Enantioselective Conjugate Additions of 2-Alkoxycarbonyl-3(2 H)-furanones

Article abstract of DOI:10.1021/acs.orglett.8b03039

Enantioselective conjugate additions of in situ generated 2-alkoxycarbonyl-3(2H)-furanones to three distinct types of π-electrophiles (terminal alkynones, α-bromo enones, and α-benzyl nitroalkenes) are reported. Catalysis by a nickel(II)-diamine complex provided alkynone-derived adducts with high enantioselectivity, preferentially as the Z-isomers, and completely suppressed the undesired O-alkylation pathway. A cupreidine-based catalyst enabled extension of the enantioselective conjugate additions to α-bromo enones and α-benzyl nitroalkenes. The densely functionalized adducts that result are useful precursors to synthetic analogs of spirocyclic natural products pseurotins.

Full text of DOI:10.1021/acs.orglett.8b03039

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Conjugate Additions of 2‑Alkoxycarbonyl-
3(2H)‑furanones
,†,‡
†,‡,§
†
†
David Chalupa,†,‡,§ Jozef Prieboj, Marek Necas, and Jakub Svenda*
̌
̌
́
̌
́
Petra Vojackova,
†Department of Chemistry, Masaryk University, Brno, 625 00, Czech Republic
‡International Clinical Research Center, St. Anne’s University Hospital, Brno, 656 91, Czech Republic
S
* Supporting Information
ABSTRACT: Enantioselective conjugate additions of in situ generated 2-alkoxycarbonyl-3(2H)-furanones to three distinct
types of π-electrophiles (terminal alkynones, α-bromo enones, and α-benzyl nitroalkenes) are reported. Catalysis by a
nickel(II)−diamine complex provided alkynone-derived adducts with high enantioselectivity, preferentially as the Z-isomers,
and completely suppressed the undesired O-alkylation pathway. A cupreidine-based catalyst enabled extension of the
enantioselective conjugate additions to α-bromo enones and α-benzyl nitroalkenes. The densely functionalized adducts that
result are useful precursors to synthetic analogs of spirocyclic natural products pseurotins.
3(2H)-Furanone is found as a substructure of numerous
bioactive natural products including pseurotin A (1),1
hyperolactone C (2),2 trachyspic acid (3),3 jatrophone (4),4
and eremantholide A (5)5 (Figure 1), where the 3(2H)-
assembly or in subsequent transformations. Enantioselective
alkylations and conjugate additions of achiral 3(2H)-furanones
embody the latter approach, and powerful methodologies for
controlling the C2 stereochemistry were reported. Most of the
previous studies employed benzo-3(2H)-furanones however,7
with only few reports focusing on 3(2H)-furanones.8 In the
context of enantioselective synthesis of two natural pseurotins,
cephalimysins B and C, we have reported a single example of
stereoselective 1,4-addition of a 3(2H)-furanone onto an
alkynone catalyzed by nickel(II)−diamine complex 7 (Figure
2).9 Since we found no precedent for the use of this catalyst in
conjugate additions to alkynones,10 we now disclose details of
a study that examined 1,4-additions between differently
substituted 2-alkoxycarbonyl-3(2H)-furanones and terminal
alkynones under the catalysis of 7. We included also two other
types of π-electrophilesan α-bromo enone and an α-benzyl
Figure 1. Representative natural products featuring the 3(2H)-
furanone or benzo-3(2H)-furanone substructure.
furanone ring is most often polysubstituted and carries a
quaternary stereocenter at the C2 position (furan numbering).
Benzo-3(2H)-furanone is a closely related ring-fused analog
and, though less frequent in natural products, can be found in
the FDA-approved antifungal agent griseofulvin (6)6 (Figure
1).
Synthetic methods that enable flexible and stereoselective
construction of highly substituted 3(2H)-furanones are
valuable in accessing these families of natural products or
analogs thereof. Conceptually, the stereochemistry at the C2
position can be established during the 3(2H)-furanone
Figure 2. Structures of nickel(II)−diamine (S,S)-7 and cupreidine
derivative 8 employed as catalysts in this study.
Received: September 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03039
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Enantioselective 1,4-Additions of 2-Alkoxycarbonyl-3(2H)-furanones to Terminal Alkynones
a
The two-step single-flask transformation was carried out with 1.0 equiv of diazo carbonyl compound and 1.0 equiv of alkynone. The enantiomeric
ratio (er) was determined by HPLC analysis of purified 1,4-adducts, while the Z/E ratio was determined by 1H NMR analysis of the crude product
mixture in acetone-d6. The yield corresponds to the isolated yield of 1,4-adducts over two steps. The experiment leading to adduct 21 was carried
out on a 0.9 mmol scale. Adduct 26 was prepared differently, starting from commercially available 2-ethoxylcarbonyl benzo-3(2H)-furanone (see
SI). nd = not determined.
nitroalkeneas the corresponding 1,4-adducts can be readily
elaborated to analogs of spirocyclic natural products pseurotins
(see below).
Seidel14 provided the most promising levels of enantioselec-
tivity (see SI) for the catalyst screening). Furthermore, the
nickel(II)−diamine catalysis was essentially free of O-
alkylation products, a known competing reaction pathway
particularly pronounced for Michael additions to alkynones.15
Indeed, O-alkylation was dominant with most of the cinchona
alkaloid-derived catalysts we examined (see SI). The
enantioselectivity of the nickel(II)−diamine-catalyzed process
depends inversely on temperature (for ent-21: 88:12 er at 23
°C, 94:6 er at −20 °C, 97:3 er at −40 °C) and, critically, on
conversion due to a rapid background (non-enantioselective)
1,4-addition during the workup.16
The mild reaction conditions permitted adoption of a 1:1
stoichiometry between the reacting partners, despite the
above-mentioned stability issues of 2-alkoxycarbonyl-3(2H)-
furanones. Our control experiments showed that the rate and
the enantioselectivity of the 1,4-addition were not significantly
affected by rhodium(II) residues carried over from the 3(2H)-
furanone formation step.
To prepare a set of differently substituted 2-alkoxycarbonyl-
3(2H)-furanones (R1 and R2 group), we relied on a highly
efficient rhodium(II)-catalyzed cyclization of stable α-diazo
carbonyl precursors (see Scheme 1).11 Many of the prepared 2-
alkoxycarbonyl-3(2H)-furanones had limited stability in
solution and air oxidation (hydroxylation) at the nucleophilic
C2 position was identified as one significant side reaction (see
Supporting Information (SI)).12
With access to diverse 2-alkoxycarbonyl-3(2H)-furanones
secured, we turned our attention to their enantioselective 1,4-
additions to terminal alkynones. Due to the above-mentioned
stability issues, we have adopted a general procedure, wherein
3(2H)-furanone formation and subsequent reaction with a π-
electrophile were performed in a single flask13 under an inert
atmosphere. During the initial screening of catalysts, we found
that nickel(II)−diamine complex 7 described by Evans and
B
DOI: 10.1021/acs.orglett.8b03039
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We examined over 20 different 3(2H)-furanone−alkynone
combinations under our optimized conditions (10 mol % of
(S,S)-7, −40 °C, 120 h), with the results depicted in Scheme 1.
We were pleased to find that, in most cases, the 1,4-adducts
were isolated in good enantiomeric ratio (er) and synthetically
useful yields over the two steps. In terms of the electrophile
structure, differently substituted aryl and heteroaryl alkynyl
ketones (R3) were accommodated. Lower enantioselectivities
were observed mostly for alkyl alkynyl ketones (e.g., adducts
19 and 20), with the interesting exception of methyl alkynyl
ketone (adduct 18). Variation in substitution at the 3(2H)-
furanone component (R1) had little influence on the reaction
and good enantioselectivity was maintained across the different
substrates examined (21−25, 94:6−98:2 er). The choice of
ester group (R2) located in the vicinity of the newly formed
quaternary stereocenter is important. More specifically, methyl
and trifluoroethyl esters gave comparably good results, while
the enantioselectivity dropped for the larger phenyl and tert-
butyl esters (compare adducts 27, 28, 29, and 30). Finally,
adduct 26 (93:7 er) demonstrates that chiral benzo-3(2H)-
furanones are also accessible by this methodology. While
preferential formation of the Z-isomers was observed in most
cases,17 we note that the Z configuration is labile and, in
consequence, the reported Z/E ratios may not accurately
reflect the inherent selectivity (for example, Z → E
isomerization was observed in deuterated chloroform by
NMR).
The absolute configuration at the quaternary stereocenter
established with nickel(II)−diamine (S,S)-7 had previously
been assigned by us as R through the conversion of adduct 21
to cephalimysin C (44).9 To secure these previous assignments
further, we have now determined the crystal structure of
bromine-containing adduct 22 (Scheme 1, left bottom).18
While a detailed mechanistic study would be required to
rationalize the observed sense of asymmetric induction, our
preliminary data support the formation of a nickel(II)-bound
3(2H)-furanone enolate (see SI).14
Changing the structure of the π-electrophile from a terminal
alkynone to α-bromo enone 31 or α-benzyl nitroalkene 37
resulted in a dramatic decrease in enantioselectivity (see SI),
pointing to limitations of the nickel(II)−diamine-based
methodology. In order to re-establish good levels of
enantioselectivity for these alternative Michael acceptors
featuring a less frequently studied substitution pattern, we
performed a new round of catalyst screening (see SI) and
identified cupreidine derivative 8 (Figure 2) as a promising
catalyst.19 The catalyst was prepared by a single-step
demethylation of a commercially available precursor (see SI).
The presence of the 6′-hydroxyquinoline group in cupreidine 8
was found to be beneficial to the enantioselectivity and the rate
of the 1,4-addition, in agreement with the original findings of
Deng and colleagues.20 As shown in Schemes 2 and 3, both α-
bromo enone 31 and α-benzyl nitroalkene 37 readily
participated in enantioselective conjugate additions in the
presence of catalytic amounts of 8 (10 mol %, 0−23 °C, 1−2
h) and provided the corresponding 1,4-adducts in the er range
90:10−98:2.
Scheme 2. Enantioselective 1,4-Additions of 2-
Alkoxycarbonyl-3(2H)-furanones to α-Bromo Enone
a
a
The two-step single-flask transformation was carried out with 1.0
equiv of diazo carbonyl and 1.0 equiv of α-bromo enone. The
enantiomeric ratio (er) was determined by HPLC analysis of the
purified 1,4-adducts, while the diastereomeric ratio (dr) was
1
determined by H NMR analysis of the crude product mixture. The
yield corresponds to the combined isolated yield for both
diastereomers over two steps.
the low diastereoselectivity is not a consequence of a rapid
epimerization under the reaction conditions.
The absolute configuration of the 1,4-adducts obtained
under cupreidine 8 catalysis was determined by X-ray
crystallography. The crystal structure of α-bromo enone
adduct 36 (Scheme 2) revealed the S configuration at position
C2, which is opposite to that observed above for alkynones
with nickel(II)−diamine (S,S)-7.21 Reductive debromination
(zinc, acetic acid) performed on a diastereomeric mixture of
enantiomerically enriched α-bromo adduct 35 further con-
firmed that both diastereomers have the same absolute
configuration at the quaternary stereocenter (see SI). For α-
benzyl nitroalkene adducts, the absolute configuration at the
quaternary stereocenter was the same (S), as determined after
a single-step conversion of a nitroalkene adduct into spirocyclic
lactam 43 (X-ray in Scheme 3).
The three types of 1,4-adducts described in Schemes 1−3
can be elaborated further (Scheme 4). We have shown
previously that alkynone adduct 21 is a synthetic precursor of
natural product cephalimysin C (44).9 To convert α-bromo
enone adduct 35 into an analogous spirocyclic furanone−γ-
lactam (45), the bromide was first displaced with sodium
azide, and subsequent treatment with tri-n-butylphosphine
promoted a reductive cyclization. α-Benzyl nitroalkene adduct
39 underwent lactamization to 46 directly upon exposure to
zinc in acetic acid (see SI for additional examples).
The enantioselectivity was only moderately dependent on
the reaction temperature. The diastereoselectivity (1,3-stereo-
chemical relationship) proved difficult to control under these
and many other conditions attempted (see SI). Control
experiments performed with nitroalkene adduct 41 suggest that
In summary, we have shown that nickel(II)−diamine
complex 7 is a useful catalyst for enantioselective 1,4-additions
of in situ generated 2-alkoxycarbonyl-3(2H)-furanones onto
various terminal alkynones. The method yields enantiomeri-
C
DOI: 10.1021/acs.orglett.8b03039
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Organic Letters
Letter
Scheme 3. Enantioselective 1,4-Additions of 2-
Alkoxycarbonyl-3(2H)-furanones to α-Benzyl Nitroalkene
ASSOCIATED CONTENT
* Supporting Information
■
a
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03039.
Detailed experimental procedures and spectroscopic
data for all new compounds (PDF)
Accession Codes
CCDC 1866443−1866447 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: svenda@chemi.muni.cz.
ORCID
̌
Jakub Svenda: 0000-0001-9232-3218
Author Contributions
§P.V. and D.C. contributed equally.
Notes
a
The two-step single-flask reaction was carried out with 1.0 equiv of
diazo carbonyl and 1.0 equiv of α-benzyl nitroalkene. The
enantiomeric ratio (er) was determined by HPLC analysis after
conversion of the 1,4-adducts into spirocyclic lactams (see SI). The
diastereomeric ratio was determined by 1H NMR analysis of the crude
product mixture. The yield corresponds to the combined isolated
yield for both diastereomers over two steps.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
the Marie Curie Career Integration Grant (322001), the Bader
Philanthropies grant (17573), and the National Program of
Sustainability II (LQ1605) funded by MEYS CR. We
acknowledge the CIISB research infrastructure project (X-ray
Core Facility, LM2015043) and the National Infrastructure for
Chemical Biology (CZ-OPENSCREEN, LM2015063) funded
Scheme 4. Elaboration of Prepared 1,4-Adducts into
Spirocyclic Furanone−γ-Lactams
́
by MEYS CR. We thank Prof. Tibor Soos (Hungarian
Academy of Sciences) for providing us with the squaramide-
based catalysts.
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E
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