Asymmetric conjugate reductions with samarium diiodide: Asymmetric synthesis of (2S,3R)- And (2S,3S)-[2-2H,3-2H]-leucine-(S)- phenylalanine dipeptides and (2S,3R)-[2-2H,3-2H]- phenylalanine methyl ester

Article abstract of DOI:10.1039/b500566c

The highly diastereoselective samarium diiodide and D₂O-promoted conjugate reduction of homochiral (E)- and (Z)-benzylidene and isobutylidene diketopiperazines (E)-5,7 and (Z)-6,8 has been demonstrated. This methodology allows the asymmetric synthesis of methyl (2S,3R)-dideuteriophenylalanine 27 in ≥95% de and >98% ee, and (2S,3R)- or (2S,3S)-dideuterioleucine-(S)- phenylalanine dipeptides 37 and 38 in moderate de, 66% and 74% respectively. A mechanism is proposed to account for this process. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b500566c

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A R T I C L E
Asymmetric conjugate reductions with samarium diiodide:
asymmetric synthesis of (2S,3R)- and (2S,3S)-
[2-2H,3-2H]-leucine-(S)-phenylalanine dipeptides and
(2S,3R)-[2-2H,3-2H]-phenylalanine methyl ester
Stephen G. Davies,* Humberto Rodr´ıguez-Solla, Juan A. Tamayo, Andrew R. Cowley,
Carmen Concello´n, A. Christopher Garner, Alastair L. Parkes and Andrew D. Smith
Department of Organic Chemistry, University of Oxford, Chemistry Research Laboratory,
12 Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@chem.ox.ac.uk
Received 13th January 2005, Accepted 22nd February 2005
First published as an Advance Article on the web 17th March 2005
The highly diastereoselective samarium diiodide and D2O-promoted conjugate reduction of homochiral (E)- and
(Z)-benzylidene and isobutylidene diketopiperazines (E)-5,7 and (Z)-6,8 has been demonstrated. This methodology
allows the asymmetric synthesis of methyl (2S,3R)-dideuteriophenylalanine 27 in ≥95% de and >98% ee, and
(2S,3R)- or (2S,3S)-dideuterioleucine-(S)-phenylalanine dipeptides 37 and 38 in moderate de, 66% and 74%
respectively. A mechanism is proposed to account for this process.
acetamide7 or HMPA8 are typically required to facilitate this
reaction, Concello´n et al. have recently shown that conjugate
Introduction
The incorporation of isotopically labelled a-amino acid residues
into proteins has become a vital tool in the determination of pro-
reductions can be carried out using SmI2 and either H2O or
D2O.9,10 Although the diastereoselective conjugate reduction
tein structure by NMR techniques. The indiscriminate incorpo-
of a,b-unsaturated carbonyl systems using this methodology
ration of the NMR active isotopes 15N and 13C enables the effec-
has received only minimal attention, it was envisaged that
tive employment of heteronuclear correlation experiments, while
the reductive deuteration of an alkylidene diketopiperazine
the incorporation of 2H simplifies the assignment of the residual
template11 has the potential to stereoselectively generate two
1H resonances facilitating structural determination through the
interpretation of NOE data. Within this context, the incorpora-
new stereogenic centres and provide a route to a,b-dideuterated
a-amino acids. We report herein full studies concerning the
tion of regio- and stereoselectively deuterated a-amino acids into
conjugate reduction of diketopiperazine enamide template 4 and
polypeptides is a powerful tool in the structural determination
studies into the mechanism and scope of the reaction. Part of
of large biomolecules.1 The asymmetric synthesis of residues
this work has been previously communicated.12
which are stereoselectively deuterated at the a position has
been reported,2 along with the asymmetric synthesis of residues
Results and discussion
stereoselectively labelled in both the side chain and the a and b
positions.3 Side chain isotopically labelled a-amino acids have
To examine the potential for diastereoselective reductive deuter-
ation of diketopiperazine enamides, initial studies focused on
also found utility as valuable probes into biosynthetic pathways.4
Previous work from this laboratory has demonstrated the
utility of diketopiperazine enolate 1, prepared by conjugate
addition to the methylene diketopiperazine 2 or deprotonation
of a substituted diketopiperazine 3, for the asymmetric synthesis
of (S)-a-amino acids via stereoselective protonation5 (Fig. 1).
the preparation of the diastereoisomeric 3-benzylidene and 3-
isobutylidene substituted templates, (E)-5, (Z)-6, (E)-7 and (Z)-
8. It was envisaged that the (E)-diastereoisomers 5 and 7 could
be prepared utilising Horner–Wadsworth–Emmons (HWE)
methodology from a diketopiperazine phosphonate reagent.13
(2S,5S)-Chloro 9, prepared from 10 via an electrophilic flu-
orination and transhalogenation protocol,14 was treated with
triethylphosphite to give a 67 : 33 mixture of cis-(2S,5S)-
phosphonate 11 and trans-(2R,5S)-phosphonate 12 in a 60%
combined yield over three steps (Scheme 1). Chromatographic
separation of this mixture afforded cis-(2S,5S)-11 and a 20 : 80
mixture of cis-(2S,5S)-11 and trans-(2R,5S)-12, respectively. On
standing, trans-12 partially epimerised to cis-11, and data for the
minor isomer trans-12 were obtained from the 20 : 80 mixture of
11 and 12. The relative configuration within cis-(2S,5S)-11 was
1
evident from H NMR spectroscopic data15 and supported by
1H NMR NOE difference experiments (Fig. 2).
The HWE reaction of phosphonate 11 with benzaldehyde
and isobutyraldehyde proceeded with high levels of E stereos-
electivity affording (E)-3-ylidenes 5 and 7 in >98% and 97%
de and 63% and 67% yield respectively after chromatography
(Scheme 2). The (E)-double bond geometry of 5 and 7 was
established from 1H NMR NOESY data with correlations
between both the benzylic and the ortho-aromatic hydrogen
resonances of the N-4-p-methoxybenzyl group upon irradiation
of the double bond CH. The assigned double bond geometry of 7
was unequivocally confirmed by X-ray crystallographic analysis
Fig. 1 Generation of substituted diketopiperazine enolates.
In seeking to develop reductive processes to extend this
methodology we have noted that samarium diiodide6 promotes
=
the reduction of the C C double bond of a,b-unsaturated
esters and amides, and while additives such as N,N-dimethyl-
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 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 3 5
©

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Fig. 3 Chem 3DꢀR representation of the X-ray crystal structure of
(3E,6S)-7 (some H omitted for clarity).
Scheme 1 Reagents and conditions: (i) LHMDS, THF, −78 ◦C,
(PhSO2)2NF; (ii) TMSCl, CH2Cl2, room temperature; (iii) P(OEt)3,
room temperature, 3 d.
Attention then turned to the preparation of the corresponding
Z-alkylidene templates 6 and 8. Benzylidene 6 was prepared
from N,Nꢀ-diacetyl-diketopiperazine 13 via a modified litera-
ture procedure.16 The potassium tert-butoxide mediated aldol
condensation of diacetyl 13 with benzaldehyde proceeded with
concomitant N-4 deacylation and elimination to afford (3Z,6S)-
3-isobutylidene 14 in >98% de, which was subsequently N-
1 deacylated to afford 15 in >98% de and 74% yield over 2
steps. N-Alkylation at N-1 and N-4 with sodium hydride and
p-methoxybenzyl chloride then gave (3Z,6S)-6 in 57% yield
(Scheme 3).
Fig. 2 Selected 1H NMR NOE difference enhancement for 11.
Scheme 2 Reagents and conditions: (i) NaH, PhCHO or iPrCHO, THF,
0
◦C.
(Fig. 3). The diastereoselectivity in these thermodynamically
controlled reactions presumably derives from the steric demand
imposed by the N-4-p-methoxybenzyl N protecting group which
disfavours the Z isomers.
Scheme 3 Reagents and conditions: (i) tBuOK, PhCHO, THF; (ii)
NaOH, MeOH; (iii) p-methoxybenzyl chloride, NaH, DMF.
Unfortunately similar treatment of diacetyl 13 with potassium
tert-butoxide and isobutyraldehyde gave complex mixtures of
unidentified material and therefore the aldol condensation of
a template bearing alternative N-protection was investigated.
N-1-Boc-N-4-p-methoxybenzyl 16 was prepared from the N-4-
p-methoxybenzyl 1717 by treatment with (Boc)2O and DMAP in
89% yield. Treatment of 16 with LHMDS and isobutyraldehyde
at low temperature then afforded a mixture from which the
major component, aldol adduct (3S,6S,1ꢀR)-18 was isolated
in moderate yield (52%) as a single diastereoisomer. The
Selected 1H NMR NOESY correlations for 5 and 7.
1 4 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

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cis-(3S,6S) relative configuration of the diketopiperazine ring
substituents within 18 was apparent from H NMR spectro-
3-dideuterated-diketopiperazine (3S,6S,1ꢀR)-21 with >99% in-
corporation of two deuterium atoms (Scheme 6). Examination
of the 1H NMR spectrum of the crude reaction mixture
indicated an approximate 92 : 8 ratio of (3S,6S,1ꢀR)-21 and
combined (3S,6S,1ꢀS)-22, (3S,6R,1ꢀR)-23 and (3S,6R,1ꢀS)-24
diastereoisomers, respectively and a 95.5 : 4.5 ratio of cis-(3S,6S)
21 + 22 to trans-(3S,6R) 23 + 24 diastereoisomers respectively.
Chromatographic removal of the samarium residues afforded
21 (as a ∼92 : 8 mixture of 21 and minor diastereoisomers 22–
24) in 96% yield. Careful chromatographic separation of the
95.5 : 4.5 cis-21 + 22 : trans-23 + 24 mixture derived from
reduction of 5 afforded a 26 : 74 mixture of trans-(3S,6R,1ꢀR)-
23 and trans-(3S,6R,1ꢀS)-24 in 2% yield, and a 97.5 : 2.5 mixture
of cis-(3S,6S,1ꢀR)-21 and cis-(3S,6S,1ꢀS)-22 in 51% yield. The
chromatographic separation of diastereoisomers differing in
isotopic substitution at C1ꢀ is not expected and these data
indicate a 93 : 2.5 : 1 : 3.5 ratio of cis-21, cis-22, trans-23 and
trans-24, respectively in the original mixture.
1
scopic data while the (1ꢀR) configuration of 18 was tentatively
assigned from the coupling constant between H-1ꢀ and H-
3.18 Subsequent deprotonation of 18 with KHMDS effected
elimination and deacylation, affording Z-isobutylidene 19 in
96% de and moderate isolated yield (62%) after chromatography.
N-Alkylation of 19 with NaH and p-methoxybenzyl chloride
then gave (3Z,6S)-isobutylidene 8 in 96% de and 44% yield after
chromatography (Scheme 4).
Scheme 4 Reagents and conditions: (i) (BOC)2O, NaHCO3, EtOH; (ii)
LHMDS, iPrCHO, THF; (iii) KHMDS, THF; (iv) PMBCl, NaH, DMF.
With representative alkylidene templates in hand, preliminary
studies focused on the conjugate reduction of benzylidene
templates 5 and 6 with SmI2 and H2O, a process leading to the
generation of a C-3 stereogenic centre. Treatment of (3E,6S)-5
with SmI2 in THF and subsequent addition of deoxygenated
H2O led to clean reduction of the a,b-unsaturated enamide
to afford the known cis-(3S,6S)-20 in 95% de,5c–e and in
93% isolated yield. Similar reduction of the diastereoisomeric
benzylidene (3Z,6S)-6 also afforded cis-(3S,6S)-20 in 96% de
and 89% isolated yield (Scheme 5).
Scheme 5 Reagents and conditions: (i) SmI2, THF, H2O, room
temperature.
The high levels of cis-selectivity afforded in both these reduc-
tions are similar to the selectivity observed in the protonation
of substituted enolates derived from organocuprate additions to
enamide 2 or deprotonation of substituted diketopiperazines 3.
This selectivity is consistent with the formation of a common
samarium enolate intermediate which also undergoes stereose-
lective protonation anti to the isopropyl group. In accordance
with this hypothesis, the geometry of the enamide has no effect
on the diastereoselectivity in this reduction.
Having established that the auxiliary confers high levels of
diastereofacial selectivity in the generation of a single stereogenic
centre, studies turned to the dideuteration of these enamide
templates, a process which has the potential to stereoselectively
generate two new stereogenic centres at C-6 and C-1ꢀ. Treatment
of either (3E,6S)-5, (3Z,6S)-6, or a 7 : 1 mixture of (3E,6S)-5 :
(3Z,6S)-6 with a solution of SmI2 in THF and D2O gave C-1ꢀ,C-
Scheme 6 Reagents and conditions: (i) SmI2, THF, D2O, room
temperature.
The (3S,6S,1ꢀR)-configuration within dideuterio 21 was estab-
lished by conversion to the known methyl (2S,3R)-N-acetyl-2-
amino-2,3-dideuterio-3-phenylpropionate 25.19 N-Deprotection
of diastereoisomeric reduction mixture 21–24 with ceric ammo-
nium nitrate afforded (3S,6S,1ꢀR)-dideuterio-diketopiperazine
26, as a corresponding mixture of diastereoisomers, in 90%
yield. Subsequent hydrolysis followed by esterification yielded
a mixture of (2S,3R)-dideuterio-phenylalanine methyl ester 27
and (S)-valine methyl ester 28 as the hydrochloride salts which
were separated by distillation of the free amino esters to afford
(2S,3R)-dideuterio-phenylalanine methyl ester 27 in 93% de
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 3 7

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and 90% ee.20 N-Acetylation of 27 afforded, after chromato-
graphic purification, N-acetyl (2S,3R)-25 in 71% overall yield
(Scheme 7).
Scheme 7 Reagents and conditions: (i) ceric ammonium nitrate, H2O,
MeCN, rt; (ii) HCl conc., D; (iii) SOCl2, MeOH, D, NaHCO3, distillation;
(iv) Ac2O, NEt3, DMAP, DCM, room temperature.
The relative configuration within 25 was identified unam-
biguously by comparison with an authentic 42 : 58 mixture
of racemic dideuterio (2SR,3RS)-rac-25 and dideuterio epimer
(2SR,3SR)-29, derived from the D2O promoted SmI2 reduction
of methyl (Z)-a-acetamido-cinnamate, and comparison with
Scheme 8 Reagents and conditions: (i) SmI2, THF, D2O, room
temperature.
1
the H NMR spectroscopic data of the literature.19 The abso-
lute configuration of (3S,6S,1ꢀR)-diketopiperazine 21 and the
(2S,3R)-phenylalanine derivatives 25 and 27 follows from the
configuration of the (S)-valine derived stereogenic centre of
the starting auxiliary and was confirmed by the sign of the
specific rotation of the hydrochloride salt of methyl (2S,3R)-
2-amino-2,3-dideuterio-3-phenylpropionate 27 {[a]2D1 +29.9 (c
0.70 in EtOH), lit.21 [a]D +35.7 (c 1.06 in EtOH)}. The
observed ee and de for 25 are consistent with a 93 : 2.5 :
1 : 3.5 ratio of 21 : 22 : 23 : 24 in the original reduction
mixture, within an experimental error of 0.5%, and allow the
assignment of the major trans diastereoisomer as (3S,6R,1ꢀS)-
24. While the deprotection and hydrolysis of the mixture of
diastereoisomers allows confirmation of the observed reduction
de, the deprotection and hydrolysis of a sample of purified cis-
(3S,6S,1ꢀR)-21 + cis-(3S,6S,1ꢀS)-22 (97.5 : 2.5, 21 : 22) provided
homochiral (2S,3R)-dideuterio-phenylalanine methyl ester 27 in
≥95% de and >98% ee.20
The conjugate reduction of the isobutylidene templates (E)-
7 and (Z)-8 was next examined. Treatment of (E)-7 with a
solution of SmI2 in THF and D2O gave a 79 : 16 : 5 mixture of
dideuterio cis-(3S,6S,1ꢀR)-30, cis-(3S,6S,1ꢀR)-31 and combined
trans-(3S,6R,1ꢀR)-32 + trans-(3S,6R,1ꢀS)-33, respectively, with
>98% deuterium incorporation, in 94% purified yield after
chromatographic removal of the samarium residues (Scheme 8).
Similar conjugate reduction of (Z)-8 with SmI2 in THF and
D2O gave a 13 : 85 : 2 mixture of dideuterio cis-(3S,6S,1ꢀR)-30,
cis-(3S,6S,1ꢀS)-31 and combined trans-(3S,6R,1ꢀR)-32 + trans-
(3S,6R,1ꢀS)-33, respectively, with >98% deuterium incorpora-
tion, in 98% purified yield after chromatographic removal of the
samarium residues (Scheme 9).
The relative configuration of the C-3 and C-6 diketopiper-
azine ring substituents within cis-(3S,6S,1ꢀR)-30 and cis-
(3S,6S,1ꢀS)-31 was readily determined by comparison of the
1H NMR spectra with the known protio cis-(3S,6S)-6-isobutyl-
diketopiperazine 34.5c,e Trans isomers (3S,6R,1ꢀRS)-32 and
(3S,6R,1ꢀSR)-33 were identified by comparison with the 1H
NMR spectrum of protio 35, prepared by the diastereoselective
trans alkylation of parent auxiliary (S)-10 with isobutyl bromide.
The alkylation of the lithium enolate of (S)-10 with this hindered
electrophile proceeded slowly, giving a 50 : 50 mixture of
(3S,6R)-35 in 90% de and hydroxylated (3S,6R)-36 at 66%
Scheme 9 Reagents and conditions: (i) SmI2, THF, D2O, room
temperature.
conversion, from which 35 was isolated in 31% yield and
>98% de after chromatography (Scheme 10). The by-product
hydroxy-(3S,6R)-3615 presumably derives from oxidation of the
intermediate enolate by adventitious oxygen despite degassing
of the solvent.
The relative configuration of the C-1ꢀ stereogenic centre within
(3S,6S,1ꢀR)-30 and (3S,6S,1ꢀS)-31 was established by depro-
tection, hydrolysis and derivatisation of the dideuterioleucine
residues with (S)-N-CBz-phenylalanine to afford methyl (S)-
N-CBz-phenylalanyl-(2S,3R)-[2,3-2H2]-leucinate 37 and methyl
(S)-N-CBz-phenylalanyl-(2S,3S)-[2,3-2H2]-leucinate 38, respec-
tively. N-Deprotection of (1ꢀR)-30 (83 : 17, 30 : 31) or
1 4 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

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Scheme 10 Reagents and conditions: (i) LHMDS, iPrCH2I, THF,
−78 ◦C.
(1ꢀS)-31 (13 : 87, 30 : 31) with ceric ammonium nitrate
afforded the corresponding (3S,6S,1ꢀR)- or (3S,6S,1ꢀS)-
dideuterio-diketopiperazine 39 or 40 (as corresponding mixtures
of diastereoisomers) with subsequent hydrolysis followed by es-
terification yielding a mixture of (2S,3R)- or (2S,3S)-dideuterio-
leucine methyl ester 41 or 42 and (S)-valine methyl ester 28
as hydrochloride salts. The direct coupling of these mixtures
with (S)-N-CBz-phenylalanine afforded a mixture of deuterio-
dipeptide 37 or deuterio-dipeptide 38 and (S)-N-Cbz-Phe-(S)-
Val·OMe 43, which were separated by chromatography to afford
dipeptides 37 and 38, respectively (Scheme 11 and 12).
Scheme 12 Reagents and conditions: (i) ceric ammonium nitrate, H2O,
MeCN, room temperature; (ii) HCl conc., D; (iii) SOCl2, MeOH, room
temperature; (iv) NEt3, HOBT, (S)-CBz-N-phenylalanine, EDC, CHCl3,
room temperature, chromatography.
Scheme 13 Reagents and conditions: (i) NEt3, HOBT, (S)-CBz-N-
phenylalanine, EDC, CHCl3, room temperature.
Scheme 11 Reagents and conditions: (i) ceric ammonium nitrate, H2O,
MeCN, room temperature; (ii) HCl conc., D; (iii) SOCl2, MeOH, room
temperature; (iv) NEt3, HOBT, (S)-CBz-N-phenylalanine, EDC, CHCl3,
room temperature, chromatography.
For comparison purposes, an authentic sample of the protio
dipeptide 44 was prepared from the appropriate amino acid
derivatives by standard coupling methods (Scheme 13), while
dideuterio methyl (S)-N-CBz-phenylalanyl-(2S,3S)-[2,3-2H2]-
leucinate 38 was prepared via a rhodium catalysed deutero-
genation protocol. (Z)-N-Acetyl-dehydroleucine 45 (>98% de),
prepared in 3 steps from N-acetyl glycine methyl ester 46 in 61%
yield,22 was stereospecifically cis deuterogenated with deuterium
gas and Wilkinson’s catalyst23 to afford racemic (2RS,3RS)-
[2,3-2H2]-N-acetyl-leucine 47 in >98% de and provided the hy-
drochloride salt of (2RS,3RS)-[2,3-2H2]-N-acetyl-leucine methyl
ester 42 after protecting group manipulation. Coupling of
this material with (S)-N-CBz-phenylalanine afforded a 50 : 50
mixture of (S)-N-CBz-phenylalanyl-(2S,3S)-[2,3-2H2]-leucinate
38 and (S)-N-CBz-phenylalanyl-(2R,3R)-[2,3-2H2]-leucinate 48,
which were separated by chromatography to afford 38 in 89%
yield (Scheme 14).
Scheme 14 Reagents and conditions: (i) NBS, AIBN, CCl4; (ii) P(OMe)3;
(iii) tetramethylguanidine, iPrCHO; (iv) RhCl(PPh3)3, 1 atm D2;
(v) HCl conc., D; (vi) MeOH, SOCl2, room temperature; (vii) NEt3,
HOBT, (S)-CBz-N-phenylalanine, EDC, CHCl3, room temperature,
chromatography.
Mechanistic proposal for conjugate reductions
(3S)-diastereoisomeric products 21, 30 and 31 in high de. The
overall reduction of these enamides may be rationalized by
a mechanism which proceeds via two stepwise single electron
The reductions of benzylidenes (3E,6S)-5 and (3Z,6S)-6 and
isobutylidenes (3E,6S)-7 and (3Z,6S)-8 all proceed to give cis-
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 3 9

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reductions of the a,b-unsaturated system. Assuming that pro-
tonation of the initially formed radical anion is relatively slow,
successive reductions will generate a dianionic species,24 poten-
tially constituted with one or two bound samarium(III) moieties,
represented by 49-I or 49-II respectively, from which sequential
deuteration at C-1ꢀ then C-6 will afford the dideuterated product.
The high levels of stereoselectivity in the generation of the
C-6 stereogenic centre observed in all these reductions then
arise from a stereoselective deuteration of a samarium enolate
intermediate 50 at C-6, trans to the isopropyl group, consistent
with the previously observed re face selective protonation of the
related lithium enolates (Fig. 4).
Fig. 4 Proposed mechanism for the stereoselective conjugate reduction
with SmI2.
Fig. 5 Proposed mechanism for the stereospecific conjugate reduction
of 6 and 8 with SmI2.
The reduction of isobutylidene (3E,6S)-7 and (3Z,6S)-8
proceeds stereoselectively and stereospecifically to generate two
new stereogenic centres at C-6 and C-1ꢀ, while reduction of either
benzylidene (3E,6S)-5 or (3Z,6S)-6 stereoselectively, but not
stereospecifically, generates the same product diastereoisomer.
Mechanistically, the diastereoselective generation of the C-1ꢀ
stereogenic centre most probably derives from the stereospecific
deuteration with retention of configuration25 of a stereodefined
C-1ꢀ organosamarium intermediate.26 For reduction of isobutyli-
denes (3E,6S)-7 and (3Z,6S)-8 the major product diastereoiso-
mers 30 and 31 respectively, derive from syn dideuteration of
the re face of the auxiliary, consistent with deuteration with
retention of configuration of organosamarium intermediates 51
and 52 respectively. While the exact nature of these intermediates
has not been established, the proposed C-1ꢀ configurations of 51
and 52 are consistent with a formal addition of samarium to the
C-1ꢀ of ketyl precursors 53 and 54 respectively, anti to the C-
6 isopropyl group. Following this mechanism the isobutylidene
double bond geometry determines the C-1ꢀ configuration with
E-7 affording predominantly (3S,6S,1ꢀR)-30 (83 : 17, 1ꢀR-30 :
1ꢀS-31) while reduction of Z-8, via an analogous mechanism,
will afford (3S,6S,1ꢀS)-31 (13 : 87, 1ꢀR-30 : 1ꢀS-31) (Fig. 5).
Reduction of benzylidenes (3E,6S)-5 or (3Z,6S)-6 both fur-
nish the same product diastereoisomer. One possible mechanism
accounting for this reduction selectivity involves the interconver-
sion of (3E,6S)-5 and (3Z,6S)-6 under the reaction conditions
to the thermodynamically more stable benzylidene prior to
reduction. To investigate this possibility, partial reductions of
(3E,6S)-5 and (3Z,6S)-6 were carried out. Treatment of either
(3E,6S)-5 or (3Z,6S)-6 with a solution of SmI2 (1 eq) in
THF and D2O proceeded to ∼50% conversion, giving only
the expected diketopiperazine (3S,6S,1ꢀR)-21 and unchanged
starting material, in each case. Furthermore, treatment of a 50 :
50 mixture of (3E,6S)-5 : (3Z,6S)-6 under identical conditions
proceeded to 50% conversion, furnishing (3S,6S,1ꢀR)-21 and
returning a 50 : 50 mixture of (3E,6S)-5 : (3Z,6S)-6, indicating
that the rates of reduction of the two diastereoisomeric dike-
topiperazines are identical.
by a two-step reduction process similar to that proposed for
isobutylidenes 7 and 8. In the benzylidene case, initial single
electron reduction of either 5 or 6 by SmI2 will generate an allylic
ketyl radical intermediate (E)- or (Z)-55, which is sufficiently
stabilised by the C-2ꢀ phenyl group to allow isomerization of
the double bond to the thermodynamically more stable (E)-55,
prior to stereoselective formation of organosamarium 56 which
is then deuterated with retention of configuration to eventually
afford 21 (Fig. 6).
Fig. 6 Proposed mechanism for the stereoselective conjugate reduction
of 5 and 6 with SmI2.
Conclusion
In conclusion, conjugate reductions of 3-alkylidene substituted
diketopiperazine templates have been carried out using samar-
ium diiodide in THF and D2O. Isobutylidene enamides (E)-7
The observed stereoselectivity in the reductions of the benzyli-
dene geometric isomers (E)-5 or (Z)-6 may then be rationalized
1 4 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

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and (Z)-8 have been shown to be reduced stereoselectively
and stereospecifically to provide diastereoisomeric dideuterated
products (3S,6S,1ꢀR)-30 and (3S,6S,1ꢀS)-31 respectively, while
benzylidene enamides (E)-5 and (Z)-6 are highly stereoselec-
tively, but non-stereospecifically, dideuterated to afford the same
product diastereoisomer (3S,6S,1ꢀR)-21.
workup afforded crude 20, 21, 30, or 31 which was purified by
chromatography (silica, petrol 40–60/ethyl acetate, 3 : 1).
General procedure 3. CAN-mediated N-deprotection.
Compound 21, 30, or 31 (1.0 mmol) was dissolved in a mixture
of CH3CN/H2O, 3 : 2 (25 mL) and CAN (6.0 mmol) was added.
The mixture was stirred for 1 h at room temperature. The organic
solvent was evaporated, 20 ml of ether were added, the solid (26,
39, or 40) was filtered and washed with ether.
Experimental
General procedure 4. Hydrolysis and amino acid esterifica-
tion.
General experimental
All reactions involving organometallic or moisture sensitive
reagents were performed under an atmosphere of nitrogen via
standard vacuum line techniques. All glassware was flame-
dried and allowed to cool under vacuum. In all cases, the
reaction diastereoselectivity was assessed by peak integration
in the 1H 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. Chro-
matography was performed on Kieselgel 60 silica. Nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
AC 200 (1H: 200 MHz and 13C: 50.3 MHz), Bruker DPX 400
(1H: 400 MHz and 13C: 100.6 MHz) or Bruker AMX 500 (1H:
500 MHz and 13C: 125.7 MHz) spectrometer in the deuterated
solvent stated. All chemical shifts (d) 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 cm−1. Optical
rotations were recorded on a Perkin-Elmer 241 polarimeter
with a path length of 1 dm. Concentrations are quoted in g
100 ml−1. 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 upon a
Micromass AutoSpec or a Micromass ToFSpec spectrometer.
Elemental analyses were performed by the microanalysis service
of the Inorganic Chemistry Laboratory, University of Oxford.
A solution of the diketopiperazine 26, 39 or 40 (4.0 mmol) in
HCl conc. (25 mL) was subject to reflux for 36 h. Aqueous
HCl was then evaporated in vacuo to afford a mixture of
amino acid and (S)-valine hydrochlorides that were dissolved
◦
in MeOH (20 mL) and cooled to 0 C before thionyl chloride
(7.5 mmol) was added. The reaction mixture was stirred at room
temperature for 12 h. Concentration under vacuum afforded a 1 :
1 mixture of the methyl ester amino hydrochloride 27, 41, or 42
and methyl (S)-valinate hydrochloride 28 as a colourless solid.
General procedure 5. Dipeptide synthesis.
Triethylamine (4.3 mmol), 1-hydroxybenzotriazole hydrate
(1.05 mmol), (S)-N-Cbz-phenylalanine (0.86 mmol), and EDC
(1.05 mmol) were added successively to a solution of the
corresponding aminoester salt (0.86 mmol) in CHCl3 (40 ml),
at 0 ◦C, then allowed to warm to ambient temperature. After
16 hours, the reaction mixture was washed with 1 M HCl,
aqueous NaHCO3, and brine, dried and concentrated in vacuo.
Purification by chromatography (silica, petrol 30–40/ether, 5 :
1) afforded 37, 38, 43, 44 or 48 as a colourless solid.
[(2S,5S)-N,Nꢀ -Bis-(4-methoxybenzyl)-5-isopropyl-3,6-dioxo-
piperazin-2-yl]-phosphonic acid diethyl ester, 11 and [(2R,5S)-
N,Nꢀ -bis-(4-methoxybenzyl)-5-isopropyl-3,6-dioxo-piperazin-2-
yl]-phosphonic acid diethyl ester, 12. To
a solution of
105a,b (1.55 g, 3.91 mmol) in THF (50 ml) at −78 ◦C was
added LHMDS (4.3 ml, 1.0 M in THF, 4.3 mmol) and the
mixture stirred for 1 h. N-Fluorobenzenesulfonamide (1.36 g,
4.31 mmol) was then added and the mixture stirred at −78 ◦C for
30 min, after which time it was allowed to warm to −30 ◦C when
saturated aqueous NH4Cl (10 mL) was added. The mixture
was then partitioned between water (100 mL) and ether and
the aqueous phase extracted with ether. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to yield a
1 : 1 mixture of cis- and trans-fluorides as a yellow oil (2.07 g).
This crude mixture was then dissolved in dichloromethane
(10 ml) and chlorotrimethylsilane (3.25 ml) was added. The
mixture was stirred for 2 h at room temperature and then
concentrated in vacuo to yield 914 as an orange foam (2.1 g).
This crude product was then dissolved in dry dichloromethane
(15 ml), triethylphosphite (0.80 ml, 4.67 mmol) was added and
the mixture stirred at room temperature for 3 days. Solvents were
removed in vacuo to yield an orange oil (2.1 g). Chromatography
(ether/petroleum ether 1 : 1, then ethyl acetate/petroleum ether
1 : 1) yielded a 6 : 1 mixture of 11 and 12 as an oil (1.24 g, 60%).
Further chromatography yielded a pure sample of 11 and a
sample comprising a 4 : 1 mixture of 12 and 11, from which data
for the former were obtained. 11: [a]2D4 −237.1 (c 0.25, CHCl3);
General procedures
General procedure 1. Horner–Wadsworth–Emmons synthe-
sis of 5 and 7.
Sodium hydride (2.20 mmol) was stirred in THF (10 ml) and
the slurry was cooled to 0 ◦C. To this, 11 (0.94 mmol) and
benzaldehyde or isobutyraldehyde (3.0 mmol) in THF (10 ml)
were added at 0 ◦C via cannula over approximately 5 min. The
◦
reaction mixture was stirred at 0 C for 2 h and then allowed
to warm to room temperature over 15 min, after which time
saturated NH4Cl(aq.) (15 ml) was added and the mixture extracted
with EtOAc (3 × 15 ml). The combined organics were dried
(MgSO4) and concentrated in vacuo to yield compounds 5 and 7
after chromatography (silica, petrol 40–60/ethyl acetate, 3 : 1).
mmax/cm−1 (CHCl3) 1666 (C O); dH (400 MHz, CDCl3) 1.12
=
(3H, d, J 6.7, (CH3)2CH), 1.17 (3H, d, J 6.7, (CH3)2CH), 1.37
(3H, d, J 7.1, CH3CH2), 1.40 (3H, d, J 7.2, CH3CH2), 2.59 (1H,
dsept, J 9.8, 6.7, (CH3)2CH), 3.54 (1H, d, J 9.8, (CH3)2CHCH),
3.79 (1H, d, J 14.8, NCH2Ar), 3.81 (3H, s, CH3O), 3.81 (3H, s,
CH3O), 3.88 (1H, d, J 14.6, NCH2Ar), 4.18–4.30 (4H, m, 2 ×
CH2CH3), 4.39 (1H, d, 2JPH 22.6, PCHN), 5.42 (1H, d, J 14.8,
NCH2Ar), 5.56 (1H, d, J 14.6, NCH2Ar), 6.80–6.86 (4H, m,
Ar), 6.99–7.10 (4H, m, Ar); dC (125 MHz, CDCl3) 16.8 (d, 3JPC
General procedure 2. Samarium reductions.
Under nitrogen, a solution of SmI2 (10 mmol) in THF
27
(100 mL) was added dropwise to a stirred solution of 5–8
(4.0 mmol) in THF (20 ml) at room temperature. The reaction
mixture was stirred for 10 min and then deoxygenated H2O
or D2O (10 ml) was added. After stirring for 1 hour the
mixture was treated with 0.1 M aqueous HCl (50 ml). Standard
3
6.3), 16.9 (d, JPC 6.3), 20.5, 21.5, 33.9, 48.0, 50.8, 55.7, 55.7,
1
2
2
58.9 (d, JPC 147.1), 63.8 (d, JPC 7.5), 64.2 (d, JPC 7.5), 66.7,
114.7, 114.8, 127.6, 128.2, 129.4, 130.2, 159.8, 160.0, 162.3,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 4 1

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166.4; m/z (ES+) 533 (100%, MH+), 555 (66%, MNa+); (found:
MH+, 533.2415; C27H38N2O7P+ requires 533.2417).
reflections were used in the refinement. The final parameters
were wR2 = 0.0354 and R1 = 0.0316 [I > 3r(I)].†
4 : 1 of mixture 12 : 11: [a]2D4 −70.0 (c 0.32, CHCl3); mmax/cm−1
(6S,3Z)-3-Benzylidene-6-isopropyl-piperazine-2,5-dione 15.
Potassium tert-butoxide (1.85 g, 16.5 mmol) was added to
a stirred solution of diacetate 1329 (4.35 g, 18.1 mmol) and
benzaldehyde (1.67 ml, 16.5 mmol) in THF (60 ml) at room
temperature. After 30 min the mixture was partitioned between
ethyl acetate and aqueous NH4Cl, the aqueous layer extracted
with ethyl acetate, the combined organic layers dried (MgSO4)
and the solvents removed in vacuo to provide 14 as a viscous oil.
Chromatography (silica, hexane/ethyl acetate, 4 : 1) afforded
14 as a colourless solid (4.30 g, 83%). To a solution of 14
(4.30 g, 15 mmol) in methanol (20 ml) was added NaOH
(600 mg, 15.0 mmol) and the mixture stirred for 30 min at
room temperature. Methanol was then removed in vacuo, ether
added and the colourless solid collected by filtration to afford
15 (3.26 g, 89%). [a]2D3 −1.0 (c 1.0, DMSO); mmax/cm−1 (thin
=
(CHCl3) 1659 (C O); dH (400 MHz, CDCl3) 0.87 (3H, d, J 6.7,
(CH3)2CH), 1.16 (3H, d, J 6.7, (CH3)2CH), 1.28 (3H, d, J 7.1,
CH3CH2), 1.39 (3H, d, J 7.2, CH3CH2), 2.41 (1H, dsept, J
6.7, 2.5, (CH3)2CH), 3.81 (3H, s, CH3O), 3.81 (3H, s, CH3O),
3.83 (1H, dd, J 4.1, 2.5, (CH3)2CHCH), 3.93 (1H, d, J 15.2,
NCH2Ar), 4.11–4.28 (5H, m, 2 × CH2CH3 and NCH2Ar), 4.31
(1H, d, 2JPH 14.9, PCHN), 5.48 (1H, d, J 14.6, NCH2Ar), 5.49
(1H, d, J 15.2, NCH2Ar), 6.84–6.89 (4H, m, Ar), 7.19–7.25
3
(4H, m, Ar); dC (125 MHz, CDCl3) 15.3, 16.2 (d, JPC 5.0),
16.3 (d, 3JPC 5.0), 20.0, 29.4, 45.8, 47.1, 55.2, 55.2, 57.3 (d, 1JPC
2
2
139.5), 61.9, 63.5 (d, JPC 7.5), 63.6 (d, JPC 7.5), 114.2, 114.3,
126.9, 127.0, 129.5, 130.4, 159.1, 159.4, 161.8, 165.9; m/z (ES+)
533 (100%, MH+), 555 (77%, MNa+); (found: MH+, 533.2419;
C27H38N2O7P+ requires 533.2417).
=
film) 3480, 3411, 1680, 1636 (C O); dH (400 MHz, DMSO-d6)
(6SE,)-3-Benzylidene-6-isopropyl-1,4-bis-(4-methoxybenzyl)-
piperazine-2,5-dione 5. 11 (500 mg, 0.94 mmol) was
treated following general procedure 1 to afford a yellow
oil. Chromatography afforded 5 as a colourless solid (285 mg,
63%). Mp 110–112 ◦C; [a]D25 −186.1 (c 0.84, CHCl3); mmax/cm−1
0.81 (3H, d, J 6.3, (CH3)2CH), 0.89 (3H, d, J 6.6, (CH3)2CH),
2.03–2.17 (1H, m, (CH3)2CH), 3.73 (1H, s, (CH3)2CHCH), 6.75
=
(1H, s, C CHCH), 7.20–7.30 (1H, m, Ph), 7.30–7.40 (2H, m,
Ph), 7.45–7.55 (2H, m, Ph), 8.49 (1H, br s, NH), 9.98 (1H,
br s, NH); dC (100 MHz, DMSO-d6) 17.8, 19.1, 34.3, 61.4,
114.5, 128.6, 129.4, 130.0, 134.5, 161.5, 167.4; m/z (CI+) 245
=
(KBr) 1678 (C O); dH (400 MHz, CDCl3) 1.10 (3H, d, J 6.8,
(CH3)2CH), 1.18 (3H, d, J 6.8, (CH3)2CH), 2.32 (1H, dsept, J
7.2, 6.8, (CH3)2CH), 3.76 (1H, d, J 7.2, (CH3)2CHCH), 3.80
(6H, s, 2 × CH3O), 3.82 (1H, d, J 14.7, NCH2Ar), 4.78 (1H, d,
J 15.4, NCH2Ar), 5.12 (1H, d, J 15.4, NCH2Ar), 5.44 (1H, d, J
14.7, NCH2Ar), 6.59 (1H, s, PhCHC), 6.82–6.89 (4H, m, Ar),
7.12–7.20 (4H, m, Ar), 7.25–7.36 (5H, m, Ph); dC (100 MHz,
CDCl3) 19.1, 19.9, 33.2, 47.8, 48.9, 55.3, 55.3, 65.9, 114.2, 114.3,
123.7, 127.9, 128.0, 128.3, 128.6, 129.3, 129.6, 131.2, 134.2,
159.0, 159.3, 160.5, 166.0; m/z (ES+) 485 (100%, MH+), 507
(20%, MH+), 106 (100); (found: MH+, 245.1281; C14H17N2O2
+
requires 245.1290).
(6S,3Z)-N,Nꢀ-Bis-(4-methoxybenzyl)-3-benzylidene-6-isopro-
pyl-piperazine-2,5-dione 6. NaH (687 mg, 17.2 mmol, 60%
dispersion in mineral oil) was washed with hexane and
suspended in dimethylformamide (30 ml). The mixture was
cooled to 0 ◦C and 15 (1.87 g, 7.66 mmol) was added, followed
by the dropwise addition of p-methoxybenzyl chloride (2.60 ml,
19.1 mmol) over a period of 30 min. The reaction mixture was
stirred for a further 4 hours before the cautious addition of
water (5 ml) followed by excess saturated ammonium chloride
solution. The mixture was partitioned between ethyl acetate
(50 ml) and water (50 ml), and the aqueous phase extracted with
ethyl acetate (2 × 50 ml). The combined organic layers were
washed with 0.1 M HCl (2 × 30 ml), dried and concentrated in
vacuo. Chromatography (silica, petrol 40–60/ethyl acetate, 2 :
1) yielded 6 as a colourless oil (2.11 g, 57%). [a]2D3 −7.6 (c 1.0,
(34%, MNa+); (found: MH+, 485.2437; C30H33N2O4 requires
+
485.2440).
(6S,3E)-3-Isobutylidene-6-isopropyl-1,4-bis-(4-methoxybenzyl)-
piperazine-2,5-dione 7. 11 (500 mg, 0.94 mmol) was treated
following general procedure 1 to afford a yellow oil. After
chromatography, 7 was obtained as a colourless solid (285 mg,
◦
67%). Mp 89–90 C; [a]2D3 −238.1 (c 0.53, CHCl3); mmax/cm−1
=
(KBr) 1680, 1658 (C O); dH (400 MHz, CDCl3) 0.93 (3H, d,
=
J 6.6, (CH3)2CHCH C), 0.99 (3H, d, J 6.9, (CH3)2CHCHN),
1.01 (3H, d, J 6.6, (CH3)2CHCH C), 1.09 (3H, d, J 6.9,
CHCl3); mmax/cm−1 (thin film) 1685, 1615 (C O); dH (400 MHz,
=
=
CDCl3) 1.10 (3H, d, J 6.9, (CH3)2CH), 1.12 (3H, d, J 7.0,
(CH3)2CH), 2.17–2.26 (1H, m, (CH3)2CH), 3.61 (1H, d, J 7.9,
(CH3)2CHCH), 3.78 (1H, d, J 14.9, NCH2Ar), 3.76 (3H, s,
CH3O), 3.79 (3H, s, CH3O), 3.94 (1H, d, J 14.5, NCH2Ar), 5.17
(1H, d, J 14.5, NCH2Ar), 5.45 (1H, d, J 14.9, NCH2Ar), 6.70
(2H, m, Ar), 6.75 (2H, m, Ar), 6.81 (2H, m, Ar), 6.86 (2H, m,
(CH3)2CHCHN), 2.17 (1H, m, (CH3)2CHCHN), 3.57 (1H, m,
(CH3)2CHCH C), 3.69 (1H, d, J 6.8, (CH3)2CHCH), 3.80
=
(6H, s, 2 × CH3O), 3.86 (1H, d, J 14.8, NCH2Ar), 4.78 (1H,
AB, NCH2Ar), 4.85 (1H, AB, NCH2Ar), 5.37 (1H, d, J 14.8,
=
NCH2Ar), 5.46 (1H, d, J 10.0, C CHCH), 6.81–6.87 (4H,
m, Ar), 7.08–7.14 (4H, m, Ar); dC (100 MHz, CDCl3) 18.9,
19.8, 22.9, 23.0, 26.5, 32.9, 47.6, 48.6, 55.2, 55.3, 65.9, 114.0,
114.3, 128.1, 128.5, 128.9, 128.9, 129.3, 135.0, 158.9, 159.3,
161.2, 165.6; elem. anal. found C, 72.10, H, 7.61, N, 6.22;
C27H34N2O4 requires C, 71.97, H, 7.61, N, 6.22%; m/z (ES+) 451
=
Ar), 7.01 (2H, d, J 8.6, Ar), 7.19 (1H, s, C CHCH), 7.35–7.45
(5H, m, Ph); dC (62.5 MHz, CDCl3) 19.4, 20.3, 33.2, 47.5, 49.4,
55.4 (x 2), 67.0, 113.9, 114.4, 122.7, 128.1, 128.9, 129.1, 129.5,
129.7, 129.9, 133.9, 159.2, 159.3, 163.4, 167.5; m/z (ES+) 485
(100%, MH+); (found: MH+, 485.2434; C30H33N2O4 requires
+
+
(100%, MH+); (found: MH+, 451.2595; C27H35N2O4 requires
485.2440).
451.2597).
(3S)-N-1-(tert-Butoxycarbonyl)-N-4-(4-methoxybenzyl)-3-
isopropyl-piperazine-2,5-dione 16. To 1717 (2.00 g, 7.25 mmol)
in EtOH (50 ml) was added tert-butoxycarbonyl anhydride
(1.74 g, 7.97 mmol) followed by NaHCO3 (2.40 g, 29 mmol).
The mixture was sonicated for 12 h then the residue was filtered
and the solvent removed in vacuo to afford a crude oil which
was purified by chromatography (silica, EtOAc) to give 16 as
a clear oil (2.43 g, 89%). [a]2D5 −71.2 (c 1.0, CHCl3); mmax/cm−1
X-Ray crystal structure data for 7
Data were collected using an Enraf-Nonius Kappa CCD
diffractometer with graphite monochromated Mo–Karadiation
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.28
=
(KBr) 1677, 1750 (2 × C O); dH (400 MHz, CDCl3) 1.05 (3H,
d, J 6.8, (CH3)2CHCH), 1.11 (3H, d, J 6.8, (CH3)2CHCH), 1.24
Crystal data for 7 [C27H34N2O4], colourless plate, M = 450.58,
˚
monoclinic, space group P 1 21 1, a = 13.3830(4) A, b =
3
˚
˚
˚
7.0716(2) A, c = 13.9236(5) A, U = 1230.8 A , Z = 2, l =
0.081, crystal dimensions 0.18 × 0.30 × 0.30 mm, a total of
2996 unique reflections were measured for 5 < h < 28 and 2510
† CCDC reference numbers 260374. See http://www.rsc.org/suppdata/
ob/b5/b500566c/ for crystallographic data in .cif or other electronic
format.
1 4 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

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(9H, s, (CH3)3CO), 2.17–2.26 (1H, m, (CH3)2CH), 3.66 (1H, d,
J 6.8, (CH3)2CHCH), 3.80 (3H, s, CH3O), 3.83 (1H, d, J 14.9,
NCH2Ar), 4.21 (1H, d, J 17.7, NCOCH2), 5.37 (1H, d, J 14.6,
NCH2Ar), 5.58 (1H, d, J 17.7, NCOCH2), 6.86 (2H, d, J 8.7,
Ar), 7.15 (2H, d, J 8.7, Ar); dC (100 MHz, CDCl3) 18.6, 20.0,
27.9, 32.1, 48.3, 55.3, 66.4, 114.4, 127.1, 129.7, 150.3, 160.5,
164.2, 165.3; m/z (ES+) 377 (100%, MH+).
ethyl acetate (2 × 50 ml). The combined organic layers were
washed with 0.1 M HCl (2 × 30 ml), dried and concentrated in
vacuo. Chromatography (silica, petrol 40–60/ethyl acetate, 2 :
1) yielded 8 as a colourless oil (330 mg, 44%). [a]2D3 −50.4 (c 1.0,
CHCl3); mmax/cm−1 (thin film) 1684, 1663 (C O); dH (400 MHz,
=
CDCl3) 0.99 (3H, d, J 6.8, (CH3)2CHCHN), 1.01 (3H, d, J
=
6.9, (CH3)2CHCHN), 1.06 (3H, d, J 6.8, (CH3)2CHCH C),
=
1.14 (3H, d, J 6.8, (CH3)2CHCH C), 2.05–2.14 (1H, m,
(6S,3S,1ꢀR)-N -1-(4-Methoxybenzyl)-N -4-(tert-butoxycar-
bonyl)-3-(1-hydroxy-2-methylpropyl)-6-isopropyl-piperazine-2,5-
dione 18. A solution of 16 (600 mg, 1.6 mmol) in degassed
THF (30 ml) was cooled to −78 ◦C, and LHMDS (1.0 M in
THF, 1.76 ml) was added. The mixture was stirred for 1 hour
then isobutyraldehyde (0.16 ml, 1.76 mmol) was added and
the mixture stirred for 30 min at −78 ◦C. Saturated aqueous
NH4Cl (30 ml) was added and the mixture was extracted
with ethyl acetate (3 × 25 ml), dried (MgSO4), and the
solvent removed in vacuo to afford a mixture from which the
major product was purified by chromatography (silica, petrol
30–40/ethyl acetate, 3 : 1) to◦ yield 18 as a colourless solid
(400 mg, 52%). Mp 156–158 C; [a]2D5 −99.1 (c 1.0, CHCl3);
=
(CH3)2CHCHN), 2.66–2.75 (1H, m, (CH3)2CHCH C), 3.55
(1H, d, J 7.8, (CH3)2CHCH), 3.77 (1H, d, J 14.8, NCH2Ar),
3.79 (3H, s, CH3O), 3.80 (3H, s, CH3O), 4.40 (1H, d, J 14.9,
NCH2Ar), 5.13 (1H, d, J 14.9, NCH2Ar), 5.37 (1H, d, J 14.8,
=
NCH2Ar), 6.07 (1H, d, J 10.8, C CHCH), 6.75 (2H, d, J 8.6,
Ar), 6.80 (2H, d, J 8.6, Ar), 6.91 (2H, d, J 8.6, Ar), 7.06 (2H, d, J
8.6, Ar); dC (100 MHz, CDCl3) 19.0, 20.1, 21.7, 22.2, 27.2, 32.5,
49.2, 49.9, 55.2, 55.3, 66.7, 113.9, 114.1, 128.0, 128.5, 128.6,
128.8, 129.0, 129.8, 130.0, 130.5, 133.6, 158.9, 159.1, 163.5,
166.9; m/z (ES+) 451 (100%, MH+); (found: MH+, 451.2582;
+
C27H35N2O4 requires 451.2597).
(3S,6S)-N,Nꢀ -Bis-(4-methoxybenzyl)-benzyl-6-isopropyl-
mmax/cm−1 (KBr) 1681, 1748 (2 × C O); dH (400 MHz, CDCl3)
piperazine-2,5-dione 20. (E)-Benzylidene
5
(755 mg,
=
1.55 mmol) was treated with SmI2 and H2O according to
general procedure 2 to yield 20 (95% de) as a colourless oil
(698 mg, 93%). Similar treatment of (Z)-benzylidene 6 (755 mg,
1.55 mmol) afforded 20 (96% de) as an oil (672 mg, 89%).
Spectroscopic data was identical to the authentic sample.5c–e,1
1.02 (3H, d, J 6.8, (CH3)2CHCHOH), 1.03 (3H, d, J 6.8,
(CH3)2CHCHOH), 1.05 (3H, d, J 6.8, (CH3)2CHCH), 1.10
(3H, d, J 6.8, (CH3)2CHCH), 1.45 (9H, s, (CH3)3CO), 1.94–2.03
(1H, m, (CH3)2CHCHOH), 2.22–2.30 (1H, m, (CH3)2CHCH),
3.61 (1H, d, J 4.4, (CH3)2CHCH), 3.79 (3H, s, CH3O), 3.80
(1H, d, J 15.2, NCH2Ar), 4.22 (1H, d, J 2.4, CHCH(OH)iPr),
5.24 (1H, dd, J 2.4, 8.4, (CH3)2CHCHOH), 5.53 (1H, d, J
14.8, NCH2Ar), 5.91 (1H, s, OH), 6.85 (2H, d, J 8.4, Ar), 7.16
(2H, d, J 8.4, Ar); dC (100 MHz, CDCl3) 17.5, 18.4, 18.6, 19.7,
21.8, 23.1, 27.7, 30.3, 31.6, 47.3, 54.7, 55.2, 63.4, 78.8, 82.4,
114.3, 127.3, 129.4, 152.8, 159.2, 165.1, 166.8; m/z (ES+) 449.2
(3S,6S,1ꢀR)-N,Nꢀ-Bis-(4-methoxybenzyl)-3-deuterio-3-(deuterio-
phenylmethyl)-6-isopropyl-piperazine-2,5-dione
21. (E)-
Benzylidene 5 (1.94 g, 4.00 mmol) was treated with SmI2 and
D2O according to general procedure 2 to yield a 92 : 8 mixture
of 21 and (22 + 23 + 24) as a colourless oil (1.87 g, 96%).
Similar treatment of (Z)-benzylidene 6 or a 7 : 1 mixture of 5
and 6 afforded identical mixtures.
(100%, MH+); (found: MH+, 449.2645; C24H37N2O6 requires
+
449.2652).
Data for 21: [a]D25 −267.5 (c 1.0, CHCl3); mmax/cm−1 (thin
=
film) 1654 (C O); dH (500 MHz, CDCl3) 1.08 (3H, d, J 7.0,
(6S,3Z)-N-1-(4-Methoxybenzyl)-3-isobutylidene-6-isopropyl-
piperazine-2,5-dione 19. A solution of 18 (565 mg, 1.3 mmol)
in THF (30 ml) under N2, was cooled to −78 ◦C, and stirred for
30 minutes then KHMDS (0.5 M in toluene, 2.86 ml, 1.43 mmol)
was added. The mixture was stirred for 1 hour at −78 ◦C, and
then allowed to warm to ambient temperature. After a further
2 hours, saturated aqueous NH4Cl (30 ml) was added and the
reaction mixture was extracted with ethyl acetate (3 × 25 ml),
dried (MgSO4), and the solvent removed in vacuo. Purification
by chromatography (silica, petrol 30–40/EtOAc, 2 : 1) afforded
19 as a colourless oil (265 mg, 62%). [a]2D5 −116.6 (c 1.0, CHCl3);
(CH3)2CH), 1.14 (3H, d, J 7.0, (CH3)2CH), 1.88–1.99 (1H, m,
(CH3)2CH), 3.09 (1H, d, J 14.6, NCH2Ar), 3.40 (1H, s, CHD),
3.63 (1H, d, J 7.9, (CH3)2CHCH), 3.77 (3H, s, CH3O), 3.79
(3H, s, CH3O), 3.80 (1H, d, J 14.9, NCH2Ar), 5.18 (1H, d,
J 14.9, NCH2Ar), 5.41 (1H, d, J 14.9, NCH2Ar), 6.74–6.84
(6H, m, Ar), 7.02–7.05 (2H, m, Ar), 7.25–7.37 (5H, m, Ph); dC
1
(125 MHz, CDCl3) 19.7, 20.8, 34.1, 40.0 (t, JCD 19.8), 47.4,
1
49.7, 55.7 (x 2), 60.5 (t, JCD 21.8), 65.8, 114.4, 114.7, 128.7,
128.2, 128.3, 129.1, 129.4, 129.6, 129.8, 129.9, 130.1, 130.7,
130.4, 130.8, 137.9, 159.7, 159.8, 166.7, 166.6; m/z (ES+) 489
(100%, MH+); (found: MH+, 489.2723; C30H33D2N2O4+ requires
489.2722).
mmax/cm−1 (thin film) 1637, 1681 (2 × C O); dH (400 MHz,
=
CDCl3) 0.94 (3H, d, J 7.1, (CH3)2CHCHN), 1.06 (3H, d, J
(3S,6S,1ꢀR)-3-Deuterio-3-(deuteriophenylmethyl)-6-isopropyl-
piperazine-2,5-dione 26. Compound 21 (488 mg, 1.0 mmol)
was treated according to general procedure 3. After washing the
solid with ether, product 26 was obtained as a colourless solid
=
6.6, (CH3)2CHCHN), 1.08 (3H, d, J 6.5, (CH3)2CHCH C),
=
1.09 (3H, d, J 6.5, (CH3)2CHCH C), 2.20–2.28 (1H, m,
=
(CH3)2CHCHN), 2.44–2.53 (1H, m, (CH3)2CHCH C), 3.79
(1H, d, J 4.8, (CH3)2CHCHN), 3.80 (3H, s, CH3O), 3.90 (1H,
d, J 15.0, NCH2Ar), 5.41 (1H, d, J 14.9, NCH2Ar), 6.00 (1H,
◦
(229 mg, 90%). Mp 178–180 C; [a]2D5 −15.4 (c 0.50, DMSO);
mmax/cm−1 (KBr) 1667 (C O); dH (400 MHz, DMSO-d6) 0.24
=
d, J 10.1, CHCH C), 6.86 (2H, d, J 8.6, Ar), 7.19 (2H, d, J
=
8.6, Ar), 7.79 (1H, br, NH); dC (100 MHz, CDCl3) 16.8, 19.4,
21.9, 22.0, 25.5, 32.6, 47.7, 55.3, 64.4, 114.0, 124.9, 126.2, 127.7,
129.7, 158.9, 162.2, 164.8; m/z (ES+) 331.0 (100%, MH+);
(3H, d, J 6.8, (CH3)2CH), 0.63 (3H, d, J 6.8, (CH3)2CH),
1.65–1.73 (1H, m, (CH3)2CH), 2.84 (1H, s, CHD), 3.52 (1H,
br s, (CH3)2CHCH), 7.13–7.25 (5H, m, Ph), 7.37 (1H, s, NH),
8.10 (1H, s, NH); dC (125 MHz, CDCl3) 17.1, 19.1, 31.9, 38.3
(found: MH+, 331.2019; C19H27N2O3 requires 331.2022).
+
1
1
(t, JCD 18.8), 55.5 (t, JCD 20.3), 60.1, 127.3, 128.8, 131.1,
(6S,3Z)-N,Nꢀ -Bis-(4-methoxybenzyl)-3-isobutylidene-6-iso-
propyl-piperazine-2,5-dione 8. NaH (75 mg, 1.83 mmol, 60%
dispersion in mineral oil) was washed with hexane (3 × 5 ml)
and suspended in dimethylformamide (30 ml). The mixture was
cooled to 0 ◦C and 19 (550 mg, 1.66 mmol) was added, followed
by the dropwise addition of p-methoxybenzyl chloride (0.25 ml,
1.83 mmol) over a period of 30 min. The reaction mixture was
stirred for a further 6 hours before the cautious addition of
water (5 ml) followed by excess saturated ammonium chloride
solution. The mixture was partitioned between ethyl acetate
(50 ml) and water (50 ml), and the aqueous phase extracted with
137.1, 167.3, 167.5; m/z (ES+) 249 (100%, MH+); (found: MH+,
249.1580; C14H17D2N2O2 requires 249.1580).
+
(2S,3R)-2-Amino-2,3-dideuterio-3-phenylpropionic acid methyl
ester 27 and (S)-valine methyl ester 28. 26 (800 mg, 3.22 mmol)
was treated following general procedure 4 to afford a mixture of
27 and 28 as a colourless solid (700 mg). dH (400 MHz, CDCl3)
1.07 (3H, d, J 7.1, (CH3)2CH), 1.09 (3H, d, J 7.1, (CH3)2CH),
2.26–2.35 (1H, m, (CH3)2CH), 3.21 (1H, s, CHD), 3.82 (3H, s,
CH3O), 3.86 (3H, s, CH3O), 3.94 (1H, d, J 4.6, (CH3)2CHCH),
7.27–7.40 (5H, m, Ph). Methyl (S)-valinate hydrochloride was
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 4 3

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then removed by washing the mixture with a saturated solution
of NaHCO3 and removal of the free (S)-valine methyl ester
under vacuum afforded the free amino ester 27. dH (400 MHz,
CDCl3) 3.04 (1H, s, CHD), 3.69 (3H, s, CH3O), 7.09–7.36 (5H,
hexamethyldisilazide (0.55 ml, 1 M solution in THF, 0.55 mmol)
at −78 ◦C; after stirring for 1 hour the mixture was treated
with isobutyliodide (0.063 ml, 0.55 mmol). The mixture was
◦
stirred for 1 hour at −78 C and then allowed to slowly warm
1
m, Ph); dC (100 MHz, CDCl3) 40.6 (t, JCD 20), 51.9, 55.5
to room temperature over 12 hours. Aqueous saturated NH4Cl
(10 ml) was added and the mixture was partitioned between
ether and water, extracted with ether, the combined organic
layers were dried (MgSO4) and the solvent removed to afford
a 34 : 33 : 33 mixture of 10, 35 and 36. Chromatography
(silica, 30–40 petrol/ether, 1 : 1) afforded 35 as a colourless oil
(69 mg, 31%). [a]D20 +25.4 (c 0.50, CHCl3); mmax/cm−1 (KBr) 1650
1
(t, JCD 21), 126.7, 128.6, 129.6, 137.1, 175.4. Specific rotation
for the hydrochloride salt, 27·HCl: [a]2D1 +29.9 (c 0.70, EtOH),
{lit.21 +35.7 (c 1.06, EtOH)}.
Methyl (2S,3R)-[2,3-2H2]-N-acetyl-phenylalaninate 25. To a
cooled solution of the free amino ester 27 (225 mg, 1.26 mmol),
Et3N (0.55 mL, 3.9 mmol) and DMAP (50 mg) in dry
dichloromethane (30 mL), was added acetic anhydride (0.38 mL,
3.9 mmol) and the mixture was stirred at room temperature for
6 h. The reaction mixture was washed with 0.1 M aqueous HCl,
saturated aqueous NaHCO3 and brine. The organic phase was
dried over MgSO4 and the solvent removed in vacuo. Purification
by chromatography (silica, petrol 40–60/ethyl acetate, 4 : 1)
afforded 25 (197 mg, 71%). dH (400 MHz, DMSO) 1.81 (3H, s,
COMe), 2.97 (1H, s, C(3)HS), 3.61 (3H, s, CO2Me), 7.21–7.35
(5H, m, ArH), 8.37 (1H, br s, NH).
=
(C O); dH (400 MHz, CDCl3) 0.77 (3H, d, J 7.1, (CH3)2CH),
0.82 (3H, d, J 6.6, (CH3)2CHCH2), 0.92 (3H, d, J 6.8,
(CH3)2CHCH2), 1.11 (3H, d, J 6.8, (CH3)2CH), 1.62–1.75 (1H,
m, (CH3)2CHCH2), 1.89–1.95 (1H, m, (CH3)2CHCH2), 2.00–
2.05 (1H, m, (CH3)2CHCH2), 2.28–2.39 (1H, m, (CH3)2CH),
3.75 (1H, d, J 14.6, ArCH2), 3.80 (1H, d, J 7.6, (CH3)2CHN),
3.81 (3H, s, CH3O), 3.82 (3H, s, CH3O), 3.88 (1H, d, J 14.6,
ArCH2), 3.96–4.00 (1H, m, (CH3)2CHCH2CH), 5.32 (1H, d, J
14.6, ArCH2), 5.47 (1H, d, J 14.6, ArCH2), 6.84–6.87 (4H, m,
aromatic CH), 7.16–7.24 (4H, m, aromatic CH); dC (100 MHz,
CDCl3) 16.3, 19.9, 22.6, 23.5, 24.1, 31.4, 38.9, 45.4, 46.8, 55.2,
55.3, 56.4, 62.8, 114.0, 114.1, 127.2, 127.7, 130.0, 130.1, 159.2.
Selected literature data19 for methyl (RS)-N-acetyl-phenyl-
alaninate (1H 400 MHz, DMSO) 2.86 (1H, dd, J 13.7, 9.3,
C(3)HR), 3.00 (1H, dd, J 13.7, 5.4, C(3)HS), 4.44 (1H, ddd,
J 9.3, 7.3, 5.4, C(2)H); for methyl (2S,3R)-[3-2H]-N-acetyl-
phenylalaninate (1H 800 MHz, DMSO) 2.98 (1H, d, J 5.5,
C(3)HS); methyl (2S,3S)-[2,3-2H2]-N-acetyl-phenylalaninate
(1H 400 MHz, DMSO) 2.84 (1H, s, C(3)HR).
+
159.3, 165.3, 167.1; m/z (ES+) 511.4 (100%, MNH4 + MeCN);
(found: MH+, 453.2742; C27H37N2O4 requires 453.2753).
+
(3S,6S,1ꢀR)-3-Deuterio-3-(1-deuterio-2-methylpropyl)-6-isopro-
pylpiperazine-2,5-dione 39. 30 (908 mg, 2.0 mmol) was treated
according to general procedure 3. After washing the solid
with ether, product 39 was obtained as a colourless solid
(3R,6S,1ꢀR)-N,Nꢀ -Bis-(4-methoxybenzyl)-3-deuterio-3-
(deuteriophenylmethyl)-6-isopropyl-piperazine-2,5-dione
30.
◦
(334 mg, 78%). Mp 151–153 C; [a]2D5 −28.5 (c 1.0, DMSO);
Isobutylidene 7 (1.8 g, 4.0 mmol) was treated according to
general procedure 5 to yield 30 [79 : 16 : 5 mixture of 30 : 31 :
(32 + 33)] as a colourless oil (1.78 g, 98%). [a]2D5 −219.6 (c 1.0,
mmax/cm−1 (KBr) 1657, 1662 (2 × C O); dH (400 MHz, DMSO-
=
d6) 0.84 (3H, d, J 6.8, (CH3)2CHCD), 0.85 (3H, d, J 6.3,
(CH3)2CHCD), 0.87 (3H, d, J 6.6, (CH3)2CHCH), 0.94 (3H,
d, J 7.1, (CH3)2CHCH), 1.58 (1H, d, J 8.8, (CH3)2CHCHD),
1.78–1.87 (1H, m, (CH3)2CHCHD), 2.04–2.16 (1H, m,
(CH3)2CHCHN), 3.60–3.61 (1H, m, (CH3)2CHCHN), 8.04
(1H, br s, NH), 8.16 (1H, br s, NH); dC (100 MHz, CDCl3) 18.2,
19.6, 22.6, 23.9, 24.3, 32.3, 44.3 (t, 1JCD 18.8), 52.9 (t, 1JCD 23.4),
60.4, 167.7, 169.3; m/z (ES+) 215.1 (100%, MH+); (found: MH+,
CHCl3); mmax/cm−1 (thin film) 1660 (C O); dH (400 MHz,
=
CDCl3) 0.96 (3H, d, J 6.6, (CH3)2CHCD), 0.97 (3H, d, J 6.3,
(CH3)2CHCD), 1.11 (3H, d, J 6.8, (CH3)2CHCH), 1.18 (3H,
d, J 6.8, (CH3)2CHCH), 1.82 (1H, d, J 5.1, (CH3)2CHCHD),
1.95–2.01 (1H, m, (CH3)2CHCHD), 2.13–2.22 (1H, m,
(CH3)2CHCHN), 3.65 (1H, d, J 7.6, (CH3)2CHCHN), 3.78
(1H, d, J 14.7, NCH2Ar), 4.79 (1H, d, J 14.7, NCH2Ar), 3.81
(6H, s, 2 × CH3O), 5.23 (1H, d, J 14.7, NCH2Ar), 5.40 (1H,
d, J 14.7, NCH2Ar), 6.83–6.87 (4H, m, Ar), 7.06–7.10 (4H, m,
Ar); dC (100 MHz, CDCl3) 19.8, 20.7, 21.8, 23.1, 25.8, 33.4, 43.4
+
215.1731; C11H19D2N2O2 requires 215.1729).
(2S,3R)-2-Amino-2,3-dideuterio-4-methylpentanoic acid methyl
ester 41 and (S)-valine methyl ester 28. 39 (450 mg, 2.10 mmol)
was treated following general procedure 5 to afford a mixture of
41 and 28 as a colourless solid (400 mg) which was used without
further purification. dH (400 MHz, CD3OD) 1.01 (3H, d, J 6.5,
(CH3)2CHCHD), 1.02 (3H, d, J 6.5, (CH3)2CHCHD), 1.07 (3H,
d, J 7.1, (CH3)2CHCHN), 1.09 (3H, d, J 7.1, (CH3)2CHCHN),
1.75–1.85 (2H, m, (CH3)2CHCHD and CHD), 2.26–2.35 (1H,
m, (CH3)2CHCHN), 3.86 (3H, s, OCH3), 3.87 (3H, s, OCH3),
3.95 (1H, d, J 4.4, (CH3)2CHCH).
1
1
(t, JCD 18.8), 46.6, 48.9, 55.3, 56.8 (t, JCD 20.2), 65.3, 114.2,
114.3, 126.9, 127.9, 128.1, 128.2, 128.3, 129.1, 129.3, 159.2,
159.3, 166.1, 167.7; m/z (ES+) 455.1 (100%, MH+); (found:
MH+, 455.2879; C27H35D2N2O4 requires 455.2879).
+
(3S,6S,1ꢀS)-N,Nꢀ -Bis-(4-methoxybenzyl)-[3-2H,1ꢀ -2H]-3-
benzyl-6-isopropyl-piperazine-2,5-dione 31. Isobutylidene
8
(0.90 g, 2.0 mmol) was treated according to general procedure 2
to yield 31 [13 : 85 : 2 mixture of 30 : 31 : (32 + 33)] as a colourless
oil (860 mg, 95%). [a]2D5 −181.0 (c 1.0, CHCl3); mmax/cm−1 (thin
N-Cbz-(S)-phenylalanine-(2S,3R)-2-amino-2,3-dideuterio-4-
methyl-pentanoic acid methyl ester 37. Amino-ester
hydrochloride salts 28 and 41 (400 mg) were treated following
general procedure 5. Purification by chromatography afforded
37 as a colourless solid (350 mg, 84%). Mp 87 ◦C; [a]D25 −3.0 (c 1.0,
=
film) 1643 (C O); dH (400 MHz, CDCl3) 0.95 (3H, d, J 6.6,
(CH3)2CHCD), 0.96 (3H, d, J 6.6, (CH3)2CHCD), 1.10 (3H,
d, J 6.8, (CH3)2CHCH), 1.16 (3H, d, J 6.8, (CH3)2CHCH),
1.52 (1H, d, J 9.1, (CH3)2CHCHD), 1.93–2.02 (1H, m,
(CH3)2CHCHD), 2.11–2.20 (1H, m, (CH3)2CHCHN), 3.64
(1H, d, J 7.6, (CH3)2CHCHN), 3.76 (1H, d, J 14.9, NCH2Ar),
3.78 (1H, d, J 14.7, NCH2Ar), 3.79 (6H, s, 2 × CH3O), 5.22
(1H, d, J 14.7, NCH2Ar), 5.38 (1H, d, J 14.9, NCH2Ar),
6.81–6.83 (4H, m, Ar), 7.05–7.09 (4H, m, Ar); dC (100 MHz,
CHCl3); mmax/cm−1 (KBr) 1667, 1692 & 1655 (3 × C O); dH
=
(500 MHz, CDCl3) 0.89 (6H, t, J 6.1, (CH3)2CH), 1.48–1.56
(2H, m, (CH3)2CH and CHD), 3.05 (1H, dd, J 7.0, 13.9,
CH2Ph), 3.13 (1H, dd, J 6.3, 14.0, CHCH2Ph), 3.70 (3H, s,
OCH3), 4.43–4.47 (1H, m, CHCH2Ph), 5.10 (2H, s, OCH2Ph),
5.31 (1H, br s, NHCH), 6.14 (1H, s, NHCD), 7.20–7.39 (10H,
m, 2 × Ph); dC (125 MHz, CDCl3) 21.8, 22.5, 24.5, 38.2,
1
CDCl3) 19.8, 20.7, 21.8, 23.1, 25.8, 33.4, 43.4 (t, JCD 18.3),
1
46.6, 48.9, 55.3, 56.8 (t, JCD 20.0), 65.3, 114.2, 114.3, 127.9,
128.1, 129.1, 129.3, 159.2, 159.3, 166.1, 167.7; m/z (ES+) 455.1
(100%, MH+); (found: MH+, 455.2876; C27H35D2N2O4+ requires
455.2879).
40.9 (t, JCD 19.3), 50.4 (t, JCD 21.4), 52.1, 55.9, 67.0, 126.9,
127.9, 128.1, 128.4, 128.5, 129.3, 136.0, 136.1, 159.8, 170.4,
172.6; m/z (ES+) 429 (100%, MH+); (found: MH+, 429.2359;
1
1
+
C24H29D2N2O5 requires 429.2359).
(3S,6R)-N,Nꢀ -Bis(4-methoxybenzyl)-3-isopropyl-6-isobutyl-
piperazine-2,5-dione 35. To a degassed solution of 105a,b
(200 mg, 0.5 mmol) in dry THF (10 ml) was added lithium
(3S,6S,1ꢀS)-3-Deuterio-3-(1-deuterio-2-methylpropyl)-6-isopro-
pylpiperazine-2,5-dione 40. 31 (908 mg, 2.0 mmol) was treated
1 4 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

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according to general procedure 3. After washing the solid with
ether, product 40 was obtained as a colourless solid (355 mg,
(5.45 g, 85%) as a pale orange oil. dH (400 MHz, CDCl3)
2.11 (3H, s, CH3), 3.87 (3H, s, CH3O), 6.48 (1H, d, J 10.3,
CH), 7.10 (1H, br d, J 10.3, NH); dC (100 MHz, CDCl3)
23.3, 48.8, 53.7, 167.3, 169.2. To a solution of a-bromo-N-
acetylglycine methyl ester (1.45 g, 6.9 mmol) in ethyl acetate
(38 ml) was added trimethyl phosphite (0.81 mL, 6.9 mmol). The
resulting solution was stirred at room temperature overnight.
The mixture was evaporated to afford methyl-2-(acetylamino)-
2-(dimethylphosphoryl) acetate (1.31 g, 80%) as a yellow oil.
◦
83%). Mp 154–156 C; [a]2D5 −31.0 (c 0.50, DMSO); mmax/cm−1
=
(KBr) 1662 (2 × C O); dH (400 MHz, DMSO-d6) 0.84 (3H,
d, J 6.8, (CH3)2CHCD), 0.86 (3H, d, J 6.6, (CH3)2CHCD),
0.87 (3H, d, J 6.8, (CH3)2CHCH), 0.94 (3H, d, J 7.1,
(CH3)2CHCH), 1.41 (1H, d, J 5.3, (CH3)2CHCHD), 1.77–1.87
(1H, m, (CH3)2CHCHD), 2.06–2.14 (1H, m, (CH3)2CHCHN),
3.60–3.61 (1H, m, (CH3)2CHCHN), 8.05 (1H, br s, NH), 8.16
(1H, br s, NH); dC (100 MHz, CDCl3) 18.2, 19.6, 22.6, 23.9,
mmax/cm−1 (thin film) 1747, 1653 (2 × C O); dH (400 MHz,
=
1
1
24.3, 32.3, 44.3 (t, JCD 18.9), 52.9 (t, JCD 22.9), 60.4, 167.7,
CDCl3) 2.09 (3H, s, CH3), 3.80 (3H, s, CH3O), 3.83 (3H, s,
CH3O), 3.85 (3H, s, CH3O), 5.22 (1H, d J 8.87, PCH), 6.60
169.3; m/z (ES+) 215.1 (100%, MH+); (found: MH+, 215.1727;
C11H19D2N2O2 requires 215.1729).
+
1
(1H, br s, NH); dC (100 MHz, CDCl3) 22.7, 50.0 (d, JPC
148.9), 53.3, 54.2, 54.4, 167.0, 170.0; m/z (ES+) 298 (100%,
(2S,3S)-2-Amino-2,3-dideuterio-4-methylpentanoic acid methyl
ester 42 and (S)-valine methyl ester 28. 40 (350 mg, 1.65 mmol)
was treated following general procedure 4 to afford a colourless
solid (320 mg) which was used without further purification.
dH (400 MHz, CD3OD) 1.01 (3H, d, J 6.5, (CH3)2CHCHD),
1.02 (3H, d, J 6.5, (CH3)2CHCHD), 1.08 (3H, d, J 7.2,
(CH3)2CHCHN), 1.09 (3H, d, J 7.2, (CH3)2CHCHN), 1.68
(1H, d, J 6.9, CHD), 1.75–1.85 (1H, m, (CH3)2CHCHD), 2.27–
2.35 (1H, m, (CH3)2CHCHN), 3.86 (3H, s, OCH3), 3.87 (3H, s,
OCH3), 3.95 (1H, d, J 4.4, (CH3)2CHCH).
MNH4 + MeCN); (found: MNa+, 262.0463; C7H14NONaP+
+
requires 262.0456).
Finally, to
a
solution of methyl-2-(acetylamino)-2-
(dimethylphosphoryl) acetate (680 mg, 2.84 mmol) in
tetrahydrofuran (10.5 ml) at −78 ◦C under nitrogen, was
added 1,1,3,3-tetramethylguanidine (0.43 mL, 2.70 mmol).
After stirring for fifteen minutes, isobutyraldehyde (0.3 ml,
2.58 mmol) was added in one portion. The mixture was stirred
for 2 h at −78 ◦C, then 30 min at 25 ◦C. After diluting with
ethyl acetate, the solution was washed with aqueous ammonium
chloride. Then the aqueous layer was extracted with ethyl
acetate and finally the solvent was evaporated in vacuo to
recover a yellow oil. Chromatography (petrol 40–60/ethyl
acetate, 1 : 1) afforded 45 as a pale yellow oil (473 mg, 90%). dH
(400 MHz, CDCl3) 1.05 (6H, d, J 6.48, (CH3)2CH), 2.12 (3H, s,
CH3), 2.45–2.68 (1H, m, (CH3)2CH), 3.77 (3H, s, CH3O), 6.52
(1H, d, J 10.5, CH), 6.72 (1H, br s, NH); dC (100 MHz, CDCl3)
21.5, 23.3, 28.1, 52.3, 122.9, 145.9, 165.4, 169.1; m/z (CI+) 186
N-Cbz-(S)-phenylalanine-(2S,3S)-2-amino-2,3-dideuterio-4-
methyl-pentanoic acid methyl ester 38. An amino-ester
hydrochloride mixture of 28 and 42 (300 mg) was treated
following general procedure 5 to afford 38 (280 mg, 75%) as a
colourless solid. Mp 89 ◦C; [a]D25 −2.0 (c 1.0, CHCl3); mmax/cm−1
=
(KBr) 1650, 1690, 1749 (3 × C O); dH (400 MHz, CDCl3) 0.89
(6H, t, J 6.1, (CH3)2CH), 1.43 (1H, d, J 7.5, CHD), 1.48–1.56
(1H, m, (CH3)2CH), 3.04–3.13 (2H, m, CH2Ph), 3.13 (1H, dd,
J 6.3, 14.0, CHCH2Ph), 3.70 (3H, s, OCH3), 4.45–4.50 (1H, m,
CHCH2Ph), 5.09 (2H, s, OCH2Ph), 5.43 (1H, br s, NHCH),
6.36 (1H, s, NHCD), 7.18–7.38 (10H, m, 2 × Ph); dC (100 MHz,
(100%, MH+); (found: MH+, 186.1129; C9H16NO3 requires
+
186.1130).
(RS)-2-Acetylamino-2,3-dideuterio-4-methyl-pentanoic acid
1
1
CDCl3) 21.9, 22.6, 24.6, 32.4, 40.9 (t, JCD 19.6), 50.4 (t, JCD
22.0), 52.3, 56.0, 67.0, 127.0, 128.0, 128.2, 128.5, 128.6, 129.4,
136.1, 136.3, 155.9, 170.6, 172.8; m/z (ES+) 429 (MH+, 100%);
methyl ester 47.
A
solution of (Z)-2-acetylamino-4-
methylpent-2-enoic acid methyl ester 45 (300 mg, 1.62 mmol)
and Wilkinson’s catalyst (75 mg) in deuterated methanol (12 ml)
was degassed under nitrogen. The atmosphere inside the flask
was replaced with deuterium gas and the mixture stirred for
2 days under 1 atmosphere of deuterium gas. The reaction
(found: MH+, 429.2355; C24H29D2N2O5 requires 429.2359).
+
N -Cbz-(S)-phenylalanine-(2S)-2-amino-4-methylpentanoic
acid methyl ester 44. (S)-Leucine methylester hydrochloride
(400 mg, 2.20 mmol) was treated following general procedure
5. After work up and purification by chromatography, 44 was
afforded as a colourless solid (863 mg, 92%). [a]2D0 −2.4 (c 0.50,
R
mixture was then filtered through Celiteꢀ and the filter cake
washed with diethyl ether. Solvents were removed in vacuo
and rac-2-acetylamino-2,3-dideuterio-4-methylpentanoic acid
methyl ester 47 was obtained as a pale yellow oil (294 mg, 97%).
CHCl3); mmax/cm−1 (KBr) 1667, 1692, 1749 (3 × C O); dH
=
mmax/cm−1 (thin film) 1747, 1656 (2 × C O); dH (400 MHz,
=
(400 MHz, CDCl3) 0.90 (6H, m, (CH3)2CH), 1.43–1.62 (3H,
m, (CH3)2CH and (CH3)2CHCH2), 3.06 (1H, dd, J 6.8, 13.9,
CHCH2Ph), 3.12 (1H, dd, J 6.6, 13.9, CHCH2Ph), 3.71 (3H, s,
OCH3), 4.44–4.60 (2H, m, CHNH and CHCH2Ph), 5.10 (2H, s,
OCH2Ph), 5.38 (1H, br s, NHCH), 6.27 (1H, s, NHCD),
7.19–7.39 (10H, m, 2 × Ph); dC (100 MHz, CDCl3) 21.8, 22.6,
24.6, 32.3, 41.4, 50.7, 52.2, 56.0, 67.0, 127.0, 128.0, 128.2,
128.5, 128.6, 129.3, 136.1, 136.2, 156.0, 170.5, 172.7; m/z (ES+)
CDCl3) 0.90 (3H, d, J 6.56, CH3CH), 0.91 (3H, d, J 6.56,
CH3CH), 1.47 (1H, br d, J 5.30, CHD), 1.59–1.67 (1H, m,
(CH3)2CH), 1.99 (3H, s, CH3CO), 3.70 (3H, s, CH3O), 6.14
(1H, br s, NH); dC (100 MHz, CDCl3) 21.9, 22.7, 23.1, 24.7, 41.2
1
1
(t, JCD 19.2), 50.5 (t, JCD 23.2), 52.2, 169.9, 173.7; m/z (CI+)
190.2 (100%, MH+); (found: MH+, 190.1410; C9H16D2NO3
+
requires 190.1412).
485.4 (100%, MNH4 + MeCN); (found: MH+, 427.2236;
+
2-Amino-2,3-dideuterio-4-methyl-pentanoic acid methyl ester
hydrochloride 42. Rac-2-acetylamino-2,3-dideuterio-4-methyl-
pentanoic acid methyl ester 47 (100 mg, 0.53 mmol) was
refluxed in HCl conc. for 12 h. After 12 h, aqueous HCl was
evaporated at low pressure and rac-2-amino-2,3-dideuterio-4-
methylpentanoic acid hydrochloride as a colourless solid was
recovered. Yield: quant.; mmax/cm−1 (KBr) 3428 (OH), 1610
+
C24H31N2O5 requires 427.2233).
(Z)-2-Acetylamino-4-methyl-pent-2-enoic acid methyl ester 45.
R
To a suspension of N-acetylglycine (Aldrichꢀ, 11.7 g, 100 mmol)
in MeOH (60 ml), SOCl2 was added (14.6 ml, 200 mmol)
at 0 ◦C. The resulting clear solution was stirred at room
temperature overnight. The reaction mixture was evaporated
to give N-acetyl glycine methyl ester 46 as a colourless solid
(11.79 g, 90%). dH (400 MHz, MeOD-d4) 2.03 (3H, s, CH3), 3.73
(3H, s, CH3O), 3.95 (2H, s, CH2).
A mixture of the glycine derivative 46 (3.99 g, 30.5 mmol)
and N-bromosuccinimide (5.97 g, 33.5 mmol) in CCl4 (250 mL)
was heated at reflux for five hours under nitrogen, whilst being
irradiated with a sunlamp. The mixture was then cooled to
room temperature and filtered, and the filtrate was concentrated
under reduced pressure, to afford the a-bromoglycine derivative
=
(C O); dH (400 MHz, D2O) 0.84 (3H, d, J 6.06, CH3CH),
0.86 (3H, d, J 6.06, CH3CH), 1.59–1.68 (2H, m, (CH3)2CH
1
and CHD); dC (100 MHz, D2O) 21.2, 21.9, 24.2, 28.5 (t, JCD
19.2), 38.8 (t, 1JCD 20.0), 173.4.
2-Amino-2,3-dideuterio-4-methylpentanoic acid hydrochlo-
ride (84.7 mg, 0.5 mmol) was stirred for 12 h in SOCl2 (0.068 mL,
0.90 mmol) and MeOH (25 mL) then the solvent was evaporated
at low pressure and 42 was recovered as a colourless solid
(83.5 mg, 91%); dH (400 MHz, CD3OD) 0.90–0.93 (6H, br m,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 4 5

View Article Online
(CH3)2CH), 1.58–1.70 (2H, br m, (CH3)2CH and CHD), 3.77
(3H, s, CH3O); dC (125 MHz, CD3OD) 25.0, 25.2, 27.9, 42.8
(t, 1JCD 20.0), 54.9 (t, 1JCD 23.0), 56.9, 173.7.
4 For example, see: J. E. Baldwin, R. M. Adlington, D. G. Marquess,
A. R. Pitt, M. J. Porter and A. T. Russell, Tetrahedron, 1996, 52, 2515;
N. J. Church and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 1998,
52, 1475; M. C. Pirrung, Acc. Chem. Res., 1999, 32, 711.
5 (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, S. W.
Epstein and J. V. A. Ouzman, Tetrahedron: Asymmetry, 1998, 2795;
(e) S. D. Bull, S. G. Davies, A. C. Garner and M. D. O’Shea, J. Chem.
Soc., Perkin Trans. 1, 2001, 3281.
6 J. L. Namy, P. Girard and H. B. Kagan, Nouv. J. Chim., 1977, 1, 5;
J. A. Soderquist, Aldrichimica Acta, 1991, 24, 15; G. A. Molander,
Chem. Rev., 1992, 92, 29; G. A. Molander, in Organic Reactions,
ed. L. A. Paquette, John Wiley, New York, 1994, vol. 46, 211;
G. A. Molander and C. R. Harris, Chem. Rev., 1996, 96, 307; G. A.
Molander and C. R. Harris, Tetrahedron, 1998, 54, 3321; A. Krief
and A. M. Laval, Chem. Rev., 1999, 99, 745; P. G. Steel, J. Chem. Soc.,
Perkin Trans. 1, 2001, 99, 2727; J. M. Concello´n and H. Rodr´ıguez-
Solla, Chem. Soc. Rev., 2004, 33, 599.
7 J. Inanaga, S. Sakai, Y. Handa, M. Yamaguchi and Y. Yokoyama,
Chem. Lett., 1991, 2117.
8 A. Cabrera and H. Alper, Tetrahedron Lett., 1992, 33, 5007.
9 (a) J. M. Concello´n and H. Rodr´ıguez-Solla, Chem. Eur. J., 2001,
7, 4266; (b) J. M. Concello´n, P. L. Bernad and H. Rodr´ıguez-Solla,
Angew. Chem., Int. Ed., 2001, 40, 3897; (c) J. M. Concello´n and H.
Rodr´ıguez-Solla, Chem. Eur. J., 2002, 8, 4493.
N-Cbz-(S)-phenylalanine-(2S,3S)-2-amino-2,3-dideuterio-4-
methyl-pentanoic acid methyl ester 38 and N-Cbz-(S)-phenyl-
alanine-(2R,3R)-2-amino-2,3-dideuterio-4-methyl-pentanoic acid
methyl ester 48. Methyl aminoester hydrochloride salt
(2RS,3RS)-42 (400 mg, 2.18 mmol) was treated following
general procedure 5 which after work up afforded a 1 : 1 mixture
of 38 and 48 as a colourless solid (933 mg, 89%). Purification
by chromatography (silica, petrol 30–40/ether, 5 : 1) afforded
a sample of 48 (∼10% contaminated with 38) followed by
38. Data for 48: mp 90 ◦C; mmax/cm−1 (KBr) 1736, 1675 (2 ×
=
C O); dH (400 MHz, CDCl3) 0.87–0.93 (6H, m, (CH3)2CH),
1.35–1.41 (2H, m, (CH3)2CH and CHD), 3.03–3.22 (2H, m,
CH2Ph), 3.72 (3H, s, CH3O), 4.42–4.54 (1H, m, CHCH2Ph),
5.12 (2H, s, OCH2Ph), 5.39 (1H, br s, NHCH), 6.10 (1H, s,
NHCD), 7.21–7.41 (10H, m, 2 × Ph); dC (100 MHz, CDCl3)
21.8, 22.6, 24.5, 38.5, 40.7 (t, 1JCD 19.3), 50.2 (t, 1JCD 21.9), 52.1,
56.1, 67.0, 126.9, 127.9, 128.1, 128.4, 128.5, 129.3, 136.0, 136.1,
159.8, 170.4, 172.6; m/z (ES+) 487 (100%, MNH4 + MeCN);
+
(found: MH+, 429.2362; C24H29D2N2O5 requires 429.2359).
+
Acknowledgements
10 For conjugate reduction with SmI2 in MeOH, see: P. Girard, J. L.
Namy and H. B. Kagan, J. Am. Chem. Soc., 1980, 102, 2693.
11 For a review on the application of similar templates in synthesis, see:
J. Liebscher and S. Jin, Chem. Soc. Rev., 1999, 28, 251.
12 S. G. Davies, H. Rodr´ıguez-Solla, J. A. Tamayo, A. C. Garner and
A. D. Smith, Chem. Commun., 2004, 2502.
The authors thank New College, Oxford for a Junior Research
Fellowship (A. D. S.) and the Ministerio de Educacion, Cultura
y Deporte (Spain) for postdoctoral fellowships (H. R. S.
and J. A. T.).
13 For examples of related diketopiperazine phosphonates in synthesis,
see: (a) A. Lieberknecht and H. Griesser, Tetrahedron Lett., 1987, 28,
4275; (b) L. E. Overman and M. D. Rosen, Angew. Chem., Int. Ed.,
2000, 39, 4596; (c) S. Jin, P. Wessig and J. Liebscher, J. Org. Chem.,
2001, 66, 3984.
14 S. D. Bull, S. G. Davies, A. C. Garner, E. D. Savory, E. J. Snow and
A. D. Smith, Tetrahedron: Asymmetry, 2004, 15, 3989.
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17 S. G. Davies and J. E. Thomson, unpublished data.
18 The (3S,6S) relative stereochemistry was assigned from the 1H NMR
data with a diagnostic isopropyl methyl group shift difference DdMe
=
0.05 ppm (see ref. 15) while the (R) configuration of the 1ꢀ stereogenic
centre was tentatively assigned from the 3-H-1ꢀ-H coupling of 2.4 Hz
ꢀ
=
assuming a hydrogen bond between the 1 -COH and 2-C O.
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20 Enantiomeric excess (ee) was established by examination of the 19F
NMR spectrum of the (R)-Moshers amide derivative and comparison
with the authentic racemic sample.
21 B.-C. Chen, A. P. Skoumbourdis, P. Guo, M. S. Bednarz, O. R. Kocy,
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22 Tetramethylguanidine proved to be the base of choice for the HWE
reaction in this sequence: D. A. Evans, F. E. Michael, J. S. Tedrow
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23 J. Halpern, Inorg. Chim. Acta, 1981, 50, 11.
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tion of acyclic enamides, see: J. M. Concello´n, M. Huerta and E.
Bardales, Tetrahedron, 2004, 60, 10059.
25 For examples of protonation or deuteration of C–Sm(III) species with
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1 4 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7

View Article Online
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28 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge and
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Laboratory, Oxford, UK, 2001.
29 Prepared by the method of: P. Cledera, C. Avendan˜o and J. C.
Mene´ndez, Tetrahedron, 1998, 54, 12349.
27 SmI2 in THF was very rapidly generated, by reaction of di-
iodomethane with samarium powder in the presence of sonic waves:
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 4 3 5 – 1 4 4 7
1 4 4 7