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

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Chapter 3 – Oxazoline synthesis & removal Since neither the aza-allylic nor amide N-benzyl bonds were apparently susceptible to hydrogenolysis, it was hoped that this bond in the corresponding secondary amine would be. This could be made by reduction of the amide or by treating oxazolines directly with DIBAlH (section 3.2.1.c). 3.2.3.b DIBAlH reduction Ph O N Ph DIBAlH solvent, 0 °C H N Ph OH Ph 101m 210 205 O H N Ph OH Ph solvent 210/% 205/% THF (wet) 40 20 THF 60 20 Toluene 80 10 Table 3.8 – DIBAlH reduction of oxazolines Whilst the procedure 137 did not specify whether wet or dry solvent should be used the reduction worked well on test substrate 101m using dry THF. The structure of amine 210 was confirmed by synthesis from benzaldehyde and amino alcohol 175. Catalyst bar / ° C solvent Pd/C 80 / 50 AcOH in MeOH (10% to 100%) Pd(OH) 2 /C 70 / rt AcOH H N Ph OH Ph H 2 Conditions nr Pd(OH) 2 /C 70 / rt TFA/MeOH 210 Table 3.9 – hydrogenolysis of secondary amine 210 The benzylic C–N bond of amine 210 was resistant to hydrogenolysis under a similar range of conditions as the parent compound. Whilst hydrogenation was only conducted under acid conditions, it is not thought this jeopardised the reaction since similar N-debenzylations have been conducted in TFA-MeOH. 140 Recently Li has shown that an equimolar mixture of Pd and Pd(OH) 2 catalysts on carbon can be more active than either individual catalyst, 141 but this, nor transfer hydrogenation are thought likely to prove more productive than the methods already attempted. 117
3.2 – Oxazoline removal 3.2.3.c Amide hydrolysis Amides 204 and 205 were stable to acid and alkaline hydrolysis. Following the protocol of Clayden, 142 the hydrolysis of N-nitroso amides was attempted, but both nitrosation and hydrolysis proceeded slowly and in poor yield. McClure had previously hydrolysed secondary amides by conversion to the imidate and subsequent acid hydrolysis, but unfortunately it was found that the imidate could only be formed from aromatic amides. 143 3.2.4 Oxazoline hydrolysis Ph Ph NH 3 Cl Ph HCl O N Ph O O Ph Reflux NH 2 Ph OH c-Hex c-Hex 101m 211.HCl 175 Entry Conditions Time 211 / % 175 / % a 6N HCl:THF, 3:1 2 min 91 0 b 3N HCl:THF, 2:1 2 min 85 0 c 6N HCl:EtOH, 3:1 1 hr 50 40 d 6N HCl:EtOH, 3:1 16 hr 0 70 Table 3.10 – hydrolysis of 2-cyclohexyloxazoline Hydrolysis of cyclohexane 101m was found to proceed in a similar manner to that described by Meyers (section 3.2.1.a). Gentle heating quickly gave ester 211.HCl as the crystalline ammonium salt which could be isolated by simple filtration. Continued heating allowed amine 175 to be recovered after aqueous work up, although cyclohexanecarboxylic acid was not isolated. In light of this possible isolation problem methods for reducing the ester were studied (Scheme 3.27). 118
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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 131 and 132: 4.1 - Introduction HO OH OH HO OH O
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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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4.5 - 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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