Total synthesis of nigellicine and nigeglanine hydrobromide

Article abstract of DOI:10.1021/ol050769m

(Chemical Equation Presented) The first syntheses of the pyridazinoindazolium alkaloids nigellicine and nigeglanine hydrobromide via a common intermediate are described. Ortho-lithiation/acylation and the direct amination of an isatin ring system are the

Full text of DOI:10.1021/ol050769m

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2449-2451
Total Synthesis of Nigellicine and
Nigeglanine Hydrobromide
Eric L. Elliott, Simon M. Bushell, Marta Cavero, Brian Tolan, and T. Ross Kelly*
E. F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
ross.kelly@bc.edu
Received April 8, 2005
ABSTRACT
The first syntheses of the pyridazinoindazolium alkaloids nigellicine and nigeglanine hydrobromide via a common intermediate are described.
Ortho-lithiation/acylation and the direct amination of an isatin ring system are the key steps in the synthesis.
The tricyclic pyridazino[1,2-a]indazolium ring system is
rarely encountered. Apart from being the subject of one
patent,1 it has appeared in the literature only in the context
of three natural products. The first member of the family,
nigellicine (1), was isolated in 1985 from the seeds of Nigella
satiVa.2 Subsequently, two additional alkaloids containing
the same ring system, nigeglanine (2) and nigellidine (3),
were isolated from Nigella glandulifera3 and Nigella satiVa,4
respectively. Herein we report the first syntheses of any
member of this natural product family5,6 and the independent
confirmations of the structures of 1 and 2.
ketohydrazine 5, potentially attainable via either direct
amination or diazotization/reduction of the corresponding
amine precursor. Finally, the synthesis was anticipated to
proceed through aniline 6 via regiospecific ortho-lithiation7
and quenching with a suitable oxalate derivative.
Figure 1. Retrosynthetic analysis of nigellicine (1).
Retrosynthetic analysis (Figure 1) suggested that 1 might
arise from the double alkylation of substituted indazole 4
with 1,4-dibromobutane. The indazole core structure was
envisioned to come from the intramolecular cyclization of
With confidence that the total synthesis of nigellicine could
be achieved in the above-mentioned manner, the preparation
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of 13’s reactive ketone functionality as the dimethyl acetal
(f14) finally enabled (Scheme 3) direct N-amination via
Scheme 1. Synthesis of Isatin 13
Scheme 3. Synthesis of Indazole 17
deprotonation with sodium hydride and quenching with
O-(diphenylphosphinyl)hydroxylamine (DppONH2)13 to af-
ford isatin derivative 15. Gratifyingly, treatment of 15 with
aqueous sulfuric acid then produced the desired indazole core
(16), which was most conveniently manipulated as its methyl
ester (17).
of a specific embodiment of synthon 5 was commenced
(Scheme 1). In anticipation of the regiospecific ortho-
lithiation reaction, it was necessary to protect the known
aniline derivative 9, accessible in two steps from com-
mercially available 2-chloro-5-methylphenol (7),8 with re-
giochemical realignment occurring via a benzyne interme-
diate.8c Thus, treatment of 9 with pivaloyl chloride yielded
protected amine 10. Subsequent reaction of 10 with 2.2 equiv
of n-butyllithium at 0 °C effected ortho-lithiation to produce
dianion 11, which, upon quenching with diethyl oxalate,
afforded 12 as a single regioisomer.9 Attempts to aminate
12, however, either directly10 or via diazotization/reduction11
met with failure. In the end, the only productive transforma-
tion that could be achieved was acidic cleavage of the
pivaloyl group and subsequent cyclization to isatin 13.
Conversion of 13 to the corresponding indazole via a
hydrolysis/diazotization/reduction protocol (Scheme 2) failed,
The final ring-forming transformation was accomplished
as shown in Scheme 4. Although a one-pot, double nucleo-
Scheme 4. Synthesis of 1
Scheme 2. Isatin-Indazole Transformation
philic displacement of dibromobutane by 17 was not suc-
cessful, monoalkylation of 17 afforded regioisomer 1814 in
good yield along with a small amount of both regioisomer
19 and double alkylation product 20. Subsequent heating of
18 in anhydrous methanol effected cyclization of the third
despite ample precedent.12 Subsequent attempts to aminate
13, either via diazotization/reduction or directly with an
electrophilic aminating reagent, also failed. But protection
(6) For the synthesis of some monocyclic analogues of nigellicine, see:
Schmidt, A.; Habeck, T.; Kindermann, M. K.; Nieger, M. J. Org. Chem.
2003, 68, 5977-5982.
(7) For a recent review see: Whisler, M. C.; MacNeil, S.; Snieckus, V.;
Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206-2225.
(8) (a) Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett. 1986, 27,
5397-5400. (b) Claudi F.; Giorgioni, J. G.; Di Stefano, A.; Abbracchio,
M. P.; Paoletti, A. M.; Balduinio. W. J. Med. Chem. 1992, 35, 4408-
4414. (c) Saari, W. S. (Merck), U.S. Patent 3671636, 1972; Chem. Abstr.
1972, 77, 88083.
(9) Regiochemistry confirmed by nOe difference spectra (see Supporting
Information).
(10) (a) Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 3133-3135. (b)
Ragnarsson, U. Chem. Soc. ReV. 2001, 30, 205-213.
(11) Coleman, G. H. Org. Synth. 1964, I, 442-445.
(1) Chugai Pharmaceutical Co., Ltd., Japan, Japanese Patent 60004185,
1985; Chem. Abstr. 1985, 102, 220870.
(2) Atta-ur-Rahman; Malik, S.; He, C.; Clardy, J. Tetrahedron Lett. 1985,
26, 2759-2762.
(3) Liu, Y.; Yang, J.; Liu, Q. Chem. Pharm. Bull. 2004, 52, 454-455.
(4) Atta-ur-Rahman; Malik, S.; Hasan, S. S.; Choudhary, M. I.; Ni, C.
Z.; Clardy, J. Tetrahedron Lett. 1995, 36, 1993-1996.
(5) A SciFinder Scholar search leads to a Ph.D. thesis titled “The
Total Synthesis of Three Natural Products: Nigellicine, Nigellidine, and
Chilenone-A” (Guneratne, R. D., Cornell University, 1988), but the title is
misleading since the thesis does not describe the synthesis of 1 nor 3.
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Org. Lett., Vol. 7, No. 12, 2005

and final ring in the nigellicine core to afford bromide 21.
Removal of both methyl protecting groups from 21 with BBr3
completed the total synthesis of 1, with an overall yield of
18% in 12 steps from commercially available starting
materials. The spectral properties (1H NMR, 13C NMR, and
UV-vis) and melting behavior of synthetic 1 are in excellent
agreement with those reported for the natural product.15
convert 18 to 21 by heating in aqueous acetone, that not
only did the expected cyclization occur (Scheme 5), but
hydrolysis and decarboxylation also happened, to yield 22
directly. Demethylation of 22 with BBr3 in refluxing meth-
ylene chloride afforded the hydrobromide salt 2b in 89%
yield from 18. The 1H, 13C, and HMBC spectra of synthetic
2b are in excellent agreement with those reported for
naturally derived material.18
Scheme 5. Synthesis of Nigeglanine Hydrobromide (2b)
Originally, it was anticipated that 1 could be converted
into 2 by heat-induced decarboxylation.16 Attempts to achieve
this transformation have, as yet, been unsuccessful.17 It was
discovered serendipitously, however, while attempting to
In summary, the present work provides the first synthesis
of nigellicine and affirms the structure originally reported.
This work also affords the first synthetic access to the
nigeglanine alkaloid family and affirms its tricyclic core
structure.
(12) (a) Snyder, H. R.; Thompson, C. B.; Hinman, R. L. J. Am. Chem.
Soc. 1952, 74, 2009-2012. (b) Buu-Hoi, N. P.; Hoeffinger, J. P.;
Jacquignon, P. J. Heterocycl. Chem. 1964, 1, 239-241.
Acknowledgment. We thank Dr. J. Clardy2,4 for helpful
exchange of information.
(13) Shen, Y.; Friestad, G. K. J. Org. Chem. 2002, 67, 6236-6239.
(14) Regiochemistry confirmed by 1D-NOESY (see Supporting Informa-
tion).
Supporting Information Available: General information
and experimental details and selected spectra for 8, 9, 12-
18, 21, 1, 22, and 2b. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Some differences were noted between the IR spectrum of synthetic
1 and the IR of the natural product. An authentic sample of natural 1 was
not available. See the Supporting Information for a tabulated comparison
of the spectra of synthetic 1 and the natural material.
(16) For examples of the thermal decarboxylation of indazole-3-
carboxylic acids see: (a) Behr, L. C.; Fusco, R.; Jarboe, C. H. In Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; Wiley, R. H.,
Ed.; Chemistry of Heterocyclic Compounds, Vol. 22; Wiley: New York,
1967. (b) Borsche, W.; Diacont, K. Justus Liebigs Ann. Chem. 1934, 510,
287-296. (c) von Auwers, K. Chem. Ber. 1922, 55, 1141-1157.
(17) Unreacted starting material is recovered upon heating under neutral
conditions up to 200 °C in a variety of solvents, at which point
nonproductive decomposition occurs. Heating in 1 M HCl, on the other
hand, yields unreacted starting material up to 150 °C, at which point
nonproductive decomposition occurs.
OL050769M
(18) There is apparently a significant effect of the counterion and pH of
2 on spectra of this material. The 1H NMR, 13C NMR, and HMBC spectra
of synthetic 2 as its HBr salt most closely match (and are in excellent
agreement with: see the Supporting Information) the spectra reported for
naturally derived 2‚H2O. Despite that compelling congruence, the IR and
UV-vis spectra of synthetic 2 are different (see the Supporting Information)
from those reported for the natural material. Unfortunately, we have been
unable to obtain an authentic sample of the natural material or spectra
thereof, despite repeated acknowledged requests.
Org. Lett., Vol. 7, No. 12, 2005
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