Total syntheses of leuconoxine, leuconodine B, and melodinine e by oxidative cyclic aminal formation and diastereoselective ring-closing metathesis

Article abstract of DOI:10.1021/ol500903e

Total syntheses of leuconodine B, melodinine E, and leuconoxine were accomplished via a divergent route. The [5.5.6.6]diazafenestrane skeleton was constructed from an indole-3-acetamide derivative via DMDO oxidation to hydroxylindolenine, TMSOTf/2,6-lutidine mediated cyclic aminal formation, and diastereoseletive ring-closing metathesis of a triene derivative.

Full text of DOI:10.1021/ol500903e

Letter
pubs.acs.org/OrgLett
Total Syntheses of Leuconoxine, Leuconodine B, and Melodinine E
by Oxidative Cyclic Aminal Formation and Diastereoselective Ring-
Closing Metathesis
Atsushi Umehara, Hirofumi Ueda, and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: Total syntheses of leuconodine B, melodinine
E, and leuconoxine were accomplished via a divergent route.
The [5.5.6.6]diazafenestrane skeleton was constructed from an
indole-3-acetamide derivative via DMDO oxidation to
hydroxylindolenine, TMSOTf/2,6-lutidine mediated cyclic
aminal formation, and diastereoseletive ring-closing metathesis
of a triene derivative.
lants of the genus Leuconotis, such as L. eugenifolia and L.
griffithii inhabiting Indonesia and Peninsular Malaysia,
of these monoterpene indole alkaloids, and initiated a research
program.
P
provide structurally diverse monoterpene indole alkaloids.
Among them, leuconoxine (1),1 isolated from L. eugenifolia,
leuconodine B (2)2 (a.k.a. scholarisine G2b), isolated from L.
griffithii, and the related compound, melodinine E (3),3
isolated from other genus Melodinus henryi Craib., possess an
unprecedented [5.5.6.6]diazafenestrane skeleton containing an
aminal functionality and a quaternary carbon center (Figure 1).
So far, we have completed the total syntheses of
(−)-rhazinilam (5a) and (−)-rhazinicine (5b) by utilizing our
originally developed gold-catalyzed cascade double cyclization.8i
In addition, a concise total synthesis of (−)-mersicarpine (6)
was achieved by employing regiospecific reductive ring
expansion of cyclic oxime with DIBALH for key construction
of an azepino[3,2-b]indole skeleton.11f,g Recently, Zhu and co-
workers established an elegant unified synthesis to provide
(−)-leuconoxine (1), (−)-leuconodine B (2), (+)-melodinine
E (3), (−)-leuconolam (4), and (−)-mersicarpine (6).12
Herein we describe the total syntheses of leuconoxine (1),
leuconodine B (2), and melodinine E (3) via a divergent route
featuring an oxidative cyclic aminal formation and a
diastereoselective ring-closing metathesis.
A retrosynthetic analysis is outlined in Scheme 1.
Considering that leuconoxine (1) and melodinine E (3) should
be easily derived from leuconodine B (2) by deoxygenation and
dehydration, respectively, we designed a divergent route to
these compounds via leuconodine B (2) as a pivotal
intermediate. We envisioned that the characteristic [5.5.6.6]-
diazafenestrane skeleton would be constructed by sequential
cyclizations including an oxidative cyclic aminal formation13
using indole-3-acetamide 8 and a diastereoselective ring-closing
olefin metathesis using triene 7.14 The quaternary gem-divinyl
carbon center on the indole C2 position of compound 8 would
be constructed via an intramolecular Mizoroki−Heck reaction15
of N-acyl-2-iodoindole 9 having an ethylidene moiety on the
acyl chain. N-Acylindole 9 should be readily assembled by
condensation of 2-iodoindole-3-acetate 1016 with carboxylic
acid 11.
Figure 1. Structures of leuconoxine, rhazinilam, mersicarpine, and
their congeners.
In addition to their intriguing structures, these compounds have
attracted considerable attention from a biosynthetic point of
view.4 Thus, it was suggested that these compounds would be
biosynthesized from Aspidosperma alkaloids,5 through leucono-
lam (4), which is related to antitumor (−)-rhazinilam (5a).6−9
Furthermore, Kam and co-workers proposed that melodinine E
(3) would be biogenetically converted to (−)-mersicarpine
(6),10−12 which possesses an unusual azepino[3,2-b]indole ring
system. We became interested in the highly diverse ring
systems, as well as the proposed biosynthetic interrelationship
The synthesis commenced with preparation of N-acylindole-
3-acetate 9 (Scheme 2). Baeyer−Villiger oxidation of 1,4-
Received: March 26, 2014
Published: April 22, 2014
© 2014 American Chemical Society
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Letter
Boc2O followed by addition of 10 in the presence of DMAP
and Et3N was effective to furnish the desired acylindole 9 in a
good yield.
Scheme 1. Retrosynthetic Analysis
An intramolecular Mizoroki−Heck reaction of 9 in the
presence of Pd2(dba)3·CHCl3, P(o-tol)3, 1,2,2,6,6-pentamethyl-
piperidine (PMP) proceeded smoothly to provide the expected
δ-lactamindole 15 in a satisfactory yield with concomitant
formation of a quaternary carbon center (Scheme 3).11g,15,19
Scheme 3. Construction of Quaternary Carbon Center and
Conversion to Indole-3-acetamide 8
Scheme 2. Preparation of N-Acylindole 9
The gem-divinyl group was then formed by removing the TBS
group and subsequent dehydration of the resultant primary
alcohol by the Grieco−Nishizawa protocol.20 Finally, methyl
ester 16 was converted to N-allylamide 8 by demethylation
using a combination of TMSCl and NaI and condensation of
the resultant carboxylic acid with allylamine in the presence of
HATU and Hunig’s base.
̈
Having prepared the indole-3-acetamide 8 in hand, we then
turned to the crucial oxidative cyclic aminal formation.
Treatment of 8 with DMDO21 or Davis’ oxaziridines22 as
oxidants did not promote the expected sequential oxidative
cyclization starting from the oxidation of the indole C2−C3
bond, ring opening, and cyclization to form the cyclic aminal
product 7. However, the starting compound 8 was simply
recovered (Scheme 4). The low reactivity of 8 toward oxidants
should be attributed to an insufficient electron density of the
cyclohexanedione (12) with m-CPBA17 gave ketolactone 13,
which was converted to ketoester 1418 by methanolysis and
protection of the resultant alcohol as TBS ether. Wittig reaction
of ketoester 14 was not straightforward and required careful
optimizations. The desired ethylidene product was obtained as
an E/Z mixture in 39% yield at best with recovery of 14 (37%)
when the reaction was carried out at −78 °C. After the reaction
proceeded through four cycles, an ethylidene product was
obtained in 57% total yield, which was then saponified with
LiOH·H2O to provide carboxylic acid 11. Unexpectedly,
condensation of carboxylic acid 11 with 2-iodoindole-3-acetate
10 under the conventional dehydration conditions or using the
corresponding acid chloride resulted in poor yields. After
extensive optimizations, we found that treatment of 11 with
Scheme 4. Attempts for Oxidative Cyclization
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Organic Letters
Letter
indole ring, so we decided to cleave the lactam ring and
examined the oxidation reaction. Thus, methyl ester 19, which
was obtained by treating 8 with sodium hydroxide and
subsequently with trimethylsilyldiazomethane, was subjected
to DMDO oxidation (Scheme 5). The expected oxidation of
the unsuccessful results, possibly due to the activation of the
imine moiety with Lewis acids, we then turned to the activation
of the amide moiety.24 In fact, we have observed significant
acceleration of the cyclic aminal formation upon treating
hydroxyindolenine 20 with a combination of TMSOTf and 2,6-
lutidine to afford the desired aminal product 24 in 93% yield
without formation of oxindole 21 (entry 3).25 We reasoned that
the facile cyclization should be attributed to the formation of a
sily imidate intermediate to enhance the inherent nucleophil-
icity of the amide moiety.24
Scheme 5. Preparation of Hydroxyindolenine 20
The remaining task in synthesizing leuconodine B (2) was to
construct the crucial [5.5.6.6]diazafenestrane framework by
ring-closing metathesis. Before the key ring-closing metathesis
was examined, the δ-lactam ring was formed by treating aminal
24 with t-BuOK with concomitant removal of the TMS group
(Scheme 6). The expected ring-closing metathesis of triene 7
Scheme 6. Total Synthesis of Leuconodine B (2)
the indole C2−C3 bond proceeded smoothly at −78 °C to
afford hydroxyindolenine 20 in a high yield. Unfortunately, the
following intramolecular aminal formation did not take place,
despite an elevated reaction temperature and prolonged
reaction time.
The failure of the sequential oxidative aminal cyclization
prompted us to establish a stepwise protocol for cyclic aminal
formations. A possible side reaction during the cyclization of a
hydroxyindolenine such as 20 is a rearrangement reaction to
afford a 3,3-disubstituted oxindole derivative, which was
reported by Movassaghi et al.23 As anticipated, the treatment
of hydroxyindolenine 20 with BF3·Et2O gave 3,3-disubstituted
oxindole 21 with recovery of starting compound 20 (Table 1,
entry 1). It was proposed that the rearrangement was initiated
by the formation of epoxide 22 and a subsequent ring opening
to give 23, followed by a semipinacol rearrangement to provide
3,3-disubstituted oxindole 21.23 A reaction using Sc(OTf)3 also
provided undesired oxindole 21 in 60% yield (entry 2). Given
proceeded quite smoothly by heating with Hoveyda−Grubbs
second generation26 catalyst to furnish the pentacyclic[5.5.6.6]-
diazafenestrane compound 25 as a sole isomer. The complete
diastereoselectivity can be explained by starting with the
reaction at the N-allyl moiety, followed by a ring-closing
metathesis with one of the two vinyl groups to form a more
thermodynamically stable piperidine ring. Finally, a total
synthesis of leuconodine B (2) was completed by hydro-
genation of two olefinic bonds.
Table 1. Optimization of Cyclic Aminal Formation
Having established a synthetic route to leuconodine B (2),
we then focused our attention on converting the pivotal
intermediate leuconodine B (2) to leuconoxine (1) and
melodinine E (3) (Scheme 7). First, the hydroxy group in
leuconodine B (2) was reductively removed through its
xanthate. Thus, alcohol 2 was treated sequentially with sodium
hydride, carbon disulfide, and iodomethane to obtain methyl
xanthate 26, which was subjected to standard Barton−
McCombie deoxygenation to furnish leuconoxine (1). In
addition, the elimination12 reaction of xanthate 26 took place
by employing DBU and microwave heating to afford
melodinine E (3). The spectroscopic data of these synthetic
compounds were identical to those reported in the
literature.3,6b,27
yield (%)
In summary, we have accomplished divergent total syntheses
of three monoterpene indole alkaloids: leuconoxine (1),
leuconodine B (2), and melodinine E (3). For the construction
of the characteristic [5.5.6.6]diazafenestrane skeleton, we have
devised a strategy consisting of an oxidative cyclic aminal
formation and a diastereoselective ring-closing metathesis.
entry
reagents (equiv)
temp
time
21
24
1
2
3
BF3·OEt2 (1.0)
Sc(OTf)3 (1.0)
TMSOTf (2.05)
2,6-lutidine (2.05)
0 °C to rt
0 °C to rt
0 °C
3 h
20
60
0
0
0
3 h
5 min
93
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(8) For synthesis of ( )-rhazinilam, see: (a) Ratcliffe, A. H.; Smith,
G. F.; Smith, G. N. Tetrahedron Lett. 1973, 52, 5179. (b) Johnson, J.
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K.; Ueda, H.; Tokuyama, H. Angew. Chem., Int. Ed. 2013, 52, 7168.
Scheme 7. Total Syntheses of Leuconoxine (1) and
Melodinine E (3)
́ ́
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and procedures, compound character-
1
ization data, copies of H and 13C NMR spectra for all new
compounds. This materials is available free of charge via the
Internet at http://pubs.acs.org.
(14) Fukuda, Y.; Shindo, M.; Shishido, K. Org. Lett. 2003, 5, 749.
(15) For a review on the intramolecular Mizoroki−Heck reaction,
see: Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(16) (a) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T.
Synthesis 2000, 429. (b) Tokuyama, H.; Fukuyama, T. Chem. Rec.
2002, 2, 37.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: tokuyama@mail.pharm.tohoku.ac.jp.
Notes
(17) Van der Ende, A. E.; Kravitz, E. J.; Harth, E. J. Am. Chem. Soc.
2008, 130, 8706.
The authors declare no competing financial interest.
(18) Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L. J. Am.
Chem. Soc. 2010, 132, 3009.
(19) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman,
L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
(20) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
(21) A selected report on the oxidation of indoles with DMDO, see:
Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964.
(22) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
(23) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett.
2008, 10, 4009.
(24) Downey, C. D.; Fleisher, A. S.; Rague, J. T.; Safran, C. L.;
Venable, M. E.; Pike, R. D. Tetrahedron Lett. 2011, 52, 4756.
(25) A reaction with 1 equiv of TMSOTf gave 24 (48%) and the
corresponding alcohol product 24′ (25%). In addition, a reaction with
TBSOTf gave the alcohol 24′ in 88% yield, indicating silylation of the
hydroxy group in 20 was not key to preventing the rearrangement to
the oxindole (see Supporting Information).
ACKNOWLEDGMENTS
■
This work was financially supported by the Cabinet Office,
Government of Japan through its Funding Program for Next
Generation World-Leading Researchers (LS008), a Grant-in aid
for Young Scientists (B) (24790003) (for H.U.), and Platform
for Drug Discovery, Informatics, and Structural Life Science
from the MEXT, Japan.
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