2-Aryl-5-epoxynitrile anion cyclizations : Total syntheses of (±)-α-cuparenone and (±)-epilaurene

Article abstract of DOI:10.1246/cl.2000.512

Total syntheses of the cyclopentane sesquiterpenes of the title using an epoxynitrile anion cyclization reaction as key step, are described. The preferential formation of the cyclopentane ring from a terminal disubstituted 5-epoxynitrile (e.g. 2b) had not previously been observed. The 2-aryl substituent is reasonably assumed to be responsible for this divergence.

Full text of DOI:10.1246/cl.2000.512

512
Chemistry Letters 2000
2-Aryl-5-epoxynitrile Anion Cyclizations : Total Syntheses of ( )-α-Cuparenone
and ( )-Epilaurene
J. Gustavo Avila-Zárraga and Luis A. Maldonado*
Instituto de Química and División de Estudios de Posgrado, Facultad de QuÌmica, UNAM, Ciudad Universitaria,
Coyoacán, 04510 México D.F., México
(Received February 14, 2000; CL-000154)
Total syntheses of the cyclopentane sesquiterpenes of the
cyclization are unknown. Now we wish to report an interesting
deviation of the expected result in the cyclization of a substrate
containing an α-aryl group as substituent, which has led us to a
simple, new total synthesis of ( )-α-cuparenone 1b.5 From these
studies, a total synthesis of ( )-epilaurene 1c has also been
achieved.6
title using an epoxynitrile anion cyclization reaction as key
step, are described. The preferential formation of the cyclopen-
tane ring from a terminal disubstituted 5-epoxynitrile (e.g. 2b)
had not previously been observed. The 2-aryl substituent is rea-
sonably assumed to be responsible for this divergence.
Cyclization of several acyclic and cyclic 6,6-disubstituted-5-
epoxynitrile anions was reported by Stork and Cohen1b to give
cyclobutanes in good yields (58-80%). No cyclopentanes were
detected in these experiments. However, in our hands cyclization
of epoxynitrile 2b7 with 2.5 eq of lithium hexamethyldisilazide
(LHMDS) in refluxing C6H6 for 1 h gave a 60% yield of a 2:1
mixture of the cyclopentane (3b) and the cyclobutane (4b) iso-
mers, respectively.8 Although the isomers could be separated by
preparative tlc in silica gel (hexanes-ethyl acetate, 4:1, 5 elu-
tions), for practical purposes PCC oxidation (3 eq, rt, CH2Cl2) of
the cyclized crude mixture gave cyclopentanone 5 and unreacted
cyclobutylcarbinol 4b, more easily separated by flash column
chromatography in silica gel (hexanes-ethyl acetate, 7:3) (see
Scheme 1).
The 5-epoxynitrile anion cyclizations were originally pro-
posed by Stork and coworkers in 1974 as a general method for
cyclobutane formation and this was exemplified by a simple
synthesis of the monoterpene grandisol.1-3 Shortly afterwards,
Lallemand and Onanga in 1975 made the important observation
that the ring size of the cyclized product was dependent of the
geometry of the epoxide: epoxides from cis-olefins give exclu-
sively cyclobutanes and those from trans-olefins give mixtures
of cyclobutanes and cyclopentanes, predominating the latter.4
From the above studies it is clear that until now a special
attention has been given to the epoxide environment, but investi-
gations concerning the influence of large substituents in the α-
position of the nitrile group towards the regiochemistry of
The structure of cyanocyclopentanone 5 was easily
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
513
assigned from spectroscopic data [IR (film) 2232, 1747 cm-1;
1H-NMR (200 MHz, CDCl3) δ 7.27 (m, 4H), 2.80-2.50 (m,
4H), 2.35 (s, 3H), 1.32 (s, 3H, anti-CH3 to the aryl group), 0.63
(s, 3H, syn-CH3 to the aryl group)] and by its eventual conver-
sion to α-cuparenone 1b following the standard reactions
shown in the Scheme (40% overall yield from 5).
Am. Chem. Soc., 96, 5270 (1974).
2
3
For examples of the closely related 6-epoxynitrile anion
cyclization see Ref. 1 and R. Achini and W. Oppolzer,
Tetrahedron Lett., 1975, 369. Recently, a 7-epoxynitrile
anion cyclization has also been reported: A. Nitta, A.
Ishiwata, T. Noda, and M. Hirama, Synlett, 1999, 695.
For a review on reactions of nitrile carbanions see: S.
Arseniyadis, K. S. Kyler, and D. S. Watt, Org. React.
(N.Y.), 31, 1 (1984).
The cyclization reaction was next studied with substrate
2a7,9 (LDA, THF, rt, 7 h) but in this case no influence by the
aryl substituent was found, since a 3:1 mixture of cyclopentanol
3a and cyclobutylcarbinol 4a was obtained in good accord with
the results of Lallemand and Onanga4 for α-unsubstituted sub-
strates. Yields were 44 and 15% respectively (59 and 20%
based on recovered epoxide). The anti relationship of the aryl
and methyl groups in 3a was established by the normal chemi-
4
5
J. Y. Lallemand and M. Onanga, Tetrahedron Lett., 1975,
585.
For previous synthesis of α-cuparenone see: a) M. G.
Kulkarni and D. S. Pendharkar, Tetrahedron, 53, 3167
(1997). b) J. Cossy, B. Gille, S. BouzBouz, and V.
Bellosta, Tetrahedron Lett., 38, 4069 (1997) and references
cited in these papers.
For previous synthesis of epilaurene see: A. Fadel, J.-L.
Canet, and J. Salaun, Tetrahedron : Asymmetry, 4, 27
(1993) and references cited therein. For a recent synthesis
of a 1:1 mixture of epilaurene and laurene see: M. G.
Kulkarni and D. S. Pendharkar, J. Chem. Soc., Perkin
Trans. 1, 1997, 3127.
2-Aryl-5-epoxynitriles 2a and 2b were obtained in ~60%
yields by alkylating the 4-methylphenylacetonitrile carban-
ion (LDA, THF, -78º) with the corresponding alkenyl
iodides (-78º→ rt, overnight), followed by epoxidation
(mcpba, CH2Cl2, rt). Some dialkylated product (5-10%)
was also isolated in the alkylation reaction.
With LDA in THF at rt only traces of epoxide ring opening
products were detected after 24 h. Hence, the base and sol-
vent were changed to allow heating.
1
cal shift observed for the CH3 doublet (δ 1.12) in the H-NMR
spectrum. If this relationship were syn, it would be expected a
strong high field shift of this signal due to the aromatic ring (cf.
6
7
1
the syn-CH3 chemical shift in the H-NMR spectrum of com-
pound 5). Finally, the conversion of 3a into the known ketone
1a11 (35% overall yield) completed the formal syntheses of epi-
laurene 1c and also α-cuparenone 1b.5b
The reaction mechanism to explain the preference for the
cyclopentane formation in the cyclization of 2b is unclear, but
steric interference between the aryl group and the gem-dimethyl
group in the transition state leading to the cyclobutane isomer
should play a significant role. On the other hand, the similar
results obtained in the cyclization reaction with other aryl sub-
stituted substrates (phenyl and 3-methoxy-4-methylphenyl) sug-
gest a negligible electronic effect caused by the aryl substituent.
Finally, in the case of cyanocyclopentanol 3a the observed
stereochemistry can be explained as the result of minimum
steric interactions in the transition state for the cyclization (pre-
ferred Ar,H eclipsing vs. Ar,CH3 eclipsing).12
In summary, we have achieved new total syntheses of ( )-
α-cuparenone 1b and ( )-epilaurene 1c using the previously
unobserved 2-aryl-5-epoxynitrile anion cyclization as key step.
The potential use of the results described in this paper for the
enantioselective syntheses of these sesquiterpenes, is being
investigated in our laboratories.
8
9
Since the alkenyl iodides were obtained by the cyclopropyl-
carbinyl-homoallyl cation rearrangement in the presence
of iodide anion,10 the geometry of the olefin precursor was
reasonably assumed to be E.
10 W. Biernacki and A. Gdula, Synthesis, 1979, 37.
11 Cyclopentanone 1a was first prepared by T. Irie, T. Suzuki,
Y. Yasunari, E. Kurosawa, and T. Masamune,
Tetrahedron, 25, 459 (1969), but in this paper the relative
stereochemistry of the 2-methyl and 3-(p-tolyl) groups was
incorrectly assigned as syn. See: J. E. McMurry and L. A.
von Beroldingen, Tetrahedron, 30, 2027 (1974). See also
Ref. 5b for an alternative synthesis of 1a.
12 In the case of cyclobutylcarbinols 4a and 4b the indicated
stereochemistry is proposed based on that found, by X-ray
analysis, for the derived carboxamide of the phenyl ana-
logue of 4b: G. Avila, L. A. Maldonado, and R. A.
Toscano, J. Chem. Cryst., 27, 125 (1997).
We are grateful to Alejandrina Acosta, Marisela Gutiérrez,
Graciela Chávez, Claudia Contreras, Luis Velasco, Javier
Pérez-Flores and Wilber Matus, for their assistance in acquiring
spectral data. We also thank DGAPA-UNAM for a fellowship
financial support.
References and Notes
1
a) G. Stork, L. D. Cama, and R. D. Coulson, J. Am.
Chem.Soc., 96, 5268 (1974). b) G. Stork and J. F. Cohen, J.