Stereocontrolled intermolecular radical additions to methylidenepiperazine-2,5-diones

Article abstract of DOI:10.1039/a900771g

The use of latent amino acid functionalities for the syntheses of methylidenepiperazine-2,5-diones is reported. These piperazinediones are potential chiral templates in the synthesis of functionalised piperazinediones and amino acids. Carbon-carbon bond f

Full text of DOI:10.1039/a900771g

View Article Online / Journal Homepage / Table of Contents for this issue
Stereocontrolled intermolecular radical additions
to methylidenepiperazine-2,5-diones
Christina L. L. Chai*a and Alison R. Kingb
a Department of Chemistry, The Faculties, Australian National University, ACT 0200, Australia
b Research School of Chemistry, Institute of Advanced Studies, Australian National University,
ACT 0200, Australia
Received (in Cambridge) 28th January 1999, Accepted 10th March 1999
The use of latent amino acid functionalities for the syntheses of methylidenepiperazine-2,5-diones is reported.
These piperazinediones are potential chiral templates in the synthesis of functionalised piperazinediones and amino
acids. Carbon–carbon bond formation utilising radical addition reactions between the methylidenepiperazinediones
and a number of alkyl radicals resulted in good yields of the addition adduct. Moderate to high diastereoselectivities
were observed and factors controlling the chiral induction are discussed here.
of stereogenic centres. In view of this, mild, regio- and stereo-
Introduction
selective routes for building the carbon framework of piper-
The potential applications of dehydroamino acids and deriv-
azinediones are highly coveted. As radical chemistry has been
atives as versatile intermediates in asymmetric synthesis have
successfully applied to the difficult syntheses of some natural
long been recognised.1 The reactivity of the double bond is
products,11 it was envisaged that such chemistry may be utilised
unique due to the captodative nature2 of the adjacent substitu-
in the synthesis of complex piperazinediones. Hence our efforts,
directed at investigating the scope and limitations of alkyl
ents and this accounts for the range of reactions that can take
place.3 In addition, these alkenes are prochiral synthons and
radical additions will employ methylidenepiperazine-2,5-diones
highly regio- and stereoselective functionalisation of the double
as the key precursors for regio- and stereocontrolled carbon
bond, particularly in new carbon–carbon bond formation, have
functionalisation. Some preliminary results from this work have
been exploited in the synthesis of chiral molecules. One such
been published in communication form.7
type of reaction utilises radical additions to the alkene moiety.4–6
These reactions have been shown to be efficient and with cyclic
Results
derivatives, new carbon–carbon bond formation occurs with
moderate to high diastereoselectivities. An elegant application
of this has been demonstrated by Beckwith and co-workers
where new optically active α-amino acids were synthesised via
radical addition reactions with methylideneoxazolidinones
(1).5,6 The reactions occur with high stereocontrol, directed by
Synthesis of methylidenepiperazine-2,5-diones
Dehydroamino acids and derivatives can be readily obtained
from a number of suitably derived α-amino acid precursors
such as O-tosylserine, β-chloroalanine and sulfoxides and sul-
fones derived from cysteine.12 In contrast, dehydropiperazine-
2,5-diones such as the alkylidenes and arylidenes are commonly
synthesised via condensation procedures.13 In spite of this,
efficient routes to the synthesis of methylidenepiperazine-
2,5-diones (2) are not well established and our targets, methyl-
idenepiperazinediones of types 2a–d, were chosen to represent
piperazine-2,5-dione precursors with varying N-substitution
patterns. In our strategies to these compounds, the latent
functionalities of the amino acids alanine, serine and glycine
are exploited for the introduction of the double bond.
Unfortunately there is no one universal method for the
synthesis of methylidenepiperazinediones 2a–d, as the method
of choice depends on the N-substitution pattern on the piper-
azinedione ring. Thus the three routes presented here nicely
complement each other.
O
O
O
R1
O
N
But
N
N
R3
R2
O
R1
1
2 a R1=Ac, R2=H or Me, R3=Ac
b R1=Ac, R2=H or Me, R3=Me
c R1=Me, R2=H or Me, R3=Ac
d R1=Me, R2=H or Me, R3=Me
the substituents present in the ring system. α-Amino acids
were subsequently isolated following hydrolysis of the oxazol-
idinones. In a similar manner, dehydropiperazine-2,5-diones
(cyclic dehydrodipeptides) (2) can also be utilised to direct
the stereochemical outcome of reactions.7,8 For example,
dehydropiperazine-2,5-diones have been employed as chiral
templates in the synthesis of optically active α-amino acids and
derivatives via catalytic asymmetric hydrogenation reactions.9
However, to date there are only few reports of new carbon–
carbon bond forming reactions involving dehydropiperazine-
2,5-diones.7,10 A number of naturally occurring piperazine-2,5-
diones have complex structures and the syntheses of such
natural products are often difficult; complicated by sensitive
functionalities present as well as, in numerous cases, the number
From serine. Methylidenepiperazine-2,5-diones of types 2a
and 2b can be readily prepared from the corresponding serinyl
dipeptide esters (3–5) following the route shown in Scheme 1.
Protection of the free hydroxy group as the TBDMS ether,
followed by hydrogenolysis of the benzyloxycarbonyl (Z) group
gave the free dipeptide, which cyclised in situ to the piper-
azinedione. However, for the N-benzyloxycarbonyl-N-Me
derivative (8), cyclisation of the deprotected dipeptide did not
occur readily and in order to effect piperazinedione formation,
heating the dipeptide in toluene in the presence of base was
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182
1173

View Article Online
OTBDMS
O
OH
OMe
R1
N
O
OTBDMS
OMe
R1
N
O
(b)
(a)
9 R1=R2=H
HN
Z
N
H
Z
N
H
10 R1=H, R2=Me
11 R1=R2=Me
N
R2
O
R2
O
O
R1
3 R1=R2=H
4 R1=H, R2=Me
5 R1=R2=Me
6 R1=R2=H
7 R1=H, R2=Me
8 R1=R2=Me
R2
(c)
OAc
H
O
O
N
12 R1=Ac, R2=H
13 R1=Ac, R2=Me
14 R1=R2=Me
15 R1=Ac, R2=H 75%
16 R1=Ac, R2=Me 70%
17 R1=Me, R2=Me nde
Ac
O
O
Ac
O
(d)
N
N
N
Me
N
N
R1
O
R1
R2
R2
18
Scheme 1 Reagents and conditions: (a) TBDMSCl, imidazole, DMF (79–94%); (b) i, H2, MeOH, 10% Pd/C (95%) ii, for 8 ∆, toluene, NEt3;
(c) i, Ac2O, ∆. ii, Ac2O, FeCl3 (75–86%); (d) NEt3, CH2Cl2; (e) yield not determined.
necessary. The free nitrogen atom(s) of the piperazinediones
was then acetylated and conversion of the protected serine
moiety to the α,β-unsaturated moiety was achieved via the
acetoxy derivatives. Unexpectedly, the preparation of methyl-
idenepiperazinedione 17 from the corresponding acetoxy
derivative proved to be problematic. Under typical conditions,
where triethylamine was employed as the base, only starting
material was recovered. Various attempts to effect the elimin-
ation with different bases repeatedly failed to give the desired
methylidenepiperazinedione. The ‘best’ conditions for elimin-
ation utilised t-BuOK (2 equiv.) and the sole product isolated
was identified as 1,6-dimethyl-3-methylidenepiperazine-2,5-
dione 18 (70%). This presumably arises from hydrolysis of the
acetoxy moiety to the alkoxide followed by intramolecular
(N→O) acyl transfer. Elimination of the intermediate acetoxy
compound then gives methylidenepiperazinedione 18.
excess of sodium iodide. It is important to note that this syn-
thetic route is only applicable to methylidenepiperazinediones
of type 2c. Bromination of piperazinedione precursors 26 and
28 will result in preferential bromination of the glycyl center.
From glycine. As discussed above, radical bromination
reactions can also be used in the α-functionalisation of glycine-
derived piperazinediones. The corresponding bromides can
then be utilised as precursors to phosphonate esters, which in
turn can be used in Wittig–Horner chemistry for the instal-
lation of the double bond. Using this methodology (Scheme 3),
Br
O
O
R1N
R1N
(a)
NR3
NR3
O
O
R2
R2
From alanine. Our previous studies have shown that radical
bromination of piperazine-2,5-diones can occur in a highly
regioselective fashion depending on the nature of the substitu-
ents present.14–16 For example, bromination can be directed to
an alanyl in preference to a glycyl centre when the N-substituent
adjacent to the glycyl center is deactivating (e.g. N-Ac) as
compared to the N-substituent adjacent to the alanyl centre
(e.g. N-Me). Thus, in the synthesis of methylidenepiperazine-
diones of type 2c (Scheme 2), bromination of piperazinediones
29 R1=Me, R2=H, R3=Ac
30 R1=R2=Me, R3=Ac
31 R1=R3=Me, R2=H
32 R1=R2=R3=Me
25 R1=Me, R2=H, R3=Ac
26 R1=R2=Me, R3=Ac
27 R1=R3=Me, R2=H
28 R1=R2=R3=Me
(b)
O
P(OEt)2
O
O
R1N
R1N
(c)
O
O
R
N
NR3
NR3
N
OEt
(a)
O
O
NH
Z
N
H
O
R2
R2
O
R
23 R1=Me, R2=H, R3=Ac
24 R1=R2=Me, R3=Ac
37 R1=R3=Me, R2=H
38 R1=R2=R3=Me
33 R1=Me, R2=H, R3=Ac
34 R1=R2=Me, R3=Ac
35 R1=R3=Me, R2=H
36 R1=R2=R3=Me
R=H or Me
R=H or Me
(b)
Br
Br
Scheme 3 Reagents and conditions: (a) NBS, AlBN, CCl4, ∆; (b)
P(OEt)3, CH2Cl2; (c) NaH, CH2O, CH2Cl2.
O
O
O
(d)
(c)
N
N
N
N
N
N
O
Ac
O
Ac
O
Ac
the synthesis of methylidenepiperazinediones 23, 24, 37 and 38
were achieved in moderate to good yields as was previously
reported by us.18
R
R
R
21 R=H
22 R=Me
19 R=H
20 R=Me
23 R=H
24 R=Me
Scheme 2 Reagents and conditions: (a) i, H2 MeOH, 10% Pd/C, ii, ∆,
toluene, NEt3 (80–100%); (b) Ac2O, ∆ (77–84%); (c) NBS, AlBN, CCl4,
∆ (80–100%); (d) NaI, CH3CN (79–87%).
Intermolecular radical additions to methylidenepiperazine-2,5-
diones
With the methylidenepiperazinediones in hand, the synthetic
utility of these derivatives in radical carbon–carbon bond
forming reactions was systematically investigated (Scheme 4).
The regioselectivities of radical addition were initially
investigated using methylidenepiperazinediones 15 and 23
19 and 20 with NBS (two equivalents) gave the dibromopiper-
azinediones 21 and 22 respectively, consistent with previous
observations.15,17 Debromination to yield the desired methyl-
idenepiperazine-2,5-diones (23,24) was then achieved with an
1174
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182

View Article Online
Table 1 Radical addition to methylidenepiperazinediones 15 and 23
was carried out under either infinite dilution conditions or
via the catalytic tin method. The catalytic tin method boasts
easier purification procedures (due to smaller amounts of tin
by-products) but cannot be utilised in certain systems. For
example, our studies show that when radical additions to
piperazinedione 16 were carried out using the catalytic tin
method (Method 2), cis-1,4-diacetyl-3,6-dimethylpiperazine-
2,5-dione (cis-1,4-diacetylated alanine anhydride) was the only
product isolated (Table 2, entries 3, 5). This reduced compound
presumably arises from direct borohydride reduction of the
double bond, as has been observed previously with enamines.19
It is interesting to note that analogous direct reduction of the
double bond was not observed for piperazinedione 24 under
similar catalytic tin conditions. The different chemical outcome
is apparently dependent on the N-substitution pattern of the
piperazinedione ring and this in turn may be related to the
relative reactivities of the double bonds. The use of highly
reactive alkyl halides, e.g. tert-butyl iodide, in our reactions
were also incompatible with the catalytic tin method as alanine
anhydride derivatives as well as tarry reaction mixtures result.20
We also note that the choice of either a tin mediated or an
alkylmercury method for radical addition has little or no effect
on the diastereoselectivity of the addition despite the increase
in reaction temperatures when the catalytic tin method is used.
Methylidene
piperazinedione
Yield
(%)
Entry
Radical
Product
1
2
3
4
15
15
23
23
Pri
39
40
41
42
48
46
32
57
c-Hex
Pri
c-Hex
R4
R4
O
R1N
O
O
O
R4
R1N
MH
R1N
NR3
NR3
NR3
O
O
R2
R2
R2
(39)-(55)
Scheme 4
(Table 1) using the alkylmercury method. In all of the cases
examined, only one regioisomer, that resulting from β-addition
to the double bond was observed.
Effect of different alkyl radicals on the stereoselectivity of
addition. In cases where there is a C-6 substituent in the 3-
methylidenepiperazinediones, a mixture of stereoisomers can
result. Thus the diastereoselectivities of the addition reactions
Discussion
Despite much interest in recent literature on the stereo-
controlled formation of new carbon–carbon bonds of piper-
azinediones,21,22 the utilisation of methylidenepiperazinediones
as chiral templates has not been fully exploited.10 Our studies
above show that high diastereoselectivity in radical carbon–
carbon bond formation can be achieved by a combination of
judicious choice of N-substituents on the piperazinedione ring
as well as the nature of the alkyl radicals added. The addition
reaction proceeds in all cases in a regioselective fashion to yield
the captodatively stabilised, α-carbon centred piperazinedione
radical. In all the cases studied above, the major cis-isomer
results from quenching of the intermediate piperazinedione
radical from the opposite face to the remote α-carbon substitu-
ent. This is presumably due to the more hindered approach of
the reducing agent (tributyltin hydride or alkylmercury hydride)
to one face of the planar or the nearly planar radical intermedi-
ate (Scheme 4). This is nicely supported by AM1 calculations of
the piperazinedione radical 56. It is evident that the remote
1
were determined using a combination of methods. Careful H
NMR integration of appropriate resonances of the stereo-
isomers and/or quantitative gas chromatographic analysis of
the crude reaction mixtures gave the tabulated ratios of the
stereoisomers (Table 2).
For each of the methylidenepiperazinediones, it is apparent
that increasing the size of the adding radical causes a marked
improvement in the diastereoselectivity of addition. For
example, addition of a methyl radical to methylidenepiper-
azinedione 16 gives rise to a diastereoselectivity of 4:1 whereas
addition of an isopropyl radical only yields one stereoisomer.
Similar trends are also observed with the other methyl-
idenepiperazinediones.
The major isomer in each of the addition reactions above was
determined to be cis. The assignment of the relative stereo-
chemistry of the addition products was carried out in most
cases using NOE experiments. In the case of the addition
adducts 45 and 51, further confirmation of the stereochemical
assignment was obtained through the independent synthesis of
piperazinediones 45 and 51 starting from suitably protected
dipeptide esters of -leucyl--alanine.
R1
O
O
R1N
N
NR2
Effect of N-substituents on the stereoselectivity of addition. It
is apparent from entries 2, 11, 12 and 18 in Table 2 that the
stereochemical outcome for radical addition is in part depend-
ent on the structure of the methylidenepiperazinediones. For
example, the cis:trans ratio for ethyl radical addition increases
in the order of 1,4-dimethyl < 1-acetyl-4-methyl < 1,4-diacetyl
derivatives of methylidenepiperazinediones (1.5:1 to 4:1 to
5:1). Similar trends were also observed in the addition of
methyl and isopropyl radicals.
N
O
Ac
O
59 R1=Me
60 R1=Pri
61 R1=But
56 R1=R2=Ac
57 R1=Me, R2=Ac
58 R1=R2=Me
α-methyl group adopts a pseudoaxial position, consistent with
other conformational studies on piperazinediones and that this
renders the β-face less accessible to the approach of the
reducing agent. Previous workers have shown that the conform-
ation of piperazinediones is dramatically affected by the sub-
stituents present on the piperazinedione ring.23 The sensitivity
of the ring conformation to such changes is also illustrated by
AM1 calculations of piperazinedione radicals 57 and 58. A
measure of the degree of folding of the piperazinedione ring
is the Hooker parameter (β).24 In 1,4-diacetylated piperazine-
dione radical 56, the β-value is 26.0Њ as compared to that for
the 1-acetyl-4-methyl piperazinedione radical 57 and 1,4-
dimethylated piperazinedione radical 58 with values of 20.5 and
Method of radical addition. Both tin mediated as well as
alkylmercury mediated methods to effect radical additions were
examined. In general, both methods of addition are efficient in
the synthesis of new carbon–carbon bonds of the piperazine-
diones. Both methods can be conducted under mild reaction
conditions and gave good to moderate yields of the addition
product in our studies. Whereas the alkylmercury method is
limited by the ready availability of alkylmercurys, the tin
methods are more versatile in that commercially available alkyl
iodides are utilised. For the latter, tin mediated radical addition
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182
1175

View Article Online
Table 2 Radical addition to methylidenepiperazinediones 16, 24 and 38
Methylidene
piperazinedione
Entry
Radical
Methoda
Product
cis:transb
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
16
16
16
16
16
16
16
16
24
24
24
24
24
24
24
24
24
38
Me
Et
1
1
2
3
2
3
1
1
1
2
1
2
2
3
3
1
1
2
43
4:1
5:1
—
1:0
—
52
55
ndd
66
ndd
49
65
63
56
ndd
54
65
53
45
37
77
38
73
44
Et
Reducedc
Pri
45
Pri
Reducedc
46
c-Hex
But
CH2Ph
Me
Me
Et
1:0
1:0
1:0
2:1
2:1
4:1
4:1
6:1
6:1
1:0
1:0
1:0
1.5:1
47
48
49
49
50
Et
50
Pri
51
Pri
51
c-Hex
But
CH2Ph
Et
52
53
54
55
a Method 1: Bu3SnH, RI, AIBN. Method 2: Bu3SnCl, NaCNBH3, RI, AIBN. Method 3: RHgCl, NaBH4. For details, see Experimental. b Determined
by NMR and/or gas chromatography. c cis-1,4-Diacetylated alanine anhydride was obtained. d nd: yield not determined.
18.3Њ respectively (Fig. 1). Thus, it is suggestive that the increase
in the β-value translates to an increase in steric crowding on
the β-face. This in turn leads to better observed diastereo-
selectivities for methylidenepiperazinedione 16 > 24 > 38,
for the same adding radical. Similar trends were also observed
in the AM1 geometry minimisation of the intermediate
radicals 59, 60 and 61, each of which results from the addition
of an ethyl, isopropyl and tert-butyl radical to methylidene-
piperazinedione 24. The general trend shows that there is
an increase in β-values (21.5, 22.4 and 26.7Њ respectively for
radicals 59, 60 and 61), consistent with the improvement
in diastereoselectivities with the size of the incoming alkyl
radical.
The dehydropiperazinedione ring system evidently exerts
stereochemical control through steric effects amplified by
particular ring conformations. Although similar steric effects
must also operate for other cyclic dehydroalanine systems e.g.
the dehydrooxazolidinones, the precise stereochemical outcome
cannot be easily predicted and is highly sensitive to a number of
factors. In the methylideneoxazolidinones, the stereochemical
preference can even be reversed by changing the N-substituents
on the oxazolidinone ring.5 In radical addition reactions, the
greater sensitivity of the oxazolidinones to the influence of
the N-substituents as compared to that of the methylidene-
piperazinediones must be intimately linked to the more com-
pact five-membered ring system in the former.
Conclusion
The three methods developed for the synthesis of
methylidenepiperazine-2,5-diones allow for efficient access to
this important class of prochiral synthetic precursors. The
methodologies developed here utilise readily available piper-
azinediones, synthesised from simple amino acid derivatives
and the routes lead to the desired methylidenepiperazinediones
in moderate to excellent yields. These methylidenepiperazine-
diones have been shown to be excellent precursors in asym-
metric carbon skeleton extension and hence have applications
in the stereoselective synthesis of new α-amino acids as well as
functionalised piperazine-2,5-diones. There are a number of
factors which influence the stereoselectivity of intermolecular
radical addition to methylidenepiperazinediones. These param-
eters, such as the nature of the N-substituents as well as
the adding alkyl radical, indirectly affect the degree of 1,4-
inductive effects of the remote α-methyl substituent of the
piperazinedione ring. Substituent effects similar to this have
Fig. 1 AM1 geometry optimisation of radical structures 56–58.
also been observed in suitably substituted piperazinediones
where certain combinations of N- and C-substituents enhance
the diastereoselectivities of alkylation reactions via a chiral
relay network.21 Our study on methylidenepiperazinediones
is another example where stereocontrol is affected through the
combination of substituents present.
1176
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182

View Article Online
acetate (60 cm3) and washed with water (30 cm3), dried
Experimental
(MgSO4) and the solvent removed in vacuo. The protected
dipeptide ester was purified by column chromatography (1:1
light petroleum–ethyl acetate, Rf 0.6) to give the desired product
as a white solid (4.85 g, 94%). mp 50–52 ЊC (ethyl acetate–light
petroleum) (Found: C, 57.2; H, 8.1; N, 6.3. Calc. for
C21H34N2O6Si: C, 57.5; H, 7.8; N, 6.4%); νmax(KBr)/cmϪ1 3301,
1748, 1685, 1647, 1534, 1264, 1055, 780; δH (300 MHz; CDCl3)
0.02 (3H, s, SiCH3), 0.03 (3H, s, SiCH3), 0.86 (9H, s,
SiC(CH3)3), 1.43 (3H, d, J 7, CHCH3), 3.74 (3H, s, OCH3), 3.81
(1H, dd, J 3 and 10, CHCHAHB), 4.07 (1H, dd, J 3 and 10,
CHCHAHB), 4.31 (1H, m, CHCH3), 4.64 (1H, dt, J 3 and 8,
CHCH2), 5.12 (2H, m, CH2Ph), 5.37 (1H, br d, NH), 6.63 (1H,
General
Melting points (mp) were determined on a Reichert hot-stage
apparatus and are uncorrected. Infrared spectra were recorded
as KBr discs (solids) or as a thin film on KBr or NaCl plates
(oils) on a Perkin-Elmer spectrometer. NMR spectra were
recorded on a Varian Gemini BB 300 or Gemini 1 300 at 300
MHz for proton NMR and at 75 MHz for carbon NMR. For
1H NMR spectra, chemical shifts are reported by using the
following as references: in CDCl3, by referencing either the
residual solvent (CHCl3) at 7.26 ppm or relative to tetramethyl-
silane (TMS) at 0.0 ppm; in CD3OD, by referencing the residual
solvent (CHD2OD) at 3.4 ppm; in D2O, by referencing the
residual solvent (HOD) at 4.7 ppm. J Values are given in Hz.
For 13C NMR spectra recorded in CDCl3, the centre line of
the triplet due to CDCl3 was referenced to 77.0 ppm. Nuclear
Overhauser experiments were carried out on an Innova 500
instrument at 500 MHz with solvent used as a reference in all
cases. Diastereoselectivities were determined by accurate peak
integration of the 1H NMR spectra of the crude reaction
products or by GC. Gas chromatography was performed on a
Varian 3400 Gas Chromatograph employing a Supelco SPB-2
(30 m × 0.25 mm, 0.25 µm film) column. Low resolution mass
spectra (m/z) were recorded on a VG Micromass 7070F mass
spectrometer or a Hewlett Packard HP-5995C instrument at 70
eV. Microanalyses were performed by the Analytical Facility of
the Australian National University. Column chromatography
employed Merck Kieselgel 60 (230–400 mesh ASTM). Solvents
used were of AR grade, with benzene being dried over sodium
and deoxygenated prior to use. Light petroleum refers to
fractions with bp 60–80 ЊC. Methylidenepiperazine-2,5-diones
23 and 38 were prepared as reported previously15 as was
piperazine-2,5-dione 20.25 Dipeptides were prepared by stand-
ard methods (DCC, HOBt).26
ϩ
ؒ
br d, J 8, NH), 7.36 (5H, s, Ph); m/z (EI) 438 (M , 1%), 381
(33), 91 (100).
Methyl N-(N-benzyloxycarbonyl-N-methyl-L-alanyl)-O-tert-
butyldimethylsilyl-L-serinate 8
To a stirred solution of methyl N-(N-benzyloxycarbonyl-N-
methyl--alanyl)--serinate (2.87 g, 8.5 mmol) in DMF (12 cm3)
was added tert-butyldimethylsilyl chloride (1.53 g, 10.2 mmol)
and imidazole (0.69 g, 10.2 mmol). The reaction mixture was
stirred at room temperature for a further 16 hours, following
which the solvent was removed under reduced pressure. The
residue was taken up in ethyl acetate (30 cm3) and washed with
water (15 cm3), dried (MgSO4) and the solvent removed in
vacuo. The protected dipeptide ester was purified by flash
chromatography (7:3 light petroleum–ethyl acetate, Rf 0.4) to
give the product as a yellow oil (85%) (Found: C, 58.2, H, 7.8,
N, 6.3. Calc. for C22H36N2O6Si: C, 58.4, H, 8.0, N, 6.2%);
νmax(film)/cmϪ1 2954, 2931, 2857, 1750, 1693, 1511, 1399, 1309,
1255, 1157, 1111, 836, 779; δH (300 MHz; CDCl3) 0.01 (6H, s,
Si(CH3)2), 0.84 (9H, s, C(CH3)3), 1.38 (3H, d, J 7, CHCH3), 2.87
(3H, s, NCH3), 3.74 (3H, s, OCH3), 3.78 (1H, dd, J 3 and 10,
CHCHAHB), 4.04 (1H, dd, J 3 and 10, CHCHAHB), 4.62 (1H,
dt, J 3 and 8, CHCH2), 4.9 (1H, br m, CHCH3), 5.17 (2H, br s,
Molecular modelling calculations were carried out with
Spartan SG1 Ver. 5.0.1 © Wavefunction Inc., using AM1
parameters.
ϩ
ؒ
PhCH2), 7.36 (5H, s, Ph); m/z (EI) 452 (M , 0.2%), 437 (2), 421
(1.5), 395 (57), 192 (35), 148 (58), 91 (100).
Methyl N-(N-benzyloxycarbonylglycyl)-O-tert-butyldimethyl-
silyl-L-serinate 6
General procedure for the conversion of benzyloxycarbonyl
dipeptide esters to piperazine-2,5-diones
This was prepared following the procedure of Corey.27 To a
stirred solution of methyl Z-glycyl--serinate (1 g, 3.23 mmol)
in DMF (4 cm3) was added tert-butyldimethylsilyl chloride
(0.58 g, 3.88 mmol) and imidazole (0.55 g, 3.88 mmol). The
reaction mixture was stirred at room temperature for a further
16 hours following which the solvent was removed under
reduced pressure. The residue was taken up in ethyl acetate
(20 cm3) and washed with water (10 cm3), dried (MgSO4) and
the solvent removed in vacuo. The protected dipeptide ester was
purified by column chromatography (7:3 light petroleum–ethyl
acetate, Rf 0.3) to give the desired product as a colourless
oil (1.1 g, 79%) (Found: C, 56.6; H, 7.9; N, 6.6. Calc. for
C20H32N2O6Si: C, 56.6; H, 7.6; N, 6.6%); νmax(film)/cmϪ1 3330,
2957, 2926, 1756, 1709, 1529, 1264, 1102, 1054; δH (300 MHz;
CDCl3) 0.077 (3H, s, Si(CH3)CH3), 0.083 (3H, s, Si(CH3)CH3),
0.91 (9H, s, SiC(CH3)3), 3.79 (3H, s, OCH3), 3.8–4.2 (4H, m,
CH2 and CHCH2), 4.73 (1H, m, CHCH2), 5.63 (1H, br s, NH),
5.19 (2H, s, CH2Ph), 6.89 (1H, br s, NH), 7.41 (5H, s, Ph); m/z
To a solution of the Z-dipeptide ester (typically 2 g) in meth-
anol (25 cm3 gϪ1) was added a catalytic amount of 10% Pd/C
and two drops of triethylamine. The reaction flask was evacu-
ated and charged with H2 (3×) and then left to stir for a further
16 hours at room temperature under a hydrogen atmosphere.
The reaction mixture was filtered over Whatman glass micro-
fibre filters and the filtrate evaporated under reduced pressure.
(3S)-3-(tert-Butyldimethylsilyloxymethyl)piperazine-2,5-
dione 9. The protected dipeptide ester 6 was converted to the
corresponding piperazine-2,5-dione 9 following the general
procedure above. The product was obtained as a white solid
(90%), mp 233–234 ЊC (decomp.) (methanol) (Found: C, 50.9;
H, 8.8; N, 10.6. Calc. for C11H22N2O3Si: C, 51.1; H, 8.6; N,
10.8%); νmax(KBr)/cmϪ1 3202, 3086, 2929, 2857, 1695, 1677,
1463, 1334, 1114, 837, 779; δH (300 MHz; D2O) 0.02 (6H, s,
Si(CH3)2), 0.78 (9H, s, SiC(CH3)3), 3.45 (2H, m, CH2), 3.8–3.6
ϩ
ؒ
(2H, m, CHCH2), 4.56 (1H, t, CHCH2); m/z (EI) 258 (M ,
ϩ
ؒ
(EI) 424 (M , 2%), 367 (43), 91 (100).
1%), 201 (100), 73 (50).
Methyl N-(N-benzyloxycarbonyl-L-alanyl)-O-tert-butyldimeth-
ylsilyl-L-serinate 7
(3S,6S)-3-tert-Butyldimethylsilyloxymethyl-6-methylpiper-
azine-2,5-dione 10. The protected dipeptide ester 7 was con-
verted to the corresponding piperazine-2,5-dione 10 following
the general procedure above. The product was obtained as a
white solid (63%), mp 136–138 ЊC (decomp.) (methanol)
(Found: C, 52.9; H, 8.9; N, 10.6. Calc. for C12H24N2O3Si: C,
52.6; H, 8.7; N, 10.3%); νmax(KBr)/cmϪ1 3218, 2955, 1685, 1465,
1107, 833, 777; δH (300 MHz; CD3OD) 0.19 (6H, s, Si(CH3)2),
To a stirred solution of methyl -Z-alanyl--serinate (3.85 g,
11.8 mmol) in DMF (20 cm3) was added tert-butyldimethylsilyl
chloride (2.15 g, 14.3 mmol) and imidazole (2.02 g, 29.7 mmol).
The reaction mixture was stirred at room temperature for a
further 16 hours following which the solvent was removed
under reduced pressure. The residue was taken up in ethyl
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182
1177

View Article Online
1.00 (9H, s, SiC(CH3)3), 1.57 (3H, d, J 7, CHCH3), 3.86 (1H,
dd, J 1 and 11, CHCHAHB), 4.09 (2H, m, CHCH3 and
CHCHAHB), 4.18 (1H, dd, J 1 and 11, CHCHAHB); m/z (EI)
272 (M , 2%), 215 (100), 73 (48) (Found: 272.1553. Calc. for
C12H24N2O3Si 272.155).
(10 equiv. by weight) for 4 hours. Upon completion of the reac-
tion, excess acetic anhydride was removed by co-evaporating
several times with toluene. The crude residue was purified by
column chromatography (8:2 light petroleum–ethyl acetate,
Rf 0.55) to give (3S,6S)-1,4-diacetyl-3-tert-butyldimethylsilyl-
oxymethyl-6-methylpiperazine-2,5-dione as a clear oil (86%)
(Found: C, 54.2; H, 8.2; N, 7.8. Calc. for C16H28N2O5Si: C, 53.9;
H, 7.9; N, 7.9%); νmax(film)/cmϪ1 2955, 2933, 2858, 2359, 1706,
1372, 1237, 1100, 838; δH (300 MHz; CDCl3) 0.004 (3H, s,
SiCH3), 0.03 (3H, s, SiCH3), 0.84 (9H, s, SiC(CH3)3), 1.63
(3H, d, J 7, CHCH3), 2.52 (3H, s, NAc), 2.53 (3H, s, NAc), 3.98
(1H, dd, J 3 and 11, CHCHAHB), 4.22 (1H, dd, J 2 and 11,
CHCHAHB), 5.11 (2H, m, CHCH3 and CHCHAHB); m/z
ϩ
ؒ
(3S,6S)-3-tert-Butyldimethylsilyloxymethyl-1,6-dimethyl-
piperazine-2,5-dione 11. The dipeptide ester 8 was deprotected
following the general procedure above. As cyclisation did not
occur in situ, the deprotected dipeptide ester was refluxed in
toluene in the presence of base (NEt3) for several days. The
desired piperazine-2,5-dione 11 was isolated as a white solid
following column chromatography (9:1 ethyl acetate–
methanol, Rf 0.5) (92%), mp 92–95 ЊC (ethyl acetate) (Found: C,
54.1; H, 8.9; N, 9.7. Calc. for C13H26N2O3Si: C, 54.5; H, 9.15;
N, 9.8%); νmax(KBr)/cmϪ1 2930, 1688, 1671, 1649, 1463, 1337,
1252, 1105, 834, 782; δH (300 MHz; CDCl3) 0.03 (6H, s,
Si(CH3)2), 0.84 (9H, s, SiC(CH3)3), 1.53 (3H, d, J 7, CHCH3),
2.91 (3H, s, NCH3), 3.83 (2H, m, CHCH3 and CHCHACHB),
3.94 (1H, d, J 10, CHCHAHB), 4.02 (1H, m, CHCHAHB); δC (75
MHz; CDCl3) Ϫ5.58 (SiCH3), Ϫ5.51 (SiCH3), 17.63 (CHCH3),
18.07 (SiC(CH3)3), 25.71 (SiC(CH3)3), 31.91 (NCH3), 54.94
(CHCH3), 58.10 (CHCH2), 63.99 (CHCH2), 164.17 (CO),
ϩ
ؒ
(EI) 357 (MH , 1%), 299 (72), 257 (89), 215 (100), 158 (83), 73
(82).
To a solution of the piperazine-2,5-dione above (1.31 g, 3.68
mmol) in acetic anhydride (2 cm3, 22.1 mmol) at 0 ЊC was added
iron trichloride (0.30 g, 1.85 mmol). The reaction mixture was
stirred at ambient temperature and monitored by TLC for the
disappearance of the starting piperazinedione. Upon complete
consumption of the starting materials, light petroleum (10 cm3)
was added to the reaction mixture and the organic layer washed
with water. The aqueous phase was extracted with ethyl acetate
(3 × 10 cm3) and the combined organic layers dried (Na2SO4).
The solvent was removed in vacuo and was co-evaporated
several times with toluene. The residue was purified by flash
chromatography (7:3 light petroleum–ethyl acetate, Rf 0.4) to
give the desired product 13 as a clear oil (0.66 g, 80%) (Found:
C, 50.7; H, 5.75; N, 9.6. Calc. for C12H16N2O6: C, 50.7; H, 5.7;
N, 9.85%); νmax(film)/cmϪ1 2917, 1753, 1709, 1373, 1226, 447; δH
(300 MHz; CDCl3) 1.69 (3H, d, J 7, CHCH3), 2.04 (3H, s,
OAc), 2.54 (6H, s, NAc), 4.43 (1H, dd, J 3 and 12, CHCHAHB),
4.62 (1H, dd, J 4 and 12, CHCHAHB), 5.18 (1H, q, J 7,
ϩ
ؒ
168.54 (CO); m/z (EI) 286 (5%, M ), 271 (29), 256 (23), 229
(100), 158 (49), 116 (31), 89 (31).
(3S)-1,4-Diacetyl-3-acetoxymethylpiperazine-2,5-dione 12
Piperazine-2,5-dione 9 (1.5 g) was refluxed in acetic anhydride
(10 equiv. by weight) for 4 hours. Upon completion of the
reaction, excess acetic anhydride was removed by repeated co-
evaporation with toluene. The residue was then purified by flash
chromatography (1:1 light petroleum–ethyl acetate, Rf 0.7)
to give (3S)-1,4-diacetyl-3-(tert-butyldimethylsilyloxymethyl)-
piperazine-2,5-dione as a clear oil (74%) (Found: C, 52.4; H,
7.95; N, 8.4. Calc. for C15H26N2O5Si: C, 52.6; H, 7.65; N,
8.2%); νmax(film)/cmϪ1 2654, 2929, 2859, 1716, 1369, 1308,
1220, 1106, 839; δH (300 MHz; CDCl3) 0.02 (6H, s, Si(CH3)2),
0.85 (9H, s, SiC(CH3)3), 2.58 (3H, s, NAc), 2.59 (3H, s, NAc),
3.95 (1H, dd, J 3 and 10, CHCHAHB), 4.22 (1H, dd, J 3 and
10, CHCHAHB), 4.27 (1H, d, J 18, CHCHD), 4.85 (1H, d, J 18,
ϩ
ؒ
CHCH3), 5.33 (1H, m, CHCHAHB); m/z (EI) 284 (M , 4%),
254 (31), 242 (19), 212 (90), 182 (36), 170 (100), 157 (38), 140
(40), 128 (81), 111 (30), 82 (42).
(3S,6S)-1-Acetyl-6-acetoxymethyl-3,4-dimethylpiperazine-2,5-
dione 14
Piperazine-2,5-dione 11 (1.26 g, 4.4 mmol) was refluxed in
acetic anhydride (10 equiv. by weight) for 4 hours. Upon com-
pletion of the reaction, excess acetic anhydride was removed
by repeated co-evaporation with toluene. The crude residue
was purified by column chromatography (1:1 light petroleum–
ethyl acetate, Rf 0.4) and recrystallisation (ethyl acetate–light
petroleum) to give 1-acetyl-6-tert-butyldimethylsilyloxymethyl-
3,4-dimethylpiperazine-2,5-dione as white crystals (84%), mp
56–58 ЊC (Found: C, 54.7; H, 8.4; N, 8.4. Calc. for C15H28N2-
O4Si: C, 54.9; H, 8.6; N, 8.5%); νmax(KBr)/cmϪ1 2960, 2850,
1722, 1698, 1665, 1650, 1390, 1254, 1104; δH (300 MHz; CDCl3)
0.01 (3H, s, SiCH3), 0.02 (3H, s, SiCH3), 0.83 (9H, s, SiC-
(CH3)3), 1.62 (3H, d, J 7, CHCH3), 2.53 (3H, s, NAc), 2.95 (3H,
s, NCH3), 3.94 (1H, dd, J 3 and 11, CHCHAHB), 4.10 (2H, m,
CHCH3 and CHCHAHB), 4.91 (1H, m, CHCHAHB); m/z (EI)
ϩ
ؒ
CHCHD), 5.13 (1H, m, CHCHAHB); m/z (EI) 342 (M , 6%),
300 (9), 285 (100), 243 (96), 201 (94), 158 (69), 116 (59), 73
(62).
To a solution of the piperazine-2,5-dione above (0.22 g, 0.64
mmol) in acetic anhydride (0.4 cm3, 3.84 mmol) at 0 ЊC was
added iron trichloride (52 mg, 0.32 mmol). The reaction
mixture was stirred at ambient temperature and the reaction
was monitored by TLC for the disappearance of the starting
piperazinedione. Upon complete consumption of the starting
piperazinedione, light petroleum (5 cm3) was added to the reac-
tion mixture and the organic layer washed with water. The
aqueous phase was extracted with ethyl acetate (3 × 5 cm3) and
the combined organic layers dried (Na2SO4). The solvent was
removed in vacuo and was co-evaporated several times with
toluene. The residue was purified by flash chromatography (1:1
light petroleum–ethyl acetate, Rf 0.27) to give 12 as a yellow oil
(63%) (Found: C, 49.3; H, 5.4; N, 10.3. Calc. for C11H14N2O6: C,
48.9; H, 5.2; N, 10.4%); νmax(film)/cmϪ1 3012, 2943, 1749, 1715,
1371, 1309, 1220, 1140, 1046, 975, 941; δH (300 MHz; CDCl3)
2.06 (3H, s, OAc), 2.58 (3H, s, NAc), 2.59 (3H, s, NAc), 4.21
(1H, d, J 18, CHCHD), 4.47 (1H, dd, J 4 and 14, CHCHAHB),
4.55 (1H, dd, J 4 and 14, CHCHAHB), 4.98 (1H, d, J 18,
ϩ
ؒ
328 (M , 0.6%), 313 (4), 298 (2.5), 285 (1.5), 271 (10), 243 (25),
229 (100), 158 (32), 116 (26), 73 (44).
To a solution of the piperazinedione above (1.01 g, 3.1 mmol)
in acetic anhydride (2 cm3) at 0 ЊC was added iron trichloride
(0.25 g, 1.5 mmol). The reaction mixture was stirred at ambient
temperature and monitored by TLC for the disappearance of
the starting piperazinedione. Upon complete consumption of
the starting material, light petroleum (10 cm3) was added to the
reaction mixture and the organic layer washed with water. The
aqueous phase was extracted with ethyl acetate (3 × 10 cm3)
and the combined organic layers dried (Na2SO4). The solvent
was removed in vacuo and was co-evaporated several times with
toluene. The residue was purified by flash chromatography
(ethyl acetate, Rf 0.4) to give the product 14 as a clear oil (84%)
(Found: C, 51.6; H, 6.2; N, 10.9. Calc. for C11H16N2O5: C, 51.6;
ϩ
ؒ
CHCHD), 5.35 (1H, m, CHCHAHB); m/z (EI) 270 (M , 4%),
240 (15), 228 (69), 198 (77), 186 (29), 168 (35), 156 (100), 126
(37), 114 (71).
(3S,6S)-1,4-Diacetyl-3-acetoxymethyl-6-methylpiperazine-2,5-
dione 13
Piperazine-2,5-dione 10 (1.5 g) was refluxed in acetic anhydride
1178
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182

View Article Online
H, 6.3; N, 10.9%); νmax(film)/cmϪ1 1749, 1709, 1670, 1381,
1232, 1046; δH (300 MHz; CDCl3) 1.67 (3H, d, J 7, CHCH3),
2.03 (3H, s, OAc), 2.54 (3H, s, NAc), 2.99 (3H, s, NCH3), 4.16
(1H, q, J 7, CHCH3), 4.38 (1H, dd, J 3 and 12, CHCHAHB),
4.56 (1H, dd, J 3 and 12, CHCHAHB), 5.14 (1H, m,
CHCHAHB); m/z (EI) 256 (M , 1.3%), 241 (0.5), 226 (9), 214
(20), 196 (35), 184 (56), 154 (24), 142 (100), 127 (36), 113 (25),
84 (10), 58 (45).
(20) (49.5 mg, 0.27 mmol) in refluxing CCl4 (5 cm3) under N2
was added N-bromosuccinimide (95.7 mg, 0.54 mmol) and
catalytic amounts of AIBN. The reaction mixture was stirred
at reflux (80 ЊC) for a further two hours or until no more
succinimide was generated. The reaction mixture was then
cooled to room temperature, the succinimide filtered off and
the filtrate concentrated under reduced pressure to give the
dibromopiperazine-2,5-dione 22 as a yellow oil (95%). Due to
the instability of this compound, it was used without further
purification; δH (300 MHz; CDCl3) 1.67 (3H, d, J 7, CHCH3),
2.63 (3H, s, NAc), 3.12 (3H, s, NCH3), 4.09 (1H, d, J 11,
CHAHB), 4.75 (1H, d, J 11, CHAHB), 5.15 (1H, q, J 7, CHCH3);
ϩ
ؒ
1,4-Diacetyl-3-methylidenepiperazine-2,5-dione 15
To a solution of acetoxypiperazine-2,5-dione 12 (55 mg, 0.2
mmol) in dichloromethane (2 cm3) was added triethylamine (28
µL, 0.2 mmol). The reaction mixture was monitored by TLC
(1:1 light petroleum–ethyl acetate) for the disappearance of the
starting piperazinedione. Upon completion of the reaction,
the reaction mixture was washed with water and the organic
layer dried over Na2SO4. The solvent was evaporated under
reduced pressure to give a white solid 15 (31 mg, 75%). The
methylidenepiperazinedione was purified by either column
chromatography (1:1 light petroleum–ethyl acetate, Rf 0.65)
or recrystallisation (ethyl acetate–hexane), mp 105–106 ЊC
(Found: C, 51.2; H, 5.0; N, 13.2. Calc. for C9H10N2O4: C, 51.4;
H, 4.8; N, 13.3%); νmax(KBr)/cmϪ1 3442, 3007, 2931, 1717, 1699,
1629, 1368, 1313, 1202, 1117, 1037, 1012, 961, 941; δH (300
MHz; CDCl3) 2.59 (3H, s, NAc), 2.62 (3H, s, NAc), 4.55 (2H, s,
m/z (EI) 355 [(M Ϫ H)ϩ , 1%], 275 (50), 169 (62), 157 (100),
ؒ
111 (77), 55 (49) (Found: 277.0010. Calc. for C9H12N2O381Br
277.0011).
(6S)-1-Acetyl-4,6-dimethyl-3-methylidenepiperazine-2,5-dione
24
To a solution of the dibromopiperazinedione 22 (110 mg, 0.3
mmol) in acetonitrile (5 cm3) was added NaI (446 mg, 3 mmol).
The clear yellow solution was observed to become opaque brick
red in colour. The reaction was monitored by TLC for the
disappearance of starting materials. When the reaction was
complete, the mixture was filtered and the filtrate concentrated
under reduced pressure. The dark red residue was taken up in
chloroform (10 cm3) and washed with 10% sodium thiosulfate
solution (2 × 10 cm3) and water (5 cm3). The organic layer was
dried (Na2SO4) and the solvent evaporated to give a clear oil
(79%). The data for this compound is consistent with that
reported previously; δH (300 MHz; CDCl3) 1.45 (3H, d, J 7,
CHCH3), 2.57 (3H, s, NAc), 3.23 (3H, s, NCH3), 5.12 (2H, m,
CHAHB and CHCH3), 5.13 (1H, d, J 1.5, CHAHB).
CH ), 6.07 (1H, s, C᎐CH H ), 6.52 (1H, s, C᎐CH H ); m/z (EI)
᎐
᎐
2
A
B
A
B
ϩ
ؒ
210 (M , 8%), 168 (75), 126 (56), 111 (100), 98 (43) (Found:
210.0641. Calc. for C9H10N2O4 201.0641).
(6S)-1,4-Diacetyl-6-methyl-3-methylidenepiperazine-2,5-dione
16
To a solution of piperazinedione 13 (110 mg, 0.4 mmol) in
dichloromethane (4 cm3) was added triethylamine (56 µL, 0.4
mmol). The reaction mixture was monitored by TLC (7:3 light
petroleum–ethyl acetate) for the disappearance of the starting
piperazinedione. Upon completion of the reaction, the reaction
mixture was washed with water and the organic layer dried over
Na2SO4. The solvent was evaporated under reduced pressure
to give a white solid which was recrystallised from dichloro-
methane–hexane (70%), mp 121–124 ЊC (Found: C, 53.3; H,
5.15; N, 12.4. Calc. for C10H12N2O4: C, 53.6; H, 5.4; N, 12.5%);
νmax(KBr)/cmϪ1 3020, 2943, 1727, 1630, 1455, 1399, 1369, 1301,
1240, 1203, 1137, 1039; δH (300 MHz; CDCl3) 1.49 (3H, d, J 7,
CHCH3), 2.58 (3H, s, NAc), 2.62 (3H, s, NAc), 2.59 (1H, q, J 7,
General procedures for radical addition reactions
Method 1. To a degassed solution of the methylidene-
piperazine-2,5-dione (typically 100 mg) in benzene (5 cm3 per
250 mg substrate) was added the alkyl iodide (10 equiv.). The
mixture was irradiated with a UV lamp at room temperature
while a solution of tributyltin hydride (1.2 equiv.) and AIBN
(catalytic) in benzene (either a 0.06 mol LϪ1 or 0.12 mol LϪ1
solution) was added slowly with a syringe pump at a rate of
5 cm3 hϪ1. The reaction was monitored by TLC and upon
completion of the reaction, the solvent was removed under
reduced pressure. The diastereoselectivities of the reaction were
determined by 1H NMR spectroscopy and/or GC analysis. The
crude product was redissolved in acetonitrile and the
acetonitrile solution was washed several times with hexane.
The acetonitrile layer was then concentrated in vacuo and the
residue purified by flash chromatography.
CHCH ), 6.10 (1H, d, J 1, C᎐CH H ), 6.53 (1H, d, J 1,
᎐
3
A
B
C᎐CH H ); δC (75 MHz; CDCl3) 18.2 (CHCH3), 26.6
᎐
A
B
(NCOCH ), 27.8 (NCOCH ), 53.3 (CHCH ), 122.1 (C᎐CH ),
᎐
3
3
3
2
131.8 (C᎐CH ), 161.8 (CO), 168.1 (CO), 170.3 (CO), 171.1
᎐
2
ϩ
ؒ
(CO); m/z (EI) 224 (M , 14%), 182 (64), 154 (70), 140 (80), 111
(100), 97 (58).
Method 2. A solution of the methylidenepiperazine-2,5-dione
(typically 100 mg) and the alkyl iodide (20 equiv.) in t-BuOH
(1 cm3 per 10 mg substrate) was heated to reflux (80 ЊC).
Tributyltin chloride (0.1 mol equiv.), AIBN (catalytic) and
NaCNBH3 (2 equiv.) were added to the reaction mixture and
this was refluxed under N2. The reaction was monitored by
TLC and when completed, the reaction mixture was cooled and
the solvent removed under reduced pressure. The diastereo-
selectivities of the reaction were determined by 1H NMR
spectroscopy and/or GC analysis. The resulting residue was
subsequently purified by flash chromatography.
(6S)-1,6-Dimethyl-3-methylidenepiperazine-2,5-dione 18
To a solution of piperazinedione 14 (109 mg, 0.4 mmol) in t-
BuOH (2.2 cm3) and ether (7.6 cm3) at 0 ЊC was added t-BuOK
(101 mg, 0.85 mmol). The reaction was monitored by TLC
(ethyl acetate) and upon complete consumption of the starting
material (typically 1 hour), the reaction mixture was diluted
with water and extracted repeatedly with ethyl acetate to yield
the product as a white solid (69%). Due to the unstable nature
of the compound, the methylidenepiperazinedione was used
without further purification; δH (300 MHz; CDCl3)28 1.54 (3H,
d, J 7, CHCH3), 3.03 (3H, s, NCH3), 4.00 (1H, q, J 7, CHCH3),
ϩ
ؒ
4.90 (1H, s, CHAHB), 5.61 (1H, s, CHAHB); m/z (EI) 154 (M ,
88%), 139 (24), 111 (100), 58 (23).
Method 3. To a vigorously stirred solution of the methyl-
idenepiperazine-2,5-dione (typically 50 mg) and the alkyl-
mercury chloride (2.4 equiv.) in dichloromethane (1 cm3 per
0.04 mmol of substrate) was added rapidly dropwise a solution
of NaBH4 (10 equiv.) in water (1 cm3 per 0.4 mmol of sub-
strate). The reaction mixture immediately turned dark grey and
(3R,6S)- or (3S,6S)-1-Acetyl-3-bromo-3-bromomethyl-4,6-di-
methylpiperazine-2,5-dione 22
To a solution of 1-acetyl-3,4,6-trimethylpiperazine-2,5-dione
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182
1179

View Article Online
with time, the reaction mixture clarified to give a colourless
solution with droplets of mercury. The reaction was monitored
by TLC for the disappearance of starting materials and when
the reaction was completed, the mixture was filtered over Celite
and the filtrate dried over Na2SO4. Evaporation of the solvent
gave a residue and the diastereoselectivities of the reaction
were determined by 1H NMR spectroscopy and/or GC analysis.
The crude residue was subsequently purified by flash chrom-
atography.
23%), 170 (100), 141 (41), 128 (66), 99 (72), 57 (82) (Found:
266.1630. Calc for C14H22N2O3 266.1631).
(3S,6S)- and (3R,6S)-1,4-Diacetyl-3-ethyl-6-methylpiperazine-
2,5-dione 43
This was prepared from methylidenepiperazine-2,5-dione 16
following Method 1 with methyl iodide (20 equiv. rather than
10 equiv.) and the addition of a 0.06 M solution of tributyltin
hydride in benzene to give the products as a 4:1 mixture of
diastereomers (NMR). The residue was purified by flash
chromatography (7:3 light petroleum–ethyl acetate, Rf 0.5) to
give the product as a clear oil (52%). Data for major (3S,6S)-
isomer (Found: C, 54.8; H, 6.9; N, 11.8. Calc. for C11H16N2O4:
C, 55.0; H, 6.7; N, 11.7%); νmax(film)/cmϪ1 1710, 1586, 1370,
1230; δH (300 MHz; CDCl3) 1.08 (3H, t, J 7, CH2CH3), 1.61
(3H, d, J 7, CHCH3), 1.87 (2H, m, CHCH2), 2.53 (3H, s, NAc),
2.55 (3H, s, NAc), 5.05 (1H, t, J 7, CHCH2), 5.17 (1H, q, J 7,
CHCH3); δC (75 MHz; CDCl3) 10.5 (CH2CH3), 19.6 (CHCH3),
26.3 (CHCH2), 26.9 (COCH3), 28.0 (COCH3), 53.5 (CHCH3),
58.0 (CHCH2), 167.9 (CO), 169.7 (CO), 170.8 (CO), 171.1
(3R)- and (3S)-1,4-Diacetyl-3-(2-methylpropyl)piperazine-2,5-
dione 39
This was prepared from methylidenepiperazine-2,5-dione 15
following Method 3 using isopropylmercury chloride and
purified by flash chromatography (7:3 light petroleum–ethyl
acetate, Rf 0.6) to give the product as a white solid (48%)
mp 86–89 ЊC (ethyl acetate–hexane) (Found: C, 56.6; H, 7.35;
N, 10.8. Calc. for C12H18N2O4: C, 56.7; H, 7.1; N, 11.0%);
νmax(KBr)/cmϪ1 2961, 1709, 1455, 1415, 1368, 1205, 979, 565; δH
(300 MHz; CDCl3) 0.98 (3H, d, J 6, CH(CH3)2), 1.05 (3H, d,
J 6, CH(CH3)2), 1.55 (1H, m, CH(CH3)2, 1.70 (2H, m, CHCH2),
2.56 (3H, s, NAc), 2.59 (3H, s, NAc), 4.09 (1H, d, J 18, CHAHB),
5.15 (1H, d, J 18, CHAHB), 5.30 (1H, q, CHCH2); m/z (EI) 255
ϩ
ؒ
(CO); m/z (EI) 240 (M , 21%), 212 (56), 198 (100), 155 (69),
113 (89), 86 (64), 58 (79).
ϩ
ؒ
(MH , 27%), 212 (32), 198 (54), 169 (48), 156 (100), 127 (58),
114 (48), 100 (39), 85 (56), 72 (39).
(3S,6S)- and (3S,6R)-1,4-Diacetyl-3-methyl-6-propylpiperazine-
2,5-dione 44
This was prepared from methylidenepiperazine-2,5-dione 16
following Method 1 with ethyl iodide and a 0.06 M solution of
tributyltin hydride in benzene to give the addition product as a
5:1 mixture of diastereomers (NMR). The residue was purified
by flash chromatography (7:3 light petroleum–ethyl acetate, Rf
0.45) to give the products as a clear oil (55%). Data for the
major (3S,6S) isomer (Found: C, 56.7; H, 7.45; N, 10.7. Calc.
for C12H18N2O4: C, 56.7; H, 7.13; N, 11.0%); νmax(film)/cmϪ1
1711, 1385, 1370, 1231; δH (300 MHz; CDCl3) 0.97 (3H, t, J 7,
CH2CH3), 1.51 (2H, m, CH2CH3), 1.62 (3H, d, J 7, CHCH3),
1.80 (2H, m, CH2CH2), 2.54 (3H, s, NAc), 2.56 (3H, s, NAc),
5.17 (2H, m, CHCH3 and CHCH2); δC (75 MHz; CDCl3) 13.5
(CH2CH3), 19.7 (CH2CH2), 20.1 (CHCH3), 26.8 (COCH3), 27.4
(COCH3), 37.3 (CHCH2), 54.0 (CHCH3), 57.1 (CHCH2), 168.5
(3R)- and (3S)-1,4-Diacetyl-3-(cyclohexylmethyl)piperazine-2,5-
dione 40
This was prepared from methylidenepiperazine-2,5-dione 15
following Method 3 using cyclohexylmercury chloride and
purified by flash chromatography (7:3 light petroleum–ethyl
acetate, Rf 0.5) to give the product as a clear oil (46%) (Found:
C, 60.9; H, 7.5; N, 9.8. Calc. for C15H22N2O4: C, 61.2; H, 7.5; N,
9.5%); νmax(film)/cmϪ1 2919, 2848, 1707, 1369, 1212, 1138, 1041,
963; δH (300 MHz; CDCl3) 0.98–1.78 (13H, m, CH2C6H11), 2.56
(3H, s, NAc), 2.59 (3H, s, NAc), 4.06 (1H, d, J 19, CHAHB), 5.13
(1H, d, J 19, CHAHB), 5.33 (1H, m, CHCH2); m/z (EI) 294
ϩ
ؒ
(M , 11%), 198 (54), 156 (100), 114 (48) (Found: 294.1580.
Calc. for C15H22N2O4 294.1580).
ϩ
ؒ
(CO), 170.3 (CO), 171.2 (CO), 171.5 (CO); m/z (EI) 255 (MH ,
30%), 212 (100), 170 (82), 141 (34), 127 (53), 115 (24), 99 (37),
86 (35).
(3R)- and (3S)-1-Acetyl-4-methyl-3-(2-methylpropyl)piperazine-
2,5-dione 41
This was prepared from methylidenepiperazine-2,5-dione 23
following Method 3 using isopropylmercury chloride and
purified by flash chromatography (1:1 light petroleum–ethyl
acetate, Rf 0.3) to give the product as a white solid (32%), mp
69–71 ЊC (ethyl acetate–hexane) (Found: C, 58.2; H, 7.9; N,
12.0. Calc. for C11H18N2O3: C, 58.4; H, 8.0; N, 12.4%);
νmax(film)/cmϪ1 2963, 2936, 1708, 1676, 1499, 1449, 1367, 1261,
1211, 1169, 1123, 565; δH (300 MHz; CDCl3) 1.01 (7H, m,
CH(CH3)2 and CH(CH3)2), 1.68 (2H, m, CHCH2), 2.58 (3H, s,
NAc), 3.01 (3H, s, NCH3), 3.93 (1H, d, J 18, CHAHB), 3.95
(1H, m, CHCH2), 4.86 (1H, d, J 18, CHAHB); m/z (EI) 227
(3S,6S)-1,4-Diacetyl-6-methyl-3-(2-methylpropyl)piperazine-
2,5-dione 45
This was prepared from methylidenepiperazine-2,5-dione 16
following Method 3 using isopropylmercury chloride to give the
addition product as a single diastereomer (NMR). The residue
was purified by flash chromatography (7:3 light petroleum–
ethyl acetate, Rf 0.6) to give the product as a clear oil (66%)
(Found: C, 58.1; H, 7.4; N, 10.7. Calc. for C13H20N2O4: C, 58.2;
H, 7.5; N, 10.4%); νmax(film)/cmϪ1 2954, 1713, 1371, 1227, 1085,
1024, 729; δH (300 MHz; CDCl3) 0.99 (3H, d, J 6, (CH3)2CH),
1.06 (3H, d, J 6, (CH3)2CH), 1.63 (3H, d, J 7, CHCH3), 1.77
(3H, m, CHCH2CH and CHCH2CH), 2.54 (3H, s, NAc), 2.57
(3H, s, NAc), 5.19 (1H, q, CHCH3), 5.25 (1H, m, CHCH2); m/z
ϩ
ؒ
(MH , 55%), 170 (73), 141 (86), 127 (65), 99 (100), 84 (39), 57
(86).
ϩ
ؒ
(3R)- and (3S)-1-Acetyl-3-cyclohexylmethyl-4-methylpiperazine-
2,5-dione 42
(EI) 269 (MH , 3%), 226 (8), 112 (52), 183 (24), 170 (100), 128
(66), 141 (34), 113 (23), 86 (57), 70 (36).
This was prepared from methylidenepiperazine-2,5-dione 23
following Method 3 using cyclohexylmercury chloride and
purified by flash chromatography (1:1 light petroleum–ethyl
acetate, Rf 0.4) to give the product as a clear oil (57%) (Found:
C, 63.45; H, 8.0; N, 10.6. Calc. for C14H22N2O3: C, 63.14; H,
8.3; N, 10.5%); νmax(film)/cmϪ1 2992, 2850, 1712, 1682, 1449,
1367, 1262, 1215; δH (300 MHz; CDCl3) 1.24-1.68 (11H, m,
cyclohexyl protons), 1.85 (2H, m, CH2C6H11), 2.58 (3H, s,
NAc), 3.01 (3H, s, NCH3), 3.96 (1H, d, J 18, CHAHB), 3.99 (1H,
(3S,6S)-1,4-Diacetyl-3-cyclohexylmethyl-6-methylpiperazine-
2,5-dione 46
This was prepared from methylidenepiperazine-2,5-dione 16 by
Method 3 using cyclohexylmercury chloride and only a single
diastereomer (NMR) was detected. The residue was purified by
flash chromatography (7:3 light petroleum–ethyl acetate) to
give the product as a clear oil (49%) (Found: C, 62.4; H, 8.1; N,
9.0. Calc. for C16H24N2O4: C, 62.3; H, 7.8; N, 9.1%); νmax(film)/
cmϪ1 2923, 2850, 1716, 1698, 1385, 1226; δH (300 MHz; CDCl3)
ϩ
ؒ
t, CHCH2), 4.86 (1H, d, J 18, CHAHB); m/z (EI) 267 (MH ,
1180
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182

View Article Online
0.96 (2H, m, cyclohexyl), 1.26 (5H, m, cyclohexyl), 1.63 (3H, d,
J 6, CHCH3), 1.70 (6H, m, CHCH2 and cyclohexyl), 2.54 (3H,
s, NAc), 2.57 (3H, s, NAc), 5.19 (1H, q, CHCH3), 5.29 (1H, m,
CHCH2); m/z (EI) 309 (MH , 74%), 267 (23), 212 (48), 170
(100), 128 (51), 99 (25), 86 (33), 55 (23).
(3S,6S)- and (3R,6S)-1-Acetyl-4,6-dimethyl-3-propylpiperazine-
2,5-dione 50
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 2 using ethyl iodide to give the products as
a 4:1 mixture of diastereomers. The products were purified by
flash chromatography (1:1 light petroleum–ethyl acetate, Rf
0.26 (major), 0.3 (minor)) to give a clear oil (65%). This was
also prepared following Method 1 which also gave the products
as a 4:1 mixture of diastereomers (54%). Data for the major
(3S,6S) isomer (Found: C, 58.2; H, 8.0; N, 12.4. Calc. for
C11H18N2O3: C, 58.4; H, 8.0; N, 12.4%); νmax(film)/cmϪ1 2963,
1709, 1669, 1390, 1369, 1238, 1155, 1031, 980, 573; δH (300
MHz; CDCl3) 1.01 (3H, t, J 7, CH2CH3), 1.54 (2H, m, CH2CH3),
1.54 (3H, d, J 7, CHCH3), 1.90 (2H, m, CHCH2), 2.56 (3H, s,
NAc), 3.00 (3H, s, NCH3), 3.98 (1H, m, CHCH2), 4.96 (1H,
q, J 7, CHCH3); δC (75 MHz; CDCl3) 13.5 (CH2CH3), 19.4
(CH2CH3), 19.9 (CHCH3), 27.4 (COCH3), 32.5 (NCH3), 35.3
(CH2CH2), 52.6 (CHCH3), 63.4 (CHCH2), 166.9 (CO), 168.4
ϩ
ؒ
(3S,6S)-1,4-Diacetyl-3-(2,2-dimethylpropyl)-6-methylpiper-
azine-2,5-dione 47
This was prepared from methylidenepiperazine-2,5-dione 16
following Method 1 with tert-butyl iodide and a 0.12 M solu-
tion of tributyltin hydride in benzene to give the product as a
single diastereomer (NMR). The product was purified by flash
chromatography (8:2 light petroleum–ethyl acetate, Rf 0.7) to
give the product as a clear oil (65%) (Found: C, 59.7; H, 8.2; N,
10.1. Calc. for C14H22N2O4: C, 59.6; H, 7.9; N, 9.9%); νmax(film)/
cmϪ1 3408, 1711, 1383, 1230; δH (300 MHz; CDCl3) 1.01 (9H, s,
C(CH3)3), 1.62 (1H, m, CHCHAHB), 1.65 (3H, d, J 7, CHCH3),
1.82 (1H, m, CHCHAHB), 2.46 (3H, s, NAc), 2.53 (3H, s, NAc),
5.18 (1H, q, J 7, CHCH3), 5.34 (1H, m, CHCHAHB); δC (75
MHz; CDCl3) 19.8 (C(CH3)3), 26.5 (COCH3), 27.9 (COCH3),
29.3 (CHCH3), 31.0 (CHCH2), 49.6 (C(CH3)3), 54.3 (CHCH3),
54.6 (CHCH2), 169.5 (CO), 170.4 (CO), 171.1 (CO), 171.7
ϩ
ؒ
(CO), 171.5 (CO); m/z (EI) 226 (M , 6%), 184 (37), 155 (21),
141 (72), 127 (13), 113 (100), 98 (16), 86 (49), 70 (32), 57 (43).
Data for the minor (3R,6S)-isomer: δH (300 MHz; CDCl3) 0.95
(3H, t, J 7, CH2CH3), 1.1–1.4 (2H, m, CH2CH3), 1.44 (3H, d, J
7, CHCH3), 1.97 (1H, m, CHCHAHB), 2.20 (1H, m,
CHCHAHB), 2.48 (3H, s, COCH3), 2.96 (3H, s, NCH3), 4.08
(1H, dd, J 3 and 5, CHCH2), 4.93 (1H, q, J 7, CHCH3); δC (75
MHz; CDCl3) 13.8 (CH2CH3), 16.5 (CH2CH3), 20.2 (CHCH3),
28.9 (COCH3), 30.9 (NCH3), 33.3 (CH2CH2), 52.5 (CHCH3),
61.3 (CHCH2), 169.0 (CO), 169.6 (CO), 171.2 (CO); m/z (EI)
ϩ
ؒ
(CO); m/z (EI) 282 (M , 61%), 267 (83), 240 (61), 225 (85), 183
(96), 169 (53), 155 (64), 141 (87), 127 (60), 113 (58), 99 (79), 86
(94), 71 (60), 57 (100).
(3S,6S)-1,4-Diacetyl-3-methyl-6-phenethylpiperazine-2,5-dione
48
ϩ
ؒ
226 (M , 7%), 184 (40), 155 (22), 141 (85), 127 (11), 113 (100),
98 (17), 86 (47), 70 (29), 57 (41).
This was prepared from methylidenepiperazine-2,5-dione 16
following Method 1 with benzyl iodide and a 0.06 M solution
of tributyltin hydride in benzene to give the product as a single
diastereomer (NMR). The product was purified by flash chro-
matography (7:3 light petroleum–ethyl acetate, Rf 0.5) to give
the product as a clear oil (63%); νmax(film)/cmϪ1 1709, 1385,
1369, 1229; δH (300 MHz; CDCl3) 1.62 (3H, d, J 7, CHCH3),
2.12 (2H, m, CHCH2), 2.54 (3H, s, NAc), 2.58 (3H, s, NAc),
2.84 (2H, m, PhCH2), 5.19 (2H, m, CHCH2 and CHCH3), 7.2
(5H, m, aromatic); δC (75 MHz; CDCl3) 20.2 (CHCH3), 26.8
(COCH3), 27.4 (COCH3), 32.6 (CH2Ph), 36.9 (CHCH2), 54.0
(CHCH3), 57.1 (CHCH2), 126.4 (Ph), 128.4 (Ph), 128.6 (Ph),
139.9 (Ph), 168.3 (CO), 170.0 (CO), 171.3 (CO), 171.5 (CO); m/z
(3S,6S)- and (3R,6S)-1-Acetyl-4,6-dimethyl-3-(2-methylpropyl)-
piperazine-2,5-dione 51
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 3 using isopropylmercury chloride to give the
product as a 6:1 mixture of diastereomers (NMR, GC). The
crude residue was purified by flash chromatography (1:1 light
petroleum–ethyl acetate, Rf 0.3 (major), 0.4 (minor)) to give the
products as clear oils (45%). This compound was also prepared
following Method 2, which gave the products as a 6:1 mixture
of diastereomers (53%). Data for the major (3S,6S)-isomer
(Found: C, 60.2; H, 8.1; N, 11.9. Calc. for C12H20N2O3: C, 60.0;
H, 8.4; N, 11.7%); νmax(film)/cmϪ1 3391, 2361, 2344, 1707, 1653,
1395, 1237; δH (300 MHz; CDCl3) 1.01 (3H, d, J 7,
CH(CH3)CH3), 1.04 (3H, d, J 7, CH(CH3)CH3), 1.54 (3H, d,
J 7, CHCH3), 1.65 (1H, m, CHCHAHB), 1.7 (1H, m,
CHCHAHB), 2.56 (3H, s, NAc), 2.99 (3H, s, NCH3), 3.97 (1H,
m, CHCHAHB), 4.98 (1H, q, J 7, CHCH3); δC (75 MHz; CDCl3)
20.1 (CH(CH3)CH3), 21.8 (CH(CH3)CH3), 22.8 (CH(CH3)3),
25.3 (CHCH3), 27.7 (COCH3), 32.6 (NCH3), 43.3 (CHCH2),
52.9 (CHCH3), 62.0 (CHCH2), 167.4 (CO), 168.9 (CO), 171.8
ϩ
ؒ
(EI) 317 (MH , 28%), 275 (12), 224 (14), 212 (99), 182 (21), 170
ϩ
ؒ
(100), 140 (21), 128 (88), 91 (49) (Found: (MH ) 317.1498.
Calc. for C17H21N2O4 317.1501).
(3S,6S)- and (3R,6S)-1-Acetyl-3-ethyl-4,6-dimethylpiperazine-
2,5-dione 49
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 1 with methyl iodide and a 0.12 M solution
of tributyltin hydride in benzene to give the desired addition
adducts as a 2:1 mixture of diastereomers. The products were
purified by flash chromatography (1:1 light petroleum–ethyl
acetate, Rf 0.2 (major), 0.3 (minor)) to give the isomers as clear
oils (56%). Data for major (3S,6S)-isomer; νmax(film)/cmϪ1 2973,
2941, 1709, 1668, 1390, 1236; δH (300 MHz; CDCl3) 1.10 (3H,
t, J 7, CH2CH3), 1.54 (3H, d, J 7, CHCH3), 1.95 (1H, m,
CHCHAHB), 2.05 (1H, m, CHCHAHB), 2.56 (3H, s, NAc), 3.01
(3H, s, NCH3), 3.92 (1H, m, CHCHAHB), 4.97 (1H, q, J 7,
CHCH3); δC (75 MHz; CDCl3) 10.8 (CH2CH3), 20.4 (CHCH3),
26.5 (COCH3), 27.7 (CH2CH3), 32.8 (NCH3), 52.9 (CHCH3),
65.2 (CHCH2), 167.3 (CO), 168.6 (CO), 171.8 (CO); m/z (EI)
ϩ
ؒ
(CO); m/z (EI): 241 (MH , 3%), 197 (6), 184 (84), 155 (73), 142
(39), 127 (36), 113 (100), 100 (43), 84 (39), 57 (61). Data for the
minor (3R,6S)-isomer; δH (300 MHz; CDCl3) 0.93 (3H, d, J 7,
CH(CH3)CH3), 0.97 (3H, d, J 7, CH(CH3)CH3), 1.49 (3H, d,
J 7, CHCH3), 1.74 (1H, m, CH(CH3)2), 1.94 (2H, m, CHCH2),
2.48 (3H, s, NAc), 2.99 (3H, s, NCH3), 4.03 (1H, dd, J 4 and 6,
CHCH2), 4.93 (1H, q, J 7, CHCH3); δC (75 MHz; CDCl3) 20.4
(CH(CH3)CH3), 22.2 (CH(CH3)CH3), 23.3 (CH(CH3)3), 24.7
(CHCH3), 26.7 (COCH3), 31.6 (NCH3), 40.4 (CHCH2), 52.9
(CHCH3), 62.7 (CHCH2), 167.6 (CO), 169.7 (CO), 171.4 (CO);
ϩ
ؒ
m/z (EI) 240 (M , 100%), 197 (41), 184 (47), 155 (74), 142 (42),
ϩ
ؒ
212 (M , 44%), 199 (11), 183 (33), 157 (32), 141 (41), 127 (94),
113 (100), 99 (39), 70 (62) (Found: 212.1163. Calc. for
C10H16N2O3 212.1161). Data for minor (3R,6S)-isomer; δH (300
MHz; CDCl3) 0.86 (3H, t, J 7, CH2CH3), 1.47 (3H, d, J 7,
CHCH3), 2.28 (2H, m, CH2CH3), 2.50 (3H, s, NAc), 2.98 (3H, s,
NCH3), 4.10 (1H, dd, J 3 and 5, CHCH2), 4.96 (1H, q, J 7,
CHCH3).
127 (38), 113 (71), 84 (53), 57 (77).
(3S,6S)-1-Acetyl-3-cyclohexylmethyl-4,6-dimethylpiperazine-
2,5-dione 52
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 3 using cyclohexylmercury chloride to give
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182
1181

View Article Online
the product as a single diastereomer (NMR). The residue was
purified by flash chromatography (ethyl acetate, Rf 0.5) to give
the product as a clear oil (37%) (Found: C, 64.3, H, 8.8, N, 9.7.
Calculated for C15H24N2O3: C, 64.3; H, 8.6; N, 10.0%);
νmax(film)/cmϪ1 2924, 2361, 1716, 1673, 1393, 1234; δH (300
MHz; CDCl3) 1.26–1.73 (11H, m, cyclohexyl protons), 1.52
(3H, d, J 7, CHCH3), 1.91 (2H, m, CHCH2), 2.56 (3H, s, NAc),
2.98 (3H, s, NCH3), 4.01 (1H, m, CHCH2), 4.98 (1H, q,
C10H18N2O2: C, 60.6; H, 9.15; N, 14.1%); νmax(film)/cmϪ1 2960,
1660, 1460, 1399, 1335, 1247; δH (300 MHz; CDCl3) 0.92 (3H, t,
J 7, CH2CH3), 1.2 (2H, m, CH2CH3), 1.57 (3H, d, J 7, CHCH3),
1.85 (1H, m, CHCHAHB), 2.05 (1H, m, CHCHAHB), 2.96 (3H,
s, NCH3), 2.98 (3H, s, NCH3), 3.99 (2H, m, CHCH3 and
CHCHAHB); δC (75 MHz; CDCl3) 13.7 (CH2CH3), 16.6
(CH2CH2CH3), 18.7 (CHCH3), 31.6 (NCH3), 32.2 (NCH3), 33.4
(CHCH2), 56.5 (CHCH3), 61.3 (CHCH2), 165.9 (CO), 166.9
ϩ
ؒ
ϩ
ؒ
CHCH3); m/z (EI) 280 (M , 5%), 238 (42), 184 (100), 142 (60),
113 (65), 57 (53) (Found: 280.1795. Calc. for C15H24N2O3
280.1787).
(CO); m/z (EI) 197 [(M Ϫ H) , 100%], 169 (35), 142 (8), 128
(3), 84 (32) (Found: 197.1291. Calc. for C10H17N2O2: 197.1290).
References
(3S,6S)-1-Acetyl-3-(2,2-dimethylpropyl)-4,6-dimethylpiper-
1 U. Schmidt, A. Lieberknecht and J. Wild, Synthesis, 1988, 159.
2 G. Leroy, J. P. Dewispelaere, H. Benkadour, D. R. Temsamani and
C. Wilante, Bull. Soc. Chim. Belg., 1994, 103, 367; J. J. Brocks, H. D.
Beckhaus, A. L. J. Beckwith and C. Ruchardt, J. Org. Chem., 1998,
63, 1935.
3 R. Jimenez, L. Perez, J. Tamariz and H. Salgado, Heterocycles, 1993,
35, 591; A. Nagarajan, G. Zepeda and J. Tamariz, Tetrahedron Lett.,
1996, 37, 6835.
4 D. Crich and J. W. Davies, Tetrahedron, 1989, 45, 5641.
5 J. R. Axon and A. L. J. Beckwith, J. Chem. Soc., Chem. Commun.,
1995, 549.
6 A. L. J. Beckwith and C. L. L. Chai, J. Chem. Soc., Chem. Commun.,
1990, 1087.
7 C. L. L. Chai and A. R. King, Tetrahedron Lett., 1995, 36, 4295.
8 C. Alcaraz, M. D. Fernandez, M. P. Defrutos, J. L. Marco and
M. Bernabe, Tetrahedron, 1994, 50, 12443.
9 M. Oba, S. Nakajima and K. Nishiyama, Chem. Commun., 1996,
1875.
10 B. A. Burkett, C. L. L. Chai and D. C. R. Hockless, Aust. J. Chem.,
1998, 51, 993; S. D. Bull, S. G. Davies and M. D. O’Shea, J. Chem.
Soc., Perkin Trans. 1, 1998, 3657.
11 C. P. Jasperse, D. P. Curran and T. L. Fevig, Chem. Rev., 1991, 91,
1237; D. P. Curran, J. Sisko, P. E. Yeske and H. Liu, Pure Appl.
Chem., 1993, 65, 1153.
12 P. M. T. Ferreira, H. L. S. Maia and L. S. Monteiro, Tetrahedron
Lett., 1998, 39, 9575; D. Ranganathan, K. Shah and N. Vaish,
J. Chem. Soc., Chem. Commun., 1992, 1145; E. Rothstein, J. Chem.
Soc., 1949, 1968; T. L. Sommerfeld and D. Seebach, Helv. Chim.
Acta, 1993, 76, 1702; S. A. Burrage, T. Raynham and M. Bradley,
Tetrahedron Lett., 1998, 39, 2831.
13 C. Shin, M. Fujii and J. Yoshimura, Tetrahedron Lett., 1971, 2499;
C. Shin, Heterocycles, 1983, 20, 1407; C. Gallina and A. Liberatori,
Tetrahedron, 1974, 30, 667; J. D. M. Herscheid, H. P. H. Scholten,
M. W. Tijhuis and H. C. J. Ottenheijm, Recl. Trav. Chim. Pays-Bas.,
1981, 100, 73.
14 T. W. Badran, C. L. L. Chai, C. J. Easton, J. B. Harper and D. M.
Page, Aust. J. Chem., 1995, 48, 1379.
15 C. L. L. Chai, D. B. Hay and A. R. King, Aust. J. Chem., 1996, 49,
605.
16 C. L. L. Chai, D. C. R. Hockless and A. R. King, Aust. J. Chem.,
1996, 49, 1229.
17 J. Yoshimura, Y. Sugiyama and H. Nakamura, Bull. Chem. Soc.
Jpn., 1973, 46, 2850.
18 C. L. L. Chai and A. R. King, J. Chem. Res. (S), 1997, 382.
19 R. O. Hutchins and M. K. Hutchins, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon, Oxford, 1991, vol. 8, p. 25.
20 S. D. Jin and J. Liebscher, J. Prakt. Chem., 1998, 340, 390.
21 S. D. Bull, S. G. Davies, S. W. Epstein, M. A. Leech and J. V. A.
Ouzman, J. Chem. Soc., Perkin Trans. 1, 1998, 2321; S. D. Bull,
S. G. Davies, S. W. Epstein and J. V. A. Ouzman, Chem. Commun.,
1998, 659.
22 G. Portzi and S. Sandri, Tetrahedron: Asymmetry, 1994, 5, 453.
23 I. L. Karle, in The Peptides, ed. E. Gross and J. Meinhofer,
Academic Press, New York, 1988; E. Benedetti, R. E. Marsh and
M. Goodman, J. Am. Chem. Soc., 1976, 98, 6676.
24 T. M. Hooker, Jr., P. M. Bayley, W. Radding and J. A. Schellman,
Biopolymers, 1974, 13, 549.
25 C. L. L. Chai, A. R. King and D. C. R. Hockless, Acta Crystallogr.,
Sect. C, 1995, 51, 1836.
26 W. König and R. Geiger, Chem. Ber., 1970, 103, 2024.
27 E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94,
6190.
28 J. D. M. Herscheid, R. J. F. Nivard, M. W. Tijhuis, H. P. H. Scholten
and H. C. J. Ottenheijm, J. Org. Chem., 1980, 45, 1880.
azine-2,5-dione 53
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 1 with tert-butyl iodide and a 0.12 M solu-
tion of tributyltin hydride in benzene to give the product as a
single diastereomer (NMR). The product was purified by flash
chromatography (1:1 light petroleum–ethyl acetate, Rf 0.44)
to give the product as a clear oil (77%) (Found C, 61.2; H, 8.9;
N, 10.95. Calc. for C13H22N2O3 C, 61.4; H, 8.7; N, 11.0%);
νmax(film)/cmϪ1 2957, 1711, 1674, 1388, 1370, 1238; δH (300
MHz; CDCl3) 1.04 (9H, s, C(CH3)3), 1.52 (3H, d, J 7, CHCH3),
1.58 (1H, m, CHCHAHB), 1.97 (1H, m, CHCHAHB), 2.53 (3H,
s, NAc), 2.96 (3H, s, NCH3), 3.92 (1H, dd, J 2.5 and 8,
CHCHAHB), 4.99 (1H, q, J 7, CHCH3); δC (75 MHz; CDCl3)
19.9 (C(CH3)3), 27.7 (CHCH3), 29.5 (COCH3), 30.8 (CHCH2),
32.4 (NCH3), 49.3 (C(CH3)3), 52.9 (CHCH3), 60.8 (CHCH2),
ϩ
ؒ
167.8 (CO), 169.8 (CO), 171.8 (CO); m/z (EI) 254 (M , 26%),
197 (30), 183 (45), 169 (99), 155 (44), 141 (46), 113 (100), 84
(52), 57 (80).
(3S,6S)-1-Acetyl-4,6-dimethyl-3-phenethylpiperazine-2,5-dione
54
This was prepared from methylidenepiperazine-2,5-dione 24
following Method 1 with benzyl iodide and a 0.06 M solution
of tributyltin hydride in benzene to give the product as a single
diastereomer (NMR). The product was purified by flash
chromatography (1:1 light petroleum–ethyl acetate, Rf 0.52) to
give the product as a clear oil (38%); νmax(film)/cmϪ1 3320, 1706,
1669, 1391, 1234, 1040; δH (300 MHz; CDCl3) 1.56 (3H, d, J 7,
CHCH3), 2.22 (2H, m, CHCH2), 2.58 (3H, s, NAc), 2.84 (2H,
m, PhCH2), 2.88 (3H, s, NCH3), 3.94 (1H, m, CHCH2), 4.99
(1H, q, J 7, CHCH3), 7.23–7.36 (5H, m, aromatic); δC (75 MHz;
CDCl3) 20.4 (CHCH3), 27.7 (COCH3), 32.2 (CH2CH2), 32.4
(NCH3), 35.1 (CHCH2), 52.9 (CHCH3), 62.6 (CHCH2), 126.6
(Ph), 128.5 (Ph), 128.7 (Ph), 139.6 (Ph), 167.25 (CO), 168.6
ϩ
ؒ
(CO), 171.7 (CO); m/z (EI) 288 (M , 7%), 184 (100), 155 (19),
142 (100), 127 (20), 113 (33), 91 (51) (Found: 288.1471. Calc. for
C16H20N2O3 288.1474).
(3S,6S)- and (3S,6R)-1,3,4-Trimethyl-6-propylpiperazine-2,5-
dione 55
This was prepared from methylidenepiperazine-2,5-dione 38
following Method 2 using ethyl iodide to give the product as a
1.5:1 mixture of diastereomers (NMR and GC). The products
were purified by flash chromatography (18:3 chloroform–
methanol) to give a clear oil (73%). Major (3S,6S)-isomer;
νmax(film)/cmϪ1 2961, 1663, 1466, 1402, 1336, 1251; δH (300
MHz; CDCl3) 0.96 (3H, t, J 7, CH2CH3), 1.4 (2H, m, CH2CH3),
1.53 (3H, d, J 7, CHCH3), 1.78 (1H, m, CHCHAHB), 1.91 (1H,
m, CHCHAHB), 2.97 (6H, s, NCH3), 3.90 (2H, m, CHCH3 and
CHCHAHB); δC (75 MHz; CDCl3) 13.82 (CH2CH3), 18.63
(CH2CH2CH3), 19.12 (CHCH3), 31.93 (NCH3), 32.60 (NCH3),
34.94 (CHCH2), 57.90 (CHCH3), 62.21 (CHCH2), 165.68 (CO),
ϩ
ؒ
166.88 (CO); m/z (EI) 198 (M , 18%), 169 (90), 156 (100), 141
(18), 127 (73), 113 (16), 99 (19), 86 (27), 58 (58). Data for the
minor (3S,6R)-isomer (Found: C, 60.9; H, 9.0; N, 14.1. Calc. for
Paper 9/00771G
1182
J. Chem. Soc., Perkin Trans. 1, 1999, 1173–1182