Blue light photoredox decarboxylation and tin-free Barton-McCombie reactions in the stereoselective synthesis of (+)-muscarine

Article abstract of DOI:10.1016/j.tetlet.2018.12.058

Starting from a 1,2-O-isopropylidene-α-D-xylofuranose derivative, a non-toxic free-radical approach for the synthesis of (+)-muscarine is reported. To this end, a stereoselective allylation reaction at the anomeric position of a respective xylofuranose de

Full text of DOI:10.1016/j.tetlet.2018.12.058

Accepted Manuscript
Blue Light Photoredox Decarboxylation and Tin-Free Barton-McCombie Re-
actions in the Stereoselective Synthesis of (+)-Muscarine
Victoria Rodríguez-Tzompanzi, Leticia Quintero, Dulce M. Tepox-Luna,
Silvano Cruz-Gregorio, Fernando Sartillo-Piscil
PII:
S0040-4039(18)31509-0
https://doi.org/10.1016/j.tetlet.2018.12.058
TETL 50521
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2018
19 December 2018
24 December 2018
Please cite this article as: Rodríguez-Tzompanzi, V., Quintero, L., Tepox-Luna, D.M., Cruz-Gregorio, S., Sartillo-
Piscil, F., Blue Light Photoredox Decarboxylation and Tin-Free Barton-McCombie Reactions in the Stereoselective
Synthesis of (+)-Muscarine, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.058
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Blue Light Photoredox Decarboxylation and Tin-Free
Barton-McCombie Reactions in the Stereoselective
Synthesis of (+)-Muscarine
Victoria Rodríguez-Tzompanzi, Leticia Quintero, Dulce M. Tepox-Luna, Silvano Cruz-Gregorio, * and
Fernando Sartillo-Piscil.*
Centro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de
Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570, Puebla, México.
*To whom correspondence should be addressed (fernando.sartillo@correo.buap.mx and
silvano.cruz@correo.buap.mx) Telephone:+52 222 2955500 ext. 7391. Fax number: + 52 222 2454972
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
KEYWORDS Photoredox reaction, free radicals, chiron approach, C-glycosylation

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Abstract: Starting from a 1,2-O-isopropylidene-D-xylofuranose derivative, a non-toxic free-radical
approach for the synthesis of (+)-muscarine is reported. To this end, a stereoselective allylation reaction
at the anomeric position of a respective xylofuranose derivative was employed as a new synthetic
strategy for the installation of the methyl group at the C-5 position of (+)-muscarine. Accordingly, the
allyl group was transformed into the methyl group in three sequential steps highlighting a blue-light
photoredox decarboxylation reaction. Additionally, a tin-free Barton-McCombie deoxygenation reaction
of the respective C-methyl glycoside allowed the completion of this free-radical approach to (+)-
muscarine.
The (+)-muscarine is a tetrahydrofuran-derived-alkaloid isolated by Shcmiedeberg and Richard in
1869 from Amanita Muscaria, a mushroom that grows in autumnal woods.1 Later, it has been isolated
from other species of mushrooms, mainly of Inocybe and Clitocybe species.2 Due to its physiological
activity on the peripheral nervous system,3 the (+)-muscarine is one of the most exciting and dangerous
natural occurring alkaloids.4 Furthermore, the best biological property of (+)-muscarine is that is a good

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agonist of acetylcholine receptor (muscarinic acetylcholine receptors);5 and a wide range of therapeutic
properties have been suggested. Therefore, chemist´s efforts for developing new methods and synthetic
strategies for preparing, not only (+)-muscarine but also all the eight possible stereoisomers, still remain
in force.6
Figure 1. (+)-Muscarine
Although several syntheses to (+)-muscarine and stereoisomers have been reported, which would
result in a number around 30,7 a highly recommendable strategy is the use of the chiron approach, in
which amino acids and carbohydrates are the selected starting materials.7o-aa From all of them, the
stereoselective elaboration of the tetrahydrofuran ring with the correct stereochemistry at the C-5 center
is the key step. In this regard and taking advantages from the synthetic methodology in the rapid
functionalization of furanose carbohydrates to tetrahydrofuran-derived natural products via a
stereoselective nucleophilic substitution at the anomeric position (NSAP),8 we visualized the synthesis
of the (+)-muscarine via the construction of the (5S)-methyl-tetrahydrofurane skeleton from simple
xylofuranose derivative (Scheme 1).
Scheme 1. Chiron approach featuring the stereoselective functionalization of furanose carbohydrates to
tetrahydrofuran-derived natural products

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As shown in Scheme 1, the rational use of the NSAP reaction enabled the rapid functionalization of
the allyl group into either a -lactone fragment of 7-epi-goniofufurone,7a,c Hagen´s gland lactones,7b and
cephalosporolide E,7f or being part of the carbon chain extension of 2-epi-jaspine B.7e Now, from a
furanose carbohydrate derivative (e. g., A), we envisaged the use of the stereoselective NSAP to form C-
glycoside derivative B which would be transformed into C-methyl glycoside C via a sequential double
bond oxidative dehomologation/radical decarbonylation process. Thus, the synthesis of (+)-muscarine
would be practically accomplished after radical deoxygenation of C to D (Scheme 2).
Scheme 2. Synthesis plan to (+)-Muscarine
The synthesis of (+)-muscarine commenced when dibenzylated D-xylofuranose derivative 1 was
treated with allyltrimethylsilane in the presence of BF3•OEt2 in CH2Cl2 at 0 °C to form C-glycoside 2 in

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high yield.8b,9 The high stereoselectivity can be rationalized by the Woerpel´s “inside attack” model”,
which predicts the formation of the 1,3-cis-stereoisomers in xylofuranose derivatives.10,8e Hydroxyl
group of 2 was protected with tert-butyldimethylchlorosilane (TBSCl) (3) before to subject the double
bond to an adapted ozonolysis/Pinnick oxidation to carboxylic acid 4, which was transformed into both,
ester Barton 5 with 2-mercaptopyridine N-oxide in the presence of N,N’-dicyclohexylcarbodiimide
(DCC),11 and N-acyloxyphthalimida 6 with N-hydroxyphthalimide and DCC in the presence of catalytic
amounts of 4-dimethylaminopyridine (DMAP)12 (Scheme 3).
The ester Barton 5 was exposed to a white-light photolysis (150 W tungsten lamp)13 for 2 h in CHCl3
as solvent and hydrogen atom donor, and the expected product 8 was obtained in low yield (20%) along
with two pyridyl sulfide side-products 9a and 9b, which we couldn´t isolate them with significant
purity. Chemical yield of 8 was not considerably improved even when nBu3SnH was used, albeit the
presence of byproducts 9a and 9b was reduced.
Scheme 3. Synthesis of C-methyl glycoside 8 from 1,2-O-isopropylide-D-xylofuranose derivative 1

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On the other hand, room temperature irradiation of N-acyloxyphthalimida 6 with blue-LEDs in the
presence of 1 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF6 catalyst and two equivalents of Hantzsch ester as
electron and hydrogen atom donor,12,14 provided a clean reaction crude, which after column
chromatography, yielded the desired product 8 in good yield (70% from carboxylic acid 4). Further
efforts for reaction optimization were unsuccessful; for instances, photoredox catalyst Ru(bpy)3(PF6)2
was not effective.
Having the C-glycoside 8 in hands, efforts were focused on the deoxygenation at the C-3 position of
8. An adapted Barton-McCombie-photoredox reaction of cyclic thiocarbonate 10 was explored.15
Radical precursor 10 was prepared in two-steps from 8. First, debenzylation reaction with H2 and
Pd(OH)2 gave 11 quantitatively, which was treated with 1,1’-thiocarbonyldiimidazole (TCDI) in the
presence of DMAP (Scheme 3). Unfortunately, photoredox experiments showed that cyclic

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thiocarbonate 10 was unreactive with both Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ru(bpy)3(PF6)2. Similar
result was observed with triethylborane and oxygen. Although under classical tin-radical conditions
provided the expected deoxygenated product 12 in good yield,16 the non-toxic approach of this synthesis
forced us to seek another less-contaminant strategy. Consequently, diol 11 was selectively tosylated to
13, and then acyclic thionocarbamate 14 was prepared and exposed to radical photoredox and Et3B/O2
radical conditions (Scheme 4).
Scheme 4. Deoxygenation at the C-3 position and completion of the synthesis of (+)-muscarine
As for cyclic thiocarbonate 10, photoredox catalysts were ineffective to promote radical
deoxygenation of thioimidazole 14; however, by using the Oshima´s radical conditions (Et3B/O2 in a
H2O/i-PrOH mixture),17 deoxygenated product 15 was obtained in good yield. Subsequent removal of
the silyl protecting group to 16 with BF3•OEt2 followed by substitution of tosyl group by triethyl amine,
according to known procedure,7m the synthesis of (+)-muscarine was accomplished (Scheme 4).
In summary, starting from simple xylofuranose derivative, a non-toxic-free-radical approach to (+)-
muscarine was developed. From which, an elegant way to elaborate the C-5 methyl group of the
muscarine tetrahydrofurane skeleton from the respective C-allyl glycoside is highlighted. This synthesis
strategy provides a new way to access to biologically important C-methyl glycosides.
AUTHOR INFORMATION

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*E-mail: fernando.sartillo@correo.buap.mx; silvano.cruz@correo.buap.mx
SUPPLEMENTARY MATERIAL
Procedures and NMR characterization of relevant products are provided.
CONFLICTS OF INTEREST
There are no conflicts to declare
ACKNOWLEDGMENTS
Financial support was provided by the CONACyT. V. R. T. acknowledge CONACyT for graduate
scholarship. Partial support from BUAP-VIEP.
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Blue Light Photoredox Decarboxylation and Tin-Free Barton-McCombie Reactions in the
Stereoselective Synthesis of (+)-Muscarine
Victoria Rodríguez-Tzompanzi, Leticia Quintero, Dulce M. Tepox-Luna, Silvano Cruz-Gregorio, and
Fernando Sartillo-Piscil

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Highlights
 Photoredox reaction in the synthesis of a bioactive alkaloid
 New synthetic strategy to C-methyl glycosides
 Use of the stereoselective Nucleophilic Substitution at the Anomeric Position (NSAP).
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