Stereoselective synthesis of cis-2,6-bis-hydroxyalkyl-tetrahydropyrans by the permanganate promoted oxidative cyclisation of 1,6-dienes

Article abstract of DOI:10.1016/j.tetlet.2004.08.023

The first examples of permanganate promoted oxidative cyclisations of 1,6-dienes are described, providing exclusively cis-2,6-bis-hydroxyalkyl- tetrahydropyrans. In addition, good levels of asymmetric induction have been attained using dienoyl sultam substrates.

Full text of DOI:10.1016/j.tetlet.2004.08.023

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7269–7271
Stereoselective synthesis of
cis-2,6-bis-hydroxyalkyl-tetrahydropyrans by the permanganate
promoted oxidative cyclisation of 1,6-dienes
Alex R. L. Cecil and Richard C. D. Brown*
School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 11 June 2004; revised 28 July 2004; accepted 4 August 2004
Available online 23 August 2004
Abstract—The first examples of permanganate promoted oxidative cyclisations of 1,6-dienes are described, providing exclusively cis-
2,6-bis-hydroxyalkyl-tetrahydropyrans. In addition, good levels of asymmetric induction have been attained using dienoyl sultam
substrates.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Tetrahydrofuran (THF) and tetrahydropyran (THP)
rings are key structural and functional features present
in many biologically active natural products, such as
polyether antibiotics and Annonaceous acetogenins.1,2
A powerful method for the synthesis of cis-2,5-bis-
hydroxyalkyl-tetrahydrofurans (THF diols) is by oxida-
tive cyclisation of 1,5-dienes using transition metal-oxo
species (Mn, Os, Ru, Scheme 1).3,4 When MnO4À is used
as the oxidising agent, high levels of asymmetric induc-
tion may be attained using either chiral auxiliaries or a
chiral phase-transfer catalyst.3f–j,5
Recently, Piccialli has demonstrated that ruthenium oxo
species may be used to catalyse the stereoselective oxida-
tive cyclisation of 1,6-dienes to afford racemic trans-2,6-
bis-hydroxyalkyl-tetrahydropyrans (THP diols, Scheme
1).6 In contrast, the 1,6-diene, linalyl acetate, had been
reported not to undergo cyclisation in the presence of
permanganate.3b Here we report our preliminary results
detailing the first examples of permanganate promoted
oxidative cyclisation of 1,6-dienes to afford THP diols
with the controlled creation of upto four new stereo-
genic centres.
Previous work established that 1,5-dienoyl compounds
and 1,5-dienones were excellent substrates for perman-
ganate promoted oxidative cyclisation, therefore the
homologous 1,6-dienes were prepared following estab-
lished methods (Scheme 2). Swern oxidation of alcohols
1 and 2 gave the corresponding aldehydes 3 and 4,7
which were converted to the desired a,b-unsaturated
arylketones 7 and 8 by a sequence involving aldol reac-
tion and dehydration.8 Dienoyl sultams 10 and 11 were
prepared directly from the aldehydes 3 and 4 using the
Horner–Emmons reagent 9.3j,9
Various metal-oxo
R3
R4
species
R3
OH
R4
R1
R2
R1
HO
O
O
H
H
H
H
R2
RuCl3, NaIO4
R
R
OH
HO
R = Me (63%)
R = H (15%)
R
R
R = H or Me
Scheme 1. Oxidative cyclisation of 1,5-dienes and 1,6-dienes to provide
THF diols and THP diols, respectively.
Permanganate mediated oxidative cyclisation was first
carried out on the dienone 7 using the AcOH:acetone
conditions previously reported by us (Scheme 3).3j Pleas-
ingly, THP-diol 12 (17%) was obtained as one of two
isolated products, the other being 4-methoxybenzoic
acid (15%). In an effort to improve the yield of THP
diol 12, oxidation under phase-transfer conditions was
Keywords: Oxidative cyclisation; 1,6-Dienes; Permanganate; Tetra-
hydropyran synthesis.
*
Corresponding author. Tel.: +44 (0)23 80594108; fax: +44 (0)23
80596805; e-mail: rcb1@soton.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.023

7270
A. R. L. Cecil, R. C. D. Brown / Tetrahedron Letters 45 (2004) 7269–7271
investigated.5 Carrying out the reaction in CH2Cl2 at
OH
OH
O
À60ꢁC led to a significant improvement, increasing the
yield of 12 to 38%. Aqueous permanganate conditions
were also applied but this provided the cyclised product
in only 5% yield. The corresponding 2,6-trans-disubsti-
tuted THP was not observed in any of the reactions.
i
ii
3
O
3
3
R
R
R
Ar
R = H, 3 (83%)
R = Et, 4 (70%)
R = H, 5 (70%)
R = Et, 6 (68%)
R = H, 1
R = Et, 2
O
P
O
O
OMe
iii, iv
EtO
EtO
The oxidative cyclisations of the three additional 1,6-
dienes (8, 10 and 11) were performed using the condi-
tions described above, returning the desired THP diols
in moderate yields but good diastereoselectivity (Scheme
3).10 It is noteworthy that the camphor sultam auxiliary
may be used to obtain enantiomerically enriched THP
diol-containing fragments, which will be useful in target
synthesis.
O
S
N
v
Ar =
9
R
R
O
O
S
O
N
O
Ar
R = H, 10 (90%)
R = Et, 11 (60%)
R = H, 7 (98%)
R = Et, 8 (95%)
The relative stereochemistry of the 2,6-disubstituted
THP diol product 12 was assigned as cis on the basis
1
of H NMR coupling constant data from the C2 and
Scheme 2. Reagents and conditions: (i) DMSO, (COCl)2, CH2Cl2,
À60ꢁC, then Et3N; (ii) 4-methoxy acetophenone, LDA, THF, À60ꢁC;
(iii) MsCl, Et3N, CH2Cl2; (iv) DBU, CH2Cl2; (v) NaH, CH2Cl2, then 3
or 4, 0ꢁC.
C6 protons. Assignment of the relative stereochemistry
in THP diol 12 was ultimately confirmed by X-ray crys-
tallography.11 The observed relative stereoselectivity
within the THP diol moiety may be accountedÀfor by ini-
tial suprafacial [3+2] cycloaddition of MnO4 with the
more electron deficient olefin to generate an intermedi-
ate Mn(V) diester A (Scheme 4). By analogy to the
proposed mechanism for oxidative cyclisation of 1,5-die-
nes;3b,12 oxidation of Mn(V) to Mn(VI) precedes cyclisa-
tion through a chair-like transition state B to afford
Mn(IV) diester C. Hydrolysis of intermediate C will then
lead to the THP diol product. Control of absolute stereo-
chemistry results from the camphor sultam directing the
initial attack of MnO4À to one face of the more reactive
enoyl olefin bond.3f,j
O
i or ii
R
R
O
Ar
H
H
OH
HO
O
R = H
R = Et
conditions i: 17%
conditions ii: 38%
conditions i: 30%
12
R = H
R = Et
7
8
OMe
13
O
O
O
S
O
N
H
H
OH
HO
HO
14 (20%)
ii
O
+
–
O
MnO4
H
H
S
N
O
R
R
O
O
O
10
O
S
O
H
N
COX
COX
O
H
Mn
OH
O
O
15 (3%)
A
H
O
H
O
O
O
O
O
–e
O
S
O
N
Mn
COX
H
H
H
H
OH
HO
HO
O
H
H
R
16
O
i
+
O
S
N
O
B
11
O
O
S
O
N
H
H
XOC
OH
H
2 x H2O
HO
O
O
H
17
O
O
H
Mn
16: 17 = 4: 1 (24%)a
COX
H
HO
–MnO2, –2 x HO–
O
H
H
R
R
Scheme 3. Reagents and conditions: (i) KMnO4 (1.4equiv),
AcOH:acetone (2:3), À15ꢁC; (ii) KMnO4 (1.4equiv), adogen 464
(10mol%), AcOH (16equiv), CH2Cl2, À60ꢁC. aRatio estimated from
the 1H NMR spectrum of the inseparable mixture of diastereoisomers
after column chromatography.
C
Scheme 4. Proposed mechanism for the permanganate-mediated
oxidative cyclisation of 1,6-dienes.

A. R. L. Cecil, R. C. D. Brown / Tetrahedron Letters 45 (2004) 7269–7271
7271
Caserta, V.; Gomez-Paloma, L.; Piccialli, V. Tetrahedron
Lett. 2003, 44, 3429–3429; (e) Osmium: Donohoe, T. J.;
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In conclusion, we have developed a simple permanga-
nate-mediated oxidative cyclisation of 1,6-dienes to pro-
vide cis-2,6-disubstituted THP diols with excellent
control of relative stereochemistry. Furthermore, we
have demonstrated the potential of this reaction for
the synthesis of enantiomerically enriched THP frag-
ments containing upto four new stereocentres. Further
work is underway to improve the chemical efficiency of
this new oxidative cyclisation, and to illustrate its utility
in target synthesis.
5. Brown, R. C. D.; Keily, J. F. Angew. Chem., Int. Ed. 2001,
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Acknowledgements
9. Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.;
Bernardinelli, G. Tetrahedron Lett. 1988, 29, 5885–5888.
10. Procedure for oxidative cyclisation of dienone 8 to THP
diol 13: At À15ꢁC under N2, powdered KMnO4 (51.4mg,
0.33mmol) was added in one batch to a rapidly stirring
solution of diene 8 (60mg, 0.23mmol) in AcOH/acetone
(2:3, 2mL). After 35min, the reaction was quenched with
satd Na2S2O5(aq) (5mL) and H2O (3mL). EtOAc (10mL)
was added and the organic phase separated. The aqueous
phase was extracted with EtOAc (2 · 10 mL) and the
combined organic phase was dried (MgSO4) and concen-
trated in vacuo. Purification by silica gel column chroma-
tography (EtOAc/hexane, 2:3 to 1:1) gave the THP-diol 13
as a colourless oil (21mg, 0.1mmol, 30%). IR mmax (neat)
We thank The Royal Society for a University Fellow-
ship(R.C.D.B.). Merck Sharp& Dohme, Syngenta
and Pfizer Central Research are gratefully acknowl-
edged for unrestricted grants.
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3465 (br), 2937 (s), 1675 (s), 1600 (s) cmÀ1 1H NMR
;
(400MHz, CDCl3) 7.92 (2H, d, J = 8.8Hz), 6.97 (2H, d,
J = 8.8Hz), 4.99 (1H, d, J = 2.8Hz), 3.89 (3H, s), 3.77
(1H, dt, J = 11.1, 2.8Hz), 3.40 (1H, dt, J = 4.3, 8.3Hz),
3.11 (1H, ddd, J = 2.3, 4.3, 11.2Hz), 1.97–1.17 (8H, m),
0.87 (3H, t, J = 7.3Hz); 13C NMR (100MHz, CDCl3) d
198.4, 164.2, 131.1, 127.7, 114.0, 80.5, 79.4, 75.2, 74.9,
55.7, 26.6, 24.8, 24.5, 22.8, 10.2; LRMS (ES+) m/z 639
(100%, [2M+Na]+), 331 (80%, [M+Na]+); Elemental calcd
for C17H24O5: C, 66.21; H, 7.84. Found: C, 66.33; H, 7.71.
11. Dr. M. E. Light and Professor M. B. Hursthouse are
thanked for X-ray crystallographic analysis. Crystallo-
graphic data (excluding structure factors) for THP diol 14
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
241371. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
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