Synthesis of functionalized azabicycloalkane amino acids as dipeptide mimics

Article abstract of DOI:10.1055/s-2006-926370

Functionalized bicyclic lactams serve as building blocks for the synthesis of conformationally constrained peptides. A route to these building blocks is described based on the stereoselective alkylation of an appropriate azabicycloalkane; all possible dia

Full text of DOI:10.1055/s-2006-926370

PAPER
1133
Synthesis of Functionalized Azabicycloalkane Amino Acids as Dipeptide
Mimics
Functionalized
e
A
zabicyclo
o
alkanes nardo Manzoni,*a Laura Belvisi,b Eliana DiCarlo,c Alessandra Forni,a Donatella Invernizzi,b Carlo Scolastico*b
a
b
c
C.N.R., Istituto di Scienze e Tecnologie Molecolari (ISTM) and Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali
(CISI), Via Venezian 21, 20133 Milan, Italy
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano and Centro Interdisciplinare Studi biomolecolari e
applicazioni Industriali (CISI), Via Venezian 21, 20133 Milan, Italy
Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI), Via Venezian 21, 20133 Milan, Italy
Fax +39(0250)314072; E-mail: leonardo.manzoni@istm.cnr.it; E-mail: carlo.scolastico@unimi.it
Received 21 October 2005
Abstract: Functionalized bicyclic lactams serve as building blocks
for the synthesis of conformationally constrained peptides. A route
to these building blocks is described based on the stereoselective
alkylation of an appropriate azabicycloalkane; all possible diaste-
reoisomers can be obtained stereoselectively.
COOt-Bu
COOt-Bu
COOPG
N
N
n
n
N
n
O
O
O
NHCbz
N
NHPG
I
Key words: peptidomimetics, alkylations, lactams, bicyclic com-
pounds, diastereoselective synthesis
Ph
1 n = 1
2 n = 2
3 n = 1
4 n = 2
n = 0, 1, 2, 3
COOt-Bu
COOt-Bu
The synthesis of conformationally restricted amino acids
and their utilization in the synthesis of peptide conforma-
tion mimics, such as b-turn mimics, has been of consider-
able interest.1 Azabicyclo[X.3.0]alkane amino acids are
particularly attractive constrained dipeptide mimics be-
cause of their ability to serve as conformationally fixed
surrogates of peptide turn secondary structures.2 This has
created a demand for efficient synthetic approaches to-
wards such molecules and many methods for their synthe-
sis have been introduced.3–6 While studying peptide
secondary structure mimics, we have synthesized several
5,5-, 6,5-, 7,5-, and 8,5-fused 1-aza-2-oxobicyc-
lo[X.3.0]alkane amino acids7 (Figure 1, compound I), that
can be regarded as conformationally constrained substi-
tutes for Xaa-Pro or Ala-Xaa dipeptide units.
N
n
n
N
O
O
R
R
NHBn
NHBn
a (3R)
b (3S)
5,6 n =1
7,8 n =2
COOt-Bu
n
N
O
N
9 n = 1
10 n = 2
Ph
Figure 1 Bicyclic lactams.
The possibility of functionalizing these bicyclic lactams
with lipophilic appendages is very attractive because they
could improve peptide-receptor affinity by interacting
with hydrophobic pockets. We have already synthesized
benzyl-substituted lactams via both radical8 or nonradical9
approaches. However, a versatile large-scale protocol is
still required, thus, we began to investigate a new synthet-
ic method for the preparation of these bicyclic lactams. In
this paper, we report a convenient method for the synthe-
sis of trans- and cis-fused bicyclic lactams substituted
with a benzyl or allyl group at the C3 position.
In a preliminary communication10 we reported a stereose-
lective alkylation of a Schiff base amide enolate derived
from the known lactams 1 and 27a (Figure 1). N-Deprotec-
tion and treatment with benzaldehyde gives the corre-
sponding imines 3 and 4, which upon treatment with a
base and benzyl or allyl bromide yielded the alkyl deriva-
tives 5–8 after reduction with NaBH4 (Figure 1).
The stereoselectivity and the yield of the reaction can be
modulated using different bases or additives (Table 1). In
the case of the enolate derived from 3 with LiHMDS and
NaHMDS the major isomer isolated was the 3R isomer
5a; the yields can be increased by adding DMPU as co-
solvent. The stereoselectivity is totally reversed when a
bicoordinating Lewis acid such as MgBr2·Et2O is added to
the reaction mixture. In this case the main product is the
3S isomer 5b. By contrast, the benzylation of 4 affords the
3S isomer 7b selectively, independently of the reaction
conditions. A similar behavior can be observed with allyl
bromide as the alkylating reagent.
The excellent results obtained for trans-fused bicyclic lac-
tams encouraged us to extend the protocol to the cis series.
Thus, imines 9 and 10 were obtained from the known lac-
tams 11 and 12, respectively, using the same procedure re-
ported above. As observed in the trans series, due to the
SYNTHESIS 2006, No. 7, pp 1133–1140
x
x
.
x
x
.2
0
0
6
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926370; Art ID: P16905SS
© Georg Thieme Verlag Stuttgart · New York

1134
L. Manzoni et al.
PAPER
steric and electronic factors in compounds 9 and 10, the the 3S isomer 13b as the major product (Table 2, entry 1).
reaction with the base was regioselective, only the proton It is well known that the reactivity of alkali enolates is
at C3 was removed, and there was no epimerization at C9 strongly dependent on their coordination. The best results
or C10.
were obtained when the cation is solvated, thus, when the
reaction was performed in the presence of a polar aprotic
solvent such as DMPU, a slight effect on the yield and a
dramatic effect on the stereoselectivity (diastereomeric ra-
As shown in Table 2, the alkylation with benzyl bromide
conducted with LiHMDS on imine 9, proceeded with
moderate yields but with low stereoselectivity affording
Table 1 Reaction Conditions for the Alkylation of Compounds 3 and 4
1. Base, THF, –78 °C
2. RBr
COOt-Bu
n
COOt-Bu
COOt-Bu
N
N
n
N
n
+
O
O
O
3. NaBH4, MeOH
R
R
HN
HN
N
Ph
Ph
Ph
a (3R)
b (3S)
3 n = 1
4 n = 2
5,6 n = 1
7,8 n = 2
Entry
Imine
3
Base
T (°C)a
R
Products
5a/5b
5a/5b
5a/5b
5a/5b
5a/5b
5a/5b
5a/5b
5a/5b
5a/5b
6a/6b
6a/6b
6a/6b
6a/6b
6a/6b
7a/7b
7a/7b
7a/7b
7a/7b
7a/7b
7a/7b
8a/8b
8a/8b
8a/8b
Yield (%)
56
Ratio a/b (3R/3S)
92:8b
1
2
LiHMDS
–78→r.t.
–78→r.t.
–50
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
3
LiHMDS/DMPU
86
82:18b
90:10b
75:25b
81:19b
31:69b
5:95b
3
3
LiHMDS
89
4
3
NaHMDS
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–50→–20
–78→r.t.
–78→r.t.
–50
55
5
3
NaHMDS/DMPU
KHMDS
81
6
3
24
7
3
LiHMDS/Mg2+
LiHMDS/Mg2+
LiHMDS/Sn2+
LiHMDS
43
8
3
43
>2:98b
21:79b
89:11c
84:16c
84:16c
7:93c
9
3
33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2Ph
75
3
LiHMDS
90
3
LiHMDS/DMPU
LiHMDS/Mg2+
LiHMDS/Mg2+
LiHMDS
–78→r.t.
–78→r.t.
–50→–20
–78→r.t.
–50
78
3
55
3
45
<2:>98c
21:79c
40:60c
10:90c
20:80c
9:91c
4
53
4
LiHMDS
CH2Ph
82
4
NaHMDS
–78→r.t.
–50→–20
–78→r.t.
–78→r.t.
–78→r.t.
–50
CH2Ph
81
4
NaHMDS
CH2Ph
73
4
NaHMDS/DMPU
LiHMDS/Mg2+
LiHMDS
CH2Ph
59
4
CH2Ph
68
<2:>98c
54:46c
55:45c
6:94c
4
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
67
4
LiHMDS
67
4
LiHMDS/Mg2+
–78→r.t.
20
a Base was added at –78 °C, then bromide was added at the reported temperature.
b Ratio determined by 1H NMR spectroscopy.
c Ratio determined by HPLC.
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

PAPER
Functionalized Azabicycloalkanes
1135
Table 2 Reaction Conditions for the Alkylation of Compounds 9 and 10
1. Base, THF, –78 °C
2. RBr
COOt-Bu
COOtBu
COOt-Bu
N
N
N
n
n
+
O
O
O
3. NaBH4, MeOH
R
R
HN
HN
N
Ph
Ph
Ph
9
a (3R)
b (3S)
13,14 n = 1
15 n = 2
COOt-Bu
N
O
N
Ph
10
Entry
Imine
Base
T (°C)a
R
Products
13a/13b
13a/13b
13a/13b
13a/13b
13a/13b
14a/14b
14a/14b
15a/15b
15a/15b
Yield (%)
Ratio a/b (3R/3S)
1
2
3
4
5
6
7
8
9
9
9
LiHMDS
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
–78→r.t.
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
60
69
81
58
72
63
42
30
40
39:61
17:83
23:77
7:93
LiHMDS/DMPU
NaHMDS
9
9
KHMDS
9
LiHMDS/Mg2+
LiHMDS
9:91
9
CH2CH=CH2
CH2CH=CH2
CH2Ph
10:90
<2:>98
>98:<2
>99:<1
9
LiHMDS/Mg2+
LiHMDS
10
10
LiHMDS/Mg2+
CH2Ph
a Base was added at –78 °C, then bromide was added at the reported temperature.
b Ratio determined by 1H NMR spectroscopy.
tio 17:83 in favor of the 3S stereoisomer), were observed tively the 3R isomer 15a in good yield and diastereoiso-
(Table 2, entry 2).
meric ratio. The only effect of the Lewis acid was to
enhance the yield (Table 2, entries 8 and 9).
Changing the counterion from lithium to sodium affected
both the yield, which increased to 81%, and the diastereo- The stereochemical outcome of the alkylation reaction
selectivity toward the 3S isomer 13b (Table 2, entry 3). can be assigned, as in the case of the trans series, by in-
When KHMDS was used as the base, a high diastereose- voking a pseudo-axial attack11 onto the lowest energy
lectivity in favor of the 3S isomer 13b was observed, ac- conformers obtained from ab initio calculation12 for the
companied by only a moderate yield (Table 2, entry 4).
bicyclic intermediate enolates. The preferred conforma-
tions of the enolates derived from 9 and 10 feature a pseu-
do-chair conformation for the bicyclic ring (Figure 2). If
pseudo-axial attack is hypothesized the products should
be the 3S isomer 13b and 3R isomer 15a, respectively.
The pure isomer 13b was obtained by recrystallization
from diethyl ether and its absolute configuration was as-
signed by X-ray structure analysis (Figure 3).13
A dramatic effect both on the yield and on the stereoselec-
tivity was observed when the enolate was generated with
LiHMDS in the presence of a bicoordinating Lewis acid
such as MgBr2·Et2O (Table 2, entry 5). The 3S isomer 13b
was obtained in 72% yield and 9:91 diastereoisomeric ra-
tio.
In contrast to what was observed for the 6,5-fused trans
series, the addition of a Lewis acid did not reverse the ste-
reochemistry. This behavior could be explained by postu-
lating that the preferred conformation of the enolate was
not affected by the presence of a Lewis acid or at least was
the same with or without coordinating metals. The allyla-
tion of 9 gave the same results: the presence of
MgBr2·Et2O enhanced the diastereoisomeric ratio al-
though with a moderate drop in yield (Table 2, entries 6
and 7). In contrast, the benzylation of 10 afforded selec-
The conformation of the fused five- and six-membered
rings of isomer 13b was determined according to the Cre-
mer and Pople puckering analysis.14 The conformation of
the five-membered ring is very near an envelope with
atom C7 as the flap [q2 = 0.404(2) Å, f2 = 76.6(3)°, q2 be-
ing the puckering amplitude and f2 the phase angle]. The
six-membered ring adopts a conformation intermediate
between envelope, with C5 as the flap, and half-chair,
with C5 pointing up and C4 pointing down with respect to
the mean plane of the ring [the puckering parameters in
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

1136
L. Manzoni et al.
PAPER
Figure 3 ORTEP plot of isomer 13b with atom numbering scheme.
Displacement ellipsoids at 30% probability level.
For compounds 14b and 15a the stereochemistry of the
newly formed stereocenters was assigned by NOE exper-
iments (Figure 4). In compound 14b the NOE between the
benzylamine protons and H9 result in the relative config-
uration 3S at C3. In compound 15a a NOE between the
benzyl proton, of the substituent at C3, and H7 unequivo-
cally attributes the stereochemistry at C3 as 3R.
9
8
7
8
9
H
Figure 2 (a) B3LYP/6-31++G minimum energy conformation of
the enolate derived from 6,5-fused lactam 9. (b) B3LYP/6-31++G mi-
nimum energy conformation of the enolate derived from 7,5-fused
lactam 10.
10
7
6
COOt-Bu
COOt-Bu
6
1N
2
1N
5
4
H
H
5
2
3
4
3
O
O
H
H
H
HN
13b
HN
Ph
Ph
Ph
this case are Q = 0.490(2) Å, q = 43.4(1)°, f = 225.0(3)°].
The puckering analysis on the fused rings of the
(3S,6S,9S)-diastereoisomer previously reported,10 which
differs from 13b only for the configuration at C6, indicat-
ed an intermediate twisted-envelope conformation and an
almost perfect envelope with C2 as the flap for the five-
and six-membered rings, respectively [q2 = 0.297(4) Å,
f2 = 242(1)°; Q = 0.469(4) Å, q = 54(1)°, f = 65(1)°].
The conformational differences observed in the azabicy-
clo moiety of the two diastereoisomers, together with the
different spatial disposition of the tert-butoxycarbonyl,
benzyl, and benzylamino groups, can be ascribed to their
different crystal packing.
15a
Figure 4 NOE in compounds 14b and 15a.
In conclusion we have found a new versatile method for
the functionalization of the C3 position of azabicycloal-
kanes based on a stereoselective alkylation of a Schiff
base amide enolate. With this method it is possible to ob-
tain the desired functionalized azabicycloalkane by
changing the base and/or adding coordinating metals to
the reaction mixture.
All chemicals and solvents were of reagent grade and were used
without further purification. Solvents were dried by standard proce-
dures and reactions requiring anhydrous conditions were performed
under N2 or Ar. Optical rotations were measured in a cell of 1 dm
path length and 1 mL capacity on a Perkin-Elmer 241 polarimeter.
1H and 13C NMR spectra were recorded at 300 K on a Bruker
AVANCE-400 or Bruker AC-300 or AC-200 spectrometer. Chem-
ical shifts are expressed in ppm relative to TMS as internal standard.
On the basis of an absolute stereogenic center of the mol-
ecule, as shown in Figure 3, the X-ray structure of com-
pound 13b clearly indicated that the benzyl group is cis to
the tert-butoxycarbonyl group, which implied a 3S config-
uration.
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

PAPER
Functionalized Azabicycloalkanes
1137
MS were determined with a VG 7070 EQ-HF apparatus. TLC was
carried out with precoated Merck F254 silica gel plates. Flash chro-
matography was carried out with Macherey-Nagel silica gel 60
(230–400 mesh). Elemental analyses were performed by the staff of
the microanalytical laboratory of our department.
(3S,6R,9S)-1-Aza-2-oxo-3-benzylidenamino-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (9)
Yield: 90% (2 steps); white solid.
1H NMR (200 MHz, CDCl3): d = 1.31 (s, 9 H, t-Bu), 1.60–2.13 (m,
8 H), 3.53 (m, 1 H, CHN), 3.95 (m, 1 H, CHN=CHPh), 4.23 [dd,
J = 7.2, 1.7 Hz, 1 H, CH(COOt-Bu)], 7.35 (m, 2 H, Ar), 7.72 (m, 3
H, Ar), 8.43 (s, 1 H, N=CHPh).
Lactams 3, 4, 9, and 10; General Procedure
A solution of NCbz-protected lactam (1.07 mmol) in MeOH (11
mL) containing 10% Pd/C (cat.) was stirred overnight under H2. The
catalyst was then removed by filtration through a pad of celite and
washed with MeOH. The filtrate was concentrated to dryness under
reduced pressure. The crude was dissolved in anhyd CH2Cl2 (11
mL) and anhyd Et3N (299 mL, 2.14 mmol). MgSO4 (64 mg) and
freshly distilled benzaldehyde (217 mL, 2.14 mmol) were then add-
ed. After 24 h at r.t. the mixture was filtered through a pad of celite
and washed with CH2Cl2. The solvent was removed under reduced
pressure to a volume of 10 mL and an equal volume of hexane was
added. The organic layer was washed with a sat. solution of
NaHCO3 (2 × 20 mL), H2O (2 × 20 mL), and brine (2 × 20 mL), then
dried over Na2SO4 and concentrated under reduced pressure. The
crude was used without further purification.
13C NMR (50.3 MHz, CDCl3): d = 171.2, 167.6, 163.1, 136.5,
130.7, 128.6, 128.5, 81.2, 66.5, 60.8, 59.8, 31.9, 30.0, 28.3, 27.9,
25.5.
FAB-MS: m/z calcd for C20H27N2O3 [M + 1]+: 343.43; found: 343.
Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18. Found: C,
70.16; H, 7.64; N, 8.18.
(3S,7R,10S)-1-Aza-2-oxo-3-benzylidenamino-9-(tert-butoxy-
carbonyl)bicyclo[5.3.0]decane (10)
Yield: 85% (2 steps); white solid.
1H NMR (200 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 1.55–2.40 (m,
10 H), 3.80 (m, 1 H, CHN), 4.12 (m, J = 9.8, < 1 Hz, 1 H, t-Bu), 4.56
(m, 1 H, CHN=CH), 7.40 (m, 3 H, Ar), 7.80 (m, 2 H, Ar), 8.23 (s, 1
H, N=CHPh).
13C NMR (50.3 MHz, CDCl3): d = 172.1, 162.2, 134.6, 130.8,
129.9, 129.2, 128.7, 128.5, 81.3, 72.9, 61.4, 58.9, 34.8, 33.4, 32.8,
28.3, 28.2, 27.9.
(3R,6S,9S)-1-Aza-2-oxo-3-benzylidenamino-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (3)
Yield: 92% (2 steps); white solid.
1H NMR (200 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 1.48–2.40 (m,
8 H), 3.75 (m, 1 H, CHN), 3.99 (m, 1 H, CHN=CHPh), 4.38 [dd, J =
8.5, 8.5 Hz, 1 H, CH(COOt-Bu)], 7.3–7.7 (m, 5 H, Ar), 8.34 (s, 1 H,
N=CHPh).
13C NMR (50.3 MHz, CDCl3): d = 172.0, 167.2, 163.4, 136.3,
130.9, 129.2, 128.7, 128.6, 81.6, 67.5, 60.7, 59.1, 33.1, 29.8, 28.2,
27.8, 25.3.
FAB-MS: m/z calcd for C21H29N2O3 [M + 1]+: 357.21; found: 357
Anal. Calcd for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86. Found: C,
70.77; H, 7.93; N, 7.85.
Alkylation; General Procedure A
To a solution of imine (0.2 mmol) in anhyd THF (2 mL) under an
Ar atmosphere, cooled to –78 °C, base (0.3 mmol) was added and
the temperature was adjusted according to Table 1. After 20 min
alkyl bromide was added and the solution was stirred for 3–5 h. H2O
(2 mL) was added and the mixture was extracted with EtOAc (3 × 2
mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The crude was dissolved in
MeOH (4 mL) and NaBH4 (2 mmol) was added in small portions.
After 15 min the solvent was evaporated under reduced pressure
and the crude was purified by flash chromatography (hexane–
EtOAc, 7:3).
FAB-MS: m/z calcd for C20H27N2O3 [M + 1]+: 343.43; found: 343.
Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18. Found: C,
70.20; H, 7.66; N, 8.18.
(3R,7S,10S)-1-Aza-2-oxo-3-benzylidenamino-9-(tert-butoxy-
carbonyl)bicyclo[5.3.0]decane (4)
Yield: 94% (2 steps); white solid.
1H NMR (200 MHz, CDCl3): d = 1.42 (s, 9 H, t-Bu), 1.45–2.41 (m,
10 H), 4.03 (m, 1 H, CHN), 4.21 (m, 1 H, CHN=CHPh), 4.51 [m, 1
H, CH(COOt-Bu)], 7.37 (m, 5 H, Ar), 8.22 (s, 1 H, N=CHPh).
13C NMR (50.3 MHz, CDCl3): d = 172.2, 171.6, 162.3, 136.4,
130.8, 129.2, 128.7, 128.5, 81.1, 72.9, 61.3, 58.6, 58.5, 35.1, 33.0,
32.7, 32.5, 28.2, 27.4, 27.1.
Alkylation; General Procedure B
To a solution of imine (0.2 mmol) in anhyd THF (2 mL) and DMPU
(5 mmol) under an Ar atmosphere, cooled to –78 °C, base (0.3
mmol) was added and the temperature was adjusted according to
Table 1. After 20 min alkyl bromide was added and the solution was
stirred for 3–5 h. H2O (2 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 2 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The
crude was dissolved in MeOH (4 mL) and NaBH4 (2 mmol) was
added in small portions. After 15 min the solvent was evaporated
under reduced pressure and the crude was purified by flash chroma-
tography (hexane–EtOAc, 7:3).
FAB-MS: m/z calcd for C21H29N2O3 [M + 1]+: 357.21; found: 357.
Anal. Calcd for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86. Found: C,
70.78; H, 7.92, N, 7.86.
(3R,6R,9S)-1-Aza-2-oxo-3-benzylidenamino-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (9)
Yield: 95% (2 steps); white solid.
1H NMR (200 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 1.70–2.27 (m,
8 H), 3.78 (m, 1 H, CHN), 3.97 (dd, J = 7.5, 7.5 Hz, 1 H,
CHN=CHPh), 4.35 [m, 1 H, CH(COOt-Bu)], 7.41 (m, 2 H, Ar),
7.75 (m, 3 H, Ar), 8.41 (s, 1 H, N=CHPh).
13C NMR (50.3 MHz, CDCl3): d = 171.3, 167.7, 164.5, 136.2,
130.9, 128.6, 128.5, 128.4, 81.3, 69.7, 60.4, 59.6, 31.8, 30.5, 28.5,
28.2, 28.1.
Alkylation; General Procedure C
To a solution of imine (0.2 mmol) in anhyd THF (2 mL) under an
Ar atmosphere, cooled to –78 °C, base (0.3 mmol) was added and
the temperature was adjusted according to Table 1. After 20 min
Lewis acid (MgBr2·Et2O or SnCl2) was added and after a further 20
min alkyl bromide was added and the solution was stirred for 3–5 h.
H2O (2 mL) was added and the mixture was extracted with EtOAc
(3 × 2 mL). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure. The crude was dissolved
in MeOH (4 mL) and NaBH4 (2 mmol) was added in small portions.
FAB-MS: m/z calcd for C20H27N2O3 [M + 1]+: 343.43; found: 343.
Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18. Found: C,
70.18; H, 7.64; N, 8.19.
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

1138
L. Manzoni et al.
PAPER
After 15 min the solvent was evaporated under reduced pressure
and the crude was purified by flash chromatography (hexane–
EtOAc, 7:3).
13C NMR (75.4 MHz, CDCl3): d = 171.7, 133.4, 130.9, 128.7,
128.4, 127.1, 118.7, 111.1, 81.4, 61.6, 60.1, 59.1, 48.1, 45.3, 44.1,
33.2, 29.7, 29.2, 28.0, 26.5.
FAB-MS: m/z calcd for C23H33N2O3 [M + 1]+: 385.51; found: 385.
(3R,6S,9S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[4.3.0]nonane (5a)
Anal. Calcd for C23H32N2O3: C, 71.84; H, 8.39; N, 7.29. Found: C,
71.86; H, 8.40; N, 7.28.
[a]D20 –107.1 (c = 1.05, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.51 (m, 1 H), 1.03 (m, 1 H), 1.49
(s, 9 H, t-Bu), 1.61–2.20 (m, 5 H), 2.31 (m, 1 H), 2.81 (d, J = 12.8
Hz, 1 H, PhCHHC), 3.26 (d, J = 12.8 Hz, 1 H, PhCHHC), 3.60 (m,
1 H, CHN), 3.74 (d, J = 11.6 Hz, 1 H, PhCHHNH), 3.80 (d, J = 11.6
Hz, 1 H, PhCHHNH), 4.41 [dd, J = 8.6, 8.6 Hz, 1 H, CH(COOt-
Bu)], 7.19–7.40 (m, 10 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 172.7, 172.0, 140.7, 137.4,
130.4, 128.8, 128.6, 128.3, 127.1, 126.9, 81.5, 62.6, 59.9, 59.7,
48.2, 47.2, 33.5, 29.3, 28.3, 28.2, 26.6.
(3R,7R,10S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[5.3.0]decane (7a)
Mp 113–114 °C; [a]D20 –20.1 (c = 1.06, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.49 (s, 9 H, t-Bu), 1.64–1.78 (m,
3 H), 1.78–1.96 (m, 4 H), 2.12 (m, 1 H), 2.38 (m, 2 H), 2.92 (d,
J = 13.6 Hz, 1 H, PhCHHC), 3.13 (d, J = 13.6 Hz, 1 H, PhCHHC),
3.61 (d, J = 12.5 Hz, 1 H, PhCHHNH), 3.70 (d, J = 12.5 Hz, 1 H,
PhCHHNH), 4.14 (m, 1 H, CHN), 4.55 [dd, 1 H, J = 8.4, 2.0 Hz,
CH(COOt-Bu)], 7.17–7.43 (m, 10 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 174.3, 172.1, 141.8, 136.4,
131.6, 128.3, 128.2, 127.9, 126.6, 81.2, 65.8, 62.3, 57.1, 48.1, 44.6,
34.4, 32.5, 32.2, 28.2, 26.5, 22.6.
FAB-MS: m/z calcd for C27H35N2O3 [M + 1]+: 435.57; found: 435.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C,
74.60; H, 7.88; N, 6.44.
FAB-MS: m/z calcd for C28H37N2O3 [M + 1]+: 449.60; found: 449.
(3S,6S,9S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[4.3.0]nonane (5b)
Anal. Calcd for C28H36N2O3: C, 74.97; H, 8.09; N, 6.24. Found: C,
74.96; H, 8.08; N, 6.24.
Mp 104–106 °C; [a]D20 –37.0 (c = 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.51 (s, 9 H, t-Bu), 1.65–2.12 (m,
7 H), 2.26 (m, 1 H), 2.98 (d, J = 13.1 Hz, 1 H, PhCHHC), 3.23 (d,
J = 13.1 Hz, 1 H, PhCHHC), 3.43 (m, 1 H, CHN), 3.72 (d, J = 12.0
Hz, 1 H, PhCHHNH), 3.84 (d, J = 12.0 Hz, 1 H, PhCHHNH), 4.41
[dd, J = 8.6, 8.6 Hz, 1 H, CH(COOt-Bu)], 7.20–7.37 (m, 10 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 171.9, 171.6, 137.0, 131.2,
128.5, 128.4, 128.2, 127.1, 126.6, 81.4, 61.0, 60.1, 59.5, 48.2, 44.7,
33.3, 30.5, 28.2, 28.1, 27.1.
(3S,7R,10S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[5.3.0]decane (7b)
[a]D20 +36.4 (c = 1.11, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.44 (s, 9 H, t-Bu), 1.49 (m, 3 H),
1.58–1.72 (m, 3 H), 1.80–1.97 (m, 2 H), 2.12 (m, 1 H), 2.29 (m, 1
H), 2.92 (d, J = 14.1 Hz, 1 H, PhCHHC), 3.54 (d, J = 14.1 Hz, 1 H,
PhCHHC), 3.96 (d, J = 12.1 Hz, 1 H, PhCHHNH), 4.04 (d, J = 12.1
Hz, 1 H, PhCHHNH), 4.55 [dd, J = 8.4, 3.7 Hz, 1 H, CH(COOt-
Bu)], 3.84 (m, 1 H, CHN), 7.15–7.70 (m, 10 H, Ar).
FAB-MS: m/z calcd for C27H35N2O3 [M + 1]+: 435.57; found: 435.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C,
74.61; H, 7.88; N, 6.45.
13C NMR (50.3 MHz, CDCl3): d = 174.5, 171.6, 141.0, 138.4,
131.5, 131.2, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
128.0, 126.3, 81.0, 64.0, 62.7, 57.6, 47.7, 40.3, 35.7, 33.1, 32.7,
29.9, 28.3, 26.9, 23.0.
(3R,6S,9S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (6a)
FAB-MS: m/z calcd for C28H37N2O3 [M + 1]+: 449.60; found: 449.
[a]D20 –37.3 (c = 1.00, CHCl3).
Anal. Calcd for C28H36N2O3: C, 74.97; H, 8.09; N, 6.24. Found: C,
74.99; H, 8.10; N, 6.25.
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 1.50 (m, 1 H),
1.76 (m, 1 H), 1.88–2.19 (m, 3 H), 2.18 (m, 1 H), 2.26–2.43 (m, 3
H), 2.54 (m, 1 H), 3.61 (m, 1 H, CHN), 3.61 (d, J = 11.7 Hz, 1 H,
PhCHHNH), 3.70 (d, J = 11.7 Hz, 1 H, PhCHHNH), 4.43 [dd, J =
8.6, 8.6 Hz, 1 H, CH(COOt-Bu)], 5.11 (m, 2 H, CH=CH2), 5.90 (m,
1 H, CH=CH2), 7.20–7.34 (m, 5 H, Ar).
13C NMR (75.4 MHz, CDCl3): d = 171.9, 171.3, 140.4, 134.0,
129.1, 128.7, 128.3, 128.0, 126.9, 118.7, 81.3, 60.0, 59.7, 59.4,
51.1, 48.2, 45.3, 33.2, 30.4, 28.1, 28.0, 27.8.
(3R,7R,10S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[5.3.0]decane (8a)
[a]D20 –54.0 (c = 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 9 H, t-Bu), 1.63–1.98 (m,
8 H), 2.12 (m, 1 H), 2.29 (m, 1 H), 2.49 (m, 1 H, CHHCH=CH2),
2.58 (m, 1 H, CHHCH=CH2), 3.68 (d, J = 11.6 Hz, 1 H, PhCHH-
NH), 3.73 (d, J = 11.6 Hz, 1 H, PhCHHNH), 4.07 (m, 1 H, CHN),
4.53 [dd, J = 8.3, 3.8 Hz, 1 H, CH(COOt-Bu)], 5.14 (m, 2 H,
CH=CH2), 5.88 (m, 1 H, CH=CH2), 7.26–7.42 (m, 5 H, Ar).
13C NMR (75.4 MHz, CDCl3): d = 171.8, 135.0, 128.6, 128.4,
128.3, 126.9, 118.9, 81.3, 63.1, 57.7, 48.2, 48.0, 35.2, 34.8, 32.8,
32.3, 29.9, 28.2, 26.5, 22.6.
FAB-MS: m/z calcd for C23H33N2O3 [M + 1]+: 385.51; found: 385.
Anal. Calcd for C23H32N2O3: C, 71.84; H, 8.39; N, 7.29. Found: C,
71.85; H, 8.39; N, 7.30.
(3S,6S,9S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (6b)
FAB-MS: m/z calcd for C24H35N2O3 [M + 1]+: 399.54; found: 399.
Mp 75–77 °C; [a]D20 –71.8 (c = 0.99, CHCl3).
Anal. Calcd for C24H34N2O3: C, 72.33; H, 8.60; N, 7.03. Found: C,
72.34; H, 8.60; N, 7.04.
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 9 H, t-Bu), 1.50 (m, 1 H),
1.79 (m, 1 H), 1.88–2.19 (m, 4 H), 2.22–2.55 (m, 4 H), 3.68 (d,
J = 11.7 Hz, 1 H, PhCHHNH), 3.74 (m, 1 H, CHN), 3.78 (d,
J = 11.7 Hz, 1 H, PhCHHNH), 4.40 [dd, J = 8.6, 8.6 Hz, 1 H,
CH(COOt-Bu)], 5.10 (m, 2 H, CH=CH2), 5.87 (m, 1 H, CH=CH2),
7.16–7.43 (m, 5 H, Ar).
(3S,7R,10S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[5.3.0]decane (8b)
[a]D20 +14.9 (c = 1.04, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 9 H, t-Bu), 1.44–2.34 (m,
10 H), 2.43 (dd, J = 14.4, 7.3 Hz, 1 H, CHHCH=CH2), 2.87 (dd,
J = 14.4, 7.3 Hz, 1 H, CHHCH=CH2), 3.73 (d, J = 12.7 Hz, 2 H,
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

PAPER
Functionalized Azabicycloalkanes
1139
PhCH2NH), 4.49 [dd, J = 8.3, 4.4 Hz, 1 H, CH(COOt-Bu)], 4.79
(m, 1 H, CHN), 5.16 (m, 2 H, CH=CH2), 5.86 (m, 1 H, CH=CH2),
7.20–7.40 (m, 5 H, Ar).
13C NMR (75.4 MHz, CDCl3): d = 174.4, 171.4, 141.1, 134.5,
128.7, 128.3, 126.8, 118.7, 111.4, 80.7, 67.0, 62.8, 62.5, 58.5, 57.5,
47.1, 44.7, 40.3, 35.5, 33.1, 29.7, 28.0, 26.8, 22.7.
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 9 H, t-Bu), 1.69–1.85 (m,
2 H), 1.94–2.06 (m, 5 H), 2.12 (m, 1 H), 2.54 (m, 2 H,
CH2CH=CH2), 3.59 (m, 1 H, CHN), 3.62 (d, J = 12.2 Hz, 1 H, Ph-
CHHNH), 3.70 (d, J = 12.2 Hz, 1 H, PhCHHNH), 4.37 [dd, J = 9.4,
< 1 Hz, 1 H, CH(COOt-Bu)], 5.11 (m, 2 H, CH=CH2), 6.00 (m, 1 H,
CH=CH2), 7.20–7.40 (m, 5 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 171.3, 133.6, 129.5, 129.0,
128.7, 128.6, 127.4, 119.0, 81.5, 61.5, 60.7, 60.3, 59.3, 52.3, 48.0,
43.9, 31.9, 29.9, 28.7, 28.1, 26.7.
FAB-MS: m/z calcd for C24H35N2O3 [M + 1]+: 399.54; found: 399.
Anal. Calcd for C24H34N2O3: C, 72.33; H, 8.60; N, 7.03. Found: C,
72.35; H, 8.61; N, 7.04.
FAB-MS: m/z calcd for C23H33N2O3 [M + 1]+: 385.51; found: 385.
(3R,6R,9S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[4.3.0]nonane (13a)
[a]D20 –114.7 (c = 1.02, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.48 (s, 9 H, t-Bu), 1.53–2.30 (m,
8 H), 2.51 (m, 1 H, CHN), 2.85 (d, J = 12.6 Hz, 1 H, PhCHHC),
3.06 (d, J = 12.6 Hz, 1 H, PhCHHC), 3.80 (s, 2 H, PhCH2NH), 4.24
[dd, J = 7.2, 1.7 Hz, 1 H, CH(COOt-Bu)], 7.15–7.43 (m, 10 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 172.7, 171.7, 140.6, 136.7,
130.9, 128.9, 128.5, 128.4, 128.3, 128.0, 127.9, 127.1, 126.9, 81.4,
61.9, 59.9, 59.7, 49.1, 47.1, 31.5, 30.2, 29.9, 28.6, 28.4, 28.2, 28.1.
Anal. Calcd for C23H32N2O3: C, 71.84; H, 8.39; N, 7.29. Found: C,
71.83; H, 8.38; N, 7.29.
(3R,7S,10S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[5.3.0]decane (15a)
[a]D20 –105.5 (c = 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H, t-Bu), 1.47–2.42 (m,
10 H), 2.80 (d, J = 13.2 Hz, 1 H, PhCHHC), 3.06 (d, J = 13.2 Hz, 1
H, PhCHHC), 3.37 (m, 1 H, CHN), 3.67 (d, J = 11.2 Hz, 1 H, Ph-
CHHNH), 3.73 (d, J = 11.2 Hz, 1 H, PhCHHNH), 4.39 [dd,
J = 8.2, 8.0 Hz, 1 H, CH(COOt-Bu)], 7.11–7.38 (m, 10 H, Ar).
13C NMR (50.3 MHz, CDCl3): d = 173.6, 172.0, 136.6, 130.5,
128.7, 128.5, 128.3, 128.1, 127.8, 127.0, 126.9, 81.2, 66.5, 63.2,
57.1, 48.8, 45.2, 33.6, 32.7, 31.5, 31.1, 29.9, 28.1, 27.1, 22.9, 22.1.
FAB-MS: m/z calcd for C27H35N2O3 [M + 1]+: 435.57; found: 435.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C,
74.61; H, 7.88; N, 6.45.
FAB-MS: m/z calcd for C28H37N2O3 [M + 1]+: 449.60; found: 449.
(3S,6R,9S)-1-Aza-2-oxo-3-benzylamino-3-benzyl-9-(tert-but-
oxycarbonyl)bicyclo[4.3.0]nonane (13b)
Anal. Calcd for C28H36N2O3: C, 74.97; H, 8.09; N, 6.24. Found: C,
74.98; H, 8.09; N, 6.25.
Mp 161–163 °C; [a]D20 –35.5 (c = 1.06, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.51 (s, 9 H, t-Bu), 1.79–2.13 (m,
8 H), 2.98 (d, J = 14.0 Hz, 1 H, PhCHHC), 3.10 (d, J = 14.0 Hz, 1
H, PhCHHC), 3.57 (m, 1 H, CHN), 3.61 (d, J = 12.5 Hz, 1 H, Ph-
CHHNH), 3.68 (d, J = 12.5 Hz, 1 H, PhCHHNH), 4.35 [dd, J = 9.0,
< 1 Hz, 1 H, CH(COOt-Bu)], 7.20–7.33 (m, 10 H, Ar).
Acknowledgment
The authors thank CNR and MIUR for financial support.
13C NMR (75.4 MHz, CDCl3): d = 173.1, 171.4, 140.8, 136.8,
131.2, 130.8, 128.7, 128.2, 128.1, 127.8, 126.7, 126.4, 81.1, 62.2,
60.5, 59.7, 59.0, 48.0, 44.6, 31.8, 29.7, 28.8, 28.6, 28.3, 28.0, 26.3.
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FAB-MS: m/z calcd for C27H35N2O3 [M + 1]+: 435.57; found: 435.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C,
74.63; H, 7.90; N, 6.44.
(3R,6R,9S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (14a)
[a]D20 –68.7 (c = 0.64, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 9 H, t-Bu), 1.76 (m, 1 H),
1.93–2.24 (m, 7 H), 2.39 (m, 2 H, CH2CH=CH2), 3.51 (m, 1 H,
CHN), 3.72 (d, J = 11.1 Hz, 1 H, PhCHHNH), 3.78 (d, J = 11.7 Hz,
1 H, PhCHHNH), 4.36 [dd, J = 8.8, < 1 Hz, 1 H, CH(COOt-Bu)],
5.14 (m, 2 H, CH=CH2), 5.78 (m, 1 H, CH=CH2), 7.20–7.40 (m, 5
H, Ar).
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128.5, 127.0, 119.2, 81.4, 60.6, 60.4, 60.0, 49.0, 48.1, 45.7, 44.2,
31.8, 30.2, 29.9, 28.7, 28.6, 28.1, 26.8.
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FAB+MS: m/z calcd for C23H33N2O3 [M + 1]+: 385.51; found: 385.
Anal. Calcd for C23H32N2O3: C, 71.84; H, 8.39; N, 7.29. Found: C,
71.85; H, 8.38; N, 7.28.
(3S,6R,9S)-1-Aza-2-oxo-3-benzylamino-3-allyl-9-(tert-butoxy-
carbonyl)bicyclo[4.3.0]nonane (14b)
[a]D20 –42.9 (c = 1.07, CHCl3).
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York

1140
L. Manzoni et al.
PAPER
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(12) (a) Ab initio geometry optimizations were performed at the
B3LYP/6-31++G level using Gaussian 03: Frisch, M. J.;
Frisch, A.; Trucks, G. W. Gaussian 03; Gaussian Inc.:
Pittsburgh PA, 2003. (b) Starting conformation for the 6,5-
cis and 7,5-cis fused enolates derived from 9 and 10 were
generated by molecular mechanics calculations using,
Macromodel Version 5.5 Program: Mohamadi, F.; Richards,
N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440. (c) Implementation of the AMBER
force field: Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.;
Case, D. A. J. Comput. Chem. 1986, 7, 230.
(13) X-ray data of isomer 13b were collected on a Bruker Smart
Apex CCD area detector using graphite-monochromated
Mo-Ka radiation (l = 0.71073 Å). Data reductions were
made using SAINT programs. The structures were solved by
SIR-92 and refined on F2 by full-matrix least-squares using
SHELXL-97. Crystal data: C27H34N2O3, Mr = 434.56,
colorless prism 0.34 × 0.16 × 0.13 mm, orthorhombic,
P212121, a = 10.3435 (9), b = 13.0923 (12), c = 17.8267 (15)
Å, V = 2414.1 (4) Å3, Z = 4, T = 150 (2) K, m = 0.078 mm–1;
13026 measured reflections, 4274 independent reflections,
2859 reflections with I>2s(I), 3.86<2q <64.26°, Rint = 0.041.
Refinement on 4274 reflections, 391 parameters. Final R =
0.0424, wR = 0.0801 for data with F2>2s(F2), (D/s)max
=
0.001, Drmax = 0.29, Drmin = –0.20 eÅ–3. Tables of atomic
coordinates, anisotropic thermal parameters, bond lengths
and angles of isomer 13b may be obtained free of charge
from The Director CCDC, 12 Union Road, Cambridge CB2
1 EZ, UK, on quoting the deposition number CCDC 285315,
the names of the authors, and the journal citation [fax:+44
(1223)336033; e-mail: deposit@ccdc.cam.ac.uk; web site:
http://www.ccdc.cam.ac.uk].
(14) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354.
Synthesis 2006, No. 7, 1133–1140 © Thieme Stuttgart · New York