Chiral glycine cation equivalents: N-acyliminium species derived from diketopiperazines

Article abstract of DOI:10.1039/b207457p

Studies towards a N,N′-bis(p-methoxybenzyl)diketopiperazine asymmetric glycine cation equivalent for the synthesis of homochiral α-amino acids are described. The oxidation of enolate 3 with molecular oxygen provides either a mixture of hydroxylated diketopiperazines 7 and 8 or trione 10 depending upon the reaction conditions. The nucleophilic reduction of trione 10 and the reaction of acetoxy N-acyliminium ion precursors 5 and 6, derived from 7 and 8, with allyltrimethylsilane and boron trifluoride etherate is examined and a model for the stereoselectivity observed in these additions is presented.

Full text of DOI:10.1039/b207457p

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Chiral glycine cation equivalents: N-acyliminium species derived
from diketopiperazines
Steven D. Bull, Stephen G. Davies,* A. Christopher Garner, Michael D. O’Shea,
Edward D. Savory and Emma J. Snow
1
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: steve.davies@chemistry.ox.ac.uk
Received (in Cambridge) 30th July 2002, Accepted 30th September 2002
First published as an Advance Article on the web 15th October 2002
Studies towards a N,NЈ-bis(p-methoxybenzyl)diketopiperazine asymmetric glycine cation equivalent for the synthesis
of homochiral α-amino acids are described. The oxidation of enolate 3 with molecular oxygen provides either
a mixture of hydroxylated diketopiperazines 7 and 8 or trione 10 depending upon the reaction conditions. The
nucleophilic reduction of trione 10 and the reaction of acetoxy N-acyliminium ion precursors 5 and 6, derived from
7 and 8, with allyltrimethylsilane and boron trifluoride etherate is examined and a model for the stereoselectivity
observed in these additions is presented.
Introduction
There are many auxiliary based asymmetric syntheses of α-
amino acids that employ chiral glycine anion equivalents.1
Auxiliaries acting as chiral glycine cation equivalents are less
common,2 although a number of cyclic chiral auxiliaries of
this type have been described.3 We have recently reported two
new diketopiperazine derived chiral auxiliaries 1 and 2 for the
asymmetric synthesis of homochiral α-amino acids based
upon the alkylation of chiral glycine anion equivalent 1,4 and
conjugate addition and protonation of chiral dehydroalanine
acceptor 2 (Scheme 1).5 The high diastereoselectivities obtained
for trans-alkylation of the enolate 3 with electrophiles to afford
(R)-α-amino acids, and the selectivity in protonation of inter-
mediate enolate 4 derived from 2 to afford (S )-α-amino acids,
have been proposed to arise from a novel chiral relay effect
operating to control and enhance facial selectivity.4–6
We report herein studies on a glycine cation substitution
strategy for the asymmetric synthesis of α-amino acids based
on additions of allyltrimethylsilane to N-acyliminium species
derived from a diketopiperazine chiral auxiliary.
Results and discussion
N-Acyl-O-acetyl-N,O-aminals have found extensive application
as precursors for the generation of N-acyliminium species
under Lewis acidic conditions.7 Therefore it was envisaged that
acetoxy substituted diketopiperazines 5 or 6 should provide
access to N-acyliminium species under similar conditions.8,9
Initial synthetic efforts were directed towards the preparation
of alcohols 7 and 8 via the addition of oxygen (O2) to a THF
solution of the lithium enolate 3 to afford a separable 2 : 1
mixture of (3R,6S )-7 and (3S,6S )-8 in moderate yields (36%
and 25% respectively) (Scheme 2).10 Acetylation of 7 or 8
Scheme 1 Reagents and conditions: (i) LHMDS, THF, Ϫ78 ЊC;
(ii) alkyl halide, THF, Ϫ78 ЊC; (iii) CAN (6 equivalents), H2O, CH3CN;
6 M HCl, 100 ЊC; (iv) 2 × RMgX or 2 × RLi, CuCN, BF3ؒOEt2; THF,
Ϫ78 ЊC; (v) NH4Cl (aq).
with acetic anhydride and DMAP in pyridine then provided
(3R,6S )-acetate 5 and the corresponding (3S,6S )-acetate 6
respectively in good yields (88% and 83% respectively).
The relative configurations within diastereoisomeric alcohols
7 and 8 were determined from inspection of the 1H NMR spec-
troscopic data. Examination of 1H NMR data for simple alkyl
substituted diketopiperazines4,5 reveals that the difference in
chemical shift between the two diastereotopic C-3 isopropyl
methyl groups is diagnostic for the relative (cis or trans) con-
figuration of the C-3 and C-6 ring substituents. For cis sub-
stituted diketopiperazines, derived from conjugate addition
methodology, the chemical shift differences lie in the range
0.01–0.13 ppm5 while the corresponding differences in chemical
shift for the trans-alkylation products lie in the range of 0.20–
2442
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b207457p

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mechanism, the addition of acetic anhydride to the solution of
oxygenated enolate at Ϫ78 ЊC gave a 10 : 2 : 1 mixture of trione
10 and alcohols 7 and 8. Isolation of 10 from this mixture was
hampered by the co-elution of trans-alcohol 7 and trione 10
upon chromatography (Scheme 3).
Scheme 2 Reagents and conditions: (i) O2, Ϫ78 ЊC, THF; (ii) Ac2O,
pyridine, DMAP.
0.31 ppm.4 This chemical shift difference probably arises from a
preferred conformation of the trans compounds in which one
diastereotopic isopropyl methyl group lies beneath the diketo-
piperazine ring, minimising steric interaction with the adjacent
N 4-p-methoxybenzyl group, a conformation that is disfavoured
for the cis configured compounds. This conformation for the
trans diastereoisomers has consistently been observed in the
solid state11 and is also supported in solution by a generally
small 3-H–CH(CH3)2 coupling (J3-H 2.5–4.5 Hz) for trans
configured compounds suggesting a conformation in which
CH(CH3)2 lies orthogonal to 3-H. In contrast 3-H of cis con-
figured compounds shows larger couplings to CH(CH3)2 (in the
range J3-H 7.2–8.9 Hz) consistent with the isopropyl proton
occupying a position beneath the ring. In accordance with these
observations the minor diastereoisomer (3S,6S )-8 exhibits an
isopropyl chemical shift difference typical of a cis configured
diketopiperazine (∆δMe 0.11 ppm) while the 1H NMR spectrum
of (3R,6S )-alcohol 7 was consistent with a trans configuration
(∆δMe 0.24 ppm). Acetates 5 and 6 also exhibited typical diag-
nostic 1H NMR isopropyl chemical shifts {trans-(3R,6S)-5,
∆δMe = 0.32 ppm; cis-(3S,6S)-6, ∆δMe = 0.11 ppm}. Finally, the
spectroscopic model employed for the assignment of the rela-
tive stereochemistry of these compounds was unambiguously
verified by X-ray crystallographic analysis of trans-(3R,6S )-5
(Fig. 1).
Scheme 3 Reagents and conditions: (i) O2, THF, Ϫ78 ЊC; (ii) Ac2O,
Ϫ78 ЊC–room temperature.
A pure sample of trione 10 was obtained, however, from the
oxidation of a mixture of 7 and 8 with o-iodoxybenzoic acid
(IBX) in DMSO, which provided 10 in 80% isolated yield after
chromatography. Examination of the course of the reaction
indicated that the trans-alcohol 7 was oxidised more rapidly
than the cis-alcohol 8. Considering the established mechanism
of IBX oxidation, this result is consistent with a faster rate
determining decomposition of the hypervalent iodine complex
derived from the trans-alcohol 7, which must be thermo-
dynamically less stable than the corresponding cis complex
derived from 8.13 The stereo- and regioselective reduction of
trione 10 with diisobutylaluminium hydride provided a 1 : 4
mixture of alcohols trans-7 and cis-8, from which 8 was isolated
in 69% yield via chromatography (Scheme 4).
Scheme 4 Reagents and conditions: (i) IBX (3 equivalents), DMSO; (ii)
diisobutylaluminium hydride, THF, Ϫ78 ЊC.
Due to the potential hazards associated with oxygen saturated
THF, larger scale oxidation of enolate 3 was achieved via treat-
ment with a hypervalent iodine reagent.14 Although treatment
of lithium enolate 3 with (diacetoxyiodo)benzene was not
successful, the addition of (diacetoxy)iodobenzene to the tri-
methylsilyl enol ether 11, prepared in situ from 3, followed by
aqueous work up provided a 2 : 1 mixture of alcohols 7 and 8.
Furthermore, a 2 : 1 mixture of acetates 5 and 6 could most
efficiently be accessed in good combined yield (74%) by the
addition of sodium acetate prior to aqueous work up, from
Fig. 1 Chem3D representation of X-ray crystal structure of (3R,6S )-
acetate 5.
The reaction of enolate 3 with molecular oxygen may pro-
ceed via an intermediate peroxide anion 9,12 which furnishes
alcohols 7 and 8 upon aqueous work up. In support of this
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448
2443

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which diastereoisomerically pure samples of 5 and 6 could be
obtained by column chromatography (Scheme 5).
Scheme 7 Reagents and conditions: (i) LHMDS, THF, Ϫ78 ЊC; CH2᎐᎐
CHCH2Br; (ii) 2 × CH2᎐᎐CHMgCl, CuCN, BF3ؒOEt2, THF, Ϫ78 ЊC;
NH4Cl (aq).
Scheme 5 Reagents and conditions: (i) TMSCl, 30 min, THF, Ϫ78 ЊC;
(ii) PhI(OAc)2 THF, Ϫ78 ЊC; (iii) H2O, room temperature; (iv) NaOAc,
room temperature.
The suitability of acetates 5 and 6 to act as glycine cation
equivalents was next examined. Treatment of a 1 : 1 mixture of
trans-acetate 5 and cis-acetate 6 with allyltrimethylsilane and
BF3ؒOEt2 in CH2Cl2 at Ϫ78 ЊC afforded a clean mixture of
(3S,6R)-12 and (3S,6S )-13, in a 4 : 1 ratio, that were separated
in good yield via chromatography (64% and 8% respectively)
(Scheme 6).
Scheme 8 Reagents and conditions: (i) CH2᎐᎐CHCH2SiMe3, BF3ؒOEt2,
CH2Cl2, Ϫ78 ЊC.
The facial selectivity of this addition is markedly lower
(60% de) than that observed for alkylation of enolate 3 with
allylbromide (94% de) and for the protonation of conjugate
addition intermediates (>95% de). In these systems a chiral
relay mechanism, resulting from the conformational preference
of the N-p-methoxybenzyl protecting groups, is operating4–6
and molecular modelling suggests a similar conformation and
chiral relay for N-acyliminium intermediate 14 and trione 10.15
If the reaction of 14, 3 and 10 occurs on a trajectory
perpendicular to the plane of the diketopiperazine ring then
similar selectivities in the reaction of each of the species would
be expected. However, the steric interactions encountered on
the Re and Si faces of the auxiliary will vary considerably if the
reaction of species 14, 3 and 10 occur via trajectories close to
the Bürgi–Dunitz angle.16 The observed variation in selectivity
may then derive from the different directions of reagent
approach due to the inherent structural differences between
N-acyliminium ion 14, enolate 3 and trione 10 (Fig. 2).
Scheme 6 Reagents and conditions: (i) CH2᎐᎐CHCH2SiMe3, BF3ؒOEt2,
CH2Cl2, Ϫ78 ЊC.
The relative configurations within trans-(3S,6R)-12 and cis-
(3S,6S )-13 were evident from 1H NMR spectroscopic data with
both compounds exhibiting diagnostic isopropyl methyl group
chemical shift differences (trans-(3S,6R)-12 ∆δMe = 0.26 ppm;
cis-(3S,6S)-13 ∆δMe = 0.08 ppm). The major isomer (3S,6R)-12
was confirmed unambiguously as trans by comparison with an
authentic sample prepared from the stereoselective alkylation
of the enolate of 1 with allyl bromide.4 The identity of the
minor diastereoisomer (3S,6S )-13 was confirmed unambigu-
ously via comparison with the product obtained from vinyl
cuprate addition to α,β-unsaturated acceptor 2, a procedure
which exclusively provides cis configured diketopiperazines
(Scheme 7).5
In order to establish whether an N-acyliminium species was
an intermediate in this transformation, diastereoisomerically
pure trans-acetate 5 was treated with allyltrimethylsilane and
BF3ؒOEt2 to afford a clean 4 : 1 mixture of (3S,6R)-12 and
(3S,6S )-13. Similar treatment of diastereoisomerically pure
cis-acetate 6, also afforded a 4 : 1 mixture of (3S,6R)-12
and (3S,6S )-13 (Scheme 8). The formation of the same ratio
of 12 and 13 from either 5 or 6 or a 1 : 1 mixture thereof in
these reactions is consistent with the initial formation of an
N-acyliminium ion 14. This species then reacts with allyl-
trimethylsilane by preferential addition to the Re face of
N-acyliminium species 14, anti to the C-3 isopropyl group.
Fig. 2 Directions of reagent approach to reactive species 14, 3 and 10.
Thus, the reaction of the N-acyliminium ion 14 with allyl-
trimethylsilane preferentially occurs on the Re face of the
auxiliary (60% de), as seen for the alkylation of enolate 3
2444
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448

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(94% de). However, the required direction of approach of
allyltrimethylsilane to N-acyliminium species 14 results in less
effective blocking of the Si face by the N 1-p-methoxybenzyl
and C-3 isopropyl groups (Fig. 3, A) in comparison to the
Fig. 4 Trajectories of approach to minimised molecular model: C;
trione 10.15
Fig. 3 Trajectories of approach to minimised molecular models: A;
14 and B; 3.15
was distilled under an atmosphere of dry nitrogen from sodium
benzophenone ketyl. All other solvents were used as supplied
(Analytical or HPLC grade), without prior purification. Thin
layer chromatography was performed on aluminium sheets
coated with 60 F254 silica. Sheets were visualised using 10%
phosphomolybdic acid in ethanol. Flash chromatography was
performed on Kieselgel 60 silica. Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker AC 200 (1H: 200
MHz and 13C: 50.3 MHz), Bruker DPX 400 (1H: 400 MHz and
13C: 100.6 MHz) or Bruker AMX 500 (1H: 500 MHz and 13C:
125 MHz) spectrometer in the deuterated solvent stated. All
chemical shifts (δ) are quoted in ppm and coupling constants
(J) in Hz. Coupling constants are quoted twice, each being
recorded as observed in the spectrum without averaging.
Residual signals from the solvents were used as an internal
reference. 13C multiplicities were assigned using a DEPT
sequence. Infrared spectra were recorded on a Perkin-Elmer
1750 IR Fourier Transform spectrophotometer using either
thin films on NaCl plates (film) or KBr discs (KBr) as stated.
Only the characteristic peaks are quoted in cmϪ1. Optical
rotations were recorded on a Perkin-Elmer 241 polarimeter
with a path length of 1 dm; [α]D values are given in units of
10Ϫ1 deg cm2 gϪ1. Concentrations are quoted in g/100 ml. Low
resolution mass spectra were obtained upon a VG micromass
ZAB IF, a VG MassLab 20–250, a VG Bio Q or an APCI
Platform spectrometer with only molecular ions, fragments
from molecular ions and major peaks being reported.
High resolution mass spectroscopic data was obtained upon
Micromass AutoSpec or Micromass ToFSpec spectrometers.
Elemental analyses were performed by the microanalysis
service of the Inorganic Chemistry Laboratory, University of
Oxford.
approach of an electrophile to the Si face of enolate 3 from
the alternative direction, resulting in lower diastereoselectivity
(Fig. 3, B). Alternatively, it cannot be discounted that the N-
acyliminium–allyltrimethylsilane system may also be inherently
more reactive than the corresponding enolate alkylation reac-
tion and hence exhibit poorer selectivity.
Similarly, the reduction of trione 10 with diisobutylalu-
minium hydride proceeds with Re face selectivity to afford a
1 : 4 mixture of alcohols trans-7 and cis-8. In this system the
direction of approach to the carbonyl group, over the diketo-
piperazine ring, leads to preferred addition to the Re face due to
hindrance of the Si-face by the isopropyl group. The moderate
levels of diastereoselectivity observed in this system may reflect
a competing steric interaction with the N 4-protecting group on
the Re face (Fig. 4, C).
Conclusion
We have exploited the ready oxidation of the enolate of diketo-
piperazine 1 in the preparation of N-acyliminium ion pre-
cursors 5 and 6. The addition of allyltrimethylsilane, under
Lewis acidic conditions, to 5 and 6 proceeds with Re facial
selectivity, consistent with the intermediacy of an N-acyl-
iminium species.
Experimental
General experimental
All reactions involving organometallic or moisture sensitive
reagents were performed under an atmosphere of nitrogen via
standard vacuum line techniques. All glassware was flame-dried
and allowed to cool under vacuum. In all cases, the reaction
diastereoselectivity was assessed by peak integration in the H
NMR spectrum of the crude reaction mixture. Tetrahydrofuran
Note. CAUTION: Explosion Hazard. Reactions involving
molecular oxygen in THF were performed with glassware and
magnetic stirrers that had been sequentially rinsed with concen-
trated HCl, distilled water and acetone, then oven dried and
cooled under vacuum. Reactions were performed behind a blast
shield.
1
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448
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(3S,6S )- and (3S,6R)-N,NЈ-Bis(p-methoxybenzyl)-6-hydroxy-3-
isopropylpiperazine-2,5-dione 7 and 8
161.7, 164.9, 169.5; m/z (APCIϩ) 455 (MHϩ, 0.2%), 395 (Mϩ Ϫ
OAc, 70), 121 (100).
CAUTION: Explosion Hazard: see Note in General experi-
mental section.
X-Ray crystal structure data for 5. Data were collected using
a Nonius Kappa CCD diffractometer with graphite mono-
chromated Mo-Kα radiation using standard procedures at
190 K. The structure was solved by direct methods (Sir92), all
non-hydrogen atoms were refined with anisotropic thermal
parameters. Hydrogen atoms were added at idealised positions.
The structure was refined using CRYSTALS.17
Crystal data for 5 [C25H30N2O6], colourless block, M =
454.52, orthorhombic, space group P212121, a = 7.4482(1) Å,
b = 10.8159(2) Å, c = 29.5153(4) Å, U = 2377.7 Å3, Z = 4, µ =
0.091, crystal dimensions 0.4 × 0.4 × 0.4 mm. A total of 3044
unique reflections were measured for 4.55 < θ < 27.50 and 2646
reflections were used in the refinement. The final parameters
were wR2 = 0.0201 and R1 = 0.0325 [I > 3σ(I)].
To a solution of (3S )-N,NЈ-bis(p-methoxybenzyl)-3-iso-
propylpiperazine-2,5-dione 1 (1.00 g, 2.52 mmol) in dry THF
(40 ml) at Ϫ78 ЊC was added lithium hexamethyldisilazide
(3.0 ml, 1 M solution in THF, 3.0 mmol). After stirring (1 h
at Ϫ78 ЊC) the mixture was purged with a stream of oxygen
for 15 min at Ϫ78 ЊC and then stirred for a further 30 min.
Saturated aqueous sodium metabisulfite (3 ml) was added
followed by saturated NH4Cl (10 ml) then the THF was
removed in vacuo and the residue partitioned between water
and ether. The aqueous phase was extracted with ether and the
combined organic layers were dried (MgSO4) and the solvent
removed to afford a 2 : 1 mixture of 7 and 8 respectively.
Chromatography (silica, 1 : 1 ether–hexane) gave trans-alcohol
7 (383 mg, 37%). Mp 112–114 ЊC (ether) (Found: C, 66.9;
H, 7.0; N, 6.6. C23H28N2O5 requires C, 67.0; H, 6.8; N, 6.8%);
[α]2D3 ϩ9.6 (c 0.35, CHCl3); νmax (film)/cmϪ1 3281 (OH), 1659
CCDC reference number 187479. See http://www.rsc.org/
suppdata/p1/b2/b207457p/ for crystallographic files in .cif or
other electronic format.
(NC᎐O), 1635; δ (500 MHz, CDCl3) 0.80 (3H, d, J 6.9,
᎐
H
(6S,3S )-N,NЈ-Bis(p-methoxybenzyl)-3-acetoxy-6-isopropyl-
piperazine-2,5-dione 6
CH3CHCH3), 1.04 (3H, d, J 6.9, CH3CHCH3), 2.14 (1H, dsept,
J 6.9, 5.2, CH3CHCH3), 3.75 (1H, d, J 5.2, 3-H), 3.80 (6H, s,
2 × OMe), 3.93 (1H, d, J 14.7, ArCH2), 4.27 (1H, d, J 13.9,
ArCH2), 4.55 (1H, br s, OH), 5.06 (1H, s, CHOH), 5.18 (1H,
d, J 13.9, ArCH2), 5.33 (1H, d, J 14.7, ArCH2), 6.84–6.87 (4H,
m, ortho-H ArOMe), 7.14 (2H, m, aromatic H), 7.37 (2H, m,
aromatic H); δC(125 MHz, CDCl3) 18.0, 19.8, 32.1, 43.9, 48.5,
55.2, 55.3, 64.9, 74.0, 113.8, 114.4, 126.8, 128.2, 129.5, 130.7,
159.1, 159.5, 164.6, 167.0; m/z (APCIϩ) 413 (MHϩ, 2%), 395
(MHϩ Ϫ H2O, 12), 121 (100).
To alcohol 8 (100 mg, 0.24 mmol) in pyridine (3 ml) was added
DMAP (10 mg, 0.08 mmol) followed by acetic anhydride (2 ml).
The mixture was stirred for 12 h at room temperature then
partitioned between ether saturated aqueous CuSO4 and the
organic layer washed with saturated aqueous CuSO4, dried
(MgSO4), and the solvent removed in vacuo. Chromatography
(silica, 1 : 1 ether–hexane) gave 6 as a colourless oil (91 mg,
83%). [α]2D3 Ϫ139.4 (c 1.20, CHCl3); νmax(film)/cmϪ1 2964, 2837,
Further elution provided cis-alcohol 8 as a colourless solid
(256 mg, 25%). Mp 126–127 ЊC (ether); [α]2D3 Ϫ172.3 (c 0.30,
CHCl3); νmax(film)/cmϪ1 3204 (OH), 1658 (NC᎐O), 1636; δ (500
1757 (CH C᎐O), 1681(NC᎐O), 1612, 1585, 1248, 1216; δ (400
᎐ ᎐
3 H
MHz, CDCl3) 1.06 (3H, d, J 6.8, CH3CHCH3), 1.17 (3H, d,
J 6.9, CH CHCH ), 2.00 (3H, s, CH C᎐O), 2.33 (1H, m,
᎐
᎐
H
3
3
3
MHz, CDCl3) 1.04 (3H, d, J 6.9, CH3CHCH3), 1.15 (3H, d,
J 6.9, CH3CHCH3), 2.34 (1H, dsept, J 6.9, 5.1, CH3CHCH3),
3.74 (1H, d, J 5.1, 3-H), 3.79 (3H, s, OMe), 3.81 (3H, s, OMe),
3.91 (1H, d, J 14.8, ArCH2), 4.29 (1H, d, J 14.5, ArCH2), 4.61
(1H, d, J 4.4, OH), 4.98 (1H, d, J 14.5, ArCH2), 5.12 (1H, d,
J 4.4, CHOH), 5.30 (1H, d, J 14.8, ArCH2), 6.82–6.86 (4H, m,
ortho-H ArOMe), 7.12–7.21 (4H, m, aromatic H); δC(125 MHz,
CDCl3) 18.1, 20.3, 31.9, 46.2, 48.0, 55.2, 55.3, 64.5, 77.5, 114.1,
114.3, 127.0, 127.8, 129.6, 130.1, 159.3, 159.4, 165.6, 166.0;
m/z (APCIϩ) 413 (MHϩ, 1%), 395 (MHϩ Ϫ H2O, 12), 121
CH3CHCH3), 3.72 (1H, d, J 6.2, 3-H), 3.80 (3H, s, OMe), 3.81
(3H, s, OMe), 3.83 (1H, d, J 14.8, ArCH2), 4.30 (1H, d, J 14.5,
ArCH2), 4.77 (1H, d, J 14.5, ArCH2), 5.34 (1H, d, J 14.8,
ArCH2), 6.46 (1H, s, CHOAc), 6.81–6.86 (4H, m, ortho-H
ArOMe), 7.06–7.21 (4H, m, aromatic H); δC(50 MHz, CDCl3)
18.6, 20.4, 20.7, 32.4, 47.4, 48.3, 55.2 (× 2), 64.6, 76.9, 114.0,
114.3, 126.9, 128.0, 129.5, 129.8, 159.3, 159.4, 161.4, 167.1,
169.6; m/z (APCIϩ) 455 (MHϩ, 0.3%), 395 (Mϩ Ϫ OAc, 85), 121
(100) [HRMS (TOF FI) Found: Mϩ, 454.2115. C25H30N2O6
requires 454.2104].
ϩ
(100) [HRMS (CIϩ) Found: 413.2076. C23H29N2O5 requires
413.2076].
Oxidation of 1 with (diacetoxyiodo)benzene
To a solution of 1 (5.0 g, 12.6 mmol) in dry THF (100 ml)
was added lithium hexamethyldisilazide (13.9 ml, 1 M solution
in THF, 13.9 mmol) at Ϫ78 ЊC. After stirring (1 h at Ϫ78 ЊC)
this mixture was treated with chlorotrimethylsilane (1.75 ml,
13.9 mmol) and the mixture stirred for 30 min at Ϫ78 ЊC before
(diacetoxyiodo)benzene (4.47 g, 13.9 mmol) was added. This
mixture was stirred (2 h, Ϫ78 ЊC) then sodium acetate (2.0 g,
33.4 mmol) was added and the mixture stirred (3 h, Ϫ78 ЊC)
then warmed to room temperature over 12 h. Saturated NH4Cl
(50 ml) and water (500 ml) was added and the mixture extracted
with ether, the organic layer was dried (MgSO4) and the solvent
removed to afford a 2 : 1 mixture of trans- and cis- acetates 5
and 6 respectively. Chromatography (silica, ether–hexane 1 : 1)
gave cis- acetate 6 as a colourless oil (0.96 g, 17%). Further
elution provided mixed fractions of 5 and 6 (2.85 g, 50%)
followed by trans-acetate 5 as a colourless solid (0.51 g, 9%).
Spectroscopic properties were identical to those described
above.
(6S,3R)-N,NЈ-Bis(p-methoxybenzyl)-3-acetoxy-6-isopropyl-
piperazine-2,5-dione 5
To alcohol 7 (100 mg, 0.24 mmol) in pyridine (3 ml) was added
DMAP (10 mg, 0.08 mmol) then acetic anhydride (2 ml). The
mixture was stirred for 12 h then partitioned between ether and
saturated aqueous CuSO4 and the organic layer washed with
saturated aqueous CuSO4, dried (MgSO4), and the solvent
removed in vacuo. Chromatography (silica, 1 : 1 ether–hexane)
gave 5 as a colourless solid (97 mg, 88%). Mp 148 ЊC (ether)
(Found: C, 66.1; H, 6.7; N, 6.1. C25H30N2O4 requires C, 66.1; H,
6.7; N, 6.2%); [α]2D3 Ϫ125.5 (c 1.00, CHCl3); νmax(KBr)/cmϪ1
2962, 2834, 1750 (CH C᎐O), 1678 (NC᎐O), 1615; δ (400 MHz,
᎐
᎐
3
H
C6D6) 0.62 (3H, d, J 6.9, CH3CHCH3), 1.14 (3H, d, J 7.0,
CH3CHCH3), 1.75 (3H, s, CH C᎐O), 2.04 (1H, m,
᎐
3
CH3CHCH3), 3.34 (6H, s, 2 × OMe), 3.80 (1H, d, J 14.9,
ArCH2), 3.99 (1H, d, J 3.4, 3-H), 4.14 (1H, d, J 14.4, ArCH2),
5.06 (1H, d, J 14.4, ArCH2), 5.32 (1H, d, J 14.9, ArCH2), 6.51
(1H, s, CHOAc), 6.75–6.83 (4H, m, ortho-H ArOMe), 7.17–
7.21 (2H, m, aromatic H), 7.41–7.45 (2H, m, aromatic H); δC(50
MHz, CDCl3) 16.2, 19.5, 20.7, 31.4, 45.8, 46.7, 55.2, 55.3, 63.0,
76.2, 113.9, 114.3, 126.7, 127.4, 129.7, 130.3, 159.3, 159.4,
Similar treatment of 1 (200 mg) with lithium hexamethyl-
disilazide (0.60 ml, 1 M solution in THF), chlorotrimethylsilane
(0.10 ml), (diacetoxyiodo)benzene (177 mg) omitting the
addition of sodium acetate afforded a 2 : 1 mixture of trans-
and cis-alcohols 7 and 8 respectively (166 mg, 83%).
2446
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448

View Article Online
(5S )-N,NЈ-Bis(p-methoxybenzyl)-5-isopropylpiperazine-2,3,6-
trione 10
CH3CHCH3), 2.31 (1H, m, CH3CHCH3), 2.78 (1H, dt, J 12.5,
6.0, CH CH᎐CH ), 2.97 (1H, ddt, J 15.0, 7.0 and 1.0, CH CH᎐
᎐
᎐
2
2
2
CH2), 3.78 (1H, d, J 4.0, 3-H), 3.80 (1H, d, J 15.5, ArCH2),
3.81 (3H, s, OMe), 3.81 (3H, s, OMe), 3.81 (1H, d, J 14.5,
ArCH2), 3.99 (1H, dd, J 5.0, 2.5, 6-H), 5.12 (1H, d, J 10.5,
Alcohols 7 and 8 (1 : 4 mixture of 7 and 8, 200 mg, 0.48 mmol)
and o-iodoxybenzoic acid (630 mg, 2.25 mmol)18 were stirred in
DMSO (3 ml) for 48 h at room temperature. The mixture was
then partitioned between ether (50 ml) and water (50 ml) and
the aqueous phase extracted with ether. The combined organic
layers were dried (MgSO4), filtered and concentrated in vacuo
to yield the crude product. Purification by flash column
chromatography (silica, 1 : 1 ether–hexane) yielded trione 10 as
a colourless solid (165 mg, 83%). Mp 116 ЊC; [α]2D3 Ϫ108.9
(c 0.63, CHCl3); νmax(KBr)/cmϪ1 2969, 1735 (CH C᎐O), 1675
CH CH᎐CH ), 5.19 (1H, dd, J 17, 1.5, CH CH᎐CH ), 5.41
᎐
᎐
2
2
2
2
(1H, d, J 14.5, ArCH2), 5.53 (1H, d, J 15.0, ArCH2), 5.54 (1H,
m, CH CH᎐CH ), 6.85 (2H, m, aromatic H), 6.87 (2H, m,
᎐
2
2
aromatic H), 7.16 (2H, m, aromatic H), 7.23 (2H, m, aromatic
H). Spectroscopic data identical to that of an authentic
sample.4
Further elution provided cis-allyl isomer 13 as a clear oil
(82 mg, 8%). [α]2D3 Ϫ137.8 (c 1.00, CHCl3); νmax(KBr)/cmϪ1 1660
᎐
3
(NC᎐O), 1514, 1241; δ (400 MHz, CDCl ) 0.60 (3H, d, J 7.0,
᎐
H
3
(NC᎐O), 1513, 1248; δ (500 MHz, CDCl ) 1.09 (3H, d, J 6.8,
᎐
H
3
CH3CHCH3), 0.96 (3H, d, J 7.0, CH3CHCH3), 2.22 (1H, m,
CH3CHCH3), 3.78 (3H, s, OMe), 3.80 (3H, s, OMe), 3.97 (1H,
d, J 3.6, 3-H), 3.99 (1H, d, J 13.5, ArCH2), 4.87 (1H, d, J 13.5,
ArCH2), 4.92 (1H, d, J 13.5, ArCH2), 5.35 (1H, d, J 14.7,
ArCH2), 6.79–7.41 (8H, m, aromatic H); δC(100 MHz, CDCl3)
15.9, 18.6, 31.9, 43.6, 47.9, 55.2, 55.3, 64.5, 113.7, 114.5, 126.2,
127.4, 130.1, 131.3, 153.5, 157.2, 159.4, 159.7, 166.8; m/z
(APCIϩ) 411 (MHϩ, 10%), 121 (ArCH2ϩ, 100%) [HRMS (CIϩ)
Found: MHϩ, 411.1908. C23H27N2O5ϩ requires 411.1920].
CH3CHCH3), 1.17 (3H, d, J 6.9, CH3CHCH3), 2.19 (1H, dsept,
J 6.9, 6.9, CH CHCH ), 2.56–2.65 (1H, m, CH CH᎐CH ),
᎐
3
3
2
2
2.70–2.78 (1H, m, CH CH᎐CH ), 3.67 (1H, d, J 7.0, 3-H), 3.79
᎐
2
2
(3H, s, OMe), 3.79 (3H, s, OMe), 3.83 (1H, d, J 14.8, ArCH2),
3.93 (1H, d, J 14.8, ArCH2), 3.96 (1H, t, J 6.6, 6-H), 5.15 (1H,
br t, J 1.2, CH CH᎐CH ), 5.13–5.20 (1H, m, CH CH᎐CH ),
᎐
᎐
2
2
2
2
5.22 (1H, d, 14.8, ArCH2), 5.35 (1H, d, J 14.8, ArCH2), 5.87–
5.97 (1H, m, CH CHC᎐CH ), 6.80–6.85 (4H, m, ortho-H
᎐
2
2
ArOMe), 7.03–7.10 (4H, m, aromatic H); δC(125MHz, CDCl3)
19.2, 20.4, 32.8, 38.5, 46.8, 48.5, 54.9 (× 2), 58.9, 64.7, 113.9,
118.0, 127.5, 127.6, 128.9, 129.1, 133.8, 158.9, 165.5, 166.4;
m/z (CI) 437 (MHϩ, 100%) [HRMS (CIϩ) Found: MHϩ,
437.2443. C26H33N2O4 requires 437.2440].
Preparation of trione 10 via O2 oxidation of 1
CAUTION: Explosion Hazard: see Note in General experi-
mental section.
Lithium hexamethyldisilazide (0.55 ml, 1 M in THF, 0.55
mmol) was added to 1 (200 mg, 0.50 mmol) in dry THF (10 ml)
at Ϫ78 ЊC. After stirring for 1 h at Ϫ78 ЊC the solution was
placed under an atmosphere of oxygen and stirred (2 h, Ϫ78 ЊC)
before addition of acetic anhydride (0.20 ml, 1.81 mmol). The
mixture was left to warm to room temperature overnight, before
addition of sodium metabisulfite (500 mg) in water (5 ml). The
mixture was partitioned between ether (50 ml) and water (50 ml)
and the aqueous phase extracted with ether. The combined
organic layers were dried (MgSO4), filtered and concentrated
in vacuo to yield a mixture containing 10, 7 and 8 in a ratio of
10 : 2 : 1 respectively (212 mg). Chromatography (silica, 4 : 1
ether–hexane) provided 10 contaminated with 7 (ca. 20%, 118
mg).
Treatment of either pure trans-acetate 5 or pure cis-acetate 6
under the same conditions gave similar crude mixtures with 1H
NMR spectra showing a 4 : 1 ratio of trans to cis allyl products
12 and 13 (60% de).
Preparation of 13 via cuprate addition
To a flame dried Schlenk tube charged with anhydrous
copper() cyanide (267 mg, 2.94 mmol) and anhydrous THF
(20 mL) at Ϫ78 ЊC under a nitrogen atmosphere was added
vinylmagnesium bromide (5.88 ml, 1 M in THF). The suspen-
sion was allowed to stir at Ϫ78 ЊC for 5 min prior to the removal
of the cooling bath and the mixture was allowed to slowly warm
to ca. Ϫ20 ЊC by which time it had become homogeneous. This
mixture was then recooled to Ϫ78 ЊC and BF3ؒOEt2 (0.24 ml,
2.45 mmol) was added and the reaction stirred for 10 minutes at
Ϫ78 ЊC. Acceptor 25 (1.00 g, 2.45 mmol) in THF (2 ml) was
added, the reaction stirred for 2 h at Ϫ78 ЊC then allowed to
warm to room temperature over 4 h. Saturated aqueous NH4Cl
was added and the mixture partitioned between water and
ether, the aqueous phase extracted with ethyl acetate and the
combined organic phases were washed with water, dried
(MgSO4), and the solvents removed in vacuo. Analysis of the
1H NMR spectrum of the crude reaction mixture indicated a
de > 95%. Chromatography (silica, 1 : 5 ethyl acetate–hexane)
afforded cis-allyl isomer 13 as an oil (929 mg, 87%). Spectro-
scopic properties were identical to those described above.
DIBAL-H reduction of trione 10
DIBAL-H (0.27 ml, 1 M solution in THF, 0.27 mmol) was
added to trione 10 (100 mg, 0.24 mmol) in THF at Ϫ78 ЊC. The
mixture was stirred for 4 h at Ϫ78 ЊC and then allowed to warm
to room temperature over 12 h. Saturated aqueous NH4Cl
(1 ml) and water (50 ml) were added and the mixture extracted
with ether. The organic layer was dried (MgSO4) and the
solvent removed to afford a mixture containing cis- and trans-
alcohols 7 and 8 in a ratio of 4 : 1. Chromatography (silica,
1 : 1 ether–hexane) gave cis-alcohol 6 as a colourless oil
(69 mg, 69%). Spectroscopic properties were identical to those
described above.
Acknowledgements
(3S,6S )- and (3S,6R)-N,NЈ-Bis(p-methoxybenzyl)-6-allyl-3-
isopropylpiperazine-2,5-dione 12 and 13
We would like to thank the EPSRC for a ROPA award (ACG,
MDOЈS).
To a mixture of cis- and trans-acetates 5 and 6 (1 : 1, 1.0 g, 2.20
mmol) and allylsilane (0.38 ml, 2.4 mmol) in dichloromethane
was added boron trifluoride–diethyl ether (0.30 ml, 2.4 mmol)
and the mixture stirred for 4 h at Ϫ78 ЊC. Saturated aqueous
NH4Cl was added and the mixture extracted with ether, the
organic phase dried (MgSO4) and the solvent removed to pro-
vide a gum. 1H NMR spectra of the crude material indicated a
4 : 1 mixture of trans to cis allyl products 12 and 13 (60% de).
Chromatography (silica, 1 : 1 ether–hexane) gave trans-allyl
isomer 12 as a colourless solid (613 mg, 64%). [α]2D3 ϩ23.6
(c 1.00, CHCl3) (lit.4 [α]2D3 ϩ25.8 (c 0.99, CHCl3)); δH(400 MHz,
CDCl3) 0.84 (3H, d, J 7.0, CH3CHCH3), 1.10 (3H, d, J 7.0,
Notes and References
1 For reviews of asymmetric synthesis of α-amino acids see: (a) R. M.
Williams, Synthesis of Optically Active α-amino acids, Pergamon
Press, Oxford, 1989; (b) R. O. Duthaler, Tetrahedron, 1994, 50,
1540; (c) C. Cativiela and M. D. Diaz-De-Villegas, Tetrahedron:
Asymmetry, 2000, 11, 645; (d ) C. Cativiela and M. D. Diaz-De-
Villegas, Tetrahedron: Asymmetry, 1998, 9 3517; . For examples of
chiral glycine enolate equivalents in synthesis see: (e) U. Schöllkopf,
Topics in Current Chemistry, ed. F. L. Boscke, Springer, Berlin, 1983,
vol. 109, p. 65; ( f ) Y. N. Belokan, Pure Appl. Chem., 1992, 64, 1917;
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448
2447

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(g) R. M. Williams, Aldrichimica Acta, 1992, 25, 11; (h) A. G. Myers,
J. L. Gleason and T. Y. Yoon, J. Am. Chem. Soc., 1995, 117, 8488;
(i) D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int.
Ed. Engl., 1996, 35, 2708; (j) W. Oppolzer, R. Moretti and S. Thomi,
Tetrahedron Lett., 1989, 30, 6009; (k) R. M. Williams and M. N. Im,
J. Am. Chem. Soc., 1991, 113, 9276; (l ) D. A. Evans and A. E. Weber,
J. Am. Chem. Soc., 1986, 108, 6757.
2 For a recent review of α-amino acid cation equivalents, see:
(a) P. D. Bailey, J. Clayson and A. N. Boa, Contemp. Org. Synth.,
1995, 2, 173; (b) for a more recent example, see M. J. OЈDonnell,
N. Chen, C. Zhou, A. Murray, C. P. Kubiak, F. Yang and
G. G. Stanley, J. Org. Chem., 1997, 62, 3962.
3 For examples of chiral glycine cation equivalents employed in the
asymmetric synthesis of α-amino acids, see: (a) U. Schöllkopf,
H.-J. Neubauer and M. Hauptrief, Angew. Chem., Int. Ed. Engl.,
1985, 24, 1066; (b) U. Schöllkopf, S. Grüttner, R. Anderskewitz,
E. Egert and M. Dyrbusch, Angew. Chem., Int. Ed. Engl., 1985, 26,
683; (c) C. P. Schickli and D. Seebach, Liebigs Ann. Chem., 1991,
655; (d ) R. M. Williams and J. A. Hendrix, J. Org. Chem., 1990,
55, 3723; (e) D. Zhai, W. Zhai and R. M. Williams, J. Am. Chem.
Soc., 1988, 110, 2501; ( f ) P. J. Sinclair, D. Zhai, J. Reibenspies and
R. M. Williams, J. Am. Chem. Soc., 1986, 108, 1103; (g) Yu. N.
Belokon, A. N. Popkov, N. I. Chernoglazova, V. I. Bakhmutov,
M. B. Saporovskaya and V. M. Belikov, Izv. Akad. Nauk SSSR, Ser.
Khim., 1989, 1899 (in Russian CA 112:198996); (h) C. Agami,
F. Couty, J. F. Daran, B. Princ and C. Puchot, Tetrahedron
Lett., 1990, 31, 2889; (i) G. Kardassis, P. Brungs, C. Nothfelder and
E. Steckhan, Tetrahedron, 1998, 54, 3479 and references therein.
4 (a) S. D. Bull, S. G. Davies, S. W. Epstein and J. V. A. Ouzman,
Chem. Commun., 1998, 659; (b) S. D. Bull, S. G. Davies, S. W.
Epstein, M. A. Leech and J. V. A. Ouzman, J. Chem. Soc., Perkin
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N. Mujtaba, Synlett, 2001, 781.
Tetrahedron Lett., 1990, 31, 4949; (b) for a racemic example, see:
F. Lamaty, R. Lazaro and J. Martinez, Tetrahedron Lett., 1997, 38,
3385.
9 For a related racemic diketopiperazine acyliminium species in the
synthesis of Bicyclomycin, see: (a) R. M. Williams and C. A.
Durham, Chem. Rev., 1988, 88, 511; (b) R. M. Williams, R. W.
Armstrong and J.-S. Dung, J. Am. Chem. Soc., 1984, 106, 5748;
(c) R. M. Williams, R. W. Armstrong and J.-S. Dung, J. Am. Chem.
Soc., 1985, 107, 3253; (d ) R. M. Williams, J.-S. Dung, J. Josey,
R. W. Armstrong and H. Meyers, J. Am. Chem. Soc., 1983, 105,
3214; (e) for similar N-acyliminium species in the synthesis of
racemic unsymmetrical diketopiperazines. see: R. M. Williams,
R. W. Armstrong, L. K. Maruyama, J.-S. Dung and O. P. Anderson,
J. Am. Chem. Soc., 1985, 107, 3246.
10 For basic O2 oxidation of carbonyl compounds, see: A. B. Jones, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, Vol. 7, pp. 151–191 and references
therein; a related bridgehead carbanion oxidation with O2 has been
noted, see ref. 9b.
11 One diastereoisotopic isopropyl methyl group consistently lies
beneath the diketopiperazine ring in X-ray crystal structures of trans
configured N,NЈ-bis(p-methoxybenzyl)diketopiperazines while in
the X-ray crystal structures of cis configured compounds both
methyl groups lie outside the ring. See X-ray crystal structure of
acetate 5, references 4b, 4c and unpublished data.
12 (a) E. J. Bailey, D. H. R. Barton, J. Elks and J. F. Templeton,
J. Chem. Soc., 1962, 1578; (b) H. Suginome, Y. Kurokawa and
K. Orito, Bull. Chem. Soc. Jpn., 1988, 61, 4005.
13 S. De Munari, M. Frigerio and M. Santagostino, J. Org. Chem.,
1996, 61, 9272.
14 Violent explosions have been reported. R. M. Moriarty, H. Hu and
S. C. Gupta, Tetrahedron Lett., 1981, 22, 1283.
15 Modelling was performed using the Macromodel suite of programs.
1000 starting conformations of N-acyliminium ion 14 were
generated using a Monte Carlo simulation and minimised using an
MM2 force field.
5 (a) S. D. Bull, S. G. Davies and M. D. O’Shea, J. Chem. Soc., Perkin
Trans 1, 1998, 3657; (b) S. D. Bull, S. G. Davies, A. C. Garner and
M. D. OЈShea, J. Chem. Soc., Perkin Trans. 1, 2001, 3281.
6 S. D. Bull, S. G. Davies, D. J. Fox, A. C. Garner and T. G. R. Sellers,
Pure Appl. Chem., 1998, 70, 1501.
16 (a) H. B. Bürgi, J. D. Dunitz, J. M. Lehn and G. Wipff, Tetrahedron,
1974, 30, 1563; (b) H. B. Bürgi and J. D. Dunitz, Acc. Chem. Res.,
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17 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge and
R. I. Cooper, CRYSTALS, Chemical Crystallography Laboratory,
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7 For a review of N-acyliminium chemistry in synthesis, see: (a)
H. Hiemstra and W. N. Speckamp, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon, Oxford, 1991, Vol. 2, pp.1047–
1082; (b) W. N. Speckamp and M. J. Moolenaar, Tetrahedron, 2000,
56, 3817.
18 Prepared by the method of M. Frigerio, M. Santagostino and
S. Sputore, J. Org. Chem., 1999, 64, 4537.
8 (a) A. Bernardi, F. Micheli, D. Potenza, C. Scolastico and R. Villa,
2448
J. Chem. Soc., Perkin Trans. 1, 2002, 2442–2448