One-step Synthesis for the Preparation of Quinoline Alkaloid Analogues

Article abstract of DOI:10.1021/ol9911021

(Matrix Presented) A new one-step methodology has been introduced for the synthesis of quinoline alkaloid analogues. The reaction is based on a modification of the Mukaiyama aldol condensation, making use of the high reactivity of lactones or anhrydrides. The reaction is general and allows for the construction of new hetero polycondenced molecules in a one-step synthesis.

Full text of DOI:10.1021/ol9911021

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1953-1955
One-Step Synthesis for the Preparation
of Quinoline Alkaloid Analogues
Alexandros L. Zografos, Christos A. Mitsos, and Olga Igglessi-Markopoulou*
Department of Chemical Engineering, Laboratory of Organic Chemistry, National
Technical UniVersity of Athens, Zografou Campus, 157 73 Athens, Greece
zogal@central.ntua.gr
Received September 30, 1999
ABSTRACT
A new one-step methodology has been introduced for the synthesis of quinoline alkaloid analogues. The reaction is based on a modification
of the Mukaiyama aldol condensation, making use of the high reactivity of lactones or anhrydrides. The reaction is general and allows for the
construction of new hetero polycondenced molecules in a one-step synthesis.
In the past decade, several scientific groups have managed
to isolate a large number of alkaloids that belong to the
quinoline class of compounds.1-7 Isolable natural products
of this class constitute two large groups of quinoline
derivatives, the 3,3-disubstituted quinoline-2,4-diones (1) and
the 2-substituted quinoline-4-ones (2), pertaining to the
antibacterials collectively known as “quinolones”.8 Quinoline
Esenbeckia flaVa.2 On the other hand, isolation of active
agents from Pseudomonas sp.6,7 gave a large number of 2,3-
substituted quinoline derivatives (2).
Recently, 3,3-disubstituted quinoline-2,4-dione derivatives
have been proven to be capable of protecting CEM-SS cells
from the cytopathic effects of HIV-1 in vitro.5 In addition,
they have been identified as novel antibacterials, as they
present strong antibacterial effects on Staphylococcus aureus
and Escherichia coli.3
The continuous increase of isolable natural products as
well as the pharmacological action of these quinolinediones
has generated significant synthetic interest.9-11 Simple
analogues of these products can be suitable as precursors in
the total synthesis of natural products as well as compounds
with important biological properties. In this Letter we wish
to report a simple, general, one-step method for the prepara-
tion of 3,3-disubstituted quinoline-2,4-diones to simplify
routes to total synthesis of quinolinedione natural products.
Retrosynthetic analysis of 3,3(R,R′)-quinoline-2,4-diones
leads to disconnections as shown in Scheme 1. Route B can
only be used when the enol hydroxyl and amido functional
groups are suitably protected. This demands several steps
alkaloids of the first group have been isolated from different
species of plants, such as Haplophyllum tuberculatum3 and
(1) Chamberlain, R. T.; Grundon, F. M. J. Chem. Soc. C 1971, 910.
(2) Dreyer, L. D. Phytochemistry 1980, 19, 941.
(3) Sheriha, M. G.; Abouamer, K.; Elshataiwi, Z. B. Phytochemistry 1987,
26, 3339.
(4) Neville, F. C.; Grundon, F. M.; Ramachandran, N. V.; Reisch, G.;
Reisch, J. J. Chem. Soc., Perkin Trans. 1 1991, 2261.
(5) McCormick, L. J.; McKee, C. T. J. Nat. Prod. 1996, 59, 469.
(6) Moon, S.; Kang, P. M.; Park, K. S.; Kim, C. H. Phytochemistry 1996,
42, 365.
(7) Dekker, A. K.; Inagaki, T.; Gootz, D. T.; Huang, H. L.; Kojima, Y.;
Kohlbranner, E. W.; Matsunaga, Y.; MoGuirk, R. P.; Nomura, E.;
Sakakibara, T.; Sakemi, S.; Suzuki, Y.; Yamauchi, Y.; Kojima, N. J.
Antibiot. 1998, 51, 145.
(9) Reisch, J.; Muller, M.; Mester, I. Z. Naturforsch 1981, 36b, 1176.
(10) Subramanian, M.; Mohan, S. P.; Shanmugam, P.; Rajendra Prasad,
J. K. Z. Naturforsch 1991, 47b, 1016.
(11) Sarac-Arneri, R.; Mintas, M.; Pustet, N.; Mannschreck, A. Monatsh.
Chem. 1994, 125, 457.
(8) Quinolones; Andriole T. V., Ed.; Academic Press: New York, 1988.
10.1021/ol9911021 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/18/1999

the formation of the final product (12) rather than the
intermediate (11). This could be explained by the removal
of the acetyl group due to the acidic conditions. The reaction
proceeds smoothly under argon at room temperature and
gives moderate yields (reaction A ) 58-67%, reaction B
) 48%) of the disubstituted quinolinediones, in a 3 h reaction
time.
Scheme 1
Scheme 2a
of masking and unmasking of these groups. Considering
route A, isatoic anhydride derivatives (7, 8) or 4H-3,1-
benzoxazin-4-ones12 (9) would be suitable precursors of
synthon 3.
At first, our team focused on preparing the simplest
member of the target molecules, 3,3-dimethylquinoline-2,4-
dione (1, R ) R′ ) Me). A rather complex method for
preparing this compound was proposed by Evans et al. in
1987 using strong reaction conditions to cyclize the corre-
sponding anilide by phosphorus pentoxide.13 Our first attempt
was based on the reaction between 2-methyl-4H-3,1-ben-
zoxazin-4-one and an appropriate precursor of 4 such as ethyl
isobutyrate. The reaction was unsuccessful when lithium
diisopropylamide or lithium bis(trimethylsilyl)amide was
employed as the required base, resulting the hydrolyzed
benzoxazinone, 2-acetamidobenzoic acid, in quantitative
yield.
a (a) NaH, MeI, DMF; (b) TiCl4, CH2Cl2, 25 °C; (c) 6 N HCl,
reflux 48 h, R ) Me, Ph; X ) CH, N.
Because of the sensitivity of this procedure to basic
reaction conditions, our attention turned to the use of acidic
conditions in order to initiate the reaction. In accordance with
route A, an appropriate silyl ketene acetal14 could be used
as the precursor of synthon 4. Thus, reaction of 1-methoxy-
2-methyl-1-trimethylsiloxypropene (10) with methyl isatoic
anhydride (8) or benzo[3,1]-4H-oxazin-4-ones (9, X ) CH)
in the presence of Lewis acid, as catalyst, gave the desired
products 12 and 13 (Scheme 2). Treatment of 4H-3,1-
benzoxazin-4-ones (9) with silyl ketene acetal offers the
advantage of the isolation of the indermediates (11) which
are stable using these reaction conditions. Variation of
substituent R from phenyl to methyl (Scheme 2) resulted
This is the first time that a reaction using modified
Mukaiyama conditions15-17 has been employed for lactones
or anhydrides. This modification is based on the increase in
the temperature to 25 °C in combination with the use of
titanium tetrachloride as a catalyst.18
The mechanism of reaction B is shown in Scheme 3.
Attempts to generate the desired products using other Lewis
acids such as AlCl3, SnCl2, and SnCl4 yielded only starting
material. Attempts to react the isatoic anhydride (7) without
(15) Mukaiyama, T.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503.
(16) For a review, see: Mukaiyama, T. Angew. Chem., Ind. Ed. Engl.
1977, 16, 817.
(12) For the preparation of benzo- or pyrido[3,1]oxazin-4-ones, see: (a)
Krantz A.; Spencer W. R.; Tam F. T. J. Med. Chem. 1990, 33, 464. (b)
Hund C.; Bethune V. J. Org. Chem. 1970, 35, 1471.
(13) Evans, R. A.; Martin, R.; Taylor, G.; Maurice Yap, H. C. J. Chem.
Soc., Perkin Trans. 1 1987, 1635.
(14) For review and preparation of silyl ketene acetals, see: (a)
Rasmussen, K. J. Synthesis 1977, 91. (b) Brownbridge, P. Synthesis 1983,
1. (c) Kita, Y.; Haruta, J.; Segawa, J.; Tamura, Y. Tetrahedron Lett. 1979,
44, 4311.
(17) Nelson, G. S. Tetrahedron: Asymmetry 1998, 9, 357.
(18) General Procedure. In a solution of 7 or 8 (1.5 mmol) in anhydrous
dichloromethane, silyl ketene acetal (1.5 mmol) was added. The mixture
was stirred at room temperature under argon, after which titanium
tetrachloride was added in a dropwise manner. Stirring continued for 3 h.
The mixture was quenced by water and extracted with dichlomethane. The
dichloromethane extracts were evaporated in vacuo, and the residue was
purified by column chromatography (chloroform-methanol 5:0.15) to afford
the desired product.
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Org. Lett., Vol. 1, No. 12, 1999

amount of product 14 (12%) formed by Friedel-Crafts
alkylation of the target molecule by silyl ketene acetal.
Scheme 3
A simple modification that proves the generality of this
method was to employ the suggested route to analogues such
as 4H-pyrido[2,3-d][3,1]oxazin-4-ones (9, X ) N) to obtain
3,3-disubstituted 1,8-naphthyridine-2,4-diones, a new class
of molecules (Scheme 2, reaction A).
In conlusion, a new methodology has been introduced for
the synthesis of 3,3-disubstituted quinoline-2,4-diones or 3,3-
disubstituted 1,8-naphthyridine-2,4-diones, forwarding a new
method for the preparation of natural products of this class.
Supporting Information Available: Experimental pro-
cedure and NMR characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
prior N-methylation were unsussessful due to its insolubility.
As byproducts, we should underline the observation of small
OL9911021
Org. Lett., Vol. 1, No. 12, 1999
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