Acid-induced transannular cyclization of 2-methyl- and 10-methyl-5-cyclodecenone

Article abstract of DOI:10.1016/S0040-4039(01)00618-9

2-Methyl- and 10-methyl-5-cyclodecenone were made by anionic oxy-Cope rearrangement of the corresponding 1,2-divinylcyclohexanols, and their transannular cyclizations were induced using trifluoroacetic acid. In each case, a single diastereomer of a trans fused bicyclo[4.4.0]decan-1-ol with an equatorial methyl group was isolated. The methyl substituent at C2 or C10 of the 5-cyclodecenone did not alter the regio- and stereochemistry previously observed for the parent ring system, (E)-5-cyclodecenone. The relative stereochemistry of the products was determined spectroscopically from J-value analysis and NOE.

Full text of DOI:10.1016/S0040-4039(01)00618-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3815–3817
Acid-induced transannular cyclization of 2-methyl- and
10-methyl-5-cyclodecenone
Yongliang Chu,a James B. Whiteb,* and Brian A. Duclosb
aDepartment of Chemistry and Biochemistry, Box 19065, The University of Texas at Arlington, Arlington, TX 76019, USA
bDivision of Natural Science, Pepperdine University, 24255 Pacific Coast Highway, Malibu, CA 90263, USA
Received 16 November 2000; revised 2 April 2001; accepted 3 April 2001
Abstract—2-Methyl- and 10-methyl-5-cyclodecenone were made by anionic oxy-Cope rearrangement of the corresponding
1,2-divinylcyclohexanols, and their transannular cyclizations were induced using trifluoroacetic acid. In each case, a single
diastereomer of a trans fused bicyclo[4.4.0]decan-1-ol with an equatorial methyl group was isolated. The methyl substituent at C2
or C10 of the 5-cyclodecenone did not alter the regio- and stereochemistry previously observed for the parent ring system,
(E)-5-cyclodecenone. The relative stereochemistry of the products was determined spectroscopically from J-value analysis and
NOE. © 2001 Elsevier Science Ltd. All rights reserved.
In previous work we have shown that (E)- and (Z)-5-
cyclcodecenone undergo ring closure to give products
from either transannular 1,5-cyclization or 1,6-cycliza-
tion, depending on the reaction conditions.1 1,6-
Cyclization of this ring system under acidic conditions
is particularly interesting, as it stereospecifically con-
verts the three prochiral sp2-hybridized centers at C1,
C5 and C6 of (E)-5-cyclodecenone (1) into the three
asymmetric centers in the product 2. Such cyclizations
lead to products that are far more complex structurally
than their starting materials. Indeed, among one-bond
disconnections of the bicyclo[4.4.0]decane system,
transannular cyclization of a ten-membered ring leads
to the greatest increase in complexity.2
conjugate base of the acid to the alkene. These two
phenomena lead to the relative stereochemistry among
the three stereocenters of bicyclo[4.4.0]decanol 2, i.e.
with a trans ring fusion at C1 and C6, and the sub-
stituent at C5 in an equatorial position.
In our syntheses of africanol and isoafricanol,3 we
examined the affect of a methyl group at C2 on the
transannular cyclization of a 5-cyclodecenone that
underwent 1,5-cyclization, but we have not previously
investigated such an affect in a system that would be
expected to undergo 1,6-cyclization based on its struc-
ture and the reaction conditions. Herein we report on
the preparation and acid-induced transannular cycliza-
tion of (E)-2-methyl- and (E)-10-methyl-5-cyclode-
cenones (3 and 4).
The stereospecificity of the 1,6-cyclization of 5-cyclode-
cenone 1 can be understood to arise from two phenom-
ena given that the alkene is trans. One is that the
reaction takes place from a parallel conformation, i.e.
one in which the C5ꢀC6 and C1ꢀ10 bonds of 5-cyclode-
cenone 1 are parallel, which leads to a trans ring fusion.
The other phenomenon is that the reaction takes place
with net anti addition of the carbonyl carbon and
Synthesis of (E)-2-methyl-5-cyclodecenone (3) and (E)-
10-methyl-5-cyclodecenone (4). (E)-2-Methyl-5-cyclode-
cenone (3) was prepared from commercially available
2-chlorocyclohexanone. Addition to this chloroketone
of one equivalent of vinylmagnesium bromide followed
CF3CO2
5
6
CF3CO2H
O
OH
O
O
2
1
2
3
4
Keywords: oxy-Cope rearrangement; 5-cyclodecenones; transannular cyclizations.
* Corresponding author. E-mail: jwhite@pepperdine.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00618-9

3816
Y. Chu et al. / Tetrahedron Letters 42 (2001) 3815–3817
Cl
1) CH2=CHMgBr, 0°C
KH, THF
O
18-C-6
RT, 85%
2) CH2=CH(CH3)MgBr
OH
O
3) ∆, 3h, 51%
5
7
6
3
Cl
1) CH2=CHMgBr
1) LDA, -78°C
KH, THF
O
O
18-C-6
∆, 72%
THF
2) TMSCl
HO
O
3) SO2Cl2, 52%
2) ∆, 61%
8
9
4
Scheme 1.
by one equivalent of isopropenylmagnesium bromide
gave the known divinylcyclohexanol 6,4 which in turn
underwent anionic oxy-Cope rearrangement to give
(E)-2-methyl-5-cyclodecenone (3).
makes it possible to relate relative stereochemistry at
C1, C5, and either C2 (for 14) or C10 (for 15). Irradia-
tion of the methyl group signal at around 0.8 ppm leads
to a clean enhancement of hydroxyl proton at 4 ppm.
Likewise, irradiation of the hydroxyl proton leads to an
enhancement not only of the methyl group but also of
the hydrogen on C5. Given that the hydrogens at C5
(and C6) are both axial from their J values, it follows
that the hydroxyl group at C1 must also be axial in
order to observe an NOE with the axial hydrogen at
C5. Likewise, the methyl group on C2 of 14 and C10 of
15 must be equatorial in order to observe an NOE with
the axial hydroxyl group at C1 (Scheme 3).
The synthesis of (E)-10-methyl-5-cyclodecenone (4)
began with 2-methylcyclohexanone (7). The kinetic eno-
late of 2-methylcyclohexanone was first converted into
the corresponding enolsilane, which was then treated
with sulfuryl chloride to give 2-chloro-6-methylcyclo-
hexanone (8) as a single diastereomer. Addition of an
excess of vinylmagnesium bromide to the chloroketone
gave the divinylcyclohexanol 9. Anionic oxy-Cope re-
arrangement of the alcohol led to 5-cyclodecenenone 4
(Scheme 1).
The stereochemical outcome for the 1,6-cyclizations of
5-cyclodecenones 3 and 4 is akin to that observed for
the unsubstituted cyclodecenone 1, i.e. they all take
place from a parallel conformation with net anti addi-
tion to the alkene. The additional factor in the cycliza-
tions of 5-cyclodecenones 3 and 4 is the orientation of
the methyl group at C2 or C10 during the cyclization,
as some parallel conformations would lead to an equa-
torial orientation, and others to an axial orientation.
5-Cyclodecenone 4 is also available from 1,2-divinyl-
cyclohexanol
itself,
as
previously
reported.5
Diastereomers 10 and 12 were each independently sub-
jected to oxy-Cope rearrangement under basic condi-
tions, and both gave (E)-10-methyl-5-cyclodecenone (4)
upon quenching with methyl iodide. In these reactions,
either before or during the alkylation step, both 1,5-
dienolates 11 and 13 undergo rearrangement to a 1,6-
dienolate that is trapped by methyl iodide (Scheme 2).
The observed preference for the equatorial position in
the cyclizations of both 5-cyclodecenones 3 and 4 can
be understood in terms of steric effects that destabilize
the transition states leading to an axial methyl group.
For 5-cyclodecenone 3, transition states leading to the
methyl group in an axial position would experience
gauche interactions between the methyl group and the
axial hydrogens at C4, C6 and C10 in bicyclo-
[4.4.0]decanol 14. Such interactions are absent in the
competing transition states that lead to the methyl
group in an equatorial position. For 5-cyclodecenone 4,
Acid-induced transannular cyclization of (E)-2-methyl-
and (E)-10-methyl-5-cyclcodecenone (3 and 4) and
determination of the relative stereochemistry of the prod-
ucts. Cyclization of cyclodecenones 3 and 4 in methyl-
ene chloride with trifluoroacetic acid was highly
selective, leading to bicyclo[4.4.0]decanols 14 and 15,
respectively.
The relative stereochemistry of bicyclo[4.4.0]decanols
14 and 15 was determined spectroscopically. It is appar-
ent from the splitting patterns and coupling constants
for the hydrogen alpha to the trifluoroacetoxy group at
C5 (td, J=10.2 and 4.5 Hz for 14 and td, J=10.7 and
4.6 Hz for 15) that the hydrogens at C5 and C6 are
both axial in both products. This data is consistent with
the hydrogen at C5 being axial and vicinal to two axial
hydrogens (one on C4 and one on C6) with approxi-
mately equal coupling constants (Jax–ax between 10 and
11 Hz), and vicinal to one equatorial hydrogen on C4
(Jax–eq=4.5–4.6 Hz).
CH3I
CH3I
KH
KH
OH
OK
10
11
10
O
2
4
OK
OH
12
13
The alcohol proton of bicyclo[4.4.0]decanols 14 and 15
appears as a sharp singlet at 4 ppm in DMSO-d6, which
Scheme 2.

Y. Chu et al. / Tetrahedron Letters 42 (2001) 3815–3817
3817
CF3CO2
O2CCF3
4
6
CF3CO2H
56%
H
H
H3C
2
O
OH
OH
3
14
CF3CO2
4
O2CCF3
6
CF3CO2H
65%
CH3
OH
10
O
HO
15
4
Scheme 3.
a similar argument holds, except that the steric interac-
tions would be between the methyl group and the axial
hydrogens at C2, C6 and C8 in bicyclo[4.4.0]decanol
15.
for its application in the synthesis of more highly
substituted hydronaphthanol derivatives.
Acknowledgements
It should be noted, however, that it does not follow
from this limited study that any non-hydrogen sub-
stituent at C2 or C10 of an (E)-5-cyclodecenone will
end up equatorial upon 1,6-cyclization, syn to an axial
bridgehead hydroxyl group. Substituents that are
smaller than a methyl group would experience less of a
steric effect, and other factors besides steric effects
could play a role in the diastereoselectivity of the
reaction. For example, we have previously studied the
1,5-cyclization of a 5-cyclodecenone substituted at C2
with an ethoxy group.6 Although not entirely
analogous, the trifluoroacetic acid-induced cyclization
led to the ethoxy group being anti to the bridgehead
hydroxyl group at C1 of the bicyclo[5.3.0]decan-1-ol.
We attributed the diastereoselectivity of the reaction to
an electronic effect, i.e. a minimization of the net dipole
moment in the transition state that led to the product.
However, in the acid-induced cyclizations of 5-cyclode-
cenones, absent a silyl or stannyl group to alter the
regiochemistry of the cyclization, there appears to be a
clear preference in a 1,6-cyclization for an alkyl sub-
stituent at C2 or C10 to end-up equatorial in the
product.
We thank the Robert A. Welch Foundation, the
National Institutes of Health (GM44170-01), the
Department of Chemistry and Biochemistry of The
University of Texas at Arlington and Pepperdine Uni-
versity for their generous support of this research.
Purchase of the C,H,N analyzer through a grant from
the Defense Advanced Research Projects Agency moni-
tored by the Office of Naval Research is gratefully
acknowledged. We are grateful to the Parsons Founda-
tion for funding the purchase of a Bruker Avance
DPX200 and a Nicolet Impact 400D IR spectrometers
and the construction of an organic synthesis laboratory.
We also acknowledge Professor Roger Macomber for a
stimulating discussion on the use of NMR for deter-
mining relative stereochemistry and Professor David
Green for his assistance in carrying out NOE experi-
ments.
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