Total synthesis of 8-deshydroxyajudazol B

Article abstract of DOI:10.1021/ol200331u

The total synthesis of a stereoisomer of 8-deshydroxyajudazol B (4), the putative biosynthetic intermediate of the ajudazols A (1) and B (2), is described. The key steps in the synthesis included an intramolecular Diels-Alder (IMDA) reaction to secure the

Full text of DOI:10.1021/ol200331u

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1964–1967
Total Synthesis of 8-Deshydroxyajudazol B
ꢀ
Stephen Birkett, Danny Ganame, Bill C. Hawkins, Sebastien Meiries, Tim Quach, and
Mark A. Rizzacasa*
School of Chemistry, The Bio21 Institute, The University of Melbourne,
Victoria 3010, Australia
masr@unimelb.edu.au
Received February 3, 2011
ABSTRACT
The total synthesis of a stereoisomer of 8-deshydroxyajudazol B (4), the putative biosynthetic intermediate of the ajudazols A (1) and B (2), is
described. The key steps in the synthesis included an intramolecular Diels-Alder (IMDA) reaction to secure the isochromanone fragment, a novel
selective acylation/O,N-shift to give a hydroxyamide which was cyclized to the oxazole and a high yielding Sonogashira coupling to form the
C18-C19 bond. Partial alkyne reduction then afforded the target 4.
Myxobacteria are a rich source of potentially useful
secondary metabolites with about 80 different basic com-
pounds characterized so far.1 A chemical investigation of
the myxobacteriumChondromyces crocatusCmc5resulted
in the isolation of two oxazole-containing compounds
ajudazols A (1) and B (2) (Figure 1).2 The ajudazols
contain an isochroman-1-one, an oxazole, and a Z,Z,E-
triene terminating in a 3-methoxybutenamide. Ajudazol A
(1) has an exo methylene group at C15 while 2 possesses a
methyl group with unknown stereochemistry. The relative
configuration of the isochromanone core and the stereo-
chemistry of the Z,Z,E-triene were assigned from NOESY
and H-1H coupling constant analysis; however the ab-
1
Figure 1. Structures of the ajudazols A (1) and B (2) and
8-deshydroxyajudazols A (3) and B (4).
solute configuration remains to be determined.
Both ajudazols were identified as inhibitors of the
mitochondrial respiratory energy metabolism of beef heart
submitochondrial particles (SMP). NADH oxidation in
SMP was inhibited at an IC50 of 13.0 ng/mL (22.0 nM)
for ajudazol A (1) and 10.9 ng/mL (18.4 nM) for ajudazol
B (2).3
€
Muller and co-workers have proposed that the biosynth-
esis of ajudazols A (1) and B (2) involves a series of post-
PKS (PKS, polyketide synthase) P450 mediated late stage
oxidations/desaturation of the putative intermediate 8-de-
shydroxyajudazol B (4).4 This proposal was based on
analysis of extracts from C. crocatus Cm c5 mutants in
which the genes ajuI and ajuJ that encode for post-assem-
bly-line P450 enzymes were inactivated by insertional
mutagenesis. HPLC-MS analysis of the extracts from the
ajuI knockout showed the absence of ajudazol A (1) and
an increase in the production of ajudazol B (2) while the
ajuJ knockout produced neither 1 nor 2 but afforded
(1) (a) Reichenbach, H J. Ind. Microbiol. Biotechnol. 2001, 27, 149.
€
(b) Weissman, K. J.; Muller, R. Biorg. Med. Chem. Lett. 2009, 17, 2129.
€
(2) Jansen, R; Kunze, B; Reichenbach, H.; Hofle, G. Eur. J. Org.
Chem. 2002, 917.
(3) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot.
€
(4) Buntin, K.; Rachid, S.; Scharfe, M.; Blocker, H.; Weissman, K. J.;
€
2004, 57, 151.
Muller, R. Angew. Chem., Int. Ed. 2008, 47, 4595.
r
10.1021/ol200331u
Published on Web 03/16/2011
2011 American Chemical Society

Scheme 1. Proposed Biosynthesis of the Ajudazols
Scheme 2. Retrosynthetic Analysis of 8-Deshydroxyajudazol B
(4)
8-deshydroxyajudazol A (3), which was characterized by
NMR, and what was proposed to be 8-deshydroxyajudazol
B (4) by MS analysis. Close examination of the extracts
from the wild type showed the presence of all four meta-
bolites although 3 and 4 were in much smaller quantities.
Thus, the post-PKS biosynthesis begins with 8-deshydroxy-
ajudazol B (4) as shown in Scheme 1. More recently, it has
been suggested that the rare isochromanone residue is
produced by an unusual thioesterase and not a terminal
cyclase.5
Scheme 3. Proposed Modified Synthesis of 2,4-Disubstituted
Oxazoles from a Terminal Alkene
Several synthetic approaches to the polyene/oxazole
‘eastern fragment’ of the ajudazols have been reported6
along with an approach to the isochromanone fragment.7
In this paper, we report the synthesis of a stereoisomer of
the proposed intermediate trace natural product 8-deshy-
droxyajudazol B (4) which utilizes a convergent strategy
that can afford all members of this family and a modified
oxazole synthesis from a terminal alkene.
The retrosynthetic analysis of the 15R isomer of 8-de-
shydroxyajudazol B (4) is shown in Scheme 2. The keyfinal
steps are the formation of the C18-C19 bond by a
Sonogashira coupling8 between alkyne 5 and vinyl iodide
66b followed by partial reduction to secure the Z,Z-diene.
The 2,4-disubstituted oxazole in 5 could be formed by
cyclodehydration of an amide precursor synthesized from
alkene 7 and known optically pure acid R-8 or S-8.9 In this
way, either stereoisomer of 4 could be produced in an
efficient manner. The isochromanone 7 would be formed
by the intramolecular Diels-Alder (IMDA)10 reaction of
tethered dienyne 9 and subsequent aromatization, bromi-
de-oxygen exchange, and Wittig extension.
Details of the modified 2,4-disubstituted oxazole synth-
esis from a terminal alkene is shown in Scheme 3. Dihy-
droxylation of an alkene I followed by selective acylation
of the resultant primary alcohol would provide the monoe-
ster II. Mitsunobu displacement of the hydroxyl group to
give azide III and subsequent reduction to the amine along
with a base induced O,N-shift of the acyl group11 gives the
hydroxy amide IV. Oxidation and cyclodehydration using
the Wipf protocol12 would then form the desired 2,4-
disubstituted oxazole V. This proposed synthesis of the
2,4-disubstituted oxazole would circumvent the need for
production of an amino alcohol precursor. Furthermore, a
€
(5) Buntin, K.; Weissman, K. J.; Muller, R. ChemBioChem 2010, 11,
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(6) (a) Krebs, O.; Taylor, R. J. K. Org. Lett. 2005, 7, 1063. (b)
Ganame, D.; Quach, T.; Poole, C.; Rizzacasa, M. A. Tetrahedron Lett.
2007, 48, 5841.
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(8) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
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2004, 82, 1640. (b) Pettigrew, J. D.; Bexrud, J. A.; Freeman, R. P.;
Wilson, P. D. Heterocycles 2004, 62, 445.
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novsky, S. D. Org. Lett. 2003, 5, 3357. Intermolecular examples:(b)
Yang, Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602. (c)
Geng, Z.; Danishefsky, S. J. Org. Lett. 2004, 6, 413. Intermolecular
Diels-Alder isochromanone synthesis:(d) Ghosh, A. K.; Cappiello, J.
Tetrahedron Lett. 1998, 39, 8803.
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Chem. 1986, 51, 46. (b) Popsavin, M.; Torovic, L.; Svircev, M.; Kojic, V.;
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Bogdanovic, G.; Popsavin, V. Biorg. Med. Chem. Lett. 2006, 16, 2773.
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P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
Org. Lett., Vol. 13, No. 8, 2011
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Scheme 4. Synthesis of the Diels-Alder Precursor 9
Scheme 5. Diels-Alder Synthesis of the Isochromanone 7
13C label for subsequent biosynthetic studies could be
easily introduced at C5 of the oxazole by a Wittig
extension.
The synthesis of the Diels-Alder precursor began with
the known optically pure aldehyde 10 (Scheme 4).13 Wittig
olefination with the ylide derived from phosphonium salt
1114 afforded triene 12 as a 3:1 mixture favoring the E,Z-
diene. Acid induced TBS group removal and ester ex-
change with excess methyl propiolate mediated by Otera’s
catalyst15 formed ester 13. Alkyne bromination16 gave
IMDA precursor 9.
Scheme 6. Synthesis of the Oxazole Fragment 5
The IMDA reaction was effected upon heating a
dilute solution of 9 in a sealed tube at 180 °C for 24 h
(Scheme 5). Addition of DDQ caused aromatization10a
to afford the isochroman-1-one 14. The Br-O ex-
change was best achieved in a two-step sequence.
Palladium-catalyzed borylation of the bromide with
pinacol borane (15) using Buchwald’s conditions,17
followed by oxidation and hydrolysis, gave phenol 16.
Reproducible yields were only obtained when the stable
intermediate borane was purified by silica gel chroma-
tography prior to hydrolysis. Protection of the phenol
to give the PMB ether 17 proceeded in excellent yield.
Hydroboration of the alkene in 17 proved troublesome,
with BH3•Me2S or BH3•THF giving poor yields while
9-BBN failed to react, so we turned to a Rh-catalyzed
method.18 Treatment of alkene 17 with pinacol borane
(15) and Wilkinson’s catalyst followed by oxidative
workup gave primary alcohol 18 in a reproducible
yield. Oxidation and Wittig extension afforded oxazole
precursor 7.
Dihydroxylation of alkene 7 under Upjohn conditions19
gave diol 19 as a mixture of diastereoisomers which was
selectively acylated with R-acid 89 to give the hydroxy ester
20 (Scheme 6). Conversion of 20 into 21 was achieved by a
Mitsunobureaction withthe stable ZnN3•2pyr. complex.20
The azide 21 was obtained in 52% yield for the two-step
process. After some experimentation, we found that
the azide could be reduced in high yield with pro-
pane-1,3-dithiol21 and an O,N-shift was promoted by
(13) Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006,
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Fujioka, H. J. Am. Chem. Soc. 2001, 123, 3214.
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(17) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589.
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1976, 17, 1973.
1966
Org. Lett., Vol. 13, No. 8, 2011

challenging partial reduction of 24 could only be achieved
using P2-Ni in the presence of hydrogen gas and
ethylenediamine22 as was found in our earlier studies on
the eastern fragment synthesis.6b This gave the 15R dia-
stereoisomer of 8-deshydroxyajudazol B (4) in a modest
yield; however, little over-reduction occurred and un-
reacted starting enyne could be recovered from the reac-
tion by preparative HPLC. Key changes in the 1H NMR
spectrum were the shift for H19 (5.77 ppm in 24 to 6.21
ppm in 4) and the appearance of two new alkene signals for
H17and 18at5.45and6.24ppm. Synthetic4alsoshowed a
doubling/broadening of some signals in its 13C NMR
spectrum at 25 °C due to restricted rotation about the
tertiary amide.
Scheme 7. Synthesis of 8-Deshydroxyajudazol B (4)
Since no NMR data for natural 4 were available for
direct comparison, we compared the NMR spectroscopic
data for synthetic 8-deshydroxyajudazol B (4) with litera-
ture data for both ajudazol B (2) and 8-deshydroxyajuda-
zol A (3). All the key signals compared favorably with our
synthetic material supporting the assigned structure.23
In conclusion, we have completed the synthesis of the
9R,10S,15R stereoisomer of the postulated putative bio-
synthetic intermediate and trace natural product 8-deshy-
droxyajudazol B (4). Current studies toward the synthesis
of 8-deshydroxyajudazol A (3) and the ajudazols A (1) and
B (2) using this approach are underway.
triethylamine11 to give hydroxyamide 22. The hydroxya-
mide diastereoisomers were separated by flash chromato-
graphyand characterized, butfor convenience, the mixture
was subjected to Parikh-Doering oxidation and cycliza-
tionwaseffectedbytreatmentwith1,2-dibromotetrachlor-
oethane and Ph3P in the presence of hindered base 2,6-di-
tert-butyl-4-methylpyridine.12b The use of Dess-Martin
periodinane for the oxidation of alcohol 22 was less
effective.12a Dehydrohalogenation was then induced in
one pot by addition of a hindered amine base to give the
oxazole fragment 23 in good yield. The PMB group was
then removed to circumvent any problems with late stage
deprotection in the presence of the acid labile 3-methox-
ybutenamide. Exposure of 23 to camphor sulfonic acid in
methanol gave phenol 5 ready for the coupling reaction.
The Sonogashira coupling between 5 and iodide 66b was
particularly effective in forging the key C18-C19 bond
providing enyne 24 in excellent yield (Scheme 7). The
Acknowledgment. We thank the Australian Research
Council-Discovery Grants Scheme for financial support.
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.
(22) (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226. (b)
Brown, C. A.; Ahuja, V. K. J. Chem. Soc., Chem. Commun. 1973, 553.
(23) See Supporting Information for full details.
Org. Lett., Vol. 13, No. 8, 2011
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