Michael addition of ortho-lithiated aryloxiranes to α,β- unsaturated malonates: Synthesis of tetrahydroindenofuranones

Article abstract of DOI:10.1021/ol800437s

A short and efficient synthesis of tetrahydroindenofuranones based on the Michael addition of ortho-lithiated aryloxiranes to alkylidene malonates followed by the nucleophilic oxirane ring-opening and subsequent lactonization is described. The methodology has been applied to the synthesis of a structural analogue of epipodophyllotoxins.

Full text of DOI:10.1021/ol800437s

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1947-1950
Michael Addition of Ortho-Lithiated
Aryloxiranes to r,ꢀ-Unsaturated
Malonates: Synthesis of
Tetrahydroindenofuranones
Antonio Salomone, Vito Capriati, Saverio Florio,* and Renzo Luisi
Dipartimento Farmaco-Chimico, UniVersita` di Bari, Consorzio InteruniVersitario
Nazionale Metodologie e Processi InnoVatiVi di Sintesi C.I.N.M.P.I.S.,
Via E.Orabona 4, I-70125 Bari, Italy
florio@farmchim.uniba.it
Received February 26, 2008
ABSTRACT
A short and efficient synthesis of tetrahydroindenofuranones based on the Michael addition of ortho-lithiated aryloxiranes to alkylidene malonates
followed by the nucleophilic oxirane ring-opening and subsequent lactonization is described. The methodology has been applied to the synthesis
of a structural analogue of epipodophyllotoxins.
Functionalized organolithium compounds such as ortho-
lithiated aryloxiranes and aziridines represent a class of
particularly interesting reactive intermediates as their trapping
with certain electrophiles, followed by the oxirane or
aziridine ring-opening-promoted cyclization, can be a useful
strategy for the construction of complex molecules in few
synthetic steps.1
Indeed, it has been recently found in our laboratory that
addition of ortho-lithiated arylaziridines2 or aryloxiranes3 to
carbonyl compounds results in the formation of aminomethyl-
or hydroxyalkylphthalanes, respectively.
leading to tetrahydronaphthols,4 through a highly stereose-
lective conjugate addition. Such unexpected regioselectivity,
unusual for organolithiums which generally tend to give 1,2-
addition, encouraged us to investigate the addition reaction
of ortho-lithiated aryloxiranes to R,ꢀ-unsaturated carbonyl
compounds.5
Herein, we report a short and efficient synthesis of tri-
and disubstituted tetrahydroindenofuranone derivatives based
on the conjugate addition of ortho-lithiated aryloxiranes to
benzylidene and alkylidene malonates.6 Under optimized
reaction conditions (n-BuLi, -78 °C, 15 min) for the
Moreover, we had discovered that ortho-lithiated stilbene
oxides add to R,ꢀ-unsaturated Fischer carbene complexes
(4) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Salomone, A.;
Gasparrini, F. Org. Lett. 2005, 7, 4895–4898.
(1) For selected reviews on functionalized organolithium compounds,
see:(a) Wu, G.; Huang, M. Chem. ReV. 2006, 106, 2596–2616. (b) Na´jera,
C.; Yus, M. Curr. Org. Chem. 2003, 7, 867–926.
(2) Capriati, V.; Florio, S.; Luisi, R.; Musio, B. Org. Lett. 2005, 7, 3749–
3752.
(5) Preliminary experiments were conducted using methylcinnamate,
chalcone, and trans-cinnamaldehyde: there was no reaction when ortho-
lithiated trans-stilbene oxide was treated with methylcinnamate, and only
1,2-addition products were obtained in the case of chalcone and trans-
cinnamaldehyde (see ref 3). For examples of Michael additions promoted
by organolithium compounds, see: Curtis, M. D.; Beak, P. J. Org. Chem.
1999, 64, 2996–2997, and refs cited therein.
(3) Capriati, V.; Florio, S.; Luisi, R.; Perna, F. M.; Salomone, A. J.
Org. Chem. 2006, 71, 3984–3987.
10.1021/ol800437s CCC: $40.75
Published on Web 04/19/2008
 2008 American Chemical Society

Table 1. Synthesis of Tetrahydroindenofuranones 4a-g
a Isolated yields after column cromatography on silica gel. b Diastereomeric ratio calculated by 1H NMR on the crude reaction mixture. c Separable
mixture of diastereomers.
lithium-bromine exchange on the o-bromostyrene oxide 1a
(R1 ) H), we generated the organolithium 1a-Li which
reacted with benzylidene malonate 5a (R2 ) Ph) to give the
tetrahydroindenofuranone 4a (60% yield) as an equimolar
mixture of diastereomers (Table 1, entry 1). All this could
be likely explained with a domino reaction that starts with
the 1,4-addition of 1a-Li to 5a to give the intermediate 2a-
Li which then cyclizes on the oxirane ring via a stereospecific
intramolecular SN2 (5-exo-tet mode), leading to 3a-Li;
successive lactonization furnishes 4a (Scheme 1).
Similarly, 1a-Li reacted smoothly with the electron-rich
malonate 5b [R2 ) 3,4,5-(CH3O)3C6H2] to give tricyclic
product 4b in 50% yield and with a small increase of the
diastereomeric ratio (Table 1, entry 2). An aliphatic sub-
stituent on the ꢀ-carbon of the malonate was also tolerated,
so that lithiated 1a reacted with the enolizable malonate 5c
Scheme 1
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Org. Lett., Vol. 10, No. 10, 2008

(R2 ) n-Pr) to give tetrahydroindenofuranone 4c (50% yield)
(Table 1, entry 3).
The relative configuration of (3aR*,8R*,8aS*)-4a and
(3aR*,8R*,8aS*)-4c was deduced after transformation in known
compounds. Specifically, hydrolysis of the ester moiety with
LiOH/DME and subsequent decarboxylation performed in
toluene at 100 °C with a catalytic amount of AcOH gave,
respectively, the tetrahydroindenofuranones (3aR*,8S*,8aR*)-
6a and (3aR*,8R*,8aR*)-6c whose spectral data fitted quite well
those reported by Muraoka and Momose (Scheme 2).10 By
To extend the scope of the above domino process, we
briefly investigated the substitution effect in the starting
oxirane. Monosubstituted oxirane 1b-Li, bearing a lithiated
electron-rich aryl moiety (Table 1, entry 4), reacts with 5b
affording the expected product 4d in moderate yield (50%).
In contrast, trans-disubstituted oxiranes 1c (R1 ) Me) and
1d (R1 ) Ph) react with aromatic and aliphatic malonates
5a and 5c providing, after stirring the reaction mixture
overnight at room temperature, the uncyclized Michael
adducts 2e-g (Scheme 1). The substitution of oxiranes 1c,d
could be likely responsible, for steric reasons, for the
unsuccessful intramolecular cyclization.
Scheme 2
With the Michael adducts 2e-g in hand, we checked the
suitable experimental conditions for their cyclization to the
corresponding tetrahydroindenofuranones. To this end, we
first investigated the role of the cation in the ring-opening
reaction: a solution of 2f in THF was treated at room
temperature with t-BuOK, but after 12 h stirring, only starting
material was recovered. Similarly, treatment of 2f with NaH
in DMF did not furnish any expected product. After several
attempts, we found that using EtOLi, EtONa, or t-BuOK in
EtOH or t-BuOH at room temperature, tetrahydroindeno-
furanone 4f was obtained as the sole diastereomer in a good
yield (70% yield in the case of the t-BuOK/t-BuOH system,
Table 1, entry 6).7 The same methodology was used to obtain
products 4e,g from the corresponding oxiranes 2e,g.
We also checked the possibility of making the tetrahy-
droindenofuranone 4f in one-pot simply by adding, to the
ethereal reaction medium after completion of the Michael
addition, a polar protic solvent such as EtOH. After stirring
the reaction mixture for 3 days at room temperature, we
obtained, after workup and purification by column chroma-
tography on silica gel, the desired tetrahydroindenofuranone
4f in 50% yield (dr > 98/2).8
performing the hydrolysis-decarboxylation sequence on the
second diastereomer (3aR*,8S*,8aS*)-4a, formed in the reaction
of 1a-Li with 5a, we obtained the tetrahydroindenofuranone
(3aR*,8R*,8aR*)-6a whose relative stereochemistry was as-
signed on the basis of the coupling constant value between the
benzylic proton Ha and the vicinal proton Hb in the 1H NMR,
3
the JHa-Hb (9.9 Hz) being diagnostic of a dihedral angle
Moreover, it is worth noting that the stereoselectivity of
the conjugate addition of ortho-lithiated trans-1,2-disubsti-
tuted oxiranes 1c,d to malonates was strongly improved in
the case of adduct 4f obtained as the sole diastereomer (Table
1, entry 6).9
H8-C8-C8a-H8a near zero.11,12
This observation is in agreement with the nearly absent
coupling (3JHa-Hb ≈ 0 Hz) in the epimeric compound
(3aR*,8S*,8aR*)-6a whose dihedral angle H8-C8-C8a-H8a
value is nearly 90°.
The relative configuration of tetrahydroindenofuranones
(6) The Michael addition of aryllithiums to R,ꢀ-unsaturated malonates
was reported by Kende and coworkers, as a key step in the racemic synthesis
of an epipodophyllotoxin derivative. Such a methodology was employed
in the construction of the tetrahydronaphthalene core starting from an ortho-
bromobenzylether: Kende, A. S.; King, M. L.; Curran, D. P. J. Org. Chem.
1981, 46, 2826–2828.
1
4b,d-f was achieved by H NMR analysis on the basis of
the dibenzylic H8 chemical shift analogy with the reference
product 4a. Indeed, we noted that in the diastereoisomers
bearing the ethoxycarbonyl group and the H8 on the same
side, the resonance of the latter was downfield shifted of
about 0.4-0.5 ppm with respect to the corresponding
epimers, most probably because of the anisotropic effect of
the carbonyl ester group. To support this assumption, we
noted that both epimers of tetrahydroindenofuranone 6a, in
which the carbonyl anisotropic effect is missing, show a
(7) After treating 2e-g with t-BuOK, compounds 4e-g were isolated
as a mixture of ester and the corresponding carboxylic acid, because of a
partial hydrolysis of the lactone and/or ethoxycarbonyl groups. Therefore,
it was necessary to treat the crude with EtOH/H2SO4(cat) in order to obtain
exclusively the desired indenofuranones 4e-g (for details, see Supporting
Information).
(8) The one-pot procedure was also employed for the synthesis of 4g
obtained in 50% yield (dr 80/20) after stirring the reaction mixture for one
day.
(9) Starting from cis-1d, we thought that it would be possible to make
epimeric tetrahydroindenofuranone diast-4f with the stereogenic center C3
“R”sinstead of “S”sconfigured, as previously synthesized starting from
trans-1d. All the attempts carried out by using ortho-lithiated cis-1d resulted
in a very complex mixture of products containing only traces of a 60/40
diastereomeric mixture of diast-4f. After column cromatography, it was
possible to isolate and characterize only the major diastereoisomer (for
details, see Supporting Information).
(10) Muraoka, O.; Tanabe, G.; Kyohko, S.; Minematsu, T.; Momose,
T. J. Chem. Soc., Perkin Trans. 1 1994, 1833–1845.
(11) For all tetrahydroindenofuranones 4a-g and 6a-c, it is reasonable
to assume that, for thermodynamic reasons, the γ-lactone ring may be fused
to the indane system only in a cis fashion
(12) Semiempirical calculations on the substituted indenofuranone
systems confirm such values of dihedral angles
.
.
Org. Lett., Vol. 10, No. 10, 2008
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(R)-1a-Li and (R,R)-1d-Li add to malonate 5b and 5a with
an excellent enantioselectivity leading to the formation
of a separable mixture of diastereoisomers (3aR,8S,8aS)-
4b, (3aR,8R,8aS)-4b (for both er ) 97/3), and (2R,1′R,2′R)-
2f (er ) 98/2), respectively; the latter was then isolated
and easily transformed, enantiospecifically, to the corre-
sponding lactone (3S,3aR,8R,8aS)-4f (er ) 98/2).
Compound (3aR,8S,8aS)-4b could be smoothly hydrolyzed
and decarboxylated to give the corresponding tetrahydroin-
denofuranone (3aS,8S,8aS)-6b (80%, er ) 97/3), the con-
figuration of all stereocenters remaining unaffected.
In conclusion, we have developed a simple and efficient
domino process for the assembly of unusual tetrahydroin-
deno[1,2-c]furanone systems,14 based on the Michael addi-
tion of ortho-lithiated aryloxiranes to R,ꢀ-unsaturated mal-
onates. Since organolithiums often give direct addition to
the carbonyl group (1,2-addition), the complete regioselec-
tivity of the process, toward 1,4-addition, is noteworthy.
The methodology can also be applied to the stereospecific
synthesis of highly enantiomerically enriched tetrahydroin-
denofuranone derivatives starting from chiral nonracemic
ortho-bromo aryloxiranes. Moreover, the utility of the
methodology has been underscored by preparing compound
4d as a structural analogue of the natural antitumoral
epipodophyllotoxins.15,16
Scheme 3
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” by the University
of Bari and by the Interuniversities Consortium CINMPIS.
nearly equal value of chemical shift for the H8 resonance
(∆δ < 0.1 ppm).
The relative configuration of (3R*,3aS*,8S*,8aR*)-4g was
established by detecting positive NOE effects, diagnostic of
the spatially close hydrogen relationship, after applying
selective 1H preirradiation within a double pulsed field
gradient spin-echo NOE (DPFGSE-NOE) sequence.13
The possibility of making optically active tetrahydroin-
denofuranones was also evaluated. Indeed, we found that
Supporting Information Available: Experimental pro-
cedures and compound characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800437S
(13) Neuhaus, D.; Williamson, M. The Nuclear OVerhauser Effect in
Structural and Conformational Analysis; VCH: New York, 1989; p 264.
(14) To the best of our knowledge, the sole methodology described in
the literature, concerning the construction of the tetrahydroindeno[1,2-
c]furan-1-one skeleton, was based on the photochemical rearrangement of
benzylfuranones, see: Muraoka, O.; Tanabe, G.; Sano, K.; Momose, T.
Heterocycles 1992, 34, 1093–1096.
(15) For the synthesis and biological evaluation of structural analogues
of epipodophyllotoxins, see: Klein, L. L.; Yeung, C. M.; Chu, D. T.;
McDonald, E. J.; Clement, J. J.; Plattner, J. J. J. Med. Chem. 1991, 34,
984992.
(16) For a recent strategy about the synthesis of Podophyllotoxin and
its analogues, see: Wu, Y.; Zhang, H.; Zhao, Y.; Zhao, J.; Chen, J.; Li, L.
Org. Lett. 2007, 9, 1199–1202.
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