Sulfur-assisted domino access to bicyclic dihydrofurans: Case study and early synthetic applications

Article abstract of DOI:10.1039/c3ob41324a

A DDQ-mediated domino reaction (up to six steps in a single process) has been developed to selectively provide substituted dihydrofurans from a common starting material containing a cyclic bis-thioenol ether. Study of the reaction mechanism highlighted a role played by the sulfur-containing moiety in influencing reaction rate and stereoselectivity.

Full text of DOI:10.1039/c3ob41324a

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Sulfur-assisted domino access to bicyclic dihydrofurans:
case study and early synthetic applications†
Cite this: Org. Biomol. Chem., 2013, 11,
7825
Concetta Paolella,‡ Daniele D’Alonzo,*‡ Giovanni Palumbo and
Received 27th June 2013,
Annalisa Guaragna*
Accepted 10th September 2013
DOI: 10.1039/c3ob41324a
www.rsc.org/obc
A DDQ-mediated domino reaction (up to six steps in a single
process) has been developed to selectively provide substituted
dihydrofurans from a common starting material containing a
cyclic bis-thioenol ether. Study of the reaction mechanism high-
lighted a role played by the sulfur-containing moiety in influen-
cing reaction rate and stereoselectivity.
Rapid access to bioactive molecules is often hampered by
time-consuming, costly protective group-based strategies
and lengthy purification procedures after each synthetic step.
To circumvent these inconveniences, the potential of multistep
protocols, including domino reactions,1 has been exploited for
the efficient and elegant construction of even complex inter-
mediates in a single process. In this context, our ongoing
efforts working towards the de novo synthesis of optically active
molecules of biological interest2 led us to explore the potential
of 1,2-bis-thioenol ether-containing systems3 in undergoing
domino reactions when used in combination with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ; Scheme 1). While
use of heterocycle 1 brought on C3-homologation of various
electrophiles such as 2, in many cases in a stereoselective
fashion,4,5 the versatile reactivity of DDQ – a result of its com-
bined electron-transfer, oxidative and acidic properties6
–
enabled some new multistep cyclizations of the homologation
products 3, involving sequential 4-methoxybenzyl (PMB) group
deprotection, oxidation of the resulting primary alcohol,
formyl group activation, and eventual cyclization by a suitably
unprotected hydroxyl function (Scheme 1).
Depending on further elaboration of the resulting sugar pre-
cursors, e.g. 4a and 4b, strategies leading to L-hexoses5,7 and
other structurally-related compounds8 have already been develo-
ped (Scheme 1A). Along these lines, access to dihydrofurans 5
Scheme 1 De novo approach to synthetically useful sugar-like scaffolds 4
and 5.
has been herein explored (Scheme 1B), mainly because of their
potential application in the synthesis of bioactive D- and
L-nucleosides9 and nucleic acids.2c With this aim, we first
looked at bicycle 9, which was easily synthesized as depicted in
Scheme 2. Coupling of 1 with glycolate 6 under known con-
ditions3 afforded ketone 7 in an 89% yield. After reduction10 of
7 (BH3·THF, 86%), reaction of the corresponding sec-alcohol 8
with DDQ (1.2 equiv.) in a 95/5 CH2Cl2–MeOH solution enabled
direct conversion of the latter into an α/β mixture of methyl
glycosides 9 (dr = 3.3 : 1; 83% yield) in only 30 min.
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via
Cintia 21, I-80126 Napoli, Italy. E-mail: dandalonzo@unina.it, guaragna@unina.it;
Fax: +39 081 674393; Tel: +39 081 674119
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, copies of 1H and 13C NMR spectra of all new compounds. See DOI:
10.1039/c3ob41324a
Surprisingly, minimal changes in the reaction conditions
caused additional in situ transformations. Treatment of 8 with
‡These authors contributed equally to this work.
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Scheme 3 Domino conversion of ketone 7 into acetals 11.
We started by observing that the last transformation in
Scheme 2 (step f) closely resembled the well-known Clauson-
Kaas reaction, providing 2,5-disubstituted dihydrofurans from
corresponding furans under electrochemical conditions12 or
by means of molecular bromine and chlorine.13 Herein, we
initially established that the same transformation could also
be carried out by DDQ starting from furan 17 (Scheme 4).
However, compared with the conversion of bicyclic furan 10
into 11, the one leading to 18 from 17 was less efficient (50%),
requiring harsher conditions (24 h at reflux) and resulting in
no stereoselection (α : β = 1 : 1). Therefore, the crucial influence
of the dithioethylene bridge on reaction rate and stereo-
selectivity became apparent.
We reasoned that acetalization of furan 17 involved a
double MeOH addition under electron-transfer conditions,
triggered by the in situ-originated5,6,7b acidic medium
(Scheme 5a). Although bicycle 10 could in principle follow the
same path, we more reasonably assumed that the latter under-
went an early electron abstraction from one of the sulfur
atoms, leading to formation of the radical cations 21 and 22
(Scheme 5b). A subsequent MeOH addition, followed by a
further electron abstraction, then provided oxocarbenium ions
(23 and 24). The stability of the species 21–24, due to the wide
positive charge delocalization by the sulfur atoms, could sig-
nificantly contribute to accelerate the reaction. Along these
lines, it’s also conceivable that the stereochemical outcome of
the process could be influenced by the thermodynamic equili-
brium among 23, 24 and 11 (apparently not occurring in the
Scheme 2 Domino approach to (dihydro)furans 9–11.
DDQ (1.8 equiv.) in a 75/25 C6H6–MeOH mixture led, after 3 h
at rt, to formation of bis-acetal 11 (α : β = 6 : 1) in an excellent
90% yield (Scheme 2). As for 9, the process can be considered
a domino reaction, as it proceeded across six sequential steps,
carried out in a single reaction vessel: (a) PMB group removal,
(b) oxidation of the resulting primary alcohol, (c) ring closure,
(d) acetalization, providing 9, (e) MeOH elimination, leading to
10, and (f) double acetalization. Notably, although furan 10
acted as an intermediate under these conditions, it could also
be smoothly isolated as the main product (75%) from 8 by
simply reducing the amounts of DDQ (1.2 equiv.) and MeOH
(C6H6–MeOH = 95/5; Scheme 2).
Not fully unexpected, acetal 11 could be obtained in a
single process even from ketone 7, albeit by a different
sequence of synthetic transformations (Scheme 3). Indeed,
addition of DDQ (1.2 equiv.) to a 95/5 CH2Cl2–MeOH solution
of 7 provided 11 (α : β = 6 : 1) after 3 h at rt in a very good 87%
yield. Although none of the intermediates could be isolated,
we reasonably assumed that formation of 11 was the result of
five sequential steps, including oxidative deprotection of 7,
(hemi)acetalizations of 12 and 13 and subsequent cyclization
of the latter11 (Scheme 3).
The unusual reactivity observed above apparently relies on a
combination of the excellent synthetic versatility of DDQ and
the intriguing chemical properties of the 1,4-dithiinyl group.
Given the apparent synthetic potential of the process, its
mechanism was investigated in greater detail.
Scheme 4 DDQ-mediated double acetalization of 10 and 17.
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Scheme 5 DDQ-mediated double acetalization reactions: proposed mechanisms.
absence of the dithioethylene bridge, i.e. among 19, 20, and disappearance of distinctive 1H signals belonging to 8 [e.g.
18) (Scheme 5).
H4 14 (red) at 5.17 ppm, Scheme 6a] towards the sequential for-
In support of these assumptions, 1H NMR monitoring of mation of those belonging to acetal 25 [H1α and H1β (purple)
the domino reaction (performed in an NMR tube containing 8 at 5.66 ppm and 5.92 ppm, Scheme 6b], furan 10 [e.g. H1
and 1.8 equiv. of DDQ in a 3/1 C6D6–CD3OD mixture) was (green) at 6.89 ppm, Scheme 6b], and hence to bis-acetal 26
carried out (Scheme 6). We excluded any mechanistic path [H1α and H1β (blue) at 5.62 ppm and 5.67 ppm, Scheme 6b and
other than that described in Scheme 2, by recognizing the c]. Most importantly, the ongoing changes in the α/β ratio (e.g.,
Scheme 6 1H NMR monitoring of the domino reaction.
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Table 1 DDQ-mediated double trans-acetalizations of 11αa
Entry
Compound
R
Time (h)
Yield (%)
(α : β)
6 : 1c
>20 : 1
6 : 1
>99c
71
83
b
1
2
3
4
26
CD3
24
24
48
48
27a
27b
27c
CF3CH2
HCuCH2
i-Pr
90
>20 : 1
a All reactions were carried out using large excesses of the acetalizing
agents (≥10 equiv.). b CDCl3 used in place of CH2Cl2. c Calculated by
1H NMR of the crude reaction product.
Scheme 7 Synthesis of 4’-methoxycytidines 31.
t = 2 h, α : β ∼ 2 : 1; t = 4 h, α : β ∼ 6 : 1; Scheme 6b and c) strik-
ingly proved the equilibrium occurring between 26α and 26β.
Practical experimental evidence was also provided by
treating anomerically pure 11α with DDQ in
a
3/1
desulfurized olefin 18α. The α and β anomers of 28 were
then separately subjected to desulfurization (RANEY®-Ni,
72–74%). Eventually, protective group removal from the olefin
30 (MeONa, then TBAF) released α- and β-2′,3′-dideoxy-2′,3′-
didehydro-4′-methoxy-cytidine (31α and 31β, 92–97% overall
yield).
CDCl3–CD3OD mixture (Table 1, entry 1); complete conversion
(>99%) into 26 (α : β = 6 : 1) further confirmed the existence of
an equilibrium between the two anomers. However, in our
hands the same reaction did not proceed from desulfurized
acetal 18. This demonstrated that the thioenol ether moiety
could activate neighboring acetal functions even under fairly
mild acidic conditions. To test the scope of this activation
path, DDQ-promoted double trans-acetalizations of 11α using
some readily available alcohols were also performed (Table 1,
entries 2–4). After 24–48 h at rt, the corresponding bis-alk(yn)yl
acetals 27a–c were afforded in high yields (71–90%) and in
good (27b, α : β = 6 : 1) to excellent (27a, 27c, α : β > 20 : 1)
diastereoselectivities.
It’s worth noting that in the context of nucleoside chem-
istry15 these acetalization products may represent a fruitful
source of starting materials en route to biologically interesting
4′-substituted nucleosides.16 As an early application, access to
the 2′,3′-unsaturated 4′-methoxynucleosides 31α and 31β (cyto-
sine being chosen as a model nucleobase)17 was provided after
sulfur bridge removal18 from 11α (RANEY®-Ni, 82%) and sub-
sequent Vorbrüggen N-glycosidation of the resulting 18α
(TMSOTf, 65% yield, α : β = 1 : 2) (Scheme 7).19 Alternatively,
N-glycosidation was performed directly on 11α, affording nucleo-
side 28 in a more convenient 91% yield (α : β = 1 : 1). A partici-
pating role by the sulfur bridge in anomeric centre activation
was strongly suggested by the greatly shortened reaction times
(30 min) compared with those of 18α (48 h). Looking at
anomeric stereoselectivity, while efforts to induce β-selectivity
by in situ anomerization8b of 28 failed,20 on the other hand
we found an unprecedented role played by DMF21 (6 equiv.) as
an N-glycosidation modulator, inducing moderate α-selectivity
in the formation of 28 (α : β = 4 : 1; Scheme 7). Notably,
DMF was completely ineffective in driving the stereochemical
outcome in the reaction leading to 30 (α : β = 1 : 1) from the
In summary, the study of the DDQ-mediated domino con-
version of alcohol 8 into (dihydro)furans 9–11 has enabled to
shed light on the peculiar reactivity profile of heterocycle 1.
Particularly, a key role played by the 1,4-dithiinyl moiety in
the activation of the nearby acetal functions (influencing reac-
tion rate and stereoselectivity) has been demonstrated by
experimental evidence and NMR analysis. More generally,
our results suggest that reactivity of acetal functions
(including the anomeric centres of sugar precursors) can be
remarkably increased by the presence of thioenol ether
moieties. Preliminary examples involving trans-acetalization
reactions under mild conditions (leading to bis-alk(yn)yl
acetals 26–27) and N-glycosidation reactions (leading to
4′-methoxycytidines 31) have been performed. Further appli-
cations leading to the synthesis of other biologically interest-
ing compounds are currently ongoing and will be published
elsewhere.
Acknowledgements
Financial support from MIUR (PRIN 2010–2011, prot.
20109Z2XRJ) is gratefully acknowledged.
Notes and references
1 (a) L. F. Tietze, G. Brasche and K. M. Gericke, Domino Reac-
tions in Organic Synthesis, Wiley-VCH Verlag GmbH,
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Weinheim, 2006; (b) D. Enders, C. Grondal and
M. R. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
(c) M. Ruiz, P. Lopez-Alvarado, G. Giorgi and
J. C. Menendez, Chem. Soc. Rev., 2011, 40, 3445;
(d) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237.
2 (a) D. D’Alonzo, A. Guaragna and G. Palumbo, Curr. Org.
Chem., 2009, 13, 71; (b) D. D’Alonzo, A. Guaragna and
G. Palumbo, Curr. Med. Chem., 2009, 16, 473;
(c) D. D’Alonzo, A. Guaragna and G. Palumbo, Chem. Bio-
diversity, 2011, 8, 373.
3 A. Guaragna, S. Pedatella and G. Palumbo, in e-Encyclopedia
of Reagents for Organic Synthesis, ed. L. A. Paquette, John
Wiley & Sons, New York, 2008.
4 (a) A. Guaragna, S. D’Errico, D. D’Alonzo, S. Pedatella and
G. Palumbo, Org. Lett., 2007, 9, 3473; (b) A. Guaragna,
D. D’Alonzo, C. Paolella and G. Palumbo, Tetrahedron Lett.,
2009, 50, 2045.
5 A. Guaragna, D. D’Alonzo, C. Paolella, C. Napolitano and
G. Palumbo, J. Org. Chem., 2010, 75, 3558.
6 D. R. Buckle, S. J. Collier and M. D. McLaws, in e-Encyclope-
dia of Reagents for Organic Synthesis, ed. L. A. Paquette,
John Wiley & Sons, New York, 2005 and references cited
therein.
7 (a) A. Guaragna, C. Napolitano, D. D’Alonzo, S. Pedatella
and G. Palumbo, Org. Lett., 2006, 8, 4863; (b) D. D’Alonzo,
A. Guaragna, C. Napolitano and G. Palumbo, J. Org. Chem.,
2008, 73, 5636.
8 (a) D. D’Alonzo, A. Van Aerschot, A. Guaragna, G. Palumbo,
G. Schepers, S. Capone, J. Rozenski and P. Herdewijn,
Chem.–Eur. J., 2009, 15, 10121; (b) D. D’Alonzo,
A. Guaragna, A. Van Aerschot, P. Herdewijn and
G. Palumbo, J. Org. Chem., 2010, 75, 6402; (c) D. D’Alonzo,
J. Amato, G. Schepers, M. Froeyen, A. Van Aerschot,
P. Herdewijn and A. Guaragna, Angew. Chem., Int. Ed., 2013,
52, 6662–6665.
mediated double elimination. However, 16 was not stable
enough for further synthetic manipulations.
12 M. Albert, D. De Souza, P. Feiertag and H. Hönig, Org. Lett.,
2002, 4, 3251 and references cited therein.
13 D. M. Burness, Org. Synth., 1973, 5, 403.
14 An alternative numbering to IUPAC rules was employed to
more conveniently identify the carbon atoms that will sub-
sequently belong to carbohydrate-mimicking rings.
15 (a) P. Merino, Chemical Synthesis of Nucleoside Analogues,
John Wiley & Sons, Inc., Hoboken, New Jersey, 2013;
(b) G. Oliviero, S. D’Errico, N. Borbone, J. Amato,
V. Piccialli, G. Piccialli and L. Mayol, Eur. J. Org. Chem.,
2010, 1517; (c) S. D’Errico, G. Oliviero, N. Borbone,
J. Amato, D. D’Alonzo, V. Piccialli, L. Mayol and G. Piccialli,
Molecules, 2012, 17, 13036; (d) G. N. Roviello, A. Ricci,
E. M. Bucci and C. Pedone, Mol. BioSyst., 2011, 7, 1773.
16 H. Hayakawa, S. Kohgo, K. Kitano, N. Ashida, E. Kodama,
H. Mitsuya and H. Ohrui, Antiviral Chem. Chemother., 2004,
15, 169.
17 Deoxynucleosides (especially dC analogues) are known to
exert antiviral/antitumor activity in both enantiomeric
forms (ref. 9), thus a screening of the racemic mixture will
provide an early information on the biological potential of
both stereoisomeric compounds.
18 Contrarily to previous results (see ref. 7b), no over-
reduction product was found in this case.
19 Relative stereochemistry was assigned by comparison of
the unprotected β-nucleoside with literature data:
M. Petrová, M. Buděšínský, E. Zborníková, P. Fiedler and
I. Rosenberg, Org. Lett., 2011, 13, 4200.
9 C. Mathé and G. Gosselin, Antiviral Res., 2006, 71, 276.
10 As we were interested to preliminarily explore the reactivity
of our synthon 1 rather than to directly use it for medicinal
chemistry applications, 8 was synthesized in racemic form.
In some cases, the configuration of stereocentres is arbitra-
rily defined to display the relative stereochemistry of the
newly formed stereocentres. Study of the synthetic con-
ditions enabling preparation of 8 and/or that of the follow-
ing intermediates in enantiopure form is ongoing.
20 N-Glycosidation of 11α at 60 °C provided furan 29 (formed
via nucleoside 28):
11 Replacing MeOH with H2O, an even more unexpected reac- 21 This finding was inspired by a recent report on DMF-
tivity occurred, leading to furfural 16 (83%). Analogous to
Scheme 3, the reaction was supposed to proceed through
formation of bis-hemiacetal 14, then undergoing H3O+-
mediated α-O-glycosidation: S.-R. Lu, Y.-H. Lai, J.-H. Chen,
C.-Y. Liu and K.-K. T. Mong, Angew. Chem., Int. Ed., 2011,
123, 7453.
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