Total synthesis of a thymidine 2-deoxypolyoxin C analogue

Article abstract of DOI:10.1021/jo972116s

The synthesis of the thymidine 2-deoxypolyoxin C analogue 10 from a noncarbohydrate precursor was achieved in 10 steps and 9% yield starting from a chiral, γ,δ-epoxy-β-hydroxy ester 11 readily available from cis-2- butene-1,4-diol. The main steps concern the stereo- and regioselective opening of the epoxide ring by an azide anion, the stereoselective introduction of the thymine base, and the transformation of the primary alcohol to the acid functionality of the final product. Two other approaches have also been investigated.

Full text of DOI:10.1021/jo972116s

J . Org. Chem. 1998, 63, 2601-2608
2601
Tota l Syn th esis of a Th ym id in e 2-Deoxyp olyoxin C An a logu e
Ce´cile Dehoux, Evelyne Fontaine, J ean-Marc Escudier, Michel Baltas,* and
Liliane Gorrichon*
Laboratoire de synthe`se et physicochimie organique, ESA 5068 associe´ au CNRS,
Universite´ Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 4, France
Received November 18, 1997
The synthesis of the thymidine 2-deoxypolyoxin C analogue 10 from a noncarbohydrate precursor
was achieved in 10 steps and 9% yield starting from a chiral γ,δ-epoxy-â-hydroxy ester 11 readily
available from cis-2-butene-1,4-diol. The main steps concern the stereo- and regioselective opening
of the epoxide ring by an azide anion, the stereoselective introduction of the thymine base, and the
transformation of the primary alcohol to the acid functionality of the final product. Two other
approaches have also been investigated.
Chitin (1), the â-1f4-linked polymer of N-acetylglu-
cosamine (GlcNAc), is one of the most common polysac-
charides and one of the major structural components of
the cell wall of most fungi.1 The enzyme chitin synthase
(EC 2.4.1.16)2 catalyses the production of this linear
macromolecule by polymerization of GlcNAc from the
activated precursor UDP-GlcNAc.
Chitin is not found in green plants or vertebrates,3 so
of a general synthetic route to these N-glycosides and
their analogues is a matter of considerable significance.
These important amino acid nucleosides have been
obtained either by degradation of natural polyoxins8 or
by a variety of synthetic approaches. All but one of the
synthetic strategies developed have employed existing
optically active natural products especially carbohy-
drates,9 nucleosides10, and cyclitols.11 Vogel et al.12
reported the first total asymmetric synthesis of the
deoxypolyoxin C compound without using a starting
material from the chiral pool; the synthesis (eq 1) begins
with a Diels-Alder condensation of furan and 1-cyanovi-
nyl (1S′)-camphanate. The chiral auxiliary is recovered
during the third step of the reported synthesis.
that chitin synthase and the cellular mechanisms that
regulate the activity of this enzyme can be considered
excellent targets for pharmaceutical and agricultural
pathogen management. Polyoxins form an important
class of peptidyl nucleosides isolated from the culture
broths of Streptomyces cacaoi var. asoensis4 and were
found to be potent inhibitors of chitin synthase.5 Poly-
oxin D is used as an agricultural antifungal agent to treat
rice sheath blight and pear black spot.6
Since the sugar component of the molecule is common
to all members of the polyoxins as well as to related
classes of compounds (nikkomycins),7 the development
* To whom correspondence should be addressed (M.B.). Tel.: 33 (0)5
61 55 62 93. Fax: 33 (0)5 61 55 60 11. E-mail: baltas@iris.ups-tlse.fr.
(1) Bartnicki-Garcia, S. Annu. Rev. Microbiol. 1968, 22, 87. Cabib,
E.; Shematek, E. M. In Biology of Carbohydrates; Ginsburg, V., Robius,
P. W., Ed.; J ohn Wiley and Sons: New York, 1981; Vol. I, p 51. Cabib,
E. Adv. Enzymol. 1987, 59, 59.
(2) Adams, D. J .; Causier, B. E.; Mellor, K. J .; Keer, V.; Milling, R.;
Dada, J . In Chitin Enzymology; Muzzarelli, R. A. A., Ed.; European
Chitin Society; Ancona, 1993; p 15.
(3) Gooday, G. W. In Biochemistry of Cell Walls and Membranes in
Fungi; Kuhn, P. J ., Trinci, A. P. J ., J ung, M. J ., Goosey, M. W., Copping,
L. G., Eds.; Springer-Verlag: Berlin, 1990; p 61.
(4) Isono, K.; Asahi, K.; Suzuki, S. J . Am. Chem. Soc. 1969, 91, 7490.
Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
(5) Hori, M.; Kakiki, K.; Misato, T. Agric. Biol. Chem. 1974, 38, 691
and 698.
(6) Ko, K. In Pesticide Chemistry: Human Welfare and the Environ-
ment; Miyamoto, J ., Ed.; Pergamon Press: Elmsford, NY, 1983; p 247.
(7) Konig, W. A.; Hahn, H.; Rathmann, R.; Hass, W.; Keckeisen, A.;
Hagenmeier, H.; Bormann, C.; Deheler, W.; Kurt, R.; Zahner, H.
Liebigs Ann. Chem. 1986, 407.
(8) Isono, K. J . Antibiot. 1988, 41, 1711 and references therein.
(9) (a) Naka, T.; Hashizume, T.; Nishimura, M. Tetrahedron Lett.
1971, 12, 95. (b) Ohrui, H.; Kuzuhara, H.; Emoto, S. Tetrahedron Lett.
1971, 12, 4267. (c) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa,
F. Tetrahedron 1990, 46, 265. (d) Garner, P.; Park, J . M. J . Org. Chem.
1990, 55, 3772. (e) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T. J . Chem. Soc., Chem. Commun. 1995, 2127. (f) Dondoni,
A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino, P.; Tegero, T. J .
Org. Chem. 1997, 62, 5497.
(10) Evina, C. M.; Guillerm, G. Tetrahedron Lett. 1996, 37, 163.
(11) Chida, N. Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. J .
Chem. Soc., Chem. Commun. 1994, 111.
(12) Auberson, Y.; Vogel, P. Tetrahedron 1990, 46, 7019.
(13) Escudier, J . M.; Baltas, M.; Gorrichon, L. Tetrahedron Lett.
1992, 33, 1439. Nacro, K.; Baltas, M.; Escudier, J . M.; Gorrichon, L.
Tetrahedron 1997, 53, 659.
(14) Nacro, K.; Baltas, M.; Escudier, J . M.; Gorrichon, L. Tetrahedron
Lett. 1995, 33, 7867.
(15) Devianne, G.; Escudier, J . M.; Baltas, M.; Gorrichon, L. J . Org.
Chem. 1995, 60, 7343.
S0022-3263(97)02116-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/28/1998

2602 J . Org. Chem., Vol. 63, No. 8, 1998
Dehoux et al.
selectivity in the ring opening of 2,3-epoxy-1-alkanol
derivatives under both procedures, with an increase in
regioselectivity in the presence of metal ions Li+, Mg2+
,
Zn2+, or Ti(IV). Under chelating controlled conditions,
the presence of electron-withdrawing groups at the C3
position of the epoxy alcohol dramatically decreases the
C3 selectivity.20 In all cases, introduction of the azido
group takes place with inversion of configuration at the
carbon center. In our hands, when the anti aldol adduct
11 was allowed to react with Ti(O-i-Pr)2(N3)2 complex
formed according to the procedure published by Chouk-
roun and Gervais,21 in dry benzene at 70 °C, a great
number of degradation products were obtained. The
major one (20% yield) has been identified as the isopropyl
5-azido-3,4-dihydroxy-6-[(tert-butyldiphenylsilyl)oxy]hex-
anoate arising from a C5 ring opening of the epoxide ring
and a trans esterification reaction. When compound 11
reacted under nonchelating conditions in the presence
of 5 equiv of sodium azide and 2.5 equiv of NH4Cl in
MeOH/H2O (8/1), four compounds were identified (59%
total yield). Compounds 12, 13a , and 13b arise from a
C5 ring opening of the epoxide, while compound 14 is
obtained by a nucleophilic attack at C4 of the oxirane
ring. The observed regioselectivity of the reaction is 94/6
in favor of the C5 ring opening of the epoxide. The tert-
butyl and methyl esters 13a and 13b were quantitatively
transformed in the presence of trifluoroacetic acid to the
single azido lactone 12, which is one of our key chiral
synthons in the synthetic strategy. The same reaction
was also effected with an inseparable mixture of tert-
butyl esters 13a and 14, leading quantitatively to the
furanoazidolactone 12 and the pyranoazidolactone 15,
respectively.
Reduction of the azido lactone 12 with a 1 M hexane
solution of diisobutyl aluminum hydride at -78 °C
followed by acetylation (Ac2O/pyridine) led to a mixture
of the corresponding diacetyl R- and â-furanosides 17 in
95% yield (for the two steps) and an R/â ratio of 40/60.
Glycosidation of 2,4-bis[(trimethylsilyl)oxy]-5-methylpy-
rimidine with 17 under the conditions developed by
Vorbru¨ggen and co-workers22 gave a mixture of the
expected nucleosides 18 (76% yield) in a 20/80 R/â ratio.
It is noteworthy that although there is no control by a
C2-protected hydroxy group of the sugar moiety, the
synthesis of the nucleoside proceeds with fairly good
stereoselectivity. At this stage of synthesis, the two
5-azido-2,5-dideoxynucleoside anomers can be separated
by silica gel column chromatography.
We now report an efficient de novo synthesis of the N-t-
Boc-2-deoxydeoxypolyoxin C derivative 10 by a strategy
(eq 2) that allows stereocontrolled construction of all
three contiguous asymmetric centers.
The methodology developed here is based on three key
reactions, i.e., (a) the Sharpless asymmetric epoxidation
of an allylic alcohol, (b) the stereocontrolled addition of
a lithium ester enolate to a optically active R,â-epoxy
aldehyde, and (c) the stereo- and regioselective opening
of an epoxide ring. The usefulness of this method, which
we have partly described for the synthesis of optically
active butyrolactones,13 modified nucleosides,14 or that
of the 2-deoxy-D-arabinoheptulosonic acid derivative,15
resides in its high versatility concerning the choice of the
absolute configuration of the stereocenters. In fact, the
C3, C4, and C5 carbon centers of the epoxy esters can be
controlled by (a) the aldolisation reaction (C3), (b) the
epoxidation reaction and the ring opening of the epoxide
(C4), and (c) the nature of the starting allylic alcohol, the
epoxidation reaction, and the ring opening of the epoxide
(C5).
Compound 10 was synthesized according to Scheme 1.
Synthesis of (3S,4S,5S)-tert-butyl 6-[(tert-butyldiphenyl-
silyl)oxy]-4,5-epoxy-3-hydroxyhexanoate (11) was achieved
as described previously by us.16 Compound 11 was
obtained in six steps starting from cis-2-butene-1,4-diol
(total yield 34%) as the major adduct of the aldol
condensation between the (2R,3S)-4-[(tert-butyldiphenyl-
silyl)oxy]-2,3-epoxybutan-1-al and the lithium enolate of
tert-butyl acetate.
Catalytic hydrogenolysis of the azide function (Pd/C,
EtOH, H2O) of a mixture of R,â-anomers afforded the
amino compound 19 in 80% yield. The two anomers were
also obtained in 80% yield (R/â ratio 20/80) when using
the PPh3/THF, H2O reaction conditions. The 5-amino-
2,5-dideoxynucleoside was converted into the Boc-pro-
tected derivative 20, which was then treated with 8 equiv
of HF/pyridine complex in THF/pyridine to afford the
monoalcohol 21 in 80% yield (two steps). The R,â-
anomers can be also readily separated by silica gel
column chromatography. The final two steps were car-
ried out under conditions different from those described
The regio- and stereospecific introduction of the azido
functionality can be achieved in this step by nucleophilic
oxirane ring cleavage. During the past decade, two main
methods have been applied for the ring opening of
epoxides, i.e., under nonchelating and chelating condi-
tions. Results obtained by many groups, especially
Sharpless,17 Sinou,18 or Flippin et al.,19 showed a C3
(16) Escudier, J . M.; Baltas, M.; Gorrichon, L. Tetrahedron 1993,
49, 5253.
(17) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(18) Sutovardoyo, K. I.; Sinou, D. Bull. Soc. Chim. Fr. 1991, 128,
387.
(20) Caron, M.; Carlier, P. R.; Sharpless, K. B. J . Org. Chem. 1988,
53, 5185.
(21) Choukroun, R.; Gervais, D. J . Chem. Soc., Dalton Trans. 1980,
1800.
(19) Chini, M.; Crotti, P.; Flippin, L. A.; Cardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J . Org. Chem. 1993, 58, 1221.
(22) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.

Synthesis of a Thymidine 2-Deoxypolyoxin C Analogue
J . Org. Chem., Vol. 63, No. 8, 1998 2603
Sch em e 1a
a
Key: (a) 5 equiv of NaN3, 2.5 equiv of NH4Cl, MeOH/H2O 8/1, reflux 48 h; (b) TFA, 5 min; (c) 1.3 equiv of DibaH, PhCH3; (d) 8 equiv
of Ac2O, pyridine; (e) silylated thymine, 1.2 equiv of CF3SO3SiMe3, ClCH2CH2Cl/CH3CN 1/1, 0 °C; (f) H2, Pd/C 10%, EtOH/H2O 9/1, 16 h;
(g) 1.5 equiv of Boc2O, CH2Cl2, 5 h; (h) 8 equiv of HF/Pyr, THF/Pyr; (i) 5 equiv of Pyr-SO3, 5 equiv of Et3N, DMSO, CH2Cl2; (j) 3 equiv of
NaClO2, 6 equiv isoamylene, 1 equiv of K2HPO4, THF, H2O.
previously by Guillerm10 and Ohrui.9 In fact, in our case,
we found better results when converting the primary
hydroxy function into the acid through a two-step pro-
cedure. Selective oxidation of the alcohol to the corre-
sponding aldehyde via the Doering procedure23 and then
oxidation of the crude product through a modified method
developed by Dalcanale and Montanori.24 By using
sodium chlorite and 2-methyl-2-butene as HOCl scaven-
ger,25 the pure â anomer 10 was obtained in 40% yield
after HPLC purification.
To improve the overall yield of our total synthesis we
explored two other routes, starting from the major aldol
adduct (anti) generated from an optically active cis R,â-
epoxy alcohol. The advantage over the previously de-
scribed method relies on two points: (a) the optically
active cis R,â-epoxy alcohol can be obtained from cis-2-
butene-1,4-diol in two steps instead of four for the trans
isomer, and (b) during the aldolization reaction with
lithium ester enolates the major anti aldol adduct can
be obtained in better yields when using a cis-R,â-epoxy
aldehyde. In fact, as we have already described,16 in the
case of cis-R,â-epoxy aldehyde, we obtain in 85% yield
the aldol adducts with a diastereoisomeric ratio of 94/6
in favor of the anti compound, while for trans-R,â-epoxy
aldehydes and under any of the experimental conditions
we tried the diastereoisomeric ratio is always anti/syn
75/25. The following two routes were thus investigated:
(a) (3S,4S,5R)-Methyl 6-[(p-Bromobenzyl)oxy]-4,5-epoxy-
3-hydroxyhexanoate (22) was silylated (t-BuPh2SiCl,
imidazole, DMF), leading to the fully protected compound
23 (Scheme 2). Catalytical hydrogenolysis gave a single
product in 85% yield that has been identified as the
bromohydroxy lactone 24. Apparently, cleavage of the
4-bromobenzyl protective group leads to the simultaneous
formation of hydrogen bromide that opens the oxirane
ring in a stereo- and regiospecific manner to give a bromo
derivative that lactonizes readily under the reaction
conditions leading to compound 24. Protection of the
primary hydroxy group (t-BuMe2SiCl, pyridine) and
reduction of the carbonyl function with a 1 M hexane
solution of diisobutyl aluminum hydride at -78 °C
followed by acetylation (Ac2O/pyridine) led to a mixture
of acetyl R- and â-furanosides 26 in 50% yield (three
steps). Glycosidation of compound 26 via the Vorbru¨ggen
methodology and simultaneous cleavage of the t-BuMe2-
Si protective group led to an easily separable mixture of
5′-bromo-6′-hydroxy nucleoside anomers 27 (R/â ratio 24/
76). After protection of the primary hydroxy function,
compound 28 was allowed to react with sodium azide (1.3
equiv) in DMF (60 °C, 12 h), yielding a mixture of
deprotected and protected talofuranoside 29, 32, and
dehydrohalogenated compounds 30 and 31. When com-
pound 28 (5′S configuration) was heated in DMF in the
presence of DBU, the dehydrohalogenated compound 31
was obtained in 70% yield, which upon deprotection
(APTS, MeOH) led to compound 30. During this reaction
we did not observe the 2,5′-O-cyclonucleoside 33. An
analogous cyclonucleoside was obtained by Guillerm10
(23) Parikh, J . R.; von Doering, E. W. J . Am. Chem. Soc. 1967, 89,
5505.
(24) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567.
(25) Bal, B. S.; Childers, W. E.; Pinnik, H. W. Tetrahedron 1981,
37, 2091.

2604 J . Org. Chem., Vol. 63, No. 8, 1998
Dehoux et al.
Sch em e 2a
a
Key: (a) 1 equiv of t-BuPh2SiCl, 6 equiv of imidazole, DMF; (b) H2, Pd/C 10%, EtOH; (c) 1.5 equiv of t-BuMe2SiCl pyridine; (d) 1.3
equiv of DibaH, PhCH3, -78 °C; (e) 8 equiv of Ac2O, pyridine; (f) 1.2 equiv of CF3SO3SiMe3 silylated thymine, ClCH2CH2Cl/CH3CN 1/1;
(g) 1.3 equiv of NaN3, DMF; (h) 1.5 equiv of DBU, DMF, reflux, 12 h.
Sch em e 3a
a
Key: (a) 1 equiv of MgI2, PhCH3, -78 °C, 19 h; (b) 2 equiv of HMDS, 2 equiv Me3SiCl, pyridine, 10 h; c 5 equiv of NaN3, 60 °C, DMF,
20 h.
when treating a (5′R)-mesylated nucleoside analogue
under the same experimental conditions.
°C, 20 h). The azido lactone 12 was obtained in 67%
yield; this important synthon can, therefore, now be
obtained in seven steps and 30% yield starting from the
cis-2-butene-1,4-diol, instead of eight steps and 20% yield
with the previous methodology. It can then be trans-
formed according to the same synthetic strategy de-
scribed previously (Scheme 1) to the corresponding
compound 10.
On the other hand, Vogel et al.,12 when treating a (5′R)-
bromo-6′-carboxylic nucleoside analogue with sodium
azide in DMF, obtained a mixture of allo- and talo-azido
furanosides (allo:talo ratio 1:2). They do not observe the
corresponding 2,5′-O-cyclonucleoside, but they interpret
the epimerization at the C5′ position in terms of concur-
rent participation by the nucleophilic nucleoside22,26 to
the displacement by an azide anion.
Con clu sion
The synthesis of the 2-deoxypolyoxin C analogue 10
was achieved in 9% (or 8%) total yield starting from epoxy
hydroxy ester 11 (or 34). The yield (5.5%) from the
noncarbohydrate compound cis-2-butene-1,4-diol com-
pares with that of polyoxin C obtained by two groups9f,27
(4.4 and 5.6%, respectively) starting from D-ribose. Dif-
ferently 2-substituted polyoxins can also be envisioned
depending on the enolates retained in the aldolization
step.
It seems likely that in our case we also have nucleo-
philic participation of the nucleoside, but the C5′-epimeric
2,5′-O-cyclonucleoside 33 is transformed by proton ab-
straction to the ethylenic compound 30 (or 31).
(b) (3S,4S,5R)-Methyl 6-[(tert-butyldiphenylsilyl)oxy]-
4,5-epoxy-3-hydroxyhexanoate (34) was treated with
magnesium iodide in a toluene ether solution (-78 °C,
19 h) leading in 91% yield to the single product of reaction
35 issued from a C5 ring opening of the epoxide ring
(Scheme 3). The iodo diol ester was then disilylated
(HMDS, Me3SiCl, pyridine) in 86% yield, and compound
36 was allowed to react with sodium azide in DMF (60
Exp er im en ta l Section
Commercially available reagents were used as supplied. All
solvents were distilled prior to use. Products were purified
(26) Moffatt, J . G. Nato Adv. Study Inst. Ser. 1979, A26, 71.
(27) Barrett, A. G. M.; Lebold, S. A. J . Org. Chem. 1990, 55, 3853.

Synthesis of a Thymidine 2-Deoxypolyoxin C Analogue
J . Org. Chem., Vol. 63, No. 8, 1998 2605
by medium-pressure liquid chromatography. NMR spectra
were recorded at 250 MHz for 1H and 62.9 MHz for 13C using
CDCl3 solutions with internal tetramethylsilane as reference
unless otherwise noted. Optical rotations were recorded on a
digital polarimeter at 589 nm. Mass spectra were obtained
at the inhouse facility of the Institute of Molecular Chemistry,
while elemental analyses were performed by analytical ser-
vices at the Ecole Nationale Supe´rieure de Chimie de Toulouse.
Compound (3S,4S,5S)-tert-butyl 6-[(tert-butyldiphenylsilyl)oxy]-
4,5-epoxy-3-hydroxyhexanoate and their precursors have been
previously reported.16
NH3) 443 (100, M + 18). Anal. Calcd for C22H27N3O4Si: C,
62.09; H, 6.40; N, 9.87. Found: C, 62.41; H, 6.84; N, 9.05.
(4S,5R,1′R)-5-[1′-Azido-2′-[(ter t-bu tyldiph en ylsilyl)oxy]-
eth yl]-2,4-d ih yd r oxy-1-oxa cyclop en ta n e (16). To a solu-
tion of diisobutylaluminum hydride (1 M in hexane, 0.77 mL)
was added dropwise under N2 and at -78 °C a solution of
azidolactone 12 (0.250, 0.59 mmol) in toluene (2 mL). The
reaction mixture was stirred for 15 min and then hydrolyzed
with a 0.25 N aqueous HCl solution (3 mL) and diluted with
ether (8 mL). After 1 h of stirring, the aqueous phase was
extracted with ether; the organic phases were washed with
H2O and then dried over MgSO4 and evaporated. The crude
product was purified by silica gel column chromatography
(eluent petroleum ether/Et2O/EtOAc 1/1.2/0.3), yielding com-
pound 16 (0.245 g, 97% yield) as a mixture of anomers (R: â
27:73): Rf ) 0.33; [R]D +8.0° (c 1.2, CHCl3); IR (film) ν cm-1
3408 (OH), 3073 (CH arom.), 2935, 2861 (CH), 2103 (N3), 1272
Rin g Op en in g of th e Ep oxid e 11 by Sod iu m Azid e. To
a solution of (3S,4S,5S)-tert-butyl 6-[(tert-butyldiphenylsi-
lyl)oxy]-4,5-epoxy-3-hydroxyhexanoate (11) (0.61 g, 1.35 mmol)
in MeOH/H2O (8/1 vol, 10 mL) were added ammonium chloride
(0.18 g, 2.5 equiv) and sodium azide (0.439 g, 5 equiv). The
mixture was stirred under reflux for 24 h, and then MeOH
was evaporated. The residue was dissolved in ether, dried over
MgSO4, and filtered and solvent evaporated. The crude
product was purified by silica gel column chromatography
(eluent CCl4/CH3CN 9/1) to yield pure azido lactone 12 (72.5
mg) and tert-butyl ester 13a (91 mg) along with inseparable
mixtures of azidolactone and methyl ester 13b (98 mg) and
tert-butyl esters 13a and 14 (105 mg). Compound 13a and
both mixtures were treated separately with trifluoroacetic acid
(2 mL) for 5 min under stirring. Compound 13a and the
mixture containing methyl ester 13b, after evaporation of
excess trifluoroacetic acid, gave quantitatively the azido lac-
tone 12 (76.5 and 85 mg, respectively). The crude product
obtained from starting compounds 13a and 14 gave after
purification by silica gel column chromatography (eluent CH2-
Cl2/CH3CN 9.5/0.5) furanoazido lactone 12 (93.5 mg) and
pyranoazido lactone 15 (11.5 mg): total yield for azido lactone
12 (327.5 mg, 57%) and pyranoazido lactone 15 (11.5 mg, 2%).
(3S,4R,5R)-ter t-Bu tyl [5-a zid o-6-[(ter t-bu tyld ip h en yl-
silyl)oxy]-3,4-d ih yd r oxyh exa n oa te (13a ): Rf ) 0.26 (eluent
CCl4/CH3CN 9/1); [R]D -21.8° (c 1.16, CHCl3); IR (film) ν cm-1
3474 (OH), 3073, 3038 (CH arom), 2934, 2861 (CH), 2103 (N3),
1710 (CdO), 1258 (CO), 1154 (CO + SiC), 1110 (SiO); 1H NMR
(250 MHz, CDCl3) δ 7.73-7.69 (m, 4H), 7.46-7.39 (m, 6H),
4.04 and 3.97 (AB part of an ABX system, 2H, J ) 3.2, 6.1,
10.9 Hz), 4.00 (m, 1H), 3.74 (m, 1H), 3.66 (d, 1H, J ) 3.65
Hz), 3.58 (ddd, 1H, J ) 3.2, 6.1, 6.0 Hz), 2.88 (d, 1H, J ) 4.83
Hz), 2.60 and 2.48 (AB part of an ABX system, 2H, J ) 2.9,
9.3, 16.8 Hz), 1.48 (s, 9 H), 1.09 (s, 9H); 13C NMR (62.9 MHz,
CDCl3) δ 172.9, 135.7, 135.6, 132.7, 132.6, 130.0, 127.9, 81.8,
73.1, 68.6, 64.4, 63.2, 37.2, 28.1, 26.8, 19.1; MS (DCI, NH3)
517 (66.57, M + 18), 500 (100, M + 1). Anal. Calcd for
1
(CO), 1110 (CO + SiO); H NMR (250 MHz, CDCl3) δ 7.71-
7.67 (m, 8H), 7.44-7.41 (m, 12H), 5.49 (m, 2H), 4.61 (m, 1H),
4.28 (m, 1H), 4.13 (dd, 1H, J ) 1.8, 6.1 Hz), 3.84 (m, 4H), 3.87
and 3.77 (AB part of an ABX system, 2H, J ) 7.4, 4.2, 10.7
Hz), 3.46 (m, 1H, J ) 7.4, 4.2, 6.7, 1.2 Hz), 3.30 (m, 1H), 2.72
(m, 2H), 2.43 (m, 1H), 2.13 (m, 4H), 1.09 (s, 18H); 13C NMR
(62.9 MHz, CDCl3) δ 135.8, 135.6, 132.8, 132.7, 130.0, 127.9,
99.2, 98.7, 86.0, 84.6, 72.8, 72.4, 65.7, 64.8, 64.7, 64.4, 41.8,
41.4, 26.8, 19.2; MS (DCI, NH3) 445 (100, M + 18), 428 (9.71,
M + 1), 427 (28.94, M). Anal. Calcd for C22H29N3O4Si: C,
61.80; H, 6.84; N, 9.83. Found: C, 61.42; H, 6.94; N, 9.54.
(4S,5R,1′R)-5-[1′-Azido-2′-[(ter t-bu tyldiph en ylsilyl)oxy]-
eth yl]-2,4-d ia cetoxy-1-oxa cyclop en ta n e (17). To a solution
of 16 (0.138 g, 0.32 mmol) in pyridine (0.5 mL) was added
acetic anhydride (0.24 mL, 2.56 mmol). The reaction mixture
was stirred at room temperature for 12 h. The pyridine was
evaporated, and the crude product was purified by silica gel
column chromatography (eluent petroleum ether/Et2O/EtOAc
5/4/1) to yield the desired compound (0.160 g, 98%) as a
mixture of anomers (R: â 40/60): Rf ) 0.40; [R]D +6.5° (c 1.7,
CHCl3); IR (film) ν cm-1 3074 (CH arom), 2935, 2860 (CH),
2105 (N3), 1745 (CdO), 1227 (CO), 1184 (CO + SiC), 1110
(SiO); 1H NMR (250 MHz, CDCl3) δ 6.37 (m, 2H), 5.39 (m, 1H,
J ) 3.4, 4.6, 6.9 Hz), 5.21 (m, 1H, J ) 2.7, 5.1 Hz), 4.37 (dd,
1H, J ) 2.7, 4.9 Hz), 4.20 (dd, 1H, J ) 3.4, 6.8 Hz), 3.78 and
3.86 (AB part of an ABX system, 2H, J ) 4.0, 6.6 Hz), 3.80 (d,
2H, J ) 5.6 Hz), 3.65 (m, 1H, J ) 5.6, 4.9 Hz), 3.56 (m, 1H, J
) 4.0, 6.6, 6.8 Hz), 2.52 (m, 2H), 2.29 (dd, 1H, J ) 4.6, 5.5
Hz), 2.23 (dd, 1H, J ) 5.1, 5.6 Hz), 2.12 (2s, 6H), 2.02 (2s, 6H),
1.05 (2s, 18H); 13C NMR (62.9 MHz, CDCl3) δ 170.2, 169.9,
135.6, 132.8, 132.7, 132.6, 129.9, 127.9, 98.1, 98.0, 83.8, 82.8,
74.2, 73.3, 64.8, 64.4, 64.0, 63.9, 38.9, 38.6, 26.7, 21.3, 21.1,
21.0, 20.9, 19.2; MS (DCI, NH3) 529 (100, M + 18). Anal. Calcd
for C26H33N3O6Si: C, 61.04; H, 6.50; N, 8.21. Found: C, 61.77;
H, 6.63; N, 8.10.
C
26H37N3O5Si: C, 62.50; H, 7.46; N, 8.41. Found: C, 62.99;
H, 7.52; N, 7.88.
(4S,5R,1′R)-5-[1′-Azido-2′-[(ter t-bu tyldiph en ylsilyl)oxy]-
eth yl]-4-h yd r oxy-2-oxo-1-oxa cyclop en ta n e (12): Rf ) 0.14
(eluent CCl4/CH3CN 9/1); [R]D -11.0° (c 1.6, CHCl3); IR (film)
ν cm-1 3452 (OH), 3073, 3037 (CH arom), 2935, 2861 (CH),
2108 (N3), 1787 (CdO), 1269 (CO), 1188 (CO + SiC), 1111
(SiO); 1H NMR (250 MHz, CDCl3) δ 7.71-7.66 (m, 4H), 7.48-
7.42 (m, 6H), 4.52 (ddd, 1H, J ) 3.7, 7.5, 4.9 Hz), 4.39 (dd,
1H, J ) 3.7, 5.1 Hz), 3.86 and 3.91 (AB part of an ABX system,
2H, J ) 4.8, 5.5, 10.8 Hz), 3.74 (ddd, 1H, J ) 5.1, 4., 5.5 Hz),
2.90 and 2.52 (AB part of an ABX system, 2H, J ) 4.9, 7.6,
18.0 Hz), 2.73 (br.s., 1H), 1.09 (s, 9H); 13C NMR (62.9 MHz,
CDCl3) δ 174.0, 135.6, 135.5, 132.3, 132.2, 130.2, 128.0, 85.0,
68.3, 63.9, 63.7, 37.4, 26.8, 19.2; MS (DCI, NH3) 443 (100, M
+ 18), 400 (4.93), 274 (13.19). Anal. Calcd for C22H27N3O4Si:
C, 62.09; H, 6.40; N, 9.87. Found: C, 62.52; H, 6.93; N, 8.95.
(4S,5R,6R)-5-Azid o-6-[[(ter t-b u t yld ip h en ylsilyl)oxy]-
m eth yl]-4-h yd r oxy-2-oxa cycloh exa n e (15): Rf ) 0.32 (elu-
ent CH2Cl2/CH3CN 9.5/0.5); [R]D -18.1° (c 0.74, CHCl3); IR
(film) ν cm-1 3439 (OH), 3073 (CH arom), 2934, 2860 (CH),
2114 (N3), 1733 (CdO), 1249 (CO), 1150 (CO + SiC), 1110
(SiO); 1H NMR (250 MHz, CDCl3) δ 7.72-7.67 (m, 4H), 7.47-
7.38 (m, 6H), 3.93 (m, 5H), 3.04 and 2.64 (AB part of an ABX
system, 2H, J ) 5.1, 9.2, 17.7 Hz), 2.81 (m, 1H), 1.08 (s, 9H);
13C NMR (62.9 MHz, CDCl3) δ 168.1, 135.8, 135.6, 132.6, 132.1,
130.1, 127.9, 79.3, 67.6, 62.5, 61.6, 37.3, 26.8, 19.3; MS (DCI,
(3S,4R,5R)-1-[5-Azid o-2,5-d id e oxy-6-(O-ter t-b u t yld i-
p h en ylsilyl)h exofu r a n osyl]-5-m et h ylu r a cil (18). Tri-
methylsilyl trifluoromethanesulfonate (3.0 mL, 1.2 equiv) was
added to a stirred solution of 17 (660 mg, 1.2 mmol) and freshly
distilled 2,4-bis[(trimethylsilyl)oxy]-5-methylpyrimidine (0.680
mL) in ClCH2CH2Cl/CH3CN 1/1 (20 mL) under N2 atmosphere.
After being stirred at room temperature for 3 h, the mixture
was hydrolyzed with a saturated aqueous solution of NaHCO3.
The organic extract was washed with water and dried over
MgSO4. After concentration, 750 mg (100%) was obtained. A
total of 120 mg of anomers was separated by column chroma-
tography on silica gel (eluent 2-propanol/petroleum ether 1/9)
to give 85 mg of anomer R and 17 mg of anomer â along with
16 mg of a mixture of R and â anomers.
Anomer â: [R]Hg +5.7 (c 0.5, CHCl3); IR (CHCl3) ν cm-1 3395
(NH), 2997 (CH), 2401 (N3), 1740 (CH3CdO), 1696 (CdO
1
thym), 1288 (CO), 1119 (SiO); H NMR (250 MHz, CDCl3) δ
8.71 (bs, 1H, NH), 7.70-7.64 (m, 4H), 7.49-7.36 (m, 6H), 7.31
(s, 1H), 6.30 (dd, 1H, J ) 6.0, 8.6 Hz), 5.21 (td, 1H, J ) 2.6,
6.0 Hz), 4.05 (t, 1H, J ) 2.6 Hz), 3.88 (m, 3H), 2.28 (m, 2H,
CH2CH anom), 2.01 (s, 3H), 1.94 (s, 3H), 1.09 (s, 9H); 13C NMR
(62.9 MHz, CDCl3) δ 169.9, 163.3, 150.3, 135.5, 134.7, 132.6,
132.5, 130.0, 127.9, 111.8, 84.0, 82.5, 73.3, 65.1, 64.0, 35.7, 26.7,

2606 J . Org. Chem., Vol. 63, No. 8, 1998
Dehoux et al.
20.9, 19.1, 12.8; MS (DCI, NH3) 595 (MNH4+, 100), 578 (MH+,
13). Anal. Calcd for C29H35N5O6Si: C, 60.29; H, 6.11; N, 12.12.
Found: C, 59.67; H, 6.03; N, 11.56.
1740 (CdO Boc), 1734 (CH3CdO), 1694 (CdO thym), 1198,
1169 (CO + SiC), 1110 (CO + SiC); 1H NMR (400 MHz, CDCl3)
δ 9.17 (m, 1H), 7.62-7.59 (m, 4H), 7.38-7.32 (m, 6H), 7.00
(m, 1H), 6.31 (m, 1H), 6.10 (m, 1H), 5.40 (m, 1H), 5.00 (m,
1H), 4.10 (m, 1H), 3.75 (m, 3H), 2.35 et 2.25 (m, 2H), 2.07 (m,
3H), 1.82 (m, 3H), 1.43 (m, 9H), 1.09 (m, 9H); 13C NMR (62.9
MHz, CDCl3) δ 170.1, 163.5, 156.0, 150.5, 135.6, 134.5, 132.9-
132.6, 129.9, 127.9, 127.8, 111.8, 84.5, 82.8, 80.2, 74.7, 62.9,
53.6, 36.5, 28.3, 26.9, 21.1, 19.3, 12.7; MS (DCI, NH3) 652
(MH+, 100). Anal. Calcd for C34H45N3O8Si: C, 62.65; H, 6.96;
N, 6.45. Found: C, 62.41; H, 7.15; N, 5.79.
(3S,4R,5R)-1-[5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-2,5-
d id eoxy-6-h yd r oxy)h exofu r a n osyl]-5-m eth ylu r a cil (21).
To a mixture of 20 (84 mg, 0.13 mmol) in THF (1.2 mL) and
pyridine (0.64 mL) was added HF/pyridine 70% (0.133 mL).
After being stirred for 1 h 30 min, the reaction mixture was
diluted with ethyl acetate and then hydrolyzed with a satu-
rated aqueous solution of NaHCO3. The organic extract was
washed with water and dried over MgSO4. The solvents were
evaporated, and the product was purified by column chroma-
tography on silica gel (eluent Et2O/EtOAc 3/2, Rf(â) ) 0.26,
Rf(R) ) 0.20) to give 31 mg of â anomer and 4 mg of a â,R
mixture (global yield: 70%).
Mixture of R and â anomers: R/â ) 20/80; IR (CHCl3) ν cm-1
3395 (NH), 3076-3032 (CH arom), 2935-2862 (CH), 2108 (N3),
1740 (CH3CdO), 1695 (CdO thym), 1271 (CO), 1111 (SiO). 1H
NMR (250 MHz, CDCl3) δ 8.96 (s, 1H), 8.93 (s, 1H), 7.70-
7.65 (m, 4H), 7.26-7.47 (m, 12H), 7.32 (2s, 2H), 6.31 (dd, 1H,
J ) 6.1, 8.5 Hz), 6.21 (dd, 1H, J ) 2.3, 7.5 Hz), 5.29 (ddd, 1H,
J ) 1.3, 2.8, 5.2 Hz), 5.22 (ddd, 1H, J ) 2.1, 2.3, 5.8 Hz), 4.38
(dd, 1H, J ) 1.3, 5.0 Hz), 4.05 (t, 1H, J ) 2.3 Hz), 3.87 (m,
5H), 3.54 (m, 1H, J ) 5.0, 6.4, 7.6 Hz), 2.29 (m, 4H), 2.02 (s,
3H), 1.99 (s, 3H), 1.95 (s, 6H), 1.08 (s, 18H); 13C NMR (62.9
MHz, CDCl3) δ 170.0, 163.4, 150.4, 135.5, 134.8, 132.6, 132.5,
130.1, 127.9, 111.9, 110.3, 84.0, 82.5, 73.9, 73.4, 65.1, 64.4, 64.1,
37.5, 26.7, 20.9, 19.1, 12.8; MS (DCI, NH3) 595 (MNH4+, 100),
578 (M + 1, 14). Anal. Calcd for C29H35N5O6Si: C, 60.29; H,
6.11; N, 12.12. Found: C, 60.41; H, 6.45; N, 11.21.
(3S,4R,5R)-1-[5-Am in o-2,5-dideoxy-6-(O-ter t-bu tyldiph e-
n ylsilyl)h exofu r a n osyl]-5-m eth ylu r a cil (19). A mixture of
18 (380 mg, 0.7 mmol), EtOH (16.6 mL), and 10% Pd/C (75
mg) was degassed and then pressurized with H2. After being
shaken at 20 °C for 6 h, the mixture was filtered on Celite
and then concentrated in vacuo. The residue was purified by
column chromatography on silica gel (eluent Et2O/EtOAc 3/2,
Rf ) 0.17) to yield 215 mg (60%) of the desired compound.
Anomer â: [R]Hg +5.7 (c 0.5, CHCl3); IR (CHCl3) ν cm-1 3392
(NH2 + NH), 2933 (CH), 1693 (CdO thym), 1265 (CO), 1112
(SiO); 1H NMR (250 MHz, CDCl3) δ 7.66-7.64 (m, 4H), 7.46-
7.26 (m, 8H), 6.26 (dd, 1H, J ) 5.8, 8.5 Hz), 5.40 (ddd, 1H, J
) 6.0, 2.1, 2.6 Hz), 4.00 (dd, 1H, J ) 2.6, 5.7 Hz), 3.74 and
3.72 (AB part of an ABX system, 2H, J ) 4.6, 5.9, 10.2), 3.10
(ddd, 1H, J ) 4.6, 5.7, 5.9 Hz), 2.35-2.16 (m, 2H), 2.05 (s, 3H),
1.87 (s, 3H), 1.06 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ ppm
170.2, 163.5, 150.4, 135.6, 135.5, 135.2, 133.1, 133.0, 129.9,
127.8, 111.5, 84.9, 84.0, 78.8, 65.6, 54.7, 37.6, 26.8, 21.0, 19.3,
12.6; MS (DCI, NH3) 553 (MH+, 100).
Anomer â: [R]Hg +38.9 (c 0.5, CHCl3); IR (CHCl3) ν cm-1
3628 (OH), 3440-3396 (NH), 2979 (CH), 1740 (CH3CdO), 1697
(CdO thym), 1166 (CO); 1H NMR (250 MHz, CDCl3) δ 9.05
(bs, 1H), 7.28 (s, 1H), 6.24 (dd, 1H, J ) 5.3, 9.1 Hz), 5.38 (m,
1H), 4.04 (dd, 1H, J ) 1.8, 6.7 Hz), 3.85 (m, 3H), 2.96 (m, 1H),
2.35 and 2.20 (m, 2H), 2.10 (s, 3H), 1.92 (s, 1H), 1.44 (s, 9H);
13C NMR (62.9 MHz, CDCl3) δ 170.9, 163.9, 156.2, 150.6, 135.3,
111.7, 85.0, 84.1, 80.3, 74.9, 62.0, 53.6, 36.3, 28.3, 21.1, 12.5;
MS (DCI, NH3) 431 (MNH4+, 86), 414 (MH+, 100).
Mixture of R and â anomers: mixture ) 20/80; IR (CHCl3)
ν cm-1 3640 (OH), 3446, 3396 (NH), 3030 (CH arom), 2932
(CH), 1740 (CH3CdO), 1691 (CdO thym), 1200 (CO), 1666 (CO
1
+ SiO); H NMR (400 MHz, CDCl3) δ 9.10 (m, 1H), 7.33 (m,
1H), 7.26 (1H, m), 6.21 (m, 1H), 5.40 (m, 1H), 5.33 (m, 1H),
4.02 (m, 1H), 3.80 (m, 2H), 3.72 (m, 1H), 3.00 (m, 1H), 2.20
and 2.38 (m, 2H), 2.08 (s, 3H), 1.89 (s, 3H), 1.42 (s, 9H); 13C
NMR (62.9 MHz, CDCl3) δ ppm 171.0, 163.7, 156.2, 150.5,
135.2, 111.7, 84.9, 84.3, 80.3, 75.0, 62.2, 53.6, 36.4, 28.3, 21.1,
12.6; MS (DCI, NH3) 431 (MNH4+, 100), 414 (MH+, 97).
(3S,4R,5R)-1-[5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-2,5-
dideoxy-6-(O-ter t-bu tyldiph en ylsilyl)u r on ic acid]-5-m eth -
ylu r a cil (10). A mixture of 21 (37 mg, 0.09 mmol), DMSO
(0.180 mL), Et3N (0.063 mL, 5 equiv), and pyr/SO3 (71 mg, 5
equiv) in CH2Cl2 was stirred for 25 min. After dilution with
CH2Cl2, the organic layer was washed with water and brine.
After drying and concentration, 34 mg was obtained and then
dissolved with THF (0.222 mL), KH2PO4 (8 mg, 1 equiv) in
H2O (0.09 mL), 2-methyl-2-butene (0.041 mL), t-BuOH (0.390
mL), and NaClO2 (6 mg) in 0.180 mL. After being stirred for
2 h 15 min, the reaction mixture was acidified with HCl (1 N)
and extracted with EtOAc. The product was dried and concen-
trated: [R]Hg +20.1 (c 0.5, CHCl3); IR (CH3CN) ν cm-1 3283-
3075 (OH acid), 3470, 3419 (NH), 1741 (CdO Boc), 1710 (CdO
acid), 1698 (CdO thym), 1355 (CO acid), 1169 (CO); 1H NMR
(250 MHz, CD3OD) δ 7.70 (s, 1H), 6.17 (dd, 1H, J ) 6.6 Hz),
5.54 (m, 1H), 4.34 (1H, bd, J ) 4.7 Hz), 4.28 (m, 1H), 2.60 (m,
2H), 2.09 (s, 3H), 1.90 (s, 3H), 1.44 (s, 9H); 13C NMR (62.9
MHz, CD3OD) δ 173.9, 172.1, 157.8, 152.4, 137.9, 111.9, 86.7,
86.0, 80.8, 76.0, 58.6, 37.9, 28.8, 30.8, 12.6; MS (DCI, NH3)
445 (MNH4+, 4), 428 (MH+, 3).
(3S,4S,5R)-Meth yl [6-(p-Br om oben zyloxy)-4,5-ep oxy-3-
h yd r oxy]h exa n oa te (22). The aldolization reaction was
performed as previously described.16 Starting from (2R,3R)-
4-[(p-bromobenzyl)oxy]-2,3-epoxybutan-1-al (1 g, 3.69 mmol),
we obtained after purification by silica gel column chroma-
tography (eluent petroleum ether/CH2Cl2/EtOAc 1/3.2/0.8) the
desired compound 22 (895 mg, 70% yield): Rf ) 0.25; [R]D
-23.2° (c 0.4, CHCl3); IR (CHCl3) ν cm-1 3625 and 3471 (OH),
3007 (dCH), 1731 (CdO), 1047 (CO); 1H NMR (250 MHz,
CDCl3) δ 7.50-7.45 (m, 2H), 7.23-7.20 (m, 2H), 4.56 and 4.51
(AB system, 2H, J ) 12 Hz), 3.86 (td, 1H, J ) 3.5, 8.3 Hz),
3.78 and 3.70 (AB part of an ABX(Y), 2H, J ) 4.8, 5.9, 10.8
Mixture of R and â anomers: mixture ) 20/80; IR (CHCl3)
ν cm-1 3394 (NH2 + NH), 3030 (CH arom), 2935-2862 (CH),
1740 (CH3CdO), 1686 (CdO thym), 1247 (CO), 1202-1110
(SiO); 1H NMR (250 MHz, CDCl3) δ 7.67-7.64 (8H, m), 7.43-
7.34 (14H, m), 6.27 (dd, 1H, J ) 5.8, 8.0 Hz), 6.11 (1H, dd, J
) 1.4, 7.2 Hz), 5.52 (m, 1H), 5.40 (m, 1H), 4.26 (t, 1H, J ) 2.8
Hz), 4.01 (dd, 1H, J ) 2.6, 5.7 Hz), 3.67 and 3.74 (AB part of
an ABX system, 2H, J ) 4.8, 5.8, 10.3 Hz), 3.71 (m, 2H), 3.11
(m, 1H, J ) 4.8, 5.8, 5.7 Hz), 2.82 (m, 1H), 2.21 and 2.33 (AB
part of an ABX(Y) system, 2H, J ) 1.7, 5.8, 8.0, 14.2 Hz), 2.23
(2H, m), 2.06 (3H, s), 2.02 (s, 3H), 1.90 (s, 3H), 1.87 (s, 3H),
1.06 (s, 18H); 13C NMR (62.9 MHz, CDCl3) δ ppm 170.4, 163.9,
150.7, 135.6, 135.3, 133.1, 133.0, 129.9, 127.6, 111.6, 84.9, 84.0,
73.8, 73.8, 65.6, 54.7, 37.6, 26.7, 21.1, 19.3, 12.7; MS (DCI,
NH3) 552 (MH+, 100). Anal. Calcd for C29H37N3O6Si: C, 63.13;
H, 6.76; N, 7.62. Found: C, 61.78; H, 6.83; N, 7.11.
(3S,4R,5R)-1-[5-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-2,5-
d id eoxy-6-(O-ter t-b u t yld ip h en ylsilyl)h exofu r a n osyl]-5-
m eth ylu r a cil (20). A mixture of 19 (56 mg, 0.10 mmol) and
Boc2O (33 mg, 1.5 equiv) in CH2Cl2 (1.0 mL) was stirred for
12 h. The reaction mixture was diluted with CH2Cl2 and
washed with a saturated aqueous solution of NaHCO3 and
then with brine. After drying over MgSO4 and concentration,
the crude product was purified by column chromatography on
silica gel (eluent Et2O/EtOAc 3/2, Rf ) 0.48) leading to 51 mg
(80%) of compound 20.
Anomer â: [R]Hg -9.1 (c 0.4, CHCl3). IR (CHCl3) ν cm-1
3449, 3394 (NH), 2936, 2861 (CH), 1696 (CdO), 1499 (CdC),
1
1112 (SiO); H NMR (250 MHz, CDCl3) δ 7.65-7.61 (m, 4H),
7.44-7.33 (m, 4H), 7.03 (s, 1H), 6.31 (m, 1H, J ) 5.5-8.8 Hz),
5.42 (ddd, 1H, J ) 1.2, 1.8, 5.8 Hz), 5.14 (d, 1H, J ) 8.9 Hz),
4.11 (dd, 1H, J ) 1.8, 8.6 Hz), 3.83 (m, 3H), 2.20 (m, 2H), 2.10
(s, 3H), 1.84 (s, 3H), 1.46 (s, 9H), 1.07 (s, 9H); 13C NMR (62.9
MHz, CDCl3) δ 170.1, 163.5, 155.8, 150.4, 111.7, 84.5, 82.7,
74.7, 62.9, 53.7, 36.6, 28.4, 26.9, 21.1, 19.3, 12.6; MS (DCI,
NH3); 652 (MH+, 100), 669 (MNH4+, 21).
Mixture of R and â anomers: mixture ) 22/78; IR (CHCl3)
ν cm-1 3454, 3397 (NH), 3009 (CH arom), 2936, 2862 (CH),

Synthesis of a Thymidine 2-Deoxypolyoxin C Analogue
J . Org. Chem., Vol. 63, No. 8, 1998 2607
Hz), 3.73 (s, 3H), 3.28 (ddd, 1H, J ) 4.6, 4.8, 5.9 Hz), 3.18 (m,
1H), 3.02 (dd, 1H, J ) 4.6, 8.1 Hz), 2.74 and 2.63 (A′B′ part of
an A′B′X′(Y) system, 2H, J ) 3.6, 8.5, 16.3 Hz); 13C NMR (63
MHz, CDCl3) δ 172.3, 136.4, 131.7, 129.5, 121.9, 72.7, 68.3,
66.5, 57.1, 55.1, 52.0, 38.9. Anal. Calcd for C14H17BrO5: C,
48.71; H, 4.96. Found: C, 48.75; H, 4.93.
water, and dried over MgSO4. The solvents were evaporated.
The crude product obtained (772 mg) was dissolved in pyridine
(1.8 mL). Acetic anhydride (620 mL, 4.5 equiv) was added.
After the mixture was stirred for 12 h at 20 °C, pyridine was
evaporated. The residue was purified by column chromatog-
raphy on silica gel (eluent petroleum ether/CH2Cl2/EtOAc 2/4/
1) to yield 720 mg (80%). R/â: 48/52; Rf ) 0.33; IR (film) ν
cm-1 3072 (CH arom), 2932, 2858 (CH), 1755 (CdO), 1590-
1471 (CH arom), 1111 (SiO); 1H NMR (250 MHz, CDCl3) δ
7.76-7.64 (m, 4H), 7.46-7.26 (m, 6H), 6.33 (bd, 1H, J ) 5.0
Hz), 6.22 (dd, 1H, J ) 1.4, 5.5 Hz), 4.60 (ddd, 1H, J ) 6.0, 8.0,
14.0 Hz), 4.42 (dd, 1H, J ) 1.8, 2.8 Hz), 4.34 (ddd, 1H, J )
2.0, 2.8, 7.0 Hz), 4.20 (bd, 1H, J ) 6.0 Hz), 3,66 (m, 5H), 3.36
(ddd, 1H, J ) 1.8, 6.0, 8.5 Hz), 2.38-2.02 (m, 4H), 2.10 (s, 6H),
1.07 (s, 18H), 0.88 (s, 18H), 0.03 (s, 12H); 13C NMR (62.9 MHz,
CDCl3) δ: 170.4, 170.2, 135.8, 135.7, 133.4, 133.0, 130.1, 130.0,
127.9, 127.8, 99.1, 96.9, 85.7, 84.1, 75.2, 73.3, 54.2, 54.0, 41.4,
40.5, 26.9, 26.8, 25.8, 25.7, 21.4, 21.2, 19.1, 19.0, 18.2, -5.4,
-5.3; MS (DCI, NH3) 638 (MNH4+, 83). Anal. Calcd for
C30H45BrO5Si2: C, 57.95; H, 7.30. Found: C, 57.67; H, 7.38.
(3S,4S,5S)-1-[5-Br om o-2,5-d id eoxy-3-O-(ter t-b u t yld i-
p h en ylsilyl)h exofu r a son yl]-5-m et h ylu r a cil (27). Tri-
methylsilyl trifluoromethanesulfonate (4.6 mL, 1.2 equiv) was
added to a stirred solution of 26 (1.2 g, 1.9 mmol) and freshly
distilled 2,4-bis[(trimethylsilyl)oxy]-5-methylpyrimidine (1.1
mL) in ClCH2CH2Cl/CH3CN 1/1 (30 mL) under N2 atmosphere.
After being stirred at 0 °C for 2 h, the mixture was hydrolyzed
with a saturated aqueous solution of NaHCO3. The organic
extract was washed with water and dried over MgSO4. After
concentration, the residue was purified by column chroma-
tography on silica gel (eluent petroleum ether/CH2Cl2/EtOAc
15/28/7, Rf(â) ) 0.31, Rf(R) ) 0.25). The isomer â weighed 750
mg (70%). [R]Hg +43.2 (c 0.6, CHCl3); IR (KBr) ν cm-1 3429
(OH), 2932 (CH arom), 1693 (CdO thym), 1471 (CHd arom),
1111 (SiO); 1H NMR (250 MHz, CDCl3) δ: 8.75 (bs, 1H), 7.69-
7.39 (11H, m), 6.45 (dd, 1H, J ) 5.8, 8.5 Hz), 4.37 (ddd, 1H, J
) 2.4, 2.8, 7.0 Hz), 4.02 (dd, 1H, J ) 1.9, 2.8 Hz), 3.69 (m,
2H), 3.36 (td, 1H, J ) 1.9, 6.4 Hz), 2.30 (ddd, 1H, J ) 2.4, 5.8,
13.6 Hz), 2.10 (m, 1H), 2.02 (ddd, 1H, J ) 7.0, 8.5, 13.6 Hz),
1.74 (s, 3H), 1.09 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ: 163.7,
150.4, 135.8, 135.7, 135.4, 133.0, 132.7, 130.4, 130.3, 128.1,
128.0, 111.5, 85.2, 83.7, 75.3, 64.8, 56.5, 40.1, 26.9, 19.0, 12.7;
MS (DCI, NH3) 590 (MNH4+, 90), 573 (MH+, 12).
The isomer R weighed 218 mg (20%): [R]Hg +19.5 (c 0.3,
CHCl3); IR (KBr) ν cm-1 3430 (OH), 2932 (CH), 1687 (CdO
thym), 1471 (CH arom), 1112 (SiO); 1H NMR (250 MHz, CDCl3)
δ 9.05 (s, 1H), 7.68-7.38 (m, 11H), 6.39 (dd, 1H, J ) 2.6, 7.8
Hz), 4.50 (dd, 1H, J ) 1.8, 2.3 Hz), 4.38 (td, 1H, J ) 6.8, 1.8
Hz), 4.63 (m, 2H), 3.20 (td, 1H, J ) 2.3, 6.5 Hz), 2.20 (m, 2H),
1.97 (s, 3H), 1.09 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ 164.3,
150.6, 136.3, 135.8, 135.6, 132.6, 132.1, 130.5, 130.4, 128.2-
128.1, 110.8, 88.7, 87.6, 76.5, 64.2, 55.4, 41.5, 26.9, 19.0, 12.7;
MS (DCI, NH3) 590 (MNH4+, 97), 573 (MH+, 17).
(3S,4S,5S)-1-[5-Br om o-2,5-d id eoxy-6-O-(ter t-b u t yld i-
m eth ylsilyl)-3-O-(ter t-bu tyldiph en ylsilyl)h exofu r ason yl]-
5-m eth ylu r a cil (28). A mixture of 27 (400 mg, 0.96 mmol)
and tert-butyldimethylsilyl chloride (161 mg, 1.5 equiv) in
anhydrous pyridine (4 mL) was stirred for 20 h under N2
atmosphere. After dilution with ethyl acetate, the organic
extract was washed with a saturated aqueous solution of NH4-
Cl and with brine and dried over MgSO4. After concentration
in vacuo, the crude product was purified by column chroma-
tography on silica gel (eluent petroleum ether/Et2O/EtOAc 5/4/
1). We obtained 285 mg (80%) of 28 along with 90 mg of
starting product: [R]Hg +49.0 (c 0.6, CHCl3); IR (CHCl3) ν cm-1
3392 (NH), 2984-2957 (CH), 1691 (CdO), 1111 (SiO); 1H NMR
(250 MHz, CDCl3) δ 8.72 (bs, 1H), 7.67-7.38 (m, 11H), 7.45
(dd, 1H, J ) 5.7, 8.4 Hz), 4.33 (ddd, 1H, J ) 2.4, 3.2, 7.2 Hz),
4.16 (dd, 1H, J ) 1.5, 3.2 Hz), 3.71 (m, 2H), 3.43 (ddd, 1H, J
) 1.5, 6.2, 8.0 Hz), 2.32 (ddd, 1H, J ) 2.4, 5.7, 13.6 Hz), 1.94
(ddd, 1H, J ) 7.2, 8.4, 13.6 Hz), 1.87 (s, 3H), 1.09 (s, 9H), 0.90
(s, 9H), 0.05 (s, 6H); 13C NMR (62.9 MHz, CDCl3) δ 163.9,
150.5, 135.8, 135.7, 135.6, 133.0, 132.9, 130.2, 130.1, 128.0,
127.9, 111.3, 83.8, 83.5, 75.1, 64.3, 55.0, 40.6, 26.9, 25.8, 19.0,
18.2, 12.7, -5.37, - 5.44; MS (DCI, NH3) 704 (MNH4+, 85),
(3S,4R,5R)-Met h yl [6-[(p -Br om ob en zyl)oxy]-3-[(ter t-
bu tyld ip h en ylsilyl)oxy]-4,5-ep oxy]h exa n oa te (23). To a
solution of epoxy ester 22 (516 mg, 1.5 mmol) in anhydrous
DMF (6 mL) were added imidazole (637 mg, 10 mmol) and
then tert-butyldiphenylsilyl chloride (0.582 mL, 2.25 mmol).
The mixture was stirred at room temperature for 12 h and
then hydrolyzed with an aqueous saturated NH4Cl solution
(3 mL) and extracted with ether (3 × 10 mL). The organic
phases were washed with an aqueous saturated NaCl solution
and then dried over MgSO4 and solvent evaporated. The crude
product was purified by silica gel column chromatography
(eluent petroleum ether/Et2O 8/2) to yield compound 23 (811
mg, 93%): Rf ) 0.16; [R]D +7.4° (c 0.6, CHCl3); IR (CHCl3) ν
cm-1 3029 (dCH), 1736 (CdO), 1593 (CdC), 1109 (CO); 1H
NMR (250 MHz, C6D6) δ 7.74-7.68 (m, 4H), 7.24 and 6.77
(A2B2 system, 4H, J ) 8.4 Hz), 7.17-7.14 (m, 6H), 4.18 (m,
1H), 3.98 and 3.86 (AB system, 2H, J ) 12 Hz), 3.29 (s, 3H),
2.95 (m, 2H), 2.84 (m, 1H), 2.78-2.70 (m, 3H), 1.09 (s, 9H);
13C NMR (63 MHz, C6D6) δ 170.8, 137.6, 136.3, 136.2, 133.7,
133.4, 131.6, 130.3, 129.4, 128.0, 72.0, 68.4, 68.1, 57.8, 57.2,
51.3, 41.3, 26.9, 19.5. Anal. Calcd for C30H35BrO5Si: C, 61.74;
H, 6.04. Found: C, 61.88; H, 6.03.
(4S,5S,1′S)-5-(1′-Br om o-2′-h yd r oxyeth yl)-4-[(ter t-bu tyl-
d ip h en ylsilyl)oxy]-2-oxo-1-oxa cyclop en ta n e (24). A mix-
ture of 23 (2.6 g, 3.2 mmol), EtOH (25 mL), and 10% Pd/C
(200 mg) was degassed and then pressurized with H2. After
being shaken at 20 °C for 3 h, the mixture was filtered on
Celite and then concentrated in vacuo. The residue was
purified by column chromatography on silica gel (eluent
petroleum ether/CH2Cl2/EtOAc 5/4/1) to give 1.7 g (85%) of the
desired compound: Rf ) 0.33; [R]Hg +40.16° (c 1.0, CHCl3); IR
(CHCl3) ν cm-1 3615 (OH), 3074 (CH arom.), 2934 (CH), 1786
(CdO), 1590, 1471 (CHd arom), 1111 (SiO); 1H NMR (250
MHz, CDCl3) δ 7.68-7.59 (m, 4H), 7.50-7.40 (m, 6H), 4.55
(dd, 1H, J ) 1.8, 2.2 Hz), 4.43 (ddd, 1H, J ) 2.2, 3.3, 7.5 Hz),
3.69 (m, 2H), 3.32 (td, 1H, J ) 1.8, 7.0 Hz), 2.55 and 2.85 (AB
part of an ABX system, 2H, J ) 3.3, 7.5, 18.4 Hz), 1.08 (s,
9H); 13C NMR (62.9 MHz, CDCl3) δ: 174.9, 135.7-135.6, 132.7,
132.3, 130.5, 130.4, 128.2, 128.1, 85.4, 72.3, 63.8, 54.5, 38.4,
26.8, 18.9; MS (DCI, NH3) 480 (MNH4+, 93). Anal. Calcd for
C
22H27BrO4Si: C, 57.02; H, 5.87. Found: C, 56.96; H, 6.21.
(4S,5S,1′S)-5-[1′-Br om o-2′-[(ter t-bu tyldim eth ylsilyl)oxy]-
eth yl]-4-[(ter t-bu tyld ip h en ylsilyl)oxy]-2-oxo-1-oxa cyclo-
p en ta n e (25). A mixture of 24 (446 mg, 0.96 mmol) and tert-
butyldimethylsilyl chloride (220 mg, 1.5 equiv) in anhydrous
pyridine (6 mL) was stirred for 22 h. After dilution with ethyl
acetate, the mixture was washed with a saturated aqueous
solution of NH4Cl and with brine and dried over MgSO4. After
concentration in vacuo and filtration on silica gel (eluent
petroleum ether/CH2Cl2/EtOAc 5/4/1), 580 mg (100%) was
obtained: IR (CHCl3) ν cm-1 3072 (CH arom), 2956-2932
(CH), 1796 (CdO), 1590, 1471 (CHd arom), 1112 (SiO); [R]Hg
+28.1° (c 1.3, CHCl3); 1H NMR (250 MHz, CDCl3) δ 7.65-7.58
(m, 4H), 7.48-7.39 (m, 6H), 4.73 (dd, 1H, J ) 1.5, 2.0 Hz),
4.40 (ddd, 1H, J ) 2.0, 3.3, 7.7 Hz), 3.69 (m, 2H), 3.33 (ddd,
1H, J ) 1.5, 6.1, 8.8 Hz), 2.55 and 2.87 (AB part of an ABX
system, 2H, J ) 3.3, 7.7, 18.3 Hz), 1.07 (s, 9H), 0.88 (s, 9H),
0.05 (s, 6H); 13C NMR (62.9 MHz, CDCl3) δ 174.9, 135.7, 135.6,
132.6, 130.4, 130.3, 127.7, 127.6, 84.6, 72.2, 63.6, 52.8, 38.6,
26.8, 25.7, 18.9, 18.1, -5.4; MS (DCI, NH3) 594 (MNH4+, 89).
Anal. Calcd for C28H41BrO4Si2: C, 58.21; H, 7.15. Found: C,
57.71; H, 7.15.
(4S,5S,1′S)-5-[1′-Br om o-2′-[(ter t-bu tyldim eth ylsilyl)oxy]-
et h yl]-4-[(ter t-b u t yld ip h en ylsilyl)oxy]-2-a cet oxy-1-oxa -
cyclop en ta n e (26). Diisobutylaluminum hydride (1.8 mL, 1.2
equiv) was added dropwise to a solution of 25 (800 mg, 1.4
mmol) in toluene (3.6 mL) at -78 °C under N2 atmosphere.
The mixture was stirred for 1 h and then hydrolyzed with HCl
(0.25 M). The mixture was extracted with Et2O, washed with

2608 J . Org. Chem., Vol. 63, No. 8, 1998
Dehoux et al.
687 (MH+, 15). Anal. Calcd for C33H47BrO5Si: C, 57.63; H,
6.89; N, 4.07. Found: C, 57.64; H, 7.05; N, 4.05.
(3S,4S,5R)-Meth yl [6-[(ter t-bu tyld ip h en ylsilyl)oxy]-4,5-
ep oxy-3-h yd r oxy]h exa n oa te (34). The aldolization reaction
was performed as previously described.16 Starting from
(2R,3R)-4-[(tert-butyldiphenylsilyl)oxy]-2,3-epoxybutan-1-al (1
g, 2.94 mmol), we obtained after purification by silica gel
column chromatography (eluent petroleum ether/CH2Cl2/
EtOAc 5/4/1) the desired compound 34 (960 mg, 79% yield):
Rf ) 0.27; [R]D -6.3° (c 0.7, CHCl3); IR (CHCl3) ν cm-1 3599
(OH), 3007 (dCH), 1732 (CdO), 1200, 1110 (CO); 1H NMR (250
MHz, C6D6) δ 7.78-7.72 (m, 4H), 7.24-7.20 (m, 6H), 3.90 and
3.84 (AB part of an ABX(Y) system, 2H, J ) 4.9, 6.2, 12 Hz),
3.80 (m, 1H), 3.22 (s, 3H), 3.07 (ddd, 1H, J ) 4.2, 4.9, 6.2 Hz),
2.95 (d, 1H, J ) 4 Hz), 2.79 (dd, 1H, J ) 4.2, 7.9 Hz), 2.46 and
2.38 (A′B′ part of an A′B′X′(Y) system, 2H, J ) 4, 8.1, 16.1
Hz), 1.13 (s, 9H); 13C NMR (63 MHz, C6D6) δ 172.0, 136.0,
133.5, 130.1, 128.3, 66.6, 62.9, 57.5, 57.0, 51.3, 39.3, 27.0, 19.4;
MS (DCI, NH3) 560 (MNH4+, 100). Anal. Calcd for C23H30O5-
Si: C, 66.63; H, 7.29. Found: C, 66.62; H, 7.39.
Syn th esis of 29-32. Rea ction of Com p ou n d 28 w ith
Sod iu m Azid e. A mixture of 28 (145 mg, 0.21 mmol) in DMF
(2 mL) and NaN3 (18 mg, 1.3 equiv) was stirred at 60 °C under
N2. After 24 h, the reaction was not complete. NaN3 (15 mg)
was added. The mixture was stirred for 12 h. DMF was
evaporated, and the crude product was diluted with water and
washed with a saturated aqueous solution of NaCl. After
drying and concentration, the residue was purified by column
chromatography on C18 silica gel (eluent CH3CN/H2O 3/2) to
give 27 mg of 30 (26%), 29 mg of 29 (26%), and 26 mg of a 31
and 32 mixture (3 and 17%, respectively).
(3S,4R,5S)-1-[5-Azid o-2,5-d id eoxy-6-h yd r oxy-4-O-(ter t-
bu tyld ip h en ylsilyl)h exofu r a n osyl)-5-m eth ylu r a cil (29):
[R]Hg +20.8 (c 0.8, CHCl3); IR (CHCl3) ν cm-1 3694 (OH), 3390
(NH), 3074 (CH arom), 2971, 2962, 2933 (CH), 1693 (CdO),
1590, 1507 (CdC), 1113 (SiO), 1043 (CO); 1H NMR (250 MHz,
CDCl3) δ 8.91 (bs, 1H), 7.69-7.62 (m, 4H), 7.51-7.31 (m, 6H),
7.13 (d, 1H, J ) 1.2 Hz), 6.26 (dd, 1H, J ) 5.7, 8.6 Hz), 4.42
(ddd, 1H, J ) 2.2, 2.3, 6.0 Hz), 4.02 (dd, 1H, J ) 2.3, 4.4 Hz),
3.70-3.55 (m, 2H), 3.40 (m, 1H), 2.20 and 2.24 (AB part of an
ABXY system + bs, 3H, J ) 2.2, 5.7, 6.0, 8.6, 13.4 Hz), 1.88
(s, 3H, J ) 1.2), 1.08 (s, 9H); 13C NMR (62.9 MHz, CDCl3) δ
163.5, 150.4, 135.9, 135.8, 135.7, 132.9, 132.7, 130.3, 130.2,
111.5, 86.2, 85.9, 73.3, 64.5, 62.3, 39.4, 26.9, 19.1, 12.5; MS
(DCI, NH3) 553 (MNH4+, 100), 536 (MH+, 38).
(3S )-1-[4-(2-H yd r oxye t h ylid e n e )-3-O-(t er t -b u t yld i-
p h en ylsilyl)-2,5-d id eoxyh exofu r a n osyl]-5-m et h ylu r a cil
(30): [R]Hg +13.5 (c 2.8, CHCl3); IR (CHCl3) ν cm-1 3612 (OH),
3390 (NH), 2997, 2961, 2934, 2893 (CH), 1695 (CdO thym),
1429 (CdC), 1111 (SiO), 1086, 1046 (CO); 1H NMR (250 MHz,
CDCl3) δ 8.95 (bs, 1H), 7.70-7.65 (m, 4H), 7.46-7.37 (m, 6H),
6.84 (d, 1H, J ) 1.2 Hz), 6.67 (dd, 1H, J ) 6.0, 7.4 Hz), 4.68
(dd, 1H, J ) 2.3, 5.6 Hz), 4.47 (t, 1H, J ) 6.9 Hz), 4.09 (m,
2H), 2.44 and 1.95 (AB part of an ABXY system, 2H, J ) 2.3,
5.6, 6.0, 7.4, 13.5 Hz), 1.86 (d, 3H, J ) 1.2 Hz), 1.06 (s, 9H);
13C NMR (62.9 MHz, CDCl3) δ: 163.4, 156.3, 150.1, 135.9,
135.8, 134.4, 133.0, 132.8, 130.2, 130.1, 128.0, 127.7, 112.0,
101.4, 86.1, 71.9, 56.9, 39.9, 26.8, 19.1, 12.6; MS (DCI, NH3)
510 (MNH4+, 100), 492 (MH+, 6).
(3S)-1-[4-[2-[(ter t-Bu tyld ip h en ylsilyl)oxy]eth ylid en e]-
3-O-(ter t-bu tyldiph en ylsilyl)-2,5-dideoxy-h exofu r an osyl]-
5-m eth ylu r a cil (31). A solution of 28 (60 mg, 0.096 mmol)
and diazabicycloundecene (15 µL, 1.1 equiv) in anhydrous
DMF (1 mL) was stirred for 12 h at 60 °C. The temperature
was raised to room temperature. Then, a saturated Na2SO3
solution was added. After extraction with EtOAc, the organic
layer was washed with water, dried over MgSO4, and concen-
trated. The crude product was purified on silica gel (eluent
petroleum ether/Et2O/EtOAc 5/4/1) to give 37 mg (67%) of the
compound 31: Rf ) 0.28; [R]Hg +14.2 (c 1.6, CHCl3); IR (CHCl3)
ν cm-1 3393 (NH), 2958, 2859 (CH), 1694 (CdO thym), 1110
(O-Si); 1H NMR (250 MHz, CDCl3) δ 8.63 (bs, 1H), 7.69-7.64
(m, 4H), 7.45-7.36 (m, 6H), 6.84 (d, 1H), 6.70 (dd, 1H, J )
5.9, 7.4 Hz), 4.66 (dd, 1H, J ) 2.1, 5.5 Hz), 4.46 (dd, 1H, J )
5.5, 7.6 Hz), 4.28 and 4.25 (AB part of an ABX system, 2H, J
) 5.5, 7.6, 12.5 Hz), 2.37 (m, 1H), 1.86 (m, 1H), 1.86 (d, 3H),
1.07 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H); 13C NMR (62.9 MHz,
CDCl3) δ 163.3, 154.6, 150.0, 135.9-135.8, 134.1, 133.0-132.9,
130.1-130.0, 127.9-127.7, 111.9, 102.6, 85.5, 71.8, 57.6, 40.2,
26.8, 25.6, 19.1, 18.4, 12.5, 5.2, 5.1; MS (DCI, NH3) 624
(MNH4+, 100), 607 (MH+, 2.2).
(3S,4S,5S)-Meth yl [5-Iod o-6-(ter t-bu tyld ip h en ylsilyl)-
oxy]h exa n oa te (35). A solution of 34 (2.1 g, 5.3 mmol) in
toluene (50 mL) was added at -78 °C to a suspension of MgI2
(1.4 g, 1 equiv) in Et2O. After being stirred for 19 h at -78
°C, a saturated aqueous solution of Na2SO3 was added. The
resulting mixture was extracted with Et2O. The organic layers
were washed with water and brine and dried over MgSO4.
After concentration, column chromatography on silica gel
(petroleum ether/Et2O/EtOAc 15/6/4, Rf ) 0.31) gave 2.2 g
(80%) of the desired compound: [R]Hg -12.4 (c 0.7, CHCl3); IR
(KBr) ν cm-1 3472 (OH), 3071 (CH arom), 2931, 2858 (CH),
1725 (CdO), 1173 (CO), 1110 (SiO); 1H NMR (250 MHz, CDCl3)
δ 7.73-7.64 (m, 4H), 7.46-7.37 (m, 6H), 4.74 (td, 1H, J ) 1.3-
5.0 Hz), 4.05 (d, 2H), 3.85 (dddd, 1H, J ) 2.8, 5.6, 8.7 Hz),
3.72 (s, 3H), 3.29 (d, 1H, J ) 5 Hz), 2.94 and 2.57 (AB part of
an ABX(Y) system, 2H, J ) 2.8, 8.7, 16.9 Hz), 2.86 (ddd, 1H,
J ) 1.3, 5.0, 8.7 Hz), 2.74 (d, 1H, J ) 5.6 Hz), 1.08 (s, 9H); 13
C
NMR (62.9 MHz, C6D6) δ 173.7, 135.7, 135.5, 132.6, 132.2,
130.0, 127.9, 73.8, 71.6, 68.6, 51.8, 40.7, 37.0, 26.8, 19.2; MS
(DCI, NH3) 560 (MNH4+, 100).
(3S,4S,5S)-Meth yl [5-Iod o-6-[(ter t-bu tyld ip h en ylsilyl)-
oxy]-3,4-bis[(tr im eth ylsilyl)oxy]h exa n oa te (36). To a so-
lution of 35 (500 mg, 0.92 mmol) in pyridine (5 mL) at -78 °C
under N2 atmosphere were added distilled hexamethyldisila-
zane (0.430 mL) and trimethylsilyl chloride (0.260 mL). The
mixture was stirred for 12 h. A saturated aqueous solution
NH4Cl was added. The aqueous layer was extracted with
Et2O. The organic extract was washed with water and brine
and dried over MgSO4. After concentration, 620 mg (98%) of
the desired compound was obtained: [R]Hg -2.7 (c 0.7, CHCl3);
IR (KBr) ν cm-1 3078 (CH arom), 2955, 2859 (CH), 1744 (CdO),
1
1253 (CO + SiO), 1113 (COSi); H NMR (250 MHz, CDCl3) δ
7.66-7.62 (m, 4H), 7.47-7.34 (m, 6H), 4.38 (ddd, 1H, J ) 1.6,
6.5, 8.5 Hz), 4.04 (td, 1H, J ) 3.6, 7.2 Hz), 3.88-3.85 (m, 2H),
3.69 (s, 3H), 3.35 (dd, 1H, J ) 1.6, 7.2 Hz), 2.70 and 2.51 (AB
part of an ABX(Y) system, 2H, J ) 3.6, 7.2, 14.9 Hz), 1.07 (s,
9H), 0.16-0.14 (9H, s); 13C NMR (62.9 MHz, CDCl3) δ: 172.0,
135.8, 135.7, 133.4, 133.2, 130.2, 130.1, 128.1, 128.0, 73.6, 72.9,
66.7, 51.6, 41.5, 39.3, 27.1, 19.4, 1.0-0.8; MS (DCI, NH3) 704
(MNH4+, 100).
Ack n ow led gm en t. We thank Chantal Zedde for
liquid chromatography assistance. Financial support by
MESR and CNRS is gratefully acknowledged.
J O972116S