Diastereoselective synthesis of homologous bicyclic lactams - Potential building blocks for peptide mimics

Article abstract of DOI:10.1016/j.tetlet.2004.06.051

Bicyclic lactams serve as building blocks for the synthesis of conformationally restricted peptides. A route to these building blocks is described. They can serve as cis- and trans-peptide bond surrogates. Due to the de novo synthesis, both enantiomeric forms of these products can be produced. Key steps are a lipase-catalyzed saponification of oximes and a highly diastereoselective cyclization utilizing phenylselenyl bromide. In addition, attachment to a solid support has been achieved.

Full text of DOI:10.1016/j.tetlet.2004.06.051

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5983–5986
Diastereoselective synthesis of homologous bicyclic
lactams––potential building blocks for peptide mimicsq
Bernhard Westermann,* Nicole Diedrichs, Ralf Krelaus, Armin Walter and Ina Gedrath
Leibniz-Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle (Saale), Germany
Received 27 April 2004; revised 27 May 2004; accepted 11 June 2004
Abstract—Bicyclic lactams serve as building blocks for the synthesis of conformationally restricted peptides. A route to these
building blocks is described. They can serve as cis- and trans-peptide bond surrogates. Due to the de novo synthesis, both enan-
tiomeric forms of these products can be produced. Key steps are a lipase-catalyzed saponification of oximes and a highly diaste-
reoselective cyclization utilizing phenylselenyl bromide. In addition, attachment to a solid support has been achieved.
Ó 2004 Elsevier Ltd. All rights reserved.
The synthesis of conformationally restricted amino acids
O
CO2H
( )n
and their utilization in the synthesis of peptide confor-
mation mimics such as b-turn mimics has been of con-
siderable interest.2–4 Therefore, efforts have been
directed towards the synthesis of bicyclic lactams 1,
which are effective in resembling peptidic secondary
structures.5–8 In addition, these heterocyclic products are
of particular relevance, because they mimic a Xaa-Pro
dipeptide either in the cis- or the trans-configuration
(Fig. 1).9
H2N
N
1
( )m
CO2H
O
O
CONH-peptide
peptide-HN
peptide-HN
N
N
trans-Ala-Pro
Although derivatives have been made that mimic cis-
amide bonds or trans-amide bonds, the structure of 1
offers the incorporation of both of these structural ele-
ments into a peptide utilizing the same building
block.10;11
cis-Ala-Pro
CONH-peptide
Figure 1.
Despite a large variety of methods successfully carried
out for the synthesis of derivatives of 1, strategies
leading to homologous [x,y,0]-bicyclic b-turn mimetics
are rare.5 One reason for these limitations is that most
syntheses start from products provided by the chiral
pool.12 This limits access to homologous starting mate-
rials and to the natural stereoisomer. In this communi-
cation we present the de novo synthesis of homologous
bicyclic lactams and their utilization for the synthesis of
tetrapeptides.
We recently developed a short synthetic pathway to a,a0-
disubstituted a-amino acids 4 in enantiomerically pure
form (Scheme 1).13 In addition, the intermediate lactam
3 can be envisioned as a suitable precursor leading to
bicyclic lactams 1.
The synthesis of enantiomerically pure lactams 3 can be
initiated by lipase-catalyzed transesterification of race-
mic E-oximes 5. These can be easily obtained by addi-
tion of hydroxyl amine to racemic b-ketoesters 2 under
kinetic conditions.14 The oxime is formed in pyridine/
Keywords: Peptide mimics; Lipase; Beckmann rearrangement; Seleno
annelation.
q See Ref. 1.
* Corresponding author. Tel.: +49-345-5582-1340; fax: +49-345-5582-
1309; e-mail: bwesterm@ipb-halle.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.051

5984
B. Westermann et al. / Tetrahedron Letters 45 (2004) 5983–5986
O
O
CO2Et
R
NH
1
CO2Et
( )n
2
( )n
R
n = 1,2
3
R = alkyl
O
R
NHBoc
HO
( )n CO2Et
4
Scheme 1.
Figure 2. ORTEP plot of 7a.
H7C3
O
HO
RO
N
N
N
lipase PS
The stereochemical outcome of this cyclization is con-
trolled by the carboxylate moiety at the quaternary
carbon center. Attempts to cyclize decarboxylated lac-
tams under identical conditions lead to a 1:1 mixture of
diastereomers. However, in the presence of this car-
boxylate group the thermodynamically most stable
cyclized product formed is the 5,8-trans-configurated
lactam. The configuration has been determined by
NMR and X-ray crystallography (Fig. 2). To improve
the diastereoselectivity further, the Nicolaou reagent has
been employed, but no increase can be observed.17
Furthermore, the yield decreases (27% for 6a).
O
CO2Et
vinyl acetate
n-BuOH
CO2Et
CO2Et
+
( )n
S-(+)-6a,b
K2CO3, MeOH
S-(+)-5a,b
( )n
( )n
a: n = 1
ee 95 %
b: n = 2
ee 92 %
R-(−)-5a,b
( )-5a,b
R = H
C3H7COCl
py
see ref. 14
( )-6a,b
R = C3H7CO
see ref. 14
S-(+)-3a,b
R-(−)-3a,b
Scheme 2.
The phenylselenyl substituent offers widespread oppor-
tunities for modification (Scheme 4). By oxidation with
m-chloro perbenzoic acid in the presence of KOH
(10 equiv), the seleno moiety can be oxidized and
substituted by a hydroxyl group. This leads to the
hydroxylated lactam 9 in 82% yield.18 Protection of the
hydroxyl moiety with benzyl bromide affords 10 in 86%
yield. To introduce the amide side chain, deprotonation
with lithium hexamethylsiliazide is carried out, followed
by addition of tert-butyl diazodicarboxylate to give 11 in
72% yield.19
methanol at 0 °C, which affords the E-oxime 5 almost
exclusively (50:1, GLC). For the lipase-catalyzed sepa-
ration of racemate 5, the corresponding butyrate 6 has
been proven to be a good substrate. After obtaining the
highly enantiomerically enriched oximes, the Beckmann
rearrangement towards lactams 3 is carried out under
conditions described previously (Scheme 2).13
For the synthesis of bicyclic lactams we envisioned a
seleno-mediated ring closure (Scheme 3).15 Employing
PhSeBr in the presence of silica gel affords lactams 7 and
8 in 78% and 54% yield, respectively. Furthermore, this
reaction turns out to be highly regio- and diastereo-
selective. Regioselective ring closure occurs by a 5 exo
tet process. No product from a 6 endo tet process is
formed. The diastereomeric ratio for the 6,5-bicyclized
product is 7:1. For the 7,5-bicyclized product it is 2:1 as
shown in Scheme 3.16
In this amination reaction, two diastereomers are
formed in the ratio of 4:1. These can be separated by
chromatography. Debenzylation, oxidation to the car-
boxylic acid under slightly acidic conditions and
attachment of C-protected phenylalanine gives 12 in
68% yield (over three steps). Cleavage of tert-butyl esters
and hydrogenation gives an amine derivative, which is
coupled to N-protected phenylalanine. The tetrapeptide
13 is formed in 51% yield (over three steps).
For peptide synthesis, it is useful to have one amino acid
attached to a solid support. Due to the high degree of
functionalization, lactam 9 is an ideal candidate to be
used for this purpose. Bicyclic 9 is oxidized to acid 14 in
the presence of RuCl3/NaIO4 in 85% yield. As the resin
we choose the Wang-resin 15. Attachment can be
achieved by simple agitation of the resin with lactam 14
in pyridine and dichloromethane. We have found that
the coupling reagent CIP 16 is superior to others.20 After
the reaction a loading percentage of 60% can be
obtained (Scheme 5).
PhSeBr
SePh
+
SePh
O
O
O
CH3CN
silica gel
rt
NH
N
N
n = 1,2
( )
( )
( )
n CO2Et
n CO2Et
n CO2Et
6a,b
7a,b
8a,b
a: n = 1, 78 %, trans : cis 7 : 1
b: n = 2, 54 %, trans : cis 2 : 1
Scheme 3.

B. Westermann et al. / Tetrahedron Letters 45 (2004) 5983–5986
5985
t-BuO
O
OR
SePh
OBn
O
O
O
O
1: mCPBA, KOH
82 %
LHMDS
N
DtBAD
N
N
t-BuO
N
H
N
2: NaH, BnBr
86 %
72 %
(4 : 1)
CO2Et
CO2Et
CO2Et
11
7a
9 (R = H)
10 (R = Bn)
O
t-BuO
O
O
NHPhe
O
1: CF3COOH
NHPhe
O
1: H2, Pd/C
O
PheHN
N
N
2: H2, Pt/C
3: NAc-PheOH
t-BuO
N
H
N
2: RuCl3, NaIO4
3: H2N-PheOEt
CO2Et
51 %
13
CO2Et
68 %
12
Scheme 4.
References and notes
O
O
N
O
O
OH
resin
O
1. This work has been carried out mainly at the University of
Paderborn, Germany.
2. Gante, J. Angew. Chem. 1994, 106, 1780–1802; Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699–1720.
3. Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303–
1326; Angew. Chem., Int. Ed. Engl. 1993, 32, 1244–1267.
4. Hruby, V. Biopolymers 1997, 43, 219–266.
5. Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854, and
references cited therein.
N
15, py, CH2Cl2
+
17
N
OEt
-
OEt
O
Cl
O
PF6
RuCl3
NaIO4
N
9
9
14
CIP
16
O
O
OTHP
OTHP
15, 16
py, CH2Cl2
N
N
19
6. Belvisi, L.; Bernardi, A.; Manzoni, L.; Potenzy, D.;
Scolastico, C. Eur. J. Org. Chem. 2000, 12789–12854.
7. Sun, H.; Moeller, K. D. Org. Lett. 2001, 4, 1547–1550.
OH
O
O
O
a: DHP
b: LiOH
resin
18
€
8. Maison, W.; Kuntzer, D.; Grohs, D. Synlett 2002, 1795–
OH
1798.
€
O
9. Wuthrich, K. Nature Struct. Biol. 2001, 8, 923–925.
10. Kim, K.; Dumas, J. P.; Germanas, J. P. J. Org. Chem.
1996, 61, 3138–3144.
Wang resin
15
11. Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995,
36, 191–194.
Scheme 5.
12. Sato, K.; Nagai, U. J. Chem. Soc., Perkin Trans. 1 1986,
1231–1234 (an early and prominent example).
13. Westermann, B.; Gedrath, I. Synlett 1996, 665–666.
14. Diedrichs, N.; Krelaus, R.; Gedrath, I.; Westermann, B.
Can. J. Chem. 2002, 80, 686–691.
15. Tiecco, M. Electrophilic Selenium, Selenocyclizations. In:
Topics Curr. Chem.; Springer: Berlin, 2000; Vol. 208, and
references cited therein.
16. Procedure for the synthesis of (3S,8aS)-7a: Lactam 6a
(279 mg, 1.2 mmol) was dissolved in acetonitrile (10 mL)
and stirred with silica gel (0.8 g). A solution of PhSeBr
(293 mg, 1.2 mmol) in acetonitrile (10 mL) was added
dropwise over the period of 1.5 h. Stirring was continued
for 1 d, upon which the solution was filtered, extracted
with dichloromethane and washed with sat. aqueous
sodium bicarbonate. Extracting of the aqueous phase with
dichloromethane, combining the organic phases, drying
over sodium sulfate, evaporating of the solvent and
column chromatography on silica gel (petroleum/ethyl
Whereas attachment of 14 to the resin allows for the
incorporation of cis-configured dipeptides, attachment
of the resin to the carboxyl moiety of the bicyclic het-
erocycle 18 allows for the incorporation of a trans-
peptide. To apply the same methodology, the hydroxyl
group of 9 is protected as the THP ether and the ester is
saponified with LiOH. Subsequently, the corresponding
acid 18 is coupled to the Wang-resin (Scheme 5).
In summary, we have developed a synthesis of highly
substituted bicyclic lactams that can mimic either a
trans- or a cis-peptide bond. Both heterocycles can be
attached easily to a solid support, allowing for peptide
synthesis from the C- or the N-terminus.
acetate 1:1) led to crystalline 7a (320 mg, 68%). ½aꢀ )19.9
D
(c 1.25 in chloroform). 1H NMR (CDCl3): d ¼ 1:24 (t,
3H), 1.49–2.44 (m, 10H), 3.13 (dd, J ¼ 8:4 Hz,
J ¼ 12:6 Hz, 1H), 3.57 (dd, J ¼ 2:6 Hz, J ¼ 12:6 Hz,
1H), 4.18 (q, 2H), 4.37–4.45 (m, 1H), 7.15–7.31 (m, 3H),
7.56–7.60 (m, 2H). 13C NMR (CDCl3): d ¼ 14:6, 19.1,
27.3, 29.7, 30.8, 32.2, 36.0, 57.5, 62.3, 71.5, 126.8, 129.5,
Acknowledgements
This work has been supported by the Deutsche Fors-
chungsgemeinschaft and the Fonds der Chemischen
Industrie (grants to N.D. and I.K.)

5986
B. Westermann et al. / Tetrahedron Letters 45 (2004) 5983–5986
130.5, 131.7, 170.8, 174.1. C18H23NO3Se (cal./found): C
56.80/56.87, H 6.10/6.22, N 3.68/3.59.
85%). ½aꢀ )29.0 (c 0.31 in CHCl3). 1H NMR (CDCl3):
D
d ¼ 1:26 (t, 3H), 1.43–2.10 (m, 6H), 2.24–2.53 (m, 4H),
Procedure for the synthesis of (3S,8aS)-9: To lactam 7a
(100 mg, 0.26 mmol), dissolved in THF (15 mL), freshly
powdered KOH (97 mg, 1.7 mmol) was added. The reac-
tion mixture was heated to reflux, upon which mCPBA
(227 mg, 1.3 mmol) in THF (10 mL) was added. After 8 h
under reflux conditions, the slurry was stirred for addi-
tional 12 h at room temperature. Ethyl acetate was added
and the mixture was washed with water, HCl (5%), water,
sat. NaHCO3 and water. Drying of the organic phase and
evaporating of the solvent under reduced pressure led to a
white solid, which was purified by chromatography on
silica gel (CH2Cl2/MeOH 9:1) to afford oily 9 (54 mg,
3.68 (d, J ¼ 5:3 Hz, 2H), 4.19 (q, 2H), 4.23–4.34 (m, 1H),
4.78 (s, 1H). 13C NMR (CDCl3): d ¼ 14:6, 18.7, 25.9, 30.7,
32.3, 36.3, 61.5, 62.4, 67.1, 72.0, 172.8, 173.8. C12H19NO4
(cal./found): C 59.74/60.01, H 7.94/7.86, N 5.83/6.01.
17. Webb, R. R.; Danishefsky, S. Tetrahedron Lett. 1983, 24,
1357–1360.
18. Krief, A.; Dumont, W.; Denis, J. N. J. Chem. Soc., Chem.
Commun. 1985, 571–572.
19. Gramberg, D.; Robinson, J. A. Tetrahedron Lett. 1994, 35,
861–864.
20. Katritzky, A. R.; Suzuki, K.; Singh, S. K. Arkivoc 2004,
12–35.