Farinosones A-C (1-3) were isolated from the entomo-
logic fungus Paecylomyces farinosus and displayed neuri-
togenic properties in the PC-12 cellular assay.3 Farinosone
C (1) appears to be a dead-end byproduct in the pyridone
alkaloid biosynthesis of this organism.4 However, the
absolute and relative configuration of 1-3 is unknown, and
no total synthesis has been published. In this communication,
we report the total synthesis of all four possible stereoisomers
of farinosone C (1), the assignment of the relative and
absolute configuration of the natural product, as well as
preliminary structure activity relationship (SAR) data for this
compound class concerning neuritogenic activity in the PC-
12 assay.
Scheme 1. Synthesis of Fragments 10 and ent-10
quantitative yield. After removal of the TIPS protecting
group, partial racemization of the compounds was observed
by HPLC analysis. Examination of the different intermediates
and derivatives suggested the Wittig and HWE reactions as
the responsible steps. As a separation of the isomers became
feasible at a later stage of the synthesis, we did not change
the protocols to avoid this partial racemization. A two-step
oxidation7 to the corresponding carboxylic acids 9 and ent-9
followed by tert-butylation and selective saponification of
the methyl ester afforded acids 10 and ent-10 in excellent
yields.
The carboxylic acids 10 and ent-10 were directly used in
the peptide coupling with D- or L-tyrosinol to give the amides
11 (Scheme 2). At this stage, the L-tyrosinol derived esters
11a and 11c were enriched in their diastereomeric purity up
to a ratio of 40:1 by simple column chromatography.
Cleavage of the tert-butyl esters with TFA yielded all four
possible stereoisomers of farinosone C (12a-d), which were
therefore prepared in overall yields up to 20% (ca. 90%
average yield for every single step). The NMR spectra of
compounds 12a-d were indistinguishable, and no resolution
of the stereoisomers of farinosone C could be obtained by
analytical HPLC using various chiral stationary phases.
Therefore, we chose to use the methyl esters 13a-d, which
were prepared by derivatization of both synthetic samples
12a-d and a sample of the natural product 1. The methyl
farinosones 13 could be separated by chiral HPLC, and in
combination with the optical rotation, the absolute config-
uration of the natural product farinosone C (1) was therefore
assigned as (1′S,3R) (12a ) 1).
The total synthesis of farinosone C (1) started with the
polyketide side chain (Scheme 1): We used a stereoselective
enolate alkylation reaction with commercially available
pseudoephedrine propionamide and readily accessible TIPS
protected 2-iodo ethanol 4 as reported by Myers and co-
workers.5 Both enantiomers 5 and ent-5 were obtained and
converted into the corresponding aldehyde 6 by direct
reductive cleavage6 resulting in excellent yields and enan-
tiomeric excess (up to 97% ee).6 We then proceeded with a
Wittig reaction to introduce the (E) configured double bond,
followed by reduction of the ester with DIBAH and
subsequent oxidation to aldehyde 7 using activated manga-
nese dioxide. The next double bond was introduced via a
Horner-Wadsworth-Emmons (HWE) reaction giving the
(E,E) configured esters of both enantiomers 8 and ent-8 in
(3) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.; Hamburger,
M. J. Nat. Prod. 2004, 67, 1854–1858.
(4) Biosynthesis of pyridone alkaloids: (a) Schmidt, K.; Riese, U.; Li,
Z.; Hamburger, M. J. Nat. Prod. 2003, 66, 378–383. (b) Irlapati, N. R.;
Baldwin, J. E.; Adlington, R. M.; Pritchard, G. J.; Cowley, A. R.
Tetrahedron 2006, 62, 4603–4614. (c) Bergmann, S.; Schu¨mann, J.;
Scherlach, K.; Lange, C.; Brakhage, A.; Hertweck, C. Nat. Chem. Biol.
2007, 3, 213–217. (d) Halo, L.; Marshall, J. W.; Yakasai, A. A.; Song, Z.;
Butts, C. P.; Crump, M. P.; Heneghan, M.; Bailey, A. M.; Simpson, T. J.;
Lazarus, C. M.; Cox, R. J. ChemBioChem 2008, 9, 585–594. Examples of
pyridone alkaloids: (e) MacLeod, D. M. Can. J. Bot. 1954, 32, 818–890.
(f) McInnes, G. A.; Smith, D. G.; Wat, C.; Vining, L. C.; Wright, J. C. C.
J. Chem. Soc., Chem. Commun. 1974, 281–282. (g) Isaka, M.; Tanticharoen,
M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2001, 66, 4803–4808.
(h) Wagenaar, M. M.; Gibson, D. M.; Clardy, J. Org. Lett. 2002, 4, 671–
673. (i) Fu¨rstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Angew. Chem.,
Int. Ed. 2003, 42, 5361–5364. (j) Lang, G.; Blunt, J. W.; Cummings, N. J.;
Cole, A. L.; Munro, M. H. G. J. Nat. Prod. 2005, 68, 810–811.
(5) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(7) (a) Mancuso, A. J.; Brownfan, D. S.; Swern, D. J. Org. Chem. 1979,
44, 4148–4150. (b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973,
27, 888–890.
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