SYNTHESIS OF BISHOMO-INOSITOL DERIVATIVES A THESIS...

i

SYNTHESIS OF BISHOMO-INOSITOL DERIVATIVES

A THESIS SUBMITTED TO THE GRADUATE SCHOOL OF NATURAL AND APPLIED SCIENCES

OF MIDDLE EAST TECHNICAL UNIVERSITY

BY

MERVE GÖKÇEN BEKARLAR

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR

THE DEGREE OF MASTER OF SCIENCE IN

CHEMISTRY

SEPTEMBER 2011

ii

Approval of the thesis:


submitted by MERVE GÖKÇEN BEKARLAR in partial fulfillment of the requirements for the degree of Master of Sciences in Chemistry Department, Middle East Technical University by,

Prof. Dr. Canan ÖZGEN ____________________ Dean, Graduate School of Natural and Applied Sciences Prof. Dr. İlker ÖZKAN ____________________ Head of Department, Chemistry Dept., METU Prof. Dr. Metin BALCI Supervisor, Chemistry Dept., METU ____________________ Examining Committee Members: Prof. Dr. Cihangir TANYELİ ____________________ Chemistry Dept., METU Prof. Dr. Metin BALCI ____________________ Chemistry Dept., METU Prof. Dr. Aliye ALAYLI ALTUNDAŞ ____________________ Chemistry Dept., Gazi University Assist. Prof. Dr. Raşit ÇALIŞKAN ____________________ Chemistry Dept., Süleyman Demirel University Assist. Prof. Dr. Gani KOZA ____________________ Chemistry Dept., Ahi Evran University

Date: 14.09.2011

iii

I hereby declare that all information in this document has been obtained and presented in accordance with academic rules and ethical conduct. I also declare that, as required by these rules and conduct, I have fully cited and referenced all material and results that are not original to this work.

Name, Last name : Merve Gökçen Bekarlar

Signature :

iv

ABSTRACT


Bekarlar, Merve Gökçen

M.Sc., Department of Chemistry

Supervisor: Prof. Dr. Metin Balcı

September 2011, 128 pages

Inositols belong to an important class of biologically active compounds, named as

cyclitols (cyclic polyols), which have attributed high interest in the past decade due

to the glycosidase inhbition property that affects many biological processes.

Initially, 1,3,3a,7a-tetrahydro-2-benzofuran (69) was synthesized as a key compound

to synthesize bishomo-inositol derivatives. Then photooxygenation and

manganese(III) acetate oxidation reactions of this key compound were studied in

order to obtain isomeric inositol derivatives. Moreover, dihydroxylation and acid

catalyzed ring opening reactions were investigated. Finally, new synthetic

approaches for the synthesis of bishomo-inositol derivatives have been developed. In

addition to that whole products were conscientiously purified and characterized and

mechanism for the formation of the products has been discussed.

Keywords: Cyclitol, inositol, bishomo-inositol, photooxygenation, dihydroxylation,

1,3,3a,7a-tetrahydro-2-benzofuran, manganese(III) acetate.

v

ÖZ

BİSHOMO-İNOSİTOL TÜREVLERİNİN SENTEZİ

Bekarlar, Merve Gökçen

Yüksek Lisans, Kimya Bölümü

Tez Yöneticisi: Prof. Dr. Metin Balcı

Eylül 2011, 128 sayfa

İnositoller, siklitol adı verilen biyolojik olarak aktif olan önemli bir sınıfa ait olup,

birçok biyolojik olayı etkileyen glykosidaz inhibe edici özelliği nedeniyle son

yıllarda oldukça ilgi çekmiştir.

Öncelikle bishomo-inositol türevlerinin sentezi için 1,3,3a,7a-tetrahidro-2-

benzofuran (69) anahtar molekül olarak sentezlendi. Daha sonra farklı sentez yolları

elde etmek için anahtar molekülün fotooksijenasyon ve mangan(III) asetat

oksidasyon reaksiyonları çalışıldı. Bununla beraber, dihidroksilasyon ve asit

katalizörlüğündeki halka açma reaksiyonları incelendi. Son olarak, bis-homoinositol

türevlerinin sentezi için yeni sentetik yaklaşımlar geliştirildi. Ayrıca bütün ürünler

özenle saflaştırıldı ve karakterize edildi.

Anahtar Kelimeler: Siklitol, inositol, bishomo inositol, 1,3,3a,7a-tetrahidro-2-

benzofuran, fotooksijenasyon, mangan(III) asetat, dihidroksilasyon.

vi

ACKNOWLEDGEMENTS

I would like to express my special thanks to my supervisor Prof. Dr. Metin Balcı for

his guidance, patience, supports and encouragements. It was a great chance for me to

be a student of Prof. Balcı.

I also give my thanks to the members of our research group; SYNTHOR especially

to Alper Kılıklı, Berk Müjde, Burak Südemen, Emrah Karahan, Selbi Keskin, Serdal

Kaya for their friendships and helpfulness. I am grateful to Selbi Keskin for her

assistance. I would also like to thank to Arif Baran, Dilem Doğan, Yasemin Altun,

for their helps about the study.

I wish to express my special thanks to my bench mate: Melek Sermin Özer, for her

friendship and endless helps from wherever she is. She was my best suppporter

during my master study and made this time enjoyable for me.

I would like to thank to my friends; Nagehan Keskin, Huriye Erdoğan, Sevinç

Tunçağıl for their invaluable friendship and supports.

My special thanks to Can Nebigil for his encouragement and friendship.

Thanks to all members of METU Chemistry Department.

Finally, my special appreciation and great gratitude is devoted to my family for their

endless love, and encouragement in every moment of my life. Specially, to my sister

Hande Bekarlar for her patience, moral support.

vii

TABLE OF CONTENTS

ABSTRACT ................................................................................................................ iv

ÖZ ................................................................................................................................ v

ACKNOWLEDGEMENTS ........................................................................................ vi

TABLE OF CONTENTS ........................................................................................... vii

LIST OF FIGURES ..................................................................................................... x

LIST OF SCHEMES ................................................................................................. xiv

LIST OF ABBREVIATIONS ................................................................................... xvi

CHAPTERS

1. INTRODUCTION.................................................................................................... 1

1.1 Cyclitols ............................................................................................................. 1

1.2 Inositols .............................................................................................................. 1

1.2.1 Biologic functions of inositols .................................................................... 3

1.3 Synthesis of inositol and inositol derivatives ..................................................... 4

1.3.1 Synthesis of myo-inositol ............................................................................ 4

1.3.2 Synthesis of neo-inositol (10) ..................................................................... 5

1.3.3 Synthesis of allo-inositol (11) ..................................................................... 6

1.3.4 Synthesis of chiro-inositol (7) ..................................................................... 7

1.3.5 Synthesis of epi-inositol (12) ...................................................................... 8

1.3.6 Synthesis of muco-inositol (6) .................................................................... 9

1.3.7 Synthesis of cis-inositol (9) ......................................................................... 9

1.3.8 Synthesis of scyllo-inositol (5) .................................................................. 11

1.3.9 Synthesis of bicyclic inositols ................................................................... 12

1.3.10 Synthesis of bishomo-inositols ............................................................... 13

1.4 Singlet Oxygen ................................................................................................. 17

viii

1.5 Manganese (III) Acetate Oxidation Reactions ................................................. 20

1.6 Aim of thesis .................................................................................................... 21

2. RESULTS AND DISCUSSION ............................................................................ 23

2.1 Synthesis of 3aR(S),7aS(R)-1,3,3a,7a-tetrahydro-2-benzofuran (69) ............. 23

2.2 Photooxygenation of 3aR(S),7aS(R)-1,3,3a,7a-tetrahydro-2-benzofuran (69) . 24

2.3 Rearrangement of endoperoxide 94 to bisepoxide 100 .................................... 25

2.4 Acid catalyzed ring opening reaction of the bisepoxide 100 ........................... 27

2.4.1. Ring opening reaction of the bisepoxide 100 in the presence of water ... 27

2.4.2. Ring Opening Reaction of the Bisepoxide 100 without Water .................... 29

2.4.3 Manganese (III) Acetate Oxidation Reaction of rel-(3aR,7aS)-1,3,3a,7a-

Tetrahydro-2-benzofuran (69) ............................................................................ 38

2.4.4 Upjohn Dihyroxylation ............................................................................. 43

2.4.5 Reduction of Lactone in Diacetate Isomers 120 & 121 by LiAlH4 .......... 49

3. EXPERIMENTAL ................................................................................................. 50

3.1 General ............................................................................................................. 50

3.2 Synthesis of cis-1,2,3,6,-Tetrahydrophthalyl Alcohol (91).............................. 51

3.3 Synthesis of rel-(1R, 3S)-1,3,3a,4,7,7a-Hexahydro-2-benzofuran (92) ........... 51

3.4 Synthesis of rel-(3aR,5R,6S,7aS)-5,6-Dibromooctahydro-2-benzo furan (94) 52

3.5 Synthesis of rel-(3aR,7aS)-1,3,3a,7a-Tetrahydro-2-benzofuran (69) ............... 53

3.6 Synthesis of rel-(1R,2R,6S,7S)-4,10,11-trioxa-tricyclo[5.2.2.02,6]undec-8-ene

(94) ......................................................................................................................... 53

3.7 Synthesis of rel-(1aR,1bS,2aS,2bS,5aR,5bR)-octahydrobis (oxireno)

isobenzofuran (100) ............................................................................................... 54

3.8 Synthesis of rel-(1R,5S,6R,7S,8S,9S)-3-oxabicyclo[3.3.1]nonane-6,7,8,9-

tetrayl tetraacetate (103) ......................................................................................... 55

3.9 Synthesis of rel-(1R,5S,6R,7S,8S,9S)- 3-oxabicyclo [3.3.1]nonane-6,7,8,9-

tetraol (105) ............................................................................................................ 56

ix

3.10 Synthesis of rel-(3aR,4S,5R,6R,7S,7aS)-octahydro-2-benzofuran-4,5,6,7-

tetrayl tetraacetate (102) ......................................................................................... 56

3.11 Manganese (III) Acetate Oxidation Reaction of rel-(3aR,7aS)-1,3,3a,7a-

Tetrahydro-2-benzofuran (69) ................................................................................ 57

3.12 cis-Hydroxylation of rel-(3aR,5aR,8aS,8bR)-1,3,3a,8,8a,8b Hexahydro

benzo[1,2-b:3,4-c’]difuran-7(5aH)-one (115) ........................................................ 59

4. CONCLUSION ...................................................................................................... 61

REFERENCES ........................................................................................................... 63

APPENDIX ................................................................................................................ 65

A. SPECTRAL DATA ........................................................................................... 65

x

LIST OF FIGURES

FIGURES

Figure 1. Cyclitol derivatives ....................................................................................... 1

Figure 2. Inositol Stereoisomers ................................................................................. 2

Figure 3. Molecular Orbital Diagram of O2 Molecule ............................................... 18

Figure 4. Electronic States of Molecular Oxygen ...................................................... 19

Figure 5. Formation of Singlet Oxygen with Sensitizer ............................................ 19

Figure 6. Singlet Oxygen Reactions .......................................................................... 20

Figure 7. COSY spectrum of expected product of 101 .............................................. 30

Figure 8. X-ray analysis of the product of ring opening reaction of bisepoxide 100 32

Figure 9. 1H-NMR spectrum of the product of Mn(OAc)3 reactionof diene 69. ....... 42

Figure 10 Mechanism of Upjohn Dihyroxylation ...................................................... 43

Figure 11. Optimized geometry of the molecule 115 ................................................ 44

Figure 12. Geometry Optimization of Molecule 120 ................................................. 46

Figure 13. Geometry Optimization of Molecule 121 ................................................. 46

Figure 14. Karplus-Conroy Curve............................................................................. 47

Figure A. 1 1H-NMR spectrum of compound 91 ....................................................... 65

Figure A. 2 13C-NMR spectrum of compound 91 ...................................................... 66

Figure A. 3 IR spectrum of compound 91 ................................................................. 67

xi







Figure A. 10 1H-NMR spectrum of compound 69 ..................................................... 74

Figure A. 11 13C-NMR spectrum of compound 69 .................................................... 75

Figure A. 12 IR spectrum of compound 69 ............................................................... 76

Figure A. 13 1H-NMR spectrum of compound 94 ..................................................... 77

Figure A. 14 13C-NMR spectrum of compound 94 .................................................... 78

Figure A. 15 IR Spectrum of Compound 94 .............................................................. 79

Figure A. 16 1H-NMR Spectrum of Compound 100 ................................................. 80

Figure A. 17 13C-NMR Spectrum of Compound 100 ................................................ 81

Figure A. 18 IR Spectrum of Compound 100 ............................................................ 82

Figure A. 19 DEPT-135 spectrum of compound 100 ................................................ 83

Figure A. 20 COSY spectrum of compound 100 ....................................................... 84

Figure A. 21 HSQC spectrum of compound 100 ....................................................... 85

Figure A. 22 HMBC spectrum of compound 100 ...................................................... 86

Figure A. 23 1H-NMR spectrum of compound 103 ................................................... 87

Figure A. 24 13C-NMR spectrum of compound 103 .................................................. 88

Figure A. 25 IR spectrum of compound 103 ............................................................. 89

xii




Figure A. 29 HMBC spectrum of compound 103 ...................................................... 93

Figure A. 30 1H-NMR spectrum of compound 105 ................................................... 94

Figure A. 31 13C-NMR spectrum of compound 105 .................................................. 95

Figure A. 32 IR spectrum of compound 105 ............................................................. 96




Figure A. 36 HMBC spectrum of compound 105 .................................................... 100

Figure A. 37 1H-NMR spectrum of compound 103 ................................................. 101

Figure A. 38 13C-NMR spectrum of compound 103 ................................................ 102

Figure A. 39 IR spectrum of compound 103 ........................................................... 103

Figure A. 40 DEPT-135 spectrum of compound 103 .............................................. 104

Figure A. 41 COSY spectrum of compound 103 ..................................................... 105

Figure A. 42 HSQC Spectrum of Compound 103 ................................................... 106

Figure A. 43 HMBC Spectrum of Compound 103 .................................................. 107





xiii


Figure A. 49 HSQC spectrum of compound 114 ..................................................... 113





Figure A. 54 DEPT spectrum of compound 121 ..................................................... 118


Figure A. 56 HSQC spectrum of compound 121 ..................................................... 120






Figure A. 62 COSY Spectrum of Compound 122 ................................................... 126

Figure A. 63 HSQC Spectrum of Compound 122 ................................................... 127


xiv

LIST OF SCHEMES

SCHEMES

Scheme 1. The first total synthesis of inositol ............................................................. 4

Scheme 2. Synthesis of neo-inositol 10 ....................................................................... 5

Scheme 3. Formation of allo-inositol 11 ..................................................................... 6

Scheme 4. Chiro-inositol (7) synthesis from myo-inositol 4 ....................................... 7

Scheme 5. Formation of epi-inositol 12 ....................................................................... 8

Scheme 6. Synthesis of muco-inositol 6 ...................................................................... 9

Scheme 7. Synthesis of cis-inositol 9 ......................................................................... 10

Scheme 8. Formation of scyllo-inositol 5 .................................................................. 11

Scheme 9. Synthesis of chiro-inositol derivative 55 from napthalene....................... 12

Scheme 10. Synthesis of bishomo-inositols from cyclooctatetraene ......................... 13

Scheme 11. Synthesis of inositol derivatives having bicyclo[2.2.2]octane skeleton . 14

Scheme 12. Synthesis of bishomo-myo-inositol 74 ................................................... 15

Scheme 13. Bishomo-inositol derivatives from 1,3,3a,7a-tetrahydro-2-benzofuran . 16

Scheme 14. Synthesis of hydroxy-skipped homo-inositol 81 .................................... 17

Scheme 15. Formation of the γ-lactones ................................................................... 20

Scheme 16. Reactions of benzonorbornadiene with Mn(OAc)3 ................................ 21

Scheme 17. Synthesis of benzofuran derivative 92 ................................................... 23

Scheme 18. Synthesis of key compound 69 ............................................................... 24

xv

Scheme 19. Photooxygenation reaction of 69 ............................................................ 24

Scheme 20. CoTPP-catalyzed rearrangement of endoperoxide 95 ............................ 25

Scheme 21. Mechanism of CoTPP catalyzed rearrangement of endoperoxide 98 .... 26

Scheme 22. Synthesis of compound 100.................................................................... 26

Scheme 23. Ring opening reaction of 100 ................................................................. 27

Scheme 24. Expected product of the ring opening reaction of bisepoxide 100 ......... 29

Scheme 25. Proposed mechanism of reaarrangement ................................................ 34

Scheme 26. Acetolysis reaction of tetraacetate 103 ................................................... 37

Scheme 27. Hydrolysis of the molecule 103 .............................................................. 38

Scheme 28. The mechanism of the reaction of olefins with Mn(OAc)3 in acetic acid

.................................................................................................................................... 39

Scheme 29. The Mn(OAc)3 reaction of benzonorbornadiene and acetylacetone ...... 40

Scheme 30. Reaction of diene 69 with Mn(OAc)3. .................................................... 42

Scheme 31. Upjohn dihyroxylation of molecule 115 ................................................ 44

Scheme 32. Dihydroxylation of compound 115 ........................................................ 45

Scheme 33. Acetolysis and hydrolysis reactions of the compounds 120 and 121 .... 49

Scheme 34. Synthesis of tetraacetate 102 .................................................................. 61

Scheme 35. Synthesis of tetraacetate 103 .................................................................. 62

Scheme 36. Synthesis of diacetate molecules 120& 121 ........................................... 62

xvi

LIST OF ABBREVIATIONS

DMP: 2,2 Dimethoxypropane

PTSA: Paratoluenesulfonic acid

DBH: 1,3-Dibromo-5,-dimethylhydantoin

AIBN: Azobisisobutyronitrile

NMO: N-methylmorpholine N-oxide

TsCl: Toluenesulfonyl chloride

Tf2O: Trifluoromethanesulfonic anhydride

DMF: Dimethylformamide

DBU: 1,8 Diazobicycloundec-7-ene

mCPBA: metachloroperoxybenzoic acid

TFA: Trifluoroacetic acid

NBS: n-Bromosuccinimide

NMR: Nuclear Magnetic Resonance

DEPT: Distortionless enhancement by polarization transfer

HMBC: Heteronuclear multi-bond coherence

COSY: Correlation spectroscopy

HSQC: Heteronuclear single quantum coherence

ppm: Parts per million

TBAF: Tetra-n-butylammonium floride

1

CHAPTER 1

INTRODUCTION

1.1 Cyclitols

Cyclitols are cycloalkanes, which are highly substituted with hydroxy functional

groups. This class of compounds has received high interest due to the fact that many

biologically important molecules and natural products contain a polyhydroxylated

carbocycle. Among the numbers of cyclitols the most common ones are conduritols

(1), quercitols (2) and inositols (3).

Figure 1. Cyclitol derivatives

1.2 Inositols

Inositols are cyclohexanehexols. The first cyclohexanehexol was isolated by Scherer

in 1850. He named the cyclohexanehexol as inositol since ‘inos is the Greek name of

the muscle and he isolated it from the meat extract which is a muscular tissue.1 The

name was used for the other isomers as they were discovered. There are nine possible

stereoisomers for inositol. The naturally occurring isomers are myo- 4, D-chiro- 7,

2

scyllo- 5, muco- 6, neo-inositol 10 and the unnatural synthetic isomers are cis- 9, L-

chiro 8, epi- 12 and allo-inositol 11 (Figure 1).

Figure 2. Inositol Stereoisomers

The most abundant isomer of inositols is the myo-inositol (4). It is found in

eukaryotic cells in the form of phosphate derivative. Myo-inositol which is also

commercially available, found in many foods such as beans, nuts, cantaloupe,

orange.2 Myo-inositol is a convenient precursor for the synthesis of the other inositol

derivatives.

Scyllo-inositol (5), was isolated from the organs of fish3, also present in plants like

linden, coconut pulm.4 D-chiro-inositol (7) is not abundant in most diets, they are

less widely found in seeds and plants and in significant quantities in buckwheat

farinetta.5 Neo-inositol (10) phosphates have been isolated from some mammalian

3

tissue.6 Muco-inositol (6) is an another naturally occuring inositol is present in

honey.7

The inositols are crystalline substances with high-melting points and low solubility.

Generally they are stable to heat, acids, and alkalis.3

1.2.1 Biologic functions of inositols

Inositols have remarkable biological functions such as glycosidase inhibition,

intercellular communication, phosphate storage etc. In recent years inositols and

phosphate derivatives of inositols, which have significant role in various cellular

functions which are cell migration, cell differentiation, cell growth and endocytosis,

have been studied and new derivatives have been discovered.8

Inositol is also an effective and safe option in the treatment of panic disorder,

obsessive-compulsive disorder (OCD), bulimia nervosa, binge eating and/or

depression.9

Some inositol derivatives such as chiro- (7), muco- (6) and epi-inositol (12) have

been reported to help the action of insulin, which induces glucose uptake involving

the translocation of glucose transporter 4 (GLUT4) to the plasma membrane

particularly in muscle tissues.10

Scyllo-inositol (5) has shown promise as a potential therapeutic for Alzheimer’s

disease, scyllo-inositol derivatives inhibit or disrupt Ab peptide aggregation as

atherapeutic strategy to treat AD.11

Phosphate derivative of D-myo–inositol (4) act as a messenger molecule that used in

intercellular reactions as controlling the intercellular Ca2+ concentration.12

Bishomo-inositols shows inhibition of α-glycosidase which is important in the

treatment of diabetes and HIV infection.13, 14

4

1.3 Synthesis of inositol and inositol derivatives

The first synthesis of inositol was performed from benzene by Wieland and Wishart

in 1914.15 They synthesized inositol by hydrogenation reaction of benzenehexol 15

(Scheme 1).16

Scheme 1. The first total synthesis of inositol

Due to biological importance of the inositols different synthetic pathways have been

developed during the years. Inositols have been synthesized from aromatic

compounds, tetrahydrobenzoquinones, sugars, cyclohexene and its derivatives, chiral

acids, norbornenes, naturally occurring inositols, and others.

1.3.1 Synthesis of myo-inositol

Of the nine possible stereoisomers, myo-inositol is generally the most abundant. It is

widespread in all higher organisms and most microorganisms and plays very

important roles in cellular signal transduction.12

Myo-inositol is a crystalline compound with a sweet taste which was first isolated by

Scherer in 1849. Myo-inositol was synthesized from D-glucose in several steps.15

Different synthetic pathways for myo-inositol and their phosphates derivatives have

been developed during the years because of the important biological functions.

5

1.3.2 Synthesis of neo-inositol (10)

Hudlicky et al.17 developed a method for the synthesis of different inositol

derivatives including neo-inositol from bromobenzene.

Synthesis of neo-inositol 10 started with reaction of bromobenzene with toluene

dioxygenase which provided the diol 17. The protection reaction of diol and reaction

with 1,3-dibromo-5,-dimethylhydantoin (DBH) gave 18. Epoxide formation with

KOH, followed by the ring opening reaction at elevated temperatures afforded 20.

Debromination of 20 and cis hydroxylation by OsO4 formed molecule 21 which is

then converted to neo-inositol 10 with hydrochloric acid (Scheme 2).

BrOH

OH

Br

O

O

Me

Me

HO

Br

Br

O

O

OMe

Me

Br

O

O

Me

Me

HO

OH

Br

O

O

Me

Me

HO

OH

OH

HO

OH

OH

HO

OH

OH

HO

t.dioxygenase DMP,PTSA

DBH,H2O

KOH

DME

reflux

1.Bu3SnH/AIBN

2.OsO4,NMO

16 17 18 19

202110

HCl

MeOH

Scheme 2. Synthesis of neo-inositol 10

6

1.3.3 Synthesis of allo-inositol (11)

Altenbach et al.18 introduced new synthetic pathways for inositols including

conduritols as intermediates starting from benzoquinone. Allo-inositol 11 is one of

them which has been synthesized via conduritol-E.

Dibromodiacetate 23 which was synthesized from p-benzoquinone in several steps,19

was converted to dibromodiol isomers 24 and 25 with an enzymatic reaction using

pig pancreas lipase (PPL). Conduritol E derivative 26 was obtained from the reaction

of one of these dibromo isomers with sodium acetate and aqueous acetic acid in 10

days. Then cis-hydroxylation with RuCl3 and NaIO4 provided the molecule 27, which

was then converted to allo-inositol (11) (Scheme 3).

Scheme 3. Formation of allo-inositol 11

Other inositol derivatives; neo-, epi-, chiro- and scyllo-inositol were also synthesized

from p-benzoquinone via corresponding conduritols as intermediates. Neo-inositol

(10) was obtained from conduritol E, chiro-inositol (8) from conduritol B and epi-

inositol (12) from conduritol C.17

7

1.3.4 Synthesis of chiro-inositol (7)

Among the inositols myo-inositol (4) is the most abundant in nature, and also

commercially available with low cost. It is generally good precursor for the synthesis

of other inositol derivatives.

Miyake et al.20 developed a new method for synthesis of chiro-inositol (7) from myo-

inositol (4). Synthesis started with reaction of myo-inositol (4) with camphor

dimethyl acetal which provided ketal 28. The ketal 28 was reacted with Tf2O or TsCl

then hydroxyl groups were converted to acetate groups to form triacetate 30.

Treatment of the triacetate 30 with BzOLi in DMF gave the compound 31 which was

then converted to D-chiro-inositol (7) by hydrolysis (Scheme 4).

Scheme 4. Chiro-inositol (7) synthesis from myo-inositol 4

8

1.3.5 Synthesis of epi-inositol (12)

Epi-inositol (12) was synthesized starting from methyl β-D galactopyranoside (32)

with highly stereoselective route (Scheme 5).21

The compound 33 was synthesized from the commercially available methyl β-D

galactopyranoside 32.22 Treatment of 33 with DBU resulted in the formation of

inosose 34, which was reduced selectively by catalytic hydrogenation with Raney-Ni

or with NaBH4 to give the epi-inositol derivative 35. The catalytic debenzylation of

35 gave epi-inositol (12).

O

CH2OHHO

OH

OMe

OH CHO

CH2OBnO

HO

OBn

OHDBU

Toluene

OBnH5

HO

HO

H6

BnO

H2

H3

OH

H4

H3H4

OH

OH

H5

H6

OBnOH

H1

H2

OBn

HO

O

Raney-Ni/H2

or

NaBH4, -78 oC

H3H4

OH

OH

H5

H6

OH

OH

H1

H2

OH

HO

H2,Pd(C)

MeOH

32 33 34

3512

OHOHHO

OH

OHHO

=

Scheme 5. Formation of epi-inositol 12

9

1.3.6 Synthesis of muco-inositol (6)

Hudlicky et al.17 developed a synthetic pathway for muco-inositol (6) via the

microbial oxidation of bromobenzene. The starting compound epoxide 36 was

synthesized from the diene diol 17,23 which was obtained from bromobenzene as

shown in Scheme 2. Synthesis started with epoxide opening and followed by

reduction to form diol 37. Oxidation of the diol 37 with m-CPBA gave epoxide

isomers 38 and 39. Hydrolysis of the diastereomers formed myo- and muco-inositol

mixture. Muco-inositol (6) was seperated by crystallization (Scheme 6).

Scheme 6. Synthesis of muco-inositol 6

1.3.7 Synthesis of cis-inositol (9)

Takahashi et al.24 synthesized inositol diastereoisomers from PdCl2-catalyzed

Ferrier-II carbocyclization of methyl 6-O-acetyl-5-enopyranosides. cis-Inositol was

synthesized from methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α-D-glucopyranoside 40

which was prepared from methyl glucoside. The β-hydroxyketone 41 was obtained

from corresponding glucopyranoside via Ferrier-II carbocyclization reactions.25

10

Reduction of the β-hydroxyketone 41 with NaBH4 gave the molecule 42 as a single

diastereoisomer. Removal of the benzyl groups with H2 in the presence of Pd(OH)2

resulted in the formation of pentaol 43. The regioselective protection of the pentaol

with acetone under acidic conditions provided 44. The inversion of the free hydroxyl

group of compound 44 was succeeded by the reaction of the corresponding triflate 45

with CF3COOCs and 18-crown-6 followed by saponification. Further deprotection

under acidic conditions formed the cis-inositol (9) (Scheme 7).

Scheme 7. Synthesis of cis-inositol 9

11

1.3.8 Synthesis of scyllo-inositol (5)

Synthetic pathway for the scyllo-inositol (5) was developed starting from myo-

inositol via its orthoformate.26 The benzoylation of myo-inositol 1,3,5,-orthoformate

followed by the tosylation of the remaining hydroxyl groups to form the compound

47. Removal of the benzoyl group gave the alcohol 47 which was further submitted

to Swern oxidation reaction. Resulted compound 48 treated with the sodium

borohydride for the reduction of carbonyl group. Methanolysis of the tosylates and

then acetylation formed scyllo-inositol 1,3,5,-orthoformate 50 as a triacetate.

Cleavage of the orthoformate yielded scyllo-inositol 5 (Scheme 8).

Scheme 8. Formation of scyllo-inositol 5

12

1.3.9 Synthesis of bicyclic inositols

Aromatic compounds were not used as a precursor only for the synthesis of inositols

but also for the inositol analogues. Mehta et al.27 presented the polycylitols as a new

term, which might be biologically active like conduritols and carbosugars. They

proposed bicyclic inositols that have potential for biological activity.6 They have also

synthesized conjoined and annulated inositols.

Naphthalene, anthracene and indene are the precursor for the synthesis of this new

class.

Scheme 9. Synthesis of chiro-inositol derivative 55 from napthalene

Bicyclic inositols were synthesized from napthalene by Mehta and Ramesh28

(Scheme 9). Birch reduction of naphtalene gave isotetralin 51 which was converted

to 52 in 3 steps. The reaction of 52 with NBS for allylic bromination, followed by

dehydrobromination reaction provided the diene 53. Hydroxylation of diene unit in

53 gave the tetrol 54. Hydrolysis of tetrol formed the annulated chiro-inositol 55.

13

1.3.10 Synthesis of bishomo-inositols

Balci and Kara29 introduced a new class of inositol, bishomo-inositol, which was

synthesized from cyclooctatetraene (Scheme 10).

Scheme 10. Synthesis of bishomo-inositols from cyclooctatetraene

Cyclooctatetraene (56) was reacted with mercury(II) acetate to give diacetoxydiene

57. Photooxygenation of diacetoxydiene 57 in the presence of a sensitizer

tetraphenylporphyrin (TPP) formed endoperoxide 58. Reduction of endoperoxide and

further acetylation afforded tetraacetate 59. Treatment of the tetraacetate 59 with

KMnO4 formed the cis-diol 60, which was converted to bishomo-inositol 61 by

deacetylation.

Balci et al.13 synthesized bishomo-inositol derivatives having the bicyclo[2.2.2]

octane skeleton (Scheme 11).

14

O

O O

OO

OO

O

O

OO

O

O

O

O+

OAcOAc

OAc

OAc

OAcOAc

OAc

OAc

AcO

AcO

OHOH

OH

OH

HO

HO

1. OsO4/ NMO

2. Ac2O/pyr.

NH3

MeOH

1. HCl(g),MeOH2. K2CO3,MeOH3. Ac2O,pyr.

62 63 64

65 66 67

Scheme 11. Synthesis of inositol derivatives having bicyclo[2.2.2]octane skeleton

Synthesis started with the reaction of diene 62 with vinylene carbonate to give

isomeric products 63 and 64. Hydrolysis product of the 63 was treated with K2CO3 in

MeOH for the opening of carbonate functionality and further acetylation gave the

tetraacetate 65. The hexaacetate 66 was obtained by cis-hydroxylation of 65 followed

by acetylation. Treatment of hexaacetate with ammonia gave the hexol 67.

Baran and Balci14 synthesized bishomo-inositol derivatives from 1,3,3a,7a-

tetrahydro-2-benzofuran (69). Bishomo-allo-inositol 74 was synthesized from the 1,3

diene 69, which was synthesized from the anhydride 68 (Scheme 12). One of the

double bonds in the diene 69 was subjected to cis-dihyroxylation and acetylation to

afford 70. The resulted diacetate 70 was exposed to epoxidation reaction and

converted to oxirane isomers 71 and 72. The isomer 71 was treated with sulfamic

acid for the cleavege of epoxide and furan ring, further acetylation gave hexaacetate

73. Hydrolysis of the hexaacetate provided the bishomo-myo-inositol (74).

15

Scheme 12. Synthesis of bishomo-myo-inositol 74

Baran and Balci14 synthesized several inositol analogs starting from 1,3,3a,7a-

tetrahydro-2-benzofuran (69) via different pathways (Scheme 13). Bishomo-allo-

inositols 76, 77 and bishomo-chiro-inositol 75 were also synthesized and their α-

glycosidase inhibition activities were determined.

16

Scheme 13. Bishomo-inositol derivatives from 1,3,3a,7a-tetrahydro-2-benzofuran

Recently, Mahapatra and Nanda30 synthesized hydroxy-skipped homo-inositol 81

analogs from enantiomers of 5-hydroxymethyl-2-cyclohexenone (Scheme 14).

The synthesis started with the protection of the free hydroxyl group of (S)-5-

hydroxymethyl-2-cyclohexenone 78 by tert-butyl diphenylchlorosilane (TBDPS-Cl).

Hydroxymethylation of TBDPS ether resulted in the formation of 79. Asymmetric

dihydroxylation of the compound 79 with AD-mix-α gave diol 80. The reduction

reaction with NaBH4 followed by deprotection provided the inositol 81.

17

Scheme 14. Synthesis of hydroxy-skipped homo-inositol 81

1.4 Singlet Oxygen

Singlet oxygen, which was first identified in 1924, is an important and reactive

species in chemical reactions. Not only the chemistry of singlet oxygen but also its

biological functions especially in certain blood diseases, in cancer-inducing

mechanism and in metabolic hydroxylation raise the study of singlet oxygen. Beside

its biological role, reactions and applications of singlet oxygen have also been

searched.31 The reactivity of singlet oxygen can be understood by the molecular

orbital diagram as illustrated in Figure 2.

18

Figure 3. Molecular Orbital Diagram of O2 Molecule

In the ground state, the molecular oxygen has two unpaired electrons with parallel

spin at π*2p orbitals and is shown as triplet oxygen 3O2. Because of the parallel spin

of unpaired electrons, ground state oxygen molecule is paramagnetic and biradical.

Moreover parallel electron spins are not allowed for the direct access of paired

electrons and enable the single-electron step reactions.

The O2 molecule can absorb energy in order to change its electron configuration to

one of the singlet configurations. The two lowest electronic states of molecular

oxygen known as singlet oxygen have electrons with antiparallel spins (Figure 3).

19

Figure 4. Electronic States of Molecular Oxygen

In both forms of singlet oxygen the spin restriction is removed and so the oxidizing

ability is great. Life time of the singlet oxygen is very short with respect to triplet

oxygen. The lower energy state, 1∆ is much longer lived than the other energy states.

Photosensitization reactions are the general method for the formation of singlet

oxygen in laboratory. The reactions are performed under light in the presence of a

sensitizer. Excitation of the sensitizer with light, continue with intersystem crossing

(ISC) and transfer of the energy to an adjacent oxygen molecule generating the

singlet oxygen and ground state sensitizer back (Figure 4). Generally dye molecules

are used as sensitizers such as methylene blue, rose bengal and porphyrins.

Figure 5. Formation of Singlet Oxygen with Sensitizer

There are different types of reactions of singlet oxygen with unsaturated molecules.

The three most common reaction types of singlet oxygen with olefins are the ene

20

reaction, Diels-Alder reaction, and the [2+2] cycloaddition reaction (Figure 5). As a

result of ene reaction of singlet oxygen with olefins hydroperoxides are mainly

formed. On the other hand, the reaction of 1O2 with dienes and/or electron rich

olefins generate bicyclic endoperoxides and [2+2] cycloaddition reaction provides

1,2-dioxetane All three types of singlet oxygen reactions have been utilized in

organic synthesis for the regiospecific and stereospecific oxidation of olefins.

1.5 Manganese (III) Acetate Oxidation Reactions

Mn(OAc)3, which is an oxo-centered coordination complex, is a versatile oxiding

agents for the synthesis of many important organic compounds. Heiba, Dessau,

Bush, and Finkbeiner have demonstrated in 1968 that reactions of olefins with

Mn(OAc)3 in acetic acid at reflux resulting the γ-lactones32(Scheme 15).

Scheme 15. Formation of the γ-lactones

Figure 6. Singlet Oxygen Reactions

21

This was the basis for the oxidatively initiate free radical reactions of Mn(OAc)3

which has been further developed and used in synthetic chemistry till today with its

different mechanistic pathways34.

Balci and co workers also studied Mn(OAc)3 reactions. Mn(OAc)3 treated with

benzonorbornadiene and its derivatives. The mechanism of the reaction with the

affect of the co-oxidant Cu(OAc)2 were investigated.38

Scheme 16. Reactions of benzonorbornadiene with Mn(OAc)3

1.6 Aim of thesis

Due to their potential for biological activities, developing new synthetic pathways for

the inositol derivatives is important. Various methodologies have been developed for

the synthesis of inositols and their derivatives. The synthesis of inositols was

achieved either via the transformation of other cyclitols, generally the myo-inositol,

or via appropriate substrates. Balci and co-workers formulated strategy of synthesis

based on the photooxygenation of the appropriate dienes.

22

Baran and Balci14 achieved the stereoselective synthesis of isomeric bishomo-inositol

derivatives starting from the diene 69 and introduced the complex stereochemistry by

combination of photooxygenation, epoxidation, and cis hydroxylation reactions. The

α-glycosidase inhibitory activities were also investigated and it was found that some

of the isomers showed α-glycosidase inhibitions.

In this work, we are interested in synthesis of bishomo-inositol derivatives from

1,3,3a,7a-tetrahydro-2-benzofuran 69 via different pathways. The key compound 69

is synthesized in several steps. Photooxygenation reaction of diene 69, followed by

formation of bisepoxide and acid catalyzed ring opening reactions of this epoxide

were the planned steps to perform. In the second part of the study we decided to

perform manganese (III) oxidation of the diene 69 and further cis hydroxylation

reactions.

All products will be purified and characterized also the formation mechanism of the

products would be studied.

23

CHAPTER 2

RESULTS AND DISCUSSION

In order to synthesize different bishomo-inositol derivatives we have chosen

1,3,3a,7a-tetrahydro-2-benzofuran (69) as a key compound. Using two different

pathways starting from the key compound 69, different bishomo-inositol derivatives

were synthesized. Firstly, we started to synthesize the key compound 69 from cis-

1,2,3,6-tetrahydrophytalic anhydride (90) in several steps for further reactions.

2.1 Synthesis of 3aR(S),7aS(R)-1,3,3a,7a-tetrahydro-2-benzofuran (69)

The commercially available cis-1,2,3,6-tetrahydrophytalic anhydride (90) was

reduced to corresponding alcohol 91 by LiAlH4 in THF at 0 oC. Treatment of the

resulted alcohol 91 with p-toluenesulfonyl chloride in pyridine gave the benzofuran

derivative 92. The resulted benzofuran derivative was purified by vacuum distillation

to give colorless liquid 92. The 1H NMR and 13C NMR spectra of the compounds 91

and 92 are in agreement with those reported in the literature.14

.

Scheme 17. Synthesis of benzofuran derivative 92

24

The compound 92 was submitted to bromination reaction to form addition product

93. Elimination of this dibromide 93 with DBU in benzene provided the key

compound, rel-(3aR,7aS)-1,3,3a,7a-tetrahydro-2-benzofuran (69).

Scheme 18. Synthesis of key compound 69

2.2 Photooxygenation of 3aR(S),7aS(R)-1,3,3a,7a-tetrahydro-2-benzofuran (69)

After synthesizing the key compound 69, we decided to follow two different

pathways to synthesize different bishomo-inositol derivatives. One of these pathways

started with singlet oxygen reaction. Singlet oxygen reaction was performed with

oxygen gas in the presence of a sensitizer and a light source. The key compound 69

and the sensitizer, tetraphenylporphyrine (TPP), were dissolved in CH2Cl2. The

mixture was irradiated with a projection lamp (500 W) for 12 h at room temperature

while oxygen was passed through the solution. After the reaction was completed,

singlet oxygen addition product 94 was obtained in 81 % yield.

Scheme 19. Photooxygenation reaction of 69

Formation of single isomer 94 was proved by 1H and 13C spectra. 1H and 13C spectra

were in agreement with the reported in the literature.14 Although, dissymmetric diene

unit in the key compound 69 seems to be open to attack for both sides, the structure

of the single product 94 showed that one side was favored. Baran and Balci

25

explained this favor as a result of the repulsive interaction between the nonbonded

electrons of oxygen in the tetrahydrofuran ring and on the singlet oxygen molecule.14

2.3 Rearrangement of endoperoxide 94 to bisepoxide 100

After the characterization of endoperoxide 94, the next step was treatment of 94 with

cobalt meso tetraphenylporphine (CoTPP) complex to get the rearranged product of

endoperoxide 94. Balci and coworkers39 studied the reactions of various unsaturated

bicyclic endoperoxides with CoTPP. Although diepoxides were major products, it

was seen that open-chain epoxy aldehydes were also formed (Scheme 20). From the

various product distribution with different endoperoxides, Balci et al.39 explained the

mechanism as both diepoxides and epoxy ketones formed from the oxygen-oxygen

diradicals. However, ring closures of these radicals are in competition with the 1,2-

hydrogen shift required to yield an epoxy ketone and the difference in activation

energy causes the epoxide formation to be favored.

Scheme 20. CoTPP-catalyzed rearrangement of endoperoxide 95

Adam et al.35 performed the CoTPP-catalyzed rearrangement of keto endoperoxide

98 which afford bisepoxide 99 as a major product.Decomposition reaction of the keto

endoperoxide 98 in the presence of CoTPP involves radical pathways. The possible

mechanism for the formation of bisepoxide 99 from the keto endoperoxide 98 was

given by Adam et al.35 (Scheme 21).

26

Scheme 21. Mechanism of CoTPP catalyzed rearrangement of endoperoxide 98

The CoTPP complex, synthesized from TPP, was dissolved in CH2Cl2 and was

added dropwise to a solution of endoperoxide 94 in an ice-bath. When addition was

completed, reaction mixture was stirred for additional 2 h at room temperature.

Crude product was submitted to column chromatography eluting with hexane/EtOAc

(2:3) (Scheme 22).

Scheme 22. Synthesis of compound 100

Resulting single product was characterized by 1D&2D NMR. Five sets of signals in 1H-NMR and four sets of singlets in 13C-NMR of the compound 100 indicated the

formation of symmetrical compound. Moreover both 1H-NMR and 13C-NMR spectra

showed that the signals in the olefinic region were disappeared.

In 1H-NMR spectrum methylenic protons of the furan ring resonate as an AB-system

between 3.94 to 3.62 ppm. Four epoxide protons gave two symmetrical signals which

resonate as doublet at 3.41 ppm and multiplet at 2.63 ppm. The remaining methine

protons appear at 2.97 as multiplet.

13C NMR also shows the symmetry with four signals at 126.2, 122.3, 75.0, 37.8 ppm.

27

2.4 Acid catalyzed ring opening reaction of the bisepoxide 100

There are different routes for the opening of the epoxide rings. A wide range of

nucleophiles can attack to epoxide ring under both acidic and basic conditions

resulting in ring opening. Generally in basic medium ring opening reactions followed

SN2 mechanism whereas in acidic medium depending on the type of the epoxide both

SN2 and SN1 mechanism can proceed.36

In our study we preferred an acid catalyzed ring opening reaction for the bisepoxide

100. To synthesize the tetraacetate 101, the bisepoxide was reacted with H2SO4

under two different conditions; in the presence and absence of water.

2.4.1. Ring opening reaction of the bisepoxide 100 in the presence of water

In order to open the epoxide rings in compound 100, we decided to perform acid

catalyzed ring opening reaction with H2SO4 in the presence of water followed by

acetylation of the formed tetrol by Ac2O in pyridine. Due to the presence of two

epoxide functionalities and a tetrahydrofuran ring, formation of different

configurational isomers was expected.

Scheme 23. Ring opening reaction of 100

From the spectral data it was determined that three isomers were formed with the

ratio 67 %, 16.5%, 16.5%. The mixture was submitted to column chromatography on

silica gel and as the major product rel-(3aR,4S,5R,6R,7S,7aS)-4,6,7-

tris(acetyloxy)octahydro-2-benzofuran-5-yl acetate (102), was obtained.

28

The structure of the major compound was characterized by spectroscopic methods

such as 1D- and 2D-NMR.

In 1H-NMR spectrum four acetoxy protons resonate between 5.29 to 5.02 ppm.

Methylene protons of the furan ring resonate as two distinct AB-system in the region

3.83 to 3.67 ppm. The two methine protons in the intersection of the cyclohexane and

furan ring resonate as multiplets at 2.98 and 2.35 ppm. The remaining protons of

acetate groups resonate between 1.97-1.93 ppm as singlets.

13C-NMR consist of sixteen lines containing four carbonyl group at 169.9, 169.8,

169.7, 169.6 ppm, four acetoxy carbon at 72.8, 71.1, 70.93, 70.3 ppm, two

methylenic carbons at 70.0, 67.4 ppm. Methyl and methine carbon resonances appear

at 42.2, 40.5, 20.7, 20.68, 20.57, 20.53 ppm.

Assignment of the product was done by using 2D-NMR especially the correlations in

HMBC&COSY. To determine the exact configuration of the acetate groups, the

corresponding coupling constants were measured between the relevant protons. The

acetoxy proton H-5 in 102 resonates as doublet of doublets with the couplings J45 =

9.5 Hz, J56 = 9.1 Hz, indicating the trans configuration of H-5 with respect to

neighboring protons H-4 & H-6. Beside the proton H-5 acetoxy proton H-6 also

gives coupling with H-7 with the coupling constant J76 = 10 Hz, which shows the

trans configuration of H-6 to H-7. In addition to that H-7 resonates as triplet with a

coupling constant 10 Hz, which indicated its trans position to neighboring protons.

As a result, configuration of H-7 is cis to furan ring. However for H-4 the situation is

reverse; coupling constant between H-4 and H-3a is relatively smaller, J43a = 6.0 Hz,

which shows us H-4 is trans to furan ring.

29

2.4.2. Ring Opening Reaction of the Bisepoxide 100 without Water

In order to open the bisepoxide, we have treated compound 100 with acetic

anhydride in the presence of H2SO4. Although we expected the formation of

tetraacetate isomers from the nucleophilic substitution reaction of acetic anhydride,

spectral data confirmed the formation of single isomer.

Scheme 24. Expected product of the ring opening reaction of bisepoxide 100

The 1H-NMR and 13C-NMR spectra of the resulted compound, indicate that there is

an unsymmetrical compound which involves 13 different proton signals and 15 line

carbon atoms.

Assignment of the protons and carbons were done with the combination of 1D&2D-

NMR. In addition to the chemical shifts, correlations, which were shown by HMBC

and COSY spectra, were important to label the protons and carbons.

In 1H-NMR, the presence of 10 different proton signals beside the methyl protons at

2.08-1.92 ppm, shows that bisepoxide was opened in an unsymmetrical way. Four

different protons in low field belong to methine protons of cyclohexane ring which

are adjacent to acetate groups. Acetoxy protons resonate at 5.74, 5.56 ppm as doublet

as doublets, at 5.50 ppm as doublet of doublets of doublets and at 4.96 ppm as broad

triplet. Methylenic protons of the furan ring (H-2,2’ and H-4,4’) resonate as 2

different AB systems between 4.14 and 3.54 ppm. Two signals at 2.43 and 2.29 ppm

belong to methine protons H-5 and H-1 of the compound. Six methyl protons of

acetate groups resonate at 2.08 (6H), 2.01(3H) and 1.92(3H) ppm.

13C-NMR spectra with DEPT-90 and DEPT-135 also support the formation of single

unsymmetric product. It is seen that four different carbonyl carbons exist in the

compound. DEPT-90 shows that the carbon resonances between 72.8 and 69.5 ppm

30

belongs to 4 distinct carbons to which acetoxy groups are attached and 2 carbons at

39.6 and 38.7 ppm belong to carbons C-1 and C-5. DEPT-135 indicates two

methylenic carbons of furan ring at 68.40 and 66.52 ppm. Moreover four methyl

carbons of four acetate groups can be also distinguished from 13C-NMR spectra.

Although 13C-NMR and 1H-NMR seem to fit the basic structure of the expected

product 101, and also 2D-NMR spectra mainly supports the result. There is a

contradiction between the proposed structure 101 and COSY spectrum of the product

which is shown in Figure 6.

Figure 7. COSY spectrum of expected product of 101

31

The correlation of methine protons H-1 and H-5 with neighboring methine protons of

cyclohexane ring H-9 and H-6 is an expected result since these protons interact with

each other over 3 or 4 bonds. However, it is also expected that each proton would

give different correlation by different intensities with the same proton. In COSY

spectrum of the product (Figure 6) it is seen that the correlation between H-1& H-9

and H-5&H-9 have approximately same intensities which means the couplings of the

protons are likely to be same which is not possible for the predicted structure 101.

To be sure from the structure we decided to take X-Ray analysis from the crystals.

The X-ray analysis of structure, as shown in Figure 7, confirmed that the structure of

product is not the expected one.

32

Figure 8. X-ray analysis of the product of ring opening reaction of bisepoxide 100

top:packing diagram, bottom: the molecular structure of compound.

33

X-ray analysis showed that a rearranged product was formed. Actually no change

was expected for furan ring in the bisepoxide 100 in the reaction, however X-ray

results indicated the existence of an arrangement occurred during the reaction

involving the furan ring. This rearrangement explains the doubtful correlation of the

protons. With the exact configuration of the product 103, it is reasonable for H-1 and

H-5 to have the correlations with H-9 in same intensities.

After exact structure was found, we have proposed a mechanism for this unexpected

product 103. The reaction that takes place would be a kind of neighboring group

participation which is a well-known mechanism results from the interaction of sigma

bond or pi bond electrons or lone pair electrons in an atom. Neighboring group

participation also called anchimeric assistance occurred when the nucleophilicity of

atom or bond within the molecule is compatible with the nucleophilicity of the

substance in the medium.37 In our case an alkyl substitution seems to be placed. In

the acidic medium, bisepoxide oxygen was protonated, with the substitution of furan

ring which is antiperiplanar to epoxide ring a secondary carbocation formed which is

further attacked by acetic anhydride. Second epoxide ring was opened by direct

nucleophilic attack of acetic anhydride (Scheme 25).

34

Scheme 25. Proposed mechanism of reaarrangement

37

2.4.2.1. Acetolysis Reaction of rel-(1R,5S,6R,7S,8S,9S)-3-oxabicyclo[3.3.1]

nonane-6,7,8,9-tetrayl tetraacetate (103)

After synthesizing and characterizing the compound 103, we planned to treat it with

sulfamic acid which is used for acetolysis of furan ring. Although, the rearrangement

product 103 has a tetrahydropyran instead of tetrahydrofuran ring, we applied same

procedure in acetolysis of furan ring. We have dissolved the compound 103 in a

mixture of acetic anhyride and acetic acid (1:1) and added sulfamic acid at room

temperature in catalytic amount. After the reflux for 24 hours, reaction was stopped.

The product of the reaction characterized by NMR and it was shown that there was

no change in the starting material 103. Since the reaction failed, reaction was

repeated with increasing amount of catalytic sulfamic acid. However, reaction was

not succeeded. We assume that tetrahydropyran is more stable than the furan ring to

ring opening reaction.

Scheme 26. Acetolysis reaction of tetraacetate 103

38

2.4.2.2 Hydrolysis Reaction of rel-(1R,5S,6R,7S,8S,9S)-

3oxabicyclo[3.3.1]nonane-6,7,8,9-tetrayl tetraacetate (103)

Rearranged tetraacetate molecule 103 was dissolved in absolute methanol. While dry

NH3(g) was passed through solution, the mixture was stirred for 4 h. Evaporation of

solvent and formed acetamide gave tetrol 105.

Scheme 27. Hydrolysis of the molecule 103

Full assignment of the tetrol molecule 105 was made by 1D&2D NMR. Four

methine protons (H-6,7,8,9) neighboring hydroxyl groups and one of the methylenic

protons on the tetrahydropyran ring (H-2) resonate at the same region between 4.27-

4.15 ppm. Other metylenic protons (H-4,4’) gave an AB system; A part resonate at

3.86 as doublet and B part at 3.63 ppm as doublet of doublets. H-2’ resonates at 3.5

ppm as a broad doublet. Methine protons H-5 and H-1 resonate as broad singlet at

2.29 and 2.16 ppm.

2.4.3 Manganese (III) Acetate Oxidation Reaction of rel-(3aR,7aS)-1,3,3a,7a-

Tetrahydro-2-benzofuran (69)

The second route, that we have planned for the synthesis of different inositol

derivatives from the key compound rel-(3aR,7aS)-1,3,3a,7a-tetrahydro-2-benzofuran,

started with manganese acetate oxidation reaction. Manganese(III) acetate is an

powerful one electron oxidant which mediated free radical reactions for a new bond

formation.

Heiba and Dessau proposed the mechanism of the reaction of olefins with Mn(OAc)3

in acetic acid at reflux, in which the oxidation of the radical 107 to the cation 112

39

continue with cyclization to the tetrahydrofuran derivative and then loss of a proton

to give 111 (route A).32 On the other hand, Fristad et al.33 have proposed an

alternative route B, where the formed radical 107 undergoes first a cyclization

reaction followed by oxidation (Scheme 28).

Scheme 28. The mechanism of the reaction of olefins with Mn(OAc)3 in acetic acid

Beside these conflictions in the mechanism, Balci and co workers38 investigated the

mechanism of Mn(OAc)3 reactions with benzonorbornadiene derivatives. The

Mn(OAc)3 reactions of benzonorbornadiene and its hetero derivatives;

oxabenzonorbornadiene, azabenzonorbornadiene with dimedone and acetylacetone

were performed in the presence and absence of an co-oxidant Cu(OAc)2. In order to

decide the stage at which oxidation takes place (route A or B in scheme 28), the

structure of the products and possible intermediates investigated.

It is well-known that a radical type of intermediate does not undergo rapid

rearrangement whereas a cation in a benzonorbornyl system has great tendency to

form rearranged products. Therefore, the structure of the formed products would

40

gave the information about the stage at which oxidation takes place. It was seen that

the cyclization takes place mainly after the oxidation of the formed radical (Scheme

29). 38

Scheme 29. The Mn(OAc)3 reaction of benzonorbornadiene and acetylacetone

In our study we planned to form a lactone unit in the key compound 69. We have

treated the diene 69 with Mn(OAc)3 in acetic acid in the presence of KOAc under

nitrogen atmosphere. The reaction mixture was heated to reflux temperature for 3-4

days until the color of the mixture turned to white. 1H &13C NMR spectra showed

that a single product was formed. This product could be one of the four possible

isomers 114-117 that can be formed from the reaction.

41

From the both 1H NMR & 13C NMR spectra, it was seen that symmetry in the diene

molecule 69 was distorted. There are 12 different protons and 10 different carbon

signals for the product. The appearance of carbonyl peak at 174.6 is a signal for the

formation of lactone unit. The four carbons in the olefinic region were reduced to

two; which shows the lactone formation from one of the double bond in diene

molecule 69. From the COSY spectrum we can easily eliminate the two isomers 116

and 117, which are the constitutional isomers of 114 and 115, due to presence of

correlation of H-12 with H-3 instead of H-2. In order to decide which configurational

isomer 114 or 115 is the product, correlation between the double bond proton and

alkoxy proton with the coupling constants were investigated.

In the 1H-NMR two olefinic protons resonate at 5.90 and 5.83 as doublet of doublets

of doublets and a methine proton resonance was observed at 4.82 ppm, which should

belong to the proton of the carbon at the junction of the lactone unit. Deshielding

would be due to oxygen atom. Since the product is not symmetric anymore,

methylenic protons of the furan ring resonate as two different AB systems. Beside

AB systems, an ABC system belongs to the methylenic protons of lactone unit and

neighboring methine proton. One of the methylenic proton in lactone ring H-12

resonates at 2.67 forms B part of ABC system, methine proton H-3 resonate at 2.60

and gives A part of ABC system and other metylenic proton H-12’ resonates at 2.33

and gives C part of ABC system.

42

Figure 9. 1H-NMR spectrum of the product of Mn(OAc)3 reactionof diene 69.

13C-NMR of the product contains a carbonyl group which resonates at 174.6, two

olefinic carbons appear at 131.2, 122.7, three carbons at 72.9, 71.8, 69.8 and four

carbons at 37.4, 35.6, 33.4, 32.5.

Protons of the molecule 118 are exactly assigned by 2D-NMR and seems to be fit for

two isomers 114 and 115 in which the difference is the position of lactone and furan

ring either cis or trans to each other. The product should be isomer 115, not because

trans form is energetically more favorable but also the coupling constants support the

formation of the trans form. The larger coupling constant between H-3 and H-4 (J34=

6.5 Hz) showed that trans isomer is the single product of the reaction (Scheme 30).

Scheme 30. Reaction of diene 69 with Mn(OAc)3.

43

2.4.4 Upjohn Dihyroxylation

After synthesizing and characterization of the compound 115, we have planned to

perform hydroxylation of the double bond in the molecule. Upjohn dihydroxylation

in which OsO4 used for the oxidation of the olefins in the presence of cooxidant such

as N-methylmorpholine N-oxide (NMO), is a common method for cis hydroxylation.

Figure 10 Mechanism of Upjohn Dihyroxylation

We have treated the molecule 115 with OsO4 and NMO in the presence of

acetone/water (1:1) mixture under nitrogen atmosphere at room temperature for 5

days. After removal of the solvent, pyridine and Ac2O were added to reaction

mixture for acetylation and the reaction mixture stirred for 24 h at room temperature.

Os

OO

OO

R

R'

(VIII)

Os

OO

OO

(VI)

R R'

N

O

MeO

N

O

Me

2 H2O

R

R'

OH

OH

Os

O

O

O

(VI)

44

At the end of the reaction, products were extracted by EtOAc. From the NMR

spectra, first the structure 119 was determined without the configuration of acetate

groups.

Scheme 31. Upjohn dihyroxylation of molecule 115

1H and 13C NMR spectra of the product showed that two isomers were formed from

the reaction with (1:1) ratio. Since both side of the olefin has the similar environment

for the OsO4 to approach (Figure 11), two isomers were expected: the only difference

between the isomers is the configuration of acetate groups however in both structure

the acetate groups should be cis to each other. (Scheme 32)

Figure 11. Optimized geometry of the molecule 115

45

Scheme 32. Dihydroxylation of compound 115

The isomers were separated from each other by column chromatography and purified

by crystallization. Both isomers have similar 1H and 13C NMR spectra. The protons

and carbons of two isomers resonate at nearly same region with slightly different

coupling constants. Also 2D NMR spectra results of both isomers close to each other.

Since the NMR results are not enough to distinguish spectra from each other, we

decided to investigate dihedral angles between the distinctive protons of both

isomers. We determined the dihedral angles by using SPARTAN ’08 mechanics

program.

Since the change in configuration of H-1 and H-6- mainly affects the resonance of

the proton H-2, we have calculated dihedral angles between the protons H-1&H-2

and H-2&H-3. According to SPARTAN’08, for the molecule 120 the angles between

H1-H3 is 39o and H1-H2 is 51o, whereas for the molecule 121 angles between H1-H3

is 42o and H1-H2 is 69o.

46

Figure 12. Geometry Optimization of Molecule 120

The dihedral angle between H1-H3 is 39o and H1-H2 is 51o

Figure 13. Geometry Optimization of Molecule 121

The dihedral angle between H1-H3 is 42o and H1-H2 is 69o.

In order to distinguish between the spectra of the isomers we have combined the

SPARTAN results with the coupling constants with respect to Karplus-Conroy curve.

According to Karplus-Conroy from 0-90o of the angle, coupling constants decrease

as the angle between the protons increases (Figure 12).

12

34

56

7

O 8

9

O10

11 12

OCOCH3H3COCO

O

1314

13

14

12

34

56

7

O 8

9

O10

11 12

OCOCH3H3COCO

O

47

Figure 14. Karplus-Conroy Curve

The proton H-2 resonates as doublet of doublets in both spectra, giving J21= 1.9 Hz,

J23 = 5.4 Hz coupling constants in one of them while in the other spectra J21 = 1.5 Hz,

J23 = 3.9 Hz. According to Karplus-Conroy the molecule 121 which has bigger

dihedral angle from SPARTAN geometry optimization, has the spectra with the J21 =

1.5 Hz, J23 = 3.9 Hz. coupling constants and the molecule 120 has the remaining.

Figure 12. 1H NMR of molecule 120

48

All protons and carbons are labeled with the combination of 1H&13C-NMR and 2D

NMR spectra. The methine proton H-2 resonates at 5.5 as doublet of doublets, one of

the methine protons neighboring the acetate groups H-1 resonate at 4.9 ppm as

doublet of doublets and other one H-6 at 4.70 ppm as broad triplet. Methylenic

protons on the furan ring give two different AB systems. For the first AB system, A

part belongs to H-9 which resonates at 3.77 ppm as doublet of doublets. The proton

H-9’ is the B part and appears at 3.55 as doublet of doublets. Second AB system

arises from H-7,7’ protons which resonate at 3.73 and 3.6 ppm. Two methine protons

H-3, H-4 and one of the methylenic protons H-12 resonate between 2.81-2.70 ppm.

The other methylenic proton H-12’ resonates between 2.30-2.15 ppm with the

methine proton H-5. Methyl protons of acetate groups resonate at 2.06 and 2.04 as

singlets.

Figure 13. 1H-NMR of molecule 121

As shown in Figure 13 in the 1H-NMR of diacetate isomer 121, there are 9 different

signals corresponding to 18 protons. 13C-NMR of the molecule consists of 13

different carbons. With the help of the COSY, HMBC and HSQC all proton and

carbon resonances were assigned. The proton that resonates as doublet of doublets at

the lowest field (5.60 ppm), belongs to H-2 neighboring the two oxygen atoms. The

49

multiplet at 4.7 ppm belongs to different methine protons H-1 and H-6. The

methylenic protons of the furan ring give 3 different signals: H-9 at 3.96 as triplet, H-

9’, H-7 between 3.82-3.75 ppm as multiplet and H-7’ at 3.45 ppm as triplet. Two

methine protons H-3 and H-4 at the intersections of the rings resonate at 2.7 ppm as

multiplets whereas H-5 resonates at the same region with the methylenic protons H-

12 and H-12’ between 2.60-2.51 ppm. Methyl protons of the acetate groups resonate

as singlets at 2.03 and 1.97 ppm.

2.4.5 Reduction of Lactone in Diacetate Isomers 120 & 121 by LiAlH4

After characterization and isolation of diacetate isomers 121 & 122 we planned to

perform the reduction of the lactone unit in the isomers followed by acetolysis and

hydrolysis reactions to get the corresponding inositol derivatives. However we could

not complete because of the time limitation.

Scheme 33. Acetolysis and hydrolysis reactions of the compounds 120 and 121

50

CHAPTER 3

EXPERIMENTAL

3.1 General

Nuclear magnetic resonance (1H-NMR and 13C-NMR) spectra were recorded on a

Bruker Instrument Avance Series-Spectrospin DPX-400 Ultrashield instrument in

MeOD and CDCl3 with TMS as internal reference. Chemical shifts (δ) were

expressed in units parts per million (ppm). Spin multiplicities were specified as

singlet (s), doublet (d), doublet of doublets (dd), doublet of doublets of doublets

(ddd) triplet (t) and multiplet (m) and coupling constants (J) were reported in Hertz

(Hz).

Infrared spectra were recorded on a Matson 1000 FT-IR spectrometer and Vertex 70

series FT-IR spectrometer. Band positions were reported in reciprocal centimeters

(cm-1).

Elemental analysis was performed at Atatürk University.

Column chromatographic separations were performed by using Fluka Silica Gel 60

plates with a particle size of 0.063–0.200 mm. Thin layer chromatography (TLC)

was performed by using 0.25 mm silica gel plates purchased from Fluka.

Compounds were named by using ChemDraw Ultra 11.0.

Solvents were purified as reported in the literature.37

51

3.2 Synthesis of cis-1,2,3,6,-Tetrahydrophthalyl Alcohol (91)

The cis-1,2,3,6-tetrahydrophytalic anhydride (30 g, 0.20 mol) was dissolved in 158

mL of dry THF, and then the resulting solution was added dropwise to a stirring

mixture of LiAlH4 (8.4 g,0.22 mol) in 50 mL THF in an ice-bath. After the addition,

the mixture was refluxed for 24 h. Then saturated Na2SO4 solution was added to

hydrolyze till the mixture turned to white. When the mixture was cooled to room

temperature, it was suction-filtered and washed with MeOH. The filtrate was

cextracted with EtOAc and the extracts were dried over MgSO4. After the removal of

the solvent, colorless diol 91 was obtained. (24.16 g, 85% yield)

1H NMR (400 MHz, CDCl3) δ: 5.56 (s, 2H, H-4,H-5) 3.61 (m,

2H, H-7,H-9) 3.48 (m, 2H,H-7’,H-9’), 2.07-1.93 (m, 6H, H-1,H-

2,H-3,H-3’,H-6,H-6’). 13C-NMR (100 MHz, CDCl3) : 125.6, 63.9, 37.8, 26.9.

IR (ATR): 3565, 3289, 3021, 2887, 2840, 1704, 1680, 1649, 1470, 1436, 1250,

1099, 1016, 978, 946, 923.

3.3 Synthesis of rel-(1R, 3S)-1,3,3a,4,7,7a-Hexahydro-2-benzofuran (92)

The tosyl chloride (44.82g, 0.24 mol) was dissolved in 64 mL pyridine, and added

dropwise to the refluxing solution of diol 91 (28g, 0.19 mol) in 45 mL pyridine.

After addition was completed, the mixture was refluxed for additional 4 h. When the

mixture was cooled to room temperature, it was poured into H2SO4 ice bath for

neutralization of the pyridine. The mixture was extracted with water and Et2O and

extracts dried over MgSO4. After solvent was evaporated, the crude product

submitted to vacuum distillation for purification resulting in colorless rel-(1R,3S)-

1,3,3a,4,7,7a-hexahydro-2-benzofuran (92).(15.1g, 62%).

5

43

2

16

9

OH10

OH 8

7

52

1H-NMR (400MHz,CDCl3) δ: 5.63 (s, 2H, H-5, H-6), 3.82 (dd, A

part of AB-system, J = 7.8Hz and 6.3 Hz, 2H, H-1,H-3), 3.47 (dd,

B part of AB-system, J = 7.8Hz and 5.8 Hz, 2H, H-1’, H-3’), 2.29

(m, 2H, H-3a, H-7a), 2.20-2.13 (m, 2H, H-4, H-7), 1.91-1.85 (m, 2H, H-4’,H-7’) 13C-NMR (100 MHz, CDCl3) 124.9, 73.1, 35.3, 24.1

IR (ATR): 3026, 2970, 2928, 2860, 2842, 2244, 1437, 1088, 1052, 1007, 968, 941,

907, 882, 728.

3.4 Synthesis of rel-(3aR,5R,6S,7aS)-5,6-Dibromooctahydro-2-benzo furan (94)

A solution of bromine (19.0 g, 0.12 mol) in 65 mL of CH2Cl2 was added dropwise to

a magnetically stirred solution of furan 92 (15.0 g, 0.12 mol) in 70 mL of CH2Cl2 at

0 °C. After the mixture was stirred for an additional 2 h at room temperature, the

reaction was stopped. The excess bromine was quenched with saturated Na2S2O5

solution; organic layer was taken and dried over Mg2SO4. The solvent was removed.

Crystallization of the residue from CH2Cl2 at 0 °C gave pure white crystals 93 (24.5

g, 72%). Mp: 58 – 60 oC.

1HNMR (400MHz, CDCl3) δ 4.42-4.39 (m, 1H, H-6), 4.23-4.19

(m, 1H, H-5), 3.88-3.75 (m, 3H, H-3, H-3, H-1’), 3.69-3.58 (m,

1H, H-1), 2.61-2.46 (m, 3H,H-4,H-7,H-7’), 2.42-2.36 (m,1H,H-

4’, 2.34-2.28 (m, 1H), 2.12-1.98 (m, 1H)

13C NMR (100 MHz, CDCl3) δ 72.4, 70.2, 53.4, 38.3, 37.2, 34.4, 33.2

IR (ATR) 2928, 2861, 1443, 1247, 1141, 1056, 1031, 1030, 1002, 978, 944, 905,

884, 751, 680.

5

67

7a

3a4

1

O 2

3

5

67

7a

3a4

1

O 2

3Br8

Br9

53

3.5 Synthesis of rel-(3aR,7aS)-1,3,3a,7a-Tetrahydro-2-benzofuran (69)

To a stirred solution of dibromide 93 (14.0 g, 0.08 mol) in 50 mL benzene was added

a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (19.0 g, 0.123 mol) in 20 mL of

benzene at room temperature. The reaction mixture was refluxed for 24 h and then

cooled to room temperature. The mixture suction filtered, resulted solid washed with

ether. The filtrate washed with saturated aqueous sodium bicarbonate and dried over

Mg2SO4. After the removal of the solvent, vacuum distillation was performed to

give the colorless liquid 69. (6.24 g, 64 %)

1H-NMR (400 MHz, CDCl3) δ 5.83-5.80 (m, 2H, H-4,H-7), 5.60-5.57

(m, 2H, H-5,H-6), 4.15-4.10 (m, 2H, H-1, H-3), 3.59-3.55 (m, 2H, H-

1’, H-3’), 2.94 (bs, 2H, H-3a, H-7a).

13C NMR (100 MHz, CDCl3) δ 126.2, 122.3, 75.0, 37.8

IR (ATR) 3035, 2932, 2861, 2247, 1633, 1479, 1374, 1078, 905, 726, 679, 674

3.6 Synthesis of rel-(1R,2R,6S,7S)-4,10,11-trioxa-tricyclo[5.2.2.02,6]undec-8-ene

(94)

The cyclohexadiene derivative 69 (5.0g, 0.04 mmol) and 100 mg of

tetraphenylporphyrine (TPP) were dissolved in 250 mL of CH2Cl2. The mixture was

irradiated with a projection lamp (500 W) while oxygen was passed through the

solution. After 12 h at room temperature, the reaction was stopped and solvent was

removed. The resulting crude product was purified by column chromatography on

silica gel (70g) eluting with hexane/CH2Cl2 (7:3). Eluted solvent was evaporated.

Crystallization of the residue from hexane/CH2Cl2 (7:3) gave 4.9 g of pure

endoperoxide 94 (81%) as colorless crystals. Mp: 123-126 oC.

5

67

7a

3a4

1

O 2

3

54

1H-NMR (400 MHz, CDCl3) δ 6.62 (quasi t, A-part of AA′XX′-

system, 2H, H-8, H-9), 4.65 (m, X-part of AA′XX′-system, 2H, H-1,

H-7), 3.69-3.64 (m, 2H, H-3, H-5), 3.45 (dd, J 33′(55′) = 9.3 and

J23′(65′) = 2.6 Hz, 2H, H-3’, H-5’), 2.97 (m, 2H, H-2, H-6)

13C NMR (100 MHz, CDCl3) δ 131.9, 72.5, 70.0, 39.9

IR (ATR) 3079, 2948, 2922, 2859, 2844, 1376, 1276, 1258, 1197, 1129, 1101,

1074, 1039, 1019, 1075, 1030, 1019, 965, 949, 905

3.7 Synthesis of rel-(1aR,1bS,2aS,2bS,5aR,5bR)-octahydrobis (oxireno)

isobenzofuran (100)

To a stirring solution of endoperoxide 94 (2.2g, 0.014mol) in 30 mL CH2Cl2 was

added the solution of 0.058 g cobalt tetraphenylporphyrine (CoTPP) in 25 mL of

CH2Cl2 at 0oC. After the addition was complete, the mixture was stirred for 2 h at

room temperature. Removal of the solvent gave the crude product which was

submitted to column chromatography on silica gel (50g) eluting with hexane/EtOAc

(2:3).The resulting pure bisepoxide 100 was recrystallized from chloroform (1.84g,

84%). Mp: 73-75 oC.

1H-NMR (400 MHz, CDCl3) δ 3.94-3.90 (m, 2H, H-9, H-3), 3.66-

3.62 (m, 2H, H-3’, H-5’), 3.41 (d, J = 2.7, 2H, H-1a, H-1b), 2.66-

1.60 (m, 2H, H-2a, H-5b), 2.97 (m, 2H, H-2b, H-5a)

13C NMR (100 MHz, CDCl3) δ 71.0, 50.5, 47.6, 30.9

IR (ATR) 3037, 3004, 2947, 2927, 2879, 1423, 1366, 1268, 1196, 1071, 1051,

1034,977, 970, 944,930, 894, 839

8

91

2

67

3

O 4

5

O 11O10

23

55a5b

1a

2a

O2b

1b

O1

O

4

55

3.8 Synthesis of rel-(1R,5S,6R,7S,8S,9S)-3-oxabicyclo[3.3.1]nonane-6,7,8,9-

tetrayl tetraacetate (103)

The bisepoxide (300mg, 1.94 mmol) was 100 dissolved in 6 mL of acetic anhydride.

A solution of H2SO4 (6-7 drops) in 3 mL acetic anhydride, was added dropwise to

bisepoxide solution. The reaction mixture stirred for 24 h at room temperature. When

reaction was completed, the reaction mixture was washed with saturated NaHCO3

solution. Organic phase was extracted with EtOAc (3 x 20 mL) and dried over

Mg2SO4. The solvent was evaporated, and the residue (54% was submitted to column

chromatography on silica gel (85g). Elution with hexane/EtOAc (3:1) gave single

product 3-oxabicyclo [3.3.1]nonane-6,7,8,9-tetrayl tetraacetate 103. Recrystallization

of tetraacetate from hexane/ EtOAc (1:4) gave colorless crystals. Mp: 164-166 oC.

1H-NMR (400 MHz, CDCl3) δ 5.75-5.71 (dd, J78 = 10.3

Hz, J76 = 5.4 Hz, 1H, H-7), 5.58-5.54 (dd, J78 = 10.3Hz,

J81= 4.6Hz, 1H, H-8), 5.51-5.49 (ddd, J76 = 5.4Hz, J65 =

2.3 Hz, J69 = 0.9Hz, 1H, H-6), 4.96 (bt, J = 2.7 Hz, 1H, H-9), 4.14 (bd, A-part of AB

system, J22’ = 11.4 Hz, 1H, H-2), 3.94 (d, A-part of AB system, J44’ = 12.1Hz, 1H,

H-4), 3.62 (dd, B-part of AB system, J4’5 = 2.2 Hz, J44’ = 12.1 Hz, 1H, H-4’), 3.54

(d, B-part of AB system, J22’= 11.4 Hz, 1H, H-2’), 2.43 (m, 1H, H-5), 2.29 (m, 1H,

H-1), 2.08 (s, 6H, COCH3), 2.01 (s, 3H, COCH3), 1.92 (s, 3H, COCH3)

13C NMR (100 MHz, CDCl3) δ 170.2, 170.1, 169.9, 169.87, 72.8, 71.6, 69.5, 68.4,

66.5, 39.6, 38.7, 21.2, 21, 20.9, 20.7

IR (ATR) 2978, 2856, 1735, 1369, 1216, 1171, 1132, 1114, 1035, 975, 948, 909,

862

Anal. Calcd for C16H22O9: C, 53.63; H, 6.19 Found: C, 53.55; H, 6.07

79

18

O3

OCOCH3

6 5H3COCO

H3COCOOCOCH3

4

2

56

3.9 Synthesis of rel-(1R,5S,6R,7S,8S,9S)- 3-oxabicyclo [3.3.1]nonane-6,7,8,9-

tetraol (105)

Tetraacetate 103 (100 mg, 0.28 mmol) was dissolved in 10 mL methanol. The

solution was stirred at room temperature for 24 h while NH3(g) passed through the

solution. After the evaporation of the solvent and the removal of the acetamide which

was formed during the reaction, tetrol was obtained (46 mg, 86%).

1H-NMR (400 MHz, MeOD) δ 4.27-4.15 (m, 5H, H-2, H-6, H-7,

H-8, H-9), 3.88-3.85 (d, A-part of AB system, J44’=11.8 Hz, 1H,

H-4) 3.65-3.62 (dd, B-part of AB system, J44’ = 11.8 Hz, J4’5 = 2.2

Hz, 1H, H-4’), 3.51-3.48 (bd, B-part of AB system, J22’ =11.6 Hz, 1H, H-2’), 2.29

(bs, 1H, H-5), 2.16 (bs, 1H, H-1)

13C-NMR (100 MHz, MeOD) δ 76.64, 74.84, 74.05, 70.56, 69.56, 66.94, 46.46,

43.22

IR (ATR) 3264, 3356, 2921, 2856, 1659, 1394, 1259, 1142, 1127, 1101, 1059, 970

3.10 Synthesis of rel-(3aR,4S,5R,6R,7S,7aS)-octahydro-2-benzofuran-4,5,6,7-

tetrayl tetraacetate (102)

The bisepoxide (2 g, 0.013 mol) 100 dissolved in 10 mL of water. After the addition

of H2SO4 (5 drops) was added to the solution, the reaction mixture stirred for 24 h at

room temperature. The solvent was evaporated, and the residue dissolved in 6 mL of

pyridine, then 9 mL of acetic anhydride was added to the solution. The mixture

stirred at room temperature for 24 h. When the reaction was completed, the reaction

mixture was poured into HCl-ice bath. The aq. phase was extracted with EtOAc (3 x

50 mL) and saturated NaHCO3 solution. The organic phase was dried over Mg2SO4.

7

9

56

O3

OH8 1

HO

HO OH

2

4

57

65

43a

7a7

3

O 2

1

O

O

O

O

O

O

O

O

Evaporation of the solvent gave the mixture of three isomers, the mixture was

submitted to column chromatography on silica gel (120 g). Elution with

hexane/EtOAc (4:1) gave as major product rel-(3aR,4S,5R,6R,7S,7aS)- octahydro-2-

benzofuran-4,5,6,7-tetrayl tetraacetate (102) with 67% ratio, which was

recrystallized from hexane/EtOAc (1:4) resulting white crystals.

Mp: 133-135 oC.

1H-NMR (400 MHz, CDCl3) δ 5.29-5.25 (dd, J45 = 9.5Hz, J56

= 9.1Hz, 1H, H-5), 5.24-5.21(dd, J45 = 9.5 Hz, J43a = 6.0Hz,

1H, H-4), 5.14-5.09 (t, J77a = J76 = 10Hz, 1H, H-7), 5.06-5.02

(dd, J67 = 10 Hz, J56 = 9.1Hz, 1H, H-6) 3.83 (d, J33’= 9.7 Hz,

2H, H-3, H-3’) 3.75(d, A part of AB system, J11’=8.9 Hz,1H,

H-1), 3.70-3.67(dd, B part of AB system, J1’7a = 4.4Hz,

J11’=8.9 Hz, 1H, H-1’), 3.02-2.94 (m, 1H, H-3a), 2.38-2.33 (m, 1H, H-7a), 1.97 (s,

6H, COOCH3), 1.94(s, 3H, COOCH3),1.93 (s, 3H,COOCH3)

13C-NMR (100 MHz, CDCl3) δ 169.9, 169.8, 169.7, 169.6 72.8, 71.1, 70.93, 70.3,

70.0, 67.4, 42.2, 40.5, 20.7, 20.68, 20.57, 20.53

IR (ATR) 2944, 2918, 2882, 1745, 1734, 1456, 1367, 1265, 1215, 1114, 1053, 1033,

975, 940, 923, 894


3.11 Manganese (III) Acetate Oxidation Reaction of rel-(3aR,7aS)-1,3,3a,7a-

Tetrahydro-2-benzofuran (69)

Manganese (III) acetate, potassium acetate and diene 69 (2g, 0.016 mol) were

dissolved in 300 mL acetic acid. The mixture was refluxed at constant temperature

(90 oC) under nitrogen atmosphere until it turned to white. When the reaction was

completed, the mixture was washed with CH2Cl2 (2 x 100mL), water (2 x 100mL)

58

and saturated NaHCO3 solution (2 x 50 mL). The solution was dried over MgSO4

and purified by column chromatography on silica gel (70 g) eluting with hexane /

EtOAc (7:3). After removal of the solvent, residue (1.8g, 61%) was recrystallized

from EtOAc resulting rel-(3aR,5aR,8aS,8bR)-1,3,3a,8,8a,8b-hexahydrobenzo[1,2-

b:3,4-c’]difuran-7(5aH)-one (115). Mp: 142-144 oC.

1H-NMR (400 MHz, CDCl3) δ 5.91-5.88 (ddd, J45 = 10.2 Hz,

J43a = 3.7 Hz, J45a = 0.7 Hz, 1H, H-4), 5.84-5.80 (ddd, J54 =

10.2 Hz, J55a = 3.1 Hz, J53a = 1.9 Hz, 1H, H-5) 4.82 (m, 1H,

H-5a), 3.97-3.93 (dd, A part of AB system, J33a = 7.6 Hz, J33’

= 8.5 Hz, 1H, H-3), 3.92-3.88 (dd, A part of AB system, J11’=

8.4Hz, J18b= 7.4 Hz, 1H, H-1), 3.57-3.55 (dd, B part of AB system, J3’3a = 4.9 Hz,

J33’ = 8.5 Hz, 1H, H-3’), 3.55-3.51 (dd, B part of AB system, J11’= 8.4Hz, J1’8b = 6.4

Hz, 1H, H-1’), 2.8 (m, 1H, H-3a), 2.71-2.63 (B part of ABC system, Jac = 7.4 Hz,

1H, H-8a), 2.61-2.58 (A part of ABC system, Jbc = 8.1 Hz, 1H, H-8), 2.41 (p, J = 6.5

Hz , 1H, H-8b), 2.36-2.30 (C part of ABC system, Jab = 16.5 Hz, 1H, H-8’)

13C-NMR (100 MHz, CDCl3) δ 174.6, 131.2, 122.7, 72.9, 71.8, 69.8, 37.4, 35.6,

33.4, 32.5

IR (ATR) 2929, 2871, 1752, 1370, 1229, 1176, 1057, 1035, 1001, 972, 942, 883,

758

Found HRMS [M+H]+ calcd for C10H12O3 ;Exact mass:180.07864; Found:

180.08054

1

2

345

7

O

8

O

O

6

3a

5a

8a8b

59

3.12 cis-Hydroxylation of rel-(3aR,5aR,8aS,8bR)-1,3,3a,8,8a,8b Hexahydro

benzo[1,2-b:3,4-c’]difuran-7(5aH)-one (115)

To 700 mg (0.039 mol) 115 in 14 mL acetone/water (1:1), 1.5g (13.1mmol) NMO

and 3mg (0.012mmol) OsO4 were added at 0oC. The mixture stirred at room

temperature for 72 h under nitrogen atmosphere. The reaction was stopped, and pH

of the solution adjusted to 2 with HCl. After the removal of the solvent, pyridine (7.5

mL) and Ac2O (12 mL) were added and the reaction mixture stirred for 24 h at room

temperature. When the reaction was completed, reaction mixture hydrolyzed by HCl-

ice solution, extracted with EtOAc (2x100 mL) and washed with NaHCO3 (2x100

mL). Evaporation of the organic phase gave the mixture of 2 diacetate isomers with

(1:1) ratio. The residue was submitted to column chromatography with silica gel

(70g). Elution with hexane/EtOAc (7:3) gave as the first isomer rel-

(3aR,4R,5S,5aS,8aS,8bS)-7-oxodecahydrobenzo[1,2-b:3,4-c’]difuran-4,5-diyl

diacetate 120, and as second isomer rel-(3aR,4S,5R,5aS,8aS,8bS)-7-

oxodecahydrobenzo[1,2-b:3,4-c’]difuran-4,5-diyl diacetate 121 separately.

Recrystallization of the products from EtOAc provided white crystals. Mp: 178-180 oC.

1H-NMR (400 MHz, CDCl3) δ 5.50-5.48 (dd, J55a= 1.9

Hz, J5a8a = 5.4Hz, 1H, H-5a), 4.90-4.87 (dd, J55a = 1.9Hz,

J54= 6.5 Hz, 1H, H-5), 4.70-4.67 (bt, J = 6.5 Hz, 1H, H-4),

3.79-3.75 (dd, A part of AB system, J33’ = 9.1 Hz, J33a=

6.7 Hz, H-3), 3.74-3.72 (bd, A part of AB system, J =

9.2Hz, 1H, H-1), 3.62-3.58 (dd, B part of AB system, J11’

= 9.2 Hz, J1’8b = 5.13 Hz, 1H, H-1’), 3.56-3.53 (dd, B part

of AB system, J33’ = 9.1 Hz, J3’3a= 3.4 Hz, 1H, H-3’), 2.81-2.70 (m, 3H, H-8, H-8a,

H-8b), 2.30-2.15 (m, 2H, H-8’, H-3a), 2.06 (s, 3H, H-9), 2.04 (s, 3H, H-10)

13C-NMR (100 MHz, CDCl3) 174.9, 170.14, 170.11, 79.7, 73.9, 72.2, 68.7, 68.5,

40.5, 38.8, 36.1, 34.4, 20.7, 20.8

IR (ATR) 2962, 2853, 1773, 1733, 1368, 1259, 1241, 1222, 1149, 1143, 1088, 1008,

948, 916, 839, 794

5

5a

8a8b

3a4

1

O2

3

O6

7 8

OCOCH3

H3COCO

O

9

10

60


1H-NMR (400 MHz, CDCl3) δ 5.60-5.58 (dd, J55a = 1.54

Hz, J5a8a = 3.9 Hz, 1H, H-5a), 4.73-4.67 (m, 2H, H-5, H-4

), 3.96 (t, J = 8.5Hz, 1H, H-3), 3.82-3.75 (m, 2H, H-3’,

H-1), 3.45 (t, J = 8.8 Hz, 1H, H-1’), 2.72-2.65 (m, 2H, H-

8a, H-8b) 2.60-2.51 (m, 3H, H-3a, H-8, H-8’), 2.03 (s,

3H, COCH3), 1.97 (s, 3H, COCH3)

13C-NMR (100 MHz, CDCl3) 174.4, 169.4, 168.3, 73.9, 69.88, 69.85, 68.1, 67.4,

38.7, 35.4, 33.2, 32.1, 19.7

IR (ATR) 3004, 1786, 1749, 1711, 1421, 1361, 1220, 1172, 1092, 1019, 904

Found HRMS [M+Na]+ calcd for C14H18O7; Exact mass: 298.10525; Found:

298.10846

9

10

55a

8a8b

3a4

1

O 2

3

O6

7 8

OCOCH3H3COCO

O

61

CHAPTER 4

CONCLUSION

The development of various synthetic pathways for the bishomo- inositol derivatives,

which have potential to show biological activity, is important. Different bishomo-

inositol derivatives were synthesized from the same key compound with distict

pathways.

In the first part of the study, key compound 69 was subjected to photooxygenation to

form corresponding endoperoxide 94 which is further converted to epoxide 100.

Acid catalyzed ring opening reaction of bisepoxide was performed in two different

way; in the presence and absence of water. Reactions were followed by acetylation

for the characterization. In the presence of water rel-(3aR,4S,5R,6R,7S,7aS)-

octahydro-2-benzofuran-4,5,6,7-tetrayl tetraacetate (102) was formed as a major

product.

Scheme 34. Synthesis of tetraacetate 102

However, in the absence of water, single product was formed and characterized.

Unexpected rearrangement was occured during the reaction. Formation mechanism

of the rearranged product 103 was discussed.

62

Scheme 35. Synthesis of tetraacetate 103

In the second episode, manganese acetate oxidation reaction of the key compound 69

gave the molecule 115 which was further subjected to Upjohn dihyroxylation. The

two isomers formed from the reaction were isolated and characterized.

Scheme 36. Synthesis of diacetate molecules 120& 121

In summary, synthesis of inositol derivatives were studied. Different methodologies

for the synthesis were investigated. The products were purified and characterized by

1D & 2D NMR. Spartan’08 mechanics program and NMR simulation programs

(ACD) were used for characterization.

63

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Figure A. 1 1H-NMR spectrum of compound 91

AP

PE

ND

IX

A. S

PE

CT

RA

L D

AT

A

65

Figure A. 2 13C-NMR spectrum of compound 91

26.9

2

37.8

1

63.8

5

76.7

277

.04

77.3

6

125.

55

66

Figure A. 3 IR spectrum of compound 91

67


68


5101520253035404550556065707580859095105115125135f1 (ppm)

O

69


70


71


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

O

Br

Br

72


O

Br

Br

73


74


75


O

76


-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)

4.55.05.56.06.5f1 (ppm)

2.93.13.33.53.73.9f1 (ppm)

OOO

77


78

Figure A. 15 IR Spectrum of Compound 94

79

Figure A. 16 1H-NMR Spectrum of Compound 100

80

Figure A. 17 13C-NMR Spectrum of Compound 100

0102030405060708090100110120130140150f1 (ppm)

O

O

O

81

Figure A. 18 IR Spectrum of Compound 100

82

Figure A. 19 DEPT-135 spectrum of compound 100

83

Figure A. 20 COSY spectrum of compound 100

84

Figure A. 21 HSQC spectrum of compound 100

85

Figure A. 22 HMBC spectrum of compound 100

86


87


88


89


-100102030405060708090100110120130140150160170180190200210f1 (ppm)

O

O O

CH3

O O

CH3

O

OCH3

O

OCH3

90


91


92


93


94


95


O

OHOH

OH OH

96


97


98


O

OHOH

OH OH

99


100


101


102


103


104


105

Figure A. 42 HSQC Spectrum of Compound 103

106

Figure A. 43 HMBC Spectrum of Compound 103

107


-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

5.855.905.956.00f1 (ppm)

3.53.63.73.83.94.04.1f1 (ppm)

2.32.42.52.62.72.82.9f1 (ppm)

O

O

O

108

109

Figuure A. 45 13C-NM

MR spectrum of f compound 114


110


111


112


113

114


115

Figuure A. 51 1H-NM

MR spectrum of compound 121


116


117

118

Figgure A. 54 DEP

T spectrum of coompound 121


119


O

O

O

O

O

CH3OO

CH3

120


121


122


123


124

125

Figurre A. 61 DEPT-

135 spectrum off compound 1222

Figure A. 62 COSY Spectrum of Compound 122

O

O

O

O

OCH3

O

O

CH3

126

Figure A. 63 HSQC Spectrum of Compound 122

127


O

O

O

O

OCH3

O

O

CH3

128

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