Fragment-Based Reaction Discovery of Non-Ene-Type Carbon-Carbon Bond-Forming Reactions: Catalytic Asymmetric Oxetane Synthesis by Screening Olefinic Reactants without Allylic Hydrogen

Abstract

Through fragment-based reaction discovery, catalytic asymmetric [2+2] cycloaddition was found to produce oxetanes from trifluoropyruvate and olefinic reactants without allylic hydrogen. This non-ene-type carbon-carbon bond-forming reaction smoothly proceeded under the influence of chiral Pd or Cu complexes as Lewis acid catalysts. The [2+2] cycloaddition afforded the oxetane derivatives in high yields and enantioselectivities even under 0.1 mol% catalyst loading and solvent-free conditions.

Key words

fragment-based - Lewis acid catalyst - [2+2] cycloaddition - oxetane - trifluoromethyl

References and Notes

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• For Box-Cu-catalyzed carbonyl-ene reaction with glyoxylate, see:
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• 8 For a review on the biological activity of oxetin, see: Omura S. J. Antibiot.  1984,  37:  1324 
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13

Crystal data for 16: C₂₁H₂₇F₃N₂O₅; orthorhombic; space group P2₁2₁2₁; a = 6.3390 (11) Å, b = 17.252 (3) Å, c = 20.143 (4) Å; V = 2202.9 (7) Å^³; Z = 4; D _calc = 1.340 Mgm^-³; µ = 0.112 mm^-¹. All measurements were made
with a Bruker APEXII CCD area detector with graphite monochromated Mo-Kα radiation at 93 K. Of the 9577 reflections that were collected, 3935 were unique (R _int = 0.0329). R ₁ = 0.0716, wR = 0.1805, goodness of fit = 1.052; Flack Parameter = 0.1 (13), shift/error = 0.000. CCDC-838360 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

14

Enantioselective [2+2] Cycloaddition Catalyzed by ( S , S )- t -Bu-Box-Cu(2) (Table 2, entry 1); Typical Procedure: (S,S)-t-Bu-Box-Cu(OTf)₂ catalyst was prepared by the addition of Cu(OTf)₂ (3.6 mg, 0.01 mmol) to (S,S)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline) (3.2 mg, 0.011 mmol) under an argon atmosphere. The mixture was dried under vacuum for 1 h, then Et₂O (1.0 mL) was added under an argon atmosphere and the resulting suspension was stirred vigorously for 1 h at r.t. To the solution at -40 ˚C were added ethyl trifluoropyruvate 3 (26.5 µL, 0.2 mmol) followed by tri(isopropyl)silyl enol ether (9a; 20.0 mg, 0.1 mmol). After stirring at -40 ˚C for 2.5 h, the reaction mixture was directly loaded onto a short silica gel column (hexane-EtOAc, 1:1) to remove the catalyst. The solution was evaporated under reduced pressure. Purification by silica-gel chromatography (hexane-EtOAc, 20:1) gave the corresponding oxetane 11a (84% yield) as a clear liquid. The cis/trans ratio was determined by ^¹9F NMR analysis (cis/trans, 99:1; the major configuration of the oxetane products was determined to be cis from the results of NOE experiments, which are summarized in Scheme  [4] ).
(2 S ,4 R )-Ethyl 2-Trifluoromethyl-4-(triisopropylsiloxy)-oxetane-2-carboxylate (11a): ^¹H NMR (300 MHz, CDCl₃): δ = 1.06 (m, 21 H), 1.33 (t, J = 7.2 Hz, 3 H), 2.82 (dd, J = 12.6, 4.2 Hz, 1 H), 3.11 (dd, J = 12.6, 5.1 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 5.90 (dd, J = 5.1, 4.2 Hz, 1 H); ^¹³C NMR (75.5 MHz, CHCl₃): δ = 11.8, 13.9, 17.5, 37.6 (q, J _C-F = 0.8 Hz), 62.6, 76.1 (q, J _C-F = 33.2 Hz), 95.7, 122.3 (q, J _C-F = 283.1 Hz), 167.6; ^¹9F NMR (282 MHz, CDCl₃): δ = -79.0 (s, 3 F); FTIR (neat): 2947, 2896, 2870, 1751, 1466, 1390, 1286, 1187, 1113, 1039, 919, 883, 685 cm^-¹; HRMS (APCI-TOF): m/z [M + H]⁺ calcd for C₁₆H₂₉F₃O₄Si: 371.1865; found: 371.1889; [α]_D ^²4 -4.48 (c 1.08, CHCl₃) for 98% ee (cis/trans = 99:1); GC (column, CP-Chirasil-Dex CB, i.d. 0.25 mm × 25 m, CHROMPACK; carrier gas, nitrogen 75 kPa; column temp. 120 ˚C; injection and detection temp. 150 ˚C): t _R = 36.2 (major isomer), 38.3 (minor isomer) min.
(2 S ,3 R ,4 R )-Ethyl 3-Benzyloxymethyl-2-trifluoromethyl-4-(triisopropylsiloxy)oxetane-2-carboxylate (11g): ^¹H NMR (300 MHz, CDCl₃): δ = 1.07 (m, 21 H), 1.31 (t, J = 7.2 Hz, 3 H), 3.62 (ddd, J = 9.6, 5.7, 4.2 Hz, 1 H), 3.75 (dd, J = 9.6, 4.2 Hz, 1 H), 4.13 (dd, J = 9.6, 9.6 Hz, 2 H), 4.32 (m, 2 H, OCH ₂CH₃), 4.46 (d, J = 18.6 Hz, 1 H), 4.50 (d, J = 18.6 Hz, 1 H), 5.96 (d, J = 5.7 Hz, 1 H), 7.29 (m, 5 H); ^¹³C NMR (75.5 MHz, CDCl₃): δ = 11.8, 13.9, 17.5, 47.5, 62.6, 63.1 (q, J _C-F = 2.3 Hz), 73.4, 80.3 (q, J _C-F = 32.5 Hz), 97.3, 122.2 (q, J _C-F = 285.4 Hz), 127.7, 127.8, 128.3, 137.7, 167.5; ^¹9F NMR (282 MHz, CDCl₃): δ = -72.8 (s, 3 F); FTIR (neat): 2947, 2869, 1750, 1656, 1466, 1278, 1200, 1091, 1028, 883, 688 cm^-¹; HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₃₇F₃NaO₅Si: 513.2260; found: 513.2281; [α]_D ^²5 +30.68 (c 1.39, CHCl₃) for 90% ee (cis/trans = 97:3); HPLC (column, CHIRALPAK AS-H, Hexane/2-Propanol = 97/3, flow rate 0.6 mL/min, 20 ˚C, detection, UV 218 nm): t _R = 33.6 ( minor isomer), 41.5 (major isomer) min.
Enantioselective [2+2] Cycloaddition Catalyzed by ( S )-BINAP-Pd(1b) (Table 2, entry 3); Typical Procedure:
To a solution of PdCl₂[(S)-BINAP] (8.0 mg, 0.01 mmol) in toluene (1.0 mL) was added AgSbF₆ (7.6 mg, 0.022 mmol) at r.t. under an argon atmosphere. After stirring for 30 min, ethyl trifluoropyruvate 3 (26.5 µL, 0.2 mmol) and freshly distilled vinyl acetate 9h (9.3 µL, 0.1 mmol) were added to the mixture at -20 ˚C. After stirring at -20 ˚C for 15 h, Et₃N (50 µL) was added and the mixture was directly loaded onto a short silica gel column (hexane-EtOAc, 1:1) to remove the catalyst. The solution was evaporated under reduced pressure. Purification by silica-gel chromatography (hexane-EtOAc, 4:1) gave the corresponding oxetane product 11h as a clear liquid (88% yield). The diastereo-meric ratio was determined by ^¹9F NMR analysis (dr = 77:23).
Enantioselective [2+2] Cycloaddition Catalyzed by ( S )-BINAP-Pd(1b) under Solvent-Free Conditions (Table 2, entry 7): To a solution of PdCl₂[(S)-BINAP] (4.0 mg, 0.005 mmol) in ethyl trifluoropyruvate 3 (1.3 mL, 10 mmol) was added silver hexafluoroantimonate (3.8 mg, 0.011 mmol) at r.t. under an argon atmosphere. After stirring for 30 min, freshly distilled vinyl acetate 9h (461 µL, 5 mmol) was added to the mixture at -20 ˚C. After stirring at -20 ˚C for 48 h, Et₃N (50 µL) was added and the mixture was directly loaded onto a short silica gel column (hexane-EtOAc, 1:1) to remove the catalyst. The solution was evaporated under reduced pressure. Purification by silica gel chromatography (hexane-EtOAc, 4:1) gave the corresponding oxetane product 11h as a clear liquid (86% yield). The diastereo-meric ratio was determined by ^¹9F NMR analysis (dr = 92:8).
(2 R )-Ethyl 4-Acetoxy-2-(trifluoromethyl)oxetane-2-carboxylate (11h): ^¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, J = 7.2 Hz, 3 H), 2.12 (s, 3 H), 3.04 (ddq, J = 13.2, 4.2 Hz, J _H-F = 0.6 Hz, 1 H), 3.27 (dd, J = 13.2, 5.4 Hz, 1 H), 4.36 (q, J = 7.2 Hz, 2 H), 6.48 (dd, J = 5.4, 4.2 Hz, 1 H); ^¹³C NMR (75.5 MHz, CDCl₃): δ = 13.6, 20.5, 33.4, 62.8, 78.1 (q, J _C-F = 34.0 Hz), 93.4, 122.7 (q, J _C-F = 283.1 Hz), 165.4, 168.8; ^¹9F NMR (282.4 MHz, CDCl₃): δ = -79.4 (s, 3 F, major isomer), -79.3 (s, 3 F, minor isomer); FTIR (neat): 2990, 1764, 1447, 1371, 1308, 1219, 1096, 1037, 961, 679 cm^-¹; HRMS (APCI-TOF): m/z [M + H]⁺ calcd for C₉H₁₁F₃O₅: 257.0637; found: 257.0680; [α]_D ^²5 +42.97 (c 1.21, CHCl₃) for 98% ee/94% ee (dr = 85:15); GC (column, CP-Chirasil-Dex CB, i.d. 0.25 mm × 25 m, CHROMPACK; carrier gas, nitrogen 75 kPa; column temp 85 ˚C; injection and detection temp, 115 ˚C): t _R = 20.0 ( major isomer), 22.0 (minor isomer) min.