Asymmetric synthesis of substituted 1-aminocyclopropane1-carboxylic acids via diketopiperazine methodology

Article abstract of DOI:10.1039/b303348a

Diketopiperazinespirocyclopropane 12 is prepared in > 98% d.e. via the conjugate addition of a phosphorus ylide to (6S)-N, N′-bis(p-methoxybenzyl)-3-methylenepiperazine-2,5-dione 2. Deprotection and hydrolysis of adduct 12 and subsequent peptide coupling demonstrate the applicability of this methodology to the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids for incorporation into novel peptides. A model for the high level of diastereofacial selectivity observed in the cyclopropanation reaction is presented. A highly selective asymmetric approach (> 98% d.e.) to (S)-[2,2-²H ₂]-1-aminocyclopropane-l-carboxylic acid 29 is also reported via a deuterated sulfur ylide addition to acceptor 2.

Full text of DOI:10.1039/b303348a

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Asymmetric synthesis of substituted 1-aminocyclopropane-
1-carboxylic acids via diketopiperazine methodology
Elena Buñuel,a Steven D. Bull,a Stephen G. Davies,*a A. Christopher Garner,a
Edward D. Savory,a Andrew D. Smith,a Richard J. Vickersa and David J. Watkinb
a The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY
b Department of Chemical Crystallography, University of Oxford, Parks Road, Oxford,
UK OX1 3PD. E-mail: steve.davies@chem.ox.ac.uk
Received 4th April 2003, Accepted 2nd June 2003
First published as an Advance Article on the web 19th June 2003
Diketopiperazinespirocyclopropane 12 is prepared in > 98% d.e. via the conjugate addition of a phosphorus ylide
to (6S)-N,NЈ-bis(p-methoxybenzyl)-3-methylenepiperazine-2,5-dione 2. Deprotection and hydrolysis of adduct 12
and subsequent peptide coupling demonstrate the applicability of this methodology to the asymmetric synthesis
of 1-aminocyclopropane-1-carboxylic acids for incorporation into novel peptides. A model for the high level of
diastereofacial selectivity observed in the cyclopropanation reaction is presented. A highly selective asymmetric
approach (> 98% d.e.) to (S)-[2,2-2H2]-1-aminocyclopropane-1-carboxylic acid 29 is also reported via a deuterated
sulfur ylide addition to acceptor 2.
laboratory has delineated a diketopiperazine derived chiral
Introduction
relay auxiliary for the asymmetric synthesis of (R)-α-amino
acids, via the alkylation of lithium enolate 3, and the synthesis
of (S)-α-amino acids via conjugate addition of organocuprates
to the related dehydroalanine acceptor 2, followed by dia-
stereoselective protonation of the enolate 4 (Scheme 1).10
As part of the ongoing development of N-protected di-
ketopiperazine auxiliary methodology for the asymmetric
synthesis of quaternary α-amino acids, we report herein the
cyclopropanation of acceptor 2 for the synthesis of dipeptides
containing 1-aminocyclopropane-1-carboxylic acid residues.
The construction of peptides incorporating non-proteinogenic
α-amino acids, which restrict the conformational flexibility of
the peptide, is an active area of research. Three major classes
of residue have been identified as allowing subtle perturbations
of overall structure without wholly disrupting secondary struc-
tural features: α-methyl-α-amino acids, β-methyl-α-amino acids
and 1-aminocyclopropane-1-carboxylic acids.1,2 The amino-
cyclopropanecarboxylic acids are of particular interest due to
their potent biological activity,3 and the importance of the
parent 1-aminocyclopropane-1-carboxylic acid in the bio-
synthesis of ethylene, a significant plant hormone.4 The
asymmetric synthesis of these residues has been approached
in a number of ways,5 including the alkylation of glycine
enolate equivalents with 1,2-bis-electrophiles,6 cyclisation of
γ-functionalised α-amino acids, asymmetric ylide reactions,7
and diazoalkyl cycloaddition chemistry,8 in addition to a
number of resolution approaches.9 Previous work within this
Results and discussion
The synthesis of 1-aminocyclopropane-1-carboxylic acids has
been achieved previously via the elaboration of dehydro-amino
acid derived substrates, with the application of a sulfur or
phosphorus ylide conjugate addition–elimination protocol an
attractive method for the synthesis of cyclopropane rings from
Scheme 1 Reagents and conditions: (i) LHMDS, THF, Ϫ78 ЊC; (ii) alkyl halide, THF, Ϫ78 ЊC; (iii) CAN (6 equivalents), H2O, CH3CN; then 6 M
HCl, 100 ЊC; (iv) 2 × RMgX or 2 × RLi, CuCN, BF3ؒOEt2; THF, Ϫ78 ЊC; (v) NH4Claq.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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this class of substrate.11 To evaluate the suitability of this
methodology towards diketopiperazine auxiliary chemistry,
initial model studies focused on the addition of a simple
sulfur ylide, dimethylsulfoxonium methylide,12 to the methylene
acceptor 2. Treatment of trimethylsulfoxonium iodide with
butyllithium followed by the addition of acceptor 2 at room
temperature provided (6S)-N,NЈ-bis(p-methoxybenzyl)piper-
azine-2,5-dione-3-spiro-1-cyclopropane 5 in excellent yield
(90%) after chromatographic purification (Scheme 2).
Fig. 1 Selected 1H NOESY correlations for 12.
sion in the 1H NMR spectrum, however the assigned configur-
ation was unambiguously confirmed by single crystal X-ray
crystallographic analysis, with the absolute (3S,6S)-configur-
ation being derived from the known configuration of (S)-valine
(Fig. 2).
Scheme 2 Reagents and conditions: (i) Me2SOCH2Li, THF, room
temperature.
Having established the viability of this cyclopropanation
protocol, studies focused on the extension of this methodology
to the preparation of substituted cyclopropane rings. A number
of substituted sulfur ylides 6–1013 were assayed for reaction
with acceptor 2 but, in contrast to the trimethylsulfoxonium
derived ylide, no addition products could be detected. However,
treatment of 2 with the phosphonium derived ylide, isopropyl-
idenetriphenylphosphorane 11,14 generated in situ from butyl-
lithium and isopropyltriphenylphosphonium iodide, did afford
(3S,6S)-N,NЈ-bis(p-methoxybenzyl)-6-isopropylpiperazine-
2,5-dione-3-spiro-1,1-dimethylcyclopropane 12 in an excellent
isolated yield (93%). Only a single diastereoisomer could be
detected in the 1H NMR spectrum of the crude reaction
mixture (> 98% d.e.) demonstrating excellent diastereo-
selectivity for the overall cyclopropanation process (Scheme 3).
Fig. 2 Chem3D representation of X-ray crystal structure of 12.15
In order to demonstrate the effectiveness of this strategy for
the synthesis and incorporation of 1-aminocyclopropane-1-
carboxylic acids into linear peptides, the deprotection and
hydrolysis of diketopiperazine 12, and subsequent peptide
coupling of the resultant hindered 1-aminocyclopropane-1-
carboxylic acid was investigated. Treatment of 12 with refluxing
trifluoroacetic acid provided 13 in 87% yield, with hydrolysis
in 6 M HCl at 100 ЊC affording a mixture of α-amino acid
hydrochlorides 14 and 15 which were converted to the corre-
sponding methyl ester hydrochloride salts 16 and 17 in excellent
yield (97%) (Scheme 4).
An alternative route for the preparation of methyl ester
hydrochloride salts 16 and 17, avoiding the harsh amide
hydrolysis conditions, was also achieved through conversion of
13 to bis-lactim ether 18 (86% yield) by treatment with tri-
methyloxonium tetrafluoroborate in the ionic liquid, N-butyl-
NЈ-methylimidazolium tetrafluoroborate (BmimBF4).16 Mild
hydrolysis of bis-lactim ether 18 with 2 M HCl for two hours
at room temperature afforded a mixture of methyl ester hydro-
chloride salts 16 and 17 in high yield (91%) (Scheme 5).
Scheme 3 Reagents and conditions: (i) Me2C(Li)PPh3, THF, room
temperature.
Coupling of the mixture of (S)-valine and dimethyl substi-
tuted α-amino acid methyl esters 16 and 17 with (S)-N-Cbz-
phenylalanine afforded a separable mixture of dipeptides 19
and 20, which were isolated in excellent yield (94% and 87%
respectively) (Scheme 6). Both 19 and 20 were obtained as single
diastereoisomers indicating that no epimerisation of the start-
ing (S)-valine or the cyclopropane ring stereogenic centre had
occurred during any of the synthetic manipulations.
The relative configuration of the C3 and C6 stereogenic
centres within 12 was initially assigned from 1H NMR NOESY
experiments since a cross peak was observed between the iso-
propyl Me2CH and one of the cyclopropane ring gem-dimethyl
substituents, consistent with a cis relationship between these
groups (Fig. 1). Further corroborating NOESY correlations
were not available from NOESY data due to poor signal disper-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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Scheme 7 Reagents and conditions: (i) CH3CH(Li)PPh3, THF, room
temperature.
the (1S)-configuration of major isomer 22 was determined
via the identification of the (pro S)-C2-H, from a NOESY
correlation with both N4-p-methoxybenzyl protons. A strong
correlation between C1-H and the (pro S)-C2-H then indicated
that C1-H lies on the same face of the cyclopropane ring
and allowed assignment of (S)-configuration at C1. Comple-
mentary 1H NMR NOESY data for isomer 21 showed a
correlation between the (pro S)-C2-H and a single N4-p-
methoxybenzyl-H, and a further correlation between the (pro
S)-C2-H and the C1-Me, allowing the assignment of the (1R)-
configuration at C1 and the (1R,3S,6S) absolute configuration
of 21 (Fig. 3).
Scheme 4 Reagents and conditions: (i) TFA, ∆; (ii) 6 M HCl, 100 ЊC;
(iii) SOCl2, MeOH, ∆.
Scheme 5 Reagents and conditions: (i) Me3OBF4, BmimBF4; (ii) 2 M
HClaq, THF, room temperature.
Fig. 3 Selected 1H NOESY correlations for 21 and 22.
While it is apparent that high levels of facial selectivity are
maintained in the addition of this substituted phosphorus ylide,
only very low levels of selectivity were afforded in the formation
of the new C1 stereogenic centre in the substituted cyclo-
propane rings. In order to probe further the potential for
stereocontrol at C1, an alternative route to C1 substituted 1-
aminocyclopropane-1-carboxylic acids, employing the addition
of a diazoalkane to acceptor 2, was explored.17 The treatment
of acceptor 2 with phenyldiazomethane proceeded smoothly,
and following pyrolysis of the intermediate pyrazines, provided
Scheme 6 Reagents and conditions: (i) isobutyl chloroformate, NMM,
(S)-N-Cbz-Phe, DMF, THF.
Having demonstrated that the cyclopropanation reaction
utilising the symmetrical ylide 11 exhibits high levels of dia-
stereofacial selectivity, the addition of a mono substituted
phosphorane was investigated in order to examine the potential
for the stereoselective formation of two new stereogenic centres
in the preparation of C1 mono-substituted cyclopropane
rings. In this study acceptor 2 was treated with ethylidene-
triphenylphosphorane to afford a 42 : 58 mixture of dia-
stereoisomers (1R,3S,6S)-21 and (1S,3S,6S)-22 in good
combined yield (87%). Repeated column chromatography
enabled the isolation of pure samples of diastereoisomers 21
and 22, which facilitated their characterisation (Scheme 7).
The relative configurations of the C3 and C6 substituents of
both 1-methyl substituted isomers 21 and 22 were apparent
a
clean mixture containing only four diastereoisomeric
products 23, 24, 25 and 26, in the ratio of 28 : 50 : 11 : 11
respectively, as assessed by examination of the 1H NMR
spectrum of the crude reaction mixture. The major com-
ponents (1R,3R,6S)-23 and (1S,3R,6S)-24, and minor isomer
(1S,3S,6S)-26, were isolated via column chromatography (16%,
35% and < 5% yields respectively) (Scheme 8).
The relative configurations at C1 and C3 within 23, 24 and 26
1
were determined from H NMR NOESY and NOE difference
experiments which then allowed the absolute configurations of
each to be derived from the unchanged configuration of the
starting (S)-valine derived stereogenic centre. Both trans-(3R)-
diastereoisomers 23 and 24 showed correlations between the
Me2CH and both C2-H indicating the C2 methylene group lies
on the same side of the diketopiperazine ring as the C6 iso-
propyl group. Isomer 24 showed a NOESY correlation between
both N4-p-methoxybenzyl protons and the C1-H establishing
1
from H NMR NOESY experiments. Both 21 and 22 showed
diagnostic cross peaks between the isopropyl Me2CH and both
the C1-Me and the C1-H, indicating a cis relationship between
these groups, with the (3S)-configuration derived from the
known configuration of the starting (S)-valine. Furthermore,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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Fig. 5 Selected 1H NOESY correlations for cis-3S isomer 26.
Scheme 8 Reagents and conditions: (i) PhCHN2, PhMe, room temper-
ature then 60 ЊC.
the (1S)-configuration at C1. The (1R)-C1 configuration of
23 was determined by the observation of a NOE difference
correlation between the (pro R)-C2-H and one N4-p-methoxy-
benzyl-H, allowing identification of the (pro S)-C2-H. A strong
correlation between the (pro S)-C2-H and C1-H indicated these
protons lie on the same face of the cyclopropane ring, which
then allowed the configuration of (1R) to be assigned (Fig. 4).
Fig. 6 Chem3D representation of X-ray crystal structure of 24.
will reflect the configuration of the initially formed intermedi-
ate pyrazolines 27 and 28, respectively. The 78 : 22 ratio of the
(3R)-diastereoisomers 23 and 24 to (3S)-diastereoisomers 25
and 26 indicates a modest preference for initial cycloaddition of
phenyldiazomethane on the Re face of acceptor 2, trans to
the C6 isopropyl group (Scheme 9). The low levels of facial
selectivity observed in the attack of the methylene carbon in
this reaction may be expected, given the remoteness of this
centre from stereodirecting elements in the auxiliary.
Synthesis of (S )-[2,2-2H2]-1-aminocyclopropane-1-carboxylic
acid
1
Fig. 4 Selected H NOESY correlations for trans-3R isomers 23 and
Having established a protocol for the highly selective addition
of symmetrical ylides to acceptor 2 this methodology was next
applied to the asymmetric synthesis of a deuterium labelled
1-aminocyclopropane-1-carboxylic acid, which has been pre-
viously prepared as a probe into the biosynthesis of ethylene.19
Arigoni and Hill et al. have reported the asymmetric synthesis
of both (R)- and (S)- [2,2-2H2]-1-aminocyclopropane-1-
carboxylic acid 29 utilising a Sharpless epoxidation in the
synthesis of the (R)-enantiomer, and synthetic manipulation
of resolved starting material to deliver the (S)-enantiomer.4c
The asymmetric synthesis of 29 utilising a chiral auxiliary
approach has been less successful and syntheses reported to
date all exhibit poor to moderate diastereoselectivity in the
cyclopropane ring forming step. This shortcoming is com-
pounded by the difficulty in purifying the diastereoisomeric
intermediates to homogeneity which precludes the enhance-
ment of the enantiomeric excess of the final products. For
example, Seebach et al. have prepared 29 via the alkylation of
30. No diastereoselectivity was observed during the ring
forming alkylation step, inconsistent with the generally high
24.
The cis-(3S)-configuration of the minor isomer 26 was estab-
lished by NOESY correlations between the isopropyl Me2CH
and C1-H while the (1S)-C1-configuration was apparent from
correlations between (pro S)-C2-H and one N4-p-methoxy-
benzyl-H and a strong correlation between C1-H and the (pro
R)-C2-H (Fig. 5).
In support of these NOESY based configurational assign-
ments, the relative configuration within (1S,3R,6S)-24 was
unambiguously confirmed by single crystal X-ray diffraction,
with the absolute configuration derived from the known
configuration of (S)-valine (Fig. 6).
The additions of alkyldiazomethanes to α,β-unsaturated
acceptors are considered to proceed via a concerted cyclo-
addition process to give intermediate pyrazolines which then
decompose to spiro-cyclopropanes. In similar systems the
extrusion of nitrogen to give cyclopropanes generally occurs
with retention of stereochemistry18 and the configuration of
the major addition products (1R,3R,6S)-23 and (1S,3R,6S)-24
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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Scheme 12 Reagents and conditions: (i) PhS(O)(NEt2)CH2, DMSO.
Scheme 13 Reagents and conditions: (i) (CD3)2CD2(Li)SO, THF, room
temperature.
1
examination of the H NMR spectrum of the crude reaction
mixture (Scheme 13).
Scheme 9 Reagents and conditions: (i) PhCHN2, PhCH3, room temper-
ature then 60 ЊC.
The configuration within the deuterated analogue 33 was
tentatively assigned from 1H NMR NOESY data. NOESY
studies on the related proteo spiro-cyclopropane 5 allowed the
assignment of all four resonances corresponding to the cyclo-
propane ring protons from the correlations shown in Fig. 7.
facial selectivities obtained for intermolecular alkylations, and
the α-amino acid 29 obtained in this protocol was essentially
racemic (Scheme 10).20
Scheme 10 Reagents and conditions: (i) LDA, DMPU.
Fig. 7 Selected 1H NMR NOESY correlations for 5 and 33.
Low levels of diastereofacial selectivity have also been
observed in the related cyclopropane forming step utilising
bis-lactim auxiliary 31 which afforded labelled α-amino acid
29 in 46% e.e. upon hydrolysis (Scheme 11).21
Examination of the 1H NMR spectrum of deuterated
analogue 33 revealed that deuterium was incorporated upon
the carbon cis to the C6 isopropyl group since the resonances
corresponding to these protons in the proteo analogue were
1
absent. Furthermore, H NMR NOESY experiments showed
no correlations between the C6 isopropyl Me2CH and the
residual cyclopropyl methylene signals consistent with the C6
isopropyl group being cis to the deuterated methylene group.
Finally the absolute configuration of the cyclopropyl α-amino
acid fragment was unequivocally confirmed by chemical
correlation with the known diketopiperazine 34.23 Removal of
the nitrogen protecting groups from 33 with refluxing tri-
fluoroacetic acid afforded 35 (84% yield), with acid hydrolysis (6
M HCl, 100 ЊC) and esterification giving a mixture of (S)-valine
methyl ester hydrochloride 17 and [2,2-2H2]-1-aminocyclo-
propane-1-carboxylic acid methyl ester hydrochloride 36. Sub-
sequent coupling of this mixture with (S)-N-Cbz-phenylalanine
and separation of the resultant dipeptides 37 and 19 by chrom-
atography afforded 37 as a single diastereoisomer, in good yield
(80% from 35). Hydrogenolysis of the nitrogen protecting
group afforded dipeptide 38, with thermal cyclisation giving the
known diketopiperazine 34, albeit in poor isolated yield (10%)
(Scheme 14).
Scheme 11 Reagents and conditions: (i) BuLi, THF, Ϫ78 ЊC.
In perhaps the most successful approach to date, Williams et
al. have prepared labelled cyclopropane α-amino acid 29 in 83%
e.e., via sulfur ylide addition to dehydroalanine auxiliary 32
(Scheme 12).11b
The application of N-protected diketopiperazine conjugate
addition methodology to the asymmetric synthesis of 29 was
investigated via the cyclopropanation of 2 with deuterated
dimethylsulfoxonium methylide.22 Thus, reaction of acceptor
2 with the ylide derived from d9-trimethyloxosulfonium iodide
provided
(3S,6S)-[2Ј,2Ј-2H2]-N,NЈ-bis(p-methoxybenzyl)-
piperazine-2,5-dione-3-spiro-1Ј-cyclopropane 33 in high iso-
lated yield (86%) and excellent d.e. (> 98%), as assessed by
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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on the Si face of acceptor 2 placing the leaving group in the
correct position to be displaced by attack from the Si face of
the enolate intermediate 40. Alternatively conjugate addition
may occur on the Re face of acceptor 2 followed by a conform-
ational change to place the leaving group on the Si face of
the enolate, cis to the C3 isopropyl group, prior to elimination
(Fig. 8).
Scheme 14 Reagents and conditions: (i) TFA, ∆; (ii) 6 M HCl, 100 ЊC;
(iii) isobutyl chloroformate, NMM, DMF, THF; (S)-N-Cbz-Phe;
chromatographic separation; (iv) H2, Pd/C, MeOH; (v) PhCH3, ∆.
Examination of the 1H and 2H NMR data for dipeptide
38 and diketopiperazine 34 revealed considerable solvent
dependance of the chemical shift for the cyclopropane methyl-
ene protons and deuterons which initially hampered the direct
comparison of the synthetic material and the literature data.
For comparison purposes, non-deuterated analogue 39 was
prepared from commercially available 1-aminocyclopropane-
1-carboxylic acid methyl ester and Cbz-phenylalanine via
coupling, deprotection and cyclisation. Table 1 shows selected
cyclopropyl-methylene 1H and 2H NMR chemical shift data for
dipeptide 38 in a variety of solvents. Table 2 shows selected
cyclopropyl-methylene 1H and 2H NMR chemical shift data for
diketopiperazines 34 and 39 in TFA, MeOH and AcOH along
with literature values.
Comparison of the chemical shifts of both the H and H
NMR spectra with those reported by Arigoni et al.24 allowed
correlation of the (3S,6S)-configuration of diketopiperazine
34, establishing the configuration of the synthetic (S)-[2,2-2H2]-
1-aminocyclopropane-1-carboxylic acid 29 and the (3S,6S)-
configuration of 33 (Table 2). These data demonstrate that the
cyclopropanation of 2 with the deuterated methylene sulfur
ylide also proceeds with overall Si face selectivity, cis to the
C6 isopropyl group, similar to that observed in the preparation
of 12.
Fig. 8 Mechanism of cyclopropane ring formation via Si face ring
closure.
The cyclopropane ring forming intramolecular alkylation
occurs cis to the C6 isopropyl group, upon the Si face of the
intermediate enolate, and is in complete contrast to the trans
(Re face) selectivity observed in both the intermolecular alkyl-
ation of unsubstituted lithium enolate 3 with alkyl halides
and the protonation of the substituted enolate 4.10 In the inter-
molecular alkylation of the parent enolate 3, the trans selec-
tivity is controlled by the conformationally labile N-protecting
groups which serve to relay and enhance the stereodirecting
effect of the (S)-valine derived isopropyl group via a conform-
ation which places the N4-p-methoxybenzyl group on the Si
face of the enolate (Fig. 8 A). Related conformational prefer-
ences may also operate to control the conformation of inter-
mediate enolate 40 and direct the intramolecular alkylation to
the Si face. Molecular modelling suggests that the most stable
conformation of the intermediate 40 is one in which both of the
conformationally labile N-p-methoxybenzyl groups occupy a
position on the Re face of the enolate with the pendant group
of the C3 substituent cis to the isopropyl group (for example,
intermediate enolate 40a leading to 12, Fig. 9).25 In this
arrangement the steric interactions between the (S)-valine
derived isopropyl group and the adjacent N4-p-methoxybenzyl
group are minimised. In order to minimise steric interaction
with the N1-protecting group the proximal C3 substituent
occupies a position on the Si face of the enolate and the N4-
protecting group then occupies the position away from the
C3 substituent on the Re face of the auxiliary. Displacement of
the leaving group from this conformation then affords spiro-
cyclopropane adducts in high d.e. The alternative relay
arrangement, similar to that postulated for parent auxiliary
enolate 3, would unfavourably place the C3 substituent on the
same face as the N1-p-methoxybenzyl group.
1
2
Mechanism and stereoselectivity of cyclopropanation
The formation of the new quaternary stereogenic centre upon
cyclopropanation of acceptor 2 via phosphorus or sulfur ylide
chemistry proceeds with excellent diastereofacial selectivity. In
this addition/elimination process the configuration of the new
C3 stereogenic centre is independent of the initial conjugate
addition step with the product configuration being controlled
in the intramolecular enolate alkylation ring closure. The
observed product configuration must arise from displacement
of the leaving group by attack from the Si face (cis to the C-6
isopropyl group) of the enolate intermediate 40. In terms of
the initial conjugate addition step there are two indistinguish-
able modes for the formation of diketopiperazinespirocyclo-
propanes 12, 21, 22 and 33. Firstly, initial addition may occur
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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Table 1 Selected 1H and 2H NMR data for dipeptide 38
Table 2 Selected 1H and 2H NMR data for diketopiperazines 34 and 39
Due to the hindered nature of the enolate and the strain
arising from the ring forming step, the displacement of the
leaving group by the lithium enolate intermediate is expected
be the slow step in the cyclopropanation process. It may then
be assumed that displacement of the sulfur or phosphorus
leaving group occurs from the thermodynamically most stable
conformation of enolate 40, which places the leaving group
on the Si face, leading to the observed stereoselectivity.
Equilibration to this stable conformer may occur either via
conformational rearrangement of intermediate 40 or through
reversible addition of the ylide to acceptor 2.
The high levels of facial selectivity observed in the intra-
molecular cyclopropane ring forming step from enolates of
type 40 may be interpreted as the result of a chiral relay
network which operates in a similar manner to that which
controls the facial selectivity in the intermolecular alkylations
of enolate 3. In the case of enolate 3 the system exhibits a
double relay with the C6 isopropyl group directing the N1-p-
methoxybenzyl group anti, which in turn places the N4-p-
methoxybenzyl group on the alternate face of the auxiliary. The
arrangement of stereocontrolling elements in enolate 40 may be
interpreted as a triple relay in which the proximal C6 isopropyl
and N1-p-methoxybenzyl groups along with the pendant C3
substituent and the N4-p-methoxybenzyl group each occupy
positions on alternate faces of the auxiliary, resulting in the
observed high levels of stereocontrol.
Conclusion
The conjugate addition of phosphorus and sulfur ylides to
dehydroalanine acceptor 2 proceeds to give cyclopropane
substituted diketopiperazines 12 and 33 in excellent yield and
diastereoisomeric excess (> 98%). The subsequent incorpor-
ation of the cyclopropane α-amino acids derived from this
method into simple dipeptides demonstrates the utility of this
methodology for the synthesis and incorporation of these
residues into peptide sequences.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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15 minutes and the resulting mixture was stirred for 30 min. The
reaction was cooled (0 ЊC) and saturated ammonium chloride
(50 ml) was added. The mixture was partitioned between water
and ethyl acetate and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. Chromatography (silica, petrol-
eum ether–ethyl acetate 1 : 1) of the residue afforded 5 as a
colourless oil (1.08 g, 84%). [α]D24 Ϫ94.6 (c 1.00 in CHCl3); νmax
/
cmϪ1 (thin film): 2970–2836, 1661 (C᎐O), 1613 (C᎐O), 1585,
᎐
᎐
1513, 1450, 1412; δH (400 MHz, CDCl3) 0.82 (1H, m, C1-(pro
S)-H ), 1.10 (3H, d, J 6.8, CH(CH3)2), 1.12 (1H, m, C1-(pro R)-
H ), 1.14 (3H, d, J 6.8, CH(CH3)2), 1.47 (1H, m, C2-(pro S)-H ),
1.85 (1H, m, C2-(pro R)-H ), 2.38 (1H, m, CH(CH3)2), 3.79–
3.81 (7H, m, C6-H and 2 × OMe), 3.86 (1H, d, J 14.8, N7-CH2),
4.18 (1H, d, J 15.6, N4-CH2), 4.70 (1H, d, J 15.6, N4-CH2), 5.39
(1H, d, J 14.8, N7-CH2), 6.81 (2H, m, ArH ), 6.86 (2H, m,
ArH ), 7.03 (2H, m, ArH), 7.14 (2H, m, ArH ); δC (100 MHz,
CDCl3) 11.3, 16.7, 19.2, 20.3, 31.4, 41.8, 44.9, 49.4, 55.2, 55.3,
66.3, 114.1, 114.2, 127.9, 128.1, 129.1, 129.3, 158.8, 159.1,
167.8, 168.5; HRMS for C25H31N2O4 (MHϩ) requires 423.2284,
found 423.2281.
Fig. 9 Chem3D representation of a molecular model of lowest energy
conformation of enolate 40a.25
(3S,6S )-4,7-Bis(4-methoxybenzyl)-1,1-dimethyl-6-isopropyl-
4,7-diazaspiro[2.5]octane-5,8-dione 12. To a suspension of iso-
propyltriphenylphosphonium iodide (9.32 g, 21.6 mmol) in
THF (65 ml) was added n-BuLi (13.5 ml, 1.6 M in hexane, 21.6
mmol) under nitrogen at room temperature. After 30 minutes a
solution of 2 (4.40 g, 10.8 mmol), in THF (35 ml), was added
via cannula over 15 minutes and the resulting mixture was
stirred for a further 30 minutes. The reaction mixture was co-
oled in an ice bath and quenched with saturated ammonium
chloride. The organic solvent was removed in vacuum and ethyl
acetate was added. The mixture was washed with water and
dried over MgSO4 before removal of the solvent under reduced
pressure. Flash column chromatography (silica, petroleum
ether–ethyl acetate 4 : 6) of the residue afforded the desired
compound 12 as a colourless solid (4.50 g, 93%). Mp 117 ЊC;
[α]D Ϫ222 (c 1.00 in CHCl3); νmax/cmϪ1 (KBr) 3056–2840, 1668,
1614, 1585, 1514, 1451, 1403; δH (400 MHz, CDCl3) 1.07–1.17
(12H, m, CH(CH3)2, C(CH3)2), 1.15 (1H, d, J 6.7, CCH2), 1.75
(1H, d, J 6.7, CCH2), 2.01 (1H, m, CH(CH3)2), 3.56 (1H, d,
J 11.2, C6-H ), 3.58 (1H, d, J 15.2, N4-CH2), 3.70 (1H, d, J 14.7,
N7-CH2), 3.78 (3H, s, OMe), 3.79 (3H, s, OMe), 5.29 (1H, d,
J 15.2, N4-CH2), 5.43 (1H, d, J 14.7, N7-CH2), 6.73 (2H, m,
ArH ), 6.79 (2H, m, ArH ), 6.93 (2H, m, ArH ), 7.02 (2H, m,
ArH ); δC (100 MHz, CDCl3) 19.7, 19.9, 20.3, 20.5, 22.2, 26.8,
31.4, 47.0, 49.6, 50.9, 55.1, 55.2, 68.4, 113.9, 114.1, 128.4, 128.6,
128.8, 129.3, 158.8, 159.1, 166.8, 170.4; m/z; HRMS for
C27H35N2O4 (MHϩ) requires 451.2584, found 451.2596.
Experimental
General
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
1
diastereoselectivity was assessed by peak integration in the H
NMR spectrum of the crude reaction mixture. Tetrahydrofuran
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, H: 76.7
2
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. 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 were obtained using
Micromass AutoSpec or Micromass ToFSpec spectrometers.
Elemental analyses were performed by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford.
X-ray crystal structure data for 12:
Data were collected using an Enraf Nonius Kappa CCD dif-
fractometer with graphite monochromated Mo-Kα radiation
using standard procedures at 150 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.26 Crystal data for 12 [C27H20N2O4], colourless
block, M = 436.47, monoclinic, space group P 1 21 1,
a = 9.2515(1), b = 28.6084(4), c = 9.4481(1) Å, β = 99.9280(6)Њ,
U = 2463.19(5) Å3, Z = 4, µ = 0.080, crystal dimensions 0.2 × 0.2
× 0.2 mm. A total of 5686 unique reflections were measured for
5 < θ < 27 and 5605 reflections were used in the refinement. The
final parameters were wR2 = 0.1407 and R1 = 0.0657 [I >
Ϫ3σ(I )]. Crystallographic data (excluding structure factors)
have been deposited with the Cambridge Crystallographic Data
Centre.†
(S )-4,7-Bis(4-methoxybenzyl)-6-isopropyl-4,7-diaza-
spiro[2.5]octane-5,8-dione 5. To a suspension of trimethyl-
sulfoxonium iodide (1.65 g, 7.5 mmol) in THF (50 ml) was
added n-BuLi (4.6 ml, 1.6 M in hexane, 7.5 mmol) under nitro-
gen at room temperature. After 30 minutes a solution of 2
(1.22 g, 3.0 mmol) in THF (10 ml) was added over a period of
† CCDC 198088. See http://www.rsc.org/suppdata/ob/b3/b303348a/ for
crystallographic data in .cif or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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(3S,6S )-1,1-Dimethyl-6-isopropyl-4,7-diazaspiro[2.5]octane-
5,8-dione 13. A solution of 12 (4.34 g, 9.64 mmol) in TFA
(200 ml) was subject to reflux for 48 hours. The TFA was
removed under reduced pressure and the dark green residue
obtained was triturated with diethyl ether (3 × 50 ml). The
resultant solid was suspended in dichloromethane and heated
for 30 minutes before cooling to room temperature. The solid
was isolated by filtration and recrystallised from acetone afford-
mixture was stirred for 15 minutes before a solution of the
amino esters 16 and 17 (320 mg, 1.85 mmol) in DMF (20 ml)
was added via cannula. Stirring was continued for a further
45 minutes before dilution with ethyl acetate. The organic phase
was washed with water, saturated aqueous NaHCO3, 10%
aqueous citric acid, brine, dried over MgSO4 and the solvent
removed in vacuo. Purification by column chromatography
(silica, diethyl ether–ethyl acetate 6 : 4) afforded 19 as a colour-
less solid (371 mg, 94%). δH (200 MHz, CDCl3) 0.82 (3H, d,
J 7.4, (CH3)2CH), 0.91 (3H, d, J 7.4, (CH3)2CH), 2.04–2.14 (1H,
m, (CH3)2CH ), 3.07–3.11 (2H, m, PhCH2CH), 3.70 (3H, s,
23
ing 13 as a colourless solid (1.78 g, 87%). Mp 253–257 ЊC; [α]D
ϩ8.4 (c 0.5 in EtOH); νmax/cmϪ1 (KBr) 3204, 3093, 2967, 1689;
δH (400 MHz, DMSO-d6) 0.81 (1H, d, J 5.1, CH2), 0.89 (3H, d,
J 6.7, CH(CH3)2), 0.93 (3H, d, J 6.8, CH(CH3)2), 1.06 (6H, s,
C(CH3)2), 1.27 (1H, d, J 5.1, CH2), 1.79 (1H, m, CH(CH3)2),
3.28 (1H, m, 6-H ), 8.31 (1H, s, NH ), 8.36 (1H, d, J 4.3, NH );
δC (100 MHz, DMSO-d6) 18.4, 19.1, 19.2, 20.4, 22.0, 25.8, 32.4,
44.1, 61.9, 167.3, 169.7; HRMS for C11H19N2O2 (MHϩ) requires
211.1450, found 211.1446.
i
OMe), 4.42–4.49 (2H, m, PrCH and PhCH2CH ), 5.1 (2H, s,
PhCH2O), 5.37 (1H, d, J 7.6, NH ), 6.28 (1H, d, J 8.4, NH ),
7.27–7.39 (10H, m, Ph).27
Further elution afforded 20 as a colourless solid (341 mg,
87%). Mp 140–141 ЊC; [α]D Ϫ118.0 (c 1.0 in CHCl3); νmax/cmϪ1
(KBr) 3316, 1681, 1670, 1666; δH (400 MHz, CDCl3) 0.88 (1H,
d, J 5.3, CCH2), 1.06 (3H, s, C(Me)2), 1.18 (3H, s, C(Me)2), 1.70
(1H, d, J 5.3, CCH2), 2.99 (1H, dd, J 14.0, 6.4, PhCH2CH), 3.13
(1H, dd, J 14.0, 6.5, PhCH2CH), 3.61 (3H, s, OMe), 4.51 (1H,
br s, NH ), 5.02 (2H, s, PhCH2O), 5.63 (1H, d, J 8.3, PhCH2-
CHCO), 6.82 (1H, br s, CONH ), 7.36–7.19 (10H, m, Ph); δC
(100 MHz, CDCl3) 19.5, 21.8, 27.8, 28.6, 37.8, 42.4, 52.1, 53.5,
55.8, 57.3, 66.9, 95.7, 126.9, 127.9, 128.1, 128.4, 128.5, 129.3,
129.4, 136.2, 136.6, 156.1, 171.2, 171.2; HRMS for C24H29N2O5
(MHϩ) requires 425.2079, found 425.2076.
(3S,6S )-5,8-Dimethoxy-1,1-dimethyl-6-isopropyl-4,7-diaza-
spiro[2.5]octa-4,7-diene 18. To a solution of 13 (294 mg, 1.40
mmol) in N-butyl-NЈ-methylimidazolium tetrafluoroborate
(8 ml) was added trimethyloxonium tetrafluoroborate (827 mg,
5.59 mmol). The reaction mixture was stirred under vacuum
for 4 days before the mixture was added to saturated NaHCO3
(15 ml). The product was extracted with ethyl acetate and the
combined organic phases dried over MgSO4 before removal of
solvent under reduced pressure to furnish bis-lactim ether 18 as
a colourless oil that required no further purification. [α]D ϩ15.7
(c 0.7 in CHCl3); νmax/cmϪ1 (thin film) 3004–2872, 1682,
1667, 1463, 1438; δH (400 MHz, CDCl3) 0.86 (3H, d, J 6.8,
CH(CH3)2), 0.93 (1H, d, J 4.6, CH2), 1.09 (3H, d, J 6.8,
CH(CH3)2), 1.15 (3H, s, C(CH3)2), 1.16 (3H, s, C(CH3)2), 1.59
(1H, d, J 4.6, CH2), 1.94 (1H, m, CH(CH3)2), 3.65 (3H, s, OMe),
3.68 (3H, s, OMe), 4.09 (1H, d, J 5.0, C6-H ); δC (100 MHz,
CDCl3) 17.9, 19.2, 20.6, 21.9, 27.7, 28.0, 32.7, 47.0, 52.4, 52.6,
63.1, 165.0, 165.4; HRMS for C13H23N2O2 (MHϩ) requires
239.1760, found 239.1759.
(1R,3S,6S )- and (1S,3S,6S )- 4,7-Bis(4-methoxybenzyl)-6-
isopropyl-1-methyl-4,7-diazaspiro[2.5]octane-5,8-dione 21 and
22. To a suspension of ethyltriphenylphosphonium bromide
(742 mg, 2.0 mmol) in THF (20 ml) was added a solution of
n-BuLi (1.24 ml, 1.6 M in hexane, 2.0 mmol) under an
atmosphere of nitrogen at room temperature. After 30 minutes
a solution of 2 (408 mg, 1.0 mmol) in THF (5 ml) was added via
cannula over a period of 15 minutes and the resulting mixture
was stirred for a further 30 minutes. The reaction was cooled in
an ice bath and quenched with saturated ammonium chloride.
The organic layer was separated and the aqueous layer
extracted with ethyl acetate. The combined organic layers were
dried over MgSO4, filtered and the solvent removed under
reduced pressure. Flash column chromatography (silica, diethyl
ether–hexane 4 : 6) afforded a mixture of 21 and 22 (380 mg,
87%). Further, exhaustive chromatography afforded pure
samples for characterisation. First eluting isomer 21 Oil. [α]D
Ϫ152.0 (c 0.5 in CHCl3); νmax/cmϪ1(thin film) 3500–2950, 1667,
1613, 1585, 1513, 1455, 1404; δH (500 MHz, CDCl3) 1.08 (1H,
m, C2-(pro S)-H ), 1.10 (3H, d, J 6.2, CH(CH3)), 1.16 (3H, d,
J 6.8, CH(CH3)2), 1.18 (3H, d, J 6.7, CH(CH3)2), 1.31 (1H, m,
CH(CH3)), 2.08 (1H, dd, J 9.8, 6.5, C2-(pro R)-H ), 2.22 (1H,
m, CH(CH3)2), 3.67 (1H, d, J 15.4, N4-CH2), 3.68 (1H, d,
J 10.4, C6-H ), 3.80 (1H, d, J 14.7, N7-CH2), 3.83 (3H s, OMe),
3.85 (3H, s, OMe), 5.36 (1H, d, J 15.4, N4-CH2), 5.44 (1H, d,
J 14.7, N7-CH2), 6.80 (2H, m, ArH ), 6.87 (2H, m, ArH ), 6.99
(2H, m, ArH ), 7.10 (2H, m, ArH ); δC (100 MHz, CDCl3) 12.3,
17.7, 19.6, 20.9, 22.8, 31.6, 45.1, 47.3, 50.7, 55.1, 55.2, 68.2,
114.0, 114.1, 128.4, 128.8, 129.2, 158.8, 159.1, 168.6, 170.2.
HRMS for C26H33N2O4 (MHϩ) requires 451.2440, found
451.2439.
(1S )-1-Amino-2,2-dimethylcyclopropanecarboxylic
acid
methyl ester 16 and (S )-valine methyl ester 17. Method A: a
solution of 13 (43 mg, 0.20 mmol) in HCl (3 ml, 6 M) was
subject to reflux for 24 hours. The aqueous phase was washed
with diethyl ether and concentrated under vacuum to afford
a mixture of the amino acids 14 and 15 that were dissolved
in MeOH (5 ml) and cooled to 0 ЊC before thionyl chloride
(0.15 ml) was added. The reaction mixture was subject to reflux
overnight before concentration under vacuum afforded a 1 : 1
mixture of the methyl ester amino hydrochlorides 16 and 17
as a colourless solid (69 mg) that was used without further
purification.
Method B: bis-lactim ether 18 (288 mg, 1.21 mmol) was
dissolved in THF (2 ml) and HCl (3 ml, 2 M). The reaction
mixture was stirred for 2.5 hours before dilution with DCM.
The product was extracted with water and the combined
aqueous phases concentrated under reduced pressure to furnish
a 1 : 1 mixture of amino esters 16 and 17 as a colourless solid
(379 mg) that was used without further purification.
δH (200 MHz, MeOH-d4) 0.11 (1H, d, J 7.1, CH2C(CH3)2),
1.10 (3H, d, J 2.4, CHCH(CH3)2), 1.14 (3H, d, J 2.4, CHCH-
(CH3)2), 1.31 (3H, s, CH2C(CH3)2), 1.46 (3H, s, CH2C(CH3)2),
1.47 (1H, d, J 7.13, CH2C(CH3)2), 2.29–2.47 (1H, m, CHCH-
(CH3)2), 4.02 (1H, d, J 4.2, CHCH(CH3)2), 3.88 (3H, s, OMe),
3.89 (3H, s, OMe).
Second eluting isomer 22 Oil. [α]D Ϫ80.5 (c 0.75 in CHCl3);
νmax/cmϪ1 (thin film) 3500–2830, 1660, 1613, 1585, 1513, 1462,
1412; δH (400 MHz, CDCl3) 1.09–1.10 (4H, m, CHCH3 and
CH2CHCH3), 1.14 (6H, m, CH(CH3)2), 1.51–1.60 (2H, m,
CH2CHCH3 and CH2CHCH3), 2.31 (1H, m, CH(CH3)2), 3.63
(1H, d, J 10.0, C6-H ), 3.79 (3H, s, OMe), 3.80 (3H, s, OMe),
3.80 (1H, d, J 14.8, NCH2), 4.18 (1H, d, J 15.6, NCH2), 4.68
(1H, d, J 15.6, NCH2), 5.44 (1H, d, J 14.8, NCH2), 6.79 (2H, m,
ArH ), 6.84 (2H, m, ArH ), 6.99 (2H, m, ArH ), 7.12 (2H, m,
ArH ); δH (400 MHz, C6D6) 0.8–0.92 (1H, m, CH(Me)CH2),
1.01 (3H, d, J 6.8, CH(CH3)2), 1.13 (3H, d, J 7.1, CHCH3), 1.22
(3H, d, J 6.7, CH(CH3)2), 1.41 (1H, dd, J 10, 6.4, C2-(pro S)-
N-Cbz-(S )-phenylalanine-(S )-valine methyl ester 19 and N-
Cbz-(S )-phenylalanine-(S )-2,2-dimethylcyclopropanecarboxylic
acid methyl ester 20. To a solution of (S)-N-CBz-phenylalanine
(665 mg, 2.22 mmol) in DMF (20 ml) and THF (20 ml) at 0 ЊC,
was added N-methylmorpholine (0.45 ml, 4.07 mmol) and
isobutyl chloroformate (0.29 ml, 2.22 mmol). The reaction
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
2539

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H ), 1.87 (1H, dd, J 8.1, 6.5, C2-(pro R)-H ), 2.38–2.31 (1H, m,
CH(CH3)2), 3.43 (3H, s, OMe), 3.47 (3H, s, OMe), 3.81 (1H, d,
J 14.8, N7-CH2), 3.81 (1H, d, J 9.9, CHCH(CH3)2), 4.18 (1H,
br d, J 15.4, N4-CH2), 4.60 (1H, br d, 15.6, N4-CH2), 5.62 (1H,
d, J 14.8, N7-CH2), 6.73–6.89 (4H, m, ArH ), 7.07–7.11 (2H, m,
ArH ), 7.18–7.26 (2H, m, ArH ); δC (100 MHz, CDCl3) 12.3,
16.5, 19.8, 20.3, 23.2, 31.1, 45.2, 46.5, 50.6, 55.2, 55.3, 67.5,
114.0, 114.2, 127.9, 128.4, 129.2, 129.3, 158.7, 159.2, 166.0,
169.3. HRMS for C26H33N2O4 (MHϩ) requires 451.2440, found
451.2440.
N4-CH2), 3.68 (1H, d, J 14.9, N7-CH2), 3.70 (1H, s,
CHCH(CH3)2), 5,45 (1H, d, J 15.1, N4-CH2), 5.63 (1H, d,
J 14.8, N7-CH2), 6.77 (4H, m, ArH ), 6.89 (2H, m, ArH ), 7.03
(2H, m, ArH ), 7.11–7.22 (5H, m, ArH ); δC (175 MHz, CDCl3)
16.5, 19.2, 20.8, 31.8, 34.2, 47.6, 47.9, 50.8, 55.2, 68.9, 114.0,
114.1, 127.2, 128.0, 128.2, 128.6, 128.7, 128.8, 129.2, 134.5,
158.9, 159.1, 167.9, 170.2; HRMS for C31H35N2O4 (MHϩ)
requires 499.2597, found 499.2597.
(1R,3S,6S )-25. Contaminated with 26, colourless oil (10 mg).
Selected data: δH (500 MHz, CDCl3) 0.57 (3H, d, J 6.7, CH-
(CH3)2), 1.11 (3H, d, J 6.7, CH(CH3)2), 2.00 (1H, dd, J 10.2, 7.4,
CH(CH2)), 2.23–2.28 (2H, m, CHPh or 1 × CH(CH2) and
CH(CH3)2), 2.45 (1H, dd, J 9.2, 7.4, CH(CH2) or CH(CH2)),
3.53 (1H, d, J 10.4, C6-H ), 3.60 (1H, d, J 14.8, NCH2), 3.79 (s,
3H, OMe), 3.81 (s, 3H, OMe), 4.26 (1H, d, J 15.6, NCH2), 4.85
(1H, d, J 15.6, NCH2), 5.17 (1H, d, J 14.8, NCH2), 6.81 (2H, m,
ArH ), 6.84 (2H, m, ArH ), 7.04 (2H, m, ArH ), 7.05 (2H, m,
ArH ), 7.16–7.26 (3H, m, ArH ), 7.27–7.31 (2H, m, ArH );
δC (175 MHz, CDCl3) 15.6, 19.6, 19.9, 31.5, 34.4, 45.0, 50.0,
50.8, 55.2, 67.8, 114.1, 114.2, 126.7, 128.0, 128.1, 128.3, 128.6,
129.0, 129.1, 134.4, 158.9, 159.1, 163.6, 169.7.
(1R,3R,6S )-, (1S,3R,6S )- and (1S,3S,6S )-4,7-Bis(4-meth-
oxybenzyl)-6-isopropyl-1-phenyl-4,7-diazaspiro[2.5]octane-5,8-
dione 23, 24 and 26. To a solution of tosylhydrazide (1.86 g,
10 mmol) in glacial acetic acid (5 ml) was added benzaldehyde
(1.27 g, 12 mmol) and the mixture was refluxed until precipit-
ation started. The mixture was cooled and the solid was isolated
by filtration and washed sequentially with cold acetic acid,
acetic acid–water (1 : 1), cold water and hexane to furnish the
tosylhydrazone as a colourless solid (1.92 g, 70%). A solution
of the tosylhydrazone (922 mg, 3.36 mmol) in toluene (40 ml)
was added to a solution of benzyltriethylammonium chloride
(192 mg, 0.84 mmol) in aqueous sodium hydroxide (40 ml, 14%
w/v). The mixture was heated to 70 ЊC for 2 h before cooling to
room temperature. The aqueous layer was separated, leaving
the organic solution of phenyldiazomethane, which was used
directly in the addition to acceptor 2. To this freshly prepared
solution of phenyldiazomethane in toluene was added 2 (227
mg, 0.56 mmol). The mixture was stirred at room temperature
for 4 days, before heating to 60 ЊC for 24 hours. The reaction
mixture was concentrated under reduced pressure and exam-
ination of the 1H NMR spectrum of the crude reaction mixture
indicated a 28 : 11 : 11 : 50 mixture of four diastereoisomers.
Purification by flash column chromatography (silica, hexane–
ethyl acetate 7 : 3) furnished, in order of elution, 23 (46 mg,
16%), a 1 : 1 mixture of 26 and 25 (10 mg, 3.5%) and 24 (99 mg,
35%). Exhaustive chromatography allowed for sufficient
quantities of 26 to be isolated for characterisation.
(1S,3R,6S )-24. Colourless plates (99 mg, 35%). Mp 128 ЊC;
[α]D Ϫ366.8 (c 1.00 in CHCl3); νmax/cmϪ1 (KBr) 3047–2833,
1663, 1612; δH (500 MHz, CDCl3) 1.10 (3H, d, J 6.8,
CH(CH3)2), 1.15 (3H, d, J 6.8, CH(CH3)2), 1.56 (1H, dd, J 10.4,
5.8, C2-(pro S)-H), 2.05 (1H, dd, J 8.8, 5.8, C2-(pro R)-H), 2.38
(1H, m, CH(CH3)2), 3.02 (1H, dd, J 10.4, 8.8, CHPh), 3.72 (1H,
d, J 15.0, N7-CH2), 3.80 (1H, d, J 5.6, C6-H ), 3.81 (s, 3H,
OMe), 3.83 (s, 3H, OMe), 4.26 (1H, d, J 15.9, N4-CH2), 5.03
(1H, d, J 15.9, N4-CH2), 5.31 (1H, d, J 15.0, N7-CH2), 6.79
(2H, m, ArH ), 6.86–6.91 (6H, m, ArH ), 7.11 (2H, m, ArH ),
7.19–7.25 (3H, m, ArH ); δC (175 MHz, CDCl3) 18.4, 18.9, 20.4,
30.4, 30.9, 44.8, 45.7, 47.6, 55.2, 55.4, 64.4, 114.1, 114.4, 126.5,
127.8, 128.0, 128.2, 128.4, 129.1, 135.4, 159.0, 166.5, 168.7;
HRMS for C31H35N2O4 (MHϩ) requires 499.2597, found
499.2601.
X-ray crystal structure data for 24:
(1R,3R,6S )-23. Colourless oil (46 mg, 16%). [α]D ϩ11.6
(c 0.83 in CHCl3); νmax/cmϪ1 (thin film): 3580–2837, 1661, 1613;
δH (500 MHz, CDCl3) 1.06 (3H, d, J 6.8, CH(CH3)2), 1.14 (3H,
d, J 6.8, CH(CH3)2), 1.78 (1H, dd, J 8.6, 5.8, C2-(pro S)-H ),
2.00 (1H, dd, J 10.2, 5.8, C2-(pro R)-H ), 2.50 (1H, m,
CH(CH3)2), 3.29 (1H, dd, J 10.2, 8.6, CHPh), 3.77 (s, 3H,
OMe), 3.81 (s, 3H, OMe), 3.82 (1H, d, J 6.5, C6-H ), 3.88 (1H,
d, J 15.8, N4-CH2), 3.97 (1H, d, J 14.9, N7-CH2), 4.06 (1H, d,
J 15.8, N4-CH2), 5.42 (1H, d, J 14.9, N7-CH2), 6.70 (4H, m,
ArH ), 6.86 (2H, m, ArH ), 7.11 (2H, m, ArH ), 7.14–7.18 (2H,
m, ArH ), 7.24–7.27 (3H, m, ArH ); δC (175 MHz, CDCl3) 18.1,
18.8, 20.4, 29.9, 30.7, 45.7, 47.3, 48.6, 55.1, 55.2, 65.2, 113.6,
114.3, 127.4, 127.9, 128.3, 128.6, 128.9, 129.0, 129.2, 134.4,
158.5, 159.1, 168.6, 169.3; HRMS for C31H35N2O4 (MHϩ)
requires 499. 2597, found 499.2604.
Data were collected using an Enraf Nonius Kappa CCD
diffractometer with graphite monochromated 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.26 Crystal data for 24 [C31H34N2O4], colourless
plate, M = 498.62, monoclinic, space group P 1 21 1. a =
10.4793(2), b = 10.5310(3), c = 12.0380(4) Å, β = 96.237(1)Њ, U =
1320.62(6) Å3, Z = 2, µ = 0.083, crystal dimensions 0.1 × 0.2 ×
0.3 mm, A total of 3196 unique reflections were measured for 5
< θ < 27 and 2613 reflections were used in the refinement. The
final parameters were wR2 = 0.050 and R1 = 0.051 [I > 1σ(I )].
Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre.‡
(1S,3S,6S )-26. Colourless oil (10 mg). [α]D Ϫ112 (c 0.07 in
CHCl3); νmax/cmϪ1 (KBr) 3433, 1654, 1639; δH (400 MHz,
CDCl3) 0.66 (3H, d, J 6.7, CH(CH3)2), 1.12 (3H, d, J 6.7,
CH(CH3)2), 1.84 (2H, m, C2-(pro S)-H), 2.11–2.19 (2H, m,
CH(CH3)2), 2.49–2.53 (2H, m, CHCH2 and C2-(pro R)-H), 3.52
(1H, d, J 10.6, C6-H ), 3.67 (1H, d, J 15.2, NCH2), 3.77 (1H, d,
J 14.7, NCH2), 3.79 (3H, s, OMe), 3.80 (3H, s, OMe), 5.26 (1H,
d, J 15.2, NCH2), 5.42 (1H, d, J 14.7, NCH2), 6.77 (2H, m,
ArH ), 6.78 (2H, m, ArH ), 6.96 (2H, m, ArH ), 7.00 (2H, m,
ArH ), 7.11 (2H, m, ArH ), 7.25–7.28 (1H, m, ArH ), 7.31–7.35
(2H, m, ArH ); δH (400 MHz, C6D6) 0.80 (3H, d, J 6.7,
CH(CH3)2), 0.94 (3H, d, J 6.7, CH(CH3)2), 1.63 (1H, apparent
t, C2-(pro S)-H), 2.20–2.26 (2H, m, CH(CH3)2), 2.56 (1H, dd,
J 10.2, 7.7, CHCH2), 2.74 (1H, dd, J 10.2, 6.7, C2-(pro R)-H),
3.43 (3H, s, OMe), 3.44 (3H, s, OMe), 3.58 (1H, d, J 15.2,
(3S,6S )-4,7-Bis(4-methoxybenzyl)-[1,1-2H]-6-isopropyl-4,7-
diazaspiro[2.5]octane-5,8-dione 33. To a suspension of tri-
methylsulfoxonium-d9 iodide (1.7 g, 7.5 mmol) in THF (100 ml)
was added n-BuLi (9.0 ml, 1.6 M in hexane, 15.0 mmol) under
nitrogen at room temperature. After 30 minutes the mixture was
cooled in an ice bath and a solution of 2 (2.4 g, 6 mmol) in THF
(20 ml) was added via cannula over a period of 15 minutes.
The resulting mixture was warmed to room temperature and
stirred overnight. The reaction was quenched with saturated
ammonium chloride, the organic layer separated and the
aqueous layer extracted with ethyl acetate. The combined
‡ CCDC 206108. See http://www.rsc.org/suppdata/ob/b3/b303348a/ for
crystallographic data in .cif or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
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organic phases were dried over MgSO4, filtered and the solvent
was removed under vacuum. Flash column chromatography
(silica, 1 : 1 petroleum ether–ethyl acetate) of the residue
afforded 33 as a colourless oil (2.2 g, 86%). [α]D Ϫ99.3 (c 1.00 in
CHCl3); νmax/cmϪ1 (thin film) 2963, 2935, 1661, 1613, 1585,
1513, 1455, 1415; δH (400 MHz, CDCl3) 1.10 (3H, d, J 6.8,
CH(CH3)2), 1.14 (3H, d, J 6.8, CH(CH3)2), 1.45 (1H, d, J 6.3,
C2-(pro S)-H ), 1.84 (1H, d, J 6.3, C2-(pro R)-H ), 2.39 (1H, m,
CH(CH3)2), 3.79–3.81 (7H, m, C6-H and 2 × OMe), 3.86 (1H,
d, J 14.8, N7-CH2), 4.18 (1H, d, J 15.6, N4-CH2), 4.70 (1H, d,
J 15.6, N4-CH2), 5.39 (1H, d, J 14.8, N7-CH2), 6.81 (2H, m,
ArH ), 6.86 (2H, m, ArH ), 7.03 (2H, m, ArH ), 7.14 (2H, m,
ArH ); δC (100 MHz, CDCl3) 11.3, 16.7, 19.2, 20.3, 31.4, 41.8,
44.9, 49.4, 55.2, 55.3, 66.3, 95.7, 114.1, 114.2, 127.9, 128.1,
129.1, 129.3, 158.8, 159.1, 167.8, 168.5; HRMS for C25H28
D2N2O4 (Mϩ) requires 424.2329, found 424.2331.
(S )-Phenylalanine-(S )-[2,2-2H]-cyclopropanecarboxylic acid
methyl ester 38. To a solution of peptide 37 (220 mg, 0.51
mmol) in degassed MeOH (1 ml) was added Pd/C (40 mg, 20
w/w). The resultant mixture was stirred overnight under a
hydrogen balloon (1 atm) before filtration through Celite®. The
solvent was removed under vacuum and the crude reaction
mixture was purified by flash column chromatography (silica,
diethyl ether–methanol 8 : 2) furnishing 38 as a colourless oil
(126 mg, 87%). νmax/cmϪ1 (thin film) 2360, 2340, 1727, 1670;
δH (400 MHz, AcOH-d4) 0.95 (1H, d, J 4.9, CCH2), 1.43 (1H, d,
J 4.9, CCH2), 3.21–3.34 (2H, m, PhCH2), 3.69 (3H, s, OMe),
4.57 (1H, t, J 7.1, PhCH2CHNH2), 7.29–7.37 (5H, m, Ph);
δH (200 MHz, MeOH-d4) 0.91 (1H, d, J 4.6, CCH2), 1.43 (1H, d,
J 4.6, CCH2), 2.95 (2H, dd, J 11.6, 7.0, PhCH2), 3.69 (3H, s,
OMe), 4.83 (1H, m, PhCH2CHNH2), 7.23–7.37 (5H, m, Ph); δH
(500 MHz, TFA-d1) 1.35 (1H, d, J 5.2, CCH2), 1.98 (1H, d,
J 5.2, CCH2), 3.61–3.73 (2H, m, PhCH2), 4.13 (3H, s, OMe),
4.91 (1H, t, J 7.5, PhCH2CH ); δD (76.7 MHz, TFA ref DCM-
d2) 1.30, 1.81; δC (100 MHz, MeOH-d4) 16.7, 16.9, 33.5, 41.4,
52.0, 56.4, 126.8, 127.4, 128.5, 129.4, 130.6, 137.7, 173.3, 176.9;
HRMS for C14H17D2N2O3 (MHϩ) requires 264.1441, found
264.1440.
(3S,6S )-[1,1-2H]-6-Isopropyl-4,7-diazaspiro[2.5]octane-5,8-
dione 35. A solution of 33 (2 g, 4.7 mmol) in TFA (100 ml) was
refluxed for 48 hours before concentrating under reduced
pressure. The dark green residue was triturated with diethyl
ether (3 × 25 ml) before recrystallisation from acetone afforded
35 as a colourless solid (720 mg, 84%). Mp 239–241 ЊC; [α]D
ϩ16.8 (c 0.5 in MeOH); νmax/cmϪ1 (KBr) 3300–2700, 3187,
3050, 2961, 2895, 1674, 1458; δH (500 MHz, DMSO-d6) 0.90
(3H, d, J 6.8, CH(CH3)2), 0.95 (3H, d, J 7.0, CH(CH3)2), 0.99
(1H, d, J 4.4, CH2(CH2)), 1.27 (1H, d, J 4.4, CH2(CH2)), 2.13
(1H, m, CH(CH3)2), 3.66 (1H, d, J 3.4, C6-H ), 8.18 (1H, s,
NH ), 8.25 (1H, s, NH ); δC (125 MHz, DMSO-d6) 13.2,
16.8, 17.3, 18.7, 32.8, 36.2, 60.9, 168.1, 168.6; HRMS for
C9H12D2N2O2 (Mϩ) requires 184.1186, found 184.1181.
(3S,6S )-[1,1-2H]-6-Benzyl-4,7-diazaspiro[2.5]octane-5,8-dione
34. Dipeptide 38 (125 mg, 0.46 mmol) was subject to reflux
overnight in toluene (75 ml). The solvent was then removed
under reduced pressure and the crude residue was repeatedly
triturated with diethyl ether before recrystallisation from
acetone afforded 34 as a colourless solid (11 mg, 10%). Mp 277–
280 ЊC; [α]D ϩ13.2 (c 0.5 in MeOH); νmax/cmϪ1 (KBr) 2360,
2340, 1727, 1670; δH (400 MHz, AcOH-d4) 0.90 (1H, d, J 5.5,
CCH2), 1.42 (1H, d, J 5.5, CCH2), 3.09 (1H, dd, J 13.9, 4.5,
PhCH2), 3.31 (1H, dd, J 13.9, 4.5, PhCH2), 4.61 (1H, t, J 4.5,
PhCH2CH ), 7.21–7.39 (5H, m, Ph); δH (400 MHz, MeOH-d4)
0.81 (1H, d, J 5.0, CCH2), 1.24 (1H, d, J 5.0, CCH2), 3.01 (1H,
dd, J 13.7, 4.7, PhCH2), 3.27 (1H, dd, J 13.7, 4.1, PhCH2), 4.35
(1H, t, J 4.5, PhCH2CH ), 7.19–7.37 (5H, m, Ph); δH (500 MHz,
TFA-d1) 1.27 (1H, d, J 5.4, CCH2), 1.88 (1H, d, J 5.4, CCH2),
3.57–3.74 (2H, m, PhCH2), 4.91 (1H, t, J 7.4, PhCH2CH ),
7.40–7.56 (2H, m, Ph), 7.63–7.71 (3H, m, Ph); δD (76.7 MHz,
AcOH ref DCM-d2) 0.35, 0.76; δD (76.7 MHz, MeOH ref
DCM-d2) 0.20, 0.54; δD (76.7 MHz, TFA ref DCM-d2) 0.76,
1.12; δC (125 MHz, AcOH-d4) 16.9, 14.2, 37.6, 39.9, 57.0, 127.7,
128.8, 129.0, 129.8, 130.7, 135.1, 171.6, 173.4; HRMS for
C13H12D2N2O2 (MHϩ) requires 233.1252, found 233.1252.
(S )-1-Amino-[2,2-2H]-cyclopropanecarboxylic acid methyl
ester 36 and (S )-valine methyl ester 17. A suspension of 33 (552
mg, 3.0 mmol) in HCl (30 ml, 6 M) was refluxed 24 hours before
cooling to room temperature and washing with diethyl ether.
The aqueous phase was concentrated under vacuum to afford a
mixture of amino acids that were dissolved in MeOH (75 ml)
and cooled to 0 ЊC before thionyl chloride (2.25 ml) was added.
The reaction mixture was subject to reflux overnight before
concentration under vacuum afforded a 1 : 1 mixture of the
amino ester hydrochlorides 17 and 36, as colourless solids that
were used without further purification (733 mg). δH (300 MHz,
D2O) 0.85 (3H, d, J 6.8, CH(CH3)2), 0.86 (3H, d, J 6.8,
CH(CH3)2), 1.26 (1H, d, J 6.1, CH2), 1.43 (1H, d, J 6.1, CH2),
2.18 (1H, m, CH(CH3)2), 3.63 (3H, s, OMe), 3.68 (3H, s, OMe),
3.86 (1H, d, J 4.6, ValؒHCl-CH ).
(S )-6-Benzyl-4,7-diazaspiro[2.5]octane-5,8-dione 39. To
a
N-Cbz-(S )-phenylalanine-(S )-[2,2-2H]-cyclopropanecarb-
oxylic acid methyl ester 37. To a solution of N-CBz-(S)-
phenylalanine (728 mg, 2.43 mmol) in DMF (22 ml) and THF
(22 ml) at 0 ЊC, was added N-methylmorpholine (0.49 ml, 4.46
mmol) and isobutyl chloroformate (0.32 ml, 2.43 mmol). The
reaction mixture was stirred for 15 minutes before a solution
of the amino esters 17 and 36 (355 mg, 2.03 mmol) in DMF
(30 ml) was added via cannula. Stirring was continued for a
further 45 minutes before dilution with ethyl acetate. The
organic phase was washed with water, saturated aqueous
NaHCO3, 10% aqueous citric acid, brine and dried over MgSO4
and the solvent removed in vacuo. Purification of the residues
by column chromatography (silica, diethyl ether–hexane 6 : 4)
afforded 19 as a colourless solid (338 mg, 81%). Further elution
furnished 37 as a colourless solid (376 mg, 93%). Mp 127–133
ЊC; [α]D ϩ4.6 (c 0.5 in CHCl3); νmax/cmϪ1 (KBr) 3299, 1732,
1683, 1663; δH (400 MHz, CDCl3) 0.86 (1H, d, J 4.6, CCH2),
1.43 (1H, d, J 4.6, CCH2), 3.04 (2H, m, PhCH2CH), 3.62 (3H, s,
OMe), 4.44 (1H, br s, NH ), 5.07 (2H, m, PhCH2O), 5.62 (1H, d,
J 7.2, NHCBz), 7.40–7.19 (10H, m, Ph); δC (100 MHz, CDCl3)
17.4, 33.1, 38.5, 52.5, 55.9, 67.0, 77.3, 127.0, 128.0, 128.2, 128.5,
128.6, 129.4, 136.1, 136.5, 156.0, 171.9, 172.4; HRMS for
C22H22D2N2O5Na (MNaϩ) requires 421.1702, found 421.1708.
solution of N-CBz-(S)-phenylalanine (849 mg, 2.84 mmol)
in DMF (8 ml) and THF (8 ml) at 0 ЊC, was added N-
methylmorpholine (0.31 ml, 2.84 mmol) and isobutyl
chloroformate (0.37 ml, 2.84 mmol). The reaction mixture
was stirred for 15 minutes before a solution of 1-amino-1-
cyclopropanecarboxylic acid methyl ester (391 mg, 2.58 mmol)
in DMF (8 ml) was added via cannula. Stirring was continued
for a further 45 minutes before dilution with ethyl acetate. The
organic phase was washed with water, saturated aqueous
NaHCO3, 10% aqueous citric acid, brine and dried over
MgSO4. After removal of solvent the residues were crystallised
from ethyl acetate–hexane to afford N-Cbz-(S)-phenylalanine-
(S)-cyclopropanecarboxylic acid methyl ester 41 (946 mg,
96%). [α]D ϩ2.5 (c 1.0 in CHCl3); [α]D Ϫ12.5 (c 0.2 in
MeOH); (Lit.28 [α]D20 Ϫ19.9 [c 0.2 in MeOH]), (Lit.29 [α]D20 Ϫ5
[c 0.1 in CH2Cl2]); δH (400 MHz, AcOH-d4) 0.90 (1H, d, J 5.5,
CCH2), 1.42 (1H, d, J 5.5, CCH2), 3.09 (1H, dd, J 13.9, 4.5,
PhCH2), 3.31 (1H, dd, J 13.9, 4.5, PhCH2), 4.61 (1H, t, J 4.5,
PhCH2CH ), 7.21–7.39 (5H, m, Ph).
23
24
To a solution of peptide 41 (100 mg, 0.26 mmol) in degassed
MeOH (5 ml) was added Pd/C (20 mg, 20 w/w). The resultant
mixture was stirred overnight under a hydrogen balloon (1 atm)
before filtration through Celite®. The solvent was removed
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
2541

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F. Aznar, I. Gutierrez, S. Garcia-Granda and M. A. Llorca-
Baragano, Org. Lett., 2002, 4, 4273; (c) F. Clerici, M. L. Gelmi,
D. Pocar and T. Pilati, Tetrahedron: Asymmetry, 2001, 12, 2663; (d )
N. A. Anisimova, G. A. Berkova, T. Y. Paperno and L. I. Deiko,
Russ. J. Gen. Chem., 2002, 72, 460 CA 138:39040.; (e) N. A.
Anisimova, G. A. Berkova, T. Y. Paperno and L. I. Deiko, Russ. J.
Gen. Chem., 2002, 72, 272 (Chem. Abstr., 2002, 138:4360).
9 For recent examples see (a) A. I. Jimenez, P. Lopez, L. Oliveros
and C. Cativiela, Tetrahedron, 2001, 57, 6019; (b) A. Salgado,
T. Huybrechts, A. Eeckhaut, J. Van der Eycken, Z. Szakonyi,
F. Fulop, A. Tkachev and N. De Kimpe, Tetrahedron, 2001, 57,
2781.
10 (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 Trans. 1, 1998, 2321; (c) S. D. Bull, S. G. Davies and M. D.
O’Shea, J. Chem. Soc., Perkin Trans. 1, 1998, 3657; (d ) S. D. Bull,
S. G. Davies, A. C. Garner and N. Mujtaba, Synlett, 2001, 781; (e)
S. D. Bull, S. G. Davies, A. C. Garner and M. D. O’Shea, J. Chem.
Soc., Perkin Trans. 1, 2001, 3281; ( f ) S. D. Bull, S. G. Davies,
D. J. Fox, A. C. Garner and T. G. R. Sellers, Pure Appl. Chem., 1998,
70, 1501.
11 For a review of sulfur ylide chemistry see (a) A. H. Li, L. X. Dai and
V. K. Aggarwal, Chem. Rev., 1997, 97, 2341–2372 . For examples of
sulfur ylides utilised in cyclopropanations of dehydroamino acid
acceptors see references 5,7 and for example; (b) R. M. Williams
and G. J. Fegley, J. Am. Chem. Soc., 1991, 113, 8796; (c) D. Romo
and A. I. Meyers, J. Org. Chem., 1992, 57, 6265.
12 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353.
13 (a) C. R. Johnson and P. E. Rogers, J. Org. Chem., 1973, 38, 1793; (b)
C. R. Johnson and E. R. Janiga, J. Am. Chem. Soc., 1973, 95, 7692;
(c) C. R. Johnson and C. W. Schroeck, J. Am. Chem. Soc., 1973, 95,
7418.
under vacuum and the residues were subject to reflux overnight
in toluene (25 ml). The solvent was then removed under reduced
pressure and the crude residue was repeatedly triturated with
diethyl ether before recrystallisation from acetone afforded 39
23
as a colourless solid (24 mg, 40%). [α]D ϩ20.4 (c 0.25 in
MeOH) (Lit.28 [α]D ϩ35.7 [c 0.2 in MeOH]); Mp ЊC 262–265 ЊC;
νmax/cmϪ1 (KBr) 1731, 1670; δH (400 MHz, AcOH-d4) 0.31–0.37
(1H, m, CCH2), 0.69–0.75 (1H, m, CCH2), 0.88–0.95 (1H, m,
CCH2), 1.41–1.52 (1H, m, CCH2), 3.09 (1H, dd, J 13.8, 4.6,
PhCH2), 3.31 (1H, dd, J 13.9, 4.3, PhCH2), 4.61 (1H, t, J 4.4,
PhCH2CH ), 7.20–7.40 (5H, m, Ph); δH (400 MHz, MeOH-d4)
0.18–0.24 (1H, m, CCH2), 0.52–0.58 (1H, m, CCH2), 0.81–0.86
(1H, m, CCH2), 1.25–1.45 (1H, m, CCH2), 3.01 (1H, dd, J 13.7,
4.6, PhCH2), 3.27 (1H, dd, J 13.7, 4.0, PhCH2), 4.35 (1H, t,
J 4.5, PhCH2CH ), 7.21–7.63 (5H, m, Ph); δH (500 MHz, TFA-
d1) 0.71–0.77 (1H, m, CCH2), 1.08–1.14 (1H, m, CCH2), 1.24–
1.30 (1H, m, CCH2), 1.79–1.89 (1H, m, CCH2), 3.38 (1H, dd,
J 14.3, 4.2, PhCH2), 3.52 (1H, dd, J 14.2, 4.5, PhCH2), 4.95
(1H, t, J 4.4, PhCH2CH ), 7.21–7.38 (2H, m, Ph), 7.58–7.61
(3H, m, Ph); δC (100.6 MHz, DMSO-d6) 13.7, 16.3, 36.7, 39.9,
57.2, 127.5, 128.9, 131.0, 136.8, 168.5, 168.8; HRMS for
C13H15N2O2 (MHϩ) requires 231.2705, found 231.2709.
Acknowledgements
We would like to thank Professor D. Arigoni for providing
spectroscopic data, the EPSRC for a ROPA award (ACG).
14 M. J. Devos, J. N. Denis and A. Kreif, Tetrahedron Lett., 1978, 1847.
15 Fig. 2 shows a modified representation of the X-ray co-ordinate data
due to disorder in the crystal structure. Crystals of 12 were grown
from diethyl ether–pentane; however all samples examined were
twinned and eventually a fragment cut from a twin was examined
which did not show extraneous diffraction spots. In both molecules
in the unit cell the cyclopropyl group is disordered approximately 50/
50 over two sites which leads to a splitting of the adjacent carbons
which can be successfully modelled. Further details are contained in
the CIF file available from the Cambridge Crystallographic Data
Centre†.
References
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2 For examples of cyclopropane α-amino acids incorporated peptides
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K. K. Ho and D. Moye-Sherman, Synlett, 1994, 575; (c) K. Burgess,
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60.
3 For a recent review see J. Salaun, Top. Curr. Chem., 2000, 207, 1.
4 (a) M. C. Pirrung, Acc. Chem. Res., 1999, 32, 711 and references
contained therein; (b) R. Wiesendanger, B. Martinoni, T. Boller
and D. Arigoni, J. Chem. Soc., Chem. Commun., 1986, 238; (c)
R. K. Hill, S. R. Prakash, R. Wiesendanger, W. Angst, B. Martinoni,
D. Arigoni, H.-W. Liu and C. T. Walsh, J. Am. Chem. Soc., 1984,
106, 795; (d ) R. Wiesendanger, B. Martinoni, T. Boller and
D. Arigoni, Experientia, 1986, 42, 207.
16 Reference 10d and J. D. Holbrey and K. R. Seddon, J. Chem. Soc.,
Dalton Trans., 1999, 2133.
17 For examples see references 5 and 8. For a similar addition to a
related diketopiperazine derived substrate see (a) C. Alcaraz,
A. Herrero, J. L. Marco, E. Fernandez-Alvarez and M. Bernabe,
Tetrahedron Lett., 1992, 5605; (b) C. Alcaraz, M. D. Fernandez,
M. Pilar de Frutos, J. L. Marco, M. Bernabe, C. Foces-Foces and
F. H. Cano, Tetrahedron, 1994, 50, 12443.
18 (a) R. Huisgen, 1,3-Dipolar Cycloaddition Chemistry; A. Padwa, Ed.;
Wiley: New York, 1984; Vol. 1, pp. 1–176; (b) M. J. Begley,
F. M. Dean, L. E. Houghton, R. S. Johnson and B. K. Park,
J. Chem. Soc., Chem. Commun., 1978, 461; (c) R. Takagi,
M. Hashizume, M. Nakamura, S. Begum, Y. Hiraga, S. Kojima and
K. Ohkata, J. Chem. Soc., Perkin Trans. 1, 2002, 179.
19 References 4b, 4c and 4d and H. W. Liu, R. Auchus and C. T. Walsh,
J. Am. Chem. Soc., 1984, 106, 5335.
20 D. Seebach, E. Dziadulewicz, L. Behrendt, S. Cantoreggi and
R. Fitzi, Liebigs Ann. Chem., 1989, 1215.
5 Recent review of cyclic α-amino acid synthesis: see C. Cativiela and
M. D. Diaz-De-Villegas, Tetrahedron: Asymmetry, 2000, 11, 645 and
references therein. Recent miscellaneous examples: see C. S. Lee,
K. I. Lee and A. D. Hamilton, Tetrahedron Lett., 2001, 42, 211.
6 For recent examples see (a) I. O. Donkor, X. Zheng, J. Han and
D. D. Miller, Chirality, 2000, 12, 551; (b) O. Achatz, A. Grandl
and K. T. Wanner, Eur. J. Org. Chem., 1999, 1967; (c) P. Dorizon,
G. Su, G. Ludvig, L. Nikitina, R. Paugam, J. Ollivier and J. Salaün,
J. Org. Chem., 1999, 64, 4712; (d ) Y. Y. Kozyrkov, A. Pukin,
O. G. Kulinkovich, J. Ollivier and J. Salaün, Tetrahedron Lett., 2000,
41, 6399.
7 For recent examples see (a) R. Chinchilla, L. R. Falvello, N. Galindo
and C. Najera, J. Org. Chem., 2000, 65, 3034; (b) T. Abellan,
B. Mancheno, C. Najera and J. M. Sansano, Tetrahedron, 2001, 57,
6627; (c) for racemic example see J. Czombos, W. Aelterman,
A. Tkachev, J. C. Martins, D. Tourwe, A. Peter, G. Toth, F. Fulop
and N. De Kimpe, J. Org. Chem., 2000, 65, 5469.
21 P. K. Subramanian and R. W. Woodard, J. Org. Chem., 1987, 52, 15.
22 Prepared from DMSO-d6 and MeI-d3 by the method of Corey:
reference 12.
23 References 4b, 4c and 11b and R. W. Woodard, J. Org. Chem., 1985,
50, 4796.
24 Professor
D.
Arigoni,
personal
communication,
and
R. Wiesendanger, Dissertation ETH Nr 8003, Zurich, 1987.
25 Modelling was performed using the Macromodel® suite of
programs. 1000 starting conformations of enolate 40a were
generated using a Monte Carlo simulation and minimised using an
MM2 force field.
26 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge,
R. I. Cooper, CRYSTALS, 2001, Issue 11, Chemical
Crystallography Laboratory, Oxford, UK.
27 A. S. Saha, P. Schultz and H. Rapoport, J. Am. Chem. Soc., 1989,
111, 4856.
28 E. Kasafirek, J. Moural, J. Vinsova, A. Sturc and J. Taimr, Collect.
Czech. Chem. Commun., 1997, 62, 941.
8 For recent examples see (a) A. G. Moglioni, E. Garcia-Exposito,
A. Alvarez-Larena, V. Branchadell, G. Y. Moltrasio and R. M.
Ortuno, Tetrahedron: Asymmetry, 2000, 11, 4903; (b) J. Barluenga,
29 A. R. Mcmath, D. Guillaume, D. J. Aitken and H.-P. Husson, Bull.
Soc. Chim. Fr., 1997, 134, 105.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 3 1 – 2 5 4 2
2542