Studies Towards Total Synthesis of Polyketide Natural Products and

333 Pages·2012·20.35 MB·English

by  Anastasia Hager

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München

Studies Towards Total Synthesis of Polyketide
Natural Products and Alkaloids

Vorgelegt von
Anastasia Hager (geb. Voskobojnik)
Bischkul, Kasachstan

2012
Erklärung
Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von
Herrn Prof. Dr. D. Trauner betreut

Eidesstattliche Versicherung
Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet.

München, den 16. Oktober 2012

(Anastasia Hager)

Dissertation eingereicht am: 16. Oktober 2012
1. Gutachter: Prof. Dr. Dirk Trauner
2. Gutachter: Prof. Dr. Konstantin Karaghiosoff
Mündliche Prüfung am: 14. November 2012
(cid:16)For my family(cid:16)

SUMMARY
Chapter I: Synthetic Studies Toward A-74528
A-74528 (I.1) is an unusual natural product which has recently been isolated from
Streptomyces sp. SANK 61196 by Ogita and co-workers (Scheme A).[1] Although I.1 was found
to activate the interferon system via inhibition of 2',5'-oligoadenylate phosphodiesterase (2'-
PDE),[1] no synthetic approaches to A-74528 (I.1) have been reported. With its 30 carbon atoms,
A-74528 (I.1) is one of the most complex and largest aromatic polyketides known to date.
Structurally, A-74528 (I.1) consists of a hexacyclic core with an appended (cid:68)-pyrone moiety. Its
unprecedented carbon skeleton contains two acyl resorcinol motifs typical of type II
polyketides, which flank the perhydropyrene core. This heptacyclic system also features six
contiguous stereocenters, one of which is quaternary.
Scheme A. Type II polyketide A-74528 (I.1) and its possible precursor I.2.
This research project is centerd on the development of a biomimetic synthesis of I.1 and its
precursors. We found it fascinating to test the limits of biomimetic synthesis and to explore
whether a complex polyketide pathway could be emulated in the laboratory.[2] As a key step of
our synthesis an intramolecular Michael-Michael cascade of intermediate I.1 was envisioned,
the synthesis of which demanded advanced biaryl chemistry techniques (Scheme A). These
investigations initially focused on challenging transition-metal catalyzed cross-coupling
reactions and, eventually, led to a synthetic strategy based on potentially biomimetic
condensation chemistry, thus providing the key intermediates epoxide I.2 and enone I.3
(Scheme B). At this point, extensive experimentations towards a Michael-Michael cyclization of
the model system I.3 were undertaken. Although, the desired system could not be isolated thus
far, other interesting reactions of I.3 have been observed, leading to, for example, the
dearomatized compound I.4 in a cascade reaction (Scheme B).[3] This biomimetic approach
could serve to unveil more interesting facets of polyketide type II chemistry.
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Scheme B. Synthetic progress toward A-74528 (I.1).
Chapter II: Synthetic Studies Toward Ansalactam A,
Divergolides C and D
Ansalactam A (II.1) and divergolides C and D (II.2 and II.3) are macrolactam natural
products which belong to the ansamycin polyketide family. The intruiging structures of these
three ansa macrolides attracted our interest. Thus, as a part of this PhD thesis, we envisaged to
test biomimetic steps, which are involved in the biogeneses of all three natural products.
Ansalactam A (II.1) was isolated by Moore and co-workers in 2011 from Streptomycies
sp., derived from marine sediments.[4] As we suppose, its fascinating biosynthesis presumably
involves a radical cyclization of an open ring radical system II.4, forming the 5-membered
lactam ring (Scheme C). On the other hand, divergolides C and D (II.2 and II.3) were isolated
by Hertweck and co-workers in 2011 from an endophyte (Streptomyces sp. HKI0576) of the
mangrove tree Bruguiera gymnorrhiza.[5] Hertweck and co-workers discovered, that
divergolides C and D (II.2 and II.3) originate from a similar bioprecursor. We believe, that the
biomimetic total synthesis of both divergolides could be achieved starting from the
intermediates II.5 and II.6, which may interconvert into each other by an transesterification and
double bond isomerisation process, providing swift access to both natural products (Scheme C).
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Scheme C. Type I polyketides ansalactam A (II.1) and divergolides C and D (II.2 and II.3),
as well as their possible precursor II.4, II.5 and II.6.
In the case of ansalactam A (II.1), our synthetic strategy involves the aforementioned
biomimetic radical 5-exo-trig ring closure at an early stage of the synthesis. So far, as a part of
this PhD thesis, an efficient synthesis of the naphthoquinone system II.7 was successfully
achieved (Scheme D). Suitable reaction conditions for the proposed radical ring closure have
been investigated.
In the envisioned synthesis of the divergolides II.2 and II.3 we also aimed to prove our
biomimetic hypothesis. It was planned to access both compounds II.2 and II.3 from a common
intermediate, structurally similar to the isomers II.5 and II.6, by means of a base mediated
Michael addition (for II.2), an aldol reaction (for II.3) and, finally, a transesterification. This
dissertation includes the development of the syntheses of the eastern side chain II.8 and the
western side chain II.9 (Scheme D).
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Scheme D. Synthetic progress towards ansalactam A (II.1) and divergolides C and D (II.2
and II.3).
Chapter III: Synthetic Studies Toward Stephadiamine
The hasubanan alkaloids are a subgroup of the famous natural product class of morphine
alkaloids, which have historically been an inspiration and challenge for synthetic chemists.
Many natural products of the morphine family show strong biological activities. One of the
members of the hasubanan subgroup is stephadiamine (III.1). Stephadiamine was isolated from
Stephania japonica as a minor component in 1984 by Ibuka and co-workers.[6] With its 15
carbon atom skeleton stephadiamine (III.1) is so far the only isolated representative of the nor-
C-hasubanan alkaloids. Structurally, stephadiamine (III.1) consists of a pentacyclic core,
bearing one benzene ring, two amine portions and a lactone functionality. This pentacyclic
structure features four stereocenters, one of which is a benzylic all-carbon quarternary center
and two are nitrogen containing tetrasubstituted carbon (NTC) centers (Scheme E).

Scheme E. Envisioned total synthesis of stephadiamine (III.1).
Inspired by the beautiful structure of III.1 and the challenge to introduce two NTC centers,
one of the projects of this PhD thesis was the development of a synthetic entry to III.1 and its
precursors. The precursor tetralone system III.2 has been synthesized in just six synthetic steps,
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including a C(cid:16)H activation step.[7] First attempts toward the assemnbly of enamine system III.3
have been made (Scheme E).

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