Approach to geminally alkylated azaphthalans via a consecutive double desilylation-alkylation reaction: Application to a synthesis of cerpegin

Article abstract of DOI:10.1021/ol0489797

(Equation Presented) A new approach to geminally alkylated azaphthalans and an application of this chemistry to the synthesis of the pyridone alkaloid, cerpegin, is reported.

Full text of DOI:10.1021/ol0489797

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2925-2927
Approach to Geminally Alkylated
Azaphthalans via a Consecutive Double
Desilylation−Alkylation Reaction:
Application to a Synthesis of Cerpegin
Tarun K. Sarkar* and Sankar Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India
tksr@chem.iitkgp.ernet.in
Received June 3, 2004
ABSTRACT
A new approach to geminally alkylated azaphthalans and an application of this chemistry to the synthesis of the pyridone alkaloid, cerpegin,
is reported.
Although much attention has been paid to the introduction
of two organic groups at the 1,3-positions of phthalans,1-4
practically no report is available for the synthesis of
geminally alkylated phthalans and their congeners (azaph-
thalans) from their parent molecules. Like their 1,3-
counterparts that show promising pharmacological profiles,5
geminally alkylated phthalans and azaphthalans also display
significant biological activities, most of which have been
reported in the patent literature.6 Thus, introduction of two
organic groups on the same benzylic carbon in phthalans
and azaphthalans is an important task in organic synthesis.
Current methods for the direct synthesis of 1-substituted
as well as 1,3-disubstituted phthalans and azaphthalans
involve deprotonation of the parent compounds or their Cr-
(CO)3 complexes at the R-position followed by trapping of
the resulting species with a carbon electrophile.1-4 It should
be noted that the choice of base is critical for effective
deprotonation of these systems.4 To date, only t-BuLi and
n-BuLi-lithium 2-(dimethylamino)ethoxide (LiDMAE) are
found to be useful bases.1,4 With other basic reagents such
as n-BuLi-t-BuOK, Li-naphthalene, Li-4,4′-di-tert-butylbi-
phenyl, and n-BuLi-THF, ring cleavage was observed,4,7 and
with lithium amide bases such as LDA, the lithiation was
poorly selective.2,4 Herein, we report a route to geminally
alkylated azaphthalans based on a consecutive double desi-
lylation-alkylation reaction and an application of this
chemistry to the synthesis of the pyridone alkaloid, cerpegin.
(1) Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A. J. Organomet.
Chem. 1989, 379, 81.
(2) Ewin, R. A.; Simpkins, N. S. Synlett 1996, 317.
(3) Zemolka, S.; Lex, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2002,
41, 2525.
(4) Fort, Y.; Gros, P.; Rodriguez, A. L. Tetrahedron Lett. 2002, 43, 4045.
(5) (a) A prominent example of a bioactive phthalan is the antidepressant
citalopram; see: Pollock, B. G. Expert Opin. Pharmacother. 2001, 2, 681.
(b) Lovey, R. G.; Elliott, A. J.; Kaminski, J. J.; Loebenberg, D.; Parmegiani,
R. M.; Rane, D. F.; Girijavallabhan, V. M.; Pike, R. E.; Guzik, H.;
Antonacci, B.; Tomaine, T. Y. J. Med. Chem. 1992, 35, 4221. (c) Ram, S.;
Saxena, A. K.; Jain, P. C.; Patnaik, G. K. Indian J. Chem. Sect. B 1984,
23, 1261. (d) Klohs, M. W.; Petracek, F. J. (Dart Industries. Inc.). U.S.
Patent 3471519, 1969; Chem. Abstr. 1969, 71, 124212.
(6) (a) Sun, E. T.; Anderson, M. B.; Anderes, K. L.; Christie, L. C.; Do,
Q. T.; Feng, J.; Goetzen, T.; Hong, Y.; Iatsimirskaia, E. A.; Li, H.; Luthin,
D. R.; Paderes, G. D.; Pathak, V. P.; Rajapakse, R. J.; Shackelford, S.;
Tompkins, E. V.; Truesdale, L. K.; Vazir, H. PCT Int. Appl. WO2002098363
2002, p 243. (b) Esanu, A. U.S. Patent US4602020, 1986. (c) Esanu, A.
U.S. Patent US4569939, 1986. (d) Esanu, A. U.S. Patent US4581362, 1986.
(e) Esanu, A. U.S. Patent US4585776, 1986. (f) Esanu, A. U.S. Patent
US4569938, 1986. (g) Sagara, T.; Itoh, I.; Nakashima, H.; Goto, Y.;
Shimizu, A.; Iwasawa, Y.; Okamoto, O. PCT Int. Appl. WO02088089, 2002,
p 187.
(7) (a) Baston, E.; Maggi, R.; Friedrich, K.; Schlosser, M. Eur. J. Org.
Chem. 2001, 3985. (b) Azzena, U.; Demartis, S.; Fiori, M. G.; Melloni, G.;
Pisano, L. Tetrahedron Lett. 1995, 36, 8123. (c) Foubelo, M.; Yus, M.
Trends Org. Chem. 1998, 7, 1.
10.1021/ol0489797 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

Our strategy toward geminally alkylated azaphthalans, e.g.,
4 is outlined in Scheme 1. On the basis of the stabilization
76 °C). Exposure of 7 to NaOMe in methanol gave a single
methoxy-substituted product (mp 59-60 °C) to which
structure 8 was assigned on the basis of the following
experiments. Reductive removal of chlorine in 8 (H2, Pd-
1
C, NaOAc, MeOH, rt) afforded 10. In the H NMR of 10
Scheme 1. Synthetic Strategy for Geminally Alkylated
(CDCl3), the appearance of a pair of doublets at δ 6.81 (J )
5.2 Hz) and 8.07 (J ) 5.2 Hz) confirmed its structure, thus
ruling out the alternative structure 11. Evidently, selective
displacement of one of the chlorine atoms flanking the
nitrogen atom of pyridine ring of 7 by a methoxide
nucleophile is interesting.9 Treatment of azaphthalan 8 with
2 equiv of LDA in THF at -78 °C for 1 h and subsequent
quenching of the resultant metalated product(s) with chloro-
dimethylphenylsilane (2.1 equiv) gave a disilylated aza-
phthalan 9 in one pot as a yellowish oil in 80% yield. The
position of the silyl groups in 9 is based on a single-crystal
X-ray structure determination10 of the related bis-trimethyl-
silyl-substituted azaphthalan 12 (mp 95-96 °C), obtained
in a very poor yield from 8 under similar metalation-
silylation conditions.
At this stage, sequential introduction of two alkyl groups
to 9 was studied using a tandem double desilylation-
alkylation strategy (cf. Scheme 1). Thus, the treatment of 9
with 2 equiv of CsF and MeI in DMF at room temperature
afforded 13 (R ) Me) as the major product contaminated
with only a minor amount of 14 (R ) Me). In addition, the
consecutive double desilylation-alkylation reaction was
performed with other electrophiles, and the results are
summarized in Table 1. A pure sample of 13 (R ) Me) was
Azaphthalans
of a carbanion by an R-silyl group, it was envisaged that
lithiation of monosilylated azaphthalan 2 and a followup
silylation would lead to the introduction of the new silyl
group on the same R-carbon (although it may require some
kinetic [steric] balance). The resulting species 3, upon
fluoride ion-promoted cleavage of the two C-Si bonds and
alkylation, would provide an efficient route to 1,1-dialkylated
azaphthalans, e.g., 4.
In this context, a model azaphthalan 8 was prepared from
the chloro-substituted aldehyde 58 by a standard synthetic
protocol (Scheme 2). Thus, reduction of 5 with sodium
Scheme 2. Synthesis of Bissilylated Azaphthalans
Table 1. Consecutive Double Desilylation-Alkylation
Reaction
entry
R
yield of 13 + 14 (%)
13/14
1
2
3
Me-
CH2dCHCH2-
PhCH2-
70
68
61
75/25
70/30
58/42
obtained by repeated preparative thin-layer chromatographic
purification (silica gel, petroleum ether) of the mixture of
13 and 14 (R ) Me).
It is pertinent to mention here that most of the references4,7
cited earlier in this paper describe the difficulty of carbanion
generation in the benzylic position(s) in phthalans. Since the
presence of a nitrogen atom as in azaphthalans may improve
the chances of carbanion generation at the desired site, there
is a possibility that, in these cases (cf. 8), a sequential double
alkylation would work and save the need for the desilylative
procedure.
borohydride in ethanol (0 °C f rt) yielded a separable
mixture of alcohol 6 (65%) and azaphthalan 7 (16%). For
the sake of convenience, the crude product mixture after
sodium borohydride reduction was treated with DBU in
toluene at reflux for 2 h to give only azaphthalan 7 (mp 75-
(9) At this point in time, we have no clear explanation for the
regioselective displacement 7 f 8.
(8) Sarkar, T. K.; Basak, S. Unpublished results.
(10) Unpublished work with Professor H.-K. Fun (Penang, Malaysia).
2926
Org. Lett., Vol. 6, No. 17, 2004

To address this issue, the monomethylated azaphthalan 14
(R ) Me), contaminated with 8, was made via the treatment
of 8 with LDA (2 equiv) and subsequent exposure of the
lithiated species to MeI. Further exposure of 14 (contami-
nated with 8) to LDA and a followup treatment with methyl
iodide did not give any dimethylated product. Also, treatment
of 8 with sodamide in DMSO at ambient temperature led to
uncharacterizable byproducts and no desired product, e.g.,
14 (R ) Me) was found to form. Moreover, replacement of
the base in these reactions by LiNH2 in liquid NH3 failed to
yield any 14 (R ) Me) in our hands; instead, the starting
material was returned practically quantitatively.
in 15 with hydrogen in the presence of 10% Pd-C and
NaOAc gave 16 (79%), which has been previously11d,h
converted to cerpegin 17 upon exposure to MeI. Thus, a
formal synthesis of cerpegin has been completed.
In conclusion, this is the first report wherein two alkyl
groups were introduced on the same R-carbon of aza-
phthalans in one pot by a consecutive double desilylation-
alkylation reaction. Furthermore, this chemistry proved to
be useful in a synthesis of the pyridone natural product,
cerpegin.
Acknowledgment. Financial support from DST, Govern-
ment of India, is gratefully acknowledged. S.B. is thankful
to CSIR, Government of India, for a Senior Research
Fellowship. Professor W. Dehaen (Belgium) is thanked for
sending us the 13C NMR data of 16. We also thank Professor
T. Gallagher (Bristol), Dr. C. Fehr (Firmenich, Geneva), and
Dr. S. Djuric (Abbott, Illinois) for continuing help and
support.
Scheme 3. Application of Geminally Alkylated Azaphthalans
Supporting Information Available: Spectra for charac-
terization of 6-9, 12, 13 (R ) Me), 13 (R ) allyl), and 16
and an X-ray picture of 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0489797
(11) For synthesis, see: (a) Tarasov, E. V.; Henckens, A.; Ceulemans,
E.; Dehaen, W. Synlett 2000, 625. (b) Matsuo, K.; Kobayashi, M.; Sugimoto,
K.-I. Heterocycles 1997, 45, 119. (c) Villemin, D.; Liao, L. Tetrahedron
Lett. 1996, 37, 8733. (d) Hong, H.; Comins, D. L. J. Org. Chem. 1996, 61,
391. (e) Matsuo, K.; Arase, T. Chem. Pharm. Bull. 1995, 43, 2091. (f)
Matsuo, K.; Arase, T. Chem. Pharm. Bull. 1994, 42, 715. (g) Guillier, F.;
Nivoliers, F.; Bourguingnon, J.; Dupas, G.; Marsais, F.; Godard, A.;
Queguiner, G. Tetrahedron Lett. 1992, 33, 7355. (h) Kelly, T. R.; Walsh,
J. J. J. Org. Chem. 1992, 57, 6657.
(12) (a) Sivakumar, K.; Eswaramurthy, S.; Subramanian, K.; Natarajan,
S. Acta Crystallogr., Sect. C 1990, 46, 839. (b) Adibatti, N. A.; Thirug-
nanasambantham, P.; Kulothungan, C.; Viswanathan, S.; Kameswaran, L.;
Balakrishna, K.; Sukumar, E. Phytochemistry 1991, 30, 2449.
(13) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
We then realized that the present consecutive double
desilylation-alkylation reaction could be applied to the
synthesis of cerpegin11 isolated from Ceropegia juncea, a
plant used in traditional Indian medicine for its tranquilizer,
antiinflammatory, analgesic, and antiulcer properties.12 Thus,
oxidation of geminally methylated azaphthalan 13 under
RuCl3-NaIO4 conditions13 gave 15 (47%) as a white
crystalline solid (Scheme 3). Removal of the chlorine atom
Org. Lett., Vol. 6, No. 17, 2004
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