Patent Application
20100160681
The invention relates to the design and synthesis of new chiral imines reagents which can be utilized for the synthesis of chiral drugs and their precursors. In particular, it relates to free NH2-group-attached chiral phosphoramides, chiral N-phosphonimines and the methods for forming the same. Chiral N-phosphonimines (or called N-phosphonyl imines) are prepared using new chiral phosphoramides.
The chiral imine chemistry has been one of the most active topics in asymmetric synthesis because the drug development and discovery heavily depend on the amine functionality (F. A. Davis, P. Zhou, B. C. Chen, Chem. Soc. Rev. 1998, 27, 13-18). In the past several decades, this field has been dominated by N-sulfinyl imine (or sulfinimine) chemistry which was pioneered by Davis (F. A. Davis, B. Yang, J. Am. Chem. Soc. 2006, 127, 8938-8407; F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy, P. S. Potonovo, H. Zhang, D. T. Reddy, P. Zhou, P. Carroll, J. Org. Chem. 1997, 62, 2555-2563), Ellman (D. A. Cogan, G. C. Liu, K. J. Kim, B. J. Backes, J. A. Ellman J. Am. Chem. Soc. 1998, 120, 8011-8019; D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1999, 121, 268-269; D. J. Weix, Y. L. Shi, J. A. Ellman, J. Am. Chem. Soc. 2005, 127, 1092-1093) and several others (X. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem. Soc. 2002, 124, 7880-7881; J. G. Ruano, I. Fernandez, M. del P. Catalina, A. A. Cruz, Tetrahedron Asymm., 1996, 7, 3407-3414; X. W. Sun, M. H. Xu, G. Q. Lin, Org. Lett. 2006, 8, 4979-4982; C. H. Zhao, L. Liu, D. Wang, Y. J. Chen, Eur. J. Org. Chem. 2006, 2977-2986; D. H. Hua, S. W. Miao, J. S. Chen, S. Iguchi, J. Org. Chem. 1991, 56, 4-6) (
Even though a great progress has been made on N-sulfinyl imine chemistry, there still exist some limitations during the use of N-sulfinyl imines for asymmetric synthesis. In addition to the shortcomings described in literature, the N-sulfinyl functionality is sensitive to oxidative conditions, which makes some further transformations inconvenient. The deprotection of N-sulfinyl group is performed by treating with BrØnsted-Lowry acids, which destroys the chiral functionality and makes the recovery of chiral auxiliary impossible; Or, possible racemization can occur on sulfur center if other methods are used. This functionality cannot tolerate strong Lewis acids well (G. Li, H.-X. Wei, B. Whittlesey, N. N. Batrice, J. Org. Chem. 1999, 64, 1061-1064; H.-X. Wei, J. D. Hook, K. A. Fitzgerald, G. Li, Tetrahedron: Asymmetry 1999, 10, 661-665). In addition, the preparation of the N-sulfinyl imines requires either expensive starting materials or the use of a disulfide which is very harmful to environment (toxic and smelling). Therefore, it is necessary to develop new chiral imines to overcome shortcomings of N-sulfinyl imines.
The purpose of the application is to provide free NH2 group-attached chiral phosphoramides and corresponding chiral N-phosphonyl imines as well as the methods for forming the same, so as to overcome the above shortcomings of N-sulfinyl imines.
The application provides the technical solution in following aspects:
Free NH2-group-attached chiral phosphoramides, having the structure of formula (I):
wherein R1 and R2 are independently any organic groups.
The free NH2-group-attached chiral phosphoramides, wherein R1 is a C1-C20 alkyls, such as i-Pr, Me, Et, Pr, 2-Bu; Aryl; CH2-Aryl (e.g., Aryl=Ph, 1-Naph, 2-Naph, etc.); and Ts, Bs, Ms and C1-C20-R—SO2-, Ar—SO2-; R2 is an Aryl, Alkyl; two alkyl R2 groups can be connected as cycloalkanes, i.e., diamine precursors can be 1,2-diaminocyclohexane and 1,2-diaminocyclopentane.
The compounds of formula (I) can be racemic compounds or each of the two individual enantiomers, or combination thereof.
The free NH2-group-attached chiral phosphoramides, having one of the structures of formula (II):
Chiral N-phosphonimines, having the structure of formula (III)
wherein R1, R2 and R3 are independently any organic groups.
The chiral N-phosphonimine, wherein R1 is a C1-C20 alkyls, such as i-Pr, Me, Et, Pr, 2-Bu; Aryl; CH2-Aryl (e.g., Aryl=Ph, 1-Naph, 2-Naph, etc.); and Ts, Bs, Ms and C1-C20-R—SO2-, Ar—SO2-; R2 is an Aryl, Alkyl in which two allyl R2 groups can be connected as cycloalkanes, i.e., diamine precursors can be 1,2-diaminocyclohexane and 1,2-diaminocyclopentane; R3 is an Aryl, Alkyl group.
The chiral N-phosphonimines, having one of the structures of formula (IV):
A method of forming the free NH2-group-attached chiral phosphoramides of formula (I), comprising: a) providing phosphoramides, and 2) synthesizing chiral N-phosphonimines from free NH2-group-attached chiral phosphoramides.
The method comprises the steps of:
The method comprises the reaction for synthesis of N,N′-di-primary alkyl-N-phosphoramides of formula (V):
The method comprises the reaction for synthesis of N,N′-di-secondary alkyl-N-phosphoramides of formula (VI):
The use of the free NH2-group-attached chiral phosphoramides of formula (I) in preparing of chiral N-phosphonimines.
A method of forming the chiral N-phosphonyl imines of formula (III), comprise the steps of:
The method comprises the reaction for synthesis of synthesis of chiral N-phosphonyl imines of formula (VII):
The advantages of the application are: these imines can be utilized for many asymmetric reactions, such as asymmetric aza-Darzens reaction to give aziridines (see, e.g., F. A. Davis, H. Liu, P. Zhou, T. Fang, G. V. Reddy, Y. Zhang, J. Org. Chem. 1999, 64, 7559-7567; J. B. Sweeney, A. A. Cantrill, A. B. McLaren, S. Thobhani, Tetrahedron 2006, 62, 3681-3693; N. Giubellina, S. Mangelinckx, K. W. Tornroos, N. De Kimpe, J. Org. Chem. 2006, 71, 5881-5887; J.-Y. Wang, D.-X. Wang, Q.-Y. Zheng, Z.-T. Huang, M.-X. Wang, J. Org. Chem. 2007, 72, 2040-2045), asymmetric aza-Henry reaction (see, e.g., B. Westermann, Angew. Chem. 2003, 115, 161-163; Angew. Chem. Int. Ed. Engl. 2003, 42, 151-153; M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew. Chem. Int. Ed. Engl. 2006, 45, 6366-6370; K. R. Knudsen, T. Risgaad, N. Nishiwaki, K. V. Gothelf, K. A. Jorgensen, J. Am. Chem. Soc. 2001, 123, 5843-5844; C. Palomo, M. Oiarbide, R. Halder, A. Laso, R. Lopez, Angew. Chem. Int. Ed. Engl. 2006, 45, 117-120) and other reactions.
The present invention describes free NH2 group-attached chiral phosphoramides and methods of forming the same. These compounds are important and very useful synthetic building blocks for drugs and their precursors.
In some embodiments, the present invention provides free NH2 group-attached chiral phosphoramides C. In some embodiment, the free NH2 group-attached chiral phosphoramides can be any of the compounds shown in formula (I), wherein R, R1 to R3 are independently any alkyl and aryl groups, and R1 can also be any sulfonyl groups. In some embodiments, the present invention provides compounds as formula (I); wherein R1 is a C1-C20 alkyl such as i-Pr, Me, Et, Pr, 2-Bu; Aryl; CH2-Aryl (e.g., Aryl=Ph, 1-Naph, 2-Naph, etc.); and Ts, Bs, Ms and C1-C20—R—SO2—, Ar—SO2—. R2 is a Aryl, Alkyl; two alkyl R2 groups can be connected as cycloalkanes, i.e., diamine precursors can be 1,2-diaminocyclohexane and 1,2-diaminocyclopentane.
The compounds shown in formula (I) can be racemic compounds or each of the two individual enantiomers, or combination thereof.
In some embodiments, the present invention provides new chiral N-phosphonyl imines D. In some embodiment, chiral N-phosphonyl imines D are any of the compounds shown in formula (III), wherein R, R1 to R3 are independently any alkyl and aryl groups, and R1 can also be any sulfonyl groups. In some embodiments, the present invention provides compounds as shown in
The compounds shown in formula (III) can be racemic compounds or each of the two individual enantiomers, or combination thereof.
In some embodiments, the present invention also provides methods of making of free NH2 group-attached chiral phosphoramides. The methods include: a) providing approach to phosphoramides, and b) synthesizing a chiral N-phosphonyl imines from free NH2 group-attached chiral phosphoramides.
In some embodiments, the method provides the synthesis of chiral N-phosphonyl imines.
Four steps are needed for the synthesis of phosphoramides. These steps can also be handled in situ. The synthesis of phosphoramides was performed starting from protected 1,2-diamines or aminoalcohols according to a similar procedure for the synthesis of N-alkyl phosphoramides (S. E. Denmark, Nature, 2006, 443, 40-41; S. E. Denmark, R. A. Stavenger, J. Am. Chem. Soc. 2000, 122, 8837-8847; S. E. Denmark, Y.-P. Su, Y. Nishigaichi, D. M. Coe, K. T. Wong, S. B. D. Winter, J. Y. Choi, J. Org. Chem. 1999, 64, 1958-1967).
Into a 250 mL three-neck round bottom flask equipped with a calcium chloride drying tube were taken (1R,2R)-(−)-1,2-Diaminocyclohexane 1 (2.283 g, 20.0 mmol) and 40.0 mL of ethanol. Benzaldehyde (4.062 mL, 40.0 mmol) was added drop wise to this solution at rt with the help of a pressure-equalizing funnel. After stirring 24 h at rt, the reaction mixture was cooled to 0° C. and diluted with 20.0 mL of ethanol. 1.513 g of NaBH4 (40.0 mmol) was added in portions to the reaction and stirred for another 24 h at rt. The solvent under vacuum was evaporated, and added ice was added to quench excess sodium borohydride followed by addition of water (100 mL). Reaction mixture was extracted with methylene chloride (3×100 mL) and then combined methylene chloride layer was washed with water (2×100 mL). The methylene chloride layer was dried on anhydrous sodium sulfate, filtered and evaporated under vacuum to give 5.87 g (100%) of (1R,2R)—N,N-Dibenzyl-1,2-diaminocyclohexane (2) as a colorless oil. 2 is a known compound. [α]D25=−83.9° (c=1.49, CHCl3). 1H NMR: 1.03 (m, 2H), 1.23 (m, 2H), 1.72 (m, 2H), 1.86 (br, 2H, 2×NH), 3.66 (d, 2H, J=13.5 Hz), 3.90 (d, 2H, J=13.5 Hz), 7.20-7.25 (m, 2H), 7.28-7.35 (m, 8H). 13C NMR: 25.0, 31.6, 50.9, 60.9, 126.7, 128.0, 128.3, 141.1.
To a solution of (1R,2R)—N,N-Dibenzyl-1,2-diaminocyclohexane (2, 5.87 g, 20.0 mmol) in methylene chloride (160.0 mL) was added 2.61 mL (28 mmol) of phosphorus oxychloride. Triethyl amine (6.69 mL, 48 mmol) was added drop wise to the reaction and was stirred at room temperature. After 24 h at RT, the reaction mixture was passed through a thick pad of silica gel (230-400 mesh) and washed with methylene chloride until all the product was obtained. Evaporation of solvent under vacuum gave 6.80 g (91%) of compound 3 as a white solid. mp 218-224° C. [α]D25=−22.9° (c=1.09, CHCl3). 1H NMR: 0.95-1.04 (m, 1H), 1.06-1.28 (m, 3H), 1.59-1.70 (m, 3H), 1.72-1.80 (m, 1H), 2.88-3.02 (m, 2H), 3.74 (dd, 1H, J=7.5, 15.5 Hz), 4.21 (dd, 1H, J=10.5, 15.5 Hz), 4.44 (t, 1H, J=15.5 Hz), 4.51 (t, 1H, J=15.5 Hz), 7.24-7.36 (m, 6H), 7.39-7.46 (m, 4H). 13C NMR: 23.7, 24.1, 29.0 (d, J=7.9 Hz), 29.1 (d, J=12.9 Hz), 46.5 (d, J=4.4 Hz), 47.5 (d, J=2.4 Hz), 63.1 (d, J=10.4 Hz), 63.4 (d, J=10.4 Hz), 127.3, 127.4, 127.7 (2C), 127.9 (2C), 128.3 (2C), 128.5 (2C), 137.5 (d, J=3.5 Hz), 138.0 (d, J=9.9 Hz).
In a 250 mL round bottomed flask equipped with calcium chloride drying tube were taken 5.0 g of 3 (13.4 mmol) and 50.0 mL of N,N-Dimethylformamide. To this at rt was added 1.742 g of sodium azide (26.8 mmol). Reaction was heated at 70° C. for 5 h. After cooling to rt, 100 mL cold water was added to the reaction flask and the resulting solid was filtered and dried to obtain 5.08 g of compound 4 as a white solid. mp 145-148° C. [α]D25=−14.9° (c=1.14, CHCl3). 1H NMR: 0.99-1.24 (m, 4H), 1.60-1.83 (m, 4H), 2.82-2.96 (m, 2H), 3.96 (dd, 1H, J=8.5, 15.5 Hz), 4.11 (dd, 1H, J=12.5, 15.5 Hz), 4.36 (t, 2H, J=15.5 Hz), 7.24-7.30 (m, 2H), 7.31-7.36 (m, 4H), 7.41 (d, 2H, J=7.5 Hz), 7.44 (d, 2H, J=7.5 Hz). 13C NMR: 23.9, 24.0, 29.0 (t, J=8.9, 10.4 Hz, 2C), 46.6 (d, J=3.5 Hz), 46.7 (d, J=3.9 Hz), 63.0 (d, J=10.4 Hz), 63.5 (d, J=9.8 Hz), 127.3, 127.4, 127.7 (2C), 128.0 (2C), 128.4 (2C), 128.5 (2C), 137.7 (d, J=3.0 Hz), 138.0 (d, J=5.5 Hz).
Into a 250 mL round bottom flask equipped with H2 balloon, was taken a solution of 5.0 g of 4 (13.4 mmol) in 100 mL of THF. To this was added 0.5 g of 10% palladium on charcoal. After stirring overnight at RT, the reaction mixture was diluted with methylene chloride and passed through a pad of celite. The filterate was dried on anhydrous sodium sulfate, filtered and evaporated under vacuum to give 4.65 g (100%) of pure product D1 as a white solid. mp 211-212° C.; [α]D25=−59.8° (c=0.64, CHCl3); 1H NMR: 0.95-1.24 (m, 4H), 1.60-1.80 (m, 4H), 2.50 (d, 2H, 2JPH=4.5 Hz, —NH2, exchanged in D2O), 2.72-2.77 (m, 1H), 2.84-2.89 (m, 1H), 3.90 (dd, 1H, J=7.5, 16.0 Hz), 4.02 (dd, 1H, J=9.0, 16.0 Hz), 4.36-4.43 (m, 2H), 7.21-7.25 (m, 2H), 7.29-7.33 (m, 4H), 7.43 (t, 4H, J=7.5 Hz); 13C NMR: 24.1, 24.2, 29.4 (d, J=3.5 Hz), 29.5 (d, J=5.0 Hz), 46.7 (d, J=3.0 Hz), 46.8 (d, J=4.5 Hz), 62.7 (d, J=9.4 Hz), 63.7 (d, J=10.4 Hz), 126.8, 126.9, 127.7 (2C), 127.9 (2C), 128.2 (2C), 128.3 (2C), 139.4 (d, J=4.4 Hz), 139.7 (d, J=5.0 Hz).
The same synthesis afforded a derivative of D3: 1H NMR (CDCl3, 500 Hz): 8.14-8.17 (m, 2H), 7.82-7.86 (m, 2H), 7.71-7.75 (m, 4H), 7.46-7.52 (m, 6H), 4.81-4.89 (m, 2H), 4.82 (dd, J=12.5, 15.0 Hz, 1H), 4.31 (dd, J=5.5, 16.5 Hz, 1H), 3.05-3.10 (m, 1H), 2.91-2.95 (m, 1H), 2.42 (b, 2H), 1.81-1.82 (m, 1H), 1.54-1.62 (m, 3H), 1.04-1.25 (m, 4H); 13C NMR (CDCl3, 125 Hz): 134.9, 134.9, 134.4, 134.4, 133.5, 133.4, 131.3, 131.0, 128.6, 128.5, 127.6, 127.4, 125.9, 125.8, 125.5, 125.4, 125.2, 125.2, 123.1, 123.0, 64.5, 64.4, 63.8, 63.7, 45.1, 45.0, 44.9, 44.9, 29.5, 29.4, 29.4, 24.1, 24.1.
Into a 100 mL single-neck round bottom flask were added (1R,2R)-(−)-1,2-diaminocyclohexane 1 (1.90 g, 16.7 mmol), 40.0 mL of ethanol, 6.2 mL of acetone (83.9 mmol) and 0.1 g of PtO2. H2 balloon was attached to the flask and the reaction was stirred for 24 h at rt. Filtered off PtO2 through a pad of celite and the filtrate was evaporated to give 3.31 g (100%) of (1R,2R)—N,N-diisopropyl-1,2-diaminocyclohexane (5) as a colorless oil.
To a solution of (1R,2R)—N,N-diisopropyl-1,2-diaminocyclohexane (5, 3.31 g, 16.7 mmol) in methylene chloride (103.0 mL) was added 2.20 mL (23.4 mmol) of phosphorus oxychloride. Triethyl amine (6.69 mL, 48 mmol) was added drop wise to the reaction at 0° C. The reaction temperature was then raised to rt and stirred for 24 h. The reaction mixture was passed through a thick pad of silica gel (230-400 mesh) and washed with methylene chloride until all the product was obtained. Evaporation of solvent under vacuum gave 4.65 g (100%) of compound 6 as a pale yellow oil. 1H NMR: 3.63-3.56 (m, 2H), 3.056 (t, 1H, J=11.5 Hz), 2.92 (t, 1H, J=11.5 Hz), 2.18-2.10 (m, 1H), 2.10-1.98 (m, 1H), 1.94-1.76 (m, 2H), 1.43 (d, 3H, J=6.5 Hz), 1.37 (d, 3H, J=6.5 Hz), 1.42-1.30 (m, 3H), 1.26 (d, 3H, J=6.5 Hz), 1.28-1.26 (m, 1H), 1.24 (d, 3H, J=6.5 Hz); 13C NMR: 60.6 (d, J=10.4 Hz), 58.7 (d, J=11.8 Hz), 45.0, 29.6 (d, J=12.7 Hz), 29.2 (d, J=8.8 Hz), 24.0 (d, J=1.5 Hz), 23.9 (d, J=2.0 Hz), 21.39 (d, J=5.8 Hz), 21.34 (d, J=2.5 Hz), 20.2 (d, J=2.0 Hz), 19.2 (d, J=1.4 Hz).
In a 100 mL round bottomed flask equipped with calcium chloride drying tube were taken 4.65 g of 6 (16.7 mmol) and 65.0 mL of N,N-dimethylformamide. To this at rt was added 1.742 g of sodium azide (50.1 mmol). Reaction was heated at 70° C. for 5 h. After cooling to rt, 100 mL cold water was added to the reaction flask and transferred to a separatory funnel. The water layer was then extracted with ethyl acetate (3×200 mL) and combined organic layers was washed with water and dried on anhydrous sodium sulfate. Filtered off the sodium sulfate and evaporation of the solvent gave 4.76 g (100% yield) of phosphorus azide 7 as a pale yellow oil. 1H NMR: 3.68-3.48 (m, 2H), 3.10-3.02 (t, 1H, J=11.5 Hz), 2.98-2.88 (t, 1H, J=11.5 Hz), 2.18-2.10 (m, 1H), 2.08-2.02 (m, 1H), 1.90-1.78 (m, 2H), 1.43 (d, 3H, J=7.0 Hz), 1.42-1.36 (m, 3H), 1.39 (d, 3H, J=7.0 Hz), 1.28-1.26 (m, 1H), 1.26 (d, 3H, J=6.5 Hz), 1.24 (d, 3H, J=6.5 Hz); 13C NMR: 60.6 (d, J=10.4 Hz), 58.8 (d, J=11.9 Hz), 45.0, 29.6 (d, J=12.9 Hz), 29.2 (d, J=8.9 Hz), 24.0 (d, J=1.5 Hz), 23.9 (d, J=2.0 Hz), 21.4 (d, J=6.0 Hz), 21.3 (d, J=2.5 Hz), 20.2 (d, J=2.5 Hz), 19.2 (d, J=1.5 Hz).
Into a 250 mL round bottom flask equipped was taken a solution of 4.76 g of 7 (16.7 mmol) in 100 mL of THF. To this was added 0.4 g of 10% palladium on charcoal and a H2 balloon was attached. After stirring overnight at rt, the reaction mixture was diluted with methylene chloride and passed through a pad of celite. The filtrate was dried on anhydrous sodium sulfate, filtered and evaporated under vacuum to give 4.32 g (100%) of pure product D2 as a white solid. 1H NMR: 3.58-3.42 (m, 2H), 2.92 (t, 1H, J=12.5 Hz), 2.70 (t, 1H, J=12.5 Hz), 2.47 (bs, 2H, —NH2), 2.08-1.96 (m, 2H), 1.80-1.72 (m, 2H), 1.38 (d, 3H, J=7.0 Hz), 1.35-1.25 (m, 3H), 1.33 (d, 3H, J=7.0 Hz), 1.21 (d, 3H, J=4.5 Hz), 1.19 (d, 3H, J=4.5 Hz), 1.18-1.10 (m, 1H); 13C NMR: 59.7 (d, J=10.4 Hz), 58.8 (d, J=9.4 Hz), 44.4, 44.0 (d, J=3.4 Hz), 30.1 (d, J=5.9 Hz), 30.0 (d, J=6.9 Hz), 24.27, 24.26, 21.8 (d, J=2.5 Hz), 21.7 (d, J=2.9 Hz), 20.5 (d, J=1.0 Hz), 19.9 (d, J=1.5 Hz).
The same synthesis afforded other derivatives of D2 (formula (II)): D4: 59%, 1H NMR 0.88-1.09 (m, 13H), 1.10-1.89 (m, 15H), 2.08 (d, 2H, 2JPH=4.5 Hz), 2.60-3.08 (m, 4H). D5: 67%, 1H NMR 1.05-2.10 (m, 24H), 2.40-2.50 (d, 2H, 2JPH=4.5 Hz), 2.61-2.73 (m, 1H), 2.83-2.96 (m, 1H), 3.35-3.58 (m, 2H). D6: 64%, 1H NMR 1.05-2.15 (m, 28H), 2.40-2.50 (d, 2H, 2JPH=4.5 Hz), 2.69-2.81 (m, 1H), 2.90-3.13 (m, 3H).
Typical procedure for synthesis of chiral N-phosphonyl imines: Into a dried and nitrogen flushed round bottom flask were loaded chiral phosphoramide D1 (1.07 g, 3.0 mmol), aldehyde (3.0 mmol) and CH2Cl2 (15.0 mL). The resulting mixture was protected by nitrogen and was cooled to 0° C. prior to the addition of DIPEA (1.56 mL, 9.0 mmol). Into the above mixture was added dropwise a solution of TiCla in CH2Cl2 (1 M, 1.5 mmol). The reaction was stirred at 0° C. for 30 min and at rt for 48 h. The clear solution of the crude reaction mixture was directly transferred to silica gel (200-300 mesh) packed in column for chromatography and eluted by mixed solvents of hexanes/EtOAc/Et3N (v/v/v, 90:9:1 to 60:38:2) to give imine products as viscous oils.
Compound 7: [α]D25=+12.4° (c=1.73, CHCl3); 1H NMR: 1.00-1.25 (m, 4H), 1.63-1.73 (m, 3H), 1.86-1.89 (m, 1H), 2.94-3.04 (m, 2H), 3.89 (dd, 1H, J=7.5, 15.5 Hz), 4.03 (dd, 1H, J=12.0, 15.5 Hz), 4.30 (dd, 1H, J=12.0, 15.5 Hz), 4.39 (dd, 1H, J=12.5, 15.5 Hz), 7.15-7.20 (m, 2H), 7.23-7.27 (m, 5H), 7.41-7.47 (m, 6H), 7.83 (d, 2H, J=8.0 Hz), 8.76 (d, 1H, 3JPH=33.0 Hz); 13C NMR: 24.21, 24.27, 29.4 (d, J=9.4 Hz), 29.6 (d, J=8.9 Hz), 46.9 (d, J=3.0 Hz), 47.5 (d, J=3.5 Hz), 63.4 (d, J=8.9 Hz), 63.8 (d, J=7.9 Hz), 126.8, 126.9, 127.8 (2C), 128.12 (2C), 128.19 (2C), 128.4 (2C), 128.6 (2C), 130.0, 132.9, 135.7, 136.0, 138.7 (d, J=3.5 Hz), 139.3 (d, J=4.9 Hz), 173.6 (d, J=7.0 Hz).
Compound 8: [α]D25=−1.85° (c=2.16, CHCl3); 1H NMR: 1.06-1.25 (m, 4H), 1.60-1.73 (m, 3H), 1.85-1.87 (m, 1H), 2.93-3.05 (m, 2H), 3.87 (s, 3H, —OCH3), 3.85-3.90 (dd, 1H, merged with methyl group of methoxy), 4.02 (dd, 1H, J=12.0, 15.0 Hz), 4.28 (dd, 1H, J=12.0, 16.0 Hz), 4.39 (dd, 1H, J=12.5, 15.5 Hz), 6.95 (d, 2H, J=9.0 Hz), 7.15-7.20 (m, 2H), 7.23-7.27 (m, 4H), 7.41-7.46 (m, 4H), 7.79 (d, 2H, J=9.0 Hz), 8.70 (d, 1H, 3JPH=32.5 Hz); 13C NMR: 24.22, 24.27, 29.4 (d, J=9.4 Hz), 29.6 (d, J=8.9 Hz), 46.9 (d, J=3.0 Hz), 47.5 (d, J=3.4 Hz), 55.4, 63.4 (d, J=8.5 Hz), 63.8 (d, J=7.9 Hz), 114.0 (2C), 126.8, 126.9, 127.8 (2C), 128.0 (2C), 128.1 (2C), 128.3 (2C), 128.8, 129.1, 132.0, 138.9 (d, J=3.4 Hz), 139.4 (d, J=5.0 Hz), 163.6, 172.9 (d, J=6.4 Hz).
Compound 9: [α]D25=−15.87° (c=0.46, CHCl3); 1H NMR: 1.00-1.21 (m, 4H), 1.60-1.74 (m, 3H), 1.85-1.87 (m, 1H), 2.90-3.03 (m, 2H), 3.88 (dd, 1H, J=7.5, 15.5 Hz), 4.01 (dd, 1H, J=12.0, 15.5 Hz), 4.26 (dd, 1H, J=12.0, 16.0 Hz), 4.38 (dd, 1H, J=13.0, 16.0 Hz), 5.14 (s, 2H, —OCH2—), 7.03 (d, 2H, J=9.0 Hz), 7.15-7.20 (m, 2H), 7.23-7.27 (m, 5H), 7.39-7.45 (m, 8H), 7.79 (d, 2H, J=9.0 Hz), 8.70 (d, 1H, 3JPH=33.0 Hz); 13C NMR: 24.23, 24.28, 29.4 (d, J=9.4 Hz), 29.6 (d, J=8.9 Hz), 46.9 (d, J=3.0 Hz), 47.5 (d, J=3.4 Hz), 63.4 (d, J=8.9 Hz), 63.8 (d, J=7.9 Hz), 70.1, 114.9 (2C), 126.8, 126.9, 127.4 (2C), 127.8 (2C), 128.0 (2C), 128.1 (2C), 128.2, 128.3 (2C), 128.6 (2C), 129.1, 129.3, 132.0, 136.1, 138.9 (d, J=3.5 Hz), 139.4 (d, J=4.8 Hz), 162.7, 172.9 (d, J=6.4 Hz).
Compound 10: 1H NMR: 1.00-1.21 (m, 4H), 1.62-1.74 (m, 3H), 1.85-1.87 (m, 1H), 2.42 (s, 3H, —CH3) 2.93-3.03 (m, 2H), 3.88 (dd, 1H, J=8.0, 16.0 Hz), 4.02 (dd, 1H, J=12.0, 15.5 Hz), 4.28 (dd, 1H, J=12.0, 16.0 Hz), 4.39 (dd, 1H, J=13.0, 15.5 Hz), 7.15-7.20 (m, 2H), 7.23-7.26 (m, 6H), 7.41-7.43 (m, 4H), 7.74 (d, 2H, J=8.0 Hz), 8.74 (d, 1H, 3JPH=33.0 Hz); 13C NMR: 21.7, 24.21, 24.27, 29.4 (d, J=9.4 Hz), 29.6 (d, J=8.9 Hz), 46.9 (d, J=3.0 Hz), 47.5 (d, J=3.4 Hz), 63.3 (d, J=8.9 Hz), 63.8 (d, J=7.9 Hz), 126.8, 126.9, 127.8 (2C), 128.10 (2C), 128.17 (2C), 128.3 (2C), 129.4 (2C), 130.0, 133.3, 133.5, 138.8 (d, J=3.4 Hz), 139.3 (d, J=4.9 Hz), 143.8, 173.6 (d, J=6.9 Hz)
Compound 11: 1H NMR: 1.04-1.25 (m, 4H), 1.60-1.71 (m, 3H), 1.86-1.88 (m, 1H), 2.48 (s, 3H, —CH3) 2.94 (m, 1H), 3.03 (m, 1H), 3.85 (dd, 1H, J=7.5, 16.0 Hz), 4.02 (dd, 1H, J=12.0, 15.5 Hz), 4.32 (dd, 1H, J=11.5, 16.0 Hz), 4.44 (dd, 1H, J=13.0, 15.5 Hz), 7.17-7.30 (m, 7H), 7.38-7.43 (m, 6H), 8.00 (d, 1H, J=7.5 Hz), 9.10 (d, 1H, 3JPH=33.0 Hz); 13C NMR: 19.4, 24.22, 24.29, 29.5 (d, J=9.4 Hz), 29.8 (d, J=8.9 Hz), 47.1 (d, J=3.0 Hz), 47.6 (d, J=3.5 Hz), 63.5 (d, J=8.4 Hz), 64.1 (d, J=7.9 Hz), 126.1, 126.8, 126.9, 127.7 (2C), 128.12 (2C), 128.19 (2C), 128.2 (2C), 129.1, 131.1 (d, J=1.5 Hz), 132.5, 133.6, 139.0 (d, J=3.5 Hz), 139.4 (d, J=5.5 Hz), 140.5, 172.1 (d, J=6.9 Hz).
Compound 12: 1H NMR 1.07-1.25 (m, 4H), 1.64-1.74 (m, 3H), 1.88-1.90 (m, 1H), 2.94-3.04 (m, 2H), 3.89 (dd, 1H, J=8.0, 16.0 Hz), 4.03 (dd, 1H, J=13.0, 15.0 Hz), 4.28 (dd, 1H, J=12.0, 16.0 Hz), 4.37 (dd, 1H, J=12.5, 15.5 Hz), 7.11-7.21 (m, 4H), 7.23-7.27 (m, 4H), 7.41 (m, 4H), 7.82 (t, 2H, J=7.5 Hz), 8.67 (d, 1H, 3JPH=32.5 Hz); 13C NMR 24.21, 24.27, 29.3 (d, J=9.4 Hz), 29.6 (d, J=9.4 Hz), 46.8 (d, J=3.0 Hz), 47.4 (d, J=3.4 Hz), 63.3 (d, J=8.9 Hz), 63.8 (d, J=7.9 Hz), 115.8, 116.0, 126.9, 127.0, 127.8 (2C), 128.14 (2C), 128.19 (2C), 128.4 (2C), 132.1, 132.2, 132.4, 138.6 (d, J=3.5 Hz), 139.2 (d, J=4.9 Hz), 165.7 (d, JCF=253.7 Hz), 172.1 (d, J=7.0 Hz).
Compound 13: 1H NMR 1.08-1.26 (m, 4H), 1.65-1.76 (m, 3H), 1.90-1.92 (m, 1H), 2.94-3.05 (m, 2H), 3.89 (dd, 1H, J=8.0, 16.0 Hz), 4.03 (dd, 1H, J=13.0, 15.0 Hz), 4.28 (dd, 1H, J=12.0, 15.5 Hz), 4.37 (dd, 1H, J=12.0, 15.0 Hz), 7.16-7.22 (m, 2H), 7.23-7.28 (m, 4H), 7.40-7.44 (m, 6H), 7.75 (d, 2H, J=8.5 Hz), 8.66 (d, 1H, 3JPH=32.0 Hz); 13C NMR: 24.21, 24.27, 29.3 (d, J=9.4 Hz), 29.6 (d, J=9.0 Hz), 46.7 (d, J=3.4 Hz), 47.4 (d, J=3.4 Hz), 63.3 (d, J=8.4 Hz), 63.9 (d, J=7.9 Hz), 126.9, 127.0, 127.8 (2C), 128.16 (2C), 128.21 (2C), 128.4 (2C), 129.0 (2C), 131.0, 134.2, 134.4, 138.6 (d, J=3.0 Hz), 139.1 (d, J=5.0 Hz), 139.2, 172.1 (d, J=6.4 Hz).
Compound 14: 1H NMR 1.00-1.19 (m, 4H), 1.62-1.72 (m, 3H), 1.87-1.89 (m, 1H), 2.82-2.87 (m, 1H), 2.95-3.01 (m, 1H), 3.85 (dd, 1H, J=7.0, 16.0 Hz), 4.06 (dd, 1H, J=11.5, 15.5 Hz), 4.37-4.46 (m, 2H), 7.16-7.22 (m, 2H), 7.25-7.28 (m, 4H), 7.34 (t, 1H, J=7.5 Hz), 7.39-7.46 (m, 6H), 8.17 (dd, 1H, J=1.5, 8.0 Hz), 9.25 (d, 1H, 3JPH=32.0 Hz); 13C NMR 24.17, 24.26, 29.3 (d, J=9.9 Hz), 29.7 (d, J=8.9 Hz), 46.8 (d, J=3.5 Hz), 47.7 (d, J=3.0 Hz), 63.1 (d, J=8.9 Hz), 63.9 (d, J=7.9 Hz), 126.9, 127.0, 127.7 (2C), 128.16 (2C), 128.28 (2C), 128.3 (2C), 129.2, 130.1, 132.7, 132.9, 133.7, 137.8, 138.6 (d, J=3.5 Hz), 139.3 (d, J=4.9 Hz), 168.7 (d, J=5.4 Hz).
Compound 15: [α]D25=+10.00° (c=2.10, CHCl3); 1H NMR 1.09-1.23 (m, 4H), 1.64-1.75 (m, 3H), 1.89-1.91 (m, 1H), 2.93-3.04 (m, 2H), 3.89 (dd, 1H, J=7.5, 16.0 Hz), 4.02 (dd, 1H, J=13.5, 15.0 Hz), 4.27 (dd, 1H, J=12.0, 16.0 Hz), 4.36 (dd, 1H, J=12.0, 15.0 Hz), 7.15-7.27 (m, 2H), 7.23-7.27 (m, 4H), 7.39-7.42 (m, 4H), 7.59 (d, 2H, J=8.0 Hz), 7.66 (d, 2H, J=8.0 Hz), 8.63 (d, 1H, 3JPH=32.5 Hz); 13C NMR 24.18, 24.25, 29.3 (d, J=9.4 Hz), 29.5 (d, J=9.4 Hz), 46.7 (d, J=3.0 Hz), 47.4 (d, J=3.5 Hz), 63.3 (d, J=8.9 Hz), 63.8 (d, J=8.4 Hz), 126.9, 127.0, 127.8 (2C), 128.15 (2C), 128.20 (2C), 128.4 (2C), 131.2 (2C), 132.0 (2C), 134.5, 134.8, 138.5 (d, J=2.9 Hz), 139.1 (d, J=4.4 Hz), 172.2 (d, J=7.0 Hz).
Compound 16: [α]D25=+20.8° (c=0.72, CHCl3); 1H NMR 1.10-1.24 (m, 4H), 1.60-1.73 (m, 3H), 1.83-1.85 (m, 1H), 2.96-3.03 (m, 2H), 3.93 (dd, 1H, J=8.0, 16.0 Hz), 4.01 (dd, 1H, J=12.5, 15.5 Hz), 4.23 (dd, 1H, J=12.5, 16.0 Hz), 4.397 (dd, 1H, J=12.5, 15.5 Hz), 7.13 (t, 1H, J=5.0 Hz), 7.15-7.21 (m, 2H), 7.24-7.28 (m, 4H), 7.41-7.45 (m, 4H), 7.47 (dd, 1H, J=3.5, 1.0 Hz), 7.62 (d, 1H, J=5.0 Hz) 8.83 (d, 1H, 3JPH=31.5 Hz); 13C NMR 24.23 (2C), 29.3 (d, J=9.4 Hz), 29.5 (d, =9.4 Hz), 46.7 (d, J=3.0 Hz), 47.2 (d, =3.4 Hz), 63.1 (d, J=8.4 Hz), 63.8 (d, J=8.4 Hz), 126.8, 126.9, 127.9 (2C), 128.13 (2C), 128.16 (2C), 128.3 (2C), 133.0, 135.5, 138.8 (d, J=2.9 Hz), 139.1 (d, J=4.4 Hz), 142.9, 143.1, 166.1 (d, J=5.5 Hz).
Compound 17: 76% Yield (825 mg). mp: 69-71° C. [α]D25=−21.5° (c=0.58, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=33.0 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.53-7.87 (m, 5H), 7.64 (d, J=8.1 Hz, 1H), 7.36-7.57 (m, 11H), 4.87 (dd, J=9.3, 15.0 Hz, 1H), 4.72 (dd, J=11.1, 16.2 Hz, 1H), 4.58 (t, J=16.2 Hz, 1H), 4.36 (dd, J=8.1, 15.9 Hz, 1H), 3.16-3.31 (m, 2H), 2.07-2.10 (m, 1H), 1.66-1.78 (m, 3H), 1.17-1.45 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 173.9 (d, J=6.5 Hz), 135.5 (d, J=28.1 Hz), 134.5, 134.5, 133.6, 133.5, 133.5, 132.8, 131.5, 131.2, 129.7, 128.5, 128.5, 128.4, 127.9, 127.6, 127.3, 126.0, 125.9, 125.9, 125.4, 125.4, 125.2, 125.2, 123.4, 123.4, 64.9 (d, J=7.3 Hz), 64.2 (d, J=8.3 Hz), 45.9, 45.8, 45.1, 45.1, 29.7, 29.6, 29.4, 29.4, 24.3; 31P NMR (202 MHz, CDCl3) δ 28.9.
Compound 18: 80% Yield (917 mg). mp: 61-63° C. [α]D25=+3.4° (c=0.51, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.15 (d, J=33.3 Hz, 1H), 8.24 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.99 (dd, J=1.2, 7.5 Hz, 1H), 7.75-7.85 (m, 5H), 7.66 (d, 1H, J=8.1 Hz), 7.39-7.57 (m, 7H), 6.97-7.02 (m, 1H), 6.86 (d, J=8.7, 1H), 4.97 (dd, J=10.5, 15.9 Hz, 1H), 4.72 (dd, J=11.1, 16.2 Hz, 1H), 4.48 (dd, J=12.6, 15.9 Hz, 1H), 4.33 (dd, J=7.5, 16.2 Hz, 1H), 3.77 (s, 3H), 3.19-3.31 (m, 2H), 1.89-1.92 (m, 1H), 1.62-1.73 (m, 3H), 1.14-1.39 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 170.3 (d, J=5.3 Hz), 160.7, 134.8, 134.8, 134.5, 134.3, 134.3, 133.5, 133.4, 131.2, 131.2, 128.5, 128.4, 128.0, 127.5, 127.4, 126.2, 125.9, 125.9, 125.8, 125.4, 125.3, 125.2, 125.1, 124.4, 124.1, 123.4, 123.3, 120.3, 110.9, 110.9, 65.3 (d, J=7.8 Hz), 64.3 (d, J=8.0 Hz), 55.2, 45.9, 45.8, 45.2, 45.1, 30.0, 29.9, 29.5, 29.4, 24.3; 31P NMR (202 MHz, CDCl3) δ 30.7.
Compound 19: 81% Yield (902 mg). mp: 59-60° C. [α]D25=−7.14° (c=0.63, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=33.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.71-7.83 (m, 5H), 7.64 (d, J=8.4 Hz, 1H), 7.33-7.51 (m, 8H), 7.15 (d, J=8.1, 2H), 4.82 (dd, J=9.3, 15.0 Hz, 1H), 4.72 (dd, J=10.5, 16.2 Hz, 1H), 4.47 (t, J=15.6 Hz, 1H), 4.28 (dd, J=8.1, 16.2 Hz, 1H), 3.11-3.28 (m, 2H), 2.38 (s, 3H), 1.99-2.04 (m, 1H), 1.61-1.73 (m, 3H), 1.09-1.45 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 173.9 (d, J=6.9 Hz), 143.7, 134.6, 134.6, 133.8, 133.7, 133.5, 133.4, 133.3, 133.0, 131.4, 131.2, 129.8, 129.2, 128.5, 128.5, 127.8, 127.6, 127.1, 125.9, 125.9, 125.8, 125.4, 125.3, 125.2, 125.2, 123.4, 123.4, 65.0 (d, J=7.4 Hz), 64.2 (d, J=7.9 Hz), 45.9, 45.8, 45.2, 45.1, 29.7, 29.6, 29.5, 29.4, 24.3, 21.7; 31P NMR (202 MHz, CDCl3) δ 30.4.
Compound 20: 77% Yield (864 mg). mp: 48-50° C. [α]D25=−14.8° (c=0.51, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=33.0 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H), 7.65-7.87 (m, 7H), 7.37-7.57 (m, 7H), 7.12-7.17 (m, 1H), 7.00-7.06 (m, 1H), 4.84 (dd, J=9.3, 15.0 Hz, 1H), 4.72 (dd, J=10.8, 15.9 Hz, 1H), 4.58 (t, J=15.9 Hz, 1H), 4.36 (dd, J=8.1, 16.2 Hz, 1H), 3.16-3.31 (m, 2H), 2.05-2.10 (m, 1H), 1.66-1.79 (m, 3H), 1.17-1.46 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 167 (t, J=5.5 Hz), 164.5, 162.5, 134.6, 134.5, 134.5, 134.4, 133.5, 133.4, 133.4, 133.4, 131.4, 131.2, 128.5, 128.4, 128.2, 127.9, 127.7, 127.1, 125.9, 125.8, 125.4, 125.3, 125.1, 125.1, 124.0, 124.0, 123.3, 123.3, 115.8, 115.7, 64.9 (d, J=7.5 Hz), 64.2 (d, J=8.3 Hz), 45.9, 45.8, 44.9, 44.9, 29.7, 29.6, 29.4, 29.3, 24.3; 31P NMR (202 MHz, CDCl3) δ 29.8.
Compound 21: 70% Yield (871 mg). mp: 59-61° C. [α]D25=−22.5° (c=0.60, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J=32.1 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.67-7.87 (m, 7H), 7.40-7.57 (m, 7H), 7.31-7.39 (m, 2H), 4.93 (dd, J=9.6, 15.3 Hz, 1H), 4.75 (dd, J=11.1, 16.2 Hz, 1H), 4.58 (t, J=15.3 Hz, 1H), 4.36 (dd, J=7.2, 16.2 Hz, 1H), 3.09-3.30 (m, 2H), 2.03-2.08 (m, 1H), 1.66-1.78 (m, 3H), 1.15-1.48 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 171.7 (d, J=5.4 Hz), 134.5, 134.5, 134.1, 133.9, 133.6, 133.6, 133.6, 133.5, 133.1, 131.2, 131.2, 129.5, 128.5, 127.9, 127.7, 127.5, 127.3, 127.0, 126.0, 125.9, 125.9, 125.5, 125.4, 125.2, 123.4, 123.3, 65.2 (d, J=7.3 Hz), 63.9 (d, J=8.3 Hz), 46.1, 46.0, 44.9, 44.9, 29.9, 29.8, 29.4, 29.3, 24.2; 31P NMR (202 MHz, CDCl3) δ 29.5.
Compound 22: 72% Yield (832 mg). mp: 53-55° C. [α]D25=−26.7° (c=0.60, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J=32.1 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.63-7.85 (m, 7H), 7.35-7.55 (m, 7H), 7.25-7.31 (m, 1H), 7.20-7.23 (m, 1H), 4.87 (dd, J=9.6, 15.3 Hz, 1H), 4.72 (dd, J=10.8, 15.9 Hz, 1H), 4.53 (t, J=15.6 Hz, 1H), 4.36 (dd, J=7.5, 15.5 Hz, 1H), 3.07-3.27 (m, 2H), 2.01-2.04 (m, 1H), 1.63-1.74 (m, 3H), 1.12-1.42 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 169.6 (d, J=5.0 Hz), 137.6, 134.5, 134.5, 133.6, 133.5, 133.5, 132.7, 132.7, 131.4, 131.2, 129.8, 129.8, 129.0, 128.5, 128.5, 127.9, 127.7, 127.0, 126.7, 125.9, 125.9, 125.9, 125.4, 125.4, 125.2, 125.1, 123.3, 123.3, 65.2 (d, J=7.3 Hz), 64.0 (d, J=8.4 Hz), 46.0, 46.0, 44.9, 44.9, 29.8, 29.7, 29.4, 29.3, 24.3, 24.2; 31P NMR (202 MHz, CDCl3) δ 29.8.
Compound 23: 83% Yield (925 mg). mp: 55-58° C. [α]D25=−9.6° (c=0.62, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=33.3 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.69-7.84 (m, 6H), 7.64 (d, J=8.1 Hz, 1H), 7.31-7.54 (m, 7H), 7.16-7.21 (m, 1H), 7.09 (d, J=7.5 Hz, 1H), 4.87 (dd, J=9.6, 15.3 Hz, 1H), 4.67 (dd, J=10.5, 15.9 Hz, 1H), 4.52 (t, J=15.3 Hz, 1H), 4.36 (dd, J=7.8, 16.2 Hz, 1H), 3.11-3.29 (m, 2H), 2.25 (s, 3H), 1.99-2.03 (m, 1H), 1.63-1.74 (m, 3H), 1.13-1.40 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 172.5 (d, J=6.4 Hz), 140.4, 134.6, 134.5, 133.9, 133.8, 133.6, 133.5, 133.4, 133.4, 132.4, 131.4 131.2, 130.9, 130.9, 129.2, 128.5, 128.5, 127.7, 127.6, 126.9, 125.9, 125.9, 125.4, 125.4, 125.2, 125.1, 123.3, 123.3, 65.1 (d, J=7.5 Hz), 64.2 (d, J=7.9 Hz), 45.9, 45.9, 45.2, 45.2, 29.8, 29.8, 29.4, 29.4, 24.3, 19.2; 31P NMR (202 MHz, CDCl3) δ 30.2
Compound 24: 61% Yield (697 mg). mp: 53-55° C. [α]D25=+4.7° (c=0.66, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.01 (d, J=35.7 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.73-7.85 (m, 5H), 7.65 (d, J=8.4 Hz, 1H), 7.36-7.57 (m, 6H), 7.17-7.22 (m, 1H), 6.98 (d, J=7.5 Hz, 2H), 4.98 (dd, J=10.2, 15.9 Hz, 1H), 4.72 (dd, J=10.8, 16.2 Hz, 1H), 4.45 (t, J=13.8 Hz, 1H), 4.24 (dd, J=7.2, 16.2 Hz, 1H), 3.05-3.27 (m, 2H), 2.32 (s, 6H), 1.93-1.97 (m, 1H), 1.43-1.71 (m, 3H), 1.12-1.43 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 174.0 (d, J=8 Hz), 140.4, 134.7, 134.6, 134.2, 134.2, 133.5, 133.5, 132.3, 132.1, 131.2, 131.1, 129.1, 128.5, 128.5, 127.7, 127.6, 126.3, 125.9, 125.9, 125.8, 125.4, 125.2, 125.1, 123.2, 123.1, 65.5 (d, J=7.5 Hz), 64.3 (d, J=7.8 Hz), 46.0, 46.0, 45.5, 45.5, 30.2, 30.1, 29.6, 29.5, 24.2, 21.4; 31P NMR (202 MHz, CDCl3) δ 30.2
Compound 25: 68% Yield (807 mg). mp: 48-50° C. [α]2z; =+10.8° (c=0.74, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.92 (d, J=34.2 Hz, 1H), 8.63-8.66 (m, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.71-7.83 (m, 5H), 7.55-7.63 (m, 2H), 7.30-7.54 (m, 10H), 4.87 (dd, J=9.3, 15.0 Hz, 1H), 4.73 (dd, J=10.8, 16.2 Hz, 1H), 4.53 (t, J=16.2 Hz, 1H), 4.33 (dd, J=8.1, 15.9 Hz, 1H), 3.14-3.33 (m, 2H), 2.08-2.12 (m, 1H), 1.64-1.78 (m, 3H), 1.16-1.45 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 173.2 (d, J=7 Hz), 134.5, 134.5, 133.7, 133.6, 133.5, 133.5, 132.1, 131.5, 131.5, 131.2, 130.7, 130.5, 128.5, 128.5, 128.4, 127.9, 127.7, 127.6, 127.4, 126.2, 126.0, 125.9, 125.4, 125.3, 125.2, 125.2, 124.9, 124.2, 123.4, 123.3, 65.1 (d, J=6.9 Hz), 64.2 (d, J=7.2 Hz), 46.0, 45.9, 45.2, 45.2, 29.8, 29.7, 29.4, 29.4, 24.3, 24.2; 31P NMR (202 MHz, CDCl3) δ 30.1.
Into a dried and nitrogen flushed round bottom flask were loaded chiral phosphoramide D3 (0.2 g, 0.77 mmol), aldehyde (0.77 mmol) and CH2Cl2 (2.8 mL). The resulting mixture was protected by nitrogen and was cooled to 0° C. prior to the addition of Et3N (0.32 mL, 2.31 mmol). Into the above mixture was added dropwise a solution of TiCl4 in CH2Cl2 (1 M, 0.38 mmol). The reaction was stirred at 0° C. for 30 min and at rt for 48 h. The clear solution of the crude reaction mixture was directly transferred to silica gel (200-300 mesh) packed in column for chromatography and eluted by mixed solvents of hexanes/EtOAc/Et3N (v/v/v, 90:9:1 to 60:38:2) to give imine products. Most of the products were obtained as white solids.
Compound 26: [α]D25=−12.2° (c=0.53, CHCl3); 1H NMR 9.03 (d, 1H, J=33.0 Hz), 7.96-7.88 (m, 2H), 7.56-7.52 (m, 1H), 7.51-7.45 (m, 2H), 3.50-3.34 (m, 2H), 3.09 (t, 1H, J=12 Hz), 2.84 (t, 1H, J=12 Hz), 2.12-2.02 (m, 2H), 1.86-1.75 (m, 2H), 1.45-1.31 (m, 3H), 1.30-1.22 (m, 10H), 1.11 (d, 3H, J=7.0 Hz); 13C NMR 171.5 (d, J=7.4 Hz), 136.2 (d, J=27.8 Hz), 132.7, 130.0 (2C), 128.7 (2C), 59.8 (d, J=8.4 Hz), 59.3 (d, J=8.9 Hz), 45.1, 44.5, 29.6 (d, J=10.0 Hz), 29.5 (d, J=9.4 Hz), 24.3, 24.2, 21.8 (d, J=3.5 Hz), 20.9 (d, J=3.0 Hz), 20.6, 20.4.
Compound 27: [α]D25=−86.1° (c=0.26, CHCl3); 1H NMR 8.96 (d, 1H, J=33.5 Hz), 7.88 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 3.87 (s, 3H), 3.50-3.33 (m, 2H), 3.08 (t, 1H, J=12 Hz), 2.85 (t, 1H, J=12 Hz), 2.10-2.04 (m, 2H), 1.90-1.79 (m, 2H), 1.40-1.31 (m, 3H), 1.30-1.20 (m, 10H), 1.11 (d, 3H, J=6.5 Hz); 13C NMR 170.9 (d, J=4.1 Hz), 163.4, 132.0 (2C), 129.3 (d, J=28.1 Hz), 114.1 (2C), 59.7 (d, J=7.8 Hz), 59.3 (d, J=8.8 Hz), 55.4, 45.1 (d, J=3.0 Hz), 44.4 (d, J=3.5 Hz), 29.7 (d, J=9.3 Hz), 29.4 (d, J=5.3 Hz), 24.3 (d, J=6.3 Hz), 21.7 (d, J=3.3 Hz), 20.8 (d, J=3.0 Hz), 20.6, 20.4.
Compound 28: [α]D25−32.3° (c=0.73, CHCl3); 1H NMR 8.98 (d, 1H, J=33.5 Hz), 7.82 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 3.50-3.30 (m, 2H), 3.08 (t, 1H, J=12.0 Hz), 2.84 (t, 1H, J=12.0 Hz), 2.42 (s, 3H), 2.12-2.00 (m, 2H), 1.86-1.78 (m, 2H), 1.45-1.30 (m, 3H), 1.30-1.20 (m, 10H), 1.10 (d, 3H, J=6.5 Hz); 13C NMR 171.4 (d, J=7.7 Hz), 143.5, 133.7 (d, J=27.7 Hz), 130.0 (2C), 129.4 (2C), 59.7 (d, J=8.2 Hz), 59.3 (d, J=8.8 Hz), 45.1 (d, J=2.8 Hz), 44.5 (d, J=2.8 Hz), 29.6 (d, J=9.3 Hz), 29.4 (d, J=9.3 Hz), 24.3 (d, J=5.3 Hz), 21.78 (d, J=3.0 Hz), 21.71, 20.9 (d, J=2.8 Hz), 20.6, 20.4.
Compound 29: [α]D25=−20.9° (c=0.11, CHCl3); 1H NMR 9.36 (d, 1H, J=33.5 Hz), 8.06 (d, 1H, J=7.5 Hz), 7.40 (t, 1H, J=7.5 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.23 (d, 1H, J=7.5 Hz), 3.60-3.38 (m, 2H), 3.09 (t, 1H, J=12 Hz), 2.80 (t, 1H, J=12 Hz), 2.62 (s, 3H), 2.10-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.45-1.20 (m, 13H), 1.12 (d, 3H, J=6.5 Hz); 13C NMR 169.7 (d, J=7.3 Hz), 140.2, 133.9 (d, J=26.6 Hz), 132.3, 131.0, 128.7, 126.3, 131.0 (d, J=1.0 Hz), 59.7 (d, J=7.8 Hz), 59.3 (d, J=8.8 Hz), 45.1 (d, J=3.0 Hz), 44.5 (d, J=2.8 Hz), 29.7 (d, J=10.7 Hz), 29.6 (d, J=10.3 Hz), 24.3 (d, J=3.0 Hz), 21.9 (d, J=2.8 Hz), 21.2 (d, J=3.5 Hz), 20.6, 20.4, 19.3.
Compound 30: [α]D25=−19.6° (c=0.52, CHCl3); 1H NMR 8.98 (d, 1H, J=33.0 Hz), 7.93 (t, 2H, J=7.5 Hz), 7.16 (t, 2H, J=9.0 Hz), 3.50-3.30 (m, 2H), 3.09 (t, 2H, J=12.0 Hz), 2.84 (t, 2H, J=12.0 Hz), 2.15-2.04 (m, 2H), 1.90-1.75 (m, 2H), 1.45-1.30 (m, 3H), 1.30-1.22 (m, 10H), 1.11 (d, 3H, J=5.0 Hz); 13C NMR 169.9 (d, J=7.3 Hz), 165.6 (d, JCF=253.2 Hz), 132.6 (d, J=28.1 Hz), 132.18, 132.11, 116.0, 115.91, 59.7 (d, J=7.8 Hz), 59.3 (d, J=8.8 Hz), 45.1 (d, J=3.0 Hz), 44.5 (d, J=3.0 Hz), 29.6 (d, J=9.8 Hz), 29.4 (d, J=9.3 Hz), 24.3, 24.2, 21.8 (d, J=3.0 Hz), 20.9 (d, J=3.5 Hz), 20.6, 20.4.
Compound 31: 1H NMR 8.96 (d, 1H, J=33.0 Hz), 7.86 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.50-3.30 (m, 2H), 3.09 (t, 1H, J=12.0 Hz), 2.83 (t, 1H, J=12.0 Hz), 2.15-2.02 (m, 2H), 1.90-1.75 (m, 2H), 1.45-1.30 (m, 13H), 1.30-1.20 (m, 10H), 1.10 (d, 3H, J=6.5 Hz); 13C NMR 169.9 (d, J=6.8 Hz), 139.0, 134.6 (d, J=28.1 Hz), 131.1 (2C), 129.1 (2C), 59.8 (d, J=8.3 Hz), 59.3 (d, J=8.8 Hz), 45.1 (d, J=2.8 Hz), 44.5 (d, J=2.8 Hz), 29.6 (d, J=9.8 Hz), 29.5 (d, J=9.3 Hz), 24.3 (d, J=4.5 Hz), 21.8 (d, J=3.3 Hz), 20.9 (d, J=2.8 Hz), 20.6, 20.4.
Compound 32: [α]D2537.5° (c=0.90, CHCl3); NMR 9.40 (d, 1H, J=32.5 Hz), 8.18 (d, 1H, J=7.0 Hz), 7.48-7.40 (m, 2H), 7.38-7.32 (m, 1H), 3.58-3.40 (m, 2H), 3.08 (t, 1H, J=12.0 Hz), 2.66 (m, 1H), 2.16-2.00 (m, 2H), 1.88-1.74 (m, 2H), 1.45-1.20 (m, 13H), 1.10 (d, 3H, J=6.5 Hz); 13C NMR 165.9 (d, J=5.8 Hz), 137.6, 133.3, 132.8 (d, J=27.6 Hz), 129.9 (d, J=1.5 Hz), 129.1, 127.0, 59.7 (d, J=7.8 Hz), 58.9 (d, J=9.8 Hz), 45.1 (d, J=2.5 Hz), 44.6 (d, J=3.0 Hz), 29.8 (d, J=9.3 Hz), 29.4 (d, J=10.3 Hz), 24.2, 21.8 (d, J=2.8 Hz), 21.4 (d, J=4.0 Hz), 20.57, 20.56, 20.55.
Compound 33: [α]D252.3° (c=0.42, CHCl3); 1H NMR 8.96 (d, 1H, J=32.5 Hz), 7.78 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=8.5 Hz), 3.58-3.30 (m, 2H), 3.08 (t, 1H, J=12.0 Hz), 2.82 (t, 1H, J=12.0 Hz), 2.14-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.40-1.30 (m, 3H), 1.30-1.20 (m, 10H), 1.10 (d, 3H, J=6.5 Hz); 13C NMR 169.9 (d, J=7.0 Hz), 135.1 (d, J=28.2 Hz), 132.1 (2C), 131.2 (2C), 59.8 (d, J=8.0 Hz), 59.3 (d, J=8.0 Hz), 45.1 (d, J=2.4 Hz), 44.5 (d, J=2.9 Hz), 29.6 (d, J=9.9 Hz), 29.4 (d, J=9.4 Hz), 24.2 (d, J=3.5 Hz), 21.8 (d, J=3.4 Hz), 20.9 (d, J=3.0 Hz), 20.6 (d, J=1.0 Hz), 20.4 (d, J=1.5 Hz).
Compound 34: [α]D25=−18.7° (c=0.73, CHCl3); NMR 9.28 (d, 1H, J=32.5 Hz), 8.16 (d, 1H, J=7.5 Hz), 7.63 (d, 1H, J=7.5 Hz), 7.42-7.32 (m, 2H), 3.60-3.40 (m, 2H), 3.07 (t, 1H, J=11.5 Hz), 2.62 (t, 1H, J=11.5 Hz), 2.18-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.50-1.15 (m, 13H), 1.09 (d, 3H, J=6.5 Hz); 13C NMR 168.1 (d, J=5.8 Hz), 134.3 (d, J=27.6 Hz), 133.5, 133.3, 133.2, 129.6, 127.7, 127.6, 59.8 (d, J=7.8 Hz), 58.8 (d, J=10.3 Hz), 45.2 (d, J=3.0 Hz), 44.6 (d, J=2.5 Hz), 29.9 (d, J=9.3 Hz), 29.4 (d, J=9.8 Hz), 24.2, 21.9 (d, J=3.0 Hz), 21.5 (d, J=4.0 Hz), 20.62, 20.60.
Compound 35: [α]D25−3.5° (c=0.62, CHCl3); 1H NMR 8.99 (d, 1H, J=32.0 Hz), 8.02 (d, 2H, J=8.0 Hz), 7.78 (d, 2H, J=8.0 Hz), 3.52-3.36 (m, 2H), 3.09 (t, 1H, J=12.0 Hz), 2.82 (t, 1H, J=12.0 Hz), 2.16-2.00 (m, 2H), 1.90-1.74 (m, 2H), 1.45-1.32 (m, 3H), 1.32-1.18 (m, 10H), 1.10 (d, 3H, J=6.5 Hz); 13C NMR 168.6 (d, J=7.0 Hz), 139.6 (d, J=27.6 Hz), 132.4 (2C), 130.0 (2C), 118.1, 115.6, 59.6 (d, J=8.0 Hz), 59.3 (d, J=8.8 Hz), 45.1 (d, J=2.5 Hz), 44.5 (d, J=3.5 Hz), 29.5 (d, J=5.8 Hz), 29.4 (d, J=5.5 Hz), 24.2, 21.8 (d, J=2.8 Hz), 21.0 (d, J=2.8 Hz), 20.6, 20.5.
Similar synthesis provided derivatives of 35 (formula (IV), 36-38):
Compound 36: 1H NMR 0.81-1.05 (m, 4H), 1.10-1.92 (m, 10H), 1.98-2.30 (m, 4H), 2.62-2.97 (m, 3H), 3.09 (d, 2H, J=6.6 Hz), 7.28-7.53 (m, 3H), 7.89 (d, 2H, J=8.1 Hz), 9.09 (d, 1H, 3JPH=32.4H).
Compound 37: 1H NMR 1.19-2.17 (m, 24H), 2.72-2.81 (m, 1H), 2.98-3.08 (m, 1H), 3.39-3.55 (m, 2H), 7.41-7.53 (m, 3H), 7.92 (d, 2H, J=8.4 Hz), 9.02 (d, 1H, 3JPH=33.3 Hz).
Compound 38: 1H NMR 0.92-2.07 (m, 25H), 2.89-3.10 (m, 7H), 7.41-7.58 (m, 3H), 7.93 (d, 2H, J=6.9 Hz), 9.06 (d, 1H, 3JPH=33.0 Hz).
This present invention is a continuation patent application that claims priority to PCT patent application number PCT/CN2008/071419, filed Jun. 24, 2008, which claims the benefit of U.S. Application 60/937,213, filed on Jun. 25, 2007, the entirety of which are herein incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60937213 | Jun 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CN2008/071419 | Jun 2008 | US |
| Child | 12653682 | US |
