Diversity-Oriented Synthesis of β-Lactams and γ-Lactams by Post-Ugi Nucleophilic Cyclization: Lewis Acids as Regioselective Switch

Article abstract of DOI:10.1002/ejoc.201500270

Heterocyclic fused α-methylene β-lactams were successfully synthesized by a post-Ugi In^III-catalyzed intramolecular addition reaction. Switching from InCl₃ to AlCl₃ led to the regioselective synthesis of α,β-unsaturated γ-lactams. Moreover, replacing terminal alkynes by substituted alkynes in the Ugi adducts resulted in the exclusive formation of γ-lactams with both catalytic systems. A regioselective approach for the synthesis of heterocyclic fused α-methylene β-lactams and α,β-unsaturated γ-lactams by employing a Ugi reaction followed by In^III- or Al^III-catalyzed intramolecular nucleophilic addition is reported.

Full text of DOI:10.1002/ejoc.201500270

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FULL PAPER
DOI: 10.1002/ejoc.201500270
Diversity-Oriented Synthesis of β-Lactams and γ-Lactams by Post-Ugi
Nucleophilic Cyclization: Lewis Acids as Regioselective Switch
Zhenghua Li,[a] Upendra Kumar Sharma,[a] Zhen Liu,[b] Nandini Sharma,[a]
Jeremy N. Harvey,[b] and Erik V. Van der Eycken*[a]
Keywords: Multicomponent reactions / Nucleophilic cyclization / Regioselectivity / Lewis acids / Lactams
Heterocyclic fused α-methylene β-lactams were successfully
over, replacing terminal alkynes by substituted alkynes in
synthesized by a post-Ugi InIII-catalyzed intramolecular ad- the Ugi adducts resulted in the exclusive formation of γ-lact-
dition reaction. Switching from InCl3 to AlCl3 led to the re- ams with both catalytic systems.
gioselective synthesis of α,β-unsaturated γ-lactams. More-
Introduction
2-Azetidinones, commonly known as β-lactams, are well-
established privileged scaffolds as proven by their wide-
spread applications in medicinal chemistry.[1] The core
structure of commonly used antibiotics such as penicillin,
aztreonam, nocardicin A, and the cholesterol lowering drug
ezetimibe is the β-lactam ring (Figure 1).[1,2] In addition, β-
lactams also serve as versatile building blocks for the syn-
thesis of various nitrogen-containing compounds such as
vitamins, alkaloids, and β-amino acids.[3] The classical route
for the construction of the β-lactam core is the Staudinger
reaction through the [2+2] cycloaddition of imines to
ketenes.[4] The generation of the latter requires treatment of
activated carboxylic acid derivatives such as acyl chlorides,
which sometimes lowers the synthetic utility. Considering
Figure 1. Examples of β-lactam-core-containing pharmaceuticals.
Over the last few decades, multicomponent reactions
(MCR)[8] and transition-metal-catalyzed[9] post-MCR
transformations have enabled easy access to complex het-
erocyclic scaffolds in a few steps.[10] Strategies for generating
β-lactams by employing β-amino acids[11] or β-keto acids[12]
as functionalized substrates in the Ugi reaction have also
been developed. Recently, bromoacetic acid[13] and phenyl-
propiolic acid[14] have been used to synthesize function-
alized β-lactams involving a sequential base-catalyzed tan-
dem Ugi reaction and intramolecular cyclization. Nonethe-
less, newer methodologies in terms of increased substrate
scope as well as starting material availability are always wel-
come. In continuation of our attempts towards the develop-
ment of diversity-oriented syntheses of various heterocyclic
scaffolds through post-Ugi transformations,[15] we envi-
sioned the synthesis of heterocyclic fused α-methylene β-
lactams by combination of a MCR with a metal-catalyzed
cascade cyclization. Herein, we report post-Ugi InIII-cata-
lyzed intramolecular nucleophilic cyclization for the synthe-
the vast pharmacological significance of the β-lactam
framework and the growing concern regarding bacterial re-
sistance, the development of new methodologies towards
the diversification of existing β-lactam antibiotics seems to
be imperative.[5] As a result, several new synthetic ap-
proaches have been developed,[6] with particular emphasis
on the generation of α-methylene β-lactams,[7] which are
versatile compounds delivering building blocks for the con-
struction of various β-lactam antibiotics[7c] (Scheme 1).
[a] Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, University of Leuven
(KU Leuven),
Celestijnenlaan 200F, 3001 Leuven, Belgium
E-mail: erik.vandereycken@chem.kuleuven.be
http://chem.kuleuven.be/organ/lomac/
[b] Quantum Chemistry and Physical Chemistry Section,
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F – box 2404, Leuven, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500270.
Eur. J. Org. Chem. 0000, 0–0
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E. V. Van der Eycken et al.
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entry 4). Increasing the catalyst loading of InCl3 to 20 mol-
% led to isolation of 6a in 73% yield (Table 1, entry 5).
However, a further increase in the catalyst loading to
30 mol-% did not significantly enhance the outcome of the
reaction (Table 1, entry 6). A drastic reduction in yield and
selectivity was observed upon switching the catalyst to in-
dium(III) trifluoromethanesulfonate [In(OTf)3; Table 1, en-
try 7]. Changing the solvent to toluene gave a slightly im-
proved yield of 6a (Table 1, entry 8), whereas o-xylene and
MeCN produced reduced yields (Table 1, entries 9 and 10).
Increasing the catalyst loading to 30 mol-% in toluene deliv-
ered 6a in 88% yield (Table 1, entry 11). No further im-
provement in yield or selectivity was observed upon further
increasing the amount of catalyst (Table 1, entry 12) or re-
ducing the reaction time or temperature (Table 1, entries 13
and 14). We next attempted to develop a catalytic system
for the exclusive generation of endo-cyclized product, that
is, γ-lactam 7a, which was observed as a minor product in
almost every case. Interestingly, replacing InCl3 with the
readily available Lewis acids AlCl3 and ZnCl2 resulted in
the formation of γ-lactam 7a in yields of 75 and 61%,
respectively (Table 1, entries 15 and 16). However, with CuI
and K2CO3 only decomposition of Ugi adduct 5a was ob-
served (Table 1, entries 17 and 18).
Table 1. Optimization of the intramolecular addition.[a]
Scheme 1. Synthetic methods for α-methylene β-lactams; PMB =
p-methoxybenzyl, Ms = methylsulfonyl.
sis of N-heterocyclic fused α-methylene β-lactams. Interest-
ingly, switching from InIII to AlIII resulted in the generation
of another important class of N-heterocycles, that is, unsat-
urated γ-lactams, starting from the same Ugi adduct
(Scheme 1).
Entry Catalyst
(mol-%)
Solvent
DCE
Time Temp. Conversion [%][b]
[h]
[°C]
(6a/7a)
1
2
AgOTf (10)
AgSbF6 (10) DCE
12
12
12
12
12
12
12
12
12
12
12
12
6
120
120
120
120
120
120
120
120
120
120
120
120
120
100
120
120
120
120
90 (40:50)
78 (50:28)
80 (35:45)
100 (36:18)[c]
100 (73:8)[c]
100 (74:6)[c]
100 (40:10)[c]
100 (78:8)[c]
100 (68:12)[c]
100 (72:28)
100 (88:4)[c]
100 (86:5)[c]
100 (64:5)[c]
100 (56:5)[c]
100 (0:75)[c]
100 (13:61)[c]
n.d.[d]
3
4
5
6
AuCl (10)
InCl3 (10)
InCl3 (20)
InCl3 (30)
DCE
DCE
DCE
DCE
Results and Discussion
Initially, the Ugi four-component reaction (4-CR)[16] of
imidazo[1,2-a]pyridine-2-carbaldehyde (1a), p-methoxy-
benzylamine (2a), propiolic acid (3a), and cyclohexyl iso-
cyanide (4a) in methanol at room temperature generated
adduct 5a in 84% yield, which was selected to optimize the
reaction conditions of the next step. In continuation of our
previous success with gold and silver catalysis for the acti-
vation of alkynes,[14] we began our studies by screening
these catalysts in 1,2-dichloroethane (DCE) at 120 °C for
12 h (Table 1, entries 1–3). However, none of the catalysts
7
8
9
In(OTf)3 (20) DCE
InCl3 (20)
InCl3 (20)
InCl3 (20)
InCl3 (30)
InCl3 (40)
InCl3 (30)
InCl3 (30)
AlCl3 (10)
ZnCl2 (10)
CuI (10)
toluene
o-xylene
MeCN
toluene
toluene
toluene
toluene
DCE
DCE
DCE
DCE
10
11
12
13
14
15
16
17
18
12
12
12
12
12
K2CO3
n.d.[d]
[e]
was able to complete the reaction. Moreover, the selectivity [a] All reactions were run on a 0.1 mmol scale of 5a in the indicated
solvent (2 mL). Cy = cyclohexyl. [b] Conversion and ratio based on
for desired α-methylene β-lactam 6a was not good. There-
analysis by 1H NMR spectroscopy. [c] Yield of isolated product.
fore, we turned our attention to InIII catalysts, as these have
[d] n.d.: not detected. [e] K2CO3: 1 equiv.
recently emerged as dual activators for carbonyl com-
pounds as well as for terminal alkynes in various reac-
tions.[17] Delightedly, the application of 10 mol-% of InCl3
With the optimized conditions for the synthesis of β-lact-
was able to complete the reaction, and desired exo-cyclized ams in hand (Table 1, entry 11), we evaluated the scope and
α-methylene β-lactam 6a was isolated in 36% yield (Table 1, limitations of this intramolecular addition by using a vari-
2
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Diversity-Oriented Synthesis of β-Lactams and γ-Lactams
ety of different Ugi adducts 5a–t (Table 2). The intramolec- trogen-containing aromatic aldehyde in the Ugi reaction.
ular cyclization proceeded smoothly in most cases to give Moreover, it was necessary to ensure that the use of propi-
α-methylene β-lactams 6a–t in moderate to good yields. A olic acid resulted in intramolecular anti-Michael addition,
variety of substituents in the Ugi adducts were well toler- as Ugi adduct 5r from 4-pentynoic acid failed to produce
ated. Employing the standard conditions to Ugi adducts 5n/ the desired alkylidene-β-lactam.
5o and 5p/5q prepared from 1-trityl-1H-imidazole-4-carb-
Further, the applicability of this protocol for the prepara-
aldehyde and 4-methylthiazole-2-carbaldehyde, respectively, tion of γ-lactams from Ugi adducts (e.g., 5d, 5g, 5i, 5l, 5m,
produced corresponding alkylidene-β-lactams 6n/6o and 6p/ and 5o) is shown in Table 3. Good to moderate yields were
6q in yields of 30/33 and 58/62%, respectively. However, in obtained for Ugi adducts obtained from various substituted
the case of Ugi adduct 5r derived from imidazo[1,2-a]pyr- imidazo[1,2-a]pyridine-2-carbaldehydes (e.g., 7d, 7g, 7i, 7l,
idine-3-carbaldehyde, no conversion was observed. Simi- and 7m). However, a low yield was noticed for the Ugi ad-
larly, the failure of Ugi adduct 5s derived from benzalde- duct derived from 1-trityl-1H-imidazole-4-carbaldehyde
hyde to form 6s manifests the necessity of employing a ni- (i.e., 7o, Table 3). In addition, to scrutinize the necessity of
propiolic acid, Ugi adduct 8a was prepared from imid-
azo[1,2-a]pyridine-2-carbaldehyde by replacing propiolic
acid with 2-butynoic acid (3c), and it was subjected to the
Table 2. Scope and limitations for β-lactam formation.[a]
Table 3. Scope and limitations for γ-lactam formation.[a]
[a] All reactions were run on a 0.3 mmol scale of 5 with AlCl3
(10 mol-%) in DCE (2 mL) in a screw-capped vial at 120 °C for
12 h.
Table 4. Scope and limitations for γ-lactam formation from substi-
tuted propargylamides.[a]
Product
R1
R2
R3
R4
Yield [%]
9a
9b
9c
9d
9e
9f
tBu
nBu
tBu
tBu
tBu
Cy
PMB
piperonyl Me
PMB Et
piperonyl Et
3,4-DMB Ph
PMB
Me
H
6-Cl
H
6-Cl
H
6-Me
72/69[b]
99
77
81
76
Ph
82
[a] All reactions were run on a 0.3 mmol scale of 5 with InCl3
(30 mol-%) in toluene (2 mL) in a screw-capped vial at 120 °C for
12 h. 3,4-DMB = 3,4-dimethoxybenzyl.
[a] All reactions were run on a 0.3 mmol scale of 8 with InCl3
(10 mol-%) in DCE (2 mL) in a screw capped vial at 120 °C for
12 h. [b] AlCl3 (10 mol-%) was used.
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Scheme 2. Plausible reaction mechanism.
optimized conditions. However, instead of expected α-meth- Considering the likely computational errors, the relative en-
ylene β-lactam, γ-lactam 9a was observed as the only prod- ergies of these transition states are in good agreement with
uct resulting from Michael addition (Table 4, entry 1). After experimentally observed ring-closure selectivities: the for-
checking the influence of solvents, catalysts, and so on (see mation of the four-membered ring is predicted to be more
the Supporting Information), the optimal conditions for favorable in the case of R3 = H and M = In (ΔΔE‡
=
this Michael addition process were found to be 120 °C for 3.4 kcalmol–1), whereas the barriers for five-membered ring
12 h in DCE as the solvent with InCl3 (10 mol-%) as the formation are lower in all other cases (e.g., ΔΔE‡
=
catalyst. It is notable that employment of AlCl3 (10 mol-%) –7.5 kcalmol–1 in the case of R3 = H, M = In). The prod-
gave γ-lactam 9a in 69% yield. The optimal process was ucts of these steps are vinyl–metal species that should un-
applied successfully to diversely substituted Ugi adducts dergo facile protonolysis of the C–M bonds. Partial atomic
8b–f (see the Supporting Information) to deliver γ-lactams charge calculations (see the Supporting Information) sug-
9b–f in good to excellent yields. Remarkably, upon em- gest that the relative electrophilicity of the two acetylenic
ploying a bulky substituent such as a phenyl group on the carbon atoms and thereby the selectivity is tuned by the R3
alkyne, no steric hindrance was observed, and compounds substituent and coordination to the metal.
9e and 9f were formed in yields of 76 and 82%, respectively.
On the basis of these observations and previous reports
on InIII [17]
we postulate a plausible mechanism for the nu-
,
cleophilic 4-exo-dig and 5-endo-dig additions (Scheme 2).
Moreover, preliminary DFT calculations were also per-
formed to understand the reaction mechanism and selectiv-
Conclusions
In summary, we elaborated a diversity-oriented post-Ugi
ity with the different substrates and Lewis acids (for details, intramolecular approach for the synthesis of α-methylene
see the Supporting Information). In an initial step, we as- β-lactams and α,β-unsaturated γ-lactams by employing Ugi
sume that the Lewis acid coordinates to the substrate, which adducts with terminal and substituted alkynes. The diver-
thereby generates the enolate by deprotonation. Loss of a sity of the desired products is guaranteed by the first step,
chloride ion from the Lewis acid leads to neutral enolate A, the Ugi 4-component reaction. The operational simplicity
in which the alkyne group is coordinated to the metal cen- together with the synthetic efficiency of the protocol will
ter. Transition states for 4-exo-dig and 5-endo-dig ring facilitate the development of new antibiotics for countering
closure have been located for R3 = H and Me, and for M = bacterial resistance. The biological activity of the generated
Al and In, all of which lie 8–21 kcalmol–1 above the enolate. compounds is under current investigation.
4
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Diversity-Oriented Synthesis of β-Lactams and γ-Lactams
chapter 1.18–1.20; b) M. I. Page (Ed.), The Chemistry of β-
Experimental Section
Lactams, Blackie Academic & Professional, New York, 1992;
c) R. B. Morin, M. Gorman (Eds.), Chemistry and Biology of β-
Lactam Antibiotics, vol. 1–3, Academic Press, New York, 1982.
J. W. Clader, J. Med. Chem. 2004, 47, 1–9.
a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Rev. 2007,
107, 4437–4492; b) C. Palomo, M. Oiarbide, Top. Heterocycl.
Chem. 2010, 22, 211–259.
a) A. Arrieta, B. Lecea, F. P. Cossío, Top. Heterocycl. Chem.
2010, 22, 313–347; b) R. Tuba, Org. Biomol. Chem. 2013, 11,
5976–5988; c) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiar-
bide, Curr. Med. Chem. 2004, 11, 1837–1872; d) A. Tarui, K.
Sato, M. Omote, I. Kumadaki, A. Ando, Adv. Synth. Catal.
2010, 352, 2733–2744.
a) P. D. Mehta, N. P. S. Sengar, A. K. Pathak, Eur. J. Med.
Chem. 2010, 45, 5541–5560; b) S. B. Rosenblum, T. Huynh, A.
Afonso, H. R. Davis, J. N. Yumibe, J. W. Clader, D. A. Burnett,
J. Med. Chem. 1998, 41, 973–980.
a) R. K. Khangarot, K. P. Kaliappan, Eur. J. Org. Chem. 2013,
7664–7677; b) C. R. Pitts, T. Lectka, Chem. Rev. 2014, 114,
7930–7953; c) L. Troisi, C. Granito, E. Pindinelli, Top. Hetero-
cycl. Chem. 2010, 22, 101–209; d) B. Alcaide, P. Almendros, A.
Luna, RSC Adv. 2014, 4, 1689–1707; e) A. Kamath, I. Ojima,
Tetrahedron 2012, 68, 10640–10664.
a) W. Adam, P. Groer, H.-U. Humpf, C. R. Saha-Möller, J.
Org. Chem. 2000, 65, 4919–4922; b) A. Basak, S. C. Ghosh,
Synlett 2004, 9, 1637–1639; c) X. Wang, F. Meng, Y. Wang, Z.
Han, Y. Chen, L. Liu, Z. Wang, K. Ding, Angew. Chem. Int.
Ed. 2012, 51, 9276–9282; Angew. Chem. 2012, 124, 9410–9416;
d) W. Li, C. Liu, H. Zhang, K. Ye, G. Zhang, W. Zhang, Z.
Duan, S. You, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 2443–
2446; Angew. Chem. 2014, 126, 2475–2478.
a) B. Ganem, Acc. Chem. Res. 2009, 42, 463–472; b) C.
de Graaff, E. Ruijter, R. V. A. Orru, Chem. Soc. Rev. 2012, 41,
3969–4009; c) S. S. van Berkel, B. G. M. Bögels, M. A.
Wijdeven, B. Westermann, F. P. J. T. Rutjes, Eur. J. Org. Chem.
2012, 3543–3559; d) L. H. Choudhury, T. Parvin, Tetrahedron
2011, 67, 8213–8228; e) S. Sadjadi, M. M. Heravi, Tetrahedron
2011, 67, 2707–2752.
a) I. Ojima, M. Tzamarioudaki, Z. Li, R. J. Donovan, Chem.
Rev. 1996, 96, 635–662; b) N. T. Patil, Y. Yamamoto, Chem.
Rev. 2008, 108, 3395–3442; c) H. Clavier, H. Pellissier, Adv.
Synth. Catal. 2012, 354, 3347–3403.
a) J. D. Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15, 1300–
1308; b) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew.
Chem. Int. Ed. 2011, 50, 6234–6246; Angew. Chem. 2011, 123,
6358–6371; c) D. M. D’Souza, T. J. J. Müller, Chem. Soc. Rev.
2007, 36, 1095–1108; d) A. Salcedo, L. Neuville, C. Rondot, P.
Retailleau, J. Zhu, Org. Lett. 2008, 10, 857–860; e) R. A.
De Silva, S. Santra, P. R. Andreana, Org. Lett. 2008, 10, 4541–
4544; f) L. E. Kaïm, L. Grimaud, X. L. Goff, M. Menes-Arz-
ate, L. D. Miranda, Chem. Commun. 2011, 47, 8145–8147; g)
L. Zhang, F. Zhao, M. Zheng, Y. Zhai, H. Liu, Chem. Com-
mun. 2013, 49, 2894–2896.
a) S. Gedey, J. Van der Eycken, F. Fülöp, Org. Lett. 2002, 4,
1967–1969; b) Z. Szakonyi, R. Sillanpää, F. Fülöp, Mol. Diver-
sity 2010, 14, 59–65; c) M. C. Pirrung, K. Das Sarma, J. Am.
Chem. Soc. 2004, 126, 444–445.
M. C. Pirrung, K. Das Sarma, Synlett 2004, 8, 1425–1427.
X. H. Zeng, H. M. Wang, Y. M. Yan, L. Wu, M. W. Ding, Tet-
rahedron 2014, 70, 3647–3652.
General Procedure for the Synthesis of Ugi Products 5 and 8:
Na2SO4 (0.3 g), amine 2 (1.2 equiv.), acid 3 (1.2 equiv.), and iso-
cyanide 4 (1.2 equiv.) were added successively to a solution of carb-
aldehyde 1 (200 mg, 1 equiv.) in methanol (3 mL) in a screw-capped
vial equipped with a magnetic stir bar. The mixture was stirred at
room temperature for 24–48 in the closed vial. Upon completion
of the reaction, the mixture was diluted with EtOAc (100 mL) and
was extracted with water (50 mL). The organic layer was washed
with brine (50 mL), dried with magnesium sulfate, and evaporated
under reduced pressure to obtain a residue, which was subjected to
column chromatography (silica gel, 1–5% MeOH in CH2Cl2) to
afford desired product 5 and 8 as a solid. Ugi products appear as
[2]
[3]
[4]
[5]
[6]
a mixture of two rotamers, so the H NMR and 13C NMR spectra
are not very characteristic.
1
General Procedure for the Synthesis of Alkylidene β-Lactams 6
thorough InCl3-Catalyzed anti-Michael Addition: A glass vial was
charged with InCl3 (30 mol-%) and dry toluene (2 mL). Ugi prod-
uct 5 (0.3 mmol) was added. The mixture was stirred at 120 °C
until completion of the reaction. Upon completion, the mixture
was purified by column chromatography (silica gel, 1–3% MeOH
in CH2Cl2) to afford compound 6.
[7]
[8]
General Procedure for the Synthesis of γ-Lactams 7 thorough AlCl3-
Catalyzed Michael Addition: A glass vial was charged with AlCl3
(10 mol-%) and dry DCE (2 mL). Ugi product 5 (0.3 mmol) was
added. The mixture was stirred at 120 °C until completion of the
reaction. Upon completion, the mixture was purified by column
chromatography (silica gel, 1–3% MeOH in CH2Cl2) to afford
compound 7.
General Procedure for the Synthesis of γ-Lactams 9 thorough InCl3-
Catalyzed Michael Addition: A glass vial was charged with InCl3
(10 mol-%) and dry DCE (2 mL). Ugi product 8 (0.3 mmol) was
added. The mixture was stirred at 120 °C until completion of the
reaction. Upon completion, the mixture was purified by column
chromatography (silica gel, 1–3% MeOH in CH2Cl2) to afford
compound 9.
The products were characterized by 1H NMR and 13C NMR spec-
troscopy and HRMS, and the data were all in good agreement with
the assigned structures (for detailed experimental procedures and
data, see the Supporting Information).
[9]
[10]
General Procedure for DFT Calculations: Briefly, DFT calculations
were performed by using the B3LYP functional, the SVPP basis set
for all atoms other than In, and the SDD core potential and associ-
ated basis set for In in the Gaussian 09 program package.[18] Re-
ported energies include corrections for zero-point energy and dis-
persion [-D3(BJ) correction]. Full details of the computational pro-
tocol and additional results are in the Supporting Information.
[11]
Acknowledgments
[12]
[13]
The authors wish to thank the Belgian Fund for Scientific Re-
search-Flanders (FWO) and the Research Fund of the University
of Leuven (KU Leuven) for financial support. Z. L. is grateful to
the China Scholarship Council (CSC) for providing a doctoral fel-
lowship. N. S. and U. K. S. are grateful to the University of Leuven
for F+ postdoctoral fellowships. The authors also acknowledge Ir.
Bert Damarsin (for HRMS).
[14]
[15]
E. Ghabraie, S. Balalaie, S. Mehrparvar, F. Rominger, J. Org.
Chem. 2014, 79, 7926–7934.
a) S. G. Modha, D. D. Vachhani, J. Jacobs, L. Van Meervelt,
E. V. Van der Eycken, Chem. Commun. 2012, 48, 6550–6552; b)
A. Kumar, Z. Li, S. K. Sharma, V. S. Parmar, E. V.
Van der Eycken, Chem. Commun. 2013, 49, 6803–6805; c) S. G.
Modha, A. Kumar, D. D. Vachhani, J. Jacobs, S. K. Sharma,
V. S. Parmar, L. Van Meervelt, E. V. Van der Eycken, Angew.
Chem. Int. Ed. 2012, 51, 9572–9575; Angew. Chem. 2012, 124,
[1] a) A. R. Katritzky, C. W. Rees, E. F. V. Scriven (Eds.), Compre-
hensive Heterocyclic Chemistry II, Pergamon, New York, 1996,
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/KAP1
Date: 07-05-15 12:33:49
Pages: 7
E. V. Van der Eycken et al.
FULL PAPER
9710–9713; d) A. Kumar, Z. Li, S. K. Sharma, V. S. Parmar,
E. V. Van der Eycken, Org. Lett. 2013, 15, 1874–1877; e) Z. Li,
L. Legras, A. Kumar, D. D. Vachhani, S. K. Sharma, V. S. Par-
mar, E. V. Van der Eycken, Tetrahedron Lett. 2014, 55, 2070–
2074; f) Z. Li, A. Kumar, D. D. Vachhani, S. K. Sharma, V. S.
Parmar, E. V. Van der Eycken, Eur. J. Org. Chem. 2014, 2084–
2091; g) Z. Li, A. Kumar, S. K. Sharma, V. S. Parmar, E. V.
Van der Eycken, Tetrahedron 2015, 71, 3333–3342.
17167; l) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem.
Soc. 2003, 125, 13002–13003; m) T. Fujimoto, K. Endo, H.
Tsuji, M. Nakamura, E. Nakamura, J. Am. Chem. Soc. 2008,
130, 4492–4496; n) W. Hess, J. W. Burton, Adv. Synth. Catal.
2011, 353, 2966–2970; o) S. Yamazaki, Chem. Eur. J. 2008, 14,
6026–6036; p) S. Shaw, J. D. White, J. Am. Chem. Soc. 2014,
136, 13578–13581; q) B. Montaignac, M. R. Vitale, V. Mich-
elet, V. Ratovelomanana-Vidal, Org. Lett. 2010, 12, 2582–2585.
[16] a) A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168–
3210; Angew. Chem. 2000, 112, 3300–3344; b) A. Dömling,
Chem. Rev. 2006, 106, 17–89.
[18]
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
revision B, Gaussian, Inc., Wallingford, CT, 2009.
[17] a) B. K. Banik, A. Ghatak, F. F. Becker, J. Chem. Soc. Perkin
Trans. 1 2000, 2179–2181; b) K. Takahashi, M. Midori, K.
Kawano, J. Ishihara, S. Hatakeyama, Angew. Chem. Int. Ed.
2008, 47, 6244–6246; Angew. Chem, 120, 6340–6342; c) S.
Hatakeyama, Pure Appl. Chem. 2009, 81, 217–226; d) F. Urabe,
S. Nagashima, K. Takahashi, J. Ishihara, S. Hatakeyama, J.
Org. Chem. 2013, 78, 3847–3857; e) K. Endo, T. Hatakeyama,
M. Nakamura, E. Nakamura, J. Am. Chem. Soc. 2007, 129,
5264–5271; f) R. Takita, Y. Fukuta, R. Tsuji, T. Ohshima, M.
Shibasaki, Org. Lett. 2005, 7, 1363–1366; g) G. K. Friestad,
C. S. Korapala, H. Ding, J. Org. Chem. 2006, 71, 281–289; h)
Z. Shen, S. Wang, Y. Chok, Y. Xu, T. Loh, Chem. Rev. 2013,
113, 271–401; i) D. Prajapati, R. Sarma, D. Bhuyan, W. Hu,
Synlett 2011, 5, 627–630; j) C. C. Malakar, B. U. W. Maes,
K. A. Tehrani, Adv. Synth. Catal. 2012, 354, 3461–3467; k) Y.
Itoh, H. Tsuji, K. Yamagata, K. Endo, I. Tanaka, M. Naka-
mura, E. Nakamura, J. Am. Chem. Soc. 2008, 130, 17161–
Received: February 25, 2015
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50270
/KAP1
Date: 07-05-15 12:33:49
Pages: 7
Diversity-Oriented Synthesis of β-Lactams and γ-Lactams
β-Lactam Synthesis
Z. Li, U. K. Sharma, Z. Liu,
N. Sharma, J. N. Harvey,
E. V. Van der Eycken* ....................... 1–7
Diversity-Oriented Synthesis of β-Lactams
and γ-Lactams by Post-Ugi Nucleophilic
Cyclization: Lewis Acids as Regioselective
Switch
Keywords: Multicomponent reactions
/
Nucleophilic cyclization / Regioselectivity /
Lewis acids / Lactams
A regioselective approach for the synthesis
of heterocyclic fused α-methylene β-lact-
ams and α,β-unsaturated γ-lactams by em-
ploying a Ugi reaction followed by InIII- or
AlIII-catalyzed intramolecular nucleophilic
addition is reported.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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