• No results found

The intramolecular radical carboxyarylation reaction : scope and applications to natural product synthesis

N/A
N/A
Protected

Academic year: 2019

Share "The intramolecular radical carboxyarylation reaction : scope and applications to natural product synthesis"

Copied!
419
0
0

Loading.... (view fulltext now)

Full text

(1)

Page v, 5th line: ‘was' should be ‘were'.

Page 2, 7th line up: ‘mechamism' should be ‘mechanism'.

Page 6, paragraph 2; and Table 1: the results presented are from references 15-19. Page 7, 3rd line: ‘memembered' should be ‘membered’.

Page 11: The second last sentence should read ‘In both cases the product is formed from the intermediate radical 1.61.’.

Page 12: Structure 1.66 should be:

SEt

, O T M S

1.66

Page 14, Scheme 1.12: Structures 1.74 and 1.78 should be:

OTHP

CO?Bn

THPO OTES

C02Me'oTBDPS

Page 16, 2nd line and 2nd line up: 'thiollactone' should be ‘thiolactone' Page 18, 7th line up: ‘pyrrolizadine’ should be ‘pyrrolizidine’

(2)

1.189

%

OH

1.190 1.191 OMe

1.187

1.192

1.195 1.194

OTBS

HO, OH B

OMe 1.193

Page 38: The first paragraph should read: ‘The a,ß-unsaturated ester

1.195

was also

synthesised from the aldehyde

1

.

190

.

Wittig olefination of

1.190

with methyl

(triphenylphosphoranylidene)acetate followed by deprotection of the TBS ether with

TBAF. furnished the alcohol

1.195

(Scheme 1.37).’.

Page 41: The text above scheme 1.43 should read ‘alcohol

1

.

221

,

the synthesis of which

has been reported in the literature

via

a longer sequence.’.

Page 43: The 1st paragraph should begin ‘The thionocarbonates were synthesised in a

single step from />methoxyphenylchlorothionoformate’.

Page 49: The last sentence should begin ‘The relative stereochemistry’.

Page 50: The 3rd sentence should begin 'The relative stereochemistry’.

(3)

Page 74, 6th line and 7th line: ‘spectrum’ should be ‘spectra’. Page 77, last line: ‘quarternary' should be ‘quaternary’.

Page 88. 3rd line: *dimethylphenyl-2-oxazolidinone' should be ‘diphenylmethyl-2- oxazolidinone’.

Page 88. last line: ‘3,4-dimethoxybenzyl iodide’ should be ‘3-methoxy-4-benzyloxybenzyl iodide’.

Page 93: Structures 2.47a and 2.49a should be:

2.49a Page 95, 2nd line: ‘triethyl amine' should be ‘triethylamine’. Page 101, Scheme 2.18: Structures 2.66a and 2.66b should be:

OR

Page 109. 3rd line up: ‘adenocarcionoma’ should be ‘adinocarcinoma* Page 126, scheme 3.14: Structure 3.81 should be:

OSiMe3

(4)

Page 126, 4th line up; Page 127, scheme 3.15: ‘5-exo/l-endo' should be '5 -exo ll-exo '.

Page 153. paragraph 2, 4th line: ‘demonstated" should be 'dem onstrated'. Page 154, 3rd line up: ‘hexamethyldisilizide’ should be ‘hexamethyldisilazide’. Page 162, 6th line: ‘pivalate-protected' should be ‘pivaloyl-protected’.

Page 162-195: The following references should be: re f 58 —> re f 182; ref 59 —> re f 183; ref 60 —> ref 184; ref 61 —* re f 185; ref 62 —* ref 186; ref 63 —> ref 187; ref 64 —> ref 188; ref 65 —> ref 189; ref 66 —> ref 190; ref 67 —» ref 191; ref 68 —► ref 192; ref 69 —> ref 193; ref 70 —* ref 194; ref 71 —*■ re f 195; ref 72 —> ref 196; ref 73 —*■ ref 197; re f 74 —» ref 198; ref 75 —* ref 199; ref 76 —► re f 200; ref 77 —► ref 201; re f 78 —> re f 202; ref 202 —*■ ref 203; ref 203 -* ref 204; ref 204 -+ ref 205; re f 205 -+ ref 206; re f 207 -> ref 208; re f 208 —► ref 209; ref 209 -> ref 210; ref 210 -* ref 211; ref 211 -*• ref 212; ref 212 — ref 213; ref 213 —* ref 214; ref 214 —> re f 215; ref 215 —> ref 216.

Page 165. 4th line up: ‘changing to the solvent to' should be ‘changing the solvent to’. Page 174, 13th line: ‘Unfortuantely’ should be ‘Unfortunately’.

Page 175, 4th and 6th lines up: ‘alkenic’ should be ‘vinylic’. Page 176, 4th line: ‘Trimethyl silyP should be ‘Trimethylsilyl'. Page 177, 6th line: ‘oxygentation’ should be ‘oxygenation’. Page 180, 2nd line up: ‘precendenf should be ‘precedent’.

Page 186, 9th line: ‘provides support to proposed’ should be ‘provides support to the proposed’.

Page 197, 4th line: ‘carboxyarylation reaction ’ should be ‘carboxyarylation reaction.'. Page 197. 7th line: ‘straight forward' should be ‘straightforward’.

Page 206, 6th line: ‘methylynation’ should be ‘methylenation'. Page 2 1 1 ,4th line up: ‘monitered’ should be ‘monitored'.

Page 219, 6th line: ‘methane sulphonic acid" should be 'methanesulphonic acid". Page 234, 8th line: ‘5.73' should be ‘5.37’.

Page 237, last line: ‘to pursue use an aryl triflate' should be ‘to pursue the use o f an aryl triflate’.

(5)

butyldimethylsilyloxy)propanal\

Page 266, 15th line up: ‘ 1,4-Dihydronapthalene-l-carboxylic acid” should be ‘ 1.4-

Dihydronaphthalene-1 -carboxylic acid”.

Page 266, 11th line up: ‘1,4-dihydronapthalene-l-carboxylic acid’ should be ‘ 1.4-

dihydronaphthalene-1-carboxylic acid”.

Page 304, 3rd line: ‘(30mg, 77 pmol)” should be ‘(30 mg, 77 pmol)”.

Page 306, 4th line up: ‘sulfurtrioxide-pyridine” should be ‘sulfur trioxide-pyridine”.

Page 309, 2nd line: “borontrifluoride” should be 'boron trifluoride”.

Page 316: Heading

‘(6£)-5,8,9,10-tetrahydro-4//-benzo[</||l,3]dioxacyclododecine-2-thione

(3.213)”

should

be

‘(6£)-5,8,9,10-Tetrahydro-4//-benzo[//][l,3|

dioxacyclododecine-2-thione (3.213)'.

Page 337, 7th line up: ‘chloro//7.v(triphenyl phosphine)rhodium” should be

‘chlorotm(triphenylphosphine)rhodium’.

(6)

Scope and Applications to Natural Product Synthesis

A thesis subm itted in fulfilm ent o f the requirem ents for adm ission to the degree o f

Doctor of Philosophy (Organic Chemistry)

By

Lisa A. Sharp

Research School o f Chemistry Institute o f Advanced Studies

Canberra, Australia

(7)

I declare that the material presented in this thesis

represents the result o f original work carried out by the author

and has not been submitted fo r any other degree. This thesis is

less than 100, 000 words in length.

Lisa A. Sharp

(8)

Acknowledgements

When I look back several years, I can never remember when or why I chose to study chemistry. But now looking at the last three and a half years it has been most enjoyable experience, both from the challenge of the project and the people 1 have worked with over this time.

Firstly, I would like to acknowledge my supervisor, Mick Sherbum, for provoiding me with an at times challenging project, as well for his encouragement and guidance throughout my PhD. To everyone who I have worked with over the past three years at both the University o f Sydney and the Australian National University for their helpful discussions and friendship, and to the many people who gave their time to proof reading this thesis.

(9)

1.161—>1.162). Prior to this study, four examples o f this reaction had been reported in the literature and all were unexpected transformations. Neither the scope of the reaction nor applications o f the reaction had been reported.

3

^ 5cA s

(Me3Si)3SiH,AIBN, PhH, reflux

,1 3

&

i

Ar Ar 0

1.16! alkene carboxyarylation 1.162

Ar

J W V

OMe

Scheme 1

(10)

the dibenzylbutyrolactones (-)-arctigenin 2.1 and (-)-matairesinol 2.5 (Scheme 2) is presented in Chapter 2. The key carboxyarylation reaction of the thionocarbonates 2.62a and 2.62b proceeded with high diastereoselectivity for the /nrnv-substituted lactones 2.63a and 2.63b. Silyl ethers 2.63a and 2.63b were deprotected to form 7(5)- hydroxyarctigenin derivative 2.2 and 7(S)-hydroxymatairesinol 2.6. The C7-hydroxy derivatives 2.6 and 2.2 were converted into the C7 hydroxy epimers, C7-oxo derivatives, tetrahydronaphthalene lignans and (-)-arctigenin and (-)-matairesinol.

TBSO TBSO

key carboxyarylation reaction

OTBS OTBS

2.62a R = TBS 2.62b R = Me

2.63a R = TBS

2.63b R = Me 2.6 R = H2.2 R = Me

C7-hydroxy epimers. C7-OXO derivatives, tetrahydronaphthalene lignans

2.5 R = H 2.1 R = Me

(11)

and very high diastereoselectivity. Attempts to apply the transannular carboxyarylation reaction to the synthesis of dibenzocyclooctadiene lactone lignans was unsuccessful. The cyclic thionocarbonates 3.314 did not produce any of the dibenzocyclooctadiene lactones 3.315.

R = H, OTBS

(12)

step o f the carboxyarylation reaction o f thionocarbonate 4.86 provided lactone 4.87 (Scheme 4) in good yield. 4.87 was transformed into the dihydrofuran 4.121. The B-ring o f totarol was closed via a nucleophilic acyl substitution reaction, forming the tetracycle 4.122 and completing the formation o f the carbon framework o f (+)-totarol.

key carboxyarylation reaction .

2 steps

COoMe

4.121

1 step

totarol 4.122

(13)

give the optimum yield o f the lactone product. Conversion o f the lactone 5.61 into the triflate 5.69 was achieved in 5 steps. Conversion o f triflate 5.69 into 5.28 is envisaged in one or two steps.

key carboxyarylation

reaction (

3 steps

H OMe

5.1

Viridin

5 steps

(14)

% p e r c e n t a g e y i e l d

A h e a t

°C d e g r e e / s C e l s i u s

A c C H3C O

-A I B N 2,2’- a z o b i s i s o b u t y r o n i t r i l e A O a t o m i c o r b i t a l

9 - B B N 9 - b o r o b i c y c l o [ 3 . 3 . 1 J n o n a n e

B n b e n z y l

c c o n c e n t r a t i o n ( g /L )

c a c i r c a ( a p p r o x i m a t e l y )

c a t. c a ta l y ti c

C O S Y c o r r e l a t e d s p e c t r o s c o p y

d d a y / s o r d o u b l e t / s

d b a d i b e n z y l i d e n e a c e t o n e

D B U l , 8 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 7 - e n e

D D Q 2 , 3 - d i c h l o r o - 5 , 6 - d i c y a n o - l , 4 - b e n z o q u i n o n e

d .e . d i a s t e r e o m e r i c e x c e s s

D E P T d i s t o r t i o n l e s s e n h a n c e m e n t b y p o l a r i s a t i o n t r a n s f e r

D M A P 4 - d i m e t h y l a m i n o p y r i d i n e

D M F d i m e t h y l f o r m a m i d e

D M P U l , 3 - d i m e t h y l - 3 , 4 , 5 , 6 - t e t r a h y d r o - 2 ( l / / ) - p y r i m i d i n o n e

D I B A L - H d i i s o b u t y l a l u m i n i u m h y d r i d e

D M S O d i m e t h y l s u l f o x i d e

d p p p l , 3 - ^ A ( d i p h e n y l p h o s p h i n o ) p r o p a n e

E D G e l e c t r o n d o n a t i n g g r o u p

e .e . e n a n t i o m e r i c e x c e s s

E l e l e c t r o n i m p a c t

E P H P 1- e t h y l p i p e r i d i n e h y p o p h o s p h i t e e q u iv m o l a r e q u i v a l e n t s

E t e th y l

E W G e l e c t r o n w i t h d r a w i n g g r o u p

e n d o s p a c e u n d e r o r a b o v e t h e d ie n e .

(15)

HMPA HOMO HRMS IMDA /Pr LDA LHMDS LRMS LUMO M+ MA MCPBA Me min MO Ms NMR nOe NOESY /?-chloanil Ph PhMe PhH Piv ppm PPTS q RT s SM t T hexamethylphosphoramide highest occupied molecular orbital high resolution mass spectrometry intramolecular Diels-Alder

isopropyl

lithium diisopropylamide lithium hexamethyldisilazide low resolution mass spectrometry lowest unoccupied molecular orbital molecular ion maleic anhydride 3-chloroperoxybenzoic acid methyl minute molecular orbital mesyl

nuclear magnetic resonance nuclear Overhauser effect

nuclear Overhauser and exchange spectroscopy tetrachloro-1,4-benzoquinone

phenyl toluene benzene

pivaloyl

parts per million

pyridinium p-toluenesulfonate quartet

room temperature singlet

(16)

T F A tr if lu o r o a c e tic a c id T F A A tr ilu o r o a c e tic a n h y d r id e T fO tr if lu o r o m e th a n e s u lf o n a te T B D P S /< ? r/-b u ty ld ip h e n y lsily l T H F te tr a h y d r o f u r a n T IP S tr iis o p r o p y ls ily l

tic th in la y e r c h r o m a to g ra p h y T M S tr im e th y ls ily l

(17)

Abstract... iii

Abbreviations... ix

Chapter 1

1.1. 1.1.1. 1.1.2. 1.1.3. 1.1.4. 1.1.5. 1.1.6. 1.2. 1.2.1. 1.2.2. 1.2.3. 1.2.4. 1.2.5. 1.2.6. 1.2.7. 1.2.8. Introduction... 1

Barton-McCombie Radical Deoxygenation... 1

Diversions From the Barton-McCombie Radical Deoxygenation...4

The Alkene 1,2-Carboxyarylation Reaction... 16

Related Sequences of 5-exo Cyclisation Followed By 1,4-Aryl M igration... 22

Investigating the Scope of the Alkene 1,2-Carboxyarylation Reaction...26

Aims... 33

Results and Discussion... 35

Synthesis o f the Aryl Chlorothionoformate...35

Synthesis o f Homoallylic Alcohols...35

Synthesis o f the Thionocarbonates...43

The Scope of the Carboxyary lation Reaction: The Basic System...48

Substitution at C6... 49

Substitution at C5... 55

Substitution at C4... 57

Substitution at C3... 59

(18)

1.2.10. Thionocarbonate Derivatives of Phenols, and 6-exo-trig Cyclisations.. .63

1.2.11. A Double Carboxyarylation Reaction...66

1.2.12. Thionocarbonate Derivatives of Homopropagyllic Alcohols... 67

1.2.13. Optimising the Reaction Conditions for the Carboxyarylation Reaction... 71

1.2.14. 'fl nmr Spectra of Crude Reaction M ixtures... 74

1.3 Conclusions and Future W ork...77

Chapter 2

2.1. Introduction... 81

2.1.1. Arctigenin and Matairesinol...81

2.1.2. Biosynthesis of Dibenzylbutyrolactone Lignans...83

2.1.3. Biological Activity o f (-)-Arctigenin, (-)-Matairesinol and Related Compounds...86

2.1.4. Previous Syntheses o f (-)-Arctigenin and (-)-Matairesinol... 86

2.1.5. Our Approach to the Total Synthesis o f (-)-Arctigenin and (-)-Matairesinol and their C7 Oxygenated Derivatives...91

2.2. Results and Discussion... 94

2.2.1. Preparation o f Chiral Oxazolidinone and Aldehyde Starting Materials... 94

2.2.2. Synthesis o f the Homoallylic Alcohols...95

2.2.3. Synthesis o f the Chlorothionoformate...96

2.2.4. Synthesis o f 7-(S)-Hydroxydibenzylbutyrolactone Lignans... 97

(19)

2.2.8. An Approach to Dibenzylcyclooctadiene Lignan Skeletons...104

2.2.9. Optimisation of the Key Radical Step...105

2.2.10. Conclusions and Future Work... 108

Chapter 3

3.1. Introduction...111

3.1.1. Transannular Radical Reactions... I l l 3.1.2. Strategy A-Intramolecular Cyclisations Followed by Transannular Addition/s... 114

3.1.3. Strategy B-Tandem Transannular Addition/Intramolecular Cyclisation... 120

3.1.4. Strategy C: Tandem Radical Macrocyclisation/Transannular Addition... 128

3.1.5. Strategy D : Purely Transannular Radical Cascades... 143

3.1.6. Proposed Transannular Cascade Radical Reactions... 148

3.1.7. Dibenzocyclooctadiene Lignan Lactones... 153

3.1.8. Proposed Synthesis o f the Cyclic Thionocarbonates...159

3.2. Results and Discussion...162

(20)

Reaction... 169

3.3. Conclusions and Future W ork...182

Chapter 4

4.1. Introduction... 185

4.1.1. (+)-Totarol... 185

4.1.2. Biosynthesis of Non-Conventional Diterpenoids...187

4.1.3. Biological Activity o f (+)-Totarol and Derivatives...189

4.1.4. Previous Syntheses of (+)-Totarol... 191

4.1.5. Our Approach to (+)-Totarol...197

4.2. Results and Discussion... 198

4.2.1. Synthesis o f the Alcohol Homoallylic Alcohol 4.53...198

4.2.2. Model Systems for the Key Radical Step Towards the Synthesis of Totarol... 200

4.2.3. Synthesis o f the Chlorothionofonnate... 205

4.2.4. The Key Radical Reaction... 208

4.2.5. To the McMurry precursor...210

4.2.6. The Model System...215

4.2.7. A New Approach... 217

4.2.8. The Nucleophilic Acyl Substitution Approach... 219

(21)

5.1. Introduction...225

5.1.1. Viridin...225

5.1.2. Structure and Biosynthesis of Viridin... 226

5.1.3. Biological Activity o f Viridin...227

5.1.4. Previous Synthetic Studies Towards Viridin...229

5.1.5. The Carboxyarylation Approach to Viridin...232

5.2. Results and Discussion... 234

5.2.1. The Methyl Ester Route... 234

5.2.2. The Triflate Route...237

5.2.3. A New Radical Precursor... 240

5.2.4. The Methyl Ether Route... 241

5.2.5. A Revised Approach... 244

5.2.6. A Model System For a Carbonylative Heck Coupling... 246

5.3. Conclusions and Future W ork... 248

Chapter 6-Experimental

6.1. General Methods... 251

6.1.1. General Procedure for the Formation of Thionocarbonates... 253

6.1.2 General Procedure for the Carboxyarylation Reaction...254

6.2. Experimental for Chapter 1...255

6.3. Experimental for Chapter 2 ...294

(22)

6.5. Experimental for Chapter 4 ...337

6.6. Experimental for Chapter 5 ...356

Appendix...377

(23)
(24)

1.1.

Introduction

1.1.1. Barton-McCombie Radical Deoxygenation

Barton-McCombie deoxygenation is a well-established procedure to remove secondary alcohol functional groups.1'"'' The two-step procedure involves the conversion of the alcohol to a thionocarbonyl derivative followed by exposure to a radical reducing agent such as tributyltin hydride.

The original report by Barton and McCombie described the use of xanthates and thionoester derivatives of secondary alcohols.1 Robins subsequently introduced

O-phenyl thionocarbonate derivatives as more easily prepared derivatives with improved deoxygenation profiles.6'7 The preparation of these derivatives is compatible with base sensitive and sterically hindered alcohols. Barton and Jaszberenyi later described optimised deoxygenation protocols, employing 4- chlorophenyl, 4-fluorophenyl, pentafluorophenyl and 2,4,6-trichlorophenyl thionocarbonate derivatives of alcohols.8

The generally accepted mechanism for the radical reaction involves the reversible addition of a trialkylstannyl radical to the thionocarbonyl group to generate a tertiary, heteroatom-stabilised carbon-centred radical 1.3 (Scheme 1.1). This carbon-centred radical 1.3 then undergoes irreversible ß-elimination to form an alkyl radical 1.5,

which abstracts a hydrogen atom from tributyltin hydride to give the product 1.6 and to regenerate the trialkylstannyl radical to complete the chain. The C=S 7t-bond o f the starting material 1.2 is replaced by the stronger C =0 7t-bond in the byproduct 1.4,

(25)

R'OH _ „

Jg

» rv 1

1.1 R - O ^ X1.2 r- 0 A x

1.3

s ^SnBu3

R'H «. _ _ R'- I

. J ^ \ , c C y ^ X

1.6 SnBu3 HSnBu3 * 1>4

X = SMe, Ph, OAr, Im

Scheme 1.1 Mechanism of the Barton-M cCom bie Radical Deoxygenation.

The deoxygenation is well known to work best with secondary alcohols.

Thionocarbonyl derivatives o f tertiary alcohols carrying ß-hydrogens are usually prone to Chugaev elimination (Scheme 1.2).9

Scheme 1.2

With primary alcohols the ß-elimination step o f the deoxygenation mechamism

(Scheme 1.1, 1.3 — *• 1.5) can be sluggish, with higher temperatures usually required

in order to promote this fragmentation. This problem has been largely overcome, however, by the application o f fluoro- and chloroaryl thionocarbonate derivatives o f

primary alcohols.8

(26)

radicals either under thermal or photochemical activation. To perform the reaction at ambient temperature in the absence of photochemical initiation, on derivatives of secondary or tertiary alcohols, triethylborane/oxygen can be used to initiate the reaction.11

The toxicity of organotin compounds led to the development of procedures using catalytic amounts of organotin reagents12 or avoiding the use of tin based reagents altogether. Various silanes have been introduced as radical reducing agents, most notably /m ’(trimethylsilyl)silane ((Me.^Si^SiH). (Me.iSibSiH has been shown to be a viable alternative to tin based reagents for the deoxygenation of xanthate, thionoester, aryl thionocarbonate and thiocarbonyl imidazolide derivatives o f alcohols when used with A1BN or Et.^B/Cb as an initiator. The silicon-hydrogen bond in /m ’(trimethylsilyl)silane (79 kcal mol"1) is stronger than the tin-hydrogen bond in tributyltin hydride (74 kcal mol'1).13 The poorer hydrogen-atom donating ability of (Me3Si)3SiH is also more amenable to multi-step radical sequences. There are a

number of other silane reagents, with even stronger silicon-hydrogen bonds (Me3Si(Me)2SiH (85 kcal mol"1), Et3SiH (90 kcal mol"1)),14 which have been

(27)

Diversions from this deoxygenation mechanism are known. Indeed, thionocarbonyl derivatives of alcohols are established sources o f alkyl radicals Rv The chemistry of the other radical intermediate 1.3 (Scheme 1.1) has been less thoroughly explored. Nevertheless, several examples of cyclisation reactions of Bu^SnS-O radicals derived from xanthates, thionocarbonyl imidazolides, and thioamides have been reported, following a thorough survey of the literature up until August 2004.

Cyclisation of the BujSnS-C* radicals derived from xanthates onto an alkene or alkyne gives rise to thionolactone products. Thus the reaction of xanthate 1.10

(Scheme 1.3) with tributyltin hydride and AIBN gave rise to the thionolactone 1.13

in 77% yield.15'16 Firstly, addition of a tributyltin radical to the thiocarbonyl group generates the triheterosubstituted radical 1.11. 5-Exo-trig cyclisation then occurs on to the alkene to form a secondary benzylic radical 1.12 which abstracts a hydrogen from tributyltin hydride to form the product 1.13.

Ph

1.10

a

SSnBu3 Ph

1.11

5-exo

1.13

Scheme 1.3 Reagents and Conditions: a. BihSnH, AIBN, PhH, reflux, 77%.

(28)

(Scheme 1.4).11-17 All examples to date using xanthate derivatives have been carried out on homoallylic or homopropagylic alcohols; i.e. a 5-exo cyclisation occurs.

1.14 1.15

Scheme 1.4 Reagents and Conditions: a. Bu3SnH, Et3B, PhMe, -78 °C, 53%.

Thionolactones are easily converted into the corresponding lactones via treatment with aqueous acid11-17 or by oxidation with m-CPBA.18,19

The transformation of a xanthate into a thionolactone has been used as a key step in the synthesis of the natural product enterolactone dimethyl ether 1.18.19 The xanthate

1.16 (Scheme 1.5), prepared in ten steps from w-methoxyphenylacetic acid, was treated with tributyltin hydride and A1BN in toluene at reflux. The radical cyclisation product, thionolactone 1.17, was obtained in 75% yield with a 9:1 selectivity for the tram C8-C8’ isomer. Thionolactone 1.17 was oxidised with w-CPBA to provide the natural product 1.18.

Scheme 1.5 Reagents and Conditions: a. BujSnH, A1BN, PhMe, 80 °C, 75%; b. mCPBA, ChbCh, 66%.

The xanthate 1.19, on treatment with tributyltin hydride and A1BN, formed the bicycle 1.24as a single stereoisomer (Scheme 1.6).20 The triheterosubstituted radical

(29)

ring. This creates the cis-fused bicyclic system 1.23. The second cyclisation proceeds through the chair conformation 1.22 to produce the product 1.24 with >99:1 diastereoselectivity.

Scheme 1.6 Reagents and Conditions: a. Bu?SnH, AIBN, PhMe, 80 °C, 71%.

The different xanthate derivatives of homoallylic and homopropargylic alcohols that have been converted into thionolactones via a single cyclisation are summarised in Table 1.1. These results have been taken from the work of three separate groups and the reaction conditions for the transformations differ for examples from different studies. Nevertheless, some information on effects of the different substituents on the homoallylic alcohol can be taken from these studies.

(30)

The xanthate 1.29 with an Zs-alkene gave a higher yield under the same conditions than the xanthate 1.31 containing a Z-alkene.

(31)

51%a

77%a

<2%a

72%b

50%b, 62%c

80%b, 96:4 antLsyn

77%b, 96:4 m /c w n

(32)

Thionolactone Yield Xanthate

(33)

When the thiocarbonyl imidazolide 1.53 (Scheme 1.7) was treated with tributyltin hydride and AIBN in benzene at reflux, the cyclisation onto the styrene double bond provided the thionolactone 1.13 in good yield.15 ,6

Hi

1.13

Scheme 1.7 Reagents and Conditions: a. BinSnH, AIBN, PhH, reflux, 70%.

Similarly, during an attempted radical deoxygenation at 80 °C, the thiocarbonyl imidazolide 1.56,“1 gave the diastereomeric products 1.57a and 1.57b from a 5-exo cyclisation (Scheme 1.8). Higher temperatures gave predominantly a diene 1.58 from Chugaev elimination.

1.53 1.54 1.55

OTDPS

S

1.57b

1.58

(34)

Thionolactones are not the only products which can be formed by the cyclisation o f

the Bu^SnS-O radicals derived from thiocarbonyl imidazolides. A change o f the

reaction conditions can allow the formation o f imidazole substituted

tetrahydrofurans.22,2' The thiocarbonyl imidazolide 1.59, when treated with

tributyltin hydride and A1BN formed the thionolactone 1.62 as the only isolable

product in 58% yield (Scheme 1.9). When the thiocarbonyl imidazolide 1.59 was

added to a solution containing five equivalents o f triphenyltin hydride and A1BN,

however, the imidazole-substituted tetrahydrofuran 1.63 was the sole product

obtained in 88% yield. In both the product is formed from intermediate radical 1.61.

.O T B D M S .O T B D M S u ^ O T B D M S a or b r * o

— ^

jcS

.N S f r N ^ S S n R 3 • r r S S n R 3M

o

E t0 2C U / / E t 0 2C

\^ N

1.59 L 1.60 1.61 J

Scheme 1.9 Reagents and Conditions: a. Bu3SnH (2 equiv), PhMe, reflux, 58% 1.62, 0% 1.63; b.

Ph3SnH (5 equiv), PhH, reflux, 0% 1.62, 88% 1.63.

Using triphenyltin hydride, 6-exo cyclisation also proceeds in high yield on the

thiocarbonyl triazole 1.64 (Scheme 1.10).

O T B D M S

(35)

indoles and fused quinolines. This was first seen in the synthesis o f (-)-a-kainic acid

1.73.24 Upon treatment o f the thioformimide 1.66 with tributyltin hydride and A IB N , the pyrrolidine 1.71 was produced (Scheme 1.11). Addition o f the tributyltin radical to the thiocarbonyl group forms a secondary radical 1.67. 5-Exo cyclisation proceeds with a high level o f stereoselectivity, followed by elimination o f an ethylthiyl radical, and a tetrasubstituted pyrrolidine 1.68 is produced. Homolytic substitution at sulfur forms a pyrrolidinyl radical 1.70, which abstracts a hydrogen atom from tributyltin hydride. The TV-BOC protecting group on the amine was used in the reaction to

minimise the stabilising effect o f the nitrogen atom on the adjacent radical in 1.67. A further 7 steps completed the synthesis o f the amino acid.

kOTMS 1.66 UTM S

J l

Bu3SnS N BOC 1.68 OTMS 'CC^f-Bu

EtS H jS n B u 3 * ■<

1.67

— / OTMS

^ N^ C 0 2t-Bu

BOC

1.71

— 4 OTMS

B u 3i y C ° 2 ' - BU

BOC

— / OTMS Bu3Sn 'j— f

Bu3SnS ' C02f- Bu■ - E,SH

1.70

BOC

1.69

i OH

^ n^ >,C02(-Bu

7 steps — < o- c o2h

BOC

C 0 2H

1.72 1.73

(36)

Stereocontrol led total syntheses of (+)-vinblastine2^ and (±)-caranthine2f’ relied upon analogous radical cyclisations of a thioanilide to form the indole ring system. Vinblastine 1.80was synthesised in a convergent approach, from two fragments 1.76

and 1.79, which were both synthesised by thioanilide radical cyclisations (Scheme 1.12). Thioanilide 1.74was used for the radical cyclisation to form the indole portion in the upper half of vinblastine. Treatment of 1.74 with tributyltin hydride and triethylborane at room temperature formed the indole 1.75, which was elaborated to

(37)

COoBn

OTHP THPO.

OTES OTMS

0 O 2Me OTBDPS

1.75

MeH C 0 2Me

1.80

(38)

The radical transformation of thiocarbamates, thioamides and thioureas to quinolines was found to occur optimally with /m(trimethylsilyl)silane (Scheme 1.13).27 5-Exo­ dig cyclisation of the (Me3Si)3SiS- 0 radicals 1.82 onto the alkyne forms a vinyl

radical 1.83. This undergoes 6-exo cyclisation onto the aryl group. Following oxidation of the delocalised radical 1.84 the quinoline systems 1.85 are formed.

R = Alkyl, Phenyl

(39)

An intriguing conversion of the phenyl thionocarbonate derivative of 4-phenyl-3- butenol 1.86 into thionolactone 1.13, thiollactone 1.87 and lactone 1.88 was reported by Bachi in 1989 (Scheme 1.14).15,16 The expected product was the thionolactone 1.13, which would be formed through 5-exo-trig radical cyclisation onto the styrene moiety as seen in Scheme 1.3.

Scheme 1.14 Reagents and Conditions: a. BiuSnH, AIBN, PhH, reflux.

The latter product is the result of a 5-exo-trig radical cyclisation to the styrene moiety followed by a radical O—>C 1,4-aryl migration. The mechanism for this transformation is depicted in Scheme 1.15. The 5-exo cyclisation of the triheterosubstituted radical is common to the mechanism in Scheme 1.3. Instead of abstracting a hydrogen atom, alkyl radical 1.90 can add intramolecularly to the ipso

(40)

1.89 1.90

ipso addition

1.88 1-92 1.91

(41)

published in 1990 and involved phenyl thionocarbonates 1.94a and 1.94b (Scheme 1.16),2s which were each derived in two steps from naturally occurring (+)-retronecine 1.93. The cascade reaction to the lactones 1.95a and 1.95b proceeded in moderate yield to each give a single diastereomer with a cis arrangement about the lactone and incorporation of the phenyl syn to this lactone. These pyrrolizadine systems are known to have an angle o f 1 15-130 0 between the two 5 membered rings, which forces the substituent on the ß-C7-hydroxyl group to lie directly over the double bond. In the system with the a-C7-hydroxyl, this hydroxyl group points away from the double bond. Thus, for the formation of the required deoxygenated product, thionocarbonates 1.97a and 1.97b with the opposite stereochemistry at the secondary alcohol could be derived in two steps from naturally occurring (+)-heliotridine 1.96,

the C7 epimer of (+)-retronecine 1.93.

PhO HO OH a 1.93 RO

1.94a R=SiMe2t-Bu 1.94b R=COPh

1.95a R=SiMe2/-Bu 48%

1.95b R=COPh 60%

RO

1.98a R=SiMe2/-Bu 66%

1.98b R=COPh 64%

1.96 1.97a R=SiMe2f-Bu

1.97b R=COPh

(42)

As well as the O—>C transfer of an unsubstituted phenyl group, migration of 4- fluoro- and pentafluoro- phenyl groups occurred in similar yields in the attempted radical deoxygenations on Gibberellin derivatives.29 C3-ß alcohol derivatives 1.99a, 1.99b, 1.99c, were treated with tributyltin hydride and A1BN and were converted in very high yield to the bis lactones 1.100a, 1.100b, 1.100c (Scheme 1.17). Once again the m -fused lactone and syn arrangement of the lactone and the aryl group should be noted. This system also possesses a rigid structure and with the C3-ß stereochemistry of the thionocarbonate, the carboxyarylation reaction was favoured. By using a thionocarbonate derivative of the C3-a hydroxy diastereomer, the cyclisation onto the alkene was unable take place and deoxygenation was achieved.

1.99a Ai=C6H5 1.99bAi=4-F-C6H. 1.99c Ai=C 6F5

MeO20 h

1.100a Ar=C6H5 80%

1.100bAr=4-F-C6H4 89% 1.100c Af=C6F5 80%

(43)

thionocarbonate 1.101a (Scheme 1.18), the lactone product 1.102a with the aryl group incorporated was the major product with only trace amounts of the product of deoxygenation obtained. With the p-tolyl thionocarbonate 1.101b, a higher yield of the lactone was obtained along with a reasonable quantity of the deoxygenation product. Interestingly, after deprotection of the silyl ethers of the lactone products

1.102a and 1.102b, antibacterial activity was observed against several Gram-positive organisms.

1.101a Ar = C6H5

1.101b Ar = Q H4CH3

'OTBDMS TBSO

1.102a Ar = C6H5 49%

1.102b Ar = C6H4CH3 63% + 36%

deoxygenated product

(44)

Our group has recently utilized this transformation as the key step in the asymmetric syntheses of (+)-podophyllotoxin and (-)-podophyllotoxin (Scheme 1.19).30 The thionocarbonate 1.103 was prepared in a 4 step synthesis which began with an Evans asymmetric aldol reaction to create the two stereocentres. The radical mediated transformation of the thionocarbonate 1.103 produced the skeleton of podophyllotoxin 1.104. A further six steps completed the synthesis of (+)- podophyllotoxin 1.105a. Alternatively, the thionocarbonate 1.106, accessed in enantiopure form via Meyers naphthalene dearomatisation chemistry, underwent the carboxyarylation reaction to the tetrahydronaphthalene lactone 1.107. 1.107 was converted into (-)-podophyllotoxin 1.105b in six steps.

6 steps

(+)-podophyllotoxin

1.105a

6 steps

(-)-podophyllotoxin

1.105b

Scheme 1.19 Reagents and Conditions: a. (Me3Si)3SiH, A1BN, PhH, reflux, 38%; b. (Me3Si)3SiH,

(45)

Related sequences to the alkene carboxyarylation reaction involving a 5-exo-trig cyclisation followed by a 1,4-aryl migration have been observed in studies carried out by Clive, '2 Aube,33"'4 Black, 0 and Tokuda'6 and these papers are the topic of this section.

The a-bromophenyl sulfone 1.108, when treated with triphenyltin hydride and A1BN formed bicyclic sulfone 1.111 as the major product and also the phenyl-substituted bicycle 1.114 (Scheme 1.20).'" A triphenyltin radical abstracts the bromine in 1.108

to form secondary radical 1.109. 5-Exo-trig cyclisation of radical 1.109 forms the bicyclic system and the secondary radical 1.110 can abstract a hydrogen from triphenyltin hydride to form sulfone 1.111. This secondary radical 1.110 can also add to the ipso position of the aryl group, and upon rearomatisation with the loss of SO2,

provided phenyl substituted system 1.114.

(46)

A sequence o f 5-exo-trig cyclisation and 1,4 aryl migration from carbon to carbon occurred on treatment of the oxaziridine 1.115 with [Cu(PPh3)Cl]4 and generated the

product 1.119 in 66% yield (Scheme 1.21).34 Firstly, single electron transfer to the oxaziridine forms the radical/alkoxide 1.116. Cyclisation of the nitrogen-centred radical occurs diastereoselectively to produce intermediate 1. 117, the conformation o f which allows for the ipso addition to the phenyl ring. The aryl migration takes place and with what is the formal loss of acetaldehyde and Cu(I), the product 1.119

was generated. Interestingly, none of the stereocentres of the starting material are present in the product, yet the product contains a new stereocentre which was generated before the loss of the original stereocentres such that the product was formed in >95% ee. This pathway was followed when there was an aryl group at C- 3, but other products were observed with different substituents at this position.33

1.118

Scheme 1.21 Reagents and Conditions: a. [Cu(PPh3)Cl]4, THF, 66%.

A similar result was seen following the ring opening of the oxaziridines in 6-oxa-l- azabicyclo[3.1.0]hexanes such as 1.120 (Scheme 1.22). ° Treatment of diastereomer 1.120, containing a cis arrangement of the alkenyl side chain to the phenyl group,

with [Cu(PPh3)Cl]4 cleanly gave the bicyclic lactam 1.123 in 82% yield. Treatment of the isomer 1.124, with the phenyl group and alkenyl chain in opposite sides gave exclusively 1.125. The formation of the lactam 1.123 occurs by way o f nitrogen centred radical 1.121, which undergoes 5-exo-trig cyclisation onto the alkene to

(47)

with the equilibrium lying in favour of the aminyl radical 1.121. Subsequent irreversible aryl migration when the phenyl group is proximal provides a product of the aminyl radical cyclisation.

p h 0

)<0N

Et02C

1.120

1,4 aryl migration

1.124 1.125

Scheme 1.22 Reagents and Conditions: a. [Cu(PPh3)Cl]4, THF, 82%; b. [Cu(PPh3)Cl]4, THF, no

yield prov ided.

This sequence was also observed with a 6-exo-trig cyclisation followed by aryl migration, albeit in decreased yield (Scheme 1.23). The oxaziridine 1.126 on treatment with [Cu(PPti3)Cl]4 formed a ca 1:1 mixture of the cyclised product 1.127

and the uncyclised product 1.128.

1.126 1.127 1.128

40% 41%

(48)

yV-chloroamines also serve as precursors for these cascade radical sequences.'6 The chloroamine 1.129 was treated with tributyltin hydride and A1BN, forming the product 1.134 in 60% yield (Scheme 1.24). Abstraction of chlorine from the chloroamine 1.129 by a tributyltin radical produces the A-benzylalk-4-enylaminyl radical 1.130. Cyclisation onto the alkene forms secondary radical 1.131 which

undergoes ipso addition to the aryl group. A number of electron rich and electron poor aryl groups were shown to undergo the reaction, with overall yields for the transformation ranging from 35% (/?-OMe)-67% (/?-CN).

C7H7 n 15

- Q

\

1.134 1.133 1.132

(49)

The thionocarbonate precursors to the carboxyarylation reaction are made by the coupling of an alcohol with a chlorothionoformate (Scheme 1.25). For investigating the scope of the reaction this provides an obvious disconnection into an aryl portion and a homoallylic alcohol. The aryl group in the carboxyarylation reaction has been studied previously within the group and will be discussed in this section.

Scheme 1.25

The conditions which give the highest yield of the carboxyarylated product need to be explored. The stereochemical outcome of the carboxyarylation reaction where stereochemistry is formed must also be determined. Previous studies into conditions and stereochemical outcome of the carboxyarylation reaction will also be described in this section.

/ . 1.5.1. Effect o f the Aryl Group on the Alkene 1,2-Carhoxyarylation Reaction

A number of aryl groups have been investigated in the carboxyarylation reaction on a simplified system to that used in the synthesis of podophyllotoxin

(1.140—►1.141).37'39 Table 1.2 shows the yields of the carboxyarylation reaction of the thionocarbonate with different aryl groups.

(50)

monomethoxyaryl groups. Of the methoxy substituted aryl groups, the sterically demanding 2,6-dimethoxyphenyl group gave the lowest yield. The 3,4,5-trimethoxy aryl group, as used in the synthesis of podophyllotoxin, provided the highest yield of all the aryl groups investigated.

(51)

a or b

E n t r y N u m b e r A r y l g r o u p Y i e l d

1 p h e n y l 3 8 a

2 2 - m e t h o x y p h e n y l 4 7 a 3 3 - m e t h o x y p h e n y l 4 5 a 4 4 - m e t h o x y p h e n y l 5 7 a 5 3 , 4 - d i m e t h o x y p h e n y l 4 9 a 6 2 , 6 - d i m e t h o x y p h e n y l 3 9 b 7 3 , 4 , 5 - t r i m e t h o x y p h e n y l 6 5 a 8 3 , 4 - m e t h y l e n e d i o x y p h e n y l 4 8 a 9 4 - f l u o r o p h e n y l 3 5 a 1 0 p e n t a f l u o r o p h e n y l 5 5 a

11 1- n a p h t h y l 4 3 b

12 2 - n a p h t h y l 5 3 b

13 2 - n i t r o p h e n y l 0 a 14 3 - n i t r o p h e n y l 0 a 15 4 - n i t r o p h e n y l 0 a

16 N - B o c 4 - a m i n o p h e n y l 6 4 b

17 4 - c y a n o 4 8 a

(52)

A study by Lee and coworkers40 investigated the substitution effects during aryl group translocation of the aryl group from oxygen to carbon via ipso substitution. 3- Aryloxypropyl bromides 1.142 were treated with tributyltin hydride and 0.2 equivalents of A1BN and the relative amounts of reduced product 1.144 and 1,4-aryl migration product 1.146 were measured (Scheme 1.26).

ArO

no rearrangement 1.144

ArO'

1.142

a

1.145 1.146

Scheme 1.26 Reagents and Conditions: a. Bu3SnH, A1BN, PhH.

An unsubstituted phenyl system gave only 2% of the rearranged product 1. 146.

(53)

"captodatively stabilised"

OMe OMe

Scheme 1.27 Reagents and Conditions: a. BmSnH, AI BN, PhH, reflux, 90%.

1.1.5.2. Stereochemical Outcome o f the Reaction on Cyclic Alkene Systems

(54)

hydrogen from /m(trimethylsilyl)silane then a monothioorthoester 1.158 or 1.159

will be formed, which after hydrolysis may result in the formation of a thionolactone

1.40.

1.152 1.153 1.154 all syn product

aryl group transfer not possible

Schem e 1.28

1.1.5.3. Conditions For the Carhoxyarylation Reaction

A brief study into the optimal conditions for the carhoxyarylation reaction has been undertaken in work towards the total synthesis of podophyllotoxin.41 7m(trimethylsilyl)silane was found to give higher yields of the carboxyarylated product than tributyltin hydride. 1.1 Molar equivalents o f (Me3Si)3SiH and 0.4 molar equivalents of AIBN were required for complete consumption of the starting material.

(55)
(56)

1.1.6. Aims

In this chapter of work a thorough investigation into substitution on the homoallylic alcohol portion of the thionocarbonate precursor will be undertaken. In order to make comparisons between precursors carrying different substituents on the homoallylic alcohol portion, the aryl group needs to be kept constant. The /?-methoxyaryl group was chosen as the phenol is readily available, the chlorothionoformate can be purified by distillation, it has been shown to be one of the higher yielding aryl groups and the 'H nmr spectra show symmetry. Substitution can be envisaged at carbons designated 3-6 in the thionocarbonate 1.161 (Scheme 1.29), which would incorporate substitution at the corresponding position in the benzyl lactones 1.162. Both cyclic and acyclic alkene systems will be investigated.

1.161 1-162

Scheme 1.29

Other possibilities include the use of alkynes in the reaction. Reactions of xanthates to form thionolactones were possible with both alkenes (Scheme 1.3) and alkynes (Scheme 1.4). Through the carboxyarylation reaction, a thionocarbonate of a homopropagylic alcohol 1.164 would provide lactones of the structure 1.165

(Scheme 1.30).

1.164 1-165

(57)

membered lactones 1.167 (Scheme 1.31). 6-Exo-trig cyclisation of Bu^SnS-O radicals from a thiocarbamate was seen in the example in Scheme 1.10. In Scheme 1.23 a 6-exo cyclisation followed by 1,4-aryl migration was witnessed, although not on a thiocarbonyl precursor.

1.166 1167

Scheme 1.31

(58)

1.2.

Results and Discussion

1.2.1. Synthesis of Aryl Chlorothionoformate 1.169

/7-Methoxychlorothionoformate 1.169 was synthesized from /?-methoxyphenol 1.168 8

by treatment with sodium hydroxide and thiophosgene (Scheme 1.32).

Scheme 1.32 Reagents and Conditions: a. NaOH(aq), CSCb, CH2CI2, 70%.

1.2.2. Synthesis of Homoallylic Alcohols

Alcohols but-3-enol 1.170, 4-methylpent-3-enol 1.171, 3-methylbut-3-enol 1.172, 2- methylbut-3-enol 1.173, pent-4-en-2-ol 1.174, pent-4-enol 1.175, 2-allylphenol

1.176 and but-3-ynol 1.177 were commercially available. The remaining alcohols used for the study were synthesised as follows.

The E and Z isomers of pent-3-enol were both prepared from commercially available pent-3-ynol 1.178 (Scheme 1.33). A dissolving metal reduction of 1.178 with sodium in liquid ammonia provided exclusively the E isomer 1.179.46 Hydrogenation of

1.178 with Lindlar’s catalyst in methanol gave the Z isomer 1.180 46

1.178 1.180

(59)

(2£’,4£’)-hexa-2,4-dienoic acid via acid chloride 1.1824s to ethyl ester 1.183 (Scheme 1.34) 49 Reduction o f the ester using lithium aluminium hydride furnished the diene

1.184 50

Scheme 1.34 Reagents and Conditions: a. SOCl2, PhMe, reflux, 71%; b. Et3N, EtOH, -7 8 °C—1-rt,

81%; c. LiAlH4, Et20 , reflux, 20 h, 86%.

Styrene 1.187 was synthesised in two steps from but-3-ynol 1.177 (Scheme 1.35). A radical mediated hydrostannylation of the alkyne provided predominantly the E isomer 1.185, which was contaminated with small quantities of the Z isomer and the 3-stannylated regioisomer.51 Attempted Stille coupling of the stannane 1.185 with p-bromoanisole 1.186 using either /u.v(acetonitrile)dichloropalladium in DMF at 60 °C, or triphenylarsine with /m(dibenzylideneacetone)palladium in tetrahydrofuran did not give any of the coupled product. The required styrene 1.187 was obtained, albeit in low yield using the conditions of Corey. 2

OMe

1.186

Scheme 1.35 Reagents and Conditions: a. Bu3SnH, AIBN, 80 °C, 63%; b. LiCl, CuCl, DMSO,

Pd(PPh3)4, 60 °C, 30%.

(60)

The diarylsubstituted homoallylic alcohol 1.194 was synthesised in 5 steps from 1,3- propanediol 1.188 (Scheme 1.36). Selective protection of the diol as the mono-TBS ether* and oxidation of the remaining alcohol gave the aldehyde 1.190.53 Modified Corey-Fuchs conditions54 converted the aldehyde to the dibromide 1.191. Double Suzuki coupling^ with the aryl boronic acid 1.192, derived in a single step from 4- bromoanisole 1.186, gave a high yield of the bis-coupled product 1.193.

Deprotection using TBAF gave the required homoallylic alcohol 1.194.

1.189

r ^ O T B S b

OH

1.190

^ O T B S

CHO 1.191 Br OMe 1.187 1.192 OTBS 1.194

HO, xOH

B

OMe 1.193

Scheme 1.36 Reagents and Conditions: a. NaH, TBDMSC1, THF, 94% ; b. oxalyl chloride, DMSO,

CH2C12, 84%; c. (Ph3PCH2Br2)Br, t-BuOK, THF, 55%; d. «-BuLi, THF, B(OMe)3, then HC1, 43%; e.

Pd(PPh3)4, Ba(0H )2.8H20 , THF, MeOH, H20 , 95%; f. TBAF, THF, 87%.

(61)

deprotection of the TBS ether with TBAF furnished the alcohol 1.195 (Scheme 1.37).

Scheme 1.37 Reagents and Conditions: a. (CfiH.djP^HCChCHU, CtTCh; b. TBAF, THF, 65% (2

steps).

3-Hydroxybutyltriphenylphosphonium bromide 1.198 was prepared by reaction of the ylide derived from methyltriphenylphosphonium bromide 1.196 with propylene oxide (Scheme 1.38).S6 Treatment o f 1.198 with two molar equivalents of n-butyllithium and Wittig reaction with /7-methoxybenzaldehyde 1.199 formed the styrene 1.200/

CHO

a,b

1.190 CO2M6

1.195

CH3PPh3Br

1.196

OH

OMe 1.199

OMe

1.200

(62)

Alcohol 1.204 was synthesised in four steps from cyclohexanone (Scheme 1.39). Condensation of cyclohexanone 1.201 with cyanoacetic acid under Dean-Stark conditions provided the nitrile 1.202.58 Hydrolysis with potassium hydroxide gave an acid which was esterified with diazomethane.59 A D1BALH reduction of the ester gave the desired homoallylic alcohol 1.204.

1.201 1.202 1.203 1-204

Scheme 1.39 Reagents and Conditions: a. HOOCCH2CN, CH3CO2NH4, PhH, reflux, Dean Stark

conditions, 18%; b. 10% KOH; c. CH2N2, Et20 , 41% (over 2 steps); d. D1BALH, THF, 0 °C, 75%.

A three step synthesis supplied the homoallylic alcohol 1.208 (Scheme 1.40). Alkylation50 of ethyl-2-cyclohexanone carboxylate 1.205 gave the ketone 1.206

which underwent Wittig reaction51 to install the methylene unit. A reduction of the ester provided the alcohol 1.208.

Scheme 1.40 Reagents and Conditions: a. Na, EtOH, Mel, 77%; b. CH^PPh^Br, n-BuLi, THF, 62%;

LiAlH4, THF, 82%.

The 1,1 -disubstituted cyclohexane 1.214 was synthesised in four steps (Scheme 1.41). Dialkylation of diethylmalonate 1.210 with 1,5-dibromopentane 1.209

(63)

1.209 1 210

CHO

1.212

c

Scheme 1.41 Reagents and Conditions: a. Na, EtOH, 31%; b. DIBALH, - 78 °C, CH2C12, 75%; c.

CH3PPh,Br, «-BuLi, THF, 53%; DIBALH, THF, 0 °C, 55%.

Alcohols 1.216 4 and 1.21 765 were each synthesised on multigram scale by treatment of cyclohexene firstly with Schlossers base, then addition of either paraformaldehyde or ethylene oxide (Scheme 1.42).

1.215 1.216

1.215 1.217

Scheme 1.42 Reagents and Conditions: a. /-BuOK, n-BuLi, (CHO)n, 74%; b. /-BuOK, o-BuLi,

pentane, ethylene oxide, 80%.

The alcohol 1.221 was synthesised in four steps from m-toluic acid. A Birch reduction66 of 1.218 gave a quantitative yield of the cyclohexadiene 1.219. Esterification under Fischer conditions and selective hydrogenation of the disubstitued alkene with Wilkinson’s catalyst formed the known ester67 1.220

(64)

alcohol 1.221, the of which has previously been reported in the literature via a

longeer sequence.67

1-218 1.219 1.220

Scheme 1.43 Reagents and Conditions: a. Li, NH3, H20 , quant.; b. EtOH, />TSA, CHC13; c. H2, (PPh3)3RhCl, THF, 63% over 2 steps; d. D1BALH, THF, 69%.

The cyclohexadiene 1.224 was prepared in two steps (Scheme 1.44). Birch reduction o f methyl benzoate was followed by alkylation with methyl iodide to give the ester

1.223.66,68 Reduction of the ester to the alcohol 1.224 was achieved with DIBALH.

1.222 1-223 1.224

Scheme 1.44 Reagents and Conditions: a. Li, NH3, /-BuOH, Mel, 70%; b. DIBALH, THF, 0 °C, 57%.

The alcohol 1.227 was prepared in three steps (Scheme 1.45). Birch reduction of 1-napthoic acid69 and esterification under Fischer esterification conditions provided the ester 1.226. A DIBALH reduction of the ester gave the required alcohol 1.227.

1.225

(65)

1228 1.229

Scheme 1.46 Reagents and Conditions: a. CH^PPh-sBr, «-BuLi, THF, 100%.

2,3-Dihydrofuran 1.230 was converted in a single step to the racemic diol 1.231 with titanium isopropoxide and cyclohexylmagnesium bromide (Scheme 1.48).71

r°x

a HO—^ .— OH

U /

= = / \ = =

1.230 1.231

(66)

1.2.3. Synthesis of the Thionocarbonates

The thionocarbonates were synthesised in a single from p-methoxychlorothionoformate 1.169 and the corresponding alcohol in the presence of pyridine (Scheme 1.48).* The yields of the 25 pure isolated thionocarbonates are depicted in Table 1.3.

1.169

(67)

1.179 1.232

1.184

1.234

1.235

1.187

(68)

COoMe

1.195

Ar

1.239

1.204

1.208

1.173 1.242

1.214

1.243

1.174

(69)

Yield (%) o f Thionocarbonate Thionocarbonate

Alcohol

1.200

1.246

1.247

1.224

1.248

1.227

(70)

1.175 1.166

1.176 1.252

(71)

Conditions for the radical reaction were based upon a previous study41 and involved the use of /m(trimethylsilyl)silane (1.1 equiv) as the radical carrier, and AIBN (0.4 equiv) as the initiator. The reactions were carried out at a substrate concentration of 0.02 M in benzene with the AIBN added as a solution in benzene over six hours. After a further 30 minutes the solvent was removed, a 'H nmr spectrum was run of the crude mixture and the products were purified by flash chromatography on silica.

Initially we examined thionocarbonate 1.161 of the simplest homoallylic alcohol, 3- buten-l-ol. The carboxyarylation reaction to form the benzyl lactone 1.162

proceeded in modest yield (Scheme 1.49). The crude 'H nmr spectrum of the reaction mixture did not show any other products. The various substitution patterns on carbons designated 3 through 6 on the basic system were then investigated.

1.161 1.162

(72)

1.2.5. Substitution at C6

Initial investigations focused on the effect of substitution at the C6 position. A methyl group at this position allows a comparison of yields and stereoselectivity of the reaction of the two geometrical isomers of the alkene. Under the standard conditions thionocarbonates 1.232 and 1.233 were reacted to each produce the carboxyarylation product as a mixture of diastereomers 1.254a and 1.254b (Scheme 1.50). The isolated yields of the mixtures of diastereomers of the benzyllactone products from the radical carboxyarylation reaction were comparable. Furthermore, the same major diastereomer and a similar diastereomeric ratio was obtained from both starting materials, as measured by GC analysis of the crude reaction mixture. The stereochemistry of the major diastereomer was determined by X-ray crystallography.

35%

a

1.232 1.254a 1.254b

72 : 28

Ar

37%

a

1.233 1.254a 78 : 22 1.254b

X-ray Crystal Structure of 1.254a

(73)
(74)

1.256 b 1.256 a

MeO 1.254a

1.254b

(75)

minor diastereomers obtained in this example, 1.260a and 1.260b, and the 'H nmr spectra of the corresponding major and minor diastereomers of 1.254a and 1.254b

were very similar, and this observation was used to assign the stereochemistry of

1.260a and 1.260b.

A better yield was obtained with the trisubstituted alkene 1.235. The product of the initial 5-exo cyclisation is in this case a tertiary radical.

29%

a

1.234 1.260a 8 | . , 9 1.260b

Ar

S 50%

a

Ar O

.0

1.235 1.261

(76)

Styrenes are known to be good radical acceptors as addition to the alkene forms a benzylic radical. It was not clear whether a stabilised benzylic radical would be reactive enough to participate in aryl transfer in the carboxyarylation reaction. Styrene 1.236 gave a yield of 69% of the product 1.262 (Scheme 1.52). The yield declined to 50% for the diaryl precursor 1.237, which remarkably formed the highly conjested centre with three /?-methoxyaryl groups in the product 1.263.

1.236

a 50%

1.263

(77)

explained in terms of Frontier Molecular Orbital Theory.72'7’ a,ß-Unsaturated ester system 1.238 (Scheme 1.53), on treatment with (Me.^SiX^SiH and AIBN, an overall yield of 82% was observed for the formation of two products. Both products arise from 5-exo-trig cyclisation having taken place to form intermediate 1.265. 1.265 can either abstract a hydrogen to give rise to thionolactone 1.266 or undergo 1,4-aryl transfer to give the carboxyarylated product 1.267. This result clearly shows that the electrophilic radical intermediate 1.265 undergoes 1,4-aryl transfer readily indeed. The aryl lactone 1.267 was obtained as a single diastereomer and the stereochemistry was assigned by comparison of 'H nmr spectra of 1.267 with the 'H nmr spectra

1.254a and 1.254b.*

n .

5-exo

Ue02C ^ X y/°

0 SSiR3 O 'i SSiR

M e02C Ar Ar

1.264 1.265

Scheme 1.53 Reagents and Conditions: a. (Me3Si)3SiH, AIBN (syringe pump addition over 6 hours) PhH, reflux.

(78)

1.2.6. Substitution at C5

Substitution at C5 gives rise to products with a quartemary centre that is formed on 5 -exo-trig cyclisation onto the alkene. It was pleasing to find that the formation of this centre was tolerated in the acyclic system 1.239 which formed the benzyllactone

1.268 in 35% yield (Scheme 1.54). This is in contrast to the xanthate 1.27 in Table 1.1 which gave thionolactone 1.28 in less than 2% yield. When the reaction is carried out on more substituted alkenes such as the cyclic alkene precursors 1.240

and 1.241, lower yields of the products were observed. Exocyclic alkene system

1.241 undergoes competitive 6-endo-trig cyclisation. Following this, the radical

1.273 (Scheme 1.55) does not add to the aryl group, presumably because of geometrical constraints in the formation of 1.274. Radical 1.273 abstracts a hydrogen atom, to form monothioorthoester 1.275. Hydrolysis of 1.275 giving the bicyclic lactone 1.271 occurs during chromatography, or can be cleanly achieved using PPTS in methanol and water.

35% a Ar 1.239 1.268 18% a 1.240 1.269 26% a Ar 1.270 1.271 1.241

70 : 30

(79)

>

-o

(80)

1.2.7. Substitution at C4

Under standard conditions, thionocarbonates 1.242 and 1.243 with substituents at C4 were reacted (Scheme 1.56). With a methyl group at C4 a moderate yield of 31% of a mixture of two diastereomers was obtained. In order to determine the relative stereochemistry of each of the diastereomers, 2D nmr spectroscopy was used. The 2D COSY spectra of each diastereomer was used to assign each proton in the 'H nmr spectra. Different nOe interactions were observed for the two diastereomers in their 2D nOesy spectrum as indicated in Scheme 1.56.

With a cyclohexylidene group at C4 a much higher yield of 57% of the spiro system

1.277 was obtained. This is best explained by the reactive rotomer effect, whereby placing substituents between reacting centres increases the population of the conformation leading to the cyclic product.74

Scheme 1.56 Reagents and Conditions: a. (MejSiFSiH, AIBN (syringe pump addition over 6 hours), PhH, reflux.

(81)

conformation 1.278a.

» /\/w

1.279a

Ar

major: trans 1.276a

ch3 4 H

- O

|h 2 H

A/vn/ n

less stable

1.278b 1.279b

H

Ar

minor: els 1.276b

(82)

1.2.8. Substitution at C3

Our study so far has only investigated thionocarbonate derivatives of primary alcohols, which are known not to deoxygenate readily at 80 °C. Thionocarbonates of secondary alcohols, however, are known to deoxygenate more easily at 80 °C. Whilst the carboxyarylation reaction was identified on thionocarbonates of three different secondary alcohols, these were conformationally restricted molecules where the alkene and thiocarbonyl group were in close proximity, thus favouring cyclisation over fragmentation. We were not confident that cyclisation would compete effectively with elimination in flexible acyclic systems, though it is encouraging to see cyclisation occurring in good yield on the secondary alcohol derivatives, xanthates 1.37 and 1.51 (Table 1.1) and thiocarbonyl imidazolides 1.56 (Scheme

1.8), 1.59 (Scheme 1.9) and 1.64 (Scheme 1.10).

The simplest secondary homoallylic alcohol derivative 1.244 (Scheme 1.57) underwent the transformation as readily as the analogous primary alcohol derivative, forming the benzyl lactone 1.280 in 33%. Furthermore, thionocarbonate 1.245, with an aryl substituent at the alkene terminus, underwent the reaction in 62% yield, again a similar result to that obtained with the corresponding primary alcohol derivative.

33% a

Ar

1.244 exclusively cis

1.280

OMe 1.281

1.245

(83)

In these two cases exclusively the cis products were formed, the stereochemistry assigned from nOe interactions as shown in the nOesy nmr spectra. As with the previous system, the diastereoselectivity can be explained by application of Beckwith’s rules. With the substituent at C3 adopting the equatorial orientation in conformation 1.282a, cyclisation gives rise to the cis compound (Figure 1.3).

H H Ar

ch3

more stable

1.282a .283a major: cis

1.280

H H

less stable

1.282b 1.283b not seen: trans

1.284

Figure

Table  1.1  Reagents and Conditions:  a.  Bu3SnH,  A1BN,  PhH, reflux; b.  Bu3SnH, A1BN,  PhMe,
Table  1.2  Reagents and  Conditions:  .  a.  BiuSnH,  AIBN, C6H| 2 ; b.  BiuSnH, A1BN,  PhH.
Table  1.1  which  gave  thionolactone  1.28  in  less  than  2%  yield.  When  the  reaction  is  carried  out  on  more  substituted  alkenes  such  as  the  cyclic  alkene  precursors  1.240  and  1.241,  lower  yields  of  the  products  were  observed
Figure  1.4  'H  nmr  spectra of a.  1.297  and b.  1.298.
+5

References

Related documents

The objective of this review is to compile the effects produced by the Fusarium mycotoxin ENN B, focusing on its biological properties, biochemical activity and in vitro

Bu amaçla, ücretli/yevmiyeli çalışma, kendi hesabına çalışma, işsiz ve işgücü dışında olma olarak belirlenen dört farklı istihdam durumu arasındaki yıllık

The special method attribute captures whether the impact of such methods is considered in the definition of the cohesion

Pantang larang as local widomfor Muslim community in Sepinggan Village essentially contains values or moral message, especially in the context of their relationship with

heuristics, on average, show quite a high degree of robustness with respect to changes in the reservation function and the number of products. This conclusion is especially valid

For the poorest farmers in eastern India, then, the benefits of groundwater irrigation have come through three routes: in large part, through purchased pump irrigation and, in a

UPnP Control Point (DLNA) Device Discovery HTTP Server (DLNA, Chormecast, AirPlay Photo/Video) RTSP Server (AirPlay Audio) Streaming Server.. Figure 11: Simplified

Discuss safety away from home, encourage par- ents to teach children safe behaviors, rein- force self-protective behaviors and difference between good touch and bad touch,