Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 2244−2249
Synthetic Strategy toward the Pentacyclic Core of Melodinus Alkaloids Navya Goli,†,⊥ Shivakrishna Kallepu,† Prathama S. Mainkar,‡,⊥ Jerripothula K. Lakshmi,§ Rambabu Chegondi,∥,⊥ and Srivari Chandrasekhar*,†,⊥ †
Natural Products Chemistry Division, ‡Medicinal Chemistry & Biotechnology Division, §Centre for NMR and Structural Chemistry, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India ⊥ Academy of Scientific and Innovative Research (AcSIR), New Delhi, India ∥
S Supporting Information *
ABSTRACT: The three-component Povarov reaction is efficiently utilized for construction of the pentacyclic framework of complex Melodinus alkaloids, which is amenable to expansion to other complex natural products. The key steps were Povarov reaction, one-pot reductive cyclization, and ringclosing metathesis (RCM) reaction.
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tions16 prompted us to look at the alkaloid class of natural products and analogues.17 Recently, we have demonstrated a multicomponent reaction (Povarov reaction) between aniline, cyclopentadiene, and benzaldehyde as a decent approach to the tetrahydroquinoline library having neurotrophic activity.18 Herein we describe a racemic strategy for the synthesis of the pentacyclic framework of meloscine, an important constituent of the family of Melodinus alkaloids. The retrosynthetic analysis (Scheme 1) reveals an easy threecomponent coupling reaction as the best starting point to build the tricyclic core 6 through the Povarov reaction. Functional group maneuvers will easily allow one to build the D-ring of the tetracyclic frame 5, which, with proper handles, will lead to construction of the E-ring-embedded pentacycle 4 through olefin metathesis. On the basis of this strategy, we embarked on the synthesis of the pentacyclic frame of Melodinus alkaloids.
INTRODUCTION The Melodinus class of alkaloids (Figure 1) are structurally unique, incorporating a tetrahydroquinoline frame within the
Figure 1. Structures of Melodinus alkaloids.
Aspidosperma alkaloid architecture.1 The plant Melodinus scandens Forst2 is the source of three alkaloids, viz, meloscine (1), scandine (1b), epimeloscine (2), believed to be the oxidatively rearranged products of 18,19-dehydrotabersonine (3).3 Thus, biosynthetic genesis and correlation is hypothesized between Melodinus and Aspidosperma classes of alkaloids. Some classes of Melodinus alkaloids are used in Chinese folk medicine for the treatment of inflammation.4 Early approaches to synthesize these alkaloids relied on rearranging the Aspidosperma alkaloids. Overmann et al. in 1991 were the first to develop a synthetic strategy for meloscine and epimeloscine in racemic form, engaging 24 steps with 3−4% overall yield.5 The first and only enantioselective synthesis of (+)-meloscine was reported by Bach and Selig in 15 steps with 7% overall yield.6,7 A few other strategies, viz, cascade radical annulations of divinylcyclopropane,8,9 Pd-catalyzed cycloaddition,10,11 Pauson−Khand reaction,12 allenyl azide cycloaddition,13,14 and intramolecular [3 + 2]-cycloaddition via cyclopropane ring-opening, were also reported for the synthesis of these alkaloids.15 Interestingly, most of these strategies relied on cyclopropane chemistry. Our own interest in exploiting the natural product toolbox toward medicinal chemistry applica© 2018 American Chemical Society
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RESULTS AND DISCUSSION The Povarov reaction between aniline, cyclopentadiene, and ethyl glyoxalate catalyzed by CAN resulted in tetrahydroquinoline 6 in 68% yield.19 The protection of NH in the quinoline ring was carried out by treatment with acetyl chloride and triethylamine in CH2Cl2 with 70% yield. Further functionalization of the cyclopentene (C ring) was achieved through dihydroxylation with OsO4 and NMO, which furnished diol. Exploiting the steric hindrance at the 7-OH group, the diol was selectively protected at the 6-OH group with TBDPSCl and imidazole in CH2Cl2 to give silyl ether 11 in 64% yield with a 5:1 ratio of regioselectivity.20 The Dess−Martin periodinane21 mediated oxidation of the free hydroxyl group allowed us to generate tricyclic ketone 12 in 95% yield (Scheme 2), which further enabled us to functionalize the benzylic position in 12 to install the allyl Received: December 13, 2017 Published: January 16, 2018 2244
DOI: 10.1021/acs.joc.7b03138 J. Org. Chem. 2018, 83, 2244−2249
Article
The Journal of Organic Chemistry Scheme 1. Retrosynthetic Analysis of Meloscine
Scheme 2. Synthesis of Meloscine’s A, B, C, and D Ringsa
a
All structures represent racemates
group under mild conditions. Thus, 12 on treatment with K2CO3 and allyl bromide in acetone provided 13 in 94% yield, and its relative stereochemistry was confirmed by 2D NMR analysis (Supporting Information).22 The oxidative cleavage of terminal olefin in 13 with OsO4 and NaIO4 in an acetone− water mixture furnished keto aldehyde 14 in 74% yield. The stage was now set to construct the D-ring of the Melodinus alkaloids through reductive amination−cyclization in one pot by exposure of 14 to allyl amine and NaCNBH3 in methanol to provide the tetracycle 5, which now has an allyl handle for further transformations.23 Desilylation of compound 5 upon treatment with TBAF furnished alcohol 15 in 82% yield. The relative configuration of compounds 15 was determined by single-crystal X-ray crystallography.24 Parikh−Doering oxidation of alcohol 15 with SO3·Py/DMSO gave the corresponding ketone 16 in 81% yield (see Table 1 for optimization conditions).25 To construct the E-ring of the alkaloid, ketone 16 was treated with vinylmagnesium bromide to furnish diene 17 in 56% yield as a single diastereomer. The 2D NOESY and DFT calculations unambiguously support the defined stereochemistry.26 Initial attempts of the ring-closing metathesis (RCM) reaction with tertiary alcohol 17 were unsuccessful (Scheme 3). Thus, alcohol was protected as triethylsilyl ether 18, in the presence of
Table 1. Optimization Conditions for Oxidation of Compound 15 no.
reaction condition
% yielda
1 2 3 4 5 6
IBX/DMSO, THF, rt, 2 h IBX, tBuOH, 80 °C, 4 h (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, 3 h DMP, CH2Cl2, 0 °C to rt, 1 h CrO3/H2SO4, acetone, 0 °C, 1 h SO3·Py, DMSO, DIPEA, CH2Cl2, rt, 1 h
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