Unprecedented hydrophobic amplification in noncovalent organocatalysis "on water": Hydrophobic chiral squaramide catalyzed michael addition of malonates to nitroalkenes

Article abstract of DOI:10.1021/acscatal.5b00685

In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addition of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was observed when the reaction was performed "on water" rather than in the conventional organic solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an ethyl group at the C3-position, even a highly challenging Michael donor such as dimethyl methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under "on water" conditions, the catalyst loading also significantly decreased. Thus, in the case of β-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temperature, affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.

Full text of DOI:10.1021/acscatal.5b00685

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Article
Unprecedented Hydrophobic Amplification in Noncovalent
Organocatalysis "on Water": Hydrophobic Chiral Squaramide
Catalyzed Michael Addition of Malonates to Nitroalkenes
Han Yong Bae, and Choong Eui Song
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b00685 • Publication Date (Web): 04 May 2015
Downloaded from http://pubs.acs.org on May 7, 2015
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Unprecedented Hydrophobic Amplification in
Noncovalent Organocatalysis "on Water":
Hydrophobic Chiral Squaramide Catalyzed Michael
Addition of Malonates to Nitroalkenes
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Han Yong Bae and Choong Eui Song*
Department of Chemistry, Sungkyunkwan University, Gyeonggi, 440ꢀ746, Korea. Eꢀmail:
s1673@skku.edu
ABSTRACT
In this study, water was demonstrated to be an exceptionally efficient reaction medium for the
noncovalent, hydrogenꢀbonding promoted enantioselective Michael addition of malonates to
diverse nitroolefins using cinchonaꢀbased squaramide catalysts. A significant increase in the
reaction rate was observed when the reaction was performed "on water" rather than in the
conventional organic solvents, because of the hydrophobic hydration effect. This hydrophobic
amplification was significantly dependent upon the hydrophobicity of the C3ꢀsubstituent (vinyl
or ethyl) of cinchonaꢀbased catalysts. Thus, the use of more hydrophobic catalyst with an ethyl
group at the C3ꢀposition, even a highly challenging Michael donor such as dimethyl
methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the
remarkable rate acceleration under “on water” conditions, the catalyst loading also significantly
decreased. Thus, in the case of βꢀketoesters, even 0.01 mol% of catalyst loading was enough to
complete the reaction at room temperature, affording the corresponding Michael adducts with
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perfect diastereoꢀ and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed "on
water" protocol was successfully applied for the scalable syntheses of an antidepressant (S)ꢀ
rolipram and an anticonvulsant (S)ꢀpregabalin.
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KEYWORDS: noncovalent organocatalysis "on water", malonates as Michael donors,
hydrophobic hydration, hydrophobic substituent effect, Log P
INTRODUCTION
Organic solvents are obviously the most used materials in the manufacture of active
pharmaceutical ingredients (APIs). In general, they make up >80% of the total material usage,
giving rise to considerable energy usage, expense, and industrial pollution.1 To reduce or prevent
the use of organic solvents as the reaction medium, water is supposed to be an ideal alternative
for industrial processes. Water is inexpensive, nontoxic, inflammable, and nonexplosive.
Moreover, its high heat capacity makes it ideally suited for exothermic reactions on an industrial
scale.2 In nature, water is the only medium used for biosynthetic reactions to sustain life. The
“hydrophobic effect” is one of the key elements in such enzyme catalysis.3
From the perspective of green chemistry as well as increased scientific effort to mimic nature,
significant attention has recently been directed to the development of asymmetric catalytic
reactions in aqueous environments.4 There have been a number of successful reports of metalꢀ
catalyzed asymmetric reactions4,5 and asymmetric organocatalytic reactions involving covalent
bonding activation (using primary or secondary amine catalysts) in aqueous media.4,6 However,
the introduction of water as a solvent in the noncovalent, hydrogenꢀbonding promoted
asymmetric catalysis has not yet been extensively reported, as it was believed that water can
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interfere with the catalysis, because of its capacity for disrupting hydrogen bonds. Recently, the
Schreiner7a and Rueping7b groups independently reported in their pioneering works that
noncovalent organocatalysis under aqueous environment is not unachievable and can even be
amplified by “hydrophobic hydration” 8,9. Soon after, we7c also observed the remarkable
hydrophobic amplification of enantioselective hydrogen bonding promoted organocatalysis in
aqueous medium. More recently, Armas and GarcíaꢀTellado also reported a successful result of
hydrogen bonding promoted asymmetric AzaꢀHenry reaction in aqueous medium.7d
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In recent years, the transitionꢀmetal free stereoselective preparation of γꢀaminobutyric acid
(GABA) analogs, which are widely used for inhibitory neurotransmitters such as the
antidepressants (R)ꢀphenibut and (R)ꢀbaclofen, and an anticonvulsant (S)ꢀpregabalin (marketed
by Pfizer, brand name Lyrika®), have been intensively studied by several research groups.10
Moreover, organocatalytic routes for the production of the antidepressants (R)ꢀrolipram and
paroxetine,11 and an aminopiperidineꢀfused imidazopyridine dipeptidyl peptidase IV (DPPꢀ4)
inhibitor12 were also investigated. To access the aforementioned valuable bioactive chiral
compounds, the metalꢀfree asymmetric organocatalytic Michael addition of malonates 2 to
nitroolefins 1 was shown to be a powerful approach from a green chemistry perspective (Scheme
1). Although impressive progress has been made in terms of organocatalytic synthesis of the
optically active Michael adducts 3,13 a more environmentally benign as well as scalable synthetic
protocol is still truly required.
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Scheme 1. A Strategy to Bioactive Compounds via Noncovalent Asymmetric Organocatalytic
Michael Addition of Malonates to Nitroalkenes.
In our previous communication, we reported that the enantioselective Michael addition of 1,3ꢀ
diketones or βꢀketoesters to nitroolefins using quinineꢀbased squaramide (QN-SQA) catalyst was
dramatically accelerated on brine compared to the reaction in organic solvents, because of the
hydrophobic hydration effect (Scheme 2).7c,14 However, under the same conditions, malonates as
the Michael donors proved to be very poor substrates, because of their 104 to 102 times lower
pKa values than those of 1,3ꢀdiketones and βꢀketoesters, respectively.15
We presumed that this limitation of substrate scope could be addressed simply by increasing
catalyst hydrophobicity, which might result in enforced hydrophobic interactions and,
consequently more significant rate acceleration under heterogeneous aqueous conditions. The
common approach to increase the catalyst’s hydrophobicity is installing more hydrophobic
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substituents (e.g., long alkyl chain, fluoroalkyl chain, and bulky aromatic moiety) on the catalyst
structure.16
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Herein, we report our findings on the remarkable hydrophobic amplification derived from the
catalyst substituent effect in the noncovalent asymmetric Michael addition reaction of malonates
to nitroalkenes “on water”; 17,18 i.e., the hydrophobic amplification was highly dependent upon
the hydrophobicity of the catalysts. Thus, using more hydrophobic catalyst, the substrate scope
was not limited to the αꢀunsubstituted malonates. Even highly unreactive αꢀsubstituted malonates
such as dimethyl methylmalonate also showed good reactivity. The obtained Michael adducts
were smoothly transformed into diverse bioactive compounds, which was highlighted by
synthesis of of the anticonvulsant drug (S)ꢀpregabalin on a multiꢀten gram scale. The key step of
this protocol needs no chromatography to obtain the desired product and to recover the catalyst.
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RESULT AND DISCUSSION
Our studies commenced with performing enantioselective Michael addition on brine19 using 1
mol% of differently substituted cinchonaꢀderived squaramide organocatalysts to investigate the
effect of the substituent at carbon C3 (cinchona numbering) on the catalytic efficiency.20 The
conversion and the ee value were measured after 1 h of the reaction time (Scheme 2). As
aforementioned, the quinineꢀbased squaramide QN-SQA bearing vinyl group at C3 carbon21
showed poor activity in the Michael addition of dimethyl malonate (2a) to βꢀnitrostyrene (1a),
yielding the adduct (S)ꢀ3a in only 34% of conversion with 90% ee.7c However, surprisingly,
when more hydrophobic dihydroquinine derived squaramide HQN-SQA was used, an enormous
rate acceleration was observed with excellent enantioselectivity (>99% conv., 92% ee).
Moreover, by increasing the catalyst loading to 5 mol%, the reaction completed within 30 min
retaining the enantioselectivity (91% ee). As expected, this substituent effect on the catalytic
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results can be simply ascribed to the difference in the hydrophobicity of the catalysts, i.e., C3ꢀ
ethyl group incorporated HQN-SQA is more hydrophobic than the C3ꢀvinyl group incorporated
QN-SQA. The same trends for the catalytic efficiency were also observed using the pseudoꢀ
enantiomeric catalysts (quinidineꢀbased squaramide catalyst QD-SQA: 55% conv., 90% ee;
dihydroquinidineꢀbased squaramide catalyst HQD-SQA: >99% conv., 91% ee). The remarkable
effect of the C3 substituent of the catalyst on the reactivity is shown in Figure 1.22 Notably, Liu
and coworkers quite recently reported that heterogeneous cinchonaꢀbased squaramide catalyst
bearing hydrophobic C3 substituent (ꢀCH2CH2SCH2CH2CH2ꢀ) also displayed excellent catalytic
activity and enantioselectivity in asymmetric Michael addition of 1,3ꢀdicarbonyl compounds to
nitroalkenes in brine.14f
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Scheme 2. Dramatic Effect of the Catalyst Hydrophobicity on the Reactivity in the
Enantioselective Michael Addition "on Water".a
aReactions were performed with 1a (1.0 mmol), 2a (2.0 equiv), and catalyst (1 mol%) on
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brine (3.0 mL) at room temperature (r.t.). The conversion was determined by H NMR
integration, and the %ee was determined by HPLC analysis on a chiral stationary phase.
bIsolated yield. cDCM = dichloromethane
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HQN-SQA
HQD-SQA
QN-SQA
QD-SQA
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Figure 1. Reaction progress of the Michael addition of 2a to 1a on brine catalyzed by the
squaramide catalysts: reactions were performed with 1a (1.0 mmol), 2a (2.0 mmol) and
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catalyst (1 mol%) on brine (3.0 mL) at r.t. The conversion was determined by H NMR
integration. See the Supporting Information for details.
To investigate the relationship between the catalyst structure and hydrophobicity,
computational calculation of Log P values was performed using SPARTAN 14® software (Table
1).23 As expected, the Log P values of HQN-SQA and HQD-SQA showed higher (2.68 and 5.29)
than those of QN-SQA and QD-SQA (2.41 and 5.02), respectively (see the Supporting
Information for details).
Table 1. Computational Calculation Data of Log P Values of Squaramide Catalysts.
Catalyst
HQN-SQA
QN-SQA
HQD-SQA
QD-SQA
Log P
2.68
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Evidence of the hydrophobic hydration effect on the remarkable rate acceleration was obtained
by performing HQN-SQA catalyzed Michael addition of 1a with 2 under different aqueous
conditions (see Ref. 24ꢀ25 and the Supporting Information for details). The rate of the reaction
dramatically decreased by the addition of typically antihydrophobic LiClO4 (r.t., 60 min, 14%
conv.).8 Moreover, the observation of a significant solvent isotope effect provides additional
support for the hydrophobic hydration mechanism: the reaction slowed noticeably when NaCl in
D2O was used in the place of brine (r.t., 60 min, 22% conv.).26
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With the optimized catalysts (HQN-SQA and HQD-SQA) in hand, the scope of the reaction
with diverse nitroolefins (1a–1l) and malonates (2a–c)27 was investigated using 2–5 mol% of
catalyst (Scheme 3). Excellent enantioselectivities (90–93% ee) and yields (86–99%) were
observed for diverse aryl (1a–1h), heteroaryl (1i), alkyl (1j–1l) substituted βꢀnitroolefins,
whereas less hydrophobic catalyst QN-SQA showed significantly lower activity.28 In all the
cases, significant rate acceleration was observed on brine because of the hydrophobic hydration
effect.
To highlight the significant hydrophobic amplification effect, the Michael addition reaction of
a highly challenging substrate such as dimethyl methylmalonate (2c), which shows very poor
reactivity in the conventional organic solvents,29 was examined. As shown in Figure 2, the
reaction with 2c proceeded very sluggishly using both HQN-SQA and QN-SQA in DCM (after
15 h, 7 % conv. and 4% conv., respectively). However "on water", remarkable rate acceleration
was observed when a more hydrophobic catalyst HQN-SQA was used (15 h, 95 % conv.),
whereas a less hydrophobic catalyst QN-SQA showed significantly lower activity (15 h, 32%
conv.).
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Scheme 3. Substrate Scope of the Reaction.a
aGeneral reaction conditions:
(1.0 mmol),
1
2 (2.0 mmol), and HQN-SQA (2 mol%) on
3.0 mL of brine at r.t. The yield was determined after the chromatographic purification,
and the % ee was determined by HPLC analysis on a chiral stationary phase. bUsing HQD-
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SQA as the catalyst. cUsing 5 mol% of catalyst at 0
5 mol% of the catalyst at r.t. Using 5.0 equiv. of 2c.
°
C
. dUsing 10 mol% of catalyst at r.t. eUsing
f
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HQN-SQA/ DCM
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Figure 2. Reaction progress of the Michael addition of 2c to 1a catalyzed by the squaramide
catalysts. Reactions were performed with 1a (1.0 mmol), 2c (5.0 equiv) and catalyst (5
mol%) in DCM (3.0 mL) or on brine (3.0 mL) at r.t. The conversion was determined by
1H NMR integration (see the Supporting Information for details).
Although enantioselective organocatalysis has shown significant progress in terms of noble
activation modes and excellent selectivity,30 a development of highly active catalysis is quite
reluctant.31 Thus, developing high turnover organocatalysis is a remarkably challenging task.32
We anticipated that significantly low catalyst loading can be achievable by taking advantage of
the hydrophobic amplification effect. In accordance with our expectation, when more reactive
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Michael donors such as 1,3ꢀdiketone (4a) and βꢀketoesters (4b,4c) were used, only very low
catalyst loading (up to 0.01 mol%) was enough to complete the reaction at room temperature,
affording the corresponding Michael adducts (5a–5c) with perfect stereoselectivities at r.t. (up to
>99:1 dr, up to >99% ee, Scheme 4). Notably, this high level of stereoselectivities could be
maintained even at elevated temperature (50 °C, 86% conv., 99:1 dr, 96% ee). In contrast, when
the same reaction was performed in DCM at 50 °C, only 9% conversion and much lower
stereoselectivity (3:1 dr, 69% ee) were obtained (see the Supporting Information for details).
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Scheme 4. Enantioselective Michael Addition Reactions of 2,4ꢀPentanedione (4a) and
4c) to Nitrostyrene (1a).a
βꢀ
Ketoesters (4b
,
aReactions were performed with 1a (10.0 mmol), 4 (2.0 equiv) and HQN-SQA catalyst on brine
(10.0 mL) or in DCM (10.0 mL). The conversion and the diastereomeric ratio (dr) were
1
determined by H NMR integration. The % ee was determined by HPLC analysis on a chiral
stationary phase. See the Supporting Information.
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To demonstrate the synthetic utility of our "on water" protocol, the syntheses of
pharmaceutically important γꢀamino acids such as (S)ꢀrolipram 7 and (S)ꢀpregabalin 8 were
performed. The enantiopure (S)ꢀ3g (obtained by the recrystallization from MTBE/hexane 1:4)
was smoothly converted to chiral γꢀlactam 6 by the reduction of the nitro group using Raney
Ni/H2 (85% yield). Enantiomerically pure (S)ꢀrolipram 7 ([α]D18 = + 25.9 (c = 0.50, MeOH); lit.33
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[α]D = +26.2 (c = 0.6, MeOH)) was then obtained in 82% yield by the decarboxylative
elimination of methyl ester group of 6 (Scheme 5A). Moreover, multiꢀten gram scale synthesis of
an anticonvulsant blockbuster drug (S)ꢀpregabalin was also achieved successfully (Scheme 5B,
see the Supporting Information for details). The Michael addition reaction of 1j with dimethyl
malonate (2a) using 5 mol% of HQD-SQA was performed at 250 mmol scale (Figure 3a) to
afford the desired product, (S)ꢀ3j (Figure 3b, 24 h, >95% conv., 91% ee). The catalyst HQD-
SQA was quantitatively recovered by simple filtration from the reaction mixture as a yellowish
solid (with recovery yield >99%) after the addition of methylcyclohexane (Figure 3c). After the
separation of the organic layer from the biphasic filtrate (Figure 3d) and evaporation under
reduced pressure, the crude product was hydrogenated using Raney Ni/H2, affording chiral γꢀ
lactam 8 in 86% yield (the 3,4ꢀanti selectivity was determined by the single crystal Xꢀray
analysis34). Consequently, the hydrolysis of γꢀlactam 8 with 6N HCl afforded the (S)ꢀpregabalin
9 in 95% yield and 91% ee. Enantiomerically pure (S)ꢀpregabalin was obtained by simple
recrystallization from 2ꢀpropanol/water.
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Scheme 5. Synthetic Utilities of Catalytic Michael Addition.a
aAsymmetric syntheses of (S)ꢀrolipram 7 (A) and (S)ꢀpregabalin 9 (B).
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Figure 3. Pictures of the catalyst recovery and product separation procedure from the
crude mixture of the Michael addition step appearing in Scheme 5B. (a) Before starting
the reaction; (b) after completion of the reaction; (c) after the addition of
methylcyclohexane; (d) after filtration, biphasic filtrate (product (org.)/ brine (aq.)) and
recovered catalyst.
CONCLUSIONS
In summary, we successfully developed an efficient and scalable protocol for hydrogen
bonding promoted asymmetric organocatalytic Michael addition "on water". The Michael
addition of malonates and βꢀketoesters to diverse nitroolefins using a bifunctional cinchonaꢀ
based squaramide organocatalyst was remarkably accelerated, because of the hydrophobic
hydration effect. The hydrophobic amplification could be enforced simply by increasing the
hydrophobicity of the catalyst. Thus, using more hydrophobic catalysts such as HQN-SQA and
HQD-SQA, a highly challenging substrate such as dimehtyl methylmalonate was also smoothly
converted to the desired Michael adduct. For βꢀketoesters as the Michael donors, extremely low
catalyst loading (up to 0.01 mol%) was sufficient to complete the reaction, affording the
corresponding Michael adducts with perfect stereoselectivities. Modifying catalyst
hydrophobicity is the key of this successful catalysis. The developed "on water" protocol was
successfully applied for the scalable syntheses of antidepressants, (S)ꢀrolipram, and
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anticonvulsant (S)ꢀpregabalin drugs. Further studies of other hydrogenꢀbonding promoted
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asymmetric transformations under “on water system” are ongoing in our laboratory.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for C. E. S.: s1673@skku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support provided by the Ministry of Science, ICT and Future
Planning (NRFꢀ2014R1A2A1A01005794 and NRFꢀ2012H1A2A1001158), and the Ministry of
Trade, Industry and Energy (Fundamental R&D Program for the Core Technology of Materials).
The authors also thank Mr. J. H. Sim and Mr. S. Y. Park for their experimental assistance.
Supporting Information
Experimental procedures, characterization data, kinetic data, and Log P calculation data.
Crystallographic data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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L. Synthesis 2007, 2065ꢀ2092. (g) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42–53.
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nitroolefins, see: (a) Dong, Z.; Jin, X. Q.; Wang, P. C.; Min, C.; Zhang, J.; Chen, Z.; Zhou, H. B.;
Dong, C. N. Arkivoc 2011, 367–380. (b) Dong, Z.; Qiu, G. F.; Zhou, H. B.; Dong, C. N.
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Jin, R. H.; Liu, G. H. ACS. Catal. 2014, 4, 2137–2142.
(15) The pKa values 2,4ꢀpentanedione, ethyl acetoacetate (4a) and dimethyl malonate (2a) (in
water) are 9, 11 and 13, respectively. See Evans’ pKa table.
(16) For selected reviews, see: (a) Lombardo, M.; Trombini, C. In EcoꢀFriendly Synthesis of
Fine Chemicals; Ballini, R. Ed.; RSC Publishing: Cambridge, U.K., 2009; pp 1–15. (b)
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Chimni, S. S. Org. Biomol. Chem. 2011, 9, 2731–2742. (k) For an experimental and quantum
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(17) The definition of “on water” conditions referred to insoluble reaction partners mixed in an
aqueous suspension. For more details, see: Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.;
Kolb, H. C.; Sharpless, K. B. Chem. Int. Ed. 2005, 44, 3275–3279.
(18) For selected reviews concerning organic synthesis on water, see: (a) A Chanda, A.; Fokin,
V. V. Chem. Rev. 2009, 109, 725–748. (b) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110,
6302–6337.
(19) Inorganic salts such as LiCl or NaCl decrease solubility of organic species in water by
salting out, consequently resulting in increased hydrophobic effect. See Breslow, R. Acc. Chem.
Res. 1991, 24, 159–164.
(20) Readily available quinineꢀbased sulfonamide QN-SA, thiourea QN-TU and squaramide
QN-N-SQA were also tested in this study. However, all these catalysts led to unsatisfactory
turnover numbers and low to moderate enantioselectivities (r.t., 60 min, 8–68% conv., 34–81%
ee). See the Supporting Information for details.
(21) The QN-SQA was prepared according to the literature procedure. Malerich, J. P.;
Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–14417.
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(22) Cinchonidineꢀderived squaramide CD-SQA and cinchonineꢀderived squaramide CN-SQA
was also investigated under same reaction conditions to investigate the effect of the C6′
substituent. The ee and reactivity (CD-SQA: 4% conversion, 85% ee; CN-SQA: 5% conversion,
87% ee) were conspicuously lower than those obtained with QN-SQA or QD-SQA, indicating
that the methoxy group in the C6′ꢀposition of the quinoline ring is an important moiety for
efficient catalysis. See the Supporting Information for details.
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(23) (a) The P (nꢀoctanol/ water partition coefficient) is defined as the ratio of the equilibrium
concentration of a substance dissolved in a twoꢀphase system, formed by two immiscible
solvents (ranges of P is from 10ꢀ4 to 108, Log P > 0: hydrophobic; Log P < 0: hydrophilic).
ꢀ = ꢁ (ꢂꢃꢄꢅꢆꢇꢂꢄꢈ) (b) Merck Molecular Force Field (MMFF) was employed. For detailed
ꢁ (ꢉꢇꢆꢊꢋ)
calculation data, see the Supporting Information. SPARTAN '14, Wavefunction, Inc., Irvine, CA,
2014.
(24) We performed the same reaction under different aqueous conditions (r.t., 60 min). LiClO4 in
H2O (sat.) = 14% conv.; NaCl in D2O (sat.) = 22% conv.; H2O = 96% conv.; NaCl in H2O (sat.)
(brine) = >99% conv. See the Supporting Information for details.
(25) We also performed the same reaction in organic solvents (r.t., 60 min). 1,4ꢀDioxane = 7%
conv.; MeOH = 34% conv.; Acetonitrile = ~1% conv.; THF = 21 % conv.; Toluene = 17% conv.;
DCM = 52% conv. See the Supporting Information for details.
(26) The viscosity of D2O is ca. 20% higher than that of water that makes the efficient mixing
difficult and thus reduces the hydrophobic effect. See Ref. 17.
(27) Study was conducted to determine the optimal structure of malonates for the Michael
addition to 1a on water. Among the screened substrates, superior reactivities and
enantioselectivities were observed when dimethyl malonate (2a) or dibenzyl malonate were used
as the Michael donors (5 mol% of HQN-SQA, r.t.). Dimethyl malonate (2a) = 30 min, >99%
conv., 92% ee; Dibenzyl malonate = 20 min, >99% conv., 91% ee; Diethyl malonate = 40 min,
>99% conv., 66% ee; Diisopropyl malonate = 420 min, >99% conv., 68% ee; Diꢀtertꢀbutyl
malonate = 1440 min, no reaction.
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(28) The reaction of 1j with 2a smoothly converted to (R)ꢀ3j using HQN-SQA (at r.t., 180 min,
>99% conv.), whereas the same reaction proceeded sluggishly when the less hydrophobic
catalyst QNꢀSQA was used (at r.t., 180 min, 32% conv.; 720 min, 58% conv.) (for detailed
kinetic data, see Supporting Information).
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(29) Examples of dimethyl methylmalonate (2c) as a Michael donor, see: (a) Evans, D. A.;
Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958–9959. (b) Nichols, P. J.; DeMattei, J. A.; Barnett,
B. R.; LeFur, N. A.; Chuang, T.ꢀH.; Piscopio, A. D.; Koch, K. Org. Lett. 2006, 8, 1495–1498. (c)
Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454–1455. (d) Evans, D. A.;
Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583–11592. (e) Andrés, J. M.; Manzano, R.;
Pedrosa, R. Chem. Eur. J. 2008, 14, 5116–5119.
(30) (a) List, B.; Yang, J. W. Science 2006, 313, 1584–1586. (b) MacMillan, D. W. C. Nature
2008, 455, 304–308.
(31) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406–
2447.
(32) Ratjen, L.; van Gemmeren, M.; Pesciaioli, F.; List, B. Angew. Chem. Int. Ed. 2014, 53,
8765–8769.
(33) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem. Int.
Ed. 2007, 46, 8431–8435.
(34) CCDC 1011363 contains the supplementary crystallographic data for compound 8. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre (CCDC)
via www.ccdc.cam.ac.uk/data_request/cif or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44)ꢀ1223ꢀ336ꢀ033.
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