[3+2] Cycloaddition reactions: A simple entry to the 1-aza-2-oxo-3,4,5,6- tetrahydroxybicyclo[3.3.0]octane ring system

Article abstract of DOI:10.1016/j.tetlet.2004.06.017

The [3+2] intramolecular nitrone cycloaddition (INC) reaction on appropriately designed olefinic nitrones derived from D-glucose, having the nitrone at C-1 and α,β-unsaturated ester functionalities at C-5 of the sugar backbone, afforded the isoxazolidine

Full text of DOI:10.1016/j.tetlet.2004.06.017

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5811–5814
[3+2] Cycloaddition reactions: a simple entry to the
1-aza-2-oxo-3,4,5,6-tetrahydroxybicyclo[3.3.0]octane ring system
Ashim Roy, Biswajit G. Roy, Basudeb Achari and Sukhendu B. Mandal*
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, India
Received 26 April 2004; revised 28 May 2004; accepted 3 June 2004
Abstract—The [3+2] intramolecular nitrone cycloaddition (INC) reaction on appropriately designed olefinic nitrones derived from
D
-glucose, having the nitrone at C-1 and a,b-unsaturated ester functionalities at C-5 of the sugar backbone, afforded the isoxazo-
lidine fused carbocycles 11–13, which were subsequently transformed into the chiral, tetrahydroxylated cis-azabicyclo[3.3.0]octa-
nones 14–18 in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
However, most of these methods involve long proce-
dures and the use of costly reagents so that the devel-
opment of expedient and flexible synthetic routes to
novel classes of enantiomerically pure bicyclic lactams
continues unabated. Literature reports as well as our
experience with the application of intramolecular nit-
Bicyclic lactams with the azabicyclo[3.3.0]octanone ring
system are reported to possess serine protease inhibitory
activity,1 and many of them are used as anxiolytics as
well to improve brain function.2 A bicyclic cis-lactam
having the (1S,5S)-2-azabicyclo[3.3.0]octane moiety3 is
the basic structural element of the angiotensin convert-
ing enzyme (ACE) inhibitor HOE 498. Furthermore,
hydrolytic ring opening of the cis-lactam of skeleton 1
could furnish novel restricted analogues4 of GABA,
which is regarded as a major inhibitory neurotransmit-
ter. There are many reports on the synthesis of these
compounds involving, among others, (i) cyclization of
trans-2-aminocyclopentane acetic acid with Mukai-
yama’s reagent under high dilution conditions,5 (ii)
tandem [4+2]/[3+2] cycloaddition of a nitroalkene to an
alkene followed by hydrogenolysis of the resulting cyclo-
adduct,6 (iii) iodolactamization of an olefinic amide
through an N,O-bis(trimethylsilyl)imidate derivative,7
(iv) addition of the ketene acetal or titanium enolate of a
2-pyridylthioester to an acyliminium ion followed by
ring closure,8 and (v) radical cyclization of an N-(1-cyclo-
alken-1-yl)-a-haloacetamide.9 Introduction of chirality
has been achieved by using chiral amino acids, by chiral
induction or by kinetic resolution of racemic mixtures.
rone cycloaddition (INC) reactions10;11 on various
D-
glucose derived substrates allowed us to envisage that an
appropriate a,b-unsaturated ester generated from a C-5
aldehyde should undergo prompt cycloaddition with a
nitrone at C-1 (formed by reaction of the latent aldehyde
with N-benzyl hydroxylamine). The reaction is expected
to be driven by the favourable interaction of the HOMO
of the nitrone component with the LUMO of the Z-
substituted olefin, leading to an isoxazolidine product 2.
Subsequent hydrogenolytic opening of the isoxazolidine
ring should be accompanied by spontaneous lactami-
zation, offering an expedient route to chiral cis-fused
bicyclic lactams 1. Figure 1 summarizes retrosyntheti-
cally our approach.
2. Results and discussion
5-Aldo-1,2-O-cyclohexylidene-a-
5-aldo-1,2-O-isopropylidene-a-
prepared from the respective dicyclohexylidene-/diace-
D
-glucofuranose (5) and
D
-glucofuranose (6) were
tone-D-glucose derivatives 3 and 4 through benzylation
Keywords: Nitrone cycloaddition reaction; Synthesis; Bicyclic lactams;
Azabicyclo[3.3.0]octane; D-glucose.
(PhCH2Br, CH2Cl2, 50% aq NaOH, n-Bu4NþBrꢀ, rt,
12 h) of the C-3–OH followed by selective deprotection
of the 5,6-ketal with 80% HOAc and vicinal diol
* Corresponding author. Tel.: +91-2473-3491; fax: +91-3347-35197;
e-mail: sbmandal@iicb.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.017

5812
A. Roy et al. / Tetrahedron Letters 45 (2004) 5811–5814
lactam 17. Acetylation of 15 and 17 furnished their
R
R
HO
HO
H
H
H
OH
CO2Me
tetra- and tri-acetate derivatives 16 and 18, respectively,
whose well-resolved 1H NMR spectra proved very
helpful in structure elucidation (Scheme 2).
HO
HO
O
RO
HO
O
N
N
H
H
Bn
2
1
The structures of the products were deduced unequivo-
cally from spectral studies. Of particular importance was
the finding that in the H NMR of 9, the b-hydrogen
R
R
O
MeO2C
HO
1
MeO2C
Bn
atom has a more downfield chemical shift (d 6.94 vs
6.40) and the H–C@C–H coupling constant is larger
(15.7 vs 11.7) when compared to those of 8, which set-
tled the orientation of the double bond in these com-
pounds. The d values for the b-hydrogens in 7 and 10
(6.89 and 7.06, respectively) are close to that of the
corresponding proton in 9, suggesting the geometry
shown.
O
OH
N
D- Glucose
RO
RO
OH
OH
Figure 1. Retrosynthetic analysis for the azabicyclo[3.3.0]octanone
ring system.
cleavage using NaIO4 in aq EtOH. The conjugated es-
ters used in this study were prepared by Wittig reactions.
Thus, treatment of 5 with 2-(triphenylphosphanylid-
ene)propionic acid ethyl ester led to the a,b-unsaturated
ester 712 (65%). In a similar manner, the aldehyde 6
afforded 10 (71%) with 2-(triphenylphosphanylid-
ene)succinic acid 1-methyl ester.13 However, a mixture
of olefinic compounds 8 (42%) and 9 (21%) resulted
when triphenylphosphanylidene acetic acid methyl ester
was reacted with 6 (Scheme 1).
The formation of the isoxazolidine rings in 11–13 was
1
concluded from their H and 13C NMR spectra. The IR
spectrum of 12 indicated the formation of a five-mem-
bered lactone ring (mmax at 1775 cmꢀ1), proving that the
hydroxyl (generated at C-4) and the carbomethoxy
groups must be on the same face of the intermediate
hydroxy ester. The stereochemistry at C-2, C-3 and C-4
(glucose numbering) in 12 should be the same as the
corresponding carbons in
D-glucose, as these were not
disturbed during the reaction sequence. As the two
olefinic protons in 8 were cis, they should also be cis
related in product 12.
Removal of protection from the 1,2 positions of 7, 8 and
10 created latent aldehydes at C-1, which were reacted
with N-benzyl hydroxylamine (followed by diazo-
methane treatment in the case of 10) to generate the
corresponding isoxazolidine derivatives 11–13 in good
yields, conceivably through spontaneous cyclization (the
INC reaction)14 of the expected nonisolable nitrones.
Subsequent reductive opening15 of the isoxazolidine
rings in 11 and 12 under hydrogenolytic conditions16
directly furnished the respective chiral bicyclic lactams
14 and 15. Similar reaction with 13 afforded the expected
The cis ring juncture shown is energetically favoured in
the case of the bicyclo[3.3.0]octane17 system. Molecular
modelling studies (Chem. Office 6.0 using the MM2
programme followed by molecular dynamics) revealed
that the minimum energy conformer of the cis isomer 14
has far less steric energy (12.9 kcal/mol) than its trans
isomer (26.4 kcal/mol). Similarly, the structures and
stereochemistries of 10 and 13 were concluded from the
O
O
EtO2C
O
O
O
Ph3P=C(CH3)CO2C2H5,
C6H6, rt, 4 h, N2
O
(i) BnBr, CH2Cl2, 50% NaOH,
n-Bu4N+ Br-, 16 h
H3C
O
H
H
O
H
O
HO
(ii) 80% HOAc, rt, 18 h
BnO
O
BnO
3
O
O
O
(iii) NaIO4, EtOH, H2O, 60 min
7
5
H3C
H3C
O
O
H3CO2C
O
O
O
Ph3P = C(CH2CO2H)CO2CH3,
C6H6, reflux, 4 h, N2
O
O
O
Identical reagents and
H
CH3
CH3
H
H
CH3
CH3
CH3
CH3
conditions used in the
CO2H
BnO
O
O
conversion of 3 to 5
HO
BnO
O
4
6
10
Ph3P = CHCO2CH3,
C6H6, reflux, 4 h, N2
H3CO2C
H
H
O
O
O
H3CO2C
O
H
H
BnO
CH3
CH3
CH3
O
O
BnO
CH3
9
8
Scheme 1. Preparation of olefin-esters 7–10.

A. Roy et al. / Tetrahedron Letters 45 (2004) 5811–5814
5813
H3C
HO
Me
HO
H
CO2C2H5
H
(i) 4% H2SO4, CH3CN-H2O
(3:1), 50oC, 4 h
OH
O
HO
3
3a
BnO
Pd/C (10%), cyclohexene,
EtOH, reflux, N2
O
7
(ii) N-BnNHOH, C6H6,
reflux, 4 h, N2
N
H
N
H
HO
H
HO
Bn
14
(60%)
(49%)
11
RO
H
O
H
H
OR
O
Pd/C (10%), cyclohexene,
EtOH, reflux, N2
H
RO
(i) 4% H2SO4, CH3CN-H2O
(3:1), rt, 24 h
O
BnO
N
O
8
H
H
(58%)
(ii) N-BnNHOH, C6H6,
reflux, 4 h, N2
N
RO
H
15, R = H
HO
Ac2O, Py,
rt, 12 h
Bn
16, R = Ac
(44%)
12
H3CO2C
RO
H3CO2C
OH
H
Pd/C(10%), cyclohexene,
MeOH, reflux, N2.
HO
(i) 4% H2SO4, CH3CN-H2O
(3:1), rt, 24 h
CO2CH3
RO
H
O
BnO
N
H
10
O
(50%)
H
(ii) N-BnNHOH, MeOH,
reflux, 4 h, N2
(iii) CH2N2, Et2O, CHCl3
RO
N
H
HO
17, R = H
Bn
Ac2O, Py,
rt, 12 h
13
18, R = Ac
(46%)
Scheme 2. Conversion of INC reaction products to bicyclic lactams.
stereochemistry of the olefin as well as from the absence
of a lactone moiety in the compounds, showing that the
C-4 OH and C-3 CO2CH3 groups are not close in space.
the Council of Scientific and Industrial Research for
providing a Junior Research Fellowship.
For the lactam 14, the cross peaks between C-3a H and
C-3 CH3 in its NOESY spectrum indicated their cis
relationship; the absence of similar peaks between C-3 H
and C-3a H in the NOESY spectrum of 15 suggested
their trans disposition. Likewise, the structure of 17 was
deduced based on its formation from 13.
References and notes
1. (a) Finch, H.; Pegg, N. A.; McLaren, J.; Lowdon, A.;
Bolton, R.; Coote, S. J.; Dyer, U.; Montana, J. G.; Owen,
M. R.; Dowle, M. D.; Buckley, D.; Ross, B. C.; Campbell,
C.; Dix, C.; Man-Tang, C.; Patel, C. Bioorg. Med. Chem.
Lett. 1998, 8, 2955; (b) Macdonald, S. J. F.; Clarke, G. D.
E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis,
G. A.; Johnson, M. R.; Shah, S.; Upton, R. J.; Walls, S. B.
J. Org. Chem. 1999, 64, 5166.
3. Conclusion
2. (a) Yamamoto, J.; Arima, T.; Kasahara, N.; Nanri, M.;
Ogawa, K.; Yamawaki, I.; Kaneda, M. US Patent
6004975, 1999; Chem. Abstr. 1999, 132, 35614; (b)
Yamamoto, J.; Arima, T.; Kasahara, N.; Nanri, M. PCT
Int. appl. WO9526187, 1995; Chem. Abstr. 1995, 124,
15493.
3. Linz, W.; Xiang, J.-Z.; Becker, R. H. A.; Scholkens, B. A.;
Unger, Th. Naunyn–Schmiedeberg’s Arch. Pharmacol.
1983, 324(Suppl.), R42.
4. (a) Chori, S.; Storici, P.; Schirmer, T.; Silverman, R. B. J.
Am. Chem. Soc. 2002, 124, 1620; (b) Krehan, D.; Frølund,
B.; Larsen, P. K.; Johnston, G. A. R.; Chebib, M.
Neurochem. Int. 2003, 42, 561.
In summary, we have developed a strategy to synthesize
chiral bicyclic lactam rings using intramolecular 1,3-
dipolar nitrone cycloaddition reactions on D-glucose
derived substrates. The simplicity and versatility of
precursor preparation, the feasibility of carrying out the
precursor assembly and the cycloaddition in a tandem
process, and the efficacy of the reaction make the pres-
ent approach one of the simplest and most practical to
such substituted azabicyclo[3.3.0]octanones. The scope
and limitation of the method for the synthesis of other
systems with different ring sizes is under study.
5. Kelly, H. A.; Bolton, R.; Brown, S. A.; Coote, S. J.;
Dowle, M.; Dyer, U.; Finch, H.; Goding, D.; Lowdon, A.;
McLaren, J.; Montana, J. G.; Owen, M. R.; Pegg, N. A.;
Ross, B. C.; Thomas, R.; Walker, D. A. Tetrahedron Lett.
1998, 39, 6979.
6. Denmark, S. E.; Moon, Y.-C.; Senanayake, C. B. W. J.
Am. Chem. Soc. 1990, 112, 311.
7. Knapp, S.; Levorse, A. J. Org. Chem. 1988, 53, 4006.
Acknowledgements
The work has been supported by a grant from the
Department of Science and Technology (Govt. of In-
dia). One of the authors (A.R.) gratefully acknowledges

5814
A. Roy et al. / Tetrahedron Letters 45 (2004) 5811–5814
8. Cooke, J. W. B.; Berry, M. B.; Caine, D. M.; Cardwell, K.
solution (50 mL) of the above crude residue was added N-
benzyl hydroxylamine (430 mg, 3.5 mmol) and the solution
was heated at reflux under N2 for 4 h. The crude obtained
after evaporation of the solvent was purified by chroma-
tography on a silica gel column using CHCl3–MeOH
(99.5:0.5) as eluent to afford 11 (725 mg) as a foamy
S.; Cook, J. S.; Hodgson, A. J. Org. Chem. 2001, 66, 334.
9. (a) Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.;
Ishibashi, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1
1992, 2399; (b) Ishibashi, H.; Fuke, U.; Yamashita, T.;
Ikeda, M. Tetrahedron: Asymmetry 1996, 7, 2531.
10. (a) Shing, T. K. M.; Zhong, Y.-L.; Mak, T. C. W.; Wang,
R.-J.; Xue, F. J. Org. Chem. 1998, 63, 414; (b) Bhatta-
charjee, A.; Datta, S.; Chattopadhyay, P.; Ghoshal, N.;
Kundu, A. P.; Pal, A.; Mukhopadhyay, R.; Chowdhury,
S.; Bhattacharjya, A.; Patra, A. Tetrahedron 2003, 59,
4623.
11. (a) Patra, R.; Bar, N. C.; Roy, A.; Achari, B.; Ghoshal,
N.; Mandal, S. B. Tetrahedron 1996, 52, 11265; (b) Bar, N.
C.; Roy, A.; Achari, B.; Mandal, S. B. J. Org. Chem. 1997,
62, 8948.
12. Typical procedure for a,b-unsaturated ester 7. 2-(Tri-
phenylphosphanylidene)propionic acid ethyl ester (2.87 g,
7.9 mmol) was added to a benzene solution of the aldehyde
5 (1.70 g, 5.3 mmol) and the mixture was stirred at rt under
N2 for 4 h. The solvent was evaporated in vacuo, and the
crude product was purified by chromatography over silica
gel eluting with CHCl3–Pet.ether (2:3) to afford 7 as a
material; [Found: C, 67.45; H, 6.76; N, 3.23. C24H29NO6
25
D
requires C, 67.43; H, 6.84; N, 3.28]; ½aꢁ )65.4 (c 0.58,
CHCl3); IR (KBr): mmax 3435, 1725, 1453, 1371, 1024,
740 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 1.27 (t, 3H,
;
J ¼ 7:1 Hz), 1.50 (s, 3H), 1.83 (br s, 1H, exchangeable),
2.35 (br s, 1H, exchangeable), 3.45 (m, 2H), 3.63 (t, 1H,
J ¼ 8:4 Hz), 3.86–3.94 (2H signal, one d merged at 3.88,
J ¼ 13:3 Hz), 4.04 (t, 1H, J ¼ 8:1 Hz), 4.21 (q, 2H,
J ¼ 7:1 Hz), 4.26 (d, 1H, J ¼ 13:3 Hz), 4.72 (d, 1H,
J ¼ 12:0 Hz), 4.78 (d, 1H, J ¼ 12:0 Hz), 7.34 (m, 10H).
13C NMR (CDCl3, 75 MHz): d 14.5, 18.5, 54.9, 60.1, 62.0,
71.9, 73.4, 73.5, 75.9, 84.2, 89.5, 128.0, 128.2 (2C), 128.3,
128.8 (2C), 128.9 (2C), 129.3 (2C), 137.1, 138.9, 174.8;
FABMS, m=z: 428 (Mþ+1).
15. Typical procedure for the reductive cleavage of the
isoxazolidine ring and removal of the benzyl group from
11. A mixture of 11 (300 mg, 0.7 mmol), (10%) Pd/C
(150 mg), cyclohexene (1.5 mL) and dry EtOH (25 mL) was
heated at reflux under N2 for 4 h. The catalyst was filtered
off, the solvent was evaporated and the crude product was
purified by reverse phase chromatography (adsorbent:
LiChroprepâ RP-18, particle size: 25–40 lm) using water
as eluent to yield 14 as a white solid (85 mg, 60%); mp 158–
25
D
1
colourless thick oil; ½aꢁ )36.8 (c 0.38, CHCl3); H NMR
(CDCl3, 300 MHz): d 1.31 (t, 3H, J ¼ 7:1 Hz), 1.40–1.74
(m, 10H), 1.81 (s, 3H), 3.95 (d, 1H, J ¼ 3:1 Hz), 4.24 (dq,
2H, J ¼ 0:6, 7.0 Hz), 4.47 (d, 1H, J ¼ 12:0 Hz), 4.64 (d,
1H, J ¼ 12:0 Hz), 4.65 (d, 1H, J ¼ 3:8 Hz), 4.92 (dd, 1H,
J ¼ 3:0, 7.7 Hz), 6.00 (d, 1H, J ¼ 3:7 Hz), 6.89 (dd, 1H,
J ¼ 1:4, 7.7 Hz), 7.29 (m, 5H); ESIþ, m=z: 425 (Mþ+Na).
13. Doulut, S.; Dubuc, I.; Rodriguez, M.; Vecchini, F.;
Fulcrand, H.; Barclli, H.; Cheeler, F.; Bourdel, E.;
Aumclas, A.; Lallement, J.-C.; Kitabgi, P.; Costentin, J.;
Martinez, J. J. Med. Chem. 1993, 36, 1369.
159 °C; [Found: C, 47.29; H, 6.38; N, 6.83. C8H13NO5
25
requires C, 47.29; H, 6.45; N, 6.89]; ½aꢁ )2.7 (c 0.29,
D
MeOH); IR (KBr): mmax 3374, 1693, 1248, 1495, 1103,
1010, 653 cmꢀ1; 1H NMR (D2O, 300 MHz): d 1.32 (s, 3H),
2.56 (t, 1H, J ¼ 8:8 Hz), 3.59 (dd, 1H, J ¼ 4:0, 8.4 Hz),
3.68 (dd, 1H, J ¼ 1:9, 6.2 Hz), 3.71 (dd, 1H, J ¼ 2:0,
6.6 Hz), 3.94 (t, 1H, J ¼ 8:8 Hz); 13C NMR (D2O,
75 MHz): d 25.2, 50.1, 56.9, 72.4, 74.5, 79.0, 81.2, 179.4;
FABMS, m=z: 204 (Mþ+1).
14. Typical procedure for INC reaction on 7. Compound 7
(1.40 g, 3.5 mmol) was dissolved in 4% H2SO4 in CH3CN–
H2O (3:1) mixture (20 mL) and kept at 50 °C for 4 h when
TLC showed complete disappearance of the starting
material. The solution was cooled to rt, neutralized with
solid CaCO3, filtered, and the solvent was evaporated
under reduced pressure to afford a crude residue (1.0 g),
which was dried over P2O5 in vacuo. To the benzene
16. Collins, P. M.; Ashwood, M. S.; Eder, H.; Wright, S. H.
B.; Kennedy, D. J. Tetrahedron Lett. 1990, 31, 2055.
17. Nasipuri, D. Stereochemistry of Organic Compounds;
Wiley Eastern: N. Delhi, 1992; p 316.