Synthesis of β-lactam scaffolds for ditopic peptidomimetics

Article abstract of DOI:10.1021/ol0626241

(Chemical Equation Presented) Ring opening of α-substituted-α- methoxycarbonyl-N-nosylaziridines provides a practical access to enantiopure α,α′-disubstituted β-lactam scaffolds, novel types of ditopic reverse turn surrogates. The procedure is general, short, and high yielding and starts from handy α-substituted serinates and α-amino acid derivatives.

Full text of DOI:10.1021/ol0626241

ORGANIC
LETTERS
2007
Vol. 9, No. 1
101-104
Synthesis of
Ditopic Peptidomimetics
â-Lactam Scaffolds for
Claudio Palomo,* Jesus M. Aizpurua,* Eva Balentova´, Azucena Jimenez,
Joseba Oyarbide, Raluca M. Fratila, and Jose´ Ignacio Miranda
Departamento de Qu´ımica Orga´nica-I, UniVersidad del Pa´ıs Vasco,
Facultad de Qu´ımica, Apdo 1072, 20080 San Sebastia´n, Spain
jesusmaria.aizpurua@ehu.es
Received October 25, 2006
ABSTRACT
Ring opening of
scaffolds, novel types of ditopic reverse turn surrogates. The procedure is general, short, and high yielding and starts from handy
serinates and -amino acid derivatives.
r
-substituted-
r
-methoxycarbonyl-N-nosylaziridines provides a practical access to enantiopure
r
,
r′-disubstituted
â-lactam
r-substituted
r
Since their introduction by Freidinger,1 externally scaffolded
lactam peptides 1 (Figure 1) are among the most efficient
owing to the flexibility of the CdO‚‚‚HN hydrogen bond,
and (b) incorporation of the â-turn surrogate (i + 1) - (i +
2) segment into the peptide chain is not compromised by
macrocyclization reactions.
The design of lactam peptidomimetics presents, however,
an important limitation. As the restraint element (cycle) and
recognition groups (R1, R2) are usually crammed in the
scaffold, it is very difficult to devise lactam structures free
from undesired interactions with the receptor, especially for
ditopic3 ones.
Most of the lactam peptidomimetics used routinely as
â-turn surrogates (Figure 2) require one or two cycles to
correctly overlay the dihedral angles of the â-genic (i + 1)
- (i + 2) residues to a particular â-turn type (e.g., Nagai’s
bicyclic lactams 2 or Freidinger’s lactams 3). Hence, the
Figure 1. Scaffold/ditopic receptor interaction in â-turn lactam
peptidomimetics: a bulky restraint element may preclude efficient
recognition of R1 and R2 groups.
(2) For reviews, see: (a) Souers, A. J.; Ellman, J. A. Tetrahedron 2001,
57, 7431-7448. (b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (c) Kahn, M.;
Eguchi, M. Synthesis of Peptides Incorporating â-Turn Inducers and
Mimetics. In Houben-Weyl, Methods of Organic Chemistry; Goodman, M.,
Felix, A., Moroder, L., Toniolo, C., Eds.; Thieme: Stuttgart, New York,
2003; Vol. E22c, pp 695-740 and references therein.
(3) ComprehensiVe Supramolecular Chemistry; Lehn, J.-M., Atwood, J.
L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon: Oxford,
1996.
and popular â-turn mimics.2 They present two major
advantages over cyclic peptides or internally scaffolded
peptidomimetics: (a) recognition by receptors can be tuned
(1) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brookas, J. R.;
Saperstein, R. Science 1980, 210, 656-658. (b) Freidinger, R. M. J. Med.
Chem. 2003, 46, 5553-5566.
10.1021/ol0626241 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/09/2006

derived â-lactam scaffold 68 have been reported. In both
instances, a Mitsunobu-type N1-C4 cyclization was the key
step to form the 2-azetidinone ring from R-substituted serine
dipeptides 8. Unfortunately, the general applicability of such
intermediates to the synthesis of â-lactam scaffolds 7 is
drastically limited by the low acidity of the amide moiety
and the steric hindrance of substituents nearby.9
Herein, we report a general preparation of enantiopure
ditopic â-lactam scaffolds 7 by means of an alternative
N1-C2 ester-amine cyclization strategy (Scheme 1). Our
Scheme 1
Figure 2. â-Lactam scaffold-assisted design (â-LSAD): formal
insertion in the native peptide of a carbon atom (CR-H +
H-N f CH2) provides the minimal pseudopeptide 4 required to
accommodate a â-turn conformation. PG: protecting group.
synthetic plan employed â-N-peptidyl-azaserinates 9 as
â-lactam ring precursors and involved the reaction of
R-amino esters 1110 with N-(o-nosyl)-aziridines 10,11 which
acted as N-protected, O-activated equivalents of R-substituted
serinates 12.12
design of “minimal” lactam peptidomimetics incorporating
restraint elements as small as possible becomes highly
attractive. Within this endeavor, we have undertaken the
development of pseudopeptides 4 by applying a “â-lactam
scaffold-assisted design” (â-LSAD). Mimetics resulting from
such an approach differ only in one single carbon atom from
the native peptides and are characterized by (a) an (i + 1)
residue consisting of an R-alkyl-R-amino-â-lactam ring
unsubstituted at position â and (b) a linear disposition of
the CR, N, and CR′ atoms.4
Although the synthesis of scaffolds for monotopic â-lactam
pseudopeptides 4 (R2 ) H) is known,4,5 no general method
exists to prepare the ditopic â-lactam counterparts required
for the full development of â-LSAD.6 Only the syntheses of
the racemic azapeptidomimetic â-lactam 57 and the proline-
Nosylation of methyl R-benzylserinate 15 under standard
conditions (o-Ns-Cl, Et3N, DMAP catalyst) proved surpris-
ingly troublesome (Scheme 2), yielding the expected N-
monoprotected product in less than 25% yield. Changing to
inorganic bases (K2CO3) also led to the formation of the same
product along with the unexpected oxazolidin-2-one 16,
incorporating a carbamate carbonyl group from potassium
carbonate. Gratifyingly, we found that R-substituted methyl
serinates (15 and 17) or their peptides (18) were cleanly
(7) Broadrup, R. L.; Wang, B.; Malachowski, W. P. Tetrahedron 2005,
61, 10277-10284.
(8) (a) Bittermann, H.; Gmeiner, P. J. Org. Chem. 2006, 71, 97-102.
(b) Bittermann, H.; Bo¨ckler, F.; Einsiedel, J.; Gmeiner, P. Chem.-Eur. J.
2006, 12, 6315-6322.
(9) For instance, in our hands, dipeptide CHO-(D)-Ser(RBn)-GlyOBn
failed repeatedly to cyclize to the corresponding â-lactam 7 (PG ) CHO;
R1 ) Bn; R2 ) H, R ) Bn) under several Mitsunobu conditions, including
those reported in refs 7 and 8.
(10) Alternative access to â-N-peptidyl-azaserinates 9 was also explored
from R-amino esters (including unhindered benzyl glycinate) and R-sub-
stituted serines with the hydroxy group activated as O-mesylate 13 and
lactone 14, but all attempts to prepare the desired R,â-diamino esters met
with failure.
(4) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R.
M.; Matute, C.; Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden,
A. J. Am. Chem. Soc. 2003, 125, 16243-16260.
(5) (a) Macias, A.; Ramallal, A. M.; Alonso, E.; Del Pozo, C.; Gonzalez,
J. J. Org. Chem. 2006, 71, 7721-7730. (b) Palomo, C.; Aizpurua, J. M.;
Benito, A.; Galarza, R.; Khamrai, U. K.; Vazquez, J.; DePascual-Teresa,
B.; Nieto, P. M.; Linden, A. Angew. Chem., Int. Ed. 1999, 38, 3056-3058.
(c) Wu, Z.; Georg, G. I.; Cathers, B. E.; Schloss, J. V. Bioorg. Med. Chem.
Lett. 1996, 6, 983-986.
(6) Freidinger-type â-lactam scaffolds (R1 ) H): (a) Turner, J. J.;
Sikkema, F. D.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.
Synlett 2001, 1727-1730. (b) Sreenivasan, U.; Mishra, R. K.; Johnson, R.
L. J. Med. Chem. 1993, 36, 256-263. For related â-substituted â-lactam
scaffolds, see: (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Benito, A.;
Cuerdo, L.; Fratila, R. M.; Jimenez, A.; Loinaz, I.; Miranda, J. I.; Pytlewska,
K. R.; Micle, A.; Linden, A. Org. Lett. 2004, 6, 4443-4446. (d) Alonso,
E.; Lo´pez-Ortiz, F.; Del Pozo, C.; Peralta, E.; Mac´ıas, A.; Gonza´lez, J. J.
Org. Chem. 2001, 66, 6333-6338. (e) Ojima, I. Acc. Chem. Res. 1995, 28,
383-389. (f) Maier, T. C.; Frey, W. U.; Podlech, J. Eur. J. Org. Chem.
2002, 2686-2689.
(11) Monographs on the reactivity of aziridines: (a) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599-619. (b) Pearson, W. H.; Lian, B. W.;
Bergmeier, S. C. In ComprehensiVe Heterocyclic Chemistry II; Padwa, A.,
Ed.; Pergamon: New York, 1996; Vol. 1A, p 1-60. (c) Atkinson, R. S.
Tetrahedron 1999, 55, 1519-1559. (d) Osborn, H. M. I.; Sweeney, J.
Tetrahedron: Asymmetry 1997, 8, 1693-1715.
(12) Available from (D)-serine. See: Seebach, D.; Aebi, J. D.; Gander-
Coquoz, M.; Naef, R. HelV. Chim. Acta 1987, 70, 1194-1216.
102
Org. Lett., Vol. 9, No. 1, 2007

previous hydrolysis to the corresponding â-amino acids,
followed by cyclodehydration.15 However, all attempts to
hydrolyze the methoxycarbonyl group were thwarted by
previous debenzylation or decomposition. Alternative in-
tramolecular base-promoted direct ester-amine condensation
of 24 and 25 to 7 also proved impracticle.16 These behaviors
were attributed primarily to the sterical shielding around the
CO2Me group and also to the latent acidity of the R′ proton.
To cancel this later effect, â-aminoalcohol silyl ethers 2617
were investigated as nonenolizable surrogates of R-amino
esters 22 and 23.
Scheme 2
As shown in Table 1, aziridines 19 and 20 give a smooth
ring-opening reaction with amines 26 to the corresponding
Table 1. Synthesis of â-Lactam Scaffolds 29 from Aziridines
19 and 20
transformed into the corresponding N-nosyl aziridines by
treatment with 2 equiv of o-Ns-Cl and excess KHCO3 in
acetonitrile at reflux. This reaction avoids cumbersome N-
or O-monoprotections required for conventional stepwise
transformation of R,â-aminoalcohols into N-sulfonylaziri-
dines13 and enables further in situ ring-opening reactions of
the products, vide infra.
entry
R1
R2
product yield (%)a product yield (%)c
1
2
3
4
5
6
7
CH2Ph
H
27a
27b
27c
72 (75)b
56 (67)b
56 (65)b
29a
29b
29c
62 (81)d
82
81
CH2Ph Me, (S)*
CH2Ph Me, (R)*
CH2Ph Ph, (S)*
CH2Ph Ph, (R)*
Me
Me
27d 52
29d 60
Reaction of benzyl glycinate 22 and benzyl alaninate 23
with N-nosylaziridine 19 (Scheme 3) led to a clean and
27e
27f
27g
56
-- (66)b
53
29e
29f
29g
50
-- (74)d
78
H
iPr, (R)*
a Yield of pure isolated products. bOverall yields of 27 from R-alkyl
serinates 15 and 17 by in situ ring opening of intermediate aziridines 19
and 20 with â-aminoalcohol silyl ethers 26. cOverall yields of the pure
products for transformation 27f29. dOxidation step conducted using the
TCCA/TEMPO reagent.
Scheme 3
R,â-diamino esters 27, but in contrast to their enolizable
counterparts 24 and 25, cyclization of 27f28 was now
conducted in virtually quantitative yields (90-98%) upon
treatment with LiHMDS.18 Finally, the C-terminal carboxylic
group was restored after desilylation by oxidation with Jones’
reagent or the trichloroisocyanuric acid/2,2,6,6-tetramethyl-
1-piperidinyloxyl system (TCCA/TEMPO).19 The method
was applicable both to ditopic and to monotopic â-lactam
scaffolds (see entries 1 and 6 in Table 1). Furthermore,
isolation of aziridines was not necessary to prepare â-N-
substituted azaserines 27. Indeed, slightly higher overall
yields were attained when N-nosyl aziridines obtained from
methyl serinates 15 and 17 were immediately opened in situ
with â-aminoalcohol silyl ethers (entries 1-3 and 6).
Importantly, the method could also be extended to the
synthesis of R,R′,R′-trisubstituted â-lactam scaffolds (Scheme
4, Table 2). We found that ring-opening reaction of N-o-
nosylaziridines generated in situ from R-substituted methyl
completely â-regioselective ring-opening reaction to form
the R-substituted â-N-peptidyl-azaserines 24 and 25 in good
yields.14 These compounds might be converted into 7 after
Scheme 4
(13) For a related one-pot tosylation/aziridination of R,â-aminoalcohols,
see: Bieber, L. W.; de Arau´jo, M. C. F. Molecules 2002, 7, 902-906.
(14) To the best of our knowledge, these examples represent the first
general preparation of R-substituted â-N-peptidyl-azaserines in enantiopure
form. For stereocontrolled synthesis of R-substituted â-N-alkyl-azaserines,
see: (a) Pfammatter, E.; Seebach, D. Liebigs Ann. Chem. 1991, 1323-
1336. (b) Burgaud, B. G. M.; Horwell, D. C.; Padova, A.; Pritchard, M. C.
Tetrahedron 1996, 52, 13035-13050.
Org. Lett., Vol. 9, No. 1, 2007
103

esters (e.g., H-Aib-OBn) without significant epimerization
at the phenylglycine residue.22 On the other hand, standard
N-denosylation with thiophenol and simultaneous reprotec-
tion with the Boc group was achieved in high yield.23
Conversely, inversion of the nosyl cleavage/peptide coupling
sequence in 33a permitted an efficient and epimerization-
free elaboration of the highly hindered R-amino-â-lactam
group (e.g., with Boc-Ala-H), providing the pseudopeptide
36 in high yield.
Table 2. Synthesis of â-Lactam Scaffolds 33 from
R-Substituted Serines 15, 17, 30, and 31
entry serine
R1
product
R2
R3
yield (%)a
1
2
3
4
5
15
15
17
30
31
CH2Ph
CH2Ph
Me
33a
33b
33c
33d
33e
Me
-(CH2)4-
-(CH2)4-
Me
Me
Me
70
51
59
45
40
iBu
Me
Me
CH2C6F5
In conclusion, a short, practical, and epimerization-free
procedure to obtain mono- and ditopic â-lactam scaffolds
has been developed, paving the way for the full application
of the â-LSAD concept. Several families of â-lactam
pseudopeptides resulting from this approach have been
prepared in our laboratory, and evaluation of their confor-
mational and biological behavior is underway.
a Overall nonoptimized yields of pure isolated products 33 from R-alkyl
serinates. One equivalent of R-amino ester was used in all examples.
serinates 15, 17, 30, and 31 with the R,R-disubstituted amino
esters20 32 afforded the corresponding R,â-diamino esters
in a one-pot operation. Treatment of these intermediates with
LiHMDS resulted in clean cyclization to provide the corre-
sponding â-lactams 33 in fair to good overall yields. These
results confirm the striking effect of the lack of R′ acidic
protons on the reaction and represent one of the shortest and
more efficient routes to prepare highly hindered â-lactam
peptidomimetics.
Finally, coupling reactions involving orthogonal depro-
tection reactions at the N- and C-termini of the â-lactam
dipeptides 29e and 33a were performed to illustrate the easy
incorporation of the â-lactam scaffolds prepared into
pseudopeptides (Scheme 5). After screening, N-ethoxycar-
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (MEC, Spain) (Project: CTQ2006-13891/BQU),
UPV/EHU, and Gobierno Vasco (ETORTEK-BiomaGUNE
IE-05/143) for financial support and SGIker UPV/EHU for
NMR facilities. Grants from MEC to J.O. and from the
European Commission (Marie Curie HMPT-CT-2000-00173)
to E.B. are acknowledged.
Supporting Information Available: Preparation proce-
dures and physical and spectroscopic data for compounds
13-36. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0626241
(15) For a related carboxylic acid-amine cyclization on R-unsubstituted
â-N-peptidyl azaserines, see ref 6a.
Scheme 5
(16) A survey of procedures to obtain 2-azetidinones by cyclization of
â-amino esters: Backes, J. In Houben-Weyl, Methoden der Organischen
Chemie, Band E16b; Mu¨ller, E., Bayer, O., Eds.; Thieme: Stuttgart, 1991;
pp 97-101.
(17) â-Aminoalcohol tert-butyldimethylsilyl ethers 26 were prepared in
75-95% overall yields from the corresponding R-amino acids. See
Supporting Information for details.
(18) Gennari, C.; Venturini, I.; Gilson, G.; Schimperna, G. Tetrahedron
Lett. 1987, 28, 227-230.
(19) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org.
Chem. 2003, 68, 4999-5001.
(20) For some reviews on the preparation of R,R-disubstituted amino
esters, see: (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127-
5143. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
1998, 9, 3517-3599.
(21) (a) Kiso, Y.; Yajima, H. J. Chem. Soc., Chem. Commun. 1972, 942-
943. (b) Kiso, Y.; Kai, Y.; Yajima, H. Chem. Pharm. Bull. 1973, 21, 2570-
2510.
(22) Phenylglycine derivatives are prone to loss of configurational
integrity under basic conditions. When transformation 29ef34 was tried
with EDC/HOBT/Et3N (“water-soluble carbodiimide method”), complete
epimerization was observed at the R′ position.
(23) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron
Lett. 1997, 38, 5253-5256.
bonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)21 was found
to be the dehydration reagent of choice to couple the
carboxylic function of 29e to sterically demanding R-amino
104
Org. Lett., Vol. 9, No. 1, 2007