Richard J. Stoodley

An efficient enantiocontrolled synthesis of (+)-4-demethoxydaunomycinone

Abstract A chromatography-free, seven-step synthesis of the title compound ( 3 ) is described. The tetracyclic carbon skeleton is elaborated by a Diels-Alder strategy in which the 6a,7- and 1O.1Oa-bonds are constructed the epoxy-tetrone ( 9 ) and the D-glucose-derived diene ( 10b ) serving as precursors. Interestingly, the cycloaddition reaction leads mainly to the “desired” cycloadduct ( 11b ), revealing a notable diastereofacial reactivity of the diene (10b). Hydrolysis of the cycloadduct ( 11b ) leads to the epoxy-pentone ( 12b ) which is reduced to the dihydroxy-trione ( 13b ). The reaction of the last-cited compound with ethynylmagnesium bromide affords a mixture of the ethynyl-diones ( 20b ) and ( 21b ), the latter compound arising from the precursor (13b) by a prior epimerisation at the 10a-position. The mixture of ethynyldiones ( 20b ) and ( 21b ) is converted into the anthracycline ( 14b ) by the action of lead ( IV ) acetate. By a hydrolysis-hydration sequence, the anthracycline ( 14b ) is transformed into (+)-4-demethoxydaunomycinone (3).

Hetero Diels-Alder reaction involving (E)-3-(tert-butyldimethylsiloxy)-1-(2′,3′,4′,6′-tetra- O-acetyl-β-d-glucopyranosyloxy)buta-1,3-diene and p-nitrobenzaldehyde

The title reaction, when carried out in carbon tetrachloride in the presence of a catalytic amount of Eu(fod)3, leads mainly to the cis-cycloadduct 6a; the product undergoes isomerisation to its epimer 7a in the presence of the catalyst in dichloromethane.

Asymmetric Diels–Alder reactions. Part 1. Diastereofacial reactivity of (E)-3-trimethylsilyloxybuta-1,3-dienyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside towards cyclic dienophiles

The title diene (5a) reacted with p-benzoquinone in benzene at ambient temperature to give an 89 : 11 mixture of (1R,6R,10S)-10-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy]-8-trimethylsilyoxybicyclo[4.4.0]deca-3,8-diene-2,5-dione (9a) and its (1S,6S,10R)-diastereoisomer (10a). The stereostructure of the major cycloadduct was established by its conversion into (1R,6R,10S)-10[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy]bicyclo[4.4.0]decane-2,5,8-trione (12), the structure of which was determined by X-ray crystallography. The diene (5a) showed a similar diastereofacial selectivity in its reactions with 2-methoxycarbonyl-p-benzoquinone [to give an 88 : 12 mixture of the cycloadducts (9b) and (10b)], 2-acetyl-p-benzoquinone [to yield a 75 : 25 mixture of the cycloadducts (9c) and (10c)], N-phenylmaleimide [to afford an 86 : 14 mixture of the cycloadducts (15a) and (16a)], maleimide [to produce an 85 : 15 mixture of the cycloadducts (15b) and (16b)], and malefic anhydride [to furnish mainly the cycloadduct (15c)]. In every instance, the major cycloadduct could be isolated in a pure state by crystallisation. Under mildly acidic conditions, it underwent hydrolysis resulting in the conversion of its O-silyl enol moiety into the ketone function. On the basis of c.d. spectroscopy, the ketones (11a–c)[derived from the respective cycloadducts (9a–c)] possessed the same absolute stereochemistry at positions 1, 6, and 10. The ketone (17c), formed by hydrolysis of the cycloadduct (15c), was transformed by the action of aniline and acetic anhydride into the ketone (17a), which was also obtained from the cycloadduct (15a) by hydrolysis. The conformational properties of the cycloadducts and their hydrolysis products were assessed by 300 MHz 1H n.m.r. spectroscopy.

Asymmetric Diels–Alder reactions. Part 3. Influence of butadiene structure upon the diastereofacial reactivity of (E)-1-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)buta-1,3-dienes

(E)-1-(2′,3′,4′,6′-Tetra-O-acetyl-β-D-glucopyranosyloxy)buta-1,3-diene (1c), its 3-methyl derivative (1d), its 2,3-dimethyl derivative (1e), its (3Z)-4-acetoxy-3-(t-butyldimethylsilyloxy) derivative (1f), its 3-(t-butyldimethylsilyloxy) derivative (1g), and its (3Z)-3-(t-butyldimethylsilyloxy)-2,4-dimethyl derivative (1h) have been prepared and their diastereofacial reactivities towards N-phenylmaleimide and tetracyanoethylene assessed. With the former dienophile in benzene at ambient temperature, the dienes (1c, d, f, g) gave ca. 87 : 13 mixtures of the cycloadduct pairs (2c) and (3c), (2d) and (3d), (2f) and (3f), and (2g) and (3g); however, the dienes (1e, h) afforded only the cycloadducts (2e, h). With tetracyanoethylene in benzene at ambient temperature, the aforecited dienes reacted to give mixtures of cycloadducts, ranging from a 69 : 31 mixture of the cycloadducts (6c) and (7c) in the case of the diene (1c) to an 89 : 11 mixture of the cycloadducts (6h) and (7h) in the case of the diene (1h).

Enhanced discrimination by aza dienophiles over their olefinic counterparts for the diastereotopic faces of methyl (E,E)-5-(2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyloxy)penta-2,4-dienoate

Abstract The title diene displays a notably higher diastereofacial selectivity towards 4-phenyl-1,2,4-triazoline-3,5-dione, pyridazine-3,6-dione and phthalazine-1,4-dione than toward N -phenylmaleimide, 1,4-benzoquinone and 1,4 naphthoquinone.

Regio- and stereo-selective intermolecular interceptions of a conjugated N-acylhydrazonium ion

Abstract A notable stereoinduction accompanies the 1,2-addition of nucleophiles to a cyclic N-acylhydrazonium ion.

Memory of chirality effects in aldol cyclisations of 1-(3-oxobutyryl) derivatives of l-4-oxaproline and l-proline isopropyl esters

Abstract Stereoretentive CC bond formations are features of the aldol cyclisations of the 1-(3-oxobutyryl) derivatives of l -4-oxaproline and l -proline isopropyl esters, consistent with the involvement of axially chiral enolate intermediates.

Asymmetric Diels–Alder reactions. Part 4. Influence of anomeric configuration and 2′- and 6′-O-benzyl substitution on the diastereofacial reactivity of (E)-3-(t-butyldimethylsiloxy)-1-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-buta-1,3-diene

The 1-(2′,3′,4′,6′-tetra-O-acetyl-α-D-glucopyranosyloxy), 1-(6′-O-benzyl-2′,3′,4′-tri-O-acetyl-α-D-glucopyranosyloxy), 1 -(2′-O-benzyl-3′,4′,6′-tri-O-acetyl-α-D-glucopyranosyloxy), 1-(6′-O-benzyl-2′,3′,4′-tri-O-acetyl-β-D-glucopyranosyloxy), and 1-(2′-O-benzyl-3′,4′,6′-tri-O-acetyl-β-D-glucopyra-nosyloxy) derivatives of (E)-3-(t-butyldimethylsiloxy)buta-1,3-diene, i.e.(8b–d) and (34a,b) have been prepared and their diastereofacial reactivities towardsN-phenylmaleimide assessed. Whereas the α-diene (8b) gave a 55 : 45 mixture of the cycloadducts (11b) and (12b)[the major product having the (1S,2S,3R)-configuration], its β-anomer, i.e.(1b), afforded an 85 : 15 mixture of the cycloadducts (2b) and (3b)[the major product having the (1R,2R,3S)-geometry]. Improved diastereoselections were displayed by the 6′-O-benzyl-α-diene (8c), which gave a 69 : 31 mixture of the cycloadducts (11c) and (12c), and by the 6′-O-benzyl-β-diene (34a), which yielded only the cycloadduct (38a). By contrast, reduced diastereofacial reactivities were exhibited by the 2′-O-benzyl-α-diene (8d), which afforded a 36 : 64 mixture of the cycloadducts (11d) and (12d)[the major product now having the (1R,2R,3S)-stereochemistry], and by the 2′-O-benzyl-β-diene (34b), which gave a 74 : 26 mixture of the cycloadducts (38b) and (39b).

Asymmetric Diels–Alder reactions. Part 6. Regio- and stereo-selective cycloadditions of 5-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-1,4-naphthoquinone

The title naphthoquinone 1d underwent reaction with cyclopentadiene to give a cycloadduct, established as (1R,4S,4aR,9aS)-1,4,4a,9a-tetrahydro-5-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-1,4-methano-9,10-anthraquinone 9a by X-ray crystallographic analysis. Single cycloadducts, assigned the structures 4d, 4e and 17 were also isolated from the reactions of the naphthoquinone 1d with (E)-1 -methoxy-3-trimethylsiloxybuta-1,3-diene 2b, (E)-3-methyl-1-trimethylsiloxybuta-1,3-diene 2f and (E)-2-methyl-1-trimethylsiloxybuta-1,3-diene 16. A 2:1 mixture of cycloadducts, formulated as the regioisomers 4g and 3f, arose in the reaction of the dienophile 1d with (E)-1-acetoxy-3-methylbuta-1,3-diene 2g.The sugar auxiliary was readily detached from the oxidation product of compound 9a, i.e.(1R,4S)-1,4-dihydro-5-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-1,4-methano-9,10-anthraquinone 18b, by acidic hydrolysis to give the aglycone 18a.An X-ray crystallographic analysis of compound 1d revealed that the quinone ring adopts a boat-like geometry in which the carbonyl oxygen atoms shield the syn-face of the C(2)–C(3) double bond. endo-Addition of dienes to the anti-face provides an explanation for the high diastereofacial reactivity of the naphthoquinone 1d.

An enantioselective synthesis of (+)-bostrycin leading to a revision of the absolute configuration of its natural antipode

Abstract An asymmetric Diels-Alder reaction, involving the protected naphthopurpurin (4) and the D-glucose-derived diene (9a), is used to assemble compound (22), which is transformed by way of compounds (26), (27) and (28) into (+)-bostrycin (3). An X-ray analysis of compound (28) confirms that (+)-bostrycin possesses the stereostructure (3) and, therefore, that (-)-bostrycin is its antipode, i.e. (2). The use of naphthazarin (14a) and juglone (14c) as dienophiles in the Diels-Alder reaction enables the synthesis of (+)-demethoxybostrycin (12a) and (+)-demethoxy-5-deoxybostrycin (12b) to be effected.