C-C bond formation via C-H bond activation: Synthesis of the core of teleocidin B4

Article abstract of DOI:10.1021/ja027311p

The core of teleocidin B4, a complex fragment of a natural product containing two quaternary stereocenters and a penta-substituted benzene ring, was synthesized in four C-C bond-forming steps starting from tert-butyl derivative 1. The first step involved

Full text of DOI:10.1021/ja027311p

Published on Web 09/14/2002
C-C Bond Formation via C-H Bond Activation: Synthesis of the Core of
Teleocidin B4
¨
Brian D. Dangel, Kamil Godula, So Won Youn, Bengu Sezen, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received June 16, 2002
The practice of organic synthesis has been fundamentally
changed by the introduction of metal-mediated coupling reactions,
for instance, the Heck and Suzuki reactions, the R-arylation of
carbonyl compounds,1 and multiple bond metathesis.2 However,
these now routine reactions require that both reactants contain a
reactive functional group. Thus, it seems logical that the next
frontier in organic synthesis will center on reducing the number of
required functionalities in coupling processes, namely C-C bond
formation via C-H activation.3 This would represent a powerful
synthetic method in which only one component of the coupling
reaction need to possess a reactiVe group.4
To demonstrate this point, we herein report a synthesis of the
teleocidin B4 core, a complex fragment of a natural product
containing two quaternary stereocenters and a penta-substituted
benzene ring.5 We envisioned that the final product would be
constructed from an ortho-tert-butylaniline in four key C-C bond-
forming steps, wherein the central piece of the assembly requires
two tandem cycles of directed C-H bond functionalization of the
tert-butyl group (Figure 1).6
According to the synthetic plan outlined above, we set out to
prepare intermediate 4 through alkenylation of a tert-butyl aniline
derivative (Scheme 1). We envisioned that a new transformation
of this type might be accomplished via sequential cyclometalation
and transmetalation. Consequently, Schiff base 1 was prepared (see
the Supporting Information) and submitted to a systematic screening
of metal salts in the context of directed C-H bond activation
(cyclometalation). We found that Pd(II) salts were the only reagents
capable of furnishing the desired and stable metallacycle products
(cf. 2).7 Thus, stoichiometric PdCl2 (1.2 equiv) in the presence of
NaOAc (3 equiv) led to quantitative conversion of the starting
material, affording 75% yield of pure palladacycle 2. Although two
methoxy substituents on the aldehyde portion of 1 were initially
incorporated to protect the ortho positions of the aryl imine
(metalation of arene C-H bonds is usually preferred over those of
alkanes), they emerged as an important part of the directing element.
No cyclopalladation occurred with the free aniline.
Figure 1. Teleocidin core was assembled in four key C-C bond-forming
steps (1-4): (1) alkenylation of unactivated alkyl group (tert-butyl); (2)
Friedel-Crafts reaction (racemic); (3) diastereoselective carbonylation of
an unactivated methyl group; (4) alkenylation of phenol.
The subsequent step in the route centered on the closure of the
cyclohexane ring through a formal hydroarylation process.
In this instance, the presence of the methoxy group meta to the
amine facilitated the Friedel-Crafts reaction mediated by meth-
anesulfonic acid,11 providing racemic compound 5 in 83% yield
(Scheme 1). Note that under anhydrous conditions, the Schiff base
protection was retained, and the resultant product was ready for
the second cycle of C-H activation/C-C bond formation without
interruption.
At this stage of the synthesis, a diastereoselective one-carbon
homologation of the methyl group anti to the isopropyl group (1,4-
chiral transfer) was required (Scheme 1). Thus, intermediate 5 was
again treated with PdCl2 and NaOAc to yield a mixture of
diastereomeric palladacycles (cf. 6), followed by addition of CO-
(g) and methanol. The resulting methyl esters were not isolated,
but instead acidic hydrolysis of the Schiff base, accompanied by
spontaneous cyclization, furnished lactams 7 and 8. This three-
step sequence converted compound 5 to the desired lactam without
isolation of a single intermediate. The yields and selectivity were
identical at both the cyclopalladate and the lactam stage and varied
with reaction temperature (70-100 °C). The lower end of this
temperature range (70 °C) led to both highest yield and selectivity
(65%, 6:1, 7/8). The fortunate stereochemical outcome suggested
that in the preferred transition state of the C-H activation step,
the isopropyl group occupied the pseudo-equatorial position,
therefore making the anti methyl group, also in the pseudo-
equatorial position, accessible to the metal center.
While palladacycle intermediates have been known to undergo
numerous functionalization reactions, including carbonylation,
alkylation, alkene, and alkyne insertion, halogenation, and oxygen
transfer,8 to our knowledge transmetalation with boronic acids has
not been reported.9 Therefore, we were delighted to find that
palladacycle 2 and vinyl boronic acid 3 yielded desired alkene 4
in the presence of Ag2O to furnish 86% yield of compound 4. This
two-step sequence (1 f 2 f 4) not only provided the desired
alkenylation product 4, but moreover set the stage for the develop-
ment of a new catalytic transformation.10
The desired isomer 7 was obtained in diastereomerically pure
form by crystallization, and the X-ray structure was solved to
confirm the stereochemical assignment (Figure 2). In the final stage
of the assembly, the indole ring was synthesized via intramolecular
coupling between the phenol and the vinyl bromide 9.12 Thus, the
allylation of lactam 7, followed by removal of the methyl group
* To whom correspondence should be addressed. E-mail: sames@
chem.columbia.edu.
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J. AM. CHEM. SOC. 2002, 124, 11856-11857
10.1021/ja027311p CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Two Tandem Cycles of C-H Bond Functionalization Render Two Quaternary Centers of the Teleocidin Core
Alfred P. Sloan Fellowship, and the Camille Dreyfus Teacher-
Scholar Award. We gratefully acknowledge David Churchill and
Professor Gerard Parkin (X-ray), Dr. J. B. Schwarz (editorial
assistance), and Vitas Votier Chmelar (intellectual contribution).
We also thank Professor Dirk Trauner for a stimulating discussion.
Supporting Information Available: Experimental procedures,
preparation, and spectral data for compounds 1-10 (PDF). Crystal-
lographic data for 7 (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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639. (b) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103-105. (c)
Kakiuchi, F.; Murai, S. In ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; pp 47-79. (d) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731-1769.
(4) Metal-carbene insertions serve as successful examples of this concept:
(a) Taber, D. F.; Stribia, S.-E. Chem.-Eur. J. 1998, 4, 990-992 and
references therein. (b) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J.
Am. Chem. Soc. 2000, 122, 3063-3070.
Figure 2. The final stage of the teleocidin core assembly: indole synthesis.
t
Conditions: (a) 9, BuOK, THF, 71%; (b) BBr3, CH2Cl2, 96%; (c) Pd-
(OAc)2 (15 mol %), P(tBu)3 (30 mol %), Cs2CO3, DMA, 57%. For
crystallographic data of 7, see the Supporting Information.
(5) (a) Teleocidin structure: Hitotsuyanagi, Y.; Fujiki, H.; Suganuma, M.;
Aimi, N.; Sakai, S.; Endo, Y.; Shudo, K.; Sugimura, T. Chem. Pharm.
Bull. 1984, 32, 4233-4236 and references therein. (b) Previous synthe-
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kinase C (PKC) activators: Kishi, Y.; Rando, R. R. Acc. Chem. Res. 1998,
31, 163-172.
by the action of BBr3, afforded the required phenol 10. The
subsequent intramolecular alkenylation coupling, catalyzed by Pd-
(OAc)2, produced the final product, the teleocidin B4 core. A
systematic optimization showed that the ratio of the desired indole
formation to the allyl group removal was improved by the use of
tri-tert-butylphosphine as the ligand and Cs2CO3 as the base, to
furnish the final target molecule in 57% yield.
(6) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900-
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In summary, the core of teleocidin B4 was synthesized in four
C-C bond-forming steps starting from tert-butyl derivative 1 (nine
steps in total). The key sequence of the synthesis consisted of two
C-H bond functionalization cycles, alkenylation and oxidative
carbonylation of two methyl groups. Thus, the consideration of
nontraditional disconnections in the context of synthetic strategy
has significant consequences; not only do new perspectives on
organic compounds emerge, but the development of new chemical
transformations is further inspired.
(10) The catalytic arylation and alkenylation of tert-butyl aniline have been
achieved in our laboratory. Exploration and optimization of this reaction
will be the subject of a separate communication.
(11) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998, 120, 12777-
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Acknowledgment. Funding was provided by NIGMS (R01
GM60326), The Petroleum Research Fund, and GlaxoSmithKline.
D.S. is a recipient of the Cottrell Scholar Award of Research Corp.,
(12) Hennings, D. D.; Iwasa, S.; Rawal, V. H. Tetrahedron Lett. 1997, 38,
6379-6382.
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