Asymmetric total synthesis

These days organic chemists are no longer contentmerely to synthesise target molecules in racemic form or as mixtures of stereoisomers. Instead it has become de rigeur to prepare compounds in enantio-merically pure or at least enantiomerically enriched form. This movement, which has been given additional impetus by the statutory requirement in some countries for new pharmaceutical products to be licensed as pure stereoisomers, has led to a veritable explosion of activity in the area of asymmetric synthesis. Because of this, only a representative selection of the hundreds of asymmetric total syntheses can be described in this chapter. 

---

The asymmetric total synthesis of (-)-steganone (67) was achieved through the asymmetric Mg-mediated coupling of bromide 64 and oxazoline 65, which provided a... 

Studies on asymmetric total synthesis of antitumor antibiotic, fredericamycin A 98YGK963. 

Asymmetric total synthesis of antitumor styryl lactones and related natural compounds 97H(45)367. 

Scheme 8.22 Intramolecular Sn2 reaction in the catalytic asymmetric total synthesis of quinine.

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

Mukaiyama, T., Shiina, J., Jwadare, H. et al. (1999) Asymmetric Total Synthesis of Taxol. Chemistry A European Journal, 5, 121-161. 

B. Potassium allyl- and crotyltrifluoroborates undergo addition to aldehydes in biphasic media as well as water to provide homoallylic alcohol in high yields (>94%) and excellent diastereoselectivity (dr >98 2). The presence of a phase-transfer catalyst (e.g., B114NI) significantly accelerates the rate of reaction, whereas adding fluoride ion retards the reaction (Eq. 8.70).165 The method was applied to the asymmetric total synthesis of the antiobesity agent tetrahydrolipstatin (orlistat).166... 

This procedure was used for the asymmetric total synthesis of the steroid (+)-equilenin (7-7) [3]. Cyclopropylidene derivates 7-4 could be converted into the cyclobutanones 7-5 in good yields by applying an asymmetric epoxidation using the chiral (salen)Mnm complex 7-6 (Scheme 7.2) [4]. It is of interest that the demethoxy-lated substrate 7-4b led to 7-5b with a very high enantiomeric excess of 93%, whereas 7-4a gave 7-5a with only 78% ee. 

In a very new example, the Kita group has presented a neat combination of a lipase-catalyzed kinetic resolution of a-hydroxynitrones and a 1,3-dipolar cycloaddition, which was successfully applied in the asymmetric total synthesis of (-)-ros-marinecine [25]. 

In the asymmetric total synthesis of the marine natural product, methyl sarcoate, the key step for the introduction of the chirality, was achieved by using an asymmetric Michael addition. Asymmetric addition of /-PrMgCl to aminal ester 93 in the presence of a catalytic amount of Cul, followed by acidic hydrolysis of the aminal function, afforded the chiral aldehyde 94 in 60% yield (Equation 10) <2005TL1263>. 

The Darvon alcohol-LAH complex was used in the reduction of the acetylenic ketone (93) in one step of an asymmetric total synthesis of lla-hydroxypro-gesterone (97), a key intermediate in the production of hydrocortisone acetate... 

Abstract Asymmetric total synthesis of marine natural product, nakadomarin A, is described and as further extension, a novel synthesis of quinoline and indole ring system by ring closing metathesis is also described. 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles,... 

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

Ohyabu N, Nishikawa T, Isobe M, First asymmetric total synthesis of tetrodotoxin,/Aw Chem Soc 125 8798—8805, 2003. 

C-H activation at a primary benzylic site was the key step in very short syntheses of lig-nans 206 and 207 (Scheme 14.27) [138]. Even though both the substrate 203 and the vinyl-diazoacetate 204 contain very electron-rich aromatic rings, C-H activation to form 205 (43% yield and 91% ee) is still possible because the aromatic rings are sterically protected from electrophilic aromatic substitution by the carbenoid. Reduction of the ester in (S)-205 followed by global deprotection of the silyl ethers completes a highly efficient three-step asymmetric total synthesis of (-i-)-imperanene 206. Treatment of (R)-205 in a more elaborate synthetic sequence of a cascade Prins reaction/electrophilic substitution/lacto-nization results in the total synthesis of a related lignan, (-)-a-conidendrin 207. 

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Toro, A. Nowak, P. Deslongchamps, P. (2000) Transannular Diels-Alder aitiy into stemodanes first asymmetric total synthesis of (+)-maritimol. J. Am. Chem. Soc., 122,4526-7. 

---