Amino acid derived heterocycles: Lewis acid catalyzed and radical cyclizations from peptide acetals

Article abstract of DOI:10.1021/jo010990m

Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an effective alternative for the synthesis of 5 (n = 0, 1, 2). Additional versatility in this process was demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic praziquantel, 8.

Full text of DOI:10.1021/jo010990m

J . Org. Chem. 2002, 67, 3985-3988
3985
Am in o Acid Der ived Heter ocycles: Lew is Acid Ca ta lyzed a n d
Ra d ica l Cycliza tion s fr om P ep tid e Aceta ls
Matthew H. Todd,† Chudi Ndubaku, and Paul A. Bartlett*
Center for New Directions in Organic Synthesis,‡ Department of Chemistry, University of California,
Berkeley, California 94720-1460
paul@fire.cchem.berkeley.edu
Received October 10, 2001
Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic
acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and
peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed
readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in
good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an
effective alternative for the synthesis of 5 (n ) 0, 1, 2). Additional versatility in this process was
demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic
praziquantel, 8.
Sch em e 1. Acid -In d u ced Cycliza tion s to
Heter ocycles 2, 5, a n d 6
The cyclization of simple, peptide-based precursors to
generate rigid scaffolds as peptidomimetics and combi-
natorial chemistry motifs has been the focus of several
recent investigations.1-3 In this context, we have de-
scribed the efficient and stereoselective cyclization of
acetal-containing N-(hydroxyacyl)amino acid analogues
(e.g., 1) in the presence of protic acid, leading to bicyclic
lactams such as 2 (Scheme 1). Such readily varied
structures show considerable promise as combinatorial
motifs and as â-turn mimetics.4
We sought to extend this chemistry to encompass a
new synthetic route (3 f 5) involving ring closure by
nucleophilic attack of an aromatic ring on the acylimin-
ium ion intermediate 4 instead of a heteroatom.2,4-5
However, acid-catalyzed cyclization of the phenylalanine
derivatives (e.g., 3, R ) Bn) does not generate the tricyclic
ring system as anticipated; instead, the aromatic ring of
the side chain attacks the cation to give the bridged
structures 6. The structure of this ring system was
deduced by comparison with the N-acetyl derivative (6,
R′ ) Me) prepared in a similar fashion and assigned by
X-ray analysis. This ring system is of potential interest
as an alternative combinatorial template and bears some
resemblance to the core of the saframycin antibiotic
group.6 A variety of conditions and substrates were thus
explored to optimize the reaction and also to determine
if closure to the fused-ring system could be favored.
A range of common protic acids and solvent combina-
tions was assayed for the cyclization, and methane-
sulfonic acid in nitromethane (1:4) was found to give the
best results. The substrates were varied both in the
length of the phenylacyl side chain and its electron
density (Table 1), in the expectation that increasing
either of these parameters would enable this aromatic
ring to compete better with the amino acid side chain.
Indeed, cyclization to the fused-ring isomer occurs to a
limited extent when methoxy groups are attached to the
phenylacetyl group (series e and f). However, three
methoxy groups are required before this mode of cycliza-
tion predominates, and even then the reaction proceeds
in low yield.
† Correspondence regarding the praziquantel work should be ad-
dressed to M.H.T. Current address: Department of Chemistry, Queen
Mary, University of London, Mile End, London E1 4NS, United
Kingdom.
‡ The Center for New Directions in Organic Synthesis is supported
by Bristol-Myers Squibb as a Sponsoring Member.
(1) Creighton, C. J .; Zapf, C. W.; Bu, J . H.; Goodman, M. Org. Lett.
1999, 1, 1407.
(2) Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.;
Kahn, M. J . Am. Chem. Soc. 1999, 121, 12204.
(3) Spaller, M. R.; Burger, M. T.; Fardis, M.; Bartlett, P. A. Curr.
Opin. Chem. Biol. 1997, 1, 47.
(4) Smith, L. R.; Bartlett, P. A. Molecules Online 1998, 2, 58.
(5) For a review of N-acyliminium cyclizations see Speckamp, W.
N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
The preference for cyclization to the bridged- over the
fused-ring system, which dominates electronic consider-
ations, reflects conformational influences. A conforma-
tional search7 of dihydropyrazinone 7d (H in place of Br),
(6) Myers, A. G.; Kung, D. W. J . Am. Chem. Soc. 1999, 121, 10828.
10.1021/jo010990m CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/30/2002

3986 J . Org. Chem., Vol. 67, No. 12, 2002
Todd et al.
Sch em e 2. Lew is Acid a n d Ra d ica l-Ba sed
Ta ble 1. Com p etition betw een Cycliza tion P a th w a ys for
Acylim in iu m Ion s 4 (R ) Bn )a
Ap p r oa ch es to F u sed Rin g Sca ffold 5
series
n
Y
yield of 5 (%)
yield of 6 (%)
a
b
c
d
e
f
0
1
1
1
1
1
2
2-Br
H
4-NO2
2-Br
3-MeO
3,4,5-(MeO)3
H
0
0
0
87
75
72
79
61
9c
0
11b
18c
0
g
67
Ta ble 2. F or m a tion of Dih yd r op yr a zin on es 7 a n d
Ra d ica l Cycliza tion to F u sed -Rin g P r od u cts 5
a
Treatment of 4 (R ) Bn) with MeSO3H/CH3NO2 (1:4) at 60
°C for 16 h. 1:1 mixture of regioisomers. c Isomers not separated.
b
series
n
Z
R
yield of 7a (%) yield of 5b (%)
a
d
h
i
0
1
1
1
2
H
H
H
H
Bn
Bn
i-Pr
Me
14
88
87
88
82
64
80
70
71
28
j
4,5-(MeO)2 Bn
a
b
10 mol % Sn(OTf)2, acetone, 40 °C, 32 h. Bu3SnH, AIBN,
toluene, 110 °C, 16 h.
us to apply this strategy to the acyl pyrazinone interme-
diate 7. These cyclic enediamides are readily formed from
the linear peptide acetals 3 on treatment with catalytic
tin(II) trifluoromethanesulfonate (Table 2). The condi-
tions are mild, the yields are usually over 80%, and
purification can be accomplished by filtration through a
plug of silica gel. The brominated analogue 7b is cyclized
in high yield with Bu3SnH/AIBN in refluxing toluene to
generate the fused-ring product 5b as a single diastere-
omer. This structure was confirmed by single-crystal
X-ray diffraction. The pseudoaxial amino acid side chain
directs the reaction by blocking one face of the pyrazinone
double bond, leading to the observed cis relationship
between amino acid side chain and bridgehead hydrogen.
High stereoselectivity was also observed with the valine-
and alanine-derived substrates (7h and 7i), so the same
relative configuration is inferred for the products.
F igu r e 1. Minimum-energy conformation calculated for 7d
(des-Br).
as a mimic of the intermediate acyliminium species 4,
suggested that the phenylalanine side chain adopts the
pseudoaxial position in order to minimize A1,2 and A1,3
strain from the flanking carbonyl groups (Figure 1), in
analogy to the known conformational preferences of
diketopiperazines.8 As a consequence, this side chain is
poised to attack the electrophilic center. Moreover, the
rigidity of the exocyclic amide bond hinders effective
p-orbital overlap for attack by the other aromatic ring.
The question remained as to whether the fused-ring
cyclization of these simple phenylacetyl analogues (i.e.,
to give 5 rather than 6) works with nonaromatic amino
acid substrates. Accordingly, nonaromatic versions of 3
Cyclization of the corresponding 3-(2-bromophenyl)-
propanoyl (7j) and 2-bromobenzoyl (7a ) derivatives afford
the ring-expanded and -contracted systems 5j and 5a ,
respectively. The latter ring system is less planar than
5d , from X-ray analysis, and the central piperazinone
ring displays interesting geometrical properties. The cis
relationship and proximity of the phenylalanine side
chain to the bridgehead hydrogen in 5a result in an
upfield chemical shift of 1.5 ppm for this hydrogen in the
1H NMR spectrum, in comparison to 5b. The major side
reaction in formation of the seven-membered analogue
5j is simple debromination, reflecting competition from
intermolecular reduction of the radical when intramo-
lecular addition to the double bond is less facile.
i
were synthesized (R ) Me, Pr, i.e., utilizing the amino
acids alanine and valine) and were subjected to the same
acidic cyclization conditions as before. No compounds of
type 5 were observed in the crude reaction mixture, and
only enediamide was detected. When more vigorous
heating was employed, decomposition of the enediamide
occurred.
In light of the difficulty encountered in developing a
general synthesis of the fused-ring system via the
acyliminium intermediate, we turned to radical cycliza-
tion as an alternative approach (Scheme 2). The recent
successes of Rigby9a and Ishibashi et al.9 with the ring
closure of aryl radicals onto acyclic enamides prompted
The ring system of 5 bears some relationship to that
of the antihelmintic drug praziquantel, 8 (Scheme 3), a
simple but effective antihelmintic used worldwide in the
treatment of schistosomiasis (bilharzia).10 The ring sys-
tems differ in the positions of the carbonyl groups,
although in principle they should be accessible by similar
chemistry. Indeed, the syntheses that have been reported
to date rely on a final Friedel-Crafts ring closure
(7) 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. Program version 6.5.
(8) Anteunis, M. J . O. Bull. Soc. Chim. Belg. 1978, 87, 627. Gdaniec,
M.; Liberek, B. Acta Crystallogr., Sect. C 1987, C43, 982. Radding,
W.; Donzel, B.; Ueyama, N.; Goodman, M. J . Am. Chem. Soc. 1980,
102, 5999.
(9) (a) Rigby, J . H.; Qabar, M. N. J . Org. Chem. 1993, 58, 4473. (b)
Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 1527. Ishibashi, H.; Ohata, K.; Niihara, M.; Sato, T.;
Ikeda, M. J . Chem. Soc., Perkin Trans. 1 2000, 547.
(10) (a) Redman, C. A.; Robertson, A.; Fallon, P. G.; Modha, J .; Kusel,
J . R.; Doenhoff, M. J .; Martin, R. J . Parasitology Today 1996, 12, 14.
(b) Bennett, J . L.; Day, T.; Feng-Tao, L.; Ismail, M.; Farghaly, A. Exp.
Parasitol. 1997, 87, 260. (c) Kusel, J .; Hagan, P. Parasitol. Today 1999,
15, 352. (d) Doenhoff, M. J .; Kimani, G.; Cioli, D. Parasitol. Today 2000,
16, 364.

Amino Acid Derived Heterocycles
J . Org. Chem., Vol. 67, No. 12, 2002 3987
Sch em e 3. Syn th esis of P r a ziqu a n tel 8 by Ra d ica l Cycliza tion
mediated by strong acid.11 To explore the versatility of
the pyrazinone radical cyclization reaction, we applied
it to a synthesis of praziquantel (Scheme 3). The milder
conditions of this route have the attraction that ready
incorporation of amino acids other than glycine can be
envisaged as a point of diversity.12
bromo series,11a although the tin triflate procedure
described here is milder and potentially more applicable
to functionalized analogues. The radical-initiated cycliza-
tion of pyrazinone 12 proceeded smoothly in 90% yield
to give 8, with spectral characteristics identical to those
reported for praziquantel.13 We envisage that the peptide
acetal chemistry described here could be applied to the
construction of praziquantel analogues that possess more
diverse functionality.
The peptide aldehyde-derived acyliminium and pyrazi-
none intermediates thus provide facile entry into a range
of novel heterocyclic structures. The chemistry is robust
and simple, and generates stable, rigid scaffolds with a
range of potential applications in peptidomimetic and
combinatorial chemistry. Moreover, the results we de-
scribe suggest that other stereoselective addition reac-
tions involving the pyrazinone double bond can be
developed for similar purposes.
Two routes to the pyrazinone intermediate 12 were
investigated, by analogy to those reported by Kim et al.
for the des-bromo analogues.11a These routes differ in
their degree of convergence and in the direction of acetal
cyclization (Scheme 3). The acetal unit was introduced
by reductive amination with dimethoxyacetaldehyde,
either in combination with benzyl glycinate (linear route)
or o-bromophenethylamine (convergent route). Although
this reaction proceeded in modest yield, it comes early
in the synthesis and was not optimized. The secondary
amines 9 and 13, respectively, were subjected to the
appropriate amide coupling reactions to afford the iso-
meric acetal cyclization precursors 11 and 15. Both
underwent tin triflate-catalyzed ring closure to the
pyrazinone 12 in good yield, although the cyclization of
15 proceeded more cleanly than that of its isomer 11.
These cyclizations are analogous to the methanesulfonic
acid-catalyzed reactions reported previously for the des-
Exp er im en ta l Section
Experimental procedures for representative steps are de-
scribed below; full details, including characterization, for other
compounds are provided in the Supporting Information.
Coordinates for structures 5a , 5d , and 6 have been deposited
with the Cambridge Crystallographic Data Centre (http://
www.ccdc.cam.ac.uk/).
(11) (a) Kim, J . H.; Lee, Y. S.; Kim, C. S. Heterocycles 1998, 48, 2279.
(b) Frehel, D.; Maffrand, J .-P. Heterocycles 1983, 20, 1731.
(12) The rapid construction of praziquantel analogues may become
increasingly important in light of reports that resistance to the drug
is beginning to appear.10b,c
(13) Kim, J . H.; Lee, Y. S.; Park, H.; Kim, C. S. Tetrahedron 1998,
54, 7395.

3988 J . Org. Chem., Vol. 67, No. 12, 2002
Todd et al.
1-Ben zyl-3-m eth yl-4,4a-dih ydr o-3H-3,9a-diazaflu or en e-
2,9-d ion e (5a ). A deoxygenated solution of the enediamide 7a
(41 mg, 0.11 mmol), AIBN (4.5 mg, 0.25 equiv), and tributyltin
hydride (43 µL, 1.5 equiv) in degassed toluene (6 mL) was
heated at reflux for 16 h. The reaction mixture was allowed
to cool to room temperature and concentrated in vacuo, and
the residue was purified by flash column chromatography (7:3
EtOAc/pet ether f EtOAc) to give the dione 5a as white
needles (21 mg, 64%): mp 128-131 °C; Rf (EtOAc) 0.23; IR
135.9, 133.8, 132.7, 132.5, 131.3, 130.9, 129.9, 129.6, 129.1,
128.8, 128.7, 128.1, 127.7, 127.6, 127.3, 126.8, 124.6, 116.4,
115.4, 107.9, 107.8, 60.9, 56.3, 40.4, 39.2, 36.3, 35.8, 33.6, 33.4;
MS (FAB) m/z 401.0 (39, doublet, MH+); HRMS (FAB) calcd
for C20H20BrN2O2 (MH+) 399.0708, found 399.0712.
2-(Cycloh exa n eca r bon yl)-5,6,10b,4a -tetr a h yd r op ip er -
a zin o[2,1-a ]isoqu in olin -4-on e (8, P r a ziqu a n tel). A solution
of enediamide 12 (100 mg, 0.26 mmol), AIBN (11 mg, 0.25
equiv), and tributyltin hydride (103 µL, 1.5 equiv) in degassed
toluene (25 mL) was heated at reflux for 16 h, allowed to cool
to room temperature, and concentrated in vacuo. The residue
was purified by flash column chromatography (1:1 EtOAc/pet
ether f EtOAc) to give praziquantel as white plates (72 mg,
90%); approximate 1:3 ratio of rotamers: mp 132-5 °C (lit.14
(mull) 1699, 1650, 1615, 1495 cm-1 1H NMR δ 7.90 (m, 1),
;
7.53 (m, 2), 7.28 (m, 1), 7.18 (m, 3), 7.12 (m, 2), 5.08 (t, 1, J )
5.0 Hz), 3.79 (dd, 1, J ) 11.0, 4.5 Hz), 3.66 (dd, 1, J ) 13.5,
4.0 Hz), 3.49 (dd, 1, J ) 12.0, 4.5 Hz), 3.29 (dd, 1, J ) 13.5,
5.5 Hz), 3.05 (apparent t, 1, J ) 11.5 Hz), 3.03 (s, 3); 13C NMR
δ 166.8, 166.3, 141.7, 136.8, 132.3, 131.7, 129.8, 129.1, 128.5,
126.8, 124.2, 122.0, 55.1, 53.5, 52.7, 37.7, 35.7; HRMS (FAB)
calcd for C19H18N2O2 (MH+) 307.1447, found 307.1453.
13-(2-Br om ob en zoyl)-11-m et h yl-11,13-d ia za t r icyclo-
[7.3.1.02,7]tr id eca -2(7),3,5-tr ien -10-on e (6a ). A solution of
phenylalanine derivative 3a (n ) 0, R ) Bn, Y ) 2-Br) (100
mg, 0.22 mmol) in 4:1 nitromethane/methanesulfonic acid (10
mL) was heated at 60 °C for 20 h and then allowed to cool to
room temperature. The mixture was partitioned between 5%
aqueous NaHCO3 and Et2O, and the aqueous phase was
extracted with Et2O (3 × 20 mL). The combined organic
portions were washed with brine (20 mL), dried (MgSO4), and
evaporated, and the resultant oil was purified by flash column
chromatography (EtOAc f 9:1 EtOAc/acetone) to give the
bridged dione 6a as a clear, colorless oil (75 mg, 87%): Rf
(EtOAc) 0.28; 1H NMR (two amide rotamers) δ 6.9-7.6 (m,
8), 6.00 (d, J ) 4.5 Hz) and 4.60 (dd, J ) 14.5, 4.0 Hz) (1 total),
4.25 (br d, J ) 5.0 Hz) and 5.57 (t, J ) 6.0 Hz) (1 total), 4.30
(t, J ) 4.5 Hz) and 4.14 (dd, 1, J ) 11.5, 4.5 Hz) (1 total), 3.29
(d, J ) 12 Hz) and 3.23 (d, J ) 12 Hz) (1 total), 3.07 (m, 2),
2.85 (s, 3); 13C NMR δ 167.6, 167.3, 166.1, 136.2, 133.8, 133.0,
132.3, 131.0, 130.9, 129.1, 128.1, 128.0, 127.4, 127.2, 126.8,
119.3, 71.4, 66.5, 60.6, 55.7, 55.4, 53.0, 52.7, 50.9, 47.2, 37.8,
37.5, 34.3, 33.2; MS (FAB) m/z 385, 387 (14, MH+), 183, 185
(100); HRMS (FAB) calcd for C19H18BrN2O2 (MH+) 385.0545,
found 385.0552.
1
132-3 °C); H NMR δ 7.22 (m, 4), 5.14 (dd, 1, J ) 13.5, 2.5
Hz), 4.79 (m, 2), 4.45 (d, J ) 17.5 Hz), 4.35 (d, J ) 12.5 Hz)
(total 1), 4.06 (d, J ) 17.5 Hz), 3.83 (d, J ) 18.5 Hz) (total 1),
3.23 (t, J ) 12.0 Hz), 2.85 (m) (total 4), 2.55 (m), 2.44 (m) (total
1), 1.76 (m, 5), 1.52 (m, 2), 1.26 (m, 3); 13C NMR δ 174.7, 164.3,
134.7, 132.7, 129.2, 127.4, 126.9, 125.4, 54.9, 49.0, 45.1, 40.7,
39.0, 29.2, 28.9, 28.7, 25.7; MS (FAB) m/z 313 (MH+, 100), 203
(28); HRMS (FAB) calcd for C19H25N2O2 (MH+) 313.1916, found
313.1916.
1-[2-(2-Br om op h en yl)eth yl]-4-(cycloh exa n eca r bon yl)-
1,3,4-tr ih yd r op yr a zin -2-on e (12) fr om Cycliza tion of 15.
A solution of peptide acetal 15 (332 mg, 0.73 mmol) and tin-
(II) triflate (29 mg, 0.1 equiv) in acetone (25 mL) was stirred
at 40 °C for 2 d and then concentrated in vacuo. The residue
was taken up in EtOAc (2 mL) and passed through a plug of
silica, eluting with EtOAc. The eluent was concentrated in
vacuo to give the enediamide as a white powder (218 mg, 76%);
approximate 1:5 ratio of rotamers: 1H NMR δ 7.50 (d, 1, J )
8.0 Hz), 7.19 (m, 2), 7.08 (m, 1), 6.59 (d, J ) 6.5 Hz), 6.08 (d,
J ) 6.5 Hz) (total 1), 5.49 (d, J ) 6.5 Hz), 5.38 (d, J ) 6.0 Hz)
(total 1), 4.29 (s, 2), 3.73 (t, 2, J ) 7.5 Hz), 3.02 (t, 2, J ) 7.0
Hz), 2.43 (tt, 1, J ) 12.0, 3.5 Hz), 1.74 (m, 5), 1.46 (m, 2), 1.22
(m, 3); 13C NMR δ 173.7, 163.6, 137.4, 132.9, 131.3, 128.5,
127.7, 124.5, 113.8, 108.9, 45.9, 45.8, 40.8, 34.6, 28.8, 25.6, 25.6;
MS (ESMS) m/z 413 (30, d, MNa+), 391 (100, d, MH+); HRMS
(FAB) calcd for C19H24BrN2O2 (MH+) 391.1021, found 391.0986.
3-Ben zyl-4-[2-(2-br om op h en yl)a cetyl]-1-m eth yl-3,4-d i-
h yd r o-1H-p yr a zin -2-on e (7d ). A solution of phenylalanine
derivative 3d (n ) 1, R ) Bn, Y ) 2-Br) (100 mg, 0.22 mmol)
and tin(II) trifluoromethanesulfonate (9 mg, 10 mol %) in
acetone (8 mL) was heated at 40 °C for 40 h. After being cooled
to room temperature, the reaction mixture was concentrated
in vacuo, the residue was dissolved in EtOAc, and the solution
was passed through a short plug of silica (eluting with EtOAc)
and concentrated in vacuo to yield the enediamide 7d as a
white powder (69 mg, 80%): Rf (EtOAc) 0.58; 1H NMR (mixture
of rotamers) δ 7.54 (d, J ) 8.0 Hz) and 7.46 (d, J ) 8.0 Hz) (1
total), 7.36 (m, 1), 7.21 (m, 4), 7.12 (m, 2), 7.05 (m, 1), 6.70 (d,
J ) 6.0) and 5.97 (dd, J ) 5.5, 1.5 Hz) (1 total), 5.79 (d, J )
6.0 Hz) and 5.49 (t, J ) 7.0 Hz) (1 total), 5.37 (d, J ) 6.0 Hz)
and 4.78 (t, J ) 8.0 Hz) (1 total), 3.75 + 3.8 (ABq, J ) 16.0
Hz) and 3.44 + 3.04 (ABq, J ) 16.5 Hz) (2 total), 3.16 (s), 3.07
(s) (total 3), 3.04 (m, 2); 13C NMR δ 168.5, 167.6, 165.4, 164.6,
Ack n ow led gm en t. Support for this work was pro-
vided by the National Institutes of Health (Grant No.
GM30759) and by a Research Fellowship from the
Wellcome Trust to M.H.T. We thank Dr. Frederick
Hollander (College of Chemistry Analytical Services) for
performing all the X-ray diffraction analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental condi-
tions and characterization of precursors and other analogues.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O010990M
(14) Berkowitz, W. F.; J ohn, T. V. J . Org. Chem. 1984, 49, 5269.