The use of ꢀ-allyltricarbonyliron lactone complexes in
the synthesis of the resorcylic macrolides ꢁ- and
ꢂ-zearalenol
1
Steven V. Ley* and Svenja Burckhardt
Department of Chemistry, University of Cambridge, Lensfield Rd, Cambridge,
UK CB2 1EW
Received (in Cambridge, UK) 24th July 2000, Accepted 15th August 2000
Published on the Web 29th August 2000
A highly stereoselective synthesis of ꢁ- and ꢂ-zearalenol 1
and 2 is accomplished utilising ꢀ-allyltricarbonyliron
lactone complexes 5 and 6 to establish the 1,5-stereo-
chemical relationship of oxygen functionalities present in
the natural products.
iron lactone complexes, endo-5 and exo-6, in 70% com-
bined yield and in a ratio of ca. 1:1. Separation of the two
isomers 5 and 6 was readily achieved by flash column
chromatography.
With these key intermediates in hand we were able to proceed
to the target molecules α- and β-zearalenol 1 and 2 (Scheme 1).
For example, for α-zearalenol 1, reduction of the side-chain
ketone in the endo complex 5 was achieved in 94% yield using
tripropylaluminium5 to give 7, as the sole product as deter-
The 14-membered resorcylic macrolides α- and β-zearalenol
1 and 2 are estrogenic mycotoxins produced by certain species
1
mined by 600 MHz H NMR analysis. Treatment of 7 with
sodium triacetoxyborohydride in tetrahydrofuran6 resulted in a
highly stereoselective decomplexation to afford, after TBDMS-
protection and hydrogenation, the alcohol 8. Swern oxidation
of 8 provided the corresponding aldehyde which in turn was
transformed into the vinylstannane 9 by applying the procedure
developed by Hodgson11 utilising chromium() chloride and
Bu3SnCHI2 in N,N-dimethylformamide. Stille coupling of the
stannane 9 with the known aromatic iodide 104f using Farina’s
catalyst12 provided the coupled product 11 in 82% yield. Treat-
ment of 11 with HFؒpyridine followed by hydrolysis of the
methyl ester functionality using aqueous potassium hydroxide
in ethane-1,2-diol at 120 ЊC provided the seco acid 12 in 83%
yield over two steps.
of the fungus Fusarium.1 Their hormonal activity is linked to
the close spatial similarity to 17β-estradiol,2 with the α-isomer 1
being three to four times as active as the β-isomer 2.3 While
several total syntheses of the parent compound zearalenone
were accomplished over the last 30 years,4 to our knowledge no
independent synthesis of 1 or 2 has been reported so far. Here
we report the first enantioselective preparation of 1 and 2
employing π-allyltricarbonyliron lactone complexes as key
intermediates.
We have previously shown that organoaluminium reagents
possessing active β-hydrogens, like tripropyl- and triisobutyl-
aluminium, reduce carbonyl groups appended to the allyl lig-
and of π-allyltricarbonyliron lactone complexes with excellent
diastereoselectivity.5 Also, we recently reported that sodium
triacetoxyborohydride efficiently decomplexes π-allyltricarb-
onyliron lactone complexes bearing a hydroxy group in the
side-chain to afford stereodefined 1,5-diols.6 By exploiting
this methodology in this work, we show that π-allyl-
tricarbonyliron lactone complexes can be used to set up the
relative oxygen atom stereochemistry present in the natural
products.
The route to α- and β-zearalenol 1 and 2 relied upon the
formation of the π-allyltricarbonyliron lactone intermediates
5 and 6, respectively, whose preparation is delineated in
Scheme 1. Reduction of the ester 37 using lithium aluminium
hydride followed by Swern oxidation and Horner–Wadsworth–
Emmons homologation with the phosphonate 18,† prepared
according to the methodology of Grieco,8 gave the correspond-
ing (E)-enone in 83% yield over three steps. Deprotection of
the acetonide under acidic conditions and transformation of
the liberated diol to the cyclic sulfite using thionyl chloride9
afforded the compound 4 in 82% overall yield. Treatment of
4 with diironnonacarbonyl in benzene under sonication condi-
tions10 provided the two diastereoisomeric π-allyltricarbonyl-
Cyclisation of 12 using Mukaiyama’s protocol13 afforded the
desired MEM-protected α-zearalenol in 64% yield. Final depro-
tection of the MEM-ethers with aqueous hydrochloric acid in
tetrahydrofuran at 40 ЊC provided α-zearalenol 1 in 93% yield
1
and with a de of 94% as determined by 600 MHz H NMR
analysis {[α]D32 Ϫ93.6 (c 0.55 in acetone) [optical rotation
obtained on an authentic sample‡ [α]D32 Ϫ97.3 (c 0.55 in
acetone)]}.
Application of the same sequence of reactions to the exo
complex 6 afforded the diastereoisomeric β-zearalenol 2 in simi-
lar overall yield via the intermediates 13 to 17, as shown in
Scheme 1 {de >95% as determined by 600 MHz 1H NMR
analysis; [α]D32 Ϫ12.5 (c 1.00 in acetone) [optical rotation
obtained on an authentic sample‡ [α]D32 Ϫ12.9 (c 1.00 in
acetone)]}.
These highly stereoselective syntheses of α- and β-zearalenol
1 and 2 clearly demonstrate the utility of carbonyl substituted
π-allyltricarbonyliron lactone complexes in organic syn-
thesis. Using the endo complex 5 as well as the exo complex
6 we were able to set up the required 1,5-stereochemical
relationship of oxygen functionalities present in the natural
products.
Acknowledgements
We would like to thank Stiftung Stipendien-Fonds des
Verbandes der Chemischen Industrie (to S. B.) and the Novartis
Research Fellowship (to S. V. L.) for generously funding this
work.
3028
J. Chem. Soc., Perkin Trans. 1, 2000, 3028–3030
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005942k