Unusual rearrangement of spiro β-lactams to 1,4-diazabicyclo[4,4,0] decanes and 1,4-diazabicyclo[4,3,0]nonanes. Synthesis of conformationally restricted σ-receptor ligands

Article abstract of DOI:10.1016/j.tetlet.2004.04.109

Synthesis of 1,4-diazabicyclo[4,4,0]decanes and 1,4-diazabicyclo[4,3,0] nonanes was achieved by using 4-formyl spiro β-lactams as easily available starting materials. Furthermore, the application of this protocol to the preparation of conformationally res

Full text of DOI:10.1016/j.tetlet.2004.04.109

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4657–4660
Unusual rearrangement of spiro b-lactams to
1,4-diazabicyclo[4,4,0]decanes and 1,4-diazabicyclo[4,3,0]nonanes.
Synthesis of conformationally restricted r-receptor ligands
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Alberto Macıas, Eduardo Alonso, Carlos del Pozo and Javier Gonzalez
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Departamento de Quımica Organica e Inorganica, Facultad de Quımica,Universidad de Oviedo, Julian Claverıa, 8, 33071 Oviedo, Spain
Received 30 March 2004;revised 19 April 2004;accepted 20 April 2004
Abstract—Synthesis of 1,4-diazabicyclo[4,4,0]decanes and 1,4-diazabicyclo[4,3,0]nonanes was achieved by using 4-formyl spiro b-
lactams as easily available starting materials. Furthermore, the application of this protocol to the preparation of conformationally
restricted r-receptor ligands was also performed. Theoretical calculations were carried out on a model reaction, in order to give
some understanding of the reaction mechanism.
Ó 2004 Elsevier Ltd. All rights reserved.
Nitrogen-containing heterocycles such as 1,4-diazabi-
cyclo[4,4,0]decanes and 1,4-diazabicyclo[4,3,0]nonanes
are remarkable structural units encountered in several
biologically active products (Fig. 1). Simple modifica-
tions in their skeletons impart intringuing biological
activities to the parent molecule. In this respect, several
different biological profiles were found in these pyrrolo
and pyrido pyrazines just by changing the substituent
placed at the nitrogen. Thus, compounds 1 were found
to be potent and selective 5-hydroxy tryptamine (5-HT6)
receptor antagonist and therefore, promising candidates
for the possible treatment of schizophrenia, depression
and memory dysfunction.1 Systems of type 2 that bear a
diethylamido group attached to the heterocyclic moiety
exhibited significant antifilarial activity.2 Nonachlazine
3 (n ¼ 1) is used in medical practice as an antianginal
agent.3 Finally, derivatives 4 constitute a series of con-
formationally restricted r-receptor ligands, which play a
significant role in mediating the behavioural and toxic
effects of cocaine4 (Fig. 1). Furthermore, compounds 4
were claimed for the treatment of central nervous system
(CNS) disorders such as cerebral ischaemia, psychoses
and convulsions.4
1, R =
N
SO2Ar
R
N
2, R =
3, R =
CO-NEt2
S
N
Cl
N
( )n
n=1,2
Additionally, these types of chiral diamines were used as
chiral ligands in the reduction of prochiral ketones by
treatment of a mixture of stannous chloride and a di-
amine with diisobutylaluminium hydride.5 Herein, we
wish to report the preparation of these types of hetero-
cyclic structures by means of an unusual rearrangement
of readily available 4-formyl spiro b-lactams. The
application of this protocol to the synthesis of the con-
formationally restricted r-receptor ligand 4 (n ¼ 1) will
be presented as well.
O
Cl
4, R =
Cl
Figure 1.
Keywords: Rearrangement;Spiro b-lactams;1,4-Diazabicyclo[4,4,0]-
decanes;1,4-Diazabicyclo[4,3,0]nonanes;Retro-Mannich reactions; r-
Receptors.
According to previous results from our group,6 b-lactam
8 (Scheme 1) was prepared by the [2+2]-cycloaddition of
* Corresponding authors. Tel.: +34-985103456;fax: +34-985103446;
e-mail: fjgf@uniovi.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.109

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A. Macıas et al. / Tetrahedron Letters 45 (2004) 4657–4660
4658
product rearranged under the reaction conditions to
afford the bicyclic systems 10 and 11, respectively, in
NPMP
1)
PMPN
O
R
excellent yields (Scheme 1).10
i)
7
( )n
N
Cbz
2) HCl 5%
With these data in hand, the enantioselective version of
the process was examined next. Recently, we have de-
scribed the preparation of enantiomerically pure spiro
b-lactam 13 by reaction of acid chloride 5 with chiral
imine 12a derived from glyceraldehyde acetonide
(Scheme 2).6b Removal of the PMP protecting group by
treatment with ammonium cerium(IV) nitrate (CAN),
followed by the standard protocol for the transforma-
tion of the dioxolane ring into the corresponding alde-
hyde,11 gave rise to the chiral starting aldehyde 18.
Hydrogenolysis of this spiro b-lactam led to the rear-
ranged product 20 in good yield. Reduction of com-
pound 20 to the bicyclic diamine 22 was previously
described by treatment with lithium aluminium
hydride12 (Scheme 2).
5 (n=1, R=Cl)
6 (n=2, R=OH)
O
( )n
( )n
N
H
H2/Pd-C
N
Cbz
N
N
O
PMP
AcOEt/MeOH 3/1
O
PMP
10 (n=1, 90%)
8 (n=1, 42%)
11 (n=2, 92%)
9 (n=2, 48%)
n=1: i) CH2Cl2/NEt3, -40ºC to r.t.
n=2: i) CH2Cl2/NEt3/PhSO2Cl, r.t.
Scheme 1.
the unsymmetrical cyclic ketene derived from N-benz-
yloxycarbonyl -proline acid chloride
Finally, we decided to apply this methodology to the
preparation of pyrrolopyrazine 4 (n ¼ 1) (Scheme 2),
compound that, as we have mentioned before, was
claimed for the treatment of CNS disorders.4 With this
purpose, we prepared imine 12b, which contains
attached to the nitrogen the aryl side chain present in the
target compound.
L
5
(n ¼ 1,
R ¼ Cl), with diimine 7. The reaction was carried out at
)40 °C to room temperature affording, after acidic work
up, the 4-formyl spiro b-lactam 8 as a 9/1 mixture of
diastereoisomers in 42% overall yield.7 The major
product showed a cis relative relationship between the
pyrrolidine nitrogen and the formyl substituent at the
carbon C4 of the azetidinone ring, as it was deduced
from the NOESY spectra of b-lactam 8.
Staudinger reaction with acid chloride 5 took place in a
modest 25% yield with good diastereoselectivity afford-
ing the expected spiro b-lactam 15 as a 9/1 mixture of
diastereoisomers. After chromatographic purification,
aldehyde 19 was prepared using the methodology
described before and then subjected to the rearrange-
ment conditions. The process took place nicely to afford
bicyclic system 21 that was reduced to the final diamine
4 by treatment with AlH2Cl13 (Scheme 2). In the process
of characterization of all the intermediates described
herein, we found out that optical rotation of compound
The cycloaddition reaction of N-benzyloxycarbonyl
D/L-pipecolinic acid 6 and diimine 7, using the benz-
enesulfonyl chloride method,8 afforded, after the acidic
hydrolysis, the 4-formyl spiro b-lactam 9 as a single cis
diastereoisomer (deduced from the NOESY spectra) in
48% overall yield. The starting spiro b-lactams 8, and 9
were subjected to hydrogenolysis by treatment with
hydrogen in the presence of palladium catalyst, and
after the expected removal of Cbz protecting group,9 the
O
O
O
OH
H
O
N
H
N
12
R
O
OH
p-TsOH
N
N
Cl
N
Cbz
NEt3/CH2Cl2
-78ºC to r.t.
THF/H2O
N
Cbz
Cbz
O
R
O
R
16, R=H (70 %)
17, R=Ar (80 %)
12a, R=PMP
12b, R=Ar
5
13, R=PMP (52 %)
14, R=H (65 %)
15, R=Ar (25 %)
CAN
NaIO4
H2O/MeOH
Cl
Cl
Ar=
O
H
H2/Pd-C
AlH2Cl
THF
N
N
N
H
N
Cbz
N
N
R
O
R
O
R
22, R=H
20, R=H (90 %)
18, R=H (50 %)
19, R=Ar (87 %)
4, R=Ar (70 %)
21, R=Ar (70 %)
Scheme 2.

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A. Macıas et al. / Tetrahedron Letters 45 (2004) 4657–4660
4659
the oxygen of the carbonyl group, forming the enol
intermediate H. In the transition structure I, the C3–C4
bond of the b-lactam is completely broken, while the CO
double bond is slightly elongated as compared with the
Cbz
H
O
O
OH
N
N
N
H
H
H2
N
N
N
O
R
O
R
O
R
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same bond in G (1.217 A). The normal mode associated
with the imaginary frequency of the transition structure
corresponds basically to the stretching movement of the
C3–C4 bond.15 The barrier for the ring-opening of the b-
lactam G is predicted to amount 8.7 kcal molÀ1;also, the
enol intermediate H is 3.6 kcal molÀ1 more stable than
the reactant.16 The reduced value of the activation
energy is in good agreement with the experimental evi-
dence indicating that the rearrangement of spiro b-lac-
tams A, takes place under mild conditions.
A
B
C
O
N
N
N
H2
H2
H
N
R
N
R
N
O
R
O
O
E
D
F
Scheme 3.
In the rearrangement of B to C, the sp3 C3 and C4
centres are transformed in sp2 ones, which originates the
lost of the stereochemical information. As the reduction
of the imine intermediate D is not stereoselective, the
final bicyclic compound F is obtained as a racemic
mixture.
20 was zero. This fact means that a racemization event
took place during the rearrangement, and therefore, that
we have prepared compound 20 in its racemic form.
With these considerations we proposed the mechanism
outlined in Scheme 3 as a plausible explanation for this
transformation.
In conclusion, preparation of 1,4-diazabicyclo[4,3,0]-
nonanes and 1,4-diazabicyclo[4,4,0]decanes by means of
an unusual rearrangement of readily available spiro
b-lactams was performed. The application of this pro-
tocol to the synthesis of the conformationally restricted
r-receptor ligand 4 (n ¼ 1) was carried out, although in
its racemic form since the process took place with
racemization at the carbon C3 of the initial 2-azetidi-
none ring.
After the initial removal of the Cbz group of A, a ‘retro-
Mannich’ process that involves the ring-opening of the
b-lactam in intermediate B took place. Hydrogenation
of the iminic functional group and further nucleophilic
addition of the secondary amine to the aldehyde group
affords the bicyclic enamine E. Finally, hydrogenation
of this enamine would lead to the bicyclic derivative F.
Theoretical calculations carried out at the Becke3LYP/
6-31G* level, support this assumption.14
Acknowledgements
The critical step of the mechanism outlined in Scheme 3,
the retro-Mannich reaction, was studied using the model
reaction showed in Scheme 4. The transition structure I
was found for the ring-opening of the model b-lactam G.
The hydrogen atom attached to the nitrogen of the
pyrrolidine ring in the spiro b-lactam G is transferred to
A.M. acknowledges a predoctoral fellowship from FI-
CYT (Regional Government of Principado de Asturias).
References and notes
H
O
1. Isaac, M.;Slassi, A.;Xin, T.;MacLean, N.;Wilson, J.;
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N
N
H
N
N
O
Me
O
Me
G
H
3. Nazarova, L. S.;Rozonov, Y. B.;Likhosherstov, A. M.;
Morozova, T. V.;Skoldinov, A. P.;Kaverina, N. V.;
Markin, V. A. Khim. Farm. Zh. 1985, 12, 811.
1.269 Å
1.619 Å
1.062 Å
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4. (a) De Costa, B. R.;Dom ınguez, C.;He, X. S.;Williams,
W.;Radesca, L.;Bowen, W. J. J. Med. Chem. 1992, 35,
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C3
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I
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Macıas, A.;Gonz alez, J. J. Org. Chem. 2001, 66, 6333;(b)
ꢀ
Scheme 4.

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A. Macıas et al. / Tetrahedron Letters 45 (2004) 4657–4660
4660
6.91 (m, 2H), 7.19 (m, 2H); 13C NMR (75 MHz, CDCl3) d
22.4, 25.0, 27.6, 49.9, 51.8, 55.4, 56.2, 66.3, 114.3, 127.2,
135.2, 158.1, 168.8;IR (KBr) 1651 cm À1;MS (EI) m=z (rel
intensity): 260 [(M), 25];HRMS calcd for C 15H20N2O2
260.1525. Found 260.1522.
ꢀ
Macıas, A.;Alonso, E.;del Pozo, C.;Venturini, A.;
Gonzalez, J., submitted for publication.
ꢀ
7. The ratio of diastereoisomers was determined by 1H NMR
analysis of the reaction crude.
8. It was not possible to prepare N-benzyloxycarbonyl
D/L-
pipecolinic acid chloride, so the generation of b-lactam 9
was performed by using the benzene sulfonyl chloride
11. (a) Alcaide, B.;Polanco, C.;Sierra, M. A. J. Org. Chem.
1998, 63, 6786;(b) Wagle, D. R.;Garai, C.;Monteleone,
M. G. Tetrahedron Lett. 1988, 29, 1649.
12. Paquette, L. A.;Scott, M. K. J. Org. Chem. 1968, 33,
2379.
method Sharma, S. D.;Kaur, V.;Saluja, A.
Chem. 1994, 624.
Indian J.
9. For a description of the methods available for the removal
the Cbz protecting group, see: Greene, T. W.;Wuts, P. G.
M. Protective Groups in Organic Synthesis;Wiley and
Sons: NY, 1999;pp 531–537.
10. General procedure for the synthesis of bicyclic systems
(10, 11, 20 and 21). The corresponding N-Cbz 4-for-
13. Yoon, N. M.;Brown, H. C. J. Am. Chem. Soc. 1968, 2927.
14. The calculations were carried out with the program
GAUSSIAN 98 was used: Gaussian 98, Revision A.11.3,
Frisch, M. J.;Trucks, G. W.;Schlegel, H. B.;Scuseria, G.
E.;Robb, M. A.;Cheeseman, J. R.;Zakrzewski, V. G.;
Montgomery, J. A., Jr.;Stratmann, R. E.;Burant, J. C.;
Dapprich, S.;Millam, J. M.;Daniels, A. D.;Kudin, K. N.;
Strain, M. C.;Farkas, O.;Tomasi, J.;Barone, V.;Cossi,
M.;Cammi, R.;Mennucci, B.;Pomelli, C.;Adamo, C.;
Clifford, S.;Ochterski, J.;Petersson, G. A.;Ayala, P. Y.;
Cui, Q.;Morokuma, K.;Rega, N.;Salvador, P.;Dannen-
berg, J. J.;Malick, D. K.;Rabuck, A. D.;Raghavachari,
K.;Foresman, J. B.;Cioslowski, J.;Ortiz, J. V.;Baboul,
A. G.;Stefanov, B. B.;Liu, G.;Liashenko, A.;Piskorz, P.;
Komaromi, I.;Gomperts, R.;Martin, R. L.;Fox, D. J.;
Keith, T.;Al-Laham, M. A.;Peng, C. Y.;Nanayakkara,
A.;Challacombe, M.;Gill, P. M. W.;Johnson, B.;Chen,
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myl b-lactam was dissolved in
a 3/1 mixture of
EtOAc/methanol and transferred via cannula to a flask
under H2 (1 atm) containing 20% weight of 10% Pd–C cat-
alyst. The mixture was stirred overnight, the catalyst
filtered off on Celite and the organic layer concen-
trated under vacuum to afford the diazabicyclic
compounds.
Selected characterisation. Compound 10: purified by acid–
base extraction, to afford 10 as a colourless oil, (90%
1
yield). H NMR (300 MHz, CDCl3) d 1.73–2.10 (m, 3H),
2.24 (m, 1H), 2.72 (m, 1H), 2.92–3.05 (m, 2H), 3.13 (dt,
J ¼ 11:9, J ¼ 4:3, 1H), 3.40 (t, J ¼ 8:0, 1H), 3.59 (dt,
J ¼ 11:9, J ¼ 4:3, 1H), 3.79 (s, 3H), 3.85 (m, 1H), 6.89 (d,
J ¼ 9:1, 2H), 7.18 (d, J ¼ 9:1, 2H); 13C NMR (75 MHz,
CDCl3) d 22.4, 27.4, 47.3, 49.5, 53.0, 55.3, 64.3, 114.3,
127.0, 134.9, 158.0, 170.4;IR (CH 2Cl2) 1656 cmÀ1;MS
(ESIþ) m=z (rel intensity): 269 [(M+Na), 20], 247 [(M+H),
100]. Compound 11: purified by recrystallization from
diethyl ether/hexane, to afford 11 as a white solid, (92%
yield). Mp ¼ 182–184 °C; 1H NMR (300 MHz, CDCl3) d
1.30–1.97 (m, 5H), 2.20 (dt, J ¼ 11:2, J ¼ 3:9, 1H), 2.42
(m, 1H), 2.97 (m, 2H), 3.42 (ddd, J ¼ 11:5, J ¼ 4:0,
J ¼ 1:2, 1H), 3.81 (s, 3H), 3.95 (dt, J ¼ 11:5, J ¼ 4:8, 1H),
15. All stationary points were fully optimized and character-
ized by performing the corresponding frequency calcula-
tions. G and H were showed to present only real
frequencies, while
()100.0 cmÀ1).
I had one imaginary frequency
16. The total energies (hartrees) of the stationary points
located are as follows: G ()571.99028), I ()571.97635), H
()571.99604).