Synthesis of (±)-solanapyrones A and B

Article abstract of DOI:10.1016/S0040-4039(03)00288-0

In this paper we report the development of a stereoselective IMDA approach to the phytotoxic polyketides (±)-solanapyrones A and B. The stereoselectivity of the key IMDA cycloaddition was optimized by investigating a range of 2,8,10-dodecatrienoic acid derivatives. This established that use of the Weinreb amide led to the desired exo-selectivity and also facilitated construction of the pyrone moiety. A novel approach to the installation of the C-3 formyl group in solanapyrone A is also described.

Full text of DOI:10.1016/S0040-4039(03)00288-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2529–2532
Synthesis of ( )-solanapyrones A and B
Barry Lygo,a,* Mohamed Bhatia,b Jason W. B. Cookec and David J. Hirsta
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bDepartment of Chemistry, University of Salford, Salford M5 4WT, UK
cGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 12 December 2002; revised 20 January 2003; accepted 31 January 2003
Abstract—In this paper we report the development of a stereoselective IMDA approach to the phytotoxic polyketides
( )-solanapyrones A and B. The stereoselectivity of the key IMDA cycloaddition was optimized by investigating a range of
2,8,10-dodecatrienoic acid derivatives. This established that use of the Weinreb amide led to the desired exo-selectivity and also
facilitated construction of the pyrone moiety. A novel approach to the installation of the C-3 formyl group in solanapyrone A is
also described. © 2003 Elsevier Science Ltd. All rights reserved.
The solanapyrones A–E% are a family of phytotoxic
polyketides that have been isolated from the phyto-
pathogenic fungi Alternaria solani and Ascochyta
rabiei.1 Solanapyrone C, along with the closely related
structures, solanapyrones E–G,2 has also been isolated
from an unidentified marine fungus found on the sur-
face of the green alga Halimeda monile.3 Recently
solanapyrone A has been reported to be a selective
inhibitor of mammalian DNA polymerase b and l,
suggesting that compounds of this type may have utility
in cancer chemotherapy.4
ceeds via an exo-selective Diels–Alder cycloaddition.5,6
Given this, the use of an intramolecular Diels–Alder
cycloaddition would seem to be an attractive approach
to the synthesis of compounds of this type.7 Although
such an approach has been successfully applied to the
stereoselective synthesis of solanapyrone A, this relied
on the use of crude enzyme extracts from A. solani to
promote the key Diels–Alder cycloaddition.6 To date
all other attempts at achieving an exo-selective cycload-
dition approach to these compounds have proved
unsuccessful.5,6 This highlights a significant limitation
in the Diels–Alder chemistry of 1,7,9-decatrienes of
type 1,8–10 and in this paper we present some observa-
tions relevant to this problem.
In the course of developing synthetic approaches to the
solanapyrones11 we examined whether Diels–Alder
reactions involving trienes of type 1 could be made
exo-selective simply by varying the nature of the elec-
tron-withdrawing group (EWG) (Scheme 1). There is
evidence in the literature to suggest that this may be
possible;8d,9,12 however, studies of this type have not
been applied to substrates that are appropriate for the
synthesis of the solanapyrones (A–C, E–F).
For the purposes of this study we prepared a range of
1,7,9-decatrienes bearing a range of different carbonyl
derivatives 6a–i. Compounds 6a–e were prepared by
reacting the known aldehyde 5 with an appropriate
Wittig reagent (Scheme 2).6d,8f,13 In all cases the desired
2E-alkenes were readily separated from the minor (=
10%) 2Z-isomer by-products by chromatography.
Studies utilizing A. solani indicate that the biosynthesis
of the majority of these compounds (A–C, E–F) pro-
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00288-0

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B. Lygo et al. / Tetrahedron Letters 44 (2003) 2529–2532
Scheme 1.
Scheme 3. Reagents and conditions: (i) 10% aq. LiOH,
MeOH, reflux, 96%; (ii) (COCl)2, rt; PhNHOH, aq. NaHCO3,
Et2O, rt; K2CO3, MeI, DMF, rt; (iii) i-BuOCOCl, NMM,
THF, 0°C; Et2NH, rt; (iv) (COCl)2, rt; 2-oxazolidinone, n-
BuLi, THF, 0°C.
Scheme 2.
Hydrolysis of ethyl ester 6c provided the corresponding
carboxylic acid 6f in good yield, and this in turn could
be converted into trienes 6g–i using standard
approaches (Scheme 3).10d,14,15
Thermal Diels–Alder reactions involving trienes 6a–i
were then examined (Scheme 4). In all cases the reac-
tions were performed in toluene at ca. 165°C, and all
the substrates investigated exhibited similar rates of
reaction (reactions were complete in 5–6 days). It was
found that ester derivatives 6b–d generated little or no
endo/exo selectivity. This is entirely in agreement with
observations that have been reported for Diels–Alder
reactions involving similar triene substrates.8 Ketone 6a
and carboxylic acid 6f were similarly non-selective;
however, the reactions involving amides 6e,g,h and
imide 6i proved to be more interesting. The latter
derivative resulted in selectivity for the undesired endo-
cycloadduct 8i, whereas amides 6e,g,h all favoured the
exo-adducts 7e,g,h with similar levels of selectivity. We
could find no evidence of equilibration between the two
cycloadducts under the reaction conditions employed.
Scheme 4.
Thus the stereoselectivities obtained are assumed to be
kinetic and probably reflect the asynchronous nature of
this type of Diels–Alder reaction.8d,12
These observations opened up the opportunity to
develop a diastereoselective approach to solanapyrones
(A–C, E–F). To this end we have investigated the
conversion of adduct 7e into solanapyrones A and B.
This particular cycloadduct was chosen because it could

B. Lygo et al. / Tetrahedron Letters 44 (2003) 2529–2532
2531
be readily separated from the corresponding endo-iso-
Acknowledgements
mer,17 and because the Weinreb amide functionality
appearedtoofferthebestmeansofintroducingthepyrone
moiety.
We thank the EPSRC for funding and GSK for stu-
dentship support (to D.H.).
It was found that reaction of Weinreb amide 7e with the
dianion derived from tert-butyl acetoacetate18 allowed
access to triketide 9, and that this intermediate could be
readily converted into the corresponding 4-hydroxypy-
rone10.19 IntroductionoftheC-14formylsubstituentinto
the pyrone ring of solanapyrone precursors such as 9 is
a notorious problem,6b,7,11 and all attempts at directly
introducing this substituent have so far proved unsuccess-
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Scheme 5. Reagents and conditions: (i) CH3COCH2CO2t-Bu,
NaH, THF; n-BuLi, 0°C, 81% (50% conv.); (ii) CF3CO2H,
CH2Cl2; Ac2O; NaHCO3, rt, 63%; (iii) ClCOCO2Me, Et3N,
CH2Cl2, rt; CH2N2, 83%; (iv) NaBH4, MeOH, rt; aq. NaOH
(0.2 M), rt, 70%; (v) NaIO4/SiO2, CH2Cl2, rt, 86%; (vi) NaBH4,
MeOH, rt, 79%.

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B. Lygo et al. / Tetrahedron Letters 44 (2003) 2529–2532
10. Lewis and Brønsted acid-catalysed Diels–Alder reactions
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