Short, enantioselective total synthesis of okaramine N

Article abstract of DOI:10.1021/ja034491+

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6). Copyright

Full text of DOI:10.1021/ja034491+

Published on Web 04/18/2003
Short, Enantioselective Total Synthesis of Okaramine N
Phil S. Baran, Carlos A. Guerrero, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received February 4, 2003; E-mail: corey@chemistry.harvard.edu
The okaramines are a family of biologically active tryptophan-
derived heptacyclic and octacyclic alkaloids produced by a strain
of the fungus Penicillium simplicissum (ATCC 90288) and first
described by Prof. H. Hayashi and co-workers.1 To date, no
synthesis of any member of this group of complex natural products
has been reported. We describe herein a remarkably simple synthesis
of okaramine N (1) that takes advantage of a powerful new Pd-
promoted construction of the dihydroindoloazocine cyclic subsystem
that was recently devised and applied to the austamide family of
pentacyclic dihydroindoloazocine alkaloids.2
a way up a vertical cliff that offers just a limited number of small
cracks and handholds.
The first step in the synthesis of okaramine N (1) was the
assembly of the tetracyclic intermediate 4 from (S)-tryptophan
methyl ester by reductive N-alkylation with 3-methyl-2-butenal
(Schiff base formation in CH Cl , removal of CH Cl , reaction of
2
2
2
2
1
a
the Schiff base with NaBH
removal of MeOH in vacuo to give 2) (Scheme 1), followed by
acylation of 2 with the tryptophan derivative 3. Reaction of 3
4
in MeOH at 0 °C for 30 min, and
2
(synthesized as described below) with 1.2 equiv of diisopropyl-
ethylamine and 1.2 equiv of bis(2-oxo-3-oxazolidyl)phosphinic
chloride (BOPCl) afforded the corresponding mixed anhydride,
which was allowed to react with 2 at 0 °C for 3 h to afford 4 in
3
7
0% overall yield. The second step of the synthesis, cyclization
of 4 to form the pentacycle 5, was accomplished under conditions
similar to those defined earlier for Pd-promoted dihydroindoloa-
2
zocine formation. Thus, treatment of 4 with 1 equiv of Pd(OAc)
2
in 1:3.5:1 acetic acid-dioxane-water at 23 °C for 16 h provided
3
5
in 38% isolated yield (44% yield based on recovered starting
material). Despite the presence of two indole subunits in 4, only
the N-unsubstituted subunit appeared to react, and only eight-
membered ring formation was observed (only traces of seven-
Although we were successful in developing an extremely simple-
looking route to 1 and in demonstrating the power of the Pd
methodology for generating the dihydroindoloazocine system, we
were surprised and repeatedly humbled by the large number of
completely unforeseen roadblocks. Many key transformations in
alternative routes to 1, which a priori seemed likely to succeed,
failed completely. In many respects, the development of the
synthesis of 1, which is outlined in Scheme 1, was similar to finding
2
membered cyclization product could be detected). The yield of
the transformation 4 f 5 was not diminished upon scale-up to the
gram level. Exposure of 5 to excess diethylamine in THF at 0-23
°C for 6 h resulted in Fmoc cleavage and cyclization to form the
3
diketopiperazine 6 (95%). In principle, the synthesis of okaramine N
1
(1) from 6 might be accomplished by ∆g O
2
-mediated photooxi-
Scheme 1. Enantioselective Synthesis of Okaramine N
5628
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J. AM. CHEM. SOC. 2003, 125, 5628-5629
10.1021/ja034491+ CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Scheme 2. Synthesis of 3
Scheme 3. Reversible Ene Reaction of a Dihydroindoloazocine
with MTAD
In the introductory paragraph, it was stated that our attempts to
synthesize okaramine N by alternative routes led to the surprising
failure of reactions that we had expected to proceed in the required
way. For example, we were not able to cyclize methyl ester 12a or
acid 12b to the corresponding diketopiperazine under a wide variety
of conditions. In addition, many attempts to convert 13 to the
corresponding diketopiperazine met only with failure. Another
obstacle was presented by the tendency of tert-prenylated inter-
mediates such as 14 to undergo rapid ortho Claisen rearrangement
upon acid treatment or heating above 120 °C. Finally, attempts to
add the tert-prenyl group to des-tert-prenyl 1 at the end of the
synthesis were unsuccessful.
dation of the tert-prenylated indole subunit followed by cyclization.
In actuality, photooxidation of 6 occurs most rapidly at the
N-unsubstituted indole subunit. Further, when the tert-prenylated
1
indole subunit is attacked by ∆g O
2
, the predominating reaction
is cleavage of the indole 2,3-π-bond to form an N-formyl kynure-
nine system. These facts led us to develop a new method for the
selective differentiation of the two indole subunits of 6 that involves
a novel application of the commercially available “ene” reaction
reagent N-methyltriazolinedione (MTAD). The bisindole 6 under-
2 2
went highly selective reaction with MTAD in CH Cl at -5 °C
for 10 min to form exclusively the ene product at C(3) of the
N-unsubstituted indole subunit. Subsequent photooxidation (me-
thylene blue as a photosensitizer in MeOH at -28 °C for 7.5 h
with irradiation by a sunlamp) followed by reduction of the resulting
product by Me S in MeOH (from -28 to -10 °C over 3 h) afforded
2
the hydroxylated octacycle 7 cleanly together with a minor amount
of diastereomer (ratio of 7 to diastereomer of ca. 5). Thermolysis
of the mixture of 7 and the diastereomer at 110 °C for 30 min and
3
chromatographic isolation furnished okaramine N (1) in 70% yield
from 6, based on recovered 6 (ca. 50%, due to incomplete
photooxidation).
The synthesis of tert-prenylated indole 3 was accomplished as
illustrated in Scheme 2. (S)-N-Boc-tryptophan methyl ester was
In summary, the first synthetic route to a member of the
okaramine family of polycyclic bisindole alkaloids has been
developed by careful choreography of a number of powerful
synthetic transformations.
Acknowledgment. We are grateful to the National Institutes
of Health for a Postdoctoral Fellowship to P.S.B. and to the
Undergraduate Harvard College Research Program for a summer
fellowship to C.A.G. We thank Dr. H. Hayashi for spectra of
converted to the known indoline 8 in 60% yield using excess
4
NaBH
3
CN (10 equiv) in HOAc at 23 °C for 12 h. The tert-prenyl
group was installed with formation of 9 by the following se-
quence: (1) copper(I)-catalyzed alkylation with 2-acetoxy-2-methyl-
authentic 1.
3
-butyne (0.1 equiv of CuCl, 1.1 equiv of i-Pr
2
NEt, THF, reflux,
Supporting Information Available: Detailed experimental pro-
5
95%); (2) dihydroindole f indole dehydrogenation by treatment
cedures for all compounds and full characterization of compounds 1,
3, 4, 6, and 9 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
with DDQ (1.05 equiv, 0 °C, 20 min); and (3) selective reduction
of ethynyl to vinyl (1 atm H , cat. 10% Pd-C, MeOH containing
quinoline, 87% yield for two steps). The Boc-protecting group was
then removed from 9 (1.5 equiv of SOCl , MeOH, 50 °C for 2 h)
and the resulting amino ester was saponified to the amino acid (15
equiv of LiOH, THF-H O 3:1, 0 °C, 2 h). Schotten-Baumann
acylation of the amino acid with FmocCl (CH Cl added, 10%
aqueous Na CO , 1.1 equiv of FmocCl, 0 °C, 10 min, 81% overall
yield) gave 3.
2
References
2
(
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000, 64, 103-110 and 1519-1521. (b) Hayashi, H.; Furutsuka, K.;
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Crucial to the success of the synthesis of 1 which is outlined in
Scheme 1 was the use of the MTAD reagent for selectively
protecting one of the indole subunits in 6 so as to allow site-specific
photosensitized oxidation of the other (less reactive) indole subunit.
Selective and reversible thermal ene reaction of MTAD with an
indole derivative is further exemplified in Scheme 3 by the
instantaneous and quantitative conversion of 10 to 11 and the
reformation of 10 from 11 simply by heating. This is a new and
general process with considerable promise in the chemistry of
indoles that will be delineated in a separate publication.
(2) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904-7905.
(
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for 5, a hexanes-ether gradient; for 6, a hexanes-EtOAc gradient; and
2 2
for 1, MeOH-CH Cl or EtOAc.
(
4) For a previously reported four-step preparation of 8, see: Dinh, T. D.;
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(
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