Stereoselective synthesis of α- and β-L-C-fucosyl aldehydes and their utility in the assembly of C-fucosides of biological relevance

Article abstract of DOI:10.1021/jo049406a

An efficient synthesis of O-benzylated derivatives of the title sugar aldehydes via thiazole addition to tri-O-benzyl-L-fuconolactone followed by highly stereoselective deoxygenation of the resulting thiazolylketose and thiazole to formyl transformation i

Full text of DOI:10.1021/jo049406a

Ster eoselective Syn th esis of r- a n d â-L-C-F u cosyl Ald eh yd es a n d
Th eir Utility in th e Assem bly of C-F u cosid es of Biologica l
Releva n ce
Alessandro Dondoni,* Nicola Catozzi, and Alberto Marra
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara,
Via L. Borsari 46, 44100-Ferrara, Italy
adn@dns.unife.it
Received April 9, 2004
An efficient synthesis of O-benzylated derivatives of the title sugar aldehydes via thiazole addition
to tri-O-benzyl-L-fuconolactone followed by highly stereoselective deoxygenation of the resulting
thiazolylketose and thiazole to formyl transformation is described. Wittig olefination of these
aldehydes with galactopyranose and glucopyranose 6-phosphoranes and reduction of the resulting
alkenes afforded R- and â-linked (1f6)-L-C-fucosyl disaccharides, namely, â-L-C-Fuc-(1f6)-R-D-
Gal, R-L-C-Fuc-(1f6)-R-D-Gal, and R-L-C-Fuc-(1f6)-R-D-Glc. The R-anomer of the above C-fucosyl
aldehydes was transformed into a C-fucosylmethyl triphenylphosphonium iodide from which the
corresponding C-fucosylmethylene phosphorane was generated upon treatment with BuLi. This
phosphorane reacted with the Garner aldehyde (N-Boc D-serinal acetonide) and its one-carbon higher
homologue to give alkenes whose reduction and unveiling of the glycinyl group from the oxazolidine
ring afforded C-fucosyl R-amino acids, namely R-L-linked C-fucosyl serines and C-fucosyl aspar-
agines. As a final test of the synthetic utility of the title aldehydes, the â-anomer was employed as
starting material in the stereoselective synthesis of both R- and S-epimer L-C-fucosyl phenylhydroxy
acetates. One epimer was obtained by reaction of the sugar aldehyde with phenylmagnesium
bromide, oxidation of the resulting alcohol to ketone, addition of 2-lithiothiazole to the latter, and
transformation of the thiazole ring into the carboxyl group through an aldehyde intermediate. The
other epimer was obtained by the same procedure and inverting the timing of phenyl and thiazolyl
group addition. In both routes, the key step establishing the configuration of the quaternary carbon
atom of the aliphatic chain was the highly stereoselective addition of the organometal to the ketone
intermediate.
In tr od u ction
to C-disaccharides and C-trisaccharides for conforma-
tional studies7 and Bednarski’s group pioneered the
synthesis of C-glycopeptides using a C-glycosyl amino
acid, which in turn was prepared from the corresponding
formyl C-glycoside.8 The replacement of the exocyclic
carbon-oxygen or carbon-nitrogen bond of native gly-
coconjugates with a carbon-carbon bond creates com-
pounds which are impervious to chemical and enzymatic
degradation. Therefore the ready access to C-glycoside
libraries is of great importance in modern carbohydrate
chemistry because C-glycosides may serve inter alia as
(i) biological probes in glycobiology,9 (ii) leads for the
development of metabolically stable carbohydrate-based
therapeutics,10 and (iii) building blocks for the prepara-
Anomeric sugar aldehydes, namely formyl C-glyco-
sides, have been demonstrated in recent years by exten-
sive research carried out in our laboratory1 to be readily
accessible and versatile reactive building blocks for more
complex C-glycosides, either isosteres of O- and N-
glycoside natural products such as oligosaccharides2 and
glycosyl amino acids3 or totally artificial (unnatural)
compounds such as carbohydrate-heterocycle4 and car-
bohydrate-fullerene conjugates.5 Reports by other groups
have appeared as well,6 thus demonstrating the utility
of these compounds as precursors for carbohydrate mim-
ics. Notably, Kishi and co-workers employed properly
protected anomeric sugar aldehydes in synthetic routes
(1) For reviews, see: (a) Dondoni, A.; Marra, A. Chem. Commun.
1999, 2133. (b) Dondoni, A. Pure Appl. Chem. 2000, 72, 1577.
(2) (a) Dondoni, A.; Zuurmond, H. M.; Boscarato, A. J . Org. Chem.
1997, 62, 8114. (b) Dondoni, A.; Marra, A.; Mizuno, M.; Giovannini, P.
P. J . Org. Chem. 2002, 67, 4186. (c) Dondoni, A.; Marra, A. Tetrahedron
Lett. 2003, 44, 4067.
(3) Dondoni, A.; Marra, A.; Massi, A. J . Org. Chem. 1999, 64, 933.
(4) (a) Dondoni, A.; Giovannini, P. P. Synthesis 2002, 1701. (b)
Dondoni, A.; Massi, S.; Sabbatini, S. J . Org. Chem. 2002, 67, 6979. (c)
Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Helv. Chim. Acta
2002, 85, 3331.
(6) (a) Ogawa, T.; Kikuchi, Y.; Matsui, M.; Ohrui, H.; Kuzuhara,
H.; Emoto, S. Agric. Biol. Chem. 1971, 35, 1825. (b) Trummlitz, G.;
Moffat, J . G. J . Org. Chem. 1973, 38, 1841. (c) Horton, D.; Philips, K.
D. Carbohydr. Res. 1973, 30, 367. (d) Albrecht, H.; Repke, D. B.;
Moffatt, J . G. J . Org. Chem. 1973, 38, 1836. (e) Dietrich, H.; Schmidt,
R. R. Carbohydr. Res. 1993, 250, 161. (f) Lasterra Sanchez, M. E.;
Michelet, V.; Besnier, V.; Gene´t, J . P. Synlett 1994, 705. (g) Labe´gue`re,
F.; Lavergne, J .-P.; Martinez, J . Tetrahedron Lett. 2002, 43, 7271.
(7) (a) Babirad, S. A.; Wang, Y.; Kishi, Y. J . Org. Chem. 1987, 52,
1370. (b) Wang; Y.; Babirad, S. A.; Kishi, Y. J . Org. Chem. 1992, 57,
468. (c) Haneda, T.; Goekjian, P. G.; Kim, S. H.; Kishi, Y. J . Org. Chem.
1992, 57, 490.
(5) Dondoni, A.; Marra, A. Tetrahedron Lett. 2002, 43, 1649.
10.1021/jo049406a CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/25/2004
J . Org. Chem. 2004, 69, 5023-5036
5023

Dondoni et al.
tion of a variety of biologically important natural
products11in meaningful amounts and pure state suitable
for biomedical studies. Although several syntheses of
C-glycosides have been reported based on various types
of substitution reactions at the anomeric carbon,12 most
of them were scarcely stereoselective as they afforded
mixtures of R- and â-linked products. An alternative
approach that allows this stereochemical problem to be
avoided is based on establishing first the required con-
figuration at the anomeric center by the introduction of
a carbon functionality and then exploiting the chemistry
of this functionality for the construction of the target
complex carbon chain. This program was fueled by the
effectiveness of a formylation methodology of carbohy-
drates which allowed the preparation of a collection of
formyl C-glycosides on a multigram scale and in several
cases in both R- and â-anomeric forms.13 The methodology
is based on the thiazole-aldehyde synthesis14 and consists
of the addition of lithiothiazole or lithiobenzothiazole to
readily available sugar lactones, followed by stereoselec-
tive deoxygenation of the resulting thiazolylketose and
transformation of the thiazole ring into the formyl
group.15 Wishing to extend the scope of this approach to
various C-glycosides of special biological relevance, we
would like to report here the stereoselective synthesis of
the hitherto unknown R- and â-L-fucosyl aldehydes R-1
and â-1 (Figure 1) and demonstrate their synthetic utility
in the preparation of three types of C-fucosides, i.e.,
C-fucosyl disaccharides, C-fucosyl R-amino acids, and
F IGURE 1. O-Benzylated R- and â-L-linked formyl C-fuco-
sides R-1 and â-1.
C-fucosyl phenylacetic acids. Fucosylation is very com-
mon in nature and it affects significantly the conforma-
tion and biological properties of natural glycoproteins and
glycolipids. For example, well-known fucose-containing
saccharides are sialyl Lewis x (sLex) and sialyl Lewis a
(sLea) of cell-surface glycoproteins and glycolipids. These
and other fucosylated oligosaccharide structures play a
key role in cell-cell interaction and cell migration
phenomena which are involved in vital processes.16
However, it is well-established that the R-L-linkage of
O-fucosides is very labile to acids17 and easily cleaved by
glycosidases. Therefore it has been suggested that sLex
mimics should contain the fucose unit linked throughthe
C-glycosidic bond to achieve sufficient stability in vivo
against fucosidases.18 For similar reasons, such a type
of isosteric variation should be highly beneficial for the
stability of the fucosylated trisaccharide N-linked to
asparagine of CD52 peptides.19 Another topic of great
interest is that regarding the synthesis of C-fucosylated
tumor-associated carbohydrate antigens to be used in
place of O-fucosylated analogues for the development of
potential vaccines against cancer.20 Fortunately, despite
structural investigations based on comparative NMR
studies having revealed notable conformational differ-
ences between unnatural C-glycosides and natural O-
glycosides,21 recent studies have shown that their binding
constants and biological properties are very similar.22
(8) (a) Bertozzi, C. R.; Hoeprich, P. D., J r.; Bednarski, M. D. J . Org.
Chem. 1992, 57, 6092. (b) Bertozzi, C. R.; Cook, D. G.; Kobertz, W. R.;
Gonzales-Scarano, F.; Bednarski, M. D. J . Am. Chem. Soc. 1992, 114,
10639.
(9) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Dwek, R. A. Chem.
Rev. 1996, 96, 683. (c) Essential of Glycobiology; Varki, A., Cummings,
R., Esko, J ., Freeze, H., Hart, G., Marth, J ., Eds.; Cold Spring Harbor
Laboratory Press: Cold Spring Harbor, 1999.
(10) (a) Wang, Q.; Wolff, M.; Polat, T.; Du, Y.; Linhardt, R. J . Bioorg.
Med. Chem. Lett. 2000, 10, 941. (b) Peri, F.; Cipolla, L.; Rescigno, M.;
La Ferla, B.; Nicotra, F. Bioconjugate Chem. 2001, 12, 325.
(11) For examples of C-glycoside containing natural products, see:
Palytoxin: (a) Moore, R. E.; Scheuer, P. J . Science 1971, 172, 495. (b)
Moore, R. E.; Bartolini, G. J . J . Am. Chem. Soc. 1981, 103, 2491. (c)
Suh, E. M.; Kishi, Y. J . Am. Chem. Soc. 1994, 116, 11205. (d) Usami,
M.; Satake, M.; Ishida, S.; Inoue, A.; Kan, Y.; Yasumoto, T. J . Am.
Chem. Soc. 1995, 117, 5389. Polyether macrolides: (e) Hirata, Y.;
Uemura, D. Pure Appl. Chem. 1986, 58, 701. (f) Litaudon, M.; Hickford,
S. J . H.; Lill, R. E.; Lake, R. J .; Blunt, J . W.; Munro, M. H. G. J . Org.
Chem. 1997, 62, 1868. Polyketides: (g) Trefzer, A.; Hoffmeister, D.;
Ku¨nzel, E.; Stockert, S.; Weitnauer, G.; Westrich, L.; Rix, U.; Fuchser,
J .; Bindseil, K. U.; Rohr, J .; Bechthold, A. Chem. Biol. 2000, 7, 133.
Altromycins: (h) Brill, G. M.; J ackson, M.; Whittern, D. N.; Buko, A.
M.; Hill, P.; Chen, R. H.; McAlpine, J . B. J . Antibiot. 1994, 47, 1160.
(12) For reviews, see: (a) Postema, M. H. D. C-Glycoside Synthesis;
CRC Press: Boca Raton, FL, 1995. (b) Levy, D. E.; Tang, C. The
Chemistry of C-Glycosides; Elsevier: Oxford, UK, 1995. (c) Beau, J .-
M.; Gallagher, T. Top. Curr. Chem. 1997, 187, 1. (d) Du, Y.; Linhardt,
R. J .; Vlahov, I. R. Tetrahedron 1998, 54, 9913. (e) Beau, J .-M.;
Vauzeilles, B.; Skrydstrup, T. In Glycoscience. Chemistry and Chemical
Biology; Fraser-Reid, B., Tatsuta, K., Thiem, J ., Eds.; Springer-
Verlag: Heidelberg, Germany, 2001; Vol. 3, p 2679. (f) Liu, L.; McKee,
M.; Postema, M. H. D. Curr. Org. Chem. 2001, 5, 1133. (g) Taillefumier,
C.; Chapleur, Y. Chem. Rev. 2004, 104, 263.
(13) (a) Dondoni, A.; Scherrmann, M.-C. Tetrahedron Lett. 1993, 34,
7319. (b) Dondoni, A.; Scherrmann, M.-C. J . Org. Chem. 1994, 59, 6404.
(c) Dondoni, A.; Marra, A. Tetrahedron Lett. 2003, 44, 13.
(14) (a) Dondoni, A. Synthesis 1998, 1681. (b) Dondoni, A.; Marra,
A. Chem. Rev. 2004, 104, 2557.
(15) Owing to the tolerance of the thiazole ring to a variety of
reaction conditions, including oxidative and reductive processes, and
the compatibility of the formyl unmasking process with numerous
hydroxyl protective groups and free functionalities, the methodology
was also employed for the synthesis of complex anomeric aldehydes of
O-, P-, and N-ketosides which are per se important target saccharides.
See ref 1a.
Resu lts a n d Discu ssion
Syn th esis of L-C-F u cosyl Ald eh yd es. O-Benzylated
L-C-fucosyl aldehyde anomers R-1 and â-1 were targeted
as suitably protected compounds in synthesis because the
benzyl protective group is compatible with a variety of
reactions of the formyl group and nevertheless can be
easily removed from the final products under neutral
conditions by catalytic hydrogenation. Hence the syn-
thesis of R-1 and â-1 began from known23 L-fuconolactone
3 (Scheme 1), which in turn was prepared in multigram
scale by oxidation of 2,3,4-tri-O-benzyl L-fucose 2.24
Treatment of 3 in Et2O at -78 °C with a solution of
2-lithiothiazole (2-LTT, 4), generated in situ from 2-bro-
(16) Sears, P.; Wong, C.-H. Cell Mol. Life Sci. 1998, 54, 223.
(17) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. Engl. 1988,
27, 1697.
(18) Chervin, S. M.; Lowe, J . B.; Koreeda, M. J . Org. Chem. 2002,
67, 5654.
(19) Shao, N.; Xue, J .; Guo, Z. J . Org. Chem. 2003, 68, 9003.
(20) Danishefsky, S. J .; Allen, J . R. Angew. Chem., Int. Ed. 2000,
39, 836.
(21) J imenez-Barbero, J .; Espinosa, J . F.; Asensio, J . L.; Canada,
F. J .; Poveda, A. Adv. Carbohydr. Chem. Biochem. 2000, 56, 235.
(22) (a) Wei, A.; Boy, K. M.; Kishi, Y. J . Am. Chem. Soc. 1995, 117,
9432. (b) Wang, J .; Kova´c, P.; Sinay¨, P.; Glaudemans, C. P. J .
Carbohydr. Res. 1998, 308, 191. (c) Yang, G.; Franck, R. W.; Bittman,
R.; Samadder, P.; Arthur, G. Org. Lett. 2001, 3, 197.
(23) Gervay, J .; Flaherty, T. M.; Holmes, D. Tetrahedron 1997, 53,
16355.
(24) Dejter-J uszynski, M.; Flowers, H. M. Carbohydr. Res. 1971, 18,
219.
5024 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
laboratory26 to give opposite R/â selectivities in their
reactions with various thiazolylketose acetates. Gratify-
ingly, also the reductive deoxygenation of 5b with these
reagents showed opposite R/â ratios. Specifically the use
of TMSOTf-Et3SiH afforded exclusively the â-L-linked
thiazolyl C-fucoside 6 (95%) whereas SmI2-(CH2OH)2
furnished as main product the R-linked isomer 7 (93%)
and only 6% of the stereoisomer 6 (Scheme 2). Both
reactions were carried out on preparative scale starting
from 1 to 3 g of 5b. The anomeric configurations of these
SCHEME 1
1
key intermediates, easily established by H NMR analy-
sis,27 are in agreement with earlier postulated mecha-
nisms of the deoxygenation reactions. In the case of the
TMSOTf-promoted reduction, a chairlike transition state7a
was formed by an axial attack of the hydride ion (from
silane) to the anomeric oxycarbenium ion adopting a half-
chair conformation. On the other hand, in the case of the
SmI2-induced reaction, the more thermodynamically
stable equatorial organosamarium(III) intermediate,28
formed by a thiazole-assisted two-electron reduction
process, underwent a protodesamariation with retention
of configuration.
SCHEME 2
Having constructed both the configurationally stable
thiazolyl â- and R-C-fucosides 6 and 7, the final operation
for the unveiling of the target aldehydes â-1 and R-1
entailed the transformation of the thiazole ring into the
formyl group (Th f CHO) by the highly reliable standard
protocol consisting of N-methylation (MeOTf), reduction
(NaBH4), and hydrolysis (H2O-AgNO3). Once again this
operation turned out to be particularly effective as each
crude aldehyde was isolated in high yield (ca. 90%) and
sufficiently pure form (ca. 95%) as determined by NMR
analysis.29 The whole unmasking operation required
about 2 h and was carried out with identical results on
50 mg up to 1-2 g scale.
Syn th esis of L-C-F u cosyl Disa cch a r id es. As a first
test of the reactivity and synthetic utility of aldehydes
R-1 and â-1 we considered their Wittig olefination by
sugar phosphoranes to pave the way for the synthesis of
C-fucosyl disaccharides.30 The wide scope of the Wittig-
based approach toward the stereoselective assembly of
carbohydrate units through a 1,6- or 1,5 ethylene tether2
and its superior efficiency with respect to the Henry-
based methodology employed in other laboratories31 have
been demonstrated by the preparation of a collection of
mothiazole and BuLi, afforded the thiazolylketose 5a as
a single isolated anomer (93%). This compound was
acetylated under standard conditions (Ac2O, Et3N in
CH2Cl2) to give the O-acetate 5b as a crystalline product
1
in 93% isolated yield by chromatography. The C4 struc-
ture of this L-ketoside featuring the R-linked acetoxy
group was supported by NMR coupling constant values
(J 2,3 ) 10.0 Hz) and nOe experiments showing substan-
tial interactions between the acetyl group and the axial
H-3 and H-5 protons. The same structure was assigned
to the ketose 5a .25 Afterward, compound 5b was obtained
in a preparative useful scale by the above reaction
sequence starting from 22.7 mmol (9.87 g) of O-benzy-
lated L-fucose 2 and without purification of lactone 3 and
ketose 5a . In a typical procedure, pure compound 5b was
isolated by column chromatography in 92% overall yield.
The next key step toward the stereoselective synthesis
of each aldehyde R-1 or â-1 consisted of removing the
acetoxy group from 5b to give either R-linked or â-linked
thiazolyl C-fucoside, i.e., the configurationally stable
and ultimate precursors of the target diastereomeric
aldehydes. To this aim, the thiazolylketose acetate 5b
was treated with two different deoxygenative systems,
namely the trimethylsilyl triflate-triethylsilane mixture
(TMSOTf-Et3SiH) and the samarium iodide-ethylene
glycol mixture (SmI2-(CH2OH)2) (Scheme 2). These
reagents have been shown in earlier work from our
(26) Dondoni, A.; Formaglio, P.; Marra, A.; Massi, A. Tetrahedron
2001, 57, 7719.
(27) All â-L-C-fucosides prepared, both benzylated and acetylated,
showed in their 1H NMR spectra large coupling constant values (9-
10 Hz) between the H-1, H-2 and H-2, H-3 protons of the pyranose
ring, as expected for a trans-diaxial arrangement of these protons (1C4
conformation). On the other hand, the 1H NMR analysis of the
benzylated R-L-C-fucosides indicated that these compounds did not
adopt a chair conformation (J 1,2 ) 3-4 Hz, J 2,3 ) 5-7 Hz). However,
the corresponding acetylated analogues 15, 16, 23, and 28 showed
coupling constant values typical of R-L-configured C-fucopyranosides
in a 1C4 conformation (J 1,2 ) 5.6-5.8 Hz, J 2,3 ) 10.2-10.3 Hz).
(28) (a) Maze´as, D.; Skrydstrup, T.; Beau, J .-M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 909. (b) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R.
J . J . Am. Chem. Soc. 1997, 119, 1480.
(29) Compound R-1 was prepared by Kishi and co-workers (ref 7c)
but the physical and spectroscopic data were not reported, whereas
â-1 appears to be a new compound to the best of our knowledge.
(30) For earlier syntheses of C-fucosyl di- and trisaccharides see:
(a) Sutherlin, D. P.; Armstrong, R. W. J . Org. Chem. 1997, 62, 5267.
(b) Reka¨ı, E. D.; Rubinstenn, G.; Mallet, J .-M.; Sinay¨, P. Synlett 1998,
831. (c) Miquel, N.; Doisneau, G.; Beau, J .-M. Angew. Chem., Int. Ed.
2000, 39, 4111. (d) Carpintero, M.; J aramillo, C.; Ferna´ndez-Mayoralas,
A. Eur. J . Org. Chem. 2000, 1285.
(25) No studies were carried out to establish whether 5a is the
product of the kinetic or thermodynamic control resulting from the
addition of 4 to the lactone 3. This would require the quenching of the
reaction mixture at low temperature with Ac2O. However, addressing
this issue is unimportant in the context of the present work.
J . Org. Chem, Vol. 69, No. 15, 2004 5025

Dondoni et al.
SCHEME 3
Scheme 3. These Wittig reactions afforded the alkene 12
(48%) and 14 (37%) as 4:1 and 1:1 Z,E mixtures, re-
spectively. In addition to the desired alkenes 12 and 14,
these reactions produced numerous side products as
shown by TLC and NMR analyses of the crude reaction
mixtures. One of these products was isolated (7-10%)
and characterized as the C-formyl glycal 13. Very likely
the reactions of R-1 with the above sugar phosphoranes
were sluggish and therefore base-induced â-elimination
of the benzyloxy group at C-2 leading to 13 did take place.
The alkenes 12 and 14 were elaborated in the usual way,
i.e., Pd(OH)2-catalyzed hydrogenation and acetylation, to
give the O-protected (1,6)-linked C-disaccharides R-L-C-
Fuc-(1f6)-R-D-Gal 15 (80%) and R-L-C-Fuc-(1f6)-R-D-Glc
16 (60%). The NMR spectra of both compounds 15 and
16 showed J 8,9 values of ca. 5.7 Hz in agreement with
the R-L-fucosyl linkage and J 4,5 values of 1.5 and 10.0
Hz consistent with the D-galacto and D-gluco configura-
tion, respectively.
Syn th esis of L-C-F u cosyl Am in o Acid s. Next, we
examined the possibility of preparing C-fucosyl R-amino
acids,35 especially methylene isosteres of O-fucosyl serines36
and ethylene isosteres of N-fucosyl asparagines. The
synthesis of C-glycosyl R-amino acids can be considered
as the gateway to artificial glycopeptides,37 i.e., a class
of glycomimetics of great potential for the control of
natural glycoprotein biological activity.9,38 Also in this
endeavor we planned to assemble the fucosyl and amino
acid moieties through a carbon-carbon bond generated
by a Wittig-type reaction. However, earlier work in our
laboratory39 dealing with the synthesis of â-D-C-galactosyl
L-serine (Galâ-CH2-Ser) demonstrated that the effective-
ness of this approach is optimized by coupling an ano-
meric sugar phosphorane with an aldehyde bearing a
masked glycinyl group. Therefore we envisaged the
L-fucosylmethyl phosphonium salt 19 as precursor to the
desired ylide. This salt was prepared in a few steps and
high yield by standard functional group transformations
starting from the C-fucosyl aldehyde R-1 (Scheme 5).
Succinctly, this aldehyde was reduced (NaBH4) to the
alcohol 17 and this product was transformed (PPh3, I2)
into the iodomethyl derivative 18. The 1H NMR spectrum
of 18 demonstrated (J 2,3 ) 3.5 Hz) that there was no loss
of the R-L-configuration at the anomeric carbon of the
fucosyl residue. Finally, treatment of 18 with PPh3 in the
absence of solvent at 120 °C afforded the target phos-
phonium iodide 19 in 85% overall yield from R-1.
C-disaccharides as well as various C-oligosaccharides up
to a â-D-(1f6)-pentamer. Thus, the fucosyl aldehyde â-1
was allowed to react with the acetonide-protected galac-
topyranose32 6-phosphorane generated in situ by treat-
ment of the known33 phosphonium iodide 8 with BuLi in
THF-HMPA at -30 °C (Scheme 3). The reaction afforded
the (Z)-alkene 9 in fair isolated yield (57%) and whose
configuration was established by the corresponding pro-
ton coupling constant value (J 6,7 ) 11.5 Hz). More
importantly, it was demonstrated that the configurations
at C-8 of the fucosyl moiety and C-5 of the galactosyl
moiety of 9 were the same as in the coupling reagents
â-1 and 8. Accordingly, the NMR spectrum of 9 showed
a J 8,9 value of 9.5 Hz and a J 4,5 value of 1.7 Hz.34
Next, compound 9 was subjected to hydrogenolysis over
Pd(OH)2 by which the reduction of the carbon-carbon
double bond and the concomitant removal of the benzyl
groups were accomplished. Then, the crude product was
treated with Ac2O-pyridine and the resulting O-acetyl
and O-isopropylidene-protected (1f6)-C-fucosyl-galacto-
side (â-L-C-Fuc-(1f6)-R-D-Gal) 10 was isolated in a
rewarding 84% yield.
Given the large diffusion of the native R-O-fucosidic
linkage in oligosaccharides, the synthesis of R-configured
carbon-linked analogues appeared to be quite important.
Therefore the fucosyl aldehyde R-1 was reacted with two
R-D-glycopyranose 6-phosphoranes, one derived from the
aforementioned galactose phosphonium salt 8 and the
other from the recently prepared2a,b O-benzylated glu-
copyranose phosphonium iodide 11 (Scheme 4). In both
cases the phosphorane generation and the coupling with
the sugar aldehyde R-1 were carried out as outlined in
The Wittig coupling of the ylide generated in situ from
the fucosylated triphenylmethylphosphonium iodide 19
(31) (a) Martin, O. R.; Lai, W. J . Org. Chem. 1993, 58, 176. (b)
Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J . Org. Chem. 1996,
61, 1894. (c) Spak, S. J .; Martin, O. R. Tetrahedron 2000, 56, 217.
(32) 1,2:3,4-Di-O-isopropylidene-D-galactopyranose derivatives do
not adopt a chair conformation as proved by the coupling constant
values in their 1H NMR spectra. Moreover, since in the literature there
was some confusion concerning the actual conformation of this sugar
residue, it is a common practice to draw the structure in a Haworth
presentation. However, a very recent study provided evidence that 1,2:
3,4-di-O-isopropylidene-D-galactopyranose and 6-O-glycosylated deriva-
tives adopt a 0S2 conformation in solid state as well as in solution
(Roslund, M. U.; Klika, K. D.; Lehtila¨, R. L.; Ta¨htinen, P.; Sillanpa¨a¨,
R.; Leino, R. J . Org. Chem. 2004, 69, 18). Therefore the di-O-
isopropylidene-D-galactopyranose moieties presented in this paper are
drawn in this conformation.
(35) A few syntheses of C-fucosyl amino acids have been reported
in the literature. C-Fucosyl glycines: (a) J arvest, R. L.; Berge, J . M.;
Brown, P.; Hamprecht, D. W.; McNair, D. J .; Mensah, L.; O’Hanlon,
P. J .; Pope, A. J . Bioorg. Med. Chem. Lett. 2001, 11, 715. C-Fucosyl
alanines: (b) Vincent, S. P.; Schleyer, A.; Wong, C.-H. J . Org. Chem.
2000, 65, 4440. C-Fucosyl serines: (c) Sutherlin, D. P.; Stark, T. M.;
Hughes, R.; Armstrong, R. W. J . Org. Chem. 1996, 61, 8350. C-Fucosyl
â-hydroxyserines: (d) Huwe, C. M.; Woltering, T. J .; J iricek, J .; Weitz-
Schmidt, G.; Wong, C.-H. Bioorg. Med. Chem. 1999, 7, 773.
(36) (a) Bjoern, S.; Foster, D. C.; Thim, L.; Wiberg, F. C.; Chris-
tensen, M.; Komiyama, Y.; Pedersen, A. H.; Kisiel, W. J . Biol. Chem.
1991, 266, 11051. (b) Harris, R. J .; Ling, V. T.; Spellman, M. W. J .
Biol. Chem. 1992, 267, 5102. (c) Nishimura, H.; Takao, T.; Hase, S.;
Shimonishi, Y.; Iwanaga, S. J . Biol. Chem. 1992, 267, 17520. (d) Harris,
R. J .; van Halbeek, H.; Glushka, J .; Basa, L. J .; Ling, V. T.; Smith, K.
J .; Spellman, M. W. Biochemistry 1993, 32, 6539.
(33) Secrist, J . A., III; Wu, S.-R. J . Org. Chem. 1979, 44, 1434.
(34) For all C-disaccharidic olefins and the corresponding alkanes
the same IUPAC numbering system outlined for 9 was adopted, i.e.,
counting starts from the reducing end of the disaccharide.
(37) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4935.
(38) Marcaurelle, L. A.; Bertozzi, C. R. Chem. Eur. J . 1999, 5, 1384.
(39) Dondoni, A.; Marra, A.; Massi, A. Tetrahedron 1998, 54, 2827.
5026 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
SCHEME 4
SCHEME 5
SCHEME 6
(BuLi, THF-HMPA, 0 °C) was carried out with the well-
known R-amino aldehyde40 20 (D-serinal) since this
reagent contains the masked chiral glycinyl group in the
form of the N-Boc oxazolidine ring (Scheme 6). We have
demonstrated in earlier syntheses of glycosyl amino
acids3,39,41 the advantages associated with the use of
amino acid equivalents with the desired absolute stereo-
chemistry already in place.42 Deceptively, this strategy
failed in the present case since under optimized condi-
tions (THF-HMPA, from -20 to 0 °C) the above reaction
afforded the alkene 21 (70%) as a 3:1 E,Z mixture
containing R- and S-configured N-Boc oxazolidine rings.43
Evidently, under the above conditions epimerization did
take place at the nitrogenated carbon atom of the
oxazolidine ring of 20. Unfortunately, when milder condi-
tions were adopted such as lowering the temperature
to -40 °C, the yields of 21 were in the range of only
15-30% and still substantial epimerization was ob-
served. Pressing forward nonetheless, the mixture of
alkenes 21 was duly elaborated by hydrogenation and
acetylation to give the mixture of diastereoisomers 22
which in turn was subjected to the one-step oxidative
cleavage of the oxazolidine ring by the J ones’ reagent
(CrO3, H2SO4-H2O) and esterification by diazomethane.
This reaction sequence furnished a mixture of C-fucosyl
R-amino ester R-epimers 23 in ca. 3:2 ratio by NMR
analysis. The same analysis confirmed the R-configura-
tion at the anomeric carbon of the fucosyl residue since
J 5,6 values of 5.6 Hz were observed for both diastereoi-
somers. These compounds can be considered as R-L-linked
fucosyl serine methylene isosteres (FucR-CH2-Ser), i.e.,
analogues of natural O-fucosyl serines which are widely
distributed in human coagulation factors.36 Attempts to
isolate each individual diastereoisomer by column flash
chromatography failed so far. However, the mixture of
these compounds can be profitably employed in the
synthesis of C-fucosylated peptides whose stereoisomers
(40) Garner, P. Tetrahedron Lett. 1984, 25, 5855. For a recent
account of the synthetic application of this aldehyde, see: Liang, X.;
Andersch, J .; Bols, M. J . Chem. Soc., Perkin Trans. 1 2001, 2136. For
an improved synthesis avoiding racemization, see: Dondoni, A.;
Perrone, D. Synthesis 1997, 527. Dondoni, A.; Perrone, D. Org. Synth.
1999, 77, 64.
(41) (a) Dondoni, A.; Marra, A.; Massi, A. Chem. Commun. 1998,
1741. (b) Dondoni, A.; Massi, A.; Marra, A. Tetrahedron Lett. 1998,
39, 6601. (c) Dondoni, A.; Giovannini, P. P.; Marra, A. J . Chem. Soc.,
Perkin Trans. 1 2001, 2380. (d) Dondoni, A.; Mariotti, G.; Marra, A.;
Massi, A. Synthesis 2001, 2129. (e) Dondoni, A.; Mariotti, G.; Marra,
A. J . Org. Chem. 2002, 67, 4475.
(42) This simple yet quite useful strategy has been used by other
groups. For illustration of reaction schemes and leading references,
see ref 37.
(43) The NMR spectra recorded at room temperature of all com-
pounds containing a N,N-dialkyl-N-Boc amine function showed mul-
tiple sets of signals arising from the hindered rotation around the
σ-bonds. Consistent spectra were obtained in the range 100-160 °C
due to the coalescence of signals (see the Experimental Section).
J . Org. Chem, Vol. 69, No. 15, 2004 5027

Dondoni et al.
SCHEME 7
can hopefully be more easily separable. There are two
precedents on the use of mixtures of C-glycosyl serine
R-epimers, one dealing with the preparation of decapep-
tides with potential activity on T-cell stimulation,44 the
other with the synthesis of sialyl Lewis x glycomimetics.35c
More rewarding results were obtained by the Wittig
olefination of the configurationally stable homoserine
derived aldehyde45 24 (Scheme 7). Treatment of this
aldehyde with the fucosylmethylene phosphorane derived
from 19 under the above conditions afforded the alkene
25 as a single Z-isomer in 75% isolated yield (J 4,5 ) 11.5
Hz). The Pd(OH)2-promoted hydrogenation of 25 in 1:1
MeOH-AcOEt, followed by acetylation with Ac2O-
pyridine, furnished the tetra-O-acetate 26 as the major
product. Apparently, opening the oxazolidine ring of 25
did take place in the course of the hydrogenation step,
very likely because of some content of acetic acid in the
solvent. Thus, exclusion of AcOEt appeared to be advis-
able. Since 25 was scarcely soluble in MeOH, the
hydrogenation was carried out with EtOH as the solvent.
The acetylation of the resulting product afforded the ester
26 in low yield (15%) and the desired alkyl oxazolidine
27 in fair yield (55%). The oxidative cleavage of the
oxazolidine ring of the latter product with J ones’ reagent
and esterification furnished the O-Ac and N-Boc C-fucosyl
R-amino ester 28, a suitably protected building block for
solid-phase N-Boc-based peptide synthesis. The R-fucosyl
linkage in 28 and in the precursors 25 and 27 was
F IGURE 2. Hydroxy- and phenyl-substituted C-altrosyl and
C-fucosyl acetates 29 and 30.
represents the glycosidic part of the natural antitumor
antibiotic Altromycin B. Starting from either D-glucose
or D-altrose, Pasetto and Franck succeeded in preparing
both (R)-29 and (S)-29 by a rather laborious synthetic
sequence. The reaction scheme involved first the synthe-
sis of S-glycosides and the Ramberg-Ba¨cklund rear-
rangement of their sulfones to set up the C-glycosidic
linkage. Then, a multistep elaboration of the resulting
exo-glycals was carried out to build up the chiral phen-
ylhydroxy acetate moieties with opposite configurations.
Thus, we were spurred to develop an alternative and
expeditious synthesis of C-glycosyl phenylhydroxy ace-
tates starting from formyl C-glycosides. In particular we
focused on the use of the fucosyl aldehyde â-1 as a
starting material since this would lead to the C-7 epimer
of 29, i.e., the C-fucosyl phenylhydroxy acetate 30 (Figure
2). If successful, this new synthesis would constitute a
model route for an alternative approach to 29. In addition
to that, we realized that the synthesis of chiral tertiary
alcohols, particularly those bearing complex substituents,
was a topic of current interest.47
1
confirmed by a J 6,7 value of 5.7 Hz in its H NMR spec-
We envisaged the construction of the chiral side chain
of 30 by transformation of the aldehyde â-1 into a tertiary
alcohol bearing fucosyl, phenyl, and thiazolyl substitu-
ents. The heterocycle substituent would serve as a
masked formyl group readily transformable into the
desired carboxylate. To this aim, â-1 was first reacted
with phenylmagnesium bromide in THF at low temper-
ature (-60 to -35 °C) and the resulting mixture of
diastereomeric alcohols was oxidized by pyridinium chlo-
rochromate (PCC) to furnish the ketone 31 in 67%
isolated yield (Scheme 8). Then, addition of 2-LTT 4 to
this ketone in Et2O-THF at low temperature afforded
trum. Thus, the corresponding free amino acid can be
regarded as the R-L-linked fucosyl L-asparagine ethylene
isostere (FucR-CH2CH2-Asn) although the native N-
linked analogue has not been reported to the best of our
knowledge.
Syn t h esis of L-C-F u cosyl P h en ylh yd r oxy Ac-
eta tes. The above C-fucosyl disaccharides and amino
acids belong to families of C-glycosides whose convenient
synthesis from anomeric sugar aldehydes was previously
established. A demonstration of the utility of formyl
C-glycosides in the synthesis of a new class of C-gly-
cosides was undertaken following a recent publication by
Pasetto and Franck.46 These researchers were faced with
the nontrivial task of developing a stereoselective syn-
thesis of both epimers of R-D-linked C-altrosyl phenyl-
hydroxy acetate 29 (Figure 2). One of these epimers
(45) The synthesis of this aldehyde was previously reported but the
compound was not characterized by suitable physical and spectroscopic
data (Ksander, G. M.; de J esus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.;
McMartin, C.; Bohacek, R. J . Med. Chem. 1997, 40, 495). An improved
synthesis and full characterization of this compound are described in
the Experimental Section.
(44) Tedebark, U.; Meldal, M.; Panza, L.; Bock, K. Tetrahedron Lett.
1998, 39, 1815.
(46) Pasetto, P.; Franck, R. W. J . Org. Chem. 2003, 68, 8042.
(47) Ramo´n, D. J .; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284.
5028 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
SCHEME 8 a
a
Reagents: (a) BnBr, NaH; (b) MeOTf, then NaBH4, then AgNO3, H2O; (c) J ones’ reagent; (d) CH2N2.
the tertiary alcohol 32 in 75% isolated yield. The absolute
configuration at the newly formed quaternary carbon in
this compound was assigned as detailed below. After this
stereoselective transformation was carried out, we rea-
soned that inverting the timing of phenyl and thiazolyl
group addition in the above reaction sequence might lead
to the epimer of 32, providing that the diastereofacial
selectivity of the organometal addition to the carbonyl
was the same. Accordingly, â-1 was treated with 2-tri-
methylsilylthiazole48 (2-TST, 35) (1.2 equiv) in CH2Cl2
at room temperature. Under these conditions a sluggish
reaction took place. The almost complete consumption
of â-1 was reached after 50 h and treatment with two
additional portions (1.2 equiv each) of 2-TST 35. The
resulting mixture of diastereomeric silylated alcohols49
was oxidized by the Moffat reagent (Ac2O-DMSO) to the
ketone 36, which was isolated in 72% yield from the
aldehyde â-1. The addition of phenylmagnesium bromide
to 36 in THF at -50 °C occurred with high selectivity
too as the tertiary alcohol 37 was isolated as the sole
product in almost quantitative yield.
F IGURE 3. Nuclear Overhauser effects observed for the
tertiary alcohol 32.
signals. These effects indicated a free rotation around the
C-glycosidic bond, thus excluding the possibility of any
stereochemical assignment by this NMR technique.
Hence, the S-configuration at C-1 in compound 37 was
forcedly indirectly assigned as that of the epimer of the
alcohol 32.
The R- and S-configurations of the quaternary carbon
atom of the alcohols 32 and 37, both displaying the
Completion of the synthetic plan required only the
transformation of the thiazole ring of compounds 32 and
37 into the carboxyl group. Guided by our extensive
experience in this chemistry we were well aware of the
need to proceed stepwise through aldehyde intermediates
because no mild conditions were known to transform the
thiazole ring directly into a carboxylate functionality.50
Hence the thiazole-substituted alcohols 32 and 37 were
first protected as O-benzyl ethers which in turn were
subjected to the standard thiazole-to-formyl unmasking
protocol.51 The resulting aldehydes 33 and 38 were
isolated in good to fair yields, i.e., 50% and 70%,
respectively. Finally these aldehydes were considered for
oxidation to carboxylic acids. This transformation was
conveniently carried out with compound 33 by using the
J ones’ reagent. Esterification of the carboxylic group with
2
pyranose moiety in a C5 conformation, were tentatively
assigned by nOe difference experiments (400 MHz,
CDCl3). In the case of compound 32, irradiation of the
OH-1 proton led to a strong enhancement of the H-3
signal and a weak nOe with the Hortho of the phenyl ring
at C-1. Upon irradiation of these protons, a weak nOe
with OH-1 and a strong enhancement of the H-2 signal
were observed. We concluded that the tertiary alcohol 32
adopted a preferential conformation where the OH group
was anti to H-2 and the compound was R-configured
(Figure 3). Assuming the S-configuration for this com-
pound one would expect the absence of nOe between
OH-1 and the Hortho of the phenyl ring. Similar NMR
experiments carried out on compound 37 showed strong
nOes between OH-1 and both H-2 and H-3. Moreover,
irradiation of the Hortho of the phenyl ring showed
significant enhancements of the same H-2 and H-3
(50) The cleavage of the thiazole ring to amide via reaction with
singlet oxygen has been reported in two instances (Matsuura, T.; Saito,
I. Bull. Chem. Soc. J pn. 1969, 42, 2973. Wasylyk, J . M.; Biskupiak, J .
E.; Costello, C. E.; Ireland, C. M. J . Org. Chem. 1983, 48, 4445). This
method appears to be rather impractical and requires workup opera-
tions which are hardly compatible with the integrity of stereocenters
and acid sensitive protective groups in the substrate.
(48) Although 2-TST is commercially available, the high price leads
to recommend its preparation on a multigram scale from inexpensive
2-bromothiazole. See: Dondoni, A.; Merino, P. Org. Synth. 1995, 72,
21.
(49) This material appeared to be a mixture of two diastereomeric
silyl ethers in ca. 1:1 ratio (NMR analysis) slightly contaminated by
the corresponding alcohols.
(51) It is worth noting that in this case the reduction of the N-methyl
thiazolium salt with NaBH4 required heating in ethanol at 60 °C
instead of the usual conditions (MeOH, 0 °C to room temperature).
J . Org. Chem, Vol. 69, No. 15, 2004 5029

Dondoni et al.
SmI2-mediated coupling54 of glycosylated pyridyl sulfones
with phenyl thiazolyl ketone. However, crucial to the
success of this approach is the full control of its stereo-
chemical outcome to establish the required configuration
at both the anomeric carbon of the sugar moiety and the
newly formed quaternary carbon of the side chain.
SCHEME 9
Exp er im en ta l Section
diazomethane furnished the ester 34 in 72% yield. On
the other hand, the aldehyde 38 turned out to be
impervious to the treatment by usual oxidizing sys-
tems such as the J ones’ reagent, TEMPO-BAIB, and
I2-KOH-MeOH. This may be ascribed to the heteroge-
neous conditions of these reactions since 38 was sparingly
soluble in the relevant polar solvents. Moreover it is likely
that this aldehyde is more encumbered than the isomer
33 and therefore less reactive. Deceptively, despite
intense experimentation we were unable to find suitable
conditions for the transformation of 38 to the ester 39.
This problem was overcome by using the hydroxy-free
aldehyde 40 (Scheme 9) which, fortunately enough,
displayed sufficient solubility in methanol. Noteworthy,
this aldehyde was obtained in good yield from compound
37 by thiazole-to-formyl conversion despite the presence
of the free hydroxy group, which in other systems was
incompatible with this transformation.52 Then, to our
great delight, 40 was effectively oxidized to the methyl
ester 41 simply by treatment with I2 and KOH in 5:1
MeOH-CCl4. This final transformation concluded suc-
cessfully the synthetic plan.53 Validation of this meth-
odology by extension to the synthesis of other C-glycosyl
phenylhydroxy acetates including the altrosyl derivatives
(R)-29 and (S)-29 now appears of interest.
All moisture-sensitive reactions were performed under a
nitrogen atmosphere in oven-dried glassware. Anhydrous
solvents were dried over standard drying agents55 and freshly
distilled prior to use. Commercially available powdered 4 Å
molecular sieves (5 µm average particle size) were used
without further activation. Reactions were monitored by TLC
on silica gel 60 F254 with detection by charring with sulfuric
acid and/or ninhydrin. Flash column chromatography56 was
performed on silica gel 60 (230-400 mesh). Melting points
were determined with a capillary apparatus. Optical rotations
were measured at 20 ( 2 °C in the stated solvent; [R]D values
1
are given in deg‚mL‚g-1‚dm-1. H NMR spectra (300 and 400
MHz) were recorded for CDCl3 solutions at room temperature
unless otherwise specified; chemical shifts are in ppm (δ) from
SiMe4 (TMS) as internal standard; peak assignments were
1
performed by H-1H COSY experiments. MALDI-TOF mass
spectra were acquired with use of R-cyano-4-hydroxycinnamic
acid as the matrix. Fuconolactone 323 was prepared by oxida-
tion of the corresponding hemiacetal 224 with pyridinium
chlorochromate.57 The aldehyde 24 was synthesized by oxida-
tion of the corresponding primary alcohol,58 prepared as
described.59 2-Trimethylsilylthiazole (2-TST, 31), phenylmag-
nesium bromide, and 2-bromothiazole were commercially
available. Alternatively, 2-TST 31 can be prepared as de-
scribed.48
2,3,4-Tr i-O-ben zyl-1-C-(2-th iazolyl)-L-fu copyr an ose (5a).
To a cooled (-78 °C), stirred solution of nBuLi (12.0 mL, 19.1
mmol, of a 1.6 M solution in hexane) in anhydrous Et2O (25
mL) was added dropwise a solution of freshly distilled 2-bro-
mothiazole (1.50 mL, 16.40 mmol) in anhydrous Et2O (6.5 mL)
over a 30-min period. The yellow solution was stirred at -75
°C for 30 min, then a solution of fuconolactone 3 (5.90 g, 13.64
mmol) in anhydrous Et2O (25 mL) was added slowly (30 min).
After an additional 30 min at -75 °C the mixture was allowed
to warm to -65 °C in 30 min and then poured into 150 mL of
a 1 M phosphate buffer at pH 7. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (2 × 150
mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with cyclohexane-AcOEt (from 5:1 to 2:1) to give 5a (6.56
g, 93%) as a syrup. [R]D -6.5 (c 1.3, CHCl3). 1H NMR (300
MHz) δ 7.82 (d, 1 H, J ) 3.2 Hz, Th), 7.48-7.19 and 7.08-
7.04 (2 m, 16 H, 3 Ph, Th), 5.07 and 4.78 (2 d, 2 H, J ) 12.0
Hz, PhCH2), 4.80 (s, 2 H, PhCH2), 4.70 and 4.31 (2 d, 2 H, J )
10.6 Hz, PhCH2), 4.54 (s, 1 H, OH), 4.51 (d, 1 H, J 2,3 ) 9.7 Hz,
H-2), 4.26 (dq, 1 H, J 4,5 ) 1.3 Hz, J 5,6 ) 6.4 Hz, H-5), 4.04 (dd,
1 H, J 3,4 ) 2.8 Hz, H-3), 3.77 (dd, 1 H, H-4), 1.26 (d, 3 H, 3
H-6). Anal. Calcd for C30H31NO5S: C, 69.61; H, 6.04; N, 2.71.
Found: C, 69.55; H, 5.82; N, 2.98.
Con clu sion s
The ease of preparation of L-C-fucosyl aldehyde epimers
R-1 and â-1 and their convenient use in synthetic
approaches to three families of C-fucosides demonstrate
once again the synthetic utility of anomeric sugar alde-
hydes as building blocks for complex C-glycosides without
facing the task of controlling the anomeric configuration.
Noteworthy is the new as well as highly stereoselective
approach to C-glycosyl phenylhydroxy acetates as shown
by the synthesis of the C-fucosyl derivatives (R)-30 and
(S)-30. However, the effectiveness and generality of this
approach need to be demonstrated by the use of a
significant number of C-glycosyl aldehydes. This issue
is addressed by research underway in our laboratory. In
addition to that, we foresee another possible route to
the above sugar acetates via the Beau and Skrydstrup
1-O-Acetyl-2,3,4-tr i-O-ben zyl-1-C-(2-th iazolyl)-L-fu copy-
r a n ose (5b). To a solution of 5a (6.56 g, 12.68 mmol) in
anhydrous CH2Cl2 (68 mL) were added at rt triethylamine (19
mL) and acetic anhydride (14 mL). The solution was kept at
(52) Dondoni, A.; Marra, A.; Perrone, D. J . Org. Chem. 1993, 58,
275.
(53) As requested by two reviewers, we have checked that com-
pounds 34 and 41 are quantitatively hydrogenated under standard
conditions (H2, 1 bar, Pd(OH)2, MeOH, rt, 1 h) to give R-30 and S-30,
respectively. Compound R-30: [R]D -28.4 (c 0.2, MeOH). 1H NMR (400
MHz, D2O) δ 7.54-7.50 (m, 2 H, Ar), 7.28-7.18 (m, 3 H, Ar), 4.13 (d,
1 H, J 3,4 ) 9.5 Hz, H-3), 3.67 (dd, 1 H, J 4,5 ) 9.5 Hz, H-4), 3.66 (dq, 1
H, J 6,7 ) 0.6 Hz, J 7,8 ) 6.5 Hz, H-7), 3.61 (dd, 1 H, J 5,6 ) 3.4 Hz, H-6),
3.58 (s, 3 H, OMe), 3.47 (dd, 1 H, H-5), 1.03 (d, 3 H, 3 H-8). Compound
S-30: [R]D -28.4 (c 0.6, MeOH). 1H NMR (400 MHz, D2O) δ 7.50-
7.46 (m, 2 H, Ar), 7.31-7.26 (m, 2 H, Ar), 7.24-7.20 (m, 1 H, Ar), 4.22
(d, 1 H, J 3,4 ) 9.6 Hz, H-3), 3.80 (dd, 1 H, J 4,5 ) 9.2 Hz, H-4), 3.64 (dq,
1 H, J 6,7 ) 0.8 Hz, J 7,8 ) 6.4 Hz, H-7), 3.61 (dd, 1 H, J 5,6 ) 3.6 Hz,
H-6), 3.59 (dd, 1 H, H-5), 3.46 (s, 3 H, OMe), 0.86 (d, 3 H, 3 H-8).
(54) Skrydstrup, T.; J arreton, O.; Maze´as, D.; Urban, D.; Beau, J .-
M. Chem. Eur. J . 1998, 4, 655.
(55) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth-Heinemann: Oxford, UK, 1996.
(56) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(57) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.
(58) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor,
R. J . K. J . Org. Chem. 2002, 67, 1802.
(59) Hou, D.-R.; Reibenspies, J . H.; Burgess, K. J . Org. Chem. 2001,
66, 206.
5030 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
rt for 42 h and then concentrated. Crystallization of the crude
product from hot cyclohexane gave pure 5b (3.00 g, 42%) as
white crystals. The mother liquor was concentrated and the
residue was eluted from a column of silica gel with cyclohex-
ane-AcOEt (from 3:1 to 1:1) to give 5b (3.59 g, 51%) as a
white solid. Mp 125-126 °C (cyclohexane); [R]D -41.5 (c 0.8,
2,6-An h ydr o-3,4,5-tr i-O-ben zyl-7-deoxy-a ldeh ydo-L-glyc-
er o-D-glu co-h ep tose (R-1). A mixture of 7 (960 mg, 1.91
mmol), activated 4-Å powdered molecular sieves (2.0 g), and
anhydrous CH3CN (19 mL) was stirred at rt for 10 min, then
methyl triflate (280 µL, 2.48 mmol) was added. The suspension
was stirred at rt for 15 min and then concentrated to dryness
without filtering off the molecular sieves. To a cooled (0 °C),
stirred suspension of the crude N-methylthiazolium salt in
CH3OH (19 mL) was added NaBH4 (146 mg, 3.82 mmol). The
mixture was stirred at rt for an additional 10 min, diluted with
acetone, filtered through a pad of Celite, and concentrated.
To a vigorously stirred solution of the thiazolidines in CH3CN
(20 mL) was added dropwise H2O (2 mL) and then AgNO3 in
one portion (486 mg, 2.86 mmol). The mixture was stirred at
rt for 10 min, then diluted with 1 M phosphate buffer at pH 7
(40 mL) and partially concentrated to remove CH3CN (bath
temperature not exceeding 40 °C). The suspension was ex-
tracted with CH2Cl2 (100 + 50 mL), and the combined organic
phases were dried (Na2SO4) and concentrated to give a yellow
syrup. A solution of the residue in Et2O (ca. 150 mL) was
filtered through a pad of Celite (1 × 4 cm, h × d), and
concentrated to afford R-1 (770 mg, 90%) as a colorless syrup
1
CHCl3); H NMR (400 MHz) δ 7.80 (d, 1 H, J ) 3.2 Hz, Th),
7.40-7.25 (m, 16 H, 3 Ph, Th), 5.05 and 4.75 (2 d, 2 H,
J ) 11.8 Hz, PhCH2), 4.86 and 4.78 (2 d, 2 H, J ) 11.8 Hz,
PhCH2), 4.51 and 4.25 (2 d, 2 H, J ) 10.7 Hz, PhCH2), 4.13
(dd, 1 H, J 2,3 ) 10.0 Hz, J 3,4 ) 2.3 Hz, H-3), 4.09 (d, 1 H, H-2),
3.98 (dq, 1 H, J 4,5 ) 1.3 Hz, J 5,6 ) 6.5 Hz, H-5), 3.89 (dd, 1 H,
H-4), 2.19 (s, 3 H, Ac), 1.32 (d, 3 H, 3 H-6). Anal. Calcd for
C
32H33NO6S: C, 68.67; H, 5.94; N, 2.50. Found: C, 68.77; H,
5.70; N, 2.65.
When the crude thiazolylketose 5a derived from lactone 3
(9.80 g) was directly acetylated as described above, the
compound 5b was isolated by column chromatography in 92%
overall yield from 1.
2-(2,3,4-Tr i-O-ben zyl-â-L-fu cop yr a n osyl)th ia zole (6). To
a stirred mixture of 5b (1.60 g, 2.86 mmol), activated 4-Å
powdered molecular sieves (2.8 g), and triethylsilane (4.61 mL,
28.60 mmol) in anhydrous CH2Cl2 (47 mL) was added TMSOTf
(776 µL, 4.29 mmol). The mixture was stirred at rt for 1 h,
then diluted with triethylamine (2.5 mL) and CH2Cl2 (50 mL),
filtered through Celite, and concentrated. The residue was
eluted from a column of silica gel with cyclohexane-AcOEt
(from 3:1 to 1:1) to give 6 (1.37 g, 95%) as a white solid. Mp
1
ca. 95% pure by H NMR analysis. 1H NMR (400 MHz) δ 9.79
(s, 1 H, H-1), 7.39-7.23 (m, 15 H, 3 Ph), 4.73 and 4.65 (2 d, 2
H, J ) 11.8 Hz, PhCH2), 4.72 and 4.59 (2 d, 2 H, J ) 12.0 Hz,
PhCH2), 4.67 and 4.59 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.42 (d,
1 H, J 2,3 ) 4.6 Hz, H-2), 4.21 (dd, 1 H, J 3,4 ) 7.0 Hz, H-3), 4.18
(dq, 1 H, J 5,6 ) 3.7 Hz, J 6,7 ) 6.5 Hz, H-6), 3.80 (dd, 1 H, J 4,5
) 2.8 Hz, H-5), 3.67 (dd, 1 H, H-4), 1.32 (d, 3 H, 3 H-7).
1
113-114 °C (cyclohexane); [R]D +6.3 (c 1.0, CHCl3). H NMR
2,6-An h ydr o-3,4,5-tr i-O-ben zyl-7-deoxy-a ldeh ydo-L-glyc-
er o-D-m a n n o-h ep tose (â-1). The thiazolyl C-glycoside 6 (260
mg, 0.51 mmol) was treated as described for the preparation
of R-1 to give â-1 (213 mg, 92%) as a colorless syrup ca. 95%
(300 MHz) δ 7.84 (d, 1 H, J ) 3.3 Hz, Th), 7.48-7.20 and 7.12-
7.06 (2 m, 16 H, 3 Ph, Th), 5.08 and 4.77 (2 d, 2 H, J ) 11.7
Hz, PhCH2), 4.81 (s, 2 H, PhCH2), 4.69 and 4.31 (2 d, 2 H, J )
10.7 Hz, PhCH2), 4.68 (d, 1 H, J 1,2 ) 9.5 Hz, H-1), 4.24 (dd, 1
H, J 2,3 ) 9.0 Hz, H-2), 3.76 (dd, 1 H, J 3,4 ) 2.7 Hz, H-3), 3.75-
3.68 (m, 2 H, H-4, H-5), 1.27 (d, 3 H, J 5,6 ) 6.3 Hz, 3 H-6).
Anal. Calcd for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79.
Found: C, 72.02; H, 6.10; N, 2.95.
1
1
pure by H NMR analysis. H NMR (400 MHz) δ 9.65 (d, 1 H,
J 1,2 ) 1.5 Hz, H-1), 7.40-7.28 (m, 15 H, 3 Ph), 4.99 and 4.70
(2 d, 2 H, J ) 11.6 Hz, PhCH2), 4.88 and 4.68 (2 d, 2 H, J )
10.7 Hz, PhCH2), 4.78 and 4.75 (2 d, 2 H, J ) 11.5 Hz, PhCH2),
4.06 (dd, 1 H, J 2,3 ) 10.1 Hz, J 3,4 ) 8.4 Hz, H-3), 3.73 (dd, 1 H,
H-2), 3.69-3.65 (m, 2 H, H-4, H-5), 3.56 (dq, 1 H, J 5,6 ) 0.8
Hz, J 6,7 ) 6.4 Hz, H-6), 1.22 (d, 3 H, 3 H-7).
P r ep a r a tion of th e Sm I2 Solu tion . To a stirred mixture
of commercially available samarium (1.65 g, 11.0 mmol, <40
mesh powder) and I2 (2.55 g, 10.0 mmol) in a septum-equipped
vial was added anhydrous THF (100 mL) under a nitrogen
atmosphere. An exothermic reaction took place and the solu-
tion turned brownish while large amounts of SmI3 were formed
as a yellow solid after ca. 15 min. The septum was replaced
by a gastight screw-cap and the mixture was stirred at 75 °C
for an additional 3 h. Upon stirring at high temperature the
yellow precipitate dissolved and the suspension turned deep
blue due to the formation of SmI2. The ca. 0.1 M samarium-
(II) iodide solution was stored at rt and used within 1 day.
(Z)-8,12-An h yd r o-9,10,11-tr i-O-ben zyl-6,7,13-tr id eoxy-
1,2:3,4-di-O-isopr opyliden e-R-L-glycer o-D-ma n n o-D-ga la cto-
tr id ec-6-en o-1,5-p yr a n ose (9). A mixture of phosphonium
salt 8 (280 mg, 0.44 mmol), activated 4-Å powdered molecular
sieves (0.40 g), anhydrous THF (2.3 mL), and anhydrous
HMPA (1.1 mL) was stirred at room temperature for 10 min,
then cooled to -30 °C. To the stirred mixture was added
dropwise n-butyllithium (275 µL, 0.44 mmol of a 1.6 M solution
in hexanes) and, after 5 min, a solution of â-1 (182 mg, 0.40
mmol) in anhydrous THF (1 mL) over a 10-min period. The
mixture was stirred at -30 °C for an additional 30 min, then
allowed to reach -10 °C in 1.5 h, diluted with Et2O (100 mL),
and filtered through a pad of Celite. The ethereal solution was
washed with 1 M phosphate buffer at pH 7 (3 × 10 mL), dried
(Na2SO4), and concentrated. Column chromatography (5:1
cyclohexane-AcOEt containing 0.2% of Et3N) of the residue
afforded 9 (157 mg, 57%) as a syrup. [R]D -49.8 (c 1.4, CHCl3);
1H NMR (400 MHz) δ 7.39-7.24 (m, 15 H, 3 Ph), 5.75 (ddd, 1
H, J 5,6 ) 6.9 Hz, J 6,7 ) 11.5 Hz, J 6,8 ) 1.0 Hz, H-6), 5.69 (dd,
1 H, J 7,8 ) 5.1 Hz, H-7), 5.54 (d, 1 H, J 1,2 ) 5.0 Hz, H-1), 4.99
and 4.69 (2 d, 2 H, J ) 11.7 Hz, PhCH2), 4.86 and 4.75 (2 d, 2
H, J ) 11.3 Hz, PhCH2), 4.80 (dd, 1 H, J 4,5 ) 1.7 Hz, H-5),
4.74 and 4.71 (2 d, 2 H, J ) 11.9 Hz, PhCH2), 4.51 (dd, 1 H,
J 2,3 ) 2.3 Hz, J 3,4 ) 7.8 Hz, H-3), 4.36 (dd, 1 H, H-4), 4.27 (dd,
1 H, H-2), 3.92 (ddd, 1 H, J 8,9 ) 9.5 Hz, H-8), 3.81 (dd, 1 H,
J 9,10 ) 9.2 Hz, H-9), 3.64 (dd, 1 H, J 10,11 ) 2.7 Hz, J 11,12 ) 0.9
Hz, H-11), 3.56 (dd, 1 H, H-10), 3.48 (dq, 1 H, J 12,13 ) 6.4 Hz,
H-12), 1.50, 1.46, 1.32, and 1.25 (4 s, 12 H, 4 Me), 1.17 (d, 3
H, 3 H-13). Anal. Calcd for C40H48O9: C, 71.41; H, 7.19.
Found: C, 71.13; H, 7.01.
2-(2,3,4-Tr i-O-ben zyl-R-L-fu cop yr a n osyl)th ia zole (7). A
vigorously stirred solution of 5b (1.08 g, 1.93 mmol) and
anhydrous ethylene glycol (1.20 g, 19.30 mmol) in anhydrous
THF (10 mL) was degassed under vacuum and saturated with
argon three times, then a ca. 0.1 M solution of SmI2 in THF
was added dropwise by means of a gastight syringe until
the reaction mixture turned a persistent blue (usually after
10-20 min). The mixture was stirred for an additional 10 min,
then diluted with saturated aqueous NaHCO3 (100 mL) and
concentrated to remove the THF. The residue was extracted
with Et2O (2 × 100 mL), and the combined organic phases were
dried (Na2SO4) and concentrated. The residue was eluted from
a column of silica gel with cyclohexane-AcOEt (from 4:1 to
1:1) to give first 7 (0.90 g, 93%) as a syrup. [R]D -40.5 (c 1.3,
1
CHCl3); H NMR (400 MHz) δ 7.78 (d, 1 H, J ) 3.3 Hz, Th),
7.36-7.23 and 7.11-7.06 (2 m, 16 H, 3 Ph, Th), 5.40 (d, 1 H,
J 1,2 ) 3.3 Hz, H-1), 4.69 (s, 2 H, PhCH2), 4.67 and 4.58 (2 d, 2
H, J ) 12.0 Hz, PhCH2), 4.39 and 4.36 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.34 (dq, 1 H, J 4,5 ) 4.6 Hz, J 5,6 ) 6.5 Hz, H-5), 4.19
(dd, 1 H, J 2,3 ) 5.7 Hz, H-2), 3.99 (dd, 1 H, J 3,4 ) 3.1 Hz, H-3),
3.95 (dd, 1 H, H-4), 1.42 (d, 3 H, 3 H-6). Anal. Calcd for
C
30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 71.45; H,
9,10,11-Tr i-O-a cet yl-8,12-a n h yd r o-6,7,13-t r id eoxy-1,2:
3,4-d i-O-isop r op ylid en e-R-L-glycer o-D-m a n n o-D-ga la cto-
6.01; N, 2.82. Eluted second was 6 (64 mg, 6%).
J . Org. Chem, Vol. 69, No. 15, 2004 5031

Dondoni et al.
tr id eco-1,5-p yr a n ose (10). A vigorously stirred mixture of
9 (90 mg, 0.13 mmol), 20% palladium hydroxide on carbon (31
mg), and 1:1 CH3OH-AcOEt (4 mL) was degassed under
vacuum and saturated with hydrogen (by a H2-filled balloon)
three times. The suspension was stirred at rt for 3 h under a
slightly positive pressure of hydrogen (balloon), then filtered
through a plug of cotton and concentrated. A solution of the
crude triol in pyridine (2 mL) and acetic anhydride (2 mL) was
kept at rt for 20 h, then concentrated. The residue was eluted
from a column of silica gel with cyclohexane-AcOEt (from 3:1
to 1:1) to give 10 (60 mg, 84%) as a syrup. [R]D -41.1 (c 1.0,
CHCl3); 1H NMR (300 MHz) δ 5.53 (d, 1 H, J 1,2 ) 5.1 Hz, H-1),
5.27 (dd, 1 H, J 10,11 ) 3.3 Hz, J 11,12 ) 1.2 Hz, H-11), 5.09 (dd,
1 H, J 8,9 ) 9.4 Hz, J 9,10 ) 10.0 Hz, H-9), 5.00 (dd, 1 H, H-10),
4.60 (dd, 1 H, J 2,3 ) 2.3 Hz, J 3,4 ) 8.0 Hz, H-3), 4.30 (dd, 1 H,
H-2), 4.15 (dd, 1 H, J 4,5 ) 1.8 Hz, H-4), 3.77-3.69 (m, 1 H,
H-5), 3.73 (dq, 1 H, J 12,13 ) 6.5 Hz, H-12), 3.44-3.37 (m, 1 H,
H-8), 2.19, 2.06, and 1.99 (3 s, 9 H, 3 Ac), 1.68-1.62 (m, 4 H,
2 H-6, 2 H-7), 1.53, 1.47, 1.36, and 1.34 (4 s, 12 H, 4 Me), 1.17
(d, 3 H, 3 H-13). Anal. Calcd for C25H38O12: C, 56.59; H, 7.22.
Found: C, 56.32; H, 7.11.
(Z,E)-8,12-An h ydr o-9,10,11-tr i-O-ben zyl-6,7,13-tr ideoxy-
1,2:3,4-d i-O-isop r op ylid en e-R-L-glycer o-D-glu co-D-ga la cto-
tr id ec-6-en o-1,5-p yr a n ose (12). The aldehyde R-1 (270 mg,
0.60 mmol) was allowed to react with the phosphonium salt 8
(419 mg, 0.67 mmol) in the presence of BuLi (425 µL, 0.68
mmol of a 1.6 M solution in hexanes) as described for the
preparation of 9. The crude product was eluted from a column
of silica gel with 4:1 cyclohexane-AcOEt (containing 0.3% of
Et3N) to give first syrupy 12 (194 mg, 48%) as a ca. 4:1 Z,E
mixture. (Z)-12: 1H NMR (400 MHz) (selected data) δ 5.94
(dd, 1 H, J 6,7 ) 11.5 Hz, J 7,8 ) 6.5 Hz, H-7), 5.84 (ddd, 1 H,
J 5,6 ) 7.9 Hz, J 6,8 ) 0.8 Hz, H-6), 5.53 (d, 1 H, J 1,2 ) 5.3 Hz,
H-1). (E)-12: 1H NMR (400 MHz) δ 7.40-7.25 (m, 15 H, 3 Ph),
6.04 (dd, 1 H, J 6,7 ) 16.1 Hz, J 7,8 ) 4.0 Hz, H-7), 5.97 (ddd, 1
H, J 5,6 ) 5.8 Hz, J 6,8 ) 1.4 Hz, H-6), 5.61 (d, 1 H, J 1,2 ) 5.0
Hz, H-1), 4.85 and 4.65 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.74
(s, 2 H, PhCH2), 4.67 (ddd, 1 H, J 8,9 ) 4.8 Hz, H-8), 4.65 (s, 2
H, PhCH2), 4.62 (dd, 1 H, J 2,3 ) 2.4 Hz, J 3,4 ) 7.8 Hz, H-3),
4.36 (dd, 1 H, J 4,5 ) 2.0 Hz, H-5), 4.35 (dd, 1 H, H-2), 4.22 (dd,
1 H, H-4), 4.04 (dd, 1 H, J 9,10 ) 8.1 Hz, H-9), 4.02 (dq, 1 H,
mmol) was hydrogenated and acetylated as described for the
preparation of 10 to give, after column chromatography on
silica gel (2:1 cyclohexane-AcOEt), 15 (121 mg, 80%) as a
1
syrup. [R]D -97.7 (c 0.9, CHCl3); H NMR (300 MHz) δ 5.55
(d, 1 H, J 1,2 ) 5.1 Hz, H-1), 5.35 (dd, 1 H, J 8,9 ) 5.8 Hz, J 9,10
) 10.2 Hz, H-9), 5.29 (dd, 1 H, J 10,11 ) 3.3 Hz, J 11,12 ) 1.7 Hz,
H-11), 5.22 (dd, 1 H, H-10), 4.62 (dd, 1 H, J 2,3 ) 2.3 Hz, J 3,4
)
8.0 Hz, H-3), 4.33 (dd, 1 H, H-2), 4.22-4.16 (m, 1 H, H-8), 4.16
(dd, 1 H, J 4,5 ) 1.7 Hz, H-4), 3.96 (dq, 1 H, J 12,13 ) 6.4 Hz,
H-12), 3.76-3.71 (m, 1 H, H-5), 2.18, 2.08, and 2.02 (3 s, 9 H,
3 Ac), 1.76-1.65 (m, 4 H, 2 H-6, 2 H-7), 1.56, 1.48, 1.37, and
1.36 (4 s, 12 H, 4 Me), 1.16 (d, 3 H, 3 H-13). Anal. Calcd for
C
25H38O12: C, 56.59; H, 7.22. Found: C, 56.37; H, 7.00.
Meth yl 2,3,4,9,10,11-Hexa -O-a cetyl-8,12-a n h yd r o-6,7,-
13-tr id eoxy-R-L-glycer o-D-glu co-D-glu co-tr id eco-1,5-p yr a -
n osid e (16). The alkene 14 (144 mg, 0.16 mmol) was hydro-
genated and acetylated as described for the preparation of 10
to give, after column chromatography on silica gel (1:1 cyclo-
hexane-AcOEt), 16 (58 mg, 60%) as a syrup. [R]D +31.3 (c
1
0.5, CHCl3); H NMR (400 MHz, C6D6) δ 5.84 (dd, 1 H, J 2,3
)
10.3 Hz, J 3,4 ) 9.4 Hz, H-3), 5.68 (dd, 1 H, J 8,9 ) 5.7 Hz, J 9,10
) 10.3 Hz, H-9), 5.43 (dd, 1 H, J 10,11 ) 3.5 Hz, H-10), 5.36 (dd,
1 H, J 11,12 ) 1.7 Hz, H-11), 5.08 (dd, 1 H, J 4,5 ) 10.0 Hz, H-4),
5.00 (dd, 1 H, J 1,2 ) 3.7 Hz, H-2), 4.86 (d, 1 H, H-1), 4.26 (ddd,
1 H, J 7a,8 ) 4.0 Hz, J 7b,8 ) 10.4 Hz, H-8), 3.71 (ddd, 1 H, J 5,6a
) 2.8 Hz, J 5,6b ) 7.4 Hz, H-5), 3.38 (dq, 1 H, J 12,13 ) 6.5 Hz,
H-12), 2.96 (s, 3 H, OMe), 1.72, 1.71, 1.70, 1.64, 1.62, and 1.60
(6 s, 18 H, 6 Ac), 1.72-1.65 and 1.35-1.30 (2 m, 4 H, 2 H-6, 2
H-7), 0.95 (d, 3 H, 3 H-13). Anal. Calcd for C26H38O15: C, 52.88;
H, 6.49. Found: C, 52.50; H, 6.39.
2,6-An h yd r o-3,4,5-tr i-O-ben zyl-7-d eoxy-L-glycer o-D-glu -
co-h ep titol (17). (a) To a cooled (0 °C), stirred solution of
aldehyde R-1 (730 mg, 1.63 mmol) in Et2O (9 mL) and
CH3OH (9 mL) was added NaBH4 (120 mg, 3.26 mmol). The
mixture was stirred at rt for an additional 10 min, then diluted
with acetone (1 mL), and concentrated. The residue was eluted
from a column of silica gel with 2:1 cyclohexane-AcOEt to give
17 (696 mg, 95%) as a syrup. [R]D -12.6 (c 1.1, CHCl3); 1H
NMR (400 MHz) δ 7.36-7.24 (m, 15 H, 3 Ph), 4.77 and 4.67 (2
d, 2 H, J ) 12.0 Hz, PhCH2), 4.76 and 4.62 (2 d, 2 H, J ) 11.8
Hz, PhCH2), 4.65 and 4.51 (2 d, 2 H, J ) 11.7 Hz, PhCH2),
4.12 (ddd, 1 H, J 1a,2 ) 7.8 Hz, J 1b,2 ) 4.8 Hz, J 2,3 ) 3.9 Hz,
H-2), 4.00 (dq, 1 H, J 5,6 ) 3.5 Hz, J 6,7 ) 6.7 Hz, H-6), 3.92-
J 11,12 ) 2.6 Hz, J 12,13 ) 6,5 Hz, H-12), 3.76 (dd, 1 H, J 10,11
)
2.8 Hz, H-11), 3.72 (dd, 1 H, H-10), 1.55, 1.44, 1.36, and 1.33
(4 s, 12 H, 4 Me), 1.24 (s, 3 H, 3 H-13). Anal. Calcd for
3.88 (m, 1 H, H-3), 3.81 (ddd, 1 H, J 1a,1b ) 11.6 Hz, J 1a,OH
)
C
40H48O9: C, 71.41; H, 7.19. Found: C, 71.28; H, 7.13.
3.6 Hz, H-1a), 3.81-3.78 (m, 2 H, H-4, H-5), 3.69 (ddd, 1 H,
J 1b,OH ) 8.7 Hz, H-1b), 1.97 (dd, 1 H, OH), 1.30 (d, 3 H, 3 H-7).
Anal. Calcd for C28H32O5: C, 74.97; H, 7.19. Found: C, 74.81;
H, 7.15.
Eluted second was 13 (20 mg, 8%) slightly contaminated
1
by uncharacterized byproducts. H NMR (300 MHz) δ 9.20 (s,
1 H, H-1), 7.42-7.26 (m, 10 H, 2 Ph), 5.85 (dd, 1 H, J 3,4 ) 2.4
Hz, J 3,5 ) 1.8 Hz, H-3), 5.00 and 4.76 (2 d, 2 H, J ) 11.8 Hz,
PhCH2), 4.77 and 4.73 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.47
(ddd, 1 H, J 4,5 ) 4.1 Hz, J 4,6 ) 1.3 Hz, H-4), 4.17 (ddq, 1 H,
J 5,6 ) 1.5 Hz, J 6,7 ) 6.7 Hz, H-6), 3.78 (ddd, 1 H, H-5), 1.40 (d,
3 H, 3 H-7).
(b) A mixture of 7 (1.60 g, 3.58 mmol), activated 4 Å
powdered molecular sieves (3.0 g), and anhydrous CH3CN (35
mL) was stirred at rt for 10 min, then methyl triflate (610 µL,
5.37 mmol) was added. The suspension was stirred at rt for
15 min and then concentrated to dryness without filtering off
the molecular sieves. To a cooled (0 °C), stirred suspension of
the crude N-methylthiazolium salt in CH3OH (35 mL) was
added NaBH4 (331 mg, 8.95 mmol). The mixture was stirred
at rt for an additional 10 min, diluted with acetone, filtered
through a pad of Celite, and concentrated. To a vigorously
stirred solution of the thiazolidines in CH3CN (30 mL) was
added dropwise H2O (3 mL) and then AgNO3 in one portion
(912 mg, 5.37 mmol). The mixture was stirred at rt for 10 min,
then NaBH4 (397 mg, 10.74 mmol) was added. Stirring was
continued for an additional 15 min, then the reaction mixture
was diluted with acetone, filtered through a pad of Celite, and
concentrated. The residue was eluted from a column of silica
gel with 2:1 cyclohexane-AcOEt to give 17 (1.56 g, 97%).
Meth yl 8,12-An h yd r o-2,3,4,9,10,11-h exa -O-ben zyl-6,7,-
13-t r id eoxy-R-L-glycer o-D-glu co-D-glu co-t r id ec-6-(Z,E)-
en o-1,5-p yr a n osid e (14). The aldehyde R-1 (200 mg, 0.44
mmol) was allowed to react with the phosphonium salt 11 (370
mg, 0.44 mmol) in the presence of BuLi (275 µL, 0.44 mmol of
a 1.6 M solution in hexanes) as described for the preparation
of 9. The crude product was eluted from a column of silica gel
with cyclohexane-AcOEt (from 7:1 to 4:1) to give 14 (144 mg,
37%) as a 1:1 mixture of E,Z-isomers. 1H NMR (300 MHz)
(selected data) δ 6.15 (dd, 1 H, J 6,7 ) 16.0 Hz, J 7,8 ) 4.4 Hz,
H-7E), 6.05 (dd, 1 H, J 6,7 ) 11.2 Hz, J 7,8 ) 6.8 Hz, H-7Z), 5.91
(ddd, 1 H, J 5,6 ) 6.7 Hz, J 6,8 ) 1.8 Hz, H-6E), 5.69 (ddd, 1 H,
J 5,6 ) 9.0 Hz, J 6,8 ) 1.2 Hz, H-6Z), 3.41 (s, 3 H, OMe), 3.40 (s,
3 H, OMe), 1.24 (d, 3 H, J 12,13 ) 6.5 Hz, 3 H-13), 1.10 (d, 3 H,
J 12,13 ) 6.5 Hz, 3 H-13). Anal. Calcd for C56H60O9: C, 76.69;
H, 6.90. Found: C, 76.38; H, 6.77.
2,6-An h yd r o-3,4,5-t r i-O-b en zyl-1,7-d id eoxy-1-iod o-L-
glycer o-D-glu co-h ep titol (18). To a vigorously stirred solu-
tion of alcohol 17 (760 mg, 1.69 mmol), triphenylphosphine
(1.11 g, 4.23 mmol), and imidazole (575 mg, 8.45 mmol) in
anhydrous toluene (17 mL) was added iodine (1.07 g, 4.22
mmol). The mixture was stirred at 80 °C for 1 h, then cooled
9,10,11-Tr i-O-a cet yl-8,12-a n h yd r o-6,7,13-t r id eoxy-1,2:
3,4-d i-O-isop r op ylid en e-R-L-glycer o-D-glu co-D-ga la cto-
tr id eco-1,5-p yr a n ose (15). The alkene 12 (197 mg, 0.29
5032 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
to rt, filtered through a pad of Celite, and concentrated. A
solution of the residue in Et2O (200 mL) was washed with 5%
aqueous Na2S2O3 (2 × 50 mL), dried (Na2SO4), and concen-
trated. The residue was eluted from a column of silica gel with
11:1 cyclohexane-AcOEt to give 18 (880 mg, 93%) as a white
solid. Mp 74-75 °C (MeOH); [R]D -20.3 (c 0.8, CHCl3); 1H NMR
(400 MHz) δ 7.37-7.24 (m, 15 H, 3 Ph), 4.74 and 4.63 (2 d, 2
H, J ) 12.0 Hz, PhCH2), 4.71 and 4.59 (2 d, 2 H, J ) 11.9 Hz,
PhCH2), 4.62 and 4.53 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.15
(ddd, 1 H, J 1a,2 ) 5.7 Hz, J 1b,2 ) 8.9 Hz, J 2,3 ) 3.5 Hz, H-2),
3.94 (dd, 1 H, J 3,4 ) 6.5 Hz, H-3), 3.79 (dd, 1 H, J 4,5 ) 3.0 Hz,
H-5), 3.74 (dd, 1 H, H-4), 3.34 (dd, 1 H, J 1a,1b ) 10.4 Hz,
H-1a), 3.27 (dd, 1 H, H-1b), 1.34 (d, 3 H, 3 H-7). Anal. Calcd
for C28H31IO4: C, 60.22; H, 5.60. Found: C, 60.24; H, 5.35.
(2,6-An h yd r o-3,4,5-tr i-O-ben zyl-1,7-d id eoxy-L-glycer o-
D-glu co-h ep titol-1-yl)tr ip h en ylp h osp h on iu m Iod id e (19).
A mixture of iodide 18 (830 mg, 1.48 mmol) and triphen-
ylphosphine (2.20 g, 8.45 mmol) was stirred at 120 °C under
a nitrogen atmosphere for 2 h, then cooled to ca. 80 °C, diluted
with toluene (1 mL), transferred onto a column of silica gel,
and eluted with toluene, then AcOEt, and finally 1:1 AcOEt-
acetone to give 19 (1.18 g, 97%) as a foam. [R]D -34.7 (c 1.2,
CHCl3); 1H NMR (400 MHz, acetone-d6) δ 7.98-7.86, 7.79-
7.73, and 7.41-7.26 (3 m, 30 H, 6 Ph), 4.80 (s, 2 H, PhCH2),
4.79 and 4.67 (2 d, 2 H, J ) 11.9 Hz, PhCH2), 4.73 and 4.54 (2
d, 2 H, J ) 11.6 Hz, PhCH2), 4.44 (ddd, 1 H, J 1a,1b ) 15.3 Hz,
J 1a,2 ) 11.0 Hz, J 1a,P ) 21.7 Hz, H-1a), 4.43-4.36 (m, 2 H, H-2,
H-4), 4.11-4.04 (m, 2 H, H-3, H-6), 3.92 (dd, 1 H, J 4,5 ) 3.0
cyclohexane-AcOEt (from 2:1 to 1:1) to give 22 (51 mg, 73%)
as a syrup. 1H NMR (300 MHz, DMSO-d6, 120 °C) (selected
data) δ 5.22-5.03 (m, 3 H, H-6, H-7, H-8), 4.08-3.64 (m, 5 H,
2 H-1, H-2, H-5, H-9), 2.11, 2.02, and 1.97 (3 s, 9 H, 3 Ac),
1.46 (s, 9 H, t-Bu); MALDI-TOF MS (501.58) 524.3 (M+ + Na),
540.5 (M+ + K). Anal. Calcd for C24H39NO10: C, 57.47; H, 7.84;
N, 2.79. Found: C, 57.20; H, 7.63; N, 2.88.
Met h yl 6,7,8-Tr i-O-a cet yl-5,9-a n h yd r o-2-ter t-b u t oxy-
ca r bon yla m in o-2,3,4,10-tetr a d eoxy-L-th r eo-D-gu lo- a n d
-D-id o-d econ a te (23). To a stirred, cooled (0 °C) solution of
22 (91 mg, 0.16 mmol) in acetone (3 mL) was added freshly
prepared 1 M J ones’ reagent (480 µL, 0.48 mmol). The mix-
ture was allowed to warm to rt in 30 min, stirred at rt for
an additional 2.5 h, diluted with 2-propanol (∼0.5 mL), then
with brine (10 mL), and extracted with CH2Cl2 (3 × 30
mL). The combined organic phases were dried (Na2SO4) and
concentrated. Treatment of a solution of crude acid in 1:1
Et2O-MeOH with ethereal diazomethane at 0 °C for 5 min
gave, after column chromatography on silica gel (1:1 cyclo-
hexane-AcOEt), 23 (55 mg, 70%) as a ca. 3:2 mixture of C-2
1
epimers. H NMR (300 MHz) (selected data) δ 5.32 (dd, 1 H,
J 5,6 ) 5.6 Hz, J 6,7 ) 10.2 Hz, H-6), 5.28 (dd, 1 H, J 7,8 ) 3.3 Hz,
J 8,9 ) 1.6 Hz, H-8), 5.18 (dd, 0.4 H, H-7), 5.17 (dd, 0.6 H, H-7),
4.22-4.12 (m, 1 H, H-5), 3.92 (dq, 0.4 H, J 9,10 ) 6.5 Hz, H-9),
3.90 (dq, 0.6 H, J 9,10 ) 6.5 Hz, H-9), 3.77 (s, 3 H, OMe), 1.47
(s, 1.8 H, t-Bu), 1.46 (s, 1.2 H, t-Bu), 1.17 (d, 3 H, 3 H-10);
MALDI-TOF MS (489.53) 512.3 (M+ + Na), 528.3 (M+ + K).
Anal. Calcd for C22H35NO11
: C, 53.98; H, 7.21; N, 2.86.
Hz, J 5,6 ) 3.9 Hz, H-5), 3.60 (ddd, 1 H, J 1b,2 ) 2.0 Hz, J 1b,P
)
Found: C, 53.66; H, 7.17; N, 2.98.
15.5 Hz, H-1b), 0.60 (d, 3 H, J 6,7 ) 6.5 Hz, H-7); 31P NMR (162
MHz, acetone-d6) δ 26.3. Anal. Calcd for C46H46IO4P: C, 67.32;
H, 5.65. Found: C, 67.55; H, 5.46.
3-ter t-Bu toxyca r bon yla m in o-2,3-d id eoxy-3,4-N,O-iso-
p r op ylid en e-a ld eh yd o-D-glycer o-tetr ose (24). A mixture of
(S)-N-tert-butoxycarbonyl-4-(2-hydroxyethyl)-2,2-dimethylox-
azolidine58,59 (500 mg, 2.04 mmol; crystallized from cyclohex-
ane, mp 73-75 °C), activated 4 Å powdered molecular sieves
(2.0 g), and anhydrous CH2Cl2 (10 mL) was stirred at rt for
10 min, and then pyridinium chlorochromate (2.15 g, 10.0
mmol) was added. The suspension was vigorously stirred for
40 min, then diluted with Et2O (10 mL) and cyclohexane (10
mL), stirred for an additional 5 min, and filtered through a
short pad of silica gel (7 × 2 cm, d × h) placed in a syntherized
glass filter and previously conditioned in 1:1 Et2O-cyclohex-
ane. Further elution with 1:1 Et2O-cyclohexane (ca. 200 mL)
gave pure 24 (390 mg, 79%) as a white solid that could not be
recrystallized (mp <40 °C). [R]D +34.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, DMSO-d6, 100 °C) δ 9.70 (dd, 1 H, J 1,2a ) 2.2 Hz,
J 1,2b ) 1.8 Hz, H-1), 4.25 (dddd, 1 H, J 2a,3 ) 5.3 Hz, J 2b,3 ) 7.0
5,9-An h yd r o-6,7,8-t r i-O-b e n zyl-2-t er t -b u t oxyca r b o-
n yla m in o-2,3,4,10-tetr a d eoxy-1,2-N,O-isop r op ylid en e-L-
th r eo-D-gu lo- a n d -D-id o-d ec-3-(Z,E)-en itol (21). A mixture
of phosphonium salt 19 (195 mg, 0.24 mmol), activated 4-Å
powdered molecular sieves (0.24 g), anhydrous THF (1.6 mL),
and anhydrous HMPA (1.6 mL) was stirred at room temper-
ature for 10 min, then cooled to -20 °C. The stirred mixture
was treated with n-butyllithium (180 µL, 0.28 mmol of a 1.6
M solution in hexanes), warmed to 0 °C, stirred for an
additional 30 min, and then cooled to -20 °C. To the stirred
mixture was added a solution of 20 (92 mg, 0.40 mmol) in
anhydrous THF (1.6 mL) over a 10-min period. The mixture
was allowed to reach 0 °C in 2.5 h, stirred at 0 °C for an
additional 60 min, then diluted with Et2O (150 mL), and
filtered through a pad of Celite. The ethereal solution was
washed with 1 M phosphate buffer at pH 7 (3 × 30 mL), dried
(Na2SO4), and concentrated. The residue was eluted from a
column of silica gel with cyclohexane-AcOEt (from 8:1 to 4:1,
containing 0.3% of Et3N) to give syrupy 21 (106 mg, 70%) as
a 3:1 E,Z mixture. 1H NMR (300 MHz, DMSO-d6, 120 °C)
(selected data) δ 5.86 (dd, 1 H, J ) 4.4, 15.9 Hz, CHd), 5.83
(dd, J ) 6.1, 11.0 Hz, CHd), 5.77 (ddd, J ) 0.8, 5.8, 15.9 Hz,
CHd), 5.71 (ddd, J ) 1.5, 5.0, 11.0 Hz, CHd), 5.56 (ddd, J )
1.5, 8.2, 11.3 Hz, CHd), 1.21 (d, J 9,10 ) 6.3 Hz, H-10), 1.18 (d,
J 9,10 ) 6.3 Hz, H-10), 1.16 (d, J 9,10 ) 6.3 Hz, H-10); MALDI-
TOF MS (643.83) 665.6 (M+ + Na), 681.7 (M+ + K). Anal. Calcd
for C39H49NO7: C, 72.76; H, 7.67; N, 2.18. Found: C, 72.58;
H, 7.52; N, 2.31.
6,7,8-Tr i-O-a ce t yl-5,9-a n h yd r o-2-t er t -b u t oxyca r b o-
n yla m in o-2,3,4,10-tetr a d eoxy-1,2-N,O-isop r op ylid en e-L-
th r eo-D-gu lo- a n d -D-id o-d ecitol (22). A vigorously stirred
mixture of 21 (90 mg, 0.14 mmol), 20% palladium hydroxide
on carbon (31 mg), and 1:1 CH3OH-AcOEt (4 mL) was
degassed under vacuum and saturated with hydrogen (by a
H2-filled balloon) three times. The suspension was stirred at
rt for 1 h under a positive pressure of hydrogen (5 bar), then
filtered through a plug of cotton and concentrated. A solution
of the crude triol in pyridine (1 mL) and freshly distilled acetic
anhydride (1 mL) was kept at rt for 20 h, then concentrated.
The residue was eluted from a column of silica gel with
Hz, J 3,4a ) 6.0 Hz, J 3,4b ) 2.2 Hz, H-3), 4.04 (dd, 1 H, J 4a,4b
9.2 Hz, H-4a), 3.73 (dd, 1 H, H-4b), 2.75 (ddd, 1 H, J 2a,2b
)
)
16.0 Hz, H-2a), 2.66 (ddd, 1 H, H-2b), 1.51 and 1.45 (2 s, 6 H,
2 Me), 1.44 (s, 9 H, t-Bu). Anal. Calcd for C12H21NO4: C, 59.24;
H, 8.70; N, 5.76. Found: C, 59.02; H, 8.63; N, 5.85.
6,10-An h yd r o-7,8,9-t r i-O-b en zyl-2-ter t-b u t oxyca r b o-
n yla m in o-2,3,4,5,11-p en ta d eoxy-1,2-N,O-isop r op ylid en e-
L-th r eo-D-id o-u n d ec-4-(Z)-en itol (25). A mixture of phos-
phonium salt 19 (760 mg, 0.92 mmol), activated 4-Å powdered
molecular sieves (0.90 g), anhydrous THF (7.1 mL), and
anhydrous HMPA (4.7 mL) was stirred at room temperature
for 10 min, then cooled to -20 °C. The stirred mixture was
treated with n-butyllithium (580 µL, 0.92 mmol of a 1.6 M
solution in hexanes), warmed to 0 °C, stirred for an additional
30 min, and then cooled to -20 °C. To the stirred mixture was
added a solution of 24 (336 mg, 1.37 mmol) in anhydrous THF
(7.1 mL) over a 15-min period. The mixture was allowed to
reach 0 °C in 2.5 h, stirred at 0 °C for an additional 60 min,
then diluted with Et2O (200 mL), and filtered through a pad
of Celite. The ethereal solution was washed with 1 M phos-
phate buffer at pH 7 (3 × 30 mL), dried (Na2SO4), and
concentrated. The residue was eluted from a column of silica
gel with 5:1 cyclohexane-AcOEt to give 25 (457 mg, 75%) as
a syrup. [R]D -1.1 (c 1.4, CHCl3); 1H NMR (300 MHz, DMSO-
d6, 160 °C) (selected data) δ 5.83 (dddd, 1 H, J ) 1.5, 1.5, 7.5,
11.5 Hz, CHd), 5.69-5.60 (m, 1 H, CHd), 4.78 and 4.58 (2 d,
J . Org. Chem, Vol. 69, No. 15, 2004 5033

Dondoni et al.
2 H, J ) 11.9 Hz, PhCH2), 4.76 and 4.71 (2 d, 2 H, J ) 11.5
Hz, PhCH2), 4.63 and 4.57 (2 d, 2 H, J ) 11.7 Hz, PhCH2),
1.50 and 1.44 (2 s, 6 H, 2 Me), 1.44 (s, 9 H, t-Bu), 1.19 (d, 3 H,
J 10,11 ) 6.4 Hz, 3 H-11). Anal. Calcd for C40H51NO7: C, 73.03;
H, 7.81; N, 2.13. Found: C, 72.78; H, 7.72; N, 2.29.
7,8,9-Tr i-O-a cet yl-6,10-a n h yd r o-2-ter t-b u t oxyca r b o-
n yla m in o-2,3,4,5,11-p en ta d eoxy-1,2-N,O-isop r op ylid en e-
L-th r eo-D-id o-u n d ecitol (27). The alkene 25 (190 mg, 0.28
mmol) was hydrogenated and acetylated as described for the
preparation of 22 to give, after column chromatography on
silica gel (2.5:1 cyclohexane-AcOEt), first 27 (82 mg, 55%) as
a syrup. [R]D -45.4 (c 1.0, CHCl3); 1H NMR (300 MHz, DMSO-
d6, 120 °C) δ 5.22-5.15 (m, 2 H, H-8, H-9), 5.10 (dd, 1 H, J 6,7
) 5.3 Hz, J 7,8 ) 9.3 Hz, H-7), 4.09-4.01 (m, 2 H, H-6, H-10),
3.93 (dd, 1 H, J 1a,1b ) 8.8 Hz, J 1a,2 ) 6.0 Hz, H-1a), 3.80 (dddd,
1 H, J 1b,2 ) 1.9 Hz, J 2,3a ) 4.0 Hz, J 2,3b ) 8.0 Hz, H-2), 3.68
(dd, 1 H, H-1b), 2.10, 2.03, and 1.96 (3 s, 9 H, 3 Ac), 1.51 and
H-6), 1.24 (d, 3 H, 3 H-7). Anal. Calcd for C34H34O5: C, 78.14;
H, 6.56. Found: C, 77.83; H, 6.43.
(1R)-2,6-An h yd r o-3,4,5-tr i-O-ben zyl-7-d eoxy-1-C-p h en -
yl-1-C-(2-th ia zolyl)-L-glycer o-D-m a n n o-h ep titol (32). To a
cooled (-78 °C), stirred solution of nBuLi (600 µL, 0.95 mmol
of a 1.6 M solution in hexane) in anhydrous Et2O (1.3 mL)
was added dropwise a solution of freshly distilled 2-bromothia-
zole (85 µL, 0.92 mmol) in anhydrous Et2O (0.5 mL) over a
15-min period. The yellow solution was stirred at -75 °C for
30 min, then a solution of ketone 31 (190 mg, 0.36 mmol) in
anhydrous THF (1 mL) was added slowly (10 min). After an
additional 30 min at -75 °C the mixture was allowed to warm
to -65 °C in 40 min and then poured into 20 mL of a 1 M
phosphate buffer at pH 7. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic layers were dried (Na2SO4) and concen-
trated. The residue was eluted from a column of silica gel with
cyclohexane-AcOEt (from 4:1 to 2:1) to give 32 (165 mg, 75%)
1.44 (2 s, 6 H, 2 Me), 1.46 (s, 9 H, t-Bu), 1.09 (d, 3 H, J 10,11
6.5 Hz, 3 H-11). Anal. Calcd for C25H41NO10: C, 58.24; H, 8.02;
N, 2.72. Found: C, 58.02; H, 7.91; N, 2.73.
)
1
as a syrup. [R]D -69.9 (c 1.0, CHCl3); H NMR (400 MHz) δ
7.85-7.81 (m, 2 H, Ar), 7.74 and 7.17 (2 d, 2 H, J ) 3.3 Hz,
Th), 7.39-7.18 and 7.15-7.07 (2 m, 16 H, Ar), 6.78-6.74 (m,
2 H, Ar), 4.99 and 4.63 (2 d, 2 H, J ) 11.6 Hz, PhCH2), 4.80 (s,
1 H, OH), 4.68 and 4.55 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.62
(d, 1 H, J 2,3 ) 8.9 Hz, H-2), 4.50 and 3.51 (2 d, 2 H, J ) 10.6
Hz, PhCH2), 4.10 (dd, 1 H, J 3,4 ) 8.9 Hz, H-3), 3.72 (dd, 1 H,
J 4,5 ) 2.6 Hz, H-4), 3.67-3.61 (m, 2 H, H-5, H-6), 1.05 (d, 3 H,
J 6,7 ) 6.4 Hz, 3 H-7). Anal. Calcd for C37H37NO5S: C, 73.12;
H, 6.14; N, 2.30. Found: C, 72.86; H, 6.08; N, 2.45.
Eluted second was 26 (22 mg, 15%) as a syrup. [R]D -48.9
1
(c 0.8, CHCl3); H NMR (300 MHz) δ 5.32 (dd, 1 H, J 6,7 ) 5.7
Hz, J 7,8 ) 10.2 Hz, H-7), 5.27 (dd, 1 H, J 8,9 ) 3.2 Hz, J 9,10
)
1.7 Hz, H-9), 5.21 (dd, 1 H, H-8), 4.53 (bd, 1 H, J 2,NH ) 8.5 Hz,
NH), 4.19 (ddd, 1 H, J 5a,6 ) 3.1 Hz, J 5b,6 ) 11.4 Hz, H-6), 4.14-
4.01 (m, 2 H), 3.93 (dq, 1 H, J 10,11 ) 6.4 Hz, H-10), 3.91-3.82
(m, 1 H), 2.18, 2.09, 2.08, and 2.02 (4 s, 12 H, 4 Ac), 1.43 (s, 9
H, t-Bu), 1.16 (d, 3 H, 3 H-11). Anal. Calcd for C24H39NO11: C,
55.69; H, 7.60; N, 2.71. Found: C, 55.41; H, 7.48; N, 2.85.
3,7-An h yd r o-2,4,5,6-tetr a -O-ben zyl-8-d eoxy-2-C-p h en -
yl-a ld eh yd o-L-th r eo-D-gu lo-octose (33). To a stirred solution
of 32 (110 mg, 0.18 mmol) in DMF (0.6 mL) was added NaH
(15 mg, 0.36 mmol of a 60% dispersion in oil) and, after 15
min, benzyl bromide (27 µL, 0.23 mmol). The mixture was
stirred at rt for 3.5 h, then treated with CH3OH (0.5 mL),
stirred for an additional 10 min, diluted with H2O (10 mL),
and extracted with Et2O (2 × 40 mL). The combined organic
phases were dried (Na2SO4) and concentrated. The residue was
eluted from a column of silica gel with 3:1 cyclohexane-AcOEt
to give (1R)-2,6-anhydro-1,3,4,5-tetra-O-benzyl-7-deoxy-1-C-
phenyl-1-C-(2-thiazolyl)-L-glycero-D-manno-heptitol (32-Bn) as
a syrup (123 mg). 1H NMR (300 MHz, CDCl3, 55 °C) δ 7.78 (d,
1 H, J ) 3.2 Hz, Th), 7.74-7.69 (m, 2 H, Ar), 7.42-7.00 (m,
22 H, Ar, Th), 6.51-6.46 (m, 2 H, Ar), 5.26 and 4.84 (2 d, 2 H,
J ) 12.4 Hz, PhCH2), 5.02 and 4.63 (2 d, 2 H, J ) 11.4 Hz,
PhCH2), 4.88 (d, 1 H, J 2,3 ) 9.2 Hz, H-2), 4.70 and 4.60 (2 d,
2 H, J ) 11.8 Hz, PhCH2), 4.56 and 4.19 (2 d, 2 H, J ) 11.2
Hz, PhCH2), 4.29 (dd, 1 H, J 3,4 ) 8.8 Hz, H-3), 3.83 (dq, 1 H,
J 5,6 ) 0.8 Hz, J 6,7 ) 6.5 Hz, H-6), 3.77 (dd, 1 H, J 4,5 ) 2.8 Hz,
H-4), 3.75 (dd, 1 H, H-5), 1.30 (d, 3 H, 3 H-7). A solution of
32-Bn (123 mg, 0.17 mmol) and methyl triflate (29 µL, 0.25
mmol) in anhydrous CH3CN (1.7 mL) was kept at rt for 10
min, then concentrated. To a stirred suspension of the crude
N-methylthiazolium salt in CH3OH (1.7 mL) was added NaBH4
(16 mg, 0.42 mmol). The mixture was stirred at rt for an
additional 45 min, diluted with acetone, filtered through a
pad of Celite, and concentrated. A solution of the residue in
CH2Cl2 (50 mL) was washed with 1 M phosphate buffer at pH
7 (10 mL), dried (Na2SO4), and concentrated. To a vigorously
stirred solution of the thiazolidines in CH3CN (2 mL) was
added dropwise H2O (0.2 mL) and then AgNO3 in one portion
(43 mg, 0.25 mmol). The mixture was stirred at rt for 10 min,
then diluted with 1 M phosphate buffer at pH 7 (5 mL) and
partially concentrated to remove CH3CN (bath temperature
not exceeding 40 °C). The suspension was extracted with Et2O
(50 mL) and then CH2Cl2 (50 mL), and the combined organic
phases were dried (Na2SO4) and concentrated to give a yellow
syrup. A solution of the residue in Et2O (ca. 50 mL) was filtered
through a pad of Celite (1 × 3 cm, h × d) and concentrated to
give 33 (58 mg, 50% from 32) as a colorless syrup ca. 95% pure
Meth yl 7,8,9-Tr i-O-a cetyl-6,10-a n h yd r o-2-ter t-bu toxy-
ca r b on yla m in o-2,3,4,5,11-p en t a d eoxy-L-th r eo-D-id o-u n -
d econ a te (28). Compound 27 (100 mg, 0.19 mmol) was
oxidized and methylated as described for the preparation of
23 to give, after column chromatography on silica gel (2:1
cyclohexane-AcOEt), 28 (71 mg, 73%) as a foam. [R]D -52.6
1
(c 1.0, CHCl3); H NMR (400 MHz) δ 5.28 (dd, 1 H, J 6,7 ) 5.7
Hz, J 7,8 ) 10.2 Hz, H-7), 5.24 (dd, 1 H, J 8,9 ) 3.4 Hz, J 9,10
)
1.8 Hz, H-9), 5.17 (dd, 1 H, H-8), 5.01 (bd, 1 H, J 2,NH ) 8.5 Hz,
NH), 4.30 (ddd, 1 H, J 2,3a ) 4.7 Hz, J 2,3b ) 7.8 Hz, H-2), 4.16
(ddd, 1 H, J 5a,6 ) 3.2 Hz, J 5b,6 ) 11.5 Hz, H-6), 3.90 (dq, 1 H,
J 10,11 ) 6.5 Hz, H-10), 3.74 (s, 3 H, OMe), 2.15, 2.05, and 2.00
(3 s, 9 H, 3 Ac), 1.43 (s, 9 H, t-Bu), 1.13 (d, 3 H, 3 H-11). Anal.
Calcd for C23H37NO11: C, 54.86; H, 7.41; N, 2.78. Found: C,
54.63; H, 7.30; N, 2.86.
2,6-An h yd r o-3,4,5-tr i-O-ben zyl-7-d eoxy-1-C-p h en yl-a l-
d eh yd o-L-glycer o-D-m a n n o-h ep tose (31). To a cooled (-60
°C), stirred solution of â-1 (290 mg, 0.64 mmol) in anhydrous
THF (6.4 mL) was added dropwise a solution of commercially
available phenylmagnesium bromide (430 µL, 1.29 mmol,of a
3.0 M solution in Et2O) over a 15-min period. The solution was
allowed to warm to -35 °C in 1.5 h, then poured into 20 mL
of a 1 M phosphate buffer at pH 7, and extracted with Et2O (2
× 50 mL). The combined organic layers were dried (Na2SO4)
and concentrated. A mixture of the crude alcohols, activated
4-Å powdered molecular sieves (0.6 g), and anhydrous CH2Cl2
(9 mL) was stirred at rt for 10 min, and then pyridinium
chlorochromate (0.69 g, 3.20 mmol) was added. The suspension
was vigorously stirred for 60 min, then diluted with Et2O (40
mL) and cyclohexane (20 mL), stirred for an additional 5 min,
and filtered through a short pad of silica gel (3 × 1 cm, d × h)
placed in a syntherized glass filter and previously conditioned
in 1:1 Et2O-cyclohexane. Further elution with 1:1 Et2O-
cyclohexane (ca. 100 mL) gave crude 31 (0.30 g). The residue
was eluted from a column of silica gel with 6:1 cyclohexane-
AcOEt to give 31 (225 mg, 67% from â-1) as a white solid. Mp
142-143 °C (cyclohexane); [R]D -16.8 (c 1.0, CHCl3); 1H NMR
(400 MHz) δ 8.15-8.11 (m, 2 H, 2 Hortho of Ph), 7.53 (tt, 1 H,
J ) 1.2, 7.4 Hz, Hpara of Ph), 7.43-7.28, 7.20-7.16, and 7.10-
7.07 (3 m, 17 H, Ar), 5.08 and 4.73 (2 d, 2 H, J ) 11.6 Hz,
PhCH2), 4.81 and 4.77 (2 d, 2 H, J ) 11.9 Hz, PhCH2), 4.76
and 4.56 (2 d, 2 H, J ) 10.2 Hz, PhCH2), 4.47-4.44 (m, 2 H),
3.78-3.72 (m, 2 H), 3.67 (dq, 1 H, J 5,6 ) 0.6 Hz, J 6,7 ) 6.4 Hz,
1
1
by H NMR analysis. H NMR (300 MHz) δ 9.70 (s, 1 H, H-1),
7.75-7.70 (m, 2 H, Ar), 7.43-7.24 (m, 18 H, Ar), 7.14-7.01
(m, 3 H, Ar), 6.42-6.37 (m, 2 H, Ar), 5.25 and 5.08 (2 d, 2 H,
5034 J . Org. Chem., Vol. 69, No. 15, 2004

Synthesis of R- and â-L-C-Fucosyl Aldehydes
J ) 12.0 Hz, PhCH2), 5.07 and 4.67 (2 d, 2 H, J ) 11.3 Hz,
PhCH2), 4.74 and 4.66 (2 d, 2 H, J ) 11.6 Hz, PhCH2), 4.63 (d,
1 H, J 3,4 ) 9.2 Hz, H-3), 4.51 and 4.20 (2 d, 2 H, J ) 10.2 Hz,
PhCH2), 4.26 (dd, 1 H, J 4,5 ) 9.5 Hz, H-4), 3.76-3.70 (m, 2 H,
H-5, H-6), 3.66 (dq, 1 H, J 6,7 ) 0.6 Hz, J 7,8 ) 6.4 Hz, H-7),
1.32 (d, 3 H, 3 H-8).
H-7). Anal. Calcd for C37H37NO5S: C, 73.12; H, 6.14; N, 2.30.
Found: C, 72.88; H, 6.05; N, 2.42.
3,7-An h yd r o-2,4,5,6-tetr a -O-ben zyl-8-d eoxy-2-C-p h en -
yl-a ld eh yd o-L-th r eo-D-id o-octose (38). To a stirred solution
of 37 (320 mg, 0.52 mmol) in DMF (1.7 mL) was added NaH
(44 mg, 1.05 mmol of a 60% dispersion in oil) and, after 15
min, benzyl bromide (120 µL, 0.67 mmol). The mixture was
stirred at rt for 1 h, then treated with CH3OH (1 mL), stirred
for an additional 10 min, diluted with H2O (50 mL), and
extracted with Et2O (2 × 100 mL). The combined organic
phases were dried (Na2SO4) and concentrated. The residue was
eluted from a column of silica gel with 4:1 cyclohexane-AcOEt
to give (1S)-2,6-anhydro-1,3,4,5-tetra-O-benzyl-7-deoxy-1-C-
phenyl-1-C-(2-thiazolyl)-L-glycero-D-manno-heptitol (37-Bn) as
a syrup (330 mg). 1H NMR (400 MHz) δ 7.54-7.51 (m, 2 H,
Ar), 7.46 (d, 1 H, J ) 3.3 Hz, Th), 7.41-7.09 (m, 21 H, Ar,
Th), 6.77-6.73 (m, 3 H, Ar), 5.19 and 4.75 (2 d, 2 H, J ) 12.9
Hz, PhCH2), 5.12 (d, 1 H, J 2,3 ) 9.4 Hz, H-2), 5.02 and 4.60 (2
d, 2 H, J ) 11.2 Hz, PhCH2), 4.80 and 4.46 (2 d, 2 H, J ) 11.6
Hz, PhCH2), 4.69 and 4.60 (2 d, 2 H, J ) 11.7 Hz, PhCH2),
4.33 (dd, 1 H, J 3,4 ) 9.4 Hz, H-3), 3.86 (dd, 1 H, J 4,5 ) 2.6 Hz,
Meth yl 3,7-An h yd r o-2,4,5,6-tetr a -O-ben zyl-8-d eoxy-2-
C-p h en yl-L-th r eo-D-gu lo-octon a te (34). To a stirred, cooled
(0 °C) solution of 33 (43 mg, 0.07 mmol) in acetone (1.2 mL)
was added freshly prepared 1 M J ones’ reagent (210 µL, 0.21
mmol). The mixture was allowed to warm to rt in 30 min,
stirred at rt for an additional 3 h, diluted with 2-propanol (∼0.2
mL), then with brine (10 mL), and extracted with AcOEt (3 ×
25 mL). The combined organic phases were dried (Na2SO4) and
concentrated. Treatment of a solution of crude acid in 1:1
Et2O-MeOH with ethereal diazomethane at 0 °C for 5 min
gave, after column chromatography on silica gel (3:1 cyclo-
hexane-AcOEt), 34 (32 mg, 72%) as syrup. [R]D -74.3 (c 0.7,
1
CHCl3); H NMR (400 MHz) δ 7.84-7.80 (m, 2 H, Ar), 7.41-
7.16 (m, 18 H, Ar), 7.09-6.97 (m, 3 H, Ar), 6.36-6.32 (m, 2 H,
Ar), 5.26 and 5.12 (2 d, 2 H, J ) 12.1 Hz, PhCH2), 5.04 and
4.63 (2 d, 2 H, J ) 11.1 Hz, PhCH2), 4.70 and 4.62 (2 d, 2 H,
J ) 11.6 Hz, PhCH2), 4.60 (d, 1 H, J 3,4 ) 9.2 Hz, H-3), 4.40
H-4), 3.74 (dd, 1 H, J 5,6 ) 0.5 Hz, H-5), 3.71 (dq, 1 H, J 6,7
)
6.4 Hz, H-6), 1.24 (d, 3 H, 3 H-7). A solution of 37-Bn (330
mg, 0.47 mmol) and methyl triflate (80 µL, 0.70 mmol) in
anhydrous CH3CN (4.7 mL) was kept at rt for 10 min, then
concentrated. To a warmed (60 °C), stirred suspension of the
crude N-methylthiazolium salt in CH3CH2OH (4.7 mL) was
added NaBH4 (52 mg, 1.41 mmol). The mixture was stirred at
60 °C for an additional 15 min, then cooled to rt, diluted with
acetone, and concentrated. To a vigorously stirred solution of
the thiazolidines in CH2Cl2 (0.2 mL) and CH3CN (9 mL) was
added dropwise H2O (0.4 mL) and then AgNO3 in one portion
(120 mg, 0.70 mmol). The mixture was stirred at rt for 15 min,
then diluted with 1 M phosphate buffer at pH 7 (20 mL),
partially concentrated to remove CH3CN (bath temperature
not exceeding 40 °C), and extracted with Et2O (2 × 50 mL).
The combined organic phases were dried (Na2SO4) and con-
centrated to give a yellow syrup. A solution of the residue in
Et2O (ca. 100 mL) was filtered through a pad of Celite (1 × 3
cm, h × d), and concentrated to give 38 (237 mg, 70% from
37) as a white solid ca. 95% pure by 1H NMR analysis. 1H NMR
(300 MHz) δ 9.36 (s, 1 H, H-1), 7.45-7.20 (m, 25 H, 5 Ph),
5.06 and 4.66 (2 d, 2 H, J ) 11.3 Hz, PhCH2), 5.05 and 4.56 (2
d, 2 H, J ) 12.1 Hz, PhCH2), 4.96 and 4.74 (2 d, 2 H, J ) 11.0
Hz, PhCH2), 4.81 and 4.73 (2 d, 2 H, J ) 11.6 Hz, PhCH2),
4.43 (d, 1 H, J 3,4 ) 9.5 Hz, H-3), 4.36 (dd, 1 H, J 4,5 ) 8.8 Hz,
and 4.03 (2 d, 2 H, J ) 10.2 Hz, PhCH2), 4.17 (dd, 1 H, J 4,5
)
8.8 Hz, H-4), 3.72-3.67 (m, 2 H, H-5, H-6), 3.67 (s, 3 H, OMe),
3.61 (dq, 1 H, J 6,7 ) 0.6 Hz, J 7,8 ) 6.4 Hz, H-7), 1.28 (d, 3 H,
3 H-8). Anal. Calcd for C43H44O7: C, 76.76; H, 6.59. Found:
C, 76.68; H, 6.50.
2,6-An h ydr o-3,4,5-tr i-O-ben zyl-7-deoxy-1-C-(2-th iazolyl)-
a ld eh yd o-L-glycer o-D-m a n n o-h ep tose (36). To a stirred
solution of â-1 (826 mg, 1.85 mmol) in anhydrous CH2Cl2 (9.2
mL) was added dropwise 2-TST 35 in three portions (350 µL,
2.20 mmol, each) every 12 h. The solution was kept at rt for
an additional 24 h, then concentrated. To a solution of the
crude silyl ethers in freshly distilled DMSO (33 mL) was added
freshly distilled acetic anhydride (7 mL). The solution was kept
at rt for an additional 50 h, then diluted with saturated
aqueous NaHCO3 until pH 7 (ca. 50 mL), and extracted with
Et2O (200 mL). The organic phase was dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with 3:1 cyclohexane-AcOEt to give 36 (703 mg, 72%) as
a white solid. Mp 102-104 °C (cyclohexane); [R]D +17.8 (c 1.1,
CHCl3); 1H NMR (400 MHz) δ 8.04 and 7.70 (2 d, 2 H, J ) 3.0
Hz, Th), 7.41-7.28 (m, 10 H, 2 Ph), 7.18-7.14 and 6.99-6.96
(2 m, 5 H, Ph), 5.13 (d, 1 H, J 2,3 ) 9.6 Hz, H-2), 5.03 and 4.75
(2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.85 and 4.55 (2 d, 2 H, J )
11.8 Hz, PhCH2), 4.79 and 4.76 (2 d, 2 H, J ) 11.9 Hz, PhCH2),
4.41 (dd, 1 H, J 3,4 ) 9.6 Hz, H-3), 3.81 (dd, 1 H, J 4,5 ) 2.8 Hz,
H-4), 3.75-3.69 (m, 2 H, H-5, H-6), 1.20 (d, 3 H, J 6,7 ) 6.3 Hz,
3 H-7). Anal. Calcd for C31H31NO5S: C, 70.30; H, 5.90; N, 2.64.
Found: C, 70.25; H, 5.78; N, 2.71.
H-4), 3.84 (dd, 1 H, J 5,6 ) 2.7 Hz, H-5), 3.77 (dd, 1 H, J 6,7
)
0.5 Hz, H-6), 3.64 (dq, 1 H, J 7,8 ) 6.4 Hz, H-7), 1.26 (d, 3 H, 3
H-8).
3,7-An h yd r o-4,5,6-tr i-O-ben zyl-8-d eoxy-2-C-p h en yl-a l-
d eh yd o-L-th r eo-D-id o-octose (40). A solution of 37 (140 mg,
0.23 mmol) and methyl triflate (40 µL, 0.35 mmol) in anhy-
drous CH2Cl2 (0.5 mL) and CH3CN (1.8 mL) was kept at rt for
15 min, then concentrated. To a solution of the crude N-
methylthiazolium salt in CH3CH2OH (4 mL) was added NaBH4
(25 mg, 0.69 mmol). The mixture was stirred at rt for an
additional 15 min, then diluted with acetone, and concen-
trated. A solution of the residue in CH2Cl2 (50 mL) was washed
with 1 M phosphate buffer at pH 7 (2 × 10 mL), dried
(Na2SO4), and concentrated. To a vigorously stirred solution
of the thiazolidines in CH2Cl2 (0.5 mL) and CH3CN (1.8 mL)
was added dropwise H2O (0.2 mL) and then AgNO3 in one
portion (58 mg, 0.34 mmol). The mixture was stirred at rt for
15 min, then diluted with 1 M phosphate buffer at pH 7 (50
mL), partially concentrated to remove CH3CN (bath temper-
ature not exceeding 40 °C), and extracted with CH2Cl2 (2 ×
50 mL). The combined organic phases were dried (Na2SO4) and
concentrated to give a yellow syrup. The residue was eluted
from a column of silica gel with 30:1 CH2Cl2-Et2O to give 40
(103 mg, 81%) as a foam. [R]D -122.4 (c 0.9, CHCl3); 1H NMR
(300 MHz) δ 9.54 (s, 1 H, H-1), 7.59-7.54 (m, 2 H, 2 Hortho of
Ph), 7.42-7.24 (m, 18 H, Ar), 4.99 and 4.72 (2 d, 2 H, J ) 11.9
(1S)-2,6-An h yd r o-3,4,5-tr i-O-ben zyl-7-d eoxy-1-C-p h en -
yl-1-C-(2-th ia zolyl)-L-glycer o-D-m a n n o-h ep titol (37). To a
cooled (-50 °C), stirred solution of 36 (330 mg, 0.62 mmol) in
anhydrous THF (6.2 mL) was added dropwise a solution of
commercially available phenylmagnesium bromide (510 µL,
1.55 mmol of a 3.0 M solution in Et2O) over a 15-min period.
The solution was allowed to warm to -30 °C in 1 h, stirred
for an additional 1 h at -30 °C, then poured into 20 mL of a
1 M phosphate buffer at pH 7, and extracted with Et2O (2 ×
50 mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with 2:1 cyclohexane-AcOEt to give 37 (375 mg, 99%) as
a white solid. Mp 158-159 °C (AcOEt-cyclohexane); [R]D
1
-63.2 (c 0.9, CHCl3); H NMR (400 MHz) δ 7.98-7.94 (m, 2
H, Ar), 7.70 (d, 1 H, J ) 3.2 Hz, Th), 7.39-7.24 (m, 16 H, Ar,
Th), 7.14-7.10 (m, 3 H, Ar), 5.11 (s, 1 H, OH), 4.99 and 4.59
(2 d, 2 H, J ) 11.6 Hz, PhCH2), 4.83 and 4.04 (2 d, 2 H, J )
10.6 Hz, PhCH2), 4.74 and 4.63 (2 d, 2 H, J ) 11.7 Hz, PhCH2),
4.21 (d, 1 H, J 2,3 ) 9.4 Hz, H-2), 4.10 (dd, 1 H, J 3,4 ) 9.2 Hz,
H-3), 3.77 (dd, 1 H, J 4,5 ) 2.5 Hz, H-4), 3.68 (dd, 1 H, J 5,6
)
0.6 Hz, H-5), 3.53 (dq, 1 H, J 6,7 ) 6.1 Hz, H-6), 1.13 (d, 3 H, 3
J . Org. Chem, Vol. 69, No. 15, 2004 5035

Dondoni et al.
Hz, PhCH2), 4.92 and 4.34 (2 d, 2 H, J ) 10.3 Hz, PhCH2),
4.80 and 4.67 (2 d, 2 H, J ) 11.7 Hz, PhCH2), 4.20 (dd, 1 H,
J 3,4 ) 9.4 Hz, J 4,5 ) 9.2 Hz, H-4), 4.10 (d, 1 H, H-3), 3.77 (dd,
1 H, J 5,6 ) 2.6 Hz, H-5), 3.68 (dd, 1 H, J 6,7 ) 0.6 Hz, H-6), 3.47
(dq, 1 H, J 7,8 ) 6.4 Hz, H-7), 1.09 (d, 3 H, 3 H-8). Anal. Calcd
for C35H36O6: C, 76.06; H, 6.57. Found: C, 75.81; H, 6.46.
Met h yl 3,7-An h yd r o-4,5,6-t r i-O-b en zyl-8-d eoxy-2-C-
p h en yl-L-th r eo-D-id o-octon a te (41). To a vigorously stirred
solution of 40 (83 mg, 0.15 mmol) in CCl4 (0.5 mL) and
CH3OH (2.5 mL) was added solid KOH (42 mg, 0.75 mmol)
and, after 20 min, iodine (142 mg, 1.12 mmol). One more
portion of iodine (142 mg) was added after 45 min. Stirring
was continued for an additional 45 min, then the resulting
purple suspension was treated with solid KOH (42 mg, 0.75
mmol). After 20 min of stirring the reaction mixture turned a
pale yellow, thus iodine was added portionwise (2 × 142 mg,
1.12 mmol) after 45 and 90 min. Stirring was continued for
an additional 45 min, then the reaction mixture was treated
with solid NH4Cl until pH 8 and concentrated. A suspension
of the residue in AcOEt (100 mL) was washed with saturated
aqueous NH4Cl (30 mL), then 20% aqueous Na2S2O3 (2 × 30
mL), dried (Na2SO4), and concentrated. The residue was eluted
from a column of silica gel with CHCl3-Et2O (from 30:1 to
15:1) to give 41 (61 mg, 70%) as a white solid. Mp 167-169
°C (cyclohexane); [R]D -56.4 (c 1.2, CHCl3); 1H NMR (300 MHz)
δ 7.64-7.59 (m, 2 H, 2 Hortho of Ph), 7.40-7.23 (m, 18 H, Ar),
5.09 and 4.53 (2 d, 2 H, J ) 10.5 Hz, PhCH2), 4.96 and 4.70 (2
d, 2 H, J ) 12.0 Hz, PhCH2), 4.80 and 4.71 (2 d, 2 H, J ) 11.6
Hz, PhCH2), 4.35 (dd, 1 H, J 3,4 ) 9.3 Hz, J 4,5 ) 9.5 Hz, H-4),
4.23 (d, 1 H, H-3), 4.04 (br s, 1 H, OH), 3.82 (dd, 1 H, J 5,6
)
2.8 Hz, H-5), 3.70 (dd, 1 H, J 6,7 ) 1.0 Hz, H-6), 3.48 (dq, 1 H,
J 7,8 ) 6.4 Hz, H-7), 3.28 (s, 3 H, OMe), 1.02 (d, 3 H, 3 H-8).
Anal. Calcd for C36H38O7: C, 74.21; H, 6.57. Found: C, 74.40;
H, 6.43.
Ack n ow led gm en t. We thank Mr. P. Formaglio
(University of Ferrara) for assistance in the NMR
measurements and the University of Ferrara for finan-
cial support (research project 2004).
J O049406A
5036 J . Org. Chem., Vol. 69, No. 15, 2004