Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing sidechain-functionalized tetrahydrofurans

Article abstract of DOI:10.1016/j.jinorgbio.2015.04.009

tert-Butyl hydroperoxide (TBHP) stereoselectively oxidizes substituted 4-pentenols, when activated by (ethyl)[cis-(piperidine-2,6-diyl)dimethyl] vanadates. The reaction affords (tetrahydrofuran-2-yl)methanols in up to 89% yield, and in stereoselectivity r

Full text of DOI:10.1016/j.jinorgbio.2015.04.009

JIB-09709; No of Pages 17
Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively
preparing sidechain-functionalized tetrahydrofurans
⁎
Maike Dönges, Matthias Amberg, Mark Niebergall, Jens Hartung
Fachbereich Chemie, Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
tert-Butyl hydroperoxide (TBHP) stereoselectively oxidizes substituted 4-pentenols, when activated by
(ethyl)[cis-(piperidine-2,6-diyl)dimethyl] vanadates. The reaction affords (tetrahydrofuran-2-yl)methanols in
up to 89% yield, and in stereoselectivity ranging between moderate (cis:trans = 32:68) to excellent (N99:1). Cor-
relating structures of 4-pentenols, differing by substitution at tetragonal and trigonal stereocenters, to configura-
tion of products obtained from oxidative cyclization provides a reaction model explaining the origin of
stereoselectivity by (i) intramolecular oxygen atom transfer to (ii) a chair-like folded alkenol, being
(iii) hydrogen-bonded to one of the two aminodiolate oxygens of the chelated vanadate, having (iv) substituents
in the chair-like transition structure preferentially aligned equatorially. Substituents at trigonal stereocenters im-
prove 2,5-cis- and 2,4-trans-selectivity for oxidative 4-pentenol cyclization in case of (Z)-configuration. An (E)-
substituent does not alter selectivity exerted by a terminal (Z)-substituent of similar steric size. Larger (E)-groups
increase the fraction of 2,5-trans-cyclized products. The reaction model additionally implements results from
vanadium-51 NMR spectroscopy and density functional theory. According to theory, the (dialkoxy)(oxo)vanadium
substituent exerts in the preferred end-on conformation almost no effect on structure and bonding of the peroxide
group in tert-butylperoxy vanadates. Changing conformation to a higher in energy side-on arrangement puts
the vanadate-bound tert-butylperoxy group into a position to serve in a concerted reaction as combined electron
acceptor and oxygen atom donor.
Received 14 November 2014
Received in revised form 13 April 2015
Accepted 14 April 2015
Available online xxxx
Keywords:
Alkyl hydroperoxide
Aminodiolate ligand
Density functional theory
Oxidation catalysis
Stereoselective cyclization
Vanadium
© 2015 Elsevier Inc. All rights reserved.
1. Introduction
below, allowing for addressing more complex selectivity issues in
stereoselective synthesis [15–18].
Vanadium(V) compounds activate organic hydroperoxides to con-
vert nucleophilic hydrocarbons [1–3] into oxy-functionalized products,
similar to oxidative enzymes [4]. The oxygen atom transferred to sulfur
of thioethers [5], nitrogen of amines [6], π-bonds of arenes or alkenes
[7], or carbon–hydrogen bonds of alkanes [8] in biosynthesis catalyzed
by monooxygenases comes from dioxygen (Scheme 1, top) [9]. For uti-
lizing hydrogen peroxide as electron acceptor, nature has developed
peroxidases [10]. Iron- and copper-dependent peroxidases transform a
larger variety of substrates into oxy-functionalized products than
vanadate-dependent peroxidases [11–13]. Specificity for consuming
chloride, bromide, and iodide, and chemical stability during turnover
conditions, however, make vanadate-dependent haloperoxidases
unique among oxidative enzymes (Scheme 1, bottom) [14].
Controlling selectivity in oxidation of structurally demanding
substrates requires to concisely knowing the mechanism for activat-
ing an alkyl hydroperoxide and transferring the peroxidic oxygen
atom to a reductant. The role of vanadium-catalysts thereby hardly
differs from the role of protein-bound vanadate for activating hydrogen
peroxide in haloperoxidase-catalyzed oxidations [12]. Understanding
monooxygenation of organic substrates by vanadium-activated alkyl
monooxygenases
nature
or
or
or
or
Preferred catalysts for activating hydroperoxides in organic synthesis
derive from orthotungstic acid, orthomolybdic acid, and orthovanadic
acid [2,3]. Tungsten and molybdenum compounds utilize hydroperoxides
more effectively, but require elevated temperatures to do so. Vanadium-
compounds activate alkyl hydroperoxides at room temperature or
peroxidases
Scheme 1. Biosynthesis of oxy-functionalized compounds in monooxygenase- (top) and
peroxidase-catalyzed reactions (bottom) (S = e.g. Cl−, Br−, I−, amines, or thioethers)
[9–11].
⁎
Corresponding author. Tel.: +49 631 205 2431; fax: +49 631 205 3921.
E-mail address: hartung@chemie.uni-kl.de (J. Hartung).
http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009
0162-0134/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

2
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
HO
OH
OH
O
O
OH
H
H
HH
H
H
O
O
O
9
11
OH
O
O
O
OH
cis-pityol
laherradurine
(–)-hamaudol
Fig. 1. Selection of naturally occurring sidechain-functionalized tetrahydrofurans (left and center), and an example for a modified tetrahydropyran (right) [20–22].
hydroperoxides thus adds a perspective for interpreting bioinorganic
chemistry of metal co-factors in oxidative enzymes.
(dialkoxy)(oxo)vanadium substituent, according to density functional
calculations, exerts almost no ground state effect on structure and
bonding of the peroxide group in end-on tert-butylperoxy vanadates.
Changing end-on to a higher in energy side-on-configuration activates
the tert-butylperoxy group for transferring the distal peroxide oxygen
in a concerted reaction to the π-bond of an alkenol. Approaching the
peroxide group by the alkenyl substituent preferentially directs the
vanadate-bound alkenol into a chair-like conformation, placing sub-
stituents at tetragonal stereocenters equatorially, wherever possible.
Substrate effects of this kind effectively guide stereoselectivity in
oxidative cyclization, as exemplified by stereospecific synthesis of
2,3,5-trisubstituted tetrahydrofurans, and a stereoselective cascade
providing a bistetrahydrofuran from a geraniol homologue.
In the contemporary organic synthesis, methods for preparing chiral
cyclic ethers from alkenols in a diastereodivergent approach are a con-
cern [19]. Oxepans, tetrahydropyrans, and particularly tetrahydrofurans
pose key structures of many secondary metabolites (Fig. 1) [20–22]. Me-
dicinal chemistry therefore uses sidechain-functionalized oxygen-
heterocycles as building blocks for developing convincing structure/
activity-correlations [23].
The challenge to address in synthesis via C,O-bond formation is to
gain control of chemo-, regio-, and stereoselectivity (Scheme 2). Similar
to monooxygenases in nature, cobalt(II)-bis(β-diketonate) compounds
activate dioxygen for oxidizing terminal alkenol (e.g. 1) with excellent
2,3-trans-, 2,4-cis-, and 2,5-trans-selectivity [24]. Early transition metals
catalyze oxidation of alkenols bearing two alkyl groups at the terminal
alkene carbon, providing in reactions with tert-butyl hydroperoxide
(TBHP) 2,3-cis-, 2,4-trans-, and 2,5-cis-(tetrahydrofuran-2-yl)alkanols
in synthetically useful selectivity [15]. High valent, fourth- to fifth-row
late-transition metal oxo compounds oxidize the same type of sub-
strates with complementary stereoselectivity [25–30]. Oxidizing
alkenols with carbohydrate-derived dioxiranes [31–34] furnishes for a
structurally narrow range of alkenols enantiomerically enriched epoxy
alcohols, which rearrange to tetrahydrofuranyl-2-methanols, when
treated with a Brønsted-acid [35].
The most selective reagents in use today for catalyzing oxidative
cyclization of primary and secondary alkenols by alkyl hydroperoxides
are aminodiolate-derived vanadates (e.g. 3b, 3c; Scheme 3) [36,37].
Auxiliaries of this kind stabilize vanadates in the course of oxidative
substrate turnover, improve the rate for utilizing TBHP in two-electron
oxidations, and prevent radical side reactions of the peroxide from
becoming significant [38]. Chiral aminodiols derived from (piperidine-
2,6-diyl)dimethanol, to some extent, control enantioselectivity of
2-propenol-epoxidation when coordinated to vanadate, but are
not able to direct diastereoselectivity for oxidative tetrahydrofuran
synthesis [39,40].
2. Results and interpretation
2.1. Ethyl vanadates — preparation, properties, and nomenclature
Triethyl vanadate [41] (3a) reacts with aliquots of cis-piperidine-
2,6-dimethanols H2L1–2 to afford in solutions of ethanol chelated vana-
dates 3b–c in 63–68% yields (Scheme 3). The compounds crystallize
from concentrated solutions of ethanol upon resting in a refrigerator.
Vanadates 3b–c show sharp melting points and single resonances
in vanadium-51 NMR-spectra recorded in 2/1-volumes of ethanol/
deuterochloroform. In solutions of deuterochloroform or perdeuterated
dimethyl sulfoxide, tetraphenyl-substituted vanadium compound 3c
shows more than one vanadium-51 resonance [40].
For naming vanadium compounds in this article, we used the ester
convention [42–44], since vanadates chemically behave toward TBHP
and alkenols more like main-group molecular compounds, rather than
coordination compounds. The triethyl ester of orthovanadic acid in
this nomenclature is triethyl vanadate (3a), and cis-piperidine-2,6-
dimethanol-substituted derivatives 3b–c are chelated (dialkyl)alkyl
vanadates (Fig. 2) [45].
For preparing chiral tetrahydrofurans by a diastereodivergent
oxidative approach, we addressed in present study stereoelectronic
aspects dealing with peroxide activation, and sterecontrolling effects
of alkenol substituents in vanadate-catalyzed oxidation by tert-butyl
hydroperoxide. The major results from the study show that the
2.2. Reactivity of chelated vanadates toward tert-butyl hydroperoxide
Chelated vanadate 3b reacts at room temperature with tert-butyl hy-
droperoxide, providing in a 1/1-volume of ethanol/deuterochloroform
an upfield shifted vanadium-51 resonance, while the signal of triethyl
vanadate (3a) disappears (Table 1, entry 1). The same spectral change
e.g
EtOH
VO(OEt)3 + H2Ln
VO(Ln)(OEt)
78 °C
3a
n = 1, 2
3b: 68% (n = 1)
3c: 63% (n = 2)
synthesis
Ph
H
N
H
OH
OH
OH
Ph
Ph
Ph
Ph
Ph
Ph
N
=
=
OH
N
N
e.g.
H
H
H
H
H
H
Ph
HO
OH
HO
OH
alternatively
H2L1 for 3b
H2L2 for 3c
Scheme 2. Concepts for oxidative C,O-cyclization of alkenol 1 into substituted 2-
(tetrahydrofuran-2-yl)alkan-1-ol 2 [R = H or alkyl; R1 and R2 = H, alkyl, or aryl;
open and closed circles denote carbon substituents] [15].
Scheme 3. Synthesis of chelated vanadates 3b–c from triethyl vanadate (3a) and cis-
(piperidine-2,6-diyl)dimethanols H2L1–2 [40].
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
3
O
O
NH
V OR
H3VO4
VO(OR)3
VO(OR)2(OOtBu)
O
orthovanadic acid
trialkyl vanadate
(dialkyl)alkyl vanadate alkylperoxy(dialkyl) vanadate
Fig. 2. Systematic for naming derivatives of orthovanadic acid.
occurs in a solution containing tetraphenyl-substituted vanadate 3c and
2.3.3. Quality of the model
TBHP (Table 1, entry 2) [46].
B3LYP/6-311++G**-theory reproduces bond distances and bond
angles from crystallographic studies of alkyl vanadates, deviating 2%
or less from experimental references (Table 2). Theory and experiment
show the best match for structure analysis of (ethyl)[cis-(piperidine-
2,6-diyl)dimethyl] vanadate (3c) (structure type IV), deviating for
vanadium-oxygen bond lengths, and angles involving vanadium and
oxygen no more than 0.8% (Table 2, entries 9 and 12). An exception
to the general precision is the vanadium–nitrogen bond, which is 2%
shorter in the experiment, and so still within a limit considered
acceptable for this study (Table 2, entries 8, 9, and 12).
Comparing computed structure parameters from molecules at zero
Kelvin in the gas phase (Table 2, entries 1–9) to structure data obtained
by diffracting X-rays at a thermally equilibrated ensemble of molecules
at elevated temperature (Table 2, entries 10–12) [40,61,62], in summa-
ry, provides satisfactory, but as a matter of fact, no perfect match.
Given the propensity of primary and secondary O-alkyl vanadates to
aggregate in the liquid and the solid phase, as evident, for example, from
concentration dependency of vanadium-51 NMR-chemical shifts [61]
and intermolecular vanadium–oxygen distances in crystal structures,
we investigated the driving force for triethyl vanadate (3a) and O-
methyl ester 3d to dimerize in the gas phase (Table 2, entries 1–7).
2.3. Activating tert-butyl hydroperoxide by vanadates
2.3.1. Outline
To understand how vanadium (V) compounds activate TBHP, we
investigated structure and bonding of tert-butylperoxy vanadium
compounds using electronic structure methods [47]. For developing a
mnemonic device to predict stereodirecting effects in synthesis of
sidechain-functionalized tetrahydrofurans, we examined the mode of
alcohol to binding ethyl vanadates (Section 2.3), analyzed thermochem-
istry of 4-pentenol oxidation (Section 2.4), and correlated alkenol struc-
ture to stereoselectivity in oxidative tetrahydrofuran synthesis
(Sections 2.5–2.6).
2.3.2. Theory
For computing structure and bonding of alkyl vanadates 3a–c, we
selected a triple ζ-basis set, abbreviated in the Gaussian09-systematic
as 6-311++G** [48]. The basis set adds polarization and diffuse
functions to energy functions, which differ for atoms from different
rows in the periodic table [48]. The abbreviation 6-311G specifies for
hydrogen the 6-311G-basis set [47], for oxygen, nitrogen, and carbon
the McLean–Chandler (12s,9p) → (621111,52111)-basis set [49], and
for vanadium the Wachters–Hay all electron basis set for computing en-
ergy functions associated with 3d-orbitals [50,51], having implemented
scaling factors suggested by Raghavachari and Trucksrow [52]. Parame-
trization of the basis set, particularly when combined with a hybrid
density functional considering electron correlation, allows computation
of energies of transition metal compounds, without allowing relativistic
effects of electrons being attracted by the vanadium nucleus to signifi-
cantly affect results [53].
From an assessment of methods, we selected Becke's three parame-
ter Lee–Yang–Parr hybrid functional (B3LYP) [54,55] as standard for
computations in combination with the 6-311++G**-basis set
[56–59]. For translating results from density functional-minimized en-
ergy functions to a more tutorial bonding model, we used the natural
bond orbital (NBO)-theory [60]. To obtain decisive results, we
prevented extensive electron delocalization into higher in energy or-
bitals by conducting NBO-population analysis on the B3LYP/6-31G*-
level of theory, starting from B3LYP/6-311++G**-computed atomic
coordinates.
Table 2
Selected bond lengths and angles of monomeric (I) and dimeric (II/III) trialkyl vanadates,
and (aminodialkyl)alkyl vanadates (IV).
Entry Type
Compd./R V,OA/Å V,OB/Å V,OC/Å OA,V,OB/deg V,OCV/deg
b
b
b
b
b
b
1a
I
I
I
II
3a/C2H5
3a/C2H5
3d/CH3
3d/CH3
1.581
1.579
1.579
1.578
1.573
1.571
1.577
1.586
1.575
1.768
1.769
1.769
1.779
1.799
1.792
1.782
1.767
1.781
–
–
–
108.5
108.4
108.4
102.5
105.6
107.1
109.0
–
–
–
2c
3c
4 c,d
5c,e
6c,f
7c,g
8c
1.823
1.986
2.007
2.060
109.1
109.8
109.8
109.5
trans-III 3a/C2H5
trans-III 3d/CH3
cis-III
IV
IV
II
3d/CH3
3b/C2H5
3c/C2H5
1.835 h 107.6
–
b
9c
1.857 i
108.6
101.89
1022
–
b
10 j
11k
12l
3e/C2H4Cl 1.5842 1.7712 1.8571
109.01
1052
III
IV
3d/CH3
3c/C2H5
1.515
1.845
2.034
b
1.5852 1.7892 1.8432
107.01
–
a
B3LYP/6-31 + G** (0 K).
Not available.
B3LYP/6-311++G** (0 K); all computed type-II- and type-III-dimers are C1-symmetric,
b
c
showing similar but not identical bond distances and angles in the half of the molecules
drawn to the left in the graphic associated with this Table.
Table 1
d
Additional atomic distances and bond angles: V,OB = 1.798 Å; V,OC′ = 2.417 Å; O-
Vanadium-51 chemical shifts of vanadium compounds.
B,V,OB = 113.4°; OB,V,OC = 116.9°; OB,V,OC′ = 81.6°.
e
Additional bond lengths and angles: V,OB′ = 1.798 Å; V,OC′ = 2.025 Å; OA,V,OB′
=
=
=
104.4°; OB,V,OB′ = 94.9°; OB,V,OC = 86.9°; OB′,V,OC′ = 89.9°.
f
Additional bond lengths and angles: V,OB′ = 1.799 Å; V,OC′ = 2.008 Å; OA,V,OB′
103.4°; OB,V,OB′ = 95.7°; OB,V,OC = 87.0°; OB′,V,OC′ = 88.7°; V,OC,V = 109.8°.
Entry
3
L
δ 51Va
g
Additional bond lengths and angles: V,OB′ = 1.790 Å; V,OC′ = 1.970 Å; OA,V,OB′
3/ppmb
3 + TBHP/ppmb
99.6°; OB,V,OB′ = 98.8°; OB,V,OC = 88.0°; OB′,V,OC′ = 90.0°; V,OC,V = 109.5°.
h
Additional bond lengths: V,OC′ = 1.833 Å; V,N = 2.353 Å.
1
2
b
c
L1
L2
−486
−512
−553
−552
i
Additional bond lengths: V,OC′ = 1.857 Å; V,N = 2.246 Å.
j
X-ray diffraction at room temperature [61].
a
k
Referenced versus VO(OtBu)3 (δ = −674); chemical shift for VO(OEt)3 (3a) in EtOH/
CDCl3: −596 ppm for c3a = 0.19 M.
Temperature for X-ray diffraction analysis not specified [62].
l
X-ray crystallography at 150 K; additional bond lengths: V,OC′ = 1.8612 Å, V,N =
b
Ethanol/deuterochloroform = 1:1 (v/v).
2.2032 Å (subscripts describe deviation of the last digit) [40].
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

4
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
Table 3
For practical reasons, we restricted ourselves to type II-dimers and cis/
trans-isomers of type III-dimers for computing structures and energies,
since examples for this kind of association are known from
experimental studies (Table 2) [61,62].
Energies computed for conformers of triethyl vanadate 3a and for minimum structures of
chelated ethyl vanadates 3b–c.
Entry
Compound
E + ZPVE/a.u. a
ZPVE/a.u.a
G(298)/a.u.a
Forming type II- and cis/trans-type III-dimers from two molecules of
trimethyl vanadate (3d) furnishes C1-symmetric minimum structures,
showing shorter V,OA-bonds (−0.1% to −0.5%), and longer bonds be-
tween vanadium and peripheral ether oxygens (0.7% to 1.3% for OB
and OB′), than monomer 3d. Bridging ether oxygens (OC and OC′) form
particularly long bonds to vanadium, being 3.1% wider in type II-
dimer, 12.3% in the cis-III-dimer, and 16.4% in the trans-III dimer, than
V,OB-bond lengths in trimethyl vanadate (3d) (Table 2, entries 3–4
and 6–7).
Computed Gibbs free energy differences ΔG° for dimerizing two
molecules of trimethyl vanadate (3d) under standard conditions
(1.013 bar, 298 K) increase from II (51.1 kJ mol−1) via cis-III
(86.1 kJ mol−1) to trans-III (89.9 kJ mol−1). Searching for a local
minimum of the triethyl vanadate type II-dimer starting from an ini-
tial V,OB-distance of 2.260 Å, provides two separate molecules of 3a.
Dimerizing triethyl vanadate (3a) into a C1-symmetric type trans-III-
structure is 103.4 kJ mol−1 endergonic.
1
2
3
4
5
6
7
aaa-3ab,c
saa-3ab,c
ssa-3ab,c
sss-3ab,c
sss-3ac,d
syn-3bd
anti-3cd
−1482.502373
−1482.510235
−1482.515374
−1482.517974
−1482.694821
−1810.739718
−2577.636706
0.213764
0.214132
0.214346
0.214415
0.213510
0.388655
0.598596
−1482.550382
−1482.558802
−1482.563534
−1482.565992
−1482.741784
−1810.788685
−2577.705595
1 atom unit (a.u.) = 2625.5 kJ mol−1; ZPVE = zero-point vibrational energy.
s = syn; a = anti.
B3LYP/6-31+G**//B3LYP/6-31+G**.
a
b
c
d
B3LYP/6-311++G**//B3LYP/6-311++G**.
OC/OC′ and vanadium are 4% longer than V,OB-bonds in chelated ester
3b (1.767 Å) and in triethyl vanadate (3a) (1.769 Å; Scheme 4,
Table 2, entries 2 and 8). The ethoxy group in the lowest in energy con-
former adopts a synperiplanar conformation. The non-bonding electron
pair at nitrogen, according to NBO-theory is sp5.1-hybridized, pointing
axially toward vanadium. The energy change computed for the non-
bonding electron pair at nitrogen in aminodiol H2L1 and at a distance
of 2.353 Å to vanadium in ester 3b is −0.039 atom units, which is not
considered a bonding interaction in the NBO-model. For arguments pro-
vided in the section dealing with ethanol binding to chelated vanadate
3b (vide infra), we concurred with this evaluation.
To sum up, thermochemical modeling predicts trialkyl vanadates 3a
and 3d to exist in the gas phase almost exclusively as monomers.
2.3.4. Structure and bonding in triethyl vanadate
Unconstrained energy minimization of triethyl vanadate (3a) in
B3LYP/6-311++G**-theory leads to a structure close to C3-symmetry,
without converging to minimum. In C3-symmetry, final iterations
converge providing an energy function, being 9.59 × 10−6 atom units
(0.025 kJ mol−1) lower in energy than in the unconstrained approach.
In the minimum structure, the OA,V,OB,C-segment aligns synperiplanar
(Fig. 3, left), similar to the solid state structure of tri(2-chloroeth-1-yl)
vanadate [61]. Rotating ethyl substituents about the V,OB-bond gradual-
ly increases the energy of conformers, as the number of antiperiplanar
arranged O-ethyl groups in 3a rises from zero to three (Table 3, entries
1–4).
Placing in an input structure vanadium equatorially to nitrogen
of aminodiol H2L1, hydrogen axially, and the two methanolate-
substituents equatorially in a chair-conformer of piperidine, provides a
local minimum from energy function minimization, having the nitro-
gen–hydrogen bond positioned equatorially, the non-bonding electron
pair axially, and the piperidine ring distorted to a twist chair. The
relative energy of this strained structure is beyond a value relevant for
considering in a Boltzmann-distribution at room temperature.
The lowest in energy structure of tetraphenyl-substituted vanadate
3c has the OA,V,OB,C segment arranged antiperiplanar (Scheme 5).
All remaining structural parameters, particularly vanadium–oxygen
bonds and the vanadium–nitrogen distance, are almost identical to pa-
rameters computed for tetramethyl-substituted vanadate 3b (Table 2,
entries 8 and 9). Minimizing conformer syn-3b by the chosen method
furnishes a slightly lower in energy conformer, which showed one
negative mode of vibration, and therefore was not considered further.
The conformational behavior of the ethoxy group, according to our
interpretation, reflects differences in sizes between methyl in 3b and
phenyl in 3c, and thus more pronounced steric repulsion in the latter
compound.
Oxygen OA in triethyl vanadate (3a) forms, according to NBO-theory,
a triple bond with vanadium consisting of two π(d/p)-bonds and one
σ(sd2.1/sp7.6)-bond. p-Type non-bonding electron pairs from ether oxy-
gens OB form π-bonds, using σ*(V,OB)-orbitals as acceptors, additionally
stabilizing the ground state of ester 3a (Fig. 4 and Supplementary data).
2.3.5. Aminodiol binding
Tetramethyl-substituted piperidinedimethanol H2L1 binds
equatorially to vanadium. Bonds between aminodiolate-oxygens
Fig. 3. Computed minimum conformers of vanadates: the all-syn-conformer of triethyl vanadate (3a) (left) and the syn-conformer for (ethyl)[cis-(piperidine-2,6-diyl)-(1-methyleth-1-
yl)] vanadate (3b) (right) (vanadium is depicted in yellow, oxygen in red, nitrogen in blue, carbon in gray, and hydrogen in white; coding of oxygens: OA = oxo-O; OB, OC, and OC′
=
ether-Os).
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
5
Ph
H
Ph
A
C
O
Ph
O
V
O
C'
H
B
O
OH
Ph
Ph
35.6
N
N
Ph
OH
VO(OEt)3
+
+ 2 EtOH
Ph
Ph
4.4
H2L1
syn/syn/syn-3a
anti-3c
Scheme 5. Computed energy in kJ mol−1 for synthesis of the lowest in energy conformers
of ethyl cis-(piperidine-2,6-diyl)dimethyl vanadate 3c (ΔRE printed in italics and ΔG° in
bold).
Fig. 4. π-Bonding in triethyl vanadate (3a) [NBO-calculations (B3LYP/6-31G*//B3LYP/6-
311++G**); R = C2H5; ethoxy groups in the graphics to the right were omitted for the
sake of clarity].
2.3.6. Thermochemistry of aminodiol binding
2.3.8. Alcohol binding to a chelated vanadate
Substituting piperidinedimethanol H2L1 for two molecules of etha-
nol in triethyl vanadate (3a) is −1.2 to −5.9 kJ mol−1 exergonic. The
driving force for synthesis of 3b is entropy (Scheme 4). Tetraphenyl-
substituted vanadium compound 3c forms from triethyl vanadate (3a)
and H2L2, according to theory, in a weakly endergonic reaction
(Scheme 5).
Ethanol forms hydrogen bonds with tetramethyl-substituted vana-
date 3b at ether oxygen OC′ (equivalent to OC), or ethoxy oxygen OB. En-
tropy disfavors the association, rendering ethanol binding endergonic
(Scheme 7). Minimizing an energy function having the ethanol oxygen
bound in the initial structure at a distance of 2.200 Å to vanadium, ends
up with hydrogen bonded minimum structures 3b × EtOH @ OC/OC′ or
OB (Scheme 7).
Theory, in summary, predicts low driving forces for binding Lewis-
bases to vanadium in vanadates, as exemplified by ethanol coordination
and vanadium–nitrogen interaction in chelated ester 3b. From this
information we concluded that Lewis bases will use alternatives for
binding to vanadate, when existing.
Differences in driving forces for preparing chelated vanadates 3b
and 3c coincide with V,OC- and V,OC′-distances, being longer for the
latter, possibly due to more pronounced steric repulsion between
substituents in the tetraphenyl-substituted aminodiolate-auxiliary
(Table 2, entries 8 und 9). Attempts to measure the Gibbs free energy
for synthesis of chelated vanadate 3c by isothermal microcalorimetry,
unfortunately, provided no meaningful data. Correlating the heat
flow to molar ratio of added triethyl vanadate (3a) furnishes no sigmoi-
dal curve, as required for deducing reliable thermochemical data
(Supplementary data) [63]. The experimental data show that the reac-
tion between triethyl vanadate (3a) and H2L2 at 25 °C is weakly exer-
gonic, agreeing in the order of magnitude with predictions from
theory [64]. In synthesis, chelated vanadate 3c forms in boiling ethanol,
adding entropy as additional driving force. The product crystallizes from
the reaction mixture, taking profit from lattice energy as additional
driving force in the experiment.
2.3.9. Tert-butylperoxy binding to vanadates
Substituting TBHP for ethanol in triethyl vanadate (3a) furnishes
perester 4a. According to the theory, the reaction is 5.8 kJ mol−1 ender-
gonic in the gas phase, providing a modeled equilibrium constant of
K = 9.6 × 10−2 (Scheme 8, Tables 4 and 5). Perester 4a prefers anticline
conformation for the peroxide group V,OD,OPC. For being consistent
with the convention used in peroxide chemistry, we named the oxygen
bound to tert-butyl carbon proximal (OP) and the remote oxygen distal
(OD) [65]. The mode of peroxy group binding in minimum conformer
2.3.7. Configuration at vanadium
Vanadium in chelated O-esters 3b and 3c is a center of pseudo-
asymmetry. Interchanging positions of two or more substituents at
vanadium furnishes diastereomers. In the computed lowest in energy
structure of chelated vanadate 3b, the nitrogen–hydrogen bond
and the oxo vanadium group align almost in parallels, at a H,OA-
distance of 2.652 Å (syn-3b). Diastereomer endo-3b, having the
nitrogen–hydrogen bond and the oxo vanadium group oriented in anti-
parallel mode, cannot take profit from dipolar attraction between the
substituents, and is 15.4 kJ mol−1 higher in energy (Scheme 6). From
this information we concluded that the piperidine ring is able to control
configuration at vanadium in chelated esters of the types 3b–c.
H
N
H
N
O
V
O
O
O
15.4
O
O
V
O
O
13.2
endo/anti-3b
exo/syn-3b
Scheme 6. Computed energy in kJ mol−1 associated with configurational change at
vanadium in (ethyl)[cis-(piperidine-2,6-diyl)-(1-methyleth-1-yl)] vanadate (3b) (ΔRE
printed in italics and ΔG° in bold).
H
N
O
V
O
H
EtOH
EtOH
O
OH
N
O
OH
– 20.8
– 17.3
VO(OEt)3
+
30.2
24.7
19.9
19.8
H2L1
syn/syn/syn-3a
– 1.2
– 5.9
syn-3b
H
O
N
O
H
O
N
O
V
O
B
O
O
V
A
A
C
O
C
O
H
O
V
O
C'
H
N
O
V
O
C'
B
O
C'
O
O
B
+ 2 EtOH
2 EtOH +
N
H
O
H
O
anti-3b
syn-3b
B
C'
syn-3b × EtOH @ O
syn-3b × EtOH @ O
Scheme 4. Computed zero-point vibrational energy-corrected reaction energies (ΔRE in
kJ mol−1, numbers printed in italics) and Gibbs free energy changes (ΔG° in kJ mol−1 at
1.013 bar and 298.15 K; numbers printed in bold) for the reaction between triethyl
vanadate (3a) and aminodiol H2L1.
Scheme 7. Computed energies in kJ mol−1 for hydrogen bonding of ethanol to (ethyl)[cis-
(piperidine-2,6-diyl)dimethyl] vanadate 3b (ΔRE printed in italics and ΔG° in bold).
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

6
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
This interaction is stronger in syn/syn/side-on-4a than the σ( V,OD)-
3.6
bond, and becomes even more pronounced as the V,OP-distance further
shortens, in turn weakening the σ(V,OD)-bond (Fig. 7 + 8).
5.8
VO(OEt)(OOtBu)
syn/syn/anti-4a
+ EtOH
VO(OEt)3
syn/syn/syn-3a
+ tBuOOH
Expanding the valence electron shell at vanadium by the ap-
proaching non-bonding electron pair of OP widens bonds between
vanadium and the remaining oxygens. The NBO-model associates
these structural changes to transfer of electrons from non-bonding elec-
tron pairs at OP and OD into the σ*(V,OA)-orbital, π*(V,OA)-orbitals, and
σ*(V,OB/OB′)-orbitals (Fig. 7). The structural effect is weak for the V,OA-
group (0.4%), larger for V,OB′- (0.6%) and V,OB-bonds (1.2%), and the
largest for the V,OD-bond (3.7%) (Table 5, entries 2 and 4).
Scheme 8. Modeled energies in kJ mol−1 for peresterification of triethyl vanadate (3a)
(ΔRE printed in italics and ΔG° in bold).
Table 4
Computed energies of minimum structures of tert-butylperesters 4a–c.
Entry
Compound
E + ZPVE/a.u.a
ZPVE/a.u.a
G(298)/a.u.a
2.3.10. tert-Butyl peresters from aminodialkyl vanadates
1
2
2
3
4
ssa-4ab,c
ssa-4ac,d
sso-4ad,e,f
anti-4bd,g
anti-4cd,h
−1636.234921
−1636.444923
−1636.427562
−1964.490214
−2731.390583
0.273036
0.271876
0.272078
0.447035
0.656972
−1636.286479
−1636.496610
−1636.476742
−1964.543124
−2731.466081
tert-Butyl hydroperoxide binds end-on to vanadium in tetramethyl-
substituted aminodialkyl vanadate 4b, energetically preferring an anti-
cline conformation for the peroxide group. In the computed minimum
structure of perester 4b, all oxygen-vanadium bonds, except the V,OD-
distance, are longer than in tert-butylperoxy vanadate 4a (Table 5, en-
tries 2 and 5). Substituting TBHP for ethanol in chelated ethyl vanadate
syn-3b is endergonic (6.8 kJ mol−1), similarly to perester synthesis from
the syn/syn/syn-conformer of triethyl vanadate (3a) (Scheme 9).
In a 1/1-solution of ethanol/deuterochloroform TBHP quantitatively
replaces ethanol in aminodialkyl-vanadate 3b within 72 h. Perester syn-
thesis starting from tetraphenyl-substituted vanadate 3c and TBHP in
the same solvent combination occurs quantitatively within a few
minutes.
a
1 atom unit (a.u.) per particle is equivalent to 2625.5 kJ mol−1; ZPVE = zero-point
vibrational energy.
b
B3LYP/6-31 + G**//B3LYP/6-31+G**.
s = syn; a = anti.
B3LYP/6-311++G**//B3LYP/6-311++G**.
c
d
e
sso = syn/syn/side-on.
f
One negative mode of vibration (i = −25.4 cm−1).
g
Anticline conformation.
Antiperiplanar conformation.
h
Density functional calculations reproduce differences in driving
forces for perester synthesis from 3b and 3c, predicting exergonic reac-
tion between tetraphenyl-substituted aminodialkyl vanadate anti-3c
and TBHP (Scheme 9). Perester 4c shows in the computed minimum
structure antiperiplanar conformation at the peroxide bond (Table 5),
possibly explaining high reactivity of vanadate 3c for catalyzing alkenol
oxidation with TBHP.
syn/syn/anti-4a is end-on (Fig. 5) [66,67]. Conformers of 4a having the
end-on-peroxy group arranged synperiplanar or syncline, or ethoxy
groups oriented antiperiplanar, are higher in conformational free
energy (Supplementary data).
Shortening the distance between proximal oxygen OP and vanadium
in the syn/syn/anti-conformer gradually increases the energy of perester
4a (Fig. 6). At a V,OP-distance below 2.0 Å, the peroxy group changes
conformation from antiperiplanar to orthogonal, now binding side-on
to syn/syn-(diethoxy)(oxo)vanadium (Table 5, entries 1–4, Fig. 5) [68].
At a V,OP-distance of ~1.9 Å, ~45 kJ mol−1 above the equilibrium struc-
ture syn/syn/anti-4a, vanadium and oxygens OD and OP form an almost
equilateral triangle. This intermediate, the syn/syn/side-on-isomer of
4a, is no stationary point on the potential energy surface, as obvious
from a negative mode of vibration arising from a wagging motion of
the peroxide group combined with a bending mode within one of the
ethoxy groups.
2.3.11. Effects of vanadium binding on orbitals of the tert-butylperoxy
group
In (diethoxy)(oxo)vanadium, electronegativity of atoms equilibrate
according Sanderson's principle [69–71], to a value of 2.60 on the
Pauling scale, causing the vanadium substituent to be slightly stron-
ger electron withdrawing than hydrogen (2.20) (Table 6). Substitut-
ing (diethoxy)(oxo)vanadium for hydrogen in TBHP raises the
σ(X,O)-bond energy in tert-butylperoxy compounds of the general
type XODOPtBu [X=H, (C2H5O)2V=O], without altering energies of
the σ(OD,OP)-bond and the σ*(OD,OP)-orbital significantly (Table 6,
entries 1 and 2). Neither the piperidine nitrogen in chelated tert-
Side-on binding of the tert-butylperoxy group occurs by overlapping
the p-type non-bonding electron pair at OP and the π*(V,OA)-orbital.
Table 5
Bond lengths, bond angles, and dihedral angles of tert-butylperesters 4a–c (R = C2H5).
Entry
Compd.a
V,OA/Å
V,OD/Å
V,OP/Å
V,OB,C/Å
V,OB′,C′/Å
V,N/Å
OD,OPb/Å
V,OD,OP/deg
V,OD,OP,C/deg
OAV,OD,OP/deg
d
1
2
3
4
5
6
ssa-4ac
ssa-4ae
sso-4ac,f
sso-4ae,f
anti-4be
anti-4ce
1.577
1.574
1.584
1.582
1.581
1.572
1.820
1.822
1.884
1.890
1.823
1.822
2.476
2.520
1.876
1.876
2.624
2.670
1.762
1.762
1.781
1.783
1.827
1.850
1.768
1.768
1.782
1.779
1.834
1.850
–
1.462
1.455
1.459
1.455
1.442
1.438
97.4
99.9
66.9
66.8
106.4
109.4
136.4
138.1
132.3
131.9
146.9
180.0
175.7
176.1
87.8
−86.5
178.1
180.0
d
–
d
–
d
–
2.305
2.240
a
s = syn; a = anti; o = side-on.
For TBHP: 1.461 Å (B3LYP/6-31 + G**) and 1.458 Å (B3LYP/6-311++G**).
b
c
d
e
f
B3LYP/6-31 + G** (0 K).
Not available.
B3LYP/6-311++G** (0 K).
Values refer to energy-minimized wave function having V,OP by internal coordinates constrained to 1.876 Å.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
7
Fig. 5. Ball and stick presentation of the syn/syn/anti-minimum conformer of tert-butylperoxy vanadate 4a (left) and the higher in energy syn/syn/side-on isomer of 4a (right) (vanadium is
depicted in yellow, oxygen in red, carbon in gray, and hydrogen in white; OP = proximal oxygen to the tert-butyl group; OD = distal oxygen). (For interpretation of the references to color
in this figure legend, the reader is referred to the web version of this article.)
butylperoxy vanadate 4b, nor the structural change to side-on of the
tert-butylperoxy group in 4a, change peroxide orbital energies in a
noteworthy manner (Table 6, entry 3). Similarly, the length of the per-
oxide bond in TBHP (1.458 Å) remains unchanged in the end-on
(1.455 Å) and the side-on isomer of tert-butylperoxy vanadate 4a
(Table 5, entries 2 and 4).
To sum up, vanadium-binding exerts no Lewis-acid effect on orbital en-
ergies of the peroxide bond in tert-butylperoxy vanadates. NBO-theory
predicts a stabilizing effect of the (diethoxy)(oxo)vanadium(V) group on
the tert-butylperoxy substituent, arising from π-bonds between non-
bonding electron pairs at OD and σ*(V,OB/OB′)-orbitals (Fig. 7).
develops into a full ether oxygen/vanadium σ-bond, the σ(V,OD)-bond
becomes weak and weaker until OD is transferred to the alkene carbons,
providing an epoxide (Scheme 10).
Modifying energies of bonding orbitals between vanadium and oxy-
gen, and virtual V,O-orbitals interacting with the tert-butylperoxy group
by electronically modified auxiliaries, according to the model, alters bar-
rier and rate for OD-transfer, potentially accelerating or moderating
vanadate-catalyzed oxidations with TBHP. The model moreover pre-
dicts that other triply bonded oxo metal groups should be able to
activate alkyl hydroperoxides in the same way. Reagents frequently ap-
plied in oxidation catalysis with TBHP are oxo chromium(VI) and dioxo
molybdenum(VI) compounds. In molecular orbital theory, bonding of
oxo groups to high valent and thus contracted metal ions is explicable
2.3.12. The role of the oxo vanadium (V) group for activating TBHP
Virtual orbitals from the triple bond between vanadium and oxygen
O
A provide appropriately aligned acceptors for assisting the end-on/
side-on transit, by gradually strengthening bonding interaction be-
tween vanadium and proximal oxygen OP. At the onset of the conforma-
tional change, a non-bonding electron pair from OP overlaps with the
σ*(V,OA)-orbital. As the conformation of the peroxy group turns into
side-on, π*(V,OA)-orbitals take over. Since the two π*-orbitals from the
triple bonded V,OA-group arrange orthogonally, the conformational
transit occurs without stereoelectronic barrier.
Side-on binding opens the reaction channel for transferring distal
oxygen OD to a reductant. Overlapping the π(C,C)-orbital with the
σ*(OD,OP)-orbital lowers the OP,OD-bond order, causing the peroxide
bond to break heterolytically in a SN2-manner. The leaving group is
the tert-butoxy group, activated by vanadium. As the σ(V,OP)-bond
Fig. 7. Visualization of orbital interactions associated with peroxide stabilization in the
ground state (left), and peroxide activation at the onset of V,OP-bonding (right).
Fig. 8. NBO-energies for the peroxide bond, the associated σ*-orbital, and bonds between
vanadium and peroxide oxygens OD and OP along the V,OP-reaction coordinate [for struc-
tures of the compounds and indexing of oxygens, see Fig. 5; NBO-analysis; 1 atom unit
(a.u.) = 1 Hartree = 27.2114 eV. 1 Hartree/particle = 2625.5 kJ mol−1].
Fig. 6. Conformational and energy change along the V,OP-reaction coordinate, leading
from conformer syn/syn/anti (ssa)-4a to syn/syn/side-on (sso)-4a (for labeling of oxygen
atoms, refer to Fig. 5).
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

8
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
O A
V
C
O
H
N
O
V
O
H
N
D
O P
O
2.6
O
O
+
tBuOOH
tBuOOH
+ EtOH
O
O
tBu
tBu
C'
6.8
syn-3b
anti-4b
Ph
H
Ph
H
O
O A
OC
D
O P
O
Ph
– 6.3
– 9.1
Ph
Ph
V
O
V
N
NPh
+
+ EtOH
OC'
O
Ph
Ph
anti-4c
anti-3c
Scheme 9. Computed energies in kJ mol−1 for perester formation from TBHP and chelated
vanadates 3b and 3c (ΔRE printed in italics and ΔG° in bold).
by superimposing two π-(M,OA)-bonds to one σ(M,OA)-bond. Since
orbital energies of different metals are not the same, reactivity of oxo
metal-based reagents toward TBHP vary, being consistent with experi-
mental observations [15].
Scheme 10. Valence bond (top) and molecular orbital (bottom) model describing transfer
of distal oxygen OD to an alkene, for example a 4-pentenol [R = tBu; VO denotes VO(L1–2)].
2.4. Thermochemistry of oxidative 4-pentenol cyclization by TBHP
For determining the driving force of distal oxygen atom transfer
from TBHP to a 4-pentenol, we modeled oxidative cyclization of 5-
methyl-4-hexen-1-ol (1a). Input structures were taken from a usage-
directed conformational search applying the MM+-force field [72] for
alkenol 1a, and potential energy scans for substituents and side chains
of 2-(tetrahydrofuran-2-yl)propan-2-ol (2a) and diastereomers of
tetrahydropyran-3-ols 5a on the B3LYP/6-31 + G**-level of theory
(Scheme 11).
Subtracting experimentally determined strain energy of oxirane
(110 kJ mol−1) [75] from the calculated heat of oxirane formation
provides a value of −282 kJ mol−1 as reference for preparing an un-
strained cyclic ether and tert-butanol from ethene and TBHP.
Thermochemical analysis, in summary, predicts a considerable driv-
ing force for preparing tetrahydrofuranylmethanol 2a and tert-butanol
from TBHP and 4-pentenol 1a. The barrier for the reverse reaction thus
is significant. From this information we concluded that selectivity in oxi-
dative tetrahydrofuranylmethanol synthesis arises from kinetic control.
Density functional calculations predict a strongly exergonic redox reac-
tion between alkenol 1a and TBHP to give (tetrahydrofuranyl)isopropanol
2a and tert-butanol (−258.0 kJ mol−1
;
ΔRE
=
ΔE
+
ΔZPVE = −268.3 kJ mol−1). Tetrahydropyran-3-ols eq-5a and ax-
5a are thermochemically slightly disfavored, which we relate to
backside strain imposed by vicinal dimethyl substitution at
endocyclic carbon C2 [73].
2.5. Stereochemical details, structures, indexing, and preparation of alkenols
In a cyclization, at some point on the reaction coordinate, reacting
entities have to approach for intramolecularly forming a σ-bond. Princi-
ples of conformational analysis state that the lowest in energy conform-
er of an alkenol folded for cyclization derives from a tetrahydropyran
chair [76]. All illustrations addressing stereochemical details in the
succeeding paragraphs therefore depict alkenols in a chair-like
conformation (e.g. Fig. 9).
For examining stereochemical principles of oxidative 4-pentenol
cyclization with TBHP, we used substrates differing in configuration at
tetragonal and trigonal stereocenters. In alkenes bearing substituents
of different stereochemical hierarchy, the two faces of the π-bond are
prostereogenic. An oxidant comprising stereochemical information,
such as syn/syn/side-on-4a, experiences differences in Gibbs free energy
of activation (ΔΔG‡), when approaching the Re- or the Si-face of alkene
carbons in 1 (eq. 1, Fig. 10) [77].
According to G3-theory, scaled for predicting absolute values of ΔRE
and ΔG° with higher precision than the applied density functional meth-
od, converting alkenol 1a with TBHP into (tetrahydrofuranyl)isopropanol
2a and tert-butanol is 16% stronger exergonic (−293.5 kJ mol−1
;
ΔRE = −310.6 kJ mol−1). Tetrahydropyran-3-ol eq-5a forms from the re-
actants with similar driving force as (tetrahydrofuranyl)isopropanol 2a
(ΔG° = −290.1 kJ mol−1, ΔRE = −310.9 kJ mol−1), whereas ax-5a is
thermochemically the least favored of the three oxidation products
(ΔG° = −283.5 kJ mol−1, ΔRE = −305.1 kJ mol−1; Supplementary
data).
The reaction enthalpy ΔRH0 for epoxidizing ethene (ΔfH0
52.4 kJ mol−1) by TBHP (ΔfH0 = −245.9 kJ mol−1) to give oxirane
=
(ΔfH0 = −52.6 kJ mol−1) and tert-butanol (ΔfH0 = −312.5 kJ mol−1
)
is −171.7 kJ mol−1, by consulting thermochemical reference tables [74].
Table 6
Bond energies and orbital energies associated with the peroxy group in TBHP and tert-butylperoxy vanadates, and group electronegativity χeq of substituents X.
X-OD-OP-tBu
Entry
Compd.
E[σ(X,OD)]/a.u.a
E[σ(OD,OP)]/a.u.a
E[σ*(OD,OP)]/a.u.a
E[n(OD)]b/a.u.a
E[n(OP)]b/a.u.a
χ
eq for Xc
1
2
3
TBHP
4a
4b
−0.72863
−0.46536
−0.34962
−0.69877
−0.71006
−0.70874
0.09190
0.08809
0.11844
−0.31217
−0.30697
−0.29931
−0.31594
−0.29339
2.20
2.60
2.57
d
−
a
1 atom unit (a.u.) = 1 Hartree = 27.2114 eV. 1 Hartree/particle = 2625.5 kJ mol−1; NBO-analysis (B3LYP/6-31G*// B3LYP/6-311++G**.
For the p-type non-bonding (n) electron pair (N99% p).
Based on the Pauling electronegativity scale. Iteratively calculated, assuming that the inductive effect propagates bond by bond [69–71]. The equilibrium electronegativity χeq for X in
b
c
4b was approximated by the value iterated for the dimethylamine adduct to (dimethoxy)(oxo)vanadium(V).
d
Delocalized toward vanadium forming a second bond {E[π (V,OP)] = −0.35421 a.u.}.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
9
1
Si
2
3
Re
G
G
G
G
Si
Re
G
G substrate
G
substrate
intrinsic
interaction
Scheme 11. Calculated energies in kJ mol−1 for (tetrahydrofuran-2-yl)isopropanol forma-
tion (top), and synthesis of stereoisomeric 2,2-dimethyltetrahydropyranols eq/ax-5a (center
and bottom) from alkenol 1a and TBHP (ΔRE printed in italics and ΔG° in bold; for ball-and-
stick-presentation of the lowest in energy conformer of 2a, refer to the Supplementary data).
Fig. 10. Nomenclature for topicity associated with oxidation of the internal carbon of a
π-bond (top; R = substituted 1-hydroxyprop-3-yl; numbers in italics describe gradually
decreasing stereochemical hierarchy from 1 to 3 for assigning stereodescriptors Re and Si)
[77], and equations for describing the origin of selectivity in oxidation of prostereogenic
alkene carbons in substrate 1 (bottom; [O] = tert-butylperoxy vanadate 4).
In a multicomponent system consisting of a chelated vanadate
(e.g. 3b–c), TBHP, and alkenol 1, ΔΔG‡ consists of terms reflecting ste-
reochemical information from the oxidant (ΔΔG‡[O]), the substrate
[ΔΔG‡(substrate)], and a cross term covering interactions between the
oxidant and the substrate {ΔΔG‡([O]/substrate)} (eq. 2). In the present
study, we addressed substrate control [ΔΔG‡(substrate)] for under-
standing the most fundamental controlling the stereochemical princi-
ples for 4-pentenol oxidation.
trigonal stereocenters, we used NMR-spectroscopy, showing diagnostic
differences in carbon-13 chemical shifts between (E)- and (Z)-isomers,
and differing in fine structures of proton resonances [90].
2.6. Selectivity in 4-pentenol oxidation
Alkenols 1b–k, chosen for uncovering principles of substrate control,
consider two major variations. The first variation relates to substitution
at tetragonal stereocenters, while preserving two methyl groups at the
terminal alkene carbon. In structural analogy to the terpenes, we
named substrates 1b–g prenyl-type 4-pentenols (Fig. 11) [78–83].
The second set of substrates 1h–k served to uncover stereodirecting
effects from trigonal stereocenters on oxidative tetrahydrofuran ring
closure (Fig. 12).
For preparing substrates 1b–k we adhered to published proce-
dures, which in selected instances were adapted for improving selectiv-
ity (Supplementary data) [84–86]. For synthesis of the rel-(1R,2R)-
stereoisomer of diphenylhexenol 1e, also named 1,2-like-1e, we used
diisobutyl aluminum hydride (DIBAL-H) [87] to control stereoselectivity
in ketone reduction, leading to a 98/2-mixture of rel-(1R,2R)/(1S,2R)-
diastereomers of 1e. Subjecting this mixture to the Mitsunobu-
sequence for inverting configuration at carbon C1 of the secondary
alcohol, gives a 98/2-mixture of stereoisomers, comprising the
(1S,2R)-isomer of 1e in excess (Scheme 12) [88,89].
Building blocks for preparing (E)-substituted alkenols (E)-1i, 1j,
and 1k derived from underlying α,β-unsaturated carboxylic acids,
which were modified by standard procedures (Supplementary
data). (Z)-Double bonds were constructed from nickel-assisted addition
of organomagnesium halides to 2,3-dihydropyran (Supplementary data),
since diimine reduction or the Lindlar-procedure for reducing underlying
alkynols failed in our hand to provide (Z)/(E)-ratios above 90/10. For
determining configuration of alkenes and stereochemical purity at
2.6.1. Effects by substitution at tetragonal stereocenters
2.6.1.1. Defining standard conditions. For conducting structure/selectivity-
experiments, we used alkenol/TBHP/catalyst-ratios, identified in a previ-
ous study as practical for quantitatively converting prenyl-type 4-
pentenols into 2-(tetrahydrofuran-2-yl)isopropanols with maximum
yields [40]. The reaction flask for this purpose is charged at a temperature
of 21 2 °C in an atmosphere of dry nitrogen with the starting materials.
The initial alkenol concentration is 0.16 M, the reaction time 24 h, and the
solvent chloroform, unless otherwise specified.
2.6.1.2 . Validating catalytic performance of vanadates. Ten mol% of
triethyl vanadate (3a) sufficed to activate otherwise inert TBHP, for
quantitatively turning over alkenol 1b within 24 h. From the reaction
mixture, we isolated 48% of 5-phenyltetrahydrofuranyl-2-propanol
(2b) as 95/5-ratio of 2,5-cis/trans-isomers, 25% of tetrahydropyran-2-
ol (5b) as 56/44-mixture of cis/trans-isomers, and 3% of 4,4-dimethyl-
3-benzoyloxy-γ-butyrolactone (Table 7, entry 1). For assigning cis/
trans-isomers of cyclic ethers we relied on carbon-13 and proton
NMR-shift differences, fine structures of proton resonances, and diag-
nostic cross-signals from NOESY-spectroscopy, following established
stereoanalytical guidelines [91].
Oxidations catalyzed by chelated vanadates 3b and 3c, under other-
wise identical conditions, furnish tetrahydrofuran 2b in up to 82%
R2
R1
R1
E
(S)
(S)
(R)
R2
R2
(R)
(S)
OH
OH
OH
(R)
R1
hydroxypropyl
alkenyl
(1S,2R)-1
(1R,2R)-1
(1S,2S)-1
t
substituents equatorial
one substituent axial
Fig. 9. Configuration of substituents at tetragonal and trigonal stereocenters in a chair-like
folded 4-pentenol [open circles denote (Z)-substituents, closed circles (E)-substituents].
Fig. 11. Structure formulas and indexing of prenyl-type 4-pentenols, prepared and used
for investigating selectivity effects at tetragonal stereocenters in oxidative cyclization.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

10
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
Table 7
E
Z
Z
Products formed from oxidation of prenyl-type 4-pentenols, bearing substituents in posi-
tions 1 and 2.a
E
E
Z
E
E
Z
R
Entry
1
R1
R2
R3
3
2/% (cis:trans)b
5/% (cis:trans) c
Z
R
1
2
3
4
5
6
7
1b
1b
1b
1c
1d
Ph
Ph
Ph
Ph
H
H
H
CH3
H
H
H
H
H
3a 2b: 48 (95:5) d
3b 2b: 82 (95:5) e
3c 2b: 80 (N99:1)
3c 2c: 74 (74:26)
3c 2d: 78 (95:5)
5b: 25 (56:44)
5b: 10 (41:59)
5b: 14 (42:58)
Z
E
f
–
f
tBu CH3
–
f
rel-(1S,2R)-1e Ph
rel-(1R,2R)-1e Ph
H
H
Ph 3c 2e: 89 (N99:1)g
–
Fig. 12. Structure formulas and indexing of (E)- and (Z)-alkenols.
Ph 3c 2e: 52 (38:62)h 5e: 5 (N96:4)
a
Quantitative conversion for entries 1–6; 74% conversion for entry 7; 5 mol% of vana-
dium catalyst 3b or 3c and 24 hour reaction time for entries 1–6, 48 h for entry 7.
b
(Table 7, entries 2 and 3). Given higher turnover rates, yields, and selec-
tivity, we selected tetraphenyl-substituted chelated vanadate 3c
as standard catalyst for continuing the study.
Stereodescriptor refers to configuration at positions 2 and 5.
Stereodescriptor refers to configuration at carbons 3 and 6.
Additional product: 3% of 4,4-dimethyl-3-benzoyloxy-γ-butyrolactone [40].
Additional product: 3% of 4,4-dimethyl-3-benzoyloxy-γ-butyrolactone [40].
c
d
e
f
Not detected.
g
rel-(2S,3R,5R)-2e as single diastereomer; a second run conducted in dimethyl carbonate
2.6.1.3. Selectivity in oxidative cyclization of tertiary alkenols. 1-Phenyl-1-
methyl substituted alkenol 1c furnishes 2,2,5-substituted tetrahydrofu-
ran 2c as 74/26-mixture of cis/trans-isomers (Table 7, entries 3 and 4),
which is lower than the value of N99:1 for cis/trans-ratio of product
2b, obtained from secondary alkenol 1b (Table 7, entry 3). 1-(tert-
Butyl-1-methyl)-substituted alkenol 1d gave 2,2,5-substituted tetrahy-
drofuran 2d as 95/5-mixture of cis/trans-isomers under standard
conditions (Table 7, entry 5).
Oxidizing tertiary prenyl-type 4-pentenols, in summary, shows that
the degree of selectivity for tetrahydrofuran ring closure is guided by
differences in steric size between substituents attached to a tetragonal
stereocenter.
as solvent furnished 85% of rel-(2S,3R,5R)-2e, also as single diastereomer.
h
Additional product: 4% of 4,5-epoxy-5-methyl-1,2-(diphenyl)heptan-1-one as 50/50-
mixture of diastereomers.
and bistetrahydrofuran 6 as 37/63-mixture of 2,5-cis/trans-isomers
(Scheme 13).
By analyzing products prepared from dienol (E)-1f and TBHP we con-
cluded that the prenyl-type double bond is the second to be oxidized,
once the internal has been converted into a tetrahydrofuranylmethanol-
unit.
Adding yields of cis-2f and the 2,5-cis-diastereomer of
bistetrahydrofuran 6 shows that the initial tetrahydrofuran ring
closure occurs with 50/50-selectivity. In substrate 1b, being similarly
substituted at carbon C1, oxidative cyclization occurs with N99/1-
selectivity for the 2,5-cis-ring closure under identical conditions. From
this information we concluded that (E)-configuration at the internal
double bond increases the fraction of 2,5-trans-cyclized product.
The second tetrahydrofuran ring closure 2f → 6 forms 2′,5′-cis-
specifically, and thus by far more selectively than anticipated from the
2,5-cis/trans-ratio of 74:26 for oxidizing 1-phenyl-1-methyl-substituted
pentenol 1d. This finding shows that the tetrahydrofuranyl substituent
exerts a strong 2,5-cis-directing effect in oxidative 4-pentenol cyclization.
2.6.1.4 . Stereocontrol by substituents of similar steric size at alkenol
carbons C1 and C2. The 1,2-unlike-diastereomer of secondary 1,2-
diphenyl-substituted alkenol 1e furnishes tetrahydrofuranyl-2-
propanol rel-(2S,3R,5R)-2e as single diastereomer, when oxidized
with TBHP in a vanadate-catalyzed reaction. Substituents at endocyclic
carbons C2 and C5 are in cis-position, and in trans for substituents at C3
and C5 (Table 7, entry 6). Changing the solvent from chloroform to
dimethyl carbonate [92–94] furnishes almost identical results.
The 1,2-like-isomer of 1,2-diphenyl-5-methylhex-4-enol (1e)
favors 2,5-trans tetrahydrofuran ring closure, however in low yields.
Tetrahydropyranol rel-(3S,5R,6R)-5e and 4% of 4,5-epoxy-5-methyl-
1,2-(diphenyl)heptan-1-one form as side products (Table 7, entry 7).
Phenyl substitution at carbons C1 and C2, in summary, enhances or
decreases stereocontrol for C,O-cyclization, depending on relative
configuration of stereodirecting groups.
2.6.1.6. Effect of 1,2-annulation to an arene. 2-Prenyl-4-cresol 1g gives
chromanol 5g as major and dihydrobenzofuranyl-2-propanol 2g as
2.6.1.5. Sequential cyclization onto a terminal prenyl-type double bond. In
geraniol-derivative (E)-1f, the inner π-bond is (E)-substituted, and the
terminal a prenyl-type double bond. Oxidizing substrate (E)-1f with
TBHP, using 10 mol% of chelated vanadate 3c, is complete within 48 h,
providing tetrahydrofuran 2f as 73/27-mixture of 2,5-cis/trans-isomers,
OH
H
H
OH
TBHP / 3c
O
(E)
Ph
Ph
5
2
Ph
1'
CHCl3 / 20 °C
(E)-1f
( )-2f (22%)
2,5-cis:trans = 73:27
1. DIBAL-H
CH2Cl2
1. ArCO2H
DIAD / PPh3
H
H
Ph
Ph
Ph
Ph
OH
Ph
Ph
OH
OH
H
O
H
H
(R)
(S)
O
O
5' 2'
(R)
(R)
+
5
2
2. MeOH
2. NaOH
H
H
H2O / MeOH
( )-6 (38%)
2,5-cis:trans = 37:63
rel-(1R,2R)-1e
rel-(1S,2R)-1e
67%
78%
Scheme 12. Stereoselective synthesis of diastereomers rel-(1R,2R)-1e (like-1e) and rel-
(1S,2R)-1e (unlike-1e) (DIBAL-H = diisobutyl aluminum hydride, DIAD = diisopropyl
azodicarboxylate; Ar = p-nitrophenyl) [89].
Scheme 13. Products of oxidative dienol cyclization [3 equivalents of TBHP, 10 mol% of 3c;
stereocenter at C1′ in ( )-2f not assigned; single configuration for stereocenters at
carbons 2′ and 5′ in ( )-6].
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
11
OH
2.6.2.2. Relative rates for oxidizing (E)- and (Z)-double bonds. Oxidizing
(2E,9Z)-Undeca-2,9-diene-6-ol (2E,9Z)-(1j) under standard conditions
furnishes approximately an equimolar mixture of products obtained
O
O
OH
TBHP / 3c
+
CHCl3 / 20 °C
OH
1g
2g (15%)
5g (69%)
(E)
(Z)
HO
H
H
Scheme 14. Products formed from 2-prenyl-para-cresol 1g and TBHP in a vanadium-
catalyzed reaction (5 mol% of catalyst; quantitative conversion of 1g).
TBHP / 3c
O
5
OH
(Z)
1'
2
CHCl3 / 20 °C
(2E,9Z)-1j
( )-(Z)-2j (31%)
cis:trans = 13:87
minor product in a total yield of 84%, when oxidized by TBHP in a
vanadate-catalyzed reaction. The chemical nature of products
formed from the remaining 16% of substrate 1g remained un-
identified (Scheme 14).
1,2-Annulation with a benzene nucleus, in summary, reverses 5-
exo-regioselectivity customarily observed for oxidative cyclization
of prenyl-type 4-pentenols.
OH
H
H
O
2
(E)
5
1'
+
( )-(E)-2j (27%)
cis:trans = 85:15
2.6.2. Effects by substitution at trigonal stereocenters
Scheme 15. Products formed from oxidative cyclization of dienol (2E,9Z)-1j [1.5 equiva-
lents of TBHP, 5 mol% of 3c; quantitative conversion of (2E,9Z)-1j; single diastereomer
for relative configuration at carbons 1′ and 2].
2.6.2.1. Configuration of substituents at the terminal alkene carbon. Termi-
nal alkenol 1h requires a temperature of 60 °C, for being turned over
with a rate comparable to reference alkenol 1b (see Section 2.6.1).
Under such conditions tetrahydrofuran-2-ylmethanol 2h forms in
29% yield, showing a preference for the 2,5-trans-cyclized product
(Table 8, entry 1). A gas chromatogram recorded from the reaction
mixture shows that additional products form in low yields but sig-
nificant structural diversity, which largely remained unidentified
[95].
OH
1'
H
H
O
OH
TBHP / 3c
H
(Z)
(5R)
(2R)
(E)
(R) (R)
CHCl3 / 20 °C
(3R)
HO
HO
H
(+)-1k
(+)-2k (35 %)
Alkenols (Z)-1i and (E)-1i, bearing a disubstituted internal double
bond, undergo oxidative conversion by TBHP in vanadate-catalyzed re-
action with similar rate as prenyl-type alkenol 1b. Isomer (Z)-1i cyclizes
under such conditions 2,5-cis-selectively, whereas alkenol (E)-1i favors
the 2,5-trans-mode of tetrahydrofuran ring closure. Tetrahydropyran-
3-ol 5i forms from (E)-1i as side product, and was not identified as
oxidation product from (Z)-1i (Table 8, entries 2 and 3). The search
for additional products by NMR-spectroscopy or gas chromatography
provided no meaningful information for deducing structures of
additional compounds for supplementing the mass balance.
Tetrahydrofuranylethanol cis-2i is obtained from alkenol (E)-1i and
isomer (Z)-1i as single diastereomer, however with opposed configura-
tion at carbon-C1′. We observed a stereochemical correlation for trans-
2i prepared from (E)-1i and (Z)-1i. Opposite configuration at the double
bond thus translates via oxidation into opposite relative configuration
of substituents at tetragonal stereocenters. In reaction theory, the mech-
anism explaining stereospecificity is the concerted pathway. For
explaining specificity associated with sidechain configuration we there-
fore suggest that π-bond oxidation by vanadate-activated TBHP occurs
in a concerted reaction.
Scheme 16. Synthesis of trisubstituted tetrahydrofuran (+)-2k from (+)-laurediol (+)-
1k and TBHP (1.5 equivalents) in a vanadate-catalyzed oxidation.
from oxidizing the (Z)- and the (E)-double bond. From this information
we concluded that configuration of the double bond has no effect on the
rate of alkenol oxidation (Scheme 15).
In (+)-laurediol (+)-1k [82,96], π-bond oxidation may occur at
three different double bonds and one triple bond. TBHP in combination
with vanadate-catalyst 3c oxidizes acetogenin (+)-1k selectively at the
(Z)-double bond to afford unsaturated tetrahydrofuranyl alcohol (+)-
2k as single diastereomer regarding newly formed stereocenters at
endocyclic carbon C5 and exocyclic carbon C1′ (Scheme 16). Assigning
configuration at carbon C5 is feasible by NOESY–NMR-spectroscopy
from diagnostic cross-signals. For configuration at carbon C1′ we predict
(R)-configuration, based on a model explained in the stereochemical
guideline Section (2.6.4).
Table 8
Products formed from oxidation of 4-pentenols 1h–i, differing by substitution at the terminal alkene carbon.a
Entry
1
R1
RZ
RE
conv./%
2/% (cis:trans)b
5/% (cis:trans) c
e
1
2
3
1h
(Z)-1i
(E)-1i
Ph
Ph
Ph
H
CH3
H
H
H
CH3
95
92
93
2 h: 29 (46:54)d
2i: 58 (85:15)f
2i: 49 (32:68)f,g
–
e
–
5i: 12 (95:5)
a
5 mol% of vanadium catalyst 3c for entries 1–4; reaction performed at 20 °C for entries 2–4 and at 60 °C for entry 1; reaction time: 24 h.
Stereodescriptor for configuration at endocyclic carbons C2 and C5.
Stereodescriptor for configuration at endocyclic carbons C3 and C6. Configuration at carbons 2 and 3 is trans starting from (E)-1i.
Additional product: 4% of 1-pent-4-enophenone [95].
b
c
d
e
f
Not detected.
Single diastereomer for configuration at exocyclic carbon C1′.
Additional product: 2% of (E)-1-phenylhex-4-en-1-one.
g
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

12
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
R
OP
π-bond oxidation. Structures having one or the other substituent locat-
ed equatorially direct opposite faces of the π-bond toward the peroxide
oxygen, providing different relative configuration of oxidation prod-
ucts. Configurations of this kind mismatch for effectively controlling
stereoselectivity in oxidative 4-pentenol cyclization (Scheme 18,
bottom).
H
N
O
V
O
O
OD
R1
TBHP / 3b
H
O
3
H
R1
(R)
(S)
HO
Si
R2
– EtOH
R2
2
2.6.4.4. Effect of substituents at trigonal stereocenters. Substituents at
trigonal stereocenters improve 2,5-cis- and 2,4-trans-selectivity for ox-
idative 4-pentenol cyclization in case of (Z)-configuration (Scheme 18,
top). An (E)-configured carbon substituent does not alter selectivity
exerted by a terminal (Z)-substituent of similar steric size. Larger (E)-
groups increase the fraction of 2,5-trans-cyclized products (Scheme 18,
bottom).
association
1
1
V
O-atom transfer Si-attack
H
N
O
3. Concluding remarks
O
C,O-cyclization
V OR
O
OH
H
H
The (dialkoxy)(oxo)vanadium substituent, according to density
functional theory, exerts almost no ground state effects on structure
and bonding of the peroxide group in an end-on tert-butylperoxy vana-
date. Isomerizing end-on to side-on opens a path for intramolecularly
transferring the distal oxygen from the tert-butylperoxy group to a re-
ductant. Upon approaching the peroxide group by the alkenyl substitu-
ent, a vanadate-bonded alkenol folds preferentially into chair-like
conformation, directing substituents at tetragonal stereocenters when
possible into equatorial positions, as exemplified by stereospecific tetra-
hydrofuran synthesis from (+)-laurediol (+)-1k.
The molecular orbital model used to describe structure and bonding
in this article predicts that vanadium (V) in ethyl, tert-butylperoxy
vanadates is not a typical Lewis acid, attracting alkenols by binding
the hydroxyl oxygen by the metal. When adapting this model to the
chemistry of vanadate-dependent haloperoxidases, the protein hydro-
gen bonds the co-factor, rather than forming Lewis-base/Lewis-acid
contacts. Activating hydrogen peroxide by haloperoxidases then could
follow the same pathway outlined for activating tert-butyl hydroperox-
ide by ethyl vanadates. Changing end-on bound hydroperoxy vanadate
to side-on directly furnishes a dissymmetrical protonated peroxo
vanadate for oxidizing halides, without the need to assume a peroxo
R1
O
SN2
(R)
(S)
H
O
O
R1
(R)
H
2
H
– VO(L1)(OR)
R2
R2
(S)
VI
Scheme 17. Proposed mechanism for stereoselective 4-pentenol oxidation with TBHP, cat-
alyzed starting from chelated vanadate 3b as representative example (abbreviations: R1,
R2 = Alkyl, Aryl; R3 = tert-butyl; stereodescriptors are valid for R1 and R2 = phenyl;
open and filled circles denote substituents having effects summarized in Section 2.6.4).
2.6.3. Mechanistic proposal
Selectivity for oxidizing 4-pentenols, based on the information
gained from this study, arises from a concerted, kinetic controlled reac-
tion. In proposed transition structure V the tert-butylperoxy group is
bound side-on, and the alkenol hydrogen-bonded to one of the chelat-
ing aminodiolate oxygens. In this intermediate, distal oxygen OD is
transferred to the diastereotopic face oriented toward the peroxide
group, stereoselectively providing a hydrogen-bonded epoxyalcohol
(structure VI). Strained intermediate VI rearranges in a nucleophilic
substitution, proceeding in polar aprotic solvents with inversion of con-
figuration. The substitution gives sidechain-functionalized tetrahydro-
furan 2 and leaves vanadium compound VO(L)(OR) for activating the
next molecule of TBHP for propagating the catalytic cycle (Scheme 17).
• stereochemical matching
R1(S)
OH
H
H
R2
OH
R1
O
[ O ]
(R)
R2
H
2.6.4. Stereochemical guideline
1
2
diastereoselectivity
chemoselectivity
2.6.4.1. Conformation of the intermediate. Approaching the peroxide
group intramolecularly by the alkenyl substituent folds the vanadate-
bound alkenol into chair-like conformation, directing substituents at
tetragonal stereocenters equatorially, wherever possible (Schemes 17
and 18).
= H or CH3
high
• stereochemical mismatching
OH
(R)
H
H
2.6.4.2. Effect of matching relative configuration at tetragonal stereocenters.
Two substituents in equatorial position enhance the energetic prefer-
ence of the associated chair-like folding compared to conformations
having one or more substituents positioned pseudo-equatorially,
pseudo-axially, or axially. An alkenol folding having both substituents
located in favored positions matches for stereocontrolling oxidative
4-pentenol cyclization (Scheme 18, top).
R2
OH
O
R1
[ O ]
(R)
R1
R2
H
1
2
diastereoselectivity
= H / CH3
low
chemoselectivity
H / alk(en)yl
CH3 / CH3 for R1 and R2 = phenyl
2.6.4.3. Effect of mismatching relative configuration at tetragonal
stereocenters. Disubstituted alkenols in a chair-like folded chain, having
one of the carbon substituents in equatorial and the second in axial
position, provide conformationally more flexible transition states for
Scheme 18. Guidelines for predicting stereoselectivity in oxidative 4-pentenol cyclization,
based on substituent effects at tetragonal and trigonal stereocenters.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
13
vanadate as additional more stable intermediate that needs to be pro-
tonated in a separate step [14].
1.5 mmol) in chloroform (5 ml). Reaction time: 3 h at 20 °C. Eluent
used for chromatographic purification: petroleum ether/methyl tert-
butyl ether = 3:2 (v/v). 2-(5-phenyltetrahydrofuran-2-yl)-propan-2-ol
(2b) [35]. Yield: 265 mg (1.28 mmol, 64%) as 96/4-mixture of cis/
trans-isomers. Rf = 0.25 [petroleum ether/ethyl acetate = 8:2 (v/v)].
cis-(2b): 1H NMR (CDCl3, 400 MHz) δ 1.22 (s, 3H, CH3), 1.29 (s, 3H,
CH3), 1.75–1.85 (m, 1H, CH2), 1.93–1.99 (m, 2H, CH2), 2.19 (br. s, 1H,
OH), 2.27–2.34 (m, 1H, CH2) 3.87 (t, J = 7.4 Hz, 1H, CH), 4.86 (dd, J =
8.3, 6.9 Hz, 1H, CH) 7.25–7.38 (m, 5H, Ar–H). trans-(2b): 1H NMR
(CDCl3, 400 MHz) δ 1.28 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.78–1.99
(m, 3H, CH2), 2.19 (br. s, 1H, OH), 2.30–2.42 (m, 1H, CH2) 4.03
(dd, J = 8.9, 6.3 Hz, 1H, CH), 4.98 (dd, J = 8.8, 5.9 Hz, 1H, CH)
7.25–7.38 (m, 5H, Ar–H). 2,2-Dimethyl-6-phenyltetrahydropyran-3-ol
(5b) [35]. Yield: 86.2 mg (418 μmol, 22%), as 42/58-mixture of cis/
trans-isomers. Rf = 0.22 [petroleum ether/ethyl acetate = 8:2 (v/v)].
cis-(5b): 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 3H, CH3), 1.33 (s, 3H,
CH3), 1.51 (s, 1H, OH), 1.60–1.79 (m, 2H, CH2), 1.88–1.97 (m, 2H, CH2),
3.48 (br. s, 1H, CH), 4.70 (dd, J = 11.7, 2.7 Hz, 1H, CH) 7.21–7.39 (m,
5H, Ar–H). trans-(5b): 1H NMR (CDCl3, 400 MHz) δ 1.29 (s, 3H, CH3),
1.36 (s, 3H, CH3), 1.59 (br. s, 1H, OH), 1.63–1.79 (m, 2H, CH2), 1.90–1.96
(m, 2H, CH2), 3.55 (dd, J = 11.4 , 4.3 Hz, 1H, CH), 4.56 (dd, J = 11.5,
2.0 Hz, 1H, CH) 7.22–7.25 (m, 1H, Ar–H) 7.30–7.37 (m, 4H, Ar–H).
In the mechanistic model describing stereoselective oxidation,
catalyzed by chelated ethyl vanadates, alcohols bind via hydrogen-
bond to ester oxygens. Binding of alcohols to the ligand implies that
compartmental C1-symmetric auxiliaries possibly are the key to
stereocontrol oxidative tetrahydrofuran synthesis. Auxiliaries affecting
energies of orbitals involved in peroxide activation, in turn, should mod-
erate or accelerate rates, and possibly selectivity in oxidations by TBHP
catalyzed by chelated vanadates.
The model describing oxygen atom transfer to alkenols allows pre-
dictions on relative configuration of stereocenters at exocyclic carbon
C1′ and the neighboring endocyclic tetrahydrofuran carbon C2. A mech-
anism involving stereoselective oxidation of (E)- or (Z)-double bonds in
chair-like-transition structure, followed by stereospecific SN2-
epoxyalcohol isomerization assigns (R)-configuration to C1′ by oxidiz-
ing accordingly the (Z)-double bond in (+)-laurediol. Verifying this hy-
pothesis in an experimental study would expand in a noteworthy
manner the predictive power of the stereochemical model and the
scope of the vanadate/TBHP-method for preparing secondary metabo-
lites, and is therefore being addressed at the moment in our laboratory.
4. Experimental
4.4.2. Conversion of 6-methyl-2-phenylhept-5-en-2-ol (1c)
4.1. General
Reactants: 6-methyl-2-phenylhept-5-en-2-ol (1c) (105 mg,
514 μmol) in chloroform (1.5 ml), VO(L2)(OEt) (3c) (14.0 mg,
25.0 μmol, 5 mol%), and TBHP (136 μl, 5.5 M solution in nonane,
748 µmol) in chloroform (1.5 ml). Reaction time: 24 h at 21 °C.
Eluent used for chromatographic purification: petroleum ether/ethyl
acetate = 8:2 (v/v). 2-(2-methyl-2-phenyltetrahydrofur-5-yl)propan-2-
ol (2c). Yield: 83.8 mg (380 μmol, 74%) as 74/26-mixture of cis/
trans-isomers. Rf = 0.36 [petroleum ether/ethyl acetate = 8:2 (v/v)].
cis-(2c): 1H NMR (CDCl3, 400 MHz) δ 1.13 (s, 3H), 1.30 (s, 3H), 1.50
(s, 3H), 1.82–1.91 (m, 1H), 1.94–2.03 (m, 1H), 2.09–2.23 (m, 2H), 4.00
(t, J = 7.3 Hz, 1 H), 7.21–7.27 (m, 1H), 7.31–7.36 (m, 2H), 7.41–7.45
(m, 2H). 13C NMR (CDCl3, 100 MHz): δ = 24.4, 26.3, 27.3, 29.4, 38.8,
71.6, 84.6, 85.2, 124.5, 126.5, 128.3, 148.2. trans-(2c): 1H NMR (CDCl3,
400 MHz) δ 1.18 (s, 3H), 1.31 (s, 3H), 1.52 (s, 3H), 1.70–2.28 (m, 4H),
3.82 (dd, 1H, J = 7.7, 7.1), 7.21–7.27 (m, 1H), 7.31–7.36 (m, 2H),
7.41–7.45 (m, 2H). 13C NMR (100 MHz; CDCl3) δ 24.2, 26.4, 27.3, 30.5,
39.6, 70.1, 84.6, 85.6, 124.5, 126.4, 128.2, 148.3.
For general laboratory practice and instrumentation see Ref. [97] and
the Supplementary data.
4.2. General method for vanadate-catalyzed alkenol oxidation with TBHP
A solution of TBHP in nonane (5.5 M) was added to a solution of van-
adates 3a–c in chloroform. The resulting mixture was stirred for 10 min
at 20 °C and treated with a solution of alkenol in chloroform. The reac-
tion mixture was stirred for the time specified below at 20 °C under
an atmosphere of nitrogen and filtrated through a pad of neutral alumi-
num oxide. Organic products were washed with ethyl acetate (5 ml)
from the pad of aluminum oxide. Combined filtrate and washings
were concentrated at a bath temperature of 40 °C under reduced pres-
sure to leave an oily residue, which was purified by chromatography
using the eluent specified in the procedures outlined in Sections 4.3–4.5.
4.3. Oxidation catalyzed by triethyl vanadate (3a)
4.4.3. Conversion of 2,2,3,7-tetramethyloct-6-en-3-ol (1d)
Reactants: 2,2,3,7-tetramethyloct-6-en-3-ol (1d) (96.8 mg, 525 μmol)
in chloroform (1.5 ml), VO(L2)(OEt) (3c) (14.0 mg, 25.0 μmol, 5 mol%),
and TBHP (136 μl, 5.5 M solution in nonane, 748 µmol) in chloroform
(1.5 ml). Reaction time: 24 h at 21 °C. Eluent used for chromatographic
purification: petroleum ether/ethyl acetate = 8:2 (v/v). 2-[2-(1,1-
dimethylethyl)-2-methyltetrahydrofur-5-yl)propan-2-ol (2d). Yield:
82.1 mg (410 μmol, 78%) as 95/5-mixture of cis/trans-isomers. Rf =
0.14 [petroleum ether/ethyl acetate = 8:2 (v/v)]. cis-(2d): 1H NMR
(CDCl3, 400 MHz) δ 0.94 (s, 9H), 1.14 (s, 3H), 1.15 (s, 3H), 1.23
(s, 3H), 1.45–1.52 (m, 1H), 1.64–1.73 (m, 1H), 1.79–1.87 (m, 1H), 1.96
(ddd, J = 12.3, 10.4, 4.8 Hz, 1H), 2.16 (br s, 1H), 3.72 (dd, J = 8.8,
6.7 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ 21.4, 24.3, 25.7, 26.6, 27.5,
33.2, 37.0, 71.6, 83.5, 87.4. trans-(2d): 1H NMR (CDCl3, 400 MHz) δ
0.93 (s, 9H), 1.10 (s, 3H), 1.12 (s, 3H), 1.20 (s, 3H), 1.42–2.04 (m, 4H),
2.15 (br s, 1H), 3.63 (dd, J = 11.0, 5.0 Hz, 1H).
Reactants: 5-methyl-1-phenylhex-4-en-1-ol (1b) (190 mg,
1.00 mmol) in chloroform (3 ml), VO(OEt)3 (3a) (19.6 mg of 95%
pure solution, 100 μmol, 10 mol%), and TBHP (270 μl, 5.5 M solution in
toluene, 1.5 mmol). Solvent: chloroform (3 ml). Reaction time: 24 h at
20 °C. Eluent used for chromatographic purification: ethyl acetate/
petroleum ether = 1:3 (v/v). 2-(5-phenyltetrahydrofuran-2-yl)-
propan-2-ol (2b) [35]. Yield: 98.8 mg (479 μmol, 48%) as 96/4-mixture
of cis/trans-isomers. 2,2-Dimethyl-6-phenyltetrahydropyran-3-ol
(5b) [35]. Yield: 51.8 mg (251 μmol, 25%), as 56/44-mixture of cis/
trans-isomers. 4-Benzoyloxy-5,5-dimethyl-2(3H)-dihydrofuranone
[35]. Yield: 8.00 mg (34.0 μmol, 3%). 1H NMR (CDCl3, 400 MHz) δ 1.49
(s, 3H, CH3), 1.50 (s, 3H, CH3), 2.70 (dd, J = 18.5, 2.1 Hz, 1H, CH2),
3.16 (dd, J = 18.5, 6.6 Hz, 1H, CH2), 5.44 (dd, J = 6.6, 2.1 Hz, 1H, CH),
7.45–7.48 (m, 2H, Ar–H), 7.58–7.62 (m, 1H, Ar–H), 8.02–8.04 (m, 2H,
Ar–H).
4.4.4. Conversion of rel-(1R,2R)-5-methyl-1,2-diphenylhex-4-en-1-ol
rel-(1R,2R)-(1e)
4.4. Oxidizing prenyl-type alkenols
Reactants: rel-(1R,2R)-5-methyl-1,2-diphenylhex-4-en-1-ol rel-
(1R,2R)-(1e) (266 mg, 1.00 mmol) in chloroform (3 ml), VO(L2)(OEt)
(3c) (28.7 mg, 51.3 μmol, 5 mol%), and TBHP (270 μl, 5.5 M solution in
nonane, 1.49 mmol) in chloroform (3 ml). Reaction time: 48 h at
20 °C. Eluent used for chromatographic purification: pentane/acetone =
4.4.1. Conversion of 5-methyl-1-phenylhex-4-en-1-ol (1b)
Reactants: 5-methyl-1-phenylhex-4-en-1-ol (1b) (381 mg,
2.00 mmol) dissolved in chloroform (5 ml), VO(L2)(OEt) (3c) (56.7 mg,
100 μmol, 5 mol%), and TBHP (720 μl, 4.2 M solution in toluene,
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

14
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
5:1 (v/v). 2-(rel-(2R,3R)-2,3-diphenyltetrahydrofuran-5-yl)propan-2-ol
cis-(2e). Yield: 57.0 mg (202 μmol, 20%), colorless oil. Rf = 0.56
[pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.34
(s, 3H), 1.42 (s, 3H), 2.06–2.15 (s, 1H, OH), 2.30–2.38 (m, 2H), 3.90
(q, J = 8.8 Hz, 1H), 3.97 (dd, J = 9.8, 6.2 Hz, 1H), 5.29 (d, J = 8.8 Hz,
1H), 6.87–7.33 (m, 10H). 13C NMR (CDCl3, 101 MHz) δ 25.0, 28.0, 33.5,
50.1, 71.1, 84.4, 85.7, 126.0, 126.2, 126.8, 127.5, 127.6, 128.6, 140.0,
140.2. Mass spectrometry (MS) [70 eV, electron impact (EI)] m/z (%)
280 (1), 264 (18), 247 (4), 223 (15), 205 (19), 193 (25), 180 (100),
173 (21), 165 (17), 158 (14), 143 (34), 128 (19), 115 (59), 105 (80),
91 (46), 77 (49), 70 (24), 59 (52), 51 (15). High resolution mass spec-
trometry (HRMS) calcd. for C19H22O2 282.1620; found 282.1605. 2-
(rel-(2R,3R)-2,3-diphenyltetrahydrofuran-5-yl)propan-2-ol trans-(2e).
Yield: 91.0 mg (322 μmol, 32%), colorless oil. Rf = 0.56 [pentane/
acetone = 5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 3H),
1.36 (s, 3H), 2.06–2.15 (s, 1H, OH), 2.22–2.30 (m, 1H), 2.49 (dt,
Jd = 13.0 Hz, Jt = 7.8 Hz, 1H), 3.78 (ddd, J = 7.5, 6.1, 3.8 Hz, 1H),
4.42 (t, J = 7.7 Hz, 1H), 5.39 (d, J = 5.9 Hz, 1H), 6.87–7.33
(m, 10 H). 13C NMR (CDCl3, 101 MHz) δ 24.1, 27.0, 33.9, 50.9,
72.8, 85.1, 85.3, 126.1, 126.7, 127.5, 127.8, 128.2, 128.5, 139.5,
140.5. MS (70 eV, EI) m/z (%) 280 (1), 264 (11), 247 (3), 223 (9),
205 (20), 193 (18), 180 (100), 173 (14), 165 (14), 158 (13), 143
(24), 128 (17), 115 (45), 105 (39), 91 (34), 77 (26), 72 (30), 59
(40), 51 (8). HRMS calcd. for C19H22O2–H2O 264.1514; found
264.1502. rel-(3S,5R,6R)-2,2-dimethyl-5,6-diphenyltetrahydro-2H-
pyran-3-ol rel-(3S,5R,6R)-(5e). Yield: 12.9 mg (45.7 μmol, 5%), col-
orless oil. Rf = 0.56 [pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3,
400 MHz) δ 1.37 (s, 3H), 1.50 (s, 3H), 2.06–2.15 (m, 1H, OH), 2.03
(ddd, J = 13.1, 4.9, 3.0 Hz, 2H), 3.46 (dt, Jd = 5.5 Hz, Jt = 2.8 Hz,
1H), 3.84 (dd, J = 12.1, 4.8 Hz, 1H), 5.13 (d, J = 3.1 Hz, 1H),
6.87–7.33 (m, 10 H). MS (70 eV, EI) m/z (%) 282 (1) [M+], 264
(4), 247 (3), 222 (2), 205 (1), 193 (9), 178 (60), 165 (14), 152
(4), 143 (9), 133 (11), 115 (17), 105 (25), 91 (17), 77 (18), 72
(100), 57 (11), 51 (7). HRMS calcd. for C19H22O2 282.1620; found
282.1625. 3-(3,3-dimethyloxiran-2-yl)-1,2-diphenylpropan-1-one.
Yield: 10.7 mg (38.2 μmol, 4%), colorless oil. Rf = 0.56 [pentane/acetone =
5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 3H), 1.35 (s, 3H),
2.22–2.30 (m, 1H), 3.06 (dd, J = 15.1, 9.8 Hz, 1H), 3.19 (dd, J = 15.1,
9.4 Hz, 1H), 4.56 (t, J = 9.6 Hz, 1H), 6.87–7.33 (m, 10H). MS (70 eV, EI)
m/z (%) 280 (33), 262 (22), 247 (83), 220 (28), 203 (7), 191 (27), 178
(17), 165 (14), 157 (7), 141 (8), 129 (6), 115 (31), 105 (100), 91 (13),
77 (45), 59 (12), 51 (8). HRMS calcd. for C19H20O2 280.1463; found
280.1469.
4.4.6. Oxidizing rel-(1R,2S)-5-methyl-1,2-diphenylhex-4-en-1-ol
rel-(1R,2S)-(1e) in dimethyl carbonate
Reactants: rel-(1R,2S)-5-methyl-1,2-diphenylhex-4-en-1-ol rel-
(1R,2S)-(1e) (266 mg, 1.00 mmol) in dimethyl carbonate (3 ml),
VO(L2)(OEt) (3c) (28.4 mg, 50.8 μmol, 5 mol%), and TBHP (270 μl,
5.5 M solution in nonane, 1.49 mmol) in dimethyl carbonate (3 ml).
Reaction time: 24 h at 20 °C. Eluent used for chromatographic pu-
rification: pentane/acetone = 5:1 (v/v). 2-(rel-(2S,3R,5R)-4,5-
diphenyltetrahydrofuran-2-yl)propan-2-ol rel-(2S,3R,5R)-2e. Yield:
241 mg (853 μmol, 85%), colorless solid. For spectroscopic data,
refer to Section 4.4.5.
4.4.7. Conversion of (E)-5,9-dimethyl-1-phenyldeca-4,8-dien-1-ol (E)-(1f)
Reactants: (E)-5,9-dimethyl-1-phenyldeca-4,8-dien-1-ol (E)-(1f)
(258 mg, 1.00 mmol) in chloroform (3 ml), VO(L2)(OEt) (3c)
(56.0 mg, 100 μmol, 10 mol%), and TBHP (540 μl, 5.5 M solution in
nonane, 2.97 mmol) in chloroform (3 ml). Reaction time: 48 h at
20 °C. Eluent used for chromatographic purification: pentane/acetone =
10:1 (v/v). 6-methyl-2-(rel-(2S,5R)-5-phenyltetrahydrofuran-2-yl)hept-
5-en-2-ol cis-(2f). Yield: 44.8 mg (163 μmol, 16%), colorless oil. Rf =
0.54 [pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.29
(s, 3H), 1.46 (ddd, J = 13.7, 11.4, 5.8 Hz, 1H), 1.63 (s, 3H), 1.70
(s, 3H), 1.77–1.85 (m, 1H), 1.91–2.13 (m, 6H), 2.31 (dddd, J = 12.2,
8.6, 6.7, 5.5 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 4.86 (dd, J = 8.2, 7.0 Hz,
1H), 5.14 (tt, J = 7.1, 1.3 Hz, 1H), 7.27–7.30 (m, 1H), 7.32–7.36
(m, 4H). 13C NMR (CDCl3, 101 MHz) δ 17.7, 22.1, 24.0, 25.7, 25.9, 34.2,
37.7, 73.2, 80.8, 85.6, 124.5, 125.9, 127.4, 128.4, 131.7, 142.4. MS
(70 eV, EI) m/z (%) 256 (11), 238 (10), 223 (5), 213 (13), 195 (5), 187
(34), 174 (25), 165 (6), 155 (7), 147 (21), 136 (11), 129 (23), 117
(44), 115 (44), 105 (82), 91 (100), 77 (64), 69 (54), 63 (7), 55 (18),
51 (18). Anal. calcd. for C18H26O2 (274.40): C, 78.79; H, 9.55. Found: C,
79.05; H, 9.46. 2-{(rel-2′S,5′R)-
tetrahydro-5′-[(rel-2R,5R)-5-tetrahydro-5-phenylfuran-2-yl]-5′-
(methylfuran-2′-yl)propan-2-ol trans-(6). Yield: 69.9 mg (241 μmol,
24%), colorless oil. Rf = 0.49 [pentane/acetone = 5:1 (v/v)]. 1H
NMR (CDCl3, 400 MHz) δ 1.09 (s, 3H), 1.23 (s, 3H), 1.24 (s, 3H),
1.64 (ddd, J = 12.1, 8.4, 6.7 Hz, 1H), 1.69–1.80 (m, 2H), 1.90–2.10
(m, 4H), 2.19–2.27 (m, 1H), 2.28–2.36 (m, 1H), 3.80 (t, J = 7.0 Hz,
1H), 3.98 (t, J = 7.6 Hz, 1H), 4.79 (t, J = 7.4 Hz, 1H), 7.22–7.27 (m,
1H), 7.29–7.36 (m, 4H). 13C NMR (CDCl3, 101 MHz) δ 24.2, 24.8,
25.7, 26.4, 27.7, 32.4, 34.4, 71.5, 81.0, 84.7, 85.1, 85.4, 125.7, 127.3,
128.4, 142.2. MS (70 eV, EI) m/z (%) 272 (18), 231 (9), 187 (22),
171 (8), 155 (7), 143 (88), 125 (68), 117 (59), 115 (54), 105 (35),
91 (100), 77 (43), 69 (17), 67 (20), 59 (30), 55 (24). Anal. calcd. for
C
18H26O3 (290.40): C, 74.45; H, 9.02. Found: C, 74.36; H, 9.08. 2-
4.4.5. Conversion of rel-(1R,2S)-5-methyl-1,2-diphenylhex-4-en-1-ol
rel-(1R,2S)-(1e)
{(rel-2′S,5′R)-
tetrahydro-5′-[(rel-2S,5R)-5-tetrahydro-5-phenylfuran-2-yl]-
5′(-methylfuran-2′-yl)propan-2-ol cis-(6). Yield: 39.5 mg (136 μmol,
14%), colorless oil. Rf = 0.45 [pentane/acetone = 5:1 (v/v)]. 1H NMR
(CDCl3, 400 MHz) δ 1.13 (s, 3H), 1.23 (s, 3H), 1.27 (s, 3H), 1.71–1.82
(m, 3H), 1.83–1.94 (m, 3H), 1.97–2.11 (m, 1H), 2.21 (s, 1H, OH),
2.23–2.32 (m, 1H), 3.86 (dd, J = 9.0, 6.4 Hz, 1H), 4.03 (t, J = 7.2 Hz,
Reactants: rel-(1R,2S)-5-methyl-1,2-diphenylhex-4-en-1-ol rel-
(1R,2S)-(1e) (266 mg, 1.00 mmol) in chloroform (3 ml), VO(L2)(OEt)
(3c) (28.0 mg, 50.0 μmol, 5 mol%), and TBHP (270 μl, 5.5 M solution in
nonane, 1.49 mmol) in chloroform (3 ml). Reaction time: 24 h at
20 °C. Eluent used for chromatographic purification: pentane/acetone =
5:1 (v/v). 2-(rel-(2S,3R,5R)-2,3-diphenyltetrahydrofuran-5-yl)propan-2-
ol rel-(2S,3R,5R)-(2e). Yield: 251 mg (889 μmol, 89%), colorless solid,
mp 58 °C. Rf = 0.52 [pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3,
1H), 4.89 (t, J = 7.5 Hz, 1H), 7.24–7.28 (m, 1H), 7.29–7.36 (m, 4H). 13
C
NMR (CDCl3, 101 MHz) δ 24.0, 24.1, 26.3, 27.3, 27.8, 34.4, 34.8, 70.5,
81.2, 84.6, 85.2, 87.1, 125.9, 127.2, 128.2, 143.1. MS (70 eV, EI) m/z (%)
272 (19), 187 (24), 171 (11), 155 (10), 143 (100), 125 (75), 117 (42),
115 (44), 105 (35), 91 (65), 77 (36), 69 (16), 67 (11), 59 (11), 55 (18).
Anal. calcd. for C18H26O3 (290.40): C, 74.45; H, 9.02. Found: C, 74.68; H,
8.94. 6-methyl-2-(rel-(2R,5R)-5-phenyltetrahydrofuran-2-yl)hept-5-en-2-
ol trans-(2f). Yield: 15.5 mg (56.5 μmol, 6%), colorless oil. Rf = 0.43
[pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.21
(s, 3H), 1.40 (ddd, J = 13.6, 9.2, 7.4 Hz, 1H), 1.59 (s, 3H), 1.61–1.65
(m, 2H), 1.66 (s, 3H), 1.67–1.71 (m, 1H), 1.78–1.88 (m, 1H), 1.92–2.01
(m, 1H), 2.02–2.11 (m, 2H), 2.21 (s, 1H, OH), 2.76 (dd, J = 6.8, 5.9 Hz,
1H), 4.71 (t, J = 6.3 Hz, 1H), 5.06 (tt, J = 7.1, 1.2 Hz, 1H), 7.27–7.30
(m, 1H), 7.32–7.38 (m, 4H). 13C NMR (CDCl3, 101 MHz) δ 16.4, 17.6,
400 MHz) δ 1.29 (s, 3H), 1.36 (s, 3H), 2.14 (s, 1H, OH), 2.22 (dt, Jd
=
13.0 Hz, Jt = 8.5 Hz, 1H), 2.52 (ddd, J = 13.0, 9.9, 6.5 Hz, 1H), 3.19 (q,
J = 9.0 Hz, 1H), 4.17 (dd, J = 8.5, 6.6 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H),
7.14–7.21 (m, 4H), 7.21–7.32 (m, 6H). 13C NMR (CDCl3, 101 MHz) δ
24.6, 27.0, 36.2, 53.7, 71.8, 85.3, 88.1, 126.1, 126.7, 127.7, 127.8, 128.3,
128.6, 140.2, 141.0. MS (70 eV, EI) m/z (%) 264 (17), 247 (4), 223 (8),
205 (19), 193 (32), 180 (100), 173 (15), 165 (20), 158 (18), 143 (37),
128 (19), 115 (70), 105 (67), 91 (50), 77 (47), 59 (50), 51 (18). HRMS
calcd. for C19H22O2 282.1620; found 282.1603. Anal. calcd. for
C19H22O2 (282.38): C, 80.82; H, 7.85. Found: C, 80.52; H, 7.89.
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
15
23.9, 25.3, 25.7, 35.9, 38.7, 61.3, 63.4, 74.2, 123.6, 125.9, 127.6, 128.5,
131.9, 144.4. MS (70 eV, EI) m/z (%) 256 (11), 238 (10), 223 (7), 213
(14), 195 (7), 187 (24), 174 (28), 165 (9), 155 (11), 147 (22), 136
(11), 129 (25), 117 (34), 115 (42), 105 (68), 91 (100), 77 (58), 69
(44), 63 (7), 55 (20), 51 (18). Anal. calcd. for C18H26O2 (274.40): C,
78.79; H, 9.55. Found: C, 78.68; H, 9.42.
(m, 5H, Ar–H). 13C NMR (CDCl3, 101 MHz) δ 18.1, 25.7, 35.7, 68.2,
81.7, 83.9, 126, 127, 129, 143. cis-(2i): 1H NMR (CDCl3, 400 MHz)
δ 1.22 (d, J = 6.44 Hz, 3H, CH3), 1.79–1.84 (m, 1H, CH2), 1.94–2.09
(m, 2H, CH2), 2.18 (s, 1H, OH), 2.27–2.34 (m, 1H, CH2), 3.94–3.98
(m, 1H, CH), 4.03–4.10 (m, 1H, CH), 4.88 (dd, J = 8.29, 6.73 Hz, 1H,
CH), 7.24–7.36 (m, 5H, Ar–H). 13C NMR (CDCl3, 101 MHz) δ 18.6
(CH3), 25.1 (CH2), 34.1 (CH2), 68.3 (HO–CH), 81.3 (O–CH), 83.5 (O–CH),
4.4.8. Conversion of 4-methyl-2-(3-methylbut-2-en-1-yl)phenol (1g)
Reactants: 4-methyl-2-(3-methylbut-2-en-1-yl)phenol (1g) (180 mg,
1.02 mmol) in chloroform (3 ml), VO(L2)(OEt) (3c) (28.2 mg, 50.4 μmol,
5 mol%), and TBHP (270 μl, 5.5 M solution in nonane, 1.49 mmol) in chlo-
roform (3 ml). Reaction time: 24 h at 20 °C. Eluent used for chromato-
graphic purification: pentane/acetone = 5:1 (v/v). 2-(5-methyl-2,3-
dihydrobenzofuran-2-yl)propan-2-ol (2g). Yield: 28.6 mg (149 μmol,
15%), colorless oil. Rf = 0.55 [pentane/acetone = 5:1 (v/v)]. 1H NMR
(CDCl3, 400 MHz) δ 1.20 (s, 3H), 1.26 (s, 1H, OH), 1.34 (s, 3H), 2.27
(s, 3H), 3.07–3.18 (m, 2H), 4.58 (t, J = 9.2 Hz, 1H), 6.67 (d, J = 8.0 Hz,
1H), 6.94 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H). 13C NMR (CDCl3, 101 MHz) δ
20.7, 23.9, 26.2, 30.7, 71.8, 89.2, 108.6, 125.5, 127.1, 128.2, 129.8, 157.4.
MS (70 eV, EI) m/z (%) 192 (45) [M+], 174 (4), 159 (30), 134 (100),
119 (22), 105 (44), 91 (20), 77 (18), 65 (5), 59 (34), 51 (6). HRMS
calcd. for C12H16O2 192.1150; found 192.1138. 2,2,6-trimethylchroman-
3-ol (5g) [98]. Yield: 136 mg (707 μmol, 69%), colorless oil. Rf = 0.55
[pentane/acetone = 5:1 (v/v)]. 1H NMR (CDCl3, 400 MHz) δ 1.30
(s, 3H), 1.35 (s, 3H), 1.81 (s, 1H, OH), 2.26 (s, 3H), 2.73 (dd, J = 16.9,
5.4 Hz, 1H), 3.03 (dd, J = 16.8, 4.8 Hz, 1H), 3.78 (t, J = 5.0 Hz, 1H), 6.73
(d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H). 13C NMR
(CDCl3, 101 MHz) δ 20.5, 22.3, 24.6, 31.3, 69.8, 76.5, 117.0, 118.4, 128.4,
129.8, 130.4, 150.5. MS (70 eV, EI) m/z (%) 192 (50) [M+], 159 (17), 134
(17), 121 (100), 107 (10), 91 (32), 77 (27), 65 (9), 57 (5), 51 (7). HRMS
calcd. for C12H16O2 192.1150; found 192.1147.
126 (Ar–C), 128 (Ar–C), 129 (Ar–C), 142 (Ar–C). HRMS (EI+) m/z
+
192.1149 [M+]; calculated mass for C12H16O2
192.1150. rel-
:
(2S,3R,6S)-2-Methyl-6-phenyltetrahydropyran-3-ol rel-(2S,3R,6S)-
(5i). Yield: 23.3 mg (121 μmol, 12%), Rf = 0.16 [ethyl acetate/petroleum
ether = 1:4 (v/v)]. 13C NMR (CDCl3, 101 MHz) δ 18.1, 25.7, 35.7, 68.2,
81.7, 83.9, 126, 127, 129, 143. HRMS (EI+) m/z 192.1149 [M+]; calculat-
+
ed mass for C12H16O2 : 192.1150. (E)-1-phenylhex-4-en-1-one. Yield:
2.77 mg (15.9 μmol, 2%). Rf = 0.61 [ethyl acetate/petroleum ether =
1:4 (v/v)]. Recovered (E)-1-Phenyl-4-hexen-1-ol (E)-(1i): 12.3 mg
(69.8 μmol, 7%) [99].
4.5.3. Conversion of (Z)-1-Phenyl-4-hexen-1-ol (Z)-(1i)
Reactants: (Z)-1-Phenyl-4-hexen-1-ol (Z)-(1i) (176 mg, 998 μmol)
in chloroform (3 ml), VO(L2)(OEt) (3c) (27.9 mg, 50.0 μmol, 5 mol%),
and TBHP (270 μl, 5.5 M solution in nonane, 1.5 mmol) in chloroform
(3 ml). Reaction time: 24 h at 20 °C. Eluent used for chromatographic
purification: diethyl ether/pentane
=
1:1 (v/v). 1-(5-
phenyltetrahydrofuran-2-yl)-ethanol (2i)–side chain isomer B. Yield:
112 mg (582 μmol, 58%) as 85/15-mixture of cis/trans-isomers. Rf =
0.36 [diethyl ether/pentane = 1:1 (v/v)]. cis-(2i): 1H NMR (CDCl3,
400 MHz) δ 1.22 (d, J = 6.46 Hz, 3H, CH3), 1.72–1.79 (m, 1H, CH2),
1.83–1.90 (m, 1H, CH2), 2.01–2.09 (m, 2H, CH2, OH), 2.30–2.37 (m,
1H, CH2), 3.75 (quin, J = 6.53 Hz, 1H, CH), 3.86 (q, J = 7.04 Hz, 1H,
CH), 4.93–4.95 (m, 1H, CH), 7.27–7.29 (m, 1H, Ar–H), 7.34–7.35 (m,
1H, Ar–H). 13C NMR (CDCl3, 151 MHz) δ 19.2, 28.2, 34.6, 71.0, 81.5,
84.5, 126.0, 127.6, 128.5, 142.6. trans-(2i). 1H NMR (CDCl3, 400 MHz)
δ 1.19 (d, J = 6.44 Hz, 3H, CH3), 1.67–1.80 (m, 1H, CH2), 1.81–1.94
(m, 1H, CH2), 2.03–2.15 (1H, CH2), 2.33–2.41 (m, 1H, CH2), 3.68 (m,
1H, CH), 4.01 (q, J = 7.41 Hz, 1H, CH), 4.93–5.00 (m, 1H, CH),
7.24–7.31 (m, 1H, Ar–H), 7.31–7.39 (m, 4H, Ar–H). 13C NMR (CDCl3,
151 MHz) δ 18.7, 28.9, 36.0, 70.9, 80.8, 84.7, 125.8, 127.5, 128.5, 142.9.
Anal. Calc. for C12H16O2 (192.25): C, 74.97; H, 8.39. Found: C, 74.43; H,
8.16%. Recovered (Z)-1-Phenyl-4-hexen-1-ol (Z)-(1i): 14.0 mg
(79.4 μmol, 8%).
4.5. Oxidizing alkenols varying by substitution at the terminal carbon
4.5.1. Conversion of 1-phenylpent-4-en-1-ol (1h)
Reactants: 1-phenylpent-4-en-1-ol (1h) (162 mg, 1.00 mmol) in
chloroform (3 ml), VO(L2)(OEt) (3c) (28.0 mg, 50.0 μmol, 5 mol%),
and TBHP (270 μl, 5.5 M solution in nonane, 1.5 mmol) in chloroform
(3 ml). Reaction time: 24 h at 60 °C. Eluent used for chromatographic
purification: ethyl acetate/petroleum ether = 2:1 (v/v). Rf = 0.23
[ethyl acetate/petroleum ether = 2:1 (v/v)]. (5-Phenyltetrahydrofuran-
2-yl)-methanol (2h). Yield: 50.9 mg (286 μmol, 29%), as 46/54-mixture
of cis/trans-isomers. cis-(2h): 1H NMR (CDCl3, 400 MHz) δ 1.81–1.92
(m, 2H, CH2), 2.02–2.11 (m, 1H, CH2), 2.04 (s, 1H, OH), 2.28–2.40
(m, 1H, CH2) 3.65 (dd, J = 11.6, 6.1 Hz, 1H, CH2), 3.79 (dd, J = 11.5,
3.3 Hz, 1H, CH2), 4.18–4.23 (m, 1H, CH), 4.91 (dd, J = 7.6, 6.7 Hz, 1H,
CH) 7.24–7.37 (m, 5H, Ar–H). trans-(2h): 1H NMR (CDCl3, 400 MHz)
δ 1.81–1.92 (m, 2H, CH2), 2.02–2.11 (m, 1H, CH2), 2.04 (s, 1H, OH),
2.28–2.40 (m, 1H, CH2) 3.60 (dd, J = 11.6, 6.1 Hz, 1H, CH2), 3.74 (dd,
J = 11.7, 3.3 Hz, 1H, CH2), 4.34–4.40 (m, 1H, CH), 5.00(dd, J = 8.2,
5.9 Hz, 1H, CH) 7.24–7.37 (m, 5H, Ar–H). 1-phenylpent-4-en-1-one:
7.10 mg (44.3 μmol, 4%). Recovered 1-phenylpent-4-en-1-ol (1h):
8.57 mg (52.8 μmol, 5%) [35].
4.5.4. Conversion of (2Z,9E)-Undeca-2,9-dien-6-ol (1j)
Reactants: (2Z,9E)-Undeca-2,9-dien-6-ol (1j) (169 mg, 1.00 mmol)
in chloroform (3 ml), VO(L2)(OEt) (3c) (27.9 mg, 50.0 μmol, 5 mol%),
and TBHP (270 μl, 5.5 M solution in nonane, 1.5 mmol) in chloroform
(3 ml). Reaction time: 24 h at 20 °C. Eluent used for chromatographic
purification: ethyl acetate/petroleum ether = 1:3 (v/v). 1-{5-[(E)-
pent-3-enyl]tetrahydrofuran-2-yl)ethanol (E)-(2j). Yield: 49.0 mg
(266 μmol, 27%), as 85/15-mixture of cis/trans-isomers. Rf = 0.25
[ethyl acetate/petroleum ether = 1:3 (v/v)]. (E)-cis-(2j): 1H NMR
(CDCl3, 400 MHz) δ 1.14 (d, J = 6.3 Hz, 3H, CH3), 1.46–1.55 (m, 2H,
CH2), 1.57–1.66 (m, 5H, CH2, CH3), 1.88–2.09 (m, 4H, CH2), 2.51 (br s,
1H, OH), 3.50–3.55 (m, 1H, CH), 3.64 (q, J = 6.9 Hz, 1H, CH), 3.85–
3.92 (m, 1H, CH), 5.38–5.49 (m, 2H, CH). 13C NMR (CDCl3, 151 MHz)
δ 18.1, 19.2, 27.9, 29.4, 31.5, 36.1, 71.1, 79.6, 83.8, 125.3, 130.9. (E)–
trans-(2j): 1H NMR (CDCl3, 400 MHz) δ 1.13 (d, J = 6.3 Hz, 3H, CH3),
1.46–1.55 (m, 2H, CH2), 1.57–1.66 (m, 5H, CH2, CH3), 1.88–2.09
(m, 4H, CH2), 2.51 (br s, 1H, OH), 3.50–3.55 (m, 1H, CH), 3.69–3.75
(m, 1H, CH), 3.85–3.92 (m, 1H, CH), 5.38–5.49 (m, 2H, CH). IR (CCl4)
4.5.2. Conversion of (E)-1-Phenyl-4-hexen-1-ol (E)-(1i)
Reactants: (E)-1-Phenyl-4-hexen-1-ol (E)-(1i) (176 mg, 998 μmol) in
chloroform (3 ml), VO(L2)(OEt) (3c) (28.1 mg, 50.0 μmol, 5 mol%), and
TBHP (270 μl, 5.5 M solution in nonane, 1.5 mmol) in chloroform (3 ml).
Reaction time: 24 h at 20 °C. Eluent used for chromatographic purifica-
tion: diethyl ether/pentane = 1:1 (v/v). 1-(5-phenyltetrahydrofuran-2-
yl)-ethanol (2i)–side chain isomer A. Yield: 93.5 mg (486 μmol, 49%) as
32/68-mixture of cis/trans-isomers. Rf = 0.16 [ethyl acetate/petroleum
ether = 1:4 (v/v)]. trans-(2i): 1H NMR (CDCl3, 400 MHz) δ 1.18
(d, J = 6.44 Hz, 3H, CH3), 1.80–1.92 (m, 1H, CH2), 1.94–2.09 (m, 2H,
CH2), 2.18 (s, 1H, OH), 2.35–2.42 (m, 1H, CH2), 4.03–4.10 (m, 1H, CH),
4.12–4.16 (m, 1H, CH), 5.02 (dd, J = 8.49, 5.95 Hz, 1H, CH), 7.24–7.36
ν
max/cm−1 3593, 2972, 2936, 2873, 1449, 1398, 1376, 1300, 1073,
967. HRMS (EI+) m/z 184.1463 [M+]; calculated mass for C11H20O2
+
:
184.1463. 1-{5-[(Z)-pent-3-enyl]tetrahydrofuran-2-yl}ethanol (Z)-(2j).
Yield: 56.4 mg (306 μmol, 31%), as 13/87-mixture of cis/trans-isomers.
Rf = 0.18 [ethyl acetate/petroleum ether = 1:3 (v/v)]. (Z)-trans-(2j):
1H NMR (CDCl3, 400 MHz) δ 1.12 (d, J = 6.4 Hz, 3H, CH3), 1.38–1.56
Please cite this article as: M. Dönges, et al., Activating tert-butyl hydroperoxide by chelated vanadates for stereoselectively preparing
sidechain-functionalized tetrahydrofurans, J. Inorg. Biochem. (2015), http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009

16
M. Dönges et al. / Journal of Inorganic Biochemistry xxx (2015) xxx–xxx
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(m, 2H, CH2), 1.58–1.70 (m, 5H, CH2, CH3), 1.81–1.88 (m, 2H, CH2),
2.00–2.16 (m, 3H, CH2, OH), 3.84–3.89 (m, 1H, CH), 3.94–4.01 (m, 2H,
CH), 5.35–5.49 (m, 2H, CH). 13C NMR (CDCl3, 151 MHz) δ 12.9, 18.0,
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5.49 (m, 2H, CH). IR (CCl4) νmax/cm−1 3589, 2975, 2935, 2874, 1446,
1402, 1374, 1302, 1056. HRMS (EI+) m/z 184.1458 [M+]; calculated
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4.5.5. Conversion of trans-(+)-laurediol (1k)
Procedure: general method 4.2. Reactants: trans-(+)-laurediol (+)-
(1k) (40 mg, 171 μmol) dissolved in chloroform (0.5 ml), VO(L2)(OEt)
(3c) (4.6 mg, 8.2 μmol, 5 mol%), and TBHP (46.4 μl, 5.5 M solution
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3 H), 1.94 (dd, J = 14.1, 2.9 Hz, 1H), 2.05 (quin, J = 7.0 Hz, 2 H),
2.31–2.42 (m, 3 H), 2.50 (td, Jt = 7.1 Hz, Jd = 1.1 Hz, 2 H), 2.80 (d, J =
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16.1, 1.9 Hz, 1 H), 5.57–5.69 (m, 1 H), 6.31 (dt, Jd = 15.7 Hz, Jt =
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Acknowledgments
This work was supported by the state of Rheinland Pfalz (scholarship
for M.A.) and NanoKat (scholarship for M.D). This work is part of Ph.D.
theses of M.A. and M.D. We thank Dr. Mario Demary for preliminarily
exploring synthetic routes for preparing alkenols (E)-1f and 1g. We
furthermore thank the reviewers for providing helpful comments,
suggestions, and advice.
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Appendix A. Supplementary data
Supplementary data associated with this article containing instru-
mentation, solvent purification, reagent specification and experimental
details for synthesis of alkenols can be found in the online version of the
article at http://dx.doi.org/10.1016/j.jinorgbio.2015.04.009.
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