Synthesis of (+)- and (?)-Geissman-Waiss lactone from chiral sulfonium salts

Article abstract of DOI:10.1016/j.tetlet.2020.151697

A novel series of chiral cyclic zwitterionic pyrrolidinone type intermediates was prepared via regioselective 5-exo-trig-ring-closure of the corresponding chiral sulfonium salts. This synthetic strategy allowed the rapid non-racemic synthesis of the Geissman-Waiss lactone in six steps and 35% overall yield.

Full text of DOI:10.1016/j.tetlet.2020.151697

Tetrahedron Letters 61 (2020) 151697
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Tetrahedron Letters
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Synthesis of (+)- and (À)-Geissman-Waiss lactone from
chiral sulfonium salts
Ricardo López-González a, Dino Gnecco a, Jorge R. Juárez a, María L. Orea a, Victor Gómez-Calvario a,
Sylvain Bernès b, David M. Aparicio a, Joel L. Terán a,
⇑
a Centro de Química, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Edif. IC9 Complejo de Ciencias, C.U., 72570 Puebla, Mexico
b Instituto de Física, Benemérita Universidad Autónoma de Puebla, Edif. IF2, Lab 104, C.U., 72570 Puebla, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of chiral cyclic zwitterionic pyrrolidinone type intermediates was prepared via regioselec-
tive 5-exo-trig-ring-closure of the corresponding chiral sulfonium salts. This synthetic strategy allowed
the rapid non-racemic synthesis of the Geissman-Waiss lactone in six steps and 35% overall yield.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 29 November 2019
Revised 24 January 2020
Accepted 30 January 2020
Available online 1 February 2020
Keywords:
Cyclic zwitterion
Pyrrolidinone
Enantiospecific
Geissman-Waiss lactone
Introduction
piperidine compounds starting from sulfonium salts derived from
chiral primary amines (Scheme 1, top) [13]. Following on from this
Pyrrolizidine alkaloids, specifically those that contain the 1-
hydroxypyrrolizidine core, known as ‘necine base’ alkaloids are
found in many plant families [1] and have shown a wide range of
biological activities such as anticarcinogenic, antitumor, antispas-
modic, hypotensive and anti-inflammatory (Fig. 1) [2].
work and motivated by the importance of the development of
novel strategies for the synthesis of necine alkaloids, we present
herein a novel synthetic route to GWL highlighting the preparation
of new cyclic zwitterionic pyrrolidine compounds, which were pre-
pared via regiospecific ring-closure of sulfonium salts (Scheme 1,
bottom).
In this sense, the Geissman-Waiss lactone (GWL: 2-oxa-6-
azabicyclo[3.3.0]octan-3-one) [3] has proved to be a key interme-
diate for the synthesis of a variety of pyrrolidine alkaloids with a
necine scaffold. Accordingly, a number of synthetic strategies to
GWL have been reported starting from 4-hydroxy-ʟ-proline [4],
carbohydrates [5] N-protected amino acids [6] and (R)-(+)-malic
acid [7], via enzymatic reduction of keto-proline [8] or by microbial
Baeyer-Villiger oxidation of N-Cbz-2-aza-bicycloheptanone.[9]
Methodologies for the diastereoselective syntheses of (+)- and
(À)-GWL are based on the [2 + 2] cycloaddition reactions of ene
carbamates in the presence of chiral auxiliaries [10], through
selective reductive alkylation of protected (S)-malimide [11] and
via intramolecular CAH insertion reactions of (R)-N-Cbz-3-
hydroxypyrrolidine diazoacetates promoted by a chiral Rh(II)
catalyst [12].
Results and discussion
The inseparable diastereomeric mixture of chiral sulfonium
salts from trans-fumarate and primary chiral amines (S)-
a-methyl-
benzylamine 5(a + b) and (R)-4-methoxy- -methylbenzylamine 6
a
(a + b) were prepared following our previously reported reaction
conditions [12]. We also prepared enantiopure sulfonium salts 7
and 8 from ʟ-aspartic acid (Scheme 2) [14].
The intramolecular ring-closure reaction was investigated with
the inseparable diastereomeric mixture of sulfonium salts 5(a + b)
in the presence of KOH in CH3CN:MeOH (9:1) at room temperature.
The exclusive formation of diastereomeric cyclic zwitterionic
pyrrolidine-2-one 9(a + b) was unambiguously determined by 1H
and 13C NMR and 2D HMBC spectroscopy. Typical benzylic protons
at approximately dH 5.47 ppm [15], the S-Me singlet at dH 3.01 ppm
and the ylide carbon resonance at dC 67 ppm [16] confirmed the
presence of the sulfur ylide compound (Scheme 3).
In a previous report we disclosed a methodology for the synthe-
sis and synthetic applications of new chiral cyclic zwitterionic
⇑
Corresponding author.
E-mail address: joel.teran@correo.buap.mx (J.L. Terán).
https://doi.org/10.1016/j.tetlet.2020.151697
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
R. López-González et al. / Tetrahedron Letters 61 (2020) 151697
Fig. 1. Representative pyrrolidine alkaloids isolated from plants.
Scheme 3. Regiospecific 5-exo-trig ring-closure of sulfonium salts 5(a + b) and
diagnostic signals for unequivocal assignment of the sulfur ylide pyrrolidine-2-one
compounds through HMBC correlations.
Scheme 1. Previous studies on the synthesis and reactivity of cyclic zwitterionic
intermediates and the current synthetic studies of related compounds.
Scheme 4. Chiral cyclic pyrrolidine-2-one zwitterionic structures.
Table 1
Screening experiments for the desulfurization-reduction-lactonization tandem
reaction.
S
O
O
H2, catalyst ( mol %),
EtOH,
N
CH3
O
EtO
N
CH3
O
rt, time
O
Scheme 2. Synthesis of diastereomeric mixtures of sulfonium salts 5(a + b) and 6
(a + b) and enantiopure sulfonium salts 7 and 8.
O
14(a+b)
9(a+b)
Then, the diastereomeric mixture of sulfonium salts 6(a + b)
and enantiopure sulfonium salts 7 and 8 were subjected to the
optimized reaction conditions affording the desired cyclic zwitteri-
onic intermediates 10(a + b), 11 and 12. Fortunately, compound 12
provided suitable crystals for X-ray crystallographic analysis to
Entry
Catalyst (mol%)
Time [h]
Yield [%]
1
2
3
4
Pd/C (20% mol)
PtO2 (20% mol)
Raney-Ni[a]
48
96
72
120
35
40
Raney-Ni[a]
confirm the presence of
(Scheme 4) [17].
a cyclic pyrrolidine-2-one structure
[a]
Raney-Ni slurry 50% in water was used.
Next, the desulfurization reaction of the diastereomeric mixture
of cyclic zwitterions 9(a + b) was studied. Initially the reaction was
conducted using Pd/C as the catalyst in EtOH according to our pre-
viously reported reaction conditions (Entry 1, Table 1) [13]. Unfor-
tunately, the starting material remained unchanged even after
prolonged reaction time. The use of PtO2 also proved to be unsuc-
cessful (Entry 2, Table 1). Surprisingly, when Raney-Ni catalyst was
used, not only did the desulfurization reaction occur but also the

R. López-González et al. / Tetrahedron Letters 61 (2020) 151697
3
desired reduction and lactonization proceeded in low yield to give
14(a + b). Prolonged reaction times and increasing the amount of
the catalyst did not significantly improve the yield (Entries 3 and
4, Table 1).
Due to the low yield observed in the tandem reaction, reduc-
tive desulfurization of 9(a + b) was promoted using Zn (15
equiv.) in acetic acid [18]. Once the total consumption of start-
ing material was confirmed by TLC, NMR analysis of the crude
reaction revealed the presence of the corresponding tetramic
acid 13(a + b). Unfortunately, this intermediate proved to be
unstable under SiO2 chromatographic conditions, and conse-
quently the crude reaction was directly subjected to ketone
reduction with NaBH4 (2 equiv.) in AcOH:CH2Cl2 (1:9). The
NMR spectrum of the crude reaction revealed the presence of
a diastereomeric mixture of bicyclic lactones 14(a + b) in a
30:70 diastereomeric ratio. Once the diastereomeric mixture
was separated, each diastereoisomer crystalized enabling the
determination of the new stereogenic centres as (S,S)- for the
minor diastereoisomer 14a and (R,R)- for the major diastereoiso-
mer 14b (Scheme 5) [17].
With bicyclic lactone amides 14a and 14b in hand, we pro-
ceeded to complete the total synthesis of (À)- and (+)-GWL. The
´
major diastereoisomer 14b was reacted with Lawessons reagent
(LR) to produce the desired thioamide 15b in 95% yield. X-ray crys-
tallographic analysis confirmed the molecular structure of 15b
[17]. Subsequent thioamide reduction with Raney-Ni catalyst
afforded 16b [17] which provided (+)-GWL HCl [17] after debenzy-
lation. On the other hand, following the same procedure as for 14b,
(À)-GWLÁHCl was obtained in 42% overall yield from thioamide
15a [17] (Scheme 6).
Scheme 6. Syntheses of (À)- and (+)-GWL.
Encouraged by the results described above, this approach
was applied to the enantiospecific synthesis of (À)-GWL starting
from cyclic zwitterion 11 derived from ʟ-aspartic acid. Accord-
ingly, the sequential desulfurization-reduction-lactonization
reaction afforded the desired bicyclic lactone 17 [17] which
was subsequently treated with LR to give thioamide 18 [17].
Then, reduction of the thioamide function with Raney-Ni and
subsequent hydrogenolysis gave (À)-GWLÁHCl. In addition, 17
could be reduced and debenzylated following the sequence
reaction reported by Huang [11] to afford (À)-GWLÁHCl
(Scheme 7).
Next, cyclic zwitterion 12 derived from NPMB protected
ʟ-aspartic acid was subjected to an optimization process, affording
the enantiopure bicyclic lactone 20 [17]. Then oxidative debenzy-
lation with ammonium nitrate (CAN) furnished the valuable
intermediate 21 [17], from 20 (Scheme 8).
Scheme 7. Enantiospecific synthesis of (À)-GWL.
Scheme 5. Sequential process to access bicyclic lactones 14a and 14b, and their X-
ray crystal structures.
Scheme 8. Synthesis of bicyclic lactone amide derived from enantiopure zwitterion
12.

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R. López-González et al. / Tetrahedron Letters 61 (2020) 151697
(1992) 3255–3257;
Conclusion
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by a dehydrosulfurization–reduction–lactonization sequence pro-
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We are grateful to VIEP-BUAP and CONACyT (Project A1-S-
13280 and 268178) for financial support. RLG thanks to CONACyT
for the scholarship (461532). We thank M.I. Ana Line García-Torres
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151697.
References
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