A new diastereoselective synthetic approach to the enantiopure peptidomimetic scaffold 2-oxo-1-azabicyclo[4.4.0]decane

Article abstract of DOI:10.1002/ejoc.200400709

A general method for the synthesis of unsubstituted and C-7-substituted azabicyclo[4.4.0]decane dipeptides (23, 30a, and 30b) that can serve as dipeptide mimetics has been developed. The key step of this new method involves the coupling reaction of the ox

Full text of DOI:10.1002/ejoc.200400709

FULL PAPER
A New Diastereoselective Synthetic Approach to the Enantiopure
Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
Cyrille Truchot,[a] Qian Wang,[a] and N. André Sasaki*[a]
Keywords: Asymmetric synthesis / C–C coupling / Peptidomimetics / Synthetic methods
A general method for the synthesis of unsubstituted and C-7-
substituted azabicyclo[4.4.0]decane dipeptides (23, 30a, and
30b) that can serve as dipeptide mimetics has been devel-
oped. The key step of this new method involves the coupling
reaction of the oxazolidine aldehyde 5 and the sulfone 7, both
of which are derived from -glutamic acid.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
L
range of valuable constrained dipeptides. We now wish to
report a new general method for the preparation of azabicy-
clo[4.4.0]decane dipeptides.
Introduction
Over the past ten years the synthesis of enantiopure bicy-
clic dipeptides, and azabicycloalkanes in particular, has
been extensively explored.[1,2] These structures, due to their
constrained backbone and thus reinforced metabolic sta-
bility, have been proven to be useful for many studies on
bindings of peptides to various receptors and have served
as interesting probes for the understanding of the confor-
mational requirements of the studied peptides.[3–7]
Most of the syntheses described in the literature have
aimed at the preparation of the 5,6-fused[8–24] and 5,7-
fused[8,9,19,24–32] systems (Figure 1). Other research groups
have focused on the 5,5-fused type,[19–33] while the 6,6-fused
system has remained seldom explored. To the best of our
knowledge, only one synthesis of an azabicyclo[4.4.0]decane
dipeptide has been reported by Gosselin and Lubell.[30–34]
This quinolizidinone-type dipeptide shows an excellent af-
finity for the opioid-like receptor (ORL1) in some recent
studies,[3] and thus represents a target of choice for general
synthetic methods. The possibility of incorporation of sub-
stituents on the backbone of such motifs could provide a
Results and Discussion
The strategy envisaged to synthesize the azabicyclo[4.4.0]-
decane scaffold is based on the condensation of two chiral
units − an aldehyde and a newly prepared sulfone − both
derived from l-glutamic acid. A C–C bond formation by
the coupling of the α-sulfonyl carbanion with this aldehyde,
followed by the transformation of the adduct to a β-keto
sulfone, would provide the backbone for constructing the
desired bicyclic lactam with eventual alkylation at the C-7
position (Scheme 1).
Aldehyde 5 has been previously synthesized from l-glu-
tamic acid,[35] albeit without any detailed protocols or full
characterization of all the intermediate compounds. Thus,
commercially available 1 was submitted to regioselective re-
duction of the α-carboxylic acid moiety using the procedure
described by Ohfune and co-workers[36] to afford 2 in 82%
yield (Scheme 2). This alcohol was subsequently protected
as the oxazolidine 3 in 92% yield according to a known
protocol.[37] Compound 3 was reduced to 4 in 96% yield by
treatment with LiAlH4 in THF. The resulting alcohol was
finally submitted to Swern oxidation to give the desired al-
dehyde 5 in 98% yield.
The chiral sulfone 7 was developed as a logical extension
of our previous work,[38–41] and is a homologue of synthon
6, derived from l-serine (Scheme 3). It was prepared as
shown in Scheme 4: N-Cbz-protected l-glutamic acid 8 was
converted in 98% yield into its dimethyl ester 9 using the
procedure described by Watanabe and co-workers[42] (BF3
etherate in MeOH). Compound 9 was reduced with LiBH4
and three equivalents of methanol in THF to afford 10 in
79% yield. The diol 10 was then transformed into oxazolid-
ine 11 in 88% yield by treatment with dimethoxypropane
Figure 1. Some examples of azabicycloalkanes.
[a] Institut de Chimie des Substances Naturelles, CNRS
Avenue de la Terrasse 91198 Gif-sur-Yvette Cedex, France
Fax: +33-1-6907-7247
E-mail: andre.sasaki@icsn.cnrs-gif.fr
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DOI: 10.1002/ejoc.200400709
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C. Truchot, Q. Wang, N. A. Sasaki
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Scheme 1.
Scheme 2.
Scheme 3.
in the presence of a catalytic amount of p-toluenesulfonic respectively, the possibility of epimerization of a potential
acid in dichloromethane. Alcohol 11 was mesylated and α-amino aldehyde intermediate must be taken into account.
readily converted to sulfone 12 in a novel one-pot pro- In previous work, the α-carboxylic function of a number of
cedure: the mesylate was first converted to its phenyl sulfide α-amino acids has been converted into a hydroxy function
by treatment with sodium thiophenolate in THF followed by this method. In those cases, these reductions were con-
by addition of magnesium monoperoxy phthalate (MMPP) sidered as racemization-free. However, no studies have been
to afford 12. Cleavage of the oxazolidine ring of crude 12 reported on the enantiomeric purity of these particular po-
and subsequent treatment of the resulting alcohol 13 with tentially valuable aldehyde 5[43] or alcohol 11.[44] Therefore,
tert-butyldiphenylsilyl chloride (TBDPSCl) provided tert- we decided to determine their optical purity by the follow-
butyldiphenylsilyloxy derivative 7 (in 87% yield from 11).
ing method: the pairs of Mosher esters of 4 and 11 [(2S,8R)-
As the synthesis of aldehyde 5 and sulfone 7 involves the 14 and (2S,8S)-15 and (2S,8R)-16 and (2S,8S)-17, respec-
borohydride reductions of an activated ester and a diester, tively], were synthesized (Figure 2).[45] Unfortunately, the
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Enantiopure Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
FULL PAPER
Scheme 4.
determination of the diastereomeric excess could not be signals. Based on the results of the above experiments, we
achieved by HPLC due to the fact that the mixture of dia- can now assume that the enantiomeric purity of aldehyde 5
stereomers was inseparable on every achiral column we had and sulfone 7 is more than 95%.[51]
in our possession.[46] As was to be expected in the case of
1
such compounds, the H NMR spectra of each pair of dia-
stereomers presented a rather poor resolution in several sol-
vents,[47] in particular around the methoxy chemical shift
area. This observation is mainly due to the existence of two
conformers (a well-known phenomenon, especially in the
case of five-membered rings),[48,49] which arise from the
strong steric hindrance between the Boc (or Cbz) and the
oxazolidine dimethyl groups. Indeed, a fast rotation of the
carbamate is hardly possible and thus engenders the exis-
tence of two distinct rotamers. As a consequence, the NMR
spectra of this kind of compound, in general, will feature
signal overlapping, splitting and broadening. The 19F NMR
spectrum finally allowed us to shed light on the excellent
enantiomeric purity of both compounds. In the case of 14
and 15, each compound shows a set of two signals at δ =
–72.00 and –72.12 ppm, and at δ = –72.04 and –72.15 ppm,
respectively.[50] The spectrum of the mixture of 14 and 15
displays the two sets of signals at exactly the same chemical
shifts corresponding to the four rotamers. In the case of 16
and 17, overlapping of the signals gave rise to some diffi-
Figure 2. Mosher esters synthesized for the determination of the
enantiomeric purity of alcohols 4 and 11.
The coupling of 5 and 7 was achieved under classical
culties, but the choice of deuterated acetonitrile as the sol- anionic reaction conditions: formation of the dianion by
vent finally allowed us to overcome this problem and get treatment with butyllithium in THF at –78 °C was followed
rid of the splitting of the signals generated by the rotamers. by the addition of aldehyde 5 to provide the desired hy-
We were pleased to observe that 16 and 17 both appear as droxysulfone 18 in 85% yield (Scheme 5). Both oxidative
a single peak (at δ = –72.71 and –72.78 ppm, respectively), cleavage of the oxazolidine and oxidation of the secondary
and the spectrum of their mixture exhibits these two distinct alcohol could be smoothly achieved in a single step using
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C. Truchot, Q. Wang, N. A. Sasaki
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Scheme 5.
Jones’ reagent, yielding 76% of 19. Desulfonylation was above for the unsubstituted azabicyclo[4.4.0]decane dipep-
then undertaken; it was our speculation that the presence tide was then effected. An oxidative cleavage of oxazolidine
of an epimerizable center such as the α-carbon of the car- 25 provided 26, and the desulfonylation–deprotection–re-
boxylic acid could cause some problems during this step ductive amination sequence yielded 27 in 82%. After cycli-
considering the basic reaction conditions commonly em- zation by intramolecular peptide-bond formation, a 5:1
ployed. Indeed, when desulfonylation was carried out using mixture of two diastereomers was obtained. This mixture
sodium amalgam in methanol, a 50:50 mixture of two dia- was easily separated by column chromatography on silica
stereomers was obtained. While searching for milder condi- gel to afford 28a and 28b in 78% yield. Deprotection was
tions, we determined that, under rather vigorous hydro- then carried out on each of the two isomers with TBAF in
genolysis conditions, although neutral from an acidobasic THF. The final oxidation step under either Jones or
point of view, the sulfonyl and the benzyloxycarbonyl TEMPO/NaOCl conditions failed and gave unidentifiable
groups could be simultaneously removed to allow reductive and inseparable mixtures. To our delight, this difficulty was
amination to take place. Thus, keto sulfone 19 was treated surmounted by using NaIO4/RuCl3 hydrate as the oxidising
with Raney nickel in refluxing ethanol to provide the de- agent[54] to provide the carboxylic acid. The obtained acid
sired cyclic dipeptide 20 in 85% yield. The lactam forma- was directly esterified with (trimethylsilyl)diazomethane to
tion was accomplished using the common reagents EDCI provide 30a and 30b in 69% yield.
and HOBt in DMF and 21 was isolated as a single isomer
The configuration at the ring-fusion center of 23 was ten-
in 77% yield. Finally, the alcohol deprotection to afford tatively determined by NOESY experiments.[55] Molecular
22 followed by TEMPO/NaOCl oxidation[52] furnished the modeling of the two possible diastereomers indicated that,
carboxylic acid which was, in turn, converted to methyl es- in the case of the (6S)-isomer, the hydrogen atom H6 is too
ter 23 in 84% yield (two steps).
distant from H3 or H10 to exhibit any NOE (Figure 3).
Incorporation of substituents on the scaffold backbone However, NOEs were observed between H6 (δ = 3.46 ppm)
is quite a demanding task, especially because of the prob- and H3 and/or H10 (overlapped at δ = 4.10 ppm). This al-
lems in terms of stereoselectivity. As an application of the lowed us to assign the (3S,6R,10S) configuration to this
method described above for the synthesis of such peptidom- compound.
imetic scaffolds, we decided to append a methyl group at
The configuration of the new stereogenic centers of 30a
the C-7 position to mimic an Ala-Nle (physiological equiva- and 30b was determined in the same manner (Figure 3).
lent of Ala-Met[53]) dipeptide unit (Scheme 6). Intermediate The experiments were conducted with the silyloxy deriva-
1
18 was oxidized with o-iodoxybenzoic acid (IBX) to give tives 28a and 28b, for which the H NMR spectra present
keto sulfone 24. Treatment with K2CO3 and methyl iodide no overlapping for most of the signals. Out of the four dia-
in DMF gave rise to the desired product 25 methylated at stereomers that were studied by molecular modeling, 31 and
the α-sulfonyl carbon position in an excellent 97% yield. 32 were readily discarded as, for both compounds, NOEs
Approximately the same sequence as the one discussed were observed between H3, H6 and H10, whereas 31 and 32
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Enantiopure Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
FULL PAPER
Scheme 6.
Figure 3. NOE-assisted determination of the absolute configuration of the C-6 and C-7 stereocenters of the azabicyclo[4.4.0]decanes 23,
30a, and 30b.
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clearly cannot exhibit any NOE for those hydrogen atoms easily at room temperature with the Raney nickel cata-
(δ = 4.16, 3.58 and 4.00 ppm and δ = 4.03, 3.05 and lyst,[56,57] whereas the desulfonylation step requires the reac-
3.73 ppm for 28a and 28b, respectively), as confirmed by the tion mixture to be refluxed for several hours. Besides, it is
average values of the hydrogen–hydrogen distances (around to be assumed that the reductive amination takes place only
4 Å) according to molecular modeling. Moreover, the major after the carbamate group is cleaved. The question arises
compound shows a very strong NOE between H6 (δ = whether or not the desulfonylation process occurs prior to
3.58 ppm) and H7 (δ = 1.96 ppm), and no detectable NOE the amine deprotection. As the alkylation of the keto sul-
between H6 and the methyl group at C-7 (δ = 0.90 ppm). fone 24 afforded a 50:50 mixture of diastereomers,[58] this
On the contrary, the minor isomer displays a strong NOE ratio should have been reflected in the final compounds 30a
between H6 (δ = 3.05 ppm) and the methyl group at C-7 (δ and 30b. However, the observed ratio was 5:1, which sug-
= 0.87 ppm), and no signal is detected between H6 and H7 gests that the desulfonylation proceeds after the cycliza-
(δ = 1.64 ppm). As these observations are in agreement with tion,[59–61] and should be the last step of the sequence.
the values obtained from the molecular modeling calcula-
tions, a (3S,6S,7S,10S) configuration was thus assigned to 30b can be explained by the following hypothesis. The imin-
28a, and a (3S,6S,7R,10S) configuration to 28b. ium intermediate 33 leading to piperidine 20 can exist as
The stereochemical outcome observed for 23, 30a, and
Now that the stereochemistry of 23, 30a, and 30b has two pairs of conformers[62] (34/35 and 40/41) as shown in
been assigned, the observed diastereoselectivity deserves Figure 4. Of the eight possible resulting products, 38, 39,
some comments. The step involving the Raney nickel cata- 42, and 43 require boatlike transition states and are disfa-
lyst is quite remarkable in the sense that three steps are vored kinetically. Furthermore, 36 and 37 suffer from a se-
accomplished in one-pot: the cleavage of the N-benzylcar- vere 1,3-diaxial interaction between the bulky tert-butyldi-
bamate, the reductive amination and the desulfonylation. It phenylsilyloxymethyl substituent and the incoming hydro-
has been reported that reductive amination can be achieved gen donor, therefore 44 and 45 are the more favored pos-
Figure 4. Reactive intermediates possibly involved in the reductive amination step.
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Enantiopure Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
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Figure 5. The 1,3-diaxial interaction between the electronic lone pairs explaining the observed ratio of diastereomers.
in CD3CN, and δ = 3.31 ppm in MeOD for 1H, and δ = 77.16 ppm
sibilities and explain the stereochemistry of the resulting
lactam 21. It should be noted that the selectivity of the nu-
cleophilic attack does not depend on the conformational
position of the phenylsulfonyl group. Therefore, if the α-
sulfonyl hydrogen of 33 is replaced by a methyl group, the
same conclusion accounts for the stereochemistry observed
at C-6 of 28a and 28b.
On the other hand, the cause for the observed ratio of
the C-7 isomers for 30a and 30b is not obvious. Although
the mechanism of desulfonylation with Raney nickel has
been investigated in the past,[63,64] unambiguous evidence
about the nature of the reactive intermediate is still lack-
ing.[65] The problem is to choose between a free radical,
an anionic mechanism, or a concerted mechanism, while a
cationic intermediate seems the least likely. In our case, a
concerted mechanism cannot account for the observed ra-
tio. A proposal explaining the formation of the major iso-
mer would be a 1,3-diaxial electronic repulsion between the
in CDCl3, δ = 1.32 in CD3CN, and δ = 49.00 in MeOD for 13C.
Some spectra were recorded preferentially in CD3CN because of
the significant improvement of their readability in that solvent
(presence of rotamers).
General Procedure A. Oxazolidine Oxidative Deprotection: Freshly
prepared Jones’ reagent (3 equiv., 2.67 m) was added at 0 °C to a
solution of the oxazolidine in acetone (0.1 m). The reaction mixture
was stirred for 6 h at 0 °C. A saturated solution of NaHCO3 was
added to obtain a pH value of 5–6. The aqueous phase was then
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried with Na2SO4, filtered through Celite, and
concentrated in vacuo to give the crude carboxylic acid.
General Procedure B. Piperidine Formation: Raney nickel[66]
(around 1000 wt.-%) was added to a solution of the β-keto sulfone
in ethanol (0.05 m). The mixture was refluxed until complete con-
version of the starting material into a single product (monitored
by TLC: 10% MeOH in dichloromethane). The mixture was cooled
to room temp. and filtered through a pad of Celite and Na2SO4.
lone pair of the nitrogen and the anion generated by the The solid was well rinsed with ethanol, the filtrates were combined,
and the solvents evaporated in vacuo to afford the crude piperidine.
cleavage of the phenylsulfone group (Figure 5). The more
stable conformation would then be the one involving an
axial position of the methyl group, and would lead to the
major isomer.
General Procedure C. Amino Acid Cyclization: EDCI (1.2 equiv.)
and HOBt (1.2 equiv.) were added at room temperature to a solu-
tion of the amino acid in DMF (0.2 m). The reaction mixture was
stirred for 3 h. Water was added and the aqueous phase was ex-
tracted with EtOAc. The combined extracts were washed with 1 m
HCl, H2O, saturated aqueous NaHCO3, H2O, and brine. The solu-
tion was dried with Na2SO4, filtered through Celite, and concen-
trated in vacuo to afford the crude lactam.
Conclusions
In conclusion, we have developed a general method for
the synthesis of enantiopure 6,6-fused 1-azabicyclo[4.4.0]-
decane dipeptides. We have also demonstrated the versatil-
ity of our new approach by synthesizing quinolizidinone
dipeptides 30a and 30b substituted at the C-7 position. The
incorporation of such substituted units could provide bene-
ficial information on the prerequisites of biologically active
General Procedure D. OTBDPS Deprotection: TBAF (1.05 equiv.,
1 m in THF) was added at room temperature to a solution of the
tert-butyldiphenylsilyl ether in THF (0.1 m). The reaction mixture
was stirred for 1 h, then quenched by addition of saturated aqueous
NaHCO3. After stirring for 10 min, the aqueous phase was ex-
tracted with EtOAc, and the combined organic extracts were
peptides. The preparation of 5,7-fused systems is also under washed with brine, dried with Na2SO4, filtered through Celite, and
concentrated in vacuo to give the crude alcohol.
investigation, and could be possible from the orthogonally
protected intermediate 18.
General procedure E. Ruthenium-Catalyzed Oxidation of Alcohol to
Carboxylic Acid: NaIO4 (4 equiv.) and a catalytic amount[54] of
RuCl3·nH2O were added at room temperature to a solution of the
alcohol in CCl4/CH3CN/H2O (0.15 m, 2:2:3). The reaction mixture
was stirred for 1.5 h. Dichloromethane (2 mL) and water (2 mL)
were added, and the aqueous phase was extracted with dichloro-
methane. The organic extracts were dried with MgSO4, filtered
through a pad of Celite, and concentrated in vacuo to give a pale
oil. The carboxylic acid obtained was dissolved in toluene/meth-
anol (0.1 m, 4:1) and TMSCHN2 (1.1 equiv., 2 m in hexanes) was
added dropwise. The reaction mixture was stirred for 5 min and
was quenched with acetic acid. The solvents were removed in vacuo
to afford the crude methyl ester.
Experimental Section
General Remarks: Tetrahydrofuran was distilled from sodium
benzophenone ketyl, and dichloromethane from P2O5 immediately
prior to use. All reagents obtained from commercial sources were
used without purification, unless otherwise specified. All reactions
were conducted under argon. Flash column chromatography was
performed using Kieselgel 60 (230–400 mesh, E. Merck). Optical
rotations were recorded on a JASCO P-1010 polarimeter, and IR
spectra on a Perkin–Elmer Spectrum BX spectrometer. High reso-
lution mass spectra (HRMS) were run on a Waters Micromass
LCT with an electrospray source (ZQ) in positive mode ionization
General Procedure F. Mosher Ester Formation: The preparation of
the Mosher esters from the alcohols was achieved according to the
method described in the literature.[45] Commercially available (+)-
and (–)-MTPA-Cl were used. The reactions were monitored by
1
(ESI). H and 13C NMR spectra were recorded on a Bruker AM-
300 with chemical shifts reported in ppm relative to the central line
of the solvent residual peak: δ = 7.26 ppm in CDCl3, δ = 1.94 ppm
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TLC and were quenched after complete conversion of the starting
material. Purification was performed by preparative TLC (EtOAc/
heptanes 1:1), and care was exercised that both isomers were com-
pletely collected. As these esters were prepared in very small
amounts and were obtained as rotamers, no 13C NMR spectra were
recorded.
1455, 1392, 1257, 1174, 1086 cm–1. HRMS (ESI) [M + Na]+: m/z
calcd. for C13H25NNaO4 282.1681; found 282.1684.
Aldehyde 5: a solution of DMSO (8.20 mL, 114.6 mmol, 3.3 equiv.)
in dichloromethane (30 mL) was added at –78 °C to a solution of
oxalyl chloride (4.60 mL, 52.2 mmol, 1.5 equiv.) in dichlorometh-
ane (180 mL). The reaction mixture was stirred for 15 min at
–78 °C, and a solution of 4 (9.05 g, 34.9 mmol) in dichloromethane
(30 mL) was added. The reaction mixture was stirred for 45 min
at –78 °C. Et3N (33.2 mL, 236.4 mmol, 6.8 equiv.) was then added
at –78 °C, the cooling bath removed, and the reaction mixture was
stirred for 1 h at room temp. The reaction was quenched by ad-
dition of water, and the aqueous phase was extracted with dichloro-
methane. The combined organic extracts were washed successively
with 1 m HCl, water, aqueous NaHCO3, water, and brine, dried
with Na2SO4, filtered through Celite, and the solvent was removed
in vacuo to give crude 5 (8.80 g, 98%). This aldehyde was used
without any purification for the next step. An analytical sample
(235 mg) was purified by flash chromatography on silica gel (hep-
tanes/EtOAc, 4:1) to provide pure 5 (232 mg, 99%) as a colorless
Hydroxy Ester 2: DCC (16.8 g, 80.6 mmol, 1.2 equiv.) was added
at 0 °C to a solution of 1 (22.7 g, 67.1 mmol) and N-hydroxysuc-
cinimide (9.5 g, 80.6 mmol, 1.2 equiv.) in EtOAc (220 mL, HPLC
grade). The reaction mixture was warmed to room temperature and
stirred overnight. The mixture was then filtered and the filtrate was
washed successively with aqueous NaHCO3 and brine, dried with
Na2SO4, and concentrated in vacuo to give 32 g of crude ester.
NaBH4 (2.8 g, 70.5 mmol, 1.05 equiv.) was added at 0 °C to a solu-
tion of the residue (32 g) in THF (180 mL). Absolute EtOH
(60 mL) was then added and the suspension was stirred at 0 °C for
30 min. The reaction was quenched with saturated aqueous NH4Cl
and the mixture was extracted with EtOAc. The combined organic
extracts were dried with Na2SO4 and concentrated to give crude 2
(25.0 g), which was purified by flash chromatography on silica gel
(heptanes/EtOAc, 2:1) to yield pure 2 (17.7 g, 81%) as a white solid.
oil. [α]2D5 = +26 (c = 0.5, CHCl3). H NMR (300 MHz, CD3CN):
1
δ = 9.69 (s, 1 H), 3.96–3.77 (m, 2 H), 3.68 (m, 1 H), 2.52–2.24 (m,
2 H), 1.92–1.72 (m, 2 H), 1.52 (s, 3 H), 1.43 (m, 12 H) ppm. 13C
NMR (75.5 MHz, CD3CN): δ = 203.0, 174.7, 153.2, 152.8, 94.2,
80.5, 80.2, 67.6, 57.4, 40.8, 31.0, 29.4, 28.6, 28.0, 27.2, 26.8, 26.4,
[α]2D5 = –10 (c = 1.0, MeOH); m.p. 75–76 °C. H NMR (300 MHz,
1
CDCl3): δ = 7.33 (m, 5 H), 5.10 (s, 2 H), 5.04 (br. d, J = 8.1 Hz, 1
H), 3.57 (m, 3 H), 3.26 (m, 1 H), 2.44 (t, J = 7.8 Hz, 2 H), 1.96–
1.66 (m, 2 H), 1.41 (s, 9 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 173.6, 156.3, 135.8, 128.6, 128.3, 79.6, 66.5, 64.9, 52.1, 30.9, 28.4,
24.8, 23.3 ppm. IR (CHCl ): ν = 2979, 2937, 2876, 1725, 1694,
˜
3
1390, 1367, 1257, 1173, 1084 cm–1. HRMS (ESI) [M + Na]+: m/z
26.4 ppm. IR (CHCl ): ν = 3439, 3009, 2981, 2935, 1707, 1501, calcd. for C13H23NNaO4 280.1525; found 280.1531.
˜
3
1368, 1167 cm–1. HRMS (ESI) [M
+
Na]+: m/z calcd. for
Sulfone 7: Imidazole (10.9 g, 158 mmol, 2.5 equiv.) and tert-butyldi-
phenylsilyl chloride (17.5 mL, 66 mmol, 1.05 equiv.) were added to
a solution of crude 13 (23.8 g) in DMF (80 mL). The reaction mix-
ture was stirred for 2 h at room temp. and then quenched with a
saturated aqueous NaHCO3 solution. The mixture was stirred for
30 min and the aqueous phase was extracted with EtOAc. The ex-
tracts were washed with brine, dried with Na2SO4, and filtered
through Celite. The solvents were removed in vacuo and the residue
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 9:1 then 1:1) to give pure 7 (38.6 g, 87% from 73 mmol of
11) as a white solid. [α]2D5 = –16 (c = 1.0, CHCl3); m.p. 89–91 °C.
C17H25NNaO5 346.1630; found 346.1620.
Ester 3: pTsOH (208 mg, 0.02 equiv.) was added at room tempera-
ture to a solution of 2 (17.7 g, 54.8 mmol) in dimethoxypropane
(180 mL). The reaction mixture was stirred at room temperature
for 48 h. Et3N (160 μL, 0.02 equiv.) was added and the solvent was
evaporated in vacuo. The residue was dissolved in EtOAc and
washed with saturated aqueous NaHCO3, brine, dried with
Na2SO4, and concentrated to give the crude ester (18.7 g), which
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 5:1) to afford pure 3 (18.3 g, 92%) as a clear oil. [α]2D5
=
1
+20 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.33 (m, 1H NMR (300 MHz, CDCl3): δ = 7.87 (m, 2 H), 7.61–7.49 (m, 7
5 H), 5.10 (m, 2 H), 4.03–3.78 (m, 2 H), 3.69 (d, J = 8.2 Hz, 1 H),
H), 7.42–7.34 (m, 11 H), 5.04 (s, 2 H), 4.87 (d, J = 8.3 Hz, 1 H),
2.38 (m, 2 H), 2.12–1.82 (m, 2 H), 1.56 (two br. s, 3 H), 1.45 (s, 12 3.66–3.54 (m, 3 H), 3.20–2.99 (m, 2 H), 1.82–1.60 (m, 4 H), 1.03
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 172.9, 152.4, 151.9, (s, 9 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 156.1, 139.1,
136.0, 135.9, 128.6, 128.3, 93.9, 93.4, 80.1, 79.8, 66.9, 66.3, 56.7,
136.5, 135.6, 134.9, 133.7, 133.0, 133.0, 130.0, 130.0, 129.3, 128.6,
128.2, 128.1, 127.9, 66.8, 65.5, 55.7, 51.7, 30.4, 26.9, 19.4,
56.5, 31.0, 28.9, 28.5, 27.6, 26.8, 24.4, 23.1 ppm. IR (CHCl ): ν =
˜
3
2978, 2936, 2876, 1738, 1694, 1390, 1376, 1365, 1258, 1166 cm–1.
19.3 ppm. IR (CHCl ): ν = 3440, 3020, 2932, 2860, 1717, 1507,
˜
3
HRMS (ESI) [M + Na]+: m/z calcd. for C20H29NNaO5 386.1943; 1306, 1219, 1208, 1148, 1113, 1086, 823 cm–1. HRMS (ESI) [M +
found 346.1944.
Na]+: m/z calcd. for C35H41NNaO5SSi 638.2372; found 638.2335.
Alcohol 4: LiAlH4 (2.35 g, 60.2 mmol, 1.2 equiv.) was added at 0 °C
to a solution of 3 (18.20 g, 50.1 mmol) in THF (400 mL), and the
reaction mixture was stirred for 15 min at 0 °C. Water (2.4 mL) was
then added dropwise at 0 °C, followed by 15% aqueous NaOH
(2.4 mL) and water (7.2 mL). The cooling bath was removed and
the reaction mixture was stirred for 45 min at room temp. The pre-
cipitate was filtered off and the solvents were removed in vacuo
to afford the crude alcohol (18.25 g), which was purified by flash
chromatography on silica gel (heptanes/EtOAc, 2:1) to give pure 4
(12.52 g, 96%) as a colorless oil (two rotamers). [α]2D5 = +31 (c =
Diol 10: LiBH4 (247 mg, 10.8 mmol, 3 equiv.) and MeOH
(0.44 mL, 10.8 mmol, 3 equiv.) were added successively, at 0 °C, to
a solution of 9 (1.11 g, 3.59 mmol) in THF (20 mL). The reaction
mixture was stirred for 4 h at 0 °C and was then quenched by ad-
dition of 1 m HCl. The reaction mixture was stirred for 20 min and
then extracted with dichloromethane. The organic extracts were
dried with Na2SO4 and filtered through Celite. The solvents were
removed in vacuo to afford the crude diol (768 mg), which was
purified by flash chromatography on silica gel (dichloromethane/
MeOH, 95:5) to yield pure 10 (718 mg, 79%) as a white solid.
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 4.01–3.59 (m, 5 H), [α]2D5 = –16 (c = 1.0, MeOH); m.p. 103–105 °C. 1H NMR
2.74 (br., 0.5 H), 2.12 (br., 0.5 H), 1.92–1.36 (m, 19 H) ppm. 13C (300 MHz, MeOD): δ = 7.39–7.23 (m, 5 H), 5.07 (s, 2 H), 3.67–
NMR (75.5 MHz, CDCl3): δ = 152.5, 151.9, 93.8, 93.4, 80.4, 79.6,
3.46 (m, 5 H), 1.73–1.28 (m, 4 H) ppm. 13C NMR (75.5 MHz,
67.1, 62.6, 62.4, 57.2, 30.1, 29.7, 29.5, 29.1, 28.5, 27.7, 26.9, 24.6,
MeOD): δ = 158.7, 138.4, 129.4, 128.9, 128.7, 67.3, 65.4, 62.7, 54.2,
23.3 ppm. IR (CHCl ): ν = 3444, 2979, 2936, 2871, 1694, 1478, 30.0, 28.6 ppm. IR (CHCl ): ν = 3436, 3024, 3009, 2947, 2881,
˜
˜
3
3
1772
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1765–1776

Enantiopure Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
FULL PAPER
1708, 1511, 1226, 1069 cm–1. HRMS (ESI) [M + Na]+: m/z calcd.
for C13H19NNaO4 276.1212; found 276.1213.
yellow oil (24.1 g). An analytical sample was purified by flash
chromatography on silica gel (heptanes/EtOAc, 2:3) to give pure 13
as a colorless oil. [α]2D5 = –21 (c = 5.2, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.74 (d, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.3 Hz, 1 H),
7.38 (t, J = 7.5 Hz, 2 H), 7.17 (m, 5 H), 5.48 (d, J = 8.5 Hz, 1 H),
4.90 (s, 2 H), 3.55–3.25 (m, 3 H), 2.96 (m, 2 H), 1.75–1.30 (m, 4
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 156.5, 138.6, 136.3,
133.6, 129.2, 128.4, 127.9, 127.8, 66.5, 64.2, 55.4, 52.1, 29.6,
Alcohol 11: pTsOH (13 mg, 0.07 mmol, 0.1 equiv.) and dimeth-
oxypropane (0.85 mL, 6.72 mmol, 10 equiv.) were added, at room
temp., to a solution of 10 (170 mg, 0.67 mmol) in dichloromethane
(3 mL). The reaction mixture was stirred for 24 h at room temp.
Et3N (10 μL) was then added and the solvents were evaporated in
vacuo. Ethyl acetate and 1 m HCl were added to the residue, and
the aqueous phase was extracted with EtOAc. The combined or-
ganic extracts were washed successively with 1 m HCl, water, satu-
rated aqueous NaHCO3, water, and brine. The solvents were re-
moved in vacuo to afford the crude alcohol (182 mg), which was
purified by flash chromatography on silica gel (heptanes/EtOAc,
1:1) to yield pure 11 (174 mg, 88%) as an oil. [α]2D5 = +27 (c = 1.0,
19.1 ppm. IR (CHCl ): ν = 3435, 3024, 2955, 1712, 1508, 1306,
˜
3
1228, 1148, 1087 cm–1. HRMS (ESI) [M + Na]+: m/z calcd. for
C19H23NNaO5S 400.1195; found 400.1205.
Mosher’s Ester 14: The general procedure F was applied. [α]2D5
=
+53 (c = 1.0, CHCl3). 1H NMR (300 MHz, CD3CN): δ = 7.54–
7.42 (m, 5 H), 4.33 (m, 2 H), 3.92–3.71 (m, 2 H), 3.64 (m, 1 H),
1
3.52 (m, 3 H), 1.74–1.52 (m, 4 H), 1.50–1.36 (15H). IR (neat): ν =
CHCl3). H NMR (300 MHz, CDCl3): δ = 7.36 (m, 5 H), 5.14 (m,
˜
2974, 1749, 1696, 1390, 1260, 1170, 1085 cm–1. HRMS (ESI) [M +
2 H), 4.06–3.87 (m, 2 H), 3.78 (m, 1 H), 3.66 (m, 1 H), 3.56 (m, 1
H), 2.73 (0.5 H, br), 2.08 (0.5 H, br), 1.95–1.39 (m, 10 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 153.1, 152.3, 136.6, 136.3,
128.6, 128.1, 128.0, 128.0, 94.1, 93.7, 67.2, 66.6, 62.3, 57.8, 57.1,
Na]+: m/z calcd. for C23H32F3NNaO6 498.2079; found 498.2061.
Mosher’s Ester 15: The general procedure F was applied. [α]2D5
=
–10 (c = 0.8, CHCl3). 1H NMR (300 MHz, CD3CN): δ = 7.54–7.42
30.0, 29.5, 29.2, 29.0, 27.6, 26.6, 24.6, 23.2 ppm. IR (CHCl ): ν =
˜
3
(m, 5 H), 4.33 (m, 2 H), 3.91–3.70 (m, 2 H), 3.64 (m, 1 H), 3.52
3456, 3026, 3013, 2941, 2881, 1694, 1412, 1352, 1255, 1090 cm–1.
HRMS (ESI) [M + Na]+: m/z calcd. for C16H23NNaO4 316.1525;
found 316.1522.
(m, 3 H), 1.73–1.50 (m, 4 H), 1.49–1.35 (15H). IR (film): ν =
˜
2978, 1748, 1694, 1390, 1259, 1170, 1086 cm–1. HRMS (ESI) [M +
Na]+: m/z calcd. for C23H32F3NNaO6 498.2079; found 498.2077.
Sulfone 12: Triethylamine (11.4 mL, 81 mmol, 1.1 equiv.) was
added to a solution of 11 (21.6 g, 74 mmol) in dichloromethane
(400 mL) at –20 °C. Mesyl chloride (6.0 mL, 77 mmol, 1.04 equiv.)
was then added dropwise over 10 min, and the reaction mixture
was stirred at –20 °C for 30 min. The mixture was then washed
with 1 m HCl, H2O, saturated aqueous NaHCO3, H2O, and brine,
filtered through Celite, dried with Na2SO4, and the solvents evapo-
rated in vacuo to give a colorless oil. The crude mesylate (27.4 g)
was dissolved in THF (450 mL) and NaSPh (10.7 g, 77 mmol) was
added carefully at 0 °C. The cooling bath was removed and the
reaction mixture was stirred for 1 h. Magnesium monoperoxy
phthalate (MMPP) (50.0 g, 81 mmol, 1.1 equiv.) and ethanol
(135 mL) were then added at 0 °C. The bath was removed and the
reaction mixture was stirred overnight. The solvents were removed
in vacuo, the residue was diluted with EtOAc, and filtered. The
solid was washed with EtOAc, and the filtrates were combined and
washed with water. The aqueous phase was extracted with EtOAc.
The combined organic extracts were dried with Na2SO4 and filtered
through Celite. The solvents were removed in vacuo to afford the
crude sulfone (31.4 g). An analytical sample was purified by flash
chromatography on silica (heptanes/EtOAc, 2:1) to give pure 12 as
a colorless oil (two rotamers). [α]2D5 = +20 (c = 4.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.94 (m, 2 H), 7.72 (t, J = 7.2 Hz,
1 H), 7.62 (t, J = 7.7 Hz, 2 H), 7.39 (m, 5 H), 5.16 (s, 2 H), 4.05–
3.85 (m, 2 H), 3.76 (m, 1 H), 3.20 (m, 1 H), 3.05 (m, 1 H), 1.90–
1.67 (m, 4 H), 1.67–1.45 (m, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 152.9, 152.1, 139.0, 136.4, 136.2, 133.8, 129.3, 128.6,
128.2, 128.0, 94.2, 93.7, 67.1, 67.0, 66.7, 57.3, 56.4, 55.8, 32.2, 31.4,
Mosher’s Ester 16: The general procedure F was applied. [α]2D5
=
+45 (c = 0.3, CHCl3). 1H NMR (300 MHz, CD3CN): δ = 7.54–
7.41 (m, 5 H), 7.35 (m, 5 H), 5.16–4.98 (m, 2 H), 4.29 (m, 2 H),
3.90 (m, 2 H), 3.68 (m, 1 H), 3.49 (br. s, 3 H), 1.73–1.54 (m, 4 H),
1.50 (br. s, 3 H), 1.42 (br. s, 3 H). IR (neat): ν = 3025, 2982, 1751,
˜
1700, 1696, 1410, 1351, 1260, 1170, 1089 cm–1. HRMS (ESI) [M +
Na]+: m/z calcd. for C26H30F3NNaO6 532.1923; found 532.1929.
Mosher’s Ester 17: The general procedure F was applied. [α]2D5
=
1
–8 (c = 0.3, CHCl3). H NMR (300 MHz, CD3CN): δ = 7.45 (m,
5 H), 7.35 (m, 5 H), 5.14–4.96 (m, 2 H), 4.29 (m, 2 H), 3.87 (m, 2
H), 3.68 (m, 1 H), 3.50 (br. s, 3 H), 1.75–1.56 (m, 4 H), 1.50 (br. s,
3 H), 1.42 (br. s, 3 H). IR (neat): ν = 3030, 2962, 1744, 1700, 1696,
˜
1410, 1351, 1261, 1170, 1091 cm–1. HRMS (ESI) [M + Na]+: m/z
calcd. for C26H30F3NNaO6 532.1923; found 532.1904.
β-Hydroxy Sulfone 18: a 1.6 m solution of nBuLi in hexanes
(20 mL, 32.0 mmol, 2.2 equiv.) was added dropwise, at –78 °C, to
a solution of 7 (8.84 g, 14.4 mmol) in THF (140 mL). After stirring
for 20 min, a solution of 5 (4.15 g, 16.2 mmol, 1.1 equiv.) in THF
(10 mL) was added dropwise. The reaction mixture was stirred for
1.5 h at –78 °C, the bath was then removed, and the mixture was
stirred for an additional 30 min. The reaction was then quenched
with a saturated solution of NH4Cl and stirred for 10 min. The
aqueous phase was extracted with EtOAc and the extracts were
washed with water and brine. The organic phase was dried with
Na2SO4, filtered through Celite, and concentrated in vacuo to af-
ford a crude mixture (13.10 g), which was then purified by flash
chromatography on silica gel (dichloromethane/EtOAc, 29:1 then
9:1) to give 1.06 g (12%) of recovered starting sulfone 7, and pure
18 (10.70 g, 85%) as a white foam (mixture of diastereomers and
rotamers). 1H NMR (300 MHz, CD3CN): δ = 7.89 (m, 2 H), 7.74–
7.51 (m, 7 H), 7.51–7.25 (m, 11 H), 5.55 (m, 1 H), 5.07 (m, 2 H),
4.26–3.04 (m, 9 H), 2.00–1.36 (m, 23 H), 1.03 (s, 9 H) ppm. 13C
NMR (75.5 MHz, CD3CN): δ = 157.2, 157.1, 152.9, 152.8, 152.7,
140.7, 139.5, 138.3, 136.4, 134.6, 134.2, 130.8, 130.2, 129.6, 129.4,
129.3, 128.8, 128.6, 94.0, 80.4, 79.8, 70.4, 69.8, 69.3, 67.6, 66.8,
58.1, 57.8, 53.9, 53.7, 32.6, 31.7, 31.1, 30.9, 30.3, 30.2, 28.7, 28.0,
27.5, 26.6, 24.5, 23.0, 19.4, 19.3 ppm. IR (CHCl ): ν = 3028, 3011,
˜
3
2941, 2881, 1697, 1448, 1410, 1352, 1148, 1087, 837 cm–1. HRMS
(ESI) [M + Na]+: m/z calcd. for C22H27NNaO5S 440.1508; found
440.1479.
Hydroxy Sulfone 13: CeCl3·7H2O (34.0 g, 90 mmol, 1.2 equiv.) and
oxalic acid (346 mg, 3.8 mmol, 0.05 equiv.) were added, at room
temp., to a solution of crude 12 (31.4 g) in acetonitrile (350 mL),
and the reaction mixture was stirred overnight. The mixture was
neutralized with solid NaHCO3, and concentrated in vacuo. The
residue was dissolved in EtOAc, filtered through Celite, dried with
Na2SO4, and the solvent was removed in vacuo to give a pale-
27.8, 27.3, 24.9, 23.5, 22.3, 20.7, 19.8 ppm. IR (CHCl ): ν = 3437,
˜
3
3019, 2933, 2860, 1709, 1689, 1511, 1394, 1367, 1212, 1145, 1111,
Eur. J. Org. Chem. 2005, 1765–1776
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1773

C. Truchot, Q. Wang, N. A. Sasaki
FULL PAPER
823 cm–1. HRMS (ESI) [M
+
Na]+: m/z calcd. for The reaction mixture was acidified to pH 6 with a solution of 10%
C48H64N2NaO9SSi 895.4000; found 895.3974.
KHSO4. The solvents were removed in vacuo, and the residue was
directly purified by flash chromatography on silica gel (heptanes/
EtOAc, 1:4 then dichloromethane/MeOH, 9:1). The carboxylic acid
obtained (130 mg) was dissolved in toluene/methanol (5 mL, 4:1)
and TMSCHN2 (0.22 mL, 0.44 mmol) was added dropwise. The
reaction mixture was stirred for 5 min and was then quenched with
acetic acid. The solvents were removed in vacuo and the residue
was purified by flash chromatography on silica gel (heptanes/
Carboxylic Acid 19: According to the general procedure A, oxazol-
idine 18 (2.05 g, 2.3 mmol) afforded the crude carboxylic acid
(1.95 g), which was purified by flash chromatography on silica gel
(heptanes/EtOAc, 3:1 then 1:1) to yield pure 19 (1.51 g, 76%, mix-
ture of diastereomers and rotamers) as a white foam. 1H NMR
(300 MHz, CDCl3): δ = 8.95 (br. s, 1 H), 7.78 (m, 2 H), 7.63 (m, 5
H), 7.52 (m, 2 H), 7.45–7.30 (m, 11 H), 6.3 (m, 1 H), 5.45 (m, 1
H), 5.18–5.03 (m, 2 H), 4.39–4.14 (m, 2 H), 3.60 (m, 3 H), 3.06 (m,
1 H), 2.77 (m, 1 H), 2.32–1.78 (m, 4 H), 1.74–1.34 (m, 11 H), 1.06
(s, 9 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 201.3, 175.4,
175.3, 156.3, 155.8, 136.3, 136.2, 135.5, 134.3, 132.9, 129.9, 129.3,
129.1, 128.5, 128.2, 128.1, 127.8, 81.7, 80.1, 74.5, 74.1, 66.9, 65.2,
65.1, 52.5, 51.9, 51.8, 41.2, 40.8, 28.5, 28.3, 26.8, 26.1, 25.8, 23.8,
EtOAc, 3:1) to afford 23 (126 mg, 84%) as a colorless oil. [α]2D5
=
1
–10 (c = 1.1, CHCl3). H NMR (300 MHz, CDCl3): δ = 5.52 (br.
s, 1 H), 4.18–4.07 (m, 2 H), 3.72 (s, 3 H), 3.51 (m, 1 H), 2.40 (m,
1 H), 2.15–1.48 (m, 9 H), 1.42 (s, 9 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 171.6, 170.7, 155.8, 79.5, 56.6, 54.7, 52.3, 51.2, 30.0,
28.4, 27.2, 25.4, 25.0, 20.3 ppm. IR (CHCl ): ν = 3417, 3022, 2990,
˜
3
2952, 1736, 1707, 1654, 1498, 1208, 1166 cm–1. HRMS (ESI) [M +
23.4, 19.2 ppm. IR (CHCl ): ν = 3436, 3015, 2933, 2860, 1714,
˜
3
Na]+: m/z calcd. for C16H26N2O5Na 349.1739; found 349.1776.
1505, 1310, 1154, 1113, 823 cm–1. HRMS (ESI) [M + Na]+: m/z
calcd. for C45H56N2NaO10SSi 867.3323; found 867.3364.
β-Keto Sulfone 24: IBX (3.8 g, 13.8 mmol, 3 equiv.) was added to a
solution of 18 (4.0 g, 4.6 mmol) in DMSO (50 mL) and the reaction
mixture was stirred for 4 h at room temperature. After cooling to
0 °C, the reaction was quenched with water. Diethyl ether was
added, and the white solid was washed with diethyl ether and re-
moved by filtration. The two layers were separated, and the aque-
ous phase was extracted with diethyl ether. The organic extracts
were washed with brine, dried with Na2SO4, filtered through Celite,
and concentrated in vacuo to give crude 24 (4.0 g), which was puri-
fied by flash chromatography on silica gel (heptanes/EtOAc, 3:1)
to afford pure 24 as a white foam (3.8 g, 95%, mixture of dia-
stereomers and rotamers). 1H NMR (300 MHz, CDCl3): δ = 7.80–
7.46 (m, 9 H), 7.46–7.28 (m, 11 H), 5.13–4.80 (m, 3 H), 4.25 (m, 1
H), 3.99–3.77 (m, 2 H), 3.76–3.44 (m, 4 H), 3.02–2.45 (m, 2 H),
2.11–1.36 (m, 21 H), 1.02 (s, 9 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 201.6, 201.3, 156.1, 152.7, 152.4, 151.9, 136.7, 136.4,
135.6, 134.4, 133.0, 130.0, 129.4, 129.2, 128.7, 128.2, 127.9, 93.9,
93.6, 80.3, 79.9, 74.8, 74.5, 74.3, 67.3, 67.0, 66.8, 65.7, 65.3, 65.1,
56.8, 56.5, 56.2, 52.4, 51.8, 42.0, 41.8, 41.6, 28.9, 28.5, 28.0, 27.7,
Piperidine 20: According to the general procedure B, carboxylic
acid 19 (315 mg, 0.37 mmol) afforded the crude piperidine 20
(176 mg, 84%) as a clear oil, which was used as-is for the next step.
1H NMR (300 MHz, CD3OD): δ = 7.65 (m, 4 H), 7.48–7.30 (m, 6
H), 3.95 (m, 1 H), 3.70 (m, 2 H), 3.07 (m, 1 H), 2.90 (m, 1 H),
2.05–1.44 (m, 10 H), 1.41 (s, 9 H), 1.05 (s, 9 H) ppm. 13C NMR
(75.5 MHz, CD3OD): δ = 178.7, 157.5, 136.7, 134.1, 131.2, 129.0,
80.1, 66.7, 59.7, 58.4, 56.6, 31.8, 30.8, 30.4, 28.9, 27.7, 27.5, 23.9,
20.1 ppm. HRMS (ESI) [M + H]+: m/z calcd. for C31H47N2O5Si
555.3254; found 555.3262; [M
+
Na]+: m/z calcd. for
C31H46N2NaO5Si 577.3074; found 555.3079.
Lactam 21: According to the general procedure C, amino acid 20
(128 mg, 0.23 mmol) afforded the crude lactam (126 mg), which
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 5:1) to give pure 21 (95 mg, 77%) as a colorless oil. [α]2D5
= –20 (c = 1.3, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.71–
7.62 (m, 4 H), 7.46–7.33 (m, 6 H), 5.59 (m, 1 H), 4.04 (m, 1 H),
3.96–3.77 (m, 3 H), 3.38 (m, 1 H), 2.35 (m, 1 H), 2.09–1.44 (m, 10
H), 1.44 (s, 9 H), 1.07 (s, 9 H) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 170.5, 155.9, 135.7, 133.8, 133.7, 129.7, 127.7, 79.4, 65.4, 57.8,
54.7, 51.3, 30.4, 28.4, 27.7, 27.0, 25.2, 23.9, 20.2, 19.3 ppm. IR
27.3, 27.0, 24.5, 24.0, 23.5, 23.3, 19.4 ppm. IR (CHCl ): ν = 3687,
˜
3
3030, 3015, 2934, 1717, 1684, 1507, 1394, 1226, 1106, 931,
821 cm–1. HRMS (ESI) [M
+
Na]+: m/z calcd. for
C48H62N2NaO9SSi 893.3843; found 893.3839.
(CHCl ): ν = 3407, 3073, 3011, 2951, 2860, 1705, 1651, 1465, 1428,
˜
3
1167, 1112, 824 cm–1. HRMS (ESI) [M + Na]+: m/z calcd. for
Oxazolidine 25: K2CO3 (0.83 g, 6.0 mmol, 2 equiv.) and MeI
(0.57 mL, 9.0 mmol, 3 equiv.) were added, at room temperature, to
a solution of 24 (2.60 g, 3.0 mmol) in DMF (10 mL). After stirring
for 4 h, MeI (0.29 mL, 4.5 mmol, 1.5 equiv.) was added and the
mixture was stirred for an additional 4 h. The reaction was then
quenched with water, neutralized with 1 m HCl, and extracted with
diethyl ether. The organic phase was washed with H2O, a 10% solu-
tion of Na2S2O3, and brine, dried with Na2SO4, filtered through
Celite, and concentrated in vacuo to give crude 25 (2.57 g), which
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 3:1) to afford pure 25 (2.55 g, 97%, mixture of dia-
stereomers and rotamers) as a white foam. 1H NMR (300 MHz,
CDCl3): δ = 7.77–7.57 (m, 7 H), 7.55–7.28 (m, 13 H), 5.24–4.94
(m, 3 H), 4.05–3.82 (m, 2 H), 3.80–3.50 (m, 4 H), 3.14–2.70 (m, 2
H), 2.49–1.69 (m, 6 H), 1.68–1.41 (m, 18 H), 1.04 (s, 9 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 204.1, 203.8, 203.7, 156.1,
156.0, 152.5, 152.4, 151.8, 136.6, 135.5, 135.0, 134.8, 134.2, 132.9,
130.2, 130.0, 128.9, 128.5, 128.1, 127.8, 93.8, 93.4, 80.1, 80.0, 79.7,
76.3, 76.1, 67.3, 67.0, 66.6, 65.5, 65.3, 56.8, 56.5, 56.3, 53.5, 52.7,
37.6, 37.1, 36.9, 29.6, 29.5, 29.3, 28.4, 28.0, 27.8, 27.7, 26.9, 26.4,
C31H44N2NaO4Si 559.2968; found 559.2964.
Alcohol 22: According to the general procedure D, compound 21
(148 mg, 0.28 mmol) afforded the crude alcohol (157 mg), which
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 4:1 to pure EtOAc) to give 22 (81 mg, 99%) as a white
foam. [α]2D5 = –26 (c = 1.2, CHCl3). H NMR (300 MHz, CDCl3):
1
δ = 5.50 (m, 1 H), 4.58 (m, 1 H), 4.04 (m, 1 H), 3.86 (m, 1 H), 3.73
(m, 1 H), 3.42 (m, 1 H), 3.24 (m, 1 H), 2.33 (m, 1 H), 2.20–1.85
(m, 2 H), 1.83–1.52 (m, 7 H), 1.42 (s, 9 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 169.8, 156.0, 79.7, 64.7, 64.1, 59.5, 52.6,
32.2, 28.5, 27.3, 26.5, 25.0, 23.7 ppm. IR (CHCl ): ν = 3413, 3007,
˜
3
2950, 1707, 1630, 1468, 1333, 1262, 1165, 1010, 821 cm–1. HRMS
(ESI) [M + Na]+: m/z calcd. for C15H26N2NaO4 321.1790; found
321.1782.
Methyl Ester 23: An aqueous solution of 5% NaHCO3 (0.21 mL),
KBr (6 mg, 0.05 mmol, 0.1 equiv.), and TEMPO (81 mg,
0.51 mmol, 1.1 equiv.) was added, at 0 °C, to a solution of 22
(137 mg, 0.46 mmol) in acetone (4 mL). A solution of 5% NaOCl
(0.14 mL) was then added dropwise and the reaction mixture was
stirred for 1 h at 0 °C. A solution of 5% NaOCl (0.07 mL) was
again added and the stirring was continued for an additional hour.
26.2, 24.4, 23.1, 22.7, 19.2, 16.3, 16.0, 15.8 ppm. IR (CHCl ): ν =
˜
3
3440, 3071, 3019, 3014, 2971, 1713, 1689, 1505, 1393, 1378, 1146,
1774
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1765–1776

Enantiopure Peptidomimetic Scaffold 2-Oxo-1-azabicyclo[4.4.0]decane
1106, 822 cm–1. HRMS (ESI) [M Na]+: m/z calcd. for
FULL PAPER
(m, 1 H), 3.52 (m, 1 H), 3.22 (m, 1 H), 2.25 (m, 1 H), 2.04 (m, 1
H), 1.85 (m, 2 H), 1.73–1.44 (m, 5 H), 1.38 (s, 9 H), 0.92 (d, J =
7.0 Hz, 3 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 170.7, 155.8,
79.5, 64.4, 63.8, 60.1, 52.1, 34.8, 31.3, 28.3, 25.9, 24.8, 23.0,
+
C49H64N2NaO9SSi 907.4000; found 907.3960.
Carboxylic Acid 26: According to the general procedure A, oxazoli-
dine 25 (2.53 g, 2.9 mmol) afforded the crude carboxylic acid
(2.48 g), which was purified by flash chromatography on silica gel
(heptanes/EtOAc, 2:1 then 1:2) with 30 to 70% EtOAc in heptanes
to afford pure 26 (1.78 g, 72%, a mixture of diastereomers and
rotamers) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 7.71–
7.55 (m, 7 H), 7.53–7.29 (m, 13 H), 5.46–4.91 (m, 4 H), 4.32 (m, 1
H), 3.59 (m, 3 H), 3.08–2.83 (m, 2 H), 2.28–2.01 (m, 2 H), 1.94–
1.48 (m, 4 H), 1.43 (s, 9 H), 1.03 (s, 9 H), 0.88 (m, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 204.3, 204.0, 175.6, 175.3, 175.0,
156.6, 156.5, 155.8, 136.5, 136.3, 136.0, 135.7, 134.9, 134.4, 133.1,
133.0, 130.3, 130.0, 130.0, 129.0, 128.7, 128.3, 128.2, 128.0, 80.3,
76.4, 76.2, 67.2, 67.1, 65.4, 64.5, 53.6, 53.0, 52.7, 52.5, 36.5, 29.8,
29.5, 29.2, 28.4, 27.0, 26.3, 26.1, 22.8, 19.4, 16.1 ppm. IR (CHCl3):
15.0 ppm. IR (CHCl ): ν = 3414, 3007, 2937, 2878, 1708, 1630,
˜
3
1492, 1468, 1336, 1165 cm–1. HRMS (ESI) [M + Na]+: m/z calcd.
for C16H28N2NaO4 335.1947; found 335.1950.
Alcohol 29b: According to the general procedure D, lactam 28b
(59 mg, 0.13 mmol) afforded the crude alcohol (65 mg), which was
purified by flash chromatography on silica gel (heptanes/EtOAc,
3:1 then pure EtOAc) to give 29b (32 mg, 96%) as a clear oil.
[α]2D5 = –50 (c = 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
5.45 (br. s, 1 H), 4.56 (dd, J = 3.8, 9.6 Hz, 1 H), 4.05 (dt, J = 11.7,
5.8 Hz, 1 H), 3.86 (m, 1 H), 3.72 (m, 1 H), 3.24 (m, 1 H), 3.00 (dt,
J = 10.4, 4.1 Hz, 1 H), 2.31 (m, 1 H), 2.05–1.58 (m, 7 H), 1.42 (s,
9 H), 1.35–1.22 (m, 1 H), 0.88 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 170.2, 156.1, 79.7, 65.6, 64.7, 64.2, 52.6,
ν = 3435, 3012, 2929, 2858, 1711, 1505, 1306, 1216, 1146 cm–1.
˜
HRMS (ESI) [M + Na]+: m/z calcd. for C46H58N2NaO10SSi
35.2, 33.4, 28.5, 26.9, 24.6, 23.5, 18.5 ppm. IR (CHCl ): ν = 3417,
˜
3
3020, 3008, 2981, 2934, 1708, 1631, 1468, 1219, 1166 cm–1. HRMS
(ESI) [M + Na]+: m/z calcd. for C16H28N2NaO4 335.1947; found
335.1944.
881.3479; found 881.3464.
Piperidine 27: According to the general procedure B, carboxylic
acid 26 (1.68 g, 2.0 mmol) afforded the crude piperidine (914 mg,
82%) as a clear oil, which was used as-is for the next step. 1H NMR
(300 MHz, CD3OD): δ = 7.75–7.55 (m, 4 H), 7.50–7.30 (m, 6 H),
4.04–3.46 (m, 4 H), 3.18 (m, 2 H), 2.21–1.51 (m, 9 H), 1.44 (s, 9
H), 1.11–0.88 (m, 12 H) ppm. 13C NMR (75.5 MHz, CD3OD): δ
= 178.1, 157.6, 157.2, 136.7, 136.0, 134.0, 133.8, 131.3, 131.2, 129.0,
128.6, 80.1, 71.0, 70.9, 66.2, 65.9, 63.5, 60.4, 59.6, 56.2, 56.1, 35.8,
33.1, 30.8, 30.6, 29.7, 29.3, 29.1, 28.8, 27.9, 27.6, 27.4, 22.3, 20.1,
18.6, 11.1 ppm. ESI [M + Na]+: m/z = 591; [M + H]+: m/z = 569.
Methyl Ester 30a: According to the general procedure E, alcohol
29a (75 mg, 0.24 mmol) afforded the crude methyl ester, which was
purified by flash chromatography on silica gel (heptanes/EtOAc,
4:1) to give 30a (56 mg, 69%) as a colorless oil. [α]2D5 = +16 (c =
0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.53 (m, 1 H), 4.50
(m, 1 H), 4.30 (m, 1 H), 3.81–3.64 (m, 4 H), 2.37 (m, 1 H), 2.12–
1.71 (m, 6 H), 1.66–1.40 (m, 11 H), 1.00 (d, J = 7.0 Hz, 3 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 173.4, 172.7, 155.7, 79.6, 55.4,
54.8, 52.3, 50.5, 32.8, 28.5, 25.9, 25.4, 25.2, 22.0, 16.6 ppm. IR
Lactams 28a and 28b: According to the general procedure C, amino
acid 27 (730 mg, 1.3 mmol) afforded a crude mixture of two dia-
stereomers (631 mg), which was purified by flash chromatography
on silica gel (heptanes/EtOAc, 9:1) to give pure 28a (465 mg, 66%,
TLC Rf = 0.50 in EtOAc/heptanes 1:2) as a colorless oil and 28b
(87 mg, 12%, TLC Rf = 0.55 in EtOAc/heptanes 1:2) also as a
colorless oil.
(CHCl ): ν = 3423, 3024, 3015, 2954, 1741, 1706, 1658, 1498, 1220,
˜
3
1167 cm–1. HRMS (ESI) [M + Na]+: m/z calcd. for C17H28N2NaO5
363.1896; found 363.1898.
Methyl Ester 30b: According to the general procedure E, alcohol
29b (28 mg, 0.09 mmol) afforded the crude methyl ester, which was
purified by flash chromatography on silica gel (heptanes/EtOAc,
4:1) to afford 30b (21 mg, 69%) as a colorless oil. [α]2D5 = –22 (c =
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.52 (m, 1 H), 4.10
(m, 2 H), 3.72 (s, 3 H), 3.07 (m, 1 H), 2.39 (m, 1 H), 2.18–1.52 (m,
8 H), 1.42 (s, 9 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 171.8, 171.1, 155.9, 79.7, 61.2, 56.4, 52.4,
1
28a: [α]2D5 = –10 (c = 4.2, CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.72–7.62 (m, 4 H), 7.44–7.31 (m, 6 H), 5.61 (br. s, 1 H), 4.16
(m, 1 H), 4.00 (m, 1 H), 3.90 (dd, 1 H, J = 3.8 Hz, 9.4 Hz), 3.71
(t, J = 9.2 Hz, 1 H), 3.58 (m, 1 H), 2.33 (m, 1 H), 2.04 (m, 1 H),
1.96 (m, 1 H), 1.85 (m, 1 H), 1.73 (m, 1 H), 1.58–1.40 (m, 13 H),
1.08 (s, 9 H), 0.90 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 172.1, 155.6, 135.6, 133.6, 133.5, 129.7, 127.7, 79.3,
62.4, 56.1, 55.5, 50.8, 32.9, 28.4, 26.9, 26.3, 26.0, 23.1, 22.8, 19.3,
51.2, 34.5, 30.2, 28.5, 25.2, 25.2, 24.6, 18.6 ppm. IR (CHCl ): ν =
˜
3
3422, 3019, 2963, 2935, 1740, 1707, 1655, 1497, 1368, 1226,
1166 cm–1. HRMS (ESI) [M + Na]+: m/z calcd. for C17H28N2NaO5
363.1896; found 363.1879.
16.4 ppm. IR (CHCl ): ν = 3415, 3073, 3009, 2962, 2933, 2860,
˜
3
1705, 1651, 1493, 1209, 1112, 823 cm–1. HRMS (ESI) [M + Na]+:
m/z calcd. for C32H46N2NaO4Si 573.3125; found 573.3118.
Acknowledgments
1
28b: [α]2D5 = –23 (c = 1.5, CHCl3). H NMR (300 MHz, CD3OD):
δ = 7.69–7.60 (m, 4 H), 7.48–7.34 (m, 6 H), 4.03 (m, 1 H), 3.92 (m,
2 H), 3.73 (m, 1 H), 3.05 (m, 1 H), 2.05–1.52 (m, 9 H), 1.43 (s, 9 H),
1.05 (s, 9 H), 0.87 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (75.5 MHz,
CD3OD): δ = 172.3, 158.0, 136.8, 134.8, 134.7, 130.9, 128.9, 80.4,
66.4, 63.1, 60.1, 52.1, 35.5, 31.4, 28.8, 27.5, 26.0, 25.4, 20.1,
We thank Marie-Thérèse Martin for NOESY experiments and Ma-
rie-Elise Tran Huu Dau for molecular modeling calculations.
[1] For recent reviews, see: L. Halab, F. Gosselin, W. D. Lubell,
Biopolymers (Pept. Sci.) 2000, 55, 101–122 and ref.[2]
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˜
3
1651, 1494, 1463, 1166, 1112, 823 cm–1. HRMS (ESI) [M + Na]+:
m/z calcd. for C32H46N2NaO4Si 573.3125; found 573.3139.
Alcohol 29a: According to the general procedure D, lactam 28a
(197 mg, 0.36 mmol) afforded the crude alcohol (221 mg), which
was purified by flash chromatography on silica gel (heptanes/
EtOAc, 3:1 then pure EtOAc) to give 29a (106 mg, 95%) as a clear
1
oil. [α]2D5 = –22 (c = 1.9, CHCl3). H NMR (300 MHz, CDCl3): δ
= 5.52 (m, 1 H), 4.53 (m, 1 H), 4.02 (m, 1 H), 3.82 (m, 1 H), 3.65
Eur. J. Org. Chem. 2005, 1765–1776
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1775

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Received: October 8, 2004
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