Table Of ContentRadical Approaches to
Alangium and
Mitragyna Alkaloids
A Thesis Submitted for a PhD
University of York
Department of Chemistry
2010
Matthew James Palframan
Abstract
The work presented in this thesis has focused on the development of novel and
concise syntheses of Alangium and Mitragyna alkaloids, and especial approaches towards
(±)-protoemetinol (a), which is a key precursor of a range of Alangium alkaloids such as
psychotrine (b) and deoxytubulosine (c). The approaches include the use of a key radical
cyclisation to form the tri-cyclic core.
O O O
N N N
O O O
H H
H H H H
O N
N Protoemetinol OH NH
a
HO
Psychotrine Deoxytubulosine
b c
Chapter 1 gives a general overview of radical chemistry and it focuses on the
application of radical intermolecular and intramolecular reactions in synthesis.
Consideration is given to the mediator of radical reactions from the classic organotin
reagents, to more recently developed alternative hydrides. An overview of previous
synthetic approaches to a range of Alangium and Mitragyna alkaloids is then explored.
Chapter 2 follows on from previous work within our group, involving the use of
phosphorus hydride radical addition reactions, to alkenes or dienes, followed by a
subsequent Horner-Wadsworth-Emmons reaction. It was expected that the tri-cyclic core
of the Alangium alkaloids could be prepared by cyclisation of a 1,7-diene, using a
phosphorus hydride to afford the phosphonate or phosphonothioate, however this approach
was unsuccessful and it highlighted some limitations of the methodology.
Chapter 3 explores the radical and ionic chemistry of a range of silanes. Initial
studies explored the radical addition of a range of silicon hydrides to alkenes to afford the
corresponding hydrosilylation products. The chemistry of the hydrosilylation products was
then explored – it was hoped that a subsequent Peterson olefination or Fleming-Tamao
oxidation would afford the corresponding alkene or alcohol. Subsequent investigations
looked into the possibility of combining the radical and ionic reactions, to afford alkenes or
alcohols, in a one-pot transformation.
i
Chapter 4 explores the radical cyclisation of various compounds, including
unsaturated alpha-haloamides (d and e), xanthates (f), vinyl bromides (g and h). For this, a
robust and efficient synthesis of an allyl tetrahydroisoquinoline core (i and j) was
developed, following conversion into the desired radical precursors these compounds were
treated with tributyltin hydride and a radical initiator. Finally, Chapter 4 investigates the
radical cyclisation of some unsaturated phenylselenides (k and l), which resulted in the
isolation of the desired target alkaloid (±)-protoemetinol (a) in 4 steps and in 2% overall
yield.
O O O
N O N NH
O O O
Br X X
X
X =Cl,d X=Me,g X =H,i
X =Br,e X=CO CH ,h X=Br,j
2 3
X =SC(S)OEt,f
O O
N R N
O O
SePh R
O R=H,k R=H,m
R=Me,l R=Me,a
O OH
Chapter 5, which builds on previous work within Chapter 4, discusses the
cyclisation of vinyl bromides bearing an α,β-unsaturated ester (n and o). This resulted in
short 4-step syntheses of both (±)-des-methyl-protoemetinol (m) and (±)-protoemetinol (a)
(along with some epimers). Subsequent studies then expanded the synthetic strategy to
include the synthesis of a structurally simpler analogue of mitragynine (p).
OMe
O O
Br
N N
O O
N
R N
H H
R=H,n O R=H,m R Mitragynine
R=Me,o R=Me,a
p OMe
O OH MeO C
2
ii
Contents
Abstract i
Contents iii
Acknowledgements vii
Declaration viii
Abbreviations ix
Chapter 1 Introduction
1.1 Radical chemistry 1
1.1.1 - Overview of radical chemistry 1
1.1.2 - General considerations of radical reactions 1
1.1.3 - Overview of intermolecular additions 3
1.1.4 - Overview of radical cyclisations 4
1.1.5 –Organotin radicals in synthesis 7
1.1.5.1 - Additions to carbon-carbon multiple bonds 7
1.1.5.2 - Addition to a carbon–heteroatom double bond 8
1.1.5.3 - Problems associated with tributyltin hydrides 10
1.1.6 - Single Electron Transfer Reactions 11
1.1.6.1 - Nickel mediated reactions 11
1.1.6.2 - Manganese(III) acetate mediated reactions 12
1.1.6.3 - Samarium(II) mediated reactions 13
1.1.6.4 Tetrathiofulvalenes 14
1.1.7 - Alternative hydrides 15
1.1.7.1 - Germanium hydrides 15
1.1.7.2 – Thiols 16
1.1.7.3 – Silanes 17
1.1.7.4 - Silylated cyclohexadienes 18
1.1.7.5 - Tris(trimethylsilyl)silane 19
1.1.7.6 - Organophosphorus hydrides 21
1.2 Alkaloids 25
1.2.1 –Overview of Alangium and Mitragyna alkaloids 25
1.2.2 - Alangium alkaloids 26
1.2.2.1 - Synthesis of Alangium alkaloids and related compounds 26
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1.2.2.2 - Iron catalysed cyclisation 27
1.2.2.3 A domino hetero-Diels-Alder reaction 28
1.2.2.4 Catalytic asymmetric allylation 31
1.2.2.5 - [3+3] Annulation followed by acid-catalysed cyclisation 32
1.2.2.6 - Pictet-Spengler and subsequent Strecker reaction 34
1.2.3 The Mitragyna alkaloid mitragynine (86) 35
1.2.3.1 - Synthesis of mitragynine (86) and related compounds 36
1.2.3.2 - First total synthesis of mitragynine (86) 36
1.2.3.3 - Second total synthesis of mitragynine (86) 39
1.2.3.4 - Synthesis of related alkaloids 41
1.2.3.4.1 - Synthesis of (-)-9-methoxymitralactonine (167) 41
1.2.3.4.2 - Synthesis of enantiomer of corynantheidol (183) 43
1.3 Project Aims 44
Chapter 2 - Reactions of phosphorus-centred radicals
2.1 Introduction 46
2.2 Synthesis of 1,7-dienes 48
2.2.1 Synthesis of imines by oxidation 48
2.2.2 Addition of organometallic reagents to imines 49
2.2.3 Addition of organometallic reagents to imine salts 50
2.3 Reaction of phosphorus hydrides 50
2.3.1 Reaction of phosphorus hydrides with 1,7-diene 188 50
2.3.2 Reaction of phosphorus hydrides with a model system 51
2.3.3 Reaction of phosphorus hydrides with test systems 51
2.4 Chemistry of enamines with phosphorus hydrides 53
2.4.1 Preparation of enamines 53
2.4.2 Reactions of enamines with phosphorus hydrides 54
2.5 Preparation and reactions of amide based 1,7-dienes 56
2.6 Conclusions 59
Chapter 3 - Addition Reactions of Silicon-centred Radicals
3.1 Introduction 60
3.2 Reactions of tris(trimethylsilyl)silane 61
3.3 Reactions of alkyl- and aryl-silanes 62
3.3.1 Addition of alkyl- and aryl-silanes at elevated temperature 62
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3.3.2 Addition of alkyl- and aryl-silanes at room temperature 64
3.3.3 – Ionic reactions of alkyl- and aryl-silanes 66
3.4 – Reactions of alkoxysilanes 67
3.5 – Reactions of chlorosilanes 67
3.5.1 – Addition of chlorophenylsilane 67
3.5.2 – Addition of trichlorosilane 68
3.6 Conclusion 70
Chapter 4 - Tributyltin hydride mediated cyclisation
4.1 - Synthesis of the allyl-tetrahydroisoquinoline core 72
4.1.1 – Myers approach to an allyl-tetrahydroisoquinoline core 72
4.1.2 – Methylsulfonyl approach to an allyl-tetrahydroisoquinoline core 73
4.1.3 – Phenylsulfonyl approach to an allyl-tetrahydroisoquinoline core 74
4.1.4 – N-Pivaloyl approach to an allyl-tetrahydroisoquinoline core 75
4.1.5 – N-Boc approach to an allyl-tetrahydroisoquinoline core 76
4.2 - Synthesis and reaction of a xanthate or alpha-halo amides 76
4.2.1 - Synthesis of xanthate and alpha-halo amides 77
4.2.2 – Radical reactions of xanthate (294) 79
4.2.3 – Radical reactions of alpha-halo amides (295) and (296) 79
4.3 - Cyclisation of vinyl bromides onto an N-allyl fragment 80
4.3.1 – Synthesis of vinyl bromide (307) 81
4.3.2 – Radical reaction of vinyl bromide (307) 81
4.3.3 – Synthesis of vinyl bromide (317) 83
4.3.4 – Radical reaction of vinyl bromide (307) 84
4.3.5 – Approaches to protoemtinol (88) from ester (318-a) 85
4.4 Formation and reaction of phenylselenides 87
4.4.1 Synthesis of phenylselenides (331) and (332) 87
4.4.2 Radical cyclisation of phenylselenides (331) and (332) 88
4.4.3 Synthesis and cyclisation of phenylselenide (343) 90
4.4.4 Synthesis of an α,β-unsaturated ester with a phenylselenide (349) 92
4.5 Conclusion 93
Chapter 5 - Vinyl bromide approaches to Alangium and Mitragynine
alkaloids
5.1 - Approaches to (±)-protoemetinol (88-a) 95
v
5.1.1 – Synthesis and cyclisation of a model vinyl bromide (352) 95
5.1.2 - Synthesis of (±)-des-methyl protoemetinol (342-a) 97
5.1.3 - Synthesis of protoemetinol (88-a) 100
5.1.4 - Conversion of (±)-des-methyl protoemetinol (343-a) into (±)-
protoemetinol (88-a) 103
5.1.5 - Alternative conditions for the cyclisation of the vinyl bromides 104
5.2 - Approaches to mitragynine (86) starting from a vinyl bromide 107
5.2.1 - Synthesis of vinyl bromide 395 107
5.2.2 – Radical reactions of vinyl bromide 395 109
5.2.3 –Functionalisation of ester 397 110
5.3 – Conclusion 112
Chapter 6 - Conclusions, Summary and Future Work
6.1 Chapter 2 - Summary, Conclusions and Future Work 114
6.2 Chapter 3 - Summary, Conclusions and Future Work 114
6.3 Chapter 4 – Summary, Conclusions and Future Work 115
6.4 Chapter 5 - Summary, Conclusions and Future Work 117
6.5 Summary of routes to (±)-des-methyl-protoemetinol (342-a) and (±)-
protoemetinol (88-a) 120
Chapter 7 - Experimental
7.1 General Experimental 122
7.2 Experimental for chapter 2 124
7.3 Experimental for chapter 3 139
7.4 Experimental for chapter 4 163
7.5 Experimental for chapter 5 201
Chapter 8 – Appendix 226
Appendix - NMRs
Appendix - X-ray crystal structure for the dichloromethane salt, 363
Chapter 9 - References 253
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Acknowledgements
Many people have contributed to my years of research at York, all deserve much
thanks for their help.
Firstly I would like to show my appreciation to my supervisor Dr Andrew Parsons,
first for allowing me to work within his research group. His guidance, knowledge,
enthusiasm and most of all proof-reading of this thesis has been invaluable, and with out
which this thesis would not be possible.
A great deal of thanks has to go to the technical staff with in the department; Mike
and Steve for their friendly banter, and for ensuring a supply of all the required chemicals,
Trevor for the mass spectrometry results, Adrian for the X-ray structures, and finally, but
most importantly Heather and Amanda for their support with all things NMR related, with
out which the experimental would have been possible.
Thanks to all members of the lab past and present, for their friendship and making
the past 4 years so entertaining, namely Tony, Danny, Izzi, Peter and Sharifa, and the
MChem students over the years Ivor, Mark, Christian and David, and more recently all the
POB members for making us feel at home, after our move.
Finally and most importantly a huge thanks you to my family, especially my mum
and dad for all their support over the years.
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Declaration
I declare that, to the best of my knowledge, the research presented in this thesis is
original. Due reference has been made where the work of others is quoted
M. J. Palframan
Aug 2010
viii
Abbreviations
Ac acetyl
ACCN 1,1’-azobis(cyclohexanecarbonitrile)
AIBN 2,2’-azobisisobutyronitrile
app apparent
aq. aqueous
Ar aryl
atm atmosphere
BDE bond dissociation enthalpy
Bn benzyl
Boc tert-butyloxycarbonyl
B.p. boiling point
Bu butyl
Bz benzoyl
CAN ceric ammonium nitrate
Cbz carboxybenzyl
CI chemical ionisation
conc. concentrated
COD 1,5-cyclooctadiene
COSY correlation spectroscopy
CSA camphorsulfonic acid
DCC N,N’-dicyclohexylcarbodiimide
DCM dichloromethane
DCE 1,2-dichloroethane
DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
dec decomposition
DEPT distortionless enhancement by polarisation transfer
DLP dilauroyl peroxide
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMPU N,N'-dimethyl-N,N'-propylene urea
DMSO dimethyl sulfoxide
d.r. diastereomeric ratio
d.s. diastereoselectivity
ix
Description:and dad for all their support over the years be matched. Nucleophilic radicals add faster to electron–poor double bonds due to a . more electron rich silyl enol ether are present, which leds to the selective formation of only.
