An efficient total synthesis of (±)-ar-tenuifolene

Article abstract of DOI:10.1016/j.tetlet.2015.07.087

(±)-ar-Tenuifolene was synthesized using a ring expansion mediated by a formal 1,3-alkyl shift reaction on a trans-1-aryl-2-propenyl-cyclobutancarbonitrile as the key step to generating the cyclohexene moiety. The conditions for this rearrangement are des

Full text of DOI:10.1016/j.tetlet.2015.07.087

Tetrahedron Letters 56 (2015) 5321–5323
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Tetrahedron Letters
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An efficient total synthesis of ( )-ar-tenuifolene
⇑
Adrián Vázquez-Sánchez, José Gustavo Ávila-Zárraga
Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
( )-ar-Tenuifolene was synthesized using a ring expansion mediated by a formal 1,3-alkyl shift reaction
on a trans-1-aryl-2-propenyl-cyclobutancarbonitrile as the key step to generating the cyclohexene
moiety. The conditions for this rearrangement are described.
Received 3 June 2015
Revised 22 July 2015
Accepted 27 July 2015
Available online 3 August 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
trans-1-Aryl-2-
propenylcyclobutanecarbonitriles
ar-Tenuifolene
Ring expansion
Carbocyclic cleavage
A range of marine and terrestrial sources continue to provide
interesting and structurally inspiring natural products that attract
the interest of medicinal and synthetic organic chemists alike.
Our research group focuses on the synthesis of biologically
active natural products. We recently developed an interest in
1-aryl-2-propenylcyclobutanecarbonitrile rearrangements as an
approach to a variety of carbocyclic derivatives.
Prior studies revealed the formation of benzocyclooctene ring
adducts upon treatment of substrate 1 under certain conditions.1
Later studies revealed that the application of different conditions
to substrate 1 yielded a six-membered ring instead of the antici-
pated eight-membered ring (Scheme 1).
structure 2 was prevalent, leading us to recognize the close resem-
blance between the core of the natural products ar-tenuifolene and
tenuifolene (Fig. 1). In view of this insight, we focused our efforts
on achieving on the first place the total synthesis of the natural
product using an appropriate raw material.
As described for the first time in 2004 by König4, ar-tenuifolene
is found in the essential oil of Olearia tenuifolia, together with its
reduced analog tenuifolene. O. tenuifolia presents pharmacological
properties and has been used by the Masai tribe in East Africa as a
medicine against gonorrhea5 and as an antipyretic in cattle.6
ar-Tenuifolene has also been identified in the essential oils of
Radula perrottetii7 and Callitris sulcata.8
After elucidating the structure of the unexpected product 2, we
realized that the connectivity conversion displayed by 1 could be
viewed as a formal 1,3-alkyl shift. Such rearrangements, although
rare, have been described in the past, and they are known mecha-
nistically to proceed by various pathways, depending on the nature
of the substrate.2 Methodologies involving this kind of transforma-
tion have been implemented in total syntheses.3 Data that could
elucidate the pathway through which our reaction proceeded were
not previously available; however, systems with similar function-
alities have been studied, and the determining steps of those reac-
tions were shown to depend on the particular system functionality
present.2f
The first and only synthesis of ( )-ar-tenuifolene was reported
by Srikrishna and Beeraiah in 2005.9 These researchers proposed
using a key ring-closing metathesis (RCM) step to form the
cyclohexene moiety.
In view of the evidence supporting a ring expansion mecha-
nism, we envisaged an ( )-ar-tenuifolene synthesis through a
Wolff–Kishner reduction of the aldehyde (3), which could be
reached through the chemoselective reduction of nitrile 4.
This cyclohexenecarbonitrile was affordable after
a 1,3-alkyl
shift in 1-(4-methylbenzene)-2-propenyl-cyclobutancarbonitrile
(5) (Fig. 2).
Our synthetic approach began from 4-methylbenzylcyanide 7,
which was first treated with n-BuLi in THF at a temperature of
À78 °C, followed by treatment with 5-iodo-2-methylpent-2-ene
as an alkylating agent, to generate the homoisoprenylic moiety.
Subsequently, an epoxidation protocol10 with dimethyldioxirane
(DMDO), generated in situ by OxoneÒ, was used to produce
epoxynitrile 6 in an 80% global yield.
As we ascertained the structure of compound 2, we set out to
explore rearrangements that expanded template substrates. At
the same time, we realized that the sesquiterpenoid character on
⇑
Corresponding author. Tel./fax: +52 555 622 3805.
E-mail address: gavila@unam.mx (J.G. Ávila-Zárraga).
http://dx.doi.org/10.1016/j.tetlet.2015.07.087
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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A. Vázquez-Sánchez, J. G. Ávila-Zárraga / Tetrahedron Letters 56 (2015) 5321–5323
Scheme 1. Possible reaction outcomes for substrate 1.
The next step effectuated an intramolecular anionic cyclization
according to a variant of a methodology reported previously by our
group.11 This approach was suited for the construction of this type
of carbocyclic system. The variant methodology involved the treat-
ment of 6 with sodium amide in benzene under reflux.
This approach yielded two trans-regioisomers: cyclopentane-
and cyclobutanecarbinols. The regioisomeric mixture was
dehydrated with thionyl chloride and Et3N in toluene at 0 °C.
This protocol allowed us to synthesize the trans-1-(4-methylben-
zene)-2-propenylcyclobutanecarbonitrile (5), in 45% yield.
We observed an interesting effect involving isomeric selectivity
during the dehydration step. Only the cyclobutanic adduct reacted
to produce an isomeric mixture of alkenes, leaving the cyclopen-
tanic adduct unaffected (Scheme 2). This allowed us to make the
conversion of 6 to 5 without purifying the isomeric mixture of
alcohols.
Figure 1. Structures of ( )-ar-tenuifolene and ( )-tenuifolene.
CHO
The key step of the synthesis involved the rearrangement
described above, which depended significantly on the temperature.
The reaction did not proceed at temperatures below 115 °C, and
increases in the temperature were found to reduce the necessary
reaction time. We concluded that the energetic barrier to the trans-
formation could only be overcome at temperatures exceeding
115 °C. Solvents, such as chlorobenzene and DMF, were evaluated
for their ability to reduce the reaction barrier, and ultimately ethy-
lene glycol was selected for the easy work-up that it enabled.
Treatment of 5 in ethylene glycol at 140 °C was found to yield
the cyclohexenecarbonitrile 4 in a 90% yield.
3
ar-tenuifolene
CN
CN
5
4
Finally, a two-step reduction was performed on the nitrile 4.
DIBAL-H was first used on DCM at 0 °C to generate the aldehyde
Figure 2. Retrosynthetic analysis of ( )-ar-tenuifolene.
2.7
:
1
NC
CN
CN
OH
NaNH2
PhCH3
O
OH
6
SOCl2
Et3N
0°C
2.5
:
1
CN
CN
NC
OH
5
Scheme 2. Reaction pathway from 6 to 5 through a selective dehydration.

A. Vázquez-Sánchez, J. G. Ávila-Zárraga / Tetrahedron Letters 56 (2015) 5321–5323
5323
CN
CN
CN
NC
d
a
b
c
O
6
7
5
(+/-)-ar-tenuifolene
4
Scheme 3. Synthesis of ( )-ar-tenuifolene. Reaction conditions: (a) (i) nBuLi, THF, À78 °C, 15 min; (ii) 5-iodo-2-methylpent-2-ene, À78 °C to rt, 30 min; (iii) OxoneÒ, NaHCO3,
acetone, H2O, rt. 2 h, 80% yield. (b) (i) NaNH2, PhH, reflux, 2 h; (ii) SOCl2, Et3N, toluene, 0 °C, 15 min, 45% yield. (c) Ethylene glycol, 140 °C, 3 h, 90% yield. (d) (i) DIBAL-H, DCM,
0 °C, 6 h; (ii) NH2-NH2ÁH2O, diethylene glycol, 150 °C, 1 h; (iii) KOH powder, 200 °C, 1 h, 71% yield.
3, which was subsequently subjected to a Wolff–Kishner–Huang
reaction with NH2-NH2ÁH2O in diethylene glycol at 150 °C. KOH
powder was added at 200 °C to finally give the ( )-ar-tenuifolene
in a 71% yield (Scheme 3). The spectral data obtained from the pro-
duct agreed well with the spectra obtained from the natural
product.
It is worth noting that Srikrishna and Beeraiah also synthesized
( )-tenuifolene via a Birch reduction on ( )-ar-tenuifolene, which
entitles us to say that our route also provides a formal synthesis
of ( )-tenuifolene.
assistance in acquiring the spectral data, and Oscar Palomino-
Hernández for helpful and valuable suggestions to this manuscript.
References and notes
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The methods described here provide a novel total synthesis
of ( )-ar-tenuifolene through
a formal 1,3-alkyl shift over
trans-1-(4-methylbenzene)-2-propenylcyclobutanecarbonitrile
with a global yield of 23%. This approach constitutes the most
efficient synthesis of ( )-ar-tenuifolene reported to date.
We are currently developing a deeper exploration of this type of
rearrangement, obtaining consistent results with the formation of
cyclohexane moieties. We hope these results will improve our
understanding of the reaction involved in producing ( )-ar-tenui-
folene and the possible mechanisms through which this reaction
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Acknowledgments
This research was supported by the Facultad de Química UNAM
through the assigned resources (PAIP 5000:9060), and CONACYT
through a Ph.D. scholarship awarded to A. Vázquez (235256). We
wish to thank to Rosa Del Villar and Georgina Duarte for their
9. Srikrishna, A.; Beeraiah, B. Ind. J. Chem. 2005, 44B, 1641–1643.
10. Hashimoo, N.; Kanda, A. Org. Process Res. Dev. 2002, 6, 405–406.
11. Luján-Montelongo, J. A.; Vázquez-Sánchez, A.; Ávila-Zárraga, J. G. Heterocycles
2009, 78, 2009.