Stereocontrolled total synthesis of (+)-K252a [3]

Full text of DOI:10.1021/ja990909l

J. Am. Chem. Soc. 1999, 121, 6501-6502
6501
Scheme 1a
Stereocontrolled Total Synthesis of (+)-K252a
Yoshihisa Kobayashi, Teppei Fujimoto, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, CREST
The Japan Science and Technology Corporation (JST)
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed March 22, 1999
The structurally related indolocarbazole alkaloids (+)-K252a1,2
(1) and (+)-staurosporine3 (2) have attracted considerable attention
due to the unique asymmetrical structure of the cycloglycoside
moieties as well as the strong PKC inhibitory activity. Many
efforts have been directed toward the regioselective synthesis of
the N-monoprotected aglycon moiety of K252a.4 While Wood
and co-workers have recently completed an efficient total
synthesis of (+)-K252a,5 they failed to solve the regiochemical
problem of the cycloglycosidation, resulting in the formation of
a 2:1 mixture of the desired product 3 and its regioisomer 4. In
a Reagents and yields: (a) allyl bromide, K2CO3, DMF, 23 °C, 100
min, 99%; (b) (i) NBS, CCl4, 23 °C, 90 min, 80%; (ii) NaH, MeCN, 23
°C, 10 min; 8, 23 °C, 30 min, 97%; (c) (i) Pd(PPh3)4, Ph3P, pyrrolidine,
CH2Cl2, 23 °C, 1 h; (ii) WSCD, tryptamine, CH2Cl2, 23 °C, 15 min,
72% (2 steps); (iii) DDQ (2.2 equiv), THF/H2O (9:1), 0 °C, 30 min, 93%;
(iv) 2,6-lutidine (2 equiv), DMAP (0.2 equiv), Ac2O, 60 °C, 8 h, 78%.
Scheme 2a
their total synthesis of (+)-staurosporine, Danishefsky and co-
workers also obtained a 1:1 mixture of the regioisomeric
intermediates.6 Herein we report a completely stereocontrolled
total synthesis of (+)-K252a, which is applicable to the synthesis
of a range of indolocarbazolyl glycosides.
Regiospecific bromination7 of indole 6, prepared by allylation
of indole-3-acetic acid (5), was performed by treatment with NBS
to give 2-bromoindole 7 (Scheme 1). N-Glycosidation8 of the
indole 7 was carried out by deprotonation with sodium hydride,
followed by addition of readily available 1-chloro-2-deoxy-3,5-
di-O-p-toluoyl-R-D-erythro-pentofuranose9 (8) to give â-N-gly-
a Reagents and yields: (a) DBU (0.1 equiv), MS 4 Å, THF, 60 °C,
2.5 h, 92%; (b) i-Pr2NEt, hν, CH2Cl2 (2.8 × 10-2 M), 23 °C, 5 h, 96%;
(c) (i) KOH, H2O/MeOH/THF, 23 °C, 45 min, 97%; (ii) I2, Ph3P,
imidazole, THF, 23 °C, 1 h, 82%; (iii) DBU, THF, 80 °C.
(1) (+)-K252a was isolated independently by two Japanese groups. (a)
Sezaki, M.; Sasaki, T.; Nakazawa, T.; Takeda, U.; Iwata, M.; Watanabe, T.;
Koyama, M.; Kai, F.; Shomura, T.; Kojima, M. J. Antibiot. 1985, 38, 1439.
(b) Kase, H.; Iwahashi, K.; Matsuda, Y. J. Antibiot. 1986, 39, 1059.
(2) For structure elucidation of (+)-K252a, see: (a) Nakanishi, S.; Matsuda,
Y.; Iwahashi, K.; Kase, H. J. Antibiot. 1986, 39, 1066. (b) Yasuzawa, T.;
Iida, T.; Yoshida, M.; Hirayama, M.; Takahashi, M.; Shirahata, K.; Sano, H.
J. Antibiot. 1986, 39, 1072.
(3) For isolation and structure elucidation of (+)-staurosporine, see: (a)
Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.;
Takahashi, Y.; Masuma, R. J. Antibiot. 1977, 30, 275. (b) Furusaki, A.;
Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai, Y.; Omura, S. J. Chem. Soc.,
Chem. Commun. 1978, 800. (c) Furusaki, A.; Hashiba, N.; Matsumoto, T.;
Hirano, A.; Iwai, Y.; Omura, S. Bull. Chem. Soc. Jpn. 1982, 55, 3681.
(4) (a) Magnus, P. D.; Sear, N. L. Tetrahedron 1984, 40, 2797. (b) Bru¨ning,
J.; Hache, T.; Winterfeldt, E. Synthesis 1994, 25. (c) Kobayashi, Y.; Fukuyama,
T. J. Heterocycl. Chem. 1998, 35, 1043.
coside 9 as the sole product. After deprotection of the allyl ester
9, the acid which resulted was condensed with tryptamine under
conventional conditions to give amide 10. Regioselective oxida-
tion of the more reactive indole of 10 with 2 equiv of DDQ in
aqueous THF afforded the ketone 11 exclusively.10 For the ensuing
cyclization, the ketone and the amide in 11 were both activated
by acetylation of the indole and amide nitrogens to give diacetyl
bisindole.11
Upon treatment with a catalytic amount of DBU and molecular
sieves, 12 underwent smooth cyclization to give lactam 13
(Scheme 2).12 A nonoxidative photocyclization13 was performed
by exposing lactam 13 to sunlight14 in the presence of diisopro-
(5) (a) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. J. Am. Chem. Soc. 1995,
117, 10413. (b) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.;
Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641.
(6) (a) Link, J. L.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc.
1995, 117, 552. (b) Link, J. L.; Raghavan, S.; Gallant, M.; Danishefsky, S.
J.; Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996, 118, 2825.
(7) Zhang, P.; Liu, R.; Cook, J. M. Tetrahedron Lett. 1995, 36, 3103.
(8) Girgis, N. S.; Cottam, H. B.; Robins, R. K. J. Heterocycl. Chem. 1988,
25, 361.
(10) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(11) Sarstedt, B.; Winterfeldt, E. Heterocycles 1983, 20, 469.
(12) Lactam 13 exists as a 1:1 mixture of atropisomers.
(13) For an example of a nonoxidative photochemical synthesis of
phenanthrenes, see: Cava, M. P.; Mitchell, M. J.; Havlicek, S. C.; Lindert,
A.; Spangler, R. J. J. Org. Chem. 1970, 35, 175.
(9) Hoffer, M. Chem. Ber. 1960, 93, 2777.
(14) A 500-W halogen lamp can be used in laboratories.
10.1021/ja990909l CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

6502 J. Am. Chem. Soc., Vol. 121, No. 27, 1999
Communications to the Editor
Scheme 3a
Scheme 4a
a Reagents and yields: (a) HCN (xs), Py (xs), MeCN, 0 °C, 15 min;
Ac2O, DMAP, 23 °C, 30 min, 99%; (b) HCl, HCO2H, 23 °C, 19 h, 88%;
(c) (i) KOH, H2O/MeOH/THF, 100 °C, 10 h; (ii) CH2N2, THF, 65% (2
steps).
a Reagents and yields: (a) (i) PhSeSePh, NaBH4, EtOH/THF (2:5),
23 °C, 93%; (ii) Ac2O, Py, DMAP, 23 °C, 10 min, 98%; (iii) m-CPBA,
THF, 23 °C, 10 min; NEt3, DHP, 80 °C, 30 min, 91% (2 steps); (b) KI
(6 equiv), I2 (5 equiv), DBU (2 equiv), THF, 23 °C, 40 min, 93%; (c) (i)
n-Bu3SnH, AIBN, MeCN, reflux, 50 min, 98%; (ii) K2CO3, MeOH, 23
°C, 10 min, 90%; (iii) DCC (6 equiv), Cl2CHCO2H (2 equiv), DMSO,
23 °C, 15 min, 99%.
Transformation of the ketone 25 into the corresponding
cyanohydrin under ordinary conditions resulted in the formation
of a diastereomeric mixture. However, only the desired, kinetically
favored cyanohydrin acetate 26a was obtained when treated with
hydrogen cyanide and pyridine,21 followed by acetylation.22 Since
attempted conversion of 26a to 1 in methanolic HCl gave
primarily ketone 25 along with a trace amount of the desired 1,
an indirect procedure was adopted. Namely, the nitrile 26a was
first converted to amide 27 by treatment with gaseous HCl in
formic acid at room temperature.23 Finally, the amide 27 was
subjected to alkaline hydrolysis and the resultant acid esterified
with diazomethane to give (+)-K252a (1) (Scheme 4). The
synthetic (+)-K252a proved to be identical with the natural
product24 in TLC behavior as well as in spectroscopic properties
(1H, 13C NMR, IR, MS, [R]D).
pylethylamine to provide the desired indolocarbazole 14 in near
quantitative yield. Without doubt, the photochemically induced
conversion was promoted by the facile dehydrobromination of
the incipient cyclization product.15 Following hydrolysis of all
the acyl groups in 14, the primary alcohol was selectively
converted to the corresponding iodide 16 by treatment with iodine,
triphenylphosphine, and imidazole.16 Attempts to dehydroiodinate
16 failed to give the desired olefin, and only the undesired
cycloglycoside 17 was obtained.
Conversion of iodide 16 to olefin 21 was effected by the
conventional, four-step sequence shown in Scheme 3.17 Much to
our dismay, initial attempts to construct the desired cycloglycoside
from the enol ether 21 under oxidative or acidic conditions
failed.18 Treatment of 21 with potassium tert-butoxide and iodine,
used successfully by Danishefsky in their total synthesis of
staurosporine,6 gave the desired cycloglycoside 22 in less than
10% yield. However, upon treatment with iodine, potassium
iodide, and DBU, 21 underwent a remarkably smooth iodogly-
cosidation to give the required cycloglycoside 22 in 93% yield.19
Radical-mediated deiodination,20 methanolysis of the acetate, and
the subsequent oxidation of the alcohol 24 with DCC, Cl2-
CHCO2H, and DMSO furnished ketone 25 in high yield.
In conclusion, the stereocontrolled total synthesis of (+)-K252a
has been achieved in a 23-step sequence from indole-3-acetic acid
with an overall yield of 10%. The established synthetic route
should be amenable to the preparation of a variety of interesting
analogues.
Acknowledgment. Partial financial support from the Ministry of
Education, Science, Sports and Culture, Japan is gratefully acknowledged.
Supporting Information Available: Listing of spectral data (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
(15) For syntheses of indolocarbazoles by means of less effective, oxidative
photocyclization, see: (a) Kaneko, T.; Wong, H.; Okamoto, K. T.; Clardy, J.
Tetrahedron Lett. 1985, 26, 4015. (b) Weinreb, S. M.; Garigipati, R. S.; Gainor,
J. A. Heterocycles 1984, 21, 309. (c) Harris, W.; Hill, C. H.; Keech, E.;
Malsher, P. Tetrahedron Lett. 1993, 34, 8361. (d) Xie, G.; Lown, J. W.
Tetrahedron Lett. 1994, 35, 5555. (e) Sarstedt, B.; Winterfeldt, E. Heterocycles
1983, 20, 469. (f) Bru¨ning, J.; Hache, T.; Winterfeldt, E. Synthesis 1994, 25.
(16) Classon, B.; Liu, Z.; Samuelsson, B. J. Org. Chem. 1988, 53, 6126.
(17) For the selenoxide elimination step, triethylamine and DHP were added
to prevent the undesired oxidative addtion of phenylselenous acid to the
reactive enol ether.
JA990909L
(19) The success of this cycloglycosidation might be attributable to the
attenuated reactivity of the oxidizing agent, KI3, and the heightened HOMO
level of the enol ether due to the proximate indolyl anion, enabling a concerted
reaction to take place.
(20) Kuivila, H. G.; Menapace, L. W. J. Org. Chem. 1963, 28, 2165.
(21) Use of more basic triethylamine as a base gave, after acetylation, a
3:1 mixture of 26a and 26b.
(22) The unprotected cyanohydrin was prone to lose hydrogen cyanide to
give ketone 25.
(18) Several oxidizing agents including m-CPBA, 3,3-dimethyldioxirane,
PdCl2, Hg(OAc)2, NBS, NIS, bromine, iodine, ICl, bromopyridinium pyridine
tetrafluoroborate, and acid catalysts such as CSA, PPTS, and Amberlyst were
examined. Under these conditions, 21 suffered extensive decomposition.
(23) Becke, F.; Fleig, H.; Pa¨ssler, P. Liebigs Ann. Chem. 1971, 749, 198.
(24) We are indebted to Dr. C. Murakata of Kyowa Hakko Kogyo for a
generous gift of natural (+)-K252a.