Multigram scale synthesis of a useful aza-Diels-Alder adduct in a one-step procedure

Article abstract of DOI:10.1016/S0957-4166(02)00127-1

The aza-Diels-Alder reaction between a chiral imine (derived from methyl glyoxylate and (S)-(-)-1-phenylethylamine) and cyclopentadiene, in the presence of trifluoroacetic acid and boron trifluoride diethyl etherate have been performed in a one-step proce

Full text of DOI:10.1016/S0957-4166(02)00127-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 447–449
Multigram scale synthesis of a useful aza-Diels–Alder adduct in
a one-step procedure
Jenny K. Ekegren,a Stefan A. Modin,a Diego A. Alonsob and Pher G. Anderssona,*
aDepartment of Organic Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden
bDepartamento de Quimica Organica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 25 February 2002; accepted 8 March 2002
Abstract—The aza-Diels–Alder reaction between a chiral imine (derived from methyl glyoxylate and (S)-(−)-1-phenylethylamine)
and cyclopentadiene, in the presence of trifluoroacetic acid and boron trifluoride diethyl etherate have been performed in a
one-step procedure. Without isolation of intermediates, 111.5 g of the major exo-isomer was isolated in a total yield of 56% using
a protocol where extensive chromatography was not required. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthesis of 1 was published in 1990–91 by the
groups of Stella,4 Bailey5 and Waldmann.6 A chiral
imine, derived from the condensation of 1-phenylethyl-
amine with an alkyl glyoxylate was utilized in the
aza-Diels–Alder reaction with cyclopentadiene cata-
lyzed by TFA and BF3·OEt2 which furnished the aza-
bicyclo[2.2.1]heptene derivative 1 (Scheme 1).
The hetero Diels–Alder adduct 1 (Fig. 1) has proved its
versatility and importance as synthetic intermediate for
a number of ligands which in turn have found use in a
variety of catalytic asymmetric processes. Derivatives of
1 have been used with excellent results, both by our
group1,2 and others3 in as varied applications as, for
example, the rearrangement of epoxides, the transfer
hydrogenation of prochiral ketones and addition of
diethylzinc to aldehydes.
The reaction is highly exo-selective, the exo:endo selec-
tivity reported varied from 86:14 to 98:2 and the
diastereomeric excess of the two exo-isomers have been
reported in a range from 80 to 98%.4–6 Analogues of 1,
synthesized with other chiral auxiliaries7 or using chiral
catalysts8 have also been reported in the literature. The
attractive feature of the protocol outlined in Scheme 1
lies in the use of inexpensive starting materials in
combination with the high selectivity observed when
utilizing 1-phenylethylamine as a chiral auxiliary.
Figure 1.
Scheme 1. Synthesis of aza-Diels–Alder adduct 1.
* Corresponding author. Tel.: +46-18 471 3801; fax: +46-18 51 25 24; e-mail: phera@kemi.uu.se
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00127-1

448
J. K. Ekegren et al. / Tetrahedron: Asymmetry 13 (2002) 447–449
Earlier, an extensive amount of work was needed in
order to separate the major exo-isomer 1 in the reac-
tion from its diastereomers by flash chromatography.
This was also the case in our laboratory until we
found that the methyl ester of 1 could be easily
recrystallized from pentane to afford diastereomeri-
cally pure 1a in high yields. We also found that there
was no need to purify the glyoxylate derived by
4. Experimental
4.1. Synthesis of (1R,3R,4S)-2-[(1S)-1-phenylethyl]-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylic acid methyl
ester 1a
In a 2 L round-bottomed flask equipped with a mag-
netic stirrer, dimethyl
L-tartrate (69.1 g, 0.388 mol)
cleavage of dimethyl
the reaction.
L
-tartrate nor the imine used in
was dissolved in diethyl ether (1 L) and cooled to
0°C with an ice-water bath. To this mixture, ortho-
periodic acid (88.4 g, 0.388 mol) was added over a
period of 30 min. The ice bath was then removed and
the mixture was allowed to reach ambient tempera-
ture and stirred for 30 min. The inorganic salts were
then filtered off, washed with diethyl ether into a 2 L
two-necked round-bottomed flask and the solvent was
evaporated. The two-necked flask was then equipped
with a mechanical stirrer, the methyl glyoxylate was
dissolved in dichloromethane (1.2 L), molecular sieves
Thus, we report herein an expedient synthesis of 1a,
starting from dimethyl -tartrate, (S)-(−)-1-
L
phenylethylamine and cyclopentadiene in a one step
procedure yielding 111.5 g of the single major exo-
isomer without the need for time consuming chro-
matographic purification.
,
(410 g, 4 A) were added under a N2 atmosphere and
the mixture was then cooled to approx. 4°C using
cold water. (S)-(−)-1-Phenylethylamine (100 mL, 0.776
mol) was then added to the cold mixture and stirred
for 1 h. The water bath was replaced with a dry
ice/acetone bath with an external cooler and the reac-
tion was cooled to approx. −75 to −78°C. With 10
min intervals trifluoroacetic acid (60.0 mL, 0.783
mol), boron trifluoride diethyl etherate (100 mL,
0.783 mol) and cyclopentadiene (78.0 mL, 0.931 mol)
were added to the flask. The reaction was then stirred
for 20 h at −75 to −78°C before the cooling was
removed. When the reaction had reached room tem-
perature it was quenched with Na2CO3 (aq. satd) and
stirred for 3 h. The quenched mixture was filtered
2. Results and discussion
The synthesis of 1a started with oxidative cleavage of
69 g of dimethyl L-tartrate with periodic acid yielding
the product, methyl glyoxylate as a mixture of mono-
and trimers in 1 h. This mixture was used immedi-
ately for condensation with (S)-(−)-1-phenylethyl-
amine after filtration and changing the solvent to
CH2Cl2. Imine formation was complete within an
hour with the aid of molecular sieves, which also
removed the water produced in the previous reaction
from the cleavage of dimethyl
L-tartrate. Upon com-
plete imine formation, the temperature was changed
from 4 to −75°C and TFA, BF3·OEt2 and cyclopenta-
diene were subsequently added to the mixture. For
the Diels–Alder reaction, efficient stirring was neces-
sary otherwise the reaction tended to freeze upon
addition of the cyclopentadiene. To avoid freezing, we
used a mechanical stirrer instead of a magnetic stir-
ring bar and the reaction proceeded smoothly without
problems. After quenching the acids using aqueous
Na2CO3, the crude products were filtered through a 5
cm pad of silica in order to separate the Diels–Alder
adducts from polymeric materials. Recrystallization of
the product mixture from n-pentane then afforded a
total of 111.5 g of the desired exo-isomer correspond-
ing to an overall yield of 56%.
through
a
pad of Celite and extracted with
dichloromethane (3×300 mL). The combined organic
extracts were dried (MgSO4), filtered and evaporated
to give crude product (191 g). The crude was dis-
solved in dichloromethane (600 mL) together with sil-
ica gel and the solvent was evaporated. The crude
products on the silica were filtered through a 5 cm
pad of silica in a large Bu¨chner funnel (pentane/ethyl
acetate, 90:10). The combined filtrate was evaporated
to give 168 g crude product that was dissolved in
refluxing pentane (250 mL) and allowed to crystallize
at −26°C (in
a
freezer) to give the desired
diastereomerically pure 1a as white crystals (95 g,
0.369 mol). The mother liquid was evaporated and
the remaining yellow oil was recrystallized again
according to the same procedure from pentane (80
mL) to give an additional crop of 1a (16.5 g, 0.064
mol). Combining the products resulted in a total yield
of 111.5 g (0.433 mol, 56%) of pure 1a. All physical
and spectroscopic data for the product were in com-
plete agreement with those published.2d,4b
3. Conclusion
A multigram scale synthesis of the very useful aza-
Diels–Alder adduct 1a has been performed. In this
new protocol no purification of the intermediates,
methyl glyoxylate and the imine used for the Diels–
Alder reaction, is necessary. In addition, chromato-
graphic purification of the reaction mixture in order
to isolate the major exo-isomer is not needed. Simple
filtration followed by efficient recrystallization yielded
the desired compound on a large scale and in good
yield.
Acknowledgements
We thank Solvias AG and The Swedish Research
Council for Engineering Sciences (TFR) for generous
financial support.

J. K. Ekegren et al. / Tetrahedron: Asymmetry 13 (2002) 447–449
449
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