Stereodivergent radical cyclisation reactions of cyclohexa-1,4-dienes

Article abstract of DOI:10.1016/j.tetlet.2005.03.042

Derivatives of cyclohexa-1,4-diene diol 5 undergo highly diastereoselective free-radical cyclisation reactions. Selective reaction of either double bond is possible depending on the protecting groups used.

Full text of DOI:10.1016/j.tetlet.2005.03.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2957–2959
Stereodivergent radical cyclisation reactions of
cyclohexa-1,4-dienes
Mark C. Elliott* and Nahed Nasser Eid El Sayed
Cardiff School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
Received 21 January 2005; revised 2 March 2005; accepted 8 March 2005
Available online 22 March 2005
Abstract—Derivatives of cyclohexa-1,4-diene diol 5 undergo highly diastereoselective free-radical cyclisation reactions. Selective
reaction of either double bond is possible depending on the protecting groups used.
Ó 2005 Elsevier Ltd. All rights reserved.
Desymmetrisation reactions have been used to great
effect in organic synthesis,1 offering an elegant entry into
a range of natural and non-natural compounds, includ-
ing acyclic,2 carbocyclic3 and heterocyclic.4 Cyclohexa-
diene systems have a great deal of potential in this
area, some of which has been realised in a number of
studies. The Birch-reduction/alkylation sequence allows
the easy formation of cyclohexadienes with a quaternary
centre,5 desymmetrisation of which will lead to the
stereoselective formation of a quaternary stereogenic
centre6 in addition to at least one other stereogenic
centre (Scheme 1).
In order to test the general approach, achiral substrate 2
was prepared by alkylation of Birch-reduction product
1. Although compound 2 could conceivably be prepared
in a one-pot Birch reduction/alkylation, this would
require an excess of 2-bromobenzyl bromide, so the
method shown in Scheme 2 is more convenient. Cyclisa-
tion of compound 2 under standard conditions gave
tricycle 3,8 albeit in somewhat disappointing yield.9
With this result in hand, we next set about preparing
chiral cyclohexadiene derivatives in order to examine
the diastereoselective process. Deprotonation of 1 and
reaction with 2-bromobenzaldehyde failed, but we were
able to react the same anion with 2-bromobenzoyl chlo-
ride to give ketone 4. While reduction of the ketone gave
Within this general strategy, there are many cyclisation
reactions which could be used. Similarly, there is a
broad range of potential substrates with a variety of
stereochemical directing groups. We initially set out to
investigate free-radical cyclisation reactions onto
cyclohexadiene rings, with the aim of elucidating the
conformational bias in such systems.7 We now report
a versatile cyclisation reaction, which provides both dia-
stereoisomers of the cyclised product stereoselectively by
control of the substrate conformation.
MeO2C
H
LDA, THF, -78 °C then
Br
MeO2C
2-bromobenzyl bromide
70%
1
2
Bu3SnH, AIBN
benzene, heat
32%
( )n
X
( )n
X
R
R
H
MeO2C
Scheme 1.
H
Keywords: Desymmetrisations; Free-radical reactions; Cyclisations.
*
3
Corresponding author. Tel.: +44 029 20874686; fax: +44 029
20874030; e-mail: elliottmc@cardiff.ac.uk
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.042

2958
M. C. Elliott, N. N. E. El Sayed / Tetrahedron Letters 46 (2005) 2957–2959
flexibility of the compound considerably. Formation of
this compound was accomplished without difficulty
(Scheme 4).
MeO2C
H
LDA, THF, -78 °C
Br
MeO2C
then
O
Cl
Br
52%
O
With substrates 5, 6, 7 and 9 in hand, we investigated the
free-radical cyclisation reactions as shown in Scheme 5.
In all cases, a moderate to high level of diastereoselectiv-
ity was obtained, with only the formation of compound
10 proceeding in an unacceptably low yield. The prefer-
ential formation of stereoisomer 13 from 9 was con-
firmed by NOE studies. The stereochemistry of
compounds 10 and 11 was indirectly proved by conver-
sion of 13 into compounds 14 and 15 (Scheme 6). Both
of these compounds could be clearly seen as the minor
component in the formation of compounds 10 and 11.
The stereochemistry of compound 12, for which an
impressive 10:1 isomer ratio was observed, was assigned
1
4
LiAlH4
THF, 0 °C
55%
OH
HO
Br
1
5
by comparison of the H NMR data with those of 10
and 11.
Scheme 3.
The stereochemical outcome of these reactions warrants
discussion. In the structure 9, it might be expected that
attack of the radical would only be possible on the dou-
ble bond shown. In fact, with the 1,3-dioxane ring in the
expected chair form as shown in Figure 1, the conforma-
tional bias towards the right-hand double bond is only
slight. However, this is clearly sufficient to provide good
stereocontrol. In the case of compounds 5, 6 and 7, there
is a significant bias towards a staggered conformation in
which the hydroxy group is over the cyclohexadiene ring
(Fig. 2). From this point, the radical is closer to the left-
significant quantities of 2-bromobenzyl alcohol, presum-
ably formed by retro-aldol reaction and further reduc-
tion, exhaustive reduction with lithium aluminium
hydride gave diol 5 cleanly (Scheme 3).
Based on recent work by Grainger et al.,10 we expected
the level of stereocontrol to be affected by the presence
of protecting groups on the secondary alcohol. Regiose-
lective protection of the primary alcohol in 5 as the TBS
ether 6 was straightforward, as was simultaneous pro-
tection of both hydroxy groups. Attempted acetylation
of 6 gave a small amount of the bis-acetate, while
attempted benzylation gave a low yield of compound 8
in which the silyl group had migrated from the primary
to the secondary alcohol. Tethering the two alcohols in
the acetonide 9 is of particular interest, as it reduces the
HO
OH
HO
Bu3SnH, AIBN
HO
benzene, heat
19% (50% d.e.)
H
Br
5
6
10
HO
OH
OH
1.1 eq. TBSCl
TBSO
HO
OH
Et3N, DMAP
CH2Cl2
TBSO
Bu3SnH, AIBN
Br
Br
TBSO
24 h, 58%
6
5
benzene, heat
53% (60% d.e.)
H
Br
NaH, THF
then
2.2 eq. TBSOTf
6 eq. 2,6-lutidine
11
PhCH2Br
17%
CH2Cl2, 20 h, 35%
TBSO
OTBS
Br
OTBS
Br
TBSO
OTBS
Bu3SnH, AIBN
TBSO
TBSO
HO
benzene, heat
52% (82% d.e.)
H
Br
7
12
8
7
CH3
O
H3C
O
CH3
O
H3C
O
CH3
O
H3C
O
OH
Bu3SnH, AIBN
Me2C(OMe)2, Me2CO
HO
benzene, heat
77% (67% d.e.)
camphorsulfonic acid
70%
Br
H
Br
Br
9
5
9
13
Scheme 4.
Scheme 5.

M. C. Elliott, N. N. E. El Sayed / Tetrahedron Letters 46 (2005) 2957–2959
2959
This conformational preference is presumably due in
large part to electronic repulsion between the two hy-
droxy groups giving the fully staggered conformation
shown. In the case of compounds 5 and 6 it is possible
that some hydrogen bonding may over-ride this prefer-
ence, giving significant amounts of the diastereomeric
product. However, the higher stereoselectivity in the
cyclisation of 7 may be solely attributable to steric
effects.
CH3
O
HO
H3C
HO
AcOH, H2O
72%
O
H
H
13
14
TBSCl, Et3N
DMAP, CH2Cl2
60%
In summary, the sense of diastereoselection in free-radi-
cal cyclisation reactions of cyclohexa-1,4-dienes can be
controlled by judicious choice of protecting groups,
giving products 10–15, all with good levels of
stereocontrol.
HO
TBSO
H
15
Acknowledgements
Scheme 6.
We are grateful to the Arab Republic of Egypt for finan-
cial support. We would also like to thank the EPSRC
Mass Spectrometry Centre at Swansea for provision
of high resolution mass spectrometric data, and to
Mr. Robert Jenkins for technical assistance.
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