Enantioselective Ammonium Ylide Mediated One-Pot Synthesis of Highly Substituted γ-Butyrolactones

Article abstract of DOI:10.1002/adsc.202000039

An ammonium ylide mediated access towards trans-β,γ-disubstituted, all-trans-α,β,γ-trisubstituted, and α,α,β,γ-tetrasubstituted γ-butyrolactones bearing a broad variety of functionalities was developed. Starting from widely accessible benzylidene Meldrum's acid derivatives and α-bromo carbonyl compounds, γ-butyrolactones were obtained in yields between 32–99% with up to excellent diastereoselectivities (>95:5) via a DABCO-mediated [2+1] annulation. Utilization of enantiomerically pure cinchona alkaloid derivatives enables the first asymmetric ammonium ylide mediated method to provide (3R,?4R)-β,γ-disubstituted and (2R,?3R,?4R)-α,β,γ-trisubstituted γ-butyrolactones in moderate to good yields with up to very good enantiomeric ratios (97:3). The scalability of the transformation was proven while determining the absolute configuration. (Figure presented.).

Full text of DOI:10.1002/adsc.202000039

Title: Enantioselective Ammonium Ylide Mediated One-Pot Synthesis
of Highly Substituted γ-Butyrolactones
Authors: Till Drennhaus, Laura Öhler, Saveh Djalali, Svenja Höfmann,
Clemens Müller, Jörg Pietruszka, and Dennis Worgull
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000039
Link to VoR: http://dx.doi.org/10.1002/adsc.202000039

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Ammonium Ylide Mediated One-Pot Synthesis
of Highly Substituted γ-Butyrolactones
Till Drennhaus,b§ Laura Öhler,a§ Saveh Djalali,a Svenja Höfmann,a Clemens Müller,a
Jörg Pietruszka,a,b* and Dennis Worgulla*
a
Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf located at Forschungszentrum Jülich,
Stetternicher Forst, Building 15.8, 52426 Jülich (Germany)
Phone: +49-2461-614158, Fax: +49-2461-616196, E-mail: j.pietruszka@fz-juelich.de, DennisWorgull@gmx.net
Institute of Bio- and Geosciences (IBG-1), Forschungszentrum Jülich, 52426 Jülich (Germany)
b
§
Both authors contributed equally.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An ammonium ylide mediated access towards alkaloid derivatives enables the first asymmetric
trans-β,γ-disubstituted-, all-trans-α,β,γ-trisubstituted-, and ammonium ylide mediated method to provide (3R,4R)-β,γ-
α,α,β,γ-tetrasubstituted γ-butyrolactones bearing a broad disubstituted
and
(2R,3R,4R)-α,β,γ-trisubstituted
γ-
variety of functionalities was developed. Starting from butyrolactones in moderate to good yields with up to very
widely accessible benzylidene Meldrum’s acid derivatives good enantiomeric ratios (97:3). The scalability of the
and α-bromo carbonyl compounds, γ-butyrolactones were transformation was proven while determining the absolute
obtained in yields between 32–99% with up to excellent configuration.
diastereoselectivities (>95:5) via a DABCO-mediated [2+1]
annulation. Utilization of enantiomerically pure cinchona
Keywords: Asymmetric synthesis; Asymmetric Catalysis;
Heterocycles; Lactones; Multicomponent reactions; Ylides.
Based on the demand, a broad variety of synthetic
approaches towards γ-butyrolactones has been
reported to date,[10b, 10c, 13] employing, e.g., transition
metal-,[14] organo-[15,14i] or enzyme[16] catalysis. Until
now, downsides of many methods imply often lavish
starting material synthesis or harsh reaction
conditions not tolerated by certain functional groups.
Alternative approaches employing “onium ylides”
for the synthesis of substituted γ-butyrolactones are
published in literature:[17] Cao et al. first reported a
diastereoselective synthesis of trans-β,γ-disubstituted
γ-butyrolactones, utilizing stoichiometric amounts of
arsonium ylides starting from benzylidene Meldrum’s
acid derivatives and preformed α-bromo carbonyl
arsonium salts.[17a,c] Chen et al. broadened the scope
of Michael acceptors[17e] and Wu & Cao et al.
displayed diversity in α-bromo carbonyl donors
(Scheme 1a).[17b] Closing it onto analogous nitrogen-
based reactions, Liang and co-workers[17f] reported
the ammonium ylide mediated method towards trans-
β,γ-disubstituted γ-butyrolactones. However, this is
limited to a sophisticated, yet singularly appearing
ferrocenyl substituent within the acceptor system
(Scheme 1b). Lastly, the formation of several
trisubstituted all-trans-γ-butyrolactones again using
arsonium ylides was reported by Wu et al.[17b]
applying a similar method as described previously
now employing additional alcohols as nucleophiles
(Scheme 1c).
Introduction
The use of ylides plays an important role in organic
synthesis. While phosphorus and sulfur ylides have
been exploited extensively in the past,[1] ammonium
ylides have attracted considerably less attention. Still,
pioneering work of Gaunt et al. described ammonium
ylides
in
diastereo-
and
enantioselective
cyclopropanation reactions,[2] and also three- and
five-membered heterocycles were synthesized,[3]
including aziridines and epoxides,[4] isoxazoline
N-oxides,[5] pyrazoles,[6] pyrroles,[7] spirocyclic
oxindoles[8] and dihydrofurans.[9]
γ-Butyrolactones constitute a valuable structural
motif, which is found in a myriad of natural
products[10] of which several exhibit interesting
biological activities,[11] including antitumor and
antibiotic properties (Figure 1).[12]
Figure 1. Selected examples of trans-γ-butyrolactone-
containing natural products.
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
Results and Discussion
In order to establish an initial catalytic protocol, we
examined the diastereoselective reaction of the, via
Knoevenagel condensation formed,[18] Michael
system 1a and α-bromoacetophenone (2a) in the
presence of catalytically active DABCO on the basis
of literature examples.[17] To our delight, the β,γ-
disubstituted-γ-butyrolactone 3a was obtained in 47%
yield as single trans-diastereoisomer after 24 h. We
then set out to optimize the reaction conditions. The
results are summarized in Table 1. Since water is
essential for the reaction (Table 1, entry 2), we
systematically varied the equivalents of water (entries
1–5). The highest conversion was observed with
5.0 equiv. of water. Next, the catalyst loading was
varied, which showed an increase in conversion with
higher amounts (entries 6–9). Stoichiometric amounts
of DABCO did not lead to higher conversions (entries
3+10). Further, the reaction time could be shortened
to two hours when conducting the reaction at 60 °C
instead of 40 °C (21 h) (entries 11–12). 3.0 equiv. of
base gave a higher conversion than 1.5 equiv., but a
higher loading decreased the conversion (entries 13–
14). In order to suppress the formation of byproducts,
the amount of 2a was reduced from 1.5 to 1.1 equiv.
(entry 14). When 1a and 2a were added in 4 portions
over time, the highest conversion (89%) towards
γ-butyrolactone 3a was observed after 2 h, which we
used in further reactions (entry 15).
Table 1. Screening of reaction conditions for the catalytic
trans-β,γ-disubstituted-γ-butyrolactone formation.
Scheme 1. Ylide-mediated syntheses of γ-butyrolactones.
All approaches can be rendered straightforward
granting access to densely functionalized molecules
from simple starting materials. However, from an
ecological and economical point of view, the use of
toxic arsenic compounds in stoichiometric amounts
for the provision of most given procedures in
literature is an addressable issue. The use of non-
toxic ammonium ylides as demonstrated by Liang
and co-workers reveals a practical solution to the
problem, albeit diversity concerning the Michael
systems being used may be considered. Ultimately, to
the best of our knowledge neither catalytic, nor
asymmetric approaches towards trans-substituted
y-butyrolactones using ylides are reported in
literature at all. Due to the troublesome toxicity and
generally low availability of chiral tertiary arsenic
compounds, alternatives prove inevitable for facing
the aforementioned challenges. With the abundance
of inexpensive non-chiral and chiral tertiary amines
such as alkaloids, investigations into a more general,
less toxic, catalytic and particularly enantioselective
preparation of di- and trisubstituted γ-butyrolactones
appeared to be a worthwhile endeavor to us.
Furthermore, with the in situ preparation of the
ammonium salt step-economic issues are served
(Scheme 1d).
entry
H2O
catalyst
(mol%)
time
(h)
product[a]
(%)
(equiv.)
1
2
3
4
5
6
7
8
2.5
–
5.0
10
20
20
20
20
20
2.5
5.0
10
15
150
20
20
20
20
20
24
24
24
24
24
23
23
23
23
23
21
2
47
–
56
42
42
11
17
26
37
44
52
42
50
66
89
50
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
9
10
11[b]
12[c]
13[b,c]
14[b,c,d]
2
2
2
15[b,c,d,e] 5.0
[a]
All reactions were conducted on
a 0.1 mmol scale.
Quantification via 1H NMR spectroscopy with DMF as an
[b]
[c]
internal standard. Reaction conducted with 3.0 equiv. base.
Reaction conducted at 60 °C. [d] Reaction conducted with 1.1
equiv. 2a. [e] 1a and 2a were added in portions, see SI for details.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
Scheme 2. Scope of the trans-β,γ-disubstituted γ-butyrolactone 3 synthesis. Diastereoselective reactions were conducted on a 0.25 mmol
scale, all d.r. >95:5. Michael system 1 and donor 2 were added in 4 portions. For the enantioselective transformation, C1 was employed
(e.r. determined by HPLC utilizing chiral stationary phases). [a] Yield of isolated product. [b] 0.10 mmol scale. [c] Reaction was catalyzed
with C24 (2 h). [d] 1.0 mmol scale.
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
With these optimized reaction conditions in hand,
we turned our attention towards the scope of the
method (Scheme 2). 11 Michael systems 1a–k
containing
different
substituents,
including
heteronuclear and vinylogous aromatic systems were
converted in good to excellent yields. The trans-
diastereomers (d.r. >95:5) were formed exclusively,
1
as identified via the corresponding H NMR spectra
in comparison with the literature known
trans-γ-butyrolactone 3aa.[19] The electron poor
Michael systems 1f and 1l remained on the level of
cyclopropanes, as their formation can be reasoned by
the proposed catalytic cycle (vide infra, Scheme 4).
However, the phenyl-substituted cyclopropane 4a
could be converted to the corresponding
γ-butyrolactone 3m after elongated reaction times
(6 days). Hydrolysis of Michael systems 1 might
explain the diminished yields for some examples
upon prolonged reaction time. Signals in the
1
corresponding crude H NMR spectra indicate the
presence of free aldehyde to a greater or lesser extent,
which led to the formation of various byproducts.
For the cases tested, α-bromoacetophenone (2a)
could successfully be replaced by substituted
4-methoxy- (2b) and 4-bromo-α-bromoacetophenone
(2c), or 2-(2-bromoacetyl) thiophene (2d)[20] leading
to the desired products 3a–aa in comparable yields
and without loss of any diastereoselectivity (Scheme
2). Furthermore, an access to nitrile 3ab and ester
functionalized γ-butyrolactones 3ac was enabled by
the use of bromoacetonitrile (2e) or 2,2,2-
trifluoroethyl bromoacetate (2f) as donors (Scheme 2)
or by Baeyer-Villiger oxidation of lactone 3o to ester
3ad in a subsequent reaction (Scheme 3).
Scheme 4. Proposed mechanism of lactone formation.
Due to the broad occurrence of γ-butyrolactone
moieties
bearing
configurationally
defined
substituents in natural products, the approach was
extended towards the first enantioselective catalytic
“onium” ylide mediated method. Based on our
previous work[9e] we applied cinchona alkaloid-
derivatives as chiral catalysts.
After screening of 34 catalysts[2c,8,9e,23] with the
electron-rich Michael acceptor 1g and 4-methoxy-α-
bromoacetophenone (2b) (Scheme 5), we established
a protocol obtaining good yields and up to excellent
enantiomeric ratios using adapted conditions with
longer reaction times as in the DABCO catalyzed
approaches. While the naturally occurring cinchona
alkaloids showed no conversion, we varied several
substituents on the chinolin-system and introduced
sterically demanding protecting groups for the
hydroxy- and amine-functionalities. The O-benzyl-
protected and 2′-methylated cinchonidine-derivative
C1, which we recently employed in the
enantioselective formation of dihydrofurans,[9e] gave
the best results regarding yield and enantiomeric
excess. Noteworthy, applying β-isoquinidine (C23)
the opposite trans-enantiomer was obtained with a
moderate enantiomeric ratio of 39:61.
Scheme 3. Baeyer-Villiger oxidation of γ-butyrolactone 3o.
Mechanistically, we assume in accordance to
known reports,[17] alkylation of the tertiary amine C
(diastereoselective:
DABCO,
enantioselective:
cinchona alkaloid derivative) with α-bromo carbonyl
compound 2, to form the ammonium salt I in situ.
After deprotonation to ylide II, it attacks the Michael
acceptor 1, which undergoes a cyclopropanation in a
[2+1] annulation as the key step of this approach.
Trans-substituted cyclopropanes 4 with an electron-
Subsequently, C1 was applied to examine the
scope of asymmetric β,γ-disubstituted γ-butyrolactone
formation (Scheme 2). The best enantiomeric ratio of
97:3 was obtained for the reaction with the 3,4-OMe-
disubstituted Michael system 1b and 4-methoxy-α-
bromoacetophenone (2b). For the substituted styrene
system 1k the enantioselectivity was decreased,
which can be attributed to the higher flexibility of the
substituent. In general, a more electron donating
character of used acceptors led to higher
enantioselectivities and mostly better yields. Lower
yields compared to the racemic approach might be
rich Ar1-substituent exhibit
a
donor-acceptor
a Cloke-Wilson
]
character.[21 This leads to
rearrangement[22] via the stabilized carbocation IV
under liberation of acetone and decarboxylation to
yield the β,γ-disubstituted γ-butyrolactone 3.
Electron-withdrawing Ar1-substituents led to stable
cyclopropanes 4, since the formation of carbocation
IV is not favorable (Scheme 4).[17b]
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
Scheme 5. Enantioselective screening of catalysts C. All reactions were carried out on a 0.10 mmol scale. [a] Yield of isolated product.
[b] Quantification via 1H NMR spectroscopy with DMF as an internal standard. [c] Product obtained with d.r. 3:1 (trans:cis). [d] 8.0 mol%
catalyst loading. [e] Opposite trans-enantiomer favored. [f] No more α-bromoacetophenone (2a) was added.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
attributed to longer reaction times at 60 °C leading to
partial decomposition of γ-butyrolactones and the
Michael acceptor (vide supra). In order to avoid
product degradation under these reaction conditions
over time and to obtain higher yields, β-isocupreidine
(C24) was used, which led to a dramatic shortening
of the reaction time (2 h), albeit the products were
obtained with a slightly reduced e.r. This rate
enhancement may be explained by the high
nucleophilicity of the tertiary amine, due to the
Altogether, we transferred our new method to the
first asymmetric “onium” ylide mediated formation
of (3R,4R)-β,γ-disubstituted γ-butyrolactones. The
scope was demonstrated by synthesizing 20
enantiomerically enriched γ-butyrolactones. It was
shown that mostly electron-rich donors and acceptors
led to high enantioselectivities in up to good yields.
Harnessing the full potential of our approach, we
turned our attention to the synthesis of all-trans-
α,β,γ-trisubstituted γ-butyrolactones 5. According to
the catalytic cycle proposed, the presence of an
alcohol should alter the course of the reaction.
Ultimately, decarboxylation in the last step would be
prevented by the formation of an ester following the
cleavage of the intermediate cyclopropane (Table 2,
Scheme 7).[17b] After a screening for adapted reaction
conditions, we found that lowering the amount of
water to 0.50 equiv., addition of 4.00 equiv. tert-butyl
alcohol (6a), heating at 60 °C and 2 h reaction time
resulted in the highest conversion (Table 2, entry 5).
reduced
steric
hindrance
reported
by
Hatakeyama et al.[23i] However, the usage of
stoichiometric amounts of the derivative preformed
chiral ammonium salt C31 did not led to any
formation of γ-butyrolactone 3n (Scheme 5). This is
consistent with the result of lower product formation
using stoichiometric amounts of DABCO as indicated
in the screening for reaction conditions (Table 1).
Therefore, further investigations were only performed
in a catalytic mode.
To test the general applicability of this asymmetric
method, we additionally demonstrated the scalability
of Michael system 1g with donor 2b on a 3.0 mmol
scale, which provided almost the identical yield (46%,
compared to 50%) and stable enantioselectivity
(86:14, compared to 87:13). The absolute
configuration of isolated γ-butyrolactones was
identified as (3R,4R) via chemical correlation withthe
optical rotary power of the known carboxylic acid
(3S,4S)-3af.[24] Therefore, lactone 3e was oxidized
under Baeyer-Villiger conditions to ester (3R,4R)-
3ae and was subsequently hydrolyzed providing
γ-butyrolactone 3af (Scheme 6). The measured
optical rotary power of [훼]2퐷5 +29.8 (c 1.0, MeOH)
proved the (3R,4R) configuration {literature value for
lactone (3S,4S)-3af: [훼]2퐷5 –29.4 (c 1.0, MeOH)}.[24]
Table 2. Screening of reaction conditions towards all-
trans-α,β,γ-substituted γ-butyrolactones 5.
entry HOtBu
H2O
(equiv.)
temp.
(°C)
time product[a]
(equiv.)
(h)
(%)
1
2
3
4
5
6
7
4
4
4
4
4
2
2
1
1
1
0.5
0.5
1
25
40
60
40
60
40
60
22
2
2
4
2
50
55
65
60
71
48
65
4
4
1
[a]
All reactions performed on a 0.25 mmol scale.
formation was determined by H NMR spectroscopy using DMF
as an internal standard.
Product
1
Having the conditions optimized, we again turned our
focus on the scope of the method (Scheme 7). Several
different trans-α,β,γ-trisubstituted γ-butyrolactones
containing aromatic and heteroaromatic moieties
were isolated in moderate to excellent yields of up to
92% and good to excellent diastereomeric ratios of up
to >95:5. In general, acceptor systems with higher
electron density led to excellent diastereomeric ratios
of the isolated product, whereas heteronuclear
aromatic substituents enabled higher yields with a
small decrease in diastereoselectivity. Beside tert-
butyl alcohol (6a), we showed that ethyl (6b),
benzyl (6c), allyl (6d), isopropyl (6e), and 2-furfuryl
alcohol (6f) were accepted in the reaction with
Michael system 1a and α-bromoacetophenone (2a)
leading to moderate to good yields and good to
excellent diastereoselectivities. In general, higher
Scheme 6. Determination of the absolute configuration of
lactone (3R,4R)-3e via chemical correlation.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
Scheme 7. Scope of the all-trans-α,β,γ-substituted γ-butyrolactone 5 synthesis. Above) Diastereoselective reactions were conducted on a
[a]
0.25 mmol scale. For the enantioselective transformation, C24 was employed. Yield of isolated product. [b] Reaction was carried out
[c]
on a 0.10 mmol scale. Reaction was catalyzed with C1. [d] e.r. determined after decarboxylation of malonic ester. Below) Proposed
mechanism of α,β,γ-substituted butyrolactone 5 formation.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
yields were obtained using alcohols, which provided
more base-stable esters. To test other donors 2, we
examined the reaction of 4-methoxy-(2b), 4-bromo
α-bromoacetophenone (2c) and 2,2,2-trifluoroethyl
bromoacetate (2f) with different Michael systems and
alcohols. To our delight, all reactions yielded the
desired products in good to excellent diastereomeric
ratios. The all-trans-relative configuration of
α,β,γ-trisubstituted γ-butyrolactones was determined
center are accessible, thus further demonstrating the
power of the initial MCR.
1
by comparison of the coupling constants from H
NMR spectroscopic evidence of literature-known
examples with X-ray-data.[17b,25]
Overall, we developed an effective synthetic route
towards
22
all-trans-α,β,γ-trisubstituted
γ-butyrolactones in an attractive multicomponent
reaction (MCR) using cheap and extensively
available starting materials with DABCO as catalyst.
To illustrate the synthetic usability and scalability of
this method we performed the reaction of Michael
system 1a with 4-bromo α-bromoacetophenone (2c)
and tert-butyl alcohol (6a) on a 3.00 mmol scale
obtaining a slightly decreased yield (54%, compared
to 66%) and diastereomeric ratio (93:7, compared to
>95:5) in comparison to the 0.25 mmol scale
reactions.
enantioselective version utilizing C1 and C24 for
selected examples provided enantiomerically
enriched (2R,3R,4R)-α,β,γ-trisubstituted
Furthermore,
application of the
9
γ-butyrolactones: Almost quantitative yield (99%)
was obtained for the trisubstituted lactone
(2R,3R,4R)-5k whereas the 4-methoxy- and phenyl-
substituted product (2R,3R,4R)-5a showed best
enantioselectivity (91:9). In general, the use of β-
isocupreidine (C24) led to higher yields with a
simultaneous decrease of the enantiomeric ratio
compared to catalyst C1, due to shorter reaction times
with thus less hydrolysis and decarboxylation of the
ester. (Scheme 7).
Conclusions
In summary, a highly diastereoselective method
applying DABCO-derived ammonium ylides in a
one-pot synthesis of trans-β,γ-disubstituted- and all-
Scheme 8. One-pot MCR towards tetrasubstituted
γ-butyrolactones. [a] Reaction carried out with no additional
base and by adding DMF in b) at 40 °C. Not a one-pot-
trans-α,β,γ-trisubstituted-γ-butyrolactones
was
developed. Via cinchona-derivative catalysis, the
extension to the first catalytic, enantioselective
γ-butyrolactone synthesis using ammonium ylides
was successfully established. Obviously, even higher
substituted lactones can be readily obtained: Inspired
by the work reported in literature,[14f,26] we were
[b]
synthesis: reaction started from 5i on 0.1 mmol scale.
Experimental Section
confident
that
highly
diastereoselective
α-derivatisation should be feasible in an one-pot-
approach. Preliminary experiments with Michael
system 1a and 4-bromo-α-bromoacetophenone (2c),
and various electrophiles 7[27] proved the assumption
as correct (Scheme 8). Furthermore, also α-hydroxyl
substituted γ-butyrolactone 8h was obtained in
quantitative yield when starting from lactone 5i after
only 10 minutes.[28] So finally, also tetrasubstituted γ-
butyrolactones bearing a quaternary stereogenic
General Experimental Considerations
All used chemicals were purchased from TCI International,
Sigma-Aldrich/Fluka, VWR International/Merck and Alfa
Aesar. Pure solvents were either purchased or distilled
prior to use. Dry solvents were either taken from a MBraun
drying machine (modelMB SPS-800) or distilled over
CaH2 or NaK alloy. Reactions under inert conditions were
performed using standard Schlenk-technique under dry
Ar/N2 atmosphere with magnetic stirring. NMR spectra
were recorded on a Bruker Advance DRX/600 spectrometer.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
1H NMR analysis were admitted at 600 MHz and 13C NMR
analysis were measured proton decoupled at 151 MHz.
Chemical shifts are reported in ppm relative to residual
K2CO3 (41.5 mg, 0.30 mmol, 3.00 equiv.) and 9-O-benzyl-
2´-methyl-cinchonidine (C1) (8.0 mg, 0.02 mmol, 20
mol%) were dissolved in CHCl3 (1.0 mL). DMF (7.7 µL,
0.10 mmol, 1.00 equiv., internal standard) and water (9 µL,
0.50 mmol, 5.00 equiv.) were added to the reaction mixture.
Michael system 1 (0.10 mmol, 1.00 equiv.) and bromo
donor 2 (0.11 mmol, 1.10 equiv.) were divided into 4
portions which were added each to the reaction mixture in
intervals of 3 h. The reaction was stirred at 60 °C and the
reaction was completed after 24 h, quenched saturated
aqueous NH4Cl solution and extracted with CH2Cl2 (3 ×
25 ml). The crude mixture was purified by flash column
chromatography to obtain the (3R,4R)-β,γ-disubstituted
γ-butyrolactone 3.
1
solvent signals (CDCl3: 7.26 ppm for H NMR and 77.16
1
ppm for 13C NMR; MeOD-d4: 4.87 ppm for H NMR and
49.00 ppm for 13C NMR). The multiplicity in NMR spectra
is given in the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet and its
combinations. High resolution mass spectra were recorded
on Thermo Fisher Scientifics (FT-ICR-MS) LTQ FT Ultra
using electrospray ionization (ESI+) at ZEA3 of
Forschungzentrum Jülich GmbH or on Brukers UHR-
QTOF maXis 4G at Heinrich-Heine-University Düsseldorf.
Analytical thin layer chromatography was performed by
using silica gel interlayer (Macherey-Nagel POLYGRAM®
SIL G/UV254) and visualized by UV irradiation or KMnO4
solution. Enantiomeric ratios were measured on a Dionex
Gynkotek HPLC using columns from Daicel and
Phenomenex applying heptane:2-propanol mixtures with
0.5 mL/min flow rate (used columns indicated at respective
products in SI). Flash column chromatography was
performed with silica gel (Macherey-Nagel, 0.040–
0.063 mm, 230–400 mesh). Optical rotations were
measured on an A.Krüss Optronic P8000 polarimeter in a
1 dm measuring cell at λ=589 nm. Melting points were
measured on a Büchi Melting Point B 540 device with a
heating rate of 1 °C/min.
General procedure for the synthesis of racemic all-
trans-α,β,γ-trisubstituted γ-butyrolactones (GP5).
Michael system 1 (0.25 mmol, 1.00 equiv.), bromo donor 2
(0.275 mmol, 1.10 equiv.), K2CO3 (86.4 mg, 0.625 mmol,
2.50 equiv.) and DABCO (5.6 mg, 0.05 mmol, 20 mol%)
were dissolved in CHCl3 (2.5 mL). DMF (19.2 µL,
0.25 mmol, 1.00 equiv., internal standard), water (2.25 µL,
125 µmol, 0.50 equiv.) and alcohol
6
(1.00 mmol,
4.00 equiv.) were added to the reaction mixture. The
reaction was stirred at 60 °C and after 2–5 h the reaction
was completed, quenched with saturated aqueous NH4Cl
solution and extracted with CH2Cl2 (3 × 25 ml). The crude
mixture was purified by flash column chromatography to
obtain the all-trans α,β,γ-trisubstituted γ-butyrolactone 5.
All syntheses of Michael systems 1, cyclopropanes 4,
catalysts C, β,γ-disubstituted- 3, α,β,γ-trisubstituted- 5 and
α,α,β,γ-tetrasubstituted γ-butyrolactones 8 are described
and analytically characterized in the Supporting
Information.
General procedure for the synthesis of enantiomerically
enriched
(2R,3R,4R)
α,β,γ-trisubstituted
γ-
butyrolactone (GP6).
General procedure for the synthesis of Michael systems
(GP1).
Michael system 1 (0.10 mmol, 1.00 equiv.), bromo donor 2
(0.11 mmol, 1.10 equiv.), K2CO3 (34.6 mg, 0.25 mmol,
2.50 equiv.) and β-ICD (C24) (6.2 mg, 0.02 mmol,
20 mol%) were dissolved in CHCl3 (1.0 mL). DMF (7,7
µL, 0.10 mmol, 1.00 equiv., internal standard), water (1 µL
Aldehyde (10.0 mmol, 1.00 equiv.) and Meldrum’s acid
(12.0 mmol, 1.20 equiv.) were suspended in water
(3.0 mL) and heated up to 75 °C. The reaction mixture was
stirred until the condensation was completed. After full
conversion, the reaction was cooled to ambient
temperature, the product precipitated, was filtered via a
glass funnel and dried under reduced pressure to yield the
desired Michael system 1.
0.05 mmol, 0.50 equiv.) and alcohol
6 (1.00 mmol,
4.00 equiv.) were added to the reaction mixture. The
reaction was stirred at 60 °C and after 2–7 h the reaction
was completed, quenched with saturated aqueous NH4Cl
solution and extracted with CH2Cl2 (3 × 25 ml). The crude
mixture was purified by flash column chromatography to
obtain the (2R,3R,4R) α,β,γ-trisubstituted γ-butyrolactone 5.
General procedure for the synthesis of Michael systems
(GP2).
General procedure for the synthesis of racemic α,α,β,γ-
tetra-substituted γ-butyrolactone (GP7).
Meldrum’s acid (12.0 mmol, 1.20 equiv.) was dissolved in
CH3CN (10 mL), then aldehyde (10.0 mmol, 1.00 equiv.)
and piperidine (50 µL, 5 mol%) were added. The reaction
was stirred until the condensation was completed. The
solvent was evaporated to give the desired product 1.
Michael system 1 (0.25 mmol, 1.00 equiv.), bromo donor 2
(0.275 mmol, 1.10 equiv.), K2CO3 (86.4 mg, 0.625 mmol,
2.50 equiv.) and DABCO (5.6 mg, 0.05 mmol, 20 mol%)
were dissolved in CHCl3 (2.5 mL). DMF (19.2 µL,
0.25 mmol, 1.00 equiv., internal standard), water (2.25 µL,
General procedure for the synthesis of racemic trans-
β,γ-disubstituted γ-butyrolactones (GP3).
125 µmol, 1.00 equiv.) and alcohol
6 (1.00 mmol,
4.00 equiv.) were added to the reaction mixture. The
reaction stirred at 60 °C. After 2–5 h the reaction was
completely converted to trisubstituted γ-lactone 5, K2CO3
(86.4 mg, 0.25 mmol, 1.00 equiv.) and electrophile 7
(0.38 mmol, 1.50 equiv.) were added to the reaction
mixture. When product formation was completed, the
reaction was quenched with saturated aqueous NH4Cl
solution and extracted with CH2Cl2 (3 × 25 mL). The crude
mixture was purified by flash column chromatography to
obtain the α,α,β,γ-tetrasubstituted γ-butyrolactone 8.
K2CO3 (103.7 mg, 0.75 mmol, 3.00 equiv.) and DABCO
(5.6 mg, 0.05 mmol, 20 mol%) were dissolved in CHCl3
(2.5 mL). DMF (19,2 µL, 0.25 mmol, 1.00 equiv., internal
standard) and water (22.5 µL, 1.25 mmol, 5.00 equiv.)
were added to the reaction mixture. Michael system 1 (0.25
mmol, 1.00 equiv.) and bromo donor 2 (0.275 mmol, 1.10
equiv.) were divided into 4 portions which were added
each to the reaction mixture in intervals of 15 min. The
reaction was stirred at 60 °C for 2 h. After full conversion
of the starting materials the reaction was quenched with
saturated aqueous NH4Cl solution and extracted with
CH2Cl2 (3 × 25 ml). The crude mixture was purified by
flash column chromatography to obtain the trans-β,γ-
disubstituted γ-butyrolactone 3.
Acknowledgements
We
gratefully
acknowledge
the
Deutsche
Forschungsgemeinschaft (WO-1666/4-1), the Heinrich Heine
University Düsseldorf (HHU), the Forschungszentrum Jülich
GmbH, and the Bioeconomy Science Center (BioSC) for the
support of our projects. Scientific activities within the BioSC
were supported by the Ministry of Culture and Science within the
General procedure for the synthesis of enantiomerically
enriched (3R,4R)-β,γ-disubstituted γ-butyrolactones
(GP4).
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
framework of the NRW-Strategieprojekt BioSC (no. 313/323-400-
002 13). We thank Teresa Friedrichs and Joss Pepe Strache for
synthetic support as well as Patrick Ullrich, Julian Greb, and
Marvin Mantel for their assistance, and Birgit Henßen for her
help with the analytics.
Soc. 1967, 21, 331–363; d) F. Schleth, T. Vogler, K.
Harms, A. Studer, Chem. Eur. J. 2004, 10, 4171–4185.
[11] K.-H. Lee, E.-S. Huang, C. Piantadosi, J. S. Pagano,
T. A. Geissman, Cancer Res. 1971, 31, 1649–1654.
[12] a) S. Kumar KC, K. Müller, J. Nat. Prod. 1999, 62,
817–820; b) S. H. Lone, K. A. Bhat, M. A. Khuroo,
Chem.-Biol. Interact. 2015, 240, 180–198.
References
[1] a) X.-L. Sun, Y. Tang, Acc. Chem. Res. 2008, 41, 937–
948; b) A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem.
Rev. 1997, 97, 2341–2372; c) E. M. McGarrigle, E. L.
Myers, O. Illa, M. A. Shaw, S. L. Riches, V. K.
Aggarwal, Chem. Rev. 2007, 107, 5841–5883; d) C.
Zhu, Y. Ding, L.-W. Ye, Org. Biomol. Chem. 2015, 13,
2530–2536.
[13] B. Mao, M. Fañanás-Mastral, B. L. Feringa, Chem.
Rev. 2017, 117, 10502–10566.
[14] a) R. D. Miller, G. N. Fickes, J. Org. Chem. 1985, 50,
2375–2377; b) M. Ozeki, D. Hashimoto, K. Nishide, T.
Kajimoto, M. Node, Tetrahedron: Asymmetry 2005, 16,
1663–1671; c) N. J. Kerrigan, P. C. Hutchison, T. D.
Heightman, D. J. Procter, Org. Biomol. Chem. 2004, 2,
2476–2482; d) S. N. Greszler, J. S. Johnson, Angew.
Chem. Int. Ed. 2009, 48, 3689–3691; e) M. F. Pinatto-
Botelho, A. E. M. Crotti, J. M. de Souza, L. G.
Magalhães, P. M. Donate, J. Braz. Chem. Soc. 2014, 25,
1331–1337; f) K. M. Steward, E. C. Gentry, J. S.
Johnson, J. Am. Chem. Soc. 2012, 134, 7329–7332; g)
S. Takada, K. Iwata, T. Yubune, Y. Nishii, Tetrahedron
Lett. 2016, 57, 2422–2425; h) Y. Sone, Y. Kimura, R.
Ota, T. Mochizuki, J. Ito, Y. Nishii, Eur. J. Org. Chem.
2017, 2842–2847; i) S. Singha, E. Serrano, S. Mondal,
C. G. Daniliuc, F. Glorius, Nat. Catal. 2020, 3, 48–54.
[2] a) C. D. Papageorgiou, M. A. Cubillo de Dios, S. V.
Ley, M. J. Gaunt, Angew. Chem., Int. Ed. 2004, 43,
4641–4644; b) C. D. Papageorgiou, S. V. Ley, M. J.
Gaunt, Angew. Chem., Int. Ed. 2003, 42, 828–831; c) C.
C. C. Johansson, N. Bremeyer, S. V. Ley, D. R. Owen,
S. C. Smith, M. J. Gaunt, Angew. Chem. Int. Ed. 2006,
45, 6024–6028; d) M. J. Gaunt, C. C. C. Johansson,
Chem. Rev. 2007, 107, 5596–5605.
[3]For a recent review on ammonium ylides see: L. Roiser,
K. Zielke, M. Waser, Asian J. Org. Chem. 2018, 7,
852–864.
[4] a) L. D. S. Yadav, R. Kapoor, Garima, Synlett 2009,
3123–3126; b) M. Pichler, J. Novacek, R. Robiette, V.
Poscher, M. Himmelsbach, U. Monkowius, N. Müller,
M. Waser, Org. Biomol. Chem. 2015, 13, 2092–2099;
c) J. Novacek, L. Roiser, K. Zielke, R. Robiette, M.
Waser, Chem. Eur. J. 2016, 22, 11422–11428.
[15] a) A. Sweidan, M. Chollet-Krugler, P. van de Weghe,
A. Chokr, S. Tomasi, M. Bonnaure-Mallet, L.
Bousarghin, Bioorg. Med. Chem. 2016, 24, 5823–5833;
b) S. Braukmüller, R. Brückner, Eur. J. Org. Chem.
2006, 2110–2118; c) F. Manoni, C. Cornaggia, J.
Murray, S. Tallon, S. J. Connon, Chem. Commun. 2012,
48, 6502–6504; d) K. Michigami, T. Mita, Y. Sato, J.
Am. Chem. Soc. 2017, 139, 6094–6097; e) J.-M.
Garnier, S. Robin, R. Guillot, G. Rousseau,
Tetrahedron: Asymmetry 2007, 18, 1434–1442; f) T.
Inoue, O. Kitagawa, A. Saito, T. Taguchi, J. Org. Chem.
1997, 62, 7384–7389; g) T. M. Khopade, A. D.
Sonawane, J. S. Arora, R. G. Bhat, Adv. Synth.
Catal. 2017, 359, 3905–3910.
[5] C.-Y. Zhu, X.-M. Deng, X.-L. Sun, J.-C. Zheng, Y.
Tang, Chem. Commun. 2008, 738–740.
[6] J.-R. Ma, W.-M. Shu, K.-L. Zheng, F. Ni, G.-D. Yin,
A.-X. Wu, Org. Biomol. Chem. 2015, 13, 4976–4980.
[7] S. P. Midya, E. Gopi, N. Satam, I. N. N. Namboothiri,
Org. Biomol. Chem. 2017, 15, 3616–3627.
[8] P.-F. Zheng, Q. Ouyang, S.-L. Niu, L. Shuai, Y. Yuan,
K. Jiang, T.-Y. Liu, Y.-C. Chen, J. Am. Chem. Soc.
2015, 137, 9390–9399.
[16] a) T. Classen, M. Korpak, M. Schölzel, J. Pietruszka,
ACS Catal. 2014, 4, 1321–1331; b) C. Kumru, T.
Classen, J. Pietruszka, ChemCatChem 2018, 10, 4917–
4926.
[9] a) C.-P. Chuang, K.-P. Chen, Tetrahedron 2012, 68,
1401–1406; b) K. Jiang, Y.-C. Chen, Tetrahedron Lett.
2014, 55, 2049–2055; c) P. I. Dalko, L. Moisan, Angew.
Chem. Int. Ed. 2001, 40, 3726–3748; d) N. Meisinger,
L. Roiser, U. Monkowius, M. Himmelsbach, R.
Robiette, M. Waser, Chem. Eur. J. 2017, 23, 5137–
5142; e) D. Worgull, L. Öhler, J. P. Strache, T.
Friedrichs, P. Ullrich, Eur. J. Org. Chem. 2017, 6077–
6080; f) M. Fan, L. Guo, X. Liu, W. Liu, Y. Liang,
Synthesis 2005, 391–396; g) Z. Yang, M. Fan, R. Mu,
W. Liu, Y. Liang, Tetrahedron 2005, 61, 9140–9146;
h) Z. Yang, M. Fan, W. Liu, Y. Liang, Synthesis 2005,
2188–2192.
[17] a) W. Cao, W. Ding, Y. Chen, M. Qiu, Synth.
Commun. 2000, 30, 3793–3799; b) X. Wu, W. Cao, H.
Zhang, J. Chen, H. Jiang, H. Deng, M. Shao, J. Zhang,
H. Chen, Tetrahedron 2008, 64, 10331–10338; c) W.
Cao, W. Ding, Y. Chen, J. Gao, Synth. Commun. 2000,
30, 4523–4530; d) W. Cao, W. Ding, Y. Chen, J. Gao,
Synth. Commun. 2000, 30, 4531–4541; e) Y. Chen, W.
Ding, W. Cao, C. Lu Synth. Commun. 2002, 32, 1953–
1960; f) L. Shi, Y. Han, Z. Yang, W. Liu, Y. Liang,
Synthesis 2005, 2851–2856.
[18] Castellano, S., Milite, C., Feoli, A., Viviano, M., Mai,
A., Novellino, E., Tosco, A. and Sbardella, G,
ChemMedChem 2015, 10, 144–157.
[10] a) H. M. R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed.
1985, 24, 94–110; b) P. A. Grieco, Synthesis 1975, 67–
82; c) W. Parker, J. Roberts, R. Ramage, Q. Rev. Chem.
1
[19] For a comparison of H NMR chemical shifts see
supporting information, table S1.
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
[20] Electron poor bromo acetophenones, e.g., 2-bromo-
Takahashi, J. Ishihara, S. Hatakeyama, Chem. Eur. J.
2013, 19, 12653–12656; g) Y. Wang, H. Yin, H. Qing,
J. Zhao, Y. Wu, Q. Meng, Adv. Synth. Catal. 2016, 358,
737–745; h) H. Waldmann, V. Khedkar, H. Duckert, M.
Schurmann, I. M. Oppel, K. Kumar, Angew. Chem. Int.
Ed. 2008, 47, 6869–6872; i) Y. Iwabuchi, M. Nakatani,
N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc. 1999,
121, 10219–10220; j) E. Wada, G. Kumaran, S.
Kanemasa, Tetrahedron Lett. 2000, 41, 73–76; k) C.
Palacio, S. J. Connon, Eur. J. Org. Chem. 2013, 5398–
5413; l) L. Hintermann, M. Schmitz, U. Englert, Angew.
Chem. Int. Ed. 2007, 46, 5164–5167; m) K. Kacprzak, J.
Gawroński, Synthesis 2001, 961–998.
4'-nitroacetophenone
and
2-bromo-4'-
cyanoacetophenone, showed only sluggish reaction to
the products as well as decomposition products.
[21] For
reviews
on
donor-acceptor-substituted
cyclopropane derivatives see: a) H.-U. Reissig, R.
Zimmer, Chem. Rev. 2003, 103, 1151–1196; b) T. F.
Schneider, J. Kaschel, D. B. Werz, Angew. Chem. Int.
Ed. 2014, 53, 5504–5523; c) M. A. Cavitt, L. H. Phun,
S. France, Chem. Soc. Rev. 2014, 43, 804–818.
[22] a) J. B. Cloke, J. Am. Chem. Soc. 1929, 51, 1174–
1187; b) C. L. Wilson, J. Am. Chem. Soc. 1947, 69,
3002–3004; c) A. Ortega, R. Manzano, U. Uria, L.
Carrillo, E. Reyes, T. Tejero, P. Merino, J. L. Vicario,
Angew. Chem. 2018, 130, 8357–8361; d) M. Zhang, T.
Li, C. Cui, X. Song, J. Chang, J. Org. Chem. 2020, 85,
2266–2276; e) M. L. Piotrowski, M. A. Kerr, Org. Lett.
2018, 20, 7624−7627; f) J. Zhang, Y. Tang, W. Wei, Y.
Wu, Y. Li, J. Zhang, Y. Zheng, S. Xu, Org. Lett. 2017,
19, 3043−3046.
[24] H.-C. Kim, O.-S. Park, Tetrahedron: Asymmetry 2008,
19, 896–899.
[25] For a comparison of 1H NMR coupling constants with
literature data see supporting information, table 2.
[26] a) T. Ooi, T. Miki, K. Fukumoto, K. Maruoka, Adv.
Synth. Catal. 2006, 348, 1539–1542; b) M. W. Ha, H.
Lee, H. Y. Yi, Y. Park, S. Kim, S. Hong, M Lee, M.
Kim, T.-S. Kim, H.-g. Parka, Adv. Synth. Catal. 2013,
355, 637–642.
[23] a) S. E. Denmark, R. C. Weintraub, Heterocycles
2011, 82, 1527–1540; b) Y. Liu, B. Sun, B. Wang, M.
Wakem, L. Deng, J. Am. Chem. Soc. 2009, 131, 418–
419; c) E. Yamamoto, A. Nagai, A. Hamasaki, M.
Tokunaga, Chem. Eur. J. 2011, 17, 7178–7182; d) D.
Belmessieri, A. de la Houpliere, E. D. Calder, J. E.
Taylor, A. D. Smith, Chem. Eur. J. 2014, 20, 9762–
9769; e) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C.
Guo, B. M. Foxman, L. Deng, Angew. Chem. Int. Ed.
2005, 44, 105–108; f) Y. Nakamoto, F. Urabe, K.
[27] p-Vinylbenzyl chloride showed only poor conversion
to the product with excellent diastereomeric ratio;
methyl iodine gave moderate conversion and a low d.r.
[28] Consecutive MCR by addition of m-CPBA after
lactone formation leads to a 1:1 mixture of the desired
product and an uncharacterized side product.
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000039
Advanced Synthesis & Catalysis
FULL PAPER
Enantioselective Ammonium Ylide Mediated One-
Pot Synthesis of Highly Substituted
γ-Butyrolactones
Adv. Synth. Catal. Year, Volume, Page – Page
Till Drennhaus, Laura Öhler, Saveh Djalali, Svenja
Höfmann, Clemens Müller, Jörg Pietruszka,* and
Dennis Worgull*
12
This article is protected by copyright. All rights reserved.