On the origins of diastereoselectivity in the alkylation of diketopiperazine enolates

Article abstract of DOI:10.1039/b701628j

High levels of diastereoselectivity are observed for benzylation of the lithium enolates of (S)-N,N′-bis-para-methoxybenzyl-3-iso-propyl- piperazine-2,5-dione, (S)-N(1)-para-methoxybenzyl-N(4)-methyl-3-iso-propyl- piperazine-2,5-dione and (S)-N(1)-methyl-

Full text of DOI:10.1039/b701628j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/njc | New Journal of Chemistry
On the origins of diastereoselectivity in the alkylation of diketopiperazine
enolates
Steven D. Bull, Stephen G. Davies,* A. Christopher Garner, Alastair L. Parkes,
Paul M. Roberts, Thomas G. R. Sellers, Andrew D. Smith, Juan A. Tamayo,
James E. Thomson and Richard J. Vickers
Received (in Montpellier, France) 2nd February 2007, Accepted 1st March 2007
First published as an Advance Article on the web 9th March 2007
DOI: 10.1039/b701628j
High levels of diastereoselectivity are observed for benzylation of the lithium enolates of (S)-N,N0-
bis-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-dione, (S)-N(1)-para-methoxybenzyl-N(4)-
methyl-3-iso-propyl-piperazine-2,5-dione and (S)-N(1)-methyl-N(4)-para-methoxybenzyl-3-iso-
propyl-piperazine-2,5-dione. These data suggest that the high diastereofacial selectivity observed
for alkylation of these diketopiperazine templates is mainly a consequence of the relay of
stereochemical information from C(3) to C(6) via the influence of 1,2-torsional strain introduced
by the N-alkyl substituents, rather than through minimisation of steric interactions alone.
Applying Ockham’s razor5 to these observations led to the
Introduction
proposal that the high diastereofacial selectivity observed for
The central role that homochiral a-amino acids play in Nature
the trans-alkylation of lithium enolate 2 might be the result of
has ensured that a panoply of methods have been developed
a ‘‘steric chiral relay’’ operating to enhance the facial selectiv-
for their asymmetric synthesis.1 Perhaps the most versatile and
ity; a concept which has subsequently been validated in a
number of chemical systems.6,7 In the proposed steric chiral
widely used strategy within this area is the stereoselective
alkylation of protected glycine enolates derived from simple
heterocycles that contain chiral auxiliary fragments.2 This
relay mechanism, the diketopiperazine enolate 2 occupies a
preferred conformation in which minimisation of 1,2-steric
approach relies on the homochiral component to control facial
interactions between the C(3)-iso-propyl group and the N(4)-
selectivity during alkylation of the masked glycine enolate to
para-methoxybenzyl group causes the latter to project over the
afford a major diastereoisomeric product containing one or
Re face of 2, thus causing the N(1)-para-methoxybenzyl group
more new stereogenic centres in high de. Subsequent purifica-
to preferentially occupy a position over the Si face of the
tion and cleavage of the stereoselectively-transformed glycine
auxiliary. The high levels of stereoselectivity in alkylation
equivalent affords the desired homochiral a-amino acid. We
reactions of
2 then derive from an enhanced steric
have previously reported (S)-N,N0-bis-para-methoxybenzyl-3-
iso-propyl-piperazine-2,5-dione (1) as a chiral auxiliary for the
asymmetric synthesis of homochiral a-amino acids.3 Depro-
tonation of 1 with LiHMDS generates lithium enolate 2, which
can be alkylated with a range of electrophiles to give trans-
(3S,6R)-N,N0-bis-para-methoxybenzyl-3-iso-propyl-6-alkyl-pi-
perazine-2,5-diones 3 in 490% de. Subsequent N-para-meth-
oxybenzyl deprotection with ceric ammonium nitrate (CAN)
and acid hydrolysis of the resultant diketopiperazine (DKP)
gives a mixture of the constituent a-amino acids, which may be
readily separated to afford (R)-a-amino acids 4 and (S)-valine
(Scheme 1).
bias towards Re face alkylation due to the presence of the
In our original study3 we noted that the diastereoselectivity
in alkylations of 1, bearing conformationally labile N-para-
methoxybenzyl (PMB) protecting groups, was enhanced in
comparison to the corresponding alkylations of Schollkopf’s
¨
related bis-lactim ether auxiliary 7.4 For example, methylation
of enolate 2 gave a 96.5 : 3.5 mixture of trans-5 : cis-6, whilst
methylation of enolate 8 gave a 75 : 25 mixture of trans-9 :
cis-10 (Scheme 2).
Department of Organic Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: steve.davies@chem.ox.ac.uk
Scheme 1 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C; (ii)
RX (10 equiv.), ꢀ78 1C to r.t.; (iii) CAN, MeCN–H2O (v/v 3 : 1), r.t.;
(iv) HCl (6 M, aq.), reflux, then Dowex 50-XH.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
486 | New J. Chem., 2007, 31, 486–495

View Article Online
Scheme 2 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C; (ii) BuLi, THF, ꢀ78 1C; (iii) MeI (10 equiv.), ꢀ78 1C to r.t.
alkylation of N,N0-bis-PMB enolate 2, which gave trans-5 in
93% de (Scheme 2), therefore supporting the assumption that
the enolate reactivity, relative to Schollkopf’s auxiliary 7, is
¨
not the primary source of the enhanced selectivity in alkyla-
tions of 1.
In order to probe further the validity of the proposed steric
chiral relay mechanism, we report herein the preparation and
alkylation of a series of cyclic Val-Gly templates—(S)-N,N0-
dimethyl-3-iso-propyl-piperazine-2,5-dione (11), (S)-N(1)-
methyl-N(4)-para-methoxybenzyl-3-iso-propyl-piperazine-2,5-
dione (18) and (S)-N(1)-para-methoxybenzyl-N(4)-methyl-3-
iso-propyl-piperazine-2,5-dione (22)—in which either or both
of the N-para-methoxybenzyl protecting groups within the
DKP framework have been systematically replaced with an
N-methyl substituent (Fig. 2). This strategy was proposed to
allow any contribution to the selectivity provided by either the
N(1)- or N(4)-para-methoxybenzyl groups to be delineated,
and the results of these investigations are reported herein.
Fig. 1 Proposed steric chiral relay network in the alkylation of
lithium enolate 2.
N(1)-para-methoxybenzyl group on the Si face close to the site
of alkylation at C(6) (Fig. 1).
Whilst the steric chiral relay proposal relies on the confor-
mational preference of the N-para-methoxybenzyl groups, one
alternative rationale is that reactivity differences between the
oxy-enolate 2 and the aza-enolate 8 may account for the
observed differences in diastereoselectivity between the two
templates. In preliminary studies,3 this second possibility was
investigated via the alkylation of N,N0-dimethyl substituted
DKP 11. The lithium enolate, 12, of this template was
expected to be electronically similar to the N,N0-bis-PMB
enolate 2; however, the N-methyl substituents are now incap-
able of substantially projecting onto either face of the aux-
iliary, precluding any steric chiral relay mechanism.
Alkylation of N,N0-dimethyl enolate 12 with methyl iodide
proceeded with lower levels of trans-diastereoselectivity to give
trans-13 in 33% de (Scheme 3), compared to the analogous
Results and discussion
Preparation of diketopiperazine templates
N,N0-bis-PMB-DKP 1 and N,N0-dimethyl-DKP 11 were pre-
pared as previously described3 by the bis-alkylation of (S)-
cyclo-Val-Gly.8 An alternative strategy based upon sequential
incorporation of N-substituents prior to formation of the
DKP heterocycle9 was explored in the preparation of differ-
entially N-substituted DKPs 18 and 22. Accordingly, (S)-N-
(para-methoxybenzyl)valine methyl ester hydrochloride (15),
prepared by the reductive amination of para-anisaldehyde
with (S)-valine methyl ester, was condensed with bromoacetyl
Scheme 3 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C; (ii) MeI (10 equiv.).
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007 New J. Chem., 2007, 31, 486–495 | 487
ꢁc

View Article Online
Fig. 2 DKPs 1, 11, 18 and 22.
Scheme 5 Reagents and conditions: (i) BrCH2COBr, Et3N, DCM,
ꢀ78 1C; (ii) para-methoxybenzylamine, CH3CN, D; (iii) N-methyl
morpholine, sBuOH, AcOH, reflux; (iv) NaH, THF, r.t., 30 min, then
MeI, 12 h.
bromide to give a-bromoamide 16 in 88% yield. Bromide
displacement with ammonia and concomitant cyclisation pro-
vided 17 in 86% yield. N(1)-Methylation of 17 with sodium
hydride and methyl iodide then afforded N(1)-methyl-N(4)-
PMB-DKP 18 in 72% yield (Scheme 4).
enolate 2 with the electrophile at ꢀ78 1C in THF, followed by
slow warming to r.t. Although methylation and benzylation of
1 has been reported by us to afford the corresponding trans-
alkylated diketopiperazines trans-5 and trans-23 with levels of
diastereoselectivity as high as 93 and 98% de, respectively,
several repetitions of these alkylations demonstrated that the
diastereoselectivity for methylation varied between 80–93%
de, and that for benzylation between 88–98% de, as deter-
mined by analysis of the 1H NMR spectra of the crude
reaction mixtures (Scheme 6). The relative and absolute con-
figurations of the major diastereoisomeric alkylation products
trans-5 and trans-23 have previously been established;3 how-
ever, 1H NMR spectroscopic data has also proven a powerful
indicator of C(3)–C(6) relative stereochemistry within DKP
systems.10 Diagnostic chemical shift differences (DdH) between
the two 3H doublets corresponding to the iso-propyl CH3
groups were observed for the diastereoisomeric products trans-
5 and cis-6, and trans-23 and cis-24: larger values of DdH were
observed for the trans-configured diastereoisomer than for the
corresponding cis-isomer.11
Attention turned next to the alkylation of N,N0-dimethyl-
DKP 11. Alkylation with methyl iodide proceeded to give
trans-13 in 50% de,12 whilst benzylation performed under the
same conditions afforded trans-26 in 85% de. The major
diastereoisomers, trans-13 and trans-26, were isolated in
498% de after column chromatography in 48 and 63% yield,
respectively. The relative configuration of the C(3)-iso-propyl
and C(6)-benzyl group within minor diastereoisomer cis-27
was unambiguously established by its independent synthesis
from (S,S)-cyclo-Val-Phe 25: N,N0-dimethylation of 25 with
The N(1)-PMB-N(4)-methyl-DKP 22 was prepared in an
analogous fashion. Condensation of (S)-valine methyl ester
hydrochloride (19) and bromoacetyl bromide gave a-bromo-
amide 20 in 71% yield. The addition of a-bromoamide 20 to
para-methoxybenzylamine and triethylamine in acetonitrile
afforded a seemingly complex mixture, which, upon heating
in sec-butanol, acetic acid and N-methyl morpholine (90 : 9 :
1), gave 21 in 55% yield after chromatographic purification.
Subsequent N(4)-methylation with sodium hydride and methyl
iodide gave 22 in 81% yield (Scheme 5).
Probing the steric chiral relay mechanism: alkylation of
diketopiperazine templates
The reactivity and diastereoselectivity upon alkylation of the
lithium enolates of these differentially N-substituted DKP
templates was then examined using two representative electro-
philes, viz. methyl iodide and benzyl bromide. The alkylation
of N,N0-bis-PMB-DKP 1 has been optimised previously in our
laboratory and involves reaction of the pre-formed lithium
Scheme 4 Reagents and conditions: (i) BrCH2COBr, Et3N, DCM,
ꢀ78 1C; (ii) NH3, EtOH, r.t., 48 h; (iii) NaH, THF, r.t., 30 min, then
MeI, 12 h.
Scheme 6 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C
then RX.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
488 | New J. Chem., 2007, 31, 486–495

View Article Online
Scheme 9 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C
then RX.
cis-33 (49% de), with benzylation giving a 499 : o1 mixture
of trans-34 : cis-35 (498% de). Chromatographic purification
allowed isolation of the major diastereoisomers trans-32 in
50% yield and trans-34 in 67% yield, in 498% de in both
cases (Scheme 9).
Scheme 7 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C then
RX; (ii) KOtBu, MeI, THF.
Authentic samples of the minor diastereoisomers from the
benzylation reactions were prepared in order to establish
unambiguously the de in these alkylation reactions. This was
achieved via alkylation of DKPs 18 and 22 in the presence of
an excess of base and subsequent protonation under kinetic
conditions. Treatment of DKP 18 with excess LiHMDS (3
equiv.) and benzyl bromide (1 equiv.) afforded a 17 : 15 : 51 :
17 mixture of DKP 18, trans-30, cis-31 and a fourth com-
pound, assigned as dibenzylated 36, from which cis-31 was
isolated as a single diastereoisomer in 30% yield. The N(1)-
PMB-N(4)-methyl-DKP diastereoisomer cis-35 was selectively
prepared by the treatment of DKP 22 under identical condi-
tions, which afforded cis-35 in 90% de, and 70% isolated yield
(498% de) after chromatography (Scheme 10).
The relative configuration of the C(3)-iso-propyl and C(6)-
alkyl groups within 28–35 were assigned from 1H NMR
spectroscopic data: the trans diastereoisomers 28, 30, 32 and
34 consistently showed DdH values for the iso-propyl CH3
groups that were larger than those for the corresponding cis-
diastereoisomers 29, 31, 33 and 35, respectively.10,11
Scheme 8 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C then
RX.
potassium tert-butoxide and methyl iodide gave cis-27 in 57%
yield. 1H NMR spectroscopic data for trans-13 and cis-14, and
trans-26 and cis-27 also followed the diagnostic trend in DdH
for the iso-propyl CH3 groups (Scheme 7).10,11
Alkylations of the differentially N-substituted templates 18
and 22 were then studied in order to differentiate between any
potential contributions to selectivity provided by the bulk of
the substituent on either N(1) or N(4). Methylation of N(1)-
methyl-N(4)-PMB-DKP 18 gave a 92.5 : 7.5 mixture of trans-
28 : cis-29 (85% de) whilst benzylation gave a 96 : 4 mixture of
trans-30 : cis-31 (92% de). Purification allowed isolation of
trans-28 in 62% yield and 498% de, and trans-30 in 56%
yield and 498% de (Scheme 8).
Factors controlling regioselective deprotonation and
diastereoselective alkylation of diketopiperazine templates
For a steric chiral relay to operate in these templates, the N(1)
substituent is required to project onto the Si face of the enolate
in order to provide a steric bias at the point of alkylation. In
Analogous methylation conditions applied to N(1)-PMB-
N(4)-methyl-DKP 22 gave a 74.5 : 25.5 mixture of trans-32 :
Scheme 10 Reagents and conditions: (i) LiHMDS (3 equiv.), THF, ꢀ78 1C; (ii) BnBr (1 equiv.).
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007 New J. Chem., 2007, 31, 486–495 | 489
ꢁc

View Article Online
Scheme 11 Reagents and conditions: (i) LiHMDS, THF, ꢀ78 1C then
RX, ꢀ78 1C to r.t.
the case of the N,N-dimethyl-DKP 11 and N(1)-methyl-N(4)-
PMB-DKP 18, however, the N(1)-methyl substituent cannot
sterically block either face of the enolate. In this study, the
observed diastereoselectivity for the benzylation of N(1)-
methyl-DKPs 11 and 18 is comparable to that for the N(1)-
PMB-DKPs 1 and 22. While the methylation studies reveal
more significant deviations in trans-selectivity, these data
suggest that a steric chiral relay is not the primary means by
which the stereochemical information at C(3) is relayed to the
C(6) centre undergoing alkylation (Scheme 11).
Scheme 12 Reagents and conditions: (i) KOtBu, CD3OD.
torsional strain. The alternative half-chair conformation, B,
for C(3)-deprotonation would be disfavoured due to unfa-
vourable 1,2-torsional strain between the pseudo-equatorial
C(3)-iso-propyl group and the N(4)-substituent (Fig. 3).
The deprotonation of 3,6-dialkylated DKPs is also expected
to proceed via a half-chair conformation; deprotonation of the
3,6-trans products via half-chair transition state C, however,
would result in both the C(3)-iso-propyl group and the C(6)-
alkyl group being placed in pseudo-equatorial positions, which
would be disfavoured due to severe 1,2-torsional strain (Fig.
4). The rate of epimerisation would therefore be affected by the
steric bulk of both the C(6)-substituent, and the N(1)- and
N(4)-alkyl substituents. Following this analysis, the in situ
epimerisation of C(6)-methylated products bearing N-methyl
substituents is expected to be more facile than for the N-para-
methoxybenzyl substrates. In accordance with these assump-
tions, N,N0-dimethyl-6-methyl-DKP trans-13 and N(1)-para-
methoxybenzyl-N(4)-methyl-6-methyl-DKP trans-32 are ob-
tained in poor de (50 and 49% de, respectively).
It was postulated that the marked differences in selectivity
upon methylation of these substrates (49–93% de) may be due
to epimerisation of the initially formed trans-products upon
exposure to basic species such as unreacted enolate or excess
base under the reaction conditions. Given that cis-configured
disubstituted DKPs are generally thermodynamically more
stable than the corresponding trans-isomers,13 any in situ
epimerisation of the newly formed C(6) stereogenic centre will
lead to an observed de lower than the intrinsic alkylation
diastereoselectivity. In order to investigate this possibility, the
susceptibility of 3,6-disubstituted DKPs to epimerisation upon
exposure to base, and thus the relative thermodynamic stabi-
lity of the alkylation products, was tested through equilibra-
tion of both the trans- and cis-diastereoisomers derived from
alkylation of N,N0-bis-PMB-DKP 1. Treatment of either of
the 6-methyl-substituted diastereoisomers, trans-5 (498% de)
or cis-6 (498% de), with KOtBu in CD3OD gave a 15.5 : 84.5
mixture of trans-37 : cis-38 with 498% deuterium incorpora-
tion solely at C(6) (Scheme 12). Similar equilibration of either
of the 6-benzyl-substituted diastereoisomers, trans-23 (498%
de) or cis-24 (498% de), gave a 21 : 79 mixture of trans-39 :
cis-40, with 498% deuterium incorporation solely at C(6)
(Scheme 12). These data confirm that the alkylation reaction is
not under thermodynamic control, and furthermore indicate
that product stability is not relevant when considering plau-
sible alkylation transition states.
Following this model, the preference for trans-diastereos-
electivity upon alkylation of the DKP templates may also be
due, in part, to relay of the stereochemical information
through minimisation of 1,2-torsional strain in the transition
state for alkylation at C(6). Molecular modelling studies of all
four enolates derived from diketopiperazines 1, 11, 18 and 2215
Both the regioselective C(6) deuteration observed upon
epimerisation and the regioselective enolate formation at
C(6) within the parent DKPs 1, 11, 18 and 22 are presumably
directed by stereoelectronic factors,14 which disfavour depro-
tonation adjacent to the bulky C(3)-iso-propyl group due to
the introduction of 1,2-torsional strain between the C(3)-iso-
propyl group and the N(4)-substituent. Deprotonation at C(6)
proceeds preferentially through half-chair A, with the C(3)-iso-
propyl group in a pseudo-axial position to minimise 1,2-
Fig. 3 Proposed transition state for regioselective C(6)-deprotona-
tion of DKP templates 1, 11, 18 and 22.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
490 | New J. Chem., 2007, 31, 486–495

View Article Online
significant N(4)–C(5) double bond character.16 Based on these
assumptions, two alternative transition states may be consid-
ered: half-chair F, leading to trans-substituted products, and
boat G, leading to cis-substituted products. The conforma-
tional preference of the enolate ring system in the transition
state will closely resemble that of cyclohexene, of which the
half-chair F is considerably energetically more favourable than
boat G.17 The high levels of facial selectivity observed upon
enolate alkylation derive from this stereoelectronic preference,
combined with the steric protection of the Si face afforded by
the pseudo-axial C(3)-iso-propyl group (Fig. 5).
Conclusion
An examination of the diastereoselective alkylation of a series
of (S)-cyclo-Val-Gly based DKPs, in which the steric require-
ments of both the N(1) and N(4)-substituents (PMB and
methyl) are varied, indicates that excellent levels of diastereos-
electivity can be achieved by the introduction of a para-
methoxybenzyl protecting group at either or both of the
nitrogen atoms. The observed high levels of selectivity are
inconsistent with a purely steric chiral relay and indicate that
the selectivity in these reactions may be controlled by relay of
the stereochemical information from C(3) to C(6) via the
minimisation of 1,2-torsional strain in the transition state for
C(6)-alkylation.
Fig. 4 Proposed transition state for deprotonation/epimerisation of
3,6-dialkylated DKPs.
suggest that these lithiated species preferentially adopt a
conformation D, in which the diketopiperazine ring is close
to planar with the C(3)-iso-propyl substituent occupying a
pseudo-axial position (Fig. 5). This conformation serves to
minimise 1,2-torsional strain between this group and the
neighbouring N(4)-alkyl group, which is present in the alter-
native pseudo-equatorial conformer E (Fig. 5). In conforma-
tion D, the C(3)-iso-propyl group projects onto the Si face of
the enolate, where it may hinder the approach trajectory of an
electrophile; given the high levels of stereoselectivity observed
in these alkylations, however, stereoelectronic factors must
also contribute to the observed selectivity through preferential
axial alkylation of the near planar enolate. In the alkylation
transition state, the N(1)–C(2) amide bond will remain planar,
while N(4) is expected to be sp3-hybridised, precluding any
Experimental
General
All reactions involving organometallic or other moisture-
sensitive reagents were carried out under a nitrogen or argon
atmosphere using standard vacuum line techniques, and glass-
ware that was flame dried and cooled under nitrogen before
use. Solvents were dried according to the procedure outlined
by Grubbs and co-workers.18 Water was purified by an Elixs
UV-10 system. All other solvents were used as supplied
(analytical or HPLC grade) without prior purification. Or-
ganic layers were dried over MgSO4. Thin layer chromato-
graphy was performed on aluminium plates coated with 60
F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq. KMnO4, or 10% ethanolic phosphomolybdic
acid. Flash column chromatography was performed on Kie-
selgel 60 silica.
Elemental analyses were recorded by the microanalysis
service of the Inorganic Chemistry Laboratory, University of
Oxford, UK. Melting points were recorded on a Gallenkamp
Hot Stage apparatus and are uncorrected. Optical rotations
were recorded on a Perkin-Elmer 241 polarimeter with a
water-jacketed 10 cm cell. Specific rotations are reported in
10ꢀ1 deg cm2 gꢀ1 and concentrations in g 100 mLꢀ1. IR
spectra were recorded on Bruker Tensor 27 FT-IR spectro-
meter as either a thin film on NaCl plates (film) or a KBr disc
(KBr) as stated. Selected characteristic peaks are reported in
cmꢀ1. NMR spectra were recorded on Bruker Avance spectro-
meters in the deuterated solvent stated. The field was locked by
external referencing to the relevant deuteron resonance. Low
resolution mass spectra were recorded on either a VG
Fig. 5 Proposed transition states for enolate alkylations.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 486–495 | 491

View Article Online
MassLab 20-250 or a Micromass Platform 1 spectrometer.
Accurate mass measurements were made on either a Bruker
MicroTOF (internally calibrated with polyanaline in positive
and negative modes), or a Micromass GCT instrument fitted
with a Scientific Glass Instruments BPX5 column (15 m ꢂ
0.25 mm) using amyl acetate as a lock mass.
(S)-N(1)-para-Methoxybenzyl-6-iso-propylpiperazine-2,5-dione
(17). 16 (17.8 g, 47.8 mmol) was added to a saturated solution of
ammonia in ethanol (400 mL) and stirred for 48 h before
concentration in vacuo. The reaction mixture was then extracted
with EtOAc and washed with two portions of distilled water
before the organic layer was concentrated in vacuo to yield the
crude solid. Purification by chromatography (silica, eluent
EtOAc) gave 17 as a colourless crystalline solid (11.5 g, 86%);
C15H20N2O3 requires C, 65.2; H, 7.3; N, 10.1%; found C, 65.3;
H, 7.3; N, 10.1%; mp 119–120 1C (DCM–hexane); [a]2D2 ꢀ22.8
(c 1.6 in CHCl3); nmax (KBr) 3299, 1654, 1631; dH (400 MHz,
CDCl3) 1.03 (3H, d, J = 6.9 Hz, CH3CHCH3), 1.11 (3H, d, J =
7.0 Hz, CH3CHCH3), 2.21–2.29 (1H, m, CH3CHCH3), 3.65
(1H, d, J = 4.7 Hz, C(3)H), 3.79 (3H, s, OMe), 3.84 (1H, d, J =
14.8 Hz, NCHHAr), 3.94 (1H, dd, J = 16.8, 3.5 Hz, C(6)HH),
4.10 (1H, dd, J = 16.8, 3.5 Hz, C(6)HH), 5.37 (1H, d, J = 14.8
Hz, NCHHAr), 6.84–6.87 (2H, m, Ar), 7.15–7.18 (2H, m, Ar),
7.27 (1H, app s, NH); dC (100 MHz, CDCl3) 17.7, 19.8, 31.9,
45.3, 47.7, 55.3, 64.2, 114.3, 127.5, 129.6, 159.4, 164.6, 168.1; m/z
(APCI+) 277 ([M + H]+, 85%); HRMS (APCI+) C15H21N2O3
([M + H]+) requires 277.1552, found 277.1550.
Syntheses
(S)-N-(para-Methoxybenzyl)valine methyl ester hydrochlor-
ide (15). To a stirred solution of L-valine methyl ester hydro-
chloride (10 g, 0.06 mol) in THF (100 mL) at 0 1C was added
para-anisaldehyde (8 mL, 0.07 mol), Et3N (16.7 mL, 0.12 mol)
and MgSO4 (20 g), and the reaction mixture was allowed to
warm to r.t. over 18 h. The MgSO4 was then filtered off and
washed with THF (60 mL), and the filtrate was concentrated in
vacuo. The residue was dissolved in MeOH (100 mL), and the
solution was de-gassed and placed under N2. 10% Pd/C (1 g)
was then added, and the reaction vessel was flushed with H2
and stirred at r.t. for 18 h. The reaction mixture was then
filtered through sand and Celites, and the plug washed with
MeOH and concentrated in vacuo. The residue was dissolved
in Et2O (100 mL) and HCl gas was bubbled through the
solution for a few seconds. The resulting crystals were col-
lected and washed with Et2O (100 mL) to give 15 as a white
powder (14.0 g, 82%); mp 152–154 1C; [a]2D5 +10.8 (c 1.0 in
MeOH); nmax (KBr) 3481, 1747, 1617, 1562, 1519; dH (400
MHz, CD3OD) 1.01 (3H, d, J = 7.0 Hz, CH3CHCH3), 1.12
(3H, d, J = 7.0 Hz, CH3CHCH3), 2.35 (1H, septd, J = 7.0, 4.0
Hz, CH3CHCH3), 3.81 (3H, s, OMe), 3.84 (3H, s, OMe), 3.93
(1H, d, J = 4.0 Hz, CHCHN), 4.21 (2H, A2 system,
NCH2Ar), 7.01 (2H, m, Ar), 7.43 (2H, m, Ar); dC (100 MHz,
CD3OD) 16.3, 18.7, 29.8, 50.1, 52.5, 54.9, 64.7, 114.5, 122.0,
132.2, 161.4, 168.4; m/z (ESI+) 252 ([M + H]+, 100%);
HRMS (ESI+) C14H22NO3 ([M + H]+) requires 252.1600,
found 252.1591.
(S)-N(1)-Methyl-N(4)-para-methoxybenzyl-3-iso-propylpipera-
zine-2,5-dione (18). NaH (290 mg, 7.24 mmol, 60% dispersed in
mineral oil) was added to a stirred solution of 17 (2.00 g, 7.24
mmol) in THF (200 mL). After 30 min, methyl iodide (0.50
mL, 7.9 mmol) was added. The reaction mixture was allowed
to stir at ambient temperature for 16 h before sequential
quenching with MeOH, distilled water and saturated NaHCO3
solution. The product was extracted from this mixture with
EtOAc. The organic layer was then washed with water (2 ꢂ
100 mL), dried and concentrated in vacuo. Purification via
flash column chromatography (silica, eluent EtOAc) gave 18
as a colourless oil (1.62 g, 72%); C8H14N2O2 requires C, 66.2;
H, 7.6; N, 9.7%; found C, 66.0; H, 7.8; N, 9.6%; [a]2D3 ꢀ46.0 (c
1.1 in CHCl3); nmax (film) 1668; dH (400 MHz, CDCl3) 0.74
(3H, d, J = 7.1 Hz, CH3CHCH3), 0.88 (3H, d, J = 7.1 Hz,
CH3CHCH3), 1.97–2.08 (1H, m, CH3CHCH3), 2.72 (3H, s,
NMe), 3.51 (1H, d, J = 4.3 Hz, C(3)HCN), 3.54 (3H, s, OMe),
3.67 (1H, d, J = 17.6 Hz, C(6)HH), 3.68 (1H, d, J = 14.2 Hz,
NCHHAr), 3.96 (1H, d, J = 17.6 Hz, C(6)HH), 5.12 (1H, d,
J = 14.2 Hz, NCHHAr), 6.62–6.65 (2H, m, Ar), 6.96–6.98
(2H, m, Ar); dC (100 MHz, CDCl3) 17.4, 19.7, 31.8, 33.0, 47.1,
51.8, 55.0, 64.1, 114.1, 127.6, 129.4, 159.1, 163.4, 164.9; m/z
(ESI+) 291 ([M + H]+, 100%); HRMS (ESI+) C16H23N2O3
([M + H]+) requires 291.1709, found 291.1708.
(S)-N-para-Methoxybenzyl-N-(2-bromoacetyl)valine methyl
ester (16). A solution of 15 (20 g, 69.5 mmol) and Et3N
(21.3 mL, 153 mmol) in DCM (125 mL) were added dropwise
over 1 h to a solution of bromoacetyl bromide (9.1 mL, 104
mmol) in DCM (375 mL) at ꢀ78 1C, before overnight warm-
ing to r.t. After 16 h, the crude reaction solution was washed
with distilled water, dried and concentrated in vacuo. Purifica-
tion by chromatography (silica, eluent hexane/Et2O 3 : 1) gave
16 as an orange oil (20.0 g, 88%); [a]2D2 ꢀ40.9 (c 1.6 in CHCl3);
nmax (film) 1741, 1659; dH (500 MHz, PhMe-d8, 373 K) 0.86
(3H, d, J = 6.7 Hz, CH3CHCH3), 0.91 (3H, d, J = 6.7 Hz,
CH3CHCH3), 2.27–2.37 (1H, m, CH3CHCH3), 3.26 (3H, s,
CO2Me), 3.46 (3H, s, ArOMe), 3.67 (2H, s, COCH2Br), 4.47
(1H, d, J = 14.5 Hz, NCHHAr), 4.49 (1H, d, J = 12.4 Hz,
iPrCHN), 4.54 (1H, d, J = 14.5 Hz, NCHHAr), 6.70–6.75
(2H, m, Ar), 6.99–7.10 (2H, m, Ar); dC (125 MHz, PhMe-d8,
373 K) 19.0, 20.1, 28.8, 49.0, 51.0, 55.0, 64.8, 114.3, 127.0,
129.6, 159.9, 167.7, 170.3; m/z (ESI+) 396 ([M + Na]+, 81Br,
100%), 394 (100), 374 (40), 372 (40); HRMS (ESI+)
C16H2379BrNO4 ([M + H]+, 79Br) requires 372.0810, found
372.0817.
(S)-N-(2-Bromoacetyl)valine methyl ester (20). A solution of
(S)-valine methyl ester hydrochloride (19) (5.00 g, 30.5 mmol)
and Et3N (11.1 mL, 83.9 mmol) in DCM (125 mL) were added
dropwise over 1 h to a solution of bromoacetyl bromide (5.00
mL, 45.7 mmol) in DCM (100 mL) at ꢀ78 1C, before over-
night warming to r.t. After 16 h, the crude reaction solution
was washed with distilled water, dried, concentrated in vacuo
and purified by chromatography (silica, eluent Et2O), giving
20 as an orange oily solid (6.85 g, 71%); [a]2D2 +22.6 (c 1.1 in
CHCl3); nmax (film) 3312, 1738, 1650; dH (400 MHz, CDCl3)
0.93 (3H, d, J = 6.8 Hz, CH3CHCH3), 0.96 (3H, d, J = 6.8
Hz, CH3CHCH3), 2.18–2.26 (1H, m, CH3CHCH3), 3.78
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
492 | New J. Chem., 2007, 31, 486–495

View Article Online
(3H, s, CO2Me), 3.93 (2H, s, CH2Br), 4.53 (1H, dd, J = 9.0,
7.2 Hz, iPrCHNH), 7.00 (1H, br d, J = 7.2 Hz, NH); dC (100
MHz, CDCl3) 17.7, 18.8, 28.6, 31.3, 52.4, 57.7, 165.8, 171.8;
m/z (ESI+) 254 ([M + H]+, 81Br, 100%), 252 (100); HRMS
(ESI+) C8H1479BrNO3 ([M + H]+, 79Br) requires 252.0235,
found 252.0238.
Alkylation of DKP templates
General procedure 1. LiHMDS (1.0 M in THF, 1.1 equiv.)
was added to a solution of the DKP (1 equiv.) in de-gassed
THF at ꢀ78 1C. After stirring for 1 h at ꢀ78 1C, the alkyl
halide (1 equiv.) was added and the reaction mixture allowed
to warm to r.t. over 12 h. The reaction mixture was quenched
with sat. aq. NH4Cl, extracted with EtOAc, dried and con-
centrated in vacuo to give the crude product.
(S)-N(1)-para-Methoxybenzyl-3-iso-propylpiperazine-2,5-dione
(21). A solution of 20 (580 mg, 2.30 mmol) in MeCN (10 mL)
was added dropwise over 1 h to a mixture of para-methox-
ybenzylamine (0.40 mL, 2.99 mmol) and Et3N (0.28 mL, 2.30
mmol) in MeCN (20 mL), and the resultant solution was
subjected to reflux overnight. The precipitate was then re-
moved by filtration from the crude reaction mixture before the
solvent was removed in vacuo. N-methyl morpholine (0.72 mL,
6.56 mmol), AcOH (3.25 mL, 56.8 mmol) and butan-2-ol (32.5
mL) were added to the crude reaction mixture, which was then
subjected to reflux overnight at 100 1C. The solvent was then
removed in vacuo. The product was extracted with EtOAc,
washed with distilled water and concentrated in vacuo. Pur-
ification of the residue via flash column chromatography
(silica, eluent EtOAc) gave 21 as a white solid (398 mg,
55%); mp 134–135 1C; [a]2D2 +8.0 (c 0.6 in CHCl3); nmax
(KBr) 3254, 1653; dH (400 MHz, CDCl3) 0.85 (3H, d, J =
6.9 Hz, CH3CHCH3), 1.01 (3H, d, J = 6.9 Hz, CH3CHCH3),
2.38–2.45 (1H, m, CH3CHCH3), 3.75 (1H, d, J = 17.9 Hz,
C(6)HH), 3.78 (3H, s, OMe), 3.84 (1H, d, J = 17.9 Hz,
C(6)HH), 3.89 (1H, d, J = 2.6 Hz, C(3)H), 4.34 (1H, d, J
= 14.3 Hz, NCHHAr), 4.64 (1H, d, J = 14.3 Hz, NCHHAr),
6.83–6.86 (2H, m, Ar), 7.17–7.21 (2H, m, Ar), 7.74 (1H, br s,
NH); dC (100 MHz, CDCl3) 16.1, 18.8, 33.2, 48.4, 49.0, 55.3,
60.7, 114.2, 127.3, 130.0, 159.4, 165.5, 166.6; m/z (CI+) 277
([M + H]+, 100%); HRMS (CI+) C15H21N2O3 ([M + H]+)
requires 277.1552, found 277.1554.
General procedure 2: with excess base. LiHMDS (1.0 M in
THF, 3 equiv.) was added to a solution of the DKP (1 equiv.)
in de-gassed THF at ꢀ78 1C. After stirring for 1 h at ꢀ78 1C,
the alkyl halide (1 equiv.) was added and stirring continued for
a further 4 h at ꢀ78 1C. The reaction mixture was quenched
with acetic acid at ꢀ78 1C, allowed to warm to r.t. and
partitioned between H2O and EtOAc. The organic layer was
washed with sat. aq. NaHCO3, dried and concentrated
in vacuo to give the crude product.
(3S,6R)-N,N0-Dimethyl-3-iso-propyl-6-benzylpiperazine-2,5-
dione (trans-26). 11 (100 mg, 0.54 mmol) in THF (20 mL),
LiHMDS (1.0 M in THF, 0.60 mL, 0.60 mmol) and BnBr (71
mL, 0.60 mmol) were reacted according to General procedure 1
to give a 92.5 : 7.5 mixture of trans-26 : cis-27. Chromato-
graphy (silica, eluent 40–601 petrol/EtOAc 2 : 1) gave trans-26
as a white solid (94 mg, 63%, 498% de); mp 81–83 1C; [a]D26
ꢀ1.3 (c 0.9 in CHCl3); nmax (KBr) 1640; dH (400 MHz, CDCl3)
0.78 (3H, d, J = 7.0 Hz, CH3CHCH3), 1.01 (3H, d, J = 7.0
Hz, CH3CHCH3), 2.13 (1H, m, CH3CHCH3), 2.69 (3H, s,
NMe), 2.97 (1H, d, J = 2.5 Hz, C(3)H), 3.05 (3H, s, NMe),
3.16 (1H, dd, J = 14.0, 4.1 Hz, CHHPh), 3.32 (1H, dd, J =
14.0, 3.2 Hz, CHHPh), 4.25 (1H, m, C(6)H), 7.01–7.03 (2H, m,
Ar), 7.21–7.26 (3H, m, Ar); dC (100 MHz, CDCl3) 16.5, 19.1,
31.7, 32.4, 33.2, 37.2, 62.3, 66.0, 127.3, 128.3, 129.6, 134, 165.2,
165.4; m/z (APCI+) 275 ([M + H]+, 100%).
(S,S)-N,N0-Dimethyl-3-iso-propyl-6-benzylpiperazine-2,5-dione
(cis-27). KOtBu (143 mg, 1.30 mmol) was added to (S,S)-cyclo-
Val-Phe 25 (150 mg, 0.61 mmol) and MeI (70 mL, 1.20 mmol)
in THF (10 mL). After 45 min, MeOH (50 mL) and sat. aq.
NH4OH (0.5 mL) were added. The solvent was then removed
in vacuo. Chromatography (silica, eluent EtOAc) gave cis-27
as a colourless oil (95 mg, 57%. 498% de); [a]2D6 ꢀ59.5 (c 0.9
in CHCl3); nmax (film) 1651; dH (500 MHz, CDCl3) 0.95 (3H, d,
J = 6.9 Hz, CH3CHCH3), 1.02 (3H, d, J = 6.9 Hz,
CH3CHCH3), 1.67 (1H, m, CH3CHCH3), 2.67 (3H, s,
NMe), 3.02 (3H, s, NMe), 3.09 (1H, dd, J = 14.0, 7.8 Hz,
CHHPh), 3.38 (1H, dd, J = 14.0, 4.4 Hz, CHHPh), 3.55 (1H,
d, J = 7.1 Hz, C(3)H), 4.13 (1H, dd, J = 7.8, 4.4 Hz, C(6)H),
7.23–7.33 (5H, m, Ph); dC (50 MHz, CDCl3) 19.4, 20.4, 33.4,
33.8, 40.2, 65.1, 68.9, 127.4, 129.1, 129.6, 137.3, 166.1, 166.7;
m/z (APCI+) 275 ([M + H]+, 100%).
(S)-N(1)-para-Methoxybenzyl-N(4)-methyl-3-iso-propylpipera-
zine-2,5-dione (22). NaH (535 mg, 13.4 mmol, 60% dispersed in
mineral oil) was added to a stirred solution of 21 (3.7 g, 13.4
mmol) in THF (250 mL). After 30 min, methyl iodide (0.94
mL, 15.7 mmol) was added. The reaction mixture was allowed
to stir at ambient temperature for 12 h before quenching with
distilled water. The product was extracted with EtOAc, dried
over MgSO4 and concentrated in vacuo. Purification of the
residue via flash column chromatography (silica, eluent
EtOAc) gave 22 as a white solid (3.15 g, 81%); mp 51–53
1C; [a]2D5 +64.9 (c 1.0 in CHCl3); nmax (KBr) 1652 (CQO); dH
(400 MHz, CDCl3) 0.95 (3H, d, J = 7.0 Hz, CH3CHCH3),
1.09 (3H, d, J = 7.0 Hz, CH3CHCH3), 2.24–2.28 (1H, m,
CH3CHCH3), 2.99 (3H, s, NMe), 3.75 (1H, d, J = 17.4 Hz,
C(6)HH), 3.77 (1H, d, J = 4.2 Hz, C(3)H), 3.80 (3H, s, OMe),
3.87 (1H, d, J = 17.4 Hz, C(6)HH), 4.31 (1H, d, J = 14.1 Hz,
NCHHAr), 4.72 (1H, d, J = 14.1 Hz, NCHHAr), 6.86 (2H, d,
J = 8.4 Hz, Ar), 7.20 (2H, d, J = 8.4 Hz, Ar); dC (100 MHz,
CDCl3) 18.2, 19.3, 32.8, 34.1, 48.9, 49.2, 55.3, 68.5, 114.2,
127.4, 130.0, 159.4, 164.5, 165.1; m/z (ESI+) 291 ([M + H]+,
100%); HRMS (ESI+) C16H23N2O3 ([M + H]+) requires
291.1709, found 291.1699.
(3S,6R)-N(1)-Methyl-N(4)-para-methoxybenzyl-3-iso-propyl-6-
methylpiperazine-2,5-dione (trans-28). 18 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.37 mL, 0.37 mmol)
and MeI (24 mL, 0.37 mmol) were reacted according to General
procedure 1 to give a 92.5 : 7.5 mixture of trans-28 : cis-29.
Chromatography (silica, eluent 40–601 petrol/EtOAc 3 : 1) gave
trans-28 as a colourless oil (65 mg, 62%, 498% de); [a]2D5 ꢀ48.4
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 486–495 | 493

View Article Online
(c 1.0 in CHCl3); nmax (film) 1658; dH (400 MHz, CDCl3) 0.91
(3H, d, J = 6.9 Hz, CH3CHCH3), 1.08 (3H, d, J = 6.9 Hz,
CH3CHCH3), 1.61 (3H, d, J = 6.8 Hz, C(6)Me), 2.21–2.29 (1H,
m, CH3CHCH3), 2.95 (3H, s, NMe), 3.72 (1H, d, J = 3.8 Hz,
C(3)H), 3.78 (3H, s, OMe), 3.83 (1H, d, J = 14.9 Hz,
NCHHAr), 4.05–4.11 (1H, q, J = 6.8 Hz, C(6)H), 5.37 (1H,
d, J = 14.9 Hz, NCHHAr), 6.83 (2H, d, J = 8.6 Hz, Ar), 7.12
(2H, d, J = 8.6 Hz, Ar); dC (100 MHz, CDCl3) 17.2, 19.9, 18.4,
31.0, 32.0, 47.3, 55.3, 56.0, 63.7, 114.3, 127.7, 129.5, 159.3, 165.4,
167.2; m/z (ESI+) 305 ([M + H]+, 100%); HRMS (ESI+)
C17H25N2O3 ([M + H]+) requires 305.1865, found 305.1877.
trans-30 as a colourless oil (55 mg, 42%, 498% de); [a]2D5 +99.7
(c 1.0 in CHCl3); nmax (film) 1652; dH (400 MHz, CDCl3) 0.92
(3H, d, J = 7.1 Hz, CH3CHCH3), 1.10 (3H, d, J = 7.1 Hz,
CH3CHCH3), 1.55 (3H, d, J = 6.9 Hz, C(6)Me), 2.24–2.34 (1H,
m, CH3CHCH3), 2.97 (3H, s, NMe), 3.79 (3H, s, OMe), 3.82
(1H, d, J = 4.3 Hz, C(3)H), 3.87–3.96 (1H, q, J = 6.9 Hz,
C(6)H), 4.03 (1H, d, J = 14.9 Hz, NCHHAr), 5.33 (1H, d, J =
14.9 Hz, NCHHAr), 6.85 (2H, d, J = 8.6, Ar), 7.19 (2H, d, J =
8.6, Ar); dC (100 MHz, CDCl3) 17.9, 18.0, 19.3, 32.5, 34.5, 45.4,
53.4, 55.2, 67.9, 114.1, 128.1, 129.4, 159.1, 165.8, 167.6; m/z
(ESI+) 305 ([M + H]+, 100%); HRMS (ESI+) C17H25N2O3
([M + H]+) requires 305.1865, found 305.1861.
(3S,6R)-N(1)-Methyl-N(4)-para-methoxybenzyl-3-iso-propyl-6-
benzylpiperazine-2,5-dione (trans-30). 18 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.37 mL, 0.37 mmol)
and BnBr (44 mL, 0.37 mmol) were reacted according to General
procedure 1 to give a 96 : 4 mixture of trans-30 : cis-31.
Chromatography (silica, eluent 40–601 petrol/EtOAc 1 : 1) gave
trans-30 as a colourless oil (74 mg, 56%, 498% de); [a]2D5 ꢀ76.1
(c 1.0 in CHCl3); nmax (film) 1654; dH (400 MHz, CDCl3) 0.80
(3H, d, J = 7.2 Hz, CH3CHCH3), 0.97 (3H, d, J = 7.2 Hz,
CH3CHCH3), 2.11–2.19 (1H, m, CH3CHCH3), 3.09 (3H, s,
NMe), 3.27 (1H, dd, J = 14.4, 3.6 Hz, CHHPh), 3.29 (1H, d,
J = 4.4 Hz, C(3)H), 3.46 (1H, dd, J = 14.4, 4.0 Hz, CHHPh),
3.74 (1H, d, J = 14.8 Hz, NCHHAr), 3.77 (3H, s, OMe), 4.35
(1H, m, C(6)H), 5.17 (1H, d, J = 14.8 Hz, NCHHAr), 6.52 (2H,
d, J = 8.6 Hz, Ar), 6.67 (2H, d, J = 8.6 Hz, Ar), 7.07–7.23 (5H,
m, Ph); dC (100 MHz, CDCl3) 15.9, 19.6, 31.0, 32.3, 36.5, 46.1,
55.2, 61.9, 62.0, 114.0, 126.4, 127.0, 128.7, 129.4, 129.6, 129.9,
135.0, 159.0, 165.0, 165.2; m/z (ESI+) 381 ([M + H]+, 100%);
HRMS (ESI+) C23H29N2O3 ([M + H]+) requires 381.2178,
found 381.2177.
(3S,6R)-N(1)-para-Methoxybenzyl-N(4)-methyl-3-iso-propyl-6-
benzylpiperazine-2,5-dione (trans-34). 22 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.37 mL, 0.37 mmol)
and BnBr (44 mL, 0.37 mmol) were reacted according to General
procedure 1 to give a 499 : o1 mixture of trans-34 : cis-35.
Chromatography (silica, eluent 40–601 petrol/EtOAc 1 : 1) gave
trans-34 as a white solid (70 mg, 67%, 498% de); mp 120–122
1C; [a]2D5 +52.2 (c 1.0 in CHCl3); nmax (KBr) 1646; dH (400 MHz,
CDCl3) 0.82 (3H, d, J = 7.1 Hz, CH3CHCH3), 1.07 (3H, d, J =
7.1 Hz, CH3CHCH3), 2.18–2.23 (1H, m, CH3CHCH3), 2.73 (3H,
s, NMe), 2.94 (1H, d, J = 2.6 Hz, C(3)H), 3.29 (2H, s, CH2Ph),
3.86 (3H, s, OMe), 3.97 (1H, d, J = 14.5 Hz, NCHHAr), 4.21
(1H, m, C(6)H), 5.64 (1H, d, J = 14.5 Hz, NCHHAr), 6.88–7.34
(9H, m, Ar, Ph); dC (100 MHz, CDCl3) 17.1, 19.6, 32.1, 33.5,
37.1, 46.2, 55.8, 58.8, 66.3, 114.7, 127.7, 127.8, 128.8, 129.0,
130.2, 130.6, 135.0, 159.9, 165.6, 166.2; m/z (ESI+) 381
([M + H]+, 100%); HRMS (ESI+) C23H29N2O3 ([M + H]+)
requires 381.2178, found 381.2174.
(S,S)-N(1)-Methyl-N(4)-para-methoxybenzyl-3-iso-propyl-6-
benzylpiperazine-2,5-dione (cis-31). 18 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.7 mL, 0.7 mmol)
and BnBr (44 mL, 0.37 mmol) were reacted according to
General procedure 2 to give a 17 : 15 : 51 : 17 mixture of 18 :
trans-30 : cis-31 : 36. Chromatography (silica, eluent 40–601
petrol/EtOAc 2 : 1) gave cis-31as a colourless oil (40 mg, 30%,
498% de); [a]D25 ꢀ95.2 (c 1.0 in CHCl3); nmax (film) 1658; dH
(400 MHz, CDCl3) 0.95 (3H, d, J = 6.8 Hz, CH3CHCH3),
1.10 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.80–1.88 (1H, m,
CH3CHCH3), 2.65 (3H, s, NMe), 3.12 (1H, dd, J = 3.1 Hz,
13.9, CHHPh), 3.44 (1H, J = 4.4 Hz, 13.9, CHHPh), 3.63
(1H, d, J = 6.5 Hz, C(3)H), 3.79 (3H, s, OMe), 3.85 (1H, d, J
= 14.7 Hz, NCHHAr), 4.19 (1H, m, C(6)H), 5.40 (1H, d, J =
14.7 Hz, NCHHAr), 6.83 (2H, d, J = 8.4 Hz, Ar), 7.16 (2H, d,
J = 8.4 Hz, Ar), 7.26–7.35 (5H, m, Ph); dC (100 MHz, CDCl3)
19.2, 20.8, 32.8, 33.8, 40.5, 48.6, 55.2, 64.6, 65.2, 114.3, 127.7,
127.2, 128.9, 129.4, 129.6, 137.1, 159.7, 165.6, 166.4; m/z
(ESI+) 381 ([M + H]+, 100%); HRMS (ESI+) C23H29N2O3
([M + H]+) requires 381.2178, found 381.2177.
(S,S)-N(1)-para-Methoxybenzyl-N(4)-methyl-3-iso-propyl-6-
benzylpiperazine-2,5-dione (cis-35). 22 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.7 mL, 0.7 mmol)
and BnBr (40 mL, 0.34 mmol) were reacted according to
General procedure 2 to give a 5 : 95 mixture of trans-34 : cis-
35. Chromatography (silica, eluent 40–601 petrol/EtOAc 2 : 1)
gave cis-35 as a colourless oil (95 mg, 70%, 498% de); [a]D25
ꢀ109.5 (c 1.0 in CHCl3); nmax (film) 1656; dH (400 MHz,
CDCl3) 1.03 (3H, d, J = 6.8 Hz, CH3CHCH3), 1.06 (3H, d, J
= 6.8 Hz, CH3CHCH3), 1.71–1.79 (1H, m, CH3CHCH3), 2.99
(3H, s, NMe), 3.07 (1H, dd, J = 7.7, 14.2 Hz, CHHPh), 3.31
(1H, d, J = 14.6 Hz, NCHHAr), 3.38 (1H, dd, J = 4.5, 14.2
Hz, CHHPh), 3.61 (1H, d, J = 7.35 Hz, C(3)H), 3.76 (3H, s,
OMe), 4.14 (1H, m, C(6)H), 5.22 (1H, d, J = 14.6 Hz,
NCHHAr), 6.76 (2H, d, J = 8.6 Hz, Ar), 6.92 (2H, d, J =
8.6 Hz, Ar), 7.22–7.36 (5H, m, Ph); dC (100 MHz, CDCl3) 19.8,
20.7, 32.6, 33.9, 40.2, 46.8, 55.2, 60.5, 69.1, 114.1, 127.6, 127.3,
128.9, 129.4, 129.9, 137.4, 159.3, 165.8, 166.6; m/z (ESI+) 381
([M + H]+, 100%); HRMS (ESI+) C23H29N2O3 ([M + H]+)
requires 381.2178, found 381.2182.
(3S,6R)-N(1)-para-Methoxybenzyl-N(4)-methyl-3-iso-propyl-6-
methylpiperazine-2,5-dione (trans-32). 22 (100 mg, 0.34 mmol) in
THF (20 mL), LiHMDS (1.0 M in THF, 0.37 mL, 0.37 mmol)
and MeI (24 mL, 0.37 mmol) were reacted according to General
procedure 1 to give a 74.5 : 25.5 mixture of trans-32 : cis-33.
Chromatography (silica, eluent 40–601 petrol/EtOAc 3 : 1) gave
Acknowledgements
We would like to thank to Oxford Asymmetry International
plc for financial support (S. D. B.) and the EPSRC for a
ROPA award (A. C. G.).
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
494 | New J. Chem., 2007, 31, 486–495

View Article Online
8 (S)-cyclo-Val-Gly was prepared according to the procedure of S.
D. Bull, S. G. Davies and W. O. Moss, Tetrahedron: Asymmetry,
1998, 9, 321.
9 (a) V. Favero, G. Porzi and S. Sandri, Tetrahedron: Asymmetry,
1997, 8, 599; (b) F. Paradisi, G. Porzi and S. Sandri, Tetrahedron:
Asymmetry, 2001, 12, 3319.
10 S. D. Bull, S. G. Davies, A. C. Garner, M. D. O’Shea, E. D.
Savory and E. J. Snow, J. Chem. Soc., Perkin Trans. 1, 2002,
2442.
11 The diastereoisomeric pairs of C(6)-benzyl DKPs trans-23 and cis-
24, trans-26 and cis-27, trans-30 and cis-31, and trans-34 and cis-35
also displayed the established trend of iso-propyl CH chemical
shift, in which this resonance for the cis-benzylated DKP lies
upfield to that of the corresponding resonance in the trans-benzy-
lated compound, presumably due to the cis-substituted diketopi-
perazine ring adopting a boat conformation, which results in
anisotropic shielding from the phenyl ring of the C(6) benzyl
References
1 (a) R. M. Williams, Synthesis of Optically Active Amino Acids,
Pergamon Press, Oxford, 1989; (b) R. O. Duthaler, Tetrahedron,
1994, 50, 1539; (c) L. S. Hegedus, Acc. Chem. Res., 1995, 28, 299;
(d) R. Bloch, Chem. Rev., 1998, 98, 1407; (e) M. Calmes and J.
Daunis, Amino Acids, 1999, 16, 215.
2 For selected examples, see: (a) D. A. Evans and A. E. Weber, J.
Am. Chem. Soc., 1986, 108, 6757; (b) J. F. Dellaria and B. D.
Santarsiero, J. Org. Chem., 1989, 54, 3916; (c) H. Josien, A. Martin
and G. Chassaing, Tetrahedron Lett., 1991, 32, 6547; (d) R. M.
Williams and M.-N. Im, J. Am. Chem. Soc., 1991, 113, 9276; (e) A.
N. Boa, A. L. Guest, P. R. Jenkins, J. Fawcett, D. R. Russell and
D. Waterson, J. Chem. Soc., Perkin Trans. 1, 1993, 477; (f) K.
Tanaka, M. Ahn, Y. Watanabe and K. Fuji, Tetrahedron: Asym-
metry, 1996, 7, 1771; (g) T.-L. Yeh, C.-C. Liao and B.-J. Uang,
Tetrahedron, 1997, 53, 11141; (h) A. G. Myers and J. L. Gleason,
Org. Synth., 1998, 76, 57; (i) O. Achatz, A. Grandl and T. K.
Wanner, Eur. J. Org. Chem., 1999, 1967; (j) P.-F. Xu and T.-J. Lu,
J. Org. Chem., 2003, 68, 658; (k) D. J. Dixon, R. A. J. Horan and
N. J. T. Monck, Tetrahedron: Asymmetry, 2004, 15, 913.
group; see: (a) U. Schollkopf, Tetrahedron, 1983, 39, 2085; (b) R.
¨
W. Woodard, J. Org. Chem., 1985, 50, 4796; (c) S. D. Bull, S. G.
Davies and M. O’Shea, J. Chem. Soc., Perkin Trans. 1, 1998, 3657.
12 Anomalous ‘‘contrasteric’’ alkylations with methyl iodide have
3 S. D. Bull, S. G. Davies, J. V. A. Ouzman and S. W. Epstein, J.
Chem. Soc., Perkin Trans. 1, 1998, 2321.
been reported; see: T. J. Sprules and J.-F. Lavallee, J. Org. Chem.,
´
1995, 60, 5041 and references contained therein.
4 (a) U. Schollkopf, U. Groth and C. Deng, Angew. Chem., 1981, 93,
¨
¨
793; (b) For selected recent applications of the Schollkopf auxili-
13 (a) C. Eguchi and A. Kakuta, J. Am. Chem. Soc., 1974, 96, 3985;
(b) S. D. Bull, S. G. Davies, R. M. Parkin and F. Sanchez-Sancho,
J. Chem. Soc., Perkin Trans. 1, 1998, 2313.
14 (a) E. J. Corey and R. A. Sneen, J. Am. Chem. Soc., 1956, 78, 6269;
(b) For a recent discussion of the stereoelectronic effects in
enolisation see: S. M. Benham, S. E. Benham, K. Ando, N. S.
Green and K. N. Houk, J. Org. Chem., 2000, 65, 8970.
ary, see: P. Desai, S. S. Pfeiffer and D. L. Boger, Org. Lett., 2003, 5,
5047; (c) N. Wild and U. Groth, Eur. J. Org. Chem., 2003, 4445; (d)
A. H. Fauq, M. A. Khan and C. Eckman, Synth. Commun., 2004,
34, 775; (e) C. Didier, D. J. Critcher, N. D. Walshe, Y. Kojima, Y.
Yamanuchi and A. G. M. Barrett, J. Org. Chem., 2004, 69, 7875;
(f) D. Dıez, P. Garcıa, I. S. Marcos, N. M. Garrido, P. Basabe, H.
´ ´
15 Modelling was performed using the Macromodel suite of pro-
grams. 1000 starting conformations of the lithium enolates of
DKPs 1, 11, 18 and 22 were generated using a Monte Carlo
simulation and minimised using a MM2 force field.
B. Broughton and J. G. Urones, Tetrahedron, 2005, 61, 699.
5 Ockham’s razor (also spelled Occam’s razor) is a principle attrib-
uted to the 14th Century English logician and Franciscan friar
William of Ockham. The principle states that the explanation of
any phenomenon should make as few assumptions as possible.
6 J. Clayden and N. Vassiliou, Org. Biomol. Chem., 2006, 4, 2667.
7 (a) M. P. Sibi, L. Venkatraman, M. Liu and C. P. Jasperse, J. Am.
Chem. Soc., 2001, 123, 8444; (b) L. Quaranta, O. Corminboeuf and
P. Renaud, Org. Lett., 2002, 4, 39; (c) O. Corminboeuf, L.
Quaranta, P. Renaud, M. Liu, C. P. Jasperse and M. P. Sibi,
Chem.–Eur. J., 2003, 9, 29; (d) A. V. Malkov, J. B. Hand and P.
Kocovsky, Chem. Commun., 2003, 12, 1948; (e) S. R. Hitchcock, D.
M. Casper, J. F. Vaughn, J. M. Finefield, G. M. Ferrence and J. M.
Esken, J. Org. Chem., 2004, 69, 714; (f) M. P. Sibi and L. M.
Stanley, Tetrahedron: Asymmetry, 2004, 15, 3353; (g) M. P. Sibi
and N. Prabagaran, Synlett, 2004, 2421.
16 (a) D. Seebach, T. Maetzke, W. Petter, B. Klotzer and D. A.
¨
Plattner, J. Am. Chem. Soc., 1991, 113, 1781; (b) For other
discussions of stereoelectronic constraints in lactam enolate alkyla-
tions see: A. I. Meyers, M. A. Seefeld, B. A. Lefker, J. F. Blake and
P. G. Williard, J. Am. Chem. Soc., 1998, 120, 7429; (c) K. Ando, N.
S. Green, Y. Li and K. N. Houk, J. Am. Chem. Soc., 1999, 121,
5334.
17 The half-chair conformation of cyclohexene has been shown to be
B5.5 kcal molꢀ1 more stable than the boat conformation; see: F.
A. L. Anet, D. I. Freedberg, J. W. Storer and K. N. Houk, J. Am.
Chem. Soc., 1992, 114, 10969 and references contained therein.
18 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and
F. J. Timmers, Organometallics, 1996, 15, 1518.
ꢁc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 486–495 | 495