Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/20—Oxygen atoms
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to novel enantiomerically pure intermediary compounds containing specifically substituted tetrahydrofuran structures as well as a method for preparing such intermediary compounds.
• a number of biologically active compounds e.g. compounds derived from natural sources, as well as potentially biologically active synthetic compounds, e.g. analogues of naturally occurring compounds, contain stereochemically or enantiomerically pure tetrahydrofuran or butyrolactone structure elements.
• a number of plant-derived lignans have been demonstrated to possess antitumor and other biological activities. Examples of such lignans are enterolactone, hinokin, cubebin, steganacin, steganone, podorhizon, podophyllotoxin, steganyl glycosides, etoposide and teniposide whose structures are shown below.
• one aspect of the present invention concerns a method for the preparation of compounds containing the partial formula I
• the carbon atom in the 2-position has (R)- or (S)-configuration; the substituents in the 2- and 3-positions are trans-related; the substituents in the 3- and 4-positions are cis- or trans-related; X is oxygen, sulphur or -SO 2 -;
• R 1 is a sterically hindering protecting group
• R 2 is an organic residue; and the wavy line denotes a connection to the rest of the molecule; the method comprising reacting a compound containing the partial formula II
• the conjugate addition is unusual in the sense that it proceeds with virtually complete diastereofacial selectivity because the incoming nucleophile attacks only from the less-hindered side of the dihydrofuran ring.
• An example of the reaction is illustrated below where the nucleophile is a "methyl anion" and the sterically hindering protecting group R 1 is benzyl.
• the diastereofacial selectivity is the result of steric hindrance from, in the illustrated case, the benzyloxy protecting group.
• Calculations of the preferred conformations) of the aldehydes by molecular mechanics computer programs revealed that e.g. an aromatic ring prefers to be situated close to the ⁇ , ⁇ -unsaturated aldehyde functionality, thereby effectively blocking the nucleophilic attack from that side.
• the conjugate addition at the less hindered side proceeds with virtually complete diastereofacial selectivity.
• the conjugate addition reaction of the invention can be performed in polar or apolar, aprotic or only weakly protic solvents such as ethers (e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, diglyme etc.), aliphatic or aromatic hydrocarbons (e.g. petroleum ethers (boiling points from 30oC to 150oC), benzene, toluene, xylenes etc.), aprotic amines (e.g. trimethyl or triethyl amine, TMEDA, pyridine, morpholine, quinoline, collidine, lutidine, etc.), halogenated hydrocarbons (e.g.
• ethers e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, diglyme etc.
• aliphatic or aromatic hydrocarbons e.g. petroleum
• reaction may be carried out at temperatures from -120°C to +150°C, preferably from -80oC to +30oC, for from 5 minutes to 72 hours, preferably 30 minutes to 24 hours, in particular 1-2 hours.
• the specific nature of the organic anion R 2 - is not important as long as it is ensured that the nucleophilic attack of the anion occurs in the conjugate (1,4) mode.
• This may be effected e.g. by the addition of copper salts (such as halide or cyanides) to the reaction mixture, thereby forming intermediary organocuprate reagents.
• copper salts such as halide or cyanides
• Such reagents are generally known for their ability to participate in conjugate addition reactions with ⁇ , ⁇ -unsaturated carbonyl compounds.
• other auxiliary reaction promoting agents may comprise other transition metal salts (e.g. cadmium or zinc halides or cyanides), or noble metal salts (e.g. silver halides or cyanide). Additions of small amounts of polar compounds into apolar solvents, e.g. dimethyl sulfoxide or hexamethylphosphoric triamide, may also facilitate the reaction.
• silylating agents e.g. trimethylsilyl, t-butyldimethylsilyl or phenyldimethylsilyl chloride or tosylate
• strong alkylating agents e.g. methyl iodide, dimethyl sulfate, benzyl halides etc.
• the primary product formed when using such trapping agents is normally an enol ether. These are conventionally transformed into the parent carbonyl compounds by e.g. hydrolysis or hydrogenolysis. As indicated above, R 1 is a sterically hindering protecting group.
• R 1 may be substituted or unsubstituted, branched or straight chain C 1- 8 alkyl, substituted or unsubstituted, branched or straight chain C 3-8 alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted, branched or straight chain aryl-C 1-8 alkyl, the optional substituents numbering 1-5 and being independently selected from -OCH 2 O-, OCH 3 , NO 2 , Cl, Br, and I.
• C 1-8 alkyl either as groups or as parts of groups, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, neopentyl, hexyl or octyl.
• C 3-8 alkenyl may be mentioned prop-2-enyl, but-3-enyl.
• halogen substituents are Cl, Br, I, and F.
• aryl may for example be phenyl, naphthyl, pyridyl, furyl, or thiophenyl, optionally substituted with 1-5 substituents selected from -OCH 2 O-, OCH 3 , NO 2 , Cl, Br, and I.
• groups R 1 are benzyl, p-tolyl, p-methoxyphenyl, p-methoxybenzyl, p-nitrophenyl, 2-trimethylsilylethyl, 2-bromoethyl, methyl, ethyl, propyl, butyl, octyl, allyl, 2,2,2-trichloroethyl, 3-bromo-2-bromomethylpropyl and 3-bromopropyl, where benzyl is preferred.
• the organic residue R 2 may be any organic group of which is desired that it is present, optionally in a modified form, in the final biologically active product, the preparation of which requires the intermediaries of the invention. However, it is preferred that the organic residue R 2 does not contain any groups, moieties or substituents that may interfere with the diastereoselective conjugate addition reaction where the carbanionic species R 2 - reacts with the structure of the partial formula II.
• the wavy line indicates the border line between the structure of the partial formula I and the remainder of the starting molecule containing the partial formula II and the resulting intermediary compounds containing the partial formula I.
• the remainder of the molecule may be any kind of substituent, the presence of which is desired in the intermediary containing the partial formula I.
• R 2 it is also preferred that the remainder of the molecule beyond the wavy line does not contain any groups, moieties or substituents that may seriously interfere with the addition reaction.
• a preferred aspect of the invention is a method for the preparation of a compound of the formula la
• the carbon atom in the 2-position has (R)- or (S)-configuration; the substituents in the 2- and 3-posItions are trans-related; the substituents in the 3- and 4-positions are cis- or trans-related;
• X is oxygen, sulphur or -SO 2 -;
• R 1 is a sterically hindering protecting group;
• R 2 is an organic residue connected to the tetrahydrofuran ring via a carbon atom;
• R 3 is hydrogen or an organic residue, the method comprising reacting a compound of the formula Ila
• R 3 is hydrogen or an organic residue.
• organic residue may be as above for the substituent R 2 .
• a preferred embodiment of the method of the invention concerns a process for the preparation of either compounds containing the partial formula I or of compounds of the formula la in which R 2 is a group of the formula R 4 R 5 R 6 C-, wherein R 4 , R 5 , and R 6 independently are hydrogen or a C 1 -20 saturated or unsaturated, straight or branched chain, cyclic, aliphatic or aromatic residue, optionally containing or carrying substituents comprising 1-5 heteroatoms selected from B, N, O, P and S and halogen, and R 3 is hydrogen or a C 1-20 saturated or unsaturated, straight or branched chain, cyclic, aliphatic or aromatic residue, optionally containing or carrying substituents comprising 1-5 heteroatoms selected from B, N, O, P, S and halogen.
• R 4 and/or R 5 and/or R 6 and/or R 3 may be halogenated phenyl or pyridyl.
• R 2 or R 3 containing P as a heteroatom may be when R 2 is diphenylphosphinophenylmethyl and R 3 is diphenylphosphinophenyl since such compounds, following conversion of the carbonyl function next to R 3 into methylene, in a manner known per se, may be useful as chiral compounds for chiral rhodium-complex catalysts for use in stereospecific hydrogenation of C-C functions.
• R 3 , R 4 , R 5 , and R 6 independently are hydrogen, methyl or substituted phenyl of the formula
• R 7 , R 8 , R 9 , R 10 and R 11 Independently are hydrogen, -OCH 3 , -OH or B(OH) 2 or an ester thereof or R 7 and R 8 or R 8 and R 9 together form -O-CH 2 -O-.
• esters of the boric acid group B(OH) 2 may be mentioned
• Such compounds in which there is a boric acid group present may serve as inermediary forms for preparing lignans of the steganone- or steganacinetype where there is a direct bond between a benzene ring in R 2 and a benzene ring in R 3 in formula I.
• the two benzene rings may be coupled if there is a halogen atom, in particular a iodine atom, present on the other benzene ring.
• the boric acid group may be introduced in a known manner (cf. Organic Synthesis , Coll. Vol. IV, p 68, 1963).
• R 7 , R 8 , and R 9 are as follows:
• R 7 , R 8 and R 9 are -OCH 3 , (2) R 7 and R 8 form -OCH 2 O- , and R 9 is H,
• R 7 and R 8 are H, and R 9 is -OH, or
• R 7 and R 9 are -OCH 3 , and R 8 is -OH.
• the invention further concerns compounds containing the partial formula I defined above and compounds having the formula la defined above, where- in the various substituents may have the preferred meanings given above.
• Especially preferred embodiments of the invention are compounds of the formula la as well as methods of the invention for preparing these where- in the groups R 2 and R 3 are identical with the corresponding groups in the biologically active compounds listed above, e.g. enterolactone, steganacin, podophyllotoxin, etoposide etc. and also botryodiplodin and epi-botryodiplodin.
• the present invention is concerned with novel intermediary compounds as well as methods for the preparation thereof. These are very well suited for further manipulation into biologically active compounds such as those shown above or analogues thereof.
• the groups R 2 and R 3 in the corresponding final compounds are not themselves directly coupled to each other, e.g. as in enterolactone, it is sufficient to perform functional group manipulations in order to arrive at the biologically active compounds , whereas in the case of compounds with a steganacin- or podophyllotoxin-type skeleton, carbon-carbon bond formation must be carried out, either before or after certain functional group manipulations.
• Such carbon-carbon bond formations have been reported (cf. Y. Landais et al. Tetrahedron Lett. , 1986 (27) 5377-5380, and E. Brown et al. Tetrahedron Lett. , 1986 (27) 3719-3722).
• the functional group manipulations comprise simple transformations such as acetal to hemiacetal, hemiacetal to lactone, ketone to alcohol, ketone or alcohol to methylene, thioacetal to ketone, and thioacetal to methylene, most of which conversions are illustrated In the examples below
• Desired biologically active compounds such as those listed above, e.g. enterolactone etc, predominantly carry their substituents in the 3- and 4-position of the furanoid ring (or Its occasional ring-opened counterpart such as isolariciresinol dimethyl ether) In a trans relationship.
• the present invention discloses a reaction for the preparation of intermediary compounds which as a result of the reaction aquire a predominant 3,4-trans relationship, presumably due to the steric requirements of the substituents.
• undesired product fractions may be interconverted by epimerization using e.g. catalysis by alkali as illustrated in example 2.
• Bzl benzyl
• Ph phenyl
• Me methyl
• Bu butyl
• i-PrOH isopropanol
• EtOAc ethyl acetate
• HOAc acetic acid.
• (+)-2-Benzyloxy-3-[3,4,5-trimethoxyphenyIbis(phenylthio)-methyl]-4-(3,4- methylenedioxybenzoyl)tetrahydrofuran (6) To a stirred solution of A (0.676 g, 1.70 mmol) in THF (10 mL, 4 A), kept at -78°C under a nitrogen atmosphere, a solution of BuLi (1.70 mmol, 1.48 M) in hexane (1.15 mL) was added. After 20 min, 3 (0.500 g, 1.54 mmol) in THF (5 mL) was added dropwise. After 5 min, the cooling bath was removed.
• (+)-2-Benzyloxy-3-[4-chlorophenylbis(phenylthio)methyl]-4-(3,4-methy- lenedioxybenzoyl)tetrahydrofuran (8). 3 (0.500 g, 1.54 mmol) was treated with the lithium anion of D following the procedure for the preparation of 6 to give, after chromatography (SiO 2 , EtOAc/heptane 1:8), 8 (0.412 g, 40%). Mp 60-63°C (2-propanol); [ ⁇ ] D 25 +40.2° (c 0.79, CHCI 3 ). 1 H NMR (CDCI 3 ) ⁇ 7.53 (bd, 4 H, J 8.9 Hz.
• (+)-3-(3,4,5-trimethoxybenzyl)-4-(3,4-methylenedioxybenzyl)-tetrahydrofuran ((+)-burseran, (18).
• 17 (0.800 g 1.11 mmol) in 1,2-dimethoxyethane (35 mL)
• Raney Nickel was added in portions (the reaction was monitored by TLC:SiO 2 , EtOAc/heptane 2:3). When the starting material had been consumed, the solution was separated from the Raney Nickel and filtered (Celite). The Raney Nickel was washed with 1,2-dimethoxyethane (40 mL), EtOH (40 mL), and toluene (40 mL).
• 25 (0.700 g, 1.60 mmol) was treated with the lithium anion of I following the procedure for the preparation of 6, giving, after chromatography (CH 2 CI 2 - /heptane 2:3-2:1), 26 (0.975 g, 69%) [ ⁇ ] D 25 +36.1° (c 0.85, CDCI 3 ) ; % NMR (CDCI 3 ) ⁇ 7.45-6.97 (m, 26 H, aromatic),
• the present example describes the total synthesis of both enantiomers of botryodiplodin and its epimers employing the method of the invention as part of the synthetic sequence as depicted in the scheme below.
• LiMeCNCu LiMeCNCu, t-BuMe 2 SiCl, THF, -78°C ⁇ 23°C; ii) Bu 4 NF ⁇ 3H 2 O, THF/HOAc (19:1), 23°C; iii) MeLi, Et 2 O, -78°C ⁇ 23°C; iv) (COCl) 2 , DMSO, (iPr) 2 EtN, -60°C ⁇ 23°C; v) H 2 , 1 atm, 10% Pd/C, DME/H 2 O (3:1).
• Methyl lithium (50.0 mmol) in diethyl ether (33 ml) was added to an ice-cooled slurry of cuprous cyanide (4.48 g, 50.0 mmol) in THF (160ml). After 5 min the cooling bath was changed to CO 2 /acetone. A solution of t-butyldimethylsilyl chloride (7.53 g, 50.0 mmol) in THF (38 ml) was added, followed by dropwise addition of lr (8.00 g, 38.5 mmol) In THF (118 ml). 5 minutes after the addition was completed, the reaction mixture was allowed to warm slowly to room temperature.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=8123233

Family Applications (1)

Country Status (3)

Cited By (1)

• 1987
  • 1987-07-06 DK DK346987A patent/DK346987D0/da not_active Application Discontinuation
• 1988
  • 1988-07-05 WO PCT/DK1988/000110 patent/WO1989000160A1/en unknown
  • 1988-07-05 AU AU19973/88A patent/AU1997388A/en not_active Abandoned

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events