Synthesis of branched amino acids [Elektronische Ressource] : isonorstatine, phenylisothreonine, lactacystin analogues, and amino polyols / Feng Li

Li Feng

Informations

• Publié par: universitat_stuttgart
• Publié le: 01 janvier 2007
• Nombre de lectures: 28
• Poids de l'ouvrage: 2 Mo

Extrait

Synthesis of Branched Amino Acids: Isonorstatine,
Phenylisothreonine, Lactacystin Analogues, and Amino Polyols


Von der Fakultät Chemie der Universität Stuttgart
Zur Erlangung der Würde eines
Doktors der Naturwissenschaften
(Dr. rer. nat.)
genehmigte Abhanglung



vorgelegt von
Feng Li
aus Henan/China


Hauptberichter: Prof. Dr. V. Jäger
Mitberichter: Prof. Dr. U. Beifuß
Tag der mündlichen Prüfung: 09 Feb. 2007



Institut für Organische Chemie
der Universität Stuttgart
2007




I

Part of this work has been presented:

Publications:
Li, F.; Schwardt, O.; Jäger, V.
Synthesis of (2S,3R,4S)-Isonorstatine Using a Solvent-Induced Highly Stereoselective
3-Butenyl Addition to L-Threose Imines
Synthesis 2006, 2173-2182.

Li, F.; Li, Z.-M.; Yang, H.; Jäger, V.
Synthesis of Phenylisothreonine
J. Org. Chem. in preparation.

Li, F.; Jäger, V.
Synthesis of Lactacystin β-Lactone Analogue
Org. Lett. in preparation.

Poster:
Li, F.; Schwardt, O.; Jäger, V.
New Routes to Branched Amino Acids: Synthesis of Isonorstatine and Phenylisothreonine;
ORCHEM 2004, Bad Nauheim, Germany, September 9-11 2004; Book of Abstracts, p.178.

Lecture:
Li, F.; Schwardt, O.; Jäger, V.
New Routes to Branched Amino Acids: Synthesis of Phenylisothreonine and Lactacystin
Analogues
st1 BBS symposium on Organic Chemistry: N,O-Heterocycles and More, Bratislava, Slovak
Republic, April 7-10, 2005; Book of abstracts, p. 26. II

Contents

1 Introduction 1

2 Synthesis of Isonorstatine and its Derivatives 4

2.1 Background 4
2.2 Results and discussion 7
2.2.1 Addition to L-threose-derivatived imine 7
2.2.2 Synthesis of (2S,3R,4S)-isonorstatine 13 9
2.2.3 Assignment of configuration at C-5 in 8 10
2.2.4 Synthesis of N,O-protected β-amino- γ-methyl- α-hydroxy-glutarate 12
2.2.5 Synthesis of cyclic derivatives 13
2.3 Conclusion 14

3 Synthesis of Phenylisothreonine 15

3.1 Background 15
3.2 Results and discussion 19
3.2.1 Imine formation and Grignard additions 19
3.2.2 Synthesis of (2S,3R)-phenylisothreonine 36 22
3.2.3 of the substituted tetrahydrofuran 39 24
3.3 Conclusion 25

4 Synthesis of Amino(hydroxymethyl)cyclopentanetriols 26

4.1 Background 26
4.2 Results and discussion 28
4.3 Results of biological test 29
4.4 Conclusion 30

5 Synthesis of Lactacystin Derivatives 31

5.1 Biological activities of lactacystin 31
5.2 Studies on the total syntheses of lactacystin and salinosporamide A 33
5.3 Introduction on the use of organoboron reagents 52 III

5.3.1 Asymmetric hydroboration 53
5.3.1.1 Diisopinocampheylborane and momoisopinocampheylborane 53
2 9-Borabicyclo[3.3.1]nonane 54
5.3.1.3 Thexylborane 55
5.3.2 Asymmetric allyl- and crotylboration 57
5.3.2.1 Allyl- and crotylboration of aldehydes 57
2 Allyl- and cryotylboration of N-masked imines 59
5.3.2.3 Asymmetric synthesis of vicinal diols or vicinal amino alcohols 60
5.3.3 Asymmetric reduction of ketones and ketimines 63
5.3.4 Boron-mediated asymmetric aldol reaction 64
5.4 Synthesis of lactacystin analogues 66
5.4.1 Retrosynthetic analysis and original synthetic plan of omuralide 66
5.4.2 Efforts concerning the synthesis of an analogue of the lactacystin core
120 and its enantiomer 81 67
5.4.2.1 Results and discussion 67
2 Synthesis of lactacystin core analogue 120 72
5.4.2.3 of lactcore analogue 81 74
4 Determination of the configuration of 81 and 120 75
5.4.2.5 Conclusion 76
5.4.3 Synthesis of the lactacystin β-lactone analogue 107
and its enantiomer 68 77
5.4.3.1 Results and discussion 77
2 Synthesis of the lactacystin β-lactone analogue 107 88
5.4.3.3 of the lactβ-lactone analogue 68 90
5.4.3.4 Conclusion 92
5.5 Results of biological test 92

6 Summary 93

7 Experimental Part 99

7.1 General 99
7.2 Experimental Part/Procedures 102

8 Crystal Structure Data 231
8.1 (2S,3R)-Phenylisothreonine methyl ester (36) 231 IV


8.2 (2S,3S,4R,5R)-3-N-tert-Butoxycarbonylamino-1,2-O-isopropylidene-4-
O-methoxy- methyl-5-methylhexane-1,2,4,6-tetraol (54a) 233
8.3 (2S,3R,4R)-1-tert-Butoxycarbonyl-3-hydroxy-2-(2’-methylallyl)-4-
methylproline methyl ester (61) 237
8.4 (2S,3R,4R)-1’-Deoxy-omuralide (68) 240
8.5 (2R,3S,4S)-1-tert-Butoxycarbonylamino-3-hydroxy-2-(2’-methyl-allyl)-4-
methylproline methyl ester (100) 242
8.6 (2R,3S,4S)-1’-Deoxy-omuralide (107) 246
8.7 (2S,3S,4R)-1-tert-Butoxycarbonylamino-3-hydroxy-2-isobutyl-4-
methylproline methyl ester (123) 249

9 References 253

10 Acknowledgements 270

11 Curriculum Vitae 271

12 Table of Structure Formulas 272
V

Preliminary remarks and abbreviations

Figures, equations, literature citations, Schemes, and Tables are numbered consecutively.

All the compounds prepared during this work and cited in the Experimental Part are
consecutively numbered with 1, 2, 3 etc. and are assembled in the Table of Structure
Formulas at the end of this work. Some preparations yield diastereomeric mixtures; the
diastereomers are assigned as a and b.

Starting from Chapter 1, all the other formulas and structures are consecutively labelled in
bold capitals, i. e. A, B,....., Z, AA, AB etc. VI

List of abbreviations:

Ac acetyl DMS dimethyl sulfide
AD asymmetric dihydroxylation DMSO dimethyl sulfoxide
AIBN α, α’-azodiisobutyronitrile DPPA diphenylphosphoryl azide
9-BBN 9-borabicyclo[3.3.1]-nonane DQCB dihydroquinidine 4-chloro-
BINOL 1,1’-bi-2-naphthol benzoate
Bn benzyl dr diastereomeric ratio
Boc tert-butoxycarbonyl ee enantiomeric excess
Bu butyl Eq. equation
BOPCl bis(2-oxo-3-oxazolidinyl) Et ethyl
phosphinic chloride HBCat catecholborane
CSA camphorsulfonic acid HMDS bis(trimethylsilyl)amine
CAN ceric ammonium nitrate HMPA hexamethylphosohoramide
cat. catalyst imid imidazole
Z benzyloxycarbonyl Ipc isopinocampheyl
KHMDS potassium bis(trimethyl- Chx cyclohexyl
DABCO 1,4-diazabicyclo[2,2,2]- silyl)amide
octane LDA lithium diisopro