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

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Chapter 4 – Synthesis of carbasugars Superficially, the substitution of an endocyclic oxygen with a methylene should make little difference to the structure; the conformations of cyclohexane and oxane are similar despite the C–O bonds being almost 10% shorter. However, sugar chemistry is dominated by the anomeric n O →σ* C–O interactions, which afford significant stabilisation of the α-anomer in which the glycosidic bond is axial. The absence of this interaction in carbasugars means they can adopt conformations that the parent carbasugar cannot. 4.1.2 Existing syntheses All 16 racemic carbasugars, and 25 of the possible 32 carbasugar stereoisomers have been synthesised, as well as a number of analogues. 156 Many approaches have been taken, the major difference being whether starting from chiral pool materials – normally a carbohydrate – or from simpler molecules; both methods have been recently recent reviewed by Gomez and Lopez. 156 This section will discuss syntheses of historical interest, and also some of general synthetic note and relevance to the use of compounds made in previous chapters. 4.1.2.a Chiral pool methods Often the first decision to be made when planning an asymmetric synthesis is where the source of chirality is to come from. When making analogues of sugars, carbohydrates themselves are the most widely used starting point since they are fully oxygenated, optically pure and readily available. There are, however two challenges involved in the conversion of sugars to carbasugars; the elongation of the carbon chain, and the cyclisation of the homologue. Quinic acid (Scheme 4.4) is probably the most widely used chiral pool material after monosaccharides, although the products often contain the quaternary centre of the starting material. A great number of quinic acid derivatives have been made, and have been used as starting materials themselves. HO CO 2 H CO 2 H HO OH OH HO OMe OH HO OH OH HO OH OH HO OH OH HO OH OH (−)-Quinic acid (−)-Shikimic acid myo-Inositol L-Quebrachitol Scheme 4.4 – chiral pool starting materials used in carbasugar synthesis 133
4.1 – Introduction (–)-Shikimic acid is a very appealing starting material, however with its use in the commercial synthesis of Tamiflu (oseltamivir phosphate) it is in high demand, exasperating the paucity of supply and making it unaffordable for most synthetic purposes. However this might slowly be relieved since a number of microbial biosynthesis of (–)-shikimic acid have from E. coli mutants been published, most recently by Johansson using mutants derived from the successful W3110 strain, under phosphate-limited conditions. 157 Indeed in 2005 Roche confirmed that they already get a third of the shikimic acid they use for synthesis of Tamiflu from fermentation. 158 Inositols seem to be well suited to the synthesis of cyclitols, however seven of the nine known inositols contain a mirror plane, including the most abundant myo-inositol (Scheme 4.4). L-Quebrachitol is a chiral inositol which is reported to have been used in carbasugars synthesis, but at 2000 times the cost of myo-inositol, 159 is far too expensive for common usage. Furthermore, the fully saturated system does not provide a clear synthetic handle as, shikimic acid does. 4.1.2.b Non-chiral pool methods McCasland’s approach to the first synthesis of a carbasugar proceeded through an oxanorbornene (252); an approach that has been adopted in many subsequent syntheses. McCasland synthesised ketone 254 (Scheme 4.5) by the forcing hydrolysis of bicycle 253, causing ester migration, decarboxylation, and ether hydrolysis in a single reaction. 150 Reduction, esterification and further reduction yielded the racemic carba-talopyranose 250a. Peracylation of 250a followed by reflux in strong acid led to partial epimerisation, giving peracylated carbagalatopyranose (250b) in 14% yield. 151 O OAc O O O Δ O O O i) H 3 O + HO HO O ii) OsO 4 AcO O AcO 252 253 O OH OH O H 3 O + Δ HO 2 C MeO 2 C HO HO HO 254 O OAc i) NaBH 4 ii) MeOH, TFA iii) Ac 2 O AcO AcO OAc OAc i) LiAlH 4 ii) H 3 O + HO OH HO OH 250a Scheme 4.5 – McCasland’s synthesis of α-DL-talose analogue 150 134
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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 109 and 110: 3.2 - Oxazoline removal O Me O N OM
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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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