A Route to Carbasugar Analogues - Jonathan Clayden - The ...

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Chapter 2 – Dearomatising additions to aryl oxazolines viewed as evidence of an SET reaction. One could dispute that rather than representing a kinetic resolution of the s-BuLi in solution, that addition of both s-butyl enantiomers is equally likely and that the bond rotation occurs in the butyl radical before RC. 2.4.3 Aggregation in organolithium chemistry Whilst the mechanistic studies are inconclusive, another area that might shed light on understanding the dearomatising chemistry is the role of aggregates which are implicated by the sensitivity of the reaction to the order of addition and solvent. Aggregates form since a monodentate alkyl ligand is unable to adequately stabilise its lithium counterpart, which is normally tetracoordinate. These aggregates can shift to their entropically favoured state by the addition of Lewis bases, such as THF, TMEDA and DMPU, which displace organic ligands around the cation. Deaggregation is often associated with making organolithiums more reactive since the organic portion no longer coordinates as many lithium centres, but this has been hard to prove. Indeed, Collum has authored a critique of the triad of strong solvation, lower aggregation and higher reactivity, by discussing examples of the behaviour of TMEDA in organolithium reactions. 109 Collum highlights that the lower aggregation means higher reactivity assumption is fundamentally flawed since by stabilising lower aggregates of organolithiums, one is lowering the ground state energy of the reactants without necessarily lowering the energy of the transition state. Since it is the transition state we hope to stabilise observed increases in reaction rate cannot be used to infer lower aggregation. Indeed, a stronger ligand binding lithium would be less labile and the cation disinclined to coordinate the substrate. Transition state stabilisation seems especially important when we consider that under normal conditions, dearomatisation is a very unfavourable process and it is likely that dearomatised intermediates require significant stabilisation. Hence the subtleties of how stabilisation takes place are important, and might explain why only certain cosolvents were found to assist dearomatisation. An example of a similarly solventspecific effect was observed by Streitwieser who found that the aromatic enolate of p- 89
2.4 – Mechanistic discussion phenylisobutyrophenone is strongly coordinated by HMPA, weakly by DMPU, and that PMDTA and TMEDA have no effect. 110 Unfortunately the role of co-solvents in organolithium chemistry is not thoroughly understood. The most studied co-solvent is hexamethylphosphoramide (HMPA) since it is an exceptional ligand for Li + and its interactions can be monitored by IR and 31 P NMR spectroscopy. Reich recently studied the correlation between 1,2- and 1,4- addition of dithiane to enone systems and its HMPA-induced aggregation state (Scheme 2.34). O Li O S S S −78 °C HO S THF R S S 157 100 : 0 + 2 eq HMPA 5 : 95 Scheme 2.34 – the influence of co-solvent on addition to cyclohexenone 111 The aggregation state of dithiane 157 was measured in solution and the results compared these to the regioselectivity of parallel reactions. Whilst a direct correlation was not observed, Reich concludes that the 1,4-addition is performed by trace amounts of organolithium existing as solvent-separated ion pairs (SIPs). In coming to this conclusion, he invokes a Curtin-Hammett pre-equilibrium between the predominant contact ion pairs (CIPs) and the lower concentration SIPs. Whether the conclusions of Reich are wholly valid, his experiments clearly show how an organolithium can switch its reactivity depending on its solvation. Coordinating ligands can also have unpredictable effects on the aggregation state of an organolithium. For example, Reich and co-workers also found that whilst aryllithiums 158 exist as monomers in THF, addition of excess HMPA can cause them to redimerise to form bis-chelated triple ions 158-T, with one lithium cation completely solvated by HMPA. 112 The reactivity of these triple anions has not been studied, but that HMPA is found to promote aggregation highlights that many different organolithium species can exist in solution. 90
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Dearomatising Addition of Organolit
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2.3 Synthetic Scope 64 2.3.1 Organo
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Abstract Dearomatising Addition of
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The Author The Author graduated fro
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Abbreviations & Conventions Ac acet
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RDS rate determining step R f RC rt
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Chapter 1: Introduction Chapter 1 -
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Chapter 1: Introduction controlled
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Chapter 1: Introduction diastereome
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Chapter 1: Introduction combine mor
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Chapter 1: Introduction O Ar Cl TMP
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Chapter 1: Introduction conditions,
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Chapter 1: Introduction chiral oxaz
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Chapter 1: Introduction Again a lar
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Chapter 1: Introduction 34 Scheme 1
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Chapter 1: Introduction The amino a
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Chapter 1: Introduction It was envi
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Chapter 1: Introduction COR' i) ATP
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Page 40 and 41: Chapter 1: Introduction 1.4 Nucleop
Page 42 and 43: Chapter 1: Introduction Unlike the
Page 44 and 45: Chapter 1: Introduction Diene (-)-8
Page 46 and 47: Chapter 1: Introduction A scheme su
Page 48 and 49: Chapter 1: Introduction Cl R + 93 S
Page 50 and 51: Chapter 2 - Dearomatising additions
Page 92: Chapter 2 - Dearomatising additions
Page 95 and 96: 3.1 - Oxazoline synthesis 3.1.1.a H
Page 97 and 98: 3.1 - Oxazoline synthesis O Ar OH i
Page 99 and 100: 3.1 - Oxazoline synthesis 3.1.2 Gen
Page 101 and 102: 3.1 - Oxazoline synthesis mCPBA O N
Page 103 and 104: 3.1 - Oxazoline synthesis 3.1.4.b M
Page 105 and 106: 3.1 - Oxazoline synthesis Ph Ph Ph
Page 107 and 108: 3.2 - Oxazoline removal O N O OH 3N
Page 109 and 110: 3.2 - Oxazoline removal O Me O N OM
Page 111 and 112: 3.2 - Oxazoline removal However, th
Page 113 and 114: 3.2 - Oxazoline removal 3.2.3 Reduc
Page 115 and 116: 3.2 - Oxazoline removal Ph O N Ph P
Page 117 and 118: 3.2 - Oxazoline removal 3.2.3.c Ami
Page 119 and 120: 3.2 - Oxazoline removal Ph Ph Ph Ph
Page 121 and 122: 3.2 - Oxazoline removal 3.2.5.b N-A
Page 123 and 124: 3.2 - Oxazoline removal Ph Ph O N H
Page 125 and 126: 3.2 - Oxazoline removal Ph Me Ph Me
Page 127 and 128: 3.2 - Oxazoline removal 3.2.6 Deter
Page 129 and 130: Better, however, would be a method
Page 131 and 132: 4.1 - Introduction HO OH OH HO OH O
Page 133 and 134: 4.1 - Introduction (-)-Shikimic aci
Page 135 and 136: 4.1 - Introduction followed by Flem
Page 137 and 138: 4.2 - Carbasugar synthesis 4.2 Synt
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4.2 - Carbasugar synthesis stereoce
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4.2 - Carbasugar synthesis of the o
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4.2 - Carbasugar synthesis support
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4.2 - Carbasugar synthesis Ox* Ox*
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4.2 - Carbasugar synthesis OsO 4 (c
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4.2 - Carbasugar synthesis taken on
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4.2 - Carbasugar synthesis As well
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4.4 - Revised altrose synthesis 4.4
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4.4 - Revised altrose synthesis suf
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4.4 - Revised altrose synthesis ind
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4.5 - Mannose synthesis 4.5 Synthes
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4.5 - Mannose synthesis It is clear
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4.5 - Mannose synthesis considering
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4.5 - Mannose synthesis which would
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4.5 - Mannose synthesis One clear a
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4.5 - Mannose synthesis 4.5.2.b Epo
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4.5 - Mannose synthesis hydrolysis
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4.5 - Mannose synthesis The second
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4.6 - Summary 4.6 Summary & Future
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4.6 - Summary OH CDI, NH 2 OH.HCl,
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184
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References (37) Rawson, D. J.; Meye
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References (105) Gajewski, J. J.; B
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References (169) McCormick, J. P.;
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References 192
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Experimental section 254nm, dodecam
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Experimental section General Proced
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Experimental for chapter 2 Synthesi
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Experimental for chapter 2 (CDCl 3
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Experimental for chapter 2 3H, OMe
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Experimental for chapter 2 Ph), 139
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Experimental for chapter 2 H4), 5.2
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Experimental for chapter 2 108 R f
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Experimental for chapter 2 Synthesi
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Experimental for chapter 3.1 satura
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Experimental for chapter 3.1 Na 2 S
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Experimental for chapter 3.1 Synthe
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Experimental for chapter 3.1 128.9,
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Experimental for chapter 3.1 Microw
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Experimental for chapter 3.1 R f :
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Experimental for chapter 4.1 281 R
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Experimental for chapter 4.1 combin
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Experimental for chapter 4.1 3H, OB
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Experimental for chapter 4.2 (1S*,2
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Experimental for chapter 4.2 10.0,
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Experimental for chapter 4.2 cm 3 )
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Experimental for chapter 4.2 5.7 Re
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Absolute structure parameter 1.3(11
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_diffrn_standards_interval_time ? _
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H13 H 0.8405 0.7136 -0.0889 0.026 U
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C4 C5 1.454(2) . ? C5 C6 1.324(2) .
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C24 C23 C22 120.0(2) . . ? C24 C23
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. Compound 102c Ph O N Ph Me 102c O
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_diffrn_standards_interval_time ? _
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H11 H 0.8924 0.9592 0.6829 0.022 Ui
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C2 H2 1.0000 . ? C3 C21 1.506(2) .
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C26 C21 C3 121.41(15) . . ? C23 C22
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c. Compound 213 Ph O N Ph Me OH 213
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_cell_volume 1080.9(4) _cell_formul
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_refine_ls_number_reflns 4736 _refi
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H25 H 0.7979 0.2335 0.3365 0.028 Ui
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C4 0.025(4) 0.019(4) 0.018(4) 0.001
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loop_ _geom_bond_atom_site_label_1
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C9 C4 C1 107.1(5) . . ? C10 C4 C1 1
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C36 C38 H38A 109.5 . . ? C36 C38 H3
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C29 C30 C36 C37 -90.4(7) . . . . ?
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The structure was solved by the dir
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_reflns_number_total 2447 _reflns_n
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C7 C 1.1671(4) 0.7629(7) 1.2254(4)
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C3 0.015(3) 0.016(3) 0.021(3) -0.00
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C21 H21A 0.9800 . ? C21 H21B 0.9800
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H21A C21 H21C 109.5 . . ? H21B C21
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