Organocatalyzed stereospecific C-C bond formation of β-lactams

Article abstract of DOI:10.1039/c3ob41858h

Herein, we report the development of mild, organocatalyzed routes to novel carbapenam derivatives through aldol, Mannich and Michael C-C bond forming reactions.

Full text of DOI:10.1039/c3ob41858h

Organic &
Biomolecular Chemistry
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Organocatalyzed stereospecific C–C bond formation of
β-lactams†
Cite this: Org. Biomol. Chem., 2013, 11,
8294
Sachin A. Pawar,a Saba Alapour,a Sibusiso Khanyase,a Zamani E. D. Cele,a
Received 11th September 2013,
Accepted 1st November 2013
Srinivas Chitti,a Hendrik G. Kruger,a Thavendran Govender*a and Per I. Arvidsson*a,b
DOI: 10.1039/c3ob41858h
www.rsc.org/obc
Herein, we report the development of mild, organocatalyzed
routes to novel carbapenam derivatives through aldol, Mannich
and Michael C–C bond forming reactions.
Compounds containing β-lactams (Fig. 1) are amongst the
most important molecules in clinical use today.1–3 Most
notable is their wide utility as antibacterial agents and as
related β-lactamase inhibitors; however, β-lactams are also
being explored in other therapeutic areas.4,5 Given the global
challenge of antibiotic resistance,6 there is an urgent need for
increased focus on the discovery and development of anti-
bacterial agents. Bacterial resistance may occur through a number
of pathways, e.g. production of β-lactamases,7 efflux pumps,
and mutations that alters expression and function of trans-
peptidase enzymes – the targets of most β-lactam antibiotics.8,9
As β-lactams function as both transpeptidase- and β-lactamase
inhibitors, much work is being devoted to accessing novel
analogs of these critical molecular frameworks.10 However, the
commercially viable synthesis of many β-lactams remains chal-
lenging due to a high degree of functionalization and chirality
combined with the reactive nature of the core bicyclic ring-
structures. Furthermore, most β-lactam antibiotics, except car-
bapenems and aztreonam, are being produced by biosynthetic
routes rather than through chemical synthesis. Considering
the challenges associated with synthetic modifications of the
β-lactam framework, we envisioned that the mild conditions
offered by organocatalysis might help overcome some of the
limitations of current methodologies and open en route to
hitherto unexplored β-lactams.
Fig. 1 Examples of β-lactam antibiotics: generic structure of penicillins with a
saturated penam core and of synthetic carbapenems (e.g. imipenem, thienamy-
cin, and panipenem).
Scheme 1 Novel HOMO rising strategies offering a mild and facile route to
carbapenam derivatives.
complex molecular skeletons in synthetic chemistry.14–19
Aldol,15,20–24 Mannich15,25,26 and Michael15,27,28 reactions are
some of the most powerful strategies in synthetic organic
chemistry, since it allows the formation of new C–C bonds.29
We envisaged that (2S,5R,6S)-4-nitrobenzyl 6-((R)-1-hydroxy-
During the past decade, asymmetric organocatalysis11–13
has grown extensively as a powerful tool in the construction of
ethyl)-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate
(1),
the common intermediate for the preparation of clinically
used antibiotics imipenem,30 thienamycin31,32 and panipe-
nem,33 could be further substituted via HOMO-rising amine
catalysis,34 thereby promoting reactions with electrophilic sub-
strates (Scheme 1).
aCatalysis and Peptide Research Unit, University of KwaZulu Natal, Durban,
South Africa. E-mail: govenderthav@ukzn.ac.za; Tel: +27 312601845
bScience for Life Laboratory, Drug Discovery & Development Platform & Division of
Translational Medicine and Chemical Biology, Department of Medical Biochemistry
and Biophysics, Karolinska Institutet, Stockholm, Sweden.
E-mail: per.arvidsson@scilifelab.se; Tel: +46 852481398
†Electronic supplementary information (ESI) available: Experimental details and
copies of NMR spectra. See DOI: 10.1039/c3ob41858h
In order to test our hypothesis, we subjected the “carbape-
nam ketone” intermediate 1 to a reaction with the benchmark
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Table 1 Aldol reaction of carbapenam ketone intermediate 1 with aldehyde via enamine activation
Entry
R
Catalyst/additive
Time (h)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
R = H
R = H
R = H
R = H
R = H
R = H
R = H
R = H
R = Ph
R = Ph
R = Ph
R = Ph
L-Proline
24
24
8
24
24
2
24
24
24
24
6
24
24
24
24
24
24
24
48
DMSO
DMSO
Neat
73
74
76
70
NR
60
NR
NR
NR
NR
60
L-Proline/AcOH
L-Proline/AcOH
D-Proline
Pyrrolidine
Pyrrolidine/AcOH
NEt3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Neata
DMF
DMF
DMF
DMF
DMF
NEt3/AcOH
L-Proline
9
10
11
12
13
14
15
16
17
18
19
L-Proline/AcOH
L-Proline/AcOH
L-Proline/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
Pyrrolidine/AcOH
25d
55d
54d
29d
51d
26d
46d
70d
R = Ph
R = 4-NO2 Ph
R = 4-Me Ph
R = 4-OMe Ph
R = 2,4-OMe Ph
R = 4-F Ph
R = Et
DMF
DMF
DMF
a Reactions were performed at excess amount of aldehyde to serve as a solvent (see ESI). b Isolated yields. c Diastereomeric ratio determined by 1H
NMR. d Observed yields from NMR of the crude reaction mixture.
substrate formaldehyde as the electrophile and proline as the evaluate simple pyrrolidine as a catalyst; pyrrolidine on its own
catalyst, Table 1. Various solvents such as DMF, DCM and THF did not result in any conversion but when one equivalent of
were evaluated but no conversion was observed via LC-MS acetic acid was added we obtained the product at a high con-
except when DMSO was employed (Table 1, entry 1). When the version rate (Table 1, entries 5, 6).
reactions were conducted with reagent grade DMSO as the
In order to prove that the reaction was indeed operating
solvent, we observed the presence of the product and a hydro- through the postulated enamine intermediate, and did not
lyzed form of the starting materials (+18 m/z on LC-MS). The simply involve the enol tautomer of ketone 1, we performed
use of dry DMSO resulted in no detection of the hydrolyzed the reaction with triethylamine as a catalyst, with and without
starting material but also resulted in a slower and low yielding acetic acid; however, no reaction was observed in any of these
reaction. Acid additives are common additives in the organo- cases (Table 1, entries 7, 8), thus supporting the need for
catalyzed aldol reactions,35 so we next investigated the effect of HOMO rising catalysis of the reaction. Aromatic aldehydes, i.e.
formic and acetic acids. It was observed that there was no benzaldehyde as the electrophile, did not result in any conver-
difference in the reactivity or yields when acetic acid was used sion in DMSO (Table 1, entries 9, 10). However, benzaldehyde
(Table 1, entry 2) whereas formic acid enhanced the hydrolysis and other liquid aldehydes (e.g. 4-methyl and 4-fluoro benz-
side reaction.
aldehyde) gave the corresponding aldol product under neat
Under solvent free conditions, the rate of the reaction was reaction conditions (Table 1, entry 11) as detected by LC-MS.
improved significantly (Table 1, entry 3). D-Proline gave similar Unfortunately, purification via chromatography for all analogs
results as L-proline with respect to reaction times and yields except the benzaldehyde product 3 proved difficult since the
(Table 1, entries 1 and 4), but also with respect to the diastereo- β-lactam ring is prone to hydrolysis during prolonged exposure
meric ratio of the product formed. This result shows that to silica gel. However, aromatic aldehydes, i.e. 4-nitro,
the stereochemical outcome of the reaction is dictated by the 4-methyl, 4-methoxy, 4-fluoro benzaldehyde and propionalde-
chiral ketone 1 rather than the catalyst, as might be expected hyde, gave the product upon changing the solvent from DMSO
when considering the unique bent conformation of the cyclo- to DMF, utilizing pyrrolidine/AcOH as a catalyst. Again purifi-
butanone ring at the bicyclic core. This prompted us to cation proved difficult; crude NMR yield for the reaction of
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Fig. 2 Aldol product 2, resulting from L-proline catalyzed transformation of
“carbapenam ketone” 1 and Formaldehyde.
these electrophiles with carbapenem ketone 1 was in the range
26–70% as determined by crude NMR (Table 1, entries 12–19).
The formation of the new C–C bond in product 2 was con-
firmed by observing the shift of C8 from 64.0 ppm (1) to
131.6 ppm (2) in 13C NMR and disappearance of H8 as a
singlet at 4.76 ppm (1) in H-NMR, Fig. 2. In addition, protons
at C17 showed an HMBC correlation with C8. The 2D NMR
investigation proved the excellent stereoselectivity (d.r. >99 : 1)
seen in the crude LC-MS trace and 1D spectra, and through a
correlation between H17 and H4 in the NOESY spectra, we
could establish the expected exo configuration of the newly
attached group in 2. Compound 3 showed similar HMBC corre-
lations and excellent diastereoselectivity as observed with 2 for
the formation of the C–C bond at C8. The newly formed chiral
centre C17 in compound 3 was determined to be created with a
diastereomeric ratio of 90 : 10.
Scheme 3 Michael reaction on carbapenam intermediate 1.
only formaldehydes resulted in the formation of the Mannich
adducts. A complete NMR assignment of Mannich product
9 proved that the exo-product was formed with complete
diastereoselectivity, in analogy to the aldol product 2 above. In
compound 9, the absolute configuration at C8 was confirmed
by NOE correlation (see ESI†).
Next, we explored the organocatalyzed Michael reaction to
carbapenam intermediate 1 (Scheme 3). The most commonly
studied Michael acceptors with enamine catalyzed reactions
are nitrostyrenes28,36 and enones;37 hence it was decided to
test these substrates in this first report. From the optimized
conditions reported above, we initiated the study by examining
the addition of the carbapenam intermediate 1 to trans-4-
methoxy-β-nitrostyrene in DMSO catalyzed by L-proline. The
reaction offered the product 12 in modest 41% yield in
24 hours. The modest yield was due to low catalytic turnover,
as confirmed through LC-MS analysis of the crude mixture,
where we noticed a peak that corresponded to the Michael
product still bound to the catalyst. To release the product, the
adduct had to be stirred with water and monitored by LC-MS
until only a minor amount of the trapped product could be
detected. Similarly, Michael reaction of carbapenam inter-
mediate 1 with neat cyclopentenone using L-proline as a cata-
lyst produced compound 7 in 67% yield. The observed HMBC
correlation between H17 and C8 in both compounds (12 and
13) proved the formation of the new C–C bond at this position.
Given the high potential for using organocatalysis for acces-
sing hitherto unexplored derivatives of carbapenam and carba-
penem β-lactams, we decided to explore other organocatalyzed
processes, i.e. Mannich and Michael reactions.
First, we decided to perform the direct asymmetric three-
component Mannich reaction of carbapenam intermediate 1
with different amines and aldehydes in DMSO (Scheme 2). In
the presence of 30% L-proline, aldehydes and amines were
reacted with 1 to give products 9, 10 and 11 in moderate yields
(50% to 55%) respectively. These yields are typical of the one
pot Mannich reaction and are attributed to the formation of
the competitive aldol reaction side products as noticed by
LC-MS. Various aromatic aldehydes were tested as electro-
philes, but, similarly to the aldol reaction described above,
1
From the H NMR shifts of H17 in compounds 12 and 13, the
diastereomeric ratio was established to be 88 : 12 and 90 : 10
respectively. The configuration at C8 for 12 was also estab-
lished by NOE correlation as for the aldol and Mannich reac-
tions above.
In summary, the mild reaction conditions that characterize
enamine-based organocatalysis have been shown to offer a
new route to chiral β-lactam derivatives. The reaction scope
has so far been shown to include aldol, Mannich and Michael
reactions. High distereoselectivity was observed in all of the reac-
tions, as would be expected considering the inherent chirality of
the starting carbapenam intermediate. This methodology has
the potential to offer a widely sought after, new synthetic route
to novel and potentially medically useful β-lactam antibiotics.
Scheme 2 Mannich reactions on carbapenam intermediate 1.
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The full substrate scope for the Mannich and Michael reactions 17 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40,
reported here are ongoing in our laboratories.
3726–3748.
18 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43,
5138–5175.
Acknowledgements
19 M. J. Gaunt, C. C. C. Johansson, A. McNally and N. T. Vo,
Drug Discovery Today, 2007, 12, 8–27.
20 S. G. Zlotin, A. S. Kucherenko and I. P. Beletskaya, Russ.
Chem. Rev., 2009, 78, 737–784.
We thank NRF, UKZN and Asphen Pharmacare for financial
support.
21 B. List, R. A. Lerner and C. F. Barbas, J. Am. Chem. Soc.,
2000, 122, 2395–2396.
22 W. Notz and B. List, J. Am. Chem. Soc., 2000, 122, 7386–
7387.
23 A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc.,
2002, 124, 6798–6799.
24 G. Guillena, M. del Carmen Hita, C. Najera and
S. F. Viozquez, J. Org. Chem., 2008, 73, 5933–5943.
25 B. List, P. Pojarliev, W. T. Biller and H. J. Martin, J. Am.
Chem. Soc., 2002, 124, 827–833.
26 B. List, J. Am. Chem. Soc., 2000, 122, 9336–9337.
27 S. Sulzer-Mosse and A. Alexakis, Chem. Commun., 2007,
3123–3135.
28 B. List, P. Pojarliev and H. J. Martin, Org. Lett., 2001, 3,
2423–2425.
29 J. Franzen, M. Marigo, D. Fielenbach, T. C. Wabnitz,
A. Kjaersgaard and K. A. Jorgensen, J. Am. Chem. Soc., 2005,
127, 18296–18304.
30 US 2002/0095034 A1, US 2002/0095034 A1.
31 T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen and
F. A. Bouffard, J. Am. Chem. Soc., 1980, 102, 6161–6163.
32 Y. Nagao, Y. Nagase, T. Kumagai, Y. Kuramoto,
S. Kobayashi, Y. Inoue, T. Taga and H. Ikeda, J. Org. Chem.,
1992, 57, 4238–4242.
Notes and references
1 A. C. Rodloff, E. J. C. Goldstein and A. Torres, J. Antimicrob.
Chemother., 2006, 58, 916–929.
2 R. P. Elander, Appl. Microbiol. Biotechnol., 2003, 61, 385–
392.
3 F.-R. Schmidt, in Industrial Applications, ed. M. Hofrichter,
Springer, Berlin, Heidelberg, 2010, vol. 10, pp. 101–121.
4 J. M. T. Hamilton-Miller, J. Antimicrob. Chemother., 1999,
44, 729–734.
5 T. Sperka, J. Pitlik, P. Bagossi and J. Tozser, Bioorg. Med.
Chem. Lett., 2005, 15, 3086–3090.
6 F. Rossi, Clin. Infect. Dis., 2011, 52, 1138–1143.
7 M. Baroud, I. Dandache, G. F. Araj, R. Wakim, S. Kanj,
Z. Kanafani, M. Khairallah, A. Sabra, M. Shehab, G. Dbaibo
and G. M. Matar, Int. J. Antimicrob. Agents, 2013, 41, 75–79.
8 B. G. Spratt, J. Antimicrob. Chemother., 2012, 67, 1578–
1588.
9 A. Zervosen, E. Sauvage, J.-M. Frere, P. Charlier and
A. Luxen, Molecules, 2012, 17, 12478–12505.
10 R. B. Hamed, J. R. Gomez-Castellanos, L. Henry, C. Ducho,
M. A. McDonough and C. J. Schofield, Nat. Prod. Rep.,
2013, 30, 21–107.
33 CN20111233337 20110816.
11 S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem.
Rev., 2007, 107, 5471–5569.
34 L. Dell’Amico, L. Albrecht, T. Naicker, P. H. Poulsen and
K. A. Jorgensen, J. Am. Chem. Soc., 2013, 135, 8063–8070.
35 D. Gryko, M. Zimnicka and R. Lipinski, J. Org. Chem., 2007,
72, 964–970.
36 H. Chen, Y. Wang, S. Wei and J. Sun, Tetrahedron: Asymme-
try, 2007, 18, 1308–1312.
12 D. W. C. MacMillan, Nature, 2008, 455, 304–308.
13 H. Pellissier, Tetrahedron, 2007, 63, 9267–9331.
14 B. List, Acc. Chem. Res., 2004, 37, 548–557.
15 W. Notz, F. Tanaka and C. F. Barbas, Acc. Chem. Res., 2004,
37, 580–591.
37 Y. G. Chi and S. H. Gellman, Org. Lett., 2005, 7, 4253–
4256.
16 P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew.
Chem., Int. Ed., 2008, 47, 6138–6171.
This journal is © The Royal Society of Chemistry 2013
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