Formal total synthesis of spirangien A

Article abstract of DOI:10.1021/ol3033253

A formal total synthesis of the spiroketal containing cytotoxic myxobacteria metabolite spirangien A (1) is described. The approach utilizes a late introduction of the C20 alcohol that mirrors the biosynthesis of this compound. The key steps involved a hi

Full text of DOI:10.1021/ol3033253

ORGANIC
LETTERS
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Formal Total Synthesis of Spirangien A
Claire Gregg, Christian Gunawan, Audrey Wai Yi Ng, Samantha Wimala,
Sonali Wickremasinghe, and Mark A. Rizzacasa*
School of Chemistry, The Bio21 Institute, The University of Melbourne, Victoria 3010, Australia
masr@unimelb.edu.au
Received December 4, 2012
ABSTRACT
A formal total synthesis of the spiroketal containing cytotoxic myxobacteria metabolite spirangien A (1) is described. The approach utilizes a late
introduction of the C20 alcohol that mirrors the biosynthesis of this compound. The key steps involved a high yielding cross metathesis reaction
between enone 6 and alkene 7 to give E-enone 4 and a Mn-catalyzed conjugate reduction R-oxidation reaction to introduce the C20 hydroxyl group.
Acid treatment of the R-hydroxyketone 4 gave spiroketal 19 which was converted into known spirangien A (1) advanced intermediate spiroketal 3.
The cytotoxic spiroketals spirangiens A (1) and B (2)
were isolated from the myxobacterium Sorangium cellulo-
sum (Figure 1).1 These natural products contain a highly
substituted spiroketal core and labile Z,E,Z,E,Z-penatene
side chain and differ only at the C31 position, whereby 1
has a methyl group at this position while 2 terminates in
an ethyl group. The structures of these compounds were
deduced by NMR techniques and X-ray crystallographic
analysis of a cross metathesis degradation product.1
Spirangien A (1) showed activity against several yeasts
and fungi and displayed very potent cytotoxicity against
This was based on analysis of extracts from several mutant
strains of S. cellulosum whereby the genes that encode for
the P450 enzymes SpiC and SpiL were inactivated. Both
these monooxygenases are involved with the C20 and C21
oxidation of a PKS spiroketal precusor A to produce
hydoxyketone B that cyclizes to the spiroketal core C of
the spirangiens. Although the exact role of each was not
determined, it appears that the oxidative modification and
spiroketal formation mediated by these enzymes occur
after release from the multienzyme complex.5
L929 mouse fibroblast cells with an IC50 = 0.7 ng mLꢀ1
.
To date, only one total synthesis of spirangien A (1) has
been reported,2 and this served to confirm the absolute
configuration of this compound. Several syntheses of the
cross metathesis degradation product3 and the core
spiroketal4 have also been communicated.
It has been demonstrated that the biosynthesis of spir-
angien A (1) involves several post-polyketide synthase
(PKS) P450 mediated late stage oxidations (Scheme 1).5
€
(1) Niggeman, J. N.; Bedorf, N.; Florke, U.; Steinmetz, H.; Gerth,
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K.; Reichenbach, H.; Hofle Eur. J. Org. Chem. 2005, 5013.
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Figure 1. Structures of the spirangiens A (1) and B (2).
ꢀ
ꢀ
€
(5) Frank, B.; Knauber, J.; Steinmetz, H.; Scharfe, M.; Blocker, H.;
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r
10.1021/ol3033253
XXXX American Chemical Society

We envisaged that an efficient synthesis of the spiran-
giens could be based on a late stage C20 oxidation as
proposed in the biosynthesis. However, an effective direct
conversion of a polyketide such as A into B using non-
enzymatic reagents would be challenging. As shown in
Scheme 2, an alternative introduction of the C20 hydroxyl
group is presented. The final target was the spirangien
advanced intemediate spiroketal alcohol 3, utilized by
Paterson et al. in their total synthesis of 1.2 This compound
could be formed by spiroketalization of the protected
hydroxyketone precursor 4 followed by a late-stage iron-
catalyzed alkylation4,6 to introduce the trisubstituted alkene.
Hydroxyketone 4 would then arise from a one-pot Mn-
catalyzed conjugate reduction/oxidation7,8 or regioselective
hydration of enone 5 mimicking the post-PKS introduction
of the C20 hydroxyl group in the proposed biosynthesis.
Scheme 2. Retrosynthetic Analysis of Spirangien A (1)
Scheme 1. Biosynthesis of the Spirangien Spiroketal
Enone 5 would be accessed by a cross metathesis (CM)9
between enone 6 and alkene fragment 7 that would serve
as an effective method for the key convergent CꢀC bond
forming step between two large fragments. This differs
from the reported approaches to related R-hydroxyketone
spiroketal precursors in that all rely on a late-stage aldol
condensation to form the C22ꢀC23 bond as the conver-
gent step.2ꢀ4,10 The key stereoselective CꢀC bond forming
steps for the synthesis of enone 6 include anti-propionate
and acetate aldol reactions while 7 could be formed via a
syn-aldol reaction as shown.
Scheme 3. Synthesis of the Enone Fragment 6
The synthesis of the enone fragment 6 is detailed in
Scheme 3 and begins with the known stereopentad alcohol
8,11 secured by an anti-aldol reaction, stereoselective re-
duction, hydroboration, and protection.2 Oxidation of
alcohol 8 gave the corresponding aldehyde which was
immediately subjectedtoa Nagao-type asymmetricacetate
ꢀ
(6) (a) Guerinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed.
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2007, 46, 6521. (b) Reymond, S.; Ferrie, L.; Guerinot, A.; Capdevielle,
P.; Cossy, J. Pure Appl. Chem. 2008, 80, 1665.
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aldol reaction12 with the Sn(II) enolate derived from
thiazolidine-2-thione 912b to provide adduct 10 as the only
detectable diastereoisomer. Auxiliary displacement13 with
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B
Org. Lett., Vol. XX, No. XX, XXXX

O,N-dimethylhydroxylamine and imidazole as base af-
forded the Weinreb amide 11, and subsequent methylation
of the free alcohol gave the ether 12 in high yield. The enone
6 was then formed in 98% yield by treatment of amide 15
with vinyl magnesium bromide.
Scheme 5. Synthesis of the R-Hydroxyketone 4
Scheme 4. Synthesis of the Alkene 7
The CM reaction21 between enone 6 and alkene 7 was
best mediated by the GrelaꢀGrubbsꢀHoveyda catalyst
1822 (Scheme 5). E-Enone 5 was formed in high yield as a
single geometric isomer using 12 mol % of 18. Hydration
of enone 5 by treatment with Ph3SiH and oxygen gas in the
presence the Tris-(dipivaloylmethanato)manganese(III)
{Mn(dpm)3} catalyst8a afforded the R-hydroxyketones 4
and the C20 epimer 4a in a 1:1 ratio after reductive workup
with P(OEt)3.23 These could be separated by preparative
HPLC, and their stereochemistry was assigned by conver-
sion to the corresponding spiroketals (see below). The mech-
anism of this interesting transformation possibly involves
formation of a Mn(II) hydride complex that reduces the
enone 5into a Mn enolate.8a Oxidation of the Mn(II) enolate
by O2 gives a Mn(III) peroxy complex which oxidizes the
enolate to a hydroperoxide. P(OEt)3 mediated reduction
then gives the R-hydroxyketone.
Treatment of R-hydroxyketone 4 with CSA in methanol
for 24 h resulted in deprotection and spirocyclization to
give spiroketal 19 as a single isomer in good yield (Scheme 6).
This reaction initially forms two products that eventually
equilibrate to a single compound, and at least 0.5 equiv of
CSA was required for the reaction to proceed at a reason-
ablerate. Similarly, exposureof 4atoanacidresultedinthe
formation spiroketal 20. Highly selective monoacetylation
of each of these was achieved by treatment with acetic
anhydride and pyridine to provide the C20 monoacetates
21 and 22. 1H NMR coupling constants then revealed the
The synthesis of the alkene fragment 7 began with the
preparation of diol 15by a modified route tothat described
for the synthesis of the enantiomer14 (Scheme 4). A syn-
aldol reaction15 between the Sn enolate derived from
ketone 1316 and methacrolein gave adduct 1416 in ex-
cellent yield and high diastereoselectivity. A Ti-mediated
syn-aldol reaction17 also provided 14 with a lower diaste-
reoselectivity (88%), but this was a more economical
process. EvansꢀTishchenko reduction18 of the ketone 14
followed by base hydrolysis gave the 1,3-anti-diol 15, again
with high diastereoselectivity, which was protected as
the acetonide 16. 13C NMR analysis19 confirmed that 16
possessed the desired 1,3-anti diol stereochemistry with
significant chemical shifts for the methyl groups and
acetonide carbon atom as shown in Scheme 4. Installation
of the final stereocenter was achieved by stereoselective
hydroboration20 of the 1,1-disubstituted alkene in 16 using
9-BBN followed by basic oxidative workup to give the
alcohol 17 in reasonable diastereoselectivity. Oxidation
and Wittig extension then gave the alkene fragment 7.
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 6. Spiroketal Synthesis
Scheme 7. Completion of the Formal Total Synthesis of 1
C20 stereochemistry of each as shown, and this allowed
for the assignment of the original stereochemistry of the
hydroxyketone precursors. Acid treatment of the 1:1 mix-
ture of 4 and 4a also gave the spiroketals 19 and 20 that
were easily separated by flash chromatography.
In conclusion, we have completed a formal total synthe-
sis of spirangien A (1) by the production of the known
intermediate spiroketal 3. The key transformations in the
sequence include a highly convergent CM reaction to unite
the enone 6 and alkene 7, a Mn(III)-catalyzed conjugate
reduction/oxidation sequence to introduce the C20 hydro-
xyl group at a late stage as a mimick of the biosynthesis
of spirangien A (1), acid induced spiroketalization, and
a Fe(III)-catalyzed alkylation. The synthesis of related
S. cellulosum metabolites25 using this approach is underway.
The synthesis of spirangien advanced intermediate spiro-
ketal3isshowninScheme7. Protectionofthe2° alcohols in
spiroketal 19 at TES ethers followed by removal of the
PMB ether afforded alcohol 23. Conversion into the iodide
24 was achieved by exposure of 23 to iodine, PPh3, NEt3,
and imidazole. Iodide 24 was then alkylated by a Fe(III)-
mediated cross-coupling6 with the Grignard reagent de-
rived from E-2-bromobutene to give alkene 25 in good
yield. Removal of the benzyl ether using LiDBB24 at rt then
yielded the final target alcohol 3, the physical data of which
Acknowledgment. We thank the University of Melbourne
Research Grants Support Scheme for financial support.
were identical to those reported2b {[R]22 þ19.2 (c 0.7,
D
MeOH); lit.2b [R]20D þ17.5 (c1.5,MeOH)} thuscompleting
Supporting Information Available. Experimental details
as well as characterization data and copies of the NMR
spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
a formal total synthesis of spirangien A (1).
(24) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(25) (a) Ahn, J.-W. Bull. Korean Chem. Soc. 2009, 30, 742. (b) Kwak,
J. H.; Ahn, J.-W. Arch. Pharm. Res. 2009, 32, 841. (c) Ahn, J. W. Bull.
Korean Chem. Soc. 2009, 30, 1218.
The authors declare no competing financial interest.
D
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