Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients

Article abstract of DOI:10.1021/jacs.8b08236

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Full text of DOI:10.1021/jacs.8b08236

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Article
anti-Selective Catalytic Asymmetric Nitroaldol Reaction of #-Keto
Esters; Intriguing Solvent Effect, Flow Reaction, and Synthesis of APIs
Tomoya Karasawa, Raphaël Oriez, Naoya Kumagai, and Masakatsu Shibasaki
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08236 • Publication Date (Web): 03 Sep 2018
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antiꢀSelective Catalytic Asymmetric Nitroaldol Reaction of αꢀ
Keto Esters; Intriguing Solvent Effect, Flow Reaction, and
Synthesis of APIs
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Tomoya Karasawa, Raphaël Oriez, Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), 3ꢀ14ꢀ23 Kamiosaki, Shinagawaꢀku, Tokyo 141ꢀ0021, Japan.
ABSTRACT: A rareꢀearth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling niꢀ
troalkanes and αꢀketo esters in an antiꢀselective manner to afford synthetically versatile, densely functionalized, and optically active
αꢀnitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solidꢀ
phase heterobimetallic catalyst by simple mixing via selfꢀassembly. The advantage of the solidꢀphase asymmetric catalyst was realꢀ
ized by successful application to the enantioꢀ and diastereoselective reaction in a continuousꢀflow platform. The use of closelyꢀ
related solvents in terms of structures and polarity parameters, THF and its methylated congener 2ꢀMeꢀTHF, had an unexpectedly
large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active
pharmaceutical ingredients (APIs), as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents
efinaconazole and albaconazole.
Scheme 1. Nitroaldol Reaction as a Powerful Tool for the
Synthesis of vicꢀAmino Alcohols
INTRODUCTION
The concept of sustainability has gained increasing popularity
in developing practical synthetic reactions for application to
production processes. The nitroaldol reaction is particularly
advantageous in this regard (Scheme 1a), because 1) substrates
are readily available; 2) the reaction forges a C–C bond to
construct the main skeleton of the molecule of interest; 3) the
reaction installs consecutive hydroxyl and nitro groups on
stereogenic carbons; and 4) the reaction generally proceeds
under proton transfer conditions by the actions of a catalyst
with perfect atom economy.1,2 Hence, the sheer number of
developments utilizing the catalytic asymmetric nitroaldol
reaction to stereoselectively couple aldehydes and nitroalꢀ
kanes3,4 reported since its first disclosure in 1992 is not surꢀ
prising.5 A decade of intense research revealed that this methꢀ
od is valid for αꢀketo esters as electrophiles to access vicꢀ
amino alcohols including the tertꢀalcohol substructure with an
additional carboxylate group,6 expanding the opportunity to
meet the increasing demand for densely functionalized
synthons (Scheme 1b). This catalystꢀdriven process is highly
useful in terms of atom economy, but the application of a
higher nitroalkane than nitromethane in this catalytic process
has remained elusive, and the introduction of an R3 substituent
with decent stereocontrol of an additional stereogenic center
has remained problematic. Indeed, in contrast to the extensive
literature coverage of the reaction of nitromethane to αꢀketo
esters,6ꢀ7 there are only two reports of the diastereoꢀ and enanꢀ
tioselective variant. Nagasawa et al.8 and Ooi et al.9,10 indeꢀ
pendently documented complementary synꢀ and antiꢀselective
reactions using aliphatic αꢀketo esters, but aromatic substrates
were less tractable.11 Given that arylated vicꢀamino (tertꢀ) alꢀ
cohols are privileged in marketed antifungal agents, we were
particularly interested in applying our rare earth metal
(RE)/alkali metal heterobimetallic catalyst12 to incorporate
aromatic αꢀketo esters as viable substrates in this potentially
useful catalytic process. Herein we report an antiꢀselective
catalytic asymmetric nitroaldol reaction of αꢀketo esters with
broad substrate generality (Scheme 1c). The Nd/Na heterobiꢀ
metallic system worked as a solidꢀphase catalyst to furnish
antiꢀconfigured products with high stereoselectivity. A strong
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solvent effect was observed between structurally and physicoꢀ
Table 1. antiꢀSelective Catalytic Asymmetric Nitroaldol
Reaction of αꢀKeto Ester 3a
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chemically similar THF and 2ꢀMeTHF, which was likely levꢀ
eraged by the polymeric nature of the present catalyst comꢀ
plexes. This solid catalyst system was compatible with a flow
reaction platform and the enantioenriched products obtained
here contributed to the streamlined synthesis of the antifungal
agents efinaconazole and albaconazole,13 confirming the synꢀ
thetic utility of the present catalytic system.
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RESULTS and DISCUSSION
The leucineꢀderived diamide ligand 1 having fluorophenol
units on both termini was specifically designed for the antiꢀ
selective asymmetric nitroaldol reaction with the combined
use of Nd and Na cations. Simple mixing of
1/NdO1/5(OiPr)13/5/NaHMDS in THF led to the spontaneous
formation of an insoluble catalyst via selfꢀassembly that exhibꢀ
ited high catalytic performance as a solidꢀphase catalyst in
nitroaldol reactions to aldehydes12a, 12b and αꢀtrifluoromethyl
ketones.12e The identification of inexpensive metal sources
such as NdCl3•6H2O and NaOtBu to obtain similarly compeꢀ
tent catalysts enhanced the practical aspects of this
catalysis.12cꢀe This established system displayed high catalytic
performance in a nitroaldol reaction of nitroethane 2a and
benzoyl formates 3aꢀa’’, as representative aromatic αꢀketo
esters, affording the antiꢀconfigured and enantiomerically
enriched tertiary vicꢀnitroalkanols 4aꢀa’’ with high stereoseꢀ
lectivity, irrespective of the ester substituents (Scheme 2). The
catalyst was broadly applicable to a range of αꢀketo esters 3
(Table 1). Intriguingly, the use of 2ꢀMeꢀTHF instead of THF
as a solvent enhanced the reaction rate and generally afforded
better stereoselectivity, enabling completion of the reaction
with as little as 1 mol% of catalyst loading (entry 2). Aromatic
αꢀketo esters bearing electronꢀdonating alkyl and methoxy
groups, and electronꢀwithdrawing halogen and CF3 groups
were tolerated to give the desired nitroaldol adducts with high
stereoselectivity (entries 5–21). Although the oꢀfluoro substitꢀ
uent was accommodated (entries 18,19), the catalytic system
was sensitive to the steric factor and the oꢀMe group halted the
catalysis.14 Bulky substituents at the pꢀposition were compatiꢀ
ble with less satisfactory yield and stereoselectivity in the reꢀ
action using THF as the solvent (entries 9,11), but this was
considerably improved by switching the solvent to 2ꢀMeꢀTHF
(entries 10,12). Heteroaromatic substrates were successfully
incorporated with high stereoselectivity (entries
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a2: 1.2 mmol, 3: 0.12 mmol. bIsolated yield of antiꢀ
diastereomer. cDetermined by 1H NMR of crude reaction mixture.
e
dDetermined by chiral stationary phase HPLC analysis. Run at –
78 °C. fRun for 48 h. g5 equiv of nitroalkane 2c was used.
22,23). Although the stereoselectivity was marginally lower,
reactions using αꢀketo esters with alkynyl and alkyl substituꢀ
ents proceeded smoothly (entries 24–27), exemplifying the
wide scope of the present catalysis. As for nitroalkanes, nitroꢀ
propane 2b and TBSꢀprotected 2ꢀnitroethanol 2c exhibited
acceptable reactivity, albeit with higher catalyst loading (9
mol%) (entries 28–31). The significantly enhanced yield and
enantioselectivities of nitroaldol products 4la, 4ma, 4oa, 4ab,
and 4ac with 2ꢀMeꢀTHF are noteworthy (entries
21,23,27,29,31).
Scheme 2. Nitroaldol Reaction as a Powerful Tool for the
We next turned our attention to the unexpectedly large and
beneficial solvent effect of 2ꢀMeꢀTHF. In terms of the physiꢀ
cochemical parameters and threeꢀdimensional molecular strucꢀ
ture, 2ꢀMeꢀTHF is between THF and Et2O.15 The reaction
using Et2O or other ethereal solvents, however, had markedly
diminished stereoselectivity,16 suggesting that THF molecules
were partly involved as Lewis basic ligands in the key reaction
steps. The profile of the reactions of 2a and 3a revealed signifꢀ
icant rate enhancement (ca. 6.1ꢀfold in the reaction of 3a and
4b) with 2ꢀMeꢀTHF (vide supra). Because 2ꢀMeꢀTHF posꢀ
sesses intrinsic chirality, we synthesized both (R)ꢀ and (S)ꢀ2ꢀ
MeꢀTHF to further dissect this intriguing solvent effect.17 The
first description of chemical reactions in chiral medium by
Seebach in 1975 inspired the concept of chiral solvents in enꢀ
antioselective reactions,18 which was fostered synergistically
Synthesis of vicꢀAmino Alcoholsa
a2a: 1.2 mmol, 3: 0.12 mmol. Catalyst amount was based on
Nd used. Isolated yield is reported. Ee was determined by chiral
stationary phase HPLC analysis.
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Figure 2. Reaction profile of 2b and 3a in different reaction meꢀ
dia, THF, racemic 2ꢀMeꢀTHF, and enantiopure 2ꢀMeꢀTHF. 10
equiv of nitroalkane was used. Inset: initial rates of the reaction in
THF (closed circle) and 2ꢀMeꢀTHF (plus), showing that the latter
is 6.1ꢀtimes faster.
Figure 1. Nitroaldol reactions in different media, pure THF or 2ꢀ
MeꢀTHF with varied enantiomeric excess. Catalysts were preꢀ
pared in a similar manner as shown in Scheme 2. In all cases, 10
equiv of nitroalkane was used and the reaction reached >80%
(generally >95%) conversion after the designated reaction time
and anti/syn ratio exceeds >20/1. Er denotes the enantiomeric
ratio of the depicted (2R,3S)ꢀisomer relative to the antipodal
(2S,3R)ꢀisomer. Reaction 1 in THF was performed with 6 mol%
of catalyst.
with the development of ionic liquids as designer solvents.19
Although a number of chiral ionic liquids have been disclosed
as chiral reaction media and additives,20 neutral chiral solvents
have barely been explored due to the generally subtle effect on
the reactions of interest.21
We selected two sets of reactions for inꢀdepth study, 2a+3e
and 2b+3a, where large deviations in enantioselectivity were
detected depending on the selected solvent. These substrates
were submitted to the reactions in partially enantiomerically
enriched 2ꢀMeꢀTHF media, as illustrated in the plot of the
enantiomeric excess of 2ꢀMeꢀTHF vs the enantiomeric ratio
(er: majorꢀ(2R,3S)/minorꢀ(2S,3R)) of the corresponding prodꢀ
ucts 4ea and 4ab (Figure 1). Significant enhancement of the
enantiomeric excess (99% ee, er 199) became evident with
racemic 2ꢀMeꢀTHF as shown in Table 1, and similar beneficial
effects were obtained with enantiomerically pure (R)ꢀ2ꢀMeꢀ
THF. In marked contrast, the reactions with enantiomerically
pure (S)ꢀ2ꢀMeꢀTHF afforded the products with an enantioꢀ
meric ratio similar to that observed for THF. The enantiomeric
ratio gradually increased with an increase in the fraction of
Figure 3. Divergent enantioselectivity in nitroaldol reaction of
nitromethane 2d and benzoyl formats 3a–a’’. 10 equiv of nitroalꢀ
kane was used
(R)ꢀ2ꢀMeꢀTHF over (S)ꢀ2ꢀMeꢀTHF in the reaction media, inꢀ
dicating that the Nd/Na catalyst responded to the chirality of
the solvent molecules. Considering the positive dependency of
the reaction rate on the concentration of the αꢀketo ester,22 (R)ꢀ
2ꢀMeꢀTHF was likely the matched dative ligand for the Nd/Na
complex and played a key role in forming the desired (2R,3S)ꢀ
enantiomer. When the solution was comprised of half (R)ꢀ2ꢀ
MeꢀTHF, i.e., racemic 2ꢀMeꢀTHF, the beneficial effect in the
enantiomeric ratio was saturated, presumably because the
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matched (R)ꢀ2ꢀMeꢀTHF had stronger affinity to the Nd/Na
Scheme 4. Stereoselective Synthesis of Efinaconazole and
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catalyst, which enhanced the enantioselectivity. This assumpꢀ
tion is further supported by the observed reaction rate trend in
the order of (R)ꢀ2ꢀMeꢀTHF > racꢀ2ꢀMeꢀTHF > THF > (S)ꢀ2ꢀ
MeꢀTHF (Figure 2), where the content of (R)ꢀ2ꢀMeꢀTHF dicꢀ
tated the rate acceleration. The notable difference in the reacꢀ
tion rate between THF and 2ꢀMeꢀTHF variants is intriguing,
and is tentatively ascribed to the accessibility of the Nd cation
as a Lewis acid to accept αꢀketo esters for C–C bondꢀforming
events. Given the high coordination number of the rare earth
Nd cation,23 the sterically less demanding THF molecules
might be more prone to occupy the coordination sphere, thereꢀ
by retarding the reaction.
Albaconazole
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The solvent effects were further illustrated by the observed
divergent enantioselectivity in the reaction of nitromethane 2d
(Figure 3). While the reaction of benzoyl formates 3a–a’’ in 2ꢀ
MeꢀTHF consistently afforded the corresponding products 5a–
a’’ in an identical 2Rꢀconfiguration, irrespective of the ester
groups, the same reactions of methyl and ethyl esters in THF
gave rise preferentially to the opposite 2Sꢀconfigured products,
indicating that 1) an extra methyl group of the metal nitronate
of nitroethane 2a played a pivotal role in controlling the
prochiralꢀface selection of incoming αꢀketo esters; and 2) an
extra methyl group of 2ꢀMeꢀTHF was juxtaposed in near proxꢀ
imity to direct αꢀketo esters to favor 2Rꢀproducts. This asꢀ
sumption based on sterics is consistent with the different steꢀ
reoselection trend observed with the bulkier isopropyl ester
3a’’; both THF and 2ꢀMeꢀTHF enhanced the formation of 2Rꢀ
products, presumably due to the larger steric bias of the isoꢀ
propyl group.
Reagents and conditions: (a) Pd/C, H2, Boc2O, MeOH, rt, 12 h,
92%; (b)NaBH4, THF/MeOH, rt, 12 h, 91%; (c) NCCH=PnBu3,
1,2,4ꢀtriazole, toluene, 80 °C, 3 h; after evaporation, K2CO3,
DMF, 70 °C, 11 h, 79%; (d) 4 M HCl/1,4ꢀdioxane, rt, 2 h; (e,) 10,
iPr2NEt, DMA, 80 °C, 24 h, 56% (2 steps); (f) 11, EDCI•HCl,
HOBt, 2,6ꢀlutidine, DMF, rt, 24 h; (g) Me2NCH(OMe)2, MeOH,
70 °C, 24 h, 65% (3 steps).
The heterogeneity of the Nd/Na catalyst was leveraged by
implementing the present asymmetric catalysis in a continuꢀ
ousꢀflow reaction platform.24 Flow reactions have been gainꢀ
ing increasing attention in industry as safer, more reproduciꢀ
ble, and more scalable options over traditional batch condiꢀ
tions.25 The application of asymmetric catalysis in a continuꢀ
ousꢀflow system is still limited largely due to the scarcity of
reliable solidꢀphase asymmetric catalysts.24f, 24h, 26, 27 Based on
the carbon nanotube (CNT) confinement strategy, we previꢀ
ously demonstrated that simple mixing of multiwalled CNTs
(MWNTs) in the catalyst preparation process produced the
composite material of the MWNTs and the Nd/Na heterobimeꢀ
tallic catalyst, which proved to be a durable solidꢀphase cataꢀ
lyst competent for a continuousꢀflow reaction. We confirmed
that this strategy was also valid for the reaction of αꢀketo esꢀ
ters. The substrate mixture (2a and 3a) in 2ꢀMeꢀTHF was
passed through a stainlessꢀsteel column charged with the
MWNTꢀconfined Nd/Na heterobimetallic catalyst. The desired
product was obtained in 92% yield (1.52 g) after 92 h without
any detrimental effect on stereoselectivity compared with
batch conditions. Of note, the cooling volume was significantꢀ
ly reduced to decrease energy input for cryogenic conditions
and evaporation of the eluents gave the crude product without
any workꢀup procedure, resulting in an operationally simple
protocol.
The utility of the present catalysis was demonstrated by a
streamlined stereoselective synthesis of the marketed antifunꢀ
gal agents efinaconazole and albaconazole,13 which share a
key structural motif of 2,4ꢀdifluoroarylated vicꢀamino (tertꢀ
)alcohol (Scheme 4). The nitroaldol reaction of αꢀketo ester 3k
and nitroethane 2a with antipodal ligand entꢀ1 furnished entꢀ
4ka bearing functionalities in a suitable stereochemistry. Facꢀ
ile reduction of the nitro group over Pd/C under hydrogen
atmosphere followed by Boc protection gave 6 in 92% yield.
Reduction of methyl ester with NaBH4 gave diol 7, to which
1,2,4ꢀtriazole was installed using Tsunoda’s reagent
(NCCH=PnBu3)28 via intermediary epoxide 8 to afford 9. After
deprotection of the Boc group, the exposed amine was capꢀ
tured by dibromide 10 to construct the requisite piperidine
ring,29 furnishing efinaconazole.30 From the identical intermeꢀ
diate 9, sequential amidation with 4ꢀchloroantharanic acid 11
and subsequent condensation with N,Nꢀdimethylformamide
dimethyl acetal gave rise to a quinazolone, which was folꢀ
lowed by condensation with orthoformate to deliver albaconaꢀ
zole.31
Scheme 3. antiꢀSelective Catalytic Asymmetric Nitroaldol
Reaction of αꢀKeto Ester in a ContinuousꢀFlow Platform
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CONCLUSION
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1
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In summary, we developed an antiꢀselective asymmetric niꢀ
troaldol reaction of αꢀketo esters and nitroalkanes with broad
substrate generality. A significant beneficial solvent effect of
2ꢀMeꢀTHF was observed and detailed study revealed that the
Nd/Na heterobimetallic catalyst recognized its chirality. A
continuous ꢀflow reaction was successfully executed by taking
advantage of the heterogeneity of the Nd/Na heterobimetallic
catalyst. The utility of the present catalysis culminated in a
streamlined stereoselective synthesis of the marketed antifunꢀ
gal agents efinaconazole and albaconazole.
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ASSOCIATED CONTENT MATERIAL
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectroscopic data of new comꢀ
pounds (PDF)
NMR spectra (PDF)
Crystallographic data for compound 4a (CIF)
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Tetrahedron Lett. 2008, 49, 1623.
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10. Ref 9 labels the major diastereomer as syn considering that
the ester group conforms the main skeleton. Herein, the R1
group was considered as a group that conforms the main
skeleton to give uniform syn/anti labeling for products derived
from various electrophiles (aldehydes, α-CF3 ketones, and α-keto
esters).
11. Ref 7d describes preliminary data on the reaction of
nitroethane and ethyl benzoylformate: dr = 4/1, 75% ee/88% ee
(yield and identity of diastereomers were not given).
12. (a) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860; (b) Ogawa, T.;
Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2013, 52, 6196;
(c) Nonoyama, A.; Hashimoto, K.; Saito, A.; Kumagai, N.;
Shibasaki, M. Tetrahedron Lett. 2016, 57, 1815; (d) Nonoyama, A.;
Kumagai, N.; Shibasaki, M. Tetrahedron 2017, 73, 1517; (e)
Karasawa, T.; Kumagai, N.; Shibasaki, M. Org. Lett. 2018, 20, 308.
13. Peyton, L. R.; Gallagher, S.; Hashemzadeh, M. Drugs Today
2015, 51, 705.
14. Only trace amounts of the product (if any) were obtained
with α-keto ester bearing an o-tolyl group.
15. (a) Roderic P, Q.; Kester, D. E. J. Organomet. Chem. 1977, 127,
111; (b) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1995, 117,
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AUTHOR INFORMATION
Corresponding Author
*Naoya Kumagai: nkumagai@bikaken.or.jp
*Masakatsu Shibasaki: mshibasa@bikaken.or.jp
ACKNOWLEDGMENT
This work was financially supported by ACTꢀC program
(JPMJCR12YO) from JST and KAKENHI (17H03025 and
18H04276 in Precisely Designed Catalysts with Customized Scafꢀ
folding) from JSPS and MEXT. Dr. Tomoyuki Kimura is gratefulꢀ
ly acknowledged for Xꢀray crystallographic analysis of 4a. We
are grateful to Dr. Ryuichi Sawa, Ms. Yumiko Kubota, and Dr.
Kiyoko Iijima for NMR analysis.
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