Highly stereoselective Diels-Alder reactions achieved on some hexopyranosidic templates

Article abstract of DOI:10.1055/s-2001-12333

The Diels-Alder reactions of some carbohydrate derivatives, as chiral acrylic esters, with cyclopentadiene proceed highly diastereoselectively to provide the adducts carrying a norbornene carboxylate. By reductive removal of the carbohydrate templates from the adducts, both 2S and 2R-enriched 5-norbornene-2-methanol are obtained.

Full text of DOI:10.1055/s-2001-12333

LETTER
481
Highly Stereoselective Diels-Alder Reactions Achieved on Some
Hexopyranosidic Templates
Takayuki Nagatsuka, Shuhei Yamaguchi, Kiichiro Totani, Ken-ichi Takao, Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
Fax +81-45-566-1571; E-mail: tadano@applc.keio.ac.jp
Received 18 January 2001
mixture of diastereomers (endo 2S, endo 2R, and exo iso-
mers).9 The ratio of the endo/exo isomers and the diaste-
reomeric ratio of the endo adducts (8a-10a:8b-10b) were
determined based on each 1H NMR analysis. In the case
Abstract: The Diels-Alder reactions of some carbohydrate deriva-
tives, as chiral acrylic esters, with cyclopentadiene proceed highly
diastereoselectively to provide the adducts carrying a norbornene
carboxylate. By reductive removal of the carbohydrate templates
from the adducts, both 2S and 2R-enriched 5-norbornene-2-metha- of 1, a modest diastereoselectivity was observed for 8a:8b
nol are obtained.
(entry 1). The reaction of 2 or 3, which possesses a bulkier
substituent (R = Piv or TBS) at C-3, afforded endo 2S ad-
duct 9a or 10a, respectively, with improved diastereose-
lectivity (entries 2 and 3). However, the observed endo/
exo selectivity was not sufficiently high in every case. The
absolute stereochemistry of the newly introduced stereo-
genic centers in the norbornene ring was determined by
comparison with the reported optical signs for known
5-norbornene-2-carboxylic acid and/or -2-methanol,10 af-
ter removal of the carbohydrate templates. In the case of
the substrate 3, the mixture of the endo adducts 10a/10b
was obtained by removing the minor exo adducts by chro-
matographic separation on silica gel (Scheme 3). Removal
of the carbohydrate templates from the mixture of 10a/
10b was conducted by reductive cleavage using DIBAL-
H to provide (2S) enriched 5-norbornene-2-methanol
11.11 The carbohydrate template 12 was recovered effi-
ciently. Benzoylation of the (2S) enriched 11 and HPLC
analysis (serial connection of Chiralcel OD+OD-H;
hexane:EtOH = 300:1) of the resulting benzoate verified
that the enantiomeric ratio (2S:2R) of 11 was 97:3.
Key words: asymmetric synthesis, diastereoselectivity, Diels-
Alder reaction, cyclopentadiene, norbornene derivatives
The design of chiral auxiliaries based on readily available
natural products, which would serve as a stereocontrolling
factor, is one of the promising approaches in the field of
asymmetric synthesis.1 Several carbohydrate derivatives
are sources of chiral nonracemic materials, from which
synthetically useful auxiliaries have been devised.2 We
have investigated the utility of hexopyranose derivatives
as chiral templates for asymmetric carbon-carbon bond
forming reactions. Recently, we reported the highly stere-
oselective 1,4-additions of organocopper reagents3 or
alkyl radicals4 to carbohydrate derived chiral crotonyl es-
ters. In this communication, we report the preliminary re-
sults on the intermolecular Diels-Alder reaction based on
our carbohydrate template concept.5 The substrates 1-7,
which were used for the present asymmetric Diels-Alder
reaction, were conventionally prepared from known me-
thyl -D-glycopyranosides (Scheme 1). As the dienophile
part, these substrates possess an acryloyl ester moiety at
C-4 for methyl 6-deoxy- -D-glucopyranosides, i.e., 1-3,6,7
or at C-2 for methyl -D-mannopyranosides, i.e., 4-7.8
see Tables 1, 2
1-3
O
O
exo
isomers
O
+
+
O
O
*
RO
*
endo 2R
the
D-manno-type substrates
the 6-deoxy-D-gluco-type substrates
endo 2S
*
*
RO
8c-10c
OMe
8b-10b
8a-10a
O
O
8 : R = Bn; 9 : R = Piv; 10 : R = TBS
O
BnO
O
RO
O
O
RO
BnO
Scheme 2
RO
4 : R = Bn
5 : R = Bz
6 : R = Piv
7 : R = Ac
OMe
OMe
1 : R = Bn
2 : R = Piv
3 : R = TBS
The results of the Diels-Alder reaction of 1 or 2 conducted
in the presence of EtAlCl2 as Lewis acid are shown in Ta-
ble 2. Both Diels-Alder reactions proceeded at -78 °C to
provide a mixture of the endo adducts 8a/8b or 9a/9b pre-
dominantly although the combined yield of two endo-ad-
ducts was modest in every case (entries 1 and 2). In the
case of 2, however, highly diastereoselective formation of
the endo adduct 9b was observed. Interestingly, the -fa-
cial selectivity in the Lewis acid mediated endo mode Di-
els-Alder reaction of 2 was opposite to that observed
Scheme 1
First, we investigated the Diels-Alder reactions of the
6-deoxy-D-glucosidic substrates 1-3 with cyclopentadiene
(Scheme 2). The results under thermal conditions are
shown in Table 1. In every case, the Diels-Alder reaction
proceeded at room temperature to provide the adduct as a
Synlett 2001 No. 4, 481–484 ISSN 0936-5214 © Thieme Stuttgart · New York

482
T. Nagatsuka et al.
LETTER
Table 1 Diels-Alder Reaction of the 6-Deoxy-D-gluco-type Sub-
strates 1-3 under thermal conditionsa
O
O
O
O
O
O
Me
OMe
O
Me
s-cis, syn
Me
TS 1 : under thermal conditions (entry 2 in Table 1)
aCyclopentadiene, CH2Cl2, rt, 2-5 days. Combined yield of diaste-
b
reomeric adducts (%). cDetermined by 1H NMR analysis.
O
L.A.
O
O
O
O
Me
OMe
O
Me
O
O
Me
separation
the mixture
of 10a-c
s-trans, syn
O
O
+ 10b
OMe
TBSO
TBSO
10a
TS 2 : in the presence of Lewis acid (entry 2 in Table 2)
DIBAL-H, CH2Cl2, -78 °C
O
HO
TBSO
Figure A Plausible Transition States Mechanism for the Diels-
Alder Reactions of the 6-Deoxy-D-glucosidic Substrate 2
12 =
2S
OH
enantioenriched 11
TBSO
OMe
the carbohydrate
template 12 (81%)
Next, we investigated the Diels-Alder reactions of the
D-mannopyranosidic substrates 4-7 with cyclopentadiene
in the presence of Lewis acid12 (Scheme 4). The results are
summarized in Table 3. In every case, the Diels-Alder re-
action proceeded at -78 °C to afford a mixture of two endo
adducts 13a/13b - 16a/16b with high endo/exo selectivity.
The substrates 5-7 possessing an acyloxy substituent at
C-3 afforded the respective endo 2R adducts 14b-16b
with remarkable diastereoselectivity (entry 1 vs. entries 2-
4). Furthermore, the diastereomerically homogeneous
endo 2R adduct 16b was separated from other adducts by
chromatographic separation on silica gel (Scheme 5).13
After reductive cleavage of the carbohydrate moiety,
enantiomerically pure (2R)-endo-5-norbornene-2-metha-
nol 1714 was obtained. The carbohydrate template 18 was
recovered in good yield. The Diels-Alder reactions of 5-7
afford endo 2R-adducts in good diastereoselectivity, how-
ever, at present we have no reasonable explanation for this
stereochemical outcome.
Scheme 3
under the thermal conditions (entry 2 in Table 1 vs. entry
2 in Table 2). We propose a plausible transition state
mechanism to interpret this reverse -facial selectivity ob-
served for the substrate 2 under the thermal or the Lewis
acid mediated conditions (Figure). In the case of the ther-
mal conditions, the dienophile part is apt to exist in s-cis,
syn conformation. Then cyclopentadiene approaches from
the less hindered side by reason of avoiding the steric hin-
drance expected by the presence of the substituent at C-3
such as pivaloyloxy group in the case of 2 (TS 1). Conse-
quently, the endo 2S adducts 9a or 10a were obtained pre-
dominantly. On the other hand, in the presence of EtAlCl2,
the dienophile part is likely to change to s-trans, syn con-
formation as a result of the Lewis acid coordination to
acryloyl carbonyl. Cyclopentadiene favorably approaches
to the dienophile part from the less hindered side (TS 2).
As a result, the endo 2R adduct 9b was obtained predom-
inantly in the latter conditions.
cyclopentadiene, EtAlCl2, CH2Cl2, -78 °C
4-7
O
O
exo
isomers
Table 2 Diels-Alder Reaction of the 6-Deoxy-D-gluco-type Sub-
strates 1-3 in the presence of EtAlCl2
+
+
O
O
BnO
a
*
*
O
13c-16c
BnO
endo 2S
endo 2R
*
*
RO
13b-16b
13a-16a
OMe
13 : R = Bn; 14 : R = Bz; 15 : R = Piv ; 16 : R = Ac
Scheme 4
We also investigated the influence of the stoichiometry of
EtAlCl2 on the Diels-Alder reaction by using 2 or 5 as the
substrate. The results are shown in Table 4. Although the
aEtAlCl2 (2 eq), cyclopentadiene, CH2Cl2, -78 ºC, 15 min. bCombined
yield of diastereomeric adducts (%). cDetermined by 1H NMR analy-
sis. dReaction did not take place.
Synlett 2001, No. 4, 481–484 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Highly Stereoselective Diels-Alder Reactions
483
In summary, we have found a novel asymmetric Diels-Al-
der reaction methodology realized on the carbohydrate
templates. The present work provides a practical method
to prepare optically active chiral norbornene derivatives.
In some cases, the predominant endo adducts can be readi-
ly separated from the other diastereomers. Removal of the
carbohydrate templates from the endo adducts provides
enantiomerically enriched or pure (2S) or (2R)-endo-5-
norbornene-2-methanol.
Table 3 Diels-Alder Reaction of the D-Manno-type Substrates 4-7
in the presence of EtAlCl2
a
aEtAlCl2 (2 eq), cyclopentadiene, CH2Cl2, -78 ºC, 15 min. bCom-
bined yield of diastereomeric adducts (%). cDetermined by 1H NMR
analysis.
Acknowledgement
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports and Cul-
ture, Japan.
O
References and Notes
(1) Seyden-Penne, J. Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; Wiley: New York, 1995. Rück, K.;
Kunz, H. Chiral Auxiliaries in Cycloadditions; Wiley: New
York, 1995.
(2) Cintas, P. Tetrahedron 1991, 47, 6079. Kunz, H. Rück, K.
Angew. Chem., Int. Ed. Engl. 1993, 32, 336. Hultin, P. G.;
Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53, 14823.
(3) Totani, K.; Nagatsuka, T.; Takao, K.; Ohba, S.; Tadano, K.
Org. Lett. 1999, 1, 1447.
O
BnO
BnO
separation
the mixture
of 16a-c
O
AcO
OMe
16b as a single isomer
DIBAL-H, CH2Cl2, -78 °C
OH
O
BnO
BnO
2R
18 =
HO
OH
the carbohydrate
template 18 (quant)
enantiomerically pure 17
OMe
(4) Munakata, R.; Totani, K.; Takao, K.; Tadano, K. Synlett 2000,
7, 979.
Scheme 5
(5) A representative report on the Diels-Alder reaction on
carbohydrate template, see: Kunz, H.; Müller, B.;
Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1987, 26, 267.
(6) The 6-deoxy-D-gluco-type acrylates 1-3 were prepared
analogously to the preparation of the corresponding crotonyl
esters described in references 3 and 4.
endo/exo selectivity was independent of the stoichiometry
of EtAlCl2, the larger equiv of EtAlCl2 provided the high-
er diastereoselectivity in the -facial selectivity. On the
other hand, decrease of EtAlCl2 to 1 equiv or less caused
significant decrease of the yield in the case of 2. The in-
crease of Lewis acid certainly accompanies with the coor-
dination of EtAlCl2 to the neighboring acyloxy group,
which results in the formation of a more effective asym-
metric environment.
(7) All purified new compounds were fully characterized by 1H
and 13C NMR, IR, and HRMS.
(8) The D-manno-type acrylate 4 was prepared from methyl 3,4,6-
tri-O-benzyl- -D-mannopyranoside (Eby, R.; Webster, K. T.;
Schuerch, C. Carbohydr. Res. 1984, 129, 111) by
acryloylation. The substrates 5-7 were prepared from methyl
4,6-di-O-benzyl- -D-mannopyranoside (Kong, F.; Schuerch,
C. Carbohydr. Res. 1983, 112, 141) by regioselective
acryloylation of the 2-OH,via a metal chelate as descried in
the preparation of methyl 3,4,6-tri-O-benzyl- -D-
mannopyranoside by Eby et al., followed by acylation
(benzoylation for 5, pivaloylation for 6, or acetylation for 7)
of the 3-OH.
Table 4 Influence of EtAlCl2 Stoichiometrya
(9) A typical procedure for the Diels-Alder reaction under
thermal conditions: To a solution of 3 (38.1 mg, 0.083 mmol)
in CH2Cl2 (2 mL) was added cyclopentadiene (0.10 mL) at
0 °C. The reaction mixture was stirred for 5 days at room
temperature and concentrated in vacuo. The residue was
purified by chromatography on silica gel (hexane/
EtOAc = 80:1) to give a mixture of 10a, 10b and 10c as a
colorless oil (42.2 mg, 97%).
(10) Berson, J. A.; Walia, J. S. Remanick, A.; Suzuki, S.;
Reynolds-Warnhoff, P.; Willner, D. J. Am. Chem. Soc. 1961,
83, 3986. Also, see: Ref.5.
(11) The optical rotation of enantioenriched 11:[ ]22D-69 (c 0.195,
EtOH). For (2S)-endo-5-norbornene-2-methanol: Lit.5 [ ]D
-76.6 (95% EtOH).
(12) The Diels-Alder reactions of the substrates 4-7 under thermal
conditions underwent with no significant -facial selectivities
(d.r. of two endo adducts was ca. 1: 1 in every case).
aEtAlCl2, cyclopentadiene, CH2Cl2, -78 ºC, 15 min. bCombined yield
of diastereomeric adducts (%). cDetermined by 1H NMR analysis.
Synlett 2001, No. 4, 481–484 ISSN 0936-5214 © Thieme Stuttgart · New York

484
T. Nagatsuka et al.
LETTER
(13) A typical procedure for the Diels-Alder reaction in the
presence of Lewis acid: The reaction was conducted under an
argon atmosphere. To a solution of 7 (477.1 mg, 1.01 mmol)
in CH2Cl2 (20 mL) was added 1.0 M solution of EtAlCl2 in
hexane (2.1 mL, 2.1 mmol) at 78 °C. After the mixture was
stirred at –78 °C for 40 min, cyclopentadiene (0.25 mL) was
added dropwise over 10 min. The mixture was stirred at
–78 °C for 15 min and quenched with 1 M aq. HCl (2 mL).
The mixture was allowed to warm to room temperature,
diluted with 1 M aq. HCl (40 mL) and extracted with CH2Cl2
(40 mL 2). The combined organic layers were dried and
concentrated in vacuo. The residue was purified on silica gel
chromatography (hexane/EtOAc = 5:1) to provide 467.3 mg
(86%) of 16b as a colorless oil, and 68.1 mg (12%) of an
inseparable mixture of 16a and exo-adducts 16c.
(14) The optical rotation of enantiopure 17:[ ]22D+76 (c 0.215,
EtOH). For (2R)-endo-5-norbornene-2-methanol: Lit. [ ]22
D
+76.1 (c 0.9, EtOH) (Corey, E. J.; Ensley, H. E. J. Am. Chem.
Soc. 1975, 87, 6908).
Article Identifier:
1437-2096,E;2001,0,04,0481,0484,ftx,en;Y00301ST.pdf
Synlett 2001, No. 4, 481–484 ISSN 0936-5214 © Thieme Stuttgart · New York