Directed epoxidation of cyclohexa-1,4-dienes-stereoselective formation of up to six contiguous stereogenic centres

Article abstract of DOI:10.1039/b814131m

Epoxidation/cyclisation of cyclohexa-1,4-dienes containing pendant hydroxyl groups provides stereocontrolled access to highly-functionalised reduced benzol[b]furan derivatives.

Full text of DOI:10.1039/b814131m

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Directed epoxidation of cyclohexa-1,4-dienes–stereoselective formation of up
to six contiguous stereogenic centres†
Michael Butters,b Dirk J. Beetstra,a Mark C. Elliott,*a Joseph Hill-Cousinsa and Benson M. Kariukia
Received 13th August 2008, Accepted 29th August 2008
First published as an Advance Article on the web 20th October 2008
DOI: 10.1039/b814131m
Epoxidation/cyclisation of cyclohexa-1,4-dienes containing pendant hydroxyl groups provides
stereocontrolled access to highly-functionalised reduced benzol[b]furan derivatives.
stereogenic centres. We know from our previous work that the
ring-opening of epoxides 2 should proceed with high levels of
Introduction
diastereocontrol.7 Furthermore, the reaction also has the potential
for “stereochemical proof-reading” since epoxidation of the upper
face (as drawn) will not lead to the formation of a cyclised product.
Epoxidation has previously been used to directly desymmetrise
cyclohexa-1,4-dienes.9
Desymmetrisation reactions of cyclohexa-1,4-dienes have consid-
erable synthetic potential for the preparation of fused carbocyclic
and heterocyclic systems.1,2 Landais et al. have reported extensively
on the use of asymmetric dihydroxylation reactions for the selective
oxidation of such systems,3 and these reactions have been used for
the preparation of a number of biologically important carbocyclic
sugar analogues.4 We have demonstrated that conformational
control can be used to impart high levels of diastereocontrol
in the free-radical,5 Prins6 and iodocyclisation reactions7 onto
cyclohexa-1,4-dienes. The substrates that we used in the latter
study generally contain two hydroxy groups as a result of the
Birch reduction–alkylation reaction8 used in their preparation.
We reasoned that the homoallylic alcohol in compound 1 could
be used to direct the facial selectivity in the epoxidation of the
cyclohexa-1,4-diene ring, and that conformational control could
then be used to direct the ring-opening of the resulting bis-
epoxide 2 (Scheme 1) in order to prepare highly functionalised
carbocyclic sugar analogues 3 containing five new contiguous
Results and discussion
Substrates 1a–1f were prepared as previously described
(Scheme 2).7 Epoxidation of these compounds was investigated
with a range of oxidants, of which m-CPBA proved optimal.
Cyclisation onto the epoxide is spontaneous and highly di-
astereoselective under the epoxidation conditions, resulting in the
formation of a single diastereoisomer of products containing five
new contiguous stereogenic centres! The results are summarised
in Table 1.
Scheme 1 Direct epoxidation and cyclisation of cyclohexa-1,4-dienes.
Scheme 2 Synthesis of substrates 1a–1f.
aSchool of Chemistry, Cardiff University, Park Place, Cardiff, UK, CF10
3AT. E-mail: elliottmc@cardiff.ac.uk; Fax: +44 (0)29 20874030; Tel: +44
(0)29 20874686
The reaction yields are moderate to good, and NMR spectra
of crude reaction mixtures show no other diastereoisomers. The
reason for the lower yields (entries 1 and 3) is not readily apparent,
since no other compounds were isolated, and the products 3a and
3c are stable to chromatography. Entry 4 shows a key limitation
bAstraZeneca Process R & D Avlon/Charnwood, Avlon Works, Severn Road,
Hallen, Bristol, UK, BS10 7ZE
† CCDC reference numbers 694523 and 694524. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b814131m
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Table 1 Cyclisation of compounds 1a–1f
Entry
Product
R1
R2
Yield (%)
1
2
3
4
5
6
3a
3b
3c
—
3e
3f
n-Bu
t-Bu
n-C6H13
Ph
H
H
H
H
Ph
40
75
36
0
55
52
H
Scheme
3
Epoxidation of compound 1b mediated by vanadyl
-(CH2)4-
acetylacetonate.
of the method. The presence of a benzylic alcohol in the substrate
led to no identifiable products. The stereochemistry of compound
3e was confirmed by NOESY NMR spectroscopy as described
in the Experimental section. Compound 3b was characterised
crystallographically (Fig. 1).10 The stereochemistry of the other
compounds was assigned by analogy with these results, which are
in line with the results obtained in the iodocyclisation reactions of
compounds 1.7
Table 2 Azide ring-opening of epoxides 3
Entry
Product
R1
R2
Yield (%)
1
2
3
4
5
5a
5b
5c
5e
5f
n-Bu
H
H
H
Ph
36
67
96
67
46
t-Bu
n-C6H13
H
-(CH2)4-
hindered C4 end (Fig. 1) is predicted by the Fu¨rst–Plattner rule.12
However, this attack would lead to significant steric interactions
between the incoming nucleophile and the tetrahydrofuran ring,
so attack at C5 (crystallographic numbering) is preferred.
Assignment of the regiochemistry of epoxide-opening
There are two possible outcomes for the epoxide-opening reaction
of compounds 3, each product potentially existing in one (or
both) of two chair conformations. In the case of ring-opening of
compound 3a at C-5, the two conformations 5a-eq and 5a-ax each
have three axial substituents and three equatorial substituents.
Conformer 5a-ax is presumably slightly more stable due to
the small azide group being axial. Ring-opening at C-4 would
presumably favour conformer 6-eq almost exclusively (Scheme 4).
The methylene protons at C-6 are distinct in all of the
compounds. In each case, one of these protons shows a single
trans-diaxial coupling. For conformers 6-ax and 6-eq arising by
C-4 epoxide-opening we would expect zero or two trans-diaxial
couplings to this hydrogen, whereas with either of conformers 5a-
eq or 5a-ax we would expect one, as observed. We can therefore
conclude that epoxide-opening has taken place at C-5. This
conclusion is further supported by the coupling constants of H-4
and H-7a in the azides 5. In each case, one of these protons is axial
while the other is equatorial, a situation that would not occur had
epoxide opening taken place at C-4.
Fig. 1 Structure of compound 3b from single crystal X-ray diffraction
data. Thermal ellipsoids are shown at the 50% probability level. The unit
cell contains both enantiomers. The enantiomer shown has been chosen
for consistency with reaction schemes.
Other oxidation conditions were evaluated. Very slow epoxida-
tion was observed under Payne conditions (H2O2/CH3CN) such
that no products were characterised. With vanadyl acetylacetonate
and tert-butyl hydroperoxide, a mixture of compounds 3b and
4 was obtained from compound 1b (Scheme 3). Compound 4
(stereochemistry confirmed by NOESY NMR spectroscopy) is
produced by cyclisation of a mono-epoxide, although the low yield
makes it difficult to determine whether the actual epoxidation step
is diastereoselective.
Compounds 3 are ripe for further elaboration. For example, the
epoxides can be regiospecifically opened at the less hindered end
using sodium azide,11 giving azides 5 in moderate to excellent yield
(Table 2). In fact, regioselective opening of the epoxide at the more
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Scheme 4 Regioselectivity of the epoxide-opening of compound 3a.
We have recently reported a synthesis of the tricyclic core of
lycoposerramine S, which begins with methyl 4-methylcyclohexa-
2,5-diene-1-carboxylate 7.13 In the present work, compound 7 was
deprotonated and reacted with epoxide 8 to give lactone 9 as a
1:1 mixture of diastereoisomers. This mixture was then reduced
to give a mixture of isomers 10 and 11 in good overall yield
(Scheme 5). The individual isomers were separated by extensive
chromatography on silica gel. Epoxidation of these compounds
gave in each case a single isomer of epoxides, 12 and 13, albeit
in modest yield. The stereochemistry of compounds 10 and 11
was assigned retrospectively by single-crystal X-ray diffraction of
compound 13 (Fig. 2),10 which also confirmed the stereochemistry
of that compound. The synthesis of compounds 12 and 13 feature
the formation of six new contiguous stereogenic centres, one of
them being quaternary, in a single synthetic step.14 This therefore
represents a substantial increase in molecular and stereochemical
complexity.
Scheme 5 Synthesis and oxidative cyclisation of compounds 10 and 11.
Experimental section
General Experimental Points
Melting points were determined on a Gallenkamp melting point
apparatus and are uncorrected. Infrared spectra were recorded
on a Perkin Elmer 1600 FTIR spectrophotometer. Mass spectra
were recorded on a Fisons VG Platform II spectrometer and
on a Micromass Q-TOF Micro spectrometer. NMR spectra
were recorded on a Bruker DPX 400 spectrometer operating
at 400 MHz for 1H and at 100 MHz for 13C at 25 ◦C, or
on a Bruker Avance 500 spectrometer operating at 500 MHz
for 1H and 125 MHz for 13C at 25 ◦C. All chemical shifts
are reported in ppm downfield from TMS. Coupling constants
1
(J) are reported in Hz. Multiplicity in H-NMR is reported as
singlet (s), doublet (d), double doublet (dd), double triplet (dt),
double quartet (dq), triplet (t), and multiplet (m). Multiplicity
in 13C-NMR was obtained using the DEPT pulse sequence.
Flash chromatography was performed using Matrex silica 60 35–
70 micron. Crystallographic data for compounds 3b and 13 were
recorded on a Nonius KappaCCD diffractometer equipped with
an Oxford Cryosystem cryostat. The structures were solved by
direct methods with additional light atoms found by Fourier
methods. Hydrogen atoms were added at calculated positions and
refined using a riding model. Anisotropic displacement parameters
Fig. 2 Structure of compound 13 from single crystal X-ray diffraction
data. Thermal ellipsoids are shown at the 50% probability level. Only one
of the two independent molecules in the unit cell is shown.
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were used for all non-H atoms; H-atoms were given isotropic
displacement parameters equal to 1.2 or 1.5 times the equivalent
isotropic displacement parameter of the atom to which the H-atom
is attached. Compounds 1a-b, 1d-f were prepared as previously
described.7
(1aSR,3RS,3aRS,5SR,6aRS,6bRS)-5-Butyl-octahydro-6a-
(hydroxymethyl)-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-b]furan-3-
ol (3a)
( )-1-(1-(Hydroxymethyl)cyclohexa-2,5-dienyl)octan-2-ol (1c)
n-Butyllithium (8.79 ml of a 1.6 M solution in hexanes, 14.1 mmol)
was added to a solution of diisopropylamine (1.97 ml, 14.1 mmol)
in dry THF (20 ml) at 0 ◦C, and the resulting solution was allowed
to stir at 0 ◦C for 15 minutes. The reaction mixture was then cooled
to -78 ◦C and the ester (1.74 g, 12.6 mmol) added dropwise.
After stirring at -78 ◦C for 30 minutes, n-hexyloxirane (1.8 g,
14.1 mmol) was added dropwise and the reaction mixture allowed
to warm to room temperature. The reaction was quenched with
saturated aqueous ammonium chloride solution and extracted
with diethyl ether, the combined extracts being dried over Na2SO4
before the solvent was removed in vacuo. Chromatography on
silica gel (Et2O/petroleum ether 1:19) afforded the intermediate
lactone (1.64 g, 56%) as a colourless oil. This lactone (1.64 g,
7.01 mmol) was immediately re-dissolved in dry THF (10 ml) and
added dropwise to a suspension of LiAlH4 (266 mg, 7.01 mmol)
in dry THF (20 ml). The resulting suspension was allowed to
stir for 15 minutes before the reaction was quenched with 2 M
NaOH. The solution was filtered and dried over Na2SO4 before
the solvent was removed in vacuo. Chromatography on silica gel
(eluent 2:1 hexane:ethyl acetate) afforded the diol 1c (1.33 g,
80%) as a colourless oil (found: M+ - H2O, 220.1837. C15H24O
requires M, 220.1827); nmax. (neat) 3354, 3017, 2930, 2882, 2856,
1615, 1516, 1458, 1377, 1244, 1040, 947, 877, 823 and 711 cm-1; dH
(400 MHz; CDCl3) 6.00–5.93 (2 H, m, alkene CH), 5.63 (1 H, app.
dq, J 10.2, 2.0, alkene CH), 5.37 (1 H, app. dq, J 10.9, 2.1, alkene
CH), 3.77–3.71 (1 H, m, CHOH), 3.30 (2 H, app. s, CH2OH), 2.68–
2.66 (2 H, m, ring CH2), 1.67 (2 H, broad s, 2 ¥ OH), 1.43 (1 H, dd,
J 14.2, 9.0, one of CH2CHOH), 1.36 (1 H, dd, J 14.2, 2.3, one of
CH2CHOH), 1.33–1.27 (2 H, m, CH2), 1.26–1.16 (8 H, m, (CH2)4)
and 0.81 (3 H, t, J 6.8, CH3); dC (100 MHz; CDCl3) 130.6 (CH),
129.7 (CH), 128.0 (CH), 127.4 (CH), 70.4 (CH2), 69.4 (CH),
44.9 (CH2), 42.3 (C), 38.0 (CH2), 31.9 (CH2), 29.3 (CH2), 26.6
CH2), 25.6 (CH2), 22.6 (CH2) and 14.1 (CH3); m/z (TOF EI+)
220 (M - H2O, 13%), 202 (98), 190 (90), 131 (93), 117 (97) and
104 (100).
Epoxide 3a was prepared from diene 1a (316 mg, 1.50 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 1:1 ethyl acetate:hexane) afforded
the title compound (144 mg, 40%) as a colourless oil (found: M+,
242.1519. C13H22O4 requires M, 242.1518); nmax. (neat) 3415, 2922,
2862, 1466, 1426, 1381, 1259, 1127, 1058 and 838 cm-1; dH
(400 MHz; CDCl3) 3.88–3.81 (1 H, m, H-5), 3.82 (1 H, d, J 10.9,
one of H-7), 3.79–3.74 (1 H, m, H-3), 3.74–3.72 (1 H, d, J 5.3,
H-3a), 3.67 (1 H, d, J 10.9, one of H-7), 3.39–3.38 (1 H, m, H-1a),
3.30 (1 H, broad s, OH), 3.16 (1 H, app. dd, J 4.1, 1.2, H-6b),
2.60 (1 H, broad s, OH), 2.24–2.17 (1 H, m, one of H-2), 2.13
(1 H, ddd, J 15.8, 3.8, 1.3, one of H-2), 2.02 (1 H, dd, J 12.8,
5.3, one of H-6), 1.76 (1 H, dd, J 12.8, 9.9, one of H-6), 1.60–
1.51 (1 H, m, one of CH2(CH2)2CH3), 1.43–1.35 (1 H, m, one
of CH2(CH2)2CH3), 1.32–1.19 (4 H, m, (CH2)2) and 0.83 (3 H,
t, J 7.0, CH3); dC (100 MHz; CDCl3) 78.6 (CH), 78.1 (CH), 67.6
(CH2), 67.0 (CH), 56.6 (CH), 53.5 (CH), 46.5 (C), 41.8 (CH2), 35.3
(CH2), 28.2 (CH2), 25.7 (CH2), 22.7 (CH2) and 14.1 (CH3); m/z
(TOF EI+) 242 (M, 1%), 211 (100), 149 (80) and 95 (94).
(1aSR,3RS,3aRS,5RS,6aRS,6bRS)-5-tert-Butyl-octahydro-6a-
(hydroxymethyl)-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-b]furan-3-
ol (3b)
Epoxide 3b was prepared from diene 1b (161 mg, 0.77 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 3:1 ethyl acetate:hexane) gave the
title compound (139 mg, 75%) as a colourless solid, m.p. 86–87 ◦C
(found: M+ - H2O, 224.1413. C13H20O3 requires M, 224.1412);
General procedure for epoxidation reactions
50% m-CPBA (1.04 g, 3.01 mmol) and solid NaHCO3 (379 mg,
4.51 mmol) were added to a solution of cyclohexadiene 1a-1f,
n
max. (Nujol) 3388, 2923, 2853, 1259 and 1059 cm-1; dH (400 MHz;
◦
10, 11 (1.50 mmol) in CH2Cl2 (20 ml) at 0 C. The solution was
CDCl3) 3.89 (1 H, d, J 10.9, one of H-7), 3.87–3.85 (1 H, m, H-3),
3.74–3.72 (1 H, m, H-3a), 3.72 (1 H, d, J 10.9, one of H-7), 3.60
(1 H, dd, J 10.8, 5.8, H-5), 3.46–3.43 (1 H, m, H-1a), 3.17 (1 H,
app. dd, J 4.0, 1.2, H-6b), 2.75 (2 H, broad s, 2 ¥ OH), 2.25 (1 H,
app. dt, J 15.8, 2.4, one of H-2), 2.18 (1 H, ddd, J 15.8, 3.8, 1.3,
one of H-2), 1.93 (1 H, dd, J 12.8, 10.8, one of H-6), 1.88 (1 H,
dd, J 12.8, 5.8, one of H-6) and 0.86 (9 H, s, t-Bu); dC (100 MHz;
CDCl3) 85.8 (CH), 79.3 (CH), 67.9 (CH2), 67.0 (CH), 56.7 (CH),
53.7 (CH), 46.4 (C), 37.2 (CH2), 33.6 (C), 25.7 (CH2) and 25.6 (3 ¥
CH3); m/z (TOF MS EI+) 224 (M - H2O, 3%), 185 (100), 149 (33),
121 (44) and 95 (39).
stirred for 24 hours, after which an additional 0.1 equivalents
of m-CPBA was added every hour until complete consump-
tion of the starting material (TLC; typically 2.4 equivalents of
m-CPBA was required). The reaction was quenched with saturated
aqueous sodium thiosulfate solution and extracted with CH2Cl2
(3 ¥ 25 ml). The combined organic extracts were washed with
saturated aqueous NaHCO3 solution (50 ml) and dried over
Na2SO4. The solvent was removed in vacuo and the residue purified
by flash column chromatography on silica gel to give the pure
epoxide.
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Crystallographic data for compound 3b. C13H22O4, FW =
3.90 (1 H, d, J 11.0, one of H-7), 3.86–3.83 (1 H, m, H-3a), 3.71
(1 H, dd, J 6.8, 5.0, H-6), 3.50 (1 H, broad s, OH), 3.15–3.11 (1 H,
m, H-1a), 2.77 (1 H, app. dd, J 4.2, 1.5, H-6b), 2.34–2.23 (2 H,
m, H-2) and 1.65 (1 H, broad s, OH); dC (100 MHz; CDCl3) 139.1
(C), 128.6 (2 ¥ CH), 128.5 (2 ¥ CH), 127.2 (CH), 80.6 (CH), 72.5
(CH2), 66.7 (CH2), 66.3 (CH), 55.4 (CH), 53.6 (CH), 51.5 (CH),
48.5 (C) and 25.7 (CH2); m/z (TOF ES+) 244 (M - H2O, 9%), 214
(100), 171 (21) and 104 (85).
˚
242.31, T = 150(2) K, l = 0.71073 A, monoclinic, P21/a,
˚
˚
a = 11.8532(3) A, b = 7.1565(2) A, c = 16.0428(4), b =
3
3
˚
102.4210(10), V = 1329.02(6) A , Z = 4, r(calc) = 1.211 Mg/m ,
crystal size = 0.38 ¥ 0.25 ¥ 0.10 mm3, reflections collected = 20521,
independent reflections = 3023, R(int)= 0.109, parameters = 160,
R1 [I>2s(I)]= 0.075, wR2 [I>2s(I)] = 0.19, R1 (all data) = 0.10,
wR2 (all data) = 0.21, Flack parameter = 0.056(10).
Stereochemistry was confirmed by nOe enhancement between
H-3a and H-6 and between H-6b and phenyl.
(1aSR,3RS,3aRS,5SR,6aRS,6bRS)-5-Hexyl-octahydro-6a-
(hydroxymethyl)-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-b]furan-3-
ol (3c)
(1RS,2SR,4RS,4aRS,5aSR,9aRS,9bSR)-9b-(Hydroxymethyl)-
1,2-epoxydodecahydrodibenzo[b,d]furan-4-ol (3f)
Epoxide 3c was prepared from diene 1c (509 mg, 2.14 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 hexane:ethyl acetate) afforded
the titl◦e compound (209 mg, 36%) as a colourless solid, m.p.
72–73 C (found: M+ - H2O, 252.1725. C15H24O3 requires M,
252.1725); nmax. (Nujol) 3406, 2922, 2854, 1249, 1130, 1075, 1057,
1021, 932, 840, 721 and 668 cm-1; dH (400 MHz; CDCl3) 3.89–3.84
(1 H, m, H-5), 3.85 (1 H, d, J 10.8, one of H-7), 3.82–3.77 (1 H,
m, H-3), 3.75 (1 H, d, J 3.9, H-3a), 3.69 (1 H, d, J 10.8, one of
H-7), 3.40–3.37 (1 H, m, H-1a), 3.26 (1 H, app. dd, J 4.0, 1.2,
H-6b), 2.22 (1 H, app. dt, J 15.8, 2.5, one of H-2), 2.13 (1 H,
ddd, J 15.8, 3.8, 1.4, one of H-2), 2.03 (1 H, dd, J 12.8, 5.3, one
of H-6), 1.75 (1 H, dd, J 12.8, 9.9, one of H-6), 1.58–1.50 (2 H,
m, CH2(CH2)4CH3), 1.43–1.14 (10 H, m, (CH2)4 and 2 ¥ OH)
and 0.81 (3 H, t, J 6.8, CH3); dC (100 MHz; CDCl3) 78.8 (CH),
78.1 (CH), 68.0 (CH2), 67.0 (CH), 56.6 (CH), 53.5 (CH), 46.5 (C),
41.9 (CH2), 35.7 (CH2), 31.8 (CH2), 29.3 (CH2), 26.0 (CH2), 25.8
(CH2) 22.6 (CH2) and 14.1 (CH3); m/z (TOF ES+) 252 (M - H2O,
40%), 185 (100), 123 (98) and 95 (88).
Epoxide 3f was prepared from diene 1f (85 mg, 0.41 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 1:1 ethyl acetate:hexane) afforded
the title compound (51 mg, 52%) as a colourless solid, m.p.
◦
153–154 C (found: M+ - H2O, 222.1253. C13H18O3 requires M,
222.1256); nmax. (Nujol) 3417, 2927, 2854, 1064, 1046 and 722 cm-1;
dH (400 MHz; CDCl3) 3.92–3.86 (2 H, m, H-4 and H-4a), 3.91 (1 H,
d, J 11.0, one of H-10), 3.87 (1 H, d, J 11.0, one of H-10), 3.47–
3.44 (1 H, m, H-2), 3.36–3.29 (2 H, m, H-1 and H-5a), 2.35 (1 H,
app. broad d, J 16.0, one of H-3), 2.20–2.01 (4 H, m, one of H-3,
H-9a and 2 ¥ OH), 1.85–1.77 (2 H, m, cyclohexyl CH2), 1.74–1.66
(2 H, m, cyclohexyl CH2) and 1.39–1.13 (4 H, m, 2 ¥ cyclohexyl
CH2); dC (100 MHz; CDCl3) 81.1 (CH), 79.2 (CH), 67.7 (CH), 67.1
(CH2), 53.8 (CH), 53.5 (CH), 52.3 (CH), 45.8 (C), 32.2 (CH2), 25.7
(CH2), 25.6 (CH2), 25.2 (CH2) and 23.9 (CH2); m/z (TOF ES+)
222 (M - H2O, 1%), 192 (86) and 79 (100).
(2RS,3aRS,7RS,7aRS)-2-tert-Butyl-3a-(hydroxymethyl)-
2,3,3a,6,7,7a-hexahydro-benzo[b]furan-7-ol (4)
(1aSR,3RS,3aRS,6RS,6aRS,6bRS)-Octahydro-6a-
(hydroxymethyl)-6-phenyl-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-
b]furan-3-ol (3e)
Vanadyl acetylacetonate (73 mg, 0.276 mmol) and tert-butyl hy-
droperoxide (1.22 ml of 5.0–6.0 M solution in decane, 6.08 mmol)
were added to a solution of diol 1b (580 mg, 2.76 mmol) in
CH2Cl2 (10 ml) at 0 ◦C. The reaction mixture was allowed to
warm slowly to room temperature and stirred for 16 h. The
reaction was quenched with saturated aqueous Na2SO3 solution
and extracted with CH2Cl2 (3 ¥ 10 ml). The combined organic
extracts were dried over Na2SO4 before the solvent was removed
in vacuo. Chromatography on silica gel (eluent hexane:ethyl acetate
2:1) afforded the title compound (93 mg, 15%) as a colourless
Epoxide 3e was prepared from diene 1e (136 mg, 0.59 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 3:2 hexane:ethyl acetate) afforded
the title compound (85 mg, 55%) as a colourless solid, m.p.
◦
89–90 C (found: M+ - H2O, 244.1091. C15H16O3 requires M,
244.1099); nmax. (Nujol) 3488, 3335, 2923, 2851, 1076, 1059 and
1040 cm-1; dH (400 MHz; CDCl3) 7.39–7.25 (5 H, m, Ph), 4.20
(1 H, dd, J 9.1, 5.0, one of H-5), 4.10 (1 H, dd, J 9.1, 6.8, one of
H-5), 4.03–3.98 (1 H, m, H-3), 3.92 (1 H, d, J 11.0, one of H-7),
◦
solid, m.p. 83–85 C (found: MH+ - H2O, 209.1532. C13H21O2
4430 | Org. Biomol. Chem., 2008, 6, 4426–4434
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requires M, 209.1542); nmax. (Nujol) 3186, 2922, 2856, 1205, 1171,
1131, 1043, 964, 910, 836, 776 and 746 cm-1; dH (400 MHz; CDCl3)
5.83–5.79 (1 H, m, H-5), 5.43 (1 H, d, J 10.2, H-4), 4.22 (2 H,
broad s, 2 ¥ OH), 4.05–4.01 (1 H, m, H-7), 3.88 (1 H, d, J 3.9,
H-7a), 3.62 (1 H, d, J 10.4, one of H-8), 3.55 (1 H, dd, J 10.5, 5.6,
H-2), 3.46 (1 H, d, J 10.4, one of H-8), 2.36–2.31 (1 H, m, one of
H-6), 2.04 (1 H, app. dd, J 17.9, 4.7, one of H-6), 1.52 (1 H, dd,
J 12.1, 10.5, one of H-3), 1.48 (1 H, dd, J 12.1, 5.6, one of H-3)
and 0.82 (9 H, d, C(CH3)3); dC (100 MHz; CDCl3) 129.7 (CH),
126.5 (CH), 85.2 (CH), 83.5 (CH), 68.0 (CH2), 64.7 (CH), 48.8
(C), 36.6 (CH2), 33.5 (C), 28.2 (CH2) and 25.7 (3 ¥ CH3); m/z
(TOF AP+) 209 (MH+ - H2O, 100%). In addition, compound 3b
(34 mg, 5%) was obtained.
(2RS,3aSR,4RS,5RS,7RS,7aRS)-2-tert-Butyl-5-azido-
octahydro-3a-(hydroxymethyl)benzofuran-4,7-diol (5b)
Azide 5b was prepared from epoxide 3b (101 mg, 0.42 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 hexane:ethyl acetate) af-
forded the title◦ compound (80 mg, 67%) as a colourless solid,
m.p. 155–156 C (found: M+ - H2O, 267.1581. C13H21N3O3
requires M, 267.1583); nmax. (Nujol) 3192, 2920, 2853, 2113, 1258
and 1070 cm-1; dH (400 MHz; CD3OD) 4.03–3.92 (3 H, m, one of
H-8, H-5 and H-7), 3.78 (1 H, dd, J 9.9, 6.6, H-2), 3.69 (1 H, app.
broad s, H-4 or H-7a), 3.54 (1 H, d, J 11.0, one of H-8), 3.48 (1 H,
d, J 10.3, H-4 or H-7a), 2.02 (1 H, app. dd, J 12.9, 6.6, one of
H-3), 1.93 (1 H, app. broad d, J 13.4, one of H-6), 1.67 (1 H, ddd,
J 13.4, 12.7, 3.0, one of H-6), 1.57 (1 H, app. dd, J 12.9, 9.9, one
of H-3) and 0.88 (9 H, s, t-Bu); dC (100 MHz; CD3OD) 86.5 (CH),
86.1 (CH), 76.5 (CH), 67.0 (CH), 65.0 (CH2), 60.8 (CH), 53.9 (C),
35.9 (CH2), 35.6 (C), 34.5 (CH2) and 25.9 (3 ¥ CH3); m/z (TOF
MS EI+) 267 (M - H2O, 34%), 240 (17), 182 (100), 137 (38), 111
(33) and 81 (28).
Stereochemistry was confirmed by nOe enhancement between
H-2 and one of H-6.
General procedure for azide ring-openings
Sodium azide (285 mg, 4.38 mmol) and ammonium chloride
(117 mg, 2.19 mmol) were added portionwise to a solution of
the epoxide 3a-3c, 3e, 3f (0.44 mmol) in an 8:1 mixture of
methanol/water (9 ml). The solution was stirred at 80 ◦C for
24 hours before being cooled to room temperature and quenched
with water. The crude product was extracted into CH2Cl2 (3 ¥
10 ml). The combined organic extracts were dried over Na2SO4
and the solvent removed in vacuo. The residue was purified
by flash column chromatography on silica gel to give the pure
azide 5.
(2SR,3aSR,4RS,5RS,7RS,7aRS)-5-Azido-2-hexyl-octahydro-3a-
(hydroxymethyl)benzofuran-4,7-diol (5c)
(2SR,3aSR,4RS,5RS,7RS,7aRS)-5-Azido-2-butyl-octahydro-3a-
(hydroxymethyl)benzofuran-4,7-diol (5a)
Azide 5c was prepared from epoxide 3c (67 mg, 0.25 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 hexane:ethyl acetate) afforded
the◦title compound (75 mg, 96%) as a colourless solid, m.p. 97–
Azide 5a was prepared from epoxide 3a (106 mg, 0.44 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 hexane:ethyl acetate) afforded
the t◦itle compound (45 mg, 36%) as a colourless solid, m.p. 107–
108 C (found: M+ - H2O, 267.1588. C13H21N3O3 requires M,
267.1583); nmax. (Nujol) 3185, 2923, 2853, 2111, 1082, 721 and
668 cm-1; dH (400 MHz; CD3OD) 4.02 (1 H, app. tt, J 12.9, 6.5,
H-2), 3.91 (1 H, ddd, J 12.3, 10.3, 4.3, H-5 or H-7), 3.89–3.85 (2 H,
m, one of H-8 and H-5 or H-7), 3.69 (1 H, app. broad s, H-4 or
H-7a), 3.48 (1 H, d, J 11.0, one of H-8), 3.40 (1 H, d, J 10.2, H-4
or H-7a), 2.18 (1 H, dd, J 12.7, 6.5, one of H-3), 1.88 (1 H, app.
dt, J 13.8, 3.1, one of H-6), 1.65–1.49 (2 H, m, one of H-6 and
butyl H), 1.44–1.18 (6 H, m, one of H-3 and butyl H) and 0.86
(3 H, t, J 6.8, CH3); dC (100 MHz; CD3OD) 85.1 (CH), 78.3 (CH),
76.5 (CH), 66.9 (CH), 65.0 (CH2), 60.9 (CH), 53.9 (C), 41.3 (CH2),
37.5 (CH2), 34.6 (CH2), 29.3 (CH2), 23.8 (CH2) and 14.5 (CH3);
m/z (TOF ES+) 267 (M - H2O, 26%), 208 (100), 181 (58), 155 (64)
and 72 (81).
98 C (found: M+ + NH4 , 331.2359. C15H31N4O4 requires M,
+
331.2345); nmax. (Nujol) 3199, 2927, 2853, 2114, 1256, 1183, 1068,
1037, 1009, 961, 921 and 802 cm-1; dH (400 MHz; CD3OD) 4.13–
4.03 (1 H, m, H-2), 3.97 (1 H, ddd, J 12.2, 10.2, 4.3, H-5 or H-7),
3.95–3.91 (2 H, m, one of H-8 and H-5 or H-7), 3.76–3.74 (1 H,
m, H-4 or H-7a), 3.55 (1 H, d, J 11.0, one of H-8), 3.46 (1 H,
d, J 10.2, H-4 or H-7a), 2.24 (1 H, dd, J 12.7, 6.5, one of H-3),
1.94 (1 H, app. broad d, J 13.7, one of H-6), 1.67 (1 H, ddd, J
13.7, 12.4, 3.0, one of H-6), 1.62–1.48 (1 H, m, hexyl H), 1.49–1.24
(9 H, m, hexyl H), 1.37 (1 H, dd, J 12.7, 9.0, one of H-3) and 0.91
(3 H, t, J 6.8, CH3); dC (100 MHz; CD3OD) 85.1 (CH), 78.3 (CH),
76.5 (CH), 66.9 (CH), 65.0 (CH2), 60.9 (CH), 53.9 (C), 41.3 (CH2),
37.8 (CH2), 34.6 (CH2), 33.1 (CH2), 30.5 (CH2), 27.1 (CH2), 23.7
(CH2) and 14.5 (CH3); m/z (TOF ES+) 331 (M + NH4 , 67%), 287
+
(22), 286 (100), 268 (7), 252 (2) and 222 (1).
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(3RS,3aSR,4RS,5RS,7RS,7aRS)-5-Azido-octahydro-3a-
( )-1-((1,4-trans)-1-(Hydroxymethyl)-4-methylcyclohexa-2,5-
(hydroxymethyl)-3-phenylbenzofuran-4,7-diol (5e)
dienyl)hexan-2-ol (10) and ( )-1-((1,4-cis)-1-(hydroxymethyl)-
4-methylcyclohexa-2,5-dienyl)hexan-2-ol (11)
n-Butyllithium (10.1 ml of a 2.5 M solution in hexanes, 25.3 mmol)
was added to a solution of diisopropylamine (3.55 ml, 25.3 mmol)
in dry THF (30 ml) at -78 ◦C and the resulting solution was
allowed to warm to room temperature. After re-cooling to -78 ◦C,
the ester 7 (3.50 g, 23.0 mmol) was added dropwise. After stirring
◦
for 30 minutes at -78 C, n-butyloxirane 8 (3.61 ml, 29.9 mmol)
was added and the reaction mixture allowed to warm to 5 ◦C
over 3 h. The reaction was quenched with saturated aqueous
ammonium chloride solution (50 ml) and extracted with diethyl
ether (3 ¥ 30 ml). The combined organic extracts were dried over
Na2SO4 before the solvent was removed in vacuo affording the
crude intermediate lactones 9 (5.44 g) as a yellow oil. This lactone
(3.99 g, 18.1 mmol) was redissolved in dry THF (20 ml) and added
dropwise to a suspension of LiAlH4 (688 mg, 18.1 mmol) in dry
THF (30 ml). The resulting suspension was allowed to stir for
15 minutes before the reaction was quenched slowly with 2 M
NaOH. The solution was filtered and dried over Na2SO4 before
the solvent was removed in vacuo. Chromatography on silica gel
(eluent hexane:diethyl ether 2:1) afforded a 1:1 mixture of diols 10
and 11 (2.56 g, 63%) as a colourless oil. Further chromatography
(eluent hexane:diethyl ether 4:1) provided pure samples of the
individual diastereoisomers.
Azide 5e was prepared from epoxide 3e (45 mg, 0.17 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 1:1 hexane:ethyl acetate) afforded
the t◦itle compound (35 mg, 67%) as a colourless solid, m.p. 140–
141 C (found: M+ + NH4 , 323.1734. C15H23N4O4 requires M,
+
323.1719); nmax. (Nujol) 3260, 2924, 2854, 2100, 1246, 1158, 1061
and 722 cm-1; dH (400 MHz; CD3OD) 7.24–7.12 (5 H, m, Ph), 4.21
(1 H, dd, J 9.9, 8.9, one of H-2), 4.03 (1 H, app. t, J 8.7, one of
H-2), 3.99 (1 H, d, J 10.9, one of H-8), 3.90 (1 H, app. q, J 3.1,
H-5 or H-7), 3.86 (1 H, app. d, J 2.8, H-4 or H-7a), 3.84–3.78
(1 H, m, H-5 or H-7), 3.68 (1 H, d, J 9.9, H-4 or H-7a), 3.53 (1 H,
d, J 10.9, one of H-8), 3.40 (1 H, app. t, J 9.5, H-3), 1.87 (1 H,
app. dt, J 13.5, 3.9, one of H-6) and 1.71–1.64 (1 H, m, one of
H-6); dC (100 MHz; CD3OD) 136.7 (C), 128.4 (CH), 128.3 (CH),
128.2 (CH), 126.8 (CH), 126.6 (CH), 85.9 (CH), 71.1 (CH), 69.1
(CH2), 65.8 (CH), 62.7 (CH2), 60.8 (CH), 53.9 (C), 51.0 (CH) and
+
32.5 (CH2); m/z (TOF ES+) 323 (M + NH4 , 100%), 278 (97), 260
Data for compound 10. Found: M+ - H2O, 206.1668. C14H22O
requires M, 206.1671; nmax. (neat) 3384, 3011, 2957, 2928, 2871,
1636, 1456, 1378, 1278, 1122, 1037, 918, 804 and 746 cm-1; dH
(400 MHz; CDCl3) 5.97–5.88 (2 H, m, alkene CH), 5.65 (1 H, app.
dt, J 10.3, 2.3, alkene CH), 5.38 (1 H, app. dt, J 10.8, 2.1, alkene
CH), 3.82–3.74 (1 H, broad m, CHOH), 3.35 (2 H, s, CH2OH),
2.85–2.77 (1 H, broad m, CHCH3), 1.99 (2 H, broad s, 2 ¥ OH),
1.50 (1 H, dd, J 14.2, 9.1, one of CCH2), 1.42 (1 H, dd, J 14.2,
2.1, one of CCH2), 1.38–1.22 (6 H, broad m, (CH2)3), 1.06 (3 H,
d, J 7.3, CH3) and 0.88 (3 H, t, J 6.8, CH3); dC (100 MHz; CDCl3)
134.4 (CH), 133.7 (CH), 129.5 (CH), 128.4 (CH), 70.4 (CH2),
69.2 (CH), 44.6 (CH2), 42.7 (C), 37.6 (CH2), 30.9 (CH), 27.8
(CH2), 22.8 (CH2), 22.1 (CH3) and 14.1 (CH3); m/z (TOF EI+)
206 (M - H2O, 32%), 188 (100), 176 (62), 159 (50), 145 (97) and
131 (99).
(14) and 242 (1).
(1RS,2RS,4RS,4aRS,5aSR,9aRS,9bSR)-2-Azido-9b-
(hydroxymethyl)dodecahydrodibenzo[b,d]furan-1,4-diol (5f)
Azide 5f was prepared from epoxide 3f (78 mg, 0.33 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 1:1 hexane:ethyl acetate) afforded
the title compound (42 mg, 46%) as a colourless solid, m.p. 156–
157 ◦C; nmax. (Nujol) 3418, 2922, 2103, 1303, 1064, 1036, 979, 826
and 722 cm-1; dH (400 MHz; CD3OD) 3.75 (1 H, d, J 11.1, one
of H-10), 3.72 (1 H, app. broad d, J 3.6, H-1 or H-4a), 3.70–3.65
(1 H, broad m, H-2 or H-4), 3.60 (1 H, d, J 11.1, one of H-10),
3.33–3.26 (2 H, m, H-5a and H-2 or H-4), 3.18 (1 H, app. d, J
3.1, H-1 or H-4a), 2.15 (1 H, app. broad d, J 16.0, one of H-3),
2.04 (1 H, app. ddd, J 16.0, 3.7, 1.0, one of H-3), 2.00–1.91 (2 H,
broad m, H-9a and one of CH2), 1.70–1.62 (3 H, broad m, one of
CH2 and CH2) and 1.33–1.10 (4 H, m, 2 ¥ CH2); dC (100 MHz;
CD3OD) 80.9 (CH), 78.9 (CH), 67.5 (CH), 65.0 (CH2), 53.0 (CH),
52.8 (CH), 51.8 (CH), 45.5 (C), 32.1 (CH2), 25.5 (CH2), 25.4 (CH2),
24.7 (CH2) and 23.6 (CH2).
Data for compound 11. Found: M+ - H2O, 207.1757. C14H23O
requires M, 207.1749; nmax. (Neat) 3355, 3012, 2957, 2928, 2871,
1457, 1124, 1038, 945, 899, 802 and 746 cm-1; dH (400 MHz; CDCl3)
5.96–5.89 (2 H, m, alkene CH), 5.64 (1 H, app. dt, J 10.1, 2.0,
alkene CH), 5.38 (1 H, app. dt, J 10.6, 2.0, alkene CH), 3.82–
3.75 (1 H, broad m, CHOH), 3.34 (2 H, s, CH2OH), 2.86–2.77
(1 H, broad m, CHCH3), 1.82 (2 H, broad s, 2 ¥ OH), 1.51 (1 H,
dd, J 14.2, 9.0, one of CCH2), 1.44 (1 H, dd, J 14.2, 2.3, one of
CCH2), 1.41–1.22 (6 H, broad m, (CH2)3), 1.11 (3 H, d, J 7.3, CH3)
and 0.89 (3 H, t, J 6.7, CH3); dC (100 MHz; CDCl3) 134.2 (CH),
133.7 (CH), 129.5 (CH), 128.5 (CH), 70.0 (CH2), 69.3 (CH), 44.9
(CH2), 42.7 (C), 37.7 (CH2), 30.9 (CH), 27.8 (CH2), 22.7 (CH2),
22.4 (CH3) and 14.1 (CH3); m/z (TOF AP+) 207 (M - H2O, 30%),
189 (100), 146 (3), 118 (3) and 91 (1).
4432 | Org. Biomol. Chem., 2008, 6, 4426–4434
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(1aSR,2RS,3RS,3aRS,5SR,6aRS,6bRS)-5-Butyl-octahydro-6a-
(hydroxymethyl)-2-methyl-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-
b]furan-3-ol (12)
27.9 (CH), 22.8 (CH2), 14.4 (CH3) and 14.1 (CH3); m/z (TOF EI+)
238 (M - H2O, 12%), 190 (69), 147 (100) and 121 (86).
Crystallographic data for compound 13. C14H24O4, FW =
˚
˚
256.33, T = 150(2) K, l = 0.71073 A, triclinic, P-1, a = 6.3080(2) A,
◦
◦
˚
˚
b = 13.5420(5) A, c = 17.5900(7) A, a= 73.293(2) , b = 81.756(2) ,
◦
3
3
˚
g = 79.108(2) , V = 1406.88(9) A , Z = 4, r(calc) = 1.210 Mg/m ,
crystal size = 0.50 ¥ 0.18 ¥ 0.08 mm3, reflections collected = 7267,
independent reflections = 4761, R(int) = 0.079, parameters =
333, R1 [I>2s(I)]= 0.14, wR2 [I>2s(I)] = 0.34, R1 (all data) =
0.19, wR2 (all data) = 0.37. The asymmetric unit of compound 13
consists of two independent molecules. The higher R indices for
13 are due to the poor quality of the available sample and thus
data were recorded using a twinned crystal.
Epoxide 12 was prepared from diol 10 (105 mg, 0.47 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 diethyl ether:hexane) afforded
the title compound (24 mg, 20%) as a colourless oil (found: M+ -
H2O, 238.1573. C14H22O3 requires M, 238.1569); nmax. (CH2Cl2)
3410, 2931, 1645, 1456, 1379, 1034, 899 and 837 cm-1; dH
(400 MHz; CDCl3) 3.95 (1 H, app. quintet, J 6.9, H-5), 3.76 (1 H,
d, J 10.8, one of H-7), 3.69 (1 H, d, J 10.8, one of H-7), 3.65 (1 H,
d, J 6.9, H-3a), 3.42 (1 H, app. dt, J 6.9, 4.8, H-3), 3.16 (1 H, d, J
3.8, H-1a), 3.00 (1 H, dd, J 3.8, 1.0, H-6b), 2.56 (2 H, broad s, 2 ¥
OH), 2.09–2.02 (1 H, m, H-2), 1.97 (1 H, dd, J 13.1, 7.6, one of
H-6), 1.71 (1 H, dd, J 13.1, 7.1, one of H-6), 1.61–1.52 (1 H, m, one
of CH2(CH2)2CH3), 1.45–1.36 (1 H, m, one of CH2(CH2)2CH3),
1.30–1.22 (4 H, m, (CH2)2), 1.18 (3 H, d, J 7.5, CH3) and 0.83
(3 H, t, J 7.0, CH3); dC (100 MHz; CDCl3) 81.5 (CH), 77.0 (CH),
70.7 (CH), 67.9 (CH2), 57.5 (CH), 56.9 (CH), 47.2 (C), 38.6 (CH2),
36.2 (CH2), 34.6 (CH), 28.4 (CH2), 22.7 (CH2), 15.9 (CH3) and 14.1
(CH3); m/z (TOF EI+) 238 (M - H2O, 9%), 190 (75), 147 (100),
121 (82) and 91 (71).
Conclusion
In summary, cyclohexadiene-diols 1a-1f, 10 and 11 undergo
diastereoselective epoxidation followed by diastereoselective ring-
opening to give highly functionalised benzo[b]furan derivatives 3,
12 and 13 with excellent diastereocontrol.
Acknowledgements
We are extremely grateful to AstraZeneca and the EPSRC for
financial support.
References
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(1aSR,2SR,3RS,3aRS,5SR,6aRS,6bRS)-5-Butyl-octahydro-6a-
(hydroxymethyl)-2-methyl-7-oxa-bicyclo[4.1.0]hept-1(6)-eno[3,2-
b]furan-3-ol (13)
Epoxide 13 was prepared from diol 11 (278 mg, 1.24 mmol)
according to the general procedure above. Purification by flash
column chromatography (eluent 2:1 diethyl ether:hexane) afforded
the titl◦e compound (120 mg, 38%) as a colourless solid, m.p.
66–68 C (found: M+ - H2O, 238.1574. C14H22O3 requires M,
238.1569); nmax. (Nujol) 3394, 2926, 2853, 1644, 1152, 1053 and
834 cm-1; dH (400 MHz; CDCl3) 3.86–3.77 (3 H, m, one of H-7,
H-3a and H-5), 3.66 (1 H, d, J 10.9, one of H-7), 3.59 (1 H, app.
broad s, H-3), 3.21 (1 H, d, J 4.2, H-1a), 3.17 (1 H, dd, J 4.2 1.5,
H-6b), 2.94 (2 H, broad s, 2 ¥ OH), 2.23 (1 H, app. qd, J 7.3, 3.3,
H-2), 2.02 (1 H, dd, J 12.8, 5.1, one of H-6), 1.77 (1 H, dd, J 12.8,
10.2, one of H-6), 1.59–1.51 (1 H, m, one of CH2(CH2)2CH3),
1.42–1.34 (1 H, m, one of CH2(CH2)2CH3), 1.25 (3 H, d, J 7.3,
CH3) 1.25–1.20 (4 H, m, (CH2)2) and 0.83 (3 H, t, J 7.0, CH3); dC
(100 MHz; CDCl3) 79.9 (CH), 78.3 (CH), 71.4 (CH), 67.9 (CH2),
58.9 (CH), 58.0 (CH), 46.7 (C), 42.1 (CH2), 35.3 (CH2), 28.2 (CH2),
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