Controlling 6-endo-selectivity in oxidation/bromocyclization cascades for synthesis of aplysiapyranoids and other 2,2,6,6-substituted tetrahydropyrans

Article abstract of DOI:10.1016/j.tet.2012.05.013

A cascade, composed of (i) oxovanadium(V)-catalyzed oxidation of bromide by tert-butyl hydroperoxide and (ii) stereoselective 6-endo-bromocyclization, affords 3-bromo-2-aryl-2,6,6-trimethyltetrahydropyrans from styrene-type tertiary alkenols in synthetically useful yields. (E)-Alkenols add the bromo- and the alkoxy substituent anti-selectively across the double bond, indicating a bromonium ion-mechanism for the ring closure. 6-endo-control of the alkenol cyclization thereby arises from the polar effect of the aryl substituent. Two methyl substituents bound to the alkene terminus are not similarly able to favor 6-endo-cyclization, because strain arising from methyl group repulsion, as the bromonium-activated π-bond and the hydroxyl oxygen approach, directs bromocyclization of tertiary prenyl-type substrates toward tetrahydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyclization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free radical and polar functional group interconversion.

Full text of DOI:10.1016/j.tet.2012.05.013

Tetrahedron 68 (2012) 6968e6980
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Controlling 6-endo-selectivity in oxidation/bromocyclization cascades for
synthesis of aplysiapyranoids and other 2,2,6,6-substituted tetrahydropyrans
a
a
a
a
,
b
c
*
€
€
Oliver Brucher , Uwe Bergstraßer , Harald Kelm , Jens Hartung , Marco Greb , Ingrid Svoboda ,
Hartmut Fuess c
a
€
€
Fachbereich Chemie, Organische Chemie, Technische Universitat Kaiserslautern, Erwin-Schrodinger-Straße, D-67663 Kaiserslautern, Germany
Institut fur Organische Chemie, Universitat Wurzburg, Am Hubland, 97074 Wurzburg, Germany
Technische Universitat Darmstadt, Strukturforschung, FB11 Material- und Geowissenschaften, Petersenstr. 23, D-64287 Darmstadt, Germany
b
c
€
€
€
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
A cascade, composed of (i) oxovanadium(V)-catalyzed oxidation of bromide by tert-butyl hydroperoxide
and (ii) stereoselective 6-endo-bromocyclization, affords 3-bromo-2-aryl-2,6,6-trimethyltetrahydropyrans
from styrene-type tertiary alkenols in synthetically useful yields. (E)-Alkenols add the bromo- and the
alkoxy substituent anti-selectively across the double bond, indicating a bromonium ion-mechanism for the
ring closure. 6-endo-control of the alkenol cyclization thereby arises from the polar effect of the aryl
substituent. Two methyl substituents bound to the alkene terminus are not similarly able to favor 6-endo-
Received 17 February 2012
Received in revised form 1 May 2012
Accepted 3 May 2012
Available online 11 May 2012
Keywords:
cyclization, because strain arising from methyl group repulsion, as the bromonium-activated p-bond and
Alkyl hydroperoxide
Bromocyclization
Bromoperoxidase model
Marine natural product
Molecular modeling
Oxidation catalysis
Stereoselective synthesis
Strain
the hydroxyl oxygen approach, directs bromocyclization of tertiary prenyl-type substrates toward tetra-
hydrofuran formation. A hexasubstituted bromotetrahydropyran prepared from the oxidation/bromocyc-
lization cascade served as starting material for synthesis of racemic aplysiapyranoid A, in a sequence of free
radical and polar functional group interconversion.
Ó 2012 Elsevier Ltd. All rights reserved.
Terpenol
Vanadium(V) complex
X-ray crystallography
1. Introduction
The challenge to prepare larger quantity of the aplysiapyranoids
for testing biological properties was taken on by comparatively few
Aplysiapyranoids are rare tetrahydropyran-derived natural
products, which were isolated from the midgut gland of the sea
hare Aplysia kurodai.1,2 The structure of the aplysiapyranoids shows
a remarkable accumulation of carbon- and halogen-substituents
(cf. Scheme 1).3 Nothing so far is known about the physiological
role of the aplysiapyranoids and little about their medicinal
chemical properties.1
groups. All reported strategies thereby relied on 6-endo-bromo-
cyclization of appropriately substituted alkenols, for constructing
the highly functionalized tetrahydropyran core. Jung and co-
workers, for example, prepared accordingly aplysiapyranoid A,
and derivatives named C and D, having a chlorine instead of
a bromine atom attached next to the chlorovinyl group (for aply-
siapyranoid A see Scheme 1).4e6 The yield of 6-endo-bromocyclized
products remained in all instances low. We therefore developed an
alternative approach, trying to improve the yield of tetrahy-
dropyran formation by increasing dipolar attraction between the
reacting entities.7 None of the strategies, however, satisfactorily
provided a solution to the problem of the inherent low 6-endo-
selectivity in synthesis of 2,2,6,6-substituted tetrahydropyrans
from tert-alkenols, an objective researchers had pursued from the
days of the first venustatriol-synthesis.8e11
Takai-reaction
Cl
Sharpless-degradation
O
Barton-
bromination
Ph
OH
Br
bromocyclization
Br
OR
O
O
Br
RO2C
tert-alkenol
RO2C
aplysiapyranoid A
bromotetrahydropyran
Scheme 1. Retrosynthetic scheme and named reactions for synthesis of the marine
In a more recent project we had developed an efficient new
approach for synthesis of bromotetrahydropyrans from acid labile
alkenols via oxidative bromocyclization.12e14 The convincing che-
moselectivity of this method prompted us to address the question
natural product aplysiapyranoid A.
* Corresponding author. Tel.: þ49 631 205 2431; fax: þ49 631 205 3921; e-mail
address: hartung@chemie.uni-kl.de (J. Hartung).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.013

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6969
of 6-endo-control in bromocyclization of tertiary
d
,ε-unsaturated
oxidation, which prevents reaction mixtures from becoming notably
acidic. Pyridinium hydrobromide, on the other hand, considerably
acidifies reaction mixtures.12
alcohols again. We wanted to understand why the strategy to
bromocyclize tertiary alkenols bearing two methyl substituents at
the terminal alkene carbon (prenyl-type alkenol, vide infra)
fails8,9,15,16 to direct ring closures of tertiary alkenols exclusively
toward the 6-endo-mode of cyclization, and what functional group
would be needed to do so.
The major finding from the present study shows that an aryl
group in combination with a methyl substituent at the terminal
alkene carbon (styrene-type alkenol, vide infra) directs bromo-
cyclization of tertiary alkenols almost 6-endo-specifically. Two
methyl substituents are not able to similarly control regiose-
lectivity, because strain arising from methyl group repulsion, as the
reacting entities approach for intramolecular carboneoxygen bond
formation, changes selectivity in tertiary alkenol cyclization toward
tetrahydrofuran formation (Section 2.4). A hexasubstituted bro-
motetrahydropyran prepared from the oxidation/bromocyclization
cascade served as starting material for synthesis of racemic aply-
siapyranoid A, in a sequence of free radical and polar functional
group interconversion (Section 2.5).
For peroxide activation, we use neutral oxovanadium(V) com-
plexes of the general formula V(O)L(OEt), where L2ꢁ denotes a di-
basic tridentate auxiliary with two anionic oxygen donor atoms
and one neutral nitrogen-donor atom (Scheme 3).12 From a struc-
ture reactivity survey, we selected Schiff-base derived iminodiol26
H2L1 and 2,6-substituted piperidine27 H2L2 as ligands to prepare
oxidation catalysts suitable for the present study. Both oxovana-
dium complexes were prepared by transesterifying triethyl vana-
date by diols H2L1 or H2L2 in a solution of boiling ethanol.12,22,28
The synthesis affords dark brown Schiff-base complex V(O)
L1(OEt) in 95% yield, and pale yellow piperidine-derived complex
V(O)L2(OEt) in 85% yield. The Schiff-base complex is the thermo-
chemically more stable reagent and the piperidine complex the
more reactive and selective catalyst for tert-butyl hydroperoxide
activation.
VO(OEt)3 + H2Ln
V(O)Ln(OEt)
85–95%
EtOH / 25 °C
2. Results and interpretation
2.1. Vanadium(V)-complexes
Ph
Ph
Ph
N
N
Ph
In our group, we use catalysis by transition metal complexes to
convert alkenols via oxidation/cyclization cascades into bromo-
ethers12,17e20 (Scheme 2). The preferred oxidant for oxidative bromi-
nation in polar aprotic solvents is tert-butyl hydroperoxide. tert-Butyl
hydroperoxide readily dissolves in dialkyl carbonates or acetonitrile
and binds at ambient temperature to oxovanadium(V) complexes, for
converting the nucleophilic peroxide into a strongly electrophilic re-
agent that is able to oxidize bromide into molecular bromine.12
Turnover of bromide and tert-butyl hydroperoxide for bromine gen-
eration consumes one proton per catalytic cycle. For practical reasons
H
H
H
HO
OH
OH
H2L1
OH
H2L2
Scheme 3. Synthesis of oxovanadium compounds V(O)Ln(OEt) (95% for n¼1, 85% for
n¼2) from auxiliaries H2L1 and H2L2 [acidic protons that are substituted by VO(OEt)2þ
in the course of complex formation are printed in bold; V(O)L1(OEt) crystallizes as
EtOH-adduct from ethanolic solution].12,28
2.2.
d,ε-Unsaturated alcohols
we used pyridinium hydrobromide (pyHBr)21,22 or
acid (BCA)12,23,24 as combined proton and bromide sources (Scheme
b-bromocinnamic
To identify factors that control 6-endo-selectivity in oxidative
bromocyclization of alkenols, we prepared substrates that accord-
ing to our systematic were subdivided into prenyl-type alkenols
(1aec), due to structural analogy to the terpenes,29 and styrene-
type alkenols (1def), having the alkenol carbonecarbon double
bond substituted by an aryl group (Fig. 1).
2).25
b-Bromocinnamic acid decomposes into styrene, carbon di-
oxide, bromide, and a proton, if treated at 30 ꢀC with a catalytic
amount of bromide in propylene carbonate (PC). The rate of BCA-
fragmentation under such conditions is close to the rate of bromide
styrene-type
prenyl-type
• catalytic oxidation of bromide
O
Ph
O
H
R1
H
2
OH
O
R2
R3
Br
O
or
LnV OOR
Ar
2 Br– / 2 H+
EtO2C
EtO2C
R3
ROH
R4
1a–c
1d–f
R4
H
Ar
Ph
1
R1
R2
1
O
a
b
c
CH3 CH3
d
e
f
CH3
H
ROOH
LnV OR
Br2 + H2O
CH3
H
H
H
CH3 Ph
H
CH3 p-MeOC6H4
• bromocyclization
OH
Fig. 1. Indexing of prenyl- and styrene-type d,ε-unsaturated alcohols to explore sys-
O
Ar
+ H+ + Br–
tematics of 6-endo-selectivity in bromocyclization.
+ Br2
Ar
R'O2C
R'O2C
Br
Synthesis of racemic alkenols 1aef followed a route, that is, ex-
emplified for styrene derivative 1e in Scheme 4. The procedure
solved the inherent problem of (E)/(Z)-isomerization7 of alkenols 1e
and 1f, and affords stereochemically homogeneous products with
tert-alkenol
bromotetrahydropyran
Scheme 2. Catalytic cycle for vanadium(V)-catalyzed bromide oxidation by tert-butyl
hydroperoxide for bromine formation (top; R¼tBu, n¼1e2, cf. Scheme 3),12 and its use
in synthesis of bromotetrahydropyrans (bottom; R0¼alkyl, Ar¼e.g., Ph, p-MeOC6H4).
respect to
p-bond configuration. We furthermore observed

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6970
tert-butyl hydroperoxide for oxidative alkenol bromination, however,
Br
CO2H
1. PhMgBr
Et2O
1. NaCN
DMSO
at a considerably lower rate than V(O)L1(OEt) (Table 1, entry 1).22
A
change of vanadium catalyst from Schiff-base complex V(O)L1(OEt) to
piperidine derivative V(O)L2(OEt) caused theyieldsof products 2e4 to
become smaller, but also allowed to use non-toxic propylene car-
bonate as solvent (Table 1, entries 3e4). In solutions of propylene
carbonate, the preferred in situ hydrogen bromide source is a buffer
2. H2SO4
2. KOH
aq. glycol
O
Ph
93%
Ph
88%
CO2Et
composed of sodium bromide and b-bromocinnamic acid. In such
1. EtOH / CHCl3
p-TsOHcat.
HO
solutions, no bromide oxidation by tert-butyl hydroperoxide occurs,
unless a Lewis-acid, such as V(O)L2(OEt), is added.12 For work-up,
products 2a and 3a, styrene (w10%), and styrene-derived bromides
were extracted from the reaction mixture by cyclohexane, which was
followed by chromatographic purification.
2. LDA / THF
acetone
Ph
1e
82% (2 steps)
As control, to compare efficiency of alkenol bromination from
vanadium-catalyzed oxidations to other methods, we treated
alkenol 1a with more traditional reagents, such as N-bromosucci-
nimide or molecular bromine. The highest yields (91%) of bro-
moethers 2a and 3a thereby were obtained by treating alkenol 1a
with a mixture composed of molecular bromine and sodium hy-
drogen carbonate in acetonitrile. The poorest yields (37e38%) of 2a
and 3a taken together were gained from reactions between sub-
strate 1a and either N-bromosuccinimide or bromine in dichloro-
methane (Supplementary data). By taking toxicological aspects into
Scheme 4. Preparation of styrene-type alkenol 1e as starting material for synthesis of
aplysiapyranoid A (cf. Sections 2.3 and 2.5).
isomerization at the carbonecarbon double bond, if esterification in
synthesis of anisole derivative 1f is performed with ethanol and p-
toluenesulfonic acid, instead of ethanol in combination with
dicyclohexylcarbodiimide.
account, we decided to use sodium bromide,
b-bromocinnamic
acid, and tert-butyl hydroperoxide in propylene carbonate as
standard combination for supplementing the systematic on regio-
control in alkenol bromocyclization.
2.3. Oxidation catalysis
Treatment of secondary prenyl-type alkenol 1b and primary
derivative 1c under conditions defined as standard in the previous
section provided a ratio of tetrahydropyran 2b and tetrahydrofuran
3b of 74:26 (entry 5 in Table 1) from secondary substrate 1b, and
a 90/10-mixture of tetrahydropyran 2c versus tetrahydrofuran 3c
from primary alkenol 1c (entry 6 in Table 1).
Analysis of the bromocyclization products by GCeMS and NMR
showed that eight products are formed from secondary prenyl-type
alkenol 1b and four from 1c. Structural identification of bro-
moethers 2c and 3c was feasible on the basis of one and two-
dimensional NMR-spectroscopy, including NOESY-spectroscopy. As-
signmentofconstitution and configuration ofproducts 2b and 3cwas
complicated by the existence of an additional stereocenter. In the
courseofdataanalysis, wefoundthatresonances ofmethylprotonsin
2.3.1. Prenyl-type alkenols. Foroxidative bromocyclization of tertiary
prenyl-type alkenols by pyridinium hydrobromide and tert-butyl
hydroperoxide, we modified conditions described22 for synthesis of
cyclic bromoethers from primary and secondary 4-pentenols pre-
viously. The modifications relate to exclusion of moisture by drying
V(O)L1(OEt), pyridiniumhydrobromide, tert-butyl hydroperoxide, and
the solvent acetonitrile. We furthermore performed the oxidation/
bromocyclization cascade in an atmosphere of dry nitrogen instead of
air and lowered the reactant concentration. Finally, we added smaller
portions of pyridinium hydrobromide over a longer period of time.
These adaptions improved yields of bromoethers 2a and 3a, and
lowered the fraction of unwanted dibromoalcohol 4a. The total yield
of organobromines increased from 78% to 87% (entry 2, Table 2). In
controls we noticed that pyridinium hydrobromide is able to activate
Table 1
Bromocyclization of prenyl-type alkenols 1aec in vanadium-catalyzed oxidationsa
TBHP
MBr / HX
V(O)Ln(OEt)cat.
R1
R1
Br
R1
H
O
R1
R2
O
OH
O
R2
R2
R2
Br
5
+
+
3
3
5
solvent (T)
EtO2C
EtO2C
Br
EtO2C
EtO2C
Br
1
2
3
4
Entry
1e4
MBr/HX
V(O)Ln(OEt)
Solventb/ꢀC
2/% (cis/trans)c
3/% (cis/trans)c
4/% (dr)d
1
2
3
4
5
6
a
a
a
a
b
c
pyHBr
pyHBr
pyHBr
None
CH3CN/25
CH3CN/25
CH3CN/25
PC/30
PC/30
PC/30
8 (71:29)
25 (79:21)
19 (83:17)
17 (83:17)
42 (dg)
16 (67:33)
50 (69:31)
43 (69:31)
40 (70:30)
15 (dg)
5 (58:42)
12 (59:41)
27 (60:40)
df
V(O)L1(OEt)
V(O)L2(OEt)
V(O)L2(OEt)
V(O)L2(OEt)
V(O)L2(OEt)
NaBr/BCAe
NaBr/BCAe
NaBr/BCAe
df
47 (68:32)
5 (50:50)
df
V(O)Ln(OEt) (5 mol %); for structure formulas of ligands H2L1 and H2L2 refer to Scheme 3; quantitative conversion of 1, except of entry 1 (70% conversion).
a
b
c
d
e
f
PC¼propylene carbonate.
3,5-cis/3,5-trans (1H NMR).
Diastereomeric ratio; stereoisomers not further assigned.
BCA¼
b-bromocinnamic acid.
Not detected.
g
Stereoisomers not assigned (see text).

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6971
positions 2 and 6 of bromotetrahydropyrans 2a (1.32e1.43 ppm) and
2c (1.36e1.39 ppm) are distinctively shifted from those of exocyclic
methyl groups in bromotetrahydrofurans 3a (1.69e1.74 ppm) and 3c
(1.70e1.76 ppm; shift data referring to CDCl3 as solvent). We there-
fore assigned methyl resonances between 1.68 and 1.77 ppm to the
four stereoisomers of bromotetrahydrofuran 3b. The major bromo-
cyclization product of alkenol 1b, which was separated by chroma-
tography, shows a characteristic doublet at 1.13 ppm, and two
similarly diagnostic singlets at 1.36 and 1.42 ppm for the methyl
protons. The protons attached to C4 were sufficiently shift-dispersed
inasolutionofC6D6 to showa baseline-separatedquartet(J¼13 Hz) at
2.36 ppm for one of the protons and a double doublet for H-5 (J¼13
and 4 Hz). From this information we derived that the major product
obtained from bromocyclization of secondary alkenol 1b is a tetra-
hydropyran, having the bromo-, methyl-, and ethoxycarbonyl sub-
stituent positioned equatorially, that is, rel-(2R,3R,5S)-5-bromo-
3-ethoxycarbonyl-2,6,6-trimethyl-tetrahydropyran rel-(2R,3R,5S)-
(2b).
associated with the ethoxycarbonyl- and the bromosubstituent
compares to the selectivity found in bromocyclization of prenyl-
type alkenols, and points to thermodynamic control in the selec-
tivity determining step.
From NMR-spectroscopic analysis of the product obtained from
bromocyclization of styrene-type alkenol 1d, ambiguity remained,
whether tetrahydropyran 2d or tetrahydrofuran 3d had been
formed as 93/7-mixture of stereoisomers. We therefore subjected
the latter product to a bromine/hydrogen-exchange using tribu-
tylstannane and 10 mol % of azobisisobutyronitrile (AIBN) in boiling
benzene (Scheme 5). The reaction afforded product 5 in 92% yield,
again, as a 93/7-mixture of stereoisomers. The proton-NMR of 5
shows doublets at 2.94 ppm and 2.91 ppm that are not present in
the bromocyclization product, and a singlet at 5.00 ppm (CDCl3) for
the latter, that is, not found in the spectrum of 5. All other reso-
nances experience an upfield shift without changing fine struc-
tures, comparing the spectra of the starting alkyl bromide and 5.
From these experimental details we concluded that the product of
Regarding stereoselectivity, the oxidation/bromocyclization
cascade affords 3,5-cis-isomers of bromotetrahydropyrans 2aec
and bromotetrahydrofurans 3aec as major isomers. For both
classes of cyclic ethers, the 3,5-cis-arrangement of substituents is
favored on the basis of strain and thus steric effects. We there-
fore concluded that stereoselectivity of the alkenol ring closures
described above is governed by thermodynamic effects (vide
infra).
bromocyclization of
drofuran 3d.
b
-methylstyrene-type alkenol 1d is tetrahy-
Bu3SnH
AIBN
O
O
Br
5
5
3
3
C6H6 / 80 °C
Ph
Ph
EtO2C
EtO2C
92%
3d
5
2.3.2. Styrene-type alkenols. Oxidation/bromocyclization cascades
cis:trans = 93:7
cis:trans = 93:7
of styrene-type alkenols provide tetrahydrofuran 3d from
methylstyrene derivative 1d, and tetrahydropyrans 2eef from
b
a
-
-
Scheme 5. Bromine/hydrogen exchange for synthesis of tetrahydrofuran 5 from bro-
mocyclization product 3d.
methyl styrene derivatives 1eef (entries 1e4 in Table 2). If judged
by efficiency alone, the most convincing result for synthesis of
bromotetrahydropyran 2e (73%), a compound needed in Section 2.5
for synthesis of aplysiapyranoids, was obtained from oxidative
bromination of 1e using pyridinium hydrobromide, tert-butyl hy-
droperoxide, catalytic amounts of Schiff-base complex V(O)L1(OEt)
(entry 4 in Table 2) and the conditions advanced in this study for
bromocyclization of 1a.
The major isomer of 3d crystallizes from a solution of CDCl3 and
was investigated by X-ray diffraction to determine relative config-
uration of stereocenters at C5 and C10 (Fig. 2). The crystal structure
shows relative 5R,10S-configuration, which is in line with anti-
selective addition of the bromo- and the alkoxy substituent
across the (E)-double bond in 1d. Further structural details relevant
for discussing strain effects associated with close contacts between
Table 2
Bromocyclization of styrene-type alkenols 1def in vanadium-catalyzed oxidations
TBHP
MBr / HX
V(O)Ln(OEt)cat.
H
R3
Ar
O
O
O
Br
R4
R3
6
5
5
+
3
3
Ar
R3
solvent (T)
Ar
EtO2C
EtO2C
EtO2C
Br
R4
1
( )-2
3
Entry
1e3
MBr/HX
V(O)Ln(OEt)a
Solventb/ꢀC
(ꢂ)-2/% (cis/trans)c
3/% (cis/trans)c
1
2
3
4
d
e
e
f
NaBr/BCAd
NaBr/BCAd
pyHBr
V(O)L2(OEt)
V(O)L2(OEt)
V(O)L1(OEt)
V(O)L2(OEt)
PC/30
PC/30
CH3CN/25
PC/30
de
57 (93:7)
47 (77:23)
73 (76:24)
47 (53:47)
df
df
df
NaBr/BCAd
V(O)Ln(OEt) (5 mol %); for structure formulas of auxiliaries H2L1eH2L2 refer to Scheme 3.
PC¼propylene carbonate.
a
b
c
d
e
f
3,5-cis/3,5-trans (1H NMR); 5,6-trans-configuration for 2e and 2f.
BCA¼b-bromocinnamic acid.
Not detected (NMR).
Not detected (GC).
Stereochemical analysis shows that an (E)-configuration in 1e
carbon substituents in proximal positions to the endocyclic oxygen
(Section 2.4) are depicted in Fig. 2 (red rectangle).
and 1f is copied into trans-configuration of substituents at carbons
5 and 6 in tetrahydropyrans 2e and 2f. The mechanism that ster-
eochemically explains this selectivity is the anti-addition of bro-
mine and the alkoxy substituent across the (E)-double bond,
according to a bromonium ion pathway. The cis-configuration
2.3.3. On the regioselectivity of oxidation/bromocyclization casca-
des. The experiments summarized in the previous sections show
that bromocyclization of
a-styrene-type tertiary alkenols 1eef

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6972
alkenols (such as 1e), the aryl group stabilizes positive charge at the
benzylic carbon and favors this position for an incoming nucleo-
phile by dipolar attraction. The attractive component is expected to
balance strain imposed by close contacts between substituents in
proximity of the hydroxyl oxygen, as the tetrahydropyran ring
closes (vide infra and Scheme 6). In b-styrene-type alkenol 1d, it is
the tertiary carbon atom of the bromonium ion, that is, selectively
attacked by the approaching oxygen nucleophile, due to dipolar
attraction and smaller steric repulsion between methyl groups, as
the tetrahydrofuran ring closes.
2.4. On methyl substituent effects in 6-endo alkenol ring
closures
The selectivity data summarized in the previous section
imply that the tetrahydropyran fraction of bromocyclization
products gradually decreases, as steric encroachment at oxygen in
prenyl-type alkenols rises. We therefore concluded that steric
repulsion between methyl substituents in the selectivity de-
termining step changes an inherent 6-endo-selectivity of
electrophile-induced ring closures of prenyl-type 4-pentenols
toward tetrahydrofuran formation. The selectivity determining
step, nucleophilic opening of a (tri)substituted hydroxyalkyl bro-
monium ion by the hydroxyl oxygen, is slow and therefore
should occur via a late and therefore product-like transition
state. To obtain information on strain imposed by methyl sub-
stitution in such late transition states, we computed Gibbs free
energies of 2,6- and 2,2-dimethyltetrahydropyrans as models
for the proposed intermediates, and compared the data to
Gibbs free energies of other 1,3- and geminally substituted tet-
rahydropyrans (Section 2.4.1). We also computed thermochem-
istry associated with 6-endo- and 5-exo-cyclization from a tertiary
prenyl-type alkenol (Section 2.4.2), to exemplify the role of strain
on selectivity in a thermodynamically controlled ring closure.
Fig. 2. Ellipsoid graphic (50% probability) of tetrahydrofuran cis-3d in the solid state
showing the 3T4 twist-conformation of the heterocyclic core [150 K; H-atoms are
drawn as circles of an arbitrary radius; E¼CO2Et; the (3R,5R,10S)-isomer of 3d was
arbitrarily selected from the racemate in the unit cell].
afford tetrahydropyrans, prenyl-type alkenols 1aec mixtures of
tetrahydrofurans and tetrahydropyrans, and b-styrene-type alkenol
1d a mixture of stereoisomeric tetrahydrofurans. From stereo-
chemical analysis and information gained from previous studies,12
we reasoned that the selectivity determining reagent for bromo-
cyclization formed from bromide oxidation by tert-butyl hydro-
peroxide is molecular bromine. Bromine adds to a carbonecarbon
double bond of an alkene in a kinetically controlled reaction, to
furnish a
g
-hydroxypropyl bromonium ion (Scheme 6).30,31 The
succeeding step, the anti-selective opening of the bromonium ion
by intramolecular attack of the hydroxyl oxygen, is much slower
and therefore controlled by thermochemical parameters, such as
strain and dipolar attraction.
2.4.1. Strain in dimethyltetrahydropyrans. For computing a consis-
tent set of relative Gibbs free energies of dimethyltetrahydropyrans
IeVI, we used Becke’s 3 parameter hybrid functional32,33 in com-
bination with the 6-31þG** basis set.34e36 The chosen computa-
tional method reproduces A-values of alkyl substituted
tetrahydropyrans within a precision, that is, close to the experi-
mental error.37,38 The A-value reflects the degree of steric in-
teraction between a substituent and the (hetero)cyclic core, the
substituent is attached to. The A-value therefore is a benchmark for
method assessment in conformational analysis.39
In the computational study, dimethyltetrahydropyran minimum
structures were obtained from gradient searches and verified as
such by computing second derivatives of associated wave functions,
by diagonalizing underlying Hessian matrices. Minimum structures
lacked in negative eigenvalues or imaginary frequencies. Approxi-
mate Gibbs free energies (G298.15) were computed from thermo-
chemical analysis at 298.15 K, using unscaled frequency
calculations, including zero-point vibrational energy corrections,
thermal corrections, and entropy.
minimization
of strain
O
+
e.g.
R
δ+
Br
Br
E
R'δ–
δ+
OH
3a
+
–
H
R''
E
Ph
O
e.g.
dipolar
attraction
Br
strain
E
2e
Scheme 6. Model for explaining regioselectivity in intramolecular
g
-hydroxypropyl
bromonium ion-opening directed by strain- (top) and charge effects (bottom;
E¼CO2Et; R¼H or CH3, R0¼H, CH3, or phenyl; R00¼H, CH3).
The experimental data summarized in this study show that
6-endo-regioselectivity in oxidative bromocyclization of prenyl-
type alkenols gradually improves, as steric encroachment in
proximity to the hydroxyl oxygen becomes smaller. We therefore
hypothesized that steric repulsion between methyl groups at
the bromonium-activated carbonecarbon double bond and
the hydroxyl oxygen disfavor tetrahydropyran formation from
1a, and supported this interpretation by a modeling study (Sec-
tion 2.4).
The lowest in energy isomer from the computed set of
compounds (Fig. 3), and from all possible dimethyltetrahydropyrans
(Supplementary data), is the stereoisomer of 2,6-dimethyltet-
rahydropyran Ia having both methyl groups attached equatorially.
Theory predicts for the other stereoisomers of I an increase of DG298.15
as the number of axial methyl groups grows (Ib and Ic), and the dis-
tance between methyl carbons becomes smaller (Fig. 4). Both obser-
vations are consistent with the fundamentals of conformational
analysis.40 The computed value of þ34.9 kJ molꢁ1 for Ic is larger than
twice the computed A-value for the methyl group in 2-
methyltetrahydropyran (14.9 kJ molꢁ1 for 298.15 K; experimental:38
12.0ꢂ0.8 kJ molꢁ1 at 188e173 K) on the same level of theory,
In cyclization of styrene-type alkenols, the higher substituted
carbon of the bromonium-activated
p-bond is preferentially
approached by the incoming oxygen nucleophile. In
a-styrene-type

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6973
R
R
6
R
R
=
O
O
O
O
O
2
I
Ia ( 0.0)
Ib (15.1)
Ic (34.9)
R
4
R
R
O
R
O
O
O
O
2
II
IIa (10.7)
IIb (22.2)
IIc (25.6)
IId (42.5)
R
R
5
=
R
O
O
O
O
O
3
R
III
IIIa (22.5)
IIIb (30.3)
IIIc (44.5)
Fig. 5. Correlation of a parameter describing puckering changes in dimethyltetrahy-
dropyrans Iaec, referenced toward tetrahydropyran (thp) on the basis of endocyclic
4
thp
IeIII
IV–VI
dihedral angles [S(Duij)¼S(j
u
j)ꢁS(j
u
j)] and
DG298.15-values (Fig. 3), whereby
ij
ij
O
O
O
thp
IeIII
2
3
S(ju
j)ꢁS(j
u
j) denotes summation of absolute values of endocyclic torsion angles
ij
ij
IeIII
between atoms i and j in tetrahydropyran (thp) minus S(j
u
j) for compounds IeIII
ij
IV (19.0)
V (30.9)
VI (34.5)
[for Iaec (C): Duij¼ꢁ0.80(
D
G298.15) deg mol kJꢁ1þ0.47ꢀ; R2¼0.986; for IIaec (B):
Duij¼ꢁ0.61(
Duij¼0.36(
D
G298.15
)
deg mol kJꢁ1þ6.82ꢀ, R2¼0.983; for for IIIaec (>):
Fig. 3. Structure formulas, indices, and calculated (B3LYP/6-31þG**//B3LYP/6-31þG**)
G298.15-values in kJ molꢁ1 (numbers in brackets) of dimethyltetrahydropyrans IeVI.
D
G298.15) deg mol kJꢁ1 ꢁ8.19ꢀ; R2¼0.904].
D
constructing the tetrahydropyran nucleus bears two methyl groups
in position 1, backside strain is less relevant for describing regio-
selectivity as long as no new geminally disubstituted endocyclic
carbon atom is formed in the course of the ring closure. If carbons 2
and 6 in tetrahydropyran both bear two methyl substituents, the
situation changes, since steric repulsion by the geminal methyl
groups at one carbon intensifies repulsive interactions between the
two axial substituents at C2 and C6 (cf. Section 2.4.2).42
2.4.2. On the thermochemistry of alkenol cyclization. To find out
whether methyl substitution has the potential to guide regiose-
lectivity in cyclization of tertiary prenyl type alkenols, we calculated
thermochemistry for the isomerization of prenyl-type alkenol VII
into 2,2-dimethyl-5-isopropyl tetrahydrofuran (VIII) and 2,2,6,6-
tetramethyltetrahydropyran (IX) (Scheme 7).43 Equilibrium struc-
tures of alkenol VII and tetrahydrofuran VIII (Supplementary data)
therebywere obtained fromusagedirected conformational searches
(force field) leading to minima, which served as input for density
functional theory calculations. The heterocyclic core of the mini-
mum structure of tetrahydrofuran VIII adopts a 3T4 twist confor-
mation, similar to the heterocyclic core found in the solid state
structure of cis-3d. The isopropyl substituent and one of the methyl
groups in this conformation are bound pseudoequatorially, and the
second methyl group pseudoaxially. The distances between the
secondary isopropyl carbon and the two methyl carbons at C2 are
larger than the distances between methyl carbons at positions 2 and
6 in tetrahydropyran IX. In a reversible reaction, B3LYP-theory thus
favors tetrahydrofuran formation from alkenol VII. MP2-theory
leads to the same result, although the driving force for tetrahydro-
furan formation is less pronounced (Supplementary data).
Fig. 4. Correlation between methyl carbon distances (dCꢁ,1C) and calculated
DG298.15-
ꢀ
ꢀ
values (cf. Fig. 3) of Iaec [C; dC,C¼ꢁ0.04(G298.15) A mol kJ þ4.84 A; R2¼0.978], IIaed
ꢀ
ꢁ1
ꢀ
[B; dC,C¼ꢁ0.05(
D
G298.15
)
A
mol kJꢁ1þ5.75 A; R2¼0.978], and IIIaec (>;
ꢀ
ꢀ
dC,C¼ꢁ0.08(G298.15) A mol kJ þ6.85 A; R2¼0.997).
thus pointing to steric interaction between axial methyl groups at C2
and C6 in cis-2,6-dimethyltetrahydropyran Ic. In the equilibrium
ꢀ
structure, axial methyl carbons of Ic are only 3.332 A apart, which is
41
ꢀ
less than the sum of 3.40 A for two carbon van der Waals-radii.
The carbonecarbon distance of substituents in diaxial isomers of cis-
ꢀ
2,4- and cis-3,5-dimethyltetrahydropyran is slightly larger (3.499 A for
ꢀ
IId, and 3.453 A for IIIc) but still expected to induce strain, because the
van der Waals radius of a methyl group is by the distance of the
carbonehydrogen bond larger than the corresponding radius of
a carbon atom. Since close contacts between methyl groups cause
steric repulsion, and the structural response to repulsion is strain, we
refer to the computed DG298.15-values as strain energy. Strain, partic-
To sum up, the results from the modeling study show that
substituents in axial positions 2 and 6 thermochemically disfavor
tetrahydropyran formation from tertiary prenyl-type alkenols on
the basis of strain effects, and direct alkenol cyclization toward
tetrahydrofuran formation.
ularly in compounds IeIII is evident from a flattening of tetrahy-
dropyran puckering (Fig. 5), and an offset of methyl substituents from
idealized axial positions to the periphery (see depictions of the mol-
ecules in the Supplementary data).
To quantify the effect of 1,3-dimethyl substitution on puckering,
we subtracted the sum of absolute values of the six endocyclic tor-
sion angles S(junijj) for compounds IeIII from the respective value
2.5. Functional group interconversion for synthesis of
aplysiapyranoid A
thp
S(ju
j) of the parent heterocycle tetrahydropyran (thp) (Fig. 5 and
ij
Supplementary data). A plot of the puckering parameter versus
computed relative Gibbs free energies is linear for IeIII, showing
that the effect of axial methyl substitution on flattening of the het-
erocyclic core is additive. The effect of substituents in positions 2,6
thereby is smaller than in positions 2,4 and largest in positions 3,5.
Geminal dimethyl substitution also imposes strain on the tet-
rahydropyran nucleus (see IVeVI, Fig. 3). If the alkenol used for
According to the strategy described in the introductory part, we
started from ethyl (5-bromo-2,2,6-trimethyl-6-phenyltetrahydro-
pyran)-3-carboxylate (2e) to prepare aplysiapyranoid A, and an epi-
mer with inverted configuration at C5 of the heterocyclic core. To
achieve this goal, the ethoxycarbonyl group at C5 had to be converted
into an axial bromosubstituent for aplysiapyranoid A, and an

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
4.40 Å
O
O
2.53 Å
VIII
OH
4.76 Å
–32.2 / –25.6
3.29 Å
2.50 Å
O
VII
0.0 / 0.0
O
2.50 Å
IX
4.54 Å
–24.2 / –11.5
Scheme 7. Calculated reaction energies (zero-point vibrational energy-corrected; numbers in italics) and free energy differences (bold arabic figures, D
G298 in kJ molꢁ1; B3LYP/6-
31þG**//B3LYP/6-31þG**) for isomerization of prenyl-type alkenol VII into tetrahydrofuran VIII and tetrahydropyran IX (left; see also the Supplementary data), and distances
between carbon atoms of substituents located next to the endocyclic oxygen atom in equilibrium structures of VIII and IX (right).
equatorial bromosubstituent for the 5-epimer. The carboxyl-bromine
exchange thereby was achieved by the BartoneHunsdiecker free
radical bromination.44,45 The more challenging part of the synthesis
related to transformations in the sterically encroached part of the
molecule. In our approach, oxidative degradation afforded a carboxyl
from the phenyl group.46 The carboxyl entity then was transformed in
a three step sequence, including a Takai-reaction,47 into a chlorovinyl
group. The synthesis described in the following sections focuses on
method development and expands information communicated pre-
viously7 to full detail.
mixture of cis/trans-isomers (Scheme 8). The new carbon-
ebromine bond in 8 is formed via homolytic substitution from
tetrahydropyranyl radical 9 and bromotrichloromethane. The latter
step provides dibromide 8 and a trichloromethyl radical, which
adds to the thiocarbonyl group of 7, leading to carbon dioxide, 2-
methylsulfanylpyridine (pySCCl3), and the next carbon radical 9
for propagating the chain reaction. In a stereochemical model, both
diastereotopic faces are similarly shielded by vicinal methyl groups
at C6, thus explaining the 50/50-stereoselectivity for dibromide
formation from reactive intermediate 9 (Scheme 9).
2.5.1. Decarboxylative bromination of 2,2,6,6-substituted tetrahy-
dropyrans. For synthesis of a Barton-type carbon radical precursor,
carboxylic acid ester 2e (76/24-mixture of 3,5-cis/3,5-trans-ste-
reoisomers) was saponified in aqueous dimethoxyethane (DME)
using lithium hydroxide as base, to afford carboxylic acid 6. For
analytical purposes, we recrystallized carboxylic acid 6 from
aqueous acetone, which furnished the pure 3,5-cis-isomer.48 For
synthetic purposes we directly used 76/24-mixture of stereoiso-
mers to prepare mixed anhydride 7 via condensation of crude acid
6 and N-hydroxypyridine-2(1H)-thione (PTOH) by diisopropyl
carbodiimide (DIC, Scheme 8).49
H
•
CH3
•CCl3
Ph
Br
O
H
( )-7
– pySCCl3
– CO2
H3C
CH3
( )-9
conformational equilibration
BrCCl3
50%
H
Ph
CH3
•
O
( )-8
BrCCl3
50%
H
Br
H3C
– •CCl3
CH3
Ph
Ph
O
O
50/50-mixture
LiOH
( )-9
of stereoisomers
3
5
3
5
EtO2C
HO2C
DME / H2O
20 °C
Br
Br
a
Scheme 9. Mechanistic and stereochemical model for dibromide formation from
mixed anhydride 7 (pySCCl3¼2-trichloromethylsulfanylpyridine).
H
H
a
( )-2e
( )-6 (80%)
The stereoisomers of 8 were separated by chromatography and
identified via NMR-spectroscopy. Double doublets for the protons
attached to C3 and C5 show cis-diaxial orientation of respective
hydrogens in cis-8. Vicinal coupling constants of 11e12 Hz and 5 Hz
point to axial orientation of 3-H and 5-H and thus equatorial ar-
rangement of the bromo- and the ester substituent. The same
protons in trans-8 resonate as double doublets composed of 7 Hz-
and 5 Hz-couplings, with the 7 Hz-coupling pointing to a con-
formationally flexible structure, as expected for a 3,5-trans-tetra-
hydropyran. The distances between carbon substituents at C2 and
C6 in crystal structures of cis-8 and trans-8 correlate with pre-
dictions made from theory in the gas phase (Fig. 6 and Scheme 7).
This information allows to estimate the strain imposed by 2,2,6,6-
substitution in 8, leading to a value of about 73 kJ molꢁ1, based
on 35 kJ molꢁ1 for the 2,6-diaxial substitution and 38 kJ molꢁ1 from
two geminal substitutions (cf. Figs. 3 and 4). These numbers imply
that both isomers of 8 are considerably strained.
PTOH / DIC
CH2Cl2 / 20 °C
Ph
Ph
O
O
BrCCl3/ h
S
O
5
3
3
5
Br
C6H6 / 20 °C
Br
Br
H
N O H
( )-7 a
( )-8
(52 % from 6)
b
cis:trans = 50:50
Scheme 8. Synthesis of dibromide 8 from ester 2e. a3,5-cis/3,5-trans¼76:24. bRatio of 3,5-
cis/3,5-trans isomer [PTOH¼N-hydroxypyridine-2(1H)-thione; DIC¼diisopropylcarbodi
imide; the atom numbering changes in going from 7 to 8 for reasons of functional group
hierarchy].
N-Acyloxypyridinethione 7 is a yellow photolabile compound
that decomposes, if photoexcited with tungsten light in a solution
of benzene and bromotrichloromethane, to afford 3,5-dibromo-
substituted tetrahydropyran 8 in 52% yield (from 6), as 50/50-
2.5.2. Synthesis of aplysiapyranoid A and its 5-epimer. For building
the chlorovinyl group of the aplysiapyranoids, we oxidatively

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6975
close to the values observed for dibromides cis-8 and trans-8. On
the basis of the information available from the modeling study and
the structural discussion on dibromides cis-8 and trans-8, we think
that steric crowding is the major reason for the difficulties expe-
rienced in chemical transformations of substituents in position 2 of
2,2,6,6-substituted tetrahydropyrans via an additioneelimination
sequence.
Fig. 6. Ellipsoid graphics (50% probability) of hexasubstituted tetrahydropyrans cis-8
and trans-8 in the solid state (top; 300 K; H-atoms were drawn as circles of an arbitrary
radius), and distances between carbon atoms of substituents attached in positions 2
and 6 (bottom).
Fig. 7. Ellipsoid graphics (50% probability) of hexasubstituted tetrahydropyrans cis-10
trans-10 in the solid state (top; 300 K; H-atoms were drawn as circles of an arbitrary
radius) and distances between carbon atoms of substituents in positions 2 and 6
(bottom).
degraded the phenyl into a carboxyl group at C2, by adding RuCl3
and NaIO4 to a mixture composed of tetrachloromethane, aceto-
nitrile, water,46 and one of the dibromides cis-8 and trans-8. For
unknown reasons, the reaction stopped at 80% conversion, re-
gardless of the quantity of RuCl3 and NaIO4 added in attempts to
achieve quantitative conversion. Since no other products apart
from the desired acid and starting material 8 were detected (TLC),
we treated this mixture with methanol and DIC to prepare O-
methyl carboxylates cis-10 and trans-10 (Table 3). From the work-
up, we recovered unspent cis-8 and trans-8. Alternative methods
for esterification, such as the p-toluenesulfonic acid-catalyzed
reaction with methanol or dimethoxypropane failed to provide
methyl ester 10.
In the final steps, O-methyl carboxylate trans-10 was reduced by
DIBAH to furnish the derived aldehyde, which was treated with CrCl2
47
and CHCl3 for building the chlorovinyl group of aplysiapyranoid A
(entry 1 in Table 4). The NMR-spectroscopic data of the target molecule
are consistent with the values reported for the natural product.1 By the
same reduction-chlorovinylation sequence, we prepared the 5-epimer
of the natural product from ester cis-10 (entry 2 in Table 4).
Table 4
Preparation of aplysiapyranoid A and 5-epi-A
Table 3
Cl
Preparation of methyl tetrahydropyranyl 2-carboxylates cis-10 and trans-10
1. DIBAH
CO2CH3
1. RuCl3 / NaIO4
2. DIC / CH3OH
Ph
CO2CH3
O
O
O
O
2. CrCl2 / CHCl3
R1
R2
R1
5
3
5
3
R1
R2
R1
R2
5
3
5
3
Br
Br
Br
Br
R2
( )-10
( )
( )-8
( )-10
aplysiapyranoid
R1
R2
Aplysiapyranoid/% (two steps)
Entry
(ꢂ)-8
Conv./%
R1
R2
(ꢂ)-10/% (two steps)
Entry
10
1
2
cis-8a
80
80
H
Br
Br
H
cis-10a: 36
1
2
trans-10
cis-10
Br
H
H
Br
A: 32
5-epi-A: 21
trans-8a
trans-10a: 34
a
Stereodescriptor refers to relative configuration of substituents at carbons 3 and 5.
The proton-NMR-spectrum of cis-10 shows double doublets at
3.98 and 4.56 ppm (J¼12e13 Hz and 5 Hz) being in line with axial
positioning of 3-H and 5-H. The same protons have triplet fine
structure for 3-H (J¼4 Hz) and a double doublet for 5-H (J¼13 and
4 Hz), pointing to equatorial arrangement of the former and axial of
the latter in CDCl3-solution of trans-10. Steric crowding in prox-
imity of the endocyclic oxygen in cis-10 and trans-10 is again evi-
dent from the crystal structures of the two methyl esters (Fig. 7).
The distances between carbon atoms attached to C2 and C6 are
3. Concluding remarks
A proper set of substituents to control 6-endo selectivity for
synthesis of 2,2,6,6-substituted tetrahydropyrans via alkenol bro-
mocyclization is the combination of an aryl and a methyl group. The
aryl group adds a polar component to the ring closure, which is not
available from methyl substitution. Methyl substitution moreover
induces strain, as the bromonium-activated
droxyl oxygen of a tertiary prenyl-type alkenol approach for
p-bond and the hy-

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6976
intramolecular carboneoxygen bond formation, thus favoring tet-
rahydrofuran formation from the 5-exo-reaction.
(20-hydroxyprop-20-yl)-5-methyl]-4-hexenoate (1a). Eluent used for
chromatographic purification: petroleum ether/tert-butyl methyl
ether¼10:1 (v/v). Ethyl rel-(3R,5S)-(5-bromo-2,2,6,6-tetramethylte-
trahydropyran)-3-carboxylate cis-(2a). Yield: 42 mg (14%), colorless
oil. Rf¼0.63 in petroleum ether/tert-butyl methyl ether¼10:1 (v/v).
Anal. Calcd for C12H21O3Br (293.20): C, 49.16; H, 7.22; found: C, 49.31;
H, 7.13. dH (600 MHz; CDCl3) 1.26 (3H, t, J 7.1 Hz, CO2CH2CH3),1.26 (3H,
s, CH3),1.32 (6H, s, CH3),1.43 (3H, s, CH3), 2.25 (1H, dt, Jd 13.3, Jt 3.8 Hz,
4-H), 2.54 (1H, q, J 13.3 Hz, 4-H), 2.63 (1H, dd, J 13.3, 3.8 Hz, 3-H), 3.89
(1H, dd, J 13.3, 3.8 Hz, 5-H), 4.13 (2H, 2ꢃ dq, Jd 10.8, Jq 7.1 Hz,
CO2CH2CH3). dC (150 MHz; CDCl3) 14.1 (CO2CH2CH3), 23.0 (CH3), 24.1
(CH3), 31.0 (CH3 or C4), 31.1 (CH3 or C4), 32.0 (CH3), 54.1 (C3), 56.3
(C5), 60.7 (CO2CH2CH3), 73.6 (C2), 75.5 (C6), 171.3 (CO2CH2CH3).
NOESY (cross signals) 3-H45-H, 3-H4(2-CH3)a/5-H4(6-CH3)a.
The concept used in this study to prepare organobromines from
bromide, tert-butyl hydroperoxide, and an unsaturated hydrocarbon
generally is referred to as oxidative bromination. Oxidative bromi-
nation is mechanistically related to bromide oxidation by hydrogen
peroxide, catalyzed by marine bromoperoxidases in nature.50 Vana-
dium complexes V(O)Ln(OEt) therefore can be regarded as functional
bromoperoxidase mimics, and tert-butyl hydroperoxide the bio-
mimetic electron acceptor. The results summarized in this work
show, that functional bromoperoxidase chemistry has reached a no-
table degree of maturity. Modern oxidative bromination, forexample,
uses a buffer composed of sodium bromide and b-bromocinnamic
acid to liberate protons and bromide under pH-neutral conditions,
and is feasible in solutions of propylene carbonate as nontoxic
solvent.
Ethyl
rel-(3R,5R)-(5-bromo-2,2,6,6-tetramethyltetrahydropyran)-3-
carboxylate (ꢂ)-trans-(2a) and ethyl [5-(20-bromoprop-20-yl)-2,2-
dimethyltetrahydrofuran]-3-carboxylate (3a). Yield: 8 mg (3%) rel-
(3R,5R)-2a in same column fraction with 118 mg (40%), 70/30-
mixture of cis/trans-isomers of 3a, colorless oil. Rf¼0.57 in petro-
leum ether/tert-butyl methyl ether¼10:1 (v/v). Anal. Calcd for
C12H21O3Br (293.20): C, 49.16; H, 7.22; found: C, 49.45; H, 7.19. rel-
(3R,5R)-2a [(ꢂ)-trans-2a]. dH (600 MHz; CDCl3) 1.22 (3H, s, CH3), 1.27
(3H, t, J 7.0 Hz, CO2CH2CH3), 1.35 (3H, s, CH3), 1.42 (6H, s, CH3), 2.23
(1H, ddd, J 15.1, 5.5, 4.2 Hz, 4-H), 2.53e2.61 (1H, m, 4-H), 3.01 (1H, dd, J
10.2, 4.1 Hz, 3-H), 4.10e4.22 (2H, m, CO2CH2CH3), 4.43 (1H, dd, J 5.6,
3.3 Hz, 5-H). dC (150 MHz; CDCl3) 14.2 (CO2CH2CH3), 26.1 (CH3), 27.8
(CH3), 29.3 (CH3 or C4), 29.6 (CH3 or C4), 31.4 (CH3), 46.9 (C3), 58.1
(C5), 60.6 (CO2CH2CH3), 72.9 (C2 or C6), 73.7 (C2 or C6), 172.9
(CO2CH2CH3). rel-(3R,5R)-3a [(ꢂ)-cis-3a]. dH (600 MHz; CDCl3) 1.14
(3H, s, CH3),1.27 (3H, t, J 7.1 Hz, CO2CH2CH3),1.44 (3H, s, CH3),1.74 (3H,
s, 3H),1.75 (3H, s, CH3), 2.16 (1H, ddd, J 12.5, 7.0, 5.1 Hz, 4-H), 2.33 (1H,
ddd, J 12.5, J 11.9, 11.0 Hz, 4-H), 2.93 (1H, dd, J 11.9, 7.0 Hz, 3-H), 3.97
(1H, dd, J 11.0, 5.1 Hz, 5-H), 4.12e4.18 (2H, m, CO2CH2CH3). dC
(150 MHz; CDCl3) 14.2 (CO2CH2CH3), 25.2 (CH3), 29.5 (CH3), 29.3
(CH3), 31.0 (CH3), 31.9 (C4), 54.1 (C3), 60.7 (CO2CH2CH3), 66.4 (C20),
82.4 (C2), 85.0 (C5), 171.5 (CO2CH2CH3). NOESY (cross signals) 3-
H45-H. rel-(3R,5S)-3a [(ꢂ)-trans-3a]. dH (600 MHz; CDCl3) 1.12
(3H, s, CH3),1.26 (3H, t, J 7.1 Hz, CO2CH2CH3),1.47 (3H, s, CH3),1.69 (3H,
s, CH3),1.70 (3H, s, CH3), 2.17(1H, ddd, J13.7, 9.4, 4.8 Hz, 4-H), 2.57 (1H,
ddd, J 13.7, 9.4, 8.8 Hz, 4-H), 2.88 (1H, t, J 9.4 Hz, 3-H), 3.94 (1H, dd, J
8.8, 4.8 Hz, 5-H), 4.12e4.18 (2H, m, CO2CH2CH3). dC (150 MHz; CDCl3)
14.2 (CO2CH2CH3), 22.8 (CH3), 28.2 (CH3), 29.3 (CH3), 31.0 (CH3), 31.7
(C4), 53.1 (C3), 60.6 (CO2CH2CH3), 68.9 (C20), 83.1 (C2), 83.7 (C5),171.8
(CO2CH2CH3). NOESY (cross signals) 3-H4(2-CH3)a/5-H4(2-CH3)b.
The synthetic potential of oxidative bromination for synthesis of
natural products is evident from the third part of the project dealing
with synthesis of the marine natural product aplysiapyranoid A. The
strategy to interconvert functional groups in a sequence of homolytic
and polar reactions, adds a component to synthesis of the aplysia-
pyranoids which is, not available from other concepts developed so
far. The strength of the homolytic substitution in this approach arises
from the efficiency of carbonebromine bond formation at a sterically
shielded secondary neopentyl-type carbon at tetrahydropyran. The
yields associated with chlorovinyl group formation from the phenyl
group, on the other hand, remained below expectation. With the
wisdom of hindsight we relate the reluctance of reagents to add to
substituents at C2 to strain that additionally builds up as the con-
figuration of the attacked carbon changes from planar to tetrahedral.
The increase in steric demand occurs in a severely encroached region
of the 2,2,6,6-substituted tetrahydropyran and therefore is expected
to require notable activation energy in order to effectively occur.
To continue the project, we consider the aplysiapyranoids C and
D1 as attractive targets. The latter compounds have a chlorosub-
stituent bound next to the vinyl group and synthesis of the prod-
ucts according to the outlined strategy requires development of an
efficient oxidation/chlorocyclization cascade for constructing tet-
rahydropyran rings. A survey of the literature shows that chlor-
ocyclization is just beginning to evolve.51,52 To develop a practical
method for in situ chlorine generation from transition metal-
catalyzed oxidation, therefore is a rewarding objective to pursue.
4. Experimental
4.1. General
4.2.3. Bromocyclization of ethyl 2-(10-hydroxyeth-10-yl)-5-methyl-4-
hexenoate (1b). Starting material: 200 mg (1.0 mmol) of ethyl 2-(10-
hydroxyeth-10-yl)-5-methyl-4-hexenoate (1b). Eluent used for
chromatographic purification: CH2Cl2. Yield: 156 mg (0.56 mmol/
56%) colorless liquid. Rf¼0.51e0.35 (CH2Cl2) for a 73/27-mixture of
2b/3b, as determined on the basis of 1H NMR-integral ratios of
methyl substituents (For analytical data of the mixture of 2b and 3b,
see the Supplementary data). From this mixture, rel-(2R,3R,5S)-5-
For general laboratory practice and instrumentation see Ref. 12
and the Supplementary data.
4.2. Oxovanadium-catalyzed oxidation of bromide
4.2.1. General method. To a solution of vanadium(V)-catalyst V(O)
Ln(OEt) (5.7 mg, 0.01 mmol; for structure formula refer to Section 2.2)
and NaBr(10.3 mg, 0.10mmol)inpropylenecarbonate(10 mL)at30ꢀC
was added a solution of 3-bromo-3-phenylpropionic acid (286 mg,
bromo-3-ethoxycarbonyl-2,6,6-trimethyltetrahydropyran
rel-
(2R,3R,5S)-(2b) was separated via chromatography [10/1-diethyl
ether/pentane (v/v) as eluent]. Colorless oil, Rf¼0.28 for diethyl
ether/pentane¼10:1. Anal. Calcd for C12H21O3Br (279.17): C, 47.33;
H, 6.86; found: C, 47.34; H, 6.73. dH (600 MHz; CDCl3) 1.13 (3H, d, J
6.1 Hz, CH3), 1.26 (3H, t, J 7.2 Hz, CO2CH2CH3), 1.36 (3H, s, CH3), 1.42
(3H, s, CH3), 2.33e2.38 (3H, m, 3-H, 4-H), 3.86e3.94 (2H, m, 2-H, 5-
H), 4.14 (2H, q, J 7.2 Hz, CO2CH2CH3). dC (150 MHz; CDCl3) 14.2
(CO2CH2CH3), 18.0 (CH3), 20.2 (CH3), 29.2 (CH3), 34.5 (C4), 51.7 (C3),
54.9 (C5), 60.7 (CO2CH2CH3), 67.1 (C2), 75.5 (C6),171.9 (CO2CH2CH3).
1.25 mmol), alkenol 1 (1.00 mmol), and TBHP [4.1 M in toluene, 390mL,
1.25 mmol] in propylene carbonate (3 mL) via syringe pump
(0.005 mL/min). The reaction mixture was stirred at 30 ꢀC for 24 h. The
yellowish solution was extracted with cyclohexane (4ꢃ20 mL).
Combined organic extracts were washed with brine (2ꢃ40 mL), dried
(MgSO4), and concentrated under reduced pressure to leave a residue,
which was purified by column chromatography (SiO2).
4.2.2. Bromocyclization of ethyl 2-(20-hydroxyprop-20-yl)-5-methyl-
4.2.4. Bromocyclization of ethyl 2-hydroxymethyl-5-methyl-4-
4-hexenoate (1a). Starting material: 215 mg (1.0 mmol) of ethyl [2-
hexenoate (1c). Starting material: 190 mg (1.0 mmol) of ethyl

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O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6977
2-hydroxymethyl-5-methyl-4-hexenoate (1c). Eluent used for chro-
matographic purification: diethyl ether/pentane 1:5 (v/v). Ethyl
rel-(3R,5S)-(5-bromo-6,6-dimethyltetrahydropyran)-3-carboxylate
(ꢂ)-cis-(2c). Yield: 98 mg (37%), colorless liquid. Rf¼0.36 for diethyl
ether/pentane 1:5 (v/v). Anal. Calcd for C10H17BrO3 (265.14): C,
45.30; H, 6.46; found: C, 45.17; H, 6.32. dH (600 MHz; CDCl3) 1.25 (3H,
t, J 7.2 Hz, CO2CH2CH3), 1.37 (3H, s, CH3), 1.39 (3H, s, CH3), 2.26 (1H, q,
J 13.0 Hz, 4-H), 2.44e2.51 (1H, m, 4-H), 2.76 (1H, tt, J 12.1, 4.7 Hz, 3-
H), 3.72 (1H, t, J 11.8 Hz, 2-H), 3.86e3.94 (2H, m, 2-H, 4-H), 4.13 (2H,
q, J 7.2 Hz, CO2CH2CH3). dC (150 MHz; CDCl3) 14.1 (CO2CH2CH3), 17.2
(CH3), 28.9 (CH3), 33.7 (C4), 44.2 (C3), 55.0 (C5), 60.9 (CO2CH2CH3),
61.8 (C2), 75.2 (C6), 171.0 (CO2CH2CH3). NOESY (cross signals) 3-
H45-H. Ethyl rel-(3R,5R)-(5-bromo-6,6-dimethyltetrahydropyran)-
3-carboxylate (ꢂ)-trans-(2c) and ethyl 5-(20-bromoprop-20-yl)-tetra-
hydrofuran]-3-carboxylate (3c). Yield: 47 mg (18%) of rel-(3R,5R)-2c
and 16 mg (6%) 50/50-mixture of cis/trans-isomers of 3c, colorless
oil. Rf¼0.29 for diethyl ether/pentane 1:5 (v/v). Anal. Calcd for
C10H17BrO3 (265.14): C, 45.30; H, 6.46; found: C, 45.17; H, 6.32. rel-
(3R,5R)-2c [(ꢂ)-trans-2c]. dH (400 MHz; CDCl3) 1.27 (3H, t, J 7.2 Hz,
CO2CH2CH3), 1.36 (3H, s, CH3), 1.38 (3H, s, CH3), 2.26 (1H, ddd, J 14.0,
9.3, 4.9 Hz, 4-H), 2.60 (1H, dt, Jd 14.2, Jt 4.8 Hz, 4-H), 2.74e2.82 (1H,
m, 3-H), 3.88e3.95 (1H, m, 2-H), 3.99e4.05 (1H, m, 2-H), 4.14e4.22
(2H, m, CO2CH2CH3), 4.22e4.28 (1H, m, 5-H). dC (100 MHz; CDCl3)
14.2 (CO2CH2CH3), 22.0 (CH3), 26.5 (CH3), 31.9 (C4), 40.7 (C3), 55.3
(C5), 61.0 (CO2CH2CH3), 61.8 (C2), 74.7 (C6), 172.5 (CO2CH2CH3). rel-
(3R,5R)-3c [(ꢂ)-cis-3c]: dH (400 MHz; CDCl3) 1.27 (3H, t, J 6.9 Hz,
CO2CH2CH3), 1.73 (3H, s, CH3), 1.76 (3H, s, CH3), 2.18e2.27 (1H, m, 4-
H), 2.29e2.38 (1H, m, 4-H), 3.13e3.23 (1H, m, 3-H), 3.88e3.95 (1H,
m, 5-H), 3.98e4.13 (2H, m, 2-H), 4.17 (2H, q, J 6.9 Hz, CO2CH2CH3). dC
(100 MHz; CDCl3) 14.0 (CO2CH2CH3), 29.4 (CH3), 30.8 (CH3), 32.5
(C4), 44.5 (C3), 61.0 (CO2CH2CH3), 66.9 (C6), 70.6 (C2), 87.2 (C20),
172.5 (CO2CH2CH3). NOESY (cross signals) 3-H45-H. rel-(3R,5S)-3c
[(ꢂ)-trans-3c]: dH (400 MHz; CDCl3) 1.27 (3H, t, J 7.3 Hz, CO2CH2CH3),
1.70 (3H, s, CH3), 1.76 (3H, s, CH3), 2.14 (1H, ddd, J 13.1, 9.0, 7.8 Hz, 4-
H), 2.38 (1H, ddd, J 12.9, 7.6, 4.8 Hz, 4-H), 3.12e3.22 (1H, m, 3-H),
3.87 (1H, t, J 7.5 Hz, 5-H), 3.98 (1H, dd, J 8.7, 6.0 Hz, 2-H), 4.17 (2H, q, J
7.2 Hz, CO2CH2CH3), 4.17e4.23 (1H, m, 2-H). dC (100 MHz; CDCl3) 14.2
(CO2CH2CH3), 30.2 (CH3), 30.8 (CH3), 32.30 (C4), 44.3 (C3), 61.0
(CO2CH2CH3), 68.2 (C6), 71.1 (C2), 86.4 (C20), 173.4 (CO2CH2CH3).
NOESY (cross signals) 3-H4(4-H)a/5-H4(4-H)b.
m), 7.43 (2H, d, J 7.2 Hz). dC (150 MHz; CDCl3) 14.2 (CO2CH2CH3), 24.4
(CH3), 25.2 (CH3), 30.5 (CH3), 39.0 (C4), 53.5 (C3), 60.7 (CO2CH2CH3),
63.4 (C10), 83.0 (C2), 84.0 (C5), 127.9, 128.1, 129.5, 138.6, 171.2
(CO2CH2CH3). NOESY (cross signals) 3-H45-CH3.
4.2.6. Bromocyclization of ethyl (E)-2-(20-hydroxyprop-20-yl)-5-
phenyl-4-hexenoate (1e). Starting material: 276 mg (1.0 mmol) of
ethyl (E)-2-(20-hydroxyprop-20-yl)-5-phenyl-4-hexenoate (1e). Elu-
ent used for chromatographic purification: ethyl acetate/
pentane¼1:10 (v/v). Ethyl (5-bromo-2,2,6-trimethyl-6-phenyl-
tetrahydropyran)-3-carboxylate(2e). Yield:167 mg(47%), colorlessoil,
76/24-mixture of cis/trans isomers. Rf¼0.37 for ethyl acetate/
pentane¼1:10 (v/v). Anal. Calcd for C17H23BrO3 (355.27): C, 57.47; H,
6.53; found: C, 57.37; H, 6.44. rel-(3R,5S,6R)-2e [(ꢂ)-cis-2e]. dH
(400 MHz; CDCl3) 1.29 (3H, t, J 7.2 Hz, CO2CH2CH3), 1.41 (3H, s, CH3),
1.49 (3H, s, CH3),1.89 (3H, s, CH3), 2.39 (1H, dt, J 13.5, 3.6 Hz, 4-H), 2.71
(1H, q, J 13.1 Hz, 4-H), 2.80e2.88 (1H, m, 3-H), 4.04 (1H, dd, J 12.8,
3.9 Hz, 5-H), 4.13e4.23 (2H, m, CO2CH2CH3), 7.21e7.40 (3H, m), 7.60
(2H, d, J 7.8 Hz). dC (100 MHz; CDCl3) 14.2 (CO2CH2CH3), 20.7 (CH3),
24.7 (CH3), 31.6 (C4), 32.1 (CH3), 54.0 (C3), 57.2 (C5), 60.8
(CO2CH2CH3), 74.3 (C2), 78.5 (C6), 126.1, 127.5, 127.9, 145.6, 171.1
(CO2CH2CH3). NOESY (cross signals) 3-H45-H. rel-(3S,5S,6R)-2e
[(ꢂ)-trans-2e]. dH (400 MHz; CDCl3) 0.74 (3H, s, CH3), 1.24 (3H, t, J
7.2 Hz, CO2CH2CH3),1.50 (3H, s, CH3),1.63 (3H, s, CH3), 2.33 (1H, m, 4-
H), 2.59 (1H, ddd, J 15.0,10.7, 3.1 Hz, 4-H), 3.18 (1H, dd, J 10.6, 4.1 Hz, 3-
H), 4.07e4.23 (2H, m, CO2CH2CH3), 5.27 (1H, dd, J 5.4, 3.1 Hz, 5-H),
7.21e7.38 (3H, m), 7.51 (2H, d, J 7.5 Hz). dC (100 MHz; CDCl3) 14.1
(CO2CH2CH3), 25.6 (CH3), 30.0 (C4), 31.5 (CH3), 34.0 (CH3), 47.2 (C3),
56.8 (C5), 60.6 (CO2CH2CH3), 74.5 (C2), 76.4 (C6), 126.3, 127.2, 128.0,
144.8, 172.7 (CO2CH2CH3).
4.2.7. Bromocyclization of ethyl (E)-2-(20-hydroxyprop-20-yl)-5-(p-
methoxyphenyl)-4-hexenoate (1f). Starting material: 307 mg of
1.0 mmol ethyl (E)-2-(20-hydroxyprop-20-yl)-5-(p-methoxyphenyl)-
4-hexenoate (1f). Eluent used for chromatographic purification:
dichloromethane/pentane¼4/1 (v/v). Ethyl (5-bromo-2,2,6-trimethyl-
6-(p-methoxyphenyl)tetrahydropyran)-3-carboxylate (2f). Yield:
182 mg (47%), yellowish liquid, 46/54-mixture of isomers cis/trans-
isomers. Rf¼0.18 for dichloromethane/pentane¼4/1 (v/v). Anal.
Calcd for C18H25BrO4 (385.29): C, 56.11; H, 6.54; found: C, 55.95; H,
6.35. rel-(3R,5S,6R)-2f [(ꢂ)-cis-2f]. dH (600 MHz; CDCl3) 1.29 (3H, t, J
7.2 Hz, CO2CH2CH3), 1.39 (3H, s, CH3), 1.47 (3H, s, CH3), 1.86 (3H, s,
CH3), 2.38 (1H, dt, Jd 13.8, Jt 3.7 Hz, 4-H), 2.69 (1H, q, J 13.1, 4-H), 2.83
(1H, dd, J 13.1, 3.3 Hz, 3-H), 3.80 (3H, s, CH3), 4.03 (1H, dd, J 12.9,
4.0 Hz, 5-H), 4.06e4.22 (2H, m, CO2CH2CH3), 6.86 (2H, d, J 8.7 Hz),
7.51 (2H, d, J 8.7 Hz). dC (150 MHz; CDCl3) 14.2 (CO2CH2CH3), 20.7 (CH3),
24.7 (CH3), 31.6 (C4), 32.1 (CH3), 54.1 (C3), 55.2 (CH3), 57.6 (C5), 60.8
(CO2CH2CH3), 74.3 (C2), 78.3 (C6), 113.2, 127.3, 137.9, 158.8, 171.2
(CO2CH2CH3). NOESY (cross signals) 3-H45-H. rel-(3S,5S,6R)-2f
[(ꢂ)-trans-2f]. dH (600 MHz; CDCl3)0.76(3H, s, CH3),1.24 (3H, t, J7.2 Hz,
CO2CH2CH3),1.48 (3H, s, CH3),1.61 (3H, s, CH3), 2.32 (1H, ddd, J 14.9, 5.6,
4.3 Hz, 4-H), 2.58 (1H, ddd, J 14.8, 10.2, 3.1 Hz, 4-H), 3.14 (1H, dd, J 10.2,
3.8 Hz, 3-H), 3.80 (3H, s, CH3), 4.06e4.23 (2H, m, CO2CH2CH3), 5.23 (1H,
dd, J 5.8, 3.2 Hz, 5-H), 6.84 (2H, d, J 8.7 Hz), 7.41 (2H, d, J 9.0 Hz). dC
(150 MHz; CDCl3) 14.1 (CO2CH2CH3), 25.7 (CH3), 30.1 (C4), 31.4 (CH3),
33.5 (CH3), 47.3 (C3), 55.2 (CH3), 57.0 (C5), 60.6 (CO2CH2CH3), 74.3 (C2),
76.2 (C6), 113.1, 127.5, 136.9, 158.6, 172.8 (CO2CH2CH3).
4.2.5. Bromocyclization of ethyl (E)-2-(20-hydroxyprop-20-yl)-4-
methyl-5-phenyl-4-pentenoate (1d). Starting material: 307 mg
(1.0 mmol) of ethyl (E)-2-(2-hydroxyprop-2-yl)-4-methyl-5-phenyl-
4-pentenoate (1d). Eluent used for chromatographic purification:
diethyl ether/pentane¼1/5 (v/v). Ethyl [5-(10-bromo-10-phenyl-
methyl)-2,2,5-trimethyltetrahydrofuran]-3-carboxylate (3d). Yield:
204 mg (0.574 mmol/57%), colorless liquid, 93/7-mixture of cis/trans
isomers. Rf¼0.34 for diethyl ether/pentane¼1/5 (v/v). Anal. Calcd for
C17H23BrO3 (355.27): C, 57.47; H, 6.53; found: C, 57.31; H, 6.27. rel-
(3R,5R,10S)-3d [(ꢂ)-cis-3d]. Colorless solid, mp¼65 ꢀC. dH (600 MHz;
CDCl3) 1.13 (3H, s, CH3), 1.21e1.26 (3H, m, CO2CH2CH3), 1.49 (3H, s,
CH3),1.50 (3H, s, CH3), 2.43e2.49 (1H, m, 4-H), 2.59e2.72 (2H, m, 3-H,
4-H), 4.06e4.14 (2H, m, CO2CH2CH3), 4.85 (1H, s,10-H), 7.24e7.33 (3H,
m), 7.45e7.52 (2H, m). dC (150 MHz; CDCl3) 14.2 (CO2CH2CH3), 24.8
(CH3), 28.0 (CH3), 28.6 (CH3), 38.6 (C4), 53.8 (C3), 60.7 (CO2CH2CH3),
63.0 (C10), 83.2 (C2), 84.0 (C5), 128.3, 129.7, 129.8, 138.3, 171.1
(CO2CH2CH3). X-ray crystallography: C17H23BrO3 (355.26),
ꢀ
ꢀ
T¼150(2) K,
l
¼0.71073 A, monoclinic, P21/n, a¼14.8542(4) A,
4.3. 5-Bromo-2,2,6-trimethyl-6-phenyltetrahydropyran-3-
carboxylic acid ( )-(6)
ꢀ
ꢀ
b¼7.2765(2) A, c¼15.6643(4) A,
b
¼103.562(3)ꢀ, Z¼4,
m
¼2.505 mmꢁ1
,
completeness 99.8%, (2
R indices [I>2
q
¼60.00ꢀ), goodness-of-fit on F2¼0.842, final
s
(I)]: R1¼0.0293, wR2¼0.0484. rel-(3R,5S,10R)-3d
To a solution of ethyl (5-bromo-2,2,6-trimethyl-6-phenyltet-
rahydropyran)-3-carboxylate (2e) [3.00 g, 8.79 mmol, 76/24-
mixture of rel-(3R,5S,6R)/rel-(3S,5S,6R) isomers] in dimethoxy-
ethane (120 mL) was added a solution of LiOHꢃH2O (5.94 g,
142 mmol) in H2O (180 mL). The reaction mixture was stirred for
[(ꢂ)-trans-3d]. dH (600 MHz; CDCl3) 1.20 (3H, s, CH3),1.23 (3H, s, CH3),
1.28 (3H, t, J 7.2 Hz, CO2CH2CH3), 1.43 (3H, s, CH3), 2.11 (1H, dd, J 12.8,
6.9 Hz, 4-H), 2.83 (1H, t, J 12.7 Hz, 4-H), 3.06 (1H, dd, J 12.5, 6.9 Hz, 3-
H), 4.14e4.24 (2H, m, CO2CH2CH3), 5.00 (1H, s, 10-H), 7.25e7.32 (3H,

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48e72 h at 20 ꢀC until the starting material was completely con-
sumed (TLC). The solution was acidified (pH 2) with aqueous HCl
[37%, (w/w)] and extracted with CH2Cl2 (640 mL, 3ꢃ500 mL).
Combined organic extractions were dried (MgSO4) and concen-
trated under reduced pressure. The residue was dried at 20 ꢀC/
5ꢃ10ꢁ2 mbar to provide carboxylic acid (ꢂ)-(6). Yield: 2.67 g (93%),
7.0, 4.9 Hz, 5-H), 5.03 (1H, dd, J 6.7, 4.6 Hz, 3-H), 7.24e7.38 (m, 3H),
7.52e7.57 (m, 2H). dC (63 MHz; CDCl3) 27.8 (CH3), 29.2 (CH3), 30.5
(CH3), 38.0 (C4), 56.4 (C5), 56.8 (C3), 76.2 (C6), 77.2 (C2), 126.3, 127.5,
128.0, 144.6. X-ray crystallography: crystals suitable for X-ray dif-
fraction separated from a solution of CDCl3 on standing at 20 ꢀC;
ꢀ
C14H18Br2O (362.10), T¼299(2) K,
l
¼0.71073 A, monoclinic, C2/c,
¼93.01(2)ꢀ, Z¼8,
ꢀ
ꢀ
ꢀ
tan solid, 76/24-mixture of rel-(3R,5S,6R)/rel-(3S,5S,6R) isomers.
n
a¼24.042(5) A, b¼7.519(1) A, c¼15.951(3) A,
b
(NaCl) 3463 cmꢁ1, 3046, 2912, 2361, 1689, 1299. Recrystallization of
the sample from H2O/acetone furnishes (ꢂ)-cis-6. Colorless crystals,
mp 147e148 ꢀC (dec). rel-(3R,5S,6R)-6 [(ꢂ)-cis-6]. dH (250 MHz;
CDCl3) 1.46 (3H, s, CH3), 1.53 (3H, s, CH3), 1.89 (3H, s, CH3), 2.44 (1H,
dt, Jd 13.1, Jt 3.8 Hz, 4-H), 2.70 (1H, q, J 13.1 Hz, 4-H), 2.89 (1H, dd, J
13.1, 3.8 Hz, 3-H), 4.04 (1H, dd, J 13.1, 3.8 Hz, 5-H), 7.26e7.36 (3H, m),
7.59e7.62 (2H, m). dC (63 MHz; CDCl3) 20.7 (CH3), 24.6 (CH3), 31.4
(C4), 32.0 (CH3), 53.7 (C3), 56.7 (C5), 74.2 (C2), 78.5 (C6),125.1,127.6,
128.0, 145.5, 176.6 (CO2H). The spectroscopic properties were con-
sistent with those specified above. Anal. Calcd for C15H19BrO3
(327.22): C, 55.06; H, 5.85; found: C, 54.95; H, 5.90. rel-(3S,5S,6R)-6
[(ꢂ)-trans-6]. dH (250 MHz; CDCl3) 1.11 (3H, s, CH3),1.48 (3H, s, CH3),
1.62 (3H, s, CH3), 2.29e2.36 (1H, m, 4-H), 2.41e2.48 (1H, m, 4-H),
2.81 (1H, t, J 6.3 Hz, 3-H), 4.02 (1H, dd, J 7.1, 3.8 Hz, 5-H), 7.26e7.36
(m, 3H), 7.64e7.67 (m, 2H). dC (63 MHz; CDCl3) 27.3 (CH3), 28.2
(CH3), 28.3 (C4), 28.6 (CH3), 47.4 (C3), 56.7 (C5), 73.7 (C2), 77.2 (C6),
126.0, 126.9, 127.9, 144.7, 175.8 (CO2H).
m
¼5.613 mmꢁ1, completeness 99.9%, (2
q
¼51.92ꢀ), goodness-of-fit on
F2¼0.997, final R indices [I>2
(I)]: R1¼0.0432, wR2¼0.1074.
s
4.5. Methyl tetrahydropyrancarboxylates from
phenyltetrahydropyrans
4.5.1. General method. Diasterically pure 3,5-dibromo-2,6,6-
trimethyl-2-phenyltetrahydropyran (ꢂ)-(7) (362 mg, 1.0 mmol;
Section 4.4) was added to a two-phase system composed of CCl4
(4 mL), CH3CN (4 mL) and H2O (6 mL). NaIO4 (3.41 g, 15.0 mmol) and
RuCl3∙H2O (6 mg, 3 mol %) were added to afford a dark suspension
that was well agitated at 20 ꢀC. Additional NaIO4 (213 mg, 1.0 mmol)
and RuCl3ꢃH2O (0.5 mg) were added in two portions in 24 h in-
tervals. After a total reaction time of 72 h, CH2Cl2 (5 mL), and H2O
(2 mL) were added. The colorless precipitate formed was filtered off
using a small pad of cotton. The solids were washed with CH2Cl2
(10 mL). Combined filtrate and washings were poured into separa-
tion funnel. The organic phase was separated. The aqueous phase
was extracted with CH2Cl2 (3ꢃ6 mL). The organic phase and com-
bined organic washings were dried (MgSO4) and concentrated un-
der reduced pressure to furnish 302 mg of a dark oil that
predominantly consisted of the corresponding 3,5-dibromo-
2,6,6-trimethyltetrahydropyran-2-carboxylic (Supplementary data).
This product was dissolved in dry CH2Cl2 (2 mL) and MeOH
(25.7 mg, 0.80 mmol) and treated in a dropwise manner at 0 ꢀC over
a period of 20 min with a solution of diisopropyl carbodiimide
(101 mg, 0.80 mmol) in dry CH2Cl2 (2 mL). The reaction mixture was
stirred for 30 min at 0 ꢀC and 24 h at 20 ꢀC. The solvent was removed
under reduced pressure to leave an oil that was purified by chro-
matography [petroleum ether/tert-butyl methyl ether¼10:1 (v/v)].
4.4. 3,5-Dibromo-2,6,6-trimethyl-2-phenyltetrahydropyran
( )-(8)
An amber colored flask was charged with a solution of 5-bromo-
2,2,6-trimethyl-6-phenyltetrahydropyran-3-carboxylic acid (ꢂ)-(6)
[1.82 g, 5.56 mmol, 76/24-mixture of rel-(3R,5S,6R)/rel-(3S,5S,6R)
isomers] and N-hydroxypyridine-2(1H)-thione (PTOH, 742 mg,
5.82 mmol) in dry CH2Cl2 (30 mL) and treated at 0 ꢀC in a dropwise
manner over a period of 30 min with a solution of diisopropyl car-
bodiimide (DIC, 735 mg, 5.82 mmol) in dry CH2Cl2 (25 mL). Stirring
was continued for 2 h at 0 ꢀC and 20 h at 20 ꢀC. The solvent was re-
moved underreduced pressure. The residuewastaken upinEt2O. The
solids were removed by filtration and successively washed with small
portions of Et2O. Combined filtrate and washings were concentrated
under reduced pressure. The remaining yellow oil [2.61 g, composed
predominantly (1H HMR) of an 76/24-mixture of (ꢂ)-cis/(ꢂ)-trans-8;
Supplementary data] was dissolved in dry C6H6 (45 mL). BrCCl3
(3.96 g, 20.0 mmol) was added and the solution purged with a gentle
stream of argon (15 min). The yellow solution was photolyzed under
an atmosphere of argon using tungsten light (250 W bulb) until de-
colorization had occurred (1e5 min). The solution was concentrated
under reduced pressure to leave an oil that was purified by chro-
matography [petroleum ether/Et2O¼10:1 (v/v)]. Yield: 1.05 g [52%
from acid (ꢂ)-6], colorless oil, 50/50-mixture of rel-(2R,3S,5S)/rel-
(2R,3S,5R) isomers. Anal. Calcd for C14H18Br2O (362.10): C, 46.44; H,
5.01; found: C, 46.89; H 5.08. rel-(2R,3S,5R)-8 [(ꢂ)-cis-8]. Colorless
solid, mp 81e82 ꢀC (Et2O/CH2Cl2). Rf¼0.62 for petroleum ether/
Et2O¼10:1 (v/v). dH (600 MHz; CDCl3) 1.46 (3H, s, CH3), 1.58 (3H, s,
CH3),1.89 (3H, s, CH3), 2.73 (1H, dt, Jd¼13.3, Jt¼4.2, 4-H), 2.82 (1H, dt,
Jd¼13.3, Jt¼12.7, 4-H), 4.08(1H, dd, J 12.1, 4.9 Hz, 3-H or 5-H), 4.08(1H,
dd, J 11.0, 4.5 Hz, 3-H or 5-H), 7.26e7.30 (m, 1H), 7.33e7.36 (m, 2H),
7.58e7.60 (m, 2H). dC (151 MHz; CDCl3) 20.9 (CH3), 23.9 (CH3),
30.8 (CH3), 39.3 (C4), 54.5 (C5), 55.9 (C3), 76.9 (C6), 79.1 (C2), 125.9,
127.7, 128.0, 145.1. X-ray crystallography: C14H18Br2O (362.10),
4.5.2. Methyl rel-(2R,3S,5S)-3,5-dibromo-2,6,6-trimethyltetra-
hydropyran-2-carboxylate trans-(10). Yield: 117 mg [34% from
rel-(2R,3S,5S)-3,5-dibromo-2,6,6-trimethyl-2-
phenyltetrahydropyran trans-(8)], colorless solid, mp 103 ꢀC
(CH2Cl2/Et2O). Rf¼0.44 for petroleum ether/tert-butyl methyl
ether¼10:1 (v/v). dH (600 MHz; CDCl3) 1.28 (3H, s, CH3), 1.43 (3H,
s, CH3), 1.50 (3H, s, CH3), 2.55 (1H, dt, Jd 14.9, Jt 3.5 Hz, 4-H),
2.83 (1H, ddd, J 14.9, 12.7, 3.5 Hz, 4-H), 3.76 (3H, s, CO2CH3), 4.50
(1H, dd, J 12.7, 3.5 Hz, 5-H), 4.85 (1H, t, J 3.5 Hz, 3-H). dC
(151 MHz; CDCl3) 20.1 (CH3), 29.5 (CH3), 29.6 (CH3), 38.0 (C4),
52.0 (C3), 52.5 (CO2CH3), 56.1 (C5), 76.4 (C2), 77.9 (C6), 173.2
(CO2CH3). IR (KBr)
n
3015 cmꢁ1, 3001, 2950, 1740, 1289, 1227, 1108.
Anal. Calcd for C10H16Br2O2 (344.05): C, 34.91; H, 4.69; found: C,
34.94; H, 4.64. X-ray crystallography: C10H16Br2O2, T¼300(2) K,
ꢀ
ꢀ
ꢀ
l
¼0.71073 A, monoclinic, P21/c, a¼6.6095(7) A, b¼22.789(2) A,
c¼8.6366(8) A,
b
¼104.145(9)ꢀ, Z¼4,
m
¼6.413 mmꢁ1, completeness
ꢀ
99.7%, (2
[I>2
q
¼52.76ꢀ), goodness-of-fit on F2¼0. 756, final R indices
s
(I)]: R1¼0.0283, wR2¼0.0512.
4.5.3. Methyl rel-(2R,3S,5R)-3,5-dibromo-2,6,6-trimethyltetr-
ahydropyran-2-carboxylate cis-(10). Yield: 127 mg [36% from rel-
(2R,3S,5R)-3,5-dibromo-2,6,6-trimethyl-2-phenyltetrahydropyran
cis-(8)], colorless solid, mp 72 ꢀC (CH2Cl2/Et2O). Rf¼0.42 from pe-
troleum ether/tert-butyl methyl ether¼10:1 (v/v). dH (250 MHz;
CDCl3) 1.35 (3H, s, CH3), 1.48 (3H, s, CH3), 1.70 (3H, s, CH3), 2.64 (1H,
ddd, J 13.4, 12.5 Hz,12.3 Hz, 4-H), 2.68 (1H, dt, Jd 13.4, Jt 4.6 Hz, 4-H),
3.77 (3H, s, CO2CH3), 3.98 (1H, dd, J 12.3, 4.6 Hz, 5-H), 4.56 (1H, dd, J
12.5, 4.7 Hz, 3-H). dC (151 MHz; CDCl3) 19.8 (CH3), 23.5 (CH3), 30.1
ꢀ
ꢀ
ꢀ
T¼300(2) K, ¼0.71073 A, triclinic, P1, a¼8.686(1) A, b¼9.311(1) A,
l
c¼10.428(1) A,
a
¼106.95(1)ꢀ,
b
¼110.32(1)ꢀ,
g
¼98.17(1)ꢀ, Z¼2,
ꢀ
m
¼5.550 mmꢁ1, completeness 97.8%, (2
q
¼52.76ꢀ), goodness-of-fit on
F2¼0.741, final R indices [I>2
(I)]: R1¼0.0329, wR2¼0.0610. rel-
s
(2R,3S,5S)-8 [(ꢂ)-trans-8]. Colorless oil. Rf¼0.73 for petroleum ether/
diethyl ether¼10:1 (v/v). dH (250 MHz; CDCl3) 1.07 (3H, s, CH3), 1.50
(3H, s, CH3), 1.70 (3H, s, CH3), 2.72e2.79 (2H, m, 4-H), 4.54 (1H, dd, J

€
O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6979
(CH3), 37.6 (C4), 47.8 (C3), 53.0 (CO2CH3), 53.5 (C5), 77.5 (C6), 80.0
(C2), 170.7 (CO2CH3). IR (KBr)
3015 cmꢁ1, 3001, 2950, 1740, 1289,
1227, 1108. Anal. Calcd for C10H16Br2O2 (344.05): C, 34.91; H, 4.69;
found: C, 35.32; H, 4.48. X-ray crystallography: C10H16Br2O3,
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
n
ꢀ
ꢀ
T¼296(2) K,
l
¼0.71069 A, monoclinic, P21/c, a¼10.805(2) A,
Acknowledgements
b¼9.008(2) A, c¼13.198(3) A,
b
¼100.02(2)ꢀ, Z¼4,
m
¼6.395 mmꢁ1
,
ꢀ ꢀ
completeness 100.0%, (2
final R indices [I>2
q
¼52.74ꢀ), goodness-of-fit on F2¼0. 916,
This work is part of Ph.D. Theses of O.B. and M.G., and was
supported by the Deutsche Bundesstiftung Umwelt (DBU; grant
20007/885) and the Deutsche Forschungsgemeinschaft (grant
Ha1705/8e1).
s
(I)]: R1¼0.0407, wR2¼0.0912.
4.6. Aplysiapyranoids
4.6.1. General method. A solution of methyl 3,5-dibromo-2,6,6-
trimethyltetrahydropyran-2-carboxylate (10) (91 mg, 0.27 mmol)
in CH2Cl2 (1.5 mL) was cooled to ꢁ78 ꢀC in an atmosphere of argon. A
Supplementary data
Instrumentation, preparation of alkenols 1aee, additional NMR-
spectroscopic information, calculated energies, geometrical pa-
rameters, and coordinates of cis-8, trans-8, cis-10, trans-10, tetra-
hydropyran (chair conformation), tetrahydropyrans IeVI, and
products associated with isomerization of alkenol VII into cyclic
ethers VIII and IX (75 pages). Supplementary data related to this
article can be found online at doi:10.1016/j.tet.2012.05.013.
solution of diisobutylaluminumhydride (DIBAH; 290
mL, 1 M in
CH2Cl2, 0.29 mmol) was added at that temperature in a dropwise
manner. The reaction mixture was stirred at ꢁ78 ꢀC for 3 h and then
treated with satd. aqueous NH4Cl (0.5 mL) at ꢁ70 ꢀC and sub-
sequently with aqueous HCl [0.5 mL, 4% (w/w)]. The reaction mix-
ture was allowed to warm to 0 ꢀC (ice bath) and then to 20 ꢀC.
Dichloromethane (0.5 mL) and H2O (0.5 mL) were added. The or-
ganic phase was separated and the aqueous phase extracted with
CH2Cl2 (3ꢃ1.5 mL). Combined organic layer and extracts were dried
(MgSO4) and concentrated under reduced pressure, to furnish 79 mg
(0.15 mmol) of crude 3,5-dibromo-2,6,6-trimethyltetrahydropyran-
2-carbaldehyde (Supplementary data). A solution of this material in
dry THF (0.5 mL) was added at 20 ꢀC to a purple slurry obtained from
References and notes
1. Kusumi, T.; Uchida, H.; Inouye, Y.; Ishitsuka, M.; Yamamoto, H.; Kakisawa, H. J.
Org. Chem. 1987, 52, 4597e4600.
2. Fordiscriptionof the biologyof the Aplysiomorphasee:Thompson, T. E. TheBiology
of the Opistobranch Molluscs; The Ray Society: London, 1976; Vol. 1, pp 146e161.
3. Inouye, Y.; Uchida, H.; Kusumi, T.; Kakisawa, H. J. Chem. Soc., Chem. Commun.
1987, 346e347.
4. Jung, M. E.; D’Amico, D. C. Tetrahedron Lett. 1993, 34, 923e926.
5. Jung, M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63, 2982e2987.
6. Jung, M. E.; Lew, W. J. Org. Chem. 1991, 56, 1347e1349.
7. Hartung, J.; Greb, M. Tetrahedron Lett. 2003, 44, 6091e6093.
8. Corey, E. J.; Ha, D. C. Tetrahedron Lett. 1988, 29, 3171e3174.
9. McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593e595.
anhydrous CrCl2 (110 mg, 0.90 mmol) and CHCl3 (29 mL, 0.33 mmol)
in dry THF (1.5 mL) at 65 ꢀC (oil bath). The reaction mixture was
heated under reflux for 5 h. Diethyl ether (7 mL) and H2O (5 mL)
were added at 20 ꢀC and the phases separated. The aqueous phase
was extracted with Et2O (3ꢃ4 mL). The combined organic phase and
extracts were dried (MgSO4) and concentrated under reduced
pressure to leave a residue that was purified by chromatography
[SiO2, petroleum ether/diethyl ether¼15:1 (v/v)].
€
10. For recent studies on bromocyclization see: (a) Schuch, D.; Fries, P.; Donges, M.;
ꢁ
ꢁ
Menendez-Perez, B.; Hartung, J. J. Am. Chem. Soc. 2009, 131, 12918e12920; (b)
Werness, J. B.; Tang, W. Org. Lett. 2011, 13, 3664e3666; (c) Cui, X. L.; Brown, R. S.
J. Org. Chem. 2000, 65, 5653e5658.
11. For a recent review on tetrahydropyran synthesis see: Clarke, P. A.; Santos, S.
4.6.2. Aplysiapyranoid A. From methyl rel-(2R,3S,5S)-3,5-dibromo-
2,6,6-trimethyltetrahydropyran-2-carboxylate trans-(10) (68 mg,
0.20 mmol), DIBAH (220 mL, 1 M in CH2Cl2, 0.22 mmol) in CH2Cl2
(1.5 mL) according to the general method provided 46 mg (ap-
proximately 0.13 mmol) of crude carbaldehyde that was treated
with CrCl2 (93 mg, 0.76 mmol) and CHCl3 (25 mL, 0.28 mmol) in dry
THF (2 mL) as described in Section 4.6.1. Yield: 23 mg (33%), yel-
lowish oil. Rf¼0.71 for petroleum ether/diethyl ether¼15:1 (v/v). dH
(400 MHz; CDCl3) 1.38 (3H, s, CH3), 1.43 (6H, s, CH3), 2.61e2.68 (2H,
m, 4-H), 4.39 (1H, dd, J 7.8, 5.0 Hz, 5-H), 4.47 (1H, dd, J 6.2, 4.0 Hz, 3-
H), 6.14 (1-H, d, J 13.8 Hz, CH2]CHCl), 6.18 (1H, d, J 13.8 Hz, CH2]
CHCl). dC (101 MHz; CDCl3) 27.3 (CH3), 28.7 (CH3), 29.0 (CH3), 37.3
(C4), 54.6 (C3 or C5), 55.1 (C3 or C5), 75.8 (C6), 76.0 (C2), 118.4
(CH2]CHCl), 138.4 (CH2]CHCl).
Eur. J. Org. Chem. 2006, 2045e2053.
€
12. Brucher, O.; Hartung, J. ACS Catal. 2011, 1, 1448e1454.
ꢂ
13. Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed. 2009, 48, 8424e8540.
14. For recent examples on enantioselective bromolactonozations, see: (a) Murai, K.;
Matsushita, T.;Nakamura, A.;Fukushima,S.;Shimura,M.;Fujioka,H.Angew. Chem.,
Int. Ed. 2010, 49, 9174e9177; (b) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y.
J. Am. Chem. Soc. 2010,132,15474e15476; (c) Zhang, W.; Zheng, S.; Liu, N.; Werness,
J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664e3665.
ꢁ
15. Gonzalez, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099e9108.
16. Martín, D. D.; Marcos, I. S.; Basabe, P.; Romero, R. E.; Moro, R. F.; Lumeras, W.;
Rodríguez, L.; Urones, J. G. Synthesis 2001, 1013e1022.
€
17. Wischang, D.; Brucher, O.; Hartung, J. Coord. Chem. Rev. 2011, 255, 2204e2217.
18. Hartung, J. Pure Appl. Chem. 2005, 77, 1559e1574.
19. Gottwald, T.; Greb, M.; Hartung, J. Synlett 2004, 65e68.
20. For pioneering studies on bromide oxidation catalyzed by vanadium(V) com-
plexes see: Colpas, G. J.; Hamstra, B. J.; Kampf, J. W.; Pecoraro, V. L. J. Am. Chem.
Soc. 1996, 118, 3469e3478.
21. Barhate, B. N.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999,
55, 11127e11142.
ꢂ
€
22. Greb, M.; Hartung, J.; Kohler, F.; Spehar, K.; Kluge, R.; Csuk, R. Eur. J. Org. Chem.
4.6.3. 5-epi-Aplysiapyranoid A. From methyl rel-(2R,3S,5R)-3,5-
2004, 3799e3812.
€
dibromo-2,6,6-trimethyltetrahydropyran-2-carboxylate
cis-(9)
23. Anschutz, R.; Kinnkutt, L. Chem. Ber. 1878, 11, 1221e1222.
24. Fittig, R.; Binder, F. Liebigs Ann. Chem. 1879, 195, 56e179.
25. For a survey on methods for oxidative bromination in synthesis see: Rothen-
berg, G.; Clark, J. H. Green Chem. 2000, 2, 248e251.
26. Haegele, E. Chem. Ber. 1892, 25, 2753e2756.
27. Kuczynski, L.; Wilimowski, M.; Baginska, M.; Soloducho, J. Pol. J. Pharmacol.
(91 mg, 0.27 mmol). Yield: 21 mg (22%), yellow oil. Rf¼0.80 for
petroleum ether/diethyl ether¼15:1 (v/v). dH (400 MHz; CDCl3)
1.36 (3H, s, CH3), 1.47 (3H, s, CH3), 1.53 (3H, s, CH3), 2.59e2.70 (2H,
m, 4-H), 3.84e3.91 (2H, m, 3-H, 5-H), 6.09 (1H, d, J 13.1 Hz, CH2]
CHCl), 6.29 (1H, d, J 13.1 Hz, CH2]CHCl). dC (101 MHz; CDCl3) 22.1
(CH3), 23.3 (CH3), 30.4 (CH3), 38.3 (C4), 52.8 (C3 or C5), 53.9 (C3 or
C5), 76.8 (C2), 77.1 (C6), 119.9 (CH2]CHCl), 137.8 (CH2]CHCl).
HRMS: [MþꢁCl] calcd 308.9489, found 308.9484.
1975, 27, 549e553.
28. Clague, M. J.; Keder, N. L.; Butler, A. Inorg. Chem. 1993, 32, 4754e4761.
€
29. Breitmaier, E. Terpene; Teubner Studienbucher Chemie: Stuttgart, 1999.
30. Nelson, D. J.; Ruibo, L.; Brammer, C. J. Org. Chem. 2001, 66, 2422e2428.
31. Ruasse, M.-F. Acc. Chem. Res. 1990, 23, 87e93.
32. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
33. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, B37, 785e789.
34. Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724e728.
35. Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257e2261.
36. Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209e214.
37. Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann, G. J. Am. Chem. Soc. 2004, 126,
12121e12129.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication [CCDC
859064 (cis-3d), CCDC 753370 (cis-8), CCDC 753369 (trans-8), CCDC
753371 (cis-10), CCDC 753373 (trans-10)]. Copies of the data can be

€
O. Brucher et al. / Tetrahedron 68 (2012) 6968e6980
6980
38. Eliel, E. L.; Hargrave, K. D.; Pietrusiewicz, K. M.; Manoharan, M. J. Am. Chem. Soc.
1982, 104, 3635e3643.
39. Winstein, S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562e5578.
40. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; J.
Wiley & Sons: New York, NY, 1994, pp 597e615.
45. Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413e1432.
46. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936e3938.
47. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408e7410.
48. Hartung, J.; Greb, M.; Svoboda, I.; Fuess, H. Acta Crystallogr. 2006, E62,
o1920eo1922.
41. Bondi, A. J. Phys. Chem. 1964, 68, 441e451.
42. Jung, M. E.; Piizi, G. Chem. Rev. 2005, 105, 1735e1766.
43. For a discussion on the role of strain in methylcyclohexanes see: (a) Anderson,
E. J. Top. Curr. Chem. 1974, 45, 139e167; (b) Corey, E. J.; Feiner, N. F. J. Org. Chem.
1980, 45, 765e780.
49. Greb, M.; Hartung, J. Synlett 2004, 69e72.
50. Butler, A.; Walker, J. V. Chem. Rev. 1993, 93, 1937e1944.
51. Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303e14314.
52. Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010,
132, 3298e3300.
44. Barton, D. H. R.; Ferreira, J. A. Tetrahedron 1996, 52, 9347e9366.