Chapter I: This Chapter Is Divided Into Two Sections; Section a and Section B

The thesis entitled “Towards the total synthesis of pseudopterosins, (-)- cryptocaryalactone, (R)-(+)-goniothalamin, 7-epi-goniodiol, (+)- kavalactones and epoxide functional group transformations” has been divided into three chapters.

Chapter I: This chapter is divided into two sections; Section A and Section B

Section A: This section describes the introduction and biological activity of styryl lactones and aproaches cited in the literature towards the synthesis of (-)-cryptocaryalactone, R-(+)- goniothalamin, 7-epi-goniodiol, (+)-kavalactones.

Section B: This section describes the enantio- and stereo selective approach to (-)- cryptocaryalactone, R-(+)-goniothalamin, 7-epi-goniodiol and (+)-kavalactones.

Chapter II: This chapter is divided into two sections; Section A and Section B

Section A: This section describes the introduction and biological activity of marine macrolide pseudopterosin and approaches cited in the literature towards the synthesis of pseudopterosin, including total synthesis.

Section B: This section describes the enantio- and stereo selective approach to pseudopterosins: An efficient synthesis and efforts towards the synthesis of pseudopterosins.

Chapter III: This chapter describes the development of new methodologies for epoxide functional group transformations.

ABSTRACT

1 CHAPTER-I

Section A: Introduction and biological activity of Styryl lactones: Styryl lactones represent a new class of natural and synthetic compounds with potential cytotoxicity including antitumour, antifungal and antibiotic properties. Up to now, more than twenty styryl lactones have been isolated from plants and fungi and most of the styryl-lactones are isolated from the genus Goniothalamus (Annonaceae), which are widely distributed throughout Malaysia. A number of these species were used by Malays as traditional medicine to treat various ailments and had been claimed to have connection with an antifertility effects such as procurement of abortion, undefined post-natal treatments and low birth rate. Styryl lactones posses interesting biological properties, in particular antiproliferative activity against cancer cells. In general, the cytotoxicity of styryl lactones are specific against cancer cells.

Section B: Stereoselective synthesis of (-)-cryptocaryalactone, R-(+)- goniothalamin, 7-epi-goniodiol and (+)-kavalactones: (-) cryptocaryalactone 1 and R-(+)-goniothalamin 3 are the styryl lactones isolated from the Cryptocarya species. R-(+)-goniothalamin 3 displays cytotoxic effects against colon cancer, breast cancer, lung carcinoma and normal cell lines. Similarly, 7-epi-goniodiol 2 isolated from the ethanolic extract of stem barks of Goniothalamus leiocarpus (Annonaceae) and displayed strong inhibition against HL-60 in concentration as low as 1μg/mL. α-Pyrone derivatives known as the kavalactones comprise roughly 15% of the Kava plant (Piper methysticum) rootstock and posses potential biological activity which includes local anaesthetic, sedative, analgesic, anticonvulsive, antispasmodic, antimycotic, antifungal, antithrombotic and central muscular relaxing properties. Although several successful approaches to the synthesis of these lactones have been reported, their biological significance and activity, encouraged us to design a concise and flexible stereoselective route toward the total synthesis of these lactones.

ABSTRACT

2 O O O OH OAc O O O

(-)-Cryptocaryalactone (1) 7-epi-Goniodiol (2) R-(+)-Goniothalamin (3)

OMe OMe

R-(+)-Kavain (4) S-(+)-7, 8-Dihydrokavain (5)

Figure 1

The retrosynthetic analysis shows that all these lactones can be synthesized from tert- butyldimethylsilyl (TBS) ether 8 and this could be synthesized from the inexpensive and commercially available cinnamaldehyde 6 (Scheme 1).

OTBS CHO 1, 2, 3, 4, 5

8 6 Scheme 1

Synthesis of (-)-cryptocaryalactone: Based on this disconnection we began our synthesis by the enantioselective allylation of cinnamaldehyde 6 using R-(+)-binol, allyl tri butyl tin and obtained the alcohol 7 in 80% yield (94% ee). The alcohol 7 was protected as tert-butyldimethylsilyl (TBS) ether to give 8 in 92% yield. The compound 8 was subjected to Sharpless asymmetric dihydroxylation to yield the two diols 9a and 10a in a 4:6 ratio respectively in 80% yield (Scheme 2).

ABSTRACT

3 OH OTBS CHO R- (+)-Binol, allyl tri butyl tin TBSCl, Im DCM, rt, 24 h, 80%, (94% ee) DCM, rt, 92% 6 7 8

TBSO OH OH OTBS AD-mix-, MeSO NH OH 2 2 + 0 OH t-BuOH/H2O (1:1), 0 C, 80 %

9a (Minor, 40 %) (90% ee) 10a (Major, 60 %) (96% ee)

Scheme 2 The diol 9a was mono tosylated using TsCl and further converted to epoxide 12 using NaH at 0 0C in 80% overall yield. The epoxide 12 was subjected to nucleophilic ring opening with methyl propiolate 13 using BuLi and BF3.OEt2 to obtain the δ-hydroxy ester 14 in 75% yield. The partial reduction of triple bond of the ester 14 using Lindlar’s catalyst yielded cis α,β-unsaturated ester 15 in 80% yield. The cis α,β-unsaturated ester 15 was cyclized using catalytic amount of p-toluene sulphonic acid in methanol with concomitant loss of silyl group to afford lactone 16 in 78% yield. Acylation of the hydroxy group of lactone 16 using acetic anhydride in pyridine yielded cryptocaryalactone 1 in 80% yield (Scheme 3).

OTBS OTBS OH O NaH, THF TsCl, Et3N OTs 9a 0 DCM, rt 0 C, 80% 11 12

OTBS OH COOMe OTBSOH H /Pd-BaSO BuLi, BF3.OEt2 2 4 COOMe THF, -780C, 75% EtOAc, 80% COOMe 14 15 13 O O OH O OAc O

TsOH, MeOH Ac2O, Pyridine rt, 78% 16 rt, 80% 1

Scheme 3 ABSTRACT

Synthesis of 7-epi-goniodiol:

4 The diol 10a was protected with 2,2-dimethoxy propane (DMP) and then subjected to ozonolysis to afford the aldehyde 17 in 80% overall yield. The aldehyde 17 was subjected to Still’s modification of Horner-Wodsworth-Emmons reaction using NaH and bis(2,2,2- trifluoroethyl) (methoxycarbonylmethyl) phosphonate in dry THF at –78 0C to afford the α,β- unsaturated ester 18, predominantly as the (Z)-isomer in 82% yield. The ester 18 was cyclized to 7-epi-goniodiol 2 with the loss of silyl and acetonide groups using catalytic amount of p- toluene sulphonic acid in methanol in 75 % yield (Scheme 4).

O OTBS CHO i) 2,2-DMP, TsOH, DCM, rt (CF3CH2O)2P(O)CH2COOCH3 10a ii) Ozonolysis, DMS, 80% O NaH, THF, -780 C, 82% 17

O O OTBS OH O COOMe p -TSA/MeOH O rt, 75% 18 OH 2

Scheme 4

Synthesis of R-(+)-goniothalamin & (+)-kavalactones: Synthesis of the remaining lactones 3, 4, 5 was initiated using diol 9 as the key intermediate. The dihydroxylation of tert-butyldimethylsilyl (TBS) ether 8 using OsO4/NMO gave the two diols 9 and 10 in a 8:2 ratio and 90% yield (Scheme 5).

OTBS OH OH OTBS OH OsO4, NMO 8 + OH Acetone/H2O (9:1), rt, 90% 9 (Major, 80%) 10 (Minor, 20%)

Scheme 5

ABSTRACT

5 NaIO4 promoted cleavage of diol 9 afforded the aldehyde 19 in 80% yield. Horner– Wadsworth–Emmons coupling reaction of 19 gave cis ester 20 in 82% yield. The cis ester 20 was cyclized to the goniothalamin 3 by the loss of silyl group using p-toluene sulphonic acid in 85% yield (Scheme 6).

OTBS CHO NaIO C F3CH2O)2P(O)CH2COOCH3 9 4 DCM, rt, 80% NaH, THF, -780 C, 82% 19

O OTBS TsOH /Methanol O COOMe r.t., 85% 20 3

Scheme 6

Similarly, the synthesis of kavain was initiated by the reaction of aldehyde 19 with ethyldiazoacetate using anhydrous SnCl2 to afford the β-ketoester 21 in 80% yield. The β- ketoester 21 was cyclized to kavain 4 in a single step using HCl/MeOH in 70% yield.

Dihydro kavain 5 was synthesized by the reduction of β-ketoester 21 using H2-Pd/C to afford the saturated β-ketoester 22 in 90% yield. The ester 22 was cyclized in a single step using HCl/MeOH to afford dihydrokavain 5 in 70% yield (Scheme 7).

O TBS O O anhyd SnCl2, N2CH2COOEt COOEt MeOH/HCl O 19 OMe DCM, 0 0C to rt, 80% DCM, rt, 70% 21 4

H2, Pd / C MeOH, rt, 90%

TBS O O O COOEt MeOH/HCl O

DCM, rt, 70% OMe 22 5

Scheme 7 ABSTRACT

6 CHAPTER-II

Section A: Introduction: In the recent years, the most troublesome complication is inflammation, which is occurring in 15% to 32% of cases. The cause of the inflammation may be due to viral infection or may be a consequence of coronary artery bypass grafting. The process inflammation can be explained “by which the body’s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses”. When inflammation occurs, chemicals from the body’s white blood cells are released into the blood or affected tissues in an attempt to rid the body of foreign substances. This release of chemicals increases the blood flow to the area and may result in redness and warmth. Some of the chemicals cause leakage of fluid into the tissues, resulting in swelling. The inflammatory process may stimulate nerves and cause pain. In some diseases, when there are no foreign substances to fight off called autoimmune diseases, the body’s normally protective immune system causes damage to its own tissues. The body responds as if normal tissues are infected or somehow abnormal. The type of symptoms depends on which organs are affected.

Section B: Stereoselective approach to pseudopterosins: The pseudopterosins are a class of diterpene glycosides isolated from the gorgonian (sea whip) Pseudopterogorgia elisabethae. All of the known pseudopterosins contain the amphilectane skeleton with a glycosidic linkage at either C-9 or C-10. The identity of the sugar and the degree of acetylation account for the additional structural variation of this family of diterpenes pseudopterosins A-D (Figure 1). The pseudopterosins are anti- inflammatory and analgesic agents with potencies superior to that of existing drugs such as indomethacin. Pseudopterosin A has been found to significantly inhibit phorbol myristate acetate-induced topical inti-inflammation in mice and the methyl ether of this natural product has shown promise as a treatment for contact dermatitis. Pseudopterosins are also used commercially in Resilience® skin cream. The pseudopterosins used in the skin cream and in biological evaluations have all been obtained by extractions of the harvested coral, thus imposing a potential supply issue.

ABSTRACT

O OR1 R1 R2 R3 O H H H Pseudopterosin A OH Ac H H Pseudopterosin B H Ac H Pseudopterosin C H H Ac Pseudopterosin D

Figure 1

As a part of ongoing programme towards the synthesis of biologically active molecules based on the simplicity of the reaction and ready availability of the starting materials, we herein, a flexible stereo-selective route has been described for the synthesis of pseudopterosins from inexpensive and commercially available geraniol. This approach derived its asymmetry from Sharpless asymmetric epoxidation reaction (Scheme 1).

OR OMe CHO OR' OH OMe

H O 20 12 1

OH OH COOEt

+ OTMS O

10 2 6 8

Scheme 1 ABSTRACT

8 The synthesis of pseudopterosin was started with commercially available geraniol 2. The Sharples epoxidation reaction of geraniol 2 afforded the epoxide 3 in 90% yield. The

Lewis acid-mediated reductive ring opening of epoxide 3 using NaBH3CN occurred at the higher substituted center to furnish diol 4 in 87% yield. NaIO4 promoted cleavage of diol 4 gave the aldehyde 5 in 83% yield. The aldehyde 5 was subjected to wittig reaction using ethyl (triphenylphosphoranylidene) acetate by refluxing in benzene to give the α, β-unsaturated ester 6 in 86% yield (Scheme 2)

OH OH OH (L)-(+)-DIPT, Ti(O-i-Pr)4, TBHP O NaBH CN, BF .OEt 3 3 2 OH THF, r.t., 4 h, 87% CH2Cl2, MS 4 Å, -20 °C, 1 h, 90%

COOEt NaIO4, Bu4NIO4 CHO Ph3P=CHCOOEt

H2O, CH2Cl2, 0 °C, 1 h, 83% Benzene, Reflux, 86%

Scheme 2 The trimethyl silyloxy furan 8 was prepared for in situ use as a diene by the deprotonation of 7 with LHMDS in THF at -78 0C for 3h. and subsequent reaction with anhydrous TMSCl at 0 0C (Scheme 3).

i) LHMDS, -78 0C

ii) TMSCl, 0 0C O THF OTMS O O

7 Scheme 3 8

The in situ prepared trimethyl silyloxy furan 8 was subjected to Diels-Alder reaction with α, β-unsaturated ester 6 to form the Diels-Alder adduct 9 in 50% yield. The resulting

Diels-Alder adduct 9 was subjected to aromatization using TiCl4, LAH, Et3N in THF to ABSTRACT

9 afford the aromatic ester 10 in 80% yield. The aromatic ester 10 was then reduced with LAH in THF at room temperature to afford the alcohol 11 in 92% yield. The alcohol 11 was oxidized to aldehyde 12 using pyridinium chloro chromate in 70% yield. The aldehyde 12 was subjected to Dakin reaction to obtain the catechol 13, but the reaction was not proceeded and the starting material was recovered (Scheme 4).

COOEt COOEt

OTMS OH 0 0 C to rt TiCl , LAH, Et N O 4 3 LAH 6 + 8 12 h., 50% THF, 3h, 80% THF, rt, 92%

OH CHO OH

OH OH OH PCC Dakin reaction

DCM, r.t., 70 % H2O2, NaOH

11 12 13

Scheme 4

So, we have proceeded further by the protection of both alcohol and phenol groups of 11 as its methyl ether using MeI and NaH in THF to afford the 14 in 87% yield. The double bond of 14 was epoxidized using m-CPBA in DCM at room temperature to afford the epoxide 15 in 90% yield. The epoxide 15 was then attempted to Friedal-craft alkylation using various Lewis acids to obtain the tetrahydronaphthalene derivative 16. Unexpectedly, however, complex mixture of products were obtained and could not be characterized. So the compound 14 was further subjected to reductive ozonolysis to obtain alcohol 17 in 70% yield. The alcohol 17 was then subjected to Jones oxidation to afford the acid 18 in 90% yield. The acid was then subjected to intra molecular Friedel-Crafts acylation reaction by various methods. But in all cases a complex mixture of products were obtained and could not be characterized. So the resulting acid 18 was further converted to acid chloride 17 by refluxing with thionyl chloride in 88% yield (Scheme 5).

ABSTRACT

10 OMe OMe OMe

OMe OMe OMe NaH, MeI m-CPBA 11 DCM, 90% THF, rt, 87% O OH 14 15 16

i) Ozonolysis ii) LAH, 70%

OMe OMe OMe

OMe OMe OMe Jones Oxidation SO2Cl2

(CrO3+ H2SO4), 90% Reflux, 0.5h., 88% O O

OH OH Cl 17 18 19 Scheme 5

The acid chloride 19 was attempted to Friedel-Craft acylation using aluminum chloride in heptane under reflux condition to give the cyclized product 20, which should be further converted to pseudopterosins 1. But unexpectedly, the acid chloride group of 19 was underwent unusual intra molecular cyclization at the benzylic carbanion to give the cyclized product 21 in 78% yield (Scheme 6).

OMe OR OMe OR'

O H 20 AlCl3 , Heptane 19 Ref lux, 1h, 78% 1

OMe OMe O

Scheme 6 ABSTRACT

11 CHAPTER-III

Epoxide functional group transformations: Epoxides are an ideal source for diversity in organic synthesis, because their ease of formation, wide reactivity and ability to undergo regioselective ring opening reactions contributes to their synthetic value. The electro negativity of oxygen atom and strained ring make them good electrophile and can easily be opened with many nucleophiles furnishing functionally diverse compounds. Thiiranes, Vicinal halohydrins, tetrahydropyrans and dihydropyrans, which can be prepared from epoxides, are useful precursors in the synthesis of variety natural products and other bioactive molecules.

+ Ph Ph O O major (75%) minor (25%)

ZrCl4 or BiCl3 DCM, r.t.

Cl S O OH [bmim]PF6/H2O (2:1) Ph ZrCl , DCM, r.t. O 4 KSCN, rt

[bmim]PF6 /LiX r.t.

OH X + (X = Br, I, Cl)

85% 12%

Scheme 1 ABSTRACT

12  [Bmim]PF6: A novel and recyclable ionic liquid for conversion of oxiranes to thiiranes in aqueous media: Thiiranes are the sulfur heterocycles used in various industries and synthetic transformations. Because of their industrial and synthetic importance, the development of convenient and practical methods for the preparation of thiiranes, are desirable. In the recent years, ionic liquids are emerging as a set of green solvents with unique properties such as tunable polarity, high thermal stability, immiscibility with a number of organic solvents, negligible vapor pressure, and recyclability. As a result of their green credentials and potential to enhance rates and selectivities, we herein report the use of ionic liquids for the synthesis of episulfides from oxiranes and potassium thiocyanate under mild and neutral conditions. Initially, we have carried out the experiment with 2-phenoxymethyloxirane and potassium thiocyanate for 2 h in 1-butyl-3-methylimidazolium hexafluorophosphate-water (2:1) solvent system to afford the corresponding episulfide in 95% yield (Scheme 2). Similarly, various epoxides reacted smoothly with potassium thiocyanate under these reaction conditions to produce corresponding thiiranes in excellent yields. In summary, we have developed a green strategy for the preparation of episulfides from epoxides using ionic liquids as reaction media.

O S [bmim]PF /H O (2:1) + KSCN 6 2 RO RO r.t. 1 2 Scheme 2

 Green protocol for the synthesis of vicinal-halohydrins from oxiranes

using the [Bmim]PF6/LiX reagent system: vic-Halohydrins have found wide spread application in organic synthesis. They are key intermediates in the synthesis of several halogenated marine natural products. The most common method for the preparation of halohydrins involves ring-opening of epoxides either by hydrogen halides or by hydrohalogenic acids. Substantial efforts have been made in the last few years to develop new procedures for converting epoxides into halohydrins under mild conditions. In this direction, ionic liquids have gained recognition as possible environmentally benign alternatives to more volatile organic solvents. Ionic liquids possess ABSTRACT

13 many interesting properties such as wide liquid range, negligible vapor pressure, high thermal stability and good solvating ability for a wide range of substrates and catalysts. In view of recent surge in the use of ionic liquids in organic synthesis, we herein report for the first time the use of ionic liquids as recyclable solvents for the regioselective ring-opening of epoxides with lithium halides to produce halohydrins under mild and neutral conditions (Scheme 3). Accordingly, treatment of styrene oxide with lithium bromide in 1-butyl-3-

0 methylimidazolium hexafluorophosphate [bmim]PF6 for 1.5 h at 27 C afforded the corresponding bromohydrin 3 in 85% yield along with the other regioisomer 4 in 12% yield. These results prompted us to extend this process to other epoxides. Interestingly, various epoxides such as 3-aryloxy-1,2-epoxy propanes and alkyl oxiranes underwent cleavage smoothly with lithium halides in ionic liquids to afford 1-halohydrins 4 in excellent yields. In conclusion, we have demonstrated the successful use of ionic liquids as novel and recyclable solvents for the synthesis of vic-halohydrins by regioselective ring-opening of epoxides with lithium halides.

X OH O [bmim]PF6/LiX OH + X R r.t. R R 1 X= Br, I, Cl 3 4

Scheme 3

 ZrCl4 mediated cross-cyclization between epoxides and homoallylic alcohols: synthesis of 4-chlorotetrahydropyran derivatives: The benzyl tetrahydropyran fragment is a common core structure in a number of natural products such as the apicularens. The apicularens possess highly cytotoxic activity and are potent inhibitors of human tumor cell lines such as those originating from kidney, lung and cervia. Despite their wide range of pharmacological activities, the synthesis of benzyl substituted tetrahydropyrans has received little attention. ZrCl4 has been used for various epoxide ring-opening reactions giving the products in good yield. Herein, we describe zirconium tetrachloride mediated cross-cyclization between aryl-substituted epoxides and homoallylic alcohols for the formation of tetrahydropyran derivatives. When a mixture of styrene epoxide and 3-buten-1-ol was stirred with zirconium tetrachloride in dry methylene ABSTRACT

14 chloride at room temperature, the disappearance of the starting materials was observed by TLC over 2 h. After work-up, the crude product was separated by column chromatography over silica gel. The 1H NMR spectrum showed clean formation of the two isomers of benzyl tetrahydropyran derivative 6a. By comparing the spectroscopic data with the literature values, the major product was shown to have the cis stereochemistry (Scheme 4). Similarly, various epoxides reacted smoothly with homoallylic alcohols under similar conditions to give the tetrahydropyran derivatives in high yields ranging from 80 to 95%. However, treatment of epoxides with cis-3-nonen-1-ol afforded the corresponding 2,3,4-trisubstituted tetrahydropyran with the cis-cis configuration, as the major product, whereas trans-3-hexen- 1-ol gave the 2,3,4-trisubstituted tetrahydropyran with the trans-trans configuration as the dominant product. In summary, we have described a simple and highly efficient protocol for the preparation of benzyl tetrahydropyran derivatives through the cross-cyclization between epoxides and homoallylic alcohols using zirconium tetrachloride.

Cl Cl O

ZrCl4 + OH + DCM, r.t. Ph Ph O O 1a 5 6a major (75%) minor (25%) Scheme 4

15  Mild and efficient method for the synthesis of tetrahydropyran derivatives via cross cyclization between epoxides and homoallylic alcohols mediated by bismuth (III) chloride: Substituted tetrahydropyrans are the common structural motif of many natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins and apicularens. We found that tetrahydropyrans could be formed starting with epoxide using BiCl3.

Because of low toxicity, low cost, good stability and eco-friendly nature we have used BiCl3 for tetrahydropyrans formation. The reaction was carried out by adding the bismuth chloride to a mixture of styrene epoxide and 3-buten-1-ol in methylene chloride. The mixture was stirred at room temperature for 5h to give the two isomers of tetrahydropyran derivative 6a in 90% yield. By comparing the spectroscopic data with literature values, the major product has a cis stereochemistry (Scheme 5). Similarly, various ABSTRACT epoxides were reacted with homoallylic alcohols to give the corresponding tetrahydropyran derivatives in high yields ranging from 75 to 90%. In summary, we have described a simple and highly efficient protocol for the preparation of benzyl tetrahydropyran derivatives through cross cyclization between epoxides and homoallylic alcohols using bismuth chloride.

Cl Cl O

BiCl3 + OH + Ph Ph DCM, r.t. O O 1a 5 6a major (75%) minor (25%) Scheme 5

 ZrCl4 mediated cyclization between epoxides and homopropargylic alcohols: synthesis of 4-chloro-5,6-dihydro-2H-pyran derivatives: Substituted dihydropyrans are key intermediates for the synthesis of many natural products. The olefin function particularly has great synthetic value for further functionalization to obtain polysubstituted tetrahydropyrans from dihydropyrans. Despite their potential

16 importance, we herein report the synthesis of dihydropyran derivatives through the cyclization between epoxides and homopropargylic alcohols using zirconium tetrachloride. A mixture of styrene oxide and 3-butyn-1-ol was treated with zirconium tetrachloride in dry methylene chloride. The mixture was stirred at room temperature for 30 min. and after work-up, the crude product was purified over silica gel to provide the product 8 in 70% yield (Scheme 6). A wide range of epoxides and all reacted smoothly with 3-butyn-1-ol under similar conditions to afford the corresponding dihydropyran derivatives in good yields ranging from 65-80%. In summary, we have described a simple and highly efficient protocol for the preparation of dihydropyran derivatives through the reaction between epoxides and homopropargylic alcohols using zirconium tetrachloride.

Cl O R ZrCl4 + R = H or Aryl OH DCM, r.t. Ph O 7a 1 8 R Scheme 6