Synthesis of orthogonally protected azepane β-amino ester enantiomers

Article abstract of DOI:10.1016/j.tetlet.2009.10.072

A simple and convenient route is presented for the preparation of regio- and stereoisomers of novel azepane β-amino esters, starting from bicyclic β-lactam isomers. The synthetic procedure consists of dihydroxylation of the olefinic bond of the alicyclic amino esters, followed by NaIO₄-mediated cleavage of the diol intermediate and reductive ring closure, which furnishes novel regioisomeric 5-aminoazepane-4-carboxylate and 3-aminoazepane-4-carboxylates. This method also allows the preparation of amino esters with an azepane skeleton in enantiomerically pure form.

Full text of DOI:10.1016/j.tetlet.2009.10.072

Tetrahedron Letters 51 (2010) 82–85
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Tetrahedron Letters
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Synthesis of orthogonally protected azepane b-amino ester enantiomers
a
a
a
a,b,
*
}
Brigitta Kazi , Loránd Kiss , Eniko Forró , Ferenc Fülöp
a Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
b Research Group of Stereochemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient route is presented for the preparation of regio- and stereoisomers of novel aze-
pane b-amino esters, starting from bicyclic b-lactam isomers. The synthetic procedure consists of dihydr-
oxylation of the olefinic bond of the alicyclic amino esters, followed by NaIO4-mediated cleavage of the
diol intermediate and reductive ring closure, which furnishes novel regioisomeric 5-aminoazepane-4-
carboxylate and 3-aminoazepane-4-carboxylates. This method also allows the preparation of amino
esters with an azepane skeleton in enantiomerically pure form.
Received 4 September 2009
Revised 12 October 2009
Accepted 19 October 2009
Available online 22 October 2009
Keywords:
Cyclic b-amino acids
Azepane
Ó 2009 Elsevier Ltd. All rights reserved.
Dihydroxylation
Ring closure
Enzymatic resolution
Introduction
piperidine skeleton are important elements in the synthesis of
selective small opioid receptor antagonists.6 Their enantiomers
Biologically active, conformationally restricted alicyclic b-ami-
no acids have aroused significant interest among chemists and bio-
chemists over the past two decades. These types of compounds are
found in many natural products, b-lactams and antibiotics. The
incorporation of conformationally constrained b-amino acids into
biologically active peptides is of considerable importance in the
preparation of peptide-based drug molecules.1
have been used for the preparation of cinchona alkaloids.7 It was
recently reported that the pyrrole b-amino acid moiety is a key ele-
ment in the structure of several tumor necrosis factor-a converting
enzyme inhibitors.8 b-Aminopiperidine carboxylates have been
prepared in optically pure form by lithium amide-promoted asym-
metric conjugate addition-cyclization.9 We previously reported an
efficient ring expansion method for the synthesis of novel b-amino
acid derivatives containing a piperidine skeleton, starting from ali-
cyclic 2-aminocyclopentenecarboxylates, via oxidative ring open-
ing followed by reductive ring closure.10
In recent years, conformationally rigid cyclic b-amino acids
with a heteroatom in the ring have received considerable attention
as a consequence of their biological potential. As a result of their
natural occurrence, biological activities, and chemical interest,
the number of investigations on these medicinally interesting mol-
ecules has increased rapidly. The largest group of such heterocyclic
b-amino acid derivatives are those with one N atom in the ring. b-
Peptides containing 3-aminopyrrolidine-4-carboxylic acid and 3-
aminopyrrolidine-2-carboxylic acid structural moieties have been
shown to adopt helical secondary structures, and have been re-
ported to exhibit interesting biological (e.g., antimicrobial) activi-
ties.2 b-Amino acids possessing a pyrrolidine skeleton have been
presented as potent influenza neuraminidase inhibitors.3 Both pyr-
role b-amino acids and 4-aminopiperidine-3-carboxylic acids can
be incorporated into peptides with a 14-helical structure.4 Iduronic
acid-type 1-N-iminosugars, six-membered derivatives with an N
atom in the ring, display antimetastatic and enzyme inhibitory
activities.5 Furthermore, enamino 1-carboxylates containing a
Despite the wide occurrence and importance of five- and six-
membered N-heterocyclic b-amino acid derivatives, larger ring
analogues do not appear to have been described thus far. Our goal
was to fill this gap by synthesizing enantiomerically pure b-amino
acid derivatives based on azepane. The construction of ring sys-
tems containing more than six members suffers in general from
difficulties and limitations such as low yields and unwanted
side-products.
The synthetic routes to naturally occurring compounds with
functionalized azepane rings generally involve: (a) intramolecular
metathesis of secondary aminodienes;11 (b) pinacol-type intermo-
lecular cyclization of carbonylhydrazones with a protected amino
function inserted in the chain;12 (c) intramolecular nucleophilic
displacement with ring closure of a leaving group by an amino
function;13 (d) intermolecular simultaneous nucleophilic substitu-
tion with an amine of two leaving groups at the end of a six-carbon
chain;14 and (e) intermolecular reductive amination of functional-
ized dialdehydes followed by ring closure.10,15
* Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.072

B. Kazi et al. / Tetrahedron Letters 51 (2010) 82–85
83
In a first approach to the synthesis of the desired enantiomeri-
cally pure b-amino acid derivatives, racemic bicyclic lactam 116a
was submitted to enzymatic ring opening in the presence of CAL-B
(lipase B from Candida antarctica, produced by the submerged fer-
mentation of a genetically modified Aspergillus oryzae microorgan-
ism and adsorbed on a macroporous resin) in iPr2O.16b The
unreacted b-lactam (ꢀ)-116b (ee >99%) was transformed into the
amino ester hydrochloride (ꢀ)-3 via lactam ring opening (for the
opposite enantiomer, see Ref. 16a). Amine protection then gave N-
Boc-protected ethyl 2-aminocyclohex-3-enecarboxylate (ꢀ)-4
(Scheme 1). The azepane ring construction was based on functional-
ization of the C–C double bond of amino ester (ꢀ)-4 through ring
opening and closure with ring expansion. With this aim, 2-amino-
cyclohexenecarboxylate (ꢀ)-4 was first subjected to dihydroxyla-
tion. Oxidation of the C–C double bond was achieved by
OsO4-mediated cis-dihydroxylation, using N-methylmorpholine N-
oxide (NMO) as the stoichiometric co-oxidant. The reaction afforded
a single dihydroxylated diastereomer (+)-5 in good yield (88%).
Based on our earlier studies,10,16c it may be assumed that OsO4 at-
tacks the olefin from the opposite side relative to the ester and car-
bamate function, and therefore the hydroxy groups on C-3 and C-4
are trans relative to the carboxylate on C-1 and the amino group
on C-2 (numbering for the cyclohexane skeleton) (Scheme 1).
The next step was oxidative ring cleavage of the diol. Treatment
of (+)-5 with NaIO4 gave the corresponding dialdehyde, which was
immediately submitted, without isolation, to reductive amination
with benzylamine in the presence of NaBH3CN and AcOH. This
afforded the desired azepane b-amino ester (ꢀ)-6 (36% yield for
the two steps; Scheme 1). The diastereoisomeric trans derivative
(ꢀ)-7 was prepared by epimerization of (ꢀ)-6 at C-4 in the pres-
ence of NaOEt (Scheme 1). The relatively low yield of this reaction
was due to the poor conversion of the starting material, which was
recovered during column chromatographic purification. The ee val-
ues for (ꢀ)-6 and (ꢀ)-7 were found to be >99% (HPLC).17
quent steps, the procedure presented in Scheme 1 was followed:
dihydroxylation, diol cleavage, then reductive amination with ring
closure, giving (ꢀ)-14, and following epimerization, (+)-15, both
with ee’s >99% (HPLC).17
In conclusion, four novel azepane b-amino ester diastereomers
have been prepared in enantiomerically pure form, starting from
racemic bicyclic b-lactam isomers 1 and 8, via dihydroxylation of
b-aminocyclohexenecarboxylate regioisomers, followed by ring
cleavage and ring closure on reductive amination.
Cleavage of dihydroxy compounds and ring closure with
reductive amination; general procedure
NaIO4 (420 mg, 2 mmol) was added to a stirred solution of ami-
no ester (+)-5 or (ꢀ)-13 (303 mg, 1 mmol) in THF/H2O (16.5 mL,
10/1). After stirring for 1 h at rt under an Ar atmosphere, H2O
was added until the precipitate dissolved. The mixture was then
extracted with CH2Cl2 (3 ꢁ 40 mL), the combined extract dried
over Na2SO4 and the resulting dialdehyde solution was immedi-
ately used for the next reaction without isolation. Benzylamine
(0.11 mL, 1 mmol) and oven-dried 3 Å MS were added to the solu-
tion of the dialdehyde and the mixture was stirred at 40 °C for
10 min.
A solution of NaCNBH3 (62 mg, 1 mmol) and AcOH
(1 equiv) in EtOH (2 mL) was added dropwise under an Ar atmo-
sphere over 2 h, and stirring was continued for another 1 h at
40 °C. The reaction mixture was washed with 10% Na2CO3
(3 ꢁ 80 mL) and brine (80 mL), and the organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (n-hexane/
EtOAc: 3/1).
Ethyl (3S,4S)-1-benzyl-3-(tert-butoxycarbonylamino)azepane- 4-
carboxylate [(ꢀ)-6]
The bicyclic b-lactam 818a allowed the synthesis of a new type
of b-amino acid derivative with an azepane framework, that is,
regioisomers of (ꢀ)-6 and (ꢀ)-7. Racemic azetidinone 8 was con-
verted into amino acid (ꢀ)-9 by enzymatic hydrolysis with CAL-B
in iPr2O. The optically active (ee >99%) b-amino acid (ꢀ)-918b was
transformed, via amino ester (ꢀ)-11,18a into enantiomerically pure
N-Boc-protected b-amino ester (ꢀ)-1219 (Scheme 2). In the subse-
White crystals; yield: 36% (two steps); mp 76–78 °C; ½a D20
ꢀ5.2
ꢂ
(c 0.31, EtOH); 1H NMR (CDCl3, 400 MHz) d = 1.24 (t, 3H, CH3,
J = 7.08 Hz,), 1.40 (s, 9H, CH3), 1.44–1.56 (m, 1H, CH2), 1.70–1.87
(m, 2H, CH2), 1.89–2.00 (m, 1H, CH2), 2.44–2.54 (m, 1H, H-4),
2.56–2.83 (m, 4H, 2 ꢁ N–CH2), 3.60 (m, 2H, N–CH2Ph), 4.05–4.20
(m, 3H, OCH2, H-3), 5.35 (br s, 1H, N–H), 7.19–7.33 (m, 5H, Ar-
H); 13C NMR (CDCl3, 100 MHz): d = 14.6, 24.7, 26.7, 29.5, 50.2,
R
O
S
R
O
COOH
NH2
CAL-B,
i
Pr2O,
+
70 °C
NH
NH
S
(+)-2
1
(-)-1
HCl/EtOH
0 ºC, 1 h, 81%
S
R
S
COOEt
COOEt
NHBoc
Boc2O, Et3N, THF,
20 ºC, 8 h, 93%
NH2HCl
R
(-)-3
(-)-4
OsO4/
t
BuOH, NMO/H2O,
acetone, 20 ºC, 3 h, 88%
COOEt
COOEt
R
S
S
COOEt
NHBoc
1. NaIO4, THF/H2O, 20 ºC, 1 h
NaOEt, EtOH,
NHBoc
NHBoc
2. NaCNBH3, BnNH2, CH2Cl2
AcOH, 20 ºC, 10 h
S
20 ºC, 43%
S
HO
S
N
N
36% (two steps)
OH
Ph
Ph
(-)-7
(-)-6
(+)-5
Scheme 1. Synthesis of azepane amino esters (ꢀ)-6 and (ꢀ)-7.

84
B. Kazi et al. / Tetrahedron Letters 51 (2010) 82–85
O
R
S
S
R
O
COOH
NH2
CAL-B, Pr2O,
i
+
60 ºC
ref. 17
NH
NH
(+)-10
8
(-)-9
SOCl2, EtOH, 3 h,
70 ºC, 90%
R
COOEt
NHBoc
R
S
COOEt
Boc2O, Et3N, THF,
8 h, 89%
S
NH2HCl
(-)-11
(-)-12
OsO4/
t
BuOH, NMO/H2O,
acetone, 20 ºC, 3 h, 85%
COOEt
COOEt
S
R
R
HO
HO
COOEt
1. NaIO4, THF/H2O, 20 ºC, 1 h
NaOEt, EtOH,
20 ºC, 44%
NHBoc
NHBoc
S
2. NaCNBH3, BnNH2, CH2Cl2
AcOH, 20 ºC, 10 h
N
NHBoc
N
S
S
(-)-13
32% (two steps)
Ph
(-)-14
Ph
(+)-15
Scheme 2. Synthesis of azepane amino esters (ꢀ)-14 and (+)-15.
51.0, 54.4, 57.5, 60.8, 64.0, 79.3, 127.4, 128.7, 129.3, 139.7, 155.5,
174.1; MS: (ESI): m/z = 377 (M+1). Anal. Calcd for C21H32N2O4: C,
66.99; H, 8.57; N, 7.44. Found: C, 66.69; H, 8.30; N, 7.20.
(M+1). Anal. Calcd for C21H32N2O4: C, 66.99; H, 8.57; N, 7.44.
Found: C, 66.71; H, 8.27; N, 7.19.
Ethyl (4S,5S)-1-benzyl-5-(tert-butoxycarbonylamino)aze-
pane-4-carboxylate [(+)-15]
Ethyl (4R,5S)-1-benzyl-5-(tert-butoxycarbonylamino)aze-
pane-4-carboxylate [(ꢀ)-14]
Yellowish oil; yield: 44%; ½a D20
ꢂ
+3 (c 0.315, EtOH); 1H NMR
Yellow oil; yield: 32% (two steps); ½a D20
ꢂ
ꢀ5.0 (c 0.31, EtOH); 1H
(CDCl3, 400 MHz) d = 1.19 (t, 3H, CH3, J = 7.3 Hz), 1.39 (s, 9H,
CH3), 1.71–2.03 (m, 4H, CH2), 2.43–2.53 (m, 1H, H-4), 2.58–2.74
(m, 4H, N–CH2), 3.55 (m, 2H, N–CH2Ph), 4.04–4.13 (m, 2H, OCH2),
4.14–4.25 (m, 1H, H-5), 5.34 (br s, 1H, N–H), 7.12–7.38 (m, 5H,
Ar-H). 13C NMR (CDCl3, 100 MHz): d = 14.6, 28.3, 28.8, 30.1, 49.2,
49.3, 51.4, 52.5, 60.9, 63.5, 70.2, 127.5, 128.7, 129.2, 139.4, 155.6,
174.7; MS: (ESI): m/z = 377 (M+1). Anal. Calcd for C21H32N2O4: C,
66.99; H, 8.57; N, 7.44. Found: C, 66.70; H, 8.33; N, 7.29.
NMR (CDCl3, 400 MHz) d = 1.23 (t, 3H, CH3, J = 7.05 Hz), 1.42 (s, 9H,
CH3), 1.67–1.81 (m, 2H, CH2), 1.91–2.19 (m, 2H, CH2), 2.35–2.51
(m, 1H, H-4), 2.58–2.72 (m, 2H, N–CH2), 2.77–2.89 (m, 1H, N–
CH2), 2.82–2.91 (m, 1H, N–CH2), 3.56–3.70 (m, 2H, NCH2Ph),
4.08–4.19 (m, 3H, OCH2 and H-5), 5.77 (br s, 1H, N–H), 7.20–7.35
(m, 5H, Ar-H); 13C NMR (CDCl3, 100 MHz): d = 14.6, 28.3, 28.8,
32.8, 47.9, 51.3, 51.9, 52.7, 60.7, 63.9, 79.2, 127.4, 128.7, 129.1,
139.9, 155.7, 173.9; MS: (ESI): m/z = 377 (M+1). Anal. Calcd for
C21H32N2O4: C, 66.99; H, 8.57; N, 7.44. Found: C, 66.64; H, 8.22;
N, 7.17.
Acknowledgments
The authors are grateful to the Hungarian Research Foundation
(OTKA Nos. F67970 and T049407) for financial support and for
Isomerization of the azepane amino esters; general procedure
}
the award of Bolyai János Fellowship to Loránd Kiss and Eniko
Forró.
Freshly prepared NaOEt (86 mg, 1.27 mmol) was added to a
solution of (ꢀ)-6 or (ꢀ)-14 (400 mg, 1.06 mmol) in anhydrous
EtOH (15 mL), and the mixture was stirred at rt for 72 h, and then
concentrated under reduced pressure. The residue was taken up in
EtOAc (25 mL) and the organic layer was washed with H2O
(3 ꢁ 10 mL). The organic phase was dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified from the
unreacted starting material by column chromatography on silica
gel (n-hexane/EtOAc: 5/1).
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Ethyl (3S,4R)-1-benzyl-3-(tert-butoxycarbonylamino)aze-
pane-4-carboxylate [(ꢀ)-7]
Yellowish oil; yield: 38%; ½a D20
ꢂ
ꢀ27.5 (c 0.325, EtOH); 1H NMR
(CDCl3, 400 MHz) d = 1.24 (t, 3H, CH3, J = 7.3 Hz), 1.38 (s, 9H,
CH3), 1.61–1.76 (m, 2H, CH2), 1.76–1.98 (m, 2H, CH2), 2.34–2.45
(m, 1H, H-4), 2.59–2.90 (m, 4H, 2 ꢁ N–CH2), 3.48–3.68 (m, 2H,
N–CH2Ph), 3.90–4.03 (m, 1H, H-3), 4.12 (m, 2H, OCH2), 5.27 (br s,
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d = 14.6, 26.1, 26.8, 28.8, 50.3, 50.7, 56.2, 56.9, 60.8, 64.2, 79.3,
127.6, 128.8, 129.5, 139.8, 155.4, 173.8; MS: (ESI): m/z = 377

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17. The ee value for (ꢀ)-6 was determined by HPLC on a ChiralcelÒ OD 5
lm
column (0.46 cm ꢁ 25 cm) [mobile phase: n-hexane/2-propanol (95/5); flow
rate 0.5 mL/min; detection at 205 nm; retention time (min): 11.1 (antipode:
12.8)]. The ee values for (ꢀ)-7, (ꢀ)-14, and (+)-15 were determined by HPLC on
a Chiral Pak IA 5
lm column (0.4 cm ꢁ 1 cm) {detection at 205 nm; [mobile
phase: n-hexane/2-propanol (90/10); flow rate 0.5 mL/min; retention times
(min) for (ꢀ)-7: 13.0 (antipode: 15.1); for (+)-15: 16.7 (antipode: 14.0)]; and
[mobile phase: n-hexane/2-propanol (97/3); flow rate 0.3 mL/min; retention
time (min) for (ꢀ)-14: 35.1 (antipode: 30.2)]}.
9. Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P.
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