Simple, versatile and highly diastereoselective synthesis of 1,3,4-trisubstituted-2-oxopiperazine-containing peptidomimetic precursors

Article abstract of DOI:10.1039/b416162a

The selective O-deprotection of (1'S)-4-(tert-butoxycarbonyl)-1-[1'- phenylmethyloxymethyl-2'-[(tert-butyldimethylsilyl)oxy]ethyl]-2-oxopiperazine furnished an enantiomerically pure alcohol whose regio- and diastereoselective C₃-alkylation yielded either (3R)- or (3S)-1,3,4-trisubstituted-2- oxopiperazines in high diastereomeric purity. These derivatives were efficiently transformed into (1'A)- or (1'S)-peptide templates utilizable to prepare peptidomimetics. This method provides easy access to each 1,3,4-trisubstituted- 2-oxopiperazine diastereomer and facilitates, through the large choice of substituents at the 3-position together with the chemistry that can be performed on the NI substituent, the preparation of a large number of diastereomerically pure constrained peptidomimetics from a single precursor. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416162a

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A R T I C L E
Simple, versatile and highly diastereoselective synthesis
of 1,3,4-trisubstituted-2-oxopiperazine-containing
peptidomimetic precursors
Nicolas Franceschini, Pascal Sonnet and Dominique Guillaume*
Laboratoire de Chimie The´rapeutique, EA 2629, 1 Rue des Louvels, 80000, Amiens, France.
E-mail: dominique.guillaume@sa.u-picardie.fr
Received 22nd October 2004, Accepted 9th December 2004
First published as an Advance Article on the web 21st January 2005
The selective O-deprotection of (1ꢀS)-4-(tert-butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-2ꢀ-[(tert-
butyldimethylsilyl)oxy]ethyl]-2-oxopiperazine furnished an enantiomerically pure alcohol whose regio- and
diastereoselective C3-alkylation yielded either (3R)- or (3S)-1,3,4-trisubstituted-2-oxopiperazines in high
diastereomeric purity. These derivatives were efficiently transformed into (1ꢀR)- or (1ꢀS)-peptide templates utilizable
to prepare peptidomimetics. This method provides easy access to each 1,3,4-trisubstituted-2-oxopiperazine
diastereomer and facilitates, through the large choice of substituents at the 3-position together with the chemistry
that can be performed on the N1 substituent, the preparation of a large number of diastereomerically pure
constrained peptidomimetics from a single precursor.
been reported for the synthesis of diastereomerically pure 1*,3,4-
Introduction
trisubstituted-2-oxopiperazines (Fig. 1). Lactamization of linear
N,Nꢀ-bispeptides, prepared by reacting two optically pure amino
acids and 1,2-dibromoethane, has yielded 1*,3-disubstituted-2-
oxopiperazines whose 4-position could be easily substituted.6
The best results were obtained with symmetrical bispeptides,
meaning that the 2-oxopiperazine derivatives had necessarily
similar substituents at their 3- and 1ꢀ-positions.7 When two
different amino acids were used to prepare the linear peptide
dimer a mixture of 2-oxopiperazines is obtained, necessitating
a subsequent inelegant resolution step.8 1*,3,4-Trisubstituted-
2-oxopiperazines have been also synthesized by N4–C5 bond
formation. For this, linear dipeptide analogues in which the
nitrogen atom of the i + 1 residue was substituted with an
a-aldehyde precursor have been prepared.9 Reduction of the
imine intermediate obtained by condensation of the unmasked
aldehyde function and Ni (the nascent 2-oxopiperazine N4 atom)
furnished the expected products. However, this method requires
the preliminary preparation of a dipeptide whose accessibility
can be limited if unusual side chains are desired at the 2-
oxopiperazine 3-position. Furthermore, the whole synthesis has
to be repeated if access to peptidomimetic diastereomers is
desired. 1*,3,4-Trisubstituted-2-oxopiperazines have been also
prepared by N1–C6 bond formation.10 In this case, the ring
formation was achieved by the alkylation of N1 by a bromoethyl
substituent at the nascent N4 atom. This approach is thwarted
by drawbacks similar to those depicted for the C5–N4 bond
formation strategy.
Recently, we have reported the synthesis of 1*,3,4-
trisubstituted-2-oxopiperazines by regio- and stereoselective C3-
alkylation of 1,4-disubstituted-2-oxopiperazines using various
electrophiles.11 Very high chiral induction (>95%) was achieved
when simple electrophiles were used. A rigid intermediate that
mandates approach of the electrophile from the face opposite
to a lithium chelate involving N1 and an alcohol appended
to the 1ꢀ-substituent was proposed to be at the origin of the
diastereoselectivity.11–12 L-Leucinol11 or D-phenylglycinol13 have
already been reported as chiral inductors, though almost any a-
monosubstituted-b-amino alcohol could in principle be used.14
In addition to its high diastereoselectivity, the C3-alkylation
method offers the enormous advantage of easy incorporation
of a large diversity of substituents at the 2-oxopiperazine 3-
position. However, as it is, two important drawbacks reduce its
scope: 1) as the configuration of the 2-oxopiperazine 3-position
(Aza)-lactams still receive much synthetic interest1 because
medicinal chemists used them to prepare peptidomimetics
that provide prized structure–activity relationships.2 Indeed, by
allowing a better understanding of the peptide mechanism of
action at a molecular level, peptidomimetics can permit the
design of new, and more pharmacologically potent, molecules.
At the same time, peptidomimetics can also be of higher stability
towards physiological hydrolysis or enzymatic degradation than
the parent peptide. Such improvement is of extreme importance
from a therapeutic standpoint. Among all the useful aza-
lactams, 1,3,4-trisubstituted-2-oxopiperazines whose 1-position
is bonded to a chiral carbon atom (1*,3,4-trisubstituted-2-
oxopiperazines) (general structure 1) are of particular interest.
Such scaffolds, known to stabilize inverse c-turns in small
peptides,3,4 result from the introduction of only two extra
carbon atoms, compared to the parent peptide, linking Ni
and Ni +1. This ethylene bridge not only reduces the chances
of “false negative” pharmacological responses consecutive to
the introduction of excessive steric hindrance, although a
correct conformational modification has been achieved, but
also suppresses two NHs that could be part of a hydrogen
bond network possibly stabilizing a undesirable conformer.
Additionally, the pharmacologically relevant orientation and/or
function of the i-amino-acid side chain (Ri) can possibly be
probed from structure–activity data obtained by varying the 2-
oxopiperazine 3-position substituent.
If the peptidomimetic 1 has a glycine residue at its i + 1
position (Ri +1 = H), its synthesis can be envisaged by direct N1-
alkylation of the readily available 3,4-disubstituted-2-oxopiper-
azine.5 However, most 1,3,4-trisubstituted-2-oxopiperazines tar-
getted by medicinal chemists have two stereogenic centers, one
ꢀ
intracyclic (C3) and one extracyclic (C1 ). This makes the N1-
alkylating method a poor choice. Four general methods have
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 , 7 8 7 – 7 9 3
7 8 7
©

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Fig. 1 Schematic representation of the current methods leading 1 and their main drawbacks.
is totally governed by the configuration of the chiral inductor,
only one diastereomer is accessible directly; and 2) since the N1-
substituting appendage must be chiral, peptidomimetics having
a glycine residue at their i + 1 position are difficult to obtain.
Therefore, of all the methods reported so far to prepare
1*,3,4-trisubstituted-2-oxopiperazines, none is really satisfac-
tory. General methods affording diastereomerically pure 1*,3,4-
trisubstituted-2-oxopiperazines are still required.
Herein, we report an original and versatile method allowing,
from a single precursor, the diastereoselective synthesis of each
isomer of 1 and in which the choice of the C3-substituent
is not limited by the availability of the corresponding amino
acid. This method also provides access to enantiomerically pure
peptidomimetics having a glycine residue at the i + 1 position.
Scheme 1 Reagents and yields: i) LAH, THF (80%) ii) tert-BDMSCl,
imidazole; iii) BrCH2COOH, DCC, N-methylmporpholine, CH2Cl2; iv)
NaH, THF (88%, 3 steps).
Synthesis of the 3R,1ꢀS and 3R,1ꢀR diastereomers
3R-Diastereomers should then be prepared from (1ꢀS)-2b.
Hydrogenolysis (H2, Pd–C) of 2a afforded (1ꢀS)-2b in 90% yield.
Alkylation of its enolate (LDA, THF, HMPA, −78 ◦C then
−50 ◦C) with methyl iodide, benzyl bromide, allyl bromide
and propyl bromide afforded 5a–d (75%, 82%, 72% and 77%
yield, respectively). 1H NMR analysis (500 MHz) of each
compound confirmed the anticipated high diasteroselectivity
(>95%) of the alkylation step, since only one diastereomer
was observed in each case. The 1ꢀS,3R configuration of 5a–
d was assigned by mechanistic analogy with our previous
studies in the piperazine,11–13 diazepinone15 or thiomorpholine16
fields. To obtain peptidomimetic precursors we then needed to
oxidize the primary alcohol function of 5 and chose 5b as an
example. Unfortunately, the silyl protective group was found
to be too unstable under oxidative conditions, precluding the
regioselective oxidation of 5b in good yields. Thus, we protected
the alcohol function of 5b as a benzyl ether (BnCl, NaH) and
removed the tert-BDMS protective group (Bu4NF) to obtain 6
(quantitative yield, two steps). Oxidation of the alcohol function
of 6 (Jones’ reagent) afforded the corresponding acid, whose
benzyl group hydrogenolysis furnished (1ꢀS,3R)-7 in 70% yield
(2 steps) ([a]1D7 −10 (c 0.1; EtOH)). To obtain the (1ꢀR,3R)-
derivative 8, the alcohol function of 6 was esterified (BzCl–
pyridine, quantitative) then, after hydrogenolysis (H2, Pd–C
10%, 98% yield) the resulting ester could be oxidized (Jones’
reagent) then saponified (2 N NaOH) to yield (1ꢀR,3R)-8 in 81%
yield ([a]1D7 +4 (c 0.1; EtOH)) (Scheme 2).
Results and discusion
In our view, because of the large access to commercially available
simple electrophiles the preparation of 1*,3,4-trisubstituted-2-
oxopiperazines by the C3-alkylation strategy is by far superior
to the other reported methods. This strategy chosen, we had to
design a 2-oxopiperazine substituted at N1 with a chirality induc-
tor whose 1ꢀ-configuration could be unambiguously achieved as
desired. Thus, we considered serinol-based derivative 2, in which
P1 and P2 would be two orthogonal protective groups, as the best
chemical entity to achieve our goal. We selected the benzyl (P1)
and tert-butyldimethylsilyl (P2) groups as protective groups.
Synthesis of 2-oxopiperazine 2a
Synthesis of 2a could be readily achieved from dipeptide 3.
Concomitant amide and ester reduction of 3 (LAH in THF)
afforded the expected amino alcohol 4 [80% yield, [a]1D7 +6 (c 0.1;
EtOH)], whose hydroxyl function was protected by use of tert-
butyl-dimethylsilyl chloride (tert-BDMSCl) in the presence of
imidazole. The di-O-protected derivative was then reacted with
bromoacetic acid in the presence of DCC to afford a linear
intermediate whose cyclization (NaH, THF) afforded 2a ([a]D17
−1 (c 0.1; EtOH)) (70% yield from 3) (Scheme 1).
Synthesis of the 3S,1ꢀR and 3S,1ꢀS diastereomers
For the synthesis of the 3S diastereomers, the preparation of
(1ꢀR)-2c was necessary. The latter was prepared quantitatively by
reaction of 2a with tetrabutylammonium fluoride. Diastereose-
lective C3-alkylation of (1ꢀR)-2c as described for the alkylation
of 2b afforded 9a–d (89, 80, 84 and 85% yield, respectively).
Oxidation of 9b (Jones’ reagent) afforded the corresponding
7 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3

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Scheme 2 Reagents: i) H2, Pd–C MeOH; ii) LDA, HMPA, THF, −50 ◦C, then CH3I or PhCH2Br or CH2CHCH2Br; iii) PhCH2Cl, NaH; iv)
n-Bu4NF; v) Jones’ reagent; vi) PhCOCl, pyridine; vii) 2 N NaOH; viii) Jones’ reagent, then 90 ◦C.
acid, which was transformed into the peptidomimetic precursor
(3S,1ꢀS)-10 after hydrogenolysis (H2, MeOH, quantitative) ([a]D17
−4 (c 0.1; EtOH)). To obtain (3S,1ꢀR)-11, the primary hydroxyl
group of 9b was quantitatively esterified (BzCl, pyridine)
and after hydrogenolysis and oxidation (Jones reagent, 62%),
the resulting adduct was saponified (2 N NaOH), furnishing
(3S,1ꢀR)-11 ([a]1D7 +10 (c 0.1; EtOH)) in 97% yield (Scheme 2).
number of peptidomimetics can be easily prepared from the
key intermediate 2a. Since the preparation of the latter can be
routinely performed on a multigram scale, our method should
rapidly find its place in the peptidomimetic synthesis field. In
addition, our strategy can easily be extended to the preparation
of optically pure therapeutic agents.17
Experimental
Synthesis of 1ꢀ-unsubstituted peptidomimetics
THF was dried by distillation from sodium–benzophenone. Di-
isopropylamine was dired by distillation from calcium hydride.
Thin-layer and column chromatography were carried out on
silica gel 60F254 60–15 lm and silica gel 6–35 lm, respectively,
from SDS (Peypin, France). IR spectra were recorded on a
Nicolet 210 spectrometer using KBr pellets. Optical rotations
were measured on a Perkin-Elmer 241 polarimeter; values are
given in 10−1deg cm2 g−1. Melting points were determined on a
Kofler plate and are given uncorrected. 1H and 13C NMR spectra
were recorded on a Bruker Avance 500 instrument. 1H chemical
shifts (d) are reported in ppm relative to residual solvent peak
(CDCl3 d 7.27). 13C chemical shifts (d) are reported in ppm
relative to residual solvent peak (CDCl3 d 77.7). J values are
given in Hertz. Mass spectra were recorded on a Micromass-
Waters Q–TOF Ultima spectrometer. HPLC analyses were
performed on a Shimadzu instrument using a Chirobiotic
(18 mm) column.
In addition to the four 1*,3,4-trisubstituted-2-oxopiperazine
diastereomers, 2a also provided an efficient entry to enan-
tiomerically pure peptidomimetics having a glycine residue
at their i + 1 position. We decided to illustrate this ability
from 5d and 9d, whose 3-position is substituted with a non-
proteogenic side-chain. Treatment of 5d with Bu4NF afforded
the corresponding diol in quantitative yield. Subsequent oxi-
dation (Jones’ reagent) and decarboxylation (heating at 90 ◦C)
yielded (3R)-12 ([a]1D7 −119 (c 0.1; EtOH)), in 62% overall yield
(Scheme 2). Hydrogenolysis of 9d afforded the corresponding
diol (not isolated), whose subsequent oxidation (Jones’ reagent)
◦
and decarboxylation (heating at 90 C) afforded (3S)-13 ([a]D17
+113 (c 0.1; EtOH)), in 53% overall yield (Scheme 2).
Conclusion
The four diastereomers of 1*,3,4-trisubstituted-2-oxopiper-
azines are accessible in a concise, versatile and diastereoselective
manner from 2a. Our method provides also an entry to enan-
tiomerically pure 1,3,4-trisubstituted-2-oxopiperazines. Because
of the synthetic flexibility of the 1ꢀ-group hydroxymethyl sub-
stituent, particularly its transformation into other proteogenic
or non-proteogenic amino acid side chains, and also of the
chemistry that can be performed at C3 (the allyl substituent
provides an entry to a large diversity of other structures), a huge
(2R)-6-(tert-Butoxycarbonyl)-2-phenylmethyloxymethyl-3,6-
diazahexan-1-ol 4. To a solution of 3 (15 g) in dry THF at 0 ◦C,
LAH (41 mmol) was added. The solution was stirred for 1 h at
rt then 123 mmoles of LAH were added to the solution. After
30 h of stirring, 2 mL of a 15% aqueous solution of NaOH were
slowly added. The suspension was stirred overnight at rt, then
filtered and the cake washed with CH2Cl2. The organic phase
was dried over magnesium sulfate, filtered and concentrated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3
7 8 9

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(1ꢀR)-4-(tert-Butoxycarbonyl)-1-(1ꢀ-phenylmethyloxymethyl-
2ꢀ-hydroxyethyl)-2-oxopiperazine 2c. To a solution of 2a (5 g)
in THF (130 mL), a 1M solution of Bu4NF in THF (20 mL)
was added. The solution was stirred overnight then 200 mL
of H2O were added. The solution was extracted twice with
EtOAc (250 mL) and the combined organic phases washed
with H2O. The organic phase was dried (MgSO4), filtered and
concentrated in vacuo, affording 2c in quantitative yield. [a]D17
+5 (c 0.1; EtOH); IR mmax/cm−1 3114, 2982, 2928, 1695 (CO),
1653 (CO), 1417, 1172; 1H NMR (500 MHz, CDCl3) d 7.3 (5H,
m, Ar), 4.53 (1H, d, J = 12.7, CH2CO), 4.49 (1H, d, J = 12.7,
CH2CO), 4.37 (1H, m, CH), 4.08 (2H, m, CH2O), 3.85 (2H, s,
CH2Ar), 3.79 (1H, m, CH2O), 3.69 (1H, m, CH2O), 3.58 (2H,
m, CH2N), 3.50 (1H, m, CH2N), 3.45 (1H, m, CH2N), 3.02
(1H, m, OH), 1.48 (9H, s, OC(CH3)3); 13C NMR (125 MHz,
CDCl3) d 171.5, 153.3 (CO), 138.0, 128.9, 128.3, 128.1 (Ar),
81.4 (OC(CH3)3), 73.8 (CH2Ar), 68.3 (CH2N), 62.1 (CH2OH),
60.8 (CH), 49.2 (CH2O), 47.8 (CH2CO), 40.3 (CH2N), 28.7
(OC(CH3)3); MS m/z 387 (M + Na)+, 242, 186; HRMS calc.
for (M + Na)+ 387.1896, found 387.1898.
(1ꢀS,3R)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-hydroxymethyl-2ꢀ-[(tert-
butyldimethylsilyl)oxy] ethyl]-3-substituted-2-oxopiperazine (5).
A solution of diisopropylamine (1 mL) in THF (20 mL) was
cooled at −70 ◦C and kept under nitrogen atmosphere. A 1.6 M
solution of n-BuLi in hexane (4 mL) was slowly added to the
cold solution and the mixture was stirred for 15 min. A solution
of 2b (2.1 mmol) and HMPA (6.3 mmol) in THF was slowly
poured into the cold solution and stirred for 15 min. A solution
of electrophile (6.3 mmol) ◦in THF was added and the ◦mixture
was stirred for 5 h at −50 C, then for 30 min at −15 C. The
reaction was quenched by addition of an aqueous saturated
solution of NH4Cl (80 mL) then extracted three times with
CH2Cl2. The combined organic phases were washed with H2O,
dried (MgSO4), filtered and concentrated in vacuo. Alkylation
products were finally purified by column chromatography using
cyclohexane–EtOAc (1 : 20) as an eluent.
in vacuo to afford 10.6 g of a white solid (yield 80%). [a]1D7 +6
(c 0.1; EtOH); IR mmax/cm−1 3398 and 3333 (OH, NH), 2962,
1711 (CO), 1173; H NMR (500 MHz, CDCl3) d 7.45 (5H, m,
Ar), 5.43 (1H, m, NH-Boc), 4.68 (2H, s, OCH2), 3.85 (1H, m,
OCH2), 3.72 (2H, m, OCH2), 3.71 (1H, m, OCH2), 3.52 (1H,
br s, OH), 3.39 (2H, m, NCH2), 3.08 (1H, m, CH), 3.00 (1H, m,
NCH2), 2.95 (1H, m, NCH2), 2.74 (1H, m, NH), 1.60 (9H, s,
Boc). MS m/z 347 (M + Na)+, 325 (M + H)+, 269, 247.
1
(1ꢀS)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-2ꢀ-
[(tert-butyldimethylsilyl)oxy]ethyl]-2-oxopiperazine 2a. To
a
solution of 4 (10 g) in CH2Cl2 (20 mL), imidazole (46 mmol)
then tert-butyldimethylsilyl chloride (46 mmol) were added.
The solution was stirred overnight then a saturated aqueous
solution of sodium carbonate (200 mL) was added. The organic
phase was collected, the aqueous phase washed twice with Et2O
and the combined organic phases dried over sodium sulfate.
Evaporation of the solvent furnished an oil sufficiently pure
to be directly used for the next step and that was dissolved
in a solution of CH2Cl2 (200 mL) and N-methylmorpholine
(100 mL), then slowly poured into a CH2Cl2 solution of
bromoacetic anhydride prepared by mixing bromoacetic acid
(91 mmol) and DCC (45 mmol). The reaction was stirred
overnight then extracted twice with a saturated solution of
sodium carbonate (500 mL) then twice with a 1 N HCl aqueous
solution (500 mL) and finally with brine (500 mL). The organic
phase was dried over magnesium sulfate concentrated in vacuo
to afford a yellow oil whose 1H NMR spectrum displayed
signals for an equimolar population of rotamers (MS m/z 581
(M + Na)+, 559).
To a solution ◦of the previously obtained yellow oil in dry THF
(300 mL), at 0 C, a 80% oily suspension of NaH (3 eq.) was
added. After 5 h of stirring, the reaction was quenched by careful
addition of H2O (300 mL) and the solution was extracted with
EtOAc (3 × 400 mL). The combined organic phases were washed
with H2O then dried (MgSO4) and concentrated to afford a
white powder, in 70% yield, that generally did not need the use
of further purification procedures. [a]1D7 −1 (c 0.1; EtOH); IR
(1ꢀS,3R)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-hydroxymethyl-2ꢀ-[(tert-
butyldimethylsilyl)oxy] ethyl]-3-methyl-2-oxopiperazine 5a.
Obtained in 75% yield using iodomethane as electrophile. [a]D17
−53 (c 0.1; EtOH); IR mmax/cm−1 3334 (OH), 1752, 1640 (CO),
1
mmax/cm−1 3125, 1729 (CO), 1651 (CO), 1248, 1159; H NMR
(500 MHz, CDCl3) d 7.35 (5H, m, Ar), 4.84 (1H, m, CH), 4.70
(1H, d, J = 11.9, CH2CO), 4.64 (1H, d, J = 11.9, CH2CO),
4.25 (2H, s, CH2Ar), 3.98 (2H, m, CH2O), 3.90 (1H, dd, J =
10.2, 7.2, CH2O), 3.81 (1H, dd, J = 10.2, 5.0, CH2O), 3.73 (2H,
m, CH2N), 3.62 (2H, m, CH2N), 1.64 (9H, s, OC(CH3)3), 1.04
(9H, s, SiC(CH3)3), 0.21 (6H, s, Si(CH3)2); 13C NMR (125 MHz,
CDCl3) d 162.8, 153.2 (CO), 138.6, 128.9, 128.3, 128.1 (Ar),
81.3 (OC(CH3)3), 73.5 (CH2Ar), 68.0 (CH2O), 61.7 (CH2O),
55.4 (CH), 49.2 (CH2N), 44.1 (CH2N), 43.3 (CH2CO), 28.7
(OC(CH3), 26.2 (SiC(CH3)3), 18.0 (SiC(CH3)3), 2.3 (Si(CH3)2);
MS m/z 501 (M + Na)+, 393, 301, 236, 220; HRMS (ES) (M +
Na)+ calc. for C25H42N2O5SiNa 501.2761, found 501.2762.
1
1250, 1172; H NMR (500 MHz, CDCl3) d 4.49 (1H, q, J =
6.9, CHCH3), 4.11 (1H, m, CH), 3.89 (2H, m, CH2OH), 3.79
(2H, m, CH2O), 3.77 (1H, m, CH2N), 3.53 (1H, m, CH2N),
3.36 (1H, m, CH2N), 3.19 (1H, m, CH2N), 2.27 (1H, m,
OH), 1.43 (9H, s, OC(CH3)3), 1.39 (3H, d, J = 6.9, CHCH3),
0.84 (9H, s, SiC(CH3)3), 0.01 (6H, s, Si(CH3)2); 13C NMR
(125 MHz, CDCl3) d 167.8, 155.1 (CO), 80.9 (OC(CH3)3), 61.8
(CH2O), 61.7 (CH2OH), 60.7 (CHCH3), 46.2 (CH2N), 45.1
(CH2N), 44.2(CHCO), 28.7 (OC(CH3)3), 26.2 (SiC(CH3)3),
18.4 (SiC(CH3)3), 18.1 (CHCH3), −4.2 (Si(CH3)2); MS m/z 425
(M + Na)+, 369, 325; HRMS calc. for (M + Na)+ 425.2448,
found 425.2461.
(1ꢀS)-4-(tert-Butoxycarbonyl)-1-[1ꢀ -hydroxymethyl-2ꢀ -[(tert-
butyldimethylsilyl)oxy]ethyl]-2-oxopiperazine 2b. To a solution
of 2a (5 g) in MeOH (100 mL) placed under a nitrogen
atmosphere, 0.1 g of 10% Pd–C was added. Nitrogen was slowly
replaced by hydrogen and the suspension was stirred for 48 h
then filtered over celite and concentrated in vacuo, affording 2b
as a white solid (3.7 g, 90% yield). [a]1D7 −3 (c 0.1; EtOH); IR
(1ꢀS,3R)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-hydroxymethyl-2ꢀ-[(tert-
butyldimethylsilyl)oxy] ethyl]-3-phenylmethyl-2-oxopiperazine
(5b). Obtained in 82% yield using benzyl bromide as
electrophile. [a]D20 −18 (c 0.1; EtOH); IR mmax/cm−1 3402 (OH),
1712, 1653 (CO), 1421, 1172; 1H NMR (500 MHz, CDCl3)
d 7.4–7.1 (5H, m, Ar), 4.57 (1H, m, CHCO), 3.95 (1H, m,
CH), 3.90 (1H, m, CH2OH), 3.79 (2H, m, CH2O), 3.72 (1H, m,
CH2OH), 3.45 (1H, m, CH2N), 3.41 (1H, m, OH), 3.16 (2H,
m, CH2Ar), 3.08 (2H, m, N), 2.71 (1H, m, CH2N), 1.40 (9H, s,
OC(CH3)3), 0.79 (9H, s, SiC(CH3)3), 0.00 (6H, s, 6H, Si(CH3)2);
13C NMR (125 MHz, CDCl3) d 169.5, 153.9 (CO), 137.9,
130.2, 128.8, 127.1 (Ar), 80.9 (OC(CH3)3), 62.0 (CH2OH), 61.8
(CH), 60.7 (CH2O), 59.4 (CHCO), 47.2 (CH2N), 38.1 (CH2N),
30.5 (OC(CH3)3), 26.1 (SiC(CH3)3), 18.5 (SiC(CH3)3), −1.1
(Si(CH3)2); MS m/z 501 (M + Na)+, 475, 445, 411, 255; HRMS
calc. for (M + Na)+ 501.2761, found 501.2737.
1
mmax/cm−1 3410, 2945, 1707 (CO), 1641 (CO), 1259, 1172; H
NMR (500 MHz, CDCl3) d 4.30 (1H, m, CH), 4.02 (2H, m,
CH2O), 3.82 (1H, m, CH2CO), 3.75 (2H, m, CH2N), 3.55 (4H,
m, CH2O, CH2N), 3.41 (1H, m, OH), 1.41 (9H, s, OC(CH3)3),
0.89 (9H, s, SiC(CH3)3), 0.00 (6H, s, Si(CH3)2); 13C NMR
(125 MHz, CDCl3) d 167.8, 154.2 (CO), 81.3 (OC(CH3)3),
61.7 (OCH2), 61.2 (NCH2), 60.6 (HOCH2), 59.8 (CH), 45.3
(NCH2), 34.2 (COCH2), 28.7 (OC(CH3)3), 26.1 (SiC(CH3)3),
18.4 (SiC(CH3)3), 1.1 (Si(CH3)2); MS m/z 411 (M + Na)+, 355,
297, 236, 179; HRMS calc. for (M + Na)+ 411.2291, found
411.2294.
7 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3

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(1ꢀS,3R)-3-Allyl-4-(tert-butoxycarbonyl)-1-[1ꢀ-hydroxymethyl-
2ꢀ-[(tert-butyldimethyl silyl)oxy] ethyl]-2-oxopiperazine (5c).
Obtained in 72% yield using allyl bromide as electrophile. [a]D17
−42 (c 0.1; EtOH); IR mmax/cm−1 3422 (OH), 3086, 1707, 1637
(CO), 1255, 1172; 1H NMR (500 MHz, CDCl3) d 5.77 (1H, ddd,
J = 17.1, 10.1, 4.4, CH olef), 5.06 (1H, d, J = 17.1, CH2 olef),
5.03 (1H, d, J = 10.1 CH2 olef), 4.51 (1H, m, CHCO), 4.18 (1H,
m, CH), 4.05 (1H, m, CH2N), 3.90 (2H, m, CH2O), 3.81 (1H, br
m, OH), 3.75 (1H, m, CH2O), 3.73 (2H, m, CH2O), 3.71 (1H,
m, CH2N), 3.50 (1H, m, CH2N), 3.37 (1H, m CH2N), 3.18 (1H,
m, CH2N), 2.64 (1H, ddd, J = 10.7, 7.7, 4.4, CH2), 2.54 (1H,
m, CH2), 1.41 (9H, s OC(CH3)3), 0.83 (9H, s, SiC(CH3)3), 0.00
(6H, s, Si(CH3)2); 13C NMR (125 MHz, CDCl3) d 169.5, 154.0
(CO), 134.4 (CH olef), 118.3 (CH2 olef), 80.9 (OC(CH3)3), 61.8
(CH2O), 61.3 (CH2O), 60.5 (CHCO), 57.4 (CH), 45.9 (CH2N),
37.7 (CH2), 28.6 (OC(CH3)3), 27.2 (CH2N), 26.1 (SiC(CH3)3),
18.4 (SiC(CH3)3), −5.3 (Si(CH3)2); MS m/z 451 (M + Na)+,
395, 301; HRMS calc. for (M + Na)+ 451.2604, found 451.2602.
(8 mL). The organic phases were combined, dried (MgSO4)
and concentrated affording an orange oil that was rapidly
and directly used in the next step without purification. The
previously obtained orange oil was dissolved in MeOH under a
nitrogen atmosphere and Pd–C 10% was carefully added. The
nitrogen atmosphere was replaced by a hydrogen atmosphere
and the suspension was stirred overnight. The suspension
was filtered over celite and the solution was concentrated
in vacuo. Final purification was achieved by means of SiO2
chromatography using cyclohexane–EtOAc (1 : 2) as an eluent.
[a]D17 −10 (c 0.1; EtOH); IR mmax/cm−1 3352 (OH), 1758, 1684
1
(CO), 1156; H NMR (500 MHz, CDCl3) d 10.3 (2H, s, OH),
7.0–7.3 (5H, m, Ar), 4.84 (1H, m, CHCOOH), 4.74 (1H, m,
CHCO), 4.12 (2H, m, CH2O), 3.99 (1H, m, CH2N), 3.53 (1H,
m, CH2N), 3.18 (2H, m, CH2Ar), 2.92 (1H, m, CH2N), 2.78
(1H, m, CH2N), 1.3 (9H, br s, OC(CH3)3); 13C NMR (125 MHz,
CDCl3) d 172.0, 170.8, 154.2 (CO), 137.1, 133.7, 131.5, 127.4
(Ar), 81.4 (OC(CH3)3), 61.4 (CH2Ar), 61.0 (CH2O), 59.0
(CHCOOH), 53.5 (CHCO), 46.1 (CH2N), 41.8 (CH2N), 38.2
(OC(CH3)3); MS m/z 378 (M + H)+, 377, 349, 257, 171; HRMS
calc. for M+ 377.1713, found 377.1717.
(1ꢀS,3R)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-hydroxymethyl-2ꢀ-[(tert-
butyldimethylsilyl)oxy] ethyl]-3-propyl-2-oxopiperazine (5d).
Obtained in 77% yield using 1-bromopropane as electrophile.
[a]D17 +43 (c 0.1; EtOH); IR mmax/cm−1 3438, 1760, 1632 (CO),
1259, 1172; 1H NMR (500 MHz, CDCl3) d 4.55 (1H, m, CHPr),
4.21 (1H, m, CH), 3.99 (1H, m, CH2O), 3.80 (1H, m, CH2O),
3.70 (2H, m, CH2O), 3.61 (1H, m, CH2N), 3.38 (1H, m, CH2N),
3.28 (1H, m, CH2N), 3.12 (1H, m, CH2N), 2.01 (1H, m, CH2C),
1.61 (1H, m, CH2C), 1.41 (9H, s, OC(CH3)3), 1.31 (2H, m,
CH2CH3), 0.88 (3H, t, J = 6, CH3), 0.86 (9H, s, SiC(CH3)3),
0.00 (6H, s, Si(CH3)2); 13C NMR (125 MHz, CDCl3) d 171.6,
154.7 (CO), 81.4 (OC(CH3)3), 61.3 (CH2O), 61.1 (CH2O), 60.0
(CHCO), 57.1 (CH), 45.9 (CH2N), 33.4 (CH2), 29.3 (CH2), 27.9
(SiC(CH3)3), 26.0 (SiC(CH3)3), 20.4 (CH2), 19.4 (SiC(CH3)3),
14.7 (CHCH3), −4.2 (Si(CH3)2); MS m/z 453 (M + Na)+, 397,
369, 353; HRMS calc. for (M + Na)+ 453.2761, found 453.2782.
(2R)-((3ꢀR)-4ꢀ -(tert-Butoxycarbonyl)-3ꢀ-phenylmethyl-2ꢀ-oxo-
piperazin-1ꢀ-yl)-3-hydroxypropanoic acid 8. To a solution of
6 (0.9 mmol) in pyridine (10 mL) at 0 ◦C, benzoyl chloride
(0.1 mL) was slowly added. The solution was stirred for 3 h at
rt. Then 20 mL of 2 N aqueous HCl was added into the solution
that was extracted with Et2OAc (3 × 20 mL). The organic phases
were combined, dried (MgSO4) and concentrated. The resulting
oil was oxidized then hydrogenolyzed using the conditions
depicted for the preparation of 7. Final saponification was
carried out in a 8% aqueous solution of NaOH. The solution
was stirred for 2 h then concentrated in vacuo. The obtained
residue was dissolved in H2O (20 mL) and the solution was
extracted twice with EtOAc (20 mL). The combined organic
phases were dried and concentrated, affording 8 as an oil (90%
yield from 6).
(1ꢀR,3R)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-
2ꢀ-hydroxyethyl]-3-phenylmethyl-2-oxopiperazine
6. To
a
[a]D17 −4 (c 0.1; EtOH); IR mmax/cm−1 3354, 2952, 1758, 1714,
1684, 1156; 1H NMR (500 MHz, CDCl3) d 10.3 (2H, br s, OH),
7.0–7.3 (5H, m, Ar), 4.70 (1H, m, CHCOOH), 4.58 (1H, m,
CHCO), 4.05 (1H, m, CH2N), 3.93 (2H, m, CH2O), 3.33 (1H, m,
CH2N), 2.90 (2H, m, CH2Ar), 2.79 (1H, m, CH2N), 2.57 (1H, m,
CH2N), 1.3 (9H, br s, OC(CH3)3); 13C NMR (125 MHz, CDCl3)
d 172.9, 171.2, 154.2 (CO), 137.5, 134.0, 130.6, 128.8 (Ar), 81.2
((OC(CH3)3), 61.8 (CH2Ar), 61.1 (CH2OH), 59.3 (CHCOOH),
52.6 (CHCO), 46.4 (CH2N), 41.8 (CH2N), 38.3 ((OC(CH3)3);
MS m/z 377 (M)+, 283, 277; HRMS calc. for M+ 377.1713,
found 377.1701.
solution of 5b (1 mmol) in dry THF (5 mL), NaH (3 mmol)
◦
was slowly added at 0 C. The solution was stirred for 15 min
then benzyl bromide (1.1 mmol) was added. The solution was
stirred for 6 h then H2O (3 mL) was added. The solution was
extracted twice with CH2Cl2 (15 mL). The combined organic
phases were washed with brine (15 mL), dried (MgSO4) and
concentrated in vacuo. A slightly orange oil of diprotected
derivative was quantitatively obtained. This was dissolved in
dry THF (1.3 mL) and 2 mL of a 1 M solution of n-Bu4NF
in THF added. The solution was stirred at rt overnight, then
20 mL of H2O was poured into the solution. After extraction
(CH2Cl2 30mL) of the aqueous phase, the dried (MgSO4) and
concentrated in vacuo organic phases furnish 6 as an orange oil
in quantitative yield. [a]1D7 −7 (c 0.1; EtOH); IR mmax/cm−1 3360
(OH), 2979, 2866, 1687 (CO), 1642, 1172; 1H NMR (500 MHz,
CDCl3) d 7.5–7.2 (10H, m, Ar), 4.71 (1H, m, CH(CH2)2), 4.40
(1H, d, J = 12, OCH2Ar), 4.36 (1H, d, J = 12, OCH2Ar), 4.31
(1H, t, J = 6.5, CHCO),4.10 (1H, br t, J = 6.8, OH), 3.70 (2H,
d, J = 6.5, CH2Ar), 3.55 (2H, m, J = 6.5, CH2O), 3.34 (2H,
m, CH2O), 3.32 (2H, m, CH2N), 3.09 (2H, m, CH2N), 2.96
(2H, m, CH2N), 1.2 (9H, s, OC(CH3)3); 13C NMR (125 MHz,
CDCl3) d 169.8, 154.6 (CO), 138.4, 137.5, 130.8, 129.8, 129.4,
128.9, 128.8, 128.1 (Ar), 81.7 (OC(CH3)3), 71.6 (OCH2Ar),
67.1 (OCH2), 62.6 (OCH2), 62.4 (CHCH2Ar), 56.3 (CH), 55.3
(CHCO), 45.2 (CH2N), 38.0 (CH2N), 27.5 (OC(CH3)3); MS
m/z 477 (M + Na)+, 417, 381, 367, 342, 239, 234, 121.
(1ꢀR,3S)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-
2ꢀ-hydroxy ethyl]-3-substituted-2-oxopiperazine 9. Compound
9 was prepared from 2c using the procedure reported for the
preparation of 5.
(1ꢀR,3S)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-
2ꢀ-hydroxyethyl]-3-methyl-2-oxopiperazine 9a. Obtained in
89% yield using iodomethane as electrophile. [a]1D7 +48 (c 0.1;
EtOH); IR mmax/cm−1 3220 (OH), 2964, 1704, 1655 (CO), 1183;
1H NMR (500 MHz, CDCl3) d 7.2 (5H, m, Ar), 4.44 (1H, d,
1H, J = 11.9, CH2Ar), 4.40 (1H, q, J = 7.0, CHCO), 4.38
(1H, d, J = 11.9, CH2Ar), 3.85 (2H, m, CH2O), 3.70 (2H, m,
CH2OH), 3.65 (1H, m, CH2N), 3.55 (1H, m, CH2N), 3.49 (1H,
m, CH(CH2)2), 3.43 (1H, m, CH2N), 3.26 (1H, m, CH2N), 3.10
(1H, br m, OH), 1.37 (9H, s, OC(CH3)3), 1.32 (3H, d, J = 7.0,
CHCH3); 13C NMR (125 MHz, CDCl3) d 170.9, 153.9 (CO),
138.2, 128.8, 128.2, 127.4 (Ar), 80.9 (OC(CH3)3), 73.5 (CH2Ar),
68.4 (CH2N), 61.4 (CH2OH), 57.5 (CHCH3), 53.7 (CH2O), 45.1
(CH2N), 45.0 (CHCO), 28.7 (OC(CH3)3), 18.1 (OC(CH3)3);
MS m/z 401 (M + Na)+, 345, 301, 184; HRMS calc. for (M +
Na)+ 401.2052, found 401.2041.
(2S)-((3ꢀR)-4ꢀ -(tert-Butoxycarbonyl)-3ꢀ-phenylmethyl-2ꢀ-oxo-
piperazin-1ꢀ-yl)-3-hydroxypropanoic acid 7. To a solution of
6 (0.3 mmol) in acetone (1.5 mL) at 0 ◦C, Jones’ reagent
(0.45 mL) was slowly added. The solution was stirred for 30 min
then i-propanol (6 mL) was added and the solution stirred for
30 min. The solution was extracted three times with EtOAc
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3
7 9 1

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(1ꢀR,3S)-4-(tert-Butoxycarbonyl)-1-[1ꢀ-phenylmethyloxymethyl-
2ꢀ-[hydroxyethyl]-3-phenylmethyl-2-oxopiperazine 9b. Obtained
in 80% yield using benzyl bromide as electrophile. [a]1D7 +16 (c
0.1; EtOH); IR mmax/cm−1 3364 (OH), 2974, 1687, 1641 (CO),
1172 cm−1; 1H NMR (500 MHz, CDCl3) d 7.0–7.3 (10H, m, Ar),
4.60 (1H, m, CH(CH2)2), 4.44 (1H, d, J = 11.6, ArCH2O), 4.40
(1H, d, J = 11.6, ArCH2O), 4.37 (1H, t, J = 8.3, CHCO)), 3.89
(1H, br m, OH), 3.71 (2H, d, J = 8.3, CHCH2Ar), 3.62 (2H, m,
CH2OH), 3.51 (2H, m, CH2O), 3.32 (2H, m, CH2N), 3.16 (1H,
m, CH2N), 3.10 (1H, m, CH2N), 3.00 (1H, m, CH2N), 1.20
(9H, s, OC(CH3)3); 13C NMR (125 MHz, CDCl3) d 169.5, 154.0
(CO), 138.2, 130.3, 129.4, 128.8, 128.2, 128.0, 127.1 (Ar), 80.9
(OC(CH3)3), 73.6 (CH2O), 68.6 (CH2O), 61.6 (CH2OH), 61.5
(CHCH2Ar), 59.3 (CH(CH2)2), 58.1 (CHCO), 45.1 (CH2N),
38.3 (CH2N), 28.5 (OC(CH3); MS m/z 477 (M + Na)+, 421,
377, 345; HRMS calc. for (M + Na)+ 477.2349, found 477.2343.
(1ꢀR,3S)-3-Allyl-4-(tert-butoxycarbonyl)-1-[1ꢀ-phenylmethyloxy-
methyl-2ꢀ-hydroxyethyl]-2-oxopiperazine 9c. Obtained in 84%
yield using allyl bromide as electrophile. [a]1D7 +38 (c 0.1; EtOH);
IR mmax/cm−1 3114 (OH), 2972, 1721, 1655 (CO), 1172; 1H
NMR (500 MHz, CDCl3) d 7.2 (5H, m, Ar), 5.74 (1H, m,
CH olef), 4.98 (1H, dd, J = 17.2, 0.5, CH2 olef), 4.93 (1H,
dd, J = 10.0, 0.5, CH2 olef), 4.63 (2H, m, CHCO), 4.09 (1H,
m, CH(CH2)2), 3.95 (1H, m, CH2N), 3.79 (1H, m, CH2O),
3.75 (1H, m, CH2O), 3.70 (2H, m, CH2OH), 3.51 (1H, m,
CH2N), 3.48 (1H, m, CH2N), 3.04 (2H, m, CH2N), 2.59
(1H, m, CHCH2CH), 2.48 (1H, m, CHCH2CH), 1.39 (9H, s,
OC(CH3)3); 13C NMR (125 MHz, CDCl3) d 169.7, 153.8 (CO),
134.2 (CH = CH2), 138.3, 129.3, 128.2, 127.5 (Ar), 118.2 (CH =
CH2), 81.3 (OC(CH3)3), 61.8 (OCH2), 60.2 (HOCH2), 57.4
(CHCO), 56.3 (CH(CH2)2), 45.6 (NCH2), 38.4 (CHCH2CH),
29.2 (OC(CH3)3), 27.6 (NCH2); MS m/z 427 (M + Na)+, 345,
301, 154; HRMS calc. for (M + Na)+ 404.2311, found 404.2297.
indicated for the preparation of 7. Compound 12 was obtained
in 62% yield from 5d.
[a]D17 −119 (c 0.1; EtOH); IR mmax/cm−1 1855, 1680, 1637, 1157;
1H NMR (500 MHz, CDCl3) d 8.14 (1H, br s, OH), 5.23 (2H, m,
CH2CO), 3.55 (1H, m, CH2N), 3.48 (1H, m, CHCO), 3.38 (2H,
m, CH2N), 2.61 (1H, m, CH2N), 2.35 (1H, m, CH2N), 1.93 (1H,
m, CH2CH), 1.53 (1H, m, CH2CH), 1.36 (2H, m, CH2CH3),
1.26 (9H, s, OC(CH3)3), 0.89 (3H, t, J = 6, CH2CH3); 13C NMR
(125 MHz, CDCl3) d 177.8, 168.4, 155.1 (CO), 79.2 (OC(CH3)3),
68.4 (CH2COOH), 59.1 (CHCO), 46.6 (CH2N), 33.4 (CHCH2),
28.0 (CH2N), 25.4 (OC(CH3)3), 21.5 (CH2CH3), 14.0 (CH2CH3);
MS m/z 323 (M + Na)+ 263, 215; HRMS calc. for (M + Na)+
323.1583, found 323.1587.
((3ꢀS)-4ꢀ-(tert-Butoxycarbonyl)-3ꢀ-propyl-2ꢀ-oxopiperazin-1ꢀ-yl)-
3-acetic acid 13. Hydrogenolysis of 9d was carried out
using the conditions used for the preparation of 2b.
Oxidation/decarboxylation was achieved using Jones’ reagent
and according to the procedure depicted for the preparation of
7, followed by heating at 90 ◦C for 2 h. Reaction work up was as
indicated for the preparation of 7. Compound 13 was obtained
in 53% yield (from 9d).
[a]1D7 +113 (c 0.1; EtOH). For other characteristics see 12.
Acknowledgements
We are grateful to S. Pilard and S. Da Nascimento for obtaining
the mass spectra. We thank Region-Picardie and “Re´seau de
Re´gulation de la Matrice Extra-cellulaire et Pathologie” for
supporting part of this work.
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2ꢀ-hydroxyethyl]-3-propyl-2-oxopiperazine 9d. Obtained in
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1
EtOH); IR mmax/cm−1 3114 (OH), 1650 (CO), 1164 cm−1; H
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CHCO), 4.11 (1H,m, CH(CH2)2), 4.01 (2H, s, CH2Ar), 3.87
(1H, m, CH2O), 3.71 (1H, m, CH2O), 3.58 (2H, m, CH2OH),
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1.87 (1H, m, CHCH2CH2), 1.48 (2H, m, CHCH2CH2), 1.42
(9H, s, OC(CH3)3), 1.24 (2H, m, CH2CH3), 0.78 (3H, t, J = 6,
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129.6, 129.1, 128.2 (Ar), 82.4 (OC(CH3)3), 61.8 (CH2O), 60.0
(CH2OH), 56.9 (CHCO), 55.8 (CH(CH2)2), 45.9 (CH2N), 33.2
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(2R)-((3ꢀS)-4ꢀ-(tert-Butoxycarbonyl)-3ꢀ-phenylmethyl-2ꢀ-oxopi-
perazin-1ꢀ-yl)-3-hydroxypropanoic acid 11. The procedure
reported for the preparation of 8 was repeated using 9 as
starting material. Compound 11 was obtained in 62% yield.
[a]1D7 +10 (c 0.1; EtOH). For other characteristics see 7.
((3ꢀR)-4ꢀ-(tert-Butoxycarbonyl)-3ꢀ-propyl-2ꢀ-oxopiperazin-1ꢀ-yl)-
3-acetic acid 12. Deprotection of 5d was carried out using
the procedure depicted for the preparation of 2c. Oxidation/
decarboxylation was achieved using Jones’ reagent and ac-
cording to the procedure depicted for the preparation of 7,
followed by heating at 90 ◦C for 2 h. Reaction work up was as
10 N. Mohamed, U. Bhatt and G. Just, Tetrahedron Lett., 1998, 39,
8213–8216.
7 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3

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11 A. R. Pohlmann, V. Schanen, D. Guillaume, J.-C. Quirion and H.-P.
Husson, J. Org. Chem., 1997, 62, 1016–1022.
12 (a) L. Micouin, V. Jullian, J.-C. Quirion and H.-P. Husson, Tetra-
hedron: Asymmetry, 1996, 7, 2839–2846; (b) L. Micouin, T. Varea,
C. Riche, A. Chiaroni, J.-C. Quirion and H.-P. Husson, Tetrahedron
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13 V. Schanen, C. Riche, A. Chiaroni, J.-C. Quirion and H.-P. Husson,
Tetrahedron Lett., 1994, 35, 2533–2536.
14 Unpublished observations from our laboratory.
15 A. Pohlmann, D. Guillaume, J.-C. Quirion and H.-P. Husson,
Tetrahedron Lett., 1997, 38, 5809–5810.
16 N. Franceschini, S. Da Nascimento, P. Sonnet and D. Guillaume,
Tetrahedron: Asymmetry, 2003, 14, 3401–3405.
17 For an example of an easily accessible pharmacophore see:D.-S. Su,
M. K. Markowitz, R. M. DiPardo, K. L. Murphy, C. M. Harrell,
S. S. O’Malley, R. W. Ransom, R. S. L. Chang, S. Ha, F. J. Hess, D. J.
Pettibone, G. S. Mason, S. Boyce, R. M. Freidinger and M. G. Bock,
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 8 7 – 7 9 3
7 9 3