Highly Stereoselective de Novo Synthesis of l -Hexoses

Article abstract of DOI:10.1021/jo100077k

Figure presented An efficient and general de novo synthetic route to enantiomerically pure l-hexoses has been accomplished starting from the heterocyclic homologating agent 5,6-dihydro-1,4-dithiin-2-yl[(4-methoxybenzyl) oxy]methane and methyl α,β-isopropylidene-l-glycerate. The sugar scaffold was constructed by an acid-catalyzed domino reaction, which enabled selective preparation of either methyl 2,3-dideoxy-α-l-threo-hex-2- enopyranosides or 1,6-anhydro-2,3-dideoxy-β-l-threo-hex-2-enopyranose as key intermediates. The subsequent double bond functionalization by syn or anti dihydroxylation reactions allowed introduction of the remaining stereogenic centers, leading to desired orthogonally protected l-hexopyranosides with a high degree of diastereoselectivity and with very good overall yields. These and previous results (based on the use of the corresponding l-erythro epimers) contribute to make our approach general and place it among the few methods able to synthesize the whole series of the rare l-hexoses.

Full text of DOI:10.1021/jo100077k

pubs.acs.org/joc
Highly Stereoselective de Novo Synthesis of L-Hexoses
Annalisa Guaragna,*,† Daniele D’Alonzo,† Concetta Paolella,† Carmela Napolitano,‡ and
Giovanni Palumbo†
†
ꢀ
Dipartimento di Chimica Organica e Biochimica, Universita di Napoli Federico II-Complesso Universitario
Monte Sant’Angelo, via Cinthia, 4 I-80126 Napoli, Italy, and ‡School of Chemistry, National University of
Ireland, University Road, Galway, Ireland
annalisa.guaragna@unina.it
Received January 17, 2010
An efficient and general de novo synthetic route to enantiomerically pure L-hexoses has been accomplished
starting from the heterocyclic homologating agent 5,6-dihydro-1,4-dithiin-2-yl[(4-methoxybenzyl)oxy]-
methane and methyl R,β-isopropylidene-L-glycerate. The sugar scaffold was constructed by an acid-
catalyzed domino reaction, which enabled selective preparation of either methyl 2,3-dideoxy-R-L-threo-
hex-2-enopyranosides or 1,6-anhydro-2,3-dideoxy-β-L-threo-hex-2-enopyranose as key intermediates. The
subsequent double bond functionalization by syn or anti dihydroxylation reactions allowed introduction
of the remaining stereogenic centers, leading to desired orthogonally protected L-hexopyranosides with a
high degree of diastereoselectivity and with very good overall yields. These and previous results (based on
the use of the corresponding L-erythro epimers) contribute to make our approach general and place it
among the few methods able to synthesize the whole series of the rare L-hexoses.
Introduction
life-essential metabolic processes, in signal transduction and
in immune response.2 Their involvement in health and dis-
ease events make them an attractive subject for chemical,
pharmacological, and biological research.3 In addition, in
modern organic synthesis carbohydrates are both target
molecules3d and sources of enantiopure building blocks,4
chiral auxiliaries,5 and catalysts.6
Over the past decades, carbohydrates have been at the core
of a huge body of investigations, given their abundance in
nature and their importance in chemistry, biology, and
medicine.1 Indeed, carbohydrates play diverse and crucial
roles in biological systems, as they are implicated in many
(1) (a) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
Sinay, P., Eds.; Wiley-VCH: New York, 2000. (b) The Organic Chemistry of
Sugars; Levy, D. E., F€ugedi, P., Eds.; Marcel Dekker: New York, 2006.
(2) (a) Glycochemistry: Principles, Synthesis, and Applications; Wang, P.,
Bertozzi, C., Eds.; Marcel Dekker: New York, 2001. (b) Dwek, R. A. Chem. Rev.
1996, 96, 683–720. (c) Sznaidman, M. In Bioorganic Chemistry: Carbohy-
drates; Hecht, S. M., Ed.; Oxford University Press: New York, 1999; pp 1-56. (d)
Varki, A. Glycobiology 1993, 3, 97–130. (e) Davis, B. G. J. Chem. Soc., Perkin
Trans. 1 1999, 3215–3237.
(3) (a) Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. J. Med.
Chem. 2009, 52, 5561–5577. (b) Ernst, B.; Magnani, J. L. Nat. Rev. Drug
Discov. 2009, 8, 661–677. (c) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem.,
Int. Ed. 2001, 113, 1625–1672. (d) Nicolaou, K. C.; Mitchell, H. J. Angew.
Chem., Int. Ed. 2001, 40, 1576–1624. (e) Carbohydrate Mimics; Chapleur, Y.,
Ed.; Wiley-VCH: Weinheim, 1998. (f) Koeller, K. M.; Wong, C.-H. Nat.
Biotechnol. 2000, 18, 835–841. (g) Werz, D. B.; Seeberger, P. H. Chem.;Eur.
J. 2005, 11, 3194–3206.
(4) (a) Murphy, P. V. Eur. J. Org. Chem. 2007, 4177-4187 and references
therein. (b) Carbohydrate Building Blocks; Bols, M., Ed.; John Wiley & Sons:
New York, 1996. (c) Kunz, H.; R€uck, K. Angew. Chem., Int. Ed. 1993, 32, 336–
358.
(5) (a) Boysen, M. M. K. Chem.;Eur. J. 2007, 13, 8648–8659.
(b) Kunz, H. In Asymmetric Synthesis-The Essentials; Christmann, H.,
€
Brase, M. S., Eds.; Wiley-VCH Weinheim, 2007, 32-36. (c) Pleuss, N.;
Zech, G.; Furman, B.; Kunz, H. In The Organic Chemistry of Sugars; Levy.
D., F€ugedi, P., Eds.; Marcel Dekker: New York, 2006; pp 427-488.
(d) Lichtenthaler, F. W. In Carbohydrate Synthons in Natural Product Chem-
istry; Witczak, Z. J., Tatsuta, K., Eds.; ACS Symposium Series 841; American
Chemical Society: Washington, DC, 2003; pp 47-83. (e) Hanessian, S. Total
Synthesis of Natural Products: the ‘Chiron’ Approach; Baldwin, J. E., Ed.;
Pergamon: Oxford, 1983.
ꢁ
ꢀ
(6) (a) Dieguez, M.; Pamies, O.; Claver, C. Chem. Rev. 2004, 104, 3189–
3215. (b) Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987.
3558 J. Org. Chem. 2010, 75, 3558–3568
Published on Web 02/25/2010
DOI: 10.1021/jo100077k
r
2010 American Chemical Society

Guaragna et al.
JOCArticle
As a consequence of the rapidly growing field of glyco-
biology and the development of carbohydrate-based phar-
maceutical agents, innovative procedures for the selective
construction of natural and unnatural carbohydrates have
been developed.7
novel and efficient syntheses of these compounds. The successful
approaches are divided into (a) de novo syntheses,18 in which
simple starting materials are manipulated via substrate-19 or
catalyst-controlled20 methods, and (b) D-sugar elaboration
methodologies by chemical21 or enzymatic procedures.22 Despite
the wide range of synthetic studies reported in literature to
date,23 only a few strategies enable access to the whole series of
rare L-sugars. Among them are noteworthy the total synthesis
reported by Sharpless19e and the more recent efforts by Ogasa-
wara,20e Izumori,22 Sasaki19a and MacMillan.20c,24
In this context, for the past few years we have been
working toward the de novo synthesis of polyhydroxylated
compounds using our 1,2-bis-thioenol ether synthon 1 as
three-carbon homologating agent with different chiral elec-
trophiles25 2-4 (Figure 1). As a result, we successfully
prepared uncommon monosaccharides,19b,26 and more re-
cently, we extended this methodology to the synthesis of
L-polyhydroxylated piperidines27 (i.e., L-iminosugars) and
related nucleosides,28 as well as to the synthesis of 10,50-
anhydro-L-arabino-hexitol nucleic acids (L-HNA).29
While the naturally occurring D-sugars are widely available
and frequently used as chiral sources in the synthesis of complex
natural products, the corresponding L-forms are rather rare in
nature. This fact, coupled with practical difficulties in obtaining
these compounds from inexpensive sources, has long delayed
their entry into many aspects of organic and biomolecular che-
mistry. However, recent times have witnessed an emerging inte-
rest around “mirror image” carbohydrates,8 as they have been
often recognized as components of biologically relevant mole-
cules. Indeed, L-hexoses are key constituents9 of several bioactive
oligosaccharides, antibiotics, glycopeptides, and terpene glyco-
sides, as well as steroid glycosides and other clinically useful
agents. Bleomycin A2, a glycopeptide antibiotic with significant
antitumor activity,10 contains a carbohydrate moiety consisting
of a R1f2 linked 3-O-carbamoyl-D-mannopyranose with
L-gulopyranose.11 L-Guluronic acid moieties are found in algi-
nate polysaccharides, which effect cytokine-inducing activities
by binding to Toll-like receptors (TLRs) 2 and 4.12,13 L-Glucose
is contained in the natural product (-)-littoralisone, known as a
bioactive agent for increased NGF-induced neurite outgrowth in
PC12D cells.14,15 L-Iduronic acid is a component of the dis-
accharide repeating unit of glycosaminoglycans16 (GAG), such
as the well-known heparin and heparan sulfate.17 As a result of
the interesting biological properties of unnatural carbohydrates
and of the poor commercial and natural availability of almost all
L-hexoses, several groups have shown interest in developing
Results and Discussion
In our preliminary communications19b,26a we reported a
general and efficient route for the preparation of L-hexoses,
starting from the 3-C homologating agent 1 (MPM = 4-
methoxybenzyl) and the chiral building block 2,3-O-isopro-
pylidene-L-glyceraldehyde (3), which provides the inherent
(19) See for example: (a) Ermolenko, L.; Sasaki, N. A. J. Org. Chem.
2006, 71, 693–703. (b) Guaragna, A.; Napolitano, C.; D’Alonzo, D.;
Pedatella, S.; Palumbo, G. Org. Lett. 2006, 8, 4863–4866. (c) Kim, K. S.;
Cho, B. H.; Shin, I. Bull. Korean Chem. Soc. 2002, 23, 1193–1194. (d)
Honzumi, M.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2001, 3, 1355–
1358. (e) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A. III; Sharpless,
K. B.; Walker, F. J. Tetrahedron 1990, 46, 245–264.
(20) See for example: (a) Ahmed, Md. M.; Berry, B. P.; Hunter, T. J.;
Tomcik, D. J.; O’Doherty, G. A. Org. Lett. 2005, 7, 745–748. (b) Babu, R. S.;
O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406–12407. (c) Northrup,
(7) (a) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K., Thorpe, A. J. Chem. Rev.
1996, 96, 1195-1220 and references therein. (b) Glycoscience: Chemistry and
Chemical Biology; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer:
Berlin, 2001. (c) Dondoni, A.; Marra, A. Chem. Rev. 2004, 104, 2557–2599. (d)
Limbach, M. Chem. Biodiversity 2005, 2, 825–836. (e) Kazmaier, U. Angew.
Chem., Int. Ed. 2005, 44, 2186–2188.
ꢁ
A. B.; MacMillan, D. W. C. Science 2004, 305, 1752–1755. (d) Cordova, A.;
Ibrahem, I.; Casas, J.; Sunden, H.; Engqvist, M.; Reyes, E. Chem.;Eur. J.
ꢁ
(8) See for example: Boulineau, F. P.; Wei, A. J. Org. Chem. 2004, 69,
3391–3399 and references cited therein.
2005, 11, 4772–4784. (e) Takeuchi, M.; Taniguchi, T.; Ogasawara, K.
Chirality 2000, 12, 338–341.
(21) (a) Weymouth-Wilson, A. C.; Clarkson, R. A.; Jones, N. A.; Best, D.;
(9) (a) Lee, J.-C.; Chang, S.-W.; Liao, C.-C.; Chi, F.-C.; Chen, C.-S.;
Wen, Y.-S.; Wang, C.-C.; Kulkarni, S. S.; Puranik, R.; Liu, Y.-H.; Hung,
S.-C. Chem.;Eur. J. 2004, 10, 399–415. (b) Dictionary of Carbohydrates;
Collins, P. M., Ed.; Chapman and Hall: London, 1987.
(10) (a) Burger, R. M. Chem. Rev. 1998, 98, 1153–1170. (b) Claussen,
C. A.; Long, E. C. Chem. Rev. 1999, 99, 2797–2816.
(11) Bleomycin A2, especially its disaccaride moiety, has long been at the
centre of many synthetic investigations; see for example: Hung, S.-C.;
Thopate, S. R.; Chi, F.-C.; Chang, S.-W.; Lee, J.-C.; Wang, C.-C.; Wen,
Y.-S. J. Am. Chem. Soc. 2001, 123, 3153–3154.
(12) Iwamoto, M.; Kurachi, M.; Nakashima, T.; Kim, D.; Yamaguchi,
K.; Oda, T.; Iwamoto, Y.; Muramatsu, T. FEBS Lett. 2005, 579, 4423–4429.
(13) For synthetic approaches to L-guluronic acid alginates, see: (a)
Dinkelaar, J.; van den Bos, L. J.; Hogendorf, W. F. J.; Lodder, G.;
ꢁ
Wilson, F. X.; Pino-Gonzalez, M.-S.; Fleet, G. W. J. Tetrahedron Lett. 2009,
50, 6307–6310. (b) Kulkarni, S. S.; Chi, F.-C.; Hung, S.-C. J. Chin. Chem.
Soc. 2004, 51, 1193–1200. (c) Takahashi, H.; Shida, T.; Hitomi, Y.; Iwai, Y.;
Miyama, N.; Nishiyama, K.; Sawada, D.; Ikegami, S. Chem.;Eur. J. 2006,
12, 5868–5877. (d) Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281–
2283.
(22) Izumori, K. J. Biotechnol. 2006, 124, 717-722 and references therein.
(23) For a review, see: D’Alonzo, D.; Guaragna, A.; Palumbo, G. Curr.
Org. Chem. 2009, 13, 71–98.
(24) Even though the approach to L-hexoses by MacMillan’s group was
not extended to the whole series, a recent discussion on the total synthesis of
carbohydrates by organocatalyzed aldol additions highlighted the opportu-
nity to complete the series with this method, by appropriate choice of the
reaction conditions. See: Markert, M.; Mahrwald, R. Chem.;Eur. J. 2008,
14, 40–48.
ꢁ
Overkleeft, H. S.; Codee, J. D. C.; van der Marel, G. A. Chem.;Eur. J.
2008, 14, 9400–9411. (b) Chi, F.-C.; Kulkarni, S. S.; Zulueta, M. M. L.;
Hung, S.-C. Chem. Asian J. 2009, 4, 386–390.
(14) Li, Y.-S.; Matsunaga, K.; Ishibashi, M.; Ohizumi, Y. J. Org. Chem.
2001, 66, 2165–2167.
(25) Guaragna, A.; Pedatella, S.; Palumbo, G. In e-Encyclopedia of
Reagents for Organic Synthesis (e-EROS); Paquette, L. A., Ed.; John Wiley
& Sons: New York, 2008.
(15) For a synthetic approach to littoralisone, see: Mangion, I. K.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696–3697.
(16) Linhardt, R. J.; Toida, T. Acc. Chem. Res. 2004, 37, 431–438.
(17) For an efficient synthesis of a great amount of disaccharide building
blocks for heparin and heparan sulphate assembly, see: Lu, L.-D.; Shie,
C.-R.; Kulkarni, S. S.; Pan, G.-R.; Lu, X.-A.; Hung, S.-C. Org. Lett. 2006, 8,
5995–5998.
(18) See for example: (a) Vogel, P. Robina, I. In Glycoscience: Chemistry
and Chemical Biology; Fraser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.; Springer:
Berlin, 2008; pp 857-956. (b) Yu, X., O'Doherty, G. A. In Chemical Glycobiol-
ogy; Chen, X., Halcomb, R., Wang, P. G., Eds.; ACS Symposium Series 990;
American Chemical Society: Washington, DC, 2008; pp 3-28. (c) Zhou, M.;
O'Doherty, G. Curr. Top. Med. Chem. 2008, 8, 114-125 and references therein.
(26) (a) D’Alonzo, D.; Guaragna, A.; Napolitano, C.; Palumbo, G.
J. Org. Chem. 2008, 73, 5636–5639. (b) Caputo, R.; De Nisco, M.; Festa, P.;
Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem. 2004, 69, 7033–7037.
(27) (a) Guaragna, A.; D’Alonzo, D.; Paolella, C.; Palumbo, G. Tetra-
hedron Lett. 2009, 50, 2045–2047. (b) Guaragna, A.; D’Errico, S.; D’Alonzo,
D.; Pedatella, S.; Palumbo, G. Org. Lett. 2007, 9, 3473–3476.
(28) Guaragna, A.; D’Alonzo, D.; De Nisco, M.; Pedatella, S.; Palumbo,
G. Nucleosides, Nucleotides Nucleic Acids 2007, 26, 959–962.
(29) (a) D’Alonzo, D.; Van Aerschot, A.; Guaragna, A.; Palumbo, G.;
Schepers, G.; Capone, S.; Rozenski, J.; Herdewijn, P. Chem.;Eur. J. 2009,
15, 10121–10131. (b) D’Alonzo, D.; Guaragna, A.; Van Aerschot, A.;
Herdewijn, P.; Palumbo, G. Tetrahedron Lett. 2008, 49, 6068–6070.
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On the basis of these findings, we decided to slightly change
the nature of the chiral electrophile in the elongation step using
methyl R,β-isopropylidene-L-glycerate (11). Thus, treatment of
the lithiated carbanion of 5 with 11 smoothly afforded ketone 9
in 96% yield (Scheme 3). Then, the latter was stereoselectively
reduced using NaBH4, leading to the sole desired alcohol syn-6
(98% yield). The complete diastereoselection observed could be
easily explained assuming a borohydride attack to the less
hindered face of the carbonyl of 9 in the nonchelated31 con-
formation A (Felkin-Ahn-Houk model, Figure 2). In order to
devise a more efficient route to alcohol anti-6, which repre-
sents the precursor of the already prepared L-hexoses having
gluco-configuration,26a reduction of ketone 9 with a reverse
stereoselectivity was next attempted. As shown in Table 1,
although the reaction proved to be highly efficient in all of the
tested conditions (>95% yield), only a slight stereoselection in
favor of the anti-diastereomer (6:4, anti/syn) was observed in
presence of N-Selectride (entry 5), N-Selectride/ZnCl2 (entry 6),
or DIBAL/ZnCl2 (entry 7), according to the Cram chelate
model31 B (Figure 2).
In our search for a more convenient approach to anti-6,
Mitsunobu inversion of the secondary hydroxyl group at the
C4 position of syn-6 was attempted. Hence, treatment of syn-6
with PPh3/DIAD/p-NO2BzOH and subsequent alkaline hy-
drolysis of the resulting p-nitrobenzoate (Et3N/MeOH) pro-
duced alcohol anti-6 in a 75% overall yield (o.y.) (Scheme 3).
The synthesis of galacto-configured L-hexoses proceeded
through cyclization of the main carbon chain starting from syn-
6, by a similar route to that previously described19b (Scheme 4).
This was accomplished by protection of the secondary hydroxyl
function of syn-6with a benzyl (BnBr/NaH) or acetyl (Ac2O/Py)
group, affording 12a (R = Bn) and 12b (R = Ac) in almost
quantitative yields. MPM group removal of 12a,b (DDQ) and
subsequent oxidation of the resulting primary alcohol of 13a,b
(PCC) provided aldehydes 14a,b in very good yields (73-
87% o.y. from 12). Then, acetonide cleavage of 14a (R = Bn)
(Amberlyst 15 in MeOH) followed by direct acetylation of the
crude residue (Ac2O/Py) led to acetals 16a (via alcohols 15a) as
an R/β (85:15) anomeric mixture (69% yield over two steps). On
the other hand, treatment of anomeric mixture 15a with Am-
berlyst 15 in CHCl3 enabled efficient conversion to 1,6-anhy-
drocompound 17a (85% yield). It should be pointed out that
compound 15b could not be easily isolated after reaction of 14b
with Amberlyst 15 or stoichiometric TMSOTf in MeOH, due to
its rapid conversion to acetal 17b (Scheme 4). Formation of the
latter could be observed already in reaction medium or after
common purification procedures. Alternatively, the bicyclic
compound could be easily isolated under its acetylated form
16b, by treatment of 14b with catalytic TMSOTf in MeOH and
immediate addition of Ac2O/Py to the crude residue (91% over
two steps).
FIGURE 1. De novo synthesis of polyhydroxylated compounds by
chain elongation of synthon 1.
chirality at the C5 stereocenter of the final products (Figure 1).
The aim of the project was to develop a general and stereo-
selective method that would be flexible enough to allow the
synthesis of each epimer by minor variations of a common
reaction scheme. Since this approach proved to be highly
efficient when applied19b to the synthesis of four rare L-hexo-
pyranoses with gluco-configuration, i.e., L-mannose, L-altrose,
L-allose, and L-glucose, we have been particularly interested in
extending our methodology to the preparation of the remain-
ing four epimers with galacto-configuration. As shown in the
retrosynthetic path (Scheme 1), the current strategy relies on
the use of masked olefins 7 and 8, in turn easily obtained
through a stereoselective multistep process30 starting from
alcohols syn/anti-6. In particular, synthesis of L-hexoses be-
longing to the galacto-series, whose preparation will be herein
discussed, involves the use of diastereomer syn-6, which pro-
vides the suitable configuration at the C4 position.
Critically evaluating the whole synthetic path, we realized
that the first step of the synthesis was the weak point of our
approach, as the coupling reaction of the in situ prepared C3
lithiated carbanion of 5 with aldehyde 3 (Scheme 2), while
proceeding smoothly, yields the syn/anti-6 diastereomers in a
6:4 dr. In a first attempt to overcome the low coupling
stereoselection and selectively obtain the two secondary
alcohols 6, a two-step oxidation/reduction procedure was
planned. While most of the widely used oxidizing conditions
(PCC, TEMPO, Dess-Martin oxidation) were unsuccessful,
the Swern oxidation of alcohols mixture 6 led to a mixture of
ketone 9 (48%) and diene 10 (26%). Formation of the latter,
which was at the core of some our previous synthetic
investigations19b regarding the expeditious preparation of
4-deoxy-L-hexoses, has been already observed from anti-6
under alkaline conditions.
In search for a more profitable approach to acetals 16a,b
and 17a,b, we exploited the peculiar features of the DDQ
reagent (Scheme 5). We have already discussed26a the apti-
tude by DDQ of (a) carrying out MPM group removal under
diverse conditions,32 leading to an alcohol or a formyl
(31) (a) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M. C.;
White, C. T.; VanDerveer, D. J. Org. Chem. 1980, 45, 3846–3856. (b)
Majewski, M.; Nowak, P. J. Org. Chem. 2000, 65, 5152-5160 and references
therein.
(30) Domino Reactions in Organic Synthesis; Tietze, L. F., Brasche, G.,
Gericke, K. M., Eds.; Wiley-VCH: Weinheim, 2006.
(32) Caputo, R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem.
1997, 62, 9369–9372.
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SCHEME 1. Retrosynthetic Path
SCHEME 2. Three-Carbon Homologation Reaction
TABLE 1. Reduction of Ketone 9a
entry
reducing agent
b,c
syn/anti
yield (%)
1
2
3
4
5
6
7
NaBH4
Red-Ald,e
LiAlH4
>99:1
80:20
80:20
60:40
40:60
40:60
40:60
98
96
95
97
97
97
98
d
DIBALHd
N-Selectrided
N-Selectride/ZnCl2
DIBALH/ZnCl2
d
d
aTHF used as solvent (unless otherwise stated). bReaction was at
-60 °C. cReaction carried out in MeOH. dReaction was at -78 °C.
eReaction was carried out in toluene.
SCHEME 3. Synthesis of syn/anti-6 by Homologation of
L-Glycerate 11
FIGURE 2. Nonchelated (A) and chelated (B) model in the reduc-
tion of ketone 9.
methodology, treatment of 12a,b (R = Bn or Ac) with an
excess of DDQ (2.0 equiv) in a refluxing 18:1 CH2Cl2/H2O
emulsion afforded 17a,b as single product, saving 3-4 steps
(if R = Ac or Bn, respectively) with even better overall yields
in comparison with the previous stepwise route (86-88% vs
52-68%). These results prompted us to use this domino
procedure for the synthesis of bicycle acetals 16a,b as well. In
particular, we envisioned that replacement of water with
methanol could easily lead to desired methyl glycoside
function, and (b) evolving HCN, generating an acidic environ-
ment; such remarks led to the expeditious synthesis of 1,6-
anhydrosugars by a domino process.26a Using the same
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SCHEME 4. Ring Closure from syn-6 by Stepwise Route
SCHEME 5. Ring Closure from 12a,b by Domino Reaction
(b) oxidation of the resulting primary alcohol, (c) aldehyde
dimethoxyacetalation, (d) isopropylidene group removal, and
(e) ring closure by OH at the C5 position (Scheme 5).
As underlined before, olefins 16a,b and 17a,b represent
useful intermediates for complete L-hexoses synthesis. The
double bond of 16a,b was easily unmasked by dithioethylene
bridge removal. Treating the most abundant R-epimer with
Raney-Ni in THF afforded the unsaturated pyranosides 19a,b
(Scheme 6) in good yields (75-82%). A low temperature
(0 °C) was strictly required to avoid formation of saturated
pyranosides such as 20, which could be obtained in satisfactory
yield (86%) under stronger conditions (Raney-Ni excess at rt).
Subsequent stereoselective double bond functionalization of
olefins 19a,b by syn dihydroxylation was explored, examining
both Upjohn (catalytic OsO4, NMO) and Donohoe’s (stoi-
chiometric OsO4, TMEDA) reaction conditions (Scheme 6).
The more hindered syn allylic ether 19a was chosen for the
dihydroxylation under Upjohn conditions; the osmylation
reaction proceeded anti to the pseudoaxial benzyloxy group,
thus yielding methyl 6-O-acetyl-4-O-benzyl-R-L-gulopyrano-
side33,34 (22, 84% yield; 48% o.y. from 5) On the other hand,
osmylation under Donohoe’s conditions of syn allylic alcohol
21, obtained by Zemplen’s deacetylation of 19a, was highly
syn-selective, smoothly yielding methyl R-L-talopyranoside35
(23, 80% yield; 38% o.y. from 5). The observed complemen-
tary stereoselectivity was explained by the hydrogen bond
derivatives 16a,b. Solvent change was not trivial: on one
hand, the DDQ/CH2Cl2/MeOH system was slightly more
acidic (pH ∼2) compared to the DDQ/CH2Cl2/H2O mixture
(pH ∼3); on the other hand, we observed a decrease of the
reaction rate for the oxidative MPM group removal. Thus,
use of a 18:1 CH2Cl2/MeOH solution caused isopropylidene
group removal before formation of the formyl function,
leading to undesired byproducts. Therefore, reaction condi-
tions were tuned varying the CH2Cl2/MeOH ratios; best
results were found treating 12a with DDQ (1.2 equiv) in a 3:1
CH2Cl2/MeOH solution at rt for 24 h. Subsequent acetylation
of the crude residue afforded desired bicycle 16a in a gratifying
89% yield (Scheme 5). Reaction conditions were also compa-
tible with acetyl group, as compound 12b displayed similar
reactivity (86% o.y.). Detection of dimethoxyacetals 18 as
reaction intermediates suggests that the process proceeded
across the following five steps: (a) MPM group removal,
(33) Less than 5% of the talose isomer was detected (1H NMR analysis of
the crude residue).
(34) Stereoelectronic preference for dihydroxylation anti to an allylic
hydroxyl group has been recognized previously; see: (a) Cha, J. K.; Christ,
W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247–2255. (b) Hodgston, R.; Majid,
T.; Nelson, A. J. Chem. Soc., Perkin Trans.1 2002, 1444–1454.
(35) In contrast to previous results reported on similar substrates ( Harris,
€
J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.; O’Doherty, G. A.
Carbohydr. Res. 2000, 328, 17–36.) no traces of the corresponding gulose
isomer was herein detected.
3562 J. Org. Chem. Vol. 75, No. 11, 2010

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JOCArticle
SCHEME 6. Syn Dihydroxylation of Olefins 19a,b
tion via the OH5 conformer became competitive with, and in
fact dominated over, this process. However, if an entropi-
cally favored side reaction involving intramolecular attack
by a deacetylated C6-OH function occurred, this would lead
to anhydrosugar 27. On the other hand, in the case of talo-
epoxide 25, trans-diaxial oxirane ring opening smoothly
proceeded by preferred -OH attack at the relatively unhin-
dered C3 position of the 5HO conformer (Scheme 7).
Since ring opening of 2,3-anhydrosugar 24 in its OH5
conformation did not lead to the corresponding 2,3-trans-
diequatorial diol37 (i.e., the galacto-epimer), its preparation
was envisaged starting from 1,6-anhydrosugar38 derivative
17a (Scheme 8). The masked olefin 17a was treated with
Raney-Ni in acetone,39 to give the unsaturated derivative 28
in 78% yield. Stereoselective epoxidation with in situ gener-
ated TFDO from the less hindered face of olefin 28 led to
1,6:2,3-dianhydro-4-O-benzyl-β-L-gulo-pyranose (29) in
85% yield. 2,3-Oxirane ring opening40 by means of a reflux-
ing 6 N KOH solution enabled trans-diaxial installation of
the C2 and C3 hydroxyl groups, the sugar chair being locked
in a 4C1 conformation (Scheme 8). Subsequent 1,6-ring
cleavage by treatment of the crude dihydroxylated product
30 with catalytic TMSOTf in MeOH re-established the 1C4
chair conformation, affording methyl 4-O-benzyl-R-L-galac-
topyranoside (31) as a single anomer and in excellent yield
(90% over two steps; 48% o.y. from compound 5).
formation between the pseudo-axial allylic hydroxyl group at
the C4 position and the OsO4/TMEDA complex, according to
literature data.36
Conclusion
In summary, a highly stereoselective synthesis of enantio-
merically pure L-hexoses belonging to the galacto-series
(L-gulose, L-idose, L-galactose, and L-talose) has been accom-
plished, in very good overall yields (38-48%), starting from
our 1,2-bis-thioenol ether synthon 5 and a suitable chiral
electrophile, the methyl R,β-isopropylidene-L-glycerate (11).
The core of the strategy relies on the development of a
domino reaction, in which up to six synthetic transforma-
tions were carried out sequentially, with the advantage of
increasing the efficiency of the entire process. In-depth
investigation of the parameters involved in this reaction
enabled us to selectively obtain the R-L-pyranoside 16 or
the 1,6-anhydro-β-L-pyranoside 17, depending on our syn-
thetic requirements. Moreover, syn and anti dihydroxylation
conditions were examined, affording each orthogonally pro-
tected L-hexopyranoside with high (in some cases with full)
diastereoselectivity. These and previous results contribute to
The anti dihydroxylation of olefin 19a was next planned
(Scheme 7) via double bond epoxidation. Early attempts
employing m-CPBA were unsuccessful as a result of the ex-
tremely low reactivity of the reagent to our substrate. Then,
olefin 19a was subjected to Payne’s epoxidation (PhCN/
H2O2/MeOH/NaHCO3), leading to the formation of both
gulo- and talo-epoxides 24 and 25 (60% yield, 65:35 dr).
However, even after prolonged reaction times a substantial
amount of unreacted starting material was recovered (35%).
Eventually, treatment of 19a with in situ generated TFDO
[methyl(trifluoromethyl)dioxirane], employing the oxone/
trifluoroacetone system in CH3CN/aq NaHCO3, led to the
mixture of epoxides 24 and 25 with the highest yield (79%).
Good but reversed diastereoselectivity (dr 1:9) occurred
under these conditions. As depicted in Scheme 7, ring open-
ing of talo-epoxide 25 under alkaline conditions (refluxing
1 N KOH) afforded methyl 4-O-benzyl-R-L-idopyranoside
(26) in quantitative yield (40% o.y. from 5). On the other
hand, treatment of epoxide 24 under the same conditions
proceeded in a thoroughly stereoselective manner, but lead-
ing to the unexpected 3,6-anhydrosugar 27 (99% yield).
The regioselective outcome of these ring-opening pro-
cesses deserves further comments. In the case of gulo-epoxide
24, the exclusive formation of 3,6-anhydrosugar 27 could be
explained by conjecturing that, under refluxing conditions,
both OH5 and 5HO conformations exist. In the 5HO confor-
mer, trans-diaxial opening should be prevented by the
difficulty of -OH to reach the C2 position of the dihydro-
pyrane ring from the same side of the endocyclic oxygen
atom.26b Consequently, nucleophilic attack at the C3 posi-
(37) Acidic hydrolysis of epoxide 24 was also attempted (6% aq HClO4);
however, only C6 O-deacetylation occurred, even after prolonged reaction
times.
(38) Use of 1,6-anhydrosugars has been widely applied to the construc-
tion of rare sugars and oligosaccharides; see for example: Kulkarni, S. S.;
Lee, J.-C.; Hung, S.-C. Curr. Org. Chem. 2004, 8, 475–509.
(39) Solvent substitution (acetone in place of THF) associated with a low
temperature (0 °C) was necessary to partially deactivate the reagent, with the
aim to prevent formation of 32. Stronger reduction conditions yielded 32 in
high yield (see Experimental Section for details).
(36) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.; Winter,
J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G. J. Org. Chem. 2002, 67,
7946–7956.
(40) It should be mentioned that very prolonged times were required to
complete ring opening of 29, as the C3 position was greatly hindered by both
the C4 benzyl group and the C1-C6 bridge.
J. Org. Chem. Vol. 75, No. 11, 2010 3563

Guaragna et al.
JOCArticle
SCHEME 7. Anti Dihydroxylation of Olefin 19a
SCHEME 8. Anti Dihydroxylation of Olefin 28
-78 °C and under nitrogen atmosphere. After 10 min a solution
of methyl R,β-isopropylidene-L-glycerate (11) (1.8 mL, 11.2
mmol) in the same solvent (8 mL) was added. The reaction
mixture was stirred for 3 h at -78 °C, then carefully quenched
with 10% aq NH4Cl. The mixture was extracted with EtOAc,
and the combined organic phases were washed with brine, dried
(Na2SO4) and evaporated under reduced pressure to give a crude
residue from which chromatography over silica gel column
(hexane/acetone = 8:2) gave the pure 9 (2.8 g, 96% yield): oily,
1
[R]25 -17.0 (c 0.18, CHCl3). H NMR (300 MHz, CDCl3): δ
D
1.41 (s, 3H), 1.47 (s, 3H), 3.06-3.15 (m, 2H), 3.27-3.31 (m, 2H),
3.80 (s, 3H), 4.03 (dd, J = 5.5, 8.5 Hz, 1H), 4.29 (dd, J = 7.4, 8.5
Hz, 1H), 4.42 (d, J = 14.8 Hz, 2H), 4.49 (d, J = 14.8 Hz, 2H),
5.02 (dd, J = 5.5, 7.7 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.27 (d,
J = 8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 25.3, 25.8, 26.4,
30.3, 55.1, 66.7, 71.2, 72.4, 78.5, 111.0, 113.7, 122.0, 129.3, 129.5,
144.0, 159.2, 195.1. Anal. Calcd for C19H24O5S2: C 57.55, H
6.10, S 16.17. Found: C 57.67, H 6.09, S 16.12.
(R)-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl](3-[(4-methoxyben-
zyl)oxy]methyl-5,6-dihydro-1,4-dithiin-2-yl)methanol (syn-6). To
a stirred cold (-60 °C) solution of 9 (2.40 g, 6.06 mmol) in
anhydrous methanol (60 mL) and under nitrogen atmosphere
was added NaBH4 (0.08 g, 2.02 mmol). The mixture, kept for 2 h
at -60 °C, was then quenched with acetone and concentrated
under reduced pressure. The residue was washed with saturated
aq NaHCO3 and extracted with Et2O. The combined organic
phases were dried (Na2SO4) and evaporated under reduced
pressure, to give a crude residue from which chromatography
over silica gel (hexane/Et2O = 7:3) gave the pure syn-6 (2.36 g,
98% yield). All characterization data were identical to those
reported in ref 19b. Anal. Calcd for C19H26O5S2: C 57.26, H
6.58, S 16.09. Found: C 57.12, H 6.60, S 16.13.
make our approach general and place it among the few
methods able to synthesize the whole series of the rare L-
sugars. Ongoing efforts are currently focusing on the exten-
sion of our domino approach for the synthesis of more
complex systems endowed with potential biological activity
and will be published in due course.
(S)-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl](3-[(4-methoxyben-
zyl)oxy]methyl-5,6-dihydro-1,4-dithiin-2-yl)methanol (anti-6).
To a solution of alcohol syn-6 (0.10 g, 0.25 mmol) in anhydrous
THF (1.1 mL) at 0 °C and under nitrogen atmosphere were
added triphenylphosphine (0.12 g, 0.45 mmol), DIAD (0.04 mL,
0.45 mmol), and p-nitrobenzoic acid (0.08 g, 0.45 mmol). The
reaction mixture was kept at 0 °C for 3 h, then it was diluted with
Experimental Section
[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl](3-[(4-methoxybenzyl)-
oxy]methyl-5,6-dihydro-1,4-dithiin-2-yl)methanone (9). n-BuLi
(1.6 M in hexane, 2.4 mL) was added dropwise to a stirred
solution of 5 (2.0 g, 7.46 mmol) in anhydrous THF (15 mL) at
3564 J. Org. Chem. Vol. 75, No. 11, 2010

Guaragna et al.
JOCArticle
Et2O and quenched with saturated NaHCO3. The phases were
separated, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated under reduced pressure. To a solution of crude
residue in CH3OH (0.57 mL) was added Et3N (0.1 mL, 0.75
mmol). After 16 h the mixture was concentrated and purified by
column chromatography (hexane/Et2O = 7:3) to yield the pure
anti-6 (0.08 g, 75% overall yield). All characterization data were
identical to those reported in ref 19b. Anal. Calcd for C19H26-
O5S2: C 57.26, H 6.58, S 16.09. Found: C 57.35, H 6.59, S 16.05.
Ketone 9 and (4R)-4-[(3-(Z)-1-[(4-Methoxybenzyl)oxy]me-
thylidene-1,4-dithian-2-yliden)methyl]-2,2-dimethyl-1,3-dioxo-
lane (10). To a cooled (-78 °C), stirred solution of freshly
distilled oxalyl chloride (0.05 mL, 0.56 mmol) in anhydrous
CH2Cl2 (0.40 mL) was added dropwise a solution of freshly
distilled DMSO (0.08 mL, 1.11 mmol) in the same solvent
(0.40 mL). During addition, the internal temperature was kept
below -70 °C and then allowed to reach -65 °C in 15 min.
Hence, a solution of 6 (0.15 g, 0.38 mmol, syn/anti mixture) in
CH2Cl2 (1.4 mL; internal temperature not exceeding -50 °C)
was added dropwise. The mixture was stirred at -50 °C for
5 min and then diluted with anhydrous Et3N (0.25 mL, 1.85
mmol), stirred for an additional 5 min, warmed to 0 °C in 10 min,
poured into a 1 M phosphate buffer (pH ∼7) and extracted with
CH2Cl2. The organic phase was dried (Na2SO4) and evaporated
under reduced pressure to give a crude residue from which
chromatography over silica gel (hexane/Et2O = 8:2) gave
ketone 9 (0.07 g, 48% yield) and diene 10 (0.04 g, 26% yield).
All characterization data regarding 9 and 10 were, respectively,
identical to those reported above and in ref 19b.
159.2, 169.9. Anal. Calcd for C21H28O6S2: C 57.25, H 6.41, S
14.56. Found: C 57.10, H 6.40, S 14.61.
(3-(R)-1-(Benzyloxy)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
methyl-5,6-dihydro-1,4-dithiin-2-yl)methanol (13a). To a stirred
CH2Cl2/H2O (9:1) emulsion (50 mL) containing the MPM ether
12a (0.54 g, 1.11 mmol) was added DDQ (0.38 g, 1.68 mmol) in
one portion at room temperature. After 3 h, H2O was added,
and the mixture was extracted with CH2Cl2. The organic layer
was dried (Na2SO4), and the solvent was evaporated under
reduced pressure. Chromatography of the crude residue over
silica gel (hexane/acetone = 9:1) gave the pure 13a (0.39 g, 92%
yield): oily, [R]25D þ62.3 (c 0.33, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 1.36 (s, 3H), 1.40 (s, 3H), 2.70 (bs, 1H), 3.09-3.22 (m,
3H), 3.23-3.30 (m, 1H), 3.95 (dd, J = 6.3, 8.5 Hz, 1H), 4.04 (d,
J = 12.9 Hz, 1H), 4.08 (dd, J = 6.3, 8.5 Hz, 1H), 4.14 (d, J =
12.9 Hz, 1H), 4.37-4.47 (m, 3H), 4.73 (d, J = 12.2 Hz, 1H),
7.22-7.42 (m, 5H). 13C NMR (125 MHz, CDCl3): δ 25.4, 26.5,
27.7, 29.2, 62.9, 65.6, 70.5, 77.5, 78.5, 109.9, 125.4, 127.8, 127.9,
128.3, 130.4, 137.5. Anal. Calcd for C18H24O4S2: C 58.67, H
6.56, S 17.40. Found: C 58.48, H 6.59, S 17.48.
(R)-1-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-[3-(hydroxy-
methyl)-5,6-dihydro-1,4-dithiin-2-yl]methyl Acetate (13b). Under
the same conditions reported for the preparation of alcohol 13a,
the pure 13b was obtained (82% yield) starting from MPM ether
1
12b: oily, [R]25 þ12.0 (c 0.35, CHCl3). H NMR (200 MHz,
D
CDCl3): δ 1.38 (s, 3H), 1.42 (s, 3H), 2.13 (s, 3H), 3.05-3.11 (m,
2H), 3.15-3.27 (m, 2H), 3.41 (dd, J = 3.7, 9.3 Hz, 1H), 3.81 (dd,
J = 5.6, 8.8 Hz, 1H), 3.92-4.09 (m, 2H), 4.48-4.59 (m, 2H), 5.73
(d, J = 8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 21.1, 25.4,
26.6, 27.0, 29.3, 63.3, 65.5, 74.9, 75.9, 110.5, 122.7, 131.6, 170.0.
Anal. Calcd for C13H20O5S2: C 48.73, H 6.29, S 20.01. Found: C
48.90, H 6.27, S 19.94.
(R)-(Benzyloxy)[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](3-[(4-me-
thoxybenzyl)oxy]methyl-5,6-dihydro-1,4-dithiin-2-yl)methane
(12a). NaH (0.16 g, 4.24 mmol) was added to a solution of syn-6
(1.30 g, 3.26 mmol) in anhydrous DMF (25 mL) at 0 °C under
nitrogen atmosphere. After 10 min, BnBr (0.54 mL, 4.48 mmol)
was added in one portion. The reaction mixture was warmed to
room temperature, stirred for 2 h, then carefully quenched with
10% aq NH4Cl. The mixture was extracted with EtOAc, and the
combined organic phases were washed with brine, dried
(Na2SO4), and evaporated under reduced pressure. Chroma-
tography of the crude residue over silica gel (hexane/Et2O =
8:2) afforded the pure 12a (1.56 g, 98% yield): oily, [R]25D þ33.8
3-(R)-1-(Benzyloxy)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
methyl-5,6-dihydro-1,4-dithiine-2-carbaldehyde (14a). A solu-
tion of alcohol 13a (0.35 g, 0.95 mmol) in pyridine (3 mL) was
added in one portion to a stirred suspension of PCC (0.28 g, 1.30
mmol) and Celite (0.28 g) in Py (8 mL) at room temperature. The
resulting mixture was stirred for 8 h, diluted with 10 mL of
anhydrous Et2O, kept in an ultrasound bath for 30 min and
filtered on a Celite pad. After solvent removal under reduced
pressure, chromatography of the crude residue over silica gel
(CH2Cl2) gave the pure 14a (0.33 g, 95% yield): white crystals,
1
1
(c 0.47, CHCl3). H NMR (500 MHz, CDCl3): δ 1.34 (s, 3H),
mp 83.1-84.5 °C (MeOH), [R]25 þ45.8 (c 0.52, CHCl3). H
D
1.36 (s, 3H), 3.06-3.11 (m, 1H), 3.12-3.20 (m, 2H), 3.21-3.27
(m, 1H), 3.80 (s, 3H), 3.81-3.84 (m, 1H), 3.86 (d, J = 11.7 Hz,
1H), 3.93-3.97 (m, 2H), 4.31-4.48 (m, 5H), 4.71 (d, J = 11.7
Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H),
7.24-7.28 (m, 1H), 7.29-7.34 (m, 2H), 7.35-7.39 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 25.5, 26.5, 27.3, 29.1, 55.1, 65.6,
69.6, 69.7, 72.2, 77.8, 79.2, 109.7, 113.7, 127.1, 127.4, 127.6,
127.7, 127.8, 128.1, 129.4, 137.9, 159.2. Anal. Calcd for
C26H32O5S2: C 63.91, H 6.60, S 13.12. Found: C 63.76, H
6.62, S 13.16.
NMR (400 MHz, CDCl3): δ 1.34 (s, 6H), 3.04-3.10 (m, 1H),
3.15-3.21 (m, 1H), 3.25-3.32 (m, 2H), 3.95-4.01 (m, 2H), 4.40
(q, J = 6.1 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.70 (bs, 1H), 4.78
(d, J = 12.0 Hz, 1H), 7.28-7.36 (m, 5H), 9.86 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 25.2, 25.7, 26.1, 29.7, 65.4, 71.5, 77.5, 79.0,
110.3, 128.0, 128.4, 128.7, 130.6, 130.7, 136.6, 184.6. Anal. Calcd
for C18H22O4S2: C 58.99, H 6.05, S 17.50. Found: C 59.15, H
6.03, S 17.43.
(R)-1-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(3-formyl-5,6-
dihydro-1,4-dithiin-2-yl)methyl Acetate (14b). Under the same
conditions reported for the preparation of aldehyde 14a, the
pure 14b was obtained (89% yield) starting from alcohol 13b:
white crystals, mp 132.0-134.5 °C (MeOH); [R]25D -37.0 (c 0.23
(R)-1-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(3-[(4-methoxy-
benzyl)oxy]methyl-5,6-dihydro-1,4-dithiin-2-yl)methyl Acetate
(12b). To a solution of syn-6 (0.90 g, 2.26 mmol) in pyridine (6
mL) was added Ac2O (0.42 mL, 4.5 mmol) at room temperature.
After 10 h the mixture was concentrated under reduced pressure
to give a crude residue from which chromatography over silica
gel (hexane/EtOAc = 8:2) gave the pure 12b (0.94 g, 95% yield):
1
CHCl3). H NMR (300 MHz, CDCl3): δ 1.36 (s, 3H), 1.41 (s,
3H), 2.18 (s, 3H), 3.02-3.16 (m, 1H), 3.18-3.37 (m, 3H), 3.91
(dd, J = 4.5, 8.8 Hz, 1H), 4.05 (dd, J = 6.6, 8.8 Hz, 1H),
4.41-4.47 (m, 1H), 6.09 (d, J = 6.6 Hz, 1H), 10.03 (s, 1H). 13
C
oily, [R]25 - 89.0 (c 0.12, CHCl3). 1H NMR (400 MHz,
NMR (100 MHz, CDCl3): δ 20.7, 25.2, 25.8, 26.3 29.5, 65.5,
73.1, 76.6, 110.8, 130.8, 145.9, 169.5, 183.7. Anal. Calcd for
C13H18O5S2: C 49.04, H 5.70, S 20.14. Found: C 49.21, H 5.72, S
20.07.
D
CDCl3): δ 1.36 (s, 6H), 2.11 (s, 3H), 3.06-3.10 (m, 2H),
3.14-3.22 (m, 2H), 3.79 (s, 3H), 3.86 (d, J = 11.8 Hz, 1H),
3.91 (dd, J = 6.4, 8.7 Hz, 1H), 3.96 (dd, J = 6.4, 8.7 Hz, 1H),
4.45-4.51 (m, 3H), 4.61 (d, J = 11.8 Hz, 1H), 5.73 (d, J = 6.4
[(5R,7S,8R)-8-(Benzyloxy)-5-methoxy-3,5,7,8-tetrahydro-
2H-[1,4]dithiino[2,3-c]pyran-7-yl]methanol (15a). Amberlyst 15
(3.5 g, previously washed with anhydrous MeOH) was added in
one portion to a stirred solution of 14a (0.22 g, 0.60 mmol) in
Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H). 13
C
NMR (50 MHz, CDCl3): δ 21.0, 25.6, 26.4, 27.2, 29.3, 55.1, 65.5,
70.2, 72.2, 74.4, 76.3, 110.1, 113.7, 124.1, 128.9, 129.5, 129.7,
J. Org. Chem. Vol. 75, No. 11, 2010 3565

Guaragna et al.
JOCArticle
methanol (15 mL) at 0 °C. After 10 min, the suspension was
warmed to room temperature and stirred for 1 h. Then the solid
was filtered off and washed with MeOH. Pyridine was added
until pH ∼8, then the solvents were evaporated under reduced
pressure to afford a crude residue from which chromatography
over silica gel (hexane/AcOEt = 85:15) gave the pure dihydro-
pyran 15a (0.12 g, 59.5% yield), besides a minor amount of its β-
anomer (0.02 g, 10.5% yield, 85:15 dr). Data for R-15a: white
(dd, J = 5.5, 11.4 Hz, 1H), 4.46 (ddd, J = 2.4, 5.5, 7.3 Hz, 1H),
4.82 (s, 1H), 5.19 (d, J = 2.4 Hz, 1H). 13C NMR (50 MHz,
CDCl3): δ 20.6 (2C), 27.6, 27.9, 55.6, 62.0, 65.0, 67.3, 97.6, 122.2,
125.9, 170.3 (2C). Anal. Calcd for C13H18O6S2: C 46.69, H 5.43,
S 19.18. Found: C 46.87, H 5.41, S 19.10.
Acetal 17a. Method A (from 15a). Amberlyst 15 (1.7 g,
previously washed with anhydrous CHCl3) was added in one
portion toa stirredsolutionof ananomeric mixtureof15a (0.12 g,
0.36 mmol) in CHCl3 (8 mL) at 0 °C. After 10 min, the suspension
was warmed to room temperature and further stirred for 1 h.
Then the solid was filtered off and washed with CHCl3 (100 mL),
and the resulting solution was washed with saturated NaHCO3
solution and brine. The organic layers were dried (Na2SO4), and
the solvent was evaporated under reduced pressure. Chromatog-
raphy of the crude residue over silica gel (hexane/acetone = 95:5)
gave the pure 17a (0.09 g, 85% yield).
crystals, mp 78.9-80.2 °C (MeOH); [R]25 þ55.2 (c 0.13,
D
CHCl3). 1H NMR (400 MHz, C6D6) δ 2.30-2.52 (m, 3H),
2.53-2.61 (m, 1H), 3.19 (s, 3H), 3.64 (d, J = 2.5 Hz, 1H),
3.68 (dd, J = 5.6, 11.3 Hz, 1H), 3.70 (dd, J = 7.6, 11.3 Hz, 1H),
4.16 (ddd, J = 2.5, 5.6, 7.6 Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H),
4.81 (d, J = 11.1 Hz, 1H), 4.87 (s, 1H), 7.02-7.30 (m, 3H), 7.41
(d, J = 7.0 Hz, 2H). 13C NMR (75 MHz, C6D6) δ 27.6, 28.1,
55.1, 62.1, 71.5, 72.3, 72.9, 98.6, 123.9 125.9, 127.7, 128.0, 128.3,
138.9. Anal. Calcd for C16H20O4S2: C 56.44, H 5.92, S 18.84.
Found C 56.26, H 5.94, S 18.91.
Method B (Domino Reaction from 12a). To a stirred 18:1
CH2Cl2/H2O emulsion (5 mL) containing the MPM ether 12a
(0.54 g, 1.11 mmol) was added DDQ (0.38 g, 1.68 mmol) in one
portion at room temperature. The resulting mixture was
warmed to gentle reflux and further stirred for 24 h. Then
H2O was added to the reaction, and the mixture was extracted
with CH2Cl2. The organic layer was dried (Na2SO4), and the
solvent was evaporated under reduced pressure. Chromatogra-
phy of the crude residue over silica gel (hexane/acetone = 95:5)
gave the pure 17a (0.32 g, 88% yield): oily, [R]25D þ22.2 (c 0.83,
[(5R,7S,8R)-8-(Benzyloxy)-5-methoxy-3,5,7,8-tetrahydro-
2H-[1,4]dithiino[2,3-c]pyran-7-yl]methyl Acetate (16a). Method
A (from 15a). To a stirred solution of the anomeric mixture of
15a (0.12 g, 0.36 mmol) in pyridine (4 mL) was added Ac2O (0.06
mL, 0.70 mmol) at room temperature. After 3 h, solvent removal
under reduced pressure and chromatography of the crude
residue over silica gel (CH2Cl2) afforded the pure R-16a (0.11 g,
84% yield) besides a minor amount of β-anomer (0.02 g, 15%,
85:15 dr).
1
CHCl3). H NMR (200 MHz, CDCl3): δ 3.07-3.31 (m, 4H),
Method B (Domino Reaction from 12a). To a stirred 3:1
CH2Cl2/MeOH solution (5 mL) containing the MPM ether
12a (0.34 g, 0.70 mmol) was added DDQ (0.28 g, 1.30 mmol)
in one portion at room temperature. The resulting mixture was
stirred for 24 h at the same temperature. Then pyridine (10 mL)
and Ac2O (5 mL) were added carefully at rt. The resulting
mixture was stirred at room temperature for 5 h, then H2O
was added, and the mixture was extracted with CH2Cl2. The
organic layer was dried (Na2SO4), and the solvent was evapo-
rated under reduced pressure. Chromatography of the crude
residue over silica gel (hexane/EtOAc = 8:2) gave the pure 16a,
besides a minor amount of its β-anomer (0.24 g, 89% overall
3.78 (ddd, J = 1.7, 5.5, 7.6 Hz, 1H), 4.27 (dd, J = 1.7, 7.6 Hz,
1H), 4.45-4.51 (m, 2H), 4.58 (d, J = 11.9 Hz, 1H), 4.72 (d, J =
11.9 Hz, 1H), 5.14 (s, 1H), 7.30-7.40 (m, 5H). 13C NMR (50
MHz, CDCl3): δ 26.3, 27.7, 62.6, 73.2, 73.3, 78.1, 99.1, 121.2,
123.4, 127.9, 128.0, 136.6. Anal. Calcd for C15H16O3S2: C 58.41,
H 5.23, S 20.79. Found: C 58.24, H 5.25, S 20.88.
Acetal 17b. Method A (from 14b). Amberlyst 15 (3.4 g,
previously washed with anhydrous MeOH) was added in one
portion to a stirred solution of 14b (0.25 g, 0.79 mmol) in MeOH
(10 mL) at 0 °C. After 10 min, the suspension was warmed to
room temperature and further stirred until TLC revealed the
presence of a major spot, Rf ∼0.2 (hexane/acetone = 8/2). Then
the solid was filtered off and washed with CHCl3 (100 mL), and
the resulting solution was washed with satd NaHCO3 solution
and brine. The organic layers were dried (Na2SO4), and the
solvent was evaporated under reduced pressure. During chro-
matography of the crude residue over silica gel (hexane/
acetone = 95:5), cyclization of acetal 15b occurred, giving 17b
as the major product (0.16 g, 79% yield).
yield; 85:15 dr): white crystals, mp 56.4-58.3 °C (MeOH); [R]25
D
1
þ74.6 (c 0.93, C6H6). H NMR (500 MHz, CDCl3): δ 2.06 (s,
3H), 3.16-3.40 (m, 4H), 3.44 (s, 3H), 3.71 (d, J = 1.6 Hz, 1H),
4.26-4.37 (m, 3H), 4.63 (d, J = 11.0 Hz, 1H), 4.76 (d, J = 11.0
Hz, 1H), 4.82 (s, 1H), 7.25-7.40 (m, 5H). 13C NMR (50 MHz,
CDCl3): δ 20.7, 27.7, 27.9, 55.3, 63.2, 69.4, 71.4, 71.9, 97.7,
123.3, 125.0, 127.7, 128.1, 128.2, 137.7, 170.4. Anal. Calcd for
C18H22O5S2: C 56.52, H 5.80, S 16.77. Found: C 56.38, H 5.78, S
16.84.
Method B (from 14b). Acetal 17b (0.05 g, 0.16 mmol) was
obtained (93% yield) starting from aldehyde 14b under the same
conditions reported above, but replacing amberlyst 15 with
stoich TMSOTf (0.02 mL, 0.16 mmol).
(5R,7S,8R)-5-Methoxy-7-[(methylcarbonyloxy)methyl]-3,5,7,
8-tetrahydro-2H-[1,4]dithiino[2,3-c]pyran-8-yl Acetate (16b). Method
A (from 14b). TMSOTf (0.01 mL) was added dropwise to a
stirred solution of aldehyde 14b (0.19 g, 0.60 mmol) in anhy-
drous MeOH (12 mL) at 0 °C. The resulting mixture was stirred
for 1 h at the same temperature. Then pyridine was added until
pH ∼8. MeOH was evaporated under reduced pressure and
replaced by further pyridine (15 mL); Ac2O was added to the
solution (0.06 mL, 0.6 mmol) at room temperature. After 3 h,
solvent removal under reduced pressure and chromatography of
the crude residue over silica gel (CH2Cl2) afforded pure R-16b
(0.16 g, 80% yield) in addition to a minor amount of its
β-anomer (0.02 g, 11% yield; 87:13 dr).
Method B (Domino Reaction from 12b). Under the same
conditions reported above for the preparation of the acetal
16a, an anomeric mixture of 16b (R/β = 85:15) was obtained
starting from the MPM ether 12b (86% yield). Data for R-16b:
oily, [R]25D þ52.0 (c 0.15, CHCl3). 1H NMR (400 MHz, CDCl3):
δ 2.06 (s, 3H), 2.14 (s, 3H), 3.05-3.10 (m, 1H), 3.17-3.32
(m, 3H), 3.45 (s, 3H), 4.11 (dd, J = 7.3, 11.4 Hz, 1H), 4.18
Method C (Domino Reaction from 12b). Under the same
conditions reported for the preparation of 17a, the pure 17b
was obtained starting from MPM ether 12b (86% yield): oily,
[R]25D þ14.0 (c 0.8, CHCl3). 1H NMR (200 MHz, CDCl3): δ 2.13
(s, 3H), 3.02-3.35 (m, 4H), 3.80 (ddd, J = 1.3, 5.8, 7.6 Hz, 1H),
4.18 (dd, J = 1.7, 7.6 Hz, 1H), 4.78 (ddd, J = 1.7, 4.8, 5.8 Hz,
1H), 5.20 (s, 1H), 5.75 (dd, J = 1.3, 4.8 Hz, 1H). 13C NMR (50
MHz, CDCl3): δ 20.6, 26.3, 27.8, 62.9, 72.4, 72.6, 99.3, 118.0,
126.1, 170.2. Anal. Calcd for C10H12O4S2: C 46.14, H 4.65, S
24.63. Found: C 46.29, H 4.64, S 24.55.
Methyl 6-O-Acetyl-4-O-benzyl-2,3-dideoxy-r-L-threo-hex-2-
enopyranoside (19a). A solution of 16a (0.25 g, 0.65 mmol) in
THF (7 mL) was added in one portion to a stirred suspension of
Raney-Ni (W2) (2.25 g, wet) in the same solvent (7 mL) at 0 °C.
The suspension was stirred for 2 h, then the solid was filtered off
and washed with THF. The filtrate was evaporated under
reduced pressure to afford a crude residue from which chroma-
tography over silica gel (hexane/acetone = 8/2) gave the pure
3566 J. Org. Chem. Vol. 75, No. 11, 2010

Guaragna et al.
JOCArticle
19a (0.16 g, 82% yield): oily, [R]25 þ80.9 (c 0.1, MeOH). H
10.2 Hz, 1H), 6.15 (dd, J = 5.8, 10.2 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 55.5, 62.6, 62.8, 70.0, 95.2, 128.4, 129.2. Anal.
Calcd for C7H12O4: C 52.49, H 7.55. Found: C 52.30, H 7.58.
Methyl r-L-Talopyranoside (23). TMEDA (0.07 mL, 0.45
mmol) and an OsO4 solution in anhydrous CH2Cl2 (0.45 mmol)
were dropwise added to a stirred solution of olefin 21 (0.07 g,
0.45 mmol) in anhydrous CH2Cl2 (8 mL) at -78 °C and under
nitrogen stream. The resulting mixture was stirred at the same
temperature for 3 h, then ethylenediamine (0.07 mL, 1.0 mmol)
was added. The solution was stirred for 48 h, until a dark brown
precipitate was formed. The solution was then concentrated
under reduced pressure. Chromatography of the crude residue
over silica gel (CH2Cl2/MeOH = 8:2) afforded the pure 23 as
single epimer (0.07 g, 80% yield): syrup, [R]25D-101.0 (c 0.9,
H2O). 1H NMR (500 MHz, D2O): δ 3.39 (s, 3H), 3.74 (dd,
J = 3.7, 11.0 Hz, 1H), 3.77-3.85 (m, 4H), 3.86-3.89 (m, 1H),
4.85 (s, 1H). 13C NMR (125 MHz, D2O): δ 55.1, 61.8, 65.6, 69.8,
70.2, 71.8, 101.8. Anal. Calcd for C7H14O6: C 43.30, H 7.27.
Found: C 43.19, H 7.29.
1
D
NMR (200 MHz, CDCl3): δ 2.05 (s, 3H), 3.43 (s, 3H), 3.69 (dd,
J = 2.7, 5.1 Hz, 1H), 4.19 (dt, J = 2.7, 6.2 Hz, 1H), 4.37 (d, J =
6.2 Hz, 2H), 4.53 (d, J = 11.9 Hz, 1H), 4.66 (d, J = 11.9 Hz, 1H),
4.96 (d, J = 2.7 Hz, 1H), 6.01 (dd, J = 2.7, 10.2 Hz, 1H), 6.14
(ddd, J = 0.9, 5.1, 10.2 Hz, 1H), 7.27-7.38 (m, 5H). 13C NMR
(125 MHz, CDCl3): δ 20.8, 55.4, 63.8, 66.9, 68.6, 70.8, 95.0,
126.6, 127.8, 128.4, 129.8, 138.1, 170.7. Anal. Calcd for
C16H20O5: C 65.74, H 6.90. Found: C 65.91, H 6.88.
Methyl 6-O-Acetyl-4-O-benzyl-2,3-dideoxy-r-L-threo-hexo-
pyranoside (20). Treatment of 16a (0.10 g, 0.26 mmol) with an
excess of Raney-Ni (W2) (1.8 g, wet) afforded, after common
workup and purification procedures, the pure 20 (0.07 g, 86%
yield): oily, [R]25D -10.7 (c 0.14, MeOH). 1H NMR (500 MHz,
CDCl3): δ 1.78-1.88 (m, 1H), 1.91-1.98 (m, 1H), 2.02 (s, 3H),
2.03-2.09 (m, 2H), 3.37 (s, 3H), 3.49 (bs, 1H), 3.96 (ddd, J =
1.5, 5.4, 6.9 Hz, 1H), 4.19 (dd, J = 5.4, 11.3 Hz, 1H), 4.22 (dd,
J = 6.9, 11.3 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.67 (d, J =
12.2 Hz, 1H), 4.78 (d, J = 3.4 Hz, 1H), 7.25-7.38 (m, 5H). 13
C
NMR (100 MHz, CDCl3): δ 20.4, 20.7, 23.9, 54.5, 64.6, 68.4,
70,3, 70.5, 97.9, 127.6, 127.8, 128.3, 138.1, 170.6. Anal. Calcd for
C16H22O5: C 65.29, H 7.53. Found: C 65.46, H 7.50.
Methyl 6-O-Acetyl-4-O-benzyl-2,3-anhydro-r-L-gulopyrano-
side (24) and Methyl 6-O-Acetyl-4-O-benzyl-2,3-anhydro-R-L-
talopyranoside (25). Method A. Hydrogen peroxide (0.12 mL,
50% aqueous solution) was added dropwise to a stirred suspen-
sion of olefin 19a (0.05 g, 0.17 mmol), PhCN (0.11 mL, 1.11
mmol) and NaHCO3 (0.05 g, 0.51 mmol) in MeOH (0.7 mL),
cooled at 0 °C. The resulting suspension was warmed to room
temperature and stirred for 48 h before dilution with brine and
extraction with ethyl acetate. The combined organic extracts
were dried (Na2SO4), and the solvent was evaporated under
reduced pressure. Chromatography of the crude residue over
silica gel (hexane/acetone = 8:2) gave the gulo-epoxide 24 along
with a relevant amount of the talo-epoxide 25 (0.03 g, starting
material recovered 0.02 g, 60% overall yield, 65:35 dr).
Methyl 6-O-Acetyl-4-O-benzyl-r-L-gulopyranoside (22). To
an ice-cooled solution of 19a (0.05 g, 0.17 mmol) in anhydrous
CH2Cl2 (1.5 mL) was added 4-methylmorpholine-N-oxide (0.04
g, 0.34 mmol) in one portion. After a few minutes, a catalytic
amount of a 0.05 M OsO4 solution in CH2Cl2 (0.3 mL, 0.015
mmol) was added. The resulting mixture was stirred overnight at
room temperature; then the reaction was quenched with satu-
rated aqNa2SO3 and evaporated under reduced pressure. Chro-
matography of the crude residue over silica gel (CH2Cl2) affor-
ded the pure 22 (0.05 mmol, 84% yield): oily, [R]25D -15.8 (c 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 2.01 (s, 3H), 2.50 (bs,
1H, D2O exchange), 3.20 (bs, 1H, D2O exchange), 3.46 (s, 3H),
3.65 (d, J = 3.1 Hz, 1H), 3.98 (bs, 1H), 4.05-4.10 (m, 1H),
4.11-4.16 (m, 2H), 4.28 (dd, J = 6.2, 10.2 Hz, 1H), 4.51 (d, J =
11.8 Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.82 (d, J = 3.4 Hz, 1H),
7.28-7.39 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.7, 56.0,
63.1, 63.6, 65.2, 68.7, 72.5, 76.4, 100.8, 128.1, 128.5, 137.5, 169.6.
Anal. Calcd for C16H22O7: C 58.89, H 6.79. Found: C 59.05,
H 6.77.
Methyl 4,6-Di-O-acetyl-2,3-dideoxy-r-L-threo-hex-2-enopyr-
anoside (19b). A solution of 16b (0.2 g, 0.60 mmol) in THF (5
mL) was added in one portion to a stirred suspension of Raney-
Ni (W2) (2.0 g, wet) in the same solvent (5 mL) at 0 °C. The
resulting mixture was stirred for 2 h at the same temperature,
then the solid was filtered off and washed with THF. The filtrate
was evaporated under reduced pressure to afford a crude residue
from which chromatography over silica gel (hexane/acetone =
8/2) gave the pure 19b (0.11 g, 75% yield): white solid, mp
60.5-61.5 °C (MeOH); [R]25D þ173.3 (c 0.8, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 2.04 (s, 6H), 3.43 (s, 3H), 4.23 (d, J = 5.7
Hz, 2H), 4.28-4.36 (m, 1H), 4.96 (d, J = 2.7 Hz, 1H), 5.02 (dd,
J = 2.4, 5.4 Hz, 1H), 6.02 (dd, J = 2.7, 10.0 Hz, 1H), 6.10 (dd,
J = 5.1, 10.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 20.4, 20.7,
55.5, 62.8, 66.7, 76.5, 94.9, 125.2, 130.4, 171.3, 171.6. Anal.
Calcd for C11H16O6: C 54.09, H 6.60. Found: C 53.92, H 6.62.
Methyl 2,3-Dideoxy-r-L-threo-hex-2-enopyranoside (21). A
methanolic 0.1 M MeONa solution (3 mL) was added to 19b
(0.1 g, 0.41 mmol). The resulting mixture was stirred for 4 h at
room temperature, then it was neutralized with a few drops of
acetic acid, and the solvents were evaporated under reduced
pressure. Chromatography of the crude residue over silica gel
(CHCl3/CH3OH = 9:1) gave the pure 21 (0.06 g, 98% yield):
oily, [R]25D þ69.7 (c 0.2, CHCl3). 1H NMR (300 MHz, CDCl3):
δ 2.07 (bs, 1H, D2O exchange), 2.30 (bs, 1H, D2O exchange),
3.43 (s, 3H), 3.86-3.95 (m, 2H), 3.98 (dd, J = 5.8, 11.7 Hz, 1H),
4.03-4.08 (m, 1H), 4.96 (d, J = 3.0 Hz, 1H), 5.94 (dd, J = 3.0,
Method B. Na2EDTA(4.0 ꢀ 10-4 M, 1.0mL) andCF3COCH3
(0.18 mL, 2.0 mmol) were added to a solution of 19a (0.05 g,
0.17 mmol) in CH3CN (1.5 mL) at 0 °C. After a few minutes,
a mixture of NaHCO3 (0.13 g, 1.6 mmol) and Oxone (0.61 g,
1.9 mmol) was added over 1 h. The resulting suspension was
stirred for 48 h at the same temperature. Then the reaction was
diluted with H2O and extracted with CH2Cl2. The combined
extracts were washed with brine, dried (Na2SO4), and evapo-
rated under reduced pressure. Chromatography of the crude
residue over silica gel (hexane/acetone = 8:2) afforded the talo-
epoxide 25 in addition to a minor amount of its gulo epimer 24
(0.04 g, 79% overall yield, 9:1 dr). Data for gulo-epoxide 24: oily,
[R]25D -12.0 (c 0.3, C6H6). 1H NMR (400 MHz, C6D6): δ 1.63 (s,
3H), 2.88-2.94 (m, 2H), 3.24 (s, 3H), 3.40 (bs, 1H), 4.10-4.26
(m, 4H), 4.42-4.45 (m, 1H), 4.62 (d, J = 2.8 Hz, 1H), 7.08-7.30
(m, 5H). 13C NMR (125 MHz, C6D6): δ 20.3, 49.9, 51.4, 54.8,
64.0, 66.4, 71.5, 73.0, 95.1, 127.4, 128.5, 128.6, 138.2, 169.7.
Anal. Calcd for C16H20O6: C 62.33, H 6.54. Found: C 62.18, H
6.56. Data for talo-epoxide 25: oily, [R]25D þ43.0 (c 0.3, C6H6).
1H NMR (400 MHz, C6D6): δ 1.65 (s, 3H), 2.76-2.82 (m, 2H),
3.13 (s, 3H), 3.18 (appt, J = 3.5, 4.5 Hz, 1H), 3.79-3.85 (m, 1H),
4.26 (d, J = 12.0 Hz, 1H), 4.37 (dd, J = 4.3, 11.6 Hz, 1H), 4.42
(dd, J = 7.9, 11.6 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 4.70 (s,
1H), 7.10-7.40 (m, 5H). 13C NMR (100 MHz, C6D6): δ 20.9,
48.8, 49.6, 54.7, 63.1, 66.0, 67.7, 70.1, 95.9, 127.5, 128.2, 128.3,
138.0, 169.7. Anal. Calcd for C16H20O6: C 62.33, H 6.54. Found:
C 62.20, H 6.56.
Methyl 4-O-Benzyl-r-L-idopyranoside (26). A solution of the
talo-epoxide 25 (0.05 g, 0.16 mmol) was refluxed for 12 h in a 1 N
aq KOH solution (3 mL). Then the reaction mixture was cooled
to 0 °C, and 1 N HCl was carefully added until neutrality. The
white solid was filtered off and washed with AcOEt. Solvent
removal under reduced pressure, and chromatography of the
resulting crude residue (CH2Cl2/MeOH = 9:1) afforded the
pure 26 (0.05 g, 99% yield): oily, [R]25 -40.0 (c 0.2, CHCl3).
D
J. Org. Chem. Vol. 75, No. 11, 2010 3567

Guaragna et al.
JOCArticle
1H NMR (500 MHz, CDCl3): δ 2.38 (t, J = 7.5 Hz, 1H, D2O
exchange), 3.46 (s, 3H), 3.57-3.60 (m, 1H), 3.65 (dd, J = 4.6,
11.9 Hz, 1H), 3.68-3.72 (m, 1H), 3.92 (dd, J = 7.5, 11.9 Hz,
1H), 4.06-4.15 (m, 2H), 4.52 (d, J = 11.9 Hz, 1H), 4.78 (d, J =
11.9 Hz, 1H), 4.85 (s, 1H), 7.28-7.40 (m, 5H). 13C NMR (100
MHz, CDCl3): δ 55.5, 62.5, 65.5, 66.2, 67.7, 72.7, 75.9, 102.1,
128.3, 128.4, 128.7, 128.9, 136.5. Anal. Calcd for C14H20O6: C
59.14, H 7.09. Found: C 59.32, H 7.06.
Methyl 3,6-Anhydro-4-O-benzyl-r-L-galactopyranoside (27).
As discussed in the previous section, ring opening of the gulo-
epoxide 24 (0.02 g, 0.07 mmol) with refluxing 1 N KOH (0.5 mL)
for 12 h provided, after common purification procedures, the
pure 27 (0.02 g, 99% yield) as the sole product: oily, [R]25D -12.0
(c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ 3.54 (s, 3H), 3.96
(dd, J = 2.5, 5.3 Hz, 1H), 4.03 (dd, J = 2.2, 10.0 Hz, 1H), 4.06
(d, J = 10.0 Hz, 1H), 4.34 (bs, 1H), 4.38 (d, J = 1.8 Hz, 1H), 4.50
(d, J = 5.3 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.65 (d, J = 11.9
Hz, 1H), 4.72 (d, J = 2.5 Hz, 1H), 7.27-7.38 (m, 5H). 13C NMR
(100 MHz, CDCl3): δ 57.1, 69.4, 70.2, 71.3, 75.3, 77.5, 78.3, 99.7,
127.7, 127.9, 128.4, 138.2. Anal. Calcd for C14H18O5: C 63.15, H
6.81. Found: C 63.34, H 6.79.
4-O-Benzyl-1,6:2,3-dianhydro-β-L-gulopyranose (29). Na2EDTA
(4.0 ꢀ 10-4 M, 4.0 mL) and CF3COCH3 (0.70 mL, 7.8 mmol) were
added to a solution of 28 (0.15 g, 0.69 mmol) in CH3CN (8.0 mL)
at 0 °C. After a few minutes, a mixture of NaHCO3 (0.5 g,
5.9 mmol) and Oxone (2.0 g, 6.5 mmol) was added over 1 h, and
the resulting mixture was stirred for 12 h at the same tem-
perature. Then the reaction was diluted with H2O and extracted
with CH2Cl2. The extracts were washed with brine, dried
(Na2SO4), and evaporated under reduced pressure. Chromatog-
raphy of the crude residue over silica gel (hexane/acetone = 8:2)
afforded the pure 29 (0.14 g, 85% yield) as single diastereoi-
somer: white solid, mp 74.0-76.0 °C (MeOH); [R]25D þ10.0 (c
0.7, CHCl3). 1H NMR (200 MHz, CDCl3): δ 3.02 (dd, J = 0.8,
3.8 Hz, 1H), 3.12 (dd, J = 2.2, 3.8 Hz, 1H), 3.75 (dd, J = 6.2, 8.0
Hz, 1H), 3.97 (dd, J = 0.8, 5.0 Hz, 1H), 4.16 (dd, J = 2.0, 8.0 Hz,
1H), 4.32-4.42 (m, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.74 (d, J =
12.0 Hz, 1H), 5.56 (s, 1H), 7.30-7.40 (m, 5H). 13C NMR (100
MHz, CDCl3): δ 48.4, 50.9, 63.4, 70.4, 71.9 (2C), 96.9, 127.6,
128.1, 128.5, 137.8. Anal. Calcd for C13H14O4: C 66.66, H 6.02.
Found C 66.50, H 6.04.
Methyl 4-O-Benzyl-r-L-galactopyranoside (31). Epoxide 29
(0.14 g, 0.60 mmol) was refluxed for 72 h in a 6 N aq KOH
solution (5 mL). Then the reaction mixture was cooled to 0 °C,
and 1 N HCl was carefully added until neutrality. The white solid
was filtered off and washed with AcOEt, and the solvent was
removed under reduced pressure. The resulting crude residue was
dissolved in anhydrous MeOH (5 mL), then a catalytic amount of
TMSOTf (10 μL, 0.06 mmol) was added at room temperature.
The reaction mixture was stirred at 50 °C for 48 h. Then solid
NaHCO3 was added, and the solvent was evaporated under
reduced pressure. Chromatography of the crude residue over
silica gel (CH2Cl2/MeOH = 9:1) gave the pure 31 (0.15 g, 90%
yield) assingle anomer: white crystals, mp84.0-86.0°C (EtOAc);
[R]25D -90.6 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.03
(bs, 2H, D2O exchange), 2.34 (bs, 1H, D2O exchange), 3.42 (s,
1H), 3.56-3.70 (m, 2H), 3.72-3.94 (m, 4H), 4.72 (d, J = 11.7 Hz,
1H), 4.84 (d, J = 11.7 Hz, 1H), 4.85 (d, J = 3.2 Hz, 1H),
7.26-7.42 (m, 5H). 13C NMR (50 MHz, CDCl3): δ 55.5, 62.2,
70.1, 70.7, 71.9, 74,9, 76.4, 99.4, 128.1, 128.2, 128.4, 137.9. Anal.
Calcd for C14H20O6: C 59.14, H 7.09. Found: C 59.30, H 7.07.
4-O-Benzyl-1,6-anhydro-2,3-dideoxy-β-L-threo-hex-2-enopyr-
anose (28). A solution of 17a (0.30 g, 0.97 mmol) in acetone (10
mL) was added in one portion to a stirred suspension of Raney-
Ni (W2) (3.0 g, wet) in the same solvent (10 mL) at 0 °C. The
suspension was stirred for 2 h at room temperature, then the
solid was filtered off and washed with further acetone. The
filtrate was evaporated under reduced pressure to afford a crude
residue from which chromatography over silica gel (hexane/
acetone = 9:1) gave the pure 28 (0.17 g, 78% yield): oily, [R]25
D
þ10.0 (c 0.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 3.85-3.88
(m, 1H), 4.26 (d, J = 8.0 Hz, 1H), 4.51-4.56 (m, 2H), 4.57 (d,
J = 11.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 5.49 (d, J = 2.9 Hz,
1H), 5.80 (d, J = 9.8 Hz, 1H), 5.88 (dd, J = 2.9, 9.8 Hz, 1H),
7.25-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 62.7, 71.2,
73.6, 74.8, 95.9, 127.2, 127.5, 128.2, 128.4, 129.7, 136.8. Anal.
Calcd for C13H14O3: C 71.54, H 6.47. Found: C 71.65, H 6.45.
4-O-Benzyl-1,6-anhydro-2,3-dideoxy-β-L-threo-pyranose (32).
Treatment of 17a (0.05 g, 0.16 mmol) with an excess of Raney-Ni
(W2) (1.0 g, wet) in THF (1 mL) at room temperature afforded,
after common workup and purification procedures, the pure 32
(0.03 g, 90% yield): oily; [R]25D þ30.4 (c 0.48, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 1.58-1.78 (m, 3H), 1.95-2.02 (m, 1H),
3.68-3.73 (m, 2H), 4.19 (d, J = 7.8 Hz, 1H), 4.47 (bt, J = 3.9 Hz,
1H), 4.53 (d, J = 12.2 Hz, 1H), 4.60 (d, J = 12.2 Hz, 1H), 5.48
(s, 1H), 7.26-7.40 (m, 5H). 13C NMR (100 MHz, CDCl3) δ:
22.8, 30.8, 65.1, 70.5, 73.1, 73.9, 100.9, 127.5, 127.7, 128.4, 138.3.
Anal. Calcd for C13H16O3: C 70.89, H 7.32. Found: C 71.01,
H 7.29.
Acknowledgment. 1H and 13C NMR spectra were per-
formed at the “Centro Interdipartimentale di Metodologie
ꢀ
Chimico-Fisiche” (CIMCF), Universita di Napoli Federico II.
Supporting Information Available: General methods and
1
materials and copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
3568 J. Org. Chem. Vol. 75, No. 11, 2010