Chemo-, regio-, and enantioselective Pd-catalyzed allylic alkylation of indolocarbazole pro-aglycons.

Article abstract of DOI:10.1021/ol020046s

[reaction: see text] Monosubstituted isomerically pure indolopyrrolocarbazole precursors have been prepared via palladium-catalyzed asymmetric allylic alkylation methodology, employing both achiral cyclopentenyl electrophiles and chiral glycal derivatives

Full text of DOI:10.1021/ol020046s

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2005-2008
Chemo-, Regio-, and Enantioselective
Pd-Catalyzed Allylic Alkylation of
Indolocarbazole Pro-aglycons
Barry M. Trost,* Michael J. Krische, Volker Berl, and Ellen M. Grenzer
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received February 28, 2002
ABSTRACT
Monosubstituted isomerically pure indolopyrrolocarbazole precursors have been prepared via palladium-catalyzed asymmetric allylic alkylation
methodology, employing both achiral cyclopentenyl electrophiles and chiral glycal derivatives. Chemoselective allylation of (bis)indole lactam
pro-aglycon 3 allows access to N-distally substituted indolopyrrolocarbazole derivatives; glyoxamide precursor 14 provides entry into N-proximally
substituted derivatives.
Members of the indolocarbazole family of natural products
exhibit nanomolar PKC and topoisomerase inhibitory action.1
Their remarkable biological activity and novel structure have
captured the attention of synthetic chemists.2 Since the initial
total synthesis of staurosporine3 1 and of K-252a,4 several
syntheses of indolocarbazole natural products have appeared.5-8
The vast majority of synthetic strategies involve N-glycosi-
dation of activated sugars, such as bis-glycal derivatives, with
aglycons 2a or 2b (Scheme 1). While the indolic nitrogens
of 2a are sterically equivalent, they are electronically unique
Scheme 1. Previous Synthetic Strategies
(1) For reviews on studies related to their chemistry and biology, see:
Gribble, G.; Berthel, S. Studies in Natural Products Chemistry; Elsevier
Science Publishers: New York, 1993; Vol. 12, p 365. Sapi, J.; Massiot, G.
The Alkaloids; Academic Press: New York, 1995; Vol. 47, p 173. Bergman,
J. Studies in Natural Products Chemistry; Elsevier Science Publishers: New
York, 1988; Vol. 1, p 3. Steglich, W. Pure Appl. Chem. 1989, 61, 281. For
a review on the bioactivity of staurosporine, see: Omura, S.; Sasaki, Y.;
Iwai, Y.; Takeshima, H. J. Antibiot. 1995, 48, 535.
(2) (a) Sarstedt, B.; Winterfeldt, E. Heterocycles 1983, 20, 469. (b)
Hughes, I.; Nolan, W. P.; Raphael, R. A. J. Chem. Soc., Perkin Trans. 1
1990, 2475. (c) Moody, C. J.; Rahimtoola, K. F. Chem. Soc., Chem.
Commun. 1990, 1667. (d) Xie, G.; Lown, J. W. Tetrahedron Lett. 1994,
35, 5555.
(3) Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 552; Link, J. T.; Danishefsky, S. J. Tetrahedron Lett. 1994, 35, 9131.
(c) Link, J. T.; Danishefsky, S. J. Tetrahedron Lett. 1994, 35, 9135. Link,
J. T.; Raghavan, S.; Gallant, M.; Chou, T. C.; Ballas, L. M.; Danishefsky,
S. J. J. Am. Chem. Soc. 1996, 118, 2825.
owing to the inductive effects of the remote lactam carbonyl.
Nevertheless, reported protocols for the glycosidation of 2a
(5) Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E. M.; Elbaum,
D.; Stover, D. R. Synthesis 1999, 1529. Wood, J. L.; Stoltz, B. M.;
Goodman, S. N.; Onwneme, K. J. Am. Chem. Soc. 1997, 119, 9652. Wood,
J. L.; Stoltz, B. M.; Dietrich, H. J.; Pflum, D. A.; Petsch, D. T.. J. Am.
Chem. Soc. 1997, 119, 9641. Wood, J. L.; Stoltz, B. M.; Goodman, S. N.
J. Am. Chem. Soc. 1996, 118, 10656. Wood, J. L.; Stoltz, B. M.; Goodman,
S. N.; Onwneme, K. Tetrahedron Lett. 1996, 37, 7335. (e) Stoltz, B. M.;
Wood, J. L. Tetrahedron Lett. 1996, 37, 3925.
(4) Wood, J.; Stolz, B. M.; Dietrich, H.-J. J. Am. Chem. Soc. 1995, 117,
10413.
10.1021/ol020046s CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

exhibit poor chemoselectivity. Similarly, desymmetrization
of N-glycosidated imide 2b affords mixtures of isomeric
products. In this Letter, we disclose a highly chemoselective
N-glycosidation of indolocarbazole pro-aglycons achieved
on the basis of this electronic bias via Pd-catalyzed allylic
alkylation.9
Our initial attempts at chemoselective N-glycosidation
focused on aglycons 2a and 2b. While indole itself is a viable
pro-nucleophile, it soon became apparent that 2a and 2b were
not effective participants presumably owing to steric factors
or bidentate complexation of palladium by the aglycon.
Accordingly, the catalytic allylic alkylation of bis(indole)
derivatives 3a and 3b in conjunction with cyclopentenyl
carbonate 4 and chiral ligand 510 was studied (Scheme 2).
Table 1. Asymmetric Allylic Alkylation of 3a and 3b with
Cyclopentenyl Carbonate 4
cat.
T
concn
yield
ee
entry pro-aglycon solvent (%) (°C) (mol/L) (%) (%)a
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3b
3b
THF
THF
10
10 -55
10 25
10 -20
10 -20
25
0.1
0.1
78
66
65
59
83
61
75
-22
-30
76
DCM
DCM
DCM
DCM
DCM
0.05
0.1
0.05
0.06
0.06
96
99
83
99
5
25
5
-20
a Enantionmeric excess determined by chiral stationary phase HPLC.
assignment of the cyclopentenylated adduct was unambigu-
ously established by high-field Overhauser enhancement and
homo- and heteronuclear correlation and connectivity 2D
NMR experiments (Figure 1).
Scheme 2. Asymmetric Allylic Alkylation of (Bis)indole
Lactams 3a and 3b with Cyclopentenyl Carbonate 4
Gratifyingly, catalytic allylation of 3a afforded the single
isomeric monoadduct 6a in good yields.11 Allylations
conducted in THF gave products with poor levels of
enantiomeric enrichment (entries 1 and 2). However, ally-
lation performed in DCM gave products of high enantiomeric
excess (entries 4 and 5). Remarkably, the products obtained
in DCM were of the opposite stereochemical configuration
to those obtained from THF. Overallylation in the case of
3b was circumvented through slow addition of the electro-
phile over a 12 h period. In both cases, reactions conducted
at lower temperatures gave products of higher enantiomeric
excess. These results are summarized in Table 1.
Figure 1. Selected, most indicative correlations.
Further support of the proposed structural assignment
derives from consideration of the aggregation of 6b in
solution. In low dielectric media such as chloroform and
toluene, the NMR spectra of 6b are highly concentration
dependent. However, in polar protic solvents, the NMR
chemical shifts remain unchanged over a large concentration
range. Conformational analyses12 suggest the most stable
conformation of 6b to be one in which the non-alkylated
indole NH and lactam carbonyl reside in syn-coplanar
orientation. Thus, whereas the anticipated distal regioisomer
may engage in a specific 2-fold self-association arising
through the formation of hydrogen-bonded dimer, the
alternate regioisomer should aggregate in nonspecific or
polymeric fashion through single H-bonds (Figure 2).
Dilution experiments and mathematical treatments of the
chemical shift values reveal the expected 2-fold self-assembly
event.13 The allylated adduct 6b dimerizes in chloroform with
Under the basic conditions of allylation, it was anticipated
that the more acidic indolic nitrogen, i.e., the indolic nitrogen
linearly conjugated and “distal” to the carbonyl function,
would represent the preferred site of allylation. The structural
(6) Gilbert, E. J.; Ziller, J. W.; VanVranken, D. L. Tetrahedron 1997,
53, 16553. Gilbert, E. J.; Vanvranken, D. L. J. Am. Chem. Soc. 1996, 118,
5500.
(7) Eils, S.; Winterfeldt, E. Synthesis 1999, 275. Riley, D. A.; Simpkins,
N. S.; Moffat, D. Tetrahedron Lett. 1999, 40, 3929. Royer, H.; Joseph, D.;
Prim, D.; Kirsch, G. Synth. Commun. 1998, 28, 1239. Ohkubo, M.;
Nishimura, T.; Jona, H.; Honma, T.; Ito, S.; Morishima, H. Tetrahedron
1997, 53, 5937. Merlic, C. A.; McInnes, D. M. Tetrahedron Lett. 1997, 38,
7661. Merlic, C. A.; McInnes, D. M.; You, Y. Tetrahedron Lett. 1997, 38,
6787.
(8) Kobayashi, Y.; Fujimoto, T.; Fukuyama, T. J. Am. Chem. Soc. 1999,
121, 6501
(9) Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395.
(10) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. Engl.
1992, 31, 228.
(12) Systematic conformational searches were performed with the
computer program CAChe Workstation Plus DGauss (Ver. 4.4), using
molecular mechanics with augmented MM3 parameter sets. Subsequent
geometric optimization using semiempirical PM3 potential functions.
(13) For the calculation of equilibrium constants, the computer program
CHEM-EQUILI (Ver. 6.1) was employed. For a detailed description, see:
Solov’ev, V. P.; Vnuk, E. A.; Strakhova, N. N.; Raevsky. O. A.
Thermodynamic of complexation of the macrocyclic polyethers with salts
of alkali and alkaline-earth metals; VINITI: Moscow, 1991.
(11) The good yields obtained in the cyclopentenylation reactions were
found to be crucially dependent on careful oxygen exclusion from the
reaction vessels.
2006
Org. Lett., Vol. 4, No. 12, 2002

Oxidative cyclization of the cyclopentenyl adduct 6a
(DDQ)16a and the sugar-derived adducts (photolysis in the
presence of I2)16b afford the corresponding indolopyrrolo-
carbazoles 11, 12, and 13 in 87%, 86%, and 68% yields,
respectively (Figure 3).
Figure 3. Oxidatively cyclized cyclopentenyl and sugar adducts
11, 12, and 13.
Figure 2. Different self-assembly modes of the two possible
regioisomers of 6b.
Having achieved the chemoselective synthesis of monoalky-
lated indolopyrrolocarbazoles in which the indolic nitrogen
distal to the carbonyl is functionalized, a method was sought
for chemoselective functionalization of indolic nitrogen
proximal to the lactam carbonyl. Toward this end, readily
available glyoxamide 14 was employed as pronucleophile
in the Pd-catalyzed allylation. As the site of alkylation should
again be dictated by the site of greatest acidity, it was
anticipated that the indolic nitrogen in conjugation with the
dione would represent the preferred site of allylation.
Exposure of 14 to allylic acetate 15 provides the mono-
allylated adduct 16 as a single constitutional isomer. Optimal
enantioselectivities were observed upon use of binaphthyl
ligand 17 (79% ee)17 at low catalyst loadings. The structural
assignment of 16 was established by X-ray crystallographic
analysis18 (Scheme 4).
Kdim ) 10 L‚mol-1 and in toluene with Kdim ) 50 L‚mol-1.
In analogy to the cyclopentenylation of phthalimide14a and
following our mnemonic for asymmetric induction in allylic
allylations,10,14b the absolute configuration of the newly
formed stereocenter is predicted to be R when R,R-5 was
employed.
We next explored the reaction of (bis)indole lactam 3a
with the galactose- and fucose-derived glycals 7 and 8.
Catalytic allylation utilizing these glycals afford monoadducts
9 and 10 as single regio-15 and stereoisomers in high chemical
yields (Scheme 3). On the basis of the aforementioned results,
Scheme 3. Allylation of (Bis)indole Lactam 3a with
Sugar-Derived Electrophiles 7 and 8
Scheme 4. Allylation of Dione 14 with Cyclopentenyl Acetate
15
In an effort directed toward the obtention of the sugar
adducts, dione 14 was reacted with the sugar-derived
(15) Exclusive nucleophilic attack on the π-allylpalladium complex
terminus proximal to the oxygen of the pyran was supported by NMR
chemical shift and coupling constant analyses.
(16) (a) Joyce, R.; Gainor, J.; Weinreb, S. M. J. Org. Chem. 1987, 52,
1177. (b) Link, J. T.; Raghaven, S.; Danishefsky, S. J. J. Am. Chem. Soc.
1995, 117, 552.
the site of allylation is anticipated to be the distal indolic
nitrogen.
(14) (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
(b) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. J. Am. Chem. Soc.
1992, 114, 9327.
(17) For precedence on the improvement of ee employing L2 instead of
L1, see: Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000, 65, 1569.
Org. Lett., Vol. 4, No. 12, 2002
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electrophiles. Gratifyingly, the glycosidated regioisomerically
pure adducts 18 and 19 could be obtained in 96% and 92%
yields, respectively (Figure 4).15
Scheme 5. Strategy for the Regiocontrolled Synthesis of
Indolopyrrolocarbazoles Functionalized at the Nitrogen Proximal
to the Carbonyl
Figure 4. Glycosidated diones 18 and 19.
pyrrolocarbazole natural products will be the topic of a
forthcoming report.
Elaboration of 16 to the corresponding indolocarbazole
finds close precedent in the literature,2a thus establishing a
viable synthetic route to proximally substituted indolo-
pyrrolocarbazoles (Scheme 5).
Acknowledgment. We thank the National Science Foun-
dation and the National Institute of Health, General Medical
Sciences Grant GM33049, for their generous support of our
programs. V.B. and E.M.G. thank the Alexander von
Humboldt -Foundation and the NIHGMS, respectively, for
postdoctoral fellowships. M.J.K. thanks the Veatch Founda-
tion for a graduate fellowship. NMR support was kindly
provided by Dr. Steven Lynch, Stanford University.
In summary, Pd-catalyzed asymmetric allylation method-
ology has enabled a direct means of transforming indolo-
pyrrolocarbazole precursors to isomerically pure monosub-
stituted adducts. Whereas the allylation of (bis)indole 3
provides adducts that may be transformed by distally
substituted indolopyrrolocarbazoles, the allylation of gly-
oxamide 14 allows access to proximally substituted ana-
logues. Notably, in the allylation of 14, one of three nitrogens
is chemoselectively allylated, thus circumventing the use of
protecting groups. The utilization of these protocols for the
preparation of isomerically pure monosubstituted indolo-
Supporting Information Available: Complete synthetic
procedures for the preparation of all allylated products and
their spectral data, 2D NMR structural elucidation and
solution studies on self-assembly of 6b, and X-ray crystal-
lographic data pertaining to 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Structure factors available from author upon request.
OL020046S
2008
Org. Lett., Vol. 4, No. 12, 2002