Synthesis of spirocyclic β-keto-lactams: Copper catalyzed process

Article abstract of DOI:10.1039/c1cc10916b

In the presence of catalytic amount of copper salt, an efficient and flexible synthetic method towards the synthesis of a structurally new type of spirocyclic lactams was developed.

Full text of DOI:10.1039/c1cc10916b

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COMMUNICATION
Synthesis of spirocyclic b-keto-lactams: copper catalyzed processw
Zhongxuan Xu,z Kun Huang,z Tong Liu, Mingjin Xie and Hongbin Zhang*
Received 16th February 2011, Accepted 10th March 2011
DOI: 10.1039/c1cc10916b
In the presence of catalytic amount of copper salt, an efficient
and flexible synthetic method towards the synthesis of a struc-
turally new type of spirocyclic lactams was developed.
analogues by reduction. Therefore it is highly desirable to
develop a catalytic version of this reaction as well as to
synthesize medicinally more important spiro b-ketoazetidinones
(5, R3 = Ar and alkyl group).1b
Although easy enolization of b-ketoamide 4 (R3 = Ar and
alkyl group) might lead to undesired oxazolindone 6 through
competitive oxygen–carbon bond formation (see Scheme 1),
we still decided to carry out the proposed research aiming to
create medicinally more useful building blocks through copper
mediated oxidative carbon–carbon bond formation.
The b-lactam pharmacophore is presented as the core structure
in the famous class of b-lactam antibacterial agents. This
family of antibiotics has been used widely in the treatment
of bacterial infections for decades.1 Unfortunately in the battle
of antibacterials, there is a ever-increasing problem of resistance
to clinically used b-lactam antibiotics.2 There is a dire need for
creation of structurally new and diverse molecules bearing the
b-lactam motif. Recently we reported a new oxidative carbon–
carbon bond forming process towards the synthesis of spiro
cyclohexyl-dienonyl b-lactams from derivatives of ethyl 3-oxo-
We began our research with preparing b-ketoamide 4a. The
synthetic route is outlined in Scheme 2 and ketoamide 4a was
obtained in 45% overall yield.4 Next the proposed oxidative
carbon–carbon bond formation was conducted with amide 4a.
Treatment of 4a in methanol under our previous reaction
condition (Table 1, entry 1) unfortunately provided a complex
3-(p-hydroxy-phenylamino) propanoate (4, R2 = H, R3
=
OEt; Scheme 1).3 The major drawback in our previous method
is the use of stoichiometric amounts of copper salt and
4-dimethylaminopyridine (DMAP). Besides, the b-lactams
(5, R2 = H, R3 = OEt) generated are less versatile for further
appendage decoration, for example, converted to penem
Scheme 2 Synthesis of b-ketoamide 4a.
Table 1 Optimization of reaction conditions for copper catalyzed
synthesis of spiro-b-keto-b-lactamsa
Entry
CuSO4ꢀ5H2O
DMAP
Solvents
Yields
Scheme 1 Speculation for the synthesis of spiro-b-ketoazetidinones.
1
2
3
4
5
6
7
8
1.0 eq.
1.0 eq.
0.0 eq.
0.5 eq.
0.1 eq.
0.05 eq.
0.01 eq.
0.2 eq.
1.2 eq.
1.2 eq.
1.0 eq.
0.5 eq.
0.1 eq.
0.06 eq.
0.01 eq.
0.0 eq.
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
21%
87%
0%
88%
87%
87%
83%
20%
Key Laboratory of Medicinal Chemistry for Natural Resource,
Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming, Yunnan 650091, P. R. China.
E-mail: zhanghb@ynu.edu.cn, zhang_hongbin@hotmail.com
w Electronic supplementary information (ESI) available: 1H NMR,
13C NMR spectra of all products and experimental details. CCDC
810808–810810. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc10916b
a
All reactions were conducted with IBD (iodobenzene diacetate,
1.2 eq.) in the specified solvents (50 mL). Isolated yields.
z Mr. Xu and Dr Huang contributed equally to this work
c
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Chem. Commun., 2011, 47, 4923–4925 4923

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mixture, with the desired b-lactam (5a) being isolated in low
yield. Attempts made to use other metal salts [NiCl2, CoCl3
and Mn(OAc)3] as well as other solvents (DMSO, DMF,
CH2Cl2, CH3CN and THF) were fruitless. Finally, an eco-
nomically and environmentally benign reaction condition was
found: this transformation could be promoted in the presence
of only catalytic amount of copper sulfate pentahydrate
(1–5% eq.) and DMAP (1.2–6% eq.) in absolute ethanol
(Table 1, entry 6, 7).5 No spiro-oxazolindone (6) product
was isolated in this catalytic oxidative process.
Scheme 3 Attempts for the synthesis of azetidinones with a double
spirocyclic structure unit.
A number of amides (4b–4s) were then prepared and
subjected to oxidative carbon–carbon bond formation under
catalytic condition. The results are summarized in Table 2. It
was noteworthy that this catalytic reaction condition could
also be applied to amide derivatives of ethyl 3-oxo-3-
(p-hydroxy-phenylamino) propanoate used in our previous
3a
research (see Table 2, substrate 4m, 4n and 4o).
Having established the catalytic condition for the synthesis
of spiro b-ketoazetidinones, we next set up our goal on the
synthesis of b-keto-b-lactams bearing a double spirocyclic
structure (Scheme 3). To synthesize a highly functional and
rigid double spirocyclic b-lactam by formation of two consecu-
tive quaternary carbon centers concurrently is an interesting
but challenging objective. To the best of our knowledge, no
Table 2 Synthesis of spiro-cyclohexyldienonyl azetidinones
Amides
4b - 5b
4c - 5c
R
R1
Yield
82%
80%
CH3
CH3
p-MeOPhCH2
Scheme 4 Synthesis of double spirocyclic b-lactams.
such molecular structure (13) shown in Scheme 3 has ever been
synthesized. Amide 12a and 12b which were synthesized by a
similar transformation outlined in Scheme 2 from methyl
2-oxocyclopentanecarboxylate, were subjected to copper cata-
lyzed oxidation under our optimized reaction condition.
To our delight, both phenol amides (12a and 12b) provided
a clean reaction and afforded the desired double spirocyclic
b-lactam 13a and 13b in high yields. Encouraged by this result,
we next prepared a number of structurally different amides
(12c–12h). The oxidative coupling results are indicated in
Scheme 4. It is noteworthy that amides bearing a g-lactone
(12f) and g-lactam (12g and 12h) ring system also provided
structurally interesting double spirocyclic azetidinones (13f,
13g and 13h) in good yields.
4d - 5d
4e - 5e
4f - 5f
4g - 5g
4h - 5h
CH3
CH3
CH3
Ph
(CH3)2CHCH2
o-ClPhCH2
Ph
PhCH2
p-MeOPhCH2
84%
87%
45%
92%
90%
Ph
4i - 5i
Ph
88%
4j - 5j
4k - 5k
4l - 5l
Ph
Ph
Ph
o-ClPhCH2
(CH3)2CHCH2
Ph
86%
95%
80%
4m - 5m
4n - 5n
4o - 5o
OEt
OEt
OEt
71%
74%
76%
We next explored the generality of this catalytic process. To
our delight, this procedure could be extended to the synthesis
of pharmaceutically important pyrrolidone and 2-piperidinone
containing spiro cyclohexyldienonyl units (see Scheme 5).
Even the rigid spirocyclic compounds (15a, 15b, 17a and
17b) bearing two contiguous full carbon quaternary carbon
centers can be obtained in high yields. In order to get a better
understanding of this copper catalyzed transformation, we
also conducted the reaction with substrate 1a, 12a, 14a and
PhCH2
4p - 5p
4q - 5q
4r - 5r
4s - 5s
CH3CH2
CH3CH2CH2
CH3CHQCH2 (trans)
CH3CH2CH2CH2CH2
PhCH2
PhCH2
PhCH2
PhCH2
83%
81%
85%
82%
c
4924 Chem. Commun., 2011, 47, 4923–4925
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Scheme 6 Spiro-azetidinones as building blocks in the synthesis of
complex molecules.
currently investigating the antibacterial activity of these
compounds and the results will be reported in due course.
This work was supported by grants from Natural Science
Foundation of China (20925205, 20832005), National Basic
Research Program of China (973 Program 2009CB522300).
Scheme 5 Synthesis of spirocyclic pyrrolidones and piperidones.
16a in the presence of a radical scavenger. The reactions were
completely inhibited in the presence of 2,2-diphenyl-1-picryl-
hydrazyl (DPPH, 1.0 eq.).6 The mechanism of this oxidative
carbon–carbon bond coupling should be a single electron
transfer (SET) radical process.7
Notes and references
1 For recent selected reviews, see: (a) C. Palomo, J. M. Aizpurua,
I. Ganboa and M. Oiarbide, Eur. J. Org. Chem., 1999, 3223;
(b) L. Troisi, C. Granito and E. Pindinelli, Topics in
Heterocyclic Chemistry, 2010, 22, 101 and references cited therein.
2 E. D. Brown and G. D. Wright, Chem. Rev., 2005, 105, 759.
3 (a) J. Liang, J. Chen, F. Du, X. Zeng, L. Li and H. Zhang, Org.
Lett., 2009, 11, 2820; (b) J. Liang, J. Chen, J. Liu, L. Li and
H. Zhang, Chem. Commun., 2010, 46, 3666.
4 G. S. Basarab, D. B. Jordan, T. C. Gehret and R. S. Schwartz,
Bioorg. Med. Chem., 2002, 10, 4143.
5 b-ketoamide 4a itself might also served as a ligand in this oxidative
transformation. This reaction could be carried out in the absence of
DMAP, although in low yield (see Table 1, entry 8).
6 E. N. Hristea, M. T. Caproiu, G. Pencu, M. Hillebrand,
T. Constantinescu and A. T. Balaban, Int. J. Mol. Sci., 2006, 7, 130.
7 Examples of hypervalent SET mechanism, see: T. Dohi, M. Ito,
N. Yamaoka, K. Morimoto, H. Fujioka and Y. Kita, Tetrahedron,
2009, 65, 10797 and references cited therein.
8 CCDC 810808 (for compound 7c), CCDC 810809 (for compound 5k)
and CCDC 810810 (for compound 17b) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
To show the usefulness of the b-keto-b-lactams (5) gener-
ated in this research, attaching a side chain to the a-position of
the two carbonyl groups was attempted, the desired products
(5t and 5u) were obtained by a Tsuji–Trost reaction (Scheme 6)
in high yields. Reduction of the b-ketoazetidinones (5a and 5g)
with sodium borohydride was also conducted and resulted in
an unprecedented tricyclic system bearing five stereochemical
centers (Scheme 6) in high diastereoselectivity.8
In conclusion, we have developed a general copper catalyzed
oxidative coupling process for the synthesis of spirocyclic
lactams. Through a new oxidative coupling reaction, the
molecular complexity was dramatically increased. This study
provides for the first time examples of highly functional
while rigid double spirocyclic lactams bearing two consecutive
quaternary carbon centers. These new chemical entities are not
only structurally interesting but also useful building blocks for
the synthesis of biologically active compounds. We are
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4923–4925 4925