The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part III: 2012–2017

One of the more powerful routes to enantiomerically-pure carbocycles is the desymmetrization of a prochiral ring. Karl Anker Jørgensen of Aarhus University has found (J. Am. Chem. Soc. 2007, 129, 441) that many cyclic β-ketoesters, including the vinylogous carbonate 1, can be homologated with 2 to the corresponding alkyne 3, in high ee. Sanzhong Luo of the Chinese Academy of Sciences, Beijing, and Jin-Pei Cheng, of the Chinese Academy of Sciences and Nankai University, have shown (J. Org. Chem. 2007, 72, 9350) that the catalyst 6 mediated the selective addition of 4-substituted cyclohexanones such as 4 to the nitroalkene 5, establishing three new stereogenic centers. Organocatalysts, alone or complexed with activating metals, have also been used to effect enantioselective ring construction. E. J. Corey of Harvard University has established (J. Am. Chem. Soc. 2007, 129, 12686) that the proline-derived complex 10 will mediate the 2 + 2 addition of a cyclic enol ether with an acrylate to give the cyclobutane 11. Further elaboration led to the cyclohexenone 12. Armando Córdova of Stockholm University has described (Tetrahedron Lett. 2007, 48, 5835) a novel route to cyclopentanones such as 16, via tandem conjugate addition/intramolecular alkylation. Professor Jørgensen has reported (Angew. Chem. Int. Ed . 2007, 46 , 9202) the double addition of 18 to the unsaturated aldehyde 17 to give 20. Earlier last year, Yujiro Hayashi of the Tokyo University of Science had shown (Angew. Chem. Int. Ed. 2007, 46, 4922) that the double addition of the inexpensive 21 to 5 could, depending on conditions, be directed selectively to 22, 23, or 24. As illustrated by the conversion of 8 to 13, organocatalysis can be used to effect the enantioselective construction of polycarbocyclic products. The initial ring prepared in enantiomerically-pure form by organocatalysis can also set the chirality of a polycyclic system. Professor Corey has reported (J. Am. Chem. Soc. 2007, 129, 10346) that Itsuno-Corey reduction of the prochiral diketone 25 led to the ketone 27. Cyclization followed by oxidation and reduction then delivered estrone methyl ether 28.

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The Sato/Chida Synthesis of Paclitaxel (Taxol®)

Organic Synthesis ◽

10.1093/oso/9780190646165.003.0104 ◽

2017 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Organic Synthesis ◽

Conjugate Addition ◽

Cyclic Carbonate ◽

Membered Ring ◽

Standard Protocol ◽

Protecting Group ◽

Enantiomerically Pure ◽

Facial Selectivity ◽

Starting Point ◽

Nabh4 Reduction

Paclitaxel (Taxol®) 3 is widely used in the clinical treatment of a variety of cancers. Takaaki Sato and Noritaka Chida of Keio University envisioned (Org. Lett. 2015, 17, 2570, 2574) establishing the central eight-membered ring of 3 by the SmI2-mediated cyclization of 1 to 2. The starting point for the synthesis was the enantiomerically-pure enone 5, prepared from the carbohydrate precursor 4. Conjugate addition to 5 proceeded anti to the benzyloxy substituent to give, after trapping with formaldehyde and protection, the ketone 6. Reduction and protection followed by hydroboration led to 7, that was, after protection and deprotection, oxidized to 8. The second ring of 3 was added in the form of the alkenyl lithium derivative 9, prepared from the trisylhydrazone of the corresponding ketone. Hydroxyl-directed epoxidation of 10 proceeded with high facial selectivity, leading, after reduction and protection, to the cyclic carbonate 11. Allylic oxidation converted the alkene into the enone, while at the same time oxidizing the benzyl protecting group to the benzoate, to give 12. Reduction of the ketone 12 led to a mixture of diastereomers. In practice, only one of the diastereomers of 1 cyclized cleanly to 2, as illustrated, so the undesired diastereomer from the NaBH4 reduction was oxidized back to the enone for recycling. For convenience, only one of the diastereomers of 2 was carried forward. To establish the tetrasubstituted alkene of 3, the alkene of 2 was converted to the cis diol and on to the bis xanthate 13. Warming to 50°C led to the desired tetrasubstituted alkene, sparing the oxygenation that is eventually required for 3. For convenience, to intercept 16, the intermediate in the Takahashi total synthesis, both xanthates were eliminated to give 14. Hydrogenation removed the disubstituted alkene, and also deprotected the benzyl ether. Oxidation followed by Peterson alkene formation led to 15, that was carried on to the Takahashi intermediate 16 using the now-standard protocol for oxetane construction. It is a measure of the strength of the science of organic synthesis that Masahisa Nakada of Waseda University also reported (Chem. Eur. J. 2015, 21, 355) an elegant synthesis of 3 (not illustrated).

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