synthesis of natural products with polycyclic systems
TRANSCRIPT
March 2013 251Chem. Pharm. Bull. 61(3) 251–257 (2013)
© 2013 The Pharmaceutical Society of Japan
Synthesis of Natural Products with Polycyclic SystemsSatoshi Yokoshima
Graduate School of Pharmaceutical Sciences, Nagoya University; Furo-cho, Chikusa-ku, Nagoya 464–8601, Japan.
Received November 29, 2012
Herein we present our unique strategies to synthesize natural products. To prepare mersicarpine, an atypical indole alkaloid, our procedure features an Eschenmoser–Tanabe fragmentation to synthesize an alkyne unit, a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization to construct the indole skeleton, and a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Addition-ally, we synthesized a frog poison, histrionicotoxin, via a chirality transfer from an allenylsilane to prepare a pseudosymmetrical dienyne, dienyne metathesis to produce an optically active bicyclo [5.4.0] system, and an asymmetric propargylation. To synthesize lyconadin A, a Lycopodium alkaloid, a combination of an aza-Prins reaction and electrocyclic ring opening constructed the highly fused tetracyclic compound. The synthe-sis of isoschizogamine features a facile construction of the carbon framework through a Wagner–Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring-closing metathesis via a hemiaminal ether.
Key words natural product; alkaloid; total synthesis; polycyclic system
1. IntroductionIn synthetic organic chemistry, the total syntheses of natu-
ral products have realized various methods. Because the com-plex structures of target molecules require well-considered synthetic strategies, they often inspire the development of novel reactions. Transformations of densely functionalized molecules provide opportunities to discover novel phenom-ena. Consequently, expanding synthetic organic chemistry has had a positive influence on drug development, including the construction of chemical libraries, derivatization of lead com-pounds, and large-scale preparation of drugs and drug can-didates. Hence, we have focused on continuing our synthetic studies on natural products. In this review article, our recent syntheses of four natural products with polycyclic systems are introduced.
2. Synthesis of MersicarpineMersicarpine (1), which was first isolated from the Kopsia
plant species by Kam and coworkers,1) is a highly oxidized indole alkaloid with an atypical tetracyclic structure where a nitrogen atom is substituted at the indoline 3-position and forms a seven-membered cyclic imine. A hemiaminal and a quaternary carbon are contiguously arranged adjacent to the imine. This intriguing molecule has attracted much attention, and four total syntheses, including ours, have been reported to date.2–5)
Chart 1 depicts our synthesis of mersicarpine (1). First, the quaternary carbon was constructed according to d’Angelo’s procedure.6) A Michael addition of imine 3, which was de-rived from ketone 2 and (S)-phenylethylamine, and subsequent hydrolysis furnished 4 regio- and diastereoselectively in 78%
yield and 87%ee. Recrystallization of the corresponding semicarbazone improved the optical purity to 99% ee. Oxida-tion of ketone 4 with IBX7) followed by epoxidation afforded epoxyketone 6, which was subjected to Eschenmoser–Tanabe fragmentation.8) However, treatment of 6 with tosyl or nosyl hydrazide recovered the starting material. Additionally, em-ploying aminoaziridines as reagents for the same type trans-formation did not provide the desired product.9) The poor reactivity of the ketone might be attributed to the presence of the quaternary carbon adjacent to the carbonyl group. After extensive investigations we found that 6 reacted with semi-carbazide, giving semicarbazone 7. According to Warkentin’s procedure,10) 7 was oxidized with lead tetraacetate to form the 1,3,4-oxadiazoline intermediate, which underwent an Eschen-moser–Tanabe-type fragmentation to afford 8 in 60% yield. After reduction of aldehyde 8 with sodium borohydride, Sono-gashira coupling of 9 with 2-iodoaniline gave alkynylaniline 10. Treatment of 10 with a gold(III) catalyst induced cycliza-tion to furnish indole 11 in good yield.11)
The next task was installation of the nitrogen atom via a diazo coupling. Indole 11 was treated with benzenediazonium chloride to produce 12. Subsequent lactam formation followed by mesylation of the primary alcohol afforded 13. The at-tempted cleavage of the azo group in 13 by hydrogenolysis re-sulted in the unexpected production of mersicarpine (1). After intensive investigations, including labeling experiments with 18O, it was revealed that the reaction proceeded via cyclization and then autoxidation. Based on this reaction mechanism, we developed an efficient process for this transformation, which gave mersicarpine (1) in good yield.5)
3. Synthesis of HistrionicotoxinIn 1971 Daly and coworkers isolated and characterized
Review
e-mail: [email protected]
The author declares no conflict of interest.
Review
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histrionicotoxin (16) from the poison frog Dendrobates histrionicus.12) This alkaloid has received considerable at-tention from the synthetic community due to its structural features, which include a 1-azaspiro[5.5] undecane skeleton, two enyne side chains, and a secondary hydroxy group. To date, a number of synthesis and synthetic studies have been published.13–21)
The first obstacle in our synthesis of histrionicotoxin (16) was constructing the pseudosymmetric quaternary carbon in 21 (Chart 2). To overcome this, we employed a chirality
transfer from an allenylsilane.22–25) Requisite allenylsilane 19 was prepared in an optically active form via an asymmetric reduction of a ketone under Noyori transfer hydrogenation conditions26–29) and an SN2′ reaction with a Lipshutz reagent.30) Treatment of allenylsilane 19 with paraformaldehyde in the presence of TiCl4·2THF afforded homopropargyl alcohol 20 in 52% yield. Because the product retained the trimethylsilyl (TMS) group, the reaction likely proceeded via a carbonyl-ene-type mechanism.31) Although the pseudosymmetric struc-ture prevented the optical purity of 20 from being determined,
Chart 1. Synthesis of Mersicarpine
Satoshi Yokoshima was born in 1974 in Tokyo, and grew up in Yokohama. He received his B.S. in 1997, and his Ph.D. in 2002 from The University of Tokyo under the guidance of Profes-sor Tohru Fukuyama. After working for Mitsubishi Pharma Corporation as a medicinal chemist (2002–2004), he joined Professor Fukuyama’s group at The University of Tokyo as an assistant professor. He was promoted to lecturer in 2008 and to associate professor in 2011. In 2012 he moved to Nagoya University. He has received the Poster Award of the 25th Medicinal Chemistry Symposium (2006), the Young Scientist’s Research Award in Natural Product Chemistry (2009), and the Pharmaceutical Society of Japan Award for Young Scientists (2012). His current re-search interests focus on the synthesis of natural products with polycyclic systems and molecules with biological functions, as well as development of novel synthetic methods.
Satoshi Yokoshima
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the subsequent dienyne metathesis of 21 with the first-genera-tion Grubbs catalyst32) produced 22 in 97% yield and 91%ee. It is noteworthy that the use of the second-generation Grubbs catalyst33) or the Hoveyda–Grubbs catalyst34) reduced the opti-cal purity of the product to 56%ee or 54%ee, respectively.
Regioselective functionalization of resulting diene 22 could be achieved via an iodoetherification and a subsequent a hy-droboration-oxidation sequence to give 24. After protection of the secondary hydroxy group, Zn-mediated reductive cleavage of the iodoether moiety afforded 25. The primary alcohol was sequentially oxidized to carboxylic acid 26. Then the nitrogen atom was introduced via a Curtius rearrangement to give 27. Ozonolysis of 27 furnished dialdehyde 28 in 75% yield.
The less hindered aldehyde moiety was functionalized via an asymmetric propargylation35) with a 5 : 1 diastereoselectivity, and then the remaining aldehyde was homologated using the Ohira–Bestmann reagent36,37) to afford 31. After conversion of the terminal alkyne moieties into (Z)-iodoalkene moieties, the spiro skeleton was constructed via an intramolecular SN2 reac-tion to afford 34. Sonogashira coupling followed by deprotec-tion furnished histrionicotoxin (16).38)
4. Synthesis of Lyconadin ALyconadin A (35) is a Lycopodium alkaloid originally iso-
lated by Kobayashi and coworkers.39) This alkaloid showed cy-totoxicity against some cell lines as well as enhanced mRNA
Chart 2. Synthesis of Histrionicotoxin
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expression for NGF.40) In addition to these bioactivities, the complicated polycyclic structure has attracted much attention in synthetic organic chemistry, and prior to our synthesis, two research groups reported the total synthesis of lyconadin A.41–44)
Our synthesis commenced with a Diels–Alder reac-tion between 3645) and isoprene according to Overman’s conditions46,47) (Chart 3). The Diels–Alder reaction proceeded selectively on the opposite side of the methyl group to give the product. After cleavage of the ethylene ketal in 37, the resulting ketone was subjected to a reductive amination with benzylamine to give secondary amine 38 as the sole isomer. Treatment with formalin under acidic conditions caused 38 to undergo an aza-Prins reaction to produce tricyclic compound 39.48) Cleavage of the benzyl group by hydrogenolysis and the subsequent addition of di-tert-butyl dicarbonate (Boc2O) afforded the Boc-protected compound, which was reacted with dibromocarbene to furnish 40. After cleavage of the Boc group under acidic conditions, the resulting secondary amine 41 was heated in pyridine. The crucial 2e-electrocyclic reaction proceeded to generate an allylic cation,49) which was intercepted by the amine to furnish tetracyclic compound 43 in good yield.
After establishing an efficient synthetic route toward the tetracyclic compound 43, we focused on the transformation into the α,β-unsaturated ketone. Initially, we attempted oxida-tion of the double bond in 43, but the desired product was not produced. The tertiary amine moiety in 43 was problematic under oxidative conditions. After extensive investigations, we
found that a halogen-lithium exchange of the alkenylbromide moiety in 43 proceeded smoothly. Thus, treatment of 43 with tert-buthyllithium gave an alkenyllithium, which was quenched with isoamyl nitrite to afford oxime 45. This reac-tion might proceed via the formation and isomerization of nitrosoalkene 44. Subsequent hydrolysis of the oxime under acidic conditions afforded desired enone 46. Although the yield was somewhat low due to the in situ formation of the acidic oxime, this protocol enabled the straightforward trans-formation of 43 into enone 46 in only two steps.
Finally, the pyridone ring was formed according to our procedure with some modifications.50) Thus, addition of 2-(phenylsulfinyl) acetamide to the α,β-unsaturated ketone afforded the adduct as a mixture of diastereomers, but upon treatment with methanolic hydrogen chloride underwent cycli-zation and sulfoxide elimination to afford lyconadin A (35).51)
5. Synthesis of IsoschizogamineIsoschizogamine (47) was isolated in 1963 from Schizo-
zygia caffaeoides.52) Intensive NMR studies revealed that isoschizogamine (47) is a highly fused hexacyclic compound containing tetrahydroquinoline, hexahydroquinolizine, and pyrrolidinone moieties.53) The two nitrogen atoms of these heterocycles form an aminal adjacent to a quaternary carbon. To date, one racemic total synthesis by Heathcock and two synthetic studies have been reported.54–58)
Chart 4 depicts our synthesis of isoschizogamine. Oxidation of exo-norborneol (48) and a subsequent reaction with trisyl hydrazide afforded hydrazone 49. The Shapiro reaction of 49
Chart 3. Synthesis of Lyconadin A
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proceeded smoothly to give an alkenyllithium species, which was treated sequentially with ethylene oxide and TBDPSCl to furnish 50. Oxidation of 50 with m-chloroperbenzoic acid (mCPBA) produced norbornene oxide 51 stereoselectively. Upon treatment with o-tolMgI in refluxing diethyl ether, 51 underwent a Wagner–Meerwein rearrangement to give 52 in 68% yield.59) Acylation with acryloyl chloride followed by tan-dem metathesis using 5460) in the presence of 1,6-heptadiene gave requisite lactone 55. A rhodium-catalyzed 1,4-reaction of arylboronic acid61) with 55 proceeded smoothly with complete stereoselectivity to afford 56 in 93% yield. The lactone ring was opened with allylamine to give hydroxyamide, which was
oxidized with Dess–Martin periodinane to furnish 57. After cleavage of the TBDPS ether, the resulting alcohol was heated with PPTS in toluene to give hemiaminal ether 58. The ring-closing metathesis of 58 using the second-generation Hov-eyda Grubbs catalyst34) proceeded smoothly to furnish 59.
The remaining tasks involved the introduction of the nitro-gen atom on the aromatic ring and construction of the aminal moiety. Nitration of 59 under mild conditions gave the de-sired product, which was converted into 60 via reduction and protection. Treatment with TMSOTf cleaved the hemiaminal ether moiety in 60. Oxidation of alcohol 61 followed by pro-tection of the resulting aldehyde afforded 62. Treatment of 62
Chart 4. Synthesis of Isoschizogamine
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with piperidine in N,N-dimethylformamide (DMF) cleaved the Fmoc group to afford 63, which is a known intermediate in Heathcock’s synthesis.54) This was converted to the natural product according to the published protocol.62)
6. SummaryHerein the syntheses of four natural products with poly-
cyclic systems are described. In addition to them, a variety of natural product syntheses, which include anisatin (52),63) huperzine A (53),50) kainic acid (54),64) lycoposerramine-S (55),65) morphine (56),66–68) salinosporamide A (57)69) (Fig. 1) and so on, have also been accomplished via unique strategies. These syntheses will become platforms to create molecules with structural characters of natural products, and will lead to development of novel drugs.
Acknowledgements The research in this review article was conducted at the Graduate School of Pharmaceutical Sci-ences, The University of Tokyo. I am very grateful to Profes-sor Tohru Fukuyama for his continuous support and helpful discussions. I would like to express my sincerest appreciation to all the students whose names are acknowledged in our publications cited in this review. This work was financially supported by Grants-in-Aid for Scientific Research (17790007, 19590004, 20002004, 22590002) from the Japan Society for the Promotion of Science (JSPS), the Research Foundation for Pharmaceutical Sciences, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Uehara Memorial Foundation.
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