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

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Chapter 3 – Oxazoline synthesis & removal both enantiomers of amino alcohol 175 have become commercially available, but is approximately four times the price of (+)-174. 131 3.2 Oxazoline Removal Clean and facile removal of the oxazoline moiety to a synthetically useful functional group without loss of optical purity is essential to making the dearomatising methodology described synthetically useful. Ideally any method developed would allow recovery of optically pure amino alcohol 175 since this cannot be synthesised by any other method (section 3.1.3), furthermore the ability to recycle material is often cited as one of the benchmarks of a chiral auxiliary. Ideally two or more orthogonal methods should be developed to aid synthetic design. 3.2.1 Literature methods for removal Whilst oxazolines have not seen such broad use in synthetic chemistry as other heterocycles, they are still often taught in synthetic courses as masked carboxylic acids resistant to a range of nucleophiles and reducing agents, yet removable under strong acid hydrolysis. Whilst such robustness may be beneficial in designing a synthesis, it otherwise makes removing the oxazoline more challenging. The following literature survey presents three general strategies adopted in unmasking oxazolines. Only methods compatible with chiral aliphatic substituents are reported, most are two-step methods, and when possible reference has been made to the relay of optical purity. 3.2.1.a Hydrolysis The most commonly encountered oxazolines in text books are geminal dimethyl oxazolines 185 where high temperature acid catalysed hydrolysis in ethereal or alcoholic solvent is suggested for removal to give the acid or ester. 6 107
3.2 – Oxazoline removal O N O OH 3N HCl (aq) 87-95% Δ 3 examples D D 185 Scheme 3.14 – acid hydrolysis of gem-dimethyl oxazolines 132 Whilst this has mainly been used for removal of oxazolines from stable aromatic systems, Meyers also used acid hydrolysis in his early asymmetric work (Scheme 3.15). 133 This method allowed the chiral amino alcohol 186 to be recovered without loss of optical purity, in fact, the hydrolysis intermediates were isolated and recrystallised, allowing enantiomeric ratios to be improved. Ph O H Me N R R = Et, n-Pr, n-Bu OMe HCl (aq) Δ, minutes Ph O H Me HCl (aq) Δ H Me OMe NH 2 Cl O R CO 2 H R i) NaHCO 3 ii) recryst. Ph 68-79% 4:1 e.r. 3 examples OMe NH 2 OH 186 O H Me H Me Scheme 3.15 – acid hydrolysis of chiral oxazoline 133 H N R HO CO 2 H R Ph OMe 4N HCl Δ 3 hr 51-59% 9:1 e.r. 3 examples Alternatively, alkaline hydrolysis of N-alkylated oxazolines 187 can be employed to reveal the acid (Scheme 3.16) with good retention of stereochemistry since enantiomeric excesses were generally in proportion to the preceding diastereomeric ratios. Mechanistically, alkylation can be thought of as replacing the first protonation in the hydrolysis sequence, although the amino alcohol can no longer be recycled. Ph O R HO N Ph OMe MeI, DMSO rt Ph O N Me R HO Ph 187 OMe KOH (2M) Δ 8 hr 134 Scheme 3.16 – alkylation-hydrolysis R HO CO 2 H Ph 55-73% 13 examples 108
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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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Chapter 1: Introduction O i) ATPH,
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Chapter 1: Introduction 1.4 Nucleop
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Chapter 1: Introduction Unlike the
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Chapter 1: Introduction Diene (-)-8
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Chapter 1: Introduction A scheme su
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Chapter 1: Introduction Cl R + 93 S
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Chapter 2 - Dearomatising additions
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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
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Page 131 and 132: 4.1 - Introduction HO OH OH HO OH O
Page 133 and 134: 4.1 - Introduction (-)-Shikimic aci
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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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