Regio- and stereoselective behavior of l-arabinal-derived vinyl epoxide in nucleophilic addition reactions. Comparison with conformationally restricted d-galactal-derived analogs

Article abstract of DOI:10.1016/j.tet.2015.06.057

Abstract The regio- and stereoselectivity of the addition reactions of O-, C-, N-, and S-nucleophiles to l-arabinal-derived vinyl epoxide 2, the simplest non-conformationally restricted glycal-derived vinyl epoxide, has been examined and compared with the

Full text of DOI:10.1016/j.tet.2015.06.057

Tetrahedron 71 (2015) 6276e6284
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journal homepage: www.elsevier.com/locate/tet
Regio- and stereoselective behavior of
L
-arabinal-derived vinyl
epoxide in nucleophilic addition reactions. Comparison with
conformationally restricted
D-galactal-derived analogs
,
a
a
b
Valeria Di Bussolo a , Ileana Frau , Lucilla Favero , Gloria Uccello-Barretta ,
*
Federica Balzano b, Paolo Crotti a
,
*
a
ꢀ
Dipartimento di Farmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
b Dipartimento di Chimica e Chimica Industriale, Via G. Moruzzi 3, 56124 Pisa, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The regio- and stereoselectivity of the addition reactions of O-, C-, N-, and S-nucleophiles to L-arabinal-
Received 5 March 2015
Received in revised form 4 June 2015
Accepted 16 June 2015
derived vinyl epoxide 2, the simplest non-conformationally restricted glycal-derived vinyl epoxide, has
been examined and compared with the corresponding, conformationally restricted -galactal-derived
analogs 1 and 1 -Me. Results indicated that the 1,4-/1,2-regioselectivity ratio and the related syn-1,4-/
anti-1,2-stereoselectivity observed in glycal-derived vinyl oxiranes is independent of the presence of
substituents on the six-membered unsaturated ring, and the absence of conformational freedom: it
depends only on the ability of the nucleophile to give a coordination process with the oxirane oxygen in
the form of a hydrogen bond or through a coordinating cation.
D
b
b
Available online 21 June 2015
Keywords:
Vinyl epoxides
Glycals
Regioselectivity
Stereoselectivity
Ó 2015 Elsevier Ltd. All rights reserved.
L-Sugars
1. Introduction
O-(alcohols, phenol and partially protected monosaccharides) and
C-nucleophiles (alkyl lithium compounds) (NuX, Scheme 1) leading,
D-Galactal-derived vinlyl epoxide 1
b
1aec and the corresponding
-Me1d have shown to be, under protocol B re-
through a complete 1,4-regio- and syn-stereoselective process, to
the exclusive isolation of the corresponding -O- and -C-glycosides
having at C(4) the same relative configuration ( ) as the starting
6-deoxy analog 1
b
b
action conditions,2 excellent glycosyl donors in addition reactions of
b
Scheme 1. Regio- and stereoselectivity of the addition of nucleophiles to D-galactal-derived vinyl epoxide 1b and 6-deoxy analog 1b-Me under protocol B reaction conditions.
epoxide (syn-1,4-addition products). The completely syn-stereo-
selective result obtained had been rationalized by admitting the
occurrence of an oxirane oxygen-nucleophile coordination through
a hydrogen bond, in the case of alcohols, or through a metal cation
* Corresponding authors. Tel.: þ39 (0)502219690; fax: þ39 (0)502219660; e-mail
addresses: valeria.dibussolo@farm.unipi.it (V. Di Bussolo), paolo.crotti@farm.unipi.
it (P. Crotti).
http://dx.doi.org/10.1016/j.tet.2015.06.057
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
6277
(Liþ) in the case of alkyl lithium compounds (route a, Scheme 1).1
With an azide ion (N-nucleophile) and thiols (S-nucleophiles),
anti-1,2-addition products (route b) were obtained as the only re-
action products, sometimes accompanied by a small amount of the
corresponding syn-1,4-addition products, due to the poor ability of
the nucleophile to coordinate with the oxirane oxygen.1a,d On the
basis of this observation, the simplified nomenclature of co-
ordination products was given to syn-1,4-addition products (route a),
whereas anti-1,2-addition products (route b) and the more rarely
observed anti-1,4-addition products (route c), derived by attack of
a free, non-coordinated nucleophile at C(3) and C(1), respectively,
were simply identified as non-coordination products (Scheme 1).1d,3
However, as epoxides 1
b and 1b-Me exist as the only conformer
1
b0 and 1 0-Me shown in Scheme 1 with the side chain equator-
b
Scheme 3. Conformational equilibrium in vinyl epoxides 1b, 1b-Me, and 2.
ial,1d,4 the possibility that the observed complete 1,4-regio- and
syn-stereoselective result obtained with alcohols and alkyl lithium
compounds was ascribed to the conformational rigidity of the
system, could not be ruled out. As a consequence, in order to check
if the presence of conformational effects could negatively influence
the observed 1,4-regio- and syn-stereoselectivity and to validate
our rationalization in a non-conformationally restricted glycal-
sterically encumbered TBSCl leads to the mono O-TBS derivative 6,
which was transformed into mesylate 7 by the MsCl/Py protocol.
Deprotection of 7 with TBAF/THF afforded trans hydroxy mesylate
8, the stable precursor of epoxide 2 (Scheme 4). Epoxide 2 is un-
fortunately not stable and can be prepared only in situ by base-
catalyzed cyclization (t-BuOK) of trans hydroxy mesylate
and left to react immediately with the appropriate nucleophile
(Scheme 4).
derived vinyl oxirane, we have now directed our attention to L-
8
arabinal-derived vinyl epoxide 2 and its regio- and stereoselective
behavior has been examined in nucleophilic addition reactions
under the same reaction conditions previously used for epoxides
1
b
and 1
ordinating nucleophiles (NuX) the same chemical behavior as 1
could be used as an effective and simple glycosylating agent for the
completely stereoselective construction of corresponding -series-
derived syn-1,4-addition products (coordination products) 3 as, for an
example, alkyl 2,3-dideoxy- -glycero-pent-2-enopyranosides 4
b
-Me.1 In this framework, if epoxide 2 shows with co-
b
, it
L
a-L
when alcohols (NuX¼ROH) are used as glycosyl acceptors
(Scheme 2).5 The presence of the double bond makes pyranosides 3
suitable for further elaborations toward
and of possible biological interest.
L-derivatives of synthetic
Scheme 4. Synthesis of L-arabinal-derived vinyl epoxide 2.
2.2. Reaction of epoxide 2 with O-nucleophiles
The addition reactions of simple, low-boiling alcohols, such as
MeOH, EtOH, i-PrOH, t-BuOH, to epoxide 2, carried out under pro-
tocol A reaction conditions,2 turned out to be completely 1,4-
regioselective, with exclusive nucleophilic attack at the C(1) car-
bon of the vinyl system and formation of corresponding alkyl gly-
cosides 9e12:7,8 no trace of the corresponding 1,2-addition products
was observed under these conditions (Table 1).
Scheme 2. L-Arabinal-derived epoxide 2 and the possible completely 1,4-regio- and
syn-stereoselective behavior in addition reaction with coordinating nucleophiles.
Epoxide 2 has the same absolute configuration as reference
epoxides 1b and 1b-Me and theoretical calculations have indicated
that it exists as an equilibrium 81:19 of the two corresponding
conformers 20 and 200 in which the ring conformation of the major
conformer 20 corresponds to that of the unique conformer 1b0 and
As for the stereoselectivity under protocol A, the reactions with
the less nucleophilic and more sterically hindered t-BuOH, in spite
of the presence of a large excess of nucleophile, is completely
a-
1b
0-Me present in the related 5-CH2OBn and 5-Me substituted
stereoselective with the exclusive formation of the corresponding
epoxides 1
2. Results and discussion
2.1. Synthesis of -arabinal-derived vinyl epoxide 2
b and 1b
-Me, respectively (Scheme 3).4
tert-butyl a-O-glycoside 12a with the same relative configuration
as the starting epoxide (coordination product).5 On the contrary, the
reactions with the less hindered MeOH, EtOH, and i-PrOH are not
stereoselective and mixtures of the corresponding anomers, methyl
L
9
a
and 9
b
(47:53),7 ethyl 10
and 11
a
and 10
b (69:31) and iso-propyl O-
glycosides 11
a
b
(93:7),8a are obtained.9 Even if not com-
The novel epoxide 2 was prepared starting from
D
-xylal 5, itself
pletely stereoselective, it is worth noting that in all cases, with the
exception of the reaction with the more nucleophilic MeOH, the
prepared from -xylal 5 with the
D
-xylose.6 The treatment of
D

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V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
Table 1
Glycosylation of alcohols by epoxide 2 under protocol A and B reaction conditions
Entry
O-Nucleophile
Reaction conditionsa
a-O-Glycoside
b-O-Glycoside
MeOH
9
47
>99
10
ab
R¼Me
R¼Et
9
53
<1
10
bb
1
2
Protocol A
Protocol B
EtOH
a
b
3
4
Protocol A
Protocol B
69
31
>99
11ac
93
<1
11bc
7
i-PrOH
R¼i-Pr
5
6
Protocol A
Protocol B
>99
<1
t-BuOH
12
a
R¼t-Bu
R¼Bn
12
<1
13b
<1
b
7
Protocol A
Protocol B
>99
13ad
>99
BnOH
8
a
See Ref. 2.
b
c
See Ref. 7.
See Ref. 8a for corresponding enantiomers ent-11
See Ref. 8 for corresponding enantiomer ent-13a.
a
and ent-11b.
d
corresponding
uration as the starting epoxide (
a
-anomer (10e11
a
), with the same relative config-
conditions.2 No glycosylation occurred and the unreacted glycoside
was the only compound recovered from the crude reaction
mixture. The same unsuccessful result was obtained also when the
same reaction was repeated by using -galactal derived epoxide 1b
b
), is the main product.5 However,
9a
in all cases, when the reactions are repeated under protocol B re-
action conditions (MeCN as the solvent, Table 1),2 all the reactions
D
become completely
a
-stereoselective and the corresponding
a
-O-
(prepared in situ by base-catalyzed cyclization of trans hydroxy
glycosides 9e11a (coordination products) are the only reaction
mesylate 14), as the glycosyl donor (Scheme 6).1a,b,10,11
products.5
However, as epoxide 1b had demonstrated that the same regio-
Protocol B reaction conditions were also used in the glycosyla-
tion of benzyl alcohol, as an example of an O-nucleophile for which
and completely syn-stereoselective glycosylation process ob-
tained with alcohols could be realized also with the corresponding
protocol A reaction conditions are not possible. A complete
a-ster-
metal alcoholate,1a the preformed lithium alcoholate 12
prepared by reaction of tert-butyl a-O-glycoside 12a
a
-OLi,
with LHMDS,
was used as the glycosyl acceptor and left to react with epoxide 2.
A clean reaction occurred and the 2,3-unsaturated -1,4-O-di-
eoselective result was obtained with the exclusive formation of the
corresponding coordination product, benzyl
a-O-glycoside 13a
(Table 1).5,8,9
a
As previously shown for epoxide 1
b
, the occurrence of a hy-
saccharide 15 was obtained, as the only reaction product
(Scheme 6).
Unsaturated disaccharide 15 was acetylated (Ac2O/Py) and the
corresponding O-acetyl derivative 15-OAc was dihydroxylated by
catalytic OsO4/NMO. After acetylation (Ac2O/Py) of the crude re-
action product, the functionalized disaccharide 16-pent-OAc,
drogen bond between the alcohol (ROH) and oxirane oxygen is
considered responsible for the complete 1,4-regio- and syn-ster-
eoselectivity observed with epoxide 2, conceivably reacting
through both the two possible conformers 20 and 200 (routes a,
Scheme 5).
containing two units of L-lyxopyranose through an a-1,4-O-L-lyx-
opyranosidic bond, turned out to be the only reaction product
(Scheme 6). The structure and configuration of disaccharide 16-
pent-OAc were demonstrated by considerations based on the
structure of the starting unsaturated disaccharide 15-OAc, the
complete syn-stereoselectivity of the dihydroxylation process and
examination of the corresponding 1H NMR spectrum. In particular,
0
the trans diaxial relationship found between the H3 and H3 pro-
0
tons with the adjacent H4 and H4 protons, respectively
0
0
(J3,4¼9.7 Hz and J3 4 ¼9.4 Hz), is consistent only with an
a-di-
rection of the dihydroxylation process, that is, in a direction op-
posed to the b
-direction of the allyl substituents at the C(1), C(10),
C(4), and C(40) carbons of the two units of the unsaturated di-
saccharide 15-OAc, thus confirming the assigned structure
(Scheme 6).12
Scheme 5. Completely syn-stereoselective glycosylation of alcohols by epoxide 2 un-
der protocol B reaction conditions.
The same reaction was repeated with
ide 1 , as the glycosyl donor. The reaction proceeded as expected
and, after acetylation, the mixed unsaturated -1,4-O-disaccharide
17-OAc was the only reaction product (Scheme 7).
D-galactal-derived epox-
Also the possibility of the construction of a disaccharide by
means of epoxide 2 was envisaged. As a first approach, epoxide 2
b
b
(the glycosyl donor) was left to react with methyl
a-O-glycoside 9a
(the glycosyl acceptor), following the usual protocol B reaction

V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
6279
Scheme 8. Reaction of vinyl epoxide
nucleophiles).
2
with organo-lithium compounds (C-
21-tri-OAc showed a large coupling constant value (J1,2¼9.2 Hz) for
the anomeric H1, indicative of its axial nature and of a trans diaxial
relationship with the adjacent H2 proton in the more stable con-
former 210-tri-OAc with the phenyl group equatorial. These struc-
tural data clearly indicated that, once again, the dihydroxylation
had occurred selectively from the a-face of the starting unsaturated
system, that is, from the opposite side with respect to the
b-di-
rection of the substituents at C(1) and C(4) (Scheme 9).12
Scheme 9. Catalytic dihydroxylation (OsO4/NMO) of a-C-glycoside 18a.
Scheme 6. Synthesis of 1,4-O-disaccharides 15, 15-OAc, and 16-pent-OAc.
As previously observed with epoxide 1
epoxide 2 with TMSCN in MeCN (protocol B) turned out to be
completely stereoselective, affording O-TMS protected -glycosyl
cyanide 22 -OTMS (coordination product) as the only product. The
structure of
b
-Me,1d the reaction of
a
a
a
-C-glycoside 22a-OTMS was confirmed by the pres-
ence of NOE between H1 and H5ax protons in the 1H NMR spectrum
(Scheme 10).
Scheme 7. Synthesis of b-1,4-O-disaccharide 17-OAc.
2.3. Reactions of epoxide 2 with C-nucleophiles
Alkyl lithium compounds having differently hybridized nucle-
ophilic carbons, i.e., butyllithium (sp3), phenyllithium (sp2), and
lithium phenylacetylide (sp), were taken as samples of C-nucleo-
philes and their behavior examined in their reactions with epoxide
2 (protocol B, Scheme 8).
Scheme 10. Reaction of vinyl epoxide 2 with TMSCN.
In all cases, only the corresponding C-glycosides 18a 13
,
19a 13
, having the same relative configuration as the starting
epoxide ( ) were obtained indicating for epoxide 2 a complete 1,4-
,
2.4. Reaction of vinyl epoxide 2 with N-nucleophiles
and 20
a
b
In an attempt to synthesize N-glycosides by means of epoxide 2,
the behavior of some N-nucleophiles was examined.
regio- and stereoselective behavior with formation of only the
corresponding coordination products.5 A similar behavior had been
The reaction of epoxide 2 with n-propylamine (as the solvent/
nucleophile, protocol A) and tetramethylguanidine azide (TMGA in
MeCN, protocol B)14 was not useful to our aim because only the
corresponding anti-1,2-addition product, the trans amino alcohol 23
and trans azido alcohol 24, respectively, were obtained in a com-
pletely 1,2-regio- and anti-stereoselective fashion, in accordance
with the corresponding results previously obtained with epoxides
previously found with the reference epoxides 1b and 1b-Me in the
reaction with alkyllithium compounds.1a,c,d
As an example of further stereoselective functionalization of
these 2,3-unsaturated-C-glycosides, phenyl derivative 18 was
a
dihydroxylated with catalytic OsO4/NMO. Triol 21 turned out to be
the only product, indicating a completely stereoselective behavior.
The 1H NMR spectrum of the corresponding tri-O-acetyl derivative
1b and 1b
-Me (Scheme 11).1a,d,15

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V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
regioisomeric anti-addition products (non-coordination products),
which were separated and identified as the corresponding acetates:
trans 3-phenylthio-4-O-acetyl glycal-derivative 29-OAc (anti-1,2-
addition product) and 2,3-unsaturated
b-phenylthio-glycoside
30b
-OAc (anti-1,4-addition product) (Scheme 13).5 The reduced
ability of thiols to hydrogen bond compared to alcohols is the
reason why, in this case, no trace of the corresponding syn-1,4-
addition product was found, thus illustrating the marked differ-
ence with alcohols, where the corresponding alkyl O-glycosides
having the same configuration of the epoxide 2 (syn-1,4-addition
product, coordination products) are the main or the only addition
products (Table 1).1a,b,d
Scheme 11. Reaction of vinyl epoxide 2 with n-PrNH2 and TMGA.
Decidedly different is the behavior of epoxide 2 with a further
source of azide, TMSN3 in MeCN (protocol B).1a,d In this case, the
examination of the crude reaction product clearly showed the
presence of two products in an almost 1:1 mixture: the corre-
sponding 1,2- and 1,4-addition products (1H NMR spectroscopy).
Separation/purification of this mixture by preparative TLC afforded
only the 1,2-addition product, which turned out to be O-TMS-pro-
tected cis azido alcohol 28-OTMS, a syn-1,2-addition product. On the
contrary, the 1,4-addition product, initially present in the crude
reaction mixture, was not recovered, not allowing the de-
termination of its structure and configuration (Scheme 12).
Scheme 13. Reaction of vinyl epoxide 2 with PhSH, followed by acetylation.
Phenylthio derivatives anti-1,2-29-OAc and anti-1,4-addition
product 30b-OAc derive from an anti attack of the nucleophile
(PhSH) at the oxirane C(3) carbon in a trans diaxial fashion, in the
case of 29-OAc (route a, Scheme 14) and at the vinyl C(1) carbon in
a conjugate pseudoaxial fashion, in the case of 30b-OAc (route b,
Scheme 14) with the epoxide reacting through the more stable
conformer 20.
Scheme 12. Reaction of vinyl epoxide 2 with TMSN3.
However, based on our previous experience on the azidolysis of
1a,d
glycal-derived epoxides with TMSN3
and considering that a vi-
nyl epoxide such as 2 cannot reasonably give a complete syn-1,2-
stereoselective opening process, we thought that the 1,4-addition
product accompanying cis azido alcohol 28-OTMS in the crude re-
action mixture (1H NMR spectroscopy) should correspond to O-TMS
protected a-glycosyl azide 26a-OTMS. This means that, due to the
occurrence of nucleophile-oxirane oxygen coordination as shown
in 25 through conformer 200, the reaction of epoxide 2 with TMSN3
is completely 1,4-regio- and syn-stereoselective with the formation
of
a
-glycosyl azide 26
a
-OTMS, the primary reaction product (co-
-glycosyl azide 26 -OTMS is
ordination product). Unfortunately,
a
a
not stable and rapidly isomerizes to O-protected cis-azido alcohol
28-OTMS, the stable secondary reaction product, by means of
a suprafacial [3,3] sigmatropic rearrangement (shown in 27) with
complete retention of the facial selectivity (Scheme 12). The
Scheme 14. Pathways to observed (routes a and b) and not observed addition products
(route c) in the reaction of epoxide 2 with PhSH, followed by acetylation.
isomerization process of 26
a-OTMS to 28-OTMS is operative at any
moment (reaction mixture, separation/purification process of the
In this framework, a-phenylthio glycoside 30a-OAc, the syn-1,4-
addition product (coordination product)5 is not obtained even if,
independently of the coordinating ability of the nucleophile
(PhSH), it could reasonably be formed through a favorable pseu-
doaxial attack by the free nucleophile at the C(1) carbon of con-
former 200 (route c, Scheme 14). This observation confirms that in
these glycal-derived vinyl oxiranes, the formation of syn-1,4-
addition products (coordination products) is independent of
the conformer population in the starting epoxide: it depends only
on the occurrence of a nucleophile-oxirane oxygen coordination.
crude product) to the point that
be isolated.1d
a-glycosyl azide 26a-OTMS cannot
2.5. Reaction of epoxide 2 with PhSH (S-nucleophile) (pro-
tocol B)
The reaction of epoxide 2 in anhydrous THF with PhSH (protocol
B), as an example S-nucleophile, turned out to be completely anti
stereoselective, affording a 73:27 mixture of the two possible

V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
6281
2.6. Conclusion
Anal. Calcd for C11H22O3Si: C, 57.34; H, 22.17. Found: C, 57.03; H,
21.84.
In conclusion, the results obtained with the non-
conformationally restricted epoxide 2 in the glycosylation of alco-
hols (O-nucleophiles), organolithium compounds and TMSCN (C-
nucleophiles) and TMSN3 (N-nucleophile) are substantially similar
to those previously obtained with the conformationally constrained
3.2.2. 3-O-(tert-Butyldimethylsilyl)-4-O-mesyl- -xylal (7). A solu-
D
tion of alcohol 6 (10.0 g, 43.47 mmol) in 1:1 mixture of anhydrous
CH2Cl2 (47 mL) and anhydrous pyridine (47 mL) was treated drop-
wise at 0 ꢀC with MsCl (6.7 mL, 86.94 mmol, 2.0 equiv) and the re-
action mixture was stirred 18 h at the same temperature. Dilution
with Et2O and evaporation of the washed (brine) organic solvent
afforded a crude product (8.0 g, 60% yield) consisting of practically
pure mesylate 7 (1H NMR spectroscopy), as a brown liquid, which
was used in the next step without any further purification. An an-
alytical sample of crude 7 was subjected to flash chromatography.
Elution with an 8:2 hexane/AcOEt mixture afforded pure mesylate 7
epoxides 1
b and 1b-Me. In all cases, under protocol B reaction
conditions, a complete 1,4-regioselectivity and the associated
complete syn-stereoselectivity with the exclusive isolation of the
corresponding coordination product was observed.5 Moreover, ep-
oxide 2 has been effectively used for the stereoselective construc-
tion of a 1,4-O-disaccharide containing two units of
through an -lyxopyranosidic bond, thus indicating epoxide 2 as
a versatile, useful synthetic tool. The whole results clearly indicate
that in glycal-derived vinyl epoxides 1 ,1 -Me, and 2, the observed
L-lyxopyranose
a
as a yellow liquid: Rf¼0.63 (6:4 hexane/AcOEt); FTIR (film)
n 1649,
6.47 (dd,1H, J¼6.3, 0.4 Hz),
b
b
1360,1254,1090 cmꢁ1. 1H NMR (CDCl3)
d
complete 1,4-regio- and syn-stereoselectivity is independent of the
presence of a substituent at C(5) of the six-membered unsaturated
ring, and, as a consequence, of the absence of conformational
freedom: it depends only on the ability of the nucleophile to co-
ordinate with the oxirane oxygen in the form of a hydrogen bond or
through a coordinating cation.
4.81 (ddd, 1H, J¼4.6, 1.4 Hz), 4.60e4.66 (m, 1H), 4.20 (ddd, 1H,
J¼12.1,1.4 Hz), 4.10e4.15 (m,1H), 4.09 (dd,1H, J¼12.1,1.8 Hz), 3.07 (s,
3H), 0.88 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H). 13C NMR (CDCl3)
d 145.8,
101.3, 76.0, 63.4, 62.3, 38.9, 25.9, 18.1, ꢁ4.26, ꢁ4.47. Anal. Calcd for
C12H24O5SSi: C, 46.72; H, 7.84. Found: C, 46.39; H, 7.66.
3.2.3. 4-O-Mesyl- -xylal (8). A solution of mesylate 7 (2.0 g,
D
6.49 mmol) in anhydrous THF (200 mL) was treated at 0 ꢀC with
1 M TBAF in THF (6.49 mL, 6.49 mmol, 1.0 equiv). After 40 min
stirring at the same temperature, dilution with Et2O, and evapo-
ration of the washed (brine) organic solution afforded a crude
product (1.0 g) consisting of trans hydroxy mesylate 8 (1H NMR
spectroscopy), which was subjected to flash chromatography. Elu-
tion with a 4:6 hexane/AcOEt mixture afforded pure 8 (0.508 g, 40%
yield), as a colorless liquid: Rf¼0.08 (6:4 hexane/AcOEt); FTIR (film)
3. Experimental
3.1. General
All reactions were performed in a flame-dried modified Schlenk
(Kjeldahl shape) flask fitted with a glass stopper or rubber septum
under a positive pressure of argon. Flash column chromatography
was performed employing 230e400 mesh silica gel (Macher-
eyeNagel). Analytical TLC were performed on Alugram SIL G/UV254
silica gel sheets (Macherey-Nagel) with detection by 0.5% phos-
phomolybdic acid solution in 95% EtOH. Routine 1H and 13C NMR
spectra were recorded at 250 and 62.5 MHz, respectively. 1H NMR
COSY and NOESY experiments were performed on a spectrometer
operating at 600 MHz. Elemental analyses were performed at
Dipartimento di Farmacia, Pisa, by means of Carlo Erba Automated
CHN Analyzer model 1106. Toluene, Et2O, and THF were distilled
from sodium/benzophenone. HPLC grade MeCN, MeOH, EtOH, and
i-PrOH were used without any purification. t-BuOH and benzyl
n
3460, 1651, 1245, 1080 cmꢁ1 1H NMR (CDCl3)
. d 6.53 (d, 1H,
J¼6.2 Hz), 4.89e4.98 (m, 1H), 4.71e4.80 (m, 1H), 4.20e4.27 (m, 1H),
4.15e4.19 (m, 1H), 4.10 (dd, 1H, J¼12.3, 2.5 Hz), 3.11 (s, 3H). 13C NMR
(CDCl3)
d 146.9, 100.4, 75.8, 63.6, 62.6, 38.8. Anal. Calcd for
C6H10O5S: C, 37.10; H, 10.08. Found: C, 35.94; H, 9.89.
3.3. Glycosylation of alcohols (O-nucleophiles) by vinyl ep-
oxide 2
3.3.1. Reaction of epoxide
2 with EtOH (protocol A). Typical
procedure. A solution of trans hydroxy mesylate 8 (0.094 g,
0.49 mmol) in anhydrous EtOH (3.5 mL) was treated with t-BuOK
(0.109 g, 0.98 mmol, 2.0 equiv) and the reaction mixture was stirred
for 1 h at room temperature. Dilution with Et2O and evaporation of
the washed (brine) organic solution afforded a 69:31 mixture of
alcohol were distilled from sodium.
mesylate 14,1a,c and tetramethylguanidinium azide (TMGA)14 were
prepared as previously described. Alkyl O-glycosides 9 ent-
, 9b 7
-series) and C-glycosides 18a13 and
D
-Xylal (5),6 trans hydroxy
a
,
11a 8a ent-11b 8a ent-13a8
, (D
,
19a13 were previously described.
ethyl
a-O-glycoside 10a and ethyl b-O-glycoside 10b
(1H NMR
spectroscopy), which was subjected to preparative TLC (a 4:6
hexane/AcOEt mixture was used as the eluant). Extraction of the
3.2. Synthesis of trans hydroxy mesylate 8 (precursor of L-
arabinal-derived vinyl epoxide 2)
two most intense bands (the faster moving band contained 10
afforded pure ethyl -O-glycoside 10 (0.009 g, 13% yield) and ethyl
(0.055 g, 78% yield).
a)
b
b
3.2.1. 3-O-(tert-Butyldimethylsilyl)-
D
-xylal (6). A solution of
D-xylal
a
-O-glycoside 10a
5 (6.86 g, 59.10 mmol) in anhydrous DMF (150 mL) was treated with
imidazole (6.43 g, 94.56 mmol, 1.6 equiv) and TBSCl (9.76 g,
65.0 mmol, 1.1 equiv) at 0 ꢀC and the reaction mixture was stirred
24 h at room temperature. Dilution with CH2Cl2 and evaporation of
the washed (saturated aqueous NaCl) organic solvent afforded
a crude product (10.22 g, 76% yield) consisting of practically pure
TBS-derivative 6 (1H NMR spectroscopy), as a brown liquid, which
was used in the next step without any further purification. An
analytical sample of crude 6 was purified by flash chromatography.
Elution with an 8:2 hexane/AcOEt mixture afforded pure alcohol 6
3.3.1.1. Ethyl 2,3-dideoxy-
). A liquid: Rf¼0.41 (4:6 hexane/AcOEt); [
3440, 1621, 1451, 1069 cmꢁ1. 1H NMR (CDCl3)
a-L-glycero-pent-2-enopyranoside
20
(10
a
a]
ꢁ34.6 (c 1.62,
D
CHCl3), FTIR (film)
d
n
5.95e6.06 (m, 1H), 5.77 (ddd, 1H, J¼10.2, 2.4, 1.8 Hz), 4.89e4.95
(m, 1H), 4.09e4.29 (m, 1H), 3.64e3.94 (m, 3H), 3.47e3.62 (m, 1H),
1.24 (t, 3H, J¼7.1 Hz). 13C NMR (CDCl3)
d 133.0,128.2, 94.6, 64.3, 64.1,
63.3, 15.5. Anal. Calcd for C7H12O3: C, 58.31; H, 8.39. Found: C,
58.34; H, 8.06.
as a colorless liquid: Rf¼0.58 (6:4 hexane/AcOEt); FTIR (film)
n
3.3.1.2. Ethyl 2,3-dideoxy-
(10
). A liquid: Rf¼0.29 (4:6 hexane/AcOEt); [
CHCl3), FTIR (film)
3440, 1620, 1451, 1065 cmꢁ1. 1H NMR (CDCl3)
6.08e6.17 (m, 1H), 5.89 (ddd, 1H, J¼10.1, 3.6, 0.4 Hz), 4.95 (dd, 1H,
b-L-glycero-pent-2-enopyranoside
20
3390, 1650, 1241, 1097 cmꢁ1 1H NMR (CDCl3)
.
d
6.45 (d, 1H,
b
a
]
D
ꢁ72.5 (c 0.52,
J¼6.1 Hz), 4.79 (ddd, 1H, J¼6.5, 4.7, 1.4 Hz), 3.96e4.02 (m, 2H),
n
3.87e3.95 (m, 1H), 3.66e3.72 (m, 1H), 0.88 (s, 9H), 0.09 (s, 6H).
d

6282
V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
J¼3.0, 0.4 Hz), 4.12 (dd, 1H, J¼12.2, 2.6 Hz), 3.73e3.91 (m, 3H),
70.0, 65.1, 61.3, 60.0, 29.9, 28.9, 21.2. Anal. Calcd for C16H24O6: C,
61.52; H, 7.74. Found: C, 61.59; H, 7.41.
3.46e3.62 (m, 1H), 1.23 (t, 3H, J¼7.1 Hz). 13C NMR (CDCl3)
d 129.3,
128.8, 93.2, 64,4, 63.9, 61.7, 15.4. Anal. Calcd for C7H12O3: C, 58.31;
H, 8.39. Found: C, 58.17; H, 8.12.
3.4.2. Catalytic dihydroxylation (OsO4/NMO) of disaccharide 15-
OAc. A solution of disaccharide 15-OAc (0.022 g, 0.070 mmol) in 1:1
t-BuOH/acetone mixture (0.2 mL) was added, at 0 ꢀC under stirring
and in the dark, to 50% p/v aqueous solution of N-methyl mor-
pholine-N-oxide (NMO) (0.02 mL). The resulting reaction mixture
was treated with 2.5% p/v OsO4 solution in t-BuOH (0.02 mL) and
stirred in the dark for 96 h at room temperature. Dilution with Et2O
and evaporation of the filtered (CeliteÒ) organic solution afforded
a crude liquid product (0.029 g), which was dissolved in anhydrous
pyridine (0.2 mL) and treated at 0 ꢀC with Ac2O (0.1 mL). After 18 h
stirring at room temperature, co-evaporation of the resulting re-
action mixture with toluene afforded pure tert-butyl 4-O-(20,30,40-
3.3.2. Reaction of epoxide 2 with EtOH in MeCN (protocol B). Typical
procedure. A solution of trans hydroxy mesylate 8 (0.034 g,
0.18 mmol) in anhydrous MeCN (2.3 mL) was treated with t-BuOK
(0.020 g, 0.18 mmol, 1.0 equiv) and the reaction mixture was stirred
at room temperature until complete cyclization to epoxide 2 had
occurred (TLC). EtOH (0.031 mL, 0.54 mmol, 3.0 equiv) was added
and the reaction mixture was stirred for 1 h at the same temper-
ature. Dilution with Et2O and evaporation of the washed (brine)
organic solution afforded a yellow oil consisting of ethyl
coside 10
(0.020 g, 79% yield), as the only reaction product (1H
NMR spectroscopy).
a-O-gly-
a
tri-O-acetyl-b-L-lyxopyranosyl)-2,3-di-O-acetyl-b-L-lyxopyranoside
(16-pent-OAc), as a pale yellow oil: Rf¼0.22 (1:9 hexane/AcOEt);
3.3.3. Reaction of epoxide 2 with t-BuOH (protocol A). Following the
typical procedure, the treatment of trans hydroxy mesylate 8
(0.028 g, 0.14 mmol) in anhydrous t-BuOH (1.0 mL) with t-BuOK
(0.031 g, 0.28 mmol, 2.0 equiv) afforded, after 1 h stirring at room
temperature, a pale yellow liquid consisting of tert-butyl 2,3-
[a
]
D
20 þ16.5 (c 0.21, CHCl3), FTIR (film)
n 1740, 1461, 1370, 1218, 1065,
1020 cmꢁ1. 1H NMR (CDCl3)
d
5.31 (dd, 1H, J¼9.7, 3.0 Hz), 5.30 (dd,
1H, J¼9.4, 3.3 Hz), 5.10e5.21 (m, 1H), 5.07 (t, 1H, J¼3.0 Hz), 5.02 (dd,
1H, J¼3.3, 2.0 Hz), 4.97 (d, 1H, J¼2.0 Hz), 4.92 (d, 1H, J¼3.0 Hz),
3.96e4.08 (m, 1H), 3.87 (dd, 1H, J¼11.0, 8.9 Hz), 3.86 (dd, 1H, J¼10.7,
8.3 Hz), 3.75 (dd, 1H, J¼10.7, 6.4 Hz), 3.64 (dd, 1H, J¼11.0, 9.2 Hz),
2.12 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.22 (s,
dideoxy-a-L-glycero-pent-2-enopyranoside (12a) (0.024 g, 90%
yield), as the only reaction product: Rf¼0.50 (4:6 hexane/AcOEt);
[
a
]
20 ꢁ57.3 (c 1.36, CHCl3); FTIR (film)
n
3452,1615,1436,1065 cmꢁ1
.
9H). 13C NMR (CDCl3)
d 171.1, 170.7, 170.4, 170.3, 170.1, 98.9, 92.4,
D
1H NMR (CDCl3)
d
5.97 (d, 1H, J¼10.3 Hz), 5.57e5.74 (m, 1H),
73.2, 71.8, 70.8, 69.7, 68.2, 67.2, 61.0, 60.5, 29.9, 28.6, 21.0. Anal.
Calcd for C24H36O14: C, 52.55; H, 6.62. Found: C, 51.90; H, 6.88.
5.10e5.22 (m, 1H), 4.08e4.22 (m, 1H), 3.64e3.85 (m, 2H), 1.25 (s,
9H). 13C NMR (CDCl3)
132.4, 129.9, 88.4, 75.4, 64.1, 63.2, 28.9. Anal.
Calcd for C9H16O3: C, 62.76; H, 9.36. Found: C, 62.39; H, 9.01.
d
3.4.3. Synthesis of 1,4-
mation of the lithium alcoholate of tert-butyl
(solution A). A solution of tert-butyl -O-glycoside 12a
b
-O-disaccharide 17-OAc (protocol B). For-
-O-glycoside 12
(0.050 g,
a
a
3.4. Reaction of epoxide 2 and 1
tert-butyl -O-glycoside 12
b
with lithium alcoholate of
a
a
a
0.290 mmol, 1.8 equiv) in anhydrous THF (0.6 mL) was treated at
ꢁ78 ꢀC with 1 M LHMDS in hexane (0.29 mL, 0.29 mmol, 1.8 equiv)
and the reaction mixture was stirred 1 h at the same temperature.
3.4.1. Synthesis of 1,4-
the lithium alcoholate of tert-butyl
solution of tert-butyl -O-glycoside 12
a
-O-disaccharide 15 (protocol B). Formation of
-O-glycoside 12 (solution A). A
(0.039 g, 0.228 mmol,
a
a
Formation of epoxide 1b (solution B). Following the typical procedure,
a
a
a solution of trans hydroxy mesylate 14 (0.050 g, 0.16 mmol) in an-
hydrous THF (0.6 mL) was treated with t-BuOK (0.022 g, 0.19 mmol,
1.2 equiv) and the reaction mixture was stirred until complete cy-
1.8 equiv) in anhydrous THF (0.5 mL) was treated with 1 M LHMDS
in hexane (0.23 mL, 0.23 mmol, 1.8 equiv) at ꢁ78 ꢀC and the
reaction mixture was stirred 1 h at the same temperature. Forma-
tion of epoxide 2 (solution B). Following the typical procedure,
a solution of trans hydroxy mesylate 8 (0.025 g, 0.128 mmol) in
anhydrous THF (0.5 mL) was treated with t-BuOK (0.018 g,
0.154 mmol,1.2 equiv) and the reaction mixture was stirred at room
temperature until complete cyclization to epoxide 2 had occurred
(TLC, 15 min). Solution A was added dropwise and the resulting
reaction mixture was stirred 18 h at room temperature. Dilution
with Et2O and evaporation of the washed (brine) organic solution
clization to epoxide 1b had occurred (15 min, TLC). Solution A was
added dropwise and the resulting reaction mixture was stirred 18 h
at room temperature. Typical workup afforded a crude product
(0.070 g) consisting of 1,4-b
-O-disaccharide 17 (1H NMR spectros-
copy), which was dissolved in anhydrous pyridine (0.6 mL) and
treated at 0 ꢀC with Ac2O (0.3 mL). After 18 h stirring at room tem-
perature, co-evaporation of the reaction mixture with toluene
afforded a crude product (0.088 g, 99% yield) mostly consisting of
acetylated 1,4-b
-O-disaccharide 17-OAc (1H NMR), which was sub-
afforded a crude product (0.055 g) mostly consisting of 1,4-
a
-O-
jected to preparative TLC (a 1:1 hexane/AcOEt mixture was used as
disaccharide 15 (1H NMR spectroscopy), which was subjected to
preparative TLC (a 1:1 hexane/AcOEt mixture was used as the el-
uant). Extraction of the most intense band afforded pure tert-butyl
the eluant). Extraction of the most intense band afforded pure tert-
butyl 4-[60-O-(benzyl)-20,30-dideoxy- -D-threo-(hex-20-enopyranosyl)-
b
2,3-dideoxy-a-L-glycero-pent-2-enopyranoside (17-OAc) (0.054 g, 78%
4-(20,30-dideoxy-
a
-L
-glycero-pent-20-enopyranosyl)-2,3-dideoxy-
a
-
L
-
yield), as a colorless liquid: Rf¼0.26 (1:1 hexane/AcOEt); FTIR (film)
n
glycero-pent-2-enopyranoside (15) (0.022 g, 62% yield), as a color-
1741,1464,1240,1179,1054 cmꢁ1. [
(CDCl3)
a]
D
20 ꢁ74.8 (c 0.18, CHCl3); 1H NMR
20
less oil: Rf¼0.26 (1:1 hexane/AcOEt); [
FTIR (film)
3454, 1655, 1365, 1260, 1049 cmꢁ1
5.91e6.05 (m, 2H), 5.71e5.79 (m, 1H), 5.63e5.70 (m, 1H), 5.18 (br
a
]
ꢁ60.3 (c 0.76, CHCl3);
d
7.27e7.39 (m, 5H), 6.08 (dd, 1H, J¼9.6, 4.0 Hz), 6.00 (d, 1H,
D
n
.
1H NMR (CDCl3)
J¼9.9 Hz), 5.91 (d,1H, J¼9.6 Hz), 5.68 (ddd,1H, J¼9.9, 2.2,1.8 Hz), 5.23
(br s, 1H), 5.17 (d, 1H, J¼2.2 Hz), 5.05e5.10 (m, 1H), 4.59 (d, 1H,
J¼12.2 Hz), 4.48 (d, 1H, J¼12.2 Hz), 4.32e4.43 (m, 1H), 3.93e4.01 (m,
1H), 3.85 (d, 2H, J¼7.4 Hz), 3.62 (dd, 1H, J¼6.2,1.0 Hz),1.99 (s, 3H),1.26
d
s, 1H), 5.06 (br s, 1H), 4.19e4.31 (m, 2H), 3.73e3.87 (m, 3H), 3.65
(dd, 1H, J¼11.7, 8.5 Hz), 1.28 (s, 9H). 13C NMR (CDCl3)
d 133.4, 130.5,
129.3, 127.8, 94.2, 88.6, 70.0, 63.7, 63.3, 61.3, 29.9, 28.9. Anal. Calcd
(s, 9H). 13C NMR (CDCl3)
d 171.7, 138.2, 132.9, 130.6, 129.5, 128.6, 127.9,
for C14H22O5: C, 62.20; H, 8.20. Found: C, 62.09; H, 7.78. Acetate 15-
97.0, 88.6, 79.2, 73.7, 72.9, 69.7, 69.0, 64.0, 61.2, 28.9, 21.0. Anal. Calcd
for C24H32O7: C, 66.64; H, 7.45. Found: C, 66.48; H, 7.22.
20
OAc, yellow oil, Rf¼0.63 (1:1 hexane/AcOEt); [
CHCl3); FTIR (film)
(CDCl3)
a
]
ꢁ63.1 (c 0.56,
D
n
1739, 1649, 1464, 1251, 1066 cmꢁ1 1H NMR
.
d
5.90e5.99 (m, 2H), 5.83 (ddd, 1H, J¼10.3, 2.3, 1.7 Hz), 5.67
3.5. Reactions of epoxide 2 with C-nucleophiles
(ddd, 1H, J¼10.3, 2.7, 2.0 Hz), 5.23e5.34 (m, 1H), 5.17 (br s, 1H), 5.08
(br s, 1H), 4.19e4.32 (m, 1H), 3.71e3.89 (m, 4H), 2.06 (s, 3H), 1.26 (s,
3.5.1. Reaction of epoxide 2 with lithium phenylacetylide (protocol B).
Formation of lithium phenylacetylide (solution A). A solution of
9H). 13C NMR (CDCl3)
d 170.7, 130.7, 130.5, 129.4, 129.1, 94.0, 88.6,

V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
6283
phenylacetylene (0.023 mL, 0.22 mmol,1.4 equiv) in anhydrous THF
(1.0 mL) was treated with BuLi (0.11 mL, 0.18 mmol, 1.2 equiv) and
the reaction mixture was stirred 1 h at room temperature. Forma-
tion of epoxide 2 (solution B). Following the typical procedure,
a solution of trans hydroxy mesylate 8 (0.030 g, 0.15 mmol) in an-
hydrous THF (1.6 mL) was treated with t-BuOK (0.020 g,
0.185 mmol, 1.2 equiv) and the reaction mixture was stirred until
complete cyclization to epoxide 2 had occurred (15 min, TLC). So-
lution A was added dropwise and the resulting reaction mixture
was stirred 4 h at room temperature. Typical workup afforded
C9H15NO2Si: C, 54.78; H, 7.76; N, 7.10. Found: C, 54.39; H, 7.58; N,
6.81.
3.6. Reactions of epoxide 2 with N-nucleophiles
3.6.1. Reaction of epoxide 2 with TMSN3 (protocol B). A solution of
trans hydroxy mesylate 8 (0.040 g, 0.206 mmol) in anhydrous
MeCN (1.0 mL) was treated with t-BuOK (0.028 g, 0.25 mmol,
1.2 equiv) and the reaction mixture was stirred 15 min at room
temperature. TMSN3 (0.11 mL, 0.80 mmol, 4.0 equiv) was added and
the resulting reaction mixture was stirred 18 h at the same tem-
perature. Dilution with Et2O and evaporation of the washed (brine)
organic solution afforded a crude product (0.048 g) consisting of
a crude product consisting of practically pure a-C-glycoside 20a
(1H
NMR spectroscopy) (0.032 g), which was subjected to preparative
TLC (a 4:6 hexane/AcOEt mixture was used as the eluant). Extrac-
tion of the most intense band afforded pure (3R,6R)-6-(2-
a 60:40 mixture of a-N-glycoside 26a-OTMS and cis 1,2-azido de-
phenylethynyl)-3,6-dihydro-2H-pyran-3-ol (20
a
), as a colorless oil:
rivative 28-OTMS (1H NMR spectroscopy), which was subjected to
preparative TLC (a 7:3 hexane/AcOEt mixture was used as the el-
uant). Extraction of the most intense band afforded pure 3-azido-3-
Rf¼0.50 (4:6 hexane/AcOEt); [
a
]
20 ꢁ13.7 (c 1.0, CHCl3); FTIR (film)
n
D
3460, 2120, 1465, 1069 cmꢁ1. 1H NMR (CDCl3)
d 7.45e7.54 (m, 2H),
7.27e7.37 (m, 3H), 5.99 (dd, 1H, J¼10.3, 2.5 Hz), 5.66 (dt, 1H, J¼10.3,
deoxy-4-O-(trimethylsilyl)-
uid: Rf¼0.86 (4:6 hexane/AcOEt); [
(film)
L
-arabinal (28-OTMS), as a colorless liq-
2.2 Hz), 5.19 (d, 1H, J¼2.5 Hz), 4.11e4.21 (m, 1H), 3.78 (d, 1H,
a]
20 ꢁ198.0 (c 0.99, CHCl3); FTIR
D
J¼1.5 Hz), 3.75 (d, 1H, J¼3.4 Hz). 13C NMR (CDCl3)
d
132.3, 129.9,
n
2100,1643, 1250 cmꢁ1. 1H NMR (CDCl3)
d
6.44 (dd,1H, J¼6.0,
128.9, 128.5, 122.3, 89.5, 83.8, 64.1, 63.3. Anal. Calcd for C13H12O2: C,
77.97; H, 6.03. Found: C, 77.59; H, 5.65.
0.8 Hz), 4.74 (dd, 1H, J¼6.0, 5.3 Hz), 4.08e4.17 (m, 1H), 3.85e3.92
(m, 1H), 3.83e3.84 (m, 1H), 3.80e3.82 (m, 1H), 0.19 (s, 9H). 13C NMR
(CDCl3)
d 147.3, 96.9, 67.8, 65.7, 56.2, 0.1. Anal. Calcd for
3.5.2. Catalytic dihydroxylation (OsO4/NMO) of
a
-C-glycoside 18
a
. A
C8H15N3O2Si: C, 45.04; H, 7.08; N, 19.70. Found: C, 45.12; H, 6.91; N,
19.45.
solution of
a
-C-glycoside 18a13 (0.020 g, 0.114 mmol) in 1:1 t-
BuOH/acetone mixture (0.3 mL) was added, at 0 ꢀC under stirring
and in the dark, to a 50% p/v aqueous solution of N-methyl mor-
pholine-N-oxide (NMO) (0.08 mL). The resulting reaction mixture
was treated with 2.5% p/v OsO4 solution in t-BuOH (0.08 ml) and
stirred for 96 h at room temperature. Dilution with Et2O and
evaporation of the filtered (CeliteÒ) organic solution afforded
a crude liquid product (0.015 g), which was dissolved in anhydrous
pyridine (0.4 mL) and treated with Ac2O (0.2 mL) at 0 ꢀC. After 18 h
stirring at room temperature, co-evaporation of the reaction mix-
ture with toluene afforded pure (2S,3S,4R,5S)-3,4,5-tri-acetoxy-2-
Acknowledgements
This work was supported by the University of Pisa (Research
Funds 2011e2013) and MIUR (Ministero dell’Istruzione, della
ꢀ
Universita e della Ricerca, Roma) (PRIN 2008), which are sincerely
acknowledged.
Supplementary data
phenyl-tetrahydro-2H-pyrane (21-tri-OAc) (0.022 g, 58% yield), as
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.06.057.
20
a pale yellow oil: Rf¼0.17 (1:1 hexane/AcOEt); [
CHCl3); FTIR (film)
(CDCl3)
a
]
þ19.8 (c 0.76,
D
n
1739, 1455, 1368, 1211, 1040 cmꢁ1 1H NMR
.
d
7.27e7.48 (m, 5H), 5.41 (t, 1H, J¼3.4 Hz), 5.30 (dd, 1H,
References and notes
J¼9.7, 3.4 Hz), 4.91e4.96 (m, 1H), 4.60 (d, 1H, J¼9.7 Hz), 4.01 (d, 2H,
J¼1.8 Hz), 2.35 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H). 13C NMR (CDCl3)
1. (a) Di Bussolo, V.; Caselli, M.; Romano, M. R.; Pineschi, M.; Crotti, P. J. Org. Chem.
2004, 69, 8702e8708; (b) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org.
Lett. 2002, 4, 3695e3698; (c) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P.
Org. Lett. 2003, 5, 2173e2176; (d) Di Bussolo, V.; Favero, L.; Romano, M. R.;
Pineschi, M.; Crotti, P. Tetrahedron 2008, 64, 8188e8201.
2. Reaction conditions. Protocol A: the epoxide is dissolved in a solvent/nucleo-
phile; protocol B: the nucleophile (3 equiv) is added to the epoxide dissolved in
a non-nucleophilic solvent (MeCN, THF, toluene).
d
170.0, 169.6, 169.4, 137.5, 128.9, 128.7, 128.5, 127.3, 76.5, 69.5, 69.4,
67.5, 65.9, 21.2, 21.1, 20.7. Anal. Calcd for C17H20O7: C, 60.70; H, 5.99.
Found: C, 60.37; H, 6.05.
3.5.3. Reaction of epoxide 2 with TMSCN (protocol B). A solution of
trans hydroxy mesylate 8 (0.040 g, 0.21 mmol) in anhydrous MeCN
(1.0 mL) was treated with t-BuOK (0.028 g, 0.247 mmol, 1.2 equiv)
and the reaction mixture was stirred until complete cyclization to
epoxide 2 had occurred (15 min, TLC). TMSCN (0.11 mL, 0.80 mmol,
4.0 equiv) was added and the resulting reaction mixture was stirred
30 min at room temperature. Dilution with Et2O and evaporation of
the washed (saturated aqueous NaHCO3 and saturated aqueous
NaCl) ether extracts afforded a crude liquid product (0.029 g)
3. anti-1,4-Addition products (route c, Scheme 1) are commonly obtained in
a mixture with corresponding syn-1,4-addition products in the glycosylation of
alcohols by glycal-derived epoxides 1b 1a,b -Me,1d and epoxide 2 (vide infra
1b
,
and Table 1) carried out under protocol A reaction conditions.2
4. Crotti, P.; Di Bussolo, V.; Pomelli, C. S.; Favero, L. Theor. Chem. Acc. 2009, 122,
245e256.
5. It is important to point out that, due to nomenclature rules for glycosides, the
same relative configuration (b) of the starting epoxide and corresponding ob-
tained glycosides that is the structural condition necessarily present in the
addition products for the application of the syn-1,4-addition product (co-
ordination product) simplified nomenclature, is found in (1R,4R)-
b-anomers
mostly consisting of O-TMS protected
a-glycosyl cyanide 22a-
from epoxides 1 and 1 -Me (Scheme 1) and in (1R,4S)- -anomers from ep-
b
b
a
OTMS (1H NMR spectroscopy), which was subjected to preparative
TLC (a 1:1 hexane/AcOEt mixture was used as the eluant). Extrac-
tion of the most intense band afforded pure 4-O-trimethylsilyl-2,3-
oxide 2 (Scheme 2). Accordingly, corresponding anti-1,4-addition products (non-
coordination products) have an opposite configuration at C(1).
6. Matsuo, K.; Shindo, M. Tetrahedron 2011, 67, 971e975 and references therein.
7. (a) Achamatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Za-
mojski, A. Tetrahedron 1971, 27, 1973e1996; (b) Lemieux, R. U.; Watanabe, K. A.;
Pavia, A. A. Can. J. Chem. 1969, 47, 4413e4426.
dideoxy-
a colorless oil: Rf¼0.26 (6:4 hexane/AcOEt); [
CHCl3); FTIR (film)
2250, 1445, 1269, 1089 cmꢁ1. 1H NMR (CDCl3)
a-
L
-glycero-pent-2-enopyranosyl cyanide (22
a
-OTMS), as
20
a
]
þ45.4 (c 0.27,
D
8. For ent-11
a
, ent-11
b, and ent-13
a
, see: (a) Fava, C.; Galeazzi, R.; Mobbili, G.;
n
Orena, M. Tetrahedron: Asymmetry 2001, 12, 2731e2741; For only ent-13
a, see:
d
5.99 (ddd,1H, J¼10.7, 3.2,1.5 Hz), 5.72 (ddd,1H, J¼10.7, 3.2,1.8 Hz),
(b) Naz, N.; Al-Tel, T. H.; Al-Abed, Y.; Voelter, W.; Ficker, R.; Hiller, W. J. Org.
Chem. 1996, 61, 3250e3255.
9. With respect to substituents at C(1) and C(4), the different conformer pop-
4.89 (dd, 1H, J¼5.5, 2.4 Hz), 4.24e4.36 (m, 1H), 3.93 (dd, 1H, J¼11.2,
5.5 Hz), 3.53 (dd, 1H, J¼11.2, 8.7 Hz), 0.13 (s, 9H). 13C NMR (CDCl3)
ulation present in 2,3-unsaturated anomers derived from epoxide 2 (
a-anom-
d
134.7, 128.1, 122.7, 121.7, 67.3, 65.4, 61.5, 29.9, 0.1. Anal. Calcd for
ers exist as an axial-equatorial/equatorial-axial equilibrium between

6284
V. Di Bussolo et al. / Tetrahedron 71 (2015) 6276e6284
conformers, whereas only the diequatorial conformer is present in corre-
sponding 4.00e4.40 ppm)
-anomers) makes H4 proton in 1H NMR spectra (
of all 2,3-unsaturated- -anomers (9e13 , 15, 18e20 , 22 -OTMS, 31 ) as a not
resolved multiplet and in the three -anomers obtained (alkyl O-glycosides 9
10 and 11 ) as a doublet-doublet. As a consequence, this spectral data, in
10. Epoxide 1b had been successfully used in the synthesis of oligosaccharides by
b
d
means of an effective reiterative protocol: Di Bussolo, V.; Checchia, L.; Romano,
M. R.; Pineschi, M.; Crotti, P. Org. Lett. 2008, 10, 2493e2496.
a
a
a
a
a
b
b,
11. Considering that previous and present results have indicated epoxides 1b1a,b,10
and 2 (Table 1) as excellent glycosyl donors toward primary, secondary, and
b
b
addition to appropriate NOE experiments, turned out to be a useful tool in
order to assign the configuration to the anomeric center of the obtained gly-
cosides.
tertiary alcohols, the negative results obtained with methyl a-O-glycoside 9a (a
secondary alcohol), as the glycosyl acceptor, were unexpected and an appro-
priate rationalization is not available.
12. A similar substrate-dependent facial selectivity had been previously observed
in the dihydroxylation of disaccharides prepared by means of the reiterative
process10 developed in our laboratory: Checchia, L. PhD Thesis; University of
Pisa, School of Graduate Studies “Scienza del Farmaco
Bioattive”, 2009; pp 90e91.
13. Fernandez de la Pradilla, R.; Tortosa, M.; Lwoff, N.; del Aguila, M. A.; Viso, A. J.
Org. Chem. 2008, 73, 6716e6727.
e delle Sostanze
ꢁ
ꢁ
14. Papa, A. J. J. Org. Chem. 1966, 31, 1426e1430.
15. The behavior of epoxide 2 in the aminolysis with n-PrNH2 is similar to that of
epoxides 1
the aminolysis of 1
R.; Favero, L.; Pineschi, M.; Crotti, P. Tetrahedron 2010, 66, 689e697.
b
and 1
b-Me in the same reaction. For a more detailed discussion of
b
and 1 -Me, see: Di Bussolo, V.; Checchia, L.; Romano, M.
b