Total synthesis of (+)-RK-286c, (+)-MLR-52, (+)-staurosporine, and (+)-K252a

Full text of DOI:10.1021/ja9626143

10656
J. Am. Chem. Soc. 1996, 118, 10656-10657
Scheme 1
Total Synthesis of (+)-RK-286c, (+)-MLR-52,
(+)-Staurosporine, and (+)-K252a
John L. Wood,*,† Brian M. Stoltz, and Steven N. Goodman
Sterling Chemistry Laboratory
Department of Chemistry, Yale UniVersity
New HaVen, Connecticut 06520-8107
ReceiVed July 29, 1996
The observation that nanomolar concentrations of K252a (1)
and staurosporine (2) inhibit a variety of protein kinases
continues to spawn intense efforts in the isolation and synthesis
of novel indolocarbazoles.1 Our interest in these natural
products has evolved over the past 10 months from the first
total synthesis of (+)-K252a2,3 to a general synthetic approach
to staurosporine4,5 and its congeners [e.g., RK-286c (3)6 and
MLR-52 (4)7].8 These latest developments were inspired after
considering the structural similarities of 1-4 and recognizing
that a logical common intermediate (5) might be accessible via
ring expansion of 6, a derivative of the penultimate intermediate
in our synthesis of (+)-1 (i.e., (+)-7, Scheme 1). Herein we
report the successful application of this ring expansion strategy
to the preparation of (+)-5 and its use in the total synthesis of
(+)-1-4.
The initial challenge of preparing the quantities of (+)-7
needed to initiate the synthesis was met by advancing glycine
methyl ester through the 11-step sequence developed in our
K252a synthesis.2 With multigram quantities of material
available, we set the stage for ring expansion by converting
(+)-7 to (+)-69 via a two-step sequence that involves LiBH4
reduction and Moffatt oxidation10 (63% yield overall, Scheme
2). Given that the proposed ring expansion of 6 to 5 could
proceed to a mixture of regio- and stereoisomeric products, we
were delighted to discover that treatment of (+)-6 with BF3‚
OEt2 in Et2O (2.2 equiv, 25-30 °C, 24 h) produces a single
product, (+)-59, in 85% yield! The regio- and stereochemical
outcomes of this reaction, which were confirmed by spectral
comparison to a closely related model and the conversion of
(+)-5 to (+)-1-4 (Vide infra),8a are consistent with migration
of the C-C bond engaged in the quaternary aminal linkage to
the si-face of the aldehyde; thus suggesting the syn-periplanar
alignment of the carbonyl and hydroxyl moieties illustrated in
structure 8 (Scheme 2).
In an effort to generate a more versatile intermediate, we
initiated what proved to be a futile but interesting effort to
convert (+)-5 into the corresponding methyl ether 9. Although
unproductive in terms of preparing 9, these methylation attempts
led to the unexpected observation that exposure of (+)-5 to CuCl
in MeOH results in a highly stereoselectiVe oxidation/ring
contraction sequence that produces (+)-7 in 95% yield!11,12
Turning from our inadvertent discovery of a potentially
biomimetic synthesis of (+)-K252a, to alternatives for the
troublesome methylation, we recognized that reduction of 5
would likely proceed with a high degree of stereoselectivity to
produce a diol (i.e., 10) wherein the differing steric environments
of the equatorial (C3′) and axial (C4′) hydroxyl groups might
allow selective methylation. In practice, ketone (+)-5 was
indeed found to undergo selective conversion to (+)-119 upon
sequential treatment with NaBH4 and NaH/MeI.13
Having installed all of the functional groups common to (+)-
2-4, our approach diverged into the synthesis of (+)-RK286c
and (+)-MLR-52. The former was completed via deprotection
of (+)-11 (TFA/anisole) while the latter required a three-step
sequence that was initiated by exposing (+)-11 to the Martin
Sulfurane.14 Oxidation of the derived olefin with OsO4 followed
by deprotection of the resultant diol [(+)-129] produced (+)-4.
The elusive nature of R-methoxy ketone 9 guided our
approach to staurosporine along a route wherein the 4′ nitrogen
is introduced via conversion of (+)-5 to the corresponding oxime
(-)-139,15 (H2NOH‚HCl, NaOAc, Scheme 3). Crucial for the
† 1996 Eli Lilly Grantee in Organic Chemistry.
(1) For reviews on the synthesis and biological activity of indolocarba-
zoles, see: (a) Bergman, J. Stud. Nat. Prod. Chem., Part A 1988, 1, 3. (b)
Gribble, G. W.; Berthel, S. J. Stud. Nat. Prod. Chem. 1993, 12, 365. (c)
Steglich, W. Fortschr. Chem. Org. Naturst. 1987, 51, 216. (d) Omura, S.;
Sasaki, Y.; Iwai, Y.; Takeshima, H. J. Antibiot. 1995, 48, 535.
(2) For the enantioselective total synthesis of (+)- and (-)-K252a, see:
Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. J. Am. Chem. Soc. 1995, 117,
10413.
(3) For the isolation of (+)-K252a, see: Kase, H.; Iwahashi, K; Matsuda,
Y. J. Antibiot. 1986, 39, 1059.
(4) For an excellent full account of the landmark Danishefsky-Link
synthesis of staurosporine, see: Link, J. T.; Raghavan, S.; Gallant, M.;
Danishefsky, S. J.; Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996,
118, 2825.
(5) For the isolation of (+)-staurosporine, see: Omura, S.; Iwai, Y.;
Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Masuma,
R. J. Antibiot. 1977, 30, 275.
(6) Takahashi, H.; Osada, H.; Uramoto, M.; Isono, K. J. Antibiot. 1990,
43, 168.
(7) McAlpine, J. B.; Karwowski, J. P.; Jackson, M.; Mullally, M. M.;
Hochlowski, J. E.; Premachandran, U.; Burres, N. S. J. Antibiot. 1994, 47,
281.
(8) Our initial model system work in developing this approach has been
disclosed in part, see: (a) Stoltz, B. M.; Wood, J. L. Tetrahedron Lett.
1995, 36, 8543. (b) Stoltz, B. M.; Wood, J. L. Tetrahedron Lett. 1996, 37,
3929.
(11) Model investigations of this reaction suggest that oxidation precedes
a ring contractive “benzylic acid” rearrangement.8b
(9) The structure assigned to each new compound is in accord with its
infrared and high field 1H (500 MHz) and 13C (125 MHz) NMR spectra, as
well as appropriate parent ion identification by high-resolution mass
spectrometry. Optical rotations were determined using methanol solutions
with the following exceptions: 3 (EtOAc), 5 (DMSO), 13 and 14 (CH2-
Cl2), and 15 (CHCl3).
(12) This constitutes an alternative synthesis of (+)-K252a, hence its
inclusion in the title.2
(13) Although Danishefsky reports that exposure of similar substrates
to strong bases such as NaH results in benzylic oxidation to the corre-
sponding maleimide, no such products were observed in the alkylation of
(+)-10.4
(10) Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1965, 87, 5670.
(14) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
S0002-7863(96)02614-5 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 43, 1996 10657
Scheme 2
Scheme 3
[i.e., (+)-5] have been successful in delivering (+)-2 (19 steps),
(+)-3 (17 steps), and (+)-4 (19 steps).19 In addition, these
investigations have revealed both ring expansion and contraction
reactivity that may play a central role in the biogenesis of both
the furanosylated and pyranosylated members of this important
class of natural products.20 Studies directed toward elucidating
the relevance of these biosynthetic implications are underway
and will be reported in due course.
Acknowledgment. We acknowledge the support of this investiga-
tion by Yale University, Bayer Corporation, and the Elsa U. Pardee
Foundation. The Camille and Henry Dreyfus Foundation (NF-93-0),
the American Cancer Society (JFRA-523), and Eli Lilly provided
additional support through their Junior Faculty Awards Programs.
B.M.S. thanks W. R. Grace and Bayer for graduate student fellowships.
In addition, we acknowledge the assistance of Dr. Ben Bangerter in
securing NMR spectra.
Supporting Information Available: Experimental procedures and
compound characterization data for compounds 2-6, and 10-15, along
1
success of this approach is the fact that (-)-13, unlike ketone
(+)-5, readily undergoes alkylation to the C3′ methyl ether (MeI,
KOH, n-Bu4NBr). Stereoselective reduction of the derived
methoxy oxime (-)-149,16 (H2, PtO2) to the corresponding
primary amine ((+)-15)9 followed by monomethylation (HCO2-
COCH3, BH3‚DMS)17 and deprotection (TFA) produced (+)-
staurosporine.18
with H NMR (500 MHz) spectral comparison of our synthetic (+)-2
with that prepared in the Danishefsky laboratories (17 pages). See any
current masthead page for ordering and Internet access instructions.
JA9626143
(17) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315.
(18) Spectroscopic data for our synthetic staurosporine were identical
to a sample kindly provided by Professor Danishefsky.
(19) The indicated number of steps refer to the total number of
transformations required to convert o-toluidine, glycine ethyl ester, and
methyl-2-diazo-3-oxobutyrate to the specified product.
(20) This notion is supported by the concomitant isolation of 2 with RK-
286c6 and MLR-52,7 and the recent report that Streptomyces longisporofla-
Vus R-19 produces both staurosporine and K252a, see: Fredenhagen, A.;
Peter, H. H. Tetrahedron 1996, 52, 1235.
In summary, our efforts to devise an efficient synthesis of
the pyranosylated indolocarbazoles via a common intermediate
(15) This approach was adopted following failed attempts to oxidize (+)-
11 to the elusive 9.
(16) Tanida, S.; Takizawa, M.; Takahashi, T.; Tsubotani, S.; Harada, S.
J. Antibiot. 1989, 42, 1619.