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

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Chapter 2 – Dearomatising additions to aryl oxazolines 2.2 Optimisation of Reaction Conditions Having established that this chemistry is novel, the reaction conditions were reviewed to improve the yield of dearomatised adduct, and reduce side reactions. For most of these studies the para-anisole aromatic system was be used since it showed more ortho-lithiation than the phenyl ring – the main side-reaction – and its aromatic protons are easily distinguished by 1 H NMR. Isopropyllithium was generally used for these test reactions since it gives single diastereoisomers with characteristic diastereotopic methyl signals. 2.2.1 Solvent system DMPU is a key additive for dearomatising addition, yet it is unclear whether its role is simply to deaggregate the organolithium, or to promote a specific reactivity. A direct comparison of the crude 1 H NMR spectra of reactions in the presence of DMPU, TMEDA and no co-solvent was made (Table 2.2). HMPA was not studied since Meyers had not been able to achieve dearomatisation using it, and due to its toxicity, 65 but has recently been found by Karlubíková to make little difference. 66 Ox* i) i-PrLi (1.5 eq), THF co-solvent (n eq) Ox* Ox* Me OMe 101b ii) MeI OMe 102b OMe 103b Co-solvent (eq) 102b / % 103b / % SM / % None 22 73 4 TMEDA (6 eq) 23 72 5 DMPU (6 eq) 67 20 4 Table 2.2 – crude ratios of addition with different co-solvent 57
2.2 – Reaction optimisation % Composition 80% 60% 40% 20% 102b 103b SM Misc Aromatic 0% 0 2 4 6 8 10 12 14 16 Eq. DMPU Scheme 2.7 – crude reaction composition vs. eq of DMPU (relative to oxazoline) These data show that the inclusion of TMEDA in the reaction has no impact on the course of the reaction, indicating that DMPU has a specific mode of action. This study was extended to investigate the importance of the concentration of DMPU (Scheme 2.7). The results show that whilst DMPU is essential for the dearomatising addition, higher concentrations promote side reaction. The miscellaneous aromatics were not identified, but appear to be products of lithiation, possibly ortho to the methoxy group. From these studies, it was concluded that six equivalents of DMPU with respect to the oxazoline were optimal. A small quantity of co-solvent is consistent with the guidance of Collum, who suggests that higher concentrations are rarely necessary. 67 Ethereal solvents, primarily THF and diethyl ether, are commonly used in organolithium chemistry since they are both relatively inert and good Lewis bases which coordinate lithium, making the organic counter ion more reactive. 14 Whilst both ether and THF gave similar crude reaction mixtures, toluene was also found to be a promising solvent. 58
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Dearomatising Addition of Organolit
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2.3 Synthetic Scope 64 2.3.1 Organo
Page 5 and 6: Abstract Dearomatising Addition of
Page 7 and 8: The Author The Author graduated fro
Page 9 and 10: Abbreviations & Conventions Ac acet
Page 11 and 12: RDS rate determining step R f RC rt
Page 14 and 15: Chapter 1: Introduction Chapter 1 -
Page 16 and 17: Chapter 1: Introduction controlled
Page 18 and 19: Chapter 1: Introduction diastereome
Page 20 and 21: Chapter 1: Introduction combine mor
Page 22 and 23: Chapter 1: Introduction O Ar Cl TMP
Page 24 and 25: Chapter 1: Introduction conditions,
Page 26 and 27: Chapter 1: Introduction chiral oxaz
Page 28 and 29: Chapter 1: Introduction Again a lar
Page 30 and 31: Chapter 1: Introduction 34 Scheme 1
Page 32 and 33: Chapter 1: Introduction The amino a
Page 34 and 35: Chapter 1: Introduction It was envi
Page 36 and 37: Chapter 1: Introduction COR' i) ATP
Page 38 and 39: Chapter 1: Introduction O i) ATPH,
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
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3.2 - Oxazoline removal O N O OH 3N
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3.2 - Oxazoline removal O Me O N OM
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3.2 - Oxazoline removal However, th
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3.2 - Oxazoline removal 3.2.3 Reduc
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3.2 - Oxazoline removal Ph O N Ph P
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3.2 - Oxazoline removal 3.2.3.c Ami
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3.2 - Oxazoline removal Ph Ph Ph Ph
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3.2 - Oxazoline removal 3.2.5.b N-A
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3.2 - Oxazoline removal Ph Ph O N H
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3.2 - Oxazoline removal Ph Me Ph Me
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3.2 - Oxazoline removal 3.2.6 Deter
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Better, however, would be a method
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4.1 - Introduction HO OH OH HO OH O
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4.1 - Introduction (-)-Shikimic aci
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4.1 - Introduction followed by Flem
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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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