Palladium mediated cycloisomerization of sugar alkynols: synthesis of cyclic enol-ethers and spiroketals

Article abstract of DOI:10.1016/j.tetlet.2006.03.143

Functionalized bicyclic enol-ethers and spiroketals are prepared by Pd catalyzed cycloisomerization of 3-C-alkynylfuranosyl derivatives. Cycloisomerization of differently substituted alkyne derivatives revealed a preference for 6-endo-dig cyclization over

Full text of DOI:10.1016/j.tetlet.2006.03.143

Tetrahedron Letters 47 (2006) 3649–3652
Palladium mediated cycloisomerization of sugar alkynols:
synthesis of cyclic enol-ethers and spiroketals
C. V. Ramana,* Rosy Mallik, Rajesh G. Gonnade and Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 6 February 2006; revised 15 March 2006; accepted 22 March 2006
Available online 12 April 2006
Abstract—Functionalized bicyclic enol-ethers and spiroketals are prepared by Pd catalyzed cycloisomerization of 3-C-alkynylfur-
anosyl derivatives. Cycloisomerization of differently substituted alkyne derivatives revealed a preference for 6-endo-dig cyclization
over 5-exo-dig if the substituent is not sufficiently electron withdrawing. The scope of these cycloisomerizations has been further
extended by integrating with conjugate addition.
Ó 2006 Elsevier Ltd. All rights reserved.
Construction of architecturally complex molecules from
simple building blocks has emerged as a powerful tool
in synthetic organic chemistry because of the increasing
demand for molecules with unprecedented diversity.
Designing effective routes to construct complex cyclic
structures through organotransition-metal catalyzed
reactions provides many attractive possibilities, which
by conventional procedures would need a large number
of synthetic transformations. A great deal of focus has
been directed towards sugar based molecular diversity
as these molecules offer inherent rigidity and molecular
asymmetry.1
bicyclicspiroketals and cyclic enol-ether derivatives
(Fig. 1). The key issue in our intended strategy is the
mode of cyclization, that is, 5-exo-dig versus 6-endo-
dig.6 There are several instances in the literature to indi-
cate that the obtuse angle of 120–127° for the approach
of a nucleophile to a triple bond triggers the dominance
of 5-exo-dig over 6-endo-dig for electronically unbiased
acetylenes.7 However, the majority of theoretical and
experimental studies reported to understand 5-exo-dig
versus 6-endo-dig cyclizations involve, mainly, the base
mediated cyclization with hard nucleophiles,8 investiga-
tions dealing with metal catalyzed cyclizations9 are,
however, rare.
Cycloisomerization of alkynols is utilized as a tool to
synthesize oxygen-containing heterocycles encompass-
ing functionalized furan, pyran, benzopyran and spiro-
ketal skeletons.2 Many of these cyclization studies
occur via transition metal reactions of palladium, plati-
num, tungsten, molybdenum, ruthenium, rhodium, gold
or iridium catalysts.3 It is pertinent to mention that the
metal mediated hydroalkoxylation reactions of carbo-
hydrate precursors have been less explored and mainly
confined to glycals, exo-glycals and related derivatives.4
In this article we describe a novel strategy of tandem
cycloisomerization of 3-C-acetylenic sugar derivatives
The requisite model 3-C-alkynylfuranosyl derivatives
7–10 were prepared from the easily accessible 3-ulose
derivatives 1 and 2, by reaction with the lithiated salts
B
O
B
O
O
O
A
and/or
OH
H
B
OH
Pd (II)
A
H
O
HO
5-exo-dig
6-endo-dig
A
B
O
B
O
and also present the trapping of intermediary alken-
O
O
OH
Pd (II)
O
5
ylpalladium species
with acrolein to derive novel
and/or A
OH
O
O
A
OH
Keywords: Palladium; Cycloisomerization; C-alkynylfuranose; Spiro-
5-exo-dig
6-endo-dig
ketal; Enol-ether.
*
Figure 1. Pd-mediated cycloisomerization and subsequent conjugate
Corresponding author. Tel.: +91 20 25902577; fax: +91 20
addition.
25893614; e-mail: vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.143

3650
C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 3649–3652
OTBS
O
OTBS
O
OH
O
O
O
R
Li
TBAF
R
O
R
THF, –78 oC
4–7 h
THF, 0 oC, 1 h
O
O
O
O
OH
OH
7 (R = Ph, 80%)
1
3 (R = Ph, 81%)
4 (R = n-C6H13, 88%)
8 (R = n-C6H13 83%)
O
O
HO
O
O
O
O
R
Li
0.8% H2SO4
MeOH, rt
O
HO
O
O
R
O
THF, –78 oC
2–6 h
R
O
O
O
OH
O
OH
9 (R = Ph, 70%)
10 (R = n-C6H13, 79%)
2
5 (R = Ph, 75%)
6 (R = n-C6H13, 73%)
R'
R'
O
O
O
O
O
O
R
O
Pd(CH3CN)2Cl2
O
O
O
O
O
H
O
OH
CH3CN, rt
3–24 h
OH
OH
R
R
H
12 (59%)
13 (51%)
11 (29%)
14 (30%)
R = Ph, R' = H
R = n-C6H13, R' = H
R = Ph, R' = CH2OH
15 (65%)
16 (55%)
R = n-C6H13, R' = CH2OH
ORTEP Structure of 15
Scheme 1. Synthesis of alkynols 7–10 and their Pd-mediated cycloisomerization.
ORTEP Structure of 12
of phenyl acetylene and 1-octyne (Scheme 1). The
TBS protecting groups present at O-5 of 3 and 4 were
subsequently removed using TBAF–THF to give 7
and 8. Selective hydrolysis of the 5,6-acetonide
group of 5 and 6 with cat. H2SO4 in methanol gave 9
and 10, respectively. The cycloisomerization reaction
of 7 in the presence of Pd(CH3CN)2Cl2 in MeCN
at room temperature gave the exo-product 11 (29%)
and the endo-product 12 (59%). The structure of the
The exclusive formation of 13 and 16 showed, as ex-
pected, the favorable 6-endo-dig cyclization that could
be attributed to the ÀI effect of the furanose ring over
the alkyl chain. With a view to understand the nature
of the phenyl ring on the regiochemical outcome, we
opted to prepare some specific alkynols containing func-
tional groups on the phenyl ring. Thus, the Sonogashira
coupling12 reactions of 1713 with substituted aryl iodides
provided a series of compounds 18–21. Selective hydro-
lysis of the 5,6-acetonide group of 17–21 furnished the
alkynols 22–26, respectively.
1
exo-product 11 was proposed based on H, 13C, mass
and elemental analysis. The single crystal X-ray study
(Scheme 1) of endo-product 12 unambiguously proved
its structure.10,11
The results of the Pd(CH3CN)2Cl2 catalyzed cycloiso-
merizations of the alkynol derivatives 22–26 are given
in Scheme 2. These studies revealed that the presence
of a +M substituent on the aromatic ring favoured
6-endo-dig while ÀM groups favored 5-exo-dig modes
of cyclization. Thus, there existed an electronic effect,
particularly a competitive balance between ÀI and +M
effects. The information is significant when compared
to the base mediated cycloisomerization reactions.
Padwa8c,d has extensively investigated the base-induced
cycloisomerization of several (phenylethyny1)aryl-sub-
stituted alcohols modulating one of the phenyl ring
substituents (Fig. 2), where the 5-exo-dig mode of
cyclization was exclusively independent of the nature
of the aryl substituent. Along similar lines, Hiroya
The palladium-catalyzed cycloisomerization of 8 gave
exclusively the endo-product 13, whose structure was
supported by spectral and elemental analysis. The char-
acteristic signal of the enolic proton was observed as a
singlet at 4.40 ppm in the 1H NMR spectrum of 13.
The cycloisomerization of alkynol 9 resulted in a mix-
ture of the exo-enol-ether 14 and bicyclic ketal deriva-
tive 15, whose structure was proved by single crystal
X-ray structural analysis (Scheme 1). We believe that
although the formation of 15 occurred via an endo-dig
path as noted for 7, the free hydroxyl group at C-6
underwent further cyclization to furnish the stable ketal
structure. Cycloisomerization of 10 similarly gave 16.

C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 3649–3652
3651
O
O
HO
HO
ArI, CuI,PPh3
Et3N:DMF (2:1)
0.8%H2SO4
MeOH
O
O
O
O
O
O
O
O
R
R
Pd(PPh3)2Cl2
5–10 h
70–95%
10–13 h
68–80%
O
O
O
OH
17
OH
OH
R= H– (22, 68%)
R = p-MeO-Ph– (18, 70%)
R = p-NO2-Ph– (19, 91%)
R = o-NO2-Ph– (20, 84%)
R = m-NO2-Ph– (21, 95%)
R = p-MeO-Ph– (23, 80%)
R = p-NO2-Ph– (24, 75%)
R = o-NO2-Ph– (25, 73%)
R = m-NO2-Ph– (26, 77%)
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
--
OH
Pd(CH3CN)2Cl2
CH3CN
rt, 3–10 h
R
R
R
--
--
R = H
27 (87%)13a
--
--
R = p-MeO-Ph-
R = p-NO2-Ph-
28 (82%)
--
29 (87%)
30 (72%)
31 (65%)
--
--
--
R = o-NO2-Ph-
R = m-NO2-Ph-
32 (18%)
Scheme 2. Synthesis of alkynols 22–26 and their Pd-mediated cycloisomerization.
O
O
O
O
5-exo-dig
O
R = H, OMe ,
= NO2
1) Pd(CH3CN)2Cl
LiBr, CH3CN, rt
O
2 O
O
Ph
+
O
OH
OH
7
9
HO
O
OH
OH
2) LAH
76%
Ph
R
33 (23%)
34 (53%)
R
workup H+
HO
R = CHO
= CO2Et
HO
O
O
O
O
O
"
O
O
Ph
+
54%
O
OH
O
HO
OH
OH
35 (16%)
Ph
R
36 (38%)
Figure 2. Cycloisomerization of (phenylethynyl) benzyl alcohols.8c,d
Scheme 3. Cycloisomerization and conjugate addition of alkynols 7
and 9.
et al.8a concluded that regioselectivity in base mediated
cycloisomerization reactions is not influenced by the
electronic nature of the functional group on the triple
bond, but by the steric bulkiness.
In summary, the regioselectivity of cycloisomerization
of sugar acetylene derivatives depends on electronic
factors influencing 5-exo-dig versus 6-endo-dig modes
of cyclization, which is in contrast with base-promoted
cycloisomerizations. The two-component cycloisomeri-
zation and conjugate addition gave highly functional-
ized compounds.
We next investigated our second objective, the two
component reactions involving palladium catalyzed
cycloisomerization as described above and subsequent
conjugate addition of the carbopalladium intermediates
with acrolein.5 To circumvent the problems associated
with the stability of the resulting aldehyde derivatives,
we chose to reduce them with LAH before isolation
and characterization (Scheme 3).
Acknowledgements
Financial support from the University Grants Commis-
sion (New Delhi) in the form of a research fellowship to
R.M. is gratefully acknowledged.
Thus, the successive cycloisomerization of 7 with
Pd(CH3CN)2Cl2, conjugate addition with acrolein and
LAH reduction in one-pot gave a mixture of compounds
33 (23%) and 34 (53%). NMR, mass and elemental ana-
lysis, supported their structures. Similar results were
obtained with the substrate 9, giving the products 35
(16%) and 36 (38%). Surprisingly, no conjugate addition
reactions were observed with 8 and 10, however, the
expected endo-products 13 and 16 were recovered,
respectively.
Supplementary data
NMR Spectra of compounds 11, 12, 15, 33 and 34, and
crystallographic files for 12 and 15 are available. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2006.03.143.

3652
C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 3649–3652
R. W.; Rozeboom, M. D.; Nagaze, S. J. Am. Chem. Soc.
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