An improved protocol for the Prins desymmetrisation of cyclohexa-1,4-dienes

Article abstract of DOI:10.1016/j.tetlet.2008.05.022

Improved conditions are reported for the Prins-pinacol rearrangement of cyclohexa-1,4-diene-derived acetals. The use of triflic acid gives particularly clean reaction, resulting in a mixture of regioisomers in an approximately 10:1 ratio. A tethered version of this reaction is also reported, giving a tricyclic compound with the same stereochemistry as the core of the cladiellin diterpenes.

Full text of DOI:10.1016/j.tetlet.2008.05.022

Tetrahedron Letters 49 (2008) 4446–4448
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An improved protocol for the Prins desymmetrisation of cyclohexa-1,4-dienes
a
a
a
Michael Butters b, Mark C. Elliott a, , Joseph Hill-Cousins , James S. Paine , Alexander W. J. Westwood
*
a School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
b AstraZeneca Process R&D Avlon/Charnwood, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Improved conditions are reported for the Prins-pinacol rearrangement of cyclohexa-1,4-diene-derived
acetals. The use of triflic acid gives particularly clean reaction, resulting in a mixture of regioisomers
in an approximately 10:1 ratio. A tethered version of this reaction is also reported, giving a tricyclic
compound with the same stereochemistry as the core of the cladiellin diterpenes.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 2 April 2008
Accepted 1 May 2008
Available online 10 May 2008
The Prins reaction of cyclic acetal derivatives permits an extre-
mely versatile entry into highly functionalised tetrahydropyrans,1
and has been widely used in total synthesis.2 Since the initial prod-
uct of the Prins cyclisation is a carbenium ion, there are a number
of possibilities for rearrangement reactions. Notable amongst these
is the Prins-pinacol sequence pioneered by the group of Overman.3
Application of the Prins reaction to distinguish between diastereo-
topic double bonds in chiral substrates has received limited atten-
tion.4 Due to the considerable potential of cyclohexa-1,4-diene
desymmetrisation reactions,5,6 we have initiated a programme of
research in this area,7 and have recently reported that the Prins-
pinacol rearrangement of compounds 1 give the benzo[c]furan
carboxaldehyde derivatives 2 in modest yields (Scheme 1).8
The low yields of the aldehyde products are mainly due to the
formation of a number of chlorinated by-products. We therefore
sought alternative conditions for this transformation, focusing on
the use of strong acid catalysts with non-nucleophilic counter-ions.
The use of both triflic acid and boron trifluoride etherate was
found to be effective, with the former generally giving higher
yields (1.1–5 equiv). Both gave extremely clean reactions.
R2
R2
R2
H+
O
O
HO
O
O
OH
R1
or
R1
R1
1
3
4
R1
R1
HO
O
HO
O
R2
R2
H
H
HO
HO
R1
R1
O
H
H
O
Whilst the use of titanium tetrachloride permitted regiospecific
acetal opening, triflic acid gave small amounts of ketone products 5
formed from oxocarbenium ion 4 (Scheme 2). In this instance, the
R2
H
R2
H
O
R1
H
O
H
R1
H
R2
+
O
H
H
O
O
R2
R1
O
O
O
TiCl4
R2
H
H
R1
2
5
R2
H
Scheme 2.
1
2, 20 - 44%
chirality present in the starting material is lost upon formation of
the ketone product 5. Since racemic substrates were used in the
present study, it is not possible to determine whether any diaste-
reoselection occurs during the cyclisation of oxocarbenium ion 4.
Scheme 1.
* Corresponding author. Tel.: +44 29 20874686; fax: +44 29 20874030.
E-mail address: elliottmc@cardiff.ac.uk (M. C. Elliott).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.022

M. Butters et al. / Tetrahedron Letters 49 (2008) 4446–4448
4447
R1
R
OH
H
R
R
R1
I2, NaHCO
3HO
HO
HO
O
HO
OH
+
O
I
H
O
H
O
CH3CN, 1 h
I
R2
H
R2
H
7a, R = CH3
7b, R = 2-BrC6H4
72% (8a: 9a = 7:1)
8b, 40% 9b, 32%
Scheme 4.
Scheme 3.
should be reversed, giving 11 (Scheme 5). Significantly, this is the
stereochemistry observed in the cladiellin diterpenes such as 7-
deacetoxyalcyonin acetate 12.10
The iodocyclisation of compounds 7 gives single (unassigned) ster-
eoisomers of compounds 9 (Scheme 3),9 so we would certainly not
rule out this possibility. Where R1 = Me, only the cis isomers 2 of
the aldehydes were obtained (Table 1). The reaction is reasonably
tolerant of steric bulk, although the acetal derived from pivalalde-
hyde (entry 4) gave slow conversion and low isolated yields of
products.
The substrate for such a reaction, 13, was prepared as shown in
Scheme 6. Gratifyingly, when this compound was treated with tri-
flic acid in dichloromethane, deprotection of the silyl ether groups
occurred followed by formation and Prins-pinacol rearrangement
of the oxocarbenium ion, giving compound 14. The mass balance
for this deprotection–cyclisation-rearrangement sequence is low,
such that the crude reaction mixture consists almost entirely of
the desired product as a single diastereoisomer. Attempts to
improve the efficiency of the overall process by initial deprotection
of compound 13 gave only complex mixtures of products.
Determination of the stereochemistry of compound 14 was not
straightforward, with no diagnostic cross-peaks being observed in
In examples where R1 = Ph, epimerisation to the trans aldehyde
6 occurs if longer reaction times are used, although this is essen-
tially suppressed by using an excess of acid and a short reaction
time (Table 2). The example in entry 6 is particularly noteworthy
since this compound was not formed when TiCl4 was used.8 The
product stereochemistries were determined by NOESY NMR meth-
ods, and by comparison with our previous work.
The stereochemistry of the formation of compounds 2 is deter-
mined by the minimisation of A1,3 strain in the transition state
(Scheme 4).8
CHO
H
HO
( )n
H
H
We therefore reasoned that if the R1 and R2 groups were teth-
ered, as in structure 10, the stereochemical outcome of the reaction
( )
nO
O
H
H
10
11
Table 1
H
H
Prins rearrangement of compounds 1 (R0 methyl)
H
H
R2
O
R1
H
O
O
H
H
R1
O
OAc
O
O
TfOH
HO
+
R1
O
12, 7-deacetoxyalcyonin acetate
R2
H
R2
H
Scheme 5.
1
2
5
Entry
R1
R2
Equiv TfOH
Time
Yield 2 (%)
Yield 5 (%)
1
2
Me
Me
Me
Me
Me
Me
1.6
1.1
1.1
1.1
1.1
15 min
90 min
90 min
4 h
66
60
53
11
48
6
7.5
7
O
CO2Me
n-Bu
i-Bu
t-Bu
Ph
LDA, THF, -78 ºC
MeO2C
3
4a
5
5
then 4-pentenoyl chloride
59%
90 min
Trace
a
25% starting material was recovered.
i) LiAlH4, THF
ii) TBSOTf,
2,6-lutidine,
CH2Cl2
Table 2
68%
Prins rearrangement of compounds 1 (R0 phenyl)
OTBS
OTBS
R2
9-BBN, THF, 18 h
OH
O
H
H
O
H
H
R1
O
R1
TBSO
TBSO
O
O
then H2O2, NaOH
84%
TfOH
+
O
R1
PDC, CH2Cl2
18 h, 59%
R2
R2
H
H
1
2
6
CHO
H
H
H
OTBS
Entry
R1
R2
Equiv TfOH
Time
Yield 2 (%)
Yield 6 (%)
TfOH (1 equiv.)
CHO
TBSO
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
n-Bu
i-Bu
Ph
5
15 min
1 h
1.5 h
1 h
15 min
15 min
64
50
0
51
58
61
0
8
61
4
0
0
O
CH2Cl2, 0 - 25 ºC
1.1
1.5
1.1
5
32%
H
13
14
5
Scheme 6.

4448
M. Butters et al. / Tetrahedron Letters 49 (2008) 4446–4448
J. R.; Hughes, J. R.; Parker, G. D.; Roe, R.; Willis, C. L. Chem. Commun. 2005,
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the NOESY NMR spectrum. Based on molecular modelling of the
two possible diastereoisomers, the observed NMR coupling con-
stants are far more compatible with the diastereoisomer shown.
This evidence, coupled with the mechanistic reasoning shown
above, leads us to propose the stereochemistry as shown.
In summary, the Prins-pinacol reaction of cyclohexa-1,4-diene-
derived acetals is improved significantly by the use of triflic acid. A
tethered version of this reaction has been developed which gives
the correct stereochemistry for the cladiellin diterpenes. Further
studies on this class of compound are underway, and will be re-
ported in due course.
Compound 14: Trifluoromethanesulfonic acid (0.02 ml, 0.178
mmol) was added dropwise to a solution of aldehyde 13 (78 mg,
0.178 mmol) in CH2Cl2 (2 ml) at 0 °C. The resulting brown solution
was warmed to room temperature and stirred for 20 min before
being quenched with saturated aqueous sodium hydrogen carbon-
ate solution. The crude product was extracted with CH2Cl2. The
combined extracts were dried over Na2SO4 before the solvent
was removed in vacuo. Chromatography on silica gel (1:6 EtOAc/
petroleum ether) afforded compound 14 (11 mg, 32%) as a colour-
less oil (Found: M+, 192.1141. C12H16O2 requires M, 192.1150);
mmax (neat) 2933, 2850, 1682, 1643, 1464, 1430, 1177, 1010, 872,
739 and 668 cmꢀ1; dH (400 MHz; CDCl3) 9.37 (1H, s, aldehyde),
6.97 (1H, dd, J 5.1, 4.1, alkene CH), 3.96 (1H, app. s, CH–O), 3.89
(1H, app. br s, CH–O), 2.95 (1H, d, J 8.6, ring junction CH), 2.41
(1H, app. dt, J 8.6, 5.5, ring junction CH), 2.33–2.24 (1H, m, one
of CH2 next to double bond), 2.21–2.11 (1H, m, one of CH2 next
to double bond) and 1.72–1.53 (7H, m) and 1.44–1.38 (1H, m); dC
(100 MHz; CDCl3) 194.5 (CH), 153.3 (CH), 143.8 (C), 82.5 (CH),
82.3 (CH), 39.4 (CH), 38.9 (CH), 30.7 (CH2), 30.6 (CH2), 26.5 (CH2),
23.0 (CH2) and 16.5 (CH2); m/z (TOF EI+) 192 (M, 76%), 145 (44)
and 91 (100).
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We are extremely grateful to AstraZeneca and the EPSRC for
financial support.
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