Total synthesis of (+)-cis-sylvaticin: Double oxidative cyclization reactions catalyzed by osmium

Article abstract of DOI:10.1021/ja0660148

The double oxidative cyclization of dienes is a viable procedure for making complex natural products containing cis-THF units. A double deprotection/double oxidative cyclization strategy using catalytic osmium tetroxide was used to construct the bishetero

Full text of DOI:10.1021/ja0660148

Published on Web 10/04/2006
Total Synthesis of (+)-cis-Sylvaticin: Double Oxidative Cyclization Reactions
Catalyzed by Osmium
Timothy J. Donohoe,*,† Robert M. Harris,† Jeremy Burrows,‡ and Jeremy Parker§
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford, OX1 3TA, U.K., AstraZeneca Pharmaceuticals, Department of Medicinal Chemistry R&D,
So¨derta¨lje, S-151 85, Sweden, and AstraZeneca, Process R&D AVlon/Charnwood, AVlon Works,
SeVern Road, Hallen, Bristol, BS10 7ZE, U.K.
Received August 18, 2006; E-mail: timothy.donohoe@chem.ox.ac.uk
Scheme 1
The annonaceous acetogenins are a burgeoning class of natural
products that are of interest because of their wide-ranging biological
activities.1 Examples containing multiple tetrahydrofuran (THF)
rings are of particular appeal because of the challenges that they
pose for synthetic organic chemistry. Within this class of natural
product, those containing nonadjacent THF rings are much less
commonly studied and only the squamostatins2 (C and D) and
gigantecins3 (both containing only nonadjacent trans disposed THF
rings) have been synthesized.
cis-Sylvaticin 1, isolated in 1995 from the leaf extracts of Rollinia
mucosa (Jacq.) Baill, is an interesting natural product with
nonadjacent THF rings (both cis, Scheme 1).4 This compound has
not yet been synthesized although the structure was assigned by a
Scheme 2
comprehensive NMR study by McLaughlin.4 cis-Sylvaticin displays
potent activity as an antitumor agent and exhibits nanomolar
cytotoxicity toward human solid tumor cell lines: its mode of action
is thought to include inhibition of ATP production via blockage of
mitochondrial complex I.
Our synthetic strategy for this target was to divide the molecule
into two sections, Scheme 1. The right-hand side containing the
butenolide and alkyl chain was to be prepared separately and joined
to the main fragment (containing two THF rings) by cross
metathesis. The remainder of the molecule would be constructed
by double oxidative cyclization on acyclic precursor 2. This key
oxidative cyclization to form two THF rings is based upon
methodology that we have reported recently and should proceed
with reliable stereospecificity (syn addition across a pendant alkene)
and stereoselectivity (cis-2,5-THFs are formed).5 The notion of a
double oxidative cyclization to form two rings in one reaction would
present a serious test of this new method.
The synthesis began with commercial tetradecatetraene 3,
Scheme 2. This compound was available as a mixture of the
three possible geometric isomers which could be separated by
chromatography on silica gel doped with AgNO3. Oxidation of
the pure EE isomer under AD conditions gave a tetraol which
was immediately converted into bisacetonide 4 in 37% overall
the mixture, but this reaction could be run easily on a multigram
scale.
yield.6 The outcome of the AD reaction has its origins in the
preferential oxidation of 1,2-trans-alkenes over monosubstituted
Our next task was to cleave one alkene unit within 4 in the
alkenes.7 This success led us to perform the AD reaction on
presence of another, which was difficult because they are homo-
the commercially available mixture of tetraenes, in the know-
topic. Eventually, oxidation under AD conditions gave 59% of diol
ledge that cis-alkenes are dihydroxylated approximately 11 times
6 and 31% of tetraol 5, Scheme 2. The undesired tetraol 5 was
slower than trans-alkenes.7 In this case we were able to form
recycled back into 4 by double oxidative cleavage and methylena-
tion. Meanwhile, diol 6 was cleaved and olefinated to give Z-7 in
the desired tetraol with reasonable selectivity (although the
compound could not be fully purified until it was derivatized as
81% yield. The key double oxidative cyclization was then attempted
bisacetonide 4). The yield for the two steps to 4 was 18% from
on bisacetonide 7, in the hope that in situ double deprotection would
occur allowing cyclization to take place. Pleasingly, bis-THF 8
† University of Oxford.
formed in 77% yield and as a single diastereoisomer.5 Subsequently,
‡ AstraZeneca Pharmaceuticals.
§ AstraZeneca.
the bis-THF was prepared for cross metathesis by global protection
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J. AM. CHEM. SOC. 2006, 128, 13704-13705
10.1021/ja0660148 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
Scheme 5
Scheme 6
compound 14 also had NMR spectra that matched the synthetic
and natural product data exactly.10 However, preparation of both
(R)- and (S)-tetra-Mosher’s ester derivatives of 14 and comparison
with literature values confirmed that neither it nor its enantiomer
was the natural product. Conversely, the tetra-(R) and tetra-(S)
Mosher’s ester derivatives of 1 exhibited NMR data that matched
that reported in ref 4.
To conclude we have reported the first total synthesis of the
natural product cis-sylvaticin in a route that is exceptionally concise
(13 linear steps and 19 chemical operations in total). The key step
in our synthesis was a novel double oxidative cyclization of a tetraol
onto two pendant alkene units; this was promoted by catalytic
amounts of osmium and the reaction gave complete stereoselectivity
and stereospecificity for the double THF product.
Acknowledgment. We thank the EPSRC and AstraZeneca for
supporting this project. Merck, AstraZeneca, Pfizer, and Novartis
are thanked for unrestricted funding. N. Wagner is thanked for
assistance and J. L. McLaughlin is thanked for providing copies of
the NMR spectra of cis-sylvaticin.
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Barrachina, I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
For recent examples of syntheses see (b) Marshall, J. A.; Sabatini, J. J.
Org. Lett. 2006, 8, 3557. (c) Narayan, R. S.; Borhan, B. J. Org Chem.
2006, 71, 1416. (d) Tominaga, H.; Maezaki, N.; Yanai, M.; Kojima, N.;
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44, 4766. A sacrificial alkene is added to these cyclizations to dihydroxy-
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polar and easy to separate. See also (b) Walba, D. M.; Stoudt, G.
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We devised a computer programme which predicted that the maximum
yield attainable for double dihydroxylation of the two internal alkenes of
E,E-3 was 45%, which is close to our best yield of 37%. This model
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lack of cooperative effects upon rates after a single dihydroxylation.
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and selective deprotection 9, followed by oxidation and olefination
to furnish 10, Scheme 3.
The butenolide fragment of the target was prepared according
to the work of Lee, which transformed (R)-epichlorohydrin into
compound 11 in four steps, Scheme 4.8 After synthesizing 11, we
prepared 12 for cross-metathesis by introducing the butenolide
(thermal elimination) and deprotection of the OTBS group.
The union of the two halves was accomplished by a cross
metathesis reaction between 10 and 12, Scheme 5.9 Following the
work of Lee,8 we required a 4-fold excess of compound 12 to
eradicate homodimerization of bis-THF 10 (at the expense of
homodimerization of 12). Here, our rationale for early removal of
the TBS group from 11 becomes clear, because the homodimer of
12 is more polar than the desired compound 13 and thus easy to
separate. In addition, the dimerized derivative of 12 can be reused
in the cross-metathesis reaction to give 13 in 54% yield.
The synthesis was completed by a diimide reduction of the more
symmetrical alkene within 13 and acid promoted deprotection of
the three OTBS groups, to furnish cis-sylvaticin 1 in 69% yield
from 13. The synthetic material had spectroscopic data (1H and
13C NMR, [R]D, HRMS) identical to that reported.4
As part of final studies to confirm the structure of the natural
product and relate the stereochemistry of the bis-THF portion to
that of the butenolide, we prepared a series of diastereoisomers of
the structure 1, varying stereochemistry of the butenolide at both
C-4 and C-36, Scheme 6.10 Of the four possible stereoisomers,
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