synthesis of chloralose and orthoester derivatives of l-rhamnose

EGE UNIVERSITY

Graduate School of Applied and Natural Science

SYNTHESIS OF CHLORALOSE AND

ORTHOESTER DERIVATIVES OF L-RHAMNOSE

Tolga ÖZEL

Chemistry Department

İzmir

MSc THESIS

EGE UNIVERSITY

Graduate School of Applied and Natural Science

SYNTHESIS OF CHLORALOSE AND ORTHOESTER

DERIVATIVES OF L-RHAMNOSE

Tolga ÖZEL

Supervisor: Assoc. Prof. Dr. Yeşim SALMAN

Chemistry Department

Organic Chemistry Second Cycle Programme

İzmir

L-RAMNOZUN KLORALOZ VE ORTOESTER TÜREVLERİNİN

SENTEZİ

ÖZEL, Tolga

Yüksek Lisans Tezi, Kimya Anabilim Dalı

Tez Danışmanı: Doç. Dr. Yeşim SALMAN

Şubat 2020, 70 sayfa

Kloral, asetal oluşum reaksiyonlarında aldehit gibi kullanılırsa kloraloz

olarak isimlendirilen halkalı ürünler ortaya çıkar. Bu türevler diğer asetal ve

ketallere kıyasla çok daha zor koşullara karşı dayanıklıdırlar. Kolayca hidrolize

edilmezler. Ayrıca kloraloz türevlerinden elde edilen değişik ortoester yapılarının

şeker molekülleri üzerinde bulunması karbohidrat kimyasında sentezlenmesi

hedeflenen ürünü elde etmek için kolaylık sağlamaktadır. O-Alkiliden veO-

Alkiliden türevleri halkalı asetal yapısında olan koruyucu grup özelliğine sahip

bileşiklerdir.

Bu çalışmada L-Ramnoz isimli şekerden yola çıkarak yapılan optimizasyon

çalışması ile L-Ramnokloraloz (1,2-O-trikloroetiliden-L-ramnofuranoz) sentezi

için en verimli yol belirlenmiş ve bu yol ile elde edilen ramnokloralozdan bir

ortoester (1,2,3-O-dikloroetiliden-L-ramnofuranoz) sentezi gerçekleştirilmiştir.

Bileşiklerin yapıları spektroskopik analizler (IR, 1H-NMR,

13C-NMR) ve

elementel analiz sonuçları ile teyit edilmiştir.

Sonuç olarak L-Ramnozdan elde edilen trikloroetiliden asetalleri ve

ortoester yapısı ile 2 ve daha fazla hidroksil grubu korunmuş olup yeni L-

ramnofuranozidik birimlerin hazırlanmasında yapıtaşı olarak kullanılmaya uygun

yapılar oluşturulmuştur. Aynı zamanda sentezlenen ortoester bileşiği L-

ramnofuranozidik oligosakkaritlerin hazırlanmasında glikozil donör olarak

kullanılabilme potansiyeli taşımaktadır.

Anahtar Kelimeler: Ortoester, Halkalı Asetal, Kloraloz, L-Ramnoz.

ABSTRACT

SYNTHESIS OF CHLORALOSE AND ORTHOESTER

DERIVATIVES OF L-RHAMNOSE

OZEL, Tolga

Master of Science Thesis, Department of Chemistry

Thesis Advisor: Assoc. Prof. Dr. Yeşim SALMAN

February2020, 70 pages

If chloral is used as an aldehyde in acetal formation reactions, cyclic

products called chloralose emerge. These derivatives are resistant to much more

difficult conditions than other acetals and ketals. Furthermore, the presence of

different orthoester structures obtained from chloralose derivatives on sugar

molecules makes it easy to obtain the product intended to be synthesized in the

carbohydrate chemistry.

In this study, the most efficient way for L-rhamnochloralose (1,2-O-

trichloroethylidene-L-rhamnofuranose) synthesis was determined with the

optimization study based on sugar named L-rhamnose and an orthoester (1,2,3-O-

dichloro-L-rhamnofuranose) synthesis was made from ramnocloralose obtained by

this route. The structures of the synthesized compounds were confirmed by

spectroscopic analyses (IR, 1H-NMR, 13C-NMR) and elemetal analysis.

As a result, 2 and more hydroxyl groups were protected by

trichloroethylidene acetals and orthoester structure obtained from L-rhamnose.

The synthesized orthoester compound also has the potential to be used as glycosyl

donor in the preparation of L-rhamnofuranosidic oligosaccharides.

Keywords: Orthoester, Ring Acetal, Chloralose, L-rhamnose.

CONTENTS

İÇ KAPAK .............................................................................................................. ii

KABUL ONAY SAYFASI .................................................................................... iii

ETİK KURALLARA UYGUNLUK BEYANI ....................................................... v

ÖZET ..................................................................................................................... vii

ABSTRACT ........................................................................................................... ix

CONTENTS ........................................................................................................... xi

LIST OF TABLES ................................................................................................. xv

LIST OF FIGURES .............................................................................................. xvi

LIST OF SCHEMES .......................................................................................... xviii

ABBREVIATIONS ............................................................................................... xx

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

1.1 Carbohydrates .................................................................................................... 1

1.2 Hydroxyl Group Reactions ................................................................................ 1

1.3 Some Protecting Groups in Carbohydrates........................................................ 2

1.3.1 Acetates........................................................................................................... 2

CONTENTS (continued)

1.3.2 Benzoates ........................................................................................................ 3

1.3.3 Chloroacetates ................................................................................................. 4

1.3.4 Pivalates .......................................................................................................... 4

1.3.5 Carbonates, Borates, Phosphates, Sulfates and Nitrates ................................. 5

1.3.6 Sulfonates ........................................................................................................ 5

1.3.7 Allyl Ethers ..................................................................................................... 6

1.3.8 Trityl Ethers .................................................................................................... 6

1.3.9 Silyl Ethers ...................................................................................................... 7

1.4 Acetals ................................................................................................................ 7

1.4.1 Acid Catalyzed Acetal Formation ................................................................... 8

1.4.2 Cylic Acetals ................................................................................................... 9

1.4.3 Trichloroethylidene Acetals (Chloraloses) ................................................... 10

1.5 Ortho Esters...................................................................................................... 12

1.5.1 Carbohydrate Ortho Esters ............................................................................ 14

1.5.2 1,2-Ortho Ester Structures............................................................................. 14

1.5.3 2,3-Ortho Ester and 4,6-Ortho Ester Structures ............................................ 15

1.5.4 Fluorinated 1,2-Ortho Ester Structures ......................................................... 15

1.5.5 Ortho Ester Structures with Acetal Formation of Cyclic Flax ..................... 16

1.5.6 Structures of Bicyclic Ortho Esters .............................................................. 18

1.5.7 Structures of Tricyclic Ortho Esters ............................................................. 19

1.5.8 Structures of Polycyclic Ortho Esters ........................................................... 19

1.5.9 General Physical Properties of Ortho Esters ................................................ 20

1.5.10 Reactions of carbohydrate Ortho Esters ..................................................... 20

1.5.11 Importance of Carbohydrate Ortho Esters .................................................. 21

1.5.12 Spiro Ortho Ester Structures ....................................................................... 24

2. MATERIALS AND METHOD ......................................................................... 26

2.1 General techniques and metarials .................................................................... 26

2.2 Experiments ..................................................................................................... 26

2.2.1 Preparation of anhydrous chloral .................................................................. 26

2.2.2 Reaction of L-Rhamnose with Anhydrous Chloral ...................................... 27

2.2.3 Preparation of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnofuranose (4) ................................................................................................ 28

rhamnopyranose (5) ............................................................................................... 28

rhamnopyranose (6) ............................................................................................... 29

2.2.6 Preparation of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7) .......... 29

3. RESULT AND DISCUSSION .......................................................................... 31

3.1 Formation of Rhamnochloralose (1) ................................................................ 32

3.2 Formation of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2)............. 33

3.3 Formation of1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose (3) ............. 35

3.4 Formation of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnofuranose (4) ................................................................................................ 37

3.5 Formation of 3,5-di-O-acety-l-1,2-O-trıchloroethylıdene--L-

rhamnopyranose (5) ............................................................................................... 38

3.6 Formation of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7) ............... 39

APPENDIX ............................................................................................................ 42

REFERENCES....................................................................................................... 65

ACKNOWLEDGEMENT ..................................................................................... 69

CURRICULUM VITAE ........................................................................................ 70

LIST OF TABLES

Table Page

2.1. Optimization study to find the most effective way to obtain

compound 1,2-O-trichloroethylidene-L-rhamnofuranose (1) .................... 27

3.1. 1H NMR (400 MHz) JH,Hvalues (Hz) and chemical shifts (δ ppm) of

1,2-O-trichloroethylidene--L-rhamnofuranose (1) ................................... 32

3.2. 13

C NMR of 1,2-O-trichloroethylidene--L-rhamnofuranose (1) .............. 33

1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2). ........................... 33

3.4. 13

C NMR of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2) ....... 34

1,2-O-(R)-trıchloroethylidene-L-rhamnopyranose (3). .............................. 35

3.6. 13

C NMR of 1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose (3) ....... 36

3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-rhamnofuranose (4) ......... 38

3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-rhamnopyranose (5) ........ 39

1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7) ............................... 40

3.10. 13

C NMR of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7) .......... 40

LIST OF FIGURES

Figure Page

1.1. Silyl Ethers. .................................................................................................. 7

1.2. Steric interactions in a hypothetically possible 2-trichloromethyl-1,3-

dioxane derivative. ..................................................................................... 11

1.3. Structures ofbiologically important chloraloses. ........................................ 12

1.4. Simply orthoester formation....................................................................... 12

1.5. Compounds forming 2,3-Ortho Ester and 4,6-Ortho ester. ........................ 15

1.6. Cis and Trans structure ortho ester formation reactions. ........................... 18

1.7. Bicyclic ortho ester forms. ......................................................................... 18

1.8. Tricyclic Ortho Ester. ................................................................................. 19

1.9. Structures of Polycyclic Ortho Esters. ....................................................... 19

1.10. Bleomycin A2 molecule structure with disaccharide structure. ................. 22

1.11. Polysaccharide and disaccharide structures. .............................................. 23

1.12. Structures involving ortholactone formation.............................................. 25

3.1. Structure of 1,2-O-trichloroethylidene--L-rhamnofuranose. .................... 32

3.2. Structure of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose. ............. 33

3.3. Three-dimensional structure of 1,2-O-(S)-trıchloroethylidene--L-

rhamnopyranose. ........................................................................................ 34

LIST OF FIGURES (continued)

Figure Page

3.4. Annotated NOESY spectrum of compound 1,2-O-(S)-

trıchloroethylidene--L-rhamnopyranose. ................................................. 35

3.5. Structure of 1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose. ............ 35

3.6. Annotated NOESY spectrum of compound 1,2-O-(R)-

trıchloroethylidene--L-rhamnopyranose. ................................................. 37

3.7. Structure of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnofuranose. ........................................................................................ 37

3.8 Structure of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnopyranose. ........................................................................................ 38

3.9. Structure of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose. ................ 39

3.10. Colored COSY spectrum of compound 1,2,3-O-orthodichloroacetyl-

-L-rhamnofuranose. .................................................................................. 41

LIST OF SCHEMES

Scheme Page

1.1. Formation of acetate structure as a protecting group. .................................. 2

1.2. Acetylation reaction in the presence of iodine. ............................................ 3

1.3. Selective benzoylation of a carbohydrate. .................................................... 4

1.4. Reaction of obtaining chloroacetates. .......................................................... 4

1.5. Protective group is obtained in the presence of pivalic acid. ....................... 4

1.6. Carbonates, Borates, Phosphates, Sulfates and Nitrates. ............................. 5

1.7. Allyl Ethers. ................................................................................................. 6

1.8. Trityl Ethers.................................................................................................. 7

1.9. Acetal and semi-acetal formation. ................................................................ 8

1.10. Acid catalyzed acetal formation. .................................................................. 9

1.11. Use of acetal group for protection. ............................................................. 10

1.12. Synthesis of 𝛽-ribochloralose and some derivatives. ................................. 11

1.13. Acid catalyzed orthoester hydrolysis. ........................................................ 13

1.14. 1,2-Ortho ester formation. .......................................................................... 14

1.15. Ortho ester production in the presence of alcohol...................................... 15

1.16. O-Glycoside production in the presence of fluorinated alcohol. ............... 16

LIST OF SCHEMES (continued)

Scheme Page

1.17. The relationship between cyclic flax and ortho ester structures. ............... 17

1.18. General reactions of carbohydrate ortho esters. ......................................... 20

1.19. In the acidic solution containing additional alcohols, a series of

competing reactions giving carbohydrate ortho esters and ortho

esters. ......................................................................................................... 21

1.20. Reaction of carbohydrate ortho esters with carboxylic acids and

anhydrides to give reverse structured 1-acyloxy carbohydrates ................ 21

1.21. Spiro compound production. ...................................................................... 24

2.1. General reaction of L-rhamnochloralose. ................................................... 27

2.2. General acetylation reaction of 1,2-O-trıchloroethylıdene-L-

rhamnofuranose. ........................................................................................ 28

2.3. General acetylation reaction of 1,2-O-(S)-trıchloroethylidene-α-L-

rhamnopyranose. ........................................................................................ 28

2.4. General acetylation reaction of 1,2-O-(R)-trıchloroethylidene-α-L-

rhamnopyranose. ........................................................................................ 29

2.5. Ortho ester formation reaction from of 1,2-O-trıchloroethylıdene-L-

rhamnofuranose. ........................................................................................ 29

3.1. General table of synthesis. ......................................................................... 31

ABBREVIATIONS

Abbreviation Explanation

Ac2O Acetic Anhydride

COSY Correlated Spectroscopy

DMF Dimethylformamide

HCl Hydrochloric acid

HSQC Heteronuklear Single Quantum Coherence Spectroscopy

IR Infrared Spectroscopy

m.p. Melting Point

NaOH Sodium Hydroxide

NMR Nuclear Magnetic Resonance Spectroscopy

PTSA p-Toluenesulfonicacid

r.t. Room Temperature

THF Tetrahydrofuran

TLC Thin Layer Chromotography

1. INTRODUCTION

1.1 Carbohydrates

Carbohydrates and their derivatives have important functions in living

organisms and are important compounds for organic synthesis. For this reason,

many studies have been made on carbohydrates. In all studies, protection of

hydroxyl compounds on sugars is very important. Because the protection of free

hydroxyls has brought about a difference in the ability to perform the desired

reaction types to sugar and thus many different sugar derivatives have been

introduced into the literature.

In this study, a series of reactions of different protecting groups were carried

out considering the importance of protecting groups. Starting from D-galactose

and D-mannose, 1,2-O-(R)-trichloroethylidene-ß-D-mannofuranose and 1,2-O-

Trichloroethylidene galactofuranose were obtained. The reaction of anhydrous

acetic anhydride (Ac2O) with NaOAc as a different protecting group yielded

peracetyl-ß-D-glucopyranose, peracetyl-ß-D-glucopyranose, and peracetyl-D-

mannopyranose from galactose, glucose and mannose.

These protected sugars will then be deacetylated to the number one

hydroxyls (selective hydrolysis) to obtain targeted new sugar derivatives.

1.2Hydroxyl Group Reactions

The hydroxyl groups in the carbohydrate molecule sometimes need to be

temporarily protected. A good protecting group must be resistant to the reaction

conditions and should be readily separated, if necessary, to give the free hydroxyl

group, while the shape of the molecule should not change

1.3 Some Protecting Groups in Carbohydrates

Much of today‟s chemistry is concerned with synthesis and carbohydrate

chemistry is no exception. The large pharmaceutical companies once employed

small armies of chemists to synthesize a myriad of compounds that were

necessary for lead development of a potential „block buster‟ drug. Nowadays,

however, the same companies „outsource„much of their synthetic work to smaller,

private companies, but there is still a need for synthetic chemists to do the work.

If you want to do synthesis, you need to know about protecting groups.

The protecting groups used in carbohydrates are generally the same as those

of mainstream organic chemistry; the difference; however, is that ever a

monosaccharide presents a myriad of hydroxyl groups that need protection, in

either an individual (regioselective) or a unique (orthogonal) manner. Also, the

introduced protecting groups may affect the reactivity of the resulting molecule or

even participate in some of its reactions.

1.3.1 Acetates

The acetylation of D-glucose was first performed in the mid–nineteenth

century, which helped to confirm the pentahydroxy nature of the molecule. Since

then, three sets of conditions are commonly used for the transformation:

Scheme 1.1. Formation of acetate structure as a protecting group.

The reaction in pyridine is general and convenient and usually gives the

same ratio of anomers of the penta-acetate as found in the parent free sugar. With

an acid catalyst, the reaction probably operates under thermodynamic control and

gives the more stable anomer. Sodium acetate causes a rapid anomerization of the

free suger, (Swain and Brown, 1952). The more reactive anomer is then

preferentially acetylated. Iodine has been used for various acetylations, with some

interesting and regioselective transformations (Kartha and Field, 1997):

Scheme 1.2. Acetylation reaction in the presence of iodine.

One of the features of an acetyl protecting group is its ready removel to

regenerate the parent alcohol. Generally, the acetate is dissolved in methanol, a

small piece of sodium metal is added and the required transesterification reaction

is both rapid and quantitative (Zemplen and Pacsu, 1929):

1.3.2 Benzoates

In general, benzoates are more robust groups than acetates and may give rise

to derivatives that are useful in X-ray crystallographic determinations (e.g., 4-

bromobenzoates). The robustness of benzoates is reflected both in their

preparation (benzoyl chloride, pyridine) and in their reversion to the parent

alcohol (sodium-methanol for protracted periods). Acetates can be removed in

preference to benzoates (Byramova and Ovchinnikov, 1983).

The selective benzoylation of a carbohydrate can be achieved either by

careful control of the reaction conditions or by the use of a less reactive reagent,

such as N- benzoylimidazole or 1-benzoyloxybenzotriazole (Pelyvas et al., 1991):

Scheme 1.3. Selective benzoylation of a carbohydrate.

1.3.3 Chloroacetates

Chloroacetates are easily acquired (chloroacetic anhydride in pyridine), are

stable enough to survive most synthetic transformations and yet, being more labile

than acetates, can be selectively transformed back to the hydroxyl group (thiourea,

„hydrazinedithiocarbonate or DABCO):

Scheme 1.4.Reaction of obtaining chloroacetates.

1.3.4 Pivalates

Esters of pivalic acid (2,2-dimethylpropanoic acid), for he reason of steric

bulk, can be installed preferentially at the more reactive sites of a sugar but

require reasonably vigorous conditions for their removal (Greene and Wuts,

1991):

Scheme 1.5. Protective group is obtained in the presence of pivalic acid.

1.3.5 Carbonates, Borates, Phosphates, Sulfates and Nitrates

Cyclic carbonates are occasionally used for the protection of vicinal diols,

providing the dual advantages of installation under basic (phosgene) or neutral

(1,1-carbonyldiimidazole) conditions, and easy removal (Zhu and Boons, 2001).

Scheme 1.6. Carbonates, Borates, Phosphates, Sulfates and Nitrates.

1.3.6 Sulfonates

This last group of esters is not at all characterized by protection of the

hydroxyl group but, rather, by its activation towards nucleophilic substitution:

The three sulfonates commonly encountered are tosylate (4-

toluenesulfonate), mesylate (methanesulfonate) and triflate

(trifluoromethanesulfonate), generally installed in pyridine and using the acid

chloride (4-toluenesulfonyl chloride and methanesulfonyl chloride) or

trifluoromethanesulfonic anhydride (Binkley and Ambrose, 1984). For alcohols of

low reactivity, the combination of methanesulfonyl chloride and triethylamine

(which produces the very reactive suflene, CH2SO2) is particularly effective

(Crossland and Servis, 1970).The sulfonates, once installed, show the following

order of reactivity towards nucleophilic displacement:

CF3SO2O->>CH3SO2O- > 4- CH3C6H4SO2O-

1.3.7 Allyl Ethers

Roy Gigg, more than anyone else, was responsible for the establishment of

the allyl (prop-2-enyl) ether as a useful protecting group in carbohydrate

chemistry (Gigg and Gigg, 1966). Allyl groups may be found at both anomeric

and nonanomeric positions, the latter ethers being installed under basic (allyl

bromide, sodium hydride, DMF ), acidic ( allyl trichloroacetimidate, triflic acid)

or almost neutral conditions (Lakhmiri et al., 1989). Many methods exist for the

removal of the allyl group most relying on an initial prop-2-enyl to prop-1-enyl

isomerization, and varying from the classical (potassium tert-butoxide-dimethyl

sulfoxide, followed by mercuric chlorideor acid ) to palladium-based (palladium –

on-carbon, acid) and rhodium-based procedures. Other variants of the allyl group

have found some use in synthesis (Markovic and Vogel, 2004).

Scheme 1.7. Allyl Ethers.

1.3.8 Trityl Ethers

The trityl (triphenylmethyl) ether was the earliest group for he selective

protection of a primary alcohol. Although the introduction of a trityl group has

always been straightforward (trityl chloride, pyridine),various improvements have

been made (Hanessian and Staub, 1976). The removal process has been much

studied, and the reagents used are generally either Bronsted or Lewis acids; other

methods include either conventional hydrogenolysis or reduction under Brich

conditions (Kovac and Bauer, 1972).

Scheme 1.8. Trityl Ethers.

1.3.9 Silyl Ethers

The original use of silyl ethers in carbohydrates was not so much for the

protection of any hydroxyl group but, rather, for the chemical modification of

these normally water-soluble, non-volatile compounds. For example, the per-O-

silylation of monosaccharides was a necessary preamble to succesful analysis by

gas-liquid chromatography or mass spectrometry (Dutton, 1973):

Figure 1.1. Silyl Ethers.

1.4 Acetals

Semi-acetal is formed by passing a small amount of HCl gas through the

alcohol solution of an aldehyde (or ketone). A second reaction then occurs. semi-

acetal, equivalent amount

The second one reacts with moles of alcohol to form acetal (sometimes

called ketal).

Acetal has two -OR groups bound to the same carbon atom (Figure 1.1).

Scheme 1.9. Acetal and semi-acetal formation.

1.4.1 Acid Catalyzed Acetal Formation

Proton is transferred to carbonyl oxygen (Scheme 1.10.a). The nucleophilic

addition reaction to the first alcohol molecule then takes place(Scheme

1.10.b).Proton separation from the positive oxygen produces a semi-

acetal(Scheme 1.10.c).The hydroxyl group is then protonated and causes water

separation and formation of the oxonium cation (Scheme1.10.d).Finally, a second

alcohol molecule attacks the carbon of the oxonium ion to form acetal (Scheme

1.10.e).

Scheme 1.10. Acid catalyzed acetal formation.

1.4.2 Cylic Acetals

Cyclic asetals are the condensate products of appropriate diols with

aldehydes or ketones and they are use commonly in carbohydrate chemistry as

protecting classify. They can be cushily hydrolized by rarified acids and the

configuration of the carbon atoms do unchanging (Belder, 1965).Utilization of

cyclic acetals in the organic chemistry, particullary in the synthetic organic

chemistry is of prime important. Because of these properties, the acetals provide a

convenient method for protecting the aldehyde and ketone groups from

undesirable reactions in basic solutions. We can convert an aldehyde or ketone to

acetal, by performing a reaction elsewhere in the molecule, then hydrolyzing the

acetal with aqueous acid. Take the problem of conversion from compound A to

compound B, for example. Keto groups are more easily reduced than ester groups.

A reducing agent capable of reducing the ester group of A also reduces the keto

group. However, if the keto group is converted to cyclic acetal, the ester group

may be reduced in the basic medium without acetal affinity. After the ester

reduction, the acetal can be hydrolyzed in the presence of dilute acid to form

structure B (Scheme1.11).

Scheme 1.11. Use of acetal group for protection.

Electronegativity of any substituent on the acetal carbon is very important.

It plays major role in forming longitudinal and equatorial isomers on the molecule

configuration. When the electronegativity of any substituent go up, more stable

longitudinal isomers take place. This effect it's known for “Anomeric Effect”

(Yüceer, 1978).

1.4.3Trichloroethylidene Acetals (Chloraloses)

Trichloroacetaldehydes containing electronegative substituents generate

solely five-member (1,3-dioxolane) derivatives in combination with reactions of

polyhydroxyl compounds(Richardson, 1972).We shall dispute why

trichloroethylidene acetals of sugars from 1,3-dioxolane circles instead of 1,3-

dioxane rings. For example, trichloromethyl groups are forced to advance the

axial position by reason of the anomeric impact in the hypothetically possible a 2-

trichloromethyl-1,3-dioxane (Scheme 1.3) derivative. also, at the axial position,

1,3-diaxial interactions between the trichloromethyl group and the axial ring

protons cause an unstable state. Thus, the polyhydroxyl compounds react with

chloral to form five-membered rings instead of six-membered rings (Ferrier and

Collins, 1972).

Figure 1.2. Steric interactions in a hypothetically possible 2-trichloromethyl-1,3-

dioxane derivative.

One of the most recent studies on obtaining chloralose derivative was

carried out in 2013. In this study, Ribochloralose and some derivatives were

synthesized (Ay and Halay, 2013).According to Scheme 1.4;Reagent and

conditions (a‟) cat. H2SO4. (b‟) 1.2 equivelent potassium tert- buttoxide in tert-

butanol. (c‟) acetic anhydridein pyridine, for overnight in r.t. (d‟)(i) trityl chloride

in pyridine, (ii) methyl iodide BaO/ Ba(OH)2 .8H2O in DMF.

Scheme 1.12. Synthesis of 𝛽-ribochloralose and some derivatives.

1.4.3.1 Scope of Application of Chloraloses

Some of the chloral derivatives show hypnotic properties.-Chloralose does

not have much use due to its toxic effect and low solubility in water. However,α-

chloralose is less toxic and potent hypnotic. Because of this property, α-

chloraloses are used in medicine, veterinary and agricultural fields.The first

studies on the anesthetic activity of chloralose on animals were conducted in

France in the 1900s.During World War II, some researchers tried to catch or kill

birds with chloralose As an example of the biological significance of chloraloses,

the effect of compounds 5-Amino-5-deoxy-1,2-O-trichloroethylidene-D-

arabinofuranose and 6-Amino-6-deoxy-1,2-O-trichloroethylidene-α-D-

glucofuranoseagainst bacteria Staphylococcus aureus, Escherichia coli,(e-coli)

Salmonella typhimurium and Enterobacter aerogenes againsthas been shown to

be greater than antibiotic Nalidixic acid Chloramphenicolnystatin(Yenil and Ay,

2004).

Figure 1.3. Structures of biologically important chloraloses.

1.5 Ortho Esters

Ortho ester structures are defined as structures formed by simply replacing

hydrogen atoms with alkyl functional groups in the structure of carboxylic ortho

acids. Although simple ortho esters are completely unstable structures, the

compounds derived therefrom, in particular. Carbohydrate ortho esters are stable.

Therefore, they are highly usable in new reactions(Wolfe, 1970).

Figure 1.4. Simply orthoester formation.

Ortho esters are very sensitive organic compounds that can be easily and

rapidly hydrolyzed in acid-catalyzed media, although they remain stable in neutral

and alkaline environments (Oscarson, 1989). Hydrolysis proceeds through a

reaction mechanism that takes place in three steps and is shown as follows;

Scheme 1.13. Acid catalyzed orthoester hydrolysis.

Many aliphatic ortho carboxylate compounds are present as colorless liquids

and have typical ether odor. In particular, a small proportion of ortho esters

having bicyclic and tricyclic ring structures are colorless solids and are soluble in

organic solvents. Carboxylic ortho esters do not absorb UV light. The

characteristic of infrared absorption spectra is the observation of strong C-O

tensile vibrations around 1100 cm-1

(Bellamy, 1975).

1.5.1 Carbohydrate Ortho Esters

Most carbohydrate ortho esters are bicyclic in structure. A carbohydrate

ortho ester compound comprises a 2-alkoxydioxodilane ring and a carbohydrate

furanose or pyranose ring system condensed with this ring. This ring system is

generally accomplished by combining the anomeric carbon of carbohydrate.

(Ferrier, 1972).

1.5.2 1,2-Ortho Ester Structures

In the synthesis of 1,2-ortho ester structures, 1,2-trans-glycosyl halides can

be used, as well as 1,2-cis-glycosyl halide structures. For example; It has been

observed that 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (a) can be

converted to the corresponding 1,2-ortho ester derivative (b) with a yield of 62%

(Ferrier, 1972).

Scheme 1.14. 1,2-Ortho ester formation.

The effects of the catalyst and solvent used determine the main product to

be formed in these reactions (Fletcher and Ness, 1955).For example, compound

17 and compound 18, a novel ortho ester, can be obtained from the reaction of

compound 16 with an alcohol, such as ROH, in different percentages (Kochetkov

et al, 1964).The use of 0.001 moles of mercury (II) bromide yields compound c,

which is 1,2-ortho ester as the main product, while the use of 0.05 moles of

catalyst results in the formation of compound d with the parent product. The

structure is an O-glycoside (Ferrier, 1996).

Scheme 1.15. Ortho ester production in the presence of alcohol.

1.5.32,3-Ortho Ester and 4,6-Ortho Ester Structures

Besides the synthesis of 1,2-ortho ester structures, it is also possible to form

4,6-ortho esters in the carbohydrate skeletal structure. For this purpose, the ortho

acetate compound (a) was easily synthesized from the reaction of a diol with

(MeO)3CCH2Cl or (MeO)3CCHCl2 in the presence of catalytic p-toluenesulfonic

acid (Ferrier, 1998).

Figure 1.5. Compounds forming 2,3-Ortho ester and 4,6-Ortho ester.

1.5.4 Fluorinated 1,2-Ortho Ester Structures

In the literature, there are 1,2-ortho ester structures with high surface

activity and biologically important F-alkyl chain (Charpiot et al., 1991). The non-

toxic and hydrophilic head of the molecule is the sugar structure, while the

fluorophilic tail is the lipophilic part of the molecule. The synthesis of the length

of the lipophilic alkyl chain plays an important role in the formation of the

targeted molecule. For example; The reaction of an alcohol bearing fluorine group

with compound a with KoenigsKnorr takes place as the F-alkylated 1,2-ortho

ester or F-alkylated O-glycoside structure, depending on the length of the carbon

chain of the alcohol (Greiner, 1988). The short carbon chain in the perfluoroalkyl

chain is indicative of the low nucleophilic effect of this structure. Thus, it is

difficult to remove the hydroxyl group from the perfluoroalkyl chain and the

reaction ends with the formation of 1,2-ortho ester. However, O-glycoside

structures could be obtained in reactions using fluorinated alcohol with a long

carbon chain in which the hydrophilic and lipophilic balance were established

(Millius and Greiner, 1991).

Scheme 1.16. O-Glycoside production in the presence of fluorinated alcohol.

1.5.5 Ortho Ester Structures with Acetal Formation of Cyclic Flax

Cyclic flax acetals have been used to synthesize new ortho esters (Salman et

al., 1994). Tetra-O-acetyl-α-D-hexapiranosyl bromide compounds derived from

galactose, glucose and mannose have been converted to the corresponding

carbohydrate ring flax acetal derivatives which have important roles as

intermediates in organic synthesis.

(i) Ag2O, benzene, i-Pr2Net, 6h, reflux; (ii) Ag2O, benzene, i-Pr2Net, 24h, 25 o

C,(iii) p-toluene

sulfonyl chloride, MeOH, CHCl3 (iv) camphoric acid, CH2Cl2

Scheme 1.17. The relationship between cyclic flax and ortho ester structures.

Compound f having a carbohydrate ring flax acetal structure is converted to

the corresponding 1,2-ortho ester derivative (k) with methanol under appropriate

reaction conditions, while stereo- controlled with compound g is 1,2: 3,4-di-O-

isopropylidene-α-D-galactopyranose (l). from the reaction, compound m having a

new ortho ester structure was obtained in 85% yield (Sznaidman et al., 1995).

1.5.6 Structures of Bicyclic Ortho Esters

Bicyclic ortho esters are consist of from acyclic ortho esters with

cycloalkanediols or acyclic triols. For instance, cis and trans-8-ethoxy-7,9-

dioxabicyclo [4.3.0] nonanes can be procured from the reaction of

cyclohexanediols and triethyl orthoformate (Crank and Eastwood, 1964).

Figure 1.6. Cis and Trans structure ortho ester formation reactions.

Reaction of acyclic triols with triethyl ortho formate was used to prepare

some bicyclic ortho esters. Some of these are shown (Figure1.7).

Figure 1.7. Bicyclic ortho ester forms.

1.5.7 Structures of Tricyclic Ortho Esters

Any tricyclic ortho ester may be obtained by reaction of cis, cis, cis-1,3,5-

cyclohexanthriol with an orthoformate. (Sletter and Steinacker, 1953).

Figure 1.8. Tricyclic Ortho Ester.

This rigid tricyclic ring system is similar to hydrocarbon adamantine, hence

the so-called trioxaadamantane ring. It is systematic name is 2,4,10-trioxatricyclo

[3.3.1.1] decane(R=H).

1.5.8 Structures of Polycyclic Ortho Esters

If cycllitol (cis-1,3,5-trans-2,4,6-cyclohexanhexol) is reacted with triethyl

ortho formate in dimethyl sulfoxide solution at 200 °C, pentacyclic ortho ester

forms.This compounds has an wontless thermal stability for an ortho ester.It is

stable at 400°C and has a melting point of 302°C -304°C (Vogl et al., 1969).

Figure 1.9. Structures of Polycyclic Ortho Esters.

1.5.9 General Physical Properties of Ortho Esters

Aliphatic orthocarboxylates are non-color liquids with an etheric odor. Very

large molecules such as bicyclic and tricyclic compounds are colorless solids. It is

normally stable at neutral and alkaline pH and slightly soluble in water. They are

fully or partially soluble in organic solvents. strechings (Wolfe, 1970).

1.5.10 Reactions of Carbohydrate Ortho Esters

Carbohydrate ortho esters are also stable in alkaline medium and

acetylation, methylation, tosylation and similar reactions can be carried out on

free hydroxyl groups without effecting the ortho ester function.

Carbohydrate ortho esters are sensitive to acid hydrolysis as other ortho

esters. Thus carbohydrate 1,2-O-ortho esters give 2-acyloxy carbohydrates

initially than hydrolysis proceeds to give free hydroxyl groups (Haworth et al,

1931).

+ R'OH + H+

Scheme 1.18. Generalreactions of carbohydrate ortho esters.

In acidic solution with added alcohols carbohydrate ortho esters undergo a

number of competing reactions which yield ortho esters, glycosides, acylated

glycosides and free sugars. These reactions and mechanism are given below

(McPhillamy and Elderfield, 1939).

R''OHO

-R'OH -H+

CR OR'

OR'' O H

Scheme 1.19. In the acidic solution containing additional alcohols, a series of

competing reactions giving carbohydrate ortho esters and ortho

esters.

Carbohydrate ortho esters react with carboxylic acids and anhydrides to give

1-acyloxy carbohydrates with an nverted configuration. The intermediate in this

reaction is probably a dioxolenium ion (Korytnik and Mills, 1959).

Scheme 1.20. Reaction of carbohydrate ortho esters with carboxylic acids and

anhydrides to give reverse structured 1-acyloxy carbohydrates.

1.5.11 Importance of Carbohydrate Ortho Esters

2,3-ortho ester structures (Eckstein and Cramer, 1965) such as 1,2-ortho

ester structures (Wolfrom and Lederkremer, 1965), which have carbohydrate

structures and are used as conventional glycosyl donors, can be synthesized by

suitable and simple methods. Carbohydrate ortho esters are the most suitable

compounds for the synthesis of mono-glycoside structures as synthetic

intermediates.Therefore, disaccharide structure molecules such as antibiotic

bioactive molecule Bleomycin A2, trisaccharide structure molecules and

polysaccharides having high antigenic properties are also important intermediates

used in the synthesis of certain oligosaccharides (Kochetkov et al., 1990).

Figure 1.10. Bleomycin A2 molecule structure with disaccharide structure.

Figure 1.11. Polysaccharide and disaccharide structures.

In reactions involving the formation of carbohydrate ortho ester structures,

local and stereoselectivity can be achieved as well as control of stereochemistry.

As a result, novel compounds intended to be synthesized by arrangements on the

ortho ester molecule are readily accessible. In addition, fluorosurfactants derived

from sugars are used as pharmaceutical raw materials in clinical trials because of

their biological activity. The fact that some oligosaccharides carrying F-alkyl

chains have anti-HIV activity gives such compounds a field of use for protecting

human health. Fluorinated compounds capable of carrying oxygen and

compounds formed by the combination of carbohydrate structural units They are

used as bio-surfactants since they have hydrophilic and hydrophobic (Riess,

2001).However, the protection of hydroxyl groups in carbohydrate compounds

with ortho ester functional groups can also be performed (Özgener and Yüceer,

2002). Thus, the use of ortho esters as protecting groups in carbohydrate

chemistry gives them many advantages in the subsequent reaction steps.

1.5.12 Spiro Ortho Ester Structures

Spiro-ortholactone bonds, located between glycosidic units, are important

building blocks in characterizing orthosomicin groups in oligosaccharide

antibiotics.Carbohydrate spiroortolactone units can be obtained from 2-deoxy

systems of sugar molecules.For example; The corresponding spiro-ortholactone

molecule (x) can be easily synthesized from 1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-

arabino-hexapyranose (y).In the literature, glycosidic spiro-ortho esters with

antibiotic properties, high biological activity and especially in oligosaccharide

molecule structures are found (Buchanan et al., 1992).

Scheme 1.21. Spiro compound production.

Bioactive ortholactone units are important because they may exhibit

stimulating drug properties. It has also been found that there are (a‟‟)-(b‟‟)

structural units containing ortholactone formation in Everninomycin C molecular

structure (Beau et al., 1987).

Figure 1.12. Structures involving ortholactone formation.

2. MATERIALS AND METHOD

2.1 General techniques and metarials

1H (400 MHz) and 13C NMR (100 MHz) and NOESY spectra were

enregister on a Varian AS 400 appliance.

Optical revolution measurement were a Schmidt-Haensch Polartronic E

polarimeter

Melting point determination was measured by electrothermal Gallenkamp

melting point measuring device.

L-Rhamnose and reagents were supply than Merck and Glycon.

TLC and column chromatography were make on aluminum plates (Merck

5554) and silicagel G-60 (Merck-7734), respectively. The solvents used during

column chromatography are described in the experimental sections.

IR spectra were measured by PerkinElmerSpectrum100FTIR spectrometer.

All reactions were carried out under Argon gas. All solvents were

evaporated in vacum in the evaporator.

2.2 Experiments

2.2.1 Preparation of anhydrous chloral

Chloral hydrate (325 g) in the presence of sulfuric acid (185 mL, d: 1.84)

was distilled at 98 °C. When the distillation was over, 170 mL of chloral was

obtained.

Table 2.1. Optimization study to find the most effective way to obtain

compound1,2-O-trichloroethylidene-L-rhamnofuranose(1)

Experiment

Rhamnose

Chloral

(mL) Solvent Acid

Temperature

Time (h) Yield

1 0,59 0,5 (1,5eq) DMF(3mL) H2SO4(10µL) 25 1-6-24 18,2

2 0,59 0,5 (1,5eq) DMF(3mL) H2SO4(100µL) 25 1-6-24 22,4

3 0,59 1 (3eq) DMF(3mL) H2SO4(10µL) 25 1-6-24 67,6

4 0,59 1 (3eq) DMF(3mL) H2SO4(100µL) 25 1-6-24 33

5 0,59 0,5 (1,5eq) DMF(3mL) H2SO4(10µL) 80 1-6-24 32

6 0,59 0,5 (1,5eq) DMF(3mL) H2SO4(100µL) 80 1-6-24 22

7 0,59 1 (3eq) DMF(3mL) H2SO4(10µL) 80 1-6-24 12

8 0,59 1 (3eq) DMF(3mL) H2SO4(100µL) 80 1-6-24 39

9 0,59 1 (3eq) DMF(3mL) PTSA(10mg) 25 1-6-24 32,6

10 0,59 1 (3eq) DMF(3mL) PTSA(10mg) 80 1-6-24 28

11 0,59 0,5 (1,5eq) DMF(3mL) PTSA(10mg) 110 1-6-24 33,7

12 0,59 1 (3eq) DMF(3mL) PTSA(100mg) 110 1-6-24 52

13 0,59 0,5(1,5eq) DMF(3mL) PTSA(10mg) 110 1-6-24 41

14 0,59 1 (3eq) DMF(3mL) PTSA(100mg) 110 1-6-24 35

2.2.2 Reaction of L-Rhamnose with Anhydrous Chloral

Scheme 2.1. General reaction of L-rhamnochloralose.

The dry L-rhamnose (0,59g, 3,2mmol) compound was added slowly to fresh

distilled chloral (1 mL) with continuous stirring with dry DMF. A catalytic

amount of sulfuric acid(10µL) was then added and the mixture was stirred at room

temperature (25oC) for 6 hours. Excess chloral was removed under reduced

pressure. At the end of the removal, a viscous material was obtained. When TLC

control (2:1hexane:ethyl acetate) of this compound was performed, 3 pure spots

were observed, then the compound was introduced into the silica column(0,39cm-

65cm).The products separated from the silica column were determined to be 1,2-

O-trıchloroethylıdene-L-rhamnofuranose(1)(%67,6), , mp 111,2–112 oC, []D

0,03 (c 0,8, CH2Cl2), 1,2-O-(S)-trıchloroethylidene--L-

rhamnopyranose(2)(%18)), mp 133,6–134,1oC, []D

23-0,06 (c0,99, CH2Cl2)1,2-O-

(R)-trıchloroethylidene--L-rhamnopyranose(3)(%23), []D23

-0,06 (c 1,32,

CH2Cl2),The products were observed as white crystals.

rhamnofuranose(4)

Scheme 2.2. General acetylation reaction of 1,2-O-trıchloroethylıdene-L-

rhamnofuranose.

Acetylation of 1(0,05g, 0,17mmol) in pyridine (5mL) with Ac2O (0,5 mL)

gave on diacetate(4). TLC control in the reaction was carried out with 7: 3

hexane-ethyl acetate. The reaction took two days at room temperature. Solvent air

was removed on an open evaporator (45 oC). It was then placed in a vacuum oven

at room temperature for 24 hours ([]D23

0,45 (c 0,49, CH2Cl2)).

rhamnopyranose(5)

Scheme 2.3. General acetylation reaction of 1,2-O-(S)-trıchloroethylidene-α-L-

rhamnopyranose.

2 (0,05g, 0,17mmol) and dry pyridine (5 mL) and Ac2O (0,5 mL) were

allowed to stir at room conditions for two days. TLC control was carried out with

a 7: 3 hexane-ethyl acetate system. Pure diacetate (5) product was

observed.([]D23

0,19 (c 4,29, CH2Cl2))

rhamnopyranose (6)

Scheme 2.4. General acetylation reaction of 1,2-O-(R)-trıchloroethylidene-α-L-

rhamnopyranose.

3 was diacetylated and diacetate product was observed. (procedure 2.2.4

was carried out using starting material 3) ([]D23

0,16 (c 4,37, CH2Cl2))

2.2.6 Preparation of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose

Scheme 2.5. Ortho ester formation reaction from of 1,2-O-trıchloroethylıdene-L-

rhamnofuranose.

A solution of acetal(1) (0,005g, 0,02mmol) in dry THF (0,25mL) was mixed

with potassium tert-butoxide.(0,028g) and the mixture was stirred at room

temperature for 30 hours. Meanwhile TLC showed two products. The mixture was

filtered and the filtrate was evaporated. The product was introduced onto a flash

silica column (2.5 cm-66 cm) to give a pure form. The column was eluted with 6:

4 (hexane-ethyl acetate) orthooester product (7)(0,003g, 0,013mmol, %65

yield)was obtained. ([]D23

0,10 (c 013, CH2Cl2))

3. RESULT AND DISCUSSION

Scheme 3.1. General table of synthesis.

Trichloroethylidene acetals of sugars are normally highly crystalline

derivatives and they can be obtained pretty trumpery from sugars and chloral with

a powerful acid catalyst. Trichloroethylidene acetals are known to be highly stable

under acidic conditions. This is because the acetal ring oxygen initiating

hydrolysis is difficult to protonate. The strong electron-withdrawing effect of the

trichloromethyl group is responsible for this.

The optimal route for L-rhamnochloralose (compound 1) (1,2-O-

trichloroethylidene--L-rhamnofuranose) synthesis based on sugar called L-

rhamnose and an orthoester (compound 7) (1,2,3-O-dichloro --L-

rhamnofuranose) was determined.

3.1 Formation of Rhamnochloralose (1)

Figure 3.1. Structure of 1,2-O-trichloroethylidene--L-rhamnofuranose.

Table 3.1. 1H NMR (400 MHz) JH,Hvalues (Hz) and chemical shifts (δ ppm) of

1,2-O-trichloroethylidene--L-rhamnofuranose (1)

Ha H1 H2 H3 H4 H5 H6

Compound 1 5,73 s 6,05 d

J1,2:4,3 Hz

4,98 dd

J2,3:5,7 Hz

4,48 dd

J3,4:6,0 Hz

3,81 dd

J4,5:7,8 Hz

4,12 m 1,32 d

J5,6:6,3 Hz

1H NMR spectrum data is shown in the table above.As shown in Table 3.1,

the Ha proton (proton of acetal) 5,73 appears as a singlet.The proton of H1 is seen

as doublet at 6,05 and the coupling constant with H2 is 4,3 Hz. The H2 proton is

seen as the doublet of the doublet at 4,98 and the coupling constant with H3 is 5,7

Hz. The proton of H3 is seen as doublet of the doublet at 4,48 and the coupling

constant with H4 is 6,0 Hz. The proton of H4 is seen as doublet of the doublet at

3,81 and the coupling constant with H5 is 7,8 Hz. The proton of H5 is seen as

multiplet at 4,12.Similarly, the coupling constant of H6 proton, seen as a doublet

at 1,32, with H5 is 6,3 Hz.This is consistent with similar molecules in the literature

(Salman et al., 2004).

Table 3.2. 13

C NMR of 1,2-O-trichloroethylidene--L-rhamnofuranose (1)

Acetal

CCl3 C1 C2 C3 C4 C5 C6

Compound1 110,09 99,22 105,85 81,89 71,37 84,30 67,16 19,71

The data from the 13

C NMR spectrum shown in Appendix1 is given in the

table above. According to the table, acetal carbon at 110,09 ppm, CCl3 carbon at

99,2 ppm and C1 carbon at 105,85 are compatible with the literature (Salman et al,

2004).In addition, C6 carbon at 19,71 ppm explains that the number 6 is deoxy.

As shown in Appendix 1, peaks at 3500 indicate the presence of the -OH

group. This situation supports the structure of our article.

3.2 Formation of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2)

Figure 3.2. Structure of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose.

1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2).

Compound 2 5.66 s 5.62 d

J1,2: 2.4 Hz

4.72 dd

J2,3: 3.9 Hz

3.70 dd

J3,4: 9,2 Hz

3.50 dd

J4,5: 9,0 Hz

3.38 m 1.36 d

J5,6: 6.1 Hz

1H NMR spectrum data is shown in the table above. As shown in Table 3.3,

the Ha proton (proton of acetal) 5,66 appears as a singlet. However, the proton of

H1 is seen as doublet at 5,62 and the coupling constant with H2 is 2,4 Hz. The H2

proton is seen as the doublet of the doublet at 4,72 and the coupling constant with

H3 is 3,9 Hz. Same time, the proton of H3 is seen as doublet of the doublet at

3,70and the coupling constant with H4 is 9,2 Hz. The proton of H4 is seen as

doublet of the doublet at 3,50 and the coupling constant with H5 is 9,0 Hz. The

proton of H5 is seen as multiplet at 3,38.Similarly, the coupling constant of H6

proton, seen as a doublet at 1,36, with H5 is 6,1 Hz.

Table 3.4. 13

C NMR of 1,2-O-(S)-trıchloroethylidene--L-rhamnopyranose (2)

C-Acetal CCl3 C1 C2 C3 C4 C5 C6

Compound 2 107.67 98.31 98.34 80.10 72.74 72.65 70.99 17.41

The data from the 13CNMR representation in Appendix 2 is shown in the

table above. As shown in Table3.4, acetal carbon at 107,67 ppm, CCl3 carbon at

98,31 ppm and C1 carbon at 98,31 are compatible with the literature (Salman et al,

2004).In addition, C6 carbon at 17,41 ppm explains that the number 6 is deoxy.

Figure 3.3. Three-dimensional structure of 1,2-O-(S)-trıchloroethylidene--L-

rhamnopyranose.

Figure 3.4. Annotated NOESY spectrum of compound 1,2-O-(S)-

trıchloroethylidene--L-rhamnopyranose.

3.3 Formation of1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose (3)

Figure 3.5. Structure of 1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose.

1,2-O-(R)-trıchloroethylidene-L-rhamnopyranose (3).

J1,2: 2.6 Hz

4.43 dd

J2,3: 4.1 Hz

3.81 dd

J3,4: 9.4 Hz

3.63dd

J4,5: 9,2 Hz

3.40 m 1.32 d

J5,6: 6.1 Hz

The 1H NMR spectrum data from Appendix3 is shown in the table above.

As shown in Table 3.5, the Ha proton (proton of acetal) 5,43 appears as a singlet.

However, the proton of H1 is seen as doublet at 5,45 and the coupling constant

with H2 is 2,6 Hz. The H2 proton is seen as the doublet of the doublet at 4,43 and

the coupling constant with H3 is 4,1 Hz. Same time, the proton of H3 is seen as

proton of H4 is seen as doublet of the doublet at 3,63 and the coupling constant

with H5 is 9,2 Hz. The proton of H5 is seen as multiplet at 3,40.Similarly, the

coupling constant of H6 proton, seen as a doublet at 1,32, with H5 is 6,1 Hz.

Table 3.6. 13

C NMR of 1,2-O-(R)-trıchloroethylidene--L-rhamnopyranose (3)

C-Acetal CCl3 C1 C2 C3 C4 C5 C6

Compound 3 107.93 96.71 96.35 80.91 72.33 72.03 71.43 17.34

The table created with the data from Appendix3 is as above.As shown in

Table3.6, acetal carbon at 107,93 ppm, CCl3 carbon at 96,71 ppm and C1 carbon

at 96,35 are compatible with the literature (Salman et al., 2004).In addition, C6

carbon at 17,34 ppm explains that the number 6 is deoxy.

Figure 3.6. Annotated NOESY spectrum of compound 1,2-O-(R)-

trıchloroethylidene--L-rhamnopyranose.

3.4 Formation of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnofuranose (4)

Figure 3.7. Structure of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnofuranose.

3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-rhamnofuranose (4)

Ha H1 H2 H3 H4 H5 H6 H-Ac

J1,2: 4.4 Hz

5.31 dd

J2,3: 4.4 Hz

5.12 dd

J3,4: 5,5 Hz

4.04 dd

J4,5: 9.1 Hz

5.22 m 1.35 d

J5,6: 6.3 Hz

2.11 s, 1.99 s

The 1H NMR spectrum data from Appendix4 is shown in the table above.

coupling constant of H6 proton, seen as a doublet at 1,35, with H5 is 6,3

Hz.Finally, acetyl proton 2,11 and 1,99 also gives singlet.

As shown in Appendix 4, peaks at 1700 indicate the presence of the –

Acgroup. This situation supports the structure of our article.In addition, peaks

between 2800-3000 indicate aliphatic C-H.

3.5 Formation of 3,5-di-O-acety-l-1,2-O-trıchloroethylıdene--L-

rhamnopyranose (5)

Figure 3.8. Structure of 3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-

rhamnopyranose.

3,5-di-O-acetyl-1,2-O-trıchloroethylıdene--L-rhamnopyranose (5)

Ha H1 H2 H3 H4 H5 H6 H-Ac

J1,2: 2.3 Hz

4.79 dd 5.06-5.11 m 3.58 m 1.25 d

J5,6: 6.2 Hz

2.11 s, 2.05 s

The 1H NMR spectrum data from Appendix 5 is shown in the table above.

multiplet similar to the proton of H4 is seen as multiplet. The proton of H5 is seen

as multiplet at 3,58.Similarly, the coupling constant of H6 proton, seen as a

doublet at 1,25, with H5 is 6,2 Hz.Finally, acetyl proton 2,11 and 2,05 also gives

singlet.

As shown in Appendix 5, peaks at 1700 indicate the presence of the -

Acgroup. This situation supports the structure of our article.In addition, peaks

between 2800-3000 indicate aliphatic C-H.

3.6 Formation of 1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7)

Figure 3.9. Structure of1,2,3-O-orthodichloroacetyl--L-rhamnofuranose.

1,2,3-O-orthodichloroacetyl--L-rhamnofuranose(7)

Compound 7 6,06 s 5,66 d

J1,2:2,4 Hz

5,35 dd

J2,3:3,1 Hz

4,71 dd

J3,4:2,4 Hz

3,97 dd

J4,5:8,3 Hz

4,03 m 1,33 d

J5,6:6,1 Hz

The data from 1H NMR in Appendix 7 is shown in the table above. As

shown in Table 3.9, the Ha proton (proton of acetal) 6,06 appears as a singlet.

coupling constant of H6 proton, seen as a doublet at 1,33, with H5 is 6,1 Hz.

Table 3.10. 13

C NMR of1,2,3-O-orthodichloroacetyl--L-rhamnofuranose (7)

OE C1 C2-C5 and CCl2H C6

Compound 7 118.28 102.25 85.08, 80.54, 76.36, 66.84, 64.33 20.17

The data from 13

C NMR in Appendix 7 is shown in the table above. As

shown in Table 3.10, carbon of ortho ester at 118,28 ppm,C1 carbon at

102,25observed in ppm. However, it is seen that C2 to C5 is at 85,08, 80,54, 76,36,

66,84 and 64,33 ppm. In addition, C6 carbon at 20,17 ppm explains that the

number 6 is deoxy.

Figure 3.10. Colored COSY spectrum of compound 1,2,3-O-orthodichloroacetyl-

-L-rhamnofuranose.

According to Figure 3.10; The orthoester proton observed under 6.0 is

singlet because the neighboring carbons do not contain protons. Since there was

no interference, the COSY Spectrum did not cross-peak. The doublet of the H1

proton observed at 5.66 appears to interact with the green proton H2 drawn at 5.35

on the line drawn in red.In addition to the interaction of H2 with H1, it is observed

from the cross peaks that it interacts with the H3 proton at 4.71 and the center of

the blue lines.Similarly, the cross peaks show that the H3 proton interacts with the

H4 proton at the center of the purple lines at 3.97.The H5 proton at the center of

the light green lines and at 4.03 is observed to interact with the cross peaks with

the H6 proton at 1.33 drawn by pink.

APPENDIX

Appendix 1 FTIR Spectrum, 1H-NMR Spectrum

13C-NMR and HSQC

Spectrum of Compound 1

13C-NMR and NOESY

Appendix 4 FTIR Spectrum and 1H-NMR Spectrum of Compound 4

Appendix 6 FTIR Spectrum of Compound 6

13C-NMR and COSY

13C-NMR and HSQC

100 50556065707580859095

13C-NMR and NOESY

100 6165707580859095

13C-NMR and NOESY

riptio

102 69707274767880828486889092949698100

100 52556065707580859095

110 6265707580859095100

Appendix 6 FTIR Spectrum of Compound 6

114 66707580859095100

13C-NMR and COSY

riptio

REFERENCES

Ay, K. and Halay, E., 2013, “The Newest Member of the Family of Chloralose:

Synthesis of 𝛽-Ribochloralose and Some Derivatives”, Hindawi Publishing

Corporation Journal of Chemistry, ID 748161

Ay, K. and Yenil, N., 2004, Some Carbohydrate Orthoester Derivatives Which

Have Biological Activity, Journal of Engineering and Natural Sciences

Beau, J.M., Jaurand G. and Esnault J., 1987 “Synthesis of the Disaccharide C-

D Fragment Found in Everninomicin-C and -D, Avalamycin-A and -C and

Curamycin-A: Stereochemistry at the Spiro-ortholactone Center”,

Tetrahedron Lett., 28, 1105-1108.

Bellamy, L.J., 1975, “Advences in Infrared Group Frequencies”, Vol.2, 3th.Edit.,

Halsted Press., 166-168pp.

Binkley, R.W. and Ambrose, M.G., 1984 ,J.Carbohydr. Chem.,3,1.

Buchanan, J.G., Clelland, A.P.W. and Wightman, R.H., 1992, “Synthesis of

Glycosidic and 2-Deoxyglycosidic Ortholactones from 1-Bromoglycosyl

Cyanides”, Carbohydr. Res., 237, 295-301 pp.

Byramova, N.E., Ovchinnikov, M.V., Backinowsky, L.V. and Kochetkov,

N.K., 1983,Carbohydr. Res.,124, C8.

Charpiot, B., Greiner, J. and LeBlanc, M., 1991, “Polyhyroxlated and Highly

Fluorinated Compounds, Their Preparation and Their Uses as Surfactants”,

United States Patent, No.4, 985, 550p.

Crank, G.and Eastwood, F.W., 1964, Australian J. Chem., 17:1385p.

Crossland, R.K. and Servis, K.L., 1970,J.Org. Chem.,35,3195.

De Belder, A.N., 1965,Adv. Carbohyd. Chem., 20:220-301pp.

Dutton, G.G.S., 1973,Adv. Carbohydr. Chem. Biochem.,28,11.

Eckstein, F. and Cramer, F., 1965, “Notiz Uber 2‟, 3‟-O-Athoxy-methylen-

derivate von Ribonucleosiden”, Chem. Ber., 98, 995-997pp.

Ferrier, R.J., 1998,“Carbohydrate Chemistry”, vol.30, The Royal Society of

Chemistry, 113pp

REFERENCES (continued)

Ferrier, R.J. and Collins P.M., 1972, “Monosaccharide Chemistry”, Penguin,

England, 1st. Edit., 1-317pp.

Ferrier, R.J., 1996, The Royal Society of Chemistry,“Carbohydrate Chemistry”,

111-112pp.

Fletcher, G.H. and Ness, R.K., 1955, “Orthobenzoik Acid Aerivatives of D-

Ribopyranose. Preparation and Some Properties of 1,2-O-(1-

benzyloxybenzylidene)-α-D-ribopyranose and 1,2,4-O-orthobenzoyl-)-α-D-

ribopyranose”, J. Org. Chem., 77, 5337-5340pp.

Gigg, J. and Gigg, R., 1960, J. Chem. Soc C., 82.

Greene, T.W. and Wuts, P.G.M., 1991, Prıtective Groups in Organic Synthesis,

Greiner, J., Millius, A. and Reiss, J.G., 1988, “The Abnormal Issue of the

Köenigs-Knorr Reaction with Perfluoroalkylated Alcohols”, Tetrahedron

Lett., 29, 18, 2193-2194pp.

Hanessian, S. and Staub, A.P.A., 1976 ,Methods Carbohydr. Chem.,7,63.

Kartha, K.P.R. and Field, R.A., 1997, Tetrahedron, 53, 11753p.

Kochetkov, N.K., Khorlin, A.J. and Bochkov A.F., 1964, “New Synthesis of

Glycosides”, Tetrahedron Lett., 6, 289-293pp.

Kochetkov, N.K., Nepogod’ev, S.A. and Backinowsky, L.V., 1990, “Synthesis

of Cyclo-[(1-6)]-β-Dgalactofurano-oligosaccharides”, Tetrahedron., 46,

139-150pp.

Korytnik, W. and Mills, J.A., 1959, J. Chem. Soc., 636p.

Kovac, P. and Bauer, S., 1972,Tetrahedron Lett.,2349.

Lakhmiri, R., Lhoste, P. and Sinou, D., 1989,Tetrahedrom Lett. , 30,4669.

Makrovic, D. and Vogel, P., 2004 ,Org. Lett., 6,2693.

McPhillamy, H.B. and Elderfield, R.C., 1939, J. Org. Chem., 4:150p.

Millius, A., Greiner, J. and Reiss, J.G., 1991, “Synthesis of F-Alkylated

Gylcosides as Surfactants for in vivo Uses. Effects of the Length of the

Hydrocarbonated Spacer in the a Glycone on Köenigs-Knorr Reaction,

Surface Activity and Biological Properties”, New. J. Chem., 15, 337-344pp.

Oscarson, S. and Szönyi, M., 1989, “Acidic Opening of 4,6-O-orthoesters of

Pyranosides”, J. Carbohyd. Chem.,8, 4, 663-668pp.

Özgener, H. and Yüceer, L., 2002, “2-Dichloromethyl-1,3-dioxolan-2-yl

Orthoesters. A Potential Protecting Group for Sugar Derivatives”, J.

Carbohydrate Chemistry, 21, 6, 559-567pp.

Pelyvás, I.F., Lindhorst, T.K., Streicher, H. and Thiem, J., 1991,Synthesis,

Richardson, A., 1972, Methods in Carbohydrate Chemistry VI

Riess, J.G., 2001,“Oxygen Carriers (“Blood Substitutes”) Raison d‟Etre,

Chemistry and Physiology”, Chem. Rev., 101,2797-2919pp.

Salman, Y., Kök, G. and Yüceer, L., 2004,Carbohydrate Research 2004, 1739-

1745pp.

Salman, Y.G., Makinabakan, Ö. and Yüceer, L., 1994, “Tricyclic Orthoester

Formation from Trichloroethylidene Acetals of Sugars via Ketene Acetals”,

Tetrahedron Lett., 35, 9233-9235pp.

Sletter, H. and Steinacker, K.H., 1953, Chem. Ber., 86:789p.

Swain, C.G. and Brown, J.F., Jr., 1952, J. Am. Chem. Soc. 74, 2538p.

Sznaidman, M.L., Johnson, S.C. and Crasto, C., 1995, “Carbohydrate Cyclic

Ketene Acetals”, J. Org. Chem., 60, 3942-3943pp.

Vogl, O.,Anderson, B.C. and Simons, D.M., 1969, Journal of Org. Chem.

34:203p.

Wolfe, D., 1970, Carboxylic Ortho Acid Derivatives Organic Chemistry “A

Series of Monographs, Vol-14” Academic Press, Newyork and London.

Wolfrom, M.L. and de Lederkremer, M.R., 1965, “Products from the

Orthoester Form of Acetylated Maltose”, J.Org. Chem., 30, 1560-1563pp.

Yüceer, L., 1978, Galacto and glucochloraloses steric and polar factors in

nucleophilic substitution reactions of some tosyl derivatives, Associate

Professor Thesis, Ege University, 120 p.

Zemplén, G. and Pacsu, E., 1929, Ber. Dtsch. Chem. Ges., 62, 1613.

Zhu, T. and Boons, G.J., 2001 ,Org. Lett., 3, 4201.

CURRICULUM VITAE

Personel Knowledge

Name and Surname : Tolga ÖZEL

Date/Place of Birth : 14.06.1987 / İzmir-Turkey

Nationality : Turkey

Phone number : +905557398758

E-mail : tolgaozel95@gmail.com

Educational Background

2009-2016 Faculty of Chemistry Education, Ege Universty, İZMİR

2016-2020 MSc. In Organic Chemistry, Graduate School of Natural

and Applied Sciences, Ege University, İZMİR

synthesis of chloralose and orthoester derivatives of l-rhamnose

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