Lewis-acid catalysis of the asymmetric Diels-Alder reaction of dimenthyl fumarate and cyclopentadiene

Article abstract of DOI:10.1016/S0957-4166(02)00213-6

The effects of Lewis acid catalysts, solvent, catalyst loading, and temperature on the diastereomeric excess in the Diels-Alder reaction of (+)-dimenthyl fumarate and cyclopentadiene were investigated.

Full text of DOI:10.1016/S0957-4166(02)00213-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 957–960
Lewis-acid catalysis of the asymmetric Diels–Alder reaction of
dimenthyl fumarate and cyclopentadiene
William F. Kiesman* and Russell C. Petter
Department of Medicinal Chemistry, Biogen, Inc, 14 Cambridge Center, Cambridge, MA 02142, USA
Received 4 March 2002; accepted 9 April 2002
Abstract—The effects of Lewis acid catalysts, solvent, catalyst loading, and temperature on the diastereomeric excess in the
Diels–Alder reaction of (+)-dimenthyl fumarate and cyclopentadiene were investigated. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
demonstrated that menthol was an effective and readily
available chiral auxiliary in the Et2AlCl-catalyzed
Diels–Alder reaction between fumarate and cyclopenta-
diene.4 The Hamanaka group later added that the use
of SnCl4 as the Lewis acid catalyst also gave excellent
stereoselectivity, although its use in the synthesis of a
pharmaceutical precursor would be problematic.5 We
undertook an investigation of the asymmetric Diels–
Alder reaction of dimenthyl fumarate and cyclopentadi-
ene in an effort to develop reaction conditions more
suitable for large-scale synthesis.
In conjunction with a process development project
focused on the design of a large scale synthesis strategy
for the production of the adenosine A1 antagonist
BG9719 (CVT-124)1 we saw the need for large amounts
of enantiomerically pure (2R,3R)-bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylic acid (Fig. 1).
The physical and fiscal constraints of large-scale pro-
duction of this intermediate via a chiral Diels–Alder
reaction limited our synthetic options for this process.
Thus, we turned our attention to inexpensive, recy-
clable chiral auxiliaries.2 Menthol has served as an
inexpensive chiral auxiliary in asymmetric Diels–Alder
reactions.3–10 For example, Yamamoto and co-workers
2. Results and discussion
Starting material preparation was quite straightfor-
ward. Fumaroyl chloride was heated to 50°C with
(+)-menthol to form a melt. The reaction proceeded
well without solvent and gave 85% yield of the (+)-
dimenthyl fumarate after purification (Fig. 2).
O
O
H
OH
H
The effects of Lewis acid catalysts, solvent, catalyst
loading and temperature on the diastereomeric excess in
the Diels–Alder reaction of (+)-dimenthyl fumarate and
cyclopentadiene were investigated (Table 1). The asym-
metric Diels–Alder reaction was initially examined
under a standard set of conditions (1.1 equiv. of Lewis
acid; toluene; 25°C, 2 h, Fig. 3). Poor diastereomeric
excesses (<5%) were observed with BiCl3, titanium iso-
propoxide, ZnCl2, MgCl2, and in the absence of a
Lewis acid catalyst. Aluminum-based Lewis acids gave
Diels–Alder adducts in moderate to good de (55–70%).
Within the titanium series of catalysts, TiCl4 and TiBr4
gave the highest overall de values at 75 and 80%,
respectively.
NH
N
OH
O
O
N
N
O
BG9719 (CVT-124)
Figure 1. Chiral building block for BG9719.
* Corresponding author. Tel.: 1-617-679-2790; fax: 1-617-679-2996;
e-mail: kiesman@biogen.com
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00213-6

958
W. F. Kiesman, R. C. Petter / Tetrahedron: Asymmetry 13 (2002) 957–960
OH
2 eq.
O
O
O
Cl
O
Cl
O
O
50 C, 18 h
85% yield
Figure 2. Double esterification of fumaroyl chloride.
Table 2. The effects of solvent, catalyst amounts, and
temperature on the TiCl4-mediated reaction of dimenthyl
fumarate and cyclopentadiene
Table 1. Influence of various Lewis acid catalysts on the
asymmetric Diels–Alder reaction of dimenthyl fumarate
and cyclopentadienea
Lewis acida
% Deb
Solvent
Lewis acid
% Deb
% Conversionc
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4 (2.2 equiv.)
TiCl4 (−35°C)
28
39
52
75
74
78
Benzotrifluoride
Diethyl ether
Hexane
Toluene
Toluene
None
BiCl3
ZnCl2
FeBr3
5
4
5
ND
5
100
100
100
B5
100
100
100
B5
100
100
B5
100
100
100
100
100
MgCl2
Ti(OCH(CH3)2)4
TiCl2(OCH(CH3)2)2
TiF4
TiCl4
TiBr4
BF3·Et2O
AlCl3
Me2AlCl
Et2AlCl
EtAlCl2
DADe
5d
27
44
75
80
53
55
67
69
70
66
Toluene
a Unless otherwise noted all reactions performed with 1.1 equiv.
TiCl4, 1.5 equiv. Cp, for 2 h at 25°C.
b Diastereomeric excesses determined by comparison of signals
assigned to vinylic protons in 1H NMR.
in 74% de (Table 3). Toluene, the solvent which gave
the Diels–Alder adducts with the highest diastereomeric
purity was the solvent of choice for the balance of the
investigation.
a All reactions performed with 1.1 equiv. LA, 1.5 equiv. Cp, for 2 h
in toluene at 25°C.
Increases in the amount of Lewis acid catalyst from one
equivalent to 2.2 equiv. gave mixed results with respect
to de. With TiCl4 and Me2AlCl there was little effect on
the stereoselectivity of the reaction with the addition of
excess Lewis acid.
b Diastereomeric excesses determined by comparison of signals
assigned to vinylic protons in 1H NMR.
c Determined by 1H NMR.
d Prepared from 0.5 equiv. of titanium isopropoxide and 0.5 equiv. of
TiCl4.
e Prepared from 0.5 equiv. of AlMe3 and 0.5 equiv. of BHT.
In the case of Et2AlCl, however, an improvement from
69 to 77% de was observed. As with many chiral
Diels–Alder reactions the stereoselectivity of the reac-
tion was sensitive to reaction temperature. As the reac-
tion temperature was decreased from room temperature
to −35°C a modest increase in de was observed in the
TiCl4-mediated reaction. Greater increases in de were
observed with the aluminum-based catalysts: Et2AlCl
and DAD. The catalyst loading and temperature effects
with the aluminum-based Lewis acids parallel those
reported by Yamamoto.4
The influence of solvents upon the diastereomeric
excess was dramatic. With TiCl4 catalysis the de
increased from 28% in benzotrifluoride to an optimum
of 75% in toluene (Table 2).
In the series of aluminum-based Lewis acid catalysts,
toluene again displayed the best performance except in
the case of EtAlCl2 which gave the Diels–Alder adduct
O
O
1.1 eq.Lewis Acid, Toluene
1.5 eq. Cp, rt, 2h
O
OR
H
O
O
OR
O
R = (+)-Menthyl
Figure 3. Lewis-acid catalyzed Diels–Alder reaction of (+)-dimenthyl fumarate.

W. F. Kiesman, R. C. Petter / Tetrahedron: Asymmetry 13 (2002) 957–960
959
OH
O
O
Cl
OH
Cl
H
O
OH
O
O
O
O
OR
O
H
O
OR
O
R = (+)-Menthyl
Figure 4. Recycling strategy for menthol auxiliary.
Table 3. The effects of solvent, catalyst amounts, and
temperature on the aluminum-based Lewis acid-mediated
reaction of dimenthyl fumarate and cyclopentadienea
thol (48.53 g, 0.311 mol) were combined in a round-
bottomed flask equipped with a stir bar and drying tube
and brought to 50°C. The melt was stirred overnight
(between 18 and 24 h). The reaction mixture was dis-
solved in EtOAc and the solution was washed with satd
NaHCO3, brine, dried with Na2SO4, and concentrated
in vacuo. Flash chromatography (silica) (95:5 hex-
ane:EtOAc) of the crude material yielded (+)-dimenthyl
Lewis acid
% Deb
Solvent
AlCl3
AlCl3
AlCl3
Me2AlCl
Me2AlCl (2.2 equiv.)
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl (2.2 equiv.)
Et2AlCl (−35°C)
EtAlCl2
EtAlCl2
EtAlCl2
10
28
55
67
68
38
67
70
69
77
83
37
47
70
74
MTBE
Hexane
Toluene
Toluene
Toluene
Diethyl ether
Hexane
Benzotrifluoride
Toluene
Toluene
Toluene
Benzotrifluoride
MTBE
Toluene
Hexane
1
fumarate (52.00 g, 85%). H NMR (CDCl3, 270 MHz)
l (ppm) 6.83 (s, 1H), 5.80 (dt, 1H), 2.05 (m, 1H), 1.85
(dt, 1H), 1.70 (m, 2H), 1.60–1.40 (m, 2H), 1.15–1.00 (m,
2H), 0.95–0.85 (m, 7H), 0.80 (d, 3H).
3.2. Diels–Alder reaction sample procedure
Under nitrogen, a 1 M solution of TiCl4 (2.55 mL) in
toluene was added to a solution of (+)-dimenthyl
fumarate (1.00 g, 2.55 mmol) in toluene (10 mL). The
reddish solution was stirred for 15 min and then freshly
distilled cyclopentadiene (0.315 mL, 3.82 mmol) was
added dropwise. After 2 h, satd aqueous NaHCO3 (5
mL) was added and the mixture was extracted with
Et2O (3×20 mL). The combined ether extracts were
washed with satd brine, dried with Na2SO4, and concd
in vacuo to yield the Diels–Alder adduct (1.14 g, 97%,
EtAlCl2
a Unless otherwise noted all reactions performed with 1.1 equiv. LA,
1.5 equiv. Cp, for 2 h at 25°C.
b Diastereomeric excesses determined by comparison of signals
assigned to vinylic protons in 1H NMR.
In conclusion, we have investigated a wide range of
Lewis-acid catalysts and reaction conditions for the
asymmetric Diels–Alder reaction of dimenthyl fumarate
and cyclopentadiene. The scalability of the room tem-
perature reaction catalyzed by TiCl4 in toluene and
recovery of the menthol auxiliary fit into the recycling
strategy detailed in Fig. 4 and will be the subject of
further investigation.
1
75% de). H NMR (CDCl3, 270 MHz) l (ppm) 6.25
(dd, 1H), 6.05 (dd, 1H) 4.65 (m, 2H), 3.30 (s, 1H), 3.10
(s, 1H), 2.65 (d, 1H), 2.00–1.80 (m, 5H), 1.70–1.55 (m,
7H), 1.55–1.30 (m, 7H), 1.10–0.75 (m, 14H), 0.70 (dt,
6H).
3.3. Determination of diastereoselectivities
3. Experimental
The diastereomeric excesses of the reaction products
were determined using the method described by
Kabalka et al.10 The ratios of Diels–Alder adducts were
calculated by comparison of the areas of the vinylic
3.1. (+)-Dimenthyl fumarate
1
Fumaroyl chloride (23.75 g, 0.155 mol) and (+)-men-
protons (6.5 ppm) in the H NMR.

960
W. F. Kiesman, R. C. Petter / Tetrahedron: Asymmetry 13 (2002) 957–960
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