An enantioselective strategy to macrocyclic bisindolylmaleimides. An efficient formal synthesis of LY 333531

Article abstract of DOI:10.1021/ol016666v

Equation presented The ability to employ a bromo alcohol as a nucleophile in a palladium-catalyzed dynamic kinetic asymmetric transformation leads to an efficient synthesis of a selective PKC inhibitor under clinical development.

Full text of DOI:10.1021/ol016666v

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3409-3411
An Enantioselective Strategy to
Macrocyclic Bisindolylmaleimides. An
Efficient Formal Synthesis of LY 333531
Barry M. Trost* and Weiping Tang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@leland.stanford.edu
Received August 28, 2001
ABSTRACT
The ability to employ a bromo alcohol as a nucleophile in a palladium-catalyzed dynamic kinetic asymmetric transformation leads to an
efficient synthesis of a selective PKC inhibitor under clinical development.
Protein kinase C (PKC), a family of at least 11 isomers of
serine/threonine specific kinases, has become an important
target for development of new therapies.1 Selective inhibition
of overactive PKC isozymes may offer a unique therapeutic
approach. The discovery of staurosporine (1)2 and related
compounds such as rebeccamycin (2)3 as PKC inhibitors
stimulated activities to design selective inhibitors of one or
more isozymes in order to create useful drugs. The bis-
indolylmaleimide 3 proved to be a PKC kinase selective
agent.4
group embarked on a novel approach to impart conforma-
tional restrictions via formation of macrocycles and designed
Conformationally restricted analogues represent an attrac-
tive structural type to create more effective agents.5 The Lilly
(1) Protein Kinase C: Current Concepts and Future PerspectiVes; Lester,
D. S., Epand, R. M., Eds.; Ellis Horwood: New York, 1992.
(2) Furusaki, A.; Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai, Y.;
Omura, S. Bull. Chem. Soc. Jpn. 1982, 55, 3681. Omura, S., Sasaki, Y.;
Iwai, Y.; Takeshima, H. J. Antibiot. 1995, 48, 535.
(3) Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.; Tomita, K.
J. Antibiot. 1987, 40, 668.
(4) Toullec, D.; Pianetti, P.; Coste, H.; Bellevergue, P.; Grand-Perret,
T.; Ajakane, M.; Baudet, V.; Boissin, P.; Boursier, E.; Loriolle, F.; Duhamel,
L.; Charon, D.; Kirilovsky, J. J. Biol. Chem. 1991, 266, 15771. Davis, P.
D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.;
Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177.
(5) Bit, R. A.; Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Keech,
E.; Kumar, H.; Lawton, G.; Maw, A.; Nixon, J. S.; Vessey, D. R.;
Wadsworth, J.; Wilkinson, S. E. J. Med. Chem. 1993, 36, 21.
10.1021/ol016666v CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/22/2001

LY 333531 (4a).6 This compound selectively inhibits PKCâ,
and PKCâ2 over PKCR and is several orders of magnitude
more selective for PKCâ isozymes in comparison to other
ATP-dependent kinases. Lilly is developing this compound
for the treatment of retinopathy associated with diabetic
complications.
O-alkylation to form ethylene oxide versus intermolecular
alkylation to form bromoether 7.
Commercially available 2-bromoethanol and butadiene
monoepoxide reacted smoothly in the presence of a Pd(0)
complex bearing our standard ligand 109 to give the desired
bromoether in good yield but only 58% ee (eq 3). The
enantioselectivity is consistent with our earlier results using
ligand 10 to peform a DYKAT with Epb 9. As anticipated,
switching to our naphthyl ligand 11 increased the ee to
92%.10 Performing the reaction with only 1 equiv of
bromoethanol led to a small amount of a double alkylation
product wherein the primary alcohol 7a underwent addition
of a second molecule of Epb. Using an excess of 2-bromo-
ethanol eliminated this byproduct so that 7a was isolated in
77% yield.
The retrosynthetic analysis recognizes its availability from
the alcohol 4b, which in turn should derive from a macro-
cyclization of a core bisindolylmaleimide 5 and a bis-
alkylating agent 6 (eq 1).7 The efficiency of this strategy
depends on the availability of the chiral bisalkylating agent.
A number of routes were investigated starting from scalemic
building blocks such as dimethyl (S)-maleate, (R)-glycidol,
and (R)-chloro-2,3-propanediol.7 We envisioned an alterna-
tive strategy based upon a dynamic kinetic asymmetric
transformation (DYKAT) of the simple racemic building
block Epb (epoxybutadiene) under commercial development
by Eastman Chemical Company.8 This strategy derives from
the ability of a π-allylpalladium complex to undergo facile
migration from one face to the other via π-σ-π equilibra-
tion as well as to utilize coordination to boron to direct
regioselectivity as depicted in eq 2. The synthesis of LY
Formation of this bisalkylating agent anticipated the
ultimate need to differentiate between two primary hydroxyl
groups. Thus, the primary alcohol of 7a was first silylated
to form 7b (eq 3) using TIPS-OSO2CF3 [(C2H5)3N, CH2Cl2,
0 °C]. Again, no complications from cyclization to form a
1,4-dioxane occurred. Hydroboration with 9-BBN-H fol-
lowed by oxidation with hydrogen peroxide using sodium
acetate as base provided the alcohol 12a uneventfully.
Finally, mesylation under standard conditions gave the
bisalkylating agent (12b) in four steps and 46% overall yield.
To demonstrate the viability of this bisalkylating agent
for the synthesis of LY 333531, the macrocycle was formed
following the Lilly protocol as shown in eq 4. The Lilly
group has reported yields ranging from 48% to 68% with
typical slow addition times of 60 h.7 With bisalkylating agent
12b and the N-benzyl-bisindolylmaleimide 5b, a 77% yield
was realized using an 8 h addition time at the same final
concentration of the Lilly group (0.029 M). To complete the
formal synthesis, the macrocycle 13 was converted to 4b.
Following the Lilly protocol, base hydrolysis followed by
acidic workup gave a mixture of the anhydride 14a and its
desilylated analogue 14b, which was taken directly on. Imide
formation with HMDS in methanolic DMF followed by
TBAF to complete the remaining desilylation produced the
333531 requires an alcohol such as 2-bromoethanol wherein
an interesting chemoselectivity issue arisessintramolecular
(6) Jirousek, M. R.; Gillig, J. R.; Gonzalez, C. M.; Heath, W. F.;
McDonald, J. H., III; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm, L. E.;
Melikian-Badalian, A.; Baevsky, M. Ballas, L. M.; Hall, S. E.; Faul, M.
M.; Winneroski, L. L. J. Med. Chem. 1996, 39, 2664.
(7) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. J. Org. Chem. 1998,
63, 6053. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K.
A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousck, M. R. J. Org. Chem.
1998, 63, 1961. Faul, M. M.; Krumrich, C. A. J. Org. Chem. 2001, 66,
2024.
(9) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc.
(8) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 12702. Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999, 121,
8649.
1992, 114, 9327.
(10) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35,
99.
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Org. Lett., Vol. 3, No. 21, 2001

Lilly intermediate 4b in 79% yield from N-benzyl imide 13.
The observed rotation [R]D ) -10.41 (c 0.28, CH3OH) is
in excellent agreement with the one reported.7
bisalkylating agent useful in the synthesis of LY 333531
demonstrates the utility. Starting from two inexpensive
commercially available reactants, racemic Epb and 2-bro-
moethanol plus the bisindolylmaleimide 5b, alcohol 4b, the
penultimate precursor, was available in eight steps and 28%
overall yield. Furthermore, the sequence has not been
optimized. For example, the conversion of 13 to 4b involved
a three-step sequence, although no intermediates need be
isolated. Nevertheless, a one-pot hydrogenolysis-desilylation
may be envisioned. In summary, combining the commercial
development of Epb with the palladium-catalyzed DYKAT
provides a beneficial strategy for the synthesis of chiral
synthons.
Acknowledgment. We thank the National Science Foun-
dation and the General Medical Sciences Institute of the
National Institutes of Health for their generous support of
our program. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-
San Francisco, supported by the NIH Division of Research
Resources.
The Pd-catalyzed DYKAT of racemic vinyl epoxides
serves as a useful strategy for constructing valuable chiral
building blocks. The ability to employ bromo-substituted
alkyl alcohols in such alkylations without complications
demonstrates the exquisite chemoselectivity the reaction
possesses. A simplified procedure for the synthesis of a
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL016666V
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