Facile and efficient total synthesis of (+)-preussin.

Article abstract of DOI:10.1021/ol000289p

[structure] The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone to pyrrolidine using Pearlman's catalyst.

Full text of DOI:10.1021/ol000289p

ORGANIC
LETTERS
2000
Vol. 2, No. 25
4041-4042
Facile and Efficient Total Synthesis of
(+)-Preussin
Kee-Young Lee, Yong-Hyun Kim, Chang-Young Oh, and Won-Hun Ham*
College of Pharmacy, SungKyunKwan UniVersity, Suwon 440-746, Korea
whham@speed.skku.ac.kr
Received September 29, 2000
ABSTRACT
The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-
forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone
to pyrrolidine using Pearlman’s catalyst.
(+)-Preussin (1, Figure 1), a potent antifungal agent pos-
sessing a pyrrolidine skeleton, was isolated from fermentation
broths of both Aspergillus ochraceus and Preussia sp. in the
late 1980s.1,2 Both 1 and its acetate ester 2 possess significant
activity as broad-spectrum antibiotics against yeasts and
filamentous fungi.2 A number of its synthetic approaches
have been reported due to its novel pyrrolidine structure and
its interesting biological activity.3
ring from an acyclic allylic and homoallylic amide having a
benzoyl substituent as an N-protection group. The most
significant point of this method is that it is based on the
trans-oxazoline ring formation in palladium(0)-catalyzed
conditions (Scheme 1). We envisioned that this method could
Scheme 1
Figure 1.
be utilized to set the vicinal amino alcohol stereochemistry
of the preussin. The pendant vinyl group could be converted
to the appropriate ketone which could be employed in the
stereoselective installation of the nonyl group by catalytic
hydrogenation of oxazoline.
In a previous paper,4 we described a new Pd(0)-catalyzed
procedure for the stereoselective formation of an oxazoline
(1) Schartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt, S.;
Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. Antibiot. 1988,
1744.
(2) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
1184.
10.1021/ol000289p CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/16/2000

The synthesis of 1 began with the protected L-N-benzoyl
phenylalaninol 6 as shown in Scheme 2. Oxidation of alcohol
ketone 10 in 80% yield. Hydrogenolysis of oxazoline10 10
in 1:10 AcOH/MeOH was performed under 70 psi of H2
and ambient temperature. Under these conditions, we achieved
not only hydrogenolysis of oxazoline moiety but also
cyclization of the intermediate aminoketone to pyrrolidine
11, a known precursor of preussin,3i as a single isomer in
50% yield. Spectroscopic data and the specific rotation of
11 were in good agreement with the literature values
reported.3i Finally, pyrrolidine 11 was methylated conven-
tionally11 to produce (+)-preussin in 78% yield (Scheme 3).
Scheme 2a
Scheme 3a
a (a) Dess-Martin periodinane, CH2Cl2; (b) CH2dCHMgBr,
THF, 70% for 2 steps; (c) Ac2O, pyr, CH2Cl2, 99%; (d) Pd(PPh3)4,
K2CO3, CH3CN, 83%.
6 with Dess-Martin periodinane4b,5 gave the corresponding
aldehyde without racemization,4b,5b which was reacted with
vinylmagnesium bromide in THF at 0 °C to afford the
corresponding allyl alcohol 7 as an ca. 1.1:1 mixture of syn/
anti isomers (1H NMR) in 70% yield.6 Acetylation of the
hydoxyl group yielded the secondary allylic acetate. A
standard oxazoline ring formation reaction [Pd(PPh3)4, K2-
CO3, in CH3CN] of the allylic acetate of 7 gave the desired
trans-oxazoline 8 as the major compound with high diaste-
reoselectivity (14:1) and in good yield (83%).5
a (a) 9-BBN, THF, 82%; (b) RuCl3, NaIO4, NaHCO3, CCl4/
CH3CN/H2O; (c) DCC, DMAP, NH(CH3)OCH3-HCl, Et3N, CH2Cl2,
85% for 2 steps; (d) C9H19MgBr, THF, -30 °C, 80%; (e) Pd(OH)2/
H2, AcOH/MeOH (1:9), 50%; (f) HCHO, NaBH3CN, AcOH, 78%.
Oxidation of alkene 8 with 9-BBN7 gave the corresponding
alcohol in 82% yield. This alcohol was further oxidized to
the corresponding acid with ruthenium chloride.8 The result-
ing carboxylic acid was converted to its Weinreb amide9 9
via DCC-mediated condensation with N,O-dimethylhydroxyl-
amine in 85% yield. Treatment of the amide with nonyl-
magnesium bromide (THF, -30 f 0 °C, 1 h) provided
In summary, we report a new asymmetric synthetic method
for (+)-preussin utilizing oxazoline 8. The key features in
this strategy are the diastereoselective oxazoline formation
reaction catalyzed by palladium(0) and pyrrolidine formation
by catalytic hydrogenation of oxazoline.
Acknowledgment. Financial support provided by the
KPRC is gratefully acknowledged.
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J. Org. Chem. 1998, 63, 4660. (j) Veeresa, G.; Datta, A. Tetrahedron 1998,
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Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 1 and 9-11.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL000289P
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