Skeletal diversity via a folding pathway: Synthesis of indole alkaloid-like skeletons

Article abstract of DOI:10.1021/ol047945w

(Chemical Equation Presented) Inspired by the skeletal diversity of naturally occurring indole alkaloids and the rich potential of chemistry developed by Padwa and coworkers, we conceived a pathway entailing six modes of intramolecular reactions leading t

Full text of DOI:10.1021/ol047945w

ORGANIC
LETTERS
2005
Vol. 7, No. 1
47-50
Skeletal Diversity via a Folding
Pathway: Synthesis of Indole
Alkaloid-Like Skeletons
Hiroki Oguri and Stuart L. Schreiber*
Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology,
HarVard UniVersity; Broad Institute of HarVard and MIT,
Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received October 6, 2004
ABSTRACT
Inspired by the skeletal diversity of naturally occurring indole alkaloids and the rich potential of chemistry developed by Padwa and co-
workers, we conceived a pathway entailing six modes of intramolecular reactions leading to indole alkaloid-like skeletons. In this context, an
efficient folding pathway via a rhodium-catalyzed tandem cyclization−cycloaddition involving three of the modes has been developed (two of
which are shown above) that affords densely functionalized compounds with three distinct skeletons in a stereocontrolled manner.
Diversity-oriented synthesis (DOS), which aims to yield
skeletally and stereochemically diverse products having high
appending potential, may prove to be an effective means of
exploring biology and medicine with chemistry.1-3 Two
approaches have been used to generate skeletal diversity in
a small number of steps: reagent-based differentiation and
substrate-based folding.4 The folding strategy involves the
conversion of a collection of substrates with pre-encoded
skeletal information into products having distinct skeletons
using a common set of reaction conditions. This report
presents new illustrations of the folding strategy in DOS.
To achieve the synthesis of skeletally diverse compounds
inspired by naturally occurring and biologically active indole
alkaloids (Figure 1a), we considered the rhodium(II)-cata-
lyzed consecutive cyclization-cycloaddition reactions shown
in Figure 1b developed by Padwa and co-workers.5,6 Upon
treatment of a Rh(II) catalyst with an R-diazo ketocarbonyl
such as 1, cyclization of the resulting rhodium carbenoid
and neighboring carbonyl oxygen produces a carbonyl ylide,
which can be a participant in a 1,3-dipolar cycloaddition with
an indole 2,3-double bond leading to fused skeletons 2 in a
single step.7 This powerful bond-forming reaction could lead
to multicyclic skeletons with both differing topologies and
the ability to display dense functionality.
(5) (a) Hertzog, D. L.; Austin, D. J.; Nadler, W. R.; Padwa, A.
Tetrahedron Lett. 1992, 33, 4731-4734. (b) While this paper was in review,
chemistry related to the conversion of 10 into 11 was reported by: Mejia-
Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241-3244.
(6) For reviews, see: (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A.
Synthesis 1994, 123-140. (b) Padwa, A.; Weingarten, D. M. Chem. ReV.
1996, 96, 223-269. (c) Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58,
9477-9504.
(7) Regio- and stereoselectivities of the cycloaddition may be governed
by a complex interplay of factors such as the nature of the 2,3-dipole, alkene
polarity, ring strain, and nonbonded interactions in the transition state: See
refs 5, 6, and 9.
(1) Schreiber, S. L. Chem. Eng. News 2003, 81, 51-61.
(2) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867-3870.
(3) Strausberg, R. L.; Schreiber, S. L. Science 2003, 300, 294-295.
(4) For a review of reagent-based differentiation and substrate-based
folding, see: Burke, M. D.; Schreiber, S. L. Angew Chem., Int. Ed. 2004,
43, 46-58.
10.1021/ol047945w CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/08/2004

Scheme 1. Execution of the C f A Folding Pathway
distinct modes of rhodium-catalyzed intramolecular cycload-
ditions can in principle be realized. Here we describe our
progress toward diversity-oriented syntheses that exploit this
strategy.
We first developed a mode C f A reaction sequence using
Padwa’s general protocol (Scheme 1).5b,9 Synthesis of 10
possessing R-diazoketocarbonyl and indole groups at sites
C and A, respectively, commenced with the installation of
the alkyl linker 4 on site B of 3 via C-alkylation producing
5. After conversion of 5 into an activated ester, the
â-ketoester was installed on site C by a coupling reaction
with a magnesium enolate.10
The indole functionality was attached to site A by
N-acylation of 7 with 8 using 4 Å molecular sieves as a
neutral acid scavenger. The resulting compound 9 was then
converted to the R-diazo ketoester 10 in 98% yield. Treat-
ment of 10 with a catalytic amount of rhodium(II) octanoate
dimer in benzene at 80 °C resulted in the formation of a
presumed carbonyl ylide intermediate that underwent cy-
cloaddition to produce hexacyclic 11 in 74% yield as a single
isomer.9
Next, we investigated a pathway for the mode A f B
(Scheme 2). C-Alkylation of 3 with 1211 produced 13 having
an indole group at site B. Site C was manipulated to afford
14 by installing a linker having a terminal silyl ether. The
lactam 14 was exposed to 15 in toluene at 120 °C to yield
the N-acetoacetylated product 16, which was converted to
the R-diazoimide 17. Treatment of 17 with rhodium(II)
catalyst in benzene at 50 °C gave hexacyclic 18 in good
Figure 1. (a) Naturally occurring indole alkaloids; (b) Rh(II)-
catalyzed consecutive cyclization-cycloaddition reactions to produce
fused skeletons; (c) Multiple modes of cycloaddition using versatile
scaffold 3. (Notation, e.g. A f B, is short for: carbonyl ylide on
site A reacts with dipolarophile on site B.)
Different combinations of R-diazo ketocarbonyls and
indole groups on different sites of a common scaffold 3
enable various modes of intramolecular reactions under the
same conditions (Figure 1c). We therefore envisioned
scaffold 3 having three sites (A-C), each site being capable
of installing either R-diazo ketocarbonyl or indole groups
through the use of lactam, ester, or â-ketocarbonyl func-
tionality. For example, R-diazo ketocarbonyl and indole
groups could be installed at sites A and B, respectively
(a mode of cyclization designated as A f B, where the
carbonyl ylide on site A reacts with dipolarophile on site
B). In addition, an alkyl linker with a terminal silyl ether
group, selected to allow primary protein-binding assays
using small molecule microarray technology, can be in-
stalled at site C.8 Overall, by applying a similar logic to each
of the reactive combinations indicated in Figure 1c, six
(9) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258-6259. (b)
Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556-565. (c) Padwa, A.;
Snyder, J. P.; Curtis, E. A.; Sheehan, S. M.; Worsencroft, K. J.; Kappe, C.
O. J. Am. Chem. Soc. 2000, 122, 8155-8167.
(10) Moyer, M. P.; Feldman, P. J.; Rapoport, H. J. Org. Chem. 1985,
50, 5223-5230.
(8) (a) Hergenrother, P. J.; Depew, K. M.; Schreiber, S. L. J. Am.
Chem. Soc. 2000, 122, 7849-7850. (b) Barnes-Seeman, D.; Park, S. B.;
Koehler, A. N.; Schreiber, S. L. Angew. Chem., Int. Ed. 2003, 42, 2376-
2379.
48
Org. Lett., Vol. 7, No. 1, 2005

Scheme 2. Execution of the A f B Folding Pathway
Scheme 3. Execution of the A f C Folding Pathway
a Separable 1:1 diastereomeric mixture of 24 and epi-24.
yield (74%) with complete diastereoselectivity.5a The ster-
eochemistry was unambiguously determined by X-ray crys-
tallographic analysis of crystalline p-phenylbenzoate ester
19.12,13
To synthesize a substrate for the mode A f C reaction,
we used the Ugi four-component condensation reaction (Ugi
4CC)14 as shown in Scheme 3. Carboxylic acid 6, indole-
3-carboxaldehyde 20,15 p-methoxy benzylamine 21, and tert-
butyl isocyanide 22 were joined in a single step to afford 23
in 67% yield as a 1:1 diastereomeric mixture. After conver-
sion into the â-ketoimide, the diastereomers 24 and epi-24
were separated and transformed into their diazoimides. The
Rh(II)-catalyzed consecutive reaction of the densely func-
tionalized 25 proceeded smoothly to produce hexacyclic 26
in 57% yield (two steps) in a highly stereocontrolled manner.
X-ray analysis of crystalline 2713,16 revealed the structure
and stereochemistry of the product 26 with its vicinal
quaternary carbon centers.
In conclusion, we have developed a folding pathway for
the synthesis of indole alkaloid-like skeletons using (1) a
stereocontrolled tandem reaction that can be used with
elaborate substrates and (2) a versatile scaffold that allows
for multiple modes of intramolecular reactions in a systematic
fashion (Scheme 4). The pathway A f C is expected to
provide an approach to diverse indole alkaloid-like com-
pounds in only four steps, involving a pair of complexity-
generating processes,17 a Ugi 4CC and a Rh-catalyzed tandem
reaction. A goal for the future is to achieve stereochemical
diversification in the overall pathway. It is hoped that the
pathways shown here will provide effective probes for
chemical genetic studies aimed at dissecting biology.1,18
(11) Miranda, L. D.; Cruz-Almanza, R.; Pavo´n, M.; Alva, E.; Muchowski,
J. M. Tetrahedron Lett. 1999, 40, 7153-7157.
(12) Corey, E. J.; Albonico, S. M.; Koelliker, U.; Schaaf, T. K.; Varma,
R. K. J. Am. Chem. Soc. 1971, 93, 1491-1493.
(13) CCDC-247774 (19) and CCDC-247775 (27) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif, by
emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK;
fax: +44 1223 336033.
(14) For excellent reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168-3210. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133-
1144.
(16) C-Alkylation of 3 with methyl iodide and subsequent saponification
yielded 28, which was transformed into 27 by the same transformations as
shown in Scheme 3.
(17) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712.
(18) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int.
Ed. 2002, 41, 2878-2890.
(15) Fukuyama, T.; Jow, C.-K.; Chung, M. Tetrahedron Lett. 1995, 36,
6373-6374.
Org. Lett., Vol. 7, No. 1, 2005
49

Scheme 4. Folding Strategy Yielding a Collection of Products Having Diverse Indole Alkaloid-Like Skeletons
Acknowledgment. We thank Drs. Peter Andreana and
Ryan Looper for many stimulating suggestions and insightful
observations. We also thank Dr. Richard Staples for per-
forming X-ray crystallographic analyses. A fellowship to
H.O. from Uehara Memorial Foundation is gratefully ac-
knowledged. S.L.S is an investigator at the Howard Hughes
Medical Institute in the Department of Chemistry and
Chemical Biology at Harvard University. We thank the
National Institute for General Medical Sciences and the
National Cancer Institute (NCI) for their support of this
research and the NCI for their support of the Initiative for
Chemical Genetics.
Supporting Information Available: Characterization
data for 9, 11, 16, 18, 24, epi-24, and 26 and X-ray
crystallographic files (CIF) for 19 and 27. This material is
available free of charge via the Internet at http://pubs.acs.org.
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