molecules Communication Synthesis of a Conformationally Stable Atropisomeric Pair of Biphenyl Scaffold Containing Additional Stereogenic Centers Chi-Tung Yeung 1,2 , Wesley Ting Kwok Chan 2, Wai-Sum Lo 1,2, Ga-Lai Law 1,2 and Wing-Tak Wong 1,2,* 1 The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518000, PR China; [email protected] (C.-T.Y.); [email protected] (W.-S.L.); [email protected] (G.-L.L.) 2 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon 999077, Hong Kong; [email protected] * Correspondence: [email protected]; Tel.: +852-34008789 Received: 18 January 2019; Accepted: 8 February 2019; Published: 12 February 2019 Abstract: The synthesis of a new CF3-containing stereogenic atropisomeric pair of ortho-disubstituted biphenyl scaffold is presented. The atropisomers are surprisingly conformationally stable for isolation. X-ray structures show that their stability comes from an intramolecular hydrogen bond formation from their two hydroxyl groups and renders the spatial arrangement of their peripheral CF3 and CH3 groups very different. The synthesized stereogenic scaffold proved to be effective in catalyzing the asymmetric N-nitroso aldol reaction of enamine and nitrosobenzene. Compared to similar scaffolds without CF3 groups, one of our atropisomer exhibits an increase in enantioselectivity in this reaction. Keywords: atropisomer; asymmetry; hydrogen bond; N-nitroso aldol reaction 1. Introduction The nitroso aldol reaction is one of the most powerful methods to introduce nitrogen and oxygen moieties at the α-position of an enolizable carbonyl compound to give synthetically useful N/O-substituted carbonyl intermediates for the synthesis of a variety of natural products and pharmaceutical compounds [1–5]; however, high reactivity of both the nitrogen and oxygen atoms in a nitroso compound towards the nucleophile has made it difficult to control N- or O-regioselective additions to enolate. It is generally understood that a judicious choice of a suitable promoter (hydrogen bond activator or Lewis acid, etc.) and enolate (silyl- or lithiate-) are determinant factors to control this regioselectivity to either hydroxyamino or aminooxy compounds [6–8]. The past two decades have seen great progress in the research of asymmetric organocatalytic O-nitroso aldol reactions [9–16]; in contrast, research in the N-nitroso aldol reaction is rather limited [17–21]. Most of the N-nitroso aldol stereogenic catalysts contain a 2◦ amino unit for the in situ generation of enamine prior to reacting with the nitroso compound. Another catalyst design for this reaction is to consider activating the nitroso compound and hence react with a preformed enamine of interest to selectively form the hydroxyamino product. Yamamoto and his co-workers reported a catalytic N-nitroso aldol reaction system based on a hydrogen bond forming di-alcoholic TADDOL to give the hydroxyamino products from cyclohexene enamine in good yields and enantioselectivities [22]. To the best of our knowledge, this is the only report on organocatalytic N-nitroso aldol reactions with a preformed enamine with good % ee; as such, there is still much room for improvement and investigation. Molecules 2019, 24, 643; doi:10.3390/molecules24030643 www.mdpi.com/journal/molecules Molecules 2019, 24, 643 2 of 11 Molecules 2019, 24, x FOR PEER REVIEW 2 of 11 In the the literature, literature, catalysts catalysts with with ortho ortho-tetrasubstituted-tetrasubstituted biaryl biaryl backbone backbones,s, such such as binaphthyl as binaphthyl,, are arewell well-known-known efficient efficient catalysts catalysts for many for many asymmetric asymmetric reactions reactions [23–26 [23]. –For26]. catalysts For catalysts with ortho with- ortho-disubstituteddisubstituted biphenyl biphenyl backbone backbones,s, research research in this in field this fieldis rather is rather limited. limited. The Thereason reason may may be beattributed attributed to touncontrollable uncontrollable internal internal rotation rotation at at the the biphenyl biphenyl backbone, backbone, which which leads leads to to a a co co-existence-existence of the atropisomers,atropisomers,R Raa andandS Saa,, andand thisthis isis generally generally believed believed to to adversely adversely affect affect the the enantioselectivity enantioselectivity in catalyticin catalytic reactions. reactions Although. Although limited, limited, some catalystssome catalysts based on based ortho-disubstituted on ortho-disubstituted biphenyl backbonesbiphenyl arebackbone occasionallys are occasionally reported to reported give high to give enantioselectivities high enantioselectiv in organocatalysisities in organocatalysis [27,28]. There[27,28] is. T greathere potentialis great potential to develop to efficientdevelop organocatalystsefficient organocatalysts based on based an ortho-disubstituted on an ortho-disub biphenylstituted backbonebiphenyl ifbackbone the corresponding if the corresponding rotation atrotation the biphenyl at the biphenyl axis can axis be well-regulatedcan be well-regulated by steric by effectsteric oreffect other or delicateother delicate interactions. interactions. As part of our research programprogram on studyingstudying supramolecularsupramolecular formation behavior with some stereogenic biphenyl di di-alcoholic-alcoholic compounds, we discovered that a series of strong intermolecular hydrogen bonding bonding interaction interactionss are are the the major major force force in helping in helping to mainta to maintainin a high a highatropisomeric atropisomeric ratio ratio(ratio (ratioof Ra to of SRa)a ofto a Sstereolabilea) of a stereolabile compound compound 1 (Scheme1 1)(Scheme [29]. Pure1)[ atropisomer29]. Pure atropisomer 1 can be isolated1 can but be isolateda deterioration but a deterioration in atropisomeric in atropisomeric ratio (9:1 to ratio 7:3) (9:1was toobserved 7:3) was after observed dissolution after dissolution in organic in solvents. organic solvents.Inspired by Inspired Kumad byaki Kumadaki and his co and-workers’ his co-workers’ pioneering pioneering studies on studies the develop on the developmentment of axially of axiallydissymmetric dissymmetric ligand ligandss with withenhanc enhanceded hydroxyl hydroxyl acidity acidity by byincorporating incorporating different different perfluoroalkyl perfluoroalkyl groups [[30,3130,31],], we would like to report our new findings:findings: the synthesis of a new axially stereogenic biphenyl scaffold-basedscaffold-based di-alcoholicdi-alcoholic compoundcompound 22 bearingbearing twotwo additionaladditional CFCF33 substituents. A surprise formation ofof a pair of stable and isolated atropisomers ((RRaa and Sa)) with with their their axial axial chirality chirality being fixed fixed and stabilized by intramolecular hydrogenhydrogen bondsbonds (OH(OH······OH) (O–H(O–H······O) w wasas observed. The formation of an atropisomeric pair with a substantial substantiallyly less bulky biphenyl diol was also reported by Kumadaki and his co co-workers-workers [32] [32];; h however,owever, the pair was susceptible susceptible to a atropisomerization,tropisomerization, leading to the major formation of one of their isomers.isomers. In our study, 1 and 2 were preliminar preliminarilyily screened as organocatalysts in an asymmetric N--nitrosonitroso aldolaldol reaction of enamine with nitrosobenzene. Scheme 1. Stereogenic biphenyl scaffold scaffold-based-based di-alcoholicdi-alcoholic compounds.compounds. 2. Results and Discussion 2. Results and Discussion Our approach to the synthesis of a key intermediate, enantiopure 2-(2-bromophenyl)-1,1,1- Our approach to the synthesis of a key intermediate, enantiopure 2-(2-bromophenyl)-1,1,1- trifloropropan-2-ol b, is presented in Scheme2. Firstly, the CF 3 substituent was introduced to the trifloropropan-2-ol b, is presented in Scheme 2. Firstly, the CF3 substituent was introduced to the carbonyl group of 20-bromoacetophenone a by trifluoromethylation with trifluoromethyltrimethylsilane. carbonyl group of 2′-bromoacetophenone a by trifluoromethylation with After removing the trimethylsilyl group with tetrabutylammonium fluoride, b was obtained as a racemic trifluoromethyltrimethylsilane. After removing the trimethylsilyl group with tetrabutylammonium mixture with a good yield (85%). Enantiopure b can be obtained by chiral resolution of racemic-b fluoride, b was obtained as a racemic mixture with a good yield (85%). Enantiopure b can be obtained with (1S)-(–)-camphanic chloride. The corresponding diastereomers, (R)-c or (S)-c, can be separately by chiral resolution of racemic-b with (1S)-( ─ )-camphanic chloride. The corresponding easily with column chromatography, and their diastereoselectivities are high enough without the need diastereomers, (R)-c or (S)-c, can be separately easily with column chromatography, and their for further purification with recrystallization. For (S)-b, its absolute configuration was revealed to diastereoselectivities are high enough without the need for further purification with recrystallization. be (S) at C-7 with an X-ray crystal structure (Figure1). After removing the camphanic substituent, For (S)-b, its absolute configuration was revealed to be (S) at C-7 with an X-ray crystal structure enantioselectivity of the corresponding (R)-b or (S)-b was checked with HPLC and found to be higher (Figure 1). After removing the camphanic substituent,