Phương pháp tổng hợp mới cho sản phẩm tự nhiên Hypericum - Luận án tiến sĩ

New synthetic methods for hypericum natural products by Insik Jeon A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Organic Chemistry Program of Study Committee: George A. Kraus, Major Professor Richard, C. Jenks Jacob Petrich Donald L. Reynolds Iowa State University Ames, Iowa 2006 UMI Number: 3243830 UMI Microform 3243830 Copyright 2007 by ProQuest Information and Learning Company.

All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P. Box 1346 Ann Arbor, MI 48106-1346 ii TABLE OF CONTENTS GENERAL INTRODUCTION 1 CHAPTER 1.

Synthesis of papuaforin B and related phloroglucinol natural products Introduction 2 Results and Discussion 12 Experimental 56 References 80 CHAPTER 2. Direct syntheses of 7,8-dihydroxycalamenene and mansonone C Introduction 84 Results and Discussion 89 Experimental 93 References 113 GENERAL CONCLUSION 115 ACKNOWLEDGMENTS 116 1 GENERAL INTRODUCTION Organic chemistry has served as a solid foundation for interdisciplinary research areas, such as molecular biology and medicinal chemistry. An understanding of the biological activities and structural elucidations of natural products can lead to the development of clinically valuable therapeutic options. The advancements of modern synthetic methodologies allow for more elaborate and concise natural product syntheses.

The theme of this study centers on the synthesis of natural products with particularly challenging structures and interesting biological activities. The synthetic expertise developed here will be applicable to analog syntheses and to other research problems. SYNTHESIS OF PAPUAFORIN B AND RELATED PHLOROGLUCINOL NATURAL PRODUCTS Introduction An understanding of the biological activities and effects of herbal supplements becomes essential for efficacy and safety concerns with the increasing use of dietary supplements. Recently, the antidepressant activity of Hypericum perforatum, commonly known as St.

John’s wort, has drawn much attention. John’s wort is commonly used as a natural remedy to treat moderate to mild depression. Studies of the constituents of St. John’s wort and other plants from the family Guttiferae have disclosed a class of compounds, polycyclic polyprenylated acylphloroglucinols (PPAPs), with fascinating structures and interesting biological activities.

O OH O O O OH H Me OH O O Me Me Me Me Me OO OO Me OO OO Hyperforin (1) Nemorosone (2) Garsubellin A (3) Papuaforin B (4) Figure 1. Polycyclic polyprenylated acylphloroglucinol (PPAP) natural products Hyperforin (1) was first isolated in 1971 from the species Hypericum perforatum,5 and has drawn substantial attention, because it is thought to be responsible for the antidepressant and antibacterial activities of St.6-10 Its antidepressant activity is 3 attributed to a broad inhibitory effect on the synaptosomal uptake of several neurotransmitters, such as serotonin, noradrenaline, dopamine, γ-aminobutyric acid (GABA) and L-glutamate at hyperforin concentrations as low as IC50 = 1.11 A recent report has shown that hyperforin (1) inhibits penicillin-resistant and methicillin-resistant Staphylococcus aureus, which is resistant to various antibiotics, such as the cephalosporins, erythromycin and clindamycin.12 Nemorosone (2) is the major constituent of Clusia (Clusiaceae) species resin,13 and is known to possess antimicrobial, cytotoxicity and antioxidant activities.17 Garsubellin A (3) enhances choline acetyltransferase (ChAT) activity in P10 rat septal neurons relative to a control by 154% at a 10 μM concentration.18 Choline acetyltransferase (ChAT) is involved in the biosynthesis of neurotransmitter acetylcholine (ACh) in the nervous system. Taking into account that Alzheimer’s disease has been attributed to deficiencies in the levels of acetylcholine (ACh),19 The ChAT enhancing activity of garsubellin A (3) provides potential in developing chemotherapies for Alzheimer’s disease. Its chemical structure is similar to hyperforin (1) with the additional 2,2-dimethyl-2H-pyran ring that is probably formed by cyclization of a 3-methylbut-2-enyl side chain with an enolic hydroxyl group.

The biosynthesis of hyperforin (1) was proposed using early labeling experiments, which involve acylphloroglucinols and isoprenoid moieties (Figure 2).20 The acylphloroglucinol moiety is generated by a polyketide type biosynthesis beginning with two units of pyruvate. Condensation of malonyl-CoA and acyl-CoA furnishs a tetraketide, which undergoes cyclization to acylphloroglucinol 5. Enzyme-catalyzed prenylation of 5 using 4 prenyl pyrophosphate, derived from a non-mevalonate pathway, generates 6 which, upon prenylation and cyclization, would provide hyperforin (1). CO2 O O O O O + * * COO COO * COO * COO HO * * CO2 O O HO * OH O * O * * HO SCoA O * * * * * SCoA * * * SCoA O OH O O * 5 O O O P O P O O O HO O HO OH HO OH O O O O O O 6 OPP Hyperforin (1) 7 Figure 2.

Proposed biosynthesis of Hyperforin (1) In the past decade, the significant biological activity and challenging structure of this class of natural products have drawn many synthetic chemists’ attention. However, most studies rely only on the construction of the bicyclic core structure, not surprisingly, because 5 of its synthetically formidable structural features. Indeed, two total syntheses of garsubellin A (3) have been reported.21,22 Nicolaou firstly reported a synthetic route to the highly functionalized core structure of garsubellin A (3) employing a selenocyclization approach.23 Initially, the requisite precursor 8 was synthesized from commercially available 1,3-cyclohexanedione in eight steps (Scheme 1). The selenium-mediated cyclization in the presence of N- (phenylseleno)phthalimide (N-PSP) and SnCl4 furnished the selenide 9.

Selective reduction of the bridged ketone of 9 produced a single alcohol, which, upon alkylation with trans-1,2- bis(phenylsulfonyl)ethylene, yielded vinylogous sulfone 10. The construction of tetracycle 11 by the use of n-Bu3SnH and AIBN, followed by the sequence of reactions : reduction, selective monoprotection, and oxidation formed the corresponding aldehyde 12. O O O OH 8 Steps SnCl4 SePh O O O OAc H N-PSP H CO2Me CO2Me 9 1. LiHMDS, SO2Ph PhO2S O HO O O 1) DIBAL O CO2Me O CO2Me TBSO Bu3SnH O H O O 2) TBSCl AIBN PhO2S 3) PhI(OAc)2 PhO2S SePh PhO2S 12 11 10 Scheme 1 6 The use of isopropenylmagnesium bromide effected the addition to the aldehyde with concomitant β-elimination of the sulfone side chain.

Selective hydrogenation by using H2/PtO2 produced isopropyl alcohol 13 (Scheme 2). Subsequently, selective protection of the two free hydroxyls of 13 as a cyclic carbonate, followed by hydrogenation, produced intermediate 14. After oxidation of the free hydroxyl of 14, the ensuing conversion of the saturated ketone to an α,β-unsaturated enone was accomplished to give 15. For completion of the bicyclic core, the regio- and stereoselective [2+2] cycloaddition was employed to give the protected cyclobutanone adduct 16.

Deprotection and subsequent Baeyer-Villiger oxidation completed construction of the fully functionalized bicyclic core (17) of garsubellin A (3). O HO OH HO O O O TBSO TBSO 1. Cl3CO OCCl3 OH 12 2. H2, Pd/C SO2Ph SO2Ph 1.

SeO2 14 O O O O MeO O O O O O O O O O O O TBSO TBSO CH2 1. hv, H3CO OCH3 2. H2SO4 SO2Ph SO2Ph SO2Ph Garsubellin A core (17) 16 15 Scheme 2 7 Nicolaou’s strategy introduced several interesting synthetic steps, which include biomimetic electrophile-mediated cyclizations of a pendant prenyl group and a novel bicyclic cycloaddition. However, the many steps to the core structure of garsubellin A (3) might limit its practical use towards this class of natural products syntheses.

In 2005, Shibasaki first reported the complete total synthesis of Garsubellin A (3).21 The Shibasaki synthesis began with commercially available 3-ethoxycyclohex-2-enone, which underwent prenylation, methylation, and acid hydrolysis of the vinyl ether to yield an enone (Scheme 3). O OTIPS O OTIPS OEt 1. PhSiH3, Co(acac)2, O2 4 steps 2. KHMDS, prenyl bromide Bu4NI MOMO 18 19 1.

LDA, CH3CHO 2. Martin sulfurane O OTIPS O OTIPS O O 1. Triphosgene allyl iodide O pyridine O 4. NaOAc MOMO MOMO MOMO 21 20 22 200 °C Scheme 3 Conjugate addition of an methyl cuprate and in situ trapping of the resulting magnesium enolate by isobutyraldehyde gave the anti-aldol product, which was protected by TIPS to give 18.

Protection of the prenyl group, followed by addition of an additional prenyl group, gave 19. Attempted aldol reaction with acetaldehyde occurred at the sterically less 8 demanding α-carbonyl position, which was then dehydrated to the corresponding olefin 20 using the Martin sulfurane. Highly chemoselective dihydroxylation and protection of the diol furnished carbonate 21. Cyclization precursor 22 was generated in four straightforward steps from 21: desilylation, oxidation, O-allylation and stereoselective Claisen rearrangement.

A ring-closing metathesis reaction of 22 was realized by employing the Hoveyda-Grubbs catalyst24 to construct the crucial bicyclic skeleton of 23 (Scheme 4). Mes N N Mes O Cl Ru O O O O Cl 1. (PhSe)2, PhIO2 O Pri O pyridine. CSA O O MOMO HO 1.

Na2PdCl4, TBHP I O O O O HO O HO O HO O O O O O O PdCl2/dppf, tributylprenyltin 1. PTSA HO 26 25 Garsubellin A (3) Scheme 4 Allylic oxidation, and subsequent deprotection of the MOM ether using CSA provided the alcohol 24. Upon hydrolysis of the carbonate, the secondary alcohol underwent Wacker oxidative cyclization to give 25. In order to secure two prenyl groups, 25 was further functionalized to a vinylic iodide, which was then dehydrated to regenerate the prenyl 9 group.

The total synthesis of garsubellin A (3) was completed by Stille coupling of 26 with tributylprenyltin. Shibasaki’s group completed the total synthesis of the target compound by a reasonably direct synthetic route, except for the low yield of the final step. They also mentioned that this synthesis could be extended to an asymmetric synthesis of garsubellin A (3) by early introduction of a catalytic, enantioselective alkylation method developed by Koga.25 A recent report from Danishefsky’s group described the complete synthetic effort to garsubellin A (3). It involved a unique synthetic approach.22 For the construction of the bicyclic skeleton, they dearomatized a substituted phloroglucinol, a step reminiscent of the biosynthetic pathway to hyperforin (1).

K2OsO4, K2CO3, K3Fe(CN)6 CH3SO2NH2, t-BuOH-H2O OTIPS n-BuLi then 2. PTSA, 2,2-dimethoxypropane H3CO OCH3 prenylbromide H3CO OCH3 acetone O H3CO OCH3 3. TBAF O 28 27 Pd(OAc)2, PPh3, Ti(i-PrO)4 allyl methyl carbonate O I CH2 O 1. Grubb’s 2nd cat.

O HClO4 2-methyl-2-butene H2O/dioxane H3CO OCH3 HO HO I O 2. I2, KI CH2 H O O KHCO3 H O O O 30 29 31 Scheme 5 10 The synthesis commenced with regioselective prenylation of the protected phloroglucinol derivative (Scheme 5). Dihydroxylation of 27, followed by acetonide formation and desilylation using TBAF, gave phenol 28. The product 29 was obtained by allylation of 28, either by direct allylation at the para carbon or by O-allylation, followed in sequence by rapid o-Claisen and Cope-like rearrangements.

Upon treatment with aqueous acid, the acetonide group of 29 was removed, and ensuing conjugate addition and hydrolysis provided 30 as a single diasteromer. An olefin cross metathesis reaction converted the allyl group into a prenyl group. Iodocarbocyclization led to 31, which contained the key bicyclo[3.1]nonane ring system. I I i-PrMgCl then O O O TMSI then Li2CuCl4 HO HO I2, CAN HO allyl bromide 1 N HCl I 31 H O O H O O H O O I 32 33 34 Scheme 6 Vinylic iodination of 31 using the iodine/CAN system gave triiodinated compound 32.

Metal-halogen exchange using excess isopropylmagnesium chloride with careful temperature control promoted a transannular Wurtz cyclopropanation reaction. Upon allylation of the remaining vinylic Grignard intermediate, 33 was produced, which was then successfully returned to the bicyclo[3.1]nonane skeleton by treatment with TMSI. Allyltributyltin- mediated radical allylation introduced an allyl group to the sterically favored exo face. The product was subjected to cross metathesis reactions to install two prenyl moieties.

11 Disilylation of both the tertiary alcohol and bridgehead carbon positions of 35, followed by iodination, provided 36. Metal-halogen exchange and subsequent treatment with isobutyraldehyde yielded adduct 37. Oxidation and deprotection of the TMS ether completed the synthesis of garsubellin A (3). AIBN, allyltributyltin HO then I2 TMSO I 34 2.

Grubb’s 2nd cat. H O H O O O 35 36 i-PrMgCl then isobutyraldehyde O O O OH HO TMSO 1.