 135.5 (Cq arom. NBn), 133.0, 132.7 (Cq arom.
Phe), 129.9, 128.7, 128.3, 128.0, 127.8 (CH arom.), 83.1
(C4), 78.9 (C3), 76.8 (C2), 72.2 (OCH2Ph), 60.9 (C1),
45.9 (NCH2Ph), 26.8 (CH3 tBuPh2Si), 19.1 (Cq tBuPh2Si);
MS (DCI, NH3): m/z = 627 [M+NH4]+ (100), 564
[MꢀCO2H] (35); Anal. Calcd for C36H39NO6Si: C, 70.91;
H, 6.45; N, 2.30. Found: C, 71.82; H, 6.37; N, 2.37.
4.12. (4R,5S)-3-Benzyl-5-((1S)-2-O-carbamoyl-1-benzyl-
oxyethyl)-4-vinyl-1,3-oxazolan-2-one 18
To a solution of compound 13 (0.21 g, 0.35 mmol) in anhy-
drous THF (35 mL/mmol) was added TBAF supported on
silica (0.45 g, 0.42 mmol). The mixture was stirred over-
night at rt, after which it was concentrated. The residue
was suspended in EtOAc and filtered. Then, the solvent
was evaporated under reduced pressure. The crude product
was purified by medium-pressure column chromatography
on silica gel (petroleum ether/EtOAc 5:5) to give the
deprotected product 17 (103 mg, 0.29 mmol, 83% yield):
25
Rf = 0.19 (petroleum ether/EtOAc 5:5); ½aꢁD = +65.2 (c
1.25, CHCl3); IR (film) 3425, 3074, 1740, 1421,
1058 cmꢀ1 1H NMR d ppm (250 MHz, CDCl3) 7.31–
;
7.22 (8H, m, phenyl), 7.11–7.10 (2H, m, phenyl), 5.61
4.11. (2S,3S,4S)-2-Benzoyloxy-3-O,4-N-benzyl-carbamate-
1-tert-butyldiphenylsilyloxy-pentano¨ıc acid 16
(1H, td, 3JH5/H4 = 3JH5/H6a = 9.9 Hz and 3JH5/H6b
17.0 Hz, H5), 5.23 (1H, d, JH6a/H5 = 9.9 Hz, H6a), 5.24
=
3
and 3.44 (2H, AB part of an ABX system,
2
In a solution of alkene 13 (53 mg, 90 lmol) in EtOAc
(8 mL/mmol), at ꢀ78 °C, O3 was bubbled until the solution
became blue. The ozonide formed was then decomposed by
dropping it in 150 lL of a 30% aqueous solution of hydro-
gen peroxide heated at 50 °C, and stirring the mixture at
50 °C for 30 min. The mixture was then cooled to 0 °C
and basified with 2 mL of a saturated aqueous solution
of K2CO3 and extracted with Et2O. The aqueous phase
was then acidified until pH 4 with a 1 M hydrochloric acid
aqueous solution saturated in NaCl, and extracted with
Et2O. The organic layers were successively washed with
brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was pre-purified by
medium-pressure column chromatography on silica gel
(petroleum ether/EtOAc 8:2) to give 23 mg of a mixture
of compounds 15 and 16 (15/16 3:2). This mixture was then
purified on preparative HPLC column chromatography on
silica gel (petroleum ether/CH2Cl2/EtOAc 70:24:6) to give
15 (12 mg, 19 lmol, 21% yield) and 16 (8 mg, 12 lmol,
DdHa ꢀ dHb = 224 Hz, Jgem = 15.2 Hz, NCH2Ph), 4.85
(1H, d, 3JH6b/H5 = 17.0 Hz, H6b), 4.71 and 4.43 (2H,
AB part of an ABX system, DdHa ꢀ dHb = 35 Hz,
2Jgem = 11.9 Hz, OCH2Ph), 4.30 (1H, dd, 3JH3/
3
H2 = 3.4 Hz and JH3/H4 = 7.0 Hz, H3), 3.86–3.67 (3H,
m, H1 and H4), 3.41 (1H, td, 3JH2/H1a = 3JH2/H1b
=
5.8 Hz and 3JH2/H3 = 3.4 Hz, H2); 13C NMR d ppm
(63 MHz, CDCl3) 157.8 (C@O), 137.4, 135.6 (Cq arom.),
134.5 (C5), 128.7, 128.6, 128.5, 127.9 (CH arom.), 121.8
(C6), 78.2 (C3), 76.1 (C2), 72.4 (OCH2Ph), 62.2 (C1),
59.5 (C4), 45.7 (NCH2Ph); MS (DCI, NH3): m/z = 371
[M+NH4]+ (100), 354 [M+H]+ (92); Anal. Calcd for
C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.42;
H, 6.63; N, 4.02. The para-nitrophenyl chloroformate
was purified by sublimation. Under an inert atmosphere,
to a solution of deprotected compound (37 mg, 0.10 mmol)
in anhydrous pyridine (5 mL/mmol) was added p-nitro-
phenyl chloroformate (31 mg, 0.16 mmol). After 30 min
at rt, the mixture was diluted with EtOAc and washed suc-
cessively with a saturated aqueous solution of NaHCO3
and brine. The organic phase was dried over MgSO4, fil-
tered and concentrated under reduced pressure to give a
red oil. This intermediate was then solubilised in MeOH
(15 mL/mmol), and a 7 M solution of ammonia in MeOH
(5 mL/mmol) was added at 0 °C. The mixture was stirred
for 1 h at 0 °C and then methanol was evaporated. The
crude product was purified by medium-pressure column
chromatography on silica gel (petroleum ether/EtOAc
14% yield): Rf = 0.10(petroleum ether/EtOAc 8:2). Com-
25
pound 16: ½aꢁD ¼ þ15:3 (c 0.50, CHCl3); IR (film) 2931,
2858, 1778, 1729, 1427, 1113 cmꢀ1 1H NMR d ppm
;
(400 MHz, CDCl3) 8.07 (1H, s, H acid), 7.90–7.86 (4H,
m, phenyl), 7.65–7.57 (5H, m, phenyl), 7.46–7.33 (8H, m,
phenyl), 7.05–7.00 (3H, m, phenyl), 6.89–6.82 (2H, m, phe-
3
nyl), 6.06 (1H, d, JH4/H3 = 1.7 Hz, H4), 5.53 (1H, ddd,
3JH2/H1a = 7.6 Hz,
3JH2/H1b = 6.1 Hz
and
3JH2/
H3 = 1.7 Hz, H2), 4.91 (1H, t, 3JH3/H2 = 3JH3/H4 =
1.7 Hz, H3), 4.66 and 4.14 (2H, AB part of an ABX system,
4:6) to give 18 (37 mg, 93 lmol, 90% yield): Rf = 0.23
25
2
DdHa ꢀ dHb = 130 Hz, Jgem = 15.2 Hz, NCH2Ph), 3.91
(petroleum ether/EtOAc 4:6); ½aꢁD ¼ þ89:2 (c 1.70,
and 3.83 (2H, AB part of an ABX system,
CHCl3); IR (film) 3429, 3074, 1742, 1642, 1421,

M. Collet et al. / Tetrahedron: Asymmetry 18 (2007) 1320–1329
1329
1
1058 cmꢀ1; H NMR d ppm (400 MHz, CDCl3) 7.33–7.29
136.9, 135.6 (Cq arom.), 128.7, 128.6, 128.5, 128.2 (CH
arom.), 82.3 (C4), 79.1 (C3), 73.8 (C2), 72.3 (OCH2Ph),
61.8 (C1), 45.8 (NCH2Ph); MS (DCI, NH3): m/z = 432
[M+NH4]+ (68), 292 (100); HRMS (DCI, NH3) calcd.
for C21H23N2O7 [M+H]+ 415.1505. Found: 415.1505.
(8H, m, phenyl), 7.08–7.06 (2H, m, phenyl), 5.61 (1H, td,
3JH5/H4 = 3JH5/H6a = 9.0 Hz and 3JH5/H6b = 17.0 Hz,
3
H5), 5.29 (1H, d, JH6a/H5 = 9.0 Hz, H6a), 4.96 and 3.76
(2H, AB part of an ABX system, DdHa ꢀ dHb = 240 Hz,
2Jgem = 15.0 Hz, NCH2Ph), 4.78 (1H, d, 3JH6b/H5 =
17.0 Hz, H6b), 4.70 (2H, s, NH2), 4.69 and 4.40 (2H, AB
2
part of an ABX system, DdHa ꢀ dHb = 58 Hz, Jgem
=
References
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(11); HRMS (DCI, NH3) calcd. for C22H25N2O5 [M+H]+
397.1763. Found: 397.1761.
4.13. (2S,3S,4S)-2-Benzyloxy-3-O,4-N-benzyl-carbamate-1-
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In a solution of alkene 18 (19 mg, 48 lmol) in EtOAc
(10 mL/mmol), at ꢀ78 °C, O3 was bubbled until the solu-
tion became blue. The ozonide formed was then decom-
posed by dropping it in 80 lL of a 30% aqueous solution
of hydrogen peroxide heated at 50 °C, and stirring the mix-
ture at 50 °C for 5 min. The mixture was then cooled to
0 °C and basified with 2 mL of a saturated aqueous solu-
tion of K2CO3 and extracted with Et2O. The aqueous
phase was then acidified until pH 4 with a 1 M hydrochlo-
ric acid aqueous solution saturated in NaCl, and extracted
with Et2O. The organic layers were successively washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified
by medium-pressure column chromatography on silica gel
(petroleum ether/EtOAc 5:5) to give 19 (6 mg, 15 lmol,
30% yield): Rf = 0.13 (petroleum ether/EtOAc 5:5);
25
½aꢁD ¼ þ8:6 (c 0.45, CHCl3); IR (film) 3429, 3074, 1742,
1642, 1421, 1058 cmꢀ1 1H NMR d ppm (400 MHz,
;
CDCl3) 8.01 (1H, s, H5), 7.32–7.29 (8H, m, phenyl),
7.08–7.06 (2H, m, phenyl), 5.97 (1H, d, 3JH4/
H3 = 1.8 Hz, H4), 4.80 and 4.15 (2H, AB part of an
14. Beresford, K. J. M.; Howe, J. P.; Procter, G. Tetrahedron
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2
ABX system, DdHa ꢀ dHb = 248 Hz, Jgem = 15.2 Hz,
NCH2Ph), 4.62 and 4.44 (2H, AB part of an ABX system,
2
DdHa ꢀ dHb = 78 Hz, Jgem = 12.0 Hz, OCH2Ph), 4.57
´
16. Ayad, T.; Faugeroux, V.; Genisson, Y.; Andre, C.; Baltas,
3
(2H, m, NH2), 4.47 (1H, t, JH3/H2 = 3JH3/H4 = 1.8 Hz,
M.; Gorrichon, L. J. Org. Chem. 2004, 69, 8775–8779.
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Eur. J. Org. Chem. 2001, 3089–3096.
H3), 4.36 and 4.19 (2H, AB part of an ABX system,
DdHa ꢀ dHb = 68 Hz,
3JH1a/H2 = 5.2 Hz,
3JH1b/
H2 = 7.2 Hz and 3JH1a/H1b = 12.0 Hz, H1), 4.82 (1H,
ddd, 3JH2/H1a = 5.2 Hz, 3JH2/H1b = 7.2 Hz and 3JH2/
H3 = 1.8 Hz, H2); 13C NMR d ppm (100 MHz, CDCl3)
157.4 (C5), 157.2 (C@O oxazo.), 155.9 (C@O carbamoyl),
19. Heidelberg, T.; Martin, O. R. J. Org. Chem. 2004, 69, 2290–
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