Intermediate of eribulin and preparation method therefor

Abstract

Disclosed are an intermediate of Eribulin and a preparation method therefor. In particular, disclosed are compounds as represented by formula II, formula III and formula V and a preparation method therefor. Ar is C.sub.1-10 alkyl substituted, alkyloxy substituted or unsubstituted aryl; R.sup.1 and R.sup.2 is an acetal protecting group or a thioacetal protecting group; R.sup.3 is hydrogen or a hydroxyl protecting group; and X is halogen or a leaving group. The preparation method therefor has the advantages of mild reaction conditions, high selectivity, easy purification, low synthesis cost and the like, being suitable for large scale production. ##STR00001##

Claims

1. A compound of formula V, VA, VII, VIIA, II, IX or X; ##STR00144## ##STR00145## wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl; R.sup.1 and R.sup.2 are acetal or thioacetal protecting group, and R.sup.1 and R.sup.2 are each independently C.sub.1-10 alkoxy or C.sub.1-10 alkylthio, or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form cyclic acetal or cyclic thioacetal; R.sup.3 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; Y is chloride, bromide or iodide; and X is chloride, bromide, iodide or trifluoromethanesulfonyloxy.

2. A preparation method of the compound of formula V according to claim 1, comprising conducting a NHK reaction of the compound of formula VI and the compound of formula VII to give the compound of formula V; ##STR00146## wherein Ar, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1; X is chloride, bromide, iodide or trifluoromethanesulfonyloxy.

3. A preparation method of the compound of formula VA according to claim 1, comprising conducting a NHK reaction of the compound of formula VI and the compound of formula VITA to give the compound of formula VA; ##STR00147## wherein Ar, R.sup.1, R.sup.2 and Y are as defined in claim 1; X is chloride, bromide, iodide or trifluoromethanesulfonyloxy.

4. A preparation method of the compound of formula VII according to claim 1, comprising conducting a hydroxyl protecting reaction of the compound of formula VIII to give the compound of formula VII; ##STR00148## wherein R.sup.1, R.sup.2, R.sup.3 and X are as defined in claim 1.

5. A preparation method of the compound of formula VIIA according to claim 1, comprising conducting a substitution reaction of the compound of formula VII to give the compound of formula VIIA; ##STR00149## wherein R.sup.1, R.sup.2, X and Y are as defined in claim 1; R.sup.3 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.

6. A preparation method of the compound of formula II according to claim 1, comprising conducting a reductive elimination reaction of the compound of formula IX to give the compound of formula II; ##STR00150## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

7. A preparation method of the compound of formula IV, comprising conducting a hydrolysis reaction of the compound of formula II to give the compound of formula IV; ##STR00151## wherein X, R.sup.1 and R.sup.2 are as defined in claim 1.

8. A preparation method of the compound of formula IX according to claim 1, comprising conducting an oxidation reaction of the compound of formula X to give the compound of formula IX; ##STR00152## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

9. A preparation method of the compound of formula XII, comprising conducting a hydrolysis reaction of the compound of formula IX to give the compound of formula XII; ##STR00153## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

10. A preparation method of the compound of formula X according to claim 1, comprising conducting a condensation reaction of the compound of formula III and the compound of formula XI under a basic condition; ##STR00154## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

11. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; ii) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; iii) conducting a reductive elimination reaction of the compound of formula IX to prepare the compound of formula II; iv) conducting a hydrolysis reaction of the compound of formula II to give the compound of formula IV; ##STR00155## ##STR00156## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

12. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; ii) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; iii) conducting a hydrolysis reaction of the compound of formula IX to prepare the compound of formula XII; iv) conducting a reductive elimination reaction of the compound of formula XII to give the compound of formula IV; ##STR00157## ##STR00158## wherein Ar, X, R.sup.1 and R.sup.2 are as defined in claim 1.

13. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a hydroxyl protecting reaction of the compound of formula VIII to prepare the compound of formula VII; ii) conducting a NHK reaction of the compound of formula VII and the compound of formula VI to prepare the compound of formula V; iii) conducting an intramolecular cyclization reaction of the compound of formula V to prepare the compound of formula III; iv) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; v) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; vi) conducting a reductive elimination reaction of the compound of formula IX to prepare the compound of formula II; vii) conducting a hydrolysis reaction of the compound of formula II to give the compound of formula IV; ##STR00159## ##STR00160## wherein Ar, X, R.sup.1, R.sup.2, and R.sup.3 are as defined in claim 1.

14. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a hydroxyl protecting reaction of the compound of formula VIII to prepare the compound of formula VII; ii) conducting a NHK reaction of the compound of formula VII and the compound of formula VI to prepare the compound of formula V; iii) conducting an intramolecular cyclization reaction of the compound of formula V to prepare the compound of formula III; iv) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; v) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; vi) conducting a hydrolysis reaction of the compound of formula IX to prepare the compound of formula XII; vii) conducting a reductive elimination reaction of the compound of formula XII to give the compound of formula IV; ##STR00161## ##STR00162## wherein Ar, X, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1.

15. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a hydroxyl protecting reaction of the compound of formula VIII to prepare the compound of formula VII; ii) conducting a substitution reaction of the compound of formula VII to prepare the compound of formula VIIA; iii) conducting a NHK reaction of the compound of formula VIIA and the compound of formula VI to prepare the compound of formula VA; iv) conducting an intramolecular cyclization reaction of the compound of formula VA to prepare the compound of formula III; v) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; vi) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; vii) conducting a reductive elimination reaction of the compound of formula IX to prepare the compound of formula II; viii) conducting a hydrolysis reaction of the compound of formula II to give the compound of formula IV; ##STR00163## ##STR00164## wherein Ar, X, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1; Y is chloride, bromide or iodide.

16. A preparation method of the compound of formula IV, comprising the following steps: i) conducting a hydroxyl protecting reaction of the compound of formula VIII to prepare the compound of formula VII; ii) conducting a substitution reaction of the compound of formula VII to prepare the compound of formula VIIA; iii) conducting a NHK reaction of the compound of formula VIIA and the compound of formula VI to prepare the compound of formula VA; iv) conducting an intramolecular cyclization reaction of the compound of formula VA to prepare the compound of formula III; v) conducting a condensation reaction of the compound of formula III and the compound of formula XI to prepare the compound of formula X; vi) conducting an oxidation reaction of the compound of formula X to prepare the compound of formula IX; vii) conducting a hydrolysis reaction of the compound of formula IX to prepare the compound of formula XII; viii) conducting a reductive elimination reaction of the compound of formula XII to give the compound of formula IV; ##STR00165## ##STR00166## wherein Ar, X, R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1; Y is chloride, bromide or iodide.

17. The compound of formula V, VA, VII, VIIA, II, IX or X according to claim 1, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1and R.sup.2 together with the carbon atom to which they are attached form cyclic acetal or cyclic thioacetal.

18. The compound of formula V, VA, VII, VIIA, II, IX or X according to claim 17, wherein R.sup.1and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

19. The preparation method of the compound of formula V according to claim 2, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

20. The preparation method of the compound of formula VA according to claim 3, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

21. The preparation method of the compound of formula IX according to claim 8, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

22. The preparation method of the compound of formula IV according to claim 12, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

23. The preparation method of the compound of formula IV according to claim 13, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

24. The preparation method of the compound of formula IV according to claim 14, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

25. The preparation method of the compound of formula IV according to claim 16, wherein Ar is an aryl substituted by C.sub.1-10 alkyl or alkoxy, or an unsubstituted aryl, or a phenyl substituted by C.sub.1-10 alkyl at para-position, or an unsubstituted phenyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form substituted or unsubstituted ethylene glycol acetal, or substituted or unsubstituted propanediol acetal.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) The present disclosure is described in detail with reference to the following specific examples so that those skilled in the art will understand the present disclosure in a more comprehensive manner. The specific examples are used only to illustrate the technical solution of the present disclosure, but are not intended to limit the scope of the present disclosure in any way.

(2) Structural formulas of some compounds in the Examples are shown in the following table

(3) TABLE-US-00002 No. Formula IIa IIb IIIa IIIb IIIc 0 IIId IIIe IIIf IIIg IIIh IIIi IVa Va Vb Vc 00 Vd 01 Ve 02 Vf 03 Vg 04 Vh 05 Vi 06 VAa 07 VAb 08 VAc 09 VAd 0 VIa VIb VIc VIIa VIIb VIIc VIId VIIe VIIf VIIg 0 VIIAa VIIAb VIIIa VIIIb VIIIc VIIId VIIIe VIIIf VIIIg IXa 0 IXb IXc IXd Xa Xb Xc Xd XIa XIIa XIIc 0 XIId Lig- and 1 Lig- and 2

(4) Examples 1-7 disclosed the synthesis of the compound of formula VII

Example 1: Preparation of the Compound of Formula VIIa

(5) To the solution of compound of formula VIIIa (8.17 g, 18 mmol) in THF (150 mL) was added Et.sub.3N (16.2 g) at room temperature, then MsCl (12.1 g) was added slowly. The reaction was stirred at the same temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIa (8.76 g).

(6) MS (ESI) m/z: 515 (M+H.sup.+).

(7) .sup.1HNMR (400 MHz, CDCl.sub.3): δ 6.36 (d, J=1.2 Hz, 1H), 5.84 (d, J=1.6 Hz, 1H), 5.01-4.99 (m, 1H), 4.90-4.85 (m, 2H), 4.72-4.65 (m, 1H), 4.41-4.35 (m, 1H), 4.08-4.01 (m, 1H), 3.98-3.94 (m, 2H), 3.87-3.83 (m, 2H), 3.02 (s, 3H), 2.71-2.64 (m, 1H), 2.31-2.25 (m, 1H), 2.10-2.02 (m, 1H), 1.94-1.75 (m, 4H), 1.73-1.51 (m, 6H), 1.00 (d, J=6.4 Hz, 3H).

Example 2: Preparation of the Compound of Formula VIIb

(8) A solution of the compound of formula VIIIb (1.02 g, 2.1 mmol) in dichloromethane (15 mL) was cooled to −30° C., and then pyridine (2.3 g) and Ms.sub.2O (1.59 g) were added sequentially. The reaction solution was stirred at the same temperature for 3 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIb (1.06 g).

(9) MS (ESI) m/z: 529 (M+H.sup.+).

(10) .sup.1HNMR (400 MHz, CDCl.sub.3): δ 6.36 (s, 1H), 5.85 (d, J=1.3 Hz, 1H), 5.00-4.98 (m, 1H), 4.90-4.86 (m, 1H), 4.72-4.65 (m, 1H), 4.60-4.50 (m, 1H), 4.42-4.38 (m, 1H), 4.15-4.02 (m, 2H), 3.87-3.73 (m, 2H), 3.02 (s, 3H), 2.72-2.66 (m, 1H), 2.54 (d, J=5.0 Hz, 1H), 2.40-2.26 (m, 1H), 2.19-2.06 (m, 2H), 1.79-1.28 (m, 11H), 1.01 (d, J=6.6 Hz, 3H).

Example 3: Preparation of the Compound of Formula VIII

(11) A solution of the compound of formula VIIIc (0.68 g, 1.3 mmol) in ethyl acetate (15 mL) was cooled to −10° C., and then 2,6-lutidine (2.1 g) and Ms.sub.2O (1.06 g) were added sequentially. After completion of the addition, the reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIII (0.72 g).

(12) MS (ESI) m/z: 557 (M+H.sup.+).

(13) .sup.1HNMR (400 MHz, CDCl.sub.3): δ 6.36 (s, 1H), 5.85 (d, J=1.2 Hz, 1H), 5.00-4.96 (m, 1H), 4.90-4.85 (m, 1H), 4.73-4.65 (m, 1H), 4.52-4.42 (m, 1H), 4.42-4.37 (m, 1H), 3.87-3.73 (m, 2H), 3.38-3.30 (m, 2H), 3.02 (s, 3H), 2.72-2.65 (m, 1H), 2.55 (d, J=5.0 Hz, 1H), 2.40-2.25 (m, 1H), 1.80-1.28 (m, 11H), 1.18 (s, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.71 (s, 3H).

Example 4: Preparation of the Compound of Formula VIId

(14) 2,4,6-Collidine (4.2 g) was added to a solution of the compound of formula VIIId (2.6 g, 4.8 mmol) in 2-methyltetrahydrofuran (30 mL) at 40° C. MsCl (3.9 g) was slowly added to the solution. After completion of the addition, the mixture was stirred at the same temperature for 15 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIId (2.73 g).

(15) MS (ESI) m/z: 561 (M+H.sup.+).

(16) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.36 (s, 1H), 5.86 (d, J=1.3 Hz, 1H), 5.04-5.00 (m, 1H), 4.90-4.86 (m, 1H), 4.73-4.65 (m, 1H), 4.50-4.40 (m, 1H), 4.19-4.00 (m, 1H), 3.02 (s, 3H), 2.99-2.78 (m, 4H), 2.74-2.70 (m, 1H), 2.45 (d, J=5.0 Hz, 1H), 2.37-2.23 (m, 1H), 2.20-2.05 (m, 2H), 2.05-1.28 (m, 11H), 1.01 (d, J=6.6 Hz, 3H).

Example 5: Preparation of the Compound of Formula VIIe

(17) A solution of the compound of formula VIIIe (3.2 g, 6.4 mmol) in acetonitrile (30 mL) was cooled to 0° C., and then diisopropylethylamine (1.25 g) and MsCl (1.05 g) were added slowly and sequentially. After completion of the addition, the reaction was stirred at the same temperature for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIe (3.26 g).

(18) MS (ESI) m/z: 517 (M+H.sup.+).

(19) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.37 (s, 1H), 5.76 (d, J=1.2 Hz, 1H), 5.05-5.00 (m, 1H), 4.90-4.85 (m, 1H), 4.75-4.65 (m, 1H), 4.40 (dd, J=7.0, 3.9 Hz, 2H), 3.34 (d, J=1.7 Hz, 6H), 3.03 (s, 3H), 2.38-2.25 (m, 1H), 2.15-2.10 (m, 1H), 1.83-1.28 (m, 11H), 1.01 (d, J=6.6 Hz, 3H).

Example 6: Preparation of the Compound of Formula VIIf

(20) A solution of the compound of formula VIIIf (2.8 g, 5.4 mmol) in toluene (30 mL) was cooled to 10° C., and then triethylamine (2.6 g) and MsCl (2.3 g) were added slowly and sequentially. The reaction solution was stirred at the same temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIf (2.9 g).

(21) MS (ESI) m/z: 545 (M+H.sup.+).

(22) .sup.1HNMR (400 MHz, Chloroform-d) δ 6.36 (s, 1H), 5.78 (d, J=1.2 Hz, 1H), 5.04-5.00 (m, 1H), 4.90-4.85 (m, 1H), 4.75-4.65 (m, 1H), 4.52 (t, J=5.5 Hz, 1H), 4.41 (brs, 1H), 3.72-3.47 (m, 4H), 3.03 (s, 3H), 2.75-2.68 (m, 1H), 2.52 (d, J=5.0 Hz, 1H), 2.41-2.26 (m, 1H), 1.85-1.28 (m, 11H), 1.23-1.18 (m, 6H), 1.01 (d, J=6.6 Hz, 3H).

Example 7: Preparation of the Compound of Formula VIIg

(23) A solution of the compound of formula VIIIg (1.9 g, 3.5 mmol) in N,N-dimethylformamide (30 mL) was cooled to 10° C., and then triethylamine (2.3 g) and Ms.sub.2O (1.7 g) were added slowly and sequentially. The reaction solution was stirred at the same temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIg (2.02 g).

(24) MS (ESI) m/z: 573 (M+H.sup.+).

(25) .sup.1H NMR (400 MHz, Chloroform-d) δ 6.36 (s, 1H), 5.77 (d, J=1.3 Hz, 1H), 5.04-5.00 (m, 1H), 4.92-4.88 (m, 1H), 4.73-4.65 (m, 1H), 4.57 (t, J=5.1 Hz, 1H), 4.45-4.40 (m, 1H), 3.90-3.82 (m, 2H), 3.02 (s, 3H), 2.75-2.66 (m, 1H), 2.52 (d, J=5.0 Hz, 1H), 2.41-2.26 (m, 1H), 1.85-1.28 (m, 11H), 1.26-1.09 (m, 12H), 1.01 (d, J=6.6 Hz, 3H).

(26) Examples 8-9 disclosed the synthesis of the compound of formula VIIA

Example 8: Preparation of the Compound of Formula VIIAa

(27) The compound of formula VIIa (1.6 g, 3 mmol) was dissolved in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (20 mL) at −20° C. Tributylbenzylammonium chloride (12 g) was added to this solution. The reaction solution was stirred at room temperature for 48 h. The reaction was quenched by H.sub.2O and the mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIAa (1.43 g).

(28) MS (ESI) m/z: 455 (M+H.sup.+).

(29) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.17 (d, J=1.2 Hz, 1H), 5.73 (d, J=1.2 Hz, 1H), 5.01-4.99 (m, 1H), 4.92-4.83 (m, 2H), 4.40-4.35 (m, 1H), 4.10-4.00 (m, 1H), 3.98-3.95 (m, 3H), 3.87-3.85 (m, 2H), 2.70-2.64 (m, 1H), 2.30-2.25 (m, 1H), 2.10-2.02 (m, 1H), 1.94-1.73 (m, 4H), 1.73-1.50 (m, 6H), 1.00 (d, J=6.4 Hz, 3H).

Example 9: Preparation of the Compound of Formula VIIAb

(30) The compound of formula VIIb (1.6 g, 2.9 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 60° C. Tetrabutylammonium chloride (10 g) was added to this solution. The reaction solution was stirred at the same temperature for 1 h. The reaction was quenched by H.sub.2O and the mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VIIAb (1.25 g).

(31) MS (ESI) m/z: 469 (M+H.sup.+).

(32) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.18 (d, J=1.2 Hz, 1H), 5.72 (d, J=1.2 Hz, 1H), 5.00-4.98 (m, 1H), 4.92-4.86 (m, 1H), 4.58-4.50 (m, 1H), 4.43-4.38 (m, 1H), 4.15-4.00 (m, 2H), 3.97-3.91 (m, 1H), 3.86-3.70 (m, 2H), 2.70-2.65 (m, 1H), 2.52 (d, J=5.0 Hz, 1H), 2.40-2.25 (m, 1H), 2.20-2.05 (m, 2H), 1.80-1.29 (m, 11H), 1.02 (d, J=6.6 Hz, 3H).

(33) Examples 10-18 disclosed the synthesis of the compound of formula V

Example 10: Preparation of the Compound of Formula Va

(34) To a reaction flask were added the compound of formula VIIa (4.35 g, 8.5 mmol), the compound of formula VIa (5.7 g), ligand 1 (13.1 g), CrCl.sub.2 (3.6 g) and NiCl.sub.2 (1.05 g). The mixture was dissolved by addition of THF (60 mL) and triethylamine (2.2 g). The reaction solution was heated to 60° C. and stirred for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Va (7.35 g).

(35) MS (ESI) m/z: 1017 (M+H.sup.+).

(36) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 4.99-4.86 (m, 1H), 4.89-4.84 (m, 3H), 4.79-4.76 (m, 1H), 4.36-4.35 (m, 1H), 4.19-4.16 (m, 1H), 4.05-3.68 (m, 10H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.47 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.63 (m, 1H), 2.59-2.55 (m, 1H), 2.33-1.38 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 11: Preparation of the Compound of Formula Vb

(37) To a reaction flask were added the compound of formula VIIb (0.87 g, 1.6 mmol), the compound of formula VIa (1.3 g), ligand 2 (3.1 g), CrCl.sub.2 (0.86 g) and NiCl.sub.2 (0.12 g). The mixture was dissolved by addition of 2-methyltetrahydrofuran (15 mL) and diisopropylethylamine (0.43 g). The reaction solution was heated to 30° C. and stirred for 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vb (1.32 g).

(38) MS (ESI) m/z: 1031 (M+H.sup.+).

(39) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 5.00-4.86 (m, 1H), 4.88-4.85 (m, 3H), 4.80-4.72 (m, 1H), 4.60-4.52 (m, 1H), 4.45-4.40 (m, 1H), 4.16-3.69 (m, 9H), 3.58 (dd, J=10.4, 5.2 Hz, 1H), 3.45 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.05 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.74 (q, J=7.6 Hz, 2H), 2.69-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.30-1.35 (m, 18H), 1.27 (t, J=7.6 Hz, 3H), 1.08 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 12: Preparation of the Compound of Formula Vc

(40) To a reaction flask were added the compound of formula VIII (0.87 g, 1.6 mmol), the compound of formula VIa (1.3 g), ligand 1 (2.6 g), CrCl.sub.3 (0.95 g), Mn powder (1.2 g) and NiCl.sub.2 (0.22 g). The mixture was dissolved by addition of acetonitrile (10 mL) and pyridine (0.36 g). The reaction solution was stirred at 10° C. for 24 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vc (1.16 g).

(41) MS (ESI) m/z: 1059 (M+H.sup.+).

(42) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 5.00-4.86 (m, 1H), 4.90-4.85 (m, 3H), 4.80-4.75 (m, 1H), 4.52-4.42 (m, 2H), 4.13-3.70 (m, 9H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.45 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.15 (dd, J=14, 4.8 Hz, 1H), 3.06 (dd, J=14.4, 9.6 Hz, 1H), 3.02 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.60 (m, 1H), 2.60-2.55 (m, 1H), 2.32-1.35 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.19 (s, 3H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.71 (s, 3H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 13: Preparation of the Compound of Formula Vd

(43) To a reaction flask were added the compound of formula VIId (0.87 g, 1.6 mmol), the compound of formula VIa (1.2 g), ligand 2 (2.4 g), CrCl.sub.2 (1.2 g) and NiCl.sub.2 (0.12 g). The mixture was dissolved by addition of DMSO (10 mL) and Et.sub.3N (0.44 g). The reaction solution was stirred at 0° C. for 48 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vd (1.2 g).

(44) MS (ESI) m/z: 1063 (M+H.sup.+).

(45) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 4.99-4.86 (m, 1H), 4.90-4.85 (m, 3H), 4.79-4.76 (m, 1H), 4.50-4.40 (m, 1H), 4.19-3.68 (m, 7H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.48 (dd, J=10, 5.6 Hz, 1H), 3.39 (s, 3H), 3.18 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 3.00-2.78 (m, 4H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.65 (m, 1H), 2.59-2.55 (m, 1H), 2.45 (d, J=5.0 Hz, 1H), 2.35-1.30 (m, 18H), 1.27 (t, J=7.6 Hz, 3H), 1.08 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 14: Preparation of the Compound of Formula Ve

(46) To a reaction flask were added the compound of formula VIIe (0.87 g, 1.7 mmol), the compound of formula VIa (1.2 g), ligand 1 (2.7 g), CrCl.sub.2 (1.2 g) and NiCl.sub.2 (0.12 g). The mixture was dissolved by addition of DCM (10 mL) and Et.sub.3N (0.44 g). The reaction solution was stirred at 20° C. for 36 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Ve (1.06 g).

(47) MS (ESI) m/z: 1019 (M+H.sup.+).

(48) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 4.99-4.86 (m, 1H), 4.89-4.84 (m, 3H), 4.79-4.76 (m, 1H), 4.41 (dd, J=7.0, 4.0 Hz, 1H), 4.19-4.15 (m, 1H), 4.05-3.65 (m, 5H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.47 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 2.60-2.55 (m, 1H), 2.30-1.35 (m, 17H), 1.27 (t, J=7.6 Hz, 3H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 15: Preparation of the Compound of Formula Vf

(49) To a reaction flask were added the compound of formula VIIf (0.87 g, 1.7 mmol), the compound of formula VIa (1.5 g), ligand 1 (2.8 g), CrCl.sub.2 (1.6 g) and NiCl.sub.2 (0.21 g). The mixture was dissolved by addition of ethyl acetate (10 mL) and 2, 6-lutidine (0.44 g). The reaction solution was stirred at 20° C. for 18 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vf (1.12 g).

(50) MS (ESI) m/z: 1047 (M+H.sup.+).

(51) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 4.99-4.86 (m, 1H), 4.90-4.85 (m, 3H), 4.80-4.75 (m, 1H), 4.53 (t, J=5.6 Hz, 1H), 4.41 (brs, 1H), 4.20-4.15 (m, 1H), 4.05-3.65 (m, 9H), 3.56 (dd, J=10.4, 5.2 Hz, 1H), 3.46 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 2.73-2.55 (m, 2H), 2.53 (d, J=5.0 Hz, 1H), 2.40-1.35 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.20-1.15 (m, 6H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 16: Preparation of the Compound of Formula Vg

(52) To a reaction flask were added the compound of formula VIIg (0.87 g, 1.6 mmol), the compound of formula VIa (1.5 g), ligand 1 (2.3 g), CrCl.sub.2 (1.2 g) and NiCl.sub.2 (0.16 g). The mixture was dissolved by addition of methyl t-butyl ether (10 mL) and Et.sub.3N (0.36 g). The reaction solution was stirred at 40° C. for 15 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The resultant was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vg (1.1 g).

(53) MS (ESI) m/z: 1075 (M+H.sup.+).

(54) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 4.99-4.86 (m, 1H), 4.89-4.84 (m, 3H), 4.78-4.75 (m, 1H), 4.57 (t, J=5.2 Hz, 1H), 4.45-4.40 (m, 1H), 4.20-4.15 (m, 1H), 4.05-3.65 (m, 7H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.46 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.05 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.74 (q, J=7.6 Hz, 2H), 2.74-2.66 (m, 1H), 2.60-2.55 (m, 1H), 2.52 (d, J=5.0 Hz, 1H), 2.40-1.35 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.26-1.09 (m, 12H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H), 0.05 (s, 3H), 0.03 (s, 3H), 0.00 (s, 6H).

Example 17: Preparation of the Compound of Formula Vh

(55) To a reaction flask were added the compound of formula VIIa (0.87 g, 1.6 mmol), the compound of formula VIb (1.3 g), ligand 1 (2.3 g), CrCl.sub.2 (1.1 g) and NiCl.sub.2 (0.15 g). The mixture was dissolved by addition of THF (20 mL) and Et.sub.3N (0.32 g). The reaction solution was stirred at 30° C. for 12 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vh (1.2 g).

(56) MS (ESI) m/z: 989 (M+H.sup.+).

(57) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.99-7.92 (m, 2H), 7.75-7.66 (m, 1H), 7.65-7.59 (m, 2H), 5.20 (s, 1H), 4.99-4.88 (m, 1H), 4.89-4.85 (m, 3H), 4.80-4.76 (m, 1H), 4.36-4.35 (m, 1H), 4.19-4.15 (m, 1H), 4.05-3.68 (m, 10H), 3.57 (dd, J=10.4, 5.2 Hz, 1H), 3.47 (dd, J=10, 5.6 Hz, 1H), 3.37 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.70-2.63 (m, 1H), 2.59-2.55 (m, 1H), 2.33-1.38 (m, 16H), 1.08 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 18: Preparation of the Compound of Formula Vi

(58) To a reaction flask were added the compound of formula VIIa (0.87 g, 1.6 mmol), the compound of formula VIc (1.4 g), ligand 2 (2.1 g), CrCl.sub.2 (1.6 g) and NiCl.sub.2 (0.23 g). The mixture was dissolved by addition of 2-methyltetrahydrofuran (20 mL) and proton sponge (0.36 g). The reaction solution was stirred at 30° C. for 24 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Vi (1.1 g).

(59) MS (ESI) m/z: 1003 (M+H.sup.+).

(60) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 5.20 (s, 1H), 5.00-4.88 (m, 1H), 4.86-4.82 (m, 3H), 4.80-4.76 (m, 1H), 4.39-4.35 (m, 1H), 4.19-4.15 (m, 1H), 4.05-3.66 (m, 10H), 3.57 (dd, J=10.2, 5.2 Hz, 1H), 3.46 (dd, J=10, 5.6 Hz, 1H), 3.37 (s, 3H), 3.17 (dd, J=14, 4.8 Hz, 1H), 3.04 (dd, J=14.4, 9.6 Hz, 1H), 3.01 (s, 3H), 2.70-2.65 (m, 1H), 2.59-2.55 (m, 1H), 2.46 (s, 3H), 2.33-1.38 (m, 16H), 1.08 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

(61) Examples 19-22 disclosed the synthesis of the compound of formula VA

Example 19: Preparation of the Compound of Formula VAa

(62) To a reaction flask were added the compound of formula VIIAa (1.2 g, 2.6 mmol), the compound of formula VIa (2.1 g), ligand 1 (3.8 g), CrCl.sub.2 (1.9 g) and NiCl.sub.2 (0.29 g). The mixture was dissolved by addition of tetrahydrofuran (30 mL) and Et.sub.3N (0.62 g). The reaction solution was stirred at 20° C. for 12 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VAa (1.7 g).

(63) MS (ESI) m/z: 957 (M+H.sup.+).

(64) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 5.00-4.86 (m, 1H), 4.89-4.82 (m, 3H), 4.39-4.35 (m, 1H), 4.20-4.15 (m, 1H), 4.05-3.70 (m, 11H), 3.55 (dd, J=10.4, 5.2 Hz, 1H), 3.48 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.15 (dd, J=14, 4.8 Hz, 1H), 3.05 (dd, J=14.4, 9.6 Hz, 1H), 2.75 (q, J=7.6 Hz, 2H), 2.69-2.63 (m, 1H), 2.59-2.55 (m, 1H), 2.33-1.38 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 20: Preparation of the Compound of Formula VAb

(65) To a reaction flask were added the compound of formula VIIAb (1.2 g, 2.56 mmol), the compound of formula VIa (2.1 g), ligand 2 (3.8 g), CrCl.sub.2 (1.9 g) and NiCl.sub.2 (0.29 g). The mixture was dissolved by addition of tetrahydrofuran (30 mL) and Et.sub.3N (0.62 g). The reaction solution was stirred at 60° C. for 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VAb (1.5 g).

(66) MS (ESI) m/z: 971 (M+H.sup.+).

(67) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.21 (s, 1H), 5.00-4.85 (m, 1H), 4.90-4.85 (m, 3H), 4.82-4.75 (m, 1H), 4.45-4.40 (m, 1H), 4.15-3.65 (m, 10H), 3.58 (dd, J=10.4, 5.2 Hz, 1H), 3.46 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.16 (dd, J=14, 4.8 Hz, 1H), 3.05 (dd, J=14.4, 9.6 Hz, 1H), 2.73 (q, J=7.6 Hz, 2H), 2.69-2.65 (m, 1H), 2.60-2.57 (m, 1H), 2.30-1.35 (m, 18H), 1.27 (t, J=7.6 Hz, 3H), 1.07 (d, J=7.6 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 6H).

Example 21: Preparation of the Compound of Formula VAc

(68) To a reaction flask were added the compound of formula VIIAa (1.2 g, 2.6 mmol), the compound of formula VIb (2.1 g), ligand 1 (3.8 g), CrCl.sub.2 (1.9 g) and NiCl.sub.2 (0.29 g). The mixture was dissolved by addition of 2-methyltetrahydrofuran (30 mL) and iPr.sub.2NEt (0.85 g). The reaction solution was stirred at 0° C. for 48 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VAc (1.3 g).

(69) MS (ESI) m/z: 929 (M+H.sup.+).

(70) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.97-7.88 (m, 2H), 7.70-7.63 (m, 3H), 5.22 (s, 1H), 5.00-4.85 (m, 1H), 4.90-4.80 (m, 3H), 4.37-4.35 (m, 1H), 4.18-4.13 (m, 1H), 4.03-3.70 (m, 11H), 3.54 (dd, J=10.4, 5.2 Hz, 1H), 3.48 (dd, J=10, 5.6 Hz, 1H), 3.38 (s, 3H), 3.14 (dd, J=14, 4.8 Hz, 1H), 3.03 (dd, J=14.4, 9.6 Hz, 1H), 2.70-2.65 (m, 1H), 2.60-2.52 (m, 1H), 2.30-1.35 (m, 16H), 1.05 (d, J=7.6 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.01 (s, 6H).

Example 22: Preparation of the Compound of Formula VAd

(71) To a reaction flask were added the compound of formula VIIAa (1.2 g, 2.6 mmol), the compound of formula VIc (2.1 g), ligand 2 (3.8 g), CrCl.sub.2 (1.9 g) and NiCl.sub.2 (0.29 g). The mixture was dissolved by addition of 2-methyltetrahydrofuran (30 mL) and proton sponge (1.2 g). The reaction solution was stirred at 30° C. for 24 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NaHCO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula VAd (1.6 g).

(72) MS (ESI) m/z: 943 (M+H.sup.+).

(73) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 5.23 (s, 1H), 5.02-4.86 (m, 1H), 4.88-4.81 (m, 3H), 4.36-4.35 (m, 1H), 4.18-4.10 (m, 1H), 4.03-3.72 (m, 11H), 3.53 (dd, J=10.4, 5.2 Hz, 1H), 3.46 (dd, J=10, 5.6 Hz, 1H), 3.39 (s, 3H), 3.15 (dd, J=14, 4.8 Hz, 1H), 3.02 (dd, J=14.4, 9.6 Hz, 1H), 2.70-2.65 (m, 1H), 2.60-2.50 (m, 1H), 2.46 (s, 3H), 2.30-1.35 (m, 16H), 1.05 (d, J=7.6 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.01 (s, 6H).

(74) Examples 23-35 disclosed the synthesis of the compound of formula III

Example 23: Preparation of the Compound of Formula IIIa

(75) KHMDS (0.5 M, 6.0 mL) was added dropwise to a solution of the compound of formula Va (2.0 g, 1.99 mmol) in THF (75 mL) at room temperature. The reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIa (1.06 g).

(76) MS (ESI) m/z: 944 (M+Na.sup.+).

(77) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.95-4.87 (m, 2H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.25 (brs, 1H), 4.04-3.71 (m, 8H), 3.70-3.45 (m, 4H), 3.43 (s, 3H), 3.39-3.32 (m, 1H), 3.08-2.93 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.67-2.44 (m, 2H), 2.26-1.32 (m, 16H), 1.25 (t, J=7.6 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).

Example 24: Preparation of the Compound of Formula IIIa

(78) 2,6-Di-t-butyl-4-methylpyridine (2.3 g) and AgBF.sub.4 (2.6 g) were added to a solution of the compound of formula VAa (1 g, 0.99 mmol) in t-butyl acetate (20 mL) at 0° C. The reaction solution was stirred at the same temperature for 48 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIa (0.8 g).

(79) MS (ESI) m/z: 944 (M+Na.sup.+).

(80) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.95-4.87 (m, 2H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.25 (brs, 1H), 4.04-3.71 (m, 8H), 3.70-3.45 (m, 4H), 3.43 (s, 3H), 3.39-3.32 (m, 1H), 3.08-2.93 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.67-2.44 (m, 2H), 2.26-1.32 (m, 16H), 1.25 (t, J=7.6 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).

Example 25: Preparation of the Compound of Formula IIb

(81) LiHMDS (1 M, 3 mL) was added to a solution of the compound of formula Vb (1.0 g, 0.97 mmol) in THF (20 mL) at −30° C. The reaction solution was stirred at the same temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIb (0.62 g).

(82) MS (ESI) m/z: 957 (M+Na.sup.+).

(83) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.89-7.78 (m, 2H), 7.46-7.36 (m, 2H), 4.88 (d, J=2.2 Hz, 1H), 4.83 (s, 1H), 4.76 (d, J=1.9 Hz, 1H), 4.63 (d, J=2.2 Hz, 1H), 4.55 (t, J=4.8 Hz, 1H), 4.25 (brs, 1H), 4.11-4.06 (m, 2H), 3.99-3.46 (m, 10H), 3.44 (s, 3H), 3.38-3.32 (m, 1H), 3.04-2.94 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.62-2.50 (m, 2H), 2.27-1.30 (m, 18H), 1.27 (t, J=7.6 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 0.89 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 26: Preparation of the Compound of Formula IIb

(84) 2,4,6-Trimethylpyridine (2.6 g) and AgPF.sub.6 (3.2 g) were added to a solution of the compound of formula VAb (1 g, 0.97 mmol) in isopropyl acetate (20 mL) at 30° C. The reaction solution was stirred at the same temperature for 12 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIb (0.7 g).

(85) MS (ESI) m/z: 944 (M+Na.sup.+).

(86) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.95-4.87 (m, 2H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.25 (brs, 1H), 4.04-3.71 (m, 8H), 3.70-3.45 (m, 4H), 3.43 (s, 3H), 3.39-3.32 (m, 1H), 3.08-2.93 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.67-2.44 (m, 2H), 2.26-1.32 (m, 16H), 1.25 (t, J=7.6 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).

Example 27: Preparation of the Compound of Formula IIIc

(87) LDA (1 M, 2 mL) was added dropwise to a solution of the compound of formula Vc (1.0 g, 0.95 mmol) was dissolved in 2-methyltetrahydrofuran (20 mL) at −20° C. The reaction solution was stirred at the same temperature for 3 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula Mc (0.66 g).

(88) MS (ESI) m/z: 985 (M+Na.sup.+).

(89) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.89-7.79 (m, 2H), 7.42 (d, J=8.3 Hz, 2H), 4.88 (d, J=2.2 Hz, 1H), 4.84 (s, 1H), 4.77 (d, J=1.9 Hz, 1H), 4.63 (d, J=2.2 Hz, 1H), 4.44 (dd, J=4.5 Hz, 1H), 4.25 (brs, 1H), 4.01-3.47 (m, 10H), 3.44 (s, 3H), 3.43-3.31 (m, 3H), 3.06-2.93 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.65-2.47 (m, 2H), 2.26-1.32 (m, 16H), 1.26 (t, J=7.6 Hz, 3H), 1.18 (s, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.89 (s, 18H), 0.71 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 28: Preparation of the Compound of Formula IIId

(90) BuLi (2.5 M, 1 mL) was added dropwise to a solution of the compound of formula Vd (1.0 g, 0.95 mmol) in methyl t-butyl ether (20 mL) at −10° C. The reaction solution was stirred at the same temperature for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIId (0.58 g).

(91) MS (ESI) m/z: 989 (M+Na.sup.+).

(92) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.89-7.79 (m, 2H), 7.46-7.37 (m, 2H), 4.89 (d, J=2.2 Hz, 1H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.65 (d, J=2.2 Hz, 1H), 4.26-4.20 (m, 1H), 4.05 (t, 17.2 Hz, 1H), 4.00-3.47 (m, 8H), 3.43 (s, 3H), 3.40-3.32 (m, 1H), 3.06-2.94 (m, 2H), 2.94-2.79 (m, 4H), 2.75 (q, J=7.6 Hz, 2H), 2.66-2.46 (m, 2H), 2.25-1.32 (m, 18H), 1.27 (t, J=7.6 Hz, 3H), 1.06 (d, J=6.2 Hz, 3H), 0.89 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 29: Preparation of the Compound of Formula IIIe

(93) NaHDMS (1.0 M, 1.5 mL) was added to a solution of the compound of formula Ve (1.0 g, 0.98 mmol) in toluene (20 mL) at 0° C. The reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIe (0.60 g).

(94) MS (ESI) m/z: 945 (M+Na.sup.+).

(95) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.87-7.78 (m, 2H), 7.47-7.36 (m, 2H), 4.89 (d, J=2.1 Hz, 1H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=2.2 Hz, 1H), 4.36 (t, J=5.6 Hz, 1H), 4.00-3.47 (m, 8H), 3.43 (s, 3H), 3.38-3.33 (m, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.06-2.95 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.67-2.44 (m, 2H), 2.27-1.33 (m, 16H), 1.27 (J=7.6 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 0.89 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 30: Preparation of the Compound of Formula IIIf

(96) t-BuOK (206 mg) was added to a solution of the compound of formula Vf (1.0 g, 0.96 mmol) n-heptane (20 mL) at 10° C. The reaction solution was stirred at the same temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIf (0.68 g).

(97) MS (ESI) m/z: 973 (M+Na.sup.+).

(98) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.88-7.78 (m, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.88 (d, J=2.1 Hz, 1H), 4.83 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=2.2 Hz, 1H), 4.48 (t, J=5.6 Hz, 1H), 4.25 (brs, 1H), 3.97-3.92 (m, 1H), 3.87-3.46 (m, 10H), 3.43 (s, 3H), 3.38-3.32 (m, 1H), 3.06-2.93 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.65-2.46 (m, 2H), 2.27-1.33 (m, 16H), 1.26 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.0 Hz, 6H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 31: Preparation of the Compound of Formula IIIg

(99) KHMDS (1.0 M, 1.5 mL) was added dropwise to a solution of the compound of formula Vg (1.0 g, 0.95 mmol) in n-hexane (20 mL) at 20° C. The reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIg (0.70 g).

(100) MS (ESI) m/z: 1001 (M+Na.sup.+).

(101) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.90-7.79 (m, 2H), 7.46-7.36 (m, 2H), 4.88 (d, J=2.1 Hz, 1H), 4.83 (s, 1H), 4.76 (d, J=1.9 Hz, 1H), 4.63 (d, J=2.2 Hz, 1H), 4.55 (t, J=5.1 Hz, 1H), 4.25 (brs, 1H), 4.00-3.46 (m, 10H), 3.43 (s, 3H), 3.38-3.32 (m, 1H), 3.09-2.91 (m, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.64-2.46 (m, 2H), 2.28-1.33 (m, 16H), 1.27 (t, J=7.6 Hz, 3H), 1.18 (d, J=6.0 Hz, 6H), 1.13 (d, J=6.0 Hz, 6H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 32: Preparation of the Compound of Formula IIIh

(102) NaH (102 mg) was added to a solution of the compound of formula Vh (1.0 g, 1.01 mmol) in THF (20 mL) at −20° C. The reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIh (0.59 g).

(103) MS (ESI) m/z: 915 (M+Na.sup.+).

(104) .sup.1H NMR (400 MHz, Chloroform-d) δ 7.98-7.93 (m, 2H), 7.73-7.66 (m, 1H), 7.65-7.58 (m, 2H), 4.96-4.88 (m, 2H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.25 (brs, 1H), 4.05-3.70 (m, 8H), 3.73-3.44 (m, 4H), 3.42 (s, 3H), 3.39-3.32 (m, 1H), 3.06-2.92 (m, 2H), 2.66-2.42 (m, 2H), 2.28-1.30 (m, 16H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 33: Preparation of the Compound of Formula IIIh

(105) 2,6-Lutidine (3.6 g) and Ag.sub.2O (4.5 g) were added to a solution of the compound of formula VAc (1 g, 1.08 mmol) in toluene (20 mL) at 60° C. The reaction solution was stirred at the same temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIh (0.6 g).

(106) MS (ESI) m/z: 915 (M+Na.sup.+).

(107) .sup.1H NMR (400 MHz, Chloroform-d) δ7.98-7.93 (m, 2H), 7.73-7.66 (m, 1H), 7.65-7.58 (m, 2H), 4.96-4.88 (m, 2H), 4.84 (s, 1H), 4.76 (d, J=1.8 Hz, 1H), 4.64 (d, J=1.8 Hz, 1H), 4.25 (brs, 1H), 4.05-3.70 (m, 8H), 3.73-3.44 (m, 4H), 3.42 (s, 3H), 3.39-3.32 (m, 1H), 3.06-2.92 (m, 2H), 2.66-2.42 (m, 2H), 2.28-1.30 (m, 16H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (s, 18H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 34: Preparation of the Compound of Formula IIIi

(108) t-BuONa (189 mg) was added to a solution of the compound of formula Vi (1.0 g, 1.0 mmol) THF (20 mL) at 30° C. The reaction solution was stirred at the same temperature for 10 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIi (0.72 g).

(109) MS (ESI) m/z: 929 (M+Na.sup.+).

(110) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.89-4.64 (m, 5H), 4.25 (br, 1H), 3.99-3.93 (m, 3H), 3.88-3.78 (m, 5H), 3.69-3.64 (m, 1H), 3.60-3.54 (m, 2H), 3.50-3.35 (m, 5H), 3.00-2.98 (m, 2H), 2.63-2.51 (m, 2H), 2.46 (s, 3H), 2.24-2.15 (m, 3H), 2.04-1.98 (m, 1H), 1.90-1.50 (m, 12H), 1.07 (d, J=6.4 Hz, 3H), 0.89 (s, 18H), 0.10 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

Example 35: Preparation of the Compound of Formula IIIi

(111) 2, 6-Di-t-butyl-4-methylpyridine (3.8 g) and AgOTf (6.2 g) were added to a solution of the compound of formula VAd (1 g, 1.08 mmol) in THF (20 mL) at 20° C. The reaction solution was stirred at the same temperature for 36 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIIi (0.7 g).

(112) MS (ESI) m/z: 929 (M+Na.sup.+).

(113) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.81 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.89-4.64 (m, 5H), 4.25 (br, 1H), 3.99-3.93 (m, 3H), 3.88-3.78 (m, 5H), 3.69-3.64 (m, 1H), 3.60-3.54 (m, 2H), 3.50-3.35 (m, 5H), 3.00-2.98 (m, 2H), 2.63-2.51 (m, 2H), 2.46 (s, 3H), 2.24-2.15 (m, 3H), 2.04-1.98 (m, 1H), 1.90-1.50 (m, 12H), 1.07 (d, J=6.4 Hz, 3H), 0.89 (s, 18H), 0.10 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).

(114) Examples 36-39 disclosed the synthesis of the compound of formula X

Example 36: Preparation of the Compound of Formula Xa

(115) n-BuLi (2.5 M in hexane, 0.36 mL) was added to a solution of the compound of formula IIIa (0.5 g, 0.55 mmol) in THF (10 mL) at −50° C. The reaction solution was stirred at the same temperature for 30 min. Then a solution of the compound of formula XIa (0.490 g) in THF (4 mL) was added to the reaction mixture. Then the reaction mixture was stirred for another 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with methyl t-butyl ether. The organic phase was separated and concentrated. The residual solvent was removed by evaporation with DCM, and the crude product of the compound of formula Xa was used directly for the next step without purification.

(116) MS (ESI) m/z: 1662 (M+H.sup.+).

(117) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.80 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 2H), 6.88-6.78 (m, 1H), 6.29-6.23 (m, 1H), 4.99-4.63 (m, 6H), 4.38-4.19 (m, 2H), 4.09-3.35 (m, 21H), 2.88-1.20 (m, 24H), 1.20-0.84 (m, 49H), 0.15-(−0.04) (m, 30H).

Example 37: Preparation of the Compound of Formula Xb

(118) LDA (1.0 M in hexane, 0.6 mL) was added to a solution of the compound of formula Mb (0.5 g, 0.54 mmol) in 2-methyltetrahydrofuran (10 mL). at −78° C. The reaction solution was stirred at the same temperature for 1 h. Then a solution of the compound of formula XIa (0.49 g) in THF (4 mL) was added to the reaction mixture. The reaction mixture was stirred for another 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with methyl t-butyl ether. The organic phase was separated and concentrated. The residual solvent was removed by evaporation with DCM, and the crude product of the compound of formula Xb was used directly for the next step without purification.

(119) MS (ESI) m/z: 1676 (M+H.sup.+).

(120) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.80 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 2H), 6.88-6.78 (m, 1H), 6.29-6.23 (m, 1H), 5.02-4.60 (m, 7H), 4.40-4.16 (m, 2H), 4.11-3.30 (m, 20H), 2.90-1.20 (m, 26H), 1.20-0.84 (m, 49H), 0.15-(−0.04) (m, 30H).

Example 38: Preparation of the Compound of Formula Xc

(121) LiHMDS (1.0 M in hexane, 0.6 mL) was added to a solution of the compound of formula IIIh (0.5 g, 0.56 mmol) in n-heptane (10 mL) at 0° C. The reaction solution was stirred at the same temperature for 15 min. Then a solution of the compound of formula XIa (0.49 g) in THF (4 mL) was added to the reaction mixture. The reaction mixture was stirred for another 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with methyl t-butyl ether. The organic phase was separated and concentrated. The residual solvent was removed by evaporation with DCM, and the crude compound of formula Xc was used directly for the next step without purification.

(122) MS (ESI) m/z: 1634 (M+H.sup.+).

(123) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.97-7.90 (m, 2H), 7.70-7.58 (m, 1H), 7.60-7.50 (m, 2H), 6.88-6.78 (m, 1H), 6.29-6.23 (m, 1H), 4.99-4.63 (m, 6H), 4.38-4.19 (m, 2H), 4.09-3.35 (m, 21H), 2.88-1.20 (m, 19H), 1.15-0.84 (m, 49H), 0.15-(−0.04) (m, 30H).

Example 39: Preparation of the Compound of Formula Xd

(124) KHMDS (1.0 M in hexane, 0.6 mL) was added dropwise to a solution of the compound of formula IIIi (0.5 g, 0.56 mmol) in n-heptane (10 mL) at −10° C. The reaction solution was stirred at the same temperature for 15 min. Then a solution of compound of formula XIa (0.49 g) in THF (4 mL) was added to the reaction mixture. The reaction mixture was stirred for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by saturated NH.sub.4Cl aqueous solution. The mixture was extracted with methyl t-butyl ether. The organic phase was separated and concentrated. The residual solvent was removed by evaporation with DCM, and the crude product of the compound of formula Xd was used directly for the next step without purification.

(125) MS (ESI) m/z: 1648 (M+H.sup.+).

(126) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.80-7.75 (m, 1H), 7.68-7.65 (m, 1H), 7.40-7.35 (m, 2H), 6.88-6.78 (m, 1H), 6.29-6.23 (m, 1H), 4.99-4.63 (m, 6H), 4.40-4.20 (m, 2H), 4.09-3.35 (m, 21H), 2.90-1.20 (m, 22H), 1.15-0.85 (m, 49H), 0.15-(−0.04) (m, 30H).

(127) Examples 40-43 disclosed the synthesis of the compound of formula IX

Example 40: Preparation of the Compound of Formula IXa

(128) NaHCO.sub.3(0.23 g) and DMP oxidant (0.51 g) were added to the solution of the above prepared crude product of the compound of formula Xa in DCM (5 mL) at −20° C. The reaction solution was stirred at room temperature for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by an aqueous solution of Na.sub.2S.sub.2O.sub.3 and NaHCO.sub.3. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IXa (0.78 g), which was a pair of diastereomers as shown by NMR.

(129) MS (ESI) m/z: 1660 (M+H.sup.+).

(130) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.79-7.77 (m, 1H), 7.68-7.65 (m, 1H), 7.38-7.36 (m, 2H), 6.86-6.82 (m, 1H), 6.29-6.25 (m, 1H), 5.00-4.81 (m, 5H), 4.66 (d, J=20.4 Hz, 1H), 4.40-3.37 (m, 23H), 2.89-2.48 (m, 6H), 2.45-1.00 (m, 27H), 0.88-0.80 (m, 45H), 0.11-0.01 (m, 30H).

Example 41: Preparation of the Compound of Formula IXb

(131) TEMPO (0.02 g) and PhI(OAc).sub.2 (0.43 g) were added to a solution of the above prepared crude product of the compound of formula Xb in DCM (5 mL) at 40° C. The reaction solution was stirred at room temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by an aqueous solution of Na.sub.2S.sub.2O.sub.3 and NaHCO.sub.3. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IXb (0.72 g).

(132) MS (ESI) m/z: 1674 (M+H.sup.+).

(133) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.79-7.77 (m, 1H), 7.68-7.65 (m, 1H), 7.38-7.36 (m, 2H), 6.86-6.82 (m, 1H), 6.29-6.25 (m, 1H), 5.00-4.81 (m, 5H), 4.65 (d, J=20.4 Hz, 1H), 4.60-3.35 (m, 23H), 2.90-2.48 (m, 6H), 2.45-1.00 (m, 29H), 0.88-0.80 (m, 45H), 0.11-0.00 (m, 30H).

Example 42: Preparation of the Compound of Formula IXc

(134) TEMPO (0.02 g), NaClO (5 mL) and saturated NaHCO.sub.3 aqueous solution (5 mL) were added to a solution of the above prepared crude product of the compound of formula Xc in DCM (5 mL) at 20° C. The reaction solution was stirred at room temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by an aqueous solution of Na.sub.2S.sub.2O.sub.3 and NaHCO.sub.3. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IXc (0.66 g).

(135) MS (ESI) m/z: 1632 (M+H.sup.+).

(136) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.95-7.92 (m, 2H), 7.55-7.81 (m, 3H), 6.85-6.80 (m, 1H), 6.30-6.25 (m, 1H), 5.00-4.80 (m, 5H), 4.67 (d, J=20.4 Hz, 1H), 4.40-3.37 (m, 23H), 2.89-2.48 (m, 6H), 2.45-1.00 (m, 27H), 0.88-0.80 (m, 45H), 0.11-0.01 (m, 30H).

Example 43: Preparation of the Compound of Formula IXd

(137) IBX oxidant (1.2 g) was added to a solution of the above prepared crude product of the compound of formula Xd in DMSO (5 mL) at 60° C. The reaction solution was stirred at 60° C. for 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by an aqueous solution of Na.sub.2S.sub.2O.sub.3 and NaHCO.sub.3. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IXd (0.59 g), which is a pair of diastereomers as shown by NMR.

(138) MS (ESI) m/z: 1646 (M+H.sup.+).

(139) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.78-7.76 (m, 1H), 7.68-7.64 (m, 1H), 7.38-7.36 (m, 2H), 6.86-6.82 (m, 1H), 6.28-6.25 (m, 1H), 5.01-4.80 (m, 5H), 4.66 (d, J=20.4 Hz, 1H), 4.42-3.34 (m, 23H), 2.89-2.81 (m, 2H), 2.65-2.48 (m, 2H), 2.45-1.00 (m, 27H), 0.88-0.80 (m, 45H), 0.10-0.00 (m, 30H).

(140) Examples 44-47 disclosed the synthesis of the compound of formula XII

Example 44: Preparation of the Compound of Formula XIIa

(141) 2,6-Lutidine (0.62 g) and TMSOTf (1.3 g) were added sequentially to a solution of the compound of formula IXa (0.78 g, 0.47 mmol) in DCM (10 mL) under ice-water bath. The reaction solution was stirred at the same temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula XIIa (0.625 g), which was a pair of diastereomers as shown by NMR.

(142) MS (ESI) m/z: 1615 (M+H.sup.+).

(143) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 7.78-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.39-7.35 (m, 2H), 6.86-6.82 (m, 1H), 6.29-6.25 (m, 1H), 5.01-4.81 (m, 5H), 4.34-3.43 (m, 18H), 2.88-2.86 (m, 2H), 2.85-1.02 (m, 31H), 0.90-0.78 (m, 45H), 0.13-0.01 (m, 30H).

Example 45: Preparation of the Compound of Formula XIIa

(144) Pyridine (0.55 g) and TMSOTf (1.2 g) were added sequentially to a solution of the compound of formula IXb (0.7 g, 0.42 mmol) in DCM (10 mL) at −20° C. The reaction solution was stirred at the same temperature for 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula XIIa (0.58 g).

(145) MS (ESI) m/z: 1615 (M+H.sup.+).

(146) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 7.78-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.39-7.35 (m, 2H), 6.86-6.82 (m, 1H), 6.29-6.25 (m, 1H), 5.01-4.81 (m, 5H), 4.34-3.43 (m, 18H), 2.88-2.86 (m, 2H), 2.85-1.02 (m, 31H), 0.90-0.78 (m, 45H), 0.13-0.01 (m, 30H).

Example 46: Preparation of the Compound of Formula XIIc

(147) Pyridinium p-toluenesulfonate (1.8 g) was added to a solution of the compound of formula IXc (0.6 g, 0.37 mmol) in toluene (10 mL) at 30° C. The reaction solution was stirred at the same temperature for 12 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula XIIc (0.47 g).

(148) MS (ESI) m/z: 1588 (M+H.sup.+).

(149) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.80-7.55 (m, 3H), 6.87-6.81 (m, 1H), 6.28-6.24 (m, 1H), 5.05-4.81 (m, 5H), 4.35-3.42 (m, 18H), 2.88-2.85 (m, 2H), 2.85-1.03 (m, 26H), 0.90-0.75 (m, 45H), 0.13-0.00 (m, 30H).

Example 47: Preparation of the Compound of Formula XIId

(150) Cerium ammonium nitrate (1.2 g) was added to a solution of the compound of formula IXd (0.6 g, 0.37 mmol) in acetonitrile (10 mL) at 40° C. The reaction solution was stirred at the same temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula XIId (0.51 g).

(151) MS (ESI) m/z: 1602 (M+H.sup.+).

(152) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 7.77-7.68 (m, 1H), 7.68-7.65 (m, 1H), 7.39-7.35 (m, 2H), 6.87-6.80 (m, 1H), 6.29-6.25 (m, 1H), 5.05-4.80 (m, 5H), 4.35-3.40 (m, 18H), 2.88-2.85 (m, 2H), 2.85-1.00 (m, 29H), 0.90-0.75 (m, 45H), 0.13-0.00 (m, 30H).

(153) Examples 48-51 disclosed the synthesis of the compound of formula II

Example 48: Preparation of the Compound of Formula IIa

(154) A solution of SmI.sub.2 in THF (0.1 M in THF, 2 mL) was added to a solution of the compound of formula IXa (100 mg, 0.06 mmol) in THF (3 mL) at −78° C. The reaction solution was stirred at the same temperature for 10 min. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIa (82 mg).

(155) MS (ESI) m/z: 1492 (M+H.sup.+).

(156) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.79 (s, 1H), 6.85 (dd, J=14.4, 3.6 Hz, 1H), 6.28 (dd, J=14.4, 1H), 4.99 (d, J=2 Hz, 1H), 4.89-4.85 (m, 3H), 4.79 (s, 1H), 4.34-4.33 (m, 1H), 4.06-4.02 (m, 2H), 3.89-3.43 (m, 11H), 3.33 (s, 3H), 3.23 (d, J=3.6 Hz, 1H), 2.93 (d, J=9.6 Hz, 2 Hz, 1H), 2.75-2.22 (m, 10H), 2.09-1.26 (m, 16H), 1.07 (3H, d, J=6.0 Hz), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 49: Preparation of the Compound of Formula IIa

(157) CrCl.sub.2 (205 mg) and Mn powder (300 mg) were added to a solution of the compound of formula IXc (100 mg, 0.06 mmol) in THF (3 mL) at 0° C. The reaction solution was stirred at the same temperature for 12 h. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIa (78 mg).

(158) MS (ESI) m/z: 1492 (M+H.sup.+).

(159) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.79 (s, 1H), 6.85 (dd, J=14.4, 3.6 Hz, 1H), 6.28 (dd, J=14.4, 1H), 4.99 (d, J=2 Hz, 1H), 4.89-4.85 (m, 3H), 4.79 (s, 1H), 4.34-4.33 (m, 1H), 4.06-4.02 (m, 2H), 3.89-3.43 (m, 11H), 3.33 (s, 3H), 3.23 (d, J=3.6 Hz, 1H), 2.93 (d, J=9.6 Hz, 2 Hz, 1H), 2.75-2.22 (m, 10H), 2.09-1.26 (m, 16H), 1.07 (3H, d, J=6.0 Hz), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 50: Preparation of the Compound of Formula IIa

(160) Zn powder (600 mg) and acetic acid (600 mg) were added to a solution of the compound of formula IXd (100 mg, 0.06 mmol) in THF (3 mL) at 30° C. The reaction solution was stirred at the same temperature for 6 h. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIa (63 mg).

(161) MS (ESI) m/z: 1492 (M+H.sup.+).

(162) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.79 (s, 1H), 6.85 (dd, J=14.4, 3.6 Hz, 1H), 6.28 (dd, J=14.4, 1H), 4.99 (d, J=2 Hz, 1H), 4.89-4.85 (m, 3H), 4.79 (s, 1H), 4.34-4.33 (m, 1H), 4.06-4.02 (m, 2H), 3.89-3.43 (m, 11H), 3.33 (s, 3H), 3.23 (d, J=3.6 Hz, 1H), 2.93 (d, J=9.6 Hz, 2 Hz, 1H), 2.75-2.22 (m, 10H), 2.09-1.26 (m, 16H), 1.07 (3H, d, J=6.0 Hz), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 51: Preparation of the Compound of Formula IIb

(163) A solution of SmI.sub.2 in THF (0.1 M, 3 mL) was added to a solution of the compound of formula IXb (100 mg, 0.06 mmol) in THF (3 mL) at −30° C. The reaction solution was stirred at the same temperature for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IIb (77 mg).

(164) MS (ESI) m/z: 1506 (M+H.sup.+).

(165) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.83 (dd, J=14.4, 3.6 Hz, 1H), 6.26 (dd, J=14.4, 1H), 5.00 (d, J=2 Hz, 1H), 4.90-4.85 (m, 3H), 4.78 (s, 1H), 4.62-4.51 (m, 1H), 4.42-4.38 (m, 1H), 4.16-4.00 (m, 3H), 3.90-3.42 (m, 9H), 3.34 (s, 3H), 3.21 (d, J=3.6 Hz, 1H), 2.90 (d, J=9.6 Hz, 2 Hz, 1H), 2.75-2.20 (m, 10H), 2.10-1.20 (m, 18H), 1.08 (3H, d, J=6.0 Hz), 0.95 (s, 9H), 0.92 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

(166) Examples 52-56 disclosed the synthesis of the compound of formula IVa

Example 52: Preparation of the Compound of Formula IVa

(167) A solution of SmI.sub.2 in THF (0.1 M in THF, 1 mL) was added to a solution of the compound of formula XIIa (86 mg, 0.05 mmol) in THF (2 mL) at −30° C. The reaction solution was stirred at the same temperature for 30 min. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IVa (80 mg).

(168) MS (ESI) m/z: 1448 (M+H.sup.+).

(169) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.86 (dd, J=15.0, 8.0 Hz, 1H), 6.28 (d, J=15.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.89 (dd, J=8.0, 3.0 Hz, 1H), 4.88-3.64 (m, 13H), 3.57 (dd, J=10.0, 6.0 Hz, 1H), 3.53-3.41 (m, 3H), 3.33 (s, 3H), 3.25 (d, J=2.8 Hz, 1H), 2.95 (dd, J=10.0, 2.0 Hz, 1H), 2.77-1.06 (m, 26H), 1.07 (d, J=6.0 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 53: Preparation of the Compound of Formula IVa

(170) CrCl.sub.2 (100 mg) and Mn powder (100 mg) were added to a solution of the compound of formula XIIc (50 mg, 0.03 mmol) in THF (2 mL) at −50° C. The reaction solution was stirred at the same temperature for 4 h. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IVa (39 mg).

(171) MS (ESI) m/z: 1448 (M+H.sup.+).

(172) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.86 (dd, J=15.0, 8.0 Hz, 1H), 6.28 (d, J=15.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.89 (dd, J=8.0, 3.0 Hz, 1H), 4.88-3.64 (m, 13H), 3.57 (dd, J=10.0, 6.0 Hz, 1H), 3.53-3.41 (m, 3H), 3.33 (s, 3H), 3.25 (d, J=2.8 Hz, 1H), 2.95 (dd, J=10.0, 2.0 Hz, 1H), 2.77-1.06 (m, 26H), 1.07 (d, J=6.0 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 54: Preparation of the Compound of Formula IVa

(173) Zn powder (200 mg) and acetic acid (200 mg) were added to a solution of the compound of formula XIId (50 mg, 0.03 mmol) in THF (2 mL) at 30° C. The reaction solution was stirred at the same temperature for 2 h. After completion of the reaction was indicated by TLC, the reaction was quenched by K.sub.2CO.sub.3 aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IVa (35 mg).

(174) MS (ESI) m/z: 1448 (M+H.sup.+).

(175) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.86 (dd, J=15.0, 8.0 Hz, 1H), 6.28 (d, J=15.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.89 (dd, J=8.0, 3.0 Hz, 1H), 4.88-3.64 (m, 13H), 3.57 (dd, J=10.0, 6.0 Hz, 1H), 3.53-3.41 (m, 3H), 3.33 (s, 3H), 3.25 (d, J=2.8 Hz, 1H), 2.95 (dd, J=10.0, 2.0 Hz, 1H), 2.77-1.06 (m, 26H), 1.07 (d, J=6.0 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 55: Preparation of the Compound of Formula IVa

(176) 2,6-lutidine (0.12 g) and TMSOTf (0.26 g) were added sequentially to a solution of the compound of formula IIa (80 mg, 0.05 mmol) in DCM (2 mL) at −30° C. under ice-water bath. The reaction solution was stirred at the same temperature for 24 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IVa (56 mg).

(177) MS (ESI) m/z: 1448 (M+H.sup.+).

(178) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.86 (dd, J=15.0, 8.0 Hz, 1H), 6.28 (d, J=15.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.89 (dd, J=8.0, 3.0 Hz, 1H), 4.88-3.64 (m, 13H), 3.57 (dd, J=10.0, 6.0 Hz, 1H), 3.53-3.41 (m, 3H), 3.33 (s, 3H), 3.25 (d, J=2.8 Hz, 1H), 2.95 (dd, J=10.0, 2.0 Hz, 1H), 2.77-1.06 (m, 26H), 1.07 (d, J=6.0 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

Example 56: Preparation of the Compound of Formula IVa

(179) Pyridine (0.15 g) and TMSOTf (0.22 g) were added sequentially to a solution of the compound of formula IIb (50 mg, 0.03 mmol) in DCM (2 mL) at 40° C. The reaction solution was stirred at the same temperature for 1 h. After completion of the reaction was indicated by TLC, the reaction was quenched by 1 N HCl aqueous solution. The mixture was extracted with ethyl acetate. The organic phase was separated and concentrated, and then purified by column chromatography to obtain the compound of formula IVa (33 mg).

(180) MS (ESI) m/z: 1448 (M+H.sup.+).

(181) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.78 (s, 1H), 6.86 (dd, J=15.0, 8.0 Hz, 1H), 6.28 (d, J=15.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.89 (dd, J=8.0, 3.0 Hz, 1H), 4.88-3.64 (m, 13H), 3.57 (dd, J=10.0, 6.0 Hz, 1H), 3.53-3.41 (m, 3H), 3.33 (s, 3H), 3.25 (d, J=2.8 Hz, 1H), 2.95 (dd, J=10.0, 2.0 Hz, 1H), 2.77-1.06 (m, 26H), 1.07 (d, J=6.0 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).

(182) While the present disclosure has been described with reference to the specific examples, some modifications and equivalent variations will be apparent to those skilled in the art and are also within the scope of the present disclosure.