Enantioselective total synthesis

A third variation of this strategy has been appHed to an enantioselective total synthesis of cortisone. From an appropriately functionalized, scalemic hydrindan that possessed an 11-oxo-group and a masked corticoid side-chain, (+)-cortisol was produced in an 11-step total synthesis (213). 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoidpreclavulone-A via 8-( f )-hydroperoxy-5,ll,14( Z), QfEj-eicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

Kusama, H., Hara, R., Kawahara, S. et al. (2000) Enantioselective Total Synthesis of (—)-Taxol. Journalof the American Chemical Society, 122, 3811-3820. 

For clarification, individual transformations of independent functionalities in one molecule - also forming several bonds under the same reaction conditions -are not classified as domino reactions. The enantioselective total synthesis of (-)-chlorothricolide 0-4, as performed by Roush and coworkers [8], is a good example of tandem and domino processes (Scheme 0.1). I n the reaction of the acyclic substrate 0-1 in the presence of the chiral dienophile 0-2, intra- and intermolecular Diels-Alder reactions take place to give 0-3 as the main product. Unfortunately, the two reaction sites are independent from each other and the transformation cannot therefore be classified as a domino process. Nonetheless, it is a beautiful tandem reaction that allows the establishment of seven asymmetric centers in a single operation. 

The Shibasaki group [27] developed an enantioselective total synthesis of (+)-xes-toquinone (6/1-38) using an asymmetric double Heck reaction with BINAP as chi-... 

Martin and coworkers [93] described a highly efficient enantioselective total synthesis ofmanzamine A (6/1-177) with a concise domino Stille/Diels-Alder reaction to construct the tricyclic ABC ring core in 6/1-177 as the key step. Reaction of 6/1-178 with vinyl tributylstannane in the presence of (Ph3P)4Pd afforded the triene... 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Enantioselective total synthesis of antifungal agent Sch-38516 is reported. Stereocontrolled carbohydrate synthesis is based on the 1,3-dipolar cycloaddition of chiral nitrone to vinylene carbonate, as shown in Eq. 8.53.79... 

In the course of their investigation of the enantioselective total synthesis of avarainvillamide and the stephacidins, the Baran group has developed a method for the dehydrogenation of tryptophan as well as a one-step tryptophan synthesis from pyroglutamate and substituted aniline precursors <06JACS8678>. 

The first enantioselective total synthesis of the sesquiterpenoid heliannuol D 56 has been reported by Shishido and co-workers. The key step was a base-mediated (NaOH) intramolecular cyclisation of the phenolic epoxide mixture 55 (R1 = MOM, R2 = H and R1 = H, R2 = MOM). Heliannuol D (and the eight-membered congener, heliannuol A) is an allelopathic agent isolated from cultivated sunflowers (Helianthus annuus L.SH-222) <00JCS(P 1)1807>. 

Inomata100 utilized a tandem retro-Diels-Alder-ene reaction for an enantioselective total synthesis of (+)-methyl jasmonate (Scheme 41). The TMS group on the alkene was essential to the efficiency of the reaction, by producing a higher energy level of the HOMO for the ene reaction. 

Application to the First Enantioselective Total Synthesis of the Antihypertensive Agent (S,ff,/ ,/ )-Nebivolol... 

Scheme 17. The tandem Zr-catalyzed kinetic resolution and Mo-catalyzed conversion of styrenyl ethers to chromenes is used in the first convergent and enantioselective total synthesis of the antihypertensive agent (S,R,R,R) nebivolol...

Recently, an enantioselective total synthesis of ( )-18,19-dihydroantirhine has been reported by Kametani s group (140). They started from the chiral cyclopentanone derivative 211, obtained from the previously prepared (/ )-1,2-isopropylideneglyceraldehyde (141). Utilizing a number of reaction steps, 211 was transformed to 215 with the desired stereochemistry at the future C-15 and... 

Takano s group reported the first enantioselective total synthesis of (—)-anti-rhine as well (146). Chiral product 235 was prepared via a number of stereoselective reactions. Reductive condensation of 235 with tryptamine, using sodium cyanoborohydride at pH 6, supplied lactam 236, which was reduced by di-isobutylalminum hydride to hemiacetal 237. The latter could be cyclized to (-)-antirhine by simple acid treatment (146). 

More recently, Szdntay and co-workers (232) succeeded in performing the enantioselective total synthesis of both natural and unnatural antipodes of yohimbine and -yohimbine. Utilizing second-order asymmetric induction, either the levorotatory or dextrorotatory antipode of key tetracyclic intermediate 400 could be obtained by the use of (—)- or (+)-tartaric acid, respectively. 

After completing the enantioselective total synthesis of (+)-18,19-dihydro-antirhine [(+)-14](i40), Kametani et al. reported (394) the synthesis of (—)-antirhine [(-)-ll] by using (3S)-[3-hydroxy-( )-prop-l-enyl]cyclopentanone as a chiral synthon. 

Scheme 8. Cu-Catalyzed asymmetric cyclopropanation used by Overman in the enantioselective total synthesis of scopadulcic acid A (1999).

Scheme 10. Cu-catalyzed asymmetric aldol addition used in the enantioselective total synthesis of bryostatin 2 by Evans (1998).

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

D. Sawada, M. Shibasaki Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses , Angew. Chem, Int. Ed Engl 2000,39,209-213. 

C. W. Johannes, M. S. Visser, G. S. Weatherhead, A H. Hoveyda Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed Chromene Formation in Synthesis. Enantioselective Total Synthesis of the Antihypertensive Agent (SJUUD-Nebivolol J. Am Chem Soc 1998, 120, 8340-8347. For development of the enantioselective methodology, see M. S. Visser, J. P. A. Harrity, A. H. Hoveyda Zirconium-Catalyzed Kinetic Resolution of Cyclic Allylic Ethers. An Enantioselective Route to Unsaturated Medium Ring Systems , J. Am Chem Soc 1996,118, 3779-3780. 

Jin and Weinreb reported the enantioselective total synthesis of 5,11-methano-morphanthridine Amaryllidaceae alkaloids via ethynylation of a chiral aldehyde followed by allenylsilane cyclization (Scheme 4.6) [10]. Addition of ethynylmagnesium bromide to 27 produced a 2 1 mixture of (S)- and (R)-propargyl alcohols 28. Both of these isomers were separately converted into the desired same acetate 28 by acetylation or Mitsunobu inversion reaction. After the reaction of 28 with a silyl cuprate, the resulting allene 29 was then converted into (-)-coccinine 31 via an allenylsilane cyclization. 

Scheme 4.6 Enantioselective total synthesis of the 5,11-methano-morphanthridine alkaloid (-)-coccinine via chiral allenylsilane 29.

Anionic oxy-Cope rearrangement was also employed for the enantioselective total synthesis of compounds related to marine metabolites (equation 230)305 307, as well as for the preparation of diterpenoide vinigrol (equation 231)308 and cerorubenic acid-in... 

The enantioselective total synthesis of optically pure (+)-luciduline... 

In 1978 Oppolzer and Petrzilka reported the first enantioselective total synthesis of natural (+)-luciduline from (i )-5-methyl-2-cyclohexenone (31) by a sequence of seven steps in 33% overall yield [9]. 

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