Regioselective cis,vic-Dihydroxylation of α,β,γ,δ-Unsaturated Carboxylic Esters: Enhanced γ,δ-Selectivity by Employing Trifluoroethyl or Hexafluoroisopropyl Esters

Abstract

The regioselectivity of Sharpless asymmetric dihydroxylation (AD) of α,β,γ,δ-unsaturated carboxylic esters was studied as a function of α-, β-, and δ-substituents and for fluorine-free versus fluorinated esters. The latter showed increased or complete γ,δ-selectivities: the hexafluoroisopropyl ester being superior to the tri­fluoroethyl ester. Olefinations of α,β-unsaturated aldehydes with phosphorus ylide 36 or phosphonate anion 41 provided α,β,γ,δ-unsaturated trifluoroethyl esters, leading inter alia to complete trans selectivity and to 31 with 94% E selectivity, respectively.

Key words

asymmetric dihydroxylation - hexafluoroisopropyl ester - regioselectivity - trifluoroethyl esters - α,β,γ,δ-unsaturated esters

References and Notes

• Reviews:
• 1a Lohray BB. Tetrahedron: Asymmetry  1992,  3:  1317 
• 1b Johnson RA. Sharpless KB. Asymmetric Catalysis in Organic Synthesis   Ojima I. VCH; New York: 1993.  p.227 
• 1c Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 1d Poli G. Scolastico C. Methoden der Organischen Chemie (Houben-Weyl)   Vol. E21e, 4th ed.:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.4547 
• 1e Johnson RA. Sharpless KB. Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Wiley-VCH; New York: 2000.  p.357-389  
• 1f Bolm C. Hildebrand JP. Muñiz K. Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Wiley-VCH; New York: 2000.  p.399-428  
• 1g Zaitsev AB. Adolfsson H. Synthesis  2006,  1725 
• Rationalizations of the absolute configuration of AD products:
• 1h Empirically: Kolb HC. Andersson PG. Sharpless KB. J. Am. Chem. Soc.  1994,  116:  1278 
• 1i Calculationally: Moitessier N. Henry C. Len C. Chapleur Y. J. Org. Chem.  2002,  67:  7275 
• 2a (6Z,9Z,11E)-6,9,11-Henicosatriene: Fernandez RA. Kumar P. Tetrahedron  2002,  58:  6685 
• 2b (6E,8E)-6,8-Tetradecadiene: Arizza X. Fernández N. Garcia M. López M. Montserrat L. Ortiz J. Synthesis  2004,  128 
• 2c

  (8E,10E)-8,10-Dodecadienyl acetate and (2E,4E)-2,4-hexadienyl benzoate: ref. 3.

• 2d

  (2E,4E)-2,4-Hexadiene, (2E,4E)-2,dimethyl-2,4-hexadiene, and (2E,4Z)-2,4-hexadiene: ref. 4.

• 3 Becker H. Soler MA. Sharpless KB. Tetrahedron  1995,  51:  1345 
• 4 Xu D. Crispino GA. Sharpless KB. J. Am. Chem. Soc.  1992,  114:  7570 
• 5 Zhang Y. O’Doherty GA. Tetrahedron  2005,  61:  6337 
• 6 Schmidt-Leithoff J. Brückner R. Helv. Chim. Acta  2005,  88:  1943 
• 7 Still WC. Kahn M. Mitra A. J. Org. Chem.  1978,  43:  2923 
• 9a Bennani YL. Sharpless KB. Tetrahedron Lett.  1993,  34:  2079 
• 9b See also: Tholander J. Carreira EM. Helv. Chim. Acta  2001,  84:  613 
• 10 Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2768 
• 12 VanRheenen V. Kelly RC. Cha DF. Tetrahedron Lett.  1976,  1973 
• 13 Schröder M. Chem. Rev.  1980,  80:  187 
• Compare the diminished yields of ADs of alkynyl- versus alkyl-substituted alkenes:
• 14a Jeong KS. Sjö P. Sharpless KB. Tetrahedron Lett.  1992,  33:  3833 
• 14b Tani K. Sato Y. Okamoto S. Sato F. Tetrahedron Lett.  1993,  34:  4975 
• 14c Caddick S. Shanmugathasan S. Brasseur D. Delisser VM. Tetrahedron Lett.  1997,  38:  5735 
• 14d Liu B. Chen MJ. Lo C.-Y. Liu R.-S. Tetrahedron Lett.  2001,  42:  2533 
• 14e Gardiner JM. Giles PE. Martin MLM. Tetrahedron Lett.  2002,  43:  5415 
• 21 Morphy JR. Rankovic Z. York M. Tetrahedron  2003,  59:  2137 
• 22 Trifluoroethyl(dimethylphosphonyl)acetate(38) has not been previously described and was prepared by the Arbusov reaction (Scheme 2).²⁰ This reaction is higher yielding (98%) than the synthesis of the analogous trifluoroethyl(diethyl-phosphonyl)acetate by treatment of (diethylphos-phono) acetic acid first with SOCl₂ and then with trifluoro-ethanol (Σ = 58%): Birnbaum JC. Busche B. Lin Y. Shaw WJ. Fryxell GE. Chem. Commun.  2002,  1374 
• 23 Zhu X.-F. Henry CE. Wang J. Dudding T. Kwon O. Org. Lett.  2005,  7:  1387 
• 28 Compound 40 was obtained in 78% yield by esterification of 2-bromopropionic acid. A two-step synthesis of 40 via acid chloride formation from 2-bromopropionic acid followed by trifluoroethanolysis yielded 83% of 40: Aggarwal VK. Jones DE. Martin-Castro AM. Eur. J. Org. Chem.  2000,  2939 

8

All new compounds gave satisfactory ¹H NMR and ¹³C NMR spectra and provided correct combustion analyses (5-10, 13-15, 17, 21, 22, 25, 27, 29, 30) or high-resolution mass spectra (16, 18-20, 23, 24, 26, 28, iso-30, 31-35, iso-32, 41).

11

It is interesting to note that while we mono(dihydroxylated) methyl dienoate 5 asymmetrically (see text) we could not realize its racemic dihydroxylation at identical substrate concentration using K₂Os(OH)₄O₂ (10 mol%) and NMO·H₂O¹² (1.2 equiv) in t-BuOH-H₂O (1:1) over the course of 4 d. This seems to imply that the asymmetric dihydroxylation of compound 5 benefits from a considerable ligand accelerating effect by the added amine.¹³ It was only for this reason that all cis,vic-dihydroxylations of our study were undertaken as asymmetric dihydroxylations and their ee values considered unimportant and thus undetermined [except for compounds 14 (99% ee) and 34 (84% ee)]. All asymmetric dihydroxylations of our study were performed with the AD-mix α ligand, for example, with (DHQ)₂PHAL, and never with the AD-mix β ligand, for example, with (DHQD)₂PHAL. The reason is that Sharpless et al. (ref. 3) found decreased γ,δ:α,β dihydroxylation ratios employing AD-mix β instead of AD-mix α for the dihydroxylation of α,β,γ,δ-unsaturated esters 1 (→ 2:iso-2 = 83:17 instead of 87:13) or 3 (→ 4:iso-4 = 56:44 instead of 60:40).

15

An ancillary observation of the same effect was our failure to dihydroxylate trans-1,6-bis(trimethylsilyl)-3-hexene-1,5-diyne with K₂OsO₂(OH)₄-NMO, K₂OsO₂(OH)₄-(DHQ)₂PHAL-K₃Fe(CN)₆ or KMnO₄: Schmidt-Leithoff J.; Ph.D. Dissertation; Universität Freiburg, 2006.

16

We observed 5% more γ,δ- and 5% less α,β-dihydroxylation in the mono-ADs of dienoates 1 and 3 than in the hands of Sharpless et al.³ (see Scheme [1] ). This might be due to our catalyst/ligand ratio being 1:5 and Sharpless’ being 1:1 and 1:2, respectively.

17

1,1,1,3,3,3-Hexafluoroisopropyl (2 E ,4 E )-2-Methyl-7-phenyl-2,4-heptadien-6-ynoate ( 33): ¹H NMR (400.1 MHz, CDCl₃, TMS; 4% 2Z,4E-isomer): δ = 2.07 (dd, ⁴ J _2-Me,3 = 1.4 Hz, ⁵ J _2-Me,4 = 0.5 Hz, 2-CH₃), 5.88 (sept, J _{1 ′′,F} = 6.2 Hz, 1′′-H), 6.28 (br d, J _5,4 = 15.3 Hz, 5-H), 6.97 (dd, J _4,5 = 15.4 Hz, J _4,3 = 11.7 Hz, 4-H), 7.32-7.38 (m, 3′-H, 4′-H, 5′-H), partly superimposed by 7.38 (ddq, J _3,4 = 11.7 Hz, ⁴ J _3,5 = 1.4 Hz, ⁴ J _3,2-Me = 0.9 Hz, 3-H), 7.43-7.52 (m, 2′-H, 6′-H). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₁₇H₁₂F₆O₂: 362.0741; found: 362.0735.

18

1,1,1,3,3,3-Hexafluoroisopropyl ( E ,4 S ,5 S )-4,5-Dihydroxy-2-methyl-7-phenyl-2-hepten-6-ynoate ( 34): K₃Fe(CN)₆ (273 mg, 828 µmol, 3.0 equiv), (DHQ)₂PHAL (21.5 mg, 27.6 µmol, 10 mol%), K₂CO₃ (114 mg, 828 µmol, 3.0 equiv), and MeSO₂NH₂ (26.3 mg, 276 µmol, 1.0 equiv) were suspended in t-BuOH-H₂O (4 mL:5 mL) at 0 °C. K₂Os(OH)₄O₂ (5.1 mg, 13.8 µmol, 5 mol%) and a solution of 33 (100 mg, 276 µmol) in t-BuOMe (2 mL) were added to the reaction mixture. After stirring at 0 °C for 2 d sat. aq Na₂S₂O₃ (10 mL) was added. The resulting mixture was stirred at r.t. for 30 min, the organic phase separated and extracted with EtOAc (4 × 15 mL). The combined organic phases were dried with Na₂SO₄. After evaporation of the solvent the residue was purified by flash chromatography⁷ (eluent: cyclohexane-EtOAc, 3:1) giving the title compound [43.5 mg, 40% of an inseparable E:Z mixture (95.4:4.6)] as a colorless oil. ¹H NMR (400.1 MHz, CDCl₃, TMS; 4.6% 2Z-isomer): δ = 2.07 (d, ⁴ J _2-Me,3 = 1.5 Hz, 2-CH₃), 2.66, 2.81 (2 × br s, 4-OH, 5-OH), 4.58 (d, J _5,4 = 7.0 Hz, 5-H), 4.66 (incompletely resolved dd, J _4,3 = 8.3 Hz, J _4,5 = 7.0 Hz, 4-H), 5.85 (sept, J _{1 ′′,F} = 6.1 Hz, 1′′-H), 6.94 (dq, J _3,4 = 8.4 Hz, ⁴ J _3,2-Me = 1.4 Hz, 3-H), 7.29-7.40 (m, ArH). HRMS (EI, 70 eV, fragment 1): m/z [M - C₉H₆O]⁺ calcd for C₈H₈F₆O₃: 266.0377; found: 266.0373. HRMS (EI, 70 eV, fragment 2): m/z [M - C₈H₇F₆O₃]⁺ calcd for C₉H₇O: 131.0497; found: 131.0495.

19

The only exception was hexafluoroisopropyl ester 33.¹⁷ It was obtained in 96% yield by a carbodiimide-mediated esterification of hexafluoroisopropanol with the carboxylic acid obtained from the saponification of ethyl ester 29.

20

Trifluoroethyl bromoacetate(35) was obtained in 75% yield by an H₂SO₄-catalyzed esterification from bromoacetic acid and trifluoroethanol (2.0 equiv). Previously, 35 was obtained by trifluoroethanolysis of ethyl bromoacetyl chloride in 81% yield. ²¹

24

The phosphonium bromide precursor of ylide 36 was prepared from PPh₃ and 2,2,2-trifluoroethyl bromoacetate (35)²⁰ in two steps and 100% overall yield. The same ylide was similarly obtained by Kwon et al.²³ but used en route to allenic carboxylic esters and not in a Wittig reaction.

25

Trifluoroethyl dienoate 13 was obtained as a mixture of 2E,4E-13 and 2E,4Z-13 isomers (98.5:1.5), which was inseparable by flash chromatography on silica gel.⁷ The formation of 2E,4Z-13 can be explained by an isomerization of the C³=C⁴ bond.

26

2,2,2-Trifluoroethyl (2 E ,4 E )-2-Methyl-7-phenyl-2,4-heptadien-6-ynoate ( 31): At -78 °C n-BuLi (2.5 M in hexane, 1.23 mL, 3.07 mmol, 1.4 equiv) was added to a solution of 41 (694 mg, 2.63 mmol, 1.2 equiv) in THF (15 mL). After 10 min a solution of 43 (342 mg, 2.19 mmol) in THF (10 mL) was added. Stirring was continued at -78 °C for 30 min and at 0 °C for another 2 h. Quenching by adding aq NH₄Cl (10 mL), phase separation, extraction of the aq phase with Et₂O (3 × 15 mL), drying of the combined organic phases with Na₂SO₄, and purification of the crude product by flash chromatography⁷ (eluent: cyclohexane-EtOAc, 5:1) furnished the title compound (73%) as a 2E,4E:2Z,4E:2E,4Z (90:6.4:3.6) mixture. ¹H NMR (400.1 MHz, CDCl₃, TMS): δ = 2.04 (dd, ⁴ J _2-Me,3 = 1.4 Hz, ⁵ J _2-Me,4 = 0.5 Hz, 2-CH₃), 4.56 (q, J _{1 ′′,F} = 8.5 Hz, 1′′-H₂), 6.22 (ddd, J _5,4 = 15.4 Hz, ⁴ J _5,3 = ⁶ J _{5,2 ′/6 ′} = 0.7 Hz, 5-H), 6.97 (J _4,5 = 15.4 Hz, J _4,3 = 11.8 Hz, 4-H), 7.31 [dqd, in part superimposed by m (3′-H, 4′-H, 5′-H), J _3,4 ∪11.8 Hz, ⁴ J _3,2-Me = 1.4 Hz, ⁴ J _3,5 = 0.9 Hz, 3-H], 7.32-7.37 (m, 3′-H, 4′-H, 5′-H), 7.44-7.51 (m, 2′-H, 6′-H). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₁₆H₁₃F₃O₂: 294.0868; found: 294.0867.

27

2,2,2-Trifluoroethyl 2-(Dimethoxyphosphonyl)prop-ionate ( 41): Neat 2,2,2-trifluoroethyl 2-bromopropionate (4.58 g, 19.5 mmol) was heated at 60 °C while trimethyl phosphite (2.99 mL, 3.14 g, 25.3 mmol, 1.3 equiv) was added slowly. The resulting solution was then heated at 180 °C for 4 h. Distillation (bp 25-30 °C/0.45 mbar) afforded the title compound (2.27 g, 44%). ¹H NMR (400.1 MHz, CDCl₃, TMS): δ = 1.48 (dd, J _3,P = 17.7 Hz, J _3,2 = 7.3 Hz, 3-H₃), 3.15 (dq, ² J _2,P = 23.8 Hz, J _2,3 = 7.3 Hz, 2-H), 3.79, 3.80 (2 × d, J _OMe,P = 11.0 Hz, 2 × OCH₃), AB signal (δ_A = 4.49, δ_B = 4.55, J _AB = 12.7 Hz, A and B peaks in addition split to q by J _{1 ′,F} = 8.3 Hz, B peaks further split to d by unassigned J = 0.5 Hz, 1′-H₂). HRMS (EI, 70 eV, fragment 1): m/z [M - OC₃H₃]⁺ calcd for C₄H₉F₃O₄P: 209.0190; found: 209.0187. HRMS (EI, 70 eV, fragment 2): m/z [M - CH₂CF₃]⁺ calcd for C₅H₁₀O₅P: 181.0266; found: 181.0263. HRMS (EI, 70 eV, fragment 3): m/z [M - OCH₂CF₃]⁺ calcd for C₅H₁₀O₄P: 165.0317; found: 165.0316.