Electrophilic azidation for stereoselective synthesis of 2-azido-2-deoxyaldono-1,5-lactones

Full text of DOI:10.1021/jo005728c

3220
J . Org. Chem. 2001, 66, 3220-3223
Sch em e 1
Electr op h ilic Azid a tion for Ster eoselective
Syn th esis of
2-Azid o-2-d eoxya ld on o-1,5-la cton es
J . S. Dileep Kumar,† Franc¸ois-Yves Dupradeau,‡
M. J ane Strouse,§ Michael E. Phelps,† and
Tatsushi Toyokuni*,†
Crump Institute for Molecular Imaging, Department of
Molecular and Medical Pharmacology, UCLA School of
Medicine, Los Angeles, California 90095-1770, and
Department of Chemistry and Biochemistry, UCLA,
Los Angeles, California 90095-1569
ttoyokuni@mednet.ucla.edu
Received November 8, 2000
In tr od u ction
Aldonolactones are versatile chiral synthons for the
synthesis of various natural products and their ana-
logues.1 Aldonolactones derived from 2-azido-2-deoxyal-
doses are of particular interest for the synthesis of highly
functionalized R-amino acids and nitrogen heterocycles.2
Although being abundant in nature, 2-amino-2-deoxysug-
ars, except for the gluco derivatives, are not readily
available because these sugars are difficult to isolate from
natural sources. Consequently, a number of methods
have been developed for the practical synthesis of 2-amino-
2-deoxysugars, as exemplified by azidonitration3 and
azidophenylselenylation4 of glycals. Both methods yield
2-azido-2-deoxysugars, which are not only the precursors
for 2-amino-2-deoxysugars but are also useful glycosyl
donors in oligosaccharide synthesis in which R-linked
2-amino-2-deoxysugars are required.5 The aldonolactones
are in general synthesized by oxidation of the corre-
sponding aldoses.6 However, oxidation of 2-azido-2-deoxy-
aldoses is often accompanied by partial epimerization of
the azido group.6c,7 Alternatively, 2-azido-2-deoxyaldono-
1,5-lactones can be prepared by the nucleophilic azide
ion displacement of 2-O-sulfonate lactones, which also
suffer a similar epimerization.8 It is reported that oxida-
tion of 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-mannopyra-
nose (i.e., 8 in Scheme 1) resulted in a complete epimer-
ization to the gluco isomer.6c The axial azide group at
C-2 tends to epimerize during oxidation.6c,7,9 No practical
route to 2-azido-2-deoxy-D-mannono-1,5-lactone (e.g., 7)
has yet been reported.
Electrophilic azide transfer from arylsulfonyl azides to
enolates has proven to be a practical approach to the
asymmetric synthesis of R-amino acids.10,11 Although
being highly stereoselective, this enol-azidation reaction
has never been exploited for the synthesis of aminosugar
derivatives. Here we report that the electrophilic azida-
tion reaction is a highly stereoselective route to 2-azido-
2-deoxyaldono-1,5-lactones.12
* To whom correspondence should be addressesed. Tel: (310) 206-
1675. Fax: (310) 206-8975.
Resu lts a n d Discu ssion
† School of Medicine.
2-Deoxyaldono-1,5-lactones 213 and 614 (Scheme 1) were
prepared from the corresponding glycals (115 and 5,16
‡ F.-Y.D. carried out preliminary studies at the former Biomembrane
Institute, Seattle WA. Current address: Biomole´cules et Pathologies
De´ge´ne´ratives, Faculte´ de Pharmacie et de Me´decine, UPRES EA 2629,
1-3 rue des Louvels, 80037 Amiens Cedex 1, France.
§ Department of Chemistry and Biochemistry.
(1) Some reviews: (a) Monneret, C.; Florent, J .-C. Synlett 1994,
305-318. (b) De Lederkremer, R. M.; Varela, O. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 125-209. (c) Ferrier, R. J .; Blattner, R.; Clinch,
K.; Furneaux, R. H.; Gardiner, J . M.; Tyler, P. C.; Wightman, R. H.;
Williams, N. R. Carbohydr. Chem. 1996, 28, 199-213. (d) Varela, O.
Pure Appl. Chem. 1997, 69, 621-626. (e) Lundt, I. Top. Curr. Chem.
1997, 187, 117-156. (f) Fleet, G. W. J .; Estevez, J . C.; Smith, M. D.;
Bleriot, Y.; de la Fuente, C.; Krulle, T. M.; Besra, G. S.; Brennan, P.
J .; Nash, R. J .; J ohnson, L. N.; Oikonomakos, N. G.; Stalmans, W. Pure
Appl. Chem. 1998, 70, 279-284.
(6) (a) Pravdic, N.; Danilov, B.; Fletcher, H. G., J r. Carbohydr. Res.
1974, 36, 168-180. (b) Benhaddou, R.; Czernecki, S.; Farid, W.; Ville,
G.; Xie, J .; Zegar, A. Carbohydr. Res. 1994, 260, 243-250. (c) Ayadi,
E.; Czernecki, S.; Xie, J . J . Carbohydr. Chem. 1996, 15, 191-199.
(7) (a) Kuzuhara, H.; Oguchi, N.; Ohrui, H.; Emoto, S. Carbohydr.
Res. 1972, 23, 217-222. (b) Oxidation of 2-acetamido-2-deoxyaldoses
is also reported to yield their 2-epimers, see: Pravdic, N. Carbohydr.
Res. 1971, 19, 353-364.
(8) (a) Bruce, I.; Fleet, G. W. J .; Girdhar, A.; Haraldsson, M.; Peach,
J . M.; Watkin, D. J . Tetrahedron 1990, 46, 19-32. (b) Fairbanks, A.
J .; Ford, P. S.; Watkins, D. J .; Fleet, G. W. J . Tetrahedron Lett. 1993,
34, 3327-3330.
(9) Ali, Y.; Richardson, A. C. Carbohydr. Res. 1967, 5, 441-448.
(10) (a) Evans, D. A.; Britton, T. C. J . Am. Chem. Soc. 1987, 109,
6881-6883. (b) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R.
L. J . Am. Chem. Soc. 1990, 112, 4011-4030.
(11) See also a review on the electrophilic amination of carbanions:
Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J . 2000, 6, 1281-1286.
(12) A preliminary account has been published: Dupradeau, F.-Y.;
Hakomori, S.; Toyokuni, T. J . Chem. Soc., Chem. Commun. 1995, 221-
222.
(2) For example: (a) Baird, P. D.; Dho, J . C.; Fleet, G. W.; Peach, J .
M.; Prout, K.; Smith, P. W. J . Chem. Soc., Perkin Trans. 1 1987, 1785-
1791. (b) Fairbanks, A. J .; Elliott, R. P.; Smith, C.; Hui, A.; Way, G.;
Storer, R.; Taylor, H.; Watkin, D. J .; Winchester, B. G.; Fleet, G. W. J .
Tetrahedron Lett. 1993, 34, 7953-7956. (c) Dodd, R. H. Molecules 2000,
5, 293-298.
(3) Lemieux, R. U.; Ratcliffe, R. M. Can. J . Chem. 1979, 57, 1244-
1251.
(4) (a) Santoyo-Gonza´lez, F.; Calvo-Flores, F. G.; Garc´ıa-Mendoza,
P.; Herna´ndez-Mateo, F.; Isac-Garc´ıa, J .; Robles-D´ıaz, R. J . Org. Chem.
1993, 58, 6122-6125. (b) Czernecki, S.; Ayadi, E.; Randriamandimby,
D. J . Org. Chem. 1994, 59, 8256-8260.
(5) Banoub, J .; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92,
1167-1195.
(13) Rollin, P.; Sinay¨, P. Carbohydr. Res. 1981, 98, 139-142. This
paper reported the direct oxidation of glycals to lactones. However, in
our hands, this procedure yielded 2 and 6 with various amounts of
R,â-unsaturated lactones (see also ref 6b).
10.1021/jo005728c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/29/2001

Notes
J . Org. Chem., Vol. 66, No. 9, 2001 3221
Sch em e 2
F igu r e 1. NOE between H-2ax and H-5 observed in 6, 7, 11,
and 12 implies their B2,5 conformations.
respectively) by nucleophilic hydroxylation17 and subse-
quent oxidation6 in the overall yields of 73% and 79%,
respectively. It is reported that aldono-1,5-lactones favor
half-chair and boat conformations to compromise the
constraints caused by the planarity of the lactone moi-
ety.18 Conformations of 2 and 6 were therefore estab-
lished based on their 1H NMR investigation.19 The J
values found for 2 were almost identical to those of tri-
O-benzyl-2-deoxy-D-galactose17e except for the somewhat
larger J 2eq,3 (6.5 Hz), indicating its 4C1 conformation20
with some degree of flexibility at C-2. On the other hand,
6 had J 2ax,3 ) J 2eq,3 ) J 3,4 ) 4.5 Hz and J 4,5 ) 7.5 Hz,
suggesting a slightly distorted B2,5 conformation, which
was further substantiated by NOE between H-2ax and
H-5 (Figure 1). Interestingly, 6 favors the B2,5 conforma-
tion similarly to D-mannono-1,5-lactone18c rather than the
flattened 4C1 conformation of D-glucono-1,5-lactone.18 This
explains the fact that the 2-deoxy-glucono-1,5-lactone is
more prone to the â-elimination reaction than the 2-deoxy-
galactono-1,5-lactone.13,21 For example, the B2,5 conforma-
tion of 6 orients the H-2ax and the oxygen group at C-3
anticoplanar, a required configuration for the E2 reaction.
Electrophilic azidation of 2 and 6 was then carried out
according to the procedure reported by Evans et al.10
Thus, the potassium enolates derived from 2 and 6,
generated with 1.1 equiv of potassium bis(trimethylsilyl)-
amide (potassium hexamethyldisilylamide, KHMDS) in
THF (-90 °C, 15 min), were treated with 1.2 equiv of
2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide)22 at
-90 °C for 2 min. After addition of 1.2 equiv of AcOH,
the triazine intermediates were fragmented to the cor-
responding azides by slowly warming to room tempera-
ture (overnight). The 2-azido-2-deoxyaldono-1,5-lactones
323 (from 2) and 7 (from 6) were isolated in 70% and 50%
yields, respectively, after flash column chromatography
on silica gel. In either case no corresponding 2-epimers
were detected. The H NMR data accorded with a C1 for
3 (J 2,3 ) 10.5 Hz, J 3,4 ) 2.0 Hz, J 4,5 ) ∼0.5 Hz) and a B2,5
for 7 (J 2,3 ) 3.5 Hz, J 3,4 ) 1.5 Hz, J 4,5 ) 6.0 Hz, and NOE
between H-2 and H-5). The azide transfer took place
exclusively at more accessible equatorial positions. Elec-
trophilic azidation of 2 thus allowed the first practical
synthesis of the 2-azido-2-deoxy-D-mannono-1,5-lactone
7. Selective reduction of 3 and 7 with DIBALH furnished
the 2-azido-2-deoxyaldoses 424 and 8, respectively, with-
out any epimerization at C-2. Electrophilic azidation and
subsequent DIBALH reduction can be carried out in the
same pot25 without isolation of 3 and 7.
1
4
Next, the electrophilic azidation of a disaccharide
enolate was investigated. The 2-deoxy-D-lactose 1026
(Scheme 2) was prepared from hexa-O-benzyl-D-lactal17e
(9) using the mercuration-reductive demercuration se-
quence as reported17e in 80% yield. The subsequent
oxidation of 10 with PCC gave the 2-deoxy-1,5-lactone
11 in 75% yield together with the lactal 9 in 15% yield.
It is conceivable that 9 was formed from the R-chromate
ester intermediate by competing elimination. The 1H
NMR data of the 2-deoxy-D-glucono-1,5-lactone moiety of
11 (J 2ax,3 ) J 2eq,3 ) 3.0 Hz, J 3,4 ) 2.5 Hz, J 4,5 ) 6.0 Hz,
and NOE between H-2aq and H-5) were in good agree-
ment with a slightly distorted B2,5 conformation. Elec-
trophilic azidation of the potassium enolate derived from
11 with trisyl azide, followed by workup similar to those
described above, resulted in a stereoselective azide
transfer yielding the equatorial azide derivative 12 in
60% yield, whose 1,5-lactone moiety was found to adopt
(14) Bernasconi, C.; Cottier, L.; Descotes, G.; Re´my, G. Bull. Soc.
Chim. Fr. 1979, 5-6. II-332-II-336.
(15) Bovin, N. V.; Zurabyan, S. EÄ .; Khorlin, Y. Carbohydr. Res. 1981,
98, 25-35.
(16) Boullanger, P.; Martin, J .-C.; Descotes, G. J . Heterocycl. Chem.
1975, 12, 91-93.
(17) For example: (a) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck,
J . R. J . Org. Chem. 1990, 55, 5812-5813. (b) Sabesan, S.; Neira, S. J .
Org. Chem. 1991, 56, 5468-5472. (c) Wild, R.; Schmidt, R. R.; Liebigs
Ann. Chem. 1995, 755-763. (d) Barnes, N. J .; Probert, M. A.;
Wightman, R. H. J . Chem. Soc., Perkin Trans. 1 1996, 431-438. (e)
Bettelli, E.; Cherubini, P.; D’Andrea, P.; Passacantilli, P.; Piancatelli,
G. Tetrahedron 1998, 54, 6011-6018.
1
a B2,5 conformation on the basis of its H NMR data (J 2,3
) 3.0 Hz, J 3,4 ) 1.5 Hz, J 4,5 ) 6.5 Hz, and NOE between
H-2 and H-5). In addition to the azide-transfer product
12, a 15% yield of the diazo-transfer product 13 was also
obtained.27 Although diazo compounds are useful syn-
thetic intermediates,28 only a few diazo sugars have so
(18) For example: (a) Hackert, M. L.; J acobson, R. A. Acta Crystal-
logr. 1971, B27, 203-109. (b) Nelson, C. R. Carbohydr. Res. 1982, 106,
155-159. (c) Walaszek, Z.; Horton, D.; Ekiel, I. Carbohydr. Res. 1982,
106, 193-201. (d) Hu¨rzeler, M.; Bernet, B.; Vasella, A. Helv. Chim.
Acta 1993, 76, 995-1012.
(19) See the Experimental Section for 1H NMR data of 2, 6, and
tri-O-benzyl-2-deoxy-D-galactose.
(23) Dondoni, A.; Scherrmann, M.-C. J . Org. Chem. 1994, 59, 6404-
6412.
(20) Conformations are symbolized by the first letter of the general
ring shape, e.g., chair ) C; boat ) B. A reference plane is selected to
have the maximum number of ring atoms. Superscript and subscript
numbers describe the atoms above and below the reference plane,
respectively (see Figure 1).
(21) Mlynarski, J .; Banaszek, A. Tetrahedron 1999, 55, 2785-2794.
(22) Harmon, R. E.; Wellman, G.; Gupta, S. K. J . Org. Chem. 1973,
38, 11-16.
(24) Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826-
1847.
(25) The one-pot procedure was given in the Experimental Section.
(26) Kinzy, W.; Schmidt, R. R. Carbohydr. Res. 1987, 166, 265-
276.
(27) The diazo transfer reaction using trisyl azide has been reported
for hindered enolates under phase transfer conditions: Lombardo, L.;
Mander, L. Synthesis 1980, 368-369.

3222 J . Org. Chem., Vol. 66, No. 9, 2001
Notes
(dd, 1, J ) 10.0, 9.0 Hz) (2 × H-6), 4.15 (br s, 1, H-4), 4.31 (ddd,
1, J ) 9.0, 6.0, ∼0.5 Hz, H-5), 4.59 (d, 1, J ) 10.5 Hz, H-2).
HRMS: cacld for C27H27N3O5 + Na 496.1848, found 496.1839.
Tr i-O-ben zyl-2-a zid o-2-d eoxy-D-m a n n on o-1,5-la cton e (7).
Electrophilic azidation of 6 was carried out as described above
to yield 7 (50%) as a colorless oil: [R]D +6 (c 0.06, CHCl3); 1H
NMR (500 MHz) δ 3.66 (d, 2, J ) 4.5 Hz, 2 × H-6), 3.90 (dd, 1,
J ) 6.0, 1.5 Hz, H-4), 4.05 (dd, 1, J ) 3.5, 1.5 Hz, H-3), 4.14 (d,
1, J ) 3.5 Hz, H-2), 4.33 (m, 1, H-5). HRMS: cacld for
C27H27N3O5 + Na 496.1848, found 496.1848.
far been synthesized from the corresponding keto sug-
ars29 and aldoximes30 in a stepwise fashion. According
to Evans et al.,10 the use of p-nitrobenzenesulfonyl azide
may lead to diazo transfer with minimal competing azide
transfer.
Con clu sion
We have shown that electrophilic azidation of enolates
derived from 2-deoxyaldono-1,5-lactones is a highly ste-
reoselective route to 2-azido-2-deoxyaldono-1,5-lactones.
This enol-azidation reaction, coupled with the subsequent
in situ reduction of lactone to lactol, provides a highly
stereoselective alternative to the existing methods for the
synthesis of 2-azido-2-deoxyaldoses. Further extension of
the azide transfer reaction to the synthesis of various
aminosugars and their analogues is currently under way.
Tr i-O-ben zyl-2-a zid o-2-d eoxy-D-ga la ctop yr a n ose24 (4). A
solution of 3 (100 mg, 0.21 mmol) in THF (5 mL) was cooled to
-78 °C and a pre-cooled 1 M solution of DIBALH in toluene (0.23
mL, 0.23 mmol) was added dropwise. After 30 min, H2O (30 mL)
was added and the mixture was warmed to room temperature.
The mixture was acidified by a few drops of 6 M HCl and stirred
for 15 min. The product was extracted with CH2Cl2 (3 × 30 mL),
dried, and concentrated to dryness. Flash column chromatog-
raphy on silica gel with toluene-acetone (20:1) yielded known
4 (95 mg, 95%) as a colorless oil: R/â ) ∼2/1; 1H NMR (500 MHz)
δ 2.86 (br s, 1, OHR), 3.23 (br s, 1, OHâ), 3.35 (dd, 1, J ) 10.5,
3.0 Hz, H-3â), 3.47-3.60 (m, 5H, H-5â, 2 × H-6R, 2 × H-6â),
3.76 (dd, 1, J ) 10.5, 8.0, H-2â), 3.87 (br d, 1, J ) 3 Hz, H-4â),
3.92-3.98 (m, 3, H-2R, H-3R, H-4R), 4.16 (br t, 1, J ) 6 Hz,
H-5R), 5.32 (br d, 1, J ) 1 Hz, H-1R).
Exp er im en ta l Section
Gen er a l. All commercial materials were used without puri-
fication. THF and CH2Cl2 were distilled from sodium benzophe-
none ketyl and CaH2, respectively, under positive pressure of
dry argon. Trisyl azide was prepared as reported.22 All the
reactions were performed under an argon atmosphere. 1H NMR
spectra were recorded using either a Bruker AM360, Bruker
ARX400, or Bruker Avance 500 spectrometer in CDCl3 with TMS
as internal reference. Gradient NOESY experiments were
performed to determine the presence of interaction due to the
NOE. Signal assignments were done by extensive decoupling
experiments. HRMS (FAB) were recorded on a VG Analytical
70VSE spectrometer.
Tr i-O-ben zyl-2-a zid o-2-d eoxy-D-m a n n op yr a n ose
(8).
DIBALH reduction of 7 under the same condition as above
yielded 8 (87%) as a colorless oil; R/â ) 3.5/1; 1H NMR (500 MHz)
δ 3.65 (m, 2, 2 × H-6R), 3.69 (m, 2, 2 × H-6â), 3.71 (dd, 1, J )
9.0, 3.5 Hz, H-3â), 3.78 (dd, 1, J ) 9.0, 9.0 Hz, H-4R), 3.82 (dd,
1, J ) 9.5, 9.5 Hz, H-4â), 3.92 (dd, 1, J ) 4.0, 2.5 Hz, H-2R),
3.93 (m, 1, H-2â), 3.99 (ddd, 1, J ) 9.5, 5.0, 2.5 Hz, H-5R), 4.10
(dd, 1, J ) 9.0, 4.0 Hz, H-3R), 4.69 (br s, 1, H-1â), 5.19 (br s, 1,
H-1R). HRMS: cacld for C27H29N3O5 + Na 498.2005, found
498.2010.
On e-P ot P r oced u r e (2f3f4 a n d 6f7f8). A solution of
3/6 in THF was cooled to -90 °C and a 0.5 M solution of KHMDS
(1.1 equiv) was added dropwise with vigorous stirring. After 15
min, a pre-cooled 0.2 M solution of trisyl azide in THF (1.2 equiv,
-90 °C) was added dropwise. After another 2 min, AcOH (1.2
equiv) was added and the mixture was warmed gradually to
room temperature (overnight). The mixture was again cooled to
-70 °C and precooled DIBALH (2 equiv) was added. After 30
min, H2O was added and the mixture was warmed to room
temperature. The mixture was then acidified by a few drops of
6 M HCl and stirred for 15 min. The product was extracted with
CH2Cl2 and purified by flash column chromatography on silica
gel with toluene-acetone (20:1).
Tr i-O-ben zyl-2-d eoxy-D-ga la ctop yr a n ose17e (r/â ) 3.5/1).
1H NMR (500 MHz) δ 2.01 (ddd, 1, J ) 12.0, 4.5, ∼0 Hz, H-2eqR),
2.15 (br d, 1, J ) 12 Hz, H-2eqâ), 2.21 (ddd, 1, J ) 12.0, 11.0,
4.0 Hz, H-2axR), 3.50 (dd, 1, J ) 9.5, 5.5 Hz) and 3.58 (dd, 1, J
) 9.5, 5.5 Hz) (2 × H-6R), 3.63 (dd, 1, J ) 9.5, 6.0 Hz, H-6â),
3.81 (br s, 1, H-4â), 3.87 (br s, 1, H-4R), 3.98 (ddd, 1, J ) 11.0,
4.5, 3.0 Hz, H-3R), 4.13 (ddd, 1, J ) 5.5, 5.5, ∼0 Hz, H-5R), 5.45
(br d, 1, J ) 4.0 Hz, H-1R).
Tr i-O-ben zyl-2-d eoxy-D-ga la cton o-1,5-la cton e13 (2). 1H
NMR (360 MHz) δ 2.88 (dd, 1, J ) 17.5, 6.5 Hz, H-2eq), 2.97
(dd, 1, J ) 17.5, 11.0 Hz, H-2ax), 3.66 (dd, 1, J ) 9.0 5.5 Hz)
and 3.75 (br t, 1, J ) 9 Hz) (2 × H-6), 3.86 (ddd, 1, J ) 11.0, 6.5,
1.5 Hz, H-3), 4.17 (br s, 1, H-4), 4.32 (br td, J ) 5, 1 Hz, H-5).
Tr i-O-ben zyl-2-deoxy-D-glu con o-1,5-lacton e14 (6). 1H NMR
(500 MHz) δ 2.74 (dd, 1, J ) 15.0, 4.5 Hz, H-2eq), 2.84 (dd, 1, J
) 15.0, 4.5 Hz, H-2ax), 3.70 (dd, 1, J ) 10.5, 4.0 Hz) and 3.73
(dd, 1, J ) 10.5, 4.0 Hz) (2 × H-6), 3.89 (dd, 1, J ) 7.5, 4.5 Hz,
H-4), 3.94 (dd, 1, J ) 4.5, 4.5 Hz, H-3), 4.30 (ddd, 1, J ) 7.5, 4.0,
4.0 Hz, H-5).
Di-O-ben zyl-2-d eoxy-4-O-(tetr a -O-ben zyl-â-D-ga la ctop y-
r a n osyl)-D-glu con o-1,5-la cton e (11). A mixture of 10 (1.06 g,
1.18 mmol), PCC (0.8 g, 3.63 mmol), and molecular sieves (4 Å)
in CH2Cl2 (20 mL) was stirred at room temperature for 1 h. After
addition of ether (500 mL) and subsequent filtration, the mixture
was concentrated to dryness. Flash column chromatography on
silica gel with hexanes-EtOAc (4:1) yielded 11 (0.82 g, 80%) as
a colorless syrup together with the lactal 917e (0.13 g, 15%). 11:
[R]D +12.7 (c 1.4, CHCl3); 1H NMR (400 MHz) δ 2.81 (dd, 1, J )
16, 3.0 Hz, H-2eq), 2.86 (dd, 1, J ) 16, 3.0 Hz, H-2ax), 3.55 (dd,
1, J ) 9.5, 2.5 Hz, H-3′), 3.50-3.60 (m, 3, H-5′, 2 × H-6′), 3.70
(dd, 1, J ) 12.0, 5.0 Hz,) and 3.78 (dd, 1, J ) 12.0, 4.5 Hz,) (2 ×
H-6), 3.84 (dd, 1, J ) 9.5, 8.0 Hz, H-2′), 3.96 (br d, 1, J ) 3 Hz,
H-4′), 4.15 (dd, 1, J ) 6.0, 2.5 Hz, H-4), 4.27 (br q, 1, J ) 3 Hz,
H-3), 4.42 (br q, J ) 5 Hz, H-5), 4.46 (d, 1, J ) 8.0 Hz, H-1′).
HRMS: cacld for C54H56O10 + Na 887.3756, found 887.3748.
Di-O-ben zyl-2-a zid o-2-d eoxy-4-O-(tetr a -O-ben zyl-â-D-ga -
la ctop yr a n osyl)-D-m a n n on o-1,5-la cton e (12) a n d Di-O-ben -
zyl-2-d eoxy-2-d ia zo-4-O-(tetr a -O-ben zyl-â-D-ga la ctop yr a -
n osyl)-D-glu con o-1,5-la cton e (13). Electrophilic azidation of
11 was carried out as described above except that the reaction
was done at -78 °C. After workup, flash column chromatography
on silica gel with hexanes-EtOAc (4:1) yielded 12 (60%) as a
colorless oil together with 13 (15%) as a colorless oil. 12: [R]D
Tr i-O-ben zyl-2-a zid o-2-d eoxy-D-ga la cton o-1,5-la cton e23
(3). A solution of 2 (100 mg, 0.23 mmol) in THF (3 mL) was
cooled to -90 °C and a 0.5 M solution of KHMDS in toluene
(0.51 mL, 0.26 mmol) was added dropwise with vigorous stirring.
After 15 min, a precooled 0.2 M solution of trisyl azide21 in THF
(1.5 mL, 0.3 mmol, -90 °C) was added dropwise. After another
2 min, AcOH (16 µL, 0.28 mmol) was added. The cooling bath
was then removed and the mixture was stirred at room tem-
perature overnight. After addition of H2O (30 mL), the mixture
was extracted with CH2Cl2 (3 × 30 mL). The combined CH2Cl2
layers were dried and concentrated to dryness. Flash column
chromatography on silica gel with hexanes-EtOAc (6:1) yielded
known 3 (77 mg, 70%) as a colorless oil: [R]D +63 (c 0.6, CHCl3)
[lit.23 [R]D +63.4 (c 1, CHCl3)]; 1H NMR (500 MHz) δ 3.67 (dd, 1,
J ) 10.5, 2.0 Hz, H-3), 3.65 (dd, 1, J ) 10.0, 6.0 Hz) and 3.70
(28) Some reviews on diazo chemistry: (a) Regitz, M. Synthesis 1972,
351-373. (b) Doyle, M. P.; McKervey, M. A. Chem. Commun. 1997,
983-989.
1
-4.3 (c 1.5, CHCl3); H NMR (400 MHz) δ 3.44 (dd, 1, J ) 8.0,
(29) For example: (a) Horton, D.; J ust E. K. Chem. Commun. 1969,
1116-1117. (b) Horton, D.; Philips, K. D. Carbohydr. Res. 1972, 22,
151-162. (c) Kurz, G.: Lehmann, J .; Thieme, R. Carbohydr. Res. 1985,
136, 125-133.
2.5 Hz, H-3′), 3.45-3.50 (m, 3, H-5′, 2 × H-6′), 3.61 (br d, 2, J )
5 Hz, 2 × H-6), 3.74 (dd, 1, J ) 9.5, 8.0 Hz, H-2′), 3.86 (br d, 1,
J ) 2.5 Hz, H-4′), 3.98 (d, 1, J ) 3.0 Hz, H-2), 4.06 (dd, 1, J )
6.5, 1.5 Hz, H-4), 4.24 (d, 1, J ) 8.0 Hz, H-1′), 4.21-4.27 (m, 1,
(30) Briner, K.; Vasella, A. Helv. Chim. Acta 1989, 72, 1371-1382.

Notes
J . Org. Chem., Vol. 66, No. 9, 2001 3223
H-5), 4.39-4.41 (m, 1, H-3). HRMS: cacld for C54H55N3O10
+
Institute for Molecular Imaging and the Department of
Molecular and Medical Pharmacology, UCLA School of
Medicine. The Norton Simon Fund at UCLA and partial
support from NSF (CHE 9974928) are also acknowl-
edged.
Na 928.3785, found 928.3799. 13: [R]D +6.5 (c 0.87, CHCl3); 1H
NMR (400 MHz) δ 3.42-3.54 (m, 4, H-3′, H-5′, 2 × H-6′), 3.76
(br d, 2, J ) 6 Hz, 2 × H-6), 3.79 (dd, 1, J ) 9.5, 8.0 Hz, H-2′),
3.86 (br d, 1, J ) 2.5 Hz, H-4′), 4.23 (br t, 1, J ) 3.5 Hz, H-4),
4.48 (d, 1, J ) 8.0 Hz, H-1′), 4.83 (d, 1, J ) 2.5 Hz, H-3). HRMS:
cacld for C54H54N2O10 + Na 913.3676, found 913.3652.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 2-4, 6-8, and 11-13 as well as NOE data of 6,
7, 11, and 12. This material is available free of charge via the
Internet at http://pubs.asc.org.
Ack n ow led gm en t. We thank Dr. J oseph C. Walsh
for his contribution to 1H NMR investigations. We also
thank J ennifer Leung and Philippa Reichert for techni-
cal assistance. This work was supported by the Crump
J O005728C