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

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Chapter 2 – Dearomatising additions to aryl oxazolines Chapter 2 – Dearomatising Additions to Aryl Oxazolines 2.1 Establishing a New Reaction Ph Ph Ph Ph Ph O N Ph SiO 2 O N i) RLi (1.5 eq) THF:DMPU 25:1 −78 °C ii) MeI O N Me R 100a prepared to attempt dearomatising cyclisation 101a 102a R = i-Pr, 102a, 61% s-Bu, 102a', 91% (dr 4:1) Scheme 2.1 – first dearomatising additions by Purewal 63 Whilst attempting the dearomatising cyclisation of benzoyl aziridine 100a, Purewal unintentionally prepared oxazoline 101a. When subjected to the conditions of dearomatising cyclisation 62 this material underwent nucleophilic attack by the organolithium to give dienes 102a’. This was successfully repeated with i-PrLi to give a single diastereomer, confirming that this reaction is highly diastereoselective, however dienes 102a were described as aziridines in his thesis. 63 A crystal structure later obtained by Cabedo confirmed the relative stereochemistry of the diene, and showed it to be an oxazoline rather than an aziridine, 64 making a clear link to the chemistry Meyers had developed with 2-naphthyl- and pyridyloxazolines (section 1.3.2). Personal communication with Meyers confirmed that during the oxazoline research programme in his laboratories he had been unable to achieve dearomatising addition to benzenoid aromatics. 36 With this news it was clear that this might be a novel reaction, differing from Meyers’ in both the oxazoline and co-solvent. This was confirmed by treating Meyers’ anisoyloxazoline 104b under both sets of conditions. 31 51
2.1 – A new reaction Ph OMe No DMPU No isolable products or starting material O N OMe 104b i) i-PrLi, THF ii) MeI Ph O N OMe Ph O N OMe Me + DMPU OMe 105 24% OMe 7% 106 Ph Me OMe Ph Me OMe O N Me O Me N 22% 4% OMe OMe 107 108 Scheme 2.2 – dearomatising addition using the Meyers oxazoline The contrast between the two sets of conditions was very pleasing; a similarly strong distinction was seen with the 2-phenyl oxazoline. 64 Although the Meyers’ oxazoline returned a significant amount of diene 105 (stereochemistry assigned by analogy to known compounds), it was accompanied by greater amounts of difunctionalised products 107 and 108. It was clear that the reaction of the Meyers oxazoline was plagued by side reactions that were not observed with bis-phenyl oxazoline 101a. para-Anisole 101b was treated under both sets of conditions, and equally stark results were seen (Scheme 2.3). Addition to the electron rich system was very encouraging; the structure of 102b was again confirmed by crystallography (Scheme 2.6). Ph Ph Ph Ph Ph Ph O N OMe i) i-PrLi (1.5 eq) THF, −78 °C ii) MeI O N Me OMe O N Me OMe Additive 102b 103b None 22% 73% DMPU 70% 18% 101b 102b 103b Scheme 2.3 – effect of DMPU on addition to aryl oxazolines 52
Page 1 and 2: Dearomatising Addition of Organolit
Page 3 and 4: 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 52 and 53: 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
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3.1 - Oxazoline synthesis mCPBA O N
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3.1 - Oxazoline synthesis 3.1.4.b M
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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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