A Catalytic Approach to Quinoline Fused Lactones and Lactams from Glycine Derivatives

Article abstract of DOI:10.1002/adsc.201500513

A dual catalyst system [copper(II) chloride-sulfuric acid, (CuCl₂-H₂SO₄)]-promoted aerobic oxidative reaction of glycine derivatives with 2,3-dihydrofurans or 2,3-dihydropyrroles has been explored, affording an efficient synthesis of high value quinoline fused lactones and lactams. The application of this new methodology to the synthesis of a bioactive C ring extension analogue of luotonin A has been accomplished in a concise three-step sequence.

Full text of DOI:10.1002/adsc.201500513

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DOI: 10.1002/adsc.201500513
A Catalytic Approach to Quinoline Fused Lactones and Lactams
from Glycine Derivatives
Congde Huo,a,* Yong Yuan,a Fengjuan Chen,a and Yajun Wanga
a
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education; College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, Peopleꢀs Republic of China
Fax: (+86)-931-797-1989; e-mail: Huocongde1978@hotmail.com
Received: May 27, 2015; Revised: August 15, 2015; Published online: November 18, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500513.
Abstract: A dual catalyst system [copper(II) chlo- tive C ring extension analogue of luotonin A has
ride-sulfuric acid, (CuCl2-H2SO4)]-promoted aerobic been accomplished in a concise three-step sequence.
oxidative reaction of glycine derivatives with 2,3-di-
hydrofurans or 2,3-dihydropyrroles has been ex-
plored, affording an efficient synthesis of high value Keywords: aerobic conditions; annulation; glycine
quinoline fused lactones and lactams. The application derivatives; quinoline fused lactams; quinoline fused
of this new methodology to the synthesis of a bioac- lactones
Introduction
strategy activated and catalyzed by a Cu(II)-H2SO4-
air system to construct complex quinoline fused lac-
Recently, Li and others have been investigating the tones and lactams from aromatic substituted glycine
chemistry of glycine derivatives as potential precur- derivatives with 2,3-dihydrofurans or 2,3-dihydropyr-
[1]
À
sors to novel oxidative C H functionalizations. In roles. The method incorporates an oxidative Povarov
2011, a series of substituted quinolines was synthe- reaction/acidic ring opening/aromatization/intramolec-
sized by MancheÇo et al in an interesting one-pot oxi- ular ester exchange sequence. This method was also
dative Povarov/aromatization reaction of glycine de- applied to the synthesis of the above-mentioned bio-
rivatives with alkenes.[2] After that, some notable active compound IV.
progress has been achieved in this area by our group
and others.[3] We were interested in further exploiting
this oxidative strategy for more complex heterocyclic
synthesis. In this study, we focused on the synthesis of
quinoline fused lactones and lactams because these
complex ring systems are central to a lot of bioactive
natural and synthetic compounds and are present in
many medicinal agents (Scheme 1).[4–7] For example,
luotonin A (Scheme 1, III) has garnered considerable
interest as a cytotoxic alkaloid since its isolation from
the Chinese traditional medicinal plant Peganum ni-
gellastrum in 1997.[6] Although it is not potent enough
for cancer therapy, luotonin A is an important lead
compound and many synthetic analogues have been
synthesized for bioactivity investigations. For instance,
the C ring extension analogue IV (Scheme 1) was dis-
closed to have a more potent inhibitory activity
against human topisomerase I.[7] Thus, the develop-
ment of a simple and efficient procedure for the prep-
aration of these high value heterocyclic frameworks is
highly desired. Herein, we detail a novel synthetic bioactive natural or synthetic compounds.
Scheme 1. Quinoline fused lactone and lactam skeletons in
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A Catalytic Approach to Quinoline Fused Lactones and Lactams
Results and Discussion
always added after the reaction had been carried out
for 0.5 h. We then optimized the reaction conditions
Our study commenced with the reaction of glycine by changing the metal loadings (Table 1, entries 21–
ester 1a and 2,3-dihydrofuran 2a to search for 23) and the best yield was achieved with 5 mol%
a potent catalyst system and suitable reaction condi- CuCl2. Finally, four other glycine esters with different
tions. Initially, various metal salts or non-metallic me- leaving groups were also investigated (Table 1, en-
diators were examined as catalysts for the transforma- tries 24–27) and ethyl ester 1a gave the highest yield.
tion (Table 1, entries 1–10). CuCl2 was found to be In addition, no appreciable differences of the transfor-
the most effective one. Then different solvents were mation were observed when pure oxygen gas was
surveyed (Table 1, entries 11–14). Acetonitrile was used instead of an air atmosphere. All in all, CuCl2
proven to be the best choice. To improve the efficien- (5 mol%) and H2SO4 (20 mol%) in CH3CN under an
cy of the reaction, Brønsted acids were examined as air atmosphere at room temperature were discovered
additives (Table 1, entries 15–20). The best yield was to be the optimal reaction condition (71%; Table 1,
obtained when 20 mol% of sulfuric acid (10M) was entry 16).
added. It is worth mention that Brønsted acids were
Table 1. Screening of the reaction conditions.[a]
[a]
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), solvent (20 mL), room temperature, air
(Brønsted acid was added after 0.5 h). (entries 1–14, 24 h; entries 15–27,15 h).
Isolated yields.
[b]
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Table 2. Cu(II)-H2SO4-air-catalyzed reaction of glycine esters with 2,3-dihydrofurans.
[a]
Standard reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), CuCl2 (5 mol%), MeCN
(20 mL), [H2SO4 (10M, 20 mol%) was added after 0.5 h], air, room temperature, 15–
80 h.
[b]
[c]
[d]
Isolated yields.
Isomer ratio.
On a 20-mmol scale.
With the best reaction conditions established, the
Given the importance of quinoline fused lactams in
scope and generality of this protocol was probed. Ini- pharmaceutical chemistry, we considered that an at-
tially, we investigated different substituted glycine tractive prospect might be the replacement of 2,3-di-
esters. It was observed that the desired quinoline hydrofurans with 2,3-dihydropyrroles in this protocol.
fused lactones were obtained in satisfactory yields As typical examples, the reaction of glycine esters
with both electron-donating and electron-withdrawing (1a, 1f, 1g, 1j) with Cbz- or Boc-protected 2,3-dihy-
groups on the para-position of the phenyl ring of dropyrroles under the above-mentioned standard re-
1 (Table 2, entries 1–9). Also meta- or ortho-substitut- action conditions was found to give 2,3-disubstituted
ed and poly-substituted glycine esters delivered the quinoline 5 (Table 3). Then, the treatment of com-
fused ring compounds in moderate to good yields pounds 5 with deprotection conditions resulted in the
(Table 2, entries 10–15). The preparation of halogen cyclization product, lactam 6, in moderate yields (the
atom-bearing products makes the methodology more Cbz-protected substrate gave a better yield). Like
useful for further transformations (Table 2, entries 9, 3aa, the structure of 6a was also confirmed by the X-
14, 15). Moreover, the introduction of F atoms into ray diffraction.[9] Thus, we have developed a simple
organic molecules could have a significant effect on two-step protocol to achieve the conversion of simple
their pharmacological properties.[8] It is worth noting glycine esters and 2,3-dihydropyrroles to complex
that 5-position substituted quinoline fused lactone 3ab quinoline fused lactams.
was achieved in good yield using 5-methyl-2,3-dihy-
After our optimal quinoline fused lactam synthesis
drofuran as substrate (Table 2, entry 16). To evaluate sequence was established, the potent bioactive C ring
the practicability of this method, the reaction between extension analogue of luotonin A (IV) was completed
glycine ester 1a and 2,3-dihydrofuran has been per- in one additional step from compound 6j by reaction
formed on a 20-mmol scale in a single batch. No obvi- with commercially available and cheap isatoic anhy-
ous loss of yield was observed (isolated yield: 67%).
dride to demonstrate the utility of this new reaction
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A Catalytic Approach to Quinoline Fused Lactones and Lactams
Table 3. Cu(II)-H2SO4-air-catalyzed reaction of glycine
esters with 2,3-dihydropyrroles.
or tripeptide 1u with 2a gave 2,3-disubstituted quino-
line 7ta, 8ta or 7ua, 8ua, respectively. And interesting-
ly, the six-membered lactone 3aa instead of the ex-
pected macrocyclic lactone was isolated in moderate
yield by adding an additional one equivalent of
H2SO4 (10M, 1 equiv.) at 808C in 10 h. most probably
because of the higher stability of the six-membered
ring. We also found that product 3aa could be ach-
ieved directly if more H2SO4 (10M, 1.2 equiv.) was
added at the beginning of the reaction.
To investigate the mechanism of the transforma-
tion, some control experiments were carried out. First
of all, the reaction of 1a in the absence of 2,3-dihy-
drofuran (2a) under the standard reaction conditions
was investigated. Imine A and its dimer were
achieved in low yield (Table 4, entry 1). This result in-
dicates that an imine should be an important inter-
mediate in this reaction. The reaction of 1a with 2a
under an argon atmosphere furnished no product
(Table 4, entry 2), indicating that O2 is crucial for the
reaction. When TEMPO was employed in the stan-
dard reaction as radical scavenger, no designed prod-
uct was obtained (Table 4, entry 3). This result sug-
gested that the present reaction includes a radical
process. Secondly, the results in Table 1 (entries 1 and
[a]
Standard reaction conditions: (i)
1
(1.0 mmol),
4
(1.0 mmol), CuCl2 (5 mol%), MeCN (20 mL), [H2SO4 20) and Table 4 (entries 4–6) show that CuCl2 is the
(10M, 20 mol%) was added after 1 h], air, room temper-
ature, 10 h; (ii) 4a: Pd/C, H2, MeOH, 24 h; 4b: H2SO4,
EtOAc, 36 h.
crucial catalyst for the oxidative Povarov reaction.
Thirdly, to further probe the reaction mechanism,
compound B (see Scheme 4 for structure of B) was
synthesized[11] and subjected to the standard condi-
tions, product 3aa was obtained in 85% yield (Table 4,
entry 7). This indicates that the adduct B may be in-
[b]
Isolated yields of the two steps.
(Scheme 2, 37% overall yield).[10] This demonstration volved as the key intermediate in this transformation.
reveals that a series of similar drug-like molecules can Finally, the isolation of products 7ta and 7ua
be prepared easily for bioassays.
(Scheme 3) indicates that 2,3-disubstituted quinoline
We then wondered whether this strategy could be intermediate F (Scheme 4) should be involved in this
extended to short peptides and provide a direct access process. Furthermore, as shown in Table 1 and
to macrocyclic lactones or lactams. As is illustrated in Scheme 3, the function of H2SO4 is primarily to accel-
Scheme 3, our initial attempts to construct a macro erate the following ring opening and intramolecular
ring structure under the above used standard condi- ester exchange sequence so as to reduce the reaction
tions were unsuccessful. The reaction of dipeptide 1t time and improve the reaction yield.
A plausible mechanism for this aerobic oxidative
reaction under the cooperative catalysis of a copper
salt and a Brønsted acid is illustrated in Scheme 4.
The glycine ester 1a was first oxidized by copper(II)
to give the imine intermediate A[12] which can be fur-
ther activated by the copper salt as Lewis acid, pro-
moting the aza-Diels–Alder reaction with 2,3-dihydro-
furan to generate the corresponding tetrahydroquina-
zoline intermediate B. Intermediate B is not stable
under acidic conditions and generates the 2,3-disubsti-
tuted quinoline intermediate E through an acidic ring
opening rearrangement process. Subsequently, aroma-
tization of intermediate E and the following intramo-
lecular ester exchange ring closure occurred to afford
the desired product 3aa.
Scheme 2. Synthesis of the C ring extension analogue of luo-
tonin A.
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Scheme 3. Cu(II)-H2SO4-air-catalyzed reaction of short peptides with 2,3-dihydropyrroles.
Table 4. Control experiments.
[a]
1a or A: 1.0 mmol; 2a: 2.0 mmol.
Solvent: MeCN, 20 mL, room temperature, 15 h.
[b]
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Scheme 4. Proposed mechanism for transformations of 1a and 2a.
left open to air (open flask) at room temperature for
30 min. H2SO4 (10M, 20 mol%) was then added. The solu-
tion was stirred under an air atmosphere at room tempera-
ture and the reaction was completed within 15–80 h as moni-
tored by TLC. After the reaction was completed, the reac-
tion mixture was concentrated under reduced pressure, and
the residue was purified by column chromatography to
afford the desired compounds 3.
Conclusions
In summary, we have demonstrated a simple and effi-
cient aerobic oxidative process for the construction of
quinoline fused lactones and lactams using glycine de-
rivatives and 2,3-dihydrofurans/2,3-dihydropyrroles
via the synergistic combination of copper(II) and
Brønsted acid catalysis. All of the starting materials
and catalysts are commercially available or easily pre-
pared, which allows the rapid and modular production
of a variety of fused heterocyclic cores. To highlight
this new method, the synthesis of the bioactive C ring
extension analogue of luotonin A (IV) was completed
in three chemical steps and 37% overall yield from
a simple aromatic substituted glycine ester.
General Procedure for the Preparation of Quinoline
Fused Lactams 6
Step 1: To a 50-mL round-bottom flask with a magnetic stir-
ring bar were added acetonitrile (20 mL), glycine esters (1,
1.0 mmol), 2,3-dihydropyrroles (4, 1.0 mmol) and CuCl2
(5 mol%) successively. The resulting reaction mixture was
left open to air (open flask) at room temperature for 1 hour.
H2SO4 (10M, 20 mol%) was then added. The solution was
stirred under an air atmosphere at room temperature and
the reaction was completed within 10 h as monitored by
TLC. After the reaction was completed, the reaction mix-
ture was concentrated under reduced pressure, and the resi-
due was purified by column chromatography to afford the
intermediates 5.
Step 2: Under a hydrogen atmosphere, Pd/C (20%) was
added to a solution of 5 in MeOH (30 mL). The resulting
mixture was stirred at room temperature until TLC showed
that the reaction was completed. Then the reaction mixture
was filtered to remove the catalyst. The filtrate was evapo-
rated to afford products 6.
Experimental Section
General Information
All reagents were commercially available and used without
further purification. Literature procedures were used for the
preparation of glycine derivatives.[1b] Reactions were moni-
tored by TLC and compounds were detected with UV light.
Flash chromatography was carried out using silica gel 200–
300. The melting points were determined on a melting point
1
instrument. H NMR (400 or 600 MHz) and 13C NMR (100
or 151 MHz) spectra were measured with TMS as internal
standard. High resolution mass spectra (HR-MS) were re-
corded under electrospray ionization (ESI) conditions.
Acknowledgements
General Procedure for the Preparation of Quinoline
Fused Lactones 3
We thank the National Natural Science Foundation of China
(21262029) and the Fok Ying Tong Education Foundation
(141116) for financially supporting this work.
To a 50-mL round-bottom flask with a magnetic stirring bar
were added acetonitrile (20 mL), glycine esters (1,
1.0 mmol), 2,3-dihydrofurans (2, 2.0 mmol) and CuCl2
(5 mol%) successively. The resulting reaction mixtures were
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References
2008, 49, 1301–1304; b) Y. M. Bi, X. B. Bi, Q. R. Zhao,
Y. T. Chen, J. L. Xie, Helv. Chim. Acta 2004, 87, 2890–
2895.
[1] a) L. Zhao, C.-J. Li, Angew. Chem. 2008, 120, 7183–
7186; Angew. Chem. Int. Ed. 2008, 47, 7075–7078; b) L.
Zhao, O. BaslØ, C.-J. Li, Proc. Natl. Acad. Sci. USA
2009, 106, 4106–4111; c) J. Xie, Z.-Z. Huang, Angew.
Chem. 2010, 122, 10379–10383; Angew. Chem. Int. Ed.
2010, 49, 10181–10185; d) G. Zhang, Y. Zhang, R.
Wang, Angew. Chem. 2011, 123, 10613–10616; Angew.
Chem. Int. Ed. 2011, 50, 10429–10432; e) S. Zhu, M.
Rueping, Chem. Commun. 2012, 48, 11960–11962; f) C.
Huo, C. Wang, C. Sun, X. Jia, X. Wang, W. Chang, M.
Wu, Adv. Synth. Catal. 2013, 355, 1911–1916; g) C.
Huo, C. Wang, M. Wu, X. Jia, H. Xie, Y. Yuan, Adv.
Synth. Catal. 2014, 356, 411–415; h) W. Wei, R. Song, J.
Li, Adv. Synth. Catal. 2014, 356, 1703–1707; i) W.-J.
Yoo, A. Tanoue, S. Kobayashi, Asian J. Org. Chem.
2014, 3, 1066–1069.
[5] S. Zhu, U.S. Patent 0087469 Al, 2010.
[6] a) Z. Ma, Y. Hano, T. Nomura, Heterocycles 2005, 65,
2203–2219; b) Y. Liang, X. Jiang, Z.-X. Yu, Org. Lett.
2009, 11, 5302–5305; c) Y. Ju, F. Lu, C. Li, Org. Lett.
2009, 11, 3582–3585; d) V. Sridharan, P. Ribelles, M. T.
Ramos, J. C. MenØndez, J. Org. Chem. 2009, 74, 5715–
5718; e) H.-B. Zhou, G.-S. Liu, Z.-J. Yao, J. Org. Chem.
2007, 72, 6270–6272; f) H. Twin, R. A. Batey, Org. Lett.
2004, 6, 4913–4916; g) S. B. Mhaske, N. P. Argade, J.
Org. Chem. 2004, 69, 4563–4566; h) D. Osborne, P. J.
Stevenson, Tetrahedron Lett. 2002, 43, 5469–5470.
[7] M. C. Tseng, Y. W. Chu, H. P. Tsai, C. M. Lin, J.
Hwang, Y. H. Chu, Org. Lett. 2011, 13, 920–923.
[8] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320–330; b) B. E. J. Smart, J.
Fluorine Chem. 2001, 109, 3–11.
[2] H. Richter, O. G. MancheÇo, Org. Lett. 2011, 13, 6066–
6069.
[9] The X-ray crystal data (excluding structure factors) of
compounds 3aa and 6a have been deposited with the
Cambridge Crystallographic Data Centre as supple-
mentary publication nos. CCDC 990348 and CCDC
1053816. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre
[3] a) C. Huo, H. Xie, M. Wu, X. Jia, X. Wang, F. Chen, J.
Tang, Chem. Eur. J. 2015, 21, 5723–5726; b) C. Huo, Y.
Yuan, M. Wu, X. Jia, X. Wang, F. Chen, J. Tang,
Angew. Chem. 2014, 126, 13762–13765; Angew. Chem.
Int. Ed. 2014, 53, 13544–13547; c) R. Rohlmann, T.
Stopka, H. Richter, O. G. MancheÇo, J. Org. Chem.
2013, 78, 6050–6064; d) X. Jia, F. Peng, C. Qing, C.
Huo, X. Wang, Org. Lett. 2012, 14, 4030–4033; e) P.
Liu, Z. Wang, J. Lin, X. Hu, Eur. J. Org. Chem. 2012, 8,
1583–1589; f) T. Stopka, L. Marzo, M. Zurro, S. Janich,
E.-U. Würthwein, C. G. Daniliuc, J. Alemµn, O. G.
MancheÇo, Angew. Chem. 2015, 127, 5135–5141;
Angew. Chem. Int. Ed. 2015, 54, 5049–5053; g) T.
Sonobe, K. Oisaki, M. Kanai, Chem. Sci. 2012, 3, 3249–
3255.
via
www.ccdc.cam.ac.uk/data_request/cif
or
on
application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, U.K. [fax: +44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
[10] a) J. S. Yadav, B. V. S. Reddy, Tetrahedron Lett. 2002,
43, 1905–1908; b) H. Wang, A. Ganesan, Tetrahedron
Lett. 1998, 39, 9097–9098.
[11] E. Borrione, M. Prato, G. Scorrano, M. Stivanello, J.
Heterocycl. Chem. 1988, 25, 1831–1835.
[12] Z.-Q. Zhu, P. Bai, Z.-Z. Huang, Org. Lett. 2014, 16,
4881–4883.
[4] a) C. Sall, N. Desbois, S. Paquelet, J. R. Camacho, J. M.
Chezal, J.-C. Teulade, Y. Blache, Tetrahedron Lett.
3654
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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