Synthesis of axially chiral 1,8-diarylnaphthalene ligands and application in asymmetric catalysis: an intriguing fluorine effect

Tetrahedron: Asymmetry 26 (2015) 79–84

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Synthesis of axially chiral 1,8-diarylnaphthalene ligands and application in asymmetric catalysis: an intriguing fluorine effect Harisadhan Ghosh, Ravishashidhar Vavilala, Alex M. Szpilman ⇑ Schulich Faculty of Chemistry, Technion—Israel Institute of Technology, Haifa 3200008, Israel

a r t i c l e

i n f o

Article history: Received 29 October 2014 Accepted 30 November 2014 Available online 16 January 2015

a b s t r a c t A fluorinated and a non-fluorinated axially chiral 1,8-diarylnaphthalene ligand have been synthesized through an Ullmann and Suzuki coupling reaction based strategy. A practical methodology for the successful chiral resolution of the newly synthesized catechol based moiety is presented. We also disclose the preliminary application of these axially chiral molecules as ligands in asymmetric transformation reactions. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction The 1,8-diaryl substituted naphthalene scaffold possesses interesting properties due to the unique orientation of the two-aryl moieties in a parallel-stacked geometry. Molecules of this type have consequently found applications in the study of p–p interactions,1–10 parallel displaced aromatic p-interactions,11 throughspace spin–spin coupling12 and in studies of the through-space control of the kinetic decay of ortho-quinonoid intermediates.13 Chemical sensors based on this scaffold have been developed as fluorescence based detectors of dicarboxylic acids,14 for the enantioselective CD analysis of chiral amino alcohols,15 as an intramolecular excimer emitting compound,16 as well as stereodynamic chemosensors.17,18 Catechols are important in biological settings where they are ubiquitous in siderophores that control iron absorption; they also have high affinity for metal ions in high oxidation states or with high charge/radius ratios.19 Some catechol siderophores even undergo chiral recognition during enzymatic reactions as part of the iron transport pathway.20 In asymmetric catalysis, axially chiral ligands hold a unique place among privileged ligand structures such as BINOL, BINAP and their derivatives.21,22 In spite of the many potential uses mentioned, the application of 1,8-diarylnaphthalene based scaffolds as ligands in asymmetric catalysis is relatively unexplored.23,24 The development of new ligand scaffolds remains important in modern synthetic organic chemistry in order to increase the scope and efficiency of catalytic asymmetric reactions. While known privileged ligands have a wide range of applications in asymmetric

catalysis,25 new ligands must be designed and tested in order to escape the confines defined by the reactivity profiles of existing ligands. Herein we report a short and efficient synthesis of a new type of axially chiral 1,8-diarylnaphthalene based catechol ligand with both fluorinated and non-fluorinated substituents. The enantiomers were resolved using chiral pool based techniques. These compounds should be of interest, both as chiral ligands for asymmetric catalysis as well as chiral detector systems and charge transfer complexes. We also report an application in the asymmetric Mukaiyama aldol reaction in which the perfluorinated ligand 2 shows higher enantioselectivity than the non-fluorinated ligand 1.26,27 2. Results and discussion Herein, we report the preparation of two ligands; ligand 1 with an electron rich benzene ring and ligand 2 with five strongly electron withdrawing fluorine groups and an inverted quadrupole (Fig. 1). We hypothesized that these effects might result in differences in reactivity and chiral induction. The aryl groups are in a parallel-stacked geometry, but can rotate around the aryl–naphthalene prevents free rotation

1, R=

OH coordination site

Me

F F

F

F

F

R O

OH

2, R=

⇑ Corresponding author. Tel.: +972 48295953; fax: +972 4 8295703. E-mail address: [email protected] (A.M. Szpilman). http://dx.doi.org/10.1016/j.tetasy.2014.12.008 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

Figure 1. Design of axially chiral molecules 1 and 2.

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H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84

bond depending on the strength of parallel-stacked p–p interactions. In the neighbouring catechol aryl group, a methoxy group was incorporated into the design in order to prevent free rotation around the aryl-naphthyl C–C bond. The catechol would serve the double function of preventing free rotation as well being a metal coordination site for detector or catalytic applications. Our synthesis of 1 started from 1,8-diiodonaphthalene 3.28 Suzuki coupling of 3 and phenylboronic acid gave the mono arylated product 4 in 40% yield (Scheme 1). This is presumably due to the known propensity of the second iodine to react more rapidly than the first29 leading to 1,8-diphenylnaphthalene as a by-product. Indeed, a second Suzuki coupling using trimethoxy boronic acid 5 afforded 6 in 70% yield. Selective deprotection of the methylated catechol functionality was achieved in 78% yield using BBr3 to give the chiral racemic catechol rac-1. Resolution of rac-1 was achieved via chiral recognition by (S)-proline in acetonitrile at 90 °C.30 Rac-1 and (S)-proline were added to acetonitrile in equimolar amounts and refluxed for 3 h. Upon cooling to room temperature, the inclusion complex precipitated from solution as a white solid precipitated from the solution. The precipitate was hydrolysed in a mixture of ethyl acetate and water, after which crystallization from toluene furnished ligand 1 in 45% yield and with >99% ee. The enantiomer ent-1 was recovered from the mother liquor in 40% yield and with 86% ee.

Unfortunately, the inclusion complex of 1 with (S)-proline was not amenable to X-ray analysis. However, the complex was characterized by NMR. In order to investigate the applicability of ligand 1 in asymmetric catalysis, we performed an asymmetric Mukaiyama aldol reaction (Scheme 2). A titanium complex of ligand 1 was generated in situ. Ligand 1 was dissolved in dry dichloromethane, after which molecular sieves (4 Å) were added followed by freshly prepared diisopropoxide-titanium(IV) dichloride 7. Upon the addition of 7, the reaction mixture turned red, which indicated complex formation with 1. The putative complex 8 was left for one hour and then phenol and aldehyde were added. The reaction mixture was cooled to 42 °C and then silyl enol ether was added. After 4 days reaction, product 11 was isolated in 30% yield, with the mass balance being unreacted starting material. Disappointingly, the aldol product was isolated as a racemic mixture. We hypothesized that the lack of stereochemical induction from the ligand might be due to too many degrees of freedom in the catalyst–aldehyde complex. Taking note of the recent finding that fluorine, when appropriately situated in a chiral catalyst, might have a positive effect on the chiral induction,31 we prepared fluorinated ligand 2 (Fig. 1 and Scheme 3). In this ligand, the fluorines are situated in such an orientation that they might interact orthogonally with the titanium-complexed aldehyde through polar interactions as

OMe

MeO I

OMe 5

I phenylboronic acid

I

K3 PO4 , Pd(PPh 3) 4

Na 2CO3 , Pd(PPh3 )4

DMF, 4Å MS

DME/EtOH (2.5:1, V/V) H2 O, reflux 24h

3

B(OH)2

24h, 100 °C

40% yield

4

70% yield

OH resolution: (S)-proline in CH 3CN

OH

R

MeO

MeO OH

90 °C,3h

OMe

BBr3 CH 2 Cl2

OH

OMe

-78 °C to rt, 12h R=OMe

78% yield

1, 45%, 99% ee

6

rac-1

ent-1, 40%, 86 % ee

Scheme 1. Synthesis of the axially chiral catechol 1 and ent-1.

10 mol% 1 (10 mol%)

Cl Ti

+

or

O

O O

Cl

MS (4Å), DCM

Cl Ti

MeO

RT, 1 hour

O

(Sa )-2, (10 mol%) 7

O

8

OSiMe3 OH +

O2N 9 0.1 mmol

O

8 (10 mol%) phenol, dry DCM, Ar

H

10 0.15 mmol

-42 o C, 4 days

O 2N

11

1: 30% yield, 0% ee (Sa )-2: 34% yield, 28% ee

Scheme 2. Asymmetric catalytic Mukaiyama aldol reaction using 1 and 2.

Cl

81

H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84 F F

F

F

F I

F

I

F

F

F

F

OMe

I

Cu powder

F

B(OH) 2 13

12

10 mol% Pd(Ph3 P)4 , K3 PO4 ,

OMe

+ MeO

160 oC, DMSO 85%

I 3

OMe

F

5

F MeO

F OMe

F

dry DMF, 4 Å MS, 100o C, 24 hours 25%

14 BBr3 , DCM

R* =

-78 oC to RT, overnight

83% O

F5 OH

R*

O

S

F

O

R*

F R

OH

F

O

F O

O

O

S

separation of diastereomers

Cl

R=OMe (Sa)-2, >99% ee (R a)-2, >99% ee

OH F

HO

O

F then NaBH4, EtOH 0o C to RT, 2h

F

F F

OMe 15 and 16

Et3 N, MeCN 0o C to RT, 2h quantitative yield

F

OMe rac-2

80%

Scheme 3. Synthesis of the axially chiral perfluorinated catechols 2. See Figure 3 for the absolute configuration of 15.

described by Diederich.32 Compound 2 could also have other interesting properties and applications in non-chiral settings. Accordingly, we attempted to attach various fluorinated phenyl systems to 1,8-diiodonaphthalene through various coupling reactions (Scheme 3). All of our initial attempts to achieve Suzuki coupling between ortho- and meta-bis-fluoro-phenyl boronic acid with 1,8-diiodonaphthalene 3 failed. The ortho-bis-fluorine phenyl boronic acid underwent rapid proto-deboronation. This is a common problem in Suzuki coupling with electron poor aryl boronic acids.33 In contrast, Suzuki coupling between 3 and meta-bis-fluoro-phenyl boronic acid always led to the bis-arylated product. Attempts to perform Suzuki couplings between pentafluorophenylboronic acid and 3 afforded product 13 in yields of less than 10%. After exhaustive experimentation using modern catalytic procedures, we decided to attempt the classical Ullmann coupling of iodo-pentafluoro-benzene 12 and 3 using copper metal.8 To a solution of 1,8-diiodonaphthalene 3 in DMSO and iodo-pentafluorobenzene 12 (2 equiv) copper powder (2.5 equiv) was added and the reaction mixture was heated to 160 °C for 5 h with constant stirring. Product 13 was successfully obtained in 85% isolated yield. We then performed the Suzuki coupling of 1,3,5-trimethoxyphenyl boronic acid 5 with 13 to give product 14. In contrast to the second Suzuki coupling in the synthesis of ligand 1, the yield for this transformation was 25% with the rest of the material being mostly proto-deboronated 5, that is, 1,2,4-trimethoxy-benzene. The fluorinated juxtaposed aromatic ring, must somehow reduce the reactivity of the second iodine. This material could be recovered and converted back into boronic acid 5. Racemic product 14 can be crystallized from acetonitrile solvent. The crystals obtained provided proof of the structure (Fig. 2). We next performed the selective deprotection of the methylated catechol function to obtain the racemic catechol ligand rac2. In this case, our efforts to form diastereomeric salts using a variety of chiral amines and amino-acid esters failed. We also attempted the preparation of esters of various amino acids, but none of the products could be separated by crystallization or column chromatography. We were able to form separable diastereomeric (S)-camphor sulfonyl esters 15 and 16. These diastereoisomers were separated by column chromatography. The less polar diastereomer 15 could be crystallized from tetrahydrofuran and allowed us to establish the absolute stereochemistry of this diastereomer as Sa (Fig. 3).

Figure 2. ORTEP diagram of X-ray data for 14 (CCDC-1035718). Ellipsoids are at 50% probability and hydrogen atoms are omitted for the sake of clarity.

Figure 3. ORTEP diagram of the (Sa)-diastereomer of bis-(S)-camphor-sulfonyl ester 15 (CCDC-1035719). Ellipsoids are at 50% probability and hydrogen atoms are omitted for the sake of clarity.

Removal of the camphor sulfonyl group was performed using NaBH4 in an ethanol medium at 0 °C to room temperature. This reaction presumably takes place via reduction of the ketone. The

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resulting alcohol then attacks the camphorsulfonic ester leading to the free catechol 2 and the cyclic sulfonic ester. Thus, we were able to obtain both (Sa)-2 and (Ra)-2 in higher than 99% ee and 80% yield. With ligand 2 in hand the asymmetric aldol reaction shown in Scheme 2 was again used as a testing ground. The reaction lasted four days and afforded the product in 34% yield. However, in this instance the ee of the product was 28%. While the yield and enantiomeric excess for this reaction are not satisfactory, these results do show the effect of a fluorinated versus non-fluorinated ligand. This may be attributed to the effects suggested earlier33 or simply to the higher Lewis acidity of complex 8 with ligand 2 as compared to the one with ligand 1. 3. Conclusion In conclusion, we have synthesized new types of axially chiral catechol 1,8-diaryl naphthalene ligands, which were resolved in an efficient and practical manner. There are very few methods known for the resolution of this type of molecule. The fluorinated ligand 2 shows chiral induction in the titanium catalysed asymmetric Mukaiyama Aldol reaction whereas the non-fluorinated ligand 1 lacks any chiral induction. This result indicates that further studies into the use of fluorinated ligands in catalytic asymmetric synthesis would be of scientific value. 4. Experimental 4.1. General All non-aqueous reactions were carried out using oven-dried (120 °C) or heat gun dried glassware under a positive pressure of dry argon unless otherwise noted. All other commercially available reagents were used without further purification. Unless indicated otherwise, reactions were stirred magnetically and monitored by thin layer chromatography using Merck Silica Gel 60 F254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained using potassium permanganate. Chromatographic purification of products (flash chromatography) was performed on silica 32–63, 60 Å using a forced flow of eluent at 0.3–0.5 bar. Concentration under reduced pressure was performed by rotary evaporation at 40 °C at the appropriate pressure. Yields refer to chromatographically purified compounds. NMR spectra were recorded on Bruker Avance III 400 spectrometers operating at 400 MHz (1H) and 100 MHz (13C). Chemical shifts (d) are reported in ppm with the solvent resonance as the internal standard relative to chloroform (d 7.26) 1H, and chloroform (d 77.0) for 13C. All 13C NMR spectra were measured with complete proton decoupling. Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal; coupling constants in Hz. High resolution mass spectra were recorded by the MS service at Technion. ESI-MS (m/z): was recorded on a Waters Micromass LCT premier instrument at 70 eV in the positive or negative mode. APCI was recorded on the same instrument using 70% acetonitrile/30% water at 0.2 mL flowrate. 4.1.1. Preparation of 1-phenyl-8-(2,3,6-trimethoxyphenyl) naphthalene 6 Iodonaphthalene 4 (0.33 g, 1 mmol and 1 equiv), boronic acid 5 (1.06 g, 5 mmol and 5 equiv) and K3PO4 (1.272 g, 6 mmol and 6 equiv) were added to dry DMF (10 mL) and the mixture was degassed for a period of 1 h. Next, granular molecular sieves (4 Å) were added and finally tetrakis(triphenylphosphine)palladium(0) catalyst (0.1155 g, 0.1 mmol and 10 mol %), was added.

After stirring at room temperature for a period of 30 min under an argon atmosphere, the reaction vessel was placed in a preheated oil bath (100 °C) and heating was continued for 24 h under an argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with 10 mL of ethylacetate and filtered through a Celite pad. The organic layer was then evaporated and extracted with ethylacetate (10 mL) from water. The organic layer was dried over anhydrous sodium sulfate and the pure product was purified by silica gel column chromatography using hexane and ethyl acetate as eluent and isolated as a solid (0.259 g and 70% yield). 1H NMR (400 MHz, CDCl3) d 7.90 (m, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.17 (t, J = 8.0 Hz, 2H), 6.96 (m, 4H), 6.44 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.40 (s, 3H), 13C NMR (100 MHz, CDCl3) d 150.9, 146.8, 146.6, 142.9, 141.0, 134.8, 132.2, 130.6, 130.1, 129.1, 128.9, 128.8, 128.6, 127.2, 126.3, 126.1, 126.0, 124.8, 124.6, 112.2, 104.7, 60.2, 56.6, 55.3, HRMS (ES+) calcd for C25H23O3 (M+H) 371.1647, found 371.1598. 4.1.2. Procedure for the deprotection of 6 to rac-1 The reactant 6 (0.37 g, 1 mmol and 1 equiv) was dissolved in dry DCM (10 mL) under an argon atmosphere and was cooled to 78 °C with the help of a dry ice-acetone bath. Next BBr3 [1(M) solution in DCM] (1 mL, 1 mmol and 1.0 equiv) was added dropwise for a period of 30 min. The reaction mixture was stirred overnight while it warmed slowly to reach room temperature. The reaction mixture was then quenched with methanol at 0 °C and then the solvent was evaporated. The product was extracted with ethyl acetate from water and dried over anhydrous sodium sulfate. The crude product was purified through a short column of silica gel using hexane and ethyl acetate as eluent to afford a solid (0.267 g and 78% yield). 1H NMR (400 MHz, CDCl3) d 7.92 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.22 (m, 2H), 6.95 (m, 5H), 6.36 (d, J = 8.0 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 4.68 (br s, 1H), 4.62 (br s, 1H), 3.43 (s, 3H), 13C NMR (100 MHz, CDCl3) d 149.9, 142.0, 140.7, 139.8, 137.8, 135.4, 131.8, 130.2, 130.1, 129.8, 129.0, 128.7, 128.1, 126.7, 126.5, 126.4, 125.8, 125.3, 119.2, 113.6, 102.1, 55.3, HRMS (ES+) calcd for C23H19O3 (M+H) 343.1334, found 343.1326. 4.1.3. Procedures for the resolution of the phenylnaphthalene ligands 1 and ent-1 The racemic diol (0.342 g and 1.0 mmol) and (S)-proline (0.115 g and 1.0 mmol) were added to acetonitrile (2 mL). The mixture was refluxed for 3 h, and then cooled to room temperature. A white precipitate formed from the solution. The precipitate was filtered through a sintered funnel. The solid was added to a 3:2 (v/v) mixture of ethyl acetate and water and stirred at room temperature for 3 h. The solid was completely dissolved, the organic layer was separated and the water phase was extracted with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous Na2SO4 and evaporated to remove the solvents. The residue was repeatedly recrystallized in toluene to afford 1 as a shiny solid, with an overall yield of 45% and with >99% ee. The acetonitrile filtrate was evaporated and the residue was repeatedly recrystallized in toluene. The overall yield of ent-1 was 40% with 86% ee. The ee was determined by chiral stationary phase HPLC analysis Chiral Lux 5u Cellulose-2 column, isopropanol/hexane (10:90), 1 mL/min, k = 254 nm, tR: 20.7 min and 24.6 min. 4.1.4. Characterization of the 4-methoxy-3-(8-phenylnaphthalene-1-yl)benzene-1,2-diol 1 complex with (S)-proline 1 H NMR (400 MHz, CD3OD) d 7.90 (m, 2H), 7.50 (m, 1H), 7.43 (m, 1H), 7.20 (m, 1H), 7.12 (m, 2H), 7.04 (m, 1H), 6.92 (m, 3H), 6.31 (t, J = 8.2 Hz, 1H), 5.81 (d, J = 8.2 Hz, 1H), 4.87 (s, 3H), 3.97 (dd, J = 8.6, 6.3 Hz, 1H), 3.41 (s, 1H), 3.37 (m, 1H), 3.22 (m, 1H),

H. Ghosh et al. / Tetrahedron: Asymmetry 26 (2015) 79–84

2.29 (ddd, J = 7.4 Hz, 1H), 2.11 (ddd, J = 6.5 Hz, 1H), 1.96 (m, 2H), 13 C NMR (100 MHz, CD3OD) d 173.9, 144.1, 143.6, 142.5, 139.8, 136.5, 133.6, 132.5, 132.1, 130.8, 129.8, 129.6, 129.5, 129.4, 127.3, 127.1, 127.0, 126.2, 125.3, 121.4, 114.5, 101.8, 62.7, 55.4, 47.0, 30.4, 25.1. 4.1.5. Procedure for the Ullmann coupling for the preparation of 13 To a solution of 1,8-diiodonaphthalene 3 (1.14 g, 3 mmol) in DMSO (0.5 mL) was added iodoperfluorobenzene (1.76 g and 6 mmol). To this mixture was added copper powder (0.473 g and 7.5 mmol) and the reaction mixture was heated at 160 °C in an oil bath for 5 h with constant stirring. The reaction mixture was cooled and diluted with ethylacetate (30 mL) and then filtered through a sintered funnel. The organic layer was then evaporated onto Celite and the product was purified by column chromatography (100% hexane as the eluent). The product was isolated as a solid in 85% yield (1.07 g), 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 13C NMR (100 MHz, CDCl3) d 146.5, 144.0, 143.1, 142.1, 142.8, 140.5, 139.2, 136.7, 135.5, 132.5, 132.1, 131.5, 130.6, 127.3, 125.4, 124.9, 115.6, 90.3, 19F NMR (400 MHz, CDCl3) 139.1, 155.1, 163.1, HRMS (AP+) calcd for C16H6F5I (M) 419.9434, found 419.9432. 4.1.6. Procedure for the Suzuki–Miyaura coupling for the preparation of 14 Iodonaphthalene 13 (0.42 g, 1 mmol and 1 equiv), boronic acid 5 (1.06 g, 5 mmol and 5 equiv) and K3PO4 (1.27 g, 4 mmol and4 equiv) were added to dry DMF (10 mL) and the mixture was degassed for 1 h. Then, freshly activated granular molecular sieves (4 Å) were added followed by tetrakis(triphenylphosphine)palladium(0) catalyst (0.116 g, 0.1 mmol, 10 mol %). After stirring at room temperature for 30 min under an argon atmosphere, the reaction vessel was placed in a preheated oil bath (100 °C) and heating was continued for 24 h under an inert atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with 10 mL of ethyl acetate and filtered through a Celite pad. The organic layer was concentrated and extracted from water with ethyl acetate (10 mL). The organic layer was dried over anhydrous sodium sulfate and the pure product (0.115 g, 25% yield) was separated by silica gel column chromatography using hexane and ethyl acetate as eluent. 1 H NMR (400 MHz, CDCl3) d 8.04 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 3.47 (s, 3H), 13 C NMR (100 MHz, CDCl3) d 151.6, 147.9, 146.7, 135.1, 131.4, 131.3, 131.27, 131.20, 131.0, 129.4, 125.4, 125.3, 124.6, 123.5, 112.2, 103.9, 60.6, 56.4, 55.3, 19F NMR (400 MHz, CDCl3) 136.4, 139.4, 157.7, 164.7, 165.2. HRMS (AP+) calcd for C25H18F5O3 (M+H) 461.1176, found 461.1170. The X-ray data can be obtained from the Cambridge Crystallographic Data Centre registration number: CCDC 1035718. 4.1.7. Procedure for the deprotection of 14 to rac-2 Compound 14 (0.460 g, 1 mmol and 1 equiv) was dissolved in dry DCM (10 mL) under an argon atmosphere and cooled to 78 °C with a dry ice-acetone mixture. Next, a solution of BBr3 in DCM (1 mL, 1 mol/L, 1 mmol and 1 equiv) was added dropwise over a period of 30 min. The reaction mixture was stirred over night while being warmed slowly to reach room temperature. The reaction mixture was quenched with methanol at 0 °C and then the solvent was evaporated. The product was extracted from water with ethyl acetate and dried over anhydrous sodium sulfate.

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The crude product was purified by column chromatography using hexane and ethyl acetate as the eluent to afford a solid (0.358 g, yield 83%). 1H NMR (400 MHz, CDCl3) d 8.06 (m, 2H), 7.61 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 4.97 (br s, 1H), 4.81 (br s, 1H), 3.46 (s, 3H), 13C NMR (100 MHz, CDCl3) d 150.7, 140.9, 138.2, 135.5, 132.1, 131.7, 131.6, 131.1, 130.7, 128.8, 126.2, 125.4, 123.5, 117.2, 113.9, 101.2, 55.1, 19F NMR (400 MHz, CDCl3) 138.2, 140.3, 156.1, 164.3, 164.5, HRMS (AP+) calcd for C23H14F5O3 (M+H) 433.0863, found 433.0858. 4.1.8. Procedure for the synthesis of sulfonate esters 15 and 16 Triethylamine (0.42 mL and 3 mmol) was added to a solution of rac-2 (0.432 g, 1 mmol and 1 equiv) in DCM (10 mL) under ice-cold conditions. (1S)-(+)-10-Camphor sulfonyl chloride (0.75 g and 3 mmol) was then added in one portion. The reaction was allowed to reach room temperature and stirred at ambient temperature overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was diluted with the addition of 10 mL of DCM and washed with 10% HCl solution (10 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude product is a mixture of two diastereomers. The diastereomeric mixture of the sulfonate esters 15 and 16 (Rf separation of 0.07 in the solvent mixture CHCl3/Et2O (5:0.2) ratio) was separated by silica gel column chromatography using chloroform and diethyl ether as the eluents. (Sa)-15: 0.344 g, 40% yield and (Ra)-16: 0.344 g, 40% yield. Diastereomer 15: 1H NMR (400 MHz, CDCl3) d 8.07 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.69 (s, 3H), 3.61(d, J = 12.0 Hz, 1H), 2.86 (d, J = 16.0 Hz, 1H), 2.43 (m, 2H), 2.10 (m, 4H), 1.95 (m, 3H), 1.76 (m, 3H), 1.44 (m, 1H), 1.24 (m, 2H), 1.13 (s, 3H), 0.93 (s, 6H), 0.67 (s, 3H), 13C NMR (100 MHz, CDCl3) d 213.7, 213.4, 155.7, 139.8, 135.7, 134.9, 132.8, 132.0, 131.5, 130.8, 130.6, 128.7, 126.5, 125.5, 125.2, 122.6, 108.3, 58.4, 57.9, 56.0, 49.4, 49.3, 48.2, 47.6, 43.2, 43.1, 42.6, 42.3, 27.0, 26.8, 25.6, 24.9, 19.9, 19.8, 19.6, 19F NMR (400 MHz, CDCl3) 137.8, 138.7, 154.5, 159.8, 164.5, HRMS (ES+) calcd for C43H42F5O9S2 (M+H) 861.2190, found 861.2178. The X-ray data can be obtained from Cambridge Crystallographic Data Centre registration number: CCDC 1035719. Diastereomer 16: 1H NMR (400 MHz, CDCl3) d 8.03 (m, 2H), 7.60 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.29 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 3.90 (d, J = 16.0 Hz, 1H), 3.67 (s, 3H), 3.46 (d, J = 12.0 Hz, 1H), 2.53 (m, 1H), 2.41 (m, 1H), 2.10 (m, 5H), 1.85 (m, 5H), 1.48 (m, 2H), 1.26 (m, 2H), 1.14 (s, 3H), 0.88 (s, 3H), 0.75 (s, 3H), 0.59 (s, 3H), 13C NMR (100 MHz, CDCl3) d 213.8, 213.3, 155.8, 139.9, 135.7, 134.9, 133.2, 131.8, 131.5, 130.8, 130.5, 128.7, 126.5, 125.9, 125.1, 123.1, 122.3, 108.2, 58.2, 58.0, 55.9, 49.7, 49.1, 48.2, 47.7, 43.0, 42.6, 42.4, 31.7, 27.2, 26.8, 25.3, 25.1, 22.8, 19.7, 19.6, 19.5, 19.4, 14.3, 19F NMR (400 MHz, CDCl3) 138.2, 138.7, 154.5, 160.4, 164.4, HRMS (ES+) calcd for C43H42F5O9S2 (M+H) 861.2190, found 861.2184. 4.1.9. Deprotection of the sulfonate ester 15 or 16 to enantiopure (Sa)-2 or (Ra)-2 In a 25 mL round bottom flask, sulfonate ester 15 (0.43 g and 0.5 mmol) was dissolved in ethanol (10 mL). The flask was placed in a cooling bath to maintain the temperature at 15 °C to 20 °C with the help of ice and salt. Next sodium borohydride (0.185 g, 5 mmol) was added portionwise. The reaction mixture was stirred allowing the temperature to slowly reach room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, saturated ammonium chloride solution (1 mL) was added to the reaction mixture and then stirred for one hour. The product was extracted from water (10 mL) with

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ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated and the product (Sa)-2 was purified by column chromatography using hexane and ethyl acetate as eluent and isolated as a solid (0.345 g, 80% yield). Compound (Ra)-2 was produced in an identical yield from 16 using this procedure. The ee was determined by chiral stationary phase HPLC analysis CHIRALPAKÒ OD-H HPLC Analytical Columns column, isopropanol/hexane (10:90), 1 mL/min, k = 254 nm, tR: 23.0 min and 24.6 min. 4.2. General procedure for the Mukaiyama aldol reaction To a solution of the ligand (Sa)-2 (0.01 mmol and 4 mg) in (dry) DCM, freshly activated molecular sieves (4 Å) were added and stirred for 10 min. Next, metal catalyst diisopropoxidetitanium(IV) dichloride 7 [0.01 mmol, from a 1 M solution in DCM, prepared freshly from TiCl4 and Ti(OiPr)4] was added to this suspension. Upon the addition of the metal catalyst, the reaction mixture turned a red colour. The reaction mixture was stirred at room temperature for an hour under an argon atmosphere. After preparation of the catalyst phenol (0.1 mmol and 9.4 mg) and 4-nitrobenzaldehyde 9 (0.1 mmol and 15 mg) were added to the reaction mixture and stirred for 15 min. Silylenol ether 10 (0.15 mmol and 31 lL) was then added to the reaction mixture at 42 °C. The reaction mixture was stirred at this temperature for 4 days. The reaction mixture was quenched with ammonium chloride solution, diluted with dichloromethane, and filtered. The product was hydrolysed with 1 M HCl in DCM and separated by preparative TLC to give product 11 (9 mg, 34% yield and 28% ee). When the reaction was carried out using ligand 1 on the same scale, the product was isolated in 30% yield (8 mg) in racemic form. The ee of the products were determined by chiral stationary phase HPLC analysis using a Lux 5u Amylose-2 (250  4.60 mm) column, isopropanol/hexane (15:85), 1 mL/min, k = 254 nm, tR: 19.1 min (minor), 23.9 min (major), 1H NMR (400 MHz, CDCl3) d 8.24 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.1 Hz, 3H), 7.48 (t, J = 7.7 Hz, 2H), 5.46 (m, 1H), 3.84 (d, J = 3.1 Hz, 1H), 3.42 (dd, J = 17.9, 3.1 Hz, 1H), 3.34 (dd, J = 17.9, 8.9 Hz, 1H), 13C NMR (100 MHz, CDCl3) d 199.7, 150.3, 147.5, 136.3, 134.2, 129.0, 128.3, 126.7, 124.0, 69.4, 47.1. Acknowledgement This research was supported by an Israel Science Foundation FIRST Grant (Grant No. 1636/11).

References 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.

House, H. O.; Magin, R. W.; Thompson, H. W. J. Org. Chem. 1963, 28, 2403–2406. House, H. O.; Campbell, W. J.; Gall, M. J. Org. Chem. 1970, 35, 1815–1819. Clough, R. L.; Roberts, J. D. J. Org. Chem. 1978, 43, 1328–1331. Tsuji, R.; Komatsu, K.; Takeuchi, K.; Shiro, M.; Cohen, S.; Rabinovitz, M. J. Phys. Org. Chem. 1993, 6, 435–444. Bossenbroek, B.; Sanders, D. C.; Curry, H. M.; Shechter, H. J. Am. Chem. Soc. 1969, 91, 371–379. Staab, H. A.; Ipaktschi, J. Chem. Ber. 1971, 104, 1170–1181. Wahl, P.; Krieger, C.; Schweitzer, D.; Staab, H. A. Chem. Ber. 1984, 117, 260–276. Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, J. S. J. Am. Chem. Soc. 1992, 114, 5729–5733. Cozzi, F.; Cinquini, M.; Annuziata, R.; Siegel, J. S. J. Am. Chem. Soc. 1993, 115, 5330–5331. Cozzi, F.; Ponzini, F.; Annunziata, R.; Cinquini, M.; Siegel, J. S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1019–1020. Lima, C. F. R. A. C.; Rocha, M. A. A.; Gomes, L. R.; Low, J. N.; Silva, A. M. S.; Santos, L. M. N. B. F. Chem. Eur. J. 2012, 18, 8934–8943. S8934/1–S8934/47. Ernst, L.; Sakhaii, P. Magn. Reson. Chem. 2000, 38, 559–565. Moorthy, J. N.; Mandal, S.; Parida, K. N. Org. Lett. 2012, 14, 2438–2441. Kusukawa, T.; Tanaka, S.; Inoue, K. Tetrahedron 2014, 70, 4049–4056. Ghosn, M. W.; Wolf, C. J. Am. Chem. Soc. 2009, 131, 16360–16361. Hu, J.-Y.; Pu, Y.-J.; Yamashita, Y.; Satoh, F.; Kawata, S.; Katagiri, H.; Sasabe, H.; Kido, J. J. Mater. Chem. C 2013, 1, 3871–3878. Bentley, K. W.; Wolf, C. J. Am. Chem. Soc. 2013, 135, 12200–12203. Bentley, K. W.; Wolf, C. J. Org. Chem. 2014, 79, 6517–6531. Borgias, B. A.; Cooper, S. R.; Koh, Y. B.; Raymond, K. N. Inorg. Chem. 1984, 23, 1009–1016. Abergel, R. J.; Zawadzka, A. M.; Hoette, T. M.; Raymond, K. N. J. Am. Chem. Soc. 2009, 131, 12682–12692. McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809–3844. Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. (Washington, DC, U.S.) 2003, 103, 3155–3211. Sabater, L.; Lachaud, F.; Hureau, C.; Aukauloo, A. Tetrahedron Lett. 2006, 47, 569–571. Vyskocil, S.; Meca, L.; Tislerova, I.; Cisarova, I.; Polasek, M.; Harutyunyan, S. R.; Belokon, Y. N.; Stead, R. M. J.; Farrugia, L.; Lockhart, S. C.; Mitchell, W. L.; Kocovsky, P. Chem. - Eur. J. 2002, 8, 4633–4648. Zhou, Q.-L. Privileged Chiral Ligands and Catalysts; Wiley-VCH: Weinheim, 2011. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011–1014 Matsuo, J.-I.; Murakami, M. Angew. Chem., Int. Ed. 2013, 52, 9109–9118. House, H. O.; Koepsell, D. G.; Campbell, W. J. J. Org. Chem. 1972, 37, 1003–1011. Lima, C. F. R. A. C.; Rodriguez-Borges, J. E.; Santos, L. M. N. B. F. Tetrahedron 2011, 67, 689–697. Hu, X.; Shan, Z.; Chang, Q. Tetrahedron: Asymmetry 2012, 23, 1327–1331. Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011, 50, 11860– 11871. Fischer, F. R.; Schweizer, W. B.; Diederich, F. Angew. Chem., Int. Ed. 2007, 46, 8270–8273. Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones, G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156–5160. S5156/1–S5156/68.