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Published in final edited form as: ChemistryEurope. 2023 May 3;1(1):e202300015. doi: 10.1002/ceur.202300015

Isothiourea-Catalyzed Enantioselective Functionalisation of Glycine Schiff Base Aryl Esters via 1,6- and 1,4-Additions

Lotte Stockhammer a,#, Rebecca Craik b,#, Uwe Monkowius c, David B Cordes b, Andrew D Smith b,*, Mario Waser a,*
PMCID: PMC7616101  EMSID: EMS196535  PMID: 38882579

Abstract

The enantioselective α-functionalisation of glycine Schiff base aryl esters through isothiourea catalysis is successfully demonstrated for 1,6-additions to para-quinone methides (21 examples, up to 95:5 dr and 96:4 er) and 1,4-additions to methylene substituted dicarbonyl or disulfonyl Michael acceptors (17 examples, up to 98:2 er). This nucleophilic organocatalysis approach gives access to a range of α-functionalised α-amino acid derivatives and further transformations of the activated aryl ester group provide a straightforward entry to advanced amino acid-based esters, amides or thioesters.

Keywords: 1,6- and 1,4-addition; α-amino acid derivatives; enantioselective; glycine Schiff base; isothiourea

Introduction

The development of new catalytic enantioselective methods to access enantioenriched α-amino acid derivatives (α-AA) is of huge significance and interest to the synthetic community.[1–9] A plethora of effective synthetic methods has been developed and widely reviewed,[2–9] allowing for the synthesis of non-natural α-amino acid derivatives that incorporate novel structural motifs not found within the chiral pool.[2] One of the most common and direct strategies in this area is to selectively α-functionalise glycine derivatives via formal generation of a nucleophilic glycine anion equivalent.[4,5] Of the many methods developed, the enantioselective α-functionalisation of glycine derived Schiff base derivatives may be the most popular.[5] Since the pioneering work of O’Donnell[10,11] who utilized them as substrates for enantioselective ammonium salt phase transfer catalysis (PTC),[12] they have since been used and developed in a range of enantioselective (organo)-catalytic processes such as α-Csp3-alkylations, Michael reactions, or Mannich type approaches (considering the most valuable C−C-bond forming strategies only).[5,13] Michael type additions are of fundamental importance to access structurally diverse chiral target molecules[14] and the use of glycine Schiff bases for asymmetric Michael type reactions has been successfully explored using non-covalent (organo)-catalytic strategies through exploiting phase transfer ion pairing catalysis, Brønsted base catalysis and Lewis acid approaches (Scheme 1A).[5,15] Usually, these non-covalent activation strategies allow for high levels of stereo-selectivity especially when a sterically demanding t-butyl ester of the glycine Schiff base is used as a starting material (Me-esters have been used too but usually with lower selectivities only). However, due to the stability of this ester further direct manipulations such as transamination or transesterification require a stepwise approach, consisting of ester hydrolysis followed by activation of the free carboxylic acid towards nucleophilic attack.

Scheme 1.

Scheme 1

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(a) Established strategies for glycine Schiff base Michael addition reactions. (b) The generation of C(1)-ammonium enolates and their established synthetic utilization. (c) The merger of these two concepts to carry out the α-functionalization of glycine Schiff bases under covalent ITU catalysis.

To the best of our knowledge the enantioselective functionalisation of glycine Schiff base derivatives through covalent catalytic activation strategies such as asymmetric Lewis base catalysis has not yet been developed. Within this area, the generation and reactivity of C(1)-ammonium enolates using tertiary amine Lewis bases as catalysts has been widely exploited.[16] Originally exploiting isolable or in-situ generated ketenes from acid chlorides as starting materials,[17] in recent years their in-situ generation from either carboxylic acids or electron-deficient aryl ester derivatives (i. e. p-nitrophenol (PNP) or pentafluorophenol (PFP)) has been extensively investigated.[18] In particular, the use of easily accessible (chiral) isothioureas (ITUs) as Lewis base catalysts in enantioselective transformations has developed widely in this context.[19] The unique potential of this activation strategy lies in the fact that the covalently bound catalyst forms a well-defined chiral C(1)-ammonium enolate (Scheme 1B) which is capable of reacting in a highly face-selective manner with a range of either C- or heteroatom-electrophiles.[20] After the asymmetric α-functionalization the catalyst is liberated by nucleophilic displacement either in an intermolecular manner (i. e. from an aryl ester starting material the generated aryloxide will promote turnover to give an activated aryl ester suited for further displacements)[21] or via an intramolecular cyclization (when carrying out Michael type additions where the in situ formed enolate acts as the catalyst releasing nucleophile). A frequently encountered limitation in this area is the restricted structural variation allowed within the α-substituted carboxylic acid or ester derivative that can be employed in intermolecular reactions. Specifically, most processes require an α-aryl-, α-heteroaryl,[22] or α-alkenyl-substituted derivative[23] to achieve reactivity, with limited exceptions within the literature (Scheme 1B).[24] In this context, and as part of ongoing studies concerning the exploitation of isothioureas in C(1)-ammonium enolate generation, in this manuscript we demonstrate that glycine Schiff base-derived activated aryl esters are viable precursors for enantioselective 1,6- and 1,4-conjugate additions using isothioureas as Lewis base organocatalysts (Scheme 1C). To the best of our knowledge this represents the first example for a covalent asymmetric organocatalytic activation of glycine Schiff bases, providing a conceptually unprecedented approach to access α-amino acid derivatives. In addition, considering the reactivity of the activated aryl ester, further direct manipulations by transamination and transesterification are also demonstrated.

Results and Discussion

Synthesis of the activated glycine Schiff base 1

The syntheses of glycine Schiff base alkyl esters (such as the t-butyl ester, Scheme 1A) are well established.[5,25] However, due to the more reactive nature of the targeted electron-deficient aryl ester variants a careful optimization of the synthesis procedure was necessary.[26] As outlined in Scheme 2, synthesis of the PNP ester 1 was possible by starting from N-Boc-protected glycine (2) via an esterification – Boc-deprotection – imine formation sequence. Because of the pronounced sensitivity of the activated ester towards hydrolysis column chromatographic purification was omitted, with isolation and purification by crystallization and trituration developed, allowing a scalable and robust process to access 1 on gram scale. The same strategy was also tested to access the analogous PFP ester, but unfortunately isolation in satisfactory purity by crystallization or chromatography was not possible due to its sensitivity to hydrolysis.

Scheme 2. Synthesis of the glycine Schiff base PNP ester 1.

Scheme 2

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Asymmetric 1,6-conjugate addition reactions of 1

The asymmetric 1,6-addition of glycine Schiff base alkyl esters to para-quinone methides (p-QMs, 7)[27,28] has previously been demonstrated utilizing chiral ammonium salt phase transfer catalysts and Cu-catalysts.[29] Considering the structural diversity of β-functionalized α-AA derivatives that should be accessible by reacting aryl ester Schiff base 1 with p-QMs 7,[30] and the potential of the products to undergo further transesterifications or transaminations, the addition of 1 to p-QM 7a utilizing established Lewis base catalysts (Figure 1) was investigated.[31]

Figure 1. Isothio- and isoselenourea catalysts tested herein.

Figure 1

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Table 1 gives an overview of a detailed screening and optimization of the addition of 1 to 7a. First experiments showed that the uncatalyzed racemic background reaction is facile (entry 1) and that the addition of achiral ITU-1 does not lead to enhanced yield (entry 2). First trials with the established chiral catalysts HyperBTM (ITU-2, entry 3) and HBTM (ITU-3, entry 5) as well as the HyperBTM isoselenourea analogue ISeU-2 (entry 4) gave only moderate levels of enantioselectivity. Interestingly the product er increased significantly when using the bicyclo[3.3.0]octene-based ITUs BTM (ITU-4) and tetramisole hydrochloride (TM·HCl, ITU-5). Both of these catalysts allowed for promising initial enantioselectivities higher than 80:20 (entries 6 and 7) for the major diastereoisomer. Further optimization of the reaction conditions used ITU-5 as a catalyst (entries 7–16). After testing different solvents and bases, as well as variation of catalyst loading and temperature, the use of low temperature conditions allowed satisfactory isolated yields (77%), good diastereoselectivity (85:15), and high enantioselectivity (93:7) for the major diastereoisomer (entry 16). It is noteworthy that the minor diastereomer was obtained in essentially racemic form. Product 8a, as well as the other addition products of ester 1 described herein, do not undergo further alkylation when treated with an excess of acceptor and ITU, nor do they epimerize when stirred with an achiral ITU. These results indicate that addition of the ITU is much more hindered for α-alkylated products like compound 8a as compared to the prochiral substrate 1.

Table 1. Optimization of the 1,6-addition of glycine Schiff base 1 to p-QM 7a.a.

Inline graphic
Entry ITU Base T [°C] Yield[%]b drc erd,e
1 – Et3N 25 70 75:25 –
2 ITU-1 Et3N 25 53 75:25 –
3 ITU-2 Et3N 25 85 70:30 42:58 (45:55)
4 ISeU-2 Et3N 25 73 60:40 26:74 (44:56)
5 ITU-3 Et3N 25 79 75:25 38:62 (40:60)
6 ITU-4 Et3N 25 66 65:35 18:82 (69:31)
7 ITU-5 Et3N 25 66 75:25 84:16 (40:60)
8 ITU-5 DIPEA 25 67 75:25 90:10 (45:55)
9 ITU-5 DABCO 25 58 70:30 90:10 (40:60)
10 ITU-5 K2CO3 25 73 70:30 87:13 (40:60)
11f ITU-5 DIPEA 25 41 60:40 89:11 (59:41)
12g ITU-5 DIPEA 25 78 65:35 89:11 (38:62)
13 ITU-5(5%) DIPEA 25 71 75:25 80:20 (46:54)
14 ITU-5
(20%) 		DIPEA 25 60 70:30 90:10 (43:57)
15 ITU-5 DIPEA − 20 72 80:20 93:7 (52:48)
16 ITU-5 DIPEA − 40 77 85:15 93:7 (56:44)
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a

All reactions were run using 0.05-0.1 mmol 1, 7a (1 equiv.) and base (1 equiv.) in acetonitrile under the given conditions unless otherwise stated.

b

Isolated yields of the mixture of diastereomers.

c

Determined by 1H NMR of the crude product.

d

Determined by HPLC using a chiral stationary phase (values in brackets refer to the er of the minor diastereoisomer).

e

For the major stereoisomer the depicted (R,R)-configuration was assigned in analogy to the results obtained by single crystal X-ray analysis of derivative 9d (see below) and comparison of the analytical details of products 8 (Scheme 3) and derivatives thereof (Scheme 4) with reported data.[29]

f

CH2Cl2 as the solvent.

g

Acetone as the solvent.

Having identified suited conditions for the asymmetric addition of 1 to p-QM 7a (Table 1, entry 16) the scope for this transformation was investigated (Scheme 3). A variety of different arylidene-based p-QMs 7 were reasonably well tolerated (giving products 8 a–r) although the nature of the substituents had a notable effect on diastereo- as well as enantioselectivity. For example, the α-naphthyl-containing product 8o was accessible with very high selectivity (95:5 dr, 97:3 er on 1 mmol scale) while the pyridyl-based product 8r was obtained with lower levels of stereoselectivity (80:20 dr, 78:22 er).

Scheme 3. Asymmetric application scope of the 1,6-addition of 1 to p-QMs 7.

Scheme 3

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[a] Due to solubility issues this reaction was carried out in CH2Cl2 for 64 h. [b] er was determined by analysing the corresponding morpholine amides (compare with Scheme 4, compound 9 b). [c] 1 mmol scale. [d] Using ITU-4.

In addition, the use of two alkylidene-based p-QMs gave products 8s and 8t. Interestingly, while the use of the p-CF3-containing p-QM[32] (giving 8t) gave poor enantioselectivity, the methyl-substituted product 8s was obtained in high selectivity when using BTM (ITU-4) instead of ITU-5 (it should be noted that ITU-4 was also tested for several arylidene-based QMs but in those cases ITU-5 was found to be superior).

The high reactivity of electron-deficient aryl esters was expected to allow efficient follow up transformations. The suitability of the α-Np-based product 8o to undergo further trans(thio)esterifications and transaminations was investigated (Scheme 4) demonstrating that 8o reacts readily with primary and secondary amines to access dipeptide 9a and the amides 9b–d in good chemical yields without any erosion of er or dr The relative and absolute configuration of secondary amide 9d was determined by single crystal X-ray diffraction analysis,[33] with all other products 8–12 assigned by analogy (in addition to comparison with literature data).[29] Alongside these amide-formations, synthesis of the thioester 11 as well as the methylester 12 was also achieved.

Scheme 4. Further functionalizations of the PNP ester 8o. Conditions:

Scheme 4

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a) nucleophile (benzylamines, morpholine, thiophenol), DMAP, MeCN, r. t.;

b) methyl glycinate hydrochloride, DIPEA, DMAP (20 mol%), MeCN, r. t.;

c) DMAP, MeOH, r. t.; d) HCl (1 M), THF, 0 °C.

o-OH-containing p-QMs like compound 13a are versatile precursors to access (chiral) bicyclic target molecules upon reaction with suited (pro)-nucleophiles.[34] The ITU-catalysed addition of glycine Schiff base 1 to compound 13a (Scheme 5). led to direct formation of the targeted product 14a but in a racemic manner (and modest diastereoselectivity) despite extensive testing of catalytic conditions. The most rational explanation for this outcome is that addition of the phenol group to the activated ester or acyl ammonium intermediate proceeds first, followed by 1,6-addition to the p-QM motif in an intramolecular manner without the ITU-catalyst being covalently bound.[35] A variety of O-protected p-QMs 13 was next tested, with the MOM-protected derivative 13b giving addition product 15. Further treatment of 15 with MgBr2 and Me2S[36] allowed for MOM-deprotection and concomitant cyclization giving product 14a in good overall yield (63% over two steps) and good diastereo- and enantioselectivity (90:10 dr, 90:10 er). By utilizing the analogous naphthyl-based starting material, the corresponding product 14b could be accessed with significantly higher levels of stereoselectivity.

Scheme 5. Use of o-OH-containing p-QMs 13.

Scheme 5

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Asymmetric 1,4-conjugate addition reactions of 1

Subsequent work considered the ITU-catalysed addition of glycine Schiff base 1 to α,β-unsaturated bis-sulfone Michael acceptor 16 (Scheme 6A). In this series, while isolation of the corresponding PNP ester product proved facile, assessment of its enantiopurity by HPLC analysis was unreliable, and consequently addition of benzylamine to yield a stable derivative 17 was investigated. Screening of a range of ITUs showed that ITU-4 ((R)-BTM) gave the highest product er, while using an excess (5 equiv.) of benzylamine led to a 15:85 mixture of amine 18 (92:8 er) to imine 17 as a result of transamination and amide formation. However, using 1 equiv. of benzylamine led to selective amide formation, giving 17 in 81% yield and 93:7 er. Further investigation showed that this competitive transamination event did not occur upon addition of secondary amines, with morpholine, pyrrolidine and N-Boc-piperazine giving the corresponding amides 20a–20c, while methanol gave the ester 20d in good yield and er (61–81% yield, up to 94:6 er, Scheme 6B). In the case of 20a, further optimisation showed that dropwise addition of the bis-sulfone Michael acceptor 16 allowed the catalyst loading to be reduced to 5 mol%, giving 20a in 89% yield and 98:2 er. Unfortunately, extension of these protocols to alternative di-ketone or diester Michael acceptors gave 20e and 20f with reduced product er, particularly for diester product 20f (58:42 er), necessitating re-optimisation to find a generally applicable protocol.

Scheme 6. Initial optimisation of reaction with bis-sulfone electrophile 16.

Scheme 6

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[a] er determined by HPLC analysis on a chiral stationary phase. [b] 16 added dropwise by syringe-pump over 6 h. [c] For step (ii) MeOH and DMAP (20 mol%) were used.

Further investigation re-optimised the reaction process to find a more general protocol applicable to bis-sulfone, di-ketone and di-ester Michael acceptors (Scheme 7A). Screening of a range of ITU catalyst and solvent combinations (see Supporting Information for full optimisation) showed that the use of the recently developed isoselenourea ISeU-2 (20 mol%) in an MeCN/iPrOH solvent mixture provided the most generally applicable protocol, giving bis-sulfone derivative 20a in 80% yield and 91:9 er, di-ester derivative 20f in 60% yield and 95:5 er, and diketone derivative 20e in 89% yield and 89:11 er. The generality of this process was explored through extension to a range of di-aryl ketone Michael acceptors, with electron donating (4-OMeC6H4; 4-NMe2C6H4; 3,4-(OMe)2C6H3), halogen (4-BrC6H4; 4-ClC6H4), 1- and 2-naphthyl, as well as heterocyclic variants (2-thienyl, 3-thienyl; 2-furyl) explored, giving products 20g–20q in up to 74% yield and 90:10 er. Interestingly the 2-thienyl derivative gave preferentially the corresponding isopropyl ester (68% yield, 66:34 er) under the standard conditions, with EtOAc used as the reaction solvent to generate 20n. Unfortunately, extension to the use of alternative Michael acceptors containing a single electron withdrawing substituent (COPh or SO2F) led to consistently low product yields and enantioselectivity (Scheme 7B). Furthermore, the use of ethyl (E)-4-oxo-4-phenylbut-2-enoate led to the formation of 20t, presumably arising from formal [4 + 2]-cycloaddition and elimination, in unoptimized 36% yield (Scheme 7C).

Scheme 7. Scope and limitations using (2S,3R)-HyperSe (ISeU-2) in MeCN/iPrOH.

Scheme 7

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[a] er determined by HPLC analysis on a chiral stationary phase. [b] Reaction carried out in EtOAc; in MeCN/iPrOH the corresponding isopropyl ester was isolated in 68% yield and 66:34 er.

Having demonstrated the scope of this transformation, further derivatisation focused upon hydrolysis of the Schiff base imine functionality to yield the free amine by treatment with 1 M HCl in THF. This was readily applied to the bis-sulfone 20a and diester 20f derivatives (Scheme 8), giving the desired amines 21 and 23 respectively in good yields and without erosion of enantiopurity. The absolute configuration within 21 was established unambiguously by derivatisation to N-4-bromobenzenesulfonyl (NBs) derivative 22 and subsequent single crystal X-ray diffraction analysis.[33] When applied to the corresponding diphenyl-ketone derivative 20e (86:14 er), imine hydrolysis, followed by intramolecular cyclisation onto the dicarbonyl gave a mixture of tautomeric species, that followed by treatment with benzoyl chloride gave N−Bz protected pyrrolidine 24 in 86:14 er and excellent yield.

Scheme 8. Further product derivatization.

Scheme 8

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[a] er determined by HPLC analysis on a chiral stationary phase; dr determined by 1H NMR spectroscopic analysis. Bs=4-bromobenzenesulfonyl.

Conclusions

In conclusion, this manuscript demonstrates the enantioselective α-functionalisation of glycine Schiff base aryl esters through chiral isothiourea catalysis. Successful applications in the 1,6-additions to para-quinone methides (21 examples, up to 95:5 dr and 96:4 er) and 1,4-additions to methylene substituted dicarbonyl or disulfonyl Michael acceptors (17 examples, up to 98:2 er) demonstrate the generality of this Lewis base activation protocol. Overall, this approach gives access to a range of α-functionalised α-amino acid derivatives, with further transformations of the activated aryl ester group and the imine protecting group providing straightforward access to a range of advanced amino acid-based esters, amides or thioesters as well as pyrrolidine derivatives.[37]

Experimental Section

General experimental details, further optimizations, analytical details and characterization, as well as copies of NMR spectra and HPLC chromatograms can be found in the online Supporting Information.

General procedure for the 1,6-addition of 1 to p-QMs

Schiff base 1 (1 equiv.) and TM.HCl (ITU-5; 10 mol%) were dissolved in freshly degassed MeCN (0.07 mol L−1) at −40 °C. Then, DIPEA (1 equiv.) was added and the mixture was stirred for 5 min. The respective quinone methide (1 equiv.) was added in one portion and the mixture was further stirred for 15 h. After this, the circulation chiller was turned off, and the mixture was allowed to reach rt over 1 h. It was filtered over Na2SO4 and washed with CH2Cl2 (3×). The filtrate was concentrated on the rotary evaporator and the crude products were purified by column chromatography on deactivated silica (heptanes followed by heptanes/EtOAc 10/1 and 5/1). Products were obtained as a mixture of diastereomers in indicated yields and enantiopurities.

General procedure for the 1,4-addition of 1 to different Michael acceptors

The Schiff base 1 (1.0 equiv.), the Michael acceptor (1.0 equiv.) and the ITU or ISeU (20 mol%) were added to a flame dried vial. IPA (0.5 M) and MeCN (1.3 M) were then added, and the reaction was stirred at rt and monitored by 1H NMR. When all the Michael acceptor was consumed, the nucleophile (Nuc-H) was added, and the reaction was stirred for 10 min at rt. The reaction mixture was diluted with EtOAc (40 volumes) and NaOH (1 M) solution (40 volumes). The aq. layer was extracted with EtOAc (× 2 vol). The organic layer was then washed with NaOH (1 M) (× 2 vol), brine (× 1 vol), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography using the solvent system stated in the Supporting Information. Products were obtained as a mixture of diastereomers in indicated yields and enantiopurities.

Supplementary Material

SI

Acknowledgements

The St Andrews team thanks the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/ L016419/1) (R. C.) for funding. The Linz team gratefully acknowledges generous financial support by the Austrian Science Funds (FWF) through project No. P31784.

Footnotes

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are openly available in University of St Andrews Research Portal. at https://doi.org/10.17630/631a7545-ad96-427c-aa3f-a18664e93537, reference number 37.

References

  • [1].Hughes AB. Amino Acids, Peptides and Proteins in Organic Chemistry. 1–5 Wiley-VCH; 2009. [Google Scholar]
  • [2].Saghyan AS, Langer P. Asymmetric Synthesis of Non-proteinogenic Amino Acids. Wiley-VCH; 2016. [Google Scholar]
  • [3].Selected reviews for asymmetric α-AA syntheses: Najera C, Sansano JM. Chem Rev. 2007;107:4584–4671. doi: 10.1021/cr050580o. Vogt H, Bräse S. Org Biomol Chem. 2007;5:406–430. doi: 10.1039/b611091f. Cativiela C, Ordóñez M. Tetrahedron: Asymmetry. 2009;20:1–63. doi: 10.1016/j.tetasy.2009.01.002. Perdih A, Sollner Dolenc M. Curr Org Chem. 2011;15:3750–3799. Metz AE, Kozlowski MC. J Org Chem. 2015;80:1–7. doi: 10.1021/jo502408z.
  • [4].Jakubowska A, Kulig K. Curr Org Synth. 2013;10:547–563. [Google Scholar]
  • [5].O’Donnell MJ. Tetrahedron. 2019;75:3667–3696. [Google Scholar]
  • [6].Wang Y, Song X, Wang J, Moriwakim H, Soloshonok VA, Liu H. Amino Acids. 2017;49:1487–1520. doi: 10.1007/s00726-017-2458-6. [DOI] [PubMed] [Google Scholar]
  • [7].Larionov VA, Stoletova NV, Maleev VI. Adv Synth Catal. 2020;362:4325–4367. [Google Scholar]
  • [8].Almhjell PJ, Boville CE, Arnold FH. Chem Soc Rev. 2018;47:8980–8997. doi: 10.1039/c8cs00665b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Ikunaka M, Maruoka K. In: Asymmetric Catalysis on Industrial Scale. 2nd ed. Blaser HU, Federsel H-J, editors. Wiley-VCH; 2010. pp. 151–169. [Google Scholar]
  • [10].For an early racemic approach: O’Donnell MJ, Boniece JM, Earp SE. Tetrahedron Lett. 1978;19:2641–2644.
  • [11].For the seminal asymmetric contribution: O’Donnell MJ, Bennett WD, Wu S. J Am Chem Soc. 1989;111:2353–2355.
  • [12].Selected reviews on asymmetric phase-transfer catalysis: Brière J-F, Oudeyer S, Dalla V, Levacher V. Chem Soc Rev. 2012;41:1696–1707. doi: 10.1039/c1cs15200a. Shirakawa S, Maruoka K. Angew Chem Int eeed. 2013;52:4312–4348. doi: 10.1002/anie.201206835. Angew. Chem. 2013., 125, 4408–4445. Brak K, Jacobsen EN. Angew Chem Int eeed. 2013;52:534–561. doi: 10.1002/anie.201205449. Angew. Chem. 2013., 125, 558–588. Tan J, Yasuda N. Org Process Res Dev. 2015;19:1731–1746. Kaneko S, Kumatabara Y, Shirakawa S. Org Biomol Chem. 2016;14:5367–5376. doi: 10.1039/c5ob02446c. Qia D, Sun J. Chem Eur J. 2019;25:3740–3751. Otevrel J, Waser M. In: Asymmetric Organocatalysis: New Strategies, Catalysts, and Opportunities. Albrecht Ł, Albrecht A, Dell’Amico L, editors. Wiley-VCH; 2023. pp. 71–120.
  • [13].For two contributions by our group: Waser M, Gratzer K, Herchl R, Müller N. Org Biomol Chem. 2012;10:251–254. doi: 10.1039/c1ob06573d. Tiffner M, Novacek J, Busillo A, Gratzer K, Massa A, Waser M. RSC Adv. 2015;5:78941–78949. doi: 10.1039/C5RA14466C.
  • [14].For selected reviews on asymmetric Michael addition reactions: Zhang Y, Wang W. Catal Sci Technol. 2012;2:42–53. Zheng K, Liu X, Feng X. Chem Rev. 2018;118:7586–7656. doi: 10.1021/acs.chemrev.7b00692. Reznikov AN, Klimochkin YN. Synthesis. 2020;52:781–795. Pasuparthy SD, Maiti B. ChemistrySelect. 2022;7:e202104261
  • [15].For selected conceptually diverse examples see: Corey EJ, Noe MC, Xu F. Tetrahedron Lett. 1998;39:5347–5350. Kobayashi S, Tsubogo T, Saito S, Yamashita Y. Org Lett. 2008;10:807–809. doi: 10.1021/ol702958w. Bandar JS, Lambert TH. J Am Chem Soc. 2012;134:5552–5555. doi: 10.1021/ja3015764. Wen S, Li X, Yao W, Waheed A, Ullah N, Lu Y. Eur J Org Chem. 2016:4298–4301. Miguelez J, Miyamura H, Kobayashi S. Adv Synth Catal. 2017;359:2897–2900.
  • [16].a) Gaunt MJ, Johansson CCC. Chem Rev. 2007;107:5596–5605. doi: 10.1021/cr0683764. [DOI] [PubMed] [Google Scholar]; b) Fu GC. Acc Chem Res. 2000;33:412–420. doi: 10.1021/ar990077w. [DOI] [PubMed] [Google Scholar]; c) France S, Guerin DJ, Miller SJ, Lectka T. Chem Rev. 2003;103:2985–3012. doi: 10.1021/cr020061a. [DOI] [PubMed] [Google Scholar]; d) Denmark SE, Beutner GL. Angew Chem Int eeed. 2008;47:1560–1638. doi: 10.1002/anie.200604943. Angew. Chem. 2008., 120, 1584–1663. [DOI] [PubMed] [Google Scholar]; e) Taylor JE, Bull SD, Williams JMJ. Chem Soc Rev. 2012;41:2109–2121. doi: 10.1039/c2cs15288f. [DOI] [PubMed] [Google Scholar]
  • [17].a) Wynberg H, Staring EGJ. J Am Chem Soc. 1982;104:166–168. [Google Scholar]; b) Taggi AE, Hafez AM, Wack H, Young B, Drury WJ, III, Lectka T. J Am Chem Soc. 2000;122:7831–7832. [Google Scholar]; c) Hodous BL, Fu GC. J Am Chem Soc. 2002;124:1578–1579. doi: 10.1021/ja012427r. [DOI] [PubMed] [Google Scholar]; d) Wilson JE, Fu GC. Angew Chem. 2004;116:6518–6520. Angew. Chem. Int. eeed. 2004., 43, 6358–6360. [Google Scholar]; e) Bekele T, Shah MH, Wolfer J, Abraham CJ, Weatherwax A, Lectka T. J Am Chem Soc. 2006;128:1810–1811. doi: 10.1021/ja058077g. [DOI] [PubMed] [Google Scholar]; f) Xu X, Wang K, Nelson SG. JAm Chem Soc. 2007;129:11690–11691. doi: 10.1021/ja074845n. [DOI] [PubMed] [Google Scholar]; g) Paull DH, Weatherwax A, Lectka T. Tetrahedron. 2009;65:6771–6803. doi: 10.1016/j.tet.2009.05.079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].a) Morrill LC, Smith AD. Chem Soc Rev. 2014;43:6214–6226. doi: 10.1039/c4cs00042k. [DOI] [PubMed] [Google Scholar]; b) Cortez GS, Tennyson RL, Romo D. J Am Chem Soc. 2001;123:7945–7946. doi: 10.1021/ja016134+. [DOI] [PubMed] [Google Scholar]; c) Oh SH, Cortez GS, Romo D. J Org Chem. 2005;70:2835–2838. doi: 10.1021/jo050024u. [DOI] [PubMed] [Google Scholar]; d) Henry-Riyad H, Lee C, Purohit VC, Romo D. Org Lett. 2006;8:4363–4366. doi: 10.1021/ol061816t. [DOI] [PubMed] [Google Scholar]; e) Purohit VC, Matla AS, Romo D. J Am Chem Soc. 2008;130:10478–10479. doi: 10.1021/ja803579z. [DOI] [PubMed] [Google Scholar]; f) Morris KA, Arendt KM, Oh SH, Romo D. Org Lett. 2010;12:3764–3767. doi: 10.1021/ol101388h. [DOI] [PMC free article] [PubMed] [Google Scholar]; g) Leverett CA, Purohit VC, Romo D. Angew Chem Int eeed. 2010;49:9479–9483. doi: 10.1002/anie.201004671. Angew. Chem. 2010., 122, 9669–9673. [DOI] [PubMed] [Google Scholar]; h) Sikriwal D, Dikshit DK. Tetrahedron. 2011;67:210–215. [Google Scholar]; i) Belmessieri D, Morrill LC, Simal C, Slawin AMZ, Smith AD. J Am Chem Soc. 2011;133:2714–2720. doi: 10.1021/ja109975c. [DOI] [PubMed] [Google Scholar]; j) Simal C, Lebl T, Slawin AMZ, Smith AD. Angew Chem Int eeed. 2012;51:3653–3657. doi: 10.1002/anie.201109061. Angew. Chem. 2012., 124, 3713–3717. [DOI] [PubMed] [Google Scholar]; k) Morrill LC, Lebl T, Slawin AMZ, Smith AD. Chem Sci. 2012;3:2088–2093. [Google Scholar]; l) Belmessieri D, Cordes DB, Slawin AMZ, Smith AD. Org Lett. 2013;15:3472–3475. doi: 10.1021/ol401554y. [DOI] [PubMed] [Google Scholar]; m) Morrill LC, Stark DG, Taylor JE, Smith SR, Squires JA, D’Hol-lander ACA, Simal C, Shapland P, O’Riordan TJC, Smith AD. Org Biomol Chem. 2014;12:9016–9027. doi: 10.1039/c4ob01788a. [DOI] [PubMed] [Google Scholar]; n) Yeh P-P, Daniels DSB, Fallan C, Gould E, Simal C, Taylor JE, Slawin AMZ, Smith AD. Org Biomol Chem. 2015;13:2177–2191. doi: 10.1039/c4ob02408g. [DOI] [PubMed] [Google Scholar]; o) Hesping L, Biswas A, Daniliuc CG, Mück-Lichtenfeld C, Studer A. Chem Sci. 2015;6:1252–1257. doi: 10.1039/c4sc02612h. [DOI] [PMC free article] [PubMed] [Google Scholar]; p) Izquierdo J, Pericàs MA. ACS Catal. 2016;6:348–356. [Google Scholar]; q) Stark DG, Williamson P, Gayner ER, Musolino SF, Kerr RWF, Taylor JE, Slawin AMZ, O’Riordan TJC, Macgregor SA, Smith AD. Org Biomol Chem. 2016;14:8957–8965. doi: 10.1039/c6ob01557c. [DOI] [PMC free article] [PubMed] [Google Scholar]; r) Neyyappadath RM, Cordes DB, Slawin AMZ, Smith AD. Chem Commun. 2017;53:2555–2558. doi: 10.1039/c6cc10178j. [DOI] [PMC free article] [PubMed] [Google Scholar]; s) Wang S, Izquierdo J, Rodrίguez-Escrich C, Pericàs MA. ACS Catal. 2017;7:2780–2785. [Google Scholar]; t) Wang S, Rodrίguez-Escrich C, Pericàs MA. Angew Chem Int eeed. 2017;56:15068–15072. doi: 10.1002/anie.201707341. Angew. Chem. 2017., 129, 15264–15268. [DOI] [PubMed] [Google Scholar]; u) Song J, Zhang ZJ, Gong LZ. Angew Chem Int eeed. 2017;56:5212–5216. doi: 10.1002/anie.201700105. Angew. Chem. 2017., 129, 5296–5300. [DOI] [PubMed] [Google Scholar]; v) Zhang S, Taylor JE, Slawin AMZ, Smith AD. Org Lett. 2018;20:5482–5485. doi: 10.1021/acs.orglett.8b02423. [DOI] [PubMed] [Google Scholar]
  • [19].For reviews of isothioureas in catalysis see a) Merad J, Pons J-M, Chuzel O, Bressy C. Eur J Org Chem. 2016:5589–5610. [Google Scholar]; b) Birman VB. Aldrichimica Acta. 2016;49:23. [Google Scholar]; c) Biswas A, Mondal H, Maji MS. J Heterocycl Chem. 2020;57:3818–3844. [Google Scholar]; d) McLaughlin C, Smith AD. Chem Eur J. 2021;27:1533–1555. doi: 10.1002/chem.202002059. [DOI] [PMC free article] [PubMed] [Google Scholar]; e) Bitai J, Westwood MT, Smith AD. Org Biomol Chem. 2021;19:2366–2384. doi: 10.1039/d0ob02208j. [DOI] [PubMed] [Google Scholar]
  • [20].The origin of enantioselectivity in many of these reactions arises from a key S…O interaction that has been exploited widely in isothiourea catalysis: Birman VB, Li X, Han Z. Org Lett. 2007;9:37–40. doi: 10.1021/ol0623419. Liu P, Yang X, Birman VB, Houk KN. Org Lett. 2012;14:3288–3291. doi: 10.1021/ol301243f. Abbasov ME, Hudson BM, Tantillo DJ, Romo D. J Am Chem Soc. 2014;136:4492–4495. doi: 10.1021/ja501005g. Robinson ERT, Walden DM, Fallan C, Greenhalgh MD, Cheong PH-Y, Smith AD. Chem Sci. 2016;7:6919–6927. doi: 10.1039/c6sc00940a. Greenhalgh MD, Smith SM, Walden DM, Taylor JE, Brice Z, Robinson ERT, Fallan C, Cordes DB, Slawin AMZ, Richardson HC, Grove MA, et al. Angew Chem Int eeed. 2018;57:3200–3206. doi: 10.1002/anie.201712456. Angew. Chem. 2018., 130, 3254–3260. Young CM, Elmi A, Pascoe DJ, Morris RK, McLaughlin C, Woods AM, Frost AB, de la Houpliere A, Ling KB, Smith TK, Slawin AMZ, et al. Angew Chem Int eeed. 2020;59:3705–3710. doi: 10.1002/anie.201914421. Angew. Chem. 2020., 132, 3734–3739; for use of S…O interaction in asymmetric synthesis. Nagao Y, Miyamoto S, Miyamoto M, Takeshige H, Hayashi K, Sano S, Shiro M, Yamaguchi K, Sei Y. J Am Chem Soc. 2006;128:9722–9729. doi: 10.1021/ja056649r. for examples of S…O interactions in medicinal chemistry. Beno BR, Yeung KS, Bartberger MD, Pennington LD, Meanwell NA. J Med Chem. 2015;58:4383–4438. doi: 10.1021/jm501853m. for a discussion on the origin of chalcogen-bonding interactions. Pascoe DJ, Ling KB, Cockroft SL. J Am Chem Soc. 2017;139:15160–15167. doi: 10.1021/jacs.7b08511. ; For an excellent short overview see Breugst M, Koenig JJ. Eur J Org Chem. 2020:5473–5487.
  • [21].For a review see: Hartley WC, O’Riordan TJC, Smith AD. Synthesis. 2017;49:3303–3310. ; For select examples see West TH, Daniels DSB, Slawin AMZ, Smith AD. J Am Chem Soc. 2014;136:4476–4479. doi: 10.1021/ja500758n. ; c) West TH, Walden DM, Taylor JE, Brueckner AC, Johnston RC, Cheong PH-Y, Lloyd-Jones GC, Smith AD. J Am Chem Soc. 2017;139:4366–4375. doi: 10.1021/jacs.6b11851. [DOI] [PMC free article] [PubMed] [Google Scholar]; d) Schwarz KJ, Amos JL, Klein JC, Do DT, Snaddon TN. J Am Chem Soc. 2016;138:5214–5217. doi: 10.1021/jacs.6b01694. [DOI] [PubMed] [Google Scholar]; e) Fyfe JWB, Kabia OM, Pearson CM, Snaddon TN. Tetrahedron. 2018;74:5383–5391. doi: 10.1016/j.tet.2018.04.021. [DOI] [PMC free article] [PubMed] [Google Scholar]; f) Schwarz KJ, Pearson CM, Cintron-Rosado GA, Liu P, Snaddon TN. Angew Chem. 2018;130:7926–7929. doi: 10.1002/anie.201803277. Angew. Chem. Int. eeed. 2018., 57, 7800–7803. [DOI] [PMC free article] [PubMed] [Google Scholar]; g) Schwarz KJ, Yang C, Fyfe JWB, Snaddon TN. Angew Chem. 2018;130:12278–12281. doi: 10.1002/anie.201806742. Angew. Chem. Int. eeed. 2018., 57, 12102–12105. [DOI] [PMC free article] [PubMed] [Google Scholar]; h) Scaggs WR, Snaddon TN. Chem Eur J. 2018;24:14378–14381. doi: 10.1002/chem.201803543. [DOI] [PMC free article] [PubMed] [Google Scholar]; i) Hutchings-Goetz L, Yang C, Snaddon TN. ACS Catal. 2018;8:10537–10544. doi: 10.1021/acscatal.8b03507. [DOI] [PMC free article] [PubMed] [Google Scholar]; j) Scaggs WR, Scaggs TD, Snaddon TN. Org Biomol Chem. 2019;17:1787–1790. doi: 10.1039/c8ob02600a. [DOI] [PMC free article] [PubMed] [Google Scholar]; k) Arokianathar JN, Frost AB, Slawin AMZ, Stead D, Smith AD. ACS Catal. 2018;8:1153–1160. [Google Scholar]; l) Zhao F, Shu C, Young CM, Carpenter-Warren C, Slawin AMZ, Smith AD. Angew Chem Int eeed. 2021;60:11892. doi: 10.1002/anie.202016220. [DOI] [PMC free article] [PubMed] [Google Scholar]; m) Stockhammer L, Weinzierl D, Bögl T, Waser M. Org Lett. 2021;23:6143–6147. doi: 10.1021/acs.orglett.1c02256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].a) Zhang S, Greenhalgh MD, Slawin AMZ, Smith AD. Chem Sci. 2020;11:3885–3892. doi: 10.1039/d0sc00432d. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Zhang S, Hartley WC, Greenhalgh MD, Ng S, Slawin AMZ, Smith AD. ChemCatChem. 2020;12:4522–4525. [Google Scholar]; c) Zhang S, Bacheley L, Young CM, Stark DG, O’Riordan T, Slawin AMZ, Smith AD. Asian J Org Chem. 2020;9:1562–1566. [Google Scholar]
  • [23].Morrill LC, Smith SM, Slawin AMZ, Smith AD. J Org Chem. 2014;79:1640–1655. doi: 10.1021/jo402591v. [DOI] [PubMed] [Google Scholar]
  • [24].For isolated examples see Morrill LC, Lebl T, Slawin AMZ, Smith AD. Chem Sci. 2012;3:2088–2093. Stark DG, Morrill LC, Yeh PP, Slawin AMZ, O’Riordan TJC, Smith AD. Angew Chem Int eeed. 2013;52:11642–11646. doi: 10.1002/anie.201306786. Angew. Chem. 2013, 125, 11856–11860. Straub MR, Birman VB. Org Lett. 2018;20:7550–7553. doi: 10.1021/acs.orglett.8b03297.
  • [25].For a systematic study on the nucleophilicity of these compounds: Timofeeva DS, Ofial AR, Mayr H. Tetrahedron. 2019;75:459–463.
  • [26].For an early report illustrating the difficulties in synthesizing such esters: Ibata T, Singh GS. Chem Lett. 1994;23:81–84.
  • [27].For selected general quinone methide overviews: Bai W-J, David J-G, Feng Z-G, Weaver MG, Wu KL, Pettus TRR. Acc Chem Res. 2014;47:3655–3664. doi: 10.1021/ar500330x. Singh MS, Nagaraju A, Anand N, Chowdhury S. RSC Adv. 2014;4:55924–55959. Caruana L, Fochi M, Bernardi L. Molecules. 2015;20:11733–11764. doi: 10.3390/molecules200711733. Osipov DV, Osyanin VA, Klimochkin YN. Russ Chem Rev. 2017;86:625–687. Lima CGS, Pauli FP, Costa DCS, de Souza AS, Forezi LSM, Ferreira VF, de Carvalho da Silva F. Eur J Org Chem. 2020:2650–2692. Wang J-Y, Hao W-J, Tu S-J, Jiang B. Org Chem Front. 2020;7:1743–1778. Li X, Li Z, Sun J. Nat Synth. 2022;1:426–438.
  • [28].Electrophilicity of QMs: Lucius R, Loos R, Mayr H. Angew Chem Int eeed. 2002;41:91–95. doi: 10.1002/1521-3773(20020104)41:1<91::aid-anie91>3.0.co;2-p. Angew. Chem. 2002., 114, 97–102. Richter D, Hampel N, Singer T, Ofial AR, Mayr H. Eur J Org Chem. 2009:3203–3211.
  • [29].a) Zhang X-Z, Deng Y-H, Yan X, Yu K-Y, Wang F-X, Ma X-Y, Fan C-A. J Org Chem. 2016;81:5655–5662. doi: 10.1021/acs.joc.6b00390. [DOI] [PubMed] [Google Scholar]; b) He F-S, Jin J-H, Yang Z-T, Yu X, Fossey JS, Deng W-P. ACS Catal. 2016;6:652–656. [Google Scholar]
  • [30].For the addition of alternative masked α-or β-AAs to QMs: Li W, Xu X, Liu Y, Gao H, Cheng Y, Li P. Org Lett. 2018;20:1142–1145. doi: 10.1021/acs.orglett.8b00072. Zhang Z-P, Xie K-X, Yang C, Li M, Li X. J Org Chem. 2018;83:364–373. doi: 10.1021/acs.joc.7b02750. Etizinger A, Winter M, Schörgenhumer J, Waser M. Chem Commun. 2020;56:579–582. doi: 10.1039/c9cc09239k.
  • [31].For the Lewis base catalyzed addition of phenylacetic acid derivatives to p-QMs: Arokianathar JN, Hartley WC, McLaughlin C, Green-halgh MD, Stead D, Ng S, Slawin AMZ, Smith AD. Molecules. 2021;26:6333. doi: 10.3390/molecules26216333.
  • [32].Winter M, Schütz R, Eitzinger A, Ofial AR, Waser M. Eur J Org Chem. 2020:3812–3817. doi: 10.1002/ejoc.202000295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Deposition Numbers 2239320 (for 9 d), 2243587 (for 22) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service
  • [34].a) Singh G, Pandey R, Pankhade YA, Fatma S, Anand RV. Chem Rec. 2021;21:4150–4173. doi: 10.1002/tcr.202100137. [DOI] [PubMed] [Google Scholar]; b) Hussain Y, Sharma M, Kumar A, Chauhan P. Org Chem Front. 2022;9:572–592. [Google Scholar]
  • [35].Singh G, Kumar S, Chowdhury A, Vijaya Anand R. J Org Chem. 2019;84:15978–15989. doi: 10.1021/acs.joc.9b02455. [DOI] [PubMed] [Google Scholar]
  • [36].Marchart S, Gromov A, Mulzer J. Angew Chem Int eeed. 2010;49:2050–2053. doi: 10.1002/anie.200906453. Angew. Chem. 2010., 122, 2094–2097. [DOI] [PubMed] [Google Scholar]
  • [37].The research data supporting this publication can be accessed at: Stockhammer L, Craik R, Monkowius U, Cordes DB, Smith AD, Waser M. University of St Andrews Research Portal. 2023. data underpinning: “Isothiourea-Catalyzed Enantioselective Functionalisation of Glycine Schiff Base Aryl Esters via 1,6-and 1,4-additions”.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI
EMS196535-supplement-SI.pdf (18.2MB, pdf)

Data Availability Statement

The data that support the findings of this study are openly available in University of St Andrews Research Portal. at https://doi.org/10.17630/631a7545-ad96-427c-aa3f-a18664e93537, reference number 37.

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