Quassin synthesis

The Dlels-Alder reaction is a favourite way of introducing many chiral centres at once, and we saw examples of this in Chapter 36. Compound (31) was used in a synthesis of quassin." It has seven adjacent chiral centres. How many can bo introduced in one step by a Diels-Alder reaction and what should the starting materials be ... 

A Lewis-acid-catalysed Diels-Alder reaction of the diene (70) and the quinone (71) is the key step in the synthesis of compound (72) with the appropriate stereochemistry and functionality for conversion into quassin.53 The androstane derivative (73) has been transformed into (74) in model experiments towards the synthesis of quassin.54... 

A synthesis of ( )-quassin relies on the AlCh-catalyzed Diels-Alder reaction (292) + (293) (294),... 

The 2-methoxy-4a-methyl-5Q -androst-2-en-l-one system (500), corresponding to the ring a substitution pattern of quassin, has been elaborated from a 5a-androst-l-en-3-one by application of a sequence of familiar transformations.5,6(8-Epoxy-4/3-hydroxy-5/3-cholest-2-en-l-one (501) has been synthesized as a model for rings A and B of withaferin A (502). The synthesis involved multiple steps from cholesta-2,5-dien-l-one related compounds were synthesized from the 2,4-dien-l-one." ... 

This chapter follows the pattern of last year s Report with the addition of a section on Triterpenoid Saponins. The highlight of this year s Report is undoubtedly the total synthesis of /-quassin by Grieco and his co-workers.1... 

Grieco and his co-workers have completed a most notable total synthesis of /-quassin (130) (Scheme 3).1 The synthesis of the hydroxy-lactone (127) was outlined last year (see Vol. 11, p. 121). The conditions developed for the conversion of the bis-(a-hydroxy-ketone) (128) into the bis-(O-methyldiosphenol) (129) also achieved the crucial inversion of configuration at C-9.74 The close proximity of the C-7 oxygen atom to the C-ll carbon atom in the 9-epiquassin skeleton is evident from a series of reactions in which intramolecular participation occurs. Thus, for example, treatment of the epoxide (131) with lithium aluminium hydride gave the ether (132) whose structure and stereochemistry were established by A -ray analysis.75 Synthesis of the tetracyclic (133), a possible intermediate for quassinoid synthesis, involved the intramolecular cycloaddition of a quinonedimethane as the key step.78... 

Deblocking of a methyl ether with a combination of a hard Lewis acid and a thiol has been successfully applied in the total synthesis of natural products such as lythranidine (14) and quassin (15) (Scheme V). 

In recent years, a number of studies on the synthesis of quassinoids have been reported [126], Among them, total synthesis of quassin (possessing 7 chiral centers) and of castelanolide (possessing 9 chiral centers) both carried out Grieco s group constitute two successful works to synthesize natural quassinoids [1]. Below the main total synthesis of some quassinoids are described. 

This reversal of orientation has been used to prepare (4) in a projected total synthesis of quassin (5), the bitter principle of Quassia amara, which contains... 

Treatment of the enone (69) with an excess of the diene (70) in the presence of aluminium trichloride and 4,4-thiobis-(6-t-butyl-3-methylphenol) gave the tricyclic ketone (71) (40%) as the sole Diels-Alder product. Reduction then afforded the lactone (72) whose constitution and stereochemistry were established by X-ray analysis. Finally, demethylation gave the racemic alcohol (73) which differs from the quassin skeleton only in the stereochemistry at C-9. The Diels-Alder reaction also plays a key role in two other de novo syntheses. The ring A seco-derivative (75) has been prepared from the adduct (74), and the ring A nor-compound (77), a possible intermediate for the synthesis of quassimarin (78), has been obtained from the Diels-Alder product (76). ... 

Technical advances in structural analysis also initiated subsequent advances in synthesis of quassinoids, leading in particular to the first total synthesis of quassin... 

Grieco PA, Eerrino S, Vidaii G (1980) Total synthesis of dl-quassin. J Am Chem Soc 102 7586... 

The Lewis acid-catalysed orientation reversal in the reaction between substituted cyclohexa-1,3-dienes and 2,6-dimethyl-l,4-benzoquinone ° has been employed in an interesting synthesis of quassin (218). ° Thus, reaction at room temperature of the diene (215) with the above quinone in the presence of an equivalent quantity of Bp3,OEt2 gave the adduct (216) which was converted by several subsequent steps into (218). In the absence of the catalyst the alternative adduct (217) was obtained. Periodic acid oxidation of substituted o-cresols ° and of 2-methoxyphenols in methanol solution affords intermediate o-quinol methyl ethers or o-quinone dimethyl ketals which dimerize to give dienediones with structures related to those of (216) and (217). Another report concerns the formation of a Diels-Alder dimer upon hypochlorite oxidation of 2,2 -methylenebis(4-methyl-6-t-butyl)phenol. ... 

Intermolecular Diels-Alder Routes. The highly oxygenated tetracyclic framework of quassin (53) coupled with its array of stereocentres have made it a formidable synthetic target. However, it has now succumbed to the efforts of Grieco and his collaborators. A Lewis-acid-catalysed Diels-Alder reaction between (50) and (51) generated (52) in which all the stereocentres except that at C-9 have the correct relative stereochemistry. Subsequent functional group manipulation and epimerisation at C-9 served to complete the synthesis. 

However, in contrast to quassin, the synthesis of glaucarubinone and its congeners required the installation of a hydroxymethyl group (or its surrogate) at C(8) (cf. 5.20, Y = OH). It was decided that a formyl group would not only serve this purpose but also increase the reactivity of the dienophile. Unfortunately, the incorporation of an additional carbonyl onto the dienophile also compromised the stereochemistry at C(14) by providing an alternative mode for endo-cycloaddition. As noted already, the breakthrough came when 5.22 was combined with the diene carboxylate 5.10 in... 

More than ten years have elapsed since the publication of a comprehensive review on the quassinoids, the bitter principles of the Simaroubaceae family (80). Interest in these terpenoids has increased enormously in recent years due in part to the finding of the American National Cancer Institute in the early 1970s that these compounds display marked antileukemic activity. Furthermore, a wide spectrum of other biological properties for the quassinoids has been discovered and studies on chemical modifications of inactive members to yield biologically active ones were undertaken. New structures have been established also and numerous synthetic approaches have been developed which include the total synthesis of the parent compound, quassin (p. 250) and also that of castelanolide (p. 253). 

The fact that the Diels-Alder reaction is accelerated by catalysts proved a boon to the use of such cycloaddition reactions in the service of complex molecule synthesis. A myriad of creative applications and general methods to effect stereoselective Diels-Alder reactions have been documented. An illustrative example is found in Grieco s reported total synthesis of ( )-quassin, one of the bitter principles of quassin wood with potent cytotoxic properties... 

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