WO1990006311A1 - Synthese de (-)-swainsonine et composes intermediaires employes dans ladite synthese - Google Patents

Synthese de (-)-swainsonine et composes intermediaires employes dans ladite synthese Download PDF

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Publication number
WO1990006311A1
WO1990006311A1 PCT/US1988/004253 US8804253W WO9006311A1 WO 1990006311 A1 WO1990006311 A1 WO 1990006311A1 US 8804253 W US8804253 W US 8804253W WO 9006311 A1 WO9006311 A1 WO 9006311A1
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WIPO (PCT)
Prior art keywords
swainsonine
imine
enamide
group
constituent
Prior art date
Application number
PCT/US1988/004253
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English (en)
Inventor
Jin Kun Cha
Richard Bernard Bennett, Iii
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Vanderbilt University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to PCT/US1988/004253 priority Critical patent/WO1990006311A1/fr
Publication of WO1990006311A1 publication Critical patent/WO1990006311A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a method of synthesizing (-)-swainsonine and to unique intermediates used in such synthesis.
  • Swainsonine is a known compound which is a trihydroxy indolizidine alkaloid. It has been isolated from locoweed (Astragalus lentiginosus and swainsona canescens) . It has also been produced from fungus (Rhizoctonia leguminicola and Metarhizium anisopliae) . The alpha-mannosidase inhibitory and immuno- regulative properties of (-)-swainsonine have resulted in significant interest in biosynthetic and pharmacological studies of the compound.
  • Swainsonine also has been recognized as having potential for use in chemotherapy with cancer patients.
  • R is (C ⁇ Cg) alkyl
  • R ⁇ is a halide or sulfonate
  • R 2 is (a) cyclic acetal (ketal) or
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or
  • the imine is hydrolized with an inorganic base to produce an acid which is subsequently heated at reflux, temperature in a suitable organic solvent to produce an enamide of the following structure
  • R 2 is (a) (C ⁇ -Cg) cyclic acetal (ketal) or
  • R an oxygen atom or a hydrogen atom, and treating the enamide with borane, followed by 20. removal of a protective group to produce swainsonine.
  • the imine and enamide intermediates have unique compositions.
  • the present invention contemplates construction of a bicyclic imine which may be employed to create the enamide of the invention with subsequent stereospecific hydroboration of the enamide being employed to synthesize swainsonine or its analogues.
  • a highly efficient method of synthesizing swainsonine involves protecting the 1,2-diol moiety of swainsonine as an isopropylidene group followed by removal thereof as by acidic hydrolysis.
  • Swainsonine (-) (lS,2R,8R,8aR)-l,2,8- trihydroxyoctahydroindolizine has the structure
  • R is (C ⁇ -Cg) alkyl
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or ⁇ (b) (C ⁇ -Cg) alkoxymethyl or
  • arylmethyl (c) arylmethyl.
  • R methyl, ethyl, propyl and benzyl.
  • R- j _ are chloride, bromide, _p_-toluenesulfonate, benzene- sulfonate, or methanesulfonate.
  • R 2 Among the preferred materials for R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl , 2- methoxyethoxymethyl, benzyloxymethyl, or (c) benzyl, JD- methoxybenzyl or _p_-nitrobenzyl.
  • alcohol 4 was prepared with a 50-65 percent yield by coupling 2,3,-isopropylidene-D- erythrose with the known Wittig reagent ( 4- carbethoxybutyl) triphenylphosphoniu bromide and
  • R is (C ⁇ -Cg) alkyl
  • R 2 is (a) (C j -Cg) cyclic acetal (ketal) or (b) (C j -Cg) alkoxymethyl or (c) arylmethyl.
  • R examples are methyl, ethyl, propyl, or benzyl.
  • R 2 Among the preferred materials for R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, or (b) methoxymethyl, 2- methoxyethoxy ethyl, benzyloxymethyl, or (c) benzyl, _p_- methoxybenzyl or ja-nitrobenzyl.
  • an acid 8 which may be a crystalline acid was prepared. In the conversion of the imino ester to the acid, the yield was 74 percent.
  • R 2 is (a) (C ⁇ -Cg) cyclic acetal (ketal) or
  • R is an oxygen atom or a hydrogen atom.
  • R 2 are (a) methylene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene; or (b) methoxymethyl, 2- methoxyethoxymethyl, benzyloxymethyl; or (c) benzyl, _p_- methoxybenzyl or j_-nitrobenzyl.
  • crystalline acid 8 undergoes internal cyclization to provide a spiro lactone which then suffers acyl group migration and subsequent dehydration.
  • the enamide was treated with diborane in a suitable solvent such as tetrahydrofuran (THF) (CH 2 ) 4 0, to produce swainsonine acetonide which has a melting point of about 101-103 degrees C.
  • THF tetrahydrofuran
  • the synthesis to swainsonine 12 was completed by acid hydrolysis with 6N hydrochloric acid in THF to yield swainsonine. The yield of swainsonine was 85 percent.
  • (+)-(4R,cis) (Z)- 2,2-Dimethyl-5-[4-carbethoxy-l-butenyl]-1,3-dioxolane- 4-methanol 4-1 will be provided.
  • 4- carbethoxybutyltriphenylphosphonium bromide (19.52 g, 42.7 mmol) in anhydrous THF (50ml) was added dropwise potassium bis(trimethylsilyl)amide [KN(SiMe 3 ) 2 ] (82 ml, 41.0 mmol) at 0 degree C over 10 min.
  • Example II As an example of the requisite sulfonate, the production of (+)-(4R,cis) (Z)-2,2-Dimethyl-5-[4- carbethoxy-l-butenyl]-l,3 dioxolane-4-methanol _p_- toluene-sulfonate 4-2 will be provided-
  • reaction mixture was washed with H 2 0 (2 x 40 ml) , saturated aqueous NaHC0 (2 x 40 ml) and brine solution (1 x 40 ml), dried over Na SO_ j , and concentrated in vacuo to a yellow oil.
  • Example III As an example of production of the imino ester, the production of (-)-(2S, 3R)-Dimethyl-8- [3- carbethoxy-1-propyl] -7-aza-2,4-dioxabicylco [3.3.0] oct- 7-ene 6 will be provided.
  • the imino ester (884 mg, 3.46 mmol) produced by Example III was dissolved in 33 ml of methanol and 10 ml of water. Potassium carbonate (1.20g, 8.75 mmol) was added. The mixture was stirr-ed at room temperature for 12h, and was concentrated in vacuo to remove
  • Example V As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-
  • Example VI The conversion of the enamide to swainsonine acetonide, i.e. , (-)-( IS,2R,8R,8aR)-l,2- isopropylidenedioxy-8-hydroxyindolizidine was achieved.
  • Example VII Swainsonine acetonide was then converted to swainsonine, i.e., (-)-(lS, 2R, 8R, 8aR)-l,2,8- trihydroxyoctahydroindolizine 12.
  • Example VIII Examples VIII-XIV illustrate the use of a benzyloxymethyl group to protect the 1,2-diol moiety of swainsonine.
  • R is (C ⁇ -C ) alkoxymethyl, (-)-2,3-dibenzyloxymethyl-D-erythronolactone, (-)-2,3- dibenzyloxymethyl-D-erythrose, and (6S, 7R) ethyl. (Z)- 6,7-dibenzyloxymethoxy-8-hydroxy-4-butenoate were produce .
  • Example VIII in dry CH 2 C1 2 at 0 degree C there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H 2 0, saturated aqueous NaHC0 3 and brine solution, dried over Na 2 S0 4 , and concentrated in vacuo to a yellow oil. Purification by Si0 2 column chromatography yielded the _p_-toluenesulfonate.
  • Example X
  • Example XI As an example of the production of the imino acid, the production of (3S, 4R)-3,4- dibenzyloxy- methoxy-2[3-carboxy-l-propyl]-pyrrolid-1-ene will be produced.
  • the imino ester produced by Example X was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HC1, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl acetate, and methylene chloride. The organic extracts were combined, dried over a 2 S0 4 , and concentrated in vacuo to give the acid.
  • Example XII As an example of the production of the enamide, the production of (-)-(7S, 8R)-7,8-0- dibenzyloxymethoxy-2-oxo-l-azabicyclo[4.3.0]non-5-ene will be provided.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in toluene was refluxed with a Dean-Stark trap for 30 h. The solution was then cooled to room temperature, and the solvent removed in vacuo. The residue was purified by Si0 2 column chromatography to provide the enamide.
  • Example XIII A solution of the acid produced by Example XI in to
  • Example XII To a cold (0 degree C) THF solution of the enamide produced in Example XII was added 1.0M BH 3 THF solution- The reaction was brought to room temperature overnight. The solvent was removed in vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, the ethanol removed in vacuo, and the residue dissolved in H 2 0- The aqueous solution was saturated with solid NaCl, then extracted five times each with ethyl acetate, and methylene chloride.
  • Example XIV The conversion of 1,2- dibenzyloxymethylswainsonine to swainsonine, i.e. , (-)- (is, 2R, 8R, 8aR)-l,2,8-Trihydroxyoctahydroindolizidine will be provided.
  • Example XV Examples XV-XXI illustrate the use of benzyl group to protect the 1,2 diol moiety of swainsonine. -17-
  • R 2 is (C j -Cg) arylmethyl, (-)- 2 , 3-dibenzyl-D-erythronolactone, (-)-2,3-dibenzyl-D- erythrose, and (6S, 7R) ethyl ( Z)-6 ,7-dibenzyloxy-8- hydroxy-4-butenoate were produced.
  • ** R 2 is (C j -Cg) arylmethyl, (-)- 2 , 3-dibenzyl-D-erythronolactone, (-)-2,3-dibenzyl-D- erythrose, and (6S, 7R) ethyl ( Z)-6 ,7-dibenzyloxy-8- hydroxy-4-butenoate
  • Example XVI As an example of the production of the corresponding sulfonate, (6S, 7R) ethyl (Z)-6,7- dibenzyloxy-8-_p-toluenesulfonyloxy-4-butenoate was produced.
  • Example XVII As an example of production of the imino ester, the production of (3S, 4R)-3,4-dibenzyloxy-2[3- carbethoxy-l-propyl]-pyrrolid-l-ene will be provided.
  • Example XVIII To a solution of the _p_-toluenesulfonate produced by Example XVI in DMF was added sodium azide- The mixture was heated at 80 degrees C for 2 days under the N 2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H 2 0 and brine solution, dried over Na S0 4 and concentrated in vacuo. The product was purified by Si0 2 column chromatography to afford the imino ester.
  • Example XVIII To a solution of the _p_-toluenesulfonate produced by Example XVI in DMF was added sodium azide- The mixture was heated at 80 degrees C for 2 days under the N 2 atmosphere. The mixture was then diluted with ethyl acetate, washed with H 2 0 and brine solution, dried over Na S0 4 and concentrated in vacuo. The product was purified by Si0 2 column chromatography to afford the imino ester.
  • Example XIX The imino ester produced by Example XVII was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then cooled to 0 degree C. After adjusting the pH of the solution to 3 with 1N_ HCl, the solution was saturated with solid sodium chloride. The aqueous layer was repeatedly extracted with ethyl - ⁇ acetate, and methylene chloride. The organic extracts were combined, dried over Na 2 S0 4 , and concentrated in vacuo to give the acid.
  • Example XIX The imino ester produced by Example XVII was dissolved in a 3:1 mixture of methanol and water. Potassium carbonate was added. The mixture was stirred overnight at room temperature, and was concentrated in vacuo to remove MeOH. The aqueous mixture was washed with ether, and then
  • Example XX The conversion of the enamide to 1,2- dibenzylswainsonine, i.e. , (-)-lS, 2R, 8R, 8aR)-l,2- dibenzyloxymethoxy-8-hydroxyindolizidine will be provided.
  • Example XIX To a cold (0 degree C) THF solution of the enamide produced in Example XIX was added 1.0M BH 3 - THF solution. The reaction was brought to room temperature overnight. The solvent was removed _in_ vacuo, and ethanol was then added. To this solution were added sodium hydroxide and 30% hydrogen peroxide. Additional ethanol was added, and the mixture refluxed for 2 h. The mixture was cooled, ethanol removed in vacuo, and the residue dissolved in H 2 0.
  • Example XX To a 5% acetic acid - methanol solution of the protected swainsonine produced by Example XX was added 10% Pd-C- The mixture was stirred under H 2 overnight, filtered through celite and concentrated in vacuo. The concentrate was then purified by ion exchange column chromatography to give swainsonine as a white solid.
  • the present invention provides an efficient means for the synthesis of swainsonine employing unique imino ester and enamide intermediates. All of this is accomplished in an efficient and economical manner which is reliable and rapid-

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de synthèse de swainsonine et ses analogues employant une imine intermédiaire unique et une énamide intermédiaire unique.
PCT/US1988/004253 1988-11-29 1988-11-29 Synthese de (-)-swainsonine et composes intermediaires employes dans ladite synthese WO1990006311A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999021858A1 (fr) * 1997-10-24 1999-05-06 Glycodesign Inc. Synthese de sels de swainsonine
US5962467A (en) * 1995-06-07 1999-10-05 Glycodesign, Inc. Derivatives of swainsonine and their use as therapeutic agents
US6048870A (en) * 1996-10-01 2000-04-11 Glycodesign 3, 5, and/or 6 substituted analogues of swainsonine processes for their preparation and their use as therapeutic agents
US6395745B1 (en) 1997-04-15 2002-05-28 Glycodesign, Inc. Alkaloid halide salts of swainsonine and methods of use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"A short enantioselective synthesis of (-) swainsonine", R. BENNETT, J. AMERICAN: CHEMICAL SOCIETY 11 1(7), 2580 (1989). *
CHEMICAL ABSTRACTS, Volume 78, No. 21, issued 28 May 1973, (Columbus, Ohio, USA); H. HAJEK: "N-substituted 2-oxo-1 2,3,4 tetrahydropyridines and octahydroquinoline analogues", see page 366 the Abstract No. 136086a for Ger. Offen. 2,143,755. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962467A (en) * 1995-06-07 1999-10-05 Glycodesign, Inc. Derivatives of swainsonine and their use as therapeutic agents
US6048870A (en) * 1996-10-01 2000-04-11 Glycodesign 3, 5, and/or 6 substituted analogues of swainsonine processes for their preparation and their use as therapeutic agents
US6395745B1 (en) 1997-04-15 2002-05-28 Glycodesign, Inc. Alkaloid halide salts of swainsonine and methods of use
WO1999021858A1 (fr) * 1997-10-24 1999-05-06 Glycodesign Inc. Synthese de sels de swainsonine
US6051711A (en) * 1997-10-24 2000-04-18 Glycodesign Inc. Synthesis of swainsonine salts
JP2001521036A (ja) * 1997-10-24 2001-11-06 グリコデザイン インコーポレイテッド スワインソニン塩の合成

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