Design and implementation of an efficient synthetic approach to furanosylated indolocarbazoles: Total synthesis of (+)- and (-)-K252a

Article abstract of DOI:10.1021/ja9713035

The first total synthesis of the natural product (+)-K252a (2) has been achieved in 12 steps from commercially available materials, with a longest linear sequence of seven steps and an overall yield of 21%. The synthetic strategy employs novel rhodium carbenoid chemistry in the construction of both the indolocarbazole aglycon (4) and the carbohydrate moiety (9).

Full text of DOI:10.1021/ja9713035

J. Am. Chem. Soc. 1997, 119, 9641-9651
9641
Design and Implementation of an Efficient Synthetic Approach
to Furanosylated Indolocarbazoles: Total Synthesis of (+)- and
(-)-K252a
John L. Wood,* Brian M. Stoltz, Hans-Ju1rgen Dietrich, Derek A. Pflum, and
Dejah T. Petsch
Contribution from the Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity,
New HaVen, Connecticut 06520-8107
ReceiVed April 24, 1997X
Abstract: The first total synthesis of the natural product (+)-K252a (2) has been achieved in 12 steps from
commercially available materials, with a longest linear sequence of seven steps and an overall yield of 21%. The
synthetic strategy employs novel rhodium carbenoid chemistry in the construction of both the indolocarbazole aglycon
(4) and the carbohydrate moiety (9).
In 1977 Ohmura and co-workers reported that a novel alkaloid,
isolated from Streptomyces staurosporeus, possessed strong
hypotensive properties as well as broad spectrum antifungal
activity.1 The structure of this alkaloid, originally termed AM-
2282 (1), was elucidated by single-crystal X-ray analysis and
shown to possess an indolocarbazole subunit wherein the two
indole nitrogens are bridged by glycosyl linkages.2 Following
the structure elucidation, AM-2282 was renamed staurosporine,
the first of over 50 alkaloids that have since been isolated and
are characterized by the indolo[2,3-a]carbazole subunit.3 In
1985, Sezaki reported the isolation and structure of a furano-
sylated indolocarbazole, SF-2370 (2).4 A year later, Kase
described the isolation and complete structure elucidation of
K252a, a compound that proved identical to SF-2370, along
with three structurally related compounds K252b-d (3-5,
Figure 1).5 Kase found these compounds to be potent inhibitors
of protein kinase C (PKC), with K252a possessing the greatest
inhibitory power (IC50 ) 32 nM). In the same year, Tamaoki
reported that staurosporine also inhibits PKC but with a slightly
higher affinity (IC50 ) 2.7 nM).6 Following the discovery of
Figure 1.
Previous Synthetic Work. The important biological activity
potent kinase inhibitory activity, the indolocarbazoles rapidly
became the focus of several investigations that have revealed
their potential as chemotherapeutics against cancer,7 Alzheimer’s
disease,8 and other neurodegenerative disorders.9
and novel structures of 1 and 2 have inspired an intense 14
year effort by synthetic chemists to develop efficient methods
for accessing the indolocarbazole nucleus and respective
carbohydrate moieties. At the outset of our investigations, five
syntheses had been reported for the aglycon (K252c, 4a) as well
as a number of reports for the preparation of protected variants
and closely related derivatives.10-12 In contrast, only two
approaches had been developed for the preparation of a
X Abstract published in AdVance ACS Abstracts, September 15, 1997.
(1) For the isolation of (+)-staurosporine, see: Ohmura, S.; Iwai, Y.;
Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Masuma,
R. J. Antibiot. 1977, 30, 275.
(2) (a) Furusaki, A.; Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai, Y.;
Ohmura, S. J. Chem. Soc., Chem. Commun. 1978, 800. (b) Furusaki, A.;
Hashiba, N.; Matsumoto, T.; Hirano, A.; Iwai, Y.; Ohmura, S. Bull. Chem.
Soc. Jpn. 1982, 5, 3681. (c) In the course of our synthetic endeavors, the
absolute stereochemical configuration of staurosporine was determined by
X-ray analysis; see: Funato, N.; Takayanagi, H.; Konda, Y.; Toda, Y.;
Harigaya, Y.; Iwai, Y.; Ohmura, S. Tetrahedron Lett. 1994, 35, 1251.
(3) 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) Ohmura, S.;
Sasaki, Y.; Iwai, Y.; Takeshima, H. J. Antibiot. 1995, 48, 535.
(4) Sezaki, M.; Sasaki, T.; Nakazawa, T.; Takeda, U.; Iwata, M.;
Watanabe, T.; Koyama, M.; Kai, F.; Shomura, T.; Kojima, M. J. Antibiot.
1985, 38, 1437.
(5) (a) Kase, H.; Iwahashi, K.; Matsuda, Y. J. Antibiot. 1986, 39, 1059.
(b) Nakanishi, S.; Matsuda, Y.; Iwahashi, K.; Kase, H. J. Antibiot. 1986,
39, 1066. (c) Yasuzawa, T.; Iida, T.; Yoshida, M.; Hirayama, N.; Takahashi,
M.; Shirahata, K.; Sano, H. J. Antibiot. 1986, 39, 1072.
(6) Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto, M.;
Tomita, F. Biochem. Biophys. Res. Commun. 1986, 135, 397.
(7) For a comprehensive review, see ref 3d.
(8) (a) Masliah, E.; Cole, G. M.; Hansen, L. A.; Mallory, M.; Albright,
T.; Terry, R. D.; Saitoh, T. J. Neurosci. 1991, 11, 2759. (b) Gandy, S.;
Czernik, A. J.; Greengard, P. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 6218.
(9) For a recent review, see: Knu¨sel, B.; Hefti, F. J. Neurochem. 1992,
59, 1987.
(10) For approaches that deliver an intact and fully deprotected aglycon
(i.e., 4a), see: (a) Sarstedt, B.; Winterfeldt, E. Heterocycles 1983, 20, 469.
(b) Hughes, I.; Nolan, W. P.; Raphael, R. A. J. Chem. Soc., Perkin Trans.
1 1990, 2475. (c) Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Chem.
Commun. 1990, 1667. (d) Moody, C. J.; Rahimtoola, K. F.; Porter, B.; Ross,
B. C. J. Org. Chem. 1992, 57, 2105. (e) 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. (f) Harris, W.; Hill, C. H.; Keech, E.; Malsher,
P. Tetrahedron Lett. 1993, 34, 8361. (g) Xie, G.; Lown, J. W. Tetrahedron
Lett. 1994, 35, 5555.
S0002-7863(97)01303-6 CCC: $14.00 © 1997 American Chemical Society

9642 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Wood et al.
Scheme 1
Scheme 2
carbohydrate slated for use in the synthesis of a bis-glycosylated
indolocarbazole, both targeted staurosporine.13b,14a
In addition to the carbohydrate efforts, three groups had
reported protocols for the bis-indole-N-glycosidic coupling of
indolocarbazoles.13-16 For the pyranosylation of the indolo-
carbazole nucleus, a low-yielding two-step acid-catalyzed pro-
cedure was developed by McCombie.14b Danishefsky and Link
developed landmark protocols for multistep pyranosylation that
rely on successive indolyl glycosidation by endo and exo
glycals.14a,c A variant of this was recently employed in the first
total synthesis of (+)- and (-)-staurosporine.17 For the prepara-
tion of furanosylated indolocarbazoles, the viability of a single-
step acid-promoted coupling to form both glycosidic linkages
had been demonstrated in early investigations by Weinreb13a,b
and later refined by McCombie (i.e., 6 + 7a f 8a, Scheme
1).13c Although the single-step furanosylation appeared efficient,
early reports that more fully functionalized carbohydrates such
as 7b resulted in high yields of coupled products, but as a
mixture of diastereomers 8b, left the practicality of such an
approach in question.
Scheme 3
most efficient approach (i.e., 2 w 4 + 9, Scheme 2), especially
if the regio- and stereochemical issues associated with coupling
a fully functionalized furanose could be addressed. Thus, we
based our synthetic design on this most simplifying disconnec-
tion and began considering the preparation of a selectively
protected aglycon (e.g., 4, R ) protective group) and an
appropriate furanose (e.g., 9). Although several of the known
approaches to 4a (R ) H) could possibly have been modified
to deliver protected derivatives, we sought to develop a novel
protocol that would be both efficient and amenable to installing
a variety of protecting groups at the lactam nitrogen. We viewed
the latter as a particularly important design feature given the
likelihood of having to screen the suitability of several protecting
groups.20
K252a Retrosynthetic Analysis.18,19 In planning a synthesis
of K252a, we viewed the single-step cycloglycosidation as the
(11) For an approach to 4a that involves the degradation of rebeccamycin,
see: (a) Fabre, S.; Prudhomme, M.; Rapp, M. Bioorg. Med. Chem. Lett.
1992, 2, 449. (b) Fabre, S.; Prudhomme, M.; Rapp, M. Bioorg. Med. Chem.
1993, 1, 193. (c) Fabre, S. Prudhomme, M.; Sancelme, M.; Rapp, M. Bioorg.
Med. Chem. 1994, 2, 73.
Synthesis of K252c (4a): A First-Generation Approach.
With several design features in mind, a first-generation strategy
toward 4 emerged (Scheme 2). This approach called for late-
stage cyclofuranosylation (e.g., 4 + 9 f 2) and palladium-
mediated C-N bond formation in the carbazole synthesis (e.g.,
10 f 4). Diels-Alder cycloaddition of indolepyrrolidone 12
with acetylene 11 was envisioned to be the first critical step.
As a prelude to this approach, the carbazole-forming reaction
was investigated rather extensively in a model system (Scheme
3). In accord with Migita’s protocol, we initially explored a
tin amide (RNHSnBu3) as the substrate;21 however, under certain
conditions ring closure occurred in the absence of tin.22 Thus,
(12) For approaches that deliver an intact and protected aglycon but fail
to demonstrate the feasibility of deprotection, see the following. (a)
N-Protected indole: Magnus, P. D.; Sear, N. L. Tetrahedron 1984, 40, 2795.
Bru¨ning, J.; Hache, T.; Winterfeldt, E. Synthesis 1994, 25. (b) N-Protected
indole and amide: Link, J. T.; Danishefsky, S. J. Tetrahedron Lett. 1994,
35, 9135. Winterfeldt, E. In Heterocycles in Bioorganic Chemistry;
Bergman, J., Ed.; The Royal Society of Chemistry: London, 1991. (c)
N-Protected amide: Hughes, I.; Raphael, R. A. Tetrahedron Lett. 1983,
24, 1441. Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org. Chem. 1987,
52, 1177.
(13) For examples of single-step cyclofuranosylations of indolocarba-
zoles, see: (a) Weinreb, S. M.; Garigipati, R. S.; Gainor, J. A. Heterocycles
1984, 21, 309. (b) Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org. Chem.
1987, 52, 1177. (c) McCombie, S. W.; Bishop, R. W.; Carr, D.; Dobek, E.;
Kirkup, M. P.; Kirschmeier, P.; Lin, S.-I.; Petrin, J.; Rosinski, K.; Shankar,
B. B.; Wilson, O. Bioorg. Med. Chem. Lett. 1993, 3, 1537.
(14) For the construction of pyranosylated indolocarbazoles possessing
two indole-N-glycosidic bonds, see: (a) Link, J. T.; Gallant, M.; Danishef-
sky, S. J. J. Am. Chem. Soc. 1993, 115, 3782. (b) Shankar, B. B.; McCombie,
S. W. Tetrahedron Lett. 1994, 35, 3005. (c) Link, J. T.; Raghavan, S.;
Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 552.
(15) For the total synthesis of rebeccamycin, a pyranosylated indolo-
carbazole possessing a single indole-N-glycosidic linkage, see: (a) Kaneko,
T.; Wong, H.; Okamoto, K. T.; Clardy, J. Tetrahedron Lett. 1985, 26, 4015.
(b) Gallant, M.; Link, J. T.; Danishefsky, S. J. J. Org. Chem. 1993, 58,
343.
carbazole could be produced in up to 80% yield (e.g., 1523
f
16) using Pd(PPh3)4 (1.1 equiv), Na2CO3 in toluene at reflux
for 4 h. Reactions employing catalytic amounts of Pd (5 mol
%) resulted in the formation of carbazole (ca. 60%) but only
after prolonged reaction periods (5 days).24
(19) An independent approach to (()-2 was reported shortly after our
initial communication; see: Lowinger, T. B.; Chu, J.; Spence, P. L.
Tetrahedron Lett. 1995, 36, 8383.
(16) Recently, an elegant and selective monoglycosidation approach was
developed for 2,2′-indolylindolines; see: (a) Chisholm, J. D.; Van Vranken,
D. L. J. Org. Chem. 1995, 60, 6672. (b) Gilbert, E. J.; Van Vranken, D. L.
J. Am. Chem. Soc. 1996, 118, 5500.
(17) For a full-account of the Danishefsky-Link synthesis of stauro-
sporine, see: Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky, S. J.;
Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996, 118, 2825.
(18) Recently, we reported the synthesis of (+)- and (-)-K252a in a
communication; see: Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. J. Am.
Chem. Soc. 1995, 117, 10413.
(20) On the basis of a report by Raphael10b that a benzyl protecting group
could not be removed from the lactam nitrogen, it seemed wise to proceed
in this most general manner.
(21) For the palladium-catalyzed cross coupling of aryl halides with tin
amides, see: Kosugi, M.; Kameyama, M.; Migita, T. Chem Lett. 1983, 927.
(22) A similar Pd(0)-mediated ring closure has been developed for the
preparation of the â-carboline skeleton; see: Boger, D. L.; Duff, S. R.;
Panek, J. S.; Yasuda, M. J. Org. Chem. 1985, 50, 5782.
(23) For the preparation of 2-(2-iodophenyl)aniline (15), see: Cade, J.
A.; Pilbeam, A. J. Chem. Soc. 1964, 114.

Furanosylated Indolocarbazoles
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9643
Scheme 4
Scheme 6
Scheme 7
Scheme 5
the preparation of 19 produced trace amounts of a substance
possessing 1H NMR resonances in accord with K252c. Given
this glimmer of hope, we expended considerable effort optimiz-
ing the reaction. Guided by the observation of what appeared
to be benzene C-H insertion products and the fact that 20
appeared only sparingly soluble in benzene, we began screening
several nonreactive solvents. In the event, we discovered that
solvents typically employed in rhodium carbenoid reactions (i.e.,
chloroform, methylene chloride, hexafluorobenzene, 1,2-dichlo-
roethane, xylenes, toluene, and chlorobenzene) all poorly
dissolved the substrate. However, when less traditional solvents
such as ethyl acetate and acetone were employed, a striking
increase in the amount of substrate solubility was noticed along
with an appreciable increase in the production of 4a to 15%.
Reasoning that the carbenoid may be interacting unfavorably
with the medium (e.g., carbonyl ylide formation), we explored
the use of more sterically encumbered carbonyl-containing
solvents. In addition, observations that exposure to air resulted
in darkening of the reaction mixture led us to implement more
rigorous deoxygenation methods. In the end, changing the
solvent to pinacolone and degassing with N2 prior to reaction
in a sealed tube at 120 °C had a profound effect on the yield of
K252c (now isolated in 25% yield).
Further Successful Carbenoid Additions to 2,2′-Biin-
dole: Completion of 4b-e. As shown in Scheme 7, a series
of diazo compounds were prepared by the procedure used to
produce 17a. Thus, N-substituted glycine esters 24b-e,31 were
exposed to DCC/DMAP-promoted coupling with ethyl hydrogen
malonate followed by Dieckmann cyclization (NaOEt/EtOH)
to produce lactams 25b-e. A single-pot decarboethoxylation/
diazo-transfer reaction was effected by heating 25b-e in wet
acetonitrile and then treating the cooled reaction mixture (0 °C)
with MsN3 and triethylamine. The overall process involves a
single purification step, can be conveniently carried out on a
20 g scale, and results in an approximate 50% overall yield of
diazo lactams 17b-e from 24b-e.
Having established the feasibility of forming a carbazole using
Kosugi’s reaction, we turned toward preparing the actual
substrate 4 and began investigating an approach to diene 12
that called for coupling of indole 1425 to a halopyrrolidone 13
(X ) Br, I).26 Unable to effect the Stille coupling of 13 and
14, we began considering alternative strategies and were drawn
to a report from 1935 describing the preparation of ethyl
3-indoleacetate via coupling of indole with ethyl diazoacetate
in the presence of Cu metal.27 In investigating this as an
approach to 12 we discovered that known diazotetramic acid
17a28 undergoes smooth conversion to the elusive diene 19 when
exposed to Rh2(OAc)4 and indole (18) in benzene at reflux (65%
yield, Scheme 4).29
However, difficulties encountered in advancing diene 19 to
carbazole 10 via our Diels-Alder strategy led us to reconsider
the approach. Eventually we recognized that a similar diazo
addition reaction, using 2,2′-biindole as substrate, might produce
a product that, upon electrocyclization/dehydration, would
furnish K252c directly (e.g., 17a + 20 f 4a, Scheme 5).30
Synthesis of K252c (4a): Second-Generation Approach.
In accord with the revised plan, we prepared 2,2′-biindole (20)
from 23 via a double Madelung cyclization, an excellent
procedure recently published by Bergman (Scheme 6).30f Initial
attempts to implement this revised approach by combining diazo
lactam 17a with 20 under conditions identical to those used for
(24) Recently, Buchwald developed improved procedures for this type
of aryl amination; see; Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 7215.
(25) Hodson, H. F.; Madge, D. J.; Widdowson, D. A. Synlett 1992, 831.
(26) Gerike, P. U.S. Patent 3 541 111, 1970; Chem. Abstr. 1971, 74,
99861u.
(27) Jackson, R. W.; Manske, R. H. Can. J. Res. 1935, 13, 170.
(28) Lowe, G.; Yeung, H. W. J. Chem. Soc., Perkin Trans. 1 1973, 2907.
(29) Pirrung has reported the 1,3 dipolar cycloaddition of a diazo ketone
with N-acetylindole; see: Pirrung, M. C.; Zhang, J.; Lackey, K.; Sternbach,
D. D.; Brown, F. J. Org. Chem. 1995, 60, 2112.
(30) In terms of substrates, this approach is similar to attempted Diels-
Alder reactions between maleimides and biindole 20. These efforts have
met with limited success; see: (a) Kaneko, T.; Wong, H.; Okamoto, K. T.;
Clardy, J. Tetrahedron Lett. 1985, 26, 4015. (b) Somei, M.; Kodama, A.
Heterocycles 1992, 34, 1285. (c) Pindur, U.; Kim, Y.-S.; Schollmeyer, D.
Heterocycles 1994, 38, 2267. (d) Pindur, U.; Kim, Y.-S.; Schollmeyer, D.
J. Heterocycl. Chem. 1994, 31, 377. (e) Barry, J. F.; Wallace, T. W.; Walshe,
N. D. A. Tetrahedron Lett. 1993, 34, 5329. (f) Bergman, J.; Koch, E.;
Pelcman, B. Tetrahedron 1995, 51, 5631. (g) Barry, J. F.; Wallace, T. W.;
Walshe, N. D. A. Tetrahedron 1995, 51, 12797.
With ample quantities of lactams 17b-e and biindole 20
readily available, we applied our optimized reaction conditions.
To our delight, introduction of the amide protecting group
(31) Protected glycine esters were prepared according to known literature
procedures; see: (a) Mannich, C.; Kuphal, R. Chem. Ber. 1912, 45, 314.
(b) Lee, V. J.; Branfman, A. R.; Herrin, T. R.; Rinehart, K. L., Jr. J. Am.
Chem. Soc. 1978, 100, 4225.

9644 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Wood et al.
Scheme 8
Scheme 10
Scheme 9
useful in the asymmetric synthesis, this approach was amenable
to scale-up and allowed rapid access to gram quantities of the
furanose mixture.
Total Synthesis of (()-K252a. With ample quantities of
the K252a carbohydrate and protected aglycons in hand, we
began investigating the cycloglycosidation. In an initial attempt,
the coupling reaction was performed with K252c (4) and (()-9
in the presence of CSA as catalyst. The result was formation
of a complex mixture comprised in part of products derived
from lactam alkylation, thus prompting our exploration of the
amide-protected series 4b-e.35 Given that strong evidence in
the literature suggested a simple benzyl group would be resistant
to cleavage, we chose to proceed with the 3,4-dimethoxybenzyl-
protected aglycon 4c (Scheme 11). In the event, slow addition
of (()-9 (2 equiv, 24 h) to a solution of 4c and CSA (0.1 equiv)
in 1,2-dichloroethane at reflux, rapidly produced a quaternary
mixture [(()-31 and (()-32, Vide infra] which, quite remarkably,
upon prolonged heating was reduced to a 2:1 binary mixture.
Following isolation and characterization, the products were
determined to be the regioisomeric furanosylated indolocarba-
zoles (()-33 and (()-34; thus, this reaction proceeds stereo-
selectively such that the C(3′) hydroxyl is oriented syn to the
indolocarbazole moiety.36 Furthermore, the major regioisomer
corresponded to the protected K252a derivative (()-33.37
In an effort to understand the unexpected and remarkable
stereoselectivity of this reaction, we attempted to isolate and
characterize the components of the initially formed quaternary
mixture. Despite numerous crystallization and chromatographic
attempts, we were only able to separate the mixture into two
fractions. Isolated in a 2:1 ratio, these fractions were found to
be regioisomers 31 and 32; each was isolated as a 1:1 mixture
of what appeared spectroscopically to be open-chain monoamino
acetal diastereomers.38 To support this structural assignment,
we investigated the coupling of (()-9 with carbazole (16) under
identical conditions and found that this reaction produces a
separable binary mixture wherein each component possesses
spectral properties consistent with an open-chain monoamino
acetal diastereomer (i.e., 35, Scheme 12).39 Satisfied with the
structures assigned to 31 and 32, we explored the reactivity of
the isolated major diastereomeric pair (i.e., 31) and the derived
product (()-33. In the event, re-exposure of 31 to the
appeared to favorably influence the yield, particularly in
substrates possessing benzyl-type protecting groups (Scheme
8). The optimized sequence is highlighted by preparation of
the 3,4-dimethoxybenzyl-protected aglycon 4c, which was
produced in 62% yield (50% overall yield for the three steps
from o-toluidine)!
In these initial studies, reactions had been performed on
approximately 100 mg of 20 in a sealed tube at elevated
temperature using 10 mol % Rh2(OAc)4 and 3-4 equiv of the
diazo lactam (i.e., 17c). For the purposes of the K252a
synthesis, this scale was quite suitable; however, since extending
this effort to staurosporine was expected to require multigram
quantities of 4c,32 we continued our optimization efforts. To
this end, we attempted the reaction at atmospheric pressure and
reduced the stoichiometry of the Rh(II) catalyst and diazo
substrate. In the event, reaction of biindole 20, diazo lactam
17c (1:1 mol equiv), and Rh2(OAc)4 (1.0 mol %) in degassed
pinacolone at reflux for 8 h produced a 36% yield of protected
aglycon (72% yield based on recovered biindole). Typically
this reaction is run on 4.0 g of 20 and produces 2.9 g of 4c. In
the course of developing this improved multigram procedure, a
second isolable product was observed (ca. 5-10% yield) which,
upon either heating in xylenes at reflux or exposure to CSA,
undergoes quantitative conversion to 4c. Tentatively assigned
as 26 based on spectral data (Scheme 9), this product likely
forms from the initial adduct (21c) and supports our speculation
of the stepwise process outlined in Scheme 5.
Preparation of the K252a Carbohydrate (()-9. Prior to
our investigations, there were no reported syntheses of the
K252a carbohydrate. Viewing (()-9 in an open-chain form
reveals keto aldehyde 27 and clearly presents methyl acetoac-
etate as an exploitable intermediate (Scheme 10). Thus, our
initial approach to (()-9 began with the Pb(OAc)4-mediated
oxidation of methyl acetoacetate (28),33 followed by prenylation
to produce 29 (31% yield, two steps). Interestingly, reductive
ozonolysis and acid-promoted ring closure produced only two
of the four expected diastereomeric furanose products. Single-
crystal X-ray analysis unambiguously established the structures
to be C(5′) epimers 30a and 30b.34 Removal of the acetate
provided the cycloglycosidation substrate (()-9. Although not
(35) In the actual course of events, these studies paralleled our efforts
to optimize the preparation of 4a-e.
(36) The stereochemical assignment was initially based on the chemical
shift similarities of the methyl ester singlet in 33 and 34. McCombie has
reported a 0.5 ppm chemical shift difference in the 1H NMR between R
and â ester signals in 8b.
(37) Ultimately, the regio- and stereochemical outcome of the cyclogly-
cosidation was deduced from the fact that the major isomer produces the
natural product.
(32) See following paper in this issue.
(33) (a) Green, N.; LaForge, F. B. J. Am. Chem. Soc. 1948, 70, 2812.
(b) Dimroth, O.; Schweizer, R. Chem. Ber. 1923, 56, 1375.
(34) Details regarding the crystallographic analyses have been deposited
in the Cambridge Crystallographic database and are included as Supporting
Information.
(38) The regioisomeric nature of intermediates (()-31 and (()-32 was
determined based on the characteristic free N-H chemical shift difference
1
in the H NMR.

Furanosylated Indolocarbazoles
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9645
Scheme 11
Scheme 13
determined in the second step and must be the result of either
a kinetic preference in the formation of the furanose oxocar-
benium ion or the stability of the possible products to the
reaction conditions.40
At this stage, removal of the amide protecting group was all
that remained for the completion of the synthesis (Scheme 13).41
Given that the glycosidic linkages had proven quite stable to
acid, we turned to conditions originally refined by Steglich for
the removal of 2,4-DMB groups from peptides.42,43 Thus,
exposure of (()-33 to TFA and thioanisole (cation scaven-
ger)44,45 in CH2Cl2 at 25 °C for a period of 6 h resulted in the
clean production of (()-2. The latter proved spectroscopically
identical to a sample of the natural material.46
Asymmetric Synthesis of Carbohydrate Precursor 41b.
Having established 9 to be a suitable synthetic intermediate,
we turned our attention toward completing an asymmetric
synthesis. Although recent work by Enders indicated that a
(40) Of particular importance to this issue is the stability of the
unobserved diastereomer (i.e., ii) to the reaction conditions. Unfortunately,
the stereoselectivity observed in this reaction made this question impossible
to address. However, in a closely related model system the corresponding
diastereomer proved stable to these conditions.32
Scheme 12
(41) Aglycons 4b,d, and e could be cycloglycosidated with similar results;
however, only the products arising from 4d were successfully deprotected.
(42) Weygand, F.; Steglich, W.; Bjarnason, J.; Akhtar, R.; Khan, N. M.
Tetrahedron Lett. 1966, 29, 3483.
(43) More recently, substituted benzyl amides have been utilized in the
tirandamycin area and the 3,4-DMB group was successfully used in a
synthesis of the tetrapyrrole pigment precursor porphobilinogen; see: (a)
Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J. Am. Chem.
Soc. 1985, 107, 1777. (b) DeShong, P.; Ramesh, S.; Elango, V.; Perez, J.
J. J. Am. Chem. Soc. 1985, 107, 5219. (c) Jones, M. I.; Froussios, C.; Evans,
D. A. J. Chem. Soc., Chem. Commun. 1976, 472.
(44) The well-known tendency of indolocarbazoles to undergo Friedel-
Crafts reactions necessitated using a large excess of scavenger. For examples
of this Friedel-Crafts reactivity, see: (a) Nakanishi, S.; Yamada, K.;
Iwahashi, K.; Kuroda, K.; Kase, H. Mol. Pharmacol. 1990, 37, 482. (b)
Yamada, R.; Sasaki, K.; Ohmura, S. Chem. Abstr. 1991, 115, 92688.
(45) In the absence of a cation scavenger, an appreciable amount of iii
is formed along with (()-2.
cycloglycosidation conditions produced a 5:1 ratio of 33 and
34, respectively, whereas (()-33 remained unchanged under
similar conditions; thus, the regioselectivity observed in our
initial cycloglycosidation (i.e., 33:34 ) 2:1) does not necessarily
reflect the thermodynamic stability of 31 and 32. With regard
to stereochemical outcome, the intermediacy of open-chain
ketones 31 and 32 indicates that the observed selectivity is
(39) Initially, attempts to cycloglycosidate 4c with acetates (()-30a,b
failed. This result was clarified upon isolation of furan i in 53% yield
following reaction of carbazole (16) with (()-30a,b.
(46) We thank the Bayer Corp. for a sample of nat-(+)-K252a.

9646 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Wood et al.
Scheme 14
Scheme 15
chiral auxiliary controlled version of our approach to 29 would
likely be an effective solution to the difficult task of producing
the requisite enantioenriched tertiary alcohol,47 we chose a
different course wherein a similar intermediate (i.e., 41a) was
envisioned to arise via [2,3] rearrangement of a chiral carbenoid-
derived allyloxonium ion (e.g., 36 + 37 f 41a, Scheme
14).48-50 Unfortunately, investigations with benzyl ether 37 and
diazo ester 36 produced intractable mixtures. Undaunted, we
began to consider alternatives and soon developed a revised
plan wherein carbenoid-mediated O-H insertion of a chiral
allylic alcohol would serve as the primary event. In this
scenario, 41b was envisioned to arise from the insertion product,
an R-allyloxy ketone (e.g., 39), via a tandem [3,3]/[1,2]
rearrangement protocol. From the work of Koreeda we expected
that deprotonation of 39 would induce [3,3] rearrangement and
produce R-keto ester 40,51 a compound that appeared well suited
for subsequent Lewis acid-promoted [1,2]-allylic migration.52
While the bond construction was reasonably well precedented,
the issue of stereoselectivity remained speculative. However,
given the plethora of rearrangement conditions and Lewis acids,
there appeared ample opportunity to influence the stereochemical
outcome and we proceeded with the investigation.
expected 2.2 ppm. Clearly the allyloxy or allyloxonium ylide
intermediate had undergone [3,3] sigmatropic rearrangement to
alcohol (+)-40 (66% yield). Completion of the tandem rear-
rangement protocol was achieved by exposing (+)-40 to BF3‚-
OEt2 which promoted a clean [1,2]-allyl migration to furnish
(-)-41b in 74% yield. In subsequent studies, improved yields
were obtained by conducting the tandem rearrangement in one
pot. Thus, introducing 1 equiv of BF3‚OEt2 into the cooled
[3,3] reaction allows isolation of (-)-41b in an overall yield of
75%.54
With an approach firmly established, we initiated a chemical
correlation study to confirm both the sense and degree of
asymmetric induction for the tandem rearrangement. Analysis
of the purified products from both the [3,3] [i.e., (+)-40] and
[1,2] [i.e., (-)-41b] rearrangements via proton NMR in the
presence of Eu(hfc)3 gave the first indication that each step was
proceeding with a high degree of stereoselectivity.55 Conversion
of (+)-40 to 4256 as outlined in Scheme 15, followed by
comparison of the derived bis Mosher ester (43) to samples
prepared from (S)-(+)- and (R)-(-)-citramalic acid, established
that (S)-(+)-38 (98% ee) had furnished (R)-(+)-40 (95% ee).57
Stereoselectivity in the [1,2] shift was established by degradation
of (-)-41b to (R)-(-)-4558 followed by DIBAL reduction and
1H NMR analysis of the corresponding Mosher bisester (46).
In anticipation of isolating R-allyloxy ether 39, we subjected
36 to rhodium-catalyzed decomposition in the presence of (S)-
(+)-1-buten-3-ol (38).53 In the event, complete consumption
of 36 was observed after only 20 min at reflux in benzene.
Proton NMR analysis of the crude reaction indicated the clean
formation of a product similar to 39; however, the characteristic
methyl ketone singlet appeared at 1.5 ppm instead of the
(47) For a recent example describing the use of RAMP and SAMP
hydrazones in the alkylation of â-keto esters, see: Enders, D.; Zamponi,
A.; Scha¨fer, T.; Nu¨bling, C.; Eichenauer, H.; Demir, A. S.; Raabe, G. Chem.
Ber. 1994, 127, 1707.
(48) Several excellent reviews have appeared; see: (a) Padwa, A.;
Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b) Ye, T.; McKervey, M. A.
Chem. ReV. 1994, 94, 1091.
(49) For a recent review of the [2,3] Wittig rearrangement, see: Nakai,
T.; Mikami, K. Org. React. 1994, 46, 105.
(50) The Sharpless kinetic resolution protocol provides a convenient
means of accessing a variety of allylic alcohols of very high optical purity;
see: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(51) (a) Koreeda, M.; Luengo, J. I. J. Am. Chem. Soc. 1985, 107, 5572.
(b) Examples of both [2,3] and [3,3] rearrangements of R-allyloxy ketones
have been reported; see: Ziegler, F. E. Chem. ReV. 1988, 88, 1423 and
references therein.
(54) The dramatic increase in yield over the two-step procedure is
attributed to the difficulties of isolating the somewhat volatile products (+)-
40 and (-)-41b.
(55) These studies were performed simultaneously in the racemic series.
(56) Compound 42 has been prepared previously from citramalic acid
and is of known absolute configuration; see: Gill, M.; Smrdel, A. F.
Tetrahedron Asymmetry 1990, 1, 453.
(57) In the absence of rhodium, one would likely attribute the observed
stereochemistry to reaction via a chair transition structure possessing a (Z)-
enol and an equatorial methyl substituent (i.e., iv). However, unpublished
results from these laboratories suggest the apparent involvement of rhodium,
hence this rationalization may eventually require refinement.
(52) For a leading reference to the Lewis acid-catalyzed R-ketol
rearrangement, see: Crout, D. H. G.; Rathbone, D. L. J. Chem. Soc., Chem.
Commun. 1987, 290.
(53) This material was prepared from (S)-(-)-ethyl lactate; see: Klingler,
F. D.; Psiorz, M. German Patent DE-4219510-C1, 1993. Mosher ester
analysis (500 MHz 1H NMR) of the derived allylic alcohol established an
optical purity of 98% ee.

Furanosylated Indolocarbazoles
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9647
Scheme 16
Scheme 17
While the Mosher ester analysis established an ee of 92%, the
observation of (R)-(-)-45 in the degradation proved the absolute
stereochemistry in (-)-41b as S.59
Completion of (+)- and (-)-K252a. Having established the
sense and degree of asymmetric induction in the preparation of
(-)-41b, we proceeded with the asymmetric synthesis of 9. In
contrast to 29, reductive ozonolysis of (-)-41b followed by
acetal formation provided a ternary mixture. Characterization
of the purified products indicated the reaction had produced
methyl ketone (-)-47 in addition to the expected furanoses (+)-
9a and (+)-9b (Scheme 16). The additional component proved
to be of no consequence as exposure of 4c to the ternary mixture
[i.e., (+)-9a,b, and (-)-47] under our standard cycloglycosi-
dation conditions produced the expected regioisomeric mixture
of (-)-33 and (-)-34 in yields comparable to that observed in
the racemic series. Removal of the 3,4-DMB group in (-)-33
produced (-)-K252a, the enantiomer of the natural product. This
observation, in conjunction with the stereochemical assignments
made in the course of the degradation study (Vide supra),
allowed the absolute configuration of natural K252a to be
established as depicted in (+)-2 (see Figure 1).
To access (+)-2 we simply returned to the carbohydrate
synthesis and altered the absolute stereochemistry of the starting
allylic alcohol. In this series, handling of the allylic alcohol
and early intermediates was facilitated by employing the less
volatile (R)-(-)-1-nonene-3-ol (48) as our initial substrate. Thus,
exposure of (R)-(-)-48 to 36 and catalytic Rh2(OAc)4 (PhH,
80 °C, 20 min) followed by introduction of BF3‚OEt2 to the
cooled reaction mixture, furnished (+)-49 in 77% yield (see
Scheme 17). Ozonolysis of (+)-49 followed by acid-mediated
cyclization produced the expected carbohydrate mixture [i.e.,
(-)-9a,b/(+)-47] in 80% yield.60 Cycloglycosidation of 4c with
(-)-9a,b/(+)-47 produced (+)-33 and (+)-34, which upon
chromatographic separation and deprotection produced (+)-2,
a compound identical in all respects to the natural material.
Conclusion. The total synthesis of K252a was completed
by developing new rhodium carbenoid chemistry in the prepara-
tion of 4 and 9. The total synthesis requires only 12 steps from
commercially available materials, with a longest linear sequence
of 7 steps and an overall yield of 21% from ethyl glycinate.
The remarkable stereo- and regioselective cycloglycosidation
served as the cornerstone of our approach, and the overall
efficiency prompted our pursuit of staurosporine (1) and other
pyranosylated indolocarbazoles.32
Experimental Section61
Carbazole (16). A mixture of 15 (0.10 g, 0.34 mmol, 1.0 equiv),
Pd(PPh3)4 (0.43 g, 0.37 mmol, 1.1 equiv), and Na2CO3 (40 mg, 0.38
mmol, 1.1 equiv) in toluene (1.7 mL) was heated to reflux for 2 h. The
reaction mixture was then cooled and evaporated to a residue. Flash
chromatography (20:80:1 acetone/hexanes/Et3N eluent) provided 16 (44
mg, 80% yield) as a white solid.62
Indolepyrollidone 19. A mixture of indole (18) (1.40 g, 12.0 mmol,
3.0 equiv), diazo lactam 17a (0.5 g, 4.0 mmol, 1.0 equiv), and Rh2-
(OAc)4 (35 mg, 0.08 mmol, 0.02 equiv) in benzene (50 mL) was heated
to reflux for 18 h. The reaction mixture was cooled to room temperature
and concentrated in Vacuo to a brown residue which was dissolved in
EtOAc (100 mL) and extracted with 1 N NaOH solution (150 mL).
The aqueous layer was then acidified to pH 1 with 1 N HCl and
extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with H2O (150 mL) and brine solution (150 mL), dried
over MgSO4, and concentrated in Vacuo to provide a crude solid which
was recrystallized from EtOAc/heptane to afford 19 (549 mg, 65%
yield) as a white powder: mp 220-225 °C (dec); IR (thin film/NaCl)
3405.3 (br m), 2957.0 (m), 2928.3 (s), 2857.7 (m), 1656.6 (s), 1541.3
(w) cm-1; 1H NMR (500 MHz, acetone-d6) δ 10.23 (br s, 1H), 8.09 (d,
J ) 8.2 Hz, 1H), 7.76 (d, J ) 2.1 Hz, 1H), 7.36 (d, J ) 8.0 Hz, 1H),
7.05 (app t, J ) 7.8 Hz, 1H), 6.97 (app t, J ) 7.4 Hz, 1H), 6.42 (br s,
1H), 4.00 (s, 2H); 13C NMR (62.5 MHz, DMSO-d6) δ 174.3, 164.2,
135.6, 126.0, 123.6, 121.8, 120.4, 117.8, 110.8, 106.0, 101.2, 45.0;
high-resolution mass spectrum (CI) m/z 215.0805 [calcd for C12H11N2O2
(M + H) 215.0821].
General Method for the Preparation of Tetramic Acids 25b-
e.63 To a stirred solution of 23 (47.4 mmol, 1.0 equiv) in CH2Cl2 (95
mL) at 0 °C was added a solution of ethyl hydrogen malonate (6.26 g,
(61) Materials and Methods. Unless otherwise stated, reactions were
performed in flame-dried glassware under a nitrogen atmosphere, using
freshly distilled solvents. Methyl sulfoxide (DMSO), 1,2-dichloroethane,
and BF3‚OEt2 were purchased from the Aldrich Chemical Co. in Sure/Seal
containers and used without further purification. All other commercially
obtained reagents were used as received. Preparative thin-layer chroma-
tography (TLC) as well as analytical TLC was performed using silica gel
60 F254 precoated plates (0.25 mm). Silica gel (particle size 0.032-0.063
mm) was used for flash chromatography. High-performance liquid chro-
matography (HPLC) was performed with either a Rainin Microsorb 80-
(58) Compound 45 has been prepared previously and is of known absolute
stereochemistry; see: Spencer, H. K.; Khatri, H. N.; Hill. R. K. Bioorg.
Chem. 1976, 5, 177.
199-C5 or 80-120-C5 column. Melting points are uncorrected. 1H and 13
C
(59) This stereochemical outcome suggests a synperiplaner relationship
between the hydroxyl and carbonyl oxygens in the reactive conformer. Since
BF3‚OEt2 is unable to form a chelate its role, if any, in enforcing this
transition structure is not obvious.
(60) Upon large-scale preparation of (-)-9, a third furanose diastereomer
was detected as a minor byproduct. The structure of this compound was
unambiguously assigned by X-ray analysis to be the C(2′) epimer of 9a.34
chemical shifts are reported as δ values relative to tetramethylsilane. High-
resolution mass spectra were performed at The University of Illinois Mass
Spectrometry Center. Microanalyses were performed by Atlantic Microlab
(Norcross, GA). Single-crystal X-ray analyses were performed by Dr. Susan
DeGala of Yale University.
(62) The material obtained proved identical to a sample purchased from
Aldrich Chemical Co.

9648 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Wood et al.
47.4 mmol, 1.0 equiv) in CH2Cl2 (38 mL), followed by a solution of
1,3-dicyclohexylcarbodiimide (9.9 g, 48.0 mmol, 1.01 equiv) and
DMAP (290 mg, 2.37 mmol, 0.05 equiv) in CH2Cl2 (20 mL). The
mixture was stirred at 0 °C for 15 min and allowed to warm to ambient
temperature while being stirred for an additional 2 h. After this time,
the solid urea byproduct was removed by filtration. The filtrate was
washed with H2O (80 mL), dried over MgSO4, filtered, and evaporated
to a yellow semisolid. To this was added acetone (30 mL) and the
insoluble precipitate again removed via filtration. The filtrate was
concentrated in Vacuo to a yellow oil and used in the next step without
further purification.
To a solution of NaOEt/EtOH prepared from sodium metal (1.09 g,
47.4 mmol) and absolute EtOH (31 mL) was added a solution of the
crude diester in benzene (200 mL) over 5 min. The resulting mixture
was brought to reflux for 6.5 h. The reaction mixture was allowed to
cool to room temperature and then diluted with H2O (100 mL). The
layers were separated and the benzene layer further extracted with H2O
(2 × 80 mL). The aqueous layers were combined, and residual EtOH
was removed in Vacuo, followed by careful acidification to pH 1 with
concentrated HCl at 0 °C. The resultant white precipitate was filtered
and dried with a slow stream of N2 gas to give lactams 25b-e as white
powders.
chromatography (1:1 EtOAc/hexanes eluent) to provide 4a-e as pale
yellow solids.
4c. The above procedure was followed using 17c (605 mg) to afford
4c (257 mg, 62% yield): mp >202 °C (dec, EtOAc); IR (thin film/
NaCl) 3487.5 (br s), 3352.0 (br s), 3232.0 (br s), 3022.3 (m), 1579.1
(s), 1571.2 (s), 1517.7 (s), 1462.9 (s) cm-1 1H NMR (500 MHz,
;
DMSO-d6) δ 11.50 (br s, 1H), 11.35 (br s, 1H), 9.28 (d, J ) 7.9 Hz,
1H), 7.97 (d, J ) 7.8 Hz, 1H), 7.77 (d, J ) 8.1 Hz, 1H), 7.73 (d, J )
8.1 Hz, 1H), 7.45 (app t, J ) 6.9 Hz, 1H), 7.44 (app t, J ) 7.1 Hz,
1H), 7.26 (app t, J ) 7.1 Hz, 1H), 7.25 (app t, J ) 7.1 Hz, 1H), 7.02
(s, 1H), 6.92 (s, 2H), 4.94 (s, 2H), 4.82 (s, 2H), 3.74 (s, 3H), 3.71 (s,
3H); 13C NMR (62.5 MHz, DMSO-d6) δ 169.2, 148.9, 148.1, 139.1,
139.0, 130.6, 130.0, 127.7, 125.3, 124.9, 124.9, 124.8, 122.6, 122.3,
120.7, 119.9, 119.7, 118.8, 118.2, 115.4, 113.8, 112.3, 112.1, 111.7,
111.1, 55.5, 49.3, 45.4; high-resolution mass spectrum (FAB) m/z
462.1813 [calcd for C29H24N3O3 (M + H) 462.1818].
Indolocarbazole 4c and Isolation of 26. Method B. A mixture
of 20 (4.0 g, 17.2 mmol, 1.0 equiv), lactam 17c (4.74 g, 17.2 mmol,
1.0 equiv), Rh2(OAc)4 (76 mg, 0.17 mmol, 0.01 equiv), and pinacolone
(210 mL), in a three-neck round-bottom flask fitted with a reflux
condenser was degassed with a stream of N2 for 2 h. The reaction
mixture was then heated to reflux for 8 h. The mixture was allowed
to cool to room temperature, and the solvent was evaporated in Vacuo.
Flash chromatography (1:1 EtOAc/hexanes eluent) afforded unreacted
20 (2.0 g, 50% yield) as a pale yellow powder and 4c (2.9 g, 36%
yield; 72% yield based on recovered 20) as a white solid.
25c. The above procedure was followed using 24c (12.00 g) to
afford 25c (12.6 g, 83% yield): mp 154-156 °C (EtOH/CH2Cl2); IR
(thin film/NaCl) 2937.5 (br m), 2839.5 (w), 2612.4 (br w), 1704.0 (s),
1
1611.8 (s), 1514.9 (s), 1418.9 (s) cm-1; H NMR (500 MHz, DMSO-
When heating was discontinued after only 3 h and the reaction
mixture worked up in the fashion described above, 20 (1.92 g) and 4c
(1.15 g) were isolated, along with 26 (644 mg) as a yellow foam: IR
(thin film/NaCl) 3323.5 (br m), 2935.8 (w), 2829.1 (w), 1676.6 (s),
d6) δ 6.89 (d, J ) 8.2 Hz, 1H), 6.79 (d, J ) 1.6 Hz, 1H), 6.70 (dd, J
) 1.5, 8.1 Hz, 1H), 4.37 (s, 2H), 4.13 (q, J ) 7.1 Hz, 2H), 3.80 (s,
2H), 3.72 (s, 3H), 3.71 (s, 3H), 1.20 (t, J ) 7.1 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 178.8, 167.3, 162.0, 148.8, 148.0, 130.0, 119.8,
111.9, 111.5, 97.8, 59.0, 55.5, 55.4, 49.0, 44.1, 14.3; high-resolution
mass spectrum (EI) m/z 321.1209 [calcd for C16H19NO6 (M+) 321.1212].
Anal. Calcd for C16H19NO6: C, 59.81; H, 5.96; N, 4.46. Found: C,
59.93; H, 5.92; N, 4.36.
Diazo Lactams 17b-e. A solution of ester 25 (33.5 mmol, 1.0
equiv) and H2O (1mL) was heated to reflux in CH3CN (1.5 L) for 2 h.
The volume of CH3CN was reduced to approximately 35% the original
volume (ca. 560 mL) in Vacuo. The solution was cooled to 0 °C and
treated sequentially with MsN3 (8.12 g, 67.0 mmol, 2.0 equiv) in CH3-
CN (168 mL) via addition funnel followed by Et3N (9.34 mL, 67.0
mmol, 2.0 equiv) in CH3CN (96 mL). After 15 min, the ice bath was
removed and the dark orange solution was allowed to warm to 25 °C,
stirred for an additional 2 h, and concentrated in Vacuo. The dark
orange residue was dissolved in a minimum of EtOAc and filtered
through a pad of silica gel (EtOAc eluent). The filtrate was washed
once with 1 N NaOH solution, dried over MgSO4, filtered, and
concentrated to give 17b-e as yellow solids, which were recrystallized
from acetone/hexanes.
17c. The above procedure was followed using 25c (10.75 g) to
afford 17c (8.29 g, 90% yield): mp 145-147 °C (EtOAc); IR (CCl4)
2960.7 (br w), 2925.8 (br w), 2126.1 (s), 1695.2 (s), 1515.1 (m), 1451.2
(w), 1401.1 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 6.83 (d, J ) 7.8
Hz, 1H), 6.81 (d, J ) 8.6 Hz, 1H), 6.79 (s, 1H), 4.53 (s, 2H), 3.88 (s,
6H), 3.71 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 185.7, 161.7, 149.5,
149.0, 127.7, 120.8, 111.3, 111.2, 66.0, 56.0, 55.9, 53.9, 46.5; high-
resolution mass spectrum (CI) m/z 276.0981 [calcd for C13H14N3O4 (M
+ H) 276.0984]. Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N,
15.27. Found: C, 56.81; H, 4.81; N, 15.36.
Indolocarbazoles 4a-e. Method A.63 A mixture of 2,2′-biindole
(20) (200 mg, 0.86 mmol, 1.0 equiv), diazotetramic acid 17a-e (2.2
mmol, 2.5 equiv), Rh2(OAc)4 (38 mg, 0.086 mmol, 0.1 equiv), and
pinacolone (8.6 mL) in a pressure tube fitted with a rubber septum
was degassed with a stream of N2 for 1 h. The septum was removed
and the tube was flushed with N2, sealed, and placed into a preheated
sand bath (120 °C). After 6 h, the tube was removed from the sand
bath, allowed to cool to room temperature, and carefully opened. After
removing the solvent in Vacuo, the residue was dissolved in EtOAc
(15 mL), washed with 1 N NaOH (15 mL) solution, and dried over
MgSO4. Filtration and removal of the solvent was followed by flash
1
1514.6 (s) cm-1; H NMR (500 MHz, acetone-d6) δ 10.87 (br s, 1H),
8.27 (d, J ) 8.0 Hz, 1H), 7.96 (d, J ) 8.0 Hz, 1H), 7.52 (d, J ) 7.6
Hz, 1H), 7.40 (d, J ) 8.1 Hz, 1H), 7.16 (td, J ) 1.0, 7.4 Hz, 1H),
7.03-7.12 (comp m, 3H), 6.87 (s, 1H), 6.69 (s, 2H), 6.65 (s, 1H),
6.58 (s, 1H), 4.59 (d, J ) 14.9 Hz, 1H), 4.43 (s, 1H), 4.32 (d, J ) 14.8
Hz, 1H), 3.97 (d, J ) 10.1 Hz, 1H), 3.65 (s, 3H), 3.39 (d, J ) 10.2
Hz, 1H), 3.24 (s, 3H); 13C NMR (125 MHz, acetone-d6) δ 171.3, 150.0,
149.1, 138.6, 137.2, 130.5, 129.2, 127.2, 127.1, 123.3, 122.6, 121.9,
121.0, 121.0, 120.4, 120.3, 113.6, 112.0, 111.5, 111.4, 110.9, 103.8,
97.5, 87.6, 57.8, 55.5, 54.9, 53.2, 45.5; high-resolution mass spectrum
(EI) m/z 479.1845 [calcd for C29H25N3O4 (M+) 479.1845].
Acetoacetate 29. A suspension of sodium hydride (5.55 g, 60%
dispersion in mineral oil, 139 mmol, 1.01 equiv) in dioxane (135 mL)
was treated dropwise with a solution of methyl 2-(methylcarbonyloxy)-
3-oxobutanoate33 (24.1 g, 138 mmol, 1.0 equiv) in dioxane (27 mL)
over a period of 45 min. The mixture was stirred (overhead stirrer)
for an additional 45 min at 20 °C. Prenyl bromide (15.95 mL, 138
mmol, 1.0 equiv) was added over 25 min, and the mixture warmed to
reflux for 20 min. After cooling to room temperature, the mixture was
poured into 1.1 L of H2O containing acetic acid (7.9 mL, 138 mmol,
1.0 equiv). This mixture was extracted with ether (1 × 600 mL; 3 ×
300 mL). The organic layer was washed with H2O (500 mL) and
saturated NaCl solution (500 mL) and dried over MgSO4. The solvent
was evaporated and the reaction mixture distilled (bp 80-85 °C, 0.2
mmHg) to provide 29 as a colorless oil (28.53 g, 85% yield): IR (thin
film/NaCl) 2997.1 (w), 2955.7 (m), 2929.3 (m), 2917.9 (m), 2859.7
1
(w), 1747.6 (s) cm-1; H NMR (500 MHz, CDCl3) δ 4.99 (t, J ) 7.4
Hz, 1H), 3.75 (s, 3H), 2.88 (app t, J ) 6.3 Hz, 2H), 2.32 (s, 3H), 2.17
(s, 3H), 1.70 (s, 3H), 1.60 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
200.5, 169.3, 167.5, 136.7, 115.2, 87.3, 52.5, 32.5, 26.6, 25.6, 20.3,
17.5; high-resolution mass spectrum (CI) m/z 243.1233 [calcd for
C12H19O5 (M + H) 243.1232].
Acetates (()-30a,b. A solution of 29 (2.91 g, 12.0 mmol, 1.0 equiv)
and a trace of sudan red 7B dye in a mixture of THF (65 mL) and
MeOH (13 mL) was cooled to -78 °C and treated with O3 until the
dye was completely discolored (about 6 min). The mixture was purged
with argon for 10 min at -78 °C, and dimethyl sulfide (40 mL) was
added at that temperature. The reaction was brought to 0 °C with an
ice bath which was allowed to thaw (0-20 °C) over a period of 3 h.
The solvent was removed and the crude product dissoved in MeOH
(20 mL). After addition of trimethyl orthoformate (6.6 mL, 60.0 mmol,
5.0 equiv) and p-toluenesulfonic acid (22.8 mg, 0.12 mmol, 0.01 equiv),
(63) Due to space limitations, spectral data pertaining to the b, d, and e
analogs are provided as Supporting Information.

Furanosylated Indolocarbazoles
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9649
the mixture was heated to reflux for 1 h. After cooling to room
temperature, the solvent was evaporated in Vacuo. Flash chromatog-
raphy (20% EtOAc/hexanes eluent) provided a mixture of diastereomers
30a,b (2.36 g, 75% yield) as a colorless oil. The diastereomers could
be separated using HPLC (4:4:1 hexanes/CH2Cl2/EtOAc eluent).
Crystals suitable for X-ray analysis were obtained by crystallization
from EtOAc/hexanes.
mmol, 0.1 equiv) was heated to reflux in 1,2-dichloroethane (18 mL)
and treated over 30 min with a solution of (()-14a, b (0.24 g, 1.1
mmol, 2.0 equiv) in dichloroethane (12 mL). After an additional 45
min at reflux, the reaction mixture was allowed to cool to room
temperature, diluted with CH2Cl2 (25 mL), and washed with 10%
NaHCO3 solution (20 mL). The organic layer was dried with Na2SO4
and evaporated in Vacuo. Flash chromatography (1:1 EtOAc/hexanes
eluent) provided a 2:1 mixture of (()-31 and (()-32 (260 mg, 74%
yield). Separation of the regioisomers (()-31 and (()-32 was achieved
using either preparative TLC (1:20:20 MeOH/CH2Cl2/hexanes, 3
elutions) or HPLC (190:10:1 CH2Cl2/EtOAc/MeOH eluent).
30a: mp 106-107 °C; IR (thin film/NaCl) 2996.6 (w), 2953.1 (m),
1
2917.3 (m), 2837.2 (w), 1759.8 (s), 1741.3 (s) cm-1; H NMR (500
MHz, CDCl3) δ 5.11 (app t, J ) 5.7 Hz, 1H), 3.74 (s, 3H), 3.47 (s,
3H), 3.27 (s, 3H), 3.15 (dd, J ) 5.3, 15.3 Hz, 1H), 2.57 (dd, J ) 6.2,
15.3 Hz, 1H), 2.10 (s, 3H), 1.51 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 169.5, 167.3, 108.8, 104.9, 88.4, 56.4, 52.5, 48.6, 39.2, 20.8, 15.0;
high-resolution mass spectrum (CI) m/z 231.0866 [calcd for C10H15O6
(M - CH3OH + H) 231.0869].
The first diastereomeric mixture to elute was minor regioisomer (()-
32: IR (thin film/NaCl) 3388.2 (br m), 2928.3 (s), 1731.6 (s), 1668.6
1
(s), 1592.9 (m), 1514.7 (m), 1454.4 (s) cm-1; H NMR (500 MHz,
CDCl3) δ 10.08 (br s, 1H), 9.98 (br s, 1H), 9.58 (app t, J ) 8.0 Hz,
2H), 7.89 (d, J ) 7.7 Hz, 2H), 7.70 (d, J ) 4.7 Hz, 1H), 7.68 (d, J )
4.8 Hz, 1H), 7.50-7.62 (comp m, 6H), 7.41 (app t, J ) 7.6 Hz, 2H),
7.35 (app t, J ) 7.4 Hz, 2H), 6.99 (m, 4H), 6.89 (s, 1H), 6.87 (s, 1H),
6.28 (dd, J ) 3.8, 9.8 Hz, 1H), 6.22 (dd, J ) 4.6, 8.9 Hz, 1H), 4.97 (s,
4H), 4.90 (app t, J ) 17.1 Hz, 4H), 4.59 (s, 1H), 4.50 (s, 1H), 4.07 (s,
3H), 3.89 (s, 6H), 3.86 (s, 6H), 3.49 (dd, J ) 9.9, 14.5 Hz, 1H), 3.45
(s, 3H), 3.45 (s, 3H), 3.39 (s, 3H), 3.33 (dd, J ) 8.9, 14.8 Hz, 1H),
2.45 (s, 3H), 2.42 (dd, J ) 4.5, 14.8 Hz, 1H), 2.13 (dd, J ) 4.0, 14.6
Hz, 1H), 2.10 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.4, 202.9,
171.5, 170.2, 170.0, 149.4, 148.5, 139.9, 139.6, 139.5, 139.5, 130.4,
129.6, 129.6, 126.8, 126.7, 126.4, 126.4, 126.0, 125.9, 125.7, 125.6,
125.4, 123.3, 123.3, 123.2, 121.3, 121.2, 121.1, 120.8, 120.4, 120.2,
120.1, 118.4, 118.4, 116.3, 116.3, 111.2, 111.2, 110.9, 110.7, 110.6,
109.5, 109.3, 83.6, 83.6, 82.0, 81.8, 56.8, 56.6, 56.0, 55.9, 53.9, 53.6,
49.6, 46.4, 40.5, 24.9, 23.9; high-resolution mass spectrum (EI) m/z
649.2422 [calcd for C37H35N3O8 (M+) 649.2424].
30b: mp 58-59 °C; IR (thin film/NaCl) 2998.2 (m), 2952.9 (s),
2977.7 (m), 2838.7 (m), 1760.0 (s), 1739.9 (s), 1434.2 (s), 1376.6 (s)
1
cm-1; H NMR (500 MHz, CDCl3) δ 5.08 (dd, J ) 1.9, 6.5 Hz, 1H),
3.73 (s, 3H), 3.40 (s, 3H), 3.33 (dd, J ) 6.5, 15.2 Hz, 1H), 3.25 (s,
3H), 2.19 (dd, J ) 1.9, 15.2 Hz, 1H), 2.11 (s, 3H), 1.57 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 169.7, 167.7, 109.0, 104.1, 86.4, 55.9, 52.5,
48.6, 39.1, 20.9, 15.8; high-resolution mass spectrum (CI) m/z 231.0870
[calcd for C10H15O6 (M - CH3OH + H) 231.0869].
Esters (()-9a,b. A solution of 30a,b (1.31 g, 5.00 mmol) in MeOH
(50 mL) was treated with K2CO3 (1.04 g, 7.52 mmol, 1.5 equiv). The
mixture was stirred for 2 h at 20 °C. After evaporation of solvent in
Vacuo, the residue was dissolved in Et2O and filtered through silica
gel (Et2O eluent) to afford a mixture of (()-9a,b (814 mg, 74% yield)
as a colorless oil. The mixture of diastereomers could be separated by
HPLC (2:2:1 hexanes/CH2Cl2/EtOAc eluent).
Indolocarbazoles (()-33 and (()-34. A stirred solution of aglycon
4c (1.00 g, 2.17 mmol, 1.0 equiv) and camphorsulfonic acid (50 mg,
0.22 mmol, 0.1 equiv) in 1,2-dichloroethane (72 mL) was heated to
reflux and treated over 24 h with a solution of (()-9a,b (0.95 g, 4.32
mmol, 2.0 equiv) in 1,2-dichloroethane (50 mL). After an additional
24 h, the reaction mixture was allowed to cool to room temperature,
diluted with CH2Cl2 (50 mL), and washed with 10% NaHCO3 solution
(50 mL). The organic layer was dried with Na2SO4 and evaporated in
Vacuo. Flash chromatography (1:1 EtOAc/hexanes eluent) provided a
2:1 mixture of (()-33 and (()-34 (1.07 g, 80% yield). Separation of
the regioisomers (()-33 and (()-34 was achieved with either prepara-
tive TLC (60:1 70% CH2Cl2/hexanes/MeOH, three elutions) or by
HPLC (190:10:1 CH2Cl2/EtOAc/MeOH eluent).
Ketone (()-35. To a solution of (()-9a,b (230 mg, 1.00 mmol,
1.0 equiv) and carbazole (16) (167 mg, 1.00 mmol, 1.0 equiv) in 10
mL of 1,2-dichloroethane was added camphorsulfonic acid (23.0 mg,
0.10 mmol, 0.10 equiv), and the mixture was heated to reflux for 10 h.
Removal of solvent followed by flash chromatography (20% EtOAc/
hexanes eluent) afforded a mixture (1:1) of diastereomeric ketones (()-
35 (274 mg, 77% yield). The first compound to elute was diastereomer
I: IR (thin film/NaCl) 3451.2 (m), 3057.5 (w), 3046.5 (w), 2997.5
(w), 2950.2 (m), 2828.5 (w), 1746.5 (s), 1722.2 (s), 1627.3 (w), 1600.2
(m), 1483.6 (s), 1453.7 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 8.06
(d, J ) 7.7 Hz, 2H), 7.43 (t, J ) 7.4 Hz, 4H), 7.24 (t, J ) 7.5 Hz, 2H),
5.92 (dd, J ) 4.4, 8.8 Hz, 1H), 4.68 (s, 1H), 3.40 (s, 3H), 3.25 (dd, J
) 8.8, 14.8 Hz, 1H), 3.12 (s, 3H), 2.64 (dd, J ) 4.4, 14.8 Hz, 1H),
2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.7, 170.1, 139.1, 125.8,
123.7, 120.2, 119.8, 110.5, 83.4, 81.9, 55.7, 53.0, 38.7, 24.5; high-
resolution mass spectrum (FAB) m/z 355.1411 [calcd for C20H21NO5
(M+) 355.1420].
The second diastereomeric mixture to elute was major regioisomer
(()-31: IR (thin film/NaCl) 3381.1 (br m), 3009.5 (w), 2942.3 (m),
1
2841.8 (w), 1725.6 (s), 1668.7 (s), 1513.6 (s), 1454.9 (s) cm-1; H
NMR (500 MHz, CDCl3) δ 10.25 (br s, 1H), 10.15 (br s, 1H), 9.68 (d,
J ) 8.0 Hz, 2H), 7.93 (d, J ) 3.8 Hz, 1H), 7.92 (d, J ) 3.8 Hz, 1H),
7.75 (d, J ) 8.1 Hz, 1H), 7.72 (d, J ) 8.2 Hz, 1H), 7.51-7.58 (comp
m, 4H), 7.41 (app t, J ) 7.7 Hz, 2H), 7.34 (app t, J ) 7.3 Hz, 2H),
6.99 (m, 4H), 6.87 (d, J ) 8.1 Hz, 2H), 6.30 (dd, J ) 3.8, 10.0 Hz,
1H), 6.26 (dd, J ) 4.6, 8.9 Hz, 1H), 4.98 (d, J ) 14.9 Hz, 1H), 4.98
(d, J ) 14.9 Hz, 1H), 4.93 (d, J ) 15.0 Hz, 1H), 4.92 (d, J ) 15.0 Hz,
1H), 4.89 (s, 4H), 4.61 (s, 1H), 4.51 (s, 1H), 4.06 (s, 3H), 3.89 (s, 6H),
3.89 (s, 6H), 3.47 (s, 3H), 3.46 (s, 3H), 3.43-3.45 (m, 1H), 3.41 (s,
3H), 3.28 (dd, J ) 9.0, 14.8 Hz, 1H), 2.44 (s, 3H), 2.38 (dd, J ) 4.7,
14.7 Hz, 1H), 2.12 (s, 3H), 2.09 (dd, J ) 3.8, 12.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 205.0, 203.0, 171.7, 170.4, 170.1, 149.3, 148.5,
139.7, 139.5, 139.4, 139.4, 131.5, 130.4, 127.9, 127.7, 126.8, 126.8,
126.2, 125.9, 125.9, 125.6, 125.5, 125.0, 124.6, 124.4, 123.8, 123.7,
122.8, 122.8, 121.0, 121.0, 120.8, 120.7, 120.4, 120.4, 119.2, 119.1,
115.7, 115.7, 111.8, 111.6, 111.2, 111.1, 110.9, 108.5, 108.3, 107.3,
83.4, 83.4, 82.1, 81.9, 56.7, 56.4, 56.0, 55.9, 53.7, 53.7, 49.5, 46.4,
40.4, 40.4, 25.0, 23.9; high-resolution mass spectrum (EI) m/z 649.2415
[calcd for C37H35N3O8 (M+) 649.2424].
(()-K252a (2). To a stirred solution of (()-33 (17.0 mg, 0.028
mmol, 1 equiv) in CH2Cl2 (1.4 mL) at 25 °C was added thioanisole
(0.16 mL, 1.36 mmol, 50 equiv) followed by 2,2,2-trifluoroacetic acid
(1.4 mL). The solution was stirred for 6 h, followed by dropwise
addition of 2.0 mL of saturated NaHCO3 solution to neutralize the
reaction mixture. The organic layer was separated, evaporated, and
purified via preparative TLC (1:20:20 MeOH/CH2Cl2/hexanes, three
elutions) to afford (()-K252a [2, 10.8 mg, 83% yield].
The second compound to elute was diastereomer II: IR (thin film/
NaCl) 3466.3 (w), 3058.7 (w), 2996.6 (w), 2950.7 (w), 2930.0 (w),
2847.2 (w), 2828.3 (w), 1723.7 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 8.07 (d, J ) 7.7 Hz, 2H), 7.44 (t, J ) 7.4 Hz, 4H), 7.25 (t, J ) 7.3
Hz, 2H), 5.97 (dd, J ) 4.1, 9.1 Hz, 1H), 4.54 (s, 1H), 3.89 (s, 3H),
3.36 (dd, J ) 9.1, 14.5 Hz, 1H), 3.17 (s, 3H), 2.33 (dd, J ) 4.1, 14.5
Hz, 1H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.4, 171.4,
139.6, 125.9, 123.7, 120.3, 119.8, 110.6, 83.5, 81.8, 56.1, 53.5, 38.7,
24.2; high-resolution mass spectrum (FAB) m/z 355.1411 [calcd for
C20H21NO5 (M+) 355.1420].
Ketone (+)-40. A stirred solution of methyl 2-diazo-3-oxobutanoate
(33) (2.13 g, 15.0 mmol, 1.0 equiv), (S)-(+)-38 (1.3 mL, 15.0 mmol,
1.0 equiv), and Rh2(OAc)4 (66.3 mg, 0.15 mmol, 0.01 equiv) in benzene
(75 mL) was immersed into a preheated (100-110 °C) oil bath. The
mixture was heated under reflux for 20 min. After the mixture was
cooled to room temperature, the solvent was carefully evaporated (0
°C) in Vacuo. Flash chromatography (20% EtOAc/hexanes eluent)
afforded (+)-40 (1.84 g, 66% yield) as a colorless oil: bp 65-67 °C
(0.35 mmHg); [R]20 +14.65 (c 1.08, CHCl3); IR (thin film/NaCl)
D
Ketones (()-31 and (()-32. A stirred solution of aglycon 4c (250
mg, 0.54 mmol, 1.0 equiv) and camphorsulfonic acid (12.5 mg, 0.054
3521.0 (m), 3028.5 (w), 2981.5 (m), 2957.1 (m), 2937.9 (m), 2919.9
1
(m), 2857.4 (w), 1742.6 (s), 1726.1 (s) cm-1; H NMR (500 MHz,

9650 J. Am. Chem. Soc., Vol. 119, No. 41, 1997
Wood et al.
CDCl3) δ 5.57 (m, 1H), 5.35 (m, 1H), 3.88 (s, 3H), 3.28 (br s, 1H),
2.68 (dd, J ) 7.0, 14.0 Hz, 1H), 2.42 (dd, J ) 7.7, 14.0 Hz, 1H), 1.66
(d, J ) 6.42 Hz, 3H), 1.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
198.5, 162.7, 130.9, 123.5, 78.3, 52.5, 42.2, 24.1, 17.8; high-resolution
mass spectrum (CI) m/z 187.0966 [calcd for C9H15O4 (M + H)
187.0970].
Esters (-)-9a,b and Ketone (+)-47. The same procedure used for
the preparation of (+)-9a,b and (-)-47 was employed. Ketone (+)-
49 (10.6 g, 41.4 mmol) was used as starting material yielding the three-
component mixture (1:1:1), (-)-9a,b and (+)-47 (7.3 g, 80% yield).
Separation of the mixture was achieved using the same protocol
described above.
Ketone (-)-41b. A solution of (+)-40 (3.35 g, 18.0 mmol, 1.0
equiv) in benzene (180 mL) was treated with BF3‚OEt2 (2.21 mL, 18.0
mmol, 1.0 equiv), stirred for 2 h at 25 °C, and the solvent was carefully
evaporated (0 °C) in Vacuo. Flash chromatography (20% EtOAc/
hexanes eluent) provided (-)-41b (2.49 g, 74% yield) as a colorless
(-)-9b: mp 63-64 °C (EtOAc); [R]20 -9.00 (c 1.16, CHCl3); IR
D
(thin film/NaCl) 3486.7 (m), 2994.8 (m), 2954.8 (m), 2918.0 (m),
2836.2 (m), 1732.7 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 5.21 (app
t, J ) 5.7 Hz, 1H), 3.79 (s, 3H), 3.47 (s, 3H), 3.36 (br s, 1H), 3.27 (s,
3H), 2.84 (dd, J ) 5.3, 14.3 Hz, 1H), 2.34 (dd, J ) 6.2, 14.3 Hz, 1H),
1.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 172.1, 109.9, 105.4, 84.5,
56.4, 52.8, 49.0, 40.5, 14.5; high-resolution mass spectrum (CI) m/z
189.0773 [calcd for C8H13O5 (M - CH3OH + H) 189.0763].
oil: [R]20 -32.13 (c 1.08, CHCl3); IR (thin film/NaCl) 3476.1 (m),
D
3031.2 (w), 3009.6 (w), 2956.2 (m), 2921.4 (w), 2857.5 (w), 1746.9
1
(s), 1721.9 (s) cm-1; H NMR (500 MHz, CDCl3) δ 5.60 (m, 1H),
(-)-9a: mp 81-82 °C (EtOAc); [R]20 -122.55 (c 1.10, CHCl3);
5.32 (m, 1H), 4.17 (s, 1H), 3.80 (s, 3H), 2.77 (dd, J ) 6.6, 14.3 Hz,
1H), 2.63 (dd, J ) 7.6, 14.3 Hz, 1H), 2.28 (s, 3H), 1.65 (d, J ) 6.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 204.2, 170.8, 130.5, 122.9,
83.8, 53.1, 38.5, 24.7, 17.9; high-resolution mass spectrum (CI) m/z
187.0969 [calcd for C9H15O4 (M + H) 187.0970].
D
IR (thin film/NaCl) 3496.4 (m), 2998.9 (m), 2953.3 (m), 2915.1 (m),
2836.9 (m), 1748.9 (s), 1732.9 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.07 (d, J ) 5.8 Hz, 1H), 3.78 (s, 3H), 3.42 (s, 3H), 3.25 (s, 3H),
3.03 (dd, J ) 5.8, 14.1 Hz, 1H), 2.05 (d, J ) 14.1 Hz, 1H), 1.54 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.4, 110.5, 103.8, 83.1, 55.5,
52.5, 49.2, 40.5, 15.7; high-resolution mass spectrum (CI) m/z 189.0778
[calcd for C8H13O5 (M - CH3OH + H) 189.0763].
Ketone (-)-41b. Single-Pot Method. A stirred solution of methyl
2-diazo-3-oxobutanoate (36) (427 mg, 3.00 mmol, 1.0 equiv), (S)-(+)-
38 (0.286 mL, 3.3 mmol, 1.1 equiv), and Rh2(OAc)4 (13 mg, 0.03 mmol,
0.01 equiv) in benzene (15 mL) was immersed into a preheated (100-
110 °C) oil bath. The mixture was heated to reflux for 20 min, cooled
to room temperature, treated with BF3‚OEt2 (0.46 mL, 3.74 mmol, 1.25
equiv), and stirred for 2 h at 25 °C. The entire reaction mixture was
poured onto a silica column and chromatographed (20% pentane/Et2O
eluent) to provide (-)-41b (418 mg, 75% yield) as a colorless oil.
Esters (+)-9a,b and Ketone (-)-47. A solution of (-)-41b (1.31
g, 7.0 mmol, 1.0 equiv) and a trace of sudan red 7B dye in MeOH (45
mL) was cooled to -78 °C and treated with O3 until the dye was
completely discolored (about 3 min). The mixture was purged with
argon for 10 min at -78 °C, and dimethyl sulfide (20 mL) was added
at that temperature. The dry ice bath was replaced with an ice bath
which was allowed to thaw (0-20 °C) over a period of 3 h. The solvent
was removed in Vacuo and the crude product dissoved in benzene (45
mL). After addition of p-toluenesulfonic acid (20 mg, 0.11 mmol, 0.015
equiv) and MeOH (12 mL) the mixture was stirred at 25 °C for 17 h
followed by evaporation of the solvent in Vacuo. Flash chromatography
(20% EtOAc/hexanes eluent) afforded a mixture of diastereomers (+)-
9a,b and (-)-47 (1.23 g, 80% yield). The diastereomers could be
separated using HPLC. In a first run (2:2:1 hexanes/CH2Cl2/EtOAc
eluent), a mixture of (+)-9b and (-)-47 was eluted first followed by
(+)-9a which was isolated in its pure form as a colorless oil. The
two-component mixture was separated using a different system (10%
2-propanol/hexanes eluent). The first compound to elute was furanose
(+)-9b, followed by ketone (-)-47, both as colorless oils.
(+)-47: [R]20D +19.55 (c 1.12, CHCl3); IR (thin film/NaCl) 3452.5
(m), 2993.2 (m), 2954.6 (m), 2934.2 (m), 2917.5 (m), 2848.4 (m),
2838.2 (m), 1748.7 (s), 1723.1 (s) cm-1; 1H NMR (500 MHz, CDCl3)
δ 4.51 (br s, 1H), 4.50 (dd, J ) 4.9, 6.6 Hz, 1H), 3.78 (s, 3H), 3.34 (s,
3H), 3.29 (s, 3H), 2.43 (dd, J ) 4.9, 14.6 Hz, 1H), 2.38 (dd, J ) 6.6,
14.6 Hz, 1H), 2.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 204.0,
170.8, 102.0, 81.8, 54.9, 53.8, 53.2, 38.4, 24.5; high-resolution mass
spectrum (FAB) m/z 189.0775 [calcd for C8H13O5 (M - CH3OH + H)
189.0763].
Indolocarbazoles (+)-33 and (+)-34. A procedure identical to that
described for the preparation of (()-33 and (()-34 was employed, with
the exception that the mixture of (-)-9a,b and (+)-47 obtained above
was utilized in place of the racemic carbohydrate substrate.
(+)-33: mp >250 °C (dec, MeOH/CH2Cl2); [R]20 +15 (c 0.1,
D
MeOH); IR (thin film/NaCl) 3279.7 (br m), 3012.1 (m), 2952.1 (m),
2930.1 (m), 2850.1 (w), 1732.2 (m), 1646.2 (s), 1590.4 (m), 1513.7
(s) cm-1; 1H NMR (500 MHz, DMSO-d6) δ 9.26 (d, J ) 7.9 Hz, 1H),
7.99 (d, J ) 7.7 Hz, 1H), 7.92 (app t, J ) 8.0 Hz, 2H), 7.49 (app t, J
) 7.7 Hz, 1H), 7.47 (app t, J ) 7.8 Hz, 1H), 7.32 (app t, J ) 7.9 Hz,
1H), 7.30 (app t, J ) 8.1 Hz, 1H), 7.15 (dd, J ) 5.2, 6.9 Hz, 1H), 7.02
(s, 1H), 6.94 (d, J ) 9.0 Hz, 1H), 6.92 (d, J ) 9.0 Hz, 1H), 6.35 (s,
1H), 5.02 (d, J ) 17.8 Hz, 1H), 4.97 (d, J ) 17.8 Hz, 1H), 4.86 (d, J
) 15.5 Hz, 1H), 4.82 (d, J ) 15.5 Hz, 1H), 3.92 (s, 3H), 3.74 (s, 3H),
3.71 (s, 3H), 3.39 (dd, J ) 7.3, 14.0 Hz, 1H), 2.13 (s, 3H), 2.00 (dd,
J ) 4.7, 14.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 172.6, 168.6,
148.9, 148.2, 139.8, 136.7, 130.4, 130.0, 128.2, 125.3, 125.3, 124.8,
123.9, 123.8, 122.4, 120.9, 120.2, 119.8, 119.3, 118.9, 115.6, 114.6,
114.2, 112.3, 112.1, 108.8, 99.3, 84.8, 55.5, 52.4, 49.5, 45.4, 42.4, 22.6;
high-resolution mass spectrum (FAB) m/z 618.2240 [calcd for C36H32N3O7
(M + H) 618.2240].
Indolocarbazoles (-)-33 and (-)-34. A procedure identical to that
described for the preparation of (()-33 and (()-34 was employed, with
the exception that the mixture of (+)-9a,b and (-)-47 obtained above
was utilized in place of the racemic carbohydrate substrate: (-)-33,
[R]20 -17 (c 0.1, MeOH). (-)-34, [R]20 -13 (c 0.1, MeOH).
D
D
(-)-K252a (2). A procedure identical to that for the preparation of
(()-2 was employed to provide (-)-2 ([R]20D -39; c 0.1, MeOH) from
(-)-33.
(+)-34: mp 260-270 °C (dec, MeOH/CH2Cl2); [R]20 +13 (c 0.1,
D
MeOH); IR (thin film/NaCl) 3462.3 (br m), 3014.0 (m), 2952.3 (m),
2925.1 (m), 2849.7 (m), 1730.8 (s) cm-1; 1H NMR (500 MHz, DMSO-
d6) δ 9.54 (d, J ) 7.9 Hz, 1H), 8.01 (d, J ) 7.9 Hz, 1H), 7.94 (d, J )
8.2 Hz, 1H), 7.89 (d, J ) 8.5 Hz, 1H), 7.50 (app t, J ) 7.5 Hz, 1H),
7.45 (app t, J ) 7.5 Hz, 1H), 7.30 (app t, J ) 7.5 Hz, 1H), 7.29 (app
t, J ) 7.6 Hz, 1H), 7.14 (dd, J ) 5.0, 7.2 Hz, 1H), 7.01 (s, 1H), 6.92
(app t, J ) 8.2 Hz, 1H), 6.92 (dd, J ) 1.1, 8.4 Hz, 1H), 6.34 (br s,
1H), 4.98 (d, J ) 17.9 Hz, 1H), 4.95 (d, J ) 17.9 Hz, 1H), 4.84 (d, J
) 15.1 Hz, 1H), 4.80 (d, J ) 15.1 Hz, 1H), 3.92 (s, 3H), 3.74 (s, 3H),
3.71 (s, 3H), 3.40 (dd, J ) 7.5, 14.0 Hz, 1H), 2.14 (s, 3H), 2.05 (dd,
J ) 4.8, 14.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 172.6, 168.9,
149.0, 148.2, 139.7, 136.8, 130.4, 126.2, 126.1, 125.4, 125.1, 124.9,
124.3, 122.0, 121.3, 120.2, 119.8, 119.2, 118.7, 116.3, 113.9, 113.8,
112.3, 112.1, 109.4, 99.3, 84.9, 84.8, 55.5, 52.4, 49.0, 45.4, 42.5, 22.8;
high-resolution mass spectrum (FAB) m/z 618.2240 [calcd for C36H32N3O7
(M + H) 618.2240].
Ketone (+)-49. A stirred solution of methyl 2-diazo-3-oxobutanoate
(36) (10 g, 70.4 mmol, 1.0 equiv), (R)-(-)-nonen-3-ol (10.8 g, 75.9
mmol, 1.1 equiv), and Rh2(OAc)4 (19 mg, 0.04 mmol, 0.0006 equiv)
in benzene (235 mL) was immersed into a preheated (100-110 °C)
oil bath. The mixture was heated at reflux for 20 min, cooled to room
temperature, treated with BF3‚OEt2 (10.8 mL, 85.2 mmol, 1.21 equiv),
and stirred for 2 h at 25 °C. The entire reaction mixture was poured
onto a flash column and chromatographed (10% EtOAc/hexanes eluent)
to provide (+)-49 (13.9 g, 77% yield) as a colorless oil: [R]20D +19.41
(c 1.03, CHCl3); IR (thin film/NaCl) 3788.3 (m), 2954.9 (s), 2926.7
(s), 2871.3 (m), 2855.5 (s), 1746.6 (s), 1723.2 (s) cm-1; 1H NMR (500
MHz, CDCl3) δ 5.57 (m, 1H), 5.30 (m, 1H), 4.20 (s, 1H), 3.79 (s, 3H),
2.78 (dd, J ) 6.7, 14.3 Hz, 1H), 2.64 (dd, J ) 7.6, 14.3 Hz, 1H), 2.28
(s, 3H), 1.97 (q, J ) 7 Hz, 2H), 1.31-1.23 (m, 8H), 0.88 (t, J ) 7 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 204.2, 170.8, 136.2, 121.6, 83.9,
53.1, 38.6, 32.4, 31.5, 29.0, 28.6, 24.7, 22.4, 13.9; high-resolution mass
spectrum (CI) m/z 257.1745 [calcd for C14H25O4 (M + H) 257.1753].
(+)-K252a (2). A procedure identical to that for the preparation of
(()-2 was employed to provide (+)-2 from (+)-33: mp 264-267 °C
(dec, acetone); [R]20D +40 (c 0.1, MeOH); IR (thin film/NaCl) 3309.6

Furanosylated Indolocarbazoles
J. Am. Chem. Soc., Vol. 119, No. 41, 1997 9651
(br m), 3053.5 (m), 2952.6 (m), 2851.9 (m), 1735.8 (s), 1675.4 (s),
523), Eli Lilly, Glaxo-Wellcome, and Bristol Myers Squibb
provided additional support through their Junior Faculty Awards
Programs. J.L.W. is a fellow of the Alfred P. Sloan Foundation.
B.M.S. thanks W. R. Grace and Bayer for graduate student
fellowships. In addition, we acknowledge Dr. Ben Bangerter’s
assistance in securing NMR spectra and are particularly grateful
to Professor Frederick Ziegler for numerous helpful and
enlightening discussions.
1
1590.0 (m), 1458.6 (s) cm-1; H NMR (500 MHz, DMSO-d6) δ 9.20
(d, J ) 7.9 Hz, 1H), 8.63 (s, 1H), 8.05 (d, J ) 7.7 Hz, 1H), 7.93 (d,
J ) 8.5 Hz, 1H), 7.89 (d, J ) 8.3 Hz, 1H), 7.47 (comp m, 2H), 7.35
(app t, J ) 7.4 Hz, 1H), 7.28 (app t, J ) 7.4 Hz, 1H), 7.14 (dd, J )
5.0, 7.2 Hz, 1H), 6.34 (s, 1H), 5.02 (d, J ) 17.6 Hz, 1H), 4.97 (d, J )
17.6 Hz, 1H), 3.92 (s, 3H), 3.38 (dd, J ) 7.5, 14.0 Hz, 1H), 2.14 (s,
3H), 2.01 (dd, J ) 4.9, 14.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 172.9, 171.8, 139.9, 136.8, 133.0, 128.3, 125.6, 125.4, 125.1, 124.2,
123.9, 122.6, 121.3, 120.4, 119.6, 119.5, 115.8, 114.8, 114.6, 109.1,
99.4, 85.0, 85.0, 52.7, 45.5, 42.5, 22.8; high-resolution mass spectrum
(FAB) m/z 468.1561 [calcd for C27H22N3O5 (M + H) 468.1559].
Supporting Information Available: Spectral and experi-
mental data pertaining to 25b,d,e; 17b,d,e; 4a,b,d,e; 42; 44;
and 45. Crystallographic information pertaining to 30a, 30b,
and C(2′)-epi-9a (21 pages). See any current masthead page
for ordering and Internet access instructions.
Acknowledgment. We are pleased to acknowledge the
support of this investigation by Yale University, Bayer Corp.,
the Elsa U. Pardee Foundation and the NIH (Grant
1RO1GM54131). The Camille and Henry Dreyfus Foundation
(Grant NF-93-0), the American Cancer Society (Grant JFRA-
JA9713035