Total synthesis of etnangien

Article abstract of DOI:10.1021/ja9056163

(Chemical Equation Presented) The first total synthesis of the potent RNA-polymerase inhibitor etnangien is described, which establishes unequivocally the relative and absolute configuration of this sensitive macrolide antibiotic. Key features of the expe

Full text of DOI:10.1021/ja9056163

Published on Web 07/31/2009
Total Synthesis of Etnangien
Pengfei Li,† Jun Li,‡,§ Fatih Arikan,‡,| Wiebke Ahlbrecht,† Michael Dieckmann,† and Dirk Menche*,†,‡
Institut fu¨r Organische Chemie, Ruprecht-Karls-UniVersita¨t Heidelberg, INF 270, D-69120 Heidelberg, Germany, and
Helmholtz-Zentrum fu¨r Infektionsforschung, Medizinische Chemie, Inhoffenstr. 7, D-38124 Braunschweig, Germany
Received July 8, 2009; E-mail: dirk.menche@oci.uni-heidelberg.de
Etnangien presents a labile polyketide macrolide isolated by the
group of Ho¨fle from the myxobacterium Sorangium cellulosum.1
It displays potent antibiotic activity against a range of Gram-positive
bacteria, by inhibition of RNA-polymerase,2 in Vitro and in ViVo.
Importantly, it shows no cross-resistance to rifampicine, the only
clinically used RNA-polymerase inhibitor so far. Furthermore, it
also retains activity against retroviral DNA polymerase and shows
only low cytotoxicity against mammalian cell cultures, which adds
to its attractiveness for further development. This is however
severely hampered by its notorious instability.1,3 The unique
structure of etnangien comprises a 22-membered macrolactone with
a polyunsaturated side chain and includes 12 stereogenic centers.
Recently, we proposed a full stereochemical assignment, as
indicated in 1 for etnangien (Scheme 1), by extensive high-field
NMR experiments, molecular modeling, chemical derivatization,
and bioinformatics analysis.3 Herein, we disclose the first total
synthesis of etnangien and establish unequivocally its relative and
absolute configuration.
convergent, and stereocontrolled and thus offers the potential to
provide a range of structural derivatives for SAR studies to further
explore the biological potential of this promising macrolide
antibiotic.
As shown in Scheme 2, our synthesis of C32-C42 subunit 2
utilizes a tin-mediated aldol reaction4 of ethyl ketone 65 with Roche
ester derived aldehyde 5, to give the expected (1,4)-syn-product 7
with high levels of stereocontrol and yield. Subsequent (1,3)-syn
reduction of the hindered ꢀ-hdydroxyketone 7 was efficiently
accomplished after chelation [(cHex)2BCl/LiBH4] (dr > 20:1). After
acetonide protection of the derived diol and selective removal of
the primary TBS group (TBAF), the required C2 homologation to
9 was enabled by nucleophilic substitution of the derived tosylate
with sodium acetylide. Completion of the synthesis of 2 proceeded
smoothly by PMB deprotection, oxidation to the acid, and Lindlar
reduction of the alkyne.
Scheme 2. Synthesis of the C32-C42 Subunit 2
Scheme 1. Retrosynthetic Analysis of Etnangien
As shown in Scheme 3, construction of the C15-C31 subunit 4
commenced with known diene 12, prepared by an optimized route
from 10 and 11.6 The derived aldehyde 13 was homologated to
antialdol 15 with high diastereoselectivity (dr > 20:1) and yield
(97%) by a boron-mediated Paterson aldol reaction7 with lactate
derived ethyl-ketone 14. For conversion to methyl ketone 16
(5 steps, 74%) use of Pb(OAc)4 for diol cleavage was critical to
avoid deprotection of the primary TBS group. The aldehyde
coupling partner 19 was obtained in six steps (69%) from epoxide
17, readily available by Jacobsen HKR methodology.8 Introduction
of the required terminal Z-vinyl iodide proceeded with excellent
selectivity (dr ) 27:1) optimizing a general Wittig-Stork-Zhao
olefination protocol.9 Finally, the pivotal aldol coupling of 16 with
19 to install the center at C24 with the desired configuration
proceeded with high diastereoselectivity and yield (dr 14:1, 77%)
by an Ipc-boron mediated aldol coupling. Subsequent 1,3-anti
reduction of the derived hydroxyl ketone 20 with the Evans-Carreira
protocol10 and protection of the less hindered 24-OH gave building
block 4 in good yields (71%).
As outlined retrosynthetically in Scheme 1, our synthetic
approach was based on a late-stage introduction of the side chain
3 by a cross-coupling strategy. The macrocyclic core, in turn, was
envisioned to arise from building blocks 2 and 4, which should be
forged by an esterification and a Heck coupling to deliver the
30Z,32E-diene. In principle, both methodologies may be employed
for ring closure, thus offering considerable flexibility in the
synthesis. Notably, an acetonide protective group was chosen for
OH-36 and -38 to induce a conformational bias for macrocyclization
by mimicking the solution conformation of etnangien.3 Importantly,
the modular synthetic approach employed is flexible, highly
† Universita¨t Heidelberg.
‡ Helmholtz-Zentrum fu¨r Infektionsforschung.
§ Present address: Institut f. Pharmazeut. Wissenschaften, ETH Zu¨rich.
| Present address: ABX GmbH, Radeberg.
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11678 J. AM. CHEM. SOC. 2009, 131, 11678–11679
10.1021/ja9056163 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
tions (65%-HOAc). At last, enzyme catalyzed ester cleavage3 gave
etnangien (1) which was identical to an authentic sample (1H, 13C
NMR, optical rotation),1 thus allowing confident assignment of the
relative and absolute configuration and validating our earlier
proposal.3
Scheme 3. Preparation of the C15-C31 Subunit 4
Scheme 5. Completion of the Synthesis
As shown in Scheme 4, our synthesis of the side chain fragment
3 was based on a Brown allylation of readily available aldehyde
21 to give after TBS protection homoallylether 22. After conversion
to methylester 23, homologation to enal 24 proceeded smoothly
by cross metathesis in the presence of Grubbs(II) catalyst. Finally,
the required stannane was introduced by HWE reaction with 2511
to give after deprotection the desired building block 3.
In conclusion, this first total synthesis of etnangien proceeds in
23 steps (longest linear sequence) and 0.25% yield and establishes
unequivocally the relative and absolute configuration. Notable
features include highly stereoselective aldol reactions, an efficient
conformation controlled Heck macrocyclization, and a late-stage
introduction of the labile side chain. Importantly, the modular
synthesis should be amenable to designed analogues of this novel
RNA-polymerase inhibitor, thus enabling further exploration of the
promising biological potential of this macrolide antibiotic.
Scheme 4. Assembly of the C1-C13 Subunit 3
Acknowledgment. We thank the DFG, the “Fonds der Chemis-
chen Industrie”, and “Wild-Stiftung” for generous funding and Bjo¨rn
Wiegmann for technical support. Excellent NMR assistance by Markus
Enders and Beate Termin is most gratefully acknowledged.
Supporting Information Available: Experimental procedures,
1
characterization data and H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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To install the labile side chain in a late stage of the synthesis,
our strategy for fragment union relied on first closing the macro-
cyclic core (Scheme 5). After esterification of 2 and 4 by means of
the Yamaguchi protocol (97%), Heck macrocyclization proceeded
with excellent yield and diastereoselectivity (70%, E/Z > 20:1)
validating our protective group strategy.12 After selective removal
of the primary TBS group (HOAc) and allylic oxidation, the
required E-vinyl iodide was introduced by a Takai reaction (92%,
E/Z ) 4:1). Global deprotection of the macrocyclic core proved
challenging, due to a pronounced and unexpected1,3 tendency for
trans-lactonization, δ-lactone formation with the 38-OH, steric
hindrance of the 20-OTBS, and general base and acid sensitivity
of the substrate. Finally, the strategy involved first removing all
TBS groups (TBAF), attachment of the side chain by Stille coupling,
and subsequent acetonid cleavage under only mildly acidic condi-
(11) Smith, A. B., III.; Wan, Z. J. Org. Chem. 2000, 65, 3738.
(12) In contrast, intermolecular coupling resulted in E/Z mixtures confirming
the importance of conformational restraint. See also: Menche, D.; Hassfeld,
J.; Li, J.; Rudolph, S. J. Am. Chem. Soc. 2007, 129, 6100.
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