Steric control in Pd-mediated cycloisomerization of sugar alkynols: documentation of a rare allylic epimerization

Article abstract of DOI:10.1016/j.tetlet.2007.04.133

Pd-mediated cycloisomerization of C3-alkynylated glucofuranosyl derivatives revealed a dominance of steric factors over electronic factors. However, the intermediate glycals were epimerized prior to the ketalization and afforded the more stable cis-fused

Full text of DOI:10.1016/j.tetlet.2007.04.133

Tetrahedron Letters 48 (2007) 4771–4774
Steric control in Pd-mediated cycloisomerization of sugar
alkynols: documentation of a rare allylic epimerization
C. V. Ramana,* Pitambar Patel and Rajesh G. Gonnade
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008, India
Received 7 March 2007; revised 17 April 2007; accepted 26 April 2007
Available online 1 May 2007
Abstract—Pd-mediated cycloisomerization of C3-alkynylated glucofuranosyl derivatives revealed a dominance of steric factors over
electronic factors. However, the intermediate glycals were epimerized prior to the ketalization and afforded the more stable cis-fused
bicyclic ketals.
Ó 2007 Elsevier Ltd. All rights reserved.
Designing effective routes to complex cyclic structures
through organo transition-metal catalyzed cyclization
reactions has been recognized as an attractive strategy
for delivering molecular diversity.1 Transition-metal
mediated cycloisomerization of alkynols was envisioned
as a concise approach to fully functionalized oxygen-
containing heterocycles encompassing functionalized
furan, pyran, benzopyran and spiroketal skeletons.2,3
During our ongoing studies on the Pd(II)-mediated
cycloisomerization reactions of sugar alkynols, we
recently documented a systematic investigation dealing
with the influence of electronic factors on the regio-
selectivity of cyclization.4 After examining Pd-mediated
cycloisomerization of a set of 3-C-alkynyl-allo-furanosyl
derivatives, we concluded that the regioselectivity of
cyclizations is influenced by electronic factors, electron
donating substituents on the aromatic ring favouring
6-endo-dig, while electron withdrawing groups favoured
5-exo-dig modes of cyclization. Along similar lines, an
alkyl-substituted alkynol 1 (Fig. 1) also favoured 6-
endo-cyclization and gave predominantly 2.
cis-isomer 3 and 6-endo-dig cyclization from trans-iso-
mer 4. The exclusive 6-endo product formation from 4
was reasoned on strain grounds where the formation
of a trans-fused 5,5-bicyclic ring system may not be
feasible.5,6
This is a classical example of cycloisomerization influ-
enced by steric factors. Hoping to take advantage of
such an influence to synthesize 6-endo products having
–M substituted aryl groups (5-exo-preferring), we
extended our investigations to explore trans-configured
sugar derived cycloalkynols. For this work, we designed
a series of sugar alkynols (Fig. 1) and chose the alkyne 8
as our initial target molecule, which we hoped to prepare
from the chloromethyleneoxirane 9 via a base mediated
double elimination reaction.7 The synthesis of the corre-
sponding disubstituted alkynes is possible by means of
Sonogashira reactions.8
The synthesis of the key 3-C-ethynyl-1,2:5,6-di-O-iso-
propylidene-D-glucofuranoside (8) started with the prep-
aration of known allyl alcohol 11 from glucose
diacetonide (10) following the literature procedure.9 As
anticipated, epoxidation of 11 gave a single diastereo-
mer 12. The spectral and analytical data of 12 were in
agreement with the assigned structure.10 Heating 12 with
PPh3 in CCl4 in the presence of NaHCO3 afforded the
corresponding chloro derivative 9 in 68% yield.11 After
standardizing the reactions, we could prepare the requi-
site alkynol 8 in good yield by treating 9 with 3 equiv of
n-butyllithium in THF at ꢀ78 °C for 2 h.7 The spectral
data of 8 showed characteristic chemical shift differences
when compared with the corresponding known C-3 epi-
In the early 80s Utimoto5 and Schwartz6 independently
reported the highly regioselective cycloisomerization of
cis- and trans-substituted 2-(hept-3-ynyl)cyclopentanols
(3 and 4, respectively, Fig. 1) using either mercury or
Pd(II), resulting exclusively in 5-exo-dig cyclization from
Keywords: Palladium; Cycloisomerization; Double elimination;
C-Alkynyl furanose; Bicyclicketal.
*
Corresponding author. Tel.: +91 20 25902577; fax: +91 20
25902629; e-mail: vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.133

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C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 4771–4774
O
O
Hg(II)
6-endo-dig
n-C6H13
O
O
n-C4H9
n-C4H9
O
O
n-C4H9
n-C4H9
OH
or Pd(II)
O
O
HO
HO
HO
3
4
5
6
O
Pd(II)
2
n-C6H13
O
HO
O
''
O
5-exo-dig
n-C6H13
1
HO
O
O
O
O
O
O
O
O
O
OH
Base
O
O
Pd(II)
O
O
O
O
O
O
O
HO
HO
O
O
O
O
Ar
?
9
8
7
Cl
Ar
Figure 1. Influence of strain on Pd mediated cycloisomerization, model compound and intended synthesis.
meric allo derivative thus confirming the assigned struc-
ture.11 For example, in the 1H NMR spectrum of 8, H-4
(0.32 ppm) and H-1 (0.09 ppm) resonated downfield
compared to the H-4 and H-1 of the allo derivative12
(see Schemes 1 and 2).
with iodobenzene, 4-iodoanisole and 4-nitroiodobenze
to afford alkynols 13–15 in 78–85% yields. Selective
hydrolysis of the 5,6-acetonide group in 8, 13–15 fur-
nished the alkynols 16–19, respectively.
Our initial attempt to bring about the cycloisomeriza-
tion of alkynol derivative 16 in acetonitrile using
Pd(CH3CN)2Cl2 was sluggish, partially because of the
Turning to the requisite disubstituted alkynols, the
Sonogashira coupling8 reactions of 8 were carried out
O
O
O
O
O
O
O
O
O
O
O
O
ref 9
a
b
O
O
O
O
O
O
O
O
O
O
3 steps
36%
68%
77%
HO
HO
HO
Cl
10
11
12
9
O
O
HO
HO
O
O
O
O
O
O
O
c
e
d
80%
O
O
HO
HO
HO
O
O
71%
8
13 R = Ph (82%)
16 R = H (75%)
17 R = Ph (87%)
R
14 R =
15 R =
p
p
-MeOPh (85%)
-O2NPh (78%)
R
18 R =
19 R =
p
p
-MeOPh (82%)
-O2NPh (81%)
Scheme 1. Reagents and conditions: (a) m-CPBA, NaHCO3, CH2Cl2, 0 °C–rt, 8 h; (b) TPP, NaHCO3, CCl4, reflux, 8 h; (c) n-Butyllithium, THF,
ꢀ78 °C, 2 h; (d) Ar-I, CuI, TPP, Pd(PPh3)2Cl2, Et3N/DMF (1:2), rt, 3 h; (e) 0.8% aq H2SO4, MeOH–H2O (10:1), 0 °C–rt, 14 h.
HO
HO
HO
HO
HO
HO
HO
HO
O
O
O
O
O
O
O
O
HO
HO
HO
HO
O
O
O
O
18
19
17
16
(a)
(b)
Substrates
MeO
O
O2N
HO
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
ORTEP structures of compounds
(a) 21 and (b) 22
O
O
O
OH
OH
OH
O
20 (15%)
Product (yield)
Scheme 2. Reagents and conditions: Pd(CH3CN)2, THF/CH3CN (1:2), 6–7 h.
21 (51%)
22 (62%)
23 (39%)
MeO
O2N

C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 4771–4774
4773
poor solubility of 16. After experimenting with several
solvent systems, the use of a 2:1 CH3CN–THF mixed
solvent system had substantial effect on the reaction
time. However, we could only isolate 20 in low yield.
In the 1H NMR spectrum of 20, a singlet corresponding
to CH3– was observed at d 2.44, and H-4 (d 4.60) reso-
nated 0.3 ppm downfield compared to that of H-2 (d
4.31) due to the anisotropic deshielding effect of the car-
bonyl group.
tronic factors favouring the 6-endo-dig mode of cycliza-
tion was observed. However, the intermediate cyclic
enol derivatives were found to undergo a Pd-mediated
epimerization prior to ketalization.
Acknowledgement
Financial support from the UGC (New Delhi) in the
form of a research fellowship to P.P. is gratefully
acknowledged.
The cycloisomerization of 17 was carried out in the same
solvent system to afford the cycloisomerized product 21
in moderate yield (Fig. 2). To our surprise, the spectral
and analytical data of 21 were identical to the bicyclic
ketal that we had previously synthesized from the allo
derivative suggesting an inadvertent epimerization of
the quaternary-OH during the cycloisomerization.3 Sin-
gle crystal X-ray analysis of compound 21 established
the assigned structure.13,14
References and notes
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The cycloisomerization of alkynols 18 and 19 resulted in
the epimerized bicyclic ketals 22 and 23. The spectral
and analytical data of compounds 22 and 2315 were in
agreement with the assigned structure and the structure
of 22 was further established by single crystal X-ray
analysis.13,14
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The formation of compounds 21–23 is obviously the
consequence of an epimerization during the Pd-medi-
ated cycloisomerization. The formation of 20 from 16
and of 23 from 19 ruled out the possibility of epimeriza-
tion of the alkynol before the cyclization (since the epi-
mer of 19 gave the 5-exo-dig product, exclusively).16
Since the products 21–23 are expected to arise via a 6-
endo-dig cyclization, a possible explanation would be
competing formation of a p-allylpalladium complex
from the intermediate r-Pd-glycal and subsequent
hydroxy approach from the less hindered pseudo-concave
face (Fig. 2).17 Indeed Matsumura and co-workers doc-
umented the C-3 epimerization of triacetyl glucal using a
variety of metal salts but not with Pd.18
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In summary, gluco-configured 3-C-alkynyl derivatives
were prepared to examine the influence of strain over
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anticipated the dominance of steric factors over elec-
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10. Spectral data of Compound 12: [a]D +60.9 (c 1.3, CHCl3);
IR (CHCl3): m 3492, 3020, 2991, 2938, 1455, 1384, 1216,
O
HO
O
O
O
O
O
HO
O
HO
O
OH
HO
Ar
O
O
Pd(II)
O
Ar
OH
HO
O
Ar
Pd
HO
O
OH
O
O
O
σ-Pd-glycal
Ar
O
Ar
Pd
O
Pd
O
OH
O
σ-Pd-glycal
π-Pd-complex
Figure 2. Tentative mechanism for the epimerization.

4774
C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 4771–4774
1163, 1117, 1073, 845, 755 cmꢀ1
;
1H NMR (200 MHz,
14. The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as deposition
Nos. CCDC 639467 (21) and CCDC 639468 (22). Copies of
the data can be obtained, free of charge, on application to
the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk ].
CDCl3): d 1.31 (s, 3H), 1.34 (s, 3H), 1.41 (s, 3H), 1.56 (s,
3H), 2.31 (br s, 1H), 3.53 (t, J= 5.5 Hz, 1H), 3.77 (dd,
J = 12.5 Hz, 5.7 Hz, 1H), 3.90–4.07 (m, 4H), 4.32 (dd,
J = 5.7 Hz, 1.5 Hz, 1H), 4.54 (d, J = 4.2 Hz, 1H), 5.95 (d,
J = 4.2 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 25.3 (q),
26.5 (q), 26.8 (q), 26.9 (q), 57.1 (d), 62.0 (t), 66.9 (t), 68.7
(s), 72.7 (d), 76.4 (d), 82.6 (d), 104.3 (d), 109.6 (s), 112.5 (s)
ppm; ESI-MS m/z: 325.187 [M+Na]+. Anal. Calcd for
C14H22O7: C, 55.62; H, 7.33. Found: C: 55.86, H: 7.39.
25
15. Spectral data of Compound 23: ½aꢁD +3.2 (c 1, CHCl3); 1H
NMR (200 MHz, CDCl3): d 1.39 (s, 3H), 1.63 (s, 3H), 1.84
(d, J = 14.5 Hz, 1H), 2.26 (d, J = 14.5 Hz, 1H), 3.21 (br s,
1H), 3.87 (s, 1H), 4.01 (dd, J = 7.2, 5.6 Hz, 1H), 4.16 (d,
J = 3.6 Hz, 1H), 4.42 (dd, J = 7.2, 0.9 Hz, 1H), 4.95 (d,
J = 5.6 Hz, 1H), 5.96 (d, J = 3.6 Hz, 1H), 7.78 (d,
J = 8.9 Hz, 2H), 8.25 (d, J = 8.9 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d 26.7 (q), 26.8 (q), 43.1 (t), 65.8 (t),
74.4 (d), 75.1 (s), 77.8 (d), 83.6 (d), 104.1 (d), 105.5 (s),
113.0 (s), 123.5 (d), 126.4 (d), 146.3 (s), 148.1 (s) ppm; ESI-
MS m/z: 388.41 [M+Na]+. Anal. Calcd for C17H19NO8:
C, 55.89; H, 5.24; N, 3.83. Found: C, 56.17; H, 5.44; N,
3.57.
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12. Spectral data of Compound 8: [a]D +96.6 (c 1, CHCl3) IR
(CHCl3): m 3390, 3306, 3019, 2990, 2937, 2234, 1455, 1384,
1375, 1216, 1073, 998, 759 cmꢀ1 1H NMR (200 MHz,
.
CDCl3): d 1.36 (s, 3H), 1.38 (s, 3H), 1.50 (s, 3H), 1.56 (s,
3H), 2.68 (s, 1H), 3.69 (br s, 1H), 4.08–4.22 (m, 3H), 4.39–
4.48 (m, 2H), 5.90 (d, J = 3.5 Hz, 1H) 13C NMR (50 MHz,
CDCl3): d 25.4 (q), 26.6 (q), 27.0 (q), 66.6 (t), 74.3 (d), 75.4
(s), 76.3 (d), 80.5 (s), 82.4 (d), 86.9 (d), 104.7 (d), 109.9 (s),
112.8 (s) ppm. ESI-MS m/z: 307.598 [M+Na]+. Anal. Calcd
for C14H20O6: C, 59.14; H, 7.09. Found: C: 59.31, H: 7.22.
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