ASYMMETRIC SYNTHESIS of SILANEDIOL INHIBITORS for Fxia

ASYMMETRIC SYNTHESIS OF

SILANEDIOL INHIBITORS FOR ACE, FXIa, AND CHYMASE

A Dissertation

Submitted to

the Temple University Graduate Board

In Partial Fulfillment

of the Requirements for the Degree

DOCTOR OF PHILOSOPHY

Hoan Quoc Duong

May 2013

Examining Committee Members:

Scott McN. Sieburth, Advisor, Department of Chemistry

Franklin A. Davis, Committee Chair, Department of Chemistry

Rodrigo B. Andrade, Department of Chemistry

Kevin C. Cannon, Penn State University

2013

Hoan Quoc Duong

ABSTRACT

Dialkylsilanediols, a novel class of non-hydrolyzable analogues of the tetrahedral

intermediate of amide hydrolysis, have been shown to be good inhibitors of the HIV-1

protease, angiotensin converting enzyme (ACE), thermolysin, and the serine protease α-

chymotrypsin. Synthesis and biological evaluation of silanediols are therefore a priority in this research.

Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers gives

silafurans which can be used directly to make chiral β-silyl acids needed for the silanediol

peptide mimics. Absolute configuration determination of AIH products remains a

challenge. Proton nuclear magnetic resonance (1H NMR) of the Mosher ester derivative

was used to confirm the absolute configuration. This has proven to be a simple method to

determine the absolute configuration of silicon-containing primary carbinols.

Dialkylsilanediols (1.52) are known as good inhibitors of angiotensin converting

enzyme (ACE), with inhibition constants from 3.8 to 207 nM. However, the synthesis of

these silandiol peptide mimics involved a long synthetic route. A short, asymmetric

synthesis of silanediol ACE inhibitors was developed using asymmetric hydrosilylation

and addition of a silyllithium to a sulfinimine, 8 linear steps with an 8% over all yield.

Specific inhibitors of the FXIa protease could inhibit thrombosis without

completely interrupting normal hemostasis, and prevent or minimize the risk of

hemostasis complications. Based on the FXIa substrate, the design and synthesis of the

first five guanidine-containing silanediol FXIa inhibitors was developed: Ac-Arg-[Si]-

Ala-NHMe (4.15), Ac-Ala-Arg-[Si]-Ala-NHMe (4.16), Ac-Leu-Ala-Arg-[Si]-Ala-NHMe

iii

(4.17), Ac-Pro-Ala-Arg-[Si]-Ala-NHMe (4.18), and Ac-Arg-[Si]-Ala-Ala-NHMe (4.19).

Synthesis of these targets was achieved using our newly developed silyllithium preparation and silyl dianion addition to the Davis sulfinimine, 11 linear steps, gave silanediol precursor 4.60 in 1.7% yield. Inhibition constant of the FXIa inhibitors was

good in range of 76 - 980µM.

Human heart chymase (HHC), a chymotrypsin-like serine protease present in the

left ventricular tissues of the human heart, converts angiotensin I to angiotensin II, raising

blood pressure. Although the physiological role of HHC has not been fully elucidated, it

may be involved in various pathological states, particularly in cardiovascular diseases.

Synthesis of silanediol inhibitors of HHC, therefore, may contribute to the understanding

of its physiological functions and a better treatment for cardiovascular diseases. Synthesis

of a silanediol chymase inhibitor has been investigated.

ACKNOWLEDGEMENTS

First of all, I would like to thank my research advisor, Dr. Scott Sieburth, for all

the great guidance, support, extreme patience, and encouragement through the course of

my research, especially at times when success seemed so far to me. I admire his

professional spirit and enthusiasm for science, and I hope to carry it on in my future

career. Also, I would like to thank my committee members, Dr. Franklin Davis, Dr.

Rodrigo Andrade, and Dr. Kevin Cannon for their valuable time, comments and

suggestions for this work.

I also would like to thank Dr. Peter Walsh, Dr. Dipali Sinha and Dr. Wenman Wu

at Temple Medical School gave valuable suggestions and screening the inhibition of

silanediols for FXIa.

I am also grateful to my teachers during these six years, especially Dr. Grant

Krow, Dr. Kevin Cannon, Dr. DeBrosse, Dr. Williams and Dr. Andrade.

I am deeply grateful to thank Prof. Robert J. Levis, Prof. Frank C. Spano, and

Prof. Hai-Lung Dai for accepting my Ph.D application in 2007 and giving me a good

chance to improve my skills at teaching and doing research at Temple University.

I also thank for the help from the Dr. Sieburth group: Dr. Yingjian Bo, Dr.

Swapnil Singh, Svitlana Kulyk, Cui Cao, Paul Finn, and Buddha Khatri. They give me a professional environment in the Sieburth’s group. Paul Finn has spent a lot of time on

screening forty mass spectroscopy samples. I am also thankful to Dr. Serge Jasmin for his

advice in my research.

Thanks also go out to Qingquan Zhao, and Chongsong Xu in Dr. Chris

Schafmeister’s group for their generous help in doing my LC-MS samples, Dr. Charles v

DeBrosse’s support with NMR instrument and Dr. Shivaiah Vaddypally and Clifton

Hamilton for X-ray analysis.

Special thanks to Department of Chemistry and Dr. Alfred Findeisen and Dr.

Lawlor for supporting me as a teaching assistant, and Shapiro Regina, Johnson Bobbi,

Sharon Kass, Ford Jeanette for organizing all paper works for me when I need their help.

I would like to extent my sincere thanks to my M.S. degree advisor, Prof. David

P. Brown at St.john’s University who encouraged me apply to Ph.D program at Temple

and gave me so many helpful backgroups for Ph.D program when I worked in his lab. I

also would like to thank Prof. Victor Cesare, Prof. Alison G. Hyslop for their support

when I did application for Ph.D program, and Prof. Gina M. Florio, Prof. Joseph M.

Serafin and Prof. Enju Wang for helpful courses when I did M.S. degree at St.John’s

University. I also would like to thank Dr. Hung P. Le and his family for their help when I was in New York.

I would like to thank Hanoi National University of Education (HNUE), Chemistry

Department and Organic division for patience when I did M.S. and Ph.D programs. I also would like to thank Prof. Dinh H. Nguyen, Prof. Nguyet M. Bui, Prof. Quang D. Bui,

Prof. Oanh T. Dang, and Prof. Thu X. Dang for their supports.

Finally, I would like to thank my parents, parents-in-law, sisters, sister-in-law and

my brother for their loyal support, and generous love from my wife, son, and daughter.

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vii

TABLE OF CONTENTS

ABSTRACT…………………………………………………………………………….iii

ACKNOWLEDGEMENTS………………………………………………….…………v

LIST OF FIGURES……………………………………………………………………xii

LIST OF SCHEMES…………………………………………………………………...xv

LIST OF TABLES…………………………………………………………………………xix

LIST OF ABBREVIATIONS…………………………………………………………xxi

CHAPTER 1: INTRODUCTION ...... 1

1.1 Silicon ...... 1

1.2 Silicon versus Carbon ...... 1

1.3 Bioactive organosilicon compounds ...... 6

1.3.1 Where do organosilanes come from? ...... 7

1.3.2 Examples of bioactive organosilanes ...... 7

1.4 Designed organosilane drugs ...... 9

1.4.1 Random screening ...... 9

1.4.2 Drug design ...... 10

1.5 Design and synthesis of silanediols as therapeutic peptidomimics ...... 16

1.5.1 Silanediol stability and silanol acidity ...... 16

1.5.2 Design, synthesis of silanediols as therapeutic peptidomimics pioneered by

the Sieburth group ...... 17

1.6 The original approach for silanediol protease inhibitor synthesis ...... 19

1.7 29Si Nuclear magnetic resonance (NMR) ...... 22

viii

CHAPTER 2: CATALYTIC ASYMMETRIC INTRAMOLECULAR

HYDROSILYLATION OF SILYL ETHERS ...... 24

2.1 Introduction ...... 24

2.2 Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers ...... 24

2.2.1 Introduction ...... 24

2.2.2 Improved AIH of allyl silyl ethers ...... 26

2.3 Results and discussion ...... 28

2.3.1 Synthesis of oxygen-containing allylic alcohols ...... 28

2.3.2 Determination of absolute configuration ...... 35

CHAPTER 3: A SHORT, ASYMMETRIC SYNTHESIS OF SILANEDIOL

INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME (ACE) ...... 43

3.1 Introduction ...... 43

3.2 Four silanediol ACE inhibitors ...... 43

3.2.1 Retrosynthesis of silanediols via silafuran 1.74 ...... 44

3.2.2 Synthesis of fluorodiphenyl silane 3.6 ...... 44

3.2.3 Protection of fluorodiphenyl silyl alcohol 3.6 ...... 46

3.2.4 Synthesis of dithiane 3.4 ...... 47

3.2.5 Synthesis of ketones 3.3 and 3.15 ...... 48

3.3 New route for the synthesis of ACE silanediols ...... 50

3.3.1 Oxidation of the primary alcohols to acids ...... 54

3.3.2 Synthesis of (S,R,S) and (S,S,S)-3.29 ...... 56

3.3.3 Synthesis of difluorosilanes55 ...... 58

3.3.4 Hydrolysis of difluorosilanes 3.31 to silanediols 1.6455 ...... 59

3.3.5 Asymmetric synthesis of alcohol (R,S)-1.63 ...... 60

CHAPTER 4: ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS

FOR FXIa ...... 62

4.1 INTRODUCTION ...... 62

4.1.1 Hemostasis ...... 62

4.1.2 Blood Coagulation, FXI and FXIa ...... 62

4.1.3 Design and synthesis of small molecules as FXIa inhibitors ...... 64

4.2 Silanediol inhibitor design ...... 67

4.3 Synthesis of silanediols ...... 70

4.3.2 Removal of p-toluenesulfonate ...... 77

4.3.3 Synthesis of azide 4.21 ...... 78

4.3.4 Asymmetric synthesis of silanediol 4.15 ...... 84

4.3.5 Asymmetric synthesis of silanediol 4.16, 4.17, and 4.18 ...... 86

4.3.6 Asymmetric synthesis of silanediol 4.19 ...... 88

4.3.7 Silanediol inhibition of FXIa ...... 90

CHAPTER 5: TOWARD ASYMMETRIC SYNTHESIS OF A SILANEDIOL

INHIBITOR FOR HUMAN HEART CHYMASE (HHC) ...... 95

5.1 Introduction ...... 95

5.1.1 Chymotrypsin-like serine proteases ...... 95

5.1.2 Example of design and synthesis of human heart chymase inhibitors ...... 96

5.2 Design and retrosynthesis of a silanediol human heart chymase inhibitor 98

5.3 Synthesis of Chymase silanediol inhibitor ...... 99

5.4 Attempt to insert Evans auxiliary in structure ...... 102

CHAPTER 6: EXPERIMENTAL ...... 105

6.1 Instrumentations ...... 105

6.2 Reagents and solvents ...... 106

6.3 Chromatography ...... 106

6.4 Index of experimentals for chapter 2 ...... 107

6.5 Index of experimentals for chapter 3 ...... 146

6.6 Index of experimentals for chapter 4 ...... 192

6.7 Index of experimentals for chapter 5 ...... 278

REFERENCES ...... 295

APPENDIX: X-ray structure determination of compound (S,S,S)-3.29…………..312

LIST OF FIGURES

Figure 1. A double bond to silicon is unstable ...... 4

Figure 2. Organosilane commercial products ...... 7

Figure 3. Silicon-containing compounds that have entered human clinical trials ...... 8

Figure 4. Examples of bio active organosilane without carbon analog ...... 10

Figure 5. Silicon replacement can increase the binding affinity of compounds to a receptor ...... 11

Figure 6. Sila-BIRB-796 (1.29) behaves like BIRB-796 (1.28) with mitogen-activated

protein ...... 11

Figure 7. Replacement of tert-butyl with TMS does not change bioactive ability of MK-

056 (1.30) ...... 12

Figure 8. Substitution of C6 of estradiol with silicon eliminated bioactivity ...... 12

Figure 9. Examples of silicon substitution in proline ...... 13

Figure 10. Sila-substitution leucine analog ...... 13

Figure 11. Models of interaction between dipeptides and the active- site of thermolysin40

...... 14

Figure 12. Trifluperidol and Sila-trifluperidol ...... 15

Figure 13. Venlafaxine and Sila-venlafaxine ...... 15

Figure 14. Polymerization of dimethylsilanediol ...... 16

Figure 15. Design of a C2 symmetric silanediol enzyme inhibitor ...... 18

Figure 16. Almquist’s ketone and Sieburth’s silanediol ...... 18

Figure 17. Phosphinic acid inhibitor and silanediol inhibitor mimic ...... 19

xii

Figure 18. Design of serine protease chymotrypsin silanediol ...... 19

Figure 19. Core structure of silanediol, silyl ether, and silafuran analogs ...... 24

Figure 20. Chiral ligands for AIH ...... 26

Figure 21. Retrosynthesis of allylic alcohol 2.19 ...... 28

1 Figure 22. Absolute configuration determination with H NMR and Eu(fod)3 ...... 35

Figure 23. Using 1H NMR for chiral determination of natural product...... 36

1 Figure 24. Diastereotopic protons on H NMR of compound 2.58 in CDCl3 ...... 38

1 Figure 25. H NMR of Mosher esters in CDCl3 ...... 39

1 Figure 26. H NMR of Mosher esters in Eu(fod)3 in CDCl3 at rt ...... 40

Figure 27. A: [Eu(acac)3(phen)]; B: [Eu(tta)3(H2O)2] and C: complexes of Mosher esters with Eu(fod)3 ...... 41

Figure 28. Silanediol inhibitors for ACE ...... 43

Figure 29. Retrosynthesis of silanediol 1.64 ...... 44

Figure 30. New route of silanediol synthesis ...... 50

Figure 31. Monitoring lithiation progress with 1H NMR ...... 52

Figure 32. Transition state for addition to sulfinimine (R)-3.17 ...... 53

Figure 33. Stereoselectivity of nucleophilic addition to (S)-sulfinimine ...... 57

Figure 34. Hydrolysis of diphenylsilane to diflurosilane...... 59

Figure 35. Classic pathway of blood coagulation;105 TF = Tissue Factor; a = activation 63

Figure 36. Guanidine-containing FXIa inhibitors ...... 65

Figure 37. Guanidine-containing FXIa inhibitors ...... 66

Figure 38. Clavatadine A (4.11), and B (4.12)123 ...... 67

Figure 39. Docking of Clavatadine A (4.11) in FXIa123 ...... 67

xiii

Figure 40. A: Natural cleavage sites on FIX by FXIa; B: Silandiol FXI mimic ...... 68

Figure 41. Design of silanediol FXIa inhibitors ...... 69

Figure 42. Retrosynthesis of silanediol inhitbitor for FXIa ...... 70

Figure 43. N-carbamate and N-carbamate compounds are stable under TMSBr ...... 79

Figure 44. Comparision of IR spectra of azide 4.21 and carbamate 4.59 ...... 80

Figure 45. Proposed mechanism of mercuridearylation ...... 82

Figure 46. Chromogenic substrate for FXIa ...... 91

Figure 47. FXIa inhibition results, (R,S 214) = 4.15, (R,S 215) = 4.16, (R,S 216) = 4.17,

(R,S 217) = 4.18, (R,S 218) = 4.19 ...... 92

Figure 48. The catalytic mechanism of serine proteases158 ...... 95

Figure 49. Examples of synthetic chymase inhibitors ...... 96

Figure 50. Proposed binding of compound 5.9 with HHC ...... 97

Figure 51. Expected silanediol inhibitor structure for HHC ...... 98

Figure 52. Evans auxiliary compound ...... 102

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LIST OF SCHEMES

Scheme 1. Classic method to make silicon-silicon bond ...... 3

Scheme 2. Nucleophilic substituion of Si-F bond ...... 3

Scheme 3. Double bonds on silicon are unstable ...... 4

Scheme 4. Silicon stabilizes α-anions ...... 6

Scheme 5. Silicon stabilizing β-cation example ...... 6

Scheme 6. R2SiCl2 as a good starting material for organosilane chemistry ...... 7

Scheme 7. Synthesis of silanediol ACE inhibitors ...... 20

Scheme 8. Asymmetric synthesis a silanediol inhibitor of serine protease chymotrypsin 21

Scheme 9. Asymmetric produce α-amino silane ...... 21

Scheme 10. New method to synthesize α-amino silane 59 ...... 22

Scheme 11. The first asymmetric hydrosilylation, catalyzed by a chiral rhodium catalyst

...... 25

Scheme 12. Chiraphos and BINAP in AIH ...... 25

Scheme 13. AIH of 1.73 and absolute stereochemistry determination ...... 26

Scheme 14. Variety of substrates for AIH ...... 27

Scheme 15. The first attempt synthesis of allylic alcohol 2.19 ...... 29

Scheme 16. Synthesis of iodide 2.22 ...... 30

Scheme 17. Successful route to allylic alcohol 2.19 ...... 31

Scheme 18. Synthesis of allylic alcohol 2.43 ...... 32

Scheme 19. Synthesis of allyl silyl ethers ...... 33

Scheme 20. Asymmetric intramolecular hydrosilylation ...... 33

Scheme 21. Synthesis of racemate of silafurans ...... 34

Scheme 22. Silafuran opening with Grignard reagent ...... 34

Scheme 23. Synthesis of Mosher esters ...... 37

Scheme 24. Synthesis of fluorosilane 3.6 ...... 45

Scheme 25. General reactions of the silafuran 1.74 ...... 45

Scheme 26. Protecting Fluorosilane ...... 46

Scheme 27. Protecting flurosilane in neutral condition ...... 47

Scheme 28. A simple and successful protection of fluorosilane 3.6 ...... 47

Scheme 29. Synthesis of dithiane derivative 3.4 ...... 48

Scheme 30. Optimized conditions for dedithianation ...... 48

Scheme 31. Changing protecting groups from THP to a TBS group ...... 50

Scheme 32. Synthesis of sulfinamide 3.16 ...... 51

Scheme 33. Monitoring the progress of lithiation ...... 52

Scheme 34. Deprotection and Schotten-Baumann benzoylation ...... 53

Scheme 35. Alternative synthesis of compound (±)-3.19 ...... 54

Scheme 36. Skrydstrup’s oxidation attempted with TEMPO ...... 54

Scheme 37. TEMPO and BAIB oxidization ...... 55

Scheme 38. Synthesis of proline derivatives 3.29 ...... 56

Scheme 39. Synthesis of (S,R,S) and (S,S,S)-3.29 ...... 57

Scheme 40. Synthesis of difluorosilanes 3.31 ...... 58

Scheme 41. Synthesis of silanediols 1.64 ...... 59

Scheme 42. Asymmetric synthesis of (R,S)-1.63 ...... 60

Scheme 43. Synthesis of Ellman sulfinimine 4.25 ...... 71

xvi

Scheme 44. Synthesis of Ellman sulfinamide 4.24 ...... 72

Scheme 45. Unsuccessful selective removal of Ellman auxiliary ...... 72

Scheme 46. Removal of Davis and Ellman auxiliaries ...... 73

Scheme 47. Attempt of removal Ellman auxiliary and acetylation ...... 73

Scheme 48. Ts group removal is easier than Bus group ...... 74

Scheme 49. Synthesis of the Davis sulfinimine 4.41 ...... 74

Scheme 50. Synthesis of the Davis sulfinamide 4.42 ...... 75

Scheme 51. Oxidation of the alcohol 4.42 with RuCl3/NaIO4 ...... 76

Scheme 52. Failure of converting alcohol to azide ...... 77

Scheme 53. Failure of tosyl removal with magnesium in methanol ...... 78

Scheme 54. Desulfonylation of "activated" N-Boc-tosylate ...... 78

Scheme 55. Synthesis of azide 4.21 ...... 79

Scheme 56. Conversion of azide 4.21 to carbamate 4.59 ...... 80

Scheme 57. Synthesis of compound 4.20 ...... 81

Scheme 58. Insertion guanidine group and hydrolysis of the diphenylsilane ...... 81

Scheme 59. Asymmetric intramolecular hydrosilylation ...... 83

Scheme 60. Asymmetric synthesis of silanediol inhibitor 4.15 ...... 85

Scheme 61. Synthesis of amino acids and dipeptide for silanediol inhibitors ...... 86

Scheme 62. Synthesis azide compounds via coupling reaction ...... 87

Scheme 63. Silanediol analog synthesis ...... 88

Scheme 64. Synthesis of silanediol 4.19 ...... 89

Scheme 65. Cleavage of the substrate by FXIa ...... 91

Scheme 66. Synthesis of Glu-Pro-OH 5.11 ...... 99

xvii

Scheme 67. Synthesis of FmocAsp-Glu (CONH2)2 (5.13) ...... 100

Scheme 68. A successful and an unsuccessful sulfinamide synthesis ...... 100

Scheme 69. Proposed synthesis of compound 5.23 ...... 101

Scheme 70. Potential sequence for silanediol 5.10 synthesis ...... 101

Scheme 71. Attempt to synthesis of compound 5.37 ...... 103

Scheme 72. Failure of N-carbamate protection ...... 104

xviii

LIST OF TABLES

Table 1. Physical and chemical properties of silicon and carbon ...... 2

Table 2. Bond strengths and bond lengths of some silicon compounds14 ...... 5

Table 3. pKa values for selected silanols, silandiols and carbinols47 ...... 17

Table 4. Parameter of 13C and 29Si ...... 22

Table 5. Selected 29Si NMR chemical shifts ...... 23

Table 6. AIH using 1 mol% of (S,S)-ferrotane (1.77) ...... 28

Table 7. Optimization of deprotecting dithiane ...... 49

Table 8. Examples of small molercules for FXIa inhibition ...... 65

Table 9. Examples of peptide compounds for FXIa inhibition ...... 66

Table 10. Rate of hydrosilylation depends on catalyst ...... 83

Table 11. Silanediols solutions sent to test FXIa ...... 90

Table 12. Screening silanediol inhibition results ...... 93

Table 13. HHC inhibition results ...... 97

Table 14. Sample and crystal data for (S,S,S)-3.29 ...... 313

Table 15. Data collection and structure refinement for (S,S,S)-3.29 ...... 314

Table 16. Atomic coordinates and equivalent isotropic atomic displacement parameters

(Å2) for (S,S,S)-3.29 ...... 316

Table 17. Bond lengths (Å) for (S,S,S)-3.29 ...... 318

Table 18. Bond angles (°) for (S,S,S)-3.29 ...... 320

Table 19. Torsion angles (°) for (S,S,S)-3.29 ...... 321

Table 20. Anisotropic atomic displacement parameters (Å2) for (S,S,S)-3.29 ...... 324

xix

Table 21. Hydrogen atomic coordinates and isotropic atomic displacement parameters

(Å2) for (S,S,S)-3.29 ...... 326

LIST OF ABBREVIATIONS

Abs Absolute

Ac Acetyl

acac Acetylacetone

AIBN 2,2′-Azobis(2-methylpropionitrile)

Ala Alanine

Aq. Aqueous

Arg Arginine

Asp Aspartic

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Binapine (3S,3’S,4S,4’S,11bS,11’bS)-(+)-4,4′-Di-t-butyl-4,4′,5,5′-

tetrahydro-3,3′-bi-3H-dinaphtho[2,1-c:1′,2′-e]phosphepin

Bn Benzyl

Boc tert- Butoxycarbonyl

calcd calculated

Cat. Catalyst or catalytic

Chiraphos (2S,3S)-(–)-Bis(diphenylphosphino)butane

CSA Camphorsulfonic acid

D Deuterium

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCC 1,3-Dicyclohexyl carbodiimide

de diastereomeric excess

DMAP 4- Dimethylaminopyridine

xxi

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

dr diastereomeric ratio

Duan-Phos (1R,1′R,2S,2′S)-2,2′-Di-tert-butyl-2,3,2′,3′-tetrahydro-1H,1′H-

(1,1′)biisophosphindolyl ee Enantiomeric excess

eq./equiv. Equivalent

Et Ethyl

h hour

Ferrotane (-)-1,1'-Bis((2S,4S)-2,4-diethylphosphotano)ferrocene

fod 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato

Glu Glutamine

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium

hexafluorophosphate

His Histidine

HPLC High-performance liquid chromatography

IC50 Concentration for 50% inhibition

Imid. Imidazole

JosiPhos (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine

Ki Inhibition Constant

LAH Lithium aluminium hydride

MandyPhos (S,S)-(+)-2,2'-Bis[(R)-(N,N-dimethylamino)(phenyl)methyl]-1,1'-

bis(dicyclohexylphosphino)ferrocene

xxii

Me Methyl

LDA Lithium diisopropylamide

Leu Leucine lle isoleucine mol Mole

MOM Methoxymethyl ether

Mp. Melting point

MS Mass spectroscopy

NMM 4-Methylmorpholine n Normal

NMR Nuclear magnetic resonance

Ph Phenyl

Phen Phenanthroline

PivCl pivaloyl chloride

Pro Proline

Rac Racemic pKa pK for association

R Alkyl group

Rf Retention factor rt Room temperature

Sec Secondary

Ser Serine

Tang-Phos (1S,1S′,2R,2R′)-1,1′-Di-tert-butyl-(2,2′)-diphospholane tert Tertiary

xxiii

TFA Trifluoroacetic acid

TfOH Trifluoromethanesulfonic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TMS Trimethylsilyl

TPS tert-Butyldiphenylsilyl

Ts para-Toluenesulfonyl

Tta thenoyltrifluoroacetonate

xxiv

CHAPTER 1:

INTRODUCTION

1.1 Silicon

“Silicium” was discovered by Jöns Jacob Berzelius in 1824 after heating chips of

potassium in a silica container and carefully washing the residual by-product,1,2,3 although it was not until 1854 that the first example of crystalline silicon was reported by

Henri Étienne Sainte-Claire Deville.4 Silicon is a solid at room temperature with melting

and boiling points of approximately 1,400 °C and 2,800 °C, respectively.5 In its pure

crystalline form, silicon is a gray color with a metallic luster. It is rather strong, but very brittle, and prone to chipping.6 Although silicon is the second most abundant element in

the earth’s crust, it rarely occurs as the free element in nature. It is widely distributed in

dust, sand, planetoids, and as other various forms of silicon dioxide (SiO2). At temperatures above 1,900 °C, a mixture of carbon and silicon dioxide undergo the chemical reaction SiO2 + 2 C → Si + 2 CO. Liquid silicon collects in the bottom of the

furnace, which can then be drained and cooled. The silicon produced in this manner is

called metallurgical grade silicon, and is of greater than 98% purity.

1.2 Silicon versus Carbon

Silicon is a member of the third row in the periodic table with the electronic

configuration [Ne] 3s23p23d0; whereas carbon belongs to the second row with the

electronic configuration [He] 2s22p2. Silicon and carbon are group four elements, both

having four valence electrons. Therefore, not only does silicon exhibit many chemical

similarities to carbon, but also it shows differences with carbon.

In general, the important differences between silicon and carbon stem from the

differences in atomic radii, electronegativity, and the penta- and hexa- valent capacity of silicon, using its empty 3d orbitals. Since silicon is bigger than carbon, the bond lengths of silicon with other atoms and itself are longer than the corresponding bonds to carbon.

The Si-H bond is weaker than the C-H bond by about 93 kJ/mol. In contrast, the Si-O bond is 32 kJ/mol stronger than the corresponding C-O bond. The Si-F bond is the strongest single bond (Table 1).

Table 1. Physical and chemical properties of silicon and carbon

Silicon Carbon

Atomic Radii (Å) 1.17 0.77

Electronegativity 1.8 2.5

Bond length ( Å )/ 1.46 /323 (Si-H) 1.08/416 (C-H)

bond energy(kJ/mol-1) 6a,b 1.63/368 (Si-O) 1.43/336 (C-O)

1.70/582 (Si-F) 1.36/485 (C-F)

Hypevalance Common Rare

Si C

Multiple bonds Rare Common

Both silicon and carbon can form bonds with themselves to produce silicon and

carbon chains. However, the longest Si-Si chain known is only 13-silicon atoms,7a reflecting that polysilane chains are not as stable nor as easy to make long chains of carbon. Disilanes and trisilanes are easy to make, however, through Wurtz-like coupling,

Scheme 1.7b

Scheme 1. Classic method to make silicon-silicon bond

Substitution at silicon can take place with poorer leaving groups than substitution

at carbon. Thus, Si-F, Si-OR, Si-C, and Si-H bonds have the capability of being

substituted by suitable nucleophiles.8 For example, although fluoride is a poor leaving

group, and Si-F is the strongest bond, the fluorosilane 1.1 is easily substituted by 2-lithio

-1,3-dithiane giving compound 1.2 in 86% yield (Scheme 2).9

Scheme 2. Nucleophilic substituion of Si-F bond

In contrast to carbon’s ability to form stable double bonds, silicon double bonds

10 are unstable. In 1866, the term silicone was first coined by Friedel to describe Et2Si=O.

From 1905 to 1907, diphenylsilicone (Ph2Si=O) was synthesized by Dilthey and

Kipping;11,12 however, Kipping soon realized that dibenzyldichlorosilane was undergoing

13 hydrolysis to form (Bn2SiO)3 (Scheme 3) instead of Bn2Si=O.

Comparison of trimethylsilyl chloride and tert-butyl chloride reacting with methoxide is shown in Scheme 3. Trimethylsilyl chloride undergoes a rapid substitution reaction to form a silyl ether, while, tert-butyl chloride gives elimination to yield isobutene. The π-bond on silicon is weak because of the disparity in size between silicon and first row elements.

Bn2 H2O Cl2 Si Si O O Bn Bn Bn Si SiBn 2 O 2

MeO Si Cl MeO OMe X Si Si

MeO Cl MeO OMe X

Scheme 3. Double bonds on silicon are unstable

As mentioned above, Kipping was unable to isolate silicone, the silicone equivalent of acetone, because Si-O single bonds are preferred over double. In contrast, carbon prefers the ketone form. Thus silicone (silanone) is unstable and drives the equilibrium to the left, where silicon has two σ-bonds instead of one π-bond and one σ- bond in the right hand form, Figure 1.

Figure 1. A double bond to silicon is unstable

Table 2 shows bond strengths and bond lengths of selected silicon compounds.

The Si-F bond is the strongest, while the Si-O, Si-Si and Si-Cl bonds have about the same

dissociation energy, but they are much stronger than Si-H and Si-C bonds. The Si-N bond

is the weakest of the bonds from silicon to the common elements,Table 2.

Table 2. Bond strengths and bond lengths of some silicon compounds14

Compound Dissociation energy Compound Bond length (pm)

(kJmol-1)

Me3Si-F 810 H3Si-SiH3 232

Me3Si-SiMe3 540 Cl3Si-Cl 201

Me3Si-Cl 530 Me3Si-CH3 189

Me3Si-OMe 530 H3Si-N(SiH3)2 174

Me3Si-H 370 H3Si-OSiH3 163

Me3Si-CH3 360 F3Si-F 154

Me3Si-NHSiMe3 320 D3Si-H 148

Silicon is known as a good stabilizer of α-anions and β-cations. For instance, in

Sheme 4, enolate 1.3 can be added to α,β-unsaturated ketone 1.4 to make ketone 1.6. If

the substituent (R) was hydrogen, none of the desired product was observed. In contrast,

if the R group was triethylsilyl the desired product was isolated in 70% yield.15 The result

can be explained by silicon’s ability to stabilize the negative charge at this α-position in the intermediate 1.5.

O O OLi R R O O O O O O O 1.3 1.4 1.5 O R=H,0% R = H, SiEt3 R =SiEt3, 70% 1.6

Scheme 4. Silicon stabilizes α-anions

To probe the stabilization of a β-cation by silicon, para-fluorotrimethylbenzene

+ (1.7) was treated by Coea et al. with the electrophile NO2 , it was determined that reaction at the ipso-position was faster than at other positions due to the β-position being stabilized by silicon via intermediate 1.11. Substitution at the ipso-position 1.8 was the major product, isolated in 36% yield. Dinitro substitution 1.9 was observed in 3% yield only, and about 1% for all other positions, Scheme 5.16

Scheme 5. Silicon stabilizing β-cation example

1.3 Bioactive organosilicon compounds

Carbon makes up the skeleton of organic compounds, but silicon has been recognized as an essential trace element in normal metabolism of higher animals. The biochemical role of silicon is still not fully understood since silicon (as silicate) is a ubiquitous material silicate in nature. Interestingly, silica has been found to have

significant effects on the growth of animals,17 including playing an important role in

tooth pigmentation, initiation of the mineralization process in bones18 and in the

development of the skeleton and the skull of chicks.19

1.3.1 Where do organosilanes come from?

Investigations into the bioactivities of organosilicon compounds suffered from the

fact that all organosilanes are unnatural. During World War II, Eugene G. Rochow

invented a procedure that enabled the large-scale production of organosilanes from

inexpensive ingredients, named the Direct Process. Various alkyl or aryl halides can be

reacted with pure silicon in presence of a suitable catalyst to produce dialkyl and

diarylsilyl chloride products in 70-90% yield, which can be purified by fractional

distillation, Scheme 6.20

Cu 2RCl + Si R2SiCl2 + ∼ 40 by products 300 °C

Scheme 6. R2SiCl2 as a good starting material for organosilane chemistry

1.3.2 Examples of bioactive organosilanes

Flusilazole21 (1.12) and Silafluofen22 (1.13) are both successful silicon-containing commercial products for agriculture. Flusilazole is a fungicide and silafluofen is an

insecticide, Figure 2.

F F

Si N Si N O N O

F Flusilazole (1.12) Silafluofen (1.13)

Figure 2. Organosilane commercial products

Figure 3 shows several organosilane compounds that have entered clinical trials.

Morris et al. found that phthalocyamine (Pc 4, 1.14) has a concentration-dependent inhibition of PK-11195 (an isoquinoline carboxamide that binds selectively to the peripheral benzodiazepine receptor) binding to rat kidney mitochondria (RKM), IC50 = 3

µM (Figure 3).23

Figure 3. Silicon-containing compounds that have entered human clinical trials

Bis-trimethylsilylbenzamide (TAC-101 or Am555S, 1.15) was tested as a

treatment for arthritis. It was dosed at 5 and 25 mg/kg in mice to clarify the effect of

TAC-101 on collagen type II (CII) induced arthritis (CIA) in mice and experimental

autoimmune encephalomyelitis (EAE) in rats. The inhibition of the immune response to

auto-antigen appears to be the dominant mechanism of TAC-101 for the suppression of

both of these experimental autoimmune diseases.24 Karenitecin (1.16) has undergone successful Phase II clinical trials as a treatment for metastatic melanoma.25 Kocsic et al.

found that Silperisone (1.17) is a centrally acting muscle relaxant that acts on the sodium

channel.26

1.4 Designed organosilane drugs

Fundamentally, there are two methods to discover organosilicon-based agents:

random screening and molecular design.

1.4.1 Random screening

Random screening of organosilanes in a biological screen of interest has a small

possibility of success due to the fact that it relies on chance. However, this trial can give

impressive results, Figure 14. For example, silatranes 1.20 and 1.21 were discovered by

this way. Silatrane bioactivity has been reviewed by Vonronkov, M. G and

Kazimirovskaya, V. B et al.27,28 The silatrane thymidines (1.18 and 1.19) were

synthesized and tested for anti-cancer cell growth inhibition. Compound 1.18 inhibited up

to 46% growth of a breast cell line after 48 hours, and compound 1.19 inhibited 19%

growth of the same breast cell line.29 Chloromethylsilatrane (1.20) has a multitude of

attributes, especially healing and promotion of hair growth.28 The phenylsilatrane (1.21) has a strong affinity for the picrotoninin receptor, and is therefore quite toxic, with potential use as a rodenticide. Diphenylsilanediol (1.22) was found to be a possible treatment for epilepsy.30 Cisobitan (1.23) shows estrogenic activity.31

O O O Cl N N NH Si Si R O O HO O O R N O O O 1.20 1.21 O N Si O Silatrane O

R R=H(1.18) Ph HO OH O Si =Me(1.19) Si Si O O Si Ph Si O

Diphenylsilanediol (1.22) Cisobitan (1.23)

Figure 4. Examples of bio active organosilane without carbon analog

1.4.2 Drug design

Drug design, based on modification of known bioactive compounds, has a higher probability of success compared to relying entirely on chance for a discovery of significance.

1.4.2.1 Quaternary carbons-substituted silicon

Tamibarotene, (1.24, AM80, Figure 5), a retinoic acid receptor (RAR) α agonist, has been approved for treatment of recurrent acute promyelocytic leukemia (APL). AM

580 (1.26) enhances RAR γ-selectivity. Replacing selected carbons with silicon to give disila-AM80 (1.25) and disila-AM580 (1.27) led to a tenfold increase in the agonist activity at RARβ and RARγ, meaning that binding affinity of the silicon compounds to these receptors has increased.32

Figure 5. Silicon replacement can increase the binding affinity of compounds to a receptor

Substitution of the tert-butyl moiety in the p38α mitogen-activated protein kinase

inhibitor doramapimod BIRB-796 (1.28, Figure 6), with a trimethylsilyl group is a new

use of this bioisostere in medicinal chemistry. Sila-BIRB-796 (1.29, Figure 6) appears to be at least as effective as BIRB-796 with respect to both in vitro and in vivo activity.33

Figure 6. Sila-BIRB-796 (1.29) behaves like BIRB-796 (1.28) with mitogen-activated protein

MK-056 (1.30) exhibits highly potent competitive TRPV1 (transient receptor potential cation channel subfamily V member 1) antagonist effects. The 4- tert-butyl group of MK-

056 (1.30) is essential for the potency. To exploit the benefits of silicon in TRPV1, sila-

substitution (C/Si exchange) of tert-butyl group in the MK-056 series was made. All

attempts to replace the tert-butyl group of MK-056 (1.30) with other groups such as

SiMe2Et, SiEt3 groups resulted in decreased its potency. However, sila-MK-056 (1.31,

Figure 7), with a trimethylsilyl group in place of the tert-butyl group, exhibited potent

34 activity with IC50 values of 0.15 μM, almost equipotent with that of MK-056 (1.30).

Figure 7. Replacement of tert-butyl with TMS does not change bioactive ability of MK-

056 (1.30)

1.4.2.2 Methylene group carbons replaced with silicon

Replacement of the C6 methylene group of estradiol (1.32) with a dimethylsilyl

gave 1.33, which was screened for estrogenic, antiestrogenic, and postcoital activity,

Figure 8. No significant estrogenic or antiestrogenic activity was observed using doses

102−103 times that of an estradiol standard. 6,6-Dimethylsilyl estradiol 1.33 exhibited

post-coital activity in the rat model, but only at the high dose of 10 mg/kg.35,36

OH OH H 1 H H H H H HO Si HO 6 estradiol (1.32) 6,6-dimethylsilyl estradiol (1.33)

Figure 8. Substitution of C6 of estradiol with silicon eliminated bioactivity

The presence of the dimethylsilyl group confers to silaproline (Sip, 1.34) a high degree of lipophilicity and improved resistance to biodegradation, Figure 9. The retention

of receptor affinity for some polypeptides is encouraging for the use of silaproline as a

proline surrogate. Moreover, it has been shown that replacement of a Pro (1.35) by Sip

on the hydrophobic face of a Pro-rich amphipathic peptide does not perturb secondary

structure, does not prevent peptide aggregation, and greatly enhances the cellular uptake

of the peptide. In addition to highlighting the relevance of amphipathicity in cell-

penetrating peptide (CPP) design, these results also demonstrate the utility of Sip as a

new source of amphipathicity.37-39

Figure 9. Examples of silicon substitution in proline

1.4.2.3 Methine group carbons replaced with silicon

Figure 10. Sila-substitution leucine analog

The dipeptides Leu-Leu (1.36), (TMS-Ala)-Leu (1.37) and Leu-(TMS-Ala) (1.38)

(Figure 10) were screened for inhibition of thermolysin-catalyzed hydrolysis of N-[3-(2-

furyl)acryloyl]-Gly-Leu-NH2 (1.39) (Figure 11). A replacement of methine group of 1.36

with a silicon increased the Ki value of compound 1.37 to 7.92 mM, but silyl substitution

of another methine group of 1.36 gave smaller Ki value (better binding to the enzyme) for

1.38 compared with Leu-Leu 1.36.40

Figure 11. Models of interaction between dipeptides and the active- site of thermolysin40

The increase in inhibitory activity following the substitution of TMS-Ala for Leu

at the C terminus in the case of Leu-(TMS-Ala) (1.38), is presumably derived from an

increase in the hydrophobicity of the trimethylsilyl containing side-chain of the C-

terminal amino acid, which promotes binding of the peptide to thermolysin at the S2’

subsite (Figure 10). The decrease in activity of (TMS-Ala)-Leu (1.37) is believed to be

due to the bulkiness of the trimethylsilyl group that prevents the peptide from fitting the

40 S1’ subsite.

1.4.2.4 The silicon replacement in tertiary alcohols

Trifluperidol (1.40, Figure 12) is a dopamine (D2) receptor antagonist of the butyrophenone type. Sila-substitution at the 4-position of the piperidine ring gives sila-

trifluperidol (1.41, Figure 12). Human dopamine D1 and D2 receptor studies with 1.40

and 1.41 demonstrated that this carbon/silicon switch led to a 10-fold reduction of inhibition at D2 receptors, whereas the inhibitory potency of 1.40 and 1.41 at the D1

receptor was not significantly changed.41

F3C X N HO F O

X = C, Trifluperidol (1.40) X = Si, Sila-trifluperidol (1.41)

Figure 12. Trifluperidol and Sila-trifluperidol

Silyl substitution of rac-Venlafaxine (1.42, Figure 13), a serotonin/noradrenaline

reuptake inhibitor used as an antidepressant, gives rac-Sila-venlafaxine (1.43, Figure 13), which shows selective noradrenaline reuptake inhibition. This inhibition is approximately tenfold more potent at noradrenaline transporters than at serotonin and dopamine transporters.42

Figure 13. Venlafaxine and Sila-venlafaxine

1.5 Design and synthesis of silanediols as therapeutic peptidomimics

1.5.1 Silanediol stability and silanol acidity

In 1904, the first silanediol, diphenylsilandiol was reported by Dilthey and

Eduardoff. Kipping’s report of the same compound appeared in 1909. It is now known that silanediols can condense with themselves to form siloxanes, but more recent work has shown that this process is reversible, Figure 14.43

Figure 14. Polymerization of dimethylsilanediol

The steric environment around silicon plays an important role in the stability of

silanediols toward polymerization. Dimethylsilanediol (1.44) is inherently unstable

toward polymerization, but replacing the methyl on silicon with ethyl group, compound

1.45 gives a stable silandiol when pure.44 Diisobutylsilanediol (1.46) is also stable,45 and di-t-butylsilanediol (1.47) is even stable in presence of concentrated sulfuric acid.46

Table 3 shows the acidity of selected silanols, silanediols and carbinols. Silanols are slightly more acidic than corresponding carbinols. Aryl-substituted silanols are more acidic than aliphatic silanols as well. Silanols and silanediols have almost the same acidity.47

Table 3. pKa values for selected silanols, silandiols and carbinols47

Silanol/Carbinol pKa

Ph3C-OH (in DMSO) 16.97

Ph3Si-OH (in DMSO) 16.63

Ph3Si-OH (in water) 11.7

PhMe2Si-OH (in water) 12.0

12.4

11.6

1.5.2 Design, synthesis of silanediols as therapeutic peptidomimics pioneered by the Sieburth group

The design of C2 symmetry-based inhibitors that mimic the symmetry of the human immunodeficiency virus type-1 (HIV-1) was described Erickson et al.48 and

49-51 Kempf et al. Based on that strategy, Merck designed a new set of pseudo C2 symmetric inhibitors based upon L-685,434 (1.48, IC50 = 0.23 nM), named L-700,417

52 (1.49, IC50 = 0.67 nM). Silanediol 1.50 was found to have a Ki of 2.7 nM for inhibition of HIV-1, only slightly less effective than carbon analog 1.50, Figure 15.53

Ph Ph Ph OH OH H H H BocHN N N N

O O O Ph HO HO OH 1.49 1.48 IC50 =0.67nM C2 Chen and Sieburth

IC50 =0.23nM Ph Ph H HO OH H N Si N

O 1.50 O OH HO IC50 =2.7nM

Figure 15. Design of a C2 symmetric silanediol enzyme inhibitor

Silanediol protease inhibitor 1.52 was assembled as an analog of Almquist’s

ketone-based angiotensin-converting enzyme (ACE) inhibitor 1.51, Figure 16. Ketone

54 1.51 was found to have an IC50 of 1 nM, whereas silanediol 1.52 was found to have an

55 IC50 value of 3.8 nM.

Figure 16. Almquist’s ketone and Sieburth’s silanediol

Silanediol 1.54, an inhibitor of the metalloprotease thermolysin, was prepared by analogy to the phosphinic acid inhibitor 1.53, Figure 17. Inhibition of thermolysin by silanediol 1.54 (Ki = 41 nM) was comparable with that of phosphinic acid 1.53 (Ki = 10 nM). Both phosphinic acid and the silanediol hydroxyls were found by X-ray crystallography to coordinate the active site zinc. Therefore, both inhibiting the enzyme by mimicking the transition state without being hydrolysed.57

Figure 17. Phosphinic acid inhibitor and silanediol inhibitor mimic

The use of the phenylalanine isostere 1.55 by Imperiali and Abeles

underscored the importance of an aromatic substituent in chymotrypsin inhibitor design

(Figure 18).56 To evaluate a silanediol as an inhibitor of this enzyme, an Ala-[Si]-Phe dipeptide 57 was designed and synthesized. The silanediol 1.56 was found to inhibit the serine protease chymotrypsin with a Ki of 107 nM.9

Figure 18. Design of serine protease chymotrypsin silanediol

1.6 The original approach for silanediol protease inhibitor synthesis

In the original synthesis of the silanediol ACE inhibitors, the first step was the

“umpolung reagent” 2-phenyl-1,3-dithiane 1.58 which was added to

difluorodiphenylsilane. Subsequent alkylation with enantiomerically pure lithium reagent

1.60 gave dithiane 1.61. Dithiane hydrolysis with HgCl2 gave a ketone which was

reduced with LiAlH4 to give a mixture of alcohols 1.62. The α-amino silane component

of 1.56 was obtained by Mitsunobu reaction of alcohols 1.62 with phthalimide, followed

by removal of the phthalimide group with hydrazine. Schotten-Baumann conditions were

used to form the amide. Removal the benzyl ether with BBr3 gave alcohol 1.63. The two

diastereomers were separated by column chromatography on silica gel. The β-silyl acid

was obtained by oxidation of the alcohols with TPAP and NaClO2, followed by coupling

with t-butyl proline. Hydrolysis of diphenylsilane with triflic acid gave the silanediol as a

salt (1.64, Scheme 7). This route required 13 linear steps. One stereogenic center was

purchased and the other was formed without control.57

Ph2 Li OBn Ph2 S S 1. HgCl S 1. n-BuLi Si S Si OBn 2 S S F 1.60 2. Ph SiF 2 2 Ph Ph 2. LiAlH 1.58 Ph 1.59 1.61 4

H Ph2 Ph N Si OH 1. PhthNH, DEAD, Ph3P Ph2 2. N H O HO Si OBn 2 4 Ph (R,S)-1.63 3. PhCOCl Ph 1.62 4. BBr3 H Ph2 Ph N Si OH

O Ph (S,S)-1.63

Separated by column chromatography

HHO OH HHO OH Ph N Si N or Ph N Si N COONa COONa O O O O Ph Ph (R,S,S)-1.64 (S,S,S)-1.64

Scheme 7. Synthesis of silanediol ACE inhibitors

Using a different approach, Swapnil Singh prepared silanediol 1.69 from (3S)- fluorodiphenyl (3-methylbuten-4-yl) silane (1.1). Fluorosilane 1.1 was prepared in three steps from dichlorodiphenyl silane. The stereogenic center in compound 1.1 was set by 20

using Brown’s asymmetric hydroboration reagent. Fluoride 1.1 was then coupled with a

dithiane to give compound 1.2. The synthesis of the silanediol 1.69 was completed

following the same route in Scheme 7, except using CBS reduction, to give the product in

13 steps (Scheme 8).9 In this sequence, both stereogenic centers were controlled by asymmetric hydroboration.

Scheme 8. Asymmetric synthesis a silanediol inhibitor of serine protease chymotrypsin

Skrydstrup, et al. recently reported that reduction of hydridosilane 1.70 with excess lithium metal provided a silyllithium reagent that underwent a highly diastereoselective addition to optically active tert-butylsulfinimine 1.72, providing a method for preparing α-amino silane with stereocontrol (Scheme 9).58

Scheme 9. Asymmetric produce α-amino silane

Recently, Yingjian Bo of the Sieburth group discovered that lithium can directly reduce silafuran 1.74, which was derived from compound 1.73 by asymmetric hydrosilyllation in presence of the chiral rhodium catalyst (1.77). Reduction of silafuran

1.74 generates a silyl dianion that can be added to either Davis or Ellman sulfinimines

(1.75) to generate α-amino silanes 1.76 in high diastereomeric excess, Scheme 10.59

Scheme 10. New method to synthesize α-amino silane 59

1.7 29Si Nuclear magnetic resonance (NMR)

There are three isotopes of silicon 28Si (92.21%), 29Si (4.70%), and 30Si (3.09%).

Fortunately, 29Si has a spin of 1/2 and therefore a magnetic moment, Table 4. The 29Si isotope has a medium sensitivity in NMR.60

Table 4. Parameter of 13C and 29Si

Isotopes Natural Abundance (%) Nuclear Spin

13C 1.108 1/2

29Si 4.7 1/2

In 1962, Lauterbur et al. published the first report of 29Si NMR data.61 To date, there are

twenty five thousand compounds in the literature with 29Si NMR data. Table 5 shows some selected 29Si NMR chemical shifts. This is important information for characterizing silanes.62

Table 5. Selected 29Si NMR chemical shifts

Selected Silicon Compounds Chemical shift relative to trimethylsilane (ppm)

Trimethylsilane 0.0

Me3SiCl 30

Me3SiBr 26

Me3SiI 8.7

Me3SiF 31.0

Ph2SiCl2 6.2

Ph2Si(OH)2 -33.9

(-Me2Si-O-)3 (D3) -9.0

(-Me(Ph)Si-O-)3 -20.8

(-Ph2Si-O-)3 -33.8

(-Me2Si-O-)4 (D4) -20.0

Conclusions, introducing silicon atom(s) in a molecule leads to changes in the

pharmacological and medicinal properties of the molecule such as increasing

lipophilicity, partition ability, binding, and potency. Therefore, the exploration and

application of oganosilanes, especially silanediols, can lead to the discovery of useful

drugs, which is a main research priority of the Sieburth group.

CHAPTER 2:

CATALYTIC ASYMMETRIC INTRAMOLECULAR HYDROSILYLATION OF

SILYL ETHERS

2.1 Introduction

Structure 2.1 depicts the backbone of the silanediol dipeptide analogs. The

investigation of a broad range of silanediol protease inhibitors requires the insertion of

different alkyl substituents at the R1 and R2 positions of 2.1, Figure 19. Recently, the

Skrydstrup group has reported that the α-amino silane chiral center (R2) can be controlled

by adding a silyl anion to either Davis or Ellman sulfinimnes;59 however controlling the

β-silyl acid chiral center has remained a challenge.

Figure 19. Core structure of silanediol, silyl ether, and silafuran analogs

2.2 Asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers

2.2.1 Introduction

Hydrosilylation is the addition of a silicon hydride across an unsaturated bond,

such as an alkene, alkyne, a carbonyl, or an imine. In this chapter the focus will be

asymmetric intramolecular hydrosilylation (AIH) of allyl silyl ethers 2.2, the product of

which (2.3) can be used directly to make the β-silyl acids needed for the silanediol

peptide mimics (see Chapters 4 and 5).59

In 1990, Tamao and Ito reported the first asymmetric intramolecular

hydrosilylation of an allyl silyl ether 2.4, catalyzed by (-)-DIOP-[Rh(C2H4)Cl]2. The

product 2.6 was obtained in a syn:anti ratio of up to 99:1 following Tamao-Fleming oxidation of compound 2.5, Scheme 11.65

Scheme 11. The first asymmetric hydrosilylation, catalyzed by a chiral rhodium catalyst

In 1992, Bosnich et al. studied the asymmetric intramolecular hydrosilylation of

allyl silyl ethers using 1 mol% of Rh-BINAP and Rh-Chiraphos catalysts. Unfortunately,

only a 25% enantiomeric excess of 1.74 was obtained, Scheme 12.66 While other silyl

ethers with substituents larger than methyl gave high ee’s, the use of methyl was

important for the silanediol inhibitors.

Scheme 12. Chiraphos and BINAP in AIH

2.2.2 Improved AIH of allyl silyl ethers

A number of ligands for rhodium (Figure 20) were screened by Swapnil Singh for the catalytic AIH of 1.73 (Scheme 13), across multiple solvents (acetone, DCM, THF), and with a number additives (water, acid, salts).67

P PPh2 PPh2 PPh PPh2 Fe 2

PPh2 (S,S)-Chiraphos (S)-BINAP (R)-JosiPhos 2.8 2.9 2.10

NMe2 H3CH2C CH2CH3 Ph P PPh Fe 2 Fe PPh2 Ph P P P H3CH2C t-Bu CH2CH3 t-Bu NMe2 (S,S)-MandiPhos (S,S)-Ferrotane (S)-Binapine 2.11 2.12 2.13

Figure 20. Chiral ligands for AIH

Scheme 13. AIH of 1.73 and absolute stereochemistry determination

To evaluate enantioselectivity, the silafuran ring 1.74 (Scheme 13) was opened

with phenyl Grignard reagent to obtain 2.14. Alcohol 2.14 was then analyzed using an

enantio-differentiating HPLC.68 Determination of the absolute stereochemistry involved

MOM protection of alcohol 2.14 followed by Tamao-Fleming oxidation. Yingjian Bo

converted compound 2.14 to alcohol 2.15. Optical rotation of compound 2.15 (+12)

compared well with the known (S)-2.15 (-12).59,69 Therefore, compounds 1.74 and 2.14

have the (S) configuration. Ligand screening found that the ferrocene based ligands were very effective, with a maximum selectivity of 94% ee for 1.73 obtained using ferrotane

1.77 (Scheme 14), Table 6.

After the development of suitable conditions for the asymmetric intramolecular hydrosilylation of 1.73 with the catalyst 1.77, a range of substrates with different R substituents was studied (Scheme 14) to test the generality of this catalytic system. The results are listed in Table 6.

Scheme 14. Variety of substrates for AIH

Replacing methyl by ethyl (2.16c) and i-butyl (2.16d) increased the enantiomeric excess to 97%, Table 6. These examples might suggest that an increase in size at this position increases the stereoselectivity. This is consistent with Bosnich’s results.66

Nevertheless, with isopropyl and benzyl the selectivities were lower.

Table 6. AIH using 1 mol% of (S,S)-ferrotane (1.77)

Compound Substrate (R) % ee

1.73 Methyli 94

2.16a i-Propyli 56

2.16b Benzylii 45

2.16c Ethylii 97

2.16d i-Butylii 95

2.3 Results and discussion

With the AIH conditions optimized for alkyl substituents, attention turned to substituents that could be further functionalized to prepare other amino acid analogs. In this section, investigation into the AIH of oxygen-containing alkyl silyl ethers and their absolute configuration determination with Mosher esters is described.

2.3.1 Synthesis of oxygen-containing allylic alcohols

Figure 21. Retrosynthesis of allylic alcohol 2.19

i Studied by Swapnil Singh ii Studied by Cui Cao 28

Attention first turned to the synthesis of allylic alcohol 2.19. Two retrosynthesis

routes were devised (Figure 21). Route 1 used a Suzuki cross coupling reaction between

borane derivative 2.20 and vinyl iodide 2.21.70 Alternatively, the allylic alcohol could be

synthesized via Route 2, an alkylation of diethyl malonate (2.23) with iodide 2.22.

Route 1 was first attempted with pinacol 2.24 made from acetone in the classic method,71 which was then converted directly to pinacolborane 2.25.72 Allyl alcohol (2.26)

was protected with a MOM group using a catalytic amount of TsOH•H2O and LiBr. After

fractional distillation at 85 - 88 °C, compound 2.27 was isolated in quantitative yield.73a

This procedure is non-toxic, not moisture sensitive, and simple.73b,73c Alkene 2.27 was

treated with pinacolborane (2.25) to cleanly give alkyl borane 2.20, Scheme 15.74 Vinyl

iodide 2.21 was made in 92% yield from propargyl alcohol.75a,b Unfortunately, the

coupling step did not give the expected product. This result might be due to the poor

75c quality of the Pd(PPh3)4.

Scheme 15. The first attempt synthesis of allylic alcohol 2.19

Turning to the second route in Figure 21, synthesis of iodide 2.22 is well known,

route 2a, Scheme 16. This route is not economical, however, because an excess of

DIBAL-H is required in the second step. In practice, 1,3-propandiol (2.29) and trimethoxymethane (2.30) distilled as a mixture. Reduction of the mixture required more than 10 equivalents of DIBAL-H.76a Conversion of alcohol 2.32 to iodide 2.22 was also problematic because purification was complicated by the presence of imidazole, triphenyl phosphine and triphenylphosphine oxide.76b The synthesis of iodide 2.22 using this

method was abandoned.

(MeO) CH 3 DIBAL-H 2.30 O OMe 10 equiv. I2,PPh3/Imid Route # 2a: MOMO MOMO I OH OH O CSA H2O 2.29 2.31 2.32 OH 2.22

48% HBr NaI HO OH HO Br Acetone Route # 2b: 2.29 85% quantitative 2.33

MOMCl*, Et3N HO I DCM MOMO I

2.34 89% 2.22

H SO 2 4 MeOCH Cl + PhCOOMe * PhCOCl + (MeO)2CH2 2 reflux 18 h 2.35

Scheme 16. Synthesis of iodide 2.22

While route 2b, Scheme 16, is a longer pathway, it gave high yields in all steps. In this sequence, 1,3-propandiol 2.29 was treated with 48% hydrobromic acid in toluene to give 3-bromo-1-propanol 2.33 in 76-85% yield. The 1,3-dibromo propane byproduct was formed in less than 5% yield and was easily washed out with pentane. Finkelstein exchange reaction easily converted bromide 2.33 to iodide 2.34 in 83% yield.77

Protection of alcohol 2.34 as a MOM ether was readily accomplished using either

78,79 (MeO)2CH2 or MeOCH2Cl This process was scaled up to 30 g of compound 2.22.

Continuing with the route 2, Figure 21, iodide 2.22 was added to the anion of diethyl

malonate to give malonate 2.36, Scheme 17. One equivalent of KOH (or NaOH) gave the

half acid ester. Without purification, this was treated with paraformaldehyde to give α,β-

unsaturated ester 2.37.80a Reduction of the ester gave 2.19, which was isolated by

Kugelrohr distillation (120 °C, 0.3 mm Hg) in 85% yield. It is notable that while this is a

long sequence, all of the steps can be scaled to 10 g and used without purification.80b

Scheme 17. Successful route to allylic alcohol 2.19

Following the synthesis of compound 2.19, Scheme 17, alcohol 2.43 was synthesized in a straightforward fashion as shown in Scheme 18. Acrolein 2.38 was selected as a starting material and reacted with ethylene glycol and TMSCl, to give compound 2.39.81a Finkelstein conversion of chloride 2.39 to iodide 2.40 was performed

in quantitative yield. Alkylation of malonate with iodide 2.40, saponification,

decarboxylation, formylation, elimination, and reduction, as described for compound 2.19

(Scheme 17), gave the final product 2.43, Scheme 18.81b

Scheme 18. Synthesis of allylic alcohol 2.43

With the two allylic alcohols in hand, the silicon moiety could be attached.

Chlorodiphenylsilane (2.45, $205/50g) and diphenylsilane (2.44, $160/100g) are commercially available, but quite expensive. In contrast, dichlorodiphenylsilane (1.65) is inexpensive ($90/2kg, Gelest). Chlorodiphenylsilane (2.45) was made for ∼$110.00/200g including solvent. Dichlorodiphenylsilane 1.65 was slowly added to a solution of lithium aluminium hydride (LAH) at 0 °C over a period of 1 h, Scheme 19. The solution was refluxed 2 hours, followed by careful work up using the Fieser & Fieser method.82 After removal of ether, the mixture was diluted with pentane and held at room temperature to precipitate impurities. Filtration through a pad of Celite gave a clear solution that was concentrated in vacuo, distilled at 70 °C (0.3 mm Hg) gave diphenylsilane 2.44. CuCl2, a brown solid, was added to the diphenylsilane 2.44 to give chlorodiphenylsilane 2.45. The reaction was complete when the brown color turned to white. The product 2.45 was distilled by Kugelrohr distillation (120 °C, 0.3 mm Hg).82

Ph Ph LiAlH4 Ph Ph Ph Ph CuCl2/CuI (cat.) Si Si Si Cl Cl H H H Cl Et2O, 4d Et2O, reflux 1.65 2h, 95% 2.44 78% 2.45

Ph Ph Et N, 2.19 Ph Ph Si 3 Si H Cl 12h, 82% H O OMOM MOMO OH 2.45 2.46 2.19

Ph Ph Ph Ph Et3N, 2.43 Si Si HO O H O O H Cl 12h, 82% O 2.45 2.47 O 2.43

Scheme 19. Synthesis of allyl silyl ethers

The two allyl silyl ethers 2.46 and 2.47 were prepared in 82% yield from freshly made chlorodiphenylsilane 2.45, Scheme 20.59

Ph Ph Ph Ph Si Si 1.77 (1mol%) O CH CH H O OMOM H3CH2C 2 3 Et N.HCl, 3 P DCM, rt. OMOM 2.46 92%, 83% ee 2.48 Rh Fe BF4 Ph Ph Ph Ph P Si Si H CH C O 1.77 (1mol%) 3 2 CH CH H O O O 2 3 O O Et3N.HCl, 1.77 DCM, rt. 2.47 92%, 58% ee 2.49

Scheme 20. Asymmetric intramolecular hydrosilylation

AIH of silyl ethers 2.46 and 2.47 followed the Swapnil Singh protocol, using catalytic

ferrotane 1.77 (1 mol %) to give silafurans 2.48 and 2.49 in good yield, Scheme 20.

Racemates of 2.48 and 2.49 were produced using Wilkinson’s catalyst (1 mol%), Scheme

21.59,67b

Ph Ph Ph Ph Si Wilkinson cat. Si H O OMOM 1mol % O 2.46 DCM OMOM ( )-2.48

Ph Ph Rh Ph Ph Ph Cl Ph Ph Wilkinson cat. Si Si 1mol % O O Wilkinson catalyst H O O O DCM O 2.47 ( )-2.49

Scheme 21. Synthesis of racemate of silafurans

Instead of opening the silafurans with a Grignard reagent at reflux for 5 h, as described by Bosnich et al.,66 the alcohols 2.50 and 2.51 were formed by treatment of

2.48 and 2.49 with the phenylmagnesium bromide for 1 h at rt. The enantiomeric excess

of alcohols 2.50 and 2.51 was determined with enantio-differentiating HPLC. It was found that silafurans 2.48 and 2.49 were formed in 83%, and 58% ee. These substituents seem to have had a detrimental effect on the stereoselectivity of the hyrosilylation.

Ph Ph Ph Ph Si Si Ph O PhMgBr OMOM OMOM Et2O, rt HO 2.48, 83% ee 88% 2.50

Ph Ph Ph Ph Si Si O PhMgBr Ph O O Et2O, rt HO 88% 2.49, 58% ee O 2.51 O

Scheme 22. Silafuran opening with Grignard reagent

2.3.2 Determination of absolute configuration

Previously, Yingjian Bo determined the absolute configuration of methyl- substituted silafuran 1.74 (see p. 26, Scheme 13). While one might assume that the additional examples will have the same stereochemistry, verifying the absolute configuration with other substituents was important for application of this chemistry to enzyme inhibitors. Absolute configuration determination by correlation of compound

2.50 (see structure in Scheme 22) with known structures was impossible.

In 1977, Yamaguchi et al. reported the use of 1H NMR to determine the absolute configuration of compound 2.52 (26% de) with Eu(fod)3 (2.53), Figure 22. The methoxy

83 signals were recorded using 0.25 M and 0.68 M of Eu(fod)3.

1 Figure 22. Absolute configuration determination with H NMR and Eu(fod)3

In the absence of Eu(fod)3, the chemical shift of the methoxy group was the same for both diastereomers (Figure 22A). Addition of Eu(fod)3 (0.25M), Figure 22B, caused a separation of the methoxy signals, with the (R,R)-diastereomer moving further than the

(R,S) diastereomer. Increasing the concentration of Eu(fod)3 to 0.68 M, Figure 22C, led to an even larger chemical shift difference. The difference in chemical shift has been

attributed to the greater stability of the complex between the (R,R)-diastereomer with the

Eu3+compared to that with the (R,S)-diastereomer.84

In a series of studies on the stereochemistry of marine natural products,85

Kobayashi et al. used the diastereotopic protons of the methylene group of Mosher esters to determine the stereochemistry of the adjacent position. Diastereomers with an (S,S) or

(R,R) configuration had a chemical shift difference of about 0.2 ppm. In contrast, the

(S,R) or (R,S) diastereomers have very similar chemical shift values.

A B

O O S R CF3 S S CF O O 3 OMe Ph MeO Ph (S,R)-2.54 (S,S)-2.54

C D

OH O 13 R

O O O R RO R S CF RO R CF3 O O 3 O 13 13 21 MeO Ph Ph OMe O (R,S)-2.55 Amphidinolide T1 (2.56) 21 (R,R)-2.55

Figure 23. Using 1H NMR for chiral determination of natural product

For example, 1H NMR of spectra (S,R)-2.54 and (S,S)-2.54, produced from a known alcohol with (R) and (S)-Mosher acids, are shown in Figure 23A, B. The diastereotopic protons of the (R,S) diastereomer 2.54 have no difference in chemical shift

(Figure 23A). In contrast the diastereotopic protons of the (S,S)-diastereomer have a 0.2

ppm difference in chemical shift (Figure 23B).85 Compound 2.55, a fragment of natural

product Amphidinolide T1 (2.56), was studied using the same protocol as above to

confirm the (R) absolute configuration at C13, Figure 23C, D.

To investigate the use of Mosher esters with our silanes, esters 2.58, 2.59 and 2.60

were prepared by reaction of (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride

(2.57) with alcohols 2.14 (50.5% ee), 2.50 (83% ee) and the racemate of (±)-2.50,

Scheme 23. The absolute configurations of compound 2.58 were known, Scheme 13, p.

26.86

Scheme 23. Synthesis of Mosher esters

First of all, it was important to establish that the results of Kobayashi et al. were

relevant to our silanes 2.59 and 2.60. The 1H NMR spectrum of known compound 2.58 shows that the diastereotopic protons (identified with an arrow, Figure 24) of (S,R)-2.58

have a 0.055 ppm difference in chemical shift. On the other hand, the diastereotopic

protons of diastereomer (R,R)-2.58 have a 0.149 ppm difference in chemical shift, Figure

24. The “Kobayashi rule” can therefore be used to determine absolute configurations of silanes related to compound 2.58.

4.201 4.189 4.180 4.168 4.149 4.136 4.128 4.115 4.094 4.082 4.072 4.061 4.051 4.039 4.030 4.017

(S,R)-2.58 6.42 Ph Ph Ph Si O Ph OMe CF O 3 2.58

(R,R)-2.58 (R,R)-2.58 1.01 1.11

4.4 4.3 4.2 4.1 4.0 3.9 PPM

1 Figure 24. Diastereotopic protons on H NMR of compound 2.58 in CDCl3

Compound 2.59 and the mixture of diastereomers 2.60 were then analyzed by 1H

NMR. The methylene protons, identified by an arrow, are shown in Figure 25. These protons have nearly the same chemical shift (Δσ ∼ 0.0 ppm), Figure 25A. On the other hand, spectrum B shows that one set of diastereotopic protons has very different chemical shifts (Δσ = 0.173 ppm). It was therefore concluded that compound 2.59 has the (S) configuration based on its similarity to compound 2.58.

O O Ph Ph Si O Ph Ph OMe S 2.59 R O CF3

4.3 4.2 4.1 4.0 3.9 3.8 PPM 4.125 4.112 4.098 4.085 4.010 4.004 3.997 3.991 3.953 3.941 3.926 3.913

O O Ph Ph Si O Ph Ph OMe S,R R 2.60 O CF3

4.3 4.2 4.1 4.0 3.9 3.8 PPM

1 Figure 25. H NMR of Mosher esters in CDCl3

To further establish this result, Eu(fod)3 (2.53) was added to both compounds 2.59 and mixture 2.60 until the methoxy signals for both diastereomers (labeled a, Figure 26) were distinguishable in CDCl3 at rt. Spectrum A, Figure 26, clearly shows a pair of

methoxy signals at 3.42 ppm for the two diastereomers 2.60 without added Eu(fod)3.

4.399 4.394 3.422 3.420 3.413 3.410 3.174 3.139 3.129

5.5 5.0 4.5 4.0 3.5 3.0 2.5 PPM

1 Figure 26. H NMR of Mosher esters in Eu(fod)3 in CDCl3 at rt

Following addition of Eu(fod)3 (0.0327 M) to the solution of 2.60 (0.030 M), two

peaks of the same height with a ratio of 1:1 were shifted downfield, Figure 26B. In spectrum C of compound 2.59 (0.030 M), one major peak can be seen with a small right hand shoulder in Eu(fod)3 (0.032 M), Figure 26C. When the two samples were mixed,

spectrum D (Figure 26), a definite increase in height can be seen for the peak of each

diastereomer. Presumably, differences in stability of the complexes 2.63 and 2.64 are the

source of these observations, Figure 26.

Figure 27. A: [Eu(acac)3(phen)]; B: [Eu(tta)3(H2O)2] and C: complexes of Mosher esters

with Eu(fod)3

3+ 6 0 Eu has an electron configuration of [Xe] 4f 6s . Eu(fod)3 is a Lewis acid, being

capable of expanding its coordination number of six to eight.83 The complex displays a

particular affinity for "hard" Lewis bases, such as the oxygen atom in ethers and the

nitrogen of amines. For example, molecular structures of [Eu(acac)3(phen)] (Figure 27A),

[Eu(tta)3(H2O)2] (Figure 27B), confirmed by X-ray diffraction, have eight coordinations.

Thus, diastereomeric esters (R)-2.59 and (S)-2.59 coordinate with Eu(fod)3 via the

carbonyl and methoxy (a) groups resulting complexes 2.63 and 2.64 Figure 27C.83

If the complexation constant KR (equation 1, Figure 27C) for the formation of

complex 2.63 from (R)-2.59 is smaller than the constant KS (equation 2, Figure 27C) for

the formation of 2.64 from (S)-2.59, then the steady state concentration of 2.64 should

exceed that of 2.63 so that a larger chemical shift should be induced in 2.64 than 2.63, as

is observed. It is proposed that this happens because of the lower steric interaction of the

Eu(fod)3 with the hydrogen atom on the chiral center in 2.64 than with methoxymethoxypropanyl group in 2.63.

In conclusion, asymmetric intramolecular hydrosilylation of silyl ethers containing ether functional groups gave up to 83% ee. The absolute configuration was determined to be (S) using 1H NMR analysis of the Mosher's ester. These results provide

a simple method can be used for absolute configuration determination of silane alcohols.

CHAPTER 3:

A SHORT, ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS OF

ANGIOTENSIN-CONVERTING ENZYME (ACE)

3.1 Introduction

Silanediol diastereomers 1.52 are well known as inhibitors of angiotensin-

converting enzyme (ACE), Figure 28. The first synthesis of these four diastereomers was accomplished in 2005.55 In this synthesis, the β-silyl acid chiral center was purchased and the α-amino silane chiral center was formed without control (see Scheme 7, p. 20). In this chapter, a short, asymmetric synthesis of silanediol (R,S,S)-1.52 is described, with full control of stereochemistry, along with synthesis of its diastereomers.

HHO OH HHO OH Ph N Si N Ph N Si N COOH COOH O O O O Ph Ph (R, S, S)-1.52, IC50 = 3.8 nM (R, R, S)-1.52, IC50 = 207 nM

HO OH HHO OH H Ph N Si N Ph N Si N COOH COOH O O O O Ph Ph (S, S, S)-1.52, IC50 = 19 nM (S, R, S)-1.52, IC50 = 72 nM

Figure 28. Silanediol inhibitors for ACE

3.2 Four silanediol ACE inhibitors

3.2.1 Retrosynthesis of silanediols via silafuran 1.74

Silanediol 1.64 (the salt form of silanediol 1.52) and its diastereomers were first

prepared by Dr. Jaeseung Kim while a member of the Sieburth group.57 A new retrosynthesis of this compound is shown in Figure 29. Disconnection of the two amide bonds gives amine 3.1. This α-amino silane would be created by a Mitsunobu displacement of an alcohol set by an asymmetric Corey-Bakshi-Shibata reduction.9 The

stereocenter of the β-silyl acid in 1.64 derived from silafuran 1.74, obtained by

asymmetric intramolecular hydrosilylation (AIH) of silyl ether 1.73 via fluoro silane 3.5,

Figure 29.

Figure 29. Retrosynthesis of silanediol 1.64

3.2.2 Synthesis of fluorodiphenyl silane 3.6

Silyl ether 1.73 was prepared from methyl allyl alcohol and chlorodiphenylsilane in 78% yield, Scheme 24, a reaction that could be scaled up to a 20 g of chlorodiphenylsilane (2.45, see Chapter 2, Scheme 19, p. 33). Intramolecular hydrosilylation of the ether 1.73 was accomplished with Wilkinson’s catalyst to give

44 racemic silafuran (±)-1.74. Progress of the intramolecular hydrosilylation was monitored by 1H NMR.67b Silafuran (±)-1.74 was opened with 47% aqueous HF to give fluorosilane

3.6 in quantitative yield, and used without further purification.59

Scheme 24. Synthesis of fluorosilane 3.6

Silafuran (±)-1.74 was treated with 2-lithio-1,3-dithiane and lithium aluminium hydride, but both reagents gave a complex mixture and did not give the expected alcohols (±)-3.7 or (±)-3.8 However, phenyl Grignard reagent gave triphenylsilyl alcohol

(±)-2.14 in good yield, Scheme 25.66

Scheme 25. General reactions of the silafuran 1.74

3.2.3 Protection of fluorodiphenyl silyl alcohol 3.6

In an attempt to protect the alcohol, fluorosilane (±)-3.6 was treated with

imidazole and TBSCl.91 Unfortunately this resulted only in intramolecular cyclization

and return to silafuran (±)-1.74. In contrast, triphenyl silyl alcohol (±)-2.14 was readily

protected with TBSCl in good yield under identical conditions, Scheme 26. It was suggested that neutral or acidic environments would be better conditions for protecting the alcohol of fluorosilane (±)-3.6.

Ph2 Ph 2 TBSCl, Imid. Si Ph2 Si OH O Si OTBS F F )-3.6 )-1.74 )-3.9

Ph2 TBSCl, Imid. Ph2 Si OH Si OTBS Ph Ph DMF, rt )-2.14 5h, 84% )-3.10

Scheme 26. Protecting Fluorosilane

In 2006, Dudley et al. reported compound 3.11 (Dudley’s reagent) as a mild

method for O-benzylation of alcohols under neutral conditions. Unfortunately, when

fluorosilane (±)-3.6 was reacted with Dudley’s reagent, compound (±)-3.12 was obtained in only 20% isolated yield, Scheme 27.92

KOH, BnOH 18-c-6, PhMe MeOTf N OBn Reflux N OBn N Cl TfO 3.11

N O Ph Ph TfO 2 3.11 Ph2 Si OH Si OBn F F )-3.6 Ph-CF3 )-3.12 refluxed 20%

Scheme 27. Protecting flurosilane in neutral condition

Khan et al. found that cupric sulfatepentahydrate was a suitable Lewis acid for the protection of primary alcohols with tetrahydropyrane group (THP).93 Using these conditions, the fluorosilyl alcohol (±)-3.6 was protected as the THP ether in 88% yield,

Scheme 28.

Scheme 28. A simple and successful protection of fluorosilane 3.6

3.2.4 Synthesis of dithiane 3.4

Lithiodithiane, generated from dithiane with n-BuLi at -78 °C, reacted with fluorosilane 3.5 to give dithiane 3.13 in 67% yield. Dithiane 3.13 was then treated with n-

BuLi followed by benzyl bromide to form compound 3.4 in 72% yield, Scheme 29.57

Scheme 29. Synthesis of dithiane derivative 3.4

3.2.5 Synthesis of ketones 3.3 and 3.15

Many conditions were screened in order to optimize the deprotection of dithiane

3.4 to give ketone 3.3, Scheme 30. Use of mercury chloride did not give any of the expected product, but did decompose all of the starting material.57,94 Methyl iodide did

not react with any starting material when refluxing in THF overnight.95 Use of

(CF3CO2)2IPh and BAIB (bis-acetoxyiodo benzene) each gave the product in 10%

96 yield. Iodine in sat. NaHCO3 was the best reagent for this reaction, but the yield was

only 30%, Table 7.97

Ph 2 Ph2 S Si Conditions O Si S OTHP OTHP Ph Ph 3.4 3.3

Scheme 30. Optimized conditions for dedithianation

Table 7. Optimization of deprotecting dithiane

Reagent Solvent Temp./time % yield Observations

HgCl2, 5 eq. CH3CN/H2O rt 0 Decomposed (2/1)

HgCl2/CaCO3 CH3CN/H2O rt 0 decomposed (2/1)

MeI THF/water Reflux 0 No change

CH3CN/H2O 1. rt/2min. 10% Red, pink 0 (CF3CO2)2IPh (9/1) 2. 0 C/2min

BAIB CH3CN/H2O rt/2min 10% Red then pink (9/1)

0 I2/NaHCO3 CH3CN/H2O 0 C/20min 30% Dark yellow

It seemed that the THP group was not stable to the dithiane hydrolysis conditions tested, so the THP group was switched to the TBS group. Compound 3.4 was deprotected

93 with CuSO4•5H2O in methanol, reprotected with TBS in the classic method of imidazole and TBSCl, to give compound 3.14 in 68% yield. Using the best condition described in the Table 7, I2/NaHCO3, the dithiane was removed. Unfortunately, in this case ketone 3.15 was obtained in low yield (21%) and the rest of the stating material decomposed, Scheme 31.

Ph Ph 2 1. CuSO4 5H2O 2 Ph2 S Si MeOH S Si I2/NaHCO3 O Si S S OTHP OTBS 21% OTBS Ph 2. TBSCl, Imid. Ph 67%, 2 steps Ph 3.4 3.14 3.15

Scheme 31. Changing protecting groups from THP to a TBS group

3.3 New route for the synthesis of ACE silanediols

The chemistry described above did not supply enough ketone 3.3 and 3.15 to

continue, but it does illustrate the difficulties of the original route to the silanediol ACE

inhibitors. In 2007, Skrydstrup et al. reported fantastic results of adding silyllithium reagents to sulfinimines, giving α-amino silanes with control of stereochemistry in high yield and high de.98 The next generation synthesis of silanediol 1.64 was based on

Skrydstrup’s chemistry, coupled with asymmetric intramolecular hydrosilylation of silyl ether 1.73, Figure 30.

Figure 30. New route of silanediol synthesis

The synthesis of both (R,S) and (S,S) diastereomers of 3.16 was carried out first,

Scheme 32. Intramolecular hydrosilylation of silyl ether 1.73 using Wilkinson’s catalyst gave silafuran (±)-1.74. Silafuran (±)-1.74 was opened with HF at 0 °C. As mentioned above, fluorosilyl alcohol 3.6 was quite unstable on silica gel, so the crude product was protected with a MOM group using dimethoxymethane.73 Without purification of the

protected alcohol, LiAlH4 was added to convert the fluorosilane to silane (±)-3.19,

isolated in 53% yield over three steps. Using the Skrydstrup procedure, silane (±)-3.19

was combined with 20 equiv of lithium to affect lithiation. The solution turned to a dark

black color after 10 minutes at 0 °C (Note: color change does not indicate that the

reaction is complete).

1. HF Ph 2 Ph 2. (MeO)2CH2 Ph Si 2 TsOH H O, LiBr 2 H O ClRh(PPh3)3 Si 2 Si OMOM O H DCM, rt 3. LAH (±)-3.19 quantitative 53% for 3 steps )-1.74 1.73

H Ph Ph 1. Li N Si OMOM S 2. O N S Ph Ph O 3.16 (R)-3.17 45-53%

Scheme 32. Synthesis of sulfinamide 3.16

The progress of the reaction was checked every 30 minutes by quenching a 0.1 mL aliquot of the reaction solution with TMSCl, concentrating, and taking the 1H NMR

in CDCl3. After 4.5 h, the Si-H triplet (δ 4.96 ppm) disappeared, indicating that formation

of lithium reagent 3.18 was complete, Figure 33 and Scheme 33. The silyllithium (±)-

3.18 reacted with Ellman sulfinimine 3.17 at -78 °C to give sulfinamide 3.16 as a mixture of two diastereomers in 43% yield, Scheme 32. 51

Scheme 33. Monitoring the progress of lithiation

4.961

8 7 6 5 4 3 2 PPM

7 6 5 4 3 2 1 PPM

Ph2 Si OMOM Si (±)-3.20

7 6 5 4 3 2 1 0 PPM

Figure 31. Monitoring lithiation progress with 1H NMR

The high diastereoselectivity of silyllithium addition to sulfinimine (R)-3.16 can

be explained by transition state 3.21 (Figure 32). The bulky silyllithium attacks from the less hindered side of the sulfinimine (R)-3.16.98,99

Figure 32. Transition state for addition to sulfinimine (R)-3.17

The Ellman auxiliary and MOM group of (R,S) and (S,S)-3.16 could be removed with 4

M HCl in dioxane to yield a crude amine salt.98 Schotten-Baumann benzoylation of the

amino alcohol gave the desired amide 1.63 in moderate yield, which were separated via

column chromatography, Scheme 34.57,59,99g

Scheme 34. Deprotection and Schotten-Baumann benzoylation

Compound (±)-3.19 was synthesized using a six-step sequence from diphenylsilane (2.44) (see route # 1, Scheme 35). However, this required large volume(s) of solvent and involved a rather difficult work-up procedure. Alternatively, compound

(±)-3.19 was prepared using a 2-step pathway, Scheme 35 (route # 2), from the same diphenylsilane starting material (2.44). To effect this process, diphenylsilane 2.44 was treated with β-methylpropenol under radical reaction conditions to give an 80% yield of alcohol (±)-3.8.100 Without further purification, the alcohol (±)-3.8 was protected with a

MOM group using the method of Gras et al. to give (±)-3.19 in only two steps in 73%

yield, Scheme 35.73

Ph Ph Ph Ph LiAlH4 CuCl2/CuI (cat.) Si Route#1: Si H H Cl Cl Et2O, 4 d Et2O, reflux 1.65 2h, 95% 2.44 78%

Ph 2 ClRh(PPh ) OH Si 3 3 Ph2 H O Si H Cl Et N, Et O DCM, rt 2.45 3 2 12h, 78% quantitative 1.73

1. HF 2. (MeO) CH Ph2 2 2 Ph2 Si TsOH H2O, LiBr Si OMOM O H 3. LAH (±)-3.19 53% for 3 steps )-1.74

Ph2 OH (MeO) CH Ph2 2 2 Ph Si TsOH H O, LiBr 2 Route # 2: H H Si OH 2 Si OMOM AIBN, H H 2.44 ( )-3.8 SH 73% 2 steps (±)-3.19

C9H19 heptane, reflux 80%

Scheme 35. Alternative synthesis of compound (±)-3.19

3.3.1 Oxidation of the primary alcohols to acids

Skrydstrup’s group tried to oxidize primary alcohol 3.22 to carboxylic acid 3.23 in one step. TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) and NaClO2 were reported by unable to convert the alcohol 3.22 to the expected acid 3.23, Scheme 36.101

Scheme 36. Skrydstrup’s oxidation attempted with TEMPO

To oxidize alcohols 1.63, attention was turned to other literature describing

catalytic use of TEMPO. Piancatelli et al. 102 and Widlanski et al.103 were able to use

TEMPO with BAIB (bis(acetoxy)iodobenzene) to oxidize primary alcohols to aldehydes or carboxylic acids depending on the number of equivalents of BAIB used.

To alcohol 1.63, TEMPO (0.2 equiv.) and BAIB (2.5 equiv.) were successfully

used to oxidize alcohol 1.63 to give acid 3.25 in 72% yield. This reagent also worked for

iii naphthalene derivative 3.26 where use of catalytic RuCl3 resulted in less than 10%

yield, Scheme 37.

Scheme 37. TEMPO and BAIB oxidization

The coupling reaction of proline 3.28 and acids 3.25 followed the protocol of Kim et al. using diethyl cyanophosphonate, Scheme 38.55 It is worth noting that the retention

factors (Rf) of alcohols (R,S)-1.63 (Rf = 0.25) and (R,R)-1.63 (Rf = 0.19), Scheme 34, are

different by only 0.06, a difficult separation via column chromatography. In contrast,

when the proline was added to give 3.29, the retention factors of (R,S,S)-3.29 (Rf = 0.62) and (R,R,S)-3.29 (Rf = 0.32) were different by 0.3, allowing for an easy separation.

iii Buddha Khatri, Temple University 55

H N Ph Ph 2 Ph H Cl H Ph Ph N Si OH 3.28 COO-t-Bu Ph N Si N O O (EtO) POCN O O COO-t-Bu Ph 2 Ph Et3N, DMF, 80% (R,S)-3.25 (R,S,S)-3.29

H2N Ph Ph H Ph Ph Cl H Ph N Si OH 3.28 COO-t-Bu Ph N Si N

O O O O COO-t-Bu Ph (EtO)2POCN Ph Et N, DMF, 80% (R,R)-3.25 3 (R,R,S)-3.29

Scheme 38. Synthesis of proline derivatives 3.29

Although proline derivatives 3.29 are known, absolute configurations for each isomer could not be determined by NMR spectroscopy. Therefore, optical rotations were

20 55 recorded, a diastereomer had optical rotation -62.8 ([α]D = -61.8 (c 0.22, CHCl3)) which was determined (R,S,S)-3.29. Hence, another diastereomer must be (R,R,S)-3.29.

3.3.2 Synthesis of (S,R,S) and (S,S,S)-3.29

Following the procedure used for (R,S,S)-3.29 and (R,R,S)-3.29, proline derivatives (S,S,S)-3.29 and (S,R,S)-3.29 were also prepared, Scheme 39.

Compound (±)-3.19 was treated with lithium at 0 °C in THF to generate the silyllithium reagent, which was added to sulfinimine (S)-3.17 yielding an inseparable mixture of sulfinamides (S,S,R)-3.16 and (S,S,S)-31.6. Diastereoselectivity again favored the attack on sulfinimine (S)-3.17 shown in Figure 33.98

The sulfinamides (S,S,R)-3.16 and (S,S,S)-3.16 mixture were treated with 1.25 M

HCl in methanol, followed by Schotten-Baumann benzoylation to give a mixture of diastereomeric alcohols (S,R) and (S,S)-1.63. The acids (S,R) and (S,S)-3.25 were obtained by oxidation with BAIB and TEMPO reagents and then coupled with proline

3.28 using diethyl cyanophosphonate to give the separable mixture of (S,R,S) and (S,S,S)-

3.29, Scheme 39.

Ph Ph Ph2 1. Li (THF, 0 C) H 1. HCl Si OMOM N Si OMOM H S 2. 2. PhCOCl ( )-3.19 O N Ph (S,S,R)-3.16 NaHCO3 S Ph 78% O (S)-3.17 (S,S,S)-3.16 THF, -78 C- rt. 45-50%

ClH2N Ph Ph Ph Ph H H Tempo Ph N Si OH 3.28 COO-t-Bu Ph N Si OH BAIB 72% O O (EtO) POCN O Ph 2 Ph Et3N, DMF (S,R)-1.63 (S,R)-3.25 (S,S)-1.63 (S,S)-3.25

H Ph Ph Ph N Si N X-ray

O O COO-t-Bu Ph (S,S,S)-3.29, 40%

Rf = 0.57 (hexane / ethyl acetate 2:1)

H Ph Ph Ph N Si N

O O COO-t-Bu Ph

(S,R,S)-3.29, 38%

Rf = 0.36 (hexane / ethyl acetate 2:1)

Scheme 39. Synthesis of (S,R,S) and (S,S,S)-3.29iv

Figure 33. Stereoselectivity of nucleophilic addition to (S)-sulfinimine iv X-ray was studied by Dr. Shivaiah Vaddypally and Clifton Hamilton. 57

20 Stereochemistry of (S,S,S)-3.29 was confirmed by optical rotation (found [α]D = 18.9 (c

20 55 v 0.49, CHCl3), literature [α]D = 19.3 (c 0.27, CHCl3)) and X-ray (see Appendix, p.

313).

3.3.3 Synthesis of difluorosilanes55

Dearylation of compounds 3.29 was accomplished with 60 equivalents of triflic

acid (TfOH, 0.56 M), followed by addition of NH4OH and HF to produce diflurosilanes

3.31, as stable crystalline products, easily stored and easily hydrolyzed to the silanediols,

Scheme 40.

Scheme 40. Synthesis of difluorosilanes 3.31

A hydrolysis mechanism for diphenylsilanes 3.31 is shown in Figure 34. Due to silicon’s ability to stabilize β-cations, the ipso-positions of phenyl rings are easily protonated. Electron rich oxygen atoms of amide groups attack silicon (3.33) to eliminate both benzene rings to presumably give an intermediate 3.34. Addition of NH4OH

v Studied by Dr. Shivaiah Vaddypally in Dr. Zdilla Group 58

hydrolyzed these strained silafurans in 3.34, and the acidic HF condition converts the products to the difluorosilane 3.31, Figure 34.55

Figure 34. Hydrolysis of diphenylsilane to diflurosilane

3.3.4 Hydrolysis of difluorosilanes 3.31 to silanediols 1.6455

Diflurosilanes 3.31 were suspended in D2O at 5 °C, and 3.0 equiv of NaOH (0.2

19 M) in D2O was added. Progress of the reaction was monitored by F NMR showing a

peak at -122 ppm corresponding to NaF, Scheme 41.

Scheme 41. Synthesis of silanediols 1.64

3.3.5 Asymmetric synthesis of alcohol (R,S)-1.63

To synthesize only compound (R,S)-1.63, asymmetric intramolecular hydrosilylation using catalytic ferrotane-rhodium 1.77 gave silafuran (S)-1.74 from silyl ether 1.73 with 82% ee.59 The silafuran (S)-1.74 was opened by HF, the alcohol protected with a MOM group and the fluoride reduced to the hydride with LiAlH4 to give (S)-3.19.

Compound (S)-3.19 was treated with 20 equivalents of lithium resulting in a black solution of the silyllithium reagent. This was added to (R)-3.17 yielding sulfinamide 3.16

(dr = 95:5).59 Both MOM and Ellman auxiliary of the sulfinamide 3.16 were removed with HCl in methanol followed by Schotten-Baumann benzoylation to give a single diastereomer of (R,S)-1.63 in 15% over all, Scheme 42.

Scheme 42. Asymmetric synthesis of (R,S)-1.63

In summary, a short, asymmetric synthesis of silanediol (R,S,S)-1.64 along with

the synthesis of three of its diastereomers were synthesized via an asymmetric

intramolecular hydrosilylation followed addition of the derived silyllithium reagent to an

Ellman sulfinimine. The synthesis is 8 linear steps from silyl ether 1.73 in 8% over all

yield. Difluorosilane diastereomers 3.31 have been sent to Prof. Annaliese K. Franz’s

group (University of California Davis) to test for their use as catalysis. We await those results.

CHAPTER 4:

ASYMMETRIC SYNTHESIS OF SILANEDIOL INHIBITORS FOR FXIa

4.1 INTRODUCTION

4.1.1 Hemostasis

Hemostasis is a process that causes bleeding to stop, keeping blood within a damaged blood vessel. Hemostasis plays two roles: to facilitate blood flow through blood vessels, and to prevent blood loss following blood vessel damage. Most of the time the process includes blood changing from a liquid to a solid state. In the human circulatory system, the transportation of respiratory gases and nutrients to all organs and tissues is accomplished within the bloodstream. Blood is composed of plasma and several types of cells including erythrocytes that provide for respiratory gas exchange (red blood cells), leukocytes that defend the organism against infection utilizing the immune system (white blood cells), and platelets, which provide for hemostasis and at the same time maintain the blood in a fluid state within the vascular system. The mechanism of hemostasis is highly regulated.104,105

4.1.2 Blood Coagulation, FXI and FXIa

Factor XI (plasma thromboplastin antecedent) is a zymogen (an inactive enzyme precursor) of the blood coagulation protease Factor XIa that participates in the early

(“contact phase”) of blood coagulation. The physical and chemical properties of Factor

XI have been determined with purified preparations isolated from human106, 107 and bovine plasma.108-110 Its molecular weight has been reported to be between 125,000 Da

and 160,000 Da for the dimer and between 55,000 Da and 63,000 Da for the monomer.

Human Factor XI contains 5% carbohydrate whereas bovine Factor XI contains 11% carbohydrate.107

Figure 35. Classic pathway of blood coagulation;105 TF = Tissue Factor; a = activation

The coagulation cascade is a complex process which is classically divided into

two pathways: the contact activation pathway, also referred to as the intrinsic pathway,

and the tissue factor pathway, and also referred to as the extrinsic pathway, (Figure 35).

The end product is the protease thrombin, which cleaves fibrinogen to generate a fibrin

clot.111-123

In the extrinsic pathway, thrombin generation is initiated by exposure of blood to

the tissue factor/activated Factor VII (FVIIa) complex. This complex activates clotting

Factors X and IX, leading to the generation of thrombin and the formation of fibrin.114

This pathway is usually rapidly shut down by tissue factor pathway inhibitor (TFPI) and anti-thrombin.

To maintain normal hemostasis, thrombin-mediated activation of FXI initiates an amplification phase via the intrinsic pathway. Activated Factor XI (FXIa) in turn activates Factor IX which then activates protease Factor X, resulting in the formation of

additional thrombin, which takes place inside the fibrin clot. This additional thrombin

may be required for the activation of thrombin activable fibrinolysis inhibitor (TAFI) to

protect fibrin clots against lysis.115 Therefore, the role of FXI in hemostasis can be

considered as a combination of procoagulant and antifibrinolytic actions, which is critical

to the consolidation of blood coagulation when tissue factor is not available.116

Hypothetically, specific inhibition of FXIa, which is involved only in the

amplification phase via the intrinsic pathway, represents an attractive strategy for novel

antithrombotic agents. Specific inhibitors of FXIa might inhibit thrombosis without

completely interrupting the function of normal hemostasis and, thus, might prevent or

minimize the risk of hemostasis complication. High levels of FXI have been

demonstrated as risk factors for venous thrombosis117 and acute myocardial infarction

(heart attack).118

4.1.3 Design and synthesis of small molecules as FXIa inhibitors

4.1.3.1 Examples of synthesized FXIa inhibitors

Lazarova et al. began the investigation of aryl boronic acids as potential inhibitors of FXIa with the screening of commercially available substituted phenyl boronic acids.

Compounds with hydrogen bond donor substituents on the phenyl ring, that could make an electrostatic interaction with aspartate 189 of the S1 specificity pocket, were selected.

All compounds were tested in an in vitro enzyme inhibition assay against FXIa, and

boronic acid 4.1 emerged as the only compound with a half maximal inhibitory

concentration (IC50) value in the range of that of the control compound benzamidine 4.2

119 (IC50 4.1 = 77.3 µM, IC50 4.2 = 120 µM, respectively), Figure 36.

Lazarova et al. designed compounds 4.3, 4.4, 4.5, and 4.6 and screened them for inhibition activity. The results are shown in Table 9. Compound 4.6 has the best FXIa

119 inhibition (IC50 = 5.9 µM) and thrombin selectivity (IC50 = 5.5 µM).

HO OH O O HO OH B O O B O O B B B

2 NH ClH.H2N NH HN HN HN ClH.H2N HN NH .TFA HN NH HN NH .TFA 2 2 HN NH2 2 4.1 4.2 4.3 4.4 4.5 4.6

Figure 36. Guanidine-containing FXIa inhibitors

Table 8. Examples of small molercules for FXIa inhibition

Compounds IC50 , FXIa (µM) IC50 ,Thrombin (µM)

4.3 22 146

4.4 24.7 129

4.5 7.3 30.8

4.6 5.9 5.5

Based on two known thrombin inhibitors, leupeptin (Leu-Leu-ArgCHO)120 and PPACK

121 122 (Phe-Pro-ArgCH2Cl), Lin et al. synthesized compounds 4.7, 4.8, 4.9, and 4.10 to optimize the P1, P2, and P3 positions, Figure 37. They found that compound 4.10 inhibited FXIa with IC50 10 nM; however, not all compounds had good thrombin selectivities, Table 10.122

Figure 37. Guanidine-containing FXIa inhibitors

Table 9. Examples of peptide compounds for FXIa inhibition

Compounds IC50 , FXIa (nM) IC50 ,Thrombin (nM)

4.7 93 6,700

4.8 63 876

4.9 10 1,400

4.10 10 976

Clavatadines A (4.11) and B (4.12), both guanidine-containing natural products

(Figure 38), have IC50 values of 27 µM and 1.3 µM as inhibitors of FXIa. Clavatadine A

is proposed to approach/bind in the S1-S1′ pockets of FXIa by favorable interactions between Asp 189 and its guanidine group on one end and the free carboxylate on the other end to either Arg 37D or Lys 192, Figure 39.123

O O

NH NH OH 2 H Br O N Br OH N NH2 O H H O H2N N HO N O H Br NH Br

Clavatadine A, IC50 =27 M Clavatadine B, IC50 =1.3 M

Figure 38. Clavatadine A (4.11), and B (4.12)123

Figure 39. Docking of Clavatadine A (4.11) in FXIa123

4.2 Silanediol inhibitor design

In the classic pathway of blood coagulation (Figure 35, p. 62) the substrate of

FXIa is FIX (Figure 40A, 4.13), therefore understanding the recognition and cleavage of

FIX by FXIa is important to design molecules. FXIa, a trypsin-like protease, cleaves its substrates after basic amino acids such as Arg and Lys. Gailani et al. and Walsh et al. showed that FIX was cleaved at the Arg145-Ala146 bond by FXIa,124,125a therefore, Arg

125b was chosen as the P1 residue and Ala for the P1’ residue for inhibitor structures. The

amide group (-CO-NH-) between Arg and Ala was replaced by -Si(OH)2-CH2-, (Figure

40B, 4.14).

P OH P1 P ' OH A 3 O O 2O H H H H H H N N N N N N N H H H O P ' O O P2 1 NH2 N O OH H 4.13 NH -Leu-Thr-Arg-Ala-Glu-Thr- ....QTSKLTR-AET-

...... P7654321

Cleavage sites

B P P 1 P ' OH 3 O 2O H H HO OH H H H N N Si N N N N H H O P ' O O P2 1 NH2 N H NH 4.14 -Leu-Ala-Arg-(Si)-Ala-Ala-Thr- -L-A-R-(Si)-A-A-T-

Figure 40. A: Natural cleavage sites on FIX by FXIa; B: Silandiol FXI mimic

Silanediol 4.14 (Figure 40B), however, is not a suitable size for a phamarceutical agent or reasonable structure target. The simplest silanediol structure would be 4.15 (Ac-

Arg-[Si]-Ala-NHMe). Replacements of the acetyl group of 4.15 with Ac-Ala and Ac-

Leu-Ala would give silanediols 4.16 and 4.17, respectively, with more recognition site

introduction. In related research, P. N. Walsh et al. reported that a proline in the P3 position of PN2KI (Kunitz protease inhibitor domain of protease nexin 2) increased the

FXIa inhibition of this naturally occurring inhibitor.126 Silanediol 4.18 was therefore

designed with Ac-Pro-Ala for the P3-P2 positions. On the other hand, P. N. Walsh, et al.

reported that modification of the P2’ position did not change the PN2KI inhibition of

FXIa. Nevertheless, to have a broad range of silanediol inhibitors for FXIa, Ala was used as the P2', structure 4.19, Figure 41.

Figure 41. Design of silanediol FXIa inhibitors

4.3 Synthesis of silanediols

4.3.1.1 Retrosynthesis of the simplest silanediol inhibitor for FXIa

Figure 42. Retrosynthesis of silanediol inhitbitor for FXIa

4.3.1.2 Synthesis of Ellman’s sulfinimine

To prepare sulfinimine 4.15, the inexpensive starting material 1,4-butandiol 4.27 was protected with a methoxymethyl (MOM) group. Distillation of the product gave a mixture of 4.28 and 4.29 (ratio = 90/10), Scheme 43.129 The alcohol 4.28 was oxidized by

pyridinium chlorochromate and distilled to give aldehyde 4.30 in 60% yield. The

unoxidized 4.29 was removed during this distillation. Compound 4.30 was unstable on

silica gel (hexane / ethyl acetate 1/1), but could be purified when 5% triethylamine was

added to the eluent.130 Condensation of 4.30 with the Ellman sulfinamide 4.24 was accomplished in 72% yield using five equivalents of titanium (IV) ethoxide, Scheme 43.

Anhydrous cupric sulfate and cesium carbonate were also tried, but the yield was less

than 10%.

Scheme 43. Synthesis of Ellman sulfinimine 4.25

4.3.1.3 Synthesis of Ellman sulfinamide

As described in Chapter 3, racemic alcohol (±)-3.8 was easily made by radical hydrosilylation, Scheme 35, p. 54.135e Compound (±)-3.8 was treated directly with

lithium metal at 0 °C in THF and then added to Ellman sulfinimine 4.25 to give

sulfinamide 4.24.59 Ellman sulfinamide 4.24 was unstable on silica gel, but could be

purified with neutral alumina. The synthesis of Ellman sulfinamide 4.24 as a single

diastereomer was achieved using same procedure as above, using (S)-silafuran 1.74 (83 –

93% ee), Scheme 44.59

Ph Ph Ph Ph Ph Ph H Si OH Li 4.25 N Si OH H Si OLi S ( )-3.8 Li -72 C, THF O ( )-4.26 59% OMOM N S OMOM (R,R,R)and(R,R,S)-4.24 O 4.25

Ph Ph Ph Ph Ph Ph H Si Li 4.25 N Si OH O Si OLi S Li -72 C, THF O 4.26 59% (S)-1.74 OMOM (R,R,S)-4.24

Scheme 44. Synthesis of Ellman sulfinamide 4.24

4.3.1.4 Synthesis of acetamide compounds

Selective removal of the Ellman auxiliary was tried with 4M HCl in dioxane, followed by acetylation with acetyl chloride. Unfortunately, the process did not give the expected product 4.23, and gave many spots on TLC, Scheme 45. It was believed MOM group was deprotected in this condition as well, and gave a messy reaction.

Scheme 45. Unsuccessful selective removal of Ellman auxiliary

The TPS protecting group for alcohols is quite stable in an acidic environment, and both Davis and Ellman auxiliaries have been removed selectively in its presence,

Scheme 46.131

Scheme 46. Removal of Davis and Ellman auxiliaries

Therefore, the TPSCl reagent was selected to protect the alcohol of sulfinamide

4.24. Following the Hardinger et al.132 protocol with silver nitrate gave a high yield of

compound 4.31 in only 10 min. Unfortunately, removal of the Ellman auxiliary from 4.35

using 4M HCl in dioxane followed by acetylation gave compound 4.32 in low yield,

Scheme 47.

Scheme 47. Attempt of removal Ellman auxiliary and acetylation

4.3.1.5 Revised retrosynthesis of silanediol inhibitor

These deprotection difficulties led us to consider using t-butylsulfonyl group

133a (Bus) and p-tolylsulfonyl group (Ts). The Ts group can be easily removed with SmI2

or Mg in methanol (Scheme 48),133b while the Bus group can only be removed in triflic

acid.134 This difference required the current synthesis to be revised using the Davis

sulfinimine.

Scheme 48. Ts group removal is easier than Bus group

Condensation of aldehyde 4.30 and Davis sulfinamide (R)-4.40135 with stoichiometric of titanium (IV) ethoxide gave sulfinimine 4.41 in 72% yield. This reaction was scaled up to 10 g of compound 4.40, however the sulfinimine 4.41 was not stable after purification, therefore the reaction solution was kept at 0 °C, and purified when it was needed, Scheme 49.135

Scheme 49. Synthesis of the Davis sulfinimine 4.41

Following the synthesis described in Scheme 44, sulfinamide 4.42 was isolated in

75% yield, Scheme 50. That yield is higher than that using Ellman sulfinamide 4.24

possibly due to the Davis sulfinamide 4.42 being more stable on silica gel.

Ph Ph Ph Ph H Ph Ph p-Tolyl N Si OH Si OH Li 4.41 S H Si OLi Li ( )-3.8 -72 C, THF O ( )-4.26 75% OMOM (R,R,R)and(R,R,S)-4.42 Ph Ph Ph Ph H Ph Ph p-Tolyl N Si OH Si Li 4.41 S O Si OLi Li O -72 C, THF 4.26 (S)-1.74 75% OMOM (R,R,S)-4.42

p-Tolyl N S OMOM O 4.41

Scheme 50. Synthesis of the Davis sulfinamide 4.42

4.3.1.6 Attempt to synthesis of azide compound

Weinreb et al. reported that RuCl3 and NaIO4, or m-CPBA could be used to

134 oxidize sulfinyl groups to sulfonyl groups, and that catalytic RuCl3 and NaIO4 would

oxidize the primary alcohols to acids as well.59 Therefore, sulfinyl alcohol 4.42 was treated with RuCl3/NaIO4, but only 5% of the expected product 4.43 was isolated. On the

other hand, when m-CPBA was used to convert sulfinyl 4.42 to sulfonyl 4.44, oxidation of compound 4.44 to acid 4.43 using RuCl3/NaIO4 proceeded in 56% yield over two steps, Scheme 51.

Ph Ph Ph Ph H H p-Tolyl N Si OH RuCl3/NaIO4 N Si OH S Ts 5% O O (R,R)-4.43 (R,S)-4.43 (R,R,S)-4.42 OMOM OMOM (R,R,R)-4.42 Ph Ph RuCl3/NaIO4, 56% 2 steps m-CPBA H N Si OH Ts

OMOM (R,R)-4.44 (R,S)-4.44

Scheme 51. Oxidation of the alcohol 4.42 with RuCl3/NaIO4

Acid 4.43 was easily converted to amide 4.45 in quantitative yield.136 It is worth noting that forming N-methyl amide 4.45 using iso-butyl chloroformate and 40% aqueous methylamine solution was a very clean reaction. The resulting sulfonyl amide 4.45 could be used directly without purification, Scheme 52. Deprotection of the MOM group with aqueous HCl gave alcohol 4.46. Conversion to the mesylate 4.47 proceeded in 61% yield

127 over three steps. However, when mesylate 4.47 was treated with NaN3 in DMF at 50-

60 °C, cyclization of the sulfinamide gave pyrrolidine 4.48.137a This cyclization was complete after 20 min in the presence of NaN3, and 6 h without NaN3. Sodium azide might be acting as a weak base allowing hydrazoic acid (pKa = 4.6, mp. = 37 °C)137b to escape leading to 4.48.

Scheme 52. Failure of converting alcohol to azide

Dephenylation of pyrrolidine 4.48 was accomplished using the trifluoroborane and acetic acid complex138 to give difluorosilane 4.49, a precursor of the Pro-[Si]-Ala

silanediol mimic 4.50, Scheme 52. Investigating a specific enzyme for inhibition by

compound 4.50 is still ongoing.

4.3.2 Removal of p-toluenesulfonate

Amide 4.45 was treated with Mg in methanol. Unfortunately, only starting

material 4.45 was recovered, Scheme 53.

Scheme 53. Failure of tosyl removal with magnesium in methanol

Facing the same problem of tosyl removal, Ragnarsson et al.139 and Muir et al.140 found that activation of sulfonamides with an electron withdrawing N-acetyl or N-Boc groups made the Ts group more labile. Compound 4.45 was therefore treated with Boc2O catalyzed by DMAP to give compound 4.52, followed by Mg (10 equiv.) and methanol at room temperature for 2 h to give carbamate 4.53 in good yield, Scheme 54.

Scheme 54. Desulfonylation of "activated" N-Boc-tosylate

4.3.3 Synthesis of azide 4.21

The next step in the sequence was a substitution of a guanidine group in place of the MOM group in 4.53. There is no precedent, however, for the selective removal of a

MOM group in the presence of an N-Boc group similar to compound 4.53 (Scheme 54) and 4.54 (Figure 43). In comparision to Boc group 4.54, the functional groups carbonate

4.55141a and carbamate 4.56141b (Figure 43) have been reported to survive under TMSBr

conditions.

Figure 43. N-carbamate and N-carbamate compounds are stable under TMSBr

To evaluate this procedure, compound 4.53 was added to TMSBr at -78 °C.

Under these conditions the MOM group was selectively removed in about 45 sec. The resulting crude alcohol was converted to the mesylate with MsCl and triethylamine. The mesylate was then displaced with NaN3 to give azide 4.57 in 52% yield over three steps.

Unfortunately, the TMSBr process could not be scaled up to more than 0.4 g of 4.53

because this led to formation of an unknown byproduct. The Boc group of 4.57 was removed by 4M HCl in dioxane to give crude amine salt 4.58. Acetylation of 4.58 could be accomplished with acetyl chloride142a or with HATU142b and acetic acid. The acetyl

chloride reaction gave a clean azide product 4.21 following a simple work up but in low

yield. HATU and HOAc gave compound 4.21 in 72% yield, but suffered from a difficult

separation of the 1,1,3,3-tetramethylurea byproduct, Scheme 55.

Scheme 55. Synthesis of azide 4.21

The first attempt to reduce azide 4.21 to an amine by hydrogenation (1 atm) using

Lindlar’s catalyst gave a complex mixture. The stability of the free amine on silica gel might be a reason for this observation. When Boc2O was added along with Lindlar’s catalyst, the amine product was trapped to give carbamate 4.59 in good yield, Scheme

56.143 Reaction progress was monitored by infrared spectroscopy: the azide absorption at

2095 cm-1 had disappeared when the reaction was complete, Figure 44.144

Scheme 56. Conversion of azide 4.21 to carbamate 4.59

Figure 44. Comparision of IR spectra of azide 4.21 and carbamate 4.59 80

To complete this portion of the target, the amine needed to be converted to a

guanidine. K.S. Kim, et al. reported an improved method for preparation of a guanidine from an ammonium salt with N,N’-di-(tert-butoxycarbonyl)thiourea 4.20 in up to 90%

yield.145a Instead of ordering this expensive reagent 4.20 from Aldrich ($114/g), it was

readily prepared from thiourea, Scheme 57.145b

Scheme 57. Synthesis of compound 4.20

A crude ammonium salt was produced from N-Boc 4.59 by treatment with a 4M

HCl solution. A straightforward synthesis of the guanidine silanediol precursor 4.60 was

performed in 85% yield. Following guanidine deprotection, mecuridearylation of 4.60

with mercury acetate gave 4.15, Scheme 58.146 The proposed mechanism is shown in

Figure 45.

Scheme 58. Insertion guanidine group and hydrolysis of the diphenylsilane

to silanediol 4.15

Similar to dephenylation with triflic acid (Figure 34, p. 58), ipso-positions on

benzene rings are attacked by mercury (II) acetate to form transition state 4.62. The

oxygen of the neighboring amide displaces the activated phenyl group to give 4.63 and

phenyl mercury acetate. Continuing in the same manner, the second phenyl group leaves

forming the spirocyclic intermediate 6.64. Hydrolysis released the expected silanediol

4.15, Figure 45.

Figure 45. Proposed mechanism of mercuridearylation

4.3.3.1 Asymmetric intramolecular hydrosilylation

After the successful synthesis of silanediol 4.15 as a diastereomeric mixture, a synthesis with full stereo control was then considered. However, at that time asymmetric intramolecular hydrosilylation of 1.73 had only been on one gram scale (Scheme 59).

This was not enough for this synthesis.

Scheme 59. Asymmetric intramolecular hydrosilylation

Dr. Swapnil Singh et al. had achieved good results (Table 6, Chapter 2, p. 28); however, the concentration of ferrotane 1.77 had not been screened, nor had the reaction been scaled up. Three AIH reactions were set up with varying amount of DCM, but kept

0.5 mol % of ferrotane 1.77. The concentration of ferrotane 1.77 was 17.6 mM, 8.8 mM, and 5.8 mM for reactions 1, 2, and 3 (Table 10). The progress of reaction was monitored by 1H NMR.67b

Table 10. Rate of hydrosilylation depends on catalyst

and silyl ether concentration using 0.5 mol% catalyst 1.77

Concentration of DCM Time/Conversion Reaction Ferrotane 1.77/ Observation % ee (mL) (%) silyl ether 1.73

As soon as silyl ether was 15min/∼85% 1 5 17.6 mM / 4.72 M added, solution warmed to 84.8 30min/∼100% 42 °C

1day/∼50% Temperature 2 10 8.8 mM / 2.36 M 82.5 3day/∼100% did not change

2day/∼50% Temperature 3 15 5.8 mM / 1.57 M 71.5 4day/∼100% did not change

After the addition of silyl ether 1.73 (6.0 g, 23.6 mmol) in one portion, the temperature in reaction 1 increased to 40 °C (recorded by infrared thermometer), but no change was observed for reactions 2 and 3. Completion of the reaction was achieved after

30 min for reaction 1, but it took 3 or 4 days to completely convert silyl ether 1.73 to silafuran 1.74 in reactions 2 and 3. The difference in temperature and concentration of catalyst 1.77 did not have a significant effect on selectivity, as the ee for each reaction was similar, Table 10.67b

4.3.4 Asymmetric synthesis of silanediol 4.15

The successful scale up of this AIH allowed for an asymmetric synthesis of the first guanidine-containing silanediol inhibitor 4.15 with silafuran 1.74 (84% ee).

Guanidine 4.60, a precursor of silanediol 4.15, was produced as a foam (262 mg) in 1.7% yield over all in 11 linear steps from silyl ether 1.73 (6.0 g, 23.6 mmol), Scheme 60.

Ph2 Ph Ph Si Ph Ph H O Li 4.41 p-Tolyl N Si OH m-CPBA Si OLi S Li -72 C, THF 4.25 O DCM, rt, 89% (S)-1.74 75% OMOM p-Tolyl N S OMOM (R,R,S)-4.42 O 4.41 O Ph Ph Ph Ph H H Cl N Si OH RuCl ,NaIO N Si OH O Ts 3 4 Ts O DCM/CH3CN/water NMM, THF (1/1/1) -40 °C-rt, 92% OMOM 68% OMOM (R,S)-4.44 (R,S)-4.43

Ph Ph H 2 H Boc 2 H Mg, MeOH N Si N Boc2O N Si N Ts Ts O DMAP, 74% O rt, 2h quantitative OMOM OMOM (R,S)-4.45 (R,S)-4.52 1. TMSBr Ph 2 H -78 C, 45sec. Ph2 H BocHN Si N BocHN Si N HCl (4M, dioxane) 2. MsCl, Et3N O O then, AcCl, Et N 3. NaN 3 3 88% OMOM 52% 3 steps N3 (R,S)-4.53 (R,S)-4.57

Lindlar/H 2 Ph H Ph2 H Boc O H 2 H HCl (4M, dioxane) N Si N 2 N Si N quantitative HgCl , 90% O O O O 2 S

N3 NH BocHN NHBoc (R,S)-4.21 (R,S)-4.59 Boc 4.20

HO OH H Ph2 H H H N Si N 1. HOAc/DCM N Si N

O O 2. Hg(OAc)2 O O HOAc, DCM

NH NH2 CH3COO

BocN NHBoc HN NH2 (R,S)-4.60 (R,S)-4.15

Scheme 60. Asymmetric synthesis of silanediol inhibitor 4.15

4.3.5 Asymmetric synthesis of silanediol 4.16, 4.17, and 4.18

To synthesize silanediols 4.16, 4.17, and 4.18, Figure 41 (p. 68), dipeptides 4.64,

4.66, and aminoacid 4.68 were needed, Scheme 61. Peptide 4.64 was synthesized from L-

proline (4.61)147 by acetylation followed by coupling with alanine benzyl ester 4.63 using

iso-butylchloroformate.146 Removal of the benzyl group was accomplished by

hydrogenation over Pd/C.148 Product 4.64 was recrystallized from ethyl acetate.

Dipeptide 4.66 was synthesized by the same method from commercially available 4.65 to

give crystalline 4.66, Scheme 61.148 N-Methyl alanine salt 4.68 was made from N-Boc

alanine 4.67 by coupling with methyl amine followed by deprotection of the Boc group

with HCl.149

O O O H O O Ac O N 2 N N OH OH OH N H 1. iso-butyl chloroformate O 4.61 4.62 4.64, 75% O 2. 4.63 H O H N OH 3. H ,Pd/C N N 2 H OH O O O O Ph 4.66, 93% 4.65 TsOH3N O 4.63

1. O Cl O O BocHN O ClH.H3N OH CH NH (aq.) N 3 2 H 4.67 2. HCl 4.68 72% over 2 steps

Scheme 61. Synthesis of amino acids and dipeptide for silanediol inhibitors

Preparation of the next three FXIa inhibitors began with 4.57. Boc removal from

4.57 was complete in about 5 h with a 4M HCl solution in dioxane to give a crude

86 ammonium salt. Acids 4.64, 4.66, and 4.69 were coupled with the crude ammonium salt using HATU and NMM to give compounds 4.70a, b, and c in 70-75% yield, Scheme 62.

Ph H Ph2 H 2 H N Si N BocHN Si N 1. HCl (4M, dioxane) P O O 2. X, HATU, NMM rt N3 N3 (R,S)-4.57 P=Ac-Ala-(4.70a), 76%

Ac-Leu-Ala- (4.70b), 75%

Ac-Pro-Ala- (4.70c), 72%

O O O O H OH N OH N OH X: N N N H H H O O O O Ac-Ala-OH (4.69) Ac-Leu-Ala-OH (4.66) Ac-Pro-Ala-OH (4.64)

Scheme 62. Synthesis azide compounds via coupling reaction

The NMR spectra of 4.70a and 4.70c in CDCl3 were quite complicated, presumably due to amide rotamers and self-association. Changing the solvent to DMSO-

13 d6 at 360 - 380 °K resulted in clean proton NMR spectra, but the C NMR spectra were still very poor. Changing again to CD3OD gave the best spectra (see p. 236, 237).

Azides 4.70a, b and c were converted to N-Boc 4.71a, b and c. Removal of the

Boc group and coupling with thiourea 4.20 established the guanidine group, compounds

4.72a, b and c. Lastly, silanediols 4.16, 4.17, and 4.18 were prepared by mecuricdephenylation, Scheme 63.57

Lindlar/H 2 Ph H Ph2 H Boc O H 2 H HCl (4M, dioxane) N Si N 2 N Si N P P quantitative HgCl , 90% O O 2 S Boc N N BocHN NHBoc 3 H 4.20 P=Ac-Ala-(4.70a) P = Ac-Ala-(4.71a), 86%

Ac-Leu-Ala- (4.70b) Ac-Leu-Ala- (4.71b), 80%

Ac-Pro-Ala- (4.70c) Ac-Pro-Ala- (4.71c), 82%

HO OH H Ph2 H 1. HCl (4M, dioxane) H H N Si N N Si N P or HOAc/DCM P O 2. Hg(OAc)2 O HOAc, DCM

NH NH2 CH3COO

BocN NHBoc HN NH2

P=Ac-Ala-(4.72a), 84% P=Ac-Ala-(4.16)

Ac-Leu-Ala- (4.72b), 91% Ac-Leu-Ala- (4.17) Ac-Pro-Ala- (4.72c), 86% Ac-Pro-Ala- (4.18)

Scheme 63. Silanediol analog synthesis

4.3.6 Asymmetric synthesis of silanediol 4.19

Silanediol 4.19 was prepared by the same method, Scheme 63, however almost all of steps have lower yield than the sequence leading to silanediol 4.15, Scheme 60 (p. 84).

The acid 4.43 was coupled with an alanine unit to give 4.73 in 62% yield. Boc protection of the sulfonyl amide 4.73 gave 4.74 in low yield along with byproducts, whose structures have not been determined. Removal of the tosyl group from 4.74 with Mg in methanol gave 4.75 in 85% yield. This reaction required immediate work-up after Mg was consumed to avoid forming an unknown compound. Azide 4.76 was prepared in only

25% yield from carbamate 4.75. Boc group removal followed acetylation of the carbamate 4.76 gave acetamide 4.77 in 68% yield. Reduction of the azide 4.77 with hydrogen (1 atm) on Lindlar’s catalyst (20 wt%) gave carbamate 4.78 in quantitative yield. Boc removal of 4.78 with a 4 M HCl in dioxane gave a crude ammonium salt. The

ammonium salt was reacted with a stoichiometric amount of thiourea 4.20 and mercuric

chloride to give guanidine 4.79 in 85% yield. Deprotection of the guanidine and

mercuridephenylation gave silanediol 4.19, Scheme 64.

O Ph Ph ClH. H2N Ph Ph O H N H H N Si OH 4.68 H N Si N Boc2O Ts Ts N H O HATU, NMM, O DMAP, 54% DMF, rt, 62% OMOM OMOM (R,S)-4.43 4.73 1. TMSBr Ph Ph O Ph Ph O -78 C, 45sec. Boc H Mg, MeOH H N Si N BocHN Si N 2. MsCl, Et3N Ts N N H H O rt, 2h, 82% O 3. NaN3 25% 3 steps OMOM OMOM 4.74 4.75

Ph Ph O Ph Ph O H H H BocHN Si N 1. HCl (4M, dioxane) N Si N N N H H O O O 2. HOAc,NMM HATU, rt, 68% N3 4.76 N3 4.77

Ph Ph O Lindlar/H Ph Ph O 2 H H H H Boc O N Si N 2 N HCl (4M, dioxane) N Si N H N quantitative O O H HgCl2, 85% O O S NHBoc NH 4.78 BocHN NHBoc 4.20 BocN NHBoc 4.79 HO OH O H H N Si N N 1. HOAc, DCM H O O

2. Hg(OAc)2 HOAc, DCM NH2OAc

HN NH2 4.19

Scheme 64. Synthesis of silanediol 4.19

4.3.7 Silanediol inhibition of FXIavi

All silandiols were dissolved in water, Table 11, and screened at Temple

University Medical School using the laboratory facilities of Prof. Walsh for their inhibition ability to inhibit FXIa by Dr. Wenman Wu.

Table 11. Silanediols solutions sent to test FXIa

Silanediol Volume/concentration

4.15 6 mL / 0.1 M

4.16 6 mL / 0.065 M

4.17 12 mL / 0.03 M

4.18 4.5 mL / 0.05 M

4.19 4.8 mL / 0.1 M

Chromogenic substrate 4.80, was used for the test, Figure 46, and the hydrolysis of 4.80 by FXIa is shown in Scheme 65, where the peptide bond of Arg-p-NA is cleaved to give Glu-Pro-Arg-OH (4.81) and p-nitroaniline (4.82)

vi Studied by Dr. Wenman Wu in Dr. Peter Walsh, Temple Medical School 90

O NO2 N O H N N H O

NH2Cl

HN NH2 4.80

Chemical name: L-Pyroglutamyl-L-prolyl-L-arginine-p-nitroaniline hydrochloride

Formula: Glu-Pro-Arg-pNA.HCl S-2366TM

Figure 46. Chromogenic substrate for FXIa

Scheme 65. Cleavage of the substrate by FXIa

The inhibition of FXIa amidolytic activity by the silanediols was used to

determine their inhibitory effect. The Kieq for the compounds 4.15 – 4.19 are 980 µM, 76

µM, 180 µM, 160 µM and 820 µM, Figure 47 and Table 13.126,150

Figure 47. FXIa inhibition results, (R,S 214) = 4.15, (R,S 215) = 4.16, (R,S 216) = 4.17,

(R,S 217) = 4.18, (R,S 218) = 4.19

The results show that the simplest silanediol inhibitor 4.15 has relatively poor

activity with Kieq = 980 µM. Modification of 4.15 by addition of an alanine unit in the P2’ position to give 4.19 did not improve inhibition activity, Kieq = 820 µM. The addition of

an alanine in the P2 position, 4.16 gave the best inhibition for FXIa with a Kieq = 76 µM.

The addition of a leucine or proline to the P3 position, silanediols 4.17, and 4.18

decreased the inhibition activity of FXIa slightly with a Kieq = 180 and 160 µM, Table 13.

Table 12. Screening silanediol inhibition results

Compound Kieq (µM)

980

O HHO OH H N Si N N H O O

NH2OAc 76

4.16 HN NH2

180

160

HO OH O H H N Si N N H O O

NH2OAc 820

HN NH2 4.19

In conclusion, five silanediol inhibitors for FXIa were designed and synthesized based on the structure of substrate FIX, using a scaled up asymmetric intramolecular hydrosilylation reaction and addition of silyllithium reagent to a Davis sulfinimine. These silanediols are the most highly functionalized silanediol inhibitors prepared to date. The inhibition activity of these silanediols for FXIa is good with Kieq in range of 76-980 µM.

The asymmetric synthesis gave two key compounds 4.43 and 4.57, from which guanidine-containing silanediols could be modified easily to prepare novel silanediol inhibitor structures.

CHAPTER 5:

TOWARD ASYMMETRIC SYNTHESIS OF A SILANEDIOL INHIBITOR FOR

HUMAN HEART CHYMASE (HHC)

5.1 Introduction

5.1.1 Chymotrypsin-like serine proteases

Chymotrypsin-like serine proteases are synthesized in enzymatically inactive form and

are folded into a structure comprising double six-stranded β-barrels.151-156 The catalytic

domain contains a triad of His57, Asp102 and Ser195 (chymotrypsin numbering system),

Figure 48.157

Figure 48. The catalytic mechanism of serine proteases158

The generally accepted mechanism for chymotrypsin-like serine proteases that

cleave the peptide bond is shown in Figure 48. In the acylation half of the reaction,

Ser195 attacks the carbonyl of the peptide substrate, assisted by His57 acting as a general base (see 5.1), to yield a tetrahedral intermediate 5.2. The resulting His57-H+ is stabilized

by the hydrogen bond to Asp102. The oxyanion of the tetrahedral intermediate 5.2 is

stabilized by interaction with the main chain NHs of the oxyanion hole. The tetrahedral

intermediate 5.2 collapses with expulsion of leaving group, assisted by His57-H+ acting

as a general acid, to yield the acylenzyme intermediate 5.3. The deacylation half of the

reaction essentially repeats the above sequence: water attacks the acylenzyme 5.3,

assisted by His57, yielding a second tetrahedral intermediate 5.4. This intermediate

collapses, expelling Ser195 5.5 and carboxylic acid product.158-162

5.1.2 Example of design and synthesis of human heart chymase inhibitors

Human heart chymase (HHC), a chymotrypsin-like serine protease, converts

angiotensin I to angiotensin II. Angiotensin II raises blood pressure.163-165 Kinoshita et al.

reported that substrate and inhibitor specificities of chymase and chymotrypsin are

similar. However, the good inhibitors of chymase, which can control blood pressure are

not good inhibitors of the digestive enzymes such as chymotrypsin, elastase, cathepsin

D.158

P1 P1 Ph Ph P3 O P1' P3' Z-Ile-Glu-Pro OMe Z = O O Glu-Asp-Arg-OMe N F N P2 H H P2' O O 5.6 5.7 P1 Ph P3 O P1' P3' Z-Ile-Glu-Pro Glu-Asp-Arg-OMe N N H P2' P2 H O 5.8

Figure 49. Examples of synthetic chymase inhibitors

Bastos et al. synthesized chymase inhibitors selective over chymotrypsin, 5.6, 5.7 and 5.8, Figure 49.166 Results are shown in Table 13. Compound 5.6 was constructed

with P2, P3 positions by Pro and Glu. They found that compound 5.6 was 10 times more

selective for chymase than it was for chymotrypsin. When Glu-Asp-Arg were used for

the P1’-P2’ groups, compound 5.7 exhibited 100-fold selectivity for chymase over

chymotrypsin. Compound 5.8, a combination structure of both 5.6 and 5.7, gave 400fold

selectivity for chymase.166

Table 13. HHC inhibition results

Compound Ki, µM

Chymotrypsin Chymase

5.6 0.01 0.001

5.7 100 1

5.8 40 0.1

Figure 50. Proposed binding of compound 5.9 with HHC

In 1995, Eda et al. reported a model shown in Figure 50, where the Glu side chain of compound 5.9 is flipped toward Ser218 forming a hydrogen bond and the Boc group is in van der Waals contact with the side chain of Tyr215. The S2 pocket fits with His57 and the carboxylate hydrogen bonds with Lys40.167

5.2 Design and retrosynthesis of a silanediol human heart chymase inhibitor

Silanediol 5.10 was designed by analog with 5.8 except the amino terminal Glu was acetylated and amidated Glu was used for P3’. Compound 5.10 is the most functionalized silanediol designed in the Sieburth group to date.

Figure 51. Expected silanediol inhibitor structure for HHC

Retrosynthesis of silanediol 5.10 involves cleavage of peptide bond linkages into three fragments: FmocNH-Glu-Pro 5.11, sulfinamide 5.12 and FmocNH-Asp-Glu (NH2)2

5.13, Figure 51. Fragments 5.11 and 5.13 could be synthesized from amino acids 5.14

and 5.16. The sulfinamide 5.12 would be synthesized by an addition of a silyl lithium dianion, generated from silafuran 2.48, with Ellman sulfinimine 3.17.59

5.3 Synthesis of Chymase silanediol inhibitor

To prepare silanediol 5.10, we began with dipeptides 5.11 and 5.13.

Commercially available FmocGlu(t-Bu)OH 5.14 was coupled with Pro(OBz) 5.17 using

HATU and NMM to give dipeptide 5.18 in good yield.142b The yield of reaction was best

when NMM (2.1 equiv.) was added slowly due to the instability of the Fmoc group to

basic conditions. Hydrogenation of 5.18 over Pd/C gave acid 5.11 as pale yellow foam in

excellent yield, Scheme 66.148

Scheme 66. Synthesis of Glu-Pro-OH 5.11

BocNH-Glu(OH)2 5.19 was amidated with tert-butyl pyrocarbonate/pyridine and

then treated with ammonium bicarbonate to give 5.16 in 83% yield.168 A comparable

reaction using iso-butyl chloroformate, NMM and aqueous ammonia gave compound

169 5.16 in only 38% yield. The Boc group of 5.16 was removed with TFA and the crude ammonium salt was then coupled with acid 5.15 using HATU and NMM to give peptide

5.13 in good yield, Scheme 67.142b

Scheme 67. Synthesis of FmocAsp-Glu (CONH2)2 (5.13)

To prepare the central component 5.20, racemic silafuran 2.48 was opened with

lithium followed by addition to sulfinimine (R)-3.17 to give sulfinamide 5.12 in 45%

yield, Scheme 68. In contrast, (±)-2.49 was opened with lithium as well, followed by

addition to sulfinimine (R)-3.17, but the expected product 5.20 was not formed. The

reason for this falure is not understood.59

OMOM

Ph Ph Si H Ph Ph O 1. Li N Si OH S 2. O N Ph 5.12 ( )-2.48 OMOM S Ph O (R)-3.17 45% O O Ph Ph Si O 1. Li H Ph Ph N Si OH S O 2. N O ( )-2.49 O S Ph Ph O (R)-3.17 5.20

Scheme 68. A successful and an unsuccessful sulfinamide synthesis

Sulfinamide 5.12 was protected using TPSCl and silver nitrate to give sulfinamide

5.21 in 85% yield .132 The Ellman auxiliary and MOM group of 5.21 were removed with

4M HCl in dioxane, and the resulting product was coupled with acid 5.11 using DCC

(N,N'-Dicyclohexylcarbodiimide) to give compound 5.22, Scheme 69.

100

OMOM OMOM

AgNO3 H Ph Ph TPSCl H Ph Ph N Si OH N Si OTPS S S O O Ph Ph 5.21 5.12

OH 1. HCl H Ph Ph N N Si OTPS FmocHN O 2. O Ph N OH 5.22 FmocHN t-BuOOC O O 5.11 t-BuOOC OH O H Ph Ph N N Si OTPS 1. DBU HN O O Ph 2. AcCl t-BuOOC 5.23

Scheme 69. Proposed synthesis of compound 5.23

Fmoc group of 5.22 can be removed with organic bases such as 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or pyridine,170 followed by acylation to complete the left side of the molecule to give compound 5.23, Scheme 69.

Scheme 70. Potential sequence for silanediol 5.10 synthesis

101

To complete this synthesis, alcohol 5.23 would be oxidized to a carboxylic acid,

and the protected as a tert-butyl ester 5.24.171Removal of TPS protecting group, oxidation

of the alcohol to an acid and coupling with 5.13 will give 5.25. Hydrolysis of diphenyl

silane 5.25 to a silanediol 5.10 will give the expected silanediol chymase inhibitor 5,

Scheme 70.57

In summary, in this chapter, a short review of human heart chymase (HHC)

inhibitors was presented. Based on the known HHC inhibitors, silanediol inhibitor 5.10

was designed. Important progress toward the synthesis of this inhibitor has been made.

5.4 Attempt to insert Evans auxiliary in structure

Synthesis of silanediol dipeptides has a challenge in stereoselectively forming two

chiral centers, an α-amino silane and a β-silyl acid (2.1, Figure 19, p. 24). The α-amino silane stereogenic center has been nicely solved using nucleophilic addition of silyllithium reagents to sulfinimines.59 The β-silyl acid chiral center was established by

AIH. However, this transformation requires using the expensive ferrotane catalyst ($394 /

500 mg), and in some cases led to a long and low yield synthesis of silyl ethers 2.2, (see

Chapter 2).

Figure 52. Evans auxiliary compound

102

As is well known, deprotonation at the α-carbon of the Evans oxazolidinone imide

5.26 will give (Z)-enolate, which can undergo diastereoselective alkylation to produce

5.27.172 A potential alternative reaction of cyclization elimilating Evans auxiliary 5.30 will give a cyclic 5.29, Figure 52.173

To evaluate the approach in Figure 52, allyl acohol 5.31 was prepared in one step via radical addition with diphenyl silane (2.44) in 80% yield, Scheme 71.100

Ph OH 2 Ph Ph Ph Si 2 Li 4.41 H Si H H OH Si OLi AIBN, -H Li -72 C, THF 2.44 5.31 2 SH 5.32 75%

C9H19 Tolyl N S OMOM heptane, reflux 4.41 80% O

Ph Ph Ph Ph H m-CPBA H Tolyl N Si OH N Si OH S Ts RuCl3,NaIO4 O DCM, rt, 89% DCM/CH3CN/water (1/1/1) OMOM OMOM 68% 5.33 5.34 OMOM

Ph Ph Ph Ph H Ph2 (S)-oxazolidione, H O N Si OH PivCl, Et N, LiCl, THF Si N Si N Ts 3 Ts O 92% TsN O O

O OMOM OMOM 5.35 5.36 5.37

Scheme 71. Attempt to synthesis of compound 5.37

Compound 5.31 was reduced with lithium to generate silyllithium 5.32 and added to sulfinimine 4.41 to give sulfinamide 5.33.59 Oxidation of sulfinyl 5.33 to sulfonyl

amide-alcohol 5.34 with m-CPBA followed by oxidation with NaIO4 and catalytic RuCl3 gave sulfonamide acid 5.35 in moderate yield. Unfortunately, coupling acid 5.35 with

103

(S)-oxazolidione did not give the expected product 5.37, but was instead transformed to

lactam 5.36 in quantitative yield.174

Ph Ph Ph Ph Ph Ph H H Boc N Si OH N Si OBoc N Si OH Ts Ts Ts Boc2O (1eq.)

DMAP (0.2 eq.) OMOM CH3CN, 3h, 90% OMOM OMOM 5.34 5.38 5.39

Boc2O(2eq.)

Ph Ph Ph Ph Ph Ph Boc BocHN Si N O N Si OBoc Mg, MeOH BocHN Si OBoc Ts O O

OMOM OMOM OMOM 5.40 5.41 5.42 Scheme 72. Failure of N-carbamate protection

In an attempt to remove the tosyl group of 5.34, treatment with one equivalent of

Boc2O and catalytic DMAP gave carbonate 5.38 instead of the expected N-carbamate

5.39, Scheme 72. Perhaps, steric effects led to carbonate formation. Silyl lactam 5.36

might be a good starting point for interesting chemistry.174,175 Sulfonyl 5.34 might be N-

protected with a Boc group followed by desulfonation with Mg in methanol to give carbamate 5.41, which might be a good starting point for preparing of 5.42.

104

CHAPTER 6:

EXPERIMENTAL

6.1 Instrumentations

IR spectra were recorded on Mattson 4020 GALAXY Series FT-IR.

For all compounds, 1H and 13C NMR spectra were recorded on a Varian Inova

300 Bruker Avance, 400 Bruker, and Avance III 500 spectrometers. Chemical shifts were

measured relative to the residual solvent resonance for 1H and 13C NMR. Coupling constants, J, are reported in hertz (Hz). The following abbreviations were used to designate signal multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; m, multiplet; br, broad. 29Si NMR spectra were recorded

based on calibrating the machine with tetramethylsilane, under supervision from Dr.

DeBrosse.

Mass spectra were obtained from Mass Spectrometry Facility of University of

California at Riverside and Mass Spectrometry Facility on the second floor (Beury Hall)

under supervision from Paul B. Finn. Thomas Hoover UNI-MELT capillary melting

point apparatus was used for melting point measurement.

Glassware was oven-dried at 120 °C, assembled while hot, and cooled to ambient

temperature under an inert atmosphere. Unless noted otherwise, reactions involving air

sensitive reagents and/or requiring anhydrous conditions were performed under nitrogen

or argon atmosphere.

105

6.2 Reagents and solvents

Reagents and solvents were purchased from Aldrich Chemical Company, Fisher

Scientific, Strem, Alfa Aesar or Acros Organics. Most silicon reagents were purchased

from Gelest Inc. Liquid reagents such as TMEDA and Et3N were purified by distillation

when necessary. Unless otherwise noted, solid reagents were used without further

purification. S-2266TM was purchased from Chromogenix-Instrumentation Laboratory

SpA (Italy) for testing FXIa inhibition. Lindlar catalyst is ,5% palladium on calcium

carbonate, was used for hydrogenation.

Reaction solvents (THF, CH2Cl2, DMF, and Et2O) were taken from a “Grubbs-

style” Solvent Dispensing System purchased from Glass Contour or distilled as described

in the literature.176 HPLC grade solvents were purchased from Fisher Scientific.

6.3 Chromatography

Silica gel (60 Å, 170–400 mesh) or neutral alumina (aluminum oxide, 50–200

micron, activated) was used for flash column chromatography. Analytical thin layer

chromatography (TLC) was performed using Analtech UniplateTM Silica Gel GF (250

micron) pre-coated glass plates. Spots were detected by 254 nm UV lamp, Iodine, and phosphomolybdic acid solution.

Perkin-Elmer Series 200 system, made by Perkin Elmer, US in 1999 with UV/Vis detector was used for HPLC. TotalChrom Station software was used to generate chromatograms.

106

6.4 Index of experimentals for chapter 2

MOMO OH

2.19, p. 115

Ph Ph Si Ph O O HO 2.51, p. 128

107

2-[3-(Methoxymethoxy)propyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.20)

To a solution of 2.27 (3.0 g, 29.4 mmol) in DCM (20 mL) was added 4,4,5,5-tetramethyl-

1,3,2-dioxaborolane (2.25) at 0 °C. The solution was stirred at 0 °C for 1 h and rt for 20 h. The solution was cooled to 0 °C, methanol (3 mL) was added, after stirring for 30 min, concentrated in vacuo. Column chromatography gave 2.20 as colorless oil (4.6 g, 70% yield).

Rf = 0.4 (hexane / ethyl acetate 9:1)

IR: 2977, 2933, 2885, 1517, 1446, 1373, 1147, 1045, 846, 673 cm-1;

1 H NMR (400 MHz, CDCl3): δ 4.5 (s, 2H), 3.44-3.40 (t, J = 7.4 Hz, 2H), 3.28 (s, 3H),

1.66-1.60 (m, 2H), 1.17 (s, 12H), 0.77-0.73 (t, J = 7.5 Hz, 2H);

13 C NMR (100 MHz, CDCl3): δ 96.4, 83.2, 69.6, 55.2, 25.0, 24.3, 8.1

108

7.199 4.543 3.442 3.425 3.408 3.290 3.283 1.663 1.644 1.625 1.608 1.223 1.173 1.123 0.775 0.756 0.737

O B OMOM O 2.20 12.14

3.44 3.17

2.00 2.02 2.08

10 8 6 4 2 0PPM

8.156 7.965 96.754 96.587 83.347 77.699 77.379 77.059 69.803 55.412 25.153 24.947 24.505

O B OMOM O 2.20

180 160 140 120 100 80 60 40 20 0 PPM

109

Diethyl-2-[3-(methoxymethoxy)propyl]malonate (2.36)

To a solution of NaH (60% dispersion in mineral oil, 2.0 g, 50 mmol) in THF (50 mL)

was added diethyl malonate (10 mL, 62 mmol) at 0 ºC over 15 min. The mixture was

stirred at 0 ºC in 10 min, and rt 20 min, and then 3-iodo-1-methoxymethoxypropane

(2.22) (9.2 g, 40 mmol) was added. The reaction was refluxed for 1h, partitioned between

water (100 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl

acetate (3 x 10 mL). The combined organics were washed with water (50 mL), brine (30

mL), dried over MgSO4, and concentrated in vacuo to give a pale yellow liquid. The

excess diethyl malonate was recycled with fractional distillation at 60 ºC (3 mm Hg).

Flash column chromatography (hexane / ethyl acetate 4:1) gave 2.36 (7.6 g, 81%) as a clear liquid.

Rf = 0.42 (hexane / ethyl acetate 4:1)

IR: 2981, 2939, 2885, 1729, 1540, 1465, 1369, 1224, 1151, 919, 858 cm-1

1 HNMR: (400 MHz, CDCl3): δ 4.6 (s, 2 H), 4.2 (q, J = 6.8 Hz, 4H), 3.5 (t, J = 6.3 Hz,

2H), 3.35 (t, J = 6.3 Hz, 1H), 3.3 (s, 3H), 2.0-1.95 (m, 2H), 1.66-1.59 (m, 2H), 1.25 (t, J

= 6.8Hz, 6H);

13 C NMR (100 MHz, CDCl3): δ 169.7, 96.7, 67.3, 61.7, 55.5, 52.0, 27.7, 26.0, 14.4;

+ + Exact mass: [M-H] calcd. for [C12H23O6 ] 263.1488, found 263.1489

110

7.244 4.586 4.188 4.185 4.170 4.167 4.152 3.536 3.520 3.504 3.346 3.333 2.151 1.981 1.961 1.264 1.246 1.228

6.35 COOEt MOMO COOEt 2.36 4.03 3.97

2.28 2.00 2.04 2.00

10 8 6 4 2 0PPM

96.605 77.565 77.451 77.245 76.932 67.207 61.574 55.415 51.940 27.633 25.857 14.302 169.631

COOEt MOMO COOEt 2.36

180 160 140 120 100 80 60 40 20 0 PPM

111

Ethyl -5-(methoxymethoxy)-2-methylenepentanoate (2.37)

To a solution of diethyl-3-methoxymethoxypropyl malonate (2.36) (7.0 g, 26.7 mmol) in

absolute ethanol (5.0 mL) was added slowly over 2 h a solution of KOH (1.5 g, 26.7 mmol) in absolute ethanol (30 mL), and stirred 30 h at rt. The mixture was heated to 50

°C and filtered to give a clear solution, concentrated in vacuo and diluted with water (100 mL). The organic layer was extracted with ether (3 x 15 mL). The ethereal was saved to recycle diethyl-3-methoxymethoxypropyl malonate. The aqueous phase was acidified with 5% HCl to pH = 5, and extracted with ethyl acetate (3 x 20 mL). Combined organic layers were washed with water (3 x 50 mL), brine (30 mL), dried over with MgSO4, and concentrated in vacuo to give crude ethylhydrogen-3-methoxymethoxypropyl malonate

(5.2 g, 83%).

The crude ethyl hydrogen-3-methoxymethoxypropyl malonate (5.2 g, 22 mmol) was dissolved in ethyl acetate (50 mL), cooled at 0 ºC, added N, N-diethyl amine (2.65 mL,

25.4 mmol). The mixture was allowed to gradually warm to rt., then added in a portion of paraformaldehyde (1.0 g, 33 mmol), refluxed at 90 ºC for 2 h. The mixture was cooled down to rt. and acidified with 5% HCl until pH = 5, extracted with ethyl acetate (3 x 10 mL). The organics were washed with water (2 x 50 mL), brine (2 x 20 mL), dried over

MgSO4, and concentrated in vacuo. Flash column chromatography gave 2.37 (3.6 g,

81%) as a colorless liquid.

Rf = 0.64 (hexane / ethyl acetate 5:1)

112

IR: 2981, 2933, 2881, 1720, 1631, 1446, 1301, 1197, 1039, 919 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 6.1 (d, J = 1.7 Hz, 1H), 5.5 (d, J = 1.7 Hz, 1H), 4.6 (s,

2H), 4.2 (q, J = 7.2 Hz, 2H), 3.5 (t, J = 6.6 Hz, 2H), 3.3 (s, 3H), 2.4 (t, J = 7.2 Hz, 2H),

1.7 (m, 2H), 1.3 (t, J = 7.2 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 167.5, 140.7, 125.1, 96.7, 67.4, 60.9, 55.5, 28.9, 28.8,

14.5;

+ + Exact mass: [M-H] , calcd for [C10H19O4] 203.1276, found 203.1278

113

7.258 6.157 6.156 6.154 5.548 5.544 4.663 4.612 4.228 4.210 4.192 4.174 3.556 3.540 3.523 3.356 2.394 2.392 2.374 2.373 1.792 1.776 1.772 1.770 1.754 1.312 1.295 1.277

MOMO COOEt 2.37

10 8 6 4 2 0 PPM

96.658 77.565 77.245 76.932 67.260 60.842 55.392 28.852 28.685 14.424 167.383 140.569 124.951

MOMO COOEt 2.37

180 160 140 120 100 80 60 40 20 0 PPM

114

5-(Methoxymethoxy)-2-methylenepentan-1-ol (2.19)

To a solution of ethyl-2-methylene-5-methoxymethoxypentanoic ester (2.37) (4 g, 20

mmol) in THF (50 mL) was added slowly DIBAL-H (1M in hexane, 40 mL, 40 mmol) in

30 min at - 40 ºC. After stirring at – 40 ºC for 1 h, the mixture was allowed to gradually

warm to 0 ºC, dropped slowly dry MeOH (10 mL), and added 37.5% potassium sodium

tartrate solution (20 mL) to give a biphasic solution, and then stirred at rt overnight. The

aqueous layer was extracted with ether (3 x 20 mL). The combined organics were washed

with water (3 x 50 mL), brine (2 x 30 mL), dried over with MgSO4, and concentrated in

vacuo. Kugelrohr distillation (120 ºC, 0.3 mm Hg) gave alcohol 2.19 (2.7 g, 85%) as a

colorless liquid.

Rf = 0.62 (hexane / ethyl acetate 1:1)

IR: 3415 (broad), 2933, 2879, 1652, 1558, 1452, 1386, 1213, 1147, 1039, 917, 790 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 5.03-5.02 (m, 1H), 4.88 -4.87 (m, 1H), 4.6 (s, 2H), 4.06

(d, J = 4.9 Hz, 2H), 3.5 (t, J = 6.4 Hz, 2H), 3.3 (s, 3H), 2.1 (t, J = 7.8 Hz, 2H), 1.79-1.72

13 (m, 2H); C NMR (100 MHz, CDCl3): δ 148.7, 110.0, 96.7, 67.7, 66.2, 55.5, 29.8, 28.1;

+ + Exact mass (FAB) MH calcd for [C8H17O3] 161.1171, found 161.1172

115

4.982 4.980 4.979 4.977 4.975 4.832 4.829 4.826 4.823 4.551 4.021 4.009 3.498 3.482 3.466 3.294 2.110 2.091 2.071 1.816 1.724 1.721 1.708 1.704 1.702 1.688 1.686 1.183

3.35

2.86 MOMO OH

2.19 2.05 1.98 1.98 1.96

1.00 1.00

10 8 6 4 2 0PPM

96.635 77.572 77.260 76.940 67.557 66.071 55.385 29.904 29.737 28.037 148.602 109.867

MOMO OH

2.19

180 160 140 120 100 80 60 40 20 0PPM

116

4-(1,3-Dioxolan-2-yl)-2-methylenebutan-1-ol (2.43)

Following the procedure of 2.19 (p.115), using ethyl-2-methylene-5-methoxymethoxypentanoic ester (2.42) (6.0 g, 30 mmol) in THF (80 mL), and DIBAL-H (1M in hexane,

66.0 mL, 66.0 mmol), Kugelrohr distillation (110 ºC, 0.3 mm Hg) gave alcohol 2.43 (4.0 g, 85%) as a colorless liquid.

1 H NMR (400 MHz, CDCl3): δ 5.0 (dd, J = 0.7, 1.4 Hz, 1H), 4.88 (d, J = 1.4 Hz, 1H),

4.87 (t, J = 4.6 Hz, 1H), 4.0 (s, 2H), 3.97-3.91 (m, 2H), 3.88-3.82 (m, 2H), 2.1 (t, J = 8.0

Hz, 2H), 1.85-1.80 (m, 2H).

7.253 5.031 5.029 5.027 5.026 5.024 4.890 4.886 4.883 4.879 4.868 4.068 3.974 3.961 3.958 3.956 3.952 3.948 3.940 3.914 3.884 3.857 3.850 3.845 3.841 3.838 3.836 3.823 3.706 2.202 2.183 2.162 1.857 1.845 1.841 1.836 1.833 1.830 1.825 1.821 1.817 1.804

3.52

HO O

2.20 2.17 O 2.12 2.43 2.03 2.00

1.05

10 8 6 4 2 0 PPM

117

[5-(Methoxymethoxy)-2-methylenepentanoxy]diphenylsilane (2.46)

To a solution of chlorodiphenylsilane (2.45) (1.27 mL, 1.4 g, 6.5 mmol) in ether (100

mL) was added a mixture of 5-methoxymethoxy-2-methylenepentanol (2.19) (1.0 g, 6.5

mmol) and triethyl amine (0.9 mL, 6.5 mmol) in ether (10 mL) in 15 min via a cannula at

rt and stirred at the same temperature overnight. After filtration, the mother liquid was

concentrated in vacuo, and distilled (200ºC, 0.3 mm Hg) to give 2.46 (1.8 g, 81%) as a

colorless liquid.

IR: 3070, 2931, 2881, 2125, 1652, 1589, 1429, 1147, 1124, 917, 734 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 7.6-7.3 (m, 10H), 5.4(s, 1H), 5.1 (s, 1H), 4.9 (t, J = 1.2

Hz, 1H), 4.6 (s, 2H), 4.2 (s, 2H), 3.5(t, J = 6.6 Hz, 2H), 3.3 (s, 3H), 2.1 (t, J = 7.7 Hz,

2H), 1.7 (m, 2H);

13 C NMR (100 MHz, CDCl3): δ 147.2, 135.0, 134.7, 130.8, 128.3, 110.4, 96.8, 67.7,

67.6, 55.5, 29.6, 28.1;

+ + Exact mass: [M-H] calcd. for [C20H27O3Si] 343.1722, found 343.1724

118

7.674 7.670 7.667 7.657 7.654 7.651 7.647 7.462 7.449 7.446 7.428 7.411 7.409 7.394 5.466 5.463 5.130 4.913 4.910 4.614 4.612 4.248 3.537 3.520 3.504 3.359 3.357 2.142 1.741

Ph Ph Si H O OMOM

2.46 12.03

3.00 1.99 2.01 1.97 2.00 2.02

0.94 1.03 1.06

10 8 6 4 2 0PPM

96.635 77.573 77.260 76.940 67.611 67.519 55.339 29.455 27.984 147.070 134.913 134.540 133.960 130.637 130.447 128.251 128.175 110.248

Ph Ph Si H O OMOM

2.46

160 140 120 100 80 60 40 20 0 PPM

119

[4-(1,3-Dioxolan-2-yl)-2-methylenebutanoxy]diphenylsilane (2.47)

Following the procedure of silyl ether 2.46 (p. 118), using chlorodiphenylsilane (2.2 g, 10.2

mmol) in ether (200 mL), 4-(1,3-dioxolan-2-yl)-2-methylenebutan-1-ol (2.43) (1.0 g,

10.2 mmol) and triethylamine (1.6 mL, 11.3 mmol) in ether (30 mL), Kugelrohr

distillation (210 ºC, 0.4 mm Hg) gave compound 2.47 (2.3 g, 68%) as a colorless oil.

IR: 3070, 1952, 2879, 2125, 1589, 1429, 1122, 1056, 734, 689 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.6-7.3 (m, 10H), 5.4 (d, J = 1.0 Hz, 1H), 5.1 (d, J = 0.8

Hz, 1H), 4.9 (s, 1H), 4.8 (t, J = 4.7 Hz, 1H), 4.2 (s, 2H), 3.97-3.91 (m, 2H), 3.88-3.82 (m,

2H), 2.1 (t, J = 8.6 Hz, 2H), 1.84-1.79 (m, 2H);

13 C NMR (100 MHz, CDCl3): δ 147, 135, 134.7, 130.7, 128, 110, 104, 67, 65, 32, 27;

+ + Exact mass: [M-H] calcd. for [C20H25O3Si] 341.1567, found 341.1568

120

7.676 7.671 7.668 7.667 7.656 7.654 7.652 7.588 7.586 7.569 7.462 7.447 7.443 7.440 7.429 7.411 7.392 7.378 7.361 5.466 5.464 5.462 5.132 5.130 4.919 4.871 4.250 3.977 3.960 3.955 3.950 3.943 3.863 3.855 3.849 3.846 3.828 2.207 2.188 2.167 1.833 1.823 1.812 1.807

Ph Ph Si H O O

O 12.56 2.47

4.09

2.01 2.00 2.00 2.04 0.93 1.01

10 8 6 4 2 0 PPM

77.729 77.404 77.091 67.775 65.257 32.375 27.294 147.076 135.066 134.691 134.089 130.772 130.592 128.397 128.325 110.220 104.477

Ph Ph Si H O O O 2.47

160 140 120 100 80 60 40 20 PPM

121

4-[3-(Methoxymethoxy)propyl]-2,2-diphenyl-2-silafuran (2.48, racemic)

Non-asymmetric hydrosilylation

To a stirred solution of Wilkinson’s catalyst (27 mg, 0.03 mmol) in DCM (5 mL) was added silyl ether 2.46 (1.0 g, 3 mmol). The reaction was monitored by 1H NMR. The

mixture was concentrated in vacuo and distilled at 230 ºC (0.3 mm Hg) to give silafuran

(±)-2.48 (0.89 g, 87%) as colorless liquid.

4-[3-(Methoxymethoxy)propyl]-2,2-diphenyl-2-silafuran (2.48)

Asymmetric hydrosilylation:

To a stirred solution of the ferrotane catalyst 1.77 (6.0 mg, 8.2 µmol) and triethylammonium chloride (2.2 mg, 16.4 µmol) in DCM (3 mL) at rt. was added alcohol

133 (0.28 g, 0.8 mmol). Progress of the reaction was monitored with 1H NMR. The mixture was concentrated and distilled at 230 ºC (0.3 mm Hg) yielding silafuran (S)-2.48,

(0.21 g, 79%) as a colorless liquid.

122

IR: 3068, 2931, 2879, 1589, 1429, 1145, 1118, 1022, 917, 700 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 7.6-7.3 (m, 10H), 4.6 (s, 2H), 4.3 (dd, J = 6.4, 9.1 Hz,

1H), 3.6 (t, J = 9.5 Hz, 1H), 3.5(t, J = 6.4 Hz, 2H), 3.3 (s, 3H), 2.3-2.2 (m, 1H), 1.8-1.5

(m, 4H), 1.5 (dd, J = 6.3, 15.0 Hz, 1H), 0.9 (dd, J = 6.3, 15.0 Hz, 1H);

13 C NMR (100 MHz, CDCl3): δ 134.8, 134.7, 130.5, 128.3, 96.7, 73.8, 68.1, 55.5, 39.8,

31.5, 28.5, 17.5;

+ + Exact mass: [M-H] calcd. for [C20H27O3Si] 343.1724, found 343.1730

123

7.625 7.624 7.609 7.608 7.605 7.590 7.586 7.439 7.423 7.421 7.420 7.404 7.387 7.369 4.615 3.603 3.530 3.514 3.353 3.330

Ph Ph Si O OMOM (S)-2.48

13.10

6.39

3.45 3.77

2.22

0.97 1.00 1.14

10 8 6 4 2 0PPM

96.658 77.572 77.260 76.940 73.678 67.984 55.377 39.676 31.398 28.388 17.435 134.753 134.677 130.424 128.190 128.091

Ph Ph Si O OMOM (S)-2.48

180 160 140 120 100 80 60 40 20 PPM

124

(±)-4-[2-(1,3-Dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran (2.49)

Non-asymmetric hydrosilylation

Following the procedure of compound 2.48 (p. 122), using Wilkinson's catalyst (50 mg,

54 µmol) in dichloromethane (5 mL) and alcohol 134 (2.0 g, 5.9 mmol), Kugelrohr distillation (220 ºC, 0.3 mm Hg) gave 2.49 (1.8 g, 90%) as a colorless liquid.

4-[2-(1,3-Dioxolan-2-yl)ethyl]-2,2-diphenyl-2-silafuran (2.49)

H3CH2C CH2CH3 P Ph Ph 1.77 (1 mol%) Rh Fe Ph Ph Si O BF4 Si O P H O O O DCM, rt, 91% H CH C 3 2 CH CH O 2 3 2.47 2.49 1.77

Asymmetric hydrosilylation

Following the procedure of compound 2.48 (p. 122), using ferrotane catalyst (8 mg, 11

µmol) and triethylamonium chloride (2.8 mg, 23 µmol) in DCM (6 mL), and silyl ether

134 (0.38 g, 1.1 mmol), Kugelrohr distillation (230 ºC, 0.3 mmHg) gave a compound

2.49 (0.3 g, 80%) as a colorless liquid.

IR: 3061, 2948, 2879, 1589, 1558, 1429, 1116, 1043, 1043, 734, 700 cm-1;

125

1 H NMR (400 MHz, CDCl3): δ 7.62-7.36 (m, 10H), 4.8 (t, J = 4.8 Hz, 1H), 4.29 (dd, J =

6.4, 9.2 Hz, 1H), 3.98-3.92 (m, 2H), 3.89-3.83 (m, 2H), 3.6 (t, J = 10.1Hz, 1H), 2.36-2.24

(m, 1H), 1.82-1.79 (m, 1H), 1.76-1.70 (m, 1H), 1.66-1.60 (m, 1H), 1.5 (dd, J = 6.4, 14.8

Hz, 1H), 1.49-1.45 (m, 1H), 0.8 (dd, J = 10.4, 14.8 Hz, 1H);

13 C NMR (100 MHz, CDCl3): δ 136, 135.6, 129.8, 128.3, 104.9, 67.1, 65.1, 36.8, 30.9,

28.2, 17.4.

126

7.629 7.626 7.622 7.613 7.610 7.606 7.597 7.595 7.590 7.444 7.438 7.435 7.430 7.428 7.426 7.424 7.422 7.409 7.391 7.374 7.369 7.349 7.261 4.877 4.866 4.853 4.299 4.292 3.984 3.971 3.968 3.966 3.962 3.957 3.950 3.869 3.861 3.856 3.852 3.848 3.835 3.629 3.606 3.580 1.704 1.526 1.506 1.492 1.489 0.914 0.885 0.877 0.849

Ph Ph Si O O O

11.98 2.49

5.84

4.17

1.38 1.00 0.92 0.99 0.94 0.80

10 8 6 4 2 0 PPM

77.712 77.390 77.067 73.736 65.256 39.776 32.587 28.977 17.494 134.874 134.801 134.669 130.550 128.308 104.724

Ph Ph Si O O O

2.49

160 140 120 100 80 60 40 20 0 PPM

127

(+)-4-(1,3-Dioxolan-2-yl)-2-[(triphenylsilyl)methyl]butan-1-ol (2.51)

To a solution of silafuran 2.49 (0.1 g, 0.3 mmol) in ether (5 mL) was added 3M ethereal

phenyl magnesium bromide solution (0.3 mL, 0.9 mmol). The mixture was stirred at rt

for 1 h, and then quenched with saturated ammonium chloride solution (5 mL). The

aqueous layer was extracted with ether (3 x 5 mL). Combined ether layers were washed

with brine (2 x 5 mL), dried over with Na2SO4, concentrated in vacuo. Column

chromatography gave compound (±)-2.51 (120 mg, 78%) as a colorless oil.

Rf = 0.72 (hexane / ethyl acetate 2:1)

20 [α]D = + 4.38 (c 1.095, CHCl3)

IR: 3426 (br), 3068, 2921, 2879, 1587, 1473, 1427, 1108, 727, 701 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.5-7.3 (m, 15H), 4.6 (t, J = 5.2 Hz, 1H), 3.88-3.85 (m,

2H), 3.81-3.75 (m, 2H), 3.4 (t, J = 6.2 Hz, 2H), 1.8 (s, J = 5.8 Hz, 1H), 1.61-1.51 (m,

4H), 1.51-1.45 (m, 1H), 1.45-134 (m, 1H);

13 C NMR (100 MHz, CDCl3): δ 136.0, 135.6, 129.8, 128.3, 104.9, 67.1, 65.1, 36.8, 30.8,

28.2;

+ + Exact mass: [M-Na] calcd. for [C26H30NaO3Si] 441.1856, found 441.1854.

128

7.577 7.572 7.568 7.564 7.558 7.553 7.549 7.424 7.420 7.415 7.406 7.398 7.392 7.388 7.383 7.382 7.378 7.377 7.374 7.363 7.359 7.346 7.343 7.338 7.260 4.670 4.660 4.648 3.880 3.875 3.872 3.866 3.861 3.858 3.793 3.785 3.781 3.775 3.771 3.433 3.420 3.405 1.608 1.602 1.596 1.591 1.584 1.578 1.566 1.565 1.511 1.493 1.473 1.455 1.449 1.432 1.402 1.386 1.262 0.079

Ph Ph Si 16.11 Ph O O HO

2.51 8.81

4.21

1.99 1.00 1.08 0.89

10 8 6 4 2 0 PPM

77.692 77.382 77.064 67.148 65.175 36.814 30.889 28.194 15.594 136.005 135.636 129.816 128.282 104.957

Ph Ph Si Ph O O HO 2.51

160 140 120 100 80 60 40 20 0 PPM

129

Enatiomer analysis with HPLC:

HPLC samples of (±)-2.51 and (+)-2.51 (5 mg) were prepared in hexane/isopropanol

(90/10, 0.5 mL) (note: if it can be visualized by UV lamp on silica gel TLC, it is ready for

HPLC analysis). These samples (20 µL) were added into Perkin-Elmer Series 200 system that was calibrated until getting straight baseline with elution of hexane/ isopropanol

(90/10). UV-vis detector was set in range of 254-380 nm in 20 min of experiment. Flow rate of elution was 1mL/min.

130

Ph Ph Si Ph

HO O 2.51 O

131

Ph Ph Si Ph O HO 2.51 O

132

(+)-5-(Methoxymethoxy)-2-[(triphenylsilyl)methyl]pentan-1-ol ((+)-2.50)

Following the procedure for synthesis of compound (±)-2.51 (p.128), using

compound 2.48 (0.2g, 0.58 mmol) in ether (7 mL) and 3M phenylmagnesium bromide

(0.56 mL, 1.74 mmol) gave compound 2.50 (198 mg, 82%).

Rf = 0.65 (hexane / ethyl acetate 1:1)

20 [α]D = +3.08 (c 0.665, CHCl3);

IR: 3450 (br), 3068, 2927, 2877, 1587, 1484, 1427, 1147, 1112, 1037, 917, 701cm-1;

1 HNMR: (400 MHz, CDCl3): δ 7.25-7.35 (m, 15H), 4.5 (s, 2H), 3.44 (d, J = 5.3 Hz, 2H),

3.32 (t, J = 6.6 Hz, 2H), 3.30 (s, 3H), 1.92-1.83 (m, 1H), 1.6-1.3 (m, 6H);

13 C NMR (100 MHz, CDCl3): δ 136.0, 135.7, 129.8, 128.3, 96.7, 68.3, 67.3, 55.4, 36.9,

30.8, 27.0, 15.6;

+ + Exact mass: [M-Na] calcd. for [C26H32O3SiNa] 443.2013, found 443.2018.

133

7.579 7.575 7.565 7.560 7.556 7.405 7.393 7.388 7.384 7.377 7.363 7.359 7.343 7.253 4.526 3.441 3.427 3.316 3.299 3.292 1.392

Ph Ph Si Ph

HO OMOM 2.50 14.67

8.13

4.91

1.95 2.07 1.00

10 8 6 4 2 0PPM

96.551 77.572 77.260 76.940 68.220 67.207 36.795 30.659 26.878 15.499 135.866 135.546 129.700 128.152

Ph Ph Si Ph

HO OMOM 2.50

180 160 140 120 100 80 60 40 20 PPM

134

Enatiomer analysis with HPLC:

Following the analysis protocol of (±)-2.51 and 2.51 (p.130), using compounds (±)-2.50 and 2.50 confirmed enantiomeric excess 83%.

Ph Ph Si Ph

HO OMOM 2.50

135

Ph Ph Si Ph

HO OM OM 2.50

136

(-)-(R)-((S/R)-5-(Methoxymethoxy)-2-[(triphenylsilyl)methyl)pentyl]-3,3,3-trifluoro-

2-methoxy-2-phenylpropanoate (2.59)

To a solution of 2.50 (50 mg, 0.12 mmol) in dry dichloromethane (3 mL) was added dry

pyridine (30.0 µL, 0.37 mmol) and then (R)-(-)-α-methoxy-α-(trifluoromethyl)phenyl

acetyl chloride ((R)-MTPACl) (33.6 µL, 0.18 mmol). The solution was stirred at room

temperature overnight, and then diluted with DCM (5 mL). The aqueous phase was

extracted with DCM (3 x 3 mL). Combined organic layers were washed with 5% HCl (2

x 5 mL), brine (2 x 5 mL), dried over with Na2SO4, concentrated in vacuo and purified

with prep-TLC to give 2.59 (69 mg, 87%) as a colorless oil.

Rf = 0.4 (hexane / ethyl acetate 4:1)

20 [α]D = -1.403 (c 0.620, CHCl3)

IR: 3068, 2929, 2823, 1746, 1731, 1588, 1427, 1258, 1107, 1027, 699 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 7.5-7.3 (m, 20H), 4.5 (s, 2H), 4.10-4.08 (dd, J = 2.8 Hz, J

= 5.5 Hz), 3.5 (s, 3H), 3.3 (s, 3H), 3.24-3.21 (t, J = 6.5 Hz, 2H), 2.1-2.0 (m, 1H), 1.5-1.3

(m, 6H);

13 C NMR (100 MHz, CDCl3): δ 166.8, 135.9, 135, 132.7, 130, 128.7, 128.3, 128, 127,

125, 96.6, 84.7 (q, J = 27.3 Hz), 70, 67.8, 55.7, 55.3, 33.8, 30.8, 30, 26.9, 14.5;

+ + Exact mass: [M-Na] calcd. for [C36H39F3O5SiNa] 659.2411, found 659.2403

137

7.532 7.528 7.525 7.517 7.512 7.508 7.417 7.401 7.398 7.394 7.387 7.378 7.373 7.370 7.359 7.355 7.338 7.260 4.490 3.504 3.501 3.267 3.230 1.273

O O Ph Ph Si O Ph Ph OMe 20.52 O CF3 2.59

7.86

5.02 3.09 2.00 2.05 1.17 0.31

10 8 6 4 2 0PPM

96.625 77.702 77.586 77.388 77.072 70.431 67.888 55.750 55.370 33.817 30.802 30.061 26.905 15.483 166.849 135.932 135.099 132.748 129.966 129.920 128.759 128.354 127.680 125.168 85.108 84.833 84.559 O O Ph Ph Si O Ph Ph OMe

O CF3 2.59 85.4 85.2 85.0 84.8 84.6 PPM

160 140 120 100 80 60 40 20 PPM

138

Compound 2.60 (mixture of two diastereomers)

Following the procedure for synthesis of 2.59 (p. 137), using (±)-2.50 (50 mg, 0.12 mmol) in dry dichloromethane (3 mL), dry pyridine (30.0 µL, 0.37 mmol), and (R)-(-)-

MTPACl (33.6 µL, 0.18 mmol) gave 2.60 (69 mg, 87%) as a mixture of diastereomers.

Rf = 0.4 (hexane / ethyl acetate 4:1)

IR: 3068, 2929, 2823, 1746, 1731, 1588, 1427, 1258, 1107, 1027, 699 cm-1;

1 HNMR: (400 MHz, CDCl3): δ 7.5-7.3 (m, 20H), 4.48 (s, 2H), 4.47 (s, 2H), 4.2- 4.1 (dd,

J = 11.0 Hz, 5.2 Hz, 1H), 4.10-4.08 (dd, J = 5.3, 2.7 Hz, 2H), 4.03-3.99 (dd, J = 11.0, 5.2

Hz, 1H ), 3.5 (s, 3H), 3.49 (s, 3H) 3.2 (s, 3H), 3.25 (s, 6H), 3.24-3.19 (ddd, J = 6.5, 4.4,

4H), 2.08-2.01 (m, 2H), 1.5-1.24 (m, 12H);

13 C NMR (100 MHz, CDCl3): δ 166.8, 135.9, 135, 132.7, 130, 128.7, 128.3, 128, 127,

125, 96.6, 89.3 (q, J = 27.3 Hz), 70, 67.8, 55.7, 55.3, 33.8, 30.8, 30, 26.9, 14.5

139

7.524 7.520 7.515 7.504 7.500 7.495 7.474 7.428 7.409 7.403 7.395 7.392 7.388 7.379 7.366 7.347 7.330 7.327 7.255 4.483 4.478 3.506 3.504 3.497 3.494 3.258 3.223 3.213

20.39

O O Ph Ph Si O Ph Ph OMe

O CF3

2.60

6.72

4.97

2.98 2.00 0.99 1.09 0.57 0.53 0.26

10 8 6 4 2 0PPM

96.269 96.255 89.302 77.273 77.019 76.912 76.759 76.663 70.071 67.525 55.428 55.400 55.023 33.556 33.461 32.420 30.443 30.337 29.712 26.604 26.552 15.224 15.127 168.653 166.494 135.567 134.734 132.375 129.609 129.552 128.400 128.385 127.982 127.327 123.906

O O 85.108 84.788 84.651 Ph Ph Si O Ph Ph OMe

O CF3

2.60

85.6 85.4 85.2 85.0 84.8 84.6 84.4 PPM

160 140 120 100 80 60 40 20 PPM

140

Compound 146 (mixture of two diastereomers)

Cl Ph Ph Ph OMe Si Ph O CF3 Ph Ph Si O Ph Ph OMe

HO Pyr., DCM O CF3 2.14 77% 2.58

Following the procedure for synthesis of 2.59 (p. 137), using 2.14 (56 mg, 0.17 mmol,

50.5% ee) in dry dichloromethane (3 mL), dry pyridine (35.0 µL, 0.42 mmol), and

(R)-(-)-MTPACl (36.6 µL, 0.18 mmol) gave 2.58 (72 mg, 77%) as a mixture of diastereomers.

Rf = 0.6 (hexane / ethyl acetate 8:1)

1 HNMR: (500 MHz, CDCl3): δ 7.56 – 7.37 (m, 20H), 4.2-4.0 (m, 2H), 3.55 (s, 3H), 2.22-

2.19 (m, 1H), 1.57 (dd, J = 15.2, 5.3 Hz, 1H), 128 (dd, J = 15.2, 9.3 Hz, 1H), 0.87 (d, J =

6.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 166.5 135.6, 134.8, 132.4, 129.8, 128.4, 128.0, 127.3,

124.5, 122.2, 100.0, 84.7 (q, J = 27.3 Hz), 73.1, 55.4, 19.0, 19.9, 17.1

141

7.565 7.562 7.559 7.556 7.553 7.549 7.546 7.542 7.539 7.531 7.528 7.462 7.454 7.448 7.443 7.437 7.433 7.430 7.407 7.398 7.394 7.391 7.381 7.378 7.375 7.275 4.128 4.115 4.094 4.082 3.559 3.557 3.550 3.547 1.583 1.309 1.291 0.874 0.861 0.850

20.91

Ph Ph Si O Ph Ph OMe

O CF3 2.58

3.09 3.19 2.04 1.33 1.00 1.24

10 8 6 4 2 0 PPM

84.775 84.551 77.336 77.083 76.830 73.096 55.466 55.451 29.024 29.010 19.888 19.794 17.143 166.577 135.643 135.622 135.593 134.892 132.444 129.620 128.450 128.435 128.016 127.987 127.922 127.865 127.373 124.571 122.274 100.029 84.775 84.551

Ph Ph Si O Ph Ph OMe

O CF3 2.58

85.2 85.0 84.8 84.6 84.4 84.2 PPM

160 140 120 100 80 60 40 20 0PPM

142

Absolute configuration determination of primary alcohol using Mosher ester with

1H NMR

Eu(fod)3 solution

Eu(fod)3 (19 mg, 18.3 mmol) was dissolved in chloroform-d (0.3 mL) making 0.061 M

Eu(fod)3 solution.

Mosher ester solution:

The mixture of two diastereomers 2.60 (21 mg, 33.0 µmol) was dissolved in CDCl3 (0.5

1 mL). To the solution was added a Eu(fod)3 solution (0.5 mL). H NMR was then

recorded.

Compound 2.59 (24 mg, 37.7 µmol) was dissolved in CDCl3 (0.6 mL) making 0.055 M.

1 The solution was added by the Eu(fod)3 solution (650 µL) then recorded H NMR.

143

7.592 7.588 7.584 7.574 7.568 7.561 7.557 7.547 7.542 7.538 7.367 7.365 7.354 7.350 7.341 7.333 7.328 7.317 7.310 7.295 7.289 7.183 4.491 4.435 1.707 1.701 1.690 1.669 1.612 1.374 1.361 1.357 1.183

O O Ph Ph Si O Ph Ph OMe a O CF3 2.60

2.60:0.030M 22.69 19.31 Eu(fod)3: 0.0327M

5.32 2.91 1.92 2.00 2.08 1.63

10 8 6 4 2 0PPM

7.595 7.592 7.586 7.578 7.572 7.546 7.541 7.367 7.365 7.352 7.333 7.320 7.312 7.183 4.467 1.386 1.182 -0.001

O O Ph Ph Si O Ph Ph OMe a O CF3 2.59

2.59:0.030M 30.26

Eu(fod) 3:0.032M 20.55

5.57 3.00 2.21 1.99 2.05 1.31 0.19

10 8 6 4 2 0 PPM

144

7.588 7.584 7.580 7.570 7.564 7.557 7.554 7.544 7.539 7.534 7.366 7.363 7.354 7.349 7.344 7.338 7.332 7.316 7.312 7.309 7.183 4.447 4.393 1.350 1.348 1.183 -0.001

Mixed 2.59 (0.3mL)

with 2.60 (0.3mL)

26.32

20.76

5.73

3.00 2.23 2.08 2.07 1.41

10 8 6 4 2 0 PPM

145

6.5 Index of experimentals for chapter 3

H Ph Ph Ph N Si OH

O Ph (S,R)-1.63 (S,S)-1.63, p. 180

Ph2 Ph2 Si OH Si OTBS H Ph 3.8, p. 170 (±)-3.10, p. 150

H Ph Ph H Ph Ph N Si N Si OMOM S S O OMOM O Ph Ph (S,S,R)-3.16 (R,R,S)-3.16 (R,R,R)-3.16,p.172 (S,S,S)-3.16,p.175

146

3-(Fluorodiphenylsilyl)-2-methylpropan-1-ol ((±)-3.6)

To a solution of compound (±)-1.74 (5.0 g, 19.7 mmol) in 95% ethanol (30 mL) and DCM (10 mL) at 0 °C was added slowly 47% HF aqueous solution (1.7 mL, 98.5 mmol). The solution was stirred at 0 °C 5 h. The mixture was concentrated in vacuo by one third, and then diluted with ethyl acetate (50 mL). The mother liquid was washed with water several times until neutral condition, and then washed with brine (10 ml), dried over Na2SO4, concentrated in vacuo to yield crude (±)-3.6 (5.3 g, 99%).

147

3-(Fluorodiphenylsilyl)-2(S)-methylpropan-1-ol ((S)-3.6)

Following the procedure for synthesis of (±)-3.6 (p.147), using (S)-3.6 (10.0 g, 39.4

mmol), 95% ethanol (70 mL), and DCM (30 mL), and 47% HF (3.5 mL, 197 mmol) gave

crude (S)-3.6 (10.2 g, 98%).

IR: 3359, 3062, 2954, 2912, 2877, 1589, 1423, 1114, 701 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.63-7.25 (m, 10H), 3.4 (d, J = 6.4 Hz, 2H), 2.0-1.9 (m,

1H), 1.48 (br, 1H), 1.4 (ddd, J = 15.2, 9.6, 7.1 Hz, 1H), 0.98 (d, J = 6.6 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 134.3 (d, J = 7.3 Hz), 134.2, 134.1, 130.7 (d, J =

13.6Hz), 130.8, 128.3, 70.3, 31.7, 19.6, 18.7 (d, J = 14.0 Hz);

19 F NMR (282.2 MHz, CDCl3): δ -169.2

148

7.635 7.631 7.628 7.624 7.620 7.615 7.611 7.604 7.600 7.457 7.453 7.439 7.435 7.420 7.414 7.401 7.396 7.254 3.447 3.431 2.043 0.990 0.973

Ph 2 Si OH F

(S)-3.6

10.50

3.09 2.44 2.00

1.01 1.08

10 8 6 4 2 0PPM

77.520 77.267 77.014 70.297 31.746 19.647 18.903 18.795 134.302 134.288 134.244 134.230 134.121 133.789 130.900 130.820 130.734 128.379 128.365

Ph 2 Si OH F

(S)-3.6

180 160 140 120 100 80 60 40 20 PPM

149

tert-Butyldimethyl[2-methyl-3-(triphenylsilyl)propoxy]silane ((±)-3.10)

To a solution of (±)-2.14 (1.0 g, 3.0 mmol) and imidazole (61.2 mg, 9.0 mmol) in DMF

(5 mL) at room temperature was added a solution of TBSCl (50 mg, 3.3mmol) in DMF (2

mL). The solution was stirred at room temperature for 12h. The solution was diluted with water (20 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 10% HCl (3 x 5 mL) and water (10 x 10 mL), and brine (10 mL). The organic was dried over with Na2SO4, concentrated in vacuo. Flash column chromatography with hexane and ethyl acetate (4/1) gave compound 3.10 (1.1 g, 84%) as a colorless liquid.

Rf = 0.84 (hexane / ethyl acetate 4:1)

IR: 3062, 2954, 2912, 2877, 1589, 1423, 1114, 701 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.6-7.4 (m, 15H), 3.3-3.4 (m, 2H), 1.96-1.94 (m, 1H),

1.68 (dd, J = 14.6, 4.6 Hz, 1H), 1.1 (dd, J = 14.6, 8.8 Hz, 1H), 0.9 (s, 9H), 0.78 (d, J =

6.4, 3H), 0.0 (s, 6H);

13 C NMR (100 MHz, CDCl3): δ 135.9, 135.8, 129.5, 128.0, 70.7, 32.1, 26.1, 20.0, 18.6,

17.0, -5.2;

+ + Exact mass: [M-H] calcd. for [C28H39OSi2] 447.2534, found 447.2549

150

7.589 7.573 7.569 7.385 7.367 0.894 0.787 0.770 0.002 -0.000

Ph2 Si OT BS Ph (±)-3.10

15.08

9.52

6.05

3.37

2.03 1.00 1.05 1.14

10 8 6 4 2 0 PPM

-5.171 -5.202 77.520 77.200 76.887 70.714 32.154 26.163 20.004 16.994 135.897 129.487 127.993

Ph2 Si OT BS Ph (±)-3.10

140 120 100 80 60 40 20 0 PPM

151

[3-(Benzyloxy)-2-methylpropyl]fluorodiphenylsilane ((±)-3.12)

A solution of (±)-3.6 (0.8 g, 2.9 mmol), MgO (0.24 g, 6 mmol) and Dudley reagent 179

(2.0 g, 5.7 mmol) in PhCF3 (10 mL) was refluxed 24 h. The mixture was filtered through

a pad of Celite, and then concentrated in vacuo. Column chromatography gave compound

(±)-3.12 (0.2 g, 20%) as a colorless oil.

Rf = 0.84 (hexane / ethyl acetate 4:1)

IR: 3058, 2942, 2873, 1592, 1430, 1122, 1029, 705 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.6-7.3 (m, 15H), 4.4 (s. 2H), 3.3 (d, J = 6.4 Hz, 2H), 2.2-

2.1 (m, 1H), 1.5 (ddd, J = 15.1, 10.2, 5.4 Hz, 1H), 1.1 (ddd, J = 15.2, 8.6, 6.4 Hz, 1H) 1.0

(s, J = 6.7 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 138.9, 134.3 (d, J = 7.2 Hz), 134.0 (d, J = 15.2 Hz),

130.7, 128.5, 128.2, 127.8, 77.7, 73.0, 19.4, 20.1, 19.2 (d, J = 13.7 Hz);

19 F NMR (282.2 MHz, CDCl3): δ -169.0

+ + Exact Mass: [M-Na] calcd. for [C23H25FNaOSi] 387.1551, found 387.1547

152

7.667 7.663 7.647 7.644 7.641 7.625 7.621 7.477 7.471 7.458 7.456 7.454 7.434 7.432 7.430 7.414 7.357 7.355 7.352 7.338 7.319 7.313 7.302 4.431 3.307 3.291 1.035 1.019

16.45

Ph2 Si OBn F

(±)-3.12

3.07

2.00 2.01 1.01 1.19 1.03

10 8 6 4 2 0PPM

77.694 77.588 77.268 76.955 73.015 29.416 20.156 19.287 19.150 138.899 134.509 134.357 134.280 133.892 130.698 128.640 128.541 128.282 128.114 128.030 127.771 127.664

Ph2 Si OBn F

(±)-3.12

140 120 100 80 60 40 20 PPM

153

Fluoro[2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]diphenylsilane (3.5)

Ph 2 O Ph2 Si OH Si O O F F CuSO4 5H2O )-3.6 3.5

To compound (±)-3.6 (10 g, 36.5 mmol) and CuSO4•5H2O (1.8 g, 7.3 mmol) in a round

bottom flask was added 3,4-dihydro-2H-pyran (TDP, 30 mL). The solution was stirred at

room temperature for 2 h. The progress of the reaction was monitored by TLC. The

solution was filtered through a Celite pad, and then concentrated in vacuo. Column chromatography gave 3.5 (11.5 g, 88% yield from crude 3.6).

Rf = 0.67 (hexane / ethyl acetate 5:1)

IR: 3058, 2942, 2873, 1592, 1430, 1122, 1029, 705 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.6-7.4 (m, 10H), 4.5-4.48 (m, 1H), 3.82-3.80 (m, 1H),

3.56-3.52 (m, 1H), 3.47-3.43 (m, 1H), 3.20-3.15 (m, 1H), 2.1-2.0 (m, 1H), 1.83-1.87 (m,

1H), 1.68-1.63 (m, 1H), 1.58-1.44 (m, 5H), 1.1-1.0 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 134.3 (d, J = 5.7 Hz), 134.0 (d, J = 16.1 Hz), 130.7,

128.3, 99.0, 74.9, 62.4, 30.8, 29.4, 25.7, 20.1, 19.8, 19.0 (d, J = 13.8 Hz);

19 F NMR (282.2 MHz, CDCl3): δ -169.1

+ + Exact Mass: [M-H] calcd. for [C21H28FO2Si] 359.1837, found 359.1895

154

7.643 7.639 7.627 7.623 7.619 7.603 7.600 7.416 7.408 7.398 7.393 7.390 7.260 1.550 1.001 0.993 0.985 0.976

Ph 2 Si O O 10.25 F 3.5

5.69

3.00

1.01 1.00 1.01 1.02 0.99 1.03 1.01 1.07 1.08

8 7 6 5 4 3 2 1 0 PPM

99.112 99.036 77.984 77.580 77.466 77.260 76.947 74.928 74.798 62.466 62.290 30.888 30.834 29.416 29.333 25.727 20.102 19.820 19.691 19.317 19.180 19.058 18.921 134.501 134.372 134.319 134.044 133.884 130.721 128.289

Ph 2 Si O O F 3.5

160 140 120 100 80 60 40 20 0 PPM

155

(1,3-Dithian-2-yl)[2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl] diphenyl silane

(3.13)

To a solution of dithiane (2.0 g, 16.7 mmol) in THF (15 mL) at -78 °C was added slowly

1.6 M n-BuLi solution in hexane (11.5 mL, 18.4 mmol). The solution was stirred at -78

°C for 2h and then transferred through a cannula to a solution of compound 3.5 (0.55 g,

15.3 mmol) in THF (20 mL) at -78 °C in 10min. The mixture was stirred at -78 °C for 3

h, and room temperature 12 h, and then quenched with 30% ammonium chloride solution

(50 mL) at 0 °C, extracted with ethyl acetate (3 x 20 mL). The combined organic layers

were washed with water (3 x 30 mL) and brine (2 x 10 mL), dried over with Na2SO4, concentrated in vacuo. Column chromatography with eluent of hexane and ethyl acetate

(10/1, 5/1, and 2/1) gave compound 3.13 (4.7 g, 67%) as a pale yellow oil.

Rf = 0.3 (hexane / ethyl acetate 10:1); IR: 3054, 2946, 2900, 1735, 1503, 1423, 1373,

1238, 1110, 1037, 709 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.7-7.3 (m, 10H), 4.5-4.3 (m, 1H), 4.2 (s, 1H), 3.8-3.7 (m,

1H), 3.5-3.4 (m, 2H), 3.1-3.0 (m, 1H), 2.9-2.8 (m, 2H), 2.7-2.68 (m, 2H), 2.1-1.97 (m,

2H), 1.84-1.80 (m, 1H), 1.7-1.48 (m, 6H), 1.16-1.01(m, 1H), 0.93-0.84 (m, 1H), 0.86 (d,

J = 6.5 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 136.0 (134.6), 132.9, 130.1 (129.7), 127.9 (127.8), 98.9

(98.7), 74.9 (74.7), 62.2 (62.0), 33.2, 31.8, 30.8, 29.7, 26.2 (25.7), 20.5 (20.4), 19.67

(19.6), 16.0 (15.9), 14.3.

156

+ + Exact mass: [M-H] calcd. for [C25H35O2S2Si] 459.1842, found 459.1843

7.736 7.732 7.729 7.724 7.721 7.717 7.712 7.709 7.705 7.700 7.443 7.428 7.425 7.421 7.410 7.394 7.391 7.378 7.374 7.369 7.291 4.256 4.253 2.726 2.918 2.724 1.574 1.562 1.530 1.519 1.505 1.493 1.481 0.900 0.861 0.852 0.844 0.836

14.33

10.69 Ph 2 S Si OTHP S 3.13

5.73

3.36

2.74

2.05 2.04 1.56 1.32 1.38 1.37 1.24 1.00

10 8 6 4 2 0 PPM

98.899 98.807 98.739 77.572 77.260 76.940 74.950 74.699 62.222 62.084 33.281 33.212 31.817 30.803 29.691 29.668 26.200 25.704 20.567 20.468 20.346 19.683 19.599 16.040 15.910 14.325 136.056 134.715 132.931 132.794 130.111 129.722 127.924 127.824

Ph 2 S Si OTHP S 3.13

160 140 120 100 80 60 40 20 0 PPM

157

(2-Benzyl-1,3-dithian-2-yl)[2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]

diphenylsilane (3.4)

To a solution of compound 3.13 (3.0 g, 6.5 mmol) in THF (20 mL) at -78 °C was slowly

added 1.6 M in hexane of n-BuLi (4.5 mL, 7.2 mmol). The solution was stirred at -78 °C

for 2 h, and then a solution of BnBr (0.85 mL, 7.15 mmol) in THF (20 ml) was added.

The mixture was stirred at -78 °C for 3 h, then at rt. for 5 h. The solution was cooled

down to 0 °C, quenched with saturated NH4Cl (30 mL), diluted with water (100 mL), and then extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo. Column chromatography gave compound 3.4 (2.5 g,

72%).

Rf = 0.65 (hexane / ethyl acetate 5:1)

IR: 3054, 2927, 2858, 1592, 1461, 1253, 1099, 701 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.8-7.1 (m, 15H), 4.4-4.3 (m, 1H), 3.8-3.37 (m, 1H), 3.4-

3.3 (m, 3H), 3.0-2.9 (m, 1H), 2.4-2.2 (m, 4H), 1.9-1.4 (m, 9H), 1.13-1.04 (m, 1H), 0.9-

0.85 (m, 1H), 0.68-0.64 (m, 3H);

13 C NMR (125 MHz, CDCl3): δ 138.4, 137.3, 133.7, 131.8, 129.9, 127.9, 127.7, 126.9,

98.8, 75.1, 62.0, 47.2, 38.1, 32.3, 30.9, 29.9, 25.8, 23.7, 20.3, 19.6, 15.1;

+ + Exact mass: [M-H] calcd. for [C32H41O2S2Si] 549.2312, found 549.2306

158

7.875 7.871 7.868 7.864 7.860 7.857 7.855 7.851 7.844 7.841 7.837 7.436 7.420 7.417 7.392 7.388 7.377 7.373 7.369 7.357 7.352 7.348 7.334 7.329 7.314 7.262 7.209 7.205 7.199 7.187 3.402 3.386 1.492 0.980 0.676 0.663 0.659 0.646

Ph2 S Si OTHP S Ph 3.4

16.21

12.28

3.78 3.00 1.90 1.93 0.89 0.97 0.91 1.31 1.29

10 8 6 4 2 PPM

98.853 98.824 77.475 77.220 76.965 76.641 75.155 74.889 70.468 62.059 47.404 47.294 47.240 38.131 38.058 32.341 30.902 29.900 29.839 25.832 25.483 23.691 23.647 20.373 20.319 19.943 19.641 15.194 15.132 138.761 137.308 137.191 133.692 131.791 129.973 129.846 127.963 127.908 127.792 127.726 127.639 126.947 126.878

Ph2 S Si OTHP S Ph 3.4

160 140 120 100 80 60 40 20 0 PPM

159

1-{[2-Methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]diphenylsilyl}-2-phenyl

ethanone (3.3)

Dithiane 3.4 (1.0 g, 1.8 mmol) was dissolved in MeCN (30 mL) and saturated NaHCO3

solution (10 mL) then cooled to 4 °C, where upon iodine (0.9 g, 7.2 mmol) was added

portionwise over 5min. The reaction mixture was then allowed warm to rt. over 1 h

before quenching with a 1:1 solution of saturated NaHCO3 and Na2S2O3 (20 mL). The

solution was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were

washed with water (3 x 20 mL) and brine (2 x 10 mL), dried over with MgSO4, concentrated in vacuo. Column chromatography gave pure ketone 3.3 (165 mg, 20% yield).

Rf = 0.6 (hexane / ethyl acetate 5:1)

IR: 3058, 2950, 2927, 2861, 1708, 1596, 1458, 1427, 1257, 1087, 689 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.6-6.8 (m, 15H), 4.4-4.3 (m, 1H), 3.8 (s, 2H), 3.79-3.74

(m, 1H), 3.48-3.40 (m, 2H), 3.1-3.0 (m, 1H), 1.97-1.90 (m, 1H), 1.80-1.74 (m, 1H), 1.67-

1.41 (m, 5H), 1.1-1.0 (m, 1H), 0.8 (d, J = 6.5 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 158.2, 136.0, 135.7, 132.4, 130.4, 130.1, 128.6, 126.7,

122.8, 99.1, 75.0, 62.5, 56.1, 30.9, 29.8, 25.8, 20.5 (20.4) 19.9 (19.8), 16.5(16.4)

160

7.610 7.607 7.603 7.599 7.596 7.591 7.587 7.583 7.578 7.465 7.448 7.442 7.432 7.429 7.426 7.399 7.397 7.382 7.378 7.365 7.361 7.358 7.257 7.194 7.177 7.171 6.882 6.877 6.870 6.864 6.862 4.436 3.868 3.481 3.467 3.465 3.458 3.444 3.442 3.094 3.078 3.071 1.552 1.540 1.534 1.529 1.517 1.505 1.494 1.467 1.456 1.116 0.810 0.793 0.077

Ph2 O Si

OTHP Ph 3.3

7.12 7.28

4.58 3.27 3.36 2.02 2.00 2.28 2.32 1.03 1.23 1.04 1.35

10 8 6 4 2 0 PPM

Ph2 O Si

OTHP Ph 3.3

161

(2-Benzyl-1,3-dithian-2-yl)[3-(tert-butyldimethylsilyloxy)-2-methylpropyl]

diphenylsilane (3.14)

To a solution of benzyl dithiane 3.4 (1.0 g, 1.8 mmol) in MeOH (10 mL) was added

CuSO4.5H2O (0.45 g, 1.18 mmol). The mixture was stirred at rt for 24 h, diluted with

water (100 mL), and extracted with ethyl acetate (3 x 15 mL). The combined ethyl

acetate layers were washed with water (3 x 10 mL), washed with brine (1 mL), dried over

with MgSO4, and then concentrated in vacuo to give crude alcohol.

The crude alcohol was dried carefully in vacuo, dissolved in DMF (7 mL), added

imidazole (122 mg, 1.8 mmol) and TBSCl (0.32 g, 2.1 mmol). The solution was stirred at

rt for 12 h, diluted with water (15 mL), extracted with ethyl acetate (3 x 10 mL). The

combined organic layers were washed with 15% HCl (3 x 10 mL) and water (5 x 20 mL)

and brine (2 x 10 mL), dried over with Na2SO4, and then concentrated in vacuo. Column

chromatography gave dithiane 3.14 (0.7 g, 67%) as a pale yellow oil.

Rf = 0.55 (hexane / ethyl acetate 4:1)

IR: 3054, 2927, 2858, 1592, 1461, 1427, 1253, 1099, 702 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.8-7.1 (m, 15H), 3.3 (s, 2H), 3.24-3.19 (m, 2H), 2.4-2.2

(m, 4H), 1.8-1.7 (m, 3H), 1.6 (dd, J = 15.4, 4.3 Hz, 1H), 1.05 (dd, J = 15.3, 8.7 Hz, 1H),

0.8 (s, 9H), 0.6 (d, J = 6.4 Hz, 3H), 0.0 (s, 6H);

13 C NMR (100 MHz, CDCl3): δ 138.7, 137.2, 136.1, 133.6, 131.7, 129.9, 127.9, 126.9,

70.6, 47.3, 37.8, 32.2, 26.2, 25.4, 23.6, 19.7, 18.6, 14.5, -5.1;

+ + Exact mass: [M-Na] calcd. for [C33H46NaOS2Si2] 601.2421, found 601.2415

162

3.376 0.875 0.872 0.617 0.600 -0.017 -0.027 -0.029

17.60

Ph 2 S Si S OTBS Ph

3.14 10.16

6.51

3.82

3.03 2.99

2.00 2.09

1.00 1.14

10 8 6 4 2 0PPM

-5.111 77.572 77.260 76.940 70.614 47.351 32.054 26.230 25.484 25.461 23.601 19.790 14.470 138.724 137.238 133.640 132.992 131.735 129.882 127.946 127.710 127.672 126.895

Ph 2 S Si S OTBS Ph 3.14

160 140 120 100 80 60 40 20 0 PPM

163

1-{[3-(tert-Butyldimethylsilyloxy)-2-methylpropyl]diphenylsilyl}-2-phenylethanone

(3.15)

Following the procedure for synthesis of ketone 3.3 (p.160), using dithiane 3.14 (0.5 g,

0.86 mmol), MeCN (20 mL), saturated NaHCO3 solution (6 mL) and iodine (0.45 g, 3.6

mmol) gave ketone 3.15 (172 mg, 21%).

Rf = 0.5 (hexane / ethyl acetate 5:1)

IR: 3058, 3016, 2950, 2861, 1712, 1596, 1458, 1427, 1257, 1087, 702 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.6-6.8 (m, 15H), 3.8 (s, 2H), 3.2 (dd, J = 6.4, 2.6 Hz,

2H), 1.8-1.7 (m, 1H), 1.5 (dd, J = 15.0, 4.5 Hz, 1H), 0.98 (dd, J = 15.0, 9.5 Hz, 1H), 0.85

(s, 9H), 0.76 (d, J = 6.6 Hz, 3H), 0.0 (s, 6H);

13 C NMR (100 MHz, CDCl3): δ 135.9, 133.1, 132.4 (132.3), 130.3, 130.1, 128.5, 128.5,

126.8, 70.4, 56.0, 32.0, 26.2, 19.8, 18.6, 15.7, -5.1;

164

7.595 7.591 7.588 7.575 7.572 7.569 7.442 7.425 7.392 7.377 7.374 7.357 7.256 7.169 3.847 3.283 3.277 3.267 3.261 0.865 0.858 0.851 0.829 0.734 0.718 -0.034 -0.037

Ph2 O Si

OTBS Ph 3.15

19.59

11.06

7.08

3.34 1.99 2.26 1.17 1.32 1.03

10 8 6 4 2 0 PPM

-5.134 -5.165 77.580 77.260 76.940 70.408 56.063 32.000 26.200 19.775 18.586 15.674 135.904 133.084 132.383 132.291 130.332 130.142 128.549 128.411 127.863 126.834

Ph2 O Si

OTBS Ph 3.15

160 140 120 100 80 60 40 20 0 PPM

165

(±)-[3-(Methoxymethoxy)-2-methylpropyl]diphenylsilane ((±)-3.19)

Procedure 1:

To a solution (±)-1.74 (10 g, 39.3 mmol) in a mixture of DCM and 95% ethanol

(4/1, 150ml) at 0 ºC was added slowly 48% hydrofluoric acid (3.6 mL, 98.3 mmol). The

mixture was stirred for 5 h, concentrated in vacuo, partitioned between ethyl acetate (100

mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 30

mL). The combined organic layers were washed with water until neutral, brine (30 mL),

dried over with MgSO4 and concentrated in vacuo to give fluoro(3-hydroxy-2-

methylpropan-1-yl)diphenylsilane (10.5 g, 84%) as a colorless oil.

This liquid was dissolved with dimethoxymethane (20 mL), added p- toluenesulfonic acid monohydrate (0.73 g, 3.9 mmol) and lithium bromide (0.66 g, 7.7 mmol). The mixture was stirred for 1 h, diluted with ether (100 mL). The water layer was extracted with ether (3 x 20 mL). Combined organic layers were washed with 10%

NaHCO3 (3 x 10 mL), water (3 x 20 mL), dried over with magnesium sulfate,

concentrated in vacuo to give crude fluorosilane.

The fluorosilane above was dissolved in ether (120 mL), cooled down to 0 °C,

and then added lithium aluminum hydride (LAH) (730 mg, 19.1 mmol). The mixture was

refluxed for 2 h. To the resulting mixture was carefully added sequentially water (0.8

mL), 15% sodium hydroxide (0.8 mL) and water (2.3 mL). The solution was filtered

through Celite. The aqueous layer was extracted with ether (3 x 20 mL). The combined

organic layers were washed with water (3 x 30 mL), brine (3 x 10 mL), dried over with

166

magnesium sulfate, and then concentrated in vacuo. Flash column chromatography (9:1

hexane/ethyl acetate, Rf = 0.68) gave racemic of compound (±)-3.19 (6.5 g, 53% for 3

steps) as a colorless oil.

Procedure 2:

To a solution of alcohol (±)-3.8 (5.0 g, 19.5 mmol) in dimethoxymethane (10 mL) was

added TsOH•H2O (0.74 g, 3.4 mmol) and LiBr (0.33 g, 3.4 mmol). The solution was

stirred at rt for 30min, diluted with diethyl ether (50 mL). The aqueous layer was

extracted with ether (3 x 20 mL). The combined organic layers were washed with 10%

NaHCO3 (3 x 10 mL) and brine (20 mL), dried over with sodium sulfate, concentrated in vacuo. Column chromatography gave pure (±)-3.19 (5.5 g, 95%) as a colorless oil.

167

(S)-[3-(Methoxymethoxy)-2-methylpropyl]diphenylsilane ((S)-3.19)

Following the procedure 1 for synthesis of 3.19 (p.166), using silafuran (S)-1.74 (1.0 g,

3.9 mmol), 47% HF (0.36 mL, 9.3 mmol), dimethoxymethane (5 mL), TsOH•H2O (0.1 g,

0.5 mmol), LiBr (43 mg, 0.5 mmol), and LAH (0.14 g, 3.9 mmol) gave (S)-3.19 (0.62 g,

53%).

Rf = 0.6 (hexane / ethyl acetate 10:1)

20 [α]D = +3.8 (c 0.7, CHCl3);

IR: 3068.2, 2950, 2883, 2121, 1589, 1429, 1112, 1045, 700 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.64-7.39 (m, 10H), 5.04 (dd, J = 4.5, 3.5 Hz, 1H), 3.46

(s, 2H), 3.41 (dd, J = 6.1, 3.2 Hz, 2H), 3.38 (s, 3H), 2.12-2.00 (m, 1H), 1.45 (dt, J = 15.0,

5.0 Hz, 1H), 1.11 (ddd, J = 15.0, 8.9, 3.5 Hz, 1H), 1.08 (d, J = 7.7 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 135.52, 135.47, 129.9, 128.4, 96.9, 75.4, 55.5, 30.7,

20.2, 17.5;

+ + Exact mass: [M-Na] calcd. for [C18H24NaO2Si] 323.1438, found 323.1430

168

7.656 7.653 7.649 7.643 7.637 7.629 7.429 7.425 7.420 7.410 7.406 4.617 3.432 3.424 3.416 3.408 3.379 1.087 1.070

Ph 2 Si OM OM H

(S)-3.19

10.07

4.91 4.01

2.00

0.95 1.00 1.00

10 8 6 4 2 0PPM

96.666 77.580 77.260 76.947 75.210 55.301 30.514 19.980 17.290 135.332 135.286 135.081 134.822 129.745 128.206

Ph 2 Si OM OM H

(S)-3.19

160 140 120 100 80 60 40 20 PPM

169

3-(Diphenylsilyl)-2-methylpropan-1-ol ((±)-3.8)

Ph 2 OH Ph Si 2 H H Si OH AIBN, H 2.44 3.8 SH

C9H19 heptane, reflux 80%

To a solution of diphenylsilane (2.44) (10.0 g, 54.3 mmol) in heptane (150 mL) was

added β-methyl allylic alcohol (5.5 mL, 65.2 mmol), tert-dodecylmercaptan (1.2 mL, 5.4 mmol) and AIBN (0.44 g, 0.26 mmol). The resulting mixture was heated to 75 °C for 19 h, and then concentrated in vacuo. Flash column chromatography using a gradient eluent

(100:1 to 95:5 hexane and ethyl acetate) gave alcohol 3.8 (11.2 g, 85%) as a colorless oil.

Rf = 0.6 (hexane / ethyl acetate 6:1)

IR: 3334(br), 3068, 301, 2929, 2873, 2117, 1535, 1427, 1116, 700 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.6-7.3 (m, 10H), 5.0 (t, J = 4.5 Hz, 1H), 3.5 (ddd, J =

10.0, 6.1 Hz, 2H), 1.9-1.8 (m, 1H), 1.6 (br, 1H), 1.36 (dt, J = 14.6, 4.6 Hz, 1H), 1.05 (dd,

J = 10.0, 4.6 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 135.3, 135.2, 134.9, 134.7, 129.7, 128.2, 70.3, 32.7,

19.3, 16.8;

+ + Exact mass: [M-Na] calcd. for [C16H20NaOSi] 279.1176, found 279.1189

170

7.618 7.614 7.611 7.600 7.437 7.421 7.404 7.386 7.371 5.013 5.004 4.993 3.477 3.462 3.458 3.442 1.623 1.389 1.352 1.062 1.038 1.029 1.012 1.003

Ph2 Si OH H 10.71 3.8

4.16

2.00

0.95 0.98 0.99 1.04

10 8 6 4 2 PPM

70.309 32.732 19.363 16.787 135.271 135.226 129.776 129.761 128.228 128.213

Ph2 Si H OH 3.8

180 160 140 120 100 80 60 40 20 PPM

171

(R)-N-{[(3-(Methoxymethoxy)-2(R/S)-2-methylpropyl)diphenylsilyl]-2(R)-2-

phenylethyl}-2-methyl-2-propanesulfinamide ((R, R, S) and (R,R,R)-3.16)

Ph2 H Ph Ph Si OMOM 1. Li N Si OMOM H S 2. O (±)-3.19 N S Ph Ph O (R,R,R)-3.16 (R)-3.17 (R,R,S)-3.16

Lithium (90 mg, 13 mmol) was washed with THF (3 x 5 ml), added solution of

compound (±)-187 (1.0 g, 3.3 mmol) in THF (7 mL). The mixture was stirred at 0 °C.

Progress of reaction was monitored by 1H NMR.vii The silyllithium solution was

transferred via syringe to (R)-3.17 (0.225 g, 1.1 mmol) in THF (5 mL) at -78 ºC. The

resulting solution was stirred at -78 °C for 3h and at rt for overnight. The solution was

quenched by saturated NH4Cl solution (50 mL). The aqueous phase was extracted with

EtOAc (3 x 20 mL). Combined organic layers were washed with ater (3 x 10 mL), brine

(2 x 10 mL), dried over with MgSO4, and then concentrated in vacuo. Flash

chromatography with eluent gave 3.16 (0.2 g, 40%) as a mixture of two diastereomers.

Rf = 0.43 (hexane / ethyl acetate 1:1)

IR (neat): 3068, 2953, 2883, 1504, 1454, 1427, 1149, 1068, 920, 702 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.57-7.20 (m, 15H), 4.44-4.43(d, J = 1.2 Hz (one

diastereomer), d, J = 2.2 Hz, (another diastereomer), 2H), 3.84-3.77 (m, 1H), 3.256 and

3.248 (s, 3H (two diastereomers)), 3.17-2.97 (m, 4H), 1.72-1.65 (m, 1H), 1.26-1.16 (m,

vii 0.1 mL of reaction solution was added TMSCl, concentrated and recorded 1H NMR. The reaction was completed when proton of Si-H bond disapeared. 172

1H), 1.00-0.99 (s, 9H (two diastereomers)), 0.9-0.8 (m, 1H) 0.71-0.69 (d, J = 5.6 Hz, d, J

= 5.3 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 139.4, 136.0, 133.5, 133.4, 130.1, 128.7, 128.3, 128.2,

126.8, 96.7, 75.3 (75.29), 56.9, 55.4, 47.9 (47.7), 40.0, 30.0, 23.0, 20.5, 17.1 (17.09);

+ + Exact mas: [M-H] calcd. for [C30H42NO3SSi] 524.2649, found 524.2655

173

7.571 7.555 7.552 7.532 7.516 7.512 7.389 7.372 7.358 7.354 7.347 7.258 7.220 7.215 7.203 4.441 4.438 4.433 4.427 3.254 3.246 3.112 1.416 1.007 0.994 0.716 0.702 0.700 0.686

H Ph Ph N Si OMOM S O Ph (R,R,R)-3.16 (R,R,S)-3.16

14.75

8.84

6.93

2.47 1.79 1.54 0.78 1.00

10 8 6 4 2 0 PPM

96.701 77.768 77.654 77.448 77.128 75.359 75.291 56.937 55.412 47.943 47.752 40.062 30.023 24.574 22.996 20.473 17.135 17.097 139.384 136.008 133.569 133.439 133.310 130.139 130.063 128.729 128.607 128.348 128.271 128.172 126.831

H Ph Ph N Si OMOM S O Ph (R,R,R)-3.16 (R,R,S)-3.16

160 140 120 100 80 60 40 20 PPM

174

(S)-N-{[(3-(Methoxymethoxy)-2(R/S)-2-methylpropyl)diphenylsilyl]-2(R)-2- phenylethyl}-2-methyl-2-propanesulfinamide (3.16)

Ph Ph Ph H 2 1. Li N Si OMOM Si OMOM S H 2. ( )-3.19 N O S Ph Ph O (S,S,R)-3.16 (S)-3.17 (S,S,S)-3.16

Following the procedure for synthesis of compound 3.16 (p. 172), using (±)-3.19 (5.0 g,

16.7 mmol), Li (1.4 g, 167 mmol), and (S)-3.17 (1.2 g, 5.6 mmol) gave sulfinamides

(S,S,R) and (S,S,S)-3.16 (1.4 g, 50%).

Rf = 0.34 (hexane / ethyl acetate1:1)

1 H NMR (400 MHz, CDCl3): δ 7.7-7.2 (m, 15H), 4.44-4.43 (m, 2H), 3.84-3.78 (m, 1H),

3.2 (s, 3H), 3.1-2.8 (m, 4H), 1.73-1.65 (m, 1H), 1.2-1.0 (m, 1H), 1.0 (s, 9H), 0.9-0.8 (m,

1H), 0.75-0.64 (m, 3H);

13 C NMR (100 MHz, CDCl3): δ 139.1, 135.9, 133.4, 133.2, 129.9, 128.5, 128.2, 128.0,

126.6, 96.5, 75.1 (75.0), 56.7, 55.2, 47.7 (47.5), 39.8, 29.8, 22.8 (22.6), 20.3, 16.9.

175

7.578 7.563 7.558 7.539 7.523 7.519 7.408 7.391 7.379 7.376 7.368 7.361 7.357 7.354 7.350 7.260 7.230 7.224 7.216 7.210 4.444 4.441 4.436 4.430 3.256 3.248 3.118 3.102 1.412 1.014 1.001 0.943 0.724 0.710 0.694

H Ph Ph N Si OMOM S O Ph 19.24 (S,S,R)-3.16 (S,S,S)-3.16

9.61 8.92

3.08 2.36 2.52 1.85 0.99 0.95

10 8 6 4 2 0PPM

96.506 77.618 77.298 76.978 75.156 75.088 56.734 55.210 47.748 47.557 39.874 29.836 22.808 22.686 20.293 16.955 16.909 139.189 135.973 135.820 133.396 133.267 129.943 129.875 128.533 128.419 128.244 128.152 128.076 126.636

H Ph Ph N Si OMOM S O Ph (S,S,R)-3.16 (S,S,S)-3.16

160 140 120 100 80 60 40 20 PPM

176

(S)-N-{[(3-(Methoxymethoxy)-2(S)-2-methylpropyl)diphenylsilyl]-2(R)-2-

phenylethyl}-2-methyl-2-propanesulfinamide ((R,R,S)-3.16)

Following the procedure for synthesis of compound 3.16 (p. 172), using (S)-3.19 (1.0 g,

3.3 mmol), Li (50 mg, 7 mmol), and (R)-3.17 (12 mg, 1.12 mmol) gave sulfinamide

(R,R,S)-3.16 (0.3 g, 50%) as a colorless solid.

Rf = 0.3 (hexane / ethyl acetate 1:1)

Mp. 63-64ºC;

20 [α]D = -6.1 (c 0.8, CHCl3);

IR: 3068, 2953, 2883, 1504, 1454, 1427, 1149, 1068, 920, 702 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.5-7.2 (m, 15H), 7.4 (d, J = 2.3 Hz, 2H), 3.8 (dt, J = 9.8,

6.5 Hz, 1H), 3.25-3.24 (s, 3H), 3.16-3.06 (m, 1H), 3.1 (d, J = 6.7 Hz, 2H), 3.02 (t, J = 3.7

Hz, 1H), 3.0 (s, 1H (N-H)), 1.7-1.6 (m, 1H), 1.2-1.1(dd, J = 15.0, 5.0 Hz, 1H), 1.0 (s,

9H), 0.9-0.8 (dd, J = 15.0, 8.6 Hz, 1H), 0.69 (d, J = 6.8 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 139.4, 136.0, 135.9, 133.5, 133.4, 130.1, 130.0, 128.7,

128.3, 128.2, 128.1, 126.8, 96.7, 75.3, 56.9, 55.4, 47.9, 40.0, 30.0, 22.9, 20.4, 17.0;

+ + Exact mass: [M-H] calcd. for [C30H42NO3SSi] 524.2649, found 524.2655.

177

7.550 7.509 7.404 7.361 7.359 7.355 7.343 7.256 7.209 7.198 4.429 4.423 3.251 3.244 3.105 1.002 0.990 0.696 0.680

16.15

H Ph Ph N Si OMOM S O Ph (R,R,S)-3.16 8.16

4.83

3.38 3.00

2.01 2.02 1.47 0.95 1.10

10 8 6 4 2 PPM

96.544 77.565 77.252 76.932 75.133 56.764 55.263 47.778 39.912 29.859 22.839 20.308 16.932 139.242 135.866 135.812 133.411 133.282 129.974 129.905 128.556 128.183 128.107 128.015 126.666

H Ph Ph N Si OMOM S O Ph (R,R,S)-3.16

160 140 120 100 80 60 40 20 0 PPM

178

Compound (R,S)- and (R,R)-1.63

To a solution of two diastereomers (R,R,S)- and (R,R,R)-3.16 (1.0 g, 1.9 mmol) in methanol (2 mL) was added 1.25M HCl (6.0 mL, 7.6 mmol) in methanol.viii The solution

was stirred at rt for 5 h, concentrated in vacuo, dissolved in ethyl acetate (8 mL), added

saturated NaHCO3 (3 ml) followed benzoyl chloride (0.26 mL, 2.28 mmol). The mixture

was stirred at rt. for 3h, diluted with water (30 ml). The aqueous layer was extracted with

ethyl acetate (3 x 10 mL). Combined organic layers were washed with water (3 x 10 mL),

brine (2 x 10 mL), dried over with Na2SO4, and then concentrated in vacuo. Column

chromatography gave (R,S)-163 (327 mg, 35%) and (R,R)-163 (227 mg, 25%).

N-{(R)-1-[((S)-3-hydroxy-2-methylpropyl)diphenylsilyl]-2-phenylethyl}benzamide

(R,S)-1.63

Rf = 0.25 (hexane / ethyl acetate 2:1)

1 H NMR (400 MHz, CDCl3): δ 7.6-7.1 (m, 20H), 5.9 (d, J = 10.2 Hz, 1H), 4.99-4.92 (m,

1H), 3.5 (dd, J = 10.9, 5.2 Hz, 1H), 3.2-3.1 (m, 2H), 2.6 (br, 1H), 2.6 (dd, J = 15.2, 12.2

Hz, 1H), 1.9-1.8 (m, 1H), 1.52 (dd, J = 14.8, 5.2 Hz, 1H), 0.92 (dd, J = 14.8, 7.8 Hz, 1H),

0.69 (d, J = 6.5 Hz, 3H).

viii Or using aqueous HCl in MeOH 179

N-{(R)-1-[((R)-3-hydroxy-2-methylpropyl)diphenylsilyl]-2-phenylethyl}benzamide

(R,R)-1.63

H Ph Ph Ph N Si OH

O Ph (R,R)-1.63

Rf = 0.19 (hexane / ethyl acetate 2:1)

1 H NMR (400 MHz, CDCl3): δ 7.6-7.1 (m, 20H), 5.8 (d, J = 9.3 Hz, 1H), 4.8 (td, J =

10.6, 4.2 Hz, 1H), 3.3 (dd, J = 10.4, 6.2 Hz, 1H), 3.2 (dd, J = 10.4, 6.3 Hz, 1H), 3.1 (dd, J

= 14.4, 4.2 Hz, 1H), 2.6 (dd, J = 14.4, 11.0 Hz, 1H), 1.7-1.6 (m, 1H), 1.6 (br, 1H), 1.3

(dd, J = 15.2, 5.6 Hz, 1H), 1.0 (dd, J = 15.0, 8.0 Hz, 1H), 0.7 (d, J = 6.6 Hz, 3H).

Mixture of (S,R)- and (S,S)-1.63

Ph Ph H 1. HCl H Ph Ph H N Si OMOM S Ph N Si OH 2. PhCOCl O NaHCO O Ph 3 Ph

(S,S,R)-3.16 (S,R)-1.63 (S,S)-1.63 (S,S,S)-3.16

Following the procedure for synthesis of (R,S)-1.63 and (R,R)-1.63 (p.178), using the mixture of two diastereomers (S,S,S)- and (S,S,R)-3.16 (1.0 g, 1.9 mmol), 1.25M HCl (6.0 mL, 7.6 mmol). Column chromatography gave (S,R)-1.63 and (S,S)-1.63 mixture (637 g,

70% yield).

Rf = 0.5 (hexane / ethyl acetate 1:1)

(S)-3-[((R)-1-Benzamido-2-phenylethyl)diphenylsilyl]-2-methylpropanoic acid

((R,S)-3.25)

180

To a solution of (R,S)-1.63 (0.5 g, 1.04 mmol) in acetonitrile and water (2/1, 10 mL) at rt

was added (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO, 32 mg, 0.2 mmol), and

bis(acetoxy)iodobenzene (BAIB, 0.73 g, 2.2 mmol). The solution was stirred at rt for 2 h,

quenched with 30% Na2S2O3 (20 mL). The aqueous layer was extracted with DCM (3 x

10 mL). The combined DCM layers were washed with water (3 x 10 mL), brine (2 x 5

mL), dried over with MgSO4, and then concentrated in vacuo. Column chromatography

gave (R,S)-3.25 (369 mg, 72%).

Rf = 0.31 (hexane / ethyl acetate 3:1)

1 H NMR (400 MHz, CDCl3): δ 10-9.5 (br, 1H), 7.5-7.0 (m, 20H), 6.0 (d, J = 10.2 Hz,

1H), 4.8 (dt, J = 10.2, 4.2 Hz, 1H), 3.1 (dd, J = 14.7, 4.5 Hz, 1H), 2.6 (dd, J = 14.7, 11.3

Hz, 1H), 2.5 (m, 1H), 1.7 (dd, J = 15.2, 6.8 Hz, 1H), 1.3 (dd, J = 15.8, 7.9 Hz, 1H), 1.0

(d, J = 6.8 Hz, 3H).

(R)-3-[((R)-1-Benzamido-2-phenylethyl)diphenylsilyl]-2-methylpropanoic acid

((R,R)-3.25)

Following the procedure for synthesis of (R,S)-3.25 (p. 181), using (R,R)-1.63 (0.5 g,

1.04 mmol), TEMPO (32 mg, 0.2 mmol), and BAIB (0.73 g, 2.2 mmol) gave (R,R)-3.25

(369 mg, 72%yied).

181

Rf = 0.29 (hexane / ethyl acetate 3:1)

1 H NMR (400 MHz, CDCl3): δ 10.0-9.2 (br, 1H), 7.6-7.0 (m, 20H), 6.0 (d, J = 10.3 Hz,

1H), 5.0 (td, J = 10.9, 4.3Hz, 1H), 3.3 (dd, J = 14.0, 4.3 Hz, 1H), 2.7 (dd, J = 14.0, 10.9

Hz, 1H), 2.6-2.5 (m, 1H), 1.8 (dd, J = 15.2, 7.9 Hz, 1H), 1.45 (dd, J = 15.2, 6.7 Hz, 1H),

1.1 (d, J = 6.7 Hz, 3H).

3-[((S)-1-Benzamido-2-phenylethyl)diphenylsilyl]-2-methylpropanoic acid (mixture of (S,R) and (S,S)-3.25)

Following the procedure for synthesis of (R,S)-3.25 (p. 181), using the mixture of (S,R)-

1.63 and (S,S)-1.63 (1.0 g, 2.1 mmol), TEMPO (62 mg, 0.4 mmol), and BAIB (1.4 g, 4.4

mmol) gave a mixture of (S,R)-3.25 and (S,S)-3.25 (750 mg, 72%yied).

Rf = 0.29 (tail) (hexane / ethyl acetate 3:1)

182

(S)-tert-Butyl-1-{(S)-3-[((R)-1-benzamido-2-phenylethyl)diphenylsilyl]-2-

methylpropanoyl}pyrrolidine-2-carboxylate ((R,S,S)-3.29)

To a 0 °C solution of acid (R,S)-3.25 (0.5 g, 1.0 mmol) and 3.28 (0.21 g, 1.0

mmol) in DMF (10 mL) was added 90% diethyl cyanophosphonate (0.23 mL, 1.2 mmol)

followed by triethylamine (0.46 mL, 3.3 mmol). The reaction was stirred at 0 °C for 3 h,

and at rt overnight. The mixture was diluted with ethyl acetate (30 mL) and water (50

mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined

organic layers were washed with 5% HCl (3 x 10 mL), saturated NaHCO3 (3 x 10 mL),

water (3 x 10 mL), brine (10 mL), dried over with Na2SO4, and concentrated in vacuo.

Column chromatography gave (R,S,S)-3.29 (0.53 g, 80%) as a colorless foam.

Rf = 0.62 (hexane / ethyl acetate 2:1)

20 20 55 [α]D = -62.8 (c 0.21, CHCl3), literature [α]D = -61.8 (c 0.22, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 7.82-7.00 (m, 21H, included NH), 4.69-4.63 (m, 1H),

3.55 (dd, J = 8.4, 3.6 Hz, 1H), 3.05-3.02 (m, 1H), 2.99 (dd, J = 14.0, 4.4 Hz, 1H), 2.77

(dd, J = 14.0, 9.2 Hz, 1H), 2.42-2.37 (m, 1H), 2.30-2.25 (m, 1H), 1.63-1.51 (m, 5H), 1.35

(s, 9H), 1.23-1.19 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H).

183

(S)-tert-Butyl-1-((R)-3-(((R)-1-benzamido-2-phenylethyl)diphenylsilyl)-2-

methylpropanoyl)pyrrolidine-2-carboxylate ((R,R,S)-3.29)

Following the procedure for synthesis of (R,S,S)-3.29 (p.183), using acid (R,R)-

3.25 (0.5 g, 1.0 mmol), proline salt 3.28 (0.21 g, 1.0 mmol) in DMF (10 mL), 90%

diethyl cyanophosphonate (0.23 mL, 1.2 mmol), triethylamine (0.46 mL, 3.3 mmol) gave

(R,R,S)-3.29 (0.53 g, 80%) as a colorless foam.

Rf = 0.38 (hexane / ethyl acetate 2:1)

20 [α]D = -73.9 (c 0.935, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 7.74-7.13 (m, 20H), 5.96 (d, J = 9.6 Hz, 1H), 4.78-4.72

(m, 1H), 3.00 (dd, J = 14.2, 4.0 Hz, 1H), 3.61 (dd, J = 7.9, 3.8 Hz, 1H), 3.13-3.06 (m,

8H), 2.85-2.71 (m, 3H), 2.60-2.32 (m, 5H), 2.08-2.01 (m, 1H), 1.81-1.38 (m, 12H), 1.35

(s, 9H), 1.34 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H).

TLC A:(R,S,S)-3.29 AA B:(R,R,S)-3.29

184

Following the procedure for synthesis of (R,S,S)-3.29 (p.183), using mixture of acid (S,R)-3.25 and (S,S)-3.25 (0.8 g, 1.6 mmol), salt 3.28 (0.33 g, 1.6 mmol) in DMF

(10 mL), diethyl cyanophosphonate (0.4 mL, 3.2 mmol), triethylamine (0.67 mL, 4.8 mmol) gave (S,S,S)-3.29 (0.22 g, 40%) and (S,R,S)-3.29 (0.2 g, 38%).

(S)-tert-Butyl 1-{(S)-3-[((S)-1-benzamido-2-phenylethyl)diphenylsilyl]-2- methylpropanoyl}pyrrolidine-2-carboxylate ((S,S,S)-3.29)

Rf = 0.57 (hexane / ethyl acetate 2:1)

20 20 55 [α]D = 18.9 (c 0.49, CHCl3), literature [α]D = 19.3 (c 0.27, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 7.59-7.12 (m, 20H), 6.56 (d, J = 10.0 Hz, 1H), 4.75 (dt, J

= 11.1, 4.0, Hz, 1H), 4.20 (dd, J = 8.4, 4.0 Hz, 1H), 3.37-3.32 (m, 1H), 3.19 (dd, J = 14.0,

4.0 Hz, 1H), 2.97- 2.91 (m, 1H), 2.70-2.64 (m, 1H), 2.52 (dd, J = 14.0, 11.2 Hz, 1H),

2.02-1.72 (m, 5H), 1.43 (s, 9H), 1.29-1.24 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

185

(S)-tert-Butyl 1-{(R)-3-[((S)-1-benzamido-2-phenylethyl)diphenylsilyl]-2-

methylpropanoyl}pyrrolidine-2-carboxylate ((S,R,S)-3.29)

Rf = 0.36 (hexane / ethyl acetate 2:1)

20 [α]D = -6.7 (c 0.35, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 7.74-7.13 (m, 40H), 6.00 (d, J = 10.0 Hz, 1H), 4.78-4.72

(m, 2H), 4.23 (dd, J =8.4, 3.6 Hz, 1H), 3.61 (dd, J = 8.0, 3.8 Hz, 1H), 3.13-3.06 (m, 8H),

2.85-2.71 (m, 3H), 2.60-2.32 (m, 5H), 2.08-2.01 (m, 1H), 1.81-1.38 (m, 12H), 1.35 (s,

9H), 1.34 (s, 9H), 1.09 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H)

TLC

B A:(S,R,S)-3.29 B

A A B:(S,S,S)-3.29

(S)-1-{(S)-3-[((R)-1-benzamido-2-phenylethyl)difluorosilyl]-2-methylpropanoyl} pyrrolidine-2-carboxylic acid ((R,S,S)-3.31)

1. TfOH Ph Ph 2. NH4OH F F H 3.HF H Ph N Si N Ph N Si N

O O COO-t-Bu O O COOH Ph Ph

(R, S, S)-3.29 (R, S, S)-3.31

186

To a 0 °C solution of (R,S,S)-3.29 (0.2 g, 0.3 mmol) in DCM (10 mL) was added

trifluoromethane sulfonic acid (1.8 mL, 8.4 mmol). The solution was stirred for 1h at 0

°C, diluted with DCM (10.0 mL) followed by 14.8 N NH4OH (1.0 mL) and stirred for 35

min at 0 °C, and then added 48% HF solution (0.6 mL) to give a pH of 2-3. Stirring was

continued for 10 min. After addition of DCM (20 mL), the solution was washed with

water (10 mL), saturated NaCl (10 mL), dried over Na2SO4, concentrated to give (R,S,S)-

3.31 (145 mg, 92%) as a light yellow foam.

1 H NMR (400 MHz, DMSO_d6): δ 10.1 (br, 1H), 7.91-7.17 (m, 10H), 4.0 (dd, J = 7.2,

4.1 Hz, 1H), 3.47-3.45 (m, 2H), 3.1 (dd, J = 14.0, 4.2 Hz, 1H), 3.0-2.98 (m, 1H), 2.9 (dd,

J = 14.0, 8.0 Hz, 1H), 2.8-2.7(m, 1H), 1.84 – 1.69 (m, 4H), 1.0 (d, J = 6.9 Hz, 3H), 0.9-

0.8 (m, 1H), 0.7-0.6 (m, 1H).

(S)-1-{(R)-3-[((R)-1-Benzamido-2-phenylethyl)difluorosilyl]-2-methylpropanoyl} pyrrolidine-2-carboxylic acid ((R,R,S)-3.31

Following the procedure for synthesis of (R,S,S)-3.31 (p.186), using (R,R,S)-3.29 (0.2 g,

0.3 mmol) in DCM (10 mL), trifluoromethane sulfonic acid (1.8 mL, 8.4 mmol), 14.8 N

NH4OH (1.0 mL), and 48% HF solution (0.6 mL) gave (R,R,S)-3.29 (145 mg, 92%) as a

light yellow foam.

187

1 H NMR (400 MHz, CD3CN): δ 8.10 (brs, 1H), 7.80-7.21 (m, 10H), 4.42 (dd, J = 8.0,

2.8 Hz, 1H), 3.47 (m, 2H), 3.18 (dd, J = 14.0, 3.4 Hz, 1H), 3.12-3.08 (m, 1H), 2.85- 2.82

(m, 1H), 2.77 (dd, J = 13.6, 10.0 Hz, 1H), 2.17-2.11 (m, 1H), 2.01-1.96 (m, 1H), 1.88-

1.68 (m, 2H), 1.30-1.15 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.99-0.93 (m, 1H).

(S)-1-{(S)-3-[((S)-1-benzamido-2-phenylethyl)difluorosilyl]-2-methylpropanoyl} pyrrolidine-2-carboxylic acid ((S,S,S)-3.31)

Following the procedure for synthesis of (R,S,S)-3.31 (p.186), using (S,S,S)-3.29

(0.2 g, 0.3 mmol) in DCM (10 mL), trifluoromethane sulfonic acid (1.8 mL, 8.4 mmol),

14.8 N NH4OH (1.0 mL), and 48% HF solution (0.6 mL) gave (S,S,S)-3.31 (145 mg,

92%) as a light yellow foam.

1 H NMR (400 MHz, acetone_d6): δ 8.2 (br s, 1H), 7.99-7.20 (m, 10H), 4.15 (dd, J = 8.0,

2.8 Hz, 1H), 3.56-3.47 (m, 2H), 3.24-3.15 (m, 2H), 2.93-2.73 (m, 2H), 1.86-1.81 (m, 2H),

1.60-1.56 (m, 2H), 1.22-1.18 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H), 1.04-1.01 (m, 1H).

(S)-1-{(R)-3-[((S)-1-benzamido-2-phenylethyl)difluorosilyl]-2-methylpropanoyl}

pyrrolidine-2-carboxylic acid ((S,R,S)-3.31)

188

Following the procedure for synthesis of (R,S,S)-3.31 (p.186), using (S,R,S)-3.29 (0.2 g,

0.3 mmol) in DCM (10 mL), trifluoromethane sulfonic acid (1.8 mL, 8.4 mmol), 14.8 N

NH4OH (1.0 mL), and 48% HF solution (0.6 mL) gave (S,R,S)-3.31 (145 mg, 92%) as a

light yellow solid.

1 H NMR (400 MHz, acetone_d6): δ 8.27 (br s, 1H), 7.9-7.3 (m, 10H), 4.5 (dd, J = 8.0,

2.9 Hz, 1H), 3.76 (m, 1H), 3.63 (m, 1H), 3.3 (dd, J =14.0, 3.6 Hz, 1H), 3.2-3.1 (m, 1H),

3.07-3.02 (m, 1H), 2.96-2.85 (m, 1H), 2.2-2.17 (m, 1H), 2.1- 2.06 (m, 1H), 2.04-1.97 (m,

1H), 1.88-1.79 (m, 1H), 1.4-1.29 (m, 1H),1.28 (d, J = 6.4 Hz, 3H), 1.08- 0.92 (m, 1H)

Sodium (S)-1-{(S)-3-[((R)-1-benzamido-2-phenylethyl)dihydroxysilyl]-2- methylpropanoyl}pyrrolidine-2-carboxylate ((R,S,S)-1.64)

H F F H HO OH Ph N Si N Ph N Si N NaOH O O COOH O O COONa Ph Ph

(R, S, S)-1.64 (R, S, S)-3.31

To a 0 °C solution of acid (R,S,S)-3.31 (9.0 mg, 19.0 µmol) in 1:99 CD3CN/D2O (0.4 mL) was added a 0.2 M NaOH solution in D2O (0.3 mL, 57.0 µmol). The reaction was

monitored by 19F NMR, and gave silanediol sodium salt (R,S,S)-1.64.

189

1 H NMR (400 MHz, 1% CD3CN in D2O): δ 7.47-7.10 (m, 10H), 4.02 (dd, J = 8.7, 4.4

Hz, 1H), 3.66 (dd, J = 13.0, 3.2Hz, 1H), 3.43-3.29 (m, 2H), 3.07 (dd, J = 14.0, 3.2Hz,

1H), 2.72-2.66 (m, 2H), 1.97-1.92 (m, 1H), 1.76-1.65 (m, 2H), 1.60-1.54 (m, 1H), 1.08

(d, J = 6.5 Hz, 3H), 0.78 (dd, J = 14.8, 3.6 Hz, 1H), 0.58 (dd, J = 15.0, 10.8 Hz, 1H).

Sodium (S)-1-{(R)-3-[((R)-1-benzamido-2-phenylethyl)dihydroxysilyl]-2- methylpropanoyl}pyrrolidine-2-carboxylate ((R,R,S)-1.64

H HO OH Ph N Si N

O O COONa Ph (R, R, S)-1.64

1 H NMR (400 MHz, 1% CD3CN in D2O): δ 7.50-7.10 (m, 10H), 4.12 (dd, J = 8.8, 4.4

Hz, 1H), 3.58 (dd, J = 13.0, 3.6 Hz, 1H), 3.51-3.31 (m, 2H), 3.01 (dd, J =14.0, 3.2 Hz,

1H), 2.87-2.86 (m, 1H), 2.70 (t, J = 13.0 Hz, 1H), 2.14-2.08 (m, 1H), 1.89-1.69 (m, 3H),

1.03 (d, J = 6.0 Hz, 3H), 0.76 (dd, J = 15.2, 4.4 Hz, 1H), 0.60 (dd, J = 15.0, 10.5 Hz, 1H).

Sodium (S)-1-{(S)-3-[((S)-1-benzamido-2-phenylethyl)dihydroxysilyl]-2- methylpropanoyl}pyrrolidine-2-carboxylate ((S,S,S)-1.64)

H HO OH Ph N Si N

O O COONa Ph (S, S, S)-1.64

190

1 H NMR (400 MHz, 1% CD3CN in D2O): δ 7.49-7.11 (m, 10H), 4.08 (dd, J = 8.8, 4.4

Hz, 1H), 3.62 (dd, J = 13.0, 3.6 Hz, 1H), 3.53-3.32 (m, 2H), 3.05 (dd, J = 14.0, 3.6 Hz,

1H), 2.86-2.79 (m, 1H), 2.68 (t, J = 13.0 Hz, 1H), 2.04-2.00 (m, 1H), 1.82-1.62 (m, 3H),

1.06 (d, J = 6.5 Hz, 3H), 0.76 (dd, J = 15.1, 4.4 Hz, 1H), 0.60 (dd, J = 15.0, 10.0 Hz, 1H).

Sodium (S)-1-{(R)-3-[((S)-1-benzamido-2-phenylethyl)dihydroxysilyl]-2- methylpropanoyl}pyrrolidine-2-carboxylate ((S,R,S)-1.64)

1 H NMR (400 MHz, 1% CD3CN in D2O): δ 7.50-7.10 (m, 10H), 4.28 (dd, J = 8.8, 4.4

Hz, 1H), 3.61 (dd, J = 12.8, 3.0 Hz, 1H), 3.34- 3.28 (m, 2H), 2.97 (dd, J =14.0, 3.0 Hz,

1H), 2.70-2.67 (m, 1H), 2.63 (t, J = 7.6 Hz, 1H), 2.05-1.84 (m, 2H), 1.63-1.56 (m, 2H),

0.94 (d, J = 6.5 Hz, 3H), 0.83 (dd, J = 15.2, 4.0 Hz, 1H), 0.68 (dd, J = 15.2, 5.0 Hz, 1H).

191

6.6 Index of experimentals for chapter 4

OH H HO H N Si N

O O

NH2 CH3COO

HN NH2 4.15,p.232

H Ph2 H N Si N

O O

N3 4.21,p.224

Ph Ph H N N Si OH S OMOM S O O 4.25, p. 196 OMOM 4.24, p. 201 Ph Ph H N Si O OTPS

OMOM 4.36, p. 205

Ts Ph2 H N Si N

(R,S)-4.48, p. 214

H Ph2 H N Si N

O O

NH Boc 4.59, p. 227

192

O O H Ph2 H N N Si N N H O O

N3 4.70c, p. 241

O H H Ph2 H N N Si N N H O O O

NHBoc 4.71b, p. 245

O O H H Ph2 H O N N Si N H Ph2 H N N N Si N H N O O O H O O NH NH BocN NHBoc BocN NHBoc

4.72b,p.251 4.72c, p. 253

Ph Ph O Boc H N Si N Ts N H O

OMOM 4.74,p.263 Ph Ph O Ph Ph O H H H BocHN Si N N Si N N N H H O O O

N3 N3 4.76, p. 267 4.77,p.269

193

(N(E),(R)-{N-[4-(Methoxymethoxy)butylidene]}-2-p-toluenesulfinamide (4.41)

To a solution of (R)-Davis sulfinamide 4.40 (10 g, 65.5 mmol) in DCM (130 mL) was added Ti(OEt)4 (75.0 g, 327.5 mmol) followed by the aldehyde 4.30 (10.3 g, 78.6 mmol).

The mixture was stirred at room temperature for 48 h. The reaction mixture was added

waterix (500 mL), DCM (200 mL), and then filtered through a pad of Celite. The solid

was rinsed with DCM (3 x 50 mL). The aqueous layer was extracted with DCM (3 x 20 mL). Combined organic layers were washed with water (3 x 50 mL) and brine (2 x 20

mL), dried over with Na2SO4, and concentrated in vacuo. Column chromatography with

eluent of hexane and ethyl acetate (2/1) gave sulfinimine 4.41 (12.6 g, 72%) as a pale

yellow liquid.

20 Rf = 0.52 (hexane / ethyl acetate 2:1); [α]D = -261.4 (c, 1.34, CHCl3)

IR: 3030, 2929, 2884, 1722, 1621, 1596, 1149, 1041, 918, 625 cm-1;

1 H NMR (400 MHz, CDCl3): δ 8.2 (t, J = 5.2 Hz, 1H), 7.5 (dd, J = 8.0, 1.1 Hz, 2H), 7.3

(d, J = 8 Hz, 2H), 4.5 (s, 3H), 3.5 (t, J = 6.3 Hz, 2H), 3.3 (s, 3H), 2.6-2.5 (m, 2H), 2.4 (s,

3H), 1.92 (dt, J = 7.5 Hz, 2H);

13 C NMR (100 MHz, CDCl3): δ 167.0, 142.1, 142.0, 130.1, 124.9, 96.7, 66.9, 55.5, 33.1,

+ + 25.8, 21.7; Exact mass: [M-H] calcd. for [C13H20NO3S] 270.1158, found 270.1161

ix Kept under 0 °C and worked up partial portion gave fresh sulfinimine for next step 194

8.265 7.569 7.566 7.549 7.313 7.293 7.292 7.268 4.567 3.558 3.541 3.527 3.314 2.605 2.593 2.403 1.940 1.924 1.636

N S OM OM O 4.41

3.08 2.98 2.36 1.97 2.00 2.02 1.95 1.96 0.96

10 8 6 4 2 0 PPM

96.727 77.684 77.368 77.048 66.890 55.514 33.162 25.825 21.754 166.978 142.168 142.010 130.119 124.913

N S OM OM O 4.41

180 160 140 120 100 80 60 40 20 0 PPM

195

{N(E),(R)-[N-(4-Methoxymethoxy)butylidene]}-2-methylpropanesulfinamide (4.25)

Following the procedure for synthesis of sulfinimine 4.41 (p.194), using (R)-Ellman sulfinamide 4.24 (5.0 g, 40.3 mmol), Ti(OEt)4 (46.0 g, 201.5 mmol), DCM (100 mL), and aldehyde 4.30 (6.4 g, 48.4 mmol) gave Ellman sulfinamide 4.25 (8.0 g, 85%)

Rf = 0.55 (hexane / ethyl acetate 2:1)

20 [α]D = -227.2(c, 1.23, CHCl3)

IR: 3230, 2949, 2929, 28.84, 283, 1623, 1474, 1456, 1150, 918 cm-1

1 H NMR (400 MHz, CDCl3): δ 8.1 (t, J = 3.6 Hz, 1H), 4.6 (s, 2H), 3.5 (t, J = 6.6 Hz, 2H),

3.3 (s, 3H), 2.6 (dt, J = 8.0, 5.1 Hz, 2H), 1.97-1.90 (m, 2H), 1.18 (s, 9H).

13 C NMR (125 MHz, CDCl3): δ 169.2, 96.7, 66.9, 56.8, 55.4, 33.2, 25.8, 22.6.

+ + Exact mass: [M-H] calcd. for [C10H22NO3Si] 236.1315, found: 236.1310

196

8.045 7.199 4.551 3.541 3.525 3.509 3.292 1.128 1.125

N S OMOM O 4.25

10.22

3.19 2.48 2.00 2.11 2.17 1.08

10 8 6 4 2 0PPM

96.681 77.580 77.260 76.940 66.917 55.469 33.197 25.811 22.572 169.235

N S OMOM O 4.25

180 160 140 120 100 80 60 40 20 0PPM

197

(R)-N(1R)-[(2S)-3-hydroxyl-2-methylpropanyl]diphenylsilyl(4-methyoxymethoxy)

butyl-p-toluenesulfinamide (4.42)

To a solution of silafuran (S)-1.74 (5.0 g, 19.6 mmol) in dry THF (30 mL) at 0 °C was

added lithium metal (2.7 g, 386 mmol). The mixture was stirred at 0 °C for 48 h to

generate silyl dianion 4.26 that was transferred via a cannula to -78 °C solution of Davis sulfinimine 4.41 (1.75 g, 6.5 mmol) in THF (10 mL). The mixture was stirred at -78 °C for 5 h, and at rt for overnight. The solution was cooled down to 0 °C, and then added

30% NH4Cl solution (50 mL) and water (100 ml). The aqueous layer was extracted with

ethyl acetate (3 x 20 mL). Combined organic layers were washed with water (3 x 50 mL)

and brine (2 x 30 mL), dried over with Na2SO4, and then concentrated in vacuo. Column

chromatography on silica gel with eluent of hexane and ethyl acetate (1/1, 1/2, 4/1, 0/1)

gave sulfinamide 4.42 (2.5 g, 75%). Further purification with column chromatography on

neutral alumina oxide gave quality sample for analysis.

Rf = 0.35 (hexane / ethyl acetate 1:2)

20 [α]D = - 33.6 (c 0.11, CHCl3)

IR: 3323(br), 3220, 3107, 2924, 2873, 1595, 1492, 1088, 1046, 703 cm-1.

198

1 H NMR (500 MHz, CDCl3): δ 7.64 (dd, J = 8.0, 1.6 Hz, 2H), 7.54 (dd, J = 8.3, 1.6 Hz,

2H), 7.48-7.33 (m, 8H), 7.2 (d, J = 7.9 Hz, 2H), 4.52 (s, 2H), 3.72 (d, J = 9.6 Hz, 1H),

3.65 (dt, J = 9.0, 3.2 Hz, 1H), 3.43-3.31 (m, 4H), 3.28 (s, 3H), 2.39 (s, 3H), 1.97 (br, 1H),

1.87-1.73 (m, 3H), 1.58 (dd, J = 15.1, 5.2 Hz, 1H), 1.56 – 1.49 (m, 1H), 1.41 -1.33 (m,

1H), 1.0 (dd, J = 15.1, 8.3 Hz, 1H), 0.78 (d, J = 6.8 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 142.8, 141.2, 135.7, 135.6, 133.4, 133.2, 129.9, 129.8,

129.4, 128.1, 125.6, 96.2, 70.1, 67.3, 55.0, 44.4, 31.9, 29.7, 27.6, 21.3, 19.8, 16.1;

+ + Exact mass [MNa] calcd. for [C29H39NNaO4SSi] 548.2267 found 548.2261

199

7.648 7.635 7.633 7.548 7.535 7.532 7.433 7.418 7.377 7.361 7.346 7.276 7.211 4.523 3.280 2.388 1.610 0.786 0.772

Ph Ph H p-Tolyl N Si OH S O 8.45

OMOM 4.42

4.38

3.90

3.19 2.96 3.07 3.00

2.23 2.00 1.98 1.91

1.27 0.97 1.04 1.06 1.07

10 8 6 4 2 0PPM

96.218 77.336 77.278 77.025 76.765 70.120 67.281 55.096 44.413 31.938 29.706 27.582 21.305 19.781 16.105 142.808 141.168 135.707 135.599 133.453 133.157 129.892 129.820 129.358 128.137 128.101 125.623

Ph Ph H p-Tolyl N Si OH S O

OMOM 4.42

160 140 120 100 80 60 40 20 0P P M

200

(R)-N(1R)-[((2S)-3-Hydroxyl-2-methylpropanyl)diphenylsilyl](4-methyoxymethoxy)

butyl-2-methylpropanesulfinamide (4.24)

Following the procedure for synthesis of sulfinamide 4.42 (p. 198), using silafuran (S)-

1.74 (5.0 g, 19.6 mmol), THF (30 mL), lithium metal (0.54 g, 77.1 mmol), Ellman sulfinimine 4.25 (1.53 g, 6.5 mmol) in THF (10 mL) gave sulfinamide 4.24 (1.6 g, 53%).

Further purification with column chromatography on neutral alumina oxide gave a quality sample for analysis.

Rf = 0.35 (hexane / ethyl acetate 1:2)

20 [α]D = - 28.6 (c 0.31, CHCl3)

IR: 3398 (br), 3068, 3048, 2950, 2923, 2871, 1456, 1427, 1110, 1040, 701 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.6-7.35 (m, 10H), 4.58 (s, 2H), 3.53-3.40 (m, 3H), 3.35-

3.27 (m, 2H), 3.3 (s, 3H), 2.8 (d, J = 9.7 Hz, 1H), 2.2-1.94 (m, 2H), 1.77-1.64 (m, 3H),

1.53-1.47 (m, 1H), 1.38 (dd, J = 15.2, 5.0 Hz, 1H), 0.77 (d, J = 6.7 Hz, 3H).

13 C NMR (100 MHz, CDCl3): δ 135.8, 133.5, 130.1, 130.0, 128.3128.3, 96.5, 70.3, 67.6,

56.7, 55.3, 46.5, 32.1, 30.2, 27.9, 22.9, 20.0, 16.5

+ + Exact mass: [M-H] calcd. for [C26H42NO4SSi] 492.2598, found 492.2578

201

7.575 7.572 7.398 7.260 4.559 3.354 3.316 3.296 1.207 1.097 1.033 1.015 0.789 0.771

Ph Ph H N Si OH S O

OMOM 4.24

10.00 9.85

5.46

3.27 3.18 3.38

2.10 2.07 1.88

0.89 0.90

10 8 6 4 2 0PPM

96.498 77.534 77.222 76.902 70.309 67.611 56.734 55.324 46.467 32.138 30.194 29.889 27.915 22.984 22.793 19.927 16.528 135.797 133.495 130.104 129.989 128.297 128.160

Ph Ph H N Si OH S O

OMOM 4.24

160 140 120 100 80 60 40 20 PPM

202

(R)-N(1R)-{[(2S)-(3-(tert-Butyldiphenylsilyl)oxa)-2-methylpropanyl]

diphenylsilyl}(4-methyoxymethoxy)butyl-2methylpropanesulfinamide (4.35)

To a solution of the sulfinamide 4.24 (1.0 g, 2.0 mmol) and TPSCl (0.66 mL, 2.4 mmol) in DMF (7.0 mL) at rt was added AgNO3 (1.02 g, 6 mmol). The solution was stirred at rt

for 10 min, diluted with water (40 mL), and ethyl acetate (40 mL), filtered through a pad of Celite. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). Combined organic layers were washed with water (3 x 15 mL), brine (2 x 10 mL), dried over

Na2SO4, and concentrated in vacuo. Column chromatography on silica gel gave 4.35 (1.2

20 g, 82%). Rf = 0.42 (hexane / ethyl acetate 1:1), [α]D = - 22.6 (c 0.11, CHCl3)

IR: 3397, 3069, 3047, 2953, 2928, 2858, 1588, 1471, 1427, 1110, 702 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.6-7.3 (m, 20H), 4.55 (s, 2H), 3.52-3.46 (m, 2H), 3.39-

3.32 (m, 2H), 3.3 (t, J = 6.7 Hz, 1H), 3.2 (s, 3H), 2.6 (d, J = 10.4 Hz, 1H), 2.0-1.9 (m

2H), 1.76-1.64 (m, 2H), 1.4 (dd, J = 14.9, 4.0 Hz, 1H), 1.02 (s, 9H), 1.00 (s, 9H), 0.93

(dd, J = 15.0, 9.0 Hz, 1H), 0.7 (d, J = 6.6 Hz, 3H).

13 C NMR (100 MHz, CDCl3): δ 135.8, 134.1, 133.5, 133.4, 130.0, 129.9, 129.7, 128.2,

128.1, 127.8, 96.5, 71.2, 67.6, 56.7, 55.3, 46.8, 32.1, 30.4, 27.9, 27.1, 23.0, 19.8, 19.5,

16.3.

+ + Exact mass: [M-H] calcd. for [C42H60NO4SSi2] 730.3776, found 730.3783

203

7.570 7.553 7.530 7.358 7.343 7.338 7.259 4.551 3.283 3.262 1.025 1.021 1.004 0.746 0.730

Ph Ph H N Si OTPS S O

OMOM 4.35

20.86

18.37

3.78 3.21 2.00 2.04 2.59 2.05 2.33 1.97 1.07 1.58

10 8 6 4 2 PPM

96.475 77.550 77.435 77.237 76.917 71.208 67.641 56.696 55.286 46.764 32.115 30.354 27.923 27.099 22.961 19.782 19.485 16.253 135.866 135.797 134.113 133.472 133.358 130.035 129.913 129.722 128.259 128.122 127.779

Ph Ph H N Si OTPS S O

OMOM 4.35

160 140 120 100 80 60 40 20 PPM

204

N(1R)-({(2S/R)-[3-(tert-Butyldiphenylsilyl)oxa]-2-methylpropanyl}diphenylsilyl)(4- methyoxymethoxy)butylacetamide (4.36)

To a solution of sulfinamide 4.35 (0.2 g, 0.27 mmol) in Bu2O (4 mL) was added 4 M HCl

in dioxane (67.0 µL, 0.27 mmol). The solution was stirred at rt for 20 min, concentrated

in vacuo to give a crude ammonium salt. The crude ammonium salt was dissolved in

DCM (3 mL) and cooled down to 0 °C, added trimethyl amine (113 µL, 0.81 mmol). The

mixture was stirred at rt. for 5h and diluted with DCM (10 mL). The aqueous layer was

extracted with ethyl acetate (3 x 5 mL). Combined organic layers were washed with 5%

HCl (2 x 5 mL) and 5% NaHCO3 (2 x 5 mL), dried over with Na2SO4, concentrated in

vacuo. Column chromatography gave amide 4.36 (27 mg, 20%).

Rf = 0.4 (hexane / ethyl acetate 1:2)

IR: 3282, 3069, 3048, 2930, 2857, 1643, 1539, 1427, 1110, 702 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.6-7.3 (m, 20H), 4.9 (d, J = 10.8 Hz, 1H), 4.5 (s, 2H),

4.3-4.2 (m, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (m, 2H), 3.2 (s, 3H), 1.87 (s, 3H), 1.9-1.5 (m,

4H), 1.3 (dd, J = 15.4, 4.6 Hz, 1H), 1.0 (s, 9H), 0.9-0.7 (m, 1H), 0.7 (d, J = 6.9 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 169.6, 135.6, 135.5 (135.4), 133.96 (133.91), 133.90

(133.86), 133.6(133.4), 132.8(132.6), 129.84 (129.80), 129.5 (129.4), 128.1(128.0),

127.6(127.5), 96.34(96.31), 71.2(71.05), 67.2, 55.08(55.06), 36.8(36.7), 31.8(31.7),

28.4(28.35), 27.3(27.2), 26.93(26.91), 23.4, 19.5, 19.3 (19.2), 15.4(15.2).

+ + Exact mass: [M-H] calcd. for [C40H54NO4Si2] 668.3586, found 668.3572

205

7.373 7.368 7.355 7.351 7.260 4.550 4.528 3.283 3.266 1.872 1.846 1.041 1.020

21.10

Ph Ph H N Si OTPS

OMOM 4.36 9.30

5.01

3.71 3.35 3.40

2.00 1.92 1.87 1.60 1.50 1.01 1.01 0.62

10 8 6 4 2 0 PPM

96.340 96.319 77.322 77.271 77.069 76.809 71.153 71.052 67.238 55.088 55.067 36.821 36.756 31.808 31.765 28.435 28.312 27.308 27.243 26.932 26.918 23.407 19.543 19.319 19.268 15.455 15.223 169.599 135.693 135.613 135.599 135.519 135.469 133.966 133.916 133.901 133.865 133.598 133.439 132.811 132.623 129.849 129.799 129.560 129.531 129.517 129.495 128.188 128.173 128.130 128.087 127.632 127.610 127.595 127.574

Ph Ph H N Si OTPS

OMOM 4.36

200 150 100 50 PPM

206

N-{(R)-1-[((S)-3-Hydroxy-2-methylpropyl)diphenylsilyl]-4-(methoxymethoxy)butyl}-

4-methylbenzenesulfonamide (4.44)

To a solution of 4.42 (6.0 g, 9.5 mmol) in CH2Cl2 (50 mL) at 0 °C was added 77% m-

CPBA (2.8 g, 12.3 mmol). The reaction mixture was stirred at the same temperature for 1

h, quenched with saturated NaHSO3 solution (50 mL), and then saturated NaHCO3 (50 mL). The aqueous layer was extracted with DCM (3 x 25 mL). Combined organic layers were dried over with Na2SO4, concentrated in vacuo. Column chromatography gave

compound 4.44 (4.7 g, 91%) as a viscous, colorless oil.

20 Rf = 0.45 (hexane / ethyl acetate 1:1), [α]D = - 8.1 (c 0.64 CHCl3);

IR: 3516, 3261, 3354, 3068, 2928, 2878, 1598, 1527, 1427, 1158, 1039, 703 cm-1;

1 H NMR (500 MHz, CDCl3): δ 7.7 (d, J = 8.2 Hz, 2H), 7.53-7.30 (m, 10H), 7.2 (d, J =

8.2 Hz, 2H), 5.0 (d, J = 10.0 Hz, 1H), 4.4 (s, 2H), 3.62-3.51 (m, 1H), 3.3 (dd, J = 10.4,

5.4 Hz, 1H), 3.20-3.17 (m, 2H), 3.12 (t, J = 6.0 Hz, 1H), 2.38 (s, 3H), 2.34 (br, 1H), 1.68-

1.60 (m, 1H), 1.6-1.55 (m, 1H), 1.31 (dd, J = 15.8, 5.4 Hz, 2H), 1.27-1.20 (m, 2H), 0.9

(dd, J = 15.3, 8.2 Hz, 1H), 0.65 (d, J = 6.5 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 143.1, 139.1, 135.7, 135.6, 133.1, 130.0, 129.6, 128.2,

128.1, 127.1, 96.2, 70.1, 67.3, 55.1, 42.5, 31.6, 28.8, 27.1, 21.6, 20.0, 15.6;

+ + Exact mass: [M-Na] calcd. for [C29H40NO5SSi] 564.2216, found 564.2221

207

7.483 7.462 7.311 7.295 7.291 7.275 7.259 7.255 7.121 7.107 7.103 7.089 7.034 6.998 6.979 4.207 4.161 2.991 2.964 2.157 0.439 0.422

Ph Ph H N Si OH Ts

OMOM 4.44

10.04

7.06

4.37 3.94 3.00 2.07 2.07 1.89 2.11 1.28 0.73 1.06

10 8 6 4 2 0 PPM

96.373 77.821 77.509 77.189 70.268 67.531 55.336 42.729 31.891 29.101 27.394 21.837 20.214 15.900 143.371 139.400 135.916 135.802 135.688 133.371 130.215 129.880 128.500 128.424 127.349

Ph Ph H N Si OH Ts

OMOM 4.44

140 120 100 80 60 40 20 PPM

208

(S)-3-{[(R)-4-(Methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl}

-2-methylpropanoic acid (4.43)

To a solution of compound 4.44 (10.0 g, 18.5 mmol) in a mixture of solvent

DCM/CH3CN/water (1/1/1, 300 mL) was added RuCl3 (3.8 mg, 0.18 mmol), and NaIO4

(15.8 g, 55.5 mmol) in 1 h. The mixture was stirred at rt. for 5 h, diluted with water (300 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over with Na2SO4, concentrated in vacuo. Column chromatography gave acid 4.43 (6.7 g,

78%). Rf = 0.47 (tail) (hexane / ethyl acetate 1:1)

20 [α]D = -21.4 (c 0.425, CHCl3)

IR: 3515-1500 (br.), 3269, 3237, 3069, 3046, 2933, 2884, 2647, 1706, 1598, 1454, 1427,

1326, 1156, 1111, 1038, 914, 735, 702 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.3 Hz, 2H), 7.5-7.3 (m, 10H), 7.2 (d, J =

10.0Hz, 2H), 4.5 (d, J = 10.0 Hz, 1H), 4.4 (s, 2H), 3.58-3.53 (m, 1H), 3.27 – 3.18 (m,

2H), 3.21 (s, 3H), 2.4 (s, 3H), 2.3 (dd, J = 14.3, 7.1 Hz, 1H), 1.7-1.6 (m, 1H), 1.5 (dd, J =

15.4, 6.5 Hz, 1H), 1.44-1.37 (m, 1H), 1.36-1.23 (m, 2H), 1.17 (dd, J = 15.4, 7.7 Hz, 1H),

0.97 (d, J = 7.1 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 182.7, 143.3, 138.9, 135.8, 135.7, 131.8, 131.7, 130.3,

129.7, 128.4, 127.2, 96.2, 67.3, 55.2, 42.6, 35.1, 29.0, 27.2, 21.7, 20.3, 16.0;

+ + Exact mass: [M-Na] calcd. for [C29H37NNaO6SSi] 578.2003, found 578.2014

209

7.694 7.673 7.503 7.499 7.495 7.486 7.482 7.479 7.475 7.342 7.339 7.327 7.258 7.207 4.447 4.435 3.223 3.216 2.381 0.980 0.962

Ph Ph H N Si OH Ts O

OMOM 4.43

9.48

4.86 4.02 3.16 2.98 1.92 2.04 1.98 0.92 0.97 1.00 0.99 1.09

10 8 6 4 2 PPM

96.262 77.588 77.268 76.947 67.344 55.209 42.572 35.148 29.051 27.221 21.665 20.346 15.971 182.673 143.320 138.907 135.820 135.721 131.857 131.758 130.317 129.745 128.396 127.215

Ph Ph H N Si OH Ts O

OMOM 4.43

150 100 50 0PPM

210

(S)-3-{[(R)-4-(Methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl}

-N,2-dimethylpropanamide (4.45)

Procedure 1:

To a solution of sulfonyl acid 4.43 (2.0 g, 3.8 mmol) and HATU (2.2 g, 5.7 mmol) in

DMF (20 mL) was added slowly NMM (1.3 mL, 11.4 mmol) at 0 °C for 10 min, and then

added methylamine hydrochloride (0.3 g, 4.6 mmol), stirred at rt for 12 h, diluted with

ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 mL).

Combined organics were washed with 5% HCl (3 x 5 mL) then 10% NaHCO3 (3 x 5 mL), brine (10 mL), dried over with Na2SO4, concentrated in vacuo to 5 mL solution, and

then cooled down to 0ºC for 30min. The precipitate was filtrated and then washed the

cake with cold ethyl acetate (2 x 5 mL). The mother liquid was concentrated in vacuo.

Column chromatography with eluent (hexane/ethyl acetate = 1/1 then 1/2) gave amide

4.45 (1.8 g, 84%) as a colorless foam

Procedure 2:

To a solution of sulfonyl acid 4.43 (5.0 g, 9.0 mmol) in THF (30 mL) at -20 °C was

added NMM (1.0 mL, 9.0 mmol) and then iso-butyl chloroformate (1.35 mL, 9.9 mmol),

stirred 5 minutes, and then added 40% methyl amine aqueous solution (0.85 mL, 9.9

mmol). The resulting solution was stirred at -20 °C for 10 min, then gradually warmed

up to rt. and stirred 1 h. The aqueous layer was extracted with ethyl acetate (3 x 20 mL).

Combined organic layers were washed with 10% NaHCO3 (2 x 10 mL) then 5% HCl (3 x

211

10 mL), water (2 x 10 mL) and brine (10 mL), dried over with sodium sulfate,

concentrated in vacuo. Column chromatography gave expected product 4.45 (4.7 g, 92%)

Rf = 0.65 (hexane / ethyl acetate 1:2)

20 [α]D = +49.6 (c 0.365, CHCl3)

IR: 3377, 3293, 3091, 3048, 2928, 2877, 1648, 1598, 1549, 1427, 1324, 1154, 1109,

1038, 702 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.3 Hz, 2H), 7.4-7.2 (m, 12H), 5.6 (d, J = 9.6

Hz, 1H), 5.3 (d, J = 4.6 Hz, 1H), 4.4 (s, 2H), 3.66-3.60 (m, 1H), 3.2 (s, 3H), 3.1-3.0 (m,

2H), 2.6 (d, J = 5.0 Hz, 3H), 2.4 (s, 3H), 2.3-2.2 (m, 1H), 1.67 (dd, J = 15.1, 8.3 Hz, 1H),

1.6-1.5(m, 1H), 1.3-1.1 (m, 4H), 1.0 (d, J = 6.8 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 178.1, 143.0, 139.5, 135.7, 135.5, 133.4, 132.9, 130.0,

129.9, 129.6, 128.2, 128.1, 127.1, 96.1, 67.3, 55.1, 42.1, 36.9, 28.6, 27.1, 26.4, 21.7, 21.6,

16.6;

+ + Exact mass: (FAB) MH , calcd for [C30H41N2O5SSi] 569.2500, found 569.2512

212

7.776 7.756 7.459 7.455 7.443 7.439 7.435 7.321 7.291 7.260 7.240 4.369 3.190 2.571 2.558 2.405 1.012 0.994

Ph Ph H H N Si N Ts O

OM OM

4.45 9.42

3.95 3.09 3.07 2.73 2.42 2.59 1.88 1.75 1.67 0.82 0.88 0.86 1.00 0.93 0.94

10 8 6 4 2 0PPM

96.141 77.520 77.200 76.880 67.322 55.104 42.062 36.918 28.610 27.146 26.399 21.757 21.635 16.567 178.093 143.047 139.518 135.699 135.470 133.405 132.894 130.082 129.960 129.655 128.245 128.108 127.124

Ph Ph H H N Si N Ts O

OM OM 4.45

180 160 140 120 100 80 60 40 20 PPM

213

(S)-3-[Diphenyl((R)-1-tosylpyrrolidin-2-yl)silyl]-N,2-dimethylpropanamide (4.48)

To a solution of sulfone 4.45 (0.15 mg, 0.26 mmol) in methanol (1.0 mL) at rt. was added

36% HCl solution (0.82 ml, 1.0 mmol). The resulting solution was stirred overnight. The solution was diluted with water (20 mL), extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (3 x 10 mL), brine (10 mL), dried over with Na2SO4, and concentrated in vacuo to give crude alcohol (136 mg, 99%).

+ + Exact mass: [M-H] calcd. [C28H37N2O4SSi] 525.2238, found 525.2261

The crude alcohol (136 mg, 0.26 mmol) was dissolved in DCM (5 mL), and added

triethyl amine (108 µL, 0.78 mmol) and methanesulfonyl chloride (72.5 µL, 0.3 mmol) at

0°C. The reaction mixture was stirred 30 min, diluted with water (10 mL). The aqueous

part was extracted with DCM (3 x 5 mL). The combined organic layers were washed with

brine (5 mL), dried over with Na2SO4, concentrated in vacuo to give crude mesylate.

+ + Exact Mass: [M-H] [C29H39N2O6S2Si] 603.2013, found 603.2026

214

The crude mesylate was dissolved in DMF (5 mL), added NaN3 (84.5 mg, 1.3 mmol),

heated at 60 °C for 1 h. The solution was diluted with water (20 mL), extracted with ethyl

acetate (3 x 5 mL). Combined organic layers were washed with water (5 x 10 mL),

washed with brine (10 mL), concentrated in vacuo. Column chromatography gave

compound 4.48 (105 mg, 78% over 3 steps).

Rf = 0.7 (hexane / ethyl acetate1:1)

20 [α]D = -38.9 (c 0.32 CHCl3)

IR: 3364, 2970, 2880, 1631, 1569, 1330, 1155, 732 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.2 Hz, 2H), 7.6-7.3 (m, 12H), 6.2 (d, J = 4.5

Hz, 1H), 4.1 (dd, J = 9.7, 4.8 Hz, 1H), 3.2 (ddd, J = 12.7, 7.8, 4.8 Hz, 1H), 2.7 (d, J =

4.8Hz, 3H), 2.65-2.59 (m, 1H), 2.44 (s, 3H), 2.41 (dt, J = 12.3, 7.8 Hz, 1H), 1.97 (dd, J =

15.0, 4.1 Hz, 1H), 1.73-1.60 (m, 2H), 1.38 (dd, J = 15.0, 10.4 Hz, 1H), 1.0-0.89 (m, 2H),

0.78 (d, J = 6.7 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 178.5, 143.9, 136.0, 135.9, 135.5, 133.8, 133.7, 130.2,

130.1, 130.0, 128.4, 128.2, 127.9, 49.6, 48.6, 35.9, 27.5, 26.3, 24.6, 21.7, 19.4, 18.3;

+ + Exact mass: (FAB) MH , calcd for [C28H35N2O3SSi] 507.2132, found 507.2132

215

7.762 7.745 7.588 7.575 7.572 7.570 7.558 7.409 7.394 7.343 7.339 7.337 7.327 7.261 2.696 2.687 2.444 0.780 0.766

Ts Ph2 H N Si N

4.48

11.82

4.04 3.34 2.76 2.95 1.93 2.17 0.94 0.97 1.00 1.16 0.97 1.00

10 8 6 4 2 0PPM

77.500 77.245 76.994 49.596 48.613 35.946 27.490 26.320 24.649 21.735 19.372 18.308 178.509 143.933 136.022 135.946 135.480 133.852 133.710 130.214 130.152 130.079 128.360 128.203 127.959

Ts Ph2 H N Si N

4.48

180 160 140 120 100 80 60 40 20 PPM

216

3-{[(R)-4-(Methoxymethoxy)-1-[N-(tert-butyl)carbamoyl-4-methylphenylsulfon

amido] butyl}diphenylsilyl)-N,2-dimethylpropanamide (4.52)

To a solution of amide 4.45 (5.0 g, 8.8 mmol) and DMAP (0.2 g, 1.76 mmol) in

acetonitrile (50 mL) was added Boc2O (3.8 g, 17.6 mmol) in acetonitrile (10 mL) via

syringe pump in 1h. The progress of reaction was monitored with TLC. The solution was

concentrated in vacuo and diluted in ethyl acetate (100 mL). The aqueous layer was

extracted with ethyl acetate (2 x 10 mL). Combined organic phases were washed with 5%

HCl (3 x 10 mL), water (2 x 30 mL), brine (2 x 10 mL), dried over with Na2SO4, and concentrated in vacuo. Column chromatography gave compound 4.52 (5.2 g, 88%).

20 Rf = 0.42 (hexane / ethyl acetate 1:2); [α]D = 32.2 (c 0.115, CHCl3); IR: 3314.1, 3071,

-1 1 2931, 2881, 1715, 1655, 1540, 1349, 1152, 1110, 733 cm ; H NMR (500 MHz, CDCl3):

δ 7.6 (dd, J = 16.5, 7.7 Hz, 4H), 7.4-7.2 (m, 8H), 7.1 (d, J = 8.3 Hz, 2H), 5.3 (d, J = 4.4

Hz, 1H), 4.6 (dd, J = 9.5, 5.0 Hz, 1H), 4.5 (s, 2H), 3.5-3.4 (m, 2H), 3.2 (s, 3H), 2.5 (d, J =

4.7 Hz, 3H), 2.4 (s, 3H), 2.3-2.2 (m, 1H), 1.97-1.81 (m, 2H), 1.85 (dd, J = 15.3, 6.6 Hz,

1H), 1.73-1.57 (m, 2H), 1.36 (dd, J = 15.4, 7.2 Hz, 1H), 1.24 (s, 9H), 0.94 (d, J = 6.8 Hz,

13 3H); C NMR (125 MHz, CDCl3): δ 177.9, 151.6, 144.0, 137.4, 136.4, 136.2, 135.0,

134.2, 129.7, 129.6, 129.2, 128.4, 128.0, 127.9, 95.5, 84.7, 67.3, 55.2, 48.0, 36.9, 28.3,

28.0, 27.8, 26.3, 21.7, 21.3, 17.4;

+ + Exact mass: [M-Na] calcd. for [C35H48N2NaO7SSi] 691.2844, found 691.2851

217

7.432 7.412 7.384 7.367 7.259 7.127 7.106 4.526 4.524 3.262 2.491 2.480 2.382 1.241 0.951 0.934

Ph Ph Boc H N Si N Ts O

OM OM 4.52

10 8 6 4 2 PPM

96.506 84.737 77.573 77.458 77.260 76.940 67.351 55.271 47.984 36.940 28.334 28.083 27.808 26.276 21.757 21.276 17.420 177.955 151.590 144.021 137.444 136.392 136.178 134.974 134.158 129.738 129.639 129.204 128.381 128.008 127.962

Ph Ph Boc H N Si N Ts O

OM OM 4.52

180 160 140 120 100 80 60 40 20 PPM

218

tert-Butyl-1-[(1(R)-N-methylamino-2(S)-methylpropionyl)diphenylsilyl](4-

(methoxymethoxy)butyl carbamate (4.53)

To a solution of compound 4.52 (4.0 g, 6.0 mmol) and Mg (1.44 g, 60 mmol) in

anhydrous methanol (40 mL) was stirred at rt until all Mg consumed. The methanol was

removed in vacuo by a half of volume, and then diluted with 5% hydrochloric acid till a

clear solution was formed (or acidic environment). The solution was extracted with ethyl

acetate (3 x 20 mL). The combined organics were washed with 30% sodium bicarbonate

(3 x 10 mL), dried over with sodium sulfate, concentrated in vacuo. Column

chromatography gave 4.53 (3.0 g, 96%) as a colorless foam.

Rf = 0.48 (ethyl acetate/ hexane=2/1);

20 [α]D = - 28.75 (c 0.24, CHCl3)

IR: 3325, 3070, 3048, 2874, 2881, 1694, 1647, 1520, 1245, 1108, 701 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.51-7.32 (m, 10H), 5.5 (d, J = 5.0 Hz, 1H), 4.5 (s, 2H),

3.88 (dt, J = 11.3, 2.1 Hz, 1H), 3.4 (s, 3H), 2.6 (d, J = 4.8 Hz, 3H), 2.34-2.25 (m, 1H),

1.77-1.66 (m, 2H), 1.64-1.52 (m, 1H), 1.6 (dd, J = 14.3, 5.7 Hz, 1H), 1.4 (s, 9H), 1.36-

1.22(m, 1H), 1.24 (dd, J = 15.1, 7.8 Hz, 1H), 0.93 (d, J = 6.6 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 177.9, 156.7, 135.4, 133.2, 133.1, 129.8, 128.1, 128.0,

96.3, 79.1, 67.2, 55.1, 37.6, 36.5, 28.4, 28.3, 27.1, 26.1, 20.6, 16.4;

+ + Exact mass: [M-H] calcd. for [C28H43N2O5Si] 515.2936, found 515.2939

219

7.498 7.257 4.535 3.269 2.593 2.580 1.410 0.944 0.928

Ph Ph H BocHN Si N

OMOM 4.53

10.99 9.18

2.96 3.07 2.89 3.17 3.00 2.10 2.18 2.16 1.37 0.88 0.90

10 8 6 4 2 PPM

96.326 79.120 77.307 77.264 77.054 76.802 67.187 55.074 37.652 36.510 28.449 28.276 27.120 26.174 20.619 16.408 177.905 156.669 135.433 135.418 133.244 133.128 129.849 128.094 128.036

Ph Ph H BocHN Si N

OMOM 4.53

180 160 140 120 100 80 60 40 20 0PPM

220

tert-Butyl-1-[(1(R)-N-methylamino-2(S)-methylpropionyl)diphenylsilyl]-4-azidobutyl carbamate (4.57)

To a solution of carbamate 4.53 (0.3 g, 0.58 mmol, (Note: this reaction cannot be scaled up) in DCM (5 mL) at -78 °C was added TMSBr (0.3 mL, 2.32 mmol). The

solution was stirred for 45 sec, and quenched with saturated NaHCO3 (5 mL) and water

(10 ml), extracted with DCM (3 x 10 mL). The organics were dried with sodium sulfate,

and concentrated in vacuo to give crude alcohol. The same amount of carbamate 4.53 was repeated for this reaction to accumulate up to 5.0 g of the crude alcohol that was confirmed by mass spectroscopy.

Ph Ph H BocHN Si N

+ + Exact mass: [M-H] calcd. for [C26H38N2NaO4Si] 493.2493, found 493.2487

The crude alcohol (5.0 g, 10.0 mmol) was dissolved in dry DCM (40 mL) at 0 °C

was added triethyl amine (2.1 mL, 15.0 mmol), followed by methanesulfonyl chloride

(1.16 mL, 15 mmol). Progress of reaction was monitored by TLC (reaction was

completed about 1 h). The solution was diluted with water (100 mL), extracted with

DCM (3 x 15 mL). The combined organic layers were washed with 10% HCl (2 x 10 mL)

and water (2 x 20 mL), brine (10 mL), dried over with Na2SO4, concentrated in vacuo, 221

and dried under high pressure several hours. Mesylate was confirmed by mass

spectroscopy.

+ + Exact mass: [M-H] calcd. for [C27H41N2O6SSi] 549.2449, found 549.2451

The crude mesylate was dissolved in DMF (30 mL), and added NaN3 (2.6 g, 40

mmol). The mixture was warmed up at 60 °C for 5 h, diluted with water (150 mL) and

ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3 x 10 ml).

Combined organic layers were washed with water (6 x 50 mL), and brine (2 x 20 mL),

dried over with Na2SO4, and concentrated in vacuo. Column chromatography gave 4.57

(2.6 g, 53%) as a foam.

20 Rf = 0.75 (hexane / ethyl acetate 1:2); [α]D = -30.5 (c 0.445, CHCl3)

IR: 3319, 3070, 3049, 2973, 2931, 2095, 1699, 1647, 1251, 1170, 1109, 701 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.5-7.3 (m, 10H), 5.4 (d, J = 4.9 Hz, 1H), 4.7 (d, J = 10.6

Hz, 1H), 3.9 (t, J = 12.3 Hz, 1H), 3.3-3.2 (m, 2H), 2.6 (d, J = 4.8 Hz, 3H), 2.33-2.26 (m,

1H), 1.68-1.56 (m, 3H), 1.63 (dd, J = 15.0, 7.1 Hz, 1H), 1.43 (s, 9H), 1.4-1.3 (m, 1H),

1.27 (dd, J = 15.0, 7.0 Hz, 1H), 1.0 (d, J = 6.7 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 177.9, 156.7, 135.6, 135.5, 133.4, 133.3, 130.0, 128.3,

79.4, 51.0, 37.6, 37.0, 29.0, 28.6, 26.4, 26.3, 21.3, 16.5;

+ + MS: Exact mass: [M-Na] calcd. for [C26H37N5NaO3Si] 518.2558, found 518.2562

222

7.530 7.516 7.513 7.500 7.399 7.388 7.373 7.275 2.607 2.598 1.436 1.417 1.014 1.000 0.086

Ph Ph H BocHN Si N

N3 4.57

11.12

8.75

4.13 3.55 3.08 2.00 2.43 1.13 0.79 0.96 0.86 0.13

10 8 6 4 2 PPM

79.414 77.455 77.200 76.945 51.073 37.656 36.924 29.043 28.621 28.570 26.388 26.312 21.286 16.504 177.892 156.885 135.664 135.573 135.511 133.399 133.286 130.081 128.304 127.972

Ph Ph H BocHN Si N

N3 4.57

200 150 100 50 0 PPM

223

(S)-3-[((R)-1-acetamido-4-azidobutyl)diphenylsilyl]-N,2-dimethylpropanamide

(4.21)

Ph Ph Ph Ph 1. HCl H H H N Si N BocHN Si N O O O 2. HATU, NMM HOAc, DMF, rt 72% N3 N3 4.57 4.21

To a solution of azide 4.57 (0.3 g, 0.6 mmol) in DCM (5 mL) was added 4M HCl solution (0.6 ml, 2.4 mmol). The solution was stirred over night at rt, concentrated in vacuo to give a crude ammonium salt.

Route 1:

Acetic acid (43 µL, 0.72 mmol) in DMF (2 mL) at 0 °C was added HATU (0.34 mg, 9.0 mmol), followed NMM (0.1 mL, 0.9 mmol). The resulting solution was stirred at 0 °C for

10 min. The above crude ammonium salt was dissolved in DMF (2 mL), and then added

NMM (0.1 mL, 0.9 mmol). The resulting solution was transferred to activated acetic acid.

The mixture was stirred at rt overnight, diluted with ethyl acetate (20 mL), water (20 mL). The aqueous layer was extracted with ethyl acetate (3 x 5 mL). Combined organic layers were washed with 5% HCl (3 x 5 mL), 5% NaHCO3 (3 x 5 mL), water (5 x 10

mL), and brine (10 mL), concentrated in vacuo to 3 mL volume. The solution was cooled

at 0 ºC 30 min to form excess HATU and its byproduct (tetra methyl urea). After

filtration, the mother solution was concentrated. Column chromatography with eluent

ethyl acetate and methanol (100/0-100/5) gave 4.21 (0.19 g, 72%).

224

Route 2:

The crude ammonium salt (made above) was dissolved in DCM (5.0 mL) at 0 °C; added triethyl amine (0.25 mL, 1.8 mmol), followed acetyl chloride (65 µL, 0.9 mmol).

The solution was stirred at 0 ºC 30 min. and at rt. 3 h, and then diluted with water (10 mL), extracted with DCM (3 x 5 mL). The combined organic layers were washed with

5% HCl (2 x 5 mL), water (2 x 10 mL) and brine (10 mL), dried over with sodium sulfate, concentrated in vacuo. Column chromatography gave 4.21 (60 mg, 23%) as a

colorless oil.

Rf = 0.25 (ethyl acetate) or 0.75 (DCM/MeOH 6:1)

20 [α]D = - 39.6 (c 0.375, CHCl3)

IR: 3288, 3069, 3050, 2960, 2929, 2874, 2095, 1644, 1549, 1427, 1257, 1109, 700 cm-1.

1 H NMR (500 MHz, CDCl3): δ 7.52-7.32 (m, 10H), 6.4 (d, J = 10.5 Hz, 1H), 5.5 (br,

1H), 4.3 (dt, J = 10.5, 2.7 Hz, 1H), 3.3-3.1 (m, 2H), 2.6 (d, J = 4.9 Hz, 3H), 2.38-2.29 (m,

1H), 2.0 (s, 3H), 1.7-1.5 (m, 4H), 1.42-1.32 (m, 1H), 1.27 (dd, J = 15.2, 6.4 Hz, 1H), 1.0

(d, J = 6.7 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 178.3, 170.6, 135.4, 135.3, 133.7, 132.9, 130.1, 128.3,

51.0, 36.9, 36.2, 28.6, 26.5, 26.3, 23.5, 21.5, 16.0;

+ + Exact mass: [M-H] calcd. for [C23H32N5O2Si] 438.2320, found 438.2328

225

7.470 7.467 7.454 7.450 7.447 7.372 7.370 7.361 7.352 7.260 2.572 2.560 1.993 1.028 1.011

Ph Ph H H N Si N

O O

N3 4.21

10.39

4.22 3.50 3.03 3.23 2.00 1.25 1.46 0.82 0.96 0.98 0.98 0.14

10 8 6 4 2 0 PPM

77.543 77.223 76.910 51.003 36.933 36.201 28.587 26.468 26.346 23.488 21.506 16.003 178.321 170.646 135.409 135.287 135.196 133.679 132.925 130.143 130.104 128.306

Ph Ph H H N Si N

O O

N3 4.21

180 160 140 120 100 80 60 40 20 0 PPM

226 tert-Butyl (R)-4-acetamido-4-{[(S)-2-methyl-3-(methylamino)-3-oxopropyl] diphenylsilyl}butylcarbamate (4.59)

To a solution of azide 4.21 (0.35 g, 0.8 mmol) and Boc2O (0.2 g, 9.6 mmol), and Lindlar catalyst (70 mg) in anhydrous methanol (5 mL) was degassed with hydrogen and H2- filled balloons was applied. Progress of reaction was monitored by IR spectroscopy. The solution was filtered through a short pad of Celite and the cake filter was washed with methanol (6 mL). The combined solutions were concentrated in vacuo. Flash column chromatography using 2% MeOH in ethyl acetate afforded carbamate 4.59 (360 mg,

87%) as a foam.

Rf = 0.40 (acetate / methanol 100:5);

20 [α]D = -29.0 (c 0.155, CHCl3)

IR: 3302, 3070, 2975, 2875, 1697, 1647, 1538, 1171, 1109, 701cm-1.

1 H NMR (500 MHz, CDCl3): δ 7.6-7.3 (m, 10H), 6.3 (d, J = 10.0 Hz, 1H), 5.6 (br, 1H),

4.5 (br, 1H), 4.3 (t, J = 10.6 Hz, 1H), 3.05 (m, 2H), 2.6 (d, J = 4.3 Hz, 3H), 2.4 -2.3 (m

1H), 2.0 (s, 3H), 1.7-1.5 (m, 3H), 1.4 (s, 9H), 1.35-1.2 (m, 3H), 1.0 (d, J = 6.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 178.2, 170.6, 156.2, 135.5, 135.3, 133.8, 133.2, 130.1,

128.3, 79.1, 40.4, 36.9, 36.8, 28.9, 28.6, 27.9, 26.3, 23.5, 21.4, 16.4;

+ + Exact mass: [M-Na] calcd. for [C28H41N3NaO4Si] 534.2759, found 534.2761

227

7.481 7.466 7.409 7.399 7.374 7.361 7.276 2.588 2.579 2.003 1.925 1.420 1.404 1.017 1.003

Ph Ph H H N Si N

O O

NHBoc 4.59

10.60 10.92

3.76 3.49 3.00 2.86 1.91 2.22 1.15 0.78 0.63 1.07 0.87 0.65

10 8 6 4 2 0 PPM

77.455 77.200 76.945 36.949 36.840 28.879 28.609 27.903 26.319 23.482 21.431 16.384 178.241 170.575 156.219 135.511 135.376 135.314 133.843 133.267 130.103 130.073 128.311

Ph Ph H H N Si N

O O

NHBoc 4.59

180 160 140 120 100 80 60 40 20 0PPM

228

3-((R)-1-Acetamido-4-[N,N-(bis-tert-butylcarbanoyl)guanidino]}butyldiphenylsilyl)-

N,2(S)-dimethylpropanamide (4.60)

To a solution of carbarmate 4.59 (0.2 g, 0.4 mmol) in DCM (2 mL) was added 4M HCl

(in dioxane, 0.5 mL, 2 mmol). The solution was stirred 5 h, concentrated in vacuo. The residue was diluted with DMF (5 mL) then cooled down with ice bath, added triethyl amine (0.17 mL, 1.2 mmol) and N,N’-di-(tert-butoxycarbonyl)thiourea (112 mg, 0.4 mmol) followed mercury chloride (120 mg, 4.4 mmol). The resulting mixture was stirred at 0 ºC for 20 min, diluted with ethyl acetate (20 mL), and filtered through a pad of

Celite. The filter solution was washed with water (6 x 10 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo. Flash column chromatography on silica gel eluting with ethyl acetate/ methanol (100/5) afforded guanidine 4.60 (220 mg, 85%) as a colorless foam.

Rf= 0.5 (ethyl acetate / methanol 100:5)

20 [α]D = -9.1 (c 0.36, CHCl3)

IR: 3326, 3070, 2978, 2854, 1716, 1652, 1559, 1133, 700 cm-1

1 H NMR (500 MHz, CDCl3): δ 8.2 (t, J = 4.8 Hz, 1H), 7.5-7.27 (m, 10H), 6.5 (d, J = 10.0

Hz, 1H), 5.6 (d, J = 3.9 Hz, 1H), 4.3 (dt, J = 11.7, 2.7 Hz, 1H), 3.40-3.37 (m, 1H), 3.3-3.2

(m, 1H), 2.6 (d, J = 4.6 Hz, 3H), 2.4-2.33 (m, 1H), 2.0 (s, 3H), 1.7-1.6 (m, 2H), 1.56 (dd,

229

J = 15.2, 7.0 Hz, 2H), 1.38-1.30 (m, 1H), 1.26 (dd, J = 15.2, 7.0 Hz, 1H), 1.1 (d, J = 6.6

Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 178.0, 170.3, 163.5, 156.3, 153.2, 135.3, 135.2, 133.4,

133.0, 129.8, 128.1, 128.0, 83.0, 79.1, 40.5, 37.1, 36.5, 28.3, 28.0, 27.9, 27.3, 26.1, 23.3,

20.8, 16.4;

29 Si NMR (99.3, CDCl3): δ -8.53;

+ + Exact mass: [M-Na] calcd. for [C34H51N5NaO6Si] 676.3501, found 676.3504

230

7.276 2.618 2.609 2.039 1.508 1.499 1.494 0.970 0.957

H Ph Ph H N Si N

O O NHBoc N H NBoc 4.60

17.06

9.54

5.49

3.23 3.51 2.77 3.06 0.89 0.91 0.91 0.93 0.84 1.02 1.00

10 8 6 4 2 0 PPM

82.997 79.148 77.217 76.962 76.707 40.485 37.087 36.533 28.314 28.062 27.957 27.359 26.085 23.270 20.826 16.430 178.033 170.327 163.494 156.280 153.202 135.328 135.244 135.040 133.456 133.037 129.843 128.102 128.051

H Ph Ph H N Si N

O O NHBoc N H NBoc 4.60

180 160 140 120 100 80 60 40 20 PPM

231

4(R)-Acetamido-4-[dihydroxyl-3-(N,3(S)-dimethyl-3-oxopropyl)silyl]butyl guanidinium acetate (4.15)

To a solution of guanidine 4.60 (120 mg, 0.18 mmol) in acetic acid and DCM (2/8, mL)

was stirred at room temperature 6 h, and then cooled down at 0 ºC and added Hg(OAc)2

(576 mg, 1.8 mmol). The resulting solution was stirred at that condition for 2 h. The excess Hg(OAc)2 was filtered off through a pad of Celite. The mother liquid was

concentrated in vacuo to give a viscous liquid. To the viscous liquid was diluted with

ether (5 mL) and stirred with a rod to form white precipitate. The precipitate was

collected and washed several times with ether, transferred to a 10 mL round bottom flask

and then added water (3 mL). The resulting solution was stirred at 5 ºC for 2 h. The solid

was filtered off. The mother liquid was concentrated in vacuo to yield silanediol 4.15.

1 H NMR (500 MHz, D2O): δ 4.7 (br, 9H, including protons from HOAc and water), 3.3-

3.0 (m, 3H), 2.6 (d, J = 3.7 Hz, 3H), 2.4 (m, 1H), 2.0 (s, 3H, including protons from

HOAc), 1.59-1.45 (m, 4H), 1.07 (d, J = 5.8 Hz, 3H), 0.97 (dd, J = 13.3, 5.0 Hz, 1H), 0.7

(dd, J = 14.1, 7.5 Hz, 1H).

13 C NMR (125 MHz, D2O): δ 180.8, 178.7, 173.85, 173.81, 41.2, 39.7, 38.1, 29.0, 27.0,

26.1, 25.9, 22.1, 21.5, 21.3;

29 Si NMR (99.3MHz, D2O) -48.6 (-57.9 rotomers)

+ + Exact mass: [M-Na] calcd. for [C14H31N5NaO6Si] 416.1936, found 416.1963

232

4.775 4.749 4.735 4.694 4.654 4.634 4.614 3.212 3.191 3.098 2.631 2.623 2.472 2.460 2.112 2.063 2.026 2.017 1.984 1.943 1.936 1.930 1.922 1.906 1.853 1.596 1.579 1.467 1.450 1.089 1.079 1.068 0.930 0.921 0.764 0.749

H HO OH H N Si N

O O

NH2OAc 41.19

HN NH2 29.16 4.15

4.65 3.00 3.25 1.19 2.05 0.20 0.50 0.96 0.98 0.94

10 8 6 4 2 0PPM

41.191 39.749 38.107 38.038 29.053 27.035 26.318 26.179 25.895 22.210 22.133 21.463 21.307 180.841 178.729 173.852 173.801 137.138

H HO OH H N Si N

O O

NH2OAc

HN NH2 4.15

180 160 140 120 100 80 60 40 20 PPM

233

(S)-2-((S)-2-Acetamido-4-methylpentanamido)propanoic acid (4.66)

To a solution of acid 4.65 (3.0 g, 17.3 mmol) in dry THF (40 mL) at -20 °C was added NMM (1.7 mL, 17.3 mmol) followed by iso-butyl chloroformate (2.2 mL, 19.0 mmol). The mixture was stirted at the same temperature for 5 min, and then added a solution of compound 4.63 (6.7 g, 19.0 mmol) in THF and NMM (1.9 mL, 19.0 mmol).

The reaction solution was stirred at –20 °C for 30 min and at room temperature 1 h. The solution was diluted with water (100 mL) and ethyl acetate (60 mL). The organic layers were washed with 10% HCl (3 x 10 mL), water (10 mL) and 10% NaHCO3 (3 x 10 mL),

water (3 x 10 mL) and brine (2 x 10 mL), then dried over with Na2SO4. After filtration,

the solution was concentrated in vacuo to give clear, crude oil (6.5 g, 93%). The oil was

dissolved in absolute ethanol (40 mL) containing 10% Pd/C (560 mg). An H2-filled balloon was applied for 3 h. The solution was filtered through a pad of Celite, concentrated in vacuo to give acid 4.66 (2.6 g, 74%), recrystallized from ethyl acetate.

20 Mp. = 178-179 °C; [α]D = -57.6 (c 0.255, MeOH); IR: 3286 (br), 3050, 1727, 1654,

-1 1 1589, 1535, 1400, 1211, 975 cm ; H NMR (500 MHz, CD3OD): δ 4.9 (br, 1H), 4.4, (dd,

J = 10.0, 5.6 Hz, 1H), 4.3 (ddd, J = 7.5 Hz, 1H), 1.9 (s, 3H), 1.73-1.66 (m, 1H), 1.62-1.5

(m, 2H), 1.4 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); 13C

NMR (125 MHz, CD3OD): δ 175.9, 174.8, 173.3, 53.1, 49.6, 42.1, 25.9, 23.5, 22.5, 22.1,

17.7;

+ + Exact mass: [M-Na] calcd. for [C11H20N2NaO4] 267.1315, found 267.1314

234

4.399 4.384 3.330 3.327 2.003 1.989 1.619 1.593 1.422 1.408 0.988 0.979 0.974 0.954 0.948 0.941

O H N OH N H O O 6.07

4.66

3.16 3.00 3.06

1.99 2.05

1.02

10 8 6 4 2 0PPM

49.669 53.143 49.503 49.387 49.329 49.156 48.990 48.816 48.650 42.150 25.972 23.559 22.541 22.187 17.723 175.926 174.814 173.369

O H N OH N H O O

4.66

180 160 140 120 100 80 60 40 20 PPM

235

(S)-3-{[(R)-1-((S)-2-Acetamidopropanamido)-4-azidobutyl]diphenylsilyl}-N,2- dimethylpropanamide (4.70a)

Ph Ph 1. HCl O Ph Ph H H H N Si N BocHN Si N N H O 2. HATU, NMM O O ,DMF,rt 76% O N3 N3 OH 4.57 N 4.70a H O 4.69

Following the procedure for synthesis of 4.21 (p.224), using 4.57 (0.3 g, 0.6

mmol), 4M HCl (0.6 mL, 2.4 mmol), (S)-2-acetamidopropanoic acid 4.69 (86.5 mg, 0.66

mmol), HATU (0.34 g, 0.9 mmol), NMM (0.22 mL, 2.0 mmol), and DMF (6 mL) gave

4.70a (231mg, 76%) as a colorless foam.

Rf= 0.6 (ethyl acetate / methanol 100:15)

20 [α]D = -22.8 (c 0.425, CHCl3)

IR: 3286, 3066, 2969, 2935, 2098, 1643, 1542, 1253, 1106, 705 cm-1

1 H NMR (400 MHz, CD3OD): δ 7.4-7.3 (m, 12H, including 2H from NH), 4.2-4.0 (m,

2H), 3.18-3.12 (m, 2H), 2.3 (d, J = 9.0 Hz, 3H), 1.86, 1.85, 1.82 (s, 3H), 1.62-1.17 (m,

6H), 1.18, 1.11 (d, J = 7.0 Hz, 3H), 0.99, 0.93 (d, J = 7.0 Hz, 3H).

13 C NMR (100 MHz, CD3OD): δ 180.3, 175.1, 175.0, 173.1, 136.9, 136.8, 134.2 (134.1),

133.9, 131.1, 129.2, 51.8 (51.78), 50.9 (50.8), 38.2, 37.7 (37.73), 29.1, 27.4(27.3),

26.4(26.39), 22.6 (22.5), 22.1, 18.3 (18.1) 16.9;

+ + Exact mass: [M-Na] calcd. for [C26H36N6NaO3Si] 531.2510, found 531.2492

236

7.490 7.473 7.463 7.459 7.339 7.329 7.316 7.299 4.781 2.361 2.349 2.339 1.846 1.828 1.200 1.183 1.118 1.100 0.942 0.925

O H Ph Ph H N Si N N H O O

N3 4.70a

10 8 6 4 2 0 PPM

51.833 51.787 50.934 50.895 50.812 49.790 49.577 49.363 49.150 48.937 48.723 48.510 38.212 37.770 37.732 29.089 27.420 27.320 26.436 26.391 22.648 22.580 22.107 18.311 18.128 16.932 175.059 175.036 173.107 180.333 136.933 136.918 136.804 134.220 134.121 133.961 131.118 129.242

O H Ph Ph H N Si N N H O O

N3 4.70a

200 150 100 50 0 PPM

237

7.502 7.375 7.360 7.344 7.330 3.236 3.180 3.173 3.162 2.512 2.416 2.408 1.173 0.946 0.934

O H Ph Ph H N Si N N H O O

N3 4.70a in DMSO-d ,at380°K 6 12.82

7.27

5.46 4.63

3.43 3.00

1.64 1.79 1.30 0.92 0.85 0.75 0.57

10 8 6 4 2 0PPM

238

(S)-2-Acetamido-N-[(S)-1-((R)-4-azido-1-{[(S)-2-methyl-3-(methylamino)-3-

oxopropyl] diphenylsilyl}butylamino)-1-oxopropan-2-yl]-4-methylpentanamide

(4.70b)

Following the procedure for synthesis of 4.21 (p.224), using 4.57 (0.3 g, 0.6 mmol), 4M

HCl (0.6 mL, 2.4 mmol), acid 4.66 (161 mg, 6.6 mmol), HATU (0.34 g, 0.9 mmol),

NMM (0.22 mL, 2.0 mmol), and DMF (6 mL) gave 4.70b (280 mg, 75%) as a colorless

foam.

20 Rf= 0.5 (ethyl acetate / methanol 100:15); [α]D = -14.4 (c 0.25, CHCl3)

IR: 3286, 3062, 2954, 2098, 1646, 1542, 1376, 1253, 1106, 701 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.6-7.4 (m, 10H), 7.1 (d, J = 7.8 Hz, 1H), 7.0 (d, J = 7.8

Hz, 1H), 6.9 (d, J = 10.0 Hz, 1H), 5.4 (d, J = 4.9 Hz, 1H), 4.60-4.55 (m, 1H), 4.5 (tt, J =

7.8 Hz, 1H), 4.2 (dt, J = 10.0, 2.6 Hz, 1H), 3.26-3.17(m, H), 2.6 (d, J = 4.6 Hz, 3H), 2.23

(m, 1H), 2.0 (s, 3H), 1.87 (ddd, J = 13.5, 8.1, 5.0 Hz, 1H), 1.8-1.74 (m, 1H), 1.74-1.68 (m

1H), 1.66-1.61 (m, 1H), 1.58 -1.54 (m, 1H), 1.58-1.50 (m, 1H), 1.52 (dd, J = 14.7, 6.7

Hz, 1H), 1.38 (d, J = 7.3 Hz, 3H), 1.33 -1.26 (m, 1H), 1.3 (dd, J = 15.0, 7.8 Hz, 1H), 1.02

(d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz, 3H); 13C NMR (125

MHz, CDCl3): δ 178.3, 172.4, 172.0, 170.6, 135.4, 135.3, 133.0, 132.7, 130.0, 129.9,

128.1, 128.09, 51.7, 50.8, 50.0, 40.9, 37.1, 36.2, 28.6, 26.28, 26.19, 24.9, 23.0, 22.9, 21.9,

+ + 21.4, 17.4, 15.54; Exact mass: [M-Na] calcd. for [C32H47N7NaO4Si] 644.3351 found

644.3327

239

7.573 7.561 7.558 7.533 7.520 7.517 7.440 7.426 7.413 7.409 7.406 7.394 7.392 7.275 2.615 2.605 2.034 2.018 1.393 1.379 1.025 1.012 0.991 0.978 0.976 0.962

10.35

O Ph H H 2 H 8.46 N N Si N N H O O O

N3 4.70b

3.32 2.97 2.95 2.84 2.83 2.55 2.63 2.00

1.01 0.97 1.01 1.01 0.82 0.82 0.88 0.96 0.90

10 8 6 4 2 0PPM

77.206 76.951 76.697 51.738 50.853 48.996 40.896 37.123 36.268 26.281 28.612 26.190 24.898 22.989 22.873 21.937 21.419 17.399 15.549 178.339 172.483 171.980 170.607 135.441 135.321 133.081 132.760 130.014 129.931 128.142 128.091

O H H Ph2 H N N Si N N H O O O

N3 4.70b

150 100 50 0PPM

240

(S)-1-Acetyl-N-[(S)-1-((R)-4-azido-1-{[(S)-2-methyl-3-(methylamino)-3-oxopropyl] diphenylsilyl}butylamino)-1-oxopropan-2-yl]pyrrolidine-2-carboxamide (4.70c)

Following the procedure for synthesis of 4.21 (p.224), using 4.57 (0.3 g, 0.6 mmol), 4M

HCl (0.6 mL, 2.4 mmol), acid 4.64 (150 mg, 0.66 mmol), HATU (0.34 g, 0.9 mmol),

NMM (0.22 mL, 2.0 mmol), and DMF (6 mL) gave 4.70c (270 mg, 72%) as a colorless foam.

20 Rf= 0.5 (ethyl acetate / methanol 100:20); [α]D = -26.9 (c 0.42, CHCl3)

IR: 3295, 3069, 2972, 2933, 2876, 2095, 1641, 1545, 1427, 1250, 1108, 701 cm-1; 1H

NMR (500 MHz, CD3OD): δ 7.6-7.3 (m, 10H), 4.4-4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H),

4.1 (t, J = 7.5 Hz, 1H), 3.6-3.5 (m, 2H), 3.1 (t, J = 5.8 Hz, 2H), 2.5-2.42 (m, 1H), 2.4 (d, J

= 4.5 Hz, 3H), 2.1-2.0 (m, 1H), 2.07-2.01 (m, 1H), 1.95 (s, 3H), 1.9-1.87 (m, 2H), 1.7-1.6

(m, 2H), 1.61 – 1.53 (m, 2H), 1.40-1.29 (m, 2H), 1.21 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 6.6

Hz, 3H).

13 C NMR (125 MHz, CD3OD): δ 180.47, 175.1, 174.6, 171.6, 137.0, 136.9, 134.73,

134.69, 130.93, 130.88, 129.1, 61.8, 52.0, 51.2, 48.6, 39.1, 38.0, 30.7, 28.8, 27.5, 26.4,

26.2, 22.4, 22.2, 18.0, 16.7;

+ Exact mass: Calcd. for [C31H44N7O4Si] 606.3219, found 606.3304

241

7.555 7.533 7.359 7.345 7.337 4.784 2.399 2.390 1.952 1.221 1.207 1.004 0.991

12.23

O O H Ph2 H N N Si N N H O O

N3 4.70c

3.06 3.00 2.78 2.69 2.50 2.50 2.13 2.21 1.90 1.98 1.70

1.14 1.11 0.94

10 8 6 4 2 PPM

61.762 52.085 51.281 49.667 49.500 49.329 49.157 48.986 48.819 48.647 39.131 38.031 30.740 28.777 27.462 26.381 26.206 22.393 22.211 18.012 16.693 180.474 175.092 174.614 171.588 137.001 136.906 134.735 134.695 130.933 130.882 129.265 129.090 129.072

O O H Ph2 H N N Si N N H O O

N3 4.70c

180 160 140 120 100 80 60 40 20 PPM

242

tert-Butyl (R)-4-((S)-2-acetamidopropanamido)-4-{[(S)-2-methyl-3-(methylamino)-3-

oxopropyl]diphenylsilyl}butylcarbamate (4.71a)

Following the procedure for synthesis of 4.59 (p. 227), using 4.70a (0.3 g, 0.6

mmol) and Boc2O (157 mg, 0.66 mmol), and Lindlar catalyst (60 mg) in anhydrous

methanol (5 mL), and H2-filled balloons gave carbamate 4.71a (300 mg, 86%) as a colorless foam.

Rf= 0.5 (ethyl acetate / methanol 100:15)

20 [α]D = -5.1 (c 0.33, CHCl3)

IR: 3301, 3058, 2969, 2931, 1649, 1538, 1419, 1164, 701 cm-1

1 H NMR (400 MHz, CD3OD): δ 8.0-7.9 (d, J = 7.5 Hz, 1H), 7.50-7.25 (m, 12H,

including 2H from NH), 6.4 (br, 1H), 4.2-4.0 (m, 2H), 2.90-2.84 (m, 2H), 2.3 (d, J = 4.4

Hz, 3H), 2.3 (m, 1H), 1.84 (s, 3H), 1.6-1.5 (m, 1H), 1.5(dd, J = 7.7, 2.5 Hz, 1H), 1.47

(dd, J = 7.7, 2.5 Hz, 1H), 1.3 (s, 9H), 1.3-1.2 (m, 2H), 1.24 (dd, J = 14.7, 7.3 Hz, 2H), 1.0

(d, J = 7.3 Hz, 3H), 0.9 (d, J = 7.0 Hz, 3H).

13 C NMR (125 MHz, CD3OD): δ 184.0, 175.0, 173.2, 158.7, 137.0, 136.96, 134.5, 134.4,

131.2, 129.3, 80.0, 51.0, 50.1, 41.2, 39.2, 37.9, 29.1, 26.5, 22.8, 22.2, 18.5, 18.2, 17.3.

+ + Exact mass: [M-Na] calcd. for [C31H46N4NaO5Si] 605.3130 found 605.3128

243

7.459 7.443 7.313 7.299 7.281 4.777 3.255 2.356 2.345 2.335 2.324 1.845 1.820 1.302 1.103 1.085 0.922 0.917 0.905 0.900

O H Ph2 H N Si N N H O O

NHBoc 4.71a

12.65 11.55

4.18 4.09 3.21 3.34 3.43 2.11 2.00 0.33 0.44

10 8 6 4 2 PPM

80.071 51.074 51.001 50.954 50.156 49.814 49.643 49.475 49.304 49.133 48.965 48.794 41.234 39.212 38.054 37.985 37.941 29.707 29.641 29.131 26.571 26.531 22.831 22.252 22.190 18.497 18.268 17.375 17.324 180.486 180.413 174.987 173.206 158.737 137.053 136.962 134.602 134.565 134.525 134.379 131.193 131.164 129.386 129.354

O H Ph2 H N Si N N H O O

NHBoc 4.71a

180 160 140 120 100 80 60 40 20 PPM

244

tert-Butyl (R)-4-[(S)-2-((S)-2-acetamido-4-methylpentanamido)propanamido]-4-

{[(S)-2-methyl-3-(methylamino)-3-oxopropyl]diphenylsilyl}butylcarbamate (4.71b)

Following the procedure for synthesis of 4.59 (p. 227), using 4.70b (0.4 g, 0.64 mmol) and Boc2O (154 mg, 0.65 mmol), and Lindlar catalyst (60 mg) in anhydrous

methanol (5mL), and H2-filled balloons gave carbamate 4.71b (356 mg, 80%) as a

colorless foam.

Rf= 0.4 (ethyl acetate / methanol 100:15)

20 [α]D = - 17.0 (c 0.37, CHCl3)

IR: 3297, 3062, 2962, 2935, 1650, 1535, 1369, 1253, 1168, 732 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.6-7.3 (m, 12H, including 2H from NH), 7.14 (d, J = 7.2

Hz, 1H), 7.0 (d, J = 7.6 Hz, 1H), 6.8 (d, J = 10 Hz, 1H), 5.6 and 4.72 (br, 1H), 4.6-4.25

(m, 2H), 4.2 (t, J = 10.5 Hz, 1H), 3.07-2.95 (m, 2H), 2.56 (d, J = 4.5 Hz, 3H), 2.0, 1.95

(s, 3H), 1.8-1.4 (m, 7H), 1.4 (s, 9H), 1.36 (d, J = 7.2 Hz, 3H), 1.3-1.23 (m, 2H), 1.0 (d, J

= 7.2 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 178.4, 172.6, 172.1, 171.0, 156.2, 135.6, 135.5, 133.5,

130.0, 128.2, 79.1, 52.1, 49.6, 40.9, 40.5, 37.1, 29.0, 28.6, 27.9, 27.5, 26.4, 25.0, 23.4,

23.0, 22.2, 21.4, 17.7, 16.0

+ + Exact mass: [M-Na] calcd. for [C37H57N5NaO6Si] 718.3970, found 718.3952

245

1 400 2.283 2.052 2.040 2.003 1.999 1.955 1.941 1.919 1.740 1.686 1.672 1.660 1.646 1.620 1.614 1.602 1.595 1.580 1.565 1.559 1.550 1.547 1.529 1.525 1.517 1.497 1.484 1.477 1.460 1.440 1.438 1.435 1.413

O H H Ph2 H N N Si N N 33.25 H O O O

NHBoc 4.71b

11.96

7.04

3.13 2.96 2.01 1.87 2.02 0.78 0.98 0.89 0.52 0.73 0.56 0.45 0.39

10 8 6 4 2 0PPM

79.108 77.433 77.178 76.923 52.155 40.894 40.479 37.139 36.917 36.855 29.021 28.886 28.613 27.896 27.499 26.402 26.279 25.044 23.434 23.052 22.214 21.428 17.709 16.380 15.921 178.424 172.178 156.197 135.609 135.529 135.340 133.486 133.253 130.070 130.012 128.252

O H H Ph2 H N N Si N N H O O O

NHBoc 4.71b

180 160 140 120 100 80 60 40 20 PPM

246

tert-Butyl (R)-4-[(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)propanamido]-4-

{[(S)-2-methyl-3-(methylamino)-3-oxopropyl]diphenylsilyl}butylcarbamate (4.71c)

Following the procedure for synthesis of 4.59 (p. 227), using 4.70c (0.4 g, 0.66 mmol) and Boc2O (158 mg, 0.73 mmol), and Lindlar catalyst (60 mg) in anhydrous

methanol (5 mL), and H2-filled balloons gave carbamate 4.71c (368 mg, 82%) as a

colorless foam.

Rf = 0.4 (ethyl acetate / methanol 100:20)

20 [α]D = -38.3 (c 0.06, CHCl3)

IR: 3305, 3070, 2975, 2933, 2876, 1650, 1538, 1427, 1250, 1170, 701 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.6-7.3 (m, 13H, including 3H from NH bonds), 6.3 (br,

1H), 4.4-4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H), 4.1 (t, J = 7.5 Hz, 1H), 3.66 – 3.56 (m,

2H), 3.01-2.89 (m, 2H), 2.5 (dt, J = 13.6, 6.8 Hz, 1H), 2.4 (d, J = 4.5 Hz, 3H), 2.20-2.14

(m, 1H), 2.12-2.01 (m, 1H), 2.01 (s, 3H), 1.98-1.89 (m, 2H), 1.71-1.45 (m, 4H), 1.40 (s,

9H), 1.37-1.27 (m, 2H), 1.24 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 6.7 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 180.4, 175.0, 174.5, 171.7, 158.5, 136.9, 136.8, 134.8,

134.7, 130.8, 129.0, 79.8, 61.7, 51.2, 49.9, 48.6, 41.1, 39.8, 37.9, 30.7, 28.98, 28.92,

26.3, 26.1, 22.4, 22.1, 18.0, 16.7;

+ Exact Mass: calcd. for [C36H54N5O6Si] 680.3838, found 680.3929

247

7.589 7.586 7.575 7.559 7.402 7.396 7.391 7.385 7.382 7.376 7.368 7.353 4.827 3.360 3.324 3.321 3.317 3.314 2.434 2.425 2.012 1.404 1.247 1.233 1.035 1.022

O O H Ph2 H N N Si N N H O O

Boc N 4.71c H

11.41 10.24

4.67 3.98 2.80 3.08 2.96 3.09 2.00 1.74 0.76 0.79 1.06

10 8 6 4 2 0PPM

60.184 49.794 48.453 48.115 47.944 47.772 47.605 47.434 47.263 47.091 38.303 36.486 36.410 29.246 27.498 27.440 27.243 24.825 24.639 20.961 20.910 20.666 16.496 15.257 178.947 173.601 172.989 170.181 157.023 135.466 135.361 133.325 133.256 129.475 129.326 129.275 127.680 127.505

O O H Ph2 H N N Si N N H O O

Boc N 4.71c H

180 160 140 120 100 80 60 40 20 PPM

248

Compound 4.72a

Following the procedure for synthesis of 4.60 (p.229), using compound 4.71a (0.2

g, 0.34 mmol), DCM (2 mL), 4M HCl in dioxane (0.5 mL, 2 mmol), triethyl amine (0.17

mL, 1.2 mmol), N,N’-di-(tert-butoxycarbonyl)thiourea (103 mg, 0.37 mmol), and mercury chloride (100 mg, 0.37 mmol) afforded guanidine 4.72a (202 mg, 84%) as a

colorless foam.

Rf= 0.5 (ethyl acetate / methanol 100:15)

20 [α]D = -12.0 (c 0.60, CH3OH)

IR: 3320, 3290, 3072, 2981, 2935, 1720, 1646, 1411, 1330, 1155, 700 cm-1

1 H NMR (500 MHz, CD3OD): δ 7.6-7.37 (m, 10H), 4.3 -4.2 (m, 1H), 4.2-4.1(m, 1H),

3.4-3.2(m, 2H), 2.46-2.3 (m, 1H), 2.3 (s, 3H), 1.9 (s, 3H), 1.6-1.5 (m, 1H), 1.5(dd, J =

7.7, 2.5 Hz, 1H), 1.47 (dd, J = 7.7, 2.5 Hz, 1H), 1.44 (s, 9H), 1.41 (s, 9H), 1.3-1.2 (m,

2H), 1.24 (dd, J = 14.7, 7.3 Hz, 1H), 1.0 (d, J = 7.3 Hz, 3H), 0.9 (d, J = 7.0 Hz, 3H).

13 C NMR (125 MHz, CD3OD): δ 180.2, 174.9, 173.0, 164.7, 157.7, 154.3, 136.96, 136.8,

134.3, 134.1, 131.0, 129.2, 84.6, 80.5, 50.8, 41.3, 38.8, 37.8, 29.3, 28.8, 28.4, 28.0, 26.4,

29 22.6, 22.1, 18.3, 17.1; Si NMR (99.3MHz, CD3OD): δ -8.2

+ + Exact mass: [M-Na] calcd. for [C37H56N6NaO7Si] 747.3872, found 747.3878

249

7.505 7.502 7.491 7.359 7.344 7.329 4.780 3.263 2.389 2.370 1.888 1.868 1.462 1.413 1.163 1.149 0.971 0.957

O H Ph 2 H N Si N N H O O

30.05 NH

4.72a BocN NHBoc

10.05

3.95 3.29 3.02 2.00

10 8 6 4 2 PPM

84.525 80.450 50.859 50.801 49.625 49.453 49.282 49.115 48.943 48.772 48.601 41.292 38.801 38.750 37.788 37.752 29.328 29.255 28.767 28.414 28.032 27.915 26.342 22.631 22.084 22.048 18.333 18.176 17.168 17.109 180.213 174.914 173.006 164.713 157.662 154.279 136.929 136.896 136.776 134.299 134.110 131.036 130.992 129.230 129.186 129.157

O H Ph 2 H N Si N N H O O

4.72a BocN NHBoc

180 160 140 120 100 80 60 40 20 PPM

250

Compound 4.72b

Following the procedure for synthesis of 4.60 (p.229), using compound 4.71b

(0.28 g, 0.4 mmol), DCM (2 mL), 4M HCl in dioxane (0.5mL, 2mmol), triethyl amine

(0.17mL, 1.2 mmol), N,N’-di-(tert-butoxycarbonyl)thiourea (119 mg, 0.43 mmol), and

mercury chloride (117 mg, 0.43 mmol) afforded guanidine 4.72b (305 mg, 91%) as a colorless foam.

Rf= 0.4 (ethyl acetate / methanol 100:15)

20 [α]D = +1.5 (c 0.86, CH3OH)

IR: 3322, 3282, 3070, 2975, 2935, 2873, 1720, 1652, 1612, 1153, 667 cm-1

1 H NMR (500 MHz, CDCl3): δ 8.3 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.6-7.3

(m, 13H, including 3H from NH), 4.35-5.25 (m, 2H), 4.20-4.13 (m, 1H), 3.3-3.15(m,

2H), 2.5-2.4 (m, 1H), 2.4 (d, J = 4.5 Hz, 3H), 1.94 (s, 3H), 1.7-1.55 (m, 7H), 1.51 (s, 9H),

1.46 (s, 9H), 1.4-1.3 (m, 2H), 1.3 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 7.0 Hz, 3H), 0.98 (d, J =

6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H).

13 C NMR (125 MHz, CDCl3): δ 180.4, 174.9, 174.6, 173.2, 164.6, 157.6, 154.2, 136.9,

136.7, 134.5, 130.9, 129.1, 84.6, 80.5, 54.0, 51.1, 41.8, 41.3, 39.5, 37.9, 29.1, 28.7, 28.4,

29 27.8, 26.3, 26.1, 23.4, 22.8, 22.4, 22.1, 18.3, 16.7; Si NMR (99.3 MHz, CD3OD): δ -8.7

+ + Exact mass: [M-Na] calcd. for [C43H67N7NaO8Si] 860.4713, found 860.4714

251

7.566 7.553 7.409 7.402 7.400 7.391 7.389 7.386 7.376 4.837 3.324 3.320 2.437 2.428 1.942 1.519 1.469 1.295 1.280 1.039 1.025 0.990 0.977 0.951 0.938

O H H Ph2 H N N Si N N H O O O 39.34

4.72b BocN NHBoc

12.78

4.46 3.00 2.99 3.32 0.60

10 8 6 4 2 0PPM

52.496 49.619 48.126 47.955 47.783 47.616 47.445 47.273 47.102 40.343 39.833 37.797 36.468 27.593 27.265 26.919 26.321 24.879 24.588 21.900 21.139 20.859 20.775 16.823 15.261 178.871 135.459 135.375 135.295 135.244 129.406 129.370 127.600

O H H Ph2 H N N Si N N H O O O

4.72b BocN NHBoc

180 160 140 120 100 80 60 40 20 PPM

252

Compound 271c

Following the procedure for synthesis of 4.60 (p.229), using compound 4.71c

(0.26 g, 0.38mmol) in DCM (2 mL), 4M HCl (in dioxane (0.5 mL, 2mmol), triethyl amine (0.17 mL, 1.2 mmol), N,N’-di-(tert-butoxycarbonyl)thiourea (112 mg, 0.4 mmol), and mercury chloride (120 mg, 4.4 mmol) afforded guanidine 4.72c (220 mg, 71%) as a colorless foam.

Rf = 0.4 (ethyl acetate / methanol 100:20);

20 [α]D = -18.5 (c 0.275, CHCl3); IR: 3319, 3292, 3070, 2978, 2933, 1722, 1643, 1332,

-1 1 1134, 754 cm ; H NMR (500 MHz, CDCl3): δ 7.6-7.3 (m, 13H, Including 3H from NH

bonds) 4.4-4.25 (m, 1H), 4.2 (t, J = 7.1 Hz, 1H), 4.1 (t, J = 7.5 Hz, 1H), 3.6-3.4 (m, 2H),

3.25-3.18 (m, 2H), 2.48-2.40 (m, 1H), 2.34 (d, J = 4.5 Hz, 3H), 2.14-2.09 (m, 1H), 2.07-

1.99 (m, 1H), 1.97 (s, 3H), 1.93 – 1.86 (m, 2H), 1.67-1.52 (m, 4H), 1.46 (s, 9H), 1.41 (s,

9H), 1.38 – 1.30 (m, 2H), 1.2 (d, J = 7.1 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 180.6, 175.1, 174.7, 171.9, 164.9, 157.7, 154.4, 137.1,

137.0, 134.9, 134.8, 130.9, 129.1, 84.6, 80.5, 61.8, 51.3, 50.1, 48.7, 41.5, 39.6, 38.1, 30.9,

29.9, 28.6, 27.9, 26.5, 26.3, 22.6, 22.3, 18.2, 16.9;

29 Si NMR (99.3 MHz, CD3OD): 649 δ -8.72;

+ + Exact mass: (FAB) MH , calcd for [C42 H64N7O8Si] 822.4580, found 822.4634

253

7.586 7.583 7.580 7.564 7.396 7.388 7.369 7.355 4.831 3.360 2.438 2.429 2.019 1.518 1.468 1.272 1.258 1.034 1.020

O O H Ph2 H N N Si N N 43.26 H O O

4.72c BocN NHBoc

12.43

3.18 2.04 1.93

10 8 6 4 2 PPM

78.365 49.794 49.593 60.184 48.453 48.115 47.944 47.772 47.605 47.434 47.263 47.091 39.669 38.303 36.486 36.410 29.246 27.498 27.440 27.243 24.825 24.639 21.073 20.961 20.910 20.666 16.496 15.257 178.947 173.601 172.989 170.181 157.023 135.466 135.361 133.325 133.256 129.475 129.326 129.275 127.680 127.505

O O H Ph2 H N N Si N N H O O

4.72c BocN NHBoc

180 160 140 120 100 80 60 40 20 PPM

254

Silanediol 4.16

Following the procedure for synthesis of 4.15 (p.232), using compound 4.72a

(0.22 g, 0.3 mmol), 20% acetic acid in DCM (6 mL), and mercury (II) acetate (0.49 g,

1.53 mmol) gave silanediol 4.16.

1 H NMR (500 MHz, CDCl3): δ 4.69 (br, 10H including protons from HOAc and water),

4.07 -4.04 (m, 1H), 3.27-3.12 (m, 1H), 3.06-2.95 (m, 2H), 2.55 (d, J = 5.4 Hz, 3H), 2.41-

2.33 (m, 1H), 1.95 (s, 3H), 1.91 (methyl protons of acetic acid), 1.85 (s, 3H), 1.58-1.3 (m,

5H), 1.22-1.18 (m, 3H due to rotamers), 0.96 (d, J = 6.8 Hz, 3H), 0.84-0.63 (m, 1H)

13 C NMR (125 MHz, CDCl3): δ 181.1, 180.8, 178.6, 175.1, 174.1, 50.1, 41.1, 39.7, 35.5,

30.0, 29.0, 26.2, 26.0, 22.0, 21.2, 18.1, 17.1

29 Si NMR (99.3 MHz, D2O) -14.2, -48.6 (-57.9 rotomers)

+ + Exact mass: [M-H] calcd. for [C15H33N6O5Si] 405.2276, found 405.2281

255

4.732 4.692 2.556 2.547 2.542 1.896 1.883 1.858 1.849 1.215 1.207 1.200 1.193 1.186 1.076 1.015 1.002 0.995 0.987

32.48

28.82 O HHO OH H N Si N N H O O

NH2 OAc

4.16 HN NH2

4.21 3.00 3.25 3.32 1.91 0.78 0.97 0.91 0.59 0.29

10 8 6 4 2 0PPM

50.245 41.151 39.767 35.543 30.054 29.082 26.198 25.906 22.039 21.489 21.205 19.963 17.126 180.837 178.634 175.123

O HHO OH H N Si N N H O O

NH2 OAc

4.16 HN NH2

180 160 140 120 100 80 60 40 20 PPM

256

Silanediol 4.17

Following the procedure for synthesis of 4.15 (p. 232), using compound 4.72b (0.30 g,

0.36 mmol), 20% acetic acid in DCM (8 mL), and mercury (II) acetate (0.57 g, 1.53

mmol) gave silanediol 4.17.

1 H NMR (500 MHz, CDCl3): δ 4.69 (br, 11H including protons from acetic acid and water), 4.19-4.05 (m, 2H), 3.34-3.10 (m, 1H), 3.96-2.95 (m, 2H), 2.57 (d, J = 5.4 Hz,

3H), 2.43 -2.35 (m, 1H), 1.95 (s, 3H), 1.91 (methyl protons of acetic acid), 1.86 (s, 3H),

1.59-1.33 (m, 5H), 1.24 (d, J = 7.2 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.85-0.67 (m, 1H),

0.80 (d, J = 6.3 Hz, 3H), 0.75 (d, J = 6.3 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 180.7, 180.6, 178.4, 175.0, 174.5, 174.1, 52.8, 50.8,

39.3, 35.228.4, 27.0, 25.8, 24.2, 21.9, 21.4, 21.0, 20.8, 20.6, 19.6, 17.5, 16.5;

29 Si NMR (99.3 MHz, D2O) -14.2 (-50.9 rotomers)

+ + Exact mass: [M-H] calcd. for [C21H44N7O6Si] 518.3117, found 518.3153

257

4.732 4.691 4.651 2.867 2.866 2.711 3.180 2.709 2.576 2.568 2.563 2.079 1.924 1.904 1.877 1.873 1.867 1.863 1.502 1.483 1.339 1.257 1.252 1.243 1.035 1.021 1.016 1.007 1.002 0.800 0.788 0.758 0.746

O H HHO OH H N N Si N N H O O O 65.26

NH2OAc

4.17 HN NH2

32.54

8.77 8.36

3.69 3.38 3.86 1.76 1.71 1.68 1.00

10 8 6 4 2 0 PPM

39.396 35.113 25.780 24.170 21.902 21.389 21.006 20.847 20.775 20.645 19.554 17.539 180.777 178.386 174.139

O H HHO OH H N N Si N N H O O O

NH2OAc

4.17 HN NH2

180 160 140 120 100 80 60 40 20 PPM

258

Silanediol 4.18

Following the procedure for synthesis of 4.15 (p.232), using compound 4.72c

(0.30 g, 0.36 mmol), 20% acetic acid in DCM (8 mL), and mercury (II) acetate (0.57 g,

1.53 mmol) gave silanediol 4.18.

1 H NMR (500 MHz, CDCl3): δ 4.69 (br, all exchangeable protons), 4.24-4.20 (m, 1H),

4.18 – 4.05 (m, 1H), 3.53-3.45 (m, 2H), 3.27 -3.12 (m, 1H), 3.00 (dd, J = 8.3, 4.8 Hz,

2H), 2.55 (d, J = 7.5 Hz, 3H), 2.42-2.33 (m, 1H), 2.15-2.08 (m, 1H), 1.95 (s, 3H), 1.91

(methyl protons of acetic acid), 1.97 -1.76 (m, 3H), 1.56-1.20 (m, 5H), 1.02 (d, J = 6.9

Hz, 3H), 0.84-0.64 (m, 1H).

13 C NMR (125 MHz, CDCl3): δ 181.0, 180.8, 178.2, 174.6, 173.3, 173.0, 60.6, 50.4,

49.0, 41.0, 39.7, 35.5, 30.0, 29.0, 26.0, 24.6, 24.5, 21.6, 20.8, 19.9, 18.0, 16.8.

29 Si NMR (99.3 MHz, D2O) -14.2, -48.6, -50.9 (rotomers)

+ + Exact mass: [M-H] calcd. for [C20H40N7O6Si] 502.2804, found 502.2822

259

4.733 4.693 4.653 2.562 2.554 2.547 1.957 1.949 1.915 1.904 1.891 1.817 1.784 1.247 1.238 1.232 1.224 1.082 1.022 1.008 0.991

O O HHO OH H N N Si N N H O O

NH2 OAc

87.23 4.18 HN NH2

7.73 7.05 6.66 3.69 6.44 3.00 3.30 2.38 0.62 0.85 1.71 1.45

10 8 6 4 2 0 PPM

60.566 60.341 50.056 49.043 48.982 41.079 39.727 39.647 35.495 30.120 29.993 29.905 28.998 26.147 26.074 25.837 25.775 24.675 24.519 21.711 21.645 21.430 20.859 19.912 18.051 17.971 16.856 178.211 174.675 173.364 137.094

O O HHO OH H N N Si N N H O O

NH2 OAc

4.18 HN NH2

180 160 140 120 100 80 60 40 20 0 PPM

260

(S)-3-{[(R)-4-(methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl}

-2-methyl-N-[(S)-1-(methylamino)-1-oxopropan-2-yl]propanamide (4.73)

Following the procedure for synthesis of 4.45 (p.211), using 4.43 (1.0 g, 1.8

mmol), HATU (1.02 g, 2.7 mmol), NMM (0.6 mL, 5.4 mmol), (S)-2-amino-N-

methylpropanamide hydrochloride (273.2 mg, 1.98 mmol), and DMF (10 mL) gave

compound 4.73 (713.5 mg, 62%) as a colorless foam.

20 Rf = 0.42 (ethyl acetate); [α]D = -71.4 (c 0.134, CHCl3)

IR: 3292, 3182, 3070, 2930, 2879, 1650, 1531, 1428, 1322, 1154, 1038, 732 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.76 (d, J = 8.6 Hz, 2H), 7.5-7.3 (m, 10H), 7.26 (d, J =

8.0 Hz, 2H), 6.47 (ddd, J = 5.0 Hz, 1H), 6.07 (d, J = 7.0 Hz, 1H), 5.7 (d, J = 9.5 Hz, 1H),

4.38 (s, 2H), 4.25-4.19 (m, 1H), 3.66-3.62 (m, 1H), 3.2 (s, 3H), 3.06 (t, J = 4.9 Hz, 3H),

2.4 (s, 3H), 2.38-2.30 (m, 1H), 1.7 (dd, J = 14.8, 8.4 Hz, 1H), 1.60-1.54 (m, 1H), 1.30-

1.14 (dd, J = 15.3, 5.9 Hz, 1H), 1.1 (d, J = 6.9 Hz, 3H), 1.0 (d, J = 7.4 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 177.7, 173.1, 143.2, 139.5, 135.7, 135.5, 133.4, 132.7,

130.1, 129.7, 128.3, 127.1, 96.2, 67.3, 55.1, 49.0, 42.0, 36.9, 28.6, 27.3, 26.3, 21.7, 21.6,

17.7, 16.5;

+ + Exact mass: [M-Na] calcd. for [C33H45N3NaO6SSi] 662.2691, found 662.2571

261

7.771 7.754 7.475 7.462 7.459 7.453 7.440 7.437 7.335 7.329 7.314 7.275 7.272 7.271 7.255 4.383 3.217 3.204 2.757 2.748 2.419 2.412 1.118 1.104 1.020 1.007

12.51

Ph Ph O H H N Si N Ts N H O

OMOM 4.73

5.01

3.67 3.64 3.72 3.27 3.24 3.19

2.49 2.21 1.85

1.11 0.96 1.02 1.00 0.98 1.10 1.04 0.90 0.82

0.00

10 8 6 4 2 0P P M

96.236 77.455 77.200 76.945 67.352 55.134 49.059 42.077 36.891 28.613 27.269 26.351 21.686 21.617 17.680 16.493 177.699 173.074 143.170 139.495 135.722 135.489 133.399 132.732 130.161 129.706 128.303 127.291 127.145

Ph Ph O H H N Si N Ts N H O

OMOM 4.73

180 160 140 120 100 80 60 40 20 PPM

262

2(S)-{3-[((R)-4-(methoxymethoxy)-1-(N-(tert-butyl)carbamoyl-4-methyl phenylsulfonamido)butyl)diphenylsilyl]-2(S)-methylpropanamido}-N- methylpropanamide (4.73)

Following the procedure for synthesis of 4.52 (p. 217), using compound 4.73 (0.5 g, 0.78

mmol), DMAP (19.1 mg, 0.16 mmol), Boc2O (0.34 g, 1.56 mmol), and acetonitrile (30

mL) gave compound 4.74 (311 mg, 54%) as a colorless foam.

20 Rf = 0.5 (ethyl acetate); [α]D = -24.8 (c 0.35, CHCl3); IR: 3305, 3071, 2978,1715, 1650,

-1 1 1596, 1538, 1348, 1152, 1109, 732 cm ; H NMR (500 MHz, CDCl3): δ 7.65 (d, J =

6.6Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.45-7.3 (m, 3H), 7.1 (d, J = 8.1 Hz, 2H), 6.7 (br,

1H), 6.0 (br, 1H), 4.67 (dd, J = 10.0, 5.1 Hz, 1H), 4.55, 4.54 (s, 2H), 4.22-4.16 (m, 1H),

3.51 -3.45 (m, 2H), 3.28 (s, 3H), 2.74 (d, J = 4.8 Hz, 3H), 2.39 (s, 3H), 2.37-2.31 (m,

1H), 2.0 - 1.95 (m, 1H), 1.94 (dd, J = 15.4, 6.6 Hz, 1H), 1.92-1.85 (m, 1H), 1.74 - 1.67

(m, 1H), 1.67-1.57 (m, 1H), 1.39 (dd, J = 15.8, 7.3 Hz, 1H), 1.25 (s, 9H), 1.08 (d, J = 7.0

13 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H); C NMR (125 MHz, CDCl3): δ 177.5, 172.9, 151.5,

143.7, 137.4, 136.2, 135.8, 134.7, 133.6, 129.6, 129.5, 128.9, 128.1, 127.8, 96.3, 84.5,

62.7, 55.0, 48.6, 47.97, 36.8, 36.6, 28.1, 27.9, 27.6, 26.1, 21.5, 20.9, 17.1;

+ + Exact mass: [M-Na] calcd. for [C38H53N3NaO8SSi] 762.3215, found 762.3195

263

7.580 7.414 7.400 7.359 7.343 7.299 7.275 4.551 4.545 3.285 2.743 2.734 2.388 1.273 1.264 1.259 1.250 1.092 1.078 0.972 0.959

11.17

10.37 Ph Ph O Boc H N Si N Ts N H O

OMOM 4.74 4.76

3.63 3.54 3.34 3.19 2.98

2.36 2.48 2.27 2.19 2.19 2.22

1.11 0.99 0.95 0.87 0.92

10 8 6 4 2 0PPM

96.345 84.549 77.261 77.010 76.755 67.166 55.053 48.585 48.148 47.969 36.781 36.566 28.161 27.891 27.607 26.107 21.481 20.928 17.140 177.487 172.880 151.498 143.701 137.404 136.238 135.845 134.727 133.587 129.625 129.541 128.944 128.113 127.873

Ph Ph O Boc H N Si N Ts N H O

OMOM 4.74

180 160 140 120 100 80 60 40 20 PPM

264

2(S)-[3-({(R)-4-(methoxymethoxy)-1-[N-(tert-butyl)carbamoyl]butyl}diphenylsilyl)-

2(S)-methylpropanamido]-N-methylpropanamide (4.75)

Following the procedure for synthesis of 4.53 (p.219), using compound 4.74 (0.5 g, 0.68

mmol), Mg (163 mg, 6.8 mmol), and methanol (10 mL) gave compound 4.75 (326 mg,

82%) as a colorless foam.

Rf = 0.4 (ethyl acetate)

20 [α]D = - 85.8 (c 0.19, CHCl3)

IR: 3305, 3070, 2975, 2932, 2885, 1690, 1644, 1537, 1504, 1168, 1109, 733 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.56-7.34 (m, 10H), 6.5 (d, J = 5.1 Hz, 1H) 5.96 (d, J =

7.8 Hz, 1H), 4.6 (d, J = 10.2 Hz, 1H), 4.5 (s, 2H), 4.24-4.16 (m, 1H), 3.8 (dt, J = 10.0, 2.1

Hz, 1H), 3.51-3.45 (m, 2H), 3.3 (s, 3H), 2.7 (d, J = 5.0 Hz, 3H), 2.3-2.2 (m, 1H), 1.75-

1.67 (m, 2H), 1.63 (dd, J = 15.1, 7.5 Hz, 1H), 1.60-1.53 (m, 1H), 1.34-1.21 (m, 1H), 1.26

(dd, J = 15.4, 7.2 Hz, 1H), 1.1 (d, J = 7.2 Hz, 3H), 1.0 (d, J = 5.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 177.3, 172.9, 156.6, 135.6, 135.5, 133.4, 133.1, 130.0,

128.3, 128.2, 96.5, 79.2, 67.5, 55.2, 48.8, 38.3, 37.0, 28.7, 28.6, 27.3, 26.3, 21.7, 18.8,

16.2;

+ + Exact mass: [M-Na] calcd. for [C31H47N3NaO6Si] 608.3126, found 608.3101

265

7.370 7.368 7.275 4.542 3.280 2.738 2.729 1.407 1.111 1.097 1.063 1.049

10.47

Ph Ph O H 9.01 BocHN Si N N H O

OM OM 4.75

4.12

3.14 2.95 3.00 2.91 2.75

2.09 2.01

0.96 0.95 1.08 0.99 0.74 0.80

10 8 6 4 2 PPM

96.539 79.196 77.451 77.200 76.945 67.469 55.210 48.768 38.297 37.004 28.697 28.595 27.298 26.293 21.690 17.804 16.234 177.346 172.910 156.601 135.711 135.616 135.555 133.395 133.129 130.037 128.282 128.242

Ph Ph O H BocHN Si N N H O

OM OM 4.75

180 160 140 120 100 80 60 40 20 0PPM

266 tert-Butyl (R)-4-azido-1-(((S)-2-methyl-3-((S)-1-(methylamino)-1-oxopropan-2- ylamino)-3-oxopropyl)diphenylsilyl)butylcarbamate (4.76)

Following the procedure for synthesis of 4.57 (p.221), using compound 4.75 (0.45 g, 0.76 mmol), DCM (5 mL), TMSBr (0.42 mL, 3.0 mmol), Et3N (0.16 mL, 1.14 mmol), MsCl

(87 µL, 1.14 mmol), NaN3 (197 mg, 3.0 mmol), and DMF (8 mL) gave compound 4.76

(108 mg, 25%) as a colorless foam.

Rf = 0.68 (hexane / ethyl acetate 1:2)

20 [α]D = -60.6 (c 0.165, CHCl3)

IR: 3299, 3071, 2975, 2932, 2877, 2096, 1689, 1645, 1503, 1167, 1109, 702 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.6-7.3(m, 10H), 6.4 (d, J = 4.8 Hz, 1H), 5.9 (d, J = 7.1

Hz, 1H), 4.7 (d, J = 10.3 Hz, 1H), 4.27-4.16 (m, 1H), 3.84 (dt, J = 10.0, 2.0 Hz, 1H),

3.34-3.26 (m, 1H), 3.25-3.21 (m, 1H), 2.75 (d, J = 4.7 Hz, 3H), 2.33 -2.22 (m, 1H) 1.75-

1.67 (m, 2H), 1.63 (dd, J = 15.1, 7.5 Hz, 1H), 1.60-1.53 (m, 1H), 1.34-1.21 (m, 1H), 1.26

(dd, J = 15.4, 7.2 Hz, 1H), 1.1 (d, J = 7.2 Hz, 3H), 1.09 (d, J = 5.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 177.3, 172.8, 156.7, 135.5, 135.4, 133.3, 132.9, 130.1,

128.1, 79.4, 51.1, 48.8, 37.9, 37.1, 29.1, 28.6, 26.4, 26.3, 21.9, 17.7, 16.1;

+ + Exact mass: [M-Na] calcd. for [C29H42N6NaO4Si] 589.2929, found 589.2896

267

7.387 7.372 7.275 2.757 2.747 1.945 1.423 1.413 1.261 1.116 1.102 1.097 1.084

Ph Ph O H BocHN Si N N H O

N3 4.76

12.97

10.06

6.73 7.27 5.03 3.99 2.59 1.40 0.97 1.17 0.90 1.00 1.33

8 7 6 5 4 3 2 1 0 PPM

79.374 77.601 77.444 77.193 76.938 76.781 51.113 48.808 37.911 37.102 29.178 28.613 28.092 26.384 26.337 21.865 17.753 16.092 177.316 172.819 156.710 135.959 135.704 135.591 135.474 133.340 132.943 130.157 129.203 128.369 128.183 128.096

Ph Ph O H BocHN Si N N H O

N3 4.76

180 160 140 120 100 80 60 40 20 0PPM

268

(S)-3-(((R)-1-Acetamido-4-azidobutyl)diphenylsilyl)-2-methyl-N-((S)-1-

(methylamino)-1-oxopropan-2-yl)propanamide (4.77)

Following the procedure for synthesis of 4.21 (p.224, route 1), using compound

4.76 (0.34 g, 0.6 mmol), 4M HCl in dioxane (0.6 mL, 2.4 mmol), HOAc (38 µL, 0.66

mmol), HATU (342 mg, 0.9 mmol), NMM (0.2 mL, 1.8 mmol), and DMF (5.0 mL) gave compound 4.77 (207 mg, 68%) as a colorless foam.

Rf= 0.6 (ethyl acetate / methanol 100:17)

20 [α]D = -101.3(c 0.145, CHCl3)

IR: 3294, 3070, 2971, 2933, 2876, 2095, 1645, 1538, 1109, 701 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.5-7.3 (m, 10H), 6.4 (br, 1H), 6.37 (d, J = 7.2 Hz, 1H),

6.05 (d, J = 10.7 Hz, 1H), 4.32-4.21 (m, 2H), 3.31-3.26 (m, 1H), 3.26-3.20 (m, 1H),

2.75(d, J = 5.1 Hz, 3H), 2.49-2.42 (m, 1H), 1.97 (s, 3H), 1.75-1.67 (m, 2H), 1.63 (dd, J =

15.1, 7.5 Hz, 1H), 1.60-1.53 (m, 1H), 1.34-1.21 (m, 1H), 1.26 (dd, J = 15.4, 7.2 Hz, 1H),

1.15 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 5.7 Hz, 3H);

13 C NMR (125 MHz, CDCl3): δ 177.4, 172.7, 170.3, 135.3, 135.2, 132.9, 132.5, 130.1,

128.3, 128.2, 50.1, 48.6, 36.3, 36.1, 28.3, 26.3, 26.2, 23.3, 20.9, 17.8, 15.9;

+ + Exact mass: [M-Na] calcd. for [C26H36N6NaO3Si] 531.2510, found 531.2498

269

7.495 7.492 7.489 7.486 7.481 7.478 7.476 7.473 7.439 7.428 7.425 7.413 7.400 7.387 7.372 7.275 4.240 2.758 2.749 1.974 1.918 1.589 1.576 1.559 1.546 1.245 1.164 1.150 0.988 0.974

Ph Ph O H H N Si N N H O O

N3 4.77

10.38

8.55

4.09 3.06 3.22

1.75 2.02 2.00 0.97 0.83

10 8 6 4 2 0PPM

77.322 77.069 76.816 50.776 48.624 36.380 36.164 28.326 26.340 26.232 23.350 20.894 17.824 15.895 177.436 172.719 170.270 135.324 135.230 132.905 132.457 130.138 128.318 128.289 128.238

Ph Ph O H H N Si N N H O O

N3 4.77

180 160 140 120 100 80 60 40 20 PPM

270

tert-Butyl (R)-4-acetamido-4-({(S)-2-methyl-3-[(S)-1-(methylamino)-1-oxopropan-2-

ylamino]-3-oxopropyl}diphenylsilyl)butylcarbamate (4.78)

Following the procedure for synthesis of 4.59 (p.227), using compound 4.77 (0.26

g, 0.5 mmol), Boc2O (120 mg, 0.55 mmol), Lindlar catalyst (52 mg), H2-balloon, and

anhydrous methanol (3 mL) gave compound 4.78 (262 mg, 91%) as a colorless foam.

Rf= 0.5 (ethyl acetate / methanol 100:15)

20 [α]D = - 49.3 (c 0.075, CHCl3)

IR: 3301, 3066, 2969, 2931, 1693, 1650, 1538, 1168, 701 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.5-7.3 (m, 10H), 6.64 (br, 1H), 6.60 (d, J = 7.0 Hz, 1H),

6.2 (d, J = 10.0 Hz, 1H), 4.7 (br, 1H), 4.3 (dt, J = 10.0, 2.5 Hz, 1H), 4.28-4.18 (m, 1H),

3.3 -3.1 (m, 1H), 3.07 (d, J = 6.1 Hz, 1H), 2.74 (d, J = 5.1 Hz, 3H), 2.51- 2.43 (m, 1H),

1.7-1.5 (m, 3H), 1.4 (s, 9H), 1.35-1.2 (m, 3H), 1.19 (d, J = 7.4 Hz, 3H), 0.96 (d, J = 6.7

Hz, 3H)

13 C NMR (125 MHz, CDCl3): δ 177.6, 173.0, 170.3, 156.3, 135.5, 135.4, 133.0, 130.1,

128.4, 128.3, 79.2, 49.0, 40.3, 37.0, 36.6, 28.6, 28.5, 28.0, 26.3, 23.5, 21.1, 18.0, 16.6;

+ + Exact mass: [M-Na] calcd. for [C31H46N4NaO5Si] 605.3130, found 605.3128

271

7.474 7.471 7.468 7.463 7.460 7.458 7.455 7.420 7.411 7.405 7.401 7.393 7.391 7.387 7.383 7.375 7.367 7.352 7.350 7.339 7.336 7.275 2.747 2.742 2.738 2.733 2.031 1.964 1.957 1.405 1.387 1.249 1.193 1.179 0.974 0.971 0.957

Ph Ph O H H N Si N N H 23.98 O O

NHBoc 4.78

10.50

3.06 1.74 2.00 1.95 0.77 0.61 0.82

10 8 6 4 2 PPM

79.016 77.250 76.995 76.740 48.756 40.117 36.788 36.723 36.421 28.390 28.284 27.818 26.132 23.270 20.913 17.767 17.639 16.401 177.399 172.789 170.123 156.127 135.310 135.233 135.168 134.341 134.294 132.768 129.971 128.212 128.124 127.767

Ph Ph O H H N Si N N H O O

NHBoc 4.78

180 160 140 120 100 80 60 40 20 0 PPM

272

Di-tert-Butyl (R)-4-acetamido-4-{(S)-2-methyl-3-[(S)-1-(methylamino)-1-oxopropan-

2-ylamino]-3-oxopropyl}diphenylsilyl)butyl guanidine carbamate (4.79)

Following the procedure for synthesis of 4.60 (p.229), using compound 4.78 (0.22

g, 0.37 mmol) in DCM (2 mL), 4M HCl (in dioxane, 0.5 mL, 2 mmol), triethyl amine

(0.17 mL, 1.2 mmol), N,N’-di-(tert-butoxycarbonyl)thiourea (4.20) (112 mg, 0.4 mmol),

and mercury chloride (120 mg, 4.4 mmol) afforded guanidine 4.79 (227 mg, 85%) as a

colorless foam.

Rf= 0.5 (ethyl acetate / methanol 100:15)

20 [α]D = -49.0 (c 0.055, CHCl3); IR: 3293, 3066, 2977, 2935, 1720, 1643, 1550, 1415,

-1 1 1153, 736 cm ; H NMR (400 MHz, CDCl3): δ 11.4 (s, 1H), 8.28 (t, J = 5.4 Hz, 1H), 7.5-

7.3 (m, 10H), 6.63 (d, J = 4.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 10.2 Hz,

1H), 4.39-4.23 (m, 2H), 3.3 (dt, J = 6.1 Hz, 2H), 2.7 (d, J = 4.9 Hz, 3H), 2.56-2.48 (m,

1H), 1.98 (s, 3H), 1.7-1.6 (m, 2H), 1.57 -1.49 (m, 1H), 1.8 (dd, J = 15.4, 6.8 Hz, 1H), 1.3-

1.19 (m, 1H), 1.2 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,

CDCl3): δ 177.9, 172.9, 170.5, 163.5, 156.5, 153.3, 135.4, 135.3, 133.29, 133.28, 130.1,

128.4, 128.2, 83.3, 79.5, 48.9, 40.6, 37.2, 36.5, 28.4, 28.2, 27.6, 27.5, 26.3, 23.5; 29Si

NMR (99.3MHz, CD3OD): δ -8.82;

+ + Exact mass: [M-Na] calcd. for [C37H56N6NaO7Si] 747.3872, found 747.3860

273

7.258 2.763 2.751 1.985 1.479 1.471 1.458 1.243 1.225 0.962 0.945

Ph Ph O H H N Si N N H 15.07 O O

BocN NHBoc 10.03 4.79

5.44

4.37

3.38 3.00 2.36 2.20 1.75 1.91 1.51 0.83 0.83 0.86 0.37 0.06

10 8 6 4 2 PPM

83.553 79.704 77.722 77.608 77.402 77.090 49.101 40.771 37.455 36.677 28.659 28.423 27.866 27.767 26.555 23.751 20.938 18.377 17.135 178.066 173.104 170.703 163.752 156.702 153.523 135.642 135.535 133.493 133.028 130.367 130.329 128.630 128.500

Ph Ph O H H N Si N N H O O

BocN NHBoc 4.79

180 160 140 120 100 80 60 40 20 PPM

274

(R)-4-Acetamido-4-({(S)-2-methyl-3-[(S)-1-(methylamino)-1-oxopropan-2-ylamino]-

3-oxopropyl}dihydroxylsilyl)butyl guanidinium acetate (4.19)

Following the procedure for synthesis of 4.15 (p.232), using compound 4.79 (180

mg, 0.25 mmol), 20% HOAc in DCM (8 mL), and Hg(OAc)2 (0.4 g, 1.25 mmol) gave

silanediol 4.19.

1 H NMR (500 MHz, D2O): δ 4.69 (br, including all exchangeable protons), 4.15-4.08 (m,

1H), 3.32-3.19 (m, 1H), 3.15-3.05 (m, 2H), 2.64 (s, 3H), 2.82-2.51 (m, 1H), 1.66-1.40

(m, 4H), 1.26 (d, J = 7.3 Hz, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.02-0.88 (m, 1H), 0.8 – 0.7

(m, 1H);

13 C NMR (125 MHz, D2O): δ 180.3, 178.8, 175.7, 173.8, 50.0, 41.2, 39.3, 29.0, 27.0,

26.1, 22.1, 21.2, 20.0, 17.9, 17.0.

29 Si NMR (99.3MHz, CD3OD): δ -48.8, -56.1 (rotamer)

+ + Exact mass: [M-Na] calcd. for [C15H33N6O5Si] 405.2276, found 405.2289

275

4.775 4.695 4.654 4.614 2.643 1.981 1.939 1.925 1.273 1.259 1.095 1.089

65.02

HO OH O H H N Si N N H O O

NH2Ac

HN NH2 25.22 4.19

3.11 3.20 3.34 3.46 2.31 2.35 2.12 1.05 1.00 0.24

10 8 6 4 2 0PPM

50.038 41.188 39.928 39.349 38.099 35.273 28.991 27.028 26.300 26.245 26.107 25.899 22.166 21.394 21.274 20.017 16.962 180.346 178.834 175.746 173.783 137.131 129.497

HO OH O H H N Si N N H O O

NH2Ac

HN NH2 4.19

180 160 140 120 100 80 60 40 20 0P P M

276

Screening silanediol inhibition for FXIax

The FXIa (Haematologic Technologies Inc., VT, USA), final concentration 1 nM,

was incubated with silanediol inhibitors (concentration range from 0 - 15 mM) in

TBS/BSA buffer (Tris (50 mM), NaCl (125 mM), and BSA 0.1%, pH 7.5) and the FXIa

amidolytic activity was determined by the initial reaction velocity of the cleavage of S-

2366 (l-pyroGlu-Pro-Arg-pNA-HCl, Chromogenix, DiaPharma Group, Inc., OH) by

FXIa. The readings was performed at 37 °C for 10 min in a microplate reader

(Molecular Devices Thermo Max) and the fraction of amidolytic activity remaining was

used to plot the curve against the inhibitor concentration. The values of IC50 were

determined using Igor pro 6 software (WaveMetrics, Inc., Lake Oswego, OR). The

inhibition constants (Kieq) were derived from their IC50 values using the following

equation: Kieq = IC50/(1+{[S]/Km}) where [S] is the substrate concentration and Km is the

Michaelis constant.

O NO2 N O H N N H O

NH2Cl

HN NH2 4.80

Chemical name: L-Pyroglutamyl-L-prolyl-L-arginine-p-nitroaniline hydrochloride

Formula: Glu-Pro-Arg-pNA.HCl S-2366TM

x Studied by Dr. Wenman Wu 277

6.7 Index of experimentals for chapter 5

OH FmocHN N O O t-Bu-OOC 5.11, p. 279

Ph Ph H N Si OH Ts

OMOM 5.34, p. 287

Ph Ph H N Si OBoc Ts

OMOM 5.38, p. 293

278

(S)-1-{(S)-2-[(9H-Fluoren-9-yl)methylamino]-5-tert-butoxy-5-oxopentanoyl} pyrrolidine-2-carboxylic acid (5.11)

To a solution of 5.14 (1.0 g, 1.85 mmol) in DMF (10 mL) at 0 °C was added HATU (1.06 g, 2.8 mmol), followed NMM (2.0 mL, 1.85 mmol). The solution was stirred at 0 °C for

10 min, added solution of compound 5.17 (475.6 mg, 1.85 mmol), and NMM (2.0 mL,

1.85 mmol) in DMF (5 mL). The mixture was stirred at 0 °C for an hour and at rt. for 5 h, diluted with water (100 mL), extracted with ethyl acetate (4 x 10 mL). The combined organic layers were washed with 5% HCL (3 x 5 mL), water (2 x 10 mL) and brine (10 mL), dried over Na2SO4, concentrated in vacuo to give colorless oil. The crude oil was dissolved in absolute ethanol (7 mL) was added 10% Pd/C (100 mg), and H2-filled balloon was applied for 5 h. The solution was filtered through a pad of Celite, concentrated in vacuo. Column chromatography gave compound 5.11 (0.65 g, 65%) as a white solid.

20 Rf = 0.5 (hexane / ethyl acetate 1:1); [α]D = -47.6 (c 0.105, CHCl3); Mp. = 157-158

(decomposed); IR: 3290 (br), 3058, 2977, 1720, 1639, 1531, 1450, 1249, 1157, 736 cm-1;

1 H NMR (400 MHz, CDCl3): δ 7.7 (d, J = 7.6 Hz, 2H), 7.6 (t, J = 7.6 Hz, 2H), 7.4 (t, J =

7.2 Hz, 2H), 7.3-7.2 (m, 2H), 5.9 (d, J = 9.0 Hz, 1H), 4.6-4.5 (m, 2H), 4.3 (d, J = 7.2 Hz,

2H), 4.2 (t, J = 7.2 Hz, 1H), 3.78-3.74 (m, 1H), 2.4-1.8 (m, 8H), 1.4 (s, 9H); 13C NMR

279

(100 MHz, CDCl3): δ 174.5, 172.6, 172.2, 156.5, 144.1, 143.9, 141.5, 127.9, 127.3,

125.4, 120.1, 81.0, 67.3, 59.5, 51.8, 47.6, 47.3, 30.8, 28.6, 28.3, 27.6, 25.1; 7.765 7.746 7.596 7.393 7.308 7.261 4.328 1.464 1.446

OH FmocHN N O O t-Bu-OOC 5.11

10.51

8.23 7.07

2.33 2.00 1.72 1.71 0.75 1.13

10 8 6 4 2 0PPM

77.722 77.608 77.402 77.090 67.509 59.658 52.005 47.737 47.463 31.007 28.766 28.446 27.775 25.298 174.644 172.754 172.365 156.709 144.278 144.110 141.640 128.081 127.456 125.581 120.337

OH FmocHN N O O t-Bu-OOC 5.11

180 160 140 120 100 80 60 40 20 PPM

280

(S)-tert-butyl 3-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-4-((S)-1,5-diamino-1,5-

dioxopentan-2-ylamino)-4-oxobutanoate (5.13)

To a solution of compound 5.19 (3.0 g, 12.2 mmol) in DCM (15 mL) was added TFA

(1.8 mL, 24.4 mmol), stirred at rt. for 5 h, concentrated in vacuo, and then dissolved in

DMF (10 mL) followed triethyl amine (1.7 mL, 12.2 mmol). The solution was transferred

to a solution of compound 5.15 (5.0 g, 12.2 mmol), diethyl cyanophosphonate (2.4 mL,

13.4 mmol) in DMF (10 mL) at 0 °C, followed by triethyl amine (1.7 mL, 12.2 mmol).

The reaction was maintained at 0 °C for 3 h, and warmed to room temperature overnight.

The mixture was diluted with ethyl acetate (50 mL) and water (50 mL), the organic phase

was washed with 5% HCl (2 x 10 mL), 5% Na2CO3 (3 x 10 mL), water (5 x 20 mL), brine

(20 mL), dried over Na2SO4, concentrated in vacuo to give a white solid.

Recrystallization in ethyl acetate gave compound 5.13 (3.2 g, 50%) as a white crystalline.

Mp. = 178-179 °C

20 [α]D = + 10.0 (c 0.13, DMSO)

IR: 3417, 3316, 3208, 2966, 2927, 1708, 1677, 1631, 1535, 1265, 767 cm-1

1 H NMR (400 MHz, CDCl3): δ 8.0 (d, J = 8.0 Hz, 1H), 7.8 (d, J = 7.5 Hz, 2H), 7.7 (d, J =

8.5 Hz, 1H), 7.69 (t, J = 8.2 Hz, 2H), 7.4 (t, J = 7.5 Hz, 2H), 7.3 (s, 1H), 7.3 (dt, J = 7.7,

281

0.9 Hz, 2H), 7.1 (s, 1H), 6.8 (s, 1H), 4.4-4.1 (m, 5H), 2.7 (dd, J = 16.1, 5.0 Hz, 1H), 2.47

(dd, J = 16.1, 9.0 Hz, 1H), 2.1 (t, J = 7.7 Hz, 2H), 1.94-1.86 (m, 1H), 1.8-1.72 (m, 1H),

13 1.3 (s, 9H); C NMR (100 MHz, CDCl3): δ 174.3, 173.5, 170.8, 169.8, 156.2, 144.1,

144.0, 128.0, 127.4 125.5, 120.4, 80.6, 66.1, 52.5, 51.8, 46.8, 37.7, 31.6, 28.1, 27.9;

+ + Exact mass: [M-Na] calcd. for [C28H34N4NaO7Si] 561.2325, found 561.2307

282

7.888 7.869 7.718 7.697 7.414 7.395 7.342 7.339 7.323 7.321 7.304 7.302 4.290 3.587 3.537 3.488 2.507 2.503 2.088 1.363

CONH2

O FmocHN N CONH2 H COOt-Bu 5.13

9.07 6.27 5.05 2.89 2.28 1.86 2.00 1.03 1.00 0.97 1.00 0.95 0.96

10 8 6 4 2 0PPM

80.577 66.126 52.559 51.858 46.865 40.272 40.067 39.853 39.647 39.442 39.228 39.022 37.765 31.621 28.123 27.970 174.282 173.513 170.830 169.816 156.173 144.099 143.970 140.989 127.994 127.422 125.547 120.402

CONH2

O FmocHN N CONH2 H COOt-Bu 5.13

180 160 140 120 100 80 60 40 20 PPM

283

(R)-N-((R)-1-[{(S)-2-[(tert-Butyldiphenylsilyloxy)methyl]-5-(methoxymethoxy)

pentyl} diphenylsilyl]-2-phenylethyl)-2-methylpropane-2-sulfinamide (5.21)

OMOM OMOM Ph Ph Ph Ph AgNO Si H 3 Ph Ph O 1. Li N Si OH TPSCl H S N Si OTPS S 2. O N Ph O OMOM S Ph Ph 2.48 O (R)-3.17 (R,R,R)-5.21 (R,R,S)-5.12 (R,R,S)-5.21 (R,R,r)-5.12

Following the procedure for synthesis of 4.42 (p.198) and 4.25 (p. 196), using compound

(±)-2.48 (3.3 g, 9.6 mmol) in THF (15 mL), lithium (0.46 g, 192 mmol), (R)-3.17 (0.71 g,

3.3 mmol) in THF (10 mL) gave a mixture of diastereomer sulfinamides 5.12 (0.85 g,

45%). The sulfinamide was dissolved in DMF (10 mL) at 0 °C, added TPSCl (0.61 mL,

2.4 mmol), and AgNO3 (1.1 g, 6.4 mmol). The solution was stirred at 0 °C, diluted with

water (50 mL), ethyl acetate (30 mL), filtered though a pad of Celite. The aqueous phase

was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed

with water (5 x 10 mL), brine (2 x 10 mL), concentrated in vacuo. Flash column chromatography gave compound 5.21 (1.5 g, 86%) as a colorless foam.

Rf= 0.3 (hexane / ethyl acetate 1:2)

IR: 3311, 3070, 2929, 2858, 1589, 1471, 1427, 1384, 1112, 1070, 701 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.5-7.1 (m, 25H), 4.5 (s, 2H), 3.8-3.7 (m, 1H), 3.37 (dd, J

= 10.0, 4.7 Hz, 1H), 3.3 (s, 3H), 3.23-3.16 (m, 2H), 3.13 (d, J = 5.2 Hz, 1H), 3.08-3.00

(m, 1H), 2.9 (dd, J = 10.0, 5.3 Hz, 1H), 1.65-1.55 (m, 1H), 1.35-1.23 (m, 4H), 1.08 (s,

9H), 1.05 (s, 9H), 09 (m, 1H).

284

13 C NMR (100 MHz, CDCl3): δ 139.1, 135.8, 134.0, 133.3, 133.0, 132.9, 129.8, 129.7,

128.5, 128.2, 128.0, 127.7, 126.6, 96.4, 77.4, 68.0, 56.7, 55.1, 47.7, 39.9, 36.7, 30.0, 27.1,

26.7, 22.8, 19.4, 14.6

+ + Exact mass: [M-H] calcd. for [C48H64NO4SSi2] 806.4089, found 806.4103

285

7.454 7.450 7.446 7.427 7.396 7.380 7.319 7.301 7.261 7.242 7.234 7.225 7.208 7.205 7.115 7.073 4.390 4.384 3.179 3.178 3.172 3.171 0.943 0.933 0.908 0.888

OMOM

H Ph Ph N Si OTPS S O Ph

(R,R,R)-5.21 26.22

(R,R,S)-5.21 19.87

10.00

4.69

2.00 0.91 0.98

10 8 6 4 2 PPM

96.414 77.572 77.466 77.260 76.940 68.068 56.734 55.179 47.770 47.709 39.996 39.950 36.711 30.064 29.935 27.145 26.749 22.823 19.485 14.660 14.500 139.174 135.820 134.067 134.036 134.006 133.373 133.312 133.030 132.947 129.959 129.882 129.753 128.556 128.198 128.099 127.771 126.651

OMOM

H Ph Ph N Si OTPS S O Ph

(R,R,R)-5.21 (R,R,S)-5.21

160 140 120 100 80 60 40 20 0 PPM

286

(R)-N-{1-[(3-hydroxypropyl)diphenylsilyl]-4-(methoxymethoxy)butyl}-4-

methylbenzenesulfonamide (5.34)

Following the procedure for synthesis of 4.42 (p.198), using compound 5.31 (3.0

g, 12.4mmol), lithium (1.73 g, 247 mmol), THF (20 mL), compound 4.41 (0.73 g, 4.1

mmol) gave sulfinamide 5.33 (1.3 g, 76%).

Following the procedure of compound 4.44 (p.207), using the sulfinamide 5.33

(1.3 g, 3.1 mmol), 77% m-CPBA (0.83 g, 3.72 mmol) gave sulfone 5.34 (1.45 g, 89%) as

a colorless oil.

Rf= 0.58 (hexane / ethyl acetate 1:2)

20 [α]D = + 9.4 (c 0.085, CHCl3)

IR: 3289, 3068, 2926, 2874, 1598, 1540, 1155, 1111, 702 cm-1

1 H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.4 Hz, 2H), 7.5-7.3 (m, 10H), 7.2 (d, J = 8.0

Hz, 2H), 3.56-3.50 (m, 1H), 3.46 (t, J = 6.5 Hz, 2H), 3.25-3.20 (m, 2H), 3.21 (s, 3H), 2.4

(s, 3H), 1.87 (br, 1H), 1.72- 1.62 (m, 1H), 1.5-1.3 (m, 5H), 1.0 (m, 2H);

13 C NMR (100 MHz, CDCl3): δ 143.2, 138.7, 135.7, 135.5, 132.6, 131.9, 130.1, 19.6,

128.3, 127.2, 96.2, 67.2, 65.2, 55.2, 42.0, 29.1, 27.3, 26.6, 21.6, 7.45.

+ + Exact mass: [M-Na] calcd. for [C28H37NNaO5SSi] 550.2054, found 550.2035

287

7.677 7.657 7.481 7.475 7.465 7.461 7.459 7.455 7.407 7.345 7.342 7.326 7.258 7.225 4.434 3.467 3.215 2.395 1.252

Ph Ph H N Si OH Ts

10.88 OMOM 5.34

4.76

3.30 3.22 2.87 2.33 2.09 2.04 2.03 2.20 1.53 1.19 1.06 1.20

10 8 6 4 2 PPM

7.451 96.240 77.512 77.398 77.192 76.880 67.291 65.233 55.165 42.040 29.821 29.113 27.321 26.643 21.613 143.230 135.661 138.748 135.478 132.566 131.949 130.112 130.089 129.815 129.647 128.344 128.321 127.170

Ph Ph H N Si OH Ts

OMOM 5.34

140 120 100 80 60 40 20 0PPM

288

(R)-3-{[4-(Methoxymethoxy)-1-(4-methylphenylsulfonamido)butyl]diphenylsilyl} propanoic acid (5.35)

Following the procedure for synthesis of 4.43 (p. 209), using 5.34 (1.0 g, 1.9

mmol) in a mixture of solvent DCM/CH3CN/water (1/1/1, 50 mL), RuCl3 (3.9 mg, 0.019

mmol), and NaIO4 (1.6 g, 7.6 mmol) gave acid 5.35 (0.7 g, 68%) as a colorless oil.

Rf = 0.4 (tail) (hexane / ethyl acetate 2/1)

20 [α]D = +12.0 (c 0.05, CHCl3)

IR: 3205-2560 (br), 3284, 3070, 2883, 1705, 1592, 1111, 734 cm-1

1 H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.5-7.3 (m, 10H), 7.2 (d, J = 7.8

Hz, 2H), 4.56 (d, J = 9.4 Hz, 1H), 4.44 (s, 3H), 3.57-3.51 (m, 1H), 3.17-3.19 (m, 2H),

3.22 (s, 3H), 2.3 (s, 3H), 2.22-2.17 (m, 1H), 1.71 – 1.62 (m, 1H), 1.46-1.40 (m, 1H), 1.37

(dd, J = 8.6, 4.2 Hz, 1H), 1.36-1.30 (m 3H)

13 C NMR (125 MHz, CDCl3): δ 179.5, 143.4, 138.6, 135.6, 135.5, 131.7, 131.1, 130.4,

129.7, 128.5, 127.1, 96.2, 67.3, 55.2, 41.9, 29.1, 28.2, 27.3, 21.6, 6.5;

+ + Exact mass: [M-Na] calcd. for [C28H35NNaO6SSi] 564.1847, found 564.1819

289

7.670 7.649 7.475 7.471 7.459 7.455 7.451 7.368 7.365 7.363 7.349 7.344 7.255 7.216 7.196 4.446 3.222 2.376

Ph Ph H N Si OH Ts O

OMOM 5.35

11.91

5.70 5.44 4.24

2.41 2.40 2.00 2.12 1.37 1.10 1.54

10 8 6 4 2 0PPM

6.521 96.247 77.520 77.406 77.200 76.887 67.284 55.195 41.910 29.166 28.183 27.268 21.628 179.518 143.397 135.646 138.580 135.501 131.713 131.111 130.387 130.364 129.754 128.504 127.132

Ph Ph H N Si OH Ts O

OMOM 5.35

180 160 140 120 100 80 60 40 20 PPM

290

(R)-2-[3-(Methoxymethoxy)propyl]-3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one (5.36)

To solution of acid 5.35 (0.1 g, 0.18 mmol) in THF (4mL) at -20 °C was added triethyl

amine (63 µL, 0.45 mmol) followed by PivCl (22 µL, 0.18 mmol). The solution was

stirred at -20 °C for an h, and then added LiCl (11.3mg, 0.27mmol) followed (S)-

oxazolidione (25.5 mg, 0.2 mmol). The mixture was stirred at the same temperature for

an hour, and then at 0 °C for 2 h, quenched with saturated NH4Cl (5 mL), extracted with

ethyl acetate (3 x 5 mL). The combined organic layers were washed brine (10 mL), dried

over with Na2SO4, and concentrated in vacuo. Column chromatography gave 5.36 (90

mg, 92%)

Rf = 0.7 (hexane / ethyl acetate 1/1)

20 [α]D = +47.0 (c 0.39, CHCl3)

IR: 3070, 3012, 2926, 2883, 1694, 1591, 1343, 1107, 715cm-1

1 H NMR (400 MHz, CDCl3): δ 7.7 (d, J = 8.0 Hz, 2H), 7.6-7.3 (m, 10H), 6.98 (d, J = 8.0

Hz, 1H), 4.89-4.84 (m, 1H), 4.5 (s, 2H), 3.48-3.40 (m, 2H), 3.22 (s, 3H), 2.93-2.79 (m,

2H), 2.3 (s, 3H), 1.86-1.72 (m, 3H), 1.65 (ddd, J = 15.3, 6.0, 4.0 Hz, 1H), 1.62-1.54 (m,

1H), 1.36 (ddd, J = 15.3, 13.3, 7.2 Hz, 1H);

13 C NMR (100 MHz, CDCl3): δ 173.2, 144.2, 136.4135.2, 135.2, 132.6, 132.3, 130.7,

129.1, 128.9, 128.8, 128.6, 96.3, 67.0, 55.2, 45.2, 33.8, 30.4, 28.3, 21.7, 4.3;

+ + Exact mass: [M-Na] calcd. for [C28H33NNaO5SSi] 546.1741, found 546.1724

291

7.719 7.702 7.699 7.547 7.544 7.527 7.523 7.512 7.493 7.398 7.380 7.306 7.286 7.258 6.996 6.976 4.504 3.228 2.322 1.234

OMOM 8.36

Ph2 Si

TsN

O 5.36

3.15 2.99 2.94

2.35 2.05 2.01 1.98 1.94 1.90 1.98

1.34 1.00

8 7 6 5 4 3 2 1 0 PPM

4.349 96.316 77.513 77.398 77.200 76.880 67.002 55.203 45.210 33.831 30.424 28.335 21.689 173.215 144.205 136.362 135.196 135.112 132.605 132.345 130.676 129.144 128.954 128.771 128.550

OMOM

Ph2 Si

TsN

O 5.36

160 140 120 100 80 60 40 20 PPM

292

(R)-tert-Butyl 3-{[4-(methoxymethoxy)-1-(4-methylphenylsulfonamido)

butyl]diphenylsilyl}propyl carbonate (5.38)

Following the procedure for synthesis of 4.52 (p. 217), using compound 5.34 (0.2 g, 0.57

mmol), DMAP (13.8 mg, 0.11mmol), and Boc2O (137 mg, 0.62 mmol) gave compound

5.38 (320 mg, 90%).

Rf= 0.72 (hexane / ethyl acetate 1:1)

20 [α]D = -4.7 (c 0.26, CHCl3)

IR: 3285.2, 3070, 3012, 2926, 2883, 1741, 1597, 1343, 1107, 702cm-1

1 H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.6 Hz, 2H), 7.5-7.3 (m, 10H), 7.2 (d, J = 8.6

Hz, 2H), 4.4 (s, 2H), 4.17 (d, J = 9.5 Hz, 1H), 3.85 (t, J = 6.9 Hz, 2H), 3.53-3.48 (m, 2H),

3.28-3.25 (m, 2H), 3.23(s, 3H), 2.4 (s, 3H), 1.74-1.68 (m, 1H), 1.56 – 1.46 (m, 2H), 1.43-

1.38 (m, 1H), 1.38-1.30 (m, 2H), 1.02-0.90 (m, 2H)

13 C NMR (100 MHz, CDCl3): δ 153.6, 143.3, 138.6, 135.6, 135.5, 132.0, 131.4, 130.2,

129.7, 128.4, 128.3, 127.2, 96.3, 81.9, 69.2, 67.3, 55.1, 41.9, 29.2, 27.9, 27.3, 22.9, 21.6,

7.6

+ + Exact mass: [M-Na] calcd. for [C33H45NNaO7SSi] 650.2578, found 650.2581

293

7.674 7.654 7.454 7.451 7.448 7.438 7.434 7.420 7.372 7.353 7.334 7.260 7.234 4.462 3.858 3.236 2.406 1.456

11.39

10.23

Ph Ph H N Si OBoc Ts

OMOM 5.38

3.06 3.14 2.81 2.39 2.14 2.13 2.10 1.95 2.00 2.10

1.43 0.99 1.06

10 8 6 4 2 0PPM

7.565 96.278 81.941 77.512 77.398 77.200 76.880 69.212 67.291 55.172 41.940 29.227 27.908 27.314 22.908 21.620 153.588 143.298 138.672 135.646 135.509 132.079 131.431 130.219 129.685 128.420 128.390 127.178

Ph Ph H N Si OBoc Ts

OMOM 5.38

160 140 120 100 80 60 40 20 PPM

294

REFERENCES

(1) Weeks, M. E., Discovery of the Elements. Kessinger Publishing Reprints, 2003,

p. 162.

(2) Emsley, J. Nature's Building Blocks: An A-Z Guide to the Elements, Oxford

University Press. 2002, p. 387.

(3) Berzelius, J. J. Ann. Phys. Chemie. 1824, 1, 169-230.

(4) Sainte-Claire Deville, H. E. Compt. Rend. Acad. Sci. 1854, 39, 321.

(5) Gray, T. The ELements: A Visual Exploration of Every Known Atom in the

Universe. Black Dog and Leventhal Publishers, 2009, p. 43.

(6) a) O'Mara, W. C.; Herring, R. B.; Hunt, L. P. Handbook of Semiconductor

Silicon Technology, William Andrew, 1990, p. 349–352.

b) Voronkov, M. G.; Dyakov, V.M.; Baryshok, V. P. Zh. Obshch. Khim. 1977,

47, 797.

c) Voronkov, M. G.; Dyakov. V.M.; Lukina, Y. A.; Samsonova, G. A.;

Kudykov, N. Zh. Obshch. Khim. 1975, 45, 2010.

(7) a) Dvornic, P. R.; Owen, M. J., Silicon-Containing Dendritic Polymers,

Springer, 2009, p.92.

b) Lickiss, P. D.; Lucas, R. J. Organomet. Chem. 1993, 444, 25 – 28.

(8) Fleming, I., Chem. and Ind. (London) 1975, 449-455.

(9) Singh, S.; Sieburth, S. M. Org. Lett. 2012, 14, 4422–4425.

(10) Friedel, C. Ann. Chim. Phys. 1866, 9, 5-51.

(11) Dilthey, W. Ber. 1905, 38, 4132-4136.

295

(12) Kepping, F. S. J. Chem. Soc., Trans. 1907, 91, 209-240.

(13) Robison, R.; Kipping, F. S. J. Chem. Soc., Trans. 1908, 93, 439-456.

(14) Ebsworth, E. A. V., Organometallic Compounds of the Group IV Elements,

A.G. McDiaemid, Dekker, New York, 1968, vol. I, part 1, chapter 1.

(15) Stork, G.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 6152-6153.

(16) Coe, P. L.; Stuart, A. M.; Moody, D. J. J. Fluorine Chem. 1998, 92, 27-32.

(17) Schwarz, K.; Milne, D. B., Nature 1972, 239, 333-334.

(18) Carlisle, E. M., Science 1970, 167, 279-280.

(19) Carlisle, E. M., Science 1972, 178, 619-621.

(20) Rochow, E. G. An Introduction to the Chemistry of Silicones, Wiley, New York,

1964.

Zuckerman, J. J. Adv. Inorg. Chem. Radiochem. 1964, 6, 383-432.

c) Bazant, V.; Joklik, J.; Rathousky, J. Angew. Chem. Int. Ed. 1968, 7, 112-120

(21) Moberg, W. K.; “Fungicidal imidazoles and triazoles containing silicon”, 1985,

US Patent # 4,530,922.

(22) Sieburth, S. M.; Manly, C. J.; Gammon, D. W. Pestic. Sci. 1990, 28, 289-307.

(23) Morris, R. L.; Varnes, M. E. Photochem. Photobiol. 2002, 75, 652-661.

(24) a) Miyagawa, N.; Homma, T.; Kagechika, H.; Shudo, K.; Nagai, H.

Pharmacology 2003, 67, 21-31.

b) Shudo, K.; Kagechika, H.; Yamazaki, N.; Igarashi, M.; Tateda, C. Biol.

Pharm. Bull. 2004, 27, 1887-1889.

(25) Daud, A.; Valkov, N.; Centeno, B.; Derderian, J.; Sullivan, P.; Munster, P.;

Urbas, P.; DeConti, R. C.; Berghorn, E.; Liu, Z.; Hausheer, F.; Sullivan, D.

296

Clin. Cancer Res. 2005, 11, 3009-3016.

(26) Kocsis, P.; Farkas, S.; Fodor, L.; Bielik, N.; Thán, M.; Kolok, S.; Gere, A.;

Csejtei, M.; Tarnawa, I. J. Pharmacol. Exp. Ther. 2005, 315, 1237-1246.

(27) Vonronkov, M. G.; Baryshok, V. P. Pharm. Chem. J. 2004, 38, 3-9.

(28) Kazimirovskaya, V. B.; D’yakov, V. M. Pharm. Chem. J. 2001, 35, 465-467.

(29) Black, C. A.; Ucci, J. W. Bioorg. Med. Chem. Lett. 2002, 12, 3521-3523.

(30) Cunningham, J. G.; Ford R. B.; Gifford, J.A.; Hulce, V. D; Chandler, M. L.;

LeVier, R. R. Amer. J. Vet. Res. 1981, 42, 2178-2181.

(31) Alfthan, O.; Andersson, L.; Esposti, P. L.; Fosså, S. D.; Gammelgaard, P.A.;

Gjöres, J. E.; Isacson, S.; Rasmussen, F.; Ruutu, M.; Schreeb, T.; Setterberg,

G.; Strandell, P.; Strindberg, B. Scand. J. Urol. Nephrol. 1983, 17, 37-43.

(32) Tacke, R.; Müller, V.; Büttner, M. W.; Lippert, W. P.; Bertermann, R.; Daiß, J.

O.; Khanwalkar, H.; Furst, A.; Gaudon, C.; Gronemeyer, H. Chem. Med. Chem.

2009, 4, 1797-1802.

(33) Barnes, M. J.; Conroy, R.; Miller, D. J.; Mills, J. S.; Montana, J. G.; Pooni, P.

K.; Showell, G. A.; Walsh, L. M.; Warneck, J. B. H. Bioorg. Med. Chem. Lett.

2007, 17, 354-357.

(34) Chang, M.; Park, S.-R.; Kim, J.; Jang, M.; Park, J. H.; Park, J. E.; Park, H.-G.;

Suh, Y.-G.; Jeong, Y. S.; Park, Y.-H.; Kim, H.-D. Bioorg. Med. Chem. 2010,

18, 111-115.

(35) Barcza, S.; Hoffman, C. W. Tetrahedron 1975, 31, 2363-2367.

(36) Pitt, C. G.; Friedman, A. E. Tetrahedron 1975, 31, 2369-2377.

(37) Cavelier, F.; Vivet, B. J. Am. Chem. Soc. 2002, 124, 2917-2923.

297

(38) Cavelier, F.; Marchand, D. J. Peptide Res. 2004, 63, 290-296.

(39) Pujals, S.; Fernández-Carneado, J. J. Am. Chem. Soc. 2006, 128, 8479-8483.

(40) Ishikawa, H.; Yamanaka, H., Kawamoto, T.; Tanaka, A. Appl. Microbiol.

Biotechnol. 1999, 53, 19-22.

(41) Tacke, R.; Nguyen, B.; Burschka, C.; Lippert, W. P.; Hamacher, A.; Urban, C.;

Kassack, M. U. Organometallics 2010, 29, 1652-1660.

(42) Daiss, J. O.; Burschka, C.; Mills, J. S.; Montana, J. G.; Showell, G. A.;

Warneck, J. B. H.; Tacke, R. Organometallics 2006, 25, 1188-1198.

(43) Cypryk, M.; Rubinsztajn, S.; Chojnowski, H. J. Organomet. Chem. 1993, 446,

91-97.

(44) Sommer, L. H.; Tyler, L. J. J. Am Chem. Soc. 1954, 76, 1030-1033.

(45) Bunning, J. C; Lydon, J. E.; Eaborn, C.; Jackson, P. M.; Goodby, J. W.; Gray,

G. W. J. Chem. Soc., Faraday Trans. 1 1982, 78, 713-724.

(46) Sommer, L. H.; Tyler, L. J. J. Am. Chem. Soc 1954, 76, 1030-1033.

(47) Steward, O. W.; Fussaco, D.R. J. Organomet. Chem. 1977, 129, C28-C32;

Tran, N. T.; Min, T.; Franz, A. K. Chem. Eur. J. 2011, 17, 9897-9900.

(48) Erickson, J; Neidhart, D. J.; Vandire, J.; Kempf, D. J.; Wang, X. C.; Norbeck,

D.; Platner, J. J.; Rittenhouse, J.; Turon, M; Wideburg, N.; Kohlbrenner, W. E.;

Simmer, R.; Helfrich, R.; Paul, D.; Knigge, M. Science 1990, 249, 527-533.

(49) Kempf, D. J.; Marsh, K.; Paul, D. A.; Knigge, M. F.; Norbeck, D. W;

Kohlbrenner, W. E.; Codacovi, L.; Vasavanonda, S.; Byrant, P.; Wang, X. C.;

Wideburg, N. E.; Clement, J. J.; Plattner, J. J.; Erickson, J. W. Antimicrob.

Agents Chemother. 1991, 35, 2209-214.

298

(50) Kempf, D. J.; Codacovi, L.; Wang, X. C.; Norbeck, D.; Kohlbrenner, W. E.;

Wideburg, N. E.; Paul, D. A.; Knigge, M. F.; Vasavanonda, S.; CraigKennard,

A.; Salivar, A.; Rosenbrook, W. J.; Clement, J. J.; Plattner, J. J.; Erickson, J. W.

J. Med. Chem. 1990, 33, 2687-2689.

(51) Kempf, D. J.; Codacovi, L.; Wang, X. C.; Kohlbrenner, W. E.; Wideburg, N.

E.; Salivar, A.; Vasavanonda, S.; Marsh, K. C.; Byrant, P.; Sham, H. L.; Green,

B. E.; Betebenner, D. A.; Erickson, J. W.; Norbeck, D. W. J. Med. Chem. 1993,

36, 320-330.

(52) Bone, R.; Vacca, J. P.; Anderson, P. S.; Hollyoway, M. K. J. Am. Chem. Soc.

1991, 113, 9382-9384.

(53) Chen, C. A.; Sieburth, S. M.; Glekas, A.; Hewitt, G. W.; Trainor, G. L.;

Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffrey, S.; Klabe, R. M.

Chem. Biol. 2001, 8, 1161-1166.

(54) Almquist, R. G.; Crase, J.; Jennings-White, C.; Meyer, R. F.; Hoefle, M. L.;

Smith, R. D.; Essenburg, A. D.; Kaplan, H. R. J. Med. Chem. 1982, 25, 1292-

1299.

(55) Kim, J.; Hewitt, G.; Carroll, P.; Sieburth, S. M. J. Org. Chem. 2005, 70, 5781-

5789.

(56) Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25, 3760–3767.

(57) Kim, J.; Sieburth, S. M. J. Org. Chem. 2004, 69, 3008-3014.

(58) Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org.

Chem., 2007, 72, 10035–10044

Hemández, D.; Nielsen, L.; Lindsay, K. B.; López-García, M. Á.; Bjerglund, L.;

299

K.; Skrydstrup, T. Org. Lett. 2010, 12, 3528-3531.

(59) Bo, Y.; Singh, S.; Duong, H. Q.; Cao, C.; Sieburth, S. M. Org. Lett. 2011, 13,

1787–1789.

(60) Brevard, C.; Granger, P. “Handbook of High Resolution Multinuclear NMR”

John Wiley & Sons, Chichester, 1981.

(61) Lauterbur, P. C. Determination Org. Struct. Phys.Methods 1962, 2, 511.

(62) Uhlig, F.; Marsmann, H. C., Silicon Compound: Silanes & Silicones, Gelest

Catalog 4000-A, 2008, p. 208-222.

(63) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito, Y. J. Am.

Chem. Soc. 1986, 108, 6090-6093.

(64) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y. J. Am. Chem. Soc.

1988, 110, 3712-3714.

(65) Tamao, K.; Tohma, T.; Inui, N.; Nakayama, O.; Ito, Y. Tetrahedron Lett. 1990,

31, 7333-7736.

(66) Bergens, S. H.; Noheda, P.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1992,

114, 2121-2128.

(67) Singh, S. In hibition of the serine protease chymotrypsin by a silanediol peptide

mimic: asymmetric synthesis and inhibition studies, PhD thesis in Chemistry at

Temple University, 2012

(68) Trzupek, J. D.; Lee, D.; Crowley, B. M.; Marathias,V. M.; Danishefsky, S. J. J.

Am. Chem. Soc. 2010, 132, 8506-8512.

(69) a) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.

b) Boeckman, J., R. K.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am.

300

Chem. Soc. 1991, 113, 5337-5353.

(70) Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2575–2578.

(71) Adams, R.; Adams, E. W. Org. Synth. 1925, 5, 87-90 (Org. Synth. 1941, Coll.

Vol. 1, 459)

(72) Berree, F.; Gernigon, N.; Hercouet, A.; Chia, H. L.; Carboni, B. Eur. J. Org.

Chem. 2009, 3, 329 – 333.

Ely, R. J.; Morken, J. P. J. Am. Chem. Soc. 2010 , 132, 2534 – 2535.

(73) a) Gras, J. L.; Chang, Y. Y. K. W.; Guerin, A. Synthesis, 1985, 74.

b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc, 1988, 110, 1535

– 1538.

(74) Sato, M.; Miyaura, Suzuki, A. Chem. Lett. 1989, 1405-1408.

Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J.

Am. Chem. Soc. 1989, 111, 314–321.

(75) a) Nicolaou, K. C.; Koide, K. Tetrahedron Lett. 1997, 38, 3667-3670.

b) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett. 1990, 675-676.

c) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313-10318.

(76) a) Takasu, M.; Naruse, Y.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 1947-

1950.

b) Garegg, P. J.; Regberg, T.; Stawinski, J.; Strornber, R. J. Chem. Soc. Perkin

Trans. II 1987, 271-274.

(77) Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528.

(78) Reggelin, M.; Doerr, S. Synlett. 2004, 6, 1117.

(79) Piers, E.; Wai, J. M. Can. J. Chem. 1994, 72, 146 – 157.

301

(80) a) Kummer, D. A.; Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers, A. G. J.

Am. Chem. Soc. 2008, 130, 13231 – 13233.

b) Prasad, K.; Houlihan, W. J.; Chen, C-P.; Underwood, R. L.; Repic, O.

Tetrahedron: Asymmetry 1996, 7, 837-842.

(81) a) Shrestha-Dawadi, P. B.; Lugtenburg, J. Eur. J. Org. Chem. 2003, 23, 4654-

4663.

b) Gil, G. Tetrahedron Lett. 1984, 25, 3805-3808.

(82) a) Fleming, I.; Winter, S. B. D. J. Chem. Soc., Perkin Trans. 1 1998, 2687-

2700.

b) Kunal, A.; Kawakami, T.; Toyoda, E,; Ishikawa, M. Organometallics, 1992,

11, 2708-2711.

c) Seyden-Penne, J., Reductions by the Alumino-and Borohydrides in Organic

Synthesis, 2nd Ed., Wiley-VCH, New York, 1997, p.4.

d) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis, Hoboken: John

Wiley & Sons, Inc. 1967, p. 581-595.

(83) a) Yasuhara, F. Yamaguchi, S. Tetrahedron Lett. 1977, 18, 4085-4088.

b) Thompson, L. C.; Berry, S. J. Alloys Compd. 2001, 323–324, 177–180.

c) Binnemans, K. “Rare-earth beta-diketonates” Handbook on the Physics and

Chemistry of Rare Earths, Vol. 35, edited by Gschneidner, K.A.; Bünzli, Jr. J.-

C.G.; Pecharsky, V. K. 2005, p. 128-144.

(84) Shimoma, F.; Kusaka, H.; Wada, K.; Azami, H.; Yasunami, M.; Suzuki, T.;

Hagiwara, H.; Ando, M. J. Org. Chem. 1998, 63, 920-929.

(85) Tsuda, M.; Toriyabe, Y.; Endo, T.; Kobayashi, J. Chem. Pharm. Bull. 2003, 51,

302

448–451.

Fontana, A.; Ishibashi, M.; Kobayashi, J. Tetrahedron, 1998, 54, 2041-2048.

Shigemori, H.; Sato, Y.; Kagata, T.; Kobayashi, J. J. Nat. Prod. 1999, 62, 372-

374.

Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2000, 65, 1349-1352;

Kobayashi, J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem. 2001, 66, 134-

142.

Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363-1366.

(86) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nature Protocols, 2007, 2, 2451-2458

(87) Ritter, S. K. C&EN. 2011, 89, 34; C&EN. 2012, 90, 40-41.

(88) Schafer, A. G.; Wieting, J. M.; Mattson, A. E. Org. Lett. 2011, 13, 5228-5231.

(89) Ngon T. Tran, N. T.; Wilson, S. O.; Franz, A. K. Org. Lett. 2012, 14, 186-189.

(90) Tran, N, T.; Min, T.; Franz, A. K. Chem. Eur. J. 2011, 17, 9897-9900.

(91) a) Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem. 1979, 44, 1421-

1424.

b) Ronald, R. C.; Lansinger, J. M.; Lillie, T. C.; Wheeler, C. J. J. Org. Chem.

1982, 47, 2541-2549.

(92) Poon, K. W.C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923-3927.

(93) Khan, A. T.; Choudhury, L. H.; Shosh, S. Tetrahedron Lett. 2004, 45, 7891-

7894.

(94) Corey, E. J.; Dock, M. D. Tetrahedron Lett. 1975, 16, 2643-2646.

(95) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287-290.

(96) Takano, S.; S. Hatakeyama, S; Ogasawara, I. J. Am. Chem. Soc. 1976, 98, 3022-

303

3023.

Fetizon, M.; Jurion, M. Chem. Commun. 1972, 382-383.

(97) Russell, G. A.; Ochrymowycz, L. A. J. Org. Chem. 1969, 34, 3618-3624.

(98) Nielsen, L.; Lindsay, K.B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org.

Chem. 2007, 72, 10035-10044.

(99) a) Ballweg, D. M.; Miller, R. C.; Gray, D. L.; Scheidt, K. A. Org. Lett. 2005, 7,

1403-1406.

b) Zhou, P.; Chen, B.-C.; Davis, F. A.; Tetrahedron 2004, 60, 8003-8030.

c) Davis, F. A. J. Org. Chem. 2006, 71, 8993-9003.

d) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.

e) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600-3740.

f) Morton, D.; Stockman, R. A. Tetrahedron, 2006, 62, 8869-8905.

g) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Geraldine C. B. Harriman

Bioorg. Med. Chem. Lett.1994, 4, 335-338.

(100) Chatgilialoglu, C. Organosilanes in Radical Chemistry, Principles, Methods

and Applications, John Wiley & Sons Ltd: Chichester, 2004.

(101) Hernández, D.; Lindsay, K.B.; Nielsen, L.; Mittag, T.; Bjerglund, K.; Friis, S.;

Skrydstrup, T. J. Org. Chem. 2010, 75, 3283–3293.

(102) Mico, A. D.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org.

Chem. 1997, 62, 6974-6977.

(103) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.

(104) Troy, G. C. Vet. Clin. N. Am-Small. 1988, 18, 5-20.

(105) Schumacher, W. A.; Luettgen, J. M.; Quan, M. L.; Seiffert, D. A. Arterioscler.

304

Thromb. Vasc. Biol. 2010, 30, 388-392.

(106) Bouma, B. N.; Griffin, J. H. J. Biol. Chem. 1977, 252, 6432-6437.

(107) Kurachi, K.; Davie, E. W. Biochemistry 1977, 16, 5831-5839.

Kurachi, K.; Davie, E. W. Methods Enzymol. 1981, 80, 211-220.

(108) Koide, T.; Kato, H.; Davie, E. W. Methods Enzymol. 1976, 45, 65-73.

(109) Koide, T.; Kato, H.; Davie, E. W. Biochemistry 1977, 16, 2279-2286.

(110) Kurachi, K.; Fujikawa, K.; Davie, E. W. Biochemistry 1980, 19, 1330-1338.

(111) Mackman, N.; Tilley, R. E.; Nigel, S.; Key, N. S. Arterioscler. Thromb. Vasc.

Biol. 2007, 27, 1687–1693.

(112) Gailani, D.; Renné, T. Arterioscler.Thromb. Vasc. Biol. 2007, 27, 2507–2513.

(113) Gailani, D, Renné, T. J. Thromb. Haemost. 2007, 5, 1106–1112.

(114) Davie, E. W.; Fujikawa, K.; Kisiel, W. Biochemistry 1991, 30, 10363-10370.

(115) (a) von dem Borne, P. A. K.; Meijers, J. C. M.; Bouma, B. M. Blood 1995, 86,

3035-3042.

(b) Minnema, M. C.; Friederich, P. W.; Levi, M.; von dem Borne, P. A. K.;

Mosnier, L.O.; Meijers, J. C. M.; Biemond, B. J.; Hack, C. E.; Bouma, B. M.;

Cate, H. J. Clin. Invest. 1998, 101, 10-14.

(116) Wielders, S. J. H.; Béguin, S.; Hemker, H. C.; Lindhout, T. Arterioscler.

Thromb. Vasc. Biol. 2004, 24, 1138-1142.

(117) Meijers, J. C. M.; Tekelenburg, W. L. H.; Bouma, B. N.; Bertina, R. M.;

Rosendaal, F. R. New Engl. J. Med. 2000, 342, 696- 701.

(118) Blow, D. M., Birktoft, J. J.; Hartley, B. S. Nature 1969, 221, 337–340.

305

(119) Lazarova,T. I.; Jin, L.; Rynkiewicz, M.; Gorga, J. C.; Bibbins, F.; Meyers, H.

V.; Babine, R.; Strickler, J. Bioorg. Med. Chem. Lett. 2006, 16, 5022–5027.

(120) Witting, J. I.; Pouliott, C.; Catalfamo, J. L.; Fareed, J.; Fenton, J. W. Thromb.

Res. 1988, 50, 461-467.

(121) (a) Kettner, C.; Shaw, E. Thromb. Res. 1979, 14, 969-973.

(b) Hauptmann, J.; Markwardt, F. Thromb. Res. 1980, 20, 347-351.

(122) Lin, J.; Deng, H.; Jin, L.; Pandey, P.; Quinn, J.; Cantin, S.; Rynkiewicz, M. J.;

Gorga, J. C.; Bibbins, F.; Celatka, C. A.; Nagafuji, P.; Bannister, T. D.; Meyers,

H. V.; Babine, R. E.; Hayward, N. J.; Weaver, D.; Benjamin, H.; Stassen, F.;

Abdel-Meguid, S. S.; Strickler, J. E. J. Med. Chem. 2006, 49, 7781-7791.

(123) Buchanan, M. S.; Carroll, A. R.; Wessling, D.; Jobling, M.; Avery,V. M.;

Davis, R. A.; Feng, Y.; Xue,Y.; Öster, L.; Fex, T.; Deinum, J.; Hooper, J. N.

A.; Quinn, R. J. J. Med. Chem. 2008, 51, 3583–3587.

(124) Smith, S. B.; Verhamme, I. M.; Sun, M. F.; Bock, P. E.; Gailani, D. J. Biol.

Chem. 2008, 283, 6696-6705.

(125) a) Sinha, D.; Marcinkiewicz, M.; Navaneetham, D.; Walsh, P. N. Biochemistry.

2007, 46, 9830-9839.

b) Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun. 1967, 27, 157-

162.

(126) Navaneetham, D.; Jin, L.; Pandey, P.; Strickler, J. E.; Babine, R. E.; Abdel-

Meguid, S. S.; Walsh, P. N. J. Biol. Chem. 2005, 280, 36165-36175.

(127) Desai, J.; Argade, A.; Gite, S.; Shah, K.; Pavase, L.; Thombare, P.; Patel, P.

Synth. Commun. 2011, 41, 748–753.

306

(128) a) Kim, K.S.; Qian, L., Tetrahedron Lett. 1993, 34, 7677-7680.

b) Expósito, A.; Fernández-Suárez, M.; Iglesias, T.; Muñoz, L.; Riguera, R. J.

Org. Chem. 2001, 66, 4206-4213.

(129) Yoshida, T.; Murai, M.; Abe, M.; Ichimaru, N.; Harada, T.; Nishioka, T.;

Miyoshi, H. Biochemistry, 2007, 46, 10365-10372.

Bertini, V.; Lucchesini, F.; Pocci, M.; Munno, A. D. Heterocycles, 1995, 41,

675-688.

(130) Corey, E. J.; Suggs, J. W., Tetrahedron Lett. 1975, 16, 2647-2650.

(131) Davis, F. A.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73, 9619–

9626.

Fullera, A. A.; Dua, D.; Liu, F.; Davoren, J. E.; Bhabhad, G.; Kroon, G.; Casee,

D. A.; Dyson, H. J.; Powers, E. T.; Wipf, P.; Gruebele, M.; Kelly, J. W. Proc.

Natl. Acad. Sci. 2009, 106, 11067-11072.

(132) Hardinger, S. A.; Wijaya, N. Tetrahedron Lett. 1993, 34, 3821-3824.

(133) a) Anker, T.; Hilmersson, G. Org. Lett. 2009, 11, 503-506;

b) Nenajdenko, V. G.; Karpov, A. S.; Balenkova, E. S. Tetrahedron;

Asymmetric 2001, 12, 2517-2527.

(134) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604–8608.

(135) a) Hulce, M.; Mallomo, J. P.; Frye, L. L; Kogan, T. P.; Posner, G. H. Org.

Synth. 1990, 7, 495-451.

b) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy, G.V.; Burns, D. M.;

Davis, F. A. Org. Synth. 2004, 10, 47-54.

c) Amonoo-Neizer, E. H.; Shaw, R. A.; Skovlin, D. O.; Smith, B. C. Inorg.

307

Synth. 1966, 8, 19.

d) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H.

J. Am. Chem. Soc. 2002, 124, 7880 – 7881.

e) Jingjian Bo, Methods in organosilane assembly, 2012, PhD thesis, Temple

University.

(136) Shendage, D. M.; Fröhlich, R.; Haufe, G. Org. Lett. 2004, 6, 3675-3678.

(137) a) Bäckvall, J-E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55, 826 –

831.

b) Patnaik, P. Handbook of Inorganic Chemicals. McGraw-Hill, 2002, p. 341.

(138) Schmidt, A. W.; Olpp, T.; Schmid, S.; Jäger, A.; Knölker, H-J. Tetrahedron

2009, 65, 5484–549.

(139) a) Nyasse, B.; Grehn, L.; Ragnarsson, U. J. Chem. Soc. Chem.Commun. 1997,

1017-1018.

b) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis 1997, 1429-1432.

c) Vedejs, E.; Lin S, Klapars A, Wang J. J. Am. Chem. Soc. 1996, 118, 9796-

9797.

d) Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. J. Org. Chem. 1995, 60,

5969-5972.

(140) Matthews, J. L.; McArthur, D. R.; Muirm, K, W. Tetrahedron Lett. 2002, 43,

5401–5404.

(141) a) Judd, T. C.; Williams, R. M. Angew. Chem. Int. Ed. 2002, 41, 4683-4685

b) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984, 25, 2515–

2518.

308

(142) a) Gould, S. J.; Ben, S.; Yvonne G. W. J. Am. Chem. Soc. 1989, 111, 7932-

7938.

b) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397-4398.

(143) Reddy, P. G.; Pratap, V. T.; Kumar, G. D. K.; Mohanty, S. K.; Baskaran. S.

Eur. J. Org. Chem. 2002, 3740-3743.

(144) Lieber, E.; Rao, C. N. R.; Chao, T. S.; Hoffman, C. W. W. Anal. Chem. 1957,

29, 916–918.

(145) a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677-7680.

b) Expósito, A.; Fernández-Suárez, M.; Iglesias, T.; Munňoz, L.; Riguera, R. J.

Org. Chem. 2001, 66, 4206-4213.

(146) a) Chipperfield, J. R; France, G. D.; Webster, D. E. J. Chem. Soc. Perkin II

1972, 405-410.

b) Moody, C. J.; Shah, P. J. Chem. Soc. Perkin I 1989, 2463-2471.

(147) Harris, W. T.; Tenjarla, S. N.; Holbrook, J. M.; Smith, J.; Mead, C.; Entrekin, J.

J. Pharm. Sci. 1995, 84, 640-642.

(148) Challis, B. C.; Milligan, J. R.; Mitchell, R. C. J. Chem. Soc., Perkin Trans. 1:

1990, 11, 3103 – 3108.

(149) Shendage, D. M.; Froehlich, R.; Haufe, G. Org. Lett. 2004, 6, 3675 – 3678.

(150) Navaneetham, D.; Sinha, D.; Walsh, P. N. J. Biochem. 2010, 148, 467-479.

(151) Blow, D. M. The Enzymes, Boyer, P. D., Ed., Academic Press, New York,

1971, Vol. 3, 3rd ed., p.185.

(152) Kraulis, P. J. J. Appl. Crystallogr. 1991, 24, 946-950.

(153) Ruhlmann, A.; Kukla, D.; Schwager, P.; Bartels, K.; Huber, R. J. Mol. Biol.

309

1973, 77, 417-436.

(154) Krieger, M.; Kay, L. M.; Stroud, R. M., J. Mol. Biol. 1974, 83, 209-230.

(155) Matthews, B. W.; Sigler, P. B.; Henderson, R.; Blow, D. M. Nature 1967, 214,

652-656.

(156) Steitz, T. A.; Henderson, R.; Blow, D. M. J. Mol. Biol. 1969, 46, 337-348.

(157) Blow, D. M. Trends Biochem. Sci. 1997, 22, 405-408.

(158) a) Hedstrom, L. Chem. Rev. 2002, 102, 4501-4523.

b) Kraut, J. Annu. Rev. Biochem. 1977, 46, 331-358.

(159) Hess, G. P.; McConn, J.; Ku, E.; McConkey, G. Philos. Trans. R. Soc. Lond., B,

Biol. Sci. 1970, 257, 89-104.

(160) Bender, M. L.; Killhefer, J. V. Crit. Rev. Biochem. 1973, 1, 149-199.

(161) Steitz, T. A.; Shulman, R. G. Annu. Rev. Biophys. Bioeng. 1982, 11, 419-444.

(162) Polgár, L. Mechanism of Protease Action; CRC Press: Boca Raton, 1989.

(163) Kinoshita, A.; Urata, H.; Bumpus, F. M.; Husain, A. J. Biol. Chem. 1991, 266,

19192-19197.

(164) Urata, H.; Healy, B.; Stewart, R. W.; Bumpus, F. M.; Husain, A. Circ. Res.

1990, 66, 883-890.

(165) Urata, H.; Kinoshita, A.; Misono, K. S.; Bumpus, F. M.; Husain, A. J. Biol.

Chem. 1990, 265, 22348-22357.

(166) Bastos, M.; Maeji, N, J.; Abeles, R. H. Proc. Natl. Acad. Sci. USA. 1995, 92,

6738-6742.

(167) Eda, M.; Ashimori, A.; Akahoshi, F.; Yoshimura, T.; Inoue, Y.; Fukaya, C.;

Nakajima, M.; Fukuyama, H.; Imada, T.; Nakarnura. N. Bioorg. Med. Chem.

310

Lett. 1998, 8, 919-924.

(168) Chou; Shan-Yen; King; Richard, C-H. TaiGen Biotechnology Co., Ltd. Patent:

US2010/152452 A1, 2010.

(169) Poulos, C.; Stavropoulos, G.; Brown, J. R.; Jordan, C. C. J. Med. Chem. 1987,

30, 1512-1515.

(170) Sheppeck II, J. E.; Kar, H.; Hong, H. Tetrahedron Lett. 2000, 41, 5329-5333.

(171) Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn,

1981, 54, 1470 – 1473.

(172) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc. 1984, 106, 1154-1156.

(173) Orwig, K. S.; Dix, T. A. Tetrahedron Lett. 2005, 46, 7007–7009.

(174) Adav, J.S.; Yadav, N. N.; Rao, T. S.; Reddy, B.V.; Ghamdi, A. A. K. A. Eur. J.

Org. Chem. 2011, 2011, 4603-4608.

(175) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994 , 59, 1904 – 1906.

(176) Leonard, J.; Lygo, B.; Procter, G. Advanced Practical Organic Chemistry, 2nd

Ed.; Chapman & Hall: London, U.K., 1995.

(177) a) Flack, H. D.; Bernardinelli, G. Acta Cryst. 1999, A55, 908-915.

b) Flack, H. D.; Bernardinelli, G. J. Appl. Cryst. 2000, 33, 1143-1148.

311

APPENDIX

X-ray structure determination of compound (S,S,S)-3.29xi,177

A clear light colourless block-like specimen of C40H46N2O4Si, approximate dimensions 0.090 mm x 0.100 mm x 0.130 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured.The total exposure time was 4.91 hours.

xi Studied by Dr. Shivaiah Vaddypally and Clifton Hamilton, Temple University. 312

The frames were integrated with the Bruker SAINT software package using a narrow-

frame algorithm. The integration of the data using a monoclinic unit cell yielded a total of

14595 reflections to a maximum θ angle of 27.99° (0.76 Å resolution), of which 6839 were independent (average redundancy 2.134, completeness = 97.5%, Rint = 3.08%, Rsig =

4.20%) and 6092 (89.08%) were greater than 2σ(F2). The final cell constants of a =

10.167(5) Å, b = 10.667(6) Å, c = 17.219(9) Å, β = 99.423(9)°, volume = 1842.2(16) Å3, are based upon the refinement of the XYZ-centroids of 5947 reflections above 20 σ(I) with 4.796° < 2θ < 54.92°. Data were corrected for absorption effects using the multi- scan method (SADABS). The ratio of minimum to maximum apparent transmission was

0.839. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.9865 and 0.9906. The structure was solved and refined using the Bruker

SHELXTL Software Package, using the space group P 1 21 1, with Z = 2 for the formula

2 unit, C40H46N2O4Si. The final anisotropic full-matrix least-squares refinement on F with

429 variables converged at R1 = 4.29%, for the observed data and wR2 = 11.67% for all data. The goodness-of-fit was 1.031. The largest peak in the final difference electron density synthesis was 0.376 e-/Å3 and the largest hole was -0.231 e-/Å3 with an RMS

deviation of 0.048 e-/Å3. On the basis of the final model, the calculated density was 1.166

g/cm3 and F(000), 692 e-.

Table 14. Sample and crystal data for (S,S,S)-3.29

Chemical formula C40H46N2O4Si

Formula weight 646.88

Temperature 173(2) K

313

Wavelength 0.71073 Å

Crystal size 0.090 x 0.100 x 0.130 mm

Crystal habit clear light colourless block

Crystal system monoclinic

Space group P 1 21 1

Unit cell dimensions a = 10.167(5) Å α = 90°

b = 10.667(6) Å β = 99.423(9)°

c = 17.219(9) Å γ = 90°

Volume 1842.2(16) Å3

Z 2

Density (calculated) 1.166 g/cm3

Absorption coefficient 0.105 mm-1

F(000) 692

Table 15. Data collection and structure refinement for (S,S,S)-3.29

Theta range for data collection 2.03 to 27.99°

Index ranges -13<=h<=12, -13<=k<=13, -16<=l<=22

Reflections collected 14595

Independent reflections 6839 [R(int) = 0.0308]

Coverage of independent 97.5% reflections

314

Absorption correction multi-scan

Max. and min. transmission 0.9906 and 0.9865

Structure solution technique direct methods

Structure solution program SHELXS-97 (Sheldrick, 2008)

Refinement method Full-matrix least-squares on F2

Refinement program SHELXL-97 (Sheldrick, 2008)

2 2 2 Function minimized Σ w(Fo - Fc )

Data / restraints / parameters 6839 / 1 / 429

Goodness-of-fit on F2 1.031

6092 data; Final R indices R1 = 0.0429, wR2 = 0.1110 I>2σ(I)

all data R1 = 0.0510, wR2 = 0.1167

2 2 2 w=1/[σ (Fo )+(0.0691P) +0.3229P] Weighting scheme 2 2 where P=(Fo +2Fc )/3

Absolute structure parameter 0.0(1)

Largest diff. peak and hole 0.376 and -0.231 eÅ-3

R.M.S. deviation from mean 0.048 eÅ-3

315

Table 16. Atomic coordinates and equivalent isotropic atomic displacement parameters

(Å2) for (S,S,S)-3.29

x/a y/b z/c U(eq)xii

Si1 0.88925(5) 0.80634(5) 0.81157(3) 0.02224(13)

O1 0.21727(17) 0.00833(19) 0.62896(9) 0.0412(4)

O2 0.3812(2) 0.1492(2) 0.62582(14) 0.0679(7)

O3 0.58903(17) 0.92937(16) 0.68852(8) 0.0331(4)

O4 0.65207(16) 0.47126(15) 0.76498(8) 0.0308(4)

N1 0.51519(18) 0.0668(2) 0.76946(10) 0.0315(4)

N2 0.65327(17) 0.68268(17) 0.74897(9) 0.0222(4)

C1 0.0223(4) 0.9537(6) 0.5443(2) 0.0950(17)

C2 0.1428(3) 0.0337(3) 0.54913(15) 0.0435(6)

C3 0.2271(4) 0.0008(11) 0.4917(2) 0.172(4)

C4 0.1000(7) 0.1659(6) 0.5447(5) 0.179(4)

C5 0.3287(2) 0.0702(2) 0.65806(14) 0.0344(5)

C6 0.3775(2) 0.0258(3) 0.74261(13) 0.0360(5)

C7 0.3003(3) 0.0887(4) 0.80121(18) 0.0595(9)

C8 0.3781(3) 0.2093(4) 0.8230(2) 0.0688(11)

C9 0.5238(3) 0.1712(3) 0.82711(15) 0.0445(6)

C10 0.6142(2) 0.0127(2) 0.73929(11) 0.0264(4)

xii U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 316

x/a y/b z/c U(eq)xii

C11 0.7575(2) 0.0583(2) 0.76654(12) 0.0290(5)

C12 0.7814(3) 0.1785(3) 0.72086(15) 0.0410(6)

C13 0.8577(2) 0.9560(2) 0.75220(12) 0.0299(5)

C14 0.9873(2) 0.8413(2) 0.91221(11) 0.0284(5)

C17 0.1347(3) 0.8789(3) 0.06421(15) 0.0570(9)

C15A 0.9512(3) 0.9290(3) 0.96389(16) 0.0536(8)

C16A 0.0236(3) 0.9467(4) 0.03926(17) 0.0636(10)

C18A 0.1795(3) 0.7946(4) 0.01352(18) 0.0661(10)

C19A 0.1067(3) 0.7757(3) 0.93785(16) 0.0517(8)

C20 0.9930(2) 0.7030(2) 0.75619(11) 0.0263(4)

C21 0.0981(2) 0.7563(3) 0.72307(13) 0.0354(5)

C22 0.1775(3) 0.6839(3) 0.68213(14) 0.0432(6)

C23 0.1546(3) 0.5563(3) 0.67372(15) 0.0466(7)

C24 0.0521(3) 0.5008(3) 0.70534(14) 0.0420(6)

C25 0.9711(2) 0.5742(2) 0.74590(12) 0.0308(5)

C26 0.7357(2) 0.7116(2) 0.82522(10) 0.0221(4)

C27 0.6504(2) 0.7662(2) 0.88406(12) 0.0296(5)

C28 0.5526(2) 0.6720(2) 0.90614(11) 0.0291(5)

C29 0.4250(2) 0.6588(3) 0.86265(15) 0.0419(6)

C30 0.3394(3) 0.5656(3) 0.88027(16) 0.0494(7)

317

x/a y/b z/c U(eq)xii

C31 0.3766(3) 0.4865(3) 0.94214(16) 0.0502(7)

C32 0.5027(3) 0.4969(4) 0.98485(17) 0.0601(9)

C33 0.5903(3) 0.5869(3) 0.96679(14) 0.0486(7)

C34 0.61607(19) 0.5654(2) 0.72509(10) 0.0210(4)

C35 0.52926(19) 0.5539(2) 0.64511(10) 0.0219(4)

C36 0.4914(2) 0.6557(2) 0.59546(11) 0.0292(5)

C37 0.4140(2) 0.6364(3) 0.52166(12) 0.0358(5)

C38 0.3748(2) 0.5156(2) 0.49690(12) 0.0334(5)

C39 0.4113(2) 0.4147(2) 0.54610(12) 0.0324(5)

C40 0.4882(2) 0.4338(2) 0.62040(11) 0.0275(4)

Table 17. Bond lengths (Å) for (S,S,S)-3.29

Si1-C20 1.888(2) Si1-C14 1.889(2)

Si1-C13 1.894(2) Si1-C26 1.907(2)

O1-C5 1.336(3) O1-C2 1.482(3)

O2-C5 1.183(3) O3-C10 1.244(3)

O4-C34 1.238(3) N1-C10 1.337(3)

N1-C6 1.468(3) N1-C9 1.485(3)

N2-C34 1.351(3) N2-C26 1.470(2)

C1-C2 1.484(4) C2-C3 1.454(5)

318

C2-C4 1.474(7) C5-C6 1.534(3)

C6-C7 1.531(4) C7-C8 1.524(5)

C8-C9 1.527(4) C10-C11 1.534(3)

C11-C13 1.541(3) C11-C12 1.544(3)

C14-C15A 1.382(4) C14-C19A 1.408(4)

C17-C16A 1.350(5) C17-C18A 1.382(5)

C15A-C16A 1.396(3) C18A-C19A 1.404(4)

C20-C25 1.399(4) C20-C21 1.411(3)

C21-C22 1.389(4) C22-C23 1.385(5)

C23-C24 1.386(4) C24-C25 1.402(3)

C26-C27 1.551(3) C27-C28 1.506(3)

C28-C33 1.389(4) C28-C29 1.395(3)

C29-C30 1.386(4) C30-C31 1.363(4)

C31-C32 1.375(4) C32-C33 1.379(5)

C34-C35 1.514(2) C35-C40 1.393(3)

C35-C36 1.396(3) C36-C37 1.396(3)

C37-C38 1.396(4) C38-C39 1.382(3)

C39-C40 1.400(3)

319

Table 18. Bond angles (°) for (S,S,S)-3.29

C20-Si1-C14 108.91(10) C20-Si1-C13 106.16(10)

C14-Si1-C13 110.24(11) C20-Si1-C26 106.81(10)

C14-Si1-C26 108.13(9) C13-Si1-C26 116.34(10)

C5-O1-C2 122.1(2) C10-N1-C6 119.31(19)

C10-N1-C9 128.13(19) C6-N1-C9 112.52(19)

C34-N2-C26 123.80(16) C3-C2-C4 113.4(6)

C3-C2-O1 108.6(3) C4-C2-O1 108.9(3)

C3-C2-C1 113.4(5) C4-C2-C1 108.2(4)

O1-C2-C1 103.8(2) O2-C5-O1 126.6(2)

O2-C5-C6 124.4(2) O1-C5-C6 109.0(2)

N1-C6-C7 103.1(2) N1-C6-C5 110.5(2)

C7-C6-C5 111.7(2) C8-C7-C6 103.3(2)

C7-C8-C9 104.3(3) N1-C9-C8 102.6(2)

O3-C10-N1 120.0(2) O3-C10-C11 121.2(2)

N1-C10-C11 118.82(19) C10-C11-C13 110.27(19)

C10-C11-C12 109.15(18) C13-C11-C12 110.1(2)

C11-C13-Si1 124.64(16) C15A-C14-C19A 116.1(2)

C15A-C14-Si1 124.65(18) C19A-C14-Si1 119.20(18)

C16A-C17-C18A 119.5(2) C14-C15A-C16A 122.3(3)

C17-C16A-C15A 120.7(3) C17-C18A-C19A 120.0(3)

320

C18A-C19A-C14 121.1(3) C25-C20-C21 117.4(2)

C25-C20-Si1 123.18(18) C21-C20-Si1 119.46(19)

C22-C21-C20 121.5(3) C23-C22-C21 119.9(3)

C22-C23-C24 120.2(3) C23-C24-C25 119.9(3)

C20-C25-C24 121.2(2) N2-C26-C27 111.38(17)

N2-C26-Si1 111.07(13) C27-C26-Si1 115.98(15)

C28-C27-C26 112.16(19) C33-C28-C29 117.1(2)

C33-C28-C27 120.9(2) C29-C28-C27 121.8(2)

C30-C29-C28 121.1(2) C31-C30-C29 120.7(3)

C30-C31-C32 118.9(3) C31-C32-C33 121.1(3)

C32-C33-C28 121.0(3) O4-C34-N2 122.66(17)

O4-C34-C35 120.94(19) N2-C34-C35 116.38(17)

C40-C35-C36 119.31(17) C40-C35-C34 116.96(18)

C36-C35-C34 123.72(19) C35-C36-C37 120.1(2)

C38-C37-C36 120.3(2) C39-C38-C37 119.83(19)

C38-C39-C40 120.0(2) C35-C40-C39 120.5(2)

Table 19. Torsion angles (°) for (S,S,S)-3.29

C5-O1-C2-C3 63.9(5) C5-O1-C2-C4 -60.0(5)

C5-O1-C2-C1 -175.2(3) C2-O1-C5-O2 -0.5(4)

C2-O1-C5-C6 177.7(2) C10-N1-C6-C7 169.1(2)

321

C9-N1-C6-C7 -13.2(3) C10-N1-C6-C5 -71.4(3)

C9-N1-C6-C5 106.3(2) O2-C5-C6-N1 -16.1(4)

O1-C5-C6-N1 165.7(2) O2-C5-C6-C7 98.1(3)

O1-C5-C6-C7 -80.1(3) N1-C6-C7-C8 31.1(3)

C5-C6-C7-C8 -87.6(3) C6-C7-C8-C9 -38.1(3)

C10-N1-C9-C8 167.4(3) C6-N1-C9-C8 -10.1(3)

C7-C8-C9-N1 29.5(3) C6-N1-C10-O3 0.6(3)

C9-N1-C10-O3 -176.8(2) C6-N1-C10-C11 178.7(2)

C9-N1-C10-C11 1.3(3) O3-C10-C11-C13 -24.1(3)

N1-C10-C11-C13 157.82(19) O3-C10-C11-C12 96.9(2)

N1-C10-C11-C12 -81.2(2) C10-C11-C13-Si1 -72.6(2)

C12-C11-C13-Si1 166.91(16) C20-Si1-C13-C11 168.75(17)

C14-Si1-C13-C11 -73.4(2) C26-Si1-C13-C11 50.1(2)

C20-Si1-C14-C15A 169.6(3) C13-Si1-C14-C15A 53.5(3)

C26-Si1-C14-C15A -74.7(3) C20-Si1-C14-C19A -9.8(3)

C13-Si1-C14-C19A -125.9(2) C26-Si1-C14-C19A 105.9(2)

C19A-C14-C15A-C16A -4.0(5) Si1-C14-C15A-C16A 176.6(3)

C18A-C17-C16A-C15A 2.4(6) C14-C15A-C16A-C17 1.2(6)

C16A-C17-C18A-C19A -2.8(6) C17-C18A-C19A-C14 -0.2(5)

C15A-C14-C19A-C18A 3.5(5) Si1-C14-C19A-C18A -177.1(3)

C14-Si1-C20-C25 103.25(18) C13-Si1-C20-C25 -138.06(17)

322

C26-Si1-C20-C25 -13.30(19) C14-Si1-C20-C21 -76.75(18)

C13-Si1-C20-C21 41.94(18) C26-Si1-C20-C21 166.70(15)

C25-C20-C21-C22 -0.3(3) Si1-C20-C21-C22 179.70(17)

C20-C21-C22-C23 -0.5(4) C21-C22-C23-C24 0.6(4)

C22-C23-C24-C25 0.0(4) C21-C20-C25-C24 1.0(3)

Si1-C20-C25-C24 -179.00(16) C23-C24-C25-C20 -0.9(3)

C34-N2-C26-C27 -103.8(2) C34-N2-C26-Si1 125.23(18)

C20-Si1-C26-N2 -63.84(16) C14-Si1-C26-N2 179.08(14)

C13-Si1-C26-N2 54.46(17) C20-Si1-C26-C27 167.67(14)

C14-Si1-C26-C27 50.59(17) C13-Si1-C26-C27 -74.03(17)

N2-C26-C27-C28 65.7(2) Si1-C26-C27-C28 -166.00(14)

C26-C27-C28-C33 85.5(3) C26-C27-C28-C29 -88.8(3)

C33-C28-C29-C30 0.9(4) C27-C28-C29-C30 175.3(2)

C28-C29-C30-C31 1.9(5) C29-C30-C31-C32 -2.8(5)

C30-C31-C32-C33 1.1(5) C31-C32-C33-C28 1.7(5)

C29-C28-C33-C32 -2.6(4) C27-C28-C33-C32 -177.1(3)

C26-N2-C34-O4 -2.2(3) C26-N2-C34-C35 179.07(16)

O4-C34-C35-C40 2.4(3) N2-C34-C35-C40 -178.85(19)

O4-C34-C35-C36 -176.3(2) N2-C34-C35-C36 2.4(3)

C40-C35-C36-C37 -0.4(3) C34-C35-C36-C37 178.3(2)

C35-C36-C37-C38 -0.5(4) C36-C37-C38-C39 0.9(4)

323

C37-C38-C39-C40 -0.4(4) C36-C35-C40-C39 0.9(3)

C34-C35-C40-C39 -177.90(19) C38-C39-C40-C35 -0.5(3)

Table 20. Anisotropic atomic displacement parameters (Å2) for (S,S,S)-3.29

U11 U22 U33 U23 U13 U12

Si1 0.0218(3) 0.0216(3) 0.0222(2) -0.0016(2) 0.00030(18) 0.0003(2)

O1 0.0359(9) 0.0429(11) 0.0406(8) 0.0073(8) -0.0062(7) -0.0152(8)

O2 0.0582(13) 0.0511(14) 0.0819(14) 0.0368(12) -0.0256(11) -0.0278(11)

O3 0.0423(9) 0.0207(8) 0.0323(7) -0.0030(6) -0.0062(6) 0.0028(7)

O4 0.0397(9) 0.0198(8) 0.0298(7) 0.0038(6) -0.0039(6) 0.0011(7)

N1 0.0278(9) 0.0285(10) 0.0361(9) -0.0070(8) -0.0010(7) -0.0031(8)

N2 0.0259(9) 0.0198(9) 0.0194(7) 0.0004(6) -0.0007(6) 0.0005(7)

C1 0.082(3) 0.127(4) 0.0620(19) 0.030(2) -0.0298(18) -0.067(3)

C2 0.0337(12) 0.0470(17) 0.0448(13) 0.0152(11) -0.0087(10) -0.0091(12)

C3 0.056(2) 0.414(14) 0.0424(18) -0.038(4) 0.0014(16) 0.000(5)

C4 0.138(5) 0.068(3) 0.270(8) 0.020(4) -0.146(6) 0.008(4)

C5 0.0304(11) 0.0238(12) 0.0461(12) 0.0034(10) -0.0024(9) 0.0004(10)

C6 0.0297(12) 0.0345(13) 0.0412(12) -0.0012(10) -0.0018(9) -0.0044(10)

C7 0.0345(14) 0.089(3) 0.0551(15) -0.0162(17)0.0075(11) -0.0030(16)

C8 0.0466(17) 0.080(3) 0.079(2) -0.044(2) 0.0063(15) 0.0107(17)

324

U11 U22 U33 U23 U13 U12

C9 0.0405(14) 0.0450(16) 0.0477(13) -0.0210(12) 0.0063(11) -0.0016(13)

C10 0.0327(11) 0.0189(10) 0.0252(9) 0.0033(8) -0.0026(8) 0.0024(9)

C11 0.0295(11) 0.0240(11) 0.0315(10) 0.0001(8) -0.0010(8) 0.0004(9)

C12 0.0385(13) 0.0257(12) 0.0570(14) 0.0071(11) 0.0025(11) -0.0030(11)

C13 0.0288(11) 0.0275(12) 0.0334(10) 0.0057(9) 0.0052(8) 0.0030(9)

C14 0.0276(11) 0.0287(12) 0.0268(9) -0.0034(8) -0.0020(8) -0.0027(9)

C17 0.0661(19) 0.058(2) 0.0377(12) -0.0106(13) -0.0197(13) -0.0058(16)

C15A 0.0486(16) 0.0552(19) 0.0502(14) -0.0201(13) -0.0120(12) 0.0121(15)

C16A 0.0640(19) 0.075(2) 0.0460(14) -0.0305(16) -0.0100(14) 0.0062(18)

C18A 0.0672(19) 0.059(2) 0.0585(16) -0.0085(16) -0.0292(15) 0.0174(19)

C19A 0.0552(16) 0.0459(18) 0.0479(13) -0.0108(12) -0.0101(12) 0.0146(14)

C20 0.0244(10) 0.0311(12) 0.0220(8) -0.0018(8) -0.0002(7) 0.0040(9)

C21 0.0319(12) 0.0384(13) 0.0366(11) 0.0030(10) 0.0073(9) 0.0007(11)

C22 0.0324(13) 0.0597(19) 0.0400(12) 0.0014(12) 0.0129(10) 0.0057(13)

C23 0.0365(13) 0.062(2) 0.0422(12) -0.0129(13) 0.0099(10) 0.0163(14)

C24 0.0401(14) 0.0371(15) 0.0474(13) -0.0144(11) 0.0030(10) 0.0093(12)

C25 0.0261(10) 0.0298(12) 0.0357(10) -0.0058(9) 0.0025(8) 0.0018(10)

C26 0.0249(10) 0.0218(10) 0.0187(8) -0.0014(7) 0.0008(7) 0.0004(8)

C27 0.0336(11) 0.0299(12) 0.0262(9) -0.0064(8) 0.0073(8) -0.0024(10)

C28 0.0319(11) 0.0346(12) 0.0226(9) -0.0042(9) 0.0095(8) -0.0018(10)

325

U11 U22 U33 U23 U13 U12

C29 0.0322(13) 0.0451(16) 0.0480(13) 0.0080(12) 0.0049(10) -0.0001(12)

C30 0.0381(14) 0.0557(19) 0.0546(15) -0.0022(14) 0.0082(11) -0.0105(14)

C31 0.0561(17) 0.0492(18) 0.0513(14) -0.0045(13) 0.0263(13) -0.0178(15)

C32 0.0660(19) 0.068(2) 0.0493(15) 0.0248(15) 0.0190(14) -0.0030(18)

C33 0.0451(15) 0.065(2) 0.0352(11) 0.0169(13) 0.0053(10) -0.0043(15)

C34 0.0214(9) 0.0220(10) 0.0199(8) -0.0004(7) 0.0041(7) 0.0008(8)

C35 0.0218(9) 0.0235(11) 0.0207(8) -0.0019(7) 0.0042(7) -0.0017(8)

C36 0.0374(12) 0.0223(11) 0.0260(9) -0.0013(8) -0.0002(8) -0.0027(9)

C37 0.0439(13) 0.0325(13) 0.0273(10) 0.0040(9) -0.0050(9) -0.0035(11)

C38 0.0369(12) 0.0379(14) 0.0233(9) -0.0042(9) -0.0015(8) -0.0070(11)

C39 0.0372(12) 0.0276(12) 0.0308(10) -0.0081(9) 0.0007(9) -0.0067(10)

C40 0.0320(11) 0.0205(11) 0.0288(9) -0.0006(8) 0.0013(8) -0.0021(9)

Table 21. Hydrogen atomic coordinates and isotropic atomic displacement parameters

(Å2) for (S,S,S)-3.29

x/a y/b z/c U(eq)

H2 0.6266 0.7454 0.7170 0.027

H1A 0.0489 0.8654 0.5494 0.143

H1B -0.0352 0.9669 0.4935 0.143

H1C -0.0265 0.9760 0.5870 0.143

326

x/a y/b z/c U(eq)

H3B 0.3029 1.0587 0.4965 0.257

H3C 0.1753 1.0067 0.4385 0.257

H3A 0.2599 0.9149 0.5013 0.257

H4A 0.0132 1.1732 0.5621 0.268

H4C 0.0925 1.1954 0.4903 0.268

H4B 0.1658 1.2168 0.5789 0.268

H6 0.3707 0.9326 0.7461 0.043

H7A 0.2073 1.1070 0.7765 0.071

H7B 0.2992 1.0352 0.8481 0.071

H8A 0.3616 1.2415 0.8745 0.083

H8B 0.3529 1.2746 0.7825 0.083

H9A 0.5777 1.2414 0.8117 0.053

H9B 0.5628 1.1427 0.8806 0.053

H11 0.7698 1.0778 0.8241 0.035

H12A 0.7714 1.1595 0.6645 0.061

H12B 0.8717 1.2097 0.7394 0.061

H12C 0.7163 1.2425 0.7296 0.061

H13A 0.9452 0.9982 0.7559 0.036

H13B 0.8321 0.9298 0.6966 0.036

H17 1.1816 0.8891 1.1162 0.068

327

x/a y/b z/c U(eq)

H15A 0.8744 0.9791 0.9476 0.064

H16A 0.9944 1.0070 1.0733 0.076

H18A 1.2598 0.7493 1.0299 0.079

H19A 1.1385 0.7178 0.9034 0.062

H21 1.1150 0.8437 0.7289 0.043

H22 1.2473 0.7219 0.6599 0.052

H23 1.2095 0.5066 0.6462 0.056

H24 1.0366 0.4132 0.6995 0.05

H25 0.9002 0.5357 0.7668 0.037

H26 0.7699 0.6292 0.8477 0.027

H27A 0.7101 0.7940 0.9322 0.036

H27B 0.6011 0.8404 0.8602 0.036

H29 0.3962 0.7145 0.8202 0.05

H30 0.2540 0.5568 0.8489 0.059

H31 0.3163 0.4253 0.9555 0.06

H32 0.5300 0.4412 1.0275 0.072

H33 0.6778 0.5908 0.9963 0.058

H36 0.5184 0.7381 0.6119 0.035

H37 0.3878 0.7059 0.4882 0.043

H38 0.3231 0.5026 0.4464 0.04

328

x/a y/b z/c U(eq)

H39 0.3843 0.3324 0.5295 0.039

H40 0.5124 0.3642 0.6542 0.033

329