Highly stereoselective radical cyclization of haloacetals controlled by the acetal center

Article abstract of DOI:10.1002/chem.200390180

A systematic investigation of radical haloacetal cyclizations (Ueno-Stork reaction) where the acetal center is the unique stereogenic element is reported. This highly diastereoselective reaction can be used for the preparation of polysubstituted tetrahydrofurans and γ-lactones. We report herein the full experimental details of reactions where up to three new chiral centers are created. To demonstrate the potential of this approach, short syntheses of (+)-eldanolide and of tricyclic acetals related to biologically active lignans have been achieved.

Full text of DOI:10.1002/chem.200390180

FULL PAPER
Highly Stereoselective Radical Cyclization of Haloacetals Controlled by the
Acetal Center
Fe¬lix Villar,[a] Tanja Kolly-Kovac,[a, b] Olivier Equey,[a] and Philippe Renaud*[a, b]
Abstract: A systematic investigation of
radical haloacetal cyclizations (Ueno
Stork reaction) where the acetal center
is the unique stereogenic element is
reported. This highly diastereoselective
reaction can be used for the preparation
of polysubstituted tetrahydrofurans and
g-lactones. We report herein the full
experimental details of reactions where
up to three new chiral centers are
created. To demonstrate the potential
of this approach, short syntheses of (‡)-
eldanolide and of tricyclic acetals relat-
ed to biologically active lignans have
been achieved.
Keywords: asymmetric synthesis
¥
cyclizations ¥ haloacetals ¥ lactones
¥ radical reactions
Introduction
Eighteen years ago, Ueno and Stork reported independently
6]
the very efficient 5-exo cyclization of bromoacetals.[1 This
reaction is one of the most useful radical reaction described to
date and has been applied for the synthesis of natural
14]
products.[4, 7 The use of chiral alcohol allows the synthesis
of polysubstituted lactones in enantiomerically pure form
with good to excellent diastereoselectivity (Scheme 1).[4, 15] In
these processes, the allylic chiral center controls completely
the stereochemical outcome of the reaction. Apparently, the
second stereogenic center at the acetal does not influence the
diastereoselectivity of the reaction. In the original work,
chair-like transition states where the ethoxy group is either
occupying an axial or an equatorial position were proposed
(Scheme 1).[3] These first experiments suggested that the
control of the stereochemical outcome of Ueno Stork
cyclizations from the acetal center is very hypothetical.
However, several reports indicates that the role of the acetal
center was overlooked, and that it has a determinant influence
Scheme 1. Stereoselective Ueno Stork reactions for the synthesis of
trans-b,g-disubstituted g-butyrolactone.
Application to the synthesis of optically pure lactones such as
(‡)-eldanolide, the pheromone of the male African sugarcane
stem borer Eldana saccharina, is described. A stereoselective
cascade cyclization reaction leading to tricyclic compounds is
also described. A computational study of the stereoselectivity
of the reaction is described in the following paper.[25]
19]
at several occasions[16 can provide some degree of stereo-
Results and Discussion
23]
control.[20
Diastereoselectivity of the cyclization reactions
Therefore, a few years ago, we started a systematic
investigation of cyclization reactions where the acetal center
is the unique stereogenic element.[12, 13, 24] We report here our
effort to define the scope and limitations of this approach.
4-Substituted 2-alkoxytetrahydrofurans: The bromoacetals
1
6 have been prepared by treatment of a mixture of the
corresponding enol ethers and allylic alcohols with NBS. The
cyclization reactions were conducted at À788C using tribu-
tyltin hydride and triethylborane/oxygen as initiator [Eq. (1)]
results are summarized in Table 1. In all cases, the major
[a] Prof. P. Renaud, Dr. F. Villar, T. Kolly-Kovac, O. Equey
University of Fribourg, Department of Chemistry
¬
Perolles, 1700 Fribourg (Switzerland)
E-mail: philippe.renaud@ioc.unibe.ch
RO
O
Br
OR
Bu3SnH
[b] Prof. P. Renaud, T. Kolly-Kovac
Present address: University of Berne
Department of Chemistry and Biochemistry
Freiestrasse 3, 3000 Bern 9 (Switzerland)
Fax : (‡41)31-631-3426
O
(1)
Et3B, O2
-78 °C
4
Rt
Rt
Rc
1–6
Rc
7–12
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1566 1577
Table 1. Radical cyclization of 1 6 according to Equation (1).
Entry Bromide OR
Rt
Rc
Product Yield [%] cis/trans
1
2
3
4
5
6
1
2
3
4
5
6
OEt
OtBu
OEt
H
H
nPr
H
H
H
H
7
8
9
71
68
75
71
80
83
> 98:2
> 98:2
92:8
92:8
77:23
77:23
OtBu nPr
OEt
OtBu Me Me 12
10
Me Me 11
4,5-Disubstituted 2-alkoxytetrahydrofurans: The radical pre-
cursors 19 and 21 are easily prepared from 1,4-pentadien-1-ol
and 4-hydroxy-4-methyl-2,5-cyclohexadien-1-one by haloace-
talization with ethyl vinyl ether and tert-butyl vinyl ether,
respectively. Reaction of 19 with tributyltin hydride at À788C
furnishes essentially (r-2,c-4,t-5)-20 [Eq. (5)]. At 808C, the
tetrahydrofuran product 7 12 possesses a cis configuration.
The size of the alkoxy group has no influence on the
stereochemical outcome as demonstrated by comparing
entries 1, 3 and 5 (OR ˆ OEt) with entries 2, 4 and 6 (OR ˆ
OtBu), respectively. However, the substitution of the alkene
moiety has a marked influence. With terminal alkenes (Rt and
Rc ˆ H), the cis isomer was produced with an excellent
stereoselectivity (entries 1 and 2, cis/trans >98:2). When the
alkene moiety is monosubstituted at the terminal position
(Rt ˆ nBu, Rc ˆ H), the stereoselectivity decreased (cis/trans
92:8). With an alkene disubstituted at the terminal position
(Rt ˆ Rc ˆ Me), the cis/trans ratio dropped to 77:23 (entries 5
and 6).
EtO
O
Br
EtO
O
Bu3SnH
initiator
(5)
4
5
19
Et3B/O2 (–78 °C): 65%, >98% ds
AIBN (80 °C): 61%, 86% ds
(r-2,c-4,t-5)-20
stereoselectivity drops to 86% ds. The reaction of 21 leading
to the bicyclic compound 22 shows the same tendency
[Eq. (6)]: a very high diastereoselectivity in favor of the exo
Finally, a good control of the stereochemistry was obtained
with the allene 13. Cyclization of 13 afforded 2-tert-butoxy-
4-vinyl tetrahydrofuran 14 as
a
cis/trans 92:8 mixture
[Eq. (2)].
tBuO
I
tBuO
O
H
Bu3SnH
initiator
(6)
O
Me
tBuO
Br
OtBu
Me
Bu3SnH, Et3B, O2
71%, cis/trans 92:8
O
(2)
O
O
O
exo-22
21
•
74%, >98% ds
71%, 89% ds
Et3B/O2 (–78 °C):
AIBN (80 °C):
14
13
isomer is achieved at low temperatures whereas lower stereo-
control (89% ds) is observed at 808C. Interestingly, the
cyclization of 21 can be coupled with an allylation of the final
radical enolate to give 23 [Eq. (7)]. Three new chiral centers
3,4-Disubstituted 2-alkoxytetrahydrofurans: The isopropyl
substituted system 15 was examined first. Under our standard
radical cyclization conditions, the tetrahydrofuran 16 was
isolated as a 1:1 mixture of isomers [Eq. (3)], the stereo-
chemistry at C(4) is fully controlled by the acetal center but
the stereochemistry at C(3) is not controlled.
COOMe
tBuO
I
tBuO
H
O
O
SnBu3
COOMe
Me
(7)
Me
AIBN, 80 °C
O
O
21
23 (68%, 81% ds)
EtO
O
OEt
OEt
3
Bu3SnH
3
O
O
+
(3)
Br
Et3B, O2, -78 °C
1 : 1
4
4
44%
are generated in this process with a diastereoselectivity of
81% ds at 808C. This allylation process does not work
efficiently at lower temperature.
15
(r-2,c-3,c-4)-16
(r-2,t-3,c-4)-16
The a-iodoketone 17 was examined next. Under iodine
atome transfer conditions (5 mol% Bu3SnSnBu3, hn,
108C),[26] the reaction afforded (r-2,t-3,c-4)-18 as a single
diastereomer [Eq. (4)].[27] The relative configuration
of the main isomer was assigned from difference NOE
spectra.
3,4,5-Trisubstituted 2-alkoxytetrahydrofurans: The gem-di-
methyl substituted bromide 24 was prepared from 1-ethoxy-2-
methyl-propene. At low temperature, it affords predominant-
ly the (r-2,c-4,t-5)-25 [Eq. (8)]. The gem-dimethyl substitution
induces a slight decrease of the diastereoselectivity relative
to the unsubstituted system [compare with Eq. (5)]. The
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P. Renaud et al.
FULL PAPER
EtO
Br
alkoxy substituent occupies an axial position (Scheme 2,
model A). The substituent at C(5) lies in a pseudoequatorial
EtO
O
Bu3SnH
initiator
O
(8)
(r-2,c-4,t-5)-25
24
Et3B/O2 (–78 °C): 75%, >86% ds
AIBN (80 °C): 88%, 74% ds
Scheme 2. Model for the Ueno Stork cyclization controlled by the acetal
center.[25]
a-iodoester 26 is prepared from the corresponding enolether
and gives the polysubstituted tetrahydrofuran 27 under iodine
atom transfer conditions at 108C [Eq. (9)]. Three new chiral
position as predicted by the Beckwith Houk model. The
substituent at C(3) can occupy either a pseudoaxial (Rax)
position which would minimize the steric interactions with the
C(2)-alkoxy substituents, or a equatorial (Req) position as in
the Beckwith Houk model. An exception to this model is the
reaction of the cyclic haloacetal 21. In this case, the major
isomer arises from the twist-like transition state B. Interest-
ingly, in both models, the exo-alkoxy group is in a pseudoaxial
position that allows to maximize the anomeric effect. The
models presented in Scheme 2 are based on the results of the
abinito calculations that are reported in the following
paper.[25]
EtO
O
CO2Me
I
EtO
O
CO2Me
I
3
(Bu3Sn)2
4
(9)
hν, 10 °C
71%, 77% ds
5
(r-2,t-3,c-4,t-5)-27
26
centers are created during this process and the major isomer
(r-2,t-3,c-4,t-5)-27 represents 77% of the whole mixture of
diastereomers. The isopropyl derivative 28 has also been
examined [Eq. (10)]. The control of the stereochemistry at the
Cascade cyclization process
EtO
O
EtO
O
Bu3SnH
Br
(10)
Et3B/O2, –78 °C
66%, 63% ds
Polycyclic lactones are substructure of many natural products.
Our interest in the synthesis of analogues of (À)-podophyllo-
toxin,[28, 29] a tetracyclic lignan with potent antimitotic activity,
prompted us to examine a cascade cyclization process for the
preparation of tricyclic lactones. To validate such an ap-
proach, the iodoacetal 36 was prepared from the monopro-
tected 1,4-benzoquinone 32 by allylation with lithiated allyl
methyl ether followed by methylation of the tertiary alcohol,
iodoacetalization with N-iodosuccinimide and allyl alcohol
and deprotection of the dioxolanyl acetal with hydrated
magnesium sulfate (Scheme 3). Treatment of the iodoacetal
(r-2,t-3,c-4,t-5)-29
28
C(3) center is moderate (63% ds) and (r-2,t-3,c-4,t-5)-29 is
isolated as major isomer. However, two out of the three newly
formed centers (C(4) and C(5)) are created with high
stereocontrol since the principal minor isomer is epimeric at
position C(3).
Tetrahydropyran derivatives: The stereochemical outcome of
6-exo cyclizations leading to tetrahydropyran derivatives can
also be controlled by the acetal center. For instance, the
desymmetrization of 1,6-heptadien-4-ol via the acetal 30 is
totally diastereoselective at À788C [Eq. (11)]. The moderate
O
O
O
OMe
sBuLi, THF,
NaH, MeI
OMe
O
O
OH
33
–78°C
32
OtBu
OtBu
O
OH
O
Bu3SnH
Br
O
O
MgSO4•H2O
(11)
O
NIS, Et3N
80%
O
Et3B, O2, –78 °C
O
C6H6
95%
43%
OMe
OMe
I
OMe
OMe
(r-2,t-4,t-6)-31
30
35
34 (48% over 2 steps)
H
O
O
yield of this process is due to the formation of the acyclic
reduced product. The relative configuration of the 2,4,6-
trisubstitued tetrahydropyran 31 was deduced from 1H NMR
coupling constants. Beckwith has recently reported a related
example of stereoselective bromoacetal cyclization leading to
2,4-disubstituted tetrahydropyran.[22]
Et3B (6 equiv), O2
O
O
OMe
CH3C6H5, –95 °C
OMe H
37 (84%, ds > 84%)
OMe
I
OMe
36
H
H
pTsOH, CH(OMe)3
MeO
MeOH, reflux
O
96%
OMe
(r-2,t-3,c-4)-38
Discussion of the stereochemical outcome: The stereochem-
ical outcome of the above reactions for all acyclic precursors
can be rationalized by a chair-like transition state where the
Scheme 3. Preparation of the tricyclic acetal 38 related to podophyllotox-
in.
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Stereoselective Radical Cyclizations
1566 1577
36 with triethylborane in toluene at À958C afforded the
desired tricyclic compound 37 in good yield. The efficiency of
this tin-free cyclization is striking and best explained by the
mechanism depicted in Scheme 3. Indeed, this reaction is
mediated by a stoichiometric amount of triethylborane which
reacts with the tricylic enolate radical to give a boron enolate
and an ethyl radical that can abstract an iodine atom from the
substrate and propagates the chain reaction (Scheme 4).[30]
The diastereoselectivity (84% ds) is remarkable considering
39[36] and 1,2-butadien-4-ol. The bromoacetalization furnished
40 as a 1:1 mixture of two diastereomers which were separated
by flash chromatography.[23, 37] Reaction of the diastereomeri-
cally pure (R)-40 with tributyltin hydride gave the 2-alkoxy-4-
vinyl tetrahydrofuran in 88% yield as a cis/trans 90:10
mixture. After elimination of the minor diastereomer by flash
chromatography, hydrolysis of the pure cis isomer followed by
oxidation of the lactol gave the enantiomerically pure (>99%
ee) lactone 41 (Scheme 5). During the hydrolysis step, the
chiral auxiliary was recovered in 84% yield.
Ph
Ph
•
flash
chromatography
HO
O
O
Br
O
NBS
78%
39
(R,S)-40
(dr 50:50)
•
Ph
Ph
O
1) Bu3SnH, Et3B, O2
(88%, cis/trans 90:10)
O
Br
OH
O
(R)
(5)
O
(R)
recovered
in 84% yield
2) HCl, THF (63%)
3) PCC, Al2O3 (90%)
•
(R)-41 (>99% ee)
(R)-40
Scheme 4. Proposed mechanism for the triethylborane mediated cycliza-
tion of 36.
Scheme 5. Preparation of the enantiomerically enriched (>99% ee)
lactone (R)-41.
that the position 3 of 3,4-disubstituted 2-alkoxytetrahydrofur-
an is usually difficult to control (see below) and that four new
stereogenic centers are created in a single reaction. After
treatment of the major isomer with p-toluenesulfonic acid in
methanol and trimethyl orthoformate, the aromatic com-
pound (r-2,t-3,c-4)-38 was isolated and its trans relative
Synthesis of (‡)-eldanolide: The utility of our approach was
demonstrated by the preparation of the naturally occuring
(‡)-eldanolide, the pheromone of the male African sugarcane
48]
stem borer Eldana saccharina (Scheme 6).[38
For this
purpose, the bromoacetal 42 was prepared from the chiral
6.4%
no
NOE
R*O
O
Br
H
R*O
O
H
H
HO
1) Bu3SnH, Et3B, O2
1) (85%, >98% ds)
Ph
MeO
cross peak in
COSY spectra
(W arrangement)
4
NBS
O
2
3
O
2) Flash
2) chromatography
75%
H
H
O
= R*
Me
(r-2,t-3,c-4)-38
39
42
(2S,4S,5R)-43
O
O
configuration was unambiguously established from NOE
difference and COSY spectra.
R*O
O
1) HCl, H2O (68%)
1) 62% R*OH recovered
2) PCC, Al2O3 (73%)
1) 9-BBN then H2O2/NaOH (93%)
2) CO2Cl2, DMSO (95%)
3) Ph3PC(CH3)2 (51%)
Preparation of optically pure lactones
44
45 (+)-eldanolide
(>99%ee)
Optically pure chiral enol ethers are easily available from
diverse chiral alcohols and are very valuable starting material
for asymmetric synthesis.[31] Since our reactions are producing
acetals as final products, it was anticipated that the chiral
alcohol could be recovered by simple hydrolysis. We have
previously shown [Eq. (1), Table 1] that the size of the exo-
alkoxy group has no influence on the stereochemistry of the
radical cyclization, therefore, we were expecting that the
acetal center will be the only control element of the
cyclization reactions.
Scheme 6. Synthesis of (‡)-eldanolide.
vinyl ether 39 by bromoacetalization with 1,4-pentadien-3-ol.
The haloacetalization step is not stereoselective, the required
diastereomerically pure 42 could be obtained after flash
chromatography; however, since the separation of the dia-
stereomers is easier after the cyclization reaction, the mixture
of diastereomers was used for the next step. The bromoacetal
42 (1:1 mixture of two diastereomers) was submitted to
cyclization conditions to afford 43 as a 1:1 mixture of two
diastereoisomers, the cyclization process is completely dia-
stereoselective (ds > 98%) for each diastereomer of 42. At
this stage, the two diastereomers were separated by flash
Synthesis of 3-vinyl-g-butyrolactone: 3-Vinyl-g-butyrolactone
is an important building block widely that has been used in
several natural product synthesis.[32 35] The acetal 40 has been
prepared from the (1R,2S)-2-phenylcyclohexyl vinyl ether
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P. Renaud et al.
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heterogeneous mixture was stirred for 2 h at rt. The organic layer was
washed with H2O, dried over MgSO4 and evaporated under reduced
pressure. The crude product was purified by flash chromatography
(pentane/Et2O) to afford the tetrahydrofuran. The diasteroisomeric ratios
were determined by 1H NMR before and after FC. Attempts to measure
the diasteroselectivity by GC failed due to partial decomposition of the
products. The relative configuration have been assigned by NOE difference
experiments.
chromatography and (2S,4S,5R)-43 was used for the rest of the
synthesis. The g-chain was modified in a straightforward
manner by hydroboration, Swern oxidation and Wittig
reaction. Finally, hydrolysis of the acetal 44 furnished the
lactol together with recovered (1R,2S)-2-phenylcyclohexanol
(62%). Oxidation of the lactol with PCC gave (‡)-eldanolide
45 (optical purity >99% by gas chromatography on a chiral
column).
General procedure 3 (GP 3): A solution of Bu3SnH (735 mg, 2.52 mmol),
AIBN (17 mg, 0.11 mmol) and the haloacetal (2.1 mmol) was heated under
reflux in benzene (20 mL). The reaction was monitored by TLC. After
cooling, a 1m NaOH solution (30 mL) was added and the heterogeneous
mixture was stirred for 2 h at rt. The organic layer was washed with H2O,
dried over MgSO4 and evaporated under reduced pressure. The crude
product was purified by FC (hexane/Et2O).
Conclusion
We have demonstrated on several examples that the Ueno
Stork radical cyclization of haloacetal can be highly stereo-
selective. The key element for the control of the stereo-
chemical outcome is the acetal center. This allows an excellent
control of the stereochemistry at C(4) and C(5) of the newly
formed tetrahydrofuran. The control of the stereochemistry at
C(3) is lower due to antagonist effect of the two neighbouring
substituents. The used of easily recovered chiral auxiliary
offers an entry for the synthesis of enantiomerically pure
compounds. At the moment, the diastereoselectivity of the
haloacetalization step is not controlled and separation of the
diastereomers by chromatography is necessary. Further
efforts toward stereoselective haloacetalization reaction are
currently underway in our laboratory and will be reported in
due course.
General procedure 4 (GP 4): A solution of the haloacetal (1 mmol) and
(Bu3Sn)2 (58 mg, 0.1 mmol) in benzene (5 mL) was irradiated with a sun
lamp for 2 h at 108C. A KF aqueous solution was added and the mixture
was stirred for 2 h. The organic layer was washed with water, dried over
MgSO4 and evaporated. The crude product was purified by FC (hexane/
Et2O).
3-(2-Bromo-1-ethoxyethoxy)-1-propene (1): According to GP 1 from ethyl
vinyl ether (1.13 g, 15.7 mmol), allyl alcohol (1.00 g, 17.2 mmol) and NBS
(2.79 g, 15.7 mmol). The bromoacetal 1 (2.73 g, 76%) was obtained as a
colorless oil after FC (hexane/Et2O 40:1). IR (KBr): nÄ ˆ 3081, 2978, 2877,
1423, 1346, 1126, 1057 cmÀ1; 1H NMR (360 MHz, CDCl3): d ˆ 5.97 (m, 1H,
ˆ
ˆ
CH CH2), 5.25 (dq, J ˆ 1.8, 17.4 Hz, 1H, CH CHH), 5.20 (dq, J ˆ 1.2,
ˆ
10.4 Hz, 1H, CH CHH), 4.72 (t, J ˆ 5.5 Hz, 1H, OCHCH2Br), 4.16 (ddt,
ˆ
J ˆ 1.5, 5.5, 12.8 Hz, 1H, OCHHCH CH2), 4.07 (ddt, J ˆ 1.5, 6.1, 12.2 Hz,
ˆ
1H, OCHHCH CH2), 3.75 3.53 (m, 2H, CH2CH3), 3.38 (d, J ˆ 5.2 Hz,
2H, OCHCH2Br), 1.23 (t, J ˆ 7.0 Hz, 3H, CH2CH3); 13C NMR (50 MHz,
CDCl3): d ˆ 134.0 (d), 117.4 (t), 100.9 (d), 67.6 (t), 62.4 (t), 31.7 (t), 15.17 (q);
‡
CI-MS (CH4): m/z (%): 209 (3) [M ], 165 (74), 163 (72), 153 (97), 152 (100),
115 (84), 85 (5), 83 (8); elemental analysis calcd for C7H13O2Br (209.08): C
40.21, H 6.27; found: C 40.34, H 6.21.
Experimental Section
3-(2-Bromo-1-tert-butoxyethoxy)-1-propene (2): According to GP 1 from
tert-butyl vinyl ether (2.07 g, 20.7 mmol), allyl alcohol (1.20 g, 20.7 mmol)
and NBS (3.68 g, 20.7 mmol). The bromoacetal 2 (3.73 g, 91%) was
obtained as a colorless oil after FC (hexane/Et2O 40:1). IR (KBr): nÄ ˆ 3082,
2978, 2953, 2874, 1369, 1182, 1109, 925 cmÀ1; 1H NMR (360 MHz, CDCl3):
General remarks: THF was freshly distilled from K under N2; CH2Cl2 and
benzene from CaH2 under N2; toluene from Na under N2. Et3B solution
(1m) in hexane or toluene was freshly prepared from commercially
available Et3B (95%, Aldrich). Other reagents were obtained from
commercial sources and used as received. Flash column chromatography
(FC) and filtration: Baker silica gel (0.063 0.200 mm); AcOEt, Et2O,
CH2Cl2 and hexane as eluents. Thin-layer chromatography (TLC): Merck
silica gel 60 F254 analytical glass plates; detection either with UV or by
spraying with a solution of vanillin or a solution of 25 g phosphomolybdic
acid, 10 g Ce(SO4)2 ¥ 4H2O, 60 mL conc. H2SO4 and 940 mL H2O with
subsequent heating. FT-IR: Mattson Unicam 5000 and Perkin Elmer 1600.
NMR: Varian Gemini 200 (1H 200 MHz, 13C 50.3 MHz), Bruker AM 360
(1H 360 MHz, 13C 90.5 MHz), Bruker Avance DRX 500 (1H 500.13 MHz,
13C 125.8 MHz), Bruker DRX 400 (1H 400 MHz, 13C 100.6 MHz); chemical
shift in ppm relative to tetramethylsilane (ˆ0 ppm) or CHCl3 (ˆ7.26 ppm)
for 1H and CDCl3 (ˆ77.0 ppm) for 13C. Intensity of the NOE effect: w
(weak), m (medium), s (strong). MS: Vacuum Generators Micromass VG
70/70E, DS 11-250 and VG Autospec; CI (CH4), EI (70 eV). High
ˆ
d ˆ 5.95 5.86 (m, 1H, CH CH2), 5.30 (dq, J ˆ 1.8, 17.4 Hz, 1H,
ˆ
ˆ
CH CHH), 5.17 (dq, J ˆ 1.5, 10.4 Hz, 1H, CH CHH), 4.92 (t, J ˆ 5.5 Hz,
1H, OCHCH2Br), 4.08 4.06 (m, 2H, OCHCH2Br), 3.39 (dd, J ˆ 5.8,
ˆ
ˆ
10.7 Hz, 1H,CHHCH ), 3.29 (dd, J ˆ 5.2, 10.4 Hz, 1H, CHHCH ), 1.27 (s,
9H, tBu); 13C NMR (50 MHz, CDCl3): d ˆ 134.4 (d), 116.8 (t), 95.7 (d), 75.1
‡
(s), 64.8 (t), 33.1 (t), 28.6 (q); CI-MS (CH4): m/z (%): 239 (13) [M ‡H], 237
(14), 221 (17), 181 (100), 179 (97), 165 (68), 163 (67), 115 (47), 101 (14), 57
(99); elemental analysis calcd for C9H17O2Br (237.14): C 45.59, H 7.23;
found: C 45.39, H 7.06.
1-(2-Bromo-1-ethoxyethoxy)-2-hexene (3): According to GP 1 from ethyl
vinyl ether (655 mg, 9.1 mmol), 2-hexen-1-ol (1.0 g, 10.0 mmol) and NBS
(1.62 g, 9.1 mmol). The bromoacetal 3 (1.78 g, 78%) was obtained as a
colorless oil after FC (hexane/Et2O 40:1). IR (KBr): nÄ ˆ 2959, 2872, 1436,
1377, 1187, 1118, 1055, 970 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 5.72
resolution mass spectra (HRMS) were recorded on
a FTICR mass
ˆ
ˆ
5.69 (m, 1H, OCH2CH CH), 5.60 5.52 (m, 1H, CH CHCH2), 4.70 (t, J ˆ
spectrometer Bruker 4.7 BioApex II and VG Autospec. Elementary
analysis: Ilse Beetz, Mikroanalytisches Laboratorium, 96317 Kronach
(Germany).
5.5 Hz, 1H, OCHCH2Br), 4.11 (ddd, J ˆ 1.2, 6.1, 11.9 Hz, 1H,
ˆ
ˆ
OCHHCH CH), 4.02 (ddd, J ˆ 0.9, 6.4, 11.6 Hz, 1H, OCHHCH CH),
3.71 3.50 (m, 2H, OCH2CH3), 3.38 (d, J ˆ 5.5 Hz, 2H, OCHCH2Br),
ˆ
2.06 2.00 (m, 2H, CH CHCH2CH2), 1.46 1.36 (m, 2H, CH2CH2CH3),
General procedure 1 (GP 1): N-Halosuccinimide (10 mmol) was added in
portions to a solution of enol ether (10 mmol) and alcohol (11 mmol) in
CH2Cl2 (10 mL) cooled at À208C. The resulting mixture was stirred at the
same temperature for 2 3 h until disappearance of the starting material.
The mixture was diluted with hexane, filtered and washed successively with
KOH (5%), water and NaCl. After drying and evaporation of the solvent,
the residue was purified by FC (hexane/Et2O).
1.24 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.90 (t, J ˆ 7.6 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d ˆ 135.3 (d), 125.6 (d), 100.6 (d), 67.7 (t), 62.3 (t), 34.3
‡
(t), 31.9 (t), 22.2 (t), 15.2 (q), 13.7 (q); CI-MS (CH4): (2) [M ], 235 (19), 233
(18), 211 (13), 165 (14), 153 (90), 151 (89), 125 (16), 83 (100); elemental
analysis calcd (%) for C10H19O2Br (251.16): C 47.82, H 7.63; found: C 47.69,
H 7.60.
General procedure 2 (GP 2): A solution of the haloacetal (2.1 mmol) and
Bu3SnH (735 mg, 2.5 mmol) in toluene (52 mL) was cooled at À788C and a
1m solution of Et3B in hexane (2.9 mL, 2.9 mmol) was added. Air (2.0 mL)
was then bubbled into the reaction mixture with a syringe. The solution was
kept at À788C for 3 h. A 1m NaOH solution (30 mL) was added and the
1-(2-Bromo-1-tert-butoxyethoxy)-2-hexene (4): According to GP 1 from
tert-butyl vinyl ether (910 mg, 9.1 mmol), 2-hexen-1-ol (1.0 g, 10.0 mmol)
and NBS (1.62 g, 9.1 mmol). The bromoacetal 4 (1.8 g, 71%) was obtained
as a colorless oil after FC (hexane/Et2O 40:1). IR (KBr): nÄ ˆ 2974,
2872, 1464, 1367, 1110, 1010, 969 cmÀ1
;
1H NMR (360 MHz, CDCl3):
1570
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1570 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 7

Stereoselective Radical Cyclizations
1566 1577
ˆ
ˆ
d ˆ 5.71 5.66 (m, 1H, OCH2CH CH), 5.58 5.50 (m, 1H, CH CHCH2),
(100), 57 (33); HRMS (CI, isobutane): calcd for C9H19O2: 159.13795;
found: 159.13791 [M ‡H].
‡
4.88 (t, J ˆ 5.5 Hz, 1H, OCHCH2Br), 4.01 (dd, J ˆ 0.9, 6.1 Hz, 2H,
ˆ
OCHCH2Br), 3.39 (dd, J ˆ 5.5, 10.4 Hz, 1H, OCHHCH CH), 3.28 (dd,
cis-4-Butyl-2-ethoxytetrahydrofuran (9): According to GP 2 from the
bromoacetal 3 (220 mg, 0.84 mmol), Bu3SnH (294 mg, 1.01 mmol) and 1m
Et3B (1.2 mL, 1.2 mmol) to afford the acetal 9 (115 mg, 75%, cis/trans 92:8)
as a colorless oil after FC (pentane/Et2O 40:1). cis-9: 1H NMR (360 MHz,
CDCl3): d ˆ 5.12 (dd, J ˆ 3.4, 5.5 Hz, 1H, OCHCH2), 3.93 (t, J ˆ 7.9 Hz, 1H,
OCHHCH), 3.78 3.70 (dq, J ˆ 7.0, 9.5 Hz, 1H, OCHHCH3), 3.48 3.42
(m, 2H, OCHHCHnBu, OCHHCH3), 2.30 2.23 (m, 1H, CHnBu), 2.18
2.09 (m, 1H, OCHCHH), 1.50 1.40 (m, 3H, OCHCHH, CH2nPr), 1.34
1.17 (m, 4H, CH2CH2CH2CH3), 1.20 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.89 (t,
J ˆ 7.1 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 104.4 (d), 71.9 (t),
63.0 (t), 39.2 (t), 38.7 (d), 32.7 (t), 30.9 (t), 22.8 (t), 15.3 (q), 14.0 (q); trans-9:
1H NMR (360 MHz, CDCl3): d ˆ 4.05 (t, J ˆ 7.9 Hz, 1H, OCHH); cis/trans-
9: IR (KBr): nÄ ˆ 2960, 2926, 2860, 1446, 1404, 1114, 1043, 1004 cmÀ1; EI-
ˆ
J ˆ 5.5, 10.4 Hz, 1H, OCHHCH CH), 2.05 2.00 (m, 2H,
ˆ
CH CHCH2CH2), 1.40 1.31 (m, 2H, CH2CH2CH3), 1.26 (s, 9H, tBu),
0.89 (t, J ˆ 7.3 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 134.5 (d),
125.1 (d), 95.7 (d), 75.0 (s), 67.0 (t), 33.3 (t), 28.6 (q), 22.2 (t), 13.7 (q); CI-
‡
MS (CH4): m/z (%): 279 (1) [M ], 183 (9), 181 (13), 179 (13), 164 (12), 157
(15), 139 (13), 99 (9), 83 (100), 57 (56); elemental analysis calcd for
C12H23O2Br (279.22): C 51.62, H 8.30; found: C 51.63, H 8.26.
1-(2-Bromo-1-ethoxyethoxy)-3-methyl-2-butene (5): According to GP 1
from ethyl vinyl ether (1.20 g, 16.6 mmol), 3-methyl-2-buten-1-ol (1.57 g,
18.3 mmol) and NBS (2.95 g, 16.6 mmol). The bromoacetal 5 (2.66 g, 81%)
was obtained as a colorless oil after FC (hexane/Et2O 20:1). IR (KBr): nÄ ˆ
2975, 2879, 1444, 1348, 1118, 1056, 684 cmÀ1; 1H NMR (360 MHz, CDCl3):
‡
ˆ
d ˆ 5.40 (m, 1H, CH CMe2), 4.70 (t, J ˆ 5.5 Hz, 1H, OCHCH2Br), 4.14
MS: m/z (%): 173 (9) [M ‡H], 128 (13), 127 (96), 109 (45), 99 (22), 85 (52),
ˆ
(dd, J ˆ 7.0, 11.3 Hz, 1H, OCHHCH CMe2), 4.08 (dd, J ˆ 7.2, 11.4 Hz, 1H,
83 (51), 75 (61), 70 (66), 57 (100); elemental analysis calcd (%) for C10H20O2
(172.27): C 69.72, H 11.70; found: C 69.86, H 11.83.
ˆ
OCHHC CMe2), 3.74 3.55 (m, 2H, CH2CH3), 3.39 (d, J ˆ 5.5 Hz, 2H,
OCHCH2Br), 1.76 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.25 (t, J ˆ 7.0 Hz, 3H,
CH2CH3); 13C NMR (50 MHz, CDCl3): d ˆ 137.7 (s), 120.3 (d), 100.8 (d),
63.2 (t), 62.1 (t), 31.8 (t), 25.8 (q), 18.0 (q), 15.2 (q); CI-MS (CH4): m/z (%):
cis-2-tert-Butyl-4-butyltetrahydrofuran (10): According to GP 2 from the
bromoacetal 4 (243 mg, 0.84 mmol), Bu3SnH (294 mg, 1.01 mmol) and 1m
solution Et3B (1.2 mL, 1.2 mmol) to afford the acetal 10 (126 mg, 71%, cis/
trans 92:8) as a colorless oil after FC (pentane/Et2O 40:1). cis-10: 1H NMR
(360 MHz, CDCl3): d ˆ 5.38 (dd, J ˆ 4.6, 5.8 Hz, 1H, OCHCH2), 3.87 (t, J ˆ
7.6 Hz, 1H, OCHHCHnBu), 3.49 (t, J ˆ 8.2 Hz, 1H, OCHHCHnBu),
2.26 2.18 (m, 1H, CHnBu), 2.13 2.03 (m, 1H, OCHCHH), 1.45 1.37 (m,
3H, OCHCHH, CHCH2nPr), 1.33 1.18 (m, 4H, CH2-CH2CH3), 1.22 (s,
9H, tBu), 0.88 (t, J ˆ 7.0 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ
99.4 (d), 73.9 (s), 71.1 (t), 40.4 (t), 38.9 (d), 32.4 (t), 30.9 (t), 29.0 (q), 22.8 (t),
14.1 (q); trans-10: 1H NMR (360 MHz, CDCl3): d ˆ 4.06 (t, J ˆ 7.6 Hz, 1H,
OCHH), 3.37 (dd, J ˆ 7.0 Hz, J ˆ 8.2 Hz, 1H, OCHH); cis/trans-10: IR
(KBr): nÄ ˆ 2972, 2930, 2860, 1467, 1365, 1199, 1008 cmÀ1; CI-MS (CH4): m/z
‡
236 (10) [M À H], 171 (10), 153 (100), 151 (99), 125 (34), 123 (37), 101 (63),
85 (78), 83 (41), 69 (46); elemental analysis calcd for C9H17O2Br (237.14): C
45.59, H 7.23; found: C 45.56, H 7.21.
1-(2-Bromo-1-tert-butoxyethoxy)-3-methyl-2-butene (6): According to
GP 1 from tert-butyl vinyl ether (0.34 g, 3.43 mmol), 3-methyl-2-buten-1-
ol (0.33 g, 3.80 mmol) and NBS (2.97 g, 0.61 mmol). The bromoacetal 6
(0.65 g, 72%) was obtained as a colorless oil after FC (hexane/Et2O 20:1).
IR (KBr): nÄ ˆ 2975, 1446, 1366, 1179, 1100, 1014, 935 cmÀ1
;
1H NMR
ˆ
(360 MHz, CDCl3): d ˆ 5.37 5.30 (m, 1H, CH CMe2), 4.89 (t, J ˆ 5.8 Hz,
1H, OCHCH2Br), 4.05 (d, J ˆ 7.0 Hz, 2H, OCHCH2Br), 3.41 (dd, J ˆ 5.5,
‡
ˆ
ˆ
10.4 Hz, 1H, OCHHCH C), 3.30 (dd, J ˆ 5.8, 10.7 Hz, 1H, OCHHCH C),
1.75 (s, 3H, CH3), 1.68 (s, 3H, CH3), 1.27 (s, 9H, tBu); 13C NMR (50 MHz,
CDCl3): d ˆ 136.8 (s), 120.8 (d), 95.8 (d), 74.9 (s), 60.6 (t), 33.3 (t), 28.7 (q),
(%): 201 (76) [M ‡H], 145 (18), 128 (9), 127 (100), 109 (7); elemental
analysis calcd for C10H24O2 (200.32): C 71.94, H 12.08; found: C 71.96, H
11.90.
‡
25.7 (q), 18.0 (q); CI-MS (CH4): m/z (%): 267 (6) [M ‡ 3], 265 (6) [M ‡ 1],
cis-2-Ethoxy-4-isopropyltetrahydrofuran (11): According to GP 2 from the
bromoacetal 5 (0.5 g, 2.1 mmol), Bu3SnH (735 mg, 2.52 mmol) and 1m Et3B
(2.9 mL, 2.9 mmol) to afford the acetal 11 (266 mg, 80%, cis/trans 77: 23) as
a colorless oil after FC (pentane/Et2O 20:1). cis-11: 1H NMR (360 MHz,
CDCl3): d ˆ 5.13 (dd, J ˆ 3.7, 5.8 Hz, 1H, OCHCH2), 3.91 (t, J ˆ 7.6 Hz, 1H,
OCHHCHiPr), 3.79 3.66 (m, 1H, CHHCH3), 3.54 3.39 (m, 2H, OCHH-
CHiPr, CHHCH3), 2.30 2.21 (m, 1H, OCH2CHiPr), 1.90 1.80 (m, 1H,
CHMe2), 1.60 1.42 (m, 2H, OCHCH2CH), 1.20 (t, J ˆ 7.0 Hz, 3H,
CH2CH3), 0.92 (d, J ˆ 6.7 Hz, 3H, CH3), 0.87 (d, J ˆ 6.7 Hz, 3H, CH3);
13C NMR (50 MHz, CDCl3): d ˆ 104.6 (d), 70.6 (t), 63.1 (t), 46.7 (d), 37.9
(d), 31.6 (d), 21.1 (q), 21.6 (q), 15.3 (q); trans-11: 1H NMR (360 MHz,
CDCl3): d ˆ 5.09 (d, J ˆ 4.9 Hz, 1H, OCHCH2), 4.05 (t, J ˆ 8.2 Hz, 1H,
OCHHCHiPr), 1.2 (t, J ˆ 7.0 Hz, 3H, CH2CH3), 0.91 (d, J ˆ 6.7 Hz, 3H,
CH3), 0.86 (d, J ˆ 6.7 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 104.2
(d), 71.6 (t), 62.5 (t), 44.3 (d), 37.6 (t), 32.3 (d), 21.5 (q), 21.3 (q), 15.3 (q); cis/
trans-11: IR (KBr): nÄ ˆ 2962, 2874, 1467, 1371, 1114, 1068, 1006 cmÀ1; MS-
199 (10), 197 (10), 181 (100), 179 (98), 155 (74), 143 (86), 137 (28), 125 (68);
elemental analysis calcd for C11H21O2Br (265.19): C 49.82, H 7.98; found: C
49.81, H 7.89.
cis-2-Ethoxy-4-methyltetrahydrofuran (7): The reaction was performed in
CH2Cl2 due to the high volatility of the resulting tetrahydrofuran.
According to the GP 2 from bromoacetal 1 (438 mg, 2.1 mmol), Bu3SnH
(735 mg, 2.52 mmol) and 1m Et3B (2.9 mL, 2.9 mmol) in CH2Cl2 (52 mL).
After flash chromatography (pentane/Et2O 40:1), cis-7 (71%, 98% ds) was
obtained as a colorless oil. IR (KBr): nÄ ˆ 2974, 2876, 1446, 1373, 1112, 1076,
987 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 5.13 (dd, J ˆ 3.1, 5.5 Hz, 1H,
OCHCH2), 3.93 (t, J ˆ 6.7 Hz, 1H, OCHHCHMe), 3.75 (dq, J ˆ 7.0, 9.5 Hz,
1H, OCHHCH3), 3.49 3.40 (m, 2H, OCHHCHMe, OCHHCH3), 2.32
2.20 (m, 2H, CH2), 1.49 1.42 (m, 1H, CHMe), 1.20 (t, J ˆ 7.0 Hz, 3H,
OCH2CH3), 1.08 (d, J ˆ 6.7 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ
104.7 (d), 73.2 (t), 63.1 (t), 40.8 (t), 33.0 (d), 17.1 (q), 15.3 (q); CI-MS (CH4):
‡
‡
‡
m/z (%): 131 (12) [M ‡H], 113 (13), 85 (100), 73 (41); HRMS (CI/
CI (CH4): m/z (%): 159 (13) [M ‡H], 157 (19) [M À H], 127 (8), 113
‡
isobutane): calcd for C7H15O2: 131.10665, found: 131.10661 [M ‡H].
(100), 95 (16), 85 (43), 75 (14), 56 (19); HRMS (CI, isobutane): calcd for
C9H19O2: 159.13795; found: 159.13794 [M ‡H].
‡
cis-4-Methyl-2-tert-butoxytetrahydrofuran (8): According to GP 2 from
the bromoacetal 2 (0.5 g, 2.1 mmol), Bu3SnH (735 mg, 2.52 mmol) and 1m
Et3B (2.9 mL, 2.9 mmol) to afford the acetal cis-8 (226 mg, 68%, 98% ds)
as a colorless oil after FC (pentane/Et2O 10:1). IR (KBr): nÄ ˆ 2974, 2876,
cis-4-Isopropyl-2-tert-butoxytetrahydrofuran (12): According to GP 2 from
the bromoacetal 6 (0.3 g, 1.13 mmol), Bu3SnH (395 mg, 1.36 mmol) and 1m
Et3B (1.6 mL, 1.6 mmol) to afford the acetal 12 (174 mg, 83%, cis/trans
77:23) as a colorless oil after FC (pentane/Et2O 20:1). cis-12: 1H NMR
(360 MHz, CDCl3): d ˆ 5.40 (dd, J ˆ 5.4, 5.5 Hz, 1H, OCHCH2), 3.87 (t, J ˆ
7.9 Hz, 1H, OCHHCHiPr), 3.56 (dd, J ˆ 8.2, 10.1 Hz, 1H, OCHHCHiPr),
2.24 2.18 (m, 1H, CHiPr), 1.91 1.74 (m, 1H, CHMe2), 1.58 1.41 (m, 2H,
OCHCH2), 1.24 (s, 9H, tBu), 0.92 (d, J ˆ 6.7 Hz, 3H, CH3), 0.86 (d, J ˆ
6.4 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 99.6 (d), 74.0 (s), 70.5
(t), 46.6 (d), 39.1 (t), 31.6 (d), 28.9 (q), 21.8 (q), 21.6 (q); trans-12: 1H NMR
(360 MHz): d ˆ 4.08 (t, J ˆ 7.9 Hz, 1H, OCHHCHiPr), 3.44 (t, J ˆ 7.9 Hz,
1H, OCHHCHiPr), 1.23 (s, 9H, tBu), 0.91 (d, J ˆ 6.7 Hz, 3H, CH3), 0.87 (d,
J ˆ 6.4 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 99.2 (d), 73.9 (s),
71.1 (t), 44.4 (d), 38.7 (t), 32.3 (d), 21.3 (q), 21.2 (q); cis/trans-12: IR (KBr):
nÄ ˆ 2972, 2874, 1469, 1365, 1197, 1006 cmÀ1; MS-CI (CH4): m/z (%): 187
1460, 1366, 1259, 1194, 1018, 993 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ
5.40 (dd, J ˆ 4.3, 1H, 5.2 Hz, OCHCH2), 3.87 (t, J ˆ 7.9 Hz, 1H,
OCHHCHCH3), 3.46 (t, J ˆ 8.2 Hz, 1H, OCHHCHCH3), 2.27 2.18 (m,
2H, OCHCH2CHCH3), 1.43 139 (m, 1H, CHCH3), 1.25 (s, 9H, tBu), 1.07
(d, J ˆ 6.4 Hz, 3H, CH3); NOE difference spectra (500 MHz): d ˆ 5.41
5.38 (tBuOCH) ! 2.27 2.18 (2.05%), 1.26 1.21 (1.71%), 3.90 3.83
(OCHH) ! 3.49 3.43 (6.57%), 2.27 2.18 (1.37%), 1.26 1.21 (0.14%),
3.49 3.43 (OCHH) ! 3.90 3.83 (6.89%), 2.27 2.18 (0.57%), 1.26 1.21
(0.36%), 1.08 1.05 (1.80%), 2.27 2.18 (tBuOCHCHH) ! 5.41 5.38
(1.21%), 3.90 3.83 (0.56%), 3.49 3.43 (0.11%), 1.43 1.39 (4.25%),
1.26 1.21 (0.25%), 1.08 1.05 (1.0%), 1.43 1.39 (CHMe) ! 5.41 5.38
(0.46%), 3.49 3.43 (0.36%), 2.27 2.18 (7.06%), 1.08 1.05 (2.29%),
1.08 1.05 (CH-CH3) ! 3.49 3.43 (0.49%), 2.26 2.18 (0.87%); 13C NMR
(50 MHz, CDCl3): d ˆ 99.6 (d), 74.0 (s), 73.1 (t), 42.1 (t), 33.2 (d), 28.9 (q),
‡
(16) [M ‡H], 141 (7), 131 (45), 129 (21), 113 (100), 95 (17), 85 (12), 69 (7),
57 (40); HRMS (CI, isobutane): calcd for C11H23O2: 187.16925; found:
‡
‡
17.0 (q); MS-CI (CH4): m/z (%): 159 (36) [M ‡H], 103 (27), 101 (18), 85
187.16905 [M ‡H].
Chem. Eur. J. 2003, 9, No. 7
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1571 $ 20.00+.50/0
1571

P. Renaud et al.
FULL PAPER
4-(2-Bromo-1-tert-butoxyethoxy)-1,2-butadiene (13): According to GP 1
from tert-butyl vinyl ether (750 mg, 7.5 mmol), 2,3-butadien-1-ol (525 mg,
3.80 mmol) and NBS (1.33 g, 7.5 mmol). The bromoacetal 13 (1.20 g, 64%)
was obtained as a colorless oil after FC (hexane/Et2O 40:1). IR (KBr): nÄ ˆ
2.02 1.93 (m, 1H, CHMe), 1.75 1.65 (m, 1H, CH(CH3)2), 1.48 (dt, J ˆ 2.8,
7.3 Hz, 1H, CHiPr), 1.20 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 1.05 (d, J ˆ 6.7 Hz,
3H, CHCH3), 0.95 (d, J ˆ 2.8 Hz, 3H, CH3), 0.94 (d, J ˆ 2.8 Hz, 3H, CH3).
NOE difference spectra (500 MHz): 4.83 4.80 (EtOCH) ! 3.96 3.90 (w),
3.77 3.68 (m), 3.50 3.40 (s), 2.13 1.93 (w), 1.74 1.65 (m), 1.50 1.44 (m),
1.23 1.17 (m), 0.97 0.91 (s), 3.96 3.90 (OCHH) ! 3.50 3.40 (s), 2.13
1.93 (m), 2.13 1.93 (CHCH3) ! 4.83 4.80 (m), 3.96 3.90 (s), 3.50 3.40
(m), 1.74 1.65 (m), 1.50 1.44 (m), 1.07 1.03 (s), 0.97 0.91 (s), 1.74 1.65
(CHMe2) ! 4.83 4.80 (m), 2.13 1.93 (w), 1.50 1.44 (w), 0.97 0.91 (s),
1.50 1.44 (CH-iPr) ! 4.83 4.80 (m), 2.13 1.93 (m), 1.74 1.65 (m), 1.07
1.03 (m), 0.97 0.91 (s), 1.07 1.03 (CH-CH3) ! 3.50 3.40 (s), 2.13 1.93
(s), 1.50 1.44 (s); 13C NMR (50 MHz, CDCl3): d ˆ 108.2 (d), 73.7 (t), 63.0
(t), 60.1 (d), 36.8 (d), 29.8 (d), 20.7 (q), 17.2 (q), 15.4 (q).
1
2978, 2939, 1957, 1471, 1369, 1105, 846 cmÀ1; H NMR (360 MHz, CDCl3):
ˆ ˆ
d ˆ 5.25 (quint, J ˆ 6.7 Hz, 1H, OCH2CH C CH2), 4.93 (t, J ˆ 5.5 Hz, 1H,
ˆ ˆ
OCHCH2Br), 4.80 (dt, J ˆ 2.4, 6.7 Hz, 2H, CH C CHH), 4.10 (dt, J ˆ 2.4,
ˆ
6.7 Hz, 2H, OCH2CH C), 3.39 (dd, J ˆ 5.8, 10.7 Hz, 1H, OCHCHHBr),
3.29 (dd, J ˆ 5.5, 10.7 Hz, 1H, OCHCHHBr), 1.27 (s, 9H, tBu); 13C NMR
(50 MHz, CDCl3): d ˆ 209.1 (s), 95.7 (d), 88.0 (d), 76.0 (t), 75.1 (s), 62.0 (t),
‡
‡
33.3 (t), 28.7 (q); MS-CI (CH4): m/z (%): 251 (12) [M ‡2], 249 (13) [M ],
181 (34), 176 (36), 127 (71), 113 (23), 109 (19), 57 (100); elemental analysis
calcd for C10H17O2Br (249.15): C 48.21, H 6.88; found: C 47.83, H 6.99.
Mixture of diasteroisomers: IR (KBr): nÄ ˆ 2962, 2933, 2874, 1469, 1375,
cis-2-tert-Butyl-4-vinyltetrahydrofuran (14): According to GP 2 from the
bromoacetal 13 (523 mg, 2.1 mmol), Bu3SnH (735 mg, 2.52 mmol) and 1m
solution Et3B (2.94 mL, 2.94 mmol) to afford the acetal 14 (252 mg, 71%,
cis/trans 92:8) as a colorless oil after FC (pentane/Et2O 40:1). cis-14:
1H NMR (360 MHz, CDCl3): d ˆ 5.82 (ddd, J ˆ 8.6, 10.4, 17.1 Hz, 1H,
‡
1114, 1076, 1028, 981 cmÀ1; CI-MS (CH4): m/z (%): 173 (15) [M ‡H], 171
(19), 155 (13), 127 (100), 115 (10), 97 (12), 83 (11); HRMS (ESI): calcd for
C10H20O2Na: 195.13554; found: 195.13565.
2-Iodo-3-(2-propenoxy)-3-methoxy-1-phenyl-1-propanone (17): N-Iodo-
succinimide (1.4 g, 6.2 mmol) was added in portions at 08C protected from
ˆ
CHCH CH2), 5.43 (dd, J ˆ 4.0, 5.5 Hz, 1H, OCHCH2), 5.09 5.54 (m, 2H,
ˆ
CHCH CH2), 3.88 (t, J ˆ 7.9 Hz, 1 H, OCHHCH), 3.62 (t, J ˆ 8.5 Hz, 1H,
the light to
a solution of the 3-methoxy-1-phenylpropenone (1.0 g,
ˆ
OCHHCH), 2.85 2.73 (m, 1H, CHCH CH2), 2.26 (ddd, J ˆ 5.8, 8.9,
6.2 mmol) and allyl alcohol (1.70 g, 29.4 mmol) in CH2Cl2 (10 mL). The
mixture was stirred at rt for 2 d. Hexane was added and the precipitated
was filtered off. The filtrate was washed with H2O and NaCl, dried and
evaporated. FC (hexane/Et2O 10:1) afforded 17 (1.26 g, 59%) as a yellow
oil and starting material (0.32 g, 32%). IR (KBr): nÄ ˆ 3067, 2989, 2931, 1680,
1597, 1448, 1294, 1047 cmÀ1. Major diasteroisomer: 1H NMR (360 MHz,
CDCl3): d ˆ 7.96 (d, J ˆ 7.3 Hz, 2H, arom. H), 7.59 (t, J ˆ 7.3 Hz, 1H, arom.
H), 7.47 (t, J ˆ 7.6 Hz, 2H, arom. H), 5.79 (ddt, J ˆ 5.8, 10.4, 17.1 Hz, 1H,
13.4 Hz, 1H, OCHCHH), 1.64 (ddd, J ˆ 4.0, 8.5, 12.8 Hz, 1H, OCHCHH),
1.26 (s, 9H, tBu); 13C NMR (50 MHz, CDCl3): d ˆ 139.0 (d), 115.1 (t), 99.4
(d), 74.0 (s), 70.8 (t), 43.3 (d), 40.5 (t), 28.9 (q); trans-14: 1H NMR
(360 MHz, CDCl3): d ˆ 4.10 (t, J ˆ 7.9 Hz, 1H, OCHH), 3.49 (t, J ˆ 7.3 Hz,
1H, OCHH); cis/trans-14: IR (KBr): nÄ ˆ 3080, 2964, 2872, 1643, 1365, 1194,
1010, 914 cmÀ1; CI-MS (CH4): m/z (%): 171 (5) [M ‡H], 115 (29), 97 (100),
‡
85 (3), 69 (6), 57 (60); HRMS (CI, isobutane): calcd for C10H19O2:
‡
171.13795; found: 171.13807 [M ‡H].
ˆ
OCH2CH CH2), 5.43 (d, J ˆ 8.6 Hz, 1H, MeOCHCHI), 5.16 (d, J ˆ 8.2 Hz,
ˆ
1H, MeOCHCHI), 5.22 5.10 (m, 2H, OCH2CH CH2), 4.21 4.10 (m, 2H,
2-Bromo-1-ethoxy-3-methyl-1-(2-propenoxy)-butane (15): According to
GP 1 from ethyl 3-methyl 1-butenyl ether (2.6 g, 23.0 mmol), allyl alcohol
(1.3 g, 23.0 mmol) and NBS (4.1 g, 23.0 mmol). The bromoacetal 15 (1.4 g,
24%) was obtained as a colorless oil after FC (hexane/Et2O). IR (KBr):
OCH2CH CH2), 3.49 (s, 3H, CH3O); 13C NMR (50 MHz, CDCl3): d ˆ
ˆ
193.4 (s), 134.4 (s), 133.8 (d), 133.7 (d), 128.8 (d), 128.6 (d), 117.6 (t), 103.4
‡
(d), 70.3 (t), 54.0 (d), 24.3 (q); CI-MS (CH4): m/z (%): 347 (7) [M ‡H], 329
(13), 315 (99), 289 (61), 267 (13), 219 (60), 189 (51), 163 (68), 160 (20), 101
(100); elemental analysis calcd for C13H15IO3 (346.17): C 45.11; H 4.37;
found: C 45.15, H 4.37.
nÄ ˆ 3082, 2970, 2933, 2877, 1464, 1386, 1112, 1055, 925 cmÀ1
;
1H NMR
ˆ
(360 MHz, CDCl3): d ˆ 6.00 5.90 (m, 1H, OCH2CH ), 5.33 (dq, J ˆ 1.5,
ˆ
ˆ
17.1 Hz, 1H, CHH CH), 5.19 (dq, J ˆ 1.5, 10.5 Hz, 1H, CHH CH), 4.64 (d,
(r-2,t-3,c-4)-[4-(Iodomethyl)-2-methoxytetrahydro-3-furanyl](phenyl)me-
thanone (18): A solution of iodoacetal 17 (2.5 g, 7.25 mmol) and (Bu3Sn)2
(5%, 0.21 g, 0.36 mmol) in benzene (36 mL) was irradiated with a sun lamp
at 108C for 3 h. Then a saturated aqueous solution of KF (20 mL) was
added and the resulting mixture was stirred for 2 h. The organic phase was
washed with H2O, dried over MgSO4 and evaporated under reduced
pressure. Purification by FC (hexane/Et2O 8:1) gave 18 (1.85 g, 74%, one
diastereomer) as a yellow oil. IR (KBr): nÄ ˆ 3061, 2933, 2833, 1687, 1597,
J ˆ 7.9 Hz, 1H, OCHCHBr), 4.15 (ddt, J ˆ 1.5, 5.5, 8.9 Hz, 2H,
ˆ
OCH2CH CH2), 4.02 (dd, J ˆ 3.1, 7.6 Hz, 1H, OCHCHBr), 3.73 3.53
(m, 2H, OCH2CH3), 2.15 2.07 (m, 1H, CH(CH3)2), 1.22 (t, J ˆ 7.0 Hz, 3H,
OCH2CH3), 1.07 (d, J ˆ 7.0 Hz, 3H, CH3), 0.95 (d, J ˆ 7.0 Hz, 3H, CH3);
13C NMR (50 MHz, CDCl3): d ˆ 134.2 (d), 117.1 (t), 102.5 (d), 67.8 (t), 63.9
(d), 62.6 (t), 29.4 (d), 21.9 (q), 17.3 (q), 15.2 (q); CI-MS (CH4): m/z (%): 206
‡
(7) [M À 45], 204 (7), 195 (26), 193 (26), 171 (10), 115 (100), 113 (21), 85
(32), 73 (24), 57 (13); elemental analysis calcd for C10H19O2Br (251.16): C
47.82, H 7.63; found: C 47.78, H 7.65.
1448, 1379, 1228, 1064 cmÀ1
;
1H NMR (500 MHz, [D8]toluene): d ˆ 8.00
(dd, J ˆ 1.3, 8.4 Hz, 2 arom. H), 7.14 6.97 (m, 3 arom. H), 4.91 (d, J ˆ
2.1 Hz, 1H, MeOCHCH), 3.98 (dd, J ˆ 7.7, 8.4 Hz, 1H, OCHHCHCH2I),
3.62 (dd, J ˆ 2.0, 6.0 Hz, 1H, MeOCHCHCOPh), 3.54 (t, J ˆ 8.4 Hz, 1H,
OCHHCHCH2I), 3.16 3.12 (m, 1H, OCHHCHCH2I), 3.06 (s, 3H, CH3O),
2.79 (dd, J ˆ 6.6, 9.8 Hz, 1H, CHCHHI), 2.70 (dd, J ˆ 7.9, 9.7 Hz, 1H,
CHCHHI). NOE difference spectra (500 MHz): 4.91 4.89 (MeOCH) !
8.02 7.98 (1.45%), 3.63 3.60 (1.09%), 4.01 3.96 (OCHH) ! 8.02 7.98
(0.05%), 4.91 4.89 (0.18%), 3.56 3.50 (10.74%), 3.16 3.11 (2.46%),
3.63 3.60 (MeOCHCHCOPh) ! 8.02 7.98 (8.11%), 4.91 4.89 (1.50%),
4.01 3.96 (0.29%), 2.82 2.78 (1.61%), 2.72 2.68 (1.73%), 3.56 3.50
(OCHH) ! 4.01 3.96 (11.53%), 2.82 2.78 (1.01%), 2.72 2.68 (1.35%),
3.16 3.11 (CH-CH2I) ! 8.02 7.98 (0.40%), 7.14 6.97 (0.92%), 4.91 4.89
(0.56%), 4.01 3.96 (2.26%), 3.63 3.60 (0.73%), 3.56 3.50 (0.09%),
2.82 2.78 (1.11%), 2.72 2.68 (1.12%); 13C NMR (50 MHz, CDCl3): d ˆ
196.3 (s), 134.0 (s), 133.7 (d), 128.8 (d), 107.4 (d), 73.0 (t), 61.1 (d), 55.3 (d),
(r-2,c-3,c-4)- and (r-2,t-3,c-4)-2-Ethoxy-4-methyl-3-isopropyltetrahydrofur-
an (16): According to GP 2 from the bromoacetal 15 (527 mg, 2.1 mmol),
Bu3SnH (735 mg, 2.52 mmol) and 1m solution Et3B (2.94 mL, 2.94 mmol) to
afford the acetal 16 (160 mg, 44%, 1:1 mixture of two diasteromers) after
FC (pentane/Et2O 40:1). These diastereomers were separated by FC and
characterized. Their relative stereochemistry was assigned by NOE experi-
ments.
(r-2,c-3,c-4)-16: 1H NMR (360 MHz, CDCl3): d ˆ 4.88 (d, J ˆ 4.9 Hz, 1H,
OCHCHiPr), 4.03 (t, J ˆ 7.0 Hz, 1H, OCHHCHMe), 3.74 (dq, J ˆ 7.0,
9.8 Hz, 1H, OCHHCH3), 3.67 (dd, J ˆ 2.1, 8.2 Hz, 1H, O-CHHiPr), 3.37
(dq, J ˆ 7.0, 9.8 Hz, 1H, OCHHCH3), 2.25 (dq, J ˆ 2.1, 7.3 Hz, 1H,
CHCH3), 1.91 1.82 (m, 1H, CH(CH3)2), 1.61 (ddd, J ˆ 4.9, 7.3, 12.2 Hz,
1H, CHiPr), 1.20 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 1.10 (d, J ˆ 7.0 Hz, 3H,
CH-CH3), 0.95 (d, J ˆ 6.1 Hz, 3H, CH3), 0.93 (d, J ˆ 6.4 Hz, 3H, CH3).
NOE difference spectra (500 MHz): 4.90 4.87 (EtOCH) ! 4.05 4.00 (w),
3.78 3.65 (m), 3.41 3.33 (s), 1.64 1.58 (s), 0.99 0.90 (m), 4.05 4.00
(OCHH) ! 3.69 3.65 (s), 2.30 2.21 (m), 1.64 1.58 (w), 3.69 3.65
(OCHH) ! 4.90 4.00 (m), 4.05 4.00 (s), 1.20 1.15 (m), 2.30 2.21
(CH3CH) ! 4.05 4.00 (s), 3.69 3.65 (w), 1.64 1.58 (s), 1.11 1.09 (s),
0.92 0.90 (m), 1.64 1.58 (CHiPr) ! 4.90 4.87 (s), 4.05 4.00 (w), 2.30
2.21 (m), 0.98 0.90 (s); 13C NMR (50 MHz, CDCl3): d ˆ 104.2 (d), 75.6 (t),
62.9 (t), 55.0 (d), 33.0 (d), 24.0 (d), 21.8 (q), 21.5 (q), 16.0 (q), 15.4 (q).
‡
42.8 (q), 6.4 (t); CI-MS (CH4): m/z: 347 (10) [M ‡H], 315 (100), 287 (40),
219 (28), 159 (32), 105 (100); elemental analysis calcd for C13H15IO3
(346.17): C 45.11, H 4.37; found: C 45.15, H 4.47.
3-(2-Bromo-1-ethoxy)-1,4-pentadiene (19): According to GP 1 from ethyl
vinyl ether (0.72 g, 10 mmol), 1,4-pentadien-3-ol (840 mg, 10 mmol) and
NBS (1.78 g, 10 mmol). FC (hexane/Et2O 40:1) gave 19 (2.02 g, 86%) as a
colorless oil. IR (KBr): nÄ ˆ 3029, 2978, 2883, 1420, 1115, 1028, 928 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 5.92 5.71 (m, 2H, 2CH CH2), 5.32 5.15
ˆ
(r-2,t-3,c-4)-16: 1H NMR (360 MHz, CDCl3): d ˆ 4.82 (d, J ˆ 2.8 Hz, 1H,
OCHCHiPr), 3.94 (t, J ˆ 7.9 Hz, 1H, OCHHCHMe), 3.72 (dq, J ˆ 7.0,
9.8 Hz, 1H, OCHHCH3), 3.50 3.40 (m, 2H, OCHHCHMe, OCHHCH3),
(m, 4H, 2CH2 CH), 4.77 (t, J ˆ 5.2 Hz, 1H, OCHCH2Br), 4.54 (tt, J ˆ 1.2,
ˆ
ˆ
6.1 Hz, 1H, CH(CH CH2)2), 3.65 (dq, J ˆ 7.0, 9.2 Hz, 1H, CH3CHH), 3.58
(dq, J ˆ 7.0, 9.5 Hz, 1H, CH3CHH), 3.39 (dd, J ˆ 2.7, 5.2 Hz, 2H, CH2Br),
1572
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1572 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 7

Stereoselective Radical Cyclizations
1566 1577
1.23 (t, J ˆ 7.0 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 137.4 (d),
Methyl-2-{[2-(tert-butoxy)-7a-methyl-5-oxo-2,3,3a,4,5,7a-hexahydro-1-
136.9 (d), 117.5 (t), 116.3 (t), 99.5 (d), 78.8 (d), 62.0 (t), 32.1 (t), 15.2 (q); MS
benzofuran-4-yl]methyl}acrylate (23): A solution of 2-(methoxycarbonyl)-
propenyltributylstannane (1.55 g, 4 mmol), AIBN (4 mg, 0.025 mmol) and
the iodoacetal 21 (0.18 g, 0.5 mmol) in benzene (6 mL) was heated under
reflux. The reaction was monitored by TLC until disappearance of the
starting material. An aqueous KF solution was added and the mixture was
stirred at rt for 2 h. The organic layer was washed with H2O, dried over
MgSO4 and evaporated. FC (hexane/Et2O 2:1) gave 23 (0.11 g, 68%, 81%
ds) as a mixture of diastereomers. IR (KBr): nÄ ˆ 3030, 2976, 1722, 1680,
1440, 1347, 1199, 1143 cmÀ1. Major diastereomer: 1H NMR (360 MHz,
‡
‡
(EI): m/z (%): 153 (65) [M À 81], 151 (65) [M À 83], 125 (36), 123 (37),
67 (100), 65 (20); elemental analysis calcd for C9H15O2Br (235.12): C 45.98,
H 6.43; found: C 46.00, H 6.38.
5-Ethoxy-3-methyl-2-vinyltetrahydrofuran (20): According to the GP 2
from 19 (0.49 g, 2.1 mmol), Bu3SnH (735 mg, 2.5 mmol) and a 1m solution
of Et3B in hexane (2.9 mL, 2.9 mmol). FC (hexane/Et2O 10:1) gave 20
(0.21 g, 65%, 98% ds). IR (KBr): nÄ ˆ 3082, 2974, 2876, 1448, 1375, 1107,
985, 923 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 5.77 (ddd, J ˆ 7.3, 10.4,
ˆ
CDCl3): d ˆ 6.50 (dd, J ˆ 1.5, 10.1 Hz, 1H, CH CHCMe), 6.26 (d,
ˆ
ˆ
17.4 Hz, 1H, CH CH2), 5.32 5.16 (m, 2H, CH2 CH), 5.15 (dd, J ˆ 4.0,
ˆ
ˆ
J ˆ 1.2 Hz, 1H, CHH CCO2Me), 5.80 (d, J ˆ 10.1 Hz, 1H, CH CO), 5.56
ˆ
5.8 Hz, 1H, OCHCH2), 3.93 (t, J ˆ 8.2 Hz, 1H, CHCH CH2), 3.79 (dq, J ˆ
ˆ
(d, J ˆ 1.2 Hz, 1H, CHH CCO2Me), 5.27 (d, J ˆ 5.2 Hz, 1H, OCHCH2),
7.0, 9.5 Hz, 1H, CH3CHH), 3.45 (dq, J ˆ 7.0, 9.5 Hz, 1H, CH3CHH), 2.40
(ddd, J ˆ 5.8, 8.9, 13.4 Hz, 1H, OCHCHH), 1.91 1.77 (m, 1H, CHMe),
1.57 (ddd, J ˆ 3.7, 9.2, 13.1 Hz, 1H, OCHCHH), 1.20 (t, J ˆ 7.0 Hz, 3H,
CH3), 1.03 (d, J ˆ 6.4 Hz, 3H, CH3). NOE difference spectra (500 MHz):
ˆ
3.76 (s, 3H, CH3O), 2.75 2.72 (m, 2H, CHC O, CHCHCO), 2.64 2.62
ˆ
(m, 2H, CH2C CH2), 2.03 (ddd, J ˆ 0.9, 7.0, 12.8 Hz, 1H, CHHCHCHCO),
1.85 (dt, J ˆ 5.2, 12.5 Hz, 1H, CHHCHCHCO), 1.59 (s, 3H, CH3), 1.23 (s,
9H, tBuO). NOE difference spectra (500 MHz): 5.29 5.24 (tBuOCH) !
2.06 1.99 (0.70%), 1.90 1.81 (5.67%), 1.25 1.21 (6.37%), 2.78 2.70
(tBuOCHCH2CH) ! 2.65 2.60 (0.31%), 2.06 1.99 (2.43%), 1.90 1.81
ˆ
5.83 5.72 (OCHCH CH2) ! 5.20 5.16 (s), 3.97 3.90 (m), 1.89 1.79 (m),
5.16 5.12 (EtOCH) ! 5.83 5.72 (m), 3.50 3.41 (m), 2.45 2.36 (m),
ˆ
3.97 3.90 (OCHCH CH2) ! 5.83 5.72 (m), 5.31 5.25 (s), 1.89 1.79 (m),
ˆ
(0.48%), 1.61 1.58 (1.41%), 2.65 2.60 (CH2C CH2) ! 2.78 2.70
1.56 1.48 (m), 1.05 1.01 (s), 2.45 2.36 (EtOCHCHH) ! 5.16 5.12 (m),
1.89 1.79 (m), 1.56 1.48 (s), 1.89 1.79 (CH-Me) ! 5.83 5.72 (m), 5.16
5.12 (w), 3.97 3.90 (w), 2.45 2.36 (m), 1.56 1.48 (w), 1.05 1.01 (s), 1.56
1.48 (EtOCHCHH) ! 5.16 5.12 (w), 3.97 3.90 (w), 2.45 2.36 (s), 1.89
1.79 (w), 1.05 1.01 (m), 1.05 1.01 (CH-CH3) ! 3.97 3.90 (s), 1.89 1.79
(s), 1.56 1.48 (s); 13C NMR (50 MHz, CDCl3): d ˆ 137.1 (d), 117.2 (t), 103.7
(d), 85.4 (d), 63.4 (t), 41.2 (t), 39.2 (d), 15.8 (q), 15.3 (q); MS (EI): m/z (%):
(2.73%), 1.61 1.58 (2.04%), 2.06 1.99 (tBuOCHCHH) ! 5.29 5.24
(1.95%), 2.78 2.70 (7.79%), 1.90 1.81 (23.54%), 1.90 1.81
(tBuOCHCHH) ! 5.29 5.24 (9.28%), 2.78 2.70 (2.92%), 2.06 1.99
(18.91%), 1.61 1.58 (CH3) ! 2.78 2.70 (2.72%), 2.65 2.60 (2.01%),
1.25 1.21 (0.13%); 13C NMR (50 MHz, CDCl3): d ˆ 199.8 (s), 166.9 (s),
149.8 (d), 137.5 (t), 127.4 (s), 124.9 (d), 96.9 (d), 78.3 (s), 74.1 (s), 51.8 (q),
47.9 (d), 46.0 (d), 41.1 (t), 35.1 (t), 29.1 (q), 28.8 (q). Minor diastereoisomer:
1H NMR (360 MHz, CDCl3): d ˆ 6.66 (dd, J ˆ 1.22, 10.07 Hz, 1H,
‡
157 (5) [M ‡H], 111 (69), 100 (100), 93.10 (71), 85 (74), 82 (27), 72 (38), 67
(76), 57 (74); HRMS (CI, isobutane): calcd for C9H15O2: 155.10665; found:
ˆ
CH CH), 5.59 (d, J ˆ 1.22 Hz, 1H, tBuOCH), 3.79 (s, 3H, CH3), 1.19 (s,
‡
155.10660 [M À H].
‡
9H, tBuO); MS (CI, CH4): m/z (%): 323 (8) [M ‡H], 267 (21), 235 (30),
217 (63), 169 (24), 151 (100), 136 (15), 57 (78); elemental analysis calcd for
C18H26O5 (322.46): C 67.06, H 8.13; found: C 67.10, H 8.09.
4-[1-(tert-Butoxy)-2-iodomethoxy]-4-methyl-2,5-cyclohexadien-1-one
(21): According to the GP 1 from tert-butyl vinyl ether (1.00 g, 10 mmol),
4-hydroxy-4-methyl-2,5-cyclohexadien-1-one[49] (1.24 g, 10 mmol) and NIS
(2.25 g, 10 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at rt
overnight protected from the light. After usual workup, FC (hexane/Et2O
5:1) gave 21 (2.80 g, 80%) as a colorless oil. IR (KBr): nÄ ˆ 3043, 2978, 2931,
1668, 1631, 1338, 1091 cmÀ1; 1H NMR (360 MHz, CDCl3): d ˆ 7.04 (dd, J ˆ
3-(2-Bromo-1-ethoxy-2-methylpropoxy)-1,4-pentadiene (24): According to
GP 1 from 1-ethoxy-2-methyl-1-propene[50] (1.00 g, 10 mmol), 1,4-penta-
dien-3-ol (840 mg, 10 mmol) and NBS (1.78 g, 10 mmol). FC (hexane/Et2O
20:1) afforded 24 (1.12 g, 43%) as a colorless oil. IR (KBr): nÄ ˆ 3084, 2978,
2876, 1464, 1383, 1112, 1055, 927 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ
ˆ
ˆ
3.1, 5.1 Hz, 1H, CH CH), 7.01 (dd, J ˆ 3.1, 5.1 Hz, 1H, CH CH), 6.31 (dd,
ˆ
ˆ
5.92 5.73 (m, 2H, 2CH CH2), 5.32 5.15 (m, 4H, 2CH2 CH), 4.56 (tt, J ˆ
ˆ
ˆ
J ˆ 3.1, 10.1 Hz, 1H, CH CH), 6.22 (dd, J ˆ 3.1, 10.1 Hz, 1H, CH CH),
4.69 (dd, J ˆ 4.0, 5.8 Hz, 1H, OCHCH2I), 3.15 (dd, J ˆ 4.0, 5.8 Hz, 2H,
CH2I), 1.48 (s, 3H, CH3), 1.19 (s, 9H, tBu); 13C NMR (50 MHz, CDCl3): d ˆ
185.0 (s), 152.5 (d), 151.2 (d), 129.6 (d), 128.0 (d), 95.0 (d), 75.4 (s), 72.5 (s),
ˆ
0.9, 5.8 Hz, 1H, CH(CH CH2)2), 4.54 (s, 1H, OCHCBrMe2), 3.82 (dq, J ˆ
7.0, 9.1 Hz, 1H, CH3CHH), 3.68 (dq, J ˆ 7.0, 9.2 Hz, 1H, CH3CHH), 1.74 (s,
3H, CH3), 1.73 (s, 3H, CH3), 1.23 (t, J ˆ 7.0 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d ˆ 137.7 (d), 137.1 (d), 117.7 (t), 116.2 (t), 105.2 (d), 80.4
‡
‡
29.1 (q), 27.5 (q), 10.0 (q); MS (EI): m/z (%): 351 (2) [M ‡H], 153 (25), 125
(d), 67.1 (t), 29.1 (q), 28.4 (q), 15.4 (q); MS (EI): m/z (%): 181 (63) [M
À
‡
(63), 124 (16), 109 (20), 108 (14), 107 (100), 77 (28), 57 (66), 53 (12);
elemental analysis calcd for C13H19O3I (350.20): C 44.59, H 5.47; found: C
44.41, H 5.45.
81], 179 (65) [M À 83], 153 (9), 151 (9), 75 (20), 67 (100); elemental
analysis calcd for C11H19O2Br (263.18): C 50.20, H 7.28; found: C 50.83, H
7.46.
2-Ethoxy-3,3,4-trimethyl-5-vinyltetrahydrofuran (25): According to the
GP 2 from the bromoacetal 24 (0.55 g, 2.1 mmol), Bu3SnH (735 mg,
2.5 mmol) and a 1m solution of Et3B in hexane (2.9 mL, 2.9 mmol). FC
(hexane/Et2O 10:1) gave 25 (0.29 g, 75%, 86% ds) as a mixture of
diastereomers. According to the GP 3 from 24 (0.55 g, 2.1 mmol), Bu3SnH
(735 mg, 2.52 mmol) and AIBN (17 mg, 0.11 mmol), compound 25 (0.34 g,
88%, 74% ds) was obtained after FC. IR (KBr): nÄ ˆ 3082, 2974, 2877, 1645,
1469, 1388, 1109, 1020, 922 cmÀ1. (r-2,c-4, t-5)-25 (major): 1H NMR
2-(tert-Butoxy)-7a-methyl-2,3,3a,4,5,7a-hexahydrobenzo[b]furan-5-one
(22): According to the GP 2 from the iodoacetal 21 (0.74 g, 2.1 mmol),
Bu3SnH (735 mg, 2.52 mmol) and a 1m solution of Et3B in hexane (2.9 mL,
2.9 mmol). FC (hexane/Et2O 5:1) afforded 22 (0.35 g, 74%, 98% ds).
According to the GP 3 from the iodoacetal 21 (0.18 g, 0.5 mmol), Bu3SnH
(174 mg, 0.60 mmol) and AIBN (4 mg, 0.025 mmol) gave 22 (0.08 g, 71%,
89% ds). IR (KBr): nÄ ˆ 3032, 2976, 2872, 1689, 1369, 1099 cmÀ1. exo-22
(major diastereomer): 1H NMR (360 MHz, CDCl3): d ˆ 6.50 (dd, J ˆ 1.8,
ˆ
(360 MHz, CDCl3): d ˆ 5.80 (ddd, J ˆ 7.3, 10.1, 17.1, 1H, CH CH2), 5.23
ˆ
ˆ
10.8 Hz, 1H, CH CHCMe), 5.84 (d, J ˆ 10.4 Hz, 1H, CH CO), 5.29 (d,
ˆ
(ddd, J ˆ 0.9, 1.5, 17.1 Hz, 1H, CHH CH), 5.13 (ddd, J ˆ 0.9, 1.5, 10.1 Hz,
J ˆ 5.2 Hz, 1H, OCHCH2), 2.88 2.78 (m, 1H, CHCH2CO), 2.64 (dd, J ˆ
ˆ
1H, CHH CH), 4.69 (s, 1H, OCHCMe2), 4.00 (dd, J ˆ 7.3, 8.2 Hz, 1H,
ˆ
5.5, 17.0 Hz, 1H, CHCHHC O), 2.54 (dd, J ˆ 2.1, 16.8 Hz, 1H,
ˆ
CHCH CH2), 3.82 (dq, J ˆ 7.0, 9.5 Hz, 1H, CH3CHH), 3.48 (dq, J ˆ 7.0,
ˆ
CHCHHC O), 1.96 (dd, J ˆ 7.0, 12.5 Hz, 1H, CHHCH-O), 1.86 (dt, J ˆ
9.8 Hz, 1H, CH3CHH), 1.57 (dq, J ˆ 7.0, 8.2 Hz, 1H, CHMe), 1.20 (t, J ˆ
7.0 Hz, 3H, CH3CH2), 1.00 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.86 (d, J ˆ
6.7 Hz, 3H, CHCH3); 13C NMR (50 MHz, CDCl3): d ˆ 138.8 (d), 116.0 (t),
111.1 (d), 84.8 (d), 64.5 (t), 48.5 (d), 43.9 (s), 25.9 (q), 16.0 (q), 15.3 (q),
11.2 (q). Minor diastereoisomer: 1H NMR (360 MHz, CDCl3): d ˆ 4.51
5.2, 12.5 Hz, 1H, CHHCH-O), 1.52 (s, 3H, CH3), 1.23 (s, 9H, tBu-O). NOE
difference spectra (500 MHz): 5.31 5.27 (tBuOCH) ! 1.91 1.81 (s),
1.25 1.22 (s), 2.87 2.78 (tBuOCHCH2CH) ! 2.68 2.51 (s), 1.99 1.92
(m), 1.91 1.81 (w), 1.53 1.51 (m), 1.99 1.92 (tBuOCHCHH) ! 5.31 5.27
(w), 2.87 2.78 (m), 1.91 1.81 (s), 1.25 1.22 (m), 1.91 1.81
(tBuOCHCHH) ! 5.31 5.27 (s), 1.99 1.92 (s), 1.53 1.51 (CH3) ! 2.87
2.78 (s), 2.67 2.59 (m); 13C NMR (50 MHz, CDCl3): d ˆ 197.6 (s), 151.8 (d),
126.0 (d), 97.1 (d), 79.3 (s), 74.1 (s), 41.6 (d), 39.7 (t), 39.4 (t), 29.1 (q), 25.6
(q). endo-22 (minor diastereomer): 1H NMR (360 MHz, CDCl3): d ˆ 6.70
ˆ
(s, 1H, OCHCMe2), 3.95 (t, J ˆ 8.5 Hz, 1H, CHCH CH2); elemental
analysis calcd for C11H20O2 (183.99): C 71.70, H 10.94; found: C 71.42,
H 10.93.
Methyl 3-ethoxy-2-iodo-3-[(1-vinyl-2-propenyl)-oxy]propanoate (26): NIS
(2.92 g, 13 mmol) at 08C was added in portions to a solution of methyl (E)-
3-ethoxy-2-propenoate[51] (1.69 g, 13 mmol) and 1,4-pentadien-3-ol (0.93 g,
11 mmol) in CH2Cl2 (10 mL). The resulting mixture, protected from the
light, was stirred at rt for 3 d. The precipitate was diluted in hexane and
ˆ
(dd, J ˆ 1.8, 10.1 Hz, 1H, CH CH), 1.73 (s, 3H, CH3), 1.21 (s, 9H, tBuO);
‡
MS (CI, CH4): m/z (%): 225 (12) [M ‡H], 197 (32), 169 (86), 152 (13), 150
(100), 122 (8), 57 (13); elemental analysis calcd for C13H20O3 (224.30): C
69.51, H 8.97; found: C 69.61, H 8.99.
Chem. Eur. J. 2003, 9, No. 7
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1573 $ 20.00+.50/0
1573

P. Renaud et al.
FULL PAPER
filtered off. The filtrate was washed with sat. Na2S2O3, brine and dried.
Evaporation in vacuo afforded a yellow oil that was purified by FC
(hexane/Et2O 10:1) to give the iodoacetal 26 (2.24 g, 60%). IR (KBr): nÄ ˆ
HRMS (CI, isobutane): calcd for C12H23O2: 199.16925; found: 199.17066
[M ‡H].
‡
4-(2-Bromo-1-tert-butoxyethoxy)-1,6-heptadiene (30): According to the
GP 1 from 1,6-heptadien-3-ol (1.0 g, 8.9 mmol), tert-butyl vinyl ether
(0.89 g, 8.9 mmol) and NBS (1.58 g, 8.9 mmol). FC (hexane/Et2O 40:1)
afforded the bromoacetal 30 (1.74 g, 67%) as a colorless oil. IR (KBr): nÄ ˆ
3082, 2978, 2895, 1741, 1435, 1303, 1253, 1109, 1030, 929 cmÀ1 1H NMR
;
ˆ
(360 MHz, CDCl3): d ˆ 5.85 5.60 (m, 2H, 2CH CH2), 5.30 5.15 (m, 4H,
ˆ
2CH2 CH), 5.03 (d, J ˆ 8.6 Hz, 1H, CHICO2Me), 4.55 (dt, J ˆ 1.2, 7.3 Hz,
ˆ
1H, CH(CH CH2)2), 4.46 (d, J ˆ 8.5 Hz, 1H, OCHCHICO2Me), 3.82
1
3076, 2978, 2935, 1641, 1367, 1033, 914 cmÀ1; H NMR (360 MHz, CDCl3):
3.61 (m, 2H, OCH2CH3), 3.73 (s, 3H, CH3O), 1.24 (t, J ˆ 7.3 Hz, 3H,
CH3CH2O); 13C NMR (50 MHz, CDCl3): d ˆ 169.9 (s), 137.2 (d), 136.4 (d),
117.7 (t), 116.4 (t), 100.2 (d), 79.7 (d), 61.6 (t), 52.8 (d), 21.4 (q), 14.9 (q); MS
ˆ
ˆ
d ˆ 5.91 5.78 (m, 2H, CH CH2), 5.12 5.02 (m, 4H, CH2 CH), 4.87 (dd,
ˆ
J ˆ 4.6, 6.1 Hz, 1H, OCHCH2Br), 3.66 (m,1H, OCH(CH2CH CH2)2), 3.36
(dd, J ˆ 6.1, 10.7 Hz, 1H, OCHCHHBr), 3.27 (dd, J ˆ 4.3, 10.4 Hz, 1H,
‡
(EI): m/z (%): 257 (56) [M À 83], 229 (17), 197 (17), 169 (19), 127 (12), 103
ˆ
OCHCHHBr), 2.31 (t, J ˆ 6.4 Hz, 4H, 2 CH2CH CH2), 1.27 (s, 9H, tBu);
13C NMR (50 MHz, CDCl3): d ˆ 134.7 (d), 134.3 (d), 117.6 (t), 117.1 (t), 95.9
(d), 74.8 (s), 38.8 (t), 38.2 (t), 34.5 (t), 28.9 (q); MS (EI): m/z (%): 293 (4)
(19), 89 (34), 67 (100), 55 (16); elemental analysis calcd for C11H17O4I
(340.16): C 38.84, H 5.04; found: C 39.10, H 5.18.
‡
‡
[M ‡2], 291 (3) [M ], 219 (26), 217 (26), 201 (9), 199 (9), 169 (40), 127
(56), 95 (100), 81 (39), 57 (65); elemental analysis calcd for C13H23O2Br
(291.23): C 53.62, H 7.96; found: C 53.48, H 8.13.
Methyl 2-ethoxy-4-iodomethyl-5-vinyltetrahydro-3-furancarboxylate (27):
According to the GP 4 from the iodoacetal 26 (0.34 g, 1 mmol) and
(Bu3Sn)2 (58 mg, 0.1 mmol). FC (hexane/Et2O 5:1) afforded 27 (0.24 g,
71%, 77% ds). IR (KBr): nÄ ˆ 3082, 2978, 1739, 1437, 1199 cmÀ1. (r-2,t-3,c-
4,t-5)-27 (major): 1H NMR (360 MHz, CDCl3): d ˆ 5.85 (ddd, J ˆ 7.6, 10.2,
6-(3-Propenyl)-4-methyltetrahydro-2H-pyran-2-yl tert-butyl ether (31):
According to the GP 2 from the bromoacetal 30 (0.61 g, 2.1 mmol),
Bu3SnH (735 mg, 2.5 mmol) and a 1m solution of Et3B in hexane (2.9 mL,
2.9 mmol). FC gave the acetal 31 (0.19 g, 43%) as a single diastereomer. IR
ˆ
ˆ
17.2 Hz, 1H, CH CH2), 5.39 (dt, J ˆ 1.1, 17.1 Hz, 1H, CHH CH), 5.33 (d,
J ˆ 2.5 Hz, 1H, OCHCHCO2Me), 5.28 (ddd, J ˆ 0.8, 1.4, 10.2 Hz, 1H,
CHH CH), 4.25 (t, J ˆ 8.0 Hz, 1H, CHCH CH2), 3.77 (dq, J ˆ 7.0, 9.7 Hz,
1H, CH3CHH), 3.75 (s, 3H, CH3), 3.49 (dq, J ˆ 7.0, 9.4 Hz, 1H, CH3CHH),
3.39 (dd, J ˆ 4.9, 10.3 Hz, 1H, CHCHHI), 3.28 (dd, J ˆ 6.3, 10.3 Hz, 1H,
CHCHHI), 3.00 (dd, J ˆ 2.5, 7.4 Hz, 1H, CHCO2Me), 2.29 (m, 1H, CH),
1.22 (t, J ˆ 7.2 Hz, 3H, CH3CH2); 13C NMR (50 MHz, CDCl3): d ˆ 171.7 (s),
135.7 (d), 118.9 (t), 104.5 (d), 84.2 (d), 63.5 (d), 57.7 (d), 52.5 (q), 48.7 (d),
(KBr): nÄ ˆ 3078, 2976, 2930, 2872, 1458, 1375, 1112, 1001 cmÀ1
;
1H NMR
ˆ
ˆ
ˆ
(500 MHz, CDCl3): d ˆ 5.82 (ddt, J ˆ 7.0, 10.3, 17.0 Hz, 1H, CH CH2), 5.15
(dm, J ˆ 3.3 Hz, 1H, tBuOCHCH2), 5.05 (ddt, J ˆ 1.4, 2.1, 17.1 Hz, 1H,
ˆ
ˆ
CHH CH), 5.00 (ddt, J ˆ 1.1, 2.1, 10.1 Hz, 1H, CHH CH), 3.91 (dddd, J ˆ
ˆ
2.2, 5.6, 7.1, 11.6 Hz, 1H, OCHCH2CH CH2), 2.20 (dtt, J ˆ 1.3, 6.9, 14.1 Hz,
ˆ
1H, CHHCH CH2), 2.12 (dddt, J ˆ 1.0, 6.1, 7.3, 14.1 Hz, 1H,
15.1 (q), 6.0 (q). Minor diastereomer: 1H NMR (360 MHz, CDCl3): d ˆ 4.38
CHHCH CH2), 1.98 (tqt, J ˆ 6.5 Hz, 1H, CHMe), 1.60 (ddt, J ˆ 1.5, 3.8,
ˆ
‡
ˆ
ˆ
(t, J ˆ 7.9 Hz, 1H, CHCH CH2); MS (EI): m/z (%): 341 (4) [M ‡H], 295
12.9 Hz, 1H, OCH(CH2CH CH2)CHH), 1.54 (ddt, J ˆ 1.5, 3.0, 12.9 Hz,
(100), 254 (7), 127 (4), 58 (6); elemental analysis calcd for C11H17IO4
(340.16): C 38.84, H 5.04; found: C 38.74, H 5.09.
1H, tBuOCHCHH), 1.22 (s, 9H, tBu), 1.21 (ddd, J ˆ 3.7, 12.3, 12.9 Hz, 1H,
tBuOCHCHH), 0.86 (d, J ˆ 6.5 Hz, 3H, CH3), 0.85 (ddd, J ˆ 11.7, 11.7,
12.9 Hz, 1H, OCH(CH2CH CH2)CHH); 13C NMR (50 MHz, CDCl3): d ˆ
ˆ
3-(2-Bromo-1-ethoxy-3-methylbutoxy)-1,4-pentadiene (28): According to
GP 1 from (Z/E)-1-ethoxy-3-methyl-1-butene[50] (1.14 g, 10 mmol), 1,4-
pentadien-3-ol (840 mg, 10 mmol) and NBS (1.78 g, 10 mmol). FC (hexane/
135.5 (d), 116.2 (t), 91.8 (d), 73.7 (s), 67.8 (d), 40.9 (t), 40.0 (t), 39.8 (t), 28.8
‡
(q), 24.2 (d), 22.3 (q); MS (EI): m/z (%): 213 (16) [M ‡H], 171 (11), 157
(43), 139 (78), 115 (38), 95 (27), 69 (22), 57 (100); HRMS (ESI): calcd for
C13H24O2Na: 235.16685; found: 235.16711.
Et2O 20:1) gave 28 (0.47 g, 17%) as
a colorless oil. Mixture of
diastereomers. IR (KBr): nÄ ˆ 3084, 2968, 2877, 1464, 1386, 1109, 1035,
925 cmÀ1; 1H NMR (360 MHz, CDCl3): d ˆ 5.95 5.65 (m, 2H, 2 CH CH2),
8-Methoxy-8-[(2Z)-3-methoxyprop-2-enyl]-1,4-dioxaspiro[4.5]deca-6,9-di-
ene (34): Allyl methyl ether (656 mg, 9.1 mmol) dissolved in THF (5 mL)
was added to a 0.5m solution of sBuLi (9.8 mmol) in dry THF at À788C.
After 30 min a solution of ketone 32[52] (690 mg, 4.5 mmol) in THF (5 mL)
was added. The reaction medium was kept at À788C for 1 h. After dilution
with Et2O, H2O was added and the solution was allowed to warm up to rt.
The aqueous phase was extracted with Et2O and the organic layer was dried
and evaporated to give crude alcohol 33 (880 mg). To a suspension of NaH
(912 mg, ca. 50% in paraffin, 19 mmol) in dry THF (15 mL) was added at
08C the crude alcohol 33 (880 mg) dissolved in THF (5 mL) and the
mixture was allowed to warm up to rt. After 20 min, MeI (1.2 mL, 19 mmol)
was added at 08C and the mixture was stirred at rt overnight. H2O was
added and the mixture was extracted with Et2O. The organic layer was
dried over MgSO4 and evaporated, FC (hexane/ethylacetate 10:1) gave the
vinyl ether 34 (521 mg, 2.2 mmol, 48% from 32) as a colorless oil. IR
ˆ
ˆ
5.32 5.15 (m, 4H, 2 CH2 CH), 4.70 (d, J ˆ 7.0 Hz, 1H, OCHCHBr), 4.56
ˆ
(t, J ˆ 6.1 Hz, 1H, CH(CH CH2)2), 4.03 (dd, J ˆ 3.1, 7.3 Hz, 1H,
OCHCHBr), 3.68 3.56 (m, 2H, CH3CH2O), 2.18 2.05 (m, 1H,
CH(CH3)2), 1.20 (t, J ˆ 7.0 Hz, 3H, CH3CH2O), 1.01 (d, J ˆ 6.7 Hz, 3H,
CH3), 0.96 (d, J ˆ 6.7 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 137.6
(d), 137.5 (d), 117.6 (t), 116.3 (t), 100.8 (d), 79.4 (d), 64.5 (d), 61.4 (t), 29.4
‡
(d), 22.0 (q), 17.7 (q), 15.2 (q); MS (EI): m/z (%): 195 (98) [M À 81], 193
‡
(100) [M À 83], 167 (8), 165 (8), 137 (26), 113 (84), 85 (57), 75 (31), 55 (62);
HRMS (ESI): calcd for C12H21O2BrNa: 299.06171; found: 299.06128.
2-Ethoxy-3-isopropyl-4-methyl-5-vinyltetrahydrofuran (29): According to
the GP 2 from the bromoacetal 28 (0.58 g, 2.1 mmol), Bu3SnH (735 mg,
2.5 mmol) and a 1m solution of Et3B in hexane (2.9 mL, 2.9 mmol). FC
(hexane/Et2O 40:1) gave 29 (0.27 g, 66%, 63:37 mixture of diastereomers).
The two diastereomers were separated by further FC. (r-2,t-3,c-4,t-5)-29
(CHCl3): nÄ ˆ 3020, 2936, 2889, 2827, 1666, 1464, 1407, 1206, 1109 cmÀ1
;
1
1H NMR (360 MHz, CDCl3): d ˆ 5.92 (d, J ˆ 10.5 Hz, 2H,
(major): H NMR (500 MHz, CDCl3): d ˆ 5.79 (ddd, J ˆ 7.5, 10.3, 17.2 Hz,
ˆ
ˆ
1H, CH CH2), 5.27 (ddd, J ˆ 1.0, 1.7, 17.2 Hz, 1H, CHH CH), 5.17 (ddd,
ˆ
2CH CHC(OMe)), 5.90 5.93 (m, 1H, CHOMe), 5.77 (d, J ˆ 10.4 Hz,
ˆ
J ˆ 0.8, 1.7, 10.3 Hz, 1H, CHH CH), 4.83 (d, J ˆ 2.7 Hz, 1H, OCHCHiPr),
ˆ
ˆ
2H, 2CH CHC(OMe)), 4.23 (dt, J ˆ 6.4, 7.3 Hz, 1H, CH2CH CH), 4.02 (s,
ˆ
3.99 (t, J ˆ 8.3 Hz, 1H, CHCH CH2), 3.77 (dq, J ˆ 7.1, 9.7 Hz, 1H,
4H, OCH2CH2O), 3.51 (s, 3H, OCH3), 3.09 (s, 3H, OCH3), 2.36 (d, J ˆ
7.3 Hz, 2H, CH2CH CH); 13C NMR (90.5 MHz, CDCl3): d ˆ 147.8 (d),
CH3CHH), 3.45 (dq, J ˆ 7.0, 9.7 Hz, 1H, CH3CHH), 1.73 1.68 (m, 1H,
CH-Me2), 1.59 1.55 (m, 1H, CHMe), 1.51 1.46 (m, 1H, CHiPr), 1.20 (t,
J ˆ 7.1 Hz, 3H, CH3CH2), 1.1 (d, J ˆ 6.4 Hz, 3H, CHCH3), 0.95 (d, J ˆ
2.7 Hz, 3H, CH3), 0.93 (d, J ˆ 2.7 Hz, 3H, CH3); 13C NMR (50 MHz,
CDCl3): d ˆ 137.2 (d), 117.2 (t), 107.1 (d), 85.9 (d), 63.1 (t), 60.3 (d), 42.9 (d),
29.8 (d), 20.7 (q), 20.5 (q), 16.0 (q), 15.3 (q). 29 (minor): 1H NMR
ˆ
134.7 (d), 129.9 (d), 99.9 (d), 99.2 (s), 73.7 (s), 65.2 (t), 65.0, 59.3 (q), 51.8 (q),
‡
34.4 (t); EI-MS: m/z (%): 238 (3) [M ], 167 (100), 136 (18), 115 (21), 95
(26), 72 (82); HRMS (ESI-MS): calcd for C13H18O4Na: 261.10973; found:
‡
261.10943 [M ‡Na].
8-[3-(Allyloxy)-2-iodo-3-methoxypropyl]-8-methoxy-1,4-dioxaspiro[4.5]-
deca-6,9-diene (35): According to GP 1 from enol ether 34 (5.76 g,
24 mmol), allyl alcohol (11 mL), NEt3 (2.3 mL, 12 mmol) and NIS
(16.3 g, 72 mmol, addition at À508C) in CH2Cl2 (70 mL). FC (CH2Cl2/
Et2O 60:1) gave the iodoacetal 35 (8.2 g, 19.4 mmol, 81%) as a colorless oil.
IR (CHCl3): nÄ ˆ 3007, 2936, 2889, 2829, 1464, 1406, 1336, 1206, 1116,
ˆ
(360 MHz, CDCl3): d ˆ 5.86 (ddd, J ˆ 6.7, 10.4, 17.1 Hz, 1H, CH CH2), 5.20
ˆ
(dt, J ˆ 1.5, 17.1 Hz, 1H, CHH CH), 5.04 (dt, J ˆ 1.2, 10.4 Hz, 1H,
ˆ
CHH CH), 4.97 (d, J ˆ 4.6 Hz, 1H, OCHCHiPr), 4.21 (dquint, J ˆ 1.2,
ˆ
6.4 Hz, 1H, CHCH CH2), 3.76 (dq, J ˆ 7.3, 9.8 Hz, 1H, CH3CHH), 3.40
(dq, J ˆ 7.2, 9.7 Hz, 1H, CH3CHH), 2.04 1.94 (m, 1H, CHMe), 1.91 1.80
(m, 1H, CHMe2), 1.72 1.65 (m, 1H, CHiPr), 1.20 1.14 (m, 6H, CH3CH2,
CH3), 0.94 (d, J ˆ 6.4 Hz, 3H, CH3), 0.90 (d, J ˆ 6.7 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3): d ˆ 139.5 (d), 114.0 (t), 104.9 (d), 87.6 (d), 62.9 (t), 53.4
(d), 39.1 (d), 23.9 (d), 21.8 (q), 21.5 (q), 16.0 (q), 15.4 (q). Mixture of isomers
967 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 6.20 5.80 (m, 5H,
ˆ
ˆ
ˆ
2CH CHC(OMe), CH2 CH), 5.28 (dm, J ˆ 17.2 Hz, 1H, CHH CH),
ˆ
5.16 (dm, J ˆ 10.4 Hz, 1H, CHH CH), 3.93 4.17 (m, 8H, CHCH2O,
OCH2CH2O, ICHCHOMe), 3.34 (s, 3H, OCH3), 3.07 (s, 3H, OCH3), 2. 51
(dd, J ˆ 15.3, 4.3 Hz, 1H, CHHCI), 2.26 (dd, J ˆ 15.4, 6.6 Hz, 1H, CHHCI);
of 29. IR (KBr): nÄ ˆ 3082, 2960, 2876, 1465, 1377, 1093, 989, 922 cmÀ1
;
1574
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1574 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 7

Stereoselective Radical Cyclizations
1566 1577
13C NMR (90.5 MHz, CDCl3): d ˆ 134.4 (d), 134.0 (d), 130.9 (d), 130.8 (d),
(CHHO) ! 3.66 3.64
(20.5%),
2.66 2.59
(6.4%),
3.66 3.64
117.2 (t), 104.7 (d), 98.9 (s), 73.6 (s), 68.9 (t), 65.4 (t), 65.1 (t), 55.3 (q), 51.6
(CHHO) ! 4.18 4.11 (22.8%), 2.78 2.74 (1.2%), 2.51 2.48 (2.5%),
2.66 2.59 (CH2CHCH2O) ! 4.18 4.11 (5.2%), 3.66 3.64 (0.6%);
13C NMR (125 MHz, CDCl3): d ˆ 158.2 (s), 139.3 (s), 129.8 (s), 127.9 (d),
113.3 (d), 111.2 (d), 110.8 (d), 72.3 (d), 55.3 (q), 54.6 (q), 45.9 (d), 37.3 (d),
‡
(q), 44.8 (t), 25.82 (d); EI-MS: m/z (%): 422 (1.1) [M ], 167 (100), 233 (1.6),
149 (22), 128 (12), 107 (11), 101 (70), 71 (15), 41 (63); HRMS (EI-MS):
‡
calcd for C16H23O5I: 422.05903; found 422.05902 [M ].
‡
33.4 (t), 30.3 (t); EI-MS: m/z (%): 234 (31) [M ], 172 (100), 202 (82), 159
(71), 144 (28), 128 (53), 115 (56), 91 (27), 77 (21); HRMS (EI-MS): calcd for
C14H18O3: 234.12560; found: 234.12584 [M ].
4-[3-(Allyloxy)-2-iodo-3-methoxypropyl]-4-methoxycyclohexa-2,5-dien-1-
one (36): A solution of 35 (5.27 g, 12.5 mmol) in benzene (2 L) saturated
with H2O (0.5 mL) was stirred for 1 h with anhydrous MgSO4 (210 g) until
the TLC shows no starting material. The mixture was filtered and the
filtrate was concentrated to give 36 (4.50 g, 11.9 mmol, 95%) as a yellow oil
that was used without further purification for the next step. IR (CHCl3):
‡
(1R)- and (1S)-2-Bromo-1-[(1R,2S)-(2-phenylcyclohexyl)oxy]ethyl 2,3-
butadienyl ether (40): According to GP 1 from (1R,2S)-2-phenylcyclohexyl
vinyl ether (39)[53] (1.11 g, 5.5 mmol), 2,3-butadien-1-ol (0.42 g, 6.05 mmol)
and NBS (0.98 g, 5.5 mmol) in CH2Cl2 (10 mL). FC (hexane/Et2O 20:1)
gave a 1:1 mixture of the two diasteroisomers of 40 (1.5 g, 78%). The two
diasteroisomers were separated by FC (hexane/Et2O 60:1). (S)-40: Rf ˆ
0.64 (hexane/Et2O 5:1); [a]2D1 ˆ À14.88 (c ˆ 1, CH2Cl2); 1H NMR
(360 MHz, CDCl3): d ˆ 7.31 7.16 (m, 5 arom. H), 4.91 (quint, J ˆ 6.4 Hz,
1
nÄ ˆ 3009, 2933, 1670, 1635, 1507, 1460, 1394, 1071, 929, 861 cmÀ1; H NMR
ˆ
ˆ
(360 MHz, CDCl3): d ˆ 6.90 (dd, J ˆ 10.5, 3.2 Hz, 1H, CH CHC O), 6.76
ˆ
ˆ
(dd, J ˆ 10.0, 3.2 Hz, 1H, CH CHC O), 6.34 6.39 (m, 2H,
ˆ
ˆ
ˆ
2CH CHC O), 5.87 (ddt, J ˆ 17.3, 10.4, 5.9 Hz, 1H, CH2 CH), 5.28 (dd,
ˆ
ˆ
J ˆ 17.3, 1.4 Hz, 1H, CHH CH), 5.18 (d, J ˆ 10.5, 1H, CHH CH), 4.23 (d,
J ˆ 4.1, 1H, CHOMe), 4.12 (dd, J ˆ 12.7, 5.5 Hz, 1H, CHHCI), 4.02 (dd, J ˆ
12.7, 5.9 Hz, 1H, CHHCI), 3.95 (ddd, J ˆ 8.2, 4.5, 3.2, 1H, CHI), 3.38 (s, 3H,
OCH3), 3.16 (s, 3H, OCH3), 2.71 (dd, J ˆ 15.4, 2.7 Hz, 1H, CHHCI), 2.27
(dd, J ˆ 15.9, 8.2 Hz, 1H, CHHCI); 13C NMR (90.5 MHz, CDCl3): d ˆ 185.2
(s),150.6 (d), 149.6 (d), 133.7 (d), 131.7 (d), 131.6 (d), 117.6 (t), 105.4 (d),
74.7 (s), 69.1 (t), 55.6 (d), 52.8 (q), 44.4 (t), 23.9 (q); EI-MS: m/z (%): 378
ˆ ˆ
ˆ ˆ
1H, CH C CH2), 4.73 (dt, J ˆ 2.4, 6.7 Hz, 2H, CH2 C CH), 4.66 (dd, J ˆ
4.6, 6.6 Hz, 1H, OCHCH2Br), 3.61 (dt, J ˆ 4.3, 10.1 Hz, 1H, OCHCHPh),
ˆ
3.42 (tq, J ˆ 3.4, 7.1 Hz, 1H, OCHHCH C), 3.21 (dd, J ˆ 6.4, 10.7 Hz, 1H,
OCHCHHBr), 3.12 (dd, J ˆ 4.6, 10.4 Hz, 1H, OCHCHHBr), 3.03 (tq, J ˆ
ˆ
2.4, 6.7 Hz, 1H, OCHHCH C), 2.56 (dt, J ˆ 3.7, 10.4 Hz, 1H, OCHCHPh),
2.20 2.13 (m, 1H), 1.92 1.87 (m, 2H), 1.77 1.74 (m, 1H), 1.61 1.50 (m,
1H), 1.42 1.29 (m, 3H); 13C NMR (50 MHz, CDCl3): d ˆ 209.0 (s), 144.3
(s), 128.2 (d), 1281 (d), 126.3 (d), 99.9 (d), 87.9 (d), 79.5 (d), 75.7 (t), 61.9 (t),
50.8 (d), 33.7 (t), 33.0 (t), 32.4 (t), 25.8 (t), 24.9 (t). (R)-40: Rf ˆ 0.60
(hexane/Et2O 5:1); [a]D21 ˆ ‡1.08 (c ˆ 1.2, CH2Cl2); 1H NMR (360 MHz,
‡
(0.2) [M ], 41 (100), 289 (1.4), 255 (1.4), 210 (12), 162 (25),152 (19), 123
(64), 101 (81), 71 (29); HRMS (EI-MS): calcd for C14H19O4I: 378.03281;
‡
found 378.03275 [M ].
1,8a-Dimethoxy-1,3a,4,4a,5,8a,9,9a-octahydronaphtho[2,3-c]furan-6(3H)-
one (37): A solution of 36 (909 mg, 2.4 mmol) in toluene (60 mL) was
cooled to À908C and a 1m solution of Et3B in toluene (12 mL, 12 mmol)
was added, followed by addition of air (6 mL) over 6 h with a syringe pump.
The solution was filtered over silica gel and the solvent was evaporated
under reduced pressure. The crude product was purified by FC (hexane/
EtOAc 7:3) to afford 37 (518 mg, 2.06 mmol, 86%, dr 84:8:5:2:1, 84% ds)
as a mixture of 5 diastereomers. The diastereomeric ratios were determined
by 1H NMR spectroscopy of the crude product before FC. The major
diastereomer was isolated by FC together with one of the minor
diastereomers. IR (CHCl3): nÄ ˆ 3009, 2934, 1678, 1446, 1386, 1206, 1078,
1035, 1010, 972 cmÀ1; 1H NMR (360 MHz, CDCl3): d ˆ 6.79 (d, J ˆ 10.4 Hz,
CDCl3): d ˆ 7.33 7.20 (m,
5
arom. H), 5.22 (quint, J ˆ 6.4 Hz, 1H,
ˆ ˆ
ˆ ˆ
CH C CH), 4.80 (dt, J ˆ 2.4, 6.4 Hz, 2H, CH2 C CH), 4.25 (dd, J ˆ 3.4,
ˆ
7.3 Hz, 1H, OCHCH2Br), 4.10 3.97 (m, 2H, OCH2CH C), 3.50 (dt, J ˆ
5.8, 10.1 Hz, 1H, OCHCHPh), 2.78 (dd, J ˆ 7.0, 10.7 Hz, 1H,
OCHCHHBr), 2.54 (dt, J ˆ 3.9, 12.5 Hz, 1H, OCHCHPh), 2.53 (dd, J ˆ
3.4, 10.9 Hz, 1H, OCHCHHBr), 2.20 2.16 (m, 1H), 1.92 1.85 (m, 2H),
1.78 1.74 (m, 1H), 1.63 1.29 (m, 4H); 13C NMR (50 MHz, CDCl3): d ˆ
209.2 (s), 144.0 (s), 128.3 (d), 128.0 (d), 126.7 (d), 101.4 (d), 87.7 (d), 82.2 (d),
75.9 (t), 63.7 (t), 51.5 (d), 34.1 (t), 33.4 (t), 31.5 (t), 25.8 (t), 25.3 (t). Mixture
of diastereomers: IR (KBr): nÄ ˆ 3063, 3028, 2931, 2856, 1957, 1448, 1111,
1037 cmÀ1; CI-MS (CH4): m/z (%): 283 (35), 281 (36), 211 (11), 159 (100),
91 (8).
ˆ
1H, H2C CHCOMe, minor diast.), 6.67 (dd, J ˆ 10.0, 1.8 Hz, 1H,
ˆ
ˆ
ˆ
H2C CHCOMe, major diast.), 6.11 (d, J ˆ 10.5 Hz, 1H, CH CHC O,
(1R,2S)-2-Phenylcyclohexyl-(2R,4R)-4-vinyltetrahydro-2-furanyl ether:
According to GP 2 from (R)-40 (175 mg, 0.5 mmol), Bu3SnH (174 mg,
0.6 mmol) and 1m solution of Et3B in hexane (0.8 mL, 0.76 mmol). FC
(hexane/Et2O 20:1) gave (1R,2S)-2-phenylcyclohexyl-(2R,4R)-4-vinylte-
trahydro-2-furanyl ether (0.12 g, 88%, 90% ds). [a]2D1 ˆ ‡14.28 (c ˆ 1,
ˆ
ˆ
major diast.), 6.06 (d, J ˆ 10.5 Hz, 1H, CH CHC O, minor diast.), 5.06 (d,
J ˆ 4.1 Hz, 1H, OCHOMe, major diast.), 5.01 (d, J ˆ 3.2 Hz, 1H,
OCHOMe, minor diast.), 4.01 (dd, J ˆ 8.6, 6.4 Hz, 1H, CHHO, minor
diast.), 3.80 3.87 (m, 2H, CH2O, major diast.), 3.69 (dd, J ˆ 8.2, 4.5 Hz,
1H, minor diast.), 3.45 (s, 3H, OMe, major diast.), 3.38 (s, 3H, OMe, minor
diast.), 3.33 (s, 3H, OMe, major diast.), 3.25 (s, 3H, OMe, major diast.), 3.07
CH2Cl2); IR (KBr): nÄ ˆ 3028, 2930, 2858, 1448, 1095, 1049, 1008 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ 7.30 7.15 (m, 5 arom. H), 5.71 (ddd, J ˆ
ˆ
(dd, J ˆ 16.8, 5.0 Hz, 1H, CHHC O, major diast.), 2.70 (dd, J ˆ 16.8,
ˆ
8.5, 10.1, 18.6 Hz, 1H, CH CH2), 4.94 (ddd, J ˆ 0.9, 1.8, 17.1 Hz, 1H,
ˆ
4.6 Hz, 1H, CHHC O, minor diast.), 2.56 1.35 (m, 8H, C(O)CHH,
ˆ
ˆ
CH CHH), 4.91 (ddd, J ˆ 0.9, 1.8, 10.1 Hz, 1H, CH CHH), 4.43 (dd, J ˆ
CHCH2CH, MeOCCH2CH); 13C NMR (100 MHz, CDCl3): 37 (major): d ˆ
199.5 (s), 148.9 (d), 132.6 (d), 108.3 (d), 73.4 (s), 68.7 (t), 57.2 (q), 50.6 (q),
40.3 (t), 39.2 (d), 36.3 (d), 36.2 (d), 28.5 (t). 37 (minor): d ˆ 153.4 (d), 131.8
(d), 109.8 (d), 71.4 (t), 55.9 (q), 50.8 (q), 43.2 (d), 40.4 (t), 35.0 (d), 33.6 (d),
ˆ
3.1 5.5 Hz, 1H, OCHCH2), 3.81 (t, J ˆ 8.2 Hz, 1H, OCHHCHCH CH2),
3.55 3.50 (m, 1H, OCHCHPh), 3.52 (t, J ˆ 8.5 Hz, 1H,
ˆ
ˆ
OCHHCHCH CH2), 2.66 2.55 (m, 1H, CHCH CH2), 2.48 (ddd, J ˆ 3.7,
10.1, 13.7 Hz, 1H, OCHCHPh), 2.16 2.11 (m, 1H), 1.89 1.71 (m, 4H),
1.61 1.56 (m, 1H), 1.44 1.27 (m, 4H); 13C NMR (50 MHz, CDCl3): d ˆ
144.5 (s), 138.9 (d), 128.0 (d), 126.1 (d), 115.1 (t), 105.5 (d), 81.6 (d), 70.7 (t),
51.5 (d), 43.0 (d), 39.0 (t), 35.0 (t), 32.9 (t), 25.9 (t), 25.3 (t); CI-MS (CH4):
‡
31.0 (t), 27.2 (t); EI-MS: m/z (%): 252 (0.7) [M ], 124 (100), 220 (23), 189
(31), 150 (26), 109 (41), 91 (35), 77 (25), 69 (32), 41 (46); HRMS (EI-MS):
‡
calcd for C14H20O4: 252.13616; found: 252.13641 [M ].
‡
m/z (%): 273 (18) [M ‡H], 159 (12), 115 (6), 113 (5), 97 (100), 91 (9);
1,6-Dimethoxy-1,3,3a,4,9,9a-hexahydronaphtho[2,3-c]furan (38): The
enone 37 (538 mg, 2.13 mmol, mixture of diastereomers, 84% ds) was
dissolved in MeOH (140 mL) in the presence of trimethylorthoformate
(14.2 mL) and pTsOH (30 mg). The reaction mixture was heated at reflux
for 1 h and was allowed to cool down to rt. Sat. NaHCO3 (40 mL) was
added and the mixture was extracted with Et2O. The organic phase was
washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo
to afford 38 (480 mg, 2.0 mmol, 96%, 87% ds). Diastereomers were
separated by FC (hexane/EtOAc 20:1).
elemental analysis calcd (%) for C18H24O2 (272.39): C 79.37, H 8.88; found:
C 79.33, H 8.91.
(4R)-4-Vinyltetrahydro-2-furanol: A solution of (1R,2S)-2-phenylcyclo-
hexyl-(2R,4R)-4-vinyltetrahydro-2-furanyl ether (120 mg, 1.05 mmol) in
THF (3 mL) and 10% HCl (2 mL) was kept at rt for 30 min. After
extraction with Et2O, the organic phases were washed with sat. NaHCO3
and H2O, dried over MgSO4 and evaporated under reduced pressure. The
crude product was purified by FC (pentane/Et2O 4:1) to give (1R,2S)-
phenylcyclohexanol (62 mg, 84%), the (4R)-4-vinyltetrahydro-2-furanol
(29 mg, 63%) and starting material (10 mg). Mixture of diasteroisomers:
1H NMR (360 MHz, CDCl3): d ˆ 5.85 (ddd, J ˆ 7.9, 10.1, 18.3 Hz, 1H,
(r-2,t-3,c-4)-38 (major): IR (CHCl3): nÄ ˆ 3010, 2950, 2837, 1612, 1500, 1449,
1
1368, 1208 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.04 (d, J ˆ 7.8 Hz, 1H,
arom. H), 6.73 6.69 (m, 2H, arom. H), 4.71 (s, 1H, CHOMe), 4.17 (dd, J ˆ
8.6, 7.1 Hz, 1H, CHHO), 3.78 (s, 3H, CH3OAr), 3.65 (dd, J ˆ 8.6, 2.8 Hz,
1H, CHHO), 3.33 (s, 3H, CHOCH3), 2.87 2.81 (m, 1H, CHHCHCOMe),
2.76 (dd, J ˆ 14.2, 6.1 Hz, 1H, CHHCHCH2O), 2.66 2.59 (m, 1H,
CH2CHCH2O), 2.51 2.44 (m, 3H, CHHCHCOMe, CHHCHCH2O,
CH2CHCH2OMe). NOE difference spectra (500 MHz): 4.18 4.11
ˆ
ˆ
CH CH2, 1 diast.), 5.71 (ddd, J ˆ 8.2, 10.4, 18.3 Hz, 1H, CH CH2, 1 diast.),
ˆ
5.58 5.54 (m, 1H, HOCHCH2), 5.14 (dt, J ˆ 0.9, 5.5 Hz, 1H, CH CHH, 1
ˆ
diast.), 5.08 (dt, J ˆ 0.9, 5.5 Hz, 1H, CH CHH, 1 diast.), 5.05 5.01 (m, 2H,
ˆ
ˆ
CH CH2, 1 diast.), 4.19 (t, J ˆ 8.2 Hz, 1H, OCHHCHCH CH2, 1 diast),
ˆ
3.98 (t, J ˆ 7.9 Hz, 1H, OCHHCHCH CH2, 1 diast.), 3.76 (t, J ˆ 8.2 Hz,
Chem. Eur. J. 2003, 9, No. 7
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1575 $ 20.00+.50/0
1575

P. Renaud et al.
FULL PAPER
ˆ
1H, OCHHCHCH CH2,
1
diast.), 3.57 (t, J ˆ 8.2 Hz, 1H,
2.54 2.46 (m, 1H, OCHCHPh), 2.25 2.16 (m, 1H, CHCH3), 1.91 1.22
(m, 10H, CH2), 0.66 (d, J ˆ 7.0 Hz, 3H, CH3); mixture of diastereoisomers:
IR (KBr): nÄ ˆ 3030, 2930, 2856, 1448, 1084, 987 cmÀ1; MS (CI, CH4): m/z
ˆ
ˆ
OCHHCHCH CH2, 1 diast.), 3.22 3.10 (m, 1H, CHCH CH2, 1 diast.),
ˆ
2.92 2.81 (m, 1H, CHCH CH2, 1 diast.), 2.63 (broad, 1H, OH, 1 diast.),
‡
2.55 (brs, 1H, OH, 1 diast.), 2.35 (ddd, J ˆ 5.2, 8.9, 13.7 Hz, 1H, OCHCHH,
1 diast.), 2.09 (dd, J ˆ 7.5, 12.1 Hz, 1H, OCHCHH, 1 diast.), 1.84 1.68 (m,
2H).
(%): 287 (17) [M ‡H], 187 (5), 159 (67), 111 (100), 93 (30), 91 (11);
elemental analysis calcd for C19H26O2 (286.42): C 79.68, H 9.15; found: C
79.78, H 9.10.
(4R)-Vinyl-g-butyrolactone (41):[33, 34] A solution of the (4R)-4-vinyltetra-
hydro-2-furanol (15 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added to a
mixture of PCC (100 mg, 0.5 mmol) and Al2O3 neutral (Woelm N,
activity Y, 0.19 g). The orange mixture was stirred overnight, diluted with
Et2O (3 mL) and filtered though Florisil to afford the lactone 41 (13 mg,
90%) as a colorless oil. The optical purity (>99% ee) was determined by
GC (g-cyclodextrin 65% diacetoxy, 1108C. tR ˆ 39.98 min for (R)-41. tR ˆ
40.97 min for (S)-41). [a]D21 ˆ À6.48 (c ˆ 1 in EtOH) (ref. [34]) [a]2D1 ˆ À5.68
(c ˆ 1.6 in EtOH); 1H NMR (360 MHz, CDCl3): d ˆ 5.78 (ddd, J ˆ 7.3, 10.1,
(2R,4S,5R)-4-Methyl-5-(2-hydroxy-ethyl)tetrahydro-2-furanyl-(1R,2S)-2-
phenylcyclohexyl ether: A solution of (2S,4S,5R)-43 (540 mg, 2.0 mmol) in
THF (1 mL) was added to a solution of 9-BBN 0.5m in THF (4.1 mL,
2.1 mmol) under N2. The solution was heated at reflux for 3 h, cooled at
08C and a 3m NaOH solution (2.3 mL) was added dropwise followed by
30% H2O2 (2.3 mL). The reaction mixture was stirred at rt for 1 h and
extracted with Et2O. The organic phases were washed with NaCl, dried
over MgSO4 and the solvent was removed under reduced pressure.
Purification by FC (hexane/Et2O 2:1) afforded the desired alcohol
(0.57 g, 93%). [a]2D0 ˆ ‡50.08 (c ˆ 1, CH2Cl2); IR (KBr): nÄ ˆ 3421, 2931,
ˆ
ˆ
17.1 Hz, 1H, CH CH2), 5.20 (dt, J ˆ 1.2, 14.0 Hz, 1H, CH CHH), 5.16 (dt,
J ˆ 1.2, 6.8 Hz, 1H, CH CHH), 4.45 (dd, J ˆ 7.6, 9.2 Hz, 1H,
2858, 1602, 1448, 1340, 1064, 993 cmÀ1
;
1H NMR (360 MHz, CDCl3): d ˆ
ˆ
ˆ
ˆ
OCHHCHCH CH2), 4.03 (dd, J ˆ 7.9, 9.2 Hz, 1H, OCHHCHCH CH2),
7.29 7.16 (m, 5 arom. H), 4.43 (dd, J ˆ 3.4, 5.8 Hz, 1H, OCHCH2), 3.77
3.72 (m, 2H, CH2OH), 3.64 (dt, J ˆ 3.1, 9.2 Hz, 1H, OCHCH2CH2OH),
3.48 (dt, J ˆ 4.3, 10.1 Hz, 1H, OCHCHPh), 2.71 (t, J ˆ 5.8 Hz, 1H, OH),
2.52 2.44 (m, 1H, OCHCHPh), 2.13 2.10 (m, 1H, CHCH3), 1.88 1.11
(m, 12H), 0.92 (d, J ˆ 6.7 Hz, 3H, CHCH3); 13C NMR (50 MHz, CDCl3):
d ˆ 144.9 (s), 128.5 (d), 128.5 (d), 126.5 (d), 105.3 (d), 84.0 (d), 82.5 (d), 62.2
(t), 51.9 (d), 41.0 (t), 38.9 (d), 35.6 (t), 35.5 (t), 33.4 (t), 26.4 (t), 25.8 (t), 16.7
ˆ
3.30 3.18 (m, 1H, CHCH CH2), 2.68 (dd, J ˆ 8.2, 17.4 Hz, 1H, COCHH),
2.39 (dd, J ˆ 8.2, 17.4 Hz, 1H, COCHH); 13C NMR (50 MHz, CDCl3): d ˆ
176.4 (s), 135.7 (d), 117.5 (t), 72.2 (t), 39.8 (d), 34.1 (t).
(1R)- and (1S)-2-Bromo-1-[(1R,2S)-(2-phenylcyclohexyl)oxy]ethyl 1-vi-
nyl-2-propenyl ether (42): According to GP 1 from 39 (0.72 g, 3.6 mmol),
1,4-pentadien-3-ol (0.45 mL, 3.9 mmol) and NBS (0.73 g, 3.6 mmol) in
CH2Cl2 (6 mL). FC (hexane/Et2O 10:1) gave a 1:1 mixture of the two
diasteroisomers of 42 (0.98 g, 75%). In preliminary experiments, the
diastereoisomers were separated by FC (hexane/Et2O 80:1) to afford (R)-
42 and (S)-42. However, on larger scale, it was convenient to continue the
synthesis with the mixture of diastereoisomers and to separate by FC after
the radical cyclization step (see below). (1S)-42: Rf ˆ 0.70 (hexane/Et2O
5:1); 1H NMR (360 MHz, CDCl3): d ˆ 7.31 7.20 (m, 5 arom. H), 5.86 5.66
‡
(q); CI-MS: m/z: 305 (5) [M ‡H], 257 (11), 159 (5), 129 (100), 111 (5), 85
(22); elemental analysis calcd for C19H28O3 (344.43): C 74.96, H 9.27; found:
C 74.83, H 9.17.
2-((2R,3S,5R)-3-Methyl-5-{[(1R,2S)-2-phenylcyclohexyl]oxy}tetrahydro-
2-furanyl)acetaldehyde: A solution of DMSO (0.29 mL, 4.0 mmol) in
CH2Cl2 (2 mL) was added to a solution of oxalyl chloride (0.18 mL,
2.1 mmol) in CH2Cl2 (13 mL) cooled at À788C. After 5 min, a solution of
the (2R,4S,5R)-4-methyl-5-(2-hydroxy-ethyl)tetrahydro-2-furanyl-(1R,2S)-
2-phenylcyclohexyl ether (0.54 g, 1.8 mmol) in CH2Cl2 (1 mL) was added
slowly. The white mixture was stirred at À788C for 30 min and Et3N
(1.22 mL, 8.8 mmol) was added. The mixture was stirred at rt for 2 h and
sat. NaCl (10 mL) was added. The mixture was extracted with CH2Cl2 and
the organic phase was washed with sat. NaCl, dried over MgSO4 and
evaporated under reduced pressure. Purification by FC (hexane/Et2O 1:1)
afforded the desired aldehyde (0.50 g, 95%). [a]2D0 ˆ ‡23.38 (c ˆ 0.3,
ˆ
ˆ
(m, 2H, CH CH2), 5.25 5.15 (m, 4H, CH2 CH), 4.38 (t, J ˆ 6.1 Hz, 1H,
ˆ
OCH(C CH2)2), 4.25 (dd, J ˆ 3.5, 6.7 Hz, 1H, OCHCH2Br), 3.46 (dt, J ˆ
4.5, 10.0 Hz, 1H, OCHCHPh), 2.75 (dd, J ˆ 6.7, 10.7 Hz, 1H,
OCHCHHBr), 2.58 2.53 (m, 1H, OCHCHPh), 2.50 (dd, J ˆ 3.5,
10.7 Hz, 1H, OCHCHH-Br), 2.19 2.11 (m, 1H), 1.91 1.82 (m, 2H),
1.77 1.71 (m, 1H), 1.61 1.27 (m, 4H); 13C NMR (50 MHz, CDCl3): d ˆ
144.5 (s), 138.1 (d), 137.8 (d), 128.8 (d), 128.6 (d), 127.0 (d), 117.7 (t), 116.6
(t), 101.0 (d), 82.1 (d), 79.1 (d), 51.8 (d), 34.6 (t), 33.8 (t), 32.8 (t), 26.2 (t),
25.7 (t); (1R)-42: Rf ˆ 0.72 (hexane/Et2O 5:1); 1H NMR (360 MHz,
CH2Cl2); IR (KBr): nÄ ˆ 2930, 2856, 1728, 1448, 1085, 989 cmÀ1
;
1H NMR
ˆ
CDCl3): d ˆ 7.32 7.19 (m, 5 arom. H), 5.60 5.44 (m, 2H, 2CH CH2),
(360 MHz, CDCl3): d ˆ 9.76 (dd, J ˆ 2.1, 3.1 Hz, 1H, CHO), 7.29 7.18 (m, 5
arom. H), 4.42 (dd, J ˆ 3.4, 5.8 Hz, 1H, OCHCH2), 3.95 (dt, J ˆ 3.7, 8.6 Hz,
1H, OCHCH2CHO), 3.50 (dt, J ˆ 4.3, 10.1 Hz, 1H, OCHCHPh), 2.56 (ddd,
J ˆ 2.1, 4.0, 16.2 Hz, 1H, CHHCHO), 2.50 2.47 (m, 1H, OCHCHPh), 2.41
(ddd, J ˆ 2.7, 8.2, 15.9 Hz, 1H, CHHCHO), 2.15 2.13 (m, 1H, CHCH3),
1.90 1.17 (m, 10H), 0.97 (d, J ˆ 6.4 Hz, 3H, CHCH3); 13C NMR (50 MHz,
CDCl3): d ˆ 201.6 (d), 144.9 (s), 128.5 (d), 128.4 (d), 126.5 (d), 105.3 (d),
82.4 (d), 78.8 (d), 51.9 (d), 47.7 (t), 41.1 (t), 39.0 (d), 35.5 (t), 33.4 (t), 26.4 (t),
ˆ
5.12 4.91 (m, 4H, 2CH CH2), 4.57 (dd, J ˆ 3.7, 7.0 Hz, 1H, OCHCH2Br),
ˆ
3.57 3.53 (m, 1H, OCHCHPh), 3.53 3.50 (m, 1H, OCH(CH CH2), 3.21
(dd, J ˆ 7.0, 10.4 Hz, 1H, OCHCHHBr), 3.07 (dd, J ˆ 3.7, 10.7 Hz, 1H,
OCHCHHBr), 2.61 2.54 (m, 1H, OCHCHPh), 2.13 1.32 (m, 8H, CH2);
13C NMR (50 MHz, CDCl3): d ˆ 144.8 (s), 138.1 (d), 137.6 (d), 128.7 (d),
128.6 (d), 126.9 (d), 117.6 (t), 116.3 (t), 99.1 (d), 80.2 (d), 77.7 (d), 51.2 (d),
34.3 (t), 33.9 (t), 26.2 (t), 25.4 (t). Mixture of diastereoisomers: IR (KBr):
nÄ ˆ 3028, 2931, 2858, 1448, 1114, 1028 cmÀ1; MS (CI-CH4): m/z (%): 365 (1)
‡
25.8 (t), 16.8 (q); MS-CI: m/z: 303 (2) [M ‡H], 285 (22), 259 (5), 159 (27),
‡
[M ], 283 (6), 225 (14), 175 (16), 159 (100), 91 (11), 67 (51); elemental
127 (100), 101 (4), 81 (11); HRMS (ESI-MS): calcd for C19H26O3Na:
‡
analysis calcd (%) for for C19H25O2Br (365.31): C 62.47, H 6.90; found: C
62.43, H 6.83.
325.17741; found: 325.17710 [M ‡Na].
(2R,4S,5R)-4-Methyl-5-(3-methyl-2-butenyl)tetrahydro-2-furanyl-
(2S,4S,5R)- and (2R,4R,5S)-4-Methyl-5-vinyltetrahydro-2-furanyl (1R,2S)-
2-phenylcyclohexyl ether [(2S,4S,5R)-43 and (2R,4R,5S)-43]: According to
GP 2 from 42 (1:1 mixture of diast., 0.98 g, 2.7 mmol), Bu3SnH (0.94 g,
3.24 mmol) and 1m solution of Et3B in hexane (3.8 mL, 3.8 mmol). FC
(hexane/Et2O 30:1) gave 43 (0.66 g, 85%). The two diastereomers were
separated by FC (hexane/Et2O 30:1). (2S,4S,5R)-43: [a]2D0 ˆ ‡22.38 (c ˆ 1.5,
(1R,2S)-2-phenylcyclohexyl ether (44): nBuLi (2.21m in hexane, 0.3 mL,
0.66 mmol) was added dropwise to a suspension of isopropyltriphenyl-
phosphonium iodide (0.37 g, 0.86 mmol) in THF (4 mL). The red mixture
was stirred at À308C for 20 min, cooled at À788C and a solution of the
2-((2R,3S,5R)-3-methyl-5-{[(1R,2S)-2-phenylcyclohexyl]oxy}tetrahydro-2-
furanyl)acetaldehyde (0.19 g, 0.66 mmol) in THF (2 mL) was added. The
mixture was stirred at the same temperature for 1 h, poured into water,
extracted with Et2O and the organic phases were washed with brine. After
drying and evaporation of the solvent the crude product was purified by FC
1
CH2Cl2); H NMR (360 MHz, CDCl3): d ˆ 7.30 7.15 (m, 5 arom. H), 5.67
ˆ
(ddd, J ˆ 7.4, 10.1, 17.1 Hz, 1H, CH CH2), 5.22 (ddd, J ˆ 0.9, 1.5, 17.1 Hz,
ˆ
ˆ
1H, CH CHH), 5.13 (ddd, J ˆ 0.9, 1.8, 10.4 Hz, 1H, CH CHH), 4.42 (dd,
J ˆ 3.5, 5.5 Hz, 1H, OCHCH2), 3.85 (t, J ˆ 8.2 Hz, 1H, OCHCH CH2),
(hexane/Et2O 40:1) to give 44 (0.11 g, 51%) as a colorless oil. [a]D20
ˆ
ˆ
3.55 (dt, J ˆ 4.6, 10.4 Hz, 1H, OCHCHPh), 2.52 2.45 (m, 1H,
OCHCHPh), 2.20 2.13 (m, 1H, CHCH3), 1.90 1.16 (m, 10H), 0.92 (d,
J ˆ 7.1 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): d ˆ 144.5 (s), 137.5 (d),
128.0 (d), 127.9 (d), 126.1 (d), 116.8 (t), 104.9 (d), 85.2 (d), 81.7 (d), 51.6 (d),
40.9 (t), 39.0 (d), 35.1 (t), 33.0 (t), 25.9 (t), 25.3 (t), 15.8 (q); (2R,4R,5S)-43:
[a]2D0 ˆ À98.48 (c ˆ 0.5, CH2Cl2); 1H NMR (360 MHz, CDCl3): d ˆ 7.30
‡38.58 (c ˆ 1, CH2Cl2); IR (KBr): nÄ ˆ 3030, 2930, 2856, 1448, 1377, 1066,
991 cmÀ1
;
1H NMR (360 MHz): d ˆ 7.22 7.15 (m, 5 arom. H), 5.16 5.12
ˆ
(m, 1H, CH CMe2), 4.40 (dd, J ˆ 3.1, 5.8 Hz, 1H, OCHCH2), 3.56 3.50
ˆ
(m, 2H, OCHCHPh, OCHCH2CH CMe2), 2.51 2.44 (m, 1H,
ˆ
OCHCHPh), 2.24 2.08 (m, 3H, CH2CH CMe2, CHCH3), 1.68 (s, 3H,
CH3), 1.58 (s, 3H, CH3), 1.88 1.12 (m, 10H), 0.92 (d, J ˆ 6.7 Hz, 3H,
CHCH3); 13C NMR (50 MHz, CDCl3): d ˆ 145.1 (s), 133.5 (s), 128.5 (d),
128.4 (d), 126.4 (d), 120.8 (d), 105.0 (d), 84.0 (d), 81.8 (d), 52.0 (d), 41.5 (t),
38.0 (d), 35.5 (t), 33.5 (t), 32.6 (t), 26.4 (t), 26.2 (q), 25.8 (t), 18.4 (q), 17.7 (q);
ˆ
7.23 (m, 5 arom. H), 5.56 (ddd, J ˆ 7.6, 10.4, 18.0 Hz, 1H, CH CH2), 5.21
ˆ
(dd, J ˆ 1.8, 5.5 Hz, 1H, OCHCH2), 5.05 4.93 (m, 2H, CH CH2), 3.80 (td,
ˆ
J ˆ 4.0, 10.4 Hz, 1H, OCHCHPh), 2.60 (t, J ˆ 7.2 Hz, 1H, OCHCH ),
1576
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2003, 9, No. 7

Stereoselective Radical Cyclizations
1566 1577
‡
¬
¬
MS (CI, CH4): m/z (%): 329 (1) [M ‡H], 259 (8), 159 (65), 153 (34), 117
[18] J. C. Lopez, A. M. Gomez, B. Fraser-Reid, Aust. J. Chem. 1995, 48,
(10), 109 (29), 91 (100), 69 (46); HRMS (CI, isobutane): calcd for C22H33O2:
329.24750; found: 329.24887 [M ‡H].
(4S,5R)-4-Methyl-5-(3-methyl-2-butenyl)dihydro-2(3H)-furanone
eldanolide] (45): A solution of 44 (0.12 g, 0.36 mmol) in THF (1.3 mL)
and 10% HCl (1 mL) was kept at rt for 30 min. After extraction with Et2O,
the organic phases were washed with sat. NaHCO3 and H2O, dried over
MgSO4 and evaporated under reduced pressure. The crude product was
purified by FC (pentane/Et2O 6:1) to afford (1R,2S)-phenylcyclohexanol
(40 mg, 62%) and the lactol (42 mg, 68%) as a mixture of diastereoisomers.
333.
‡
¬
[19] J. C. Lopez, B. Fraser-Reid, Chem. Commun. 1997, 2251.
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[27] For the stereochemistry nomenclature used in this paper, see: R.
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[(‡)-
1
Mixture of diasteroisomers. H NMR (360 MHz, CDCl3): d ˆ 5.52 (dt, J ˆ
3.8, 5.7 Hz, 1H, OCHO, 1 diast.), 5.42 (t, J ˆ 3.6 Hz, 1H, OCHO, 1 diast.),
ˆ
5.27 5.18 (m, 2H, CH CMe2), 3.78 3.72 and 3.58 3.52 (m, 1H,
ˆ
OCHCH2CH CMe2), 2.70 2.67 and 2.52 2.50 (m, 1H, OH), 2.42 2.03
(m, 8H), 1.92 1.78 (m,1H), 1.73 and 1.72 (2s, 3H, CH3), 1.53 1.46 (m,
1H), 1.09 and 1.08 (2d, J ˆ 7.5 Hz, 3H, CHCH3).
A solution of the lactol (0.42 g, 0.25 mmol) in CH2Cl2 (4 mL) was added to
a
mixture of PCC (0.19 g, 0.9 mmol) and Al2O3 neutral (Woelm N,
activity Y, 0.35 g). The orange mixture was stirred overnight then diluted
with Et2O (6 mL) and filtered through Florisil to afford the (‡)-eldanolide
45 (32 mg, 76%) as a colorless oil. The optical purity (>99% ee) was
determined by GC (g-cyclodextrin 65% diacetoxy, 1408C, tR ˆ 20.68 min
for (4S,5R)-45 and tR ˆ 21.23 min for (4R,5S)-45). [a]2D0 ˆ ‡43.48 (c ˆ 1,
EtOH) [lit.:[39] [a]2D0 ˆ ‡51.58, c ˆ 1.15, MeOH]. All spectral data were in
accordance with literature data.[39] 1H NMR (360 MHz, CDCl3): d ˆ 5.17
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ˆ
ˆ
(brt, 1H, CH CMe2), 4.06 (q, J ˆ 7.0 Hz, 1H, OCHCH2CH CMe2), 2.67
(dd, J ˆ 7.6, 16.5 Hz, 1H, CHHCHCH3), 2.46 2.22 (m, 3H, CHCH3,
[32] K. Kondo, F. Mori, Chem. Lett. 1974, 741.
ˆ
CHCH2CH CMe2), 2.17 (dd, J ˆ 9.2, 16.8 Hz, 1H, CHHCHCH3), 1.73 (s,
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3H, CH3), 1.64 (s, 3H, CH3), 1.14 (d, J ˆ 6.7 Hz, 3H, CHCH3); 13C NMR
(50 MHz, CDCl3): d ˆ 176.4 (s), 135.4 (s), 118.0 (d), 87.0 (d), 37.1 (t), 35.1
(d), 32.2 (t), 25.8 (q), 17.9 (q), 17.7 (q); MS (CI, CH4): m/z (%): 169 (100)
‡
[M ‡H], 151 (25), 123 (12), 109 (89), 99 (26), 84 (7), 69 (35).
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Acknowledgement
¬
[38] Determination of the absolute configuration: J. P. Vigneron, R. Meric,
We are very grateful to the Swiss National Science Foundation and the
Federal Office for Science and Education (Project COST-D12) for financial
support.
√
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¬
¬
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Received: September 16, 2002 [F4427]
Chem. Eur. J. 2003, 9, No. 7
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0907-1577 $ 20.00+.50/0
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