I2-PPh3 mediated spiroannulation of unsaturated β-dicarbonyl compounds. the first synthesis of (±)-negundoin A

Article abstract of DOI:10.1039/c3cc45921g

An efficient and stereoselective spiroannulation of unsaturated enols is reported. Unsaturated β-dicarbonyl compounds undergo cyclization by reaction with catalytic I₂-PPh₃, affording the corresponding spiro enol ether derivatives, with complete regio- and stereoselectivity, under mild conditions. Utilizing this new methodology, the first total synthesis of the anti-inflammatory diterpene negundoin A and a naturally occurring trypanocidal aldehyde is reported.

Full text of DOI:10.1039/c3cc45921g

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I2–PPh3 mediated spiroannulation of unsaturated
b-dicarbonyl compounds. The first synthesis
of (Æ)-negundoin A†
a
Cite this: Chem. Commun., 2013,
49, 10257
Received 2nd August 2013,
a
a
a
a
Accepted 9th September 2013
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Ruben Tapia, M Jose Cano, Hanane Bouanou, Esteban Alvarez,
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Ramon Alvarez-Manzaneda, Rachid Chahboun* and
DOI: 10.1039/c3cc45921g
Enrique Alvarez-Manzaneda*a
www.rsc.org/chemcomm
An efficient and stereoselective spiroannulation of unsaturated enols
is reported. Unsaturated b-dicarbonyl compounds undergo cyclization
by reaction with catalytic I2–PPh3, affording the corresponding spiro
enol ether derivatives, with complete regio- and stereoselectivity,
under mild conditions. Utilizing this new methodology, the first total
synthesis of the anti-inflammatory diterpene negundoin A and a
naturally occurring trypanocidal aldehyde is reported.
Fig. 1 Some bioactive natural spiro ethers.
Spirocompounds, with two rings joined at a single atom, are
widely found in Nature. Among these, some spiroethers present
particular interest due to their important biological properties.
Spirodihydrobenzofuran derivatives, such as the complement
inhibitor K-76,1 the antagonist of endothelin and an inhibitor
of HIV-1 protease stachybotrylactam,2 or cytotoxic stypoldione (1),3
are some representative bioactive spiroethers. A series of nor-
diterpenes, bearing a characteristic tricyclic structure containing a
spiro enol ether group with an a,b-unsaturated aldehyde, acid or
ester, have recently been isolated from different species of the
genus Vitex, which are widely used in folk medicine in some Asian
countries. Representative examples are negundoin C (2), a potent
anti-inflammatory aldehyde isolated from V. negundo, acid 3
(negundoin B) and ester 4 (negundoin A),4 together with the
trypanocidal aldehydes 5 and 6, found in V. trifolia5 (Fig. 1).
Only a few syntheses have been reported for some of these
spirodihydrobenzofuran derivatives, i.e. K-76 and stachybotryl-
actam; in all cases, the key step is the spiroannulation of the
suitable drimane (bicyclic sesquiterpene) phenol, under acidic
conditions.1b,c,6 To date, no syntheses for spiro enol ether
derivatives, such as compounds 2–6, have been reported.
Spiro tetrahydrofurylidene systems similar to that presented
by negundoin A (4) have been previously elaborated by reaction of an
oxirane with the dianion of a b-ketoester and the subsequent
treatment with acid.7,8 The construction of the spiro enol ether
framework of compounds 2–6 could be achieved by spiro annulation
of the enol derived from the corresponding unsaturated b-dicarbonyl
compound 7 under suitable reaction conditions (Scheme 1). Alter-
natively, O-alkylation can take place affording the corresponding
pyran derivative. Cyclization of b-dicarbonyl compound type 7 can
also occur through the C-alkylation of the corresponding enol,
leading to type 8 compounds. In some cases other C-cyclization
processes can take place after the attack of an olefinic or an allyl
carbon on the carbonyl group, affording the corresponding
b-hydroxy carbonyl compound.9 In most of the reactions
described under acidic conditions processes involving C-cyclization
have been reported.10–12 Some examples of obtention of tetra-
hydrofurylidene derivatives by cyclization of unsaturated b-ketoesters
13
catalyzed using SnCl4 or Pd(II)14 have been described. Under
these conditions, alkyl 6-methyl-3-oxo-6-heptenoates afford
a
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Departamento de Quımica Organica, Facultad de Ciencias,
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Instituto de Biotecnologıa, Universidad de Granada, 18071 Granada, Spain.
E-mail: eamr@ugr.es, rachid@ugr.es; Fax: +34 958 24 80 89;
Tel: +34 958 24 80 89
b
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Departamento de Quımica Organica, Facultad de Ciencias,
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Universidad de Almerıa, 04120 Almerıa, Spain
† Electronic supplementary information (ESI) available: Full experimental proce-
dures, spectroscopic data and copies of 1H and 13C NMR spectra. See DOI:
10.1039/c3cc45921g
Scheme 1 Alternative cyclization processes for unsaturated b-dicarbonyl
compounds.
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Table 1 I2–PPh3 mediated spiroannulation of some b-dicarbonyl compounds
the corresponding spiro compound resulting from the favour-
able enol O-attack on the most substituted olefinic carbon. The
stereoselectivity of these processes remains uncertain.13a,14
However, the spiroannulation of unsaturated b-dicarbonyl
compounds bearing a tetrasubstituted olefinic bond, such as
compound 7, to achieve compounds 2–6 involves certain difficulty
due to the variety of possible alternative cyclizations discussed
above. In order to search cyclization conditions favouring the
required O-alkylation process, the behaviour of unsaturated
b-ketoesters 9, 10, 12 and 13 under different cyclization conditions,
including acidic ones, was studied. In most cases the cyclization
process is not stereoselective, leading to a mixture of compounds,
resulting from a C-alkylation reaction.15
Entry
1
b-Dicarbonyl compound
t (h)
Product
8
2
3
8
5
In the course of our investigations into the use of the
I2–PPh3 system16 we found that unsaturated b-ketoesters are
efficiently transformed, in the presence of catalytic amounts of
this reagent, into the corresponding spiro enol ethers. Thus,
the b-ketoester 9 was converted with complete regio- and
stereoselectivity into the spiro compound 21 by treatment with
this system, in dichloromethane, at room temperature for 8 h
(see Table 1). Ketoester 10 gave the same results under the
above reaction conditions. Similarly, compound 11 was trans-
formed in good yield into the spiro compound 22. In order
to optimize the reaction conditions and establish the scope of
this reaction, some other b-ketoesters, b-ketoaldehydes and
b-diketones were then studied. In all cases the corresponding
spiro enol ethers were obtained with complete regio- and
stereoselectivity. b-Ketoaldehydes (entries 7 and 8) show a
similar behaviour. It should be noted that aldehyde 25 was
the only spirane derivative obtained as a mixture of E–Z
stereoisomers (4 : 1); the reason for this behaviour remains
unclear. Compound 16 was transformed under the same reac-
tion conditions into the spirane 5, a trypanocidal aldehyde
isolated from V. trifolia.5 The optical rotation of synthetic
aldehyde 5 ([a]D +1.2; c 8.6, CHCl3) and the spectroscopic
properties were similar to those reported for the natural
product. b-Diketones (entries 9 and 10) also produced the
corresponding spiro enol ether derivatives. The relative stereo-
chemistry of all the above spiro compounds was established on
the basis of nOe experiments. On the other hand, b-ketoester 19
and b-diketone 20, containing a prenyl substituent, afforded
under the above conditions the corresponding enol ether
bearing a dihydropyran ring. In order to rule out the participation
of hydriodic acid in this I2–PPh3 mediated process, the behaviour of
b-ketoester 9 against this acid reagent was investigated. Compound
9 remained unaltered after treating with 55% aq. HI in dichloro-
methane at room temperature for 48 h. Under reflux, decomposi-
tion was observed.
4
5
5
5
6
7
8
9
5
5
5
3
10
11
5
5
5
A first fact to be considered in rationalizing these results is
the complete anti stereoselectivity of the addition process.
When the I2–PPh3 system is utilized, an anti concerted process, 12
precluding the formation of an intermediate carbocation,
must take place. A possible mechanism, consistent with the
experimental results, is postulated. The spirocyclization process is
depicted in Scheme 2. Under the reaction conditions, the trisub- tetrasubstituted derivatives. The enol hydroxyl group acts as a
stituted or exocyclic carbon–carbon double bond (compounds 9 nucleophile and a proton donor simultaneously. The OH group,
and 13; 14 and 16) undergoes isomerization to the most stable activated by the phosphonium ion +PPh3I, transfers the proton by
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Notes and references
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Scheme 2
A possible mechanism for the I2–PPh3 mediated cyclization of
b-dicarbonyl compounds.
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11 A. Abad, C. Agullio, A. C. Cunat, A. Gonzalez-Coloma and A. Pardo,
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12 The treatment of ketoester 10 with 98% aq. H2SO4 afforded a
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Scheme 3 Synthesis of negundoin A (4).
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the b side of the olefinic bond of the adjacent molecule. The latter
undergoes the simultaneous intramolecular nucleophilic O-attack
on carbon 1, affording intermediate I, which is a precursor of
the spirane compound (Scheme 2). The complete regioselectivity of
the cyclization process could be attributed to the preference for the
transference of protons on the less hindered carbon 2. The
preference for the b side proton transference could be attributed
to the a side steric hindrance due to the keto ester moiety. As
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substituted olefinic carbon.
15 The results obtained by treating b-ketoesters 9, 10, 12 and 13 with
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17 Compounds 12, 13 and 16 were obtained after methoxycarbonyla-
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mediate hydroxyketone 32, a terpenoid found in Copaiba oil,20
which is easily prepared by the titanocene-catalyzed cyclization
´
(b) E. Alvarez-Manzaneda, R. Chahboun, E. Alvarez, A. Fernandez,
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thesis, University of Granada, 2012.
19 T. Narender, S. Sarkar, K. Venkateswarlu and J. K. Kumar, Tetra-
scopic properties of synthetic negundoin A (4) were identical to
those reported for the natural product.4
hedron Lett., 2010, 51, 6576.
The authors thank the Spanish Ministry of Science and 20 H. Monti, N. Tiliacos and R. Faure, Phytochemistry, 1996, 42,
1653.
Innovation (Project CTQ2009-09932) and the Regional Government
of Andalucia (Project P11-CTS-7651 and assistance for the FQM-348
group) for financial support.
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21 J. Justicia, A. Rosales, E. Bunuel, J. L. Oller-Lopez, M. Valdivia,
´
A. Haidour, J. E. Oltra, A. F. Barrero, D. Cardenas and J. M. Cuerva,
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Chem. Commun., 2013, 49, 10257--10259 10259