Synthesis of (-)-Gloeosporone, a fungal autoinhibitor of spore germination using a π-allyltricarbonyliron lactone complex as a templating architecture for 1,7-diol construction

Article abstract of DOI:10.1039/b308793j

The synthesis of the germination self-inhibitor (-)-Gloeosporone is reported. The embedded 1,7-diol motif in the product is constructed by an ironcarbonyl tether controlled Mukaiyama aldol reaction. The key step in the synthesis is the reductive removal of the ligating iron species by treatment of an acetoxycomplex 6 with lithium naphthalenide.

Full text of DOI:10.1039/b308793j

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Synthesis of (؊)-Gloeosporone, a fungal autoinhibitor of spore
germination using a ꢀ-allyltricarbonyliron lactone complex as a
templating architecture for 1,7-diol construction†
Steven V. Ley,* Ed Cleator, Jürgen Harter and Christopher J. Hollowood
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: ϩ44 (0) 1223 336442;
Tel: ϩ44 (0) 1223 336398
Received 28th July 2003, Accepted 20th August 2003
First published as an Advance Article on the web 29th August 2003
The synthesis of the germination self-inhibitor (؊)-Gloeo-
sporone is reported. The embedded 1,7-diol motif in the
product is constructed by an ironcarbonyl tether controlled
Mukaiyama aldol reaction. The key step in the synthesis
is the reductive removal of the ligating iron species by
treatment of an acetoxycomplex 6 with lithium naphthal-
enide.
yield upon treatment of 5 with acetic anhydride in dichloro-
methane (Scheme 1).
The isolation of the germination self-inhibitor (Ϫ)-Gloeo-
sporone 1, from conidia of Collectotrichum gloeosporioides,1
aroused considerable interest both structurally and for its bio-
logical properties. The synthesis of the now accepted correct
macrocyclic structure (Fig. 1) has been reported by several
groups.2
Scheme 1 Synthesis of key intermediate (6). Reagents and conditions:
(a) TMSOTf, Et3N, CH2Cl2, 0 ЊC, 1 h, 84%; (b) OHC(CH2)2OBn (3),
BF3ؒOEt2, CH2Cl2, Ϫ78 ЊC then Et3N, HF–pyr, THF, 63%; (c) TBSOTf,
i
Et3N, CH2Cl2, 0 ЊC, 18 h, 100%; (d) Bu3Al (1 M solution in toluene),
CH2Cl2, 0 ЊC, 30 min, 83%; (e) Ac2O, Et3N, DMAP, CH2Cl2, 0 ЊC
2 h, 98%.
rt,
Fig. 1 (Ϫ)-Gloeosporone.
Here we wish to report a conceptually different synthetic
approach using a π-allyltricarbonyliron lactone complex,3 as
the templating architecture to set-up the embedded 1,7-diol
motif of the natural product. We have previously reported on
the use of such complexes in natural product synthesis,4 how-
ever, we wish to exploit not only the stereocontrolling aspects of
these complexes,5 but also a new reductive detachment of the
ligating iron species using lithium napthalenide.6
In the next phase of the synthesis 6 was treated with lithium
naphthalenide in THF at Ϫ78 ЊC, and on warming the reaction
mixture to room temperature afforded an inseparable mixture
of alkenes 7-E,E, 7-Z,E and 7-E,Z in an excellent 98% yield,6,9
(Scheme 2). Reduction of the diene mixture with simultaneous
benzyl deprotection gave mono-protected triol 8 (83%). The
primary alcohol was then selectively oxidised to aldehyde 9
using Oshima conditions.10 It was noted that in order for this
reaction to proceed smoothly two equivalents of K2CO3 needed
to be added to the reaction mixture, this afforded aldehyde 9
in a respectable 78% yield. Acylation of 9 with 4-pentenoyl
chloride occurred in a 65% yield. This reaction was found to
be capricious and often led to incomplete conversion which
necessitated recycling of unreacted 9. Nevertheless 10 could
be readily methylenated with methyl phosphonium chloride
upon treatment with KOtBu in THF,11 to provide the known
precursor 11 to (Ϫ)-Gloeosporone.2g
Treatment of a boiling dichloromethane solution of com-
pound 11 with 3 mol% of tricyclohexylphosphine[1,3-bis(2,4,6-
trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidine]-
ruthenium()-dichloride (Grubbs’ second generation RCM
catalyst),12 formed cyclic lactone 12-E and 12-Z as a 1 : 1 mix-
ture of alkene isomers in a 99% yield. The conversion of alkene
mixtures of 12 to the natural product, using KMnO4 in acetic
anhydride,13 followed by desilylation/cyclisation upon treatment
with HF in acetonitrile affords 1 in a 56% yield.2b,g
The synthesis begins with the known π-allyltricarbonyliron
lactone complex 2.7 This complex is available in gramme quan-
tities by an established route in greater than 95% e.e. at the key
C-6 stereogenic centre. Following our established protocol,
treatment of a dichloromethane solution of 2 with TMSOTf in
the presence of NEt3 gave an intermediate trimethylsilyl enol
ether in an 84% yield. This silyl enol ether was used immediately
in the highly diastereoselective Mukaiyama aldol coupling reac-
tion with 3-benzyloxy-propionaldehyde 3,8 giving rise to alco-
hol 4 in a 63% yield after work-up with HF–pyridine complex
in THF. Reprotection of the alcohol with TBSOTf, followed by
i
stereoselective reduction with Bu3Al in a toluene–dichloro-
methane mixture gave the mono-protected diol 5 in an 83%
yield over two steps. The acetate intermediate for the reductive
removal of the ligating iron moiety 6 was prepared in a 98%
† Electronic supplementary information (ESI) available: experimental
procedure and data for 7. See http://www.rsc.org/suppdata/ob/b3/
b308793j/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 6 3 – 3 2 6 4
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Notes and references
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Scheme 2 Synthesis (Ϫ)-Gloeosporone intermediate 1. Reagents and
conditions: (a) Li naphthalenide, THF, Ϫ78 ЊC rt, 17 h, 98%; (b) Pd/
C, H2, EtOAc, 12 h, 83%; (c) RuCl2(PPh3)3, benzene, K2CO3 (2 eq.), rt,
20 h, 78%; (d) 4-pentenoylchloride, DMAP (6 eq.), CH2Cl2, 0 ЊC rt,
3 h, 65%; (e) (Ph)3PCH3Cl, KOtBu, THF, 0 ЊC
rt, 85%; (f ) RuCl2-
8 S. V. Ley, L. R. Cox, B. Middleton and J. M. Worrall, Chem.
Commun., 1998, 1339.
9 Experimental procedure and data for 7 available free of charge from
ESI.
(᎐CHPh)[1,3-ImH2]P(Cy)3, CH2Cl2, 40 ЊC, 5 h, 99%; (g) KMnO4, Ac2O,
᎐
then, HF, MeCN, 4 h, 56%.
In conclusion, this work demonstrates the applicability of
π-allyltricarbonyliron lactone complexes for natural product
synthesis. In particular the use of the new lithium naphthal-
enide decomplexation protocol is an especially attractive route to
enantiopure 1,7-diol units.
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Acknowledgements
We gratefully acknowledge the financial support from the
ESPRC, BP endowment and the Novartis Research Fellowship
(to S. V. L.).
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