Stereoselective total

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

The synthesis of an epothilone model system via an alternative C9-C10 disconnection was first examined by Danishefsky in 1997. However, extension of this C9-C10 strategy to a fully functionalized epothilone intermediate was not successful, demonstrating the limitations of RCM with the early catalysts A and B [116]. In 2002, Sinha and Sun disclosed the stereoselective total syntheses of epoA (238a) and epoB (238b) by the RCM of epoxy compounds 242 in the presence of catalyst C (Scheme 50) [117]. The reaction furnished an inconsequential mixture of isomers 243 (E/Z 1 1) in high yield. Subsequent selective hydrogenation of the newly formed double bond followed by deprotection led to epothilones A and B. 

In the seven-step stereoselective total synthesis of ptilocaulin 44 [21 ], a potent antileukemic and antimicrobial agent isolated [22] from marine sponges, the oxime 36 was treated with NaOCl providing the tricyclic isoxazoline 38 in 89% yield without isolation of the nitrile oxide intermediate 37 (Scheme 5) [23]. Isoxazoline 38 was obtained as a mixture of four diastereomers and their ratio was... 

Stork, G., Niu, D., Fujimoto, A. etal. (2001) The First Stereoselective Total Synthesis of Quinine. Journal of the American Chemical Society, 123, 3239-3242. 

This catalytic process has been used for the key step of a convergent synthesis of ( )-monomorine [298] and for a stereoselective total synthesis of (+)-preussin [299]. 

Oppolzer and Robbiani have reported highly stereoselective total syntheses of alkaloids such as chelidonine by an intramolecular o-quinodimethene/nitrostyrene-cycloaddition (Scheme S.7).34 (Benzocyclobutane is used as a source of quinodimethene). The high regio- and stereoselectivity in the intramolecular cycloaddition is remarkable a strong preference for transition state, exo-N02, over transition state, emfo-N02, is responsible for the stereoselectivity. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

A stereoselective total synthesis of erythronolide A, using two Mg/z-mediated cycloadditions of nitrile oxides has been described. Of broader significance, the strategy not only facilitates the synthesis of specific polyketide targets (i.e., natural products) but also opens up new possibilities for the preparation of nonnatural analogs (482). 

Kibayashi and co-workers103 implemented the palladium-catalyzed cycloisomerization reaction in a stereoselective total synthesis of enantiomerically pure (+)-streptazolin. The cycloisomerization of enyne 172 to provide diene 173 was remarkably selective when performed in the presence of A,Ar -bis(benzylidene)ethylenediamine (BBEDA) as a ligand and water as a proton source (Scheme 44). 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

A stereoselective total synthesis of ( )-hirsutine has been developed by Brown et al. (179). Catalytic hydrogenation of hydroxycyclopentenone 327, prepared previously (180), afforded a mixture of isomeric diols 328, which were quantitatively cleaved by sodium periodate to supply 329. Reductive amination of 329 with tryptamine resulted in tetrahydropyridine 330, which upon treatment with aqueous methanol in the presence of hydrochloric acid gave indolo-[2,3-a]quinolizine 321 with pseudo stereochemistry. Conversion of 321 to ( )-hirsutine was accomplished in a similar manner by Wenkert et al. (161) via selective reduction with diisobutylaluminum hydride and methylation with methanol (179). 

Beracierta AP, Whiting DA (1978) Stereoselective total syntheses of the ( )-di-0-methyl ethers of agatharesinol, sequirin-A, and hinokiresinol, and of ( )-tri-0-methylsequrin-E, characteristic norlignans of Coniferae. J Chem Soc Perkin Trans 1 1257-1263 Birch AJ, Liepa AJ (1978) Biosynthesis. In Rao CBS (ed) Chemistry of lignans. Andhra University Press, Andhra Pradesh, pp 307-327... 

Stork Q Niu D, Fujimoto A, Koft ER, Balkovec JM, Tata JR, Dake GR. (2001) The first stereoselective total synthesis of quinine. J Amer Chem Soc 123 3239-3242. 

Yadav JS, Satheesh R, Babn, Sabitha G. (2003) Stereoselective total synthesis of (-i-)-artemisinin. Tetrahedron Lett 44 387-389. 

Finally, saponification of 26 followed by acid treatment (Dowex resin) afforded racemic NeuSAc, whose NMR spectrum (490 MHz) and chromatographic properties were identical with those of authentic NeuSAc. An efficient and stereoselective total synthesis of Neu5Ac had been accomplished as shown in Figure 6. 

Ito s regio- and stereoselective total synthesis relied on dicyclopentadiene as starting material The derived ketone 755 was cleaved to provide 756 which was crafted into 757 (Scheme LXXXV). FoUowing reduction of the carbomethoxy group, conversion to iodo ketone 758 was realked with trimethylsilyl iodide. Reaction of 758 with DBU resulted chiefly in conversion to 752 which was transformed into silphinene essentially as described above. 

A stereoselective total synthesis of the antifungal mould metabolite ( )-LL-Z1271a (165) from the readily available Wieland-Miescher diketone, via the keto-lactone (164), has been described. A synthesis of grindelic acid (167) from the unsaturated 7-toluene-p-sulphonate (166) utilized an intramolecular solvolysis of the toluene-p-sulphonate to construct the 9—13 ether bridge. 

An alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been reported. In a stereoselective total synthesis of ( )-callitrisic acid and ( )-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). 

Hudlicky et al. (65) reported a formal stereoselective total synthesis of the oxygenated pyrrolizidine alkaloids platynecine (336), dihydroxyheliotridane (337), hastanecine (341), and tumeforcidine (342), involving an intramolecular azide-diene cycloadditions (Scheme 9.65). Intramolecular 1,3-dipolar cycloaddition of... 

Preference will be given to those methods that have proven to be applicable to the stereoselective total synthesis of demanding target molecules, such as naturally occurring biaryls. Of special interest are those methods that allow the optional synthesis of either of the two atropisomers in question. 

A stereoselective total synthesis of dendrobatide toxin 251 D was developed by Overman et al.237) involving an epoxidation of the (S)-proline derivative (237) to furnish the oxirane (238) as major product. In their approach towards the total synthesis of the same natural product Thomas et al.238) investigated the stereoselectivity of the epoxide formation from (S)-5-acetylpyrrolidin-2-one and dimethyloxosulfonium methylide. A diastereoselectivity of d.s. 50-60% was achieved 238. ... 

Monkovic, I., Bachand, C., Wong, H. A stereoselective total synthesis of 14-hydroxymorphinans. Grewe approach, J. Am. Chem. Soc. 1978, 100, 4609-46. 

S. Jeganaihan and P. Vogel, Highly stereoselective total syntheses of octoses and derivatives, J. Org. Chem. 56 1133 (1991) P. Vogel, D. Fattori.F. Gasparini, and C. Le Drian, Optically pure 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives ( naked sugars ) as new chirons, Synlett. p. 173 (1990). 

Other approaches to the stereoselective total synthesis of nonaromatic steroids include the carbocationic, biomimetic cyclizntion reactions. Generally, these cyclizations begin with the synthesis of an appropriately functionalized cyclopentenol. Acid-catalyzed cyclization forms the B-C-D rings of the steroid nucleus with the natural relative stereochemistry in a single step. 

Stereoselective total syntheses of (-)-deoxoprosopinine (20) and (-)-deoxoprosophylline (21), derived respectively from the natural bases prosopinine and prosophylline, have been described the route adopted should be applicable to other related piperidine bases.20 Prosafrinine (22), a piperidine alkaloid of Prosopis africana, has been synthesized stereoselectively, along with pseudocar-pamic acid (23), as racemic varieties.21 Additional stereoselective syntheses of ( )-carpamic and ( )-azimic acids have been described.22... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

Chakraborty, T. K. Das, S. Synthesis of chiral 1,3-diols by radical-mediated regioselective opening of 2,3-epoxy alcohols using Cp2TiCl2. Tetrahedron Lett. 2002, 43, 2313-2315. Nakajima, N. Tanaka, T. Hamada, T. Oikawa, Y. Yonemitsu, O. Highly stereoselective total synthesis of pikronolide, the aglycon of the... 

Avery, M. A. Chong, W. K. M. Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L. /. Am. Chem. Soc. 1992,... 

The key step in the stereoselective total synthesis of erythronolide A is the Mg(II)-mediated 1,3-dipolar cycloaddition of the functionalized nitrile oxide (45) with the allylic alcohol (46) to produce the isoxazoline (47) as a single diastereomer in high... 

Bach, T. (2002) Stereoselective total synthesis of the tricyclic sesquiterpene (i)-kelsoene by an intramolecular Cu(I)-catalyzed [2 + 2]-photocycloaddition reaction. Synlett, 1305-1307. 

Indolines and indoles were prepared by a direct electrochemical reduction of arenediazonium salts. As a result, radical intermediates were generated from which 3,4-disubstituted tetrahydrofuran skeleta were constructed <02OL2735>. A short and stereoselective total synthesis of furano lignans was realized by radical cyclization of epoxides using a transition-metal radical source <02JOC3242>. Other preparations of tetrahydrofurans using radical cyclization include the synthesis of novel amino acids L-bis-... 

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