Total synthesis of (-)-rhazinilam: Asymmetric C-H bond activation via the use of a chiral auxiliary

Article abstract of DOI:10.1021/ja026130k

The antitumor agent (-)-rhazinilam was synthesized in three major steps, namely the pyrrole synthesis, selective C-H bond activation, and direct macrolactam formation. The key step involved asymmetric C-H bond functionalization (dehydrogenation) of the di

Full text of DOI:10.1021/ja026130k

Published on Web 05/23/2002
Total Synthesis of (-)-Rhazinilam: Asymmetric C-H Bond
Activation via the Use of a Chiral Auxiliary
James A. Johnson, Ning Li, and Dalibor Sames*
Contribution from the Department of Chemistry, Columbia UniVersity,
New York, New York 10027
Received March 7, 2002
Abstract: The antitumor agent (-)-rhazinilam was synthesized in three major steps, namely the pyrrole
synthesis, selective C-H bond activation, and direct macrolactam formation. The key step involved
asymmetric C-H bond functionalization (dehydrogenation) of the diethyl group segment in intermediate 6.
This was achieved by the attachment of chiral platinum complexes to the proximal nitrogen atom. A high
degree of selectivity (60-75% ee) was achieved via the use of oxazolinyl ketone chiral auxiliaries.
Introduction
metal complex to a specific hydrocarbon segment of the
substrate in such a way as to prevent interference by other
The introduction of functional groups via C-H bond activa-
tion has significant synthetic potential owing to the ubiquitous
nature of such bonds in organic substances. However, the low
reactivity of unactivated C-H bonds poses a considerable
challenge with regard to the selective execution of functional-
ization reactions. Thus, the central tenet of synthetic chemistry,
achieving control over the reactivity and selectivity profile of
reagents and catalysts, resurfaces with pressing clarity in this
context. Although significant progress has been made, C-H
bond functionalization represents a major unsolved problem in
synthetic chemistry.1 Hitherto, organic and organometallic
chemistry has not succeeded in providing generally applicable
guidelines for practitioners of organic synthesis to employ these
reactions in routine synthetic tasks.2
functional groups. We have recently demonstrated the feasibility
of this approach in the context of a racemic synthesis of the
antitumor agent rhazinilam.6 In this report, we describe the
asymmetric synthesis of (-)-rhazinilam founded on asymmetric
C-H bond functionalization (dehydrogenation) through the use
of a chiral auxiliary. The synthesis of (-)-rhazinilam was
achieved in three major steps: first, pyrrole annulation to
construct the diethyl pyrrole intermediate; second, asymmetric
dehydrogenation of the pro(R) ethyl group; and finally, macro-
lactam formation via direct carbonylation (Figure 1).
Results and Discussion
Platinum-Mediated C-H Bond Functionalization: The
Racemic Sequence. In the first phase of the investigation,
intermediate 6 was synthesized in a short sequence as depicted
in Scheme 1. Iminium salt 4 was generated from readily
available imine 27 and o-nitrocinnamyl bromide 3. Heating of
4 in the presence of silver carbonate accomplished both
cyclization and aromatization yielding pyrrole intermediate 5
in 70% yield.8 The methyl carboxylate group was then installed
With the exception of intramolecular metal-carbene chem-
istry,3 most transition metal complexes capable of C-H bond
activation are sensitive to functional groups and have a strong
preference for aryl and other activated C-H bonds.4 We
proposed to overcome these limitations via coordination-directed
C-H bond actiVation.5 Following this strategy, a suitable
heteroatomic function would be utilized to direct an activated
(5) “Cyclometalation” is a well-established term for stoichiometric reactions
of this type. Also, “remote functionalization” is used in this context. The
term “directed C-H bond activation” refers to both stoichiometric and
catalytic processes. Reviews: Ryabov, A. D. Chem. ReV. 1990, 90, 403-
424. Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698-1712. For recent
examples of directed functionalization of arene or activated (sp3)C-H bonds
see: Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616-
6623. Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi,
F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882-12883. Jia, C.; Piao,
D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287,
1992-1995. Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 9692-9693. For an example of directed
activation of C-C bonds see: Suggs, J. W.; Jun, C. H. J. Am. Chem. Soc.
1984, 106, 3054-3056.
(6) Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321-6322. For
a recent rhazinilam synthesis see: Magnus, P.; Rainey, T. Tetrahedron
2001, 57, 8647-8651. Rhazinilam is of medicinal interest: Banwell, M.;
Edwards, A.; Smith, J.; Hamel, E.; Pinard-Verdier, P. J. Chem. Soc., Perkin
Trans. 1 2000, 1497-1499 and references therein.
(7) Liebowitz, S. M.; Belair, E. J.; Witiak, D. T.; Lednicer, D. Eur. J. Med.
Chem. Chim. Ther. 1986, 21, 439-444.
(8) Grigg, R.; Myers, P.; Somasunderam, A.; Sridharan, V. Tetrahedron 1992,
48, 9735-9744.
* Corresponding author. E-mail: sames@chem.columbia.edu.
(1) (a) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc.
Chem. Res. 1995, 28, 154-162. (b) Crabtree, R. H. Chem. ReV. 1995, 95,
987-1007. (c) Shilov, A. E.; Shul’pin, G. B. ActiVation and Catalytic
Reactions of Saturated Hydrocarbons in the Presence of Metal Complexes;
James, B. R., Ed.; Kluwer Academic Publishers: Dordrecht, The Nether-
lands, 2000; Catalysis by Metal Complexes, Vol. 21.
(2) For the use of nitrogen- or oxygen-centered radicals in intramolecular
functionalization of alkyl group see: (a) Corey, E. J.; Hertler, W. R. J.
Am. Chem. Soc. 1958, 80, 2903-2904. (b) Buchschacher, P.; Kalvoda, J.;
Arigoni, D.; Jeger, O. J. Am. Chem. Soc. 1958, 80, 2905-2906. (c) Barton,
D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083-4089. (d)
Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.; Washburn,
W. J. Am. Chem. Soc. 1973, 95, 3251-3262. (e) Jung, M. E.; Johnson, T.
W. J. Am. Chem. Soc. 1997, 119, 12412-12413.
(3) (a) Taber, D. F.; Stribia, S.-E. Chem. Eur. J. 1998, 4, 990-992. (b) For a
recent example of intramolecular metal-mediated nitrene insertion see:
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc.
2001, 123, 6935-6936.
(4) Murai, S. ActiVation of UnreactiVe Bonds and Organic Synthesis;
Springer: Berlin, Germany, 1999.
9
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J. AM. CHEM. SOC. 2002, 124, 6900-6903
10.1021/ja026130k CCC: $22.00 © 2002 American Chemical Society

Total Synthesis of (−)-Rhazinilam
A R T I C L E S
pyrrole ring from the platinum metal and the generation of a
transient and reactive methylplatinum species should be feasible.
Indeed, this proved to be the case. Thermolysis of complex 8
in CF3CH2OH10 or CH2Cl2 afforded alkene-hydride 9 in high
yield (90% by 1H NMR). The presence of the phenyl substituent
on the Schiff base ligand was crucial as the corresponding
aldehyde-derived Schiff base yielded only traces of the desired
product, favoring decomposition. Addition of Bu4NCl to 9 in
dichloromethane led to quantitative formation of 10 wherein
the platinum metal is σ-bonded to the methylene carbon of the
ethyl group (Figure 2). This observation may suggest that the
initial C-H bond activation took place at the methylene carbon.
Decomplexation of the platinum by aqueous KCN followed by
removal of the Schiff base provided racemic alkene 11. The
entire sequence from protonation of 7, through C-H activation
and functionalization, decomplexation, and finally transamina-
tion to furnish 11 occurred in 60% overall yield. It is worth
noting that all of the platinum complexes were prepared by using
standard techniques and appeared quite stable to air and
moisture, allowing easy manipulation of the compounds.
Asymmetric C-H Bond Activation: The Total Synthesis
of (-)-Rhazinilam. Examples of asymmetric C-H bond
activation and functionalization are rare since most efforts to
date have focused on solving the chemo- and regioselective
issues of these reactions.11,12 Having developed a highly selective
C-H bond functionalization process in the case discussed
herein, we then became interested in the possibility of dif-
ferentiating the two enantiotopic ethyl groups via the introduc-
tion of a chiral ligand. The platinum chemistry proved to be
robust and insensitive to air and moisture, and therefore seemed
likely to accommodate a broader range of ligands. Analysis of
the X-ray structure of 8 suggested that in order to maximize
interaction between the diethyl segment of the substrate and
the chiral auxiliary, the platinum complex should be desym-
metrized by placing an R group above or below (not outside)
the complex framework (Figure 2 and Figure 3). Taking these
design directives into account, as well as practical issues related
to accessibility of the ligands, we set out to explore oxazolinyl
ketones as chiral auxiliaries (Table 1).13
Figure 1. (-)-Rhazinilam was assembled in three major steps. The central
step involved asymmetric dehydrogenation of the diethyl group segment.
Scheme 1 a
a Conditions: (a) DMF, 100 °C, 90%; (b) Ag2CO3 (2eq), toluene, reflux,
70%; (c) CCl3COCl; (d) NaOMe, MeOH; (e) H2 (1 atm), Pd/C, 88% for
steps c-e.
Scheme 2
Oxazoline Schiff base complexes, prepared according to the
method developed for pyridine complex 7, were submitted to
the C-H functionalization sequence including treatment with
1 equiv of TfOH and gentle heating (Supporting Information).
(9) (a) Falvello, L. R.; Fornie´s, J.; Navarro, R.; Sicilia, V.; Toma´s, M. Angew.
Chem., Int. Ed. Engl. 1990, 29, 891-893. (b) Brunkan, N. M.; White, P.
S.; Gagne, M. R. J. Am. Chem. Soc. 1998, 120, 11002-11003. (c)
Kocovsky, P.; Malkov, A. V.; Vyskocil, S.; Lloyd-Jones, G. C. Pure Appl.
Chem. 1999, 71, 1425-1433. (d) Albrecht, M.; Gossage, R. A.; Spek, A.
L.; van Koten, G. J. Am. Chem. Soc. 1999, 121, 11898-11899. (e)
Kaminskaia, N. V.; Johnson, T. W.; Kostic, N. M. J. Am. Chem. Soc. 1999,
121, 8663-8664.
as a temporary protection to stabilize the electrophile-sensitive
pyrrole ring, followed by reduction of the nitro group to furnish
amine 6.
For the racemic synthesis, the pivotal platinum complex 7
was prepared from aniline 6 by sequential treatment with
2-benzoylpyridine (Schiff base preparation) and dimethyl-
platinum reagent [Me2Pt(µ-SMe2)]2 (Scheme 2). Addition of 1
equiv of triflic acid to 7 resulted in rapid liberation of methane
and formation of complex 8, which was fully characterized
including an X-ray structure (Figure 2B). The unusual η1-
complexation mode between the platinum metal and the pyrrole
ring (carbon 4) should be noted. In fact, pyrrole C4 exists as a
distorted tetrahedron suggesting sp3-hybridization of this center.
The distortion of aryl rings by electrophilic platinum metals is
precedented,9 and by analogy to these reports, complex 8 should
be kinetically labile. In such a system, decomplexation of the
(10) Johansson, L.; Ryan, O. B.; Tilset, M. J. Am. Chem. Soc. 1999, 121, 1974-
1975.
(11) (a) Sokolov, V. I.; Troitskaya, L. L.; Reutov, O. A. J. Organomet. Chem.
1979, 182, 537-546. (b) Ma, Y.; Bergman, R. G. Organometallics 1994,
13, 2548-2550 (correction: Organometallics 1994, 13, 4648). (c) Keyes,
M. C.; Young, V. G., Jr.; Tolman, W. B. Organometallics 1996, 15, 4133-
4140. (d) Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani, N.; Murai, S. Chem.
Lett. 1997, 425-426. (e) Mobley, T. A.; Bergman, R. G. J. Am. Chem.
Soc. 1998, 120, 3253-3254. (f) Mikami, K.; Hatano, M.; Terada, M. Chem.
Lett. 1999, 55-56. (g) Punniyamurthy, T.; Katsuki, T. Tetrahedron 1999,
55, 9439-9454. (h) Zhou, X.-G.; Yu, X.-Q.; Huang, J.-S.; Che, C.-M.
Chem. Commun. 1999, 2377-2378.
(12) For examples of asymmetric carbene insertion see: (a) Doyle, M. P.;
Kalinin, A. V.; Ene, D. G. J. Am. Chem. Soc. 1996, 118, 8837-8846. (b)
Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000,
122, 3063-3070.
(13) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.
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J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002 6901

A R T I C L E S
Johnson et al.
Figure 2. The racemic sequence. (A) Selective functionalization (dehydrogenation) of one ethyl group was accomplished in the presence of many functional
groups via coordination-directed C-H bond activation. (B) X-ray structure of complex 8 (triflate anion removed for clarity).
complex preparation and purification was problematic providing
only low yields of the corresponding crude complex (<10%
conversion). In addition to oxazoline ligands, chiral pyridyl
ketone 1714 was prepared and studied; however, both the
chemical yield and selectivity obtained were inferior to those
of the oxazoline ligands. The Schiff base diastereomers were
separated on a preparative scale by HPLC, and the Schiff base
ligand was removed quantitatively (for ease of purification,
hydroxylamine was used to cleave the Schiff base) to afford
alkene 11 in high optical purity (96% ee, determined by chiral
HPLC). The absolute stereochemical assignment was confirmed
by conversion of (-)-11 to (-)-rhazinilam.
By a procedure developed for achiral complex 7, treatment
of the oxazoline complex (cf. 18, Figure 3) with TfOH yielded
a mixture of diastereomers 19 and 20 in a ratio greater than
one in all studied cases. This suggests a measurable interaction
between the R group of the ligand and the rest of the molecule,
most likely the diethyl segment. The C-H functionalization
sequence then yielded a mixture of enantiomers 11, in a ratio
that differs from that of 19/20. This observation suggests two
mechanistic scenarios: first, that decomplexation of the platinum
from the pyrrole ring in 19 and 20 generates a species wherein
free rotation around the biaryl C-C bond occurs (the rate of
Figure 3. The asymmetric sequence. The proposed model explains the
rotation is faster than the rate of C-H functionalization); second,
that each diastereomer reacts with a different rate (the rate of
rotation is slower that the rate of C-H functionalization). The
former mechanism is supported by the observation that both
ratios (19/20 and (-)-11/(+)-11) remained constant (and
different from one another!) during the course of the reaction
(1H NMR measurements at 24, 48, and 72 h).
sense and magnitude of asymmetric induction. The bulkier R group affords
greater enantiomeric excess of alkene 11. The final ratio of enantiomers 11
differs from the ratio of diastereomers 19/20.
Decomplexation of the platinum metal yielded a mixture of
Schiff base diastereomers (cf. 12, Table 1) that was analyzed
by HPLC to determine starting material conversion and the
diasteromeric ratio of products (for experimental details see
Supporting Information). As evident from Table 1, reaction
temperature and bulkiness of the ligand affected both yield and
selectivity of the functionalization reaction. Two major trends
became apparent: first, higher temperatures improved yields,
however at the expense of diastereoselectivity; second, bulkier
ligands afforded better selectivity. For instance, the cyclohexyl
oxazoline was superior to the phenyl-substituted ligand (7.5:1
vs 6:1 (R/S) at 60 °C, 72 h). The best selectivity was observed
with the bulky oxazoline 16 derived from tert-butylglycinol,
which afforded a single diastereomer. Unfortunately in this case,
In the last stage of the synthesis, conversion of alkene 11 to
rhazinilam required one-carbon homologation of the alkene
moiety, macrolactam formation, and methyl ester deprotection.
To avoid the multistep sequence reported by us previously, we
have contemplated direct hydroamidation of 11. This plan was
reduced to practice, and as a result, the optically pure alkene
(-)-11 was converted to (-)-rhazinilam in two steps (Scheme
3). The macrolactam formation, achieved in one step (58% yield)
(14) Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. Org. Lett. 2000, 2,
3047-3049.
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Total Synthesis of (−)-Rhazinilam
A R T I C L E S
Table 1. Diastereoselective Directed C-H Bond Functionalization Studies
a Determined by 1H NMR (platinum hydride, not shown), and HPLC (Schiff base 12). b Determined by HPLC. c Low conversion is due to the low yield
of the complexation step. The crude mixture was submitted to the reaction sequence since the corresponding complex could not be purified; cHex ) cyclohexyl;
reaction and purification conditions are detailed in the Supporting Information.
Scheme 3. Direct Macrolactam Formation via Catalytic
multiple functional groups including an ester, pyrrole, and arene
rings. Furthermore, asymmetric control over this transformation
Carbonylationa
was achieved through the use of a chiral auxiliary, as 62-76%
enantiomeric excess was achieved with the cyclohexyloxazoline
ligand. This work illustrates the concept of directed C-H bond
functionalization and its applicability to asymmetric processes.
Acknowledgment. Funding was provided by NIGMS (R01
GM60326), The Petroleum Research Fund, and GlaxoSmith-
Kline. J.A.J. received the Bristol-Myers Squibb Fellowship in
Organic Synthetic Chemistry; D.S. is a recipient of the Camille
and Henry Dreyfus New Faculty Award, the Cottrell Scholar
Award, and an Alfred P. Sloan Fellowship. We gratefully
acknowledge Paul M. Wehn (preparation of chiral ligands),
Professor Gerard Parkin (X-ray), Dr. J. B. Schwarz (manuscript
preparation), and Vitas Votier Chmelar (intellectual contribu-
tion).
a Reaction conditions: (a) 10% Pd-C (5 mol %), dppb, HCOOH, DME,
CO (10 atm), 150 °C, 58%; (b) NaOH(aq), MeOH then HCl(aq), 50 °C,
90%.
in the presence of Pd-C (5 mol %), dppb (1,4-bis(diphenyl-
phosphino)butane), formic acid, and carbon monoxide,15 fol-
lowed by deprotection of the methyl ester, furnished optically
pure (-)-rhazinilam.
Conclusion
In summary, the total asymmetric synthesis of rhazinilam was
accomplished in three major steps, including the pyrrole
synthesis, selective C-H bond activation, and direct macro-
lactam formation. This strategy centered on selective dehydro-
genation of the ethyl group in a complex substrate containing
Supporting Information Available: Experimental procedures
for compounds 1-17, experimental details for C-H bond
activation, product separation, and characterization, and X-ray
structure of complex 8 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) El Ali, B.; Vasapollo, G.; Alper, H. J. Org. Chem. 1993, 58, 4739-4741.
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