Comprensión lectora

Cleavage of the C-15/C-16 bond when oxidising the hydroxylated lactols appears to be a common problem in quassinoid synthesis. During their total synthesis of simalikalactone D, Moher et al. (1992) reported that oxidation with manganese dioxide of hydroxyhemiacetals (6 6 ) (diasterioisomers at C-16) led to substantial quantities of

the C-(15)/(C-16) cleavage product (67) in addition to the desired hydroxy lactone (6 8). Fleck et at. (1992) also reported cleavage products when they oxidised (69) and

(70) using conventional conditions (Mn0 2 ,CHCl3; Fetizon reagent; AgjO.CHjCN;

Swem) in the course of synthesising glaucarubolone and holacanthone. They found that oxidation of (70) with Dess-Martin periodinane furnished the expected lactone but (69) resulted in cleavage products. Formation of (70) arises from (69) via equilibration at C(16) which was achieved by exposing (69) to 5% HCl-THF (1:2) resulting in a 2:3 OMOM OMOM MOMO MeO ■OH OH ( 6 6 ) MOMO MeO CHO OCHO OMOM MOMO MeO ,0H ( 6 8 ) ( 6 7 )

equilibrium mixture of (69) and (70) which could be separated. However, Grieco et al. (1993) recently synthesised (-)-chaparrinone, (-)glaucarubinone and (+)- glaucarubinone via the same intermediates (69) and (70) and report that they also

O M O M O M O M M eO OTBDPS ^O H 'OH ( 6 9 ) M eO O TBDPS ^ O H '"OH ( 7 0 ) O H ( 7 1 )

obtained cleavage products after oxidation with the usual reagents but were able to overcome this problem by using hydroxyiodinane oxide (71), which readily oxidised both compounds into the desired tetracyclic lactone in excellent yield (8 8 %).

2.4.3 Déméthylation of Hydroxyquassin (62)

Hydrolysis of the C-2 methoxy group in hydroxyquassin (62) was achieved with hydrochloric acid in acetic acid under reflux to provide norhydroxyquassin (72) while exposure to BBr^ in CH2CI2 at -78°C afforded triol (73). Both compounds gave a grey-

,0 H HO. ( 7 2 ) O H HO. ,0 H ( 7 3 )

2.5.1 Reduction of ring A ketone

Before introducing the glaucarubinone type ring A functionality into quassin (10) it was necessary to find a method of reducing the C-1 keto group. As mentioned above, reduction of quassin (1 0 ) with sodium borohydride in ethanol at room temperature

displays some regioselectivity in the presence of hindered C-1 and C-11 keto groups to furnish the corresponding lactol, neoquassin (52). Attempts to reduce the C-1 carbonyl with NaBH^ in the presence of 10% sodium hydroxide at 80°C as reported by Ceccherelli et al. (1987) were unsuccessful. Studies have shown that the usual reaction selectivity of sodium borohydride can be substantially modified by various metal salts such as aluminium (Brown et al., 1956), cobalt (Satoh et al., 1969); Chung, 1979) and nickel (Lin and Roth, 1979) to give complex reagents which are capable of synthetically useful conversions. An effort to reduce neoquassin with sodium borohydride in the presence of cobalt chloride in methanol did not yield the desired product. Gemal and Luche (1970; 1981) have reported that lanthanide chlorides (LnClj) are efficient catalysts for the regioselective 1,2 reduction of a - enones by sodium borohydride in methanol solution. Hence reduction with cerium EH chloride heptahydrate, CeCl3.7 H2 0 was investigated. Neoquassin (52) and CeCl3.7 H2 0

were dissolved in methanol and sodium borohydride in methanol was added to the solution at -10°C with stirring; a vigorous hydrogen evolution occurred. The carbonyl at C-1 was reduced to yield C -lp alcohol (74) as a mixture of hemiacetal isomers. The major effect of L n^ is the catalysis of B H / decomposition by the hydrolytic solvent to afford alkoxyborohydrides [NaBH4.n(0 R )J which maybe responsible for the

observed regioselectivity. ‘O H (5 2) O H ‘O H (74)

2.5.2 Construction of ring A functionality of G laucarubinone (Exp.pages 237-240) In order to functionalise ring A it was necessary to protect the ketone in ring D. Conversion of quassin (10) into its corresponding lactol with sodium borohydride followed by treatment with concentrated HCl in methanol at room temperature provided the methyl acetal (75). Transformation of (75) into (77) was carried out according to the method of Nakamura et al. (1992). The carbonyl at C-1 was reduced with sodium borohydride in the presence of CeClg.YHgO in methanol at -10®C to give enol ether (76). Hydrolysis of the C-2 methoxy group in (76) proceeded smoothly with

pyridinium p-toluene sulphonate (PPTS) in aqueous acetone at reflux to afford a- ketol (77). Compound (77) was subjected to acylation with acetic anhydride and dimethylaminopyridine in CHjClj to afford acetate (78). The lactone in ring D could

OCH3 "OCH (75) O H "OCH 3 (76)

be generated in two steps. Deprotection of lactol (78) with 10% HCl-THF (1:1) furnished lactol (79) in 75% yield which was transformed into lactone (80) in 44% yield with pyridinium chlorochromate in CH2CI2 at room temperature.

O H

O C H

(77)

O C H 3

(78)

An olefin between carbons 3 and 4 was introduced into ethyl acetal (81) in which the lactol had been protected by treatment with concentrated HCl in ethanol instead of

’O H

( 7 9 ) _{( 8 0 )}

methanol. Bromination of (81) with pyridinium hydrobromide perbromide (Fieser and Fieser,1967) in acetic acid led to the formation of a mixture of products. Phenyltrimethylammonium perbromide (Q H5N^(CH3)3Br3 ) (Fieser and Fieser, 1967)

in dry THF at 0°C was the best reagent for this reaction giving rise to the C-3 brominated product (82).

( 8 1 ) ( 8 2 )

Dehydrobromination with LiCOj-LiBr (1:1) in refluxing dimethylformamide then furnished tetracyclic enone (83) in 52% yield, possessing the fully functionalised ring A of glaucarubinone. ‘H NMR (p.308) showed that the protons at C-1, C-3 and C-16 resonate at 5 5.25, 6.04 and 5.0 ppm respectively.

2.5.3 Déméthylation of Quassin (10) (Exp. pages 241-242)

Déméthylation of quassin (10) at C-2 was carried out by two methods. Déméthylation according to Kawada et al. (1989b) was brought about by treating quassin with chlorotrimethylsilane and sodium iodide in acetonitrile at room temperature to afford picrasin B (84) in 62% yield. The vinylic proton at C-3 was clearly absent in ‘H NMR spectra which revealed the C-2 proton as a multiplet at ô 4.85 and the C-12 methoxy as a singlet at Ô 3.67. In the second method, déméthylation was effected by refluxing quassin (10) with 10% HCl in acetic acid to yield norquassin (85) with the vinylic proton intact. Exposure of quassin to boron tribromide (Casinovi et al., 1965) in CH2CI2 at -78°C demethylated both methoxy groups to furnish diol (8 6 ).

2.6 Synthesis of Quassin Analogues

Quassin lacks an ester substituent which is present in many quassinoids with strong antimalarial and antileukemic activity. In order to investigate the effect of various substituents on the quassin molecule on biological activity, a series of quassin derivatives were prepared. Estérification was mainly carried out in CH2CI2 with an

acylating agent in the presence of dimethylaminopyridine (DMA?) and (l-ethyl-3(3- dimethylaminopropyl)carbodimide (EDC) (Neises and Steglich, 1978). Various lipidic amino acids, R[NHC0 2 C(CH3)3]C0 0 H, (Toth et al., 1992) were used in estérification

OCHa O C H3

because of their potential in drug delivery systems. They have been covalently conjugated with a number of drugs in order to enhance their passage across biological membranes due to the similarity and affinity with membrane components.

2.6.1 Analogues of hydroxyquassin (62) (Exp. pages 242-246)

OCH3 ,0 R (6 2 ) R = H ( 87 ) R = COCH 3 ( 88 ) R = C O C H =C (C H3 ) 2 ( 89 ) R = COCH[NHCO zCCCH 3) 3KCH 2) 7 CH 3 ( 9 0 ) R = C H2O C H2C H2O C H3

Acylation of hydroxyquassin (62) with acetic anhydride, 3,3-dimethylacryloyl chloride and 2-(tert-butoxycarbonylamino)-decanoic acid, yielded esters (87), (8 8 ) and (89)

respectively. Compound (8 8 ) has the D-ring moiety of brusatol. Acylation of ring D

shifts the proton at C-15 downfield to 5.2 ppm (d, J=ca.l0.5 Hz) from 4.5 ppm in (62). Treatment of (62) with methoxyethoxymethyl chloride (MEMCl) and DMAP in CH2CI2 afforded MEM ether (90). The presence of a MEM group in quassinoids was

reported by Patel et al. (1989; 1990) to enhance in vitro antimalarial activity.

O H

HO.