Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0] alkane as a Potential Scaffold for Targeted Chemotherapy Strategies

Article abstract of DOI:10.1055/s-2003-42400

A stereoselective synthesis of functionalized 2-oxo-1-azabicyclo[5.3.0] alkane is presented. Key events of the synthetic sequence were the stereoselective propenylation of an N-acyliminium ion and a ring-closing metathesis reaction forming a 7-membered la

Full text of DOI:10.1055/s-2003-42400

PAPER
2363
Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0]alkane
as a Potential Scaffold for Targeted Chemotherapy Strategies
Stereoselective
Sy
n
nthesis of
a
F
t
unctio
o
nalised2-O
x
n
o-1-azabicyc
i
lo[5.3.
o
a
Dipartimento di Chimica Organica e Industriale and Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali (CISI),
Università degli Studi di Milano, Via Venezian 21, 20133 Milano Italy
E-mail: carlo.scolastico@unimi.it
b
Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Venezian 21, I-20133 Milano, Italy
Fax +39(02)50314072; E-mail: Leonardo.manzoni@istm.cnr.it
Received 20 June 2003; revised 23 July 2003
Abstract: A stereoselective synthesis of functionalized 2-oxo-1-
azabicyclo[5.3.0]alkane is presented. Key events of the synthetic
sequence were the stereoselective propenylation of an N-acylimini-
um ion and a ring-closing metathesis reaction forming a 7-mem-
bered lactam.
O
CO2H
CO2H
( )n
N
N
N
Arg
Gly
O
O
O
H2N
HN
NH2
Asp
3 ST1646
Key words: metathesis, ring closure, lactams, bicyclic compounds,
asymmetric synthesis, peptides
1 n = 1, 2
2
Figure 1
Many physiological processes including cell activation,
migration, proliferation and differentiation require direct
contact between cells and the extracellular matrix. These
interactions are mediated through several different fami-
lies of CAMs (cell adhesion molecules) including the se-
lectins, the integrins, the cadherins and the
to conjugate the most frequently used anticancer drugs to
the integrin binders. Although many reports on the syn-
thesis of bicyclic lactams8,9 can be found in the literature,
only a few describe the preparation of azabicy-
clo[x.y.0]alkanes bearing functionalised side-chains.10 In
the course of our studies on peptide secondary structure
mimics we have already synthesized a functionalised 7,5-
fused bicyclic lactam using a Horner–Emmons based
strategy.11 However, the number of steps of this approach
and the importance of these compounds forced us to in-
vestigate new synthetic routes. We now report a stereose-
lective synthesis based on ring closing metathesis
(RCM)9k of a 7,5-trans-fused bicyclic lactam with a suit-
ably functionalised side-chain.
immunoglobulins. In particular, integrins are
/
het-
erodimeric cell surface receptors which play a major role
in cell–cell and cell–matrix adhesive interactions1 and
represent the best opportunity of targeting small-molecule
antagonists for both therapeutic and diagnostic use in var-
ious key diseases.2 Bicyclo[x.y.0]alkanes 1 have served as
scaffolds for the synthesis of integrin antagonists.3 In par-
ticular, we have found that the 2-oxo-1-azabicyc-
lo[5.3.0]alkane (2)4 when incorporated in a cyclic RGD
(Arg-Gly-Asp) peptide appears to force the two pharma-
cophoric groups of Asp and Arg to adopt the correct dis-
position to interact with the receptors5 (Figure 1).
Compound 3 has shown to be highly active and selective
The starting material for the synthesis was the known 4-
allyl pyroglutamic ester 412 (Scheme 1) which, after pro-
tecting group manipulation, was converted to the corre-
sponding alcohol 5 via ozonolysis followed by in situ
NaBH4 reduction (80% over 3 steps). Hydroxy group pro-
tection as the silyl ether (thexyldimethylsilyl chloride, im-
idazole in DMF) followed by N-Boc nitrogen protection
using standard conditions afforded the corresponding pro-
tected pyroglutamic acid 7 in 92% yield over the two
steps. The order of the synthetic sequence was found to be
crucial. If the ozonolysis and NaBH4 reduction were per-
formed starting from the N-Boc-protected pyroglutamate
8, an irreversible ‘ring switching’ to the lactone 9 was ob-
served (Scheme 1).13
toward the
integrin which are expressed on the sur-
v
3
face of a variety of cell types and are implicated in many
pathological processes, such as tumor metastasis, angio-
genesis, and osteoporosis.6 Therefore, 3 could be a poten-
tial antitumor drug, and is currently under study in various
animal models.
Since the
3 integrin is overexpressed by many tumors,
v
ST1646 could also be seen as a tumor-homing peptide
and, as such, it could be used to improve the therapeutic
index of other cancer chemotherapeutics7 by selective cell
targeting. Thus, our recent efforts have been directed to-
ward the synthesis of functionalised bicyclo[5.3.0]alkane
scaffolds bearing appropiate side-chains that can be used
Selective reduction of the imide 7 to the hemiaminal 11
(Scheme 2) was best performed with lithium triethylboro-
hydride at –78 °C (99%). According to ample literature
precedent14 and to our own experience on similar sub-
strates,15 the hemiaminal 11 was first converted to the cor-
responding C5-methoxy derivative 12 by PPTS in MeOH
(95%) and then subjected to boron trifluoride mediated 1-
SYNTHESIS 2003, No. 15, pp 2363–2367
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42400; Art ID: P05303SS
© Georg Thieme Verlag Stuttgart · New York

2364
A. Bracci et al.
PAPER
TDSO
TDSO
TDSO
a
a, b
O
O
CO2t-Bu
CO2Me
O
HO
CO2t-Bu
CO2t-Bu
N
N
H
N
N
Boc
8
Boc
7
Boc
11
4
c
a, b, d
b
HO
HO
d
O
MeO
CO2t-Bu
CO2t-Bu
N
N
O
O
CO2t-Bu
CO2t-Bu
N
N
H
5
Boc
18
Boc
12
Boc
AcO
AcO
c, d
e
e
TDSO
TDSO
MeO
CO2t-Bu
CO2t-Bu
N
N
O
Boc
14
Boc
13
CO2t-Bu
HN
O
CO2t-Bu
O
N
H
6
AcO
AcO
f
Boc
9
g
c
CO2t-Bu
CO2t-Bu
NHCbz
N
H
N
O
15
O
CO2t-Bu
N
Boc
7
16
h, i
Scheme 1 (a) NaOH, THF, H2O, quant.; (b) O-tert-butyl-N,N-diiso-
propylisourea, CH2Cl2, quant.; (c) Boc2O, TEA, DMAP, THF, 94%;
(d) O3, MeOH, NaBH4, 80%; (e) TDSCl, imidazole, DMF, 98%.
AcO
PCy3
Ru
Ph
Cl
Cl
CO2t-Bu
N
PCy3
propenyl cuprate addition as described by McClure et
al.14e However, the main product observed after cuprate
addition was 18 arising by intramolecular nucleophilic at-
tack of the hydroxy group on the intermediate hemiami-
nal. To avoid oxygen deprotection in the reaction
conditions, the protecting group was changed from silyl
ether to acetate. The propenyl cuprate addition occurred
O
Grubbs catalyst
NHCbz
17
Scheme 2 (a) LiEt3BH, THF, –78 °C, 99%; (b) MeOH, PPTS, 95%;
(c) TBAF, THF, 96%; (d) AcCl, Et3N, CH2Cl2, 90%; (e) 1-propenyl
bromide, Li, CuBr·Me2S, BF3·Et2O, 64%; (f) t-BuOAc, HClO4, 0 °C
to r.t., 79%; (g) allyl glycine, NMM, isopropyl chloroformate, THF,
smoothly on the acetate 13 to yield the 5-propenyl proline –30 °C to r.t., 64%; (h) Grubbs catalyst, CH2Cl2, 83%; (i) NaBH4–
NiCl2, MeOH, 80%.
14, as the only isomer. The product configuration was es-
tablished by NOE experiments. Selective removal of the
tert-butoxycarbonyl protecting group from 14 with HClO4
in t-BuOAc gave the desired amine 15 (79%).
In summary, we have reported a convenient synthetic
route for the preparation of a substituted 2-oxo-1-
aza[5.3.0]bicycloalkane based on RCM cyclization. This
bicyclic lactam could be used as scaffold for the synthesis
of a cyclopentapeptide containing the RGD sequence for
targeted chemotherapy strategies.
The coupling of this hindered amine to a racemic mixture
of N-Cbz allyl glycine proceeded with complete kinetic
resolution and afforded 16 as the only isomer in 64% yield
using 3.3 equiv of acylating agent. The coupling reaction
proceeded equally well by using either the acyl fluoride16
or the mixed anhydride preactivation methods. The con-
figuration of the amino acid moiety in 16 was not estab-
lished at this point but was determined by NOE
experiment on the final target 17.
1H and 13C NMR spectra were recorded in CDCl3 solution as indi-
cated, at 200 (or 300, 400) and 50.3 MHz, respectively. The chem-
ical shift values are given in ppm and the coupling constants J in Hz.
Optical rotation data were obtained with a Perkin–Elmer model 241
polarimeter. TLC was carried out using Merck precoated silica gel
F-254 plates. Flash chromatography was carried out using Mach-
erey–Nagel silica gel 60, 230–400 mesh. Solvents were dried ac-
cording to standard procedures, and reactions requiring anhyd
conditions were performed under nitrogen. Petroleum ether refers to
the fraction with bp 40–60 ºC. Solutions containing the final prod-
ucts were dried (Na2SO4), filtered, and concentrated under reduced
Thus the stage was set for the RCM reaction of the dienyl
precursor 16. The reaction proceeded in 16 h in refluxing
CH2Cl2 in the presence of 10% of the Grubbs first gener-
ation catalyst17 to give the functionalized bicyclic scaffold
in 83% yield. The reduction of the double bond was
achieved by NaBH4–NiCl2 in MeOH (80%).18
Synthesis 2003, No. 15, 2363–2367 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0]alkane
2365
pressure using a rotary evaporator. Elemental analyses were per-
formed by the staff of the microanalytical laboratory in our depart-
ment. The (Z)-1-lithio-1-propene was prepared from cis-1-bromo-
1-propene (Aldrich) and lithium powder (high sodium, Aldrich) in
Et2O at –25 °C under an argon atmosphere in ca. 65% yield (based
on the bromide).19 Concentrations of the nearly colorless ethereal
solutions of the alkenyllithium were typically ca. 0.7 M as deter-
mined by titration.20 Abbreviations: DMAP, 4-(dimethylamino)py-
ridine; TBAF tetrabutylammonium fluoride; DMF, N,N-
dimethylformamide; THF tetrahydrofuran; Boc2O di-tert-butyl di-
carbonate; TDSCl, thexyldimethylsilyl chloride; PPTS, pyridinium
paratoluensulphonate; NMM, N-methylmorpholine.
h, to the reaction mixture was added brine (8 mL) and the organic
layers were extracted with CH2Cl2. The organic phases were dried
(Na2SO4) and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (EtOAc–petro-
leum ether, 2:8) to yield 7.
Yield: 1.04 g (94%); yellow oil.
(2S,4R)-4-{2-[Dimethyl-(1,1,2-trimethylpropyl)silanyloxy]eth-
yl}-5-hydroxypyrrolidine-1,2-dicarboxylic Acid tert-Butyl Es-
ter (11)
To a solution of 7 (0.660 g, 1.40 mmol) in anhyd THF (14 mL),
LiEt3BH (1 M in THF; 1.68 mL) was added at –78 °C and the solu-
tion was stirred for 50 min, then sat. aq NH4Cl solution (15 mL) was
added. The aq phase was extracted with EtOAc, the combined or-
ganic layers were dried (Na2SO4), filtered and the solvent was re-
moved under reduced pressure. The crude product, as a yellowish
oil, was submitted to the next reaction without further purification.
1H NMR (200 MHz, CDCl3): = 0.12 [s, 6 H, Si(CH3)2], 0.86 (m,
12 H, CH3), 1.45 [s, 9 H, C(CH3)3], 1.50–2.20 (m, 16 H), 3.60 (m,
2 H, CH2OTDS), 4.15 (m, 1 H, CHCOO-t-Bu), 5.25, 5.32 (2 m, 1
H, CHOH).
(2S,4R)-4-Hydroxyethyl-5-oxopyrrolidine-2-carboxylic Acid
tert-Butyl Ester (5)
A stirred solution of 4 (2.1 g, 9.32 mmol) in MeOH (93 mL) was
cooled to –78 °C, whereupon O3 was bubbled through it (flow
rate 30 L/h). After 1.5 h, N2 was bubbled through the reaction mix-
ture in order to eliminate the excess of O3. NaBH4 was then added
in portions until the ozonide had completely disappeared. The sol-
vent was evaporated under reduced pressure and the residue was re-
dissolved in EtOAc and washed with brine. The organic phases
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography
(EtOAc) to yield alcohol 5.
Yield: 1.8 g (84%); white solid; mp 82–83 °C; [ ]D20 –14.2 (c 1.0,
CHCl3).
1H NMR (400 MHz, CDCl3): = 1.48 [s, 9 H, C(CH3)3], 1.75 (m, 1
H, HCHCH2OH), 1.81 (m, 1 H, HCHCHCOO-t-Bu), 2.04 (m, 1 H,
HCHCH2OH), 2.69 (m, 1 H, CHC=O), 2.72 (m, 1 H, HCHCHCOO-
t-Bu), 3.65 (m, 1 H, HCHOH) 3.79 (m, 2 H, HCHOH, OH), 4.15 (m,
1 H, CHCOO-t-Bu), 5.92 (br s, 1 H, NH).
(2S,4R)-4-{2-[Dimethyl-(1,1,2-trimethylpropyl)silanyloxy]eth-
yl}-5-methoxypyrrolidine-1,2-dicarboxylic Acid tert-Butyl Es-
ter (12)
To a solution of 11 (0.598 g, 1.26 mmol) in MeOH (14 mL), PPTS
(0.453 g, 1.80 mmol) was added. After 12 h, the solvent was evap-
orated and to the residue was added a phosphate buffer solution (10
mL), the aq phase was extracted with CH2Cl2, the combined organic
layers were dried (Na2SO4), filtered and the solvent was removed
under reduced pressure. The residue was purified by flash chroma-
tography (EtOAc–petroleum ether, 1:9) to yield 12.
13C NMR (50.3 MHz, CDCl3): = 179.4, 170.0, 81.8, 60.7, 54.4,
40.0, 33.4, 31.7, 27.3.
Yield: 0.580 g (94%); colorless oil.
1H NMR (200 MHz, CDCl3): = 0.12 [s, 6 H, Si(CH3)2], 0.86 (m,
12 H, CH3), 1.45 [s, 9 H, C(CH3)3], 1.50–2.35 (m, 15 H), 3.40 (s, 3
H, OCH3), 3.60 (m, 2 H, CH2OTDS), 4.10 (m, 1 H, CHCOO-t-Bu),
5.01, 5.10 (2 m, 1 H, CHOCH3).
MS (FAB): m/z calcd for C11H19NO4: 229.13; found: 230.
Anal. Calcd for C11H19NO4 (229.13): C, 57.62; H, 8.35; N, 6.11.
Found C, 57.70; H, 8.36; N, 6.11.
MS (FAB): m/z calcd for C25H49NO6Si: 487.33; found: 488.
(2S,4R)-4-{2-[Dimethyl-(1,1,2-trimethylpropyl)silanyloxy]eth-
yl}-5-oxopyrrolidine-2-carboxylic Acid tert-Butyl Ester (6)
To a stirred solution of the alcohol 5 (0.708 g, 3.09 mmol), in DMF
(4.4 mL), thexyldimethylsilyl chloride (1.82 mL, 9.27 mmol) and
imidazole (1.26 g, 18.55 mmol) were added sequentially. After 16
h the solvent was evaporated and the crude was purified by flash
chromatography (hexane–EtOAc, 1:1) to yield 6.
Anal. Calcd for C25H49NO6Si (487.33): C, 61.56; H, 10.13; N, 2.87.
Found: C, 61.68; H, 10.15; N, 2.87.
(2S,4R)-4-(2-Acetoxyethyl)-5-methoxypyrrolidine-1,2-dicar-
boxylic Acid tert-Butyl Ester (13)
To a solution of 12 (0.170 g, 0.35 mmol) in THF (3.5 mL) was add-
ed a solution in THF of TBAF (1 M; 0.450 mL) and the mixture was
stirred for 6 h at r.t. To this was added brine (3 mL) and the reaction
mixture was extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4), filtered and the solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(EtOAc–petroleum ether, 1:9) to yield the alcohol.
Yield: 1.12 g (98%); colorless oil; [ ]D20 +10.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): = 0.12 [s, 6 H, Si(CH3)2], 0.83–0.90
[m, 12 H, CH3), 1.50 [s, 9 H, C(CH3)3], 1.55 (m, 1 H, HCHCH2OSi),
1.63 [m, 1 H, CH(CH3)2], 1.90 (m, 1 H, HCHCH2OSi), 2.15 (m, 1
H, HCHCHCOO-t-Bu), 2.60 (m 1 H, CHC=O), 2.71 (m, 1 H, HCH-
CHCOO-t-Bu), 3.75 (m, 2 H, CH2OSi), 4.12 (m, 1 H, CHCOO-t-
Bu), 6.22 (br s, 1 H, NH).
Yield: 0.115 g (95%); colorless oil.
1H NMR (200 MHz, CDCl3): = 1.50 [s, 9 H, C(CH3)3], 1.55 [s, 9
H, C(CH3)3], 1.70 (m, 1 H, HCHCH2OH), 1.80 (m, 1 H, HCHCH-
COO-t-Bu), 1.90 (m, 1 H, HCHCH2OH), 2.15 (m, 1 H, HCHCH-
COO-t-Bu), 2.35 (m, 1 H, CHCH2CH2OH), 3.40 (s, 3 H, OCH3),
3.70 (m, 2 H, CH2OH), 4.15 (m, 1 H, CHCOO-t-Bu), 5.01, 5.10 (2
m, 1 H, CHOCH3).
13C NMR (50.3 MHz, CDCl3): = 179.1, 170.8, 60.8, 54.4, 38.7,
34.0, 33.8, 32.1, 27.8, 20.2, 18.4, –3.5, –3.6.
MS (FAB): m/z calcd for C19H37NO4Si: 371.25; found: 372.
Anal. Calcd for C19H37NO4Si (371.25): C, 61.41; H, 10.04; N, 3.77.
Found: C, 61.51; H, 10.06; N, 3.87.
13C NMR (50.3 MHz, CDCl3): = 171.7, 154.4, 88.6, 81.0, 80.7,
63.2, 59.7, 56.7, 40.7, 33.7, 28.6, 28.4, 28.3.
(2S,4R)-4-{2-[Dimethyl-(1,1,2-trimethylpropyl)silanyloxy]eth-
yl}-5-oxopyrrolidine-1,2-dicarboxylic Acid tert-Butyl Ester (7)
To a solution of 6 (0.874 g, 2.35 mmol) in CH2Cl2 (4.8 mL) were
added Et3N (0.361mL, 2.59) and a solution of DMAP (0.287 g, 2.35
mmol) and Boc2O (0.667 g, 3.06 mmol) in CH2Cl2 (3 mL). After 3
MS (FAB): m/z calcd for C17H31NO6: 345.22; found: 346.
Anal. Calcd for C17H31NO6 (345.22): C, 59.11; H, 9.05; N, 4.05.
Found: C, 59.20; H, 9.06; N, 4.05.
Synthesis 2003, No. 15, 2363–2367 © Thieme Stuttgart · New York

2366
A. Bracci et al.
PAPER
To a solution of the alcohol (0.102 g, 0.30 mmol) in THF (3.0 mL)
were added, at 0 °C, Et3N (0.049 mL, 0.32 mmol) and acetyl chlo-
ride (0.023 mL, 0.35 mmol). After 2 h, a buffer phosphate solution
(3 mL) was added and extracted with CH2Cl2. The combined organ-
ic layers were dried (Na2SO4), filtered and the solvent was removed
under reduced pressure. The residue was purified by flash chroma-
tography (EtOAc–petroleum ether, 2:8) to yield 13.
CH=CHCH3), 1.83 (m, 2 H, HCHCH2OAc, HCCH2CH2OAc), 2.10
(s, 3 H OCOCH3), 2.50 (m, 1 H, HCHCHCOO-t-Bu), 3.2 (s, 1 H,
NH), 3.75 (m, 1 H, CHCH=CHCH3), 3.90 (m, 1 H, CHCOO-t-Bu),
4.10 (m, 2 H, CH2OAc), 5.35 (m, 1 H, CH=CHCH3), 5.68 (m, 1 H,
CH=CHCH3).
13C NMR (100.6 MHz, HETCOR, CDCl3): = 131.4, 129.0, 63.9,
61.1, 60.0, 43.6, 36.9, 36.6, 31.6, 28.5, 21.6, 13.9.
Yield: 0.098 g (84%); colorless oil.
MS (FAB): m/z calcd for C16H27NO4: 297.19; found: 298.
1H NMR (200 MHz, CDCl3): = 1.50 [s, 9 H, C(CH3)3], 1.55 [s, 9
H, C(CH3)3], 1.70 (m, 1 H, HCHCH2OAc), 1.80 (m, 1 H, HCHCH-
COO-t-Bu), 1.90 (m, 1 H, HCHCH2OAc), 2.05 (s, 3 H, OCOCH3),
2.15 (m, 1 H, HCHCHCOO-t-Bu), 2.35 (m, 1 H, CHCH2CH2OAc),
3.40 (s, 3 H, OCH3), 4.10 (m, 2 H, CH2OAc), 4.15 (m, 1 H,
CHCOO-t-Bu), 5.01, 5.10 (2 m, 1 H, CHOCH3).
Anal. Calcd for C16H27NO4 (297.19): C, 64.62; H, 9.15; N, 4.71.
Found C, 64.70; H, 9.16; N, 4.70.
(2S,4R)-4-(2-Acetoxyethyl)-1-(2-benzyloxycarbonylaminopent-
4-enoyl)-5-propenylpyrrolidine-2-carboxylic Acid tert-Butyl
Ester (16)
13C NMR (50.3 MHz, CDCl3): = 171.7, 171.5, 154.4, 88.6, 81.0,
80.7, 63.2, 59.7, 56.7, 40.7, 33.7, 28.6, 28.4, 28.3, 21.1.
To a solution of ( )-N-(Z)-allylglycine (0.0526 g, 0.211 mmol) in
anhyd THF (0.5 mL) was added at –30 °C N-methylmorpholine
(0.0563 mL, 0.511 mmol) and isobutyl chloroformate (0.0293 mL,
0.224 mmol). After 30 min, 15 (0.019 g, 0.064 mmol) was added,
then the reaction mixture was stirred for 12 h. The suspension was
filtered on a Celite pad and the solvent was evaporated under re-
duced pressure. To the crude was added H2O and the mixture was
extracted with EtOAc. The combined organic layers were dried
(Na2SO4), filtered and the solvent was removed under reduced pres-
sure. The residue was purified by flash chromatography (EtOAc–
petroleum ether, 35:65) to yield 16.
MS (FAB): m/z calcd for C19H33NO7: 387.23; found: 388.
Anal. Calcd for C19H33NO7 (387.23): C, 58.90; H, 8.58; N, 3.61.
Found: C, 59.00; H, 8.60; N, 3.62.
(2S,4R)-4-(2-Acetoxyethyl)-5-[(Z)-propenyl]pyrrolidine-1,2-di-
carboxylic Acid tert-Butyl Ester (14)
To a vigorously stirred suspension of CuBr·DMS (0.114 g, 0.56
mmol) in anhyd Et2O (0.5 mL) was added a solution of (Z)-1-lithio-
1-propene (0.63 M in Et2O, 0.803 mL) via cannula at –50 °C under
an argon atmosphere. The resulting dark brown mixture was stirred
for 30 min at –50 °C before being cooled to –78 °C. BF3·Et2O
(0.074 mL, 0.56 mmol) was then added slowly. After 10 min, a so-
lution of 13 (0.098 g, 0.25 mmol) in anhyd Et2O (0.450 mL) was
then added dropwise via cannula. The black reaction mixture was
slowly allowed to warm to r.t. and stirred for 12 h. After this period
a mixture of sat. aq NH4Cl and concd NH4OH was then added. The
mixture was vigorously stirred for 45 min and extracted with
EtOAc. The combined organic layers were dried (Na2SO4), filtered
and the solvent was removed under reduced pressure. The residue
was purified by flash chromatography (EtOAc–petroleum ether,
2:8) to yield 14.
Yield: 0.020 g (61%); yellowish oil; [ ]D20 –9.5 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): = 1.48 [s, 9 H, C(CH3)3], 1.75 (m, 2
H, HCHCH2OAc, HCHCHCOOBu-t), 1.90 (m, 3 H, CH=CHCH3),
1.95 (m, 1 H, HCHCH2OAc), 2.10 (m, 4 H, HCCH2CH2OAc,
OCOCH3), 2.35 (m, 1 H, HCHCHCOO-t-Bu), 2.45 (m, 2 H,
CH2CHNHCbz), 4.10 (m, 2 H, CH2OAc), 4.32 (m, 1 H, CHCOO-t-
Bu), 4.60 (m, 1 H, CHNHCbz), 4.75 (m, 1 H, CHCH=CHCH3), 5.10
(m, 4 H, CH2Ph, CH=CH2), 5.30 (m, 1 H, NH), 5.40 (m, 1 H,
CH=CHCH3), 5.70 (m, 2 H, CH=CH2, CH=CHCH3), 7.35 (m, 5 H,
aromatics).
13C NMR (50.3 MHz, CDCl3): = 171.5, 171.0, 170.5, 157.0,
133.4, 131.2, 128.6, 128.1, 127.7, 118.3, 81.4, 66.9, 62.7, 61.3,
60.1, 51.3, 43.9, 33.1, 31.2, 28.0, 21.0, 13.5.
Yield: 0.064 (64%); yellowish oil; [ ]D20 +0.11 (c 1.03, CHCl3).
1H NMR (400 MHz, CDCl3): = 1.45 [s, 9 H, C(CH3)3], 1.50 [s, 9
H, C(CH3)3], 1.58 (m, 1 H, HCHCH2OAc), 1.60 (m, 1 H, HCHCH-
COO-t-Bu), 1.70 (m, 3 H, CH=CHCH3), 1.90 (m, 2 H,
HCHCH2OAc, HCCH2CH2OAc), 2.05 (s, 3 H OCOCH3), 2.40 (m,
1 H, HCHCHCOO-t-Bu), 4.10 (m, 2 H, CH2OAc), 4.20 (m, 1 H,
CHCOO-t-Bu), 4.38 (m, 1 H, CHCH=CHCH3), 5.30 (m, 1 H,
CH=CHCH3), 5.60 (m, 1 H, CH=CHCH3).
MS (FAB): m/z calcd for C29H40N2O7: 528.28; found: 529.
Anal. Calcd for C29H40N2O7 (528.28): C, 65.89; H, 7.63; N, 5.30.
Found C, 66.00; H, 7.64; N, 5.30.
(3S,7S,8R,10S)-1-Aza-2-oxo-3-benzyloxycarbonylamino-8-ace-
toxyethyl-10-carbo-tert-butoxybicyclo[5.3.0]decane (17)
To a solution of 16 (0.019 g, 0.0369 mmol) in anhyd CH2Cl2 (0.9
mL) under nitrogen was added Grubbs catalyst (0.004 g, 0.005
mmol). After stirring at 40 °C for 60 h, the solvent was evaporated
under reduced pressure. The crude was purified by flash chromatog-
raphy (EtOAc–petroleum ether, 35:65) to yield the cyclized prod-
uct.
13C NMR (100.6 MHz, HETCOR, CDCl3): = 131.5, 124.0, 63.1,
61.0, 60.5, 42.8, 34.3, 34.2, 31.6, 28.7, 28.3, 21.3, 13.7.
MS (FAB): m/z calcd for C21H35NO6: 397.25; found: 398.
Anal. Calcd for C21H35NO6 (397.25): C, 63.45; H, 8.87; N, 3.52.
Found C, 63.60; H, 8.88; N, 3.52.
Yield: 0.015 g (83%); yellowish oil; [ ]D20 –41.1 (c1.0, CHCl3).
(2S,4R)-4-(2-Acetoxyethyl)-5-[(Z)-propenyl]pyrrolidine-2-car-
boxylic Acid tert-Butyl Ester (15)
1H NMR (400 MHz, CDCl3): = 1.48 [s, 9 H, C(CH3)3], 1.70 (m, 1
H, HCHCHCOO-t-Bu ), 2.04 (m, 1 H, HCHCH2OAc), 2.08 (s, 3 H,
COCH3), 2.10 (m, 1 H, HCHCH2CH2OAc), 2.20 (m, 1 H, HCHCH-
NHCbz), 2.40 (m, 1 H, HCHCHCOO-t-Bu), 2.67 (m, 1 H,
HCHCH2OAc), 2.70 (m, 1 H, HCHCHNHCbz), 4.10 (m, 2 H,
CH2OAc), 4.30 (m, 2 H, CHCOO-t-Bu, CHCH=CH), 4.70 (m, 1 H,
CHNHCbz), 5.10 (m, 2 H, CH2Ph), 5.50 (m, 1 H, CHCH=CH), 5.7
(m, 1 H, CHCH=CH), 6.10 (m, 1 H, NH), 7.35 (m, 5 H, aromatics).
To a solution of 14 (0.034 g, 0.09 mmol) in t-BuOAc (0.85 mL), at
0 °C, HClO4 (0.077 mL, 0.13 mmol) was added. After 1 h, the reac-
tion was warmed to r.t. and stirred for 4 h, and then Et3N (0.6 mL)
was added. The mixture was extracted with EtOAc, the combined
organic layers were dried (Na2SO4), filtered and the solvent was re-
moved under reduced pressure. The residue was purified by flash
chromatography (EtOAc–petroleum ether, 8:2) to yield 15.
Yield: 79%; orange oil; [ ]D20 –6.7 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): = 1.48 [s, 9 H, C(CH3)3], 1.52 (m, 1
H, HCHCH2OAc), 1.55 (m, 1 H, HCHCHCOO-t-Bu), 1.76 (m, 3 H,
13C NMR (50.3 MHz, CDCl3): = 170.7, 170.2, 155.5, 136.6,
128.7, 128.6, 128.4, 128.2, 128.0, 81.9, 66.9, 62.4, 61.8, 61.3, 51.6,
44.2, 33.2, 32.2, 31.8, 31.1, 28.0, 21.1.
MS (FAB): m/z calcd for C26H34N2O7: 486.24; found: 487.
Synthesis 2003, No. 15, 2363–2367 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of a Functionalized 2-Oxo-1-azabicyclo[5.3.0]alkane
2367
Anal. Calcd for C26H34N2O7 (486.24): C, 64.18; H, 7.04; N, 5.76.
Found C, 64.30; H, 7.05; N, 5.75.
(8) For recent reviews for the use of lactam-based
peptidomimetics, see: (a) Hanessian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997,
53, 12789. (b) Halab, L.; Lubell, W. D. Biopolymers (Pept.
Sci.) 2000, 55, 101. (c) Kim, H.-O.; Kahn, M. Comb. Chem.
High Throughput Screening 2000, 3, 167.
To a solution of the cyclized compound (0.0249 g, 0.051 mmol) in
MeOH (0.5 mL) were added NiCl2·6 H2O (0.012 g, 0.051 mmol)
and NaBH4 (0.01 g, 0.256 mmol). After 1 h, silica gel was added
and the solvent was evaporated under reduced pressure. The residue
was purified by flash chromatography (EtOAc–petroleum ether,
4:6) to yield 17.
(9) For recent examples for the synthesis of bicyclic lactams,
see: (a) Manzoni, L.; Belvisi, L.; Scolastico, C. Synlett 2000,
1287. (b) Manzoni, L.; Colombo, M.; May, E.; Scolastico,
C. Tetrahedron 2001, 57, 249. (c) Beal, L. M.; Liu, B.; Chu,
W.; Moeller, K. D. Tetrahedron 2000, 56, 10113. (d) See
ref.4. (e) Hanessian, S.; McNaughton-Smith, G. Bioorg.
Med. Chem. Lett. 1996, 6, 1567. (f) Hanessian, S.; Ronan,
B.; Laoui, A. Bioorg. Med. Chem. Lett. 1994, 4, 1397.
(g) Kim, H.-O.; Nakanishi, H.; Lee, M. S.; Kahn, M. Org.
Lett. 2000, 2, 301. (h) Boatman, P. D.; Ogbu, C. O.; Eguchi,
M.; Kim, H. O.; Nakanishi, H.; Cao, B.; Shea, J. P.; Kahn,
M. J. Med. Chem. 1999, 42, 1367. (i) Wang, W.; Xiong, C.;
Hruby, V. J. Tetrahedron Lett. 2001, 42, 3159. (j) Gu, X.;
Tang, X.; Cowell, S.; Ying, J.; Hruby, V. J. Tetrahedron
Lett. 2002, 43, 6669. (k) Grossmith, C. E.; Senia, F.;
Wagner, J. Synlett 1999, 1660.
Yield: 0.021 g (80%); yellowish oil; [ ]D20 –24.9 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3):
= 1.30 (m,
2
H,
HCHCH2CH2CHNH), 1.48 [s, 9 H, C(CH3)3], 1.48 (m, 2 H,
CH2CHNH), 1.70 (m, 1 H, HCHCHCOO-t-Bu), 1.60–1.80 (m, 2 H,
HCHCHCOO-t-Bu, CH3COCH2HCH), 1.80–2.10 (m,
3 H,
HCHCH2CHNH, CH3COCH2HCH, CH3COCH2CH2HCH), 2.09 (s,
3 H, COCH3), 2.12 (m, 1 H, HCHCH2CHNH), 2.43 (m, 1 H, HCH-
CHCOO-t-Bu), 3.62 (m, 1 H, HCCH2CH2OAc), 4.11 (m, 2 H,
CH2OAc), 4.28 (m, 1 H, CHNHCbz), 4.33 (m, 1 H, CHCOO-
t-Bu), 5.11 (m, 2 H, CH2Ph), 6.28 (m, 1 H, NH), 7.35 (m, 5 H, aro-
matics).
13C NMR (50.3 MHz, CDCl3): = 171.2, 171.1, 170.7, 155.5,
136.7, 128.6, 128.1, 81.7, 66.7, 65.0, 62.6, 61.3, 55.0, 43.8, 35.1,
33.0, 32.5, 31.8, 28.1, 27.3, 21.1.
(10) (a) Polyak, F.; Lubell, W. D. J. Org. Chem. 2001, 66, 1171.
(b) Feng, Z.; Lubell, W. D. J. Org. Chem. 2001, 66, 1181.
(11) Artale, E.; Banfi, G.; Belvisi, L.; Colombo, L.; Colombo,
M.; Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59, 6241.
(12) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887.
MS (FAB): m/z calcd for C26H36N2O7: 488.25; found: 489.
Anal. Calcd for C26H36N2O7 (488.25): C, 63.92; H, 7.43; N, 5.73.
Found C, 63.98; H, 7.44; N, 5.73.
(13) Steger, M.; Young, D. W. Tetrahedron 1999, 55, 7935.
(14) (a) Celimene, C.; Dhimane, H.; Bail, M. L.; Lhommet, G.
Tetrahedron Lett. 1994, 35, 6105. (b) Skrinjar, M.; Nilsson,
C.; Wistrand, L.-G. Tetrahedron: Asymmetry 1992, 10,
1263. (c) Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K.
J. Org. Chem. 1986, 51, 2590. (d) Asada, S.; Kato, M.;
Asai, K.; Ineyama, T.; Nishi, S.; Izawa, K.; Shono, T. J.
Chem. Soc., Chem. Commun. 1989, 8, 486. (e) McClure, K.
F.; Renold, P.; Kemp, D. S. J. Org. Chem. 1995, 60, 454.
(f) Grossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999,
1660. (g) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org.
Chem. 1995, 60, 5011. (h) St-Denis, Y.; Augelli-Szafran, C.
E.; Bachand, B.; Berryman, K. A.; DiMaio, J.; Doherty, A.;
Edmunds, J. J.; Leblond, L.; Lévesque, S.; Narasimhan, L.
S.; Penvose-Yi, J. R.; Rubin, R. R.; Tarazi, M.; Winocour, P.
D.; Siddiqui, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 3193.
(i) Celimene, C.; Dhimane, H.; Lhommet, G. Tetrahedron
1998, 54, 10457. (j) Mulzer, J.; Schuelzchen, F.; Bats, J.-W.
Tetrahedron 2000, 56, 4289.
(15) Chiesa, M. V.; Manzoni, L.; Scolastico, C. Synlett 1996,
441.
(16) Carpino, L. A.; Mansour, E.-S. M. E.; Sadat-Aalaee, D. J.
Org. Chem. 1991, 56, 2611.
(17) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039.
(18) Fukui, H.; Tsuchiya, Y.; Fujita, K.; Nakagawa, T.; Koshino,
H.; Nakata, T. Bioorg. Med. Chem. Lett. 1997, 7, 2081.
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Acknowledgment
The authors thank CNR and MIUR (COFIN research programs) for
financial support.
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Synthesis 2003, No. 15, 2363–2367 © Thieme Stuttgart · New York