Ring closure reactions of disubstituted 4-penten-1-oxyl radicals - Towards a stereoselective synthesis of allo-muscarine

Article abstract of DOI:10.1002/(sici)1099-0690(200005)2000:9<1677::aid-ejoc1677>3.0.co;2-x

The trisubstituted functionalized tetrahydrofurans 10, 11, 16, 18, and 19 were photochemically prepared from 2,3-syn- and 2,3-anti-configured N-(3- benzoyloxy-5-hexen-2-oxy)thiazole-2(3H)-thione anti-6, pyridinethiones 7, anti-8, and BrCCl₃. The formation of tetrahydrofurans was achieved by an efficient and highly regioselective alkoxyl radical cyclization (5-exo-trig). The 2,3-anti substituted intermediates 9 and 12 cyclize stereoselectively whereas a 2,3-syn-configured O-radical affords both possible diastereomeric addition products in equal amounts. The cyclized tetrahydrofuryl methyl radicals were trapped with the bromine atom donor BrCCl₃ to afford the bromomethyl-substituted cyclic ethers 10, 11, 18, and 19 in excellent yields. The utility of this reaction was stressed by conversion of one of the newly prepared tetrahydrofurans in a two-step synthesis into (+)-allo-muscarine (+)-20.

Full text of DOI:10.1002/(sici)1099-0690(200005)2000:9<1677::aid-ejoc1677>3.0.co;2-x

SHORT COMMUNICATION
Ring Closure Reactions of Disubstituted 4-Penten-1-oxyl Radicals ؊ Towards
a Stereoselective Synthesis of allo-Muscarine
Jens Hartung,*[a] and Rainer Kneuer[a]
Dedicated to Professor Dr. Bernd Giese on the occasion of his 60th birthday
Keywords: Radicals / Cyclizations / Pyridinethione / Tetrahydrofurans / Asymmetric synthesis / Thiazolethione
The trisubstituted functionalized tetrahydrofurans 10, 11, 16,
18, and 19 were photochemically prepared from 2,3-syn- and ucts in equal amounts. The cyclized tetrahydrofuryl methyl
2,3-anti-configured N-(3-benzoyloxy-5-hexen-2-oxy)thia- radicals were trapped with the bromine atom donor BrCCl3
zole-2(3H)-thione anti-6, pyridinethiones 7, anti-8, and to afford the bromomethyl-substituted cyclic ethers 10, 11,
radical affords both possible diastereomeric addition prod-
BrCCl3. The formation of tetrahydrofurans was achieved by
an efficient and highly regioselective alkoxyl radical cycliza-
18, and 19 in excellent yields. The utility of this reaction was
stressed by conversion of one of the newly prepared tetrahy-
tion (5-exo-trig). The 2,3-anti substituted intermediates 9 and drofurans in a two-step synthesis into (+)-allo-muscarine
12 cyclize stereoselectively whereas a 2,3-syn-configured O-
(+)-20.
Introduction
Results and Discussion
The discovery of N-alkoxythiazole-2(3H)-thiones[1] and
their corresponding pyridine-2(1H)-thiones[2] as efficient
precursors of free alkoxyl radicals has enabled us to study
tetrahydrofuran syntheses from substituted 4-penten-1-oxyl
radicals.[3Ϫ5] We have observed that 2,5-trans-, 2,4-cis-,
and 2,3-trans-dialkyl-substituted tetrahydrofurans are ac-
cessible from monosubstituted pentenoxyl radicals in spite
of their high reactivities (rate constants of 5-exo-trig cyc-
The 2,3-syn- and 2,3-anti-configured hexenols 2 were
chosen as starting materials for our studies (Scheme 1).
These compounds are readily available from methyl lactate
by adapting the method of Chan and Li.[6] Since the major
aim of the present work was an elucidation of the general
scope of hitherto unknown cyclizations of 3-substituted 5-
hexen-2-oxyl radicals we could have started with racemic
methyl lactate. For economic reasons, however, we used
methyl S-(Ϫ)-lactate (1) as substrate. The α-hydroxy ester 1
was converted into the p-methoxybenzyl-protected[7] 2-(p-
methoxybenzyloxy)propanal, which was reacted with allyl
magnesium bromide at Ϫ78 °C in diethyl ether in a one-pot
reaction to afford a 14:86 mixture of anti- and syn-2. The
diastereomers 2 were separated by column chromatography
to afford pure syn-2 and anti-2. Reaction of syn-2 with
lizations: kcycl ഠ 108 Ϫ1). The efficiency of these trans-
s
formations has raised the question whether O-radical reac-
tions could be usefully applied in stereoselective syntheses
of multiply substituted tetrahydrofurans, such as the mus-
carine alkaloids which, according to the best of our know-
ledge, have never been prepared using free radical chemistry.
The feasibility of such reactions, however, is dependent on
a precise stereocontrol of the central O-radical reaction by
substituent effects. If, for instance, cyclizations of disubsti-
tuted 4-pentenoxyl radicals would follow similar guidelines
as those of monosubstituted 4-penten-1-oxyl radicals with
regard to stereoselectivity, tetrahydrofuran syntheses using
alkoxyl radical chemistry should become of notable syn-
thetic utility. These considerations initiated the present in-
vestigation on substituent effects in alkoxyl radical ring
closures of 3-substituted 5-hexen-2-oxyl radicals.
benzoyl
chloride
and
1,4-diazabicyclo[2.2.2]octane
(DABCO) was followed by removal of the p-methoxybenzyl
protecting group with DDQ[7] and tosylation[8] of the free
hydroxyl group in position 2 to afford syn-3 (Scheme 1).
A similar procedure which uses the reaction of alcohol
syn-2 with TBDMSCl and imidazole in DMF in the first
step was applied for the synthesis of tosylate syn-4 from
syn-2. The alcohol anti-2 was converted into anti-3 in 87%
overall yield as described for its diastereomer syn-2. Based
on our experience, the N-alkoxy derivatives of pyridine-
2(1H)-thione and of 4-methylthiazole-2(3H)-thione[9,10]
were selected as O-radical precursors. To the best of our
knowledge there is no report in the literature on the utility
of N-alkoxy-4-methylthiazole-2(3H)-thiones as sources of
O-radicals. Synthesis of a 4-methylthiazolethione-derived
radical precursor anti-6 was achieved by treatment of the
N-hydroxy-4-methylthiazole-2(3H)-thione tetraethylammo-
[a]
Institut für Organische Chemie, Universität Würzburg,
Am Hubland, D-97074 Würzburg, Germany
Fax: (internat.) ϩ 49-931/888-4606
E-mail: hartung@chemie.uni-wuerzburg.de
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Eur. J. Org. Chem. 2000, 1677Ϫ1683
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0509Ϫ1677 $ 17.50ϩ.50/0
1677

J. Hartung, R. Kneuer
SHORT COMMUNICATION
Scheme 2. Preparation of alkoxyl radical precursors 6Ϫ8
Scheme 1. Synthesis of tosylates syn-3Ϫ4; reagents and conditions:
(a) NaH, p-methoxybenzyl chloride (PMBCl), DMF (75%); (b) DI-
BAH, Et2O, Ϫ78 °C; (c) allyl magnesium bromide, Et2O, Ϫ78 °C
(94% step b and c); (d) column chromatography, SiO2, petroleum
ether/CH2Cl2/MeOH, 10/4/1(v/v/v); (e) PhCOCl, DABCO, CH2Cl2
(99%); (f) DDQ, H2O/CH2Cl2 (94%) [84%]; (g) TosCl, DABCO,
CH2Cl2 (94%) [96%]; (h) (tert-butyl)dimethylsilyl chloride, imida-
zole, DMF (94%); yields in square brackets refer to the synthesis
of syn-4
nium salt (5)[9] with syn-3. The reaction proceeded with a
clean inversion of configuration at carbon C-2 (Scheme 2)
and afforded the 2,3-anti-configured alkoxyl radical pre-
cursor anti-6 (83% yield, tan oil). The respective 5-hexen-2-
oxypyridinethione anti-7 was obtained in 63% yield as a
yellow oil. Reaction of the TBDMS-substituted tosylate
syn-4 and N-hydroxypyridine-2(1H)-thione tetrabutylam-
monium salt[9] gave the alkoxyl radical precursor anti-8 in
45% yield (yellow oil). The tosylate anti-3 was treated with
N-hydroxypyridine-2(1H)-thione tetrabutylammonium salt
to afford the 2,3-syn-configured N-alkoxypyridinethione
syn-7 (76% yield, yellow oil). The pyridinethiones 7 and 8
Scheme 3. Photoreaction of anti-6Ϫ7 and BrCCl3
were only moderately stable and had to be kept in the dark, inethione anti-7 as source of O-radical 9, since the N-alk-
while thiazolethione anti-6 was stable towards visible light oxypyridine-2(1H)-thiones are highly sensitive to visible
and did not deteriorate upon storage at room temperature. light. Thus, solutions of anti-7 and BrCCl3 were thermo-
The photochemical reaction (λ ϭ 350 nm, T ϭ 20 °C) of stated in a mirrored Dewar vessel at Ϫ40 °C or at Ϫ78 °C
N-(3-benzoyloxy-5-hexen-2-oxy)thiazole-2(3H)-thione anti- and were irradiated using incandescent light. The results of
6 (co ϭ 0.18 ) and BrCCl3 (co ϭ 1.4 ) in C6H6 gave, this study (Scheme 3) indicated that the selectivity for the
upon workup of the colourless solution, the trisubstituted formation of the desired product 10 increased from 10:11 ϭ
tetrahydrofuran 10 (55%) as major and 11 (27%) as minor 67:33 at 20 °C to 80:20 at Ϫ78 °C. Quantification of our
product (Scheme 3). The heterocycles 10 and 11 originated results using n-C14H30 as internal standard for GC analysis
from a homolysis of the N,O bond in ester anti-6 to afford showed that yields of 10 and 11 at Ϫ40 °C corresponded to
the alkoxyl radical 9. The intermediate 9 cyclized stereose- the isolated yields given in Scheme 3 for the photoreaction
lectively to give carbon centred tetrahydrofurylmethyl rad- of thiazolethione anti-6 and BrCCl3 at room temperature.
icals (not shown in Scheme 3) which were trapped by A further decrease of the reaction temperature to Ϫ78 °C
BrCCl3 to afford heterocycles 10 and 11 (Scheme 3). The can, however, not be recommended for synthetic purposes.
tetrahydrofurans 10 and 11 were isolated as pure diastereo- Although the selectivity for the formation of 10 increased,
mers by column chromatography. In order to increase the yields of 10 and 11 dropped and became hard to quantify
selectivity for the formation of tetrahydrofuran 10 the in a reproducible manner. Furthermore, photochemical
photoreactions were carried out at lower temperatures. conversion of anti-7 at Ϫ78 °C became sluggish and
This, however, was more conveniently achieved using pyrid- stopped without complete consumption of starting mat-
1678
Eur. J. Org. Chem. 2000, 1677Ϫ1683

Towards a Stereoselective Synthesis of allo-Muscarine
SHORT COMMUNICATION
erial. In addition, new side products were formed in minor transition state is of significance for O-radical cyclizations
amounts which have not yet been characterized. which have been described in this work, both substituents
Increasing the steric bulk of the β-oxy substituent was in the 2,3-anti-substituted radical 9 (derived from anti-6 and
thought to be a straightforward approach to further im- anti-7) would be located preferentially in pseudo-equatorial
prove the stereoselectivity of the O-radical cyclization of positions (this corresponds to a trans-configuration in cyclic
2,3-anti-substituted alkoxyl radicals (Scheme 4). Thus, the systems, Scheme 3) and will favour formation of trisubsti-
TBDMS-substituted N-hexenoxypyridinethione anti-8 tuted tetrahydrofuran 10. If radicals derived from 2,3-syn
(co ϭ 0.18 ) was subjected to photolysis in the presence of substituted pyridinethione syn-7 would cyclize via a chair-
BrCCl3 (co ϭ 1.4 ). The starting material was consumed like transition state, either the methyl or the benzoyloxy
within one minute. Upon workup of the reaction mixture, group has to be situated in a pseudo-axial arrangement.
only a single stereoisomer of tetrahydrofuran 16 was isol- Therefore, we refer to the 2,3-anti configuration in anti-6
ated. Its yield, however, was poor (16%). Besides heterocy- and anti-7 as matched for the stereoselective synthesis of
cle 16, four additional products were identified from this trisubstituted tetrahydrofurans via alkoxyl radical 5-exo-
experiment which pointed to a β-cleavage of radical 12. One trig ring closures. In the same manner, the 2,3-syn arrange-
major product of this fragmentation was acetaldehyde (14) ment in syn-7 appears to be the mismatched case.
(54%); it was only identified when the reaction was run in
an NMR tube. Upon extrusion of the CϪ2 unit of the par-
ent alkoxyl radical 12 a carbon centred butenyl radical (not
shown in Scheme 4) should originate which is thought to
give rise to products 13, 15, and 17. Fragmentation of the
β-silyloxy-substituted O-radicals are known processes in bi-
cyclic systems.[11] However it was surprising to note from
the present example that such fissions can get more efficient
Scheme 5. Preparation of tetrahydrofurans 18 and 19 from syn-7
than the 5-exo-trig cyclization of O-radical 12.
In order to underline the utility of the new stereoselective
tetrahydrofuran synthesis described in this work, the
benzoyl ester 10 was saponified to afford a 3-hydroxyl-sub-
stituted 2-methyl-5-bromomethyltetrahydrofuran which was
reacted with NMe3 in ethanol at 60 °C in a sealed tube (no
elevated pressure).[14] According to our results, substitution
of trimethylamine for bromine stopped at 38% conversion
of the starting material and afforded (ϩ)-allo-muscarine
(ϩ)-20 as colourless crystals as well as 60% of starting mat-
erial (Scheme 6). The NMR spectroscopic data of (ϩ)-20
are in agreement with the published values for the enanti-
omer (Ϫ)-allo-muscarine (Ϫ)-20.[14]Ϫ[18]
Scheme 6. Synthesis of (ϩ)-allo-muscarine (ϩ)-20: (a) 76% yield;
(b) 38% yield and 60% of recovered starting material
Scheme 4. Photolysis of TBDMS-protected alkoxyl radical pre-
cursor anti-8 in the presence of BrCCl3; Figures in parentheses de-
note yields of volatile aldehydes as derived from a separate NMR
experiment in C6D6
Conclusion
If the 2,3-syn-substituted pyridinethione syn-7 was
The 5-exo-trig ring closures of 2,3-syn- and 2,3-anti 5-
photoreacted at room temperature with BrCCl3 (incandes- hexen-2-oxyl radicals have been studied for the first time.
cent light) the (bromomethyl)tetrahydrofurans 18 and 19 The stereochemical course of these radical cyclizations
were isolated in 80% yield. However, no stereoselectivity for point to matched (2,3-anti substituted 5-hexen-2-oxyl rad-
the formation of either product was observed (Scheme 5). icals 9, 12) and mismatched (2,3-syn substitution) cases in
In earlier work we have studied 4-penten-1-oxyl radical cyc- O-radical cyclizations. Based on these findings we were able
lizations by ab initio theoretical methods.[12] According to to complete the first synthesis of a muscarine alkaloid
these data the lowest energy transition state for 5-exo-trig whose central ring was built by an O-radical reaction. These
ring closure of alkoxyl radicals is reminiscent of a flattened findings should be of significant importance for an applica-
chair-like conformer, which is similar to the Beckwith trans- tion of alkoxyl radical chemistry in synthetic organic chem-
ition structure of 5-hexenyl radical cyclizations.[13] If such a istry.
Eur. J. Org. Chem. 2000, 1677Ϫ1683
1679

J. Hartung, R. Kneuer
SHORT COMMUNICATION
1
anti-2: Yield 0.42 g (13%), colourless oil, Rf ϭ 0.44. Ϫ H NMR
Experimental Section
(250 MHz): δ ϭ 1.18 (d, J ϭ 6.3 Hz, 3 H), 1.92 (br. s, 1 H), 2.24
(mc, 2 H), 3.50 (dq, Jd ϭ 4.0 Hz, Jq ϭ 6.3 Hz, 1 H), 3.76 (mc, 1
H), 3.81 (s, 3 H), 4.43 (d, J ϭ 11.2 Hz, 1 H), 4.56 (d, J ϭ 11.2 Hz,
1 H), 5.11 (d, J ϭ 11.5 Hz, 1 H), 5.12 (d, J ϭ 17.0 Hz, 1 H), 5.84
(mc, 1 H), 6.88 (d, J ϭ 8.7 Hz, 2 H), 7.26 (d, J ϭ 8.7 Hz, 2 H). Ϫ
13C NMR (63 MHz): δ ϭ 14.0, 37.2, 55.5, 70.6, 72.7, 77.2, 114.0,
117.7, 129.4, 130.7, 135.2, 159.4.
General Remarks: Methyl S-(Ϫ)-lactate (1) was purchased from Al-
drich and used as received. Petroleum ether refers to the fraction
boiling between 55Ϫ60 °C. Unless otherwise noted, NMR spectra
were recorded in CDCl3. IR spectra were measured in CCl4 in NaCl
cuvettes (0.5 mm). C,H,N,S analyses were carried out in the Mic-
roanalytical Laboratory in the department of Inorganic Chemistry
at the Universität Würzburg. Combustion analyses of compounds
2, 3, 7, 10, 11, 18, and 19 (diastereomers) were obtained from
samples which contained both possible diastereomers. All solvents
were distilled prior to use and were purified according to stand-
ard procedures.[19]
syn-2-(4-Methoxybenzyl)-5-hexen-3-yl Benzoate: Alcohol syn-2
(552 mg, 2.34 mmol) and DABCO (536 mg, 4.78 mmol) were dis-
solved at 0 °C in reagent grade CH2Cl2 (2.4 mL) and treated drop-
wise with neat benzoyl chloride (493 mg, 3.51 mmol). The mixture
was stirred for 30 min at 0 °C. Methyl tert-butyl ether (MTB,
10 mL) was added and the precipitate was dissolved by acid-
ification of the reaction mixture with 2  aqueous HCl (10 mL).
The organic phase was separated and the aqueous layer was ex-
tracted with MTB (2 ϫ 5 mL). The combined organic solutions
were successively washed with 2  HCl, satd. aqueous NaHCO3,
brine (10 mL each), and then dried (MgSO4). The solvent was re-
moved in vacuo to afford pure syn-2-(4-methoxybenzyl)-5-hexen-3-
yl benzoate: yield 791 mg (99%), colourless oil. Ϫ C21H24O4
(340.4): calcd. C 74.09, H 7.11; found C 73.88, H 6.82. Ϫ 1H NMR
(250 MHz): δ ϭ 1.22 (d, J ϭ 6.4 Hz, 3 H), 2.40Ϫ2.58 (m, 2 H),
3.76 (mc, 1 H), 3.80 (s, 3 H), 4.47 (d, J ϭ 11.2 Hz, 1 H), 4.60 (d,
J ϭ 11.6 Hz, 1 H), 5.04 (d, J ϭ 10.1 Hz, 1 H), 5.09 (d, J ϭ 17.4 Hz,
1 H), 5.25 (ddd, J ϭ 4.6, 4.9, 7.9 Hz, 1 H), 5.79 (mc, 1 H), 6.84 (d,
J ϭ 8.9 Hz, 2 H), 7.27 (d, J ϭ 8.9 Hz, 2 H), 7.44 (mc, 2 H), 7.55
(mc, 1 H), 8.05 (mc, 2 H). Ϫ 13C NMR (63 MHz): δ ϭ 15.4, 34.2,
55.2, 70.8, 74.2, 75.4, 113.7, 117.7, 128.3, 128.9, 129.3, 129.6, 130.6,
132.9, 133.8, 159.1, 166.1.
Preparation of Tosylates 3 and 4
Methyl 2-(4-Methoxybenzyloxy)propionate: Methyl 2S-(Ϫ)-lactate
(1) (2.95 g, 28.3 mmol) was added dropwise at 0 °C to a mixture of
p-methoxybenzyl chloride (4.44 g, 28.3 mmol) and sodium hydride
(0.608 g, 28.3 mmol) under argon in anhydrous DMF (35 mL). The
suspension was stirred for 18 h at room temp. and was poured into
a mixture of H2O and diethyl ether (30 mL each). The aqueous
phase was separated and extracted with diethyl ether (2 ϫ 20 mL)
The combined organic phases were washed with water (2 ϫ 20 mL)
and with brine (20 mL) and dried (MgSO4). The solvent was re-
moved in vacuo and the remaining oil was distilled to afford methyl
2-(4-methoxybenzyloxy)propionate (4.76 g, 75%). Ϫ Colourless li-
quid, bp 98 °C/1.6 ϫ 10Ϫ2 mbar. Ϫ MS (70 eV, EI): m/z (%) ϭ 224
(5), 137 (63), 121 (100). Ϫ IR (NaCl): ν˜ ϭ 2920 cmϪ1, 1730, 1590,
1
1490, 1440, 1230, 1130, 1100, 1020, 810. Ϫ H NMR (250 MHz):
δ ϭ 1.42 (d, J ϭ 6.7 Hz, 3 H), 3.75 (s, 3 H), 3.80 (s, 3 H), 4.05 (q,
J ϭ 6.7 Hz, 1 H), 4.39 (d, J ϭ 11.3 Hz, 1 H), 4.62 (d, J ϭ 11.3 Hz,
1 H), 6.88 (d, J ϭ 8.9 Hz, 2 H), 7.29 (d, J ϭ 8.9 Hz, 2 H). Ϫ 13C
NMR (63 MHz): δ ϭ 18.7, 51.9, 55.2, 71.6, 73.6, 113.7, 129.5,
129.6, 159.3, 173.8. Ϫ C12H16O4 (224.3): calcd. C 64.27, H 7.19;
found C 64.06, H 7.06.
anti-2-(4-Methoxybenzyl)-5-hexen-3-yl Benzoate: This compound
was obtained in the same manner as described for its syn isomer:
yield 790 mg (99%), colourless oil. Ϫ 1H NMR (250 MHz): δ ϭ
1.26 (d, J ϭ 6.4 Hz, 3 H), 2.51Ϫ2.57 (m, 2 H), 3.74 (dq, Jd
ϭ
syn- and anti 2-(4-Methoxybenzyloxy)-5-hexen-3-ol (2): A solution
of methyl 2-(4-methoxybenzyloxy)propionate (3.05 g, 13.6 mmol)
in anhydrous diethyl ether (70 mL) was treated at Ϫ78 °C under
nitrogen atmosphere dropwise with a solution of diisobutylalumi-
num hydride (1  in n-hexane, 17.7 mL). The reaction mixture was
stirred for 30 min at Ϫ78 °C and was reacted at this temperature
dropwise with a solution of allyl magnesium bromide in diethyl
ether (prepared from 0.727 g, 29.9 mmol of magnesium turnings
and 3.29 g, 27.2 mmol of allyl bromide in 14 mL of anhydrous di-
ethyl ether). The reaction mixture was stirred for 6 h at Ϫ78 °C
and was allowed to warm to 0 °C. 2  HCl (25 mL) was added and
the aqueous phase was separated and was extracted with diethyl
ether (2 ϫ 20 mL). The combined ethereal phases were washed with
a satd. solution of NaHCO3 (20 mL) and H2O (20 mL), and then
dried (MgSO4). The solvent was removed in vacuo and the re-
maining oil was purified by column chromatography [(SiO2, petro-
leum ether/CH2Cl2/ MeOH, 10:4:1 (v/v/v)]. Mixture of isomers:
C14H20O3 (236.3): calcd. C 71.16, H 8.53; found C 70.82, H 8.50.
4.6 Hz, Jq ϭ 6.4 Hz, 1 H), 3.78 (s, 3 H), 4.52 (s, 2 H), 5.04 (d, J ϭ
10.1 Hz, 1 H), 5.11 (d, J ϭ 17.1 Hz, 1 H), 5.26 (ddd, J ϭ 4.6, 5.5,
7.3 Hz, 1 H), 5.81 (mc, 1 H), 6.83 (d, J ϭ 8.5 Hz, 2 H), 7.26 (d,
J ϭ 8.5 Hz, 2 H), 7.44 (mc, 2 H), 7.56 (mc, 1 H), 8.05 (mc, 2 H).
Ϫ
13C NMR (63 MHz): δ ϭ 15.9, 34.5, 55.2, 70.7, 74.9, 75.4, 113.7,
117.7, 128.3, 128.9, 129.2, 129.6, 130.5, 132.8, 133.8, 159.1, 166.0.
syn-3-Benzoyloxy-5-hexen-2-ol: syn-2-(4-Methoxybenzyl)-5-hexen-
3-yl benzoate (699 mg, 2.03 mmol) was dissolved in CH2Cl2
(22 mL). Water (1.1 mL) and DDQ (658 mg, 2.90 mmol) were ad-
ded. The resulting slurry was stirred for 30 min at 20 °C. The pre-
cipitate was filtered off and was thoroughly washed with CH2Cl2.
The combined liquid phases were extracted with satd. aqueous
NaHCO3 and with brine (10 mL each), and then dried (MgSO4).
The solvent was removed in vacuo and the remaining residue was
purified by column chromatography [SiO2, petroleum ether/diethyl
ether, 2:1 (v/v)]: yield 419 mg (94%) colourless oil. Ϫ MS (70 eV,
EI): m/z (%) ϭ 179 (2), 176 (2), 105 (100), 77 (44). Ϫ C13H16O3
(220.3): calcd. C 70.89, H 7.32; found C 70.59, H 7.15. Ϫ 1H NMR
(250 MHz): δ ϭ 1.26 (d, J ϭ 6.4 Hz, 3 H), 2.00 (s br., 1 H),
2.43Ϫ2.64 (m, 2 H), 3.99 (dq, Jd ϭ 4.9 Hz, Jq ϭ 6.4 Hz, 1 H), 5.06
(d, J ϭ 10.1 Hz, 1 H), 5.08 (d, J ϭ 17.1, 1 H), 5.83 (mc, 1 H), 7.44
(mc, 2 H), 7.57 (mc, 1 H), 8.06 (mc, 2 H). Ϫ 13C NMR (63 MHz):
δ ϭ 19.5, 35.2, 68.4, 77.4, 118.2, 128.4, 129.6, 130.1, 133.1, 133.2,
166.3.
syn-2: Yield 2.60 g (81%), colourless oil, Rf ϭ 0.48. Ϫ IR (NaCl):
ν˜ ϭ 3420 cmϪ1, 3040, 2920, 2900, 1600, 1500, 1240, 1120, 1060,
1
900, 810. Ϫ H NMR (250 MHz): δ ϭ 1.19 (d, J ϭ 6.0 Hz, 3 H),
2.11Ϫ2.41 (m, 3 H), 3.41 (qd, Jq ϭ 6.0 Hz, Jd ϭ 6.1 Hz, 1 H),
3.46Ϫ3.55 (m, 1 H), 3.81 (s, 3 H), 4.37 (d, J ϭ 11.0 Hz, 1 H), 4.60
(d, J ϭ 11.0 Hz, 1 H), 5.08 (d, J ϭ 10.7 Hz, 1 H), 5.10 (d, J ϭ
16.0 Hz, 1 H), 5.87 (mc, 1 H), 6.88 (d, J ϭ 8.7 Hz, 2 H), 7.26 (d,
J ϭ 8.9 Hz, 2 H). Ϫ 13C NMR (63 MHz): δ ϭ 15.4, 37.5, 55.2, anti-3-Benzoyloxy-5-hexen-2-ol: yield 371 mg (83%), colourless oil.
70.7, 74.2, 77.2, 113.8, 117.1, 129.4, 130.4, 134.8, 159.2. Ϫ MS
(70 eV, EI): m/z (%) ϭ 236 (1), 135 (28), 121 (100), 77 (27).
Ϫ 1H NMR (250 MHz): δ ϭ 1.26 (d, J ϭ 6.4 Hz, 3 H), 2.17 (s br.,
1 H), 2.42-Ϫ2.62 (m, 2 H), 4.05 (dq, Jd ϭ 4.9 Hz, Jq ϭ 6.4 Hz, 1
1680
Eur. J. Org. Chem. 2000, 1677Ϫ1683

Towards a Stereoselective Synthesis of allo-Muscarine
SHORT COMMUNICATION
H), 5.07 (d, J ϭ 10.1 Hz, 1 H), 5.15 (mc, 1 H), 5.84 (ddt, Jd ϭ 10.1,
CH2Cl2 (3 ϫ 10 mL). The combined organic phases were washed
17.1 Hz, Jt ϭ 7.0 Hz, 1 H), 7.45 (mc, 2 H), 7.57 (mc, 1 H), 8.05 with satd. aqueous NaHCO3, brine (15 mL each), and then dried
(mc, 2 H). Ϫ 13C NMR (63 MHz): δ ϭ 18.1, 34.4, 69.0, 77.6, 117.9, (MgSO4). The solvent was distilled off in vacuo to afford a colour-
128.4, 129.6, 130.2, 133.1, 133.6, 166.5.
less oil which was purified by column chromatography [SiO2, petro-
leum ether/diethyl ether, 2:1 (v/v)]. Yield 485 mg (84%), colourless
oil. Ϫ H NMR (250 MHz): δ ϭ 0.09 (s, 3 H), 0.09 (s, 3 H), 0.91
(s, 9 H), 1.13 (d, J ϭ 6.4 Hz, 3 H), 2.10 (br. s, 1 H), 2.14Ϫ2.25 (m,
1 H), 2.40 (mc, 1 H), 3.48 (dt, Jd ϭ 4.6 Hz, Jt ϭ 6.7 Hz, 1 H), 3.65
(dq, Jd ϭ 4.6 Hz, Jq ϭ 6.4 Hz, 1 H), 5.06 (d, J ϭ 10.4 Hz, 1 H),
5.07 (d, J ϭ 17.1 Hz, 1 H), 5.81 (mc, 1 H). Ϫ 13C NMR (63 MHz):
δ ϭ Ϫ4.7, Ϫ4.2, 18.1, 19.4, 25.8, 38.4, 68.8, 76.1, 117.4, 134.2. Ϫ
MS (70 eV, EI): m/z (%) ϭ 185 (13), 75 (100), 41 (8). Ϫ C12H26O2Si
(230.4): C 62.55, H 11.37; found C 62.26, H 11.19.
syn-3-(Benzoyloxy)-5-hexen-2-yl p-Toluenesulfonate [syn-(3)]: A so-
lution of syn-3-(benzoyloxy)-5-hexen-2-ol (399 mg, 1.81 mmol) and
DABCO (406 mg, 3.62 mmol) in reagent grade CH2Cl2 (2 mL) was
treated with p-toluenesulfonyl chloride (517 mg, 2.17 mmol) at 0
°C. The slurry was stirred for 1 h at 0 °C, diluted with MTB (5 mL),
and treated with aqueous 2 HCl (5 mL) to dissolve the precipitate.
The organic layer was separated and the aqueous phase was washed
with MTB (2 ϫ 5 mL). The combined organic phases were ex-
tracted with 2 aqueous HCl, satd. aqueous NaHCO3, and brine
(10 mL each), and then dried (MgSO4). The solvent was removed
in vacuo to afford pure syn-3 as a colourless oil. Yield 636 mg
(94%). Ϫ 1H NMR (250 MHz): δ ϭ 1.33 (d, J ϭ 6.6 Hz, 3 H), 2.37
(s, 3 H), 2.28Ϫ2.46 (m, 2 H), 4.86 (dq, Jd ϭ 5.0 Hz, Jq ϭ 6.6 Hz,
1 H), 5.05 (d, J ϭ 10.1 Hz, 1 H), 5.07 (d, J ϭ 17.2 Hz, 1 H), 5.18
(dt, Jd ϭ 5.0 Hz, Jt ϭ 6.9 Hz, 1 H), 5.71 (ddt, Jd ϭ 10.1, 17.2 Hz,
Jt ϭ 6.9 Hz, 1 H), 7.22 (d, J ϭ 8.4 Hz, 2 H), 7.42 (mc, 2 H), 7.57
(mc, 1 H), 7.75 (d, J ϭ 8.4 Hz, 2 H), 7.96 (mc, 2 H). Ϫ 13C NMR
(100 MHz): δ ϭ 17.4, 21.6, 34.9, 74.0, 78.7, 118.9, 127.6, 128.3,
129.6, 129.8, 132.2, 133.1, 134.2, 144.6, 165.6. Ϫ MS (70 eV, EI);
m/z (%): 200 (23), 172 (14), 155 (43), 91 (100), 77 (24).
1
syn-3-[(tert-Butyl)dimethylsilyloxy]-5-hexen-2-yl p-Toluenesulfonate
[syn-(4)]: syn-3-[(tert-Butyl)dimethylsilyloxy]-5-hexen-2-ol (484 mg,
2.10 mmol) and DABCO (472 mg, 4.21 mmol) were dissolved in
anhydrous CH2Cl2 and were treated with p-toluenesulfonyl chloride
(601 mg, 3.16 mmol) as described for the synthesis of syn-3 to af-
ford p-toluenesulfonic acid ester syn-4. Crude syn-4 was purified by
column chromatography [SiO2, petroleum ether/ethyl acetate, 3:1
1
(v/v)]. Yield 773 mg (96%), colourless oil. Ϫ H NMR (250 MHz):
δ ϭ Ϫ0.06 (s, 3 H), Ϫ0.03 (s, 3 H), 0.82 (s, 9 H), 1.17 (d, J ϭ
6.4 Hz, 3 H), 2.03Ϫ2.15 (m, 1 H), 2.25Ϫ2.35 (m, 1 H), 2.44 (s, 3
H), 3.66 (dt, J ϭ 4.3, 8.2 Hz, 1 H), 4.46 (dq, Jd ϭ 4.3 Hz, Jq
ϭ
6.4 Hz, 1 H), 5.03 (d, J ϭ 11.6 Hz, 1 H), 5.04 (d, J ϭ 15.6 Hz, 1
H), 5.72 (mc, 1 H), 7.34 (d, J ϭ 7.9 Hz, 2 H), 7.79 (d, J ϭ 8.2 Hz,
2 H). Ϫ 13C NMR (63 MHz): δ ϭ Ϫ4.8, Ϫ4.7, 14.3, 17.9, 21.6,
25.7, 35.6, 72.6, 80.4, 117.5, 127.8, 129.8, 134.4, 134.7, 144.6. Ϫ
MS (70 eV, EI): m/z (%) ϭ 343 (8), 229 (100), 155 (10), 91 (37), 73
(63), 41 (18). Ϫ C19H32O4SSi (384.6): calcd. C 59.33, H 8.39, S
8.34; found C 59.66, H 8.41, S 8.14.
anti-3-(Benzoyloxy)-5-hexen-2-yl p-Toluenesulfonate [anti-(3)]: This
compound was obtained from anti-3-(benzoyloxy)-5-hexen-2-ol as
described above for the syn-isomer. Yield 636 mg (94%). Ϫ 1H
NMR (250 MHz): δ ϭ 1.42 (d, J ϭ 6.6 Hz, 3 H), 2.29 (s, 3 H),
2.37Ϫ2.60 (m, 2 H), 4.83 (dq, Jd ϭ 3.2 Hz, Jq ϭ 6.6 Hz, 1 H), 5.04
(d, J ϭ 10.1 Hz, 1 H), 5.04Ϫ5.08 (m, 1 H), 5.08 (d, J ϭ 17.3 Hz,
1 H), 5.69 (ddt, Jd ϭ 10.1, 17.3 Hz, Jt ϭ 6.9 Hz, 1 H), 7.16 (d, J ϭ
8.3 Hz, 2 H), 7.41 (mc, 2 H), 7.56 (mc, 1 H), 7.74 (d, J ϭ 8.4 Hz,
2 H), 7.90 (mc, 2 H). Ϫ 13C NMR (100 MHz): δ ϭ 16.8, 21.6, 32.3,
74.5, 78.7, 118.5, 127.8, 128.3, 129.6, 129.7, 130.2, 132.7, 133.1,
133.7, 144.6, 165.6. Ϫ Mixture of syn-3 and anti-3: C20H22O5S
(374.5): calcd. C 64.15, H 5.92, S 8.56; found C 63.86, H 5.80,
S 8.50.
Preparation of Alkoxyl Radical Precursors 6؊8
N-(2,3-anti-3-Benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H)-
thione [anti-(6)]: A flame-dried round-bottomed flask was charged
with N-hydroxy-4-methylthiazole-2(3H)-thione tetraethylammo-
nium salt (5)[9] (1.42 g, 5.15 mmol), anhydrous DMF (20 mL) and
tosylate syn-3 (1.78 g, 4.78 mmol). The reaction mixture was stirred
for 5 d at 20 °C and was then poured into a mixture of H2O and
MTB (100 mL each). The organic phase was separated and the
aqueous layer was washed with MTB (3 ϫ 50 mL). The combined
organic phases were extracted with 2  NaOH and brine (50 mL
each), and then dried (MgSO4). The solvent was removed in vacuo
to afford a tan oil which was purified by column chromatography
[SiO2, petroleum ether/diethyl ether, 1:1 (v/v)] to afford anti-6 (tan
oil) (1.00 g, 83%, based on a conversion of 72% of syn-3) and tosyl-
syn-3-[(tert-Butyl)dimethylsilyloxy]-2-(4-methoxybenzyloxy)-5-
hexene: Small portions of tert-butyldimethylsilyl chloride (573 mg,
3.79 mmol) were added at 20 °C to a solution of imidazole (462 mg,
6.78 mmol) and alcohol syn-2 (641 mg, 2.71 mmol) in DMF. The
solution was stirred for 18 h at 20 °C and diluted afterwards with
H2O (20 mL). The solution was extracted with diethyl ether (3 ϫ
15 mL). The combined organic washings were dried (MgSO4) and
concentrated in vacuo to afford a colourless oil which was purified
by column chromatography [SiO2, petroleum ether/diethyl ether,
2:1, (v/v)]. Yield 899 mg (94%), colourless oil. Ϫ 1H NMR
(250 MHz): δ ϭ 0.00 (s, 3 H), 0.03 (s, 3 H), 0.88 (s, 9 H), 1.14 (d,
J ϭ 6.4 Hz, 3 H), 2.13 (mc, 1 H), 2.35Ϫ2.44 (m, 1 H), 3.49 (dq,
Jd ϭ 4.9 Hz, Jq ϭ 6.4 Hz, 1 H), 3.74 (mc, 1 H), 3.82 (s, 3 H), 4.46
(d, J ϭ 11.6 Hz, 1 H), 4.54 (d, J ϭ 11.6 Hz, 1 H), 5.03 (d, J ϭ
10.1 Hz, 1 H), 5.06 (d, J ϭ 17.1 Hz, 1 H), 5.84 (mc, 1 H), 6.89 (d,
J ϭ 8.6 Hz, 2 H), 7.28 (d, J ϭ 8.6 Hz, 2 H). Ϫ 13C NMR (63 MHz):
δ ϭ Ϫ4.5, Ϫ3.0, 14.0, 18.1, 25.9, 36.3, 55.3, 70.7, 73.8, 113.7, 116.5,
129.1, 131.1, 136.2, 159.0. Ϫ MS (70 eV, EI): m/z (%) ϭ 121 (100),
73 (86), 57 (20), 41 (9). Ϫ C20H34O3Si (350.6): C 68.52, H 9.78;
found C 69.09, H 9.90.
1
ate syn-3 (0.50 g, 28%). Ϫ H NMR (250 MHz): δ ϭ 1.41 (d, J ϭ
6.4 Hz, 3 H), 2.12 (d, J ϭ 1.2 Hz, 3 H), 2.49Ϫ2.71 (m, 2 H), 5.09
(d, J ϭ 10.1 Hz, 1 H), 5.15 (d, J ϭ 17.1 Hz, 1 H), 5.50 (ddd, J ϭ
3.4, 6.1, 7.6 Hz, 1 H), 5.77 (dq, Jd ϭ 3.4 Hz, Jq ϭ 6.4 Hz, 1 H),
5.86 (ddt, Jd ϭ 10.1, 17.1 Hz, Jt ϭ 7.0 Hz, 1 H), 6.13 (q, J ϭ
1.2 Hz, 1 H), 7.46 (mc, 2 H), 7.59 (mc, 1 H), 8.06 (mc, 2 H). Ϫ 13C
NMR (100 MHz): δ ϭ 13.2, 13.8, 35.5, 73.3, 81.1, 102.7, 118.6,
128.5, 129.7, 130.2, 132.6, 133.2, 138.9, 165.7, 181.0. Ϫ MS (70 eV,
EI): m/z (%)
ϭ 349 (2), 131 (14), 105 (100), 77 (41). Ϫ
C17H19NO3S2 (349.5): calcd. C 58.43, H 5.48, N 4.01, S 18.35;
found C 58.53, H 5.76, N 3.97, S 18.07.
N-(2,3-anti-3-Benzoyloxy-5-hexen-2-oxy)pyridine-2(1H)-thione
[anti-(7)]: Compound anti-7 (210 mg, 63% based on a conversion
of syn-5 of 64%) was obtained from the reaction of tosylate syn-3
(594 mg, 1.59 mmol) and N-hydroxypyridine-2(1H)-thione tetrabu-
syn-3-[(tert-Butyl)dimethylsilyloxy]-5-hexen-2-ol: A mixture of syn-
3-[(tert-butyl)dimethylsilyloxy]-2-(4-methoxybenzyloxy)-5-hexene
(880 mg, 2.51 mmol) in CH2Cl2 (12 mL) and H2O (0.6 mL) was
treated for 15 min at 20 °C with DDQ (639 mg, 2.82 mmol). The tylammonium salt[9] (643 mg, 1.74 mmol) after 5 d at 20 °C in an-
reddish precipitate was filtered off and washed thoroughly with
hydrous DMF (8 mL) in the dark.[4] The crude product was ob-
Eur. J. Org. Chem. 2000, 1677Ϫ1683
1681

J. Hartung, R. Kneuer
SHORT COMMUNICATION
tained in pure form after column chromatography [SiO2, petroleum
ether/diethyl ether, 1:2 (v/v)] as yellow oil as well as unreacted syn-
3 (216 mg, 36%). Ϫ 1H NMR (250 MHz): δ ϭ 1.59 (d, J ϭ 6.1 Hz,
3 H), 2.33Ϫ2.61 (m, 2 H), 5.05 (d, J ϭ 10.1 Hz, 1 H), 5.12 (d, J ϭ
17.2 Hz, 1 H), 5.27 (dq, Jd ϭ 2.2 Hz, Jq ϭ 6.1 Hz, 1 H), 5.57 (ddd,
J ϭ 2.2, 5.5, 7.7 Hz, 1 H), 5.74 (ddt, Jd ϭ 10.1, 17.2 Hz, Jt ϭ
6.9 Hz, 1 H), 6.59 (dt, Jd ϭ 1.8 Hz, Jt ϭ 6.9 Hz, 1 H), 7.14 (ddd,
J ϭ 1.7, 6.8, 8.7 Hz, 1 H), 7.47 (mc, 2 H), 7.61 (mc, 1 H), 7.67 (dd,
J ϭ 1.8, 8.7 Hz, 1 H), 7.96 (dd, J ϭ 1.7, 6.9 Hz, 1 H), 8.07 (mc, 2
H). Ϫ 13C NMR (100 MHz): δ ϭ 12.7, 35.7, 72.0, 81.9, 112.4,
118.7, 128.5, 129.7, 129.9, 132.4, 132.8, 133.3, 138.0, 139.9, 166.1,
176.0. Ϫ MS (70 eV, EI): m/z (%) ϭ 105 (100) 77 (42).
35.7, 77.5, 79.7, 80.5, 128.5, 129.6, 129.9, 133.2, 166.1. Ϫ MS
(70 eV, EI): m/z (%) ϭ 205 (2), 176 (14), 178 (14), 105 (100), 77 (62).
trans-3-Benzoyloxy-5-bromomethyl-cis-2-methyltetrahydrofuran
(11): 1H NMR (250 MHz): δ ϭ 1.36 (d, J ϭ 6.7 Hz, 3 H),
2.10Ϫ2.32 (m, 2 H), 3.48 (dd, J ϭ 5.2, 10.7 Hz, 1 H), 3.55 (dd,
J ϭ 4.9, 10.1 Hz, 1 H), 4.26 (dq, Jd ϭ 2.8 Hz, Jq ϭ 6.7 Hz, 1 H),
4.36Ϫ4.46 Hz, (m, 1 H), 5.16 (mc, 1 H), 7.45 (mc, 2 H), 7.58 (mc,
1 H), 8.03 (mc, 2 H). Ϫ 13C NMR (100 MHz): δ ϭ 19.9, 34.9, 36.9,
77.7, 80.1, 81.2, 128.4, 129.6, 130.0, 133.2, 166.1. Ϫ Mixture of 10
and 11: C13H15BrO3 (299.2): calcd. C 52.19, H 5.05; found C 51.92,
H 5.23.
Synthesis of 2,3-cis-Configured Tetrahydrofurans 18 and 19: Pyrid-
inethione syn-7 (36.1 mg, 0.110 mmol) and BrCCl3 (174 mg,
0.877 mmol) were dissolved in degassed (Ar) C6H6 (0.6 mL). The
yellow reaction mixture was photolyzed with incandescent light
(2 min) and was worked up as described for isomers 10 and 11
[chromatography: SiO2, petroleum ether/diethyl ether, 2:1 (v/v)].
Tetrahydrofurans 18 and 19 were isolated as a 50:50 mixture of
isomers. Yield 26.1 mg, (80%).
N-(syn-3-Benzoyloxy-5-hexen-2-oxy)pyridine-2(1H)-thione [syn-(7)]:
The radical precursor syn-7 (176 mg, 76%) was obtained by treat-
ment of tosylate anti-3 (262 mg, 0.70 mmol) and N-hydroxypyrid-
ine-2(1H)-thione tetrabutylammonium salt[9] (284 mg, 0.77 mmol)
for 5 d at 20 °C in anhydrous DMF (4 mL) in the dark.[4] Column
chromatography [SiO2, petroleum ether/diethyl ether, 1:2 (v/v)] af-
forded syn-7 as a yellow oil. Ϫ H NMR (250 MHz): δ ϭ 1.36 (d,
J ϭ 6.6 Hz, 3 H), 2.61Ϫ2.68 (m, 1 H), 2.79Ϫ2.86 (m, 1 H), 5.08
(d, J ϭ 9.9 Hz, 1 H), 5.15 (d, J ϭ 17.3 Hz, 1 H), 5.47 (ddd, J ϭ
1
trans-3-Benzoyloxy-5-bromomethyl-trans-2-methyltetrahydrofuran
4.4, 4.8, 8.8 Hz, 1 H), 5.63 (dq, Jd ϭ 4.8 Hz, Jq ϭ 6.6 Hz, 1 H), (18): 1H NMR (250 MHz): δ ϭ 1.29 (d, J ϭ 6.4 Hz, 3 H),
5.87 (mc, 1 H), 6.43 (dt, Jd ϭ 1.8 Hz, Jt ϭ 7.0 Hz, 1 H), 7.04, (ddd,
2.19Ϫ2.42 (m, 2 H), 3.51 (d, J ϭ 5.2 Hz, 2 H), 4.38 (dq, Jd ϭ
J ϭ 1.8, 6.6, 8.5 Hz, 1 H), 7.43 (mc, 2 H), 7.57 (mc, 1 H), 7.61Ϫ7.64 3.4 Hz, Jq ϭ 6.4 Hz, 1 H), 4.55 (mc, 1 H), 5.57 (mc, 1 H), 7.46 (mc,
(m, 2 H), 8.01 (mc, 2 H). Ϫ 13C NMR (100 MHz): δ ϭ 14.5, 35.3, 2 H), 7.59 (mc, 1 H), 8.06 (mc, 2 H). Ϫ 13C NMR (63 MHz): δ ϭ
76.6, 79.9, 112.2, 118.5, 128.4, 129.7, 129.9, 132.4, 132.9, 133.2,
138.2, 139.4, 165.9, 176.5. Mixture of syn- and anti-7:
C18H19NO3S (329.4): calcd. C 65.63, H 5.81, N 4.25, S 9.37; found
C 65.42, H 5.52, N 4.25, S 9.54.
14.8, 36.1, 38.3, 76.4, 76.5, 78.2, 128.5, 129.6, 129.9, 133.2, 165.8.
Ϫ
cis-3-Benzoyloxy-5-bromomethyl-cis-2-methyltetrahydrofuran (19):
1H NMR (250 MHz) δ ϭ 1.32 (d, J ϭ 6.4 Hz, 3 H), 2.07 (ddd, J ϭ
5.2, 5.5, 14.7 Hz, 1 H), 2.62 (ddd, J ϭ 6.4, 8.2, 14.7 Hz, 1 H), 3.45
(dd, J ϭ 6.7, 10.1 Hz, 1 H), 3.54 (dd, J ϭ 5.8, 10.1 Hz, 1 H), 4.15
(dq, Jd ϭ 3.7 Hz, Jq ϭ 6.4 Hz, 1 H), 4.25 (mc, 1 H), 5.50 (ddd, J ϭ
3.7, 5.5, 8.2 Hz, 1 H), 7.46 (mc, 2 H), 7.59 (mc, 1 H), 8.05 (mc, 2
H). Ϫ 13C NMR (63 MHz): δ ϭ 14.6, 35.0, 38.0, 75.5, 77.1, 78.8,
128.5, 129.6, 130.2, 133.3, 165.9. Ϫ Mixture of isomers 18 and 19:
C13H15BrO3 (299.2): calcd. C 52.19, H 5.05; found C 52.36, H 4.85.
N-{[anti-3-(tert-Butyl)dimethylsilyloxy]-5-hexen-2-oxy}pyridine-
2(1H)-thione [anti-(8)]: Pyridinethione anti-8 (89 mg, 45%) was ob-
tained from the reaction of tosylate syn-4 (226 mg, 0.59 mmol) and
N-hydroxypyridine-2(1H)-thione
tetrabutylammonium
salt[9]
(326 mg, 0.88 mmol) for 2 d at 20 °C in anhydrous DMF (4 mL) in
the dark.[4] Column chromatography [SiO2, petroleum ether/diethyl
ether, 1:1 (v/v)] afforded analytically pure anti-8 as a yellow oil. Ϫ
1H NMR (250 MHz): δ ϭ 0.05 (s, 3 H), 0.06 (s, 3 H), 0.87 (s, 9 H),
1.23 (d, J ϭ 6.4 Hz, 3 H), 2.28 (mc, 2 H), 4.24 (dt, Jd ϭ 1.8 Hz,
Jt ϭ 6.6 Hz, 1 H), 5.01Ϫ5.11 (m, 3 H), 5.82 (mc, 1 H), 6.52 (dt,
Jd ϭ 2.0 Hz, Jt ϭ 6.8 Hz, 1 H), 7.09 (dt, Jd ϭ 1.7 Hz, Jt ϭ 6.8 Hz,
1 H), 7.64 (m, 2 H). Ϫ 13C NMR (100 MHz): δ ϭ Ϫ4.4, Ϫ4.3,
11.7, 18.1, 25.8, 38.9, 72.7, 83.5, 112.0, 117.5, 132.4, 134.3, 137.8,
139.9, 176.0. Ϫ MS (70 eV, EI): m/z (%) ϭ 282 (2), 212 (8), 127
(19), 73 (100). Ϫ C17H29NO2SSi (339.6): calcd. C 60.13, H 8.61, N
4.13, S 9.44; found C 60.54, H 8.46, N 3.92, S 9.16.
Photoreaction of TBDMS-substituted Pyridinethione anti-8 and
BrCCl3: Pyridinethione anti-8 (205 mg, 0.604 mmol) and BrCCl3
(1.03 g, 5.18 mmol) were dissolved in benzene (3.5 mL). The yellow
solution was irradiated with incandescent light (Philips 150 W
Spotline R80) until the yellow colour of the radical precursor had
faded (1 min). The reaction mixture was then purified by column
chromatography [SiO2, petroleum ether/diethyl ether, 5:1 (v/v),
Rf ϭ 0.62].
5-bromomethyl-cis-3-[(tert-butyl)dimethylsilyloxy)]-trans-2-meth-
yltetrahydrofuran (16). Yield 30.2 mg (16%), colourless liquid. Ϫ
IR (NaCl): ν˜ ϭ 2920 cmϪ1, 2900, 2820, 1240, 1080, 1020. Ϫ 1H
NMR (250 MHz): δ ϭ 0.06 (s, 6 H), 0.88 (s, 9 H), 1.16 (d, J ϭ
6.1 Hz, 3 H), 1.87 (mc, 1 H), 2.31 (mc, 1 H), 3.47 (mc, 2 H),
3.82Ϫ3.97 (m, 2 H), 4.30 (mc, 1 H). Ϫ 13C NMR (100 MHz): δ ϭ
Ϫ4.9, Ϫ4.7, 18.9, 25.7, 36.1, 38.9, 77.4, 77.8, 81.9. Ϫ MS (70 eV,
EI): m/z (%) ϭ 253 (5), 131 (79), 97 (22), 75 (55), 57 (76), 43 (100).
Ϫ All samples which eluted faster than heterocycle 16 on chroma-
tographic purification (vide supra) were collected and concentrated
in vacuo (T ϭ 20 °C, p ϭ 20 mbar) to afford a colourless volatile
liquid (44.7 mg). According to NMR analysis the isolated product
was a mixture of compounds 13, 15, and 17.
Preparation of Bromomethyltetrahydrofurans 10 and 11: Thiazole-
thione anti-6 (560 mg, 1.60 mmol) and BrCCl3 (2.54 g, 12.8 mmol)
were dissolved in C6H6 (9 mL). The solution was flushed for 5 min
at 20 °C with a gentle stream of argon and then photolyzed for
25 min at 20 °C in a Rayonet chamber reactor equipped with
350 nm light bulbs. The reaction mixture was concentrated in vacuo
to afford a tan oil which was purified by column chromatography
(SiO2, petroleum ether/diethyl ether, 5:1, v/v) to afford 10 (263 mg,
55% yield, colourless oil, Rf ϭ 0.39) and 11 (130 mg, 27% yield,
colourless oil, Rf ϭ 0.42).
cis-3-Benzoyloxy-5-bromomethyl-trans-2-methyltetrahydrofuran
(10): 1H NMR (250 MHz): δ ϭ 1.30 (d, J ϭ 6.7 Hz, 3 H), 2.16
(ddd, J ϭ 3.7, 4.9, 14.3 Hz, 1 H), 2.63 (ddd, J ϭ 6.7, 7.9, 14.3 Hz,
cis-1-(tert-Butyl)dimethylsilyloxy-1,3-butadiene (13):[20] yield 20%.
1
1 H), 3.47 (dd, J ϭ 7.3, 10.1 Hz, 1 H), 3.55 (dd, J ϭ 5.8, 10.1 Hz, Ϫ H NMR (250 MHz): δ ϭ 0.15 (s, 6 H), 0.89 (s, 9 H), 4.89 (d,
1 H), 4.39 (dq, Jd ϭ 2.8 Hz, Jq ϭ 6.7 Hz, 1 H), 4.44Ϫ4.51 (m, 1
J ϭ 10.4 Hz, 1 H, 4-H), 5.06 (d, J ϭ 17.4 Hz, 1 H, 4-H), 5.20 (dd,
H), 5.17 (dt, Jd ϭ 6.7 Hz, Jt ϭ 2.8 Hz, 1 H), 7.46 (mc, 2 H), 7.59 J ϭ 5.8, 10.7 Hz, 1 H, 2-H), 6.19 (d, J ϭ 5.8 Hz, 1 H, 1-H), 6.75
(mc, 1 H), 8.02 (mc, 2 H). Ϫ 13C NMR (100 MHz): δ ϭ 19.0, 35.1, (ddd, J ϭ 10.4, 10.7, 17.4 Hz, 1 H, 3-H).
1682
Eur. J. Org. Chem. 2000, 1677Ϫ1683

Towards a Stereoselective Synthesis of allo-Muscarine
SHORT COMMUNICATION
[9]
1,1-bis[(tert-Butyl)dimethylsilyloxy]-3-butene (17):[21] yield 11%. Ϫ
1H NMR (250 MHz): δ ϭ 0.08 (s, 6 H), 0.11 (s, 6 H), 0.94 (s, 18
H), 2.31 (mc, 2 H, 2-H), 5.02Ϫ5.08 (m, 2 H, 4-H), 5.13 (t, 1 H, J ϭ
5.2 Hz, 1-H), 5.82 (mc, 1 H, 3-H). Ϫ 13C NMR (63 MHz): δ ϭ
Ϫ5.4, Ϫ4.2, Ϫ3.7, Ϫ3.6, 18.0, 18.3, 25.5, 25.6, 45.6, 93.3, 111.2,
113.0, 117.2, 129.8, 140.5.
J. Hartung, R. Kneuer, M. Schwarz, I. Svoboda, H. Fueß, Eur.
J. Org. Chem. 1999, 97Ϫ106.
[10]
D. H. R. Barton, D. Crich, G. Kretzschmar, J. Chem. Soc.,
Perkin Trans. 1 1986, 39Ϫ53.
[11] [11a]
P. Dowd, W. Zhang, Chem. Rev. 1993, 93, 2091Ϫ2155. Ϫ
[11b] A. Nishida, Y.ϪI. Kakimoto, Y. Ogasawara, N. Kawahara,
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5519Ϫ5522.
[12]
J. Hartung, R. Stowasser, D. Vitt, G. Bringmann, Angew.
Chem. 1996, 108, 3056Ϫ3059, Angew. Chem. Int. Ed. Engl.
1996, 35, 2820Ϫ2823.
A. L. J. Beckwith, Chem. Soc. Rev. 1993, 22, 143Ϫ151.
A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985,
41, 3925Ϫ3941.
2-Butenal (15): yield 3%.
On repetition of the photoreaction of anti-8 and BrCCl3 in C6D6
using 2,2-dichloro-5,5-dimethylcyclohexane-1,2-dione as internal
standard, yields of volatile aldehydes were quantified more pre-
cisely.
[13] [13a]
[13b]
Ϫ
[14]
A. M. Mubarak, D. M. Brown, J. Chem. Soc., Perkin Trans. 1
1982, 809Ϫ813.
1
Acetaldehyde (14): yield 54%. Ϫ H NMR (400 MHz, C6D6): δ ϭ
[15] [15a]
S. Pochet, T. HuynhϪDinh, J. Org. Chem. 1982, 47,
[15b]
1.52 (d, J ϭ 3.0 Hz, 3 H), 9.20 (q, J ϭ 3.0 Hz, 1 H).
´
P. ϪC. Wang, M. M. Joullie, The Alkaloids
193Ϫ198. Ϫ
1984, 23, 327Ϫ380.
2-Butenal (15): yield 40%. Ϫ 1H NMR (400 MHz, C6D6): δ ϭ 1.39
(d, J ϭ 6.6 Hz, 3 H), 5.81 (dd, J ϭ 7.7, 15.4 Hz, 1 H), 6.07 (dq,
Jd ϭ 15.7, Jq ϭ 6.6 Hz, 1 H), 9.17 (d, J ϭ 7.7 Hz, 1 H).
[16]
The observed optical rotation of our sample of (ϩ)-20
20
{[α]D ϭ ϩ 22.4 (c ϭ 0.41, EtOH)} was lower than the refer-
ence value for (ϩ)-20 {[α]D ϭ ϩ39.1 (c ϭ 0.38, EtOH)}.[15]
25
The non-stereorigidity is probably due to the first step in the
synthesis[17] of methyl p-methoxybenzyl lactate. In order to
verify that the stereochemical leak is not related to the central
radical reactions of this work, the benzoate groups in the rad-
ical precursor anti-6 and in the trisubstituted tetrahydrofuran
10 were removed by NaOH in MeOH and the respective alco-
hols were converted into their S-Mosher esters.[18] 1H NMR
investigation of these products indicated an ee value of 34% for
both compounds and therefore, presumably, for anti-6 and 10.
P. Varelis, B. L. Johnson, Aust. J. Chem. 1995, 48, 1775Ϫ1779.
J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543Ϫ2549.
Acknowledgments
This work was generously supported by the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft.
[17]
[18]
[1]
J. Hartung, M. Schwarz, I. Svoboda, H. Fueß, M.ϪT. Duarte,
Eur. J. Org. Chem. 1999, 1275Ϫ1290.
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B. P. Hay, A. L. J. Beckwith, J. Org. Chem. 1989, 54,
4330Ϫ4334.
J. Hartung, F. Gallou, J. Org. Chem. 1995, 60, 6706Ϫ6716.
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J. Hartung, M. Hiller, P. Schmidt, Liebigs Ann. 1996,
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[19]
[20]
D. D. Perrin, W. L. F. Armatego, D. R. Perrin, Purification of
Laboratory Chemicals, 2nd, ed., Pergamon Press, Oxford, 1980.
A. Defoin, J. Pires, J. Streith, Helv. Chim. Acta 1991, 74,
[3]
[4]
3
1653Ϫ1670. Z-Geometry of 13 is based in analysis of JH,H
coupling constants according to P. Cazeau, F. Duboudin, F.
Moulines, O. Babot, J. Dunogues, Tetrahedron 1987, 43,
2089Ϫ2100.
[5]
[6]
[21]
Chemical shifts for CϪ1 (δ ϭ 93.3) and CϪ2 (δ ϭ 45.6) are
characteristic for 1,1-bistrialkylsilyloxyacetals: M. E. Scheller,
B. Frei, Helv. Chim. Acta 1984, 67, 1734Ϫ1747.
Received October 22, 1999
[7]
[8]
[O99590]
Eur. J. Org. Chem. 2000, 1677Ϫ1683
1683