Sulfoxide-directed desymmetrisation of cyclohexa-1,4-dienes

Article abstract of DOI:10.1016/j.tetlet.2007.04.138

Cyclohexa-2,5-dien-1-ylmethanol derivatives have been subjected to a short sequence featuring esterification to introduce a malonate side-chain, oxidation of the doubly allylic position and stereoselective cyclisation. When used in conjunction with a chiral sulfoxide, the cyclisation is diastereoselective (2:1) favouring one of the diastereotopic double-bonds.

Full text of DOI:10.1016/j.tetlet.2007.04.138

Tetrahedron Letters 48 (2007) 4561–4564
Sulfoxide-directed desymmetrisation of cyclohexa-1,4-dienes
Mark C. Elliott,a,* Nahed Nasser Eid El Sayeda,b and Li-ling Ooia
aSchool of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
bNational Organisation for Drug Control and Research (NODCAR), Agouza: 51 Wezaret El-Ziraa Street, Giza, Egypt
Received 29 March 2007; accepted 26 April 2007
Available online 1 May 2007
Abstract—Cyclohexa-2,5-dien-1-ylmethanol derivatives have been subjected to a short sequence featuring esterification to introduce
a malonate side-chain, oxidation of the doubly allylic position and stereoselective cyclisation. When used in conjunction with a
chiral sulfoxide, the cyclisation is diastereoselective (2:1) favouring one of the diastereotopic double-bonds.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
for inducing asymmetry. For our preliminary studies
we were attracted to the use of chiral sulfoxides,7 since
these can readily be formed with high enantiomeric
excess.8 This would constitute a diastereoselective
approach, and so a single enantiomer of the sulfoxide
would not actually be necessary in order to prove the
validity of the method.9
The stereoselective formation of quaternary stereogenic
centres, particularly all-carbon quaternary stereogenic
centres, is a significant challenge for the modern syn-
thetic chemist.1 As an alternative to the direct formation
of such a stereogenic centre using carbon–carbon bond
forming reactions, the indirect approach of desymmet-
rising a suitable precursor is attractive.2 Cyclohexa-
1,4-dienes are attractive substrates for such reactions,
and have been desymmetrised by way of free-radical,3
and anionic4 cyclisation reactions as well as by asym-
metric oxidation5 and cycloaddition.6 In a prototype
reaction, the cyclisation of compound 1 leads to the for-
mation of two new stereogenic centres, one of which is
quaternary. The double-bonds in diene 1 are enantio-
topic, and so preferential attack on one of them would
result in the enantioselective formation of the cyclised
product 2 (Scheme 1).
2. Discussion
Initially we chose to prepare achiral substrates which
would allow us to test the key bond-forming reactions
without the added stereochemical complexities, and for
this purpose selected a malonate-type nucleophile for
cyclisation. The formation of substrates 5a and 5b was
straightforward as shown in Scheme 2. Compounds
O
O
R
(i)
OH
R
There are a wide range of possible substrates for such a
reaction, these differing mainly in the choice of nucleo-
phile and tether length, but also in the method used
O
OEt
3a,b
4a, 47%
4b, 94%
(ii)
( )
( )
n
n
R
Nu
R
Nu
H
O
O
O
a, R = CH
b, R = allyl
3
R
OEt
O
O
1
2
O
5a, 36%
5b, 51%
Scheme 1.
Scheme 2. Reagents and conditions: (i) Ethyl malonyl chloride, Et3N,
DMAP, CH2Cl2; (ii) PDC, t-BuOOH in decane, celite, benzene.
*
Corresponding author. E-mail: elliottmc@cardiff.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.138

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M. C. Elliott et al. / Tetrahedron Letters 48 (2007) 4561–4564
3a10 and 3b were prepared by Birch reduction/alkyl-
ation11 of benzoic acid followed by reduction. Reaction
of alcohols 3a and 3b thus formed with ethyl malonyl
chloride gave mixed malonate esters 4a and 4b in mod-
erate yields. The allylic oxidation12 of these compounds
under standard conditions was a clean reaction, and
completely chemoselective, but unfortunately the iso-
lated yields of dienones 5a and 5b after chromatography
were relatively poor. Nevertheless, this method allowed
the formation of sufficient quantities of these com-
pounds for evaluation in the key cyclisation reaction.
Cyclisation of 5a or 5b could give rise to the formation
of four diastereomeric products. In the event, we have
only ever observed the formation of a single diastereo-
isomer (Table 1). Using sodium ethoxide in ethanol,
the desired product 6a was accompanied by significant
amounts of phenol 7a. This is presumably formed by
transesterification of 5a followed by deformylation.
Similar results were obtained with substrate 5b. Using
potassium t-butoxide as base in THF, only the desired
product 6a was formed from 5a, although with 5b,
compound 7b was also formed under these conditions
(Table 1). The stereochemistry of compounds 6a and
6b were deduced by extensive 2D NMR spectroscopy,
and are supported by the crystal structure determination
of a related compound (vide infra).
give stereoisomer 9, this will be followed by rapid proton
transfer under the reaction conditions to give malonate
anion 10. The observed stereochemistry will then be
defined upon protonation during work-up.
With these results in hand, our attention then turned to
the preparation of a chiral sulfoxide in order to carry
out an auxiliary-controlled cyclisation reaction. Cou-
pling of alcohols 3a and 3b with phenylsulfanylacetyl
chloride13 gave esters 11a and 11b in moderate yield.
Oxidation as before also gave clean oxidation of the
sulfide to the required sulfoxides 12a and 12b with no
evidence for over oxidation to the sulfone (Scheme 4).
With these two key substrates in hand, the cyclisation
step was attempted next (Scheme 5). Cyclisation of com-
pounds 12a and 12b both proceeded cleanly to give a
mixture of three compounds (2:1 mixture of the main
two compounds in both cases, plus small variable
amounts of a very minor component). These were sepa-
rated by column chromatography, although significant
losses occurred so that the isolated yields do not neces-
sarily reflect the stereoselectivity of the reaction.
Sufoxides 14a and 13b and sulfone 15a were character-
ised by single crystal X-ray diffraction (Figs. 1–3).14 Iso-
lation of the sulfones was somewhat surprising given the
Although the relative stereochemistry of compounds 6a
and 6b can easily be rationalised by the geometry shown
in structure 8 in Scheme 3, the actual scenario may not
be as straightforward. While this attack will most likely
O
R
(i)
OH
R
SPh
O
Table 1. Cyclisation of compounds 5a and 5b
5
11a, 77%
11b, 46%
O
O
O
O
H
R
R
R
O
OEt
(ii)
CO Et
2
+
H
O
O
O
a, R = CH3
b, R = allyl
OH
R
S
O
O
Ph
5a,b
6a,b
7a,b
Substrate
R
Conditionsa
Yield of 6 (%) Yield of 7 (%)
O
12a, 45%
12b, 23%
5a
5a
5b
5b
CH3 NaOEt, EtOH 35
CH3 KOt-Bu, THF 92
Allyl NaOEt, EtOH 31
Allyl KOt-Bu, THF 38
35
0
27
8
Scheme 4. Reagents and conditions: (i) Phenylsulfanylacetyl chloride,
Et3N, DMAP, CH2Cl2; (ii) PDC, t-BuOOH in decane, Celite, benzene.
a All reactions were carried out at 25 ꢁC.
O
O
S
R
O
O
H
O
O
O
Ph
H C
3
H C
3
O
O
H
5a
H
OEt
OEt
O
12a,b
(i)
O
O
8
9
O
O
H
O
O
O
O
R
H
R
R
H
O
O
O
O
H C
3
S
S
SO
Ph
+
+
2
H
H
H
O
H
Ph
Ph
6a
H
OEt
O
O
O
O
13a, 35%
13b, 16%
14a, 11%
14b, 15%
15a, 2%
15b, 4%
10
Scheme 3. Proposed reaction geometry and proton transfer.
Scheme 5. Reagents and conditions: (i) KOt-Bu, THF, 25 ꢁC.

M. C. Elliott et al. / Tetrahedron Letters 48 (2007) 4561–4564
4563
O
O
H C
3
H
(i)
(i)
SO
Ph
13a
2
14a
H
O
15a
Scheme 6. Reagents and conditions: (i) Oxoneꢂ, H2O, MeOH.
tion was carried out to approximately 50% conversion,
there was no isomerisation of the residual starting mate-
rial, confirming that both sulfoxides are stereochemi-
cally stable under the conditions used for oxidation.
In summary, we have demonstrated for the first time
that chiral sulfoxides can be used to direct the cyclisa-
tion of enolate nucleophiles onto cyclohexadienones.
Figure 1. Structure of compound 15a from X-ray crystallographic
data.
3. Experimental
3.1. Cyclisation of sulfoxide 12a
In a flame-dried flask and under a nitrogen atmosphere,
potassium t-butoxide (7 mmol, 0.78 g, 2 equiv) was
added to a cooled solution of sulfoxide 12a (1.059 g,
3.48 mmol) in dry THF (130 ml) at 0 ꢁC. The mixture
was stirred at this temperature for 5.5 h, and then at
room temperature for 17.5 h. The resulting mixture
was quenched with saturated NH4Cl solution (50 ml),
and the organic material was extracted into CH2Cl2
(3 · 50 ml). The combined extracts were dried over
Na2SO4 and concentrated in vacuo to afford 592 mg of
a crude mixture of compounds 15a, 14a, and 13a as a
golden solid. Purification by flash chromatography
(eluting with CH2Cl2–ethyl acetate 9.3:0.7) afforded,
on order of elution, pure products 15a, 14a and 13a.
Figure 2. Structure of compound 14a from X-ray crystallographic
data.
3.2. (SSR,4SR,4aRS,8aSR)-4-Benzenesulfinyl-8a-methyl-
1,4a,5,8a-tetrahydro-4H-isochromene-3,6-dione (13a)
Off-white solid (372 mg, 35%), mp 132–134 ꢁC (Found:
MH+ 305.0843. C16H17SO4 requires M, 305.0842); mmax
(CH2Cl2)/cmꢀ1 3055, 2985, 1724, 1686, 1424, 1265,
1050, 738; dH (400 MHz; CDCl3) 7.61–7.50 (5H, m,
5 · aromatic CH), 6.54 (1H, dd, J 10.3, 1.8 CH@CH–
C@O), 6.03 (1H, d, J 10.3, CH@CH–C@O), 3.86 (1H,
d, J 5.6, CH–SO), 3.75 (1H, d, J 11.3, one of O–CH2),
2.90–2.84 (3H, m, one of O–CH2, ring junction CH
and one of CH2–C@O), 2.47 (1H, dd, J 18.7, 4.0, one
of CH2–C@O), 1.09 (3H, s, CH3); dC (100 MHz; CDCl3)
195.2 (C@O), 163.6 (O–C@O), 152.2 (CH@CH–C@O),
139.3 (Cq–S), 132.7 (p-aromatic CH), 132.1 (CH@CH–
C@O), 129.5 (2 · o-aromatic CH), 125.1 (2 · m-aro-
matic CH), 74.5 (O–CH2), 66.5 (CH–SO), 40.6 (CH2–
C@O), 36.2 (Cq ring), 36.1 (ring junction CH), 20.7
(CH3); m/z (APCI) 305 (MH+, 100%), 247 (19), 179 (34).
Figure 3. Structure of compound 13b from X-ray crystallographic
data.
lack of sulfone impurities in sulfoxides 12a and 12b, and
we speculate that some oxidation of the cyclised sulfox-
ides is occurring upon chromatography. Although the
similarity in spectroscopic data between 13a and 13b
and between 14a and 14b strongly supports the assign-
ment of diastereoisomers at sulfur, this was confirmed
for 13a and 14a by oxidation of both compounds to give
sulfone 15a (Scheme 6). Furthermore, when this oxida-
3.3. (SSR,4RS,4aSR,8aRS)-4-Benzenesulfinyl-8a-methyl-
1,4a,5,8a-tetrahydro-4H-isochromene-3,6-dione (14a)
Yellowþsolid (118 mg, 11%), mp 108–110 ꢁC (Found:
MNH4 322.1111. C16H20SO4N requires M, 322.1108);

4564
M. C. Elliott et al. / Tetrahedron Letters 48 (2007) 4561–4564
mmax (CDCl3)/cmꢀ1 1737, 1685, 1445, 1404, 1247, 1060,
909, 733; dH (400 MHz; CDCl3) 7.61–7.56 (2H, m,
2 · aromatic CH), 7.55–7.50 (3H, m, 3 · aromatic CH),
6.63 (1H, dd, J 10.2, 1.8, CH@CH–C@O), 5.98 (1H,
d, J 10.2, CH@CH–C@O), 4.32 (1H, d, J 11.2, one of
O–CH2), 4.05 (1H, d, J 11.2, one of O–CH2), 3.25
(1H, d, J 5.1, CH–SO), 2.91–2.85 (1H, m, ring junction
CH), 2.36 (1H, dd, J 17.3, 5.2, one of CH2–C@O), 1.23
(3H, s, CH3), 0.93 (1H, dd, J 17.3, 2.7, one of CH2–
C@O); dC (100 MHz; CDCl3) 195.0 (C@O), 167.0 (O–
C@O), 152.9 (CH@CH–C@O), 140.2 (Cq–S), 132.3 (p-
aromatic CH), 131.7 (CH@CH–C@O), 129.8 (2 · o-aro-
matic CH), 124.0 (2 · m-aromatic CH), 74.7 (O–CH2),
69.4 (CH–SO), 39.8 (CH2–C@O), 36.5 (Cq ring), 33.6
(ring junction CH), 20.4 (CH3); m/z (APCI) 305
(MH+, 39%), 235 (35), 197 (10), 180 (12), 179 (100),
149 (10), 125 (37).
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3.4. (4RS,4aSR,8aRS)-4-Benzenesulfonyl-8a-methyl-
1,4a,5,8a-tetrahydro-4H-isochromene-3,6-dione (15a)
5. Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org.
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Off-white solid (21 mg, 2%), mp 185–186 ꢁC (Found:
þ
MNH4 338.1062. C16H20O5NS requires M, 338.1057);
mmax (CH2Cl2)/cmꢀ1 3056, 2940, 1737, 1680, 1319,
1265, 1149, 736; dH (400 MHz; CDCl3) 7.80 (2H, app.
dd, J 8.4, 1.2, 2 · o-aromatic CH), 7.66 (1H, app. tt, J
7.4, 1.2, p-aromatic CH), 7.56–7.50 (2H, m, 2 · m-aro-
matic CH), 6.63 (1H, dd, J 10.3, 2.0, CH@CH–C@O),
6.03 (1H, d, J 10.3, CH@CH–C@O), 4.51 (1H, d, J
11.3, one of O–CH2), 4.17 (1H, d, J 11.3, one of O–
CH2), 3.72 (1H, d, J 5.4, CH–SO2), 3.3 (1H, app. tt, J
5.0, 2.5, ring junction CH), 2.95 (1H, dd, J 17.5, 5.0,
one of CH2–C@O), 2.56 (1H, dd, J 17.5, 2.5, one of
CH2–C@O), 1.34 (3H, s, CH3); dC (100 MHz; CDCl3)
194.8 (C@O), 162.4 (O–C@O), 152.0 (CH@CH–C@O),
136.0 (Cq–S), 135.0 (CH@CH–C@O), 132.0 (p-aromatic
CH), 129.4 (2 · o-aromatic CH), 129.3 (2 · m-aromatic
CH), 75.2 (O–CH2), 69.6 (CH–SO2), 40.5 (CH2–C@O),
38.4 (ring junction CH), 36.9 (Cq ring), 20.3 (CH3);
m/z (APCI) 321 (MH+, 100%), 319 (11), 121 (16).
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8. For a review see: Kagan, H. B. Asymmetric Oxidation of
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Acknowledgements
We are extremely grateful to the Government of the
Arab Republic of Egypt for financial support, and to
the EPSRC National Mass Spectrometry Service, Uni-
versity of Wales, Swansea, for provision of high-resolu-
tion mass spectrometric data.
9. Sulfoxides have been used to direct intermolecular conju-
gate addition reactions onto cyclohexa-1,4-diene-3-ones:
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