Brucine Diol-Catalyzed Enantioselective Morita-Baylis-Hillman Reaction in the Presence of Brucine N-Oxide

catalysts

Article Brucine Diol-Catalyzed Enantioselective Morita-Baylis-Hillman Reaction in the Presence of Brucine N-Oxide

Venkatachalam Angamuthu 1 , Chia-Hung Lee 2,* and Dar-Fu Tai 1,*

1 Department of Chemistry, National Dong-Hwa University, Hualien 974003, Taiwan; [email protected] 2 Department of Life Science, National Dong-Hwa University, Hualien 974003, Taiwan * Correspondence: [email protected] (C.-H.L.); [email protected] (D.-F.T.); Tel.: +886-3-890-3677 (C.-H.L.); +886-3-890-3579 (D.-F.T.); Fax: +886-3-890-0163 (C.-H.L.); +886-3-890-0162 (D.-F.T.)

Abstract: Brucine diol (BD) catalyzed asymmetric Morita–Baylis–Hillman (MBH) reaction is observed for the ﬁrst time. Brucine N-oxide (BNO) was found to not have an effective chiral catalyst. Faster reaction rate was obtained using unsaturated ester or aromatic aldehydes in the presence of BNO. 4-Nitrobenzaldehyde and α,β-unsaturated ketone/ester were converted to the MBH adduct in moderate yields (up to 74%) with 70% ee value by this catalytic system. The mechanism of BD catalysis is probably initiated by conjugating the vicinal diol of BD to the carbonyl group of the aromatic aldehyde through hydrogen bonding. The tertiary amine of BD acts as a nucleophile to activate vinyl ketone for coupling with the carbonyl of aldehyde through an intramolecular carbonylated reaction. Finally, the breakdown of the complex caused the formation of the MBH adduct (a benzyl-allyl alcohol). The chirality of the benzyl-allyl alcohol is likely affected by the

interaction of the bulky asymmetric plane of BD. Keywords: dihydroxy brucine; Morita–Baylis–Hillman reaction; brucine-N-oxide Citation: Angamuthu, V.; Lee, C.-H.; Tai, D.-F. Brucine Diol-Catalyzed Enantioselective Morita-Baylis- Hillman Reaction in the Presence of Brucine N-Oxide. Catalysts 2021, 11, 1. Introduction 237. https://doi.org/10.3390/ Chiral amines are continuing to play a pivotal role as a catalyst in asymmetric synthe- catal11020237 sis [1]. The asymmetric induction of chiral secondary amines originates from the α-carbon chiral center to the nitrogen in the structure of the amine molecule [2–5]. In the case of Academic Editor: Takeshi Okhuma chiral tertiary amines, the asymmetric induction by these catalysts is primarily derived Received: 23 January 2021 from the nitrogen chiral center and a secondary anchoring group is often necessary. These Accepted: 5 February 2021 chiral tertiary amines are usually classified as nucleophilic catalysts [6–9]. A number of Published: 10 February 2021 tertiary amine N-oxides [10] have been developed and utilized for various asymmetric reactions. They are mainly cyclic aliphatic N-oxides [11] and pyridine N-oxides [12–15], Publisher’s Note: MDPI stays neutral acting as a ligand to coordinate with low valent transition metals [16] for metal-catalyzed with regard to jurisdictional claims in reactions. Chiral natural products with bulky shapes and inflexibility [7,17] are used, such published maps and institutional affil- as brucine derivatives (1). iations. As shown in Scheme1, Oh et al., used brucine N-oxide (BNO) as a chiral ligand for metal catalyzed asymmetric epoxidation [18]. They also reported the use of BNO 1a or 1b to catalyze asymmetric Morita–Baylis–Hillman (MBH) reaction, but the chiral induction was due to the presence of (L)/(D)-proline [19,20]. Moreover, brucine diol (BD) was found to Copyright: © 2021 by the authors. incorporate with copper (I) salt to catalyze an asymmetric Henry reaction [21]. Integration Licensee MDPI, Basel, Switzerland. of BD 2 with zinc was able to perform 1,3-dipolar cycloaddition [22–24] (Scheme1). This article is an open access article The classical MBH reaction can be broadly defined as the C–C bond forming reaction distributed under the terms and between the α-position of an activated alkene and aldehyde to provide α-methylene-β- conditions of the Creative Commons hydroxycarbonyl compound. The MBH reaction probably involves the mildest reaction Attribution (CC BY) license (https:// condition and has been comprehensively reviewed [6,23,25–29]. creativecommons.org/licenses/by/ 4.0/).

Catalysts 2021, 11, 237. https://doi.org/10.3390/catal11020237 https://www.mdpi.com/journal/catalysts CatalystsCatalysts 20212021, 11, 11, x, 237FOR PEER REVIEW 2 of 10 2 of 10

SchemeScheme 1. 1.Brucine Brucine derivatives derivatives in asymmetric in asymmetric synthesis. synthesis. The mechanism of the MBH reaction is complicated. There are several types of mechanismThe classical proposed MBH in the reaction literature. can Type be I isbroadly consistent defined with a nucleophilicas the C–C 1,4bond addition forming reac- totion the α between,β-unsaturated the compound α-position by the of catalyst an activated (a tertiary aminealkene or N and-oxide, aldehyde phosphines) to provide toα- formmethylene a Michael-addition-β-hydroxycarbonyl species, which compound. further reactsThe MBH with the reaction aromatic probably aldehyde involves to the formmildest a ternary reaction complex condition [28]. Decompositionand has been comprehensively of the ternary complex reviewed results [6,23,25 in the MBH–29]. adductThe and mechanism regenerates the of catalyst.the MBH reaction is complicated. There are several types of mechanismType II mechanism proposed proceedsin the literature. the same routeType asI is type consistent I at the beginningwith a nucleophilic to form the 1,4 addi- ternary complex, according to Aggarwal [30,31] and McQuade [32,33]. The addition of tion to the α,β-unsaturated compound by the catalyst (a tertiary amine or N-oxide, the fourth element (a protic polar solvent or another aldehyde) produces a 4-component species.phosphines) Finally, to this form 4-component a Michael species-addition decomposes species, towhich result further in the MBH reacts adduct with andthe aromatic regeneratesaldehyde to the form catalyst. a ternary complex [28]. Decomposition of the ternary complex results in the MBHThe type adduct III mechanism and regenerates is proposed the by catalyst. Oh as a dual catalytic system [18]. It proceeds the sameType route II mechanism as Type I at proceeds the earlier the stage, sameN-oxide route reactsas type with I at an theα, βbeginning-unsaturated to form the carbonylternary complex, compound according to form a Michael-additionto Aggarwal [30,31] species and and McQuade then the ternary [32,33] complex.. The addition of Meanwhile,the fourth element another aldehyde(a protic reactspolar withsolvent an L-prolineor another to aldehyde) create a chiral produces iminium a 4 ion,-component which is attacked by the Michael-addition species to form a 3 plus 2 complexes. After species. Finally, this 4-component species decomposes to result in the MBH adduct and decomposition, the nucleophile and hydrolysis of imine produce a chiral MBH adduct. The rateregenerates of this dual the system catalyst. would be low without L-proline, which also induces the chirality of MBHThe adduct. type III mechanism is proposed by Oh as a dual catalytic system [18]. It pro- ceedsThe the type same IV mechanismroute as Type is based I at the on earlier the catalyst stage, attached N-oxide with reacts a hydroxyl with an group α,β-unsaturated (a tertiarycarbonyl aminol) compound to enhance to form the rate a ofMichael the MBH-addition reaction. species Many catalysts and then with the a hydroxylternary complex. amineMeanwhile, functional another group aldehyde demonstrate reacts rate with enhancement. an L-proline As shown to create in Scheme a chir2,al both iminium ion, Markowhich [34is ]attacked and Barrett by [35 the] proposed Michael a- similaraddition concept species to complex to form the a substrates3 plus 2 incomplexes. which After decomposition, the nucleophile and hydrolysis of imine produce a chiral MBH adduct. The rate of this dual system would be low without L-proline, which also induces the chirality of MBH adduct. The type IV mechanism is based on the catalyst attached with a hydroxyl group (a tertiary aminol) to enhance the rate of the MBH reaction. Many catalysts with a hydroxyl amine functional group demonstrate rate enhancement. As shown in Scheme 2, both Marko [34] and Barrett [35] proposed a similar concept to complex the substrates in

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which the Michael-addition species is bonded to the aldehyde with the help of the hy- thedroxyl Michael-addition group. Formation species is bondedof the to hydrogen the aldehyde bonded with the intermediate help of the hydroxyl is considered group. the rate Formationdetermining of the step. hydrogen bonded intermediate is considered the rate determining step.

O OH O N H MeO X Ar X O Ar 7S H O Marko's intermediate

NO2 OH O N Ar X O H O H 7R O M X Ar Barret's intermediate Scheme 2. 2. Proposed type type IV IV mechanism: mechanism: a tertiarya tertiary aminol aminol catalyzed catalyzed Morita–Baylis–Hillman Morita–Baylis–Hillman (MBH)(MBH) reaction. reaction.

BD has not been studied as a catalyst for asymmetric MBH reaction so far. However, it possessesBD has a vicinal not diolbeen which studied can actas asa catalyst carbonyl for activator asymmetric through MBH hydrogen reaction bindings. so far. In However, additionit possesses to its a unique vicinal aminol diol structure,which can we act anticipated as carbonyl that BDactivator could interact through with hydrogen various bindings. reactantsIn addition to act to as its a nucleophilic unique aminol catalyst struc forture, asymmetric we anticipated MBH reaction. that BDBased could on the interact with proposedvarious reactants type IV mechanism to act as ina nucleophilic Scheme2, catalytic catalyst activity for ofasymmetric BD is expected. MBH Although reaction. Based on BNOthe proposed [18,19] can’t type function IV mechanism asymmetrically in Scheme alone, aliphatic 2, catalyticN-oxides activity [11,36 of] haveBD is been expected. Alt- known as a good nucleophile. N-oxides are easy to synthesize and preserve. Therefore, hough BNO [18,19] can’t function asymmetrically alone, aliphatic N-oxides [11,36] have BNO was also considered as a co-catalyst with BD for asymmetric reaction. Herein, we reportbeen the known investigation as a good of catalytic nucleophile. ability of BD N alone-oxides and areBD with easy BNO to as synthesize a co-catalyst and in preserve. asymmetricTherefore, MBHBNO reaction. was also considered as a co-catalyst with BD for asymmetric reaction. Herein, we report the investigation of catalytic ability of BD alone and BD with BNO as a 2.co Results-catalyst and in Discussionasymmetric MBH reaction. The BNO 1b [37] and BD 2 [20] was synthesized as previously reported. Initially, 4-nitrobenzaldehyde2. Results and Discussion and methyl vinyl ketone (MVK) were used as substrates in an MBH reaction to study the catalytic efﬁciency of BD. As shown in Table1, variation in nonpolar solventThe with BNO 5 mol% 1b of[37] BD and led toBD low 2 yields[20] was and poorsynthesized ee values as (entries previously 1–4). Increasing reported. Initially, the4-nitrobenzaldehyde catalytic ratio of BD toand 10 methyl mol% in vinyl polar solventketone (ethanol(MVK) orwere dioxane) used gaveas substrates moderate in an MBH yieldsreaction and to ee study values the (entries catalytic 5,6). efficiency As the catalytic of BD. loadAs shown was increased in Table to 1, 20 variation mol% in in nonpolar acetonitrilesolvent with (entry 5 mol% 7), the of yield BD (61%) led to and low ee valueyields (59 and %)also poor increased. ee values The (entries reaction 1 time–4). Increasing was monitored for 6 days. When BD increased to 30 mol%, the yield also increased to 69%, butthe thecatalytic ee value ratio reduced of BD to 53% to 10 (entry mol% 8). Thein polar optimized solvent condition (ethanol for BD or is dioxane) thus settled gave to moderate 20yields mol% and BD, ee 2 equivalents values (entries of MVK 5,6). in acetonitrile As the catalytic for 6 days load at room was temperature increased (entryto 20 7).mol% in ace- BNOtonitrile (10~20 (entry mol%) 7), alone the inyield acetonitrile (61%) and resulted ee value in >5% (59 of yield %) also (entries increased 9,10). . The reaction time was monitored for 6 days. When BD increased to 30 mol%, the yield also increased to 69%, but the ee value reduced to 53% (entry 8). The optimized condition for BD is thus settled to 20 mol% BD, 2 equivalents of MVK in acetonitrile for 6 days at room temperature (entry 7). BNO (10~20 mol%) alone in acetonitrile resulted in >5% of yield (entries 9,10).

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Table 1. Asymmetric MBH reaction with catalyst brucine N-oxide (BNO) and brucine diol (BD) [a].

[b] [c] [d] Catalysts 2021, 11, x FOR PEER REVIEW 5 Solvent 4 of 10 Yield Ee EntryCatalysts Catalyst11 Mol% Time [days] 2021, , 237 [Equiv] [Vol] 4 of 10 [%] [%] 1 BD 5 2 DCM 6 22 23 Table 1. Asymmetric MBH reaction with catalyst brucine N-oxide (BNO) and brucine diol (BD) [a]. 2 BDTable 1. Asymmetric5 MBH reaction with2 catalyst brucine N-oxideDCE (BNO) and brucine diol (BD) [a]6 . 21 27 3 BD 5 2 iPrOH 6 31 23 3 BD 5 2 Toluene 6 23 27 4 BD 10 2 Ethanol 6 30 34 5 BD 10 2 1,4-dioxane 6 43 44 5 Solvent [b] Yield [c] Ee [d] Entry Catalyst Mol% 5 Solvent [b] Time [days] Yield [c] Ee [d] 6 Entry BDCatalyst Mol%20 [Equiv]2 [Vol]AcetonitrileTime [days] [%]6 [%] 61 59 [Equiv] [Vol] [%] [%] 7 1BD BD30 52 2 DCMAcetonitrile 6 226 23 69 53 1 2BD BD5 52 2DCM DCE 66 2122 27 23 8 2 3BNOBD BD105 52 10 2DCE iPrOHAcetonitrile 66 311021 23 27 >5 10 3 BD 5 2 Toluene 6 23 27 3 BD 5 2 iPrOH 6 31 23 9 4BNO BD20 1010 2 EthanolAcetonitrile 6 3010 34 >5 19 [a] Reaction3 5 conditionBD BDs are as5 follows: 10 all2 reaction 2s wereToluene 1,4-dioxane carried out in 65 mL6 screw 43 capped23 bottle, 44 27 4 -nitrobenzaldehyde (0.25 mmol)4 6 . [b] SolventsBD BD used10 without20 drying.2 2 [c] IsolatedEthanol Acetonitrile yield . [d] Determined 66 by chiral 61 30High performance 59 34 liquid chro- 5 7BD BD10 302 21,4-dioxane Acetonitrile 66 6943 53 44 matography8 (HPLC BNO). 10 10 Acetonitrile 10 >5 10 6 9BD BNO20 202 10Acetonitrile Acetonitrile 106 >561 19 59 7 BD 30 2 Acetonitrile 6 69 53 [a] Reaction conditions are as follows:This all reactions is the were first carried report out in 5 about mL screw using capped bottle,BD as 4-nitrobenzaldehyde a catalyst in (0.25 an mmol). asymmetric MBH reaction. 8[b] Solvents usedBNO without drying.10[c] Isolated yield.10[d] DeterminedAcetonitrile by chiral High performance liquid10 chromatography (HPLC).>5 10 9 BNO Stereochemical20 10 outcomeAcetonitrile can be explained10 in the proposed>5 mechanism19 as shown in This is the ﬁrst report about using BD as a catalyst in an asymmetric MBH reac- [a] Reaction conditions are asScheme follows: all3. reaction BD formeds were carried the outternary in 5 mL complex screw capped (transition bottle, 4-nitrobenzaldehyde state A) with diol by Michael ad- [b] tion. Stereochemical[c] outcome can[d] be explained in the proposed mechanism as shown (0.25 mmol). Solvents useddition without to drying. the α,β Isolated-unsaturated yield. Determined carbonyl by chiral5 and High hydrogen performance bonded liquid chro- with the carbonyl groups matography (HPLC). in Scheme3. BD formed the ternary complex (transition state A) with diol by Michael ofaddition aromatic to the α aldehyde,β-unsaturated 6a carbonyl. The coupling5 and hydrogen between bonded with enone thecarbonyl and aldehyde groups induced the for- mationof aromaticThis isof aldehydethe the first chiral report6a. The aboutMBH coupling using adduct between BD as 7a enoneR catalyst. Due and in aldehydeto an the asymmetric bulky induced MBHstructure the formation reaction. of BD, the other side of the chiral MBH adduct 7R. Due to the bulky structure of BD, the other side attack is less attackStereochemical is less outcomefavored. can be explained in the proposed mechanism as shown in Schemefavored. 3. BD formed the ternary complex (transition state A) with diol by Michael addition to the α,β-unsaturated carbonyl 5 and hydrogen bonded with the carbonyl groups of aromatic aldehyde 6a. The couplingOM e between enone and aldehyde induced the for- O mation of the chiral MBH adduct 7R. Due to the bulky structure of BD, the other side OMe attack is less favored. N O H H O O OMe X O H 1 OMe Ar R N O 6 H H N 5 O O HO X H OH Ar R1 BD 6 N 5 HO OH BD OMe O OMe O OMe N OMe H N H H OH O OH O H H O O OH O N H H Ar X N X Ar X HO X HOO O 7R O Ar BD 7R H Ar H O BD Transition state A Scheme 3. ProposedTrans mitiechanismon state of A BD catalyzed MBH reaction. SchemeScheme 3. Proposed 3. Proposed mechanism mechanism of BD catalyzed of BD MBH catalyzed reaction. MBH reaction.

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Catalysts 2021, 11, 237 5 of 10 To speed up the reaction rate, cooperation of BD with a co-catalyst BNO was evaluated. As shown in Scheme 4, a co-catalytic mechanism was proposed. First, this dual catalyticTo speed system up the could reaction be rate, initiated cooperation by conjugating of BD with a co-catalystthe vicinal BNO diol was of evaluated. BD to the carbonyl Asgroup shown of in the Scheme aromatic4, a co-catalytic aldehyde mechanism and vinyl was ketone proposed. through First, this hydrogen dual catalytic bonding, respec- systemtively. could Second, be initiated the N by-oxide conjugating of BNO the vicinal acts as diol a ofnucleophile BD to the carbonyl to activate group of vinyl the ketone for aromaticcoupling aldehyde with the and carbo vinylnyl ketone of aldehyde through hydrogen through bonding, an intramolecular respectively. Second,carbonyl the ene reaction. N-oxide of BNO acts as a nucleophile to activate vinyl ketone for coupling with the carbonyl Finally, the breakdown of the dual catalytic system caused the formation of the MBH of aldehyde through an intramolecular carbonyl ene reaction. Finally, the breakdown of theadduct. dual catalytic The interaction system caused of the the formation asymmetric of the plane MBH adduct.of BD withThe interaction BNO could of the promote the asymmetricchirality of plane the product of BD with. BNO could promote the chirality of the product.

SchemeScheme 4. 4.Proposed Proposed catalytic catalytic cycle cycle for BD for catalyzed BD catalyzed MBH reaction MBH withreaction BNO. with BNO.

Unfortunately, the proposed mechanism in Scheme4 was not validated by the experi- Unfortunately, the proposed mechanism in Scheme 4 was not validated by the ex- mental data. The co-catalytic system was evaluated and is shown in Table2. Compared toperimental BD alone (Tabledata.1 ,The entry co 8),-catalytic adding 20system mol% was of BNO evaluated had no effectand onis shown ee value in and Table 2. Com- yieldpared (Table to BD2, entry alone 1). (Table As the amount1, entry of 8), BD/BNO adding were 20 mol% further of increased BNO had (25/50%), no effect an on ee value improvementand yield (Table to 67% 2, yield entry was 1). observed As the butamount the ee valueof BD/BNO reduced were to 54% further (Table2, increased entry 2). (25/50%), an improvement to 67% yield was observed but the ee value reduced to 54% (Table 2, entry 2). Interestingly, the yield increased up to 74% when increasing the mol% of BNO, but there was no effect on the ee values (entries 3–6). Finally, with 20 mol% of BD [21] and 100 mol% of BNO in acetonitrile using 4 equivalents of MVK, 74% yield and 70% ee value (entry 7) was reached. The activity was also compared with catalyst mixtures of other N-oxide, such as pyridine N-oxide (PNO) and morpholine N-oxide with BD. These catalytic mixtures gave only 17% of yield and the duration was too long (entry 8). Therefore,

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N-oxides are clearly less involved in the activation of α,β-unsaturated aldehydes or ketones. This clearly reveals that the BNO is not responsible for either acylation of the rate or chiral induction. Cooperative effect between BD and BNO was not observed as Catalysts 2021, 11, 237 Scheme 4. BNO simply increased the chiral concentration in the solution to promote the 6 of 10 yield and ee value.

Table 2. Asymmetric MBH reaction with duel catalytic system [a]. Table 2. Asymmetric MBH reaction with duel catalytic system [a].

Cat.1 5 Cat. 2 Yield [b] Entry Cat.1 5 Cat. 2 Time [days] Yield [b] Ee [c] [%] [MolEntry %] [Equiv] [Mol %]Time [days] [%] Ee [c] [%] [Mol %] [Equiv] [Mol %] [%] 1 BD [20] 2 BNO [20] 6 60 59 2 BD [25]1 BD [20] 22 BNOBNO [50] [20] 66 6760 59 54 3 BD [25]2 BD [25] 42 BNOBNO [60] [50] 46 6967 54 56 4 BD [25]3 BD [25] 44 BNOBNO [70] [60] 44 7169 56 54 5 BD [25]4 BD [25] 44 BNOBNO [80] [70] 44 7271 54 55 6 BD [25] 4 BNO [100] 4 74 57 7 BD [20]5 BD [25] 44 BNOBNO [100] [80] 44 7472 55 70 8 BD [20]6 BD [25] 44 PNOBNO [100] [100] 84 1774 57 - [a] Reaction condition: all reactions7 BD were [20] carried out in4 5 mL screwBNO capped [100] bottle, 4-nitrobenzaldehyde4 (0.2574 mmol). [b] Isolated70 yield. [c] Determined by chiral HPLC.8 BD [20] 4 PNO [100] 8 17 - [a] Reaction condition: all reactions were carried out in 5 mL screw capped bottle, 4-nitrobenzaldehydeInterestingly, (0.25 mmol). the yield [b] Isolated increased yield up. [c] Determined to 74% when by chiral increasing HPLC the. mol% of BNO, but there was no effect on the ee values (entries 3–6). Finally, with 20 mol% of BD [21] and Substrate100 mol% scope of BNO was inevaluated acetonitrile with using this 4 combination equivalents ofby MVK, changing 74% yieldthe Michael and 70% ac- ee value ceptors(entry and substituted 7) was reached. aromatic The aldehyde activity wasas shown also compared in Table 3. with The catalystco-catalytic mixtures system of other providedN-oxide, moderate such to as good pyridine yields N-oxide (up to (PNO) 74%) and morpholineee values (up N-oxide to 78%) with using BD. optimal These catalytic reactionmixtures condition. gave Generally, only 17% acyclic of yield esters and the are duration less reactive was buttoo longin this (entry case 8). hydroxyl Therefore, N- substitutedoxides acrylate are clearly (3-hydroxyphenyl less involved in acrylate) the activation provided of α ,bβ -unsaturatedin moderated aldehydes yield and or ee ketones. value (TableThis clearly 3, entry reveals 2). Reaction that the of BNO cyclohexenone is not responsible with for4-nitrobenzaldehyde either acylation of theprovided rate or chiral 7c in 78%induction. of ee value Cooperative and 54% of effect yield. between A simple BD phenyl and BNO aldehyde was not gave observed 7d in 61% as Scheme of yield4. BNO and 55%simply of ee increasedvalue (entry the chiral4), which concentration is relatively in theless solution than 4-nitro to promote-substituted the yield aromatic and ee value. aldehyde withSubstrate MVK scope(Table was 3, entry evaluated 1). The with results this combinationshowed the cyclic by changing enone coul thed Michael be ac- better candidateceptors and for substitutedthe Michael aromatic acceptors aldehyde which provided as shown 78% in Tableof ee value3. The (entry co-catalytic 3). This system is probablyprovided due to moderate the effective to good binding yields of (upcyclic to enone 74%) andwith ee BD values [38]. (up to 78%) using optimal reaction condition. Generally, acyclic esters are less reactive but in this case hydroxyl Table 3. Substratesubstituted scope acrylate with co- (3-hydroxyphenylcatalytic system for MBH acrylate) reaction provided [a]. b in moderated yield and ee value (Table3, entry 2). Reaction of cyclohexenone with 4-nitrobenzaldehyde provided 7c in 78% of ee value and 54% of yield. A simple phenyl aldehyde gave 7d in 61% of yield and 55% of ee value (entry 4), which is relatively less than 4-nitro-substituted aromatic aldehyde with MVK (Table3, entry 1). The results showed the cyclic enone could be better candidate for the Michael acceptors which provided 78% of ee value (entry 3). This is probably due to the effective binding of cyclic enone with BD [38].

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N-oxides are clearly less involved in the activation of α,β-unsaturated aldehydes or ketones. This clearly reveals that the BNO is not responsible for either acylation of the rate or chiral induction. Cooperative effect between BD and BNO was not observed as Scheme 4. BNO simply increased the chiral concentration in the solution to promote the yield and ee value.

Table 2. Asymmetric MBH reaction with duel catalytic system [a].

Cat.1 5 Cat. 2 Yield [b] Entry Time [days] Ee [c] [%] [Mol %] [Equiv] [Mol %] [%] 1 BD [20] 2 BNO [20] 6 60 59 2 BD [25] 2 BNO [50] 6 67 54 3 BD [25] 4 BNO [60] 4 69 56 4 BD [25] 4 BNO [70] 4 71 54 5 BD [25] 4 BNO [80] 4 72 55 6 BD [25] 4 BNO [100] 4 74 57 7 BD [20] 4 BNO [100] 4 74 70 8 BD [20] 4 PNO [100] 8 17 - [a] Reaction condition: all reactions were carried out in 5 mL screw capped bottle, 4-nitrobenzaldehyde (0.25 mmol). [b] Isolated yield. [c] Determined by chiral HPLC.

Substrate scope was evaluated with this combination by changing the Michael acceptors and substituted aromatic aldehyde as shown in Table 3. The co-catalytic system provided moderate to good yields (up to 74%) and ee values (up to 78%) using optimal reaction condition. Generally, acyclic esters are less reactive but in this case hydroxyl substituted acrylate (3-hydroxyphenyl acrylate) provided b in moderated yield and ee value (Table 3, entry 2). Reaction of cyclohexenone with 4-nitrobenzaldehyde provided 7c in 78% of ee value and 54% of yield. A simple phenyl aldehyde gave 7d in 61% of yield and 55% of ee value (entry 4), which is relatively less than 4-nitro-substituted aromatic aldehyde with MVK (Table 3, entry 1). The results showed the cyclic enone could be better candidate for the Michael acceptors which provided 78% of ee value (entry 3). This is probably due to the effective binding of cyclic enone with BD [38]. Catalysts 2021, 11, 237 7 of 10 Table 3. Substrate scope with co-catalytic system for MBH reaction [a]. Table 3. Substrate scope with co-catalytic system for MBH reaction [a].

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Entry. Product Ar in RCHO Enone Time [h] Yield [b] Ee [c] Ref. Entry. Product Ar in RCHO Enone Time [h] Yield [b][b] Ee[b] [c][c] Ref.[c] EntryEntry. . ProductProductO H O Ar inAr RCHO in RCHO Enone1 Enone Time Time [h] [h]Yield Yield Ee Ee Ref. Ref. 1Entry. Product Ar in3 RCHO-NO2C6H4 R = EnoneCH3 96 Time74[b] [h] [c]70 [39] Yield [b] Ee [c] Ref. Entry. ProductOH O Ar in RCHO2 6 4 Enone11 1 3 Time [h] Yield Ee Ref. 1 1 OH OH O 3--NO32-CNO6H24C 6H4 R = CHR =3 CH3 96 96 74 74 70 [b]70[39][39] [c] [39] Entry. Product Ar in RCHO1 1 Enone Time [h] Yield Ee Ref. 1 1 OH O 3-NO3-NO2C6H2C46H4 R = RCH=3 CH3 96 74 9670 [39] 74 70 [39] OH O 1 1 O N 3-NO2C6H4 R = CH3 96 74 70 [39] 2 R1 = O N 7a 1 O22N O2N R 1 = 1 7a 7a R = R = O2N 1 2 7a 3-NO2C6H4 R = 96 58 61 - O 2N 1 2 2 7a 3--NO322-CNO66H244C 6H4 R = 96 96 58 58 61 61 -- - O H O 2 OH OOH O 3-NO2C6H4 96 58 61 - O OH 2 6 4 2 OH O 3-NO C H 96 58 61 - 2O O OH OH 3-NO C H 96 58 61 - O2N 7b OH O 2 6 4 O N O OH O22N O2N 7b 7b 1 OH O O OH R = O2N 7b OH OOH O O2N 7b 3 OH O 3-OCH3C6H4 96 54 78 [40,41] 3 OH O 3-OCH3C6H4 96 54 78 [40,41] 3 33 O2N 3-OCH3-OCH33C-6OCHH3C46H34C 6H4 96 96 54 9654 78 78[40,41] [40,41] 54 78 [40,41] O N 7c 3 O22N O2N 3-OCH3C6H4 96 54 78 [40,41] 7c 7c 3 O2N 3-OCH3C6H4 96 54 78 [40,41] 7cOH O OOH2N OOH O OH O 7c OH O 6 5 1 3 4 C H R =1 CH 96 61 55 [39] 4 4 C HC6H5 R11 = CHR 1 =3 CH 96 61 9655 [39] 61 55 [39] 4 4 OH O 6 C56H5C 6H5 R = RCH =3 CH33 96 96 61 61 55 55[39] [39] 4 7d C6H5 R1 = CH3 96 61 55 [39] 7d 7d 1 [a] Reaction condition:4 all reactions were carried out in 5 mL screwC 6cappedH5 bottle,R 4=- nitrobenzaldehydeCH3 96 (0.2561 mmol). 55[b] [39] [a] [a][a] 7d [b] [b] [b][c] [a] Reaction ReactionReaction condition: condition:[c] condition: all reaction allall reactions reactions were weres werecarried carried carried out out inin out 55 mL mLinscrew 5 screw mL capped screw capped bottle, capped bottle, 4-nitrobenzaldehyde bottle, 4-nitrobenzaldehyde 4-nitrobenzaldehyde (0.25 mmol). (0.25 (0.25mmol).Isolated mmol). [b] yield. Determined by chiral HPLC by following reference given in table. IsolatedReaction yield condition:. Determined all reaction bys chiral were HPLCcarried7d by out following in 5 mL reference screw capped given inbottle, table. 4 -nitrobenzaldehyde (0.25 mmol). IsolatedIsolated[a] ReactionIsolated yieldyield condition: .yield. [c][c] Determined. [c] Determined all reaction by chiral sby were chiral HPLC carried HPLC by following out by followingin 5 mLreference screw reference givencapped given in table.bottle, in table. 4-nitrobenzaldehyde (0.25 mmol). [b] Isolated yield[a] Reaction. [c] Determined condition: by all chiral reaction HPLCs were by following carried out reference in 5 mL given screw in table.capped bottle, 4-nitrobenzaldehyde (0.25 mmol). [b] [c] However, we were pleased to find that BD combined with BNO in view of increas- Isolated yield. DeterminedHowever, by chiral we HPLC were bypleased following to find reference that BDgiven combined in table. with BNO in view of increas- ingHowever, the However,chiral we concentration were we were pleased pleased in tothe find tosolution findthat thatBD to combinedgiveBD combined the allyl with alcoholwith BNO BNO in 7a view– ind inview of 4 increas-days of increas- and inging thetheingHowever, chiralchiralthe chiral concentrationconcentration we concentrationwere pleased inin thethe toin solutionsolutionfindthe solutionthat to toBD givegive combinedto givethethe allylallylthe with allylalcoholalcohol BNO alcohol 7a in– dview 7a inin– d44 of indaysdays increas- 4 days andand and provided moderateHowever, yield we were and eepleased value. to This find is thatimportant BD combined because withthere BNO is no inreport view about of increas- provideding theprovided chiral moderate moderateconcentration yield yield and in eeand the value. ee solution value. This Thisisto important give is important the allyl because alcoholbecause there 7athere is– dno in is report 4no days report about and about using ingBD theas achiral catalyst concentration in asymmetric in the MBH solution reactions. to give BD the was allyl reported alcohol previously 7a–d in 4 only days and usingprovidedusing BD moderateas BD a ascatalyst a catalyst yield in andasymmetric in eeasymmetric value. MBH This MBH isreactions. important reactions. BD because wasBD wasreported there reported is previously no report previously about only only for asymmetricprovided moderateHenry reaction yield andwith ee copper value. ( ⅠThis) salt is [20] important. The absolute because configuration there is no report of the about forforusing asymmetricasymmetricfor BD asymmetric as a catalyst HenryHenry Henry reaction reactionin asymmetric reaction withwith with coppercopper MBH copper ( (Ⅰreactions.Ⅰ)) saltsalt (Ⅰ) [20] [20]salt .. BD [20]TheThe was. absoluteabsoluteThe reported absolute configurationconfiguration previouslyconfiguration ofof only thethe of the productsusing was BD assigne as a catalystd as R0 -inbased asymmetric on a correlation MBH reactions. with known BD wascompounds reported [39,41,42]. previously only productsfor asymmetricproducts was assignewas Henry assigned reactionas Rd 0as--based R with0-based on copper a oncorrelation a ( Ⅰcorrelation) salt [20] with. The withknown absolute known compounds configurationcompounds [39,41,42]. [39,41,42]. of the productsfor was asymmetric assigned asHenry R0-based reaction on awith correlation copper (withⅠ) salt known [20]. The compounds absolute configuration[39,41,42]. of the 3. Materialsproducts and was Methods assigne d as R0-based on a correlation with known compounds [39,41,42]. 3.. Materials3. Materials and Methodsand Methods 3. 3Materials.1. General and Information Methods 3.1..1. General3.1. General InformationInformation Information All3. Materialssolvents were and Methodscommercially available grade unless otherwise stated. The alde- 3.1. GeneralAll solvents Information were commercially available grade unless otherwise stated. The aldehydes,All3 solvents.1.MVKAll General solvents and were Information3- hydroxylphenylwere commercially commercially availableacrylate available were grade gradeused unless as unless purchased. otherwise otherwise stated.The stated.products The Thealde- were aldehydes,hydes,All MVK solvents MVK and 3andwere--hydroxylphenyl 3 -commerciallyhydroxylphenyl acrylate available acrylate were grade were used unlessused as purchased. as otherwise purchased. The stated. productsThe productsThe werealde- were purified byAll neutral solvents column were commercially chromatography available on 70 grade–230 orunless 230– otherwise400 mesh stated. silica gels.The alde- purifiedhydes,purified MVK by neutral and by neutral3-hydroxylphenyl column column chromatography chromatography acrylate were on used 70 on–230 as 70 –purchased. or230 230 or– 400 230 The – mesh400 products mesh silica silica were gels. gels. Spectrahydes, obtained MVK were and 31H-hydroxylphenyl NMR and 13C acrylate NMR fwererom used 400 and as purchased. 100.6 MHz The NMR products spec- were SpectrapurifiedSpectra obtained by obtainedneutral were column were 1H NMR1H chromatography NMR and and13C 13CNMR on NMR f romrom 70– f230 rom 400 400 or and and400 230 and100.6 100.6–400 100.6 MHz MHz mesh MHz NMR NMR silica NMR spec- spec- gels. spectrometer,purified respectively by neutral (Supplementary column chromatography Materials). Chemical on 70–230 shifts or 230 (δ)– 400 are reported mesh silica in gels. trometer,trometer,Spectratrometer, obtained respectively respectively respectively were (Supplementary(Supplementary1H (Supplementary NMR and 13C Materials) Materials) NMR Materials) f..rom Chemical Chemical. 400 Chemical and shifts shifts 100.6 shifts (δ) (δ) MHz are are (δ) reported reportedNMR are reported spec- in in in parts Spectraper million obtained (ppm) were from 1H residual NMR solvent and 13C resonance NMR from as the 400 internal and 100.6 standard. MHz NMRCou- spec- partstrometer,parts per millionper respectively million (ppm) (ppm) (Supplementary from from residual residual solvent Materials) solvent resonance. resonance Chemical as the as shifts internalthe (δ)internal arestandard. reportedstandard. Cou- in Cou- pling trometer, constants respectively are reported (Supplementary in Hertz (Hz) and Materials) the mult. Chemicaliplicities are shifts indicated (δ) are as reported br = in plingpartspling per constants million constants are (ppm) reported are reportedfrom inresidual Hertz in Hertz (Hz)solvent (Hz) and resonance andthe mult the multiplicitiesiplicitiesas theiplicities internal are are indicatedindicated are standard. indicated as as Cou- br br as = = br = broad,parts s = singlet, per million d = doublet, (ppm) from dd = residualdoublet ofsolvent doublet, resonance t = triplet, as them = internal multiple standard.. Enanti- Cou- broad,plingbroad, constants s = singlet, s = singlet, are d = reported doublet, d = doublet, in dd Hertz = dddoublet = (Hz) doublet andof doublet, of the doublet, mult t =iplicities triplet, t = triplet, m are = indicatedmultiplem = multiple.. Enanti-Enanti- as br. Enanti- = omericpling excesses constants were determined are reported using in Hertz chiral (Hz) high and performance the multiplicities liquid chromatography. are indicated as br = omericbroad,omeric sexcesses = singlet, excesses were d =were determined doublet, determined dd using = doublet using chiral chiralof high doublet, highperformance performancet = triplet, liquid m liquid= chromatography.multiple chromatography.. Enanti- IR spectrabroad, were s = singlet,obtained d =from doublet, a Jasco dd FT/IR = doublet-480 Plusof doublet, instrument t = triplet, using mKBr = multiple disks. Ele-. Enanti- IRIRomeric spectraspectraIR spectraexcesses werewere were wereobtainedobtained obtained determined fromfrom from aa JascoJascousing a Jasco FT/IR FT/IRchiral FT/IR-- 480high -Plus480 performance Plusinstrument instrument liquid using chromatography.using KBr KBrdisks. disks. Ele- Ele- mentalomeric analysis excesses (EA) was were obtained determined from using ThermoQuest chiral high (Flash performance 1112EA, ITALY).liquid chromatography. mentalIR spectramental analysis were analysis (EA) obtained (EA) was obtainedwasfrom obtained a Jasco from fromFT/IR ThermoQuest ThermoQuest-480 Plus (Flashinstrument (Flash 1112EA, 1112EA, using ITALY). KBr ITALY). disks. Ele- mental analysisIR spectra (EA) were was obtained obtained from from a ThermoQuest Jasco FT/IR-480 (Flash Plus 1112EA, instrument ITALY). using KBr disks. Ele- 3.2. Generalmental P rocedureanalysis 1(EA): MBH was R eactionobtained with from Single ThermoQuest Catalytic Processes (Flash 1112EA, ITALY). 3.2..2. General3.2. General Procedurerocedure Procedure 11:: MBH 1: MBH Reactioneaction Reaction withwith withSingleingle S ingle Catalytic Catalytic Processesrocesses Processes Catalysts BNO and BD (0.25 mmol) were used. In a screw caped vial, a single cata- 3.2. GeneralCatalysts Procedure BNO and 1: MBH BD (0.25 Reaction mmol) with were Single used. Catalytic In a screw Processes caped vial, a single cata- lystCatalysts (0.253.2.Catalysts General mmol) BNO BNO P and inrocedure 0.2 andBD mL (0.251BD: MBH of (0.25 mmol) given R mmol)eaction were solvent, werewith used. S 4used.ingle- nitrobenzaldehydeIn a CInscrewatalytic a screw caped Processes caped vial, and vial,a singl MVK a single cata- (givene cata- lystlyst lyst (0.25 (0.25Catalysts (0.25 mmol) mmol) BNO mmol) in in and 0.2 0.2 in BD mL mL 0.2 (0.25 ofmL of given givenmmol) of given solvent, solvent, were solvent, used. 4 4--nitrobenzaldehyde In 4- nitrobenzaldehydea screw caped vial, and anda MVK singl MVK (givene cata- (given equivalentCatalysts) were mixed BNO at and room BD temperature (0.25 mmol). Thewere resulting used. In solution a screw wascaped stirred vial, ata singlroome cata- equivlyst equiv (0.25alent alent)) mmol) werewere) were mixedmixed in 0.2mixed at at mL rroom at of r oomtt givenemperature temperature solvent,.. TheThe 4. - resultingresultingThenitrobenzaldehyde resulting solutionsolution solution waswas and stirredwasstirred MVK stirred atat (given roomroom at room temperaturelyst (0.25 for mmol) 6–8 days. in 0.2The mL reaction of given was solvent, monitored 4-nitrobenzaldehyde by TLC. After completion, and MVK the (given temperaturetemperatureequivtemperaturealent) were for for 6 6mixed for–8 days. 6–8 at days. rTheoom The r teactionemperature reaction was . was monitored The monitoredresulting by solution TLC. by TLC. After was After completion, stirred completion, at room thethe the mixtureequiv wasalent diluted) were with mixed ethyl at acetate room t(1emperature mL) and concentrated. The resulting under solution reduce wasd stirredpressure. at room mixturetemperaturemixture was dilutedwas for 6diluted–8 with days. withethyl The ethyl acetate reaction acetate (1 wasmL) (1 mL) monitoredand concentratedand concentrated by TLC. under After under reduce completion, reduced pressure.d pressure. the The resultanttemperature crude for was6–8 days. purified The by reaction column was chromatography monitored by TLC. on After silica completion, gel (hex- the Themixture The resultant was resultant diluted crude crude with was ethyl was purified acetate purified by (1 columnmL) by columnand chromatography concentrated chromatography under on reduce silica on silica d gelpressure. (hex-gel (hexanes/EtOAc,mixture 90:10) was diluted to provide with allylic ethyl alcoholacetate 7a.(1 mL) and concentrated under reduced pressure. anes/EtOAc,The anes/EtOAc, resultant 90:10) crude 90:10) to provide was to provide purified allylic allylic alcohol by alcohol column 7a. 7a. chromatography on silica gel (hexanes/EtOAc,The resultant90:10) to provide crude allylic was purified alcohol 7a. by column chromatography on silica gel (hex- 3.3. Generalanes/EtOAc, Procedure 90:10) 2: MBH to provide Reaction allylic with alcoholBD and BNO7a. Co-catalytic Processes 3.3..3. General3.3. General Procedurerocedure Procedure 22:: MBH 2: MBH Reactioneaction Reaction withwith withBD and BD BNO and BNO Co--catalyticcatalytic Co-catalytic Processesrocesses Processes Catalytic mixtures BD/BNO (0.25 mmol (total molar ratio)) were dispersed in 0.2 mL 3.3. GeneralCatalytic Procedure mixtures 2: BD/BNOMBH Reaction (0.25 withmmol BD (total and molarBNO C ratio))o-catalytic were P rocessesdispersed in 0.2 mL of Catalytic given3.3.Catalytic solvent.General mixtures mixtures P Therocedure BD/BNO semi BD/BNO 2-:homogeneous MBH (0.25 R(0.25 mmoleaction mmol (total with solution (total BDmolar and molar was ratio)) BNO stirred ratio)) Cwereo- catalytic forwere dispersed 10 dispersed min,Processes in the 0.2 in corre-mL 0.2 mL of givenofCatalytic given solvent. solvent.mixtures The The semiBD/BNO semi--homogeneous- (0.25homogeneous mmol solution (total solution molar was ratio)) was stirred stirred were for dispersed 10 for min, 10 min, the in 0.2 corre- the mL corre- of given solvent.Catalytic The mixtures semi-homogeneous BD/BNO (0.25 solution mmol (total was stirredmolar ratio)) for 10 were min, dispersed the corre- in 0.2 mL of given solvent. The semi-homogeneous solution was stirred for 10 min, the corre-

Catalysts 2021, 11, 237 8 of 10

However, we were pleased to ﬁnd that BD combined with BNO in view of increasing the chiral concentration in the solution to give the allyl alcohol 7a–d in 4 days and provided moderate yield and ee value. This is important because there is no report about using BD as a catalyst in asymmetric MBH reactions. BD was reported previously only for asymmetric Henry reaction with copper (I) salt [20]. The absolute conﬁguration of the products was assigned as R0-based on a correlation with known compounds [39,41,42].

3. Materials and Methods 3.1. General Information All solvents were commercially available grade unless otherwise stated. The aldehydes, MVK and 3-hydroxylphenyl acrylate were used as purchased. The products were puriﬁed by neutral column chromatography on 70–230 or 230–400 mesh silica gels. Spec- tra obtained were 1H NMR and 13C NMR from 400 and 100.6 MHz NMR spectrometer, respectively (Supplementary Materials). Chemical shifts (δ) are reported in parts per million (ppm) from residual solvent resonance as the internal standard. Coupling constants are reported in Hertz (Hz) and the multiplicities are indicated as br = broad, s = singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiple. Enantiomeric excesses were determined using chiral high performance liquid chromatography. IR spectra were obtained from a Jasco FT/IR-480 Plus instrument using KBr disks. Elemental analysis (EA) was obtained from ThermoQuest (Flash 1112EA, ITALY).

3.2. General Procedure 1: MBH Reaction with Single Catalytic Processes Catalysts BNO and BD (0.25 mmol) were used. In a screw caped vial, a single catalyst (0.25 mmol) in 0.2 mL of given solvent, 4-nitrobenzaldehyde and MVK (given equivalent) were mixed at room temperature. The resulting solution was stirred at room temperature for 6–8 days. The reaction was monitored by TLC. After completion, the mixture was diluted with ethyl acetate (1 mL) and concentrated under reduced pressure. The resultant crude was puriﬁed by column chromatography on silica gel (hexanes/EtOAc, 90:10) to provide allylic alcohol 7a.

3.3. General Procedure 2: MBH Reaction with BD and BNO Co-Catalytic Processes Catalytic mixtures BD/BNO (0.25 mmol (total molar ratio)) were dispersed in 0.2 mL of given solvent. The semi-homogeneous solution was stirred for 10 min, the corresponding aldehyde (0.25 mmol) and methyl vinyl ketone (given equivalent) or acrylate (4 equiv) was added. The resulting solution was stirred at room temperature. Completion of the reaction was monitored by TLC. After the indicated reaction time, ethyl acetate (1 mL) was added, and the extracts were easily separated by applying a separating funnel. The extracts were combined and concentrated. Further puriﬁed by column chromatography on silica gel (hexanes/EtOAc, 90:10) provided corresponding allylic alcohol.

3.4. 3-Hydroxyphenyl 2-(hydroxy(4-nitrophenyl)methyl)acrylate (7b) 1 Brownish oil: H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.60–6.55 (m, 3H), 6.47 (s, 1H), 6.05 (s, 1H), 5.62 (s, 1H): 13C NMR (100 MHz, CDCl3) δ 164.7, 156.6, 151.1, 141.3, 139.9, 131.7, 130.2, 128.2, 122.1, 113.5, 113.4, 109.1, 72.5.

4. Conclusions We studied in detail the comparative catalytic efﬁciency by single and combined catalytic systems using BNO and BD in an MBH reaction. In a process with a single catalyst, BD (20 mol%) gave respective MBH adduct of 7a in moderate yield and ee value (59%). In a co-catalytic system, the mixture of BD/BNO provided better results. MBH adducts were achieved up to 74% yield and 78% ee value. In this asymmetric reaction, chiral induction was mainly due to tertaryamino-1,2-diol of BD which activated the carbonyl group through hydrogen bonding. The BD/BNO cooperative catalytic system provides rate enhancement Catalysts 2021, 11, 237 9 of 10

which may be due to increasing the chiral concentration in the solution by BNO in the mixture.

Supplementary Materials: The following are available online at https://www.mdpi.com/2073-4 344/11/2/237/s1, Figure S1: 1H NMR of BD. Figure S2: 13C NMR of BD. Figure S3: LRMS of BD. Figure S1. 1H NMR of BD. Figure S4: 1HNMR of compound 7a. Figure S5: 1H NMR of compound 7b. Figure S6: 13C NMR of compound 7b. Figure S7: HPLC of compound 7a (racemic). Figure S8: HPLC of compound 7a. Figure S9: HPLC of compound 7b. Author Contributions: V.A. and D.-F.T. designed the experiments and wrote the manuscript; D.-F.T. Supervised study; V.A. performed the experiments; V.A., D.-F.T., C.-H.L. contributed to scientific discussions. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Taiwan Ministry of Science and Technology grant number [NSC100-2622-M-259-001-CC2]. Data Availability Statement: Not applicable. Acknowledgments: We thank Taiwan Ministry of Science and Technology for providing the financial support (NSC100-2622-M-259-001-CC2). Conflicts of Interest: The authors declare no conflict of interest.

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