Double annulative cascade of tryptophan-containing peptides triggered by selectfluor

Article abstract of DOI:10.1021/ol403281t

A common dearomative strategy toward the kapakahines B/F and chaetominine natural products is reported. The proposed biomimetic strategy generates the tetracyclic α-carboline core in a single step, featuring a selectfluor-mediated dearomatization of preactivated N-Phth-Trp-Xaa-OR dipeptides at the C-terminus. The pivotal cascade includes a double annulation and the formation of three carbon-heteroatom bonds while gaining, for the first time, some insight on the diastereoselectivity outcome during the formation of the α-carboline fragment.

Full text of DOI:10.1021/ol403281t

Letter
pubs.acs.org/OrgLett
Double Annulative Cascade of Tryptophan-Containing Peptides
Triggered by Selectfluor
Bret Treguier and Stephane P. Roche*
́
́
Department of Chemistry and Biochemistry, Florida Atlantic University, Physical Science Building, 777 Glades Road, Boca Raton,
Florida 33431, United States
S
* Supporting Information
ABSTRACT: A common dearomative strategy toward the kapakahines B/F and chaetominine natural products is reported. The
proposed biomimetic strategy generates the tetracyclic α-carboline core in a single step, featuring a selectfluor-mediated
dearomatization of preactivated N-Phth-Trp-Xaa-OR dipeptides at the C-terminus. The pivotal cascade includes a double
annulation and the formation of three carbon−heteroatom bonds while gaining, for the first time, some insight on the
diastereoselectivity outcome during the formation of the α-carboline fragment.
he kapakahine natural products are a family of six cyclic
peptides isolated from the marine sponge Cribrochalina
olemda by Scheuer, including the most active metabolite
kapakahine B (1, Figure 1) having antileukemia activity (IC50 of
center, supposedly arising from a facial discrimination via an
anti-approach of the electrophile (away from N-Trp) during
the dearomatization step.
α
T
A similar anti-relationship is observed in both natural
products 1/2 and 3, which could arise from analogous
biosynthetic pathways in the Cribrochalina olemda and
Chaetomium sp. organisms. Based on this hypothesis, we
decided to examine a common dearomative strategy for both
families of natural products (Figure 1). Our approach takes
advantage of a peptidic activation at the C-terminus esters to
enable an unprecedented cascade transformation, forming three
carbon−heteroatom bonds consecutively in a single step. While
dearomative cyclization of Trp building blocks to hexahydro-
[2,3-b]pyrroloindole (HPI) fragments has been extensively
studied, providing high exo-selectivity,3 we are now reporting
for the first time the stereochemical outcome for the synthesis
of several hexahydro[2,3-b]pyridoindole (α-carboline) skeleton.
Previously, Papeo, Snider, Evano, Huang, Rainer, and Baran
reported elegant constructions of the tricyclic skeleton (A, B,
and C rings) during their total syntheses campaigns to the
kapakahines B/F (1−2)4 and chaetominine (3).5 All previous
synthetic strategies exploit the chiral pool as starting material
(L- or D-tryptophans and corresponding dipeptides) for the key
dearomatization step, but none of these syntheses achieved the
assembly of the full tetracyclic core in a single operation.
Our biomimetic tactic to form the tetracyclic α-carboline in a
single step requires mild oxidative conditions which will not
only dearomatize the activated dipeptide 4, but will also be
amenable to the overall cascade of events (Figure 1).
Dearomatized indolenium 5 should then undergo intra-
molecular cyclization at the C-2 position to unveil a
Figure 1. Hypothesis for a unified biomimetic construction of the
tetracyclic α-carboline core of natural products (1−3).
5.4 μM) against P388 murine leukemic cells.1 A related
alkaloidal metabolite, chaetominine (3) was isolated from the
fungus Chaetomium sp. by Tan and presents even more
important cytotoxic activity against the human leukemic K562
and colon cancer SW1116 cell lines with the corresponding
IC50 values of 21.0 and 28.0 nM.2 Chaetominine (3) and the
kapakahine metabolites 1−2 have similar architectural features
that drew us to propose a unified biomimetic design to access
both tetracyclic α-carboline skeletons 6 (Figure 1). The
substituents at the fused junction of the B and C rings present
an anti stereorelationship to the tryptophan (Trp) α-nitrogen
Received: November 13, 2013
Published: December 11, 2013
© 2013 undefined
278
dx.doi.org/10.1021/ol403281t | Org. Lett. 2014, 16, 278−281

Organic Letters
Letter
nucleophilic sec-aniline which would collapse onto the activated
ester to form the last required peptidic bond of the tetracyclic
α-carboline 6. Such double annulative strategy6 would complete
the expedient entry to both families of natural products.
As anticipated, the dearomative cascade transformation of
unprotected dipeptides 7−10 and 16 proved to be a difficult
task. Most of the typical oxidative reagents known to achieve
indole dearomatization were screened: tBuOCl, NBS, NCS,
Selectfluor, Br2, N-PSP, Oxone, m-CPBA, DMDO, Davis’
oxaziridine, iodine(III) reagents (PIDA, PIFA), and others.7
tetracyclic α-carboline 11 in 35% and 27% yield, respectively
(entries 2 and 9). Surprisingly, both substrates 9 and 10
showed an opposite innate diastereofacial selectivity when
reacting with Selectfluor, as much as 1.0:1.2 to 1.3:1.0 anti-syn
ratios, respectively. These results diverge from the typical syn-
selectivity (also called exo-selectivity) reported for most
halocyclizations forming HPIs.3 Reactions performed without
base lead mostly to decomposition (entries 3 and 4). To date,
the standard conditions in acetone with NaHCO3 proved to be the
most reproducible and general in respect of all dipeptide substrates
tested in the cascade reaction.
1
Reactions were followed by H NMR, and after addition of
We then screened chiral quinuclidine Cinchona alkaloidic
dimers known to synergistically react with Selectfluor
promoting enantioselective fluorination reactions (entries 5−
8, 10, and 11).11 As suggested in previous work, different
orientation of the substrates inside of the dimeric alkaloid
pocket can occur depending on the type of ligand used (PHAL,
PYR or AQN) which will greatly affect the reaction
stereochemical-outcome.12 We observed such situation (entries
5−8) as shown by the inefficacy of (DHQ)2PYR in promoting
the cascade (entry 5), while both PHAL and AQN frameworks
enable the cascade, leading to the desired tetracyclic compound
11 in 28% and 31% yield respectively (entries 6 and 7).
Encouraged by the noticeable increase in facial-selectivity when
using (DHQ)2PHAL (entry 7; 1.8:1.0 dr), we tested the
catalytic version of the reaction, for a catalyst-controlled
cascade. This attempt yielded compound 11 in only 13% (no
catalysis observed) with a surprising reversal of stereoselectivity
leading to the syn-product 11 as major diastereomer (1.0:1.8
dr). Reaction in acetonitrile afforded the anti-product 11 with a
much higher anti-stereoselectivity (3.7:1.0 dr) in 20% yield
(entry 8). Finally, dipeptide 10 was subjected to the cascade
upon fluorination with (DHQ)2PHAL in acetone and
acetonitrile (entry 10 and 11) to deliver the desired anti-
product 11 respectively in 37% yield (2.9:1.0 dr) and 34% yield
(4.1:1.0 dr). The use of (DHQ)2PHAL enabled a complete switch
and an increase in antidiastereoselectivity for the cascade reaction
affording the desired α-carboline anti-11. Anti and syn products
11 relative stereochemistry were determined by NOE studies.7
Our first study completed, we prepared the suitable precursor
for the dearomatization step in large scale (Scheme 1). Trp was
first protected to the N-Phth-Trp-OH 13. Compound 13 was
engaged directly in a one pot coupling-hydrolysis sequence in
tetrahydrofuran using first EDCi-HOBt as activators and
lithium hydroxide for the in situ saponification to yield
dipeptide N-Phth-Trp-Phe-OH 15 in 84%. Finally, decagram
quantities of activated dipeptide N-Phth-Trp-Phe-OC6F5 16
two-thirds of the oxidant, no starting dipeptides remained in
solution,7 confirming that a destructive pathway through
elimination and overoxidation of the indolic core may occur.8
From this extensive study on dipeptide dearomatization,
Selectfluor was found to be the only reagent to successfully
initiate the dearomatization and achieve the cascade in valuable
yields.9
The cascade triggered by Selectfluor was first examined on
activated dipeptides N-Phth-Trp-Gly-OR 7−10 (Table 1).7,9b
Dearomatization of a dipeptide methylester 7 did not enable
the cascade to take place; instead, a sensitive indolenine
product 12 was isolated.10
Table 1. Initial Discovery of a Dearomative Cascade of
Unprotected Indole To Form the Tetracyclic α-Carboline 11
a
b
entry
dipeptide/solvent/additive
% yield (anti-syn dr)
1
8/acetone/−
9/acetone/−
9/acetone/−
0
2
35 (1.0:1.2)
0
c
3
4
9/acetonitrile/−
0
5
9/acetone/(DHQ)2PYR
0
6
9/acetone/(DHQ)2AQN
28 (1.1:1.0)
31 (1.8:1.0)
20 (3.7:1.0)
27 (1.3:1.0)
37 (2.9:1.0)
34 (4.1:1.0)
d
7
9/acetone/(DHQ)2PHAL
8
9/acetonitrile/(DHQ)2PHAL
10/acetone/−
10/acetone/(DHQ)2PHAL
9
10
11
10/acetonitrile/(DHQ)2PHAL
a
Reagents: Selectfluor (1.2 equiv), NaHCO3 (1.2−2.0 equiv), additive
(1.2 equiv), solvent [0.01 M]. See the Supporting Information for
b
detailed procedures. Anti-syn diastereomeric ratios determined by 1H
c
NMR analysis of the crude reaction mixtures. No base was used.
d
Scheme 1. Synthesis of Activated Dipeptide N-Phth-Trp-
When (DHQ)2PHAL was used in a catalytic amount (20 mol %),
a
Phe-OPFP 16
product 11 was isolated in 13% yield (1.0:1.8 dr).
This result endorses Evano’s approach in which the α-
carboline unit was obtained with unavoidable overoxidation.5c
Thus, several known C-terminus activating groups for peptide
assembly were tested on dipeptides 8−10 to facilitate the
cascade. Dearomatization of the activated N-hydroxysuccini-
mide dipeptide ester 8, proved unsuccessful, leading mostly to
decomposition (entry 1). Then we turned our attention to
phenolic activated ester (pentafluorophenol) 9 and (p-
chlorophenol) 10 (entries 2−11). Both dipeptide 9 and 10
readily endure the dearomatization upon addition of Selectfluor
and underwent the double annulative cascade to furnish the
a
For a study on dipeptides 14 and 16 epimerization, see the
Supporting Information.
279
dx.doi.org/10.1021/ol403281t | Org. Lett. 2014, 16, 278−281

Organic Letters
Letter
were prepared in 73% yield, requiring no chromatography
purification through the overall three-step sequence. To our
surprise, the activated dipeptide 16 is extremely sensitive to
decomposition (silica or alumina flush), it required careful
handling and was found to be fully epimerized.7 We also
observe that high level of epimerization (19%) occurred during
the preparation of dipeptide 14.7,13 Results of an intensive
effort to synthesize the rather simple dipeptide 14, HATU/2,6-
lutidine was found to be the best activating protocol to deliver
14 in 98% yield with less epimerization (10%).7 Unfortunately,
these efforts appeared rather futile, because of the unavoidable
racemization occurring (αH Phe or Ala residues) during the
final activation step with pentafluorophenol, leading to
dipeptide 16 as a 1:1 epimeric mixture.7 1H NMR studies
confirmed that the synthetic Trp-containing dipeptides are
epimerized and not mixtures of rotamers.14
Table 2. Cascade Reaction en Route to Chaetominine (3)
entry
additive
% yield (anti:syn:epi-anti: epi-syn dr)
1
2
29% (1.1:1.6:1.0:1.2)
25% (1:10:1:5)
(DHQ)2PHAL
Figure 2 proposes an explanation for the observed
diastereoselectivity during dearomatization of the Trp-contain-
The 1:1 epimeric mixture of dipeptide 16 was used for the
key dearomatization step to determine the level of selectivity
during the dearomative cascade reaction (Scheme 2). Under
Scheme 2. Cascade Reaction to Produce the Tetracyclic
Core 17 in a Single Step with Facial Syn-Stereoselectivity
a
Figure 2. Proposed arrangements of dipeptide 18 for syn vs anti
stereoselectivity mediated by (DHQ)2PHAL.
ing dipeptides 18 with the Cinchona alkaloid (DHQ)2PHAL.16
Based on reported models by Corey, we envisioned that both
side of the (DHQ)2PHAL dimer play a role in the reaction; the
methoxyquinoline moiety promoting π-interaction with the
indolic aromatic core while the quinuclidine will promote the
electrophilic fluorination reaction from the other side.17
Stereochemical outcome of the cascade proved to depend on
the bulkiness of the Xaa residue side chain (Gly vs Ala vs Phe)
and the C-terminus peptidic activating group. While we were
able to completely reverse the diastereoselectivity by using
(DHQ)2PHAL on the model glycine derivative 9 (Table 1,
entry 11), both dipeptides 16 and 18, having larger side chains,
which may sterically clash with the quinuclidine moiety,
afforded preferentially the more favorable syn-diastereomer
arrangement.
In summary, we developed a novel double-annulative cascade
reaction initiated by a fluorine-mediated dearomatization which
demonstrates our ability to construct tetracyclic α-carboline
architectures in a single step with reasonable diastereoselectiv-
ity. This strategy is the most efficient to date to build the
stereochemically dense tetracyclic α-carbolines and the result of
our design using a peptidic C-terminus activation mode to
conclude the cascade.6 Finally, C−F bond functionalizations18
at the B−C ring junction to finalize both kapakahines B/F and
chaetominine total syntheses are in progress and will be
reported in due course.
a
Innate anti-syn diastereocontrol (3:5 dr).
the aforementioned optimized dearomative conditions, the
tetracyclic α-carboline 17 was obtained in 42% yield as a
mixture of four separable diastereomers (2.0:1.0:1.0:4.0;
anti:syn:epi-anti:epi-syn dr). Product 17 was not isolated in
equimolar ratio of epimers, but in a 3:5 ratio overall (syn/anti vs
epi-syn/epi-anti). This result shows that a kinetic resolution15,7
is likely operating during the reaction, leading to the epi-syn-17
diastereomer as major product. The diastereomers were
separated and relative stereochemistry was confirmed by
NOE studies and X-ray characterization of epi-syn-11 (Scheme
2). Dearomative cascade using (DHQ)2PHAL was then
logically attempted on dipeptide 16 to counteract the kinetic
resolution and promote the desired anti-diastereodiscrimina-
tion. Unfortunately, the reaction proceeded in extremely low
yields (5−13%) without improving the desired anti-diaster-
eoselectivity (2.5:5.0: 1.0:1.0; anti:syn:epi-anti:epi-syn dr).7
Facing this unexpected diastereoselectivity issues, we then
examined the reactivity of N-Phth-D-Trp-Ala-OPFP dipeptide
18 for an approach to chaetominine (3) (Table 2). Dipeptide
18 successfully underwent the cascade to afford tetracyclic α-
carboline 19 in 29% yield (entry 1), while the innate substrate-
induced diastereocontrol is quasi-non existent (1.1:1.6:1.0:1.2;
anti:syn:epi-anti:epi-syn dr).7 To finalize our study, reaction was
also attempted in presence of (DHQ)2PHAL (entry 2). In this
case, an impressive syn-selectivity was observed with an overall
15:2 syn/anti-diastereomeric ratio.7
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral and crystallo-
graphic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
280
dx.doi.org/10.1021/ol403281t | Org. Lett. 2014, 16, 278−281

Organic Letters
Letter
Am. Chem. Soc. 2001, 123, 7001. (c) Wang, M.; Wang, B. M.; Shi, L.;
Tu, Y. Q.; Fan, C. A.; Wang, S. H.; Hu, X. D.; Zhang, S. Y. Chem.
Commun. 2005, 5580. (d) Fukuzumi, T.; Shibata, N.; Sugiura, M.;
Nakamura, S.; Toru, T. J. Fluorine Chem. 2006, 127, 548.
(12) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998,
39, 2507.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sroche2@fau.edu.
Notes
1
The authors declare no competing financial interest.
(13) H NMR and OR analyses of N-Phth-Trp-Xaa-OMe dipeptides
showed clearly the level of epimerization of the Xaa residue. This
observation was not reported in earlier work: ref 3b and 4b,c.
(14) Hu, D. X.; Grice, P.; Ley, S. V. J. Org. Chem. 2012, 77, 5198.
(15) A kinetic resolution could be occurring (see also Table 2 entry
2; 11:6 epimeric ratio of product 19), but the low yields obtained for
products 17 and 19 may also be the result of a severe decomposition
of one of the epimers unable to undergo the cascade.
(16) Yin, Q.; You, S.-L. Org. Lett. 2013, 15, 4266.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from Florida
Atlantic University, Prof. M. Pink (Indiana University) for X-
ray analysis, and Dr. A. Kleinke (Dart Neuroscience) for helpful
scientific discussions and editing this manuscript.
(17) (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1994, 116, 12109. (b) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda,
N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47,
4157.
(18) Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur,
V. Org. Lett. 2012, 14, 2754.
REFERENCES
■
(1) (a) Nakao, Y.; Yeung, B. K. S.; Yoshida, W. Y.; Scheuer, P. J.;
Kelly-Borges, M. J. Am. Chem. Soc. 1995, 117, 8271. (b) Yeung, B. K.
S.; Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer, P.
J.; Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168. (c) Nakao, Y.; Kuo,
J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5, 1387.
(2) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.; Ding, H.; Xu, C.; Zhu, H.
L.; Tan, R. X. Org. Lett. 2006, 8, 5709.
(3) For selected examples of high exoselectivity in hexahydro[2,3-b]
pyrroloindole syntheses, see: (a) Marsden, S. P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143. (b) May, J. P.;
Patrick, B. O.; Perrin, D. M. Synlett 2006, 3403. (c) Iwasa, E.;
Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078. Review: (d) Iwasa, E.;
Hamashima, Y.; Sodeoka, M. Isr. J. Chem. 2011, 51, 420.
NOTE ADDED AFTER ASAP PUBLICATION
References 5e−f were added on January 3, 2014.
■
(4) (a) Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc.
2009, 131, 6360. (b) Newhouse, T.; Lewis, C. A.; Eastman, K. J.;
Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119. (c) Espejo, V. R.;
Rainier, J. D. Org. Lett. 2010, 12, 2154. (d) Rainier, J. D.; Espejo, V. R.
Isr. J. Chem. 2011, 51, 473.
(5) (a) Snider, B. B.; Wu, X. Org. Lett. 2007, 9, 4913. (b) Toumi, M.;
Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027. (c) Coste,
A.; Karthikeyan, G.; Couty, F.; Evano, G. Synthesis 2009, 2927.
(d) Malgesini, B.; Forte, B.; Borghi, D.; Quartieri, F.; Gennari, C.;
Papeo, G. Chem.Eur. J. 2009, 15, 7922. (e) Huang, P.-Q.; Liu, L.;
Peng, Q. Method for synthesizing cytotoxic alkaloid chaetominine and
its epimer. Faming Zhuanli Shenqing Gongkai Shuomingshu. Chinese
Patent CN 101463074 A, June 24, 2009. (f) Simultaneously to our
work a communication was reported for an expedient synthesis of
chaetominine, see: Peng, Q.-L.; Luo, S.-P.; Xia, X.-E.; Liu, L.-X.;
Huang, P.-Q. Chem. Commun. 2013, DOI: 0.1039/C3CC48833K.
(6) (a) Gonzalez-Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R.
Tetrahedron 2007, 63, 9229. (b) Gonzalez-Vera, J. A.; Garcia-Lopez,
M. T.; Herranz, R. J. Org. Chem. 2007, 72, 5395. (c) Ventosa-Andres,
P.; Gonzalez-Vera, J. A.; Valdivielso, A. M.; Garcia-Lopez, M. T.;
Herranz, R. Bioorg. Med. Chem. 2008, 16, 9313. See also refs 5e,f for a
similar tactic of double annulation under neutral conditions.
(7) See the Supporting Information for a complete list of screening
conditions and experimental details.
(8) For an example of a cascade reaction highlighting the issue of
substrate overoxidation, see the elegant work from Evano: refs 5b,c.
(9) (a) Shibata, N.; Tarui, T.; Doi, Y.; Kirk, K. L. Angew. Chem., Int.
Ed. 2001, 40, 4461. (b) Lozano, O.; Blessley, G.; Martinez, d. C. T.;
Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman,
R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105.
(10) Dearomatization of dipeptide 7 afforded the chlorinated α-
carboline 12, whose chlorination may result from fluoride−chloride
exchange via a plausible carbocation intermediate.
(11) (a) Cahard, D.; Audouard, C.; Plaquevent, J. C.; Roques, N. Org.
Lett. 2000, 2, 3699. (b) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J.
281
dx.doi.org/10.1021/ol403281t | Org. Lett. 2014, 16, 278−281