Total synthesis of the antibiotic Elansolid B1

Article abstract of DOI:10.1021/ol403441c

The antibiotic elansolid B1 was prepared by a convergent strategy that relied on a highly diastereoselective, biomimetic intramolecular Diels-Alder cycloaddition (IMDA) that furnished the tetrahydroindane unit. Other key features are a double Sonogashira cross-coupling and a substratecontrolled Yamamoto aldol reaction.

Full text of DOI:10.1021/ol403441c

Letter
pubs.acs.org/OrgLett
Total Synthesis of the Antibiotic Elansolid B1
Arne Weber, Richard Dehn, Nadin Schlager, Bastian Dieter, and Andreas Kirschning*
̈
Institut fur Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universitat Hannover, Schneiderberg 1B,
̈
̈
30167 Hannover, Germany
S
* Supporting Information
ABSTRACT: The antibiotic elansolid B1 was prepared by a convergent
strategy that relied on a highly diastereoselective, biomimetic intramolecular
Diels−Alder cycloaddition (IMDA) that furnished the tetrahydroindane unit.
Other key features are a double Sonogashira cross-coupling and a substrate-
controlled Yamamoto aldol reaction.
atural products continue to be an important source of
inspiration for the development of medicines that have
the polyketide kendomycin7 in which the p-quinone methide
moiety is either stabilized by an extended conjugated system or
by electron-donating groups, features that are absent in 3.
We proposed a plausible biosynthesis that was based on
genetic analysis and preliminary synthetic model studies. The
rare p-quinone methide moiety in elansolid A3 (3) plays a key
role for the formation of all other elansolid members. Water or
methanol can add to the re face of the p-quinone methide
moiety in elansolid A3 (3) and subsequently yield the
elansolids B1 (2a) and B2 (2b). We provided evidence that
the remarkable bicyclo[4.3.0]nonane unit is formed by a unique
intramolecular Diels−Alder cycloaddition (IMDA), in which
the acyclic p-quinone methide intermediate engages the diene
system.4
Herein, we report on the first total synthesis of one of the
elansolids, elansolid B1 (2a). We devised a convergent strategy
that lays the foundation for further studies involving the
synthesis of derivatives and exploring the biosynthesis of this
unique natural product family. Our synthetic strategy follows
one key feature of elansolid biosynthesis, the IMDA, and
provides further details on the unique reactivity of the C25
carbinol carbon. Nucleophilic additions to p-quinone methides
have been previously reported;5 however, they have never been
demonstrated in such a complex context, and in the present
setting we reveal a unique case where such a reactive
intermediate is sterically stabilized and the stereoelectronic
effects that govern its reactivity. This has consequences for
biosynthesis and for the further development of reactions that
involve p-quinone methides.
N
the potential to benefit human health and quality of life. There
is a pressing need for the development of new antibiotics that
operate through a novel mechanism and can combat resistance;
indeed, most antibiotics are natural products or derivatives
thereof. The elansolids comprise the first example of
polyketides isolated from the gliding bacterium Chitinophaga
sancti (formerly Flexibacter). They show antibacterial activity
against several strains including methicillin-resistant Staph-
ylococcus aureus MRS3 (MIC 0.3 μg mL−1) and Micrococcus
luteus (MIC 4.2 μg mL−1).1,2 Their core structure is based on a
bicyclo[4.3.0]nonane unit. In the case of elansolids A1/A2 (1)
this unit is part of a 19-membered macrolactone ring. The
related seco acids elansolid B1 (2a) and elansolid B2 (2b) differ
in the moiety present at C25. By employing careful isolation
techniques the unique p-quinone methide elansolid A3 (3)
could be obtained from the same culture broth (Figure 1).2−4
This compound is key for understanding the occurrence of the
other elansolids.
The uniqueness of 3 is evident when comparing it with the
known triterpenoid celastrol,5 the diterpenoid taxodone,6 and
Retrosynthetically, we envisioned dissecting 2a into the
western and eastern fragments, which could be joined through a
linchpin fragment 5. Substrate 4 could be accessed through a
biomimetic Diels−Alder reaction of linear precursor 7.
Controlling the stereochemistry of the olefins should directly
Received: November 27, 2013
Figure 1. Elansolids A1/A2, B1, B2, and A3 (1, 2a−c, 3).
© XXXX American Chemical Society
A
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yield the correct relative stereochemistry found in 4. We
anticipated that the desired facial selectivity would be directed
by the C20 stereocenter.6 Interestingly, this stereocenter is
proposed to be introduced at the very end of the biosynthesis,
and thus the stereoselective outcome at the outset was
unknown. Modeling suggested that the correct facial selectivity
could be achieved through the more favorable endo transition
state TS-I (Scheme 1).7 The eastern fragment 6 could be
further disconnected via a convergent vinylogous Yamamoto
aldol reaction to give fragments 8 and 9.8−10
alkynyl substituent. The two geminal methyl groups at C-22
block the si face so that the re face is exposed to attack of
nucleophiles. This facial differentiation consequently results in
the wrong absolute configuration of the carbinol when hydride
serves as nucleophile. Hence we attempted to invert the
stereochemistry at C25 by Mitsunobu reaction on the (25S)
isomer 17 (prepared as single isomer from 15 by LiBH4
reduction) with no success. On the basis of our biosynthetic
considerations2,4 we pursued an alternative approach to invert
the stereochemistry that relied on the formation of the p-
quinone methide 19, which could be generated from (25S)-
configured phenol 18.17
Scheme 1. Retrosynthetic Strategy and Proposed endo
We tried to activate the acyl and phenol groups in 18 under
acidic or basic conditions, respectively. Once the p-quinone
methide was generated, re face attack of water would create the
correct (25R) configuration. However, we were unable to
convert (25S) 18 into the (25R) epimer under basic, acidic, or
high pressure conditions (Figure 2). Apparently, for steric
Transition States for the IMDA Cycloaddition
The starting point for this synthesis began with the synthesis
of allyl alcohol 10, prepared as described before.4 The alcohol
was converted to the corresponding aldehyde,11 and we
introduced an aryl group bearing a benzyldimethylsilyl group,
which would then be unveiled as the phenol.12 This was best
achieved by trapping of the intermediate aldehyde with the aryl
Grignard reagent 11 to give a mixture of allylbenzyl alcohols 12
(dr 1:1). A second oxidation provided the enone, which in the
presence of the mild Lewis acid MgBr2·OEt2 directly yielded
the desired IMDA product 13 via TS-I (Scheme 1) with
excellent endoselectivity in favor of the desired diastereomer
(dr ∼30:1). Subsequent cleavage of the PMB-ether provided
14.
The stereoselective reduction of the keto group turned out to
be troublesome. Common reducing agents such as NaBH4 and
LiBH4 exclusively provided (25S)-epimer 15, resulting from
hydride transfer from the re face of the carbonyl group, which
was unequivocally proven by an X-ray crystallographic analysis
with the phenol 15.13 Other efforts to reduce ketone 13, such
as dibal-H, CBS-reduction,14 glucofuranoside-borane com-
plexes,15 and the Mandyphos Ir complex,16 left the starting
material untouched. Only LiAlH4 prefentially gave the
separable (25R) epimer 4 (dr 3:1).13
Figure 2. Efforts to selectively prepare the (25R) isomer from (25S)
tetrahydroindanes 17 and 18, respectively; 3D models of ketone 14
and methide quinone 20, rationalizing the re facial selectivities of
nucleophiles at C-25.
reasons, the acetate leaving group cannot adopt a coplanar
orientation to the aromatic π-system, a stereoelectronic
requirement necessary for facile quinone methide formation.
In contrast the (25R) epimer 4 can be activated, to smoothly
yield the methoxy derivative 16 (dr ∼3:1) when exposed to
mildly acidic conditions in methanol (Scheme 2). It is
noteworthy that the diastereomeric ratio is lower after
methanol addition to the p-quinone methide intermediate 20
as compared to the analogous reactions of nucleophiles with
elansolid A3 (3).2,3
The total synthesis was finalized by C2-extension utilizing a
Sonogashira−Hagihara coupling of known alkyne 710 with the
MIDA-boronic ester 518−20 The boronate was then trans-
formed into the vinyl iodide 21 in a straightforward manner
(Scheme 3). The second Sonogashira−Hagihara reaction
between alkyne 4 and vinyl iodide 21 also proceeded smoothly
Molecular models indicate that the ketone 14 adopts a
conformation similar to that of the p-quinone methide moiety
in the simplified elansolid A3 model (20). In both cases the aryl
group is preferentially in a conformation anti to the pseudoaxial
B
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Scheme 2. Preparation of Western Fragment 4
Scheme 4. Trapping the Quinone Methide by Attack of the
Nucleophilic Solvent
unit was reduced while only one of the two alkynes were
hydrogenated. Optimization of metal alloy preparation13,24 was
crucial to obtain full conversion at room temperature. Selective
hydrogenation yield Z-E-Z triene 23 and the monohydro-
genated yne-diene 24 without affecting the C2−C5 diene
system. Compound 24 was resubjected to the reduction
conditions to provide 23. Finally, saponification of the ester
group provided elansolid B1 (2a).25 Comparison of the 1H and
13C NMR data (d6-DMSO) with those of the authentic natural
product showed a few deviations (1H: 2H, 3H, 5H; 13C: C1−
C5), which was not the case in d6-acetone. We had encountered
these deviations before, during the purification of carboxylates
by HPLC.1b It is likely due to the formation of an ammonium
salt.
Scheme 3. End Game of Elansolid B1 (2a) Synthesis
The structure of synthetic elansolid B1 (2a) was unequiv-
ocally secured after preparation of methyl ester 25, which
showed NMR data (δ, J) identical to that of the authentic
sample (obtained from the natural source).1b
At this stage we were able to prove that the stereochemistry
and conformation around C25 plays a crucial role for p-quinone
methide formation in elansolids (see 4 → 20 in Figure 2).
Likewise, the two 25-epimers, 25 and 26,26 also show this
unique difference in reactivity (Scheme 4). Removal of the
acetonide group in (25R)-25 under acidic conditions in ethanol
proceeded smoothly but exclusively yielded the (25R)
configured ethoxy product 28. Thus, the p-quinone methide
intermediate is formed and is trapped by ethanol with total
stereocontrol. When the (25S) alcohol 27 was subjected to the
same cleavage conditions, only deprotection of the acetonide
took place while the benzyl alcohol at C25 remained
untouched.
In conclusion, we accomplished the first total synthesis of a
member of the elansolid family, elansolid B1 (2a). The
synthesis is based on a biomimetic and highly stereoselective
intramolecular Diels−Alder cycloaddition. Metal-catalyzed C−
C bond formations served to assemble the precursor for the Z-
E-Z triene unit. We also revealed the stereoelectronic effects
governing the remarkable reactivity at C25 and unfolding the
role of p-quinone methide intermediates, information that is
highly relevant to elucidate the chemical details of late stage
elansolid biosynthesis.
so that acetonide removal under mild acid and aqueous
conditions provided ene-diyne 22. Aqueous conditions were
crucial to avoid side reactions of the p-quinone methide
intermediate that forms under acidic condition (see Scheme 4).
As expected, selective reduction of the alkynes proved to be
challenging.21 Use of the Lindlar catalyst failed because the
olefinic double bonds at C2−C5 were reduced prior to the
sterically more hindered alkyne at C-14−C-15. Other standard
methods such as 2-nitrobenzenesulfonyl hydrazide22 (NBSH)
or copper-NHC catalyzed reductions23 were also unsatisfactory.
The alloy Zn(Cu/Ag) was the first reagent system that
promoted the desired transformation. At elevated temperatures
we mainly isolated products in which also the C2−C5 diene
C
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(18) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716−
6717.
(19) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc.
ASSOCIATED CONTENT
* Supporting Information
■
S
Descriptions of experimental procedures for compounds and
analytical characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
2008, 130, 466−468.
(20) Use of MIDA building blocks in total syntheses: (a) Fuji, S.;
Chang, S. Y.; Burke, M. D. Angew. Chem. 2011, 123, 8008−8010;
Angew. Chem., Int. Ed. 2011, 50, 7862−7864. (b) Fijita, K.; Matsui, R.;
Suzuki, T.; Kobayashi, S. Angew. Chem. 2012, 124, 7383−7386; Angew.
Chem., Int. Ed. 2012, 51, 7271−7274.
AUTHOR INFORMATION
Corresponding Author
■
(21) Oger, C.; Balas, L.; Durand, T.; Galano, J.-M. Chem. Rev. 2013,
113, 1313−1350.
*E-mail: andreas.kirschning@oci.uni-hannover.de.
Notes
(22) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507−7507.
The authors declare no competing financial interest.
(23) Whittaker, A. M.; Lalic, G. Org. Lett. 2013, 15, 1112−1115.
(24) Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta
1987, 70, 1025−1040.
ACKNOWLEDGMENTS
■
(25) HPLC purification: column C18 ISIS-SP; eluent H2O/50 mM
NH4OAc:MeOH = 65:35 → 55:45).
(26) The 25-epimer 29 was prepared from benzyl alcohol 16 in an
The work was funded by the Deutsche Forschungsgemeinschaft
(grant Ki 379/16-1). R.D. thanks the Fonds der Chemischen
Industrie for a Ph.D. scholarship. We thank the X-ray division
(head, Dr. M. Wiebcke) at the Institute of Inorganic and
Analytical Chemistry (Leibniz University Hannover) for expert
support.
analogous fashion as described for (25R)-28.
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D
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