Construction of Chiral β-Trifluoromethyl Alcohols Enabled by Catalytic

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Construction of Chiral β‑Trifluoromethyl Alcohols Enabled by Catalytic Enantioselective Aldol-Type Reaction of CF3CHN2 Meng-Yu Rong,†,§ Lijun Yang,†,§ Jing Nie,† Fa-Guang Zhang,*,† and Jun-An Ma*,†,‡ †

Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P. R. of China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China

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S Supporting Information *

ABSTRACT: A zinc-/quinine-mediated enantioselective Aldol-type reaction of trifluorodiazoethane (CF3CHN2) with various aldehydes is described. This study demonstrated the feasibility of utilizing CF3CHN2 as an effective hard nucleophile in catalytic asymmetric transformations. Furthermore, the synthetic utility of this protocol is exemplified by the construction of a diverse set of chiral β-trifluoromethylated alcohols, including a valuable HDAC inhibitor precursor. Scheme 1. Catalytic Asymmetric Preparation of Chiral βCF3 Alcohols with Trifluoroethyl Nucleophiles

C

hiral trifluoromethylated alcohols are attractive structural motifs owing to their wide occurrence in biological molecules and active pharmaceutical ingredients (Figure 1),

Figure 1. Selected examples of bioactive molecules containing a chiral CF3−alcoholic unit.

Shibasaki group recently enabled the engagement of α-CF3 enolates in catalytic asymmetric Aldol reaction by employing a special 7-azaindoline moiety, thus offering a viable protocol to access densely functionalized enantioenriched β-CF3 alcohols (Scheme 1b).5 Despite these pioneering advances, available approaches for the asymmetric construction of various decorated chiral β-CF3 alcohols are often not straightforward.6 Therefore, aiming to tackle the ongoing challenge, we initiated a project by utilizing 2,2,2,-trifluorodiazoethane (CF3CHN2)

thus increasingly stimulating high interest in organic synthesis and medicinal chemistry.1 In this context, direct asymmetric trifluoromethylation of carbonyl compounds represents a powerful approach to generate various enantioenriched αCF3 aclohols.2 In stark contrast, accomplishing the analogous trifluoroethylation variant has proven extremely challenging due to the notorious β-elimination of fluoride in the trifluoroethyl nucleophiles.3 To overcome this limitation, Krische and co-workers described a remarkable enantioselective carbonyl allylation reaction with aldehydes or alcohols for the rapid assembly of chiral β-CF3 alcohols, albeit in a noble metal-catalyzed manner (Scheme 1a).4 Subsequently, the © XXXX American Chemical Society

Received: April 26, 2019

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DOI: 10.1021/acs.orglett.9b01468 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters as a potential trifluoroethyl source.7 While this unique fluorinated building block has found considerable applications in synthetic chemistry, the number of reports involving asymmetric C−C bond-forming transformations is still distinctly limited.8 Herein, we report our efforts to render CF3CHN2 as a feasible masked trifluoroethyl nucleophile in an enantioselective Aldol-type reaction with aldehydes (Scheme 1c).9−11 The synthetic utility of this method is demonstrated by facile construction of the corresponding chiral β-CF3 alcohols, including a valuable HDAC inhibitor precursor.1i The investigation was started by employing 2-naphthaldehyde 1a as the model substrate and diethyl zinc as the organometallic base. On the basis of previous studies,12,13 we initially anticipated that the widely used chiral BINOL compounds probably could perform as effective ligands in this transformation. Indeed, the desired diazo-Aldol adduct 2a was obtained in as high as 86% isolated yield, albeit with poor enantioselectivities (Table 1, entries 1−4). Subsequently, a set of various chiral amino alcohols (chloramphenicol-amine

derivative, Trost ligand, and several cinchona alkaloids) were evaluated to induce asymmetry in the reaction (entries 5−11). While acceptable yield was observed in most cases, the enantioselectivity was still far from satisfying. Interestingly, lowering the reaction temperature led to a dramatic increase in the ee values of product 2a (entries 12−15). Among them, the most competent result (90% ee of 2a with 85% yield) was obtained when the reaction was operated at −50 °C with quinine L7 as the chiral ligand (entry 14). Further optimizations including changing the reaction media or ligand loadings either completely suppressed the reaction (entries 16 and 17) or gave no significant improvements (entries 18 and 19). Finally, the opposite enantiomer of 2a could also be smoothly afforded by employing quinidine L8 as the choice of asymmetry inductor (entry 20). With the optimized conditions in hand, we subsequently turned our attention toward the scope of this catalytic enantioselective transformation. As summarized in Scheme 2, a wide range of aromatic aldehydes with electronically varied substituents, such as Me, OMe, F, Cl, Br, I, and CF3, at different positions on the phenyl ring, could readily participate in the ZnEt2/quinine-mediated reaction, thus affording the corresponding enantioenriched adducts 2b−2p in good yields with good to high enantioselectivities (80−88% yields and 81− 89% ee). Remarkably, phenyl aldehydes bearing a nitro group are well compatible with this transformation, as exemplified by the smooth generation of products 2q and 2r. Aldehydes with two or three substituted groups are also suitable substrates to afford the products 2s and 2t in good yields and enantioselectivities. Furthermore, this diazo-Aldol reaction could also be extended to naphthyl and heteroaryl aldehydes, giving rise to 2u−2b′ with pleasing results. In particular, pyridine, the most prevalent heteroaromatic core in pharmaceuticals,14 was also tolerated under identical conditions and furnished 2x−2b′ in good yields with acceptable enantiopurities. Aside from aromatic substrates, cinnamaldehyde, phenylethyl aldehyde, and phenylpropyl aldehyde could also engage in this transformation smoothly, thus delivering the corresponding CF3-containing alcohols 2c′−2e′ with comparable results. In addition, a series of simple aliphatic aldehydes could also be rendered as feasible substrates in this reaction, albeit by converting to CF3-hydrazones 3a−3e via a following ready hydrogenation process (Scheme 2, bottom).15 Finally, the absolute configurations of the obtained adducts are assigned by analogue via X-ray crystallographic analysis of hydrazone derivative 3f, which was generated by hydrogenation of corresponding diazo-Aldol adduct 2f′ under mild conditions (Scheme 3a). The valuable synthetic utility of the obtained diazo-Aldol adducts is showcased by the preparation of a diverse set of chiral β-CF3 alcohols (Scheme 3b and 3c). For instance, complete elimination of the diazo moiety can be achieved under hydrogen atmosphere with Pd/C, thus giving rise to βCF3 alcohol 4a in decent yield with constant ee values (Scheme 3b, 62%, 90% ee). The enantioenriched trifluoromethyl hydrazone 3g could also be afforded as a single geometric isomer via slightly changing the reduction conditions (Scheme 3b, 90%, 94% ee, E/Z > 20:1). Furthermore, enantioenriched trifluoromethyl-containing 1,2diol 7 has been facilely provided from 2a without any erosion of enantiopurity through a sequence of protection with acetic anhydride, direct oxidation with oxone, stereoselective reduction with NaBH4, and deacylation with potassium

Table 1. Optimization of the Reaction Conditionsa

entry

ligand

solvent

temp (°C)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d 19e 20

L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L7 L7 L7 L7 L7 L7 L7 L7 L8

THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF CH2Cl2 toluene THF THF THF

−10 −10 −10 −10 −10 −10 −10 −10 −10 −10 −10 −30 −40 −50 −60 −50 −50 −50 −50 −50

86 82 68 52 76 68 85 83 87 85 86 90 84 85 42 0 0 85 84 88

20 0 16 16 12 7 25 24 20 23 18 75 84 90 91 91 80 −87

a General reaction conditions: Under Ar atmosphere, a mixture of 1a (0.3 mmol), CF3CHN2 (0.9 mmol), chiral ligand (0.06 mmol), and ZnEt2 (0.6 mmol) in solvent (1.0 mL) was stirred at indicated temperature for 24 h unless otherwise noted. bIsolated yields. c Determined by HPLC analysis on a chiral stationary phase. d0.15 mmol of L7 was employed. e0.045 mmol of L7 was employed.

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DOI: 10.1021/acs.orglett.9b01468 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope of Catalytic Enantioselective Aldol-Type Reaction between CF3CHN2 and Aldehydes

Scheme 3. Preparation of Versatile Chiral β-CF3 Alcohols from the Diazo-Aldol Adducts

carbonate. Notably, by utilizing the developed enantioselective Aldol-type reaction as a key step, the HDAC inhibitor precursor 4b has been prepared in just two steps from simple aldehyde 1g′ with 88% ee in a total yield of 75% (Scheme 3c). In summary, we have developed the first catalytic enantioselective transformation that employs trifluorodiazoethane as an effective nucleophile with aldehydes. The use of ZnEt2-quinine as a chiral additive at low temperature serves as the key to the establishment of this asymmetric C−C bondforming reaction. Furthermore, the synthetic utility of this method is highlighted by facile preparation of chiral βtrifluoromethylated alcohols. Mechanistic elucidation, substrate scope expansion, and further applications are underway in our laboratory and will be reported in due course.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01468. Experimental details and spectral data of all the new compounds (PDF) Accession Codes

CCDC 1910918 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. C

DOI: 10.1021/acs.orglett.9b01468 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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(7) (a) Qiu, D.; Qiu, M.; Ma, R.; Zhang, Y.; Wang, J. Huaxue Xuebao 2016, 74, 472. (b) Mertens, L.; Koenigs, R. M. Org. Biomol. Chem. 2016, 14, 10547. (8) For reported catalytic asymmetric reactions with CF3CHN2, see: (a) Le Maux, P.; Juillard, S.; Simonneaux, G. Synthesis 2006, 2006, 1701. (b) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 1101. (c) Chai, Z.; Bouillon, J.-P.; Cahard, D. Chem. Commun. 2012, 48, 9471. (d) Xiong, H.-Y.; Yang, Z.-Y.; Chen, Z.; Zeng, J.-L.; Nie, J.; Ma, J.-A. Chem. - Eur. J. 2014, 20, 8325. (e) Tinoco, A.; Steck, V.; Tyagi, V.; Fasan, R. J. Am. Chem. Soc. 2017, 139, 5293. (f) Kotozaki, M.; Chanthamath, S.; Fujii, T.; Shibatomi, K.; Iwasa, S. Chem. Commun. 2018, 54, 5110. (9) For a previous nonenantioselective variant of the Aldol-type reaction between CF3CHN2 and aldehydes: (a) Pieber, B.; Kappe, C. O. Org. Lett. 2016, 18, 1076. For a sequential reaction involving anionic triflyldiazomethane and nitroolefins under basic conditions: (b) Das, P.; Gondo, S.; Tokunaga, E.; Sumii, Y.; Shibata, N. Org. Lett. 2018, 20, 558. (10) Alternatively, Morandi and Carreira reported a Lewis-acidcatalyzed homologation reaction of CF3CHN2 with aldehydes that led to β-trifluoromethyl ketones: Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 9085. (11) For an example of direct Mannich-type reaction of CF3CHN2 with imines: Guo, R.; Lv, N.; Zhang, F.-G.; Ma, J.-A. Org. Lett. 2018, 20, 6994. (12) For selected examples of enantioselective Aldol-type reactions of diazo compounds, see: (a) Yao, W.; Wang, J. Org. Lett. 2003, 5, 1527. (b) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390. (c) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009, 131, 1674. (d) Wang, F.; Liu, X.; Zhang, Y.; Lin, X.; Feng, X. Chem. Commun. 2009, 7297. (e) Benfatti, F.; Yilmaz, S.; Cozzi, P. G. Adv. Synth. Catal. 2009, 351, 1763. (f) Cui, H.-F.; Wang, L.; Yang, L.J.; Nie, J.; Zheng, Y.; Ma, J.-A. Tetrahedron 2011, 67, 8470. (g) Trost, B. M.; Malhotra, S.; Koschker, P.; Ellerbrock, P. J. Am. Chem. Soc. 2012, 134, 2075. (h) Du, F.; Zhou, J.; Peng, Y. Org. Lett. 2017, 19, 1310. (i) Ray, S. K.; Sadhu, M. M.; Biswas, R. G.; Unhale, R. A.; Singh, V. K. Org. Lett. 2019, 21, 417. (13) For a previous study on the reactivity of zinc trifluorodiazoethylide: Qin, S.; Zheng, Y.; Zhang, F.-G.; Ma, J.-A. Org. Lett. 2017, 19, 3406. (14) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (15) The direct diazo-Aldol adducts from these simple aliphatic aldehydes were too volatile to be isolated, thus a subsequent hydrogenation conversion to corresponding hydrazones was carried out. Please see the Supporting Information for details.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Fa-Guang Zhang: 0000-0002-0251-0456 Jun-An Ma: 0000-0002-3902-6799 Author Contributions §

M.-Y.R. and L.Y. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21472137, 21532008, and 21772142) and the National Basic Research Program of China (973 Program, 2014CB745100).

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REFERENCES

(1) (a) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455. (b) Huang, Y.-Y.; Zhang, X.; Chen, Z.; Verpoort, F.; Shibata, N. Chem. - Eur. J. 2015, 21, 8664. (c) Li, S.; Ma, J.-A. Chem. Soc. Rev. 2015, 44, 7439. (d) Noda, H.; Kumagai, N.; Shibasaki, M. Asian J. Org. Chem. 2018, 7, 599. (e) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822. (f) Chen, S.-H.; Lamar, J.; Guo, D.; Kohn, T.; Yang, H.-C.; McGee, J.; Timm, D.; Erickson, J.; Yip, Y.; May, P.; McCarthy, J. Bioorg. Med. Chem. Lett. 2004, 14, 245. (g) Martinborough, E.; Shen, Y.; Oeveren, A.; Long, Y. O.; Lau, T. L.; Marschke, K. B.; Chang, W. Y.; Lopez, F. J.; Vajda, E. G.; Rix, P. J.; Viveros, O. H.; Negro-Vilar, A.; Zhi, L. J. Med. Chem. 2007, 50, 5049. (h) Cavet, M. E.; Harrington, K. L.; Ward, K. W.; Zhang, J.-Z. Mol. Vis. 2010, 16, 1791. (i) Keana, J. F. W.; Ordentlich, P.; Goodenow, R. PCT Int. Appl. WO2009015237 A1, 2009. (j) Dahlgren, M.; Greenwood, J. R.; Harriman, G. C.; Kennedy-Smith, J. K.; Masse, C. E.; Romero, D. L.; Shelley, M.; Wester, R. T. PCT Int. Appl. WO 2016138352 A1, 2016. (2) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (b) Sodeoka, M.; Hamashima, Y. Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Ed.; 2012; Vol. 4, p 210. (c) Kawai, H.; Shibata, N. Chem. Rec. 2014, 14, 1024. (d) Huang, Y.-Y.; Yang, X.; Chen, Z.; Verpoort, F.; Shibata, N. Chem. - Eur. J. 2015, 21, 8664. (e) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683. (3) (a) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41, 817. (b) Uneyama, K.; Yamazaki, T. J. Fluorine Chem. 2017, 203, 3. (4) Gao, X.; Zhang, Y. J.; Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 4173. (5) (a) Yin, L.; Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2014, 136, 17958. (b) Brewitz, L.; Arteaga, F. A.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2015, 137, 15929. (c) Saito, A.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2017, 56, 5551. (d) Matsuzawa, A.; Noda, H.; Kumagai, N.; Shibasaki, M. J. Org. Chem. 2017, 82, 8304. (6) For alternative methods to access chiral β-CF3 aclohols: (a) Schedel, H.; Dmowski, W.; Burger, K. Synthesis 2000, 12, 1681. (b) Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier, W. R. Org. Lett. 2002, 4, 4671. (c) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875. (d) Shimada, T.; Yoshioka, M.; Konno, T.; Ishihara, T. Org. Lett. 2006, 8, 1129. (e) Franck, X.; Seon-Meniel, B.; Figadere, B. Angew. Chem., Int. Ed. 2006, 45, 5174. (f) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986. (g) Ni, Y.; Li, C.-X.; Wang, L.-J.; Zhang, J.; Xu, J.-H. Org. Biomol. Chem. 2011, 9, 5463. (h) Shen, N.-D.; Ni, Y.; Ma, H.-M.; Wang, L.-J.; Li, C.-X.; Zheng, G.-W.; Zhang, J.; Xu, J.-H. Org. Lett. 2012, 14, 1982. (i) Li, G.; Gagare, P. D.; Ramachandran, P. V. Tetrahedron Lett. 2014, 55, 5736. D

DOI: 10.1021/acs.orglett.9b01468 Org. Lett. XXXX, XXX, XXX−XXX