Palladium (II) catalyzed 5-endo epoxynitrile cyclizations: total syntheses of enokipodins A and B

Article abstract of DOI:10.1016/j.tetlet.2010.02.072

New total syntheses of the cuparenic sesquiterpenes enokipodins A and B were accomplished. The key step involves a novel, cationic-controlled and palladium (II) improved, 5-endo cyclization of an α-aryl-δ-epoxynitrile. The cyclization occurs with unmatched regioselectivity and high stereoselectivity. The synthesis is completed in 5 steps achieving yields of 50% for enokipodin A and 55% for enokipodin B.

Full text of DOI:10.1016/j.tetlet.2010.02.072

Tetrahedron Letters 51 (2010) 2232–2236
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium (II) catalyzed 5-endo epoxynitrile cyclizations: total syntheses
of enokipodins A and B
*
Jesús Armando Luján-Montelongo, José G. Ávila-Zárraga
Facultad de Química, Universidad Nacional Autónoma de México, D.F., 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
New total syntheses of the cuparenic sesquiterpenes enokipodins A and B were accomplished. The key
Received 23 January 2010
Revised 8 February 2010
Accepted 12 February 2010
Available online 19 February 2010
step involves a novel, cationic-controlled and palladium (II) improved, 5-endo cyclization of an
a-aryl-
d-epoxynitrile. The cyclization occurs with unmatched regioselectivity and high stereoselectivity. The
synthesis is completed in 5 steps achieving yields of 50% for enokipodin A and 55% for enokipodin B.
Ó 2010 Elsevier Ltd. All rights reserved.
Enokipodins A–D (1–4) are four cuparenic sesquiterpenes iso-
lated from the edible mushroom Flammulina vellutipes (Enokitake)
by Ishikawa et al.1 From this specie, a variety of compounds with
pharmacological activity have been isolated.2 Being structurally
similar to coprinol3 (5) and lagopodin A4 (6) (Fig. 1), in terms of
their polycyclic skeleton, enokipodins show similar biological
activity against the Gram-positive bacteria Bacillus subtilis and
Staphylococcus aureus;1,3,4 however, they were ineffective against
Gram-negative bacteria.3
It’s been recognized that cuparenic sesquiterpenes are interesting
synthetic targets5–9 due to the difficulty on constructing the quater-
nary carbon centers over the cyclopentane moiety. Concerning the
statedabove, enokipodinsA–B(1–2)havebeenattractivetoscreendi-
verse methodologies intended to build cyclopentanic systems9a–c as
well as the application of asymmetric building protocols for benzylic
centers.9d–f There is no doubt enokipodins have been the most recur-
ring synthetic targets among all the oxidized cuparenic species.
Although the RCM,5 dicarbonyl compound intramolecular con-
densation6 and cyclobutane rearrangment7 are frequently chosen
as cuparene-type sesquiterpene syntheses methodologies, the
intramolecular nucleophilic displacement8 hasn’t been a widely
accepted approach to assemble the cyclopentane system on those
compounds. As expected, the enokipodin’s five-membered system
is mainly synthesized by the first three approaches only.9
solvents, promote a 5-endo pathway of cyclization; on the other
hand, sodium hexamethyldisilamide in low boiling hydrocarbonat-
ed solvents leads to 4-exo cyclizations. Therefore, it could be pro-
posed the Stork cyclization (Scheme 1)13 could be applied not
only in constructing cyclobutane-containing molecules originally
stated by the author, but to species which include cyclopentanic
rings like cuparenic derivatives as well.
These results established that Lewis’ acids involved in these sys-
tems had an important effect in terms of reaction regioselectivity
which could be directly translated to control the carbocycles pro-
portion in the product mix. This is a complementary work to pre-
vious studies where the cyclization preferred pathway was
attributed just to the reagent’s sterical profile,13,14 and became
possible the regiochemical outcome modification by modulating
experimental conditions and base.
Recently, we reported a study regarding the cyclization of
a-
aryl-d-epoxynitrile type compounds featuring a novel cationic me-
tal regioselectivity control.10 This type of regiocontrol is barely
known;11 however, an analogous control has been found in reac-
tions which show divergence in their stereoselectivity by the
involvement of different alkaline cations.12 It was found the use
of lithium or potassium salts of the hexamethyldisilamide base
in these systems, employing high boiling point hydrocarbonated
* Corresponding author. Tel.: +525 556 223 784; fax: +525 556 223 722.
E-mail address: gavila@correo.unam.mx (J.G. Ávila-Zárraga).
Figure 1. Enokipodins A–D (1–4) and some related oxidized cuparenic species.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.072

J. A. Luján-Montelongo, J. G. Ávila-Zárraga / Tetrahedron Letters 51 (2010) 2232–2236
2233
Scheme 3. Synthesis of the d-epoxynitrile 9.
Table 1
Lewis acid catalyzed d-epoxynitrile 9 anionic cyclization study
Entry
Base
Catalyst
Cat. load (% mol)
Yielda (%)
8a:8bb
1
2
3
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
DIPEA
—
—
20
20
20
20
20
20
20
20
20
10
5
90
20(60)
79
60
74
27
0(100)
19
65
79
80
85
0(100)
0(100)
80
2.8:1
2.9:1
1:2.1
1:4.9
3:1
Ti(OiPr)4
InCl3
Cu(OTf)2
Cu(OTf)2
BiI3
Bi(OTf)3
Sc(OTf)3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Scheme 1. Cation controlled regioselective cyclizations of a-aryl-d-epoxynitriles.
4
5c
6
2.2:1
—
Keeping this in mind we decided to include in this type of cycli-
zation other acidic species, in order to evaluate if an additional 5-
endo promotion could emerge to improve yield of cyclopentanic
structures over cyclobutanic with no chemo and stereoselectivity
sacrifice whatsoever. In that way, we developed a new divergent
route towards the enokipodins A and B (1, 2) total syntheses by
employing a methodology based on intramolecular nucleophilic
7
8
9
3.7:1
1:4.8
3.2:1
1:4.7
1:4.9
—
10c
11
12
13
14
15
10
10
5
—
PdCl2
PdCl2
—
1.2:1
carbocyclization of an
a-aryl-d-epoxynitrile which features high
LHMDS
regioselectivity by alkaline metal cationic modulation, assisted by
additional Lewis acids.
Scheme 2 depicts the retrosynthetic plan for Enokipodins A and
B (1, 2). It was expected that cyclopentanone 7 could be precursor
a
b
c
Parentheses indicate the recovered yield of epoxynitrile 9.
Determined by 1H NMR of the crude product.
In these cases benzene was used as solvent.
Scheme 2. Retrosynthetic plan for the enokipodins syntheses.

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J. A. Luján-Montelongo, J. G. Ávila-Zárraga / Tetrahedron Letters 51 (2010) 2232–2236
of 1 and 2, as described by Srikrishna.9a Key intermediate 9 synthe-
sis was conducted as shown in Scheme 3. Starting from 2,5-dime-
thoxy-4-methylphenyl acetonitrile10,15 (11), homoisoprenilic oxide
moiety was constructed by an alkylation–oxidation protocol.10
With d-epoxynitrile 9 on hand, we looked for the regioselectiv-
ity improvement of its cyclization by adding Lewis acids (Table 1).
Considering epoxynitrile cyclization, comparable in some way to
an intramolecular aldolic reaction, applied criteria attempted to
mimetize these species catalytic role, especially on Pd(II),16
Cu(II),17 Ti(IV),18 Sc(III),19 In(III)20 y Bi(III)21 cases. Furthermore,
some of these metals are involved in epoxide catalytic openings.22
As shown on Table 1, both PdCl2 (entry 9) and Cu(OTf)2 (entry 4)
are outstanding catalysts to enhance regioselectivity when the
reaction was carried out with KHMDS in toluene (which showed
best results at the absence of any additive). However, the reaction
where Pd (II) took part, showed the best yield as well as a ‘‘cleaner”
profile (entry 9). Once the appropriate catalyst was selected, the
best result was achieved with a 5% mol of PdCl2 (entry 12), which
kept good regioselectivity and slightly improved yield. As we antic-
ipated, reactions in benzene didn’t show preference on the 5-endo
pathway (entries 5 and 10).
dinated to O-coordinated specie. At this point, once activated the
oxiranyl function and promoting the C–O bond weakening of the
more substituted carbon, 5-endo pathway would be accessible.
Alternatively, regiospecific formation of a chlorohydrin intermedi-
ate23 could take place, fixing the reactive position on the more
substituted carbon. Interestingly, usage of lithium base showed
poor regioselectivity (Table 1, entry 15) and usage of DIPEA or ab-
sence of base afforded no cyclization products (Table 1, entries 13
and 14). This way, it was established that both base nature and
metallic counter-ion are essential to achieve good regioselectivity.
Important to mention Lewis acid catalized cyclization is com-
pletely stereoselective; this was concluded by inspecting 1H
NMR, 13C NMR and GC/EIMS spectra on both regioisomers. The
cyclopentanic isomer relative stereochemistry (8b) was assigned
as like by means of NOESY experiments (vide infra).
Next step involved the reduction of cyano to methyl and oxida-
tion of hydroxyl group of the cyclopentane moiety (Scheme 5). At
first step, cyanocyclopentyl alcohol 8b was treated with DIBAH
(along with the corresponding acidic workup) affording an alde-
hyde derivative which was used with no further purification in
the next step. The Huang-Minlon24 procedure applied to the resi-
due yields the reduced cyclopentanol 13 in an outstanding yield
(2 steps, 97%). Later on, cyclopentenone 7 was obtained in 87%
yield by Dess–Martin25 oxidation of 13, which was slightly inferior
but less harmful to the environment compared to PCC oxidation
(91%).26
5-Endo promotion effected by PdCl2 can be understood by
inspecting two presumably side effects (Scheme 4). First, PdCl2
could be forming a coordination entity, where nitrogen of the cya-
no function could participate in the metallic core, in such way that
a rearrangement would take place into, changing from an N-coor-
Scheme 4. Possible pathways of PdCl2 assisted 5-endo cyclization of 9.

J. A. Luján-Montelongo, J. G. Ávila-Zárraga / Tetrahedron Letters 51 (2010) 2232–2236
2235
Marisela Gutiérrez, Margarita Guzmán, Nayeli López and Georgina
Duarte for all their valuable assistance at acquiring spectral data.
Supplementary data
Supplementary data (experimental procedures and spectral
data for compounds 1–2, 7, 8a–b, 13) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
02.072.
Scheme 5. Preparation of precursor 7.
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This research work was sponsored by Facultad de Química
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