Guidelines for stereocontrolled Diels-Alder reactions of chiral methylidene piperazine-2,5-diones with cyclopentadiene

Article abstract of DOI:10.1016/S0040-4039(01)00151-4

The reactivities and stereoselectivities of Diels-Alder cycloaddition reactions of methylidene piperazine-2,5-diones with cyclopentadiene can be manipulated by appropriate choice of N- and α-carbon substituents. Good to excellent exo/endo and facial selectivities were obtained.

Full text of DOI:10.1016/S0040-4039(01)00151-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2239–2242
Guidelines for stereocontrolled Diels–Alder reactions of chiral
methylidene piperazine-2,5-diones with cyclopentadiene
Brendan A. Burketta and Christina L. L. Chaib,*
aResearch School of Chemistry, Australian National University, Canberra 0200, ACT, Australia
bDepartment of Chemistry, Australian National University, Canberra 0200, ACT, Australia
Received 5 December 2000; revised 17 January 2001; accepted 25 January 2001
Abstract—The reactivities and stereoselectivities of Diels–Alder cycloaddition reactions of methylidene piperazine-2,5-diones with
cyclopentadiene can be manipulated by appropriate choice of N- and a-carbon substituents. Good to excellent exo/endo and facial
selectivities were obtained. © 2001 Elsevier Science Ltd. All rights reserved.
The use of cyclic dehydroalanine derivatives as
dienophiles in Diels–Alder reactions has gained promi-
nence in recent years.1–5 With the appropriate choice of
cyclic dehydroalanine systems, high regio- and stereose-
lectivities can frequently be achieved in cycloaddition
reactions relative to acyclic systems.6 Thus, cyclic dehy-
droalanine systems have been used as templates in the
asymmetric synthesis of cycloaliphatic amino acids and
derivatives.3–5,7 Our recent studies have added to the
repertoire of cyclic dehydroalanine derivatives available
for the synthesis of amino acids and derivatives.8 In
particular, we have shown that methylidene piperazine-
2,5-diones are excellent and versatile dienophiles in
Diels–Alder reactions.9 Our present studies suggest that
chiral methylidene piperazine-2,5-diones have a distinct
advantage over other cyclic dehydroalanine derivatives
as templates in asymmetric synthesis as they offer three
sites for reaction control. This in turn may allow for the
attenuation or enhancement of reactivities and selectivi-
ties in Diels–Alder reactions. In this study, we demon-
strate that by suitable choices of N- and C-substituents
on the piperazine-2,5-dione template, good to excellent
exo/endo and/or facial selectivities can be obtained.
piperazine-2,5-diones whereas under basic conditions,
only the monoacetylated methylidene derivatives were
isolated (Scheme 1). Methylidene piperazine-2,5-dione
1c was synthesised by treating cyclo-(Ser-N-MeAla)
with acetic anhydride to form the intermediate N,O-
diacetyl derivative, followed by treatment with 2 equiv.
of potassium tert-butoxide (Scheme 1). The methyli-
dene piperazine-2,5-diones were then treated with
freshly cracked cyclopentadiene (10 equiv.) at room
temperature.
The cycloadditions of chiral methylidene piperazine-
2,5-diones 1–3 can potentially give rise to four
diastereomers resulting from the approach of the diene
syn or anti to the remote a-carbon substituent, in either
an exo or endo orientation (Scheme 2). As summarised
in Table 1, at least three of the four possible cycload-
ducts were observed in each of the reactive systems.
The exo cycloadducts can be readily identified from the
1
endo isomers by comparison of the H NMR chemical
shifts of the olefinic resonances.† In some cases this
correlation is supported by X-ray data and 2D NMR
correlation studies. The facial isomers are not easily
identified and our assignments are based on X-ray
studies as well as NOE experiments.
Methylidene piperazine-2,5-diones 1a–3a, 1b–3b and 1c
were synthesised from the corresponding cyclo-(Ser-
amino acid) derivatives.10 Treatment of cyclo-(Ser-
amino acid) with acetic anhydride under thermal
conditions gave the N,N-diacetylated methylidene
For a constant remote a-carbon substituent (Me) and a
constant proximal N-substituent (N-H), reactivity
towards Diels–Alder cycloaddition is sluggish when the
distal N-substituent is Me versus Ac (entries 3 and 1
respectively, Table 1). This reactivity pattern is consis-
Keywords: amino acids and derivatives; bicyclic aliphatic compounds;
Diels–Alder reactions.
* Corresponding author. Fax: +61-2-6125-0760; e-mail: christina.
chai@anu.edu.au
† All new compounds gave satisfactory spectroscopic and analytical
data.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00151-4

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B. A. Burkett, C. L. L. Chai / Tetrahedron Letters 42 (2001) 2239–2242
1a R=Me (60%)
2a R=isopropyl (71%)
3a R=4-AcO-C6H4CH2- (60%)
H
O
O
Ac2O, NEt3,
DMAP
N
OH
N
Ac
R'=H
H
O
O
R
N
N
R'
R'=H
Ac
O
R
1b R=Me (72%)
N
Ac2O, heat
2b R=isopropyl (81%)
3b R=4-AcO-C6H4CH2- (55%)
N
O
Ac
1. Ac2O, heat
2. KOBut,
R=R'=Me
(60%)
R
t-BuOH/ether, 0oC
The yields are shown in brackets
H
N
O
1c
N
O
Me
Me
Scheme 1. Routes to methylidene piperazine-2,5-diones.
O
R1
N
O
R
N R1
R2
N
O
N
R2
R2
O
O
N
R
exo/Re (A)
N
exo/Si (B)
O
R1
R2
N
O
R
R2
N
1-3
R
O
O
N
N
O
R1
endo/Si (D)
R1
R
endo/Re (C)
Scheme 2. The four possible diastereomers from cycloaddition.
Table 1. Outcomes of cycloadditions of methylidene piperazinediones with cyclopentadiene
Entry
Methylidene piperazinedione
Isolated yields
Product distribution (A:B:C:D)
1
2
3
4
5
6
7
1a
1b
1c
2a
2b
3a
3b
60%a
10:17:1:1
50%b
Trace:1.2:trace:1
Not determined
12:1.4:1:0
Not determined
7:1:1:0
B10%a
60%a
Tracec
60%a
Tracec
Not determined
a Conditions: cyclopentadiene (10 equiv.), room temperature, 16 h.
b Conditions: cyclopentadiene (10 equiv.), room temperature, 72 h with addition of fresh cyclopentadiene (10 equiv.) after every 16 h.
c Conditions: cyclopentadiene (10 equiv.), toluene, 100°C, 16 h.
tent with our previous observations with achiral methyl-
idene piperazine-2,5-diones.9 Thus in the first instance,
in order to fulfil the reactivity requirement for syntheti-
cally useful conversions to cycloadducts, a distal N-Ac
group is deemed a necessary but not exclusive require-
ment.
substituent) via competitive rate studies show that
reactivity is attenuated for systems where the proximal
N-substituent is Ac versus H. Similar observations are
also made for methylidene piperazine-2,5-diones 2a and
b as well as 3a and b.
The major cycloadducts resulting from the reaction of
methylidene piperazine-2,5-dione 1a with cyclopenta-
diene are the exo cycloadducts (exo/endo selectivity
Comparisons of the reactivities of methylidene piper-
azine-2,5-diones 1a and b (constant distal N- and a-

B. A. Burkett, C. L. L. Chai / Tetrahedron Letters 42 (2001) 2239–2242
2241
Table 2. Summary of stereochemical outcomes with manipulations of substituents on methylidene piperazinediones
Desired outcome
Proximal N-substituent
Distal N-substituent
Remote a-carbon substituent for best facial selectivity
High exo selectivity
High endo selectivity
H
Ac
Ac
Ac
\ Me (e.g. iPr)
Me
Me, to 8.6:1 in R=isopropyl, to 7:1, in R=CH2Ar.
The major isomer in the latter two cases were deter-
mined by NOE studies and X-ray crystallography to be
that resulting from Re addition to the olefin (i.e. anti to
the remote a-carbon substituent). These studies suggest
that high facial discrimination of the two faces of the
olefin can be effected by the choice of a remote a-car-
bon substituent larger than a methyl group.
Thus in the presence of a distal N-Ac group (to fulfil
the reactivity requirement), the manipulations required
for the best control of exo/endo and facial selectivity
are summarised in Table 2.
Figure 1. AM1 calculated ground-state structure of 1b.
As the methods for cleavage of piperazine-2,5-diones to
the constituent a-amino acids are well established,12–15
the studies described here enable the utilisation of one
type of cyclic dehydroalanine template to provide
access to all the stereoisomers of the biologically active
ꢀ13:1), with facial selectivity only slightly in favour of
the approach of cyclopentadiene syn to the remote
a-Me substituent (i.e. Si addition) as determined by
X-ray crystallography of the deacetylated derivative. In
contrast, cycloaddition of 1b occurred with complete
facial selectivity to favour Si addition but the exo/endo
selectivity is severely compromised. This supports previ-
ous observations that the presence of the proximal N-H
group strongly enhances exo/endo selectivity.9 The
extremely high Si facial selectivity observed for methyl-
idene piperazine-2,5-dione 1b may be rationalised by
comparing the ground-state structures of the methyl-
idene piperazine-2,5-diones 1a and b. Molecular mod-
elling studies‡ suggest that piperazine-2,5-dione 1b
adopts a more boat-like conformation as compared to
1a, presumably in order to reduce 1,3-allylic strain. This
in turn results in greater shielding of the Re face of the
olefin to attack by cyclopentadiene. Thus the steric
shielding by the proximal N-Ac group (1,3-relationship)
is greater than that due to the presence of the remote
a-methyl substituent (1,5-relationship) and Si face
attack is favoured (Fig. 1). The role of N-substituents
in influencing the stereochemical outcomes of reactions
in heterocyclic systems is well documented11 and has
recently been exploited in piperazine-2,5-dione chiral
relay systems.12,13
norbornyl amino acids.16 For example, the use of
D-
amino acids as the directing groups in methylidene
piperazine-2,5-diones will lead to cycloadducts with the
opposite configuration to that when the
are used.
L-amino acids
From our studies here, it is apparent that methylidene
piperazine-2,5-diones have several advantages over
existing cyclic dehydroalanine templates. In particular,
a feature of the piperazine-2,5-dione systems is that the
exo/endo and facial selectivity can be easily manipu-
lated by appropriate choice of N- and remote a-carbon
substituents.
Acknowledgements
We thank the Australian Research Council for financial
support, and Pacific Dunlop for the award of a research
scholarship (B.A.B.).
Comparisons of the Diels–Alder reactions of methyl-
idene piperazine-2,5-diones 1a, 2a and 3a with cyclo-
pentadiene show that for a constant proximal and distal
N-H and N-Ac groups respectively, high exo/endo
selectivities are obtained (typically >8:1). In addition,
with increasing bulk of the remote a-carbon sub-
stituent, facial selectivity improves from 1.7:1 in R=
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