Enantioselective Iridium-Catalyzed Allylic Alkylations - Improvements and Applications Based on Salt-Free Reaction Conditions

Abstract

Simplified procedures for the Ir-catalyzed asymmetric allylic alkylation reaction are described that often allow substitution products to be obtained with ≥99% ee. Applications to syntheses of important chiral building blocks, such as the Taniguchi lactone and dimethyl 2-vinylcyclopropane-1,1-dicarboxylate, are presented.

Key words

Taniguchi lactone - iridium - enantioselectivity - allylic substitution - catalysis

References and Notes

• 1a Helmchen G. Dahnz A. Dübon P. Schelwies M. Weihofen R. Chem. Commun.  2007,  675 
• 1b Takeuchi R. Kezuka S. Synthesis  2006,  3349 
• 2a Feringa BL. Acc. Chem. Res.  2000,  33:  346 
• 2b Tissot-Croset K. Polet D. Gille S. Hawner C. Alexakis A. Synthesis  2004,  2586 
• 3a Bartels B. Helmchen G. Chem. Commun.  1999,  741 
• 3b Bartels B. Garcia-Yebra C. Rominger F. Helmchen G. Eur. J. Inorg. Chem.  2002,  2569 
• 3c Lipowsky G. Miller N. Helmchen G. Angew. Chem. Int. Ed.  2004,  43:  4595 ; Angew. Chem. 2004, 116, 4695
• 3d Streiff S. Welter C. Schelwies M. Lipowsky G. Miller N. Helmchen G. Chem. Commun.  2005,  2957 
• 3e Polet D. Alexakis A. Tissot-Croset K. Corminboeuf C. Ditrich K. Chem. Eur. J.  2006,  12:  3596 ; and references cited therein
• 4a Ohmura T. Hartwig JF. J. Am. Chem. Soc.  2002,  122:  15164 
• 4b Welter C. Koch O. Lipowsky G. Helmchen G. Chem. Commun.  2004,  896 
• 4c Leitner A. Shu C. Hartwig JF. Org. Lett.  2005,  7:  1093 ; and references cited therein
• 4d Polet D. Alexakis A. Org. Lett.  2005,  7:  1621 ; and references cited therein
• 4e Weihofen R. Dahnz A. Tverskoy O. Helmchen G. Chem. Commun.  2005,  3541 
• 5a López F. Ohmura T. Hartwig JF. J. Am. Chem. Soc.  2003,  125:  3426 
• 5b Shu C. Hartwig JF. Angew. Chem. Int. Ed.  2004,  43:  4794 ; Angew. Chem. 2004, 116, 4898
• 6 Kiener CA. Shu C. Incarvito C. Hartwig JF. J. Am. Chem. Soc.  2003,  125:  14272 
• 7a Dai L.-X. Tu T. You S.-L. Deng W.-P. Hou X.-L. Acc. Chem. Res.  2003,  36:  659 
• 7b Trost BM. Jiang C. Org. Lett.  2003,  5:  1563 ; and references cited therein
• 8a Weihofen R. Tverskoy O. Helmchen G. Angew. Chem. Int. Ed.  2006,  45:  5546 ; Angew. Chem. 2006, 118, 5673
• 8b Dahnz A. Helmchen G. Synlett  2006,  697 
• 9 Tsuji J. Shimizu I. Minami I. Ohashi Y. Tetrahedron Lett.  1982,  23:  4809 
• 10 Ishibashi F. Taniguchi E. Bull. Chem. Soc. Jpn.  1988,  61:  4361 
• 11a Stork G. Niu D. Fujimoto A. Koft ER. Balkovec JM. Tata JR. Dake GR. J. Am. Chem. Soc.  2001,  123:  3239 
• 11b Raheem IT. Goodman SN. Jacobsen EN. J. Am. Chem. Soc.  2004,  126:  706 
• 20a Carson CA. Kerr MA. Angew. Chem. Int. Ed.  2006,  45:  6560 ; Angew. Chem. 2006, 118, 6710
• 20b Quinkert G. Schmalz H.-G. Dzierzynski EM. Dürner G. Bats JW. Angew. Chem., Int. Ed. Engl.  1986,  25:  992 ; Angew. Chem. 1986, 98, 1023
• 21 Quinkert G. Schwartz U. Stark H. Weber WD. Adam F. Baier H. Frank G. Dürner G. Liebigs Ann. Chem.  1982,  1999 
• 22 Danishefsky S. Rovnyak G. J. Chem. Soc., Chem. Commun.  1972,  821 
• 23 Hayashi T. Yamamoto A. Ito Y. Tetrahedron Lett.  1988,  29:  669 

12

General Procedure for the Ir-Catalyzed Allylic Alkylation under Salt-Free Conditions Under argon, a solution of [Ir(COD)Cl]₂ (13.4 mg, 0.02 mmol) and L* (0.04 mmol) in anhyd THF (1.0 mL, content of H₂O <30 mg/L, Karl-Fischer titration) was treated with anhyd 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 11.1 mg, 0.08 mmol) and stirred for 5 min (L2) or 2 h (L1, L3).
Then, carbonate 1 (1.0 mmol), anhyd THF (4 mL) and the pronucleophile (1.4 mmol) were added, and the solution was stirred for the time and at the temperature stated in Table [1] . Conversion was monitored by TLC or GC. The solvent was removed under reduced pressure and the residue was analyzed with respect to the ratio of branched and linear product by ¹H NMR. Pure reaction products were obtained by flash column chromatography.

13

Analytical Data for (+)-( R )-Dimethyl {1-[(Trityl-oxy)methyl]prop-2-en-1-yl}malonate (2c) Oil; [α]_D ²⁰ +38.9 (c 0.99, CHCl₃; 99.5% ee (R)]. ¹H NMR (300 MHz, CDCl₃): δ = 3.05-3.25 (m, 3 H, OCH₂CH, OCH₂), 3.61, 3.67 (2 s, 6 H, OCH₃), 3.84 [d, J = 8.4 Hz, 1 H, CH(CO₂CH₃)₂], 5.14 (d, J = 8.4, 1 H, CH=CH _EH_Z), 5.16 (d, J = 17.3 Hz, 1 H, CH=CH_E H _Z), 5.94 (ddd, J = 17.1, 10.3, 8.8 Hz, 1 H, CH=CH₂), 7.25-7.34 (m, 9 H, Ph), 7.41-7.44 (m, 6 H, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 44.46 (d, OCH₂ CH), 52.22, 52.34 (2 s, OCH₃), 53.29 [d, CH(CO₂CH₃)₂], 64.25 (t, OCH₂), 86.68 (s, CPh₃), 118.01 (t, CH=CH₂), 126.97, 127.73, 128.68 (3 d, Ph), 135.67 (d, CH=CH₂), 143.78 (s, Ph), 168.53, 168.62 (2 s, CO₂CH₃). Anal. Calcd for C₂₈H₂₈O₅: C, 75.65; H, 6.35. Found: C, 75.52; H, 6.56. HRMS-FAB: m/z calcd for C₂₈H₂₇O₅
[M - H]⁺: 443.1858; found: 443.1838.

14

Synthesis of (+)-( S )-Methyl 3-[(Trityloxy)methyl]pent-4-enoate (2c′)
A suspension of (+)-(R)-2c (2.23 g, 5.01 mmol), NaCl (0.44 g, 7.52 mmol) and H₂O (0.56 mL, 31.06 mmol) in DMSO (8.2 mL) was stirred for 22 h at 160 °C. Then, the reaction mixture was cooled to r.t., diluted with H₂O (45 mL), and the aqueous layer was extracted with Et₂O (3 × 90 mL). The organic layers were combined, washed with brine (45 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatog-raphy.
HPLC Data for 2c′
Daicel Chiralcel AD-H, 250 × 4.6 mm, 5 µm, with guard cartridge 10 × 4 mm, 5 µm, n-hexane-i-PrOH 98:2, flow = 0.5 mL min^-1, r.t., 210 nm: t _R[(+)-(S)-2c′] = 13 min, t _R[(-)-(R)-2c′] = 18 min.
Analytical Data for (+)-( S )-(2c′) Oil; [α]_D ²⁰ +12.9 [c 1.00, CHCl₃; >99% ee (S)]. ¹H NMR (300 MHz, CDCl₃): δ = 2.37 (dd, J = 15.0, 8.2 Hz, 1 H, CH _aH_bCO₂CH₃), 2.67 (dd, J = 15.3, 5.9 Hz, 1 H, CH_a H _bCO₂CH₃), 2.82-2.96 (m, 1 H, CHCH₂O), 3.03 (dd, J = 8.7, 6.9 Hz, 1 H, CH _aH_bO), 3.16 (dd, J = 8.8, 5.3 Hz, 1 H, CH_a H _bO), 3.63 (s, 3 H, OCH₃), 5.06 (ddd, J = 10.3, 1.4, 0.9 Hz, 1 H, CH=CH _EH_Z), 5.09 (ddd, J = 17.2, 1.4, 1.3 Hz, 1 H, CH=CH_E H _Z), 5.78 (ddd, J = 17.4, 10.1, 7.4 Hz, 1 H, CH=CH₂), 7.20-7.37 (m, 9 H, Ph), 7.39-7.50 (m, 6 H, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 36.58 (t, CH₂CO₂CH₃), 40.68 (d, CHCH₂O), 51.42 (q, OCH₃), 65.91 (t, CH₂O), 86.49 (s, CPh₃), 116.05 (t, CH=CH₂), 126.93, 127.72, 128.70 (3 d, Ph), 138.22 (d, CH=CH₂), 144.05 (s, Ph), 172.91 (s, CO₂CH₃). Anal. Calcd for C₂₆H₂₆O₃: C, 80.80; H, 6.78. Found: C, 80.50; H, 6.82. HRMS-FAB: m/z calcd for C₂₆H₂₆O₃Na [M + Na]⁺: 409.1779; found: 409.1784.

15

Synthesis of the Taniguchi Lactone (+)-( S )-(4) ZnCl₂ (0.71 g, 5.15 mmol) was added to a solution of (+)-(S)-2c′ (1.89 g, 4.90 mmol) in CH₂Cl₂ (10 mL). The suspension was stirred at r.t. for 15 h. Phosphate buffer (pH 7, 100 mL) was added and the aqueous layer was extracted with Et₂O (3 × 100 mL). The organic layers were combined, dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatog-raphy.
GC Data for 4 Chrompack permethyl-β-cyclodextrin, 25 m × 0.25 mm, temperature program: 70 °C (20 min), then gradient 10 °C/min (11 min), then 180 °C (10 min), injector temperature 200 °C: t _R [(+)-(S)-4] = 27.0 min, t _R [(-)-(R)-4] = 27.1 min.
Analytical Data for (+)-( S )-4 Colorless oil; [α]_D ²⁰ +7.6 [c 1.10, EtOH, >99% ee (S)]. ¹H NMR (250 MHz, CDCl₃): δ = 2.35 (dd, J = 17.2, 8.9 Hz, 1 H, CH _aH_bCO₂), 2.64 (dd, J = 17.4, 8.2 Hz, 1 H, CH_a H _bCO₂), 3.07-3.30 (m, 1 H, CH), 3.98 (dd, J = 8.4, 8.4 Hz, 1 H, CH _a H_bO), 4.40 (dd, J = 8.4, 8.2 Hz, 1 H, CH_a H _bO), 5.13 (d, J = 10.1 Hz, 1 H, CH=CH _EH_Z), 5.15 (d, J = 17.1 Hz, 1 H, CH=CH_E H _Z), 5.74 (ddd, J = 17.3, 9.9, 7.5 Hz, 1 H, CH=CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 34.04 (d, CH), 39.69 (t, CH₂CO₂), 72.11 (t, CH₂O), 117.35 (t, CH=CH₂), 135.72 (d, CH=CH₂), 176.35 (s, CO₂). HRMS (EI): m/z calcd for C₆H₈O₂ [M]⁺: 112.0524; found: 112.0523.

16

HPLC and GC Data for 2 and 3 (Table 1) HPLC (Daicel columns, 250 × 4.6 mm, 5 µm with guard cartridge, 10 × 4 mm, 0.5 mL min^-1): 2a (Chiralcel OJ-H, n-hexane-i-PrOH 97:3, r.t., 210 nm) t _R[(-)-(S)-2a] = 58 min, t _R[(+)-(R)-2a] = 64 min; 2b (Chiralcel AD-H, n-hexane-i-PrOH 99:1, 20 °C, 220 nm) t _R[(+)-(R)-2b] = 12 min, t _R[(-)-(S)-2b] = 14 min, t _R[3b] = 15 min; 2c (Chiralcel OD-H, n-hexane-i-PrOH 98:2, 20 °C, 210 nm) t _R[(+)-(R)-2c] = 16 min, t _R[(-)-(S)-2c] = 19 min, t _R[3c] = 22 min.
GC [Chiraldex γ-Trifluoroacetyl (G-TA), 30 m × 0.25 mm × 0.125 µm, 50-100 °C, 1 °C/min, injector temperature 200 °C, detector temperature 250 °C]: t _R[(+)-(R)-2d] = 33 min, t _R[(-)-(S)-2d] = 34 min.

17

Product 5a was obtained as a ca. 2:1 mixture of diastereomers, which were not individually characterized.

18

HPLC Data for 5 (Table 2)
For 5a determined after demethoxycarbonylation to give (S)-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)pent-4-enenitrile (5a′).
Daicel Chiralcel OD-H, 250 × 4.6 mm, 5 µm, with guard cartridge 10 × 4 mm, 5 µm, n-hexane-i-PrOH 99:1, flow = 0.5 mL min^-1, 20 °C, 210 nm: t _R[(-)-(R)-5′a] = 15 min, t _R[(+)-(S)-5′a] = 24 min; t _R[(-)-(S)-5b] = 18 min, t _R[(+)-(R)-5b] = 22 min.^4b

19

Procedure for the Ir-Catalyzed Cyclization According to Scheme 6 The catalyst solution was prepared as described above¹² and was diluted with anhyd THF (4 mL).
(a) Preparation of 8a
The solution of the catalyst was cooled to the temperature stated in Table 3 and carbonate 7a (0.5 mmol) was added through a septum with a syringe. Conversion was monitored by TLC or GC. When conversion was complete or no further conversion was detected, Et₂O (5 mL) and sat. NH₄Cl solution (5 mL) were added without warming, and the mixture was extracted with Et₂O (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography.
As the reaction is reversible, work-up has to be started at low temperature by adding aq NH₄Cl solution. In order to prove reversibility, an enantiomerically enriched sample of (R)-7a (91% ee) was treated at r.t. according to the general procedure with ent-L2. In doing so, the ee decreased to 39% (R) within 19 h.
(b) Preparation of 8b
Carbonate 7b (0.5 mmol) was added to the catalyst solution prepared as described above, and the reaction mixture was stirred for the time stated in Table 3. For work-up, the mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography.

24

Analytical Data for (-)-( S )-Dimethyl 2-Vinylcyclo-butane-1,1-dicarboxylate ( ent -8b)
Colorless oil; [α]_D ²⁰ -154.7 [c 1.00, CHCl₃; 98.8% ee (S)]. ¹H NMR (500 MHz, CDCl₃): δ = 1.97-2.04 (m, 1 H, CHCH _aH_b), 2.06-2.19 (m, 2 H, CHCH_a H _b, CHCH₂CH _aH_b), 2.54-2.61 (m, 1 H, CHCH₂CH_a H _b), 3.64 (ddd, J = 8.0, 8.0, 8.0 Hz, 1 H, CHCH₂CH₂), 3.67, 3.72 (2 s, 6 H, CO₂CH₃), 5.06 (dt, J = 10.2, 1.3 Hz, 1 H, CH=CH _EH_Z), 5.07 (dt, J = 17.2, 1.4 Hz, 1 H, CH=CH_E H _Z), 5.82 (ddd, J = 17.1, 10.5, 6.7 Hz, 1 H, CH=CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 21.03 (t, CHCH₂), 25.69 (t, CHCH₂ CH₂), 43.51 (d, CHCH₂), 52.17, 52.47 (2 q, CO₂ CH₃), 57.84 [s, C(CO₂CH₃)₂], 116.37 (t, CH=CH₂), 136.42 (d, CH=CH₂), 170.00, 171.90 (2 s, CO₂CH₃). Anal. Calcd for C₁₀H₁₄O₄: C, 60.59; H, 7.12. Found: C, 60.46; H, 7.18. HRMS (EI): m/z calcd for C₁₀H₁₄O₄ [M]⁺: 198.0892; found: 198.0890.

25

GC Data for 8a and 8b (Table 3) Compound 8a [Chiraldex γ-Trifluoroacetyl (G-TA), 30 m × 0.25 mm × 0.125 µm, 70 °C isothermal, injector temperature 200 °C, detector temperature 250 °C]: t _R[(-)-(S)-8a] = 45 min, t _R[(+)-(R)-8a] = 54 min.
Compound 8b [Varian CP-Chirasil-Dex (β-CD), 25 m × 0.25 mm × 0.25 µm, 100 °C isothermal, injector temperature 200 °C, detector temperature 250 °C]: t _R[(-)-(S)-8b] = 16 min, t _R[(+)-(R)-8b] = 17 min.

26

The absolute configuration is as expected^4b and was verified in the case of 8a by comparison of the optical rotation of (S)-8a {95.5 % ee, [α]_D ²⁰ -54.6 (c 0.98, CCl₄)} with reported²¹ data: [α]_D ²⁵ -55.2 (c 0.98, CCl₄).