A novel application of a [3+2] cycloaddition reaction for the synthesis of the piperazinone rings of pseudotheonamides A1 and A2

Article abstract of DOI:10.1016/S0040-4039(02)00133-8

A novel approach to synthesize the piperazinone ring system of pseudotheonamide A₁ and A₂ is described. The key step is the intramolecular [3+2] cycloaddition reaction of a suitably orientated azide and an α,β-unsaturated ester.

Full text of DOI:10.1016/S0040-4039(02)00133-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1897–1900
A novel application of a [3+2] cycloaddition reaction for
the synthesis of the piperazinone rings of pseudotheonamides
A1 and A2
Mukund K. Gurjar,* Sukhen Karmakar, Debendra K. Mohapatra and Usha D. Phalgune
National Chemical Laboratory, Pune 411 008, India
Received 11 October 2001; revised 7 January 2002; accepted 18 January 2002
Abstract—A novel approach to synthesize the piperazinone ring system of pseudotheonamide A1 and A2 is described. The key step
is the intramolecular [3+2] cycloaddition reaction of a suitably orientated azide and an a,b-unsaturated ester. © 2002 Elsevier
Science Ltd. All rights reserved.
The four major classes of protease enzymes1–4 (aspartic,
serine, cysteine and metallo) selectively catalyze the
hydrolysis of polypeptide bonds. Proteases of these
classes are also crucial for disease propagation, and
inhibitors of such proteases are emerging with promis-
ing therapeutic uses.3,5 Among them, serine protease
inhibitors are useful for the treatment of diseases like
cancer,6–8 viral infections (e.g. HIV,9–11 hepatitis,12,13
herpes14,15), and neurodegenerative disorders including
Alzheimer’s disease.16 To be effective as biological
tools, protease inhibitors must not only be very potent
but also highly selective in binding to a particular
protease.
Our retrosynthesis (Scheme 1) evolved from the strat-
egy of disconnection of amide bonds leading to piper-
azinone derivative (3) and piperadinoiminoimidazolone
(4), as key intermediates. This communication describes
a first synthetic approach to obtain the syn- and anti-
piperazinone moieties present in pseudotheonamides A1
(1) and A2 (2), respectively.
A dipolar cycloaddition reaction was chosen as the
preferred strategy for controlling issues related to stere-
ochemistry and regiochemistry.18 For assembling the
Recently, Fusetani and co-workers17 have isolated pseu-
dotheonamides from the marine sponge Theonella swin-
hoe, which possess potent serine protease inhibitor
activity. Their absolute stereochemistry was determined
by exhaustive spectroscopic studies coupled with chemi-
cal degradation. Interestingly, the mode of action of
these natural products was elucidated by X-ray crystal-
lographic studies of the complex between cyclotheon-
amide
A
and human a-thrombin or trypsin.
Pseudotheonamides A1 and A2 are characterized by
novel piperazinone and piperadinoiminoimidazolone
ring systems. The novel structural features and pro-
nounced inhibitory properties of pseudotheonamides
A1 and A2 (Fig. 1) have attracted our attention for
synthetic investigations.
Keywords: azides; enamines; olefins; stereoselective; Dess–Martin
reagents.
* Corresponding author. Tel.: +91-20-5893614; fax: +91-20-5882456;
e-mail: gurjar@dalton.ncl.res.in
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00133-8

1898
M. K. Gurjar et al. / Tetrahedron Letters 43 (2002) 1897–1900
Scheme 1. Retrosynthetic analysis of pseudotheonamide A2.
functional groups, the cycloaddition reaction between an
azide and an a,b-unsaturated ester was selected for
investigation.19 It is pertinent to mention that methods
to synthesize the piperazinones, substituted at position
C-3 are found in the literature,20 however, the correspond-
ing 3,5-disubstituted compounds are rather rare.
followed by saponification with LiOH in methanol
provided the desired (R)-a-azido acid (6) (Scheme 2).
p-Methoxyphenylalaninol (7) was prepared (Scheme 2)
following standard reaction conditions.24
The coupling reaction (Scheme 3) of p-methoxyphenyl-
alaninol (7) with the (R)-a-azido acid (6) promoted with
DCC–HOBT in CH2Cl2 provided the required dipeptide
(15) along with the dipeptide ester (16) as a minor
component. Subsequent hydrolysis of 16 with LiOH in
methanol gave an additional quantity of 15. The resulting
alcohol was then exposed to Dess–Martin periodinane
oxidation to obtain the aldehyde 17. The crude aldehyde
17 was subjected to a two carbon homologation with
(ethoxycarbonylmethylene)triphenylphosphorane to fur-
nish the a,b-unsaturated ester (5) (Scheme 3) in 92%
overall yield.
Our first concern was the preparation of the (R)-a-azido
acid (6) for which an efficient and practical synthetic route
was contemplated involving well known reactions.21
Accordingly, the asymmetric dihydroxylation of methyl
cinnamate (8) using (DHQD)2–PHAL as a chiral ligand
proceeded in 92% yield and 98% ee (HPLC).22,23 The
resulting (2S,3R)-dihydroxy derivative (9) was subjected
to reduction of the benzylic hydroxyl group with Raney®
Ni in refluxing ethanol to give the (2S)-hydroxy derivative
(10) as the exclusive product. Nucleophilic displacement
of the mesylate with sodium azide in DMF at 60°C
Scheme 2. (a) (DHQD)2–PHAL, CH3SO2NH2, K3Fe(CN)6, K2CO3, OsO4, t-BuOH:H2O (2:1), 0°C, 11 h, 92%; (b) Raney Ni,
ethanol (degassing), reflux, 3 h, 81%; (c) (i) MsCl, Et3N, CH2Cl2, 0°C–rt, 4 h; (ii) NaN3, DMF, 60°C, 6 h, 86% (two steps); (d)
LiOH, MeOH, rt, 1 h, 94%; (e) Boc2O, KOH, dioxane:H2O (1:1), rt, 6 h, 92%; (f) Me2SO4, K2CO3, acetone, reflux, 7 h, 90%; (g)
LiCl, NaBH4, EtOH:THF (2:1), 4 h, 87%; (h) 15% HCl, EtOAc, 0°C–rt, 1 h, 86%.

M. K. Gurjar et al. / Tetrahedron Letters 43 (2002) 1897–1900
1899
Scheme 3. (a) DCC, HOBT, CH2Cl2, 0°C–rt, 16 h, 82%; (b) LiOH, MeOH, rt, 30 min, 94%; (c) Dess–Martin periodinane,
CH2Cl2, rt, 7 h; (d) Ph3PꢀCHCO2Et, CH2Cl2, rt, 12 h, 92% (two steps).
Scheme 4. (a) Et3N (catalytic), toluene, reflux, 7 h, 56%; (b) NaCNBH3, MeOH, 5% HCl, 0°C, rt, 2 h, 90%.
In conclusion, we have demonstrated the applicability
of an intramolecular 1,3-dipolar cycloaddition reaction
of an azide with an a,b-unsaturated ester for the syn-
thesis of the 3,5-disubstituted piperazinone ring system
present in pseudotheonamide A1 and A2. Our work
represents a first synthesis of the piperazinone ring
system present in pseudotheonamides A1 and A2
(Scheme 4). The synthesis of pipradinoiminoimida-
zolone 4 leading to the total synthesis of pseudotheon-
amides A1 and A2 is in progress.
Our next plan was to optimize the cycloaddition reac-
tion of the azido group on the double bond followed by
elimination of nitrogen to give the enamine system.
Satisfactory results were obtained when compound 5
was heated under reflux in toluene containing a cata-
lytic amount of triethylamine.25,26 The structure of 18
was established by 1H NMR, 13C NMR and mass
spectroscopic analysis.
Finally, reduction of the enamine bond of 18 was
carried out with sodium cyanoborohydride27 in
methanol while maintaining the pH at 4 with intermit-
tent addition of 5% HCl to give a 3:7 mixture of
piperazinones (3A1) and (3A2), which were easily sepa-
rated by silica gel column chromatography. The struc-
ture and relative stereochemistries of 3A1 and 3A2 were
Acknowledgements
The Council of Scientific and Industrial Research, New
Delhi is acknowledged for the financial assistance
(D.K.M. and S.K.).
1
determined by NMR studies.28 For example, in the H
NMR spectrum of 3A1, the peak corresponding to the
proton Tyr Hb, appeared at l 3.00, and showed cou-
pling with the Tyr Hg (proton attached to the g-carbon
relative to the carbonyl group of ester) with J=9.0 Hz
indicating the trans relationship. NOE studies on 3A1
showed the interaction of Tyr Hb with Phe Ha confirm-
ing the syn geometry of the piperazinone ring system.
In addition, 13C NMR and mass spectral data further
substantiated the assigned structure of compound 3A1.
In a similar manner the structure of the other
diastereomer was established as 3A2. It is pertinent to
mention that catalytic hydrogenation over Pt–C in
methanol at 50 psi provided 3A2 in a 9:1 diastereomeric
ratio.
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13
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1
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