Liposidomycins - Synthetic studies towards the ribosyldiazepanone moiety

Article abstract of DOI:10.1002/1099-0690(200108)2001:16<3089::AID-EJOC3089>3.0.CO;2-L

A synthesis of the enantiopure 2-ribosyl-1,4-diazepan-3-one core of liposidomycins, a class of complex lipid nucleoside antibiotics, according to a flexible asymmetric synthesis strategy is described. It involves two building blocks, an enantiopure α-azido-β,γ-epoxybutanol readily available from L-ascorbic acid, and an α-ribosylamino acid obtained from D-ribose. Subsequent cyclization by regiospecific nucleophilic opening of the epoxide by the amino acid followed by peptidic coupling affords the target ribosyl diazepanone.

Full text of DOI:10.1002/1099-0690(200108)2001:16<3089::AID-EJOC3089>3.0.CO;2-L

FULL PAPER
Liposidomycins ؊ Synthetic Studies Towards the Ribosyldiazepanone Moiety
Christine Gravier-Pelletier,[a] Maria Milla,[b] Yves Le Merrer,*[a] and
Jean-Claude Depezay[a]
Keywords: Antibiotics / Ribosylamino acid / Liposidomycins / Diazepanone / Asymmetric synthesis / Oxazolidinones /
Oxazolines
A synthesis of the enantiopure 2-ribosyl-1,4-diazepan-3-one
core of liposidomycins, a class of complex lipid nucleoside ribose. Subsequent cyclization by regiospecific nucleophilic
antibiotics, according to a flexible asymmetric synthesis opening of the epoxide by the amino acid followed by pep-
strategy is described. It involves two building blocks, an en- tidic coupling affords the target ribosyl diazepanone.
ascorbic acid, and an α-ribosylamino acid obtained from
D-
antiopure α-azido-β,γ-epoxybutanol readily available from L-
Introduction
Due to their potent inhibition of bacterian peptidoglycan
synthesis, which makes liposidomycins good candidates for
the elaboration of potential new antibacterial entities, and
in view of their chemical complexity, we have embarked on
the synthesis of these challenging molecules. Our goal has
been first to determine the absolute configuration of the
natural product, and then to establish structure-activity re-
lationships of modified subunits. To this end, our aim has
been to develop a flexible strategy that would allow facile
access to various configurations at the chiral centers.
Several factors were taken into account in proposing a
definite absolute configuration for the target molecule.
First, assuming that the biosynthetic route to liposidomy-
cins involves naturally occurring amino acids, we postulated
an (S) absolute configuration at C-2Ј and C-5Ј. Secondly,
by comparing coupling constants for the uridinyldia-
zepanone part of liposidomycins, which suggest a trans rel-
ative configuration for C-5ЈϪC-6Ј, with those of cis- and
trans-5,6-disubstituted 1,4-diazepan-3-ones obtained by
Knapp et al.,[4b] we have tentatively assigned the (S) config-
uration at the four chiral centers (C-5, C-2Ј, C-5Ј, C-6Ј) of
the ribosyldiazepanone core of liposidomycins. In accord-
ance with these hypotheses, our retrosynthetic analysis is
indicated in Figure 2. Disconnections at N-1ЈϪC-7Ј on one
hand, and at C-3ЈϪN-4Ј on the other, lead to two enantiop-
ure building blocks: an α-azido-β,γ-epoxybutanol and an α-
ribosylamino acid. Part of this work has already been re-
ported in a preliminary form;[4h] an additional route to the
α-ribosylamino acid, allowing access to different relative
configurations at C-2ЈϪC-5, has since been devised and we
now wish to report our results concerning both approaches.
Liposidomycins are nucleoside antibiotics isolated from
Streptomyces griseosporeus[1] that are involved in the inhibi-
tion of bacterian peptidoglycan synthesis.[2] Based on chem-
ical degradations,[3] it has been shown that these molecules
are characterized by a 5Ј-substituted uridine, a 5-amino-5-
deoxyribose, and a disubstituted 1,4-diazepan-3-one moiety
(Figure 1). Several members of this family are known,
which differ mainly in the nature of their lipid side chain
and in the presence or absence of a sulfate on the sugar.
Because of the great structural complexity of these antibi-
otics, only a few approaches have been developed for their
synthesis[4] and the absolute configuration at the chiral cen-
ters (C-5, C-2Ј, C-5Ј, C-6Ј) remains hypothetical. However,
recent work[5] related to the synthesis of a simplified molec-
ule, which may represent the minimum structure responsible
for the activity of tunicamycins, liposidomycins, and murei-
domycins towards translocase (MraY), has demonstrated
improved activity of the (5S) compared to the (5R) derivat-
ive. This observation is in agreement with the (5S,2ЈS) abso-
lute configuration suggested by Ubukata et al.[4a] on the
basis of NMR-spectroscopic data.
Results and Discussion
Figure 1. Structure of liposidomycins
Access to (2R,3R)-3-azido-4-tert-butyldiphenylsilyloxy-
1,2-epoxybutane (2) in enantiomerically pure form was ac-
complished from ethyl 3,4-O-methylethylidene--threonate
(4), which is readily available from -ascorbic acid[6]
(Scheme 1). The carboxylic acid moiety of 4 was reduced
to a primary alcohol for stability reasons, which was then
[a]
´
´
Universite Rene Descartes, Laboratoire de Chimie et Biochimie
Pharmacologiques et Toxicologiques, CNRS UMR 8601,
`
45, rue des Saints-Peres, 75270 Paris Cedex 06, France
Fax: (internat.) ϩ 33-1/42868387
E-mail: Yves.Le-Merrer@biomedicale.univ-paris5.fr
Aventis,
[b]
102, route de Noisy, 93235 Romainville Cedex, France
Eur. J. Org. Chem. 2001, 3089Ϫ3096
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0816Ϫ3089 $ 17.50ϩ.50/0
3089

C. Gravier-Pelletier, M. Milla, Y. Le Merrer, J.-C. Depezay
FULL PAPER
of 10), followed by N-methylation with methyl iodide in the
presence of silver oxide. This gave ZϪSarϪOtBu (11) in
70% yield. The diastereoselectivity of this condensation re-
action of the aldehyde 9 favored exclusive formation of the
cis-oxazolidinones 12a and 12b (3J5,6 ϭ 7.8 Hz)[14] with a
large predominance of 12a. Thus, the 12a/12b ratio in our
experiments ranged from 100:0 to 97:3. The cis-oxazolidi-
none 12a could either be isolated and quantitatively isomer-
ized to the trans-oxazolidinone 13a (3J5,6 ϭ 2 Hz) in the
presence of DBU in acetonitrile at 80 °C[15] (overall yield
of 13a: 26% based on 9) or isomerized by refluxing with
ethanolic potassium hydroxide in a one-pot reaction. Under
the latter conditions, concomitant saponification of the tert-
butyl ester moiety occurred to intermediately afford a mix-
ture of acids 14a/14b (in the corresponding proportion of
100:0 to 97:3), which was then esterified with diazomethane
to give the trans-oxazolidinone esters 15a/15b (in the same
proportion as 14a/14b) so as to facilitate purification.
Flash-chromatographic separation furnished the enantiom-
erically pure trans-oxazolidinones 15a and 15b (3J5,6 ϭ 2.5
and 5 Hz, respectively) in an overall yield of 47% based on
aldehyde 9.[16] Basic hydrolysis of the oxazolidinone moiety
Figure 2. Retrosynthetic analysis towards the 2-ribosyl-1,4-di-
azepan-3-one core of the postulated natural liposidomycins
protected as its tert-butyldiphenylsilyl derivative 5b. Intro-
duction of the azido group with inversion of the configura-
tion required a two-step, one-pot protocol involving initial
activation of the secondary alcohol function as a triflate
followed by nucleophilic substitution with tetramethylguan-
idinium azide,[7] which furnished the azido compound 6 in
81% yield. Acetal hydrolysis in a 3:3:1 trifluoroacetic acid/
H2O/THF mixture afforded the corresponding diol 7.
Epoxidation was then efficiently achieved under Mitsunobu
conditions[8] to give the target building block 2.
Scheme 1. (a) LiAlH4, THF, 95%; (b) TBDPSCl, ImH, DMF, 97%;
(c) Tf2O, 2,6-lutidine, CH2Cl2, Ϫ78 °C, then excess TMGA, Ϫ78
°C to 20 °C, 81%; (d) TFA, H2O, THF, 0 °C, 65%; (e) PPh3, DIAD,
130 °C, 0.01 Torr, 79%
The α-ribosylamino acid synthon 3a was obtained ac-
cording to two different pathways (Scheme 2), both of
which started from enantiomerically pure aldehyde 9. The
latter was derived from -ribose in two steps involving con-
comitant protection of the anomeric hydroxy group and
secondary alcohols[9] followed by oxidation of the primary
alcohol.[10] Both synthetic pathways involve the formation
of a heterocyclic compound, an oxazolidinone or an oxazo-
line, which can be isomerized to give the thermodyn-
amically more stable trans isomer so as to ensure predomin-
ant formation of the threo isomer.[11] In the first route, alde-
hyde 9 was condensed with the anion of tert-butyl N-
benzyloxysarcosinate (11), generated at Ϫ78 °C using li-
thium diisopropylamide in THF,[12] as outlined in path
A.[13] Compound 11 was readily prepared in two steps
(Scheme 3) from commercially available tert-butyl glycinate
hydrochloride by N-protection of the amino acid with
Scheme 2. (a) Me2C(OMe)2, Me2CO, MeOH, HCl (g), 75%; (b) i.
DMSO, DCC, pyridine, H3PO4, ii. (CO2H)2, 60%; (c) LDA, Ϫ78
°C, 30 min at Ϫ78 °C and 10 min at 20 °C prior to addition of 9
at Ϫ78 °C; (d) DBU, CH3CN, 48 h, 80 °C, 26% based on 9 for 9
Ǟ 12a/12b Ǟ 13a; (e) KOH, EtOH, 80 °C; (f) CH2N2, CH2Cl2,
47% based on 9 for 9 Ǟ 12a/12b Ǟ 14a/14b Ǟ 15a/15b; (g) KOH,
H2O, 100 °C, 72%; (h) CNCH2CO2Et, Et3N, THF; (i) i. Me3OBF4,
CH2Cl2, ii. NaHCO3 (aq.), 76% based on 9; (j) 2  KOH, 80 °C,
benzyl chloroformate in the presence of pyridine (90% yield 4 h, 50%
3090
Eur. J. Org. Chem. 2001, 3089Ϫ3096

Liposidomycins Synthetic Studies Towards the Ribosyldiazepanone Moiety
FULL PAPER
of 15a and 15b using aqueous potassium hydroxide at 100 ing to the predominantly observed (5S) absolute configura-
°C cleanly afforded the expected α-ribosylamino acid 3a tion.
and its isomer 3b (up to 3%) in 72% yield.
Scheme 3. (a) BzlO2CCl, CH2Cl2, pyridine, 90%; (b) CH3I, Ag2O,
DMF, 70%
The absolute configuration at the newly created chiral
center C-6 of the diastereomeric amino acids 3a and 3b was
determined by the Cotton effect,[17] and that at C-5 could
then be deduced from the trans relationship observed in ox-
Figure 3. Interpretation of the observed diastereoselectivity for ox-
azolidinone (path A) or oxazoline (path B) formation
azolidinones 15a and 15b. The absolute configurations de-
duced for each compound are as indicated in Scheme 2.
In the second route, the α-ribosylamino acid building
block was synthesized by diastereoselective condensation of
ethyl isocyanoacetate[18] with the aldehyde 9 (path B).[4h]
This reaction was carried out at 10 °C in THF in the pres-
ence of triethylamine and led to a 3:7 mixture of trans-ox-
azolines 16a and 16b (3J5,6 ϭ 5.2 and 7.2 Hz, respect-
ively).[19] The corresponding N-methylformamides 17a and
17b (ratio 3:7) were then obtained in 76% overall yield by
subsequent treatment with a solution of trimethyloxonium
tetrafluoroborate in dichloromethane and hydrolysis with
aqueous sodium hydrogen carbonate.[20] Basic hydrolysis of
the 17a/17b mixture with 2  aqueous KOH at 80 °C af-
forded the α-ribosylamino acids 3a/3b in 50% yield (ratio
3:7) after purification by flash chromatography. Again, ab-
solute configurations at the chiral centers of each com-
pound were deduced from both the Cotton effect measured
for 3a and 3b[17] and from the trans relationship observed
in oxazolines 16a and 16b.
With both threo diastereomers 3a and 3b of the ribosyl-
amino acid in hand, we next turned to the synthesis of the
ribosyldiazepanone (Scheme 4). Regiospecific opening of
the azido epoxide 2 by the amine of the amino acid 3a (or
3b, respectively) was efficiently achieved in the presence of
sodium tert-butoxide at 100 °C in 48 h. This was followed
by reduction of the azide in the presence of palladium on
charcoal in methanol to afford the amine 18a (or 18b, re-
spectively) in 65% overall yield. Intramolecular peptidic
Thus, by following path A or path B, both possible threo
diastereomers of the ribosylamino acid may be predomin-
antly obtained by selecting appropriate experimental condi-
tions. Furthermore, if the relative configuration of the tar-
get ribosyldiazepanone moiety happened to differ from the
natural one, path A should facilitate efficient access to the
(5S,6R) isomer of the ribosylamino acid since this absolute
configuration corresponds to that of the major product
(12a) obtained prior to isomerization. Finally, although ac-
cess to the (5R,6S) isomer of the ribosylamino acid would
not be possible according to our method, it does not seem
to be relevant in view of the biological evaluation reported
by Dini et al.[5]
The different behavior seen in the condensation of the
anion of ZϪSarϪOtBu and of ethyl isocyanoacetate may
be explained in terms of a Felkin model (Figure 3) leading
preferentially to the (5R) configuration (path B). However,
in path A, the reaction involves addition of the nucleophile
to the carbonyl group on the opposite side of the furanoside
moiety in a stabilized conformation involving chelation be-
tween the lithium cation and the furanoside ring, thus lead- Scheme 4
Eur. J. Org. Chem. 2001, 3089Ϫ3096
3091

C. Gravier-Pelletier, M. Milla, Y. Le Merrer, J.-C. Depezay
(m, 10 H, Ph), 4.19 (ddd, J2,1a ϭ 6.8 Hz, J2,1b ϭ 6.5 Hz, J2,3
4 Hz, 1 H, 2-H), 3.97 (dd, J1a,1b ϭ 8 Hz, J1a,2 ϭ 6.8 Hz, 1 H, 1a-
H), 3.79 (dd, J1b,1a ϭ 8 Hz, J1b,2 ϭ 6.5 Hz, 1 H, 1b-H), 3.73Ϫ3.55
(m, 3 H, 3-H, 4a-H, 4b-H), 1.39, 1.35 (2 s, 6 H, CMe2), 1.05 (s, 9
H, tBu). Ϫ 13C NMR: δ ϭ 135.5, 133.0, 129.8, 127.7 (Ph), 109.1
(CMe2), 76.4, 71.9 (C-2, C-3), 66.0, 65.0 (C-1, C-4), 26.8, 19.2
(tBu), 26.4, 25.3 (CMe2). Ϫ C23H32O4Si (400.59): calcd. C 68.96,
H 8.05; found C 68.93, H 7.92.
FULL PAPER
ϭ
coupling with an excess of dicyclohexyl carbodiimide in
CH2Cl2 at 0 °C smoothly led to the expected lactam 19a
(or 19b, respectively), which was then desilylated to give the
target ribosyldiazepanone 1a (or 1b, respectively).
Conclusion
By means of two distinct approaches that rely on the
formation of a heterocyclic compound, an oxazolidinone or
an oxazoline, which can be isomerized to the thermodyn-
amically more stable trans isomer, we describe a straightfor-
ward route to two threo diastereomers of the ribosyldia-
zepanone encountered in liposidomycins. Our strategy also
allows access to an erythro stereomer of this moiety. Fur-
thermore, by selecting -ascorbic or -isoascorbic acid as
the starting material for the synthesis of the α-azido epox-
ide, different absolute configurations at C-5Ј and C-6Ј can
be achieved. Although coupling constants observed for the
obtained molecules do not allow a definitive assignment of
the absolute configuration of the natural product, notably
because available NMR-spectroscopic data concern the uri-
dinyldiazepanone core of the liposidomycins, the results re-
ported herein can be expected to facilitate efficient access
to the uridinyldiazepanone part of liposidomycins based on
similar strategies. Work towards this goal is currently in
progress.
(2R,3R)-3-Azido-4-tert-butyldiphenylsilyloxy-1,2-O-isopropylidene-
butane-1,2-diol (6): To a solution of the alcohol 5b (14.5 g,
36.25 mmol) in CH2Cl2 (110 mL), 2,6-lutidine (5.90 mL, 1.4 equiv.)
and trifluoromethanesulfonic anhydride (7.92 mL, 1.3 equiv.) were
successively added dropwise at Ϫ78 °C. TLC monitoring (cyclohex-
ane/EtOAc, 8:2) revealed complete transformation of the alcohol
into its corresponding triflate (Rf ϭ 0.60) within 30 min. Tetra-
methylguanidinium azide (28.64 g, 5 equiv.) was then added at Ϫ78
°C. The temperature was raised to 20 °C over a period of 1 h and
stirring was maintained overnight to complete the reaction. After
concentration in vacuo, the residue was dissolved in ethyl acetate
and filtered through a silica pad to remove the precipitated lutidin-
ium salts. Flash chromatography of the concentrated mixture
(cyclohexane/EtOAc, 95:5; Rf ϭ 0.45) gave 12.48 g (81%) of the
azido derivative 6 as a yellow oil; [α]D ϭ Ϫ11 (c ϭ 1.11, CH2Cl2).
1
Ϫ H NMR: δ ϭ 7.69Ϫ7.38 (2 m, 10 H, Ph), 4.10Ϫ3.95 (m, 2 H,
1a-H, 2-H), 3.91Ϫ3.87 (m, 1 H, 1b-H), 3.86 (dd, J4a,4b ϭ 11 Hz,
J4a,3 ϭ 3.5 Hz, 1 H, 4a-H), 3.74 (dd, J4b,4a ϭ 11 Hz, J4b,3 ϭ 6 Hz,
1 H, 4b-H), 3.55 (ddd, J3,2 ϭ J3,4b ϭ 6 Hz, J3,4a ϭ 3.5 Hz, 1 H, 3-
H), 1.35, 1.30 (2 s, 6 H, CMe2), 1.06 (s, 9 H, tBu). Ϫ 13C NMR:
δ ϭ 135.6, 132.8, 129.8, 127.7 (Ph), 109.6 (CMe2), 74.6, 64.9 (C-2,
C-3), 66.7, 64.4 (C-1, C-4), 26.7, 19.1 (tBu), 26.5, 25.2 (CMe2). Ϫ
C23H31O3N3Si (425.61): calcd. C 64.91, H 7.34, N 9.87; found C
64.96, H 7.42, N 9.91.
Experimental Section
1
General Remarks: H NMR (250 MHz) and 13C NMR (63 MHz)
(2R,3R)-3-Azido-4-(tert-butyldiphenylsilyloxy)butane-1,2-diol (7):
To a solution of acetonide 6 (3.4 g, 8 mmol) in THF (20 mL) and
H2O (57 mL), trifluoroacetic acid (57 mL) was added at 0 °C. After
stirring for 2 h, the resulting mixture was neutralized at 0 °C with
25% aqueous NH4OH solution until pH ϭ 8, and then extracted
with diethyl ether (5 ϫ 50 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. Flash chromatography
of the residue (cyclohexane/EtOAc, 6:4; Rf ϭ 0.28) afforded 2.0 g
(65%) of the diol 7 as an oil; [α]D ϭ Ϫ30 (c ϭ 1.00, CH2Cl2). Ϫ
1H NMR: δ ϭ 7.68Ϫ7.39 (m, 10 H, Ph), 3.92, 3.86 (AB from ABX,
J4a,4b ϭ 11 Hz, J4b,3 ϭ 5.6 Hz, J4a,3 ϭ 4.8 Hz, 2 H, 4a-H, 4b-H),
spectra were recorded with samples in CDCl3 (unless otherwise in-
dicated). Ϫ High-resolution mass spectra (HRMS) were recorded
´
´
by the Service de Spectrometrie de Masse, Ecole Normale Superi-
eure. Specific rotations were measured with a PerkinϪElmer 241C
polarimeter using light from sodium (589 nm) or mercury (365 nm)
lamps. Ϫ All reactions were carried out under nitrogen using dried
solvents and were monitored by thin-layer chromatography on
Merck glass-backed 60F-254 precoated silica plates (thickness
0.2 mm). Ϫ Flash chromatography was performed on Merck Kie-
selgel 60H (5Ϫ40 µm). Spectroscopic (1H and 13C NMR, MS) and/
or analytical data were obtained using chromatographically homo-
geneous samples. In many cases, chemical shifts and coupling con-
stants were assigned with the aid of 2D NMR experiments (COSY
45 and HMQC). To simplify interpretation of NMR-spectroscopic
data, the signal assignments are in accordance with the atom num-
berings indicated in the schemes which do not always correspond
with nomenclature.
3.74Ϫ3.66 (m, 3 H, 1a-H, 1b-H, 2-H), 3.53 (X of ABX, J3,2
ϭ
6 Hz, J3,4b ϭ 5.6 Hz, J3,4a ϭ 4.8 Hz, 1 H, 3-H). Ϫ 13C NMR: δ ϭ
135.4, 132.6, 129.8, 127.7 (Ph), 70.9, 64.1 (C-2, C-3), 64.2, 63.4 (C-
1, C-4), 26.6, 19.0 (tBu). Ϫ C20H27O3N3Si (385.54): calcd. C 62.31,
H 7.06, N 10.90; found C 62.32, H 7.09, N 11.04.
(2R,3R)-3-Azido-4-tert-butyldiphenylsilyloxy-1,2-epoxybutane (2):
Prior to the reaction, both triphenylphosphane (1.58 g, 1.17 equiv.)
and the diol 7 (1.985 g, 5.16 mmol) were taken up in toluene
4-O-tert-Butyldiphenylsilyl-1,2-O-isopropylidene-L-threitol (5b): To
a solution of the diol 5a, obtained by LiAlH4 reduction of the ester (20 mL) and the respective solutions were concentrated in vacuo to
4 (6.08 g, 37.5 mmol) in DMF (170 mL) in the presence of imida-
zole (5.62 g, 2.2 equiv.), a solution of tert-butyldiphenylsilyl chlor-
remove any traces of water. This procedure was repeated twice
more. To a solution of the dried triphenylphosphane in toluene
ide (10.74 mL, 1.1 equiv.) in DMF (30 mL) was added dropwise (10 mL), diisopropyl azodicarboxylate (1.2 mL, 1.19 equiv.) was
at Ϫ10 °C. After stirring overnight at Ϫ10 °C, the mixture was added at 0 °C. The mixture was stirred for 10 min and then a solu-
concentrated in vacuo. The residue was taken up in water (20 mL) tion of the diol 7 in toluene (10 mL) was added and stirring was
and extracted with dichloromethane (3 ϫ 60 mL). The combined continued for 30 min at 0 °C. After concentration under reduced
organic layers were dried (MgSO4) and concentrated in vacuo.
Flash chromatography of the residue (cyclohexane/EtOAc/Et3N,
pressure, the residue was gradually heated to 130 °C in vacuo
(0.01 Torr) for 2.5 h. Flash chromatography of the crude product
8:2:0.01; Rf ϭ 0.32) afforded 14.6 g (97%) of the silyl ether 5b as (cyclohexane/EtOAc, 97:3; Rf ϭ 0.38) gave 1.26 g (79%) of the ex-
an oil; [α]D ϭ ϩ5.6 (c ϭ 1.07, CH2Cl2). Ϫ 1H NMR: δ ϭ 7.65Ϫ7.37
pected epoxide 2 as a pale-yellow oil; [α]D ϭ Ϫ19 (c ϭ 1.04,
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Liposidomycins Synthetic Studies Towards the Ribosyldiazepanone Moiety
FULL PAPER
1
CH2Cl2). Ϫ H NMR: δ ϭ 7.69Ϫ7.41 (2 m, 10 H, Ph), 3.86, 3.79 THF (5 mL), n-butyllithium (1.6  in hexanes, 2.16 mL, 1.4 equiv.)
(AB of ABX, J4a,4b ϭ 10.5 Hz, J4b,3 ϭ 5.5 Hz, J4a,3 ϭ 4 Hz, 2 H, was added dropwise at Ϫ78 °C. After stirring for 30 min at this
4a-H, 4b-H), 3.39 (X of ABX, J3,2 ϭ J3,4b ϭ 5.5 Hz, J3,4a ϭ 4 Hz, temperature, then for 10 min at Ϫ40 °C, and finally for a further
1 H, 3-H), 3.08 (XЈ of AЈBЈXЈ, J2,3 ϭ 5.5 Hz, J2,1a ϭ 4 Hz, J2,1b ϭ
2.8 Hz, 1 H, 2-H), 2.78, 2.72 (AЈBЈ of AЈBЈXЈ, J1a,1b ϭ 5.5 Hz, ate (11) (0.76 g, 1.1 equiv.) in THF (2 mL) was added. The resulting
J1a,2 ϭ 4 Hz, J1b,2 ϭ 2.8 Hz, 2 H, 1a-H, 1b-H), 1.06 (s, 9 H, tBu).
mixture was stirred at Ϫ78 °C for 30 min, in the course of which
13C NMR: δ ϭ 135.6, 132.6, 129.9, 127.9 (Ph), 64.3 (C-4), 63.4 a yellow coloration appeared. It was then allowed to warm to 20
10 min at Ϫ78 °C, a solution of the tert-butyl N-benzyloxysarcosin-
Ϫ
(C-2), 50.3 (C-3), 44.9 (C-1), 26.6, 19.0 (tBu). Ϫ C20H25O2N3Si °C and stirring was continued for 30 min. After cooling to Ϫ78 °C
(367.53): calcd. C 65.36, H 6.86, N 11.43; found C 65.37, H 6.87, once more, a solution of the aldehyde 9 (0.5 g, 2.47 mmol) in THF
N 11.41.
(2 mL) was added dropwise and the mixture was slowly allowed to
warm to 20 °C over a period of 16 h. After concentration in vacuo,
the residue was taken up in water and extracted with ethyl acetate
(3 ϫ 15 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography of the
crude product (EtOAc/cyclohexane/Et3N, 8:2:0.01; Rf ϭ 0.5) af-
forded 0.24 g (26%) of 12a. Ϫ 1H NMR: δ ϭ 4.90 (s, 1 H, 1-H),
4.84 (d, J3,2 ϭ 6 Hz, 1 H, 3-H), 4.58 (d, J2,3 ϭ 6 Hz, 1 H, 2-H),
Methyl 2,3-O-Isopropylidene-β-D-ribofuranoside (8): Prepared ac-
cording to ref.[9]; [α]D ϭ Ϫ82 (c ϭ 1.00, CH2Cl2), [α]D ϭ Ϫ82.3
[9]
1
(c ϭ 1.00, CH2Cl2). Ϫ H NMR: δ ϭ 4.94 (s, 1 H, 1-H), 4.80 (d,
J3,2 ϭ 6.0 Hz, 1 H, 3-H), 4.55 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.39
(dd, 1 H, J4,5a ϭ J4,5b ϭ 2.8 Hz, 4-H), 3.65Ϫ3.57 (m, 2 H, 5-H),
3.40 (s, 3 H, OMe), 1.45, 1.28 (2 s, 6 H, CMe2). Ϫ 13C NMR: δ ϭ
111.8 (CMe2), 109.5 (C-1), 87.9, 86.0, 85.4 (C-2, C-3, C-4), 63.5
(C-5), 54.9 (OMe), 26.1, 24.4 (CMe2). Ϫ C9H16O5 (204.22): calcd.
C 52.93, H 7.90; found C 52.74, H 7.98.
4.49 (dd, J5,4 ϭ 10.8 Hz, J5,6 ϭ 7.8 Hz, 1 H, 5-H), 4.38 (d, J4,5
ϭ
10.8 Hz, 1 H, 4-H), 4.11 (d, J6,5 ϭ 7.8 Hz, 1 H, 6-H), 3.36 (s, 3 H,
OMe), 2.82 (s, 3 H, NMe), 1.50 (s, 9 H, tBu), 1.43, 1.28 (2 s, 6 H,
CMe2). Ϫ 13C NMR: δ ϭ 166.7 (CO2tBu), 156.9 (NCO), 112.6
(CMe2), 110.1 (C-1), 84.9, 83.8, 82.4 (C-2, C-3, C-4), 83.5 (tBu),
73.5 (C-5), 63.1 (C-6), 55.6 (OMe), 29.6 (NMe), 27.8 (tBu), 26.3,
24.9 (CMe2). Ϫ MS (70 eV, CI, NH3): m/z ϭ 374 [M ϩ 1]ϩ, 391
[M ϩ 18]ϩ.
Methyl
2,3-O-Isopropylidene-β-D-ribo-pentodialdo-1,4-furanoside
(9): Prepared according to ref.[10]; [α]D ϭ Ϫ204 (c ϭ 1.00, CH2Cl2),
[α]D [10] ϭ Ϫ214 (c ϭ 0.10, CHCl3). Ϫ 1H NMR: δ ϭ 9.53 (s, 1 H,
5-H), 5.03 (s, 1 H, 1-H), 4.99 (d, J 3,2 ϭ 6.0 Hz, 1 H, 3-H), 4.45 (d,
J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.42 (s, 1 H, 4-H), 3.41 (s, 3 H, OMe),
1.44, 1.28 (2 s, 6 H, CMe2). Ϫ 13C NMR: δ ϭ 200.7 (C-5), 112.6
(CMe2), 109.2 (C-1), 89.5, 83.9, 80.5 (C-2, C-3, C-4), 55.7 (OMe),
26.2, 24.8 (CMe2).
tert-Butyl (4ЈS,5ЈS)-3Ј-Methyl-5Ј-[methyl (4R)-2,3-O-isopropylid-
ene-β-D-erythrofuranosid-4-yl]-2Ј-oxooxazolidine-4Ј-carboxylate
(13a): To a solution of cis-oxazolidinone 12a (30 mg, 0.08 mmol)
in acetonitrile (3 mL), DBU (13.2 µL, 1.1 equiv.) was added drop-
wise. The resulting colorless mixture was then refluxed for 48 h.
After concentration in vacuo, the residue was treated with saturated
aqueous NH4Cl solution and extracted with CH2Cl2 (3 ϫ 5 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo to afford 30 mg of the oxazolidinone 13a
tert-Butyl N-(Benzyloxycarbonyl)glycinate (10): To a solution of
tert-butyl glycinate hydrochloride (0.86 g, 5.15 mmol) in CH2Cl2
(15 mL) and pyridine (1.8 mL), benzyl chloroformate (1.25 mL,
1.7 equiv.) was added at 0 °C and the mixture was stirred at 20 °C
for 15 h. Saturated aqueous NaHCO3 solution was then added and
the mixture was extracted with CH2Cl2 (3 ϫ 15 mL). The combined
organic layers were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Flash chromatography of the crude product
(cyclohexane/EtOAc, 8:2; Rf ϭ 0.36) afforded 1.3 g (90%) of com-
1
(quantitative yield) as an oil (EtOAc; Rf ϭ 0.65). Ϫ H NMR: δ ϭ
4.96 (s, 1 H, 1-H), 4.82 (d, J3,2 ϭ 6 Hz, 1 H, 3-H), 4.59 (d, J2,3
ϭ
6 Hz, 1 H, 2-H), 4.36 (dd, J5,4 ϭ 10 Hz, J5,6 ϭ 2 Hz, 1 H, 5-H),
4.08 (d, J6,5 ϭ 2 Hz, 1 H, 6-H), 4.06 (d, J4,5 ϭ 10 Hz, 1 H, 4-H),
3.32 (s, 3 H, OMe), 2.90 (s, 3 H, NMe), 1.48 (s, 9 H, tBu), 1.44,
1.28 (2 s, 6 H, CMe2).
1
pound 10 as a colorless oil. Ϫ H NMR: δ ϭ 7.34Ϫ7.29 (m, 5 H,
Ph), 5.10 (s, 2 H, Bzl), 3.85 (d, J2,NH ϭ 5.4 Hz, 2 H, 2-H), 1.44 (s,
9 H, tBu). Ϫ 13C NMR: δ ϭ 168.9 (C-1), 156.1 (CO2Bzl), 136.2,
128.2, 127.8, 126.6 (Ph), 81.8 (CMe3), 66.6 (Bzl), 43.2 (C-2), 27.8
(CMe3). Ϫ C14H19NO4 (265.31): calcd. C 63.38, H 7.22, N 5.28;
found C 63.24, H 7.19, N 5.21.
Methyl (4ЈS,5ЈS)-3Ј-Methyl-5Ј-[methyl (4R)-2,3-O-isopropylidene-β-
D-erythrofuranosid-4-yl]-2Ј-oxooxazolidine-4Ј-carboxylate (15a) and
Its (4ЈR,5ЈR) Isomer 15b: To a solution of diisopropylamine
(1.04 mL, 1.5 equiv.) in THF (5 mL), n-butyllithium (1.6  in hex-
anes, 4.33 mL, 1.4 equiv.) was added dropwise at Ϫ78 °C. After
stirring for 30 min at this temperature, the mixture was allowed to
warm to Ϫ40 °C for a few minutes and then cooled to Ϫ78 °C
once more, whereupon ZϪSarϪOtBu (11) (1.52 g, 1.1 equiv.) was
added. After stirring for 30 min at Ϫ78 °C, the mixture was allowed
to warm to 20 °C for 10 min and then cooled to Ϫ78 °C once
more, whereupon a solution of the aldehyde 9 (1.0 g, 4.95 mmol)
in THF (5 mL) was added dropwise. The resulting mixture was
allowed to warm to 20 °C over a period of 40 min and then a 0.49
 ethanolic solution of potassium hydroxide (20 mL, 2 equiv.) was
added. After stirring for 25 min at 80 °C, the mixture was cooled
to 0 °C and concentrated in vacuo. The residue was partitioned
between water and Et2O (1:1; 40 mL) and the aqueous layer was
extracted with further Et2O (2 ϫ 20 mL). The aqueous phase was
then acidified to pH ϭ 2 with 0.1  HCl and extracted with CH2Cl2
tert-Butyl N-(Benzyloxycarbonyl)sarcosinate (11): To a solution of
compound 10 (0.5 g, 1.88 mmol) in DMF (5 mL), methyl iodide
(0.94 mL, 8 equiv.) followed, in darkness, by silver oxide (1.75 g,
4 equiv.) were added at 20 °C. The resulting mixture was stirred for
16 h at 20 °C in the dark. After hydrolysis and CH2Cl2 extraction
(3 ϫ 20 mL), the combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to afford 0.37 g (70%) of pure
ZϪSarϪOtBu (11) (single spot by TLC, cyclohexane/EtOAc, 2:8;
Rf ϭ 0.7). The presence of rotamers was evident from both the 1H
and 13C NMR spectra through increased multiplicities. Ϫ 1H
NMR: δ ϭ 7.33Ϫ7.30 (m, 5 H, Ph), 5.14, 5.11 (2 s, 2 H, Bzl), 3.92,
3.85 (2 s, 2 H, 2-H), 2.98, 2.96 (2 s, 3 H, NMe), 1.44, 1.39 (2 s, 9
H, CMe3). Ϫ 13C NMR: δ ϭ 168.5 (C-1), 156.5, 156.0 (CO2Bzl),
136.5, 128.3, 127.8, 127.6 (Ph), 81.6 (CMe3), 67.1 (Bzl), 51.2 (C-2),
35.9, 35.1 (NMe), 27.9 (CMe3). Ϫ C15H21O4N (279.34): calcd. C
64.50, H 7.58, N 5.01; found C 64.33, H 7.51, N 5.04.
tert-Butyl (4ЈR,5ЈS)-3Ј-Methyl-5Ј-[(methyl (4R)-2,3-O-isopropylid- (2 ϫ 20 mL). The combined extracts were dried (MgSO4), concen-
ene-β- -erythrofuranosid-4-yl]-2Ј-oxooxazolidine-4Ј-carboxylate trated in vacuo, and the residue was taken up in CH2Cl2. The re-
(12a): To a solution of diisopropylamine (0.52 mL, 1.5 equiv.) in sulting solution was treated with an excess of diazomethane in Et2O
D
Eur. J. Org. Chem. 2001, 3089Ϫ3096
3093

C. Gravier-Pelletier, M. Milla, Y. Le Merrer, J.-C. Depezay
FULL PAPER
until a yellow color persisted. After stirring for 30 min, concentra-
1H NMR: δ ϭ 8.14 (s, 0.7 H, NCHbO), 8.12 (s, 0.3 H, NCHaO),
tion in vacuo and flash chromatography (toluene/EtOAc/Et3N, 4.98 (s, 0.3 H, 1a-H), 4.97 (s, 0.7 H, 1b-H), 4.96Ϫ4.92 (m, 0.7 H,
5:5:0.01) afforded a mixture of oxazolidinones 15a/15b in a propor- 3b-H), 4.90Ϫ4.82 (m, 0.3 H, 3a-H), 4.62Ϫ4.54 (m, 1 H, 2-H), 4.40
tion ranging from 100:0 to 97:3 in an overall yield of 47% based (m, 0.7 H, 4b-H), 4.28Ϫ4.16 (m, 3.3 H, 4a-H, 5-H, OEt), 4.15Ϫ3.99
on the aldehyde 9.[16] Ϫ Compound 15a: Rf ϭ 0.3 (cyclohexane/
EtOAc, 2:8); m.p. 137 °C. Ϫ [α]D ϭ Ϫ62 (c ϭ 0.24, CDCl3). Ϫ H (s, 2.1 H, NMeb), 2.96 (s, 0.9 H, NMea), 1.58, 1.45 (2 s, 6 H, CMe2),
NMR: δ ϭ 4.97 (s, 1 H, 1-H), 4.81 (d, J3,2 ϭ 6 Hz, 1 H, 3-H), 4.58 1.29, 1.26 (2 m, 3 H, OEt). Ϫ MS (70 eV, CI, NH3): m/z ϭ 348 [M
(d, J2,3 ϭ 6 Hz, 1 H, 2-H), 4.38 (dd, J5,4 ϭ 10 Hz, J5,6 ϭ 2.5 Hz, 1 ϩ 1]ϩ.
(m, 1 H, 6-H), 3.39 (s, 2.1 H, OMeb), 3.37, (s, 0.9 H, OMea), 3.11
1
H, 5-H), 4.24 (d, J6,5 ϭ 2.5 Hz, 1 H, 6-H), 4.07 (d, J4,5 ϭ 10 Hz, 1
Methyl 6-Deoxy-2,3-O-isopropylidene-6-(methylamino)-
L
-glycero-
L-
H, 4-H), 3.79 (s, 3 H, CO2Me), 3.32 (s, 3 H, OMe), 2.91 (s, 3 H,
NMe), 1.44, 1.28 (2 s, 6 H, CMe2). Ϫ 13C NMR: δ ϭ 169.7
(CO2Me), 156.1 (NCO), 112.7 (CMe2), 110.3 (C-1), 85.6, 84.9, 81.3
(C-2, C-3, C-4), 74.9 (C-5), 61.5 (C-6), 55.8 (OMe), 52.8 (CO2Me),
30.2 (NMe), 26.3, 24.7 (CMe2). Ϫ MS (70 eV, CI, NH3): m/z ϭ 332
[M ϩ 1]ϩ, 349 [M ϩ 18]ϩ. Ϫ Compound 15b: Rf ϭ 0.15 (cyclohex-
ane/EtOAc, 2:8). Ϫ 1H NMR: δ ϭ 4.99 (s, 1 H, 1-H), 4.81 (dd,
talo-heptafuranosiduronic Acid (3a) and Its β- -glycero-
D
D
-allo Iso-
mer 3b. ؊ From Oxazolidinone 15a: The oxazolidinone 15a (20 mg,
0.06 mmol) was added to 2  aqueous KOH solution (270 µL,
9 equiv.) and the resulting mixture was refluxed for 5 h. After cool-
ing to 0 °C, the mixture was acidified to pH ϭ 2 by the addition
of Dowex Hϩ (50X8-100) resin. The resulting suspension was then
loaded onto a H2O-packed column of Dowex 50X8-100 resin.
Elution with 5% aqueous ammonia solution followed by lyophiliz-
ation of the appropriate fraction furnished the expected amino acid
3a (12.6 mg, 72%) in its zwitterionic form (beige powder; m.p. 216
°C). Ϫ From Formamides 17a/17b: A mixture of formamides 17a/
17b (204 mg, 0.58 mmol) in 2  aqueous KOH solution (1.37 mL,
9 equiv.) was heated at 80 °C for 4 h. The resulting mixture was
then cooled to 0 °C and acidified to pH ϭ 5 by the addition of a 2
 aq. HCl. After lyophilization and flash chromatography (CH2Cl2/
MeOH/H2O/AcOEt, 7:3:0.6:1.5) of the residue, the expected amino
J3,2 ϭ 6 Hz, J3,4 ϭ 1.3 Hz, 1 H, 3-H), 4.64 (d, J2,3 ϭ 6 Hz, 1 H, 2-
H), 4.50 (dd, J5,6 ϭ 5 Hz, J5,4 ϭ 4.6 Hz, 1 H, 5-H), 4.30 (dd, J4,5 ϭ
4.6 Hz, J4,3 ϭ 1.3 Hz, 1 H, 4-H), 4.21 (d, J6,5 ϭ 5 Hz, 1 H, 6-H),
3.82 (s, 3 H, CO2Me), 3.30 (s, 3 H, OMe), 2.95 (s, 3 H, NMe), 1.44,
1.28 (2 s, 6 H, CMe2). Ϫ 13C NMR: δ ϭ 169.7 (CO2Me), 156.7
(NCO), 112.8 (CMe2), 110.5 (C-1), 86.8, 85.5, 80.5 (C-2, C-3, C-
4), 75.6 (C-5), 60.1 (C-6), 55.7 (OMe), 52.9 (CO2Me), 30.4 (NMe),
26.5, 24.9 (CMe2).
Ethyl (4ЈS,5ЈS)-5Ј-[methyl (4R)-2,3-O-isopropylidene-β-D-erythrofu-
ranosid-4-yl]-2Ј-oxazoline-4Ј-carboxylate (16a) and Its (4ЈR,5ЈR) acids 3a and 3b (Rf ϭ 0.28 and 0.38, respectively) were isolated in
Isomer 16b: To a solution of Et3N (2.0 mL, 14.9 mmol) in THF 50% yield. Ϫ Compound 3a: [α]D ϭ Ϫ14 (c ϭ 1.0, 0.1  NaOH). Ϫ
(10 mL), first ethyl isocyanoacetate (1.3 mL, 11.9 mmol) and then 1H NMR (D2O): δ ϭ 5.17 (s, 1 H, 1-H), 5.03 (d, J3,2 ϭ 6.0 Hz, 1
a solution of the aldehyde 9 (2.0 g, 9.9 mmol) in THF (10 mL) were
added at Ϫ10 °C. The resulting mixture was stirred at 20 °C for
24 h. Concentration in vacuo afforded the crude oxazolines 16a/
H, 3-H), 4.84 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.25 (d, J4,5 ϭ 10.1 Hz,
4-H), 4.17 (dd, J5,4 ϭ 10.1 Hz, J5,6 ϭ 2.3 Hz, 1 H, 5-H), 3.76 (d,
J6,5 ϭ 2.3 Hz, 1 H, 6-H), 3.49 (s, 3 H, OMe), 2.85 (s, 3 H, NMe),
16b as a 3:7 mixture. Due to partial hydrolysis of the oxazoline 1.58, 1.44 (2 s, 6 H, CMe2). Ϫ 13C NMR: δ ϭ 172.5 (CO2 H), 116.1
moiety during purification by flash chromatography, only a sample
(CMe2), 112.2 (C-1), 88.7, 87.1, 84.6 (C-2, C-3, C-4), 71.5 (C-5),
of the mixture was purified (toluene/EtOAc/Et3N, 8:2:0.01; 16a:
67.4 (C-6), 58.8 (OMe), 34.5 (NMe), 28.2, 26.7 (CMe2). Ϫ C.D.
1
Rf ϭ 0.37, 16b: Rf ϭ 0.52). Ϫ Compound 16a: H NMR: δ ϭ 6.85 (c ϭ 3 ϫ 10Ϫ3 , 20 °C, H2O): λ (∆ε) ϭ 235 nm (0), 215 (ϩ0.37),
(d, JNCH,6 ϭ 2 Hz, 1 H, NCH), 4.96 (s, 1 H, 1-H), 4.78 (d, J3,2
ϭ
210 ϩ(0.90), 196 (ϩ2.17), 190 (ϩ1.50). Ϫ HRMS (FABϩ): calcd.
6 Hz, 1 H, 3-H), 4.74 (dd, J5,4 ϭ 7.2 Hz, J5,6 ϭ 5.2 Hz, 1 H, 5-H), for C12H18O7N: 292.1396; found 292.1394. Ϫ Compound 3b: [α]D ϭ
1
4.61 (dd, J6,5 ϭ 7.2 Hz, J6,NCH ϭ 2 Hz, 1 H, 6-H), 4.56 (d, J2,3
ϭ
Ϫ38 (c ϭ 1.0, 0.1  NaOH). Ϫ H NMR (D2O): δ ϭ 5.18 (s, 1 H,
6 Hz, 1 H, 2-H), 4.28Ϫ4.19 (m, 3 H, 4-H, OEt), 3.29 (s, 3 H, OMe), 1-H), 5.04 (d, J3,2 ϭ 6.0 Hz, 1 H, 3-H), 4.85 (d, J2,3 ϭ 6.0 Hz, 1
1.46, 1.30 (2 s, 6 H, CMe2), 1.28 (t, 3 H, JEt ϭ 7 Hz, OEt). Ϫ H, 2-H), 4.50 (d, J4,5 ϭ 10.1 Hz, 4-H), 4.03 (dd, J5,4 ϭ 10.1 Hz,
Compound 16b: 1H NMR: δ ϭ 6.89 (d, JNCH,6 ϭ 2 Hz, 1 H, NCH),
J5,6 ϭ 2.2 Hz, 1 H, 5-H), 3.84 (d, J6,5 ϭ 2.2 Hz, 1 H, 6-H), 3.50 (s,
4.94 (s, 1 H, 1-H), 4.79 (d, J3,2 ϭ 6 Hz, 1 H, 3-H), 4.70 (dd, J5,4 ϭ 3 H, OMe), 2.81 (s, 3 H, NMe), 1.56, 1.43 (2 s, 6 H, CMe2). Ϫ 13C
9.2 Hz, J5,6 ϭ 5.2 Hz, 1 H, 5-H), 4.64 (dd, J6,5 ϭ 5.2 Hz, J6,NCH ϭ NMR: δ ϭ 174.2 (CO2 H), 116.1 (CMe2), 112.4 (C-1), 88.3, 87.3,
2 Hz, 1 H, 6-H), 4.60 (d, J2,3 ϭ 6 Hz, 1 H, 2-H), 4.19 (q, JEt
7 Hz, 2 H, OEt), 3.93 (d, J4,5 ϭ 9.2 Hz, 1 H, 4-H), 3.25 (s, 3 H,
ϭ
84.8 (C-2, C-3, C-4), 72.6 (C-5), 67.6 (C-6), 58.9 (OMe), 36.3
(NMe), 28.3, 26.7 (CMe2). Ϫ C.D. (c ϭ 3 ϫ 10Ϫ3 , 20 °C, H2O):
OMe), 1.43, 1.28 (2 s, 6 H, CMe2), 1.26 (t, JEt ϭ 7 Hz, 3 H, OEt). λ (∆ε) ϭ 235 nm (0), 215 (Ϫ1.16), 210 (Ϫ1.64), 196 (Ϫ2.65), 190
(Ϫ2.47). Ϫ HRMS (FABϩ): calcd. for C12H18O7N: 292.1396;
Ethyl (Methyl 6-deoxy-6-[formyl(methyl)amino]-2,3-O-isopropylid-
ene-β- -glycero- -talo-heptafuranosid)uronate (17a) and Its -gly-
cero- -allo Isomer 17b: To a solution of the crude mixture of oxazo- Methyl 6-Deoxy-2,3-O-isopropylidene-6-{methyl[(2ЈS,3ЈR)-3-amino-
found 292.1402.
L
L
D
D
lines 16a/16b (3.472 g, 9.9 mmol) in CH2Cl2 (42 mL), trimethy-
loxonium tetrafluoroborate (1.919 g, 12.9 mmol) was added at
20 °C and stirring was maintained at this temperature for 12 h.
4Ј-(tert-butyldiphenylsilyloxy)-2Ј-hydroxybutyl]amino}-β-
-talo-heptafuranosiduronic Acid (18a) and Its -glycero-
mer 18b: To a solution of sodium tert-butoxide, prepared from so-
L
-glycero-
L
D
D-allo Iso-
After the addition of water (15.8 mL), aqueous NaHCO3 solution dium hydride (9.6 mg, 0.4 mmol) and tert-butyl alcohol (2 mL),
was added until pH ϭ 7. After decantation and extraction with
CH2Cl2 (2 ϫ 30 mL), the combined organic layers were washed
was added the enantiomerically pure amino acid 3a or 3b (60 mg,
0.2 mmol), followed, after 30 min, by a solution of the epoxide 2
with H2O (50 mL) and brine (50 mL). After drying (Na2SO4) and (75.7 mg, 0.2 mmol) in tert-butyl alcohol (2 mL). The mixture was
concentrating in vacuo, flash chromatography (CH2Cl2/Et2O, 7:3)
of the residue afforded a 3:7 mixture of the diastereomeric formam-
then stirred at 100 °C for 48 h. After concentration in vacuo, the
residue was taken up in chloroform. This solution was filtered
ides 17a/17b (Rf ϭ 0.30 and 0.36, respectively) in 76% overall yield through a Celite pad and concentrated in vacuo once more. The
based on aldehyde 9. However, the products could not be efficiently
separated under these conditions and hence the reported NMR
spectroscopic data correspond to those of the mixture 17a/17b. Ϫ
crude product was dissolved in methanol (3 mL) and reduced with
dihydrogen in the presence of palladium on charcoal (10%, 40 mg).
The catalyst was removed by filtration through a Celite pad and
3094
Eur. J. Org. Chem. 2001, 3089Ϫ3096

Liposidomycins Synthetic Studies Towards the Ribosyldiazepanone Moiety
FULL PAPER
the filtrate was concentrated in vacuo prior to purification by flash
chromatography (CH2Cl2/cyclohexane/H2O/EtOAc, 14:4:0.5:2) to 1H NMR (500 MHz): δ ϭ 7.67Ϫ7.40 (m, 10 H, Ph), 5.99 (d,
afford 85 mg of 18a or 18b (65% overall yield based on the amino JNH,5Ј ϭ 4.0 Hz, 1 H, NH), 4.92 (s, 1 H, 1-H), 4.91 (d, J3,2
acid 3a or 3b). Ϫ Compound 18a: TLC (same conditions as for 6.0 Hz, 1 H, 3-H), 4.54 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.37 (d, J4,5 ϭ
purification by flash chromatography): Rf ϭ 0.36. Ϫ [α]D ϭ Ϫ105 8 Hz, 1 H, 4-H), 4.00 (dd, JCH OSi ϭ 11 Hz, JCH OSi,5Ј ϭ 3.0 Hz, 1
chromatography): Rf ϭ 0.35. Ϫ [α]D ϭ ϩ43 (c ϭ 0.9, CH2Cl2). Ϫ
ϭ
2
a
1
(c ϭ 1.0, MeOH). Ϫ H NMR (CD3OD): δ ϭ 4.89 (s, 1 H, 1-H), H, CHaOSi), 3.95 (dd, J5,4 ϭ 8 Hz, J5,2Ј ϭ 4.5 Hz, 1 H, 5-H), 3.86
4.94 (d, J3,2 ϭ 6.0 Hz, 1 H, 3-H), 4.59 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-
H), 4.26 (d, J4,5 ϭ 10.1 Hz, 4-H), 3.92Ϫ3.78 (m, 5 H, 5-H, 6-H, 8-
H, 10-H), 3.40Ϫ3.20 (m, 4 H, 9-H, OMe), 2.88 (dd, J7a,7b ϭ 13 Hz,
(dd, JCH OSi ϭ 11 Hz, JCH OSi,5Ј ϭ 3.0 Hz, 2 H, CHbOSi, 6Ј-H),
2
3.56 (d, J2Ј,5 ϭ 4.5 Hz, 1 Hb, 2Ј-H), 3.30 (s, 3 H, OMe), 3.26 (m, 1
H, 5Ј-H), 3.26 (dd, J7Јb,7Јa ϭ 14 Hz, J7Јb,6Ј ϭ 4.0 Hz, 1 H, 7Јb-H),
J
7a,8 ϭ 7.5 Hz, 1 H, 7a-H), 2.74 (dd, J7b,7a ϭ 13 Hz, J7b,8 ϭ 4.8 Hz, 2.84 (J7Јa,7Јb ϭ 14 Hz, J7Јa,6Ј ϭ 10.5 Hz, 1 H, 7Јa-H), 2.56 (s, 3 H,
1 H, 7b-H), 2.44 (s, 3 H, NMe), 1.41, 1.26 (2 s, 6 H, CMe2), 1.09 NMe), 1.46, 1.29 (2 s, 6 H, CMe2), 1.07 (s, 9 H, tBu). Ϫ 13C NMR
(s, 9 H, tBu). Ϫ 13C NMR: δ ϭ 138.5, 135.6, 133.0, 130.8 (Ph),
(126 MHz): δ ϭ 175.1 (C-3Ј), 135.5, 132.4, 130.3, 128.0 (Ph), 112.1
115.1 (CMe2), 113.6 (C-1), 91.3, 88.2, 85.4 (C-2, C-3, C-4), 71.6 (CMe2), 110.1 (C-1), 85.6 (C-4), 85.2 (C-2), 81.4 (C-3), 70.9 (C-5),
(C-5), 67.5 (C-8), 65.3 (C-6, C-10), 62.0 (C-7), 60.6 (C-9), 58.3 65.0 (C-7Ј), 62.6 (C-6Ј), 62.1 (C-2Ј, CH2OSi), 58.2 (C-5Ј), 55.5
(OMe), 42.8 (NMe), 29.2, 28.6 (CMe2), 27.0, 21.9 (tBu). Ϫ MS (OMe), 38.0 (NMe), 26.9, 19.2 (tBu), 26.4, 24.8 (CMe2). Ϫ MS
(FABϩ, thioglycerol): m/z ϭ 633 (100), 589 (17), 587 (12), 469 (13), (FABϩ, thioglycerol): m/z ϭ 615 (37), 583 (12), 412 (24), 411 (17).
272 (13), 214 (10), 199 (16), 197 (17), 137 (12), 133 (13). Ϫ HRMS Ϫ HRMS (FABϩ) calcd. for C32H47O8N2Si: 615.3102; found
(FABϩ) calcd. for C32H46O9N4Si: 633.3207; found 633.3212. Ϫ 615.3120.
Compound 18b: TLC (same conditions as for purification by flash
1
Methyl (5S)-5-Hydroxy-5-C-[(2ЈR,5ЈS,6ЈR)-6Ј-hydroxy-5Ј-(hydroxy-
methyl)-1Ј-methyl-3Ј-oxo-1Ј,4Ј-diazepan-2Ј-yl]-2,3-O-isopropylidene-
β-D-ribofuranoside (1a) and Its (5R,2ЈS) Isomer 1b: To the silylated
chromatography): Rf ϭ 0.47. Ϫ [α]D ϭ 22 (c ϭ 1.0, MeOH). Ϫ H
NMR (CD3OD): δ ϭ 4.92 (s, 1 H, 1-H), 4.87 (d, J3,2 ϭ 6.0 Hz, 1
H, 3-H), 4.55 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.39 (d, J4,5 ϭ 5.3 Hz,
4-H), 4.10Ϫ3.80 (m, 5 H, 5-H, 6-H, 8-H, 10-H), 3.42Ϫ3.20 (m, 4
H, 9-H, OMe), 3.05Ϫ2.70 (m, 2 H, 7a-H, 7b-H), 2.51 (s, 3 H,
NMe), 1.42, 1.29 (2 s, 6 H, CMe2), 1.10 (s, 9 H, tBu). Ϫ 13C NMR:
δ ϭ 136.7, 133.7, 133.1, 131.1, 129.9, 128.9 (Ph), 113.2 (CMe2),
111.3 (C-1), 89.5, 86.8, 82.3 (C-2, C-3, C-4), 72.8 (C-5), 65.8 (C-8),
63.0 (C-6, C-10), 61.3 (C-7), 58.7 (C-9), 56.1 (OMe), 43.2 (NMe),
27.3, 26.8 (CMe2), 25.0, 22.2 (tBu). Ϫ MS (FABϩ, thioglycerol): m/
z ϭ 633 (100), 589 (16), 587 (13), 272 (11), 234 (10), 199 (13), 197
(14), 135 (28), 133 (13), 109 (13). Ϫ HRMS (FABϩ): calcd. for
C32H46O9N4Si: 633.3207; found 633.3232.
lactam 19a or 19b (10 mg, 16.2 µmol) in THF (375 µL) at 20 °C
was added tetrabutylammonium fluoride (1  in THF, 17.9 µL,
1.1 equiv.) and the mixture was stirred for 15 h. Concentration in
vacuo was followed by chromatographic purification on a Merck
60F-254 precoated silica plate (thickness 0.2 mm; eluent CH2Cl2/
EtOAc/MeOH, 7:3:1.2) to give 4.5 mg (74%) of the expected
ribosyldiazepanone 1a or 1b. Ϫ Compound 1a: TLC (same condi-
tions as for purification by flash chromatography): Rf ϭ 0.17. Ϫ
[α]D ϭ Ϫ3 (c ϭ 1.0, CH2Cl2). Ϫ 1H NMR (CD3OD, 500 MHz):
δ ϭ 4.92 (s, 1 H, 1-H), 4.90 (d, J3,2 ϭ 6.2 Hz, 1 H, 3-H), 4.59 (d,
J2,3 ϭ 6.2 Hz, 1 H, 2-H), 4.23 (d, J4,5 ϭ 9.2 Hz, 1 H, 4-H), 4.10
Methyl
(5S)-5-C-[(2ЈR,5ЈS,6ЈR)-5Ј-(tert-Butyldiphenylsilyloxy- (ddd, J5Ј,6Ј ϭ 9 Hz, J5Ј,CH OH ϭ 5 Hz, J5Ј,CH OH ϭ 3.3 Hz, 1 H, 5Ј-
a
methyl)-6Ј-hydroxy-1Ј-methyl-3Ј-oxo-1Ј,4Ј-diazepan-2Ј-yl]-5- H), 3.93 (dd, J5,4 ϭ 9.2 Hz, J5,2Ј ϭ 2.2 Hz,b1 H, 5-H), 3.81Ϫ3.70
hydroxy-2,3-O-isopropylidene-β-
(5R,2ЈS) Isomer 19b: To a solution of 18a or 18b (35 mg, 55 µmol)
D-ribofuranoside (19a) and Its (m, JCH OH ϭ 11 Hz, JCH OH,5Ј ϭ 5 Hz, JCH OH,5Ј ϭ 3.3 Hz, 3 H,
CH2OH, 6Ј-H), 3.44 (d, 1 H, J2Ј,5 ϭ 2.2 Hzb, 2Ј-H), 3.37 (s, 3 H,
2
a
in CH2Cl2 (1 mL) was added dicyclohexyl carbodiimide (16 mg, 77 OMe), 3.01 (dd, J7Јb,7Јa ϭ 15 Hz, J7Јb,6Ј ϭ 3.3 Hz, 1 H, 7Јb-H), 2.90
µmol) and the mixture was stirred at 0 °C for 15 h. H2O (300 µL) (dd, J7Јa,7Јb ϭ 15 Hz, J7Јa,6Ј ϭ 3.5 Hz, 1 H, 7Јa-H), 2.46 (s, 3 H,
was then added to convert the excess DCC into dicyclohexylurea
and stirring was continued at 0 °C for 30 min. After concentration δ ϭ 7.08 (s, 1 H, NH), 4.97 (s, 1 H, 1-H), 4.93 (d, J3,2 ϭ 6.0 Hz, 1
NMe), 1.43, 1.30 (2 s, 6 H, CMe2). Ϫ 1H NMR (CDCl3, 250 MHz):
in vacuo, cold EtOAc (2 mL) was added and the precipitated di-
cyclohexylurea was removed by filtration through a Celite pad.
H, 3-H), 4.56 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-H), 4.46 (d, J4,5 ϭ 4.3 Hz,
1 H, 4-H), 4.15Ϫ4.05 (m, 1 H, 5-H), 3.95Ϫ3.75 (m, 4 H, CH2OH,
Concentration of the filtrate in vacuo was followed by purification 5Ј-H, 6Ј-H), 3.41 (s, 3 H, OMe), 3.39 (d, J2Ј,5 ϭ 5.8 Hz, 1 H, 2Ј-
by flash chromatography (CH2Cl2/MeOH/EtOAc, 7:1:3) to afford H), 3.10 (br. d, J7Јb,7Јa ϭ 14 Hz, 1 H, 7Јb-H), 2.95 (br. d, J7Јa,7Јb
11.4 mg (34%) of the expected lactam 19a or 19b. Ϫ Compound 14 Hz, 1 H, 7Јa-H), 2.52 (s, 3 H, NMe), 1.46, 1.31 (2 s, 6 H, CMe2).
19a: TLC (CH2Cl2/MeOH/EtOAc, 7:0.25:3): Rf ϭ 0.33. Ϫ [α]D
13C NMR (126 MHz, CD3OD): δ ϭ 175.7 (C-3Ј), 113.3 (CMe2),
ϩ7 (c ϭ 1.0, CH2Cl2). Ϫ 1H NMR (500 MHz): δ ϭ 7.75Ϫ7.40 (m,
111.6 (C1), 88.5 (C-4), 86.6 (C-2), 83.3 (C-3), 75.9 (C-2Ј), 72.7 (C-
10 H, Ph), 6.00 (d, JNH,5Ј ϭ 2.5 Hz, 1 H, NH), 4.96 (s, 1 H, 1-H), 5), 69.7(C-6Ј), 61.4 (CH2OH), 61.3 (C-7Ј), 56.9 (C-5Ј), 56.5 (OMe),
4.95 (d, J3,2 ϭ 6.0 Hz, 1 H, 3-H), 4.54 (d, J2,3 ϭ 6.0 Hz, 1 H, 2-
44.6 (NMe), 26.8, 25.2 (CMe2). Ϫ MS (FABϩ, thioglycerol): m/z ϭ
H), 4.49 (d, J4,5 ϭ 2.8 Hz, 1 H, 4-H), 4.10Ϫ4.00 (m, 1 H, 5-H), 377 (100), 345 (52), 309 (21), 282 (22), 259 (12). Ϫ HRMS (FABϩ)
ϭ
ϭ
Ϫ
3.92 (dd, JCH OSi ϭ 11 Hz, JCH OSi,5Ј ϭ 4.0 Hz, 1 H, CHaOSi),
calcd. for C16H29O8N2:377.1924; found 377.1933. Ϫ Compound 1b:
a
3.87Ϫ3.78 (m,23 H, 5Ј-H, CHbOSi, 6Ј-H), 3.40 (s, 3 H, OMe), 3.38 TLC (same conditions as for purification by flash chromato-
(br. d, J2Ј,5 ϭ 5.6 Hz, 1 H, 2Ј-H), 3.10 (dd, J7Јb,7Јa ϭ 14.5 Hz, graphy): Rf ϭ 0.30. Ϫ [α]D ϭ ϩ73 (c ϭ 0.81, CH2Cl2). Ϫ 1H NMR
J7Јb,6Ј ϭ 2.5 Hz, 1 H, 7Јb-H), 2.87 (dd, J7Јa,7Јb ϭ 14.5 Hz, J7Јa,6Ј
4 Hz, 1 H, 7Јa-H), 2.52 (s, 3 H, NMe), 1.46, 1.30 (2 s, 6 H, CMe2), 1-H), 4.57 (d, J3,2 ഠ 5.5 Hz, 1 H, 3-H), 4.23 (d, J2,3 ഠ 5.3 Hz, 1
1.06 (s, 9 H, tBu). Ϫ 13C NMR (126 MHz): δ ϭ 172.7 (C-3Ј), 135.6,
H, 2-H), 4.06 (d, J4,5 ϭ 6.8 Hz, 1 H, 4-H), 3.78 (dd, JCH OH
ϭ
(500 MHz): δ ϭ 5.79 (d, JNH,5Ј ϭ 3.4 Hz, 1 H, NH), 4.58 (s, 1 H,
ϭ
2
132.6, 130.1, 128.0 (Ph), 112.1 (CMe2), 110.2 (C-1), 89.2 (C-4), 85.5 10 Hz, JCH OH,5Ј ϭ 4.0 Hz, 1 H, CHaOH), 3.92 (dd, J5,4 ϭ 6.8 Hz,
a
(C-2), 80.3 (C-3), 74.1 (C-2Ј), 71.5 (C-5), 67.7, 56.1 (C-5Ј, C-6Ј), J5,2Ј ϭ 4.3 Hz, 1 H, 5-H), 3.67 (ddd, J6Ј,7Јa ϭ 9 Hz, J6Ј,5Ј ഠ 8.5 Hz,
62.4 (CH2OSi), 59.2 (C-7Ј), 55.8 (OMe), 44.5 (NMe), 26.9, 19.3
J6Ј,7Јb ϭ 3.4 Hz, 1 H, 6Ј-H), 3.60 (dd, JCH OH ϭ 10 Hz, JCH OH,5Ј ϭ
2
b
(tBu), 26.4, 24.8 (CMe2). Ϫ MS (FABϩ, thioglycerol): m/z ϭ 615 3.0 Hz, 1 H, CHbOH), 3.38 (d, J2Ј,5 ϭ 4.3 Hz, 1 H, 2Ј-H), 3.21
(100), 583 (35), 412 (26), 411 (32), 307 (24), 289 (17). Ϫ HRMS (dddd, J5Ј,6Ј ϭ 8.5 Hz, J5Ј,CH OH ϭ 4.0 Hz, J5Ј,CH OH ϭ 3.0 Hz,
a
b
(FABϩ): calcd. for C32H47O8N2Si: 615.3102; found 615.3101. Ϫ
Compound 19b: TLC (same conditions as for purification by flash
J5Ј,NH ϭ 3.4 Hz, 1 H, 5Ј-H), 3.11 (dd, J7Јb,7Јa ϭ 12.6 Hz, J7Јb,6Ј
3.4 Hz, 1 H, 7Јb-H), 3.14 (s, 3 H, OMe), 2.81 (dd, J7Јa,7Јb
ϭ
ϭ
Eur. J. Org. Chem. 2001, 3089Ϫ3096
3095

C. Gravier-Pelletier, M. Milla, Y. Le Merrer, J.-C. Depezay
FULL PAPER
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12.6 Hz, J7Јa,6Ј ϭ 9.0 Hz, 1 H, 7Јa-H), 2.44 (s, 3 H, NMe), 1.46,
1.29 (2 s, 6 H, CMe2). Ϫ 13C NMR (126 MHz): δ ϭ 175.6 (C-3Ј),
112.2 (CMe2), 110.2 (C-1), 86.7 (C-4), 85.2 (C-2), 81.3 (C-3), 70.9
(C-5), 65.5 (C-7Ј), 63.3, 62.1, 61.6 (C-2Ј, C-6Ј, CH2OH), 58.1 (C-
5Ј), 55.6 (OMe), 37.9 (NMe), 26.4, 24.8 (CMe2). Ϫ MS (FABϩ,
thioglycerol): m/z ϭ 377 (100), 345 (95), 309 (22), 282 (28), 257
(12). Ϫ HRMS (FABϩ): calcd. for C16H29O8N2: 377.1924; found
377.1952.
[8]
Acknowledgments
We are grateful to Dr. G. Chottard (Laboratoire de Chimie des
[9]
´
´
Metaux de Transition, CNRS, Universite Pierre et Marie Curie)
for recording the circular dichroism spectra. We also warmly thank
Prof. J.-P. Girault and Mr. B. Septe of our laboratory for per-
forming 2D NMR experiments.
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Received December 22, 2000
[O00654]
Asymmetry 1998, 9, 3601Ϫ3605.
3096
Eur. J. Org. Chem. 2001, 3089Ϫ3096