Williams’ total synthesis

A striking application of Seebach s and Prater s approach for the installation of a quaternary stereogenic center can be found in Williams total synthesis of the antitumor antibiotic lankacidin C (62, Scheme 3.9) [59]. Treatment of 60 with excess NaHMDS and prenyl bromide gave 61 in 80% yield... 

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxy-neodolabelline (70) was accomplished by D. R. Williams et al. [58]. The trans-disubstituted dihydropyran moiety in key intermediate 69 was efficiently prepared from mixed acetal 66 by RCM with second-generation catalyst C and subsequent Lewis acid-catalyzed allylation of ethyl glycosides 67 with allylsi-lane 68 (Scheme 12) [59]. 

Looking at Schemes 4 and 5, it is obvious that Woodward-Doering s synthetic route suffered from the lack of stereocontrol, which led to the production of their precursors of homomeroquinene target compound as a mixture of stereoisomers. The fact that the yield of such a transformation was not clearly determined, in addition to the anticipated difficult separation of the four isomers obtained at the end of the reaction (cf. Rabe-Kindler reaction), rendered this reaction commercially unpractical. Moreover, it is well accepted that Woodward and Doering never physically produced any quinine in their lab, and the success of their method is based on the assumption that Rabe and Kindler partial synthesis was a fact. This would be the center of the controversy when Stork later characterized what he called the quasi-universal impression that Woodward and Doering achieved the total synthesis of quinine as a widely believed myth . The whole story is very juicy and interested readers should refer to the amazing review published in Angewandte Chemie by Seeman in 2007. Nevertheless, in 2008, Smith and Williams successfully revisited the Rabe-Kindler conversion... 

Fig. 13 Overview of Williams convergent total synthesis of (+)-4,5-deoxyneodolabelline (50)(2003)...

The total synthesis of racemic neodolabellenol (rac-45) was reported by the Williams group in 1995 as a short communication [59]. To gain a complete overview, it is advisable to consider a publication from 1993 in which Williams described the synthesis of an advanced precursor as well as the aforementioned full publication from 2003 [45, 60]. As summarized in Scheme 19, the synthesis of the bicyclic neodolabellenol (45) utilized an in-... 

The apparently latest total synthesis of a dolastane diterpene was published by Williams and coworkers in 1993 as a short communication (Fig. 16) [91]. (-)-Clavulara-l(15),17-dien-3,4-diol (129) was synthesized using a strategy that relied on the availability of the enantiomerically pure building block 162 from (+)-9,10-dibromocamphor (163) (Fig. 16). Cornerstones of the synthesis are a macrocyclization that afforded the 11-membered (A+B)C-ring (160) and a transannular cyclization that converted a bicyclic into a tricyclic ring system. Two of the seven chirality centres in the synthetic clavu-... 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

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. 

Stocking, E.M. Sanz-Cervera, J.F. Williams, R.M. (2000) Total synthesis of VM55599. Utilization of an intramolecular Diels-Alder cycloaddition of potential biogenetic relevance. J. Am. Chan. Soc., 122, 1675-83. 

As part of on going efforts of Williams and his coworkers [46] to elucidate the biosynthesis of the core bicyclo[2.2.2] ring system of the related alkaloids the brevianamides [51], they have applied methodology originally developed for the stereocontrolled total synthesis of (-)-brevianamide B [52] to complete the first stereocontrolled total synthesis of (+)-PHB. 

The biological activity and the interesting structure stimulated efforts towards its total synthesis. Evans and Calter reported the first synthesis by an efficient aldol method.4 Toshima and co-workers also succeeded in the total synthesis of bafilomycin Aj.5 This chapter is based on the enantioselective total synthesis by William R. Roush and co-workers, which was published in 1999.6... 

Scheme 2. Total synthesis of spirotryprostatin B (2) by Sebahar and Williams (2000).

The transmetallation process was extended to the preparation of vinylboranes709,710, and the superior reactivity of organotins over organosilicons was elegantly demonstrated by Williams and coworkers for the preparation of the optically active allylborane 24 from the corresponding allylic stannane in the total synthesis of (—)-Hennoxazole A711 (equation 54). 

Comins, D.L. and Williams, A.L. (2001) Model studies toward the total synthesis of the lycopodium alkaloid spirolucidine. 

As many advances in indole side-chain modification are bom out of focused efforts in total synthesis, a vast amount of the literature has been devoted toward descriptions of tactics for controlled access to the polycyclic lattices that adorn the indole core. To that end, Williams... 

Lee CH, Westling M, Livinghouse T, Williams AC (1992) Acybiitrilium Ion Initiated Heteroannulations in Alkaloid Synthesis. An Efficient, Stereocontrolled, Total Synthesis of Orchidaceae Alkaloid ( )-Dendrobine. J Am Chem Soc 114 4089... 

This chapter is based on the enantioselective total synthesis by William R. Roush and co-workers, which was published in 1999. ... 

Butlerow MA (1861) Ann Chem 120 295 Jones JKN, Szarek WA (1973) In ApSimon J (ed) Total Synthesis of Natural Products. Wiley-Interscience, New York, p 1 Zamojski A, Grynkiewicz G (1984) In ApSimon J (ed) Total Synthesis of Natural Products. Wiley-Interscience, New York, p 141 McGarvey GJ, Kimura M, Oh T, Williams JM (1984) J Carbohydr Chem 3 125 Schmidt RR (1987) Pure Appl Chem 59 415 Zamojski A (1997) In Hanessian S (ed) Prep. Carbohydr. Chem. Dekker, New York, p 615 Kirschning A, Jesberger M, Schoning K-U (2001) Synthesis 507... 

D.R. Williams and co-workers accomplished the first total synthesis of marine dolabellane diterpene (+)-4,5-deoxyneodolabelline. The Type I carbon-Ferrier reaction was utilized to assemble the key frans-2,6-disubstituted dihydropyran with complete stereoselectivity (a-anomer). The macrocyclization was carried out with a vanadium-based pinacoi coupiing. 

During the late stages of the asymmetric total synthesis of capreomycidine IB it was necessary to transform an asparagine residue into a diaminopropanoic acid residue." R.M. Williams et al. employed a chemoselective Hofmann rearrangement, thereby avoiding protection and deprotection steps that would have been necessary had the diaminopropanoic acid been introduced directly. The complex pentapeptide was treated with FIFA and pyridine in the presence of water to afford the primary amine in high yield. 

During the final stages of the asymmetric total synthesis of antimitotic agents (+)- and (-)-spirotryprostatin B, the C8-C9 double bond had to be installed, and at the same time the carboxylic acid moiety removed from C8. R.M. Williams et al. found that the Kochi- and Suarez modified Hunsdiecker reaction using LTA or PIDA failed and eventually the Barton modification proved to be the only way to achieve this goal. After the introduction of the bromine substituent at C8, the C8-C9 double bond was formed by exposing the compound to sodium methoxide in methanol. This step not only accomplished the expected elimination but also epimerized the C12 position to afford the desired natural product as a 2 1 mixture of diastereomers at C12. The two diastereomers were easily separated by column chromatography. 

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

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