Scholarly article on topic 'Design, synthesis and applications of new families of chiral sulfonic acids'

Design, synthesis and applications of new families of chiral sulfonic acids Academic research paper on "Chemical sciences"

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Abstract of research paper on Chemical sciences, author of scientific article — Pavol Jakubec, Michael E. Muratore, Isabelle Aillaud, Amber L. Thompson, Darren J. Dixon

Abstract Two new families of chiral arenesulfonic acids were synthesised in a short, robust and scalable synthetic sequence involving a key cross-coupling step of an aromatic scaffold with a suitable chiral auxiliary. The flexibility of the synthetic route and the ready availability of a range of naturally occurring chiral auxiliaries allowed us to prepare nine enantiomerically pure sulfonic acids with a tunable stereochemical environment. Application of the strong chiral Brønsted acids was demonstrated in an enantioselective nitrone/enol ether 1,3-dipolar cycloaddition.

Academic research paper on topic "Design, synthesis and applications of new families of chiral sulfonic acids"

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Tetrahedron: Asymmetry

journal homepage: www.elsevier.com/locate/tetasy

Tetrahedron:

Asymmetry

Design, synthesis and applications of new families of chiral sulfonic acids

Pavol Jakubec, Michael E. Muratore, Isabelle Aillaud, Amber L. Thompson, Darren J. Dixon *

The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK

ARTICLE INFO ABSTRACT

Two new families of chiral arenesulfonic acids were synthesised in a short, robust and scalable synthetic sequence involving a key cross-coupling step of an aromatic scaffold with a suitable chiral auxiliary. The flexibility of the synthetic route and the ready availability of a range of naturally occurring chiral auxiliaries allowed us to prepare nine enantiomerically pure sulfonic acids with a tunable stereochemical environment. Application of the strong chiral Br0nsted acids was demonstrated in an enantioselective nitrone/enol ether 1,3-dipolar cycloaddition.

© 2015 Elsevier Ltd. All rights reserved.

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Article history: Received 17 October 2014 Accepted 5 February 2015 Available online 19 March 2015

1. Introduction

Stronger chiral Brensted acids have recently emerged as powerful synthetic tools for important and often novel enantioselective bond forming reactions.1 Arguably, the most important class is the BINOL-derived chiral phosphoric acids 1a,b (BPA, Fig. 1) and related compounds introduced by Akiyama and Terada.2 With the expansion of the field came the need for enhanced acidity, which has been realised in the form of phosphorodiamidic acid derivative 1c3 and N-triflyl phosphoramides 1d4 and related derivatives.5 These derivatives can impart high levels of enantio-control in reactions where the original class of BPAs are either poor controllers of asymmetry or are catalytically inferior or showed no catalytic activity.4,5 Therefore, the importance of the contribution of stronger Br0nsted acids to the field is apparent, however there is an upper limit to the acidity of such classes of acids.

Accordingly, future opportunities will arise from other classes of higher acidity chiral organic acids, such as chiral sulfonic acids, which could potentially give rise to a broader range of catalytic applicability. Several enantiomerically pure chiral aliphatic sul-fonic acids, including long-known camphor sulfonic acid 1i (CSA), have been prepared for use mostly as resolving reagents.6 The most recent examples of this class of stronger Brensted acids are represented by enantiomerically pure sulfonic acids 1j, which emerged from a stereoselective addition of sodium bisulfite to a suitable Michael acceptor.7 An even higher Br0nsted acidity of chiral sul-fonic acid was calculated for the simplest member of BINOL-derived bis-sulfonic acids 1e (BINSA, pKa in DMSO -9.06).5c

* Corresponding author. E-mail address: Darren.dixon@chem.ox.ac.uk (D.J. Dixon).

http://dx.doi.org/10.1016Zj.tetasy.2015.02.002 0957-4166/© 2015 Elsevier Ltd. All rights reserved.

Although BINSA has been known since 1928, its applications in acid-catalysed transformations remained unexplored until 2008 when it was obtained in enantiomerically pure form.8 Shortly after, more advanced descendants of BINSA's 1f8 (R = Ar, Me3Si) and related disulfonimides 1g,h8 were synthesised.8,9

Recently, Enders and Blanchet reported the syntheses of novel planar chiral sulfonic acids 1k, 1l and novel axially chiral sulfonic acids 1m, respectively.10,11 We believed that enhanced reactivity and enantiocontrol, potentially in a wide range of acid catalysed reactions, could be harnessed from alternative, novel and readily accessible classes of chiral sulfonic acids. Herein we report new, efficient and general routes to a range of novel single enantiomer arenesulfonic acids and report preliminary enantioselectivity data in an acid catalysed nitrone/enol ether 1,3-dipolar cycloaddition reaction.

2. Results and discussion

Our initial design plan was to construct an arenesulfonic acid bearing two chiral appendages attached to the 2- and 6-positions, thus creating a chiral environment around the sulfonic acid group (Scheme 1). Our synthesis plan was therefore to develop straightforward, yet synthetically powerful routes through standard cross-coupling protocols (such as Ulmann, Goldberg, Suzuki, etc.) on commercial (or readily accessible) arene derivatives to afford novel stronger Br0nsted-acids that could have general applicability in enantioselective acid catalysed reactions.

We designed two distinctive synthetic routes. In our first approach (Scheme 1, Route A), the plan was to first construct a chiral substituted benzene scaffold 4, and subsequently introduce the sulfonic acid moiety. This approach would be short in step

hydrolysis

hydrolysis

cross coupling

R1 = chiral auxiliary, f-Bu, H

X = chiral appendage

cross coupling

M /L M

R2= Br or f-Bu

1. o-lithiation

2. borylation

M = boronic acid derivative

Scheme 1. Retrosynthesis of novel chiral arenesulfonic acids.

count, would not suffer from regioselectivity problems and would be amenable to library generation. In our second, (Scheme 1, Route B) we planned to use a sulfonate ester 10 on an appropriate arene ring as both a directing group for the regioselective introduction of chiral appendages and a masked acid. Specifically a Snieckus directed ortho metalation12 would allow the regiocontrolled synthesis of an aryl boronic acid 9 which under appropriate conditions would undergo cross-coupling with a range of chiral coupling partners. Finally a mild hydrolysis of sulfonates 7 would finish the synthesis of 2 in five steps.

2.1. Route A

In choosing the cross-coupling reaction for the synthesis of the chiral arene scaffolds, we considered the availability/accessibility of a small library of chiral appendages/auxiliaries, suitably substituted arenes, and the robustness/reliability of the coupling reaction itself. Accordingly, the well-precedented Cu-catalysed UlmannGoldberg coupling of suitable aryl halides with chiral oxazolidi-nones became our first choice.13 Chiral enantiopure oxazolidinones 5a-d were the nitrogen-containing heterocycles of choice since they are commercially available or easily made in both enan-tiomeric forms from natural or unnatural aminoacids.14

Using catalytic amounts of copper iodide in the presence of DMEDA and potassium carbonate, C3 and C2 symmetrical deriva-tised arenes were readily synthesised in a single operation in good yields from brominated arenes 6a and 6b using oxazolidinones 5a-d (Scheme 2).

With electron rich C3-symmetrical chiral scaffolds 4a-d and C2-symmetrical 4e-g in our hands we then investigated the introduction of the sulfonic acid moiety. Using a modified literature

procedure for the chlorosulfonation of 1,3,5-trisubstituted benzenes, we isolated directly the desired sulfonic acid and not the intermediate sulfonyl chloride (Scheme 2).15 Our short route allowed us to produce significant quantities of novel chiral ben-zenesulfonic acids in a 2 step sequence. The structure of 2b, was determined from single crystal X-ray diffraction studies and is reported as the hydroxonium salt in the solid state (Fig. 2).

2.2. Route B

In our first route (Route A, above) the sulfonic acid functionality was introduced in the last step of the synthesis. However, with the knowledge that arene sulfonate esters are powerful ortho-directing groups in the Snieckus reaction, in our second route, we decided to employ these as starting materials.12 Treatment of ethylsulfonate 10 with butyllithium for 6 h at -78 °C,16 followed by quenching of the lithiated intermediate with trimethylborate yielded boronic acid 11 in excellent yield via this scalable one-pot procedure (Scheme 3).17

Subsequent Suzuki coupling18 with readily prepared men-thenyltriflate 8a19 provided sulfonate 12 in good yield (Scheme 3). A second tandem ortho-lithiation/boronate ester quench provided boronic acid 13, which was a suitable precursor for further diversification. Coupling of 13 with readily available tri-flates 8a, 8b19,20 provided structurally varied sulfonates 7a and 7b in good yields (Scheme 4). A convenient, high yielding alkaline hydrolysis of sulfonic esters 7a, 7b followed by acidification with dilute HCl afforded chiral sulfonic acids 2h, 2i.

With a library of two classes of structurally diverse sulfonic acids 2a-g and 2h, 2i in hand, our next aim was to provide a proof of principle that they were indeed capable of imparting asymmetry

Route A

Route B

2...... O

N. ^X -N

2a 47% o

2b 47»% O

2c 88% O

2d 54»% O_/ I

Y V»,

R Wl t

^ ° 4a 46% O

4 b 62% O

4d 60%

HN-"^.

R y A O

<°-f Yl

-f SO3H]--\

/■fYf

^ SO3H

/-f NX I

Scheme 2. Synthesis of chiral arenesulfonic acids. Reagents and conditions: (i) 1,3,5-tribromobenzene, 6a, Cul, K2CO3, N,N-dimethylethylenediamine (DMEDA), toluene, reflux 20-30 h; (ii) 1,3-dibromo-5-tert-butylbenzene 6b, Cul, K2CO3, DMEDA, toluene, reflux 24 h; (iii) ClSO3H, chloroform, reflux, 24-48 h.

Figure 2. Thermal ellipsoids for 2b drawn at 30% probability and selected solvent omitted for clarity. See Section 4 for details.

B(OH)2

Scheme 3. Synthesis of common precursor for the divergent synthesis of chiral arenesulfonic acids. Reagents and conditions: (i) (a) n-BuLi, THF, -78 "C, 5 h then (b) B(OMe)3, -78 "C ? rt, 12 h, 92%; (ii) 8a, Cs2CO3, Pd(PPh3)4, DME, H2O, 70 "C, 1 h, 78%.

in an acid-catalysed reaction. Inspired by the recent report of Yamamoto21 we decided to test the new chiral sulfonic acids in the 1,3-dipolar cycloaddition of nitrone 15 and ethyl vinyl ether 16 (Schemes 5 and 6). Initially, systematic solvent, temperature and concentration variations were undertaken to determine the reaction conditions for the optimal catalytic performance of acid 2b in the 1,3-dipolar cycloaddition. This survey revealed that the best results in terms of enantioselectivity and isolated yield were obtained when the reaction was performed in chloroform at -35 "C at a moderate dilution (Scheme 5, entry 4). With the established conditions in hand, sulfonic acids 2a-g were screened (Scheme 5, entries 3-9). In all cases a high diastereoselectivity

4c 72%

B(OH)2

8b 7b 83% 14b 91% 2i 97%

Scheme 4. Synthesis of chiral arenesulfonic acids 2h, 2i. Reagents and conditions: (i) (a) n-BuLi, THF, -78 "C, 6.5 h then (b) B(OMe)3, -78 "C ? rt, 1 h, ~100% (crude); (ii) ROTf 8, Cs2CO3, Pd(PPh3)4, DME, H2O, 70 "C, 2 h; (iii) NaOH, EtOH, 14 h, reflux; (iv) HCl, rt, 5 min.

Ph^O N

H^Ph 15

Ph^O Ph"

endo-(R,R)-17

Scheme 5. Application of catalysts 2a-g in the enantioselective nitrone/enol ether 1,3-dipolar cycloaddition. Reagents and conditions: (i) arenesulfonic acid catalyst, 4 A MS, CHCl3, -35 "C, 24 h, for the yields and stereoselectivities, see the table below.

Entrya Catalyst endo:exoc Yieldd (%) eee(%)

1 _ — 0 _

2 PTSAb 80:20 78 -

3 2a 95:5 83 32

4 2b 93:7 83 30

5 2c 95:5 79 17

6 2d 93:7 83 26

7 2e 94:6 81 19

8 2f 94:6 83 8

9 2g 94:6 81 14

aUnless otherwise stated all reactions were performed on a 0.3 mmol scale, 0.05 M at -35 "C using 10 mol % of catalyst.

bReaction performed at rt for 20 min under the standard reaction conditions. cDetermined by 1H NMR of the isolated product.

isolated yield after column chromatography purification.eDetermined by HPLC of the isolated product, ee and the absolute configuration of the minor diastereomer was not determined.

without any catalyst showed no background reaction (Scheme 5, entry 1).

Due to the significant structural differences and different physical-chemical properties of acids 2a-g and 2h and 2i, an independent reaction condition screen was performed for the latter acids. As a result, slightly modified reaction conditions were established for acids 2h and 2i (CH2Cl2, -40 "C, Scheme 6). Similar to the previous results, acids 2h and 2i efficiently catalysed the 1,3-dipolar cycloaddition and gave up to 30% ee of isoxazolidine (S,S)-17 (Scheme 6). It is noteworthy that the opposite (S,S)-enantiomer of the major endo-diastereomer 17 was formed in the reactions catalysed by acids 2h, 2i when compared to 2a-g.

3. Conclusion

In conclusion, we have successfully designed and executed cross-coupling based syntheses of 2 new classes of stronger chiral Br0nsted acids. The catalytic activity and synthetic utility of the novel chiral sulfonic acids have been demonstrated in a highly diastereoselective and enantioselective 1,3-dipolar nitrone/enol ether cycloaddition reaction. Further exploration of the synthetic utility of these and related sulfonic acids is ongoing in our laboratory and the results will be disclosed in due course.

4. Experimental

PtK©„OS N

Ph' endo-(S,S)-17

Scheme 6. Application of catalysts 2h, 2i in the enantioselective 1,3-dipolar cycloaddition. Reagents and conditions: (i) 4 A MS, CH2Cl2, -40 "C, 24 h; using catalyst 2h (10mol%): 86%, endo:exo 81:19, 30% ee, using catalyst 2i (10mol%): 78%, endo:exo 81:19,19% ee.

towards the endo-product was observed and full conversion to the desired enantiomerically enriched isoxazolidine (R,R)-17 was achieved after 24 h at -35 "C.

Although the obtained enantioselectivities ranged from low to moderate (ee 8-32%), these results provided a sufficient proof of principle for the ability of acids 2a-g to induce enantioselectivity in an acid-catalysed reaction. As expected, a control experiment

For all reactions conducted under anhydrous conditions the glassware was dried in an oven at ~100 "C and the reactions were carried out under a nitrogen atmosphere, unless otherwise stated. Bulk solutions were evaporated under reduced pressure using a Buchi rotary evaporator. Reagents used were obtained from commercial suppliers or purified according to standard procedures. Petrol ether (PE) refers to distilled light petroleum of fraction (40-65 "C). Flash column chromatography was performed with commercial solvents using Merck Kieselgel 60 silica gel (200400 mesh). Thin layer chromatography (TLC) was performed on aluminium or glass plates pre-coated with Merck Kieselgel 60 F254 and visualised by ultra-violet radiation or by staining with either aqueous basic potassium permanganate or vanillin. Enantiomeric excesses were determined using high performance liquid chromatography (HPLC) performed on a Hewlett-Packard Series 1050 series system (column conditions are given with the compound). Melting points were recorded on a Gallenkamp melting point apparatus with the sample contained in a thin glass tube at ambient pressure and are uncorrected.

Infrared spectra (IR) were recorded on a Perkin Elmer Spectrum RX1 FTIR. Only selected absorbances (vmax in cm-1) are reported. 1H, 13C, DEPT, COSY and HMQC NMR spectra were recorded on Bruker 500 MHz, Bruker 400 MHz and Varian 300 MHz spectrometers. Chemical shifts (dH) are quoted in parts per million (ppm ± 0.01 ppm) downfield of tetramethylsilane, relative to the residual protio solvent (dH (CHCl3) = 7.26 ppm) against an internal deuterium lock. Coupling constants (J) are given in Hertz (Hz ± 0.1 Hz). The 1H NMR spectra are reported as follows: d/ppm (multiplicity, number of protons, coupling constants J/Hz, assignment). DEPT and two-dimensional NMR spectroscopy (COSY and HMQC) were used where appropriate to assist the assignment of the signals in the 1H NMR and 13C NMR spectra. Low resolution mass spectrometry (electron impact/chemical ionisation) was recorded on a Micromass Trio 2000 quadrupole mass spectrometer and (electrospray) on a Micromass Platform II spectrometer. High resolution mass spectra (accurate mass) were recorded on a Thermo Finnigan Mat95XP mass spectrometer. Optical rotations were recorded using an Optical Activity AA-1000 polarimeter; specific rotations ([a]D) are reported in 10-1 degcm2g-1; concentrations (c) are quoted in g(100mL)-1; D refers to the D-line of sodium (589 nm); temperatures (T) are given in degrees Celsius (°C). Compounds 5a-d, 6a,b, 10 and 16 are commercially available, compounds 8a,19 8b20 and 1522 were prepared according to literature procedures.

4.1. General procedure A for the preparation of C-3 symmetrical N-aryloxazolidinones 4a-d

1,3,5-Tribromobenzene 6a (1 equiv), potassium carbonate (4equiv), copper(I) iodide (1 equiv) and an oxazolidinone 5 (4 equiv) were placed in a dry flask, and 2 sequences vacuum/nitrogen were applied. Under nitrogen, dry toluene was added (2 mL per mmol), and the suspension was stirred vigorously while N,N'-dimethylethylenediamine was added in one portion (1 equiv). The resulting dark suspension was refluxed for 18 h (turned blue after few minutes of heating). It was then cooled to room temperature and under nitrogen. When the conversion was not complete, another portion of copper(I) iodide (0.5 equiv), oxazolidinone 5 (1 equiv) as well as N,N'-dimethylethylenediamine (0.5 equiv) was added, and the suspension refluxed to completion. The mixture was allowed to cool to room temperature and purified by chro-matography on silica gel (the large amount of solid can be filtered on Celite prior to purification, washing with ethyl acetate thoroughly).

4.1.1. (4S,4'S,4"S)-3,3',3"-Benzene-1,3,5-triyltris(4-propyl-1,3-oxazolidin-2-one) 4a

Prepared according to general procedure A, on a 5.22 mmol scale of 1,3,5-tribromobenzene 6a. Refluxed for 30 h (complete conversion). Purified by column chromatography on silica gel elut-ing with petroleum ether/ethyl acetate (1:1) and the recovered solid was recrystallised from CH2Cl2/PE 2:3 to give 4a (1.12 g, 46%) as a colourless crystalline solid. Mp 83-86 °C; IR 1746 (C=O), 1603 (C=C), 1471 (C=C), 1399 (CH3); 1H NMR (CDCl3, 400 MHz) dH 0.96 (t, 9H, J 7.5 Hz, 3 x CH3CH2CH2), 1.27-1.47 (m, 6H, 3 x CH3CH2CH2), 1.58-1.72 (m, 3H, 3 x CH3CH2CHAHB), 1.761.87 (m, 3H, 3 x CH3CH2CHAHB), 4.17 (dd, 3H, J 8.0 Hz, 4.0 Hz, 3 x NCHCHAHBO), 4.41-4.49 (m, 3H, 3 x NCHCHAHBO), 4.49-4.56 (m, 3H, 3 x NCHCHAHBO), 7.60 (s, 3H, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 13.8 (CH3CH2CH2), 17.4 (CH3CH2CH2), 33.8 (CH3CH2CH2), 55.9 (NCHCH2O), 66.9 (NCHCH2O), 108.2 (CH-Ar), 138.4 (Cquat-Ar), 155.7 (C=O); m/z (ES+) 482 ([M+Na]+, 45%), 941 ([2M+Na]+, 100%), HRMS (ES+) exact mass calculated for [M+Na]+ (C24H33N3O6Na+) requires m/z 482.2262, found m/z 482.2255; [a]D5 =+142.0 (c 1.0, CHCl3).

4.1.2. (4S,4'S,4"S)-3,3',3"-Benzene-1,3,5-triyltris(4-isopropyl-1,3-oxazolidin-2-one) 4b

Prepared according to general procedure A on a 3 mmol scale of 1,3,5-tribromobenzene 6a. Refluxed for 18 h + 4 h. Purified on silica gel eluting with PE/EtOAc 1:1 ? 2:3 to give 4b (0.860 g, 62%) as a colourless crystalline solid. Mp 158-161 °C; IR 1745 (C=O), 1603 (C=C), 1473 (C=C), 1402/1393 (CH3); 1H NMR (CDCl3, 400 MHz) dH 0.88 (d, 9H, J 7.0 Hz, 3 x CH3CHCH3), 0.95 (d, 9H, J 7.0 Hz, 3 x CH3CHCH3), 2.22 (td, 3H, J 7.0 Hz, 3.5 Hz, 3 x CH3CHCH3), 4.27 (dd, 3H, J 8.0 Hz, 3.5 Hz, 3 x NCHCHAHB), 4.39-4.49 (m, 6H, 3 x NCHCHAHB), 7.62 (s, 3H, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 14.5 (CH3CHCH3), 17.8 (CH3CHCH3), 27.7 (CH3CHCH3), 60.2 (NCHCH2), 62.6 (NCHCH2), 109.7 (CH-Ar), 138.4 (Cquat-Ar), 155.7 (C=O); m/z (ES+) 482 ([M+Na]+, 100%), HRMS (ES+) exact mass calculated for [M+Na]+ (C24H33N3O6Na+) requires m/z 482.2262, found m/z 482.2262; [a]D5 = +101.4 (c 1.0, CHCl3).

4.1.3. (4S,4'S,4"S)-3,3',3"-Benzene-1,3,5-triyltris(4-isobutyl-1,3-oxazolidin-2-one) 4c

Prepared according to general procedure A, on a 1.75 mmol scale of 1,3,5-tribromobenzene 6a. Refluxed for 24 h (complete conversion). Purified by chromatography on silica gel eluting with PE/EtOAc 1:1. The recovered solid was further purified by recrys-tallisation from PE/EtOAc 1:1 to give 4c (0.630 g, 72%) as a colourless crystalline solid. Mp 170-174 °C; IR 1754 (C=O), 1603 (C=C), 1471 (C=C), 1398 (CH3); 1H NMR (CDCl3, 400 MHz) <5h 0.96 (d, 9H,J 6.5 Hz, 3 x CH3CHCH3), 1.02 (d, 9H, J 6.5 Hz, 3 x CH3CHCH3), 1.501.60 (m, 3H, 3 x CHCHAHBCH), 1.62-1.74 (m, 3H, 3 x CH3CHCH3),

I.79 (ddd, 3H, J 13.0 Hz, 9.0 Hz, 1.5 Hz, 3 x CHCHAHBCH), 4.17 (dd, 3H, J 8.0 Hz, 4.0 Hz, 3 x NCHCHAHBO), 4.47 (ddd, 3H, J 10.5 Hz, 7.5 Hz, 3.0 Hz, 3 x NCHCHAHBO), 4.53 (t, 3H, J 8.0 Hz, 3 x NCHCHAHBO), 7.63 (s, 3H, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 21.7 (CH3CHCH3), 23.6 (CH3CHCH3), 24.8 (CH3CHCH3), 40.7 (CHCH2CH), 54.9 (NCHCH2O), 67.3 (NCHCH2O), 107.3 (CH-Ar), 138.5 (Cquat-Ar), 155.2 (C=O); m/z (ES+) 519 ([M+NH4]+, 95%), 560 ([M+CH3CN+NH4]+, 100%), HRMS (ES+) exact mass calculated for [M+Na]+ (C27H39N3O6Na+) requires m/z 524.2731, found m/z 524.2735; [a]D5 = +171.9 (c 1.0, CHCl3).

4.1.4. (4S,4'S,4"S)-3,3',3"-Benzene-1,3,5-triyltris{4-[(2S)-butan-2-yl]-1,3-oxazolidin-2-one} 4d

Prepared according to general procedure A, on a 1.4 mmol scale of 1,3,5-tribromobenzene 6a. Refluxed for 20 h (complete conversion). Purified by chromatography on silica gel eluting with PE/ EtOAc 3:2 ? 2:3. The recovered solid was further purified by recrystallisation from PE/EtOAc 2:1 to give 4d (0.420 g, 60%) as a colourless crystalline solid. Mp 139-143 °C; IR 1748 (C=O), 1603 (C=C), 1472 (C=C), 1400 (CH3); 1H NMR (CDCl3, 400 MHz) <5h 0.87 (d, 9H, J 7.0 Hz, 3 x CH3CH), 0.97 (t, 9H, J 7.5 Hz, 3 x CH3CH2), 1.16-1.29 (m, 3H, 3 x CH3CHaHb), 1.29-1.40 (m, 3H, 3 x CH3CHAHB), 1.91-2.03 (m, 3H, 3 x CH3CH), 4.25 (dd, 3H, J 9.0 Hz, 4.0 Hz, 3 x NCHCHAHB), 4.41 (t, 3H, J 9.0 Hz, 3 x NCHCHAHB), 4.57 (dt, 3H, J 9.0 Hz, 4.0 Hz, 3 x NCHCH2), 7.63 (s, 3H, 3 x H-Ar); 13C NMR (CDCl3, 100 MHz) dC 11.8 (CH3CH),

II.9 (CH3CH2), 25.3 (CH3CH2), 34.3 (CH3CH), 59.0 (NCH), 62.5 (NCHCH2), 109.4 (CH-Ar), 138.3 (Cquat-Ar), 155.7 (C=O); m/z (ES+) 519 ([M+NH4]+, 95%) 560 ([M+CH3CN+NH4]+, 100%), HRMS (ES+) exact mass calculated for [M+Na]+ (C27H39N3O6Na+) requires m/z 524.2731 found m/z 524.2737; [a]D5 = +121.1 (c 1.0, CHCl3).

4.2. General procedure B for the preparation of C-2 symmetrical N-aryloxazolidinones 4e-g

1,3-Dibromo-5-tert-butylbenzene 6b (1 equiv), potassium carbonate (3 equiv), copper(I) iodide (1 equiv) and an oxazolidinone

5 (3 equiv) were placed in a dry flask, and 2 sequences vacuum/nitrogen were applied. Under nitrogen, dry toluene was added (2 mL per mmol), and the suspension was stirred vigorously while N,N'-dimethylethylenediamine was added in one portion (1 equiv). The resulting dark suspension was refluxed for 24 h (turned blue after few minutes heating). The mixture was then allowed to cool to room temperature under nitrogen and purified by chro-matography on silica gel (the large amount of solid can be filtered on Celite prior to purification, washing with ethyl acetate thoroughly).

4.2.1. (4S,4'S)-3,3'-(5-tert-Butyl-1,3-phenylene)bis(4-isopropyl-1,3-oxazolidin-2-one) 4e

Prepared according to general procedure B, on a 2.00 mmol scale of 1,3-dibromo-5-tert-butylbenzene 6b. Refluxed for 24 h. Purified by chromatography on silica gel eluting with PE/Et2O 1:2 ? Et2O to afford 4e (0.528 g, 68%) as a colourless solid. Mp 61-63 "C; IR 1746 (C=O), 1601 (C=C), 1457 (C=C), 1393 (CH3); 1H NMR (CDCl3, 400 MHz) dH 0.87 (d, 6H, J 7.0 Hz, 2 x CH3CHCH3), 0.92 (d, 6H, J 7.0 Hz, 2 x CH3CHCH3), 1.33 (s, 9H, (CH3)3C), 2.14 (sept. d, 2H, J 7.0 Hz, 3.5 Hz, 2 x CH3CHCH3), 4.214.29 (m, 2H, 2 x NCHCH2), 4.38-4.46 (m, 4H, 2 x NCHCH2), 7.35 (d, 2H, J 2.0 Hz, H-Ar), 7.37-7.41 (m, 1H, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 14.4 (CH3CHCH3), 17.7 (CH3CHCH3), 27.8 (CH3CHCH3), 31.2 ((CH3)3C), 35.1 ((CH3)3C)), 60.7 (NCHCH2), 62.5 (NCHCH2), 113.1 (CH-Ar), 116.4 (CH-Ar), 137.2 (Cquat-Ar), 153.3 (C=O), 155.9 (Cquat-Ar); m/z (ES+) 411 ([M+Na]+, 40%), 799 ([2M+Na]+), 100%, HRMS (ES+) exact mass calculated for [M+Na]+ (C22H32N2O4Na+) requires m/z 411.2254, found m/z 411.2252; [a]D5 = +71.7 (c 1.0, CHCl3).

4.2.2. (4S,4'S)-3,3'-(5-tert-Butyl-1,3-phenylene)bis(4-isobutyl-1,3-oxazolidin-2-one) 4f

Prepared according to the general procedure, on a 1.63 mmol scale of 1,3-dibromo-5-tert-butylbenzene 6b. Purified by chromatography on silica gel eluting with PE/EtOAc 7:3 ? 1:1 to afford 4f (0.633 g, 93%) as a colourless crystalline solid. Mp 138-141 "C; IR 1754 (C=O), 1603 (C=C), 1471 (C=C), 1398 (CH3); 1H NMR (CDCl3, 500 MHz) dH 0.94 (d, 6H, J 6.5 Hz, 2 x CH3CHCH3), 0.98 (d, 6H, J 6.5 Hz, 2 x CH3CHCH3), 1.33 (s, 9H, (CH3)3C), 1.51 (ddd, 2H, J 13.0 Hz, 10.0 Hz, 4.5 Hz, 2 x CHCHAHBCH), 1.56-1.68 (m, 2H, 2 x CH3CHCH3), 1.73 (ddd, 2H, J 13.0 Hz, 10.0 Hz, 3.0 Hz, 2 x CHCHAHBCH), 4.13 (dd, 2H, J 8.0 Hz, 5.0 Hz, 2 x NCHCHAHBO), 4.45 (dddd, 2H, J 10.0 Hz, 8.0 Hz, 5.0 Hz, 3.0 Hz, 2 x NCHCHaHbo), 4.55 (t, 2H, J 8.0 Hz, 2 x NCHCHAHBO), 7.25 (d, 2H, J 2.0 Hz, H-Ar), 7.54 (t, 1H, J 2.0 Hz, H-Ar); 13C NMR (CDCl3, 125 MHz) dC 21.7 (CH3CHCH3), 23.6 (CH3CHCH3), 24.8 (CH3CHCH3), 31.2 ((CH3)3C)), 35.1 ((CH3 )3C)), 41.1 (CHCH2CH), 55.0 (NCHCH2O), 67.6 (NCHCH2O), 111.9 (CH-Ar), 114.8 (CH-Ar), 137.3 (Cquat-Ar), 153.3, 155.5 (Cquat-Ar, C=O); m/z (ES+) 439 ([M+Na]+, 40%), 855 ([2M+Na]+, 100%, HRMS (ES+) exact mass calculated for [M+Na]+ (C24H36N2O4Na+) requires m/z 439.2567, found m/z 439.2566; [a]D5 =+108.9 (c 1.0, CHCl3).

4.2.3. (4S,4'S)-33'-(5-tert-Butyl-13-phenylene)bis{4-[(2S)-butan-2-yl]-1,3-oxazolidin-2-one} 4g

Prepared according to general procedure B, on a 1.47 mmol scale of 1,3-dibromo-5-tert-butylbenzene 6b. Purified by chromatography on silica gel eluting with PE/EtOAc 7:3 ? 1:1 to give a solid that was crystallised from EtOAc/Et2O/PE (1:2:4, 7 mL), affording 4g (0.525 g, 86%) as a colourless crystalline solid. Mp 123-125 "C; IR 1748 (C=O), 1601 (C=C), 1458 (C=C), 1399 (CH3); 1H NMR (CDCl3, 500 MHz) dH 0.87 (d, 6H, J 6.5 Hz, 2 x CH3CH), 0.95 (t, 6H, J 7.5 Hz, CH3CH2), 1.17-1.37 (m, 13H, (CH3)3C, 2 x CH3CH2), 1.85-1.95 (m, 2H, 2 x CH3CH), 4.24 (dd, 2H, J 9.0 Hz, 4.5 Hz, 2 x NCHCHAHB), 4.41 (t, 2H, J 9.0 Hz,

2 x NCHCHaHb), 4.51-4.57 (m, 2H, 2 x NCHCHAHB), 7.34 (d, 2H, J 2.0 Hz, H-Ar), 7.44 (t, 1H, J 2.0 Hz, H-Ar); 13C NMR (CDCl3, 125 MHz) dC 11.7 (CH3CH), 11.9 (CH3CH2), 25.3 (CH3CH2), 31.2 ((CH3)3C)), 34.3 (CH3CH), 35.1 ((CH3)3C), 59.2 (NCHCH2), 62.4 (NCHCH2), 112.6 (CH-Ar), 115.9 (CH-Ar), 137.1 (Cquat-Ar), 153.3 (C=O), 155.9 (Cquat-Ar); m/z (ES+) 439 ([M+Na]+, 40%), 855 ([2M+Na]+, 100%, HRMS (ES+) exact mass calculated for [M+Na]+ (C24H36N2O4Na+) requires m/z 439.2567, found m/z 439.2569; [a]D5 = +76.2 (c 1.0, CHCl3).

4.3. General procedure C for the preparation of sulfonic acids 2a-g

In a dry flask under nitrogen, the substituted N-aryl oxazolidi-none 4 (1 equiv) was dissolved in dry chloroform (30-50 mL per mmol). The solution was stirred vigorously at room temperature while chlorosulfonic acid (10 equiv) was added dropwise. The cloudy solution was then heated at reflux, with a reverse Dean-Stark apparatus (heavy solvent goes back in the flask) for 2448 h. The resulting brown biphasic mixture was allowed to cool down to room temperature and poured onto ice (50 mL per mmol), washing the flask twice with dichloromethane (5 mL per mmol each time) and three times with DI water (10 mL per mmol each time). The aqueous phase was collected and the organic layer was extracted with DI water (5 x 20 mL per mmol). Aqueous layers were combined and concentrated under reduced pressure to give a brown oily residue which was purified by column chromatography on silica gel and/or crystallisation.

The acids purified by column chromatography were placed into 1 M HCl (1 mL per 0.100 g of acid) and stirred with CH2Cl2 (1 mL per 0.100 g of acid). The organic phase was separated and the aqueous phase was extracted with CHCl3/isopropanol 4:1 (2 x 1 mL per 0.100 g of acid). The combined organics were concentrated in vacuo and dried to give free acid 2.

4.3.1. 2,4,6-Tris[(4S)-4-propyl-2-oxo-1,3-oxazolidin-3-yl]benze-nesulfonic acid 2a

Prepared according to general procedure C on a 2.17 mmol of 4a. Refluxed for 36 h. Purified by chromatography on silica gel elut-ing with CH2Cl2/MeOH 9:1 to give 1.15 g of a light brown solid that was crystallised from hot water (30 mL) to afford 2a (0.540 g, 47%) as colourless crystals. Mp (water) 231-235 "C (dec); IR 3430 (OH), 2962 (C-H), 1745 (C=O), 1200 (SO3), 1064 (SO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.86-0.91 (m, 9H, CH2CH3), 1.16-1.41 (m, 6H,

3 x CH2CH3), 1.45-1.74 (m, 6H, 3 x CH2CH2CH3), 4.04 (dd, 2H, J 8.0 Hz, 4.5 Hz, NCHCHaHb), 4.19 (dd, 1H, J 8.5 Hz, 4.5 Hz, NCHCHaHb), 4.47 (t, 2H, J 8.0 Hz, NCHCHAHB), 4.56 (t, 1H, J 8.5 Hz, NCHCHaHb), 4.65-4.75 (m, 3H, NCH), 7.35 (s, 2H, H-Ar); 13C NMR (DMSO-d6, 500 MHz, 373 K) dC 13.0 (CH2CH3), 13.2 (CH2CH3), 16.2 (CH2CH3), 16.7 (CH2CH3), 32.9 (CH3CH2CH2), 34.2 (CH3CH2CH2), 54.3 (NCH), 57.4 (NCH), 66.3 (NCHCH2O), 67.2 (NCHCH2O), 123.7 (CH-Ar), 135.3 (NCquat-Ar), 136.4 (NCquat-Ar), 141.0 (HO3SCquat-Ar), 154.2 (C=O), 155.6 (C=O); m/z (ES-) 538 ([M-H]-, 100%), HRMS (ES-) exact mass calculated for [M-H]-(C24H32N3O9S-) requires m/z 538.1865, found m/z 538.1854; [a]D5 = +26.2 (c 1.0, MeOH).

4.3.2.2,4,6-Tris[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]ben-zenesulfonic acid 2b

Prepared according to general procedure C on a 1.85 mmol scale of 4b. Refluxed for 48 h. Purified by recrystallisation from acetoni-trile to afford 2b (0.470 g, 47%) as colourless crystals suitable for single crystal X-ray diffraction studies. Mp (acetonitrile) 130-133 "C (dec); IR 3400 (OH), 2965 (C-H), 1752 (C=O), 1395 (CH3), 1202 (SO3), 1056 (SO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.76 (d, 3H, J 6.9 Hz, CH3CHCH3), 0.80 (d, 6H, J 6.9 Hz, 2 x CH3CHCH3), 0.89 (d,

3H,J 6.9 Hz, CH3CHCH3), 0.95 (d, 6H,J 6.9 Hz, 2 x CH3CHCH3), 1.731.83 (m, 2H, 2 x CH3CHCH3), 1.98 - 2.06 (m, 1H, CH3CHCH3), 2.07 (s, 1H, CH3CN, ratio 2b:CH3CN 1:1), 4.18 (dd, J 8.4, 3.3 Hz, 2H, 2 x NCHCHaHbO), 4.26-4.37 (m, 3H, 2 x NCHCHAHBO, NCHCHaHbO), 4.39-4.47 (m, 3H NCHCHaHbO, 2 x NCHCHaHbO), 4.73 (dt, 1H, J 8.5, 3.5 Hz, NCHCHaHbO), 7.42 (s, 2H, H-Ar); 13C NMR (DMS0-d6, 125 MHz) dC 1.2 (CH3CN), 14.2 (CH3CHCH3), 14.7 (CH3CHCH3), 17.1 (CH3CHCH3), 17.7 (CH3CHCH3), 27.3 (CH3CHCH3), 28.3 (CH3CHCH3), 58.6 (NCHCH2), 62.50, 62.53 (NCHCH2, NCHCH2O), 63.4 (NCHCH2O), 118.1 (CH3CN), 123.7 (CHAr), 135.7 (CqUat-Ar), 137.0 (CqUat-Ar), 140.3 (Cquat-Ar), 154.9 (C=0), 156.6 (C=0); m/z (ES-) 538 ([M-H]-, 100%), HRMS (ES-) exact mass calculated for [M-H]- (C24H32N309S-) requires m/z 538.1865, found m/z 538.1871; [a]D5 = +42.1 (c 1.0, Me0H).

Single crystal X-ray diffraction data were collected at 150 K23 with a Nonius Kappa-CCD diffractometer and processed with Denzo-SMN/SCALEPACK24 as per the SI (CIF). The structure was solved with SuperFlip25 and refined with CRYSTALS.26 The structure is highly disordered with one isopropyl-oxo-oxazolidin modelled in two possible orientations. The compound is reported as the sulfonate hydroxonium salt based on the S-0 bond distances (which are statistically indistinguishable) and the hydrogen bonding in the solvent/water sphere. Careful examination of the difference Fourier map in the solvent region, although suggestive of further disorder in the solvent space, supports this conclusion. Full crystallographic data (in CIF format) are available as ESI and has been deposited with the Cambridge Crystallographic Data Centre (reference code 1027606).

4.3.3. 2,4,6-Tris[(4S)-4-isobutyl-2-oxo-1,3-oxazolidin-3-yl]benz-enesulfonic acid 2c

Prepared according to general procedure C on a 1.26 mmol of 4c. Refluxed for 48 h. Purified by chromatography on silica gel elut-ing with dichloromethane/methanol 9:1 to give 2c (0.640 g, 88%) as a light yellow amorphous solid. Acid 2c exists in DMS0-d6 as a mixture of rotamers (according to 1H and 13C NMR at room temperature). This observation was confirmed by variable temperatures (VT) NMR in DMS0-d6 at 100 °C. Mp 242-245 °C (dec); IR 3468 (0H), 2958 (C-H), 1751 (C=0), 1201 (SO3), 1087 (SO3), 758 (ArCH 00P); 1H NMR (DMS0-d6, 500 MHz, 298 K) dH Major rotamer 0.75 (d, 6H, J 6.6 Hz, 2 x CH3CHCH3), 0.84 (d, 6H, J 6.6 Hz, 2 x CH3CHCH3), 0.87 (d, 3H, J 6.6 Hz, CH3CHCH3), 0.94 (d, 3H, J 6.6 Hz, CH3CHCH3), 1.35-1.60 (m, 8H, 2 x CHCH2CH, 2 x CH3CHCH3, CHCH2CH), 1.61-1.69 (m, 1H, CH3CHCH3), 4.07 (dd, 2H, J 8.0 Hz, 5.0 Hz, 2 x NCHCHaHbO), 4.21 (dd, 1H, J 8.5 Hz, 4.5 Hz, NCHCHaHbO), 4.43-4.53 (m, 2H, 2 x NCHCHAHB), 4.58 (t, 1H, J 8.0 Hz, NCHCHaHbO), 4.65 (app. tt, 2H, J 9.0 Hz, 4.5 Hz, 2 x NCH), 4.66-4.76 (m, 1H, NCH), 7.31 (s, 2H, H-Ar); 13C NMR (DMS0-d6, 125 MHz, 298 K) dC 21.7 (CH3CHCH3), 21.9 (CH3CHCH3), 23.48 (CH3CHCH3), 23.54 (CH3CHCH3), 24.0 (CH3CHCH3), 24.1 (CH3CHCH3), 40.3 (CHCH2CH), 42.0 (CHCH2CH), 53.4 (NCH), 56.7 (NCH), 67.1 (NCHCH20), 67.2 (NCHCH20), 124.6 (CH-Ar), 135.5 (Cquat-Ar), 136.9 (Cquat-Ar), 140.6 (Cquat-Ar), 154.7 (C=0), 156.3 (C=0); 1H NMR (DMS0-d6, 500 MHz, 298 K) Minor rotamer (observable) 0.65 ('t', 6H, J 6.0 Hz, 2 x CH3CHCH3), 0.74 (d, 3H, J 6.5 Hz, CH3CHCH3), 1.04-1.10 (m, 1H, CH3CHCH3), 1.731.83 (m, 1H, CHCHAHBCH), 3.80-3.87 (m, 1H, NCHCHaHbO), 3.984.03 (m, 1H, NCH), 5.00-5.09 (m, 1H, NCH), 7.26 (br d, 1H, J 1.9 Hz, H-Ar), 7.52 (s, 1H, J 2.2 Hz, H-Ar); 13C NMR (DMS0-d6, 125 MHz, 298 K) Minor rotamers (observable) 21.95, 22.06, 22.9, 23.2, 23.4 23.9, 24.2 (CH3CHCH3), 40.4, 41.9 (CHCH2CH), 54.0, 55.6, 58.3, 67.3, 68.8, 68.9 (NCHCH20), 123.0, 125.1, 136.0, 136.4,

137.4, 142.0, 154.7, 156.1, 156.2 (CH-Ar, Cquat-Ar, C=0).

4.3.3.1. VT NMR. 1H NMR (DMS0-d6, 500 MHz, 373 K) dH 0.79 (d, 6H, J 6.0 Hz, 2 x CH3CHCH3), 0.85 (d, 6H, J 5.5 Hz,

2 x CH3CHCH3), 0.91 (d, 3H, J 6.5 Hz, CH3CHCH3), 0.96 (d, 3H, CH3CHCH3, J 6.5 Hz), 1.40-1.62 (m, 8H, 2 x CHCH2CH, 2 x CH3CHCH3, CHCH2CH), 1.63-1.74 (m, 1H, CH3CHCH3), 4.02 (m, 2H, 2 x NCHCHaHbO), 4.19 (dd, 1H, J 8.5 Hz, 4.5 Hz, NCHCHaHbO), 4.51 (t, 2H, J 8.0 Hz, 2 x NCHCHaHbO), 4.60 (t, 1H, J 8.0 Hz, NCHCHaHbO), 4.66 (ddd, 1H, J 13.0 Hz, 8.5 Hz, 4.5 Hz, NCH), 4.76 (br, 2H, 2 x NCH), 7.31 (s, 2H, H-Ar); 13C NMR (DMSO-d6, 125 MHz, 373 K) SC 22.3 (CH3CHCH3), 22.5 (CH3CHCH3), 23.5 (br, CH3CHCH3), 23.7 (CH3CHCH3), 24.5 (CH3CHCH3), 24.7 (CH3CHCH3), 40.5 (CHCH2CH), 42.6 (br, CHCH2CH), 54.4 (NCH), 67.8 (CH20), 68.9 (br, CH20), 125.2 (br, CH-Ar), 136.4 (Cquat-Ar), 155.1 (C=0), 156.7 (C=0) (the other carbons were not detected at 373 K); m/z (ES—) 580 ([M-H]-, 100%), HRMS (ES—) exact mass calculated for [M—H]— (C27H38N309S—) requires m/z 580.2334, found m/z 580.2323; [a]D5 = +30.7 (c 1.0, MeOH).

4.3.4. (2,4,6-Tris{(4S)-4-[(2S)-butan-2-yl]-2-oxo-1,3-oxazolidin-3-yl}benzenesulfonic acid 2d

Prepared according to general procedure C on a 0.80 mmol scale of 4d. Refluxed for 24 h. Purified by chromatography on silica gel eluting with CH2Cl2/Me0H 95:5 ? 93:7 to give 0.450 g of a pale brown amorphous solid that was crystallised from CH2Cl2 to afford 2d (250 mg, 54%) as light tan crystals. Mp 166-168 °C (dec); IR 3435 (0H), 2965 (C-H), 1749 (C=0), 1200 (SO3), 1053 (SO3); 1H NMR (DMS0-d6, 500 MHz) SH 0.75 (d, 3H, J 6.5 Hz, CHCH3), 0.82 (t, 6H, J 7.5 Hz, 2 x CH2CH3), 0.90 (t, 3H, J 7.5 Hz, CH2CH3), 0.97 (d, 6H, J 6.5 Hz, CHCH3), 1.06-1.26 (m, 5H, 2 x CH2CH3, CHAHBCH3), 1.27-1.39 (m, 1H, CHAHBCH3), 1.47-1.58 (m, 2H, 2 x CHCH3), 1.72-1.81 (m, 1H, CHCH3), 4.18 (dd, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCHCHaHbo), 4.32 ('t', 3H, J 8.5 Hz, 2 x NCHCHaHbO, NCHCHaHbO), 4.42 (t, 1H, J 8.5 Hz, NCHCHaHbO), 4.52 (dt, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCH), 4.82-4.87 (m, 1H, NCH), 7.39 (s, 2H, H-Ar); 13C NMR (DMS0-d6, 125 MHz) Sc 11.1 (CHCH3), 11.73 , 11.78 (CH3CH2, CHCH3), 24.3 (CH2CH3), 24.8 (CH2CH3), 33.9 (CHCH3), 35.2 (CHCH3), 57.5 (NCH), 62.0 (NCH), 62.4 (NCHCH20), 63.6 (NCHCH20), 123.5 (CH-Ar), 135.7 (NCquat-Ar), 136.9 (NCquat-Ar), 140.4 (H03SCquat-Ar), 155.0 (C=0), 156.7 (C=0); m/z (ES—) 580 ([M—H]—, 100%), HRMS (ES—) exact mass calculated for [M—H]— (c27H38N3O9S—) requires m/z 580.2334 found m/z 580.2341; [a]D5 = +38.4 (c 1.0, MeOH).

4.3.5. 4-tert-Butyl-2,6-bis[(4S)-4-isopropyl-2-oxo-1,3-oxazo-lidin-3-yl]benzenesulfonic acid 2e

Prepared according to general procedure C on a 1.0 mmol scale of 4e. Refluxed for 48 h. Purified by chromatography on silica gel eluting with CH2Cl2/Me0H 9:1 to afford 2e (0.440 g, 94%) as an off-white foamy solid. Mp 260-262 °C (dec); IR 3437 (0H), 2965 (C-H), 1733 (C=0), 1229 (S03), 1079 (S03), 1035 (S03); 1H NMR (DMS0-d6, 500 MHz) SH 0.81 (d, 6H, J 7.0 Hz, 2 x CH3CHCH3), 0.99 (d, 6H, J 7.0 Hz, 2 x CH3CHCH3), 1.28 (s, 9H, C(CH3)3), 1.731.79 (m, 2H, 2 x CH3CHCH3), 4.19 (dd, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCHCHAHB0), 4.31 (t, 2H, J 8.5 Hz, 2 x NCHCHAHB0), 4.41 (dt, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCH, 7.10 (s, 2H, H-Ar); 13C NMR (DMS0-d6, 125 MHz) SC 14.7 (CH3CHCH3), 17.7 (CH3CHCH3), 28.4 (CH3CHCH3), 30.6 (C(CH3)3), 34.0 (C(CH3)3), 62.4 (NCH), 63.4 (NCHCH20), 129.1 (CH-Ar), 134.9 (NCquat-Ar), 142.0 (H03SCquat-Ar), 151.4 (Cquat-Ar), 156.8 (C=0); m/z (ES—) 467 ([M—H]—, 100%), HRMS (ES—) exact mass calculated for [M—H]— (C22H31N207S—) requires m/z 467.1857, found m/z 467.1860; [a]D5 = +56.7 (c 1.0, MeOH).

4.3.6. 4-tert-Butyl-2,6-bis[(4S)-4-isobutyl-2-oxo-1,3-oxazolidin-3-yl]benzenesulfonic acid 2f

Prepared according to general procedure C on a 1.44 mmol of 4f. Refluxed for 24 h. Purified by chromatography on silica gel eluting

with CH2Cl2/MeOH 95:5 ? 93:7 to give 0.633 g of a light tan foamy solid that was recrystallised from CH2Cl2/Et2O (1:2, 3 mL) to afford 2f (0.350 g, 49%). Acid 2f exists in DMSO-d6 as a mixture of rota-mers (according to 1H NMR at room temperature). This observation was confirmed by variable temperatures (VT) NMR in DMSO-d6 at 100 "C. Mp 223-226 "C (dec); IR 3437 (OH), 2958 (C-H), 1740 (C=O), 1227 (SO3), 1077 (SO3), 1029 (SO3), 755 (ArCH OOP); 1H NMR (DMSO-d6, 500 MHz, 298 K) Major rotamer dH 0.74 (d, 6H, J 6.3 Hz, CH3CHCH3), 0.82 (d, 6H, J 6.3 Hz, CH3CHCH3), 1.28 (s, 9H, C(CH3)3), 1.32-1.52 (m, 6H, 2 x NCHCH2CH), 4.02 (dd, 2H, J 7.9 Hz, 5.0 Hz, 2 x NCHCHAHBO), 4.43-4.46 (m, 2H, 2 x NCHCHAHBO), 4.60 (ddd, 2H, J 13.1 Hz, 8.8 Hz, 4.6 Hz, 2 x NCH), 7.12 (s, 2H, H-Ar); 13C NMR (DMSO-d6, 125 MHz, 298 K) dC 22.0 (CH3CHCH3), 23.3 (CH3CHCH3), 24.1 (CH3CHCH3), 30.7 ((CH3)3C), 34.0 ((CH3)3C), 41.9 (CHCH2CH), 56.4 (NCH), 68.1 (NCHCH2O), 130.0 (CH-Ar), 134.6 (Cquat-Ar), 141.9 (Cquat-Ar),

151.2 (Cquat-Ar), 156.3 (C=O); 1H NMR (DMSO-d6, 500 MHz, 298 K) Minor rotamers (observable) 0.63 ('t', 6H, J 6.0 Hz, 2 x CH3CHCH3), 0.67-0.70 (m, 3H, CH3CHCH3), 0.98-1.06 (m, 1H, CH3CHCH3), 1.26 (s, 9H, C(CH3)3), 1.75-1.80 (m, 1H, CHCHAHBCH), 3.81 (dd, 1H, J 10.1 Hz, 8.2 Hz, CHCHAHBO), 3.94 (dd, 1H, J 7.7 Hz, 6.1 Hz, CHCHAHBO), 4.31-4.37 (m, 1H, NCH), 4.90-4.96 (m, 1H, NCH), 7.38 (d, 1H, J 1.6 Hz, H-Ar); 13C NMR (DMSO-d6, 125 MHz, 298 K) Minor rotamers dC 21.7, 22.3, 22.8, 22.9 (CH3CHCH3), 30.7 ((CH3)3C), 34.2 ((CHO3C), 40.1, 42.9 (CHCH2CH), 55.4, 57.9, 62.0, 68.7, 68.8 (NCHCH2O), 126.7, 129.9, 135.0, 135.5, 142.6, 152.0, 156.3, 156.3 (CH-Ar, Cquat-Ar, C=O).

4.3.6.1. VT NMR. 1H NMR (DMSO-d6, 500 MHz, 373 K) dH 0.74-0.80 (br m, 6H, CH3CHCH3), 0.80-0.86 (br m, 6H, CH3CHCH3), 1.31 (s, 9H, ((CH3)3C)), 1.36-1.60 (br m, 6H, 2 x NCHCH2CH), 3.95-4.02 (br m, 2H, 2 x NCHCHAHBO), 4.49 (t, 2H, J 8.0 Hz, 2 x NCHCHaHbO), 4.60-4.90 (br m, 2H, 2 x NCH), 7.14 (br s, 2H, H-Ar); m/z (ES-) 495 ([M-H]-, 100%), HRMS (ES-) exact mass calculated for [M-H]- (C24H35N2O7S-) requires m/z 495.2170, found m/z 495.2173; [a]D5 = +44.4 (c 1.0, MeOH).

4.3.7. 2,6-Bis{(4S)-4-[(2S)-butan-2-yl]-2-oxo-1,3-oxazolidin-3-yl}-4-tert-butylbenzenesulfonic acid 2g

Prepared according to general procedure C on a 1.22 mmol scale of 4g. Refluxed for 24 h. Purified by chromatography on silica gel eluting with CH2Cl2/MeOH 95:5 ? 93:7 to give 2g (0.556 g, 92%) as a colourless amorphous solid. Mp 233-236 "C (dec); IR 3436 (OH), 2965 (C-H), 1739 (C=O), 1227 (SO3), 1078 (SO3), 1033 (sO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.82 (t, 6H, J 7.5 Hz, 2 x CH2CH3), 0.99 (d, 6H, 2 x CHCH3, J 7.0 Hz), 1.07-1.21 (m, 4H, 2 x CH2CH3), 1.28 (s, 9H, C(CH3)3), 1.42-1.56 (m, 2H, 2 x CHCH3), 4.16 (dd, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCHCHAHBO), 4.31 (t, 2H, J 8.5 Hz, 2 x NCHCHaHbO), 4.51 (dt, 2H, J 8.5 Hz, 3.0 Hz, 2 x NCHCHaHbO), 7.09 (s, 2H, H-Ar); 13C NMR (DMSO-d6, 125 MHz) dC 11.7 (CH2CH3, CHCH3), 24.8 (CH2CH3), 30.5 (C(CH3)3), 34.0 (C(CH3)3), 35.0 (CHCH3), 61.7 (NCHCH2O), 63.4 (NCHCH2O), 129.0 (CH-Ar), 134.8 (Cquat-Ar), 142.0 (HO3SCquat-Ar),

151.3 (Cquat-Ar), 156.8 (C=O); m/z (ES-) 495 ([M-H]-, 100%), HRMS (ES-) exact mass calculated for [M-H]- (C24H35N2O7S-) requires m/z 495.2170, found m/z 495.2176; [a]D5 = +74.2 (c 1.0, MeOH).

4.4. [2-(Ethoxysulfonyl)phenyl]boronic acid 11

To a solution of ethyl benzenesulfonate 10 (15.60 mmol, 2.900 g) in THF (39 mL) was added dropwise n-BuLi (1.1 equiv, 17.10 mmol, 6.90 mL of 2.5 M solution in hexanes) at -78 "C. The resulting yellow solution was stirred for 5 h before being quenched with B(OMe)3 (1.5 equiv, 23 mmol, 3.4 g, 4.0 mL) at -78 "C. The resulting mixture was warmed to rt over 1 h and 1 M HCl

(40 mL) was added. The resulting mixture was stirred at rt for 12 h. The organic phase was separated and the water phase was extracted with Et2O (3 x 30 mL). Dried combined organics (Na2SO4) were concentrated in vacuo and the residue was recrys-tallised (PE/Et2O 5:1) to afford 11 (3.310 g, 92%) as a mixture of the acid with the dehydrated form, which was used in the next step. Further recrystallisation afforded pure 11. Mp 62-65 "C (PE-Et2O); IR 3456 (OH), 2988 (C-H), 1338, 1180 (SO3EO; 1H NMR (CDCl3, 400 MHz) dH 1.33 (t, 3H, J 7.2 Hz, OCH2CH3), 4.15 (q, 2H, J 7.2 Hz, OCH2CH3), 4.88 (br s, 2H, B(OH)2), 7.61 (dt, 1H, J 7.7 Hz, 1.5 Hz, H-Ar), 7.69 (dt, 1H, J 7.5 Hz, 1.2 Hz, H-Ar), 8.048.08 (m, 2H, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 14.6 (OCH2CH3), 67.7 (OCH2CH3), 128.8 (CH-Ar), 130.3 (CH-Ar), 133.3 (CH-Ar), 136.8 (CH-Ar), 138.9 (Cquat-Ar); HRMS (FI+) exact mass calculated for [M-H2O]+ (C8H9BO4S+) requires m/z 212.0309, found m/z 211.9832.

4.5. Ethyl 2-[(3R,6S)-6-isopropyl-3-methylcyclohex-1-en-1-yl]benzenesulfonate 12

A mixture of boronic acid 11 (10.50 mmol, 2.414 g), Cs2CO3 (10.50 mmol, 3.414 g) and triflate 8a (8.70 mmol, 2.500 g of tri-flate) in dimethoxyethane (30 mL) and water (5 mL) was degassed and filled with nitrogen. Next, (Ph3P)4Pd (0.05 equiv, 0.44 mmol, 0.505 g) was added and the mixture was stirred at 70 "C. After all starting material had been consumed (TLC monitoring, 1 h) the mixture was cooled to rt and concentrated in vacuo. Water (35 mL) was added and the mixture was extracted with Et2O (3 x 10 mL). Dried combined organics (Na2SO4) were concentrated in vacuo and the residue was purified by column chromatography (PE ? PE/Et2O 98:2 ? PE/Et2O 95:5) to yield 12 (2.191 g, 78%) as a colourless oil. IR 2958, 2932, 2869 (C-H), 1356, 1182 (SO3Et); 1H NMR (CDCl3, 400 MHz) dH 0.70 (d, 3H, J 6.8 Hz, CH3CHCH3), 0.84 (d, 3H, J 6.8 Hz, CH3CHCH3), 1.01 (d, 3H, J 7.1Hz, CH3CHCH2), 1.27-1.45 (m, 5H, OCH2CH3, CHAHBCHCHCH3, CHAHBCHCH3), 1.48-1.56 (m, 1H, CH3CHCH3), 1.77-1.86 (m, 2H, CHAHBCHCHCH3, CHAHBCHCH3), 2.22-2.29 (m, 1H, CH3CHCH2), 2.97 (broad s, 1H, CH3CHCH), 3.99-4.12 (m, 2H, OCH2CH3), 5.48 (s, 1H, CH-CH=Cquat), 7.30 (dd, 1H, J 7.6 Hz, 1.3 Hz, H-Ar), 7.37 (td, 1H, J 7.7 Hz, 1.3 Hz, H-Ar), 7.53 (td, 1H, J 7.6 Hz, 1.2 Hz, H-Ar), 7.98 (dd, 1H, J 8.1 Hz, 1.3 Hz, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 14.7 (OCH2CH3), 16.2 (CH3CHCH3), 20.9 (CH3CHCH3), 21.4 (CHCHCH2), 21.6 (CH3CHCH2), 28.4 (CH3CHCH3), 30.5 (CH2CHCH3), 31.4 (CH2CHCH3), 43.0 (CH3CHCH), 66.6 (OCH2CH3), 126.7 (CH-Ar), 129.7 (CH-Ar), 132.5 (CH-Ar), 133.0 (CH-Ar), 134.0 (Cquat-Ar), 136.6 (CH-CH=Cquat), 141.1 (Cquat), 143.9 (Cquat); HRMS (ES+) exact mass calculated for [M+Na]+ (C18H26NaO3S+) requires m/z 345.1495, found m/z 345.1497; [a]D5 = +50.7 (c 4.02, CHG3).

4.6. {2-(Ethoxysulfonyl)-3-[(3R,6S)-6-isopropyl-3-methyl-cyclohex-1-en-1-yl]phenyl}boronic acid 13

To a solution of benzenesulfonate 12 (3.100 mmol, 1.000 g) in THF (13.2 mL) was added dropwise n-BuLi (1.1 equiv, 3.4 mmol, 1.4 mL of 2.5 M solution in hexanes) at -78 "C. The resulting yellow-orange solution was stirred for 6.5 h at -78 "C before being quenched with B(OMe)3 (1.5 equiv, 4.70 mmol, 0.679 g, 0.792 mL) at -78 "C. The resulting mixture was warmed to rt over 1 h, after which 1 M HCl (40 mL) was added and the mixture was stirred at rt for 1 h. The organic phase was separated and the aqueous phase was extracted with Et2O (3 x 30 mL). The combined organics were washed (brine, 10 mL), dried (Na2SO4) and concentrated in vacuo affording 13 (1.141 g, ~100%) as a colourless oil. The crude product containing a mixture of boronic acid and its dehydrated forms was used in the next step without further purification.

4.7. General procedure D for Suzuki coupling of boronic acid 13 with triflates 8a,b

A mixture of boronic acid 13 (1.5-2 equiv), Cs2CO3 (2 equiv) tri-flate 8 (1 equiv) in dimethoxyethane/water(5:1) was degassed and filled with nitrogen. Next, (Ph3P)4Pd (0.05 equiv) was added and the mixture was stirred at 70 °C. After all starting material had been consumed (TLC monitoring, typically 1-2 h) the mixture was cooled to rt and concentrated in vacuo. Water (8.4 mL per mmol of 8) was added and the mixture was extracted with Et2O (3 x 8.4 mL per mmol of 8). Dried combined organics (Na2SO4) were concentrated in vacuo and the residue was purified by column chromatography.

4.7.1. Ethyl 2,6-bis[(3R,6S)-6-isopropyl-3-methylcyclohex-1-en-1-yl]benzenesulfonate 7a

According to general procedure D (for 1.19 mmol, 0.435 g of 13 used 0.030 mmol, 0.034 g of (Ph3P)4Pd; 0.590 mmol, 0.170 g of tri-flate 8a; 1.19 mmol, 0.384 g of Cs2CO3; 2.0 ml of dimethoxyethane, 0.4 mL of water at 70 °C for 1 h) 7a (0.205 g, 76%) was obtained as a colourless oil after column chromatography (PE ? PE/Et2O 98:2 ? PE/Et2O 95:5). IR 2957, 2931, 2869 (C-H), 1355, 1179 (SO3Et); 1H NMR (CDCl3, 400 MHz) dH 0.77 (d, 6H, J 6.8 Hz, 2 x CH3CHCH3), 0.86 (d, 6H, J 6.8 Hz, 2 x CH3CHCH3), 1.04 (d, 6H, J 7.0 Hz, 2 x CH3CHCH2), 1.30-1.50 (m, 7H, OCH2CH3, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 1.58-1.65 (m, 2H, 2 x CH3CHCH3), 1.79-1.84 (m, 4H, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 2.19-2.30 (m, 2H, 2 x CH3CHCH2), 2.96 (broad s, 2H, 2 x CH3CHCH), 4.05-4.17 (m, 2H, OCH2CH3), 5.48 (s, 2H, 2 x CH-CH=Cquat), 7.15 (d, 2H, J 7.5 Hz, H-Ar), 7.35 (t, 1H, J 7.7 Hz, H-Ar); 13C NMR (CDCl3, 100 MHz) dC 15.2 (OCH2CH3), 16.9 (CH3CHCH3), 21.3, 21.4, 21.6 (CH3CHCH3, CH3CHCH2, CH2CHCHCH3), 28.3 (CH3CHCH3), 30.3 (CH2CHCH3), 31.2 (CH2CHCH3), 43.2 (CHCHCH3), 65.6 (OCH2CH3), 130.7 (CH-Ar), 131.4 (CH-Ar), 134.2 (Cquat), 135.1 (CHCH=Cquat), 142.5 (Cquat), 144.6 (Cquat); HRMS (EI/FI) exact mass calculated for [M]+ (C28H42O3S+) requires m/z 458.2855, found m/z 458.3151; [a]D5 = +78.6 (c 0.22, CHCh).

4.7.2. Ethyl 4 -tert-butyl-3-[(3R,6S)-6-isopropyl-3-methylcyclo-hex-1-en-1-yl]biphenyl-2-sulfonate 7b

According to general procedure D (for 0.75 mmol, 0.275 g of 13 used 0.025 mmol, 0.029 g of (Ph3P)4Pd; 0.50 mmol, 0.141 g of tri-flate 8b; 0.75 mmol, 0.244 g of Cs2CO3; 2.0 ml of dimethoxyethane, 0.4 mL of water at 70 °C for 1 h) 7b (0.142 g, 83%) was obtained as a colourless oil after column chromatography ((PE ? PE/Et2O 98:2 ? PE/Et2O 95:5). IR 2958, 2933, 2869 (C-H), 1354, 1177 (SO3Et); 1H NMR (CDCl3, 500 MHz) d 0.68 (d, 3H, J 6.6 Hz, CH3CHCH3), 0.92 (d, 3H, J 6.9 Hz, CH3CHCH3), 1.03 (t, 3H, J 6.9 Hz, OCH2CH3), 1.06 (d, 3H, J 6.9 Hz, CH3CHCH2), 1.33-1.49 (m, 11H, (CH3)3C, CHAHBCHCHCH3, CHAHBCHCH3), 1.60-1.67 (m, 1H, CH3CHCH3), 1.85-1.89 (m, 2H, CHAHBCHCHCH3, CHAHBCHCH3), 2.24-2.35 (m, 1H, CH3CHCH2), 3.03-3.12 (m, 1H, CH3CHCH), 3.72-3.84 (m, 2H, OCH2CH3), 5.63 (s, 1H, CH-CH=Cquat), 7.25 (d, 1H, J 7.6 Hz, H-Ar), 7.29 (d, 1H, J 7.6 Hz, H-Ar), 7.37 (broad s, 2H, H-Ar), 7.42-7.48 (m, 3H, H-Ar); 13C NMR (CDCl3, 125 MHz) d 14.5 (OCH2CH3), 16.4 (CH3CHCH3), 21.0 (CH3CHCH3), 21.7, 21.7 (CH3CHCH2, CH2CHCHCH3), 28.8 (CH3CHCH3), 30.3 (CH2CHCH3), 31.4, 31.5 ((CH3)3C, CH2CHCH3), 34.6 ((CHO3C), 43.4 (CHCHCH3), 65.7 (OCH2CH3), 124.6 (CH-Ar), 128.6 (Cquat), 131.4 (CH-Ar), 131.4 (CH-Ar), 131.7 (CH-Ar), 133.7 (Cquat), 135.3 (CHCH=Cquat), 138.4 (Cquat), 142.9 (Cquat), 143.4 (Cquat), 145.2 (Cquat), 150.5 (Cquat); HRMS (ES1+) exact mass calculated for [M+Na]+ (C28H38NaO3S+) requires m/z 477.2434, found m/z 477.2438; [a]D5 = +78.1 (c 1.12, CHCl3).

4.8. General procedure E for the synthesis of sodium salts of sulfonic acids 14

A mixture of ester 7 (0.100 g) in EtOH (10 mL) and 1 M NaOH (10 mL) was stirred at reflux. After 14 h the mixture was cooled to rt and concentrated in vacuo. Water (30 mL) was then added and the suspension was stirred at rt for 10 min. The insoluble solid was filtered off, washed (water) and dried to yield the sodium salt of sulfonic acid 14 as a colourless solid.

4.8.1. Sodium 2,6-bis[(3R,6S)-6-isopropyl-3-methylcyclohex-1-en-1-yl]benzenesulfonate 14a

According to general procedure E (for 1.07 mmol, 0.490 g of the ester 7a used 66 mL of 1 M solution of NaOH, 66 mL of EtOH) the salt 14a (0.480 g, 99%) was obtained as a colourless solid. Mp 152-156 °C; IR 2957, 2929, 2868 (C-H), 1366, 1191 (SO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.69 (d, 6H, J 6.8 Hz, 2 x CH3CHCH3), 0.76 (d, 6H, J 6.8 Hz, 2 x CH3CHCH3), 0.94 (d, 6H, J 6.9 Hz, 2 x CH3CHCH2), 1.27-1.35 (m, 4H, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 1.57-1.71 (m, 6H, 2 x CH3CHCH3, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 2.06-2.17 (m, 2H, 2 x CH3CHCH2), 3.15 (broad s, 2H, 2 x CH3CHCH), 5.15 (s, 2H, 2 x CH-CH=Cquat), 6.82 (d, 2H, J 7.3 Hz, H-Ar), 7.04 (t, 1H, J 7.6 Hz, H-Ar); 13C NMR (DMSO-d6, 125 MHz) dC 16.9 (CH3CHCH3), 21.1 (CH3CHCHCH2), 21.3 (CH3CHCH3), 21.9 (CH3CHCH2), 27.7 (CH3CHCH3), 29.9 (CH2CHCH3), 30.6 (CH2CHCH3), 42.1 (CHCHCH3), 125.8 (CH-Ar), 129.5 (CH-Ar), 130.4 (CHCH=Cquat), 141.6 (Cquat), 144.8 (Cquat), 145.1 (Cquat); HRMS (ESI+) exact mass calculated for [M-Na+]- (C26H37O3S-) requires m/z 429.2469, found m/z 429.2477; [a]D5 = +51.3 (c 1.18, MeOH).

4.8.2. Sodium 4 -tert-butyl-3-[(3R,6S)-6-isopropyl-3-methyl-cyclohex-1-en-1-yl]biphenyl-2-sulfonate 14b

According to general procedure E (for 0.22 mmol, 0.102 g of 7b used 11 mL of 1.0 M NaOH, 11 mL of EtOH) 14b (0.094 g, 91%) was obtained as a colourless solid. Mp 288-290 °C; IR (film) 2957, 2931, 2868 (C-H), 1364, 1218 (SO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.57 (d, 3H, J 6.9 Hz, CH3CHCH3), 0.79 (d, 3H, J 6.9 Hz, CH3CHCH3), 0.94 (d, 3H, J 6.9 Hz, CH3CHCH2), 1.24-1.31 (m, 11H, (CH3)3C, CHAHBCHCHCH3, CHAHBCHCH3), 1.53-1.63 (m, 1H, CH3CHCH3), 1.64-1.76 (m, 2H, CHAHBCHCHCH3, CHAHBCHCH3), 2.12-2.23 (m, 1H, CH3CHCH2), 3.42-3.51 (m, 1H, CH3CHCH), 5.26 (broad s, 1H, CH-CH=Cquat), 6.91 (d, 1H, J 7.6 Hz, H-Ar), 6.99 (d, 1H, J 7.3 Hz, H-Ar), 7.17 (t, 1H, J 7.3 Hz, H-Ar), 7.25 (d, 2H, J 8.5 Hz, H-Ar), 7.35 (d, 2H, J 8.2 Hz, H-Ar); 13C NMR (DMSO-d6, 125 MHz) dC 16.4 (CH3CHCH3), 21.0 (CH3CHCH3), 21.4 (CHCHCH2), 22.0 (CH3CHCH2), 28.3 (CH3CHCH3), 30.0 (CH2CHCH3), 30.9 (CH2CHCH3), 31.4 (C(CH3)3), 34.0 (C(CH3)3), 41.7 (CH3CHCH), 123.3 (CH-Ar), 127.1 (CH-Ar), 128.7 (CH-Ar), 129.9 (CH-Ar), 130.3, 130.4 (CH-Ar, CH-CH=Cquat), 141.0 (Cquat), 142.0 (Cquat), 142.7 (Cquat), 144.0 (Cquat), 146.6 (Cquat), 147.1 (Cquat); HRMS (ESI—) exact mass calculated for [M-Na+]-(C26H33O3S+) requires m/z 425.2156, found m/z 425.2164; [a]D5 = +55.5 (c 0.55, MeOH).

4.9. General procedure F for the synthesis of sulfonic acids 2h,i from their salt 14

A suspension of Na-salt 14 in 0.5 M HCl (10 mL per 0.100 g) was extracted with Et2O (10 mL). The organic layer was concentrated by a stream of nitrogen to afford acid 2.

4.9.1. 2,6-Bis[(3R,6S)-6-isopropyl-3-methylcyclohex-1-en-1-yl]-benzenesulfonic acid 2h

According to general procedure F (for 0.070 mmol, 0.030 g of 14a used 3 mL of 0.5 M HCl and 3 mL of Et2O) 2h (0.025 g, 86%)

was obtained as a white solid. Mp 76-81 °C; IR 2958, 2932, 2870 (C-H), 1367, 1173 (SO3); 1H NMR (DMSO-d6, 500 MHz) dH 0.70 (d, 6H, J 6.6 Hz, 2 x CH3CHCH3), 0.77 (d, 6H, J 6.9 Hz, 2 x CH3CHCH3), 0.94 (d, 6H, J 6.9 Hz, 2 x CH3CHCH2), 1.23-1.36 (m, 4H, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 1.56-1.69 (m, 6H, 2 x CH3CHCH3, 2 x CHAHBCHCHCH3, 2 x CHAHBCHCH3), 2.082.18 (m, 2H, 2 x CH3CHCH2), 3.00-3.13 (m, 2H, 2 x CH3CHCH), 5.19 (broad s, 2H, 2 x CH-CH=Cquat), 6.87 (d, 2H, J 7.6 Hz, H-Ar), 7.11 (t, 1H, J 7.6 Hz, H-Ar); 13C NMR (DMSO-d6, 125 MHz) dC 16.9 (CH3CHCH3), 21.1 (CH3CHCHCH2), 21.3 (CH3CHCH3), 21.8 (CH3CHCH2), 27.7 (CH3CHCH3), 29.9 (CH2CHCH3), 30.6 (CH2CHCH3), 42.4 (CHCHCH3), 126.6 (CH-Ar), 129.7 (CH-Ar), 131.2 (CHCH=Cquat), 141.8 (Cquat), 143.6 (Cquat), 144.1 (Cquat); MS (ES-) m/z (relative intensity) 429.64 (M-H+, 100%); [a]D5 = +52.9 (c 0.38, MeOH).

4.9.2. 4-tert-Butyl-3-[(3R,6S)-6-isopropyl-3-methylcyclohex-1-en-1-yl]biphenyl-2-sulfonic acid 2i

According to general procedure F (for 0.20 mmol, 0.094 g of 14b used 10 mL of 1.0 M HCl and 20 mL of Et2O) 2i (0.086 g, 97%) was obtained as a white solid. Mp 78-84 °C; 1H NMR (DMSO-d6, 500 MHz) dH 0.57 (d, 3H, J 6.6 Hz, CH3CHCH3), 0.79 (d, 3H, J 6.6 Hz, CH3CHCH3), 0.94 (d, 3H, J 6.9 Hz, CH3CHCH2), 1.23-1.33 (m, 11H, (CH3)3C, CHAHBCHCHCH3, CHAHBCHCH3), 1.53-1.61 (m, 1H, CH3CHCH3), 1.65-1.71 (m, 2H, CHAHBCHCHCH3, CHAHBCHCH3), 2.14-2.22 (m, 1H, CH3CHCH2), 3.44 (broad s, 1H, CH3CHCH), 5.27 (broad s, 1H, CH-CH=Cquat), 6.92 (d, 1H, J 7.3 Hz, H-Ar), 7.00 (d, 1H, J 7.3 Hz, H-Ar), 7.19 (t, 1H, J 7.6 Hz, H-Ar), 7.25 (d, 2H, J 8.5 Hz, H-Ar), 7.34 (d, 2H, J 7.9 Hz, H-Ar); 13C NMR (DMSO-d6, 125 MHz) dC 16.4 (CH3CHCH3), 21.0 (CH3CHCH3), 21.4 (CHCHCH2), 22.0 (CH3CHCH2), 28.3 (CH3CHCH3), 30.0 (CH2CHCH3), 31.0 (CH2CHCH3), 31.4 (C(CH3)3), 34.1 (C(CH3)3), 41.7 (CH3CHCH), 123.4 (CH-Ar), 127.3 (CH-Ar), 128.7 (CH-Ar), 130.0, 130.4, 130.6 (CH-Ar, CH-Ar, CH-CH=Cquat), 141.0 (Cquat-Ar), 141.9 (Cquat-Ar), 142.7 (Cquat-Ar), 143.6 (Cquat-Ar), 146.5 (Cquat-Ar), 147.2 (Cquat-Ar); MS (ES-) m/z (relative intensity) 425.45 (M-H+, 100%); [a]D5 = +57.5 (c 0.16, MeOH).

4.10. General procedure G for the enantioselective synthesis of isoxazolidines (R,R)-17 using catalyst 2a-g

Ethyl vinyl ether 16 (1.50 mmol, 0.108 g, 0.143 mL) was added to a mixture of nitrone 15 (0.300 mmol, 0.0590 g) and 4 A MS (powder, 0.020 g) in CHCl3 (6.0 mL). The resulting mixture was cooled to -35 °C and catalyst 2 (0.0300 mmol) was added under nitrogen. After 24 h NaHCO3 (saturated aqueous solution, 6 mL) was added and the separated aqueous layer was extracted with CH2Cl2 (6 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by column chromatography (PE/Et2O 98:2 ? 95:5) yielding a diastereomeric mixture of isoxazolidines 17 as a colourless solid.27 The enan-tiomeric excess was determined by HPLC using a chiral stationary phase (Chiralcel 1A column, 99:1 hexanes/i-PrOH, 1.0mL/min, 220 nm, minor enantiomer tr = 6.2 min, major enantiomer tr = 8.1 min).28 All spectroscopic NMR characterisation data (1H and 13C NMR) are in good agreement with the published data.21

4.11. General procedure H for the enantioselective synthesis of isoxazolidines (S,S)-17 using catalyst 2h,i

Ethyl vinyl ether 16 (1.50 mmol, 0.108 g, 0.143 mL) was added to a mixture of nitrone 15 (0.300 mmol, 0.0590 g) and 4 A MS (powder, 0.020 g) in CH2Cl2 (6.0 mL). The resulting mixture was cooled to -40 °C, after which catalyst 2 (0.0300 mmol) was added under nitrogen. After 24 h NaHCO3 (saturated aqueous solution, 6 mL) was added and the separated aqueous layer was extracted

with CH2Cl2 (6 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by column chromatography (PE/Et2O 98:2 ? 95:5) yielding a diastereomeric mixture of isoxazolidines 17 as a colourless solid.27 The enantiomeric excess was determined by HPLC using a chiral stationary phase (Chiralcel AI column, 99:1 hexanes/i-PrOH, 1.0 mL/ min, 220 nm, major enantiomer tr = 6.2 min, minor enantiomer tr = 8.1 min).28 All spectroscopic NMR characterisation data (1H and 13C NMR) are in good agreement with the published data.21

Acknowledgements

We thank the EPSRC (Leadership Fellowship to D.J.D., Studentship to M.E.M., Pfizer (studentship to M.E.M.), and the EC [1EF to I.A. (P1EF-GA-2009-254068)]. UK Catalysis Hub is kindly thanked for resources and support provided via our membership of the UK Catalysis Hub Consortium and funded by EPSRC (portfolio grants EP/K014706/1, EP/K014668/1, EP/K014854/1 and EP/ K014714/1). We also thank Alison Hawkins and David Barber for assistance with the X-ray analysis.

References

1. For a classification of stronger Bransted acids, see: Akiyama, T. Chem. Rev. 2007, 107, 5744-5758.

2. (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566-1568; (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 53565357; For a review, see: (c) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 39093912; (d) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047-9153.

3. Terada, M.; Sorimachi, K.; Uraguchi, D. Synlett 2006,133-136.

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8. For the first synthesis of racemic B1NSA, see: (a) Barber, H. J.; Smiles, S. J. Chem. Soc. 1928,1141-1149; For the synthesis of enantiomerically pure B1NSA via a classic resolution, see: (b) Armarego, W. L F.; Turner, E. E. J. Chem. Soc. 1957, 13-19; For applications of B1NSA, see: (c) Kampen, D.; Ladepeche, A.; ClaSen, G.; List, B. Adv. Synth. Catal. 2008, 350, 962-966; (d) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe, M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130, 1685816860; (e) Pan, S. C.; List, B. Chem. Asian J. 2008, 3, 430-437; (f) Hatano, M.; Ishihara, K. Synthesis 2010, 3785-3801; For syntheses and applications of substituted BINSA-derivatives, see: (g) Garcia-Garcia, P.; Lay, F.; Garcia-Garcia, P.; Rabalakos, C.; List, B. Angew. Chem., Int. Ed. 2009, 48, 4363-4366; (h) LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem., Int. Ed. 2010, 49, 598-601; (i) Hatano, M.; Sugiura, Y.; Ishihara, K. Tetrahedron: Asymmetry 2010, 21, 1311-1314; (j) Hatano, M.; Ozaki, T.; Nishikawa, K.; Ishihara, K. J. Org. Chem. 2013, 78,10405-10413; For a review on synthesis and applications of B1NSA derivatives, see: (k) Hatano, M.; 1shihara, K. Asian J. Org. Chem. 2014, 3, 352-365.

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17. Boronic acid 11 appeared to be unstable over storage, presumably due to dehydration. However, the composition of the resulting mixture had no impact on the chemical yield of the next cross-coupling step.

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27. The isolated epimeric mixture of isoxazolidines showed ~92-95% purity.

28. The absolute configurations of the major endo-diastereomer 17 were assigned by comparison of the measured HPLC retention times with literature retention times using OD-H column, see Ref. 21.