Concise and practical synthesis of C-glycosyl ketones from sugar benzothiazoles and their transformation into chiral tertiary alcohols

Article abstract of DOI:10.1021/jo051377w

A collection of 13 unsymmetrical ketones, each one featuring a sugar (D-glucosyl, D-galactosyl, D-mannosyl, and L-fucosyl) and an aglycone moiety (phenyl, 2-thiazolyl, TMS-ethynyl, allyl, and 1-propenyl) was prepared by a uniform route based on the use of

Full text of DOI:10.1021/jo051377w

Concise and Practical Synthesis of C-Glycosyl Ketones from Sugar
Benzothiazoles and Their Transformation into Chiral Tertiary
Alcohols
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 July 4, 2005
A collection of 13 unsymmetrical ketones, each one featuring a sugar (D-glucosyl, D-galactosyl,
D-mannosyl, and L-fucosyl) and an aglycone moiety (phenyl, 2-thiazolyl, TMS-ethynyl, allyl, and
1-propenyl) was prepared by a uniform route based on the use of benzothiazole as a carbonyl group
equivalent. Succinctly, C-glycosylbenzothiazoles readily prepared by addition of 2-lithiobenzothiazole
to sugar lactones and deoxygenation, were subjected to a one-pot reaction sequence involving
N-methylation of the heterocyclic ring by MeOTf, treatment of the N-methylbenzothiazolium salt
with a Grignard reagent, and HgCl2-promoted hydrolysis of the benzothiazoline thus formed. The
resulting ketones were isolated in yields varying from 35 to 80%. Treatment of the sugar ketones
with various organometals containing the phenyl, 2-thiazolyl, TMS-ethynyl, or ethynyl group as a
substituent afforded chiral tertiary alcohols. These addition reactions were highly stereoselective
as observed by crude NMR analysis and isolation of a single epimer in high yield in each case
examined. However, because of the complexity of the reagents involved, the stereochemical outcome
of these reactions appears to be difficult to rationalize by simple classical steric models, thus, ab
initio studies taking into account the role of the sugar fragment are advisable. An interesting
synthetic elaboration of a propargylic alcohol containing the thiazole ring into a propargylic alcohol
bearing the formyl and carboxylate groups is reported.
Introduction
methods have been developed to attain the latter goal,
which rely on internal stereoselection by stereocenters
resident in either of the reactants3 or external stereose-
lection by chiral organic molecules either in a free form
or as ligands in metal complexes.4 Recently, in connection
with our ongoing research on C-glycoside synthesis,5 we
became particularly interested in accessing the (R)- and
(S)-configured tertiary alcohols 4a and 5a bearing fuco-
syl, phenyl, and thiazolyl groups6 (Scheme 1). The
synthesis of each stereoisomer was performed starting
from the â-L-C-fucosyl aldehyde 1 and use of metalated
phenyl and thiazolyl derivatives in a reversed order.
Specifically, the (R)-epimer 4a was obtained by reaction
Asymmetric nucleophilic additions on prochiral ketones
that display a high amount of neighboring functionality
to afford tertiary alcohols in almost complete enantio-
meric purity are key processes in a multitude of complex
natural and designed product syntheses. This is notori-
ously a challenging task because, in addition to difficul-
ties inherent to the construction of the quaternary carbon
center through a highly congested transition state,1,2
there is the need to control the relative positions of the
four different substituents so that a carbon stereocenter
with the desired configuration is formed. A variety of
(1) For reviews concerning the asymmetric construction of quater-
nary carbon centers, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419.
(b) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503. (c) Fuji, K.
Chem. Rev. 1993, 93, 2037. (d) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388. (e) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591. (f) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688. (g) A. Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105.
(2) For recent papers with leading references to earlier publications,
see: (a) Burke, E. D.; Gleason, J. L. Org. Lett. 2004, 6, 405. (b) Jiang,
B.; Xu, M. Angew. Chem., Int. Ed. 2004, 43, 2543. (c) Kera¨nen, M. D.;
Eilbracht, P. Org. Biomol. Chem. 2004, 2, 1688. (d) Kennedy, J. W. J.;
Hall, D. G. J. Org. Chem. 2004, 69, 4412.
(3) (a) Huryn, D. M. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 1, p
49.
10.1021/jo051377w CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/18/2005
J. Org. Chem. 2005, 70, 9257-9268
9257

Dondoni et al.
SCHEME 1. Synthesis of the Tertiary Alcohols 4a
and 5a (Th ) 2-thiazolyl)
lacked generality and afforded ketones as R- and â-ano-
mers in low overall yields. A second reason that led us
to embark on this new piece of work stemmed from the
potential use of C-glycosylated tertiary alcohols in syn-
thetic approaches to complex glycoconjugates such as the
family of natural antitumor antibiotics altromycins9 and
flavonoids hydroxyaloins.10 Recent works by Pasetto and
Frank11a and by Koo and McDonald11b served to focus
some attention on these C-glycoconjugates while showing
the need for expeditious syntheses.
Results and Discussion
Synthesis of C-Glycosyl Ketones. In 1988, Chikash-
ita et al. reported on a new synthesis of ketones involving
2-substituted N-methylbenzothiazolium salts as key in-
termediates.12 The method followed an earlier report by
Corey13 focusing on the use of benzothiazole (BTh) as a
masked carbonyl equivalent. In fact, the Japanese group’s
synthesis relied on the easy carbon-carbon bond forma-
tion at C-2 of BTh by organometallic chemistry, followed
by nitrogen methylation, then nucleophilic addition of an
organometallic reagent to the benzothiazolium fragment,
and finally carbonyl unmasking by hydrolysis of the
benzothiazoline ring. By this method, a collection of six
ketones was prepared, all bearing an achiral hydroxy-
alkyl group. Apparently, the Chikashita synthesis of
unsymmetrical ketones did not attract a great deal of
attention over the years,14 very likely because of a
plethora of other popular methods.15 However, after our
many-year involvement with thiazole as a synthetic
auxiliary,7 we set for ourselves a program to develop the
synthesis of C-glycosyl ketones by the Chikashita reac-
tion as shown in Scheme 2. This decision was made after
several unsuccessful attempts to establish an effective
thiazole-based version of the Chikashita route because
of the lack of satisfactory addition of organometallic
reagents to N-methylthiazolium salts.16
of 1 with phenylmagnesium bromide (PhMgBr), oxidation
of the resulting alcohol to ketone 2a, and addition of
2-lithiothiazole (2-ThLi) to the latter. The (S)-epimer 5a
was instead formed by first adding 2-trimethylsilylthi-
azole (2-TST) to 1, oxidizing the alcohol to ketone 3a, and
then reacting the latter with PhMgBr. This synthesis of
ketones 2a and 3a can be viewed as a thiazole-based
route because the progenitors of the aldehyde 1 were a
protected fuconolactone derivative and 2-ThLi, the latter
serving as a masked formylating agent.7 In light of the
key role of ketones 2a and 3a as ultimate precursors to
the chiral tertiary alcohols 4a and 5a, we envisaged a
more concise and direct entry to these compounds from
fuconolactone, avoiding the intermediacy of aldehyde 1.
The new method is based on a seemingly trivial change
such as the use of benzothiazole in place of thiazole as a
masked carbonyl functionality. The resulting improved
route was successfully validated by the synthesis of other
ketones containing sugar residues of the D-gluco, D-
galacto, and D-manno series. Hence, in the present report,
we describe a benzothiazole-based route to C-glycosylated
ketones and their stereoselective transformation into
tertiary alcohols. One aim of this research was to provide
a general synthesis of C-glycosyl ketones that avoids the
chemical and stereochemical problems associated with
the introduction of an acyl group at the anomeric center
of a sugar residue. Earlier methods8 via coupling of C-1-
metalated derivatives with electrophilic acylating agents
We first examined the synthesis of the L-fucosyl
ketones 2a and 3a because this constituted a test of the
efficiency of the new method compared to that shown in
Scheme 1. The benzothiazolyl â-L-C-fucoside 10a, the
starting material according to the synthetic plan in
(4) For selected recent papers, see: (a) Dosa, P. I.; Fu, G. C. J. Am.
Chem. Soc. 1998, 120, 445. (b) Tietze, L. F.; Vo¨lkel, L.; Wulff, C.;
Weigand, B.; Bittner, C.; McGrath, P.; Johnson, K.; Scha¨fer, M. Chem.
Eur. J. 2001, 7, 1304. (c) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001,
123, 6195. (d) Waltz, K. M. Gavenonis, J.; Walsh, P. J. Angew. Chem.,
Int. Ed. 2002, 41, 3697. (e) Garc´ıa, C.; LaRochelle, L. K.; Walsh, P. J.
J. Am. Chem. Soc. 2002, 124, 10970. (f) Jeon, S.-J.; Walsh, P. J. J.
Am. Chem. Soc. 2003, 125, 9544. (g) Tian, S.-K.; Hong, R.; Deng, L. J.
Am. Chem. Soc. 2003, 125, 9900. (h) Wada, R.; Oisaki, K.; Kanai, M.,
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910. (i) Li, H.; Walsh, P.
J. J. Am. Chem. Soc. 2004, 126, 6538. (j) Ramo´n, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2004, 43, 284
(5) For reviews and recent papers, see: (a) Dondoni, A.; Marra, A.
Chem. Commun. 1999, 2133. (b) Dondoni, A. Pure Appl. Chem. 2000,
72, 1577. (c) Dondoni, A.; Marra, A. Chem. Rev. 2000, 100, 4395. (d)
Dondoni, A.; Massi, A. Mol. Diversity 2003, 6, 261. (e) Dondoni, A.,
Giovannini, P. P., Marra, A. J. Chem. Soc., Perkin Trans. 1 2001, 2380.
(f) Dondoni, A.; Marra, A.; Mizuno, M.; Giovannini, P. P. J. Org. Chem.
2002, 67, 4186. (g) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem.
2002, 67, 4475. (h) Dondoni, A.; Massi, S.; Sabbatini, S.; Bertolasi, V.
J. Org. Chem. 2002, 67, 6979. (i) Dondoni, A.; Massi, A.; Minghini, E.,
Bertolasi, V. Helv. Chim. Acta 2002, 85, 3331. (j) Dondoni, A.; Massi,
A.; Sabbatini, S.; Bertolasi, V. Tetrahedron Lett. 2004, 45, 2381. (k)
Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929.
(6) Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem. 2004, 69, 5023.
(7) For the use of thiazole as a synthetic auxiliary, see: (a) Dondoni,
A. Synthesis 1998, 1681. (b) Dondoni, A.; Marra, A. Chem. Rev. 2004,
104, 2557.
(8) (a) Frey, O.; Hoffmann, M.; Wittmann, V.; Kessler, H.; Vasella,
A. Helv. Chim. Acta 1994, 77, 2060. (b) Belosludtsev, Y. Y.; Bhatt, R.
K.; Falck, J. R. Tetrahedron Lett. 1995, 36, 5881. (c) DeShong, P.; Soli,
E. D.; Slough, G. A.; Sidler, D. R.; Elango, V.; Rybczynski, P. J.;
Vosejpka, L. J. S.; Lesse, T. A.; Le, T. X.; Anderson, G. B.; von
Philipsborn, W.; Vo¨hler, M.; Rentsch, D.; Zerbe, O. J. Organomet.
Chem. 2000, 593, 49.
(9) Brill, G. M.; Jackson, M.; Whittern, D. N.; Buko, A. M.; Hill, P.;
Chen, R. H.; McAlpine, J. B. J. Antibiot. 1994, 47, 1160.
(10) Dagne, E.; Bisrat, D.; Van Wyk, B.-E.; Viljoen, A. J. Nat. Prod.
1998, 61, 256.
(11) (a) Pasetto, P.; Franck, R. W. J. Org. Chem. 2003, 68, 8042. (b)
Koo, B.; McDonald, F. E. Org. Lett. 2005, 7, 3621.
(12) Chikashita, H.; Ishibaba, M.; Ori, K.; Itoh, K. Bull. Chem. Soc.
Jpn. 1988, 61, 3637.
(13) Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 5.
(14) From the date of publication to the present, the Chikashita
paper has received only 26 citations by other authors.
(15) (a) Waring, A. J. In Comprehensive Organic Chemistry; Barton,
D., Ollis, W. D., Eds.; Pergamon Press: Oxford, U.K., 1979; Vol. 1, p
1017. (b) Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989.
(16) The addition at low temperature (-30 to -15 °C) of PhMgBr
to the N-methylthiazolium salt derived from 2-(2,3,4,6-tetra-O-benzyl-
â-d-glucopyranosyl)thiazole followed by Ag-assisted hydrolysis led to
a complex mixture of products from which the corresponding C-glycosyl
ketone 2b was isolated in ca. 10% yield.
9258 J. Org. Chem., Vol. 70, No. 23, 2005

Concise and Practical Synthesis of C-Glycosyl Ketones
SCHEME 2. Synthesis of C-Glycosyl Ketones
through Benzothiazolium Salts
instead of a large excess of MeI allowed the N-methyla-
tion of the benzothiazole ring to be performed in a few
minutes and almost quantitatively. Finally, AgNO3 was
replaced by the more thiophilic salt HgCl2 in the carbonyl
unmasking step.19 However, the addition of 1.0 equiv of
Et3N was needed to keep the reaction mixture under
neutral conditions and allow the hydrolysis of the het-
erocycle to proceed rapidly to completion.
Encouraged by the above results, the improved ketone
synthesis was applied to benzothiazoles bearing three
common sugar residues, namely, the â-D-C-glucosyl 10b,
C-galactosyl 10c, and C-mannosyl 10d derivatives (Table
1, entries 3-13). The preparation of 10b and 10c from
1,5-glucono- and galactonolactone, respectively, and 2-BTh-
Li 7 was recently reported by us.5f,20 In a similar way,
10d was prepared from 2,3,4,6-tetra-O-benzyl-D-man-
nonolactone (see Experimental Section).21
SCHEME 3
Starting from C-glycosyl benzothiazoles 10b, 10c, and
10d, the corresponding pairs of nonsymmetrical C-
glycosyl ketones 2b and 3b (entries 3 and 4), 2c and 3c
(entries 6 and 7), and 2d and 3d (entries 9 and 10)
bearing the phenyl or 2-thiazolyl group were prepared
by the standard reaction sequence involving methylation,
Grignard addition, and hydrolysis (Table 1).21 The yields
of all isolated products were close to the average value
of ca. 70%. It is worth noting that the ketones 2c and 3b
were formed in as low a yield as only ca. 35% when pre-
pared via the thiazole route. Furthermore, as a validation
of the methodology, the addition of TMS-ethynylmagne-
sium bromide to each of the individual C-glycosylben-
zothiazoles 10b-10d was carried out to afford the
corresponding alkynyl ketones 11b-11d, although in
lower yields (35-55%). Finally, the addition of allylmag-
nesium bromide to the C-mannosylbenzothiazole 10d was
performed as well. In this case, the reaction product
varied depending on the conditions under which the
HgCl2-mediated hydrolysis was carried out. Specifically,
hydrolysis in the presence of Et3N afforded the allyl
ketone 12d (entry 12), whereas in the absence of the
amine, acid-catalyzed isomerization of the latter product
occurred to give the thermodynamically more stable
1-propenyl isomer 13d (entry 13). In summary, the
collection of C-glycosyl ketones prepared appears to
Scheme 2, was prepared by the standard method devel-
oped in our laboratory that allows the introduction of the
thiazole or benzothiazole ring at the anomeric carbon of
carbohydrates.5a-c This involved the addition of 2-lithioben-
zothiazole (2-BThLi, 7) to 2,3,4-O-benzyl-L-fuconolactone
6, followed by reductive dehydroxylation of 8a through
the O-acetate 9a (Scheme 3).
Then, the one-pot reaction sequence outlined in Scheme
2 was performed. This involved N-methylation of 10a
with methyl triflate (MeOTf), addition of the organomag-
nesium reagent RMgBr to the crude benzothiazolium
salt, and finally HgCl2-promoted hydrolysis of the C-2-
disubstituted benzothiazoline. The use of PhMgBr (Table
1, entry 1) in the second step of this sequence afforded
the ketone 2a, whereas the use of 2-ThMgBr furnished
the ketone 3a (entry 2). The overall yield of each ketone
from the lactone 6 (51 and 53%) was similar to that (50
and 54%) obtained in the thiazole route via the aldehyde
1 shown in Scheme 1. Hence, from the standpoint of
chemical efficiency, there is no difference to carrying on
the synthesis of ketones 2a and 3a by either the thiazole
or benzothiazole route. However, in general, the latter
route should be preferred because it requires a small
number of steps and avoids the intermediacy of sugar
aldehydes whose stability and manipulability can be
much lower than those of 1. Finally, the benzothiazole
route appears to be more economical owing to the lower
price of commercially available reagents compared to the
thiazole counterparts.17 It has to be pointed out that
different reagents and conditions were employed com-
pared to those in the Chikashita procedure. First, the
key for a successful synthesis was the use of the Grignard
reagents PhMgBr and 2-ThMgBr, as very poor results
were obtained with PhLi and 2-ThLi. In this respect, the
improved preparation of a simple yet useful organome-
tallic reagent such as 2-ThMgBr was crucial in this
program.18 Moreover, the use of 1.5 equiv of MeOTf
(17) This preference for benzothiazole over thiazole as a carbonyl
group equivalent should not be taken as a general rule because, in
some syntheses, the use of the latter is highly preferred if not crucial.
For comments on this issue, see footnote 144 in ref 7b above and
footnote 16 in ref 5f above.
(18) The preparation of this reagent (see Experimental Section)
required adjustments of older (Metzger, J.; Koether, B. Bull. Soc. Chim.
1953, 702) and more recent (Abarbri, M.; Thibonnet, J.; Be´rillon, L.;
Dehmel, F.; Rottla¨nder, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618)
methods, which, in fact, in our hands, produced a material that failed
to react with C-glycosyl benzothiazolium salts.
(19) Various salts with different metal cations (silver, copper,
mercury) have been employed in the hydrolysis of the thiazolidine and
benzothiazoline rings (Dondoni, A.; Marra, A.; Perrone, D. J. Org.
Chem. 1993, 58, 275). However, although AgNO3 and CuCl2/CuO are
quite effective in the thiazole route, HgCl2 gave the best results in the
benzothiazole route. Unfortunately, the latter salt is quite toxic.
(20) Dondoni, A.; Marra, A. Tetrahedron Lett. 2003, 44, 13.
(21) For the C-mannopyranoside derivatives 2d-5d and 10d-13d,
the â-D configuration was established by nOe experiments showing
substantial enhancements between the anomeric proton and the other
axial hydrogen atoms of the pyranose ring. The â-D anomeric config-
uration of the ketones 2b,c, 3b,c, and 11b,c and the alcohols 4b,c,
5b,c, and 14b-20b was assigned on the basis of the large vicinal
coupling constants (ca. 9 Hz) between the anomeric hydrogen atom
(H-2) and H-3.
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Dondoni et al.
TABLE 1. C-Glycosyl Ketones Prepared by the Reaction Sequence Shown in Scheme 2 (BTh ) 2-benzothiazolyl; Th )
2-thiazolyl)
a Isolated yields in parentheses. b Also, the isomer 13d was isolated in 10% yield.
demonstrate that the benzothiazole-based entry to this
class of nonsymmetrical ketones bears a good degree of
generality and therefore should be extensible to the
preparation of a larger library of these compounds.
Synthesis of C-Glycosyl Tertiary Alcohols. Whereas
the highly stereoselective addition of 2-ThLi to the
C-fucosyl ketone 2a and the addition of PhMgBr to 3a
to give the epimer tertiary alcohols 4a and 5a, respec-
tively (Scheme 1), were described in our earlier paper,6
we were delighted to observe that similarly effective
addition reactions occurred with other C-glycosyl ketones
reported in Table 1. Hence, the glucosyl derivatives 2b
and 3b were transformed into the pair of (S)- and (R)-
epimers 4b and 5b, the galactosyl derivatives 2c and 3c
into the pair 4c and 5c, and the mannosyl derivatives
2d and 3d into the pair 4d and 5d (Table 2).21 Appar-
ently, these reactions occurred with high stereoselectivity
as judged by crude 1H NMR analysis and isolation in each
case of a single stereoisomer in remarkably high yield of
up to the 99% value for the alcohol 5d. The lower yields
of the two alcohols 4c and 4d (73 and 70%) with respect
to the other isomers can be ascribed to the partial
consumption of the respective ketones 2c and 2d as
shown by their presence (5-16%) in the crude reaction
mixtures. The scarce reactivity of these ketones, the low
temperature (-75 to -65 °C), and impurities in the
solution of 2-ThLi might be responsible for this result.
Experimentation with the ketone 2c showed that the use
of 2-ThMgBr at higher temperature (from -80 to 20 °C,
3 h) solved the problem, as the recorded yield was fairly
high (95%), but introduced another drawback in that the
two epimers were formed in 3:1 ratio. Given the impor-
tance of optically active propargylic alcohols as synthetic
intermediates in asymmetric syntheses,4j,22 the construc-
tion of the tertiary propargylic alcohol moiety as a carbon-
linked side chain of glucose was considered. Hence, the
pair of diastereomeric (S)- and (R)-alcohols 14b and 16b
featuring the sugar residue and the 2-thiazolyl ring as
9260 J. Org. Chem., Vol. 70, No. 23, 2005

Concise and Practical Synthesis of C-Glycosyl Ketones
TABLE 2. Chiral Tertiary Alcohols Prepared by Addition of Organometal Reagents to C-Glycosyl Ketones (Th )
2-thiazolyl)
a Isolated yields in parentheses.
the other two substituents at the quaternary carbon atom
were obtained by addition of 2-ThLi to C-glucosyl TMS-
ethynyl ketone 11b and by addition of the cerium TMS-
acetylide reagent5g to the C-glucosyl thiazolyl ketone 3b,
respectively. Also, these reactions occurred with excellent
selectivity, as demonstrated by the formation of a single
diastereoisomer in both cases. Optimized yields should
be considered those reported in Table 2 by the use of the
reagents employed because 2-ThMgBr gave only 35%
yield of 14b and other ethynyl organometals (TMS-Ct
CMgBr, HCtMgBr, TMS-CtCLi) produced 16b in 20%
yield or even lower values. The second pair of tertiary
(R)- and (S)-propargylic alcohols 18b and 19b in which
the phenyl ring was the fourth substituent at the
quaternary carbon atom were obtained by addition of
ethynyl and phenyl Grignard reagents to the suitable
sugar ketones 2b and 11b, respectively.21 Also in these
cases, the yields were quite satisfactory, and the dia-
steroselectivity was practically complete. It is worth
noting that the TMS group was easily removed from the
substituted propargylic alcohols 14b, 16b, and 19b upon
treatment with KOH in MeOH-CH2Cl2, thus affording
the desilylated products 15b, 17b, and 20b in almost
quantitative yields.
The absolute configurations of the C-1 quaternary
carbon atom of alcohols 4b-d and 5b-d, all featuring a
5C2 conformation, were assigned by mono- and bidimen-
sional nuclear Overhauser effect (nOe) experiments. The
(1S)-configured alcohols 4b and 5d appeared to adopt a
preferential conformation where the 2-thiazolyl ring was
anti to H-2 and the OH group anti to the C-2-O-6 bond
(Figure 1). This arrangement was mainly deduced by the
strong nOe between OH-1 and both H-2 and H-3, in the
case of 4b, and both H-3 and the benzylic protons of the
BnO group at C-3, in the case of 5d. Moreover, the NMR
spectra of these alcohols showed a significant nOe
between the Hortho of the phenyl ring at C-1 and H-2. The
absence of nOe between the latter aromatic protons and
H-3 or the benzylic protons of the BnO group at C-3
supported the conformation proposed for 4b and 5d. The
nOe observed between OH-1 and H-3 and between the
(22) For recent papers with leading references, see: (a) Frantz, D.
E.; Fa¨ssler, R., Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
33, 373. (b) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2003, 5, 3197.
(c) Li, M.; Zhu, X. Z.; Yuan, K.; Cao, B. X.; Hou, X. L. Tetrahedron:
Asymm. 2004, 15, 219. (d) Xu, Z. Q.; Chen, C.; Xu, J. K.; Miao, M. B.;
Yan, W. J.; Wang, R. Org. Lett. 2004, 6, 1193. (e) Dahmen, S. Org.
Lett. 2004, 6, 2113. (f) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc.
2004, 126, 12432. (g) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem.
Soc. 2005, 127, 6170. (h) Raminelli, C.; da Silva, N. C.; Dos Santos, A.
A.; Porto, A. L. M.; Andrade, L. H.; Comasseto, J. V. Tetrahedron 2005,
61, 409. (i) Han, Z. J.; Wang, R.; Zhou, Y. F.; Liu, L. Eur. J. Org. Chem.
2005, 934.
H
ortho of the phenyl ring at C-1 and H-2 of compounds 4c
J. Org. Chem, Vol. 70, No. 23, 2005 9261

Dondoni et al.
2-ThLi and PhMgBr, respectively, to give to the alcohols
(R)-4a and (S)-5a, whereas the C-glucosyl pair 2b and
3b reacted with the same organometallic reagents to give
to the alcohols (S)-4b and (R)-5b. Moreover, it can be
observed that ketones 2b-d and 3b-d featuring the
pyranose ring in the same 4C1 conformation and display-
ing the same absolute configuration (â-D) at the carbon
atom adjacent to the carbonyl function, did not produce
identically configured tertiary alcohols 4b-d and 5b-
d, respectively (Table 2). Also quite intriguing is the
observation that the L-fucosyl ketones 2a and 3a, i.e.,
7-deoxy enantiomers of the D-galactosyl ketones 2c and
3c, did not show opposite stereochemical outcome in
reactions with the same organometals 2-ThLi and Ph-
MgBr, as both pairs of ketones led to alcohols with the
same (R)- and (S)-configuration, i.e., (R)-4a and (S)-5a
from the former pair and (R)-4c and (S)-5c from the
latter. Hence, from these observations, it appears that
the sugar residue plays an important and rather complex
role in the stereochemical outcome of the addition of
organometallic reagents to C-glycosyl ketones. Because
of the complexity of the substrates as well as the different
natures of the organometallic reagents employed, the
stereochemical outcome of the reactions is hard to
rationalize by simple classical steric models.23 In line with
the modern trend focusing on ab initio studies,24 we plan
to provide some insight into the transition states occur-
ring in the above nucleophilic additions to C-glycosyl
ketones by an ab initio approach that is underway in our
laboratory.
FIGURE 1. Nuclear Overhauser effects observed for the
tertiary alcohols shown in Table 2.
and 4d indicated a (1R)-configuration for these alcohols
adopting the conformation depicted in Figure 1. Unfor-
tunately, the nOe experiments indicated a free rotation
about the C-glycosidic bond of the alcohols 5b and 5c, so
their configurations were indirectly assigned as those of
the epimers of 4b and 4c, respectively.
Conclusions
Although the development of a new and effective
synthesis of important C-glycoconjugates such as C-
glycosyl ketones based on benzothiazole chemistry was
a key issue in this program, the use of these ketones as
substrates leading to C-glycosylated tertiary alcohols
appeared to be the most attractive result from this work.
Quite noteworthy is the high level of diastereofacial
selectivity occurring in the addition of organometal
reagents to the above ketones and through which chiral
tertiary alcohol fragments carbon linked to the anomeric
center of various sugars were assembled. The nonsugar
residues that were present in these alcohols were pre-
cious tools for convenient synthetic elaborations. For
instance, the presence of the thiazole ring was not
fortuitous, as this heterocycle was deliberately introduced
with the aim of exploiting its potential as a formyl group
equivalent.7 A demonstration of the useful service of this
heterocycle was reported in our recent paper6 showing
the transformation of 4a and 5a (see Scheme 1) into the
corresponding L-fucosyl phenylhydroxy acetates. The
reaction sequence shown in Scheme 4 is also centered
on the use of the thiazole ring as a formyl group
Similar NMR experiments allowed the tentative at-
tribution of the absolute configuration at C-1 of the
propargylic alcohols 17b, 18b, and 20b (Figure 1),
whereas that of 15b could only be deduced as being the
opposite of 17b. In particular, the presence of a weak nOe
between the acetylenic hydrogen atom and H-3, as well
as the concomitant lack of nOe between the former atom
and the anomeric proton H-2, indicated that the acetylene
moiety was anti to H-2 in all three cases. Moreover, the
spectra of 17b and 18b showed a strong nOe between
OH-1 and H-2, as well as medium nOes between the
former atom and both H-3 and the benzylic protons of
the BnO group at C-3. These effects suggested that OH-1
was anti to the C-2-O-6 bond and therefore that the
configuration of these alcohols was 1R (Figure 1). On the
other hand, OH-1 of 20b showed a substantial nOe only
with H-2 and the Hortho of the phenyl ring at C-1. This
finding, together with the strong nOe observed between
the latter aromatic protons and H-2, indicated that the
phenyl ring at C-1 was anti to the C-2-O-6 bond. The
conformation deduced by the NMR data (Figure 1) led
us to assign the (1S)-configuration to the alcohol 20b.
(23) (a) Cram models: Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem.
Soc. 1952, 74, 5828. (b) Cornforth dipolar model: Cornforth, J. W.;
Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112. (c)
Karabatsos model: Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367.
(d) Felkin model: Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron
Lett. 1968, 2199. For a review, see: Mengel, A.; Reiser, O. Chem. Rev.
1999, 99, 1191.
(24) (a) Yamazaki, S.; Yamabe, S. J. Org. Chem. 2002, 67, 9346. (b)
Takahashi, O.; Saito, K.; Kohno, Y.; Suezawa, H.; Ishihara, S.; Nishio,
M. New J. Chem. 2004, 28, 355.
Each pair of C-glycosyl ketones bearing the same sugar
fragment appears to undergo the addition of various
organometallic reagents to the same carbonyl diastereo-
face. However, the sense of diastereofacial selectivity
varied with the type of sugar residue. For example, the
pair of the L-fucosyl ketones 2a and 3a reacted with
9262 J. Org. Chem., Vol. 70, No. 23, 2005

Concise and Practical Synthesis of C-Glycosyl Ketones
of nBuLi (1.7 mL of a 1.6 M solution in hexane, 2.70 mmol) in
anhydrous Et2O (6 mL) was added dropwise a solution of
freshly distilled benzothiazole (0.30 mL, 2.70 mmol) in anhy-
drous Et2O (3 mL) over a 15-min period. The yellow solution
was stirred at -70 °C for 30 min, and then a solution of
fuconolactone 6 (842 mg, 1.95 mmol) in anhydrous Et2O (6 mL)
was added slowly (15 min). After an additional 1 h at -70 °C,
the mixture was allowed to warm to -50 °C in 1 h and then
poured into 30 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 concentrated to give crude 8a (1.23 g) as
SCHEME 4
1
a yellow-green syrup. H NMR (300 MHz): δ 8.10-8.07 and
7.89-7.86 (2m, 2H, BTh), 7.54-7.30 and 7.12-6.88 (2m, 17H,
BTh, Ar), 5.10 and 4.79 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.82 (s,
2H, PhCH2), 4.81 (bs, 1H, OH), 4.72 and 4.43 (2d, 2H, J )
11.0 Hz, PhCH2), 4.52 (d, 1H, J2,3 ) 9.7 Hz, H-2), 4.31 (dq,
1H, J4,5 ) 0.8 Hz, J5,6 ) 6.4 Hz, H-5), 4.10 (dd, 1H, J3,4 ) 2.6
Hz, H-3), 3.80 (dd, 1H, H-4), 1.28 (d, 3H, 3H-6).
equivalent. The TMS-protected propargylic alcohol 16b
containing the thiazole ring as one of the substituents
was transformed into the TMS-free chiral aldehyde 21b,
which, in turn, was oxidized to the ester 22b in good
yield. This reaction sequence provides an entry to a
special and new class of propargylic alcohols featuring a
C-glycosyl residue and a carboxylate group. The asym-
metric synthesis of structurally related but nonglycosy-
lated propargylic alcohols of this type has been recently
reported as an important achievement by Jiang and co-
workers25 via chiral amino alcohol-catalyzed nucleophilic
addition of terminal alkynes to R-ketoesters.
To a solution of crude 8a (1.23 g) in anhydrous CH2Cl2 (10
mL) were added at room temperature triethylamine (2.9 mL)
and acetic anhydride (2.1 mL). The solution was kept at room
temperature for 48 h and then concentrated. The residue was
eluted from a column of silica gel with cyclohexane/AcOEt
(from 2:1 to 1:2) to give 9a (1.02 g, 86% from 6) as a white
1
solid. Mp 147-148 °C (Et2O); [R]D ) -35.3 (c 1.0, CHCl3). H
NMR (400 MHz): δ 8.06-8.03 and 7.83-7.80 (2m, 2H, BTh),
7.47-7.28 (m, 12H, BTh, Ar), 7.15-7.12 (m, 2H, Ar), 7.09-
7.05 (m, 1H, Ar), 6.99-6.94 (m, 2H, Ar), 5.04 and 4.73 (2d,
2H, J ) 11.9 Hz, PhCH2), 4.86 and 4.79 (2d, 2H, J ) 11.8 Hz,
PhCH2), 4.56 and 4.38 (2d, 2H, J ) 11.0 Hz, PhCH2), 4.16 (app
d, 2H, J ) 0.8 Hz, H-2, H-3), 3.97 (dq, 1H, J4,5 ) 1.3 Hz,
J5,6 ) 6.4 Hz, H-5), 3.78 (app q, 1H, H-4), 2.21 (s, 3H, Ac),
1.31 (d, 3H, 3H-6). Anal. Calcd for C36H35NO6S: C, 70.91; H,
5.79; N, 2.30. Found: C, 71.08; H, 5.82; N 2.18. The anomeric
configuration of this ketose was assigned on the basis of the
nOe between the protons of the acetyl group and H-5.
Experimental Section
All moisture-sensitive reactions were performed under a
nitrogen atmosphere using oven-dried glassware. Anhydrous
solvents were dried over standard drying agents26 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. Flash column chromatography27 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 are given in
2-(2,3,4-Tri-O-benzyl-â-L-fucopyranosyl)benzothia-
zole (10a). To a stirred mixture of 9a (880 mg, 1.44 mmol),
activated 4-Å powdered molecular sieves (1.4 g), and trieth-
ylsilane (2.33 mL, 14.44 mmol) in anhydrous CH2Cl2 (24 mL)
was added TMSOTf (392 µL, 2.17 mmol). The mixture was
stirred at room temperature for 1 h, then diluted with
triethylamine (1.3 mL) and CH2Cl2 (25 mL), filtered through
Celite, and concentrated. The residue was eluted from a
column of silica gel with cyclohexane/AcOEt (from 5:1 to 3:1)
to give 10a (700 mg, 88%) as a syrup. [R]D ) +38.8 (c 1.5,
CHCl3). 1H NMR (300 MHz, C6D6): δ 8.08-8.05 (m, 1H, BTh),
7.43-7.39 (m, 2H, Ar), 7.37-7.32 (m, 3H, Ar), 7.24-7.06 and
7.03-6.92 (2m, 13H, BTh, Ar), 5.00 and 4.62 (2d, 2H, J ) 11.5
Hz, PhCH2), 4.84 (d, 1H, J1,2 ) 9.3 Hz, H-1), 4.62 and 4.54
(2d, 2H, J ) 11.5 Hz, PhCH2), 4.58 and 4.41 (2d, 2H, J ) 10.7
Hz, PhCH2), 4.42 (dd, 1H, J2,3 ) 9.3 Hz, H-2), 3.45 (dd, 1H,
J3,4 ) 2.8 Hz, H-3), 3.26 (dd, 1H, J4,5 ) 0.8 Hz, H-4), 3.12 (dq,
1H, J5,6 ) 6.3 Hz, H-5), 1.16 (d, 3H, 3H-6). Anal. Calcd for
C34H33NO4S: C, 74.02; H, 6.03; N, 2.54. Found: C, 74.20; H,
6.24; N, 2.60.
1
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 performed
by 1H-1H COSY experiments. MALDI-TOF mass spectra were
acquired using 2,6-dihydroxy-benzoic acid as the matrix.
L-Fuconolactone 628 and 2,3,4,6-tetra-O-benzyl-D-mannonolac-
tone29 were prepared by oxidation of the corresponding hemi-
acetals30,31 with pyridinium chlorochromate.32 Known33 tri-
methylsilylethynylmagnesium bromide was prepared by a
slightly modified procedure. Phenylmagnesium bromide, al-
lylmagnesium bromide, ethynylmagnesium bromide, benzo-
thiazole, and 2-bromothiazole were commercially available.
1-O-Acetyl-2,3,4-tri-O-benzyl-1-C-(2-benzothiazolyl)-r-
L-fucopyranose (9a). To a cooled (-70 °C), stirred solution
2-(2,3,4,6-Tetra-O-benzyl-â-D-mannopyranosyl)benzo-
thiazole (10d). 2,3,4,6-Tetra-O-benzyl-D-mannonolactone (5.80
g, 10.77 mmol) was allowed to react with 2-lithiobenzothiazole
as described for the preparation of 8a to give crude 2,3,4,6-
tetra-O-benzyl-1-C-(2-benzothiazolyl)-D-mannopyranose. The
crude ketose derivative was acetylated as described for the
preparation of 9a to give, after column chromatography on
silica gel (3:1 cyclohexane/AcOEt), 1-O-acetyl-2,3,4,6-tetra-O-
benzyl-1-C-(2-benzothiazolyl)-R-D-mannopyranose (6.50 g, 84%
from the perbezylated D-mannonolactone) as a white solid. Mp
133-134 °C (cyclohexane); [R]D ) +0.7 (c 1.1, CHCl3). 1H NMR
(300 MHz): δ 8.02-7.98 and 7.92-7.88 (2m, 2H, BTh), 7.50-
7.25 (m, 17H, Ar), 7.12-7.05 (m, 1H, Ar), 7.00-6.94 (m, 2H,
Ar), 6.82-6.76 (m, 2H, Ar), 4.97 and 4.70 (2d, 2H, J ) 10.7
Hz, PhCH2), 4.95 and 4.73 (2d, 2H, J ) 11.6 Hz, PhCH2), 4.85
(25) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451.
(26) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 5th ed.; Butterworth-Heinemann: Amsterdam, 2003.
(27) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(28) Gervay, J.; Flaherty, T. M.; Holmes, D. Tetrahedron 1997, 53,
16355.
(29) Aebischer, B. M.; Hanssen, H. W.; Vasella, A. T.; Schweizer,
W. B. J. Chem. Soc., Perkin Trans. 1 1982, 2139.
(30) Dejter-Juszynski, M.; Flowers, H. M. Carbohydr. Res. 1971, 18,
219.
(31) Koto, S.; Morishima, N.; Miyata, Y.; Zen, S. Bull. Chem. Soc.
Jpn. 1976, 46, 2639.
(32) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
(33) Cimarusti, C. M.; Bonner, D. P.; Breuer, H.; Chang, H. W.; Fritz,
A. W.; Floyd, D. M.; Kissick, T. P.; Koster, W. H.; Kronenthal, D.;
Massa, F.; Mueller, R. H.; Pluscec, J.; Slusarchyk, W. A.; Sykes, R. B.;
Taylor, M.; Weaver, E. R. Tetrahedron 1983, 39, 2577.
J. Org. Chem, Vol. 70, No. 23, 2005 9263

Dondoni et al.
and 4.79 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.63 and 4.18 (2d, 2H,
J ) 11.0 Hz, PhCH2), 4.59 (d, 1H, J2,3 ) 2.7 Hz, H-2), 4.35
(dd, 1H, J3,4 ) 9.5 Hz, J4,5 ) 9.7 Hz, H-4), 4.25 (dd, 1H, H-3),
4.06 (dd, 1H, J5,6a ) 4.0 Hz, J6a,6b ) 12.3 Hz, H-6a), 3.95 (dd,
2H, J5,6b ) 1.6 Hz, H-6b), 3.92 (ddd, 1H, H-5), 2.11 (s, 3H, Ac).
Anal. Calcd for C43H41NO7S: C, 72.15; H, 5.77; N, 1.96.
Found: C, 72.23; H, 5.83; N, 1.82. The anomeric configuration
of this ketose was assigned on the basis of the nOes between
the protons of the acetyl group and both H-3 and H-5.
The ketose acetate (1.16 g, 1.62 mmol) was deoxygenated
as described for the preparation of 10a to give, after column
chromatography on silica gel (from 7:1:1 to 3:1:1 cyclohexane/
AcOEt/CH2Cl2), 10d (0.88 g, 83%) as a white solid. Mp 129-
130 °C (cyclohexane/pentane); [R]D ) +18.4 (c 1.2, CHCl3). 1H
NMR (300 MHz): δ 7.96-7.92 (m, 2H, BTh), 7.54-7.48 (m,
1H, Ar), 7.45-7.24 (m, 21H, Ar), 4.97 and 4.66 (2d, 2H, J )
10.8 Hz, PhCH2), 4.93 (d, 1H, J1,2 ) 1.3 Hz, H-1), 4.83 and
4.72 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.82 and 4.70 (2d, 2H, J )
11.7 Hz, PhCH2), 4.68 and 4.40 (2d, 2H, J ) 11.5 Hz, PhCH2),
4.56 (dd, 1H, J2,3 ) 2.6 Hz, H-2), 4.13 (dd, 1H, J3,4 ) 9.3 Hz,
J4,5 ) 9.7 Hz, H-4), 3.91 (d, 2H, J5,6 ) 3.5 Hz, 2 H-6), 3.87 (dd,
1H, H-3), 3.75 (dt, 1H, H-5). Anal. Calcd for C41H39NO5S: C,
74.86; H, 5.98; N, 2.13. Found: C, 74.98; H, 6.07; N, 2.01.
Preparation of the Thiazolylmagnesium Bromide So-
lution (ca. 0.5 M). To a cooled (0 °C), stirred solution of
ethylmagnesium bromide (3.34 mL of a 3 M solution in Et2O,
10.0 mmol) in anhydrous THF (16 mL) was added dropwise
freshly distilled 2-bromothiazole (900 µL, 10.00 mmol) over a
5-min period. The pale yellow solution was stirred for 30 min
at 0 °C and then allowed to warm to 20 °C in 30 min and
stirred for an additional 1 h. The resulting deep red solution
was stored at 25 °C and used within 8 h. Upon prolonged
storage at room temperature, the solution turned to a black
suspension.
and concentrated. The residue was eluted from a column of
silica gel with 8:1 toluene/AcOEt to give 2a (71 mg, 68%) as a
white solid. The physical and spectroscopic data of 2a were
identical to those of the product prepared by another route.6
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-aldehydo-
D-glycero-D-gulo-heptose (2b). Compound 10b (500 mg, 0.76
mmol) was treated as described for the preparation of 2a to
give, after column chromatography on silica gel (6:1 cyclohex-
ane/AcOEt), 2b (334 mg, 70%) as a white solid. Mp 99-100
°C (MeOH); [R]D ) +16.1 (c 0.7, CHCl3). 1H NMR (300 MHz):
δ 8.12-8.08 (m, 2H, Ar), 7.63-7.58 (m, 1H, Ar), 7.50-7.44 (m,
2H, Ar), 7.38-7.18 (m, 18H, Ar), 7.06-7.00 (m, 2H, Ar), 4.96
(s, 2H, PhCH2), 4.88 and 4.63 (2d, 2H, J ) 10.8 Hz, PhCH2),
4.74 and 4.62 (2d, 2H, J ) 10.5 Hz, PhCH2), 4.67 (d, 1H,
J2,3 ) 9.5 Hz, H-2), 4.58 and 4.52 (2d, 2H, J ) 11.8 Hz, PhCH2),
4.07 (dd, 1H, J3,4 ) 9.0 Hz, H-3), 3.92-3.85 (m, 1H), 3.82-
3.67 (m, 4H). Anal. Calcd for C41H40O6: C, 78.32; H, 6.41.
Found: C, 78.18; H, 6.35.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-aldehydo-
D-glycero-L-manno-heptose (2c). Compound 10c (487 mg,
0.74 mmol) was treated as described for the preparation of 2a
to give, after column chromatography on silica gel (5:1 cyclo-
hexane/AcOEt), 2c (350 mg, 75%) as a white solid. Mp 103-
105 °C (cyclohexane); [R]D ) +7.5 (c 0.8 CHCl3). 1H NMR (400
MHz): δ 8.12-8.07 (m, 2H, Ar), 7.56-7.51 (m, 1H, Ar), 7.41-
7.24 (m, 17H, Ar), 7.19-7.15 (m, 3H, Ar), 7.04-7.00 (m, 2H,
Ar), 5.04 and 4.64 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.81 and 4.75
(2d, 2H, J ) 11.7 Hz, PhCH2), 4.75 and 4.52 (2d, 2H, J ) 10.5
Hz, PhCH2), 4.55 (d, 1H, J2,3 ) 9.6 Hz, H-2), 4.47 (dd, 1H,
J3,4 ) 9.5 Hz, H-3), 4.47 and 4.41 (2d, 2H, J ) 11.7 Hz, PhCH2),
4.06 (dd, 1H, J4,5 ) 2.6 Hz, J5,6 ) 0.6 Hz, H-5), 3.75 (dd, 1H,
H-4), 3.74 (ddd, 1H, J6,7a ) 5.7 Hz, J6,7b ) 7.0 Hz, H-6), 3.65
(dd, 1H, J7a,7b ) 9.5 Hz, H-7a), 3.62 (dd, 1H, H-7b). Anal. Calcd
for C41H40O6: C, 78.32; H, 6.41. Found: C, 78.22; H, 6.30.
Preparation of the Trimethylsilylethynylmagnesium
Bromide Solution (ca. 1 M). To a cooled (0 °C), stirred
solution of commercially available trimethylsilylacetylene (565
µL, 4.00 mmol) in anhydrous THF (2.7 mL) was added
dropwise ethylmagnesium bromide (1.33 mL of a 3 M solution
in Et2O, 4.00 mmol) over a 15-min period. The colorless
solution was stirred at 0 °C for 30 min and then allowed to
warm to 25 °C in 30 min and used within 3 h.
2,6-Anhydro-3,4,5-tri-O-benzyl-7-deoxy-1-C-phenyl-al-
dehydo-L-glycero-D-manno-heptose (2a). A mixture of 10a
(110 mg, 0.20 mmol), activated 4-Å powdered molecular sieves
(0.20 g), and anhydrous CH3CN (2 mL) was stirred at room
temperature for 10 min, and then methyl triflate (34 µL, 0.30
mmol) was added. The suspension was stirred at room tem-
perature for 15 min, concentrated to dryness, diluted with CH2-
Cl2, filtered through a pad of Celite, and concentrated to give
the N-methylbenzothiazolium salt as a white foam (150 mg).
To a cooled (-10 °C), stirred solution of phenylmagnesium
bromide (200 µL of a 3 M solution in Et2O, 0.60 mmol) in THF
(2.5 mL) was added a solution of the crude N-methylben-
zothiazolium salt (150 mg) in anhydrous THF (1.5 mL). The
solution was stirred for an additional 2 h at -10 °C, then
diluted with 1 M phosphate buffer at pH 7 (20 mL), and
extracted with AcOEt (2 × 50 mL). The combined organic
phases were washed with brine (2 × 20 mL), dried (Na2SO4),
and concentrated to give the corresponding benzothiazolines
as a yellow syrup (115 mg).
To a vigorously stirred solution of the crude benzothiazolines
in a CH3CN (2 mL) and CH2Cl2 (0.2 mL) mixture was added
dropwise H2O (0.2 mL) and then HgCl2 in one portion (109
mg, 0.40 mmol). The mixture was stirred at room temperature
for 15 min and then diluted with Et3N (ca. 28 µL, 0.20 mmol)
to reach pH 7. After an additional 30 min of stirring, the
mixture was diluted with 1 M phosphate buffer at pH 7 (20
mL) and partially concentrated to remove CH3CN (bath
temperature not exceeding 40 °C). The suspension was ex-
tracted with CH2Cl2 (2 × 40 mL), and the combined organic
phases were washed with 20% aqueous KI, dried (Na2SO4),
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-aldehydo-
D-glycero-D-galacto-heptose (2d). Compound 10d (600 mg,
0.91 mmol) was treated as described for the preparation of 2a
to give, after column chromatography on silica gel (6:1 cyclo-
hexane/AcOEt), 2d (366 mg, 64%) as a syrup. [R]D ) -1.8 (c
1.5, CHCl3). 1H NMR (300 MHz): δ 8.12-8.08 (m, 2H, Ar),
7.57-7.51 (m, 1H, Ar), 7.42-7.12 (m, 22H, Ar), 4.96 and 4.66
(2d, 2H, J ) 10.9 Hz, PhCH2), 4.82 and 4.53 (2d, 2H, J ) 11.2
Hz, PhCH2), 4.80 and 4.73 (2d, 2H, J ) 11.7 Hz, PhCH2), 4.64
and 4.57 (2d, 2H, J ) 12.2 Hz, PhCH2), 4.47 (dd, 1H, J2,3
)
1.3 Hz, J3,4 ) 3.0 Hz, H-3), 4.45 (d, 1H, H-2), 4.08 (dd, 1H,
J4,5 ) 9.3 Hz, J5,6 ) 9.7 Hz, H-5), 3.83 (dd, 1H, J6,7a ) 3.0 Hz,
J7a,7b ) 11.0 Hz, H-7a), 3.79 (dd, 1H, J6,7b ) 4.5 Hz, H-7b),
3.78 (dd, 1H, H-4), 3.59 (ddd, 1H, H-6). Anal. Calcd for
C41H40O6: C, 78.32; H, 6.41. Found: C, 78.11; H, 6.55.
2,6-Anhydro-3,4,5-tri-O-benzyl-7-deoxy-1-C-(2-thiazolyl)-
aldehydo-L-glycero-D-manno-heptose (3a). A mixture of
10a (110 mg, 0.20 mmol), activated 4-Å powdered molecular
sieves (0.20 g), and anhydrous CH3CN (0.20 mL) was stirred
at room temperature for 10 min, and then methyl triflate (34
µL, 0.30 mmol) was added. The suspension was stirred at room
temperature for 15 min, concentrated to dryness, diluted with
CH2Cl2, filtered through a pad of Celite, and concentrated to
give N-methylbenzothiazolium salt as a white foam (150 mg).
To a cooled (0 °C), stirred solution of thiazolylmagnesium
bromide in Et2O/THF (1.20 mL of a ca. 0.5 M solution prepared
as described above, 0.60 mmol) was added a solution of crude
N-methylbenzothiazolium salt in anhydrous THF (1.5 mL).
The mixture was allowed to warm to room temperature in 30
min, then diluted with 1 M phosphate buffer at pH 7 (20 mL),
and extracted with AcOEt (2 × 50 mL). The combined organic
phases were washed with brine (2 × 20 mL), dried (Na2SO4),
and concentrated to afford the corresponding benzothiazolines
as a yellow syrup (125 mg).
To a vigorously stirred solution of the crude benzothiazolines
in a CH3CN (2 mL) and CH2Cl2 (0.2 mL) mixture was added
dropwise H2O (0.20 mL) and then HgCl2 in one portion (109
mg, 0.40 mmol). The mixture was stirred at room temperature
9264 J. Org. Chem., Vol. 70, No. 23, 2005

Concise and Practical Synthesis of C-Glycosyl Ketones
for 1 h and then diluted with Et3N (ca. 28 µL, 0.20 mmol) to
reach pH 7. After an additional 2 h of stirring, the mixture
was diluted with 1 M phosphate buffer at pH 7 (20 mL) and
partially concentrated to remove CH3CN (bath temperature
not exceeding 40 °C). The suspension was extracted with CH2-
Cl2 (2 × 40 mL), and the combined organic phases were washed
with 20% aqueous KI, dried (Na2SO4), and concentrated. The
residue was eluted from a column of silica gel with 5:1
cyclohexane/AcOEt to give 3a (74 mg, 70%) as a white solid.
The physical and spectroscopic data of 3a were identical to
those of the product prepared by another route.6
mL) over a 15-min period. The mixture was allowed to warm
to room temperature in 30 min and then diluted with 1 M
phosphate buffer at pH 7 (20 mL) and extracted with AcOEt
(100 mL). The organic phase was washed with brine (2 × 20
mL), dried (Na2SO4), and concentrated to give the correspond-
ing benzothiazolines as a yellow syrup (640 mg).
To a vigorously stirred solution of the crude benzothiazolines
in a CH3CN (4 mL) and CH2Cl2 (2 mL) mixture was added
dropwise H2O (0.5 mL) and then HgCl2 in one portion (320
mg, 1.18 mmol). The mixture was stirred at room temperature
for 15 min and then diluted with Et3N (ca. 0.11 mL, 0.79 mmol)
to reach pH 7. After an additional 15 min of stirring, the
mixture was diluted with 1 M phosphate buffer at pH 7 (20
mL) and partially concentrated to remove CH3CN (bath
temperature not exceeding 40 °C). The suspension was ex-
tracted with CH2Cl2 (2 × 60 mL), and the combined organic
phases were washed with 20% aqueous KI, dried (Na2SO4),
and concentrated. The residue was eluted from a column of
silica gel with 7:1 cyclohexane/AcOEt to give 11b (281 mg,
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiazolyl)-al-
dehydo-D-glycero-D-gulo-heptose (3b). Compound 10b (170
mg, 0.26 mmol) was treated as described for the preparation
of 3a to give, after column chromatography on silica gel (4:1
cyclohexane/AcOEt), 3b (105 mg, 64%) as a solid. Mp 86-87
1
°C (MeOH); [R]D ) -8.6 (c 1.0, CHCl3). H NMR (400 MHz,
C6D6): δ 7.43 and 6.46 (2d, 2H, J ) 3.0 Hz, Th), 7.30-6.94
(m, 20H, Ar), 5.46 (d, 1H, J2,3 ) 9.7 Hz, H-2), 4.81 (s, 2H,
PhCH2), 4.80 and 4.63 (2d, 2H, J ) 11.2 Hz, PhCH2), 4.79 and
4.57 (2d, 2H, J ) 11.3 Hz, PhCH2), 4.40 and 4.28 (2d, 2H, J )
12.0 Hz, PhCH2), 4.34 (dd, 1H, J3,4 ) 8.8 Hz, H-3), 3.84 (dd,
1H, J4,5 ) 8.8 Hz, J5,6 ) 9.2 Hz, H-5), 3.79 (dd, 1H, H-4), 3.64
(dd, 1H, J6,7a ) 4.1 Hz, J7a,7b ) 11.2 Hz, H-7a), 3.58 (dd, 1H,
J6,7b ) 1.8 Hz, H-7b), 3.56 (ddd, 1H, H-6). Anal. Calcd for
C38H37NO6S: C, 71.79; H, 5.87; N, 2.20. Found: C, 71.58; H,
5.75; N, 2.11.
1
55%) as a syrup. [R]D ) +14.6 (c 1.5, CHCl3). H NMR (400
MHz): δ 7.39-7.28 (m, 18H, Ar), 7.24-7.20 (m, 2H, Ar), 4.89
(s, 2H, PhCH2), 4.84 and 4.62 (2d, 2H, J ) 10.8 Hz, PhCH2),
4.77 and 4.65 (2d, 2H, J ) 10.6 Hz, PhCH2), 4.65 and 4.58
(2d, 2H, J ) 12.1 Hz, PhCH2), 3.94 (d, 1H, J2,3 ) 9.5 Hz, H-2),
3.83 (dd, 1H, J3,4 ) 8.6 Hz, H-3), 3.76 (dd, 1H, J4,5 ) 8.8 Hz,
H-4), 3.74 (d, 2H, J6,7 ) 3.1 Hz, 2H-7), 3.68 (dd, 1H, J5,6 ) 9.6
Hz, H-5), 3.53 (dt, 1H, H-6), 0.18 (s, 9H, 3Me). Anal. Calcd for
C40H44O6Si: C, 74.04; H, 6.83. Found: C, 73.81; H, 6.96.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiazolyl)-al-
dehydo-D-glycero-L-manno-heptose (3c). Compound 10c
(1.60 g, 2.43 mmol) was treated as described for the prepara-
tion of 3a to give, after column chromatography on silica gel
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-trimethylsilyl-
ethynyl-aldehydo-D-glycero-L-manno-heptose (11c). Com-
pound 10c (743 mg, 1.13 mmol) was treated as described for
the preparation of 11b to give, after column chromatography
on silica gel (6:1:1 cyclohexane/AcOEt/CH2Cl2), 11c (403 mg,
55%) as a syrup. [R]D ) +2.8 (c 0.5, CHCl3). 1H NMR (400
MHz): δ 7.41-7.25 (m, 20H, Ar), 5.00 and 4.63 (2d, 2H, J )
11.8 Hz, PhCH2), 4.88 and 4.70 (2d, 2H, J ) 10.5 Hz, PhCH2),
4.79 and 4.73 (2d, 2H, J ) 11.7 Hz, PhCH2), 4.52 and 4.45
(2d, 2H, J ) 11.8 Hz, PhCH2), 4.26 (dd, 1H, J2,3 ) 9.6 Hz,
J3,4 ) 9.4 Hz, H-3), 4.02 (dd, 1H, J4,5 ) 2.8 Hz, J5,6 ) 0.5 Hz,
H-5), 3.91 (d, 1H, H-2), 3.68 (dd, 1H, H-4), 3.67-3.62 (m, 3H,
H-6, 2H-7), 0.20 (s, 9H, 3Me). Anal. Calcd for C40H44O6Si: C,
74.04; H, 6.83. Found: C, 73.88; H, 6.92.
(4:1 cyclohexane/AcOEt), 3c (1.00 g, 65%) as a syrup. [R]D
)
-5.5 (c 0.8, CHCl3). 1H NMR (300 MHz): δ 8.05 and 7.71 (2d,
2H, J ) 3.0 Hz, Th), 7.41-7.24 (m, 15H, Ar), 7.20-7.14 (m,
3H, Ar), 6.98-6.94 (m, 2H, Ar), 5.18 (d, 1H, J2,3 ) 9.7 Hz, H-2),
5.01 and 4.68 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.86 and 4.54
(2d, 2H, J ) 10.8 Hz, PhCH2), 4.80 and 4.74 (2d, 2H, J ) 11.5
Hz, PhCH2), 4.46 and 4.40 (2d, 2H, J ) 11.7 Hz, PhCH2), 4.43
(dd, 1H, J3,4 ) 9.5 Hz, H-3), 4.07 (dd, 1H, J4,5 ) 2.8 Hz, J5,6
)
0.7 Hz, H-5), 3.84 (dd, 1H, H-4), 3.82 (dt, 1H, J6,7 ) 6.4 Hz,
H-6), 3.62 (d, 2H, 2H-7). Anal. Calcd for C38H37NO6S: C, 71.79;
H, 5.87; N, 2.20. Found: C, 71.61; H, 5.96; N, 2.03.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiazolyl)-al-
dehydo-D-glycero-D-galacto-heptose (3d). Compound 10d
(600 mg, 0.91 mmol) was treated as described for the prepara-
tion of 3a to give, after column chromatography on silica gel
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-trimethylsilyl-
ethynyl-aldehydo-D-glycero-D-galacto-heptose (11d). Com-
pound 10d (269 mg, 0.41 mmol) was treated as described for
the preparation of 11b to give, after column chromatography
on silica gel (5:1:1 cyclohexane/AcOEt/toluene), 11d (94 mg,
35%) as a syrup. [R]D ) +5.7 (c 0.8, CHCl3). 1H NMR (300
MHz): δ 7.42-7.20 (m, 20H, Ar), 4.94 and 4.64 (2d, 2H, J )
11.2 Hz, PhCH2), 4.90 and 4.63 (2d, 2H, J ) 10.8 Hz, PhCH2),
4.80 and 4.74 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.78 and 4.58
(2d, 2H, J ) 11.5 Hz, PhCH2), 4.46 (dd, 1H, J2,3 ) 1.3 Hz,
J3,4 ) 2.9 Hz, H-3), 4.04 (dd, 1H, J4,5 ) 9.3 Hz, J5,6 ) 10.0 Hz,
H-5), 3.97 (d, 1H, H-2), 3.88 (d, 2H, J6,7 ) 3.5 Hz, 2H-7), 3.70
(dd, 1H, H-4), 3.54 (dt, 1H, H-6), 0.20 (s, 9H, 3Me). Anal. Calcd
for C40H44O6Si: C, 74.04; H, 6.83. Found: C, 73.80; H, 6.89.
1-C-Allyl-2,6-anhydro-3,4,5,7-tetra-O-benzyl-aldehydo-
D-glycero-D-galacto-heptose (12d). A mixture of 10d (1.00
g, 1.52 mmol), activated 4-Å powdered molecular sieves (1.52
g), and anhydrous CH3CN (10 mL) was stirred at room
temperature for 10 min, and then methyl triflate (260 µL, 2.28
mmol) was added. The suspension was stirred at room tem-
perature for 15 min, concentrated to dryness, diluted with CH2-
Cl2, filtered through a pad of Celite, and concentrated to give
the N-methylbenzothiazolium salt as a white foam.
(6:1 cyclohexane/AcOEt), 3d (423 mg, 73%) as a syrup. [R]D
)
+20.0 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.86 and
7.62 (2d, 2H, J ) 3.0 Hz, Th), 7.42-7.25 (m, 13H, Ar), 7.20-
7.16 (m, 2H, Ar), 7.09-7.02 (m, 5H, Ar), 5.00 (d, 1H, J2,3 ) 1.3
Hz, H-2), 4.90 and 4.59 (2d, 2H, J ) 10.7 Hz, PhCH2), 4.82
and 4.76 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.74 (dd, 1H, J3,4
)
2.7 Hz, H-3), 4.73 and 4.50 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.66
(s, 2H, PhCH2), 3.99 (dd, 1H, J4,5 ) J5,6 ) 9.5 Hz, H-5), 3.88
(dd, 1H, H-4), 3.85 (dd, 1H, J6,7a ) 2.2 Hz, J7a,7b ) 11.0 Hz,
H-7a), 3.81 (dd, 1H, J6,7b ) 5.7 Hz, H-7b), 3.63 (ddd, 1H, H-6).
Anal. Calcd for C38H37NO6S: C, 71.79; H, 5.87; N, 2.20.
Found: C, 71.58; H, 5.80; N, 2.08.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-trimethylsilyl-
ethynyl-aldehydo-D-glycero-D-gulo-heptose (11b). A mix-
ture of 10b (520 mg, 0.79 mmol), activated 4-Å powdered
molecular sieves (0.80 g), and anhydrous CH3CN (4 mL) was
stirred at room temperature for 10 min, and then methyl
triflate (135 µL, 1.18 mmol) was added. The suspension was
stirred at room temperature for 15 min, concentrated to
dryness, diluted with CH2Cl2, filtered through a pad of Celite,
and concentrated to give the N-methylbenzothiazolium as a
white foam.
To a cooled (0 °C), stirred solution of trimethylsilylethynyl-
magnesium bromide in THF (2.37 mL of a ca. 1 M solution
prepared as described above, 2.37 mmol) was added a solution
of crude N-methylbenzothiazolium salt in anhydrous THF (1.5
To a cooled (-30 °C), stirred solution of allylmagnesium
bromide in anhydrous THF (4.6 mL of a 1 M solution in Et2O,
4.60 mmol) was added a solution of the crude N-methylben-
zothiazolium salt in anhydrous THF (3 mL) over a 15-min
period. The mixture was stirred for an additional 1 h at -30
°C and then diluted with 1 M phosphate buffer at pH 7 (20
mL) and extracted with AcOEt (2 × 100 mL). The combined
J. Org. Chem, Vol. 70, No. 23, 2005 9265

Dondoni et al.
organic phase were washed with brine (2 × 50 mL), dried (Na2-
SO4), and concentrated to afford the corresponding benzothia-
zolines as a yellow syrup.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-D-gulo-heptitol (4b). To a cooled
(-78 °C), stirred solution of nBuLi (250 µL of a 1.6 M solution
in hexane, 0.40 mmol) in anhydrous Et2O (1 mL) was added
dropwise a solution of freshly distilled 2-bromothiazole (36 µL,
0.40 mmol) in anhydrous Et2O (0.5 mL) over a 15-min period.
The yellow solution was stirred at -75 °C for 30 min, and then
a solution of ketone 2b (130 mg, 0.20 mmol) in anhydrous Et2O
(2 mL) was added slowly (15 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 and extracted with AcOEt (2 × 50 mL). The combined
organic layers were dried (Na2SO4) and concentrated. The
residue was eluted from a column of silica gel with cyclohex-
To a vigorously stirred solution of the crude benzothiazolines
and Et3N (0.2 mL,1.52 mmol) in CH3CN (15 mL) and CH2Cl2
(5 mL) was added dropwise H2O (1.5 mL) and then HgCl2 in
one portion (618 mg, 2.28 mmol). The mixture was stirred at
room temperature for 15 min and then diluted with 1 M
phosphate buffer at pH 7 (50 mL) and partially concentrated
to remove CH3CN (bath temperature not exceeding 40 °C). The
suspension was extracted with CH2Cl2 (150 + 50 mL), and the
combined organic phases were washed with 20% aqueous KI,
dried (Na2SO4), and concentrated. The residue was eluted from
a column of silica gel with 5:1 cyclohexane/AcOEt to give first
1
ane/AcOEt (3:1) to give 4b (130 mg, 88%) as a syrup. [R]D
)
12d (640 mg, 71%) as a syrup. [a]D ) +1.9 (c 1.1, CHCl3). H
+33.2 (c 0.6, CHCl3). 1H NMR (400 MHz): δ 7.87-7.82 (m,
2H, Hortho of Ph), 7.78 (d, 1H, J ) 3.2 Hz, Th), 7.36-7.16 (m,
22H, Th, Ar), 6.90-6.85 (m, 2H, Ar), 5.09 (s, 1H, OH), 4.74
and 4.69 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.68 and 4.54 (2d, 2H,
J ) 11.1 Hz, PhCH2), 4.50 (d, 1H, J2,3 ) 7.5 Hz, H-2), 4.44
and 3.95 (2d, 2H, J ) 10.9 Hz, PhCH2), 4.42 and 4.33 (2d, 2H,
J ) 12.4 Hz, PhCH2), 3.84 (dd, 1H, J3,4 ) 7.5 Hz, H-3), 3.77
(dd, 1H, J4,5 ) 7.0 Hz, H-4), 3.68-3.61 (m, 1H, H-5), 3.60-
3.53 (m, 3H, H-6, 2H-7). Anal. Calcd for C44H43NO6S: C, 74.03;
H, 6.07; N, 1.96. Found: C, 74.20; H, 6.15; N, 1.78.
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-L-manno-heptitol (4c). (a) Com-
pound 2c (280 mg, 0.44 mmol) was treated as described for
the preparation of 4b to give, after column chromatography
on silica gel (4:1 cyclohexane/AcOEt), 4c (232 mg, 73%) as a
syrup. [R]D ) +44.2 (c 1.8, CHCl3). 1H NMR (400 MHz): δ
7.87-7.82 (m, 2H, Hortho of Ph), 7.74 (d, 1H, J ) 3.3 Hz, Th),
7.39-7.10 (m, 22H, Th, Ar), 6.82-6.77 (m, 2H, Ar), 4.94 and
4.55 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.79 (s, 1H, OH), 4.74 (d,
1H, J2,3 ) 8.9 Hz, H-2), 4.68 and 4.54 (2d, 2H, J ) 11.6 Hz,
PhCH2), 4.53 and 3.58 (2d, 2H, J ) 10.7 Hz, PhCH2), 4.27 and
4.23 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.14 (dd, 1H, J3,4 ) 8.9 Hz,
H-3), 3.96 (dd, 1H, J4,5 ) 2.8 Hz, J5,6 ) 1.0 Hz, H-5), 3.78 (ddd,
1H, J6,7a ) 6.8 Hz, J6,7b ) 5.8 Hz, H-6), 3.74 (dd, 1H, H-4),
3.52 (dd, 1H, J7a,7b ) 9.7 Hz, H-7a), 3.40 (dd, 1H, H-7b). Anal.
Calcd for C44H43NO6S: C, 74.03; H, 6.07; N, 1.96. Found: C,
74.15; H, 6.10; N, 1.88.
(b) To a cooled (-80 °C), stirred solution of ketone 2c (40
mg, 0.06 mmol) in anhydrous THF (1.0 mL) was added
dropwise a solution of thiazolylmagnesium bromide (380 µL
of a 0.5 M solution prepared as described above, 0.19 mmol)
over a 5-min period. The solution was allowed to warm to 20
°C in 3 h, then poured into 10 mL of a 1 M phosphate buffer
at pH 7, and extracted with AcOEt (2 × 30 mL). The combined
organic layers were washed with brine (2 × 30 mL), dried (Na2-
SO4), and concentrated. The residue was eluted from a column
of silica gel with 4:1 cyclohexane/AcOEt to give first 4c (33
mg, 73%). Eluted second was 5c (10 mg, 22%).
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-D-galacto-heptitol (4d). Com-
pound 2d (140 mg, 0.22 mmol) was treated as described for
the preparation of 4b to give, after column chromatography
on silica gel (5:1 cyclohexane/AcOEt), 4d (111 mg, 70%) as a
syrup. [R]D ) -16.7 (c 0.8, CHCl3). 1H NMR (400 MHz): δ
7.85-7.80 (m, 2H, Hortho of Ph), 7.65 and 7.12 (2d, 2H, J ) 2.5
Hz, Th), 7.50-7.20 (m, 23H, Ar), 5.65 (bs, 1H, OH), 5.00 and
4.10 (2d, 2H, J ) 10.3 Hz, PhCH2), 4.84 and 4.63 (2d, 2H, J )
11.0 Hz, PhCH2), 4.70 and 4.63 (2d, 2H, J ) 11.7 Hz, PhCH2),
4.52 (d, 1H, J2,3 ) 0.7 Hz, H-2), 4.45 and 4.30 (2d, 2H, J )
11.8 Hz, PhCH2), 3.98 (dd, 1H, J4,5 ) J5,6 ) 9.5 Hz, H-5), 3.77
(dd, 1H, J3,4 ) 2.5 Hz, H-3), 3.71 (dd, 1H, J6,7a ) 2.5 Hz, J7a,7b
) 11.3 Hz, H-7a), 3.68 (dd, 1H, J6,7b ) 4.0 Hz, H-7b), 3.62 (dd,
1H, H-4), 3.57 (ddd, 1H, H-6). Anal. Calcd for C44H43NO6S:
C, 74.03; H, 6.07; N, 1.96. Found: C, 74.22; H, 6.20; N, 1.81.
NMR (400 MHz): δ 7.38-7.20 (m, 20H, Ar), 5.95 (dddd, 1H,
J ) 6.8, 7.0, 10.3, and 17.0 Hz, CH2dCH), 5.16 (dddd, 1H,
J ) 1.0, 1.0, 1.0, and 10.3 Hz, CH2dCH), 5.04 (dddd, 1H, J )
1.0, 1.0, 1.0, and 17.0 Hz, CH2dCH), 4.90 and 4.48 (2d, 2H,
J ) 11.5 Hz, PhCH2), 4.89 and 4.59 (2d, 2H, J ) 11.5 Hz,
PhCH2), 4.79 and 4.68 (2d, 2H, J ) 11.7 Hz, PhCH2), 4.67 and
4.59 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.34 (dd, 1H, J2,3 ) 1.2 Hz,
J3,4 ) 3.0 Hz, H-3), 3.93 (dd, 1H, J4,5 ) J5,6 ) 9.5 Hz, H-5),
3.85 (d, 1H, H-2), 3.81 (dd, 1H, J6,7a ) 2.0 Hz, J7a,7b ) 11.0 Hz,
H-7a), 3.76 (dd, 1H, J6,7b ) 5.0 Hz, H-7b), 3.64 (dd, 1H, H-4),
3.53 (dddd, 1H, J ) 1.0, 1.0, 6.8, and 19.4 Hz, CH2dCHCH2),
3.50 (ddd, 1H, H-6), 3.40 (dddd, 1H, J ) 1.0, 1.0, 7.0, and 19.4
Hz, CH2dCHCH2). Anal. Calcd for C38H40O6: C, 77.00; H, 6.80.
Found: C, 77.18; H, 6.87. Eluted second was 13d (90 mg, 10%)
as a syrup.
2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(1-propenyl)-al-
dehydo-D-glycero-D-galacto-heptose (13d) A mixture of 10d
(100 mg, 0.15 mmol), activated 4-Å powdered molecular sieves
(0.15 g), and anhydrous CH3CN (1 mL) was stirred at room
temperature for 10 min, and then methyl triflate (26 µL, 0.23
mmol) was added. The suspension was stirred at room tem-
perature for 15 min, concentrated to dryness, diluted with CH2-
Cl2, filtered through a pad of Celite, and concentrated to give
the N-methylbenzothiazolium salt as a white foam.
To a cooled (-30 °C), stirred solution of allylmagnesium
bromide in anhydrous THF (150 µL of a 1 M solution in Et2O,
0.15 mmol) was added a solution of the crude N-methylben-
zothiazolium salt in anhydrous THF (0.5 mL) over a 15-min
period. The mixture was stirred for an additional 1 h at -30
°C and then diluted with 1 M phosphate buffer at pH 7 (5 mL)
and extracted with AcOEt (2 × 50 mL). The combined organic
phase were washed with brine (2 × 50 mL), dried (Na2SO4),
and concentrated to afford the corresponding benzothiazolines
as a yellow syrup.
To a vigorously stirred solution of the crude benzothiazolines
in a CH3CN (2 mL) and CH2Cl2 (0.2 mL) mixture was added
dropwise H2O (0.2 mL) and then HgCl2 in one portion (62 mg,
0.23 mmol). The mixture was stirred at room temperature for
1 h and then diluted with 1 M phosphate buffer at pH 7 (10
mL) and partially concentrated to remove CH3CN (bath
temperature not exceeding 40 °C). The suspension was ex-
tracted with CH2Cl2 (2 × 30 mL), and the combined organic
phases were washed with 20% aqueous KI, dried (Na2SO4),
and concentrated. The residue was eluted from a column of
silica gel with 5:1 cyclohexane/AcOEt to give 13d (72 mg, 80%)
as a syrup. [R]D ) +3.9 (c 1.0, CHCl3). 1H NMR (300 MHz): δ
7.42-7.20 (m, 20H, Ar), 7.04 (dq, 1H, J ) 6.8 and 15.5 Hz,
CH3CH), 6.81 (dq, 1H, J ) 1.5 and 15.5 Hz, C(O)CHdCH),
4.93 and 4.60 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.83 and 4.56
(2d, 2H, J ) 11.3 Hz, PhCH2), 4.77 and 4.67 (2d, 2H, J ) 11.7
Hz, PhCH2), 4.70 and 4.63 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.39
(dd, 1H, J2,3 ) 1.4 Hz, J3,4 ) 2.8 Hz, H-3), 3.94 (dd, 1H, J4,5
)
9.3 Hz, J5,6 ) 9.7 Hz, H-5), 3.91 (d, 1H, H-2), 3.84 (dd, 1H,
J6,7a ) 2.3 Hz, J7a,7b ) 11.0 Hz, H-7a), 3.79 (dd, 1H, J6,7b ) 5.5
Hz, H-7b), 3.68 (dd, 1H, H-4), 3.55 (ddd, 1H, H-6), 1.90 (dd,
3H, J ) 1.5 and 6.8 Hz, CH3CH). Anal. Calcd for C38H40O6:
C, 77.00; H, 6.80. Found: C, 77.24; H, 6.93.
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-D-gulo-heptitol (5b). To a cooled
(-80 °C), stirred solution of ketone 3b (160 mg, 0.25 mmol) in
9266 J. Org. Chem., Vol. 70, No. 23, 2005

Concise and Practical Synthesis of C-Glycosyl Ketones
anhydrous THF (2.5 mL) was added dropwise a solution of
commercially available phenylmagnesium bromide (250 µL of
a 3.0 M solution in Et2O, 0.75 mmol) over a 15 min period.
The solution was allowed to warm to -35 °C in 2 h, then
poured into 20 mL of a 1 M phosphate buffer at pH 7, and
extracted with AcOEt (2 × 50 mL). The combined organic
layers were washed with brine (2 × 30 mL), dried (Na2SO4),
and concentrated. The residue was eluted from a column of
silica gel with 3:1 cyclohexane/AcOEt to give 5b (156 mg, 87%)
as a white solid. Mp 133-134 °C (cyclohexane); [R]D ) +46.1
(c 0.6, CHCl3). 1H NMR (400 MHz): δ 7.91-7.86 (m, 2H, Hortho
of Ph), 7.70 and 7.17 (2d, 2H, J ) 3.3 Hz, Th), 7.40-7.21 (m,
21H, Ar), 7.13-7.08 (m, 2H, Ar), 5.09 (s, 1H, OH), 4.86 and
4.76 (2d, 2H, J ) 11.0 Hz, PhCH2), 4.76 and 4.58 (2d, 2H, J )
10.8 Hz, PhCH2), 4.74 and 4.17 (2d, 2H, J ) 10.8 Hz, PhCH2),
4.43 and 4.38 (2d, 2H, J ) 12.3 Hz, PhCH2), 4.32 (d, 1H,
J2,3 ) 8.6 Hz, H-2), 3.84 (dd, 1H, J3,4 ) 8.5 Hz, J4,5 ) 8.3 Hz,
H-4), 3.68 (dd, 1H, H-3), 3.62 (dd, 1H, J5,6 ) 9.5 Hz, H-5), 3.62
(d, 2H, J6,7 ) 2.6 Hz, 2H-7), 3.52 (dt, 1H, H-6). Anal. Calcd for
C44H43NO6S: C, 74.03; H, 6.07; N, 1.96. Found: C, 73.95; H,
6.01; N, 1.90.
Hz, PhCH2), 4.84 and 4.75 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.83
and 4.64 (2d, 2H, J ) 11.0 Hz, PhCH2), 4.70 (s, 1H, OH), 4.60
and 4.53 (2d, 2H, J ) 12.2 Hz, PhCH2), 4.24 (d, 1H, J2,3 ) 8.5
Hz, H-2), 3.92 (dd, 1H, J3,4 ) 8.7 Hz, H-3), 3.84 (dd, 1H, J4,5
7.6 Hz, H-4), 3.78 (dd, 1H, J6,7a ) 3.9 Hz, J7a,7b ) 11.5 Hz,
H-7a), 3.73 (dd, 1H, J6,7b ) 1.8 Hz, H-7b), 3.70 (dd, 1H, J5,6
)
)
9.5 Hz, H-5), 3.64 (ddd, 1H, H-6), 0.23 (s, 9H, 3Me). Anal. Calcd
for C43H47NO6SSi: C, 70.36; H, 6.45; N, 1.91. Found: C, 70.54;
H, 6.43; N, 1.74.
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiazolyl)-
1-C-trimethylsilylethynyl-D-glycero-D-gulo-heptitol (16b).
.
Commercially available CeCl3 7H2O (158 mg, 0.42 mmol) was
heated in a reaction flask at 120 °C/0.1 mbar for 1 h and 140
°C/0.1 mbar for 1 h and then cooled to 0 °C in a nitrogen
atmosphere, diluted with anhydrous THF (1.7 mL), stirred at
room temperature for 30 min, and then cooled to -78 °C. To
a cooled (-78 °C), stirred solution of commercially available
trimethylsilylacetylene (82 µL, 0.59 mmol) in anhydrous THF
n
(0.6 mL) was slowly added BuLi (368 µL of a 1.6 M solution
in hexane, 0.59 mmol). The solution was stirred at -78 °C for
45 min and then transferred via cannula into the stirred
suspension of CeCl3 in THF, prepared immediately before the
use. The resulting yellow mixture was stirred at -78 °C for
30 min, and then a solution of ketone 3b (107 mg, 0.17 mmol)
in anhydrous THF (1 mL) was added dropwise. The mixture
was stirred at -78 °C for an additional 15 min and then
allowed to reach room temperature in 3 h. The reaction
mixture was diluted with 0.1 M HCl (10 mL) and extracted
with AcOEt (2 × 30 mL). The combined organic layers were
washed with 1 M phosphate buffer at pH 7 (2 × 10 mL), dried
(Na2SO4), and concentrated. The residue was eluted from a
column of silica gel with 4:1 cyclohexane/AcOEt to give 16b
(102 mg, 82%) as a syrup. [R]D ) -6.9 (c 1.0, CHCl3). 1H NMR
(300 MHz): δ 7.80 (d, 1H, J ) 3.2 Hz, Th), 7.39-7.25 (m, 21H,
Th, Ar), 5.27 (bs, 1H, OH), 5.13 and 4.95 (2d, 2H, J ) 10.5
Hz, PhCH2), 5.00 and 4.92 (2d, 2H, J ) 10.9 Hz, PhCH2), 4.88
and 4.71 (2d, 2H, J ) 11.8 Hz, PhCH2), 4.53 and 4.38 (2d, 2H,
J ) 12.1 Hz, PhCH2), 4.19 (dd, 1H, J2,3 ) 9.3 Hz, J3,4 ) 9.0
Hz, H-3), 3.90 (dd, 1H, J4,5 ) 9.2 Hz, H-4), 3.87 (d, 1H, H-2),
3.76 (dd, 1H, J5,6 ) 9.7 Hz, H-5), 3.67 (dd, 1H, J6,7a ) 4.3 Hz,
J7a,7b ) 12.0 Hz, H-7a), 3.55 (dd, 1H, J6,7b ) 1.3 Hz, H-7b),
3.44 (ddd, 1H, H-6), 0.26 (s, 9H, 3Me). Anal. Calcd for C43H47-
NO6SSi: C, 70.36; H, 6.45; N, 1.91. Found: C, 70.60; H, 6.57;
N, 1.83.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-L-manno-heptitol (5c). Com-
pound 3c (200 mg, 0.31 mmol) was treated as described for
the preparation of 5b to give, after column chromatography
on silica gel (8:2:1 cyclohexane/AcOEt/CH2Cl2), 5c (182 mg,
81%) as white solid. Mp 113-115 °C (cyclohexane); [R]D
)
+63.5 (c 0.5, CHCl3). 1H NMR (300 MHz): δ 7.97-7.92 (m,
2H, Hortho of Ph), 7.66 and 7.13 (2d, 2H, J ) 3.3 Hz, Th), 7.41-
7.25 (m, 19H, Ar), 7.23-7.19 and 7.14-7.10 (2m, 4H, Ar), 5.12
(s, 1H, OH), 4.98 and 4.54 (2d, 2H, J ) 11.6 Hz, PhCH2), 4.85
and 4.06 (2d, 2H, J ) 10.6 Hz, PhCH2), 4.77 and 4.63 (2d, 2H,
J ) 11.6 Hz, PhCH2), 4.32 and 4.27 (2d, 2H, J ) 11.7 Hz,
PhCH2), 4.22 (d, 1H, J2,3 ) 9.3 Hz, H-2), 4.14 (dd, 1H, J3,4
)
9.0 Hz, H-3), 4.03 (dd, 1H, J4,5 ) 2.6 Hz, J5,6 ) 0.5 Hz, H-5),
3.80 (dd, 1H, H-4), 3.67-3.60 (m, 2H, H-6, H-7a), 3.50-3.42
(m, 1H, H-7b). Anal. Calcd for C44H43NO6S: C, 74.03; H, 6.07;
N, 1.96. Found: C, 73.90; H, 5.98; N, 1.87.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-(2-thiazolyl)-D-glycero-D-galacto-heptitol (5d). Com-
pound 3d (230 mg, 0.36 mmol) was treated as described for
the preparation of 5b to give, after column chromatography
on silica gel (4:1 cyclohexane/AcOEt), 5d (256 mg, 99%) as a
syrup. [R]D ) -28.4 (c 1.0, CHCl3). 1H NMR (400 MHz): δ 7.83
(d, 1H, J ) 3.4 Hz, Th), 7.76-7.72 (m, 2H, Hortho of Ph), 7.34-
7.10 (m, 24H, Th, Ar), 6.38 (s, 1H, OH), 5.04 and 4.17 (2d, 2H,
J ) 10.0 Hz, PhCH2), 4.85 and 4.63 (2d, 2H, J ) 10.8 Hz,
PhCH2), 4.78 and 4.73 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.49 (d,
1H, J2,3 ) 0.5 Hz, H-2), 4.40 and 4.23 (2d, 2H, J ) 11.8 Hz,
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-ethynyl-1-
C-phenyl-D-glycero-D-gulo-heptitol (18b). To a cooled (0
°C), stirred solution of ketone 2b (200 mg, 0.32 mmol) in
anhydrous THF (2 mL) was added dropwise a solution of
commercially available ethynylmagnesium bromide (1.92 mL
of a 0.5 M solution in THF, 0.96 mmol) over a 15-min period.
The solution was allowed to warm to room temperature in 30
min, stirred an additional 2 h at room temperature, then
poured into 20 mL of a 1 M phosphate buffer at pH 7, and
extracted with AcOEt (2 × 50 mL). The combined organic
layers were washed with brine (2 × 30 mL), dried (Na2SO4),
and concentrated. The residue was eluted from a column of
silica gel with 8:1 cyclohexane/AcOEt to give 18b (190 mg,
91%) as a syrup. [R]D ) +5.6 (c 2.4, CHCl3). 1H NMR (300
MHz): δ 7.73-7.68 (m, 2H, Hortho of Ph), 7.41-7.22 (m, 23H,
Ar), 5.34 (s, 1H, OH), 5.16 and 4.97 (2d, 2H, J ) 10.5 Hz,
PhCH2), 5.04 and 4.94 (2d, 2H, J ) 11.0 Hz, PhCH2), 4.84 and
4.68 (2d, 2H, J ) 11.0 Hz, PhCH2), 4.47 and 4.33 (2d, 2H, J )
11.8 Hz, PhCH2), 4.28 (dd, 1H, J2,3 ) 9.1 Hz, J3,4 ) 9.0 Hz,
H-3), 3.88 (dd, 1H, J4,5 ) 9.0 Hz, H-4), 3.74 (dd, 1H, J5,6 ) 9.7
Hz, H-5), 3.62 (dd, 1H, J6,7a ) 4.1 Hz, J7a,7b ) 11.6 Hz, H-7a),
3.50 (dd, 1H, J6,7b ) 1.4 Hz, H-7b), 3.38 (d, 1H, H-2), 3.26 (ddd,
1H, H-6), 2.82 (s, 1H, CtCH). Anal. Calcd for C43H42O6: C,
78.87; H, 6.46. Found: C, 78.70; H, 6.39.
PhCH2), 4.18 (dd, 1H, J3,4 ) 2.5 Hz, H-3), 3.98 (dd, 1H, J4,5
)
J5,6 ) 9.5 Hz, H-5), 3.79 (dd, 1H, H-4), 3.67 (dd, 1H, J6,7a ) 2.3
Hz, J7a,7b ) 12.0 Hz, H-7a), 3.63 (dd, 1H, J6,7b ) 4.8 Hz, H-7b),
3.44 (ddd, 1H, H-6). Anal. Calcd for C44H43NO6S: C, 74.03; H,
6.07; N, 1.96. Found: C, 74.28; H, 6.16; N, 1.81.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-(2-thiazolyl)-
1-C-trimethylsilylethynyl-D-glycero-D-gulo-heptitol (14b).
To a cooled (-78 °C), stirred solution of nBuLi (288 µL of a 1.6
M solution in hexane, 0.46 mmol) in anhydrous Et2O (2 mL)
was added dropwise a solution of freshly distilled 2-bromothia-
zole (40 µL, 0.46 mmol) in anhydrous Et2O (0.2 mL) over a
15-min period. The yellow solution was stirred at -75 °C for
30 min, and then a solution of ketone 11b (100 mg, 0.15 mmol)
in anhydrous Et2O (2 mL) was added slowly (15 min). After
an additional 2 h at -75 °C, the mixture was allowed to warm
to -65 °C in 40 min, then poured into 20 mL of a 1 M
phosphate buffer at pH 7, and extracted with AcOEt (2 × 50
mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with cyclohexane/AcOEt (3:1) to give 14b (69 mg, 61%) as
a syrup. [R]D ) +4.8 (c 0.8, CHCl3). 1H NMR (300 MHz): δ
7.78 and 7.16 (2d, 2H, J ) 3.2 Hz, Th), 7.38-7.18 (m, 18H,
Ar), 7.02-6.97 (m, 2H, Ar), 4.87 and 4.79 (2d, 2H, J ) 11.3
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-phenyl-1-
C-trimethylsilylethynyl-D-glycero-D-gulo-heptitol (19b).
To a cooled (-20 °C), stirred solution of ketone 11b (162 mg,
0.25 mmol) in anhydrous THF (3 mL) was added dropwise a
J. Org. Chem, Vol. 70, No. 23, 2005 9267

Dondoni et al.
solution of commercially available phenylmagnesium bromide
(250 µL of a 3.0 M solution in Et2O, 0.75 mmol) over a 15-min
period. The solution was allowed to warm to room temperature
in 1 h, then poured into 20 mL of a 1 M phosphate buffer at
pH 7, and extracted with AcOEt (2 × 30 mL). The combined
organic layers were washed with brine (2 × 30 mL), dried (Na2-
SO4), and concentrated. The residue was eluted from a column
of silica gel with 6:1 cyclohexane/AcOEt to give 19b (136 mg,
75%) as a syrup. [R]D ) +1.1 (c 0.7, CHCl3). 1H NMR (300
MHz): δ 7.75-7.70 (m, 2H, Hortho of Ph), 7.44-7.16 (m, 21H,
Ar), 6.78-6.73 (m, 2H, Ar), 4.84 and 4.70 (2d, 2H, J ) 11.0
Hz, PhCH2), 4.83 and 4.67 (2d, 2H, J ) 10.9 Hz, PhCH2), 4.74
and 4.46 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.68 and 4.62 (2d, 2H,
J ) 12.2 Hz, PhCH2), 4.41 (s, 1H, OH), 3.86-3.67 (m, 6H),
3.60 (ddd, 1H, J5,6 ) 9.2 Hz, J6,7a ) 2.0 Hz, J6,7b ) 3.8 Hz,
H-6), 0.22 (s, 9H, 3Me). Anal. Calcd for C46H50O6Si: C, 76.00;
H, 6.93. Found: C, 76.18; H, 7.01.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-ethynyl-1-
C-(2-thiazolyl)-D-glycero-D-gulo-heptitol (15b). A solution
of 14b (150 mg, 0.20 mmol) in 5:1 CH3OH/CH2Cl2 (6 mL) was
treated at room temperature for 30 min with 1 N KOH (0.4
mL), then neutralized with 1 N HCl, and concentrated to
remove the organic solvent. The residue was diluted with
AcOEt (50 mL), washed with brine, dried (Na2SO4), concen-
trated, and filtered through a short column of silica gel (1.5 ×
5 cm, d × h) with 4:1 cyclohexane/AcOEt to afford 15b (127
mg, 98%) as a syrup. [R]D ) +13.8 (c 0.5, CHCl3). 1H NMR
(400 MHz, C6D6): δ 7.43 and 6.48 (2d, 2H, J ) 3.2 Hz, Th),
7.26-7.00 (m, 20H, Ar), 5.05 (s, 1H, OH), 4.99 and 4.93 (2d,
2H, J ) 11.3 Hz, PhCH2), 4.72 and 4.67 (2d, 2H, J ) 11.3 Hz,
PhCH2), 4.68 and 4.46 (2d, 2H, J ) 11.5 Hz, PhCH2), 4.35 and
4.28 (2d, 2H, J ) 12.2 Hz, PhCH2), 4.31 (d, 1H, J2,3 ) 8.7 Hz,
H-2), 4.10 (dd, 1H, J3,4 ) 8.2 Hz, H-3), 3.67 (dd, 1H, J4,5 ) 8.3
Hz, H-4), 3.61 (dd, 1H, J5,6 ) 9.5 Hz, H-5), 3.50 (dd, 1H,
J6,7a ) 4.1 Hz, J7a,7b ) 11.6 Hz, H-7a), 3.46 (dd, 1H, J6,7b ) 2.2
Hz, H-7b), 3.36 (ddd, 1H, H-6), 2.17 (s, 1H, CtCH). Anal. Calcd
for C40H39NO6S: C, 72.59; H, 5.94; N, 2.12. Found: C, 72.41;
H, 5.82; N, 2.00.
(1R)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-ethynyl-1-
C-(2-thiazolyl)-D-glycero-D-gulo-heptitol (17b). Compound
16b (25 mg, 0.03 mmol) was desilylated as described for the
preparation of 15b and filtered through a short column of silica
gel (1 × 2 cm, d × h) with CH2Cl2 and then 10:1 CH2Cl2/AcOEt
to give 17b (22 mg, 98%) as a syrup. [R]D ) +4.6 (c 0.8, CHCl3).
1H NMR (400 MHz): δ 7.67 (d, 1H, J ) 3.1 Hz, Th), 7.26-
7.10 (m, 21H, Th, Ar), 5.23 (s, 1H, OH), 4.98 and 4.83 (2d, 2H,
J ) 10.5 Hz, PhCH2), 4.89 and 4.80 (2d, 2H, J ) 11.0 Hz,
PhCH2), 4.73 and 4.56 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.39 and
4.26 (2d, 2H, J ) 12.0 Hz, PhCH2), 4.12 (dd, 1H, J2,3 ) 9.3 Hz,
J3,4 ) 9.0 Hz, H-3), 3.78 (dd, 1H, J4,5 ) 8.9 Hz, H-4), 3.71 (d,
1H, H-2), 3.59 (dd, 1H, J5,6 ) 9.8 Hz, H-5), 3.55 (dd, 1H,
J6,7a ) 4.5 Hz, J7a,7b ) 11.7 Hz, H-7a), 3.49 (dd, 1H, J6,7b ) 1.7
Hz, H-7b), 3.34 (ddd, 1H, H-6), 2.72 (s, 1H, CtCH). Anal. Calcd
for C40H39NO6S: C, 72.59; H, 5.94; N, 2.12. Found: C, 72.71;
H, 6.02; N, 1.94.
(1S)-2,6-Anhydro-3,4,5,7-tetra-O-benzyl-1-C-ethynyl-1-
C-phenyl-D-glycero-D-gulo-heptitol (20b). Compound 19b
(38 mg, 0.05 mmol) was desilylated as described for the
preparation of 15b and filtered through a short column of silica
gel (1 × 3 cm, d × h) with 3:1 cyclohexane/AcOEt to give 20b
(33 mg, 98%) as a syrup. [R]D ) +8.7 (c 1.2, CHCl3). 1H NMR
(400 MHz): δ 7.74-7.70 (m, 2H, Hortho of Ph), 7.39-7.16 (m,
21H, Ar), 6.81-6.78 (m, 2H, Ar), 4.86 and 4.71 (2d, 2H, J )
11.5 Hz, PhCH2), 4.79 and 4.63 (2d, 2H, J ) 11.0 Hz, PhCH2),
4.74 and 4.40 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.64 and 4.60
(2d, 2H, J ) 12.0 Hz, PhCH2), 4.44 (s, 1H, OH), 3.86 (d, 1H,
J2,3 ) 9.0 Hz, H-2), 3.81-3.77 (m, 2H, 2H-7), 3.77 (dd, 1H,
J3,4 ) 8.6 Hz, J4,5 ) 8.5 Hz, H-4), 3.69 (dd, 1H, H-3), 3.64 (dd,
1H, J5,6 ) 9.7 Hz, H-5), 3.59 (ddd, 1H, J6,7a ) J6,7b ) 2.9 Hz,
H-6), 2.72 (s, 1H, CtCH). Anal. Calcd for C43H42O6: C, 78.87;
H, 6.46. Found: C, 79.02; H, 6.53.
3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-C-ethynyl-alde-
hydo-D-erythro-L-talo-octose (21b). A solution of 16b (72
mg, 0.10 mmol) and methyl triflate (17 µL, 0.15 mmol) in
anhydrous CH2Cl2 (0.5 mL) and CH3CN (0.5 mL) was kept at
room temperature for 15 min and then concentrated. To a
solution of the crude N-methylthiazolium salt in EtOH (1 mL)
was added NaBH4 (9 mg, 0.30 mmol). The mixture was stirred
at room temperature for an additional 15 min, then diluted
with acetone, and concentrated. 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 (50 mg, 0.30 mmol). The
mixture was stirred at room temperature for 15 min, then
diluted with 1 M phosphate buffer at pH 7 (20 mL), partially
concentrated to remove CH3CN (bath temperature not exceed-
ing 40 °C), and extracted with CH2Cl2 (2 × 30 mL). The
combined organic phases were dried (Na2SO4) and concen-
trated to give syrupy 21b (37 mg, 64%) at least 95% pure by
1
1H NMR analysis. H NMR (300 MHz): δ 9.41 (s, 1H, H-1),
7.40-7.18 (m, 20H, Ar), 4.99 and 4.86 (2d, 2H, J ) 11.2 Hz,
PhCH2), 4.86 and 4.44 (2d, 2H, J ) 10.4 Hz, PhCH2), 4.82 and
4.64 (2d, 2H, J ) 10.8 Hz, PhCH2), 4.67 (s, 2H, PhCH2), 4.04
(bs, 1H, OH), 3.84 (dd, 1H, J7,8a ) 1.8 Hz, J8a,8b ) 11.6 Hz,
H-8a), 3.81-3.64 (m, 5H), 3.58 (ddd, 1H, J6,7 ) 9.5 Hz, J7,8b
4.5 Hz, H-7), 2.68 (s, 1H, CtCH).
)
Methyl 3,7-Anhydro-4,5,6,8-tetra-O-benzyl-2-C-ethynyl-
aldehydo-D-erythro-L-talo-octonate (22b). To a vigorously
stirred solution of crude 21b (37 mg, 0.06 mmol) in CCl4 (0.5
mL) and CH3OH (2.5 mL) was added solid KOH (33 mg, 0.60
mmol) and, after 15 min, iodine (152 mg, 0.60 mmol). Stirring
was continued for an additional 45 min, and then the reaction
mixture was treated with solid NH4Cl until pH 8 and concen-
trated. A suspension of the residue in AcOEt (100 mL) was
washed with saturated aqueous NH4Cl (30 mL) and then 20%
aqueous Na2S2O3 (2 × 30 mL), dried (Na2SO4), and concen-
trated to give 22b (40 mg, white solid) as an adduct with HI
(MS analysis). A solution of this product and EtiPr2N (10 µL)
in toluene (1 mL) was stirred at 80 °C for 3 h and then
concentrated. The residue was eluted from a column of silica
gel with 3:1 cyclohexane/AcOEt to give pure 22b (32 mg, 85%)
1
as an amorphous solid. [R]D ) +33.8 (c 0.5, CHCl3). H NMR
(400 MHz, C6D6): δ 7.39-7.36 (m, 2H, Ar), 7.25-7.22 (m, 2H,
Ar), 7.20-6.97 (m, 16H, Ar), 4.94 and 4.47 (2d, 2H, J ) 10.6
Hz, PhCH2), 4.84 and 4.72 (2d, 2H, J ) 11.2 Hz, PhCH2), 4.71
and 4.52 (2d, 2H, J ) 11.4 Hz, PhCH2), 4.58 and 4.54 (2d, 2H,
J ) 12.0 Hz, PhCH2), 4.02 (d, 1H, J3,4 ) 9.5 Hz, H-3), 4.01 (s,
1H, OH), 3.97-3.92 (m, 1H, H-4), 3.76 (dd, 1H, J7,8a ) 1.7 Hz,
J8a,8b ) 11.6 Hz, H-8a), 3.68-3.61 (m, 3H, H-5, H-6, H-8b),
3.48-3.43 (m, 1H, H-7), 3.08 (s, 3H, OMe), 2.05 (s, 1H, Ct
CH). Anal. Calcd for C39H40O8: C, 73.56; H, 6.33. Found: C,
73.35; H, 6.24.
Acknowledgment. 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).
JO051377W
9268 J. Org. Chem., Vol. 70, No. 23, 2005