Synthesis of enantiopure (2R)-configured muscarine alkaloids via selective alkoxyl radical ring-closure reactions

Article abstract of DOI:10.1016/j.tetasy.2003.06.006

A new synthesis of (-)-muscarine, (+)-allo-muscarine, (-)-epi-muscarine, and (-)-epiallo-muscarine has been devised which utilizes selective alkoxyl radical cyclizations for constructing tri-substituted tetrahydrofuran units. Photolysis of (2R,3S)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H) thione in the presence of BrCCl₃ provided (2R,3S,5S)-3-benzoyloxy-5- bromomethyl-2-methyltetrahydrofuran as the major product and the corresponding (2R,3S,5R)-isomer as the minor. These building blocks were converted into enantiomerically pure (+)-allo-muscarine (from the major alkoxyl radical cyclization product) and (-)-muscarine (from the minor product). Temperature and substituent effects on the diastereoselectivity of the underlying alkoxyl radical cyclization have been investigated. (-)-epi-Muscarine and (-)-epiallo-muscarine have been prepared likewise, starting from (2R,3R)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H)thione.

Full text of DOI:10.1016/j.tetasy.2003.06.006

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3019–3031
Synthesis of enantiopure (2R)-configured muscarine alkaloids via
selective alkoxyl radical ring-closure reactions
Jens Hartung* and Rainer Kneuer
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received 30 May 2003; accepted 24 June 2003
Abstract—A new synthesis of (−)-muscarine, (+)-allo-muscarine, (−)-epi-muscarine, and (−)-epiallo-muscarine has been devised
which utilizes selective alkoxyl radical cyclizations for constructing tri-substituted tetrahydrofuran units. Photolysis of (2R,3S)-N-
(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H)thione in the presence of BrCCl3 provided (2R,3S,5S)-3-benzoyloxy-5-bro-
momethyl-2-methyltetrahydrofuran as the major product and the corresponding (2R,3S,5R)-isomer as the minor. These building
blocks were converted into enantiomerically pure (+)-allo-muscarine (from the major alkoxyl radical cyclization product) and
(−)-muscarine (from the minor product). Temperature and substituent effects on the diastereoselectivity of the underlying alkoxyl
radical cyclization have been investigated. (−)-epi-Muscarine and (−)-epiallo-muscarine have been prepared likewise, starting from
(2R,3R)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthiazole-2(3H)thione.
© 2003 Published by Elsevier Ltd.
1. Introduction
allo-muscarine 1b under mild and neutral (i.e. non
oxidative) conditions.15,16 In view of this achievement
and the relevance of muscarine alkaloids in particular,
we have extended our preliminary investigation to
address three major areas. (i) The development of a
synthesis of (2R,3S)- and (2R,3R)-(3-benzoyloxy-5-
hexen-2-oxy)-4-methylthiazole-2(3H)thione. (ii) Accom-
plishment of a synthesis of all four (2R)-configured
muscarine alkaloids 1a–d (Fig. 1) starting from alkoxyl
The observation that (+)-muscarine chloride reliably
reproduces some of the responses to a stimulation of
the parasympathetic nervous system is generally
regarded as the beginning of modern pharmacology.1,2
The significance of this alkaloid and its naturally occur-
ring three diastereomers has led to a growing demand
which at present cannot be covered from the current
natural resources, such as fungi of the genera Amanita,3
Clitocybe4 and Inocybe5 alone. Therefore, methods for
selectively preparing enantiomerically pure (+)-mus-
carine ent-1a,6 the major muscarine alkaloid from
Amanita muscaria,7 and its diastereomers (−)-allo-mus-
carine ent-1b,8 (+)-epi-muscarine ent-1c,9 and (+)-
epiallo-muscarine ent-1d,10 have received considerable
attention over the last few decades.11 Two major strate-
gies have evolved for this purpose: (i) selective transfor-
mations of monosaccharides12 and (ii) electrophile-
induced ring-closure reactions of ex-chiral pool-
derived substituted bis(homoallylic) alcohols.13,14 The
latter approach has been supplemented recently by a
concept that utilizes a selective alkoxyl radical cycliza-
tion for the construction of the heterocyclic core of
* Corresponding author. Present address: Fachbereich Chemie,
Organische Chemie Universita¨t Kaiserslautern, Erwin-Schro¨dinger-
Straße 54, D-67663 Kaiserslautern, Germany. Tel.: +49-(0)631-205-
2431; fax: +49-(0)631-205-3921; e-mail: hartung@chemie.uni-kl.de
Figure 1. Structures of (2R)-configured muscarine alkaloids
1a–d. X−=monovalent anion.
0957-4166/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2003.06.006

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J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
radial cyclization products. (iii) An investigation of the
substituent and temperature effects on the diastereose-
lectivity of 5-exo-trig cyclizations using 2,3-unlike-
configured 3-substituted 5-hexen-2-oxyl radicals.15,17
was achieved with a mixture of 1,4-diazabicyclo-
[2.2.2]octane (DABCO)19 and benzoyl chloride in
CH2Cl2 (82%). This step was followed by removal of
the THP protecting group under acidic conditions20 to
yield a 54:46 mixture of 3-benzoyloxy-5-hexen-2-ols 4
and 5. Separation of this mixture into equal amounts of
(2S,3S)-configured alkenol 4 and its (2S,3R)-stereoiso-
mer 5 was accomplished on a preparative scale by
HPLC (4:5=50:50). Both purified products 4 and 5
were esterified with the combination of p-toluenesul-
fonyl chloride and DABCO19 in dry CH2Cl2 (94% for
both transformations, not shown in Scheme 1) followed
by treatment with N-hydroxy-4-methylthiazole-
2(3H)thione tetraethylammonium salt21 in anhydrous
DMF to provide 83% of (2R,3S)-N-(3-benzoyloxy-5-
hexen-2-oxy)thiazolethione 6 and 73% of its (2R,3R)-
diastereomer 7, respectively both as tan oils.
2. Results
2.1. Synthesis of alkoxyl radical precursors
The selective O-protection of methyl (S)-lactate 2 using
3,4-dihydro-2H-pyran and pyridinium p-toluenesul-
fonate (PPTS) in CH2Cl2 provided (2S)-(2-tetra-
hydropyranyloxy)propanal (92%, not shown in Scheme
1)18 which was treated with 1.5 equiv. of diisobutylalu-
minum hydride (DIBAH) in hexane/Et2O and subse-
quently with allyl magnesium bromide in Et2O (both
steps at −78°C) to furnish 2-tetrahydropyranyloxy-5-
hexen-3-ol 3 as a mixture of diastereomers (69% start-
ing from 2, Scheme 1). O-Acylation of compound 3
2.2. Preparation of muscarine alkaloids
A
solution of (2R,3S)-N-(3-benzoyloxy-5-hexen-2-
oxy)thiazolethione 6 (co=0.18 M) and BrCCl3 (co=1.4
M) was photolyzed at 20°C in a Rayonet® photoreactor
equipped with 350 nm light bulbs (Scheme 2). The
starting material 6 was consumed within 25 min to
afford after work-up 26% of (2R,3S,5R)-tetra-
Scheme 1. Preparation of (2R,3S)-N-(3-benzoyloxy-5-hexen-
2-oxy)thiazolethione
6 and its (2R,3R)-diastereomer 7.
Scheme 2. Formation of (2R)-configured muscarine alkaloids
1a–d starting from (2R,3S)-N-(3-benzoyloxy-5-hexen-2-
oxy)thiazolethione 6 and its (2R,3R)-diastereomer 7. Reagents
and conditions: (a) 8 equiv. of BrCCl3, hw (350 nm), C6H6,
20°C, column chromatography; (b) NaOH, CH3OH, 20°C
(92% from 8a, 66% from 8b, 84% from 8c, 78% from 8d); (c)
N(CH3)3, EtOH, 60°C (89% for 1a, 73% for 1c, 65% for 1c,
68% for 1d). a In addition, 77% of 2-trichloromethylsulfanyl-
4-methylthiazole 9 were isolated (also see Fig. 3).
Reagents and conditions: (a) 3,4-Dihydro-2H-pyran, PPTS,
CH2Cl2, 41°C (92%); (b) DIBAH in hexanes/Et2O, −78°C; (c)
H2CꢀCHꢁCH2MgBr, Et2O, −78“0°C (75% for steps b and
c); (d) BzCl, DABCO, CH2Cl2, 20°C (82%); (e) PPTS, EtOH,
78°C; (f) HPLC (91% for steps e and f); (g) TsCl, DABCO,
CH2Cl2, 20°C (94% for conversion of 4 and 5); (h) N-
hydroxy-4-methylthiazole-2(3H)thione tetraethylammonium
salt, DMF, 20°C (83% of 6 and 73% of 7).

J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
3021
Figure 2. 1H NMR spectra of muscarine alkaloids 1a–d (D2O) showing the resonances of protons attached to C-4 (see text).
Scheme 2) which were heated in a solution of N(CH3)3
in EtOH to yield (−)-epi-muscarine 1c {[h]2D5=−62.7 (c
0.42, EtOH)} and (−)-epiallo-muscarine 1d {[h]2D5=0.0
(c 0.33, EtOH)}.†,22
hydrofuran 8a, 53% of the (2R,3S,5S)-diastereomer 8b,
and 77% of 2-trichloromethylsulfanyl-4-methylthiazole
9 (for structure see Fig. 3). Benzoates 8a and 8b were
saponified using a solution of NaOH in CH3OH to
yield the corresponding 5-bromomethyl-2-methyltetra-
hydrofuran-2-ols (92% from 8a and 66% from 8b, both
not shown in Scheme 2). These products were treated in
a hot solution of N(CH3)3 (4.2 M) in EtOH for 7 days
to furnish, after work-up, analytically pure (−)-mus-
carine 1a in 89% yield {[h]2D5=−15.5 (c 0.64, EtOH)}
and (+)-allo-muscarine 1b in 73% yield {[h]2D5=+36.8 (c
0.57, EtOH)}.22
The determined specific rotations of likewise prepared
alkaloids 1a and 1b were in accord with the reported
values for enantiomerically pure compounds.22
2.3. Stereochemical analysis
Relative configurations of alkoxyl radical cyclization
products 8a–d and alkaloids 1a–d were established from
1H NMR analysis (chemical shifts and NOE experi-
(−)-epi-Muscarine 1c and (−)-epiallo-muscarine 1d were
obtained starting from (2R,3R)-N-(3-benzoyloxy-5-
hexen-2-oxy)thiazolethione 7 (Scheme 2). Near UV-
light photolysis of a 0.18 M solution of thione 7 in the
presence of 8 equiv. of BrCCl3 afforded an equimolar
ratio of (2R,3R,5R)-3-benzoyloxy-5-bromomethyl-2-
methyltetrahydrofuran 8c along with its (2R,3R,5S)-
stereoisomer 8d in a total yield of 79%. Products 8c and
8d were separated by column chromatography and
subsequently treated with NaOH in CH3OH to furnish
the corresponding tetrahydrofuranols (not shown in
† A specific rotation of [h]2D5 50 has been reported for enantiopure
(−)-epiallo-muscarine 1d.22 The negative sign for the specific rota-
tion of alkaloid (−)-1d has been assigned in extension to Ref. 22
where the authors recorded negative a-values at 578, 546, 436, and
365 nm, but no specific roation at 589 nm for an enantiomerically
pure sample.

3022
J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
ments). A chemical shift difference of ꢀ0.6–1.0 ppm
between both protons at C-4 was indicative of a 3,5-cis-
configuration [i.e. tetrahydrofurans 1b, 1c (Fig. 2) and
8b, 8c (Scheme 2)].16 Smaller Dl values of ꢀ0–0.5
between signals for 4-Hs and 4-Ha pointed to 3,5-trans-
diastereomers 1a, 1d (Fig. 2) and 8a, 8d (Scheme 2).16
A
2,5-cis-arrangement of substituents at C-2 and C-5 such
as in 1a, 1d and 8a, 8d, was derived from the positive
results of the NOE experiments: Upon irradiation at
2-H enhancements were observed at 5-H and vice versa.
Scheme 3. Preparation of 2,3-unlike-configured 5-hexen-2-
oxythiazolethiones 10 and 11. Reagents and conditions: (a)
NaOH, CH3OH, 20°C (97%); (b) (CF3CO)2O, DABCO,
CH2Cl2, 20°C (82%); (c) (C6H5O)2P(O)Cl, DABCO, 20°C
(42%).
The enantiomeric purity of bromocyclization products
8a–d was determined via their derived (R)-Mosher
esters23 which exhibited, in all instances, a single set of
resonances (1H NMR). This result was indicative of
>96% ee for heterocycles 8a–d for the following reason:
The enantiomers of 8a–d (>96% ee) and enantiomeri-
cally enriched tetrahydrofurans 8a and 8b (34% ee)
were available from earlier studies.14,15 These samples
were converted into the corresponding (R)-configured
Addition of O2 into a solution of 2,3-unlike-3-benzoyl-
25
oxy-N-hexenoxythiazolethione 6, BrCCl3, and BEt3 in
C6H6 at −10°C provided tetrahydrofurans 8a–b in 75%
yield (8a:8b=27:73, Table 1). If the same experiment
was conducted at −78°C, only 32% of the target com-
pounds 8a–b were formed (8a:8b=21:79).
1
Mosher esters. Their H NMR spectra exhibited either
a double set of resonances in a 68:32 ratio [i.e. for
(R)-Mosher esters obtained from partially racemized 8a
and 8b (both 34% ee)15] or markedly shifted signals
(from ent-8a–d).14
Photolysis
of
2,3-unlike-N-(3-trifluoroacetyloxy-5-
hexen-2-oxy)thiazolethione 10 in the presence of
BrCCl3 at 20°C furnished 64% (1H NMR) of trisubsti-
tuted tetrahydrofurans 12a–b (12a:12b=30:70). The
conversion of the mixed phosphate 11, under these
conditions provided 69% of cyclic ethers 13a–b (1H
NMR, 13a:13b=29:71).
2.4. Temperature and substituent effects in the cycliza-
tions of 2,3-unlike-configured 3-substituted 5-hexen-2-
oxyl radicals
Temperature effects on the diastereoselectivity of 5-exo-
trig reactions were investigated using an enantiomeri-
cally enriched sample of (2R,3S)-N-(3-benzoyloxy-
5-hexen-2-oxy)thiazolethione 6 (34% ee).15 3-O-Substi-
tuted derivatives of the alkoxyl radical precursor 6 were
prepared in two steps. Saponification of the benzoate
functionality was accomplished via the treatment of
ester 6 with a solution of NaOH in CH3OH. This step
3. Discussion
The results from the present study indicate that alkoxyl
radicals serve as useful intermediates26 for the construc-
tion of the heterocyclic core of enantiomerically pure
muscarine alkaloids 1a–d via selective ring-closure reac-
tions. Key issues to be addressed in the present investi-
gation were associated with the synthesis of
(2R,3S)-N-(3-benzoyloxy-5-hexen-2-oxy)thiazole-2(3H)-
thione 6, its 3-epimer 7 and a study on substituent and
temperature effects in cyclizations of 2,3-unlike 3-substi-
tuted 5-hexen-2-oxyl radicals (e.g. 14, Fig. 3).
provided
(2R*,3S*)-N-(3-hydroxy-5-hexen-2-oxy)-
thiazole-2(3H)thione24 (not shown in Scheme 3) which
was treated with DABCO and either trifluoroacetic acid
anhydride (formation of trifluoroacetate 10, 81% from
6) or diphenylchlorophosphate (synthesis of mixed
phosphate 11, 41% from 6).
Table 1. Substituent and temperature effects on the synthesis of tetrahydrofurans 8, 12, and 13a
Entry
R
T °C
Cond.
Products
Yield a+b (%)
Selectivity a:b
1
2
3
4
C6H5CO
C6H5CO
CF3CO
(C6H5O)2P(O)
−10
−78
20
a
a
b
b
8a, 8b
8a, 8b
12a, 12b
13a, 13b
75
32
64
69
27:73
21:79
30:70
29:71
20
a Reagents and conditions: (a) BrCCl3, BEt3/O2, C6H6; (b) BrCCl3, C6D6, hw.

J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
3023
Figure 3. The synthesis of muscarine and allo-muscarine precursors 8a and 8b starting from (2R,3S)-(3-benzoyloxy-5-hexen-2-
oxy)thiazolethione 6 and BrCCl3—selected elementary steps and transition state models.
3.1. Stereoselective synthesis of alkoxyl radical precur-
sors and functional group interconversion
was not associated with the formation of the isomeric
(S)-alkylation products (i.e. 2-alkenylsulfanylthiazole-
N-oxides).28
The synthesis of (2R,3S)-N-(3-benzoyloxy-5-hexen-2-
oxy)thiazole-2(3H)thione
6
and
its
(2R,3R)-
Functional group interconversion starting from thione
6 was feasible and provided trifluoroacetate 10 and
mixed phosphate 11 in two synthetic steps. This result
is noteworthy since the compatibility of cyclic thiohy-
droxamic acid O-esters in selective transformations was
until then largely unexplored.29,30 It was, however
refrained from preparing the same derivatives starting
from (2R,2R)-N-(3-benzoyloxy-5-hexen-2-oxy)thiazole-
thione 7 because the like-configured 5-hexen-2-oxyl
radical 16 underwent 5-exo-trig cyclizations without
notable facial selectivity (Fig. 4, Scheme 2).
diastereomer 7 has been achieved in six synthetic steps
starting from methyl (S)-lactate 2 (Scheme 1). The
strategy to THP-protect the hydroxyl substituent in the
starting material 2 was the key to conserving the
stereointegrity at C-2, which had been the major obsta-
cle in previous investigations.15,27 The synthetic
sequence which is outlined in Scheme 1 provided
alkenol 3 as a mixture of four diastereomers. No
attempts were made at this stage of the synthesis to
purify and characterize any of these compounds, since
the separation of (2S,3S)-3-benzoyloxy-5-hexen-2-ol 4
and its (2S,3R)-diastereomer 5 was attainable via
HPLC. Alkenols 4 and 5 were converted into their
derived tosylates (not shown in Scheme 1) which served
as selective O-alkylation reagents for the synthesis of
alkoxyl radical precursors 6 and 7 starting from
3.2. Generation and ring-closure reactions of 3-substi-
tuted 5-hexen-2-oxyl radicals
Photochemically induced or BEt3/O2-initiated reactions
between
(2R,3S)-(3-benzoyloxy-5-hexen-2-oxy)-4-
N-hydroxy-4-methylthiazole-2(3H)thione
tetraethyl-
methylthiazole-2(3H)thione 6 and BrCCl3 furnished
bromocyclization products 8a and 8b in synthetically
ammonium salt. According to TLC analysis, this step

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J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
Figure 4. Generation of the (2R,3R)-3-benzoyloxy-5-hexen-2-oxyl radical 16 from thiazolethione 7 (top) and transition state
models for the synthesis of epi-muscarine (center) or epiallo-muscarine precursors (bottom).
useful yields (Fig. 3). Signals of 6-endo-cyclized prod-
ucts (i.e. substituted tetrahydropyrans) were not noted
in 1H NMR spectra of the crude or purified prod-
ucts.31,32 The underlying radical chain reaction of this
sequence started either with a photochemical excitation
of the radical precursor 633 or the addition of suitable
radicals to the C,S p-bond of this compound (BEt3/O2
system) in order to induce selective N,O-homolysis.
This step provided the (2R,3S)-(3-benzoyloxy-5-hexen-
2-oxyl radical 14 which underwent diastereoselective
5-exo-trig ring closures. Subsequent bromine atom
trapping of cyclized intermediates 15a and 15b fur-
nished (+)-allo-muscarine precursor 8b as the major
product and the (2R,3S,5R)-diastereomer 8a as the
minor. The CCl3 radical, which was formed in the latter
reaction, added preferentially to the C,S double bond in
thione 6 thus leading to 2-mercaptothiazole derivative 9
in a yield that nearly matched that of the bromides 8a
and 8b when taken together. No efforts were made to
use alternative bromine atom donors for the synthesis
of products 8a–b since this aspect had been addressed
in an earlier investigation.16
estimate differences in activation parameters for both
modes of ring closure (DDH‡=DH‡14“15a−DH1‡4“15b
=
3.0 kJ mol−1, DDS‡=DS1‡4“15a−DS1‡4“15b=−3×10−3 kJ
mol−1 K−1).32,34 Based on this estimate, the observed
diastereoselectivity for the O-radical reaction 14“15b
predominantly originated from its favorable activation
enthalpy. This result in combination with data from
earlier experimental32 and theoretical investigations35
was translated into stereochemical models (Figs. 3 and
4). An approach of reacting entities in intermediate 14
leads to a restriction of conformational freedom—from
freely rotating to a cyclic intermediate with a long and
therefore weak C,O-bond. In this picture, a methylene,
methyl, and a benzoyloxy group will be preferentially
arranged in positions that resemble equatorial locations
in cyclohexane (see chair-like I, Beckwith–Houk
model).36–38 These stereochemical requirements are also
fulfilled in the intermediate twist-I. This geometry is
based on an ab-initio-calculated lowest transition struc-
ture for the 4-penten-1-oxyl radical cyclization.35
A
similar arrangement has recently been located as lowest
energy transition structure in ab initio calculations deal-
ing with 5-exo-trig cyclizations of anomeric carbon
radicals.39 Geometry twist-I, which probably reflects
substituent effects onto the conformational behavior of
such energetically favored transition structures more
adequately, transposes the benzoyloxy and the methyl
group into equatorial positions whereas the methylene
end of the radical chain resides in the bisectional40
location that has the largest distance from the C-1ꢁC-2
The stereochemical preference for the formation of
bromocyclization product 8b increased from 34% de at
20°C to 58% de upon lowering the reaction temperature
to −78°C. Since it had been shown in previous work
that under these conditions 4-penten-1-oxyl radical 5-
exo-trig cyclizations follow kinetic control, the temper-
ature–selectivity data compiled in Table 1 were used to

J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
3025
bond (hereafter exo-bisectional). Both models favor
4. Conclusion
an attack of the O-radical onto the Si face of C-4
thus leading to allo-muscarine precursor 8b as major
bromocyclization product. Cyclization onto the Re
face of C-4 on the intermediate 14, e.g. by transpos-
ing the methylene group into an axial (Beckwith–
Houk model) or an endo-bisectional location
(twist-model, both not shown), is for steric reasons
associated with higher activation enthalpies (see
above) and therefore disfavors the formation of
product 8a. By virtue of the same arguments the lack
in diastereoselectivity in ring-closure reactions of the
(2R,3R)-(3-benzoyloxy)-5-hexen-2-oxyl radical 16 was
realized. The use of either chair-like-II and III (Beck-
with–Houk) or twist-II and III as stereochemical
models indicated no significant preference for any of
the given structures.
Ring-closure reactions of the (2R,3S)-3-benzoyloxy-5-
hexen-2-oxyl radical 14 and its (2R,3R)-diastereomer
16 have been investigated and applied for the synthe-
sis of enantiomerically pure (−)-muscarine 1a, (+)-
allo-muscarine
1b
(both
from
14),
and
(−)-epi-muscarine 1c, (−)-epiallo-muscarine 1d (the lat-
ter two from 16). Cyclizations of the unlike-
configured 5-hexen-2-oxyl radical 14 exhibited
a
marked 2,5-trans-3,5-cis selectivity that was improved
upon lowering the reaction temperature. In addition,
diastereoselectivities of cyclizations using unlike-
configured 3-trifluoroacetyloxy- and 3-diphenylphos-
phatyl-substituted 5-hexen-2-oxyl radicals have been
investigated. In both instances minor improvements in
diastereoselectivity were noted in comparison to the
ring closure of the 3-benzoyloxy derivative 14.13,14
The observation that b-trifluoroacetyloxy- and b-
(diphenyl)phosphatyl-substituted 5-hexen-2-oxyl radi-
cals furnished upon cyclisation and subsequent
bromine atom trapping trisubstituted tetrahydrofurans
(i.e. 12a–b and 13a–b) served in combination with
results from the sequence 6“8a,8b to establish the
following guideline: b-O-acceptor-substituted 5-hexen-
2-oxyl radicals prefer 5-exo-trig cyclization to b-C,C-
5. Experimental
5.1. General remarks
cleavage.
In
turn,
b-hydroxy-,
a
b-tert-butyldimethylsilyloxy and, less pronounced, b-
benzyloxy substituent in 5-hexen-2-oxyl radicals favor
b-C,C-cleavages to intramolecular additions.15,24 This
observation may be indicative of additional secondary
1H and 13C NMR spectra were recorded with Bruker
AC 200, AC 250, WM 400, AC 400 instruments at
20°C in CDCl3 solutions unless otherwise noted.
Residual protons of deuterated solvents [e.g. lH=7.26
(CDCl3)] and the corresponding carbon resonances in
13C NMR spectra [e.g. lC=77.0 (CDCl3)] were taken
as internal standards. Optical rotations were measured
using a Perkin Elmer 241 polarimeter. IR spectra
were recorded on either NaCl plates or samples
embedded in KBr disks using a Perkin Elmer FT/IR
1600 spectrometer. C,H,N,S analyses were carried out
in the Microanalytical Laboratory in the department
of Inorganic Chemistry at the Universita¨t Wu¨rzburg
using Carlo Erba 1106 or LECO CHNS-932
machines. MS spectra were recorded with a Varian
MATCH 7 spectrometer (electroimpact, EI, 70 eV).
Column chromatography was performed with the use
of SiO2 (Merck, 0.063–0.2 mm). Photoreactions were
carried out using a Southern New England Ultravio-
let RPR-100 Rayonet® photoreactor, equipped with
RPR 350 nm lamps. All solvents were distilled prior
to use and were purified according to standard proce-
dures.42 Methyl (S)-lactate 2, diisobutylaluminum
hydride (DIBAH, 1 M in hexanes), 1,4-diazabicy-
clo[2.2.2]octane (DABCO), pyridinium p-toluenesul-
fonate (PPTS), diphenylchlorophosphate, trifluoro-
acetic acid anhydride, BrCCl3, BEt3 (1 M in hexane),
(S)-a-methoxy-a-trifluoromethylphenylacetyl chloride,
N(CH3)3 (4.2 M in EtOH) were obtained from com-
mercial sources (Fluka, Aldrich and Merck) and were
used as received. Methyl 2-(tetrahydropyran-2-yl)-
’
orbital interactions within the ROꢁCꢁCꢁO fragment
that, however, have not been considered in the mod-
els which are depicted in Figures 3 and 4.41 Effects of
a b-CF3CO2 or a pseudo tetrahedral (C6H5O)2P(O)O
group on alkoxyl radical 5-exo-trig cyclizations in this
study were qualitatively similar to that of the
C6H5CO2 substituent, but furnished slightly improved
diastereoselectivities (8b: 34% de, 12b: 40% de, 13b:
42% de, Scheme 3, Table 1).
3.3. Synthesis and stereochemical analysis of muscarine
alkaloids
The final steps in the synthesis of (2R)-configured
muscarine alkaloids 1a–d were performed starting
from enantiomerically pure alkoxyl radical cyclization
products 8a–d. 5-Bromomethyl-2-methyltetrahydro-
furanols, which were prepared in the initial step
turned out to be surprisingly volatile compounds.
Therefore, it was advisable not to completely remove
the solvent in the work-up step on a synthetic scale,
but to purify target compounds 1a–d via two consec-
utive crystallizations. The stereochemical purity of
target compounds 1a–d has been verified at different
stages of the synthesis. The overall yields of likewise
prepared alkaloids 1 starting from methyl (S)-lactate
2 ranged from 4% (1a, 1c, and 1d) to 5% (1b). These
values were competitive to results obtained from syn-
theses that applied polar bromocyclizations for con-
structing the tetrahydrofuran nucleus, e.g. of
allo-muscarine 1b and epi-muscarine 1c.14
oxypropanoat,18
N-hydroxy-4-methylthiazole-2(3H)-
thione43 and the corresponding tetraalkylammmonium
salt21 were prepared according to literature proce-
dures. Petroleum ether refers to the fraction boiling
between 35 and 50°C.

3026
J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
5.2. Preparation of alkoxyl radical precurors
20.16, 25.79, 25.86, 25.93, 31.10, 31.21, 31.26, 31.32,
34.82, 34.88, 34.96, 35.67, 62.28, 62.40, 63.19, 63.34,
68.86, 69.37, 71.21, 74.98, 75.23, 76.38, 77.77, 78.03,
95.06, 95.67, 98.99, 100.7, 118.1, 118.2, 118.2, 118.6,
128.7, 128.8, 128.8, 129.3, 130.0, 130.1, 130.5, 130.9,
131.0, 133.2, 133.3, 133.5, 133.7, 134.0, 134.2, 134.4,
134.9, 162.8, 166.4, 166.4, 166.7. MS (70 eV, EI): m/z
5.2.1. 2-(Tetrahydropyran-2-yl)oxy-5-hexen-3-ol 3. A
solution
of
methyl
2-(tetrahydropyran-2-
yl)oxypropanoat18 (1.18 g, 6.28 mmol) in dry Et2O (30
mL) was treated under argon at −78°C dropwise with a
solution of DIBAH (9.4 mL, 1 M in hexanes). The
reaction mixture was stirred for 30 min at −78°C and
treated at this temperature dropwise with a solution of
allyl magnesium bromide in Et2O prepared from mag-
nesium turnings (336 mg, 13.8 mmol) and allyl bromide
(1.52 g, 12.6 mmol) in dry Et2O (13 mL). The reaction
mixture was stirred for 16 h at −78°C and allowed to
warm to 0°C. A saturated aqueous solution of NH4Cl
(25 mL) was added. The aqueous phase was separated
from this mixture and was extracted with Et2O (2×20
mL). The combined organic phases were successively
washed with a saturated solution of aq. NaHCO3 (20
mL) and H2O (20 mL). The organic phase was dried
over MgSO4 and the solvent was removed under
reduced pressure to provide an oil which was then
purified by chromatography [SiO2, petroleum ether/
AcOEt, 5:1 (v/v)]. Yield: 955 mg (4.77 mmol, 76%),
colorless liquid as a mixture of diastereomers; Rf=0.37
(%)=122 (70) [C7H6O2 ], 105 (100) [C7H5O+], 85 (15)
+
[C5H9O+], 77 (68) [C6H5 ]. C18H24O4 (304.4) calcd: C,
+
71.03; H, 7.95. Found: C, 70.98; H, 7.66.
5.2.3. (2S,3S)-3-Benzoyloxy-5-hexen-2-ol 4 and (2S,3R)-
3-benzoyloxy-5-hexen-2-ol 5. A solution of (2S,3S)-3-
benzoyloxy-2-(tetrahydropyran-2-yl)oxy-5-hexene
or
the corresponding (2S,3R)-diastereomer (491 mg, 1.61
mmol) in EtOH (16 mL) was treated at 20°C with
PPTS (40.5 mg, 0.160 mmol). The reaction mixture was
refluxed for 6 h. Afterwards, the solvent was removed
under reduced pressure to afford an oil, which was
purified by chromatography [SiO2, petroleum ether/
Et2O, 1:1 (v/v)]. Yield: 323 mg (1.47 mmol, 91%),
colorless oil as a mixture of diastereomers (4:5=54:46).
Diastereomeric pure alkenols 4 and 5 were obtained via
HPLC [Nova Pak HR column, silica 6–8 mm, 19 mm×
30 cm, 2-propanol/n-hexane, 99:1 (v/v)]; isomer 4:
[h]D20=−4.1 (c 0.63, CHCl3). isomer 5: [h]2D0=+13.0 (c
0.64, CHCl3). Spectroscopic data of the alkenols 4 and
5 are in accord with published values.15
1
(petroleum ether/AcOEt, 5:1). H NMR (250 MHz): l
1.16–1.29 (m, 3H, 1-H), 1.44–1.83 (m, 6H, CH2), 2.14–
2.39 (m, 2H, 4-H), 3.33–4.03 (m, 4H, 2-H, 3-H, OCH2),
4.98–5.21 (m, 3H, 6-H, OCHO), 5.73–5.94 (m, 1H,
5-H). 13C NMR (63 MHz): l 14.1, 17.1, 17.7, 18.0,
19.3, 19.5, 19.9, 20.6, 25.4, 29.6, 30.7, 32.5, 33.9, 34.2,
34.5, 36.2, 36.7, 36.8, 36.9, 38.0, 62.2, 62.6, 67.3, 69.8,
73.7, 74.9, 77.7, 77.8, 81.2, 81.3, 82.6, 82.6, 98.7, 103.2,
103.3, 107.8, 117.5, 117.5, 118.0, 118.1, 133.7, 133.7,
134.3, 134.8. MS (70 eV, EI): m/z (%)=127 (14)
5.2.4. (2S,3S)-3-Benzoyloxy-5-hexen-2-yl p-toluenesul-
fonate, (2S,3R)-3-benzoyloxy-5-hexen-2-yl-p-toluenesul-
fonate. (2S,3S)-3-Benzoyloxy-5-hexen-2-yl p-toluene-
sulfonate {[h]2D0=−1.5 (c 0.63, CHCl3)} and (2S,3R)-3-
benzoyloxy-5-hexen-2-yl p-toluenesulfonate {[h]2D0=
−43.9 (c 0.73, CHCl3)} were prepared by a literature
procedure. All spectroscopic data of the compounds 8a
and 8b were in accord with published values.15
[C7H11O2 ], 84 (89) [C5H8O+], 83 (48) [C5H7O+], 75
+
(100) [C3H7O2 ], 71 (34) [C4H7O+], 57 (100) [C3H5O+];
+
C11H20O3 (200.3) calcd: C, 65.97; H, 10.07. Found: C,
65.46; H, 10.28.
5.2.5.
methylthiazol-2(3H)thione 6. Compound 6 was pre-
pared from (2S,3S)-3-benzoyloxy-5-hexen-2-yl
p-toluenesulfonate by adapting a published procedure
{[h]2D0=−50.2 (c 0.81, CHCl3)}. All spectroscopical data
of thione 6 were in agreement with those reported for
an enantiomerically enriched sample.15
(2R,3S)-N-(3-Benzoyloxy-5-hexen-2-oxy)-4-
5.2.2. 3-Benzoyloxy-2-(tetrahydropyran-2-yl)oxy-5-hex-
ene. A solution of 2-(tetrahydropyran-2-yl)oxy-5-hexen-
3-ol 3 (481 mg, 2.40 mmol) and DABCO (538 mg, 4.80
mmol) in dry CH2Cl2 (2.4 mL) was treated at 0°C
dropwise with neat benzoyl chloride (506 mg, 3.60
mmol). The reaction mixture was stirred for 30 min at
20°C and was then diluted with Et2O (10 mL). The
precipitated salts were dissolved in 2 M HCl (10 mL).
The organic phase was separated and the aqueous layer
was extracted with Et2O (2×5 mL). The combined
organic phases were successively washed with a satu-
rated aqueous solution of NaHCO3 (10 mL) and brine
(10 mL). The organic phase was dried over MgSO4 and
the solvent removed under reduced pressure to provide
an oil that was purified by chromatography [SiO2,
petroleum ether/Et2O, 5:1 (v/v)]. Yield: 596 mg (1.96
mmol, 82%), colorless oil, mixture of diastereomiso-
5.2.6.
(2R,3R)-N-(3-Benzoyloxy-5-hexen-2-oxy)-4-
methylthiazol-2(3H)thione 7. A flame-dried round-bot-
tomed flask was charged with N-hydroxy-4-
methylthiazole-2(3H)thione
tetraethylammmonium
salt21 (174 mg, 0.630 mmol) and (2S,3R)-3-benzoyloxy-
5-hexen-2-yl p-toluenesulfonate15 (216 mg, 0.577 mmol)
in dry DMF (3 mL) under argon. The reaction mixture
was sealed with a drying tube (CaCl2), wrapped
in aluminium foil, and stirred for 5 days at 20°C
to furnish
a
dark brown solution which was
1
mers. Rf=0.65 (petroleum ether/Et2O, 5:1). H NMR
poured into H2O (10 mL) and subsequently extracted
with Et2O (3×10 mL). The combined organic phases
were successively washed with 2 M NaOH (20 mL)
and brine (20 mL) and dried over MgSO4. The solvent
was removed under reduced pressure to afford an
oil that was purified by chromatography [SiO2,
petroleum ether/Et2O, 1:1 (v/v)]. Yield: 104 mg (0.298
(250 MHz): l 1.16–1.33 (m, 3H, 1-H), 1.45–1.85 (m,
6H, CH2), 2.41–2.62 (m, 2H, 4-H), 3.41–3.56 (m, 1H,
OCH), 3.80–4.10 (m, 2H, OCH), 4.71–5.31 (m, 4H,
3-H, 6-H, OCHO), 5.74–5.92 (m, 1H, 5-H), 7.40–7.71
(m, 3H, Ar-H), 8.01–8.18 (m, 2H, Ar-H). 13C NMR (63
MHz): l 17.37, 17.97, 18.56, 19.46, 19.52, 19.88, 20.13,

J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
3027
mmol, 73%, based on a conversion of 71% of (2S,3R)-
3-benzoyloxy-5-hexen-2-yl p-toluenesulfonate, which
was recovered in 62.5 mg (0.167 mmol, 29%), tan oil.
Rf=0.36 (petroleum ether/Et2O, 1:1). [h]2D0=−108.4 (c
0.39, CHCl3); 1H NMR (250 MHz): l 1.28 (d, 3H,
5.3.3. Saponification of bromomethyltetrahydrofurans
8a–d (general procedure). 3-Benzoyloxy-5-bromomethyl-
2-methyltetrahydrofuran 8 was dissolved in a solution
of NaOH (0.18 M) in CH3OH. The reaction mixture
was stirred for 1 h at 20°C and subsequently poured
into a mixture of Et2O (20 mL) and H2O (20 mL). The
organic layer was separated and the aqueous phase was
extracted with Et2O (3×10 mL). The combined organic
phases were dried over MgSO4 and the solvent removed
under reduced pressure to furnish an oil that was
purified by chromatography [SiO2, petroleum ether/
Et2O, 1:1 (v/v)].
4
3J=6.6 Hz, 1-H), 2.25 (d, 3H, J=1.2 Hz, CH3), 2.60–
2.72 (m, 1H, 4-H), 2.79–2.89 (m, 1H, 4-H), 5.09 (d, 1H,
3
3J=10.1 Hz, 6-H), 5.18 (d, 1H, J=17.1 Hz, 6-H), 5.41
(mc, 1H, 3-H), 5.79–5.93 (m, 2H, 2-H, 5-H), 6.12 (q,
4
1H, J=1.2 Hz, 5%-H), 7.45 (mc, 2H, Ar-H), 7.58 (mc,
1H, Ar-H), 8.06 (mc, 2H, Ar-H). 13C NMR (100 MHz):
l 13.94, 14.64 (C-1, CH3), 35.26 (C-4), 74.50, 79.93
(C-2, C-3), 102.9 (C-5%), 118.6 (C-6), 128.4, 129.7, 130.8,
132.8, 133.2, 138.9 (C-4%), 165.9 (CꢀO), 180.7 (CꢀS).
5.3.3.1.
(2R,3S,5R)-5-Bromomethyl-2-methyltetra-
+
hydrofuran-3-ol. A solution of 8a (87.4 mg, 0.292 mmol)
was treated with a solution of NaOH in CH3OH (5.7
mL, 0.18 M) as outlined above. Rf=0.26 (petroleum
ether/Et2O, 1:2), 53.0 mg (0.272 mmol, 92%), colorless
MS (70 eV, EI): m/z (%)=131 (6) [C4H5NS2 ], 105
(100) [C7H5O+], 77 (35) [C6H5 ]. C17H19NO3S2 (349.5)
+
calcd: C, 58.43; H, 5.48; N, 4.01; S, 18.35. Found: C,
58.26; H, 5.37; N, 3.97; S, 17.95.
1
3
liquid. H NMR (250 MHz): l 1.25 (d, 3H, J=6.4 Hz,
CH3), 1.95 (s br., 1H, OH), 2.02 (mc, 2H, 4-H), 3.43–
5.3. Preparation of muscarine alkaloids 1a–d
3
3
3.49 (m, 2H, CH2Br), 3.95 (dq, 1H, Jd=3.5 Hz, Jq=
3
3
6.4 Hz, 2-H), 4.06 (dt, 1H, Jd=3.5 Hz, Jt=4.7 Hz,
3-H), 4.37 (mc, 1H, 5-H). 13C NMR (CDCl3, 63 MHz):
l 19.6, 35.8, 39.3, 76.9, 77.4, 83.1.
5.3.1. Formation of 3-benzoyloxy-5-bromomethyl-2-
methyltetrahydrofurans 8a and 8b.
A solution of
(2R,3S)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthia-
zol-2(3H)thione 6 (377 mg, 1.08 mmol) and BrCCl3
(1.71 g, 8.64 mmol) in dry C6H6 (6 mL) was flushed for
5 min at 20°C with a gentle stream of argon. This
solution was photolyzed for 25 min at 20°C in a
Rayonet® chamber photoreactor and was subsequently
concentrated under reduced pressure to furnish an oil
that was purified by chromatography [SiO2, petroleum
ether/Et2O, 5:1 (v/v)]. 8a: Rf=0.42 (petroleum ether/
Et2O, 5:1), 84.4 mg (0.282 mmol, 26%), colorless oil.
[h]2D0=+2.2 (c 0.69, CHCl3). 8b: Rf=0.39 (petroleum
ether/Et2O, 5:1), 172 mg (0.574 mmol, 53%), colorless
oil. [h]2D0=−28.7 (c 0.59, CHCl3); All spectroscopic data
of the compounds 8a and 8b were in agreement with
published values.15
5.3.3.2.
(2R,3S,5S)-5-Bromomethyl-2-methyltetra-
hydrofuran-3-ol. A solution of 8b (36.7 mg, 0.123 mmol)
was treated with a solution of NaOH in CH3OH (2.4
mL, 0.18 M) as described previously. Rf=0.40
(petroleum ether/Et2O, 1:2), 15.9 mg (81.5 mmol, 66%),
1
colorless liquid. H NMR (250 MHz): l 1.19 (d, 3H,
3J=6.4 Hz, CH3), 1.83–1.92 (m, 2H, 4-H, OH), 2.44
3
2
(ddd, 1H, J=6.1, 7.9 Hz, J=14.0 Hz, 4-H), 3.52 (d,
3
2H, J=5.8 Hz, CH2Br), 4.01–4.11 (m, 2H, 3-H, 2-H),
4.34 (ddd, 1H, J=5.8, 7.9, 11.3 Hz, 2-H). 13C NMR
3
(CDCl3, 63 MHz): l 18.5, 36.5, 38.5, 76.6, 77.2, 82.2.
5.3.3.3.
(2R,3R,5R)-5-Bromomethyl-2-methyltetra-
hydrofuran-3-ol. A solution of 8c (51.7 mg, 0.173 mmol)
was treated with a solution of NaOH in CH3OH (3.4
mL, 0.18 M) as outlined above. Rf=0.42 (petroleum
ether/Et2O, 1:2), 28.2 mg (0.145 mmol, 84%), colorless
5.3.1.1.
2-Trichloromethylsulfanyl-4-methylthiazole
924. Rf=0.52 [petroleum ether/Et2O/acetone, 10:1:1 (v/
1
1
3
v/v)], 207 mg (77%). H NMR (250 MHz): l 2.57 (d,
liquid. H NMR (250 MHz): l 1.30 (d, 3H, J=6.4 Hz,
3
3H, CH3), 7.31 (q, 1H, CH). C5H4Cl3NS2 (248.6): MS
(70 eV, EI): m/z (%)=247/249/251/253 (15/13/5/2) [M+],
212/214/216 (53/38/9) [M+−Cl], 130 (100) [M+−CCl3].
CH32), 1.83 (s. br., 1H, OH), 1.88 (ddd, 1H, J=1.4, 4.9
3
Hz, J=14.3 Hz, 4-H), 2.41 (ddd, 1H, J=6.0, 8.9 Hz,
2J=14.3 Hz, 4-H), 3.50 (dd, 1H, J=4.6 Hz, J=10.4
3
2
3
2
Hz, CH2Br), 3.61 (dd, 1H, J=5.3 Hz, J=10.4 Hz,
3
3
5.3.2. Synthesis of 3-benzoyloxy-5-bromomethyl-2-
CH2Br), 3.86 (dq, 1H, Jd=3.1 Hz, Jq=6.4 Hz, 2-H),
4.13–4.22 (m, 2H, 3-H, 5-H). 13C NMR (CDCl3, 63
MHz): l 14.1, 36.5, 40.5, 74.2, 76.1, 79.0.
methyltetrahydrofurans 8c and 8d.
A solution of
(2R,3R)-N-(3-benzoyloxy-5-hexen-2-oxy)-4-methylthia-
zole-2(3H)thione (7) (212 mg, 0.607 mmol) and BrCCl3
(963 mg, 4.86 mmol) in dry C6H6 (3.4 mL) was flushed
for 5 min at 20°C with a gentle stream of argon This
solution was photolyzed for 25 min at 20°C in a
Rayonet® chamber photoreactor and was subsequently
concentrated under reduced pressure to furnish an oil
that was purified by chromatography [SiO2, petroleum
ether/Et2O, 5:1 (v/v)]. 8c: Rf=0.29 (petroleum ether/
Et2O, 5:1), yield: 72.4 mg (0.242 mmol, 40%), colorless
oil. [h]2D0=+16.2 (c 0.53, CHCl3); 8d: Rf=0.37
(petroleum ether/Et2O, 5:1), 71.2 mg (0.238 mmol,
39%), colorless oil. [h]2D0=−45.1 (c 0.20, CHCl3). All
spectroscopic data of the compounds 8c and 8d were in
agreement with published values.15
5.3.3.4.
(2R,3R,5S)-5-Bromomethyl-2-methyltetra-
hydrofuran-3-ol. A solution of 8d (17.4 mg, 5.82 mmol)
was treated with a solution of NaOH in CH3OH (1.1
mL, 0.18 M) as described above. Rf=0.39 (petroleum
ether/Et2O, 1:2), 8.9 mg (4.56 mmol, 78%), colorless
1
3
liquid. H NMR (250 MHz): l 1.27 (d, 3H, J=6.3 Hz,
3
CH32), 1.69 (s. br., 1H, OH), 2.04 (ddd, 1H, J=4.7, 9.2
3
Hz, J=13.8 Hz, 4-H), 2.20 (ddd, 1H, J=1.2, 6.7 Hz,
2J=13.8 Hz, 4-H), 3.46 (d, 1H, J=5.8 Hz, CH2Br),
3
3
3
3.46 (d, 1H, J=4.9 Hz, CH2Br), 4.12 (dq, 1H, Jd=2.8
3
Hz, Jq=6.3 Hz, 2-H), 4.25 (mc, 1H, 3-H), 4.43–4.53
(m, 1H, 5-H). 13C NMR (CDCl3, 63 MHz): l 13.9,
36.7, 39.8, 73.3, 76.4, 79.7.

3028
J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
5.3.4. Conversion of 5-bromomethyl-2-methyltetra-
hydrofuran-3-ols into (R)-configured Mosher esters (gen-
eral procedure). A 1 M solution of the corresponding
5.3.5.1. (2R,3S,5R)-Muscarine 1a. (2R,3S,5R)-5-Bro-
momethyl-2-methyltetrahydrofuran-3-ol (34.9 mg,
0.179 mmol) was dissolved in a solution of N(CH3)3 in
EtOH (0.51 mL, 4.2 M). The reaction mixture was
stirred for 6 days at 60°C and worked up as described
above to furnish 40.4 mg (0.159 mmol, 89%) of the
alkaloid 1a as colorless hygroscopic crystals. [h]2D0=
5-bromomethyl-2-methyltetrahydrofuran-3-ol
(5–20
mmol) CH2Cl2 (1 mL) was treated with dimethyl-
aminopyridine (DMAP, 2.0 equiv.) at 0°C. Neat (S)-a-
methoxy-a-trifluoromethylphenylacetyl chloride (1.5
equiv.) was added dropwise at 0°C and the mixture was
stirred for 1 h at 20°C. The solution was diluted with
Et2O (2 mL). It was washed with 2N HCl, a satd aq.
solution of NaHCO3 and brine (2 mL each). Drying
(MgSO4) and concentration of the organic phase under
reduced pressure afforded the derived Mosher esters in
quantitative yields.
1
−15.5 (c 0.64, EtOH). H NMR (250 MHz, D2O): l
3
3
1.16 (d, 3H, J=6.4 Hz, CH3), 1.94 (ddd, 1H, J=5.2,
2
3
9.5 Hz, J=13.7 Hz, 4-H), 2.06 (ddd, 1H, J=2.8, 6.4
2
Hz, J=13.7 Hz, 4-H), 3.15 (s, 9H, NCH3), 3.42 (dd,
1H, 3J=9.2 Hz, 2J=14.0 Hz, CH2N), 3.55 (dd, 1H,
3J=1.8 Hz, 2J=14.0 Hz, CH2N), 4.01 (dq, 1H, 3Jd=2.4
3
3
Hz, Jq=6.4 Hz, 2-H), 4.08 (ddd, 1H, J=2.4, 2.8, 5.2
Hz, 3-H), 4.61 (mc, 1H, 5-H).
5.3.4.1. (R)-Mosher-ester of (2R,3S,5R)-5-bromo-
methyl-2-methyltetrahydrofuran-3-ol (derived from 8a).
1H NMR (250 MHz): l 1.31 (d, 3H, 6.6 Hz, CH3),
2.13–2.18 (m, 2H, 4-H), 3.46 (mc, 2H, CH2Br), 3.53 (q,
3H, 5J=1.2 Hz, OCH3), 4.07 (dq, 1H, 3Jd=2.7 Hz,
3Jt=6.6 Hz, 2-H), 4.24 (mc, 1H, 5-H), 5.12 (mc, 1H,
3-H), 7.39–7.45 (m, 3H, Ar-H), 7.49–7.52 (m, 2H,
Ar-H).
5.3.5.2. (2R,3S,5S)-allo-Muscarine 1b. (2R,3S,5S)-5-
Bromomethyl-2-methyltetrahydrofuran-3-ol (12.2 mg,
62.5 mmol) was dissolved in a solution of N(CH3)3 in
EtOH (0.20 mL, 4.2 M). The reaction mixture was
stirred for 7 days at 60°C and worked up as described
above to afford 11.6 mg (45.6 mmol, 73%) of alkaloid
1b as colorless hygroscopic crystals. [h]2D0=+36.8 (c
1
0.57, EtOH). H NMR (250 MHz, D2O): l 1.16 (d, 3H,
3J=6.1 Hz, CH3), 1.55–1.65 (m, 1H, 4-H), 2.56 (ddd,
5.3.4.2. (R)-Mosher-ester of (2R,3S,5S)-5-bromo-
methyl-2-methyltetrahydrofuran-3-ol (derived from 8b).
1H NMR (250 MHz): l 1.23 (d, 3H, 6.4 Hz, CH3), 2.09
(ddd, 1H, 3J=2.9, 3.5 Hz, 3J=14.5 Hz, 4-H), 2.56
3
2
1H, J=6.4, 8.2 Hz, J=14.8 Hz, 4-H), 3.14 (s, 9H,
3
2
NCH3), 3.36 (dd, 1H, J=1.8 Hz, J=14.0 Hz, CH2N),
3.63 (dd, 1H, J=10.1 Hz, J=14.0 Hz, CH2N), 4.03
3
2
3
3
(mc, 2H, 3-H, 2-H), 4.67 (mc, 1H, 5-H).
(ddd, 1H, J=6.6, 7.9 Hz, J=14.5 Hz, 4-H), 3.16 (dd,
3
2
1H, J=7.9 Hz, J=10.1 Hz, CH2Br), 3.30 (dd, 1H,
3J=5.6 Hz, J=10.1 Hz, CH2Br), 3.53 (q, 3H, J=1.2
Hz, OCH3), 4.21 (dq, 1H, 3Jd=2.4 Hz, 3Jt=6.4 Hz,
2-H), 4.39 (mc, 1H, 5-H), 5.14 (mc, 1H, 3-H), 7.41–7.46
(m, 3H, Ar-H), 7.48–7.54 (m, 2H, Ar-H).
2
5
5.3.5.3. (2R,3R,5R)-epi-Muscarine 1c. (2R,3R,5R)-5-
Bromomethyl-2-methyltetrahydrofuran-3-ol (15.5 mg,
79.5 mmol) was dissolved in a solution of N(CH3)3 in
EtOH (0.22 mL, 4.2 M). The reaction mixture was
stirred for 7 days at 60°C and worked up as described
above to provide 13.1 mg (51.5 mmol, 65%) of alkaloid
1c as colorless hygroscopic crystals. [h]2D0=−62.7 (c
5.3.4.3. (R)-Mosher-ester of (2R,3R,5R)-5-bromo-
methyl-2-methyltetrahydrofuran-3-ol (derived from 8c).
1H NMR (250 MHz): l 1.22 (d, 3H, 6.6 Hz, CH3), 1.83
(mc, 1H, 4-H), 2.49 (mc, 1H, 4-H), 2.91 (mc, 1H,
CH2Br), 3.18 (mc, 1H, CH2Br), 3.51 (q, 3H, 5J=1.2 Hz,
OCH3), 3.92–4.16 (m, 2H, 2-H, 5-H), 5.31 (mc, 1H,
3-H), 7.30–7.39 (m, 3H, Ar-H), 7.41–7.51 (m, 2H,
Ar-H).
1
0.42, EtOH). H NMR (250 MHz, D2O): l 1.24 (d, 3H,
3J=6.4 Hz, CH3), 1.62 (ddd, 1H, 3J=1.8, 5.8 Hz,
2J=14.0 Hz, 4-H), 2.61 (ddd, 1H, 3J=6.1, 8.9 Hz,
2J=14.0 Hz, 4-H), 3.18 (s, 9H, NCH3), 3.50 (dd, 1H,
2
3
3J=3.1 Hz, J=14.0 Hz, CH2N), 3.58 (dd, 1H, J=8.5
2
3
Hz, J=14.0 Hz, CH2N), 3.95 (dq, 1H, Jd=3.4 Hz,
3Jq=6.4 Hz, 2-H), 4.24 (ddd, 1H, J=1.8, 3.4, 6.1 Hz,
3
3-H), 4.46 (mc, 1H, 5-H).
5.3.4.4. (R)-Mosher-ester of (2R,3R,5S)-5-bromo-
methyl-2-methyltetrahydrofuran-3-ol (derived from 8d).
1H NMR (250 MHz): l 1.20 (d, 3H, 6.4 Hz, CH3),
2.18–2.23 (m, 2H, 4-H), 3.43 (mc, 2H, CH2Br), 3.54 (q,
3H, J=1.2 Hz, OCH3), 4.21–4.36 (m, 2H, 2-H, 5-H),
5.46 (mc, 1H, 3-H), 7.38–7.46 (m, 3H, Ar-H), 7.52–7.54
5.3.5.4.
(2R,3R,5S)-epiallo-Muscarine
1d.
(2R,3R,5S)-5-Bromomethyl-2-methyltetrahydrofuran-3-
ol (10.1 mg, 51.8 mmol) was dissolved in a solution of
N(CH3)3 in EtOH (0.14 mL, 4.2 M). The reaction
mixture was stirred for 7 days at 60°C and worked up
as described above to yield 8.9 mg (35.0 mmol, 68%) of
the alkaloid 1d as colorless hygroscopic crystals. [h]2D0=
5
(m, 2H, Ar-H).
5.3.5. Muscarine alkaloids 1a–d (general procedure).
Bromomethyl-2-methyltetrahydrofuran-3-ols (derived
from 8a–d, see above) were dissolved in a solution of
N(CH3)3 in EtOH (4.2 M). The solution was stirred in
a sealed tube for 6–7 days at 60°C. The solvent was
removed under reduced pressure. Products 1a–d crystal-
lized from the residue upon addition of Et2O The crude
material was recrystallized from petroleum ether/
acetone.
1
0.0 (c 0.41, EtOH). H NMR (250 MHz, D2O): l 1.19
3
3
(d, 3H, J=6.4 Hz, CH3), 1.92 (ddd, 1H, J=4.9, 8.5
Hz, 2J=14.0 Hz, 4-H), 2.20 (dd, 1H, 3J=7.0 Hz,
2J=14.0 Hz, 4-H), 3.16 (s, 9H, NCH3), 3.35 (dd, 1H,
2
3
3J=1.8 Hz, J=14.0 Hz, CH2N), 3.50 (dd, 1H, J=9.7
2
3
Hz, J=14.0 Hz, CH2N), 4.07 (dq, 1H, Jd=2.7 Hz,
3Jq=6.4 Hz, 2-H), 4.21 (dd, 1H, J=2.7, 4.9 Hz, 3-H),
3
4.58 (mc, 1H, 5-H).

J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
3029
5.4. Preparation of 3-substituted N-hexenoxythiazol-
5.4.3. (2R*,3S*)-N-(3-Diphenoxyphosphoryl-5-hexen-2-
oxy)-4-methylthiazole-2(3H)thione 11. A solution of
(2R*,3S*)-N-(3-hydroxy-5-hexen-2-oxy)-4-methylthia-
zole-2(3H)thione (22.1 mg, 90.1 mmol) and DABCO
(20.2 mg, 0.180 mmol) in dry CH2Cl2 (0.2 mL) was
treated dropwise at 0°C with neat diphenylchlorophos-
phate (36.3 mg, 0.135 mmol). The reaction mixture was
stirred for 24 h at 20°C and subsequently diluted with
tert-butyl methyl ether (2 mL). The precipitated salts
were dissolved in 2 M HCl (2 mL) and the organic
phase separated. and washed with a saturated aq. solu-
tion of NaHCO3 (2 mL) and brine (2 mL). After drying
over MgSO4 the organic solvent was removed under
reduced pressure to provide an oily residue that was
purified by chromatography [SiO2, petroleum ether/
tert-butyl methyl ether, 1:2 (v/v)]. Rf=0.46 (petroleum
ether/tert-butyl methyl ether, 1:2), 20.1 mg (42.1 mmol,
47%), tan oil. 1H NMR (250 MHz): l 1.29 (d, 3H,
ethiones
5.4.1.
(2R*,3S*)-N-(3-Hydroxy-5-hexen-2-oxy)-4-
methylthiazole-2(3H)thione. (2R,3S)-N-(3-Hydroxy-5-
hexen-2-oxy)-4-methylthiazole-2(3H)thione (6, 37.8 mg,
0.108 mmol, 34% ee)15 was dissolved in a solution of
NaOH in CH3OH (2.1 mL, 0.18 M). The reaction
mixture was stirred for 16 h at 20°C and then poured
into a mixture of Et2O (20 mL) and H2O (20 mL). The
aqueous phase was separated and extracted with Et2O
(3×10 mL). The combined organic phases were dried
over MgSO4 and concentrated under reduced pressure
to afford an oil which was purified by chromatography
[SiO2, petroleum ether/Et2O, 1:2 (v/v)]. Rf=0.16
(petroleum ether/Et2O, 1:2), 25.6 mg (0.104 mmol,
97%), tan oil. 1H NMR (250 MHz): l 1.36 (d, 3H,
3J=6.4 Hz, 1-H), 2.08–2.22 (m, 1H, 4-H), 2.27–2.39 (m,
4
4
1H, 4-H), 2.31 (d, 3H, J=1.2 Hz, CH3), 4.03–4.13 (m,
3J=6.6 Hz, 1-H), 2.08 (d, 3H, J=1.2 Hz, CH3), 2.47
3
3
2H, 3-H, OH), 4.50 (dq, 1H, Jd=1.5 Hz, Jq=6.4 Hz,
2-H), 5.09 (d, 1H, 3J=10.7 Hz, 6-H), 5.14 (d, 1H,
(mc, 1H, 4-H), 2.71 (mc, 1H, 4-H), 5.09–5.20 (m, 3H,
3
2-H, 6-H), 5.62 (mc, 1H, 3-H), 5.80 (ddt, 1H, Jd=10.4,
3
3
4
3J=17.1 Hz, 6-H), 5.83 (ddt, 1H, Jd=10.7, 17.1 Hz,
16.9 Hz, Jt=6.7 Hz, 5-H), 6.10 (d, 1H, J=1.2 Hz,
4
3Jt=7.0 Hz, 5-H), 6.25 (q, 1H, J=1.2 Hz, 5%-H). 13C
5%-H), 7.14–7.36 (m, 10H, Ar-H); 13C NMR (63 MHz):
l 12.1, 13.8 (CH3, C-1), 36.7 (d, JC,P=2.9 Hz, C-4),
3
NMR (63 MHz): l 11.3, 13.7 (C-1, CH3), 36.6 (C-4),
68.6 (C-3), 87.6 (C-2), 104.0 (C-5%), 117.5 (C-6), 134.2
(C-5), 138.7 (C-4%), 182.4 (CꢀS). IR (NaCl): w=3381
cm−1 (s), 3078 (m), 2937 (s), 1643 (m), 1594 (m), 1434
(m), 1391 (m), 1318 (s), 1175 (m), 1141 (m), 1040 (s),
1011 (s), 983 (s), 917 (m), 835 (w), 720 (s). MS (70 eV,
80.0 (d, JC,P=6.7 Hz), 80.9 (d, JC,P=6.7 Hz) (C-2, C-3),
3
102.6 (C-5%), 119.3, 120.0 (d, JC,P=4.8 Hz), 120.1 (d,
3JC,P=5.7 Hz), 125.3, 129.7, 129.8, 131.5, 139.1, 150.6
2
(d, JC,P=8.6 Hz), 180.7 (CꢀS). MS (70 eV, EI): m/z
(%)=264 (52) [C13H13O4P], 131 (75) [C4H5NS2], 77 (67)
EI): m/z (%)=245 (2) [M+], 147 (100) [C4H5NOS2 ],
[C6H5 ]. C22H24NO5PS2 (477.5) calcd: C, 55.33; H, 5.07;
+
+
131 (34) [C4H5NS2 ], 71 (23) [C4H7O+]. C10H15NO2S2
N, 2.93; S, 13.45. Found: C, 54.00; H, 5.19; N, 2.72; S,
12.25.
+
(245.4) calcd: C, 48.95; H, 6.16; N, 5.71; S, 26.14.
Found: C, 49.04; H, 5.97; N, 5.61; S, 25.89.
5.5. Photolysis of thiazolethiones 10 and 11 in the pres-
ence of BrCCl3
5.4.2.
(2R*,3S*)-N-(3-Trifluoroacetyloxy-5-hexen-2-
oxy)-4-methylthiazole-2(3H)thione 10. A solution of
(2R*,3S*)-N-(3-hydroxy-5-hexen-2-oxy)-4-methylthia-
zole-2(3H)thione (100 mg, 0.408 mmol) and DABCO
(91.4 mg, 0.815 mmol) in dry CH2Cl2 (0.4 mL) was
treated at 0°C dropwise with neat trifluoroacetic anhy-
dride (129 mg, 0.612 mmol). The reaction mixture was
stirred for 2 h at 20°C. Afterwards it was diluted with
tert-butyl methyl ether (2 mL). The precipitated salts
were dissolved in 2N HCl (2 mL). The organic phase
was separated. and washed with a saturated aq. solu-
tion of NaHCO3 (2 mL) and brine (2 mL). The com-
bined organic phases were then dried over MgSO4 and
concentrated under reduced pressure to furnish an oil
that was purified by chromatography [SiO2, petroleum
ether/Et2O, 1:1 (v/v)]. Rf=0.34 (petroleum ether/Et2O,
5.5.1. General procedure. A Schlenk flask was charged
with a solution of thiazolethione 10 or 11 in the dark
(c0=0.18 M). A defined amount of anisole or 2,2-
dichloro-5,5-dimethylcyclohexane-1,3-dione
(internal
1
standards for H NMR analysis) was then added. The
flask was closed with a rubber septum and cooled to
liquid-nitrogen temperature. The flask was evacuated
(1×10−2 mbar) and subsequently flushed with argon
after which BrCCl3 was added. The sample was
degassed by two freeze–pump–thaw cycles, subse-
quently thermostated to 18°C (H2O bath) and then
photolyzed for 25 min in a Rayonet® photoreactor to
furnish a reaction mixture that was immediately ana-
1
1:1), 114 mg (0.333 mmol, 82%), tan oil. H NMR (250
1
lyzed by either H NMR or GC.
3
MHz): l 1.33 (d, 3H, J=6.4 Hz, 1-H), 2.18 (d, 3H,
4J=1.2 Hz, CH3), 2.53 (mc, 2H, 4-H), 5.18 (d, 1H,
3J=12.2 Hz, 6-H), 5.19 (d, 1H, J=17.4 Hz, 6-H), 5.58
5.5.1.1.
5-Bromomethyl-3-trifluoroacetyloxy-2-
3
3
3
(dt, 1H, Jd=2.4 Hz, Jd=7.3 Hz, 3-H), 5.68–5.84 (m,
2H, 2-H, 5-H), 6.19 (q, 1H, 4J=1.2 Hz, 5%-H). 13C
NMR (100 MHz): l 12.2, 13.6 (C-1, CH3), 35.0 (C-4),
methyltetrahydrofuran 12 and 12b. To a solution of
thiazolethione 10 (17.4 mg, 51.0 mmol) and BrCCl3
(80.9 mg, 0.408 mmol) in dry deoxygenated C6D6 (0.8
1
1
77.0, 79.8 (C-2, C-3), 103.0 (C-5%), 114.5 (q, JC,F=286
mL) was added anisole (internal standard, H NMR).
Hz, CF3), 120.0 (C-6), 131.0 (C-5), 138.6 (C-4%), 156.6
The solution was treated as described in the general
procedure and analyzed by H NMR and MS. Yield:
32.9 mmol (64%), mixture of diastereomers (12a:12b=
29:71). C8H10O3BrF3 (291.1). HRMS (C7H8F3O3, M+−
CH2Br) calcd: 197.0426. Found: 197.0425. MS (70 eV,
2
1
(q, JC,F=42.9 Hz, CꢀO), 180.8 (CꢀS). MS (70 eV, EI):
m/z (%)=341 (19) [M+], 147 (84) [C4H5NOS2 ], 131
+
(100) [C4H5NS2 ]. HRMS (C12H14F3NO3S2, M+) calcd:
+
341.0367. Found: 341.0360.

3030
J. Hartung, R. Kneuer / Tetrahedron: Asymmetry 14 (2003) 3019–3031
+
EI): m/z (%)=197 (100) [C7H8O3F3 ], 167 (39)
(7.4 mL) was then bubbled through the reaction mix-
ture using a syringe pump over a period of 30 min at
−10°C. The solvent was removed under reduced pres-
sure and the residue purified by chromatography [SiO2,
petroleum ether/Et2O, 2:1 (v/v)] to furnish 74.5 mg
(0.249 mmol, 75%) of a 27:73 mixture of tetra-
hydrofurans 8a and 8b as a colorless oil.
[C6H6O2F3 ], 83 (54) [C5H7O+], 43 (85) [C2H3O+]. 12a:
+
1H NMR (250 MHz, C6D6): l 0.88 (d, 3H, J=6.6 Hz,
3
CH3), 1.47–1.57 (m, 2H, 4-H), 2.85–2.93 (m, 2H,
CH2Br), 3.66–3.75 (m, 2H, 2-H, 5-H), 4.45 (mc, 1H,
1
3-H). 12b: H NMR (250 MHz, C6D6): l 0.70 (d, 3H,
3J=6.6 Hz, CH3), 1.37–1.45 (m, 1H, 4-H), 1.75 (ddd,
3
2
1H, J=6.6, 7.6 Hz, J=14.5 Hz, 4-H), 2.89 (dd, 1H,
3J=7.6 Hz, J=10.1 Hz, CH2Br), 3.01 (dd, 1H, J=5.5
2
3
2
Hz, J=10.1 Hz, CH2Br), 3.77–3.87 (m, 2H, 2-H, 5-H),
4.40 (dt, 1H, Jt=3.1 Hz, Jq=6.6 Hz, 3-H).
Acknowledgements
5.5.1.2. (5-Bromomethyl-2-methyltetrahydrofuran-3-
yl)diphenoxyphosphate 13a and 13b. To a solution of
thiazolethione 11 (14.1 mg, 29.5 mmol) and BrCCl3
(47.6 mg, 0.239 mmol) in dry and deoxygenated C6D6
(0.8 mL) was added 2,2-dichloro-5,5-dimethylcyclohex-
ane-1,3-dione. The solution was treated as described in
the general procedure to provide a reaction mixture
Generous financial support was provided by the
Deutsche Forschungsgemeinschaft (Grants, Ha 1705/3-
2 and 3-3) and the Fonds der Chemischen Industrie.
We also express our gratitude to Dipl.-Chem. Thomas
Gottwald for helpful discussions and technical
assistance.
1
that was analyzed by H NMR and MS. Yield: 20.4
mmol (69%), mixture of diastereomers (13a:13b=30:70).
C18H20O5PBr (427.2). MS (70 eV, EI): m/z (%)=264
(100) [C13+H13O4P+], 251 (15) [C12H12O4P+], 170 (66)
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Schlenk flask was charged with a solution of thiazo-
lethione 6 (70.2 mg, 0.201 mmol, 34% ee)15 in CH2Cl2
(1.2 mL) in the dark (c0=0.18). The flask was sealed
with a rubber septum, cooled to liquid-nitrogen temper-
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sample was flushed with argon. BrCCl3 (319 mg, 1.61
mmol) was then added and the reaction mixture deaer-
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allowed to warm to 18°C (H2O bath). A solution of
BEt3 (0.1 mL, 1 m in hexane) was and the reaction
mixture cooled to −78°C. O2 (4.4 mL) was then bub-
bled through the reaction mixture (syringe pump) over
a period of 30 min The solvent was removed under
reduced pressure and the residue purified by chro-
matography [SiO2, petroleum ether/Et2O, 2:1 (v/v)] to
furnish 19.2 mg (64.2 mmol, 32%) of a 21:79-mixture of
tetrahydrofurans 8a and 8b as a colorless oil.
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(116 mg, 0.332 mmol, 34% ee),15 BrCCl3 (658 mg, 3.32
mmol), and BEt3 (0.17 mL, 1 M in hexane) in dry
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L
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L
-rhamnose: (b)
L
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−
For
41, 2401–2410; From
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DH‡14“15b
and
DDS‡=DS‡14“15a−DS1‡4“15b
.
Hardegger, E.; Ko¨gl, F.; Liechti, P.; Lohse, F.; Salemink,
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