Process for the preparation of calanolide precursors

Details Process for the preparation of calanolide precursors Process for the preparation of calanolide precursors

2000-04-25

2001-11-06

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06313320

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of a class of tricyclic monophenols which are key intermediates in the synthesis of the calanolide group of xanthones.
BACKGROUND OF THE INVENTION
A family of xanthone natural products with antiviral activity has been isolated from plants of the genus Calophyllum. In particular, (+)-calanolide A, isolated from
Calophyllum lanigerum
var
austroconiaceum
is a potent inhibitor of HIV-1 reverse transcriptase (Galinis et al,
J. Med Chem.,
1996, 39, 4507 and references contained therein). The structures of certain such;compounds are as follows.
A number of syntheses of calanolide A have been reported. See, for example, Chenera et al,
J. Org. Chem.,
1993, 58, 5605; Deshpande et al,
J. Org. Chem.,
1995, 60, 2964; Rehder and Kepler,
Synth. Commun.,
1996 26 4005; Khilevich et al,
Tetrahedron: Asymmetry,
1996, 7, 3315; Flavin et al,
J. Med Chem.,
1996, 39, 1303; and Trost and Toste,
J. Am. Chem. Soc.,
1998, 120, 9074.
Of the reported syntheses of calanolide A, only the syntheses of Deshpande et al and Trost and Toste are asymmetric. In particular, only the synthesis of Trost and Toste uses asymmetric catalysis in the key stereodifferentiating reaction, which comprises palladium-catalysed asymmetric allylic substitution of tiglyl methyl carbonate with 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chroman-8-one. Following asymmetric allylic substitution, benzylic oxidation with DDQ is used to introduce the unsaturation in the C ring, and further steps to calanolide B comprise diastereoselective hydroboration, Dess Martin oxidation, and cyclisation with zinc chloride. Calanolide A is obtained by Mitsunobu inversion of calanolide B. This methodology is readily extended to the preparation of natural and unnatural analogues of calanolides A and B.
An alternative nucleophile in the asymmetric allylic substitution reaction of Trost and Toste or other D-ring annulation procedures, which would result in a shorter overall synthesis by elimination of the C-ring dehydrogenation step, would be 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (in which the C-ring double bond is already present). This compound was originally prepared by unselective 1-step chromene annulation of 4-propyl-5,7-dihydroxycoumarin (Games and Haskins,
J. Chem. Soc. Chem. Commun.,
1971, 1005).
The preparation of 5,7-dihydroxycoumarin monosulphonate esters by direct sulphonylation of 5,7-dihydroxycoumarin has been reported by Desai and Parghi,
J Indian Chem. Soc.,
1956, 33, 661. The yield obtained for the preparation of 4-methyl-8-hydroxy-7-coumarinyl-4-toluenesulphonate by this procedure was 36%.
SUMMARY OF THE INVENTION
This invention is based on the discovery of an efficient process that, starting from a 5,7-dihydroxycoumarin, provides a 5-hydroxy-2H-pyrano[2,3-f]chromen-8-one according to the overall transformation depicted below, thus providing the ABC portion of the calanolide ring system.
In these formulae, R
1
, R
2
, R
3
, R
4
and R
6
each represent H or an organic group of up to 20 C atoms, or any pair of R
2
and R
3
or R
2
and R
6
or R
4
and R
6
forms a cyclic group, and R
5
SO
2
is a cleavable protecting group in which R
5
is an organic group of up to 20 C atoms.
More particularly, the present invention provides a novel four-step procedure for accomplishing this regioselective chromene annulation, in which the key step is the unexpected 5-selective desulphonylation of a 5,7-disulphonyl ester of a 5,7-dihydroxycoumarin, to give a 5-hydroxy-7-coumarinyl sulphonate. Chromene annulation with, e.g. a propargyl halide or &agr;,&bgr;-unsaturated aldehyde or ketone, provides the 5-hydroxy-2H-pyrano[2,3-f]chromen-8-one ring system. In particular, reaction of the compound wherein R
1
=propyl with a C
5
synthon, e.g. 3-chloro-3-methylbut-1-yne, followed by cleavage of the remaining 7-sulphonyl group, provides 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one. Palladium-catalysed asymmetric allylic substitution of this tricyclic phenol with tiglyl methyl carbonate, analogous to the process disclosed by Trost and Toste, provides both (R)- and (S)-5-(1,2-dimethyl-2-propenyloxy)-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one in enantiomerically enriched form, thereby giving overall a particularly effective synthesis of calanolide A, e.g. by means of the steps disclosed by Trost and Toste and summarised above.
DESCRIPTION OF THE INVENTION
The preparation of 2H-pyrano[2,3-f]chromen-8-ones from 5,7-dihydroxycoumarins and the use of the invention for the formal synthesis of (+) and (−)-calanolides A and B are shown in Scheme I. Typically, R
1
, R
2
, R
3
, R
4
and R
6
are each H, or alkyl or aryl, e.g. of up to 10 carbon atoms. Any ring that they form may be within the given definitions, including any (optional) substituents. Preferably, R
1
is propyl, R
2
and R
3
are each methyl, and R
4
and R
6
are each H.
Step (i) of the Scheme is the disulphonylation reaction. This is achieved using a sulphonyl chloride R
5
SO
2
Cl in which R
5
may be an aryl group such as 4-tolyl or an alkyl group such as methyl.
Step (ii) is the 5-selective desulphonylation. This is preferably achieved using a fluoride reagent which may be a quaternary ammonium salt such as tetra-n-butylammonium fluoride or a metal salt such as potassium fluoride.
Step (iii) is the chromene annulation reaction. This is preferably achieved using, e.g. a propargyl halide or &agr;,&bgr;-unsaturated aldehyde or ketone.
Step (iv) is the cleavage of the 7-sulphonyl group. This is preferably achieved using a fluoride reagent which may be tetra-n-butylammonium fluoride (TBAF).
Step (v) is the asymmetric allylic substitution reaction. This is achieved using a tiglyl electrophile which may be (E)-2-methyl-2-butenyl methyl carbonate, a base which may be caesium carbonate and a catalyst prepared from a phosphine ligand which may be (+)-1,2-bis-N-[2′-diphenylphosphino)benzoyl]-1(R),2(R)-diaminocyclohexane or (+)-1,2-bis-N-[2′-diphenylphosphino)benzoyl]-11(R), 12(R)-diamino-9,9,10-dihydro-9, 10-ethanoanthracene for the synthesis of (+)-calanolides A or B, or the opposite enantiomeric ligands for the synthesis of (−)-calanolides A or B, and a palladium reagent which may be tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct.
The remaining steps shown by the Scheme are representative of the conversions required to complete the synthesis of calanolide compounds, as disclosed by Trost and Toste and summarised above.
Thus, the present invention provides a practical route by means of certain novel intermediates, to the ABC ring synthon for the calanolides and analogous antiviral xanthones. In particular, the 5-selective desulphonylation provides an efficient means for preparation of a robust 7-protected 5,7-dihydroxycoumarin. Protection of the 7-phenol ensures direction of the chromene annulation to the free 5-phenol, resulting in a selective overall process.


REFERENCES:
patent: 5840921 (1998-11-01), Flavin et al.
patent: 9414789 (1994-07-01), None
Desai, R. D. et al. (1957) “Heterocyclic compounds. XXXI. Synthesis of partially methylated esters of polyhydroxy coumarins”Chemical Abstracts, vol. 51, No. 19, Oct. 10, 1957, Columbus, Ohio, U.S.; abstract No. XP-00212876.
Games, D. E. et al. (1971) “Synthesis of Some Dimethylpyrano-and 3-Methylbut-2-enyl-4-phenyl-and -4-n-propyl-coumarins”Chemical Communicationspp. 1005-1006.
Trost, B. M. et al. (1998) “A Catalytic Enantioselective Approach to Chromans and Chromanols. A Total Synthesis of (—)-Calanolides A and B and the Vitamin E Nucleus”J. Am. Chem. Soc.120:9074-9075.
Deshpande, P. P. et al. (1995) “Synthesis of Optically Active Calanolides A and B”J. Org. Chem.60:2964-2965.

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