Synthesis of optically pure 3,4-disubstituted L-glutamases from a novel 2,3-aziridino-γ-lactone 4-carboxylate derivative

Article abstract of DOI:10.1021/jo951983z

The synthesis of the N-acetyl and N-Cbz derivatives of (1S,4S,5R)-4-(methoxycarbonyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (24 and 27, respectively) from D-ribose is described. While compound 24 reacted with methanol in the presence of boron trifluoride etherate to give the novel 2,3-iminoglutamate derivative 28, compound 27 afforded, under the same conditions, the 4(S)-hydroxy-3(S)-methoxy-L-glutamate 31. Similarly, reaction of 27 with ethanol and benzyl alcohol gave the corresponding 3(S)-ethoxy and 3(S)-(benzyloxy) analogues of 31. This represents the first example of the use of a carbohydrate for the preparation of L-glutamate derivatives as well as the first example of a stereocontrolled synthesis of glutamate analogues dissymmetrically substituted at the β,γ-positions.

Full text of DOI:10.1021/jo951983z

2488
J . Org. Chem. 1996, 61, 2488-2496
Syn th esis of Op tica lly P u r e 3,4-Disu bstitu ted L-Glu ta m a tes fr om a
Novel 2,3-Azir id in o-γ-la cton e 4-Ca r boxyla te Der iva tive
Philippe Dauban, Ange`le Chiaroni,1 Claude Riche,1 and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique,
91198 Gif-sur-Yvette Cedex, France
Received November 8, 1995X
The synthesis of the N-acetyl and N-Cbz derivatives of (1S,4S,5R)-4-(methoxycarbonyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (24 and 27, respectively) from D-ribose is described. While compound
24 reacted with methanol in the presence of boron trifluoride etherate to give the novel 2,3-imino-
glutamate derivative 28, compound 27 afforded, under the same conditions, the 4(S)-hydroxy-3(S)-
methoxy-L-glutamate 31. Similarly, reaction of 27 with ethanol and benzyl alcohol gave the corre-
sponding 3(S)-ethoxy and 3(S)-(benzyloxy) analogues of 31. This represents the first example of
the use of a carbohydrate for the preparation of L-glutamate derivatives as well as the first example
of a stereocontrolled synthesis of glutamate analogues dissymmetrically substituted at the â,γ-
positions.
In tr od u ction
positions have been particularly well-studied synthetic
targets. In contrast, much less attention has been paid
to 3,4-disubstituted derivatives of glutamic acid despite
the synthetic challenge and therapeutic potential which
these molecules present.
A few examples of 3,4-disubstituted glutamic acid
derivatives have been found in nature. Thus, two ste-
reoisomers of 3-hydroxy-4-methyl-L-glutamic acid (1a )
have been isolated from the seeds of the legume Gym-
nocladus dioicius6 while the seeds of Gleditsia caspica7
and Lepidium8 are sources of 3-hydroxy-4-methylene- and
3,4-dihydroxy-L-glutamic acid, respectively (1b and 1c).
In addition to being a constituent of a myriad of nat-
urally occurring peptides and proteins, L-glutamic acid
is the most important excitatory neurotransmitter in the
mammalian brain, acting on various subclasses of the
glutamate receptor.2 Moreover, this amino acid is im-
plicated in a wide variety of metabolic processes.3 For
example, L-glutamic acid serves as a precursor in the cen-
tral nervous system for the inhibitory neurotransmitter
γ-aminobutyric acid (GABA) via the action of glutamate
decarboxylase while glutamine synthetase transforms
glutamic acid into glutamine. It also has a pivotal role
in transaminase-catalyzed biosyntheses of other amino
acids.
The biological importance of L-glutamic acid has incited
a great deal of effort to chemically modify its structure
in order to modulate its biological activity. Analogues
carrying substituents at either the C-34 or the C-44dgi,5
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) Responsible for the X-ray crystallographic study.
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0022-3263/96/1961-2488$12.00/0 © 1996 American Chemical Society

Synthesis of 3,4-Disubstituted L-Glutamates
J . Org. Chem., Vol. 61, No. 7, 1996 2489
Sch em e 1
Sch em e 2
In the case of hard nucleophiles (e.g., alcohols), the
reactivity pattern of the 2,3-aziridino-γ-lactones was
observed to also depend on the type of electron-with-
drawing group activating the aziridine ring.16 Thus, the
N-acetate 2a gave exclusively aziridine-2-carboxylic es-
ters 4a , the result of nucleophile-induced lactone ring
opening and N-deacetylation. In the case of the N-Cbz
derivative 2b, however, both the lactone and the aziridine
rings were opened by the nucleophile, the latter being
effected this time exclusively at the C-3 position, furnish-
ing 3(S)-alkoxy-4(S)-hydroxy-L-amino acids 5b. These
experimental results were rationalized in terms of HO-
MO-LUMO theories and MNDO calculations.16,17
The ability to synthesize amino acids such as 5b from
aziridino-γ-lactone 2b suggested to us a convenient
pathway to the little known 3,4-disubstituted glutamate
class of compounds. As shown in Scheme 1, 3-alkoxy-4-
hydroxyglutamates 5c should be accessible starting from
a 2,3-aziridino-γ-lactone carrying a carboxylate function
at the C-4 position (i.e., 2c). In this paper, we report the
synthesis of such a compound from D-ribose and its
exploitation in the preparation of novel, stereochemically
pure, and defined 3,4-disubstituted glutamate derivatives
of type 5c.
have been reported. By way of diastereoselective Michael
additions of lithium enolates to R,â-unsaturated esters,
Kanemasa and co-workers4g were able to prepare 3-alkyl-
4-carboxy-L-glutamates (e.g., 1f) having two optically pure
chiral centers. Finally, the cyclopropyl-L-glutamic acid
derivatives 1g, found in certain fruits,11 have been
prepared both in their racemic4h and stereochemically
pure12 forms. These types of compounds have since been
shown to interact selectively with certain subclasses of
the glutamate receptor,13 as has the methylene cyclopen-
tyl derivative 1h .14 Both 1g and 1h were prepared from
R,â-unsaturated esters via cyclopropanation and cycload-
dition reactions, respectively.
We have recently reported the synthesis of the 4-(meth-
oxymethyl)-2,3-aziridino-γ-lactone derivatives 2a ,b from
D-ribose.15,16 These molecules, which may be considered
as cyclic analogues of the synthetically useful aziridine-
2-carboxylic esters, were subsequently shown to have a
distinctive reactivity pattern with respect to nucleophiles
(Scheme 1). In particular, it was observed that, in the
presence of a Lewis acid, soft nucleophiles (indole, thiols,
halogen, acetate)16,17 attack the aziridine ring of 2a and
2b exclusively at the C-2 position to give lactones of type
3, in contrast to the reactivity of such nucleophiles with
aziridine-2-carboxylic esters, in which the C-3 position
is preferentially attacked.18
Resu lts a n d Discu ssion
P r epar ation of 4-(Meth oxycar bon yl)-2,3-azir idin o-
γ-la cton e Der iva tives (24 a n d 27). In our original
preparation of the 4-(methoxymethyl) derivatives 2a ,b,
the aziridine ring was formed by reductive cyclization of
a 3-azido-2-tosylate, the azide function being introduced
by nucleophilic attack of the 2,3-O-sulfinyl precursor
derived from methyl 5-O-methylribofuranoside.15 We
thus initially attempted to adapt this route to the
synthesis of the desired 4-(methoxycarbonyl) analogue of
type 2c starting from the known methyl uronate 6.19
However, as shown in Scheme 2, it was quickly realized
that this would not be practicable since treatment of the
2,3-O-sulfinyl derivative 7 (prepared by reaction of 6 with
thionyl chloride in the presence of triethylamine) with
sodium azide in DMF gave the elimination product 9
instead of the expected 3-azido compound 8 due, no doubt,
to the increased acidity of the C-4 proton of uronates
compared to ordinary ribofuranosides.20
(8) (a) Mueller, A. L.; Uusheima, K. Acta Chem. Scand. 1965, 19,
1987. (b) Virtanen, A. I.; Ettala, T. Acta Chem. Scand. 1957, 11, 182.
(9) Liebster, J .; Kopoldova, J .; Babicky, A. Radiat. Res. 1963, 19,
551.
(10) Alekseeva, L. V.; Burde, N. L.; Podgornaya, I. V.; Ivakin, A. A.
Zh. Obshch. Khim. 1977, 47, 695; Chem. Abstr. 1977, 87, 38648b.
(11) Fowden, L.; Smith, A.; Millington, D. S.; Sheppard, R. C.
Phytochemistry 1969, 8, 437.
(12) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J . Org.
Chem. 1991, 56, 4167.
(13) Ohfune, Y.; Shimamoto, K.; Ishida, M.; Shinozaki, H. Bioorg.
Med. Chem. Lett. 1993, 3, 15 and references therein.
(14) Raghavan, S.; Ishida, M.; Shinozaki, H.; Nakanishi, K.; Ohfune,
Y. Tetrahedron Lett. 1993, 34, 5765.
Our strategy was thus modified such that the azide
group was introduced prior to formation of the 4-car-
boxylate function. As shown in Scheme 3, the starting
(15) Dubois, L.; Dodd, R. H. Tetrahedron 1993, 49, 901.
(16) Dauban, P.; Dubois, L.; Tran Huu Dau, E.; Dodd, R. H. J . Org.
Chem. 1995, 60, 2035.
(17) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J . Org. Chem.
1994, 59, 434.
(18) For reviews, see: (a) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. (b) Legters, J .; Willems, J . G. H.; Thijs, L.; Zwanenburg,
B. Recl. Trav. Chim. Pays-Bas 1992, 111, 59 and references therein.
(19) J ung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1979, 1426.
(20) Schmidt, R. R.; Heermann, D.; J ung, K.-H. Liebigs Ann. Chem.
1974, 1856.

2490 J . Org. Chem., Vol. 61, No. 7, 1996
Dauban et al.
Sch em e 3
material for these transformations was methyl 5-O-trityl-
â-D-ribofuranoside (10).21 Gero and co-workers22 have
described the preparation of the 2,3-di-O-tosyl derivative
of 10. However, these authors were not able to displace
either of the tosyl groups by azide anion, presumably due
to steric hindrance produced by the trityl group. Since
the cyclic sulfinyl moiety is generally a better leaving
group than tosyl,23 we chose to prepare the former
derivative of 10 by the usual treatment with thionyl
chloride and triethylamine. The resulting compound 11,
which is stable and easily purified by chromatography,
then reacted smoothly with sodium azide in HMPA at
100 °C to give 12. Although DMF could also be used as
a solvent in this reaction, higher temperatures (145 °C)
were necessary, more degradation products were ob-
served, and product yield was 2-fold lower. Nucleophilic
attack of azide anion exclusively at the C-3 position of
11 was evident from the 1H NMR spectrum of the product
12 in which the anomeric proton was observed as a
singlet, indicative of a trans arrangement with H-2. Such
complete regioselectivity of attack of carbohydrate cyclic
sulfinyl groups by azide anion has previously been
observed.23
As a prelude to the formation of the aziridine ring and
also to protect the C-2 hydroxyl function during the
subsequent oxidation of the C-5 position, compound 12
was tosylated to give 13. The latter, dissolved in a 1:2
mixture of 0.5 M sulfuric acid and dioxane, was selec-
tively hydrolyzed to the 5-hydroxy derivative 14 after 90
min at 100 °C. Oxidation of the free hydroxy group of
14 could then be effected in high yield using conditions
described by Sharpless.24 Thus, treatment of 14 with a
catalytic quantity of ruthenium trichloride and excess
sodium metaperiodate in a mixture of water, CCl4, and
acetonitrile gave a 91% yield of the carboxylic acid 15.
This compound was transformed into its methyl ester 16
by the action of thionyl chloride in methanol. The IR
spectrum of 16 showed the expected absorptions corre-
sponding to azide, sulfonyl, and ester functions, while the
1H NMR spectrum revealed the presence of the three
methyl groups belonging to the ether, ester, and tosyl
functionalities. The two-singlet nature of each of these
signals indicated that anomerization (â:R ) 3:2) had
occurred during the esterification step. However, since
(21) Kawana, M.; Kuzuhara, H.; Emoto, S. Bull. Chem. Soc. J pn.
1981, 54, 1492.
(22) Cleophax, J .; Gero, S. D.; Hildesheim, J .; Sepulchre, A. M.;
Guthrie, R. D.; Smith, C. W. J . Chem. Soc. C 1970, 1385.
(23) Guiller, A.; Gagnieu, C. H.; Pacheco, H. Tetrahedron Lett. 1985,
26, 6343.
(24) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.

Synthesis of 3,4-Disubstituted L-Glutamates
J . Org. Chem., Vol. 61, No. 7, 1996 2491
a γ-lactone structure was our ultimate goal, this isomer-
ization was not considered an impediment and no effort
was made to separate the anomers.
Before we proceeded with aziridine ring formation, the
anomeric methyl ether of 16 was transformed into the
tert-butyldimethylsilyl ether 18. This exchange of ano-
meric blocking groups is necessary at this point since,
unlike the methyl ether, the silylated derivative can be
deprotected (i.e., by fluoride ion) in the presence of the
sensitive aziridine ring. Thus, hydrolysis of 16 with
aqueous trifluoroacetic acid (conditions being carefully
optimized to avoid concomitant hydrolysis of the ester
function)25 followed by treatment of the product 17 with
tert-butyldimethylsilyl chloride and imidazole in DMF26
afforded 18 in approximately 70% overall yield.
Formation of the 2,3-aziridine ring was then studied.
In the 4-(methoxymethyl) series (2a ,b), the aziridine ring
was obtained by a modified Staudinger reaction, that is,
treatment of the corresponding 3-azido-2-tosylate with
triphenylphosphine followed by hydrolysis of the inter-
mediate triphenylphosphinimine with hot aqueous so-
dium hydroxide.15,27 The presence of the ester function
in 18, however, clearly precluded use of this methodology.
Hashimoto and co-workers28 have reported the formation
of an aziridine ring from a 2-azido-3-mesylpyranose
derivative by way of catalytic hydrogenation (palladium
on carbon) of the azide followed by base-promoted cy-
clization (sodium acetate in aqueous DMF at 90 °C).
Applied to compound 18, these conditions effectively
produced the desired aziridine 19, but in only mediocre
yields. Much better results were obtained when sodium
acetate was replaced by triethylamine in the cyclization
step and the presence of water was eliminated. In this
case, 19, characterized as its N-acetyl derivative 21 after
treatment of the crude reaction product with acetic
F igu r e 1. X-ray crystal structure of compound 24.
Since, as discussed above, the N-Cbz (2b) and the
N-acetyl (2a ) 4-(methoxymethyl) derivatives were shown
to have different reactivity patterns toward nucleo-
philes,16 the N-Cbz analogue of ester 24 was also pre-
pared. Aziridine 19 was thus treated with benzyl chlo-
roformate, DMAP, and triethylamine in DMF, giving the
N-Cbz furanoside 2531 which was transformed into lac-
tone 27 after sequential treatment with fluoride anion
and TPAP/NMO.
The structural identities of both key compounds 24 and
27 were fully consistent with the spectroscopic and
analytical data. In particular, both compounds showed
three carbonyl absorptions in the infrared spectrum, one
of which, in the 1800 cm-1 region, is characteristic of the
lactone structure. Moreover, in the 1H NMR spectra, the
bridging protons H-2 and H-3 are shifted downfield in
going from the lactols (3.2-3.5 and 3.5-3.7 ppm, respec-
tively) to the lactones (3.6-4.0 ppm).32 Finally, the
structure of the N-acetylaziridino-γ-lactone 24 was con-
firmed by X-ray crystallography (Figure 1).33
Rea ctivity of 24 a n d 27 tow a r d Alcoh ols:P r ep a -
r a tion of 3,4-Disu bstitu ted Glu ta m a te Der iva tives.
We have previously shown16 that the 4-(methoxymethyl)-
N-acetyl-2,3-aziridino-γ-lactone 2a reacts with hard nu-
cleophiles such as methanol in the presence of a Lewis
acid catalyst (boron trifluoride etherate) to give exclu-
sively the product arising from lactone ring opening by
the nucleophile and N-deacetylation (i.e., 4a , R3 ) CH3).
The latter process deactivates the aziridine ring, protect-
ing it from further nucleophilic attack. The reactivity
anhydride in pyridine, was obtained in 70% yield.
A
second minor product (15%) formed with 21 after the
sequence hydrogenation/base treatment/acetylation, was
shown to be the uncyclized acetamide 22. Interestingly,
though the starting material 18 and the major product
21 of this series of reactions were R,â anomeric mixtures,
1
compound 22 was observed by H NMR spectroscopy to
be composed exclusively of the R-anomer on the basis of
the H1-H2 coupling constant of 3.5 Hz. This suggested
that the R-anomer of the intermediate 3-amino-2-tosylate
(20) cyclizes less readily than its â-anomer. This was
conclusively demonstrated by running the cyclization
reaction in refluxing acetonitrile instead of in DMF at
100 °C. In this case, only the â-anomer of the intermedi-
ate amine cyclized to give pure (â)-aziridine 21 in 55%
yield after acetylation, the R-anomer leading entirely to
the uncyclized compound 22 in 30% yield.29
Preparation of the desired lactone from 21 then pro-
ceeded uneventfully. Thus, treatment of 21 with tet-
rabutylammonium fluoride in dichloromethane afforded
the aziridino furanose 23 in good yield. Oxidation of the
free hydroxyl group of the latter with catalytic tetrapro-
pylammonium perruthenate (TPAP)30 in the presence of
4-methylmorpholine N-oxide (NMO) then gave the 2,3-
aziridino-γ-lactone 24, a stable, crystalline solid.
(29) As pointed out by a reviewer, the relative proportion of â- to
R-anomer decreases in transforming 17 (â:R ) 2:1) into the reaction
products 21 and 22 (â-21:R-21 + R-22 ) 1:1). Because none of the
reaction conditions used for this transformation is likely to cause
anomerization in favor of the R-anomer, it is more probable that the
apparent enrichment in R-anomer may be due to the greater chemical
instability of â-21 (or its precursor â-19) compared to R-21 and R-22
under the conditions of the cyclization reaction (DMF and triethy-
lamine at 100 °C). Thus, when milder conditions are used (acetonitrile
and triethylamine at 82 °C), the â:R ratio of the final products remains
2:1, as in the starting material.
(30) For a review, see: Ley, S. V.; Norman, J .; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.
(31) The starting material 19 used for the synthesis of 25 was
prepared from 18 using acetonitrile rather than DMF during the
cyclization step in order to provide exclusively the â-anomer (together
with uncyclized R-20). The small proportion (<10%) of R-25 formed
during Cbz-chloride treatment of the mixture of â-19 and 20 is probably
the result of the use of DMF and triethylamine in this step, conditions
observed to promote cyclization of 20 to R-19.
(32) For simplicity of discussion, carbohydrate ring numbering (i.e.,
as in Scheme 1) has been used throughout for all compounds despite
the fact that the ring atoms of some of these compounds (e.g., 24, 27,
29, 32, 34) are numbered differently in the official IUPAC nomencla-
ture (see Experimental Section).
(33) The authors have deposited atomic coordinates for compound
24 with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK.
(25) Gesson, J . P.; J acquesy, J . C.; Mondon, M. Tetrahedron Lett.
1989, 30, 6503.
(26) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(27) Pinter, I.; Kovacs, J .; Messmer, A.; Kalman, A.; Toth, G.;
Lindberg, B. K. Carbohydr. Res. 1979, 72, 289.
(28) Araki, K.; Kawa, M.; Saito, Y.; Hashimoto, H.; Yoshimura, J .
Bull. Chem. Soc. J pn. 1986, 59, 3137.

2492 J . Org. Chem., Vol. 61, No. 7, 1996
Dauban et al.
Sch em e 4
etherate showed that, as with methanol, both lactone ring
opening and aziridine ring opening had occurred. How-
ever, partial transesterification of the 4-(methoxycarbo-
nyl) group to a 4-(ethoxycarbonyl) group (∼15%) was also
evident. In view of this, the reaction time was extended
to 45 h, thereby allowing complete conversion of 27 into
the diethyl 3-ethoxy-4-hydroxy-L-glutamate derivative 33.
Partial cyclization of 33 to the lactone 34 was again
observed during the course of its purification on silica
gel.
Finally, the reaction of benzyl alcohol with 27 was
studied. By use of only 1 equiv of boron trifluoride
etherate and by heating the reaction mixture for only 2
h, lactone and aziridine ring opening could be selectively
achieved while transesterification of the methyl ester was
completely suppressed. Relactonization of this product
(35) could in turn be prevented by acetylation of its free
hydroxyl group (36). Alternatively, when the reaction
of 27 with benzyl alcohol was run at room temperature,
only the product of lactone ring opening (37) was ob-
tained. The presence of a hydroxyl group in 37 was
evident from both the IR and 1H NMR spectra of the
compound, relactonization apparently being prevented by
the rigidity imparted by the intact aziridine ring.
Compound 37, an aziridine-2-carboxylate, is a poten-
tially valuable intermediate for the preparation of hith-
erto unknown 3,4-disubstituted glutamate derivatives in
view of the general observation that this class of com-
pounds reacts with all types of nucleophiles (hard or soft)
practically always at the C-3 position to give R-amino
acids.18,35 In contrast, the distinctive feature of the 2,3-
aziridino-γ-lactones is, as we have described here and
elsewhere, their propensity to react selectively with
nucleophiles at the C-2 or C-3 positions depending on
whether these nucleophiles are, respectively, soft or hard.
Inasmuch as an aziridino-γ-lactone such as 27 allows
either direct access to 3,4-disubstituted glutamates (e.g.,
31, 33, 35) or to an intermediate 37 in turn susceptible
to conversion to such compounds, the methodology re-
ported here may be considered to be the only one
available at present for the stereocontrolled synthesis of
3,4-disubstituted L-glutamates. We are currently explor-
ing the use of 27 and 37 for this purpose, as well as
investigating the biological properties which these novel
molecules may possess.
pattern of the 4-(methoxycarbonyl) analogue 24 proved to
be identical (Scheme 4), reaction with methanol at 20 °C
in the presence of 2 equiv of boron trifluoride etherate
producing the novel dimethyl iminoglutamate derivative
28. The IR spectrum of 28 showed only one carbonyl
1
(ester) band, while in the H NMR spectrum the H-2 and
H-3 signals of the aziridine ring were shifted to high field
(2.86 and 2.52 ppm, respectively) and the N-acetyl signal
was no longer visible.
With respect to soft nucleophiles, the reactivity of ester
24 also paralleled that of the methoxy derivative 2a 16
since, in the presence of ethanethiol, only compound 29,
the product of nucleophilic attack of the aziridine ring
at C-2, was observed. This regioselectivity is evident
from the 1H NMR spectrum of 29 in which H-2 is
observed as a doublet, trans to H-3 (J ) 5.8 Hz), itself
coupled to three protons (NH, H-2, H-4).
In view of these results, it seemed reasonable to
assume that the N-Cbz-aziridino-γ-lactone 27 would
behave in the same manner toward methanol as its
4-(methoxymethyl) analogue 2b. In the latter case, the
N-Cbz blocking group was found to be stable under the
conditions of the reaction (2 equiv of Lewis acid, 20 °C),16
thus allowing opening of both the lactone ring and the
aziridine ring (at C-3) to give a 3-methoxy-4-hydroxy
R-amino acid derivative (i.e., 5b, R3 ) CH3). Surpris-
ingly, however, the crude product obtained from the
reaction of the 4-(methoxycarbonyl)-N-Cbz derivative 27
with methanol under identical conditions yielded only the
product of lactone ring opening 30 (Scheme 5), the
aziridine ring having resisted nucleophilic attack despite
the presence of the activating N-Cbz group. By heating
the reaction mixture at 50 °C for 90 min, aziridine ring
opening could be achieved, affording in good yield (60%)
the 3(S)-methoxy-4(S)-hydroxy-L-glutamate derivative
31. This represents the first example of a stereocon-
trolled preparation of a 3,4-disubstituted glutamate as
well as the first example of the use of a carbohydrate
(D-ribose) for the synthesis of an L-glutamic acid deriva-
tive.34
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra of
samples were obtained as films (i.e., by application of a CHCl3
solution to an NaCl plate followed by evaporation of the
solvent). 1H NMR and 13C NMR chemical shifts are given as
δ values with reference to Me4Si as internal standard. TLC
and preparative chromatography were performed on Merck
silica gel 60 plates with fluorescent indicator. The plates were
visualized with UV light (254 nm) and, for TLC, with a 3.5%
solution of phosphomolybdic acid in ethanol. All column
chromatography was conducted on Merck 60 silica gel (230-
240 mesh) at medium pressure (200 mbar). All solvents were
distilled and stored over 4 Å molecular sieves before use.
Boron trifluoride etherate, TPAP, 4-methylmorpholine N-
oxide, and benzyl chloroformate were purchased from Aldrich
Chemical Co. and were used without further purification.
Compound 31 underwent partial cyclization to the
lactone form 32 during the course of its purification on
silica gel. The formation of this compound from 31
confirmed the structure and stereochemistry of the latter
1
since the H NMR data for 32 were consistent with the
introduction of the methoxy group at C-3 of the lactone,
trans to both substituents at C-2 and C-4 (i.e., via an SN2
pathway).32 Thus, H-2 and H-3 were observed as dou-
blets of doublets with a coupling constant of 5.5 Hz while
the H3-H4 coupling constant was 4.5 Hz.
A
1H NMR spectrum of the crude product obtained
when aziridino-γ-lactone 27 was reacted with ethanol at
70 °C for 3 h in the presence of 2 equiv of boron trifluoride
(35) We have confirmed that compound 37 reacts with nucleophiles
in the same manner as the classical aziridine 2-carboxylic esters. Thus,
for example, ethanethiol attacks 37 exclusively at the C-3 position to
give the corresponding 3-(ethylthio)-4-hydroxy-L-glutamate derivative.
The preparation of a variety of disubstituted glutamates from 37 will
be the subject of a separate report.
(34) For a review of the use of carbohydrates for the stereocontrolled
synthesis of amino acids, see: Cintas, P. Tetrahedron 1991, 47, 6079.

Synthesis of 3,4-Disubstituted L-Glutamates
J . Org. Chem., Vol. 61, No. 7, 1996 2493
Sch em e 5
Element analyses were performed at the ICSN, CNRS, Gif-
sur-Yvette, France.
CDCl3) δ 3.20 (s, 1.5 H, endo (or exo) isomer), 3.23 (s, 1.5H,
exo (or endo) isomer), 3.10-3.50 (m, 2H), 4.37 (dd, 0.5 H, J 4,3
) 0.8 Hz, J 4,5 ) 6.3 Hz), 4.69 (dd, 0.5H, J 4,3 ) 1.3 Hz, J 4,5
)
Meth yl (Meth yl 2,3-O-Su lfin yl-â-D-r ibofu r a n osid )u r -
on a te (7). To a solution of the diol 6 (41 mg, 0.21 mmol) and
triethylamine (0.12 mL, 0.84 mmol) in THF (2 mL) was added
at -25 °C under nitrogen freshly distilled thionyl chloride (30
µL, 0.42 mmol). The reaction mixture was stirred for 15 min
at -25 °C and diluted with ethyl acetate (5 mL) before addition
of saturated aqueous NaCl solution (5 mL). The organic phase
was separated, washed with aqueous NaCl solution (2 × 5 mL),
and dried over Na2SO4. Removal of the solvents under reduced
pressure left a yellow oil which was purified by passing
through a pad of silica gel (dichloromethane-ethanol 98:2).
Compound 7 (48 mg, 95%), an oil, was thus obtained as a 1:1
mixture of exo and endo isomers: 1H NMR (200 MHz, CDCl3)
δ 3.40 (s, 1.5 H), 3.41 (s, 1.5 H), 3.79 (s, 3H), 4.70 (s, 0.5 H),
4.96 (s, 0.5 H), 5.00 (d, 0.5 H, J 2,3 ) 6.5 Hz), 5.14 (s, 0.5 H),
5.25 (d, 0.5 H, J 2,3 ) 5.9 Hz), 5.31 (s, 0.5 H), 5.80 (d, 0.5 H),
5.99 (d, 0.5 H); IR (film) 1738, 1450, 1212 cm-1; mass spectrum
(CI) m/z 239 (MH)+. Anal. Calcd for C7H10O7S: C, 35.29; H,
4.23; O, 47.02; S, 13.46. Found: C, 35.60; H, 4.07; O, 47.38;
S, 13.32.
Met h yl (4R,5R)-4,5-Dih yd r o-4-h yd r oxy-5-m et h oxy-2-
fu r a n ca r boxyla te (9). A solution of compound 7 (48 mg, 0.2
mmol) in DMF (2 mL) was heated for 1 h at 100 °C in the
presence of sodium azide (39 mg, 0.6 mmol). (Caution!
Hazardous chemical.) The solvent was then removed in vacuo,
the residue was taken up in ethyl acetate (5 mL), and the
solution was washed with saturated aqueous NaCl solution
(2 × 5 mL). The organic phase was dried over Na2SO4, the
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography on silica gel
using CH2Cl2-ethanol (95:5) as eluent. Compound 9 was
obtained as a colorless oil in 70% yield (25 mg): 1H NMR (200
MHz, CDCl3) δ 2.50 (m, 1H, exchangeable with D2O), 3.54 (s,
3H), 3.85 (s, 3H), 4.71 (m, 1H), 5.28 (d, 1H, J 5,4 ) 1.0 Hz),
6.03 (d, 1H, J 3,4 ) 2.7 Hz); 13C NMR (50 MHz, CDCl3) δ 56.7,
59.3, 78.6, 111.6, 113.1, 149.9, 171.3; IR (film) 3425, 1734, 1631
cm-1; mass spectrum (CI) m/z 175 (MH)+, 157 (MH - H2O)+.
Anal. Calcd for C7H10O5‚1/4H2O: C, 47.06; H, 5.92; O, 47.02.
Found: C, 47.44; H, 5.92; O, 47.32.
5.7 Hz), 4.93 (d, 0.5 Hz, J 2,3 ) 6.5 Hz), 5.00 (s, 0.5H), 5.13 (dd,
0.5H), 5.17 (d, 0.5H), 5.25 (s, 0.5H), 5.37 (d, 0.5H), 7.15-7.50
(m, 15H); 13C NMR (50 MHz, CDCl3) δ 55.2, 55.3, 64.0, 64.3,
84.6, 85.4, 86.1, 87.3, 87.7, 88.9, 90.9, 108.2, 108.7, 127.4, 128.1,
128.7, 143.7; IR (film) 1215 cm-1; mass spectrum (CI) m/z 452
(M)+. Anal. Calcd for C25H24O6S: C, 66.35; H, 5.35; O, 21.22;
S, 7.08. Found: C, 66.53; H, 5.42; O, 21.14; S, 7.14.
Meth yl 3-Azid o-3-d eoxy-5-O-(tr ip h en ylm eth yl)-â-D-xy-
lofu r a n osid e (12). A solution of compound 11 (11.6 g, 25.6
mmol) in anhydrous HMPA (120 mL) (Warning! Toxic solvent)
was heated at 100 °C for 15 h in the presence of sodium azide
(5.0 g, 76.9 mmol). (Caution! Hazardous chemical.) The
solvent was then removed in vacuo, and the crude reaction
product was taken up in ethyl acetate (200 mL). The solution
was washed with water (3 × 150 mL), the organic phase was
dried over Na2SO4, and the solvent was removed under
reduced pressure. The oily residue was purified by column
chromatography on silica gel. Elution of the column with 3:1
heptane-ethyl acetate resulted in isolation of unreacted 11
(1.0 g, 9%). Further elution with 2:1 heptane-ethyl acetate
afforded compound 12 as a colorless oil (8.8 g, 80%): [R]22
D
1
-51.5° (c 0.5, CHCl3); H NMR (200 MHz, CDCl3) δ 2.46 (m,
1H, exchangeable with D2O), 3.28 (dd, 1H, J 5,4 ) 5.5 Hz, J 5,5′
) 9.7 Hz), 3.35 (s, 3H), 3.40 (dd, 1H, J 5′,4 ) 6.3 Hz), 3.96 (dd,
1H, J 3,2 ) 2.4 Hz, J 3,4 ) 5.7 Hz), 4.24 (m, 1H), 4.50 (pseudo q,
1H, J 4,5 ) 5.8 Hz), 4.82 (s, 1H), 7.15-7.50 (m, 15H); 13C NMR
(50 MHz, CDCl3) δ 55.8, 63.4, 66.9, 79.9, 80.0, 87.3, 109.5,
127.2, 127.9, 128.9, 144.0; IR (film) 3415, 2106 cm-1; mass
spectrum (EI) m/z 431 (M)+. Anal. Calcd for C25H25N3O4: C,
69.59; H, 5.84; O, 14.83; N, 9.74. Found: C, 69.57; H, 5.87;
O, 15.01; N, 9.73.
Meth yl 3-Azido-3-deoxy-2-O-(p-tolylsu lfon yl)-5-O-(tr iph -
en ylm eth yl)-â-D-xylofu r a n osid e (13). A solution of com-
pound 12 (11.5 g, 26.7 mmol) in pyridine (200 mL) was treated
at 0 °C with p-toluenesulfonyl chloride (15.2 g, 80.0 mmol),
and the reaction mixture was stirred for 72 h at rt. The solvent
was then removed under reduced pressure, and the solid
residue was partitioned between ethyl acetate (300 mL) and
water (300 mL). The phases were separated, and the organic
phase was dried over Na2SO4. Removal of the solvent in vacuo
left a yellow oil which was purified by column chromatography
on silica gel (heptane-ethyl acetate 9:1 followed by 8:1),
Meth yl 2,3-O-Su lfin yl-5-O-(tr ip h en ylm eth yl)-â-D-r ibo-
fu r a n osid e (11). To a solution of diol 10 (11.5 g, 28.3 mmol)
and triethylamine (16 mL, 113 mmol) in anhydrous THF (150
mL) held at -25 °C was added dropwise over 45 min a solution
of freshly distilled thionyl chloride (4.1 mL, 56.6 mmol) in THF
(10 mL). The reaction mixture was stirred for a further 45
min at -25 °C. At the end of the reaction period, ethyl acetate
(150 mL) was added followed by saturated aqueous NaCl
solution (200 mL). The aqueous layer was separated, and the
organic phase was washed with NaCl solution (2 × 100 mL).
The organic phase was dried (Na2SO4), the solvents were
removed under reduced pressure, and the oily residue was
purified by column chromatography on silica gel (heptane-
ethyl acetate 4:1), yielding compound 11 (11.0 g, 86%) as a
faintly colored solid: mp 101-102 °C; 1H NMR (200 MHz,
affording 13 (14.0 g, 90%) as a colorless oil: [R]22 -27.9° (c
D
1
0.5, CHCl3); H NMR (200 MHz, CDCl3) δ 2.46 (s, 3H), 3.23
(s, 3H), 3.24 (dd, 1H, J 5,4 ) 6.0 Hz, J 5,5′ ) 9.7 Hz), 3.38 (dd,
1H), 4.08 (d, 1H, J 3,4 ) 5.8 Hz), 4.41 (pseudo q, 1H), 4.74 (s,
1H), 4.82 (s, 1H), 7.23-7.46 (m, 17H), 7.82 (d, 2H, J ) 8.2
Hz); 13C NMR (50 MHz, CDCl3) δ 23.5, 55.9, 62.9, 64.9, 80.0,
86.0, 87.3, 106.8, 127.1, 127.8, 128.2, 128.7, 130.2, 133.0, 143.8,
145.8; IR (film) 2110, 1180 cm-1; mass spectrum (EI) m/z 585
(M)+. Anal. Calcd for C32H31N3O6S: C, 65.62; H, 5.34; O,
16.39; N, 7.17; S, 5.47. Found: C, 65.70; H, 5.59; O, 15.99; N,
6.80; S, 5.27.

2494 J . Org. Chem., Vol. 61, No. 7, 1996
Dauban et al.
Meth yl 3-Azid o-3-d eoxy-2-O-(p-tolylsu lfon yl)-â-D-xylo-
fu r a n osid e (14). A solution of compound 13 (4.6 g, 7.85
mmol) and sulfuric acid (20 mL of a 0.5 M solution) in dioxane
(40 mL) was heated at 100 °C for 90 min. The reaction mixture
was then cooled to rt, diluted with saturated aqueous NaCl
solution (25 mL), and extracted with ethyl acetate (3 × 100
mL). The combined organic extracts were dried (Na2SO4), the
solvents were evaporated under reduced pressure, and the
residue was purified by column chromatography on silica gel
(heptane-ethyl acetate 2:1 followed by 1:1), affording com-
following step. An analytical sample was obtained by column
chromatography of this crude product on silica gel using
heptane-ethyl acetate (6:4) as eluent: 1H NMR (200 MHz,
CDCl3) δ 2.48 (s, 3H), 3.80 (s, 1H, R anomer), 3.84 (s, 2H, â
anomer), 4.52 (dd, 0.6 H, J 3,2 ) 2.0 Hz, J 3,4 ) 6.9 Hz), 4.53
(dd, 0.4H, J 3,2 ) 5.6 Hz, J 3,4 ) 7.2 Hz), 4.65 (dd, 0.4H, J 2,1
)
3.9 Hz), 4.76 (d, 0.6H), 4.87 (d, 0.4H), 4.93 (d, 0.6H), 5.29 (s,
0.6H), 5.60 (d, 0.4H), 7.40 (d, 2H, J ) 8.0 Hz), 7.83 (d, 2H);
13C NMR (75 MHz, CDCl3) δ 21.7, 52.5, 52.9, 63.8, 65.4, 75.5,
79.9, 80.7, 85.8, 95.0, 101.7, 128.1, 128.2, 130.2, 130.4, 132.3,
145.9, 146.1, 168.8, 170.1; IR (film) 3460, 2118, 1750, 1181
cm-1; mass spectrum (CI) m/z 358 (MH)+. Anal. Calcd for
C13H15N3O7S: C, 43.70; H, 4.23; N, 11.76; S, 8.97. Found: C,
43.54; H, 4.16; N, 11.61; S, 8.91.
Meth yl [ter t-Bu tyld im eth ylsilyl 3-a zid o-3-d eoxy-2-O-
(p-tolylsu lfon yl)-r,â-D-xylofu r a n osid ]u r on a te (18). To a
solution of compound 17 (5.5 g, 15.4 mmol) in anhydrous DMF
were successively added imidazole (2.8 g, 30.8 mmol) and tert-
butyldimethylsilyl chloride (4.6 g, 23.1 mmol). The reaction
mixture was stirred for 20 h at rt, and it was then evaporated
to dryness under reduced pressure. The residue was taken
up in ethyl acetate (250 mL), and the mixture was washed
pound 14 (2.3 g, 85%) as a colorless oil: [R]22 -78.8° (c 0.5,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.47 (s, 3H), 3.34 (s, 3H),
3.70 (m, 2H), 4.21 (dd, 1H, J 3,2 ) 4.4 Hz, J 3,4 ) 7.2 Hz), 4.35
(dt, 1H, J 4,5 ) 7.8 Hz), 4.81 (dd, 1H, J 2,1 ) 1.5 Hz), 4.91 (d,
1H), 7.39 (d, 2H, J ) 8.2 Hz), 7.83 (d, 2H); 13C NMR (75 MHz,
CDCl3) δ 21.6, 56.1, 61.8, 65.0, 81.0, 86.7, 106.9, 128.2, 130.2,
132.7, 145.8; IR (film) 3400, 2110, 1178 cm-1; mass spectrum
(EI) m/z 312 (M - OCH3)+. Anal. Calcd for C13H17N3O6S: C,
45.47; H, 4.99; N, 12.24; S, 9.34. Found: C, 45.85; H, 4.94; N,
12.12; S, 9.23.
Meth yl 3-Azid o-3-d eoxy-2-O-(p-tolylsu lfon yl)-â-D-xylo-
fu r a n osid u r on ic Acid (15). A biphasic mixture of water (75
mL), CCl4 (50 mL) (Warning! Toxic solvent), and acetonitrile
(50 mL) containing compound 14 (8.6 g, 25.0 mmol), ruthenium
trichloride hydrate (260 mg, 1.25 mmol), and sodium meta-
periodate (22.0 g, 102.5 mmol) was stirred vigorously for 4.5
h at rt. The reaction mixture was then diluted with water
(100 mL) and extracted with CH2Cl2 (3 × 200 mL). The
combined organic extracts were dried (Na2SO4), the solvents
were removed under reduced pressure, and the dark green oily
residue was triturated with diethyl ether in order to precipitate
the ruthenium salts. The latter were removed by filtration of
the mixture through Celite. The filtrate was concentrated in
vacuo, leaving compound 15 (8.13 g, 91%) as a lightly colored
oil which was used in the following reactions without further
purification: 1H NMR (200 MHz, CDCl3) δ 2.49 (s, 3H), 3.43
(s, 3H), 4.35 (d, 1H, J 3,4 ) 6.4 Hz), 4.80 (s, 1H), 4.95 (d, 1H),
4.99 (s, 1H), 7.42 (d, 2H, J ) 8.2 Hz), 7.84 (d, 2H), 8.56 (m,
1H, exchangeable with D2O); 13C NMR (62.5 MHz, CDCl3) δ
21.8, 56.2, 65.1, 80.0, 84.6, 107.7, 128.2, 130.5, 132.5, 146.3,
172.2; IR (film) 3300, 2125, 1747, 1170 cm-1; mass spectrum
(CI) m/z 358 (MH)+.
with water (200 mL). Drying of the organic phase over Na2
-
SO4, removal of the solvent in vacuo, and purification of the
crude product by column chromatography on silica gel (hep-
tane-ethyl acetate 4:1 followed by 3:1) afforded compound 18
(6.6 g, 90%) as a colorless oil:
1H NMR (200 MHz, CDCl3) δ
0.00-0.13 (4 × s, 6H), 0.83 (s, 5.4H, â anomer), 0.90 (s, 3.6 H,
R anomer), 2.46 (s, 1.2H), 2.48 (s, 1.8H), 3.78 (s, 3H), 4.26 (d,
0.6H, J 3,4
) 5.8 Hz), 4.51 (d, 0.4H, J 3,4 ) 5.4 Hz), 4.52 (d, 0.4H,
J 2,1 ) 2.8 Hz), 4.67 (s, 0.6H), 4.79 (m, 1H), 5.29 (s, 0.6H), 5.50
(d, 0.4H), 7.40 (d, 2H, J ) 8.0 Hz), 7.83 (d, 2H); 13C NMR (75
MHz, CDCl3) δ -4.8, -4.7, 17.8, 17.9, 21.7, 25.4, 25.5, 52.2,
52.5, 63.1, 64.7, 75.0, 79.7, 81.2, 86.1, 94.9, 101.6, 127.6, 128.0,
130.1, 130.3, 132.5, 132.7, 145.6, 146.0, 167.9, 168.7; IR (film)
2120, 1775, 1177 cm-1; mass spectrum (CI) m/z 472 (MH)+.
Anal. Calcd for C19H29N3O7SSi: C, 48.39; H, 6.20; N, 8.91; S,
6.80. Found: C, 48.39; H, 5.98; N, 8.93; S, 6.81.
Met h yl (ter t-Bu t yld im et h ylsilyl 2,3-a zir id in o-2,3-d i-
d eoxy-r,â-D-lyxofu r a n osid )u r on a te (19) a n d Meth yl [ter t-
Bu tyldim eth ylsilyl 3-am in o-3-deoxy-2-O-(p-tolylsu lfon yl)-
r,â-D-xylofu r a n osid ]u r on a te (20). A solution of compound
18 (2.81 g, 5.96 mmol) in ethyl acetate (60 mL) was hydroge-
nated at atmospheric pressure for 3 h in the presence of 10%
palladium on carbon (260 mg). The reaction was then filtered
through Celite, and the filtrate was evaporated to dryness
under reduced pressure. The residue was dissolved in DMF
(30 mL), triethylamine (8 mL) was added to the solution, and
the latter was heated at 100 °C for 6 h. Removal of the
solvents under reduced pressure at the end of the reaction
period left a brown oil composed of aziridine 19 and uncyclized
amine 20 (4:1 respectively, by NMR). This mixture was
subjected to the next step without further purification. An
analytical sample of 19 was obtained by chromatography of
part of the mixture on silica gel using heptane-ethyl acetate
(1:1) as eluent: 1H NMR (200 MHz, CDCl3) δ 0.13, 0.15, 0.16
(3 × s, 6H), 0.90, 0.92 (2 × s, 9H), 2.65 (d, 0.4H, J 2,3 ) 4.0 Hz,
R anomer), 2.72 (d, 0.6H, J 2,3 ) 3.4 Hz, â anomer), 2.86 (dd,
0.6H, J 3,4 ) 2.0 Hz), 2.97 (dd, 0.4H, J 3,4 ) 1.8 Hz), 3.79, 3.81
(2 × s, 3H), 4.43 (d, 0.6H), 4.63 (d, 0.4H), 5.46 (s, 0.4H), 5.50
(d, 0.6H, J 1,2 ) 0.8 Hz); 13C NMR (75 MHz, CDCl3) δ -4.4,
-4.3, 17.9, 18.0, 25.6, 25.7, 35.5, 36.6, 38.5, 39.4, 52.3, 52.5,
Meth yl [Meth yl 3-a zid o-3-d eoxy-2-O-(p-tolylsu lfon yl)-
r,â-D-xylofu r a n osid ]u r on a t e (16). To a solution of com-
pound 15 (8.13 g, 22.8 mmol) in anhydrous methanol (50 mL)
held at -20 °C was added thionyl chloride (3.3 mL, 45.5 mmol)
dropwise. After completion of the addition, the reaction
mixture was allowed to stir for 20 h at rt and the solvent and
excess reagent were removed under reduced pressure. The
crude material remaining was purified by column chromatog-
raphy on silica gel (heptane-ethyl acetate 7:3), affording
compound 16 (7.5 g, 89%), an oil, as an inseparable mixture
of R and â anomers (2:3, respectively): 1H NMR (250 MHz,
CDCl3) δ 2.46, 2.48 (2 × s, 3H, R and â anomer), 3.34 (s, 1.2H,
R anomer), 3.43 (s, 1.8H, â anomer), 3.79, 3.80 (2 × s, 3H),
4.34 (d, 0.6H, J 3,4 ) 6.5 Hz), 4.50 (dd, 0.4H, J 3,4 ) 7.9 Hz, J 3,2
) 7.3 Hz), 4.62 (dd, 0.4H, J 2,1 ) 4.2 Hz, J 2,3 ) 7.3 Hz), 4.75 (d,
0.4H), 4.77 (d, 0.6H, J 2,1 ) 0.8 Hz), 4.93 (d, 0.6H), 4.95 (s, 0.6H),
4.98 (d, 0.4H), 7.41 (d, 2H, J ) 8.2 Hz), 7.83 (d, 2H); 13C NMR
(62.5 MHz, CDCl3) δ 21.7, 52.4, 52.5, 55.8, 55.9, 63.5, 65.2,
75.1, 80.0, 80.4, 84.8, 100.7, 107.3, 128.1, 128.2, 130.0, 130.4,
132.5, 145.6, 168.3, 168.4; IR (film) 2120, 1765, 1181 cm-1
mass spectrum (CI) m/z 372 (MH)+. Anal. Calcd for C14
H17N3O7S‚0.04C7H16 C, 45.69; H, 4.74; N, 11.19; S, 8.54.
Found: C, 45.70; H, 4.81; N, 11.10; S, 8.64.
;
-
74.8, 74.9, 98.3, 98.4, 169.5, 169.9; IR (film) 3285, 1760 cm-1
;
mass spectrum (HRCI) calcd for C12H24NO4Si (MH)+ m/z
274.1475, found 274.1469.
:
The amine 20 was characterized as its acetamide derivative
22, prepared as described below.
Meth yl 3-Azid o-3-d eoxy-2-O-(p-tolylsu lfon yl)-r,â-D-xy-
lofu r a n u r on a te (17). A solution of compound 16 (7.6 g, 20.5
mmol) in trifluoroacetic acid and water (120 mL of a 9:1
mixture) was stirred at rt for 70 h. The reaction mixture was
then concentrated under reduced pressure at rt, saturated
aqueous NaHCO3 (50 mL) was added, and the mixture was
extracted with ethyl acetate (2 × 150 mL). The combined
organic extracts were dried (Na2SO4), affording, after removal
of solvents in vacuo, compound 17 (5.5 g, 75%) as a lightly
colored oil (a 1:2 mixture of R and â anomer, respectively)
which could be used without further purification in the
Meth yl (ter t-Bu tyld im eth ylsilyl N-a cetyl-2,3-a zir id in o-
2,3-d id eoxy-r,â-D-lyxofu r a n osid )u r on a te (21) a n d Meth yl
[ter t-Bu tyldim eth ylsilyl 3-acetam ido-3-deoxy-2-O-(p-tolyl-
su lfon yl)-r-D-xylofu r a n osid ]u r on a te (22). The 4:1 mixture
of 19 and 20 obtained in the preceding experiment was
dissolved in pyridine (35 mL), the solution was cooled to 0 °C,
and acetic anhydride (6 mL) was added. The reaction mixture
was stirred for 24 h at 5 °C after which the solvents were
removed under reduced pressure. Chromatography of the

Synthesis of 3,4-Disubstituted L-Glutamates
J . Org. Chem., Vol. 61, No. 7, 1996 2495
residue on silica gel (heptane-ethyl acetate 2:1) afforded
aziridine 21 (1.3 g, 70% based on 18) as a mixture of R and â
anomers (2:3, respectively). Careful preparative TLC using
the same eluents allowed isolation of pure â-21 as a white
solvent in vacuo and chromatography of the residue on silica
gel (heptane-ethyl acetate 2:1) gave compound 25 as a white
solid (2.03 g, ∼95% yield based on the estimated weight of 19
in the crude starting material) containing a small amount of
1
solid: mp 108-109 °C; [R]22 -39.1° (c 0.33, CHCl3); 1H NMR
the R anomer (<10% by H NMR) which was used as such in
D
(250 MHz, CDCl3) δ 0.13, 0.16, 0.17, 0.19 (4 × s, 6H), 0.90 (s,
3.6H, R anomer), 0.93 (s, 5.4H, â anomer), 2.11 (s, 1.2H), 2.19
(s, 1.8H), 3.32 (d, 0.6H, J 2,3 ) 4.3 Hz), 3.33 (d, 0.4H, J 2,3 ) 4.3
Hz), 3.52 (dd, 0.6H, J 3,4 ) 2.2 Hz), 3.61 (dd, 0.4H, J 3,4 ) 1.9
Hz), 3.82 (s, 1.8H), 3.85 (s, 1.2H), 4.41 (d, 0.6H), 4.61 (d, 0.4H),
5.43 (d, 0.6H, J 1,2 ) 0.9 Hz), 5.53 (d, 0.4H, J 1,2 < 0.7 Hz); 13C
NMR (62.5 MHz, CDCl3) δ -5.2, -5.1, -4.3, -4.2, 18.1, 23.4,
23.7, 25.6, 25.7, 40.6, 40.9, 43.2, 44.3, 52.3, 52.6, 74.3, 74.6,
96.8, 97.4, 168.7, 180.7; IR (film) 1760, 1700, 1680 cm-1; mass
spectrum (CI) m/z 316 (MH)+. Anal. Calcd for C14H25NO5Si:
C, 53.30; H, 7.99; N, 4.44. Found: C, 53.18; H, 7.78; N, 4.28.
Continued elution of the chromatography column provided
compound 22 (450 mg, 15%) also as a solid: mp 133-135 °C;
[R]22D +83.5° (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.08
(s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.86 (s, 3H), 2.45 (s, 3H),
3.70 (s, 3H), 4.86 (d, 1H, J 4,3 ) 8.5 Hz), 4.88 (dd, 1H, J 2,3 ) 8.0
Hz), 5.00 (ddd, 1H), 5.42 (d, 1H, J 1,2 ) 3.5 Hz), 6.47 (d, 1H,
J NH,3 ) 7.9 Hz), 7.33 (d, 2H), 7.80 (d, 2H); 13C NMR (75 MHz,
CDCl3) δ -4.8, 17.9, 21.6, 22.4, 25.4, 52.0, 52.2, 75.3, 80.0, 94.2,
128.0, 129.8, 133.2, 145.1, 170.1, 170.6; IR (film) 3360, 3280,
1750, 1665, 1540 cm-1; mass spectrum (CI) m/z 488 (MH)+.
Anal. Calcd for C21H33NO8SSi: C, 51.72; H, 6.82; N, 2.87; S,
6.58. Found: C, 51.55; H, 6.66; N, 2.91; S, 6.68.
Met h yl N-Acet yl-2,3-a zir id in o-2,3-d id eoxy â-D-lyxo-
fu r a n u r on a te (23). A solution of compound 21 (560 mg, 1.77
mmol) in CH2Cl2 (15 mL) was treated at -65 °C and under a
nitrogen atmosphere with tetrabutylammonium fluoride (600
mg, 1.9 mmol). The reaction mixture was gradually allowed
to come to rt over 1.5 h. The solvent was then removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel (ethyl acetate), affording com-
pound 23 (275 mg, 77%) as a colorless oil: 1H NMR (250 MHz,
CDCl3) δ 2.11 (s, 3H), 3.43 (d, 1H, J 2,3 ) 4.3 Hz), 3.65 (dd, 1H,
J 3,4 ) 1.9 Hz), 3.86 (s, 3H), 3.96 (m, 1H, exchangeable with
D2O), 4.74 (d, 1H), 5.60 (d, 1H, J 1,2 ) 0.3 Hz); 13C NMR (75
MHz, CDCl3) δ 23.4, 40.7, 43.5, 52.7, 74.5, 96.1, 169.1, 180.6;
IR (film) 3400, 1756, 1700 cm-1; mass spectrum (HRCI) calcd
for C8H12NO5 (MH)+ m/z 202.0715, found 202.0711.
the following step. For analytical purposes, the major â
anomer was isolated in pure form by preparative chromatog-
raphy of an aliquot of 25 (heptane-ethyl acetate 2:1): mp 86-
87 °C; [R]22D - 27.6° (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3)
δ 0.16 (s, 3H), 0.18 (s, 3H), 0.92 (s, 9H), 3.32 (dd, 1H, J 1,2
)
1.4 Hz, J 2,3 ) 4.6 Hz), 3.55 (dd, 1H, J 3,4 ) 2.3 Hz), 3.77 (s,
3H), 4.40 (d, 1H), 5.11 (s, 2H), 5.44 (d, 1H), 7.33 (s, 5H); 13C
NMR (75 MHz, CDCl3) δ -4.2, 18.1, 25.7, 41.9, 43.9, 52.3, 68.2,
74.5, 97.3, 128.2, 128.4, 135.5, 161.0, 168.2; IR (film) 1765,
1730 cm-1; mass spectrum (CI) m/z 408 (MH)+. Anal. Calcd
for C20H29NO6Si. 0.15 H2O: C, 58.55; H, 7.20; N, 3.41.
Found: C, 58.28; H, 7.14; N, 3.29.
Met h yl 2,3-Azir id in o-N-(b en zyloxyca r b on yl)-2,3-d i-
d eoxy-â-D-lyxofu r a n u r on a te (26). Following the same pro-
cedure as for the preparation of 23 from 21, compound 25 (937
mg, 2.3 mmol) afforded 26 (510 mg, 75%) as a white solid after
chromatography of the crude reaction mixture on silica gel
(heptane-ethyl acetate 1:1). Only traces of the R anomer could
be observed by 1H NMR: mp 105-107 °C; 1H NMR (250 MHz,
CDCl3) δ 3.27 (d, 1H, J 2,3 ) 3.8 Hz), 3.57 (dd, 1H, J 3,4 ) 1.9
Hz), 3.62 (s, 3H), 4.21 (m, 1H, exchangeable with D2O), 4.73
(d, 1H), 4.96 (d, 1H, J gem ) 12.1 Hz), 5.19 (d, 1H), 5.64 (s, 1H),
7.35 (s, 5H); 13C NMR (75 MHz, CDCl3) δ 40.3, 42.7, 52.4, 68.5,
73.8, 95.5, 128.5, 128.6, 135.3, 159.6, 169.8; IR (film) 3450,
1760, 1730 cm-1; mass spectrum (EI) m/z 293 (M+). Anal.
Calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C,
57.28; H, 5.29; N, 4.59.
(1S,4S,5R)-N-(Ben zyloxyca r b on yl)-4-(m et h oxyca r b o-
n yl)-3-oxa -6-a za bicyclo[3.1.0]h exa n -2-on e (27). Using the
same procedure as for the preparation of 24, compound 26 (230
mg, 1.96 mmol) was oxidized using TPAP and 4-methylmor-
pholine N-oxide, affording lactone 27 (290 mg, 77%) as a
colorless oil which crystallized on standing: mp 90-92 °C;
[R]27D -25.5° (c 1.0, CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.59
(d, 1H, J 1,5 ) 4.0 Hz), 3.78 (s, 3H), 4.01 (dd, 1H, J 5,4 ) 3.6 Hz),
5.00 (d, 1H), 5.10 (d, 1H, J gem ) 12.1 Hz), 5.17 (d, 1H), 7.36 (s,
5H); 13C NMR (75 MHz, CDCl3) δ 37.9, 41.3, 52.9, 69.4, 74.9,
128.4, 128.6, 128.7, 134.6, 158.5, 165.7, 167.4; IR (film) 1805,
1765, 1735 cm-1; mass spectrum (EI) m/z 291 (M+). Anal.
Calcd for C14H13NO6: C, 57.73; H, 4.50; N, 4.81. Found: C,
57.53; H, 4.36; N, 4.66.
(1S ,4S ,5R )-N -Ace t yl-4-(m e t h oxyca r b on yl)-3-oxa -6-
a za bicyclo[3.1.0]h exa n -2-on e (24). To a mixture of 4-me-
thylmorpholine N-oxide (130 mg, 1.11 mmol) and powdered 4
Å molecular sieves (372 mg) were successively added under
nitrogen at rt a solution of compound 23 (180 mg, 0.90 mmol)
in acetonitrile (7 mL) and TPAP (26 mg, 0.09 mmol). The
reaction mixture was stirred for 4 h, after which it was
evaporated to dryness under reduced pressure. The residue
was dissolved in ethyl acetate and filtered through a pad of
silica gel affording, after removal of the solvent in vacuo,
compound 24 (120 mg, 67%) as a colorless oil which slowly
crystallized on standing. An analytical sample of 24 was
obtained by preparative TLC on silica gel using heptane-ethyl
Dim eth yl (2S,3R,4S)-4-Hyd r oxy-2,3-im in op en ta n e-1,5-
d ioa te (28). To a solution of compound 24 (160 mg, 0.8 mmol)
in anhydrous methanol (10 mL) was added at -20 °C and
under nitrogen boron trifluoride etherate (200 µL, 1.6 mmol).
The reaction mixture was allowed to come to rt over 3 h, after
which it was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (15 mL), and the solution
was neutralized by addition of aqueous NaHCO3 (8 mL of a
0.2 M solution). After separation of the phases, the aqueous
phase was extracted with ethyl acetate (2 × 10 mL), and the
combined organic phases were dried over Na2SO4. Evapora-
tion of the solvents in vacuo and column chromatography of
the residue on silica gel (ethyl acetate) afforded compound 28
acetate (1:4) as eluent: mp 94-95 °C; [R]27 -56.1° (c 1.0,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 2.21 (s, 3H), 3.70 (d,
1H, J 1,5 ) 4.1 Hz), 3.89 (s, 3H), 4.03 (dd, 1H, J 5,4 ) 3.4 Hz),
4.74 (d, 1H); 13C NMR (62.5 MHz, CDCl3) δ 23.4, 37.3, 40.8,
(95 mg, 62%) as a colorless oil: [R]27 +97.0° (c 1.0, CHCl3);
D
53.1, 75.2, 166.2, 167.6, 178.9; IR (film) 1800, 1768, 1715 cm-1
;
1H NMR (250 MHz, CDCl3) δ 2.52 (dd, 1H), 2.63 (m, 2H,
exchangeable with D2O), 2.86 (d, 1H, J 2,3 ) 6.0 Hz), 3.79 (s,
3H), 3.80 (s, 3H), 4.24 (d, 1H, J 4,3 ) 8.1 Hz); 13C NMR (75 MHz,
CDCl3) δ 34.2, 40.1, 52.8, 52.9, 69.7, 171.0, 172.6; IR (film)
3370, 3280, 1740 cm-1; mass spectrum (CI) m/z 190 (MH)+.
Anal. Calcd for C7H11NO5‚0.07C7H16: C, 45.86; H, 6.23; N,
7.14. Found: C, 45.82; H, 5.97; N, 6.84.
mass spectrum (CI) m/z 200 (MH)+. Anal. Calcd for C8H9-
NO5.0.05 C7H16: C, 49.12; H, 4.84; N, 6.86. Found: C, 49.32;
H, 5.05; N, 6.51.
Meth yl [ter t-Bu tyld im eth ylsilyl 2,3-a zir id in o-N-(ben -
zyloxyca r b on yl)-2,3-d id e oxy-r,â-D -lyxofu r a n osid ]u r -
on a te (25). To a solution of crude aziridine â-19 (2.37 g of
the crude product containing ∼30% of 20 and ∼55-60% of
â-19),31 triethylamine (2.43 mL, 17.3 mmol), and DMAP (106
mg, 0.87 mmol) in DMF (40 mL) was added dropwise at 0 °C
a solution of benzyl chloroformate (2.47 mL, 17.3 mmol) in
DMF (3 mL). The reaction mixture was stirred for 30 min at
0 °C and then for 2.5 h at 20 °C, at which point the solvent
was removed under reduced pressure. The residue was taken
up in ethyl acetate and water, the phases were separated, and
the organic phase was dried over Na2SO4. Removal of the
Meth yl (2S,3S,4R)-Tetr a h yd r o-3-a ceta m id o-4-(eth ylth -
io)-5-oxo-2-fu r a n ca r boxyla te (29). To a solution of com-
pound 24 (30 mg, 0.15 mmol) in ethanethiol (1 mL) and
chloroform (1 mL) was added at -25 °C under nitrogen boron
trifluoride etherate (18 µL, 0.15 mmol). The reaction mixture
was slowly brought to rt over 4 h. It was then diluted with
ethyl acetate (5 mL), and aqueous NaHCO3 (1.5 mL of a 0.2
M solution) was added. The phases were separated, the
aqueous phase was extracted with ethyl acetate (2 × 5 mL),

2496 J . Org. Chem., Vol. 61, No. 7, 1996
Dauban et al.
and the combined organic extracts were dried over Na2SO4.
Removal of the solvents under reduced pressure and chroma-
tography of the residue on silica gel (heptane-ethyl acetate
4:6) provided 29 (28 mg, 71%) as a white solid: mp 88-90 °C;
[R]22D +95.3° (c 0.5, CHCl3); 1H NMR (250 MHz, CDCl3) δ 1.31
(t, 3H, J ) 7.4 Hz), 2.02 (s, 3H), 2.78 (m, 2H), 3.71 (d, 1H, J 3,4
(m, 2H), 4.71 (d, 1H, J 2,NH ) 9.0 Hz), 5.12 (2H, J gem ) 12.2
Hz), 5.70 (d, 1H, exchangeable with D2O), 7.36 (s, 5H); 13C
NMR (75 MHz, CDCl3) δ 14.1, 15.4, 54.5, 61.7, 61.9, 67.5, 67.9,
70.6, 81.1, 128.2, 128.3, 128.6, 136.0, 157.1, 170.7, 172.3; IR
(film) 3390, 1740, 1520 cm-1; mass spectrum (HRCI) calcd for
C19H28NO8 m/z 398.1815, found 398.1784.
) 5.8 Hz), 3.81 (s, 3H), 4.84 (ddd, 1H, J 3,NH ) 8.1 Hz, J 3,2
)
1-Ben zyl 5-Meth yl (2S,3S,4S)-3-(Ben zyloxy)-2-[N-(ben -
zyloxyca r bon yl)a m in o]-4-h yd r oxyp en ta n ed ioa te (35). To
a solution of 27 (116 mg, 0.4 mmol) in CHCl3 (1.5 mL) and
benzyl alcohol (1.5 mL) was added at 0 °C under nitrogen boron
trifluoride etherate (60 µL, 0.48 mmol). The reaction mixture
was stirred for 30 min at rt and then heated at 60 °C for 2 h.
After being cooled to 0 °C, the solution was worked up in the
manner described for 31 and 32. The resulting crude product
was purified by chromatography on silica gel (heptane-ethyl
acetate 9:1 followed by 3:1) affording 35 (80 mg, 39%) as a
colorless oil: 1H NMR (250 MHz, CDCl3) δ 3.70 (s, 3H), 3.86
(m, 1H, exchangeable with D2O), 4.14 (m, 1H), 4.17 (d, 1H,
J gem ) 11.0 Hz), 4.23 (dd, 1H, J 2,3 ) 1.3 Hz, J 3,4 ) 8.4 Hz),
4.30 (d, 1H), 4.82 (dd, 1H, J 2,NH ) 9.1 Hz), 5.12 (s, 2H), 5.14
(s, 2H), 5.71 (d, 1H, exchangeable with D2O), 7.25-7.37 (m,
15H); 13C NMR (75 MHz, CDCl3) δ 53.1, 55.2, 68.2, 68.4, 71.0,
74.6, 81.3, 128.5, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2, 129.3,
129.4, 135.4, 136.4, 137.5, 157.7, 171.0, 173.1; IR (film) 3425,
3350, 1730, 1520 cm-1; mass spectrum (CI) m/z 490 (MH -
H2O)+.
6.2 Hz), 5.25 (d, 1H, J 2,3 ) 6.5 Hz), 7.00 (d, 1H, exchangeable
with D2O); 13C NMR (62.5 MHz, CDCl3) δ 14.2, 22.8, 25.4, 45.0,
53.0, 53.7, 77.4, 167.9, 170.7, 172.3; IR (film) 3280, 1790, 1748,
1665, 1545 cm-1; mass spectrum (CI) m/z 262 (MH)+. Anal.
Calcd for C7H11NO5‚0.02C7H16: C, 46.32; H, 5.88; N, 5.31; S,
12.15. Found: C, 46.57; H, 5.86; N, 5.15; S, 12.48.
Dim eth yl (2S,3S,4S)-2-[N-(Ben zyloxyca r bon yl)a m in o]-
4-h yd r oxy-3-m eth oxyp en ta n e-1,5-d ioa te (31) a n d Meth yl
(2S,3S,4S)-Tetr a h yd r o-4-[N-(ben zyloxyca r bon yl)a m in o]-
3-m eth oxy-5-oxo-2-fu r a n ca r boxyla te (32). To a solution
of 27 (96 mg, 0.33 mmol) in anhydrous methanol (7 mL) was
added at 0 °C under nitrogen boron trifluoride etherate (80
µL, 0.65 mmol). The reaction mixture was allowed to come to
rt, stirring was maintained for 30 min, and the reaction
mixture was then heated to 50 °C for 90 min. After being
cooled to 0 °C, the solution was diluted with ethyl acetate (15
mL), saturated aqueous NaHCO3 was added (5 mL), and the
phases were separated. The aqueous phase was further
extracted with ethyl acetate (2 × 10 mL), and the combined
organic extracts were dried over Na2SO4. Removal of the
solvent under reduced pressure left an oily residue which was
purified by chromatography on silica gel using heptane-ethyl
acetate (1:1) as eluent. Lactone 32 (16 mg, 15%), a colorless
1-Ben zyl 5-Meth yl (2S,3S,4S)-4-Acetoxy-3-(ben zyloxy)-
2-[N-(ben zyloxyca r bon yl)a m in o]p en ta n ed ioa te (36).
A
solution of 35 (56 mg, 0.11 mmol) in pyridine (2 mL) and acetic
anhydride (0.3 mL) was kept at 5 °C for 3 days. The solvents
were then removed under reduced pressure, and the residue
was purified by chromatography on silica gel (heptane-ethyl
oil, was the first product to be eluted: [R]22 +9.0° (c 1.0,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 3.50 (s, 3H), 3.86 (s, 3H),
4.23 (dd, 1H), 4.32 (dd, 1H, J 3,4 ) 5.5 Hz, J 4,NH ) 7.7 Hz), 4.77
(d, 1H, J 2,3 ) 4.5 Hz), 5.14 (s, 2H), 5.50 (d, 1H, exchangeable
with D2O), 7.35 (s, 5H); IR (film) 3356, 1800, 1740, 1718, 1525
cm-1; mass spectrum (HREI) calcd for C15H17NO7 m/z 323.1004,
found 323.1008.
acetate 3:1), yielding 36 (55 mg, 91%) as a colorless oil: [R]22
D
1
-5.6° (c 0.25, CHCl3); H NMR (250 MHz, CDCl3) δ 2.11 (s,
3H), 3.67 (s, 3H), 4.18 (d, 1H, J gem ) 10.9 Hz), 4.30 (d, 1H),
4.45 (dd, 1H, J 2,3 ) 1.4 Hz, J 3,4 ) 8.4 Hz), 4.74 (dd, 1H, J 2,NH
) 10.0 Hz), 4.98 (d, 1H), 5.10 (s, 2H), 5.13 (s, 2H), 5.53 (d, 1H,
exchangeable with D2O), 7.05-7.37 (m, 15H); 13C NMR (75
MHz, CDCl3) δ 19.9, 52.1, 54.4, 66.8, 67.2, 70.3, 73.8, 77.7,
127.3, 127.4, 127.7, 127.9, 128.0, 128.2, 134.4, 136.0, 155.9,
168.9, 169.1, 169.6; IR (film) 3356, 1750, 1725, 1520 cm-1; mass
spectrum (CI) m/z 550 (MH)+. Anal. Calcd for C30H31NO9: C,
65.57; H, 5.69; N, 2.55. Found: C, 65.35, H, 5.93; N, 2.44.
Continued elution of the column afforded compound 31 (70
mg, 60%), slightly contaminated by its lactonic form 32: 1H
NMR (250 MHz, CDCl3) δ 3.31 (s, 3H), 3.79 (s, 3H), 3.80 (s,
3H), 4.00 (dd, 1H, J 2,3 ) 1.4 Hz, J 3,4 ) 8.3 Hz), 4.10 (d, 1H),
4.86 (dd, 1H, J 2,NH ) 8.9 Hz), 5.13 (s, 2H), 5.66 (d, 1H,
exchangeable with D2O), 7.35 (s, 5H); IR (film) 3390, 1740,
1520 cm-1; mass spectrum (CI) m/z 356 (MH)+.
1-Ben zyl 5-Meth yl (2S,3R,4S)-2,3-[N-(Ben zyloxyca r bo-
n yl)im in o]-4-h yd r oxyp en ta n ed ioa te (37). To a solution of
27 (54 mg, 0.18 mmol) in CHCl3 (1 mL) and benzyl alcohol
(1.5 mL) was added at 0 °C under nitrogen boron trifluoride
etherate (23 µL, 0.18 mmol). The reaction mixture was then
stirred for 3 h at rt and worked up in the manner described
for 31 and 32. The crude product was purified by chromatog-
raphy on silica gel (heptane-ethyl acetate 9:1 followed by 4:1
Diet h yl (2S,3S,4S)-2-[N-(Ben zyloxyca r b on yl)a m in o]-
3-eth oxy-4-h yd r oxyp en ta n e-1,5-d ioa te (33) a n d Eth yl
(2S,3S,4S)-Tetr a h yd r o-4-[N-(ben zyloxyca r bon yl)a m in o]-
3-eth oxy-5-oxo-2-fu r a n ca r boxyla te (34). A solution of 27
(131 mg, 0.45 mmol) in anhydrous ethanol (12 mL) was treated
with boron trifluoride etherate (140 µL, 1.14 mmol) and heated
for 45 h at 70 °C. At the end of the reaction period, the
reaction mixture was cooled to 0 °C and worked up as
described for compounds 31 and 32. Chromatography of the
crude product on silica gel (heptane-ethyl acetate 3:2) afforded
compound 34 (25 mg, 16%), an amorphous white solid as a
minor product: [R]22D +6.8° (c 0.8, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.21 (t, 3H, J ) 6.8 Hz), 1.32 (t, 3H, J ) 7.1 Hz),
3.68 (m, 2H), 4.30 (m, 4H), 4.74 (d, 1H, J 2,3 ) 4.2 Hz), 5.13 (s,
2H), 5.50 (d, 1H, exchangeable with D2O, J 4,NH ) 6.2 Hz), 7.35
(s, 5H); 13C NMR (75 MHz, CDCl3) δ 14.3, 15.4, 57.1, 62.7, 66.6,
67.9, 79.2, 81.8, 128.4, 128.6, 128.8, 157.6, 167.8, 171.4; IR
(film) 3360, 1806, 1730, 1525 cm-1; mass spectrum (CI) m/z
352 (MH)+. Anal. Calcd for C17H21NO7: C, 58.11; H, 6.02; N,
3.99. Found: C, 58.31; H, 6.31; N, 3.97.
and then 2:1) affording 37 (52 mg, 70%) as a colorless oil: [R]22
D
1
-14.6° (c 0.5, CHCl3); H NMR (250 MHz, CDCl3) δ 2.97 (dd,
1H, J 2,3 ) J 3,4 ) 6.6 Hz), 3.16 (m, 1H, exchangeable with D2O),
3.33 (d, 1H), 3.57 (s, 3H), 4.43 (d, 1H), 5.15 (s, 2H), 5.21 (2 ×
d, 2H, J gem ) 12.1 Hz), 7.35-7.37 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 39.3, 44.7, 53.1, 67.9, 68.4, 69.3, 128.6, 128.9, 129.0,
135.3, 135.4, 161.2, 166.9, 171.8; IR (film) 3480, 1740 cm-1
;
mass spectrum (CI) m/z 400 (MH)+. Anal. Calcd for C21H21
-
NO7: C, 63.15; H, 5.30; N, 3.51. Found: C, 62.87; H, 5.44; N,
3.64.
Ack n ow led gm en t. We thank the French Ministry
of Defence for generous financial support (Contract No.
93/133) and for a fellowship (P.D.) as well as Prof. P.
Potier for discussions and encouragement.
Continued elution of the chromatography column yielded
the major product, compound 33 (105 mg, 58%), as an oil,
slightly contaminated by 34: 1H NMR (250 MHz, CDCl3) δ
1.07 (t, 3H, J ) 7.0 Hz), 1.30 (2 × t, 6H, J ) 7.1 Hz), 3.45 (m,
2H), 3.91 (m, 1H, exchangeable with D2O), 4.07 (m, 2H), 4.24
J O951983Z