Aza-C-disaccharides: Synthesis of 6-deoxygalactonojirimycin β-C(1→3) linked with D-altrofuranosides and D-galactose

Article abstract of DOI:10.1021/jo970151t

Cross-aldolization of 3-O-benzyl-N-(benzyloxycarbonyl)-2,6,7-trideoxy- 2,6-imino-4,5-O-isopropyl-idene-β-D-glycero-L-mannoheptose((-)-12, derive from D-glycero-D-gulo-heptono-1,4-lactone in eight steps) with (+)- (1R,4S,5S,6S)- and (-)-(1S,4R,5R,6R)-6-chloro-5-(phenylseleno)-7- oxabicyclo[2.2.1]heptan-2-one (obtained in one step from the 'naked sugars' (-)- and (+)-7-oxabicyclo[2.2.1]hept-5-en-2-one) were highly stereoselective (lithium enolates, like modes), giving aldols (-)-14 and (+)-16, respectively. Stereoselective methods were developed for the conversion of (- )-14 into methyl 3-deoxy-3-C-[(1'R)-2',6',7'-trideoxy-2',6'-imino-β-D- glycero-L-manno-heptitol-1'-yl]-α- and -β-D-altrofuranoside ((+)-1α,β). The aza-C-disaccharide 1α prefers a anti conformation (bonds C(2')-C(3') and C(1')-C(3) are antiperiplanar) for the β-D-galactoside moiety (³J(H,H) coupling constants, NOEs). Aldol (+)-16 was converted stereoselectively into 3-deoxy-3-C-[(1'S)-2',6'7'-trideoxy-2',6'-iminio-β-D-glycero-L-manno- heptitol-1'-yl]-β-D-galactose trifluoroacetate.

Full text of DOI:10.1021/jo970151t

6252
J . Org. Chem. 1997, 62, 6252-6260
Aza -C-d isa cch a r id es: Syn th esis of 6-Deoxyga la cton ojir im ycin
â-C(1f3) Lin k ed w ith D-Altr ofu r a n osid es a n d D-Ga la ctose
Alain Baudat and Pierre Vogel*
Section de Chimie de l’Universite´, BCH, 1015 Lausanne-Dorigny, Switzerland
Received J anuary 27, 1997X
Cross-aldolization of 3-O-benzyl-N-(benzyloxycarbonyl)-2,6,7-trideoxy-2,6-imino-4,5-O-isopropyl-
idene-â-D-glycero-L-mannoheptose ((-)-12, derived from D-glycero-D-gulo-heptono-1,4-lactone in eight
steps) with (+)-(1R,4S,5S,6S)- and (-)-(1S,4R,5R,6R)-6-chloro-5-(phenylseleno)-7-oxabicyclo-
[2.2.1]heptan-2-one (obtained in one step from the “naked sugars” (-)- and (+)-7-oxabicyclo[2.2.1]hept-
5-en-2-one) were highly stereoselective (lithium enolates, like modes), giving aldols (-)-14 and (+)-
16, respectively. Stereoselective methods were developed for the conversion of (-)-14 into methyl
3-deoxy-3-C-[(1′R)-2′,6′,7′-trideoxy-2′,6′-imino-â-D-glycero-L-manno-heptitol-1′-yl]-R- and -â-D-altro-
furanoside ((+)-1R,â). The aza-C-disaccharide 1R prefers a anti conformation (bonds C(2′)-C(3′)
and C(1′)-C(3) are antiperiplanar) for the â-D-galactoside moiety (3J H,H coupling constants, NOEs).
Aldol (+)-16 was converted stereoselectively into 3-deoxy-3-C-[(1′S)-2′,6′,7′-trideoxy-2′,6′-iminio-â-
D-glycero-L-manno-heptitol-1′-yl]-â-D-galactose trifluoroacetate.
Glycosidases are key enzymes in the biosynthesis and
J ohnson and co-workers6 applying the Suzuki reaction.
Other examples of “linear” aza-C-disaccharides were
prepared recently by Martin et al.7 In preliminary
communications8,9 we reported the synthesis of the first
examples of “branched” aza-C-disaccharides in which
trihydroxypiperidines are C-linked at position C(3) of
hexoses.10,11 We describe here the details of our synthe-
ses of two aza-C-disaccharides in which 1,5,6-trideoxy-
1,5-imino-â-D-galactose is linked at C(3) of methyl D-al-
trofuranosides (1R, 1â) for one case, and at C(3) of
D-galactose for the second case, through a hydroxymeth-
ylene bridge. The aza-C-disaccharide 2 mimics the
cancer marker or antigen T (Thomsen-Friedenreich)
which has the structure â-D-Gal-O(1f3)-R-D-GalNAc-O-
Ser(Thr).5,12 A study by high-field NMR shows that an
anti conformation (C(1′)-C(3) and C(2′)-C(3′) bonds are
antiperiplanar) is preferred for 1-R for pH 4.4 to 9.8. The
pKa values of the conjugate acids of 1R and 1â have also
been determined.
processing of glycoproteins, which are macromolecules
involved in recognition (cell-cell, host-pathogen interac-
tions) and control of biological mechanisms and struc-
tures.1 Inhibition of glycosidases2 may be useful for the
treatment of diseases such as diabetes, cancer, viral and
bacterial infections, and inflammation.3 Polyhydroxypi-
peridines, pyrrolidines (azasugars), and azepanes are
promising inhibitors;4 unfortunately, they often inhibit
more than one enzyme in vivo. It is believed that
selectivity would be increased if the azasugar would
include not only the steric and charge information of the
glycosyl moiety which is liberated during the glycosidase-
catalyzed hydrolysis but also that of the aglycon which
it is attached to. Such inhibitors could be dideoxyimi-
noalditols linked to other sugars through nonhydrolyz-
able links such as in the aza-C-disaccharides. These
disaccharides mimics could also be candidates as haptens
for the generation of catalytic antibodies.5 A first ex-
ample (1,5-dideoxy-1,5-imino-D-mannitol linked at C(6)
of D-galactose through a CH2 unit) has been prepared by
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) See, e.g.: Rademacher, T. W.; Parekh, R. B.; Dwek, R. A. Annu.
Rev. Biochem. 1988, 57, 785. Hindsgaul, O.; Khare, D. P.; Bach, M.;
Lemieux, R. U. Can. J . Chem. 1985, 63, 2653. Feizi, T. In Carbohydrate
Recognition in Cellular Function; Ciba Geigy Symposium 145; Wiley:
Chichester, 1989; pp 62-79. Kornfeld, R.; Kornfeld, S. Annu. Rev.
Biochem. 1985, 54, 631. Moremen, K. W.; Trimble, R. B.; Herscovics,
A. Glycobiology 1994, 4, 113. Rice, G. E.; Bevilacqua, M. P. Science
1989, 246, 1303. Smith, C. A.; Davis, T.; Anderson, D.; Solam, L.;
Beckmann, M. P.; J erzy, R.; Dower, S. K.; Cosman, D.; Goodwin, R. G.
Science 1990, 248, 1019.
(2) See, e.g.: Sinnott, M. L. Chem. Rev. 1990, 90, 1171. Legler, G.
Adv. Carbohydr. Chem. Biochem. 1990, 48, 319. Franck, R. W. Bioorg.
Chem. 1992, 20, 77. Kirby, A. J . Adv. Phys. Org. Chem. 1994, 5, 605.
(3) See e.g.: Winchester, B.; Fleet, G. W. J . Glycobiol. 1992, 2, 199.
Karlsson, G. B.; Butters, T. D.; Dwek, R. A.; Platt, R. M. J . Biol. Chem.
1993, 268, 570. Colman, P. M. Pure Appl. Chem. 1995, 67, 1683.
(4) See, e.g.: Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem.
Res. 1993, 26, 182. Wong, C.-H.; Provencher, L.; Porco, J . A.; J ung,
S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J . Org. Chem.
1995, 60, 1492. Wang, Y.-F.; Takaoka, Y., Wong, C.-H. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1242. Asano, N.; Oseki, K.; Kizu, H., Matsui,
K. J . Med. Chem. 1994, 37, 3701. McCarter, J . D.; Withers, S. G. Curr.
Opin. Struct. Biol. 1994, 4, 885. Papandreou, G.; Tong, M. K.; Ganem,
B. J . Am. Chem. Soc. 1993, 115, 11682. Moris-Varas, F.; Qian, X.-H.;
Wong, C.-H. Ibid. 1996, 118, 7647. Ganem, B. Acc. Chem. Res. 1996,
29, 340. Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y., Kajimoto, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 521.
Syn th esis of Aza -C-â(1f3)-ga la ctosid es of Altr o-
fu r a n osid es. The commercially available D-glycero-D-
(6) J ohnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram, H.;
Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991.
(7) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37, 1991.
(8) Baudat, A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483.
(9) Fre´rot, E.; Marquis, C.; Vogel, P. Tetrahedron Lett. 1996, 37,
2023.
(10) An azapyranosyl disaccharide with a thioglycosidic linkage has
been described: Suzuki, K.; Hashimoto, H. Tetrahedron Lett. 1994,
35, 4119.
(11) â-L-Xylopyranosides (1f6) of 2,5-dideoxy-2,5-iminoaltitols have
been prepared: Mikkelsen, G.; Christensen, T. V.; Bols, M.; Lundt, I.;
Sierks, M. R. Tetrahedron Lett. 1995, 36, 6541. See also: Andrews, J .
S.; Weimar, T.; Frandsen, T. P.; Svensson, B.; Pinto, B. M. J . Am.
Chem. Soc. 1995, 117, 10799.
(5) See, e.g.: Rye, P. D.; Bovin, N. V.; Vlasova, E. V.; Walker, R. A.
Glycobiology 1995, 5, 385.
(12) See, e.g.: MacLean, G. D.; Longenecker, B. M. Can. J . Oncol.
1994, 4, 249.
S0022-3263(97)00151-5 CCC: $14.00 © 1997 American Chemical Society

Aza-C-disaccharides
J . Org. Chem., Vol. 62, No. 18, 1997 6253
gulo-heptono-1,4-lactone ((-)-3) (two steps from D-glu-
cose) is converted into a 1:13 (80%)13 or 1:10 (73%)14
mixture of the bis-acetonides (-)-4 and (-)-5 on treat-
ment in acetone with H2SO4 (20 °C) and ZnCl2/H3PO4 (20
°C), respectively. Although (-)-4 and (-)-5 can be readily
separated and (-)-5 reequilibrated into a mixture of (-)-4
and (-)-5, we searched for conditions under which a
larger proportion of (-)-4, our starting material, could
be obtained. This was indeed the case when the acetal-
ization was carried at 150 °C in acetone in the presence
of p-toluenesulfonic acid and CaSO4. After 1.5 h a 2:3
mixture of (-)-4 and (-)-5 was formed (63% yield, 76%
conversion). Conversion of (-)-4 into the corresponding
azide (-)-7 was achieved through SN2 displacement of
the intermediate triflate 6. Addition of MeLi in Et2O/
THF gave (+)-8, the hydrogenation of which gave the
corresponding primary amine which equilibrated with
the corresponding imine resulting from intramolecular
addition of the ulose moiety. Hydrogenation of the latter
gave (+)-9 selectively (58% based on (-)-4).15 Benzylation
of (+)-9 afforded (-)-10 (79%). Protection with benzyl
chloroformate provided (+)-11 (97%). Treatment of (+)-
11 with 8:1 AcOH/H2O and NaIO4 led to selective
hydrolysis of the 7,8-O-isopropylidene group and oxida-
tive cleavage into aldehyde (-)-12 (94%).
Cross-aldolization of aldehyde (-)-12 with the lithium
enolate of the bicyclic ketone (+)-1316 in THF at -95 °C
led to a mixture of aldols (-)-14 and (+)-15 isolated in
45 and 26% yield, respectively (92% of conversion of (-)-
12). Aldol (+)-15 arises from the debenzylation of (-)-
14 as its proportion grew with the time of reaction. We
have no good explanation to offer for this unexpected
selective debenzylation. Perhaps the lithium aldolate
generates mixed aggregates with the excess of (Me3Si)2NLi
which displaces the benzyl ether. Under the same
conditions, the lithium enolate of (-)-1316 reacted with
aldehyde (-)-12 to give a single aldol (+)-16 (70%, 82%
conversion).17 Under similar conditions, the lithium
enolate of racemic ketone (()-13 reacted with aldehyde
(-)-12 to give (-)-14 (30%), (+)-15 (6%), and (+)-16 (35%)
after separation and purification by flash column chro-
matography on silica gel. The structures of (-)-14 and
(+)-16 were established in the following way. Reduction
of ketone (-)-14 with NaBH4 in THF/MeOH provided the
endo alcohol (+)-17 (3J (H-C(3′),H-C(4′)) ) 5.8 Hz18) in
88% yield. Treatment of (+)-17 with (t-Bu)2Si(OSO2CF3)2
and 2,6-lutidine gave the cyclic silyl acetal (+)-18, the
1H NMR spectrum of which showed typical vicinal
was difficult to analyze because of signal overlappings
(mixtures of rotamers resulting from the benzyl carbam-
ate). We thus treated 20 with m-chloroperbenzoic acid
1
(mCPBA) in CH2Cl2; this furnished (+)-21 (74%), the H
NMR spectrum of which displayed typical vicinal cou-
pling constants 3J (H-C(4),H-C(4a)) ) 10.8 Hz, 3J (H-
C(8),H-C(8a)) ) 4.4 Hz, 3J (H-C(4a),H-C(5) = 0 Hz,
consistent only with an exo-anti aldol (+)-16, as for aldol
(-)-14. NOEs measured between protons Hexo-C(8a) and
H-C(4) confirmed structures (+)-18 and (+)-21.
3
3
coupling constants J (H-C(4),H-C(4a)) ) 11.1 Hz, J (H-
C(8),H-C(8a)) ) 4.6 Hz, 3J (H-C(4a),H-C(5)) = 0 Hz.
Similarly, aldol (+)-16 was converted into diol (-)-19
(96%) and silyl acetal 20, the 1H NMR spectrum of which
For steric reasons only the exo face of the bicyclic
lithium enolates of (+)-13 and (-)-13 can react with the
aldehyde moiety of (-)-12. Both cross-aldolizations fol-
lowed Zimmerman-Traxler models19 (chair transition
states) or Evans models20 (boat transition states; steric
repulsion minimization leads to the like mode21 of addi-
(13) Brimacombe, J . S.; Tucker, L. C. N. Carbohydr. Res. 1966, 2,
341.
(14) Shing, T. K. M.; Zhou, Z.-H.; Tsui, H.-C.; Mak, T. C. W. J . Chem.
Soc., Perkin Trans. I 1992, 887.
(15) Baudat, A.; Picasso, S.; Vogel, P. Carbohydr. Res. 1996, 281,
277.
(16) (a) Black, K. A.; Vogel, P. J . Org. Chem. 1986, 51, 5341. (b)
Gasparini, F.; Vogel, P. Ibid. 1990, 55, 2451. (c) Vogel, P.; Fattori, D.;
Gasparini, F.; Le Drian, C. Synlett 1990, 173. (d) Reymond, J .-L.; Vogel,
P. Tetrahedron: Asymmetry 1990, 1, 729.
(17) For alternative methods of preparations of enantiomerically
pure 7-oxabicyclo[2.2.1]hept-5-en-ones precursors of (+)-13 and (-)-
13, see: Saf, R.; Faber, K.; Penn, G.; Griengl, H. Tetrahedron 1988,
44, 389. Ronan, B.; Kagan, H. B. Tetrahedron: Asymmetry 1991, 2,
75. Corey, E. J .; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979.
(18) Gagnaire, D.; Payo-Subiza, E. Bull. Soc. Chim. Fr. 1963, 2627.
Ramey, K. C.; Lini, D. C. J . Magn. Reson. 1970, 3, 94. Nelson, W. L.;
Allen, D. R. J . Heterocycl. Chem. 1972, 9, 561. Kienzle, F. Helv. Chim.
Acta 1975, 58, 1180. Mahaim, C.; Vogel, P. Ibid. 1982, 65, 866.
(19) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920. See also: Kleschick, W. A.; Buse, C. T.; Heathcock, C. H.
Ibid. 1977, 99, 247. Fellmann, P.; Dubois, J . E. Tetrahedron 1978, 34,
1349. Evans, D. A.; Vogel, E.; Nelson, J . V. J . Am. Chem. Soc. 1979,
101, 6120. Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung,
M. C.; Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066. Anh, N.
T.; Elka¨ım, L.; Thanh, B. T.; Maurel, F.; Flament, J . P. Bull. Soc. Chim.
Fr. 1992, 129, 468.
(20) Evans, D. A.; Nelson, J . V.; Taber, T. R. Topics Stereochem.
1982, 31, 1.
(21) Seebach, D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21,
654.

6254 J . Org. Chem., Vol. 62, No. 18, 1997
Baudat and Vogel
F igu r e 1. Representations of possible like mode of cross-
aldolizations.
tion, Figure 1) giving anti aldols. Contrary to R-methyl
aldehydes22 that lead to anti aldols with good double
diastereoselectivity only with one of the two enantiomeric
7-oxanorbornanone lithium enolates (matched pair when
the Felkin-Anh addition is compatible with the like mode
of addition23), aldehyde (-)-12 behaves as if the two
R-substituents were of the same size.
F igu r e 2. Representations of possible conformers for 1r: (A)
Newman projections along C(2′)-C(1′); (B) along C(3)-C(1′).
er o-L-ma n n o-h eptitol-1′-yl]-R-D-a ltr ofu r a n osid e. The
1
600 MHz H NMR spectrum of the mixture of (+)-1R,â
taken in 1:1 CD3OD/D2O at pH 5.7 suggested an anti
conformation B (Figure 2A) for the aza-C-galactoside 1R
for the following reasons. A coupling constant of 1.3 Hz
was measured between the anomeric proton H-C(2′) and
H-C(1′) of the hydroxymethylene link. This excludes
conformation C (Figure 2A) which features antiperipla-
nar protons H-C(2′) and H-C(1′). Since no NOE (2D
NOESY spectrum) could be detected between protons Me-
C(6′) of the 6-deoxygalactonojirimycin moiety and protons
H-C(2), H-C(4) of the altrofuranoside unit, the gauche
conformation A (Figure 2A) can be rejected. This con-
formation is expected to be destabilized due to steric
Acylation of diol (+)-17 with Ac2O/pyridine/DMAP
provided the diacetate (-)-22. Oxidative elimination of
the phenylseleno group with mCPBA led to (-)-23 (90%,
based on (+)-17). Double hydroxylation of the chloro-
alkene (-)-23 (Me3NO, OsO4, NaHCO3) followed by
acetylation (as above) gave the R-acetoxy ketone 24, an
unstable compound that was directly treated with mCPBA/
NaHCO3 to generate uronolactone (-)-25 (67%). Metha-
nolysis of (-)-25 under acidic conditions (MeOH, SOCl2)
furnished a 5:1 mixture of the R- and â-furanoside (+)-
26. No trace of the corresponding methyl pyranoside
could be seen in the 1H NMR spectrum of the crude
reaction mixture. Reduction of (+)-26 with LiAlH4 or
with DIBAH in THF, followed by acetylation (Ac2O/
pyridine/DMAP), led to untractable mixtures. Finally we
found that the reduction of (+)-26 with LiBH4/THF,
followed by acetylation and hydrogenolysis, provided a
5:1 R/â-mixture of the semiprotected aza-C-disaccharide
(+)-27 (72%). Transalcoholysis of (+)-27 with MeOH/
NH3, followed by chromatography on an ion-exchange
column, delivered a 5:1 mixture of 1R and 1â ((+)-1R,â).
repulsive effects between the two sugar moieties.
A
coupling constant of 10.1 Hz was measured between
protons H-C(1′) of the link and H-C(3) of the aglycon. It
is consistent only with an antiperiplanar arrangement
for these two protons as shown in Figure 2B.
The other coupling constants (Figure 3) and the 2D
NOESY spectrum of 1R were consistent with the average
conformation shown (Figures 2 and, 3). For numerous
C-disaccharides with a CH2 link, anti conformations of
type B have been reported.24 Data for C-lactose and
derivatives with a CH(OH) link have shown that gauche
conformations may be more populated than the corre-
sponding anti conformations.25
Further discussion of our data for 1R must await data
for the corresponding O-disaccharide that are not avail-
(22) Roush, W. R. J . Org. Chem. 1991, 56, 4151.
(23) Sevin, A. F.; Vogel, P. J . Org. Chem. 1994, 59, 5920. Kernen,
P.; Vogel, P. Helv. Chim. Acta 1995, 78, 301.
(24) Haneda, T.; Goekjian, P. G.; Kim, S. H.; Kishi, Y. J . Org. Chem.
1992, 57, 490. Ferritto, R.; Vogel, P. Tetrahedron: Asymmetry 1994,
5, 2077. Wei, A.; Boy, K. M.; Kishi, Y. J . Am. Chem. Soc. 1995, 117,
9432. Wei, A.; Haudrechy, A.; Audin, C.; J un, H.-S.; Haudrechy-Bretel,
N.; Kishi, Y. J . Org. Chem. 1995, 60, 2160. Berthault, P.; Birlirakis,
N.; Rubinstenn, G.; Sinay¨, P.; Desvaux, H. J . J . Biomolecular NMR
1996, 8, 23.
(25) Espinosa, J .-F.; Dietrich, H.; Mart´ın-Lomas, M.; Schmidt, R.
R., J ime´nez-Barbero, J . Tetrahedron Lett. 1996, 37, 1467. Espinosa,
J .-F.; Can˜ada, F. J .; Asensio, J . L.; Mart´ın-Pastor, M.; Dietrich, H.;
Mart´ın-Lomas, M.; Schmidt, R. R.; J ime´nez-Barbero, J . J . Am. Chem.
Soc. 1996, 118, 10862.
Qu a lit a t ive con for m a t ion a l a n a lysis of m et h yl
3-d eoxy-3-[(1′R)-2′,6′,8′-tr id eoxy-2′,6′-im in o-â-D-glyc-

Aza-C-disaccharides
J . Org. Chem., Vol. 62, No. 18, 1997 6255
arises probably from the K2CO3-induced epimerization
of (-)-34. The formation of (-)-34 can be interpreted in
terms of a SNi process that follows the MeOH addition
onto the uronolactone and liberalization of the intermedi-
ate R-furanose 33.26
3
F igu r e 3. (A) Vicinal J (H,H) coupling constants (Hz) mea-
sured for 1r; (B) three-dimensional representation of the
average conformation of 1r with indication of the major NOE’s
(by 600 MHz NOESY).
able yet, as well as quantitative J and NOE analyses.
As it has been shown for C-lactose and derivatives,25 the
conformational population of a C-disaccharide may de-
pend on solvent and temperature. In order to test for
an eventual temperature effect, we measured the 1H
NMR (600 MHz) spectrum of 1R at 11, 25, 39, and 60 °C
(pH 5.7, 1:1 CD3OD/D2O). No change could be detected
for the vicinal coupling constants. We also tested for an
eventual pH dependence of the conformation of 1R and
measured its 1H NMR spectrum at pH ) 4.4, 5.7, 8.0,
9.0, and 9.8 at 40 °C (1:1 CD3OD/D2O, addition of AcOH
or NaOH diluted in 1:1 CD3OD/D2O). Expect for some
changes in the chemical shifts, the largest effect being
observed for proton H-C(2′), as expected (δH ) 3.20 ppm
at pH 4.4, 2.47 ppm at pH 9.8), no change of the vicinal
Reduction of (-)-34 with LiBH4 in THF afforded (+)-
36 (82%). Debenzylation (H2/Pd/C, THF, H2O) of (+)-36
gave (+)-37 (97%). Treatment (+)-37 with HCl in various
media gave untractable mixtures of compounds, some of
them resulting from aromatization through water elimi-
nation (formation of pyridine from the piperidine moiety).
Finally smooth deprotection of (+)-37 was achieved
through acidic hydrolysis with CF3COOH in 1:8 H2O/THF
at 37 °C (15 h). This led to a 68:32 mixtures of the
galactopyranoses 2R + 2â (R:â, 2:3) and galactofuranoses
38R + 38â (R:â, 1:2), the structures of these aza-C-
disaccharides being confirmed by NMR methods (1H, 13C,
COSY-DQF, XHCOR, DEPT) for solutions in MeOH. All
the structures given for the other compounds described
above were consistent with their spectral data and
elemental analyses (see Experimental Section) as well
as with their modes of formation.27
3
coupling constants were observed, except for J (H-C(2),
H-C(3)) of the altrofuranoside unit which varied from 1.3
Hz at pH <5.7 to 3 Hz at pH >8.0. Apart from a possible
change in the population of the conformations of the
furanoside ring, the average conformation around the
aza-C-glycosidic link and around the C-link and the
aglycon was not affected by the pH.
By measuring the chemical shifts of the methyl groups
of the 6-deoxygalactopyranoside moieties of 1R and 1â
as a function of pH (titration curves) we evaluated the
pKa of the conjugate acid 1RH+ and 1âH+ to be 7.7 and
7.4, respectively, at 40 °C in 1:1 CD3OD/D2O.
Syn th esis of a n a za -C-â-ga la ctosid e (1f3) of Ga -
la ctose. Oxidative elimination of the PhSe group of (-)-
19 (mCPBA, CH2Cl2) afforded (+)-28 (95%). Its diol
moiety was then protected as MOM ethers to obtain (+)-
29 (95%). Double hydroxylation of the chloroalkene (+)-
29 (Me3NO, OsO4, NaHCO3, THF) led to an unstable
R-hydroxy ketone 30 which was esterified without puri-
fication with 4-BrC6H4SO2Cl (Et3N/CH2Cl2) into brosylate
(-)-31 (84%). Baeyer-Villiger oxidation of (-)-31 fur-
nished uronolactone (+)-32, the methanolysis of which
(MeOH/DMF, anhydrous K2CO3) gave a 10:1 mixture of
(-)-34 (66%) and (+)-35 (6%). The latter compound
Although the related (+)-3,7,8-trideoxy-3,7-imino-D-
threo-L-galacto-octitol derived from (+)-11 was found to
be a competitive inhibitor of â-glucosidases from almonds
and from Caldocellum saccharolyticum, the more com-
plicated aza-C-galactosides (+)-1R,â and 2R,â showed no
significant (IC50 >10 mM) inhibition of these enzymes,
nor did they inhibit the following commercially available
glycosidases: R-glucosidases form yeast and rice, â-xy-
losidase from Aspergillus niger, R-L-fucosidase form
bovine epididymis, â-mannosidase from Helix pomatia
and R-mannosidases from beans and from almonds. As
expected, the aza-C-disaccharides (+)-1R,â and 2R,â
(26) Kraehenbuehl, K.; Vogel, P. Tetrahedron Lett. 1995, 36, 8595.
(27) Conformational analysis of 2R,â and 31R,â could not be carried
out because of too many overlapping proton signals in the 600 MHz
1H NMR spectrum of this mixture.
(28) Gasparini, F.; Vogel, P. J . Org. Chem. 1990, 55, 2451.

6256 J . Org. Chem., Vol. 62, No. 18, 1997
Baudat and Vogel
54.8, 54.5 (4d), 21.5 (q, OCCH3); 15.3 (q, C(7′)); CI-MS (NH3)
m/ z 355 (3), 354 (7), 322 (20), 292 (20), 278 (15), 250 (25), 160
(26), 146 (81), 123 (47), 109 (88), 97 (80), 81 (100); CI-MS
(electrospray) 354.7 (100); for C14H27O9N (353.16).
might be inhibitors of glycosidases that cleave specifically
â-galactoside-O(1f3) links, what the above enzymes are
not specialized for, apparently. Work will be initiated to
search for such enzymes and for biological systems
capable to interact with our aza-C-disaccharides.
3-Deoxy-3-[(1′S)-2′,6′,7′-tr ideoxy-2′,6′-im in io-â-D-glycer o-
L-ma n n o-h eptitol-1′-yl]-â-D-galactose Tr iflu or oacetate an d
Isom er s ((-)-2r,â,38r,â). A solution of (+)-37 (24 mg, 0.06
mmol) in trifluoroacetic acid/H2O 8:2 (3 mL) was stirred at 37
°C for 15 h. Evaporation led to 23.4 mg (98%) of a mixture of
Con clu sion
The syntheses of branched, long-chain carbohydrates
containing 13 carbon centers, a 1,5,6-trideoxy-1,5-imino-
D-galactitol moiety â-C-linked to various hexoses has been
possible through stereoselective (like mode) aldol con-
densations of a protected 3,4,5-trihydroxy-6-methylpip-
eridine-2-carbaldehyde with the lithium enolates of
(+)-(1R,4S,5S,6S)- and (-)-(1S,4R,5R,6R)-6-chloro-5-
(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one. Stereo-
selective transformations of the aldols so-obtained led to
two “branched” aza-C-disaccharides. In the first case,
6-deoxy-D-galactonojirimycin is â-linked at position C(3)
of methyl R- and â-altrofuranoside (1) through a hy-
droxymethylene bridge. In the second case, 6-deoxy-D-
galactonojirimycin is â-linked at position C(3) of D-ga-
lactose, through a hydroxymethylene group. The latter
aza-C-disaccharide resembles somehow the tumor specific
carbohydrate antigen D-Galâ(1f3) GalNAc (Thomsen-
Friedenreich antigen (T)).29 Conjugates with peptides
will be tested as potential “anticancer vaccine”.30
2R,â and 38R,â: a slightly yellow oil; [R]25 ) -4.1, [R]25
)
D
577
-6.2, [R]25 ) -7.0 (c ) 1.2, MeOH); IR (film) ν 3425, 2925,
546
1685, 1435, 1210, 1135, 945, 840, 805, 725 cm-1; 1H NMR (600
MHz, CD3OD) of 2R (signal attributions for 2R in the mixture
relies, when possible, upon 2D spectra (COSY, HMQC, DEPT))
3
3
δ 5.28 (d, 0.2 H, J ) 4.4, HC(1), â-Galf), 5.26 (d, 0.1 H, J )
4.5, HC(1), R-Galf), 5.23 (d, 0.4 H, 3J ) 4.5, HC(1), â-Galp),
3
5.21 (d, 0.3 H, J ) 4.5, HC(1), R-Galp), 4.63-4.55 (m, 1.2 H),
4.52-4.43 (m, 1.5 H), 4.38-4.30 (m, 1.8 H, HC(2), Galf), 4.26-
4.16 (m, 1.5 H, HC(2), Galp, HC(4′)), 4.10-3.85 (m, 6.8 H),
3.77-3.53 (m, 4.8 H), 3.51-3.38 (m, 1.9 H, H-C(6′)), 3.31-
3.22 (m, 1.3 H), 2.80-2.62 (m, 1.5 H, H-C(2′), H-C(3)), 1.48-
1.40 (m, 3 H, H3-C(7′)); 13C-NMR (150.92 MHz, CD3OD) of 2â
and 2R (â-Galp), δ 161.0 (s, CF3COO), 117.3 (q, CF3COO), 96.6
(d, C(1)), 80.8 (d, C(4′)), 75.5, 72.8, 71.8, 70.5, 67.5, 65.3 (6d,
C(2), C(4), C(5), C(1′), C(3′), C(5′)), 64.3 (t, C(6)), 64.2, 56.9,
48.8 (3d, C(6′), C(2′), C(3)), 15.1 (q, C(7′)), (R-Galp), δ 161.2 (s,
CF3COO), 117.3 (q, CF3COO), 96.6 (d, C(1)), 81.8 (d, C(4′)),
78.8, 75.5, 74.4, 71.7, 70.4, 67.4 (6d, C(2), C(4), C(5), C(1′), C(3′),
C(5′)), 64.8 (d, C(6′)), 64.2 (t, C(6)), 56.6, 43.8 (2d, C(2′), C(3)),
15.1 (q, C(7′)); CI-MS (electrospray) 339 (100), 322 (33); CI-
MS (NH3) m/ z 341 (1), 340 (1), 322 (5), 285 (8), 267 (7), 175
(8), 146 (26), 137 (39), 123 (100), 115 (25), 95 (60), 80 (44).
Anal. Calc for C13H25O9N‚CF3COOH (339.34 + 113.99): C,
39.72; H, 5.78. Found: C, 39.84; H, 5.84.
Exp er im en ta l Section
Gen er a l Rem a r k s. See refs 23, 28. None of the proce-
dures were optimized. Flash column chromatography (FC)
was performed on Merck silica gel (230-400 mesh). Thin layer
chromatography (TLC) was carried out on silica gel (Merck
aluminum foils). 1H NMR signal assignments were confirmed
by double irradiation experiments and, when required, by 2-D-
NOESY and COSY spectra. J values are given in hertz. 600
MHz 1H NMR spectra were recorded on a Bruker AMX-600
FT spectrometer.
Meth yl 3-Deoxy-3-[(1′R)-2′,6′,7′-tr id eoxy-2′,6′-im in o-â-
D-glycer o-L-m a n n o-h ep titol-1′-yl]-R- a n d â--D-a ltr ofu r a -
n osid e ((+)-1R,â). Aqueous NH3 (50%, 1 mL) was added to a
stirred solution of (+)-27 (12 mg, 0.02 mmol) in MeOH (2 mL).
After 2 h of stirring, the solvent was evaporated. The residue
was taken up in MeOH (0.2 mL) and 2 N HCl (0.5 mL) and
deposited on a Dowex 50W X8 column (H+ form, 3 g, 200-400
mesh) and washed first with H2O, then with MeOH, and
finally with 5% aqueous NH3 to provide (+)-1R,â (7 mg, 95%)
as a 5:1 mixture of R- and â-anomer which precipitated from
2,3:6,7-Di-O-isop r op ylid en e-D-glycer o-D-gu lo-h ep ton o-
1,4-la ct on e ((-)-4) a n d 3,5:6,7-Di-O-isop r op ylid en e-D-
glycer o-D-gu lo-h ep ton o-1,4-la cton e ((-)-5). D-glycero-D-
gulo-Heptono-1,4-lactone ((-)-3, Aldrich) (8 g, 38.4 mmol),
p-toluenesulfonic acid (0.2 g, 1.05 mmol), and CaSO4 (1 g, 7.64
mmol) were stirred in acetone (80 mL) in an autoclave at 150
°C. After 1.5 h the mixture was neutralized with Na2CO3 and
then filtered. Silica gel (40 g) was added and the suspension
carefully evaporated in vacuo. FC (silica gel (400 g), EtOAc/
petroleum ether 3: 2, then EtOAc) yielded 2.78 g (25%) of (-)-
4, 4.22 g (38%) of (-)-5, and 1.03 g (13%) of starting material
((-)-3). Recyclin g of (-)-5 a n d (-)-3. The same procedure
as above was used starting with D-glycero-D-gulo-heptono-1,4-
lactone ((-)-3) (1 g, 5.0 mmol) and (-)-5 (4.2 g, 14.6 mmol),
yielding 1.0 g (18%) of (-)-4, 2.1 g (37%) of (-)-5 and 0.3 g
(7%) of (-)-3. All spectral and physical data of (-)-4 and (-)-5
were identical to those published.13,14
4-O-Ben zyl-3,7,8-tr id eoxy-3,7-im in o-1,2:5,6-d i-O-isop r o-
p ylid en e-D-th r eo-L-ga la cto-octitol ((-)-10). Heptono-1,4-
lactone (-)-4 was converted into 3,7,8-trideoxy-3,7-imino-1,2:
5,6-di-O-isopropylidene-D-threo-L-galacto-octitol (+)-9 as already
described.15 NaH, 55% in oil (302.4 mg, 6.93 mmol), benzyl
bromide (0.85 mL, 6.93 mmol), and tetrabutylammonium
iodide (60 mg, 0.17 mmol) were added successively to a stirred
solution of (+)-9 (995 mg, 3.46 mmol) in THF (10 mL). After
15 h of stirring, the mixture was poured into aqueous
saturated NaHCO3 solution (100 mL) and the aqueous layer
was extracted with EtOAc (50 mL, 4 times). The combined
organic extracts were dried (MgSO4), the solvent was evapo-
rated, and the residue was purified by FC (silica gel (20 g),
EtOAc/petroleum ether, 1:4): 1.03 g (79%) of (-)-10, colorless
oil; [R]25D ) -1.9 (c ) 1.5, CHCl3); 1H NMR (400 MHz, CDCl3)
MeOH/Et2O: mp 208-210 °C dec; [R]25 ) +1.3, [R]25
)
D
577
+1.8, [R]25 ) +2.2, [R]25 ) +3.4, [R]25 ) +4.0 (c ) 0.7,
546
435
405
MeOH); IR (KBr) ν 3135, 2010, 1765, 1410 cm-1; 1H NMR (600
MHz, CD3OD/D2O, pH 5.7) δ 4.80 (br s, HC(1)), 4.36 (d, 3J (2,3)
) 1.3, HC(2)), 4.28 (dd, 3J (1′,3) ) 10.1, 3J (1′,2′) ) 1.5, HC(1′)),
4.04 (d, 3J (2′,3′) ) 10.2, 3J (3′,4′) ) 9.8, HC(3′)), 4.00 (ddd,
3
3
3J (4′,5′) ) 2.8, J (5′,6′) ) 0.8, HC(5′)), 3.92 (dd, J (4,5) ) 8.4,
3J (3,4) ) 5.3, HC(4)), 3.88 (dd, 2J ) 11.8, 3J ) 2.6) & 3.73 (dd,
11.8, 5.0, H2C(6)), 3.77 (ddd, 8.4, 5.0, 2.6, HC(5)), 3.69 (dd, 9.5,
2.8, HC(4′)), 3.54 (qd, 6.7, 0.8, HC(6′)), 3.20 (dd, 10.2, 1.5,
HC(2′)), 2.40 (ddd, 10.1, 5.3, 1.3, HC(3)), 1.43 (d, 6.7, Me-C(6′));
13C-NMR (100.61 MHz, CDCl3, 50 °C) δ 110.9 (d, C(1)), 79.3,
79.0, 76.3, 75.3, 71.2, 67.0, 66.7 (7d), 64.4 (t, C(6)), 62.2, 56.1,
2
3
(29) Springer, G. F. Science 1984, 224, 1198. MacLean, G. D.,
Longenecker, B. L. Semin. Cancer Biol. 1991, 2, 443. Samuel, J .;
Nouaim, A. A.; MacLean, G. D.; Suresh, M. R.; Longenecker, B. M.
Cancer Res. 1990, 250, 4801. Zhuang, D.; Yousef, S.; Dennis, J . W.
Cancer Biochem. Biophys. 1991, 12, 185. Rabinovich, N. R.; McInnes,
P.; Klein, D. L.; Hall, P. F. Science 1994, 265, 1401.
(30) See, e.g.: MacLean, G. D.; Reddish, M.; Koganty, R. R.; Wong,
T.; Gaudhi, S.; Smolenski, M.; Samuel, J .; Nabholtz, J . M.; Longe-
necker, B. M. Cancer Immunol. Immunother. 1993, 36, 215. See also:
Hanessian, S.; Qiu, D.; Prabhanjan, H.; Reddy, G. V.; Lou, B. Can. J .
Chem.1996, 74, 1738.
δ 7.36-7.26 (d, m), 4.93, 4.57 (2d, J ) 11.4), 4.24 (ddd, J )
3
3
7.9, 6.2, 5.2), 4.12 (dd, J ) 6.9, 5.4), 4.05 (dd, J ) 5.4, 2.6),
2
3
2
3
3.97 (dd, J ) 8.1, J ) 6.2), 3.89 (dd, J ) 8.1, J ) 7.9), 3.41
(dd, 3J ) 10.0, 6.9), 3.03 (dd, 3J ) 6.7, 2.6), 2.44 (dd, 3J ) 10.0,
3
5.2), 1.55, 1.42, 1.40, 1.34 (4s), 1.28 (d, J ) 6.7).
4-O-Ben zyl-N-(ben zyloxyca r bon yl)-3,7,8-tr id eoxy-3,7-
im in o-1,2:5,6-d i-O-isop r op ylid en e-D-th r eo-L-ga la cto-octi-
tol ((+)-11). Meth od A (fr om (-)-10). NaHCO3 (400 mg,
4.80 mmol) and benzyl chloroformate (0.48 mL, 3.28 mmol)

Aza-C-disaccharides
J . Org. Chem., Vol. 62, No. 18, 1997 6257
were added to a stirred solution of (-)-10 (1.03 g, 2.73 mmol)
in 50% aqueous EtOH (16.2 mL). After 2 h of stirring at 20
°C, the mixture was poured into aqueous saturated NaHCO3
(100 mL) and the aqueous layer was extracted with EtOAc
(50 mL, four times). The combined organic extracts were dried
(MgSO4), and the solvent was evaporated. The residue was
purified by FC (silica gel (20 g), EtOAc/petroleum ether, 1:6):
1.35 g (97%) of (+)-11, colorless oil.
) +34.4 (c ) 1.2, CHCl3); 1H NMR (400 MHz, CDCl3, 50 °C) δ
2
2
7.37-7.30 (m), 5.16, 5.13 (2d, J ) 12.3), 4.85, 4.60 (2d, J )
11.5), 4.67 (dq, 3J ) 7.1, 7.1), 4.35 (dd, 3J ) 8.3, 7.1), 4.24 (dd,
3
3
3J ) 8.3, 6.1), 4.11 (dd, J ) 7.9, 6.4), 3.93 (dd, J ) 7.9, 6.1),
3.93-3.90 (m), 3.65-3.63, 3.59-3.57 (2m), 2.62 (br s), 2.55 (d,
3J ) 6.9), 1.55, 1.36 (2s), 1.27 (d, J ) 7.1).
3
(1R,3R,4S,5S,6S)-3-exo-[(1′R)-3′-O-Ben zyl-N-(ben zylox-
yca r b on yl)-2′,6′,7′-t r id e oxy-2′,6′-im in o-4′,5′-O-isop r o-
p ylid en e-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-6-en d o-ch lo-
r o-5-exo-(p h e n ylse le n o)-7-oxa b icyclo[2.2.1]h e p t a n -2-
on e ((-)-14) a n d (1R,3R,4S,5S,6S)-3-exo-[(1′R)-N-(Ben zyl-
oxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-isop r o-
pyliden e-â-D-glycer o-L-ma n n o-h eptitol-1′-yl]-6-en do-ch lo-
r o-5-exo-(p h e n ylse le n o)-7-oxa b icyclo[2.2.1]h e p t a n -2-
on e ((+)-15). A 1.6 M solution of BuLi in hexane (1.61 mL,
2.5 mmol) was added to a stirred solution of HMDS (0.37 mL,
1.76 mmol) at -10 °C in anhydrous THF (3.5 mL). After 20
min of stirring at -5 °C, the mixture was cooled to -78 °C,
and a solution of ketone (+)-1316a (463 mg, 1.53 mmol) in
anhydrous THF (3.5 mL) was added dropwise over a period of
30 min. At the end of the addition, the mixture was left at
-78 °C for 20 min and then cooled to -95 °C. Aldehyde (-)-
12 (739 mg, 1.68 mmol) in anhydrous THF (1.2 mL) was added
dropwise, and the mixture was maintained at -95 °C for 5.5
h and then poured into a 10% solution of AcOH in THF (40
mL) previously cooled to -95 °C. After being warmed to -10
°C, the mixture was quenched with a saturated aqueous
solution of NaHCO3 and extracted with CH2Cl2 (50 mL, four
times). The resulting organic phases were dried (MgSO4), and
the solvent was evaporated. FC (silica gel, 100 g, CH2Cl2/
petroleum ether/Et2O, 1:5:1) afforded 90 mg of the starting
ketone (19%), 60 mg of the starting aldehyde (-)-12 (8%), 505
mg of (-)-14 (45%), and 260 mg (26%) of (+)-15 both as white
crystals.
Meth od B, fr om N-(Ben zyloxyca r bon yl)-3,7,8-tr id eoxy-
3,7-im in o-1,2:5,6-d i-O-isop r op ylid en e-D-th r eo-L-ga la cto-
octitol (A). NaH, 55% in oil (47 mg, 0.95 mmol), benzyl
bromide (0.12 mL, 0.93 mmol), and tetrabutylammonium
iodide (6 mg, 0.02 mmol) were added successively to a stirred
solution of A (124 mg, 0.94 mmol) in THF (2.5 mL). After 15
h of stirring at 20 °C, the mixture was poured into aqueous
saturated NaHCO3 solution (15 mL), and the aqueous layer
was extracted with EtOAc (30 mL, four times). The combined
organic extracts were dried (MgSO4), and the solvent was
evaporated. The residue was purified by FC (silica gel (20 g),
EtOAc/ petroleum ether 1:6): 145 mg (97%) of (+)-11, colorless
oil; [R]25 ) +50 (c ) 0.9, CHCl3); 1H NMR (400 MHz, CDCl3)
D
δ 7.36-7.28 (m), 5.12 (s), 4.87, 4.63 (2d, 2J ) 7.4), 4.78 (qd, 3J
) 7.4, 7.4), 4.40-4.33 (m), 4.20 (dd, 3J ) 8.2, 6.7), 4.08 (dd, 2J
) 8.7, 3J ) 4.5), 4.03 (dd, 2J ) 8.7, 3J ) 6.8), 3.90 (dd, 3J )
8.7, 8.2), 3.47 (dd, 3J ) 8.7, 8.7), 1.56, 1.53, 1.36, 1.33 (4s),
3
1.28 (d, J ) 7.4).
N-(Ben zyloxyca r b on yl)-3,7,8-t r id eoxy-3,7-im in o-1,2:
5,6-di-O-isopr opyliden e-D-th r eo-L-ga la cto-octitol (A). NaH-
CO3 (58 mg, 0.69 mmol) and benzyl chloroformate (0.07 mL,
0.47 mmol) were added to a stirred solution of (-)-915 (113 mg,
0.394 mmol) in 50% aqueous EtOH (2 mL). After 2 h of
stirring at 20 °C for 2 h, the mixture was poured into aqueous
saturated NaHCO3 (10 mL), and the aqueous layer was
extracted with EtOAc (5 mL, five times). The combined
organic extracts were dried (MgSO4), and the solvent was
evaporated. The residue was purified by FC (silica gel (8 g),
EtOAc/petroleum ether, 1:2): 124 mg (75%) of A, colorless oil;
Da ta for (-)-14: mp 138.5-140 °C (Et2O/petroleum ether);
[R]25 ) -7.5 (c ) 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, 50
D
°C) δ 7.72-7.48, 7.34-7.26 (2m), 5.24, 5.16 (2d, 2J ) 12.4),
[R]25 ) +78.3 (c ) 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ
4.96 (br s), 4.88, 4.63 (2d, J ) 11.5), 4.69 (dq, J ) 7.3, 7.3),
4.42 (dd, 3J ) 5.7, 1.0), 4.34 (ddd, 3J ) 5.7, 2.8, 4J ) 1.0), 4.27
(dd, 3J ) 7.2, 6.8), 4.20 (dd, 3J ) 7.3, 6.8), 4.16-4.05 (m), 3.40
(d, 3J ) 2.8), 3.15 (br s), 2.29 (d, 3J ) 9.3), 1.52, 1.34 (2s), 1.07
2
3
D
7.39-7.30 (m), 5.14 (s), 4.52-4.44 (m), 4.39 (dd, 3J ) 8.1, 7.8),
3
3
4.23 (ddd, J ) 9.7, 8.3, 3.0), 4.03 (dd, J ) 8.3, 8.1), 3.98 (dd,
3J ) 9.7, 4.5), 3.93 (dd, J ) 8.7, 6.0), 3.62 (dd, J ) 8.7, J )
8.7), 3.00 (d, J ) 3.0), 1.50, 1.37, 1.35, 1.35 (4s), 1.24 (d, J )
7.4).
2
2
3
3
3
3
(d, J ) 7.3).
Da ta for (+)-15: mp 195-196 °C (Et2O); [R]25 ) +35.0 (c
D
3-O-Ben zyl-N-(ben zyloxyca r bon yl)-2,6,7-tr id eoxy-2,6-
im in o-4,5-O-isop r op ylid e n e -â-D-glycer o-L-m a n n o-h e p -
tose ((-)-12). Meth od A. A mixture of (+)-11 (203 mg, 0.397
mmol) and NaIO4 (102 mg, 0.477 mmol) in acetic acid/water
8:1 (4.15 mL) was allowed to stand at 20 °C overnight. The
mixture was poured into aqueous saturated NaHCO3 solution
(20 mL), and the aqueous layer was extracted with CH2Cl2
(20 mL, four times). The combined organic extracts were dried
(MgSO4), the solvent was evaporated, and the residue was
purified by FC (silica gel (15 g), EtOAc/petroleum ether, 1:4):
) 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61-7.58, 7.37-
2
3
7.28 (2m), 4.80 (br s), 4.76, 4.55 (2d, J ) 11.6), 4.41 (dd, J )
7.4, 3.8), 4.35 (d, 3J ) 5.7), 4.33 (dd, 3J ) 5.7, 2.6), 4.26 (dd, 3J
) 6.0, 6.0), 4.12 (dd, 3J ) 6.0, 2.8), 3.84 (dd, 3J ) 7.4, 7.4),
3.63 (dq, 3J ) 7.1, 2.8), 3.47 (d, 3J ) 2.6), 2.64 (d, 3J ) 3.8),
3
1.66 (d, J ) 7.1), 1.51, 1.38 (2s).
(1S,3S,4R,5R,6R)-3-exo-[(1′S)-3′-O-Ben zyl-N-(ben zylox-
yca r b on yl)-2′,6′,7′-t r id e oxy-2′,6′-im in o-4′,5′-O-isop r o-
pyliden e-â-D-glycer o-L-ma n n o-h eptitol-1′-yl]-6-en do-ch lo-
r o-5-exo-(p h e n ylse le n o)-7-oxa b icyclo[2.2.1]h e p t a n -2-
on e ((+)-16). A 1.6 M solution of BuLi in hexane (0.41 mL,
0.66 mmol) was added to a stirred solution of HMDS (0.22 mL,
0.72 mmol) at -10 °C in anhydrous THF (1.5 mL). After 20
min of stirring at -5 °C, the mixture was cooled to -78 °C
and a solution of racemic ketone (()-1316a (199 mg, 0.66 mmol)
in anhydrous THF (1.5 mL) was added dropwise over a period
of 30 min. At the end of the addition, the mixture was left at
-78 °C for 20 min and then cooled to -95 °C. The aldehyde
(-)-12 (278 mg, 0.63 mmol) in anhydrous THF (0.4 mL) was
added dropwise, and the mixture was maintained at -95 °C
for 3.5 h and then poured into a 10% solution of AcOH in THF
(35 mL) previously cooled to -78 °C. After being warmed to
-10 °C, the mixture was quenched with a saturated aqueous
solution of NaHCO3 and extracted with CH2Cl2 (30 mL, four
times). The combined organic phases were dried (MgSO4), and
the solvent was evaporated. FC (silica gel, 40 g, CH2Cl2/
petroleum ether/Et2O, 1:5:1) afforded 53 mg of the starting
ketone (()-13 (27%), 120 mg of (+)-16 (35%) as a colorless oil,
148 mg (30%) of (-)-14 as white crystals, 50 mg (18%) of (-)-
12 and 25 mg (6%) of (+)-15 as white crystals.
167 mg (94%) of (-)-12, colorless oil; [R]25 ) -2.7 (c ) 1.4,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.68 (s), 7.36-7.30 (m),
5.14 (s), 4.78, 4.61 (2d, 2J ) 11.5), 4.52 (qd, 3J ) 7.0, 6.9), 4.49
3
3
3
(d, J ) 7.9), 4.39 (dd, J ) 8.0, 6.9), 4.30 (dd, J ) 7.9, 5.7),
3
3
4.05 (dd, J ) 8.0, 5.7), 1.55, 1.36 (2s), 1.27 (d, J ) 7.0).
Meth od B. An aqueous solution of NaIO4 (105 mg, 0.49
mmol in 1 mL of H2O) was added to a stirred solution of B
(see below) (115 mg, 0.244 mmol) in THF (2 mL). After 15
min at 20 °C, the mixture was diluted with CH2Cl2 (15 mL)
and washed twice with brine. The aqueous layer was ex-
tracted with CH2Cl2 (5 mL, twice), and the combined organic
extracts were dried (MgSO4). The solvent was evaporated, and
the residue was purified by FC (silica gel (15 g), EtOAc/
petroleum ether, 1:4): 95 mg (89%) of (-)-12, a colorless oil.
(+)-4-O-Ben zyl-N-(ben zyloxyca r bon yl)-3,7,8-tr id eoxy-
3,7-im in o-5,6-O-isop r op ylid en e-D-th r eo-L-ga la cto-oct i-
tol (B). Dowex 50W-X8 (633 mg) was added to a solution of
(+)-11 (422 mg, 0.83 mmol) in 90% aqueous MeOH (6 mL).
After being stirred at 20 °C overnight, the mixture was filtered,
and the solvent was evaporated with toluene (15 mL, twice).
FC (silica gel (15 g), EtOAc/petroleum ether, 1:4) of the residue
permitted the recovery of 228 mg of starting material (conver-
Da ta for (+)-16: [R]25 ) +27.4 (c ) 0.5, CHCl3); 1H NMR
D
2
(400 MHz, CDCl3, 50 °C) δ 7.39-7.25 (m), 5.16, 5.12 (2s, J )
14.5), 4.88 (br s), 4.89, 4.69 (2d, J ) 10.8), 4.68 (dq, J ) 7.3,
sion 46%), together with 154 mg (40%) of B, colorless oil: [R]25
2
3
D

6258 J . Org. Chem., Vol. 62, No. 18, 1997
Baudat and Vogel
3
3
3
7.3), 4.47 (dd, J ) 9.0, 7.2), 4.40 (br d, J ) 5.7), 4.38 (dd, J
dropwise to the stirred solution of 20 (50 mg, 0.056 mmol) in
anhydrous CH2Cl2 (3 mL) cooled to -78 °C. After 3 h of
stirring at -78 °C, the mixture was allowed to warm up to 20
°C over 10 h. CH2Cl2 (5 mL) was added, and the solution was
washed with a saturated aqueous solution of NaHCO3 (10 mL).
The aqueous phase was extracted with CH2Cl2 (10 mL, four
times). The combined organic phases were washed with brine
(15 mL) and dried (MgSO4). After solvent evaporation in
vacuo, the residue was purified by FC (silica gel, 15 g, EtOAc/
petroleum ether, 1:4), yielding 28 mg (74%) of (+)-21 as a foam
3
3
4
) 8.2, 7.3), 4.24 (dd, J ) 8.2, 7.2), 4.21 (ddd, J ) 5.7, 2.7, J
) 1.0), 4.18 (br d, 3J ) 9.8), 3.85 (dd, 3J ) 9.0, 1.7), 3.35 (br s),
3
3
3
3.05 (d, J ) 2.7), 2.71 (d, J ) 9.8), 1.54, 1.38 (2s), 1.23 (d, J
) 7.3).
(1R,2S,3S,4S,5S,6S)-3-exo-[(1′R)-3′-O-Ben zyl-N-(b en -
zyloxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-iso-
p r op ylid en e-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-6-en d o-
ch lor o-5-exo-(p h en ylselen o)-7-oxa bicyclo[2.2.1]h ep ta n -2-
en d o-ol ((+)-17). NaBH4 (30 mg, 0.78 mmol) was added to a
stirred solution of (-)-14 (197 mg, 0.27 mmol) in THF/MeOH,
1:1 (8 mL), cooled to 0 °C. After 0.5 h of stirring, the mixture
was neutralized with a saturated aqueous solution of NH4Cl
and extracted with CH2Cl2 (20 mL, four times). The combined
organic extracts were dried (MgSO4) and the solvents evapo-
rated. Purification of the residue by FC (silica gel, 15 g,
(66% based on (-)-19): [R]25 ) +12.8 (c ) 0.3, CHCl3); 1H
D
NMR (400 MHz, CDCl3) δ 7.37-7.24 (m), 5.58 (br s), 5.17, 5.10
2
2
(2d, J ) 12.2), 4.76, 4.45 (2d, J ) 10.4), 4.76 (br s), 4.57 (d,
3J ) 4.4), 4.55 (dd, J ) 4.4, 1.2), 4.49 (dq, J ) 7.3, 7.1), 4.36
3
3
(dd, 3J ) 8.3, 7.1), 4.31 (dd, 3J ) 8.3, 4.1), 4.33-4.24 (m), 4.15
3
3
(dd, J ) 10.8, 5.5), 1.82 (br d, J ) 10.8), 1.52, 1.35 (2s), 1.26
3
(d, J ) 7.1), 1.04, 0.99 (2s).
EtOAc/petroleum ether, 1:1) afforded 174 mg (88%) of (+)-17
as a colorless oil: [R]25 ) +17.3 (c ) 0.6, CHCl3); H NMR
(1R,2S,3S,4S,5S,6S)-3-exo-[(1′R)-1′-O-Acetyl-3′-O-ben zyl-
N-(ben zyloxyca r bon yl)-2′,6′,7′-tr id eoxy-2′,6′-im in o-4′,5′-O-
isopr opyliden e-â-D-glycer o-L-ma n n o-h eptitol-1′-yl]-6-en do-
ch lor o-5-exo-(p h en ylselen o)-7-oxa b icyclo[2.2.1]h ep t -2-
en d o-yl Aceta te ((-)-22). A solution of (+)-17 (167 mg, 0.225
mmol) in a 3:2 mixture of pyridine/Ac2O (5 mL) was stirred
overnight with DMAP (2 mg). After evaporation of the
solvents, FC of the residue (silica gel, 15 g, EtOAc/petroleum
ether, 1:6) afforded 184 mg (99%) of (-)-22 as a colorless oil:
1
D
(400 MHz, CDCl3, 50 °C) δ 7.65-7.26 (m), 5.09, 5.05 (2d, 2J )
2
3
11.3), 4.77, 4.62 (2d, J ) 11.6), 4.60 (dq, J ) 7.4, 7.2), 4.51
(br s), 4.37 (m), 4.31 (dd, 3J ) 8.3, 7.4), 4.22 (dd, 3J ) 8.3, 5.8),
3
3
3
4.12 (dd, J ) 7.7, 5.4), 3.97 (dd, J ) 7.7, 5.8), 3.86 (br dd, J
) 6.2, 5.4), 3.41 (br s), 2.65, 1.98 (2 br s), 1.89 (br dd, 3J ) 6.2,
3
4,4), 1.41, 1.34 (2s), 1.27 (d, J ) 7.2).
(4R,4a R,5S,6S,7S,8R,8a S)-[(1′R)-2′-O-Ben zyl-N-(b en -
zyloxyca r b on yl)-1′,5′,6′-t r id eoxy-1′,5′-im in o-3′,4′-O-iso-
p r op ylid en e-â-D-ga la cto-h exitol-1′-yl]-2,2-d i-ter t-bu tyl-7-
ch lor o-4a,5,6,7,8,8a-h exah ydr o-6-(ph en ylselen o)-5,8-epoxy-
4H-1,3-dioxa-2-silan aph th alen e ((+)-18). 2,6-Lutidine (0.009
mL, 0.07 mmol) and di-tert-butylsilyl ditriflate (0.001 mL,
0.028 mmol) were added to a stirred solution of (+)-17 (17 mg,
0.023 mmol) in anhydrous CHCl3 (1 mL). After 14 h of stirring
at 50 °C, the mixture was neutralized with ice cold aqueous 1
M solution of HCl and extracted with CH2Cl2 (5 mL, four
times). The combined organic extracts were dried (MgSO4)
and the solvents evaporated. Purification of the residue by
FC (silica gel, 8 g, EtOAc/petroleum ether, 1:4) afforded 5 mg
(25%) of (+)-18 as a colorless oil: [R]25D ) +6.2 (c ) 0.4, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.70-7.20 (m), 5.02, 4.94 (2d, 2J
[R]25 ) -8.8 (c ) 1.3, CHCl3); 1H NMR (400 MHz, CDCl3, 50
D
°C) δ 7.62-7.26 (m), 5.51 (dd, 3J ) 6.0, 5.8), 5.08 (s), 5.08 (m),
4.77 (dd, 3J ) 4.4, 4.4), 4.70, 4.53 (2d, 2J ) 11.5), 4.57 (s), 4.53
3
3
(m), 4.36 (m), 4.26 (dd, J ) 7.2, 7.0), 4.20 (dd, J ) 8.2, 5.4),
3
3
4.18 (m), 3.79 (dd, J ) 7.2, 5.4), 3.28 (br s), 2.51 (d, J ) 5.8,
4.7), 1.98, 1.92 (2s), 1.38, 1.32 (2s), 1.20 (d, J ) 7.1).
3
(1R,2S,3S,4S)-3-exo-[(1′R)-1′-O-Acet yl-3′-O-b en zyl-N-
(b en zyloxyca r b on yl)-2′,6′,7′-t r id eoxy-4′,5′-O-isop r op yl-
id en e-2′,6′-im in o-â-D-glycer o-L-m a n n o-h ep t it ol-1′-yl]-6-
ch lor o-7-oxa b icyclo[2.2.1]h ep t -5-en -2-en d o-yl Acet a t e
((-)-23). A solution of 85% mCPBA (42.3 mg, 0.21 mmol) in
anhydrous CH2Cl2 (1 mL) was added dropwise in 30 min to a
stirred solution of (+)-22 (164 mg, 0.20 mmol) in anhydrous
CH2Cl2 (2 mL) cooled to -78 °C. After 3 h of stirring at -78
°C, the mixture was allowed to warm up to 20 °C in 10 h.
CH2Cl2 (10 mL) was added, and the solution was washed with
2
) 12.3), 4.74, 4.59 (2d, J ) 11.6), 4.58-4.50 (m), 4.51-4.45
3
3
(m), 4.35 (dd, J ) 4.6, 4.6), 4.27 (dd, J ) 8.0, 5.1), 4.22 (dd,
3J ) 4.6, 0.3), 4.21 (dd, 3J ) 8.0, 6.2), 3.97 (br d, 3J ) 6.9),
3.79 (m), 3.58 (dd, 3J ) 11.1, 3.1), 3.28 (br s), 1.91 (dd, 3J )
a
saturated aqueous solution of NaHCO3 (10 mL). The
3
11.1, 1.0), 1.52, 1.35 (2s), 1.20 (d, J ) 7.0), 1.01, 0.93 (2s).
aqueous phase was extracted with CH2Cl2 (15 mL, four times),
and the combined organic extracts were dried (MgSO4). After
solvent evaporation in vacuo the residue was purified by FC
(silica gel, 15 g, EtOAc/petroleum ether, 1:4), yielding 119 mg
(90%) of (-)-23, colorless oil; [R]25D ) -61 (c ) 0.7, CHCl3); 1H
(1S,2R,3R,4R,5R,6R)-3-exo-[(1′S)-3′-O-Ben zyl-N-(b en -
zyloxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-iso-
p r op ylid en e-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-6-en d o-
ch lor o-5-exo-(p h en yselen o)-7-oxa bicyclo[2.2.1]h ep ta n -2-
en d o-ol ((-)-19). NaBH4 (45 mg, 1.17 mmol) was added to a
stirred solution of (+)-16 (300 mg, 0.42 mmol) in THF/MeOH
1:1 (10 mL) cooled to 0 °C. After 0.5 h of stirring, the mixture
was neutralized with an aqueous saturated solution of NH4Cl
and extracted with CH2Cl2 (30 mL, four times). The combined
organic extracts were dried (MgSO4), and the solvents were
evaporated. Purification of the residue by FC (silica gel, 15
g, EtOAc/petroleum ether, 1:1) afforded 300 mg (96%) of (-)-
NMR (400 MHz, CDCl3
, 50 °C) δ 7.38-7.27 (m), 5.93 (br s),
3
2
5.57 (dd, J ) 6.5, 5.2), 5.20 (br s), 5.18, 5.15 (2d, J ) 12.3),
2
4.95 (br s), 4.87 (d,
3J ) 4.3), 4.75, 4.56 (2d, J ) 10.9), 4.68
(dq, 3J ) 7.3, 7.3), 4.35-4.32 (m), 4.32 (dd, 3J ) 8.1, 7.3), 4.23
(dd, 3
J ) 8.3, 6.2), 3.78 (dd, 3J ) 8.1, 6.2), 2.13-2.20 (m), 2.00
3J ) 7.3).
(2s), 1.54, 1.35 (2s), 1.22 (d,
(1R,2S,3R,4S,5S)-3-exo-[(1′R)-1′-O-Acetyl-3′-O-ben zyl-N-
(b en zyloxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-
isop r op ylid en e-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-6-oxo-
7-oxa bicyclo[2.2.1]h ep ta n e-2-en d o,5-exo-d iyl Dia ceta te
(24). Me3NO (23 mg, 0.2 mmol) in THF/H2O, 5:1 (0.6 mL),
was added dropwise to a stirred solution of (-)-23 (45 mg, 0.07
mmol) in THF/H2O, 5:1 (0.6 mL), NaHCO3 (30 mg, 0.4 mmol),
and 0.1 M solution of OsO4 in CCl4 (0.05 mL). After 2.5 h of
stirring at 20 °C, EtOAc (10 mL) was added and the solution
was washed with a saturated aqueous solution of NaHSO3 (10
mL, three times) and then with brine (10 mL, twice). The
combined aqueous phases were extracted with EtOAc (10 mL,
three times), and the combined organic phases were dried
(MgSO4). After solvent evaporation in vacuo at 20 °C, the
residue was dissolved in anhydrous pyridine (1 mL) and Ac2O
(0.8 mL), and DMAP (5 mg) was added. After 15 h of stirring
at 20 °C for 15 h the solvents were removed in vacuo.
Filtration through Florisil (5 g) eluting with EtOAc/petroleum
ether, 1:4, afforded, after evaporation in vacuo at 20 °C, a very
instable oil which was used without further purification. An
analytical sample of 24 was purified by FC (Florisil, 5 g,
EtOAc/petroleum ether, 1:4): 1H NMR (400 MHz, CDCl3, 50
19: colorless oil; mp 170-171 °C (Et2O); [R]25 ) -15.5 (c )
D
0.6, CHCl3); 1H NMR (400 MHz, CDCl3, 50 °C) δ 7.53-7.26
2
(m), 5.13 (s), 4.66, 4.58 (2d, J ) 11.3), 4.48-4.42 (m), 4.39-
4.36 (m), 4.31-4.11 (m), 3.38 (d, 3J ) 3.7), 2.50 (br s), 2.07
3
3
(dd, J ) 6.1, 4.7), 1.50, 1.33 (2s), 1.30 (d, J ) 6.6).
(4S,4a R,5R,8S,8a R)-[(1′S)-2′-O-Ben zyl-N-(b en zyloxy-
ca r b on yl)-1′,5′,6′-t r id eoxy-1′,5′-im in o-3′,4′-O-isop r op yl-
id en e-â-D-ga la cto-h exitol-1′-yl]-2,2-d i-ter t-bu tyl-7-ch lor o-
4a ,5,8,9-t et r a h yd r o-5,8-ep oxy-4H -1,3-d ioxa -2-sila n a p h -
th a len e ((+)-21). 2,6-Lutidine (0.024 mL, 0.21 mmol) and di-
tert-butylsilyl ditriflate (0.029 mL, 0.084 mmol) were added
to a stirred solution of (-)-19 (52 mg, 0.07 mmol) in anhydrous
CH2Cl2. After 20 h of stirring at 20 °C, the mixture was
neutralized with ice cold aqueous 1 M solution of HCl and
extracted with CH2Cl2 (10 mL, four times). The combined
organic extracts were dried (MgSO4), and the solvents were
evaporated. Purification of the residue by FC (silica gel, 8 g,
EtOAc/petroleum ether, 1:4) afforded 55 mg (89%) of a mixture
of rotamers 20 as colorless oil. A solution of 85% mCPBA (12
mg, 0.06 mmol) in anhydrous CH2Cl2 (1.2 mL) was added

Aza-C-disaccharides
°C) δ 7.40-7.26 (m), 5.58 (dd, J ) 6.3, 3.5), 5.24 (br s), 5.18,
J . Org. Chem., Vol. 62, No. 18, 1997 6259
3
ca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-isop r op yl-
id e n e -â-D -glycer o-L -m a n n o-h e p t it ol-1′-yl]-6-ch lor o-7-
oxa bicyclo[2.2.1]h ep t-5-en -2-en d o-ol ((+)-28). A solution
of 85% mCPBA (61 mg, 0.3 mmol) in anhydrous CH2Cl2 (1.2
mL) was added dropwise to a stirred solution of (-)-19 (190
mg, 0.26 mmol) in anhydrous CH2Cl2 (5.4 mL) cooled to -78
°C over 30 min. After 3 h of stirring at -78 °C, the mixture
was allowed to warm up to 20 °C over 10 h. CH2Cl2 (15 mL)
was added, and the solution was washed with saturated
aqueous solution of NaHCO3 (20 mL). The aqueous phase was
extracted with CH2Cl2 (15 mL, four times). The combined
organic phases were washed with brine (15 mL) and dried
(MgSO4). After solvent evaporation in vacuo the residue was
purified by FC (silica gel, 15 g, EtOAc/petroleum ether, 1:1)
2
2
5.13 (2d, J ) 12.2), 4.82-4.64 (m), 4.77, 4.56 (2d, J ) 11.1),
3
3
4.72 (br s), 4.62 (dq, J ) 7.3, 6.9), 4.50 (br d, J ) 5.6), 4.33
3
3
3
(dd, J ) 7.2, 6.9), 4.27 (dd, J ) 7.2, 6.0), 4.24 (dd, J ) 7.7,
6.0), 3.80 (dd, 3J ) 7.7, 6.3), 2.57 (dd, 3J ) 5.4, 3.5), 2.12, 1.94,
3
1.91 (3s), 1.55, 1.35 (2s), 1.18 (d, J ) 7.3).
(1S,4S,5S,6R,7S)-6-exo-[(1′R)-1′-O-Acetyl-3′-O-ben zyl-N-
(b en zyloxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-
isop r op ylid en e-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-3-oxo-
2,8-d ioxa bicyclo[3.2.1]octa n e-4-exo,7-en d o-d iyl Dia ceta te
((-)-25). NaHCO3 (10 mg, 0.16 mmol) and a solution of 85%
mCPBA (17.5 mg, 0.07) in anhydrous CH2Cl2 (0.3 mL) were
added successively to the crude product 24 obtained above
dissolved in anhydrous CH2Cl2 (2 mL). After 14 h of stirring
at 25 °C, CH2Cl2 (5 mL) was added and the mixture washed
with a saturated aqueous solution of NaHCO3 (5 mL, twice)
and then brine (5 mL, twice). The combined aqueous phases
were extracted with CH2Cl2 (15 mL, 3 times). The combined
organic extracts were dried (MgSO4), and the solvents were
evaporated in vacuo, giving a residue which was purified by
FC (silica gel, 8 g, EtOAc/petroleum ether, 1:2) yielding 34 mg
(67%) of (-)-25 as a colorless oil: [R]25D ) -55 (c ) 0.3, CHCl3);
1H NMR (400 MHz, CDCl3, 50 °C) δ 7.40-7.27 (m), 5.99 (br
s), 5.55 (dd, 3J ) 6.0, 5.8), 5.18, 5.12 (2d, 2J ) 12.2), 5.17-
5.12 (2m), 4.76, 4.55 (2d, 2J ) 11.1), 4.61-4.53 (2m), 4.33 (dd,
3J ) 7.2, 5.8), 4.24 (2dd, 3J ) 7.8, 5.8), 3.83 (dd, 3J ) 7.8, 5.8),
yielding 144 mg (95%) of (+)-28 as a foam: mp 76-79 °C; [R]25
D
1
) +10 (c ) 1.7, CHCl3); H NMR (400 MHz, CDCl3, 50 °C) δ
2
7.34-7.25 (m), 6.35 (br s), 5.25, 5.10 (2d, J ) 12.3), 4.77 (d,
3
2
3J ) 1.7), 4.75 (d, J ) 4.6), 4.67-4.63 (m), 4.61, 4.57 (2d, J
3
3
) 11.5), 4.58-4.54 (m), 4.47 (br d, J ) 10.1), 4.41 (dd, J )
3
3
8.0, 6.2), 4.30 (dd, J ) 8.0, 2.0), 4.22 (dq, J ) 6.3, 6.2), 4.13
3
3
(dd, J ) 3.5, 2.0), 1.78 (dd, J ) 2.6, 2.5), 1.56, 1.36 (2s), 1.35
3
(d, J ) 6.3).
(1S,2R,3R,4R)-3-exo-[(1′S)-3′-O-Ben zyl-N-(b en zyloxy-
c a r b o n y l)-2′,6′,7′-t r id e o x y -2′,6′-im in o -4′,5′-O -is o p r o -
pyliden e-1′-O-(m eth oxym eth yl)-â-D-glycer o-L-ma n n o-h ep-
t it ol-1′-yl]-6-ch lor o-2-en d o-(m e t h oxym e t h oxy)-7-oxa -
bicyclo[2.2.1]h ep t-5-en e ((+)-29). Methoxymethyl chloride
(2.5 mL, 33 mmol) was added to a stirred solution of (+)-28
(374 mg, 0.64 mmol) in anhydrous CH2Cl2 (5 mL) and
anhydrous diisopropylethylamine (5 mL) cooled to 0 °C. After
addition of tetrabutylammonium iodide (30 mg, 0.08 mmol),
the mixture was allowed to warm up to 20 °C in 18 h. MeOH
(2 mL) was added and the mixture stirred for an additional
hour. Then the mixture was diluted with CH2Cl2 (30 mL) and
poured into ice cold 1 M HCl (30 mL). The organic phase was
separated and the aqueous phase extracted with CH2Cl2 (30
mL, four times). The combined organic phases were dried
(MgSO4). After solvent evaporation in vacuo, the residue was
purified by FC (silica gel, 15 g, EtOAc/petroleum ether, 1:1),
3
5
2.71 (ddd, J ) 5.4, 4.0, J ) 1.4), 2.12, 2.00, 1.91 (3s), 1.54,
3
1.35 (2s), 1.19 (d, J ) 7.2).
Meth yl {Meth yl 2,5-di-O-acetyl-3-deoxy-3-C-[(1′R)-1′,4′,5′-
t r i-O-a cet yl-3′-O-b en zyl-N-(b en zyloxyca r b on yl)-2′,6′,7′-
tr id eoxy-2′,6′-im in o-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-
r- a n d -â-D-a lt r ofu r a n osid }u r on a t e ((+)-26). Freshly
distilled SOCl2 (0.01 mL, 0.153 mmol) was added dropwise to
a stirred solution of (-)-25 (8 mg, 0.01 mmol) in anhydrous
MeOH (0.5 mL) cooled to 0 °C. After 28 h of stirring, the
solvent was evaporated in vacuo. The residue was dissolved
in pyridine (0.5 mL) and Ac2O (0.3 mL), and DMAP (3 mg)
was added. After 14 h of stirring at 20 °C, the solvents were
removed, the residue was taken up with toluene, and the
solvent was evaporated (three times). Purification of the
residue by FC (silica gel, 8 g, EtOAc/petroleum ether, 1:4, then
CH2Cl2/petroleum ether/MeOH, 4:4:1) afforded 6 mg (73%) of
yielding 144 mg (95%) of (+)-29 as a colorless oil: [R]25
)
D
+16 (c ) 1.5, CHCl3); 1H NMR (400 MHz, CDCl3, 50 °C) δ
7.41-7.28 (m), 5.61 (br s), 5.17, 5.13 (2d, 2J ) 12.2) 4.89, 4.52
a 5:1 mixture of R- and â-anomer (+)-26: colorless oil; [R]25
(2d, J ) 10.8), 4.85 (br s), 4.79, 4.62 (2d, J ) 6.3), 4.72, 4.59
(2d, 2J ) 5.6), 4.70 (dq, 3J ) 7.4, 7.3), 4.67 (br d, 3J ) 4.6),
4.40-4.35 (m), 4.31 (dd, 3J ) 8.1), 4.25 (dd, 3J ) 8.1, 6.6), 4.02-
3.96 (m), 3.41, 3.34 (2s), 2.24 (dd, 3J ) 10.8, 2.3), 1.53, 1.36
2
2
D
) +32.6 (c ) 0.5, CHCl3); 1H NMR (400 MHz, CDCl3, 50 °C) δ
3
3
7.53-7.28 (m), 5.52 (d, J ) 3.2), 5.46 (dd, J ) 6.8, 2.2), 5.36
2
3
(d, J ) 11.4), 5.27 (d, J ) 2.4), 5.20-5.00 (2m), 4.85 (br s),
2
3
3
4.75, 4.70, 4.68 (3d, J ) 10.7, 11.4, 10.7), 4.48 (dq, J ) 6.9,
(2s), 1.25 (d, J ) 7.3).
3
3
6.8), 4.30 (br d, J ) 8.5), 3.86 (br d, J ) 5.3), 3.80 (s), 3.49
(1R,2R,4S,5R,6R)-6-exo-[(1′S)-3′-O-Ben zyl-N-(ben zylox-
yca r b on yl)-2′,6′,7′-t r id e oxy-2′,6′-im in o-4′,5′-O-isop r o-
pyliden e-1′-O-(m eth oxym eth yl)-â-D-glycer o-L-ma n n o-h ep-
t i t o l-1′-y l]-5-en d o-(m e t h o x y m e t h o x y )-3-o x o -7-o x a -
bicyclo[2.2.1]h epta n -2-en d o-yl 4-Br om oben zen esu lfon a te
((-)-31). Me3NO (160 mg, 1.44 mmol) in a 5:1 mixture of THF/
H2O (1 mL) was added dropwise to a stirred solution of (+)-
29 (330 mg, 0.49 mmol) in 5:1 THF/H2O (9 mL) containing
NaHCO3 (216 mg, 2.57 mmol) and 0.1 M solution of OsO4 in
CCl4 (0.37 mL). After 2.5 h of stirring at 20 °C, EtOAc (20
mL) was added, and the solution was washed with a saturated
aqueous solution of NaHSO3 (20 mL, twice) and then with
brine (20 mL). The combined aqueous phases were extracted
with EtOAc (20 mL, 3 times), and the combined organic
extracts were dried (MgSO4). After solvent evaporation in
vacuo, the residue was dissolved in anhydrous CH2Cl2 (11.5
mL) at 0 °C, and then brosyl chloride (193 mg, 0.76 mmol)
and Et3N (0.215 mL, 1.55 mmol) were added. After 15 h of
stirring at 20 °C, the mixture was diluted with CH2Cl2 (30
mL) and poured over ice cold 1 M HCl (30 mL). The organic
phase was separated and the aqueous phase extracted with
CH2Cl2 (30 mL, four times). The combined organic phases
were dried (MgSO4). After solvent evaporation in vacuo the
residue was purified by FC (silica gel, 20 g, EtOAc/petroleum
ether, 1:3), yielding 367 mg (84%) of (-)-31 as a foam: mp
59-62 °C; [R]25D ) -20.4 (c ) 1.5, CHCl3); 1H NMR (400 MHz,
CDCl3, 50 °C) δ 7.56-7.32 (m), 5.17 (s), 4.89, 4.57 (2d, 2J )
(s), 2.94 (dd, 3J ) 8.5, 3.2), 2.36, 2.12, 2.01 (3s), 1.79, 1.64 (2s),
3
1.01 (d, J ) 6.9).
Meth yl 2,5,6-Tr i-O-a cetyl-3-d eoxy-3-C-[(1′R)-1′,4′,5′-tr i-
O-a cetyl-2′,6′,7′-tr id eoxy-2′,6′-im in o-â-D-glycer o-L-m a n n o-
h ep titol-1′-yl]-r- a n d -â-D-a ltr ofu r a n osid e ((+)-27). LiBH4
(5 mg, 0.23 mmol) was added to a stirred solution of (+)-26
(25 mg, 0.03 mmol) in anhydrous THF (4 mL) at 0 °C, and the
temperature was allowed to reach 20 °C. After 4 h of stirring,
AcOEt (0.5 mL) was added, and the reaction was left for an
additional hour. Acetic acid (0.5 mL) followed 20 min later
by pyridine (3 mL), Ac2O (1 mL), and DMAP (5 mg) was added
to the mixture. After 14 h of stirring at 20 °C, the solvent
was removed and the residue filtered (silica gel, 8 g, EtOAc/
petroleum ether, 3:2). The residue was taken up in 70%
aqueous acetic acid (1 mL) and MeOH (1 mL) and was
hydrogenolyzed in the presence of 10% Pd on charcoal (5 mg).
After 24 h the mixture was filtered through Celite, and the
solvents were evaporated. Purification of the residue by FC
(silica gel, 8 g, CH2Cl2/MeOH 95:5) afforded 13 mg (72%) of a
5:1 mixture of R- and â-anomer (+)-27: colorless oil; [R]25
)
D
+61 (c ) 0.6, CHCl3); 1H NMR (400 MHz, CDCl3, 50 °C) δ 5.41
3
3
3
(ddd, J ) 8.9, 2.5, 2.0), 5.36 (dd, J ) 10.0, 2.5), 5.24 (dd, J
3
) 3.0, 1.2), 4.98 (s), 4.96 (dd, J ) 9.9, 3.0), 4.87 (s), 4.63 (dd,
2J ) 12.6, J ) 2.0), 4.17 (dd, J ) 12.6, J ) 8.9), 4.02 (dd, J
) 6.2, 2.5), 3.35 (dd, 3J ) 9.9, 8.0), 3.32 (s), 3.12 (br q, 3J )
6.7), 2.79 (br dd, 3J ) 10.0, 6.2), 2.70 (br d, 3J ) 8.0), 2.23,
3
2
3
3
3
2
2.18, 2.15, 2.11, 2.10, 2.05, 2.03 (6s), 1.01 (d, J ) 6.7).
10.8), 4.69-4.63 (m), 4.70, 4.58 (2d, J ) 5.9), 4.65, 4.44 (2d,
3
(1S,2R,3R,4R)-3-exo-[(1′S)-3′-O-Ben zyl-N-(b en zyloxy-
2J ) 6.6), 4.40 (dd, J ) 10.0, 6.1), 4.36-4.38 (m), 4.35-4.28

6260 J . Org. Chem., Vol. 62, No. 18, 1997
Baudat and Vogel
3
3
(m), 4.09 (s), 3.87 (dd, J ) 10.9, 0.5), 3.50 (br d, J ) 10.0),
Da ta for (+)-35: [R]25 ) +33.4 (c ) 0.8, CHCl3); 1H NMR
D
3
3
3.37, 3.14 (2s), 2.69 (br d, J ) 10.9), 1.54, 1.40 (2s), 1.22 (d,
(400 MHz, CDCl3, 50 °C) δ 7.50-7.28 (m), 5.54 (d, J ) 2.4),
3J ) 7.3).
5.30-4.90 (m), 5.06 (br s), 4.63, 4.48 (2d, J ) 7.0), 4.60, 4.52
2
2
2
3
(1R,4R,5R,6S,7R)-6-exo-[(1′S)-3′-O-Ben zyl-N-(ben zylox-
yca r b on yl)-2′,6′,7′-t r id e oxy-2′,6′-im in o-4′,5′-O-isop r o-
pyliden e-1′-O-(m eth oxym eth yl)-â-D-glycer o-L-ma n n o-h ep-
t i t o l-1′-y l]-7-en d o-(m e t h o x y m e t h o x y )-3-o x o -2,8-d i -
oxabicyclo[3.2.1]octan -4-exo-yl 4-Br om oben zen esu lfon ate
((+)-32). NaHCO3 (30 mg, 0.96 mmol) and a solution of 95%
mCPBA (76 mg, 0.44 mmol) in anhydrous CH2Cl2 (1.5 mL)
were added successively to a solution of (-)-31 (355 mg, 0.399
mmol) in anhydrous CH2Cl2 (7.5 mL) at 0 °C. After 15 h of
stirring at 25 °C, further CH2Cl2 (15 mL) was added and the
mixture washed with an aqueous saturated solution of NaH-
CO3 (25 mL, twice) and brine (25 mL, twice). The combined
aqueous phases were extracted with CH2Cl2 (25 mL, three
times). The combined organic extracts were dried (MgSO4),
and the solvents were evaporated in vacuo, giving a residue
which was purified by FC (silica gel, 20 g, EtOAc/petroleum
ether, 1:2), yielding 345 mg (95%) of (+)-32 as a foam: mp
62-65 °C; [R]25D ) +34.7 (c ) 0.8, CHCl3); 1H NMR (400 MHz,
CDCl3, 50 °C) δ 7.63-7.27 (m), 5.75 (d, 3J ) 3.5), 5.24, 5.13
(2d, 2J ) 12.1), 4.85, 4.57 (2d, 2J ) 10.5), 4.88-4.83 (m), 4.74,
4.57 (2d, 2J ) 6.8), 4.73-4.68 (m), 4.70, 4.55 (2d, 2J ) 5.8),
4.42-4.37 (m), 4.36-4.28 (2m), 4.22 (dd, 3J ) 4.3, 3.5), 3.97
(2d, J ) 11.5), 4.56, 4.54 (2d, J ) 6.6), 4.46 (dq, J 7.6, 7.0),
3
4.24-4.16 (2m), 4.12-4.07 (2m), 3.92 (dd, J ) 2.8, 2.4), 3.69
3
3
(dd, J ) 8.7, 1.6), 3.60 (dd, J ) 10.0, 1.6), 3.29 (s), 3.15, 3.20
3
3
(2s), 2.33 (dd, J ) 8.7, 2.8), 1.23, 1.05 (2s), 0.94 (d, J ) 7.6).
1,5-An h yd r o-3-C-[(1′S)-3′-O-ben zyl-N-(ben zyloxyca r bo-
n yl)-2′,6′,7′-tr id eoxy-2′,6′-im in o-4′,5′-O-isop r op ylid en e-1′-
O-(m eth oxym eth yl)-â-D-glycer o-L-m a n n o-h ep titol-1′-yl]-
3-d eoxy-2-O-(m eth oxym eth yl)-r-D-ga la ctofu r a n ose ((+)-
36). LiBH4 (15 mg, 0.69 mmol) was added to a stirred solution
of (-)-34 (132 mg, 0.19 mmol) in anhydrous THF (5 mL). After
5 h of stirring, the mixture was cooled to -5 °C, neutralized
with a 1 N solution of HCl and extracted with CH2Cl2 (15 mL,
four times). The combined organic extracts were dried (Mg-
SO4), and the solvents were evaporated. Purification of the
residue by FC (silica gel, 15 g, EtOAc/petroleum ether, 3:2)
afforded 105 mg (82%) of (+)-36 as a foam: mp 49-54 °C;
1
[R]25D) +1.1 (c ) 0.9, CHCl3); H NMR (400 MHz, CDCl3, 50
°C) δ 7.42-7.26 (m), 5.50 (d, 3J ) 2.4), 5.19, 5.15 (2d, 2J )
2
2
12.4), 4.94, 4.53 (2d, J ) 10.8), 4.75, 4.61 (2d, J ) 6.5), 4.70
(dq, 3J ) 7.3, 6.4), 4.68, 4.55 (2d, 2J ) 5.9), 4.53 (br s), 4.38
3
3
3
(dd, J ) 9.6, 6.5), 4.35 (dd, J ) 8.1, 6.5), 4.25 (dd, J ) 8.1,
3
6.4), 4.01, 3.96 (2m), 3.92 (dd, J ) 10.7, 1.2), 3.41, 3.35 (2s),
3
3
(br d, J ) 10.0), 3.65 (dd, J ) 9.8, 1.2), 3.43, 3.34 (2s), 2.77
3.30-3.17 (m), 2.21 (dd, 3J ) 10.7, 2.6), 1.53, 1.36 (2s), 1.23
3
3
3
(ddd, J ) 10.0, 4.3, 2.1), 1.55, 1.41 (2s), 1.22 (d, J ) 7.3).
Meth yl 1,5-An h yd r o-3-C-[(1′S)-3′-O-ben zyl-N-(ben zyl-
oxyca r b on yl)-2′,6′,7′-t r id eoxy-2′,6′-im in o-4′,5′-O-isop r o-
pyliden e-1′-O-(m eth oxym eth yl)-â-D-glycer o-L-ma n n o-h ep-
t it o l-1′-y l]-3-d e o x y -2-O -(m e t h o x y m e t h y l)-r-D -g a la c -
tofu r a n u r on a te ((-)-34) a n d Meth yl 1,5-An h yd r o-3-C-
[(1′S)-3′-O-ben zyl-N-(ben zyloxyca r bon yl)-2′,6′,7′-tr id eoxy-
2′,6′-im in o-4′,5′-O-isop r op ylid en e-1′-O-(m eth oxym eth yl)-
â-D-glycer o-L-m a n n o-h ep t it ol-1′-yl]-3-d eoxy-2-O-(m et h -
oxym eth yl)-r-L-a ltr ofu r a n u r on a te ((+)-35). K2CO3 (18.2
mg, 1.32 mmol) was flame-dried under an Ar atmosphere and
then dissolved in anhydrous DMF (0.25 mL). Successively a
solution of (+)-32 (40 mg, 0.44 mmol) in anhydrous DMF (0.4
mL) and anhydrous MeOH (0.2 mL) were added. After 2.5 h,
the mixture was evaporated in vacuo, taken up in with EtOAc
(5 mL), and washed with aqueous saturated NH4Cl solution
(10 mL). The aqueous phases were extracted with EtOAc (8
mL, three times), and the combined organic extracts were dried
(MgSO4). The solvent was evaporated in vacuo, giving a
residue which was purified by FC (silica gel, 8 g, EtOAc/
petroleum ether, 1:2), yielding first 2 mg of (+)-35 (6%) and
then 20 mg (66%) of (-)-34 as a foam.
(d, J ) 7.3).
1,5-An h yd r o-3-d eoxy-3-C-[(1′S)-2′,6′,7′-t r id eoxy-2′,6′-
im in o-4′,5′-O-isop r op ylid en e-1′-O-(m eth oxym eth yl)-â-D-
glycer o-L-m a n n o-h ep titol-1′-yl]-2-O-(m eth oxym eth yl)-r-
D-ga la ctofu r a n ose ((+)-37). A solution of (+)-36 (36 mg, 0.08
mmol) and 10% Pd on charcoal (5 mg) in THF/H2O (10 mL)
was stirred at 20 °C under a H2 atmosphere for 24 h.
Filtration through Celite, evaporation, and FC (silica gel (8
g), CH2Cl2/MeOH, 9:1) yielded (+)-37 (36 mg, 97%) which
precipitated from Et2O/ petroleum ether, colorless crystals: mp
78-79 °C; [R]25D ) +54.2 (c ) 1.4, CHCl3); 1H NMR (400 MHz,
CD3OD) δ 5.48 (d, 3J ) 2.4), 4.84, 4.69 (2d, 2J ) 7.0), 4.82,
4.63 (2d, 2J ) 6.6), 4.58 (br s), 4.11 (dd, 3J ) 5.1, 2.7), 3.97
3
3
3
(dd, J ) 3.1, 2.4), 3.94 (dd, J ) 7.4, 5.1), 3.81 (dd, J ) 7.4,
5.5), 3.78 (dd, 3J ) 8.6, 3.2), 3.65 (dd, 3J ) 10.6, 7.4), 3.47,
3.39 (2s), 3.42-3.39 (m), 3.13 (dq, 3J ) 6.7, 2.7), 2.79 (dd, 3J )
3
3
10.6, 3.2), 2.33 (dd, J ) 8.6, 3.1), 1.54, 1.39 (2s), 1.28 (d, J )
6.7).
Ack n ow led gm en t . We thank the Swiss National
Science Foundation and the Fonds Herbette (Lausanne)
for generous financial support.
Da ta for (-)-34: mp 52-54 °C; [R]25 ) -5.7 (c ) 1.9,
D
1
CHCl3); H NMR (400 MHz, CDCl3, 50 °C) δ 7.38-7.26 (m),
Su p p or t in g In for m a t ion Ava ila b le: Spectral data and
elemental analyses for all new compounds (18 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.
3
2
5.66 (d, J ) 2.3), 5.19, 5.15 (2d, J ) 12.2), 4.97 (br s), 4.91,
4.58 (2d, 2J ) 11.1), 4.74, 4.60 (2d, 2J ) 6.6), 4.66 (dq, 3J )
2
3
7.3, 7.0), 4.65, 4.54 (2d, J ) 5.9), 4.38 (dd, J ) 9.3, 6.4), 4.34
3
3
3
(dd, J ) 8.0, 6.4), 4.26 (dd, J ) 8.0, 7.0), 4.01 (dd, J ) 9.3,
3
3
2.1), 3.97 (br dd, J ) 2.9, 2.3), 3.91 (dd, J ) 10.7, 2.1), 3.29
(s), 3.41, 3.32 (2s), 2.34 (dd, 3J ) 10.7, 2.9), 1.53, 1.35 (2s),
3
1.24 (d, J ) 7.3).
J O970151T