C2-Symmetric Chiral Squaramide, Recyclable Organocatalyst for

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C2-Symmetric Chiral Squramide – Recyclable Organocatalyst for Asymmetric Michael Reactions Alexander Sergeevich Kucherenko, Alexey Alexeevich Kostenko, Andrey Nikolaevich Komogortsev, Boris V. Lichitsky, Michael Yu. Fedotov, and Sergei G. Zlotin J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00252 • Publication Date (Web): 05 Mar 2019 Downloaded from http://pubs.acs.org on March 6, 2019

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The Journal of Organic Chemistry

C2-Symmetric Chiral Squramide – Recyclable Organocatalyst for Asymmetric Michael Reactions

Alexander S. Kucherenko, Alexey A. Kostenko, Andrey N. Komogortsev, Boris V. Lichitsky, Michael Yu. Fedotov and Sergei G. Zlotin* N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991, Moscow, Russian Federation. O

O

O OH

O

N

OH R1

+ R

R3

R3

N

R1

O

NO2

R 2

O

N H

2

O O

N H

12 examples IVb, 1 mol % NO2 up to >99% ee in green solvents Simple one-step available catalyst O O Recycled up to 7 cycles R3 R3 NO2 R2 6 examples up to >99% ee

ABSTRACT: A very simple and highly efficient C2-symmetric tertiary amine–squaramide organocatalyst for asymmetric Michael reactions has been elaborated. In the presence of only 1 mol% of this catalyst, kojic acid derivatives and -dicarbonyl compounds reacted with nitroolefins affording corresponding adducts in nearly quantitative yield with enantioselectivity up to 99% ee. The kojic acid-derived adducts could be efficiently produced under ‘green’ conditions (in 96% EtOH or pure water). Moreover, due to very low solubility in organic solvents, the developed non-supported catalyst could be readily recovered and reused in catalytic reactions up to 7 times. Utmost availability (one-step synthesis without chromatographic purification), high level of stereoinduction, low efficient loading and recyclability make it attractive for industrial application in pharmaceutical industry.

Introduction Over the past decades asymmetric organocatalysis has become a power synthetic tool which allows facile stereoselective assembling complex molecular scaffolds, in particular, those present in natural compounds and active pharmaceutical ingredients, from available pro-chiral or

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racemic precursors.1 This method is now quite complementary or, in some cases, even superior to well-recognized organometallic catalysis in terms of enantioselectivity and application area2. Furthermore, it eliminates the risk of contaminating the reaction products with rather toxic heavy metals inherent in organometallic catalysis. Since List, Lerner and Barbas recognized proline as a very simple enzyme-like catalyst for asymmetric aldol reactions,3 a number of new, more complex Lewis or Brønsted base- or acid-derived organocatalysts for various enantioselective catalytic transformations have been developed.4 Among them, bifunctional tertiary amine-based organocatalysts developed by Jacobsen,5 Takemoto,6 Rawal7 and other researchers attract considerable attention due to their versatility and high level of stereocontrol. Unlike primary and secondary amine derivatives, these catalysts activate carbonyl-free reagents and properly located them in a transition state via stereoselective formation of hydrogen bonds rather than covalent enamine or iminium intermediates.4a Tertiary amines I,8 II9 and III10 bearing chemically resistant H-bonding squaramide group are considered as most robust catalysts for a variety of non-covalently controlled asymmetric Michael reactions11 (Scheme 1). However, compounds I containing lipophilic aryl groups (often fluorinated) have appreciable solubility in organic solvents, which complicates their separation from chiral products unless they are modified by specific polymeric or ionic groups making them heterogeneous (such modification commonly takes several additional synthetic steps).12 Catalysts II and III are characterized by rather high molecular weight and should be used in amounts comparable to those of other reagents, which interferes with product isolation. Therefore, simple, highly available, and readily separable from reaction mixture organocatalysts are still needed for useful practical applications (first of all, in pharmaceutical industry13). Inspired by unique availability, simplicity and efficacy of natural proline, we assumed whether the simplest C2-symmetric low-molecular tertiary amines IV of the squaramide catalytic family, which do not contain lipophilic aryl (fluorinated aryl) groups, would act as efficient organocatalysts of asymmetric Michael reactions. Recently, Du and coworkers14 casually mentioned that IVb provided the poorest stereoinduction (17% ee) in asymmetric sulfa-Michael addition of thioacetic acid to -disubstituted nitroolefins. However, no experimental procedure and/or characterization data for compound IVb were given. Moreover, neither IVb, nor its homologs can be found in major database systems (SciFinder, Reaxys). Therefore, we decided to prepare compounds IVa and IVb and examine their catalytic performance in various Michael reactions.


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O

O

[ ]

Ar

nN

R2 *

N H

H

R1

I

R' * *

N * *

R''

R1 = Alk; R1,R1 = -(CH2)m-; R = aryl, hetaryl; R2,R2 = -(CH2)4-; n = 0, 1; m = 4, 5 O

2 * R

N

* *

R1

H N [ ] Ar

H N

n

N

N R1

R1

II

N

O O HN

NH III

R1

R1

O

O

N H

N H

* *

O

O

R2 R2 * * HN NH

O

2

R1

N R1

*

*

R1

IV

* *

N

R1

R1 = Me (a); R1,R1 = -(CH2)5- (b)

Scheme 1. Research strategy

Results and Discussion Bifunctional tertiary amine–squaramides IVa, IVb and ent-IVb (Figure 1) were synthesized in one step from commercially available inexpensive dimethyl squarate and the corresponding chiral (1R,2R)- or (1S,2S)-diaminocyclohexane derivatives in 80-95% yields. Analytically pure samples of compounds IV were obtained without chromatographic purification as colorless high-melting powders (Mp > 250 oС (dec.)), poorly soluble in common organic solvents and water. O Ar

N H

N H Ia

O O

O

O

(R)(R)

(R) (R)

N

(R) (R)

(S)

H N

H N

O

O

MeO

N

N

O

O

N

(S)

Ar

IIa

I, II: Ar = 3,5-(CF3)2C6H3

(R) (R)

N

N H

O

HN

(R) (R)

N H

N

Ib

NH HN NH

Ar

O

(R) (R)

N

O

N H

IIIa

N H IVa

Figure 1. Bifunctional tertiary amine-squaramides I-IV


(R) (R)

N

(R) (R)

N

O

O

N H

N H

IVb

(R) (R)

N


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Then, we compared catalytic performance of the newly synthesized compounds (IVa, IVb and ent-IVb) and known squaramides (Ia,7c Ib,7c IIa15 and IIIa16) in the model reaction between 5hydroxy-2-methyl-4H-pyran-4-one 1a and nitrostyrene 2a under similar conditions (CH2Cl2, r.t., catalyst loading 1 mol%) (Table 1). In all the cases, product 3aa was generated in high yield (7392% over 6 h) (entries 1-6). Compound 3aa belongs to kojic acid derivatives, which exhibit useful biological activities (antimicrobial17, pesticide/insecticide18, and antitumor19). The best enantiomeric enrichment of product (95% ee) was attained over catalyst IVb (entry 6). Having the best catalyst in hand, we examined catalytic reaction between 1a and 2a in various solvents. Alcohols appeared the media of choice for this asymmetric transformation. Among the tested solvents, the highest stereoinduction of 97% ee (entry 11) was observed in 96% EtOH. This level of stereoinduction even exceeded corresponding ee value (95% ee) attained for this reaction in the presence of quinine–thiourea bifunctional catalyst20a (5 mol%, iPrOH, 5 oС, 7 h) (entry 11, data in square brackets) and was notably higher than enantiomeric enrichments (81-94% ee) in similar reactions catalyzed by 1,2-diaminocyclohexane-derived tertiary amine-thiourea catalyst20b (10 mol%, MeOH, -10 oС, 96 h). It is worthy to note that the aforementioned results provided by the Reddy and Zhang groups are the only available data on the asymmetric Michael reactions with kojic acid derivatives. Moreover, with catalyst IVb the reagent loadings can be increased at least 60-fold and chromatographic purification can be avoided from the workup (entry 11, data in parenthesis). Pure 3aa was obtained by diluting the reaction mixture with water, filtering the precipitate formed, and washing it with cold (0-5 oC) aqueous EtOH (1:1, v/v). A somewhat reduced yield (94%) may be attributed to insignificant solubility of 3аa in aqueous EtOH. Performing the reaction in aqueous EtOH (1:1, v/v) or even in pure water led to noticeable reduction of the yield and enantioselectivity (entries 12 and 13). Nevertheless, entry 13 represents the first asymmetric organocatalytic synthesis of kojic acid derivatives in aqueous medium (only -cyclodextrin-catalyzed racemic syntheses performed at 100 oС21f or under microwave irradiation22 have been reported so far). Reactions in 96% EtOH (Method A) and water (Method B), which do not require chromatographic purification, are prospective from the green chemistry viewpoint23. The reaction in 96% EtOH catalyzed by entIV with the opposite (S)-configuration of stereocenters afforded enantiomeric product ent-3aa with similar yield (99%) and enantiomeric enrichment 96% (entry 14). Table 1. Optimization of the model reaction.a


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O

O OH + Me

O 1a

NO2

Ph

OH

Catalyst (1 mol %) Solvent, r.t.

2a

Me

NO2

O 3aa

Ph

Entry

Cat (1 mol%)

Solvent

T, h

Yield b, 3aa (%)

ee, c(%)

1

Ia

CH2Cl2

6

73

50

2

Ib

CH2Cl2

6

81

85

3

IIa

CH2Cl2

6

82

(-) 81

4

IIIa

CH2Cl2

6

75

84

5

IVa

CH2Cl2

6

90

82

6

IVb

CH2Cl2

6

92

95

7

IVb

THF

6

88

92

8

IVb

EtOAc

6

80

90

9

IVb

i-PrOH

6

96

95

10

IVb

MeOH

6

97

94

11

IVb

EtOH (96%)

6 (10) [7e]

97 (94d)[96e]

97 (96d) [95e]

12

IVb

EtOH/H2O (1/1 v/v)

12

80

85

13

IVb

H2O

12

77

70

14

еnt-IVb

EtOH (96%)

6

97f

(-) 96f

Unless otherwise specified, the reactions were carried out with catalysts I-IV (1 mol%), 1a (30.0 mg, 0.24 mmol) and 2a (35.8 mg, 0.24 mmol) in the corresponding solvent (0.4 mL) at r.t. b Yield after flash chromatography on SG. c HPLC data were obtained on the chiral phase (CHIRALPAK OD-H column, nhexane/i-PrOH 70:30, flow rate 1.00 mL/min, 254 nm; tmajor = 14.9 min, tminor = 20.0 min). d The reaction was carried out with IVb (1 mol%, 70.3 mg), 1a (2.0 g, 15.9 mmol) and 2a (2.37 g, 15.9 mmol) in EtOH (7.0 mL) at r.t. e Ref 20a. fThe reaction product was ent-3aa. a

Kojic acid derivatives 1a-f, bearing methyl, chloromethyl, methoxymethyl and arylthiomethyl groups abundant in bioactive compounds, reacted with aryl- or hetaryl-substituted nitroolefins 2a-e over catalyst IVb (1 mol%) in 96% EtOH to give the corresponding Michael adducts 3 in nearly quantitative yield (80-99%) with excellent enantioselectivity (96-99% ee) (Scheme 2). Lower enantiomeric enrichment of adducts 3ga and 3ha derived from pyrrolidinomethyl- and morpholinomethyl-substituted kojic acids 1g and 1h may be attributed to concurrent non-selective catalysis (auto-catalysis) of the corresponding reactions with tertiary amino groups incorporated into the starting substrates. Surprisingly, excellent stereochemical outcome (up to >99% ee) was also attained in the IVb-catalyzed reactions of functionalized



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substrates 1b-f with nitrostyrene 2a in aqueous medium. However, the aqueous procedure was generally inferior to the catalytic reactions in EtOH with regard to substrate scope, product yield and reaction time. The absolute (R)-configuration of adduct 3aa was established based on a comparison of its specific optical rotation [([]25D = +37.1 (c = 1.0, CHCl3, 97% ee)] with the literature data [([]27D = +36.6 (c = 0.5, CHCl3, 95% ee)].20a,b The same (R)-configuration was assigned to other products 3 by analogy. Scheme 2. IVb-Catalyzed reactions between compounds 1 and 2 in 96% EtOH and pure watera O

O IVb (1 mol. %)

OH +

R1

R1

Method A: EtOH, r.t., 6-24 h Method B: H2O, r.t., 12-24 h

O 2a-e

1a-h

OH

NO2

R2

2

N (g);

NO2

R

3

N

1: R1 = H (a); Cl (b); -OMe (c); -SPh (d); 2-F-C6H4S (e); 4-Cl-C6H4S (f);

O

(h)

O 2

2: R = Ph (a); 4-MeOC6H4 (b); 2,4-diClC6H3 (c); 3-cyclopentyl-4-MeOC6H3 (d); Thienyl (e) Me

O O

O

OH NO2

Ph

O Ph

O

OH NO2

3fa; A: 99%, >99% ee, 12 h B: 80%, 99% ee, 24 h Me Cl

OH NO2

MeO 3ab; A: 95%, 92% ee, 6 h B: 77%, 70% ee, 24 h

OH NO2

Ph

O Ph

Me

O O

OH NO2

OH NO2

O

OH NO2

MeO

Cl

3ad; A: 80%, 99% ee, 24 h B: no reaction

3ac; A: 95%, 91% ee, 24 h B: no reaction

O

N O

O Ph

OH NO2

3ga; A: 99%, 53% ee, 6 h 3ha; A: 99%, 90% ee, 6 h B: 80%, 16% ee, 24 h B: 75%, 50% ee, 24 h

O O

O

N

OH NO2

Ph

Cl

O O

O

OH NO2

Ph

O

S

3ea; A: 99%, >99% ee, 12 h B: 72%, 99% ee, 12 h Me

O

O

PhS

3ba; A: 99%, >99% ee, 8 h 3ca; A: 99%, >99% ee, 6 h 3da; A: 99%, >99% ee, 8 h B: 64%, >99% ee, 12 h B: 67%, 99% ee, 12 h B: no reaction

O

S

O

MeO

OH NO2

Ph

3aa; A: 99%, 97% ee, 6 h B: 77%, 70% ee, 24 h F

O

Cl

a

O

MeO O

OH NO2

S 3ce; A: 99%, 98% ee, 20 h B: 55%, 81% ee, 12 h

All reactions were carried out with catalyst IVb (1 mol %, 1.0 mg), 1 (0.24 mmol) and 2 (0.24 mmol) in EtOH or water (0.4 mL) at r.t. b Yield after flash chromatography on SG. c HPLC data were obtained on chiral phases (CHIRALPAK OD-H or OJ-H column).


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Simple tertiary amine–squaramide IVb exhibited high catalytic activity and excellent stereoinduction in asymmetric Michael reactions of nitroolefins 2 with -dicarbonyl compounds 4 (Scheme 3). In this reaction, the best enantioselectivity (up to >99% ee) was attained in CH2Cl2 medium in the presence of only 1 mol% of the bifunctional catalyst. Further reduction of catalyst loading (to 0.5 mol%) resulted in enhanced reaction time and inferior enantioselectivity (see Scheme 3, footnote d). The absolute (R)-configuration of adduct 5aa was assigned based on a comparison of its specific optical rotation [([]25D = -163.1 (c = 0.5, CHCl3, 94% ee)] with the literature data [([]27D = -200.2 (c = 1.0, CHCl3, 99% ee)]7a and [([]25D = -147.6 (c = 3.0, CHCl3, 95% ee)].24 Similar (R)-configuration was assigned to other products 5 by analogy. Scheme 3. Selected examples demonstrating broad application scope of catalyst IVb.a O

1

1

R

R

O

O

O +

R

4: 1 R = Me (a), MeO (b)

IVb (1 mol %)

NO2

2

R1 NO2

R1

CH2Cl2, r.t., 6-24 h

R2 5

2a,c,d-f

2: R2 = Ph (a); 2,4-diClC6H3 (c); 3-cyclopentyl-4-MeOC6H3 (d); Thienyl (e); 3-MeOC6H4 (f) MeOC

COMe

MeOC

NO2

NO2

5aa: 99%, 94% ee, 6 h 5aa: 99%, 94% eeb, 6 h 5aa: no reactionc, 6 h 5aa: 97%, 92% eed, 18 h MeOC

5ac: 85%, 91% ee, 6 h

MeOC

COMe

O

NO2

5ad: 99%, 95% ee, 12 h

MeO2C

COMe

MeO

NO2

COMe

MeO

Cl

Cl

MeOC

COMe

NO2

O

CO2Me NO2

MeO

S 5ae: 85%, >99% ee, 16 h

5af: 99%, 98% ee, 6 h

5bd: 55%, 90% ee, 24 h

a

Unless otherwise specified, the reactions were carried out with catalyst IVb (1 mol %, 1.0 mg), 4 (0.48 mmol) and 2 (0.24 mmol) in CH2Cl2 (0.4 mL) at r.t. b 1 mol% of TFA was added. c 2 mol% of TFA was added.d 0.5 mol% of IVb was used.

Quite different solubility of catalyst IVb and products 5 in organic solvents significantly simplified workup and purification of the products. Furthermore, due to extremely low solubility in common organic solvents, catalyst IVb could be readily recovered from the reaction mixture and reused in the same reaction. After catalytic reaction completion, the solvent (CH2Cl2) was



Page 8 of 20

evaporated and product 5aa was extracted from the residue with Et2O. Sedimentation of finely suspended catalyst was achieved by means of ultra-centrifuge. The organic solution was decanted, fresh portions of 2a, 4a and CH2Cl2 were added to the remained catalyst and the reaction was re-performed. The catalyst retained similar activity and stereoinduction level over at least 7 cycles (Table 2). Actually, the recycling allowed reducing efficient catalyst loading by nearly an order of magnitude (to 0.15 mol%), which underlines excellent efficiency of the catalytic process. Furthermore, the fresh and the 6-fold used catalyst samples exhibited very similar catalytic activity in kinetic experiments. The conversions were measured after 0.5 h, 1.0 h and then after each 1.0 h from the reaction start based on 1H NMR data (see Supporting Information, S32). The obtained results confirmed sustainability of the developed catalyst IVb in the reaction conditions. Notably, the recycling gave much worse results when more lipophilic Rawal catalyst Ib was used. In this case, the yield of product 5aa is significantly reduced already in the second cycle due apparently to catalyst leaching into the organic solution (Et2O) during workup. Table 2. Recycling of catalyst IVb in the reaction between 2a and 4a.a

aThe

Cycle

Yield of 5aa, % b

ee of 5aa, % b

1

99 (99)

94 (94)

2

98 (22)

94 (94)

3

97 (n.r.)

94

4

95

92

5

93

93

6

90

94

7

85

94

reactions were carried out with catalyst IVb (1 mol %, 1.0 mg), 4a (49 L, 0.48 mmol) and 2a (35.8

mg, 0.24 mmol) in CH2Cl2 (0.4 mL) at r.t for 6 h. bData for the corresponding reaction in the presence of catalyst Ib are given in parenthesis.

To find out if one or both tertiary amino groups in catalyst IVb participate in the catalytic transformation, we estimated relationships between ee values of the catalyst and the corresponding products 3aa and 5aa in protic and aprotic solvents (96% EtOH, H2O and CH2Cl2) (Figure 2). Irrespective of the solvent, a linear effect was observed for both compounds. This fact testifies to the absence of diastereomeric associates (especially, meso forms) between C2-symmetric catalyst IVb and the reaction product, which may be achieved only if desymmetrization occurs and only one of the two tertiary amino groups in catalyst IVb acts as


Page 9 of 20

deprotonating agent in the corresponding transition states TS1 and TS2 (Figure 3). This assumption was also confirmed by catalytic experiments in the presence of an acidic additive. Addition of 1 mol% of TFA to IVb-catalyzed reaction between 2a and 4a exerted no negative impact on the yield and/or enantiomeric enrichment of 5aa, whereas in the presence of 2 mol% of TFA, which is sufficient to protonate both tertiary amine unites, the catalyst was completely deactivated (see Scheme 3, data for 5aa).

100.0

Product 3aa or 5aa, ee %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 0.0

20.0

40.0

60.0

80.0

100.0

Catalyst IVb, ee %

Figure 2. Linear effect for reactions of 2a with 1a in EtOH or H2O and with 4a in CH2Cl2

O

O

N+

N H

N H

H O O O-N O O

R1

O

N+

N

O N H

N H

H O O N O R1 O R1

R2

R2 TS2

TS1


N


Page 10 of 20

Figure 3. Plausible transition states for IVb-catalyzed asymmetric reactions of nitroolefin 2 with 1 (TS1) or 4 (TS2) (For detailed catalytic cycle of similar Michael reactions see ref7d) Synthetic utility of Michael adducts 3 was demonstrated by selective acylation of 3aa with bioactive acids, namely (E)-5,9-dimethyldeca-4,8-dienoic acid (6, cholesterol-lowering agent24a) and lipoic acid (7, cofactor of many enzyme complexes24b) in the presence of DCC/DMAP (Scheme 4). Corresponding chiral esters 8 and 9 were generated in these reactions in 60-86% yield. Among the two, compound 9 bearing two stereogenic centers was isolated as a single diastereomer, the result proved complete retention of stereochemistry in starting compound 3aa over the esterification reaction. Products 8 and 9 containing two privileged pharmacophoric motifs are likely to selectively bind with different cellular receptors and have unusual pharmacological profiles (the ‘twin drugs’ concept24c). Enantiomerically enriched compounds 5 are extensively used for asymmetric synthesis of valuable -amino acids25 and chiral nitrogen heterocycles.26 Adduct 5bd is a close precursor to antidepressants (R)-rolipram and (3S,4R)paroxetine.27 Scheme 4. Synthetic application of 3aa. O OH Me

O 3aa

O

O

Ph

6, 8: R =

O NO2 + RCOOH 6, 7

R

DCC, DMAP (cat) CH2Cl2, r.t.,3 h 60-86%

;

Me

7, 9: R =

NO2

O 8, 9

Ph

S S

Conclusion A very simple and highly efficient tertiary amine–squaramide organocatalyst for asymmetric Michael reactions between carbon nucleophiles and nitroolefins has been developed. In the presence of only 1 mol% of this catalyst, the corresponding Michael adducts were generated in nearly quantitative yield with enantioselectivity up to 99% ee. The reactions with kojic acid derivatives could be efficiently performed under ‘green’ conditions (in 96% EtOH or even in pure water). Moreover, due to extremely low solubility in organic solvents, the developed non-supported catalyst could be recovered and reused in catalytic reactions up to 7 times. Utmost availability, high level of stereoinduction, low efficient loading and recyclability make it attractive for industrial application in pharmaceutical industry.


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Experimental section General information. The 1H and 13C NMR spectra were recorded on a 300 MHz spectrometer. The high-resolution mass spectra (HRMS) were measured using electrospray ionization (ESI) and a time-of-ﬂight (TOF) mass analyzer. The measurements were taken in the positive ion mode (interface capillary voltage 4500 V) in the mass range from m/z = 50 Da to m/z = 3000 Da; external and internal calibrations were done with the electrospray calibrant solution. Optical rotations were measured on a polarimeter and calibrated with a pure solvent as a blank. HPLC analyses were performed on an HPLC system equipped with chiral stationary phase columns (AD-H, OD-H, OJ-H), detection at 254 nm. Silica gel (0.060−0.200 mm) was used for column chromatography. All reagents and solvents were purified and dried according to standard procedures. Synthesis of catalysts IVa,b (General Procedure). Dimethyl squarate (0.45 g, 2.35 mmol) was added to a solution of the corresponding chiral (1R,2R)- or (1S,2S)-diaminocyclohexane derivative (4.75 mmol) in MeOH (2.0 mL) in one portion. After stirring for 8-10 h at ambient temperature, the precipitate was filtered, washed with Et2O (3 x 5 mL) and dried under reduced pressure (60 oC, 10 Torr) to afford the corresponding compound IVa, IVb or ent-IVb as a colorless solid (Mp > 250 oC with decomposition). Spectroscopic data for IVa,b are given below. 3,4-Bis(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)cyclobut-3-ene-1,2-dione

(IVa):

Yield

0.68 g (80%). 1H NMR (300 MHz, DMSO-d6): δ 7.30 (br s, 2H), 3.82-3.71 (m, 2H), 2.40-2.33 (m, 4H), 2.21 (s, 12H), 1.84-1.65 (m, 6H), 1.37-1.12 (m, 8H) ppm.

13C{1H}

NMR (75 MHz,

DMSO-d6): δ 182.9, 168.8, 67.6, 52.6, 42.3, 36.9, 34.3, 23.9, 24.0, 22.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H35N4O2 363.2755; found 363.2748. 3,4-Bis(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione (IVb): Yield 1.0 g (95%). 1H NMR (300 MHz, DMSO-d6): δ 7.04 (d, J = 2.1 Hz, 2H), 3.85-3.79 (m, 2H), 2.752.40 (m, 4H), 2.40-2.25 (m, 5H), 2.04 (m, 2H), 1.83-1.67 (m, 6H), 1.35-1.22 (m, 20H) ppm. 13C{1H}

NMR (75 MHz, DMSO-d6): δ 182.4, 168.6, 68.7, 54.2, 49.8, 35.2, 26.8, 25.3, 25.1,

25.0, 24.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H43N4O2 443.3381; found 443.3375. The analytical data for enantiomeric compound ent-IVb were similar to those for IVb. Catalytic Michael reaction between 1 and 2 (General Procedure, Methods A and B). Kojic acid derivative 1 (0.24 mmol) and nitroolefin 2 (0.24 mmol) were added to a mixture of catalyst



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IVb (1.0 mg, 0.0024 mmol) and 96% EtOH (0.4 mL) (Method A) or H2O (0.4 mL) (Method B). The reaction mixture was stirred at ambient temperature for 6-24 h (See scheme 2). Products 3 were isolated by column chromatography (silica gel, EtOAc). Spectroscopic data for known compounds 3aa and 3fa are in accordance with literature.20a Spectroscopic and HPLC data for novel compounds 3 are given below. (R)-6-(Chloromethyl)-3-hydroxy-2-(2-nitro-1-phenylethyl)-4H-pyran-4-one (3ba): Yield 74.2 mg (99%). >99% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min–1, 254 nm, tminor = 13.8 min, tmajor = 30.3 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.58 (s, 1H), 7.45-7.26 (m, 5H), 6.56 (s, 1H), 5.39-5.07 (m, 3H), 4.70 (s, 2H) ppm. 13C{1H} NMR (75 MHz, DMSO-d6): δ 173.9, 161.4, 148.7, 142.8, 136.5, 129.4, 129.4, 128.4, 113.0, 75.6, 41.9, 41.7, 25.9 ppm. HRMS (ESITOF) m/z: [M + H]+ calcd for C14H13ClNO5 310.0477; found 310.0463. (R)-3-Hydroxy-6-(methoxymethyl)-2-(2-nitro-1-phenylethyl)-4H-pyran-4-one (3ca): Yield 73.2 mg (99%). >99% ee [HPLC Chiralcel OD-H column, n-hexane/iPrOH 70:30, 1 mL min–1, 254 nm; tmajor = 15.9 min, tminor = 22.9 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 7.397.31 (m, 5H), 6.37 (s, 1H), 5.41-5.00 (m, 3H), 4.31 (s, 2H), 3.30 (s, 3H) ppm. 13C{1H} NMR (75 MHz, DMSO-d6): δ 173.8, 163.7, 148.3, 142.7, 136.6, 129.4, 128.3, 111.6, 75.7, 69.8, 58.6, 42.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H16NO6 306.0972; found 306.0960. (R)-3-hydroxy-2-(2-nitro-1-phenylethyl)-6-((phenylthio)methyl)-4H-pyran-4-one (3da): Yield 91.9 mg (99%). >99% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tminor = 13.1 min, tmajor = 27.6 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.52-7.17 (m, 10H), 6.26 (s, 1H), 5.18-4.95 (m, 3H), 4.23 (s, 2H) ppm. 13C{1H} NMR (75 MHz, DMSOd6): δ 173.7, 163.7, 148.4, 142.3, 136.6, 134.4, 129.9, 129.6, 129.3, 128.4, 128.3, 127.3, 112.2, 75.5, 41.7, 34.4, 25.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18NO5S 384.0900; found 384.0914. (R)-6-(((2-Fluorophenyl)thio)methyl)-3-hydroxy-2-(2-nitro-1-phenylethyl)-4H-pyran-4-one (3ea): Yield 96.2 mg (99%). >99% ee [HPLC Chiralpak OD-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tmajor = 27.3 min, tminor = 34.1 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.48-7.42 (t, J = 7.73 Hz, 1H), 7.35-7.25 (m, 7H), 7.18-7.13 (t, J = 7.44 Hz, 1H), 6.22 (s, 1H), 5.20-5.00 (m, 3H), 4.20 (s, 2H) ppm. 13C{1H} NMR (75 MHz, DMSO-d6): δ 173.6, 163.1, 148.2, 142.4, 136.6, 132.8, 130.1, 130.0, 129.4, 128.4, 128.3, 125.6, 125.5, 116.5-116.2 (d, JCF = 22.0 Hz), 112.4, 75.5, 41.8, 33.9, 25.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17FNO5S 402.0806; found 402.0818.


Page 13 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(R)-3-Hydroxy-2-(2-nitro-1-phenylethyl)-6-(piperidin-1-ylmethyl)-4H-pyran-4-one (3ga): Yield 85.9 mg (99%). 53% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tmajor= 9.3 min, tminor = 14.0 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.39 (m, 5H), 6.31 (s, 1H), 5.35-5.02 (m, 3H), 3.43 (s, 2H), 2.35 (m, 4H), 1.48-1.34 (m, 6H) ppm.

13C{1H}

NMR (75 MHz, DMSO-d6): δ 173.9, 164.5, 148.2, 142.5, 136.7, 129.5, 129.4, 128.5, 128.3, 112.5, 75.3, 59.3, 53.8, 41.9, 26.0, 24.0 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H23N2O5 359.1601; found 359.1623. (R)-3-Hydroxy-6-(morpholinomethyl)-2-(2-nitro-1-phenylethyl)-4H-pyran-4-one (3ha): Yield 86.4 mg (99%). 90% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tmajor = 26.1 min, tminor = 38.4 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.39 (br s, 1H), 7.45-7.24 (m, 5H), 6.35 (s, 1H), 5.37-5.06 (m, 3H), 3.69-3.66 (m, 1H), 3.58-3.55 (m, 4H), 3.41-3.36 (m, 1H), 2.39-2.37 (m, 4H) ppm. 13C{1H} NMR (75 MHz, DMSO-d6): δ 173.8, 163.8, 148.3, 142.5, 136.6, 129.4, 128.3, 112.7, 75.7, 66.6, 58.8, 53.1, 46.9, 42.1, 25.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21N2O6 361.1394; found 361.1385. (R)-3-hydroxy-2-(1-(4-methoxyphenyl)-2-nitroethyl)-6-methyl-4H-pyran-4-one (3ab): Yield 69.5 mg (99%). 92% ee [HPLC Chiralcel OD-H column, n-hexane/iPrOH 70:30, 1.00 mL/min-1, 254 nm; tminor = 21.5 min, tmajor = 35.7 min]. 1H NMR (300 MHz, CDCl3): δ 7.30-7.28 (d, J = 7.80 Hz, 2H), 6.90-6.87 (d, J = 7.90 Hz, 2H), 6.23 (s, 1H), 5.20-4.87 (m, 3H), 3.79 (s, 3H), 2.31 (s, 3H) ppm.

13C{1H}

NMR (75 MHz, CDCl3): δ 174.1, 165.6, 159.6, 146.9, 141.6, 129.0, 127.3,

114.7, 111.0, 75.7, 55.4, 42.5, 20.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H16NO6 306.0972; found 306.0965. (R)-2-(1-(2,4-dichlorophenyl)-2-nitroethyl)-3-hydroxy-6-methyl-4H-pyran-4-one

(3ac):

Yield

78.4 mg (99%). 91% ee [HPLC Chiralpak OD-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tminor= 10.1 min, tmajor = 14.6 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.37 (s, 1H), 7.70 (s, 1H), 7.58-7.49 (m, 2H), 6.24 (s, 1H), 5.49 (m, 1H), 5.28 (m, 2H), 2.25 (s, 3H) ppm.

13C{1H}

NMR

(75 MHz, DMSO-d6): δ 174.0, 165.2, 145.7, 142.7, 134.5, 133.9, 133.2, 131.3, 129.7, 128.4, 111.9, 74.8, 38.6, 19.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H12Cl2NO5 344.0087; found 344.0095. (R)-2-(1-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-nitroethyl)-6-methyl-4H-pyran-4-one

(3ad):

Yield 74.7 mg (99%). 99% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tminor = 9.1 min, tmajor = 11.0 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.20 (br s, 1H), 6.986.83 (m, 3H), 6.21 (s, 1H), 5.35 - 5.13 (m, 2H), 5.00 (m, 1H), 4.91 – 4.77 (m, 1H), 3.71 (s, 3H), 2.26 (m, 3H), 1.78-1.46 (m, 8H) ppm.

13C{1H}

NMR (75 MHz, DMSO-d6): δ 174.0, 164.8,



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149.8, 148.3, 147.6, 141.9, 128.8, 120.5, 114.9, 112.9, 111.7, 80.0, 76.0, 56.0, 41.6, 32.6, 24.0, 19.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H24NO7 390.1574; found 390.1565. (R)-3-Hydroxy-6-(methoxymethyl)-2-(2-nitro-1-(thiophen-2-yl)ethyl)-4H-pyran-4-one

(3ce):

Yield 74.6 mg (99%). 98% ee [HPLC Chiralpak OJ-H, n-hexane/iPrOH 70:30, 1 mL min-1, 254 nm, tmajor = 16.7 min, tminor = 28.6 min]. 1H NMR (300 MHz, DMSO-d6): δ 9.60 (br s, 1H), 7.517.49 (m, 1H), 7.14-7.13 (m, 1H), 7.00 (m, 1H), 6.38 (s, 1H), 5.40-5.16 (m, 3H), 4.31 (s, 2H), 3.31 (s, 3H) ppm.

13C{1H}

NMR (75 MHz, DMSO-d6): δ 173.9, 163.8, 147.3, 142.6, 140.1,

137.8, 127.7, 127.0, 126.6, 111.7, 76.2, 69.9, 58.6, 37.4 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H14NO6S 312.0536; found 312.0527. Large-scale reaction. 5-Hydroxy-2-methyl-4H-pyran-4-one 1a (2.00 g, 15.9 mmol) and nitrostyrene 2a (2.37 g, 15.9 mmol) were added to a mixture of catalyst IVb (70.3 mg, 0.16 mmol) and 96% EtOH (7 mL). The reaction mixture was stirred at ambient temperature for specified time (TLC-monitoring) and deluded with water (7 mL). The precipitate was filtered, washed with cooled (5 oС) EtOH - H2O (5 mL, 1:1 (v/v)) and dried in air to afford 3aa as yellowish powder: yield 4.10 g (94%), Mp 119-122 oC (lit.20 Mp 120-122 oC). Catalytic Michael reaction between 4 and 2 (General Procedure). -Dicarbonyl compound 4 (0.48 mmol, 2 equiv.) and nitroolefin 2 (0.24 mmol) were added to a mixture of catalyst IVb (1.0 mg, 0.0024 mmol) and CH2Cl2 (0.4 mL). After stirring at ambient temperature for 6-24 h (See scheme 3), the solvent was evaporated under reduced pressure (10 Torr). Raw products 5 were extracted with Et2O (3 x 1 mL) and purified by column chromatography (silica gel, n-hexane/EtOAc (2:1)) to afford pure 5, in particular known compounds 5aa, yield 59.2 mg (99%); 5ac, yield 64.9 mg (85%); 5ae, yield 52.0 mg (85%); 5af, yield 66.4 mg (99%) and 5bd, Yield 52.2 mg, (55%). Spectroscopic data for compounds 5aa,28 5ac,29 5ae,25b 5af,29 5bd26 are in accordance with literature. Spectroscopic and HPLC data for novel product 5ad are given below. (R)-3-(1-(3-(Cyclopentyloxy)-4-methoxyphenyl)-2-nitroethyl)pentane-2,4-dione

(5ad):

Yield

86.3 mg (99%). 95% ee [HPLC Chiralpak AD-H, n-hexane/iPrOH 90:10, 1 mL min-1, 254 nm, tmajor = 15.9 min, tminor = 17.9 min]. 1H NMR (300 MHz, DMSO-d6): δ 6.91-6.74 (m, 3H), 4.824.60 (m, 4H), 4.03-3.94 (m, 1H), 3.70 (s, 3H), 2.23 (s, 3H), 1.91 (s, 3H), 1.86-1.84 (m, 2H), 1.75-1.51 (m, 6H) ppm.

13C{1H}

NMR (75 MHz, DMSO-d6): δ 202.4, 202.2, 149.6, 147.2,

129.2, 121.3, 115.4, 112.5, 80.0, 78.9, 69.6, 55.8, 43.0, 32.6, 31.1, 30.8, 24.0 ppm. HRMS (ESITOF) m/z: [M + H]+ calcd for C18H21N2O6 361.1394; found 361.1385. Catalyst recycling procedure. Sedimentation of finely suspended catalyst IVb in Et2O was achieved by means of ultra-centrifuge. The organic solution was decanted and the remained


Page 15 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


catalyst was dried in vacuo (1.0 torr, 60 oC, 10 min). Then fresh portions of 2a, 4a and CH2Cl2 were added to the catalyst and the reaction was re-performed as described above (Table 2). Synthesis of esters 8 and 9 (General procedure). DMAP (cat) was added to a stirring solution of DCC (113.5 mg, 0.55 mmol), (R)-3aa (137.5 mg, 0.5 mmol) and acid 6 (98.0 mg, 0.5 mmol) or (R)-7 (103.0 mg, 0.5 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at ambient temperature for 10 h and washed with water (2 × 5 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure (10 Torr). The residue was purified by flash chromatography (n-hexane/EtOAc 2 : 1 to 1 : 1) to afford the corresponding compound (R)-8 and (R,R)-9. (R,E)-6-Methyl-2-(2-nitro-1-phenylethyl)-4-oxo-4H-pyran-3-yl

5,9-dimethyldeca-4,8-dienoate

((R)-8): colorless oil, yield 195.0 mg, (86%). 1H NMR (300 MHz, DMSO-d6): δ 7.39-7.37 (m, 3H), 7.28-7.26 (m, 2H), 6.21 (s, 1H) 5.22-4.86 (m, 5H), 2.67-2.60 (m, 2H), 2.47-2.42 (m, 2H), 2.31 (s, 3H), 2.10-2.02 (m, 4H), 1.73-1.62 (m, 9H) ppm. 13C{1H} NMR (75 MHz, DMSO-d6): δ 172.2, 169.6, 165.1, 156.3, 137.7, 137.2, 134.2, 129.4, 128.8, 127.7, 124.2, 122.6, 121.8, 114.5, 75.2, 42.5, 39.6, 33.8, 31.9, 26.6, 26.5, 25.7, 23.3, 19.5, 17.7, 16.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H31NO6 453.2151; found 453.2155. 6-Methyl-2-((R)-2-nitro-1-phenylethyl)-4-oxo-4H-pyran-3-yl

5-((R)-1,2-dithiolan-3-

yl)pentanoate ((R,R)-9): colorless oil, yield 139.0 mg, (60%). 1H NMR (300 MHz, DMSO-d6): δ 7.39-7.37 (m, 3H), 7.28-7.26 (m, 2H), 6.20 (s, 1H), 5.09-4.85 (m, 3H), 3.63-3.58 (m, 2H), 3.243.08 (m, 2H), 2.64-2.59 (m, 2H), 2.53-2.43 (m, 1H), 2.31 (s, 3H), 2.00-1.89 (m, 1H), 1.79-1.70 (m, 4H), 1.61-1.52 (m, 2H) ppm.

13C{1H}NMR

(75 MHz, DMSO-d6): δ 172.2, 169.6, 165.0,

156.2, 134.0, 129.4, 128.8, 127.6, 114.5, 75.2, 56.2, 42.5, 40.1, 38.5, 34.5, 33.3, 28.5, 24.4, 19.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H25NO6S2 463.1123; found 463.1123.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: XX.

Copies of 1H, 13C, and HPLC spectra (PDF) AUTHOR INFORMATION Corresponding Author



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*E-mail: E-mail: [email protected]. ORCID Sergei G. Zlotin: 0000-0002-2280-3918 Alexander S. Kucherenko: 0000-0002-6423-7627 Alexey A. Kostenko: 0000-0002-8012-0082 Andrey N. Komogortsev: 0000-0001-7364-3478 Boris V. Lichitsky: 0000-0002-9615-4519 Notes The authors declare no competing financial interest

Acknowledgements The research was supported by the Russian Science Foundation (Grant 16-13-10470).

References (1) (a) Science of Synthesis: Asymmetric Organocatalysis. (Eds. B. List and K. Maruoka), volumes 1 and 2. Thieme, Stuttgart, 2012, 1928 pp.; (b) Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. (Ed. P.I. Dalco). Wiley-VCH, Weinheim, 2013, p. 1638. (c) Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774-793; (d) James, T.; Gemmeren, M.; List, B. Development and Applications of Disulfonimides in Enantioselective Organocatalysis. Chem. Rev. 2015, 115, 9388-9409. (e) Bulfield, D.; Huber, S. M. Halogen Bonding in Organic Synthesis and Organocatalysis. Chem. Eur.J. 2016, 22, 14434-14450. (f) Zhan, G.; Du, W.; Chen, Y. C. Switchable divergent asymmetric synthesis via organocatalysis. Chem. Soc. Rev. 2017, 46, 1675-1692. (2) Song, J.; Chen, D. F.; Gong, L. Z. Recent progress in organocatalytic asymmetric total syntheses of complex indole alkaloids. Natl Sci Rev 2017, 4, 381–396. (3) (a) List, B.; Lerner, R. A.; Barbas C. F. Proline-Catalyzed Direct Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122, 10, 2395-2396. (b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. The Proline-Catalyzed Direct Asymmetric Three-Component Mannich Reaction: Scope, Optimization, and Application to the Highly Enantioselective Synthesis of 1,2-Amino Alcohols. J. Am. Chem. Soc. 2002, 124, 5, 827–833.


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(4) (a) Doyle, A. G.; Jacobsen, E. N. Small-Molecule H-Bond Donors in Asymmetric Catalysis. Chem. Rev. 2007, 107, 12, 5713–5743. (b) Banik, S. M.; Levina, A.; Hyde, A. M.; Jacobsen, E. N. Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 2017, 358, 761-764. (5) (a) Park, Y.; Schindler, C.S.; Jacobsen, E.N. Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base. J. Am. Chem. Soc. 2016, 138, 14848-14851. (b) Klausen, R. S.; Kennedy, C. R.; Hyde, A. M.; Jacobsen, E. N. Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction. J. Am. Chem. Soc. 2017, 139, 12299-12309. (6) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael Reaction of Malonates to Nitroolefins Catalyzed by Bifunctional Organocatalysts. J. Am. Chem. Soc. 2003, 125, 1267212673. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. Thiourea-catalyzed nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes. Tetrahedron Lett. 2003, 44, 28172821. (c) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Enantioselective Aza-Henry Reaction Catalyzed by a Bifunctional Organocatalyst. Org. Lett. 2004, 6, 625-627. (d) Hoashi, Y.; Okino, T.; Takemoto, Y. Enantioselective Michael addition to alpha,beta-unsaturated imides catalyzed by a bifunctional organocatalyst. Angew. Chem., Int. Ed. 2005, 44, 4032- 4035. (e) Inokuma, T.; Hoashi, Y.; Takemoto, Y. Thiourea-Catalyzed Asymmetric Michael Addition of Activated Methylene Compounds to α,β-Unsaturated Imides: Dual Activation of Imide by Intraand Intermolecular Hydrogen Bonding. J. Am. Chem. Soc., 2006, 128, 9413- 9419. (f) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. Catalytic Enantioselective Petasis-Type Reaction of Quinolines Catalyzed by a Newly Designed Thiourea Catalyst. J. Am. Chem. Soc., 2007, 129, 21, 6686– 6687. (g) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593-601. (7) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416–14417. (b) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Squaramide-catalyzed enantioselective Michael addition of diphenyl phosphite to nitroalkenes. Angew. Chem. Int. Ed. 2010, 49, 153–156. (c) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Enantioselective α-Amination of 1,3-Dicarbonyl Compounds Using Squaramide Derivatives as Hydrogen Bonding Catalysts. Org. Lett. 2010, 12, 2028-2031. (d) Varga, E.; Mika, L. T.; Csampai, A.; Holczbauer, T.; Kardos, G.; Soos, T. Mechanistic investigations of a bifunctional squaramide organocatalyst in asymmetric Michael reaction and observation of stereoselective retro-Michael reaction. RSC Adv. 2015, 5, 95079−95086.



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(8) Qian, Y.; Ma, G.; Lv, A.; Zhu, H. L.; Zhao, J.; Rawal, V. H. Squaramide-catalyzed enantioselective Friedel–Crafts reaction of indoles with imines. Chem. Comm. 2010, 4, 6, 3004– 3006. (9) Iriarte, I.; Olaizola, O.; Vera, S.; Gamboa, I.; Oiarbide, M.; Palomo, C. Controlling the α/γReactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions. Angew. Chem. Int. Ed. 2017, 56, 8860 – 8864. (10) Kostenko, A. A.; Kucherenko, A. S.; Zlotin, S. G. Recyclable C2-symmetric tertiary aminesquaramide organocatalysts: Design and application to asymmetric synthesis of g-nitrocarbonyl compounds. Tetrahedron 2018, 74, 4769-4776. (11) (a) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. Eur. J. 2011, 17, 6890–6899. (b) Tsakos, M.; Kokotos, C.G. Primary and secondary amine-(thio)ureas and squaramides and their applications in asymmetric organocatalysis. Tetrahedron 2013, 69, 10199-10222. (c) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal. 2015, 357, 253–281. (d) Held, F.E.; Tsogoeva, S.B. Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: recent advances. Catal. Sci. Technol. 2016, 6, 645–667. (e) Han, X.; Zhou, H.-B.; Dong, C. Applications of Chiral Squaramides: From Asymmetric Organocatalysis to Biologically Active Compounds. Chem. Rec. 2016, 16, 897–906. (12) (a) Kasaplar, P.; Rodriguez-Escrich, C.; Pericas, M. A. Continuous Flow, Highly Enantioselective Michael Additions Catalyzed by a PS-Supported Squaramide. Org. Lett. 2013, 15, 3498–3501. (b) Xu, X.; Veverkova, T. E.; Bilka, S.; Baran, R.; Sebesta, R. SquaramideCatalyzed Michael Addition as a Key Step for the Direct Synthesis of GABAergic Drugs. Synthesis 2016, 48, 1474–1482. (13) D. L. Hughes. Asymmetric Organocatalysis in Drug Development—Highlights of Recent Patent Literature. Org. Process Res. Dev. 2018, 22, 574–584. (14) Yang, W.; Du, D. M. Squaramide-catalysed enantio- and diastereoselective sulfa-Michael addition of thioacetic acid to α,β-disubstituted nitroalkenes. Org. Biomol. Chem. 2012, 10, 68766884. (15) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J. Y.; Song, M. J.; Lee, S.; Zhang, Y. J.; Song, C. E. Organocatalytic Enantioselective Michael Addition of Malonic Acid Half Thioesters to β Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of γ-Amino Acids. Adv. Synth. Catal. 2011, 353, 3196 – 3202.


Page 19 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(16) Kostenko, A. A.; Kucherenko, A. S.; Komogortsev, A. N.; Lichitsky, B. V.; Zlotin, S. G. Asymmetric Michael addition between kojic acid derivatives and unsaturated ketoesters promoted

by

C2-symmetric

organocatalysts.

Org.

Biomol.

Chem.

2018,

DOI:

10.1039/c8ob02523a. (17) Fassihi, A.; Abedi, D.; Saghaie, L.; Sabet, R.; Fazeli, H.; Bostaki, G. Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3hydroxypyran-4-one derivatives. Eur. J. Med. Chem. 2009, 44, 2145- 2157. (18) Alverson, J. Effects of mycotoxins, kojic acid and oxalic acid, on biological fitness of Lygus hesperus (Heteroptera: Miridae). Invertebr. Pathol. 2003, 83, 60-62. (19) (a) Higa, Y.; Kawawbe, M.; Nabae, K.; Toda, Y.; Kitamoto, S.; Hara, T. Kojic acid absence of tumor-initiating activity in rat liver, and of carcinogenic and photo-genotoxic potential in mouse skin. J. Toxicol. Sci. 2007, 32, 143- 159. (b) Yamato, M.; Hashigaki, K.; Yasumoto, Y.; Sakai, J.; Luduena, R. F. Banerjee, A. Synthesis and antitumor activity of tropolone derivatives. Structure-activity relationships of antitumor-active tropolone and 8hydroxyquinoline derivatives. J. Med. Chem. 1987, 30, 1897-1900. (20) (a) Subba Reddy, B. V.; Reddy, S. M.; Swain, M.; Dudem, S.; Kalivendi, S. V.; Reddy, C. S. Enantioselective 1,4-addition of kojic acid derivatives to β-nitroolefins catalyzed by a cinchonine derived sugar thiourea. RSC Adv. 2014, 4, 9107–9111. (b) Wang, J.; Zhang Q.; Zhang, H.; Feng, Y.; Yuan, W.; Zhang, X. Organocatalytic enantioselective Michael addition of a kojic acid derivative to nitro olefins. Org. Biomol. Chem., 2012, 10, 2950–2954. (21) Kataev, E. A.; Reddy, M. R.; Reddy, G. N.; Reddy, V. H.; Reddy C. S.; Subba Reddy, B. V. Supramolecular catalysis by β-cyclodextrin for the synthesis of kojic acid derivatives in water. New. J. Chem. 2016, 40, 1693–1697. (22) Likhar, P. R.; Reddy, G. N.; Reddy, M. R. Microwave-assisted, water-mediated Michael addition for synthesis of kojic acid derivatives. Research on Chemical Intermediates 2016, 42, 6, 5983-5989. (23) (a) Arends, I.; Sheldon, R. A.; Hanefeld, U. Green Chemistry and Catalysis., I. 2007, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; (b) Sheldon, R. A. The E Factor: fifteen years on. Green Chem. 2007, 9, 1273–1283. (24) (a) Rosenberg, S. H. Squalene Synthase Inhibitors 1998. Expert Opin. Ther. Pat. 1998, 8, 521-530. (b) Raddatz, G.; Bisswanger, H. Receptor site and stereospecifity of dihydrolipoamide dehydrogenase for R- and S-lipoamide: a molecular modeling study. J. Biotechnol. 1997, 58, 89−100. (c) Contreras J.-M.; Sippl W. in The Practice of Medicinal Chemistry, 3rd edn., (Ed. C. G. Wermuth), Academic Press, Amsterdam, 2008, p. 380.



Page 20 of 20

(25) Wang, J.; Li, H.; Duan, W. H.; Zu, L. S.; Wang, W. Organocatalytic Asymmetric Michael Addition of 2,4-Pentandione to Nitroolefins. Org. Lett. 2005, 7, 4713-4716. (26) (a) Liu, B.; Han, X.; Dong, Z.; Lv, H.; Zhou, H. B.; Dong, C. Highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by designer chiral BINOL–quinine–squaramide: efficient access to optically active nitro-alkanes and their isoxazole derivatives. Tetrahedron: Asymmetry 2013, 24, 1276–1280. (b) Tukhvatshin, R. S.; Kucherenko, A. S.; Nelyubina, Y. V.; Zlotin, S. G. Tertiary Amine-Derived Ionic LiquidSupported Squaramide as a Recyclable Organocatalyst for Noncovalent “On Water” Catalysis. ACS Catalysis 2017, 7, 6, 2981-2989. (27) (a) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Organocatalytic Asymmetric Total Synthesis of (R)-Rolipram and Formal Synthesis of (3S,4R)-Paroxetine. Org. Lett. 2008, 10, 7, 1389-1391. (b) Bae, H. Y.; Song, C. E. Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis “on Water”: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes. ACS Catalysis, 2015, 5, 6, 3613-3619. (28) Bécart, D.; Diemer, V.; Salaün, D.; Oiarbide, M.; Nelli, Y.R.; Kauffmann, B.; Fischer, L.; Palomo, C.; Guichard, G. Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C–C Bond-Forming Reactions. J. Am. Chem. Soc. 2017, 139, 12524-12532. (29) Vural, U.; Durmaz, M.; Sirit, A. A novel calix[4]arene-based bifunctional squaramide organocatalyst for enantioselective Michael addition of acetylacetone to nitroolefins. Org. Chem. Front. 2016, 3, 730–736.


C2-Symmetric Chiral Squaramide, Recyclable Organocatalyst for

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