Asymmetric synthesis of podophyllotoxin analogs

Abstract

Two analogs of podophyllotoxin, with the same absolute stereochemistry as the natural product, have been synthesized from the cycloadduct between a-hydroxy-a'-phenyl-o-quinodirnethane and the furnarate of S-methyl lactate. After initial attempts to produce the cycloadduct from photochemically generated a-hydroxy-a'-phenyl-o-quinodirnethane failed, a study of the thermal generation and reaction of a-hydroxy-o-quinodirnethane with the fumarate and acrylate of S-methyl lactate was made. A comparison was made of the diastereoselectivity of these cycloaddition reactions to those previously reported, in which the o-quinodirnethane was generated photochemically. The a-hydroxy-o-quinodirnethane was produced both by the known thermolysis of benzocyclobutenol and by therrnolysis of l-hydroxy-l,3-dihydrobenzo[c]thiophene-2,2-dioxide. The diastereorneric excess for the cycloaddition reactions was found to be greater than 95% with modest (ca. 55%) isolated yields of the major cycloadducts. Following these model studies, it was found that a-hydroxy-a'-phenyl-o-quinodirnethane produced thermally from l-hydroxy-3-phenyl-1,3-dihydrobenzo[c]thiophene-2,2-dioxide could be added to the furnarate of S-methyl lactate with high diastereoselectivity and good yield. The product of this reaction was converted to the podophyllotoxin analogs 7 and 17. Utilisant le cycloadduit obtenu par condensation de I'a-hydroxy-a'-phtnyl-o-quinodirnkthane et du fumarate du lactate de S-rnCthyle, on a synthCtisC deux analogues de la podophyllotoxine possCdant la m&rne stCrCochirnie que le produit naturel. I1 n'a pas Ct C possible de produire le cycloadduit B partir de l'a-hydroxy-a'-phenyl-o-quinodimkthane obtenu photochirniquernent; on a donc utilist une rnkthode thermique pour gCnCrer I'a-hydroxy-o-quinodirnCthane et pour rCaliser sa rCaction avec le furnarate du lactate de S-rnCthyle. On a effectuk une cornparaison de la diastkrCosClectivitC de ces rCactions de cycloaddition avec celles rapportCes antkrieurernent, alors que 1'0-quinodirnethane avait CtC gCnerC d'une f a~o n photochirnique. L'-a-hydroxy-oquinodirnkthane a CtC obtenu par la thermolyse connue du benzocyclobutCno1 ainsi que par la therrnolyse du 1-hydroxy-1,3-dihydrobenzo[c]thiophkne-2,2-dioxyde. On a trouvC que l'excks de diastCrCornkres eit plus grand que 95% alors que le rendernent en cycloadduits principaux isolCs n'est que de 55%. A la suite de ces Ctudes rnodkles, on a trouvC que I 'a-hydroxy-a'-phCnyl-o-quinodirnkthane obtenu therrniquernent B partir du l-hydroxy-3-phCnyl-l,3-dihydrobenzo[c]thiophkne-2,2-dioxyde peut &tre addition& au furnarate du lactate de S-rnkthyle avec une excellente diasterkosklectivitC et un excellent rendernent. Le produit de cette rkaction peut &tre transform6 dans les analogues 7 et 17 de la podophyllotoxine.Mots clis : o-quinodirnkthanes, asyrnetrique, Diels-Alder, lactate, podophyllotoxine, lignane.[Traduit par la revue] Introduction The synthesis of aryl tetralin ligans such as dimethyl isolariciresinol or podophyllotoxin requires the stereoselective a...

The mechanism of stereoselectivity in the cycloaddition reactions of α-hydroxy-ortho-quinodimethanes with the fumarate of methyl lactate and mandelate

“…For all cycloadducts H1 appear between 4.6 and 5.2 ppm (in CDCl,) and endo (cis-1,2) coupling constants, J,,, are 2-5 Hz, while exo (trans-1,2) coupling constants are 7-12 Hz (for previous examples see refs. [2][3][4][5][6]17). The results of the product study are shown in Table 1.…”

“…We recently published several accounts of the stereoselective and asymmetric Diels-Alder reactions of a-hydroxy-ortho-quinodimethanes (a-hydroxy-o-QDMs) with the fumarate of methyl lactate or methyl mandelate (1)(2)(3)(4)(5).…”

“…While these reactions are proving useful in asymmetric synthesis (1,3,6 ) , a satisfactory explanation of the stereoselectivity observed has not yet been proposed. Such an explanation would have to account for both the absolute stereoselectivity and the unusual relative stereoselectivity observed.…”

Podophyllotoxin and Antitumor Synthetic Aryltetralines. Toward a Biomimetic Preparation

“…(1) www.intechopen.com d6): A Diels-Alder cycloaddition between the fumarate of methyl ( S )-mandelate (46) and α-hydroxy-α'-aryl-o-quinodimethane (45) gives optically pure (-)-α-dimethylretrodendrin (47) having a 1,2-trans-2,3-trans stereochemistry, and three of its diastereomers (Scheme 13) (Charlton et al, 1990), (Charlton & Koh, 1992), (Maddaford & Charlton, 1993). …”

Stereoselectivity in the TiCl4-Catalyzed [4+2] Cycloaddition of Cyclopentadiene to (2R)-Bornane-10,2-sultam Derivatives of Fumaric Acid Monoesters

“…± We recently presented the complete p-facial selectivity observed in the TiCl 4 -catalyzed [4 2] cycloaddition of cyclopentadiene to N,N'-fumaroylbis[(2R )-bornane-10,2-sultam] ((À)-1a) [1] under the influence of diverse Lewis acids, as well as its application to diverse dienes [2]. Although these kinds of cycloadducts have been employed for the synthesis of several natural products [3] and analogues [4], their use is usually limited to symmetric or specific targets where the two carbonyl moieties can be distinguished by either iodolactonization [5] or selective steric approach of the reagent 3 ). For this reason, nonsymmetrical chiral fumarates were earlier developed [9] 4 ), where one carbonyl moiety may be chemoselectively transposed into a suitable functionality, either by selective saponification [9b], acidic hydrolysis [12], hydrogenation [13], or hydride reduction [14] 5 ).…”