PICOLINAMIDE COMPOUNDS WITH FUNGICIDAL ACTIVITY

Abstract

This disclosure relates to picolinamides of Formula I and their use as fungicides.

##STR00001##

Claims

1. A compound of Formula I ##STR00063## wherein X is hydrogen or C(O)R.sub.5; Y is hydrogen, C(O)R.sub.5, or Q; Q is ##STR00064## R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl, optionally substituted with 0, 1 or multiple R.sub.8; alternatively, R.sub.1 and R.sub.11 may be taken together to form a 3-6 membered saturated or partially saturated carbocyclic or heterocyclic ring, optionally substituted with 0, 1 or multiple R.sub.8; R.sub.2 and R.sub.12 are independently chosen from hydrogen, alkyl, aryl, or alkenyl, each optionally substituted with 0, 1 or multiple R.sub.8; R.sub.3 is methyl; R.sub.4 is chosen from alkyl, aryl, or acyl, each optionally substituted with 0, 1 or multiple R.sub.8; R.sub.5 is chosen from alkoxy or benzyloxy, each optionally substituted with 0, 1, or multiple R.sub.8; R.sub.6 is chosen from hydrogen, alkoxy, or halo, each optionally substituted with 0, 1, or multiple R.sub.8; R.sub.7 is chosen from hydrogen, —C(O)R.sub.9, or —CH.sub.2OC(O)R.sub.9; R.sub.8 is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl, each optionally substituted with 0, 1, or multiple R.sub.10, R.sub.9 is chosen from alkyl, alkoxy, or aryl, each optionally substituted with 0, 1, or multiple R.sub.8; and R.sub.10 is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl.

2. A compound according to claim 1, wherein X and Y are hydrogen.

3. A compound according to claim 2, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl.

4. A compound according to claim 2, wherein R.sub.2 and R.sub.12 are independently chosen from hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8.

5. A compound according to claim 2, wherein R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

6. A compound according to claim 2, wherein R.sub.1 and R.sub.11are independently chosen from hydrogen or alkyl, R.sub.2 and R.sub.12 are independently hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8, and R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.7.

7. A compound according to claim 1, wherein X is C(O)R.sub.5 and Y is hydrogen.

8. A compound according to claim 7, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl.

9. A compound according to claim 7, wherein R.sub.2 and R.sub.12 are independently chosen from hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8.

10. A compound according to claim 7, wherein R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

11. A compound according to claim 7, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl, R.sub.2 and R.sub.12 are independently hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8, and R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

12. A compound according to claim 1, wherein X is hydrogen and Y is Q.

13. A compound according to claim 12, wherein R.sub.6 is alkoxy.

14. A compound according to claim 13, wherein R.sub.7 is hydrogen.

15. A compound according to claim 14, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl.

16. A compound according to claim 14, wherein R.sub.2 and R.sub.12 are independently chosen from hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8.

17. A compound according to claim 14, wherein R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

18. A compound according to claim 14, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl, R.sub.2 and R.sub.12 are independently hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8, and R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

19. A compound according to claim 13, wherein R.sub.7 is chosen from —C(O)R.sub.9, or —CH.sub.2OC(O)R.sub.9.

20. A compound according to claim 19, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl.

21. A compound according to claim 19, wherein R.sub.2 and R.sub.12 are independently chosen from hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8.

22. A compound according to claim 19, wherein R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

23. A compound according to claim 19, wherein R.sub.1 and R.sub.11 are independently chosen from hydrogen or alkyl, R.sub.2 and R.sub.12 are independently hydrogen or alkyl, each optionally substituted with 0, 1 or multiple R.sub.8, and R.sub.4 is aryl, optionally substituted with 0, 1 or multiple R.sub.8.

24. A compound according to claim 23, wherein R.sub.9 is chosen from —CH.sub.3, —CH.sub.2OCH.sub.2CH.sub.3, —CH.sub.2CH.sub.2OCH.sub.3, —CH(CH.sub.3).sub.2, —CH.sub.2CH.sub.2CH.sub.2CH.sub.3, or -cyclopropyl.

25. A composition for the control of a fungal pathogen including mixtures of at least one of the compounds of claim 1 and another pesticide including fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides and combinations thereof.

26. (canceled)

27. (canceled)

Description

EXAMPLES

[0085] The chemistry in the following examples may be conducted using either enantiomer of 2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala-OH) or either protected (PMB or Bn) enantiomer of ethyl lactate.

Example 1A

Preparation of ethyl (S)-2-phenoxypropanoate

[0086] ##STR00024##

[0087] A 250 mL round-bottom flask was charged with triphenylbismuth(V) acetate (9.22 g, 16.51 mmol) and copper(II) acetate (0.231 g, 1.270 mmol) and purged with N.sub.2 gas. Anhydrous toluene (85 mL) was then added, followed by (S)-ethyl 2-hydroxypropanoate (1.456 mL, 12.70 mmol) and N-cyclohexyl-N-methylcyclohexanamine (3.13 mL, 14.60 mmol). The resulting blue/green reaction was then heated to 40° C. and stirred for 96 hours (h). The reaction was cooled to room temperature (rt) and filtered through a plug of Celite®. The filter cake was washed with DCM, and then concentrated to afford a dark yellow oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.10% ethyl acetate in hexanes) to afford the title compound (2.43 g, 98%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.31-7.23 (m, 2H), 6.96 (tt, J=7.3, 1.1 Hz, 1H), 6.92-6.83 (m, 2H), 4.74 (q, J=6.8 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 1.61 (d, J=6.8 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.24, 157.64, 129.51, 121.55, 115.16, 72.66, 61.23, 18.57, 14.12; IR (thin film) 2986, 1753, 1733, 1494, 1239, 1134, 752 cm.sup.−1.

Example 1B

Preparation of (S)-ethyl 2-((triisopropylsilyl)oxy)propanoate

[0088] ##STR00025##

[0089] In a 500 mL round-bottom flask, (9-ethyl 2-hydroxypropanoate (9.71 mL, 85 mmol) and imidazole (13.83 g, 203 mmol) were dissolved in DCM (220 mL) under N.sub.2 and cooled to 0° C. in an ice/water bath. Chlorotriisopropylsilane (21.74 mL, 102 mmol) was then added via syringe over 30 minutes (min). The reaction mixture was allowed to warm to rt and was stirred overnight. After 18 h, TLC indicated consumption of starting material. The reaction mixture was poured into a separatory funnel and washed with H.sub.2O (100 mL), saturated aqueous NaHCO.sub.3 (100 mL), brine (100 mL), 1M HCl (100 mL), and then finally brine (100 mL). The organic layer was passed through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0410% ethyl acetate in hexanes) to afford the title compound (21.68 g, 93%) as a clear, colorless oil: .sup.1NMR (400 MHz, CDCl.sub.3) δ4.41 (q, J=6.7 Hz, 1H), 4.18 (qd, J=7.1, 2.7 Hz, 2H), 1.43 (d, J=6.7 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.17-0.97 (m, 21H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ174.23, 68.55, 60.66, 21.80, 17.85, 14.22, 12.16.

Example 1C

Preparation of Ethyl (S,E)-2-((4,4,4-trifluorobut-2-en-1-yl)oxy)propanoate

[0090] ##STR00026##

[0091] Ethyl (S)-2-hydroxypropanoate (0.971 mL, 8.47 mmol) was dissolved in dry THF (42.3 mL). Pd.sub.2(dba).sub.3 (0.194 g, 0.212 mmol) and dppf (0.235 g, 0.423 mmol) were added and the mixture was heated to reflux. (E)-tert-butyl (4,4,4-trifluorobut-2-en-1-yl) carbonate (2.87 g, 12.70 mmol) was then added and the reaction was monitored until complete by TLC. The reaction was cooled to rt and carefully concentrated to afford an oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.10% MTBE in hexanes) to afford the title compound (1.59 g, 79%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.47-6.37 (m, 1H), 6.03-5.91 (m, 1H), 4.34-4.16 (m, 3H), 4.11-3.97 (m, 2H), 1.45 (d, J=6.8 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ172.67, 135.95 (q, J=6.4 Hz), 123.01 (q, J=269.2 Hz), 118.98 (q, J=34.1 Hz), 75.01, 67.71, 61.08, 18.53, 14.20; IR (thin film) 2988, 1742, 1686, 1302, 1264, 1202, 1112, 1087, 1018, 959 cm.sup.−1.

Example 1D

Preparation of Methyl Ethyl (S)-2-((4-methoxybenzyl)oxy)propanoate

[0092] ##STR00027##

[0093] In a 500 mL round-bottom flask, a solution of (S)-ethyl 2-hydroxypropanoate (10.15 mL, 89 mmol) was prepared in DCM (89 mL). To this solution was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (28.9 g, 102 mmol) followed by camphorsulfonic acid (2.065 g, 8.89 mmol), and the resulting orange/brown colored reaction was stirred at rt for 72 h. Hexanes (100 mL) was added, and the reaction mixture was stirred for 30 min. The precipitated solids were filtered, and the filtrate was concentrated to afford an oil. The oil was again diluted with 200 mL DCM/Hexanes (1:1). The mixture was stirred at rt for 30 min. The solids were filtered, and the filtrate was washed with saturated aqueous NaHCO.sub.3 (100 mL), followed by brine (100 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to afford a brown oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.10% ethyl acetate in hexanes) to afford the title compound (11.96 g, 56%) as a pale yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.34-7.24 (m, 2H), 6.91-6.84 (m, 2H), 4.62 (d, J=11.3 Hz, 1H), 4.39 (d, J=11.2 Hz, 1H), 4.21 (qd, J=7.1, 2.4 Hz, 2H), 4.03 (q, J=6.8 Hz, 1H), 3.80 (s, 3H), 1.41 (d, J=6.9 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ173.41, 159.37, 129.68, 113.83, 73.74, 71.66, 60.84, 55.31, 18.76, 14.28; IR (thin film) 2984, 1730, 1513, 1247, 1198, 1031, 822 cm.sup.−1.

Example 1E

Preparation of Ethyl (S)-2-(benzyloxy)propanoate

[0094] ##STR00028##

[0095] In a 500 mL round-bottom flask, a solution of (S)-ethyl 2-hydroxypropanoate (11.65 mL, 102 mmol) was prepared in anhydrous DCM (203 mL). To this solution was added (bromomethyl)benzene (18.12 mL, 152 mmol) followed by silver(I) oxide (24.72 g, 107 mmol) and potassium iodide (1.686 g, 10.16 mmol). The resultant black reaction mixture was heated to reflux and stirred overnight. After 24 h, TLC indicated nearly complete consumption of starting material. The reaction mixture was filtered through a pad of Celite®, flushed with DCM, and concentrated to an oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.5% ethyl acetate in hexanes) to afford the title compound (11.93 g, 56%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.48-7.14 (m, 5H), 4.69 (d, J=11.6 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.21 (qd, J=7.1, 2.6 Hz, 2H), 4.05 (q, J=6.9 Hz, 1H), 1.43 (d, J=6.9 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ173.27, 137.63, 128.43, 127.98, 127.84, 74.09, 72.00, 60.85, 18.74, 14.27; IR (thin film) 2984, 1743, 1454, 1196, 1140, 1064, 1024, 736, 697 cm.sup.−1.

Example 1F

Step 1

Preparation of tris(4-fluoro-2-methylphenyl)bismuthane

[0096] ##STR00029##

[0097] In a 250 mL round-bottom flask, a solution of 1-bromo-4-fluoro-2-methylbenzene (5.24 mL, 42.3 mmol) was prepared in THF (171 mL) and cooled to −78° C. in a dry ice/acetone bath. After ˜10 min, butyllithium (2.5 M in hexanes, 17.8 mL, 44.4 mmol) was added dropwise via syringe, and the resulting clear, colorless reaction was stirred for 1 hr. After 1 hr, trichlorobismuthane (4.30 g, 13.63 mmol) was added as a solution in THF (71 mL) via syringe, and the reaction was stirred at −78° C. for 1 hr, and then warmed to rt and stirred overnight. After 18 h, the reaction was concentrated and the remaining residue was extracted with toluene (200 mL) and a yellowish-white solid was removed via filtration. The filtrate was then concentrated to dryness to afford the title compound (7.25 g, 99%) as an off white solid which was used directly in the next step without further purification: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.40 (dd, J=8.2, 6.7 Hz, 3H), 7.04 (dd, J=10.3, 2.7 Hz, 3H), 6.78 (td, J=8.6, 2.7 Hz, 3H), 2.41 (s, 9H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ-113.91.

Example 1F

Step 2

Preparation of ethyl (S)-2-(4-fluoro-2-methylphenoxy)propanoate

[0098] ##STR00030##

[0099] A solution of tris(4-fluoro-2-methylphenyl)bismuthane (3.41 g, 6.35 mmol) was prepared in DCM (21.16 mL) at room temperature, and peracetic acid (1.225 mL, 7.20 mmol) was then added via syringe slowly over 5 min. Bubbling was observed, and reaction became a light orange color. The resulting reaction was allowed to stir at rt for 30 min. After 30 min, ethyl (S)-2-hydroxypropanoate (0.485 mL, 4.23 mmol) and copper(II) acetate (0.154 g, 0.847 mmol) were added, the flask was fitted with a reflux condenser, and the opaque blue/green reaction mixture was heated to 45° C. and stirred overnight. After 20 h, TLC indicated ˜75% consumption of starting material and conversion to several higher R.sub.f spots. The reaction was cooled to room temperature and then filtered through a plug of celite, filtering with DCM (2×10 mL), and then concentrated to afford an oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (318.8 mg, 33%) as a pale yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.85 (dd, J=9.0, 3.1 Hz, 1H), 6.76 (td, J=8.5, 3.1 Hz, 1H), 6.63 (dd, J=8.9, 4.6 Hz, 1H), 4.66 (q, J=6.8 Hz, 1H), 4.20 (qd, J=7.1, 1.4 Hz, 2H), 2.26 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.24 (t, J=7.1 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ-123.28; .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.18, 157.40 (d, J=239.0 Hz), 152.11 (d, J=2.3 Hz), 129.75 (d, J=7.7 Hz), 117.58 (d, J=22.8 Hz), 113.42 (d, J=8.5 Hz), 112.37 (d, J=22.8 Hz), 73.81, 61.19, 18.64, 16.40 (d, J=1.3 Hz), 14.12; IR (thin film) 3350, 2987, 1750, 1496, 1191, 1134, 718 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.12H.sub.16FO.sub.3].sup.+, 227.1078; found, 227.1089.

Example 2

Preparation of (9-2-((triisopropylsilyl)oxy)propanal

[0100] ##STR00031##

[0101] In a 1 L round-bottom flask, (9-ethyl 2-((triisopropylsilyl)oxy)propanoate (21.68 g, 79 mmol) was dissolved in DCM (395 mL) under N.sub.2 and cooled to −78° C. in an dry ice/acetone bath. Diisobutylaluminum hydride (1 M in hexanes, 158 mL, 158 mmol) was added via syringe over 4 h. The reaction was stirred at −78° C. for an additional 30 min. After 30 min, ethyl acetate (75 mL) was added to quench the reaction, and the reaction mixture was warmed to 0° C. in an ice/water bath. A solution of saturated aqueous potassium sodium tartrate (˜200 mL) was added, and the reaction was vigorously stirred overnight, slowly warming to rt as the ice bath melted. After 18 h, the biphasic mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (3×150 mL). The combined organic layers were passed through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (silica gel (SiO.sub.2), 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (15.85 g, 87%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ9.66 (d, J=1.7 Hz, 1H), 4.18 (qd, J=6.8, 1.7 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.11-1.01 (m, 21H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ204.54, 73.83, 18.95, 17.89, 12.14.

Example 3A

Preparation of (3R,45)-2-methyl-4-phenoxypentan-3-ol

[0102] ##STR00032##

[0103] In a 250 mL flask, a solution of isopropylmagnesium bromide (2M in Et.sub.2O, 9.01 mL, 18.02 mmol) and lithium borohydride (2M in THF, 5.86 mL, 11.71 mmol) was prepared in THF (33 mL). The reaction was cooled to 0° C. in an ice bath. After ˜10 min, ethyl (S)-2-phenoxypropanoate (1.75 g, 9.01 mmol) was added dropwise via syringe as a solution in THF (9 mL w/ 2×1.5 mL washes) over 3 h via syringe pump. The resultant pale yellow clear reaction mixture was stirred overnight, slowly warming to rt as the ice bath melted. The reaction was quenched with water (100 mL, caution GAS EVOLUTION) and diluted with Et.sub.2O (100 mL). The layers were separated and the aqueous layer was extracted with Et.sub.2O (3×100 mL). The combined organic layers were dried over MgSO.sub.4, filtered and concentrated to afford an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% ethyl acetate in hexanes) to afford the title compound (849 mg, 49%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.34-7.26 (m, 2H), 6.95 (tt, J=7.4, 1.1 Hz, 1H), 6.93-6.87 (m, 2H), 4.48 (qd, J=6.2, 3.8 Hz, 1H), 3.54 (dt, J=7.9, 3.4 Hz, 1H), 2.09 (d, J=3.1 Hz, 1H), 1.79 (dp, J=7.9, 6.7 Hz, 1H), 1.30 (d, J=6.3 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ157.39, 129.58, 121.08, 116.04, 78.00, 74.79, 29.87, 18.89, 18.71, 13.11; IR (thin film) 3425, 2955, 1598, 1493, 1240, 1055, 752 cm.sup.−1. Also isolated (3S,4S)-2-methyl-4-phenoxypentan-3-ol (216 mg, 1.11 mmol, 12% yield) as a clear, colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) δ7.34-7.21 (m, 2H), 7.00 6.86 (m, 3H), 4.38 (p, J=6.1 Hz, 1H), 3.36 (q, J=5.1 Hz, 1H), 2.35 (d, J=5.1 Hz, 1H), 1.87 (pd, J=6.8, 5.0 Hz, 1H), 1.28 (d, J=6.2 Hz, 3H), 1.04-0.95 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ157.73, 129.58, 121.18, 116.15, 79.40, 75.37, 30.07, 20.00, 16.60, 16.04; IR (thin film) 3434, 2955, 1598, 1494, 1240, 1051, 752 cm.sup.−1. Also isolated (S)-2-phenoxypropan-1-ol (44.4 mg, 0.292 mmol, 3.2% yield) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.33-7.25 (m, 2H), 7.00-6.90 (m, 3H), 4.50 (pd, J=6.3, 3.8 Hz, 1H), 3.81-3.66 (m, 2H), 2.12 (s, 1H), 1.27 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ157.73, 129.58, 121.22, 116.18, 74.77, 66.27, 15.84; IR (thin film) 3381, 2932, 1598, 1493, 1240, 1051, 752 cm.sup.−1.

Example 3B

Preparation of (3R,4S)-4-((triisopropylsilyl)oxy)pent-1-en-3-ol

[0104] ##STR00033##

[0105] A solution of (S)-2-((triisopropylsilyl)oxy)propanal (5.0 g, 21.70 mmol) in Et.sub.2O (108 mL) was prepared in a 250 mL round bottom flask and cooled to −78° C. in a dry ice/acetone bath under an atmosphere of N.sub.2. Vinylmagnesium bromide (1.0 M in THF, 23.87 mL, 23.87 mmol) was then added via syringe over 30 min. The reaction mixture was stirred at −78° C. for 30 min, and then was allowed to slowly warm to rt over 2 h. The reaction was poured over saturated aqueous NH.sub.4Cl (200 mL) and extracted with Et.sub.2O (3×100 mL). The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to afford a pale yellow oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (4.30 g, 77%, d.r. 6:1) as a clear, colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) δ5.80 (ddd, J=17.0, 10.6, 6.0 Hz, 1H), 5.31 (dt, J=17.3, 1.7 Hz, 1H), 5.20 (dt, J=10.6, 1.6 Hz, 1H), 4.16 (dddt, J=6.4, 4.8, 3.2, 1.8 Hz, 1H), 4.00 (qd, J=6.4, 3.5 Hz, 1H), 2.45 (d, J=3.3 Hz, 1H), 1.12 (d, J=6.4 Hz, 3H), 1.08 (s, 21H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ136.42, 116.31, 71.40, 60.35, 21.00, 18.02, 14.17, 12.38; IR (neat) 3483, 2943, 2866, 1463, 676 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.14H.sub.30NaO.sub.2Si].sup.+, 281.1907; found, 281.1920.

Example 3C

Preparation of (2S,3R)-2-((triisopropylsilyl)oxy)hex-5-en-3-ol

[0106] ##STR00034##

[0107] A 500 mL round bottom flask was charged with (+)-Ipc.sub.2-allylborane (1M in pentane, 25.0 mL, 25.00 mmol) under N.sub.2 and diluted with Et.sub.2O (100 mL). The resultant clear, colorless solution was cooled to −78° C. in an acetone/dry ice bath. (S)-2-((triisopropylsilyl)oxy)propanal (4.61 g, 20.01 mmol) was added as a solution in anhydrous Et.sub.2O (60 mL) via syringe over 1.5 h.

[0108] The clear, colorless reaction was cooled for an additional 1.5 h at −78° C., after which TLC indicated consumption of starting material. MeOH (50 mL) was then added, and the reaction was stirred for 5 min at −78° C. pH 7 buffer (70 mL) was added, and the reaction was warmed to 0° C. in an ice/water bath. H.sub.2O.sub.2 (30%, 60 mL) was then added, and the resulting biphasic reaction mixture was vigorously stirred at 0° C. for 2.5 h, and then warmed to room temperature as the ice melted and stirred for 30 h. The layers were separated, and the aqueous phase was extracted with Et.sub.2O (3×100 mL). The aqueous layer was carefully quenched with saturated aqueous Na.sub.2S.sub.2O.sub.3 on ice until KI-starch test paper indicated the disappearance of residual H.sub.2O.sub.2. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to a clear oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.15% ethyl acetate in hexanes) to afford the title compound (5.00 g, 92%) as a clear, light rose colored oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ5.85 (ddt, J=17.2, 10.2, 7.0 Hz, 1H), 5.22-4.97 (m, 2H), 3.93 (qd, J=6.2, 3.3 Hz, 1H), 3.70 (ddt, J=8.3, 5.7, 2.9 Hz, 1H), 2.34 (d, J=2.6 Hz, 1H), 2.30-2.09 (m, 2H), 1.14 (d, J=6.3 Hz, 3H), 1.12-1.03 (m, 21H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ134.91, 117.07, 74.48, 70.77, 36.72, 18.06, 16.59, 12.37; IR (neat) 3480, 2943, 2866, 1463, 1067, 881 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.15H.sub.33O.sub.2Si].sup.+, 274.2270; found, 274.2274.

Example 4A

Preparation of 1-((((2S,3R)-3-(benzyloxy)-4-methylpentan-2-yl)oxy)methyl)-4-methoxybenzen

[0109] ##STR00035##

[0110] In a 250 mL round bottom flask, a suspension of sodium hydride (0.329 g, 13.72 mmol) was prepared in DMF (42.7 mL) under an atmosphere of N.sub.2 and cooled to 0° C. in an ice/water bath. After 5 min, (2S,3R)-2-((4-methoxybenzyl)oxy)-4-methylpentan-3-ol (1.868 g, 7.84 mmol) was added via syringe as a solution in DMF (10 mL with 2×5 mL washes). The resultant bright yellow reaction mixture was brought to rt and was stirred for 3 h. The reaction was cooled to 0° C. and (bromomethyl)benzene (1.617 mL, 14.89 mmol) was added in one portion, followed by tetrabutylammonium iodide (0.290 g, 0.784 mmol). The reaction mixture was warmed to 40° C. and stirred overnight. The reaction was cooled to 0° C. and diethylamine (2.433 mL, 23.51 mmol) was added via syringe over 15 seconds. The pale yellow reaction was warmed to rt and was stirred for 1 h, at which point the reaction became a clear, yellow solution. After 1 h, the reaction was quenched with saturated aqueous NH.sub.4Cl (200 mL) and extracted with Et.sub.2O (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO.sub.4, filtered, and concentrated to afford a yellow oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (1.73 g, 67%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.39-7.29 (m, 4H), 7.29-7.22 (m, 3H), 6.90-6.84 (m, 2H), 4.80 (d, J=11.3 Hz, 1H), 4.58 (d, J=11.3 Hz, 1H), 4.54 (d, J=11.4 Hz, 1H), 4.43 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.65 (qd, J=6.3, 4.5 Hz, 1H), 3.24 (dd, J=6.2, 4.4 Hz, 1H), 1.88 (dq, J=13.4, 6.7 Hz, 1H), 1.26 (d, J=6.2 Hz, 3H), 0.96 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.08, 139.27, 131.04, 129.09, 128.21, 127.81, 127.31, 113.77, 86.75, 76.06, 74.59, 70.33, 55.29, 30.11, 20.03, 18.44, 15.04; IR (thin film) 2959, 2871, 1513, 1247, 1099, 1066, 1036 cm.sup.−1.

Example 4B

Preparation of triisopropyl(((2S,3R)-3-((4-methoxybenzyl)oxy)pent-4-en-2-yl)oxy)silane

[0111] ##STR00036##

[0112] In a 250 mL round bottom flask, a suspension of sodium hydride (1.165 g, 29.1 mmol) was prepared in DMF (93 mL) under an atmosphere of N.sub.2 and cooled to 0° C. in an ice/water bath. After 5 min, (3R,4S)-4-((triisopropylsilyl)oxy)pent-1-en-3-ol (4.301 g, 16.64 mmol, d.r. ˜6:1) was added via syringe as a solution in DMF (20 mL with 2×10 mL washes). The resultant bright yellow reaction mixture was brought to rt and was stirred for 3 h. The reaction was cooled to 0° C. and 4-methoxybenzyl bromide (4.61 mL, 31.6 mmol) was added in one portion, followed by tetrabutylammonium iodide (0.615 g, 1.664 mmol), after which the reaction underwent a distinct color change to light orange. The reaction mixture was warmed to rt and was stirred overnight. After 20 h, TLC indicated consumption of starting material. The reaction was cooled to 0° C. and diethylamine (5.16 mL, 49.9 mmol) was added via syringe over 15 seconds. The pale yellow reaction was warmed to rt and was stirred for 1 h, at which point the reaction became a clear, yellow solution. After 1 h, the reaction was quenched with saturated aqueous NH.sub.4Cl (150 mL) and extracted with Et.sub.2O (3×150 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO.sub.4, filtered, and concentrated to afford a yellow oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.15% MTBE in petroleum ether) to afford the title compound (4.063 g, 65%, d.r.˜6:1) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.34-7.19 (m, 2H), 6.92-6.79 (m, 2H), 5.84 (ddd, J=17.1, 10.5, 7.4 Hz, 1H), 5.43-5.08 (m, 2H), 4.55 (d, J=11.5 Hz, 1H), 4.38 (d, J=11.5 Hz, 1H), 3.98 (qd, J=6.3, 4.5 Hz, 1H), 3.80 (s, 3H), 3.63 (ddt, J=7.5, 4.4, 1.0 Hz, 1H), 1.19 (d, J=6.2 Hz, 3H), 1.10-0.98 (m, 21H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ158.96, 136.47, 131.02, 129.29, 118.19, 113.62, 85.07, 71.35, 70.35, 55.26, 19.87, 18.15, 12.55; IR (neat) 2942, 2865, 1513, 1246, 1039, 677 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.22H.sub.38NaO.sub.3Si].sup.+, 401.24824; found, 401.24711.

Example 4C

Preparation of methyl (R)-2-((tert-butyldimethylsilyl)oxy)-2-phenylacetate

[0113] ##STR00037##

[0114] A solution of ethyl (R)-2-hydroxy-2-phenylacetate (5.00 g, 30.1 mmol), TBSCl (6.80 g, 45.1 mmol), and imidazole (4.10 g, 60.2 mmol) was prepared in DMF (31.7 mL) and stirred overnight at rt. After 20 h, the solution was diluted with Et.sub.2O and water. The organic phase was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.5% ethyl acetate in hexanes) to afford the title compound (7.53 g, 85%) as a clear, colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) δ7.42-7.31 (m, 2H), 7.28-7.17 (m, 3H), 5.13 (s, 1H), 3.57 (s, 3H), 0.81 (s, 9H), 0.00 (s, 3H), −0.07 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ172.61, 139.11, 128.33, 128.09, 126.33, 74.39, 52.18, 25.71, 18.35, −5.09, −5.16; IR (thin film) 2952, 2929, 2886, 2857, 1758, 1737, 1472, 1253, 1207, 1191, 1170, 1125, 861, 836, 778, 725, 696 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.15H.sub.25O.sub.3Si].sup.+, 281.1567; found, 281.1578.

Example 5A

Preparation of (2S,3R)-3-(benzyloxy)-4-methylpentan-2-ol

[0115] ##STR00038##

[0116] In a 250 mL flask, 1-((((2S,3R)-3-(benzyloxy)-4-methylpentan-2-yl)oxy)methyl)-4-methoxybenzene (1.7255 g, 5.25 mmol) was dissolved in acetonitrile (96 mL) and H.sub.2O (9.55 mL) and was cooled to 0° C. in an ice bath. After ˜5 min, ceric ammonium nitrate (14.40 g, 26.3 mmol) was added, and the orange reaction mixture was stirred at 0° C. for 3 h. After 3 h, the mixture was quenched with saturated aqueous NaHCO.sub.3 (100 mL), and then extracted with DCM (3×100 mL). The combined organic layers were poured through a phase separator and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.50% ethyl acetate in hexanes) to afford the title compound (401 mg, 37%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.39-7.22 (m, 5H), 4.66 (d, J=0.9 Hz, 2H), 3.93 (qd, J=6.4, 4.2 Hz, 1H), 3.13 (dd, J=6.4, 4.2 Hz, 1H), 1.92 (s, 1H), 1.86 (dq, J=13.5, 6.8 Hz, 1H), 1.20 (d, J=6.5 Hz, 3H), 1.03 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ138.91, 128.40, 127.60, 127.58, 88.50, 74.84, 68.43, 30.07, 19.94, 18.66, 18.08; IR (thin film) 3406, 2962, 1454, 1093, 1063, 734, 697 cm.sup.−1.

Example 5B

Preparation of (2S,3R)-3-((4-methoxybenzyl)oxy)pent-4-en-2-ol

[0117] ##STR00039##

[0118] A solution of triisopropyl(((2S,3R)-3-((4-methoxybenzyl)oxy)pent-4-en-2-yl)oxy)silane (4.06 g, 10.7 mmol, d.r.˜6:1) was prepared in a 250 mL round bottom flask in THF (53.7 mL) under N.sub.2 and cooled to 0° C. After 5 min, TBAF (12.88 mL, 12.88 mmol) was added dropwise via syringe over 2 min. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated aqueous NH.sub.4Cl (100 mL) and extracted with Et.sub.2O (3×100 mL). The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to afford a clear, colorless oil. The oil was purified by flash column chromatography (SiO.sub.2, 0430% ethyl acetate in hexanes) to afford the title compound (1.272 g, 53%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.25 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 5.82 (ddd, J=17.4, 10.4, 8.1 Hz, 1H), 5.40 (ddd, J=10.4, 1.9, 0.8 Hz, 1H), 5.30 (ddd, J=17.3, 1.9, 0.9 Hz, 1H), 4.57 (d, J=11.5 Hz, 1H), 4.31 (d, J=11.4 Hz, 1H), 3.92-3.78 (m, 4H), 3.71-3.62 (m, 1H), 2.21 (d, J=3.9 Hz, 1H), 1.13 (d, J=6.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.19, 134.66, 130.34, 129.39, 120.20, 113.80, 83.96, 69.95, 69.27, 55.27, 17.94; IR (thin film) 3447, 2976, 2868, 1612, 1513, 1545, 1033, 819 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.13H.sub.18NaO.sub.3].sup.+, 245.11482; found, 245.1134. Also isolated (2S,3S)-3-((4-methoxybenzyl)oxy)pent-4-en-2-ol (325 mg, 1.46 mmol, 14% yield) as a clear, colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) δ7.31-7.21 (m, 2H), 6.94-6.85 (m, 2H), 5.79-5.62 (m, 1H), 5.45-5.15 (m, 1H), 4.57 (d, J=11.2 Hz, 1H), 4.28 (d, J=11.1 Hz, 1H), 3.81 (s, 3H), 3.74-3.64 (m, 1H), 3.50 (t, J=7.9 Hz, 1H), 2.83-2.69 (m, 1H), 1.18 (d, J=6.2 Hz, 1H), 1.12 (d, J=6.2 Hz, 3H); IR (thin film) 3455, 2869, 1513, 1247, 1069, 1034, 820 cm.sup.−1.

Example 5C

Preparation of (1R,2S)-1-((4-methoxybenzyl)oxy)-1-phenylpropan-2-ol

[0119] ##STR00040##

[0120] A solution of lithium borohydride (2M in THF, 3.93 mL, 7.86 mmol) and methylithium (1.6M in THF, 3.93 mL, 6.29 mmol) was prepared in Et.sub.2O (29.1 mL) and cooled to −78° C. in a dry ice/acetone bath. After ˜5 min, a solution of methyl (R)-2-((4-methoxybenzyl)oxy)-2-phenylacetate (1.5 g, 5.24 mmol) dissolved in Et.sub.2O (9 mL) was added slowly via addition funnel. The reaction was allowed to warm to rt slowly overnight. After 20 h, the reaction was carefully quenched with saturated aqueous NH.sub.4Cl and extracted with Et.sub.2O. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude material was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.15% ethyl acetate in hexanes) to afford the title compound (744 mg, 50%) as a thick oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.43-7.29 (m, 5H), 7.25-7.18 (m, 2H), 6.90-6.85 (m, 2H), 4.48 (d, J=11.3 Hz, 1H), 4.26 (d, J=5.0 Hz, 1H), 4.23 (d, J=11.3 Hz, 1H), 4.01-3.91 (m, 1H), 3.81 (s, 3H), 1.93 (s, 1H), 1.11 (d, J=6.4 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ159.24, 138.27, 130.20, 129.45, 128.42, 128.02, 127.84, 113.82, 84.63, 70.82, 70.46, 55.28, 18.15; IR (thin film) 3440, 2867, 2835, 1611, 1512, 1492, 1452, 1301, 1244, 1172, 1134, 1060, 1030, 952, 818, 755, 701 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.17H.sub.20 O.sub.3Na].sup.+, 295.1305; found, 295.1300. Also isolated (R)- 1-((4-methoxybenzyl)oxy)-2-methyl-1-phenylpropan-2-ol (353 mg, 1.17 mmol, 22% yield) as a thick oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.40-7.29 (m, 5H), 7.25-7.19 (m, 2H), 6.93-6.85 (m, 2H), 4.45 (d, J=11.2 Hz, 1H), 4.23-4.15 (m, 2H), 3.81 (s, 3H), 2.53 (s, 1H), 1.16 (s, 3H), 1.09 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ159.23, 138.13, 130.19, 129.47, 128.36, 128.03, 127.86, 113.79, 87.70, 72.85, 70.65, 55.28, 26.17, 24.38; IR (thin film) 3418, 2973, 2933, 2866, 2835, 1611, 1512, 1452, 1370, 1351, 1244, 1170, 1085, 1062, 1028, 819, 742, 702 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.18H.sub.22O.sub.3Na].sup.+, 309.1461; found, 309.1462.

Example 6A

Preparation of 1-methoxy-4-((((3R,4S)-4-phenoxypent-1-en-3-yl)oxy)methyl)benzene

[0121] ##STR00041##

[0122] A solution of (2S,3R)-3-((4-methoxybenzyl)oxy)pent-4-en-2-ol (1.272 g, 5.72 mmol), triphenylbismuth(V) acetate (4.15 g, 7.44 mmol) and copper(II) acetate (0.104 g, 0.572 mmol) was prepared in anhydrous toluene (38.1 mL) in a 100 mL flask under an atmosphere of N.sub.2. N-cyclohexyl-N-methylcyclohexanamine (1.410 mL, 6.58 mmol) was then added via syringe in one portion. The resulting blue/green reaction was heated to 40° C. yielding a pale blue/green reaction mixture. The mixture was stirred at temperature for 96 h. The reaction was cooled to rt and was filtered through a plug of Celite®, washing with DCM, and then concentrated to afford a dark yellow oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (1.43 g, 84%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.31-7.20 (m, 4H), 6.96-6.81 (m, 5H), 5.87 (ddd, J=17.5, 10.0, 7.4 Hz, 1H), 5.35 (dt, J=2.6, 1.7 Hz, 1H), 5.33-5.30 (m, 1H), 4.60 (d, J=11.6 Hz, 1H), 4.44-4.35 (m, 2H), 3.91 (ddt, J=7.4, 4.7, 1.0 Hz, 1H), 3.79 (s, 3H), 1.32 (d, J=6.3 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ159.07, 157.93, 135.53, 130.48, 129.40, 129.32, 120.78, 118.99, 116.15, 113.69, 81.88, 76.17, 70.34, 55.25, 15.69; IR (thin film) 2934, 1598, 1512, 1493, 1242, 1068, 753 cm.sup.−1.

Example 6B

Preparation of 1-(((2S,3R)-3-(benzyloxy)-4-methylpentan-2-yl)oxy)-2,4-difluorobenzene

[0123] ##STR00042##

[0124] A solution of (2S,3R)-3-(benzyloxy)-4-methylpentan-2-ol (91.5 mg, 0.439 mmol) was prepared in DMF (1.76 mL) at rt in a small vial. To this solution was added potassium tert-butoxide (71.5 mg, 0.637 mmol) followed by 1,2,4-trifluorobenzene (138 1.318 mmol). The mixture was stirred at 60° C. for 72 h. The reaction was quenched with AcOH (72 μL) and then diluted with hexanes (1.76 mL). The mixture was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (122.6 mg, 87%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.43-7.37 (m, 2H), 7.37-7.31 (m, 2H), 7.31-7.25 (m, 1H), 7.01 (ddd, J=10.7, 8.9, 5.4 Hz, 1H), 6.68 (ddd, J=9.8, 6.7, 3.0 Hz, 1H), 6.58 (ddt, J=8.9, 7.7, 3.1 Hz, 1H), 4.88 (d, J=11.1 Hz, 1H), 4.61 (d, J=11.1 Hz, 1H), 4.51 (qd, J=6.2, 3.8 Hz, 1H), 3.42 (dd, J=6.9, 3.8 Hz, 1H), 1.89 (h, J=6.8 Hz, 1H), 1.38 (d, J=6.3 Hz, 3H), 1.01 (d, J=6.7 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ158.73 (dd, J=242.0, 2.5 Hz), 149.83 (dd, J=241.2, 3.2 Hz), 146.37 (dd, J=12.5, 10.4 Hz), 138.86, 128.29, 127.99, 127.52, 116.51 (dd, J=21.2, 10.3 Hz), 106.87 (dd, J=23.9, 7.0 Hz), 104.17 (dd, J=27.0, 2.1 Hz), 86.00, 77.45, 74.87, 30.42, 19.66, 18.78, 14.46; .sup.19F NMR (376 MHz, CDCl.sub.3) δ-116.80 (d, J=15.0 Hz), −138.81 (d, J=15.0 Hz); IR (thin film) 2963, 1624, 1510, 1205, 1150, 1099, 698 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.19H.sub.26F.sub.2NO.sub.2].sup.+, 338.1926; found, 338.192.

Example 6C

Preparation of 1-methoxy-4-((((2R,3S)-3-((2-methylallyl)oxy)-1-phenylbutan-2-yl)oxy)methyl)benzene

[0125] ##STR00043##

[0126] A solution of (2S,3R)-3-((4-methoxybenzyl)oxy)-4-phenylbutan-2-ol (0.145 g, 0.506 mmol) was prepared in THF (1.688 mL). Sodium hydride (0.030 g, 0.760 mmol) and TBAI (0.019 g, 0.051 mmol) were then added. 3-bromo-2-methylprop-1-ene (0.153 mL, 1.519 mmol) was added in one portion and the reaction was allowed to reflux. The reaction was then quenched with water and extracted with Et.sub.2O (2×), dried over Na.sub.2SO.sub.4, filtered, and concentrated to an oil. The crude material was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.10% ethyl acetate in hexanes) to afford the title compound (144.1 mg, 79%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.33-7.18 (m, 5H), 7.12-7.01 (m, 2H), 6.83-6.77 (m, 2H), 5.01-4.92 (m, 1H), 4.89-4.80 (m, 1H), 4.47 (d, J=11.0 Hz, 1H), 4.26 (d, J=11.0 Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.89 3.80 (m, 1H), 3.78 (s, 3H), 3.63 (dt, J=8.5, 4.4 Hz, 1H), 3.46 (qd, J=6.3, 4.3 Hz, 1H), 2.89 (dd, J=13.9, 4.4 Hz, 1H), 2.79 (dd, J=13.9, 8.1 Hz, 1H), 1.74 (t, J=1.1 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ159.00, 142.65, 139.42, 130.77, 129.57, 129.49, 128.19, 126.01, 113.59, 111.73, 82.70, 76.66, 72.84, 72.64, 55.26, 37.96, 19.68, 15.29; IR (thin film) 3027, 2932, 1612, 1512, 1495, 1453, 1301, 1246, 1172, 1081, 1035, 898, 820, 743, 699 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.22H.sub.29O.sub.3].sup.+, 341.2111; found, 341.2095.

Example 7

Preparation of (2R,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutan-1-ol

[0127] ##STR00044##

[0128] In a 100 mL flask, 1-methoxy-4-((((3R,4S)-4-phenoxypent-1-en-3-yl)oxy)methyl)benzene (0.908 g, 3.04 mmol) and sodium bicarbonate (0.026 g, 0.304 mmol) were dissolved in anhydrous DCM (29.5 mL) and anhydrous MeOH (0.928 mL). To this solution was added 5 drops of a 1% DCM solution of sudan III indicator, producing a light pink solution. The reaction was cooled to −78° C. in a dry ice/acetone bath. After ˜5 min, O.sub.3 was bubbled through the reaction until the pink color disappeared. The reaction was then purged with N.sub.2 gas, and additional MeOH (9.28 mL) was added followed by solid sodium borohydride (0.345 g, 9.13 mmol) in one portion. The solution was allowed to warm to rt via removal of the dry ice/acetone bath, and the reaction was stirred overnight. After 18 h, TLC indicated conversion to a single lower R.sub.f spot. The reaction was quenched with H.sub.2O (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were passed through a phase separator and concentrated to afford a colorless oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.100% ethyl acetate in hexanes) to afford the title compound (893.7 mg, 97%) as a clear, colorless oil:.sup.1H NMR (300 MHz, CDCl.sub.3) δ7.32-7.22 (m, 5H), 6.99-6.84 (m, 5H), 4.70 (d, J=11.2 Hz, 1H), 4.60 (d, J=11.2 Hz, 1H), 4.56 -4.46 (m, 1H), 3.80 (s, 3H), 3.76 (dt, J=6.0, 4.6 Hz, 2H), 3.65 (td, J=5.0, 4.4 Hz, 1H), 1.36 (d, J=6.3 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) δ159.41, 157.49, 130.15, 129.67, 129.59, 121.14, 115.99, 113.93, 81.20, 73.81, 72.66, 61.49, 55.29, 16.09; IR (thin film) 3427, 2934, 1612, 1585, 1512, 1493, 1240, 1067, 1031, 752, 692 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.18H.sub.22NaO.sub.4].sup.+, 325.1410; found, 325.1396.

Example 8A

Preparation of (((2R,3S)-2-((4-methoxybenzyl)oxy)butane-1,3-diyl)bis(oxy))dibenzene

[0129] ##STR00045##

[0130] A solution of (2R,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutan-1-ol (180 mg, 0.595 mmol), triphenylbismuth(V) acetate (499 mg, 0.893 mmol) and copper(II) acetate (16.22 mg, 0.089 mmol) was prepared in anhydrous toluene (3.97 mL) in a 20 mL vial under an atmosphere of N.sub.2. N-cyclohexyl-N-methylcyclohexanamine (166 μL, 0.774 mmol) was then added via syringe in one portion. The resulting blue/green reaction was heated to 40° C. yielding a pale blue/green reaction mixture and stirred for 48 h. After 48 h, TLC indicated consumption of starting material and conversion to a single higher R.sub.f spot. The reaction was cooled to room temperature and filtered through a plug of Celite® with DCM, and the organics were concentrated to afford a dark yellow oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (208.5 mg, 93%) as a clear, colorless oil:.sup.1H NMR (400 MHz, CDCl.sub.3) 6 7.33-7.20 (m, 6H), 6.98-6.82 (m, 8H), 4.71 (s, 2H), 4.68-4.60 (m, 1H), 4.17 (dd, J=10.0, 4.8 Hz, 1H), 4.10 (dd, J=10.0, 5.5 Hz, 1H), 3.98 (q, J=5.1 Hz, 1H), 3.78 (s, 3H), 1.40 (d, J=6.2 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.31, 158.67, 157.61, 130.42, 129.66, 129.53, 129.45, 120.95, 120.92, 115.92, 114.62, 113.80, 78.80, 73.70, 73.03, 67.81, 55.26, 15.52; IR (thin film) 2933, 1598, 1492, 1237, 1081, 1032, 751, 691 cm.sup.−1; HRMS-ESI (m/z) calcd for [C.sub.24H.sub.26NaO.sub.4].sup.+, 401.1723; found, 401.1725.

Example 8B

Preparation of 1-methoxy-4-((((2R,3S)-1-methoxy-3-phenoxybutan-2-yl)oxy)methyl)benzene

[0131] ##STR00046##

[0132] In a small vial, (2R,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutan-1-ol (150 mg, 0.496 mmol) was dissolved in DCM (2.48 mL) under an atmosphere of N.sub.2. N.sub.1,N.sub.1,N.sub.8,N.sub.8-tetramethylnaphthalene-1,8-diamine (319 mg, 1.488 mmol) was added in one portion, followed by trimethyloxonium tetrafluoroborate (110 mg, 0.744 mmol). The resulting clear, colorless solution was stirred at rt overnight. After 20 h, TLC indicated complete consumption of starting material. The reaction was carefully quenched with sat. aq. NaHCO.sub.3 (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with 1N HCl (2×20 mL) followed by brine (20 mL). The organic layers were filtered through a phase separator and concentrated to afford a pale yellow oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% ethyl acetate in hexanes) to afford the title compound (117.5 mg, 75%) as a pale yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.31-7.22 (m, 4H), 6.97-6.81 (m, 5H), 4.65 (s, 2H), 4.54 (qd, J=6.2, 4.9 Hz, 1H), 3.79 (s, 3H), 3.74 (q, J=5.0 Hz, 1H), 3.56 (dd, J=10.3, 4.6 Hz, 1H), 3.51 (dd, J=10.2, 5.3 Hz, 1H), 3.33 (s, 3H), 1.34 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.20, 157.78, 130.71, 129.50, 129.48, 120.79, 115.91, 113.73, 79.30, 73.71, 72.64, 72.32, 59.22, 55.26, 15.44; IR (thin film) 2894, 1598, 1513, 1493, 1240, 1083, 1034, 752, 692 cm.sup.−1; HRMS-ESI (m/z) calcd for [C.sub.19H.sub.24NaO.sub.4].sup.+, 339.1567; found, 339.1569.

Example 8C

Preparation of 1-((((2R,3S)-1-(benzyloxy)-3-phenoxybutan-2-yl)oxy)methyl)-4-methoxybenzene

[0133] ##STR00047##

[0134] In a 20 mL vial, a solution of (2R,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutan-1-ol (145 mg, 0.480 mmol) was prepared in DMF (3.84 mL) and cooled to 0° C. in an ice water bath. After ˜5 min, sodium hydride (33.6 mg, 0.839 mmol) was added, and the resulting reaction mixture was stirred for 2 h, slowly warming to rt. After 2 h, the reaction was cooled to 0° C., and (bromomethyl)benzene (99 0.911 mmol) was added in one portion via syringe, followed by tetrabutylammonium iodide (17.71 mg, 0.048 mmol). The reaction was allowed to stir overnight, slowly warming to rt as the ice bath melted. After 18 h, TLC indicated complete consumption of starting material. The reaction was quenched with sat. aq. NH.sub.4Cl (20 mL) and extracted with Et.sub.2O (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO.sub.4, filtered, and concentrated to afford a yellow oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (148.4 mg, 79%) as a clear, colorless oil:.sup.1H NMR (400 MHz, CDCl.sub.3) δ7.34-7.20 (m, 9H), 6.96-6.87 (m, 3H), 6.87-6.82 (m, 2H), 4.65 (s, 2H), 4.63-4.55 (m, 1H), 4.51 (d, J=2.0 Hz, 2H), 3.82-3.74 (m, 4H), 3.68-3.57 (m, 2H), 1.34 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.19, 157.76, 138.25, 130.69, 129.51, 129.48, 128.32, 127.58, 127.54, 120.75, 115.86, 113.72, 79.41, 73.65, 73.37, 72.67, 69.77, 55.25, 15.40; IR (thin film) 3029, 2862, 1597, 1512, 1493, 1240, 1086, 1033, 751, 693 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.25H.sub.28NaO.sub.4].sup.+, 415.1880; found, 415.1876.

Example 8D

Preparation of 1-((((2R,3S)-1-(allyloxy)-3-phenoxybutan-2-yl)oxy)methyl)-4-methoxybenzene

[0135] ##STR00048##

[0136] In a 20 mL vial, a solution of (2R,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutan-1-ol (145.4 mg, 0.481 mmol) was prepared in DMF (3.85 mL) and cooled to 0° C. in an ice water bath. After ˜5 min, sodium hydride (33.7 mg, 0.842 mmol) was added, and the resulting reaction mixture was stirred for 2 h while slowly warming to rt. After 2 h, the reaction was cooled to 0° C., and allyl bromide (79 μL, 0.914 mmol) was added in one portion via syringe, followed by tetrabutylammonium iodide (17.76 mg, 0.048 mmol). The reaction was allowed to stir overnight, slowly warming to rt as the ice bath melted. After 20 h, TLC indicated consumption of starting material. The reaction was quenched with sat. aq. NH.sub.4Cl (20 mL) and extracted with Et.sub.2O (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO.sub.4, filtered, and concentrated to afford a yellow oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (145.4 mg, 88%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.31-7.20 (m, 4H), 6.96-6.82 (m, 5H), 5.87 (ddt, J=17.1, 10.8, 5.5 Hz, 1H), 5.25 (dq, J=17.2, 1.7 Hz, 1H), 5.16 (dq, J=10.4, 1.4 Hz, 1H), 4.66 (s, 2H), 4.56 (qd, J=6.2, 4.8 Hz, 1H), 3.97 (dt, J=5.5, 1.5 Hz, 2H), 3.85-3.73 (m, 4H), 3.62 (dd, J=10.2, 4.8 Hz, 1H), 3.56 (dd, J=10.2, 5.5 Hz, 1H), 1.35 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ159.20, 157.78, 134.75, 130.74, 129.52, 129.47, 120.76, 116.81, 115.91, 113.73, 79.35, 73.77, 72.72, 72.30, 69.84, 55.26, 15.37; IR (thin film) 2865, 1598, 1513, 1493, 1240, 1084, 1034, 752 cm.sup.−1; HRMS-ESI (m/z) calcd for [C.sub.21H.sub.26NaO.sub.4].sup.+, 365.1723; found, 365.1731.

Example 9

Step 1

Preparation of (2S,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutanal

[0137] ##STR00049##

[0138] In a 100 mL flask, 1-methoxy-4-((((3R,4S)-4-phenoxypent-1-en-3-yl)oxy)methyl)benzene (0.500 g, 1.676 mmol) and sodium bicarbonate (0.014 g, 0.168 mmol) were dissolved in anhydrous DCM (15.23 mL) and anhydrous MeOH (1.523 mL). To this solution was added 5 drops of a 1% DCM solution of sudan III indicator, producing a light pink solution. The reaction was cooled to −78° C. in a dry ice/acetone bath. After ˜5 min, O.sub.3 was bubbled through the reaction until the pink color disappeared. The reaction was then purged with nitrogen gas for ˜5 min, and then dimethylsulfide (1.231 mL, 16.76 mmol) was added in one portion via syringe. The resulting solution was allowed to warm to rt via removal of the dry ice/acetone bath, and the reaction was stirred overnight. After 18 h, TLC indicated consumption of starting material and conversion to a major lower R.sub.f product. The reaction was quenched with H.sub.2O (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were passed through a phase separator and concentrated to afford a colorless oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% ethyl acetate in hexanes) to afford the title compound (385.2 mg, 77%) as a clear, colorless oil:.sup.1H NMR (400 MHz, CDCl.sub.3) δ9.69 (d, J=1.6 Hz, 1H), 7.34-7.21 (m, 4H), 7.00-6.81 (m, 5H), 4.81-4.55 (m, 3H), 4.00 (dd, J=3.9, 1.7 Hz, 1H), 3.80 (s, 3H), 1.36 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ202.57, 159.62, 157.03, 129.86, 129.63, 129.20, 121.50, 116.02, 113.97, 84.11, 74.29, 73.09, 55.29, 15.70; IR (thin film) 2934, 2836, 1731, 1513, 1491, 1232, 1087, 1031, 752 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.18H.sub.24NO.sub.4].sup.+, 318.1700; found, 318.1703.

Example 9

Step 2

Preparation of 1-((((2S,3S)-1,1-difluoro-3-phenoxybutan-2-yl)oxy)methyl)-4-methoxybenzene

[0139] ##STR00050##

[0140] A solution of (2S,3S)-2-((4-methoxybenzyl)oxy)-3-phenoxybutanal (0.361 g, 1.202 mmol) was prepared in DCM (12.02 mL) and cooled to 0° C. in an ice/water bath. After ˜5 min, Deoxofluor (˜50% in toluene, 2.66 g, 6.01 mmol) was added in one portion followed by 1 drop of MeOH. The solution was stirred overnight, slowly warming to rt as the ice melted. After 18 h, TLC indicated consumption of starting material, and the mixture was concentrated to afford an orange oil. The crude oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.100% ethyl acetate in hexanes) to afford the title compound (342.1 mg, 88%) as a clear, colorless oil:.sup.1H NMR (400 MHz, CDCl.sub.3) δ7.32-7.23 (m, 4H), 7.01-6.94 (m, 1H), 6.92-6.83 (m, 4H), 5.91 (td, J=55.0, 3.4 Hz, 1H), 4.77 (d, J=11.1 Hz, 1H), 4.69 (d, J=11.1 Hz, 1H), 4.56 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 4H), 1.37 (d, J=6.3 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) δ-127.71 (dd, J=290.8, 2.1 Hz), −130.30 (dd, J=290.8, 4.0 Hz); IR (thin film)2937, 1598, 1514, 1494, 1241, 1074, 1035, 754 cm.sup.−1.

Example 10A

Preparation of (2R,3S)-1-phenyl-3-propoxybutan-2-ol

[0141] ##STR00051##

[0142] To a magnetically stirred mixture of 1-methoxy-4-((((2R,3S)-1-phenyl-3-propoxybutan-2-yl)oxy)methyl)benzene (90 mg, 0.274 mmol) in DCM (2466 μL) and water (274 μL) was added DDQ (65.3 mg, 0.288 mmol), and the reaction was stirred at 0° C. in an ice bath. The reaction was allowed to gradually warm to rt and was stirred overnight. The reaction was quenched with NaOH (1N) extracted with DCM (3×). The combined organic layers were passed through a phase separator and then concentrated. The crude material was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.10% ethyl acetate in hexanes). The product coeluted with undesired p-anisaldehyde byproduct. The material was diluted with DCM (2 mL), and PS-TsNHNH.sub.2 (300 mg, solid support) was added and the mixture was stirred at rt for 1 h. The reaction was filtered, and the filtrate was concentrated to provide the title compound (51.2 mg, 85%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.36-7.28 (m, 2H), 7.27-7.19 (m, 3H), 3.92 (dq, J=8.3, 4.0 Hz, 1H), 3.48 (dt, J=9.1, 6.6 Hz, 1H), 3.42-3.32 (m, 2H), 2.80 (dd, J=13.9, 4.6 Hz, 1H), 2.72 (dd, J=13.9, 8.7 Hz, 1H), 2.01 (d, J=3.5 Hz, 1H), 1.64-1.52 (m, 3H), 1.20 (d, J=6.3 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ138.74, 129.24, 128.49, 126.32, 77.44, 74.26, 70.62, 38.86, 23.30, 13.98, 10.67; IR (thin film) 3441, 2962, 2933, 2875, 1604, 1495, 1453, 1381, 1330, 1253, 1133, 1091, 1031, 984, 745, 699 cm.sup.−1.

Example 10B

Preparation of (1R,2S)-2-phenoxy-1-phenylpropan-1-ol

[0143] ##STR00052##

[0144] A solution of tert-butyldimethyl((1R,2S)-2-phenoxy-1-phenylpropoxy)silane (359.8 mg, 1.050 mmol) was prepared in a 20 mL vial in THF (5.25 mL) under N.sub.2 and was cooled to 0° C. After 5 min, TBAF (1.05 mL, 1.050 mmol) was added dropwise via syringe over 2 min. The reaction mixture was allowed to warm to rt and was stirred for 4 h. The reaction was quenched with saturated aqueous NH.sub.4Cl (25 mL) and extracted with Et.sub.2O (3×25 mL). The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated to afford a clear colorless oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% ethyl acetate in hexanes) to afford the title compound (96.0 mg, 40%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.40 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.27 (td, J=7.1, 2.0 Hz, 3H), 7.00-6.88 (m, 3H), 5.02 (t, J=3.3 Hz, 1H), 4.55 (qd, J=6.3, 3.5 Hz, 1H), 2.63 (d, J=3.0 Hz, 1H), 1.17 (d, J=6.3 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ157.44, 140.15, 129.65, 128.34, 127.64, 126.39, 121.37, 116.31, 77.93, 75.12, 13.01; IR (thin film) 3443, 2985, 1598, 1493, 1239, 1063, 752, 701 cm.sup.−1.

Example 10C

Preparation of 1-(((2S,3R)-3-(benzyloxy)-4-methylpentan-2-yl)oxy)-3-chloro-5-fluorobenzene

[0145] ##STR00053##

[0146] In a small vial, 1-(((2S,3R)-3-(benzyloxy)-4-methylpentan-2-yl)oxy)-3-chloro-5-fluorobenzene (160.0 mg, 0.475 mmol) was dissolved in ethanol (1.58 mL) and cyclohexene (0.79 mL). To this solution was added palladium on carbon (5 wt %, 50.6 mg, 0.024 mmol) in one portion, and the resulting reaction mixture was heated to 70° C. and stirred overnight. The reaction was cooled to rt, filtered through a plug of Celite® eluting with ethyl acetate, and concentrated to an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.50% acetone in hexanes) to afford the title compound (114.0 mg, 97%) as a yellow oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.69 (dp, J=4.2, 2.0 Hz, 2H), 6.51 (dt, J=10.5, 2.3 Hz, 1H), 4.40 (qd, J=6.2, 4.0 Hz, 1H), 3.52 (dd, J=7.5, 4.0 Hz, 1H), 2.02 (s, 1H), 1.80 (dq, J=13.7, 6.9 Hz, 1H), 1.30 (d, J=6.2 Hz, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ163.45 (d, J=248.0 Hz), 159.06 (d, J=12.1 Hz), 135.54 (d, J=13.5 Hz), 112.29 (d, J=3.3 Hz), 108.95 (d, J=25.2 Hz), 102.10 (d, J=24.8 Hz), 77.96, 75.72, 29.85, 18.95, 18.38, 13.13; .sup.19F NMR (376 MHz, CDCl.sub.3) δ-109.95; IR (thin film) 3464, 2963, 1606, 1452, 1140, 1044, 917, 833 cm.sup.−1.

Example 11

Preparation of (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-yl (tent-butoxycarbonyl)-L-alaninate

[0147] ##STR00054##

[0148] In a small vial, (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-ol (114 mg, 0.462 mmol), (tent-butoxycarbonyl)-L-alanine (109 mg, 0.578 mmol) and DMAP (5.65 mg, 0.046 mmol) were dissolved in DCM (2.31 mL) under N.sub.2 and cooled to 0° C. in an ice/water bath. After ˜5 min, EDCI (143 mg, 0.924 mmol) was added in one portion, and the resulting pale yellow reaction was stirred overnight, slowly warming to rt as the ice melted. The reaction was concentrated to afford an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% ethyl acetate in hexanes) to afford the title compound (171.0 mg, 89%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.72-6.63 (m, 2H), 6.49 (dt, J=10.5, 2.3 Hz, 1H), 5.04 (d, J=8.1 Hz, 1H), 5.00 (t, J=5.8 Hz, 1H), 4.45 (p, J=6.1 Hz, 1H), 4.35 (p, J=7.5 Hz, 1H), 2.05 (dq, J=13.5, 6.7 Hz, 1H), 1.46 (s, 9H), 1.43 (d, J=7.2 Hz, 3H), 1.30 (d, J=6.2 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.7 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.97, 163.41 (d, J=248.0 Hz), 159.01 (d, J=12.3 Hz), 155.12, 135.49 (d, J=13.4 Hz), 112.14 (d, J=3.2 Hz), 109.04 (d, J=25.3 Hz), 102.09 (d, J=24.8 Hz), 79.89, 79.28, 73.49, 49.56, 28.78, 28.35, 19.22, 18.65, 17.34, 15.01; .sup.19F NMR (376 MHz, CDCl.sub.3) δ-110.00; IR (thin film) 3373, 2974, 1713, 1605, 1140, 1063 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.20H.sub.29ClFNNaO.sub.5].sup.+, 440.1611; found, 440.1611.

Example 12A

Preparation of (3R,4S)-2-methyl-4-propoxypentan-3-yl (tert-butoxycarbonyl)-L-alaninate

[0149] ##STR00055##

[0150] In a vial containing (2S,3R)-2-(allyloxy)-4-methylpentan-3-yl (tert-butoxycarbonyl)-L-alaninate (0.1 g, 0.304 mmol) and 5% palladium on carbon (0.097 g, 0.046 mmol) was added EtOAc (1.52 mL) under a N.sub.2. The atmosphere was then replaced with hydrogen via balloon, and the reaction was left to stir overnight. After 20 h, the reaction was then filtered through Celite® and was washed with EtOAc. The filtrate was then concentrated and the crude was analyzed via NMR to confirm complete conversion. The crude material was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.20% ethyl acetate in hexanes) to afford the title compound (92.2 mg, 87%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ5.09 (d, J=7.8 Hz, 1H), 4.85 (t, J=5.9 Hz, 1H), 4.39-4.22 (m, 1H), 3.49 (p, J=6.2 Hz, 1H), 3.46-3.27 (m, 2H), 2.03 (h, J=6.7 Hz, 1H), 1.59-1.48 (m, 2H), 1.44 (s, 9H), 1.41 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.2 Hz, 3H), 0.94-0.86 (m, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ172.97, 155.07, 79.86, 79.65, 74.27, 70.63, 49.53, 28.57, 28.33, 23.22, 19.34, 18.98, 17.32, 15.34, 10.66; IR (thin film) 3359, 2967, 2936, 2877, 1716, 1502, 1455, 1366, 1340, 1248, 1167, 1107, 1066, 1021 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.17H.sub.33NO.sub.5Na].sup.+, 354.2251; found, 354.2251.

Example 12B

Preparation of (2S,3R)-2-phenoxyhexan-3-yl (tert-butoxycarbonyl)-L-alaninate

[0151] ##STR00056##

[0152] To a 20 mL vial containing (S)-(2S,3R)-2-(2,4-dichlorophenoxy)hex-5-en-3-yl 2-((tert-butoxycarbonyl)amino)propanoate (166.7 mg, 0.386 mmol) and palladium (5% wt on carbon, dry basis, 82 mg, 0.039 mmol) was added ethyl acetate (3.86 mL). The black reaction mixture was flushed with H.sub.1 gas via balloon. The resulting reaction was stirred at room temperature overnight. After 18 h, TLC and UPLC indicated consumption of starting material. The reaction was filtered through a plug of celite, eluting with EtOAc (2×10 mL). The resulting solution was concentrated to afford a yellow oil. The crude material was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.40% ethyl acetate in hexanes) to afford the title compound (108.7 mg, 77%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.33-7.19 (m, 2H), 7.00-6.91 (m, 1H), 6.91-6.81 (m, 2H), 5.09 (dt, J=8.7, 4.2 Hz, 1H), 5.05-4.91 (m, 1H), 4.45 (qd, J=6.3, 4.3 Hz, 1H), 4.29 (t, J=7.6 Hz, 1H), 1.79-1.57 (m, 2H), 1.53-1.16 (m, 2H), 1.45 (s, 9H), 1.36 (d, J=7.2 Hz, 3H), 1.30 (d, J=6.3 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.96, 157.80, 155.05, 129.51, 121.19, 116.26, 115.59, 79.71, 76.45, 74.82, 49.49, 31.85, 28.32, 18.66, 15.64, 13.91; IR (thin film) 3368, 2963, 1712, 1493, 1239, 1163, 1057, 752 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.20H.sub.31NNaO.sub.5].sup.+, 388.2097; found, 388.2077.

Example 13A

Step 1

Preparation of (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-yl L-alaninate hydrochloride

[0153] ##STR00057##

[0154] In a small vial, (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-yl (tert-butoxycarbonyl)-L-alaninate (171.0 mg, 0.409 mmol) was dissolved in DCM (2 mL). Hydrogen chloride (4M in dioxane, 1.534 mL, 6.14 mmol) was added in one portion via syringe. The resulting clear, colorless reaction was stirred at room temperature for 3 h. After 3 h, TLC indicated complete consumption of starting material and conversion to a baseline product. The reaction was concentrated under a stream of N.sub.2 and dried in a vacuum oven to provide the title compound (145 mg, quant. yield) as a clear, colorless oil that was used directly in the next step: ESIMS m/z 318.2 [(M+H).sup.+].

Example 13A

Step 2

Preparation of (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-yl (3-hydroxy-4-methoxypicolinoyl)-L-alaninate

[0155] ##STR00058##

[0156] To a vial containing (2S,3R)-2-(3-chloro-5-fluorophenoxy)-4-methylpentan-3-ylL-alaninate hydrochloride (145 mg, 0.409 mmol) was added 3-hydroxy-4-methoxypicolinic acid (90 mg, 0.532 mmol) and ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (277 mg, 0.532 mmol). DCM (8.18 mL) was added followed by N-ethyl-N-isopropylpropan-2-amine (428 μL, 2.454 mmol) dropwise over 45 seconds. After 10 min, most of the solids solubilized and the resultant pale pink colored reaction was stirred at rt overnight. The reaction was then concentrated under reduced pressure to yield an orange oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.50% acetone in hexanes) to afford the title compound (174.9 mg, 91% over two steps) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ12.11 (s, 1H), 8.49 (d, J=7.9 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.88 (d, J=5.2 Hz, 1H), 6.74-6.59 (m, 2H), 6.48 (dt, J=10.5, 2.3 Hz, 1H), 5.04 (t, J=5.8 Hz, 1H), 4.77 (p, J=7.3 Hz, 1H), 4.47 (p, J=6.1 Hz, 1H), 3.95 (s, 3H), 2.07 (dq, J=13.4, 6.7 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H), 1.30 (d, J=6.2 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.7 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ171.71, 168.87, 163.40 (d, J=248.1 Hz), 158.95 (d, J=12.2 Hz), 155.44, 148.84, 140.54, 135.51 (d, J=13.5 Hz), 130.46, 112.15 (d, J=3.2 Hz), 109.55, 109.10 (d, J=25.2 Hz), 102.06 (d, J=24.7 Hz), 79.77, 73.50, 56.09, 48.11, 28.76, 19.26, 18.31, 17.30, 15.05; .sup.19F NMR (376 MHz, CDCl.sub.3) δ-109.89 ; IR (thin film) 3370, 2968, 1743, 1605, 1527, 1438, 1139, 730 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.22H.sub.27ClFN.sub.2O.sub.6].sup.+, 469.1536; found, 469.1531.

Example 13B

Step 1

Preparation of (3R,4S)-2-methyl-4-((2-methylallyl)oxy)pentan-3-yl L-alaninate

[0157] ##STR00059##

[0158] (3R,4S)-2-methyl-4-((2-methylallyl)oxy)pentan-3-yl (tert-butoxycarbonyl)-L-alaninate (0.155 g, 0.451 mmol) was dissolved in DCM (2.26 mL) and cooled to 0° C. in an ice bath. After ˜5 min, TFA (0.522 mL, 6.77 mmol) was added dropwise via syringe over 30 seconds. The reaction was brought to rt via removal of the ice water bath and allowed to stir at rt for 2 h. After 2 h, TLC indicated consumption of starting material. The reaction was diluted with DCM and washed with saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with DCM (3×). The combined organic layers were passed through a phase separator and concentrated to afford the crude title compound as a thick oil that was used directly in the next step without further purification: IR (thin film) 3361, 2969, 1735, 1677, 1456, 1374, 1179, 1126, 1101, 907, 721 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.13H.sub.26NO.sub.3].sup.+, 244.1907; found, 244.1910.

Example 13B

Step 2

Preparation of (3R,4S)-2-methyl-4-((2-methylallyl)oxy)pentan-3-yl (3-hydroxy-4-methoxypicolinoyl)-L-alaninate

[0159] ##STR00060##

[0160] Crude (3R,4S)-2-methyl-4-((2-methylallyl)oxy)pentan-3-ylL-alaninate was dissolved in anhydrous DCM (4.4 mL). 3-hydroxy-4-methoxypicolinic acid (0.084 g, 0.496 mmol), PyBOP (0.258 g, 0.496 mmol), and ethyl-N-isopropylpropan-2-amine (0.260 mL, 1.489 mmol) were added. The reaction was then stirred at rt for 2 h. After 2 h, the material was concentrated to an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.30% acetone in hexanes) to afford the title compound (74.4 mg, 42% over 2 steps) as a thick colorless oil: .sup.1H NMR (500 MHz, CDCl.sub.3) δ12.18 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 4.96-4.91 (m, 2H), 4.88-.83 (m, 1H), 4.80-4.71 (m, 1H), 3.95 (s, 3H), 3.92 (d, J=12.4 Hz, 1H), 3.85 (d, J=12.3 Hz, 1H), 3.62-3.56 (m, 1H), 2.04 (dq, J=13.4, 6.8 Hz, 1H), 1.72 (t, J=1.1 Hz, 3H), 1.60-1.57 (m, 3H), 1.14 (d, J=6.3 Hz, 3H), 0.92 (d, J=3.5 Hz, 3H), 0.91 (d, J=3.7 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ171.83, 168.69, 155.34, 148.73, 142.32, 140.46, 130.54, 112.11, 109.40, 80.21, 73.54, 72.68, 56.07, 48.13, 28.62, 19.59, 19.34, 18.53, 17.56, 15.09; IR (thin film) 3370, 2968, 2939, 1739, 1649, 1576, 1527, 1481, 1438, 1366, 1330, 1280, 1263, 1212, 1182, 1150, 1101, 1060, 943, 849, 800 cm.sup.−1; ESIMS m/z 395.3 [(M+H).sup.+].

Example 14A

Preparation of (3R,4S)-2-methyl-4-phenoxypentan-3-yl (3-acetoxy-4-methoxypicolinoyl)-L-alaninate

[0161] ##STR00061##

[0162] To a small vial containing (3R,4S)-2-methyl-4-phenoxypentan-3-yl (3-hydroxy-4-methoxypicolinoyl)-L-alaninate (83.8 mg, 0.201 mmol) was added pyridine (0.976 mL, 12.1 mmol) followed by acetic anhydride (0.951 mL, 10.1 mmol) via syringe. The resultant clear and colorless reaction mixture was stirred at rt for 1 h. The reaction was concentrated, diluted with 5 mL toluene, and reconcentrated to afford an oil. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.50% acetone in hexanes) to afford the title compound (78.1 mg, 85%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.57 (d, J=6.9 Hz, 1H), 8.32 (d, J=5.4 Hz, 1H), 7.30-7.21 (m, 2H), 7.00 (d, J=5.5 Hz, 1H), 6.93 (tt, J=7.3, 1.0 Hz, 1H), 6.90-6.80 (m, 2H), 5.06 (dd, J=6.3, 5.3 Hz, 1H), 4.76 (p, J=7.3 Hz, 1H), 4.50 (p, J=6.2 Hz, 1H), 3.90 (s, 3H), 2.40 (s, 3H), 2.16-2.09 (m, 1H), 1.56 (d, J=7.1 Hz, 3H), 1.28 (d, J=6.2 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.24, 168.88, 162.49, 159.50, 157.43, 146.68, 141.58, 137.55, 129.53, 121.09, 115.92, 109.79, 80.11, 72.60, 56.29, 48.28, 28.71, 20.73, 19.37, 18.72, 17.01, 15.52; IR (thin film) 3383, 2967, 1771, 1677, 1507, 1198, 1174 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.24H.sub.31N.sub.2O.sub.7].sup.+, 459.2126; found, 459.2096.

Example 14B

Preparation of (3R,4S)-2-methyl-4-phenoxypentan-3-yl (3-(acetoxymethoxy)-4-methoxypicolinoyl)-L-alaninate

[0163] ##STR00062##

[0164] In a small vial, (S)-(3R,4S)-2-methyl-4-phenoxypentan-3-yl 2-(3-hydroxy-4-methoxypicolinamido)propanoate (81.9 mg, 0.197 mmol) was dissolved in acetone (1.5 mL). To this solution was added potassium carbonate (54.4 mg, 0.393 mmol) in one portion, followed by bromomethyl acetate (0.039 mL, 0.393 mmol) in one portion via syringe. The resulting cloudy white solution was stirred at 50° C. for 2 h. After 2 h, TLC indicated complete consumption of starting material. The reaction was then concentrated to a white oil under a stream of N.sub.2. The oil was purified by flash column chromatography (SiO.sub.2, 0.fwdarw.50% acetone in hexanes) to afford the title compound (77.4 mg, 81%) as a clear, colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.40 (d, J=7.7 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 7.31-7.20 (m, 2H), 6.99-6.84 (m, 4H), 5.80-5.71 (m, 2H), 5.07 (dd, J=6.4, 5.1 Hz, 1H), 4.80 (p, J=7.2 Hz, 1H), 4.50 (p, J=6.2 Hz, 1H), 3.91 (s, 3H), 2.21-2.09 (m, 1H), 2.07 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.30 (d, J=6.2 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) δ172.39, 170.27, 163.07, 160.32, 157.45, 145.73, 144.05, 142.58, 129.56, 121.11, 115.93, 109.61, 89.62, 80.12, 72.63, 56.20, 48.43, 28.72, 20.88, 19.42, 18.69, 16.98, 15.63; IR (thin film) 3389, 2968, 1753, 1678, 1496, 1239, 1203, 1004 cm.sup.−1; HRMS-ESI (m/z) calc'd for [C.sub.25H.sub.33N.sub.2O.sub.8].sup.+, 489.2231; found, 489.2212.

Example A

Evaluation of Fungicidal Activity: Leaf Blotch of Wheat (Zymoseptoria tritici; Bayer Code SEPTTR)

[0165] Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of water (H.sub.2O) containing 110 ppm Triton X-100. The fungicide solutions were applied onto wheat seedlings using an automated booth sprayer to run-off. All sprayed plants were allowed to air dry prior to further handling. All fungicides were evaluated using the aforementioned method for their activity vs. all target diseases, unless stated otherwise. Wheat leaf blotch and brown rust activity were also evaluated using track spray applications, in which case the fungicides were formulated as EC formulations, containing 0.1% Trycol 5941 in the spray solutions.

[0166] Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Zymoseptoria tritici either prior to or after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two to three days in a lighted dew chamber at 20° C.) to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 20° C. for disease to develop. When disease symptoms were fully expressed on the 1.sup.st leaves of untreated plants, infection levels were assessed on a scale of 0 to 100 percent disease severity. Percent disease control was calculated using the ratio of disease severity on treated plants relative to untreated plants.

Example B

Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia triticina; Bayer Code PUCCRT)

[0167] Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Puccinia triticina either prior to or after fungicide treatments. After inoculation the plants were kept in a dark dew room at 22° C. with 100% relative humidity overnight to permit spores to germinate and infect the leaf The plants were then transferred to a greenhouse set at 24° C. for disease to develop. Fungicide formulation, application and disease assessment followed the procedures as described in the Example A.

Example C

Evaluation of Fungicidal Activity: Wheat Glume Blotch (Leptosphaeria nodorum; Bayer Code LEPTNO)

[0168] Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50% mineral soil/50% soil-less Metro mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Leptosphaeria nodorum 24 h after fungicide treatments. After inoculation the plants were kept in 100% relative humidity (one day in a dark dew chamber followed by two days in a lighted dew chamber at 20° C.) to permit spores to germinate and infect the leaf The plants were then transferred to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment followed the procedures as described in the Example A.

Example D

Evaluation of Fungicidal Activity: Apple Scab (Venturia inaequalis; Bayer Code VENTIN):

[0169] Apple seedlings (variety McIntosh) were grown in soil-less Metro mix, with one plant per pot. Seedlings with two expanding young leaves at the top (older leaves at bottom of the plants were trimmed) were used in the test. Plants were inoculated with a spore suspension of Venturia inaequalis 24 h after fungicide treatment and kept in a 22° C. dew chamber with 100% relative humidity for 48 h, and then moved to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Example E

Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets (Cercospora beticola; Bayer Code CERCBE)

[0170] Sugar beet plants (variety HH88) were grown in soil-less Metro mix and trimmed regularly to maintain a uniform plant size prior to test. Plants were inoculated with a spore suspension 24 h after fungicide treatments. Inoculated plants were kept in a dew chamber at 22° C. for 48 h then incubated in a greenhouse set at 24° C. under a clear plastic hood with bottom ventilation until disease symptoms were fully expressed. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Example F

Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsora pachyrhizi; Bayer Code PHAKPA)

[0171] Technical grades of materials were dissolved in acetone, which were then mixed with nine volumes of H.sub.2O containing 0.011% Tween 20. The fungicide solutions were applied onto soybean seedlings using an automated booth sprayer to run-off All sprayed plants were allowed to air dry prior to further handling.

[0172] Soybean plants (variety Williams 82) were grown in soil-less Metro mix, with one plant per pot. Two weeks old seedlings were used for testing. Plants were inoculated either 3 days prior to or 1 day after fungicide treatments. Plants were incubated for 24 h in a dark dew room at 22° C. and 100% relative humidity then transferred to a growth room at 23° C. for disease to develop. Disease severity was assessed on the sprayed leaves.

Example G

Evaluation of Fungicidal Activity: Barley Scald (Rhyncosporium secalis, Bayer Code RHYNSE):

[0173] Barley seedlings (variety Harrington) were propagated in soil-less Metro mix, with each pot having 8 to 12 plants, and used in the test when the first leaf was fully emerged. Test plants were inoculated by an aqueous spore suspension of Rhyncosporium secalis 24 h after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 h. The plants were then transferred to a greenhouse set at 20° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Example H

Evaluation of Fungicidal Activity: Rice Blast (Pyricularia oryzae; Bayer Code PYRIOR)

[0174] Rice seedlings (variety Japonica) were propagated in soil-less Metro mix, with each pot having 8 to 14 plants, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Pyricularia oryzae 24 h after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 h to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse set at 24° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Example I

Evaluation of Fungicidal Activity: Tomato Early Blight (Alternaria solani; Bayer Code ALTESO)

[0175] Tomato plants (variety Outdoor Girl) were propagated in soil-less Metro mix, with each pot having one plant, and used when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Alternaria solani 24 h after fungicide treatments. After inoculation the plants were kept at 22° C. in 100% relative humidity for 48 h to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room at 22° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

Example J

Evaluation of Fungicidal Activity: Cucumber Anthracnose (Colletotrichum lagenarium; Bayer code COLLLA)

[0176] Cucumber seedlings (variety Bush Pickle) were propagated in soil-less Metro mix, with each pot having one plant, and used in the test when 12 to 14 days old. Test plants were inoculated with an aqueous spore suspension of Colletotrichum lagenarium 24 hr after fungicide treatments. After inoculation the plants were kept in a dew room at 22° C. with 100% relative humidity for 48 hr to permit spores to germinate and infect the leaf. The plants were then transferred to a growth room set at 22° C. for disease to develop. Fungicide formulation, application and disease assessment on the sprayed leaves followed the procedures as described in the Example A.

TABLE-US-00001 Lengthy table referenced here US20170360038A1-20171221-T00001 Please refer to the end of the specification for access instructions.

TABLE-US-00002 Lengthy table referenced here US20170360038A1-20171221-T00002 Please refer to the end of the specification for access instructions.

TABLE-US-00003 Lengthy table referenced here US20170360038A1-20171221-T00003 Please refer to the end of the specification for access instructions.

TABLE-US-00004 Lengthy table referenced here US20170360038A1-20171221-T00004 Please refer to the end of the specification for access instructions.

TABLE-US-00005 Lengthy table referenced here US20170360038A1-20171221-T00005 Please refer to the end of the specification for access instructions.

TABLE-US-00006 Lengthy table referenced here US20170360038A1-20171221-T00006 Please refer to the end of the specification for access instructions.

TABLE-US-00007 Lengthy table referenced here US20170360038A1-20171221-T00007 Please refer to the end of the specification for access instructions.

TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).