Diastereoselective synthesis of quaternary α-amino acids from diketopiperazine templates

Article abstract of DOI:10.1039/b704475e

Sequential enolate alkylations of (S)-N(1)-methyl-5-methoxy-6-isopropyl-3, 6-dihydropyrazin-2-one and (S)-N(1)-p-methoxybenzyl-5-methoxy-6-isopropyl-3,6- dihydropyrazin-2-one proceed with excellent levels of diastereoselectivity (>90% de) affording quaternary α-amino acids in high enantiomeric excess (>98% ee) after deprotection and hydrolysis. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b704475e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Diastereoselective synthesis of quaternary a-amino acids from
diketopiperazine templates†
Stephen G. Davies,* A. Christopher Garner, Jaqueline V. A. Ouzman, Paul M. Roberts, Andrew D. Smith,
Emma J. Snow, James E. Thomson, Juan A. Tamayo and Richard J. Vickers
Received 23rd March 2007, Accepted 17th May 2007
First published as an Advance Article on the web 29th May 2007
DOI: 10.1039/b704475e
Sequential enolate alkylations of (S)-N(1)-methyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one
and (S)-N(1)-p-methoxybenzyl-5-methoxy-6-isopropyl-3,6-dihydropyrazin-2-one proceed with
excellent levels of diastereoselectivity (>90% de) affording quaternary a-amino acids in high
enantiomeric excess (>98% ee) after deprotection and hydrolysis.
Introduction
Results and discussion
Alkylation of N,Nꢀ-bis-p-methoxybenzyl-3-isopropyl-6-
alkyl-piperazine-2,5-dione templates
The asymmetric synthesis of non-proteinogenic quaternary (a,a-
disubstituted) amino acids is of interest due to the biological
activity of these small molecules and peptides containing such
residues.1 Furthermore these materials have application in protein
engineering due to their ability to restrict the conformational
flexibility of peptides and allow the subtle perturbations of
overall structure without wholly disrupting secondary structural
features.2 The asymmetric synthesis of this class of a-amino
acid has been reviewed1 and recently a wide variety of ap-
proaches including phase transfer catalysis,3 asymmetric catalytic
allylation,4 chiral auxiliary,5 rearrangement,6 and chiral memory7
have been reported.8 We have previously reported the asymmetric
synthesis of both (R) and (S) tertiary a-amino acids from
the alkylation of N,Nꢀ-bis-p-methoxybenzyl-3-isopropyl-diketo-
piperazine (DKP) templates 19 and 210 (Fig. 1) and wished
to extend the alkylation chemistry of these templates to the
asymmetric preparation of quaternary a-amino acids. We describe
herein the results of these investigations, and the use of modified
diketopiperazine derived templates for the efficient asymmetric
synthesis of tertiary and quaternary a-amino acids.
In preliminary investigations alkylations of the lithium enolates
of the known substituted 6-methyl-DKP 3 and 6-benzyl-DKP 4
with a range of alkyl halides were found to proceed with poor
conversion and yield. The corresponding potassium enolates 5
and 6, however, were found to be more reactive and afforded
dialkylated products 7–9 in moderate yield and de. Notably the
alkylation of 5 with sterically hindered isopropyl iodide gave 8 in
only 36% isolated yield (Scheme 1).
Scheme 1 Reagents and conditions: (i) KHMDS (3 eq.), THF, −78 ◦C;
(ii) R2X.
Fig. 1 DKPs 1 and 2.
These results are in marked contrast to the reactivity and high
levels of diastereoselectivity observed upon mono-alkylation of
the lithium enolate of DKP 1. The poor reactivity and selectivity
observed in the present case is presumably due to an increase in
steric hindrance at the substituted carbon centre of the enolate
undergoing alkylation. The presence of the N(1)-alkyl substituent
close to the site of alkylation may also contribute to the steric
crowding of these enolates and it was therefore proposed that
Department of Organic Chemistry, Chemistry Research Laboratory, Uni-
versity of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.
davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b704475e
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mono-lactim ether substrates such as 18 and 19 (Fig. 2) may show
greater reactivity in alkylation reactions, allowing the efficient
alkylation of substituted enolates. In support of this hypothesis
the dialkylations of Scho¨llkopf’s bis-lactim ether auxiliary 1011
and N(1)-benzyl mono-lactim ether template 1112 (Fig. 2) have
been reported to proceed efficiently, and with high levels of trans
diastereofacial selectivity. We chose to investigate systematically
the reactivity and selectivity of templates N(1)-methyl 18 and N(1)-
p-methoxybenzyl 19 in order to appraise their general utility for
the preparation of a range of quaternary a-amino acids.
afforded the corresponding trans-(3R,6S)-product as the major
diastereoisomer, and the diastereoselectivity was independent of
the choice of N-alkyl substituent: both the N(1)-methyl and N(1)-
p-methoxybenzyl templates 18 and 19 delivered similar levels of
diastereoselectivity. Good to excellent diastereoselectivities were
observed in the alkylations with benzyl bromide (>98% de) and
isopropyl iodide (88 and 95% de), whilst lower levels of selectivity
were observed in the alkylations with methyl iodide (68 and 70%
de) (Scheme 3).16 In each case, the diastereoisomeric excess of the
1
alkylation reaction was determined by analysis of the H NMR
spectrum of the crude reaction mixture. The lower selectivity
observed for alkylation with methyl iodide was not the result of
epimerisation of the alkylation products during the reaction since
treatment of either trans-22 (>98% de) or cis-23 (>98% de) with
0.5 eq. of the lithium enolate of mono-lactim ether 19 returned
diastereoisomerically pure starting material.
Fig. 2 Scho¨llkopf’s bis-lactim ether auxiliary 10, and mono-lactim ether
templates 11, 18 and 19.
Mono-alkylation of N(1)-methyl and N(1)-p-methoxybenzyl
mono-lactim ether templates
Scheme 3 Reagents and conditions: (i) BuLi (1.0 eq.), THF, −78 ◦C then
R1X (1.1 eq.) [a crude; b purified].
N(1)-Methyl and N(1)-p-methoxybenzyl mono-lactim ether tem-
plates 18 and 19 were prepared in 39 and 44% overall yield,
respectively, from the appropriate (S)-N-alkyl-valine methyl ester
hydrochlorides 1213 and 13,14 via N-acylation with bromoacetyl
bromide, bromide displacement and concomitant cyclisation with
ammonia, and subsequent O-methylation with trimethyloxonium
tetrafluoroborate under vacuum in the ionic liquid solvent
N-butyl-Nꢀ-methyl-imidazolium tetrafluoroborate (BmimBF4)15
(Scheme 2).
Due to the high levels of diastereoselectivity (>98% de) observed
in the benzylation of mono-lactim ether templates 18 and 19
authentic samples of minor diastereoisomers cis-25 and cis-27 were
prepared separately via epimerisation of trans-24 and trans-26 to
enable unambiguous determination of the stereoselectivities in the
benzylation reactions. Treatment of trans-24 with BuLi followed
by reprotonation with acetic acid, afforded a 25 : 75 mixture of
trans-24 : cis-25 from which diastereoisomerically pure trans-24
and cis-25 were isolated in 15 and 32% yield respectively. Similar
treatment of trans-26 gave a 25 : 75 mixture of trans-26 : cis-27
from which trans-26 and cis-27 were isolated in 24 and 58% yield
respectively (Scheme 4).
Scheme 2 Reagents and conditions: (i) BrCH2COBr, Et3N, DCM, −78 ◦C;
(ii) NH3, EtOH, rt, 48 h; (iii) Me3OBF4, BmimBF4, vacuum, rt.
Scheme 4 Reagents and conditions: (i) BuLi, THF, −78 ◦C, then AcOH.
Efficient and exclusive C(3)-alkylation of mono-lactim ether
templates 18 and 19 was achieved with 1.0 eq. of BuLi followed by
addition of 1.1 eq. of three representative electrophiles viz. methyl
iodide, benzyl bromide and isopropyl iodide. All alkylations
The relative trans configuration of the C(3) and C(6) ring sub-
stituents of the major trans diastereoisomeric alkylation products
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20, 22 and 30, and the relative cis configuration within minor
diastereoisomer 25, were assigned from 1H NMR NOE difference
experiments, with the relative configurations of the remaining
diastereoisomers being assigned by analogy. The stereochemical
outcome in these alkylation reactions is also in accord with
previously reported alkylations of structurally related mono-
lactim ether templates12,17 (Fig. 3).
Scheme 5 Reagents and conditions: (i) TFA, reflux; (ii) HCl (10 M aq.),
reflux; (iii) SOCl2, MeOH, reflux, then conc. NH3, then distillation.
group. In N,Nꢀ-bis-p-methoxybenzyl protected DKP 1, and
Scho¨llkopf’s bis-lactim ether auxiliary 10, the regioselectivity of
deprotonation is controlled by the isopropyl substituent which
serves to direct deprotonation exclusively to the unsubstituted
position due to steric and stereoelectronic factors arising from
1,2-torsional strain.20 The related mono-lactim ether template
41, meanwhile, undergoes deprotonation of the more acidic C(3)
proton to give the corresponding O-stabilised enolate 42 (Fig. 4).21
Fig. 3 Selected NOE enhancements for trans-20, trans-22, cis-25 and
trans-30.
The relative and absolute configuration of trans-26 was estab-
lished via deprotection and hydrolysis to afford (R)-phenylalanine
methyl ester 38 which also demonstrated the viability of this
template for the asymmetric synthesis of tertiary a-amino acids.
N-Deprotection and lactim ether hydrolysis was achieved by
treatment with refluxing TFA to give DKP 34 in 72% yield.
Treatment of DKP 34 with refluxing 10 M HCl furnished a mixture
of (S)-valine and (R)-phenylalanine hydrochloride salts 35 and
36 respectively, in 98% yield, which was converted to a mixture
of the corresponding methyl ester hydrochloride salts 37 and
38. Neutralisation, followed by removal of the (S)-valine methyl
ester 37 under vacuum gave (R)-phenylalanine methyl ester 38 in
98% ee18 and 61% overall yield from trans-26 {[a]2D3 −32.2 (c 1.0
in EtOH) for 38·HCl, lit.19 [a]2D5 −37.0 (c 2.0, EtOH) for 38·HCl}
(Scheme 5).
Fig. 4 Regioselective deprotonation of templates 1, 10 and 41.
In order to examine the potential limitations enforced by the
competing contributions of a bulky substituent and lactim ether
functionality to deprotonation regioselectivity, isopropyl lactim
ethers 47 and 48 were prepared and alkylated. Templates 47 and
48 were prepared from the corresponding N(1)-alkyl DKPs 4522
and 46,23 by treatment with trimethyloxonium tetrafluoroborate in
BmimBF4.15 The deprotonation of 47 and 48 with BuLi (1 eq.) and
subsequent alkylation with either methyl iodide or benzyl bromide
afforded 49–52, products arising exclusively from alkylation at
C(3) bearing the isopropyl substituent (Scheme 6).
Regioselectivity of deprotonation and alkylation
Having examined the mono-alkylation chemistry of both N(1)-
methyl and N(1)-p-methoxybenzyl mono-lactim ether templates
18 and 19, studies were directed toward the alkylation of sub-
stituted templates. The effective dialkylation of these templates
is reliant upon regioselective deprotonation of the substituted
auxiliary at C(3), away from the C(6) stereodirecting isopropyl
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Scheme 6 Reagents and conditions: (i) Me3OBF4, BmimBF4, vacuum, rt;
(ii) BuLi (1 eq.), THF, −78 ◦C, then RX.
◦
Scheme 7 Reagents and conditions: (i) BuLi, THF, −78 C, then R2X
It is apparent that the regioselectivity of deprotonation of 45
and 46 is predominantly controlled by the significant difference
in stability of the two alternative O- or N-stabilised anions.
Furthermore the high yields of alkylated materials 49–52 obtained
from this protocol indicate that even templates bearing very bulky
substituents should be good substrates for the stereoselective
generation of quaternary amino acids.
[a crude; b purified].
Alkylation of substituted templates
The stereoselective alkylation of the substituted templates 20,
22, 24, 26, 28 and 30 was then examined. In an initial study,
deprotonation of N(1)-p-methoxybenzyl-3-methyl template trans-
22 with BuLi (1 eq.) followed by addition of benzyl bromide gave
(3R,6S)-N(1)-p-methoxybenzyl-3-benzyl-3-methyl 59 in 98% de,
which was isolated in 78% yield and as a single diastereoisomer
(>98% de). The diastereoisomer (3S,6S)-N(1)-p-methoxybenzyl-
3-benzyl-3-methyl 60 was prepared by deprotonation and methyla-
tion of N(1)-p-methoxybenzyl-3-benzyl template trans-26, to give
60 in 96% de, isolated in 68% yield as a single diastereoisomer
(>98% de) (Scheme 7). The general utility of this procedure was
further investigated by the alkylation of the range of substituted
N-methyl and N-p-methoxybenzyl protected templates 20, 22,
24, 26, 28 and 30, furnishing quaternary templates 53–64 with
absolute regioselectivity and high trans-diastereoselectivity in all
cases. Comparison of the reactions for the N-methyl and N-
p-methoxybenzyl templates indicated that the nature of the N-
protecting group has little effect on the reaction diastereoselectiv-
ity (Scheme 7).
Fig. 5 Selected NOE enhancements for 60 and 64.
stituted diastereoisomer 60, resulting from alkylation trans to
the C(6)-isopropyl group, in 98% de. This result demonstrates
that, as expected, the alkylation is a stereoselective and not a
stereospecific process, and that selectivity is independent of the
relative stereochemistry of the starting material (Scheme 8).
Scheme 8 Reagents and conditions: (i) BuLi (1 eq.), THF, −78 ◦C, then
MeI.
The relative configuration of dialkylation products 53–64
was assigned by analogy to the diastereoselectivity observed
in mono-alkylation reactions.12 This assignment was further
supported by NOE difference studies performed on 60 and 64,
where enhancements consistent with a cis relative configuration
of the C(3)-R1 and C(6)-isopropyl substituents were observed
(Fig. 5).24
In order to probe further the utility of this alkylation protocol,
alkylation with the functionalised N-Boc-3-bromomethylindole
65 was examined, as this may give access to the biologically im-
portant quaternary amino acid tryptophan hydrolase substrates.25
N(1)-p-Methoxybenzyl template 19 was alkylated with bromide
65 under standard conditions, to give 66 in 93% de, which was
isolated in 76% yield as a single diastereoisomer (Scheme 9).
The methylation of cis-27 under identical conditions to those
employed for methylation of trans-26 afforded the same disub-
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Scheme 9 Reagents and conditions: (i) BuLi (1 eq.), THF, −78 ◦C, then
65; (ii) BuLi (1 eq.), THF, −78 ◦C, then MeI.
The relative configuration within 66 was established by 1H NMR
NOESY spectroscopy (Fig. 6) and unambiguously confirmed
by X-ray crystallographic analysis‡, with the absolute (3R,6S)
configuration known from the (S)-valine derived stereocentre
(Fig. 7). Subsequent deprotonation of 66 and methylation gave
67 in 94% de, isolated in 76% yield as a single diastereoisomer
(Scheme 9). X-Ray crystallography unambiguously established the
trans-configuration of the isopropyl and methyl substituents, with
the absolute (3S,6S) configuration following from the (S)-valine
derived stereocentre (Fig. 8).
Fig. 7 Chem3D representation of the X-ray crystal structure of 66 (some
H atoms removed for clarity).
Fig. 6 Selected NOESY data for 66.
Deprotection and hydrolysis of templates
The deprotection and hydrolysis of the disubstituted N-p-
methoxybenzyl protected substrates to afford the desired qua-
ternary a-amino acids was then investigated. Subjecting 59–64
to reflux in TFA for 4 days furnished diketopiperazines 68–73 in
good yield (60–87%) as single diastereoisomers (Scheme 10).
The isomeric 3-benzyl-3-methyl quaternary substituted dike-
topiperazines 68 and 69 were then hydrolysed in concentrated HCl
to give a mixture of the corresponding amino acid hydrochloride
salts 35 and 74, which were subsequently converted to mixtures
of the corresponding methyl esters 37 and 75, and the (S)-valine
methyl ester 37 was removed via distillation under vacuum to
Fig. 8 Chem3D representation of the X-ray crystal structure of 67 (some
H atoms removed for clarity).
‡ CCDC reference numbers 292510 (66) and 292511 (67). For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b704475e
Scheme 10 Reagents and conditions: (i) TFA, reflux.
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give the enantiomeric (R)- and (S)-2-methyl-phenylalanine methyl
esters (R)-75 and (S)-75 in 66 and 72% overall yield from 68 and
69, respectively, and in 99% ee18 (Scheme 11).
HCl and under more forcing conditions (concentrated HI, 120 ◦C,
or 5 M aq. KOH, 100 ◦C) did not effect the hydrolysis of the dike-
topiperazine. Given the recalcitrance of 72 or 73 to hydrolysis, an
alternative deprotection strategy to afford dipeptides containing
the a-isopropyl-a-benzyl disubstituted amino acids was examined.
Hydrolysis of the lactim ether functionality of the N-methyl
templates 57 and 58 was achieved by treatment with concentrated
hydrochloric acid to afford N-methyl dipeptides 81 and 82 in good
yields. Furthermore, lactim ether hydrolysis and N-deprotection
of N-p-methoxybenzyl template 63 was achieved via treatment
with ceric ammonium nitrate (CAN) in aqueous acetonitrile to
afford dipeptide 83 in 80% yield,26 while analogous treatment of
the diastereoisomeric 3-isopropyl-3-benzyl template 64 afforded
dipeptide 84 in 67% isolated yield (Scheme 14).
Scheme 11 Reagents and conditions: (i) conc. HCl, reflux; (ii) SOCl2,
MeOH, reflux, then conc. NH3, then distillation.
Repetition of this protocol with the diastereoisomeric 3-
isopropyl-3-methyl templates 70 and 71 furnished a mixture of
(S)-valine methyl ester 37 and the corresponding homochiral
quaternary a-amino ester 76, which due to similarities in both
volatility and polarity could not be separated by distillation or
chromatography (Scheme 12). However, direct hydrolysis of the N-
methyl templates 55 and 56 with hydrochloric acid gave a mixture
of 77 and 78; subsequent esterification followed by neutralisation
afforded a mixture of N-methyl-valine methyl ester hydrochloride
79 and the corresponding homochiral quaternary a-methyl-a-
isopropyl a-amino acid methyl ester 80, which were then readily
separated by chromatography as the free amino esters and re-
acidified to afford (R)-80 and (S)-80 from 55 and 56 respectively,
in 99% ee18 (Scheme 13).
Scheme 14 Reagents and conditions: (i) HCl, reflux; (ii) CAN, H2O–
MeCN.
Conclusion
Mono lactim-ether templates 18 and 19 undergo highly stereose-
lective alkylations to generate tertiary and quaternary stereocen-
tres, with a range of unbranched, branched and functionalised
electrophiles, in high levels of diastereoisomeric purity. The
deprotection and hydrolysis of these templates affords homochiral
quaternary amino acids or (S)-valine-quaternary a-amino acid
dipeptides.
Scheme 12 Reagents and conditions: (i) conc. HCl, reflux; (ii) SOCl2,
MeOH, reflux, then conc. NH3.
Experimental
General experimental
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. Solvents were
dried according to the procedure outlined by Grubbs and co-
R
workers.27 Water was purified by an Elixꢀ UV-10 system. All other
solvents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin
layer chromatography was performed on aluminium plates coated
with 60 F254 silica. Plates were visualised using UV light (254 nm),
iodine, 1% aq. KMnO4, or 10% ethanolic phosphomolybdic acid.
Flash column chromatography was performed on Kieselgel 60
silica.
Scheme 13 Reagents and conditions: (i) conc. HCl, reflux; (ii) SOCl2,
MeOH, reflux, then conc. NH3, then chromatography, then HCl.
Treatment of the sterically encumbered 3-isopropyl-3-benzyl
substituted diketopiperazines 72 or 73 in refluxing concentrated
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Elemental analyses were recorded by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford,
UK. Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Optical rotations were recorded
on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm
cell. Specific rotations are reported in 10−1 deg cm2 g−1 and
concentrations in g per 100 mL. IR spectra were recorded on
Bruker Tensor 27 FT-IR spectrometer as either a thin film on
NaCl plates (film) or a KBr disc (KBr), as stated. Selected
characteristic peaks are reported in cm−1. NMR spectra were
recorded on Bruker Avance spectrometers in the deuterated
solvent stated. The field was locked by external referencing to
the relevant deuteron resonance. Low-resolution mass spectra
were recorded on either a VG MassLab 20-250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements were run
on either a Bruker MicroTOF and were internally calibrated
with polyanaline in positive and negative modes, or a Micro-
mass GCT instrument fitted with a Scientific Glass Instruments
BPX5 column (15 m × 0.25 mm) using amyl acetate as a lock
mass.
This mixture was taken up into an aq. solution and conc. aq.
NH3 was added dropwise until pH 10 was reached when it was
extracted with DCM. The combined organic extracts were dried
and concentrated in vacuo to furnish a mixture of amino acid
methyl esters. Valine methyl ester was distilled off under vacuum
yielding the desired amino acid methyl ester.
(S)-N(1)-p-Methoxybenzyl-5-methoxy-6-isopropyl-3,
6-dihydropyrazin-2-one 19
Following General procedure 1, DKP 17 (6.20 g, 22.4 mmol) and
Me3OBF4 (6.64 g, 44.9 mmol) in BmimBF4 (30 mL) gave, after
purification via flash column chromatography (eluent Et2O), 19 as
a pale brown crystalline solid (1.66 g, 61%); mp 94–96 ◦C (DCM–
heptane); [a]2D3 +23.4 (c 1.0 in CHCl3); mmax (KBr) 1697, 1658; dH
(400 MHz, CDCl3) 0.92 (3H, d, J 6.4, CH3CHCH3), 1.02 (3H, d,
J 7.0, CH3CHCH3), 2.16–2.24 (1H, m, CH3CHCH3), 3.67 (3H, s,
C(5)OMe), 3.69 (1H, ddd, J 2.0, 1.1, 1.0, C(6)H), 3.82 (3H, s,
ArOMe), 3.84 (1H, d, J 14.9, NCHHAr), 4.12 (1H, dd, J 19.6,
1.1, C(3)HH), 4.24 (1H, dd, J 19.6, 1.0, C(3)HH), 5.42 (1H, d, J
14.9, NCHHAr), 6.83–6.89 (2H, m, Ar), 7.15–7.18 (2H, m, Ar);
dC (100 MHz, CDCl3) 17.4, 19.9, 31.8, 46.5, 50.9, 52.7, 55.2, 60.9,
114.2, 127.9, 129.6, 159.2, 161.0, 168.0; m/z (ESI+) 313 ([M + Na]+,
83%), 291 (100); HRMS (ESI+) C16H23N2O3 ([M + H]+) requires
291.1709; found 291.1707.
General procedure 1 for mono-lactim ether formation
A mixture of DKP (1.0 eq.) and Me3OBF4 (2.0 eq.) was stirred
in BmimBF4 for 96 h under vacuum before quenching with
sat aq. NaHCO3 solution. The product was extracted with
Et2O, dried, concentrated in vacuo and purified by flash column
chromatography.
(3R,6S)-N(1)-p-Methoxybenzyl-3-benzyl-5-methoxy-6-isopropyl-
3,6-dihydropyrazin-2-one trans-26
General procedure 2 for mono-lactim ether alkylation
Following General procedure 2, BuLi (1.6 M in hexanes, 6.39 mL,
10.2 mmol), 19 (2.70 g, 9.29 mmol), and BnBr (1.22 mL,
10.2 mmol) in THF (120 mL) gave a >99 : <1 mixture of trans-
26 : cis-27. Purification via flash column chromatography (eluent
7 : 3 40–60 ◦C petrol : EtOAc) gave trans-26 as a colourless oil
(3.29 g, 94%, >98% de); [a]2D2 +3.1 (c 1.1 in CHCl3); mmax (film)
1648; dH (400 MHz, CDCl3) 0.88 (3H, d, J 7.0, CH3CHCH3),
0.98 (3H, d, J 7.0, CH3CHCH3), 2.12–2.20 (1H, m, CH3CHCH3),
3.37–3.39 (2H, m, C(3)CH2), 3.50 (1H, dd, J 5.0, 1.3, C(6)H), 3.68
(3H, s, C(5)OMe), 3.72 (1H, d, J 15.2, NCHHAr), 3.77 (3H, s,
ArOMe), 4.40 (1H, td, J 4.6, 1.3, C(3)H), 5.44 (1H, d, J 15.2,
NCHHAr), 6.72–6.76 (4H, m, Ar), 7.26–7.28 (3H, m, Ph), 7.35–
7.37 (2H, m, Ph); dC (100 MHz, CDCl3) 17.3, 19.8, 31.3, 39.6,
46.1, 52.5, 55.2, 59.3, 60.9, 114.1, 126.1, 127.7, 129.1, 130.7, 127.3,
138.4, 158.9, 159.1, 160.3; m/z (ESI+) 381 ([M + H]+, 100%);
HRMS (ESI+) C23H29N2O3 ([M + H]+) requires 381.2178; found
381.2180.
BuLi (solution in hexanes, 1.0 eq.) was added dropwise to a stirred
◦
solution of template (1.0 eq.) in THF at −78 C. After 45 min,
the electrophile (1.1 eq.) was added dropwise via syringe. The
reaction solution was then allowed to warm slowly to rt. After 16 h,
the reaction mixture was quenched with sat. aq. NH4Cl solution
and stirred for a further 10 min. The product was then extracted
with EtOAc, washed with H2O, dried, concentrated in vacuo and
purified by flash column chromatography.
General procedure 3 for lactim-ether hydrolysis
The alkylated template was dissolved in TFA and subjected to
reflux for 4 days. After this time the solvent was removed in vacuo.
The remaining solid residue was triturated with Et2O, filtered
under suction and then dried under vacuum.
General procedure 4 for DKP hydrolysis
(3S,6R)-3-Isopropyl-6-benzyl-piperazine-2,5-dione 34
The DKP was dissolved in conc. aq. HCl and subjected to reflux
for 3 days. Concentration of the reaction mixture in vacuo yielded a
mixture of amino acid hydrochloride salts which were dried under
vacuum.
Following General procedure 3, 26 (1.45 g, 3.81 mmol) and TFA
(50 mL) gave 34 (676 mg, 72%) as an off white solid; mp 256–
◦
257 C; [a]2D3 −58.3 (c 1.0 in AcOH); mmax (KBr) 3193, 1670; dH
(400 MHz, DMSO-d6) 0.75 (3H, d, J 6.8, CH3CHCH3), 0.82 (3H,
d, J 7.1, CH3CHCH3), 1.99–2.08 (1H, m, CH3CHCH3), 2.87 (1H,
dd, J 13.6, 4.9, C(6)CHHPh), 2.95 (1H, dd, J 2.5, 2.0, C(3)H),
3.15 (1H, dd, J 13.6, 3.8, C(6)CHHPh), 4.17 (1H, ddd, J 4.9, 3.8,
2.0, C(6)H), 7.18–7.28 (5H, m, Ph), 7.96 (1H, app br s, N(4)H),
8.15 (1H, app br s, N(1)H); dC (100 MHz, DMSO-d6) 17.4, 19.0,
32.4, 38.8, 56.0, 59.8, 127.5, 128.8, 131.0, 136.9, 167.9, 168.2;
General procedure 5 for formation of amino acid methyl esters
SOCl2 (3.0 eq.) was added to a solution of amino acid hydrochlo-
ride salts (1.0 eq.) in MeOH at 0 ◦C, and subsequently set at
reflux. After 16 h this solution was concentrated in vacuo to
yield a mixture of amino acid methyl ester hydrochloride salts.
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m/z (ESI+) 247 ([M + H]+, 100%); HRMS (ESI+) C14H19N2O2
3.83 (1H, d, J 14.0, NCHHAr), 5.41 (1H, d, J 14.0, NCHHAr),
6.82–6.88 (2H, m, Ar), 7.08–7.16 (2H, m, Ar), 7.18–7.27 (5H, m,
Ph); dC (100 MHz, CDCl3) 15.8, 20.4, 29.7, 30.8, 46.2, 46.4, 52.0,
55.2, 60.7, 61.9, 114.1, 126.4, 127.7, 129.4, 131.2, 128.3, 137.6,
155.9, 159.0, 172.1; m/z (ESI+) 417 ([M + Na]+, 100%), 395 (35);
HRMS (ESI+) C24H31N2O3 ([M + H]+) requires 395.2335; found
395.2333.
([M + H]+) requires 247.1447; found 247.1437.
(R)-Phenylalanine methyl ester 38
Following General procedure 4, 34 (275 mg, 1.11 mmol) and conc.
HCl (30 mL) gave a mixture of amino acid hydrochloride salts
35 and 36 (447 mg); dH (400 MHz, MeOD) 1.11 (6H, d, J 7.2,
CH3CHCH3), 2.28–2.40 (1H, m, CH3CHCH3), 3.23 (1H, dd,
J 14.5, 7.2, CHHPh), 3.33 (1H, dd, J 14.5, 5.8, CHHPh), 3.89
(3R,6S)-3-Benzyl-3-methyl-6-isopropyl-piperazine-2,5-dione 68
i
(1H, d, J 4.1, PrCH), 4.29 (1H, app t, J 6.5, CHCH2Ph), 7.31–
Following General procedure 3, 59 (1.29 g, 3.26 mmol) and TFA
(50 mL) gave 68 as an off white solid (509 mg, 60%); mp 280–
7.41 (5H, m, Ph). Subsequently, following General procedure 5, the
mixture of amino acid salts 35 and 36, SOCl2 (0.28 mL, 2.26 mmol)
and MeOH (40 mL) gave a mixture of methyl ester hydrochloride
salts which was neutralised and distilled as outlined in General
procedure 5, to give 38 as a colourless oil (142 mg, 74%); [a]D23
−32.2 (c 1.0 in EtOH) for 38·HCl, {lit.19 [a]D25 −37.0 (c 2.0 in
EtOH) for 38.HCl}; mmax (film) 3378, 1738; dH (400 MHz, CDCl3)
1.51 (2H, br s, NH2), 2.84 (1H, dd, J 13.6, 7.9, CHHPh), 3.07
(1H, dd, J 13.6, 5.1, CHHPh), 3.68 (3H, s, OMe), 3.71 (1H, m,
CH), 7.15–7.31 (5H, m, Ph); dC (100 MHz, CDCl3) 41.1, 51.9,
55.8, 126.8, 128.5, 129.2, 137.2, 175.4; m/z (ESI+) 180 ([M + H]+,
100%); HRMS (ESI+) C10H14NO2 ([M + H]+) requires 180.1025;
found 180.1020.
◦
282 C; [a]2D3 −22.0 (c 0.9 in CH3CO2H); mmax (KBr) 3193, 1670;
dH (400 MHz, DMSO-d6) 0.70 (3H, d, J 6.8, CH3CHCH3), 0.78
(3H, d, J 6.8, CH3CHCH3), 1.42 (3H, s, C(3)Me), 1.93–2.02 (1H,
m, CH3CHCH3), 2.67 (1H, dd, J 2.5, 1.7, C(6)H), 2.67 (1H, d, J
12.9, C(3)CHHPh), 3.08 (1H, d, J 12.9, C(3)CHHPh), 7.11–7.15
(2H, m, Ph), 7.22–7.26 (3H, m, Ph), 7.76 (1H, app br s, N(1)H),
8.24 (1H, app br s, N(4)H); dC (100 MHz, DMSO-d6) 17.3, 18.9,
28.6, 31.8, 47.3, 59.6, 60.4, 127.6, 128.7, 131.1, 137.0, 167.1, 170.4;
m/z (CI+) 261 ([M + H]+, 100%); HRMS (CI+) C15H21N2O2 ([M +
H]+) requires 261.1603; found 261.1610.
(3S,6S)-3-Benzyl-3-methyl-6-isopropyl-piperazine-2,5-dione 69
(3R,6S)-N(1)-p-Methoxybenzyl-3-benzyl-3-methyl-5-methoxy-6-
Following General procedure 3, 60 (775 mg, 1.96 mmol) and
TFA (40 ◦mL) gave 69 as an off white solid (459 mg, 66%); mp
283–285 C; [a]2D3 −11.7 (c 1.1 in AcOH); mmax (KBr) 1656; dH
(400 MHz, DMSO-d6) 0.11 (3H, d, J 6.8, CH3CHCH3), 0.57 (3H,
d, J 7.1, CH3CHCH3), 1.44 (3H, s, C(3)Me), 1.66–1.74 (1H, m,
CH3CHCH3), 2.61 (1H, d, J 13.1, C(3)CHHPh), 3.19 (1H, d, J
13.1, C(3)CHHPh), 3.59 (1H, dd, J 3.3, 1.8, C(6)H), 7.12–7.23
(5H, m, Ph), 7.72 (1H, app br s, N(1)H), 8.21 (1H, br, s, N(4)H);
dC (100 MHz, DMSO-d6) 16.6, 18.8, 30.4, 31.5, 45.3, 59.8, 60.6,
127.3, 128.6, 131.4, 137.5, 166.7, 170.0; m/z (CI+) 261 ([M + H]+,
100%); HRMS (CI+) C15H21N2O2 ([M + H]+) requires 261.1603;
found 261.1607.
isopropyl-3,6-dihydropyrazin-2-one 59
Following General procedure 2, BuLi (2.5 M in hexanes, 0.21 mL,
0.53 mmol), 22 (162 mg, 0.53 mmol), THF (10 mL) and BnBr
(70 lL, 0.59 mmol) gave a 99 : 1 mixture of 59 : 60. Purification via
flash column chromatography (eluent 3 : 1 hexane : Et2O) gave 59
as a colourless oil (164 mg, 78%, >98% de); C24H30N2O3 requires
C, 73.1; H, 7.7; N, 7.1%; found C, 72.9; H, 7.7; N, 7.1%; [a]D22
−53.1 (c 1.3 in CHCl3); mmax (film) 1651; dH (400 MHz, CDCl3)
0.81 (3H, d, J 6.8, CH3CHCH3), 0.89 (3H, d, J 6.8, CH3CHCH3),
1.63 (3H, s, C(3)Me), 1.98–2.09 (1H, m, CH3CHCH3), 2.90 (1H,
d, J 12.7, C(3)CHHPh), 3.26 (1H, d, J 2.8, C(6)H), 3.42 (1H,
d, J 12.7, C(3)CHHPh), 3.63 (1H, d, J 15.0, NCHHAr), 3.70
(3H, s, C(5)OMe), 3.75 (3H, s, ArOMe), 5.38 (1H, d, J 15.0,
NCHHAr), 6.44–6.47 (2H, m, Ar), 6.64–6.67 (2H, m, Ar), 7.20–
7.28 (5H, m, Ph); dC (100 MHz, CDCl3) 17.1, 20.1, 28.9, 29.4,
45.1, 48.7, 52.1, 55.1, 59.6, 62.4, 113.9, 126.2, 126.9, 127.8, 129.4,
130.8, 137.7, 156.5, 158.8, 171.0; m/z (ESI+) 395 ([M + H]+, 100%);
HRMS (ESI+) C24H31N2O3 ([M + H]+) requires 395.2335; found
395.2328.
(R)-a-Methyl-phenylalanine methyl ester (R)-75
Following General procedure 4, 68 (297 mg, 1.14 mmol) and
conc. HCl (35 mL) gave a mixture of amino acid hydrochloride
salts 35 and (R)-74 (360 mg); dH (400 MHz, MeOD) 1.12 (6H,
d, J 6.8, CH3CHCH3), 1.66 (3H, s, CMe), 2.30–2.39 (1H, m,
CH3CHCH3), 3.16 (1H, d, J 14.3, CHHPh), 3.33 (1H, d, J
i
14.3, CCHHPh), 3.89 (1H, d, J 4.4, PrCH), 7.29–7.41 (5H, m,
(3S,6S)-N(1)-p-Methoxybenzyl-3-benzyl-3-methyl-5-methoxy-6-
Ph). Subsequently, following General procedure 5, the mixture
of amino acid hydrochloride salts 35 and 74 (360 mg), SOCl2
(0.21 mL, 2.75 mmol) and MeOH (40 mL) gave a mixture of amino
acid methyl ester hydrochloride salts, which was neutralised and
distilled to give (R)-75 as a colourless oil (166 mg, 66%); [a]2D4 +11.9
(c 0.9 in CHCl3); mmax (film) 3368, 1734; dH (400 MHz, CDCl3) 1.39
(3H, s, CMe), 2.82 (1H, d, J 13.1, CHHPh), 3.09 (1H, d, J 13.1,
CHHPh), 3.68 (3H, s, OMe), 4.81 (2H, br s, NH2), 7.12–7.32
(5H, m, Ph); dC (100 MHz, CDCl3) 24.9, 46.2, 51.6, 58.8, 127.1,
128.4, 130.0, 136.6, 176.8; m/z (ESI+) 194 ([M + H]+, 100%);
HRMS (ESI+) C11H16NO2 ([M + H]+) requires 194.1181; found
194.1182.
isopropyl-3,6-dihydropyrazin-2-one 60
Following General procedure 2, BuLi (1.6 M in hexanes, 0.28 mL,
0.45 mmol), 26 (158 mg, 0.45 mmol), THF (10 mL) and MeI
(28 lL, 0.45 mmol) gave a 2 : 98 mixture of 59 : 60. Purification
via flash column chromatography (eluent 3 : 1 hexane : Et2O) gave
60 as a colourless oil (112 mg, 68%, >98% de); [a]2D3 −17.0 (c 0.95
in CHCl3); mmax (film) 1644; dH (400 MHz, CDCl3) 0.26 (3H, d, J
6.8, CH3CHCH3), 0.89 (3H, d, J 6.8, CH3CHCH3), 1.43 (3H, s,
C(3)Me), 1.85–1.95 (1H, m, CH3CHCH3), 3.02 (1H, d, J 12.9,
C(3)CHHPh), 3.35 (1H, d, J 12.9, C(3)CHHPh), 3.63 (3H, s,
C(5)OMe), 3.64 (1H, d, J 3.2, C(6)H), 3.80 (3H, s, ArOCH3),
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(S)-a-Methyl-phenylalanine methyl ester (S)-75
12 F. Paradisi, G. Porzi and S. Sandri, Tetrahedron: Asymmetry, 2001,
12, 3319; R. Galeazzi, M. Garavelli, A. Grandi, M. Monari, G.
Porzi and S. Sandri, Tetrahedron: Asymmetry, 2003, 14, 2639; D.
Balducci, G. Porzi and S. Sandri, Tetrahedron: Asymmetry, 2004,
15, 1085; D. Balducci, A. Grandi, G. Porzi, P. Sabatino and S.
Sandri, Tetrahedron: Asymmetry, 2004, 15, 3929; D. Balducci, S.
Crupi, R. Galeazzi, F. Piccinelli, G. Porzi and S. Sandri, Tetrahedron:
Asymmetry, 2005, 16, 1103; D. Balducci, A. Grandi, G. Porzi and
S. Sandri, Tetrahedron: Asymmetry, 2005, 16, 1453; D. Balducci, A.
Grandi, G. Porzi and S. Sandri, Tetrahedron: Asymmetry, 2006, 17,
1521.
Following General procedure 4, 69 (266 mg, 1.02 mmol) and conc.
HCl (30 mL) gave a mixture of amino acid hydrochloride salts 35
and (S)-74 (351 mg). Subsequently, following General procedure
5, the mixture of amino acid hydrochloride salts 35 and (S)-74
(351 mg), SOCl2 (0.04 mL, 0.73 mmol) and MeOH (10 mL) gave a
mixture of methyl ester hydrochloride salts, which was neutralised
and distilled to give (S)-75 as a colourless oil (129 mg, 74%); [a]D23
−14.1 (c 1.6 in CHCl3).
13 (S)-N-Methyl-valine methyl ester hydrochloride 12 was prepared
according to the procedure of L. Aurelio, R. T. C. Brownlee, A. B.
Hughes and B. E. Sleebs, Aust. J. Chem., 2000, 53, 425.
14 (S)-N-p-Methoxybenzyl-valine methyl ester hydrochloride 13, 15 and
17 were prepared according to the procedure of S. D. Bull, S. G. Davies,
A. C. Garner, A. L. Parkes, P. M. Roberts, T. G. R. Sellers, A. D. Smith,
J. A. Tamayo, J. E. Thomson and R. J. Vickers, New J. Chem., 2007,
31, 486.
Acknowledgements
We would like to thank the EPSRC for a ROPA award (A. C. G.).
15 J. D. Holbrey and K. R. Seddon, J. Chem. Soc., Dalton Trans., 1999,
2133. For a review of the application of ionic liquids in organic
synthesis see: H. Zhao and S. V. Malhotra, Aldrichimica Acta, 2002, 35,
75.
References and notes
16 In keeping with the anticipated increase in dialkylation reactivity of
these substrates the use of excess BuLi (1.1 eq.) and electrophile
(1.1 eq.) in the alkylations of 18 and 19 with methyl iodide and benzyl
bromide led to varying amounts of the corresponding dialkylation
products in the crude reaction mixtures (∼5%). Authentic samples of
the dialkylated products 32 and 33, derived from N(1)-p-methoxybenzyl
template 19, were prepared via treatment of mono-alkylated trans-22
and trans-26 with 1.0 eq. of BuLi and the respective electrophile.
1 C. Cativiela and M. D. Diaz-De-Villegas, Tetrahedron: Asymmetry,
1998, 9, 3517 and references contained therein.
2 For instance see: V. J. Hruby, Life Sci., 1982, 31, 189; R. Kaul, P. and P.
Balaram, Bioorg. Med. Chem., 1999, 7, 105; S. E. Gibson, N. Guillo and
M. J. Tozer, Tetrahedron, 1999, 55, 585; V. J. Hruby, Acc. Chem. Res.,
2001, 34, 389; J. Venkatraman, S. C. Shankaramma and P. Balaram,
Chem. Rev., 2001, 101, 3131.
3 T. Ooi, M. Takeuchi, M. Kameda and K. Maruoka, J. Am. Chem. Soc.,
2000, 122, 5228; J. Casas, C. Najera, J. M. Sansano, J. Gonzalez, J. M.
Saa and M. Vega, Tetrahedron: Asymmetry, 2001, 12, 699; K. Maruoka
and T. Ooi, Chem. Rev., 2003, 103, 3013; Y. N. Belokon, D. Bhave,
D. D’Addario, E. Groaz, V. Maleev, M. North and A. Pertrosyan,
Tetrahedron Lett., 2003, 44, 2045; Y. N. Belokon, N. B. Bespalova,
T. D. Churkina, I. Cisarova, M. G. Ezernitskaya, S. Harutyunyan,
R. Hrdina, H. B. Kagan, P. Kocovsky, K. A. Kochetkov, O. V.
Larionov, K. A. Lyssenko, M. North, M. Polasek, A. S. Peregudov,
V. V. Prisyazhnyuk and S. Vyskocil, J. Am. Chem. Soc., 2003, 125,
12860; T. Ooi, M. Takeuchi, Y. Uematsu and K. Maruoka, Tetrahedron
Lett., 2004, 45, 1675; Y. N. Belokon, D. Bhave, D. D’Addario,
E. Groaz, M. North and V. Tagliazucca, Tetrahedron, 2004, 60,
1849.
4 B. M. Trost and K. Dogra, J. Am. Chem. Soc., 2002, 124, 7256.
5 T. Abellan, R. Chinchilla, N. Galindo, C. Najera and J. M. Sansano,
J. Heterocycl. Chem., 2000, 37, 467; M. Tanaka, M. Oba, K. Tamai
and H. Suemune, J. Org. Chem., 2001, 66, 2667; S.-H. Lee, E.-K. Lee
and S.-M. Jeun, Bull. Korean Chem. Soc., 2002, 23, 931; C.-J. Koch,
S. Simonyiova, J. Pabel, A. Kartner, K. Polborn and K. T. Wanner,
Eur. J. Org. Chem., 2003, 1244.
Reagents and conditions: (i) BuLi, THF, −78 ◦C then RX.
17 V. Favero, G. Porzi and S. Sandri, Tetrahedron: Asymmetry, 1997, 8,
599; P. Di Felice, G. Porzi and S. Sandri, Tetrahedron: Asymmetry,
1999, 10, 2191; P. Di Felice, M. Maestri, F. Paradisi, G. Porzi and S.
Sandri, Tetrahedron: Asymmetry, 1999, 10, 4709.
18 Enantiomeric excesses were determined by 19F NMR spectroscopic
analysis of the homochiral and racemic Mosher’s amide derivatives;
see: J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543.
19 S.-T. Chen, K.-T. Wang and C.-H. Wong, J. Chem. Soc., Chem.
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6 M. Matsushita, H. Maeda and M. Kodama, Tetrahedron Lett., 1998,
39, 3749.
7 T. Kawabata, H. Suzuki, Y. Nagae and K. Fuji, Angew. Chem., Int.
Ed., 2000, 39, 2155; T. Kawabata, S.-P. Kawakami and K. Kaoru,
Tetrahedron Lett., 2002, 43, 1465.
20 S. D. Bull, S. G. Davies, A. C. Garner, A. L. Parkes, P. M. Roberts,
T. G. R. Sellers, A. D. Smith, J. A. Tamayo, J. E. Thomson and R. J.
Vickers, New J. Chem., 2007, 31, 486.
21 T. Fukuyama, R. K. Frank and A. A. Laird, Tetrahedron Lett., 1985,
26, 2955.
8 For examples of other routes leading to homochiral quaternary a-
amino acids see: A. Avenoza, J. H. Busto, C. Cativiela, J. M. Peregrina,
D. Sucunza and M. M. Zurbano, Tetrahedron: Asymmetry, 2003, 14,
399; S. Saaby, K. Nakama, M. A. Lie, R. G. Hazell and K. A. J␾rgensen,
Chem.–Eur. J., 2003, 9, 6145.
9 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.
22 45 was prepared from (S)-N(1)-p-methoxybenzyl-N(4)-methyl-3-
isopropyl-diketopiperazine-2,5-dione via debenzylation with CAN;
(S)-N(1)-p-methoxybenzyl-N(4)-methyl-3-isopropyl-diketopipera-
zine-2,5-dione was prepared according to the procedure of S. D. Bull,
S. G. Davies, A. C. Garner, A. L. Parkes, P. M. Roberts, T. G. R.
Sellers, A. D. Smith, J. A. Tamayo, J. E. Thomson and R. J. Vickers,
New J. Chem., 2007, 31, 486.
10 S. D. Bull, S. G. Davies, A. C. Garner and M. D. O’Shea, J. Chem. Soc.,
Perkin Trans. 1, 2001, 3281.
11 U. Scho¨llkopf, U. Groth and C. Deng, Angew. Chem., 1981, 93, 793; U.
Scho¨llkopf, U. Groth and C. Deng, Angew. Chem., Int. Ed. Engl., 1981,
20, 798. For selected recent di-alkylations of the Scho¨llkopf auxiliary,
see: S. Vassiliou, C. Dimitropoulos and P. A. Magriotis, Synlett, 2003,
2398; M. Andrei and K. Undheim, Tetrahedron: Asymmetry, 2004,
15, 53; M. Andrei, J. Efskind, T. Viljugrein, C. Romming and K.
Undheim, Tetrahedron: Asymmetry, 2004, 15, 1301; M. Andrei, C.
Romming and K. Undheim, Tetrahedron: Asymmetry, 2004, 15, 2711;
S. Vassiliou and P. A. Magriotis, Tetrahedron: Asymmetry, 2006, 17,
1754.
Reagents and conditions: (i) CAN, MeCN–H2O (3 : 1), rt.
23 46 was prepared according to the procedure of S. D. Bull, S. G. Davies,
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A. C. Garner, A. L. Parkes, P. M. Roberts, T. G. R. Sellers, A. D. Smith,
J. A. Tamayo, J. E. Thomson and R. J. Vickers, New J. Chem., 2007,
31, 486.
25 D. Shirlin, F. Gerhart, J. M. Hornsperger, M. Harmon, I. Wagner and
M. Jung, J. Med. Chem., 1988, 31, 30.
26 Attempted chromatographic purification of dipeptide 83 led to consid-
erable mass loss.
27 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.
Timmers, Organometallics, 1996, 15, 1518.
24 NOESY cross-peaks consistent with the assigned stereochemistry were
observed for all dialkylated products 53–64, with NOE difference
studies performed on selected samples only.
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Org. Biomol. Chem., 2007, 5, 2138–2147 | 2147
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