On the proposed structures and stereocontrolled synthesis of the cephalosporolides

Article abstract of DOI:10.3762/bjoc.8.146

The synthesis of four candidate stereoisomers of cephalosporolide H is described, made possible by a zinc-chelation strategy for controlling the stereochemistry of oxygenated 5,5-spiroketals. The same strategy likewise enables the first stereocontrolled synthesis of cephalosporolide E, which is typically isolated and prepared admixed with its spiroketal epimer, cephalosporolide F.

Full text of DOI:10.3762/bjoc.8.146

On the proposed structures and stereocontrolled
synthesis of the cephalosporolides
Sami F. Tlais and Gregory B. Dudley*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1287–1292.
Department of Chemistry and Biochemistry, Florida State University,
Tallahassee, FL 32306-4390 USA, Fax: (850) 644-8281
doi:10.3762/bjoc.8.146
Received: 19 April 2012
Accepted: 14 July 2012
Published: 14 August 2012
Email:
Gregory B. Dudley* - gdudley@chem.fsu.edu
* Corresponding author
Associate Editor: S. Bräse
Keywords:
© 2012 Tlais and Dudley; licensee Beilstein-Institut.
License and terms: see end of document.
cephalosporolides; chelation; spiroketals; stereocontrol; zinc chloride
Abstract
The synthesis of four candidate stereoisomers of cephalosporolide H is described, made possible by a zinc-chelation strategy for
controlling the stereochemistry of oxygenated 5,5-spiroketals. The same strategy likewise enables the first stereocontrolled
synthesis of cephalosporolide E, which is typically isolated and prepared admixed with its spiroketal epimer, cephalosporolide F.
Introduction
The spiroketal moiety is common in natural products of marine, Byers et al showed that the spiroketal (2R,5R)-isomer induces
plant, insect, and bacterial origins [1-11]. The rigidity of the the strongest responses from both females and males [16]. In
spiroketal provides defined orientation of pendant functional such cases it is interesting to conjecture that the natural
groups, and there is a strong correlation between bioactivity and pheromone signal may include a “time stamp”: release of a
spiroketal stereochemistry in many natural spiroketals. For stereodefined, nonthermodynamic and labile spiroketal enables
example, cephalostatin and ritterazine feature thermodynami- the detecting insect to gauge the age of the message based on
cally disfavored spiroketals that are more cytotoxic than their the integrity of the spiroketal center. To duplicate such commu-
stereoisomers [12]. Other prominent cytotoxic spiroketals nication (e.g., for insect population control) requires the ability
include spongistatin [7] and norhalichondrin [13,14].
to prepare specific spiroketal stereoisomers. Anomeric effects
typically guide the stereochemical preferences in 6,6 and 5,6-
Spiroketal-containing pheromones are especially prominent in spiroketals [7,17-20], whereas 5,5-spiroketal stereochemistry is
insect communication, with the spiroketal stereochemistry often more difficult to predict [21] and control [22-25].
relaying important information [15]. For example, the R-enan-
tiomer of the olive-fly sex pheromone is attractive to males, This report focuses on 5,5-spiroketal lactones of the
while the S-enantiomer attracts females (Figure 1). Chalcogran, cephalosporolide and related families (Figure 2) [26,27].
a sex pheromone secreted by the male bark beetle, is isolated Cephalosporolides E and F are co-isolated as a mixture, and
from natural sources as a mixture of diastereomers. However, previous syntheses likewise produce these compounds as a mix-
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Beilstein J. Org. Chem. 2012, 8, 1287–1292.
Figure 1: Pheromone spiroketals.
Figure 2: Reported structures of the cephalosporolides and penisporolides.
ture in the absence of methods to control the spiro-center [28- Here, we report the synthesis of all four possible diastereomers
30]. However, it is quite possible that the microorganism with respect to C9 and the spiroketal center (C6). Data from this
produces one or the other of these isomers selectively, and that study allows us to comment on the proposed structure for
this material scrambles over time to a thermodynamic mixture. cephalosporolide H and, by analogy, cephalosporolide I and the
It is this mixture that is ultimately extracted, and if this conjec- penisporolides. Expanding on the zinc chelation method,
ture is true, then the natural extract (mixture) would misrepre- we investigated a new approach to the synthesis of
sent the compound as used in the biological system. cephalosporolide E, which resulted in the first stereocontrolled
Cephalosporolide H, I, and the penisporolides, on the other assembly of this spiroketal core.
hand, were isolated as single isomers [31]. The structures of
these related spiroketals were tentatively proposed based on Our synthesis of the reported structure of cephalosporolide H
NOESY experiments, and by analogy to each other and to the (1) and its spiroketal isomer (1b) are outlined in Scheme 2. The
confirmed structures of cephalosporolide E and F.
synthesis starts from D-pantolactone (4), which was converted
into terminal alkyne 5 [32]. Alkyne 5 was coupled with (R)-1,2-
epoxynonane to obtain internal alkyne 6, which was submitted
Results and Discussion
We recently reported the stereocontrolled synthesis of to gold-catalyzed cycloisomerization [33] to afford spiroketals
cephalosporolide H (reported structure) and its spiroketal 7a and 7b (the silyl ether is concomitantly hydrolyzed) as a 1:1
isomer [32]. Our strategy featured the use of zinc salts to mixture of isomers. Exposure of this mixture to zinc chloride
control the spiro-center using either steric biases or chelation, promoted isomerization to provide 7a in >20:1 dr. TEMPO oxi-
depending on pendant functionality (Scheme 1). Unfortunately, dation then completed the synthesis of 1, the reported structure
neither of the synthetic isomers provided data in complete of cephalosporolide H. The opposite spiroketal isomer 1a was
agreement with data reported for the natural material.
prepared from 6 by palladium-catalyzed cycloisomerization
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Beilstein J. Org. Chem. 2012, 8, 1287–1292.
Scheme 1: Stereocontrol of oxygenated 5,5-spiroketals.
Scheme 2: Synthesis of the reported cephalosporolide H and its spiro isomer.
(steric control), desilylation and TEMPO oxidation. In neither converted to 10a in 15:1 dr by zinc-catalyzed isomerization.
case did the characterization data match that of the natural Both isomers (10a and 10b) were independently subjected to
material, and it is worth noting that NOE and NOESY TEMPO oxidation to afford spiroketal lactones 1b and 1c.
experiments conducted on both isomers were inconclusive in Spectroscopic data of 1b and 1c were similar to 1a and 1,
attempts to differentiate them: similar NOESY cross-peaks respectively.
were observed from both isomers.
Attempts to secure an authentic sample and/or copies of orig-
We prepared the two remaining core diastereomers by similar inal NMR spectra for the natural material were unsuccessful,
routes (Scheme 3), starting by coupling terminal alkyne 5 with but two candidates emerged as good fits to the reported data
(S)-1,2 epoxynonane. Gold-catalyzed cycloisomerization (with (Figure 3). Spectroscopic data for 1a and 1b were both nearly
desilylation) provided spiroketal diols 10a and 10b in a 32:68 consistent with the data reported for cephalosporolide H,
ratio and in 89% total yield. Major spiroketal 10b could be whereas data for 1 and 1c did not match (see Supporting Infor-
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Beilstein J. Org. Chem. 2012, 8, 1287–1292.
Scheme 3: Synthesis of the reported C9-epi-cephalosporolide H and its spiro isomer.
Figure 3: Reported and synthesized cephalosporolide H isomers.
mation File 1, Table S1 for a full comparison). In the absence of Cephalosporolide E was isolated (and has been prepared [28])
an authentic sample, a definitive assignment will not be admixed with cephalosporolide F, whereas cephalosporolide H
possible, although we note that the relative stereochemistry of was isolated as single isomer. (2) Cephalosporolide E (and F)
1b corresponds to that of cephalosporolide F, the structure of has a C2 methylene; C2 of cephalosporolide H is quaternary.
which has been confirmed.
(3) Cephalosporolide E (and F) has a methyl group at C9, as
opposed to the n-heptyl chain in cephalosporolide H.
A central feature of this study is our ability to prepare the four
diastereomers selectively. Specifically, we found that chelation Synthesis of cephalosporolide E started with the known alcohol
of zinc salts between the spiroketal oxygen and appropriately 12, which was prepared from the commercially available diester
positioned hydroxyls overrides normal steric biases to guide the 11 (Scheme 4) [34]. PMB protection of alcohol 12 followed by
formation of the spiroketal. Cephalosporolide E was targeted Sharpless dihydroxylation afforded diol 14 [35,36]. DDQ oxi-
for validation of this approach. There are three main differ- dation of PMB ether produced 1,3-dioxane 15 [37]. Protecting
ences between cephalosporolides E and H (Figure 2): (1) group manipulation led to the formation of primary alcohol 17
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Beilstein J. Org. Chem. 2012, 8, 1287–1292.
Scheme 4: Synthesis of homopropargyl silyl ether.
[38], which was converted into homopropargyl silyl ether 19 (2, admixed with a minor diastereomer tracing back to the
over two steps, i.e., DMP oxidation and subsequent Ohira–Best- Sharpless dihydroxylation reaction). Spectroscopic data for our
mann ethynylation [39].
synthetic material was in full agreement with the reported data
for cephalosporolide E [28-30].
Coupling of the propargyl silyl ether 19 with the (R)-propylene
oxide produced the internal alkyne 20 (Scheme 5). Gold(I) chlo- Conclusion
ride in MeOH induced the spiroketalization of alkyne 20 with We have completed the stereocontrolled synthesis of the
concomitant cleavage of the PMP acetal and partial cleavage of reported structure of cephalosporolide H and three diastereoiso-
the TBS ether. After completion of the desilylation with TBAF, mers, leading us to suggest a potential structure for natural
a mixture of 5,5-spiroketals 21a and 21b was obtained in 71% cephalosporolide H (i.e., 1b, or perhaps 1a). Chelation by using
overall yield from 20. The mixture of diols 21a and 21b zinc chloride plays a key role in accessing the otherwise contra-
converged to 21a (epimer 21b no longer observable by thermodynamic spiroketal stereoisomers. This strategy was
1H NMR) upon treatment with zinc chloride. TEMPO oxi- expanded to enable synthetic production of cephalosporolide E
dation of diol 21a led to the formation of cephalosporolide E for the first time in a stereocontrolled manner.
Scheme 5: Synthesis of cephalosporolide E.
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Supporting Information File 1
General experimental procedures, experimental and
characterization data for new compounds, copies of NMR
spectra, and comparison of characterization data reported
for cephalosporolide H and obtained for the four synthetic
diastereomers reported here.
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