Iodine(III)-Catalyzed Cascade Reactions Enabling a Direct Access to β-Lactams and α-Hydroxy-β-amino Acids

Article abstract of DOI:10.1021/acs.orglett.6b01658

In the presented method, a one-pot metal-free access to β-lactams is provided. The developed strategy employs a hypervalent iodine(III)-triggered bromination/rearrangement/cyclization cascade reaction that allows the straightforward synthesis of a broad r

Full text of DOI:10.1021/acs.orglett.6b01658

Letter
pubs.acs.org/OrgLett
Iodine(III)-Catalyzed Cascade Reactions Enabling a Direct Access to
β‑Lactams and α‑Hydroxy-β-amino Acids
Christoph Patzelt, Alexander Pothig, and Tanja Gulder*
̈
Department of Chemistry and Catalysis Research Center (CRC), Technical University of Munich, Lichtenbergstrasse 4, 85747
Garching, Germany
S
* Supporting Information
ABSTRACT: In the presented method, a one-pot metal-free
access to β-lactams is provided. The developed strategy
employs a hypervalent iodine(III)-triggered bromination/
rearrangement/cyclization cascade reaction that allows the
straightforward synthesis of a broad range of structurally
different lactams from cheap and easily available imides. This triple cascade reaction is furthermore extendable by an in situ ring-
opening reaction, giving direct access to isoserine derivatives from simple imines in a four-step, one-pot reaction.
he impact of nitrogen-containing heterocycles on the well-
being of mankind is impressively demonstrated by the β-
T
lactams (azetidin-2-ones). With the discovery of the “magic”
drug penicillin (1) in 1928 (Figure 1),1 the golden age of
antibiotic discovery was ignited. Many natural, synthetic, and
semisynthetic antibacterial subclasses2 within the β-lactam family
have been identified since Fleming’s landmark discovery, for
example, the cephalosporins, clavulanates, penemes, carbape-
nems, or the monocyclic monobactams [aztreonam (2)3]. All of
these family members make β-lactams the most frequently
prescribed drugs to cure infections caused by both Gram-positive
and Gram-negative bacteria. In general, the β-lactam nucleus
constitutes a privileged structural motif in medicinal chemistry
and drug development, with its applications reaching far beyond
that of antibiotics, as shown, by the cholesterol-lowering
ezetimibe (3).4 Due to its overall importance, considerable
efforts to introduce reliable and effective methods for the
synthesis of the β-lactam core have been conducted, resulting in
manifold versatile approaches available today,5 spanning from
classical methods, such as the Staudinger ketene cyclo-
addition5c,f,h,6 or the cyclization of β-amino acids,7 to the
Kinugasa reaction,8 intramolecular C−H insertions,5a,i,9 and
carbonylations of aziridines.10 Nevertheless, the construction of
such four-membered heterocycles remains a challenging task
with still a lot of problems to be solved, such as complicated
access to starting materials, nonpractical reaction conditions, low
structural variability, etc. It is therefore not surprising that the
majority of the commercially available β-lactams are still
produced by biotechnological processes. To overcome the
problems in azetidin-2-one synthesis, a perpetual exploration of
new pathways toward these highly rewarding structures is
necessary.
Figure 1. Examples of important drugs and synthetic building blocks
bearing a β-lactam nucleus.
variety of structurally diverse α,α-disubstituted α-hydroxy
carboxylamides 7 equipped with a methylene bromide side
chain. The latter structural feature constitutes a versatile handle
to introduce further structural complexity into these scaffolds,
thus proving amides 7 as useful building blocks. Interestingly,
upon treatment with sterically demanding non-nucleophilic
bases, such as K-selectride, isolated 7a was converted into lactam
8a in 91% yield (Table 1, entry 2). Inspired by this observation,
we were intrigued by the idea of developing a one-pot protocol
for this two-step procedure, which would give straightforward
access to the highly desired target structures 8, directly from
imides 5.
Cyclization of the β-halocarboxyl amides 7 by N,C3-bond
assembly (step b, Table 1) is generally performed using metallic
amides or hydrides, both bases requiring anhydrous conditions,
as exemplified in our two-step synthesis of lactam 8a (Table 1,
entries 1 and 2). Such a reaction setup is not feasible in the
planned reaction cascade, as at least 1 equiv of water is needed to
trigger the ring opening of the oxazolidinonium intermediate
during the rearrangement of imides 5 (step a, Table 1 and SI).12
Based on this precondition, we set out to search for a suitable
Within our research program dealing with the exploration of
unusual reactivities and selectivities triggered by hypervalent λ3-
iodanes,11 we recently reported the iodine(III)-catalyzed
rearrangement of imides 5 using 10 mol % of o-iodobenzamide
6 as the catalyst with N-bromosuccinimide (NBS) as the oxidant
(Table 1, entry 1).12 This method provided access to a huge
Received: June 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01658
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Organic Letters
Letter
a
Table 1. Selected Conditions Applied during the Optimization for the Synthesis of Lactam 8a
b
base
additive
solvent
HFIP
t
conversion, %
>99
7a/8a
112
212
rt
rt
100:0
0:100
c
85
e
K-selectride
1. HFIP
2. THF
HFIP
DCM
THF
>99
df
,
0 °C
77
>99
>99
85
g
3
4
5
6
7
CsF
reflux
reflux
reflux
reflux
reflux
100:0
100:0
9:91
g
CsF
NH4Cl
g
CsF
NH4Cl
g
CsF
NH4Cl, TEBA
NH4Cl, TEBA
THF
85
9:91
CsF
CsF
THF
>99
9:91
f
76
h
8
NH4Cl, TEBA
THF/DCM
reflux
>99
7:93
f
85
h
h
9
CsF
CsF
TEBA
THF/DCM
THF/DCM
reflux
reflux
70
53:47
55:45
10
NH4Cl
>99
a
Unless noted otherwise, the reactions were carried out using imide 5a (20.3 mg, 0.10 mmol, 1.0 equiv), catalyst 6 (3.05 mg, 10.0 μmol, 0.1 equiv),
NBS (19.5 mg, 0.11 mmol, 1.1 equiv), 5 μL aq saturated NH4Cl solution, TEBA (6.83 mg, 30.0 μmol, 0.3 equiv), and CsF (106 mg, 0.07 mmol, 7
b
c
d
equiv) in a 0.10 M solution at reflux. Determined by 1H NMR spectroscopy of the crude mixture. Isolated yield of 7a. Two-step procedure: 7a
e
f
g
h
was isolated and purified before base treatment. 1.2 equiv of base. Isolated yield of 8a. 5 equiv of base. 1:1 mixture. HFIP =
hexafluoroisopropanol; TEBA = triethylbenzylammonium chloride.
base, which is compatible to the λ3-iodane bromination/
Scheme 1. Scope of the Iodine(III)-Catalyzed Triple Cascade
rearrangement conditions and additionally facilitates the
cyclization event. Mild fluoride bases proved to be valuable in
lactam formations in the past7b,13 and should also be tolerated in
step a of our protocol. To our delight, the addition of CsF did not
affect the formation of amide 7a at all using the standard solvents
for this reaction: HFIP or DCM (>99%, entries 3 and 4).
In the latter case, the activation of the in situ formed
iodine(III)-bromo species was necessary using catalytic amounts
of NH4Cl to achieve sufficient conversion of 5a (entry 4).12,14
Unfortunately, in both cases, no ring closure to the desired
heterocycle 8a occurred. Only linear product 7a was detectable
in the crude mixture. More polar solvents, such as THF, however,
led to the fluoride-assisted N,C-cyclization, predominantly giving
rise to 8a (entry 5). Interestingly, the corresponding imino
oxetane (not shown) arising from the likewise possible O-
cyclization of amide 7a was never observed in the reaction
mixture. Adding 30 mol % of phase-transfer catalyst TEBA (entry
6) together with increasing the amount of CsF (entry 7) further
improved the synthesis of lactam 8a (76% yield). By additionally
changing the solvent from pure THF to a 1:1 mixture of THF
and DCM, the optimum conditions for this reaction sequence
were reached and product 8a was furnished directly from starting
material 5a in 5 h and 85% yield (entry 8). The presence of both
ammonium salts (NH4Cl and TEBA) in the reaction mixture was
inevitable for the success of this transformation. Omitting either
of them significantly hampered the lactam formation (entries 9
and 10). This observation clearly showed that NH4Cl played a
decisive role in both parts of the cascade reaction.
Reaction to Lactams 8
groups),15 alkyl and phenyl moieties at the second carboxyl
fragment (R1) were equally well-accepted. The same was true for
variations at the alkene moiety (R3). There, the range of tolerated
substituents spans from simple linear and branched alkyl
portions to benzyl and even heteroaryl fragments.
Even α,β-disubstituted Michael systems, such as in imide 5l,
were smoothly converted to the densely substituted lactam 8l in
68% yield. This process occurred with complete stereoselectivity
conserving the relative configuration of the starting material 5l
(Scheme 2).
With the optimized reaction conditions in hand, we started to
evaluate the substrate scope of this triple cascade. In all cases, the
conversion of imides 5 to the corresponding lactams 8 bearing a
tertiary O-functionality at C-2 proceeded regio- and chemo-
selectively in excellent 60−95% yield (Scheme 1). Side reactions,
such as aromatic bromination, O- instead of N-cyclization, or
carbocyclization, were not observed. Besides structural alter-
ations at the amide nitrogen (R2 = alkyl, aryl, and benzyl
Besides the unique utility of the β-lactam nucleus as a
pharmacophore, its distinct applicability as a key building block
in organic synthesis makes it even more valuable, as it gives access
to most diverse, important nitrogen-containing compound
B
DOI: 10.1021/acs.orglett.6b01658
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Organic Letters
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Scheme 2. Conversion of Trisubstituted Olefin 5l Using the
Iodine(III)-Catalyzed Triple Cascade Reaction
Scheme 4. Scope of the Iodine(III)-Catalyzed Four-Step,
a
One-Pot Reaction to α-Hydroxy-β-amino Acids 9
classes of biological and medicinal interest.5d,16 These reach from
“simple” cyclic and linear molecules, such as amino acids and N-
heterocycles, to structurally complex (macro)cyclic structures
found in alkaloids, taxoids, and other types of natural products.
One prominent example is the Ojima lactam (4, Figure 1),17
which served as the precursor for the α-hydroxy-β-amino acid
fragment in many total synthetic routes to the anticancer agent
taxol.18 As already observed in previous studies in our group,
such α-hydroxy-β-amino acids are obtained in 94% yield by
treating the isolated β-bromocarboxyl amide 7a with NaH
followed by an aqueous workup.12 As this reaction has to involve
the ring opening of the in situ formed lactam 8a (Scheme 3, step
Scheme 3. Concept of the Four-Step, One-Pot Reaction
Sequence to α-Hydroxy-β-amino Acids 9
a
Poducts 9 were all isolated as the corresponding TFA salts.
Scheme 5. Further Transformations of the Obtained Lactams
8 and Isoserines 9
c), we were curious if this heterocycle cleavage can be added on
top of the λ3-iodane-catalyzed halogenation/rearrangement/
cyclization sequence. If so, our protocol can be further extended
to a one-pot, four-step procedure yielding isoserines 9 with a
quaternary center in the α-position, right from the corresponding
imides 5.
Therefore, we adjusted the reaction conditions of the lactam
synthesis described above (Scheme 1). Conversion of lactams to
β-amino acids is typically accomplished by a nucleophilic attack
to the carbonyl group under basic conditions. Unfortunately, this
is not compatible with the rearrangement process of imide 5
(step a), as the formation of the iodine(III)-bromo species is
completely abolished under such conditions.14a Because of this,
ring opening under acidic conditions was envisaged. The best
results for the preparation of 9a were obtained by adding TFA to
the reaction mixture (for details, see SI). All imides 5 employed
in the β-lactam synthesis were easily converted to the
corresponding β-amino acids 9 in good yields of up to 71%
and under complete stereocontrol (dr > 95:5; Scheme 4).
Obtained products 8 and 9 show a quaternary carbon center in
the α-position bearing a hydroxy function, a structural feature
that is difficult to install otherwise. There, the products 10−12
were obtained in good 63−83% yield (Scheme 5a). More
interestingly, treating 8d with alkali metals in liquid ammonia did
not result in the expected reductive debenzylation of β-lactam 8d.
Instead, the ring-extended γ-lactams 13 and 14 having a α,β-
trans-diol functionality were obtained with good diastereose-
lectivities and yields (Scheme 5b). Formation of these intriguing
structures possibly involves a rearrangement reaction with
concomitant ring enlargement, followed by ring opening.
Subsequent reductive ring closure by an intramolecular Pinacol
coupling finalized the five-membered ring formation (see SI).
In summary, we established an as yet unprecedented and
efficient synthetic strategy to highly desirable targets, the β-
lactams 8 and α,α-disubstituted α-hydroxy-β-amino acids 9. To
realize our goal, we combined the unusual reactivity triggered by
hypervalent iodine(III)-catalyzed halogenations with a variety of
other transformations, leading to three-step and even four-step
conversions that can now be conducted in one pot. The broad
compatibility of λ3-iodane chemistry demonstrated here opens
completely new opportunities for the introduction of benign and
straightforward synthetic pathways to interesting structural
scaffolds with novel architectures.
C
DOI: 10.1021/acs.orglett.6b01658
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01658.
■
S
X-ray data of lactam 8a (CIF)
Experimental procedures, characterization of all com-
pounds (PDF)
AUTHOR INFORMATION
Corresponding Author
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H. Chem. Rev. 1980, 80, 429. (c) Hameed, A.; Alharthy, R. D.; Iqbal, J.;
Langer, P. Tetrahedron 2016, 72, 2763.
■
*E-mail: tanja.gulder@tum.de.
Notes
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Eur. J. 2012, 18, 10834. (b) Stodulski, M.; Goetzinger, A.; Kohlhepp, S.
V.; Gulder, T. Chem. Commun. 2014, 50, 3435.
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Crystallographic Data Centre (no. CCDC 1483038). The data can be
obtained free of charge from CCDC via www.ccdc.cam.ac.uk/data_
request/cif.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by a Liebig fellowship of the Fonds der
Chemischen Industrie and the Emmy-Noether program of the
DFG (GU 1134/3-1). C.P. thanks the Fonds der Chemischen
Industrie for a fellowship.
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