Synthesis of Chiral Nonracemic α-Difluoromethylthio Compounds with

Letter Cite This: Org. Lett. 2018, 20, 7044−7048

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Synthesis of Chiral Nonracemic α‑Difluoromethylthio Compounds with Tetrasubstituted Stereogenic Centers via a PalladiumCatalyzed Decarboxylative Asymmetric Allylic Alkylation Hiroya Kondo,† Mayaka Maeno,† Kenta Sasaki,† Ming Guo,† Masaru Hashimoto,‡ Motoo Shiro,§ and Norio Shibata*,†,⊥

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†

Department of Nanopharmaceutical Sciences and Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan ‡ Faculty of Agriculture and Life Science, Hirosaki University, 3-Bunkyo-cho, Hirosaki 036-8561, Japan § Rigaku Corporation, 3-9-12, Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan ⊥ Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue, 321004 Jinhua, China S Supporting Information *

ABSTRACT: The synthesis of chiral, nonracemic difluoromethylthio (SCF2H) compounds that contain a tetrasubstituted stereogenic center is reported. Racemic α-SCF2H-β-ketoallylesters 5 were initially prepared by an electrophilic difluoromethylthiolation of β-ketoallylesters 6, followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA) to provide a wide variety of chiral, nonracemic α-allyl-α-SCF2H-ketones (4) with high enantiopurity. This strategy can be extended to the enantioselective synthesis of chiral, nonracemic α-allyl-α-trifluoromethylthio(SCF3)-ketones (7). luorine and fluoro functional groups are important tools for the evolution of pharmaceuticals and agrochemicals.1 Sulfur-containing molecules represent another attractive scaffold in pharmaceuticals and agrochemicals.2 Against this background, the creation of new functional groups that contain fluorine and sulfur (e.g., SCF3, SO2CF3, and SF5) is of great importance for the academic and industrial development of novel therapeutics.3 In particular, the organic synthetic chemistry of SCF3-containing molecules has bloomed in recent decades.4,5 One of the most attractive properties of the SCF3 group that justifies its introduction into biologically active molecules is its remarkable lipophilicity, quantified by the Hansch hydrophobic parameter (πSCF3 = 1.44),6a−c which induces higher permeation across biological membranes and results in enhanced bioavailability.6d,e,7 However, drugs with high lipophilicity generally suffer from a high risk of metabolic clearance that may result in high toxicity.8 The difluoromethylthio (SCF2H) group is less lipophilic (πSCF2H = 0.68), and a weak hydrogen-bonding donor can provide drug candidates with an attractive balance between hydrophilic and lipophilic properties.7 Yet, synthetic routes to SCF2H-containing compounds are fewer compared to those to SCF3-contaning compounds.9 More surprisingly, reports on chiral, nonracemic SCF2H compounds with a tetrasubstituted stereogenic center remain, to the best of our knowledge, elusive in the SciFinder

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© 2018 American Chemical Society

database (assessed on August 31, 2018; Figure 1a). In recent years, several shelf-stable, electrophilic difluoromethylthiolation reagents (1−3) have been reported7a,b (Figure 1b).7b We have recently reported the asymmetric synthesis of α-trifluoromethoxy allyl ketones from trifluoromethoxy allyl enol carbonates by Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA)10 (Figure 1c).11 Encouraged by the success

Figure 1. Synthesis of chiral SCF2H-containing compounds with a tetrasubstituted stereogenic center. Received: September 19, 2018 Published: November 8, 2018 7044

DOI: 10.1021/acs.orglett.8b02998 Org. Lett. 2018, 20, 7044−7048

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Table 1. Optimization of the DAAA Reaction Conditionsa

of the aforementioned studies, we successfully developed the highly enantioselective synthetic protocol for the preparation of chiral, nonracemic SCF2H-containing compounds (4) with a tetrasubstituted chiral stereogenic carbon center (Figure 1d). For that purpose, racemic α-SCF2H-β-ketoallylesters (5) were initially prepared by an electrophilic difluoromethylthiolation of β-ketoallylesters (6) followed by a Pd-catalyzed DAAA to provide a wide variety of chiral, nonracemic α-allyl-α-SCF2Hketones (4) with high enantiopurity. The application of this strategy to the synthesis of chiral, nonracemic α-allyl-α-SCF3ketones is also disclosed. We initially prepared α-SCF2H-β-ketoallylesters 5 from βketoallylesters 6 by electrophilic difluoromethylthiolation using 17a (with a stoichiometric amount of K2CO3 in CH2Cl2) or 27b (with a catalytic amount of CuF2 and K2CO3 in DMAc) at rt in good yield (Scheme 1). Scheme 1. Preparation of α-SCF2H-β-ketoallylesters 5 by Electrophilic Difluoromethylthiolationa

run

ligand

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14d 15e

L1 L2 L3 L4 L5 L6 L7 L7 L7 L7 L7 L7 L7 L7 L7

THF THF THF THF THF THF THF CH2Cl2 1,4-dioxane CPME TBME TBME TBME TBME TBME

temp (°C) time (h) yield (%)b rt rt rt rt rt rt rt rt rt rt rt −40 −80 −40 −40

1 4 0.5 1.5 1.5 1.5 0.5 1 1.5 0.5 1 1 1 1 1

91 77 89 94 91 97 97 53 94 90 99 92 92 93 95

ee (%)c 5 5 4 43 31 34 70 73 60 73 79 91 89 89 90

a Reaction condition: 5a (0.05 mmol, 1.0 equiv), Pd2dba3 (5 mol %), ligand (12.5 mol %) in solvent (0.05 M) at prescribed temperature, unless otherwise noted. bIsolated yield. cEnantioselectivity was determined by HPLC. dReaction was performed at 0.05 M. eReaction was performed at 0.01 M.

Method A: β-ketoallylester 6 (1.0 equiv), 1 (1.2 equiv), and K2CO3 (1.1 equiv) in CH2Cl2 (0.175 M). Method B: β-ketoallylester 6 (1.0 equiv), 2 (2.0 equiv), CuF2 (20 mol %), and K2CO3 (20 mol %) in DMAc (0.08 M). bReaction was carried out at 40 °C. a

Scheme 2. Substrate Scope of α-SCF2H-β-ketoallylestersa

Subsequently, we examined the second step of this sequence in more detail. Optimization of the reaction conditions for the DAAA from allyl-2-SCF2H-1-indanone carboxylate 5a to the targeted chiral, nonracemic α-allyl-α-SCF2H-indanone 4a was examined using 5 mol % of Pd2(dba)3 (dba = dibenzylideneacetone) and 12.5 mol % of ligand L, in different solvents, at different temperatures (Scheme 2 and Table 1). Using L1 ((R)BINAP) in THF at rt afforded 4a in 91% yield with 5% ee (run 1, Table 1). L2 ((R)-(+)-SEGPHOS) and L3 ((S)-t-Bu-PHOX) also afforded 4a in good yield, albeit with low ee (runs 2 and 3). On the other hand, Trost-type ligands L4−L6 furnished 4a in good yield with 31−43% enantioselectivity (runs 4−6). Ligand L7 was identified as the most effective ligand for the DAAA reaction, and a remarkable increase of the ee was observed (70% ee; run 7). Subsequently, we optimized the solvent (runs 8−11) and found that the use of tert-butyl methyl ether (TBME) provided 4a in 99% yield with 79% ee (run 11). Moreover, the reaction temperature and concentration were examined (runs 12−15). The highest enantioselectivity (91% ee) was achieved at −40 °C in 0.05 M TBME (run 12). With the optimized reaction conditions in hand, we examined the substrate scope for this DAAA (Scheme 2). A variety of indanone-derived α-SCF2H-β-ketoallylesters (5) was converted into the corresponding products (4b−e), which contain

a

Reactions were carried out using 0.05−0.15 mmol of 1 in TBME (0.05 M) at −40 °C for 1 h with 5 mol % of Pd2(dba)3 and 12.5 mol % of L7, unless otherwise noted. bReaction was carried out at 40 °C.

electron-donating (Me or MeO) and electron-withdrawing (EW) halogen moieties (Cl or Br) on the aromatic rings, in good 7045

DOI: 10.1021/acs.orglett.8b02998 Org. Lett. 2018, 20, 7044−7048

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Organic Letters yield and excellent enantioselectivity (≤94% ee). The α-SCF2Hβ-ketoallylesters containing benzo-fused six- (5f−j) or sevenmembered rings (5h) also furnished the desired α-SCF2Hallylketones (4f−k) in good yield with high enantioselectivity. The DAAA proceeded with acyclic β-ketoallylester 5l to afford acyclic α-SCF2H-allylketone 4l, albeit with merely 19% yield with 33% ee. The lower reactivity of acyclic 5l is presumably due to the steric hindrance of the acyclic tetrasubstituted stereogenic carbon center. On the other hand, cyclic oxindole derivative 5m furnished 3-allyl-3-SCF2H-oxindole 4m in 67% yield with 74% ee, smoothly. It should be noted that our strategy can be extended to the synthesis of chiral, nonracemic α-allyl-α-SCF3-ketones (7) (Scheme 3). Similar to the case of the preparation of chiral,

ring and the benzene-fused ring size, whereas acyclic substrates and oxindole afforded a lower enantioselectivity (29−49% ee) (Scheme 5). Scheme 5. Substrate Scope of α-SCF3-β-ketoallylestersa

Scheme 3. Synthetic Sequence for the Preparation of Chiral, Nonracemic α-Allyl-α-SCF3-ketones (7) from 6 via 8

nonracemic SCF2H-ketones (4), α-SCF3-β-ketoallylesters (8) were initially synthesized by an electrophilic SCF3 reaction of βketoallylesters (6) using 9 or 10 (Scheme 4).

a

Reactions were carried out using 0.05−0.15 mmol 1 in TBME (0.05 M) at −80 °C for 1 h using 5 mol % of Pd2(dba)3 and 12.5 mol % of L7, unless otherwise noted. bReaction was performed at −20 °C. c Reaction was performed at 40 °C.

Scheme 4. Preparation of α-SCF3-β-ketoallylesters 8 by Electrophilic Trifluoromethylthiolationa

Unexpectedly, we found it very difficult to produce single crystals of SCF2H-substituted 4 and SCF3-substituted 7 suitable for single-crystal X-ray diffraction analyses. Derivatization of 7e (88% ee) to its 2,4-dinitrophenylhydrazone derivative 11 gave only the racemic crystals with structural disorder associated with SCF3 and allyl moieties (CCDC 1868015, Figure 2).

Figure 2. X-ray crystallography of 11 (racemic). Method A: β-ketoallylester 6 (1.0 equiv), 9 (1.3 equiv), and NaH (1.1 equiv) in THF (0.05 M) or DMAP (2.0 equiv) in toluene (0.1 M). Method B: β-ketoallylester 6 (1.0 equiv), 10 (2.0 equiv), CuF2 (20 mol %), and K2CO3 (20 mol %) in DMAc (0.08 M). a

Therefore, we estimated the absolute stereochemistry of the newly generated stereogenic center of the products based on a combination of their ECD and UV spectra, as well as theoretical calculations. First, the ECD spectra of 7a (five-membered ring) and 7f (six-membered ring) were measured (Figure 3). Surprisingly, they look like mirror images of each other. The Cotton effects at ∼320−330 nm can be assigned to the n → π* electron transition related to the carbonyl chromophores based on the UV absorption (or spectrum) (SI). However, application of the Octant rule12 is not practical due to the very weak intensities and the nearly symmetric structure of the stereogenic carbon center. Although characteristic Cotton effects were found at ∼210 nm for both 7a and 7f, the assignment of these bands is not straightforward given that these comprise plural electron excitation modes. DFT calculations based on the BHLYP/def2-TZVP model nicely reproduced these ECD spectra,13 which allowed us to conclude that both 7a and 7f

Under reaction conditions similar to those for the preparation of 4 (for the details of the optimization of the reaction conditions, see the Supporting Information (SI)), the DAAA reaction of α-SCF3-β-ketoallylesters 8 proceeded smoothly in the presence of Pd2(dba)3 (5 mol %) and L7 (12.5 mol %) in TBME (0.05 M) at −80 °C for 1 h to afford chiral, nonracemic SCF3-containing ketones (7). The substrate scope and the product distribution are almost identical to results from the DAAA reaction of the SCF2H substrates. All cyclic substrates were readily transformed into the desired α-allyl-α-SCF3containing ketones in high yield with high enantioselectivity (88−95% ee), independent of the substitution on the benzene 7046

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property of SCF3 and SCF2H presumably accelerate the initial decarboxylation followed by the stabilization of the resulting anion. As the chiral, nonracemic SCF2H-containing compounds with a tetrasubstituted stereogenic center were not available before, the results of this study constitute a useful addition to the toolkit for chiral drug discovery research.

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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.8b02998. Experimental and spectral details for all new compounds and all reactions (PDF)

Figure 3. Experimental ECD spectra of 7a (91% ee) and 7f (93% ee), as well as the calculated ECD spectra of (S)-7a and (R)-7f.

Accession Codes

CCDC 1868015 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

exhibit an S-configuration. The absorption bands at ∼250 nm can be assigned to the electron transitions of aromatic ring as well as the carbonyl group, although they are difficult to discuss with respect to the relation to their conformation. The strongest characteristic Cotton effect was observed at ∼210 nm, whereas the assignment of the electron transitions is difficult. As the determination of the absolute configuration using ECD spectra based on the octant rule proved to be very difficult, we used DFT calculations (BHLYP/def2-TZVP) of the corresponding ECD spectra. According to our previous report for the Pd-catalyzed Tsuji DAAA reaction of trifluoromethoxy allyl enol carbonates (Figure 1c), the formation of (S)-7a and (R)-7f was expected. It should be noted that the calculated ECD spectra for (S)-7a and (R)-7f are also mirror images of each other, which is consistent with their experimental spectra (Figure 2a). Thus, 7a and 7f were assigned as (S)-7a and (R)-7f. These results are in good agreement with the previous report of OCF3 analogues.11 It should be noted that this method is also applicable to the DAAA reaction of nonfluorinated substrate 12, although the enantioselectivity of product 13 was moderate (65% ee) (Scheme 6).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Masaru Hashimoto: 0000-0002-4508-2105 Norio Shibata: 0000-0002-3742-4064 Author Contributions

M.H. performed DFT calculations, and M.S. performed X-ray crystallographic analysis. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grants JP 18H02553 (KIBAN B) and JP 18H04401 (Middle Molecular Strategy).

Scheme 6. DAAA Transformation of Nonfluorinated 12 into 13

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REFERENCES

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In conclusion, we have achieved the first synthesis of chiral, nonracemic SCF2H-containing compounds with a tetrasubstituted stereogenic center via a two-step sequence that involves an electrophilic difluoromethylthiolation of β-ketoallylesters followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation. Using Trost-type chiral ligands allows the construction of tetrasubstituted stereogenic centers via a DAAA with very high enantiomeric excess (≤94% ee). A wide variety of chiral, nonracemic α-allyl-α-SCF2H-containing ketones with cyclic skeletons based on indanone, tetralone, benzosuberone, and oxindole were obtained for the first time, whereas acyclic αallyl-α-SCF2H-ketones were obtained with acceptable enantiopurity. Chiral, nonracemic α-allyl-α-SCF3-ketones can also be synthesized using a similar approach (≤95% ee). Both reactions are performed at a temperature much lower than that of general catalytic asymmetric Tsuji DAAA reactions. The high EW 7047

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