Exceptional stereoselectivity in the synthesis of 1,3,4-trisubstituted 4-carboxy β-lactam derivatives from amino acids

Article abstract of DOI:10.1021/ol070533d

Equation presented The base-promoted cyclization of optically pure N-(p-methoxybenzyl)-N-(2-chloro)propionyl amino acid derivatives resulted in a diastereo- and enantioselective approach to valuable 1,3,4,4-tetrasubstituted β-lactams. The stereochemical outcome of the reaction is exclusively governed by the configuration of the N-(2-chloro)propionyl moiety.

Full text of DOI:10.1021/ol070533d

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1593-1596
Exceptional Stereoselectivity in the
Synthesis of 1,3,4-Trisubstituted
4-Carboxy
Amino Acids
â-Lactam Derivatives from
Paula Pe´rez-Faginas, Fran O’Reilly, Aisling O’Byrne, Carlos Garc´ıa-Aparicio,
Mercedes Mart´ın-Mart´ınez, M. Jesu´s Pe´rez de Vega, M. Teresa Garc´ıa-Lo´pez, and
Rosario Gonza´lez-Mun˜iz*
Instituto de Qu´ımica Me´dica (CSIC), Juan de la CierVa, 3, 28006 Madrid, Spain
iqmg313@iqm.csic.es
Received March 2, 2007
ABSTRACT
The base-promoted cyclization of optically pure N-(p-methoxybenzyl)-N-(2-chloro)propionyl amino acid derivatives resulted in a diastereo- and
enantioselective approach to valuable 1,3,4,4-tetrasubstituted
by the configuration of the N-(2-chloro)propionyl moiety.
â-lactams. The stereochemical outcome of the reaction is exclusively governed
The azetidin-2-one (â-lactam) ring is widely recognized as
a key structural motif in several families of antibiotics.1 In
addition to this, differently substituted monocyclic â-lactams
function as mechanism-based inhibitors of serine proteases,
such as tryptase,2 human leukocyte elastase,3 human cy-
tomegalovirus and HIV proteases,4 and prostate specific
antigen.5 Additionally, the 1,3,4-trisubstituted 2-azetidinone
derivative Ezetimibe has recently been commercialized as
an effective acyl-CoA cholesterol acyltransferase inhibitor
for lowering cholesterol levels.6
Apart from their significance in medicinal chemistry,
enantiopure â-lactams also serve as versatile chiral interme-
diates in organic synthesis (â-lactam synthon methodology)7
and as useful building blocks to induce reverse turn second-
ary structures in peptides.8
This triple biomedical, synthetic, and structural interest
has stimulated considerable research efforts toward the
enantioselective synthesis of â-lactams.9 The stereocontrolled
Staudinger reaction (ketene-imine cycloaddition), which
relies on the use of chiral auxiliaries, and the Gilman-
(4) (a) Yoakim, C.; Ogilvie, W.; Cameron, D. R.; Chabot, C.; Guse, I.;
Hache´, B.; Naud, J.; O’Meara, J. A.; Plante, R.; De´ziel, R. J. Med. Chem.
1998, 41, 2882. (b) Gerona-Navarro, G.; Pe´rez de Vega, M. J.; Garc´ıa-
Lo´pez, M. T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.; Gonza´lez-
Mun˜iz, R. J. Med. Chem. 2005, 48, 2612. (c) Sperka, T.; Pitlik, J.; Bagossi,
P.; To¨zser, J. Bioorg. Med. Chem. Lett. 2005, 15, 3086.
(5) Adlington, R. M.; Baldwin, J. E.; Becker, G. W.; Chen, B.; Cheng,
L.; Cooper, S. L.; Hermann, R. B.; Howe, T. J.; McCoull, W.; McNulty,
A. M.; Neubauer, B. L.; Pritchard, G. J. J. Med. Chem. 2001, 44, 1491.
(6) Kvaerno, L.; Werder, M.; Hauser, H.; Carreira, E. M. J. Med. Chem.
2005, 48, 6035.
(1) For recent reviews on the biological activity of â-lactams, see: (a)
Singh, G. S. Mini-ReV. Med. Chem. 2004, 4, 69. (b) Singh, G. S. Mini-
ReV. Med. Chem. 2004, 4, 93. (c) Veinberg, G.; Vorona, M.; Shestakova,
I.; Kanepe, I.; Lukevics, E. Curr. Med. Chem. 2003, 10, 1741. (d) Kidwai,
M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem. 1999, 6, 195.
(2) Sutton, J. C.; Bolton, S. A.; Hartl, K. S.; Huang, M.-H.; Jacobs, G.;
Meng, W.; Ogletree, M. L.; Pi, Z.; Schumacher, W. A.; Seiler, S. M.;
Slusarchyk, W. A.; Treuner, U.; Zalher, R.; Zhao, G.; Bisacchi, G. S. Bioorg.
Med. Chem. Lett. 2002, 12, 3229.
(3) Clemente, A.; Domingos, A.; Grancho, A. P.; Iley, J.; Moreira, R.;
Neres, J.; Palma, N.; Santana, A. B.; Valente, E. Bioorg. Med. Chem. Lett.
2001, 11, 1065.
(7) (a) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921.
(b) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377.
10.1021/ol070533d CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/24/2007

Speeter reaction (enolate-imine condensation), using an
enantiomerically pure ester or imine component, are among
the most extensively used methodologies to achieve this
goal.10,11 In addition, several examples of the direct catalytic
enantioselective synthesis of â-lactams have lately been
reported.12
In this context, we have described that the base-promoted
cyclization of N-benzyl-N-chloroacetyl amino acid deriva-
tives I affords the corresponding 3-unsubstituted 4-alkyl-4-
alkoxycarbonyl-2-azetidinones II (Figure 1).13 Of particular
analogues II and (b) will the additional stereogenic center
in III have any influence on the memory of the chirality
process? The modulation of the memory of chirality by an
extra stereogenic center at the amino acid side chain has been
previously examined,15 but there are no reports on the
possible modulation due to the chirality of the alkylating
agent.
This piece of work deals with our initial attempts to shed
light on the above indicated points through the cyclization
of different optically pure N-(p-methoxybenzyl)-N-(2-chlo-
ro)propionyl amino acid derivatives (III, R3 ) CH3).
Because the Phe derivatives I (R1 ) Bzl) were stereose-
lectively converted into the corresponding â-lactams II, due
to the memory of chirality,14c Phe was selected as an
appropriate initial model to investigate the III to IV
transformation. To explore the stereochemical outcome of
the cyclization reaction, the four possible diastereoisomeric
intermediates were needed. Using Pmb-L-Phe-OMe (1a) as
a starting amino acid derivative, intermediates 3a and 3b
were prepared by acylation with racemic 2-chloropropionyl
chloride (2ab), followed by separation of the diastereoiso-
mers in a flash column (Scheme 1). The absolute configu-
ration of these N-chloropropionyl Phe derivatives was
assigned by unequivocal synthesis of isomer 3a by coupling
1a with enantiomerically pure 2(S)-chloropropionic acid (4a)
in the presence of BOP. This coupling reaction evolved with
lower yield than the acylation with the acyl chloride, and
some unwanted racemization of the 2(S)-chloropropionic acid
was observed. Due to this fact and to the ease of the
chromatographic separation, the racemic 2-chloropropionyl
chloride (2ab) was also used for the synthesis of diastereo-
isomeric intermediates 3c and 3d from H-Pmb-D-Phe-OMe
(1b).
The base-promoted cyclization of each diastereoisomer of
3 resulted in a unique 3,4-cis â-lactam, indicating the high
degree of diastereoselectivity in this reaction (Scheme 1).
Moreover, regardless of the R-configuration, 2′S-intermedi-
ates 3a and 3c afforded the same 3S,4S 2-azetidinone, 5a
(64%, ee >98%).16 The same cyclization reaction with
derivatives 3b and 3d, both with a 2′R configuration, resulted
in the 3R,4R â-lactam 5b (66%), the enantiomer of 5a. These
results pointed out the exquisite enantiocontrol of this
transformation, with the construction of the quaternary
stereogenic center fully directed by the configuration of the
2-chloropropionyl substituent and completely independent
of the configuration of the starting amino acid. Therefore, it
can be concluded that the asymmetry due to the memory of
chirality is not relevant at all in this case. A similar 2,3-cis
selectivity was observed in a related intramolecular alkylation
leading to azetidine-derived amino acids.17,18
Figure 1. 1,3,4-Tri- and 1,3,4,4-tetrasubstituted â-lactams from
amino acid derivatives.
interest in this synthesis is the modest enantioselectivity
observed during the â-lactam ring formation (ee up to 58%),
constituting novel examples of asymmetry due to the memory
of chirality.14
Considering that the 1,3,4-substitution pattern is frequently
observed among the bioactive monocyclic 2-azetidinones,
the development of stereoselective routes to related 1,3,4,4-
tetrasubstituted analogues could be of value to medicinal
chemistry programs. To this purpose, we decided to inves-
tigate the cyclization of enantiomerically pure N-benzyl-N-
chloroalkanoyl amino acid derivatives III (Figure 1). We
were interested in answering two main questions: (a) could
the 1,3,4,4-tetrasubstituted â-lactams IV be obtained by a
procedure similar to that described for the 1,4,4-trisubstituted
(8) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Benito, A.; Cuerdo, L.;
Fratila, R. M.; Jime´nez, A.; Loinaz, I.; Miranda, J. I.; Pytlewska, K. R.;
Micle, A.; Linden, A. Org. Lett. 2004, 6, 4443. (b) Khasanov, A. B.;
Ramirez-Weinhouse, M. M.; Webb, T. R.; Thiruvazhi, M. J. Org. Chem.
2004, 69, 5766. (c) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.;
Fratila, R. M.; Matute, C.; Domercq, M.; Gago, F.; Mart´ın-Santamar´ıa, S.;
Linden, A. J. Am. Chem. Soc. 2003, 125, 16243. (d) Alonso, E.; Lo´pez-
Ortiz, F.; Del Pozo, C.; Peralta, E.; Mac´ıas, A.; Gonza´lez, J. J. Org. Chem.
2001, 66, 6333.
(9) Singh, G. S. Tetrahedron 2003, 7631.
(10) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Curr. Med.
Chem. 2004, 11, 1837.
(11) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org. Chem. 2000,
563.
(12) (a) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem.
Res. 2004, 37, 592. (b) Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40,
4377.
(13) Gerona-Navarro, G.; Bonache, M. A.; Herranz, R.; Garc´ıa-Lo´pez,
M. T.; Gonza´lez-Mun˜iz, R. J. Org. Chem. 2001, 66, 3538.
(14) (a) Bonache, M. A.; Gerona-Navarro, G.; Mart´ın-Mart´ınez, M.;
Garc´ıa-Lo´pez, M. T.; Lo´pez, P.; Cativiela, C.; Gonza´lez-Mun˜iz, R. Synlett
2003, 1007. (b) Bonache, M. A.; Gerona-Navarro, G.; Garc´ıa-Aparicio, C.;
Al´ıas, M.; Mart´ın-Mart´ınez, M.; Garc´ıa-Lo´pez, M. T.; Lo´pez, P.; Cativiela,
C.; Gonza´lez-Mun˜iz, R. Tetrahedron: Asymmetry 2003, 14, 2161. (c)
Bonache, M. A.; Cativiela, C.; Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R.
Tetrahedron Lett. 2006, 47, 5883.
(15) (a) Kawabata, T.; Oztu¨rk, O.; Suzuki, H.; Fuji, K. Synthesis 2003,
505. (b) Kawabata, T.; Majumdar, S.; Tsubaki, K.; Monguchi, D. Org.
Biomol. Chem. 2005, 3, 1609.
(16) The S,S/R,R ratio was measured by chiral HPLC. Column: Chiral-
pack ID (0.46 × 15 cm). Eluent: EtOH/hexane 5:95. Flow rate: 1 mL/
min. tR: 5a ) 10.81 min. tR: 5b ) 9.75 min.
(17) Sivaprakasam, M.; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.;
Rama Rao, K. Synlett 2006, 781.
(18) Sivaprakasham, M.; Couty, F.; Evano, G.; Srinivas, B.; Sridhar, R.;
Rao, K. M. ARKIVOC 2007, 71.
1594
Org. Lett., Vol. 9, No. 8, 2007

Scheme 1. Synthesis of 1,3,4,4-Tetrasubstituted â-Lactams
Scheme 2. Synthesis of 1,3,4,4-Tetrasubstituted â-Lactams
from Phe Derivatives
from Different Amino Acids
a cis disposition between these groups, the final trans spatial
arrangement was confirmed after transformation of 5a into
18a (Figure 2). Thus, in 18a, there is a strong NOE (2.5%)
between the 3-CH3 protons and one proton of the 4-hy-
droxymethyl group, resulting from the reduction of the
methyl ester in 5a, while keeping the above-mentioned weak
NOE (0.3%) between Me and Bzl groups. In a similar way,
a 3.5-9% NOE value between H-3 and 4-CH3 or 4-CH2
protons in compounds 12-14 is indicative of the placement
of these protons in the same face of the four-membered ring.
In the second step, the configuration at the C4 position of
the â-lactam was indirectly assigned through the synthesis
of dipeptide derivatives 15a-17a and 15b-17b, having
L-Ala-OMe or L-Phe-OMe C-terminal residues.21 In each pair
of diastereoisomers, the dipeptide with high retention time
in HPLC and a more shielded chemical shift of the â-H
aliphatic side chain protons was assigned as the heterochiral
dipeptide, namely, 15b-17b (Table 1).22
To further evaluate the scope of this reaction, we explored
the synthesis of â-lactams from different amino acids,
namely, Ala, Lys, and Glu (Scheme 2). Due to inefficient
chromatographic separation, the enantiopure 2-chloropro-
pionyl derivatives 9a-11a and 9b-11b were prepared by
coupling of the corresponding N-Pmb amino acid derivative
with 2(S)- and 2(R)-chloropropionic acid, respectively.
PyBroP/DIEA was used to minimize as much as possible
the racemization of the starting chloropropionic acid.19,20
Again, only one â-lactam (12-14, 60-70% yield) was
obtained from each N-chloropropionyl precursor, demon-
strating the versatility and usefulness of the developed
procedure to synthesize enantiomerically pure tetrasubstituted
2-azetidinones.
These stereochemical results could be explained through
the formation of enolate intermediates in which the approach
Scheme 3. Synthesis of â-Lactam-Derived Dipeptides
The assignment of the absolute configuration of the highly
substituted â-lactams described here was performed in two
steps. First, the trans-relationship between the alkyl substit-
uents at 3,4 positions was determined by NOE experiments.
Although a weak NOE (0.5%) between the 3-CH3 protons
and one of the 4-CH2 protons in compound 5a could suggest
(19) Full details of the coupling agents and bases used for the optimiza-
tion of the synthesis of 9a are indicated in the Supporting Information.
(20) Diastereoisomeric excess values: 9a (96%), 9b (92%), 10a (83%),
10b (81%), 11a ( 98%), and 11b ( 98%). Measured by HPLC.
Org. Lett., Vol. 9, No. 8, 2007
1595

Figure 2. NOE experiments.
of the alkylating agent is dictated by the configuration of
the 2-chloropropionyl moiety. As shown in Figure 3, the
formation of the trans-3R,4S â-lactam is hindered by the
existence of close contacts between the 2′-methyl group and
the amino acid side chain, destabilizing the precursor pro-
R,S enolate.
In summary, we have developed a highly stereoselective
synthesis of tetrasubstituted â-lactams from simple amino
acid derivatives. The stereochemical control of the cyclization
to the four-membered ring is fully dictated by the configu-
ration of the 2-chloropropionyl group in the linear precursors.
In fact, the presence of the propionyl chiral center totally
abolished the asymmetric induction by memory of chirality
observed in the cyclization of the corresponding acetyl
Figure 3. Z-Enolates from 2(R)-chloropropionyl amino acid
derivatives.
analogues. In addition to the exceptional diastereo- and
enantiocontrol, the process tolerates a wide variety of
substituents, is short and mild, and is operationally simple.
Given the usefulness of â-lactams in organic and medicinal
chemistry, we believe that the procedure presented herein
may be of great applicability in these fields.
Acknowledgment. The authors thank the Spanish Min-
istry of Education and Science (SAF-2006-01205) for
financial support. P.P.-F. is a CSIC I3P predoctoral fellow.
Supporting Information Available: Experimental details
and analytical and spectroscopic data for compounds 3-18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Table 1. Chemical Shifts and Retention Times Used for
Configurational Assignments
compd
R1
R2
δ â-Ha (ppm) tR HPLC (min)
13.34b
15.02b
13.20c
15.25c
7.89d
OL070533D
15a
15b
16a
16b
17a
17b
CH2Ph
CH2Ph
CH3
CH3
CH3
CH2Ph
CH2Ph
0.84
0.71
1.46
1.37
1.85
1.72
(21) For configurational assignments in dipeptide derivatives composed
by one aliphatic and one aromatic amino acid, see: (a) Gonza´lez-Mun˜iz,
R.; Cornille, F.; Bergeron, F.; Ficheux, D.; Pothier, J.; Durieux, C.; Roques,
B. P. Int. J. Pept. Protein Res. 1991, 37, 331. (b) Fournie´-Zaluski, M. C.;
Lucas-Soroca, E.; Devin, J.; Roques, B. P. J. Med. Chem. 1986, 29, 751.
(22) The validity of these rules has unequivocally been demonstrated
for a related dipeptide derivative composed by a Phe-derived â-lactam,
without the 3-methyl substituent, and L-Ala-OMe: Gerona-Navarro, G.;
Garc´ıa-Lo´pez, M. T.; Gonza´lez-Mun˜iz, R. J. Org. Chem. 2002, 67, 3953.
CH3
(CH2)4NHBoc CH2Ph
(CH2)4NHBoc CH2Ph
8.35d
a
b
â-H of the aliphatic residue. 40:60 MeCN/H2O (0.05% TFA),
c
d
Novapak. 35:65, Novapak. 45:55, Deltapak.
1596
Org. Lett., Vol. 9, No. 8, 2007