γ-Sultam-cored N,N-ligands in the ruthenium(II)-catalyzed asymmetric transfer hydrogenation of aryl ketones

Abstract

The synthesis of new enantiopure syn- and anti-3-(α-aminobenzyl)-benzo-γ-sultam ligands 6 and their application in the ruthenium(II)-catalyzed asymmetric transfer hydrogenation (ATH) of ketones using formic acid/triethylamine is described. In particular, benzo-fused cyclic ketones afforded excellent enantioselectivities in reasonable time employing a low loading of the syn ligand-containing catalyst. A never-before-seen dynamic kinetic resolution (DKR) during reduction of a γ-keto carboxylic ester (S7) derivative of 1-indanone is realized leading as well to excellent induction.

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Introduction

The efficient asymmetric transfer hydrogenation (ATH) of ketones employing a HCO₂H/Et₃N binary mixture can be currently achieved under mild conditions by three generations of RSO₂-DPEN-based chiral Ru(II) complexes (available in both enantiomeric forms, DPEN = trans-1,2-diphenylethylenediamine) (Fig. 1).^1–5 Noyori and co-workers’ chiral [RuCl(TsDPEN)(η⁶-arene)]-type complexes (1^st generation) were the starting point of such catalyzed asymmetric transformation both on the applied and fundamental levels.^2,3 Then, intracovalent tethering of the diamine and η⁶-arene ligand units (2^nd and 3^rd generations) led to an increased longevity of the catalytic species improving thus the turnover number.^4,5

Fig. 1 “SO₂DPEN”-embedded ATH-efficient chiral Ru(II) complexes.

Exploring the origin of the stereocontrol by the structural stereoarray of the 1^st generation ligands and aiming to enhance the enantioselectivity and catalyst activity, empirical modifications of the chiral elements were undertaken (Fig. 2). In particular, TsDPEN skeletal alteration at the level of its ethylene-bridge substituents on position 1 or 2 revealed the critical importance of their aromatic nature (and inherent steric bulk) as well as the advantage of their anti disposition.^2a,6

Fig. 2 Representative results of [RuCl(TsDPEN or “altered TsDPEN”)(p-cymene)]-catalyzed ATH of acetophenone using HCO₂H/Et₃N 5 : 2.

With our ongoing research interest in this area, we present hereafter the synthesis of 5-membered cyclic minimalist TsDPEN analogs (Fig. 3) and their investigation in the ATH of various classes of ketones. This new design possesses a partial degree of stereochemical rigidity, maintaining however TsDPEN structural elements of the vic-diaryls disposition and the mono N-sulfonyl group. Such a structure gives rise to two possible pairs of syn and anti diastereomers of which preparation was targeted.

Fig. 3 Possible heterocyclic regioisomers of “structurally-simplified TsDPEN”.

Results and discussion

Synthesis of the new 5-membered cyclic N,C-SO₂-DPEN ligands

In this study, we opted for a non-asymmetric synthetic strategy emphasizing on a convenient access to these ligands with a late-stage resolution. Thus, the NaOMe-mediated Wittig reaction of sodium ortho-formylbenzenesulfonate with benzyltriphenylphosphonium chloride afforded pure sodium (E)-β-styrylbenzenesulfonate [(E)-1] in 59% yield after recrystallization (Scheme 1). Conversion into the (E)-sulfonamide (E)-2 followed by epoxidation with m-CPBA and reaction with LiOMe in MeOH led to the regioselective formation of the 6-endo-tet-cyclized trans-δ-sultam trans-4 in high overall yield (82%). Such regioselectivity is supported by ¹H, ¹³C-HMBC analysis from a correlation between the proximal aromatic hydrogen of the 1,1-dioxo-benzo-1,2-thiazinane core and the carbon atom bearing the hydroxyl group (see the ESI†).⁷ Tandem in situ O-mesylation-intra-N-alkylation furnished in 76% yield the trans-configured aziridine-cored product trans-5 (for its X-ray structure showing the aromatic rings in trans and a chiral angular N atom, see the ESI†).§ Alternatively to this circuitous approach, a straightforward single-step conversion of (E)-2 into trans-5via Rh₂(OAc)₄-catalyzed aziridination using PhI(OAc)₂ ⁸ was achieved in 57% yield. Further on, consecutive aziridine highly regioselective ring-opening with sodium azide in MeCN/H₂O (4 : 1) and Pd/C-catalyzed hydrogenation gave the syn-3-(α-aminobenzyl)-benzo-γ-sultam syn-6. The (3S,1′R)- and (3R,1′S)-configured enantiomeric ligands 6 were separated by preparative chiral HPLC in >99% ee and 78% combined yields. The absolute configuration of the 1^st eluting enantiomer was determined by X-ray analysis of its (S)-CSA salt (Fig. 4).⁹

Scheme 1 Preparation of the syn-3-(α-aminobenzyl)-benzo-γ-sultam ligand 6 enantiomers.

Fig. 4 ORTEP drawing of the (1S)-camphor-10-sulfonic acid ((S)-CSA) salt of the HPLC 1^st eluting syn-6 enantiomer at the 50% probability level ((S)-CSA was omitted for clarity; for full details, see the ESI†).

Next, the complementary diastereomer anti-3-(α-aminobenzyl)-benzo-γ-sultam anti-6 was prepared analogously, however by resorting to NaHMDS as the base¹⁰ in the Wittig step (Scheme 2). The resulting ∼1 : 1 (E/Z)-isomeric mixture 1 was directly engaged in the further transformation (via the sulfonamide 2) into the aziridine 5 upon Rh₂(OAc)₄-catalyzed aziridination. The cis and trans diastereomers 5 were separated by silica gel chromatography at this stage of the sequence (28% yield for cis-5) and the former was converted as above into the corresponding racemic anti-3-(α-aminobenzyl)-benzo-γ-sultam anti-6. Its (3R,1′R)- and (3S,1′S)-configured enantiomers were separated by preparative chiral Supercritical Fluid Chromatography (SFC) affording the ligands in >99% ee and 44% combined yields. The absolute configuration of the 1^st eluting enantiomer was equally determined by X-ray analysis of its (S)-CSA salt (Fig. 5).¹¹

Scheme 2 Preparation of the anti-3-(α-aminobenzyl)-benzo-γ-sultam ligand 6 enantiomers.

Fig. 5 ORTEP drawing of the (1S)-camphor-10-sulfonic acid ((S)-CSA) salt of the SFC 1^st eluting anti-6 enantiomer at the 50% probability level ((S)-CSA was omitted for clarity; for full details, see the ESI†).

Evaluation of the new sulfonamido-amine ligands 6 in ATH

The assessment of the efficiency in ATH of the Ru(II) complexes incorporating the new 3-(α-aminobenzyl)-benzo-γ-sultam ligands was first conducted on the representative benchmark substrates acetophenone (S1), ethyl benzoylacetate (S2), 1-indanone (S3), and α-tetralone (S4) (Table 1). The Ru complexes were prepared from a [RuCl₂(η⁶-arene)]₂ precursor and the enantiopure sulfonamido-amine ligand 6 (syn or anti; 1.1 equiv. to Ru atom) at 40 °C (1 h) in 1,2-dichloroethane. The catalysts’ screening with an S/C = 200 was performed at 40 °C using HCO₂H/Et₃N 5 : 2.

Table 1 Ru(II)-catalyzed ATH of benchmark ketones with the enantiopure ligands syn-(3R,1′S)-6 (HPLC 2^nd eluting) and anti-(3R,1′R)-6 (SFC 1^st eluting)^a

Ketone	Ligand	η^6-Arene	t (h)	Conv. (%)	ee (%)
a Reaction conditions: S/C = 200, ketone (1.0 mmol), 1,2-dichloroethane (1 mL), HCO2H/Et3N 5 : 2 (250 μL), 40 °C. Conversion was determined by ^1H NMR of the extracted crude. Isolated yields were 96–98%. ees were determined by chiral GC or HPLC. (R)-Configured alcohols were obtained [(R,R)-TsDPEN used]. For further details, see the Experimental section. b Reaction in neat HCO2H/Et3N 5 : 2 (500 μL).
	syn-6	p-Cymene	4	>99	78
			3^b	100	85
	syn-6	Mesitylene	7	80	72
	anti-6	p-Cymene	4	>99	58
	anti-6	Mesitylene	7	90	72
	TsDPEN	p-Cymene	4	25	97
			4^b	25	97
			20^b	99	97
	syn-6	p-Cymene	3	100	92
	syn-6	Mesitylene	3	100	86
	anti-6	p-Cymene	3	100	54
	anti-6	Mesitylene	3	100	82
	TsDPEN	p-Cymene	7	85	98
			7^b	>99	98
	syn-6	p-Cymene	4	100	99
	anti-6	p-Cymene	5	>99	95
	anti-6	Mesitylene	7	90	95
	TsDPEN	p-Cymene	4^b	50	-
			20^b	>99	99
	syn-6	p-Cymene	3	100	99
	syn-6	Mesitylene	7	80	98
	anti-6	p-Cymene	7	95	>99
	anti-6	Mesitylene	7	85	>99
	TsDPEN	p-Cymene	3	25	99
			3^b	40	99
			20^b	98	98

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The outcome of this exploratory profiling clearly revealed the faster reduction rate using the new sulfonamido-amine ligands 6versus the more flexible TsDPEN and “altered TsDPEN” ligands, or Wills’ conformationally locked indane-cored sulfonamido-amine ligands in Fig. 2. Also, it was noticed for TsDPEN that a supplemental amount of HCO₂H/Et₃N 5 : 2 was required in order to revitalize the reduction and drive it to completion. However, acetophenone (S1) and its α-ethoxycarbonyl-substituted derivative S2 afforded lower enantioselectivities (up to 85% ee and 92% ee, respectively) than the ones with the TsDPEN reference. Noteworthily, as (R)-1-phenylethanol was the major resulting enantiomer, the sense of induction on acetophenone (S1) of the syn-(3R,1′S)-6 and anti-(3R,1′R)-6 revealed to be in line with the one expected with the syn-(1R,2S)-TsDPEN (as its syn-(1S,2R)-enantiomer led to (S)-1-phenylethanol) or observed with anti-(R,R)-TsDPEN (Fig. 2).

Noticeably, the performance of syn-(3R,1′S)-6 was particularly good against the benzo-fused ketones, 1-indanone (S3) and α-tetralone (S4), as up to 99% ee with full conversion was obtained in reasonable times leading as well to (R)-configured alcohols.^2a Also, (R)-configured products (95 to >99% ee) were formed employing the anti-(3R,1′R)-6 demonstrating hence that the chirality on the C(3) atom (bearing the sulfonamido group) predominantly determines the enantiofacial discrimination.

Therefore, the [RuCl₂(p-cymene)]₂/(3R,1′S)-6 complex was further screened on a series of methoxycarbonyl-substituted 1-indanones (S6–S7) and methoxycarbonyl-substituted α-tetralones (S8–S10) (Table 2).

Table 2 Ru(II)-catalyzed ATH of benzo-fused cyclic ketones with the syn-(3R,1′S)-6 (HPLC 2^nd eluting) ligand^a

Ketone	S/C	t (h)	Conv. (%)	Product
				cis/trans	ee (%)
a Reaction conditions: [RuCl2(p-cymene)]2/(3R,1′S)-6, ketone (1.0 mmol), 1,2-dichloroethane (1 mL), HCO2H/Et3N 5 : 2 (250 μL), 40 °C. Conversion and cis/trans ratio (dr) were determined by ^1H NMR of the extracted crude. Isolated yields were 94–99%. ees were determined by chiral GC or HPLC. (R)-Configured alcohols were obtained in all the cases. For further details, see the Experimental section. b Determined by ^19F NMR of the (R)-Mosher ester; trans-stereoisomers were not separated.
	1000	16	95	—	99
	1000	16	>99	—	99
	1000	12	100	—	99
	200	4	100	97 : 3	>99 (cis)
	200	6	100	95 : 5	99 (cis)
					>99 (trans)
	200	6	>99	98 : 2	>99 (cis)
	100	6	>99	50 : 50	99 (cis)^b
	200	3	100	50 : 50	>99 (cis)
					>99 (trans)

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Employing an S/C = 1000, a 99% ee coupled with a high conversion was obtained within 16 h for 1-indanone (S3), α-tetralone (S4), and 4-chromanone (S5).

Shifting to functionalized variants, ATH of racemic 2- or 3-methoxycarbonyl-1-indanone (S6 and S7) using an S/C = 200 resulted in high diastereoselectivities (cis/trans 97 : 3 and 95 : 5, respectively) and 99% enantioselectivity indicating a dynamic kinetic resolution (DKR)^12,13 occurring during their reduction. Regioisomeric methoxycarbonyl-α-tetralones S8–S10 displayed as well an excellent ATH outcome. A high enantioselectivity (>99% ee) was attained in all the cases, with S8 undergoing DKR¹² in 98 : 2 cis/trans ratio. Noteworthily, S9 exhibited some kinetic resolution (KR) during ATH as, at ∼75% conversion, ¹H NMR indicated a 60 : 40 cis/trans ratio.¹⁴

Most interestingly, in a related fashion to the reported DKR during ATH of readily enolizable β-keto esters (such as S6 and S8),¹² a first-time DKR during reduction of a γ-keto ester as rac-3-methoxycarbonyl-1-indanone¹⁵ (S7) was encountered (Scheme 3). We hypothesize that this DKR occurs by keto–enol tautomerization of this 5-membered cyclic γ-keto ester via the racemization-prone dual benzylic and allylic carbon. This stereolability could be accentuated in the transition state (TS) influenced by the electrostatic interaction as shown in Scheme 3. We assume that the configuration of the GC-detected trans-product (5.3%) is as depicted supported by the 99% ee obtained with 1-indanone (S3). By contrast, the 6-membered δ-keto ester higher homolog S10 is unable to undergo racemization (under the test conditions) of its methoxycarbonyl-borne benzylic carbon precluding thus DKR.

Scheme 3 DKR of rac-3-methoxycarbonyl-1-indanone (S7) during ATH (Table 2).

The [Ru(TsDPEN)(η⁶-arene)]-catalyzed ATH mechanism was established by Noyori, Ikariya and co-workers who considered multiple CH⋯π attractive electrostatic interactions in the Ru(II)-hydride-ketone TS.¹⁶ In the case of racemic ketone S7, a more facile reduction of the (S)-enantiomer (vs. the (R)-enantiomer) is attributable to the CO₂Me group outwards orientation minimizing the steric interference in the TS.

Conclusions

We have successfully prepared diastereo- and enantiopure syn- and anti-(α-aminobenzyl)-benzo-γ-sultam ligands 6 and explored them in Ru(II)-catalyzed ATH of conventional ketones in the presence of formic acid/triethylamine 5 : 2. The ATH rate and enantioselectivity using the syn isomer ligand were better than with the anti isomer. High enantioselectivities (99 to >99% ee) were obtained for the benzo-fused cyclic ketones S3–S10 based on 1-indanone or α-tetralone. Namely, a first-time ever DKR of a γ-keto carboxylic ester occurred during reduction. In fact, ketone S7 derived from 1-indanone afforded the corresponding γ-hydroxy ester in a high cis/trans ratio (95 : 5) and excellent ee (99% ee for cis, >99% ee for trans).

Finally, this study is yet another example of how skeletal changes in a chiral ligand design can translate into unpredictable catalyst properties.

Experimental section

Materials and methods

The following non-commercial ketones were prepared according to literature procedures: 2-methoxycarbonyl-1-indanone¹⁷ and 2-methoxycarbonyl-1-tetralone¹⁸ from 1-indanone and α-tetralone, respectively, using dimethyl carbonate; 3-methoxycarbonyl-1-indanone¹⁹ by esterification of 3-oxo-1-indanecarboxylic acid; 3-methoxycarbonyl-1-tetralone²⁰ starting by a Stobbe condensation of benzaldehyde with dimethyl succinate; 4-methoxycarbonyl-1-tetralone¹⁹ from 2-phenyl-glutaric anhydride.

All reactions were conducted under an inert atmosphere (nitrogen or argon) using anhydrous solvents. HCO₂H/Et₃N 5 : 2 (azeotrope) was prepared by adding Et₃N (280 mL, 2 mol) to HCO₂H (190 mL, 5 mol) at 0 °C under a nitrogen atmosphere and used as such. Analytical thin-layer chromatography (TLC) was performed using Silica Gel 60 F254 pre-coated plates (0.25 mm thickness); R_f values are reported and visualization was accomplished by irradiation with an UV lamp (254 nm) and/or staining with KMnO₄ solution. Silica gel 60 (40–63 μm) was used for flash column chromatography. ¹H (299.9 MHz; internal Me₄Si) and ¹³C (75.4 MHz; internal CDCl₃, δ 77.00) spectra were recorded for solutions in CDCl₃ if not stated otherwise. HRMS measurements were obtained on a Q-TOF instrument equipped with an orthogonal Z-spray ESI interface.

Sodium (E)-2-β-styrylbenzenesulfonate (= sodium trans-o-stilbenesulfonate) [(E)-1]. To a freshly prepared solution of NaOMe in MeOH (80 mL, 54 mmol) was added 2-formylbenzenesulfonic acid sodium salt (10.20 g, 49.0 mmol) and the mixture was cooled on an ice-bath. Then, benzyltriphenylphosphonium chloride (19.05 g, 49.0 mmol) in MeOH (50 mL) was added dropwise. The resulting pale yellow mixture was allowed to reach rt in 1 h and left to stir for 16 h. The mixture was concentrated and the residue was suspended in cold H₂O (50 mL). The solid was filtered, and washed with cold H₂O (20 mL) and CH₂Cl₂ until TLC showed that no triphenylphosphine oxide is present. After drying, a white powder (12.5 g) was obtained as an (E/Z)-isomeric mixture in 85 : 15 ratio [by ¹H NMR in DMSO-d₆; δ 6.54 (d, J = 12.3 Hz) is the characteristic signal for the (Z)-isomer and δ 8.25 (d, J = 16.6 Hz) for the (E)-isomer]. Recrystallization from MeCN led to the title product as a white powder (8.14 g, 59% yield). ¹H NMR (300 MHz, DMSO-d₆): δ = 7.13 (d, 16.6 Hz, 1 H), 7.18–7.41 (m, 5 H), 7.50–7.53 (m, 2 H), 7.75–7.81 (m, 2 H), 8.25 (d, J = 16.6 Hz, 1 H). ¹³C NMR (76 MHz, DMSO-d₆): δ = 125.3, 126.52, 126.58, 127.1, 127.5, 128.1, 128.3, 128.7, 128.9, 134.3, 137.8, 145.7. HRMS-ESI (m/z): [M]⁺ calcd for C₁₄H₁₁²³NaO₃S, 282.0327; found, 282.0326.

Sodium (E/Z)-2-β-styrylbenzenesulfonate [(E/Z)-1]. To a cold (0 °C) suspension of benzyltriphenylphosphonium chloride (11.67 g, 30 mmol) in THF (250 mL) was added dropwise under stirring NaHMDS (2 M in THF, 15 mL, 30 mmol). After stirring for 3 h at rt, the reaction mixture was cooled to −78 °C and a solution of 2-formylbenzenesulfonic acid sodium salt (6.25 g, 30 mmol) in MeOH (70 mL) was added dropwise. After 2 h, the mixture was allowed to reach rt and then concentrated. The residue was suspended in EtOAc/2-PrOH (200 mL), filtered, and purified by column chromatography eluting with hexane/EtOAc/MeOH (7 : 2 : 1) and then EtOAc/MeOH (4 : 1). Fractions containing the product/triphenylphosphine oxide were concentrated, and the solid suspended in H₂O (400 mL) and stirred at rt for 3 h. The insoluble matter was filtered off and the filtrate concentrated and dried under high vacuum at 60 °C affording the title product with a ∼1 : 1 E/Z ratio [by ¹H NMR in DMSO-d₆; δ 6.54 (d, J = 12.3 Hz) is the characteristic signal for the (Z)-isomer and δ 8.25 (d, J = 16.6 Hz) for the (E)-isomer] (7.70 g, 91% yield) as a pale yellow powder.

(E)-2-β-Styrylbenzenesulfonamide [(E)-2]. To a cold (0 °C) suspension of (E)-1 (6.40 g, 22.68 mmol) in CH₂Cl₂ (160 mL) was added under stirring thionyl chloride (6.5 mL, 90 mmol) followed by DMF (50 μL). After heating at 50 °C for 5 h, the resulting solution was cooled to 0 °C and added dropwise to a cold (0 °C) solution of NH₄OH (25%, 100 mL)/acetone (50 mL) keeping the internal temperature below 5 °C. Then, the mixture was stirred at 0 °C for 2 h, and CH₂Cl₂ (100 mL) and brine (50 mL) were added. The aqueous layer was re-extracted with CH₂Cl₂ (2 × 100 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated. The crude was filtered through a bed of silica gel eluting with CH₂Cl₂/EtOAc (4 : 1). After concentration and trituration with iPr₂O, the title product (5.17 g, 88%) was obtained as colorless crystals; mp 145–146 °C. ¹H NMR (300 MHz, CDCl₃): δ = 4.72 (s, 2 H), 7.07 (d, J = 16 Hz, 1 H), 7.28–7.51 (m, 4 H), 7.50–7.65 (m, 3 H), 7.73 (d, J = 8 Hz, 1 H), 7.97 (d, J = 16 Hz, 1 H), 8.07 (dd, J = 8, 1 Hz, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 124.4, 127.1, 127.5, 128.0, 128.2, 128.7, 128.9, 133.0, 134.6, 136.3, 136.5, 138.9. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₄NO₂S, 260.0745; found, 260.0748.

(E/Z)-2-β-Styrylbenzenesulfonamide [(E/Z)-2]. Prepared from (E/Z)-1 (∼1 : 1) (4.00 g, 14.18 mmol) following a similar procedure to that for (E)-2. The title product (3.17 g, 86% yield; E/Z ∼1 : 1) was obtained as an amber-colored oil.

trans-o-Sulfamoyl-stilbene oxide (trans-3). To a solution of (E)-2 (4.50 g, 17.36 mmol) in CH₂Cl₂ (50 mL) was added at rt a solution of m-CPBA (5.00 g, 77%; dried over MgSO₄) in CH₂Cl₂ (50 mL). After stirring for 16 h, the mixture was washed with sat. aq. NaHCO₃ (2 × 100 mL). The organic phase was filtered through a bed of silica gel/Na₂SO₄ and concentrated affording the title product (4.59 g, 96% yield) as a slightly yellowish syrup which crystallized upon standing; mp 86–89 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.88 (d, J = 2 Hz, 1 H), 4.62 (d, J = 2 Hz, 1 H), 4.87 (br s, 2 H), 7.34–7.51 (m, 6 H), 7.57–7.71 (m, 2 H), 8.04 (d, J = 8 Hz, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 59.9, 62.3, 125.7, 126.8, 128.0, 128.2, 128.8, 133.1, 135.5, 136.0, 140.0. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₄NO₃S, 276.0694; found, 276.0689.

trans-4-Hydroxy-3-phenyl-1,1-dioxo-benzo-1,2-thiazinane (trans-4). To a cold (0 °C) solution of trans-3 (2.00 g, 7.26 mmol) in MeOH (30 mL) was added a freshly prepared solution of LiOMe in MeOH (0.5 M, 14.8 mL, 7.4 mmol) and the resulting solution was allowed to reach rt. After heating at 55 °C for 2 h, it was brought to rt and the concentrated residue was partitioned between CH₂Cl₂ (100 mL) and 0.5 M HCl (40 mL). The aq. layer was re-extracted with CH₂Cl₂ (20 mL), and the combined organic layers were filtered through a bed of silica gel/Na₂SO₄ and concentrated affording the title product (1.94 g, 97% yield) as a white crispy foam. The structure is supported by ¹H, ¹³C-HMBC analysis from a correlation between the proximal aromatic hydrogen of the 1,1-dioxo-benzo-1,2-thiazinane core and the carbon atom bearing the hydroxyl group (see the ESI†). ¹H NMR (300 MHz, CDCl₃): δ = 2.30 (d, J = 6 Hz, 1 H), 4.56–4.68 (m, 1 H), 4.92 (d, J = 9 Hz, 1 H), 5.12 (dd, J = 10 and 5 Hz, 1 H), 7.41–7.55 (m, 6 H), 7.60–7.70 (m, 1 H), 7.77–7.83 (m, 1 H), 7.86 (dd, J = 8 and 1 Hz, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 63.7, 69.8, 123.0, 126.8, 127.7, 128.4, 129.1, 129.2, 132.6, 137.1, 137.3, 137.4. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₄NO₃S, 276.0694; found, 276.0690.

trans-2,3-Benzylidene-1,1-dioxo-benzo-1,2-thiazolidine (trans-5). To a cold (0 °C) solution of trans-4 (1.50 g, 5.45 mmol) in THF (30 mL) was added Et₃N (1.7 mL, 12 mmol) followed by dropwise addition of methanesulfonyl chloride (0.69 g, 6.0 mmol). The resulting white suspension was left to stir at 0 °C for 0.5 h then at rt for 1 h. The mixture was quenched at 0 °C with H₂O (20 mL), EtOAc (20 mL) was added and layers were separated. The aq. layer was re-extracted with EtOAc (2 × 20 mL) and the combined organic layers were washed with brine (20 mL), dried (Na₂SO₄) and concentrated. The crude was purified on silica gel eluting with petroleum ether (40–60)/EtOAc (9 : 1, 8 : 2, 7 : 3 then 6 : 4) affording the title product (1.07 g, 76% yield) as colorless crystals. Its structure was determined by X-ray analysis (see the ESI†). ¹H NMR (300 MHz, CDCl₃): δ = 3.48 (d, J = 3 Hz, 1 H), 4.18 (d, J = 3 Hz, 1 H), 7.39 (m, 5 H), 7.54–7.70 (m, 3 H), 7.74–7.81 (m, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 51.2, 57.5, 123.4, 125.5, 126.4, 128.7, 129.0, 130.3, 133.5, 133.6, 134.0, 136.0. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₂NO₂S, 258.0589; found, 258.0586.

cis-2,3-Benzylidene-1,1-dioxo-benzo-1,2-thiazolidine (cis-5). To a degassed solution of (E/Z)-2 (∼1 : 1) (4.00 g, 15.4 mmol) in CH₂Cl₂ (160 mL) were successively added at rt Al₂O₃ (3.9 g, 38.6 mmol), molecular sieves 4 Å (4 g), Rh₂(OAc)₄ (341 mg, 0.77 mmol) and PhI(OAc)₂ (7.46 g, 23.17 mmol). The resulting mixture was stirred at 40 °C for 4 h, brought to rt and filtered through a plug of silica gel eluting with CH₂Cl₂. The crude was purified on silica gel eluting with toluene/EtOAc (24 : 1) affording trans-5 (0.97 g, 25% yield) and cis-5 (1.1 g, 28% yield) as an oil. cis-5: ¹H NMR (300 MHz, CDCl₃): δ = 4.31 (d, J = 5 Hz, 1 H), 4.62 (d, J = 5 Hz, 1 H), 6.92–7.02 (m, 2 H), 7.03–7.21 (m, 3 H), 7.35–7.52 (m, 2 H), 7.61–7.70 (m, 1 H), 7.71–7.82 (m, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 47.3, 55.8, 122.5, 126.4, 127.2, 127.8, 128.5, 130.3, 131.0, 133.2, 134.1, 137.1. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₂NO₂S, 258.0589; found, 258.0588.

syn-3-(α-Aminobenzyl)-1,1-dioxo-benzo-1,2-thiazolidine (syn-6). A solution of trans-5 (910 mg, 3.53 mmol) and NaN₃ (0.56 g, 8.56 mmol) in MeCN/H₂O (4 : 1, 30 mL) was heated at 55 °C for 1 h, then brought to rt and concentrated. The residue was partitioned between H₂O (pH 4.5) and CH₂Cl₂, and the combined organic layers were dried (Na₂SO₄) and concentrated. To the resulting oil (1.3 g) in EtOAc (30 mL), 5% Pd/C (130 mg) was added and the mixture was hydrogenated using Parr apparatus at 20 psig H₂ for 1 h. After filtration through Celite and concentration, the residue was purified on silica gel eluting successively with CH₂Cl₂, CH₂Cl₂/EtOAc (4 : 1 then 1 : 2) and EtOAc/EtOH (4 : 1), affording syn-6 (910 mg, 94% yield) as a yellowish syrup. ¹H NMR (300 MHz, CDCl₃): δ = 2.11 (br s, 3 H), 4.36 (d, J = 6 Hz, 1 H), 4.90 (d, J = 6 Hz, 1 H), 7.02–7.19 (m, 1 H), 7.28–7.62 (m, 7 H), 7.66–7.86 (m, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 59.0, 63.1, 121.4, 125.8, 127.1, 128.2, 128.9, 129.6, 132.5, 136.6, 137.0, 140.6. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₅N₂O₂S, 275.0854; found, 275.0849. The syn-6 enantiomers were separated by preparative HPLC on ChiralPak IC (5 μm, 250 × 30 mm), mobile phase CH₂Cl₂/EtOH (98 : 2), flow rate 42.5 mL min⁻¹, 25 °C, UV detection at 260 nm. Analytical HPLC conditions: ChiralPak IC (5 μm, 250 × 4.6 mm), mobile phase: CH₂Cl₂/EtOH (98 : 2), flow rate: 1 mL min⁻¹, 25 °C, UV detection at 230 nm.²¹

1^st eluting syn enantiomer (3S,1′R)-6. Beige-colored powder, 374 mg (40%); t_R 15.9 min; >99% ee; [α]³²_D −11.5 (c 1.0 in CHCl₃); chemical purity (area at 230 nm) = 96.9%. The indicated absolute configuration was determined by X-ray analysis of the (1S)-camphor-10-sulfonic acid salt (colorless plates from MeOH).

2^nd eluting syn enantiomer (3R,1′S)-6. Beige-colored powder, 373 mg (38%); t_R 26.9 min; >99% ee; [α]²⁵_D +11.6 (c 1.0 in CHCl₃); chemical purity (area at 230 nm) = 93.3%.

anti-3-(α-Aminobenzyl)-1,1-dioxo-benzo-1,2-thiazolidine (anti-6). Prepared from cis-5 (1.10 g, 4.27 mol) following a similar procedure to that for syn-6. The title compound (1.06 g, 90% yield) was obtained as a yellowish crispy foam. ¹H NMR (300 MHz, CDCl₃): δ = 4.25 (d, J = 6 Hz, 1 H), 4.79 (d, J = 6 Hz, 1 H), 5.51 (br s, 1 H), 6.58–6.95 (m, 1 H), 7.29–7.63 (m, 7 H), 7.68–7.99 (m, 1 H). ¹³C NMR (76 MHz, CDCl₃): δ = 59.3, 63.7, 121.4, 124.9, 127.2, 128.4, 129.0, 129.6, 132.7, 136.5, 137.5, 141.2. HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₅N₂O₂S, 275.0854; found, 275.0858. The anti-6 enantiomers were separated by preparative SFC on ChiralPak AY (20 μm, 300 × 30 mm), mobile phase ‘A’ for CO₂ and ‘B’ for 2-PrOH (0.1% NH₃ in H₂O), gradient ‘B’ 40%; flow rate 70 mL min⁻¹, back pressure 100 bar, 38 °C, UV detection at 220 nm. Analytical SFC conditions: ChiralPak AY (150 × 4.6 mm), mobile phase ‘A’ for CO₂ and ‘B’ for EtOH (0.05% Et₂NH), gradient ‘B’ 40%, flow rate 2.4 mL min⁻¹, UV detection at 210 nm.²²

1^st eluting anti enantiomer (3R,1′R)-6. Slightly greenish powder, 177 mg (20%); t_R 1.82 min; >99% ee; [α]²³_D −7.9 (c 1.0 in CHCl₃); chemical purity (area at 210 nm) = 100%. The indicated absolute configuration was determined by X-ray analysis of the (1S)-camphor-10-sulfonic acid salt (colorless needles from EtOAc/MeOH).

2^nd eluting anti enantiomer (3S,1′S)-6. Slightly greenish powder, 215 mg (24%); t_R 2.87 min; >99% ee; [α]²³_D +7.7 (c 1.0 in CHCl₃); chemical purity (area at 210 nm) = 100%.

General ATH procedure for ketones listed in Tables 1 and 2

Catalyst preparation. A mixture of the enantiopure ligand 6 (1.1 equiv. to Ru atom) and [RuCl₂(η⁶-arene)]₂ in 1,2-dichloroethane (1 mL/1.0 mmol of ketone) was degassed with N₂ back-filling and stirred at 40 °C for 1 h. The resulting orange-colored solution of the catalyst was used directly in ATH or was concentrated to dryness when the ATH was performed in neat HCO₂H/Et₃N 5 : 2.

ATH of ketones. To the above preformed solution of the [RuCl(ligand 6)(η⁶-arene)] complex (1 mL; with S/C = 100 : 0.01 mmol Ru atom; with S/C = 200 : 0.005 mmol Ru atom; with S/C = 1000 : 0.001 mmol Ru atom) was added HCO₂H/Et₃N 5 : 2 (250 μL; 500 μL when no cosolvent was used) followed by the ketone (1.0 mmol). This mixture was stirred at 40 °C with continuous mild N₂ sweeping. The reaction progress was monitored by ¹H NMR. Workup: the reaction mixture was partitioned between Et₂O (5 mL) and H₂O (5 mL). The aq. layer was re-extracted with Et₂O (5 mL) and the combined organic layers were filtered through a bed of silica gel/Na₂SO₄ and concentrated.

Preparation of racemic alcohol standards. Samples of the racemic alcohols were prepared by reduction of the corresponding ketones with NaBH₄ (3 equiv.) in MeOH (EtOH in the case of ethyl benzoylacetate) at 0 °C to rt. Workup: H₂O was added, the mixture was neutralized with aq. HCl, and the product was extracted with Et₂O. The Et₂O layer was successively washed with H₂O and brine, filtered through a bed of silica gel/Na₂SO₄, and concentrated.

Characterization and ee determination of the ATH prepared chiral alcohols

(R)-1-Phenylethanol. Colorless oil (117 mg, 96% yield); 78% ee. ¹H NMR (300 MHz, CDCl₃): δ = 1.47 (d, J = 6.4 Hz, 3 H), 2.04 (br s, 1 H), 4.86 (q, J = 6.4 Hz, 1 H), 7.35–7.33 (m, 5 H). ee was determined by chiral GC analysis^23a on a Chiralsil-DEX CB column (25 m × 0.25 mm), 120 °C (isothermal), t_R 4.6 min (R), 4.8 min (S).

Ethyl (R)-3-hydroxy-3-phenylpropionate. Colorless oil (190 mg, 98% yield); 92% ee. ¹H NMR (300 MHz, CDCl₃): δ = 1.27 (t, J = 7.2 Hz, 3 H), 2.65–2.83 (m, 2 H), 3.00 (q, J = 7.2 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 5.14 (dd, J = 8.3 and 4.5 Hz, 1 H), 7.28–7.42 (m, 5 H). ee was determined by chiral GC analysis^23b on a Chiralsil-DEX CB (25 m × 0.25 mm), 140 °C (isothermal); t_R 14.6 min (S), 14.9 min (R).

(R)-1-Indanol. Colorless oil which crystallized upon standing (130 mg, 97% yield); 99% ee. ¹H NMR (300 MHz, CDCl₃): δ = 1.75 (br s, 1 H), 1.86–2.02 (m, 1 H), 2.41–2.58 (m, 1 H), 2.74–2.91 (m, 1 H), 3.06 (m, J = 15.9, 8.5, 4.8 Hz, 1 H), 5.25 (t, J = 6.0 Hz, 1 H), 7.17–7.26 (m, 3 H), 7.33–7.47 (m, 1 H). ee was determined by chiral HPLC analysis^23a on a Chiralcel OD column (25 cm). Eluent hexane/2-PrOH (98 : 2), flow rate 1.0 mL min⁻¹, UV detection at 254 nm; racemate: t_R 22.6 min (S), 26.2 min (R).

(R)-1-Tetralol. Colorless oil (194 mg, 96% yield); 99% ee. ¹H NMR (300 MHz, CDCl₃): δ = 1.70 (br s, 1 H), 1.74–2.06 (m, 4 H), 2.66–2.89 (m, 2 H), 4.66–4.90 (m, 1 H), 7.05–7.15 (m, 1 H), 7.15–7.24 (m, 2 H), 7.43 (dd, J = 5.1, 3.9 Hz, 1 H). ee was determined by chiral GC analysis^23a on a Chiralsil-DEX CB column (25 m × 0.25 mm), 130 °C (isothermal); racemate: t_R 13.3 min (S), 13.8 min (R).

(R)-4-Chromanol. White crystals (145 mg, 97% yield); 99% ee. ¹H NMR (300 MHz, CDCl₃): δ = 1.72 (br s, 1 H), 1.95–2.22 (m, 2 H), 4.19–4.40 (m, 2 H), 4.80 (t, J = 4.0 Hz, 1 H), 6.77–7.02 (m, 2 H), 7.17–7.24 (m, 1 H), 7.31 (dd, J = 7.6, 1.4 Hz, 1 H). ee was determined by chiral HPLC analysis^23a on a Chiralcel OD-H column (25 cm). Eluent hexane/2-PrOH (95 : 5), flow rate 1.0 mL min⁻¹, UV detection at 220 nm; racemate: t_R 10.0 min (S), 11.7 min (R).

(1R,2R)-2-Methoxycarbonyl-1-indanol. Yellowish oil which crystallized upon standing (186 mg, 97% yield); cis/trans 97 : 3 by ¹H NMR; >99% ee (cis). ¹H NMR (300 MHz, CDCl₃): δ = 2.77 (d, J = 6.1 Hz, 1 H), 2.97–3.21 (m, 1 H), 3.34–3.53 (m, 2 H), 3.79 (s, 3 H), 5.35 (t, J = 5.9 Hz, 1 H), 7.23–7.32 (m, 3 H), 7.39–7.48 (m, 1 H). ee was determined by chiral GC analysis^12,23a on a Chiralsil-DEX CB column (25 m × 0.25 mm), 130 °C (isothermal); racemates (cis/trans = 55 : 45): t_R 33.7 min [cis-(R,R)], 34.8 min [cis-(S,S)], 45.0 min (trans-1), 50.0 min (trans-2).

(1R,3S)-3-Methoxycarbonyl-1-indanol. Slightly yellowish powder (184 mg, 96% yield); cis/trans 95 : 5 by ¹H NMR; 98.8% ee (cis), >99% ee (trans); mp 105–108 °C; [α]²⁰_D –37.5 (c 1.15 in CHCl₃). ¹H NMR (CDCl₃): δ = 2.20 (m, 0.05 H, trans), 2.33 (app t, J = 14.5, 8.0 and 6.8 Hz, 1 H), 2.59 (ddd, J = 14.5, 8.0 and 6.8 Hz, 1 H), 2.84 (m, 0.05 H, trans), 3.14 (br s, 1 H), 3.72 (s, 0.15 H, trans), 3.76 (s, 3 H), 4.02 (dd, J = 8.0 and 2.8 Hz, 1 H), 4.24 (dd, 0.05 H, trans), 5.16 (m, 1 H), 5.46 (t, 0.05 H, trans), 7.30–7.39 (m, 3 H), 7.50–7.53 (m, 1 H). ¹³C NMR (CDCl₃): δ = 38.5, 48.4, 52.6, 75.2, 124.8, 125.4, 128.6, 128.9, 140.3, 145.4, 175.8. HRMS-ESI (m/z): [M + Na]⁺ calcd for C₁₁H₁₂O₃²³Na, 215.0684; found, 215.0686. ees were determined by chiral GC analysis on a Chiralsil-DEX CB column (25 m × 0.25 mm), 130 °C (isothermal); racemates (cis/trans = 97 : 3): t_R 16.8 min [cis-(1S,3R)], 18.6 min [cis-(1R,3S)], 24.1 min (trans-1), 25.2 min (trans-2). Recrystallization from hexane/CH₂Cl₂ afforded colorless needles (162 mg, 84% yield, >99.9% de, >99.9% ee) which were used for absolute configuration determination by X-ray analysis (see the ESI†).

(1R,2R)-2-Methoxycarbonyl-1-tetralol. Colorless oil (202 mg, 98% yield); cis/trans = 97.6 : 2.4 by ¹H NMR; 99.4% ee (cis). ¹H NMR (300 MHz, CDCl₃): δ = 2.07–2.31 (m, 2 H), 2.75–2.99 (m, 4 H), 3.70 (s, 3 H), 4.80 (d, J = 9.0 Hz; CH, trans diastereomer), 5.05 (m, 1 H), 7.12–7.14 (m, 1 H), 7.19–7.25 (m, 2 H), 7.37–7.42 (m, 1 H). ee was determined by chiral HPLC analysis on a Chiralpak IB-3 column (25 cm). Eluent hexane/2-PrOH (97 : 3), flow rate 1.0 mL min⁻¹, UV detection at 220 nm; racemates (a mixture prepared by weighing both the corresponding ATH products derived from enantiomeric catalysts): t_R 15.4 min (trans-1), 17.4 min [cis-(R,R)], 19.7 min (trans-2), 32.7 min [cis-(S,S)].¹²

(1R,3RS)-3-Methoxycarbonyl-1-tetralol. Light violet-colored syrup (204 mg, 99% yield); cis/trans = 50 : 50 by ¹H NMR; 99% ee (cis). ¹H NMR (300 MHz, CDCl₃): δ = 1.70–1.71 (m, 1 H), 1.92–2.04 (m, 2 H), 2.22 (d, J = 8.1 Hz, 1 H), 2.35–2.42 (m, 1 H), 2.44–2.52 (m, 1 H), 2.85–3.19 (m, 6 H), 3.73 and 3.75 (2s, 2 × 3 H), 4.82–4.91 (m, 2 H), 7.10–7.28 (m, 6 H), 7.32–7.37 (m, 1 H), 7.54–7.56 (m, 1 H). HRMS-ESI (m/z): [M + Na]⁺ calcd for C₁₂H₁₄O₃²³Na, 229.0841; found, 229.0846. Racemates (cis/trans = 96 : 4). ee was determined by ¹⁹F NMR (CDCl₃) of the (R)-Mosher ester (prepared from (S)-Mosher's acid chloride): δ 71.95 [cis-(1R,3R)], 72.00 [cis-(1S,3S)], 72.24 (trans; stereoisomers not separated). The absolute configuration was assigned based on the general observed trend of enantioselectivity.

(1R,4RS)-4-Methoxycarbonyl-1-tetralol. Colorless syrup (202 mg, 98% yield); cis/trans = 50 : 50 by ¹H NMR; >99% ee (cis), >99% ee (trans). ¹H NMR (300 MHz, CDCl₃): δ = 1.72–1.80 (m, 1 H), 2.31–1.88 (m, 7 H), 2.62 (br s, 2 H), 3.67 and 3.69 (2s, 2 × 3 H), 3.75–3.83 (m, 2 H), 4.65–4.73 (m, 2 H), 7.23–7.27 (m, 6 H), 7.39–7.47 (m, 2 H). HRMS-ESI (m/z): [M + Na]⁺ calcd for C₁₂H₁₄O₃²³Na, 229.0841; found, 229.0845. ees were determined by chiral GC analysis on a Chiralsil-DEX CB column (25 m × 0.25 mm), 150 °C (isothermal); racemates (cis/trans = 72 : 28): t_R 21.1 min [cis-(1R,4S)], 21.9 min [trans-(1R,4R)], 22.7 min [cis-(1S,4R)], 24.4 min [trans-(1S,4S)]. The absolute configuration was assigned based on the general observed trend of enantioselectivity.

Acknowledgements

This work was supported by the Ministry of Higher Education, Science, and Technology of the Republic of Slovenia (grant number P1-242).

Notes and references

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7. The preparation of (R)-3-hydroxymethyl-1,1-dioxo-benzo-1,2-thiazolidine was described by following a related synthetic strategy. Therein, in addition to a 5-exo-type cyclization, the formation of trans-(3R,4S)-4-hydroxy-3-hydroxymethyl-1,1-dioxo-benzo-1,2-thiazinane derived from 6-endo-type cyclization occurred as well. For this, see: K. H. Ahn, H. H. Baek, S. J. Lee and C.-W. Cho, J. Org. Chem., 2000, 65, 7690–7696.
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10. P. A. Byrne and D. G. Gilheany, J. Am. Chem. Soc., 2012, 134, 9225–9239.
11. C₂₄H₃₀N₂O₆S₂, F_W 506.62, monoclinic, space group P2₁ (no. 4), a = 13.1356(2), b = 7.03520(10), c = 14.6189(2) Å, β = 112.8645(8)°, V = 1244.81(3) ų, Z = 2, T = 293(2) K, d_calcd = 1.352 g cm⁻³, μ = 0.256 mm⁻¹, 20 767 measured reflections, 5599 unique reflections (R_int = 0.0280), 323 refined parameters, R₁ [I > 2σ(I)] = 0.0474, wR₂ [all data] = 0.1300.
12. For DKR during Ru-TsDPEN-catalyzed (S/C = 200) ATH of 2-ethoxycarbonyl-1-indanone (S6 analog) (6 days, 81% yield, cis/trans >99 : 1, 99% ee for cis) and 2-ethoxycarbonyl-1-tetralone (S8 analog) (6 days, 90% yield, cis/trans >99 : 1, 99% ee for cis) using HCO₂H/Et₃N 5 : 2 at rt, see: A. Ros, A. Magriz, H. Dietrich, J. M. Lassaletta and R. Fernández, Tetrahedron, 2007, 63, 7532–7537.
13. For a review on DKR in ATH, see: (a) H. Pellisier, Tetrahedron, 2011, 67, 3769–3802. For selected recent DKR examples in ATH, see: (b) B. Seashore-Ludlow, F. Saint-Dizier and P. Somfai, Org. Lett., 2012, 14, 6334–6337; (c) K. M. Steward, E. C. Gentry and J. S. Johnson, J. Am. Chem. Soc., 2012, 134, 7329–7332; (d) S.-M. Son and H.-K. Lee, J. Org. Chem., 2014, 79, 2666–2681; (e) F. Xu, M. J. Zacuto, Y. Kohmura, J. Rosen, A. Gibb, M. Alam, J. Scott and D. Tschaen, Org. Lett., 2014, 16, 5422–5425; (f) P.-G. Echeverria, J. Cornil, C. Férard, A. Guérinot, J. Cossy, P. Phansavath and V. Ratovelomanana-Vidal, RSC Adv., 2015, 5, 56815–56819; (g) T. Cheng, Q. Ye, Q. Zhao and G. Liu, Org. Lett., 2015, 17, 4972–4975.
14. For a kinetic resolution of racemic cis-3-hydroxymethyl-indanol or -tetralol by oxidation in acetone using [Ru(TsDPEN)(p-cymene)], see: M. Caro, M. Torrado, C. F. Masaguer and E. Raviña, Tetrahedron: Asymmetry, 2003, 14, 3689–3696.
15. A preparation of enantiomeric 3-ethoxycarbonyl-1-indanone (96% ee) by asymmetric hydroacylation of o-formyl-atropic acid ethyl ester using {Rh[(R)-BINAP]}ClO₄ has been achieved. For this, see: K. Kundu, J. V. McCullagh and A. T. Morehead Jr., J. Am. Chem. Soc., 2005, 127, 16042–16043.
16. (a) P. A. Dub and T. Ikariya, J. Am. Chem. Soc., 2013, 135, 2604–2619; (b) A. Matsuoka, C. A. Sandoval, M. Uchiyama, R. Noyori and H. Naka, Chem. – Asian J., 2015, 10, 112–115.
17. H. O. House and C. B. Hudson, J. Org. Chem., 1970, 35, 647–651.
18. L.-Q. Cui, Z.-L. Dong, K. Liu and C. Zhang, Org. Lett., 2011, 13, 6488–6491.
19. C. J. O'Donnell, R. A. Singer, J. D. Brubaker and J. D. McKinley, J. Org. Chem., 2004, 69, 5756–5759.
20. H. Malik, F. P. J. T. Rutjes and B. Zwanenburg, Tetrahedron, 2010, 66, 7198–7203.
21. Separation of rac syn-6 enantiomers by preparative HPLC was outsourced to Chiral Technologies Europe (France).
22. Separation of rac anti-6 enantiomers by preparative SFC was outsourced to WuXi AppTec Co., Ltd (China).
23. For chiral GC analysis, see: (a) Ref. 5e; ; (b) Ref. 3b .

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Footnotes

† Electronic supplementary information (ESI) available: X-ray crystallographic data for racemic trans-5, [syn-(3S,1′R)-6]·(S)-CSA, [anti-(3R,1′R)-6]·(S)-CSA, and the S7 ATH major reduction product, HPLC and GC chromatograms of ATH products, and ¹H, ¹³C NMR and HMBC spectra. CCDC 1436151–1436154. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob02352a

‡ Present address: PhosPhoenix SARL, 115, rue de l′Abbé Groult, 75015 Paris, France.

§ CCDC 1436151 [for syn-(3S,1′R)-6·(S)-CSA], CCDC 1436152 [for anti-(3R,1′R)-6·(S)-CSA], CCDC-1436153 [for trans-5], and CCDC 1436154 [for S7-reduced] contain the crystallographic data for this paper.

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