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

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Chapter 2 – Dearomatising additions to aryl oxazolines Ox* i) i-PrLi (1.5 eq), THF, DMPU (6 eq) −78 °C 5 min Ox* Ox* Ox* Me ii) MeI R R R 101 102 116 R 103 Entry R 102 116 103 SM Colour a H 70 0 6 12 Dark green b # p-OMe 64 0 17 6 Dark green (Scheme 2.6) c m-OMe 54 * 0 9 * 20 Apple green (Scheme 2.12) d 72 m-F † 10 * 0 10 * 40 Forest green (Scheme 2.13) e 72 p-F † c. 30 20 c. 40 ‡ 5 Forest green f p-Ph 32 30 0 14 Cherry red (Scheme 2.13) g p-CN 0 0 0 0 Wine red h p-NO 2 0 0 0 >95 Wine red (Scheme 2.14) i o-OMe 72 0 90 0 0 Wine red j 2-Me-4- 0 0 65 0 Wine red OMe *1,2,3 substituted regioisomer † in toluene ‡ sum of 2 regioisomers # average of 4 reactions Table 2.8 – addition to different aromatic systems Addition to the electron-rich meta-anisole system (101c, entry c) proceeded in good, unoptimised yield and only 1,2,3-substituted regioisomers isolated; confirmed by x-ray crystallography of 102c. The same regioselectivity was observed for meta-fluoro 101d. Scheme 2.12 – crystal structure & reaction solution of meta anisole 102c The stereoelectronic preference for 1,2,3-substitution is quite clear; both oxygen and fluorine are effective π-donors and equally disfavour addition at C2 and C6, whilst 67
2.3 – Synthetic scope their electronegativity makes them strong σ-withdrawing groups, favouring C2. Furthermore by analogy to anisole's propensity to ortho-lithiation, 14 anisole 101c could direct attack towards C2, possibly explaining the significantly better yield of 102c. Whilst Meyers also observed high regioselectivity, the choice of carbons to attack was stark; addition to 1-naphthyloxazolines could only happen at the C2 since attack at C9 position would impact upon the aromaticity of the adjacent ring. Addition to substituted 2-naphthyloxazolines was not studied by Meyers. Toluene promoted addition to both fluorinated aromatic systems where THF had failed, and could be seen in a change of reaction colour from electric blue to forest green (entries e, f, Scheme 2.13a). Unfortunately these reactions were plagued by products of rearomatisation which proved hard to separate and characterise. Extensive preparatory TLC was performed by Baker to separate diene 102d from the orthomethyl 103d; yields for addition to 4-fluoro 101e are estimated from the combined fractions since mixed regioisomers 103e were not separable from diene 102e. 72 a) b) Scheme 2.13 – reaction solutions of a) 101d (3-F) in PhMe and b) 101f (p-Ph) Pleasingly, addition to biaryl 101f (entry f, Scheme 2.13b) showed addition in 60% yield, however despite being performed in THF, approximately half of the dearomatised material abstracted protons from the solvent. It is possible that this reflected the quality of the purchased THF used in this reaction compared to that distilled from sodium, but no significant depletion in yield was noticed for addition to anisole 101b under similar conditions. 68
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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 -
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
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
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Page 115 and 116: 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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