2,3-Aziridino-2,3-dideoxy-D-ribono-γ-lactone 5-Phosphonate: Stereocontrolled Synthesis from D-Lyxose and Unusual Aziridine Ring Opening

Article abstract of DOI:10.1021/jo9623494

The synthesis of (1R,4S,5S)-N-(benzyloxycarbonyl)-4-[(diethoxyphosphinyl)methyl]-3-oxa-6- azabicyclo[3.1.0]hexan-2-one (23), a new member of the 2,3-aziridino γ-lactone family of compounds, was achieved in 15 steps from D-lyxose. Like all aziridino γ-lactones known so far, 23 reacted with a soft nucleophile (ethanethiol) to give exclusively the product of aziridine ring opening at C-2 (24). On the other hand, hard nucleophiles (alcohols) did not react directly with the aziridine ring of 23 but appeared to promote intramolecular attack of the aziridine ring at C-3 by the C-5 phosphonate group, resulting, after hydrolytic workup, in formation of the 2-amino-3-hydroxy-D-ribono-1,4-lactone derivatives 25 and 26, instead of the expected 2-amino-3-alkoxy-D-xylono-1,4-lactone derivatives.

Full text of DOI:10.1021/jo9623494

J . Org. Chem. 1997, 62, 4277-4284
4277
2,3-Azir id in o-2,3-d id eoxy-D-r ibon o-γ-la cton e 5-P h osp h on a te:
Ster eocon tr olled Syn th esis fr om D-Lyxose a n d Un u su a l Azir id in e
Rin g Op en in g
Philippe Dauban† and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Received December 16, 1996X
The synthesis of (1R,4S,5S)-N-(benzyloxycarbonyl)-4-[(diethoxyphosphinyl)methyl]-3-oxa-6-azabicyclo-
[3.1.0]hexan-2-one (23), a new member of the 2,3-aziridino γ-lactone family of compounds, was
achieved in 15 steps from D-lyxose. Like all aziridino γ-lactones known so far, 23 reacted with a
soft nucleophile (ethanethiol) to give exclusively the product of aziridine ring opening at C-2 (24).
On the other hand, hard nucleophiles (alcohols) did not react directly with the aziridine ring of 23
but appeared to promote intramolecular attack of the aziridine ring at C-3 by the C-5 phosphonate
group, resulting, after hydrolytic workup, in formation of the 2-amino-3-hydroxy-D-ribono-1,4-lactone
derivatives 25 and 26, instead of the expected 2-amino-3-alkoxy-D-xylono-1,4-lactone derivatives.
In tr od u ction
cyclic analogues8-12 have been shown to have a highly
favorable influence on brain penetration and conse-
quently on in vivo activity. To date, however, very few
studies concerning the synthesis of mono- and, especially,
disubstituted derivatives of D-AP5 have been re-
ported.10,13-15
Dysfunction or hyperactivity of the N-methyl-D-aspar-
tate (NMDA) receptor, one of three subclasses of iono-
tropic glutamate receptors of the central nervous system,1
has been implicated in a large number of neurological
disorders (e.g., epilepsy, Huntington’s chorea, Alzheimer’s
and Parkinson’s disease, AIDS-related dementia, and
ischemic events resulting from stroke or cerebral
trauma).2,3 The development of compounds that can
antagonize the action of glutamate at this receptor thus
represents an important objective for the treatment of
such disorders. Presently, one of the major classes of
NMDA receptor antagonists consists of molecules belong-
ing to the (R)-2-amino-5-phosphonopentanoic acid (D-AP5,
1) family.4 While these compounds may be considered
isosteres of L-glutamic acid, they are distinguished from
the latter in having the non-natural (i.e., D) configuration,
the L isomer of AP5 being less active.
We have recently described the synthesis of 3,4-
disubstituted L-glutamic acid derivatives of type 3 by
Lewis acid-catalyzed nucleophilic ring opening of the 2,3-
aziridino γ-lactone 4-carboxylate 2, the latter having, in
turn, been synthesized from D-ribose (Scheme 1).16 Com-
pound 2 and other 2,3-aziridino γ-lactones17,18 demon-
strate remarkable regioselectivity with respect to nu-
cleophilic attack of the aziridine ring, with soft nucleo-
philes reacting exclusively at the C-2 position while hard
nucleophiles give the products of ring opening at C-3. In
order to apply this methodology to the preparation of 3,4-
disubstituted D-AP5 derivatives (i.e., of type 4, Scheme
1), two major modifications needed to be brought to the
starting 2,3-aziridino γ-lactone. The first was generation
of such a derivative having the ribo configuration (as in
5) rather than the lyxo configuration (as in 2). The ribo
The possibility of synthesizing variously substituted
analogues of D-AP5 is essential for the discovery of more
active and/or more selective ligands. For example, while
the highly polar character of D-AP5 severely limits its
penetration into the brain,5 the introduction of unsat-
uration6,7 on the D-AP5 backbone as well as formation of
(6) Fagg, G. E.; Olpe, H.-R.; Pozza, M. F.; Baud, J .; Steinmann, M.;
Schmutz, M.; Portet, C.; Baumann, P.; Thedinga, K.; Bittiger, H.;
Allgeier, H.; Heckendorn, R.; Angst, C.; Brundish, D.; Dingwall, J . G.
Br. J . Pharmacol. 1990, 99, 791.
(7) Sills, M. A.; Fagg, G.; Pozza, M.; Angst, C.; Brundish, D. E.; Hurt,
S. D.; Wilusz, E. J .; Williams, M. Eur. J . Pharmacol. 1991, 192, 19.
(8) Lehmann, J .; Hutchinson, A. J .; McPherson, S. E.; Mondadori,
C.; Schmutz, M.; Sinton, C. M.; Tsai, C.; Murphy, D. E.; Steel, D. J .;
Williams, M.; Cheney, D. L.; Wood, P. L. J . Pharmacol. Exp. Ther.
1988, 246, 65.
(9) Whitten, J . P.; Muench, D.; Cube, R. V.; Nyce, P. L.; Baron, B.
M.; McDonald, I. A. Bioorg. Med. Chem. Lett. 1991, 1, 441.
(10) Bigge, C. F.; Wu, J .-P.; Drummond, J . T.; Coughenour, L. L.;
Hanchin, C. M. Bioorg. Med. Chem. Lett. 1992, 2, 207.
(11) Whitten, J . P.; Cube, R. V.; Baron, B. M.; McDonald, I. A.
Bioorg. Med. Chem. Lett. 1993, 3, 19.
(12) Ornstein, P. L.; Schaus, J . M.; Chambers, J . W.; Huser, D. L.;
Leander, J . D.; Wong, D. T.; Paschal, J . W.; J ones, N. D.; Deeter, J . B.
J . Med. Chem. 1989, 32, 827.
(13) Whitten, J . P.; Baron, B. M.; Muench, D.; Miller, F.; White, H.
S.; McDonald, I. A. J . Med. Chem. 1990, 33, 2961.
(14) Whitten, J . P.; Baron, B. M.; McDonald, I. A. Bioorg. Med.
Chem. Lett. 1993, 3, 23.
(15) Rudisill, D. E.; Whitten, J . P. Synthesis 1994, 851.
(16) Dauban, P.; Chiaroni, A.; Riche, C.; Dodd, R. H. J . Org. Chem.
1996, 61, 2488.
(17) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J . Org. Chem.
1994, 59, 434.
(18) Dauban, P.; Dubois, L.; Tran Huu Dau, E.; Dodd, R. H. J . Org.
Chem. 1995, 60, 2035.
† Present address: Laboratoire des Re´actions Organiques Se´lectives,
Institut de Chimie Mole´culaire d’Orsay, URA-CNRS 1497, 91405 Orsay
Cedex, France.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) For reviews, see: Watkins, J . C.; Krogsgaard-Larsen, P.; Honore´,
T. Trends Pharmacol. Sci. 1990, 11, 25. Nakanishi, S. Science 1992,
258, 597. Bigge, C. F. Biochem. Pharmacol. 1993, 45, 1547. Kalb, R.
G. Neuroscientist 1995, 1, 60.
(2) Watkins, J . C. In The NMDA Receptor; Watkins, J . C., Collin-
gridge, G. L., Eds.; IRL Press at Oxford University Press: Oxford, 1989.
(3) Li, J .-H.; Bigge, C. F.; Williamson, R. M.; Borosky, S. A.;
Vartanian, M. G.; Ortwine, D. F. J . Med. Chem. 1995, 38, 1955 and
references therein.
(4) Evans, R. H.; Francis, A. A.; J ones, A. W.; Smith, D. A. S.;
Watkins, J . C. Br. J . Pharmacol. 1982, 75, 65.
(5) Meldrum, B. S.; Croucher, M. J .; Czuczwar, S. J .; Collins, J . F.;
Curry, K.; J oseph, M.; Stone, T. W. Neuroscience 1983, 9, 925.
Lehmann, J .; Schneider, J .; McPherson, S.; Murphy, D. E.; Bernard,
P.; Tsai, C.; Bennett, D. A.; Pastor, G.; Steel, D. J .; Boehm, C.; Cheney,
D. L.; Liebman, J . M.; Williams, M.; Wood, P. L. J . Pharmacol. Exp.
Ther. 1987, 240, 737.
S0022-3263(96)02349-3 CCC: $14.00 © 1997 American Chemical Society

4278 J . Org. Chem., Vol. 62, No. 13, 1997
Dauban and Dodd
Sch em e 1. Syn th esis of 3,4-Disu bstitu ted
L-Glu ta m ic Acid Der iva tives via
Sch em e 2. P r ep a r a tion of th e 5-P h osp h on o
2,3-Diol P r ecu r sor 10a
Azir id in e-γ-la cton e Ch em istr y a n d Retr osyn th etic
Sch em e for th e P r ep a r a tion of 3,4-Disu bstitu ted
Der iva tives of D-AP 5(1)
a
Key: (a) EtOH, HCl; (b) acetone, HCl (54%); (c) I2, PPh3,
configuration would then assure generation of a D(rather
than an L)-R-amino acid after nucleophilic opening of the
aziridine ring at C-3 (via an SN2 process) and of the
lactone. Such a ribo configuration should normally be
obtained if the methodology developed for the synthesis
of 2 is applied to D-lyxose. Incorporation of a 5-phospho-
nate moiety in the ribo aziridino γ-lactone structure, as
in 5, was the second modification to be envisaged. In
this paper, then, we describe the successful synthesis of
the diethyl phosphonate N-Cbz derivative of 5 (i.e., 23)
and present results concerning the unusual reactivity
pattern of this compound toward certain nucleophiles.
imidazole, toluene, 80 °C, 1.5 h (R ) Me, 75%, R ) Et, 78%); (d)
P(OEt)3, 160 °C, 24 h (R ) Me, 82%; R ) Et, 85%); (e) I2, EtOH,
reflux, 10 h (R ) Et, 66% based on consumed SM).
1
had an identical H NMR spectrum and optical rotation
as that prepared by the sodium iodide method. Com-
pound 7 was then subjected to a Michaelis-Arbuzov
reaction with triethyl phosphite using the modified
procedure of Yamamoto and co-workers,20 affording phos-
phonate 8 in excellent yield (85%).
With the phosphonate group in place, attention was
next turned to incorporation of the 2,3-aziridine func-
tionality. Attempted hydrolysis of the 2,3-O-isopropy-
lidene moiety of 8 using a variety of acidic conditions
(differing proportions of trifluoroacetic acid-water or
hydrochloric acid-water, with or without heating) gave
only mediocre yields of the desired diol 9. Szarek and
co-workers23 have described the use of iodine in refluxing
methanol as an efficient way of cleaving carbohydrate
acetals. Application of this technique to 8, however, led
to complete recovery of starting material even after
prolonged reflux. When methanol was replaced by
higher-boiling ethanol in this reaction, complete cleavage
of the isopropylidene group was finally obtained, as
indicated by the 1H NMR spectrum of the reaction
mixture. However, this spectrum also showed that two
compounds, the expected diol 9 and the product of
transacetalization of the latter, 10, had been formed in
almost equal proportion. Though longer reaction times
resulted in increased proportions of the ethyl anomer 10,
overall yields of diol suffered. Because 9 and 10 could
not be separated by chromatography, the sequence of
reactions was repeated using the ethyl furanoside 11
(prepared in one pot by reacting D-lyxose with ethanol
and HCl at 60 °C for 30 min and then with acetone at 20
°C for 24 h)24 as starting material. Thus, 11 was
iodinated at C-5 to give 12, which in turn underwent a
Michaelis-Arbuzov reaction, affording 13. Finally treat-
ment of 13 with iodine for 10 h in refluxing ethanol
provided diol 10 in moderate (40%) yield together with
unreacted 13 (40%), which could be recycled after chro-
matographic separation of the two compounds.
Resu lts a n d Discu ssion
P r ep a r a tion of th e 2,3-a zir id in o-γ-r ibon ola cton e
5-p h osp h on a te 23. On the basis of our previous experi-
ence in synthesizing aziridino-γ-lactone 2, it was judged
more expedient to incorporate the C-5 phosphonate group
on the sugar moiety before constructing the aziridine ring
or introducing any of the substituents (azide, tosyl)
necessary for this purpose for two reasons. First, the
introduction of a phosphonate group would most likely
require the use of phosphite reagents, incompatible with
an azide functionality due to the possibility of Staudinger-
type processes. Secondly, a reactive aziridine ring would
probably not withstand the harsh phosphonylation condi-
tions encountered, for example, in an Arbuzov reaction.
The efficient synthesis of methyl 5-deoxy-5-C-(diethoxy-
phosphinyl)-2,3-O-isopropylidene-â-D-ribofuranoside via
a Michaelis-Arbuzov reaction of triethyl phosphite with
its 5-iodoribofuranoside precursor has been reported.19,20
We thus chose to apply this chemistry to the lyxo series
in order to prepare the required phosphonate precursor
8 (Scheme 2) using as starting material methyl 2,3-O-
isopropylidene-R-D-lyxofuranoside (6).21 The 5-iodo de-
rivative 7 has previously been prepared in two steps from
6 by tosylation of the free hydroxy group followed by
reaction with sodium iodide at 115 °C for 66 h in a Parr
bomb.21 However, compound 7 can be prepared more
conveniently and in as high yield (75%) by treating 6 with
iodine, triphenylphosphine, and imidazole in toluene at
80 °C for 1.5 h.22 Compound 7 obtained in this manner
We have previously found 2,3-cyclic sulfite derivatives
of ribofuranosides to be excellent substrates for the
(19) Parikh, J . R.; Wolff, M. E.; Burger, A. J . Am. Chem. Soc. 1957,
79, 2778.
(20) Yamamoto, H.; Harada, M.; Inokawa, S.; Seo, K.; Armour, M.-
A.; Nakashima, T. Carbohydr. Res. 1984, 127, 35.
(21) Lerner, L. M. Carbohydr. Res. 1977, 53, 177.
(22) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866.
(23) Szarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R. Tetra-
hedron Lett. 1986, 27, 3827.
(24) Adapted from the procedure for the preparation of the ribo
analogue of 6: Levene, P. A.; Stiller, E. T. J . Biol. Chem. 1934, 104,
299.

2,3-Aziridino-2,3-dideoxy-D-ribono-γ-lactone 5-Phosphonate
J . Org. Chem., Vol. 62, No. 13, 1997 4279
Sch em e 3. In tr od u ction of th e C-3 Azid e F u n ction
a n d Sequ en ce of P r otection /Dep r otection
Rea ction sa
Sch em e 4. P r ep a r a tion of th e 2,3-Azir id in o
γ-La cton e 5-P h osp h on a te 23a
a
Key: (a) H2, Pd/C, MeOH, rt, 2.5 h then Et2NH, DMF, 105
°C, 6 h (74%); (b) CbzCl, Et3N, DMF (81%); (c) nBu4NF, CH2Cl2,
-60 °C f 20 °C, 90 min (87%); (d) TPAP, NMO, 4 Å molecular
sieves, CH3CN, 20 °C, 3 h (86%).
a
Key: (a) SOCl2, Et3N, THF, -25 °C, 30 min; (b) RuCl3, NaIO4,
rt, 2.5 h (84% from 10); (c) NaN3, DMF, 60 °C, 2.5 h then H2SO4,
H2O, THF, rt, 2 h (95%); (d) TsCl, pyr (95%); (e) CF3CO2H/H2O
9/1, 50 °C, 5 d; (f) TBDMSCl, imidazole, DMF, rt, 24 h (82% based
on 17).
Completion of the synthesis of the target molecule is
shown in Scheme 4. Compound 19 was efficiently
transformed into the 2,3-aziridine 20 by first reducing,
via catalytic hydrogenation, the azide function to an
amine. The latter, not isolated, was immediately cyclized
to 20 by the action of diethylamine in DMF at 105 °C.
We have previously shown that the benzyloxycarbonyl
moiety is an excellent blocking/activating group for the
NH function of aziridino γ-lactones16,18 and can, moreover,
be easily removed under mild, nonhydrolytic conditions
in the final step of amino acid synthesis. For these
reasons, the N-Cbz derivative of 20 was prepared by
treating the latter with benzyl chloroformate and tri-
ethylamine in DMF. The product, 21, was then desily-
lated using tetrabutylammonium fluoride in dichlo-
romethane, providing aziridinofuranose 22. Oxidation
of the latter with tetrapropylammonium perruthenate30
(TPAP)/4-methylmorpholine N-oxide (NMO) produced the
desired γ-butyrolactone 23 in 86% yield. Spectroscopic
and analytical data for 23 were in complete accord with
the proposed structure. In particular, characteristic
signals for the lactone functionality were observed in the
IR (1800 cm-1) and 13C NMR (168.2 ppm) spectra of 23,
while the 1H NMR spectrum showed the absence of
coupling between H-3 and H-4, indicative of a trans
arrangement for these protons.
selective introduction of an azide function at C-3 of
ribofuranosides, a necessary prelude to formation of the
2,3-aziridine ring.16,25 The cyclic sulfite 14 of the lyxo-
furanoside 2,3-diol 10 was thus prepared by reaction of
the latter with thionyl chloride and triethylamine in THF
at -25 °C for 30 min (Scheme 3).26 However, treatment
of 14 with sodium azide in DMF or HMPA led to
decomposition of starting material at temperatures greater
than 100 °C and no reaction below 100 °C. The chemical
instability of 14 is most probably the result of the acidity
of the C-5 protons, due to the adjacent phosphonate
group. In the presence of a basic reagent such as sodium
azide, this results in parasitic reaction pathways. In
order to increase the leaving group character of the cyclic
sulfite moiety and, thus, hopefully decrease the temper-
ature necessary for displacement by azide anion, com-
pound 14 was oxidized to the cyclic sulfate 15 using
catalytic ruthenium trichloride and sodium metaper-
iodate.27-29 Compound 15, obtained in 84% yield (based
on diol 10), then reacted smoothly with sodium azide in
DMF at 60 °C to give, after acid hydrolysis of the
intermediate 2-sulfate, the desired trans 3-azido-2-hy-
droxy derivative 16.
At this point, the successful transformation of 16 into
an aziridine-γ-lactone required a sequence of protection-
deprotection reactions. Thus, the free 2-hydroxy group
of 16 was first tosylated to give the azido tosylate 17
(Scheme 3), the immediate precursor of the aziridine ring.
Next, replacement of the anomeric protecting group
(ethyl) by an alkylsilyl group was necessary since the
latter, unlike the former, can be removed under condi-
tions mild enough not to affect an aziridine ring (e.g., by
fluoride ion) prior to oxidation to the lactone.16,25 To this
end, the anomeric acetal function of 17 was carefully
hydrolyzed using 9:1 trifluoroacetic acid-water at 50 °C
for 108 h. The furanose product 18 was then O-silylated
by treatment with tert-butyldimethylsilyl chloride and
imidazole in DMF, providing 19 as a 3:2 mixture of R-
Rea ctivity of 23 tow a r d Nu cleop h iles. Before
attempting to prepare D-AP5 analogues of type 4 from
23, we first investigated the behavior of the latter toward
nucleophiles. One of the peculiarities of aziridino γ-lac-
tones is their propensity to react with soft or hard
nucleophiles regioselectively at C-2 or C-3, respectively.
Thus, the aziridino γ-lactone 4-methyl carboxylate 2,16
as well as its 4-(methoxymethyl) analogue,17,18 react with
soft nucleophiles (e.g., thiols) in the presence of a Lewis
acid (boron trifluoride etherate) exclusively at C-2 to give
2-substituted 3-aminobutyrolactones as products. In
contrast, under the same conditions, these aziridino
γ-lactones react with hard nucleophiles (e.g., alcohols) to
give only the products of aziridine ring opening at C-3,
that is, 3-substituted 2-aminobutyrolactones. The latter
are formed via a lactone ring-opened intermediate (i.e.,
of type 3) that, depending on the workup conditions of
the reaction, can recyclize to the lactone form.16,18
We were thus very curious to see if the ribo aziridino
γ-lactone 5-phosphonate 23 was subject to the same
1
and â-anomers, respectively, as estimated by H NMR
spectroscopy.
(25) Dubois, L.; Dodd, R. H. Tetrahedron 1993, 49, 901.
(26) Guiller, A.; Gagnieu, C. H.; Pacheco, H. Tetrahedron Lett. 1985,
26, 6343.
(27) Lohray, B. B. Synthesis 1992, 1035.
(28) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(29) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(30) For a review, see: Ley, S. V.; Norman, J .; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.

4280 J . Org. Chem., Vol. 62, No. 13, 1997
Dauban and Dodd
Sch em e 5. Rea ctivity of th e 2,3-Azir id in o
γ-La cton e 23 tow a r d Rep r esen ta tive Soft a n d Ha r d
Nu cleop h ilesa
Sch em e 7. P r op osed Mech a n ism for F or m a tion of
25 fr om 23
a
Key: (a) EtSH, 2 equiv of BF3‚OEt2, 20 °C, 3 h (87%); (b) ROH,
2 equiv of BF3‚OEt2, 60 °C, 5 h then evaporation and neutralization
with NaHCO3 (R ) Et: 40%; R ) Me: 33%).
Sch em e 6. Str u ctu r a l Elu cid a tion of 26.
Cor r ela tion s betw een H-2, H-3, a n d H-5a for Acetyl
Der iva tive 27 Deter m in ed by 1D-NOESY
Exp er im en ta
chromatography on silica gel, only the product of acetic
acid elimination, furanone 28, could be isolated, further
corroborating the structural assignments of 25, 26, and
27.
Compared to 2, the reaction of ribo aziridino γ-lactone
5-phosphonate 23 with alcohols is thus unusual in two
respects.31 First, regardless of the alcohol used, only the
product arising from opening of the aziridine ring by
hydroxide is obtained. This probably occurs during the
course of the basic, aqueous hydrolytic workup of the
reaction mixture. Secondly, whereas the typical SN2
opening of the aziridine ring of aziridino γ-lactones gives
substituents having a trans relationship at C-2 and C-3,
a cis relationship is observed in the case of products 25
and 26 arising from 23. These observations may be
rationalized by invoking anchimeric assistance by the
phosphonate group of 23 in opening of the aziridine ring
(Scheme 7).32 Thus, as shown in our previous studies,16,18
the first step in the reaction of aziridino γ-lactones with
alcohols in the presence of a Lewis acid is opening of the
lactone ring to give a 4-hydroxy-2,3-aziridino ester. In
the case of compound 23, this would correspond to a
structure of type I. With the resulting release of ring
strain, the oxygen atom of the phosphonate group of
intermediate I is now favorably oriented to participate
in opening of the aziridine ring to give intermediate II.
The latter is apparently insensitive to further nucleo-
philic attack by the alcohol (except for eventual trans-
esterification when an alcohol other than ethanol is used).
Evaporation of the reaction mixture leads, as we have
also previously observed in analogous systems,18 to
relactonization (intermediate III). Base workup would
then provoke hydrolytic cleavage of III, resulting in
introduction of a hydroxy group at C-3 cis to the NCbz
moiety.
a
Key: (a) Ac2O, pyridine, 4 °C, 15 h (100%); (b) silica gel, AcOEt
(78%).
regioselectivity of ring opening as the lyxo aziridino
γ-lactone 4-carboxylate 2. Although a full study of the
reactivity of 23 toward nucleophiles has not yet been
completed, we were very gratified to observe that reaction
of 23 with a representative soft nucleophile, ethanethiol,
gave, in the presence of 2 equiv of BF3 etherate, exclu-
sively the product of C-2 ring opening, 24 (Scheme 5).
The presence of the alkylthio group at C-2 gives rise in
the 1H NMR spectrum to a characteristic high-field
doublet (δ 3.87). The need for an additional equivalent
of BF3 etherate in this reaction is probably due to the
presence of the phosphonate group with which this Lewis
acid can also complex.
In contrast, a surprising result was obtained when 23
was treated with a hard nucleophile, ethanol, in the
presence of 2 equiv of BF3 etherate. A single compound
1
(25) was obtained for which the H NMR data did not
show the expected incorporation of a supplementary
ethoxy group but, instead, suggested the presence of a
hydroxy group at C-3 of the lactone ring. That the latter
was still intact after this reaction was clear from the IR
(which showed a lactone band at 1790 cm-1) and the 13C
NMR spectra (showing a lactone carbonyl resonance at
171.9 ppm) of 25. Interestingly, the use of methanol
instead of ethanol in this reaction also gave a 3-hydroxy
derivative (26) that had for the most part undergone
transesterification to the dimethyl phosphonate. In order
to firmly establish both the regio- and stereochemistry
of 25 and 26, the latter was acetylated to give 27 (Scheme
In conclusion, we have realized the synthesis, from
D-lyxose, of a 2,3-aziridino γ-lactone 5-phosphonate (23),
a potential precursor to novel 3,4-disubstituted analogues
(4) of the non-natural but pharmacologically important
phosphono D-amino acid, D-AP5 (1). Preliminary reactiv-
ity studies of 23 indicate that, like all members of the
aziridino γ-lactone family known so far, nucleophilic
attack by a soft nucleophile (e.g., a thiol) occurs exclu-
sively at C-2. In contrast, whereas hard nucleophiles
1
6). In the H NMR spectrum of crude 27, H-2 appeared
at 4.28 ppm as a pair of doublets due to coupling with
H-3 and NH, a pattern typical of products resulting from
aziridine ring opening at C-3. Surprisingly, NOESY
experiments, which demonstrated correlations between
H-3 and H-5, H-2 and H-5, and H-2 and H-3, proved that
the C-2 and C-3 substituents of 27 (and, by analogy of
25 and 26) were in a cis (i.e., ribo) configuration and trans
to the C-4 substituent. When 27 was subjected to
(31) We have observed that the lyxo analogue of 23 reacts with
alcohols in the expected fashion, i.e., by SN2 nucleophilic opening of
the aziridine ring at C-3, to give the trans-2-amino-3-alkoxybutyro-
lactone derivative, with no participation by the C-5 phosphonate group.
Details of this work will be published elsewhere.
(32) Although unusual, this intramolecular aziridine ring opening
is not entirely unprecedented since Ho and co-workers have described
such a reaction with a benzyl ester group or a carboxamide. Ho, M.;
Chung, J . K. K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513.

2,3-Aziridino-2,3-dideoxy-D-ribono-γ-lactone 5-Phosphonate
J . Org. Chem., Vol. 62, No. 13, 1997 4281
[M + 1+]. Anal. Calcd for C13H25O7P: C, 48.15; H, 7.77; P,
9.55. Found: C, 47.94; H, 7.87; P, 9.44.
(e.g., alcohols) attack aziridino γ-lactones such as 2 at
C-3, such reagents apparently lead, in the case of 23, to
formation of a relatively stable intermediate resulting
from intramolecular attack of the aziridine ring by the
phosphonate group, the overall product of the reaction
being, after hydrolytic workup, cis 2-amino-3-hydroxy-
butyrolactones of type 25. The latter represents a
strategically important synthon (after lactone ring open-
ing) for the preparation of 3,4-dihydroxy and dialkoxy
D-AP5 derivatives of type 4. This goal is currently being
pursued.
E t h yl 5-Deoxy-5-iod o-2,3-O-isop r op ylid en e-r-D-lyxo-
fu r a n osid e (12). A suspension of D-lyxose (4.96 g, 33.0 mmol)
in ethanol (180 mL) containing concentrated HCl (0.3 mL) was
heated at 60 °C for 30 min. The resulting solution was cooled
to 20 °C, stirred overnight, and then concentrated to half
volume under vacuum. Acetone (80 mL) was added to the
reaction mixture, and the latter was stirred for a further 24 h
at 20 °C. The solution was neutralized with triethylamine,
and the solvents were removed under vacuum. The oily
residue was partitioned between ethyl acetate (150 mL) and
water (150 mL), the phases were separated, and the organic
phase was washed with water (100 mL) and dried over Na2-
SO4. Removal of the solvent under vacuum left crude ethyl
2,3-O-isopropylidene-R-D-lyxofuranoside (11, 3.9 g, 54%) as a
colorless oil. Without further purification, the latter was
dissolved in toluene (100 mL), and the solution was treated
with iodine (6.4 g, 25.2 mmol), triphenylphosphine (7.1 g, 27.0
mmol), and imidazole (3.7 g, 54.3 mmol) and heated for 1.5 h
at 80 °C. The reaction mixture was then cooled to rt, the
supernatant phase was removed by decantation, and the pasty
white residue was taken up in ether and water. The excess
iodine was destroyed by addition of sodium thiosulfate pen-
tahydrate to the biphasic mixture, and the phases were
separated. The organic phases were combined and dried over
Na2SO4, and the solvents were removed under vacuum. The
residue was triturated with ether, and the resulting precipitate
of triphenylphosphine oxide was removed by filtration through
Celite. The filtrate was purified by column chromatography
on silica gel (heptane followed by heptane-ethyl acetate 9:1),
Exp er im en ta l Section
Gen er a l Meth od s. 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, which was used as
internal standard except in the case of silylated samples.
Thin-layer chromatography was performed on Merck silica gel
60 plates with fluorescent indicator. The plates were visual-
ized with UV light (254 nm) and 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. Elemental analyses
were performed at the ICSN, CNRS, Gif-sur-Yvette, France.
Meth yl 5-Deoxy-5-iod o-2,3-O-isop r op ylid en e-r-D-lyxo-
fu r a n osid e (7). A solution of compound 621 (5.8 g, 28.4 mmol),
iodine (10.1 g, 39.8 mmol), triphenylphosphine (11.2 g, 42.7
mmol), and imidazole (5.8 g, 85.2 mmol) in toluene (120 mL)
was heated at 80 °C for 1.5 h. The reaction mixture was cooled
to rt, the supernatant phase was removed by decantation, and
the pasty white residue was partitioned between chloroform
and water. Residual iodine was removed by addition of solid
sodium thiosulfate pentahydrate (until disappearance of brown
color), and the phases were separated. The organic phases
(toluene, chloroform) were combined, dried over Na2SO4, and
evaporated to dryness under reduced pressure. The oily
residue was triturated with ether, and the resulting precipitate
of triphenylphosphine oxide was removed by filtration through
Celite. The filtrate was purified by chromatography on silica
gel (heptane followed by heptane-ethyl acetate 9:1), affording
affording compound 12 (4.6 g, 78%) as a colorless oil: [R]25
D
+74.9 (c 2.0, CH3OH); 1H NMR (250 MHz, CDCl3) δ 1.20 (t, J
) 7.1 Hz, 3H), 1.33 (s, 3H), 1.46 (s, 3H), 3.28 (dd, J ) 6.6, 9.6
Hz, 1H), 3.36 (dd, J ) 7.6, 9.6 Hz, 1H), 3.47 (oct, J ) 7.1, 9.7
Hz, 1H), 3.72 (oct, J ) 7.1, 9.7 Hz, 1H), 4.20 (dt, J ) 3.5, 7.0
Hz, 1H), 4.61 (d, J ) 5.8 Hz, 1H), 4.77 (dd, J ) 3.5, 5.8 Hz,
1H), 5.04 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 8.4, 15.6, 25.6,
25.7, 63.4, 80.1, 81.1, 85.9, 106.5, 113.2; mass spectrum (HRCI)
calcd for C10H18IO4 [M + 1+] m/z 329.0251, found m/z 329.0279.
Eth yl 5-Deoxy-5-C-(d ieth oxyp h osp h in yl)-2,3-O-isop r o-
p ylid en e-r-D-lyxofu r a n osid e (13). A solution of compound
12 (9.19 g, 28.0 mmol) in triethyl phosphite (18 mL, freshly
distilled over sodium) was heated at 160 °C under a constant
stream of nitrogen for 30 h, additional triethylphosphite being
added to the reaction mixture after 6 h (6 mL) and 21 h (2
mL) of heating. At the end of the reaction period, the excess
triethyl phosphite was removed by distillation under reduced
pressure, and the residue was purified by column chromatog-
raphy on silica gel (ethyl acetate-heptane 3:1 followed by 4:1
the 5-iodo derivative 7 (6.7 g, 75%) as a colorless oil: [R]25
D
+71.2 (c 3.0, CH3OH) (lit.21 [R]24 +72.6 (c 2.88, CH3OH)); 1H
followed by ethyl acetate), affording compound 13 (8.10 g, 85%)
D
1
as a colorless oil: [R]22 +40.2 (c 0.5, CHCl3); H NMR (250
NMR (250 MHz, CDCl3) δ 1.33 (s, 3H), 1.46 (s, 3H), 3.28 (dd,
J ) 7.0, 9.7 Hz, 1H), 3.34 (s, 3H), 3.36 (dd, J ) 7.5, 9.7 Hz,
1H), 4.20 (pseudo dt, J ) 3.4, 7.1 Hz, 1H), 4.60 (d, J ) 5.8 Hz,
1H), 4.75 (dd, J ) 5.8, 3.4 Hz, 1H), 4.92 (s, 1H); mass spectrum
(EI) m/z 314 [M+].
D
MHz, CDCl3) δ 1.19 (t, J ) 7.0 Hz, 3H), 1.31 (s, 3H), 1.33 (t,
J ) 7.0 Hz, 6H), 1.45 (s, 3H), 2.19 (ddd, J (H,H) ) 6.6, 15.3
Hz, J (H,P) ) 18.0 Hz, 1H), 2.32 (ddd, J (H,H) ) 6.6, 15.3 Hz,
J (H,P) ) 18.0 Hz, 1H), 3.45 (dq, J ) 7.0, 9.7 Hz, 1H), 3.71
(dq, J ) 7.0, 9.7 Hz, 1H), 4.14 (m, 4H), 4.29 (pseudo dq, J )
3.5, 6.8 Hz, 1H), 4.56 (d, J ) 5.8 Hz, 1H), 4.68 (dd, J ) 5.8,
3.5 Hz, 1H), 4.97 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.9,
16.3, 16.4, 25.0, 25.5 (d, J (C,P) ) 140.0 Hz), 26.1, 61.5, 61.9 (2
× d, J (C,P) ) 6.0 Hz), 62.7, 74.6, 80.4 (d, J (C,P) ) 6.6 Hz),
85.2, 105.6, 112.4; IR (film) 1250, 1025, 970 cm-1; mass
spectrum (CI) m/z 339 [M + 1+]. Anal. Calcd for C14H27O7P:
C, 49.70; H, 8.04; P, 9.15. Found: C, 49.43; H, 7.98; P, 9.36.
Eth yl 5-Deoxy-5-C-(d ieth oxyp h osp h in yl)-r-D-lyxofu r a -
n osid e (10). A solution of acetonide 13 (3.05 g, 9.0 mmol) in
absolute ethanol (300 mL) was refluxed in the presence of
iodine (1.60 g, 6.3 mmol). After 3 h, more iodine (700 mg, 2.7
mmol) was added to the reaction mixture, and the latter was
refluxed for an additional 10 h. The solution was then cooled,
sodium thiosulfate pentahydrate (4.50 g, 18.0 mmol) was
added, and the solvent was removed under vacuum. The solid
residue was dissolved in ethyl acetate (150 mL), and the
solution was washed with saturated aqueous NaCl (50 mL).
The aqueous phase was in turn extracted with ethyl acetate
(2 × 200 mL), and the organic phases were combined, dried
Met h yl 5-Deoxy-5-C-(d iet h oxyp h osp h in yl)-2,3-O-iso-
p r op ylid en e-r-D-lyxofu r a n osid e (8). Compound 7 (6.64 g,
21.1 mmol) was dissolved in triethyl phosphite (12 mL, freshly
distilled over sodium), and the solution was heated at 160 °C
under a constant stream of nitrogen. After 15 h, fresh triethyl
phosphite (6 mL) was added to the reaction mixture, and the
latter was heated for a further 9 h. The solvent was then
removed under reduced pressure, and the residue was purified
by chromatography on silica gel (ethyl acetate-heptane 3:1
followed by 4:1 followed by ethyl acetate), providing compound
8 (5.6 g, 82%) as a colorless oil: [R]22 +41.7 (c 1.0, CHCl3);
D
1H NMR (250 MHz, CDCl3) δ 1.31 (s, 3H), 1.34 (t, J ) 7.0 Hz,
6H), 1.45 (s, 3H), 2.21 (ddd, J (H,H) ) 6.6, 15.2 Hz, J (H,P) )
18.0 Hz, 1H), 2.30 (ddd, J (H,H) ) 6.8, 15.3 Hz, J (H,P) ) 18.2
Hz, 1H), 3.33 (s, 3H), 4.13 (m, 4H), 4.51 (pseudo dq, J ) 3.4,
6.7 Hz, 1H), 4.55 (d, J ) 5.8 Hz, 1H), 4.67 (dd, J ) 5.8, 3.4 Hz,
1H), 4.86 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 16.3, 16.4, 25.0,
25.5 (d, J (C,P) ) 140.0 Hz), 26.1, 54.5, 61.5, 61.9 (2 × d, J (C,P)
) 6.0 Hz), 74.6, 84.3 (d, J (C,P) ) 6.8 Hz), 85.1, 106.8, 112.5;
IR (film) 1250, 1025, 970 cm-1; mass spectrum (CI) m/z 325

4282 J . Org. Chem., Vol. 62, No. 13, 1997
Dauban and Dodd
1
over Na2SO4, and evaporated under vacuum. The oily residue
was purified by chromatography on silica gel (ethyl acetate-
ethanol, 99:1 followed by 98:2 followed by 95:5), providing
starting material 13 (1.20 g, 40%) followed by the diol 10 (1.08
g, 40%), obtained as a colorless oil: [R]22D +36.0 (c 0.5, CHCl3);
1H NMR (250 MHz, CDCl3) δ 1.20 (t, J ) 7.0 Hz, 3H), 1.34 (t,
J ) 7.0 Hz, 6H), 2.21 (ddd, J (H,H) ) 5.5, 15.2 Hz, J (H,P) )
18.7 Hz, 1H), 2.33 (ddd, J (H,H) ) 7.3, 15.2 Hz, J (H,P) ) 18.7
Hz, 1H), 3.48 (dq, J ) 7.0, 9.5 Hz, 1H), 3.71 (dq, J ) 7.0, 9.5
Hz, 1H), 4.00 (d, J ) 7.0 Hz, 1H, exchangeable with D2O), 4.13
(m, 5H), 4.34 (m, 1H), 4.40 (m, 1H), 4.53 (d, J ) 4.8 Hz, 1H,
exchangeable with D2O), 4.96 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 15.3, 16.5, 16.6, 26.5 (d, J (C,P) ) 140.0 Hz), 62.3
and 62.5 (2 × d, J (C,P) ) 6.7 Hz), 63.8, 71.5 (d, J (C,P) ) 4.0
as a colorless oil: [R]22 +70.6 (c 0.5, CHCl3); H NMR (250
D
MHz, CDCl3) δ 1.21 (t, J ) 7.0 Hz, 3H), 1.34 (2 × t, J ) 7.0
Hz, 6H), 2.24 (ddd, J (H,H) ) 4.0, 15.4 Hz, J (H,P) ) 17.5 Hz,
1H), 2.38 (ddd, J (H,H) ) 6.2, 15.4 Hz, J (H,P) ) 18.5 Hz, 1H),
3.49 (dq, J ) 7.0, 9.4 Hz, 1H), 3.72 (dq, J ) 7.0, 9.4 Hz, 1H),
3.85 (d, J ) 5.4 Hz, 1H), 4.13 (m, 5H), 4.24 (pseudo q, J ) 7.0
Hz, 1H), 4.99 (s, 1H), 5.23 (m, 1H, exchangeable with D2O);
13C NMR (75 MHz, CDCl3) δ 14.9, 16.3, 16.4, 30.0 (d, J (C,P) )
140.0 Hz), 61.8 and 62.5 (2 × d, J (C,P) ) 6.7 Hz), 63.0, 70.7
(d, J (C,P) ) 4.5 Hz), 76.9, 80.9, 107.9; IR (film) 3340, 2110,
1250, 1030, 970 cm-1; mass spectrum (CI) m/z 324 [M + 1+].
Anal. Calcd for C11H22N3O6P: C, 40.85; H, 6.86; N, 13.00; P,
9.59. Found: C, 41.15; H, 6.95; N, 12.85; P, 9.36.
Eth yl 3-Azid o-3,5-d id eoxy-5-C-(d ieth oxyp h osp h in yl)-
2-O-tosyl-r-D-a r a bin ofu r a n osid e (17). A solution of com-
pound 16 (2.49 g, 7.7 mmol) and p-toluenesulfonyl chloride
(5.15 g, 27.0 mmol) in anhydrous pyridine (45 mL) was stirred
for 90 h at 20 °C under nitrogen. The reaction mixture was
concentrated under vacuum, and the residue was partitioned
between ethyl acetate (150 mL) and water (150 mL). The
phases were separated, and the organic phase was dried over
Na2SO4. Evaporation of the solvent left the crude product,
which was purified by chromatography on silica gel (heptane-
Hz), 75.1, 77.0, 107.6; IR (film) 3380, 1220, 1030, 970 cm-1
;
mass spectrum (CI) m/z 299 [M + 1+]. Anal. Calcd for
C11H23O7P: C, 44.30; H, 7.77; P, 10.38. Found: C, 44.13; H,
7.84; P, 9.98.
E t h yl 5-Deoxy-5-C-(d iet h oxyp h osp h in yl)-2,3-O-su lfi-
n yl-r-D-lyxofu r a n osid e (14). To a solution of diol 10 (2.65
g, 8.88 mmol) and triethylamine (5.0 mL, 35.5 mmol) in THF
(100 mL) held at -25 °C was added dropwise over 15 min a
solution of freshly distilled thionyl chloride (1.3 mL, 17.8 mmol)
in THF (5 mL). After completion of the addition, the reaction
mixture was stirred for 15 min at -25 °C and then diluted
with ethyl acetate (100 mL). Saturated aqueous NaCl solution
(100 mL) was added, the phases were separated, and the
organic phase was washed with saturated aqueous NaCl
solution (100 mL). The organic phase was dried over Na2SO4,
and the solvent was removed under vacuum, leaving crude 14
(3.03 g, 98%) as an oil that was used in the following step
without further purification: 1H NMR (250 MHz, CDCl3) δ 1.21
(t, J ) 7.0 Hz, 3H), 1.35 (t, J ) 7.0 Hz, 6H), 2.29 (m, 2H), 3.51
(m, 1H), 3.75 (m, 1H), 4.15 (m, 4H), 4.54 (m, 1H), 5.07 (d, J )
5.3 Hz, 0.5 H), 5.08 (s, 0.5 H), 5.25 (d, J ) 6.1 Hz, 0.5 H), 5.27
(s, 0.5 H), 5.33 (dd, J ) 6.1, 3.6 Hz, 0.5 H), 5.46 (dd, J ) 5.6,
3.6 Hz, 0.5 H); IR (film) 1250, 1220, 1025, 970 cm-1; mass
spectrum (CI) m/z 345 [M + 1+].
Eth yl 5-Deoxy-5-C-(d ieth oxyp h osp h in yl)-r-D-lyxofu r a -
n osid e 2,3-Su lfa te (15). A vigorously stirring solution of
sulfite 14 (3.0 g, 8.7 mmol) in acetonitrile (18 mL), carbon
tetrachloride (18 mL), and water (27 mL) was treated with
ruthenium trichloride hydrate (91 mg, 0.44 mmol) and sodium
metaperiodate (3.80 g, 17.8 mmol) for 2.5 h at rt. The reaction
mixture was diluted with water (60 mL) and extracted with
dichloromethane (3 × 100 mL), and the combined organic
extracts were dried over Na2SO4. The residue left after
removal of the solvents in vacuo was purified by flash
ethyl acetate 1:2), affording pure 17 (3.52 g, 95%) as a colorless
oil: [R]22 +59.2 (c 1.0, CHCl3); H NMR (250 MHz, CDCl3) δ
1
D
1.15 (t, J ) 7.0 Hz, 3H), 1.33 (t, J ) 7.0 Hz, 6H), 2.11 (ddd,
J (H,H) ) 6.7, 15.1 Hz, J (H,P) ) 18.7 Hz, 1H), 2.21 (ddd,
J (H,H) ) 6.7, 15.1 Hz, J (H,P) ) 18.4 Hz, 1H), 2.47 (s, 3H),
3.37 (dq, J ) 7.0, 9.6 Hz, 1H), 3.66 (dq, J ) 7.0, 9.6 Hz, 1H),
3.80 (dd, J ) 2.5, 6.6 Hz, 1H), 4.12 (m, 5H), 4.66 (d, J ) 2.5
Hz, 1H), 4.98 (s, 1H), 7.39 (d, J ) 8.2 Hz, 2H), 7.83 (d, J ) 8.2
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 14.7, 16.3, 16.4, 21.7,
30.3 (d, J (C,P) ) 140.0 Hz), 61.9 and 62.1 (2 × d, J (C,P) ) 6.5
Hz), 63.3, 69.3 (d, J (C,P) ) 9.7 Hz), 76.3, 87.7, 104.3, 128.1,
130.2, 132.6, 145.7; IR (film) 2113, 1372, 1192, 1180, 1253,
1029, 965 cm-1; mass spectrum (CI) m/z 478 [M + 1+]. Anal.
Calcd for C18H28N3O8PS: C, 45.28; H, 5.91; N, 8.80; P, 6.49;
S, 6.71. Found: C, 45.07; H, 5.71; N, 8.72; P, 6.23; S, 6.66.
3-Azid o-3,5-d id eoxy-5-C-(d ieth oxyp h osp h in yl)-2-O-to-
syl-r,â-D-a r a bin ofu r a n ose (18). A solution of the furanoside
17 (3.78 g, 7.9 mmol) in trifluoroacetic acid and water (80 mL
of a 9:1 mixture) was heated at 50 °C for 54 h. The reaction
mixture was evaporated to dryness under vacuum, the residue
was redissolved in trifluoroacetic acid and water (9:1, 80 mL),
and the solution was heated for a further 54 h at 50 °C. The
solvents were again removed under vacuum, the residue was
dissolved in ethyl acetate (100 mL), and the solution was
washed with aqueous sodium carbonate (50 mL of a 5%
solution). The aqueous phase was extracted with ethyl acetate
(2 × 50 mL), the organic phases were combined and dried over
Na2SO4, and the solvent was removed under vacuum, affording
crude 18 (3.55 g) that was used in the following step without
further purification. An analytical sample of 18 was obtained
by chromatography of the crude material on silica gel (hep-
tane-ethyl acetate 1:3): 1H NMR (250 MHz, CDCl3) δ 1.32
and 1.33 (2 × t, J ) 7.0 Hz, 6H), 2.10-2.34 (m, 2H), 2.47 (s,
3H), 3.86 (dd, J ) 2.4, 6.2 Hz, 0.65 H), 3.96 (m, 0.35 H), 4.12
(m, 4H), 4.31 (dd, J ) 8.1, 6.5 Hz, 0.35 H), 4.33 (m, 0.65 H),
4.57 (dd, J ) 4.2, 8.2 Hz, 0.35 H), 4.66 (d, J ) 2.4 Hz, 0.65 H),
4.93 (m, 0.65 H, exchangeable with D2O), 5.25 (m, 0.35 H),
5.37 (s, 0.65 H), 5.42 (m, 0.35 H, exchangeable with D2O), 7.38
(d, J ) 8.2 Hz, 2H), 7.84 (d, J ) 8.2 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 16.3, 16.4, 21.7, 30.4, 32.2 (2 × d, J (C,P) )
140.0 Hz), 62.2 and 62.5 (2 × d, J (C,P) ) 6.0 Hz), 66.1 and
69.5 (2 × d, J (C,P) ) 10.0 Hz), 74.5, 76.3, 81.9, 87.9, 94.6, 99.8,
128.1, 130.0, 130.2, 132.5, 145.7; IR (film) 3260, 2115, 1368,
1190, 1180, 1220, 1030, 975 cm-1; mass spectrum (CI) m/z 450
[M + 1+]. Anal. Calcd for C16H24N3O8PS: C, 42.76; H, 5.38;
N, 9.35; P, 6.89; S, 7.13. Found: C, 42.92; H, 5.38; N, 9.34; P,
6.71; S, 7.03.
chromatography on silica gel (ethyl acetate), affording 15 (2.70
1
g, 86%) as a pale yellow oil: [R]22 +34.1 (c 1.0, CHCl3); H
D
NMR (250 MHz, CDCl3) δ 1.21 (t, J ) 7.0 Hz, 3H), 1.35 (t, J
) 7.0 Hz, 6H), 2.30 (dd, J (H,H) ) 7.0 Hz, J (H,P) ) 18.6 Hz,
2H), 3.53 (dq, J ) 7.0, 9.6 Hz, 1H), 3.76 (dq, J ) 7.0, 9.6 Hz,
1H), 4.15 (m, 4H), 4.54 (dq, J (H,H) ) 3.3, 7.1 Hz, J (H,P) )
7.1 Hz, 1H), 5.14 (d, J ) 6.0 Hz, 1H), 5.24 (s, 1H), 5.38 (dd, J
) 6.0, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.7, 16.3,
16.4, 25.2 (d, J (C,P) ) 140.0 Hz), 62.1 and 62.4 (2 × d, J (C,P)
) 6.5 Hz), 63.6, 74.1, 83.6 (d, J (C,P) ) 6.7 Hz), 86.3, 103.3; IR
(film) 1397, 1230, 1213, 1030, 970 cm-1; mass spectrum (CI)
m/z 361 [M + 1+]. Anal. Calcd for C11H21O9PS: C, 36.67; H,
5.87; P, 8.60; S, 8.90. Found: C, 36.81; H, 6.02; P, 8.89; S,
8.64.
Eth yl 3-Azid o-3,5-d id eoxy-5-C-(d ieth oxyp h osp h in yl)-
r-D-a r a bin ofu r a n osid e (16). A solution of compound 15
(3.20 g, 8.9 mmol) in DMF (45 mL) was heated at 60 °C for
2.5 h in the presence of sodium azide (1.16 g, 17.8 mmol). The
solvent was removed in vacuo, the solid residue was taken up
in THF (45 mL), and concentrated sulfuric acid (478 µL, 8.9
mmol) followed by water (160 µL, 8.9 mmol) were added. The
solution was stirred for 2 h at rt, and after neutralization by
addition of saturated aqueous sodium hydrogen carbonate, it
was extracted with ethyl acetate (3 × 80 mL). The combined
organic extracts were dried over Na2SO4, the solvents were
removed under vacuum, and the residue was purified by
chromatography on silica gel (ethyl acetate-heptane 3:1
followed by ethyl acetate), affording compound 16 (2.74 g, 95%)
ter t-Bu t yld im et h ylsilyl 3-Azid o-3,5-d id eoxy-5-C-(d i-
eth oxyph osph in yl)-2-O-tosyl-r,â-D-ar abin ofu r an oside (19).
To a solution of compound 18 (3.5 g, 7.8 mmol) in DMF (16
mL) held under nitrogen was added successively imidazole
(1.08 g, 15.8 mmol) and tert-butyldimethylsilyl chloride (1.80
g, 11.95 mmol). The reaction mixture was stirred for 24 h at

2,3-Aziridino-2,3-dideoxy-D-ribono-γ-lactone 5-Phosphonate
J . Org. Chem., Vol. 62, No. 13, 1997 4283
rt. The solvent was then removed under reduced pressure,
the residue was dissolved in ethyl acetate (60 mL), and the
solution was washed with water (40 mL). The organic phase
was dried over Na2SO4, the solvent was removed in vacuo, and
the resulting crude product was purified by chromatography
on silica gel (heptane-ethyl acetate 2:3 followed by 1:2)
providing 19 (3.65 g, 82%) as a colorless oil: 1H NMR (250
MHz, CDCl3) δ 0.04, 0.07, 0.13, and 0.15 (4 × s, 6 H), 0.84 (s,
5.4 H), 0.92 (s, 3.6 H), 1.32 (t, J ) 7.0 Hz, 6 H), 2.00-2.32 (m,
2H), 2.46 (s, 3H), 3.75 (dd, J ) 1.6, 6.0 Hz, 0.6 H), 3.95 (m, 0.4
H), 4.12 (m, 4.4 H), 4.23 (m, 0.6 H), 4.41 (dd, J ) 3.8, 8.1 Hz,
0.4 H), 4.59 (d, J ) 1.9 Hz, 0.6 H), 5.28 (s, 0.6 H), 5.32 (d, J )
3.8 Hz, 0.4 H), 7.38 (2 × d, J ) 8.2 Hz, 2H), 7.83 (2 × d, J )
8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ -4.7, -4.5, 16.3,
16.4, 17.8, 17.9, 21.7, 25.5, 25.6, 30.7, and 34.1 (2 × d, J (C,P)
) 139.0 Hz), 61.8, 62.0, and 62.1 (3 × d, J (C,P) ) 5.0 Hz),
66.8 and 69.2 (2 × d, J (C,P) ) 8.0 Hz), 75.2, 76.7, 82.3, 88.9,
95.0, 100.0, 128.0, 128.1, 130.0, 130.2, 132.7, 132.8, 145.5,
25.6, 25.8, 30.7, and 31.9 (2 × d, J (C,P) ) 138.0 Hz), 42.8 and
44.5 (2 × d, J (C,P) ) 7.8, 4.2 Hz), 44.3, 44.6, 61.9, 62.0, and
62.1 (3 × d, J (C,P) ) 6.5 Hz), 68.1, 68.3, 71.7, 72.3, 95.8, 96.3,
128.2, 128.3, 128.4, 128.5, 135.5, 135.6, 159.5, 161.3; IR (film)
1727, 1257, 1162, 1025, 965 cm-1; mass spectrum (CI) m/z 500
[M + 1+]. Anal. Calcd for C23H38NO7PSi: C, 55.29; H, 7.67;
N, 2.80; P, 6.20. Found: C, 55.41; H, 7.51; N, 2.74; P, 6.07.
2,3-[N-(Ben zyloxyca r b on yl)a zir id in o]-5-C-(d iet h oxy-
p h osp h in yl)-2,3,5-tr id eoxy-r,â-D-r ibofu r a n ose (22). A so-
lution of compound 21 (800 mg, 1.6 mmol) in dichloromethane
(18 mL) was treated at -60 °C under nitrogen with tetrabu-
tylammonium fluoride trihydrate (555 mg, 1.76 mmol). The
reaction mixture was slowly allowed to come to rt over 90 min,
after which time the solvent was removed under reduced
pressure and the residue was purified by chromatography on
silica gel (ethyl acetate) affording compound 22 (535 mg, 87%)
as a white solid that was crystallized from ethyl acetate: mp
131-132 °C; 1H NMR (250 MHz, CDCl3) δ 1.30 (t, J ) 7.0 Hz,
6H), 2.18 (ddd, J (H,H) ) 6.4, 15.2 Hz, J (H,P) ) 18.6 Hz, 1H),
2.34 (ddd, J (H,H) ) 7.4, 15.2 Hz, J (H,P) ) 18.8 Hz, 1H), 3.27
(d, J ) 3.5 Hz, 1H), 3.34 (d, J ) 3.5 Hz, 1H), 4.10 (m, 4H),
4.57 (pseudo dt, J (H,H) ) 6.9 Hz, J (H,P) ) 10.3 Hz, 1H), 5.11
(2 × d, J ) 12.1 Hz, 2H), 5.49 (s, 1H), 5.80 (m, 1H,
exchangeable with D2O), 7.34 (s, 5H); 13C NMR (62.5 MHz,
CDCl3) δ 16.4, 16.5, 31.5 (d, J (C,P) ) 138.0 Hz), 43.0 (d, J (C,P)
) 13.0 Hz), 44.0, 61.0 and 62.4 (2 × d, J (C,P) ) 7.0 Hz), 68.3,
71.2, 95.7, 128.3, 128.4, 128.6, 135.6, 159.6; IR (film) 3250,
1727, 1257, 975 cm-1; mass spectrum (CI) m/z 386 [M + 1+].
Anal. Calcd for C17H24NO7P: C, 52.99; H, 6.28; N, 3.63; P,
8.04. Found: C, 52.92; H, 6.31; N, 3.59; P, 8.15.
145.7; IR (film) 2110, 1372, 1195, 1181, 1256, 1032, 965 cm-1
;
mass spectrum (CI) m/z 564 [M + 1+]. Anal. Calcd for
C22H38N3O8PSSi: C, 46.88; H, 6.80; N, 7.45; P, 5.49; S, 5.69;
Si, 4.97. Found: C, 46.69; H, 6.68; N, 7.41; P, 5.57; S, 5.89;
Si, 5.27.
ter t-Bu t yld im et h ylsilyl 2,3-Azir id in o-5-C-(d iet h oxy-
p h osp h in yl)-2,3,5-tr id eoxy-r,â-D-r ibofu r a n osid e (20). A
solution of compound 19 (3.65 g, 6.48 mmol) in methanol (40
mL) was hydrogenated for 2.5 h at atmospheric pressure in
the presence of 10% palladium on carbon (450 mg). The
reaction mixture was filtered through Celite, and the filtrate
was evaporated under reduced pressure. The oily residue was
then dissolved in DMF (65 mL) and diethylamine (7.5 mL),
and the solution was heated at 105 °C for 6 h. After removal
of the solvents under reduced pressure, the remaining crude
material was purified by chromatography on silica gel (dichlo-
romethane-ethanol 95:5), affording aziridine 20 (1.75 g, 74%)
as a reddish oil: 1H NMR (250 MHz, CDCl3) δ 0.12 and 0.13
(2 × s, 6H), 0.91 (s, 9H), 1.33 (t, J ) 7.0 Hz, 6H), 1.95 (ddd,
J (H,H) ) 7.8, 15.1 Hz, J (H,P) ) 18.6 Hz, 0.7 H), 1.97 (m, 0.3
H), 2.09 (ddd, J (H,H) ) 6.0, 15.1 Hz, J (H,P) ) 19.2 Hz, 0.7
H), 2.12 (m, 0.3 H), 2.65 (d, J ) 2.9 Hz, 1H), 2.74 (d, J ) 3.4
Hz, 0.7 H), 3.03 (m, 0.3 H), 4.13 (m, 4H), 4.30 (m, 0.3 H), 4.43
(pseudo dt, J (H,H) ) 6.0, 8.0 Hz, J (H,P)) 8.0 Hz, 0.7 H), 5.29
(d, J ) 2.0 Hz, 0.3 H), 5.54 (s, 0.7 H); 13C NMR (75 MHz,
CDCl3) δ -4.4, 16.4, 16.5, 18.0, 25.7, 31.7 (d, J (C,P) ) 137.0
Hz), 38.4, 39.1 (d, J (C,P) ) 9.5 Hz), 61.8 (d, J (C,P) ) 6.7 Hz),
73.8, 97.3; IR (film) 3280, 1253, 1150, 1025, 965 cm-1; mass
spectrum (HRCI) calcd for C15H33NO5PSi [M + 1+] m/z
366.1865, found m/z 366.1863.
ter t-Bu t yld im et h ylsilyl 2,3-[N-(Ben zyloxyca r b on yl)-
a zir id in o]-5-C-(d iet h oxyp h osp h in yl)-2,3,5-t r id eoxy-r,â-
D-r ibofu r a n osid e (21). To a solution of aziridine 20 (1.75 g,
4.79 mmol) and triethylamine (1.68 mL, 12.0 mmol) in DMF
(20 mL) was added at 0 °C under nitrogen a solution of benzyl
chloroformate (1.37 mL, 9.6 mmol) in DMF (2 mL). The
reaction mixture was stirred for 30 min at 0 °C and then for
3 h at rt. The solution was diluted with ethyl acetate (40 mL)
and washed with water (25 mL). The organic phase was dried
over Na2SO4, the solvent was removed under vacuum, and the
residue was purified by chromatography on silica gel (hep-
tane-ethyl acetate 1:2 followed by 1:3), affording compound
21 (1.93 g, 81%) as a colorless oil. The R- and â-anomers could
be separated by careful preparative TLC of an aliquot of the
mixture (20 mg; heptane-ethyl acetate 1:3; silica gel), the
faster migrating component corresponding to the R-anomer:
1H NMR (250 MHz, CDCl3) δ 0.13 (s, 6H), 0.90 (s, 9H), 1.32 (t,
J ) 7.0 Hz, 6H), 1.95 (ddd, J (H,H)) 8.3, 15.2 Hz, J (H,P) )
18.4 Hz, 1H), 2.08 (ddd, J (H,H) ) 5.6, 15.2 Hz, J (H,P) ) 19.5
Hz, 1H), 3.31 (dd, J ) 1.2, 4.6 Hz, 1H), 3.44 (d, J ) 4.6 Hz,
1H), 4.11 (m, 4H), 4.61 (ddd, J (H,H) ) 8.3, 5.6 Hz, J (H,P) )
10.2 Hz, 1H), 5.10 (d, J ) 12.3 Hz, 1H), 5.16 (d, J ) 12.3 Hz,
1H), 5.50 (d, J ) 1.2 Hz, 1H), 7.35 (br s, 5H). â-anomer δ )
0.09 (2 × s, 6H), 0.87 (s, 9H), 1.31 (t, J ) 7.0 Hz, 6H), 2.15 (m,
1H), 2.26 (m, 1H), 3.14 (d, J ) 3.5 Hz, 1H), 3.55 (d, J ) 3.5
Hz, 1H), 4.11 (m, 4H), 4.55 (m, 1H), 5.19 (2 × d, J ) 12.1 Hz,
2H), 5.38 (s, 1H), 7.35 (br s, 5H); 13C NMR (75 MHz, CDCl3)
R- and â-anomer δ -4.9, -4.4, -4.2, 16.3, 16.4, 16.5, 17.8, 18.2,
(1R,4S,5S)-N-(Ben zyloxyca r b on yl)-4-[(d iet h oxyp h os-
ph in yl)m eth yl]-3-oxa-6-azabicyclo[3.1.0]h exan -2-on e (23).
A solution of compound 22 (535 mg, 1.39 mmol) in acetonitrile
(18 mL) was treated at 20 °C under nitrogen with 4-methyl-
morpholine N-oxide (245 mg, 2.09 mmol), finely powdered 4
Å molecular sieves (695 mg), and tetrapropylammonium
perruthenate (59 mg, 0.168 mmol). The reaction mixture was
stirred for 3 h, after which time it was concentrated under
reduced pressure. The residue was taken up in ethyl acetate,
and the mixture was filtered through a pad of silica gel,
affording, after removal of the solvent in vacuo, compound 23
(460 mg, 86%) as a colorless oil. An analytically pure sample
of 23 was obtained by chromatography of an aliquot on silica
gel using ethyl acetate as eluent: [R]22 -13.8 (c 0.5, CHCl3);
D
1H NMR (250 MHz, CDCl3) δ 1.33 (t, J ) 7.0 Hz, 6H), 2.18
(ddd, J (H,H) ) 7.8, 15.4 Hz, J (H,P) ) 18.1 Hz, 1H), 2.29 (ddd,
J (H,H) ) 4.9, 15.4 Hz, J (H,P) ) 19.7 Hz, 1H), 3.49 (d, J ) 3.3
Hz, 1H), 3.88 (d, J ) 3.3 Hz, 1H), 4.12 (m, 4H), 4.95 (ddd,
J (H,H) ) 5.1, 7.8 Hz, J (H,P) ) 15.1 Hz, 1H), 5.16 (2 × d, J )
12.1 Hz, 2H), 7.35 (s, 5H); 13C NMR (75 MHz, CDCl3) δ 16.3,
16.4, 30.3 (d, J (C,P) ) 141.0 Hz), 37.8, 44.0 (d, J (C,P) ) 7.0
Hz), 62.4 and 62.5 (2 × d, J (C,P) ) 5.5 Hz), 69.3, 72.7, 128.2,
128.5, 128.7, 134.6, 158.1, 168.2; IR (film) 1800, 1731, 1257,
1025, 970 cm-1; mass spectrum (CI) m/z 384 [M + 1+]. Anal.
Calcd for C17H22NO7P: C, 53.27; H, 5.78; N, 3.65; P, 8.08.
Found: C, 53.55; H, 5.87; N, 3.66; P, 7.79.
3-[N-(Ben zyloxyca r b on yl)a m in o]-5-C-(d iet h oxyp h os-
p h in yl)-2-(e t h ylt h io)-2,3,5-t r id e oxy-D-a r a b in o-1,4-la c-
ton e (24). To a solution of compound 23 (64 mg, 0.167 mmol)
in ethanethiol (2 mL) was added at 20 °C under nitrogen boron
trifluoride etherate (45 µL, 0.366 mmol). The reaction mixture
was stirred for 3 h and then diluted with ethyl acetate (5 mL)
and neutralized by addition of aqueous sodium hydrogen
carbonate (2 mL of a 0.5 M solution). The phases were
separated, the aqueous phase was extracted with ethyl acetate
(2 × 5 mL), and the combined organic phases were dried over
Na2SO4. Removal of the solvents under reduced pressure and
chromatography of the residue on silica gel (ethyl acetate)
provided compound 24 (65 mg, 87%) as a colorless oil: [R]22
D
1
-12.6 (c 0.5, CHCl3); H NMR (250 MHz, CDCl3) δ 1.23 (t, J
) 7.0 Hz, 3H), 1.28 (t, J ) 7.0 Hz, 6H), 2.29 (dd, J (H,H) ) 6.5
Hz, J (H,P) ) 18.5 Hz, 2H), 2.77 (q, J ) 7.3 Hz, 2H), 3.87 (d,
J ) 8.3 Hz, 1H), 4.04 (m, 5H), 4.66 (m, 1H), 5.10 (2 × d, J )
12.2 Hz, 2H), 6.74 (d, J ) 7.7 Hz, 1H, exchangeable with D2O),
7.34 (s, 5H); 13C NMR (75 MHz, CDCl3) δ 14.2, 16.2, 16.3, 25.5,
30.2 (d, J (C,P) ) 140.0 Hz), 46.3, 59.3 (d, J (C,P) ) 13.0 Hz),

4284 J . Org. Chem., Vol. 62, No. 13, 1997
Dauban and Dodd
62.1 and 62.7 (2 × d, J (C,P) ) 6.0 Hz), 67.1, 76.9, 128.2, 128.3,
128.5, 156.1, 172.3; IR (film) 3280, 1793, 1720, 1539, 1230,
1030, 970 cm-1; mass spectrum (CI) m/z 466 [M + 1+]. Anal.
Calcd for C19H28NO7PS: C, 51.23; H, 6.34; N, 3.14; P, 6.96; S,
7.20. Found: C, 51.11; H, 6.28; N, 2.98; P, 6.96; S, 7.08.
2-[N-(Ben zyloxyca r bon yl)a m in o]-2,5-d id eoxy-5-C-(d i-
eth oxyp h osp h in yl)-D-r ibon o-1,4-la cton e (25). A solution
of aziridine 23 (50 mg, 0.13 mmol) in absolute ethanol (5 mL)
was treated at 5 °C under nitrogen with boron trifluoride
etherate (34 µL, 0.27 mmol). The reaction mixture was stirred
for 30 min at 5 °C and for 5 h at 60 °C, after which time it
was evaporated to dryness under reduced pressure. The
residue was dissolved in ethyl acetate (10 mL), and the solution
was neutralized by addition of aqueous sodium hydrogen
carbonate (5 mL of a 0.5 M solution). The phases were
separated, the aqueous phase was extracted with ethyl acetate
(2 × 5 mL), and the combined organic extracts were dried over
Na2SO4. Evaporation of the solvent under reduced pressure
left a crude product that was purified by chromatography on
1H), 3.75 (2 × d, J ) 11.0 Hz, 6H), 4.15 (pseudo t, J ) 6.1 Hz,
1H), 4.59 (pseudo t, J ) 6.5 Hz, 1H), 4.95-5.10 (m, 2H, partly
exchangeable with D2O), 5.11 (s, 2H), 5.95 (d, J ) 5.4 Hz, 1H,
exchangeable with D2O), 7.35 (s, 5H); 13C NMR (75 MHz,
CDCl3) δ 25.2 (d, J (C,P) ) 140.0 Hz), 52.9 and 53.0 (2 × d,
J (C,P) ) 4.6, 6.5 Hz), 57.7, 67.7, 72.9, 76.5, 128.2, 128.4, 128.6,
135.6, 171.9; IR (film) 3310, 1790, 1715, 1535, 1260, 1030 cm-1
;
mass spectrum (CI) m/z 374 [M + 1+].
3-O -Ac e t y l-2-[N -(b e n z y lo x y c a r b o n y l)a m i n o ]-2,5-
d id e oxy-5-C-(d im e t h oxyp h osp h in yl)-D-r ib on o-1,4-la c-
ton e (27) a n d (5S)-3-[N-(Ben zyloxyca r bon yl)a m in o]-5-
(d im eth oxyp h osp h in yl)-2(5H)-fu r a n on e (28). A solution
of compound 26 (19 mg, 0.05 mmol) in pyridine (1 mL) and
acetic anhydride (0.2 mL) was left standing overnight at 4 °C.
The reaction mixture was evaporated to dryness under reduced
pressure (bath temperature < 25 °C), leaving compound 27
(20 mg, 100%) as an oil: 1H NMR (300 MHz, CDCl3) δ 2.12 (s,
3H), 2.22 (dd, J (H,H) ) 6.7 Hz, J (H,P) ) 19.2 Hz, 2H), 3.72 (2
× d, J ) 11.2 Hz, 6H), 4.28 (dd, J ) 4.9, 7.8 Hz, 1H), 5.11 (s,
2H), 5.21 (m, 1H), 5.45 (pseudo t, 1H), 6.39 (d, J ) 7.8 Hz,
1H, exchangeable with D2O), 7.33 (s, 5H); 13C NMR (75 MHz,
CDCl3) δ 20.6, 25.8 (d, J (C,P) ) 144.0 Hz), 52.7 and 53.0 (2 ×
d, J (C,P) ) 6.5 Hz), 56.1, 67.8, 74.1 (d, J (C,P) ) 9.0 Hz), 74.8,
128.3, 128.5, 128.7, 135.9, 169.8, 171.1; IR (film) 3250, 1795,
1740, 1720, 1540, 1225, 1030 cm-1; mass spectrum (CI) m/z
356 [M - CH3CO2H + 1+].
silica gel, providing pure compound 25 (21 mg, 40%) as a
1
colorless oil: [R]26 +26.6 (c 1.0, CHCl3); H NMR (250 MHz,
D
CDCl3) δ 1.34 (t, J ) 7.0 Hz, 6H), 2.22 (ddd, J (H,H) ) 6.3,
15.3 Hz, J (H,P) ) 19.3 Hz, 1H), 2.49 (ddd, J (H,H) ) 7.7, 15.3
Hz, J (H,P) ) 18.4 Hz, 1H), 4.12 (m, 5H), 4.61 (pseudo t, J )
6.3 Hz, 1H), 4.99-5.08 (m, 2H, partly exchangeable with D2O),
5.12 (s, 2H), 5.77 (d, J ) 5.5 Hz, exchangeable with D2O, 1H),
7.35 (s, 5H); 13C NMR (75 MHz, CDCl3) δ 16.3, 16.4, 26.2 (d,
J (C,P) ) 140.0 Hz), 57.9, 62.7 (d, J (C,P) ) 7.0 Hz), 67.7, 73.1
(d, J (C,P) ) 6.0 Hz), 76.7, 128.2, 128.4, 128.6, 171.9; IR (film)
3300, 1790, 1715, 1540, 1220, 1025 cm-1; mass spectrum (CI)
m/z 402 [M + 1+]. Anal. Calcd for C17H24NO8P: C, 50.87; H,
6.03; N, 3.49. Found: C, 50.82; H, 6.03; N, 3.35.
Chromatography of compound 27 on silica gel (ethyl acetate)
gave exclusively the elimination product 28 (14 mg, 78%) also
1
as a colorless oil: [R]26 +8.1 (c 0.33, CHCl3); H NMR (300
D
MHz, CDCl3) δ 2.13 (ddd, J (H,H) ) 7.3, 15.2 Hz, J (H,P) ) 18.3
Hz, 1H), 2.33 (ddd, J (H,H) ) 6.6, 15.2 Hz, J (H,P) ) 18.3 Hz,
1H), 3.78 (d, J ) 11.0 Hz, 3H), 3.81 (d, J ) 11.0 Hz, 3H), 5.21
(s, 2H), 5.32 (pseudo q, J ) 7.2 Hz, 1H), 7.02 (m, 1H), 7.22 (m,
1H), 7.38 (s, 5H); IR (film) 3210, 1768, 1730, 1660, 1545, 1218,
1025 cm-1; mass spectrum (CI) m/z 356 [M + 1+]. Anal. Calcd
for C15H18NO7P: C, 50.71; H, 5.11; N, 3.94. Found: C, 50.69;
H, 5.31; N, 3.68.
2-[N -(Be n zyloxyca r b on yl)a m in o]-2,5-d id e oxy-5-C-
(d im eth oxyp h osp h in yl)-D-r ibon o-1,4-la cton e (26). A so-
lution of aziridine 23 (77 mg, 0.20 mmol) in anhydrous
methanol (6 mL) was heated at 50 ˚C for 5 h in the presence
of boron trifluoride etherate (54 µL, 0.44 mmol). The reaction
mixture was then evaporated to dryness under reduced
pressure, the residue was dissolved in ethyl acetate (5 mL),
and the solution was neutralized with aqueous sodium hydro-
gen carbonate (2 mL of a 0.5 M solution). The phases were
separated, the aqueous phase was extracted with ethyl acetate
(2 × 5 mL), and the combined organic extracts were dried over
Na2SO4. Evaporation of the solvent under reduced pressure
and chromatography of the residue on silica gel (ethyl acetate
followed by ethyl acetate-ethanol 95:5) afforded compound 26
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 suggestions and encouragement.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
spectra of compounds 23 and 25-27 and an H NMR spectrum
of compound 28 (12 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1
(25 mg, 33%) as a colorless oil contaminated with ∼5% (by H
NMR) of the diethoxyphosphinyl and ethoxymethoxyphosphi-
nyl derivatives: [R]26 +29.2 (c 1.0, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 2.21 (ddd, J (H,H) ) 6.7, 15.5 Hz, J (H,P) ) 18.9
Hz, 1H), 2.53 (ddd, J (H,H) ) 7.0, 15.5 Hz, J (H,P) ) 18.5 Hz,
J O9623494