Enantiopure cis- and trans-2,5-disubstituted-2,5-dihydrofurans from D-allal- and D-galactal-derived vinyl epoxides

Article abstract of DOI:10.1016/j.tet.2019.06.003

Upon treatment with the metal enolates of methylene active compounds (dimethyl malonate and dibenzoylmethane) (C-nucleophiles) and benzyl carbamate (N-nucleophile), D-allal- and D-galactal-derived vinyl epoxides are stereoselectively transformed, in a sin

Full text of DOI:10.1016/j.tet.2019.06.003

Accepted Manuscript
Enantiopure cis- and trans-2,5-disubstituted-2,5-dihydrofurans from D-allal- and D-
galactal-derived vinyl epoxides
Valeria Di Bussolo, Salvatore Princiotto, Vittorio Bordoni, Elisa Martinelli, Lucilla
Favero, Stefano Crotti, Gloria Uccello Barretta, Federica Balzano, Mauro Pineschi,
Paolo Crotti
PII:
S0040-4020(19)30636-2
https://doi.org/10.1016/j.tet.2019.06.003
TET 30395
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 March 2019
Revised Date: 2 June 2019
Accepted Date: 3 June 2019
Please cite this article as: Di Bussolo V, Princiotto S, Bordoni V, Martinelli E, Favero L, Crotti S,
Uccello Barretta G, Balzano F, Pineschi M, Crotti P, Enantiopure cis- and trans-2,5-disubstituted-2,5-
dihydrofurans from D-allal- and D-galactal-derived vinyl epoxides, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.06.003.
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ACCEPTED MANUSCRIPT
Enantiopure cis- and trans-2,5-disubstituted-2,5-dihydrofurans from D-allal- and
D
-galactal-derived vinyl epoxides
Valeria Di Bussolo,a,* Salvatore Princiotto,b Vittorio Bordoni,b Elisa Martinelli,b Lucilla Favero,b
Stefano Crotti,b Gloria Uccello Barretta,a Federica Balzano,a Mauro Pineschi,b Paolo Crottib,*
aDipartimento di Chimica e Chimica Industriale, Università di Pisa, 56124 Pisa, Italy
bDipartimento di Farmacia, Università di Pisa, 56126 Pisa, Italy
OH
OH
O
O
H5
O
H5
BnO
BnO
Nu-M+
Nu-M+
H2
BnO
BnO
H2
O
2
2
5
5
Nu
Nu
O
O
6β
6α
cis/trans
cis/trans
Nu-M+ = metal enolates of 1,3-dicarbonyl compounds, lithium anion of benzyl carbamate

ACCEPTED MANUSCRIPT
Enantiopure cis- and trans-2,5-disubstituted-2,5-dihydrofurans
from D-allal- and D-galactal-derived vinyl epoxides
Valeria Di Bussolo,a,** Salvatore Princiotto,b,1 Vittorio Bordoni,b,2 Elisa Martinelli,b
Lucilla Favero,b Stefano Crotti,b,3 Gloria Uccello Barretta,a Federica Balzano,a Mauro Pineschi,b
Paolo Crottib*
aDipartimento di Chimica e Chimica Industriale, Università di Pisa,
Via G. Moruzzi 3, 56124 Pisa, Italy
bDipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
_____________________________________________________________________________________
Abstract: Upon treatment with the metal enolates of methylene active compounds (dimethyl
malonate and dibenzoylmethane) (C-nucleophiles) and benzyl carbamate (N-nucleophile),
D-
allal- and -galactal-derived vinyl epoxides are stereoselectively transformed, in a single step,
D
into diastereoisomeric, highly functionalized, enantiopure cis- and trans-2,5-disubstituted-2,5-
dihydrofurans.
_____________________________________________________________________________________
Dedicated to the memory of Professor Franco Macchia (1937-2018).
__________________________________________
Keywords: Vinyl epoxides, Glycals, 2,5-Disubstituted-2,5-dihydrofurans, Rearrangement
process, Stereoselectivity
1. Introduction
The 2,5-dihydrofuran core represents a privileged heterocyclic system which is present in
various compounds showing relevant biological activities. In particular, the 2,5-dihydrofuran
moiety can be found as common structural unit in natural products with antibiotic (α-amino acid
L
-(+)-furanomycin1a-c and diterpene (-)-guanacastepene E),1d anticancer/cytotoxic (eleutherobin,
________________________________________________________
Corresponding author.
*
** Corresponding author.
E-mail addresses: valeria.dibussolo@unipi.it (V. Di Bussolo), paolo.x.crotti@gmail.com (P. Crotti).
1
Present address: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena,
via Aldo Moro 2, 53100, Siena, Italy.
2
Present address: Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam
(Germany)
3 Present address: Kedrion Biopharma, Gallicano, Lucca, Italy.
1

ACCEPTED MANUSCRIPT
a marine diterpene glycoside)2 and antileukemic activity (liatrin, a sesquiterpene lactone).3
Moreover, the 2,5-dihydrofuran system is well represented in capsochrome derivatives,4 as
effective antiproliferative agents, and in the known synthetic antiviral nucleoside stavudine.5 For
these reasons, this system represents an important scaffold in Medicinal Chemistry for the
construction of corresponding, biologically active, synthetic products. In this framework,
multifunctionalized 2,5-dihydrofurans are particularly useful bulding blocks in organic synthesis
due to the numerous synthetic possibilities offered by the transformation of the functional groups
present in the side chains and the several functionalizations which can be introduced on the
double bond. As a consequence, the construction of 2,5-dihydrofuran rings bearing different
substitutions and functionalizations has received much attention.6-30 However, despite the great
effort made in this sense, few efficient methods are available for the obtainment of these systems
as pure chiral compounds.
Recently, diastereoisomeric enantiopure cis-2,5-disubstituted-2,5-dihydropyrroles 4 and 5
were stereoselectively obtained, in a single step, by glycosylation of metal enolates of methylene
active compounds, as dimethyl malonate and dibenzoylmethane, by
D-allal- and D-galactal-
derived vinyl N-mesyl aziridines 1α and 1β, respectively. The formation of 2,5-dihydropyrroles
4 and 5 had been demonstrated to be the result of a base-catalyzed rearrangement, with ring
contraction, of the corresponding 1,4-cis- and 1,4–trans-products, 2,3-unsaturated-α- and -β-C-
glycosides 2α,β and 3α,β, the primary reaction products (Scheme 1).31a,32a
1,4-cis- and 1,4-trans-products
Z
Z
O
Ms
N
OH
O
CH(COZ)2
1
1
BnO
BnO
MsHN
BnO
O
O
X
4
4
t-BuOK or t-BuOLi
N
Ms
THF
4
1α
2α,β
Z = OMe, Ph
X = CH(COZ)2; CH2COZ
Z
Z
O
Ms
N
OH
1
O
CH(COZ)2
1
BnO
BnO
MsHN
BnO
O
O
X
4
4
t-BuOK or t-BuOLi
N
Ms
THF
1β
3α,β
5
Scheme 1. Stereoselective synthesis of enantiopure, highly functionalized cis-2,5-disubstituted-
2,5-dihydropyrroles 4 and 5 by
1β.
D
-allal- and
D
-galactal derived vinyl N-mesyl aziridines 1α and
2

ACCEPTED MANUSCRIPT
Considering the analogy, these results prompted us to verify if such a process could be
applied also to the corresponding D-allal- and D-galactal-derived vinyl epoxides 6α and 6β. In
this case, enantiomerically pure, highly functionalized cis- and/or trans-2,5-disubstituted-2,5-
dihydrofuran systems as 7 and 8, could be obtained through a new, simple and innovative
process (Scheme 2).
6
Z
Z
5
O
1
2
OH
O
1
CH(COZ)2
BnO
BnO
HO
O
O
O
BnO
X
4
6
5
7
2
3
4
t-BuOK or t-BuOLi
O
4
3
THF
6α
cis- and/or trans- 7
1,4-cis and 1,4-trans-products
Z = OMe, Ph
X = CH(COZ)2; CH2COZ
6
Z
Z
5
O
1
2
OH
O
O
CH(COZ)2
1
BnO
BnO
HO
O
O
BnO
X
4
6
5
7
2
3
4
t-BuOK or t-BuOLi
O
4
3
THF
6β
cis- and/or trans- 8
Scheme 2. Envisaged synthesis of 2,5-disubstituted-2,5-dihydrofuran systems 7 and 8 by
reactions of vinyl epoxides 6α and 6β with metal enolates of methylene active compounds.
As a consequence, as previously done with aziridines 1α and 1β, the behaviour of vinyl
epoxides 6α and 6β, the glycosyl donors, was initially examined by glycosylation of metal (K+,
Li+) enolates of dimethyl malonate and dibenzoylmethane (C-nucleophiles, the glycosyl
acceptors). Subsequently, the behaviour of epoxides 6α and 6β with a nitrogen-based glycosyl
acceptor, as lithium anion of benzyl carbamate (N-nucleophile), was checked, too.
Vinyl epoxides 6α and 6β are not stable and can be prepared only in situ by base-catalyzed
cyclization of the corresponding stable precursor, trans-hydroxy mesylate 9α and 9β,
respectively, and let to react immediately with a nucleophile (Scheme 3).33
3

ACCEPTED MANUSCRIPT
O
O
BnO
MsO
BnO
nucleophile
t-BuOK
products
products
THF
O
OH
6α
9α
O
O
BnO
MsO
BnO
nucleophile
t-BuOK
THF
O
OH
9β
6β
Scheme 3. Preparation in situ of vinyl epoxides 6α and 6β by base-catalyzed cyclization of
corresponding stable precursor, trans-hydroxy mesylate 9α and 9β, respectively.
Theoretical computational calculations had indicated that vinyl epoxide 6β exists in solution
as the only conformer 6β’ with the side chain equatorial, whereas epoxide 6α exists as an 82:18
equilibrium between the corresponding conformers 6α’ and 6α” with the side chain axial and
equatorial, respectively (Scheme 4).34a
OBn
O
OBn
O
O
O
6β'
6β"
OBn
O
O
OBn
O
O
O
BnO
O
6α"
82 : 18
6α'
Scheme 4. Theoretical conformational analysis of vinyl epoxides 6α and 6β.
2. Results and discussion
2.1. Reactions of epoxides 6β and 6α with metal enolates of dimethyl malonate and
dibenzoylmethane
2.1.1. Reactions of epoxide 6
β
with metal enolates of dimethyl malonate and dibenzoylmethane
4

ACCEPTED MANUSCRIPT
The reaction of epoxide 6β with potassium enolate of dimethyl malonate (10-K), following
the typical protocol of addition of a preformed THF solution of the enolate (dimethyl malonate, 3
equiv, and an equimolar amount of t-BuOK) to a THF solution of epoxide 6β afforded a crude
product only consisting of the corresponding 3,4-trans-product32a 11 (Scheme 5). No trace of
other addition products or rearranged products, as the expected 2,5-dihydrofuran systems, was
present in the crude product. The same result was obtained also when the preformed lithium
enolate (from t-BuOLi) of dimethyl malonate (10-Li) was used (Scheme 5 and Table 1, entries 1
and 2).
+
−
O
M
O
O
10-K or
10-Li
BnO
BnO
t-BuOK
4
MeOOC CH=C OMe
9β
4
HO
THF
THF
(79-83% yield)
3
3
10-K, M+ = K+ (by t-BuOK)
10-Li, M+ = Li+ (by t-BuOLi)
O
MeOOC
COOMe
6β
11
Scheme 5. Reaction of epoxide 6β with potassium (10-K) and lithium enolate 10-Li prepared by
dimethyl malonate/t-BuOK and dimethyl malonate/t-BuOLi protocol, respectively.
The reason of the unsuccessful obtainment of the expected 2,5-dihydrofuran system was
clearly due to the fact that, under the reaction conditions used, no 1,4-adducts were formed, also
when more coordinating reaction conditions were used (10-Li).33,35
In spite of the negative result obtained with t-BuOLi as the base, the use of a stronger THF-
soluble base, as LHMDS in order to generate 10-LiHMDS, was attempted. The new protocol
guaranteed the presence in the reaction mixture of a higher concentration of the strongly
coordinating lithium cation which, reasonably, could favour the formation of 1,4-cis-
products.32a,33 Moreover, the presence of LHMDS, a base stronger than the previously used ones
(t-BuOK and t-BuOLi), could have a beneficial effect to the rearrangement process of 1,4-
adducts, once these products were formed.
The reaction of epoxide 6β with 10-LiHMDS (3 equiv, from equal amounts of dimethyl
malonate and LHMDS) in anhydrous THF for 4 h at room temperature afforded a crude reaction
mixture consisting of two products in a 35:65 ratio which were separated by preparative TLC
(Scheme 6 and Table 1, entry 3). Accurate 1H NMR examination of these two products indicated
that the minor product was the expected isomerization product, 2,5-dihydrofuran cis-12, bearing
at C(2) the –CH(COOMe)2 residue of enolate 10-LiHMDS. More intriguing was the
determination of the structure of the major product which corresponded to an 1,4-cis-product of
epoxide 6β in which the –CH(COOMe)2 residue of the starting nucleophile, turned out to be
5

ACCEPTED MANUSCRIPT
simplified to (methoxycarbonyl)- group (–COOMe). In other words, the –CHCOOMe portion of
1
the nucleophile, enolate 10-LiHMDS, appeared lost. All H NMR evidences allowed the
assignation of the structure of methyl β-glycosylcarboxylate derivative 13β to major reaction
product, furtherly confirmed by carrying out the same structural analysis (1H NMR) on the
corresponding acetate 13β-OAc (Scheme 6). A detailed rationalization for the formation of
methyl β-glycosylcarboxylate 13β has been recently published.36
O
COOMe
O
COOMe
1
BnO
HO
BnO
AcO
Ac2O
4
Py
O
13β-OAc
13β (65%)
1
BnO
10-LiHMDS
4
THF
OH
COOMe
(78% yield)
O
O
BnO
O−Li+
6β
COOMe
cis-12 (35%)
LHMDS
THF
CH2(COOMe)2
MeOOC-CH=C-OMe
10-LiHMDS
Scheme 6. Reaction of epoxide 6β with lithium enolate 10-LiHMDS prepared by dimethyl
malonate/LHMDS protocol in anhydrous THF.
In accordance with previous results (Scheme 1),31a 2,5-dihydrofuran cis-12 derives from α-
14α and β-C-glycoside 14β (1,4-adducts). the primary reaction products, formed by SN2’
addition of lithium enolate 10-LiHMDS to vinyl epoxide 6β. Base-catalyzed deprotonation (a
small excess of base is present in the reaction mixture) of the residual acid C-H bond of the –
CH(COOMe)2 group of C-glycosides 14β and/or 14α, generates the corresponding enolate
species 15 followed by retro oxa-Michael reaction with the formation of intermediate α,β-γ,δ-
unsaturated system 16 (Scheme 7). Acid-base equilibration between the homoallyl alcoholate
and the secondary allyl OH group present in 16 leads to the new allyl alcoholate 17. An
intramolecular oxa-Michael addition of the C(7)-O− alcoholate portion of 17 at C(4) carbon of
the α,β-unsaturated system through the folded conformer 18-Si, leads to 2,5-dihydrofuran cis-12.
Actually, in the folded conformer 18-Si, the conjugate system assumes a s-cis conformation in
order to have a three centers coordination of lithium cation with alcoholate O(7), malonate
carbonyl O(1) and secondary hydroxy functionality O(8) oxygens (cation binding). This makes
6

ACCEPTED MANUSCRIPT
the nucleophilic C(7)-O− allyl alcoholate appropriately disposed for a completely facial selective
attack, through a favoured 5-exo-trig mode, on the Si face of the α,β-conjugated system, as
shown in folded conformer 18-Si to give 2,5-dihydrofuran cis-12, in a completely syn-
stereoselective fashion32b (Scheme 7).37
COOMe
CH2(COOMe)2
δ−
OMe
LHMDS
THF
O
1
1
O
COOMe
C
BnO
HO
COOMe
δ−
C
OMe
O−
Li+
O
O
1
4
COOMe
BnO
δ−
10-LiHMDS
BnO
BnO
HO
O
base
14α
4
THF
HO
COOMe
COOMe
O
15
16
O
6β
BnO
HO
4
14β
1
O
OMe
8
H
+ O−
Li
9
MeO
2
H
COOMe
COOMe
O H
COOMe
CH
BnO
4
OH
6R
1) cyclization
2) protonation
3
8
8
Li+
BnO
O
7
O
BnO
COOMe
5R
2S
OH
4
6
5
Si
7
H
O−
cis-12
17
7
H
18-Si (folded)
Scheme 7. Rationalization of the formation of 2,5-dihydrofuran cis-12 by reaction of epoxide
6β with lithium enolate of dimethyl malonate (10-LiHMDS) prepared by LHMDS protocol.
The reaction of potassium enolate of dibenzoylmethane (19-K) with epoxide 6β carried out
by using t-BuOK as the base both for the formation in situ of the epoxide and for the formation
of the enolate, led to a crude reaction product consisting of
D-gulal-derivative 20 (3,4-trans-
product)38 (55%), accompanied by an almost 1:1 mixture of diastereoisomeric rearranged
products, 2-(benzoylmethyl)-2,5-dihydrofurans cis-21 (23%) and trans-22 (22%) (eq 1, Scheme
8 and Table 2, entry 1). All products were separated and obtained pure by preparative TLC.39
7

ACCEPTED MANUSCRIPT
t-BuOK/t-BuOLi
t-BuOK
THF
(eq. 1) 19-K
19-Li (eq. 2)
CH2(COPh)2
THF
O
OBn
O
COPh
CH
COPh
CH
COPh
M+
O
O
4
PhC
t-BuOM
O
1
O
1
BnO
+
BnO
1
COPh
eq. 1 and 2
Ph
3
4
4
HO
HO
19-K, M = K
19-Li, M = Li
6β
25β
25α
M+
O
M+O
COPh
C
H
COPh
COPh
OBn
Ph
+
4
O
M
8
7
C
O
COPh
BnO
HO
BnO
3
COPh
6
5
OH
HO
28
26
27
Ph
2
H
9
1
O
OH
H
H
BnO
9
COPh
5
O
6
8
BnO
3
4
Re
H
M+
8
5
6
H
4
7
7
M+O
Ph
Si
H
2
C
3
O
H
COPh
O
1
29-Si (folded)
29-Re (unfolded)
t--BuOK
protocol
t-BuOK/t-BuOLi
protocol
eq. 1
eq. 2
(77% yield)
(76% yield)
trans-24
t-BuOK
cis-23
not isolable
COPh
CH
COPh
CH
OH
6R
OH
6R
O
O
t-BuOK
BnO
BnO
COPh
+
COPh
2S
2R
5R
5R
OH
6R
OH
6R
trans-24 (30%)
cis-23 (44%)
1.47 : 1 ratio
CH2COPh
CH2COPh
O
O
BnO
BnO
+
2S
2R
5R
5R
+ 25β (26%)
cis-21
(23%)
almost 1 : 1 ratio
O
trans-22
(22%)
BnO
+
4
20 (55%) (see Scheme 10)
PhCOO
3
CH2COPh
Scheme 8. Reaction of epoxide 6β with potassium (19-K) and lithium enolate 19-Li prepared by
dibenzoylmethane/t-BuOK (eq.1) and dibenzoylmethane/t-BuOK/t-BuOLi protocol (eq.2),
respectively.
The formation of 2,5-dihydrofurans cis-21 and trans-22 or, better, of the corresponding 2-
(dibenzoylmethyl) derivatives cis-23 and trans-24, the primary reaction products (eq.1, Scheme
8),39 can be rationalized as previously admitted for the corresponding reaction of epoxide 6β
with lithium enolate 10-LiHMDS (Scheme 7). SN2’addition of enolate 19-K to epoxide 6β
reasonably leads to a mixture α- 25α and β-C-glycoside 25β (eq.1, Scheme 8).40 Subsequent
retro oxa-Michael reaction (26, 27), followed by equilibration to alcoholate 28 and
intramolecular oxa-Michael reaction, as shown in intermediates 29-Si and 29-Re, leads to not
8

ACCEPTED MANUSCRIPT
isolable 2,5-dihydrofurans cis-23 and trans-24 (eq. 1, Scheme 8). Actually, a fast mono-
debenzoylation process by intermolecular retro-Claisen condensation by t-BuOK transforms cis-
23 and trans-24 into the corresponding 2-(benzoylmethyl) derivatives cis-21 and trans-22, the
reaction products, as shown in Scheme 9 (for simplicity, only the transformation of trans-24 into
corresponding trans-22 is shown).39
O
O
CH
Ph
Ph
O−
CH=C
Ph
OH
OH
OH
t-BuOK
O
O
BnO
CH
BnO
O
BnO
Ph
Ph
O
t-BuO
O
22'
trans-24
protonation
t-BuO− K+
OH
O
BnO
CH2COPh
trans-22
Scheme 9. Mono-debenzoylation by retro-Claisen condensation of 2,5-dihydrofuran trans-24
with the formation of corresponding 2,5-dihydrofuran trans-22.
This result indicates that the cyclization step, with ring contraction, is not stereoselective and
indifferently occurs at both Si and Re faces of sp2 vinyl C(4)-carbon of intermediate α,β-γ,δ-
conjugated system 28 through the folded 29-Si and unfolded conformer 29-Re to the point that
an almost 1:1 mixture (45%) of the corresponding final mono-benzoylated 2,5-dihydrofurans
cis-21 and trans-22 is obtained in the crude reaction product (eq. 1, Scheme 8).41
D
-Gulal-derivative 20 is obtained by an attack of the nucleophile (potassium enolate 19-K) at
oxirane C(3)-carbon, in a trans-diaxial opening fashion of the oxirane ring, to give 3-
(dibenzoylmethyl)-derivative 30, as corresponding alcoholate 30’. The occurrence of an
intramolecular retro-Claisen condensation, as shown in intermediate 31, is accompanied by O-
benzoylation of the adjacent alcoholate group with the obtainment of the final all-protected
product 20 (Scheme 10).38,39
9

ACCEPTED MANUSCRIPT
O
O
O
OBn
O
BnO
BnO
Ph
O−
K+
Ph-C
O
4
−
O
O
O
Ph
19-K
CH
CH
Ph
Ph
3
Ph
O−
O
O
6β
31
30'
O
O
BnO
PhCOO
BnO
protonation
4
PhCOO
3
CH=C Ph
O
CH2COPh
20
20'
Scheme 10. Rationalization of the formation of D-gulal derivative 20 in the reaction of epoxide
6β with potassium enolate of dibenzoylmethane (19-K)
The same reaction of epoxide 6β was repeated with the corresponding Li-enolate (19-Li) by
means of the so-called t-BuOK/t-BuOLi protocol in which t-BuOK (1 equiv) is exclusively used
to generate epoxide 6β from trans-hydroxy mesylate 9β, whereas t-BuOLi (3 equiv) is
exclusively used for the formation of enolate 19-Li (3 equiv) (eq. 2, Scheme 8). These new
conditions would have determined the presence in the reaction mixture of a cation (Li+), more
coordinating than the previously used K+ (from t-BuOK), with beneficial effect both on the
regioselectivity of the addition process (increased 1,4-/3,4-adduct ratio) and, as a consequence,
on the formation of 2,5-disubstituted-2,5-dihydrofurans with possible syn-stereoselectivity
(increased corresponding cis/trans ratio).42
Actually, these modified reaction conditions led to a 26:44:30 mixture of β-C-glycoside 25β
(1,4-cis-product), and 2,5-dihydrofurans cis-23 and trans-24 to indicate that in this case only 1,4-
adducts were obtained33,42 and that no mono-debenzoylation process had occurred at any level.43
Moreover, as expected, 2,5-dihydrofurans cis-23 and trans-24 are obtained in a satisfactory
amount (74%)42 and a significant, even if slight, syn-stereoselectivity is observed (cis-23/trans-
24 ratio = 1.47) (eq. 2, Scheme 8 and Table 2, entry 2) (vide infra).
C-glycoside 25β was separated pure by preparative TLC, whereas 2,5-dihydrofurans cis-23
1
and trans-24 turned out to be inseparable. Even if obtained in a mixture, accurate H NMR
analysis made the structural identification of cis-23 and trans-24 possible, with determination of
their relative configuration and amount in the crude reaction mixture.
The stereoselective formation of β-C-glycoside 25β can be rationalized by admitting the
occurrence of a metal-mediated intermolecular oxirane oxygen-nucleophile (19-Li) coordination,
10

ACCEPTED MANUSCRIPT
as shown in 32, followed by, completely stereoselective, nucleophilic attack at C(1)-carbon of
epoxide 6β from the same side as the oxirane oxygen. (Scheme 11).33,44
+
−
Ph
O
Li
Ph
COPh
CH
O
Li
O
O
CH
OBn
OBn
HC
1
O
O
O
COPh
BnO
HO
4
COPh 19-Li
COPh
1
4
THF
6β
25β
32
Scheme 11. Rationalization of the formation of β-C-glycoside 25β in the reaction of epoxide 6β
with lithium enolate of dibenzoylmethane (19-Li).
The formation of dihydrofurans cis-23 and trans-24 follows the rationalization previously
given for the corresponding reaction of epoxide 6β with potassium enolate 19-K (eq. 1 and 2,
Scheme 8). In this framework, the presence in the reaction mixture of the more coordinating
lithium cation could reasonably favour the occurrence of the folded intermediate conformer 29-
Si (M = Li) and, as a consequence, the formation of 2,5-dihydrofuran cis-23 with the slight syn-
stereoselectivity observed (eq. 2, Scheme 8).32b
The obtainment of β-C-glycoside 25β made it possible to have a confirmation of the
proposed mechanism of formation of 2,5-dihydrofurans in the reaction of epoxide 6β with metal
enolates of methylene active compounds (Schemes 7 and 8). Actually, the treatment of a THF
solution of β-C-glycoside 25β with t-BuOK (2 equiv) afforded, after 3 h stirring at room
temperature, an almost 1:1 mixture of 2,5-dihydrofurans cis-21 and trans-22 (eq. 1, Scheme
12),39 a result very similar to the one obtained in the reaction of epoxide 6β with potassium
enolate 19-K (eq. 1, Scheme 8).
CH(COPh)2
t-BuOK
O
BnO
HO
1 : 1
(R = H)
cis-21
(eq. 1)
trans-22
OH
THF
OH
25β
(82% yield)
O
O
BnO
CHRCOPh
BnO
+
CHRCOPh
O
BnO
19-LiHMDS
6 : 4
(R = COPh)
cis-23
trans-24
(eq. 2)
THF
(74% yield)
O
6β
Scheme 12. The treatment of β-C-glycoside 25β with t-BuOK (eq. 1) and of epoxide 6β with
lithium enolate 19-LiHMDS prepared by dibenzoylmethane/LHMDS protocol (eq. 2).
11

ACCEPTED MANUSCRIPT
Table 1. Regio- and stereoselectivity of the reactions of epoxides 6β and 6α with lithium and
potassium enolates of dimethyl malonate.
OH
O
O
O
CO2Me
BnO
6β
BnO
BnO
HO
O
CH2(CO2Me)2
BnO
CH(CO2Me)2
HO
O
CH(CO2Me)2
Yield
(%)
Reaction
conditions
cis-12
11
13β
1) t-BuOK/THF
only product
83
79
−
−
−
−
2) t-BuOK/t-BuOLi
THF
only product
3) LHMDS/THF
78
65
35
−
CO2Me
CH
CO2Me
O
OH
CO2Me
CH
CO2Me
CO2Me
CH
CO2Me
O
O
OH
BnO
BnO
BnO
CH2(CO2Me)2
O
O
HO
HO
6α
O
OBn
OBn
CH(CO2Me)2
Yield
(%)
Reaction
conditions
cis-35
trans-36
33
34α + 34β
4) t-BuOK/THF
only product
78
75
−
38a
−
−
31b
5) t-BuOK/t-BuOLi
THF
31
−
6) LHMDS/THF
complex reaction mixture
a
C-glycosides 34α and 34β was recovered from the reaction mixture only as an inseparable
mixture of corresponding acetates 34α-OAc and 34β-OAc.
b
2,5-Dihydrofuran trans-36 was recovered from the reaction mixture only as corresponding
acetate trans-36-OAc.
12

ACCEPTED MANUSCRIPT
Table 2. Regio- and stereoselectivity of the reactions of epoxides 6β and 6α with lithium and
potassium enolates of dibenzoylmethane.
COPh
CH
R
R
OH
O
OH
O
O
BnO
HO
BnO
6β
BnO
COPh
O
CH2(COPh)2
CHCOPh
O
CHCOPh
PhCOO
OBn
OBn
O
PhCOCH2
Yield
(%)
Reaction
conditions
cis-21, R = H
cis-23, R = COPh
trans-22, R = H
trans-24, R = COPh
20
25β
1) t-BuOK/THF
77
76
55
23 (cis-21)
44 (cis-23)b
22 (trans-22)
30 (trans-24)b
−
26a
2) t-BuOK/t-BuOLi
THF
3) LHMDS/THF
−
74
60 (cis-23)b
40 (trans-24)b
−
−
COPh
CH
COPh
COPh
CH
COPh
O
O
O
O
O
BnO
BnO
BnO
BnO
HO
BnO
CH2(COPh)2
HO
PhCOO
PhCOO
6α
O
PhCOCH2
PhCOCH2
Yield
(%)
39
40
Reaction
conditions
38α
38β
1) t-BuOK/THF
78
80
68
15
17
15
−
2) t-BuOK/t-BuOLi
THF
85
−
−
3) LHMDS/THF
complex reaction mixture
a The treatment of 25β with t-BuOK afforded an almost 1:1 mixture of 2,5-dihydrofurans cis-21
and trans-22.
b
2,5-Dihydrofurans cis-23 and trans-24 were recovered from the reaction mixture as an
inseparable mixture (Scheme 12, eq.1).
Finally, the use of a stronger base was examined. In this way, the reaction of epoxide 6β with
lithium enolate 19-LiHMDS, prepared by dibenzoylmethane/LHMDS protocol, led to a crude
reaction product only consisting of a chemoselective 60:40 mixture of 2,5-dihydrofurans cis-23
and trans-24 (eq. 2, Scheme 12 and Table 2, entry 3).43 The observed slight syn-stereoselectivity
(cis-23/trans-24 ratio = 1.5, similar to that previously observed with 19-Li (t-BuOK/t-BuOLi
protocol, eq. 2, Scheme 8), even if partially satisfactory, is decidedly inferior to the complete
13

ACCEPTED MANUSCRIPT
syn-stereoselective result observed in the reaction of epoxide 6β with lithium enolate of dimethyl
malonate (10-LiHMDS) under the same conditions (Scheme 7). The higher basicity of an ester
carbonyl oxygen, as present in intermediate 17 from the reaction of 6β with 10-LiHMDS
(Scheme 7), with respect to a ketonic carbonyl oxygen, as present in intermediate 28 from the
corresponding reaction of 6β with 19-Li (Scheme 8), could be responsible of the exclusive
occurrence of the Li+-coordinated folded conformer 18-Si and, thus, of the completely syn-
stereoselective result32b found in the reaction of epoxide 6β with 10-LiHMDS (Scheme 7).
2.1.2. Reaction of epoxide 6α with metal enolates of dimethyl malonate and dibenzoylmethane
Following the protocol previously used for epoxide 6β, a THF solution of epoxide 6α was
treated with a preformed THF solution of potassium enolate of dimethyl malonate (10-K). The
reaction turned out to be completely regio- and anti-stereoselective affording D-glucal-derivative
33 (3,4-trans-product), as the only reaction product (Scheme 13 and Table 1, entry 4).45
O
O
O
BnO
HO
BnO
BnO
MsO
10-K
t-BuOK
4
4
THF
(78% yield)
THF
3
3
O
CH
OH
COOMe
MeOOC
9α
33
6α
Scheme 13. Reaction of epoxide 6α with potassium enolate of dimethyl malonate (10-K).
As expected, the behaviour of epoxide 6α drastically changes when t-BuOK/t-BuOLi
protocol was used. Actually, under these reaction conditions, the obtained crude product turned
out to be constituted by a 1:1 mixture of 2,5-dihydrofurans cis-35 (31%) and trans-36 (31%),
accompanied by a 1:1.5 mixture of diastereoisomeric 1,4-cis- and 1,4–trans-products, α- 34α
1
and β-C-glycoside 34β (38%, H NMR) which was subjected to preparative TLC (Scheme 14
and Table 1, entry 5). Only 2,5-dihydrofuran cis-35 was obtained pure and the remaining
mixture of trans-36, 34α and 34β was acetylated by Ac2O/pyridine protocol. Preparative TLC of
the obtained crude acetylated mixture afforded pure O-Ac-derived dihydrofuran trans-36-OAc,
whereas -OAc-derived α- 34α-OAc and β-C-glycoside 34β-OAc were recovered as an
inseparable 1:2 mixture (Scheme 14).
14

ACCEPTED MANUSCRIPT
OH
COOMe
CH
CH2(COOMe)2
O
BnO
COOMe
CH
1
t-BuOLi
COOMe
cis-35 (31%)
COOMe
CH
THF
O
O
O
1
BnO
BnO
MsO
t-BuOK
10-Li
THF
(75% yield)
BnO
+
COOMe
4
THF
OR
4
RO
O
O
BnO
OH
34α + 34β
(1:1.5, R= H, 38%)
COOMe
9α
6α
trans-36 (31%), R = H
Ac2O/Py
Ac2O/Py
34α-OAc + 34β-OAc
(1:2, R = Ac)
trans-36-OAc, R = Ac
Scheme 14. Reaction of epoxide 6α with lithium enolate of dimethyl malonate (10-Li) by t-
BuOK/t-BuOLi protocol.
2,5-Dihydrofurans cis-35 and trans-36 derive from a rearrangement of α- 34α and/or β-C-
glycoside 34β through a mechanism similar to the one previously described for the formation of
corresponding 2,5-dihydrofuran cis-12 from epoxide 6β (Scheme 7). The absence of syn-
stereoselectivity with epoxide 6α could be due to the different stability of the folded transition
states TS-18-Si (from 6β) and TS-37-Re (from 6α) leading to the corresponding 2,5-
dihydrofuran cis-12 and cis-35, respectively (Schemes 7 and 15).46 In this framework, an
appropriate theoretical study indicated that TS-18-Si, the folded transition state leading to 2,5-
dihydrofuran cis-12 from epoxide 6β, is 0.89 kcal/mol more stable than TS-37-Re, the folded
transition state leading to 2,5-dihydrofuran cis-35 from epoxide 6α (Supplementary data).47 The
reason of the observed different stability can reasonably be found in the different relationship
between the corresponding residual C(6)-C(7) and C(8)-C(9) bonds: a favourable anti-
relationship is present in TS-18-Si whereas a less stable gauche-relationship is found in TS-37-
Re (Scheme 15 and Figure 1 in Supplementary data).
15

ACCEPTED MANUSCRIPT
new bond
forming
O(7)-C(4)
1
O
δ−
OMe
2
δ−
Li+
1
1
H
O
O
OMe
OMe
8
8
δ−
H
H
9
2
9
MeO
MeO
2
O H
O
O H
4
C(3)
7
BnO
BnO
9
O
Si
3
3
8
8
Li+
Li+
8
O
O
H
BnO
C(8R)
R2
O
R1
7R
2
5R
2S
4
4
6
6
OMe
H
H
5
5
O
Si
1
7
7
H
H
Si
O−
O
δ−
5
cis-12
6
H
7
7
H
H
new bond
forming
O(7)-C(4)
H
Intermediate
folded conformer 18-Si
from epoxide 6β (see Scheme 7)
Transition state TS-18-Si (folded)
(anti relationship between C(6)-C(7) and C(8)-C(9) bonds)
leading to cis-2,5-disubstituted-2,5-dihydrofuran cis-12
OH
6R
R1 = BnO
R2 = CH(COOMe)2
δ−
new bond
forming
O(7)-C(4)
1
O
MeO
2
1
O
OBn
1
O
δ−
OBn
9
Li+
MeO
8
H
9
MeO
8
OMe
2
H O
OMe
2
H O
H
δ−
H
O
3
Re
8
Li+
C(3)
3
O
7
R2
8
Li+
O
4
R1
5S
O
H
O
H
2R
8
2
4
6
7S
5
C(8R)
Re
4
6
5
7
H
MeO
H
O
7
O−
1
H
Re
cis-35
H
7
O
δ−
H
5
6
7
H
new bond
forming
O(7)-C(4)
9
OBn
H
Intermediate
folded conformer 37-Re
from epoxide 6α
Transition state TS-37-Re (folded)
(gauche relationship between C(6)-C(7) and C(8)-C(9) bonds)
leading to cis-2,5-disubstituted-2,5-dihydrofuran cis-35
Scheme 15. Folded transition states TS-18-Si and TS-37-Re involved in the formation 2,5-
dihydrofurans cis-12 and cis-35 by the reaction of epoxides 6β and 6α, with lithium enolate of
dimethyl malonate (10-Li), respectively.
As previously done with epoxide 6β, also in this case the use of a stronger base was
examined. Unfortunately, the treatment of a THF solution of epoxide 6α with lithium enolate 10-
LiHMDS, by dimethyl malonate/LHMDS protocol, afforded only a complex reaction mixture
which was not furtherly examined (Table 1, entry 6).
The reaction of epoxide 6α with the potassium enolate of dibenzoylmethane (19-K) led to a
crude reaction mixture mostly consisting of α-C-glycoside 38α (1,4-cis-product) (68%)
accompanied by small amounts of
D-glucal-derivative 39 (3,4-trans-product) (15%) and the
diastereoisomeric
entry 4).38
D
-allal-derivative 40 (3,4-cis-product) (17%) (eq.1, Scheme 16 and Table 2,
16

ACCEPTED MANUSCRIPT
COPh
O
O
O
1
BnO
BnO
BnO
COPh
+
4
4
+
(eq. 1)
19-K
THF
(78% yield)
4
PhCOO
PhH2COO
HO
3
3
O
CH2COPh
CH2COPh
1
BnO
6α
40 (17%)
39 (15%)
38α (68%)
COPh
4
3
O
19-Li
O
1
t-BuOK/t-BuOLi
protoco
(80% yield)
BnO
HO
COPh
(eq. 2)
40 (15%)
+
l
4
38β (85%)
t-BuOK
t-BuOK
complex reaction
mixure
(eq. 3)
38α
38β
THF
THF
Scheme 16. Reaction of epoxide 6α with potassium (19-K) (eq. 1) and lithium enolate of
dibenzoylmethane (19-Li, eq. 2) prepared by t-BuOK and t-BuOK/t-BuOLi protocol,
respectively. Treatment of α- 38α and β-C-glycoside 38β with t-BuOK in THF (eq. 3).
The formation of 1,4-cis-product 38α is in accordance with the occurrence of a metal ion
(K+)-coordinated syn-1,4-addition process, as shown in intermediate structure 41 (route a,
Scheme 17) in which an extended oxirane oxygen-oxirane C(3) carbon is present33,34b
Nucleophilic attack on allyl C(3)-carbon of 41 can occur also by a free, non-coordinated enolate
species, necessarily from the back side because the allyl C(3)-O bond is not broken, by trans-
diaxial oxirane ring opening (route b, Scheme 17). In this way, 3,4-trans-product 43 is obtained
as a not isolable intermediate because of the rapid occurrence of the previously described
intramolecular retro-Claisen condensation which transforms 43 into 4-O-benzoyl-3-
benzoylmethyl derivative 39 (Schemes 16, 17 and 10).48 Moreover, intermediate 41 can evolve,
through an internal rearrangment, to the more carbocationic intermediate 42 in which allyl C(3)-
O bond is completely broken and C(3)-nucleophile coordination is present, as shown (Scheme
17). Entropically favoured nucleophilic attack on 42 by the coordinated nucleophile, with
retention of configuration, affords 3,4-cis-product 44 (route c).49 However, as in the case of 43,
3-dibenzoylmethyl derivative 44 is not isolable because of its transformation, under the reaction
conditions, into the isomeric derivative 40, the reaction product (Scheme 17).38
17

ACCEPTED MANUSCRIPT
O
see
Scheme 10
BnO
4
39
HO
3
43
CH(COPh)2
40
δ-
COPh
δ-
route b
BnO
O
see
Scheme 10
BnO
Ph
b
O
1
O
O
δ+
4
δ-
BnO
4
a
route c
COPh
δ-
6α
3
4
O
δ+
3
COPh
HO
c
3
Ph
δ-
+
δ-
δ-
44
+
CH(COPh)2
O
O
K
O
K
route a
38α
δ+
Ph
41
42
Scheme 17. Rationalization of the formation of 1,4-.cis-product 38α (route a), 3,4-.trans-
product 39 (route b) and 3,4-cis-product 40 (route c) in the reaction of epoxide 6α with
potassium enolate of dibenzoylmethane (19-K).
A somewhat similar result was obtained when the same reaction of epoxide 6α was repeated
by means of the t-BuOK/t-BuOLi protocol. Actually, also under these modified conditions, no
corresponding 2,5-dihydrofurans were obtained, but, contrary to expectations based on the
presence of the more coordinating Li+ in the reaction mixture, β-C-glycoside 38β (1,4-trans-
product) was the main reaction product (85%) accompanied only by D-allal-derivative 40 (15%)
(eq. 2, Scheme 16, and Table 2, entry 5).50,51
The results obtained in the reactions of epoxide 6α with metal enolates of dibenzoylmethane
(19-K and 19-Li), under different conditions, indicate that the desired corresponding 2,5-
dihydrofurans are not formed even though a necessary precursor for the rearrangement process,
as 1,4-cis- 38α or 1,4–trans-product 38β is always the main reaction product (Scheme 16, eq.
1 and 2). As a consequence, in order to force the formation of 2,5-dihydrofurans, THF solutions
of α- 38α and β-C-glycoside 38β were separately treated with t-BuOK (2 equiv) for 3 h at room
temperature. Unfortunately, only very complex reaction mixtures were obtained in both cases to
indicate an intrinsic, unexplained, difficulty of C-glycosides 38α and 38β to rearrange to 2,5-
dihydrofurans (Scheme 16, eq. 3).
2.2. Reaction of epoxides 6α and 6β with lithium anion of benzyl carbamate
The possibility to have with epoxides 6α and 6β a corresponding rearrangement to 2,5-
dihydrofuran systems by the use of a nitrogen-based anion, as the nucleophile, was checked. For
18

ACCEPTED MANUSCRIPT
this purpose, benzyl carbamate (BnOCONH2), having an N-H bond sufficiently acid (Ka=10-12)52
to be completely deprotonated by a base both in the preparation of the corresponding lithium
anion 45-LiHMDS and in the rearrangement process was thought appropriate.
2.2.1. Reaction of epoxide 6β with lithium anion of benzyl carbamate
The addition at 0° C of lithium anion of benzyl carbamate 45-LiHMDS (prepared at –78 °C
from benzyl carbamate and LHMDS) to a THF solution of epoxide 6β afforded after 18 h
stirring at room temperature, a crude reaction mixture mostly consisting of 2-
(benzyloxycarboxamido)-2,5-dihydrofuran cis-49, the expected rearrangement product (92%)
accompanied by a small amount of
3, entry 1). Only 2,5-dihydrofuran cis-49 was separated pure by preparative TLC.
D
-gulal-derivative 50 (8%) (1H NMR) (Scheme 18 and Table
C(1)-O(5) bond
Li+
cleavage
O
5
O
δ+
OBn
NHCO2Bn
O
O
OBn
BnO
HO
HN
5
BnO
4
route a
1
45-LiHMDS
O
t-BuOK
9β
a
47β
THF
4
THF
1
O
(58% yield)
base
H
3
6β
46
b
OBn
O
1
O
HN
O− Li+
H
Li+
O
OBn
2
LHMDS
THF
BnO
3
N
BnOCONH2
BnO-C=NH
8
route b
6
5
7
45-LiHMDS
Si
H
4
O
H
O
BnO
OH
48-Si
4
O
NHCO2Bn
BnO
HO
50 (8%)
3
NHCO2Bn
cis-49 (92%)
(not isolated)
Scheme 18. Reaction of epoxide 6β with lithium anion of benzyl carbamate (45-LiHMDS),
prepared by LHMDS protocol.
The presence of 2,5-dihydrofuran cis-49 and the small amount of 3,4-trans-product 50
indicate that the addition of nitrogen-based lithium anion 45-LiHMDS is particularly effective
in determining 1,4-addition process, reasonably a syn-1,4-addition process (vide infra for the
corresponding reaction of epoxide 6α). In this way, β-N-glycoside 47β (1,4-cis-product)53
initially obtained as shown in structure 46 (Scheme 18, route a) undergoes a very effective base-
catalyzed isomerization to 2,5-dihydrofuran cis-49, in a nice, completely syn-stereoselective
fashion,32b through the folded intermediate conformer 48-Si whose occurrence is due, in addition
to its anti-butane-like conformation (see Scheme 15 for the corresponding 18-Si), to the basicity
19

ACCEPTED MANUSCRIPT
of the carbamate moiety favouring the formation of the shown intramolecular cation binding
(Scheme 18).
As for
D-gulal derivative 50, its formation is due to an attack by a free, non-coordinated
nucleophile (45-LiHMDS) at C(3) oxirane carbon of epoxide 6β, as shown in 46 (Scheme 18,
route b).
Table 3. Regio- and stereoselectivity of the reactions of epoxides 6β and 6α with lithium anion
of benzyl carbamate.
OH
O
O
BnO
6β
BnO
O
NH2CO2Bn
NHCO2Bn
BnO
+
HO
O
NHCO2Bn
Yield
(%)
Reaction
conditions
cis-49
50
8a
1) LHMDS/THF
58
92
O
NHCO2Bn
O
BnO
BnO
HO
NH2CO2Bn
6α
O
Yield
(%)
Reaction
conditions
52α
only productb
2) LHMDS/THF
59
a Not isolated.
b The treatment of 52α with t-BuOK afforded a 71:29 mixture of 2,5-dihydrofurans cis-53 and
trans-54 (Scheme 20).
2.2.2. Reaction of epoxide 6α with lithium anion of benzyl carbamate
The same reaction was repeated with epoxide 6α under the same reaction conditions
previously successfully used with epoxide 6β. In this case, the crude reaction mixture showed
the exclusive presence of the corresponding α-N-glycoside 52α (1,4-cis-product),53 as the result
of a completely syn-stereoselective 1,4-addition process, as shown in structure 51 (Scheme 19
and Table 3, entry 2).
20

ACCEPTED MANUSCRIPT
OBn
5
O
1
NHCO2Bn
O
O
BnO
BnO
HO
45-LiHMDS
1
4
NH
O
THF
4
BnO
+
O
(59% yield)
O
52α
6α
Li
51
Scheme 19. Reaction of epoxide 6α with lithium anion of benzyl carbamate (45-LiHMDS),
prepared by LHMDS protocol.
The possibility of forcing the rearrangement process was tried by treating a THF solution of
52α with t-BuOK (1.5 equiv). After 3 hours stirring at room temperature, a 71:29 mixture of
diastereoisomeric 2-(benzyloxycarboxamido)-2,5-dihydrofurans cis-53 and
trans-54 was
obtained (Scheme 20), then separated by preparative TLC and their structure determined by
NMR spectroscopy.
OBn
H
52α
t-BuOK
1
O
HO
H
O
OBn
H
THF
5
6
8
2
+
Li
H
4
7
3
BnO
N
Si
H
8
6
+
O
7
Li
5
4
N
7
−O
7
H
Re
H
BnO C
BnO
O
55-Re (folded)
55-Si (unfolded)
OH
OH
O
O
NHCO2Bn
BnO
NHCO2Bn
cis-53 (71%)
trans-54 (29%)
Scheme 20. The treatment of α-N-glycoside 52α with t-BuOK.
It is interesting to note that, in the rearragement process, the formation of 2,5-dihydrofuran
cis-53, reasonably proceeding through the folded conformer 55-Re, is consistently favoured, as
expected, over the diastereosimeric 2,5-dihydrofuran trans-54, formed by the corresponding
unfolded conformer 55-Si. Also in this case, the type and strength of the intramolecular
coordination of lithium cation with carbamate carbonyl Ο(1), alcoholate O(7) and secondary
alcohol O(8) oxygens, occurring in the folded intermediate conformer 55-Re, is able to determine
the observed, satisfactory, syn-stereoselectivity (Scheme 20).32b
21

ACCEPTED MANUSCRIPT
2.3. Structures and configurations
The structural and configurational characterization of isolated products and crude reaction
mixtures were firmly established by NMR spectroscopy through compared analysis of
homonuclear and 1H-13C heteronuclear scalar correlations in the corresponding COSY
(COrrelation SpectroscopY), TOCSY (TOtal Correlation SpectroscopY), HSQC (Heteronuclear
Single Quantum Correlation) and HMBC (Heteronuclear Multiple Bond Coherence) maps and of
dipolar correlations in NOESY (Nuclear Overhauser Effect SpectroscopY) spectra. In this
framework, it is very important to keep in mind that the configuration (α or β) at C(5) carbon in
the obtained six- (3,4-cis- and 3,4-trans-procucts and 1,4-cis- and 1,4-trans-products) and five-
membered-heterocyclic systems (cis- and trans-2,5-disubstituted-2,5-dihydrofurans) is the same
as the configuration (α or β) at C(5) carbon of the starting epoxide, 6α or 6β, respectively
(Schemes 21, 22 and 23).54
3,4-trans-products
H6
H6
7
O
O
O
BnO
YO
BnO
YO
H5
BnO
2
3
6
6
6
5
NOE
5
5
4
4
7
H5
XHC
4
O
O
6α
NOE
H4
H4
XHC
2
3
BnO
6β
6
5
33, 39
11, 20
4
O
NOE
NOE
NOE
NOE
H
H7
H2
7H6 H2
O
H6
H6
H2
X
CHX
O
O
X
BnO
YO
BnO
YO
BnO
YO
6
6
6
2
2
2
5
5
5
NOE
H5
H5
H5
H4
H4
H4
34β, 34β-OAc,
38β
13β, 13β-OAc, 25β
34α, 34α-OAc,
38α,52α
1,4-cis-products
1,4-trans-products
11, 33: X = (CO2Me)2 Y = H; 13β: X = CO2Me, Y = H; 13β-OAc: X = CO2Me, Y = Ac;
20: X = HCOPh, Y = PhCO; 25β: X = CH(COPh)2 Y = H; 34α: X = CH(CO2Me)2, Y = H;
34α-OAc: X = (CO2Me)2, Y = Ac; 34β: X = (CO2Me)2, Y = H; 34β-OAc: X = CH(CO2Me)2, Y = Ac;
38α: X = CH(COPh)2, Y = H; 38β: X = (COPh)2, Y = H; 39: X = HCOPh, Y = PhCO;
52α: X = NHCO2Bn, Y = H.
Scheme 21. NOEs in 3,4-trans-products and 1,4-cis- and 1,4-trans-products from both epoxides
6α and 6β. The spatial relationship of methine proton H(5) with two methine protons, vinyl H(4)
22

ACCEPTED MANUSCRIPT
and non-vinyl H(6) in the case of 1,4-cis- and 1,4-trans-products, and non-vinyl H(6) and H(4)
in the case of 3,4-trans-products, is also shown.
The assessment of five- vs six-membered heterocyclic structure relied on the nature of OH
scalar couplings, which were detected only in CD3CN and/or DMSO-d6. In all 2,5-disubstituted-
2,5-dihydrofurans obtained, OH proton showed couplings with methine proton H(6), which was
J-coupled with non–vinyl methine proton H(5) and methylene protons H(7) and H(7'). On the
contrary, in the case of six-membered heterocyclic structures, the corresponding OH proton-
coupled methine proton H(5) was J-coupled with two methine protons: vinyl H(4) and non-vinyl
H(6) protons, in the case of 1,4-cis- and 1,4–trans-products, and non-vinyl H(6) and H(4)
protons, in the case of 3,4-trans-products. It is noteworthy that, accordingly to the structural
attribution, H(5) proton of five-membered 2,5-dihydrofuran systems was always high-
frequencies shifted with respect to H(5) proton in the corresponding six-membered compounds.
The same trend was found for the carbon, which is directly connected to it. Furthermore, H(7)
and H(7') protons of 2,5-disubstituted-2,5-dihydrofuran compounds originated dipolar interaction
with vinyl proton H(4): a similar interaction is not detected in six-membered cyclic structures
(Schemes 21 and 22).
cis-2,5-disubstituted-2,5-dihydrofurans
NOE
NOE
NOE
HO H
HO H
6H5
6 H5
7
BnO
BnO
H2
X
O
BnO
BnO
O
H2
X
2
6
5
4
H4
H '
H '
H7
H7
7
7
3
7
7
H4
O
O
NOE
NOE
BnO
2
3
2
3
BnO
6
5
6
5
cis-12,-21,-23,-49
cis-35,-53
4
4
6α
O
O
NOE
6β
NOE
YO H
6 H5
HO H
6H5
X
O
O
CHX
H2
H2
H '
H7
7
H '
H7
7
H4
H4
NOE
NOE
trans-22,-24
trans-36-OAc,-54
trans-2,5-disubstituted-2,5-dihydrofurans
cis-12: X = CH(CO2Me)2; cis-21: X = CH2COPh; trans-22: X = HCOPh; cis-23: X = CH(COPh)2;
trans-24: X = (COPh)2; cis-35: X = CH(CO2Me)2; trans-36-OAc: X = CH(CO2Me)2, Y = Ac;
cis-49, cis-53: X = NHCO2Bn; trans-54: X = NHCO2Bn, Y = H
23

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Scheme 22. NOEs in cis- and trans-2,5-disubstituted-2,5-dihydrofurans from both epoxides 6α
and 6β. The spatial relationship of proton H(6) with non–vinyl methine proton H(5) and
methylene protons H(7) and H(7') is also shown.
The regioisomeric structure of glycal-derived 3,4-trans-products and 1,4-cis- and 1,4–trans-
products was ascertained by exploiting the homonuclear scalar couplings starting from the
double bond protons, and dipolar interactions produced by substituents present at C(4) and C(6)
or C(2) and C(6) for 3,4-trans-products and 1,4-cis and 1,4–trans-products, respectively
(Scheme 21). In particular, the following valuable interactions were observed: a) NOE between
H(6) proton and CH proton at C(4) in compounds 11 and 20 (3,4-trans-products from epoxide
6β) and between H(6) and H(4) protons in compounds 33 and 39 (3,4-trans-products from
epoxide 6α; b) NOE between H(6) and H(2) protons in compounds 13β, 13β-OAc and 25β (1,4-
cis-products from epoxide 6β); c) NOE between H(2) and H(7,7’), H(2) and H(5), and H(6) and
CH proton at C(2) in compounds 34α, 34α-OAc, 38α, and 52α (1,4-cis-products from epoxide
6α); d) NOE between H(6) and H(2) protons in compound 34β, 34β-OAc and 38β (1,4-trans-
products from epoxide 6α) (Scheme 21).
The spatial relationship between the two substituents in C(2) and in C(5) of cis- and/or trans-
2,5-disubstituted-2,5-dihydrofurans was established on the basis of the dipolar interactions
(NOESY) detected between substituents at C(2) and C(5). In this way, NOE between protons
H(2) and H(5), as well, when possible, between H(6) and CH-proton of the substituent chain at
C(2) are clearly indicative of a cis-arrangement of the involved substituents and as a
consequence of the corresponding structure of cis-2,5-disubstituted-2,5-dihydrofuran derivative
(compounds cis-12, cis-21, cis-23 and cis-49 from epoxide 6β and cis-35 and cis-53 from
epoxide 6α, Scheme 23). In this framework, the presence of NOE between H(5) and CH proton
of the side chain at C(2) and between H(2) and H(6) protons are indicative of a trans-
arrangement of substituents at C(2) and C(5) as a consequence of the corresponding structure of
trans-2,5-disubstituted-2,5-dihydrofuran derivative (compounds trans-22 and trans-24 from
epoxide 6β and trans-36-OAc and trans-54 from epoxide 6α, Scheme 22).
For some compounds, NMR analysis revealed unexpected structural features. In the case of
compounds 13β and 13β-OAc, only a methoxycarbonyl group directly bound to C(2) carbon
1
was detected on the basis of H-13C long range scalar correlation (HMBC) with the endocyclic
H(2) proton, adjacent to oxygen. In both compounds, H(2) proton gave rise to a dipolar
interaction with H(6) proton, thus defining a cis-relationship between substituents at C(2) and
24

ACCEPTED MANUSCRIPT
C(6) carbons of the six-membered ring. Moreover, in the case of the acetyl derivative 13β-OAc,
a NOE between methoxy and acetyl protons was found to indicate a cis-relationship between all
the ring substituents (Scheme 23).
NOE
NOE
H6
H6
H2
COOMe
H2
C
O
O
O
BnO
HO
BnO
O
OMe
13β
O
C
13β-Ac
NOE
Me
H6
O
H6
O
H6
O
BnO
H5
BnO
H5
BnO
H5
5
5
4
5
PhCOO
PhCOO
4
4
PhCOO
NOE
H4
NOE
CH2COPh
39
CH2COPh
NOE
CH2COPh
40
20
Scheme 23. NOEs in methyl β-glycosylcarboxylate 13β, correspnding acetate 13β-OAc,
compounds 20 and 39 from epoxides 6β and 6α, respectively, and 40 from epoxide 6α.
The structures of 3,4-trans-products 20 and 39 and 3,4-cis-product 4038 were even more
surprising since the two moieties (PhCO− and PhCOCH2−) deriving from the starting
nucleophile [PhCOCH=C(Ph)-O−] resulted separately connected at two adjacent carbons C(4)
and C(5) of the six-membered cyclic system (Scheme 23). As a matter of fact, an additional
methylene moiety was detected (−CH2COPh) and the two carbonyl functions (ketone and ester,
13
1
as revealed by their C chemical shifts) showed H-13C long range scalar couplings (HMBC)
with methylene (CH2COPh) and H(5) protons, respectively. The presence of inter-NOE H(6)-
CH2COPh in 20 and 40 and inter-NOE H(6)-H(4) in 39 and all the appropriate considerations
about the ring opening process of epoxides 6α and 6β (see above) made the assignation of the
relative configuration to all substituents in compounds 20, 39 and 40 possible, as shown in
Scheme 23.
3. Conclusions
Highly functionalized, enantiomerically pure 2,5-disubstituted-2,5-dihydrofurans can be
obtained by reaction of
D
-allal- and
D
-galactal-derived vinyl epoxides 6α and 6β with metal
25

ACCEPTED MANUSCRIPT
enolates of methylene active compounds, as dimethyl malonate, dibenzoylmethane (C-
nucleophiles), and lithium anion of benzyl carbamate (N-nucleophile). The obtained 2,5-
disubstituted-2,5-dihydrofurans are the result of a base-catalyzed rearrangement of
corresponding α- and/or β-C- and -N-glycosides (1,4-cis and 1,4-trans-products), the primary
reaction products, with six-membered ring opening followed by ring contraction to five-
membered ring. The presence of a sufficiently acid C-H or N-H bond at α-carbon of the
glycoside side chain is necessary for the rearrangement process to occur. The relative strength of
the intramolecular cation binding occurring in the corresponding folded reaction intermediate
conformer and the related anti- or gauche-butane-like conformation are responsible of the
observed stereoselectivity. In this way, a complete or slight syn-stereoselectivity is observed
when the reaction proceedes only or partially through the folded intermediate conformer,
whereas a non-stereoselective result is obtained when the reaction indifferently proceedes
through the folded and unfolded intermediate conformer. In this framework epoxide 6β
exclusively leads to corresponding cis-2,5-disubstituted-2,5-dihydrofurans with lithium enolate
of dimethyl malonate and lithium anion of benzyl carbamate, whereas epoxide 6α affords, in the
same reaction conditions, only 1:1 and 71:29 mixtures of corresponding cis- and trans-2,5-
disubstituted-2,5-dihydrofurans. Due to the weaker intramolecular cation binding involved in the
corresponding folded intermediate conformer, the reactions of epoxide 6β with metal enolates of
dibenzoylmethane are not stereoselective and only mixtures of corresponding cis- and trans-2,5-
disubstituted-2,5-dihydrofurans are obtained. The same reaction with epoxide 6α does not lead
to 2,5-dihydrofurans.
26

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4. Experimental
4.1.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 230-400 mesh silica gel (Macherey-Nagel).
Analytical TLC were performed on Alugram SIL G/UV254 silica gel sheets (Macherey-Nagel)
with detection by 0.5% phosphomolybdic acid solution in 95% EtOH. t-BuOK, t-BuOLi, 1 N
LHMDS in THF, dibenzoylmethane, MsCl, Ac2O, HPLC-grade CH2Cl2 and pyridine over
molecular sieves were purchased from Aldrich and used without purification. Dimethyl
malonate, AcOEt and hexane (Aldrich) were distilled before use. THF (over molecular sieves,
Aldrich) and Et2O were distilled from sodium/benzophenone.
D-allal- and D-galactal-derived
vinyl epoxides 6α and 6β were prepared as previously described.33a,c-g Routine 1H and 13C NMR
spectra were recorded at 250 and 62.5 MHz, respectively. 1H NMR COSY, NOESY and HSQC
experiments were performed with a spectrometer operating at 600 MHz. IR spectra were
obtained by means of a FTIR spectrophotometer. Elemental analyses were performed at
Dipartimento di Farmacia, University of Pisa, by means of Carlo Erba Automated CHN
Analyzer model 1106.
4.2. Reactions of epoxide 6
β
with potassium and lithium enolates of dimethyl malonate and
dibenzoylmethane
4.2.1. Reaction of epoxide 6
β
with potassium enolate of dimethyl malonate (10-K, by t-BuOK
protocol)
Typical procedure. A solution of dimethyl malonate (0.079 g, 0.60 mmol, 3.0 equiv) in
anhydrous THF (1.3 mL) was treated in a Schlenk with t-BuOK (0.067 g, 0.60 mmol, 3.0 equiv)
and thr reaction mixture was stirred 45 min at room temperature (Solution A). In the meantime, a
solution of trans-hydroxy mesylate 9β (0.063 g, 0.20 mmol) in anhydrous THF (1.0 mL) was
treated in a second Schlenk with t-BuOK (0.023 g, 0.20 mmol, 1.0 equiv) and the reaction
mixture was stirred at room temperature the time necessary for the cyclization of trans-hydroxy
mesylate 9β to epoxide 6β (15-30 min, TLC) (Solution B). Solution A was added to Solution B.
After 24 hours stirring at room temperature, the reaction mixture was partitioned between Et2O
(20 mL) and saturated aqueous NH4Cl (5 mL) until pH = 4-5 and the organic layer was further
washed with brine, dried (MgSO4), and concentrated under vacuum. The reaction mixture was
filtered through a silica gel pad eluting first with a 9:1 hexane/AcOEt mixture to remove the
27

ACCEPTED MANUSCRIPT
excess of dimethyl malonate, then with AcOEt to obtain a crude consisting of D-gulal derivative
11 (1H NMR) (0.058 g, 83% yield) which was purified by preparative TLC. Elution with a 1:1
hexane/AcOEt mixture afforded pure dimethyl 2-(1,5-anhydro-6-O-benzyl-2,3-dideoxy-D-xylo-
hex-1-enitol-3-yl)propanedioate (11) (0.043 g, 61% yield), as a colourless oil: Rf = 0.41 (1:1
hexane/AcOEt), [α]D20 = −1.8 (c 2.0, CHCl3). FTIR (neat) ν 3313, 1731, 1469, 1259, 1179, 1095
cm-1. 1H NMR (250 MHz, CDCl3) δ 7.25-7.39 (m, 5H), 6.47 (dd, 1H, J = 6.4, 1.5 Hz), 4.62-4.70
(m, 1H), 4.58 (s, 2H), 3.85-3.96 (m, 2H), 3.81 (d, 1H, J = 5.5 Hz), 3.75 (s, 3H), 3.74 (s, 3H),
3.26 (d, 1H, J = 10.1 Hz), 2.85-3.00 (m, 2H), 1.57 (s, 1H, OH).13C NMR (62.5 MHz, CDCl3) δ
168.3, 167.9, 144.8, 137.5, 128.7, 128.1, 128.0, 98.7, 74.1, 72.4, 70.3, 67.4, 56.5, 52.9, 52.8,
38.2. Anal. Calcd for C18H22O7: C, 61.70; H, 6.33. Found: C, 61.45; H, 6.11.
The same result was observed also when the preformed lithium enolate (from t-BuOLi) of
dimethyl malonate (10-Li) was used. In this case D-gulal derivative 11 was obtained with 79%
yield.
4.2.2. Reaction of epoxide 6β with lithium enolate of dimethyl malonate (10-LiHMDS by
LHMDS protocol) in anhydrous THF
Following the typical procedure, a solution of dimethyl malonate (0.253 g, 1.92 mmol, 3.0
equiv) in anhydrous THF (7.0 mL) was added to 1M LHMDS in THF (1.92 mL, 1.92 mmol, 3.0
equiv) and the reaction mixture was stirred 30 min at room temperature (Solution A). A solution
of trans-hydroxy mesylate 9β (0.20 g, 0.64 mmol) in anhydrous THF (5.0 mL) was treated with
t-BuOK (0.072 g, 0.64 mmol, 1.0 equiv) and the reaction mixture was stirred for 15 min at room
temperature (Solution B). Solution A was dropwise added to Solution A. After 24 hours stirring at
room temperature, usual work-up and filtration (paragraph 4.2.1) afforded a crude reaction
product consisting of a 35:65 mixture of 2-[bis(methoxycarbonyl)methyl]-2,5-dihydrofuran cis-
12 and methyl β-glycosylcarboxylate derivative 13β (1H NMR) (0.151 g, 78% yield) which was
subjected to preparative TLC by using a 1:1 hexane/AcOEt mixture, as the eluant. Extraction of
the two most intense bands (the faster moving band contained cis-12) afforded pure 2,5-
dihydrofuran cis-12 (0.040 g, 18% yield) and methyl β-glycosylcarboxylate 13β (0.069 g, 39%
yield).36
Dimethyl
2-[(1S)-1,4-anhydro-6-O-benzyl-2,3-dideoxy-D-threo-hex-2-enitol-1-C-
yl]propanedioate (cis-12), a colourless oil; Rf = 0.45 (6:4 hexane/AcOEt). [α]D20 = −65.6 (c 0.36,
CHCl3). FTIR (neat) ν 3308, 1730, 1455, 1259, 1178 cm-1. 1H NMR (250 MHz, CDCl3) δ 7.25-
28