Intramolecular heck cyclisation-β-alkoxy elimination in carbohydrate chemistry. A simple route to to enantiopure annelated dioxatricyclic compounds

Article abstract of DOI:10.1055/s-1999-2717

Enantiopure cis-fused pyrano[2,3]pyrans are obtained from glycals via an intramolecular Heck cyclization followed by a palladium-β=alkoxy elimination.

Full text of DOI:10.1055/s-1999-2717

762
LETTER
Intramolecular Heck Cyclisation-β-Alkoxy Elimination in Carbohydrate
Chemistry. A Simple Route to to Enantiopure Annelated Dioxatricyclic
Compounds
Karim Bedjeguelal, Véronique Bolitt, Denis Sinou*
Laboratoire de Synthèse Asymétrique, associé au CNRS, CPE Lyon, Université Claude Bernard Lyon 1, 43, boulevard du 11 novembre
1918, 69622 Villeurbanne cédex, France
Fax + 33 (0)4 72448160; E-mail: sinou@univ-lyon1.fr
Received 9 March 1999
TBDMSO
TBDMSO
R2CH2
Abstract: Enantiopure cis-fused pyrano[2,3c]pyrans are obtained
from glycals via an intramolecular Heck cyclization followed by a
palladium-β-alkoxy elimination
O
O
i
R1
O
R1
HO
Key words: palladium, cyclisation, carbohydrates, enantiopure
2a-c, 3a-c, 4a-c
1a-c
heterocyles
a R1 = H, b R1 = OEt, c R1 = OC6H4-p-t-Bu
Br
Br
Br
Palladium-catalyzed cyclisation processes are now widely
used for the stereospecific synthesis of carbon- and het-
erocyclic systems, sometimes via a cascade reaction.1 We
recently described the use of an intramolecular palladium-
catalyzed Heck reaction in carbohydrate chemistry lead-
ing to unsaturated enantiopure bicyclo[4.3.0]nonane and
tricyclo[7.3.0.22,6]dodecane systems exhibiting at least
one exo-methylene bond,2 the last step of the catalytic cy-
cle being an unusual palladium-β-alkoxy elimination. The
cyclization leading to 5-membered rings occurred mainly
using a catalytic amount of Pd(OAc)2/PPh3 in CH3CN/
H2O in the presence of Bu4NHSO4 and NEt3. This letter
reports the results concerning the access to unsaturated
enantiopure cis-fused pyrano[2,3c]pyrans using this
methodology.
,
,
4 R2
=
2 R2
=
3 R2
=
Scheme 1: i : NaH, THF, R2CH2Br, 60 °C, 24 h
and some byproducts were observed; formation of this
compound by palladium-reduction of the starting material
was probably due to the presence of water.4 Fortunately,
going from CH3CN/H2O to DMF as the solvent, at 80 °C
(Scheme 2), we observed the formation of the expected bi-
cyclic compound 5 in 15% yield together with the ring
opened product 6 in 13% yield (Table, entry 2).
OTBDMS
OTBDMS
OTBDMS
O
The requisite hex-2-enopyranosides 2-4 chosen for the cy-
clization reaction were easily prepared (Scheme 1). Thus,
treatment of compound 1a, obtained from tri-O-acetyl-D-
glucal according to literature procedures,2,3 with NaH and
2-bromobenzyl bromide, (2-bromocyclohex-1-enyl)me-
thyl bromide, and (2-bromocyclopent-1-enyl) methyl bro-
mide, in THF at 60 °C for 24 h, gave the corresponding
bromo derivatives 2a, 3a, and 4a, in 70, 68, and 74%
yields, respectively. The same methodology was applied
to ethyl 6-O-(tert-butyldimethylsilyl)-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (1b)2 and p-tert-butylphe-
nyl 6-O-(tert-butyldimethylsilyl)-2,3-dideoxy-α-D-eryth-
ro-hex-2-enopyranoside (1c)2 to give bromo derivatives
2b, 3b, 4b, 2c, 3c, and 4c, in 86, 83, 61, 80, 53, and 63%
yields, respectively.
OH
O
i
+
O
OEt
O
O
R1
Br
2a-c
5
6
a R1 = H
b R1 = OEt
c R1 = OC6H4-p-t-Bu
Scheme 2: i : Pd(OAc)2, PPh3, Bu4NHSO4, Et3N, DMF, 80 °C, 48 h
As with our analogous work,2 initial studies involved pal-
ladium-catalyzed cyclization starting from 2b and used
Pd(OAc)2/PPh3 in CH3CN/H2O in the presence of
Bu4NHSO4 and NEt3 (Table). However, under these con-
ditions, compound 2b failed to cyclize and only formation
of ethyl 4-O-benzyl-6-O-(tert-butyldimethylsilyl)-2,3-
dideoxy-α-D-erythro -hex-2-enopyranoside in 50% yield
It was anticipated that the presence of a better leaving
group at the anomeric position would favor the formation
of the bicyclic compound.5 Indeed, unsaturated p-tert-bu-
tylphenyl hex-2-enopyranoside 2c gave the expected un-
saturated compound 5 as the sole product in 40% yield
after purification by column chromatography (Table, en-
try 3). Compound 5 was also obtained in 70% yield start-
Synlett 1999, No. 6, 762–764 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Intramolecular Heck Cyclisation-β-Alkoxy Elimination
763
ing from unsaturated substrate 2a via a usual
intramolecular Heck reaction (Table, entry 1).
Br
These new conditions were extended for the cyclization of
other hex-2-enopyranosides (Scheme 3). Compounds 3a
and 4a, having no aglycon moiety, gave the expected cy-
clized products 7 and 8 in 75 and 68% yields, respectively
(Table, entries 4 and 7). The ethyl hex-2-enopyranosides
3b and 4b gave a mixture of cyclized compounds 7 and 9
and ring opened products 8 and 10 in low yields (Table,
entries 5 and 8). However substituting the ethyl aglycon
by a p-tert-butylphenyl group gave again the cyclized
products 7 and 9 as the sole products in 44 and 47% yield,
respectively (Table, entries 6 and 9).
OTBDMS
O
OTBDMS
O
HO
O
i
OC6H4-p-t-Bu
OC6H4-p-t-Bu
12
11
OTBDMS
O
O
ii
Table Palladium(0) mediated cyclization of 2-4a
13
Scheme 4: i : NaH, THF, BrCH2C6H4-o-Br, 60 °C, 24 h, 84%; ii :
Pd(OAc)2, PPh3, Bu4NHSO4, Et3N, DMF, 80 °C, 48 h
The structures of compounds 5, 7, 9 and 13 were deter-
mined from 1H and 13C NMR and the cis stereochemistry
was confirmed by NOE experiments. For example, irradi-
ation of the H-3 signal of compound 7 at δ 2.41 ppm gave
an enhancement of the signals corresponding to H-2 and
H-4 of 7 and 10%, respectively, in agreement with the cis
arrangement of these two hydrogens. In the case of com-
pound 13, irradiation of the H-3 signal at δ 3.48 ppm gave
an enhancement of the signals of H-2, H-4 and H-5 of 7,
9 and 4%, respectively, showing that these three hydro-
gens are on the same side of the dihydropyran ring.
a
All reactions were carried out in DMF at 80 °C for 48 h using the
unsaturated substrate (10 equiv), Pd(OAc)2 (1 equiv), PPh3 (2 equiv),
Bu4NHSO4 (1 equiv), Et3N (25 equiv).
b Not optimized isolated yields.
OTBDMS
OTBDMS
OTBDMS
O
In summary, we have shown that suitably functionalized
unsaturated pyranosides gave bi- and tricyclic enan-
tiopure derivatives containing six-membered rings via an
intramolecular Heck reaction followed by a β-palladium-
alkoxy elimination. This methodology extended the field
of this type of cyclization in carbohydrate chemistry.
OH
O
i
+
O
OEt
O
O
R1
Br
n
n
n
3a-c, 4a-c
7, 9
8, 10
Acknowledgement
a R1 = H
b R1 = OEt
c R1 = OC6H4-p-t-Bu
One of us (BK) thanks the French Ministery of Education for a fel-
lowship.
3, 7, 8 : n = 1; 4, 9, 10
:
n = 0
References and Notes
Scheme 3: i : Pd(OAc)2, PPh3, Bu4NHSO4, Et3N, DMF, 80 °C, 48 h
(1) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 38.
Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press:
Oxford, 1991; Vol. 5, p 46. Grigg, R. J. Heterocycl. Chem.
1994, 31, 631. De Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379. Thebtaranonth, C.;
Finally threo hex-2-enopyranoside 12, derived from p-
tert-butylphenyl
6-O-(tert-butyldimethylsilyl)-2,3-
dideoxy-α-D-threo-hex-2-enopyranoside (11), was cy-
clized under the reported conditions to provide the cis-
fused bicycle 13 in 55% yield (Scheme 4).
Thebtaranonth, Y. In Cyclisation Reactions; CRC Press:
London, 1994; p 255. Tietze, L. F. Chem. Ind. (London) 1995,
453. Heumann, A.; Reglier, M. Tetrahedron 1995, 51, 975.
Heumann, A.; Reglier, M. Tetrahedron 1996, 52, 9289.
Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.; Lin, F. Chem.
Rev. 1996, 96, 365. Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. Rev. 1996, 96, 635.
(2) Nguefack, J. F.; Bolitt, V.; Sinou, D. J. Org. Chem. 1997, 62,
1341 and 6827.
Synlett 1999, No. 6, 762–764 ISSN 0936-5214 © Thieme Stuttgart · New York

764
K. Bedjeguelal et al.
LETTER
(3) Grynkiewicz, G. Carbohydr. Res. 1984, 128, C9.
(4) Clark, F. R. S.; Norman, R. O. C.; Thomas, B. C. J. Chem.
Soc., Perkin Trans. 1 1975, 121.
(5) Bedjeguelal, K.; Joseph, L.; Bolitt, V.; Sinou, D. Tetrahedron
Lett. 1999, 40, 87.
61.9, 68.4, 69.1, 76.6, 99.4, 126.8, 127.5, 140.5.
9: [α]D25 +233.6 (c 2.5, CH2Cl2), 1H NMR (300 MHz, CDCl3)
δ 0.08 (s, 6H, SiMe), 0.90 (s, 9H, SiCMe3), 1.86-1.98 (m, 2H,
CH2), 2.25-2.29 (m, 3H, CH2), 2.50 (m, 1H, CH2), 2.70 (m,
1H, H-3), 3.74 (dd, 1H, J = 10.7, 6.6 Hz, H-6), 3.80 (dd, 1H,
J = 10.7, 6.3 Hz, H-6), 3.84 (ddd, 1H, J = 9.2, 4.4, 1.5 Hz, H-
4), 4.17 (ddd, 1H, J = 9.2, 6.6, 6.3 Hz, H-5), 4.18 (d, 1H, J =
15.4 Hz, CH2), 4.24 (d, 1H, J = 15.4 Hz, CH2), 4.62 (ddd, 1H,
J = 6.3, 2.6, 1.5 Hz, H-2), 6.28 (dd, 1H, J = 6.3, 2.6 Hz, H-1);
13C NMR (CDCl3) δ -5.4, -5.3, 18.3, 21.93, 25.9, 29.8, 33.1,
33.3, 62.0, 65.9, 76.1, 77.4, 99.2, 132.9, 133.8, 140.8.
(6) All new compounds gave satisfactory analytical and
spectroscopic data. Selected spectroscopic data:
5: [α]D25 +128.6 (c 1, CH2Cl2), 1H NMR (300 MHz, CDCl3) δ
0.09 (s, 6H, SiMe), 0.91 (s, 9H, SiCMe3), 3.37 (bs, 1H, H-3),
3.77 (dd, 1H, J = 10.6, 7.4 Hz, H-6), 3.85 (dd, 1H, J = 10.6,
5.7 Hz, H-6), 4.10 (m, 1H, H-4), 4.28 (ddd, 1H, J = 7.4, 5.7,
2.2 Hz, H-5), 4.65 (ddd, 1H, J = 6.3, 2.2, 1.8 Hz, H-2), 4.89 (d,
1H, J = 15.1 Hz, CH2), 4.92 (d, 1H, J = 15.1 Hz, CH2), 6.30
(dd, 1H, J = 6.3, 2.6 Hz, H-1), 7.02 (bd, 1H, J = 7.3 Hz, Harom),
7.17-7.26 (m, 3H, Harom); 13C NMR (CDCl3) δ -5.4, -5.3, 18.3,
25.9, 30.6, 61.8, 68.0, 69.4, 76.6, 102.3, 124.3, 126.4, 127.2,
128.6, 134.2, 135.7, 140.6.
13: [α]D25 -23.4 (c 0.6, CH2Cl2), 1H NMR (300 MHz, CDCl3)
δ 0.12 (s, 6H, SiMe), 0.92 (s, 9H, SiCMe3), 3.48 (m, 1H, H-
3), 3.86 (dd, 1H, J = 13.2, 10.3 Hz, H-6), 4.00 (dd, 1H, J =
13.2, 8.8 Hz, H-6), 4.07 (m, 1H, H-5), 4.09 (m, 1H, H-4), 4.68
(d, 1H, J = 5.9 Hz, H-2), 4.81 (d, 1H, J = 15.4, CH2), 4.92 (d,
1H, J = 15.4, CH2), 6.37 (d, 1H, J = 5.9 Hz, H-1), 7.02 (d, 1H,
J = 5.9, Harom), ), 7.16-7.26 (m, 3H, Harom); 13C NMR (CDCl3)
δ -5.4, -5.3, 18.4, 26.0, 34.1, 61.3, 68.3, 68.4, 76.6, 104.1,
124.2, 126.4, 127.1, 128.8, 134.2, 135.9, 141.9.
7: [α]D25 +337.7 (c 2.6, CH2Cl2), 1H NMR (300 MHz, CDCl3)
δ 0.08 (s, 6H, SiMe), 0.90 (s, 9H, SiCMe3), 1.44-1.72 (m, 8H,
CH2), 2.41 (m, 1H, H-3), 3.70 (dd, 1H, J = 10.8, 7.0 Hz, H-6),
3.82 (dd, 1H, J = 10.8, 6.1 Hz, H-6), 3.93 (m, 1H, H-4), 4.01
(d, 1H, J = 16.2 Hz, CH2), 4.07 (d, J = 16.2 Hz, 1H, CH2), 4.21
(ddd, 1H, J = 9.7, 7.0, 6.1 Hz, H-5), 4.64 (ddd, 1H, J = 6.3, 2.1,
1.9 Hz, H-2), 6.29 (dd, 1H, J = 6.3, 2.5 Hz, H-1); 13C NMR
(CDCl3) δ -5.5, -5.3, 18.3, 22.3, 22.7, 25.0, 25.9, 26.9, 31.6,
Article Identifier:
1437-2096,E;1999,0,06,0762,0764,ftx,en;G09299ST.pdf
Synlett 1999, No. 6, 762–764 ISSN 0936-5214 © Thieme Stuttgart · New York