Structure elucidation and total synthesis of complex polyketides and development of direct methods for the synthesis of chiral amines [Elektronische Ressource] / vorgelegt von Dirk Menche

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Structure Elucidation and Total Synthesis of Complex Polyketides and Development of Direct Methods for the Synthesis of Chiral Amines HABILITATIONSCHRIFT Der Naturwissenschaftlichen Fakultät vorgelegt von Dr. Dirk Menche Hannover, März 2007 All results discussed within this report have been part of publications or are prepared for [52,55,57,88,94,98,103,109,110,123,128,137,139,146]publication. TABLE OF CONTENTS GENERAL SECTION..............................................................................1 1 Introduction............................................................................................................... 1 2 Structural Elucidation and Total Synthesis of the Archazolids............................ 6 2.1 Introduction.. 6 2.2 Isolation and Structural Elucidation............................................................................ 7 2.2.1 Stereochemical Determination of Archazolid A and B............................................... 7 2.2.2 Archazolid-7-O-β-D-glucopyranoside from the Myxobacterium Cystobacter violaceus: Isolation, Structural Elucidation and Solution Conformation.................. 13 2.2.3 Archazolid D: The First Hydroxylated Archazolid................................................... 20 2.3 Total Synthesis of Archazolid A............................................................................... 23 2.

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Structure Elucidation and Total Synthesis of
Complex Polyketides
and
Development of Direct Methods for the Synthesis of Chiral
Amines






HABILITATIONSCHRIFT


Der Naturwissenschaftlichen Fakultät vorgelegt von



Dr. Dirk Menche



Hannover, März 2007






























All results discussed within this report have been part of publications or are prepared for
[52,55,57,88,94,98,103,109,110,123,128,137,139,146]publication.

TABLE OF CONTENTS
GENERAL SECTION..............................................................................1
1 Introduction............................................................................................................... 1
2 Structural Elucidation and Total Synthesis of the Archazolids............................ 6
2.1 Introduction.. 6
2.2 Isolation and Structural Elucidation............................................................................ 7
2.2.1 Stereochemical Determination of Archazolid A and B............................................... 7
2.2.2 Archazolid-7-O-β-D-glucopyranoside from the Myxobacterium Cystobacter
violaceus: Isolation, Structural Elucidation and Solution Conformation.................. 13
2.2.3 Archazolid D: The First Hydroxylated Archazolid................................................... 20
2.3 Total Synthesis of Archazolid A............................................................................... 23
2.3.1 Retrosynthetic Analysis............................................................................................23
2.3.2 Synthesis of the C3-C13 subunit 25
2.3.3 the C20-C1'' subunit ............................................................................. 27
2.3.4 Synthesis of the C14-C19 subunit 28
2.3.5 Fragment union and completion of the total synthesis.............................................. 29
2.4 Design, Synthesis and Biological Evaluation of Simplified Analogues of
Archazolid................................................................................................................. 32
3 Etnangien: Stabilisation, Configurational Assignment and Modular Synthesis
of the C34 to C42 Subunit ...................................................................................... 39
3.1 Introduction............................................................................................................... 39
3.2 A Potent Novel Analogue of Etnangien: Stabilization by Esterification.................. 40
3.3 Configurational Assignment of Etnangien................................................................ 44
3.4 Retrosynthetic Analysis and Modular Synthesis of the C34 to C42 subunit ............ 50
4 Development of Practical Methods for the Stereoselective Synthesis of Chiral
Amines...................................................................................................................... 54
4.1 Introduction............................................................................................................... 54
4.2 Biomimetic Reductive Amination of Carbonyls....................................................... 55
4.2.1 Reductive Amination of Ketones.............................................................................. 56 TABLE OF CONTENTS
4.2.2 Reductive Amination of Aldehydes.......................................................................... 59
4.2.3 Synthesis of Hindered Tertiary Amines.................................................................... 62
4.2.4 Modular One-Pot Synthesis and Biological Evaluation of Tertiary Amines............ 67
4.3 Directed Reductive Amination.................................................................................. 70
4.3.1 Introduction............................................................................................................... 70
4.3.2 ination of β-Hydroxy-Ketones: Convergent Assembly of the
Ritonavir/Lopinavir Core.......................................................................................... 71
5 Summary.................................................................................................................. 76
EXPERIMENTAL SECTION .................................................................82
1 General experimental.............................................................................................. 82
1.1 Experiments of chapter 2.2.1 .................................................................................... 82
1.1.1 Tables of NMR Data and experimental procedures.................................................. 82
1.1.2 Molecular Modeling..................................................................................................93
1.2 Experiments of chapter 2.2.2 .................................................................................. 103
1.3 Experiments of chapter 2.2.3 113
1.4 Experiments of chapter 2.3 ..................................................................................... 114
1.5 Experiments of chapter 2.4 153
1.6 Experiments of chapter 3.2 156
1.7 Experiments of chapter 3.3 157
1.8 Experiments of chapter 3.4 ..................................................................................... 161
1.9 Experiments of chapter 4.2.1 .................................................................................. 175
1.10 Experiments of chapter 4.2.2 180
1.11 Experiments of chapter 4.2.3 185
1.11.1 Synthesis of tertiary amines of the type NR(R') .................................................... 185 2
1.11.2 ines of the type NRR'R'' 187
1.12 Experiments of chapter 4.2.4 190
1.13 Experiments of chapter 4.3.2 .................................................................................. 190 TABLE OF CONTENTS
ACKNOWLEDGEMENTS ...................................................................209
REFERENCES....................................................................................224

ABREVIATIONS
Abreviations
Å Ångström (100 pm) LDA Lithiumdiisopropylamid
Aq aqueous LiBH Lithiumborohydrid 4
Ac Acetyl Me Methyl
Ar Arylmg Milligramm
Bn Benzyl min Minute
BOP (benzotriazol-1-yloxy)tris- mmol Millimol
(dimethylamino)phosphonium mol Mol
hexafluorophosphat MS Molecular sieves
Bu Butyl MTBE Methyl-tert-butylether
t-Bu tert-Butyl MTPA Mosher acid
BuLi n-Butyllithium NaHMDS Sodium-bis(trimethylsilyl)amid
c Concentration [g/100 mL] NMO N-Methylmorpholin-N-oxid
cat Catalytic NOE Nuclear Overhauser Effect
CDCl Deuterated Chloroform NOESY NucleaOverEnhancement 3
COSY Correlation Spectroscopy Spectroscopy
CSA Camphersulphonic acid NMR Nuclear Magnetic Resonance
CH Cl Dichlormethane n.d. Not determined 2 2
CHCN Acetonitrile PCC Pyridiniumchlorochromat 3
δ Chemische Verschiebung PE Petroleum ether
PG Protecting group ds diastereoselectivity
DCM Dichlormethan Ph Phenyl
ppm Parts per million DDQ 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone PMB para-Methoxy-benzyl
PMBCl para-Methoxy-benzylchlorid DIBAl-H Diisobutlyaluminiumhydride
DMAP 4-Dimethylaminopyridine PPTS Pyridinium-4-toluolsulphonate
pyr Pyridine DME Dimethoxyethan
DMF N,N-Dimethylformamide R Non aromatic substituent
R Retention factor DMP Dess-Martin-Periodinane f
DMSO Dimethylsulfoxid rac Racemic
Ref Reference ee Enantiomeric excess
Et Ethyl ROESY Rotating Frame Overhauser
Enhancement Spectroscopy EtO Diethyl ether 2
EtOAc Ethyl acetate RT Room temperature
SAR Structure-Activity-Relationship eq Equivalents
exc. Excess sat. saturated
TBAF Tetra-n-butyl-ammoniumfluorid GC Gas chromatography
g Gramm TBDPS tert-Butyl-diphenylsilyl
TBS tert-Butyl-dimethylsilyl ges. Gesättigt
h Hour TBSCl tert-Butyl-dimethylsilylclorid
TBSOTf tert-Butyl-HMDS Hexamethyldisilazid
HRMS High resolution mass spectroscopy dimethylsilyltrifluormethansulfonat
TEMPO 2,2,6,6-Tetramethylpiperidine-N-HWE Horner-Wadsworth-Emmons
Hz Hertz oxid
TES triethylsilyl Ipc Isopinocampheyl
IpcBOMe Methoxydiisopinocampheylborane tert Tertiary 2
THF Tetrahydrofuran i-Pr iso-Propyl
IR Infrared TLC Thin layer chromatography
TPAP tetrapropylammonium perruthenate J Coupling constant
KHMDS Potassium-bis(trimethylsilyl)amid
L Litre
GENERAL SECTION 1
GENERAL SECTION
1 Introduction
Terrestrial and marine organisms provide a rich source of biologically active compounds with
new and exciting pharmacological properties. In fact, more than 60% of new chemical entities
1introduced as drugs during the last two decades are, or were inspired by, natural products.
However, structurally complex and, consequently, preparatively less accessible natural
1substances have received little attention as pharmaceutical leads. Providing such compounds
has traditionally been addressed by total synthesis in a target-oriented fashion, which, despite
certain achievements, tends to be lengthy, time-consuming and of limited practicality.
Conversely, in an activity-oriented approach, more accessible analogues with improved
activity would be sought. A detailed understanding of the conformational behaviour and
three-dimensional shape of natural products both in the ground and bioactive state hold
promise for the design of such substances by rational modulation of conformation and
biological activity. Studies of this kind are hardly reported in the context of natural product
2synthesis.
Myxobacteria are a particularly rich source of structurally novel and biosynthetically
intriguing bioactive secondary metabolites. These gliding bacteria, which were first described
3 in 1892 by Roland Thaxter, have a long and venerable tradition at the 'Helmholtz-Zentrum
für Infektionsforschung' (recently renamed from: Gesellschaft für Biotechnologische
Forschung). At our institute, the full biosynthetic potential of these soil living bacteria has
been discovered and explored by the pioneering work of the groups of Höfle and
4 5Reichenbach. Prominent examples of myxobacterial metabolites are the epothilones which
are now in phase III clinical trials as microtubule-stabilizing anticancer drugs or the
6tubulysins, such as tubulyin D (1, Figure 1), the most potent member of this class. These
7highly unusual natural tetrapeptides of non-ribosomal origin likewise interfere with spindle
microtubule dynamics to affect cell division. They are even more potent than the epothilones,
which renders them truly promising leads for further development. In addition to these
structures which interact with the cytoskeleton, others have been found to inhibit the electron
4transport. Furthermore, several specific inhibitors of functional proteins have been identified,
8such as ratjadon which blocks the nuclear transporter CRM1. However, for many of these
structures, the full biological potential has not been fully developed and there remains a
largely untapped pool of tremendous opportunities and chances for further advancement and GENERAL SECTION 2
9,10discoveries. Promising structures along these lines present the archazolids (2,3) and
11,12etnangien (4), highly potent macrolide antibiotics of apparently polyketide origin.

OH
O O O O HOH NN
N N N MeO
HO S R O CO H2
O N OO H
N O
S1: Tubulysin D
O

CH CH 2: Archazolid A (R = Me)3 3
3: Archazolid B (R = H)HO OH

OH O
CH CH O3 3
O
OMe
OH CH OH CH3 3
OCH OH3 4: Etnangien

Figure 1. Bioactive natural products from myxobacteria: the non-ribosomal anticancer
agent tubulysin (1) and the polyketide macrolide antibiotics archazolid A and B
(2, 3) and etnangien (4).

Fermentation broths of the myxobacterium Archangium gephyra are the natural source of the
9,10archazolids. On a molecular level, they present most active inhibitors of V-ATPase, both in
13 10vitro and in vivo, with IC values in the low nanomolar range. From the perspective of 50
14medicinal chemistry, these transmembrane enzymes present important targets. In recent
years, it became more and more evident that malfunctions of V-ATPases are correlated with
various diseases such as renal tubular acidosis, sensorineural deafness, osteoporosis, and male
14infertility. On the other hand, metastasizing cells are thought to use the plasma membrane
V-ATPase to acidify the extracellular fluid that destroys normal tissue in advance of the
15invading tumor. In bone growth, the V-ATPase is a major player since it helps to acidify the
osteoclastic lumen leading to bone resorption, and therefore in osteoporosis the dramatically
16increased bone destroyment could be diminished by a lowered V-ATPase activity. The latter
two examples make it understandable that V-ATPases turned out to be a subject for
biomedical research in cancer or osteoporosis drug therapy. In order to understand the GENERAL SECTION 3
development of V-ATPase dependent diseases and to design efficient drugs for their therapy it
is necessary to gain a comprehensive knowledge of V-ATPase inhibitors such as the
archazolids, as well as the mode of their action on the enzyme.
The polyketide metabolite etnangien (4), likewise originally isolated by the group of Höfle
from the myxobacterium Sorangium cellulosum, constitutes a structurally new type of a
11,12particularly efficient RNA polymerase inhibitor in vitro and in vivo. Bacterial DNA-
dependent RNA polymerase presents an attractive drug target for the development of novel
17,18,19antibiotics as RNA chain elongation is essential for bacterial growth. The molecular
20structure and function of this protein are increasingly well understood, which enables an
understanding of inhibitor-target interaction and adds to the attractiveness for inhibitor
21design. So far, the rifamycins are the only class of clinically used RNA polymerase
22inhibitors. However, resistance has been increasingly emerging rendering the development
of novel types of RNA polymerase targeting substances an important research goal. Etnangien
is effective against a broad panel of Gram-positive bacteria, with an average MIC value of 1
µg/ml. Furthermore, it appears to show no cross-resistance to the rifamycins. In addition, it
shows a certain activity against retroviral DNA polymerase, which adds to the attractiveness
for further development. However, preclinical advancement is severely hampered by the
notorious instability of etnangien, which is intrinsically associated with the polyene side chain
in combination with the acid functionality at C-1. Consequently, no SAR-data are available so
far.
The unique chemical structures of the archazolids and etnangien consist of a 24-membered
and 22-membered macrolactone together with a thizaole and polyketide side chain,
respectively and include an array of differently configured poly-unsaturated portions. These
polyketides contain arrays of various stereogenic centers, which have not been assigned: eight
8stereogenic centers for archazolid, leaving 2 = 256 possible diastereomers and etnangien
contains no less than 12 unassigned stereogenic centers giving rise to 4096 diastereomers.
Despite these intriguing and challenging structures with no obvious resemblance to other
known secondary metabolites and the highly attractive biological profiles, no synthetic
approaches are reported to either of these structures so far and no information on the
conformation of the archazolids or etnangien are present.
In recent years, proton – proton coupling constants and proton – carbon coupling constants
have been extensively used to assign the relative stereochemistry of vicinal and proximal
stereocenters. This method (known as Murata’s method) in combination with detailed analysis GENERAL SECTION 4
of NOE data and molecular modelling provide dihedral angles and internuclear distances for
23elucidation of the configuration of stereocenters.
A recurring structural feature in myxobacterial natural products such as the tubulysins, and in
24natural products and registered drugs in general, is the amine / amide motif. Reductive
25amination of carbonyl compounds (e.g. 5, Scheme 1) is a very important, direct and thus
synthetically economical means to synthesise primary, secondary, and tertiary amines. It
proceeds via three steps: nucleophilic addition of the amine (6) onto the C=O bond to form an
26hemi-aminal (e.g. 7), loss of water to generate the imine species 8, and subsequent
reduction, using either an appropriate hydride source or molecular hydrogen, to the
corresponding amine 9. When the carbonyl compound is an unsymmetrical ketone, the
derived amine incorporates a new stereogenic center.

direct reductive amination
1in situ reduction R
N
2 3/4R R1 3 1 3 1 3R R R R R R
2 2R 8 - R*O + H N -H O *N N2 H / 'H '2
2 4 4 4R R HO R H R1R5 6 7 9N
carbonyl ammonia, hemi-aminal 2 3/4 chiral amine R R1° or 2° aminecompound 1 2(for R , R = H)8
imineindirect reductive amination
3 4(for R or R = H) :stereogenic center*
Scheme 1. Reductive amination of carbonyl compounds.

25,27A number of methods have been developed to carry out this reaction in a 'one-pot' process.
For such a 'direct reductive amination' to succeed there should be a reasonable concentration
of the imine present and conditions should be such that there is preferential reduction of the
imine in the presence of the carbonyl compound. This situation is favoured by both Brønsted
28and Lewis acids and the most commonly employed protocol [NaBH CN, pH 3-4] relies on 3
such activation. Known methods for the stereoselective generation of the amines,
25,29however, require isolation of the corresponding N-intermediates, which is tedious and
difficult, due to their instability. Asymmetric direct reductive amination processes on the
contrary are much less developed and are mainly restricted to specific cases or proceed with
24c,30,31very low stereoinduction. A promising starting point for development of such a process
can be extracted from the biosynthesis of amines within the vitamin B cascade or the 'amino 6