Simple, highly enantioselective access to quaternary 1,3,4,4- tetrasubstituted β-lactams from amino acids: A solid-phase approach

Article abstract of DOI:10.1002/adsc.200800432

An operationally simple four-step procedure for the solid-phase synthesis of chiral (3S,4S)-1,3,4,4-tetrasubstituted β-lactams is described. The key step for the four-membered ring formation consisted in the enantioselective phosphazene base-assisted cyclization of resin-bound N-(alkyl)-N-[(S)-2- chloropropionyl]amino acid derivatives. A low-epimerization process during the incorporation of the 2S-chloropropionyl moiety into the N-alkylamino acid resins was crucial for the final stereochemical outcome, since the 3,4-stereochemistry was exclusively dictated by the configuration of this moiety. To evaluate the scope of this procedure a small library of quaternary, highly functionalized β-lactams has been generated.

Full text of DOI:10.1002/adsc.200800432

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DOI: 10.1002/adsc.200800432
Simple, Highly Enantioselective Access to Quaternary
1,3,4,4-Tetrasubstituted b-Lactams from Amino Acids:
A Solid-Phase Approach
Paula PØrez-Faginas,a M. Teresa Aranda,a Laoise Coady,a M. Teresa García-López,a
and Rosario Gonzµlez-MuÇiza,*
a
Instituto de Química MØdica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
Fax : (+34)-91-564-4853; e-mail: iqmg313@iqm.csic.es
Received: July 11, 2008; Published online: October 7, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800432.
Abstract: An operationally simple four-step proce- outcome, since the 3,4-stereochemistry was exclu-
dure for the solid-phase synthesis of chiral (3S,4S)- sively dictated by the configuration of this moiety.
1,3,4,4-tetrasubstituted b-lactams is described. The To evaluate the scope of this procedure a small li-
key step for the four-membered ring formation con- brary of quaternary, highly functionalized b-lactams
sisted in the enantioselective phosphazene base-as- has been generated.
sisted cyclization of resin-bound N-(alkyl)-N-[(S)-2-
chloropropionyl]amino acid derivatives. A low-epi-
merization process during the incorporation of the Keywords: amino acids; asymmetric synthesis; cis-b-
2S-chloropropionyl moiety into the N-alkylamino lactams; peptidomimetics; phosphazenes; solid-phase
acid resins was crucial for the final stereochemical synthesis
Introduction
achieved through the employment of chiral acid chlor-
ides or chiral aldehydes, leading to 3,4-cis-b-lactams
The 2-azetidinone (b-lactam) ring is the central core as the main isomers in all described cases.[17] The use
of the most extensively used class of antibiotics,[1–4] of of appropriate linkers on the polymeric support, such
numerous inhibitors of different proteases,[5–8] and of as benzyloxyaniline and Rink amide handles, also al-
some anticancer agents.[9,10] Moreover, b-lactams are lowed the preparation of NH-free 3,4-disubstituted b-
practical intermediates for the synthesis of a variety lactams by the [2+2]ketene-imine cycloaddition.[18]
of high added value products (b-lactam synthon Alternatively, this type of 3,4-disubstituted b-lactams
method).[11,12] In the peptidomimetics field, the b- can also be prepared through the N1-C4 ring closure
lactam nucleus has also been used to stabilize peptide of serine and threonine derivatives attached to a
conformations, namely reverse b-turns.[13]
The interest of b-lactams in these three fields, bio- cleavage with SmI2.[19]
resin-bound hydroxylamine, followed by reductive
medicine, organic synthesis and peptidomimetics, has
On the other hand, 2-azetidinones with 3,3- or 4,4-
encouraged extensive efforts toward the preparation disubstitution patterns have also been reported. Thus,
of new 2-azetidinone derivatives.[14] In addition, to quaternary 3,3-disubstituted b-lactams were obtained
make possible the generation of molecular diversity from immobilized ester enolates in a traceless tri-
on the b-lactam scaffold, most synthetic approaches
to 2-azetidinones have also been adapted to solid- ed derivatives were prepared both in solution and in
phase methodologies.[15]
the solid phase by the base-assisted intramolecular al-
azene linker and imines,[20] whereas 1,4,4-trisubstitut-
The synthesis of racemic 1,3,4-trisubstituted cis- or kylation (C3-C4 bond formation) of N-chloroacetyla-
trans-b-lactams via a [2+2]Staudinger reaction has mino acid derivatives.[21,22] These latter derivatives,
profusely been explored from both resin-bound with an uncommon substitution array, have a 4-car-
imines and carboxylic acids.[16] Moreover, the asym- boxy group, like a number of b-lactam-based protease
metric solid-phase version of this procedure has been inhibitors, but in contrast to most of these inhibitors
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they lack substituents at the C3 position.[5–7] In this
context, we have recently described that the base-pro-
moted cyclization of optically pure N-(p-methoxyben-
zyl)-N-(2-chloro)propionylamino acid derivatives re-
sulted in a diastereo- and enantioselective solution
route to valuable 1,3,4,4-tetrasubstituted cis-b-lac-
tams.[23] Theoretical calculations on the transition
states of deprotonation and intramolecular halide dis-
placement have indicated that the stereochemical
course of the reaction is entirely governed by the con-
figuration of the N-(2-chloro)propionyl moiety.[24]
Taking into account that the 1,3,4-trisubstitution pat-
tern is recurrent in bioactive monocyclic b-lactams,
the development of environmentally friendly proce-
dures for the synthesis of unusual 1,3,4,4-analogues
could be of major interest in medicinal chemistry pro-
grams. To approach the future generation of highly
substituted b-lactam combinatorial libraries, we de-
scribe here the adaptation of the above recent solu-
tion procedure to solid-phase methodology for the ex-
peditious preparation of a small set of tetrasubstituted
b-lactams.
Results and Discussion
Four representative amino acids, Ala, Phe, Lys and
Glu, were selected for the incorporation of a diversity
of appendages at the R1 position during the solid-
phase synthesis of 1,3,4,4-tetrasubstituted b-lactams,
while five diverse aldehydes, both aromatic and ali-
phatic, were used for the decoration of the N atom
(R2) (Scheme 1).[25] By employing the Fmoc-Xaa-
Wang resins 1–4 as starting materials, and after re-
moval of Fmoc protecting groups with piperidine, the
resulting amines were condensed with a 6-fold molar
excess of the corresponding aldehyde in (MeO)3CH
to yield the resin-bound imines, which were satisfacto-
rily reduced with NaBH3CN (1% AcOH) to the ex-
Scheme 1. Solid-phase synthetic approach to b-lactams 17–
20 and diversity incorporated at R1 and R2 positions.
pected N-alkylamino acid derivatives 5–8, according method for the in situ conversion of (S)-2-chloropro-
to a reported procedure.[26]
pionic acid into (S)-2-chloropropionyl chloride was
Attempts to acylate resins 5–8 with (S)-2-chloropro- required. The combination of trichloroacetonitrile
pionic acid, under the same conditions as employed in and triphenylphosphine, as chlorinating agent, and
our previous approach in solution, PyBrop/DIEA, re- DIEA as HCl scavenger, as reported by Chavarisi,[27]
sulted in very low conversions to N-alkyl-N-chloro- led to very good acylation yield, but the quasi total
propionyl derivatives 9–12 (Figure 1A, Table 1, epimerization of compound 10d at the chloropropion-
Method A). Using resin 6d as model, the formation yl residue was observed (Figure 1C, Table 1, Method
of the corresponding acyl derivative 10d was opti- C, 10d:10’d dr=53:47). Considering that DIEA was
mized. Following our first approach to quaternary also present in Method A, the observed lack of selec-
1,4,4-trisubstituted b-lactams from amino acids, the tivity could probably be due to a high conversion of
reaction of the immobilized Phe derivative 6d with an the activated (S)-2-acyl chloride into the (R)-2-isomer
excess (5 equiv.) of commercial (R,S)-2-chloropro- by means of this base, more likely than the direct epi-
pionyl chloride, in the presence of propylene oxide as merization of compound 10d. A modification of
hydrochloric acid scavenger, triggered the total trans- Method C, in which the acid scavenger DIEA was
formation to the expected chloropropionyl derivatives changed to propylene oxide, was evaluated to avoid
S,S-10d and R,S-10’d, with some kinetic resolution the presence of any base in the reaction. Under these
(Figure 1B, Table 1, 10d:10’d dr=70:30). Therefore, a virtually neutral conditions (Method D), we found the
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Simple, Highly Enantioselective Access to Quaternary 1,3,4,4-Tetrasubstituted b-Lactams
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ferent solvents (CH2Cl2, THF, DMF). From these op-
timization experiments, it can be concluded that only
stronger phosphazene bases (BEMP and BTTP) in
combination with highly polar solvents (DMF) give
satisfactory cyclization results to b-lactam 13–16, al-
though the repetition of the process was always neces-
sary. Immobilized b-lactams were finally detached
from the resin using TFA to give the expected 1,3,4,4-
tetrasubstituted 2-azetidinones 17–20. A simple filtra-
tion of the crude b-lactams through silica or reverse-
phase SPE cartridges generally resulted in high purity
of the final compounds (Table 2).
Each b-lactam was obtained as a single cis-diaste-
reoisomer, as deduced from NOE experiments.[23] The
enantiomeric purity of one of the b-lactams, namely
18a, was investigated through transformation to dia-
stereoisomeric dipeptides 21 and 22 (Scheme 2), and
evaluation of the crude reaction mixtures by HPLC
(see Supporting Information for details). These dipep-
tides are identical to those previously prepared in so-
lution from the same Phe-derived b-lactam.[23] Al-
though some kinetic resolution was observed, dipep-
tide derivatives were obtained in about 92:8 diaste-
reoisomeric ratio, quite similar to that the observed in
the related starting material N-chloropropionyl deriv-
ative 10d (Figure 1, Table 1, 10d:10’d dr=94:6). This
result is an indication of the high enantiomeric purity
in which the b-lactams are formed by this solid-phase
procedure, despite the absence of either temporary
chiral auxiliaries or chiral catalysts. This selectivity
was explained through theoretical calculations that in-
dicated a big difference in energy between the transi-
tions states leading to cis- and trans-b-lactams,[24] and
Figure 1. Optimization of the coupling procedure to inter-
mediate 10d. A: 2(S)-chloropropionic acid/PyBrop/DIEA/
THF (twice). B: 2(R,S)-chloropropionyl chloride/propylene
G
oxide/THF. C: 2(S)-chloropropionic acid/Cl3CCN/PPh3/
DIEA/THF. D: 2(S)-chloropropionic acid/Cl3CCN/PPh3/pro-
pylene oxide/THF.
best balance between conversion and selectivity the cyclization to S,S- or R,R-configured azetidinones
(Figure 1, Table 1, 10:10’d dr=94:6). Therefore, these exclusively dictated by the configuration at the N-
conditions were selected for the acylation reactions of chloropropionyl moiety in the starting derivatives 9–
all resins 5–8.
12.
To corroborate this point, acylation of resin 6a with
With resin-bound amino acid derivatives 9–12 in
hand, the next question addressed was the search for (R)-2-chloropropionic acid to R,S-10’a, followed by
suitable cyclization conditions, investigating different BTPP-mediated cyclization and cleavage with TFA
organic soluble bases (P1-t-Bu, BEMP, BTPP) in dif- afforded the 3R,4R-b-lactam 18’a (Figure 2), an enan-
Table 1. Optimization of acylation of resin 6d.
Method Acylation agent
Reaction conditions
% Conversion (1st cou- % Conversion (2nd cou-
pling)[a] pling)[a]
6d [%] 6d [%]
10d [%]
10d [%]
A
B
C
D
(S)-2-Cl
N
PyBrop/DIEA/THF
27
76
74
72
23
25
34[b]
99[c]
99[d]
94[e]
65
-
-
A
(S)-2-Cl
(S)-2-Cl
Cl3CCN/Ph3P/THF, propylene oxide 90
-
[a]
[b]
[c]
[d]
[e]
Measured by HPLC.
S,S-10d:R,S-10’d dr=97:3.
S,S-10d:R,S-10’d dr=70:30.
S,S-10:R,S-3ꢀ dr=53:47.
S,S-3:R,S-10’dꢀ dr=94:6.
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Table 2. Yield and (purity) of the array of b-lactams 17–20.
Product
Yield
Product
Yield
Product
Yield
Product
Yield
[%][a]
[%][a]
[%][a]
[%][a]
(purity)
(purity)
(purity)
(purity)
17a 14 (92)
18a 12 (41)
19a 24 (98)
20a 12 (69)
17b 47 (98)
18b 61 (93)
19b 33 (95)
20b 24 (98)
17c 26 (97)
18c 49 (86)
19c 34 (93)
20c 24 (45)
17d 47 (98)
18d 45 (94)
19d 23 (96)
20d 40 (83)
17e 29 (93)
18e 37 (94)
19e 41 (98)
20e 11 (82)
[a]
Yield of isolated compounds after cartridge purification. Purity was determined by HPLC.
tiomer of 18a. Therefore, the absolute configuration reoselective procedures for the generation of b-lac-
of the final 2-azetidinone, 3S,4S or 3R,4R, can be se- tams through the C3-C4 bond formation.[28]
lected as a function of the configuration of the start-
Additionally, the reaction can be extended to the
ing 2-chloropropionic acid. In this respect, our preparation of 2-azetidinones with substituents differ-
method favorably competes with other reported ste- ent from the methyl group at position 3. Thus, acyla-
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Simple, Highly Enantioselective Access to Quaternary 1,3,4,4-Tetrasubstituted b-Lactams
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Scheme 3.
proximately 1:1 ratio. Further efforts to optimize this
reaction, by exploring Ph2SiH2 or PhSiH3 as reducing
agents, THF or DCM as solvent, increasing the per-
centage of catalyst, and repeating the reaction up to
three times were unsuccessful. In any case, pure azeti-
dines 25 were obtained in low-to-moderate yield after
careful purification on silica gel cartridges of the aze-
tidine/azetidinone mixtures of reaction.
Scheme 2.
Conclusions
In summary, we report the first expeditious solid-
phase procedure for the preparation of optically
active quaternary cis-b-lactams with an innovative
substitution pattern. The route, which is based on the
cyclization of chiral N-2-chloroalkanoylamino acid de-
Figure 2.
tion of 6d with (S)-2-chloroisobutyric acid and comple- rivatives, does not require any chiral auxiliary or cata-
tion of the remaining three-step procedure gave the 3- lyst, since the high enantioselectivity observed in the
isopropyl-b-lactam 23 in excellent yield (Figure 2).
formation of the four-membered ring is exclusively di-
It is interesting to comment that the success of this rected by the configuration of the 2-chloroalkanoyl
solid-phase synthesis of b-lactams is highly dependent substituent. In addition, the versatility of the method
on the solid support. Thus, while Wang resin gave sat- was demonstrated by means of the satisfactory results
isfactory results (see above), the use of Wang-type obtained with the combination of different starting
(MPPA) and Rink amide-type resins should be avoid- amino acids and aldehydes. Notably, the procedure
ed, due to undesired detachment during the cycliza- also permits different configurations of the final b-lac-
tion step and to diketopiperazine formation,[21b] re- tams just by changing the configuration of the 2-chlo-
spectively.
A
In an attempt to apply the “libraries from libraries” step. It is expected that this procedure could comple-
concept,[29] the on-resin chemoselective reduction of ment other approaches for the synthesis of highly sub-
the 2-CO group in some resin-bound b-lactams 14 tituted b-lactams. Further exploration of the applica-
was also investigated (Scheme 3).[30] However, the tions of this methodology is currently underway.
solid-phase version of our previously reported proce-
dure in solution resulted in mixtures of the expected
azetidine 25 and the unreacted b-lactam 18, in an ap-
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and the resin was treated with (S)-2-chloropropionic acid
(1 mmol), Cl3CCN (2.25 mmol) and propylene oxide
(3 mmol), and cooled to 08C. Then, Ph3P (2.4 mmol) was
added and the reaction was continued at room temperature
for 5 h. The resin was filtered and washed consecutively
with THF/DMF:MeOH (1:1)/DMF/DCM/MeOH (1:1)/
DCM/THF (5”0.5 min). The reaction was repeated once
and left overnight. The following work-up was as indicated
in method A.
Experimental Section
General Procedures for the Solid-Phase Synthesis of
Quaternary b-Lactams from Amino Acids
Reductive Amination (Resins 5–8)
Fmoc-Xaa-Wang resins (0.2 mmol) were washed with DCM/
DMF/DCM/DMF (5”0.5 min) and piperidine/DMF (1:4 v/v,
1”1 min, 3”10 min). After the cleavage of the Fmoc pro-
tecting group, the resins were washed with DMF/DCM/
DMF/DCM (5”0.5 min) and TMOF (2”0.5 min). Then,
TMOF and the corresponding aldehyde (1.2 mmol) were
successively added. In the case of isobutyraldehyde and bu-
tyraldehyde an additional 1% of MeOH was also added to
the reaction mixture. Formation of the imine overnight at
room temperature was followed by filtration, and washing
with TMOF (1”0.5 min). To the resulting resin-bound
imines were added TMOF, and treated with NaBH3CN
(0.6 mmol), in the presence of AcOH (1%) for 24 h. The ob-
tained resins were filtered, washed consecutively with DMF
(5”0.5 min), DMF/MeOH (1:1, 5”0.5 min) and DCM (5”
0.5 min), and dried under vacuum.
Base-Promoted Cyclization to Resin-Bound
b-Lactams 13–16
The corresponding resins 9–12 (0.2 mmol) were washed with
DCM/DMF/DCM/DMF (5”0.5 min), swollen in DMF and
treated at room temperature with BTPP (1 mmol), under an
argon atmosphere. Reactions were continued overnight, fil-
tered and washed with DMF/DCM/DMF/DCM (5”
0.5 min). The resins were swollen in DMF and the reactions
were repeated again. Finally, resin-bound b-lactams 13–16
were filtered, washed with DMF/DCM/DMF/DCM (5”
0.5 min), and dried under vacuum.
Cleavage from the Resin to 1,3,4,4-Tetrasubstituted
b-Lactams 17–20
Resins 13–16 (0.2 mmol) were treated with TFA/H2O (95:5,
1.5 mL) at room temperature for 4 h. After filtration and
washing with DCM, the combined filtrates were concentrat-
ed to give a residue which was dissolved in mixtures of
MeCN/H2O and lyophilized. The resulting residues were pu-
rified on silica gel cartridges (for Ala, Phe and Glu deriva-
tives) or reverse-phase cartridges (for Lys-derived com-
pounds), evaporated and lyophilized from H2O or MeCN/
H2O mixtures.
Incorporation of the Chloroalkanoyl Group (Resins
9–12)
Method A: Resins 5–8 (0.2 mmol) were swollen in DCM
(5”0.5 min) and THF (2”0.5 min). Then, THF was added
and the resin was treated with (S)-2-chloropropionic acid
(1 mmol), and a mixture of PyBroP (1 mmol) and DIEA
(0.9 mmol) in THF was added, and the reaction was contin-
ued at room temperature for 5 h. The resins were filtered
and washed consecutively with THF/DMF/DCM/THF (5”
0.5 min).The reaction was repeated once and left overnight.
Finally, resins 9–12 were filtered, washed with THF/
DMF:MeOH (1:1)/DMF/DCM:MeOH (1:1)/DCM (5”
0.5 min), and dried under vacuum.
Method B: Resins 5–8 (0.2 mmol) were swollen in DCM
(5”0.5 min) and THF (2”0.5 min). Then, THF was added
and the resin was treated with propylene oxide (3 mmol)
and cooled to 08C. Then, chloropropionyl chloride (1 mmol)
was added and the reaction continued at room temperature
for 5 h. The resins were filtered and washed consecutively
with THF/DMF/DCM/THF (5”0.5 min).The reaction was
repeated once and left overnight. The following work-up
was as indicated in method A.
Method C: Resins 5–8 (0.2 mmol) were swollen in DCM
(5”0.5 min) and THF (2”0.5 min). Then, THF was added
and the resin was treated with (S)-2-chloropropionic acid
(1 mmol), Cl3CCN (2.25 mmol) and DIEA (2.25 mmol), and
cooled to 08C. Then, Ph3P (2.4 mmol) was added and the re-
action was continued at room temperature for 5 h. The
resins were filtered and washed consecutively with THF/
DMF/DCM/THF (5”0.5 min).The reaction was repeated
once and left overnight. The following work-up was as indi-
cated in method A.
Acknowledgements
The authors thank the Spanish Ministry of Education and
Science for financial support (SAF-2006–01205), and Guada-
lupe Romero for technical assistance with HPLC and
HPLC-MS. P. P.-F. and M. T. A. thank the CSIC for an I3P
predoctoral fellow and an I3P postdoctoral contract, respec-
tively.
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Simple, Highly Enantioselective Access to Quaternary 1,3,4,4-Tetrasubstituted b-Lactams
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