The synthesis of the racemic β-lactams 5
is shown in . The 4-phenylazetidin-2-one 3a
and the 4-tert
were prepared according to reported procedures.8
The acetyl group on 3
was removed with lithium hydroxide in acetone (for 3a
) or potassium carbonate in methanol (for 3b
), followed by protection with a trialkylsilyl chloride to furnish 3-trialkylsilyloxy-β-lactams 4a–e
in high to excellent yields.19,20
The 4-methoxyphenyl moiety (PMP) of 4
was removed oxidatively with ceric ammonium nitrate (CAN),21
and then treated with tert
-butyl dicarbonate to afford racemic 3-trialkylsilyloxy-4-phenylazetidin-2-ones 5a–c
was prepared from 5d
by removal of the tert
-butyldimethylsilyl protecting group with HF-pyridine, followed by triethylsilyl protection in 77% yield.
Scheme 1 (a) i. LiOH in acetone or K2CO3 in MeOH; ii. R′SiCl, imidazole/DMAP, CH2Cl2, rt; (b) i. Ce(NH4)2(NO3)6, aq CH3CN, −20 °C; ii. (Boc)2O, diisopropylethylamine, DMAP, CH2Cl2, rt; (c) i. HF-Py in Py, 0 °C to rt; ii. TESCl, (more ...)
First, we investigated the kinetic resolution between racemic 4-phenyl-2-azetidinone 5a
-triethylsilylbaccatin III (7
under several different reaction conditions (). The resulting reaction products were subsequently treated with hydrogen fluoride in pyridine to furnish 10-acetyldocetaxel (8
, ). The isomeric ratios of 8
were determined by HPLC analysis ().
Results from reactions of β-lactam 5a with 7 to furnish 8 under varied reaction conditions ().
The results for the kinetic resolution are shown in . It was found that the diastereoselectivity of the reaction decreased slightly with an increase in reaction temperature (see entries 1, 2, and 3). Although the stereoselectivity was not significantly influenced, the yield dramatically decreased when the amount of 5a
was reduced from 4 to 2 equivalents (entries 2 and 4). It has been hypothesized that chelation between the C13 lithium alkoxide of the baccatin III derivative and the carbonyl group of the β-lactam is important for the high diastereoselectivity.16
We therefore replaced LiHMDS with NaHMDS (entry 5) to study the effect of the presumably less chelating C13 sodium alkoxide on diastereoselectivity. Under these conditions, we noted a marked decrease in stereoselectivity and yield confirming the hypothesis (see entries 2 and 5) that chelation is important for high diastereoselectivity.
We next investigated the effects of different substituents at the β-lactam skeleton on the kinetic resolution (). Since it had been previously reported that the 1-tert
-butoxycarbonyl group was important to generate high diastereoselectivity in the kinetic resolution, we retained this group in our experiments.15,16
We first probed the effects of different 3-hydroxylsilyl protecting groups. Reactions of β-lactams 5a–e
were carried out using the conditions of entry 1, in . The results are shown in . As expected, it was found that the large triisopropylsilyl protecting group (entry 1) provided higher stereoselectivity than the smaller triethylsilyl group (entry 3). However, the tert
-butyldimethylsilyl group proved to be optimal (entry 2), providing a 41:1 ratio of diastereoisomers. The results imply that the size of the C3-hydroxyl protecting group influences diastereoselectivity and that the tert
-butyldimethylsilyl group, which is more sterically demanding than the triethylsilyl group, but smaller than the triisopropylsily protecting group, was optimal in this sequence of reactions.
Results of reaction between β-lactams 5a–e, 6 and 7-O-triethylsilylbaccatin III (7, ) for the formation of 8 (entries 1–3) and 9 (entries 4–6).
We also examined the effects of different substituents at the C4 position towards resolution. As is illustrated in , we observed increased stereoselectivity for the reaction of 4-tert
-butyl β-lactam 5d
(entry 5) with 7
compared to the reaction of 4-phenyl β-lactam 5a
(entry 2), which indicates that the size of the C4 substituent also influences diastereoselectivity. To evaluate whether the C3-hydroxy protecting groups have an effect for the 4-tert
-butyl β-lactam derivatives, we replaced the tert-
butyldimethylsilyl with the larger triisopropylsilyl group (entry 4) and the smaller triethylsilyl group (entry 6). Again, it was found that the triisopropylsilyl group provided higher diastereoselectivity than the triethylsilyl group, while the tert
-butyldimethylsilyl group afforded the best resolution. These results suggest that at least one sterically demanding substituent is required at either C3 or C4 for satisfactory selectivity. This is supported by Ojima’s observation that 3-triisopropylsilyloxy-4-trifluoromethyl, 3-triisopropylsilyloxy-4-isobutyl and 3-triisopropylsilyloxy-4-isobutenyl β-lactams gave high yields and stereoselectivities for the kinetic resolution with modified baccatins.19
To unambiguously prove the identity of the major product, we synthesized 10-acetyldocetaxel (8
) as shown in . Starting from 2′-O-tert
), prepared from commercially available docetaxel, triethylsilyl protection of the C7-hydroxy group followed by acylation of the C10-hydroxy group with acetic anhydride afforded intermediate 11
, which was converted to 10-acetyldocetxel (8
) by treatment with hydrogen fluoride in pyridine. Spectral data and HPLC retention times were identical for the products obtained by both methods, confirming that the major diastereomer obtained in the kinetic resolution had the same (2′R
) configuration as docetaxel. 10-Acetylbutitaxel (9
) has been synthesized previously and matched the reported spectroscopic data.23
(a) i. TESCl, imidazole, DMAP, CH2Cl2, rt; ii. acetic anhydride, DMAP, pyridine, 0 °C to rt (96 %); (b) HF-Py in pyridine, 0 °C to rt (90 %).
In conclusion, a systematic study of the kinetic resolution of racemic 4-phenyl-and 4-tert-butyl-β-lactams with 7-O-triethylsilylbaccatin III was carried out. It was found that the size of the silyl protecting groups at the 3-hydroxy moiety of β-lactams had an important influence on the diastereoselectivity of the resolution. The tert-butyldimethylsilyl protecting group was found to be superior to the smaller triethylsilyl group and the larger triisopropylsilyl group in the reactions investigated. The size of the 4-substituents at the β-lactams also influenced diastereoselectivity. The sterically more demanding 4-tert-butyl β-lactams gave rise to better kinetic resolution than the corresponding 4-phenyl β-lactams. Therefore, it can be concluded that high stereoselectivity can be obtained either by using sterically demanding C3-hydroxy protecting groups or C4 substituents.