Stereocontrol of 5-endo-trig cyclisations by hydroxyl groups: A formal short synthesis of (+)-muscarine

Article abstract of DOI:10.1016/S0040-4039(02)01518-6

5-endo-Trig iodocyclisation of the (Z)-ene-diol derivative 10 gives almost exclusively the hydroxy-tetrahydrofuran 11, a precursor of (+)-muscarine 1 in four simple steps.

Full text of DOI:10.1016/S0040-4039(02)01518-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6771–6773
Stereocontrol of 5-endo-trig cyclisations by hydroxyl groups:
a formal short synthesis of (+)-muscarine
David W. Knight* and Emily R. Staples
Chemistry Department, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 11 June 2002; accepted 19 July 2002
Abstract—5-endo-Trig iodocyclisation of the (Z)-ene-diol derivative 10 gives almost exclusively the hydroxy-tetrahydrofuran 11,
a precursor of (+)-muscarine 1 in four simple steps. © 2002 Elsevier Science Ltd. All rights reserved.
(+)-Muscarine 1 has enjoyed considerable prominence
in the chemical and biological literature for many years,
initially by reason of its ability to act as an acetyl-
choline agonist; more recently, the characterisation of
many subtypes of muscarinic receptors has further
enhanced this interest.1 Hence, there is continuing
demand for the synthetic provision of this highly active
compound that occurs in the spectacular Fly Agaric
mushroom Amanita muscara.2 It should be added that
the structure has also provided a testbed for a great
diversity of novel synthetic strategies.3
such cyclisations of (Z)-homoallylic alcohols.5 In par-
ticular, iodocyclisation of the model anti-(Z)-3-alkene-
1,2-diol (6; R-alkyl, aryl) led almost exclusively (>10:1)
to the tetrahydrofurans 7, having the precise stereo-
chemistry required for an efficient approach to mus-
carine 1 (Scheme 2). As ever, extensions of model
studies to actual targets necessitate the inclusion of
additional, potentially interfering functionality along
with a correct pattern of protection. An optimum route
to muscarine 1 using this latter methodology appeared
to demand use of a masked hydroxymethyl group in
place of the n-alkyl substituents in model 6. At the
outset, we had no information concerning the efficacy
of such 5-endo cyclisations involving additions to allylic
alcohol functions (cf. structure 10). We did, however,
HO
X
O
NMe3
I
I2, NaHCO3
1
R2
R1
R1
R2
We have recently discovered that 2,5-trans-tetra-
hydrofurans 3 can be obtained highly stereoselectively
by overall 5-endo-trig cyclisations of (E)-homoallylic
alcohols 2 upon exposure to molecular iodine.4 The
2,5-cis relationship of the a-substituents in muscarine 1
appeared to demand that the application of such elec-
trophile-driven methodology to its synthesis would
necessitate a similar cyclisation but of a suitably substi-
tuted (Z)-homoallylic alcohol, e.g. 4. Unfortunately,
our model studies4 revealed that such reactions were
quite inefficient while still exhibiting high stereocontrol
in favour of the all-cis-isomers (Scheme 1).5 However,
further studies showed that incorporation of an addi-
tional hydroxy group which would eventually be posi-
OH
MeCN, 0-200C
O
2
3 [> 90%]
I
I2, NaHCO3
R1
R1
R2
O
R2
OH
MeCN, 0-200C
4
5 [< 50%]
Scheme 1.
HO
R
HO
R
I
I2, NaHCO3
tioned at one of the b-sites in
a
product
n-alk
OH
MeCN, 0-200C
O
iodotetrahydrofuran greatly enhanced the viability of
n-alk
6
7
* Corresponding author.
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01518-6

6772
D. W. Knight, E. R. Staples / Tetrahedron Letters 43 (2002) 6771–6773
final purification was so much easier. The final product
OTBDPS
H
OTBDPS
12b exhibited spectroscopic and analytical data identi-
cal to those previously reported.9 In particular, there
was good agreement between the observed optical rota-
tion {[h]2D0 −5.8 (c 0.5, CHCl3)} and the reported values
{lit.9 [h]D20 −6.0 (c 0.5, CHCl3)}. The diol 12b has been
converted efficiently into (+)-muscarine tosylate (1; X=
OTs) by sequential selective tosylation of the primary
alcohol and thermolysis with trimethylamine in
methanol at 80°C.9 Hence, the foregoing approach
represents a nine-step synthesis of (+)-muscarine 1
starting from methyl (S)-lactate.
O
H
H
i)
HO
HO
OTBS
H
OTBS
OTBS
H
8
9
10
ii)
HO
HO
I
iii)
OTBDPS
H
I
TBS
13
O
O
HO
OR
OTBDPS
O
12 a) R = TBDPS
b) R = H
11
H
Scheme 3. Reagents and conditions: (i) H2, 5% Pd–CaCO3,
quinoline, MeOH, 20°C, 1 h; (ii) IBr (2 equiv.), MeCN,
−10°C, 5 h; (iii) H2, 5% Pd–C, Et3N, MeOH, 20°C, 5 h, then
NH4F, MeOH, 20°C, 12 h.
The origin of the excellent level of stereoselection
observed in the key cyclisation step presumably lies in
the transition state conformation 13 in which both
substituents (HO and Me) are positioned equatorially.
It remains unclear whether the additional hydroxyl
group exerts any more subtle effects, as the excellent
yield of the cyclised product 11 is in extreme contrast to
those obtained from simple (Z)-homoallylic alcohols 4.4
Whatever the explanation conformation 13 should at
least provide a model suitable for use in future syn-
thetic planning.10
know that O-protection was necessary, as unmasked
allylic alcohols undergo partial oxidation to the corre-
sponding enals when exposed to iodine. We elected to
use a large silicon based group for this necessary pro-
tection in the hope that this would be compatible with
the iodocyclisation conditions. Herein, we report a
successful outcome to these ideas.
Beginning with methyl (S)-lactate, the O-silyl aldehyde
8 was prepared in two efficient steps by sequential
O-silylation (TBSCl, imidazole, DMAP (cat.), THF, 12
h, 20°C, 97%) and Dibal-H reduction (Et2O, −78°C to
+20°C, 3 h, 97%). Non-chelation controlled and hence
highly anti-selective addition of lithiated O-TBDPS
propargyl alcohol (BuLi, 12-crown-4, −78°C, 4 h)6
favoured formation of the yne-diol 9 (ca. 85:15), which
was obtained as a single enantiomer in 60–65% yields
following column chromatography (Scheme 3). Lindlar
reduction (5% Pd–CaCO3, quinoline, MeOH, H2 (1
atm.), 20°C, 1 h, 90%) then provided the key anti-(Z)
cyclisation precursor 10.
Acknowledgements
We are grateful to Mr. R. Jenkins for help in obtaining
analytical and spectroscopic data and Cardiff Univer-
sity for financial support.
References
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the use of iodine monobromide in place of iodine in
acetonitrile at −10°C for 5 h and direct reaction of the
O-silyl derivative 10, rather than the corresponding free
alcohol, thereby obviating the need for an additional
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D. W. Knight, E. R. Staples / Tetrahedron Letters 43 (2002) 6771–6773
6773
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