Catalytic enantioselective protonation of nitronates utilizing an organocatalyst chiral only at sulfur

Article abstract of DOI:10.1021/ja3026196

The highly enantioselective protonation of nitronates formed upon the addition of α-substituted Meldrums acids to terminally unsubstituted nitroalkenes is described. This work represents the first enantioselective catalytic addition of any type of nucleophile to this class of nitroalkenes. Moreover, for the successful implementation of this method, a new type of N-sulfinyl urea catalyst with chirality residing only at the sulfinyl group was developed, thereby enabling the incorporation of a diverse range of achiral diamine motifs. Finally, the Meldrums acid addition products were readily converted to pharmaceutically relevant 3,5-disubstituted pyrrolidinones in high yield.

Full text of DOI:10.1021/ja3026196

Communication
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Catalytic Enantioselective Protonation of Nitronates Utilizing an
Organocatalyst Chiral Only at Sulfur
Kyle L. Kimmel,† Jimmie D. Weaver,† Melissa Lee, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
Herein we describe the first example of this type of
ABSTRACT: The highly enantioselective protonation of
nitronates formed upon the addition of α-substituted
Meldrum’s acids to terminally unsubstituted nitroalkenes is
described. This work represents the first enantioselective
catalytic addition of any type of nucleophile to this class of
nitroalkenes. Moreover, for the successful implementation
of this method, a new type of N-sulfinyl urea catalyst with
chirality residing only at the sulfinyl group was developed,
thereby enabling the incorporation of a diverse range of
achiral diamine motifs. Finally, the Meldrum’s acid
addition products were readily converted to pharmaceuti-
cally relevant 3,5-disubstituted pyrrolidinones in high yield.
transformation, in which the addition of α-substituted Mel-
drum’s acids provides 7 in good yields with high enantiose-
lectivities (Scheme 1b). Notably, successful addition was
achieved using the versatile new N-sulfinyl urea catalyst 3k,
which is chiral solely at sulfur and thus allowed for
straightforward exploration of a variety of achiral diamine
motifs. Importantly, the Meldrum’s acid addition products 7 are
readily converted in a convenient and high-yielding two-step
process to the therapeutically relevant class of 3,5-disubstituted
pyrrolidinones (Figure 1).9,10
ecently, we reported the enantio- and diastereoselective
R
addition of cyclohexyl Meldrum’s acid to α,β-disubstituted
nitroalkenes (Scheme 1a).1−3 This transformation represented
Scheme 1. Previous and Current Work
Figure 1. Representative bioactive 3,5-disubstituted pyrrolidinone
derivatives.
Our investigation began with the addition of α-methyl
Meldrum’s acid derivative 8a to 2-nitropropene (6a)11
(Scheme 2). While N-sulfinyl urea catalyst 3a, which had
previously been successfully employed for additions to α,β-
disubstituted nitroalkenes,1 resulted in an encouraging 50% ee,
a screen of various N-sulfinyl urea catalysts incorporating
different chiral diamines did not result in improved selectivity.
However, this screen did establish that catalysts 3a and 3b
incorporating enantiomeric (1S,2S)- and (1R,2R)-1,2-cyclo-
hexanediamine, respectively, gave equivalent selectivities with
the same sense of stereoinduction. This result suggested that
the N-sulfinyl group is the dominant stereocontrolling element
for this transformation, in contrast to previously successful N-
sulfinyl urea catalysts that relied upon the cooperative effect of
an additional chiral controlling element along with the sulfinyl
stereocenter.6a−c The potential ramifications of exclusive N-
sulfinyl stereocontrol include (1) a simplified catalyst without
multiple stereocenters and (2) a greater degree of structural
versatility in catalyst optimization.
the first example in which high enantio- and diastereoselectivity
was achieved upon addition of a carbon nucleophile to acyclic
α,β-disubstituted nitroalkenes. The key advance enabling this
transformation was kinetic protonation of the nitronate addition
product, which was possible because Meldrum’s acid (pKa = 7−
8 in DMSO)4 is considerably more acidic than the product
nitroalkane (pKa = 16−17 in DMSO),4 and thus, the newly
formed stereocenter was preserved. We hypothesized that N-
sulfinyl urea-catalyzed5,6 addition of Meldrum’s acid derivatives
to α-substituted nitroalkenes lacking β-substituents should also
be followed by kinetic protonation, which potentially could
proceed by an enantioselective process. However, no examples
of catalytic enantioselective addition of any type of nucleophile
to terminally unsubstituted nitroalkenes using either transition-
metal or organic catalysts had previously been reported.7,8
To probe whether a catalyst possessing only a sulfur
stereocenter could be used, catalyst 3c with a simplified
Received: March 17, 2012
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Scheme 2. Discovery of Dominant Sulfinyl Stereocontrol
Scheme 4. Identification of the Optimal Catalyst
ethylenediamine backbone was synthesized and evaluated; it
provided addition product 9a with 36% ee (Scheme 2). The
enantioselectivity was only marginally diminished, thereby
demonstrating that the chiral cyclohexanediamine backbone
was not an essential stereodetermining element. Furthermore,
placement of geminal dimethyl substitution on the ethylenedi-
amine linker (catalyst 3d) provided 9a with 57% ee, indicating
that this type of N-sulfinyl urea catalyst could indeed be further
modified to increase the selectivity. Importantly, catalyst 3d
displayed a significant temperature effect. Cooling the reaction
solution from room temperature to −15 °C provided the
product with 77% ee.12 Encouraged by this result, we sought to
optimize this transformation by using catalysts prepared from
achiral diamines.
reaction to become too sluggish to be considered. Interestingly,
the pyridine catalyst 3f gave relatively high conversion,
although with decreased selectivity, suggesting that the catalyst
structure was not necessarily limited to alkylamine bases.
Catalyst 3g possessing an increased tether length relative to 3c
(Scheme 2) provided the product with reduced conversion but
comparable selectivity, indicating that a three-carbon linker
could be a viable alternative to a two-carbon linker.13
Comparison of catalysts 3d and 3h−j suggested that the six-
membered piperidine ring provides the optimal amine
geometry. The high conversion observed with the less basic
pyridine catalyst 3f prompted us to explore less basic analogues
of the optimal piperidine catalyst 3d. To our delight, catalyst 3k
possessing a morpholine unit14 increased the enantioselectivity
to 88% ee. Notably, the corresponding tert-butylsulfinamide-
derived catalyst incorporating the morpholine base, 3l, gave
poor selectivity, further defining the importance of the
trisylsulfinyl group. Piperazine derivatives 3m and 3n with N-
pivaloyl and carbobenzyloxy groups, respectively, also per-
formed well. In contrast, piperazine catalyst 3o with an N-tosyl
group was much less efficient and less selective. Not
surprisingly, piperazine 3p with an additional basic site did
not perform well. The possibility of adding an exogenous base
to a simple trisylsulfinyl urea lacking amine functionality was
also explored, but all of the bases evaluated, including N-
methylmorpholine, pyridine, and inorganic bases, gave <10% ee
(see the SI for full details). Morpholine catalyst 3k was thus
selected for further experiments because of its high selectivity
and ease of preparation in a single step from commercially
available components.15
Prior to the full exploration of the diamine component of the
catalyst, Meldrum’s acid derivatives incorporating different
acetal substituents (R) were evaluated [Scheme 3; see the
Scheme 3. Influence of the Meldrum’s Acid Substituents
Supporting Information (SI) for full details]. The simplest
derivative, 5a (R = Me), gave the highest selectivity and was
employed in all subsequent studies. Meldrum’s acid 5a is
preferable to derivatives with other R groups because of its low
cost and the fact that hydrolysis of its addition products
produces volatile and easily removed acetone as the byproduct
(see below).
We next synthesized a range of N-sulfinyl urea catalysts to
explore several different aspects of the achiral diamine structure,
including the tether length, geminal substituents, and
modulation of the steric environment and basicity of the
tertiary amine base (Scheme 4). In evaluating the different
catalysts, a slight excess of Meldrum’s acid (1.5 equiv) was
employed to buffer the reaction solution, thereby ensuring that
no postreaction racemization would occur. Changing the
geminal substituents from methyl to phenyl (3e) caused the
With catalyst 3k, the reaction conditions were further
optimized for yield and enantioenrichment. The commercially
available nitroalkene was used in excess (2−3 equiv), and the
concentration was increased from 0.1 to 0.2 M. With these
changes, the reaction solution could be further cooled from
−15 to −30 °C, which provided a substantial increase in the
enantioselectivity while maintaining high conversion at
convenient reaction times (15−48 h). Finally, the addition of
B
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Journal of the American Chemical Society
Communication
3 Å molecular sieves was found to improve the consistency
from run to run (see the SI for complete data).16
With the optimized conditions in hand, we explored the
reaction scope (Table 1). A range of α-alkyl-substituted
more acidic, α-acetoxy Meldrum’s acid was also an excellent
substrate, providing product 7k in 90% yield with 94% ee.
While 2-nitropropene proved to be an excellent substrate for
the reaction, a number of other nitroalkenes performed equally
well. Specifically, comparable yields and selectivities were
observed for additions to 2-nitrobutene (adducts 7l and 7m) as
well as other linear (7n) and branched (7o) terminal
nitroalkenes.
Table 1. Catalytic Conjugate Addition/Enantioselective
Protonation of Nitroalkenes with α-Substituted Meldrum’s
Acids
We envisioned that addition products 7 would be versatile
intermediates for the asymmetric synthesis of γ-amino acid
derivatives and in particular for pharmaceutically relevant 3,5-
disubstituted pyrrolidinones. This transformation would require
reduction of the nitro group in adducts 7 without
epimerization, followed by lactamization with extrusion of
acetone and subsequent diastereoselective decarboxylative
protonation (Scheme 5). However, we could not find relevant
Scheme 5. Rapid Synthesis of α,γ-Disubstituted γ-Lactams
precedent for racemization-free reduction and cyclization of α-
substituted nitroalkanes. Although many reducing conditions
gave incomplete conversion, racemization, or multiple prod-
ucts, clean reduction and cyclization occurred in nearly
quantitative yield upon treatment of 7a with metallic indium
and HCl in H2O/THF (Scheme 5).17,18 Only a single literature
report was available for diastereoselective decarboxylative
protonation of α-substituted α-carboxypyrrolidinones, and the
transformations proceeded with only modest selectivities.19 We
therefore explored thermal decarboxylation of lactam 10a using
a range of aprotic solvents and reaction temperatures. We were
pleased to find that decarboxylative protonation in acetonitrile
at 100 °C proceeded with 95:5 dr,20 providing 11a as single
diastereomer in 70% yield after column chromatography.
Furthermore, the optimized two-step process for reduction,
cyclization, and decarboxylative protonation provided high
yields and comparably high diastereoselectivities for phenethyl-
substituted adduct 11d and α-acetoxy derivative 11k.
a
Yields are of isolated products after chromatography. Enantiomeric
b
excess was determined using chiral HPLC analysis. The absolute
stereochemistry of 7a was determined by X-ray analysis, and those of
c
7b−o were assigned by analogy to 7a. The yield and ee correspond to
a reaction run at −50 °C for 90 h. The standard conditions provided 7j
in 87% yield with 83% ee.
In summary, we have developed a catalytic enantioselective
addition of α-substituted Meldrum’s acids to α-substituted
nitroalkenes. This reaction is the first example of nucleophilic
addition to a terminally unsubstituted nitroalkene followed by
enantioselective protonation, and it demonstrates the viability
of this disconnection in asymmetric synthesis. In the develop-
ment of this transformation, a new type of N-sulfinyl urea
catalyst with chirality residing only at the sulfinyl group was
also identified, thereby allowing modifications to the diamine
portion of the catalyst structure that previously were not
possible. Finally, we have demonstrated that the addition
products can readily be converted with high diastereoselectivity
to the important class of 3,5-disubstituted pyrrolidinones,
which are present in a number of bioactive compounds and
serve as convenient intermediates to substituted γ-amino acids
and pyrrolidines.
Meldrum’s acids served as effective coupling partners, with
methyl, ethyl, isobutyl, and phenethyl substituents, providing
the addition products 7a−d in good yields with >92% ee.
Importantly, the reaction was tolerant of a number of functional
groups, including aryl ethers, aryl bromides, thioethers, and
esters (adducts 7e−i and 7k). In view of the scope of the
Meldrum’s acid component and the straightforward introduc-
tion of diverse alkyl substituents, this method should serve as
an excellent means of incorporating functionality into more
complex molecules. While α-benzyl Meldrum’s acid provided
the product with somewhat lower selectivity (83% ee) at −30
°C, decreasing the temperature to −50 °C and extending the
reaction time increased the selectivity to 87% ee (adduct 7j).
Notably, the substituent of the Meldrum’s acid derivative was
not limited to an α-alkyl group. Despite being significantly
C
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Journal of the American Chemical Society
Communication
examples of enantioselective protonation not involving nitroalkenes,
see: (b) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
(c) Kieffer, M. E.; Repka, L. M.; Reisman, S. E. J. Am. Chem. Soc. 2012,
134, 5131. (d) Sadow, A. D.; Haller, I.; Fadini, L.; Togni, A. J. Am.
Chem. Soc. 2004, 126, 14704.
ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures, product characterization,
HPLC traces, and a CIF file. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(9) (a) Gruel, J. N.; Gaertzen, O.; Helmke, H.; Hilebrand, S.; Ilg, K.;
Mattes, A.; Wasnaire, P.; Nising, C. F.; Wachendorff-Neumann, U.;
Voerste, A.; Dahmen, P.; Meisssner, R.; Braun, C. A.; Kaussmann, M.;
Hadano, H. Preparation of Analinopyrimidines as Agrochemical
Fungicides. Patent WO 2010025831 (A1). (b) Stierle, A. A.; Stierle,
D. B.; Patachini, B. J. Nat. Prod. 2008, 71, 856. (c) Aicher, T. D.;
Chicarelli, M. J.; Hinklin, R. J.; Tian, H.; Wallace, O. B.; Chen, Z.;
Marby, T. E.; McCowan, J. R.; Snyder, N. J.; Winneroski, L. L.;
Leonard, L.; Allen, J. G. Preparation of Cycloalkyl Lactam Derivatives,
Particularly N-Substituted Pyrrolidin-2-ones, as Inhibitors of 11β-
Hydroxysteroid Dehydrogenase 1. Patent WO 200649952 A1.
(d) Askew, B. C.; Smith, G. R. Synthesis and Use of Substituted
Pyrrolidin-1-yl-Hexanoic Acid Derivatives as avβ3 and avβ5 Integrin
Receptors. Patent WO2001024797 A1.
AUTHOR INFORMATION
Corresponding Author
jonathan.ellman@yale.edu
■
Author Contributions
†K.L.K. and J.D.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSF (CHE-1049571). We thank
A. Rheingold and the UCSD X-ray crystallography facility for
solving the crystal structure of 7a and Dr. C. Senanayake at
Boehringer Ingelheim for supplying trisylsulfinamide.
(10) For catalytic enantioselective methods that provide access to the
4-substituted pyrrolidinones, see: (a) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127,
119. For a general method to access 4,5-disubstituted pyrrolidinones,
see: (b) Reference 1. For access to 3,4,5-trisubstituted pyrrolidinones,
REFERENCES
■
see: (c) Duschmale,
For a nice review of diastereoselective methods, see: (d) Ordon
Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
́
J.; Wennemers, H. Chem.Eur. J. 2012, 18, 1111.
(1) Kimmel, K. L.; Weaver, J. D.; Ellman, J. A. Chem. Sci. 2012, 3,
121.
́
ez, M.;
̃
(2) For enantioselective catalytic additions of Meldrum’s acid to β-
substituted nitroalkenes proceeding with modest selectivities, see:
(a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (b) Bassas, O.; Huuskenon, J.; Rissanen, K.; Koskinen, A. M. P.
Eur. J. Org. Chem. 2009, 1340. (c) Kleczkowska, E.; Sas, W. Pol. J.
Chem. 2007, 81, 1457.
(11) Use of unsubstituted Meldrum’s acid led to overalkylation.
(12) Catalyst 3d provided 9a with 57% ee at 23 °C and 77% ee at
−15 °C, whereas 3a provided 9a with 50% ee at 23 °C and 62% ee at
−15 °C. The greater temperature effect may result from the increased
amount of rotational freedom in 3d, which upon cooling increasingly
reacts through a more selective conformer.
(3) For leading references on the organocatalytic addition of the
related malonates to β-substituted and cyclic α,β-disubstituted
nitroalkenes, see: (a) Reference 2a. (b) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun. 2005, 4481. (c) Li, H.; Wang, L. T.; Deng, L. J.
Am. Chem. Soc. 2004, 126, 9906. (d) Xu, F.; Corley, E.; Zacuto, M.;
Conlon, D. A.; Pipik, B.; Humphrey, G.; Murry, J.; Tschaen, D. J. Org.
Chem. 2010, 75, 1343. (e) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (f) Zhang, L.; Lee, M.-M.; Lee, S.-M.;
Lee, J.; Cheng, M.; Jeong, B.-S.; Park, H.-G.; Jew, S.-S. Adv. Synth.
Catal. 2009, 351, 3063. (g) Chen, W.-Y.; Li, P.; Xie, J.-W.; Li, X.-S.
Catal. Commun. 2011, 12, 502.
(13) For a nice example of the design of an innovative four-carbon
chiral diamine linker, see: Palacio, C.; Connon, S. J. Chem. Commun.
2012, 48, 2849.
(14) Morpholine is ∼2 pKa units less basic than piperidine.4
(15) Catalyst 3k was made via 1,1’-carbonyldiimidazole coupling of
commercially available trisylsulfinamide and 2-methyl-2-morpholino-
propan-1-amine in ∼80% yield on a 1 mmol scale. The synthesis of the
piperazine catalysts (3m−p) was lengthier. See the SI for full details.
(16) The racemic β-hydroxynitroalkane generated by hydration of
the nitroalkene starting material reduced the enantioselectivity of the
reaction. Molecular sieves prevented formation of this product and
consequently resulted in improved reproducibility.
(4) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(5) For reviews of H-bonding catalysis, see: (a) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b) Takemoto,
Y. Org. Biomol. Chem. 2005, 3, 4299. (c) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713. (d) Akiyama, T. Chem. Rev. 2007, 107,
5744. (e) Yu, X.; Wang, W. Chem.Asian J. 2008, 3, 516. (f) Terada,
M. Synthesis 2010, 1929. (g) Rueping, M.; Koenigs, R. M.; Atodiresei,
I. Chem.Eur. J. 2010, 16, 9350.
(17) For indium-mediated nitro reduction, see: Singh, V.; Kanojiya,
S.; Batra, S. Tetrahedron 2006, 62, 10100.
(18) Reduction occurred with preservation of the α-nitro stereo-
center under the indium/HCl conditions. Enantiomeric purities were
determined by chiral HPLC analysis.
(19) (a) Diastereoselective decarboxylative protonation of 3-
substituted pyrrolidinones has been reported only for an N-H
pyrrolidinone (with ∼3:1 dr) and an N-pivaloyl pyrrolidinone (with
55:45 dr). See: Hook, D.; Thomas, R.; Bernhard, R.; Wietfeld, B.;
Sedelmeier, G.; Napp, M.; Baenziger, M.; Hawker, S.; Ciszewski, L.;
Waykole, L. M. New Process. WO2008083967 (A2). (b) In analogy
with Meyers’ alkylations of enolates of simple N-methyl-5-methyl-
pyrrolidinone, it was expected that the decarboxylative protonation
should also take place from the face opposite the 5-substituent and
that the magnitude of the diastereoselectivity would be greater for N-H
than N-carbamoyl pyrrolidinones. For an excellent explanation of this
phenomenon, see: Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J.
F. J. Am. Chem. Soc. 1997, 119, 4565.
(6) For examples of organocatalysts containing sulfinamide, see: (a)
Reference 1. (b) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am.
Chem. Soc. 2007, 129, 15110. (c) Kimmel, K. L.; Robak, M. T.; Ellman,
J. A. J. Am. Chem. Soc. 2009, 131, 8754. (d) Kimmel, K. L.; Robak, M.
T.; Thomas, S.; Lee, M.; Ellman, J. A. Tetrahedron 2012, 68, 2704.
(e) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Tetrahedron 2011, 67,
4412. (f) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986. (g) Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun,
J. Org. Lett. 2006, 8, 5913.
(7) For an example of a chiral auxiliary approach to asymmetric [4 +
2] cycloaddition involving a terminally unsubstituted nitroalkene, see:
(a) Barluenga, J.; Aznar, F.; Ribas, C.; Valdes, C. J. Org. Chem. 1997,
́
62, 6746. For an example of nucleophilic addition to a terminally
unsubstituted nitroalkene to form a cyclic product with diastereose-
lective protonation via thermodynamic control, see entry 13 of Table 2
in: (b) Wang, Y.; Zhu, S.; Ma, D. Org. Lett. 2011, 13, 1602.
(20) The relative configuration of decarboxylated lactam 9a was
determined to be cis by correlation with literature 1H NMR data. See:
Crich, D.; Ranganathan, K. J. Am. Chem. Soc. 2005, 127, 9924.
(8) For a review of enantioselective protonation, see: (a) Mohr, J.
T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359. For selected
D
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