Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry

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Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction. Jan Otevrel, and Pavel Bobal J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00079 • Publication Date (Web): 17 Jul 2017 Downloaded from http://pubs.acs.org on July 18, 2017

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The Journal of Organic Chemistry

Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction. Jan Otevrel, and Pavel Bobal.* Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences (UVPS) Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic. Bis(thiourea); Asymmetric Henry reaction; Multifunctional Catalysts; Mirabegron; Econazole. ABSTRACT: We have developed a novel multifunctional C2-symmetric biphenyl-based diamine-tethered bis(thiourea) organocatalyst, which was tested in the asymmetric Henry reaction. Under thoroughly optimized conditions, the catalyst provided exceptionally high yields and excellent enantioselectivities especially for electron-deficient aromatic and heterocyclic substrates. Due to a high affinity of the catalyst to silica gel, a simple chromatography-free nitroaldol isolation procedure was feasible. Preliminary kinetic and spectroscopic experiments were performed in order to complete the mechanistic picture of the organocatalyzed nitroaldolization process. Finally, the developed synthetic strategy was successfully applied to the catalytic enantioselective syntheses of enantiopure (S)-econazole and (R)-mirabegron a late-stage intermediate.

Introduction The enantioenriched nitroaldol adducts have been recognized as an almost unlimited source of valuable synthetic intermediates readily convertible into a variety of building blocks (Scheme 1).

Br N

R1 OH R2

R1

+

R1

NO 2 OH R1

NO 2

a R1

d

R2

NO 2 R1

OH

c

O

O R2

NO 2

R1

R2

R1

Cl O

furilazole O

N

O

R2

R1

CF 3

O

O

R2 NO 2

Scheme 1. Overview of the functional group interconversion related to nitroaldol intermediates. Notes: processes comprising a loss of chirality are shown in gray; E = electrophile, Nu = nucleophile. Highly effective methods for their (a) reduction,1 (b) Nef-type transformation,2 (c) benzylic OH oxidation,3 (d) Ritter4 or Mitsunobu reaction,5 benzylic arylation,6 aminosulfonylation,7 deoxyhalogenation,8 (e) C-alkylation,9 α-halogenation,8a,10 (f) radical denitrations,11 (g) direct deoxygenations,12 (h) O-silylation,13 O-alkylation,9e,14 O-acylation and related kinetic resolution,14e,15 (i) dehydration16 etc. have been discovered.

HO

F

N O

O

NH 2 O

R 2 or

R1 Nu

R 2 or NHOH

b

Cl N

Cl lumefantrine NH 2

OH

OH R2

O

Cl

NO 2

e E

R2

R1

h

R1

O

Br

F 3C

OH

R2

O

Cl

NO 2

i f

O

OH

R1

g

OH

Br aplysamine 7

R2

NO 2

N O

O

OE R2

OH H N

B OH O epetraborole

H 2N

F 3C anacetrapib OH H N

HO labetalol

Figure 1. Representative bioactive compounds of natural and synthetic origin containing vicinal aryl amino alcohol structural unit. Although a number of literature reports describing chiral aryl nitroaldols as starting materials is gradually rising, methods employing their reduction to the corresponding aryl amino alcohols are still one of the most abundant. The exceptional interest of many pharmaceutical companies and research groups in compounds possessing the vicinal aryl amino alcohol unit is likely caused by the ubiquitous occurrence of this motif among bioactive substances of natural or synthetic origin and hence its promising pharmacophoric properties (Figure 1).17 All the vicinal aryl amino alcohol-based compounds bear at least one stereogenic center and both of their enantiomers usually largely differ in their biological activities. The biological

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testing of pure enantiomers rather than their racemic samples is therefore highly justifiable and the development of procedures for their asymmetric syntheses has become a longstanding critical challenge.18 The asymmetric nitroaldol (Henry) reaction can represent a powerful method to synthesize the aforementioned compounds in a substantially effective way. Although the reaction itself has been discovered in 1895,19 its first metal-catalyzed and organocatalyzed asymmetric versions have been reported by Shibasaki and Najera nearly hundred years later and the biocatalyzed asymmetric Henry reaction was recognized by Purkanhofer even in 2006.20 An exhaustive research in the organocatalysis field over last few years affected also the asymmetric Henry reaction,21 and in 2006 has finally resulted in the methodology with synthetically useful levels of enantioselectivities for aromatic and branched aliphatic aldehydes reported by Hiemstra and Nagasawa.22 Nowadays, the most effective enantioselective nitroaldolization organocatalysts (Figure 2) operate nearly exclusively through a chiral hydrogen-bonding activation of electrophile (LUMO-lowering activation).22d,23 An external base for α-proton removal is usually required to generate an active nucleophile from the corresponding neutral nitroalkane. At present, only several potent and highly enantioselective multifunctional organocatalysts being able to promote the asymmetric Henry reaction of aldehydes in the absence of an auxiliary base have been documented.22a,24 C18H 37 Ar1

H N

H N S

NH Cl

N N H H Bn Bn Nagasawa 2006

H N

H N

O N

Ar1

S

N

Ar1 HN

Ar2 Ar2

HN

HN S Ar1 Hiemstra 2006

Ar2 Ar2 NH

Ooi 2007

S Ar1

S

NH NH

NH S

HN

S

Cl H H N N P N N H H

NH Ar1 Kitagaki 2013

Bn

Ar1 NH

HN

Ar1 Ito 2013 O

O

N H OH

N H

Herrera 2016

S HN

N

NH S NH Ar1 Otevrel, Bobal 2016

Figure 2. Selected highly enantioselective nitroaldolization organocatalysts. Multifunctional catalysts capable of acting without the need for an auxiliary base are shown in red. Notes: Ar1 = 3,5-(F3C)2C6H3, Ar2 = 4-F3CC6H4. During the development of biphenyl-based organocatalyst for the asymmetric Henry reaction of aromatic aldehydes in our laboratory, we recognized 2,2’-dimethylbiphenyldiamine as a promising chiral scaffold for a design of the bis(thiourea) organocatalyst.25 Under optimized reaction conditions, the catalyst together with the TMEDA base provided a very good stereoselective outcome. Being encouraged by those results, we wanted to design a catalyst, which combines both the bis(thiourea) and dibasic moieties in its structure. These at-

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tempts led us to the development of a novel type of multifunctional biphenyl-based diamine-tethered bis(thiourea) organocatalyst (Ra)-1 (Scheme 2). By taking advantage of its C2-symmetry, a high-yield and protection-group-free synthesis of the catalyst was performed (Scheme S1). Under the optimized conditions, the exceptionally good yields of all nitroaldol adducts were reached in the reasonable reaction times. For electron-deficient aromatic and heteroaromatic nitroaldols, the excellent enantioselectivities and good diastereoselectivities were achieved (85–96% ee). Furthermore, due to a high affinity of the catalyst to silica gel, a simple chromatography-free nitroaldol isolation procedure was feasible. To shed light on the general reaction mechanism, we have performed preliminary kinetic and spectroscopic experiments. Finally, the developed synthetic strategy was successfully applied to larger scale catalytic enantioselective syntheses of enantiopure (S)-econazole and a late-stage intermediate of (R)-mirabegron.

Results and Discussion Catalysts syntheses, reaction optimization and substrate scope. Three different thiourea organocatalysts 1–3 built on the biphenyl backbones were synthesized in both of their enantiomeric forms. The corresponding enantiopure 6,6’dinitrobiphenic acid and 2,2’-dimethylbiphenyldiamine were chosen as relevant chiral educts in their syntheses (Schemes S1–S3). The aforementioned catalysts differing in their symmetry and basicity properties were tested in the model asymmetric Henry addition of 4-nitrobenzaldehyde (18m) and nitromethane with and without the auxiliary base (Scheme 2). Although the acidity of nitromethane (pKa 15.9 in DMSO) is substantially low in order to be deprotonated by the respective weakly basic aromatic dimethylamino groups of catalysts 2 or 3,26 the use of analogous 1,1’-binaphthyl-based bifunctional thiourea as 3 (Wang’s catalyst) was documented in the asymmetric Michael addition between nitrostyrenes and corresponding C-acids of acidities comparable to MeNO2.27 Catalyst 2 with duplicated aromatic dimethylamino moieties was designed to exhibit superior basicity relative to 3 due to the possible proton sponge properties of 2,2′bis(dimethylamino)biphenyl backbone, which was demonstrated to have dramatically stronger basicity than that of N,Ndimethylaniline (pKa 2.5 vs. 7.9 in DMSO).28 In contrary to our expectations, thiourea derivatives 2 and 3 showed no observable catalytic activity without an additional base, and their use together with the Hünig’s base was lacking enantiodiscrimination completely (Scheme 2, Entries 6–9). On the other hand, bis(thiourea) 1 provided promising results (Scheme 2, Entry 1), which were considerably improved by removal of the external base and by optimizations of the remaining reaction parameters (Table S1). It is noteworthy that under the optimized reaction conditions, the clean and expectable reaction outcome was obtained without any detectable amount of byproducts, e.g. self-aldolization adducts of enolizable aliphatic aldehydes. It is worth mentioning that the enantiomeric excess of (S)-19m reached synthetically useful levels of enantioselectivity (81% ee) even at ambient temperature and for −30 °C, an excellent value (92% ee) was obtained (Scheme 2, Entries 2–5). The stereoselection at ambient temperature was maintained with the catalyst loading of 5 mol% only (Scheme 2, Entry 4) but this decreased load was found inappropriate for the low-


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Scheme 2. Selection of the catalyst. Notes: a) carried out at –30 °C; ee values are based on chiral HPLC analyses of crude adducts, conversions are based on 1H NMR analyses of crude reaction mixtures; Ar = 3,5-(F3C)2C6H3. Please, see the SI for details. temperature experiments because of the prolonged reaction β-nitroalcohol 19o provided by the Kitagaki catalyst was times. Furthermore, due to a high affinity of the catalyst to 68% ee,23a and for 19p, Hiemstra documented less than 20% silica gel, nitroaldol adducts can be isolated readily by filtraee and incomplete conversion of the starting material only.22a Compared to those preceding reports, our results with the tion through a pad of silica gel rather than by timedifficult substrates 18o and 18p do not represent a real failconsuming column chromatography. ure. It was found that the catalyst can be precipitated as the oxaAddition of the higher nitroparaffins to 18e, 18i, and 18l late salt by addition of an ethereal solution of anhydrous leading to 19q–s required prolonged reaction times (168 h) oxalic acid, filtered out of the reaction mixture, and then and slightly increased reaction temperatures (−20 °C) despite recovered by means of acid–base extraction. To test the postheir higher thermodynamic acidities.26,29 This quite surprissibility of the catalyst reuse, we have performed three subsequent experiments with 18m under the abovementioned oping behavior is probably caused by a so-called nitroalkane timized conditions (Scheme 2, Entry 5), in which (Ra)-1 was anomaly.30 Anyway, adducts 19q–s were obtained in both regenerated after each run. Although the extent of this recyexcellent yields and excellent enantioselectivities of the macling study was considerably limited, about 60% of catalyst jor syn-products (89–92% ee). The rather moderate diasterewas successfully regenerated after each run with negligible oselective ratios differing slightly between the crude and changes in reactivity and selectivity of about 1% ee only. isolated products were comparable to the results of our previous study.25 With the optimized reaction conditions in hand, we have investigated the substrate scope of the developed asymmetric In summary, the catalyst (Ra)-1 was proven to work very nitroaldolization process (Scheme 3). A variety of differently well for the asymmetric Henry reaction with the exceptionally high performance for electron-deficient aromatic and hetsubstituted aromatic, several heterocyclic and aliphatic aldehydes were converted into appropriate enantioenriched nierocyclic substrates. We have examined next the use of the troaldol adducts 19a–p. The diastereoselective outcome of catalyst 1 in syntheses of several bioactive compounds. the Henry transformation was examined by addition of niSynthesis of (S)-(+)-econazole. Econazole is an azole-class troethane and 1-nitropropane to the three model aromatic antimycotic drug highly effective against dermatophytes, substrates 19q–s (Scheme 3). Adducts 19b–e, 19g–i, 19m, yeasts, actinomycetes, molds, and other fungi. Furthermore, and 19n possessing electron-poorer aromatic or heterocyclic it also affects the growth of some Gram-positive bacteria. Its systems were all formed in excellent yields and reasonable mechanism of action is likely complex in nature and inreaction times (24–72 h) and with the exception of 19h (93% volves interference with ergosterol biosynthesis as well as ee) and 19m (92% ee), this represents the highest enantioinhibition of several membrane-bound fungal enzymes. meric excesses reported for the organocatalyzed Henry reacEconazole, administered mainly for treatment of topical and tion so far.22a,23,25 For the electron-richer aromatic substrates, vaginal infections, is commonly used as the nitrate salt of the the longer reaction times (84 h) and slightly elevated reacracemic form.31 While both econazole enantiomers differ in tion temperatures (–20 °C) were necessary. The correspondtheir ability to suppress the growth of several microbial ing β-nitroalcohols 19a, 19f, and 19j were furnished in constrains, (S)-enantiomer shows a higher potency against Crypsistently high yields albeit with partially decreased enantitococcus neoformans, Penicillium chrysogenum, and Asperoselectivities (75–86% ee) apparently caused by retrogillus niger.32 nitroaldol processes (see below).23a The suitability of the We have tested the developed enantioselective nitroaldolizareaction conditions was tested also for the aliphatic subtion in the catalytic asymmetric synthesis of (S)-econazole strates. Although the respective nitroaldols 19o and 19p (Scheme 4). The corresponding nitroaldol adduct (S)-19g were isolated in excellent yields, the enantioselective outobtained by a simple filtration of the crude reaction mass come was found unsatisfactory (33–43% ee). In a wider perthrough a small pad of silica was reached in both the excelspective of organocatalyzed asymmetric nitroaldol transforlent yield and enantiopurity (98%, 96% ee). The reduction mations, the highest enantiomeric excess of aliphatic



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O

NO 2

+ R1

H

18a–p (0.1 mmol)

1) (Ra)-1 (10 µmol) Et 2O (0.1 mL) –30 or –20 °C, 24–168 h

Cl

a

NO 2

NO 2

NO 2

OH NO 2

Cl 19g 19h y. 98%, 96% ee (S) y. 97%, 93% ee (S) OH OH NO 2 F 3CO NO 2 Cl 19j y. 96%, 86% ee (S) OH NO 2

19i y. 96%, 90% ee (S) OH NO 2 Br

19k y. 94%, 87% ee (S)

19l y. 87%, 88% ee (S) OH NO 2

O 2N

F 3C

19m y. 95%, 92% ee (S)

19n y. 95%, 85% ee (S) OH OH

NO 2

NO 2

19o y. 97%, 43% ee (S) OH

19p y. 96%, 33% ee (S) OH

OH F

NO 2 Cl 19q y. 92%, dr 62:38 92% ee (1S,2S)*

NO 2 19r y. 94%, dr 63:37 86% ee (1S,2S)*

Br

NO 2 19s y. 89%,dr 69:31 90% ee (1S,2S)*

Scheme 3. Substrate scope of the asymmetric Henry addition catalyzed by (Ra)-1 catalyst. Notes: yields of isolated products, ee values are based on chiral HPLC analyses of crude adducts, dr values are based on 1H NMR analyses of purified adducts; *in all cases, ee values of anti-adducts were low (23–37% ee). step was found unexpectedly challenging, 10% Pd/C catalyzed hydrogenation carried out under 60 psi of H2 led to traces of the desired product only,33 and the previously reported Zn/HCl reduction resulted in the product of insufficient purity.34 The hydrogenation over a freshly prepared Ra–Ni catalyst followed by an HCl isolation work-up gave finally the product (S)-20 in a reasonable yield (67%) with a slightly increased enantiopurity ([α]25D: +73.8 (c 0.5; CHCl3), lit.34 98% ee [α]25D: +73.5 (c 0.51; CHCl3)). The cyclocondensation step was realized according to the literature.34-35 The imidazole product (S)-21 was obtained in a good yield (76%) with the retention of configuration ([α]25D: +82.8 (c 0.5; CHCl3), lit.36 > 99% ee [α]25D: +83.0 (c 0.5; CHCl3)). An in situ Finkelstein reaction–alkylation protocol yielded the crude enantioenriched econazole (S)-22, purified as the oxalate salt (65%).

Cl

N N c y. 76%

HO

NO 2 Cl Me 19d 19e 19f y. 97%, 96% ee (S) y. 97%, 96% ee (S) y. 96%, 76% ee (S) OH OH OH NO 2 O 2N NO 2 NO 2 F Cl

Cl (S)-20

Cl (S)-19g

Boc 19c y. 97%, 96% ee (S)

19b y. 91%, 93% ee (S) OH NO 2

Cl

y. 67% isol. as HCl

18g

N N 19a y. 95%, 75% ee (S) OH NO 2

b

Cl

y. 98% 96% ee Cl

OH

OH

OH

HO

HO

NO 2 (S) or (1S,2S)-19a–s

(2 mmol)

NH 2

NO 2

H

R2

R1

2) NH 4Cl

R2

O

OH

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Cl

Cl (S)-21

d y. 65% > 99% ee isol. as H 2C2O 4 Cl

N

O N Cl (S)-22

Scheme 4. Catalytic enantioselective synthesis of (S)econazole. Conditions: a) MeNO2, (Ra)-1, 60 h, –30 °C; b) H2 (60 psi), Ra–Ni, MeOH, 10 h, rt (isol. as HCl salt); c) H2CO, glyoxal, NH4OAc, MeOH, 12 h, 80 °C (sealed tube); d) NaH, 4-chlorobenzyl chloride, n-Bu4NI, DMF/THF (10:1), 12 h, 0–25 °C (isol. as H2C2O4 salt). The total synthesis of (S)-econazole was successfully accomplished in the 4-step longest linear sequence and provided the final product in a satisfactory overall yield (32%) and an excellent enantiopurity (> 99% ee, [α]20D: +86.8 (c 1.0; CH2Cl2), lit.32 > 99% ee, [α]20D: +87.1 (c 1.0; CH2Cl2)). Synthesis of (R)-mirabegron a direct precursor. Overactive bladder syndrome (OAB) is a common impairing condition characterized by a group of urinary symptoms such as urinary urgency, increased urination frequency, and nocturia. The identification of a predominant expression of β3adrenoreceptor in human urinary bladder and the understanding of its role in detrusor muscle relaxation and the increase in urine storage led to the development of mirabegron, the first-in-class orally available β3-adrenergic receptor agonist. Mirabegron, developed as a single (R)-enantiomer, is used for the symptomatic treatment of OAB and exhibits significantly less extent of side-effects compared to standardly administered antimuscarinic drugs.37 We have decided to apply our catalytic enantioselective Henry reaction for the synthesis of mirabegron the late-stage intermediate (Scheme 5). The nitroaldol adduct (R)-19a was isolated in an excellent yield (96%) and a good enantiopurity (75% ee) by a simple purification step as in the case above. The hydrogenation of (R)-19a over 10% Pd/C afforded the corresponding enantioenriched β-amino alcohol, which was isolated as the HCl salt (97%, 75% ee, [α]25D −46.0 (c 0.5; MeOH)). The single recrystallization step from methanol and diethyl ether afforded the desired vicinal amino alcohol hydrochloride (R)-23·HCl as a pure (R)-enantiomer (67%, > 99% ee, [α]25D: −62.0 (c 0.5; MeOH)). The acylation of its free-base by 4-nitrophenylacetic acid was found messy because a considerable amount of diacylated side-product was obtained. Modified Steglich reaction conditions (EDCl, HOBt, Et3N) led to the sole monoacylated product (R)-24 in a good yield (67%, [α]20D: +12.0 (c 0.5; MeOH)). The hydrogenation of (R)-24 over 10% Pd/C in methanol quantitatively provided (R)-25 (98%, [α]20D: −44.0 (c 0.5; CHCl3)). The subsequent reduction of the amide group of (R)-25 to amine by sodium bis(2-methoxyethoxy)aluminiumhydride


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O

NO 2

H a y. 95% 75% ee

18a

NH 2

HO

b

y. 67% > 99% ee isol. as HCl (R)-19a after 1 x recryst.

O

(R)-23

d

O

y. 98%

NH 2

e y. 95%

HN HO

HO

c y. 98%

NH 2

NO 2

HN

HO

HO

(R)-25

(R)-24 OH

H N

HN

(R)-26

O N H (R)-mirabegron

S N

NH 2

Scheme 5. Catalytic enantioselective synthesis of the mirabegron precursor. Conditions: a) MeNO2, (Sa)-1, 84 h, −20 °C; b) H2 (60 psi), 10% Pd/C, MeOH, 3 h, rt (isol. as HCl salt); c) 4-nitrobenzoic acid, EDCl, HOBt·H2O, Et3N, THF, 1 h, rt; d) H2 (60 psi), 10% Pd/C, MeOH, 3 h, rt; e) SMEAH, MePh, 48 h, rt. (SMEAH) in toluene gave the mirabegron precursor (R)-(–)26 in an excellent yield (98%, [α]20D: −32.0 (c 0.5; CHCl3)). In summary, we have accomplished successfully the synthesis of the enantiopure (R)-mirabegron precursor in a good overall yield (58%) in the 5-step longest linear sequence excluding any chromatographic purification. Although the early example of the mirabegron synthesis described the final acylation step of (R)-26 with the N-Boc protected secondary aliphatic amine,38 it has been revealed later that the reactivity of the primary aromatic amino and secondary aliphatic amino groups of (R)-26 can be distinguished fundamentally under specific reaction conditions. The Steglich-type acylation of (R)-26 with 2-amino4-thiazoleacetic acid using the EDCl reagent in acidic aqueous environment acylates selectively the incompletely protonated and hence more nucleophilic primary aromatic nitrogen of (R)-26. This implies that the use of a protecting group is therefore non-essential.39 Solvent and temperature effects. The influence of the solvent type on the enantiomeric excess of (S)-19m was determined during the optimization study (see pp. S8–S9 for details) and an excellent efficiency of etheric solvents was confirmed, which was in accordance with numerous preceding reports.22a,22b,23a,25,40 When compared to our former catalyst (Figure 2), the enantioselective outcome of (Ra)-1 catalyzed nitroaldolization exhibited more consistent ee values regardless of the solvent type (± 20% ee), with an exception of MeOH, which likely disrupted the hydrogen-bonding framework of the catalyst. Next, we have surveyed the reaction stereoselectivity upon varying the temperature. We have chosen two model derivatives 19q and 19m and plotted the natural logarithm of dia-

stereomeric (dr = syn/anti) or enantiomeric ratio (er = S/R) against the reciprocal reaction temperature.41-43 The temperature vs. stereoselectivity profile of nitroaldol 19q (Figure 3A) exhibited a linear trend intersecting at a value of the reciprocal inversion temperature (Tinv = –5 °C).43 The syn-diastereomers prevailed only at reaction temperatures lower than Tinv. At temperatures higher than Tinv, a weak temperature control of selectivity was observed and the diastereomeric reaction outcome showed the flattened trend with a slightly predominating occurrence of anti-adducts similar to the racemic standard (please, see p. S51 for details). The break in the plot might suggest a change in the reaction mechanism caused either by a reversibility of the above process at higher temperatures or by an epimerization pathway.42-43 First, we have evaluated the extent of the competing racemic background reactions in the absence of the catalyst. As depicted in Scheme 6, these pathways were sufficiently suppressed under the standard reaction conditions even at ambient temperature.

Scheme 6. Control experiments for investigations of the competing background reaction pathways in the absence of the catalyst. These findings indicate that the changes in the stereochemical outcome of 19q observed upon varying the reaction temperature are rather catalyst-mediated and may involve retronitroaldol cleavage and/or epimerization of the labile nitrosubstituted stereocenter throughout the reaction course (Scheme 7).13e,44 Therefore, we have investigated the extent of these two possible catalyst-driven racemization processes. Accordingly, the stereoenriched or racemic adduct 19q was subjected to the normal reaction conditions (Table 1). We have presumed that if the α deprotonation–reprotonation takes place solely, the stereochemistry of the hydroxy-substituted stereocenter of 19q will be preserved over time. It implies that the amount of the newly formed (1S,2S)-19q should be equal to the amount of the consumed (1S,2R)-19q and the same is true for another pair of diastereomers (1R,2S)-19q and (1R,2R)-19q. On the contrary, if the stereochemistry of both stereocenters is altered at the same time, the retro-Henry process will be likely involved. The obtained data summarized in Table 1 show that the configuration change on both stereocenters of 19q is mutually



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A

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B

C

Figure 3. (A) Nonlinear Eyring plots of the temperature-dependent enantiomeric and diastereomeric ratios of 19q. (B) Eyring plot of the temperature-dependent enantiomeric ratios of 19m. (C) Investigation of a nonlinear effect of (S)-19d with (Ra)-1 catalyst. Table 1. Control experiments for investigations of the reaction mechanism. 19q (50 µmol) (initial ee and dr) OH

Cl

Scheme 7. Working hypothesis of a selection model of the (Ra)-1 catalyzed stereoselective Henry reaction between 18e and EtNO2. Note: dashed line – epimerization by deprotonation and diastereoselective reprotonation on the nitrosubstituted stereocenter, plain line – epimerization by retronitroaldol and asymmetric nitroaldol processes. concomitant. This supports that the configuration change is caused by the microscopic reverse of the catalytic reaction, rather than by some entirely new epimerization event. Therefore the epimerization of the nitro-substituted stereocenter caused by α-deprotonation–reprotonation during the reaction course is a presumably less important consideration in this case. Instead of it, the retro-aldol cleavage and the subsequent Henry reaction are plausibly responsible for the change in stereochemistry of the 19q adduct.45 Although it is too early to present any kinetic model of the selection process, the presence of the Tinv might suggest a temperature-dependent balance between two reverse catalyst-mediated reactions – Henry and retro-Henry, which can form two distinct levels of stereoselection in the abovementioned process (Scheme 7). The formation of syndiastereomers, especially (1S,2S)-19q, is apparently kinetically favored. Their prevalence over anti-diastereomers at low-temperature region is dictated mostly by the lower barrier of formation because the retro-aldol cleavage is sufficiently suppressed. On the contrary, the barriers of formation leading to anti-diastereomers are easily surmountable at higher temperatures and the products are allowed to interconvert mutually by the retro-nitroaldol reaction. Hence, the thermodynamic mixture slightly enriched in anti-adducts is obtained.

Et 2O (50 µL) OH

NO 2

(1R,2S)-19q A

Entry

EtNO 2 (1 mmol) (R a)-1 (5 µmol)

Cl

NO 2

(1S,2R)-19q B

19q (recovered ee and dr) OH

Cl

NO 2

(1R,2R)-19q C

OH

Cl

NO 2

(1S,2S)-19q D

Adduct

initial ratio recovered ratio (A:B/C:D) (A:B/C:D) 1a) rac-19q 30:30/20:20 29:29/20:22 2b) rac-19q 30:30/20:20 28:28/21:23 3a) (1S,2S)-19q 18:11/3:68 18:11/3:68 4b) (1S,2S)-19q 18:11/3:68 32:29/14:25 5b) (1R,2S)-19q 31:29/15:25 31:29/15:25 a) Conditions: –20 °C, 168 h; b) 20 °C, 12 h. In contrast with the above somewhat complicated scenario, the (S)-19m adduct exhibited rather simple enthalpically manifested stereoselectivity (please, see p. S52). An Eyring plot of the logarithmic er of (S)-19m against the reciprocal reaction temperature showed a linear correlation with a moderate slope only (Figure 3B). This near-ideal Arrhenius behavior together with the similar sense and magnitude of the enantiomeric excesses, relatively independent of the solvent type, indicates that the reaction mechanism of this organocatalyzed process remained the same in the tested solvents and temperature range.42 Nonlinear effect. In comparison with the adduct 19m, the nitroaldol 19d provided superior enantioselective outcome while maintaining excellent reactivity. Therefore it was chosen as a probe derivative for investigations of a possible nonlinear effect (NLE). The reaction mixtures of 18d and catalyst (Ra)-1 present in the gradually increasing enantiomeric ratios were visually inspected for homogeneity in order to reduce errors of a falsely positive NLE caused by a precipitation of the racemic catalyst from the reaction mixture. Thus, a linear relationship with a strong correlation coefficient was obtained demonstrating that a monomeric form of the catalyst is involved in the studied organocatalytic process (Figure 3C).46


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A

The Journal of Organic Chemistry C

B

Figure 4. (A) Kinetic experiments using different initial loadings of 18d. (B) Determination of the kinetic order in (Ra)-1 (10– 25 mol%). (C) Plot illustrating differences in the reaction progress by using CD3NO3 (20 equiv.) instead of CH3NO2 (20 equiv.).

Scheme 8. Isotopic substitution experiment. Note: R–NO2 was used as both the co-solvent and the reactant. Kinetic studies. In order to gain better insight into the mechanistic picture of the above transformation, we have performed some preliminary kinetic studies with 18d. The standard reaction conditions used “flooding” in nitromethane natively due to its role as a reaction co-solvent (pseudo-zeroorder conditions). Moreover, a large excess of MeNO2 (20 equiv.) had also a beneficial effect on conversion rate and stereoselectivity (please, see pp. S8–S9). Under these conditions, an exponential decay of [18d] was noticed, which implies the first order kinetics with respect to 18d (please, see pp. S57–S58). Two additional kinetic experiments using different initial loadings of [18d]0 (0.39 M and 0.29 M) were done in order to test the catalyst robustness. Accordingly, the rate vs. concentration profiles indicates a well-behaved kinetics with no appreciable catalyst deactivation or product inhibition throughout the reaction (Figure 4A).47 From a set of four kinetic experiments with catalyst loadings varied within the synthetically relevant range (10–25 mol%), the first-order kinetics with respect to the catalyst 1 is assessed by excellent overlay of the concentration vs. normalized time scale [1]1·t curves (Figure 4B).48 The investigations of the reaction order in nitromethane could not be possible due to the solubility issues and its significant volatility.49 However, the role of nitromethane was surveyed by its isotopic substitution with MeNO2-d3 used in the same excess (Scheme 8). Although the twofold load of (Ra)-1 catalyst was employed in this run (20 mol%), a shift from the first-order kinetics to the zero-order kinetics in aldehyde was observed

(Figure 4C). This indicates that the reaction is no longer dependent on the aldehyde concentration and a slow deuteron abstraction from MeNO2-d3 assisted by the catalyst probably limits the overall rate of the asymmetric Henry addition.50 It is noteworthy that under the reaction conditions, only a negligible deuterium exchange between the N–H groups of the catalyst (Ra)-1 and MeNO2-d3 was noticed (please, compare the integrals of N–H signals on p. S63). The ee values of the isolated adducts 19d or 19d-d3 were virtually the same (91% vs. 90% ee). Similarly as in the above case, the higher nitroalkanes, whose kinetic acidities are appreciably lower when compared to nitromethane, presumably reflect the ratecontrolling α-deprotonation step in a retarded overall reaction rate and exhibit more or less similar saturation behavior to that of MeNO2-d3.30,50 NMR studies. Hydrogen-bonding properties of the newly developed catalyst were further studied by means of NMR spectroscopy.51 A small upfield shift of both N–H signals was observed during the fourfold dilution of the (Ra)-1 solution (Figure 5A). Moreover, protonation of a dibasic site of the catalyst using trifluoroacetic acid (TFA) in C6D6 also resulted in noticeable upfield shifts of both thiourea hydrogens (Figure 5B). These findings suggest that a possible selfassembly of the catalyst under the synthetically relevant concentrations may generate e.g. off-loop species not directly involved in the productive catalytic cycle.52 Although the reaction mechanism is not completely elucidated at this moment, we believe that the stereoselection process of the above transformation is mainly governed by the bis(thiourea) units of the catalysts. This hypothesis was supported by the 1H NMR complexation experiments that established the presence of interactions of the catalyst with the reaction components in 1:1 mixtures in C6D6 (Figure 6). The thiourea N–H proton signals experienced relatively small downfield shifts, which were accompanied by their broadening and weakening. This indicates a formation of rather weak H-bonded complexes and a possible participation of chemical exchange processes.53 The appropriate association constants (Ka) were determined by 1H NMR titration experiments in C6D6. The most obvious changes in chemical shifts were observed for the proton signal shown in red in Figures 5–6. The obtained 1H NMR shifts were plotted as a titration isotherm and fitted to a 1:1 binding model using a Python-based global fitting program



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Figure 5. (A) Changes in 1H NMR spectrum of (Ra)-1 upon fourfold dilution from 0.04 M to 0.01 M (700 MHz, 25 °C, CDCl3). (B) Changes in 1H NMR spectrum of (Ra)-1 upon addition of trifluoroacetic acid (400 MHz, 25 °C, C6D6). Bindfit developed by Thordarson and co-workers.54 To verify the expected 1:1 complexation equilibria of host and guest, the titration data were also fitted to another physically acceptable 1:2 host–guest binding model (with respect to the C2-symmetry of the catalyst). In both the abovementioned models, the residual data points were dispersed randomly around the horizontal axis, however, the 1:2 binding model was associated with larger uncertainties and in some cases provided thermodynamically non-sensible negative binding constants. Based on this evidence, the binding stoichiometries in the above cases were best represented by simple 1:1 complexes (please, see pp. S64–S76).54-55 The analysis of the obtained association constants revealed that the binding affinity of the catalyst 1 towards electronrich (18f, 19f) and electron-poor (18d, 19d) reaction components followed a decreasing order of 18f > 18d > 19f > 19d > CH3NO2 (Figure 6). The binding arrangement between (Ra)-1 and other reaction components was further studied by 2D-ROESY experiments in CDCl3.51b,c The adducts (S)-19c and (S)-19f were chosen due to their easily identifiable alkyl groups on 1H NMR spectrum, which were expected to give rise to considerable NOE interactions. This study implied that in CDCl3 at room temperature, the (Z,Z)-conformer of bis(thiourea) 1 is involved in the H-bonded complex between (Ra)-1 and OH groups of the adducts (S)-19c or (S)-19d (please, see pp. S77–S78). Although our primary intent was also to study the spatial arrangement of (Ra)-1 with 18c, 18f and 1-nitropropane, no significant intermolecular NOE interactions were detected in those cases.

Preliminary catalytic cycle proposal. According to the aforementioned mechanistic and spectroscopic experiments and the previously published computational studies on the reaction mechanism,22b,24,56 we have proposed a working hypothesis of the catalytic cycle (Scheme 9). Based on the lack of an NLE, a monomer of the organocatalyst seems to be involved in the catalytic cycle. According to our hypothesis, a large excess of nitromethane prevents the (1) non-productive association of the catalyst, which can explain the abovementioned beneficial effect of the excess on both the conversion rate and the stereoselectivity. The observed kinetic isotope effect supports that the (2) deprotonation of the nitroalkane is a rate-limiting (or a partially ratelimiting) step in the overall reaction that precedes the formation of the ternary complex (nitronate–catalyst–aldehyde). Although the binding constant of the catalyst towards nitromethane (Ka = 12.5 M−1) is lower than the association constants determined for the model aromatic aldehydes (Ka = 68.2 M–1 and 79.8 M–1), we believe that the concentration of nitromethane in the reaction medium being 20 times higher enables the successful competition thereof for the active sites of the catalyst. Additionally, we should also take into account the different binding affinities of the catalyst towards the neutral nitroalkane and its anion – nitronate. The latter species, apparently formed throughout the reaction in small equilibrium concentration only, is likely immediately consumed in the presence of the appropriate electrophile. As shown by Kelly and Hamilton, the negatively charged nitronate is essential for strong association with the hydrogenbonding network, while the charge neutral nitro group does


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Figure 6. Changes in chemical shifts of N–H signals of (Ra)-1 upon addition of different reaction components (400 MHz, C6D6, 1:1 mixtures). Notes: association constants (Ka) with standard errors and binding free energies (∆G0) for 1:1 complexes were determined by 1H NMR titrations (400 MHz, 25 °C, C6D6); Ar = 3,5-(F3C)2C6H3. not show any significant complexation.57 The association of the catalyst–nitronate pre-complex with the aldehyde composes the (3) ternary complex resulting in the (4) 1,2addition step. Next, the catalyst (5) reprotonates the intermediary alkoxide and the product is subsequently (6) liberated from the weak catalyst–nitroladol complex (Ka = 17.3 M–1 and 23.6 M–1).

Summary We have demonstrated that the atropisomeric biphenyl skeleton represents a tunable framework for a design of organocatalysts. The three novel biphenyl-based multifunctional catalysts were introduced, which were screened in the asymmetric Henry addition between several linear nitroal-

kanes and a variety of aldehydes with a special focus on benzaldehyde derivatives. One of the tested catalysts (1) exhibited a promising potential and provided consistently high yields, good to excellent enantioselectivities, and moderate syn-diastereoselectivities of the corresponding nitroaldol adducts. For electron-deficient aromatic and heterocyclic aldehydes, an exceptionally good catalytic performance was reached. The catalyst 1, offering operationally simple isolation of the respective β-nitroalcohols, was applied to the syntheses of enantiopure (S)-econazole and (R)-mirabegron the late-stage intermediate. Preliminary kinetic and spectroscopic experiments conducted in order to shed better light on the mechanistic picture of the above process revealed:



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(1) An unusual temperature effect on ee and dr values of 19q likely caused by a catalyst-mediated reversibility of the reaction at T > Tinv. On the other hand, such behavior was much less pronounced in the temperature profile of 19m, which exhibited a simple temperature effect. (2) The absence of a nonlinear effect suggesting that the active form of 1 is a monomeric species. (3) The well-behaved first order kinetics with respect to the model aldehyde (18d) and the catalyst (1) at 0 °C. (4) The proton abstraction of the nitroalkane as a ratelimiting (or a partially rate-limiting) step in the overall reaction. (5) A tendency of the catalyst 1 for self-association under the synthetically relevant conditions. (6) A complexation ability of the catalyst 1 towards all the reaction components and different binding affinities of 1 towards electron-rich (18f, 19f) and electron-poor (18d, 19d) reaction components, which followed a decreasing order of 18f > 18d > 19f > 19d > CH3NO2. (7) The (Z,Z)-conformer of bis(thiourea) 1 involved in the Hbonded complex between 1 and OH groups of the adducts 19c or 19d. N

N

5

H N

S

S N N H H Ar N N Ar O H H O N O H H R1 R 2 4 N

Ar N H

S N N H H Ar N N Ar O H H HO N O H H R1 R 2 elucidated by 6 2D-ROESY

off-loop species

OH R1

R2 NO 2

1

(R a)-1 NO 2

H N

S

2 S

N H

N

S

N H

N

N Ar O H O N O 3 H H R1 R 2

R2

H N

S

S N H

H N Ar

N H O

N Ar H

N O

R1

O

H R2

Scheme 9. Working hypothesis of the catalytic pathway. Notes: 1 = catalyst self-association, 2 = nitroalkane deprotonation, 3 = formation of the ternary complex, 4 = asymmetric 1,2-addition, 5 = alkoxide protonation, 6 = liberation of the resulting nitroaldol.

Experimental Section Special equipment and operating procedures. Moisture and air-sensitive reactions were done in oven-dried glassware (140 °C) under Ar atmosphere in anhydrous solvents. Small-scale low-temperature experiments were carried out in an aluminum heat-transfer block with a centrally placed stirring rotor and the temperature of the block was controlled by an external thermostat. Preparative separations were performed with a Büchi Sepacore flash system X10 (BÜCHI Labortechnik). Catalytic hydrogenations over Pd/C and Ra– Ni were conducted with a Parr 3910 Shaker Hydrogenation Apparatus (Parr Instrument Co.).

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Solvents and reagents. Purchased from commercial suppliers and used as received, if not stated otherwise. Anhydrous solvents and reagents were absolutized as usual and distilled prior to use. All aldehydes for small-scale experiments were purified in order to be acid-free. Raney nickel (Ra–Ni), hydrocinnamaldehyde (18o), 2,2'-dimethyl-6,6'-dinitro-1,1'-biphenyl (4), racemic adducts 19a–s, 6,6'-dimethyl-1,1'biphenyl-2,2'-diamine (14) and both of its enantiomers were prepared according to the literature.13e,58 Analytical data. The specific rotation was determined by an automatic polarimeter AA-10 (Optical Activity). Melting points were measured by a Böetius apparatus (Franz Küstner Nachf.) and are uncorrected. HPLC data were recorded on a Dionex UltiMate 3000 LC System (Thermo Fisher Scientific) and edited with Chromeleon Dionex software ver. 7.2.0.3765 (Thermo Fisher Scientific). IR spectra were collected on a SmartMIRacle ATR Zn/Se for Nicolet Impact 410 FT-IR (Thermo Scientific) and edited with Omnic software ver. 7.4 (Thermo Scientific). NMR spectra were obtained from a Varian Inova VXR-300 MHz (Agilent Technologies), a JEOL ECZR-400 MHz (Jeol Corp.), a 500 MHz spectrometer Bruker Avance III (Bruker Corp.), a 600 MHz spectrometer Varian Unity Inova VNMRS (Agilent Technologies), a 700 MHz NMR spectrometer Bruker Avance III HD (Bruker Corp.), and an 850 MHz NMR spectrometer Bruker Avance III HD (Bruker Corp.). Experiments were standardly carried out at 25 °C, chemical shifts are reported in δ parts per million (ppm) and J values in Hz, the signal of TMS or the residual solvent signals of CDCl3, C6D6 or DMSO-d6 were used as a reference. Spectra were edited with ACD/NMR processor software ver. 12.01 (Advanced Chemistry Development). HRMS measurements were performed using a LTQ Orbitrap XL high-resolution mass spectrometer (Thermo Fisher Scientific) equipped with a HESI II (Heated electrospray ionization) source operated in full scan with resolution 60 000. Spectra were acquired over a mass range 50–1000 in a positive mode and 65–1000 in a negative mode (m/z). Diffraction data. Collected on a Rigaku Saturn724+ fourcircle CCD X-ray diffractometer at 120 K using monochromated Mo-Kα radiation from MicroMax-007HF DW 1.2 kW rotating anode (Rigaku Corp.). CrystalClear–SM Expert ver. 2.1 b32 software package was used for data collection and data reduction (Rigaku Corp.). The structure was solved and refined (full matrix least-squares refinement on F2) using a SHELXL program.59 All non-hydrogen atoms were refined anisotropically. 6,6'-dinitro-[1,1'-biphenyl]-2,2'-dicarboxylic acid (5):60 The compound 5 was obtained from 2,2'-dimethyl-6,6'dinitro-1,1'-biphenyl (15 g, 55.1 mmol) according to the literature. The crude 5 obtained as pale yellow solid (13 g, yield: 71%) was used directly in the following step. The analytic racemic sample was recrystallized from glacial acetic acid. The related enantiopure samples were obtained by resolution of the corresponding diastereomeric salts of 5 with (R)-(+) and (S)-(–)-1-phenylethylamine in absolute Me2CO as reported in the literature.56b Rac-5: mp 262–263 °C; (Sa)5: mp 230–232 °C; > 99% ee (Astec Chirobiotic R column (5 µm, 100 × 4.6 mm), MeOH–AcOH–Et3N 99.7:0.2:0.1, 5 °C, 0.2 mL/min, λ = 230 nm): tS = 2.81 min; [α]25D: −170.0 (c 1.0, MeOH); (Ra)-5: mp 230–232 °C; > 99% ee; tR = 3.26 min; [α]25D: +170.0 (c 1.0, MeOH); 1H NMR (DMSO-d6, 300


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MHz) δ/ppm: 7.78 (t, JHH = 9.0, 2H), 8.25 (dd, JHH = 7.8, 1.2, 2H), 8.35 (dd, JHH = 9.0, 1.3, 2H), 13.27 (br. s, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 127.2, 129.4, 131.7, 132.4, 134.7, 148.9, 166.0; IR (neat) ṽ/cm−1: 2991br, 1688s, 1603w, 1568m, 1528s, 1456m, 1404w, 1347s, 1263m, 1142m, 1159w, 1108w, 902m, 839m, 775m, 747m, 713s; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C14H7N2O8 331.0202; Found 331.0208. N,N,N',N'-tetramethyl-6,6'-dinitro-[1,1'-biphenyl]-2,2'dicarboxamide (7):61a A suspension of 5 (1.5 g, 4.5 mmol), DMAP (55 mg, 10 mol%) and SOCl2 (3.3 mL, 10 equiv.) was heated to reflux for 2 h under Ar. The excess of SOCl2 was evaporated in vacuo to provide the crude acyl chloride 6. Meanwhile, a suspension of Me2NH·HCl (1.10 g, 3 equiv.) in dry CH2Cl2 (15 mL) was cooled to 0 °C and anhydrous Et3N (3.80 mL, 6 equiv.) was added dropwise. The resulting solution was stirred for further 10 min under Ar. The crude acyl chloride 6 was dissolved in 10 mL of dry CH2Cl2 and added dropwise to the solution of the free base of Me2NH at 0 °C. The reaction mixture was left to rise to rt and to stir overnight under Ar. Then the reaction mixture was washed with 1 M HCl, saturated solution of NaHCO3 and brine. The organic layer was dried with Na2SO4 and evaporated in vacuo to furnish 7 as white solid (1.8 g, yield: 98%). The crude amide was used directly in the following step. The analytic sample was recrystallized from CH2Cl2–nheptane. Rac-7: mp 214–216 °C; (Sa)-7: mp 274–276 °C; [α]25D: −133.0 (c 1.0, CH2Cl2); (Ra)-7: mp 276–278 °C; [α]25D: +134.0 (c 1.0, CH2Cl2); 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 2.74 (d, JHH = 6.0, 12H), 7.70 (t, JHH = 7.5, 2H), 7.78 (dd, JHH = 6.0, 1.4, 2H), 8.27 (dd, JHH = 8.1, 1.3, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 34.4, 38.6, 124.8, 128.9, 129.6, 132.1, 135.5, 149.0, 166.1; IR (neat) ṽ/cm−1: 2980w, 1638s, 1520s, 1458w, 1408w, 1397m, 1348s, 1266m, 1106m, 1060m, 950w, 866m, 825s, 773m, 758m, 749s, 739s, 730m; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C18H17N4O6 385.1148; found 385.1155. 6,6'-diamino-N,N,N',N'-tetramethyl-[1,1'-biphenyl]-2,2'dicarboxamide (8): To a solution of 7 (1.5 g, 3.9 mmol) in MeOH (50 ml), 10% Pd/C (0.5 g) was added and the resulting mixture was shaken vigorously for 3 h under H2 (60 psi). Then the reaction mass was filtered and the filtrate was evaporated in vacuo to afford 8 as white solid (1.2 g, yield: 95%). The crude product was used directly in the next step. The analytic sample was purified by trituration with cold MeOH. Rac-8: mp 270–271 °C; (Sa)-8: mp 92–94 °C; [α]25D −132.0 (c 1.0, CH2Cl2); (Ra)-8: mp 93–95 °C; [α]25D: +132.0 (c 1.0, CH2Cl2); 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 2.77 (d, JHH = 6.0, 12H), 4.38 (s, 4H), 6.48 (dd, JHH = 7.5, 1.0, 2H), 6.74 (dd, JHH = 8.1, 1.0, 2H), 7.06 (t, JHH = 7.5, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 34.1, 38.9, 114.8, 115.3, 119.6, 127.6, 147.6, 169.5, 185.5; IR (neat) ṽ/cm−1: 3674w, 3442w, 3346m, 1621s, 1579m, 1559w, 1505m, 1451m, 1436m, 1405m, 1391m, 1310m, 1301m, 1267m, 1176w, 1061m, 999m, 866w, 803m, 755m, 745m, 728w; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C18H23N4O2 327.1821; Found 327.1814. 6,6'-bis((dimethylamino)methyl)[1,1'-biphenyl]-2,2'diamine (9): To a solution of 8 (1.0 g, 3.1 mmol) in dry MePh (30 mL), 60% solution of SMEAH in MePh (15.0 mL, 46.1 mmol) was added dropwise in order to maintain the reaction temperature below 20 °C. The resulting mixture was

left stirring 48 h at rt under Ar. Then the reaction was quenched by dropwise addition of water, diluted with water and the organic phase was separated. The aqueous phase was basified with 2.5 M NaOH to pH 10 and back-extracted with several portions of fresh MePh. Combined organic extracts were washed with brine, dried with Na2SO4 and evaporated in vacuo to reach 9 as beige solid (0.87 g, yield: 95%). The crude product was used directly in the next step. The analytic sample was recrystallized from EtOAc–n-heptane. Rac-9: mp 73–74 °C; (Sa)-9: 64–66 °C; [α]23D: −125.0 (c 1.0, CH2Cl2); (Ra)-9: mp 65–66 °C; [α]23D: +126.0 (c 1.0, CH2Cl2); 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 2.01 (s, 12H), 2.89 (ABq, ∆νAB = 14.1, JAB = 13.5, 4H), 4.13 (s, 4H), 6.66 (dd, JHH = 7.9, 0.9, 2H), 6.81 (d, JHH = 6.7, 2H), 7.05 (t, JHH = 9.0, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 45.5, 60.6, 112.9, 116.4, 120.3, 127.8, 138.5, 145.3. IR (neat) ṽ/cm−1: 3646w, 3396w, 3290w, 3170w, 2980w, 2930w, 2940w, 2811w, 2755w, 2354w, 1622w, 1616w, 1580w, 1454s, 1439m, 1361m, 1294m, 1262m, 1247w, 1169m, 1150m, 1122w, 1068w, 1043m, 1028m, 983w, 948m, 855s, 768s, 755m; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C18H27N4 299.2236; Found 299.2235. 1,1'-(6,6'-bis((dimethylamino)methyl)-[1,1'-biphenyl]2,2'-diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea) (1): To a solution of 9 (100 mg, 350 µmol) in dry THF (2 mL), 3,5-bistrifluoromethylphenylisothiocyanate (131 µL, 2.05 equiv.) was added dropwise at rt. The reaction mixture was stirred overnight at rt under Ar and then evaporated in vacuo. The resulting glassy residue was triturated with nheptane and sonicated. The white fluffy solid was filtered, washed with fresh n-heptane, and subjected to flash chromatography (SiO2) EtOAc–Et3N, 99:1 to furnish 1 as white solid (250 mg, yield: 89%). Rac-1: mp 149–151 °C; (Sa)-1: mp 91–93 °C; [α]25D: −311.0 (c 0.5; CH2Cl2); (Ra)-1: mp 91– 93 °C; [α]25D: +310.0 (c 0.5; CH2Cl2); 1H NMR (CDCl3, 700 MHz) δ/ppm: 2.22 (s, 12H), 2.99 (d, JHH = 11.6, 2H), 3.15 (d, JHH = 11.9, 2H), 7.36–7.37 (m, 4H), 7.42–7.43 (m, 4H), 7.54 (t, JHH = 7.8, 2H), 8.08 (s, 4H), 11.04 (br. s, 2H); 13 C NMR (CDCl3, 176 MHz) δ/ppm: 44.4, 62.3, 118.1, 122.8 (q, 1JFC = 272.2), 124.0, 126.6, 129.8, 130.7, 131.0 (q, 2JFC = 34.1), 135.5, 136.2, 138.4, 139.4, 178.3; 19F NMR (DMSOd6, 564 MHz) δ/ppm: −61.89 (s); IR (neat) ṽ/cm−1: 3361w, 1623w, 1545m, 1472m, 1382m, 1344w, 1319w, 1270s, 1249m, 1169s, 1125s, 1104m, 1093m, 1019w, 1001w, 987m, 911w, 884s, 846m, 780m, 759w, 729w, 700s; HRMS (ESIOrbitrap) m/z: [M−H]− calcd for C36H31F12N6S2 839.1860; Found 839.1859. 6,6'-dinitro-[1,1'-biphenyl]-2,2'-dicarboxamide (10):62 To a vigorously stirred solution of concentrated aqueous ammonia (30 mL) in dioxane (30 mL), the crude acyl chloride 6 (1.7 g, 4.5 mmol) in anhydrous dioxane (20 mL) was added dropwise at rt. The resulting mixture was left stirring overnight and evaporated in vacuo. The crude product was suspended in distilled water, filtered off and washed sequentially with 1 M HCl, saturated solution of NaHCO3 and distilled water and then dried in vacuo to furnish 10 as white solid (1.4 g, yield: 94%). The crude 10 was used directly in the following step. The analytic sample was recrystallized from MeOH. Rac-10: mp 270–271 °C; (Ra)-10: mp 217–218 °C; [α]25D +250.0 (c 1.0; MeOH); (Sa)-10: mp 216–217 °C; [α]25D –249.0 (c 1.0; MeOH); 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 7.39 (br. s, 2H), 7.72 (t, JHH = 9.0, 2H), 7.84 (dd, JHH = 7.5, 1.2, 2H), 8.00 (br. s, 2H), 8.25 (dd, JHH = 8.1, 1.2,



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2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 125.3, 129.2, 129.3, 132.2, 137.7, 148.2, 168.2; IR (neat) ṽ/cm−1: 3473w, 3258br, 2350w, 1679m, 1646m, 1613m, 1530s, 1462w, 1385w, 1350s, 1283w, 1259w, 1149w, 1098w, 1061w, 1005w, 904w, 823m, 791w, 773w, 747m, 733w; HRMS (ESIOrbitrap) m/z: [M–H]– calcd for C14H9N4O6 329.0522; Found 329.0528. 6,6'-dinitro-[1,1'-biphenyl]-2,2'-diamine (11):63 The compound 11 was obtained from 10 (1.1 g, 3.3 mmol) according to the literature. The crude 11 obtained as orange solid (450 mg, yield: 45%) was used directly in the following step. The analytic sample was recrystallized from MeOH–H2O. Mp 239–240 °C; 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 5.09 (s, 4H), 7.09 (d, JHH = 6.6, 2H), 7.23–7.33 (m, 4H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 111.3, 111.7, 119.6, 129.2, 147.9, 149.6; IR (neat) ṽ/cm−1: 3478w, 3378m, 1621m, 1520s, 1456w, 1346s, 1314s, 999w, 825m, 815m, 801m, 726s, 719m, 708w; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C12H9N4O4 273.0624; Found 273.0632. N,N,N',N'-tetramethyl-6,6'-dinitro-[1,1'-biphenyl]-2,2'diamine (12):61b,64 A solution of 11 (0.4 g, 1.5 mmol) in THF (15 mL) and solid NaBH4 (0.8 g, 21.1 mmol) were simultaneously portionwise added to a mixture of 37% aqueous formaldehyde (1.8 mL, 24.2 mmol), 20% H2SO4 (3 mL) and THF (7.5 mL) at temperature below 20 °C. After 1 h, the reaction mixture was poured into saturated solution of K2CO3 and the resulting suspension was extracted with Et2O. The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated in vacuo to furnish 12 as orange crystalline solid (420 mg, yield: 85%). The crude 12 was used directly in the following step. The analytic sample was recrystallized from MeOH–H2O. Mp 160–162 °C; 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 2.30 (s, 12H), 7.50 (dd, JHH = 7.5, 1.5, 2H), 7.70 (dd, JHH = 7.9, 1.5, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 42.2, 118.6, 123.8, 125.4, 129.7, 149.0, 151.6; IR (neat) ṽ/cm−1: 2950w, 2859w, 2838w, 2787w, 1520s, 1481m, 1464w, 1452w, 1433w, 1357s, 1321m, 1278w, 1230w, 1209w, 1186w, 1159w, 1142m, 1056m, 1002m, 991m, 975m, 901w, 882m, 873s, 810s, 772m, 755m, 728s, 717s; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C16H19N4O4 331.1406; Found 331.1401. N,N,N',N'-tetramethyl-[1,1'-biphenyl]-2,2',6,6'-tetraamine (13):64 A solution of 12 (0.4 g, 1.2 mmol) in MeOH (30 mL) was hydrogenated over 10% Pd/C (0.2 g) and treated analogously to compound 8. The crude oily product was triturated with a small amount of n-heptane and sonicated. The resulting suspension was evaporated to dryness in vacuo to provide 13 as red-brown solid (260 mg, yield: 80%), which was used directly in the next step. Mp 109–110 °C; 1H NMR (DMSO-d6, 300 MHz) δ/ppm: 2.41 (s, 12H), 4.25 (br. s, 4H), 6.36 (d, JHH = 8.1, 2H), 6.41 (d, JHH = 6.0, 2H), 6.96 (t, JHH = 9.0, 2H); 13C NMR (DMSO-d6, 75 MHz) δ/ppm: 43.2, 107.7, 108.9, 115.6, 128.0, 146.4, 153.0; IR (neat) ṽ/cm−1: 3453m, 3344m, 2935w, 2817w, 2773m, 1620m, 1604m, 1570s, 1457s, 1424m, 1326w, 1285m, 1220w, 1183m, 1142m, 1111w, 1090w, 1064w, 1045m, 999s, 955w, 890w, 792s, 749s, 734s; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C16H23N4 271.1923; Found 271.1924. 1,1'-(6,6'-bis(dimethylamino)-[1,1'-biphenyl]-2,2'diyl)bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea) (2): To a solution of 13 (100 mg, 370 µmol) in dry THF (2 mL), 3,5-bistrifluoromethylphenylisothiocyanate (138 µL, 2.05

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equiv.) was added dropwise at rt under Ar. The reaction course was stirred for 2 h at the same temperature and then evaporated in vacuo. The resulting glassy residue was triturated with n-heptane and sonicated. The white fluffy solid was filtered, washed with fresh n-heptane, and subjected to flash chromatography (SiO2) n-heptane–EtOAc, 75:25 to furnish 2 as white solid (260 mg, yield: 86%). Rac-2: mp 178–180 °C; (Ra)-2: [α]25D +306.0 (c 0.5; CH2Cl2); mp 151– 153 °C; (Sa)-2: mp 151–153 °C; [α]25D –305.0 (c 0.5; CH2Cl2); 1H NMR (CDCl3, 700 MHz) δ/ppm: 2.67 (s, 12H), 7.11 (d, JHH = 7.7, 2H), 7.19 (d, JHH = 7.7, 2H), 7.42 (s, 2H), 7.52–7.54 (m, 4H), 7.87 (s, 4H), 9.25 (br. s, 2H); 13C NMR (CDCl3, 176 MHz) δ/ppm: 42.9, 118.4, 118.8, 120.9, 122.7 (q, 1JFC = 272.2), 122.9, 126.4, 130.9, 131.6 (q, 2JCF = 34.1), 135.4, 139.3, 151.6, 179.2; 19F NMR (DMSO-d6, 564 MHz) δ/ppm: –61.89 (s); IR (neat) ṽ/cm−1: 2958w, 2836w, 1592w, 1531w, 1454w, 1434w, 1384m, 1351w, 1308w, 1275s, 1182m, 1133m, 1115m, 1104w, 1042w, 1001w, 984m, 963w, 902w, 888m, 848w, 830w, 807w, 701w, 755w, 721m, 704m; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C34H29F12N6S2 813.1703; Found 813.1719. N-(2'-amino-6,6'-dimethyl-[1,1'-biphenyl]-2-yl)acetamide (15):65 Ac2O (1.1 mmol, 104 µL) was added dropwise to a solution of 6,6'-dimethyl-1,1'-biphenyl-2,2'-diamine (1.0 mmol, 212 mg) in AcOH (600 µL) and anhydrous CH2Cl2 (10 mL) at 0 °C under Ar. The resulting solution was left to rise to rt gradually and to stir overnight. Then the reaction mixture was extracted with CH2Cl2, washed with saturated solution of NaHCO3, brine, dried with Na2SO4 and evaporated in vacuo. The crude mixture was subjected to flash chromatography (SiO2) n-heptane–EtOAc, 75:25 to furnish 15 as colorless oil (180 mg, yield: 71%). 1H NMR (DMSOd6, 400 MHz) δ/ppm: 1.77 (s, 3H), 1.81 (s, 3H), 1.91 (s, 3H), 4.18 (br. s, 2H), 6.57 (d, JHH = 7.3, 1H), 6.64 (d, JHH = 7.8, 1H), 7.00 (t, JHH = 7.8, 1H), 7.14 (d, JHH = 7.3, 1H), 7.25 (t, JHH = 7.8, 1H), 7.62 (d, JHH = 7.3, 1H), 8.11 (br. s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 19.3, 19.6, 23.5, 112.6, 118.4, 120.8, 122.1, 126.7, 127.4, 128.1, 130.7, 136.2, 137.2, 145.4, 168.5; IR (neat) ṽ/cm−1: 3868w, 3463w, 3337w, 2917w, 1928w, 1682s, 1605m, 1579m, 1516s, 1462s, 1411m, 1365m, 1296m, 1245w, 1228w, 1165w, 1078w, 1037w, 1002m, 971w, 945w, 780s, 741m; HRMS (ESI-Orbitrap) m/z: [M−H]– calcd for C16H17N2O 253.1341; Found 253.1347. N-(2'-(dimethylamino)-6,6'-dimethyl-[1,1'-biphenyl]-2yl)acetamide (16): A solution of 15 (710 µmol, 180 mg) in THF (10 mL) and 37% aqueous formaldehyde (10.1 mmol, 750 µL) was stirred at rt for 15 min. Then NaBH3CN (3.2 mmol, 200 mg) was added at once the reaction mass was stirred for additional 15 min. After this period, AcOH (1 mL) was added dropwise and the resulting mixture was left to stir at rt for 1 h. Then the reaction mixture was poured into saturated solution of NaHCO3 and extracted with Et2O. The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated in vacuo. The crude product was subjected to flash chromatography (SiO2) n-heptane– EtOAc, 75:25 to provide 16 as yellowish oil (180 mg, yield: 90%). 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 1.81 (s, 3H), 1.83 (s, 3H), 1.88 (s, 3H), 2.41 (s, 6H), 6.97 (t, JHH = 8.0, 2H), 7.07 (d, JHH = 7.3, 1H), 7.23 (dt, JHH = 15.7, 7.9, 2H), 7.72 (d, JHH = 6.4, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 19.7, 23.7, 43.3, 47.6, 116.2, 120.9, 123.9, 125.9, 126.9, 128.4, 129.4, 131.4, 135.7, 136.4, 137.3, 151.9,


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168.0; IR (neat) ṽ/cm−1: 3628w, 3399w, 2943w, 2828w, 2777w, 1694s, 1604m, 1575m, 1517s, 1456s, 1407w, 1366m, 1297m, 1242m, 1228m, 1197w, 1183w, 1165w, 1096w, 1041m, 967m, 886w, 864w, 782s, 758m, 739m; HRMS (ESIOrbitrap) m/z: [M+H]+ calcd for C18H23N2O 283.1810; Found 283.1804. N,N,6,6'-tetramethyl-[1,1'-biphenyl]-2,2'-diamine (17): A mixture of 16 (640 µmol, 180 mg), 96% EtOH (15 mL) and 4 M HCl (6 mL) was refluxed for 5 h. Then the solution was basified to pH 10 with 5 M NaOH and EtOH was evaporated in vacuo. The aqueous phase was extracted with CH2Cl2, washed with brine, dried with Na2SO4 and evaporated in vacuo. The crude product was subjected to flash chromatography (SiO2) n-heptane–EtOAc, 75:25 to provide 16 as yellowish oil, which solidifies upon standing (140 mg, yield: 91%). Mp 69–70°C; 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 1.76 (s, 3H), 1.87 (s, 3H), 2.46 (s, 6H), 4.22 (br. s, 2H), 6.52 (d, JHH = 7.3, 1H), 6.59 (d, JHH = 7.8, 1H), 6.91–6.94 (m, 3H), 7.18 (t, JHH = 7.8, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 19.4, 19.8, 43.4, 112.3, 116.0, 118.4, 123.7, 124.5, 127.2, 127.8, 130.7, 135.7, 137.3, 144.9, 152.5; IR (neat) ṽ/cm−1: 3730w, 3436m, 3352m, 3053w, 2954w, 2916w, 2857w, 2823w, 2771w, 1921w, 1608s, 1574s, 1464s, 1455s, 1372w, 1308s, 1293s, 1197m, 1180m, 1168m, 1149m, 1016s, 1002m, 965m, 864w, 793s, 775s, 753s, 737s; HRMS (ESIOrbitrap) m/z: [M+H]+ calcd for C16H21N2 241.1705; Found 241.1697. 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2'-(dimethylamino)6,6'-dimethyl-[1,1'-biphenyl]-2-yl)thiourea (3): A solution of 17 (140 mg, 582 µmol) in dry THF (2 mL), was treated with 3,5-bistrifluoromethylphenylisothiocyanate (112 µL, 1.05 equiv.) analogously to compound 1. The crude yellowish fluffy solid was subjected to flash chromatography (SiO2) n-heptane–EtOAc to furnish 3 as white solid (260 mg, yield: 86%). Rac-3: mp 133–134 °C; (Ra)-3: mp 51–52 °C; [α]20D +80.0 (c 0.5; DCM); (Sa)-3: 50–52 °C; [α]20D –80.0 (c 0.5; DCM); 1H NMR (CDCl3, 700 MHz) δ/ppm: 1.95 (s, 3H), 2.16 (s, 3H), 2.43 (s, 6H), 6.98 (d, JHH = 7.5, 2H), 7.27 (t, JHH = 7.8, 1H), 7.33–7.34 (m, 1H), 7.39–7.41 (m, 2H), 7.65 (s, 1H), 7.80 (br. s, 1H), 7.85 (s, 2H), 8.15 (br. s, 1H); 13C NMR (CDCl3, 176 MHz) δ/ppm: 19.9, 20.0, 43.9, 116.5, 118.9 (q, 3JCF = 3.2), 122.9 (q, 1JCF = 271.1), 123.9 (q, 3JCF = 3.2), 124.1, 125.3, 128.3, 129.0, 129.9, 130.2, 132.1 (q, 2JCF = 35.3), 134.5, 136.3, 137.3, 139.5, 139.8, 151.3, 179.7; 19F NMR (CDCl3, 800 MHz) δ/ppm: –62.97 (s); IR (neat) ṽ/cm−1: 3738w, 3178w, 2358w, 1539w, 1506w, 1457w, 1377m, 1276s, 1174m, 1160m, 1134s, 1107w, 1018w, 1042w, 903w, 892w, 798w, 791m, 750m, 762w, 736w, 703m; HRMS (ESI) m/z: [M–H]– calcd for C25H22F6N3S 510.1439; Found 510.1449. General procedure for synthesis of enantio- and diastereoenriched nitroaldols 19a–s (GP): A solution of (Ra)-1 or (Sa)-1 (8.4 mg, 10 µmol) and an appropriate aldehyde 18a–p (100 µmol) in dry Et2O (100 µL) was treated dropwise at −20 °C (or −30 °C) with the corresponding nitroalkane (2 mmol). After the complete addition, the reaction mixture was left under stirring at the above temperature for 24–168 h under Ar. When TLC revealed full consumption of the starting material, the reaction was quenched by saturated solution of NH4Cl (or brine) and the mixture was extracted with several portions of EtOAc. Combined organic extracts were dried with Na2SO4 and passed through a Pasteur pipette col-

umn (SiO2) EtOAc, 100%. The eluate was evaporated in vacuo and the residue was dissolved in the mobile phase (1 mL) and directly subjected to HPLC analysis (Hypersil silica precolumn (3 µm, 100 × 4.6 mm) connected via a blue PEEK capillary (L 200 mm, ID 0.01”, OD 1/16”) to the Phenomenex Lux Cellulose-1 column (3 µm, 250 × 4.6 mm)). 2-nitro-1-phenylethanol (19a):66 According to GP, the adduct (S)-19a was prepared with (Ra)-1 and after 84 h at −20 °C obtained as colorless oil (15.9 mg, HPLC conv.: > 99%, yield: 95%). [α]25D: +26.3 (c 0.8; CH2Cl2); 75% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 26.44 min (minor R), tS = 32.05 min (major S). The adduct (R)-19a was prepared with (Sa)-1 analogously (16.0 mg, HPLC conv.: > 99%, yield: 96%). [α]25D: −26.5 (c 0.8; CH2Cl2); 75% ee; tR = 26.78 min (major R), tS = 33.01 min (minor S); analytical data were identical to those reported in the literature.25 2-nitro-1-(pyridin-3-yl)ethan-1-ol (19b):23a According to GP, the adduct (S)-19b was prepared with (Ra)-1 and after 48 h at −20 °C obtained as yellowish oil (15.3 mg, HPLC conv.: 96%, yield: 91%). [α]25D: +31.0 (c 0.8; CH2Cl2); 93% ee (i-PrOH–n-heptane, 25:75, 0.6 mL/min, 5 °C, λ = 205 nm): tR = 26.44 min (minor R), tS = 32.05 min (major S); analytical data were identical to those reported in the literature.25 tert-butyl 2-(1-hydroxy-2-nitroethyl)-1H-pyrrole-1carboxylate (19c):22a According to GP, the adduct (S)-19c was prepared with (Ra)-1 and after 48 h at −20 °C obtained as yellow oil (24.8 mg, HPLC conv.: 99%, yield: 97%). [α]25D: +6.0 (c 1.2; CH2Cl2); 96% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 14.57 min (minor R), tS = 15.92 min (major S); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 1.57 (s, 9H), 4.46 (dd, JHH = 12.3, 9.6, 1H), 4.92 (dd, JHH = 12.6, 3.0, 1H), 5.77 (ddd, JHH = 9.3, 5.6, 3.0, 1H), 5.98 (d, JHH = 5.5, 1H), 6.19 (t, JHH = 3.4, 1H); 6.37– 6.39 (m, 1H), 7.29 (dd, JHH = 3.2, 1.8, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 27.5, 64.3, 80.8, 84.6, 110.5, 112.5, 122.0, 133.8, 148.6; IR (neat) ṽ/cm−1: 3434br, 2979w, 2924w, 1732s, 1553s, 1478w, 1459w, 1417w, 1396w, 1372m, 1332s, 1249w, 1161w, 1126s, 1083w, 1060w, 1009w, 885w, 844m, 773w, 729m; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C11H15N2O5 255.0981; Found 255.0992. 2-nitro-1-(2-nitrophenyl)ethanol (19d):66 According to GP, the adduct (S)-19d was prepared with (Ra)-1 and after 36 h at −30 °C obtained as yellow oil (20.6 mg, HPLC conv.: > 99%, yield: 97%). [α]25D: –159.0 (c 1.0; CH2Cl2); 96% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 27.27 min (minor R), tS = 30.38 min (major S); analytical data were identical to those reported in the literature.25 1-(2-chlorophenyl)-2-nitroethanol (19e):66 According to GP, the adduct (S)-19e was prepared with (Ra)-1 and after 36 h at −30 °C obtained as colorless oil (19.6 mg, HPLC conv.: > 99%, yield: 97%). [α]25D: +43.0 (c 1.0; CH2Cl2); 96% ee (i-PrOH–n-heptane, 5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 53.11 min (minor R), tS = 56.52 min (major S); analytical data were identical to those reported in the literature.25 2-nitro-1-(o-tolyl)ethan-1-ol (19f):66 According to GP, the adduct (S)-19d was prepared with (Ra)-1 and after 84 h at −20 °C obtained as yellowish oil (17.3 mg, HPLC conv.: > 99%, yield: 96%). [α]25D: +33.1 (c 0.9; CH2Cl2); 76% ee



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(i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 24.21 min (minor R), tS = 39.13 min (major S); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 2.36 (s, 3H), 4.47 (dd, JHH = 12.8, 10.1, 1H), 4.81 (ddd, JHH = 12.6, 3.0, 1.4, 1H), 5.45– 5.48 (m, 1H), 5.99 (d, JHH = 4.6, 1H), 7.17–7.26 (m, 3H), 7.50 (d, JHH = 7.8, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 18.4, 67.1, 81.1, 126.1, 126.2, 127.8, 130.3, 134.4, 138.5; IR (neat) ṽ/cm−1: 3440br, 2919w, 1548s, 1487w, 1461w, 1417w, 1376m, 1282w, 1180w, 1120w, 1067m, 893w, 761m, 728m, 701w; HRMS (ESI-Orbitrap) m/z: [M−H]– calcd for C9H10NO3 180.0661; Found 180.0669. 1-(2,4-dichlorophenyl)-2-nitroethan-1-ol (19g):34 According to GP, the adduct (S)-19g was prepared with (Ra)-1 and after 60 h at −30 °C obtained as colorless waxy solid (23.1 mg, HPLC conv.: > 99%, yield: 98%). [α]25D: +36.7 (c 1.2; CH2Cl2); 96% ee (i-PrOH–n-heptane, 5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 26.44 min (minor R), tS = 32.05 min (major S); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 4.51 (dd, JHH = 12.8, 9.6, 1H), 4.82 (ddd, JHH = 12.8, 2.6, 1.0, 1H), 5.56 (ddd, JHH = 9.6, 5.0, 3.2, 1H), 6.41 (dd, JHH = 5.0, 0.9, 1H), 7.50 (dd, JHH = 8.5, 2.1, 1H), 7.64–7.67 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 66.8, 80.1, 127.8, 128.7, 129.8, 131.8, 133.4, 136.8; IR (neat) ṽ/cm−1: 3494br, 3056w, 1588w, 1547s, 1471w, 1418m, 1378m, 1327m, 1298w, 1214m, 1148w, 1084w, 1046m, 921w, 874m, 859w, 810m, 786s, 717w; HRMS (ESI-Orbitrap) m/z: [M−H]– calcd for C8H6Cl2NO3 233.9725, Found 233.9735. 2-nitro-1-(3-nitrophenyl)ethan-1-ol (19h):66b According to GP, the adduct (S)-19h was prepared with (Ra)-1 and after 36 h at −30 °C obtained as yellow oil (20.6 mg, HPLC conv.: > 99%, yield: 97%). [α]25D: +22.0 (c 1.0; CH2Cl2); 93% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 40.84 min (minor R), tS = 46.18 min (major S); analytical data were identical to those reported in the literature.25 1-(3-fluorophenyl)-2-nitroethanol (19i):66b According to GP, the adduct (S)-19i was prepared with (Ra)-1 and after 60 h at −30 °C obtained as colorless oil (17.8 mg, HPLC conv.: > 99%, yield: 96%). [α]25D: +31.1 (c 0.9; CH2Cl2); 90% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 23.23 min (minor R), tS = 27.10 min (major S); analytical data were identical to those reported in the literature.25 2-nitro-1-(3-(trifluoromethoxy)phenyl)ethan-1-ol (19j): According to GP, the adduct (S)-19j was prepared with (Ra)1 and after 72 h at −20 °C obtained as colorless oil (23.9 mg, HPLC conv.: > 99%, yield: 96%). [α]25D: +22.0 (c 1.2; CH2Cl2); 86% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 17.55 min (minor R), tS = 19.13 min (major S); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 4.61 (dd, JHH = 12.6, 9.8, 1H), 4.92 (dd, JHH = 12.3, 3.2, 1H), 5.33– 5.37 (m, 1H), 6.30 (d, JHH = 5.0, 1H), 7.31 (d, JHH = 7.3, 1H), 7.46–7.54 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 69.1, 81.5, 118.8, 120.1 (q, 1JCF = 256.1), 120.4, 125.4, 130.4, 143.4, 148.5; 19F NMR (DMSO-d6, 376 MHz) δ/ppm: –56.60 (s); IR (neat) ṽ/cm−1: 3454br, 1592w, 1553s, 1490w, 1450w, 1421w, 1378w, 1251s, 1208s, 1154s, 1072m, 1003w, 893w, 789w, 699m; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C9H7F3NO4 250.0327; Found 250.0332. 1-(4-chlorophenyl-2-nitroethan-1-ol (19k):66 According to GP, the adduct (S)-19k was prepared with (Ra)-1 and after 60 h at −30 °C obtained as yellowish oil (18.9 mg, HPLC conv.: > 99%, yield: 94%). [α]25D: +29.0 (c 1.0; CH2Cl2);

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87% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 23.71 min (minor R), tS = 29.94 min (major S); analytical data were identical to those reported in the literature.25 1-(4-bromophenyl)-2-nitroethan-1-ol (19l):66b According to GP, the adduct (S)-19l was prepared with (Ra)-1 at −30 °C within 60 h. The crude product was purified by column chromatography in a Pasteur pipette (SiO2) n-heptane– EtOAc, 90:10 and obtained as colorless waxy solid (21.4 mg, HPLC conv.: 92%, yield: 87%). [α]25D: +29.0 (c 1.0; CH2Cl2); 88% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 26.74 min (minor R), tS = 35.52 min (major S); analytical data were identical to those reported in the literature.25 2-nitro-1-(4-nitrophenyl)ethanol (19m):66 According to GP, the adduct (S)-19m was prepared with (Ra)-1 and after 36 h at −30 °C obtained as orange oil (20.1 mg, HPLC conv.: > 99%, yield: 95%). [α]25D: +37.8 (c 0.8; CH2Cl2); 92% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 40.54 min (minor R), tS = 50.24 min (major S); analytical data were identical to those reported in the literature.25 2-nitro-1-(4-(trifluoromethyl)phenyl)ethan-1-ol (19n):67 According to GP, the adduct (S)-19n was prepared with (Ra)1 and after 60 h at −30 °C obtained as colorless oil (22.3 mg, HPLC conv.: > 99%, yield: 95%). [α]25D: +28.0 (c 1.1; CH2Cl2); 85% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 19.89 min (minor R), tS = 25.02 min (major S); analytical data were identical to those reported in the literature.25 1-nitro-4-phenylbutan-2-ol (19o):66a According to GP, the adduct (S)-19o was prepared with (Ra)-1 and after 24 h at −20 °C obtained as colorless oil (18.9 mg, HPLC conv.: > 99%, yield: 97%). [α]25D: –4.1 (c 1.0; CH2Cl2); 43% ee (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 205 nm): tS = 45.63 min (major S), tR = 48.34 min (minor R); analytical data were identical to those reported in the literature.25 4-methyl-1-nitropentan-2-ol (19p):66 According to GP, the adduct (S)-19p was prepared with (Ra)-1 and after 48 h at −20 °C obtained as colorless oil (14.1 mg, HPLC conv.: > 99%, yield: 96%). [α]25D: –2.9 (c 0.7; CH2Cl2); 33% ee (i-PrOH–n-heptane, 5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tR = 32.26 min (minor R), tS = 34.39 min (major S). 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 0.88 (t, JHH = 6.6, 6H), 1.16 (ddd, JHH = 13.4, 9.0, 4.1, 1H), 1.33 (ddd, JHH = 13.4, 9.4, 4.4, 1H), 1.69–1.79 (m, 1H), 4.10–4.18 (m, 1H), 4.30 (dd, JHH = 12.1, 9.4, 1H), 4.64 (dd, JHH = 11.9, 3.2, 1H), 5.28 (d, J = 6.9, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 21.6, 23.3, 23.7, 42.6, 66.4, 82.0; IR (neat) ṽ/cm−1: 3411br, 2907m, 2871w, 1548s, 1469w, 1418w, 1383m, 1368m, 1292w, 1203w, 1144w, 1088w, 1041w, 919w, 886w, 847w, 820w, 734w; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C6H12NO3 146.0817; Found 146.0826. 1-(2-chlorophenyl)-2-nitropropan-1-ol (19q):68 According to GP, the adduct (S)-19q was prepared using (Ra)-1 within 168 h at −20 °C. The crude product was purified by column chromatography in a Pasteur pipette (SiO2) n-heptane– EtOAc, 90:10 and obtained as colorless oil (19.8 mg, HPLC conv.: 96%, yield: 92%). [α]25D: +22.7 (c 1.1; CH2Cl2); 92:23% ee (1S,2S)/(1R,2S); dr 71:29 (syn/anti) determined by chiral HPLC from the crude product (i-PrOH–n-heptane, 5:95, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 28.47 min (major diastereomer 1R,2S), tSR = 34.51 min (minor diastereomer


Page 15 of 20

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1S,2R), tRR = 45.63 min (minor diastereomer 1R,2R), tSS = 49.04 min (major diastereomer 1S,2S); dr 62:38 (syn/anti) determined by 1H NMR from the purified product; 1H NMR (500 MHz, CDCl3) δ/ppm: 1.45–1.47 (m, 4.86H) (syn+anti), 2.81 (d, JHH = 5.0, 1.00H) (syn), 2.88 (d, JHH = 3.8, 0.62H) (anti), 4.85–4.92 (m, 1.62H) (syn+anti), 5.61 (dd, JHH = 8.1, 4.9, 1.00H) (syn), 5.85 (t, JHH = 2.7, 0.62H) (anti), 7.28–7.42 (m, 4.86H) (syn+anti), 7.49 (dd, JHH = 7.6, 1.8, 1.00H) (syn), 7.63 (dd, JHH = 7.6, 1.5, 0.62H) (anti); 13C NMR (126 MHz, CDCl3) δ/ppm: 11.2 (anti), 16.0 (syn), 70.5 (anti), 71.9 (syn), 84.0 (anti), 88.0 (syn), 127.3 (anti), 127.7 (syn), 128.1 (anti), 128.2 (syn), 129.62 (syn), 129.65 (anti), 129.9 (syn), 130.1 (syn), 131.5 (anti), 132.8 (syn), 135.8 (anti), 136.1 (syn); IR (neat) ṽ/cm−1: 3473br, 3086w, 2992w, 2973w, 2962w, 1680w, 1594w, 1547s, 1475w, 1440w, 1388m, 1360m, 1193w, 1139w, 1099w, 1046m, 990m, 871w, 757s, 732m, 703m; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C9H9ClNO3 214.0271, Found 214.0280. 1-(3-fluorophenyl)-2-nitropropan-1-ol (19r):68 According to GP, the adduct (S)-19r was prepared using (Ra)-1 within 168 h at −20 °C. The crude product was purified by column chromatography in a Pasteur pipette (SiO2) n-heptane– EtOAc, 90:10 and obtained as colorless oil (18.7 mg, HPLC conv.: 97%, yield: 94%). [α]25D: +20.0 (c 1.0; CH2Cl2); 86:28% ee (1S,2S)/(1S,2R); dr 58:42 (syn/anti) determined by chiral HPLC from the crude product (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 16.39 min (minor diastereomer 1R,2S), tSR = 20.35 min (major diastereomer 1S,2R), tRR = 17.59 min (minor diastereomer 1R,2R), tSS = 21.09 min (major diastereomer 1S,2S); dr 63:37 (syn/anti) determined by 1H NMR from the purified product; 1 H NMR (500 MHz, CDCl3) δ/ppm: 1.36 (d, JHH = 6.9, 3.00H) (syn), 1.50 (d, JHH = 6.9, 1.77H) (anti), 2.74 (br. s, 1.00H) (syn), 2.82 (d, JHH = 2.4, 0.59H) (anti), 4.66–4.70 (m, 0.59H) (anti), 4.71–4.77 (m, 1.00H) (syn), 5.05 (d, JHH = 8.7, 1.00H) (syn), 5.43 (br. s, 0.59H) (anti), 7.01–7.17 (m, 4.77H) (syn+anti), 7.34–7.41 (m, 1.59H) (syn+anti); 13C NMR (126 MHz, CDCl3) δ/ppm: 11.9 (anti), 16.4 (syn), 73.1 (d, 4JCF = 1.8) (anti), 75.6 (d, 4JCF = 1.8) (syn), 87.2 (anti), 88.1 (syn), 113.2 (d, 2JCF = 22.5) (anti), 113.9 (d, 2JCF = 22.5) (syn), 115.4 (d, 2JCF = 21.8) (anti), 116.2 (d, 2JCF = 21.8) (syn), 121.5 (d, 4JCF = 2.7) (anti), 122.6 (d, 4JCF = 2.7) (syn), 130.4 (d, 3JCF = 8.2) (anti), 130.6 (d, 3JCF = 8.2) (syn), 140.8 (d, 3 JCF = 6.4) (syn), 141.0 (d, 3JCF = 6.4) (anti), 163.0 (d, 1JCF = 247.9) (syn+anti); 19F NMR (471 MHz, CDCl3) δ/ppm: −111.77 (s, 0.78F) (anti), –111.43 (s, 1.00F) (syn); IR (neat) ṽ/cm−1: 3471br, 3005w, 2874w, 1615w, 1591m, 1545s, 1488m, 1449m, 1389m, 1360m, 1237m, 1140m, 1050m, 1026w, 993w, 875m, 786m, 700m; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C9H9FNO3 198.0566; Found 198.0574. 1-(4-bromophenyl)-2-nitrobutan-1-ol (19s):69 According to GP, the adduct (S)-19r was prepared using (Ra)-1 within 168 h at −20 °C. The crude product was purified by column chromatography in a Pasteur pipette (SiO2) n-heptane– EtOAc, 90:10 and obtained as milky oil (24.4 mg, HPLC conv.: 95%, yield: 89%). [α]25D: +14.3 (c 1.3; CH2Cl2); 90:37% ee (1S,2S)/(1S,2R); dr 82:18 (syn/anti) determined by chiral HPLC from the crude product (i-PrOH–n-heptane, 20:80, 0.5 mL/min, 5 °C, λ = 230 nm): tRS = 15.65 min (minor diastereomer 1R,2S), tSR = 17.13 min (major diastereomer 1S,2R), tRR = 18.86 min (minor diastereomer 1R,2R), tSS = 20.37 min (major diastereomer 1S,2S); dr 69:31

(syn/anti) determined by 1H NMR from the purified product; H NMR (500 MHz, CDCl3) δ/ppm: 0.89 (t, JHH = 7.3, 3.00H) (syn), 0.94 (t, JHH = 7.5, 1.32H) (anti), 1.45 (dqd, JHH = 14.7, 7.4, 3.6, 1.00H) (syn), 1.81–1.92 (m, 1.44H) (syn+anti); 2.10–2.21 (m, 0.44H) (anti), 2.57 (d, JHH = 4.4, 1.00H) (syn), 2.75 (d, JHH = 3.1, 0.44H) (anti), 4.51–4.59 (m, 1.44H) (syn+anti), 5.02 (dd, JHH = 8.7, 4.3, 1.00H) (syn), 5.16 (dd, JHH = 4.3, 3.1, 0.44H) (anti), 7.24–7.26 (m, 2.88H) (syn+anti), 7.50–7.52 (m, 0.88H) (anti), 7.53–7.56 (m, 2.00H) (syn); 13C NMR (126 MHz, CDCl3) δ/ppm: 10.0 (syn), 10.3 (anti), 21.3 (anti), 23.9 (syn), 73.6 (anti), 74.8 (syn), 94.4 (anti), 94.9 (syn), 122.8 (anti), 123.2 (syn), 127.9 (anti), 128.5 (syn), 131.9 (anti), 132.2 (syn), 137.5 (anti), 137.6 (syn); IR (neat) ṽ/cm−1: 3487br, 2974w, 1909w, 1593w, 1545s, 1486w, 1457w, 1372w, 1298w, 1096w, 1070m, 1010m, 927w, 891w, 824m, 803m, 721w; HRMS (ESI-Orbitrap) m/z: [M–H]– calcd for C10H11BrNO3 271.9922; Found 271.9936. 2-amino-1-(2,4-dichlorophenyl)ethan-1-ol (20):34 To a solution of (S)-19g (170 mg, 720 µmol) in MeOH (15 mL), the freshly prepared Ra–Ni catalyst (200 mg) was added and the resulting reaction mixture was shaken vigorously for 10 h under H2 (60 psi). Then the reaction mass was filtered and the filtrate was evaporated in vacuo. The crude waxy product was dissolved in a small amount of MePh, filtered and treated with excess of a saturated ethereal HCl solution. The resulting suspension was left undisturbed overnight in a refrigerator. The precipitate was filtered off, washed several times with anhydrous Et2O and dried in vacuo to furnish (S)20·HCl salt as white solid (150 mg, yield: 86%). Mp 186– 188 °C; 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 2.70–2.77 (m, 1H), 2.97–3.00 (m, 1H), 5.15 (dd, JHH = 9.4, 2.5, 1H), 6.42 (br. s, 1H), 7.49 (dd, JHH = 8.5, 2.1, 1H), 7.60–7.65 (m, 2H), 8.32 (br. s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 43.8, 65.8, 127.7, 128.6, 129.5, 131.7, 133.1, 138.3; IR (neat) ṽ/cm−1: 3332br, 2974br, 2895br, 1591m, 1562m, 1505s, 1474m, 1453w, 1381w, 1299w, 1202w, 1187m, 1118w, 1100s, 1043s, 1052s, 1001s, 995w, 868s, 833s, 825s, 759m; HRMS (ESI-Orbitrap) m/z: [M−HCl+H]+ calcd for C8H10Cl2NO 206.0139; Found 206.0136. The free base of (S)-20·HCl was released with 2.5 M NaOH and extracted with CH2Cl2. Organic phase was washed with brine, dried with Na2SO4, and evaporated in vacuo to afford (S)-20 as yellow waxy solid (100 mg, overall yield: 67%). [α]25D: +73.8 (c 0.5; CHCl3). 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol (21):34 A solution of (S)-20 (100 mg, 485 µmol), 40% aqueous glyoxal (111 µL, 97 µmol), 35% aqueous formaldehyde (76 µL, 97 µmol), and NH4OAc (75 mg, 97 µmol) in methanol (1 mL) was stirred overnight at 80 °C in the pressure vial under Ar. After cooling to rt, MeOH was evaporated in vacuo and the oily residue was treated with 2 M NaOH and extracted with CH2Cl2. Organic extract was washed with brine, dried with Na2SO4, filtered and evaporated in vacuo. The crude oily product purified by flash column chromatography (SiO2) EtOAc, 100% afforded (S)-21 as yellow oil, which solidifies upon standing (95 mg, yield: 76%). [α]25D: +82.8 (c 0.5; CHCl3); 1H NMR (CDCl3, 400 MHz) δ/ppm: 3.85 (dd, JHH = 14.2, 8.2, 1H), 4.20 (dd, JHH = 14.2, 2.7, 1H), 5.23 (JHH = 8.2, 2.3, 1H), 6.82 (s, 1H), 6.89 (s, 1H), 7.29 (dd, JHH = 8.2, 2.3, 1H), 7.37 (br. s, 1H), 7.39 (d, JHH = 2.3, 1H), 7.58 (d, JHH = 8.2, 1H); 13C NMR (CDCl3, 100 MHz) δ/ppm: 53.4, 69.6, 119.7, 127.7, 128.3, 128.6, 129.0, 131.9, 134.1, 1



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137.3, 137.4; IR (neat) ṽ/cm−1: 3742w, 3648w, 3108w, 2960w, 2922w, 2851w, 1732w, 1652w, 1587w, 1559w, 1512m, 1464m, 1432w, 1378w, 1334w, 1282w, 1259m, 1234m, 1207w, 1181w, 1104m, 1088m, 1079s, 1047m, 1022s, 956w, 922s, 868s, 826s, 787s, 751m, 734m; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C11H11Cl2N2O 257.0248; Found 257.0245. 1-(2-((4-chlorobenzyl)oxy)-2-(2,4-dichlorophenyl)ethyl)1H-imidazole (22):34,70 To a solution of (S)-21 (95 mg, 365 µmol) in THF/DMF (2.5 mL, 10:1 v/v), NaH (60%, 21.9 mg, 1.5 equiv.) was added in portions at 0 °C. After 15 min, 4-chlorobenzyl chloride (47 µL, 1 equiv.) was added dropwise followed by a one-time addition of n-Bu4NI (13.5 mg, 10 mol%) and the resulting reaction mass was left stirring at rt overnight under Ar. Then the reaction mixture was evaporated in vacuo, diluted with water and extracted with CH2Cl2. Organic layer was washed with brine, dried with Na2SO4, and evaporated in vacuo. The crude oily product was treated with excess of an ethereal oxalic acid solution and the resulting white precipitate was washed with fresh anhydrous Et2O and dried in vacuo to reach (S)-2·H2C2O4 salt as white solid (148 mg, yield: 85%). Mp 146–147 °C; IR (neat) ṽ/cm−1): 3843w, 3650w, 3130w, 2572w, 1733s, 1633s, 1577m, 1541w, 1488m, 1470w, 1447w, 1409w, 1390w, 1349w, 1285w, 1226s, 1091s, 1077m, 1046m, 1014s, 895w, 868m, 852m, 828s, 797s, 786s, 762s, 722s; HRMS (ESI-Orbitrap) m/z: [M−H2C2O4+H]+ calcd for C18H16Cl3N2O 381.0328; Found 381.0329. The free base of (S)-22·H2C2O4 was released with 2.5 M NaOH and extracted with CH2Cl2. Organic phase was washed with brine, dried with Na2SO4, and evaporated in vacuo to afford (S)-22 as colorless oil (90 mg, overall yield: 65%). [α]20D: +86.8 (c 1.0; CH2Cl2); > 99% ee; 1H NMR (CDCl3, 400 MHz) δ/ppm: 4.03 (dd, JHH = 14.6, 7.8, 1H), 4.16–4.21 (m, 2H), 4.43 (d, JHH = 11.9, 1H), 4.95 (dd, JHH = 7.8, 2.7, 1H); 6.89 (t, JHH = 1.3, 1H), 7.05 (t, JHH = 8.0, 3H), 7.27–7.34 (m, 4H), 7.44–7.46 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ/ppm: 51.3, 70.7, 76.8, 119.7, 127.9, 128.4, 128.7, 129.0, 129.2, 129.6, 133.3, 133.8, 133.9, 134.9, 135.3, 137.8. 2-amino-1-phenylethan-1-ol (23):71 To a solution of 19a (250 mg, 1.5 mmol) in MeOH (50 mL), 10% Pd/C (100 mg) was added and the resulting reaction mixture was shaken vigorously for 3 h under H2 (60 psi). Then the reaction mass was filtered and the filtrate was evaporated in vacuo to furnish 23 as colorless oil, which solidifies upon standing (200 mg, yield: 97%). The crude product was treated with excess of ethereal HCl solution and the resulting precipitate was filtered and washed with anhydrous Et2O, CH2Cl2 and dried in vacuo to produce 23·HCl as white solid (245 mg, overall yield: 97%). Rac-23·HCl: mp 134–135 °C; (R)23·HCl: mp 138–140 °C; [α]25D −46.0 (c 0.5; MeOH); 75% ee. The enantioenriched (R)-23·HCl salt was dissolved in a small amount of MeOH and Et2O was added dropwise until precipitation occurred. The resulting mixture was left undisturbed for 2 h in the refrigerator. The white microcrystalline precipitate was filtered, washed with fresh anhydrous Et2O and dried in vacuo to afford enantiopure (R)-23·HCl as white powder (170 mg, overall yield: 67%). Mp 149–150 °C; [α]25D: −62.0 (c 0.5; MeOH); > 99% ee; 1H NMR (DMSOd6, 400 MHz) δ/ppm: 2.81 (dd, JHH = 12.6, 9.8, 1H), 2.99 (dd, JHH = 12.8, 2.7, 1H), 4.84 (dt, JHH = 9.9, 3.7, 1H), 6.11 (d, JHH = 3.7, 1H), 7.27–7.40 (m, 5H), 8.17 (br. s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 45.9, 69.1, 126.0,

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127.8, 128.4, 142.0; IR (neat) ṽ/cm−1: 3205br, 3031br, 1615w, 1568w, 1490m, 1460w, 1451w, 1344w, 1138w, 1124w, 1055m, 999s, 954m, 912m, 802w, 747s; HRMS (ESIOrbitrap) m/z: [M–HCl+H]+ calcd for C8H12NO 138.0919; Found 138.0911. The free base of 23·HCl was released with 2.5 M NaOH and extracted with CH2Cl2. Organic phase was washed with brine, dried with Na2SO4, and evaporated in vacuo to afford 23 as colorless oil. N-(2-hydroxy-2-phenylethyl)-2-(4-nitrophenyl)acetamide (24): To a solution of 23 (0.73 mmol, 100 mg), EDCl (1.1 equiv., 154 mg), HOBt·H2O (1.1 equiv., 110 mg), and Et3N (2.1 equiv., 215 µL) in anhydrous THF (5 mL), 4nitrophenylacetic acid (1.0 equiv., 132 mg) was added portionwise and the reaction mass was left stirring for 1 h at rt under Ar. Then the reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with 1 M HCl, saturated solution of NaHCO3 and brine, dried with Na2SO4 and evaporated in vacuo to provide 24 as white solid (140 mg, yield: 64%), which was used directly in the next step. Rac-24: mp 128–129 °C; (R)-24: mp 143– 144 °C; [α]20D: +12.0 (c 0.5; MeOH); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 3.15–3.18 (m, 1H), 3.29–3.32 (m, 1H), 3.59 (s, 2H), 4.61 (br. s, 1H), 5.52 (d, JHH = 3.7, 1H), 7.23– 7.30 (m, 5H), 7.48 (d, JHH = 7.8, 2H), 8.15 (d, JHH = 7.8, 2H), 8.27 (br. s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 41.9, 46.9, 71.3, 123.3, 126.1, 127.1, 128.1, 130.4, 143.6, 144.7, 146.3, 169.2; IR (neat) ṽ/cm−1: 3295br, 3095br, 2965w, 1651m, 1604w, 1553w, 1515m, 1494w, 1417w, 1347s, 1252w, 1203w, 1109w, 1058m, 1029w, 852m, 828w, 812w, 754w, 701s; HRMS (ESI-Orbitrap) m/z: [M+H]+ calcd for C16H17N2O4 301.1188; Found 301.1177. 2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)acetamide (25): To a solution of 24 (140 mg, 0.5 mmol) in MeOH (15 mL), 10% Pd/C (100 mg) was added and the resulting reaction mixture was shaken vigorously for 3 h under H2 (60 psi). Then the reaction mass was filtered and the filtrate was evaporated in vacuo to furnish 25 as white solid (130 mg, yield: 98%), which was used directly in the next step. Rac-25: mp 128–129 °C; (R)-25: mp 113–115 °C; [α]25D +3.0 (c 1.0; MeOH); −44.0 (c 0.5; CHCl3); 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 3.11 (ddd, JHH = 13.2, 7.9, 5.0, 1H), 3.21 (s, 2H), 3.23–3.29 (m, 1H), 3.38 (s, 1H), 4.58 (dd, JHH = 7.3, 5.0, 1H), 4.91 (br. s, 2H), 5.53 (br. s, 1H), 6.48 (d, JHH = 8.7, 2H), 6.87 (d, JHH = 8.2, 2H), 7.21–7.33 (m, 5H), 7.89 (t, JHH = 5.5, 1H); 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 41.6, 47.0, 71.3, 113.8, 123.3, 126.0, 127.0, 128.0, 129.5, 143.8, 147.1, 171.2; IR (neat) ṽ/cm−1: 3734w, 3340br, 2960w, 1652w, 1626s, 1557m, 1516s, 1494w, 1455w, 1436w, 1411w, 1253w, 1212w, 1170w, 1065m, 1028w, 918w, 838w, 814w, 785w, 761m, 703s; HRMS (ESIOrbitrap) m/z: [M+H]+ calcd for C16H19N2O2 271.1447; Found 271.1437. 2-((4-aminophenethyl)amino)-1-phenylethan-1-ol (26):72 To a solution of 25 (130 mg, 0.5 mmol) in anhydrous MePh (5 mL), 60% solution of SMEAH in MePh (2.5 mL, 7.5 mmol) was added dropwise in order to maintain the reaction temperature below 20 °C. The resulting mixture was left stirring 48 h at rt under Ar. Then the reaction was quenched by dropwise addition of water, diluted with water and the organic phase was separated. The aqueous phase was basified with 2.5 M NaOH to pH 10 and back-extracted with several portions of fresh MePh. Combined organic extracts


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were washed with brine, dried with Na2SO4 and evaporated in vacuo to provide 26 as yellowish solid (117 mg, yield: 95%). Rac-26: mp 87–88 °C; (R)-26: mp 76–77 °C; [α]25D −32.0 (c 0.5; CHCl3); 1H NMR (CDCl3, 400 MHz) δ/ppm: 1.27 (br. s, 1H), 2.67–2.94 (m, 6H), 3.66 (br. s, 2H), 4.69 (dd, JHH = 9.1, 3.3, 1H), 5.31 (br. s, 1H), 6.64 (d, JHH = 8.1, 2H), 6.99 (d, JHH = 8.0, 2H), 7.29–7.36 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ/ppm: 35.4, 50.8, 56.9, 71.6, 115.3, 125.8, 127.4, 128.3, 129.5, 129.6, 142.6, 144.6; IR (neat) ṽ/cm−1: 3324w, 2920w, 2826br, 1612m, 1515s, 1451m, 1424m, 1335w, 1261m, 1179w, 1115m, 1070m, 1041m, 983w, 908m, 884w, 856w, 812m, 755m, 700s; HRMS (ESIOrbitrap) m/z: [M+H]+ calcd for C16H21N2O 257.1654; Found 257.1642.

ASSOCIATED CONTENT

Supporting Information SI is available free of charge on the ACS Publications website. SI contains synthetic schemes, optimization, kinetic and spectroscopic experiments, HPLC, NMR, HRMS and crystallographic data for compounds 1–17, 19a–s, and 20–26. (PDF) Crystallographic data for rac-7. (CIF) Crystallographic data for rac-12. (CIF)

AUTHOR INFORMATION

Corresponding Author * E-mail: [email protected]

Author Contributions All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Financial support of the work was provided by the project 308/2017/FaF and 327/2016/FaF (IGA UVPS Brno). NMR part of the work was realized in Central European Institute of Technology (CEITEC) under open access project LM2011020 funded by the Ministry of Education, Youth and Sports of the Czech Republic (MEYS CR) under the activity “Projects of major infrastructures for research, development and innovations.” CIISB research infrastructure project LM2015043 funded by MEYS CR is gratefully acknowledged for the financial support of the measurements at the CF X-Ray Diffraction and BioSAXS. We wish to thank Radovan Fiala (CEITEC) and Otakar Humpa (CEITEC) for NMR measurements, Jaromir Marek (CEITEC) for X-ray part of the manuscript and Radim Hrdina (JLU Giessen) for fruitful discussions.

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Page 20 of 20

CF 3 S F 3C

N H N

O R1

N H

N H N

H N

CF3

S

H NO 2

R2 R1 = Ar, Het, Alk R 2 = H, Me, Et

(10 mol%) Et 2O – 30 or –20 °C

OH

CF 3

R1

R2 NO 2

up to 96% ee up to 69:31 syn/anti 87–98% yield 19 examples

ACS Paragon Plus Environment

20

Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry

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