Quaternary α,α-2-oxoazepane α-amino acids: Synthesis from ornithine-derived β-lactams and incorporation into model dipeptides

Article abstract of DOI:10.1021/jo200894d

To explore further the chemistry of amino acid-derived β-lactams, their conversion to α,α-heterocyclic quaternary amino acid derivatives is investigated. The latter derivatives, containing 2-oxoazepane as the α,α-substituent, are synthesized by a simple P

Full text of DOI:10.1021/jo200894d

ARTICLE
pubs.acs.org/joc
Quaternary r,r-2-Oxoazepane r-Amino Acids: Synthesis from
Ornithine-Derived β-Lactams and Incorporation into Model
Dipeptides
†
†
‡
†
ꢀ
Diego Nꢀu~nez-Villanueva, M. Angeles Bonache, Lourdes Infantes, M. Teresa García-Lꢀopez,
Mercedes Martín-Martínez,† and Rosario Gonzꢀalez-Mu~niz*,†
†Instituto de Química Mꢀedica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
‡Instituto de Química Física Rocasolano (IQFR-CSIC), Serrano 119, 28006 Madrid, Spain
S Supporting Information
b
ABSTRACT: To explore further the chemistry of amino acid-
derived β-lactams, their conversion to R,R-heterocyclic qua-
ternary amino acid derivatives is investigated. The latter deri-
vatives, containing 2-oxoazepane as the R,R-substituent, are
synthesized by a simple PdÀC-catalyzed hydrogenolysis of
Orn(Z)-derived 2-azetidinones. The rearrangement from four-
to seven-membered lactam ring is driven by the key intramo-
lecular opening of the 1-Boc-β-lactam, initiated by 7-exotrig
ring closure from the NH2 of the Orn side chain. The synthetic
route is applied to the stereoselective preparation of enantio-
merically pure 4-amino-3-methyl-2-oxoazepane-4-carboxylate derivatives, for which the structure and configuration is confirmed by
X-ray diffraction. Molecular modeling and NMR experiments indicate that these quaternary amino acids are able to drive the
adoption of β-turn secondary structures when incorporated in model dipeptide derivatives.
’ INTRODUCTION
However, the synthesis and conformational studies of R,
R-heterocyclic R-amino acids are much scarcer. Some R,R-
pyrrolidine amino acids have been stereoselectively prepared as
glutamate receptor ligands,14 while dithiolane and tetrahydrofur-
an analogues have been found to induce β-turn conformations
when incorporated into small peptides.15 With regard to six-
membered ring derivatives, 3,3- and 4,4-disubstituted piperidine,
pyrane, and thiopyrane amino acid derivatives have been used as
synthetic intermediates for bioactive compounds16 and as in-
ducers of different peptide secondary structures.17 Among them,
the 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic
acid has been shown to be an effective β-turn and 310/R-helix
inducer in peptides and an excellent rigid EPR probe due to the
nitroxide spin-labeling moiety.18 The examples of quaternary
amino acids bearing seven-membered or larger heterocycles are
still rarer. Thus, only a few 3-amino-2-oxoazepane-3-carboxylate
derivatives, patented as caspase inhibitors and brain function
improvers,19 and some 4,4-disubstituted azepanes as antimicrobial
agents are found in the literature.20 In addition, the stereoselective
synthesis of related 6-amino-3-azabicyclo[3.2.1]-octane-6-car-
boxylic acid has recently been reported.21
The design of peptides and proteins with defined conforma-
tions and specific properties often relies on the incorporation of
non-natural amino acid derivatives.1 Among them, R,R-disubsti-
tuted (quaternary) R-amino acids have received considerable
attention because they have been shown to affect the conforma-
tion, biological activity, and stability of peptides.2 Because they
are a subject of interest in biological chemistry as peptide R-helix-
inducing elements, quaternary amino acids have attracted great
attention in the medicinal chemistry field. In fact, these types of
amino acids can be recognized within the structure of biologically
active natural products, such as antibiotics,3 enzyme inhibitors,4
ion-channel blockers,5 and agonists or antagonists of different
receptors.6
Due to this interest, the preparation of optically pure R,
R-disubstituted amino acids constitutes a challenge,7 which, up
to date, relies either on the optical resolution of racemic forms8 or
on asymmetric transformations. These transformations are
mainly based on the alkylation of enolates from bislactim,
oxazinones, and imidazolidinones,9 and more recently on cata-
lytic processes,10 among other procedures.11
Following our interest in the chemistry of amino acid-derived
Within quaternary amino acids, special attention has been paid
to cyclic derivatives because they provide greater conformational
restriction compared with their linear analogues.12 In the case of
carbocycles, the preference for stabilizing β-turn, 310- and R-
helical conformations is highly dependent on the ring size.13
β-lactams,22 in a previous paper, we studied the controlled opening,
Received: May 3, 2011
Published: June 30, 2011
r
2011 American Chemical Society
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As expected, the cyclization under basic media of Dab-, Orn-,
and Lys-derived chloroacteyl compounds 6À10 proceeded with
formation of the 2-azetidinone ring in all cases. However, while
for Orn and Lys derivatives 12À15 the protected side chain
remained unaltered, in the case of the Dab analogue 6 the 1,
6-diazaspiro[3.4]octane-2,5-dione 11 was the only isolated pro-
duct. This spiro derivative should result from the concomitant
formation of β-lactam and pyrrolidinone rings, this latter due to a
5-exotrig ring closure between the ZNH group and the carboxylic
ester,26 followed by Z-protecting group removal.
Oxidation of the 2-azetidinones 12À15 with K2S2O8/
K2HPO4 in CH3CN/H2O at 75 °C under bubbled Ar27 yielded
the expected 1-unsubstituted analogues 16À19 in moderate
yield (30À60%). No big differences were found in the oxidation
of the 1-Pmb Orn derivative 12 and its Dmb analogue 13;
therefore the Pmb group was selected, due to better yields in the
cyclization to the β-lactam derivatives. Unfortunately, attempts
to cause benzyl group removal by oxidation with CAN or by acidic
hydrolysis with TFA were unsuccessful, resulting in overoxidation27a
and β-lactam-ring-opening, respectively. As previously described
for related 2-azetidinones,23 the next step was the acylation with
di-tert-butyldicarbonate at the β-lactam 1-position, to provide
derivatives 20À23, which could facilitate the controlled opening
of the 2-azetidinone ring through the N1ÀC2 bond. Finally,
the catalytic hydrogenation of Orn-derived N-Boc-substituted
β-lactams, in the presence of PdÀC as catalyst, led to the anticipated
2-oxoazepanes Boc-Oaz-OMe (24) and Boc-Oaz-OtBu (25)
(81 and 83% yield, respectively). The PdÀC catalyzed hydro-
genolysis process allowed the removal of the Z-protecting group,
and then, in the reaction media, the intramolecular nucleophilic
attack of the free NH2 to the carbonyl of the azetidinone ring
resulted in the 7-exotrig closure to the 2-oxoazepane derivatives.
Although a 6-exotrig cyclization to a pyrrolidinone spirolactam
system might be expected (analogous to the 5-exotrig cyclization
that gave rise to the five-membered spirolactam in the Dab-
derived 11), no traces of spirocyclic compound were observed in
the crude reaction mixtures, which could have been detected
either by MS spectrometry (MW of the spirolactam would be
254.28) or by 1H NMR through the disappearance of the signals
corresponding to methyl and tert-butyl esters. Similar attempts to
obtain the corresponding eight-membered 2-oxoazocane deriva-
tives from Lys-derived 1-Boc-azetidinones 22 and 23 (n = 3)
resulted in very complex mixtures of quite insoluble products,
probably polymeric. Also, no traces of the possible spirocyclic
azepinone byproduct (analogous to spirocyclic compounds 11)
were detected in the crude reaction mixtures, which could have
originated from a 7-exotrig ring closure between the liberated
amino group and the ester carbon. Such spirolactam could easily
have been detected by MS.
Figure 1. Intermolecular nucleophile opening of β-lactams and retro-
synthetic analysis of the intramolecular conversion to heterocyclic
quaternary amino acids.
by O- and N-nucleophiles, of the N1ÀC2 bond of 1-carbamate-
substituted 2-azetidinones II to provide access to orthogonally
protected R-alkyl aspartic acid and asparagines derivatives III
(Figure 1).23 Considering the importance of quaternary amino
acids, we now focus our attention on exploring the intramolecular
version of this opening as a potential approach to R,R-azaheter-
ocyclic disubstituted R-amino acids VI (2-oxopiperidine, n = 1;
2-oxoazepane, n = 2; 2-oxoazocane, n = 3), with the basic amino
acid-derived β-lactams V as the key intermediates (Figure 1).
Quaternary amino acids represented by VI possess many sites
of reactivity and hence opportunities for further chemical
modifications, a feature that enhances their potential usefulness
in the study of peptide conformations. Thus, they could allow the
incorporation of different substituents at positions 1 (R4) and 3
(R2) of the ring, which could facilitate additional transformations
within peptides (click chemistry,24 stapled methodologies,25
etc.), participate in molecular recognition processes, or serve to
modulate solubility. In addition, R,R-heterocyclic amino acids VI
contain a carbonyl group in the heterocyclic ring, which could
further contribute to stabilizing peptide secondary structures. All
these aspects prompted us to explore the synthesis of quaternary
heterocyclic amino acid derivatives VI as described in this paper.
The incorporation of one example of VI (n = 2) into model
dipeptides and the evaluation of their ability to induce turn-like
secondary structures are also reported.
’ RESULTS AND DISCUSSION
Exploratory Chemistry to Heterocyclic Quaternary Amino
Acids from β-Lactams. To investigate the scope and limitations
of the intramolecular opening of β-lactams, we first attempted to
prepare racemic 2-azetidinones derived from the basic amino
acids Dab, Orn, and Lys. Following our described method,22 the
first step was the reductive amination of the conveniently
protected amino acid derivatives. Thus, starting from H-Dab-
(Z)-OMe, H-Orn(Z)-OMe, H-Orn(Z)-OtBu, H-Lys(Z)-OMe,
and H-Lys(Z)-OtBu, the reaction with p-methoxy- or o,p-di-
methoxybenzaldehyde, followed by reduction of the correspond-
ing imine intermediates with NaBH4, afforded the expected N-
benzyl derivatives 1À5 in high yield (Scheme 1). Next, treatment
of the latter compounds with chloroacetyl chloride, in the
presence of propylene oxide as acid scavenger, gave compounds
6À10 almost in a quantitative manner.
In spite of the marked difference in the course of reaction with
Lys-derived 22 and 23 (n = 3), as compared with the Orn-derived
20 and 21 (n = 2), the β-lactam in both instances (n = 3 or n = 2)
is activated for cleavage, either thermodynamically by the release
of the β-lactam ring strain or kinetically by the ThorpeÀIngold
effect caused by the β-lactam C4 quaternary center.28 Thus, the
successful and high-yielding formation of the seven-membered
ring in Orn-derived 24 and 25 has evidently resulted from the
favorable kinetics of the 7-exotrig ring closure, as compared with
the other possible competing reactions, which possibly could
include the intermolecular attack of the β-lactam or ester
functions, leading to polymer formation, and intramolecular
attack on the ester, leading to spirocyclic products (des-3-methyl
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Scheme 1. Exploratory Attempts on the Formation of Hetrocyclic Quaternary Amino Acids from β-Lactams
analogs of 35c). On the contrary, the analogous but unsuccessful
8-exotrig ring closure from 22 and 23 evidently was kinetically
less favorable than one or more of the possible side reactions.
The structural characterization of compounds 24 and 25 was
performed on the basis of their 1H and 13C NMR data. Thus, the
presence in the 1H NMR spectra of the signal corresponding to
methyl and tert-butyl esters in 24 and 25, respectively, showed
that these groups remained unaltered in the final compounds.
Furthermore, in the 13C NMR spectra, the amide carbonyl
carbon resonates at considerably lower field than in the start-
ing derivative (Δδ g 10.5 ppm), indicating that the β-lactam
carbonyl is not retained in the final products. Definite support for
the 2-oxoazepane structure came from the HMBC heteronuclear
experiment performed for compound 25, in which the correla-
tion between both 7-H and 3-H protons (δ 3.20 and 2.91 ppm,
respectively) and the amide carbonyl carbon (δ 173.6 ppm)
confirmed the formation of the seven-membered ring.
Stereoselective Synthesis of 2-Oxoazepane-Derived Ami-
no Acids. After determining that the 2-azetidinones derived
from Orn (20, 21, n = 2) were the only suitable intermediates to
the target R,R-heterocyclic quaternary amino acids (24, 25), we
decided to explore the preparation of the 3-substituted analogs of
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Scheme 2. Diastereoselective and Enantiospecific Synthesis of 3-Methyl-2-oxoazepane-Derived Amino Acids
these amino acid derivatives, and to do so in enantiopure form. In
a recent publication,29 we described a highly stereoselective
synthesis of 1,3,4,4-tetrasubstituted β-lactams from simple ami-
no acids (Ala, Phe, Lys, Glu). In this process, the stereochemical
control of the cyclization to the β-lactam ring was exclusively
directed by the configuration of the N-2-chloropropionyl group.
Application of this procedure to Orn derivatives 2 and 26 allowed
the preparation, after two steps, of the desired 3S-methyl-2-
azetidinones 29 and 30 in high yield (Scheme 2). It is worth
noting that the synthesis of intermediates 27 and 28 required
strict neutral conditions to avoid racemization of the enantio-
merically pure 2S-chloropropionic acid.30 For this reason, 2S-
chloropropionyl chloride was generated in situ from the 2S-
chloropropionic acid with the chlorinating agent trichloroaceto-
nitrile and triphenyl phosphine31 and then reacted with com-
pounds 2 and 26 in the presence of excess of propylene oxide as
HCl scavenger.
Removal of the p-methoxybenzyl group by oxidation, as
indicated,27a afforded the 1-NH unprotected compounds 31
and 32 in moderate/good yield (50À70%) and approximately
20À25% epimerization at C-3. Suitable activation of mixtures
31a,b and 32a,b with di-tert-butyldicarbonate gave the corre-
sponding N-Boc-2-oxoazetidines 33a,b and 34a,b, in the same
ratio of inseparable diastereoisomers as their precursors. After
hydrogenation, compounds 33a,b and 34a,b rearranged to the
expected 3-methyl-2-oxoazepane derivatives 35a,b and 36a,b.
Fortunately, these mixtures of epimers could be separated by
column chromatography. The structure of compound 35a was
established by single-crystal X-ray diffraction study32 as shown in
Figure 2, thus confirming the ring size and configuration of the
new quaternary amino acid derivatives 35 and 36 in the
present study.
It should be noted that during the hydrogenolysis of 33a,b,
along with the diastereomeric quaternary amino acids 35a and
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Scheme 3. Synthesis of 2-Oxoazepane-Containing Dipeptide
Models
Figure 2. Molecular structure of quaternary 2-oxoazepane derivative
35a as determined by single-crystal X-ray diffraction, showing the atomic
numbering scheme. Ellipsoids are drowning at the 50% probability level
of non-H atoms, and the H atoms are denoted as spheres of 0.1 Å radius.
35b, the spiro-derivative 35c was also formed and isolated as a
single isomer. Considering the ratio of diastereoisomers in 33a,b
(3.6:1), and the relative amount of final compounds 35a:35b:35c
(13.3:1:2.6), it appears that the spiro derivative is exclusively
formed from the minor 3R,4S-33b isomer. This result seems to
indicate that the formation of the R-oxoazepane quaternary
amino acid (7-exotrig ring closure) is preferred for the 3S,
4S-configured β-lactam, while the four to seven ring rearrange-
ment of the corresponding 3R,4S isomer is more difficult, thus
competing with the spirocyclization (6-exotrig cyclization). The
fact that the Me group in the 3R,4S isomer is situated at the same
face of the four-membered ring as the reactive aminopropyl side
chain could account for this behavior. Compound 35c was not
detected in the transformation of 34a,b (a/b = 4.2:1), for which
the expected compounds 36a and 36b were formed along with
the Z-deprotected β-lactam derivative (detected by HPLC-MS).
This could be explained because the tert-butyl ester is less prone
to undergo the intramolecular cyclization to the spiro compound
than the corresponding OMe derivative.
Finally, the possibility of incorporating substituents to the
azepane NH was investigated. In particular, compounds 37a and
38a were obtained from 35a by using MeI and BnBr as the
alkylating agents and BTPP as base under microwave irradiation.
Synthesis and Conformational Analysis of Model Dipep-
tides. To demonstrate the use of these quaternary amino acids in
peptide synthesis, and to gain insight into their possible signifi-
cance as inducers of peptide secondary structures, model dipeptide
derivatives 39 and 40 were synthesized and studied. Dipeptide 39
was preparedin satisfactoryyield from the aminoester38a through
saponification and subsequent coupling with H-Ala-NHMe in the
presence of BOP/TEA (Scheme 3). Compound 39 was trans-
formed into its pivaloyl analogue 40 by removal of the N-terminal
Boc-protecting group with TFA and reaction with pivaloyl chlor-
ide in the presence of TEA and propylene oxide.
central Ala NH is totally exposed to solvent (Δδ/ΔT > 4
ppb KÀ1). As for related dipeptide derivatives containing qua-
ternary amino acids at the i + 1 position,2 the protection of the
C-terminal NHMe amide proton could be attributed to the
formation of a H-bond with the carbonyl group of residue i
t
(Boc or BuCO), stabilizing β-turn-like conformations. The low
Δδ/ΔT values for the N-terminal NH could also be attributed to a
hydrogen-bonded state, probably in this case with the oxygen of
the 2-oxoazepane carbonyl group. Although this hydrogen bond
cannot be seen in solution for the amino acid derivatives 35a and
38a (Δδ/ΔT > 4 ppb KÀ1, Table 1), the spatial disposition
between the 2-CO and the Boc-NH amide proton in the solid
structure of compound 35a (Figure 2) seems close to that ex-
pected for H-bond stabilization through the formation of a six-
membered pseudocycle (CO HN distance, 2.4 Å; H OdC
3 3 3
3 3 3
angle, 71.6°; and NÀH
O angle, 136.7°), although the
3 3 3
OdC angle is slightly lower than the accepted value.33
The temperature coefficient values (Δδ/ΔT) and the chemical
shifts in CDCl3 and DMSO-d6 for amide NH protons of com-
pounds 39 and 40 could be indicative of the possible involvement
of these NH's in hydrogen bonds (Table 1). For small peptides in
DMSO solution, Δδ/ΔT values below 3 ppb KÀ1 (in absolute
value) are indicative of solvent-shielded NH protons that usually
participate in intramolecular H-bonds.33 According to this criter-
ion, both N- and C-terminal NH's in 39 and 40 are protected from
the solvent, thus indicating the existence of intramolecular
H-bonds for these amide protons (Table 1). Contrastingly, the
H
3 3 3
A chemical shift >7.0 ppm in chloroform, and a small variation
of this shift when the solvent is changed to DMSO, could also
confirm the possible participation of the corresponding amide
proton in an H-bond.33 Application of these criteria to our
compounds indicates that the C-terminal NHMe proton of
dipeptides 39 and 40, but not the Ala NH proton, is solvent-
shielded, which reinforces their involvement in an intramolecular
H-bond. For the N-terminal amide protons, the ΔδDMSOÀCDCl
3
are very low (∼0.2 ppm), also proving the existence of H-bonded
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Table 1. Temperature Coefficients for the NH Amide Protons of 2-Oxoazepane Derivatives
Δδ/ΔT (ppb/K)a
δ (CDCl3)b
δ (DMSO)b,c
compd
N-term.
Ala
C-term.
N-term.
Ala
C-term.
N-term.
Ala
C-term.
35a
38a
39
À7.6
À5.9
À1.1
À0.8
4.86
4.98
5.31
6.58
5.87 (1.01)
5.80 (0.82)
5.51 (0.20)
6.35 (0.23)
À4.8
À5.1
À1.6
À1.1
6.37
6.08
7.12
7.03
8.00 (1.63)
7.67 (1.59)
7.46 (0.34)
7.47 (0.44)
40
a Δδ measured in DMSO-d6, 30À45 °C (each 5 °C for a total of 4 points); samples at 7À10 mM concentration. b ppm. c ΔδDMSOÀCDCl are indicated in
3
parentheses.
at the i + 1 position of model dipeptides forced the adoption of
β-turn-like conformations. Therefore, these compounds can be
considered new tools to be incorporated in the peptidomimetic
design toolbox. Further work to explore the usefulness of these
new disubstituted amino acids is currently in progress.
’ EXPERIMENTAL SECTION
Abbreviations. BOP: benzotriazole-1-yl-oxy-tris-(dimethylamino)-
phosphoniumhexafluorophosphate. BTPP: phosphazene base P1-t-Bu-tris-
(tetramethylene). Dab: 2,4-diaminobutyric acid. Md: major diastereoi-
somer. md: minor diastereoisomer. Mr: major rotamer. mr: minor
rotamer. Oaz: (3S,4S)-4-amino-3-methyl-2-oxoazepane-4-carboxylic acid.
Oaz(Bn): (3S,4S)-4-amino-1-benzyl-3-methyl-2-oxoazepane-4-carboxylic
acid. TEA: triethylamine.
Figure 3. Theoretical structure of the absolute minimum energy
conformer of compound 40. For simplicity, hydrogen atoms are not
shown, except for the amide NH's.
General Information. All reagents were of commercial quality.
Solvents were dried and purified by standard methods. 1H NMR spectra
were recorded on a 300 MHz instrument, using TMS as internal
conformations. In this case the chemical shifts below 7 ppm can
be attributed to the urethane character of these NH's.
The ability of dipeptide derivative 40 to adopt specific con-
formations was also examined by molecular dynamics. From this
study, it can be concluded that all minimum energy conformers,
within a 3 kcal/mol window from the global minimum, adopt
standard. 13C NMR spectra were registered at 75 MHz. Analytical
TLC was performed on aluminum sheets with a 0.2 mm layer of silica gel
F254. Silica gel 60 (230À400 mesh) was used for column chromatog-
raphy. Analytical HPLC was performed on a Novapak C18 (3.9 Â
150 mm, 4 μm) or on a Deltapak C18 (3.9 Â 150 mm, 4 μm) column,
with a flow rate of 1 mL/min, using a tunable UV detector set at 214 nm.
type I β-turn conformations, as deduced from the ϕ and ψ
Mixtures of MeCN (solvent A) and 0.05% TFA in H2O (solvent B) were
used in the mobile phase. Electrospray mass spectra were recorded in the
dihedral angle values, as well as the COiÀNHi+3 distance and
H-bond angles (Figure 3, Table 2). Among all the conformers,
positive mode directly in an LCÀMS apparatus with an X-bridge C18
more than 56% also showed a correct distance between the 2-CO
column (2.1 Â 100 mm, 3.5 μm). Microwave irradiations were
and the Boc-NH amide proton to be in a hydrogen-bonded state,
performed in a microwave oven. N-(p-methoxy)benzyl-, N-chloroace-
tyl-, and 2-azetidinone-amino acid derivatives 2, 7, 12, 4, 9, and 14 were
prepared as previously described.34
d(2-COÀNHi+1) < 2.5 Å,33 in agreement with previous obtained
NMR data. The H OdC angle, though, is again a bit smaller
3 3 3
than the standard values,33 as it was the case in the X-ray structure
General Prodedure for the Synthesis of N-Benzyl Amino
Acid Derivatives. A solution of H-L-Dab(Z)-, H-L-Orn(Z)-, or H-L-
Lys(Z)-OR1 HCl (13.9 mmol) in MeOH (28 mL) was successively
treated with TEA (1.93 mL, 13.9 mmol) and the corresponding benzaldehyde
(20.8 mmol). After the mixture was stirred at room temperature for 2 h,
NaBH4 (2.1 g, 55.6 mmol) was added in portions, and the stirring
continued for 2 h. Then the solvent was evaporated to dryness, the
residue was extracted with EtOAc, and the extract was washed with H2O
and brine. The organic layer was dried over Na2SO4, and after evapora-
tion the residue was purified on a silica gel column as specified in
each case.
N-(p-Pmb)-L-Dab(Z)-OMe (1). Syrup: yield, 55%; eluent, EtOAc/
hexane (2:1); HPLC tR = 5.45 min (A/B = 30:70); 1H NMR (300 MHz,
CDCl3) δ 7.35 (s, 5H), 7.21 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H),
5.82 (br s, 1H), 5.09 (s, 2H), 3.76 (s, 3H), 3.72 (m, 4H), 3.54 (d, J = 12.4
Hz, 1H), 3.40 (m, 1H), 3.29 (m, 2H), 1.91 (m, 1H), 1.69 ppm (m, 1H);
13C NMR (75 MHz, CDCl3) δ 175.2, 158.7, 156.2, 131.4, 129.5, 128.4,
128.0, 127.9, 113.7, 66.4, 59.2, 55.2, 51.9, 51.5, 39.0, 32.3 ppm. Elemental
analysis calcd (%) for C21H26N2O5: C 65.27, H 6.78, N 7.25. Found: C
65.30, H 6.75, N 7.25.
of compound 35a.
’ CONCLUSIONS
In conclusion, we have developed an operationally simple
method for the preparation of 2-oxoazepane-containing quatern-
ary amino acid derivatives by easy manipulation of Orn-derived
β-lactams. The key step of this synthesis relies on the facile
7-exotrig ring closure and concomitant intramolecular opening
of the activated 1-Boc-β-lactams by the NH2 of the Orn side
chain, after catalytic Z-removal. The potential of the procedure,
initially developed in a racemic version, has now been realized for
the synthesis of the enantiomerically pure 3-substituted analog,
3S,4S-amino-3-methyl-2-oxoazepane-4-carboxylate, as the meth-
yl and tert-butyl esters. A preliminary experiment, aimed at
ascertaining the utility of these novel quaternary heterocyclic
amino acids as peptide secondary structure inducers, indicated
that the incorporation of one of these 2-oxoazapane amino acids
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Table 2. Relevant Topographical Parameters of Minimum Energy Families of Conformers for Piv-Oaz(Bn)-Ala-NHMe 40 (within
a 3 kcal/mol Window from the Global Minimum)
H-bond anglesc
H-bond anglesc
b
b
conf family
ΔEa
d(COiÀNHi+3
)
d(2-COÀNHi+1
)
(COiÀNHi+3
)
(2-COÀNHi+1
)
ϕi+1
ψi+1
ϕi+2
ψi+2
%
40-1
40-2
40-3
40-4
0
1.99
1.96
1.95
2.03
2.47
2.47
4.70
4.71
167.0 (119.8)
168.1 (136.8)
165.1 (132.0)
167.3 (111.8)
133.9 (68.8)
133.5 (70.8)
77.6 (47.8)
77.7 (47.4)
À54.10
À54.03
À50.52
À50.87
À16.11
À18.83
À30.77
À27.30
À134.33
À67.00
À66.15
À131.41
17.11
À17.56
À14.62
21.22
29
27
30
14
0.27
2.42
2.69
a kcal/mol. b Å. c N—H O and H OdC angles; the latter is in parentheses.
3 3 3 3 3 3
N-(o,p-Dmb)-L-Orn(Z)-OtBu (3). Syrup: yield, 77%; eluent,
EtOAc/hexane (1:2); HPLC tR = 4.27 min (A/B = 50:50); H NMR
[R]D = À16.7 (c = 1.1, CHCl3); H NMR (300 MHz, CDCl3, two
rotamers, Mr/mr = 5.1:1) δ 7.34 (s, 5H), 7.13 (d, J = 8.8 Hz, 2H), 6.45
(d, J = 8.8 Hz, 2H), 5.06 (s, 2H), 4.72 (br s, 1H), 4.54 (d, J = 16.3 Hz,
1H), 4.40 (d, J = 16.3 Hz, 1H), 4.25 (d, J = 12.2 Hz, 1H), 4.17 (d, J =
12.2 Hz, 1H), 3.98 (m, 1H), 3.78 (s, 6H, Mr), 3.75 (s, 6H, mr), 3.01
(m, 2H), 1.96 (m, 1H), 1.64 (m, 1H), 1.40 (s, 9H, Mr), 1.36 (s, 9H, mr),
1.27 ppm (m, 2H); 13C NMR (75 MHz, CDCl3, two rotamers) δ 169.3,
166.8, 161.0, 158.4, 156.1, 136.5, 129.9, 128.4, 127.9, 116.1, 103.8, 98.5,
81.5, 66.4, 59.7, 55.3, 55.1, 52.1, 48.0, 41.4, 40.4, 30.6, 27.8, 26.2 ppm;
MS (ESI) m/z = 571.5 [M + Na]+. Elemental analysis calcd (%) for
C28H37ClN2O7: C 61.25, H 6.79, N 5.10, Cl 6.46. Found: C 61.20, H
6.80, N 5.05, Cl 6.40.
1
1
(300 MHz, CDCl3) δ 7.33 (s, 5H), 7.11 (d, J = 8.1 Hz, 1H), 6.43À6.37
(m, 2H), 5.41 (br s, 1H), 5.08 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.70 (d,
J = 12.9 Hz, 1H), 3.60 (d, J = 12.9 Hz, 1H), 3.17 (m, 1H), 3.10 (m, 2H),
2.06 (br s, 1H), 1.60 (m, 4H), 1.44 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 174.3, 159.9, 158.5, 156.2, 136.6, 130.3, 128.3, 127.9, 127.8,
120.3, 103.6, 98.3, 80.7, 66.2, 61.0, 55.1, 55.1, 46.8, 40.6, 30.6, 27.9, 26.1
ppm. Elemental analysis calcd (%) for C26H36N2O6: C 66.08, H 7.68, N
5.93. Found: C 66.00, H 7.55, N 5.98.
N-(p-Pmb)-L-Lys(Z)-OtBu (5). Syrup: yield, 90%; eluent, EtOAc/
hexane (1:3); HPLC tR = 6.05 min (A/B = 35:65); 1H NMR (300 MHz,
CDCl3) δ 7.28À7.23 (m, 5H), 7.16 (d, J = 8.7 Hz, 2H), 6.77 (d, J =
8.7 Hz, 2H), 5.01 (s, 2H), 4.81 (br s, 1H), 3.71 (s, 3H), 3.66 (d, J = 12.5
Hz, 1H), 3.47 (d, J = 12.5 Hz, 1H), 3.09 (m, 1H), 3.02 (t, J = 6.6 Hz, 2H),
1.74 (br s, 1H), 1.40 ppm (m, 15H); 13C NMR (75 MHz, CDCl3) δ
174.7, 158.5, 156.0, 136.5, 131.9, 129.3, 128.4, 127.9, 113.6, 80.9, 66.4,
60.9, 55.1, 51.3, 40.7, 33.0, 29.5, 28.0, 22.8 ppm. Elemental analysis calcd
(%) for C26H36N2O5: C 68.40, H 7.95, N 6.14. Found: C 68.45, H 7.85,
N 5.95.
N-Chloroacetyl-N-(p-Pmb)-L-Lys(Z)-OtBu (10). Syrup: yield,
99%; eluent, EtOAc/hexane (1:2); HPLC tR = 8.98 min (A/B = 50:50);
1
[R]D = À45.1 (c = 1.2, CHCl3); H NMR (300 MHz, CDCl3, two
rotamers, Mr/mr = 3:1) δ 7.20 (m, 5H), 7.11 (d, J = 8.8 Hz, 2H), 6.77
(d, J = 8.8 Hz, 2H, Mr), 6.68 (d, J = 8.8 Hz, 2H, mr), 4.96 (m, 3H), 4.51
(d, J = 16.7 Hz, 1H), 4.34 (d, 1H, J = 16.7 Hz, 1H), 4.14 (m, 1H), 3.90 (s,
2H), 3.67 (s, 3H, Mr), 3.61 (s, 3H, mr), 2.94 (m, 2H, Mr), 2.90 (m, 2H,
mr), 1.85 (m, 1H), 1.56 (m, 1H), 1.31 (s, 9H, Mr), 1.26 (s, 9H, mr), 1.16
(m, 4H); 13C NMR (75 MHz, CDCl3, two rotamers) δ 169.4, 167.1,
159.2, 156.3, 136.5, 129.2, 128.3, 128.2 (Mr), 127.9 (mr), 114.1 (Mr),
113.6 (mr), 82.6 (mr), 81.69 (Mr), 66.3, 59.7, 55.1, 50.8, 41.5, 40.5, 29.4,
28.8, 27.7 (Mr), 27.6 (mr), 23.6 (Mr), 23.3 (mr) ppm; MS (ESI) m/z =
533.3 [M + H]+. Elemental analysis calcd (%) for C25H31ClN2O6: C
61.16, H 6.36, Cl 7.22, N 5.71. Found: C 61.25, H 6.45, Cl 7.15, N 5.85.
General Procedure for the Synthesis of N-Chloropropio-
nyl Amino Acid Derivatives. PPh3 (7.615 g, 29.03 mmol) was
added to a solution of (S)-2-chloropropionic acid (1.9 mL, 22.02 mmol)
and Cl3CCN (2.9 mL, 28.98 mmol) in THF (50 mL) at 0 °C, and the
reaction mixture was stirred for 30 min. Then a solution of N-Pmb-L-
Orn(Z)-OR1 (14.49 mmol) and propylene oxide (15.2 mL, 217.32 mmol)
in THF (2 mL) was added dropwise to the reaction mixture. After stirring
for 48 h, the solvent was evaporated under vacuum and the resultant
residue was dissolved in Et2O, filtered over Celite, and concentrated under
vacuum. The residue was purified by column chromatography on silica gel
using the solvent system specified.
N-(p-Pmb)-L-Orn(Z)-OtBu (26). Syrup: yield, 73%; eluent,
EtOAc/hexane (1:4); HPLC tR = 12.32 min (gradient A/B from
95:5 to 20:80 over 20 min); [R]D = À7.7 (c = 0.6, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.37À7.32 (m, 5H), 7.24 (d, J = 8.5 Hz, 2H),
6.82 (d, J = 8.5 Hz, 2H), 5.24 (br s, 1H), 5.09 (s, 2H), 3.78 (s, 3H), 3.73
(d, J = 12.5 Hz, 1H), 3.56 (d, J = 12.5 Hz, 1H), 3.19 (m, 2H), 3.11 (t, J =
5.7 Hz, 1H), 1.95 (br s, 1H), 1.60 (m, 4H), 1.48 (s, 9H) ppm; 13C
NMR (75 MHz, CDCl3) δ 174.5, 159.0, 156.5, 136.9, 131.7, 129.8,
128.7, 128.3, 128.2, 114.0, 81.5, 66.7, 61.0, 55.4, 51.7, 41.0, 30.9, 28.3, 26.5
ppm; MS (ESI) m/z = 443.2 [M + H]+. Elemental analysis calcd (%) for
C25H34N2O5: C 67.85, H 7.74, N 6.33. Found: C 68.55, H 7.82, N 5.99.
General Procedure for the Synthesis of N-Chloroacetyl
Amino Acid Derivatives. A solution of the corresponding N-benzyl
amino acid derivative (4 mmol) in THF (20 mL) was treated with
propylene oxide (4.2 mL, 60 mmol) and chloroacetyl chloride (0.47 mL,
6 mmol). After stirring at room temperature for 1À2 h, the solution was
evaporated, and the resulting residue was purified on a silica gel column,
using the solvent system specified in each case.
N-[(S)-2-Chloropropionyl]-N-(p-Pmb)-L-Orn(Z)-OMe (27).
20
Syrup: yield, 87%; eluent, acetone/CH2Cl2 (1:30); [R]D = À16.4
N-Chloroacetyl-N-(p-Pmb)-L-Dab(Z)-OMe (6). Syrup: yield,
99%; eluent, EtOAc/hexane (2:1); HPLC tR = 6.35 min (A/B =
42:58); [R]D = À46.9 (c = 0.6, CHCl3); 1H NMR (300 MHz, CDCl3,
two rotamers, Mr/mr = 6:1) δ 7.25 (s, 5H), 7.10 (d, J = 8.8 Hz, 2H), 6.80
(d, J = 8.8 Hz, 2H, Mr), 6.78 (d, J = 8.8 Hz, 2H, mr), 5.00 (s, 2H), 4.80 (br
s, 1H), 4.40 (m, 2H), 4.30 (m, 1H), 4.00 (m, 2H), 3.70 (s, 3H), 3.50 (s,
3H, Mr), 3.42 (s, 3H, mr), 3.20 (m, 1H), 3.00 (m, 1H), 2.10 (m, 1H), 1.90
ppm (m, 1H); 13C NMR (75 MHz, CDCl3) δ 170.5, 167.6, 159.4, 156.3,
136.5, 128.6, 128.4, 128.0, 127.0, 114.3, 66.5, 56.3, 55.2, 52.2, 51.0, 41.4,
37.7, 29.4ppm;MS (ESI) m/z = 463.4[M + H]+. Elementalanalysiscalcd
(%) for C23H27ClN2O6: C59.67, H 5.88, Cl7.66, N6.05. Found: C 59.75,
H 5.85, Cl 7.75, N 6.10.
(c = 0.5 in CHCl3); HPLC tR = 7.36 min (A/B = 50:50); 1H NMR (300
MHz, CDCl3, two rotamers, Mr/mr = 6.7:1) δ 7.35 (m, 5H), 7.19 (d, J =
8.5 Hz, 2H, mr), 7.13 (d, J = 8.6 Hz, 2H, Mr), 6.87 (d, J = 8.6 Hz, 2H,
Mr), 6.79 (d, J = 8.5 Hz, 2H, mr), 5.08 (br s, 2H), 4.73 (m, 3H), 4.51
(m, 2H), 3.79 (s, 3H, Mr), 3.74 (s, 3H, mr), 3.58 (s, 3H, mr), 3.53 (s, 3H,
Mr), 3.14 (q, J = 6.7 Hz, 2H, Mr), 3.05 (q, partially overlapped, J =
6.7 Hz, 2H, mr), 2.02 (m, 1H), 1.74 (m, 1H), 1.63 (d, J = 6.5 Hz, 3H),
1.47 (quint, J = 6.7 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 175.6,
171.0 (Mr), 170.4 (mr), 159.4 (Mr), 158.9 (mr), 156.5, 136.7, 131.5,
129.7, 128.6, 128.2, 128.1 (Mr), 128.0 (mr), 114.4 (Mr), 113.9 (mr),
66.7, 60.2, 57.5, 55.4, 52.2 (Mr), 51.9 (mr), 50.2 (Mr), 49.4 (mr),
40.8 (mr), 40.6 (Mr), 30.7, 26.7 (Mr), 26.6 (mr), 21.0 ppm; MS
(ESI) m/z = 513.35 [M + Na]+. Elemental analysis calcd (%) for
N-(o,p-Dmb)-N-chloroacetyl-L-Orn(Z)-OtBu (8). Syrup: yield,
97%; eluent, EtOAc/hexane (1:2); HPLC tR = 9.74 min (A/B = 50:50);
6598
dx.doi.org/10.1021/jo200894d |J. Org. Chem. 2011, 76, 6592–6603

The Journal of Organic Chemistry
ARTICLE
C25H31N2O6Cl: C 61.16, H 6.36, N 5.71. Found (%): C 60.98, H 6.54,
N 5.85.
(3S,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-1-p-
methoxybenzyl-3-methyl-4-methoxycarbonyl-2-oxoazeti-
dine (29). Syrup: yield (method B), 90%; eluent, EtOAc/hexane (1:1);
N-[(S)-2-Chloropropionyl]-N-(p-Pmb)-L-Orn(Z)-OtBu (28).
20
20
[R]D = À16.8 (c = 0.5 in CHCl3); HPLC tR = 10.10 min (A/B =
Syrup: yield, 67%; eluent, EtOAc/hexane (1:6); [R]D = À18.9 (c =
40:60); 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 5H), 7.19 (d, J = 8.6 Hz,
2H), 6.82 (d, J = 8.6 Hz, 2H), 5.05 (s, 2H), 4.77 (d, J = 15.4 Hz, 1H),
4.31 (br s, 1H), 4.07 (d, J = 15.4 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.12
(q, J = 7.5 Hz, 1H), 2.85 (m, 2H), 1.73 (m, 2H), 1.27 (m, 2H), 1.14 (d,
J = 7.5 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 171.6, 169.2, 159.1,
156.2, 136.5, 129.7, 128.8, 128.5, 128.1, 114.0, 68.4, 66.6, 55.2, 53.0, 52.1,
44.5, 40.4, 31.5, 24.5, 10.1 ppm; MS (ESI) m/z = 477.45 [M + Na]+.
Elemental analysis calcd (%) for C25H30N2O6: C 66.06, H 6.65, N 6.16.
Found (%): C 65.87, H 6.72, N 6.15.
1.3 in CHCl3); HPLC tR = 12.99 min (A/B = 50:50); 1H NMR
(400 MHz, CDCl3, two rotamers, Mr/mr = 4.3:1) δ 7.34 (m, 5H),
7.20 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 8.2 Hz, 2H,
mr), 5.08 (s, 2H), 4.78 (br s, 1H), 4.64 (m, 1H), 4.56 (m, 2H), 4.28 (t,
J = 7.2, 1H), 3.79 (s, 3H, Mr), 3.73 (s, 3H, mr), 3.10 (q, J = 6.4 Hz, 2H,
Mr), 3.01 (q, partially overlapped, J = 6.8 Hz, 2H, mr), 2.04 (m, 1H),
1.66 (m, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.45 (m, 2H), 1.38 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 171.1 (mr), 169.6 (Mr), 169.4, 159.3, 156.3,
136.6, 129.4, 128.5, 128.3, 128.1, 128.0, 114.2 (Mr), 113.8 (mr), 82.7
(mr), 81.9 (Mr), 66.6 (mr), 66.5 (Mr), 61.3 (mr), 59.2 (Mr), 55.3 (Mr),
55.2 (mr), 50.3, 50.1, 40.5 (Mr), 40.2 (mr), 27.7, 26.9, 26.9, 21.0 (mr),
20.9 (Mr) ppm; MS (ESI) m/z = 533.51 [M + H]+. Elemental analysis
calcd (%) for C28H37N2O6Cl: C 63.09, H 7.00, N 5.26. Found (%): C
62.85, H 7.08, N 5.46.
General Procedure for the Synthesis of 2-Oxoazetidine
Derivatives. A solution of the corresponding N-benzyl-N-chloroalkyl
derivative (1.6 mmol) in dry CH3CN (20 mL) was treated with Cs2CO3
(1.04 g, 3.2 mmol, method A) or BTPP (1.09 mL, 2.4 mmol, method B)
and stirred at room temperature until disappearance of the starting
material. After evaporation of the solvent, the residue was partitioned
between EtOAc and H2O, and the phases were separated. The organic
layer was dried over Na2SO4 and evaporated, leaving a residue that was
purified on a silica gel column, using the solvent system specified in
each case.
(3S,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-4-tert-bu-
toxycarbonyl-1-p-methoxybenzyl-3-methyl-2-oxoazetidine
(30). Syrup: yield (method B), 94%; eluent, EtOAc/hexane (1:1);
[R]D20 = À10.7 (c = 0.7 in CHCl3); HPLC tR = 8.83 min (A/B = 50:50);
1H NMR (300 MHz, CDCl3) δ 7.32 (s, 5H), 7.19 (d, J = 8.6 Hz, 2H),
6.81 (d, J = 8.6 Hz, 2H), 5.03 (s, 2H), 4.79 (d, J = 16.2 Hz, 1H), 4.21 (br
s, 1H), 4.04 (d, J = 16.2 Hz, 1H), 3.69 (s, 3H), 3.07 (q, J = 7.5 Hz, 1H),
2.81 (m, 2H), 1.67 (m, 2H), 1.53 (m, 2H), 1.47 (s, 9H), 1.19 (d, J = 7.5
Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.2, 169.6, 159.1, 156.2,
136.5, 129.6, 129.1, 128.5, 128.1, 114.0, 82.9, 68.4, 66.6, 55.2, 53.0, 44.4,
40.5, 32.1, 28.1, 24.5, 10.5 ppm; MS (ESI) m/z = 497.47 [M + H]+.
Elemental analysis calcd (%) for C28H36N2O6: C 67.72, H 7.31, N 5.64.
Found (%): C 67.43, H 7.50, N 5.39.
General Procedure for the Removal of N-Benzyl Groups.
A solution of the corresponding 1-substituted 2-oxoazetidine (0.69 mmol)
in CH3CN/H2O (1:1, 22 mL) was treated with K2HPO4 (5.93 mmol)
and K2S2O8 (7.66 mmol) and heated to 75 °C under Ar atmosphere for
3À5 h. After evaporation of the CH3CN, the aqueous layer was extracted
with EtOAc, and the organic extract was washed with NaHCO3 (10%)
and brine, dried over Na2SO4, and evaporated. The resulting residue was
purified on a silica gel column, as indicated.
(4R,S)-1-(p-Methoxy)benzyl-1,6-diazaspiro[3.4]octane-2,
5-dione (11). Syrup: yield (method B), 58%; eluent, MeOH/CH2Cl2
1
(1:20); HPLC tR = 4.04 min (A/B = 15:85); H NMR (300 MHz,
CDCl3) δ 7.20 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.63 (br s,
1H), 4.67 (d, J = 15.1 Hz, 1H), 3.97 (d, J = 15.1 Hz, 1H), 3.78 (s, 3H),
3.30 (m, 2H), 3.23 (d, J = 14.2 Hz, 1H), 2.88 (d, J = 14.2 Hz, 1H), 2.04
ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.1, 166.0, 159.0, 129.7,
128.2, 113.8, 58.7, 55.1, 50.1, 44.3, 42.1, 20.7 ppm; MS (ESI) m/z =
261.1 [M + H]+. Elemental analysis calcd (%) for C14H16N2O3: C 64.60,
H 6.20, N 10.76. Found: C 64.65, H 6.25, N 10.70.
(4R,S)-1-(o,p-Dimethoxy)benzyl-4-tert-butoxycarbonyl-4-
[3-(benzyloxycarbonyl)amino]propyl-2-oxoazetidine (13).
Solid: mp 89À90 °C; yield (method A) , 84%; eluent, EtOAc/hexane
(1:2); HPLC tR = 6.04 min (A/B = 50:50); 1H NMR (300 MHz, CDCl3) δ
7.30 (s, 5H), 7.13 (d, J = 8.0 Hz, 2H), 6.38 (d, J = 8.0 Hz, 2H), 5.03 (s, 2H),
4.70 (m, 1H), 4.47 (d, J = 15.1 Hz, 1H), 4.20 (d, J = 15.1 Hz, 1H), 3.71 (s,
6H), 3.03 (d, J = 14.4 Hz, 1H), 2.94 (m, 2H), 2.75 (d, J = 14.4 Hz, 1H), 1.88
(m, 1H), 1.49 (m, 1H), 1.38 (s, 9H), 1.17 ppm (m, 2H); 13C NMR (75
MHz, CDCl3) δ 170.5, 166.1, 160.5, 157.9, 156.0, 136.4, 131.0, 128.3, 127.9,
116.4, 104.0, 98.0, 82.1, 66.3, 62.5, 55.1, 54.9, 45.2, 40.4, 38.6, 29.7, 27.6, 23.8
ppm; MS (ESI) m/z = 535.4 [M + Na]+. Elemental analysis calcd (%) for
C28H36N2O7: C 65.61, H 7.08, N 5.47. Found: C 65.45, H 7.15, N 5.25.
(4R,S)-1-(p-Methoxy)benzyl-4-[3-(benzyloxycarbonyl)-
amino]butyl-4-tert-butoxycarbonyl-2-oxoazetidine (15). Syr-
(4R,S)-4-Methoxycarbonyl-4-[3-(benzyloxycarbonyl)-
amino]propyl-2-oxoazetidine (16). Syrup: yield, 53%; eluent,
1
EtOAc/hexane (2:1); HPLC tR = 6.24 min (A/B = 25:75); H NMR
(300 MHz, CDCl3) δ 7.30 (s, 5H), 6.95 (br s, 1H), 5.15 (br s, 1H), 5.08
(s, 2H), 3.75 (s, 3H), 3.18 (m, 3H), 2.89 (d, J = 15.0 Hz, 1H), 2.04 (m,
1H), 1.81 (m, 1H), 1.50 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ
172.6, 166.4, 156.4, 136.3, 128.4, 128.1, 128.0, 66.6, 58.0, 52.1, 47.6, 40.4,
33.5, 25.1 ppm; MS (ESI) m/z = 321.1 [M + H]+. Elemental analysis
calcd (%) for C16H20N2O5: C 59.99, H 6.29, N 8.74. Found: C 59.68, H
6.35, N 8.53.
(4R,S)-4-tert-Butoxycarbonyl-4-[3-(benzyloxycarbonyl)-
amino]propyl-2-oxoazetidine (17). Syrup: yield, 59%; eluent,
EtOAc/hexane (1:1); HPLC tR = 3.24 min (A/B = 45:55); 1H NMR
(300 MHz, CDCl3) δ 7.24 (s, 5H), 6.89 (br s, 1H), 5.18 (br s, 1H),
4.98 (s, 2H), 3.09 (m, 2H), 2.99 (d, J = 15.0 Hz, 1H), 2.73 (d, J = 15.0
Hz, 1H), 2.04 (m, 1H), 1.67 (m, 1H), 1.42 (m, 2H), 1.36 ppm (s, 9H);
13C NMR (75 MHz, CDCl3) δ 171.4, 166.8, 156.4, 136.4, 128.4, 128.1,
82.6, 66.6, 58.5, 47.4, 40.5, 33.6, 27.8, 25.1 ppm; MS (ESI) m/z = 385.1
[M + Na]+. Elemental analysis calcd (%) for C19H26N2O5: C 62.97, H
7.23, N 7.73. Found: C 62.90, H 7.35, N 7.57.
up: yield (method A), 58%; eluent, EtOAc/hexane (1:2). HPLC tR
=
11.23 min (A/B = 45:55); 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 5H),
7.13 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.00 (s, 2H), 4.61
(br s, 1H), 4.50 (d, J = 15.3 Hz, 1H), 4.08 (d, J = 15.3 Hz, 1H), 3.68
(s, 6H), 3.10 (d, J = 14.6 Hz, 1H), 2.95 (m, 2H), 2.71 (d, J = 14.6 Hz, 1H),
1.74 (m, 1H), 1.41 (m, 1H), 1.34 (s, 9H), 1.15 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 170.3, 166.3, 158.8, 156.1, 136.3, 133.5, 129.5,
128.5, 128.3, 127.9, 113.7, 82.4, 66.4, 63.1, 55.0, 45.3, 43.9, 40.3, 33.2, 29.5,
27.6, 20.9 ppm; MS (ESI) m/z = 497.1 [M + H]+. Elemental analysis
calcd (%) for C28H36N2O6: C 67.72, H 7.31, N 5.64. Found: C 67.65, H
7.25, N 5.85.
(4R,S)-4-[3-(Benzyloxycarbonyl)amino]butyl-4-methoxy-
carbonyl-2-oxoazetidine (18). Syrup: yield, 38%; eluent, EtOAc/
hexane (3:1); HPLC tR = 3.42 min (A/B = 35:65); 1H NMR (300 MHz,
CDCl3) δ 7.28 (m, 5H), 6.38 (br s, 1H), 5.02 (s, 2H), 4.77 (br s, 1H),
3.69 (s, 3H), 3.10 (m, 3H), 2.83 (d, J = 15.5 Hz, 1H), 1.99 (m, 1H), 1.75
(m, 1H), 1.46 (m, 2H), 1.25 ppm (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 172.7, 166.5, 156.4, 136.4, 128.4, 128.0, 66.5, 58.3, 52.7, 47.6, 40.4,
36.0, 29.5, 21.7 ppm; MS (ESI) m/z = 357.1 [M + Na]+. Elemental
analysis calcd (%) for C17H22N2O5: C 61.07, H 6.63, N 8.38. Found: C
61.15, H 6.45, N 8.47.
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(4R,S)-4-[3-(Benzyloxycarbonyl)amino]butyl-4-tert-butoxy-
carbonyl-2-oxoazetidine (19). Syrup: yield, 30%; HPLC tR =3.50min
(A/B = 45:55); 1H NMR (300 MHz, CDCl3) δ 7.23 (m, 5H), 6.92 (br s,
1H), 5.18 (br s, 1H), 4.97 (s, 2H), 3.05 (m, 2H), 2.97 (d, J = 14.9 Hz, 1H),
2.71 (d, J = 14.9 Hz, 1H), 1.90 (m, 1H), 1.62 (m, 1H), 1.27 ppm (m, 13H);
13C NMR (75 MHz, CDCl3) δ 171.4, 166.9, 156.3, 136.4, 128.3, 127.9,
82.3, 66.3, 58.6, 47.3, 40.3, 35.9, 29.4, 27.6, 21.5 ppm; MS (ESI) m/z= 399.3
[M +Na]+. Elemental analysis calcd (%) for C20H28N2O5: C 63.81, H 7.50,
N 7.44. Found: C 63.95, H 7.45, N 7.37.
(3RS,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-4-meth-
oxycarbonyl-3-methyl-2-oxoazetidine (31a,b). Diastereoiso-
meric ratio (3S,4S/3R,4S), Md/md = 3.2:1. Syrup: yield, 76%; eluent,
EtOAc/hexane (1:2); HPLC tR = 15.98 min (md), 16.53 min (Md) (A/
B = 25:75); 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 5H), 6.54 (s, 1H,
md), 6.49 (s, 1H, Md), 5.09 (s, 2H), 4.89 (br s, 1H), 3.76 (s, 3H, OCH3,
Md), 3.75 (s, 3H, OCH3, md), 3.34 (qd, J = 7.6 Hz, J = 1.9 Hz, 1H, md),
3.20 (q, J = 6.5 Hz, 2H), 3.11 (q, J = 7.6 Hz, 1H, Md), 2.20 (m, 1H, Md),
2.01 (m, 1H, md), 1.71 (m, 1H), 1.47 (m, 2H), 1.26 (d, J = 7.6 Hz, 3H,
md), 1.16 (d, J = 7.6 Hz, 3H, Md) ppm; 13C NMR (75 MHz, CDCl3) δ
173.4 (md), 172.0 (Md), 170.5 (md), 170.1 (Md), 156.6, 136.6, 128.6,
128.3, 128.2, 66.8, 64.1 (Md), 61.7 (md), 55.4 (Md), 53.8 (md), 52.8
(md), 52.5 (Md), 40.6, 34.1 (Md), 29.7 (md), 25.7 (Md), 25.2 (md),
10.7 (Md), 8.8 (md) ppm; MS (ESI) m/z = 357.37 [M + Na]+.
Elemental analysis calcd (%) for C17H22N2O5: C 61.07, H 6.63, N
8.38. Found (%): C 61.36, H 6.51, N 8.13.
(3RS,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-4-tert-
butoxycarbonyl-3-methyl-2-oxoazetidine (32a,b). Diastereoi-
someric ratio (3S,4S/3R,4S), Md/md = 4.7:1. Solid: yield, 53%; eluent,
EtOAc/hexane (1:1); HPLC tR = 6.50 min (both diastereomers) (A/B =
40:60); 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 5H), 6.26 (s, partially
overlapped, 1H, md), 6.22 (s, 1H, Md), 5.09 (s, 2H), 4.83 (s, 1H), 3.29
(q, partially overlapped, J = 7.2 Hz, 1H, Md), 3.20 (m, 2H), 3.06 (q, J =
7.7 Hz, 1H, Md), 2.01 (m, 2H, Md), 1.98 (m, 2H, md), 1.67 (m, 2H),
1.48 (s, 9H), 1.25 (d, partially overlapped, J = 7.2 Hz, 3H, md), 1.22 (d,
J = 7.7 Hz, 3H, Md) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 170.1,
156.4, 136.4, 128.6, 128.2, 128.1, 82.9 (Md), 82.6 (md), 66.8, 63.8 (Md),
61.9 (md), 55.0 (Md), 53.4 (md), 40.6, 34.5, 28.1 (Md), 27.9 (md),
25.6, 10.9 (Md), 8.8 (md) ppm; MS (ESI) m/z = 399.40 [M + Na]+.
Elemental analysis calcd (%) for C20H28N2O5: C 63.81, H 7.50, N 7.44.
Found (%): C 63.48, H 7.64, N 7.16.
General Procedure for the Synthesis of N-Boc-oxoazeti-
dine Derivatives. A solution of the corresponding 1-NH oxoazetidine
(0.36 mmol) in dry CH2Cl2 (7 mL) was successively treated with TEA
(50 L, 0.36 mmol), DMAP (4 mg, 0.036 mmol), and di-tert-butyldi-
carbonate (87 mg, 0.39 mmol), and stirring continued for 5 h. Then the
solvent was evaporated to dryness, and the residue was purified on a
silica gel column as specified in each case.
169.4, 163.1, 156.3, 147.2, 136.4, 128.5, 128.1, 83.7, 82.9, 66.7, 61.0, 45.7,
40.8, 29.5, 28.0, 27.8, 24.5 ppm; MS (ESI) m/z = 485.2 [M + Na]+.
Elemental analysis calcd (%) for C24H34N2O7: C 62.32, H 7.41, N 6.06.
Found: C 62.50, H 7.30, N 6.25.
(4R,S)-4-[3-(Benzyloxycarbonyl)amino]butyl-1-tert-butoxy-
carbonyl-4-methoxycarbonyl-2-oxoazetidine (22). Syrup: yield,
78%; HPLCtR = 5.87 min (A/B = 45:55); 1H NMR (300 MHz, CDCl3) δ
7.28 (m, 5H), 5.02 (s, 2H), 4.74 (br s, 1H), 3.71 (s, 3H), 3.15 (m, 2H),
3.00 (d, J = 15.9 Hz, 1H), 2.88 (d, J = 15.9 Hz, 1H), 2.04 (m, 2H), 1.40
ppm (m, 13H); 13C NMR (75 MHz, CDCl3) δ 171.0, 162.8, 156.3, 147.0,
136.6, 128.4, 127.9, 83.6, 66.5, 60.8, 52.7, 45.5, 40.5, 31.7, 29.8, 27.9, 20.6
ppm; MS (ESI) m/z = 457.1 [M + Na]+. Elemental analysis calcd (%) for
C22H30N2O7: C 60.82, H 6.96, N 6.45. Found: C 60.75, H 6.95, N 6.67.
(4R,S)-4-[3-(Benzyloxycarbonyl)amino]butyl-1,4-di-tert-
butoxycarbonyl-2-oxoazetidine (23). Syrup: yield, 78%; elu-
1
ent, EtOAc/hexane (1:3); HPLC tR = 9.05 min (A/B = 45:55); H
NMR (300 MHz, CDCl3) δ 7.24 (s, 5H), 4.97 (s, 2H), 4.91 (br s, 1H),
3.12 (m, 2H), 2.89 (d, J = 15.9 Hz, 1H), 2.80 (d, J = 15.9 Hz, 1H), 1.95
(m, 2H), 1.39 (s, 9H), 1.37 (s, 9H), 1.32 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 169.5, 163.3, 156.3, 147.0, 136.5, 128.4, 128.0, 83.4,
82.6, 66.4, 61.2, 45.4, 40.4, 31.5, 29.8, 27.9, 27.7, 20.7 ppm; MS (ESI)
m/z = 499.3 [M + Na]+. Elemental analysis calcd (%) for C25H36N2O7: C
63.01, H 7.61, N 5.88. Found: C 63.15, H 7.45, N 5.97.
(3RS,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-1-tert-
butoxycarbonyl-4-methoxycarbonyl-3-methyl-2-oxoaze-
tidine (33a,b). Diastereoisomeric ratio (3S,4S/3R,4S), Md/md =
3.6:1. Syrup: yield, 86%; eluent, EtOAc/hexane (1:2); HPLC tR
=
31.68 min (md), 33.76 min (Md) (A/B = 40:60); 1H NMR (300 MHz,
CDCl3) δ 7.34 (m, 5H), 5.08 (s, 2H), 4.95 (s, 1H, Md), 4.84 (s, 1H,
md), 3.77 (s, 3H, Md), 3.76 (s, 3H, md), 3.37 (q, J = 7.8 Hz, 1H, md),
3.22 (m, 3H), 2.12 (m, 2H), 1.77 (m, 1H), 1.55 (m, 1H), 1.48 (s, 9H),
1.25 (d, J = 7.8 Hz, 3H, md), 1.15 (d, J = 7.5 Hz, 3H, Md) ppm; 13C
NMR (75 MHz, CDCl3) δ 170.4 (md), 170.3 (Md), 166.5, 156.5, 147.6
(md), 147.5 (Md), 136.6, 128.6, 128.2, 128.2, 83.9 (md), 83.8 (Md),
66.6, 66.4, 53.6 (md), 52.9 (md), 52.5 (Md), 52.2 (Md), 41.2 (md), 40.9
(Md), 30.3, 28.1, 25.7 (md), 24.6 (Md), 9.3 (Md), 8.9 (md) ppm; MS
(ESI) m/z = 457.3 [M + Na]+. Elemental analysis calcd (%) for
C22H30N2O7: C 60.82, H 6.96, N 6.45. Found (%): C 60.71, H 6.79,
N 6.36.
(3RS,4S)-4-[3-(Benzyloxycarbonyl)amino]propyl-1,4-di-
tert-butoxycarbonyl-3-methyl-2-oxoazetidine (34a,b). Dia-
stereoisomeric ratio (3S,4S/3R,4S), Md/md = 4.2:1. Solid: yield, 91%;
eluent, EtOAc/hexane (1:3); HPLC tR = 27.41 min (both dia-
stereomers) (A/B = 50:50). 1H NMR (300 MHz, CDCl3) δ 7.30
(m, 5H), 5.05 (br s, 3H), 3.26 (q, J = 7.5 Hz, 1H, md), 3.13 (m, 2H),
3.13 (q, J = 7.5 Hz, 1H, Md), 2.03 (m, 2H), 1.70 (m, 2H), 1.46 (s, 9H,
Md), 1.45(s, 9H), 1.43 (s, 9H, md), 1.15 (d, J = 7.5 Hz, 3H, Md), 1.11 (d,
J = 7.5 Hz, 3H, md) ppm; 13C NMR (75 MHz, CDCl3) δ 168.8 (Md),
168.7 (md), 166.9, 156.5 (md), 156.5 (Md), 147.5, 136.6, 128.7, 128.3,
128.2, 83.7 (md), 83.5 (Md), 83.3 (Md), 82.9 (md), 66.8, 66.4, 53.5
(md), 52.1 (Md), 41.2, 30.7, 28.2 (Md), 28.2 (Md), 28.0 (md), 28.0
(md), 24.8, 9.5 (Md), 9.0 (md) ppm; MS (ESI) m/z = 499.5 [M + Na]+.
Elemental analysis calcd (%) for C25H36N2O7: C 63.01, H 7.61, N 5.88.
Found (%): C 62.78, H 7.91, N 5.89.
General Procedure for the Synthesis of the 2-Oxoazepane
Derivatives. A solution of the corresponding 1-N-Boc-2-oxoazetidine
(0.71 mmol) in EtOAc or MeOH (55 mL) was treated with Pd/C
(10% w/w). The suspension was hydrogenated at room temperature
and atmospheric pressure for 4À6 h. After filtration of the catalyst, the
solvent was evaporated. Purification by column chromatograhy was
required in some instances.
(4R,S)-1-tert-Butoxycarbonyl-4-methoxycarbonyl-4-[3-
(benzyloxycarbonyl)amino]propyl-2-oxoazetidine (20). Syr-
up: yield, 83%; eluent, EtOAc/hexane (1:1); HPLC tR = 5.63 min
1
(A/B = 40:60); H NMR (300 MHz, CDCl3) δ 7.36 (s, 5H), 5.10
(s, 2H), 4.85 (br s, 1H), 3.79 (s, 3H), 3.27 (m, 2H), 3.10 (d, J = 15.9 Hz,
1H), 2.95 (d, J = 15.9 Hz, 1H), 2.14 (m, 2H), 1.71 (m, 1H), 1.54
(m, 10H); 13C NMR (75 MHz, CDCl3) δ 171.4, 163.1, 156.7, 147.5,
136.9, 128.9, 128.6, 128.5, 84.3, 67.1, 61.1, 53.3, 46.2, 41.2, 30.1, 28.3,
24.8 ppm; MS (ESI) m/z = 443.3 [M + Na]+. Elemental analysis calcd
(%) for C21H28N2O7: C 59.99, H 6.71, N 6.66. Found: C 59.66, H 6.70,
N 6.45.
(4R,S)-1,4-di-tert-Butoxycarbonyl-4-[3-(benzyloxycarbonyl)-
amino]propyl-2-oxoazetidine (21). Syrup: yield, 83%; eluent,
1
EtOAc/hexane (1:3); HPLC tR = 12.83 min (A/B = 45:55); H NMR
(300 MHz, CDCl3) δ 7.28 (s, 5H), 5.02 (s, 2H), 4.77 (br s, 1H), 3.18 (m,
2H), 2.95 (d, J =15.7 Hz, 1H), 2.83 (d, J = 15.7 Hz, 1H), 2.01 (m, 2H), 1.55
(m, 2H), 1.43 (s, 9H), 1.40 ppm (s, 9H); 13C NMR (75 MHz, CDCl3) δ
(4R,S)-4-(tert-Butoxycarbonyl)amino-4-methoxycarbonyl-
perhydro-2-oxoazepane (24). Solid: mp 179À180 °C (EtOAc/
cyclohexane); yield, 81%; eluent, MeOH/CH2Cl2 (1:15); 1H NMR
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(300 MHz, MeOD) δ 3.71 (s, 3H), 3.29 (m, 3H, including d at 3.20 ppm,
J = 13.8 Hz), 3.09 (d, J = 13.8 Hz, 1H), 1.92 (m, 4H), 1.43 ppm (s, 9H);
13C NMR (75 MHz, MeOD) δ 176.3, 176.2, 157.2, 80.6, 58.5, 52.9, 49.2,
42.3, 38.9, 28.7, 25.4 ppm; MS (ESI) m/z = 287.2 [M + H]+. Elemental
analysis calcd (%) for C13H22N2O5: C 54.53, H 7.74, N 9.78. Found: C
54.29, H 7.59, N 9.65.
(3S,4S)-4-(tert-Butoxycarbonyl)amino-1,3-dimethyl-4-
methoxycarbonyl-2-oxoazepane (37a). A solution of the corre-
sponding 2-oxoazepane derivative (0.64 mmol) in CH3CN (9 mL) was
treated with BTPP (0.59 mL, 1.93 mmol) and stirred at room tempera-
ture for 1 h. MeI (0.32 mL, 1.93 mmol) was then added to the reaction
mixture. After stirring for 48 h, the solvent was evaporated under vacuum
and the residue was extracted with EtOAc. The combined extracts were
washed with brine, dried over Na2SO4, and concentrated under reduced
pressure, leaving a residue that was purified by chromatography on silica
gel using EtOAc/hexane (1:1). Solid: mp 76À79 °C (EtOAc/cyclohexane);
yield, 21% (68% of starting material recovered); [R]D20 = À37.8 (c = 0.7 in
CHCl3);HPLCtR =5.57min(A/B=40:60);1H NMR (300 MHz, CDCl3)
δ 4.92 (s, 1H), 3.72 (s, 3H), 3.72 (m, 1H), 3.19 (q, J = 6.9 Hz, 1H), 3.15
(m, 1H), 3.01 (s, 3H), 2.97 (m, 1H), 2.21 (m, 1H), 1.70 (m, 2H), 1.41
(s, 9H), 1.04 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CHCl3) δ 172.8,
172.7, 155.3, 79.6, 61.4, 52.1, 50.5, 43.3, 36.2, 35.3, 28.2, 24.8, 12.8 ppm; MS
(ESI) m/z = 337.4 [M + Na]+. Elemental analysis calcd (%) for
C15H26N2O5: C 57.31, H 8.34, N 8.91. Found (%): C 57.18, H 8.07, N 9.04.
(3S,4S)-1-Benzyl-4-(tert-butoxycarbonyl)amino-4-methoxy-
carbonyl-3-methyl-2-oxoazepane (38a). BTPP (0.53 mL,
1.72 mmol) and BnBr (0.21 mL, 1.72 mmol) were added to a solution
of 2-oxoazepane derivative (0.57 mmol) in CH3CN (4 mL). After
microwave heating at 120 °C for 45 min, the solvent was evaporated to
dryness, and the residue was extracted with EtOAc. The combined
organic phases were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel using EtOAc/hexane (1:2). Syrup: yield,
91%; [R]D20 = À78.6 (c = 0.5 in CHCl3); HPLC tR = 11.23 min (A/B =
50:50); 1H NMR (400 MHz, CDCl3) δ 7.25À7.31 (m, 5H), 4.98
(s, 1H), 4.80 (d, J = 14.7 Hz, 1H), 4.44 (d, J = 14.7 Hz, 1H), 3.72 (s, 3H),
3.57 (m, 1H), 3.23 (q, J = 6.9 Hz, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.14
(m, 1H), 1.57 (m, 2H), 1.42 (s, 9H), 1.09 (d, J = 6.9 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 172.9, 172.6, 155.1, 137.2, 128.5, 128.4,
127.5, 79.5, 61.5, 52.2, 51.7, 48.0, 43.7, 35.2, 28.3, 23.4, 13.6 ppm; MS
(ESI) m/z = 391.5 [M + H]+, 413.3 [M + Na]+. Elemental analysis calcd
(%) for C21H30N2O5: C 64.59, H 7.74, N 7.17. Found (%): C 64.36, H
7.53, N 6.89.
(4R,S)-4-(tert-Butoxycarbonyl)amino-4-tert-butoxycarbo-
nylperhydro-2-oxoazepane (25). Solid: mp 214À215 °C (EtOAc/
1
cyclohexane); yield, 83%; H NMR (300 MHz, CDCl3) δ 6.72 (br s,
1H), 5.08 (br s, 1H), 3.20 (m, 2H), 2.91 (m, 2H), 2.50 (m, 1H), 2.04
(m, 1H), 1.75 (m, 2H), 1.43 ppm (s, 18H); 13C NMR (75 MHz,
CDCl3) δ 175.9, 173.6, 154.6, 81.7, 79.7, 57.1, 43.0, 42.0, 35.0, 28.2,
27.7, 24.6 ppm; MS (ESI) m/z = 351.2 [M + Na]+. Elemental analysis
calcd (%) for C16H28N2O5: C 58.52, H 8.59, N 8.53. Found: C 58.37,
H 8.60, N 8.40.
4-(tert-Butoxycarbonyl)amino-4-methoxycarbonyl-3-
methyl-2-oxoazepane (35). (3S,4S)-35a. Solid: mp 138À140 °C
20
(EtOAc/cyclohexane); yield, 72%; eluent, EtOAc/hexane (1:2); [R]D
=
À40.2 (c = 0.7 in CHCl3); HPLC tR = 3.28 min (A/B = 40:60); 1H NMR
(300 MHz, CDCl3) δ 6.29 (s, 1H), 4.86 (s, 1H), 3.73 (s, 3H), 3.32
(m, 1H), 3.22 (m, 1H), 3.11 (q, J = 7.0 Hz, 1H), 3.05 (m, 1H), 2.18
(m, 1H), 1.73 (m, 2H), 1.41 (s, 9H), 1.04 (d, J = 7.0 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 175.5, 172.7, 155.2, 79.8, 61.3, 52.3, 43.7, 42.0,
35.8, 28.2, 24.8, 12.8 ppm; MS (ESI) m/z = 323.3 [M + Na]+. Elemental
analysis calcd (%) for C14H24N2O5: C 55.98, H 8.05, N 9.33. Found (%):
C 55.73, H 8.18, N 9.11.
(3R,4S)-35b (md). Solid: mp 132À134 °C (EtOAc/cyclohexane);
20
yield, 6%; eluent, EtOAc/hexane (2:1); [R]D = À18.0 (c = 0.8 in
CHCl3); HPLC tR = 8.80 min (gradient A/B from 95:5 to 20:80 over 20
min); 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), 5.30 (s, 1H), 3.73
(s, 3H), 3.27 (m, 3H), 2.70 (m, 1H), 2.16 (m, 1H), 1.83 (m, 2H), 1.42
(s, 9H), 1.21 (d, J = 7.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
176.0, 173.0, 154.6, 80.3, 61.4, 52.7, 47.6, 41.7, 31.1, 28.4, 25.2, 11.4
ppm; MS (ESI) m/z = 301.2 [M + H]+, 323.1 [M + Na]+. Elemental
analysis calcd (%) for C14H24N2O5: C 55.98, H 8.05, N 9.33. Found
(%): C 55.73, H 8.18, N 9.11.
(3R,4S)-1-tert-Butoxycarbonyl-1,6-diazaspiro[3.5]nonane-
2,5-dione (35c). Syrup: yield, 14%; eluent, EtOAc/hexane (2:1);
HPLC tR = 8.58 min (gradient A/B from 95:5 to 20:80 over 20 min);
1H NMR (300 MHz, CDCl3) δ 6.91 (br s, 1H), 3.45 (q, J = 7.7 Hz, 1H),
3.35 (m, 2H), 2.38 (td, J = 13.4 Hz, J = 3.1 Hz, 1H), 2.16 (m, 1H), 2.02
(m, 1H), 1.70 (m, 1H), 1.49 (s, 9H), 1.29 (d, J = 7.7 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 171.2, 167.4, 154.5, 83.3, 60.4, 53.1, 42.4,
28.0, 26.0, 21.0, 8.6 ppm; MS (ESI) m/z = 291.0 [M + Na]+.
Boc-Oaz(Bn)-Ala-NHMe (39). A solution of compound 38a
(0.132 g, 0.34 mmol) in MeOH (2 mL) was treated with 2 N NaOH
(1.014 mL, 2.03 mmol) and stirred at room temperature for 5 days.
Then, the solvent was evaporated to dryness, and the residue was
dissolved in H2O and washed with EtOAc. The aqueous phase was
acidified with 1 M HCl to pH 3 and extracted with EtOAc. The organic
phase was separated and dried over Na2SO4, evaporated to dryness, and
dissolved in dry CH2Cl2 (7 mL). This solution was treated with H-Ala-
4-tert-Butoxycarbonyl-4-(tert-butoxycarbonyl)amino-3-
methyl-2-oxoazepane (36). (3S,4S)-36a. Solid: mp 132À135 °C
(EtOAc/cyclohexane); yield, 70%; eluent, MeOH/CH2Cl2 (1:60);
NHMe HCl (0.067 g, 0.49 mmol), BOP (0.215 g, 0.49 mmol), and
3
TEA (0.135 mL, 0.97 mmol). After being stirred for 24 h at room
temperature, the solution was washed successively with citric acid
(10%), NaHCO3 (10%), H2O, and brine. The organic phase was dried
over Na2SO4 and evaporated to dryness. The residue was purified by
chromatography on silica gel using MeOH/CH2Cl2 (1:40). Solid: mp
20
[R]D = À46.6 (c = 1.4 in CHCl3); HPLC tR = 4.91 min (A/B =
50:50); 1H NMR (300 MHz, CDCl3) δ 6.60 (s, 1H), 4.84 (s, 1H), 3.31
(m, 1H), 3.19 (m, 1H), 3.08 (q, J = 7.0, Hz, 1H), 2.98 (m, 1H), 2.11
(m, 1H), 1.65 (m, 2H), 1.44 (s, 9H), 1.38 (s, 9H), 1.09 (d, J = 7.0 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.0, 171.3, 154.8, 82.2,
79.3, 60.9, 43.7, 42.1, 35.9, 28.3, 27.9, 24.9, 12.7 ppm; MS (ESI) m/z =
365.4 [M + Na]+. Elemental analysis calcd (%) for C17H30N2O5: C
59.63, H 8.83, N 8.18. Found (%): C 59.48, H 9.12, N 8.10.
20
104À107 °C (EtOAc/cyclohexane); yield, 64%; [R]D = À70.8
(c= 1.0 in CHCl3);HPLCtR = 4.33 min (gradient A/B from 90:10 to 0:100
1
over 10 min); H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.44
(s, 1H), 7.26À7.33 (m, 5H), 5.51 (s, 1H), 4.79 (d, J = 14.5 Hz, 1H), 4.30
(d, J = 14.5 Hz, 1H), 4.22 (quint, J = 7.2 Hz, 1H), 3.66 (m, 1H), 3.41
(q, J = 7.0 Hz, 1H), 3.21 (m, 1H), 2.56 (d, J = 4.6 Hz, 3H), 2.42 (m, 1H),
2.14 (m, 1H), 1.47 (m, 1H), 1.40 (s, 9H), 1.23 (d, J = 7.2 Hz, 3H), 1.08
(m, 1H), 1.01 (d, J = 7.0 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6)
δ 173.3, 172.3, 171.1, 154.5, 138.0, 128.3, 128.1, 127.2, 79.2, 60.6, 50.8, 48.6,
47.0, 42.7, 33.5, 28.0, 25.5, 23.2, 17.6, 13.2 ppm; MS (ESI) m/z = 461.3
[M + H]+, 483.3 [M + Na]+. Elemental analysis calcd (%) for
C24H36N4O5: C 62.59, H 7.88, N 12.16. Found (%): C6 2.27, H
7.95, N 12.05.
(3R,4S)-36b (md). Syrup: yield, 5%; eluent, MeOH/CH2Cl2 (1:120);
[R]D20 = À1.5 (c = 1.3 in CHCl3); HPLC tR = 13.15 min (gradient A/B
from 95:5 to 20:80 over 20 min); 1H NMR (300 MHz, CDCl3) δ 6.31
(s, 1H), 5.36 (s, 1H), 3.27 (m, 3H), 2.71 (m, 1H), 2.07 (m, 1H), 1.83
(m, 2H), 1.45 (s, 9H), 1.42 (s, 9H), 1.18 (d, J = 7.3 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 176.1, 171.3, 154.5, 82.9, 79.8, 61.5, 46.9,
41.9, 32.1, 28.6, 28.0, 25.8, 11.5 ppm; MS (ESI) m/z = 365.2 [M + Na]+.
Elemental analysis calcd (%) for C17H30N2O5: C 59.63, H 8.83, N 8.18.
Found (%): C 59.58, H 9.02, N 8.10.
6601
dx.doi.org/10.1021/jo200894d |J. Org. Chem. 2011, 76, 6592–6603

The Journal of Organic Chemistry
ARTICLE
Piv-Oaz(Bn)-Ala-NHMe (40). Dipeptide derivative 39 (0.046 g,
0.10 mmol) was dissolved in a solution of HCl/EtOAc (2.5 mL, 3.2 M),
and the solution was stirred at room temperature for 4 h. After
evaporation of the solvent, the crude mixture was dissolved in dry
CH2Cl2 (6 mL) and TEA (0.014 mL, 0.10 mmol), propylene oxide
(0.111 mL, 1.59 mmol) and pivaloyl chloride (0.014 mL, 0.11 mmol)
were added. The solution was stirred for 18 h at room temperature, the
solvent was evaporated to dryness, and the residue was purified by
chromatography on silica gel using MeOH/CH2Cl2 (1:30). Syrup: yield,
84%; [R]D20 = À5.5 (c = 0.4 in CHCl3); HPLC tR = 11.72 min (gradient
A/B from 95:5 to 20:80 over 20 min); 1H NMR (400 MHz, DMSO-d6)
δ 7.64 (d, J = 7.2 Hz, 1H), 7.47 (q, J = 4.6 Hz, 3H), 7.24À7.34 (m, 5H),
6.36 (s, 1H), 4.68 (d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 4.25
(quint, J = 7.2 Hz, 1H), 3.71 (m, 1H), 3.43 (q, J = 6.9 Hz, 1H), 3.25
(m, 1H), 2.59 (m, 1H), 2.56 (d, J = 4.6 Hz, 3H,), 2.22 (m, 1H), 1.59
(m, 1H), 1.24 (d, J = 7.2 Hz, 3H), 1.15 (m, 1H), 1.09 (s, 9H), 1.03 (d, J =
6.9 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 178.5, 173.6, 172.2,
170.2, 137.6, 128.4, 128.2, 127.2, 60.5, 50.5, 48.3, 47.1, 42.4, 32.8, 30.7,
26.8, 25.6, 23.1, 17.6, 13.5 ppm; MS (ESI) m/z = 445.3 [M + H]+, 467.3
[M + Na]+. Elemental analysis calcd (%) for C24H36N4O4: C 64.84, H
8.16, N 12.60. Found (%): C 64.66, H 7.89, N 8.21.
’ DEDICATION
Dedicated to the memory of Professor Rafael Suau.
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Preparation of Single Crystals for X-ray Diffraction Anal-
ysis. Pure compound 35a (5 mg) was dissolved in CH2Cl2 (4 mL), and
the mixture was put in a crystallizing dish, resulting in spontaneous
crystallization after 4 days at room temperature in a closed jar.
Molecular Modeling Studies. Molecular dynamic simulations
were carried out using the Amber 10 suite of programs,35 with the ff99SB
force field. Antechamber was used to assign atom types to model dipeptide
40 and to calculate a set of point charges using the AM1-BCC charge model.
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was stored and used to start a new simulation at high temperature. This
procedure afforded samples of 100 energy-minimized conformations, which
were compared to each other to eliminate the identical ones. The resulting
structures were visually inspected using the computer program VMD36 and
analyzed using the ptraj analysis program within Amber.
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’ ASSOCIATED CONTENT
S
Supporting Information. X-ray packing of compound
b
35a, NMR spectra for all new compounds, and crystal data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Email: rosario.gonzalezmuniz@iqm.csic.es; phone: +34 91562-
2900; fax: +34 915644853.
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’ ACKNOWLEDGMENT
We thank The Ministry of Science and Innovation for supporting
grants: Consolider-Ingenio 2010 (CSD2008-00005) and SAF2009-
09323. D.N.-V. and M.A.B. thank CSIC for a predoctoral JAE
fellowship and a JAEdoc contract, respectively.
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The Journal of Organic Chemistry
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6603
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