Enantioselectve synthesis of the tetracyclic left-hand substructure of solanoeclepin A

Article abstract of DOI:10.1039/b003757p

The synthesis of the enantiopure left-hand substructure of solanoeclepin A is described. Key steps include a chromium-mediated coupling of an oxabicyclic aldehyde with a β-ketoester-derived enol triflate to give a lactone, and a ring-closing metathesis reaction to form the seven-membered ring.

Full text of DOI:10.1039/b003757p

Enantioselective synthesis of the tetracyclic left-hand substructure of
solanoeclepin A
Jorg C. J. Benningshof, Richard H. Blaauw, Angeline E. van Ginkel, Floris P. J. T. Rutjes, Jan Fraanje,† Kees
Goubitz,† Henk Schenk† and Henk Hiemstra*
Institute of Molecular Chemistry, Laboratories of Organic Chemistry and Crystallography, University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands. E-mail: henkh@org.chem.uva.nl
Received (in Liverpool, UK) 9th May 2000, Accepted 20th June 2000
Published on the Web 14th July 2000
The synthesis of the enantiopure left-hand substructure of
solanoeclepin A is described. Key steps include a chromium-
The synthesis of aldehyde 7 started with the condensation of
furfural with (R)-(2)-2-phenylglycinol and reduction of the
formed imine with sodium borohydride (Scheme 2). At this
point it was not possible to selectively acylate the amine.
Therefore the hydroxy group was first silylated, followed by N-
acylation and acidic work-up to give Diels–Alder precursor 9 in
87% overall yield from furfural. The intramolecular Diels–
Alder reaction following the Mukaiyama protocol4 afforded 8 in
excellent diastereoselectivity (89%) on a 50 g scale. The pure
diastereomer 8 was obtained after column chromatography in
69% yield.
As chemoselective hydroboration of the alkene in 8 appeared
impossible in the presence of the lactam, the latter functionality
was removed as follows. First, the N-substituent was removed
via a non-reductive procedure to keep the 7-oxabicycloheptene
moiety intact.5 The Diels–Alder product 8 was successively
treated with tosyl chloride and DBU to give an enamine, which
after hydrolysis led to lactam 10 (mp 154 °C; [a]2D2 +52.4, c =
0.8, CHCl3) in excellent yield. Lactam 10 was then N-nitrosated
and ring-opened to a hydroxy ester,4 which on THP-protection
gave 11 in moderate yield. Highly selective hydroboration of
the double bond appeared now possible with disiamylborane6§
to give the desired alcohol in a 92+8 regioisomeric ratio.
Separation of the isomers by column chromatography and
protection of the secondary hydroxy group as a silyl ether
afforded 12 in a good yield. The ester function was then
mediated coupling of an oxabicyclic aldehyde with a
-
ketoester-derived enol triflate to give a lactone, and a ring-
closing metathesis reaction to form the seven-membered
ring.
In the preceding communication1 we have disclosed a synthetic
approach to the intricate bicyclo[2.1.1]hexane moiety of
solanoeclepin A (1), the hatching agent of the potato cyst
nematode.2 In this paper we present the successful synthesis of
the tetracyclic left-hand substructure 2 of this challenging
natural product.
In our retrosynthetic analysis (Scheme 1) compound 2 was
deemed accessible via oxidative functionalisation of diene 3,
which was thought to result from a ring-closing metathesis
reaction of triene 4 as a key step. Compound 4 was expected to
arise from lactone 5, the product of a chromium-mediated3
coupling of enol triflate 6 and aldehyde 7. Diels–Alder product
8 has been previously reported by Mukaiyama and Iwasawa4a
and seemed a suitable intermediate for the construction of
aldehyde 7.
Scheme 2 Reagents: a, (R)-(2)-2-phenylglycinol, toluene, reflux; b,
NaBH4, i-PrOH; c, TMSCl, pyridine, THF; d, 3,3-dimethylacryloyl
chloride then 5% HCl, H2O; e, n-BuMgCl, Et2O, 260 °C then toluene,
reflux, 16 h; f, p-TsCl, pyridine, CH2Cl2; g, DBU, MeCN then 5 M HCl,
H2O; h, NaNO2, AcOH, Ac2O; i, KOH, EtOH then sat. NaHCO3 (aq); j,
DHP, p-TsOH, CH2Cl2; k, disiamylborane, THF then NaOH, H2O2; l,
TDBPSCl, imidazole CH2Cl2; m, LiAlH4, THF; n, TPAP, NMO, acetone;
o, Ph3P CH2, THF; p, HOAc, THF, H2O; q, SO3·pyridine, DMSO, Et3N,
CH2Cl2.
Scheme 1 Strategy for the synthesis.
DOI: 10.1039/b003757p
Chem. Commun., 2000, 1465–1466
This journal is © The Royal Society of Chemistry 2000
1465

transformed into a vinyl group by reduction to the alcohol,
followed by TPAP7 oxidation and Wittig olefination. After THP
deprotection and oxidation,8 aldehyde 7 was obtained.
A chromium-mediated coupling of enol triflate 6 with
aldehyde 7 afforded an intermediate g-hydroxy unsaturated
ester which spontaneously lactonised to a,b-unsaturated lactone
5 and its diastereomer (Scheme 3).3 This mixture of diastereo-
isomers (70:30) could be easily separated by column chroma-
tography. The major isomer was used for the rest of the
synthetic sequence and its stereochemistry was later proven to
be as given in 5.
moiety in one step using KMnO4 in Ac2O,11 but this reagent
mixture led to complete cleavage of the C C bond, resulting in
a diacid. We then decided to introduce the 1,2-diketone via a
milder three-step procedure. First the double bond was
dihydroxylated, which was only successful by following a
recent procedure of Corey and co-workers,12 using stoichio-
metric osmium tetroxide activated with DMAP. Direct double
oxidation of the resulting diol to the dione, using manganese
dioxide, TPAP or DMSO-based reagents failed and resulted in
most cases in C–C bond cleavage to give the corresponding
dialdehyde. However, we then found that is was possible to
selectively oxidise the allylic alcohol using 1 equiv. of Dess–
Martin periodinane,13 resulting in a-hydroxyketone 15. Heating
of 15 with cupric acetate14 in MeOH gave the desired
1,2-diketone, which existed completely in the enol form, and
was readily methylated to give methyl enol ether 16. In the last
few steps the silyl ether was cleaved and the liberated hydroxy
group oxidised using a TPAP oxidation. Deprotection of the
acetate group resulted in the desired 2 as a stable crystalline
compound (mp 173 °C) with a high rotation ([a]2D4 +495, c =
0.6, CHCl3). The X-ray crystal structure‡ proved its identity,
including the orientation of the hydroxy function. Compound 2
has been subjected to hatching activity tests,15 but appeared to
be devoid of any activity.
In summary, we have completed a synthesis of the tetracyclic
left-hand substructure 2 of solanoeclepin A in enantiopure form.
Compound 2 appeared to be quite stable so that the reported
instability of 1 can probably be ascribed to the bicyclo-
[2.1.1]hexanone part of the molecule. The synthesis reported
herein provides important information for the eventual synthe-
sis of 1 itself. To this end triflate 6 needs to be replaced by a
more complex molecule containing the bicyclo[2.1.1]hexane
moiety. Studies in this direction will be reported in due
course.
These investigations are supported (in part) by the Nether-
lands Research Council for Chemical Sciences (CW) with
financial aid from the Netherlands Technology Foundation
(STW).
Scheme 3 Reagents: a, CrCl2, NiCl2 (cat.), DMF, 50 °C (2.3:1); b, LiAlH4,
Et2O, rt; c, TBDMSCl, pyridine, CH2Cl2 ; d, Ac2O, pyridine, CH2Cl2; e,
CSA, MeOH; f, TPAP, NMO, acetone; g, Ph3P CH2, THF; h, 14 (15%),
toluene, reflux, 16 h.
Reduction of lactone 5 with lithium aluminium hydride
resulted in a diol, which was protected with a TBDMS group on
the primary hydroxy group, and an acetyl group on the
secondary hydroxy group to give 13. The primary alcohol was
then selectively deprotected with CSA and subsequently
oxidised with TPAP.7 Wittig olefination of the crude aldehyde
resulted in the ring-closing metathesis precursor 4. Our first
experiments to cyclise 4 were carried out with Grubbs’
ruthenium benzylidene catalyst,9 but a very slow process was
observed requiring a stoichiometric amount of the catalyst for
completion of the ring-closing metathesis. Gratifyingly, the use
of the more stable ruthenium catalyst 1410 gave quantitative
closure to form tetracyclic diene 3 after 16 h in refluxing toluene
using only 15% of the catalyst.
Notes and references
† Laboratory of Crystallography.
‡ CCDC 182/1703. See http://www.rsc.org/suppdata/cc/b0/b003757p/ for
crystallographic files in .cif format.
§ Disiamylborane = [(CH3)2CHCH(CH3)]2BH.
1 R. H. Blaauw, J. F. Brière, R. de Jong, J. C. J. Benningshof, A. E. van
Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk and H.
Hiemstra, Chem. Commun., 2000, 1463.
2 J. G. Mulder, P. Diepenhorst, P. Plieger and I. E. M. Brüggemann-
Rotgans, PCT Int. Appl. WO 93/02,083, Chem. Abstr., 1993, 118,
185844z.
With the diene 3 available we needed to functionalise the
least-substituted double bond with oxygen substituents
(Scheme 4). We first attempted to introduce a 1,2-diketone
3 P. Knochel and C. J. Rao, Tetrahedron, 1993, 49, 29.
4 (a) T. Mukaiyama and N. Iwasawa, Chem. Lett., 1981, 29; (b) M. R.
Gmünder and C. H. Eugster, Helv. Chim. Acta, 1990, 73, 2190.
5 V. Nyzam, C. Belaud, F. Zammattio and J. Villiéras, Tetrahedron:
Asymmetry, 1996, 7, 1835; O. Fains and J. M. Vernon, Tetrahedron
Lett., 1997, 38, 8265.
6 H. C. Brown, A. K. Mandal and S. U. Kulkarni, J. Org. Chem., 1977, 42,
1392.
7 For a review on TPAP oxidations, see: S. V. Ley, J. Norman, W. P.
Griffith and S. P. Marsden, Synthesis, 1994, 639.
8 J. R. Parikh and W. E. von Doering, J. Am. Chem. Soc., 1967, 89,
5505.
9 R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413.
10 M. Scholl, T. M. Trnka, J. P. Morgan and R. H. Grubbs, Tetrahedron
Lett., 1999, 40, 2247.
11 H. P. Jensen and K. B. Sharpless, J. Org. Chem., 1974, 39, 2314.
12 F. He, Y. Bo, J. D. Altom and E. J. Corey, J. Am. Chem. Soc., 1999, 121,
6771.
Scheme 4 Reagents: a, OsO4, DMAP, t-BuOH–H2O 1+1 then Na2SO3; b,
Dess–Martin, CH2Cl2 (19% dialdehyde); c, Cu(OAc)2, MeOH, 60 °C; d,
MeI, Ag2O, DMF; e, HF·pyridine; f, TPAP, NMO, acetone; g, K2CO3,
MeOH.
13 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
14 N. L. Wendler, D. Taub and R. P. Graber, Tetrahedron, 1959, 7, 173.
15 Compound 2 was tested at HLB Agricultural Research Centre, Assen,
The Netherlands
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Chem. Commun., 2000, 1465–1466