Catalytic asymmetric synthesis of enantioenriched heterocycles bearing a C-CF3 stereogenic center.

DOI: 10.1002/chem.201500361

Review

& Asymmetric Synthesis

Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a C CF3 Stereogenic Center Yi-Yong Huang,*[a] Xing Yang,[a] Zhuo Chen,[a] Francis Verpoort,[a] and Norio Shibata*[b]

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2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Review Abstract: Given the important agricultural and medicinal application of optically pure heterocycles bearing a trifluoromethyl group at the stereogenic carbon center in the heterocyclic framework, the exploration of efficient and practical synthetic strategies to such types of molecules remains highly desirable. Catalytic enantioselective synthesis has one clear advantage that it is more cost-effective than other synthetic methods, but remains limited by challenges in achieving excellent yield and stereoselectivities with a low catalyst

loading. Thus far, numerous models of organo- and organometal-catalyzed asymmetric reactions have been exploited to achieve this elusive goal over the past decade. This review article describes recent progress on this research topic, and focuses on an understanding of the catalytic asymmetric protocols exemplified in the catalytic enantioselective synthesis of a wide range of complex enantioenriched trifluoromethylated heterocycles.

1. Introduction

of Is effect and lipophilicity in drug design, and it is now a common practice to study the CF3 analogue of a candidate drug.[3] For example, when the C12-methyl group of compound 9,10-dehydro-dEpoB was replaced by CF3 functionality, it was considerably less toxic and its therapeutic index was dramatically improved.[4] In this context, the selective incorporation of a CF3 group at a specific site in molecules, especially within the heterocyclic framework, to improve their physicochemical, biological, and pharmaceutical properties, has attracted a large number of organic and medicinal chemists.[5]

Heterocycles with diverse structural motifs are highly important, and well-studied compounds for pharmaceutical, agrochemical, and materials applications in either academia or industry with a long history.[1] To obtain the most suitable molecule with a heterocyclic system for each specific application, and how it can be assembled in an efficient and practical way always needs to be considered. Therefore, a great number of publications have been dedicated to devising elegant synthetic strategies to install heterocyclic molecules with different ring sizes and ring systems.[2] On the other hand, the effect of the unique trifluoromethyl (CF3) group on the nature of organic compounds has been extensively demonstrated. Due to the highly lipophilic and strong electron-withdrawing properties of the CF3 group, the polarity, electrostatic potential, dipole moment, binding selectivity, bioavailability, and other properties of the parent molecules can be increased. Metabolic stability can also be enhanced by the strong C F bond energy. The Hansch p constant (p = log PX log PH, in which PX and PH are the partition coefficients between 1-octanol and water for a derivative and Figure 1. Seclected biologically and pharmaceutically active heterocyclic compounds bearing a CF3 group at the a parent molecule, respectively) chiral carbon center. clearly highlights the importance Within the CF3-containing heterocycle family, molecules with a CF3 group at the teriary or quaternary stereogenic carbon [a] Prof. Dr. Y.-Y. Huang, X. Yang, Z. Chen, Prof. Dr. F. Verpoort center are of particular interest. Indeed, such entities play Department of Chemistry, School of Chemistry a unique and significant role in agricultural and medicinal Chemical Engineering and Life Science chemistry. As listed in Figure 1, a great variety of biologically Wuhan University of Technology, Wuhan 430070 (P.R. China) E-mail: [email protected] and pharmaceutically active molecules that feature a heterocy[b] Prof. Dr. N. Shibata clic segment with a C CF3 stereogenic center have emerged, Department of Frontier Materials, Nagoya Institute of Technology and some of them have been employed at the clinical trial Gokiso, Showa-ku, Nagoya, 466-8555 (Japan) stage.[6] For instance, trifluoromethylated analogues of ezetiFax: (+ 81) 52-735-5442 mibe I bearing a four-membered b-lactam nucleus were evaluE-mail: [email protected] &

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Review ated as good cholesterol absorption inhibitors.[6a] 3,5-Diaryl-5CF3-2-isoxazoline derivatives II and the carbon variants pyrrolines III have been employed in pest control.[6b] Compound IV, containing a pyrrolidine ester, is recognized as a suicide inhibitor.[6c] Several six-membered trifluoromethylated heterocycles, such as antirheumatic agent V,[6d] NK-1 receptor antagonist VI,[6e] the renowned HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) VII,[6f] VIII, IX and X,[6g] as well as antimalarial agents XI,[6h] are also included. Macroheterocyclic molecules XII[6i] with one or two trifluoromethylated stereogenic centers have been identified for the treatment of cancer. Thus, the exploitation of simple and flexible methodologies for the asymmetric construction of a chiral trifluoromethylated heterocyclic system has been receiving great attention. Initial work focused on a diastereoselective strategy or used a stoichiometric amount of chiral reagent.[7] However, recent studies emphasized the discovery of the catalytic asymmetric pathway as a cost-effective strategy, although it remains a formidable challenge. Owing to the fact that asymmetric catalysis has reached a certain maturity,[8] numerous models of organo- or organometal-catalyzed asymmetric reactions have been exploited to achieve the elusive goal of CF3-substituted heterocycles over the past decade. Generally, the following three complementary synthetic procedures are employed.

2. Chiral Trifluoromethylated Heterocycles 2.1. Three-membered heterocycles of chiral trifluoromethylated epoxides (CF3-epoxides) Chiral epoxides, as small-ring heterocycles, are frequently present in or used to build biologically active and natural molecules.[10] Catalytic asymmetric electrophilic epoxidation of olefins is widely acknowledged as one of the most powerful transformations in organic synthesis, especially for the asymmetric epoxidation of allylic alcohols established by Sharpless.[11] Although tremendous efforts have been devoted to the study of catalytic systems for asymmetric epoxidation in recent years, the catalytic asymmetric epoxidation of acyclic b,b-disubstituted enones for the synthesis of multisubstituted epoxides remains a challenge.[12]

Yi-Yong Huang was born in Hunan, China. He obtained his Ph.D. under the supervision of Professor Qing-Hua Fan in 2007 at the Chinese Academy of Sciences (CAS). After working for 2 years (2007–2009) as a JSPS Postdoctoral Researcher at the Nagoya Institute of Technology with Professor Norio Shibata, he joined the Shu¯ Kobayashi group at the University of Tokyo as a NEDO Postdoctoral Researcher (2009–2012). He then moved to Wuhan University of Technology, and currently holds the position of Associate Professor and “Chutian Scholar”. His research interest focuses on homogeneous asymmetric catalysis, green synthesis, and enantioselective synthesis of chiral fluorinated compounds.

A) One-pot construction of the chiral heterocycles from prochiral non-heterocyclic trifluoromethylated building blocks through catalytic asymmetric carbo- or heterocyclization reactions, including epoxidation, cycloaddition, Diels–Alder reaction, cascade cyclization reaction, and so forth. B) Catalytic asymmetric reactions of already preformed prochiral trifluoromethylated heterocyclic reactants, for example, alkynylation, Mannich reaction, aza-Henry reaction, diynylation, Strecker reaction, decarboxylative Mannich reaction, hydrophosphonylation reactions, hydrogenation, azaFriedel–Crafts reaction and cascade cyclization reactions.[9] C) Multistep synthesis starting from the generation of an intermediate with a trifluoromethylated stereogenic center through direct catalytic asymmetric trifluoromethylation or a trifluoromethylated building block strategy, followed by cyclization or after a several step sequence.

Norio Shibata received a Ph.D. in 1993 from Osaka University under the direction of Professor Yasuyuki Kita. He worked at the Dyson Perrins Laboratory in Oxford University (1994– 1996). Then he became a Lecturer at Toyama Medical & Pharmaceutical University (1997– 2003), an Associate Professor (2003–2008) at the Nagoya Institute of Technology, and a Full Professor at the same university since 2008. He has authored around 170 articles. His research interests are synthetic and medicinal fluorine chemistry. He is currently a member of the editorial board of ChemistryOpen, and Journal of Fluorine Chemistry.

This review article pays special attention to recent progress of the manufacture of heterocycles possessing a CF3 group at the stereogenic center by entailing catalytic asymmetric reactions. Nearly all selected cases appeared after 2008. The review has been categorized based on the ring size order from monocycles with three-, four-, five-, and six-membered rings to fused heterocycles, then subdivided according to the type of heterocycles. Such a general overview, which is not yet available, will provide chemists with a comprehensive outlook on this highly important topic.

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Francis Verpoort received his D.Phil. from Ghent University in 1996. In 1998, he became Full Professor at the same university. In 2008, he became the Editor of Applied Organometallic Chemistry. Currently, alongside his position of Full Professor at Ghent University, he is the Director of the Center for Chemical and Material Engineering at Wuhan University of Technology, P.R. China. Recently, he was appointed as an “Expert of the State” in the frame of “Thousand Talents” program, P.R. China. His main research interests concern the structure and mechanisms in organometallic material chemistry, homogeneous and heterogeneous catalysts.

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Review Advancing the synthesis of chiral CF3-epoxides,[13] Shibata’s group disclosed a serendipitous approach in 2013. While attempting to use methylhydrazine and b-CF3-b-aryl enones 1 to prepare trifluoromethylated pyrazoline, an unexpected catalytic asymmetric epoxidation occurred in the presence of the phase-transfer catalyst cinchona alkaloid 3 a.[14] In this aerobic organocatalytic system, the unique methylhydrazine together with Cs2CO3 as base turned out to play an important role in the single-electron-transfer process of asymmetric epoxidation, as judged by 18O-labeling and (2,2,6,6-tetramethylpiperidin-1yl)oxidanyl (TEMPO) scavenging experiments. The supposed generation of pure hydrogen peroxide enabled the asymmetric epoxidation reaction. Under mild conditions, chiral trifluoromethylated epoxides 2 with various aryl substituents were smoothly afforded in generally excellent yields (91–99 %) with excellent diastereoselectivities (93:7 to 95:5 d.r.) and enantioselectivities (96–99 % ee) (Scheme 1).[15]

Scheme 2. Catalytic asymmetric epoxidation of enones 1 and H2O2 for CF3epoxides.

2.2. Four-membered heterocycles of chiral trifluoromethylated b-lactones (CF3-b-lactones) b-Lactone is an important subunit found in many biologically active molecules,[17] and also serves as a versatile building block for polymers, natural products, amongst others. N-Heterocyclic carbenes (NHCs) are a particular class of Lewis basic (nucleophilic) catalysts that can promote the [2+2] cycloaddition of disubstituted ketenes and ketones to form chiral b-lactones with a strained four-membered ring through umpolung.[18] To pursue the trifluoromethylated analogues of b-lactones, patented in the United States,[19] the Ye group pioneered the catalytic asymmetric synthesis starting from bisubstituted ketenes. In this reaction, the chiral NHC[20] precursor 7 served as the source of stereo induction and led to the [2+2] cycloaddition adducts of b-CF3-b-lactones 6 possessing two fully substituted stereocenters. Both electron-donating and electron-withdrawing groups in the aryl substituent of ketenes 4 or trifluoromethyl ketones 6 were subjected to the reaction conditions. The yields (56–99 %) and diastereoselectivities (1:1 to 23:1 d.r.) were very sensitive to the substituent variation, but the enantioselectivities always remained high (93–99 % ee). In particular, when ketenes bore sterically bulky substituents, such as 2chlorophenyl and isopropyl, no b-lactone products were detected. A possible catalytic cycle is depicted in Figure 2, which involved three steps of the umpolung of ketenes by the NHC, nucleophilic addition to ketones 5, and intramolecular cycload-

Scheme 1. Catalytic asymmetric aerobic epoxidation of enones 1 for CF3-epoxides.

A closely related approach was developed independently by Chen and co-workers. In place of using toxic methylhydrazine, 30 % aqueous H2O2 acted as an oxidant in the catalytic asymmetric epoxidation. Under the phase-transfer catalysis with 3 b, good to excellent yields (up to 96 %), diastereoselectivities (20:1 to 100:1 d.r.) and enantioselectivities (up to 99 % ee) were provided at 0 8C. It should be noted that when (E)-b-CF3-b-alkyl enones were tested, diastereomerically pure adducts (100:1 d.r.) with relatively lower enantioselectivity were furnished (81–82 % ee). Furthermore, both enantiomers of adduct 2 a could be obtained in a perfect enantiospecific manner (99 % ee) by only changing the stereochemistry of enone 1 a. As shown in the proposed transition state, the hydrogen bonding, as well as the possible p–p stacking force between 1 and 3 may be the key factors to direct high enantio-induction (Scheme 2).[16]

Figure 2. Proposed catalytic cycle for the [2+2] cycloaddition reaction.

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Review stereochemistry of a key adduct 2-isoxazoline 8 b could be controlled by modulating the configuration of catalyst 3. When 3 a or 3 c was used, (R)-8 b was obtained in excellent yields and good enantioselectivities, while catalyst 3 d provided an enantiodivergent formation of (S)-8 b at the same yield and enantioselectivity. To elucidate the reaction mechanism, two possible reaction pathways were hypothesized for this reaction (Scheme 5). Route B was ruled out as it prohibited the conver-

Scheme 3. NHC-catalyzed asymmetric ketene-ketone cycloaddition reaction for CF3-b-lactones.

dition to provide the product and regenerate the catalyst (Scheme 3).[21] 2.3. Five-membered heterocycles 2.3.1. Chiral trifluoromethylated 2-isoxazolines (CF3-isoxazolines) As partial saturated five-membered heterocycles, 2-isoxazolines bearing a CF3 group at the chiral center are amongst one of the most important classes of chiral trifluoromethylated heterocyclic compounds due to their remarkable biological activities when used as veterinary medicines and agrochemicals.[22] Ever since 2-isoxazoline derivatives II in Figure 1 were identified as suitable medicines against pests, more than 20 000 compounds sharing the same skeleton have been registered in SciFinder.[23] Many methods for constructing chiral 2-isoxazolines have been established, but most of them have limited substrate specificity.[24] Regarding an approach to chiral trifluoromethylated 2-isoxazolines,[25] Shibata and co-workers disclosed a novel catalytic asymmetric hydroxylamine/enone cascade reaction. Under phase-transfer catalytic conditions by using enones 1 and hydroxylamine as starting materials, a variety of CF3-isoxazolines, with the concomitant construction of a trifluoromethylated stereogenic center, could be readily accessed in high yields (80–99 %) and enantioselectivities (88–94 % ee) (Scheme 4). The

Scheme 5. Two possible reaction pathways.

sion from the condensation intermediate of imine 10 to (R)-8 a, as well as the subsequent 5-endo-trig cyclization by obeying Baldwin’s rules of guidelines for ring-closing reactions. Thus, route A of a hydroxylamine/enone sequence was favored. Furthermore, the control experiment revealed that the 9-OH group on catalyst 3, which served as a hydrogen-bonding donor, maybe a key factor in guaranteeing high asymmetric induction. A transition state model in Scheme 4 was proposed to rationalize the high enantioselectivity of the process. It was assumed that a confined sandwich-like framework was assembled by an intermolecular hydrogen bond and an ion pair, and the attack of hydroxylamine from the Re face of 1 a resulted in the R-configuration.[26] Thereafter, the same group elaborated a strategically distinct approach for the asymmetric synthesis of chiral 5-CF3-2-isoxazoline 8 a via its N-oxide.[27] Building on the use of the asymmetric epoxidation adduct 2 a with the already established synthetic method by the same group,[15] the subsequent Zn/ NH4Cl-reduction product (R)-11 underwent an oxidative N O coupling reaction mediated by [hydroxyl(tosyloxy)iodo]benzene (HTIB) to form N-oxide (R)-12. The desired product (R)-8 a was generated in 96 % yield in enantiomerically pure form by a deoxygenation reaction with P(OMe)3. Enantiopurity was not eroded in any transformation. In parallel, a new synthetic shortcut toward chiral alcohol (R)-11 was carried out with a relatively lower ee value (78 %) through the catalytic asymmetric decarboxylative aldol reaction by using trifluoromethylated ketone 5 a and b-keto acid 13 a. Finally, (R)-8 a with 78 % ee was afforded by the same series of synthetic procedures as before (Scheme 6).[28] 2.3.2. Chiral trifluoromethylated pyrrolines (CF3-pyrrolines) From a structural point of view, pyrrolines are carbon variants of 2-isoxazolines, and they have some similar biological activi-

Scheme 4. Catalytic asymmetric hydroxylamine/enone cascade reaction for CF3-isoxazolines. Chem. Eur. J. 2015, 21, 1 – 22

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Scheme 7. Catalytic asymmetric conjugate addition of nitromethane for the synthesis of b-CF3-pyrrolines.

could be preferentially produced in cyclopentyl methyl ether (CPME) as the solvent in good to excellent yields (72–96 %) with excellent diastereoselectivities (> 98:2 d.r.) and good enantioselectivities in the range of 72 to 88 % (Scheme 8).[35]

Scheme 6. Catalytic asymmetric epoxidation for the synthesis of 5-CF3-2-isoxazoline.

ty.[29] Thus far, efficient asymmetric synthesis of chiral pyrrolines remains scarce.[30] CF3-Pyrrolines III in Figure 1 were first discovered as agrochemicals and veterinary medicines in 2005, and, so far, more than 5000 racemic analogues of III have been reported for the same purpose. However, exploring the catalytic asymmetric route to chiral CF3-pyrroline is still a challenging task.[31] In 2012, Shibata and co-workers discovered the first example of organocatalytic enantioselective synthesis of b-CF3-pyrrolines with b-monosubstituted enones. The cinchona alkaloid thiourea derivative 17 a (2 mol %) was selected as the privileged chiral catalyst, which enantioselectively promoted the conjugate addition of nitromethane to b-CF3-enones 16 in high yields (88–98 %) and enantioselectivities (96–98 % ee). It is worth noting that a low catalyst loading (0.5 mol %) led to an identical enantioselectivity albeit at the expense of a longer reaction time. The resulting g-nitro ketone 18 a was later treated with Fe/CH3COOH at 65 8C by a reduction/cyclization/dehydration sequence to give the target CF3-pyrroline 19 in 92 % yield and 97 % ee. This stepwise process to CF3-pyrrolines 18 could also be operated in a one-pot sequential procedure with attractive yields (85–95 %) and excellent enantioselectivities (97– 98 % ee) (Scheme 7).[32] In the meantime, Shibata’s group went forward with the study of another sequential strategy for the construction of chiral b-CF3-pyrroline carboxylates from the same trifluoromethylated building blocks 16.[33] In this case, glycine imino esters 20 were examined as both Michael donors and protected bamino esters.[34] The challenge to construct b-CF3-pyrrolines with two consecutive chiral centers in a highly asymmetric catalytic manner was met by involving chiral phase-transfer catalyst 3 e along with Cs2CO3. Firstly, the conjugated addition of 20 to b-CF3-enones 16 was achieved, then the HCl-promoted deprotection/cyclization/dehydration sequence proceeded in situ. Eventually, various trans-b-CF3-pyrroline carboxylates 21 &

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Scheme 8. Catalytic asymmetric conjugate addition of imino-esters for the synthesis of b-CF3-pyrroline carboxylates.

Aiming at the incorporation of a CF3 group intopyrrolines, other nucleophiles have also been surveyed in the initial asymmetric conjugate addition step. A small variation of using sterically demanding b,b-disubstituted enones 1 from the above two examples can potentially yield chiral CF3-pyrrolines that have an all-carbon quaternary stereocenter if carbonucleophiles are utilized.[36] For this purpose, in 2012, the Shibata group successfully achieved the catalytic enantioselective conjugate cyanation of enones by using acetone cyanohydrin as the source of cyanide. Interestingly, cinchona alkaloids catalyst 3 f with an ether group at the 9-position worked much better than the hydroxy type. A wide range of aryl groups bearing electron-donating or -attracting substituents in enones 1 were tolerated, and high to excellent yields (90–99 %) and enantioselectivities (90–96 % ee) were obtained. The conjugate addition adduct 22 a from 1 a could be readily converted into the target 2-CF3-2,4-diarylpyrroline 23 without the loss of enantiopurity through a cyano-reduction/cyclization/dehydration sequence in the presence of Raney-Ni. However, if H2 gas was introduced in the previous reaction system, the CF3-pyrrolines could be further hydrogenated into fully saturated pyrrolidine derivative 24 (Scheme 9).[37] From a technical strategy, this achieves two objectives in a single step. Although the above case provided an efficient way to obtain two types of five-membered N-heterocycles, some 6



Review

Scheme 9. Catalytic enantioselective conjugate cyanation for the synthesis of CF3-pyrroline and CF3-pyrrolidine derivative.

drawbacks could not be avoided. For example, the harsh Raney-Ni treatment in the final cyano-reduction step led to only moderate yields (around 50 %), and the halogen group on aromatic rings was incompatible with such reaction conditions. In order to address this issue, in 2013, Shibata and co-workers developed another strategy for constructing b-CF3-pyrrolines via catalytic asymmetric conjugate addition of nitromethane to enones 1. Compared with b-monosubstituted enones 16, the lower reactivity of bisubstituted enones 1 resulted in quite different reaction conditions. Phase-transfer catalysis with cupreidine-based catalyst 3 g, in contrast to the use of thiourea-type catalyst in the previous case,[32] made the asymmetric transformation proceed smoothly. A series of enones 1 with two aryl groups were converted to the intermediates 25 in high to excellent yields (80–99 %) and high enantioselectivities (90– 93 % ee), but the aliphatic substituent (R = Me) at the b-position was detrimental to enantioselectivity (90 % yield, 63 % ee). By treating the addition adducts 25 a and 25 b with Fe-AcOH, the partially saturated diarylpyrrolines 26 a and 26 b were accessed respectively in high yields, while fully retaining their enantioselectivities. Based on the absolute configuration of adduct 25, as well as catalyst 3 g having a hydroxy group at the 6’-position of the quinoline ring, the postulated transitionstate model is illustrated in Scheme 10. The hydrogen bonding, p–p stacking and ionic interaction between catalyst 3 g and two reacting components ensured high enantio-induction. The nitromethane anion generated in situ attacks favorably the Re face of enone 1 a to afford the R enantiomer (Scheme 10).[38]

Scheme 10. Catalytic enantioselective conjugate addition of nitromethane to enones for constructing CF3-diarylpyrrolines.

Wang and co-workers screened out an efficient catalyst system of using the TF-BiphamPhos ligand 29/CuI complex. Various endo-adducts of trifluoromethylated 2,4-dicarboxyl pyrrolidines with four contiguous chiral centers were afforded in high yields with excellent diastereoselectivities and good enantioselectivities from (Z)- or (E)-trifluorocrotonates 28 and imino esters 27. The steric and electronic properties of aryl groups in 27 had a limited effect on the reaction’s result. They further found that the kinetically favored endo-adducts 31 synthesized from (Z)-28 a could be readily epimerized to the thermodynamically favored exo-products 32 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) by retaining diastereomeric and enantiomeric excess (Scheme 11). In fact, this phenomenon of epimerization widely enhances the synthetic power of this reaction for many more densely substituted CF3-heterocyles.[41]

2.3.3. Chiral trifluoromethylated pyrrolidines (CF3-pyrrolidines) Nitrogen-containing heterocycles of pyrrolidines are omnipresent in natural products and biologically active compounds.[39] For example, proline is an essential amino acid in the human body and also a widely used chiral organocatalyst, and features a pyrrolidine skeleton. As an efficient way to build chiral pyrrolidines, the catalytic asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides and electron-deficient alkenes has been studied extensively.[40] Although this type of reaction has shown advantages in the synthesis of biologically active chiral heterocycles bearing multiple stereogenic centers, the use of trifluorocrotonates as dipolarophiles for CF3-substituted heterocycles had never been reported prior to 2011. Toward this aim, Chem. Eur. J. 2015, 21, 1 – 22

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Scheme 11. CuI-catalyzed 1,3-dipolar cycloaddition of 4,4,4-trifluorocrotonates for CF3-pyrrolidines.

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Review In addition to employing a one-step cycloaddition strategy to install chiral CF3-pyrrolidines, a new stepwise synthetic route by using CF3-substituted iminoesters has also been reported. Chiral a-alkynyl amines with highly functionalizable handles are attractive to organic chemists due to their typical utility in N-heterocycle synthesis.[42] Providing continued input to the investigation of new asymmetric catalytic protocols for chiral aCF3 a-amino acids,[43] Zhang’s group studied the chiral Zn-catalyzed enantioselective addition of terminal alkynes 34 to ketoimine ester 33. After delicately tuning the substituents at the 3,3’-positions of the 1,1’-bi-2-naphthol (BINOL) ligand and reaction temperature, the desired compound 36 was obtained in 93 % yield and 95 % ee. The application of 36 in the four-step total synthesis of (R)-a-CF3-a-proline 37 was fulfilled in an overall yield of 54 %. This represents the first case of preparing a chiral trifluoromethylated proline methyl ester by means of a catalytic asymmetric reaction (Scheme 12).[44]

Scheme 13. Catalytic asymmetric synthesis of enantioenriched 2-CF3-pyrrolidines.

For example, (R)-Rolipram, consisting of a pyrrolidinone motif, is a type IV phosphodiesterase inhibitor.[46] Morever, pyrrolidinone can be the synthetic precursor to pyrrolidine. Expanding on the efforts to explore new types of heterocycles, in 2014, Liu’s group designed trifluoromethylated heterocyclic molecules that combined indole[47] and pyrrolidinone motifs. Inspired by the well-established catalytic enantioselective conjugate addition of nitroalkenes,[48] they applied b-CF3b-(3-indoyl) nitroalkenes 43 as prochiral Michael acceptors for the first time in conjunction with malonates 44 as Michael donors. Under a mild basic conditions, chiral aminothiourea catalyst 45 could address the challenge of creating all-carbon quaternary stereogenic centers composed of CF3 and indole groups, as well as a g-nitrobutyric acid ester motif. In this way, the scope of the reaction by varying the nitroalkenes resulted in moderate to good yields (up to 89 %) and enantioselectivities (up to 90 % ee), although 20 equivalents of malonates were required to achieve such high yields. The proposed transition state illustrated in Scheme 14 indicates that the bifunctional thiourea catalyst 45 arranges the two components through hydrogen bonding, and the deprotonated malonate attacks from the Si face based on the absolute configuration of product 46 b. Scheme 14 demonstrates the synthetic utility of 46 a to chiral trifluoromethylated pyrrolidinones 47 in three steps associated with reductive cyclization, decarboxylation and the removal of Ts without changing the ee value.[49]

Scheme 12. Catalytic enantioselective zinc-catalyzed alkynylation of ketoimines for CF3-pyrrolidines.

In 2014, Johnson’s group opened a new door for obtaining trisubstituted 2-CF3-pyrrolidines relying on two synthetic steps of the organocatalytic asymmetric Michael reaction and diastereoselective reductive cyclization. Firstly, g-nitro carbonyl intermediates 40 containing two stereocenters were generated from nitroolefins 38 and CF3-ketones 39 in moderate to excellent yields (42–99 %) with high enantioselectivities (73–95 % ee) and diastereoselectivities (up to > 20:1 d.r.) by using a low catalytic loading of bifunctional thiourea catalyst 17 b (2.5 mol %). The subsequent reductive cyclization in the presence of RaneyNi/H2 afforded chiral 2-CF3-pyrrolidines 41 with three consecutive stereocenters in an all-cis configuration in good yields with high enantioselectivities up to 89 % and > 20:1 d.r. Stereospecific access to the C-2 epimer 42 of 41 through DBU-mediated epimerization was also demonstrated (Scheme 13).[45]

2.3.5. Chiral trifluoromethylated tetrahydrofurans (CF3-tetrahydrofurans) Tetrahydrofuran skeletons are one of the most important and central building blocks in medicinal and pharmaceutical chemistry.[50] The efficient formation of chiral CF3-tetrahydrofuran backbones is of particular synthetic interest in drug design. In 2012, the Shibatomi group devised the first asymmetric version of CF3-containing building blocks based on the Diels– Alder reaction to achieve CF3-tetrahydrofurans. When using

2.3.4. Chiral trifluoromethylated pyrrolidinones (CF3-pyrrolidinones) Pyrrolidinone, also referred to as lactam, is a key fragment of some fairly common natural products and pharmaceuticals. &

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Review 2.3.6. Chiral trifluoromethylated tetrahydrothiophenes (CF3tetrahydrothiophenes) As already explored in several previous reports, CF3-enone 1 has two reaction sites. When compound 1 is coupled together with other reactive components that have the same function, cascade cyclizations can be triggered by chiral catalysts to assemble CF3-substituted heterocycles. Bearing this in mind, Xu and co-workers investigated the organocatalytic sulfa-Michael/aldol tandem reactions[54] to construct chiral CF3-tetrahydrothiophenes. After systematically studying various reaction parameters with 1,4-dithiane-2,5-diol 51’ as the latent precursor to mercaptoaldehyde 51, the catalytic intermolecular cascade reaction was established by using the cinchona alkaloid derived squaramide catalyst 17 c. The chiral CF3-tetrahydrothiophenes 52 featuring three continuous stereocenters and a CF3quaternary carbon center were furnished in moderate to good yields (up to 87 %), diastereoselective ratios (up to 9:1) and enantioselectivities (up to 89 %). Compound 52 a could be diastereoselectively reduced to a chiral 1,3-diol 53 with the simultaneous formation of another stereocenter, which broadens the synthetic application of this cascade reaction. A plausible transition state is proposed in Scheme 16. These results indi-

Scheme 14. Catalytic enantioselective Michael addition of malonates to nitroalkenes for CF3-pyrrolidinone.

chiral oxazaborolidine activated by SnCl4 as catalyst 49[51] and furans as dienes, they successfully obtained several chiral CF3tetrahydrofuran carboxylates. The substrate scope at 78 8C in CH2Cl2 revealed that the CF3 group in the dienophiles is critical to efficient transformation. Moreover, the regioselectivity appeared to be very dependent on the structure of the furan when employing acrylate (E)-28 a as the starting material. 3Substituted furans resulted in endo-adducts in high diastereoselectivity, while 2-methyl furans provided facile access to exoadducts exclusively (exo/endo = 99:1). It should be noted that the ee values for all cycloadducts reached 99 %. In parallel, this Diels–Alder approach was applied to other fluoroalkylated cyclohexenes as nearly pure enantiomers, greatly extending their synthetic utility (Scheme 15).[52] Recently, Sun et al. implemented the two-step synthesis of a densely substituted tetrahydrofuran (95 % ee) containing a quaternary trifluoromethylated stereogenic center by means of a novel NHC-catalyzed asymmetric a-aldol reaction of racemic g-reducible enals and trifluoropyruvates.[53] Scheme 16. Organocatalytic cascade sulfa-Michael/adol reaction for CF3-tetrahydrothiophenes.

cate that catalyst 17 c plays a crucial bifunctional role in activating both reactants. Therefore, the two reactive partners can undergo an intramolecular sulfa-Michael addition. Subsequently, the enolate intermediate attacks the Si face of the tethered aldehyde, thus delivering the final product and regenerating the catalyst (Scheme 16).[55] Scheme 15. Catalytic asymmetric Diels–Alder reaction for CF3-tetrahydrofurans. Chem. Eur. J. 2015, 21, 1 – 22

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Review 2.4. Six-membered heterocycles 2.4.1. Efavirenz Efavirenz (VII), a class of medications referred to as non-nucleoside reverse transcriptase inhibitors, occupies a very important place in the treatment of human immunodeficiency virus (HIV) infection along with other medicines.[56] This molecule consists of a 3,1-benzoxazin-2-one scaffold with a trifluoromethylated stereogenic center. Initially, only stoichiometric asymmetric synthesis of the key chiral intermediate 55 was reported, so the development of a more cost-efficient process with a catalytic amount of a chiral source to generate enantioenriched 55 and Efavirenz is in high demand. Carreira’s group took the lead in accomplishing the catalytic enantioselective synthesis of Efavirenz. Inspired by the autocatalysis idea,[57] they established a protocol of semi-autocatalytic asymmetric alkynylations of trifluoromethylated ketone 54, which was highlighted by using 0.18 equivalents of (S)-55 and 0.3 equivalents of (1R,2S)-56 as co-ligands. The key synthetic target (S)-55 was thereby obtained in 67 % yield with 99.5 % ee, which would readily pave a cost-decreasing route for Efavirenz (Scheme 17).[58]

Scheme 18. Catalytic enantioselective trifluoromethylation of alkynyl ketone to generate Efavirenz.

2.4.2. Chiral trifluoromethylated dihydroquinazolinones (CF3dihydroquinazolinones) Among the various biologically active chiral heterocycles containing a CF3 group, CF3-substituted dihydroquinazolinones[62] are one of the most noticeable types. Already shown in Figure 1, the second-generation NNRTIs of DPC 961 (VIII), DPC 963 (IX), and DPC 083 (X) all share the same skeleton of dihydroquinazoline. The main challenge to synthesize such molecules is to install the chiral tertiary carbon center with a CF3 group in a catalytic asymmetric manner. In 2000, Nugent and co-workers reported the enantioselective addition of lithium cyclopropylacetylide 60 to an unprotected ketimine 59 for the synthesis of DPC 963 (IX) (85 % yield and 99.6 % ee after recrystallization from heptanes) (Scheme 19).[63] In 2004, Jiang and co-workers managed the

Scheme 17. Asymmetric autocatalysis enables the improved synthesis of Efavirenz.

Thereafter, the Shibata group offered another simple operation and alternative to the outcome of (S)-55, which involved the asymmetric direct trifluoromethylation of alkynyl ketone 57 and TMSCF3 in the presence of a catalytic amount of cinchonidine derivative 3 h and Me4NF.[59] This yielded 88 % of product (S)-55 albeit with moderate enantioselectivity (50 % ee). After recrystallization, (S)-55 with 94 % ee was harnessed into the synthesis of Efavirenz according to Carreira’s method (Scheme 18).[60] Interest in the rapid generation of Efavirenz prompted them to accomplish a new short synthesis with superior results. In order to acquire a high degree of enantiocontrol in the asymmetric trifluoromethylation step, modifying the cinchona alkaloid derived catalyst structure with two alkyoxyl groups and a bulkier benzyl group (3 i) resulted in a substantial increasing in the ee value (the results are indicated in parentheses in Scheme 18).[61]

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Scheme 19. Asymmetric alkynylation of CF3-ketimines to synthesize DPC 963.

synthesis of 4-methoxybenzyl ether (PMB)-protected DPC 961 65 by means of a chiral amino alcohol (64 a) mediated enantioselective alkynylation addition reaction (Scheme 20).[64] However, a drawback of these two preliminary studies is the use of a stoichiometric amount of chiral mediator, which prompted 10



Review In 2011, Wang’s group addressed the multistep synthesis of DPC 083 by means a catalytic enantioselective aza-Henry reaction of ketimines 62 and nitroalkanes 69.[67] The strong electron-withdrawing nature of the CF3 group in 62 played a key role in enhancing the reactivity of ketimines (up to 97 % yield), while the challenge in enantiofacial discrimination was overcome under the catalysis of 17 d with only 1 mol % loading (up to 98 % ee). However, replacing a proton of nitromethane with other substituents, such as methyl, ethyl, and cyclopropyl methyl groups, resulted in moderate diastereoselectivity. Column chromatography could separate the two 70 a diastereomers (d.r. = 1.5:1), which were used to simultaneously prepare the final product DPC 083 in 38 and 21 % yield. No erosion of enantioselectivity occurred during the transformation of the major diastereomer of 70 a to the final DPC 083 (90 % ee), but a substantial enrichment of the S-enantiomer for a minor one took place (from 70 to 95 % ee) (Scheme 22).[68]

Scheme 20. Asymmetric alkynylation of CF3-ketimines to synthesize PMBprotected DPC 961.

chemists to investigate catalytic asymmetric ways to achieve the same result. In 2008, Jiang and co-workers developed a new synthetic strategy for DPC 083 (X) based on a catalytic asymmetric Mannich reaction.[65] When using acetone and cyclic ketimine 62 b as starting materials, the combination of chiral diamine 67 and dibenzoyl l-tartaric acid (l-DBT) at a 1:1.1 molar ratio turned out to be the best choice of catalyst for the chiral b-amino carbonyl product 68 a (92 % yield and 71 % ee). Under these optimized conditions, high regioselectivity on the methyl site of non-oxygen-substituted unsymmetrical ketones was observed in most cases. The N-protecting group of 62 was unable to improve the enantioselectivity (up to 79 % ee), but was essential to the unexpected formation of a racemic C2-symmetric heterochiral dimer of 68 through multiple hydrogen bonds in ethanol. By virtue of this interesting self-recognition phenomenon, highly enantiopure 68 (> 99.1 % ee) could be found in the mother liquor at the expense of a small loss in yield. In this way, the synthetic precursor (68 b) to DPC 083 was accessed in 67 % yield with > 99 % ee. Eventually, the concise synthesis of DPC 083 (> 99.9 % ee) was successfully carried out in three steps: 3,3’,5,5’-tetramethylbenzidine (TMB) deprotection, ketone reduction, and dehydration (Scheme 21).[66]

Scheme 22. Catalytic enantioselective aza-Henry reaction of ketimines 62 to synthesize DPC 083.

The asymmetric synthesis of DPC 083, as introduced in the above two cases, suffered from moderate yield and ee value during the key step of asymmetric catalysis. Highly catalytic enantioselective transformation to DPC 083 is still particularly demanding. Toward this end, in 2012, the Ma group envisioned that the catalytic enantioselective Strecker reaction of cyclic ketimines could incorporate a useful cyano-functional group,[69] which remained unexplored chemistry. The study of the model reaction between 62 a and trimethylsilylformonitrile (TMSCN) to give 72 a revealed that thiourea catalysts 17 b and 17 e gave opposite enantiomers with the best comparable results. Different chiral trifluoromethylated a-amino nitriles 72 with or without a PMB-protecting group were furnished in excellent yields (93–99 %) and enantioselectivities (90–97 % ee). The replacement of the CF3 group in 62 with a phenyl group proved to be unsuccessful (50 % yield and 80 % ee for 5 days). The syn-

Scheme 21. Catalytic asymmetric Mannich reaction of ketimines 62 to synthesize DPC 083. Chem. Eur. J. 2015, 21, 1 – 22

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Figure 3. Proposed reaction pathway of the catalytic asymmetric DMR.

structurally diverse, and trifluoromethylated-fused heterocycles 75 and DPC 083 were exemplified with the asymmetric DMR adducts. However, the diastereochemistry of the ketone reduction step (< 3:1 d.r.) during the transformation needed to be improved (Scheme 24).[73] Shortly thereafter, in the same year,

Scheme 23. Organocatalytic enantioselective Strecker reaction of ketimines 62 to synthesize DPC 083.

thetic utility of (R)-72 a (obtained from catalyst 17 e) to DPC 083 (98 % ee) was exhibited over three steps with total yield being 32 %. As the presumed transition state shown in Scheme 23, the thiourea catalyst captures both components through hydrogen bonding. The activated cyanide group nucleophilically attacks at the imine carbon from a favorable position, namely the Re face.[70] Later in the same year, a similar strategy, that is, an organocatalytic asymmetric Strecker reaction, under a with different solvents and at a much lower temperature was also published by Wang and co-workers.[71] Encouraged by the above result, the Ma group continued to cleave another general entry to DPC 083 entailing the catalytic enantioselective decarboxylative Mannich reaction (DMR) of 62 and b-ketoacids 13.[72] Compared to the general Mannich reaction, DMR, which has the advantage of exclusive regioselectivity, has been less studied. The methodological extension from aldimines to ketoimines, such as 62, remained unexplored until this publication.[72] At a low temperature of 20 8C, the racemic background reaction was suppressed with the aid of chiral aminothioureas 73 developed by the same group, and up to 99 % yield and > 99 % ee were exhibited. A fair amount of aromatic and alphatic b-ketoacids, as well as cyclic CF3-ketoimines 62 with various substituents on the phenyl ring, were well tolerated under the optimal conditions. However, cyclic ketoimines 62 with a methyl or phenyl group instead of a CF3 group were completely inactive. In addition, the N-protecting group of 62 is critical to high enantio-induction, which suggests a possible H p bonding interaction between 62 and catalyst 73 (Figure 3). Multiple hydrogen bonds revealed by further computational studies, together with electrostatic bonds may also play an important role in the asymmetric conversion. Thus the nucleophilic attack on the preferred Si face of 62, followed by decarboxylation, provided (R)-74 by using catalyst d(S,S)-73. Two expeditious entries to enantiomerically enriched, &

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Scheme 24. Catalytic asymmetric DMR of b-ketoacids and ketimines for DPC 083 and heterocycle 75.

Ma and co-workers expanded this asymmetric DMR methodology for less reactive malonic acid half oxyesters, and the ability of the DMR product to undergo a further five-step total synthesis of DPC 083 considerably enhanced the importance of this methodology.[74] From the point of view of drug-resistant virus strains, the exploration of new NNRTIs bearing a CF3-dihydroquinazolinone 12



Review skeleton is quite necessary. In this context, besides serving as prochiral building blocks for fabricating DPC 963 and DPC 083, cyclic ketimines 62 have been asymmetrically transformed to other enantioenriched dihydroquinazolinone derivatives to improve drug potency. In 2012, Ma and co-workers found that the catalytic enantioselective diynylation[75] of 62 proceeded smoothly under similar reaction conditions to those used in Jiang’s work,[64] albeit by using a catalytic amount of chiral amino alcohol ligand 64 b. The reaction showed good tolerance of broad functional groups in diynes 76 and delivered a series of diynylated tertiary carbinamines (R)-77 in good to excellent yields (up to 98 %) and enantioselectivities (up to 99 % ee). Additionally, further recrystallization could efficiently enhance the enantiopurity of compounds 77, which made this reaction more practical. Importantly, the resulting compound (S)-77 obtained by using the ent-64 b catalyst was turned into (E)-enyne (S)-78 (94 % yield and 93 % ee), and featured a very similar structure to DPC 083, and cerium(IV) ammonium nitrate (CAN)-mediated PMB deprotection and regioselective alkyne reduction by LiAlH4 was achieved (Scheme 25).[76]

Scheme 26. Pd-catalyzed asymmetric hydrogenation of cyclic ketoimines.

a substrate without the N-protecting group was also attempted with excellent results (94 % yield and 98 % ee).[78] The asymmetric Friedel–Crafts reaction that uses prochiral trifluoromethylated compounds as starting materials provides an excellent opportunity to access trifluoromethylated derivatives of chiral aromatic compounds.[79] In this context, as part of continuing efforts in synthetic fluorine chemistry, the Ma group became interested in combining two important heterocycles of indole and dihydroquinazolinone into a new heterocyclic molecule. With the help of a chiral BINOL-derived phosphoric acid catalyst 81,[80] the asymmetric aza-Friedel–Crafts reaction between 62 and indoles yielded CF3-dihydroquinazolinones 82 with a chiral tetrasubstituted carbon stereocenter containing CF3 and indole groups in uniformly high yields (up to 98 % yield) and enantioselectivity (up to 98 % ee) with the exception of substrate 5-cyanoindole (56 % yield and 93 % ee). The N-protecting group effect revealed that the presence of a protecting group for ketimine 62, but the absence of indoles, is beneficial to a high ee. This sheds light on the proposed transition state model of two substrates being captured concomitantly by the catalyst through favorable multiple hydrogen-bond interactions (Scheme 27).[81] In view of the importance of the a-amino phosphonate motif for mimicking a-amino acids in pharmaceutically interesting molecules,[82] in 2013 Wang’s group tested phosphites as nucleophiles in the first report of an enantioselective hydrophosphonylation reaction with cyclic ketimines 62. Employing the same catalytic strategy as their initial report in the azaHenry reaction,[68] Sos’ catalyst 83 was selected to promote the yield of various CF3-dihydroquinazolinones 84 bearing CF3 and phosphonyl groups at the quaternary stereogenic center in moderate to excellent yields (62–97 %) with a high level of chirality transfer (81–93 % ee). The plausible transition state depicted in Scheme 28 indicates that catalyst 83 acts both as a hydrogen-bond donor and acceptor. Within the preferential framework, a nucleophilic attack from the Re face of ketimines 62 leads to adduct (R)-84 (Scheme 28).[83]

Scheme 25. Catalytic enantioselective addition of diynes to cyclicketimines.

Asymmetric hydrogenation of heteroaromatic or cyclic unsaturated compounds provides a convenient way for the synthesis of optically active cyclic compounds.[77] In 2013, Ma and Zhou collaboratively studied the catalytic asymmetric hydrogenation of compounds 62 on the basis of their common research interests. Compounds 62 form a class of cyclic ketimines that have a CF3 group at the unsaturated carbon site; these compounds should be interesting candidates as starting materials for the formation of the corresponding hydrogenated adducts of CF3-dihydroquinazolinones in a highly atom-economic fashion. Guided by their achievement on asymmetric hydrogenation, CF3-dihydroquinazolinones 79 bearing various substituents on the phenyl ring were reported with high to excellent yields (89–98 %) and excellent enantioselectivities (95– 98 % ee) by utilizing a prepared chiral Pd-SynPhos complex as the catalyst and high pressure H2 gas (Scheme 26). Notably, Chem. Eur. J. 2015, 21, 1 – 22

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2.4.3. Chiral trifluoromethylated d-lactones and d-lactol (CF3d-lactones and CF3-d-lactol) d-Lactones and d-lactols constitute a class of key structural motifs present in many natural or unnatural compounds. dLactols, which are the cyclic equivalents of hemiacetals or hemiketals present in many sugars, can be formed by the in13


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Review heterocycles. Through a cascade asymmetric catalysis of the Michael and aldol reactions,[85] a,b-unsaturated trifluoromethyl ketones 85 and a-cyanoketones 86 were converted into the desired unsaturated d-lactols 88 with two non-adjacent chiral centers in the presence of a chiral piperazine-based thiourea catalyst 87. High to excellent yields (97–99 %) were obtained except for 86 with a R2 group of tert-butyl (62 % yield) or ethoxyl groups (0 % yield), which implies that yield is quite dependent on the facile enolization of a-cyanoketone substrates, but not on the substituent at the b-position of 85. However, the enantioselectivities (87–95 % ee) and diastereoselectivities (up to > 19:1) of all CF3-substituted d-lactol products were high. The catalytic cascade reaction could be operated with a scale-up to 0.5 mmol in 92 % yield and 90 % ee. Based on the absolute configuration of 88 a (4R,6S) and the bifunctional nature of catalyst 87, the presumed transition state is illustrated in Scheme 29. The a-cyanoketone is positioned to attack the Si face of the activated enones, then the catalytic cycle ends up with an intramolecular aldol cyclization to provide the target compounds (Scheme 29).[86]

Scheme 27. Catalytic asymmetric aza-Friedel–Crafts reaction of indoles and ketimines 62.

Scheme 29. Catalytic asymmetric synthesis of chiral CF3-substituted d-lactols.

In 2010, Lu and co-workers described the two-step synthesis of chiral CF3-containing d-lactones 93 through a key catalytic enantioselective Michael addition reaction of 2,2,2-trifluoroethylidene malonates 89. With the aid of a prolinol silyl ether organocatalyst 91, the a-carbon of aldehyde 90 was activated through enamine catalysis.[87] The generation of adducts 92 that have two adjacent stereocenters with good to excellent enantioselectivities (91–99 % ee) and good diastereoselectivities (syn/anti up to 5.7:1) facilitated the preparation of the final dlactones 93 with three continuous chiral carbon centers. Meanwhile, the elucidation of the stereochemistry of 93 by NOE and COSY studies was helpful to understand the origin of enantioselectivity in the initial catalytic reaction (Scheme 30).[88] Previously, taking advantage of the catalytic function of NHC, the Ye group successfully completed the synthesis of CF3-containing b-lactones,[21] while the Glorius group created CF3-substituted g-lactones in quite low d.r. and enantioselectivities.[18c] Different from the previous popular activation of the a-, b-, or carbonyl-carbon atom in the prenucleophiles by

Scheme 28. Catalytic enantioselective hydrophosphonylation reaction of ketimines 62.

tramolecular nucleophilic addition of a hydroxyl group to the carbonyl group of aldehydes or ketones. Alternatively, they can be accessed through reducing d-lactones. In this context, the efficient construction of the chiral CF3-analogues of d-lactones or d-lactols constitutes one of the most active research areas. Among the synthetic strategies, catalytic asymmetric synthesis has become a very promising tool. On the other hand, the organocatalytic cascade reaction is a highly efficient method for the synthesis of structurally complex compounds from single acyclic precursors, and has been studied extensively and recognized as a useful tool for the construction of chiral CF3-d-lactones or CF3-d-lactol with multiple stereocenters.[84] In 2009, Zhao and co-workers firstly applied chiral thiourea catalyst into the catalytic asymmetric synthesis of CF3-bearing &

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Review

Scheme 30. Enantioselective organocatalytic Michael addition for CF3-containing d-lactones.

Scheme 31. Oxidative cooperatively catalytic reaction of enals for CF3-containing d-lactones.

NHCs, Chi’s group addressed the challenge of enal g-carbon functionalization by using synergistic catalysis with NHCs and Lewis acid co-catalysts.[89] CF3-containing d-lactones 97 were accordingly synthesized through the oxidative g-addition of enals 94 to trifluoromethyl ketones 5. Mechanistically (Figure 4), in the presence of NHC 95 a and the quinone oxi-

ated in the NHC 95 b-catalyzed redox esterification of p-nitrobenzoyloxyaldehydes 98 involving the nucleophilic addition of aldehyde, deprotonation, elimination and deprotonation steps, followed by an asynchronous endo-hetero-Diels–Alder reaction with b-trifluoromethyl enones 16 (Figure 5). When 98 bearing

Figure 4. Proposed mechanism of the oxidative g-addition.

Figure 5. Proposed reaction mechanism of the oxidative g-addition.

dant 96, the key vinyl enolate intermediate I is envisioned to be oxidatively generated, followed by a nucleophilic addition to ketones 5 for the formation of intermediate II owing to the linking function of a Sc(OTf)3 or Sc(OTf)3/Mg(OTf)2 co-catalyst. The control experiment revealed that the co-catalyst is critical to the excellent remote chirality transfer. Finally, intramolecular lactonization led to the desired unsaturated d-lactones 97 featuring a CF3-containing quaternary stereogenicity at the d-position (52–82 % yield and 60–94 % ee). It is worth noting that the simultaneous existence of aromatic groups at the b-position of enals and CF3-ketones results in relatively higher enantioselectivities (Scheme 31).[90] In 2013, Smith’s group reported a NHC-catalyzed redox asymmetric [4+2] cycloaddition[91] as a means to access the CF3-containing d-lactone product. In this reaction, the important azolium enolate intermediates were assumed to be generChem. Eur. J. 2015, 21, 1 – 22

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an alkyl group at the a-position was used, the target unsaturated d-lactones 99 with two vicinal stereocenters at a- and bsites could be accessed in moderate yields (up to 81 %) with excellent diastereocontrol (up to > 95:5 d.r.) and complete enantiocontrol (at least 99 % ee). It is worth noting that the stereoselectivity of the final products could be controlled by the configuration of the injected enones. The switch from (E)-16 to (Z)-16 varied the configuration of adducts 99 from syn to anti, which was proved by a further epimerization experiment (Scheme 32).[92] In keeping with the above strategy, when enones (E)-100 instead of 16 were chosen as CF3-containing building blocks, a new type of tri- and tetrasubstituted unsaturated d-lactones 101 with substituent variations at the C(3)-, C(4)-, and C(5)-positions was obtained in moderate to excellent yields (up to 15


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Scheme 32. NHC-Catalyzed redox hetero-Diels–Alder reactions for CF3-d-lactones.

99 % yield) with excellent stereochemical integrity (up to > 95:5 d.r. and > 99 % ee) with the same NHC catalyst as the above example. The LiAlH4 reduction of 101 was conducted to give rise to enantioenriched d-lactol 102 with a CF3-containing quaternary stereogenic center with good results (76–92 % yield, up to > 95:5 d.r. and 99 % ee). To further expand the synthetic utility of this catalytic reaction, d-lactol 103 with four consecutive chiral centers in an all-syn configuration was efficiently installed by Pd/C-catalyzed diastereoselective hydrogenation (76 % yield and > 95:5 d.r.) (Scheme 33).[93]

Figure 6. Proposed catalytic cycle for the asymmetric Michael–lactonization process.

omatic enones, the enone-bearing n-pentyl chain group at the b-position was readily converted to the corresponding CF3-dlactone in 73 % yield, 78:22 d.r., and 98 % ee. Morever, both syn- and anti-d-lactones 105, as well as the corresponding LiAlH4-reduction products of lactols 106 with two adjacent stereogenic centers and a CF3-containing quaternary stereogenicity could be obtained by judiciously selecting (Z)- and (E)enones, respectively (Scheme 34). Kinetic studies by using in

Scheme 33. Asymmetric synthesis of CF3-containing d-lactones and d-lactols by NHC redox catalysis.

Scheme 34. Synthesis of chiral CF3-containing d-lactones and d-lactols through catalytic asymmetric Michael–lactonization reactions.

A conceptually different strategy of using an isothiourea-catalyzed asymmetric cascade Michael–lactonization for encompassing the synthesis of CF3-containing d-lactones and d-lactols was demonstrated by the Smith group as well. They utilized isothiourea 104 as the catalyst to promote the formation of an active chiral C(1)-ammonium enolate (B) through N-acylation and deprotonation from aromatic acetic acid 103 (Figure 6). Intermediate B has a similar function as the azolium enolates already discussed in the previous case, and hence, a series of unsaturated anti-d-lactones 105 with a prochiral CF3-substituted carbon center was smoothly generated through an asymmetric cascade Michael–lactonization[94] by using (E)-CF3-enones 85 as the starting materials. Except for ar&

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situ 19F NMR spectroscopic analysis and a deuterium isotope experiment suggests that the rate-determining step is the formation of an acyl isothiuronium ion A from catalyst 104 and anhydride formed in situ from 103. Furthermore, the increase in diastereoselectivity with time and enhanced temperature, as well as the partial deuteration at the C(3) of adduct 105 from the a,a-dideuterated 103 (> 99 % D2) indicate that the in situ equilibration and epimerization at the C(3) during the reaction process indeed took place.[95]

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Review 2.4.4. Chiral trifluoromethylated pyrans (CF3-pyrans)

nostimulatory and anticancer) and therapeutic potential, considerable effort has been oriented toward the synthesis of heliotridane analogues.[98] The total synthesis of CF3-heliotridane devised by the Shibata group began with a highly efficient enantioselective Friedel–Crafts alkylation of b-CF3 acrylates 111 and pyrroles 112 in the presence of a chiral zinc Lewis acid (113/Zn(NTf2)2). A wide array of pyrrole derivatives without any heteroatom at the CF3-substituted stereocenter were delivered in good to excellent yields (90–99 %) with moderate to excellent enantioselectivities (up to 99 % ee). Besides chiral pyrroles, the synthetic ability of this Friedel–Crafts reaction to use both chiral C-2- and C-3-substituted indole was also exhibited. The Friedel–Crafts adduct 114 enabled the total synthesis of optically active CF3-heliotridane 115 in an overall 13 % yield, including the oxazolidinone-cleavage, reduction of pyrrole, annulation, and amide reduction processes (Scheme 36).[99]

Pyran is an important class of unsaturated oxygenated heterocycle found in some carbohydrates. In the light of the profound role of the pyran core and the CF3 group in the biological activities of many compounds,[96] organic chemists were encouraged to search for facile synthetic methodologies to build a trifluoromethylated pyran structure. The asymmetric incorporation of terminal alkyne functionality into molecules can allow for the further extensive elaboration of a heterocyclic framework, such as pyran. As introduced before, the catalytic asymmetric alkynylations of imines and ketones have already been developed as the key step for the general catalytic enantioselective synthesis of CF3-dihydroquinazolinones and Efavirenz. Toward the goal of synthesizing CF3-pyran heterocycles, Pedro’s group successfully established an organometal-catalyzed asymmetric 1,4-addition of terminal alkynes to b-CF3-a,b-enones 16 in high yields (up to 99 %) and enantioselectivities (up to 99 % ee), which has the following three features: 1) Owing to the activation of the CF3 group in the electrophiles, the reaction can proceed smoothly in the presence of CuI complexes; 2) it represents the first case of creating a CF3-bearing chiral alkynyl carbon without any heteroatom in a catalytic enantioselective manner; and 3) the chiral adduct of b-CF3 b-alkynyl ketone 109 was cyclized into a stereodefined heavily substituted 4-CF3-4H-pyran 110, while maintaining the ee (85 %) initiated by I2 (Scheme 35).[97]

Scheme 36. Catalytic asymmetric Friedel–Crafts reaction for the synthesis of CF3-heliotridane115.

Scheme 35. Catalytic asymmetric conjugate alkynylation to b-CF3enones for CF3-pyrans.

2.5.2. Chiral trifluoromethylated fused lactams 2.5. Chiral trifluoromethylated fused heterocycles

Trifluoropyruvates have been extensively investigated in an assortment of catalytic asymmetric reactions for the production of non-heterocyclic products. Toward installing some unique chiral CF3-substituted heterocycles for drug surrogates, Shibata et al. harnessed the bis-electrophilic nature of trifluoropyruvate 117 and elaborated a cinchona alkaloid/Ti(OiPr)4-catalyzed enantioselective tandem condensation–cyclization reaction of cyclic enamines 116 with diverse structures.[100] In the presence of different types of cinchona alkaloids, a range of highly substituted unsaturated g-lactam-cyclohexanones or g-lactam-dlactones featuring a conjugated enamine functionality were accessed in high yields (up to 99 %) along with good levels of enantioselectivity (up to 93 %), which facilitated the multipleoutput of several fused polycyclic heterocycles with interseting

In addition to monocyclic CF3-substituted heterocycles, attempts have also been made to assemble chiral trifluoromethylated fused heterocycles with potential biological or pharmaceutical application. Typically, a multistep synthetic strategy was exemplified for the following first three types of fused heterocycles, while a cascade cyclization strategy was applied in the last case. 2.5.1. Chiral trifluoromethylated heliotridane (CF3-heliotridane) Heliotridane is a pyrrolizidine alkaloid. Because of their pharmacological properties (such as cytotoxic, antimitotic, immuChem. Eur. J. 2015, 21, 1 – 22

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Review structures containing a trifluoromethylated lactam substructure (119–121) in few steps. In some cases, the target heterocycles with both enantiomers were generated by just tuning the configuration of the cinchona alkaloid (Scheme 37).[101] These studies provide attractive approaches for the development of new drugs with fused lactam heterocycles.

Scheme 38. Catalytic enantioselective Friedel–Crafts alkylation for CF3-tetrahydro-b-carboline.

ble increase in the ee value (from 91 to 94 %) was observed during the total synthesis of 125 (Scheme 38).[103]

2.5.4. Chiral trifluoromethylated tetrahydroimidazo[1,5-c]quinazoline Except for the asymmetric construction of several monocyclic molecules, very recently cyclic ketoimines 62 were also viewed as important building blocks for advanced fused heterocycles through cascade cyclization. In terms of the imine functional group of 62, Zhao and Shi selected isocyanoacetates 126 with two unique reactive sites as another reactant in the catalytic asymmetric Mannich/cyclization cascade reaction. The challenge of creating two adjacent quaternary carbon stereocenters was met through cooperative catalysis by using cinchona alkaloid squaramide 127 and AgOAc. As depicted by the postulated transition state model in Scheme 39, the bifunction-

Scheme 37. Catalytic asymmetric enamine–trifluoropyruvate condensation– cyclization reaction.

2.5.3. Chiral trifluoromethylated tetrahydro-b-carboline (CF3tetrahydro-b-carboline) Tetrahydro-b-carboline is a nitrogen-containing polycyclic indolic compound and represents an essential fragment for many biologically important indole alkaloids with novel pharmacological activities.[102] In pursuing the development of efficient catalytic asymmetric methodologies to create chiral trifluoromethylated compounds, Lu and co-workers selected a trifluoromethylated tetrahydro-b-carboline as the target. Indoles and trifluoroethylidene malonates 122 served as substrates in an enantioselective Friedel–Crafts reaction catalyzed by the chiral complex of 123/Cu(OTf)2. This protocol features high yields (up to 99 %), high enantioselectivities (up to 96 % ee), and good functional group compatibility. The Friedel–Crafts adduct 124 was capable of being further converted to a few CF3-substituted indole derivatives, as well as the desired CF3tetrahydro-b-carboline heterocycle 125 through diastereoselective monohydrolysis, Curtius rearrangement, Pictet–Spengler cyclization and tosyl deprotection in good yields. An observa&

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Scheme 39. Catalytic enantioselective Mannich/cyclization cascade reaction for trifluoromethylated tetrahydroimidazo[1,5-c]quinazolines.

18



Review al property of catalyst 127 through hydrogen-bonding activation is the key to excellent yields (up to 99 %), diastereoselectivities (up to > 15:1 d.r.), and good to excellent enantioselectivities (up to 98 % ee). The CF3 group in 62 again proved to be irreplaceable in this protocol without which the reaction would stop completely. This elegant approach to the chiral trifluoromethylated tetrahydroimidazo[1,5-c]quinazolines[104] may trigger more novel work on the catalytic enantioselective synthesis of CF3-substituted heterocycles from cyclic ketimine 62.[105]

Acknowledgements

3. Conclusion and Outlook

Keywords: asymmetric synthesis · heterocycles · organocatalysts · organometallic catalysis · trifluoromethylation

We gratefully thank the financial support of this investigation by the National Natural Science Foundation of China (21303128), Scientific Research Foundation for Returned Scholars ([2013]1792) and the Research Fund for the Doctoral Program of Higher Education of China (20130143120003) by the Ministry of Education of China, the Platform for Drug Discovery, Informatics, and Structural Life Science from MEXT Japan, and ACT-C from JST.

As illustrated in this review, catalytic asymmetric reactions have exhibited their power and versatility toward creating a library of optically active monocyclic CF3-substituted heterocycles with three-, four-, five-, and six-membered rings containing oxygen, nitrogen, or sulfur atoms, as well as four fused cyclic CF3-substituted heterocycles. It is generally recognized that the sophisticated methods developed for trifluoromethylated substrates are not appropriate for nonfluorinated substrates, and a CF3 substituent has a major impact on governing the success of related chemistry.[106] From this survey of catalytic asymmetric synthesis of CF3-substituted heterocycles, three- and fourmembered heterocycles remain much less studied, and the catalytic asymmetric synthesis of CF3-substituted heterocycles larger than six-membered rings are still unexplored. Very rare examples of the utilization of the direct trifluoromethlyation pathway exist at this stage despite the advantage over the building-block approach. Moreover, arguably more important direct asymmetric trifluoromethylation of heterocycles, in contrast to the building block strategy, have not been identified for the retention of aromaticicity—rather a non-conjugated system is formed. Notably, in this research area, organocatalytic methods have involved more effort than organometallic catalysis, while the relatively high catalyst loading and low reactivity of organocatalysts seem to be insuperable barriers for the intensive application in large-scale industrial processes. Given the importance and high demand of CF3-substituted heterocycles in synthetic organic, medicinal, and agrochemical chemistry, there will be an ever-growing inventory of new synthetic strategies. Among future research of great interest will be the development of new asymmetric trifluoromethylation strategies with cheap reagents,[107] prochiral trifluoromethyl substrates, as well as the development of novel privileged catalysts that are able to address the challenge in catalytic asymmetric protocols for the construction of enantiopure trifluoromethylated heterocyclic frameworks with wide structural and functional diversity. In the meantime, the discovery of new drugs and agrochemicals bearing a chiral CF3-heterocyclic skeleton will further stimulate attempts to create novel catalytic asymmetric approaches. The research efforts made in this field will ultimately contribute to lowering the cost of the corresponding medicines and developing new therapeutic agents. This under-developed research topic represents one of the new directions in asymmetric synthesis with promising applications and the prospect of spreading. Chem. Eur. J. 2015, 21, 1 – 22

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Review

REVIEW & Asymmetric Synthesis Y.-Y. Huang,* X. Yang, Z. Chen, F. Verpoort, N. Shibata* && – && Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a C CF3 Stereogenic Center

A myriad of biologically and pharmaceutically active molecules featuring a heterocyclic segment with a C CF3 stereogenic center are springing up, and some of them have been employed at the clinic stage. This review article

describes recent progress on the manufacture of heterocycles possessing a CF3 group at the stereogenic carbon center, prepared from catalytic asymmetric reactions.

Asymmetric Synthesis In their Review on page && ff, N. Shibata, Y.-Y. Huang et al. illustrate how catalytic asymmetric reactions have exhibited their power and versatility toward creating a library of optically active monocyclic CF3-substituted heterocycles with three-, four-, five-, and six-membered rings containing oxygen, nitrogen, or sulfur atoms, as well as four fused cyclic CF3-substituted heterocycles. This under-developed research topic represents one of the new directions in asymmetric synthesis with promising applications and the prospect of spreading.

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Catalytic asymmetric desymmetrization approaches to enantioenriched cyclopentanes.

Asymmetric Synthesis of Dipropionate Derivatives through Catalytic Hydrogenation of Enantioenriched E-Ketene Heterodimers.

Catalytic, asymmetric synthesis of phosphonic γ-(hydroxyalkyl)butenolides with contiguous quaternary and tertiary stereogenic centers.

Catalytic asymmetric aminohydroxylation with amino-substituted heterocycles as nitrogen sources.

Amino acid chirons: a tool for asymmetric synthesis of heterocycles.

Recent advances in asymmetric synthesis of Р-stereogenic phosphorus compounds.

Catalytic Asymmetric Synthesis of Phosphine Boronates.

Catalytic asymmetric formal synthesis of beraprost.

Catalytic Asymmetric Total Synthesis of (-)-Actinophyllic Acid.

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines.

One-Pot Catalytic Asymmetric Synthesis of Tetrahydrocarbazoles.

Direct catalytic asymmetric synthesis of pyrazolidine derivatives.

Asymmetric synthesis: cascades of catalytic selectivity.

Catalytic asymmetric synthesis of [2,3]-fused indoline heterocycles through inverse-electron-demand aza-Diels-Alder reaction of indoles with azoalkenes.

Aza-Prins Cascade Reaction.

Catalytic Asymmetric Total Synthesis of Hedyosumins A, B, and C.

Asymmetric intramolecular carbolithiation of achiral substrates: synthesis of enantioenriched (R)-(+)-cuparene and (R)-(+)-herbertene.

Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates.

Asymmetric synthesis of P-stereogenic diarylphosphinites by palladium-catalyzed enantioselective addition of diarylphosphines to benzoquinones.

Asymmetric Synthesis of P-Stereogenic Phosphinic Amides via Pd(0)-Catalyzed Enantioselective Intramolecular C-H Arylation.

P-Stereogenic PCP pincer-Pd complexes: synthesis and application in asymmetric addition of diarylphosphines to nitroalkenes.

Catalytic Asymmetric Formal Total Synthesis of (-)-Triptophenolide and (+)-Triptolide.

Catalytic Asymmetric Synthesis of anti-α,β-Diamino Acid Derivatives.

Catalytic asymmetric synthesis of sterically hindered tertiary α-aryl ketones.