Inverse electron-demand Diels-Alder chemistry in the synthesis of a regioselectively protected analogue of the staurosporine aglycone

Article abstract of DOI:10.1016/S0040-4039(01)01678-1

Regioselective Weinreb amidation of the C1 ester of dimethyl pyridazino[4,5-b]indole-1,4-dicarboxylate followed by an intramolecular inverse electron-demand Diels-Alder reaction and palladium-catalyzed coupling produced regioselectively protected N^6<

Full text of DOI:10.1016/S0040-4039(01)01678-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7929–7933
Inverse electron-demand Diels–Alder chemistry in the synthesis
of a regioselectively protected analogue of the staurosporine
aglycone†
Rana Nomak and John K. Snyder*
Department of Chemistry, Boston University, 590 Commonwealth Ave., Boston, MA 02215, USA
Received 24 July 2001; revised 22 August 2001; accepted 7 September 2001
Abstract—Regioselective Weinreb amidation of the C1 ester of dimethyl pyridazino[4,5-b]indole-1,4-dicarboxylate followed by an
intramolecular inverse electron-demand Diels–Alder reaction and palladium-catalyzed coupling produced regioselectively pro-
tected N6-methylindolo[2,3-a]pyrrolo[3,4-c]carbazole (N6-methylstaurosporinone). © 2001 Elsevier Science Ltd. All rights
reserved.
1H-Indolo[2,3-a]pyrrolo[3,4-c]carbazoles represent
a
tron-demand Diels–Alder strategy that would allow for
selective protection of one of the indole nitrogens of the
aglycone. Since this aglycone is common to other bio-
logically active indolo[2,3-a]carbazole alkaloids, (Fig.
1), distinction of the indole nitrogens in the aglycone
would have application to other targets as well.
large family of natural alkaloids possessing remarkable
biological activities.1 Perhaps the best known member
of the family, staurosporine (1), isolated from Strepto-
myces staurosporeu,2 was found to have antibacterial,3
antihypertensive3 and antiedema properties,3 and fur-
ther testing revealed that it is an extremely potent
inhibitor of protein kinase C.4 Numerous synthetic
studies of the indolo[2,3-a]pyrrolo[3,4-c]carbazole
skeleton5 as well as the completed synthesis of
staurosporine6 and related natural7 and unnatural8
products have been reported. Distinction of the indole-
nitrogens (N12 and N13) with high regioselectivity,
however, remains a synthetic challenge.
The envisioned sequence of reactions centered on an
intramolecular cycloaddition of the pyridazino[4,5-b]-
indole 5 to form the 3-arylindolocarbazole 4 follow-
ing the regioselective tethering of the alkynylamine
(Scheme 1). The C4 ester group of 4 could then be
converted to aniline 3 by hydrolysis and a Curtius
rearrangement. Final ring closure to 2 would then be
achieved by an intramolecular palladium-catalyzed aryl
amination. The facile synthesis of pyridazino[4,5-b]-
indole 6a9 from the cycloaddition of indole (7) with
We initiated our efforts toward the synthesis of the
indolo[2,3-a]carbazole skeleton utilizing an inverse elec-
Figure 1. Indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids.
* Corresponding author. Tel.: 617/353-2621; fax: 617/353-6466; e-mail: jsnyder@chem.bu.edu
†
Presented at the American Chemical Society National Meeting, August 2000, Washington, DC.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01678-1

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R. Nomak, J. K. Snyder / Tetrahedron Letters 42 (2001) 7929–7933
but no cycloaddition could be accomplished with sec-
ondary amide 9c, returning only starting material.
Hydrolysis of 10 to the acid 11 was accomplished under
basic conditions (KOH, MeOH) in 80% yield, depro-
tecting the carbazole nitrogen as well under these
conditions.
With the success of this model study, the next task was
to incorporate the aryl ring onto the triple bond of the
alkyne dienophile to complete the preparation of 4-
arylpyrrolo[3,4-c]carbazoles 4. In principle, this could
be accomplished through Sonogashira coupling13 of
iodoarenes 12 with either amide 9a (Scheme 4, Route
A), or N-methylpropargylamine (13, Scheme 4, Route
B), the latter route being preferred as a more conver-
gent strategy. The former method led to unclean reac-
tions, thus we turned our attention to Route B.
Coupling of iodobenzene with N-methylpropargyl-
amine (13) proceeded very cleanly, to give 14a in 86%
yield (Scheme 4). o-Chloro, o-bromo and o-nitro ana-
logues 14b–d were synthesized similarly with good
yields for 14b and 14c, though only a modest yield for
14d. Regioselective Weinreb amidation of the tosyl
protected pyridazinoindole 6b with the alkynes 14 gave
the monoamides 5a–c (mixtures of amide rotamers in
ratios of ꢀ3:2). The o-nitrophenyl derivative 14d, how-
ever, failed to participate in the Weinreb amidation.
Intramolecular inverse electron-demand Diels–Alder
reactions of 5a–c produced the pyrrolocarbazoles 4a–c
uneventfully in diglyme (150°C) in the presence of BHT
(1 equiv.). The successful cycloadditions of 5a–c with
ortho halo-substituents produced the ortho-substituted
4-(o-halophenylpyrrolo[3,4-c]carbazoles necessary for
the final coupling step to close the E-ring of stau-
rosporinone. The methylene protons of the lactam ring
of 4b and 4c are diastereotopic, appearing as doublets
at l 4.15 and 4.06 JAB=17.8 Hz (R=Cl) and at l 4.17
and 4.03 JAB=17.8 Hz (R=Br) for the two cycload-
ducts in the 1H NMR spectra indicating restricted
rotation about the carbazoleꢀphenyl CꢀC bond and
resulting in axial chirality. Carbazoles analogous to 4
Scheme 1. Retrosynthetic analysis.
dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (8)10 pro-
vided an electron-deficient system for further cycloaddi-
tion chemistry (Scheme 2). Previously attempted
intermolecular inverse electron-demand Diels–Alder
reactions of pyridazinoindole 6a have been unsuccess-
ful,9 though Diels–Alder reactions of the related
1,4-bis(trifluoromethyl)pyridazino[4,5-b]indole with en-
amines have been reported.11 Thus, we turned our
attention to intramolecular Diels–Alder reactions.
In model studies, introduction of an acetylenic
dienophile onto the pyridazine ring at the C1 ester
group was achieved regioselectively via Weinreb
amidation12 (Scheme 3). Weinreb amidation of 6b and
6c with N-methylpropargylamine hydrochloride salt
occurred exclusively on the C1 ester to give the
monoamides 9a and 9b, respectively. The cycloaddition
of 9a proceeded smoothly in refluxing diglyme in the
presence of BHT (1 equiv.) to give carbazole 10a in
excellent yield (90%). In the absence of BHT, the
reaction was not as clean and gave a yield of only 71%.
The cycloaddition of 9b was fruitless, giving back start-
ing material, presumably due to the higher LUMO level
of 9b in comparison to 9a. Weinreb amidation of 6d
with propargylamine hydrochloride also worked well,
Scheme 3. Synthesis of pyrrolo[3,4-c]carbazole 8.
Scheme 2. Synthesis of pyridazino[4,5-b]indole 2.

R. Nomak, J. K. Snyder / Tetrahedron Letters 42 (2001) 7929–7933
7931
Scheme 4. Synthesis of 4-phenylpyrrolo[3,4-c]carbazole-5-carboxylate. (a) PdCl2(PPh3)2, CuI, NHEt2; (b) (i) AlMe3; (ii) 6b; (c)
BHT, diglyme.
have also attracted attention as staurosporine ana-
logues,14 and have been shown to be cytotoxic
through PKC inhibition and to show thrombopoietic
activity.14a Attempted demethylation of the ester of 4c
under the same conditions as 10 (KOH, MeOH)
resulted only in loss of the tosyl group providing the
deprotected carbazole with the ester still intact. How-
ever, treatment with AlBr3/EtSH15 produced carboxylic
acid 4d with the N-tosyl group also removed (Scheme
5). Presumably the highly hindered environment of
the methyl ester in 4c prevented its hydrolysis under
the more common basic conditions. Curtius
rearrangement16 of acid 4d was accomplished upon
treatment with DPPA (64%), followed by intramolecu-
lar coupling17 of the carbamate under Hartwig’s condi-
tions with an unoptimized yield of 29% to produce
indolocarbazole 2a18 with differentiated nitrogens along
with 58% of the starting carbamate.
In summary, the intramolecular inverse electron-
demand Diels–Alder reactions of pyridazino[4,5-
b]indoles with acetylenic dienophiles introduced with
exclusive regioselectivity yielded the arylcarbazole
required for the final closure of the E-ring, which was
accomplished by a palladium-catalyzed intramolecular
aryl amination. The issue of regioselective introduction
of the sugar moiety onto the indolocarbazole skeleton
has been addressed by an orthogonal nitrogen protect-
ing group strategy. Work is continuing to improve the
yield of the final ring-closing arylamination.
Acknowledgements
This work has been supported in part by NSF CHE-
9501069.
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Hz, 2H), 4.53 (s, 2H), 3.25 (s, 3H), 1.60 (t, J=7.3 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): l 169.3, 153.2,
138.7, 137.4, 130.4, 127.3, 127.1, 126.41, 126.36, 126.32,
125.9, 123.9, 123.7, 122.3, 120.5, 119.7, 119.6, 117.3,
116.8, 110.5, 64.5, 51.9, 29.6, 14.4; EIHRMS (70 eV)
m/z 397.1437 ([M+], 88%), calcd for C24H19N3O3
397.1426.
18. 1H NMR (400 MHz, CDCl3): l 10.85 (br s, NH), 9.46
(d, J=7.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.62 (d,
J=7.3 Hz, 1H), 7.53–7.44 (m, 3H), 7.39 (dd, J=8.4, 7.3
Hz, 1H), 7.31 (dd, J=7.3, 7.0 Hz, 1H), 4.57 (q, J=7.3